A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)
Phase: PHASE3
Conditions: Metastatic Hormone-Sensitive Prostate Cancer
Sponsor: Merck Sharp & Dohme LLC

Offi ci al Pr ot o c ol Titl e:
N C T n u m b er:
D o c u m e nt D at e:
A P h a s e 3, R a n d o mi z e d, D o u bl e- bli n d Tri al of 
P e m br oli z u m a b ( M K- 3 4 7 5) Pl u s E n z al ut a mi d e Pl u s 
A D T V er s u s Pl a c e b o Pl u s E n z al ut a mi d e Pl u s A D T 
i n P arti ci p a nt s Wit h M et a st ati c H or m o n e- S e n siti v e 
Pr o st at e C a n c er ( m H S P C) ( K E Y N O T E- 9 9 1)
1 5- M a y- 2 0 2 3
N C T 0 4 1 9 1 0 9 6

P R O D U C T: M K
3 4 7 5
1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Title P a ge
T HI S P R O T O C O L A N D A L L O F T H E I N F O R M A TI O N R E L A TI N G T O I T A R E 
C O N FI D E N TI A L A N D P R O P RI E T A R Y P R O P E R T Y O F M E R C K S H A R P & 
D O H M E L L C, R A H W A Y, N J, U S A ( M S D).
Pr ot oc ol Title: A P hase 3, Ra n d o mize d, D o u ble -bli n d Trial of Pe m br oliz u ma b ( M K -3 4 7 5) 
Pl us E nzal uta mi de Pl us A D T Vers us Place b o Pl us E nzal uta mi de Pl us A D T i n Partici pa nts 
Wit h Metastatic H or m o ne -Se nsiti ve Pr ostate Ca ncer ( m H S P C) ( K E Y N O T E -9 9 1)
Pr ot oc ol N u m ber: 9 9 1 -0 4
C o m p o u n d N u m ber: M K -3 4 7 5
S p o ns or N a me: Merc k S har p
& D o h me L L C ( hereafter calle d t he S p o ns or or M S D)
Le g al Re gistere d A d dress:
1 2 6 East Li nc ol n A ve n ue
P. O. B o x 2 0 0 0
Ra h wa y, NJ 0 7 0 6 5 U S A
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):
N C T
0 4 1 9 1 0 9 6
E U C T
N ot a p plica ble
E u dra C T
2 0 1 9 -0 0 3 6 3 3 -4 1
J R C T
2 0 8 0 2 2 5 1 7 1
W H O
N ot a p plica ble
U T N
N ot a p plica ble
I N D
1 2 2 7 5 3
A p pr o v al D ate: 1 5 Ma y 2 0 2 3
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
S p o ns or Si g n at or y
T y pe d Na me:
Title:
Date
Pr ot oc ol -s pecific S p o ns or c o nt act i nf or m ati o n c a n be f o u n d i n t he I n vesti g at or St u d y 
File Bi n der ( or e q ui v ale nt).
I n vesti g at or Si g n at or y
I a gree t o c o n d uct t his cli nical st u d y i n acc or da nce wit h t he desi g n o utli ne d i n t his pr ot oc ol 
a n d t o a bi de b y all pr o visi o ns of t his pr ot oc ol.
T y pe d Na me:
Title:
Date
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
D O C U M E N T HI S T O R Y
D oc u me nt
D ate of Iss ue
O ver all R ati o n ale
A me n d me nt 0 4
1 5 -M A Y -2 0 2 3
Pr ot oc ol a me n de d c o nsiste nt wit h 
rec o m me n dati o ns of t he e D M C after a n i nteri m 
re vie w of t he data; s pecificall y, t o disc o nti n ue 
t he st u d y d ue t o f utilit y.
A me n d me nt 0 3
0 7 -O C T -2 0 2 2
S p o ns or u n der we nt a n e ntit y na me c ha n ge a n d 
u p date t o t he a d dress.
A me n d me nt 0 2
1 4 -M A Y -2 0 2 1
T o u p date t he d ose m o dificati o n a n d t o xicit y 
ma na ge me nt g ui deli nes f or ir A Es.
A me n d me nt 0 1
0 9 -F E B -2 0 2 1
T o a d d a n e xte nsi o n p orti o n i n C hi na t o all o w 
f or t he re q uire d e x p os ure a n d n u m ber of e ve nts 
t o i n vesti gate efficac y a n d safet y i n partici pa nts 
e nr olle d i n C hi na.
Ori gi nal Pr ot oc ol
3 1 -O C T -2 0 1 9
N ot a p plica ble
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
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
A me n d me nt: 0 4
O ver all R ati o n ale f or t he A me n d me nts:
Pr ot oc ol a me n de d c o nsiste nt wit h rec o m me n dati o ns of t he e D M C after a n i nteri m re vie w of 
t he data; s pecificall y, t o disc o nti n ue t he st u d y d ue t o f utilit y.
S u m m ar y of C h a n ges T a ble:
Pri m ar y Re as o n f or A me n d me nt
Secti o n # a n d N a me
Descri pti o n of C h a n ge 
Brief R ati o n ale 
1 . 1 S y n o psis
State me nts a d de d t o descri be 
t he safet y a n d efficac y res ults 
of t he I A lea di n g t o t he 
deter mi nati o n of f utilit y.
T his c ha n ge was ma de t o a d dress 
rec o m me n dati o ns of t he e D M C after 
i nteri m re vie w of data.
Ot her Re as o ns f or A me n d me nt
Secti o n # a n d N a me
Descri pti o n of C h a n ge 
Brief R ati o n ale 
T hr o u g h o ut D oc u me nt
T he str uct ure of t he pr ot oc ol has 
bee n u p date d .
T o c o m pl y wit h c urre nt i n d ustr y 
re g ulati o ns a n d g ui deli nes. T his 
restr uct uri n g d oes n ot affect t he 
cli nical or re g ulat or y i nte grit y of 
t he pr ot oc ol. All ot her rele va nt 
c ha n ges a n d t heir pri mar y reas o ns 
are i ncl u de d f or c o m plete ness.
1. 1 S y n o psis, Esti mate d D urati o n 
of St u d y
T he esti mate d d urati o n of t he 
st u d y has bee n c ha n ge d.
See rati o nale f or 1. 1.
1. 1 S y n o psis, St u d y G o ver na nce 
C o m mittees
E xec uti ve O versi g ht C o m mittee 
a n d e D M C are n o l o n ger 
a p plica ble.
See rati o nale f or 1. 1.
1. 1 S y n o psis, H y p ot heses, 
O bjecti ves, a n d E n d p oi nts
Partici pa nts o n st u d y treat me nt will 
ha ve l ocal t u m or i ma gi n g 
assess me nts per S O C. Ce ntral 
t u m or res p o nse, e P R O, S S R E, P S A 
assess me nts will n o l o n ger be 
perf or me d; 
 will 
n o l o n ger be c ollecte d.
See rati o nale f or 1. 1.
1. 3 I nitial Treat me nt P hase 
( Pe m br oliz u ma b/ Place b o Pl us 
E nzal uta mi de Pl us A D T)
Partici pa nts o n st u d y treat me nt will 
ha ve l ocal t u m or i ma gi n g 
assess me nts per S O C. Ce ntral 
t u m or res p o nse, e P R O, S S R E, P S A 
assess me nts will n o l o n ger be 
perf or me d; 
 will 
n o l o n ger be c ollecte d .
See rati o nale f or 1. 1.
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ot her Re as o ns f or A me n d me nt
Secti o n # a n d N a me
Descri pti o n of C h a n ge 
Brief R ati o n ale 
2. 3 Be nefit/ Ris k Assess me nt
A nal yses of safet y e n d p oi nts will 
be perf or me d at t he e n d of t he 
st u d y. N o f urt her a nal yses of 
efficac y a n d e P R O e n d p oi nts will 
occ ur after I A 1 c ut off date.
See rati o nale f or 1. 1.
3 H y p ot heses, O bjecti ves, a n d 
E n d p oi nts
Partici pa nts o n st u d y treat me nt will 
ha ve l ocal t u m or i ma gi n g 
assess me nts per S O C. Ce ntral 
t u m or res p o nse, e P R O, S S R E, P S A 
assess me nts will n o l o n ger be 
perf or me d; 
 will 
n o l o n ger be c ollecte d.
See rati o nale f or 1. 1.
4. 1 O verall Desi g n
A d de d n ote descri bi n g acti o ns 
ta ke n wit h st u d y i nter ve nti o n a n d 
s pecif y w hic h a nal yses a n d 
pr oce d ures will n ot c o nti n ue t o be 
perf or me d.
See rati o nale f or 1. 1.
4. 2. 1. 3 Patie nt -re p orte d O utc o mes 
e P R O a ssess me nts will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
4. 4. 1 Cli nical Criteria f or Earl y 
St u d y Ter mi nati o n
S afet y a n d efficac y a nal ysis 
res ults of t he I A n ote d .
See rati o nale f or 1. 1.
6. 1 St u d y I nter ve nti o n(s) 
A d mi nistere d
All st u d y partici pa nts s h o ul d st o p 
o n g oi n g treat me nt wit h 
pe m br oliz u ma b/ place b o, u nless 
be nefitti n g a n d a p pr o ve d b y 
S p o ns or t o c o nti n ue t he 
c o m bi nati o n. All ot her st u d y 
partici pa nts s h o ul d be 
disc o nti n ue d fr o m st u d y a n d be 
offere d S O C.
See rati o nale f or 1. 1.
6. 3. 3 Bli n di n g
S t u d y u n bli n de d d ue t o res ult of 
I A 1.
See rati o nale f or 1. 1.
6. 6. 3 I m m u ne -Relate d E ve nts a n d 
D ose M o d ificati o n ( Wit h h ol d, 
Treat, Disc o nti n ue)
U p date d h y p ot h yr oi d is m a n d 
m y ocar ditis secti o ns of Ta ble 7 .
Ali g n me nt wit h t he c urre nt d ose 
m o dificati o n g ui deli nes .
7. 1 Disc o nti n uati o n of St u d y 
I nter ve nti o n
C e ntral t u m or res p o nse 
assess me nts will be disc o nti n ue d 
a n d perf or me d l ocall y per S O C i n 
partici pa nts o n st u d y treat me nt.
See rati o nale f or 1. 1.
8. 1. 1 0 Partici pa nt 
Bli n di n g/ U n bli n di n g
S t u d y u n bli n de d d ue t o res ult of 
I A 1.
See rati o nale f or 1. 1.
8. 2. 1 T u m or I ma gi n g a n d 
Assess me nt of Disease
C e ntral t u m or res p o nse 
assess me nts will be disc o nti n ue d, 
a n d l ocal t u m or i ma gi n g s h o ul d 
c o nti n ue per S O C sc he d ule. 
See rati o nale f or 1. 1.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ot her Re as o ns f or A me n d me nt
Secti o n # a n d N a me
Descri pti o n of C h a n ge 
Brief R ati o n ale 
8. 2. 1. 5 S y m pt o matic S keletal -
Relate d E ve nts
S S R E assess me nts will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
8. 2. 2 Pr ostate -s pecific A nti ge n 
Assess me nts
P S A assess me nts will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
8. 2. 4 Patie nt -re p orte d O utc o mes
e P R O a ssess me nts will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
8. 1 0. 2. 3 Sec o n d C o urse
Sec o n d C o urse has bee n 
disc o nti n ue d.
See rati o nale f or 1. 1.
8. 1 0. 3. 2 F oll o w -u p Visits
F oll o w -u p v isits will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
8. 1 0. 3. 3 S ur vi val F oll o w -u p
S ur vi val F oll o w -u p visits will be 
disc o nti n ue d.
See rati o nale f or 1. 1.
9 Statistical A nal ysis Pla n
C larif yi n g a nal yses t o be 
perf or me d .
See rati o nale f or 1. 1.
9. 1 Statistical A nal ysis Pla n 
S u m mar y
C larif yi n g a nal yses t o be 
perf or me d.
See rati o nale f or 1. 1.
9. 6 Statistical Met h o ds
C larif yi n g a nal yses t o be 
perf or me d .
See rati o nale f or 1. 1.
9. 7 I nteri m A nal yses
C larif yi n g a nal yses t o be 
perf or me d .
See rati o nale f or 1. 1.
9. 7. 2 Safet y I nteri m A nal yses
C larif yi n g a nal yses t o be 
perf or me d.
See rati o nale f or 1. 1.
9. 8 M ulti plicit y
C larif yi n g a nal yses t o be 
perf or me d .
See rati o nale f or 1. 1.
9. 9 Sa m ple Size a n d P o wer 
Calc ulati o ns
C larif yi n g a nal yses t o be 
perf or me d .
See rati o nale f or 1. 1.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
T A B L E O F C O N T E N T S
D O C U M E N T HI S T O R Y ........................................................................................................3
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 ...............................................4
1
P R O T O C O L S U M M A R Y ............................................................................................1 6
1. 1
S y n o psis .................................................................................................................1 6
1. 2
Sc he m a ..................................................................................................................2 2
1. 3
Sc he d ule of Ac ti vites ............................................................................................2 4
2
I N T R O D U C TI O N..........................................................................................................4 5
2. 1
St u d y R ati o n ale ....................................................................................................4 6
2. 2 
B ac k gr o u n d ..........................................................................................................4 6
2. 2. 1
P har mace utical a n d T hera pe utic Bac k gr o u n d .............................................4 7
2. 2. 2 
Precli nical a n d Cli nical St u dies ...................................................................4 7
2. 2. 3
O n g oi n g Cli nical St u dies i n Pr ostate Ca ncer ...............................................4 7
2. 2. 4
I nf or mati o n o n Ot her St u d y-relate d T hera p y ..............................................4 8
2. 3 
Be nefit/ Ris k Assess me nt ......................................................................................4 9
3
H Y P O T H E S E S, O B J E C TI V E S, A N D E N D P OI N T S ................................................5 1
4
S T U D Y ............................................................................................................................5 5
4. 1
O ver all Desi g n ......................................................................................................5 5
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n .................................................................5 7
4. 2. 1
Rati o nale f or E n d p oi nts ...............................................................................5 8
4. 2. 1. 1
Efficac y E n d p oi nts .............................................................................5 8
4. 2. 1. 2 
Safet y E n d p oi nts ................................................................................5 8
4. 2. 1. 3
Patie nt -re p orte d O utc o mes Assess me nts ...........................................5 8
4. 2. 1. 4
Pla n ne d E x pl orat or y Bi o mar ker Researc h .........................................5 9
4. 2. 2
Rati o nale f or t he Use of C o m parat or/ Place b o .............................................6 0
4. 3
J ustific ati o n f or D ose........................................................................................... 6 1
4. 3. 1 
Pe m br oliz u ma b ............................................................................................6 1
4. 3. 2
E nzal uta mi de ................................................................................................6 2
4. 4
Be gi n ni n g a n d E n d of St u d y Defi niti o n .............................................................6 2
4. 4. 1
Cli nical Criteria f or Earl y St u d y Ter mi nati o n .............................................6 2
5
S T U D Y P O P U L A TI O N ................................................................................................6 3
5. 1
I ncl usi o n Criteri a .................................................................................................6 3
5. 2
E xcl usi o n Criteri a ................................................................................................6 6
5. 3 
Lifest yle C o nsi der ati o ns ......................................................................................6 8
5. 3. 1
Meals a n d Dietar y Restricti o ns ....................................................................6 8
5. 3. 2
C o ntrace pti o n ...............................................................................................6 8
5. 3. 3
Pre g na nc y .....................................................................................................6 9
5. 4
Scree n F ail ures .....................................................................................................6 9
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
5. 5
P artici p a nt Re pl ace me nt Str ate g y ......................................................................6 9
6
S T U D Y I N T E R V E N TI O N ............................................................................................7 0
6. 1
St u d y I nter ve nti o n(s) A d mi nistere d ...................................................................7 0
6. 2 
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y .................................................7 2
6. 2. 1
D ose Pre parati o n ..........................................................................................7 2
6. 2. 2  
Ha n dli n g, St ora ge, a n d Acc o u nta bilit y ........................................................7 2
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 ..............................7 3
6. 3. 1
I nter ve nti o n Assi g n me nt ..............................................................................7 3
6. 3. 2
Stratificati o n .................................................................................................7 3
6. 3. 3
Bl i n di n g........................................................................................................7 3
6. 4
St u d y I nter ve nti o n C o m pli a nce ..........................................................................7 3
6. 5
C o nc o mit a nt T her a p y ..........................................................................................7 4
6. 5. 1
Pr o hi bite d C o nc o mita nt T hera p y .................................................................7 4
6. 5. 2
Resc ue Me dicati o ns a n d S u p p orti ve Care ...................................................7 6
6. 6
D ose M o dific ati o n ( Esc al ati o n/ Titr ati o n/ Ot her)...............................................7 7
6. 6. 1
C o nc o mita nt C o m bi nati o n T hera p y .............................................................7 7
6. 6. 2
D ose M o dificati o n f or E nzal uta mi de ...........................................................7 7
6. 6. 3
I m m u ne-Relate d E ve nts a n d D ose M o dificati o n ( Wit h h ol d, Treat, 
Disc o nti n ue) .................................................................................................7 8
6. 6. 4
Ma na ge me nt of O verla p pi n g T o xicities ......................................................8 4
6. 7
I nter ve nti o n After t he E n d of t he St u d y ............................................................8 5
6. 8
Cli nic al S u p plies Discl os ure ................................................................................8 5
6. 9
St a n d ar d P olicies ..................................................................................................8 5
7
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
WI T H D R A W A L
............................................................................................................8 6
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n ...............................................................8 6
7. 2
P artici p a nt Wit h dr a w al Fr o m t he St u d y ...........................................................8 7
7. 3
L ost t o F oll o w -u p .................................................................................................8 8
8
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ........................................................8 9
8. 1
A d mi nistr ati ve a n d Ge ner al Pr oce d ures ...........................................................8 9
8. 1. 1
I nf or me d C o nse nt.........................................................................................8 9
8. 1. 1. 1
Ge neral I nf or me d C o nse nt .................................................................9 0
8. 1. 2
I ncl usi o n/ E xcl usi o n Criteria ........................................................................9 0
8. 1. 3
Partici pa nt I de ntificati o n Car d .....................................................................9 0
8. 1. 4
Me dical Hist or y
...........................................................................................9 1
8. 1. 5 
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w ...............................................9 1
8. 1. 5. 1
Pri or Me dicati o ns ...............................................................................9 1
8. 1. 5. 2
C o nc o mita nt Me dicati o ns ..................................................................9 1
8. 1. 6
Assi g n me nt of Scree ni n g N u m ber ...............................................................9 1
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1. 6. 1
Treat me nt Eli gi bilit y Assess me nt F or m ............................................9 1
8. 1. 7
Assi g n me nt of Treat me nt/ Ra n d o mizati o n N u m ber .....................................9 2
8. 1. 8
St u d y I nter ve nti o n A d mi nistrati o n ..............................................................9 2
8. 1. 8. 1
Ti mi n g of D ose A d mi nistrati o n .........................................................9 2
8. 1. 8. 1. 1
Pe m br oliz u ma b/ Place b o ..........................................................9 2
8. 1. 8. 1. 2
E nzal uta mi de ............................................................................9 2
8. 1. 8. 1. 3
A D T .........................................................................................9 3
8. 1. 9
Disc o nti n uati o n a n d Wit h dra wal .................................................................9 3
8. 1. 1 0
Partici pa nt Bli n di n g/ U n bli n di n g ..................................................................9 3
8. 1. 1 0. 1
N o n- e mer ge nc y U n bli n di n g ...............................................................9 4
8. 1. 1 1
Cali brati o n of E q ui p me nt .............................................................................9 4
8. 2 
Effic ac y/I m m u n o ge nicit y Assess me nts ..............................................................9 4
8. 2. 1
T u m or I ma gi n g a n d Assess me nt of Disease ................................................9 4
8. 2. 1. 1 
I nitial T u m or I ma gi n g ........................................................................9 7
8. 2. 1. 2
T u m or I ma gi n g D uri n g t he St u d y ......................................................9 8
8. 2. 1. 3
E n d -of -Treat me nt a n d F oll o w -u p T u m or I ma gi n g ............................9 8
8. 2. 1. 4 
Sec o n d C o urse ( Retreat me nt) T u m or I ma gi n g ..................................9 8
8. 2. 1. 5
S y m pt o matic S keletal -Relate d E ve nt ( S S R E) Assess me nt ...............9 9
8. 2. 2
Pr ostate -s pecific A nti ge n Assess me nts........................................................9 9
8. 2. 3
T u m or Tiss ue C ollecti o n ............................................................................1 0 0
8. 2. 4
Patie nt -re p orte d O utc o mes a n d Q ualit y of Life Assess me nts ...................1 0 0
8. 2. 4. 1
B PI -S F ..............................................................................................1 0 0
8. 2. 4. 2
F A C T - P............................................................................................1 0 1
8. 2. 4. 3
E Q -5 D -5 L ........................................................................................1 0 1
8. 3
S afet y Assess me nts .............................................................................................1 0 1
8. 3. 1
P h ysical E xa mi nati o ns ...............................................................................1 0 2
8. 3. 1. 1
F ull P h ysical E xa mi nati o n ...............................................................1 0 2
8. 3. 1. 2
Directe d P h ysical E xa mi nati o n ........................................................1 0 2
8. 3. 2
Vital Si g ns ..................................................................................................1 0 2
8. 3. 3
Electr ocar di o gra ms ....................................................................................1 0 2
8. 3. 4
Cli nical Safet y La b orat or y Assess me nts ...................................................1 0 3
8. 3. 4. 1
La b orat or y Safet y E val uati o ns ( He mat ol o g y, C he mistr y a n d 
Uri nal ysis) ........................................................................................1 0 3
8. 3. 5
Perf or ma nce Assess me nts ..........................................................................1 0 3
8. 3. 5. 1 
Easter n C o o perati ve O nc ol o g y Gr o u p Per f or ma nce Scale..............1 0 3
8. 4
A d verse E ve nts, Seri o us A d verse E ve nts, a n d Ot her Re p ort a ble S a fet y 
E ve nts ..................................................................................................................1 0 3
8. 4. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E, a n d Ot her 
Re p orta ble Safet y E ve nt I nf or mati o n ........................................................1 0 4
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 4. 2  
Met h o d of Detecti n g A Es, S A Es, a n d Ot her Re p orta ble Safet y E ve nts ....1 0 6
8. 4. 3
F oll o w -u p of A E, S A E, a n d Ot her Re p orta ble Safet y E ve nt I nf or mati o n .1 0 6
8. 4. 4
Re g ulat or y Re p orti n g Re q uire me nts f or S A E ...........................................1 0 6
8. 4. 5
Pre g na nc y a n d E x p os ure D uri n g Breastfee di n g ........................................1 0 6
8. 4. 6
Disease -relate d E ve nts a n d/ or Disease-relate d O utco mes N ot Q ualif yi n g 
as A Es or S A Es ..........................................................................................1 0 7
8. 4. 7 
E ve nts of Cli nical I nterest ..........................................................................1 0 7
8. 5
Tre at me nt of O ver d ose ......................................................................................1 0 7
8. 6
P h ar m ac o ki netics ...............................................................................................1 0 8
8. 7
P h ar m ac o d y n a mics ............................................................................................1 0 8
8. 8
Bi o m ar kers .........................................................................................................1 0 8
8. 8. 1
Pla n ne d Ge netic A nal ysis Sa m ple C ollecti o n ............................................1 0 8
8. 9
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics .....................................1 0 9
8. 1 0
Visit Re q uire me nts .............................................................................................1 0 9
8. 1 0. 1
Scree ni n g ....................................................................................................1 0 9
8. 1 0. 2
Treat me nt Peri o d ........................................................................................1 1 0
8. 1 0. 2. 1
E xte nsi o n First C o urse .....................................................................1 1 0
8. 1 0. 2. 2
E n d of Treat me nt Visit .....................................................................1 1 0
8. 1 0. 2. 3
Sec o n d C o urse .................................................................................1 1 0
8. 1 0. 3
P ost -treat me nt Visits..................................................................................1 1 1
8. 1 0. 3. 1
Safet y F oll o w -u p Visit .....................................................................1 1 2
8. 1 0. 3. 2
F oll o w -u p Visits ...............................................................................1 1 2
8. 1 0. 3. 3 
S ur vi val F oll o w -u p ..........................................................................1 1 2
8. 1 0. 4
S ur vi val Stat us ...........................................................................................1 1 3
9
S T A TI S TI C A L A N A L Y SI S P L A N ...........................................................................1 1 4
9. 1
St atistic al A n al ysis Pl a n S u m m ar y ...................................................................1 1 4
9. 2
Res p o nsi bilit y f or A n al yses/I n -h o use Bli n di n g ...............................................1 1 7
9. 3
H y p ot heses/ Esti m ati o n ......................................................................................1 1 7
9. 4
A n al ysis E n d p oi nts .............................................................................................1 1 7
9. 4. 1
Efficac y E n d p oi nts .....................................................................................1 1 8
9. 4. 1. 1
Pri mar y .............................................................................................1 1 8
9. 4. 1. 2
Ke y Sec o n dar y .................................................................................1 1 8
9. 4. 1. 3
Sec o n dar y .........................................................................................1 1 8
9. 4. 1. 4
E x pl orat or y ......................................................................................1 1 9
9. 4. 2 
Safet y E n d p oi nts ........................................................................................1 1 9
9. 4. 3
P R O E n d p oi nts ...........................................................................................1 1 9
9. 4. 3. 1
Ti me t o Pai n Pr o gressi o n .................................................................1 1 9
9. 4. 3. 2
F A C T - P............................................................................................1 1 9
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 4. 3. 3
B PI -S F ..............................................................................................1 2 1
9. 4. 3. 4
E Q - 5 D-5 L ........................................................................................1 2 2
9. 5
A n al ysis P o p ul ati o ns ..........................................................................................1 2 2
9. 5. 1
Efficac y A nal ysis P o p ulati o ns ...................................................................1 2 2
9. 5. 2
Safet y A nal ysis P o p ulati o ns ......................................................................1 2 2
9. 5. 3
P R O A nal ysis P o p ulati o n ..........................................................................1 2 3
9. 6
St atistic al Met h o ds .............................................................................................1 2 3
9. 6. 1
Statistical Met h o ds f or Efficac y A nal yses................................................. 1 2 3
9. 6. 1. 1
Ra di o gra p hic Pr o gressi o n -Free S ur vi val .........................................1 2 3
9. 6. 1. 2
O verall S ur vi val ...............................................................................1 2 5
9. 6. 1. 3
Ti me t o I nitiati o n of t he First S u bse q ue nt A ntica ncer T hera p y 
( T F S T)..............................................................................................1 2 6
9. 6. 1. 4
Ti me t o S y m pt o matic S keletal -Relate d E ve nt ( T T S S R E) ...............1 2 6
9. 6. 1. 5
A nal ysis Strate g y f or Ke y Efficac y E n d p oi nts ................................1 2 6
9. 6. 2 
Statistical Met h o ds f or Safet y A nal yses ....................................................1 2 7
9. 6. 3
A nal ysis Met h o ds f or P R O E n d p oi nts .......................................................1 2 9
9. 6. 4  
De m o gra p hic a n d Baseli ne C haracteristics ...............................................1 2 9
9. 7
I nteri m A n al yses ................................................................................................1 2 9
9. 7. 1
Efficac y I nteri m A nal yses ..........................................................................1 3 0
9. 7. 2
Safet y I nteri m A nal yses .............................................................................1 3 1
9. 8
M ulti plicit y
.........................................................................................................1 3 2
9. 8. 1
Ra di o gra p hic Pr o gressi o n -free S ur vi val ....................................................1 3 2
9. 8. 2
O verall S ur vi val .........................................................................................1 3 4
9. 8. 3
Ti me t o I nitiati o n of t he First S u bse q ue nt A ntica ncer T hera p y ( T F S T) ...1 3 5
9. 8. 4
Ti me t o S y m pt o matic S keletal -relate d E ve nt ( T T S SR E) ..........................1 3 7
9. 9
S a m ple Size a n d P o wer C alc ul ati o ns ...............................................................1 3 8
9. 1 0
S u b gr o u p A n al yses .............................................................................................1 4 0
9. 1 1
C o m pli a nce ( Me dic ati o n A d here nce) ...............................................................1 4 0
9. 1 2
E xte nt of E x p os ure .............................................................................................1 4 0
1 0
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 4 2
1 0. 1
A p pe n di x 1: Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns ......1 4 2
1 0. 1. 1
C o de of C o n d uct f or I nter ve nti o nal Cli nical Trials ...................................1 4 2
1 0. 1. 2
Fi na ncial Discl os ure ...................................................................................1 4 5
1 0. 1. 3
Data Pr otecti o n ...........................................................................................1 4 6
1 0. 1. 3. 1 
C o nfi de ntialit y of Data ....................................................................1 4 6
1 0. 1. 3. 2
C o nfi de ntialit y of Partici pa nt Rec or ds .............................................1 4 6
1 0. 1. 3. 3
C o nfi de ntialit y of I R B/I E C I nf or mati o n ..........................................1 4 7
1 0. 1. 4
C o m mittees Str uct ure .................................................................................1 4 7
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 1. 4. 1
E xter nal Data M o nit ori n g C o m mittee .............................................1 4 7
1 0. 1. 5
P u blicati o n P olic y ......................................................................................1 4 7
1 0. 1. 6
C o m plia nce wit h St u d y Re gistrati o n a n d Res ults P osti n g Re q uire m e nts .1 4 8
1 0. 1. 7
C o m plia nce wit h La w, A u dit, a n d De bar me nt ..........................................1 4 8
1 0. 1. 8
Data Q ualit y Ass ura nc e .............................................................................1 4 9
1 0. 1. 9
S o urce D oc u me nts .....................................................................................1 5 0
1 0. 1. 1 0
St u d y a n d Site Cl os ure ...............................................................................1 5 0
1 0. 2
A p pe n di x 2: Cli nic al L a b or at or y Tests ............................................................1 5 1
1 0. 3
A p pe n di x 3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v a l u ati n g, F oll o w-u p, a n d Re p orti n g .............................................................1 5 3
1 0. 3. 1
Defi niti o ns of Me dicati o n Err or, Mis use, a n d A b use ................................1 5 3
1 0. 3. 2
Defi niti o n of A E ........................................................................................1 5 3
1 0. 3. 3
Defi niti o n of S A E ......................................................................................1 5 4
1 0. 3. 4
A d diti o nal E ve nts Re p orte d .......................................................................1 5 5
1 0. 3. 5
Rec or di n g A E a n d S A E .............................................................................1 5 5
1 0. 3. 6
Re p orti n g of A Es, S A Es, a n d Ot her Re p orta ble Safet y E ve nts t o t he 
S p o ns or ......................................................................................................1 5 9
1 0. 4
A p pe n di x 4: Me dic al De vice a n d Dr u g – De vice C o m bi n ati o n Pr o d ucts: 
Pr o d uct Q u alit y C o m pl ai nts/ M alf u ncti o ns: Defi niti o ns, Rec or di n g , a n d 
F oll o w -u p ............................................................................................................1 6 0
1 0. 5
A p pe n di x 5: C o ntr ace pti ve G ui d a nce ..............................................................1 6 1
1 0. 5. 1
Defi niti o ns ..................................................................................................1 6 1
1 0. 5. 2
C o ntrace pti ve Re q uire me nts ......................................................................1 6 2
1 0. 6
A p pe n di x 6: C ollecti o n a n d M a n a ge me nt of S peci me ns f or F ut ure 
Bi o me dic al Rese arc h ..........................................................................................1 6 3
1 0. 7
A p pe n di x 7: C o u ntr y -s pecific Re q uire me nts ..................................................1 6 4
1 0. 7. 1
La b orat or y Testi n g .....................................................................................1 6 4
1 0. 7. 2
C o u ntr y -s pecific I nf or mati o n.....................................................................1 6 4
1 0. 7. 2. 1
C hi na ................................................................................................1 6 4
1 0. 7. 2. 2
Ja pa n ................................................................................................1 6 4
1 0. 8
A p pe n di x 8: Descri pti o n of t he Pr ost ate C a ncer W or ki n g Gr o u p ( P C W G) 
Pr ocess f or Assess me nt of B o ne Lesi o ns ..........................................................1 6 5
1 0. 8. 1
I ma gi n g Met h o ds .......................................................................................1 6 5
1 0. 8. 2  
D oc u me ntati o n of B o ne Lesi o ns at Baseli ne .............................................1 6 5
1 0. 8. 3
A ssess me nt of B o ne Res p o nse at S u bse q ue nt I ma gi n g Ti me P oi nts ........1 6 5
1 0. 8. 4
Descri pti o ns of B o ne Res p o nse Cate g ories ...............................................1 6 6
1 0. 8. 4. 1
N o E vi de nce of Disease ...................................................................1 6 6
1 0. 8. 4. 2
N o n- pr o gressi o n ( N o n -P D) ..............................................................1 6 6
1 0. 8. 4. 3
U nc o nfir me d Pr o gressi ve Disease ( P D u) ........................................1 6 6
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 8. 4. 4
Pr o gressi ve Disease ( P D)................................................................ .1 6 6
1 0. 8. 4. 5
C o nfir mati o n of Pr o gressi o n ............................................................1 6 7
1 0. 8. 4. 5. 1
F or Ne w Lesi o ns Wit hi n t he Flare Wi n d o w ( < 1 2 wee ks) .....1 6 7
1 0. 8. 4. 5. 2
F or Ne w Lesi o ns O utsi de t he Flare Wi n d o w ( > 1 2 wee ks)....1 6 7
1 0. 8. 4. 6
S u persca n .........................................................................................1 6 7
1 0. 8. 4. 7
Ma na ge me nt F oll o wi n g C o nfir me d P D ...........................................1 6 8
1 0. 9
A p pe n di x 9: Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of 
Dise ase Pr o gressi o n ............................................................................................1 6 9
1 0. 1 0
A p pe n di x 1 0: A b bre vi ati o ns .............................................................................1 7 0
1 0. 1 1
A p pe n di x 1 1: E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us ..1 7 6
1 1
R E F E R E N C E S .............................................................................................................1 7 7
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
LI S T O F T A B L E S
Ta ble 1
I nitial Treat me nt P hase ( Pe m br oliz u ma b/ Place b o Pl us E nzal uta mi de 
Pl us A D T) ....................................................................................................2 4
Ta ble 2
E xte nsi o n First C o urse P hase ( E nzal uta mi de + A D T) ................................3 4
Ta ble 3
Sec o n d C o urse P hase ( Pe m br oliz u ma b Retreat me nt O N L Y) .....................3 9
Ta ble 4
La b orat or y Val ues f or A de q uate Or ga n F u ncti o n .......................................6 4
Ta ble 5
St u d y I nter ve nti o ns ......................................................................................7 1
Ta ble 6
E nzal uta mi de D ose M o dificati o n G ui deli nes f or Dr u g -Relate d A d verse 
E ve nts ...........................................................................................................7 8
Ta ble 7
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne -
relate d A d verse E ve nts Ass ociate d Wit h Pe m br oliz u ma b M o n ot hera py, 
C of or m ulati o ns, or I O C o m bi nati o ns ..........................................................7 9
Ta ble 8
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d Treat me nt  
G ui deli nes.................................................................................................... 8 3
Ta ble 9
Re p orti n g Ti me Peri o ds a n d Ti me Fra mes f or A d verse E ve nts a n d 
Ot her Re p orta ble Safet y E ve nts .................................................................1 0 5
Ta ble 1 0
Defi niti o n of Visit Res p o nse f or F A C T -P sc ore ........................................1 2 1
Ta ble 1 1
Defi niti o n of Best Sc ore f or F A C T -P sc ore ...............................................1 2 1
Ta ble 1 3 
Efficac y A nal ysis Met h o ds f or Ke y Efficac y E n d p oi nts ...........................1 2 7
Ta ble 1 4
A nal ysis Strate g y f or Safet y Para meters ....................................................1 2 9
Ta ble 2 0
Pr ot oc ol -re q uire d Safet y La b orat or y Assess me nts....................................1 5 2
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
LI S T O F FI G U R E S
Fi g ure 1
St u d y Sc he ma ...............................................................................................2 2
0 8 9 V 4 C
C CI
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nt
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
r P F S per P C W G -m o difie d R E CI S T 1. 1 as 
assesse d b y BI C R w here s oft tiss ue will be 
assesse d per R E CI S T 1. 1 m o difie d t o 
f oll o w a ma xi m u m of 1 0 tar get lesi o ns a n d 
a ma xi m u m of 5 tar get lesi o ns per or ga n, 
a n d b o ne disease will be assesse d per 
P C W G criteria.
H y p ot hesis ( H 1): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
r P F S p er P C W G -m o difie d R E CI S T 1. 1 as 
assesse d b y BI C R.
r P F S: the ti me fr o m ra n d o mizati o n t o 
ra di o gra p hic pr o gressi o n or deat h d ue t o 
a n y ca use, w hic he ver occ urs first .
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T ve rs us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o O S .
H y p ot hesis ( H 2): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o O S .
O S: t he ti me fr o m ra n d o mizati o n t o deat h 
d ue t o a n y ca use.
Sec o n d ar y O bjecti ves
Sec o n d ar y E n d p oi nt s
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T F S T .
H y p ot hesis ( H 3): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl u s 
e nzal uta mi de pl us A D T wit h res pect t o 
T F S T .
T F S T: t he ti me fr o m ra n d o mizati o n t o 
i nitiati o n of t he first s u bse q ue nt a ntica ncer 
t hera p y or deat h, w hic he ver c o mes first.
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T T S S R E .
T T S S R E: t he ti me fr o m ra n d o mizati o n t o 
t he first S S R E, defi ne d as:
•
use of E B R T t o pre ve nt or relie ve 
s keletal s y m pt o ms 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
H y p ot hesis ( H 4): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T T S S R E .
•
occ urre nce of ne w s y m pt o matic 
pat h ol o gic b o ne fract ure ( verte bral or 
n o n -verte bral) 
•
occ urre nce of s pi nal c or d c o m pressi o n
•
or t u m or -relate d orth o pe dic s ur gical 
i nter ve nti o n, w hic he ver occ urs first
T o assess pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o t he: 
-
Ti me t o P S A pr o gressi o n
-
Ti me t o r a di o gr a p hic s oft tiss ue 
pr o gressi o n per s oft tiss ue r ules of 
P C W G -m o difie d R E CI S T 1. 1, as 
assesse d b y BI C R
-
T T P P 
-
P F S 2 as deter mi ne d b y i n vesti gat or 
assess me nt
Ti me t o P S A pr o gressi o n: t he ti me fr o m 
ra n d o mizati o n t o P S A pr o gressi o n. T he 
P S A pr o gre ssi o n date is defi ne d as t he date 
of 1) ≥2 5 % i ncrease a n d ≥2 n g/ m L a b o ve 
t he na dir, c o nfir me d b y a sec o n d val ue ≥3 
wee ks later if t here is P S A decli ne fr o m 
baseli ne, or 2) ≥2 5 % i ncrease a n d ≥2 n g/ m L 
i ncrease fr o m baseli ne be y o n d 1 2 wee ks if 
t here is n o P S A decli ne fr o m baseli ne. 
Ti me t o r a di o gr a p hic s oft tiss ue 
pr o gressi o n: t he ti me fr o m ra n d o mizati o n 
t o ra di o gra p hic s oft tiss ue pr o gressi o n.
T T P P: ti me fr o m ra n d o mizati o n t o pai n 
pr o gressi o n base d o n B PI -S F Ite m # 3 
“ w orst pai n i n 2 4 h o urs” a n d o pi oi d use. 
P F S 2: ti me fr o m ra n d o mizati o n t o disease 
pr o gressi o n as deter mi ne d b y i n vesti gat or 
assess me nt of ra di ol o gical or cli nical 
pr o gressi o n after ne xt -li ne of t hera p y or 
deat h fr o m a n y ca use, w hic he ver occ urs 
first.
T o assess pe m br oliz u ma b pl us 
e nzal uta mi de pl u s A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o t he:
-
P S A res p o nse r ate 
-
P S A u n detect a ble r ate
-
O R R a n d D O R per P C W G -m o difie d 
R E CI S T 1. 1 as assesse d b y BI C R
P S A res p o nse: a P S A decli ne of ≥5 0 % 
fr o m baseli ne meas ure d t wice at least 3 
wee ks a part
P S A u n detect a ble: P S A < 0. 2 n g/ m L 
d uri n g st u d y i nter ve nti o n
O R: C R or P R
D O R: t he ti me fr o m t he earliest date of t he 
first d oc u me nte d e vi de nce of C R or P R 
u ntil earliest date of disease pr o gressi o n or 
deat h d ue t o a n y ca use, w hic he ver occ urs 
first
T o assess t he s afet y a n d t oler a bilit y of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T ve rs us place b o pl us e nzal uta mi de pl us 
A D T.
A Es 
St u d y i nter ve nti o n disc o nti n uati o n d ue t o 
A Es
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
O ver all Desi g n:
St u d y P hase
P hase 3
Pri mar y P ur p ose
Treat me nt
I n dicati o n
Pr ostate ca ncer metastatic
P o p ulati o n
Partici pa nts wit h m H S P C
St u d y T y pe
I nter ve nti o nal
I nter ve nti o n M o del
Parallel
T his is a m ulti site st u d y.
T y pe of C o ntr ol
Place b o
St u d y Bli n di n g
D o u ble -bli n d wit h i n -h o use bli n di n g
Bli n di n g R oles
I n vesti gat or
Partici pa nt
S p o ns or
Esti mate d D urati o n of St u d y
T he S p o ns or esti mates t hat t he st u d y will 
re q uire a p pr o xi matel y 5 9 m o nt hs fr o m t he 
ti me t he first partici pa nt si g ns t he i nf or me d 
c o nse nt u ntil t he last partici pa nt’s last 
st u d y-relate d tele p h o ne call or visit.
E xte nsi o n P orti o n i n C hi na: T he S p o ns or 
esti mates t hat t he st u d y will re q uire 
a p pr o xi matel y 1 a d diti o nal year ( be y o n d t he 
gl o bal st u d y’s last partici pa nt last st u d y -
relate d p h o ne call or visit) fr o m t he ti me t he 
first partici pa nt si g ns t he i nf or me d c o nse nt 
u ntil t he last partici pa nt’s last st u d y -relate d 
tele p h o ne call or visit.
N u m ber of P artici p a nts:
Gl o bal P orti o n: A p pr o xi matel y 1 2 3 2 partici pa nts will be ra n d o mize d as descri be d i n 
Secti o n 9. 1.
E xte nsi o n P orti o n i n C hi na: A p pr o xi matel y 1 8 6 partici pa nts o verall will be e nr olle d i n 
C hi na, i ncl u di n g partici pa nts e nr olle d i n eit her t he gl o bal p orti o n or t he e xte nsi o n p orti o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
I nter ve nti o n Gr o u ps a n d D ur ati o n:
Ar m N a me
I nter ve nti o n 
N a me
U nit D ose 
Stre n gt h(s)
D os a ge 
Le vel(s)
R o ute of 
A d mi nistr ati o n
Re gi me n/
Tre at me nt 
Peri o d/
V acci n ati o n 
Re gi me n
Use
Ar m 1
Pe m br oliz u ma b
2 5 m g/ m L
2 0 0 m g
I V I nf usi o n
Da y 1 of eac h 
2 1 -da y c ycle
Test 
Pr o d uct
Ar m 1
E nzal uta mi de
4 0 m g/ 8 0 m g
1 6 0 m g
Oral
F o ur 4 0 -m g 
ca ps ules/ 
ta blets orall y 
per da y/t w o 
8 0 m g ta blets 
orall y per da y
Test 
Pr o d uct
Ar m 2
E nzal uta mi de
4 0 m g/ 8 0 m g
1 6 0 m g
Oral
F o ur 4 0 -m g 
ca ps ules/ 
ta blets orall y 
per da y/t w o 
8 0 m g ta blets 
orall y per da y
Test 
Pr o d uct
Ar m 2
Place b o
N A  
N A
I V I nf usi o n
Da y 1 of eac h 
2 1 -da y c ycle
Place b o
A b bre viati o ns: D  Da y; I V  i ntra ve n o us; N A  n ot a p plica ble; P O  oral; Q 3 W  e ver y 3 wee ks; Q D 
o nce dail y.
T otal N u m ber of 
I nter ve nti o n Gr o u ps/ Ar ms
2 ar ms
D urati o n of Partici pati o n
Eac h partici pa nt will partici pate i n t he st u d y fr o m t he ti me 
t he partici pa nt si g ns t he I nf or me d Co nse nt F or m (I C F) 
t hr o u g h t he fi nal pr ot oc ol-s pecifie d c o ntact.
After a scree ni n g p hase of u p t o 4 2 da ys, eac h partici pa nt 
will be assi g ne d t o recei ve st u d y i nter ve nti o n (e nzal uta mi de 
c o m bi nati o n wit h eit her pe m br oliz u ma b or place b o) u ntil 
disease pr o gressi o n is ra di o gra p hicall y d oc u me nte d, 
verifie d b y BI C R per P C W G -m o difie d R E CI S T 1. 1, 
u nacce pta ble A Es, i nterc urre nt ill ness t hat pre ve nts f urt her 
a d mi nistrati o n of treat me nt, i n vesti gat or’s decisi o n t o 
disc o nti n ue t he partici pa nt, or a d mi nistrati ve reas o ns 
re q uiri n g cessati o n of treat me nt. All partici pa nts m ust 
mai ntai n c o nti n u o us a n dr o ge n de pri vati o n t hera p y ( A D T) 
wit h a l utei nizi n g -h or m o ne releasi n g h or m o ne ( L H R H) 
a g o nist or a nta g o nist d uri n g st u d y treat me nt or ha ve a 
hist or y of bilateral orc hiect o m y . Treat me nt wit h 
pe m br oliz u ma b/ place b o ma y c o nti n ue f or u p t o 3 5 c ycles
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
(a p pr o xi matel y 2 years starti n g wit h t he first i nf usi o n i n 
C ycle 1) or u ntil meeti n g criteria f or disc o nti n uati o n of 
st u d y i nter ve nti o n. Treat me nt wit h e nzal uta mi de will 
pr ocee d c o nti n u o usl y fr o m Da y 1 of C ycle 1 i n b ot h ar ms, 
u nless criteria f or disc o nti n uati o n of st u d y i nter ve nti o n are 
met (e g, disease pr o gressi o n). If pe m br oliz u ma b/ place b o is
c o m plete d or disc o nti n ue d f or reas o ns ot her t ha n 
pr o gressi ve disease, partici pa nts recei vi n g e nzal uta mi de 
will c o nti n ue t o recei ve e nzal uta mi de a n d A D T ( E xte nsi o n 
First C o urse ) u ntil criteria f or disc o nti n uati o n are met (e g, 
disease pr o gressi o n). Partici pa nts w h o st o p pe m br oliz u ma b 
as a res ult of o btai ni n g a n i n vesti gat or -deter mi ne d 
c o nfir me d C R or t h ose s u bjects w h o st o p after recei vi n g 3 5 
c ycles ma y be eli gi ble f o r a n a d diti o nal 1 7 c ycles of 
pe m br oliz u ma b (a p pr o xi matel y 1 year) after pr o gressi ve 
disease if t he y meet t he criteria f or re -treat me nt ( Sec o n d 
C o urse P hase) a n d t he st u d y is o n g oi n g ( Secti o n 8. 1 0. 2. 3).
Partici pa nts ra n d o mize d t o place b o will n ot be per mitt e d t o 
cr oss o ver t o pe m br oliz u ma b f oll o wi n g pr o gressi o n.
After t he e n d of treat me nt, eac h partici pa nt will be f oll o we d 
f or t he occ urre nce of a d verse e ve nts a n d s p o nta ne o usl y 
re p orte d pre g na nc y as descri be d u n der Secti o n 8. 4.
Partici pa nts w h o disc o nti n ue st u d y treat me nt 
( pe m br oliz u ma b/ place b o a n d e nzal uta mi de) f or reas o ns 
ot her t ha n ra di o gra p hic disease pr o gressi o n will ha ve p ost -
treat me nt f oll o w-u p i ma gi n g f or disease stat us u ntil disease 
pr o gressi o n is d oc u me nte d per P C W G -m o difie d R E CI S T 
1. 1 a n d verifie d by bli n de d i n de pe n de nt ce ntral re vie w , t he 
start of a ne w a ntica ncer treat me nt, wit h dra wal of c o nse nt, 
deat h, or l oss t o f oll o w -u p. All partici pa nts will be f oll o we d 
b y tele p h o ne f or o verall s ur vi val 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 .
T he o verall st u d y e n ds w he n t he last partici pa nt c o m pletes 
t he last st u d y-relate d c o ntact or visit, wit h dra ws fr o m t he 
st u d y, or is l ost t o f oll o w-u p (ie, t he partici pa nt is u na ble t o 
be c o ntacte d b y t he i n vesti gat or).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
St u d y G o ver n a nce C o m mittees:
E x ec uti ve O versi g ht C o m mittee
Yes
Data M o nit ori n g C o m mittee
Yes
Cli nical A dj u dicati o n C o m mittee
N o
Steeri n g C o m mittee
N o
St u d y g o ver na nce c o nsi derati o ns are o utli ne d i n A p pe n di x 1.
As of A me n d me nt 0 4 , t he E xec uti ve O versi g ht C o m mittee a n d D at a M o nit ori n g 
C o m mittee are n o l o n ger a p plic a ble.
St u d y Acce pts He alt h y V ol u nteers : N o
A list of a b bre viati o ns use d i n t his d oc u me nt ca n be f o u n d i n A p pe n di x 1 0 .
1. 2
Sc he m a
T he st u d y desi g n is de picte d i n Fi g ure 1 .
Fi g ure 1
St u d y Sc he ma
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Pe m br oliz u ma b ( 2 0 0 m g Q 3 W)/ place b o ( Q 3 W) treat me nt will be gi n o n Da y 1 of eac h 3 -
wee k c ycle a n d will c o nti n ue f or u p t o 3 5 c ycles (a p pr o xi matel y 2 years u nless s pecific 
wit h dra wal/ disc o nti n uati o n criteria are met). E nzal uta mi de ( 1 6 0 m g P O Q D) treat me nt will 
be gi n o n t he sa me da y as Da y 1 C ycle 1 of pe m br oliz u ma b/ place b o a n d will be c o nti n ue d o n 
a dail y d osi n g c ycle u ntil criteria f or disc o nti n uati o n are met (e g, disease pr o gressi o n). 
Partici pa nts w h o m ust disc o nti n ue 1 of t he 2 treat me nts d ue t o dr u g -relate d A Es ma y 
c o nti n ue wit h t he ot her c o m bi nati o n part ner u ntil criteria f or disc o nti n uati o n are met.
A b bre viati o ns: A D T  a n dr o ge n de pri vati o n t hera p y ( L H R H a g o ni st or a nta g o nist) or 
s ur gical castrati o n (ie. Bilateral orc hiect o m y); E C O G  Easter n C o o perati ve O nc ol o g y 
Gr o u p; m H S P C  metastatic h or m o ne -se nsiti ve pr ostate ca ncer; N  n u m ber; N H A  ne xt 
ge nerati o n h or m o nal a ge nts; P O  per oral; Q 1 2 W  e ver y 1 2 wee ks.
0 8 9 V 4 C
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
Pri or a n d 
c o nc o mita nt 
me dicati o n 
re vie w
X  
X  
X  
X  
X  
X  
X  
X
X
HI V, He p B, a n d 
He p C stat us
X
Ra n d o mizati o n
X
Tele p h o ne 
c o ntact or visit 
( C 1 D 8)
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
Cli nic al Pr oce d ures/ Assess me nts
A E m o nit ori n g
X  
X  
X  
X  
X  
X  
X  
X
X
X
F ull p h ysical 
e xa mi nati o n
X
X
Directe d p h ysical 
e xa mi nati o n
X  
X  
X  
X  
X  
X
X
Vital si g ns, 
hei g ht, a n d 
wei g ht
X  
X  
X  
X  
X  
X  
X  
X
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
1 2 lea d E C G
X
E C O G 
perf or ma nce 
stat us
X  
X  
X  
X  
X  
X  
X  
X
S S R E 
Assess me nt
X  
X  
X  
X  
X  
X  
X  
X
X
X
S u bse q ue nt 
a ntica ncer 
t hera p y stat us
X
X
X
Sec o n d 
pr o gressi o n
X
S ur vi val stat us
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
St u d y I nter ve nti o n A d mi nistr ati o n
Pe m br oliz u ma b/ 
place b o
X  
X  
X  
X  
X  
X
E nzal uta mi de 
( dis pe nse d/
ret ur ne d) 
X  
X  
X  
X  
X  
X  
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
2 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
L a b or at or y Pr oce d ures/ Assess me nts: a n al ysis perf or me d b y C E N T R A L l a b or at or y
P T or I N R a n d 
P T T/a P T T
X
C o m plete bl o o d 
c o u nt wit h 
differe ntial
X
X  
X  
X  
X  
X  
X
X
C o m pre he nsi ve 
c he mistr y pa nel
X
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
T 3 or F T 3, F T 4, 
a n d T S H
X
X  
X  
X  
X
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
Test oster o ne
X
X  
X  
X
Pr oce d ures/ Assess me nts: a n al ysis perf or me d C E N T R A L L Y
Effic ac y Me as ure me nts
P S A b y ce ntral 
la b orat or y
X
Q 3 W ( ± 7 da ys) fr o m ra n d o mizati o n 
t hr o u g h Wee k 1 2, t he n Q 1 2 W ( ± 7 
da ys) t hereafter
X
X
X
0 8 9 V 4 C
C CI
0 8 C V S X

0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Scree ni n g 
P h ase
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of 
Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5
6 t o 
3 5
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val 
F oll o w u p
Sc he d uli n g 
Wi n d o w ( Da ys)
4 2 t o 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At pe m br o/ 
place b o Disc o n.
3 0 ( + 7) 
da ys fr o m 
last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W 
( ± 7 da ys)
Treat me nt 
Eli gi bilit y 
Assess me nt 
( T E A)
X
A b bre viati o ns: A E  a d verse e ve nt; a P T T  acti vate d partial t hr o m b o plasti n ti me; BI C R  bli n de d i n de pe n de nt ce ntral re vie w; B PI
S F   Brief Pai n I n ve nt or y S h ort F or m; C T  c o m p ute d 
t o m o gra p h y; 
; Disc o n  disc o nti n uati o n; 
 E C G  electr ocar di o gra m; E C O G  Easter n 
C o o perati ve O nc ol o g y Gr o u p; E O T  e n d of treat me nt; E Q 5 D 5 L  E ur o Q ol 5 di me nsi o n, 5 le vel healt h state utilit y i n de x; F A C T P    F u ncti o nal Assess me nt of Ca ncer T hera p y Pr ostate; F T 3  
free trii o d ot h yr o ni ne; F T 4  free t h yr o xi ne; He p  he patitis; HI V  h u ma n i m m u n o deficie nc y vir us; I C F  i nf or me d c o nse nt f or m; I N R  i nter nati o nal n or malize d rati o; I R B  I nstit u ti o nal Re vie w 
B oar d; I V  i ntra ve n o us; M RI  ma g netic res o na nce i ma gi n g; P D  pr o gressi ve disease; P D L 1  pr o gra m me d cell deat h li ga n d 1; P R O  patie nt re p orte d o utc o me; P S A  pr ostate s pecific a nti ge n; 
P T  pr ot hr o m bi n ti me; P T T  partial t hr o m b o plasti n ti me; Q 3 W  e ver y 3 wee ks; Q 9 W  e ver y 9 wee ks; Q 1 2 W  e ver y 1 2 wee ks; 
; S A E  seri o us a d verse e ve nt; S C F  
S p o ns or C o m m u nicati o n F or m; S O C  sta n dar d of care; S S R E  s y m pt o matic s keletal relate d e ve nt; T E A  Treat me nt Eli gi bilit y Assess me nt ; T 3  t otal trii o d ot h yr o ni ne; T S H  t h yr oi d sti m ulati n g 
h or m o ne; W  wee k.
0 8 9 V 4 C
C CI
C CI
C CI
C CI
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles ( 8 4 -
d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt C ycle/ Title
C ycle 1 a n d be y o n d
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val F oll o w
u p
Sc he d uli n g Wi n d o w ( Da ys)
Da y 1 ( ± 7 da ys) of 
e ver y c ycle
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
F ull p h ysical e xa mi nati o n
X
Directe d p h ysical e xa mi nati o n
X
X
Vital si g ns, a n d wei g ht
X
X
X
E C O G perf or ma nce stat us
X
X
S S R E Assess me nt
X
X
X
X
S u bse q ue nt a ntica ncer t hera p y 
stat us
X
X
X
Sec o n d pr o gressi o n
X
S ur vi val stat us
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles ( 8 4 -
d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt C ycle/ Title
C ycle 1 a n d be y o n d
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val F oll o w
u p
Sc he d uli n g Wi n d o w ( Da ys)
Da y 1 ( ± 7 da ys) of 
e ver y c ycle
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
St u d y I nter ve nti o n A d mi nistr ati o n
E nzal uta mi de
( dis pe nse d/ret ur ne d) 
X
X
L a b or at or y Pr oce d ures/ Assess me nts: a n al ysis perf or me d b y C E N T R A L l a b or at or y
P T or I N R a n d P T T/a P T T
X
C o m plete bl o o d c o u nt wit h 
differe ntial
X
X
X
C o m pre he nsi ve c he mistr y 
pa nel
X
X
X
Uri nal ysis
X
X
X
T 3 or F T 3, F T 4, a n d T S H
X
X
X
Test oster o ne
X
X
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles ( 8 4 -
d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt C ycle/ Title
C ycle 1 a n d be y o n d
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val F oll o w
u p
Sc he d uli n g Wi n d o w ( Da ys)
Da y 1 ( ± 7 da ys) of 
e ver y c ycle
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
Pr oce d ures/ Assess me nts: a n al ysis perf or me d C E N T R A L L Y
Effic ac y Me as ure me nts
P S A b y ce ntral la b orat or y
Q 1 2 W fr o m 
ra n d o mizati o n
X
X
X
T u m or i ma gi n g ( C T/ M RI) 
a n d b o ne sca n
Q 1 2 W fr o m 
ra n d o mizati o n
X
X
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles ( 8 4 -
d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt C ycle/ Title
C ycle 1 a n d be y o n d
E O T Visit
Safet y 
F oll o w u p
F oll o w u p 
Visits
S ur vi val F oll o w
u p
Sc he d uli n g Wi n d o w ( Da ys)
Da y 1 ( ± 7 da ys) of 
e ver y c ycle
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
P atie nt -Re p orte d O utc o mes
B PI S F 
F A C T P 
E Q 5 D 5 L
X
X
X
A b bre viati o ns: A E  a d verse e ve nt; a P T T  acti vate d partial t hr o m b o plasti n ti me; BI C R  bli n de d i n de pe n de nt ce ntral re vie w; B PI S F  Brief Pai n I n ve nt or y S h ort F or m; C T  c o m p ute d 
t o m o gra p h y; C T C  circ ulati n g t u m or cell; ct D N A  circ ulati n g t u m or de o x yri b o n ucleic aci d; Disc o n  disc o nti n uati o n; D N A  deo x yri b o n ucleic aci d; E C G  electr ocar di o gra m; E C O G  Easter n 
C o o perati ve O nc ol o g y Gr o u p; E O T  e n d of treat me nt; E Q 5 D 5 L   E ur o Q ol 5 di me nsi o n, 5 le vel healt h state utilit y i n de x; F A C T P    F u ncti o nal Assess me nt of Ca ncer T hera p y Pr ostate; F T 3  
free trii o d ot h yr o ni ne; F T 4  free t h yr o xi ne; He p  he patitis; HI V  h u ma n i m m u n o deficie nc y vir us; I C F  i nf or me d c o nse nt f or m; 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 V  i ntra ve n o us; M RI  ma g netic res o na nce i ma gi n g; P D  pr o gressi ve disease; P D L 1  pr o gra m me d cell deat h li ga n d 1; P R O  patie nt re p orte d o utc o me; P S A  prostate s pecific a nti ge n; 
P T  pr ot hr o m bi n ti me; P T T  partial t hr o m b o plasti n ti me; Q 1 2 W  e ver y 1 2 wee ks; R N A  ri b o n ucleic aci d; S A E  seri o us a d vers e e ve nt; S C F  S p o ns or C o m m u nicati o n F or m; S O C  sta n dar d 
of care; S S R E  s y m pt o matic s keletal relate d e vent; T E A  Treat me nt Eli gi bilit y Assess me nt ; T 3  t otal trii o d ot h yr o ni ne; T S H  t h yr oi d sti m ulati n g h or m o ne; W  wee k.
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
3 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 3
Sec o n d C o urse P hase ( Pe m br oliz u ma b Retreat me nt O N L Y)
N O T E: As of A me n d me nt 0 4, S ec o n d C o urse tre at me nt is n ot a n o pti o n f or p artici p a nts. T here are c urre ntl y n o p artici p a nts
i n t he Sec o n d C o urse P h ase.
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
A d mi nistr ati ve Pr oce d ures
Eli gi bilit y criteria  
X
C o nc o mita nt 
me dicati o n re vie w
X  
X  
X  
X  
X
X
X
Cli nic al Pr oce d ures/ Assess me nts
A E m o nit ori n g
X  
X  
X  
X  
X
X
X
X
0 8 9 V 4 C
C CI
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
F ull p h ysical 
e xa mi nati o n
X
X
Directe d p h ysical 
e xa mi nati o n
X  
X  
X  
X
X
Vital si g ns a n d 
wei g ht
X  
X  
X  
X  
X
X
E C O G perf or ma nce 
stat us
X  
X  
X  
X  
X
X
S u bse q ue nt 
a ntica ncer t hera p y 
stat us
X
X
X
S ur vi val stat us
X
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
St u d y I nter ve nti o n A d mi nistr ati o n
Pe m br oliz u ma b
X  
X  
X  
X  
X
E nzal uta mi de
( dis pe nse d/ret ur ne d)
X  
X  
X  
X  
X
X
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
L a b or at or y Pr oce d ures/ Assess me nts: a n al ysis perf or me d b y C E N T R A L l a b or at or y
P T or I N R a n d 
P T T/a P T T
X
C o m plete bl o o d 
c o u nt wit h 
differe ntial
X  
X  
X  
X  
X
X
X
C o m pre he nsi ve 
c he mistr y pa nel
X  
X  
X  
X  
X
X
X
Uri nal ysis
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
T 3 or F T 3, F T 4, a n d 
T S H
X  
X
X
X
X
Test oster o ne
X
X  
X
X
Pr oce d ures/ Assess me nts: a n al ysis perf or me d b y C E N T R A L l a b or at or y
Effic ac y Me as ure me nts
P S A b y ce ntral 
la b orat or y
X
Q 3 W ( ± 7 da ys) fr o m first 
retreat me nt i nf usi o n 
t hr o u g h Wee k 1 2, t he n 
Q 1 2 W ( ± 7 da ys) 
t hereafter
X
X
X
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Tri al Peri o d
Tre at me nt C ycles
( 2 1-d a y c ycles)
E n d of Tre at me nt
P ost -Tre at me nt
N otes
Treat me nt 
C ycle/ Title
1 
2 
3 
4
5 t o 
1 7
E O T Visit
Safet y 
F oll o w u p
F oll o w u p Visits
S ur vi val 
F oll o w u p
Sc he d uli n g Wi n d o w 
( Da ys)
± 3 
± 3 
± 3 
± 3
At ti me of Disc o n
3 0 ( + 7) da ys 
fr o m last d ose
Q 1 2 W 
( ± 7 da ys)
Q 1 2 W
( ± 7 da ys)
T u m or i ma gi n g 
( C T/ M RI) a n d b o ne 
sca n
(e val uate d l ocall y)
X  
Q 1 2 W ( ± 7 da ys) fr o m 
first retreat me nt i nf usi o n
X
X
A b bre viati o ns:  A E  a d verse e ve nt; a P T T  acti vate d partial t hr o m b o plasti n ti me; C T  c o m p ute d t o m o gra p h y; Disc o n  disc o nti n uati o n; E CI  e ve nts of cli nical i nterest; E C O G  Easter n 
C o o perati ve O nc ol o g y Gr o u p; E O T  e n d of treat me nt; F T 3  free trii o d ot h yr o ni ne; F T 4  free t h yr o xi ne; i C R O  i ma gi n g c o ntract researc h or ga nizati o n; I N R  i nter nati o nal n or malize d rati o; M RI 
 ma g netic res o na nce i ma gi n g; P S A  pr ostate s pecific a nti ge n; P T  pr ot hr o m bi n ti me; P T T  partial t hr o m b o plasti n ti me; Q 3 W  e ver y 3 wee ks; Q 1 2 W  e ver y 1 2 wee ks; S A E  seri o us a d verse 
e ve nt; T 3  t otal trii o d ot h yr o ni ne; T S H  t h yr oi d sti m ulati n g h or m o ne.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
2
I N T R O D U C TI O N
Pr ostate ca ncer re prese nts t he sec o n d m ost c o m m o n mali g na nc y dia g n ose d i n me n 
w orl d wi de, wit h a n esti mate d a n n ual i nci de nce of o ver 1 milli o n a n d a n e x pecte d 3 0 0, 0 0 0 
pl us deat hs a n n uall y [ Ferla y, J., et al 2 0 1 5]. I n t he U S, a p pr o xi matel y 1 i n e ver y 9 me n will 
be dia g n ose d wit h pr ostate ca ncer i n his lifeti me [ Sie gel, R. L., et al 2 0 1 8].
W hile ma n y me n dia g n ose d wit h l ocall y c o nfi ne d disease ma y be treate d defi niti vel y wit h 
ra diati o n or s ur ger y, a p pr o xi matel y 3 0 % of me n ha ve rec urre nt disease a n d g o o n t o de vel o p 
metastatic pr ostate ca ncer. I n a d diti o n, 5 % t o 3 0 % of me n wit h pr ostate ca ncer ha ve 
metastatic disease at i nitial dia g n osis, a perce nta ge t hat varies greatl y b y re gi o n, b ut is o n a n 
i ncreasi n g tre n d t hat is e x pecte d t o c o nti n ue i n t he f ut ure [ Ca ncer re gistrati o n c o m mittee of 
t he Ja pa nese Ur ol o gical Ass ocia 2 0 0 5] [Jac k, R. H., et al 2 0 1 0] [ Sc her, H. I., et al 2 0 1 5] 
[ Kell y, S. P., et al 2 0 1 8] [ Wei ner, A. B., et al 2 0 1 6] [ S mit h, S. 2 0 1 8] [ Nati o nal Ca ncer 
I nstit ute 2 0 1 9]. O nce pr ostate ca ncer has bec o me metastatic t here are n o l o n ger a n y c urati ve 
treat me nts a n d e x pecte d me dia n s ur vi val is less t ha n 5 years. Patie nts wit h metastases ha ve 
tra diti o nall y bee n treate d first wit h A D T, us uall y wit h L H R H a g o nist or a nta g o nist t hat 
res ults i n s u p pressi o n of test oster o ne pr o d ucti o n i n t he testes. T his al o ne ofte n s uccee ds i n 
c o ntr olli n g diseas e f or s o me ti me, years i n ma n y cases. H o we ver, pr ostate ca ncer pr o gresses 
i n varia bl y a n d re q uires a d diti o nal s yste mic t hera pies t o re-esta blis h c o ntr ol of disease. 
B ot h d oceta xel a n d a birater o ne ha ve bee n s h o w n t o pr ol o n g O S w he n c o m bi ne d u pfr o nt wit h 
A D T a n d are n o w c o nsi dere d sta n dar d of care f or me n dia g n ose d wit h hi g h -v ol u me or hi g h -
ris k m H S P C. M ore rece ntl y, t he sec o n d-ge nerati o n a n dr o ge n rece pt or i n hi bit ors a pal uta mi de 
a n d e nzal uta mi de were e xa mi ne d i n patie nts wit h m H S P C. C o m bi nati o n of a pal uta mi de wit h 
A D T res ulte d i n a si g nifica nt i m pr o ve me nt i n b ot h r P F S ( H R  0. 4 8, p < 0. 0 0 1) a n d O S 
( H R 0. 6 7, p 0. 0 0 5) c o m pare d t o A D T al o ne [ C hi, K. N., et al 2 0 1 9]. T he c o m bi nati o n of 
e nzal uta mi de wit h A D T was st u die d i n t w o P hase 3 st u dies; o ne c o m pare d t o A D T al o ne a n d 
t he sec o n d c o m pare d t o A D T pl us a first-ge nerati o n a nti -a n dr o ge n. I n t he first st u d y 
( A R C H E S), t he a d diti o n of e nzal uta mi de t o A D T res ulte d i n a sig nifica nt i m pr o ve me nt i n 
r P F S ( H R 0. 3 9, p < 0. 0 0 0 1), wit h t he i nteri m O S a nal ysis bei n g i m mat ure wit h 9 3 % of 
patie nts still ali ve [ Ar mstr o n g, A. J., et al 2 0 1 9]. I n t he sec o n d st u d y, t he a d diti o n of 
e nzal uta mi de t o A D T res ulte d i n a si g nifica nt i m pr o ve me nt i n O S c o m pare d t o A D T pl us a 
first-ge nerati o n a nti -a n dr o ge n ( H R 0. 6 7, p 0. 0 0 1 6) [ Da vis, I. D., et al 2 0 1 9]. T he efficac y 
of b ot h a pal uta mi de a n d e nzal uta mi de were c o ns iste nt acr oss all s u b gr o u ps, i ncl u di n g 
patie nts wit h l o w - or hi g h -v ol u me disease, as well as t h ose wit h de n o v o metastases or wit h 
metastases after faili n g pri mar y t hera p y. 
W hile t hese t hera pies are i nitiall y effecti ve, patie nts i n varia bl y s ucc u m b t o t hei r disease a n d 
t he effecti ve ness of s u bse q ue nt t hera pies di mi nis hes after pr o gressi o n o n t he pri or t hera p y. 
T h us, t here re mai ns a si g nifica nt u n met nee d f or n o vel t hera pies or c o m bi nati o n re gi me ns f or 
patie nts wit h metastatic pr ostate ca ncer.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
2. 1
St u d y R ati o n al e
Bis h o p et al. de m o nstrate d i n a m o use xe n o graft m o del t hat e nzal uta mi de -resista nt t u m ors 
e x press si g nifica ntl y i ncrease d le vels of t u m or i ntri nsic P D -L 1 c o m pare d t o n o n 
e nzal uta mi de-resista nt t u m ors [ Bis h o p, J. L., et al 2 0 1 5]. A d diti o nall y, i n a s mall c o h ort of 
partici pa nts, it was n ote d t hat t h ose w h o pr o gresse d w hile o n e nzal uta mi de ha d a 
si g nifica ntl y i ncrease d n u m ber of P D-L 1/ P D -L 2 p ositi ve de n dritic cells i n t heir bl o o d 
c o m pare d t o treat me nt -naï ve partic i pa nts or partici pa nts w h o were res p o n di n g t o 
e nzal uta mi de. T h us, b y bl oc ki n g t he P D -1 rece pt or, pe m br oliz u ma b treat me nt ma y i ncrease 
t he i m m u ne res p o nse t o e nzal uta mi de-resista nt cells t hat e mer ge i n res p o nse t o treat me nt 
wit h e nzal uta mi de.
K E Y N O T E -3 6 5 ( K N 3 6 5), a n o n g oi n g P hase 1 b/ 2 u m brella st u d y e val uati n g pe m br oliz u ma b 
c o m bi nati o n t hera pies i n m C R P C partici pa nts, i ncl u de d a C o h ort C f or t he e val uati o n of 
pe m br oliz u ma b i n c o m bi nati o n wit h e nzal uta mi de i n partici pa nts w h o recei ve d pri or 
a birater o ne acetat e i n t he pre-c he m ot hera p y m C R P C state. As t his was a patie nt p o p ulati o n 
t hat ha d recei ve d pri or a birater o ne t he y were e x pecte d t o ha ve li mite d efficac y t o 
e nzal uta mi de al o ne. I nteri m res ults fr o m C o h ort C ( data c ut off 2 7 -J U L-2 0 1 8) s h o we d a 
c o nfir me d P S A re s p o nse (at least 5 0 % re d ucti o n i n P S A fr o m baseli ne) i n 2 6 % ( 1 8/ 6 9) of 
partici pa nts, a n d a R E CI S T o bjecti ve res p o nse ( C R + P R) i n 2 0 % ( 5/ 2 5) of partici pa nts wit h 
meas ura ble disease at baseli ne. Of n ote, t hese res p o nses were i n de pe n de nt of P D -L 1 stat us. 
T he P S A res p o nse rate was 6/ 2 0 ( 3 0 %) a n d 1 1/ 4 4 ( 2 5 %), f or P D -L 1 p ositi ve a n d P D -L 1 
ne gati ve patie nts res pecti vel y. T he O R R per R E CI S T 1. 1 was 2/ 9 ( 2 2. 2 %) a n d 2/ 1 5 ( 1 3. 3 %) 
f or P D-L 1 p ositi ve a n d P D -L 1 ne gati ve patie nts wit h meas ura ble disease at baseli ne, 
res pecti vel y. T hese res ults pr o vi de s u p p ort f or f urt her e val uati o n of t he c o m bi nati o n of 
pe m br oliz u ma b a n d e nzal uta mi de, a n d t here is o p p ort u nit y f or i m pr o ve me nt i n t he efficac y 
of t he c o m bi nati o n re gi me n if gi ve n at i nitiati o n of h or m o ne t hera p y, d ue t o t he l o n g -ter m 
effect of a n i m m u ne res p o nse.
T he prese nt trial, K E Y N O T E -9 9 1 ( K N 9 9 1) is a ra n d o mize d, m ultice nter, d o u ble -bli n d, 
place b o -c o ntr olle d, P hase 3 trial i n partici pa nts wit h m H S P C. Partici pa nts will be ra n d o ml y 
assi g ne d 1: 1 t o treat me nt wit h eit her pe m b r oliz u ma b + e nzal uta mi de + A D T or place b o + 
e nzal uta mi de + A D T.
2. 2
B ac k gr o u n d
Pe m br oliz u ma b is a p ote nt h u ma nize d I g G 4 m A b wit h hi g h s pecificit y of bi n di n g t o t he 
P D -1 rece pt or, t h us i n hi biti n g its i nteracti o n wit h P D -L 1 a n d P D -L 2. Base d o n precli nical i n 
vit r o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or bl oc ki n g acti vit y f or P D-1. 
Pe m br oliz u ma b has a n acce pta ble precli nical safet y pr ofile a n d is i n cli nical de vel o p me nt as 
a n I V i m m u n ot hera p y f or a d va nce d mali g na ncies. Ke ytr u da ® ( pe m br oliz u ma b) is i n dicate d 
f or t he treat me nt of patie nts acr oss a n u m ber of i n dicati o ns. F or m ore details o n s pecific 
i n dicati o ns refer t o t he I B.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
2. 2. 1
P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o ns has bee n k n o w n f or deca des [ Disis, M. L. 2 0 1 0]. Acc u m ulati n g e vi de nce 
s h o ws a c orrelati o n bet wee n t u m or -i nfiltrati n g l y m p h oc ytes i n ca ncer tiss ue a n d fa v ora ble 
pr o g n osis i n vari o us mali g na ncies. I n partic ular, t he prese nce of C D 8 + T -cells a n d t he rati o 
of C D 8 + effect or T -cells/ F o x P 3 + T -re gs c orrelates wit h i m pr o ve d pr o g n osis a n d l o n g-ter m 
s ur vival i n s oli d mali g na ncies, s uc h as o varia n, c ol orectal, a n d pa ncreatic ca ncer ,
he pat ocell ular carci n o ma , mali g na nt mela n o ma , a n d re nal cell carci n o ma. T u m or -i nfiltrati n g 
l y m p h oc ytes ca n be e x pa n de d e x vi v o a n d rei nf use d, i n d uci n g d ura ble o bjecti ve t u m or 
res p o nses i n ca ncers s uc h as mela n o ma [ D u dle y, M. E., et al 2 0 0 5] [ H u n der, N. N., et al 
2 0 0 8] .
T he P D -1 rece pt or -li ga n d i nteracti o n is a maj or pat h wa y hijac ke d b y t u m ors t o s u p press 
i m m u ne c o ntr ol. T he n or mal f u ncti o n of P D -1, e x presse d o n t he cell s urface of acti vate d 
T- cells u n der healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or e xcessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns. P D-1 (e nc o de d b y t he ge ne P dc d 1) is a n I g 
s u perfa mil y me m ber relate d t o C D 2 8 a n d C T L A -4 t hat has bee n s h o w n t o ne gati vel y 
re g ulate a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds ( P D -L 1 a n d/ or P D -L 2) 
[ Gree n wal d, R. J., et al 2 0 0 5] [ O kaza ki, T., et al 2 0 0 1] .
T h e str uct ure of m uri ne P D -1 has bee n res ol ve d [ Z ha n g, X., et al 2 0 0 4]. P D-1 a n d its fa mil y 
me m bers are t y pe I tra ns me m bra ne gl yc o pr otei ns c o ntai ni n g a n I g V
t y pe d o mai n 
res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic tail res p o nsi ble f or t he bi n di n g of si g nali n g 
m olec ules. T he c yt o plas mic tail of P D -1 c o ntai ns 2 t yr osi ne -base d si g nali n g m otifs, a n 
i m m u n orece pt or t yr osi ne-base d i n hi biti o n m otif, a n d a n i m m u n orece pt or t yr osi ne -base d 
s witc h m otif. F oll o wi n g T- cell sti m ulati o n, P D-1 recr uits t he t yr osi ne p h os p hatases, S H P -1 
a n d S H P -2, t o t he i m m u n orece pt or t yr osi ne -base d s witc h m otif wit hi n its c yt o plas mic tail, 
lea di n g t o t he de p h os p h or ylati o n of effect or m olec ules s uc h as C D 3ζ, P K C θ, a n d Z A P 7 0, 
w hic h are i n v ol ve d i n t he C D 3 T-cell si g nali n g casca de [ O kaza ki, T., et al 2 0 0 1] [ C he m nitz, 
J. M., et al 2 0 0 4] [ S he p par d, K-A, et al 2 0 0 4] [ Rile y, J. L. 2 0 0 9]. T he mec ha nis m b y w hic h 
P D -1 d o w n -m o d ulates T -cell res p o nses is si milar t o, b ut disti nct fr o m, t hat of C T L A-4, 
beca use b ot h m olec ules re g ulate a n o verla p pi n g set of si g nali n g pr otei ns [ Parr y, R. V., et al 
2 0 0 5] [ Fra ncisc o, L. M., et al 2 0 1 0] . As a c o nse q ue nce, t he P D -1/ P D -L 1 pat h wa y is a n 
attracti ve tar get f or t hera pe utic i nter ve nti o n i n m H S P C .
2. 2. 2
Precli nic al a n d Cli nic al St u dies
Refer t o t he pe m br oliz u ma b I B f or a s u m mar y of t he precli nical a n d cli nical e x perie nce wit h 
pe m br oliz u ma b.
2. 2. 3
O n g oi n g Cli nic al St u dies i n Pr ost ate C a ncer
K E Y N O T E -1 9 9 ( K N 1 9 9) is a n o n g oi n g, P hase 2, n o nra n d o mize d, m ulti nati o nal, m ulti -
c o h ort, o pe n- la bel st u d y of pe m br oliz u ma b i n patie nts wit h m C R P C w h o recei ve d d oceta xel-
base d c he m ot hera p y a n d eit her a birater o ne acetate or e nzal uta mi de treat me nt. At t he ti me of 
t he data c ut off ( 2 1-A U G -2 0 1 8), 1 9 9 patie nts were e nr olle d i n t he c o h orts wit h 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
R E CI S T -meas ura ble disease a n d P D -L 1 stat us: 1 3 3 i n P D -L 1 p ositi ve a n d 6 6 P D -L 1 
ne gati ve. O verall O R R was 5 % ( 9 5 % CI, 2 -1 1) f or P D -L 1 -p ositi ve pati e nts a n d 3 % ( 9 5 % CI, 
< 1 -1 1) f or P D -L 1 -ne gati ve patie nts, wit h a D C R ≥6 m o nt hs of 1 0 % a n d 9 %, res pecti vel y. 
Me dia n O S was 9. 5 m o nt hs i n P D -L 1 -p ositi ve patie nts a n d 7. 9 m o nt hs i n P D -L 1 -ne gati ve 
patie nts. T hese res ults s u g geste d p ote ntial efficac y, re gar dless of P D -L 1 stat us, t hat 
warra nte d f urt her e val uati o n. A d diti o nall y, earl y u n p u blis he d res ults fr o m Graff et al s u g gest 
a p ote ntial s ur vi val be nefit i n t he a d va nce d m C R P C p o p ulati o n wit h pe m br oliz u ma b 
m o n ot hera p y [ Graff, J. N., et al 2 0 1 6].
Graff et al [ Graff, J. N., et al 2 0 1 6], i nitiall y e nr olle d 1 0 me n i n 2 0 1 5-2 0 1 6 w h o ha d m C R P C 
wit h e vi de nce of pr o gressi o n o n e nzal uta mi de, a n d s u bse q ue ntl y e nr olle d a t otal of 2 8. 
Beca use pre vi o us i m m u n ot hera pies ( ni v ol u ma b, i pili m u ma b) ha d faile d t o pr o d uce a n 
o bjecti ve res p o nse i n m C R P C [ T o palia n, S. L., et al 2 0 1 2] [ K w o n, E. D., et al 2 0 1 4] , i nterest 
i n p urs ui n g f urt her st u dies wa ned. N o net heless, after s o me s uccess, Graff et al [ Graff, J. N., 
et al 2 0 1 8] , u n dert o o k t he P hase 2 st u d y a d di n g pe m br oliz u ma b t o e nzal uta mi de f or me n 
wit h m C R P C pr o gressi n g o n e nzal uta mi de a n d re p orte d a decli ne i n P S A ≥5 0 % ( pri mar y 
e n d p oi nt) i n 5 of 2 8 patie nts ( 1 7. 9 %) a n d a n O R (sec o n dar y e n d p oi nt) i n 3 of 1 2 patie nts 
( 2 5. 0 %) w h o ha d meas ura ble disease at baseli ne. At last re p ort, 3 of t he 5 res p o n ders 
c o nti n ue d t o res p o n d (ra n ge, 2 1. 9 -3 3. 8 m o nt hs), a n d me dia n O S was 2 2. 2 m o nt hs ( 9 5 % CI, 
1 4. 7 -2 8. 4 m o nt hs).
K N 3 6 5, a P hase 2 u m brella st u d y e val uati n g pe m br oliz u ma b c o m bi nati o n t hera pies i n 
m C R P C partici pa nts, i ncl u de d a c o h ort f or t he e val uati o n of pe m br oliz u ma b i n c o m bi nati o n 
wit h e nzal uta mi de ( C o h ort C). Partici pa nts i n t his c o h ort were re q uire d t o ha ve ha d 
pre vi o usl y recei ve d a birater o ne acetate. T he pri mar y e n d p oi nt is t he perce nta ge of 
partici pa nts wit h a decrease i n P S A le vel of ≥5 0 %. I n a rece nt a me n d me nt of t he pr ot oc ol, 
O R R base d o n R E CI S T 1. 1 b y BI C R was c h a n ge d fr o m a sec o n dar y e n d p oi nt t o a ( d ual) 
pri mar y e n d p oi nt. A d diti o nall y, t he tar get e nr oll me nt i n eac h of t he t hree c o h orts was 
e x pa n de d t o 1 0 0, a n d a ne w c o h ort f or pe m br oliz u ma b i n c o m bi nati o n wit h a birater o ne 
acetate wit h tar get e nr oll me nt of 1 0 0 m C R P C patie nts was a d de d. See Secti o n 2. 1 f or a 
s u m mar y of i nteri m res ults. 
K N 6 4 1 is a P hase 3 ra n d o mize d, place b o -c o ntr olle d st u d y e val uati n g t he efficac y a n d safet y 
of pe m br oliz u ma b i n c o m bi nati o n wit h e nzal uta mi de a n d A D T f or t he treat me nt of m C R P C.  
T he st u d y is e nr olli n g partici pa nts i n t he pre-c he m ot hera p y m C R P C state, wit h or wit h o ut 
pri or treat me nt wit h a birater o ne acetate. A p pr o xi matel y 1 2 0 0 partici pa nts will be ra n d o mize d 
1: 1 t o eit her pe m br oliz u ma b pl us e nzal uta mi de vs place b o pl us e nzal uta mi de. T h e d ual 
pri mar y e n d p oi nts are r P F S a n d O S.
F or details o n a d diti o nal o n g oi n g st u dies, i ncl u di n g i n ot her t u m or t y pes, please refer t o t he 
pe m br oliz u ma b I B.
2. 2. 4
I nf or m ati o n o n Ot her St u d y-rel ate d T her a p y
E nzal uta mi de ( Xta n di ®) is a n a n dr o ge n rece pt or i n hi bit or i n dicate d f or t he treat me nt of 
patie nts wit h m C R P C. E nzal uta mi de acts o n differe nt ste ps i n t he a n dr o ge n rece pt or 
si g nali n g pat h wa y. E nzal uta mi de has bee n s h o w n t o c o m petiti vel y i n hi bit a n dr o ge n bi n di n g 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
4 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
t o a n dr o ge n rece pt ors a n d i n hi bit a n dr o ge n rece pt or n uclear tra nsl ocati o n a n d i nteracti o n 
wit h D N A. A maj or meta b olite, N -des met h yl e nzal uta mi de, e x hi bite d si milar i n vitr o acti vit y 
t o e nzal uta mi de. E nzal uta mi de decrease d pr oliferati o n a n d i n d uce d cell deat h of pr ostate 
ca ncer cells i n vitr o a n d decrease d t u m or v ol u me i n a m o use pr ostate ca ncer xe n o graft 
m o del. Refer t o t he a p pr o ve d la beli n g f or detaile d bac k gr o u n d i nf or mati o n o n e nzal uta mi de.
F or a d diti o nal i nf or mati o n o n e nzal uta mi de, refer t o t he a p pr o ve d pr o d uct la bel.
2. 3 
Be nefit/ Ris k Assess me nt
It ca n n ot be g uara ntee d t hat partici pa nts i n cli nical st u dies will directl y be nefit fr o m 
treat me nt d uri n g partici pati o n, as cli nical st u dies are desi g ne d t o pr o vi de i nf or mati o n a b o ut 
t he safet y a n d effecti ve ness of a n i n vesti gati o nal me dici ne.
Pe m br oliz u ma b h as bee n a d mi nistere d i n a lar ge n u m ber of ca ncer partici pa nts wit h a well 
c haracterize d safet y pr ofile a n d has recei ve d re g ulat or y a p pr o val f or u nresecta ble or 
metastatic mela n o ma, metastatic N S C L C, rec urre nt or metastatic H N S C C, a d va nce d U C, 
M SI -H ca ncer, c H L, a d va nce d gastric ca ncer, a d va nce d cer vical ca ncer, H C C, a n d P M B C L. 
O verall, pe m br oliz u ma b is well t olerate d at d oses u p t o 1 0 m g/ k g e ver y 2 wee ks ( Q 2 W). 
Pe m br oliz u ma b has als o de m o nstrate d a ntica ncer cli nical acti vit y a n d efficac y i n a br oa d 
ra n ge of ca ncer i n dicati o ns (see t he pe m br oliz u ma b I B).
E nzal uta mi de has bee n a p pr o ve d b y re g ulat or y a ge ncies gl o ball y f or t he treat me nt of C R P C 
a n d has bee n rec o m me n de d f or treat me nt f or C R P C b y N C C N a n d E S M O g ui deli nes [ T orre, 
L. A., et al 2 0 1 6] . A d di n g e nzal uta mi de u pfr o nt t o A D T f or patie nts wit h m H S P C has bee n 
e val uate d i n t w o rece nt P hase 3 st u dies a n d s h o w n t o i m pr o ve efficac y w he n c o m pare d t o 
treat me nt wit h A D T al o ne or A D T pl us a first- ge nerati o n a nti -a n dr o ge n ( Secti o n 2) 
[ Ar mstr o n g, A. J., et al 2 0 1 9] [ Da vis, I. D., et al 2 0 1 9].
Preli mi nar y res ults fr o m C o h ort C of K N 3 6 5 ( Secti o n 2. 1), i n w hic h partici pa nts wit h 
m C R P C were treate d wit h t he c o m bi nati o n of pe m br oliz u ma b a n d e nzal uta mi de, s h o we d a 
c o nfir me d R E CI S T o bjecti ve res p o nse ( C R + P R) i n 2 0 % ( 5/ 2 5) of partici pa nts wit h 
meas ura ble disease at baseli ne, a n d a disease c o ntr ol rate ( C R + P R + S D ≥6 m o nt hs) of 3 4 % 
( 1 5/ 4 4). This is a patie nt p o p ulati o n t hat ha d recei ve d pri or a birater o ne a n d t h us e x pecte d t o 
ha ve li mite d efficac y t o e nzal uta mi de al o ne. I n ge neral, t he safet y a n d t olera bilit y of 
pe m br oliz u ma b pl us e nzal uta mi de was c o nsiste nt wit h t he i n di vi d ual pr ofiles of eac h a ge nt.  
As of t he m ost rece nt data base l oc k ( 2 7 -J U L-2 0 1 8), 2 8 of 6 9 ( 4 1 %) of partici pa nts ha d Gra de 
3 t o 4 T R A Es, a n d t here were n o Gra de 5 T R A Es. T here was a n i ncrease d i nci de nce of all -
Gra de ras h ( 2 3 %) a n d Gra de 3 ras h ( 1 0 %), w hic h res ol ve d wit h sta n dar d of care treat me nt.
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or partici pa nts partici pati n g i n t his 
cli nical st u d y ma y be f o u n d i n t he acc o m pa n yi n g I B a n d i nf or me d c o nse nt d oc u me nts.
N O T E: Base d o n t he data fr o m a n i nteri m safet y a n d effic ac y a nal ysis f or K E Y N O T E -9 9 1 
( data c ut off 3 1 -O C T -2 0 2 2), e D M C rec o m me n de d st o p pi n g t he st u d y f or f utilit y beca use
pe m br oliz u ma b i n c o m bi nati o n wit h e nzal uta mi de a n d A D T di d n ot de m o nstrate a n 
i m pr o ve me nt i n O S or r P F S, t he trial’s d ual pri mar y e n d p oi nts, c om pare d t o place b o pl us 
e nzal uta mi de a n d A D T a n d a p pears u nli kel y t o d o s o i n a f ut ure a nal ysis. Base d u p o n t hese 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
data a n d t he rec o m me n dati o n of t he e D M C, t he st u d y was u n bli n de d (as of 1 9 -J A N-2 0 2 3). 
All t he pres pecifie d i nteri m a nal yses after I A 1 a n d fi nal a nal ysis of t he st u d y descri be d i n t he 
S A P will n ot be perf or me d. S afet y a nal ysis will be perf or me d at t he e n d of t he st u d y; t here 
will be n o f urt her a nal yses f or efficac y a n d e P R O e n d p oi nts c ollecte d fr o m partici pa nts 
be y o n d t he I A 1 c ut off date . 
0 8 9 V 4 C
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nt
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
r P F S per P C W G -m o difie d R E CI S T 1. 1 as 
assesse d b y BI C R w here s oft tiss ue will be 
assesse d per R E CI S T 1. 1 m o difie d t o 
f oll o w a ma xi m u m of 1 0 tar get lesi o ns a n d 
a ma xi m u m of 5 tar get lesi o ns per or ga n, 
a n d b o ne disease will be assesse d per 
P C W G criteria.
H y p ot hesis ( H 1): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
r P F S p er P C W G -m o difie d R E CI S T 1. 1 as 
assesse d b y BI C R.
r P F S: the ti me fr o m ra n d o mizati o n t o 
ra di o gra p hic pr o gressi o n or deat h d ue t o 
a n y ca use, w hic he ver occ urs first .
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T ve rs us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o O S .
H y p ot hesis ( H 2): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o O S .
O S : t he ti me fr o m ra n d o mizati o n t o deat h 
d ue t o a n y ca use.
Sec o n d ar y O bjecti ves
Sec o n d ar y E n d p oi nt s
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T F S T .
H y p ot hesis ( H 3): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T F S T .
T F S T: t he ti me fr o m ra n d o mizati o n t o 
i nitiati o n of t he first s u bse q ue nt a ntica ncer 
t hera p y or deat h, w hic hever c o mes first.
T o c o m pare pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o 
T T S S R E .
T T S S R E: t he ti me fr o m ra n d o mizati o n t o 
t he first S S R E, defi ne d as:
•
use of E B R T t o pre ve nt or relie ve 
s keletal s y m pt o ms 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
H y p ot hesis ( H 4): T he c o m bi nati o n of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T is s u peri or t o place b o pl us 
e nzal uta mi de p l us A D T wit h res pect t o 
T T S S R E .
•
occ urre nce of ne w s y m pt o matic 
pat h ol o gic b o ne fract ure ( verte bral or 
n o n -verte bral) 
•
occ urre nce of s pi nal c or d c o m pressi o n
•
or t u m or -relate d ort h o pe dic s ur gical 
i nter ve nti o n, w hic he ver occ urs first
T o assess pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o t he: 
-
Ti me t o P S A pr o gressi o n
-
Ti me t o r a di o gr a p hic s oft tiss ue 
pr o gressi o n per s oft tiss ue r ules of 
P C W G -m o difie d R E CI S T 1. 1, as 
assesse d b y BI C R
-
T T P P 
-
P F S 2 as deter mi ne d b y i n vesti gat or 
assess me nt
Ti me t o P S A pr o gressi o n: t he ti me fr o m 
ra n d o mizati o n t o P S A pr o gressi o n. T he 
P S A pr o gressi o n date is defi ne d as t he date 
of 1) ≥2 5 % i ncrease a n d ≥2 n g/ m L a b o ve 
t he na dir, c o nfir me d b y a sec o n d val ue ≥3 
wee ks later if t here is P S A decli ne fr o m 
baseli ne, or 2) ≥2 5 % i ncrease a n d ≥2 n g/ m L 
i ncrease fr o m baseli ne be y o n d 1 2 wee ks if 
t here is n o P S A decli ne fr o m baseli ne. 
Ti me t o r a di o gr a p hic s oft tiss ue 
pr o gressi o n: t he ti me fr o m ra n d o mizati o n 
t o ra di o gra p hic s oft tiss ue pr o gressi o n.
T T P P: ti me fr o m ra n d o mizati o n t o pai n 
pr o gressi o n base d o n B PI -S F Ite m # 3 
“ w orst pai n i n 2 4 h o urs” a n d o pi oi d use. 
P F S 2 : ti me fr o m ra n d o mizati o n t o disease 
pr o gressi o n as deter mi ne d b y i n vesti gat or 
assess me nt of ra di ol o gical or cli nical 
pr o gressi o n after ne xt -li ne of t hera p y or 
deat h fr o m a n y ca use, w hic he ver occ urs 
first.
T o assess pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o t he:
-
P S A res p o nse r ate 
-
P S A u n detect a ble r ate
-
O R R a n d D O R per P C W G -m o difie d 
R E CI S T 1. 1 as assesse d b y BI C R
P S A res p o nse: a P S A decli ne of ≥5 0 % 
fr o m baseli ne meas ure d t wice at least 3 
wee ks a part
P S A u n detect a ble: P S A < 0. 2 n g/ m L 
d uri n g st u d y i nter ve nti o n
O R: C R or P R
D O R: t he ti me fr o m t he earliest date of t he 
first d oc u me nte d e vi de nce of C R or P R 
u ntil earliest date of disease pr o gressi o n or 
deat h d ue t o a n y ca use, w hic he ver occ urs 
first
T o assess t he s afet y a n d t oler a bilit y of 
pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T vers us place b o pl us e nzal uta mi de pl us 
A D T.
A Es 
St u d y i nter ve nti o n disc o nti n uati o n d ue t o 
A Es
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Terti ar y /E x pl or at or y O bjecti ve s
Terti ar y /E x pl or at or y E n d p oi nt s
T o assess pe m br oliz u ma b pl us 
e nzal uta mi de pl us A D T vers us place b o pl us 
e nzal uta mi de pl us A D T wit h res pect t o t he 
c ha n ge fr o m baseli ne i n sc ores f or disease -
relate d s y m pt o ms a n d H R Q o L usi n g t he 
B PI -S F, F A C T -P a n d E Q -5 D -5 L 
q uesti o n n aires
B PI -S F : pr o gressi o n i n pai n se verit y 
d o m ai n a n d c ha n ge i n pai n i nterfere nce 
d o mai n
F A C T -P: F A C T P t otal sc ore, F A C T -G 
t otal sc ore, trial o utc o me i n de x, f u ncti o nal 
well -bei n g, p h ysical well -bei n g, pr ostate 
ca ncer s u bsc ore, a n d F A C T A d va nce d 
Pr ostate S y m pt o m I n de x 6 ( F A P SI 6)
E Q -5 D -5 L: m o bilit y, se lf-care, us ual 
acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n healt h states a n d E Q -
5 D -5 L vis ual a nal o g scale ( V A S)
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Partici pa nts m ust ha ve ce ntral verificati o n of metastatic d isease d oc u me nte d b y eit her ≥2 
b o ne lesi o ns o n b o ne sca n a n d/ or visceral disease (e g, l u n g or li ver) b y C T/ M RI. Partici pa nts 
w h ose metastatic disease is li mite d t o l y m p h n o des are n ot eli gi ble. U p t o 6 c ycles of pri or 
d oceta xel t hera p y f or m H S P C is per mitt e d as l o n g as t he fi nal treat me nt a d mi nistrati o n was 
c o m plete d wit hi n 2 m o nt hs of ra n d o mizati o n a n d t here was n o e vi de nce of disease 
pr o gressi o n d uri n g or after c o m pleti o n of t hera p y. Pri or treat me nt wit h a sec o n d -ge nerati o n 
h or m o ne a ge nt, e g a birater o ne, e nzal uta mi de, a pal uta mi de, or dar ol uta mi de, is n ot all o we d. 
Partici pa nts m ust pr o vi de a t u m or tiss ue fr o m a ne wl y o btai ne d c ore or e xcisi o nal bi o ps y 
( o btai ne d wit hi n 1 2 m o nt hs of Scree ni n g) fr o m s oft tiss ue n ot pre vi o usl y irra diate d (sa m ples 
fr o m t u m ors pr o gressi n g i n a pri or site of ra diati o n are all o we d; ot her e xce pti o ns ma y be 
c o nsi dere d after S p o ns or c o ns ultati o n). Partici pa nts wit h b o ne o nl y or b o ne pre d o mi na nt 
disease ma y pr o vi de a b o ne bi o ps y sa m ple ( decalcificati o n n ot all o we d). H o we ver, if 
o btai ni n g a ne w bi o ps y is n ot feasi ble, t he n partici pa nts ma y pr o vi de a n arc hi val t u m or tiss ue 
sa m ple after S p o ns or c o ns ultati o n. A de q uac y of t hese s peci me ns f or bi o mar ker a nal ysis will 
be e val uate d b y a ce ntral la b orat or y pri or t o ra n d o mizati o n. F or c o m plete det ails a b o ut 
eli gi bilit y criteria, refer t o Secti o n 5.
Treat me nt wit h pe m br oliz u ma b/ place b o ma y c o nti n ue f or u p t o 3 5 c ycles (a p pr o xi matel y 2 
years starti n g wit h t he first i nf usi o n i n C ycle 1) or u ntil meeti n g criteria f or disc o nti n uati o n 
of st u d y i nter ve nti o n ( Secti o n 7. 1). Treat me nt wit h e nzal uta mi de will pr ocee d c o nti n u o usl y 
fr o m Da y 1 of C ycle 1 i n b ot h ar ms, u nless criteria f or disc o nti n uati o n of st u d y i nter ve nti o n 
are met ( Secti o n 7. 1). If pe m br oliz u ma b/ place b o is c o m plete d or disc o nti n ue d f or reas o ns 
ot her t ha n pr o gressi ve disease, partici pa nts still rec ei vi n g e nzal uta mi de will c o nti n ue t o 
recei ve e nzal uta mi de a n d A D T ( E xte nsi o n First C o urse) u ntil criteria f or disc o nti n uati o n are 
met (e g, disease pr o gressi o n). 
Partici pa nts will be e val uate d wit h ra di ol o gic i ma gi n g t o assess res p o nse t o treat me nt at 
re g ular i nter vals d uri n g t he st u d y ( Secti o n 8. 2. 1). 
If a partici pa nt wit h ra di o gra p hic pr o gressi o n is cli nicall y sta ble or cli nicall y i m pr o ve d, a n 
e xce pti o n ma y be c o nsi dere d t o c o nti n ue treat me nt u p o n c o ns ultati o n wit h t he S p o ns or. 
A Es will be m o nit ore d t hr o u g h o ut t he st u d y a n d gra de d i n se verit y acc or di n g t o t he 
g ui deli nes o utli ne d i n t he N CI C T C A E versi o n 5. 0. After t he e n d of treat me nt, eac h 
partici pa nt will be f oll o we d f or 3 0 da ys f or A E m o nit ori n g. Seri o us a d verse e ve nts ( S A Es) 
will be c ollecte d f or 9 0 da ys after t he e n d of treat me nt or 3 0 da ys after t he e n d of treat me nt if 
t he partici pa nt i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier. Treat me nt-relate d S A Es 
m ust be re p orte d re gar dless of t he ti me p oi nt w he n t he y occ ur. Partici pa nts w h o disc o nti n ue 
treat me nt f or reas o ns ot her t ha n ra di o gra p hic disease pr o gressi o n will c o nti n ue st u d y-relate d 
disease assess me nts u ntil ra di o gra p hic disease pr o gressi o n, i nitiati n g a ca ncer treat me nt, 
wit h dra wal of c o nse nt, or bec o mi n g l ost t o f oll o w -u p. All partici pa nts will be f oll o we d f or 
s ur vi val. T his will be d o ne i n a variet y of wa ys i ncl u di n g p h o ne, e mail, c hart re vie w, or 
re vie w of p u blic rec or ds i n c o m plia nce t o l ocal practices or re g ulati o ns.
0 8 9 V 4 C
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
4. 2. 1
R ati o n ale f or E n d p oi nts
4. 2. 1. 1
Effic ac y E n d p oi nts
T he d ual pri mar y e n d p oi nts of t he st u d y will be r P F S a n d O S. 
Ra di o gra p hic P F S is a n acce pta ble meas ure o f cli nical be nefit f or a late sta ge st u d y t hat 
de m o nstrates s u peri orit y of a ne w a nti ne o plastic t hera p y, es peciall y if t he ma g nit u de of t he 
effect is lar ge a n d t he t hera p y has a n acce pta ble ris k/ be nefit pr ofile. T he r P F S will be 
assesse d b y BI C R acc or di n g t o P C W G-m o difie d R E CI S T 1. 1 ( Secti o n 8. 2). Ti me -t o-
pr o gressi o n e n d p oi nts, i ncl u di n g D O R a n d r P F S, will be meas ure d u ntil P D per P C W G -
m o difie d R E CI S T 1. 1.
O S has bee n rec o g nize d as t he g ol d sta n dar d f or t he de m o nstrati o n of s u peri orit y of a ne w 
a nti ne o plast ic t hera p y i n ra n d o mize d cli nical st u dies.
Ti me t o i nitiati o n of t he first s u bse q ue nt a ntica ncer t hera p y ( T F S T) a n d ti me t o S S R E will be 
assesse d as ke y sec o n dar y e n d p oi nts. T F S T is s u p p orti ve of r P F S as it i nc or p orates reas o ns 
t o s witc h t hera pies i n a d diti o n t o ra di o gra p hic pr o gressi o n (e g, d ue t o t o xicit y or cli nical 
pr o gressi o n), t h us pr o vi di n g a c o m pre he nsi ve meas ure of w he n a n a ge nt is c o nsi dere d n o 
l o n ger of cli nical be nefit. S y m pt o matic s keletal-relate d e ve nts are c o m m o n i n patie nts wit h 
pr ostate ca n cer d ue t o t he b o ne -pre d o mi na nce of t he disease, a n d t hese e ve nts ha ve 
si g nifica nt, ofte n de bilitati n g, c o nse q ue nces f or patie nts i ncl u di n g pai n, re d uce d q ualit y of 
life a n d i ncrease d ris k of deat h. T h us, a dela y i n t he de vel o p me nt of t hese e ve nts re prese nts a 
cli nicall y mea ni n gf ul e n d p oi nt f or patie nts wit h metastatic pr ostate ca ncer.
4. 2. 1. 2
S afet y E n d p oi nts
Safet y para meters fre q ue ntl y use d f or e val uati n g i n vesti gati o nal -s yste mic a ntica ncer 
treat me nts are i ncl u de d as safet y e n d p oi nts i ncl u di n g, b ut n ot li mite d to, t he i nci de nce of, 
ca usalit y, a n d o utc o me of A Es/ S A Es , a n d c ha n ges i n vital si g ns a n d la b orat or y val ues. A Es 
will be assesse d as defi ne d b y C T C A E, Versi o n 5. 0 .
4. 2. 1. 3
P atie nt -re p orte d O utc o mes Assess me nts
S y m pt o matic i m pr o ve me nt is c o nsi dere d a cli nical be nefit a n d acce pte d b y healt h a ut h orities 
as a d diti o nal e vi de nce of t he ris k -be nefit pr ofile of a n y ne w st u d y i nter ve nti o n. I n t his st u d y, 
H R Q o L a n d disease -relate d s y m pt o ms will be i n vesti gate d a m o n g all partici pa nts via t he 
f oll o wi n g assess me nt t o ols: B PI -S F, F A C T -P a n d t he E Q -5 D -5 L q uesti o n naires.
T he B PI -S F , F A C T-P, a n d E Q -5 D -5 L P R Os are n ot p ure efficac y or safet y e n d p oi nts 
beca use t he y are affecte d b y b ot h disease pr o gressi o n a n d st u d y i nter ve nti o n t ol era bilit y.
T he B PI -S F  is a vali date d, 1 5-ite m d o mai n-s pecific i nstr u me nt desi g ne d t o assess t he 
se verit y of pai n a n d t he i m pact/i nterfere nce of pai n o n dail y f u ncti o ns [ Cleela n d, C. S. 
2 0 0 9a] .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
5 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
T he F A C T -P is a di sease-s pecific 3 9-ite m q uesti o n naire i ncl u de d f or t he p ur p ose of assessi n g 
H R Q o L a n d pr ostate ca ncer -s pecific s y m pt o ms. It is a well-esta blis he d meas ure of 
H R Q o L/ healt h stat us c o m m o nl y use d i n pr ostate ca ncer cli nical st u dies. T he F A C T -P was 
de vel o pe d s pec ificall y f or patie nts wit h a d va nce d pr ostate ca ncer a n d has bee n f o u n d t o be 
relia ble a n d vali d i n t his p o p ulati o n [ Es per, P., et al 1 9 9 7].
T he E Q -5 D -5 L is a sta n dar dize d i nstr u me nt f or use as a meas ure of healt h o utc o me a n d will 
pr o vi de data t o de vel o p healt h utilities f or use i n healt h ec o n o mic a nal yses [ Ra bi n, R. a n d de 
C harr o, F. 2 0 0 1] . T his i nstr u me nt has bee n use d e xte nsi vel y i n ca ncer st u dies a n d p u blis he d 
res ults fr o m t hese st u dies s u p p ort its vali dit y a n d relia bilit y [ Pic kar d, A. S., et al 2 0 0 7].
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
4. 2. 2
R ati o n ale f or t he Use of C o m p ar at or/ Pl ace b o
N or mal sali ne or de xtr ose i nf usi o n Q 3 W will be use d as place b o f or pe m br oliz u ma b. T he use 
of sali ne or de xtr ose place b o i n c o m bi nati o n wit h e nzal uta mi de will be use d t o m ai ntai n 
st u d y bli n d a n d t h us mi ni mize a n y bias d ue t o k n o w n treat me nt ar m assi g n me nt. N or mal 
sali ne is t he pri mar y dil ue nt/ place b o f or pe m br oliz u ma b; use de xtr ose o nl y if sali ne is n ot 
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
a vaila ble. T he use of a place b o will all o w f or testi n g t he h y p ot heses t hat r P F S f or partici pa nts 
treate d wit h pe m br oliz u ma b a n d e nzal uta mi de is s u peri or t o t he c o m bi nati o n of place b o a n d 
e nzal uta mi de i n partici pa nts wit h m H S P C t o be teste d. C o m bi nati o n of e nzal uta mi de wit h 
A D T has bee n s h o w n t o i m pr o ve r P F S a n d O S i n me n wit h m H S P C c o m pare d t o A D T al o ne 
a n d is t h us c o nsi dere d a n a p pr o priate c o m parat or i n t his st u d y [ Da vis, I. D., et al 2 0 1 9] 
[ Ar mstr o n g, A. J., et al 2 0 1 9].
4. 3
J ustific ati o n f or D ose
4. 3. 1
Pe m br oliz u m a b
T he pla n ne d d ose of pe m br oliz u ma b f or t his st u d y is 2 0 0 m g Q 3 W. Base d o n t he t otalit y of 
data ge nerate d i n t he Ke ytr u da de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he a p pr o priate d ose 
of pe m br oliz u ma b f or a d ults acr oss all i n dicati o ns a n d re gar dless of t u m or t y pe. As o utli ne d 
bel o w, t his d ose is j ustifie d b y t he f oll o wi n g:
•
cli nical data fr o m 8 ra n d o mize d st u dies de m o nstrati n g flat d ose - a n d e x p os ure-efficac y 
relati o ns hi ps fr o m 2 m g/ k g Q 3 W t o 1 0 m g/ k g Q 2 W;
•
cli nical data s h o wi n g mea ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g o verall s ur vi val 
at 2 0 0 m g Q 3 W acr oss m ulti ple i n dicati o ns; a n d
•
p har mac ol o g y data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati o n (i nferre d 
fr o m P K data) a n d t u m or (i nferre d fr o m P B P K a nal ysis) at 2 0 0 m g Q 3 W.
A m o n g t he 8 ra n d o mize d d ose -c o m paris o n st u dies, a t otal of 2 2 6 2 partici pa nts were e nr olle d 
wit h mela n o ma a n d N S C L C, c o veri n g differe nt disease setti n gs (treat me nt -naï ve, pre vi o usl y 
treate d, P D-L 1 e nric he d, a n d all c o mers) a n d differe nt treat me nt setti n gs ( m o n ot hera p y a n d 
i n c o m bi nati o n wit h c he m ot hera p y). Fi ve st u dies c o m pare d 2 m g/ k g Q 3 W vers us 1 0 m g/ k g 
Q 3 W ( K N 0 0 1 C o h ort B 2, K N 0 0 1 C o h ort D, K N 0 0 2, K N 0 1 0, a n d K N 0 2 1), a n d 3 st u dies 
c o m pare d 1 0 m g/ k g Q 3 W vers us 1 0 m g/ k g Q 2 W ( K N 0 0 1 C o h ort B 3, K N 0 0 1 C o h ort F 2 a n d 
K N 0 0 6). All of t hese st u dies de m o nstrate d flat d ose - a n d e x p os ure-res p o nse relati o ns hi ps 
acr oss t he d oses st u die d re prese nti n g a n a p pr o xi mate 5 - t o 7. 5-f ol d differe nce i n e x p os ure. 
T he 2 m g/ k g ( or 2 0 0 m g fi xe d -d ose) Q 3 W pr o vi de d si milar res p o nses t o t he hi g hest d oses 
st u die d. S u bse q ue ntl y, flat d ose-e x p os ure -res p o nse relati o ns hi ps were als o o bser ve d i n ot her 
t u m or t y pes i ncl u di n g hea d a n d nec k ca ncer, bla d der ca ncer, gastric ca ncer a n d classical 
H o d g ki n L y m p h o ma, c o nfir mi n g 2 0 0 m g Q 3 W as t he a p pr o priate d ose i n de pe n de nt of t he 
t u mor t y pe. T hese fi n di n gs are c o nsiste nt wit h t he mec ha nis m of acti o n of pe m br oliz u ma b, 
w hic h acts b y i nteracti o n wit h i m m u ne cells, a n d n ot via direct bi n di n g t o ca ncer cells.
A d diti o nall y, p har mac ol o g y data clearl y s h o w tar get sat urati o n at 2 0 0 m g Q 3 W. First, P K 
data i n K N 0 0 1 e val uati n g T M D D c o ncl usi vel y de m o nstrate d sat urati o n of P D -1 i n s yste mic 
circ ulati o n at d oses m uc h l o wer t ha n 2 0 0 m g Q 3 W. Sec o n d, a P B P K a nal ysis was c o n d ucte d 
t o pre dict t u m or P D-1 sat urati o n o ver a wi de ra n ge of t u m or pe netrati o n a n d P D-1 
e x pressi o n. T his e val uati o n c o ncl u de d t hat pe m br oliz u ma b at 2 0 0 m g Q 3 W ac hie ves f ull 
P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Fi nall y, p o p ulati o n P K a nal ysis of pe m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of 
b o d y wei g ht a n d ot her partici pa nt c o variates o n e x p os ure, has s h o w n t hat t he fi xe d -d osi n g 
pr o vi des si milar c o ntr ol of P K varia bilit y as wei g ht -base d d osi n g, wit h c o nsi dera ble o verla p 
i n t he distri b uti o n of e x p os ures fr o m t he 2 0 0 m g Q 3 W fi xe d-d ose a n d 2 m g/ k g Q 3 W d ose. 
S u p p orte d b y t hese P K c haracteristics a n d gi ve n t hat fi xe d -d ose has a d va nta ges of re d uce d 
d osi n g c o m ple xit y a n d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g Q 3 W fi xe d -d ose was 
selecte d f or e val uati o n acr oss all pe m br oliz u ma b pr ot oc ols.
4. 3. 2
E nz al ut a mi de
T he rec o m me n de d d ose of e n zal uta mi de is 1 6 0 m g (f o ur 4 0 -m g ca ps ules/ta blets or t w o 8 0 
m g ta blets) a d mi nistere d orall y Q D. Refer t o Secti o n 6. 6. 2 a n d t he a p pr o ve d la beli n g f or 
detaile d i nf or mati o n re gar di n g d ose re gi me n/ m o dificati o n.
4. 4
Be gi n ni n g a n d E n d of St u d y Defi niti o n
T he o verall st u d y be gi ns w he n t he first partici pa nt si g ns t he I C F. T he o verall st u d y e n ds 
w he n t he last partici pa nt c o m pletes t he last st u d y -relate d tele p h o ne-call or visit, wit h dra ws 
fr o m t he st u d y, or is l ost t o f oll o w-u p (ie, t he partici pa nt is u na ble t o be c o ntac te d b y t he 
i n vesti gat or).
F or p ur p oses of a nal ysis a n d re p orti n g, t he o verall st u d y e n ds w he n t he S p o ns or recei ves t he 
last la b orat or y test res ult or at t he ti me of fi nal c o ntact wit h t he last partici pa nt, w hic he ver 
c o mes last.
If t he st u d y i ncl u des c o u ntries i n t he E ur o pea n Ec o n o mic Area ( E E A), t he l ocal start of t he 
st u d y i n t he E A A is defi ne d as First Site Rea d y ( F S R) i n a n y Me m ber State.
4. 4. 1
Cli nic al Criteri a f or E arl y St u d y Ter mi n ati o n
T he cli nical st u d y ma y be ter mi nate d earl y if t he e xte nt (i nci de nce a n d / or se verit y) of 
e mer gi n g effects /cli nical e n d p oi nts is s uc h t hat t he ris k/ be nefit rati o t o t he st u d y p o p ulati o n 
as a w h ole is u nacce pta ble. I n a d diti o n, f urt her recr uit me nt i n t he st u d y or at (a) partic ular 
st u d y site(s) ma y be st o p pe d d ue t o i ns ufficie nt c o m plia nce wit h t he pr ot oc ol, G C P, a n d/ or 
ot her a p plica ble re g ulat or y re q uire me nts, pr oce d ure -relate d pr o ble ms or a n u nacce pta bl y 
hi g h n u m ber of disc o nti n uati o ns or wit h dra wals d ue t o a d mi nistrati ve reas o ns.
I n t he e ve nt of S p o ns or decisi o n t o n o l o n ger su p pl y st u d y i nter ve nti o ns, a m ple n otificati o n 
will be pr o vi de d s o t hat a p pr o priate a dj ust me nts t o partici pa nt treat me nt ca n be ma de.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
5
S T U D Y P O P U L A TI O N
As state d i n t he C o de of C o n d uct f or Cli nical Trials ( A p pe n di x 1. 1 ), t his st u d y i ncl u des 
partici pa nts of v ar yi n g a ge (as a p plica ble), race, et h nicit y, a n d se x (as a p plica ble). T he 
c ollecti o n a n d use of t hese de m o gra p hic data will f oll o w all l ocal la ws a n d g ui deli nes i n 
kee pi n g wit h t he nee ds f or partici pa nt c o nfi de ntialit y g ui deli nes w hile s u p p orti n g t he st u d y
of t he disease, its relate d fact ors, a n d t he I M P u n der i n vesti gati o n.
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, is n ot per mitte d.
5. 1
I ncl usi o n Criteri a
A partici pa nt will be eli gi ble f or i ncl usi o n i n t he st u d y if t he partici pa nt meets all of t he 
f oll o wi n g criteria:
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
1.
Has hist ol o gicall y - or c yt ol o gicall y -c o nfir me d (if acce pta ble acc or di n g t o l ocal healt h 
a ut h ori t y re g ulati o ns) a de n ocarci n o ma of t he pr ostate wit h o ut s mall cell hist ol o g y. 
Dia g n osis m ust be state d i n a pat h ol o g y re p ort a n d c o nfir me d b y t he i n vesti gat or .
2.
Has metastatic disease as assesse d b y i n vesti gat or a n d verifie d b y BI C R ( pri or t o 
ra n d o mizati o n) b y eit her ≥2 b o ne lesi o ns o n b o ne sca n a n d/ or visceral disease (e g, l u n g 
or li ver) b y C T/ M RI. Partici pa nts w h ose metastatic disease is li mite d t o l y m p h n o des are 
n ot eli gi ble.
3.
O nce ra n d o mize d, partici pa nt m ust be willi n g t o mai ntai n c o nti n u o us A D T wit h a L H R H 
a g o nists or a nta g o nists d uri n g st u d y treat me nt or ha ve a hist or y of bilateral orc hiect o m y.
4.
Has a n E C O G perf or ma nce stat us of 0 or 1 assesse d wit hi n 1 0 da ys of ra n d o mizati o n.
5.
Partici pa nts recei vi n g b o ne res or pti ve t hera p y (i ncl u di n g, b ut n ot li mite d t o,
bis p h os p h o nate or de n os u ma b) m ust ha ve bee n o n sta ble d oses f or ≥4 wee ks pri or t o 
ra n d o mizati o n. 
6.
De m o nstrates a de q uate or ga n f u ncti o n as defi ne d i n Ta ble 4 ; all scree ni n g la bs s h o ul d be 
perf or me d i n ce ntral la b orat or y wit hi n 1 0 da ys of t he first d os e of st u d y i nter ve nti o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 4
La b orat or y Val ues f or A de q uate Or ga n F u ncti o n
S yste m
L a b or at or y V al ue
He mat ol o gical
A N C
≥1 5 0 0/ µ L
Platelets
≥1 0 0, 0 0 0/ µ La
He m o gl o bi n
≥9. 0 g/ d L or ≥5. 6 m m ol/ L a
Re nal
Creati ni ne O R
Meas ure d or calc ulate d
b creati ni ne 
cleara nce
( G F R ca n als o be use d i n place of 
creati ni ne or Cr Cl)
≤1. 5 × U L N O R
≥5 0 m L/ mi n f or partici pa nt wit h creati ni ne 
le vels > 1. 5 × U L N
He patic
T otal bilir u bi n
≤1. 5 × U L N O R direct bilir u bi n ≤U L N f or 
partici pa nts wit h t otal bilir u bi n le vels 
> 1. 5 × U L N
A S T ( S G O T) a n d A L T ( S G P T)
≤2. 5 × U L N ( ≤5 × U L N f or partici pa nts wit h 
li ver metastases)
C oa g ulati o n
I N R or P T
a P T T or P T T
≤1. 5 × U L N u nless partici pa nt is recei vi n g 
a ntic oa g ula nt t hera p y as l o n g as P T or a P T T is 
wit hi n t hera pe utic ra n ge of i nte n de d use of 
a ntic oa g ula nts
A L T ( S G P T) = ala ni ne a mi n otra nsferase (ser u m gl uta mic -p yr u vic tra nsa mi nase); A N C = a bs ol ute ne utr o p hil 
c o u nt; a P T T = acti vate d partial t hr o m b o plasti n ti me; A S T ( S G O T) = as partate a mi n otra nsferase (ser u m 
gl uta mic -o xal oacetic tra nsa mi nase); Cr Cl = creati ni ne cleara nce; G F R = gl o mer ular filtrati o n rate; I N R = 
I nter nati o nal n or malize d rati o; P T = pr ot hr o m bi n ti me; P T T = partial t hr o m b o plasti n ti me; U L N = u p per 
li mit of n or mal.
a.
He m o gl o bi n a n d platelet re q uire me nts ca n n ot be met b y use of rece nt tra nsf usi o n or gr o wt h fact or 
s u p p ort (G C S F or er yt hr o p oieti n) wit hi n 2 wee ks pri or t o ra n d o mizati o n.
b.
Cr Cl s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.
N ote: T his ta b le i ncl u des eli gi bilit y-defi ni n g la b orat or y val ue re q uire me nts f or treat me nt; la b orat or y val ue 
re q uire me nts s h o ul d be a da pte d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes f or t he a d mi nistrati o n of 
s pecific c he m ot hera pies.
De m o gr a p hics
7.
Is male , ≥1 8 years of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt.
M ale P artici p a nts
C o ntrace pti ve use b y me n s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he met h o ds 
of c o ntrace pti o n f or t h ose partici pati n g i n cli nical st u dies.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8.
Male partici pa nts are eli gi ble t o partici pate if t he y a gree t o t he f oll o wi n g d uri n g t he 
i nter ve nti o n peri o d a n d f or at least 1 2 0 da ys after t he last d ose of st u d y i nter ve nti o n .
•
Refrai n fr o m d o nati n g s per m
P L U S eit her:
•
Be a bsti ne nt fr o m heter ose x ual i nterc o urse as t heir preferre d a n d us ual lifest yle 
(a bsti ne nt o n a l o n g-ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt
O R
•
M ust a gree t o use c o ntrace pti o n, u nless c o nfir me d t o be az o os per mic ( vasect o mize d 
or sec o n dar y t o me dical ca use [ A p pe n di x 5]), as detaile d bel o w:
◦
A gree t o use 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 C B P w h o is n ot 
c urre ntl y pre g na nt. 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 -va gi nal pe netrati o n.
9.
Male partici pa nts m ust a gree t o use male c o n d o m w he n e n ga gi n g i n a n y acti vit y t hat 
all o ws f or passa ge of ejac ulate t o a n ot her pers o n of a n y se x. 
I nf or me d C o nse nt
1 0. T he partici pa nt ( or le gall y acce pta ble re prese ntati ve if a p plica ble) pr o vi des writte n 
i nf or me d c o nse nt/asse nt f or t he st u d y
A d diti o n al C ate g ories
1 1. Has pr o vi de d ne wl y o btai ne d c ore or e xcisi o nal bi o ps y ( o btai ne d wit hi n 1 2 m o nt hs of 
Scree ni n g) fr o m s oft tiss ue n ot pre vi o usl y irra diate d (sa m ples fr o m t u m ors pr o gressi n g i n 
a pri or site of ra diati o n are all o we d; ot her e xce pti o ns ma y be c o nsi dere d after S p o ns or 
c o ns ultati o n). Partici pa nts wit h b o ne o nl y or b o ne pre d o mi na nt disease ma y pr o vi de a 
b o ne bi o ps y sa m ple ( decalcificati o n n ot all o we d). H o we ver, if o btai ni n g a ne w bi o ps y is 
n ot feasi ble, t he n partici pa nts ma y pr o vi de a n arc hi val t u m or tiss ue sa m ple after S p o ns or 
c o ns ultati o n ( S C F). F F P E tiss ue bl oc ks are preferre d t o sli des. Ne wl y o btai ne d bi o psies 
are preferre d t o arc hi ve tiss ue. A de q uac y of t hese s peci me ns f or P D -L 1 bi o mar ker 
a nal ysis will be re q uire d b y a ce ntral l a b orat or y pri or t o ra n d o mizati o n.  
N ote: Details pertai ni n g t o t u m or tiss ue s u b missi o n ca n be f o u n d i n t he Pr oce d ures 
Ma n ual.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
5. 2
E xcl usi o n Criteri a
T he partici pa nt m ust be e xcl u de d fr o m t he st u d y if t he partici pa nt meets a n y of t he f oll o wi n g 
criteria:
Me dic a l C o n diti o ns
1.
H as a k n o w n a d diti o nal mali g na nc y t hat is pr o gressi n g or has re q uire d acti ve treat me nt i n 
t he last 3 years. Partici pa nts wit h 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 carci n o ma i n sit u t hat ha ve u n der g o ne p ote ntiall y c urati ve 
t hera p y are n ot e xcl u de d.
2.
Has a n acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n past 2 years 
(ie, wit h use of disease m o dif yi n g a ge nts, c ortic oster oi ds, or i m m u n os u p pressi ve dr u gs). 
Re place me nt t hera p y (e g, t h yr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d re place me nt 
t hera p y f or a dre nal or pit uitar y i ns ufficie nc y, etc.) is n ot c o nsi dere d a f or m of s yste mic 
treat me nt.
3.
Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g c hr o nic s yste mic ster oi d t hera p y (i n 
d o si n g e xcee di n g 1 0 m g dail y of pre d nis o ne or e q ui vale nt) or a n y ot her f or m of 
i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t he first d ose of st u d y i nter ve nti o n.
4.
Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y 
t hat mi ght c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he partici pa nt’s partici pati o n 
f or t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he partici pa nt t o 
partici pate, i n t he o pi ni o n of t he treati n g i n vesti gat or.
5.
Has u n der g o ne maj or s ur ger y i ncl u di n g l ocal pr ostate i nter ve nti o n (e xcl u di n g pr ostate 
bi o ps y) wit hi n 2 8 da ys pri or t o ra n d o mizati o n a n d n ot rec o vere d a de q uatel y fr o m t he 
t o xicities a n d/ or c o m plicati o ns. 
6.
Has a gastr oi ntesti nal dis or der affecti n g a bs or pti o n (e g, gastrect o m y, acti ve pe ptic ulcer 
disease wit hi n last 3 m o nt hs).
7.
Is u na ble t o s wall o w ta blets/ca ps ules.
8.
Has a n acti ve i nfecti o n (i ncl u di n g t u berc ul osis) re q uiri n g s yste mic t hera p y.
9.
Has a hist or y of ( n o n -i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
1 0. Has k n o w n acti ve HI V, he patitis B vir us (e g, he patitis B s urface a nti ge n reacti ve) or 
H C V (e g, H C V R N A [ q ualitati ve] is detecte d). Testi n g f or He patitis B a n d He patitis C is 
n ot re q uire d u nless ma n date d b y l ocal re g ulati o n.
1 1. Has k n o w n or s us pecte d C N S metastases a n d/ or carci n o mat o us me ni n gitis. 
1 2. Has k n o w n ps yc hiatric or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h c o o perati o n 
wit h t he re q uire me nts of t he st u d y.
1 3. Has a hist or y of seiz ure or a n y c o n diti o n t hat ma y pre dis p ose t o seiz ure (i ncl u di n g, b ut 
n ot li mite d t o pri or cere br o vasc ular acci de nt, tra nsie nt isc he mic attac k, or brai n 
arteri o ve n o us malf or mati o n; or i ntracra nial masses s uc h as a sc h wa n n o ma or 
me ni n gi o ma t hat is ca usi n g e de ma or mass effect).
1 4. Has a hist or y of l oss o f c o nsci o us ness wit hi n 1 2 m o nt hs of t he Scree ni n g Visit.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 5. Has ha d m y ocar dial i nfarcti o n or u nc o ntr olle d a n gi na wit hi n 6 m o nt hs pri or t o 
ra n d o mizati o n.
N ote: Partici pa nts wit h rece nt hist or y of re vasc ularizati o n f or ac ute c or o nar y s y n dr o me 
wit hi n 3 m o nt hs pr i or t o ra n d o mizati o n are i ncl u de d.
1 6. Has Ne w Y or k Heart Ass ociati o n class III or I V c o n gesti ve heart fail ure or a hist or y of 
Ne w Y or k Heart Ass ociat io n class III or I V c o n gesti ve heart fail ure u nless a scree ni n g 
ec h ocar di o gra m or m ulti gate d ac q uisiti o n sca n perf or me d wit hi n 3 m o nt hs pri or t o 
ra n d o mizati o n date de m o nstrates a left ve ntric ular ejecti o n fracti o n > 4 5 %.
1 7. Has a hist or y of c li nicall y si g nifica nt ve ntric ular arr h yt h mias (e g, ve ntric ular tac h ycar dia, 
ve ntric ular fi brillati o n, t orsa des de p oi ntes).
1 8. Has a hist or y of M o bitz II sec o n d de gree or t hir d-de gree heart bl oc k wit h o ut a per ma ne nt 
pace ma ker i n place.
1 9. Has h y p ote nsi o n as i n dicate d b y s yst olic bl o o d press ure < 8 6 milli meters of merc ur y ( m m 
H g) at t he Scree ni n g Visit.
2 0. Has bra d ycar dia as i n dicate d b y a he art rate of < 5 0 beats per mi n ute o n t he Scree ni n g 
E C G.
2 1. Has u nc o ntr olle d h y perte nsi o n as i n dicate d b y s yst olic bl o o d press ure > 1 7 0 m m H g or 
diast olic bl o o d press ure > 1 0 5 m m H g at t he Scree ni n g Visit.
2 2. Has se vere h y perse nsiti vit y ( Gra de ≥3) t o pe m br oliz u ma b a n d/ or a n y of its e xci pie nts.  
2 3. Has h y perse nsiti vit y reacti o n t o e nzal uta mi de or a n y of its ca ps ule c o m p o ne nts, i ncl u di n g 
La bras ol, b ut ylate d h y dr o x ya nis ole, a n d b ut ylate d h y dr o x yt ol ue ne.
Pri or/ C o nc o mit a nt T her a p y
2 4. Has recei ve d a n y pri or p har mac ot hera p y, ra diati o n t hera p y or s ur ger y f or metastatic 
pr ostate ca ncer wit h t he f oll o wi n g e xce pti o ns:
a.
U p t o 3 m o nt hs of A D T wit h L H R H a g o nists or a nta g o nists or orc hiect o m y wit h or 
wit h o ut c o nc urre nt first -ge nerati o n a ntia n dr o ge ns pri or t o ra n d o mizati o n, wit h n o 
ra di o gra p hic e vi de nce of disease pr o gressi o n or risi n g P S A pri or t o ra n d o mizati o n if 
partici pa n t was n ot treate d wit h d oceta xel f or metastatic pr ostate ca ncer. 
b.
Ma y ha ve 1 c o urse of palliati ve ra diati o n or s ur gical t hera p y t o treat s y m pt o ms 
res ulti n g fr o m metastatic disease if it was a d mi nistere d at least 4 wee ks pri or t o 
ra n d o mizati o n.
c.
F or partici p a nts wit h l o w-v ol u me metastatic disease ( defi ne d as < 4 b o ne lesi o ns), 
ma y ha ve 1 c o urse of defi niti ve ra di ot hera p y (ie, E B R T) t o t he pr ostate if it was 
a d mi nistere d at least 4 wee ks pri or t o ra n d o mizati o n.
d.
U p t o 6 c ycles of d oceta xel t hera p y wit h fi nal tre at me nt a d mi nistrati o n c o m plete d 
wit hi n 2 m o nt hs of ra n d o mizati o n a n d n o e vi de nce of disease pr o gressi o n d uri n g or 
after c o m pleti o n of d oceta xel t hera p y. I n t hese partici pa nts, u p t o 6 m o nt hs of A D T 
wit h L H R H a g o nists or a nta g o nists or orc hiect o m y wit h or w it h o ut c o nc urre nt first-
ge nerati o n a ntia n dr o ge ns is per mitte d.
2 5. Has recei ve d pri or A D T as ne oa dj u va nt/a dj u va nt t hera p y f or n o n -metastatic pr ostate 
ca ncer f or > 3 9 m o nt hs i n d urati o n or wit hi n 9 m o nt hs pri or t o ra n d o mizati o n or wit h 
e vi de nce of disease pr o gre ssi o n w hile recei vi n g A D T. 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
2 6. Has ha d pri or treat me nt wit h a ne xt ge nerati o n h or m o nal a ge nt (e g, a birater o ne, 
e nzal uta mi de, a pal uta mi de, dar ol uta mi de).
2 7. Recei ve d pri or t hera p y wit h a n a nti -P D -1, a nti -P D -L 1, or a nti -P D -L 2 a ge nt , or wit h a n 
a ge nt directe d t o a n ot her sti m ulat or y or c oi n hi bit or y T -cell rece pt or (e g, C T L A -4, O X -
4 0, C D 1 3 7).
2 8. Has use d her bal pr o d ucts t hat ma y ha ve h or m o nal a nti -pr ostate ca ncer acti vit y a n d/ or are 
k n o w n t o decrease P S A le vels (e g, sa w pal mett o) wit hi n 4 wee ks pri or t o ra n d o mizati o n.
2 9. Has recei ve d treat me nt wit h 5 - α re d uctase i n hi bit ors (e g, fi nasteri de, d utasteri de), 
estr o ge ns, c y pr oter o ne acetate a n d/ or a n dr o ge ns wit hi n 4 wee ks pri or t o ra n d o mizati o n.
3 0. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys pri or t o ra n d o mizati o n. E xa m ples of li ve 
vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: measles, m u m ps, r u bella, 
varicella/z oster (c hic ke n p o x), yell o w fe ver, ra bies, B C G, a n d t y p h oi d vacci ne. Seas o nal 
i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d vir us vacci nes a n d are all o we d; 
h o we ver, i ntra nasal i nfl ue nza vacci nes (e g, Fl u Mist ®) are li ve atte n uate d vacci nes a n d 
are n ot all o we d. Refer t o Secti o n 6. 5 f or i nf or mati o n o n C O VI D -1 9 vacci nes .
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
3 1. Is c urre ntl y partici pati n g i n or has partici pate d i n a st u d y of a n i n vesti gati o nal a ge nt or 
has use d a n i n vesti gati o nal de vice wit hi n 4 wee ks pri or t o ra n d o mizati o n.
N ote: Partici pa nts w h o ha ve e ntere d t he n o n -treat me nt F oll o w-u p P hase of a n 
i n vesti gati o nal st u d y ma y partici pate as l o n g as it has bee n 4 wee ks after t he last d ose of 
t he pre vi o us i n vesti gati o nal a ge nt.
Ot her E xcl usi o ns
3 2. Has a “s u persca n” b o ne sca n. T his is defi ne d as a n i nte nse s y m metric acti vit y i n t he 
b o nes a n d di mi nis he d re nal pare nc h y mal acti vit y o n baseli ne b o ne sca n s uc h t hat t he 
prese nce of a d diti o nal metastases i n t he f ut ure c o ul d n ot be e val uate d. 
3 3. Has ha d a n all o ge neic tiss ue/s oli d or ga n tra ns pla nt.
5. 3 
Lifest yle C o nsi der ati o ns
5. 3. 1
Me als a n d Diet ar y Restricti o ns
Partici pa nts s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n 
A E s uc h as diarr hea, na usea, or v o miti n g.
5. 3. 2
C o ntr ace pti o n
Pe m br oliz u ma b ma y ha ve a d verse effects o n a fet us i n uter o. Refer t o A p pe n di x 5 f or 
a p pr o ve d met h o ds of c o ntrace pti o n.
Partici pa nts s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks 
t o t he fet us ( u n b or n ba b y) if pre g na nc y of fe m ale part ner were t o occ ur d uri n g t he st u d y . I n 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
6 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
or der t o partici pate i n t he st u d y, partici pa nts wit h c hil d beari n g- p ote ntial fe male part ners m ust 
a d here t o t he c o ntrace pti o n re q uire me nt ( A p pe n di x 5 ) fr o m t he da y of st u d y me dicati o n 
i nitiati o n ( or 1 4 da ys prior t o t he i nitiati o n of st u d y me dicati o n f or oral c o ntrace pti o n) 
t hr o u g h o ut t he st u d y peri o d u p t o 1 2 0 da ys after t he last d ose of st u d y me dicati o n. If t here is 
a n y q uesti o n t hat a partici pa nt wit h c hil d beari n g- p ote ntial fe male part ner will n ot relia bl y 
c om pl y wit h t he re q uire me nts f or c o ntrace pti o n, t hat partici pa nt s h o ul d n ot be e ntere d i nt o 
t he st u d y.
5. 3. 3
Pre g n a nc y
If a partici pa nt i m pre g nates his fe male part ner, t he st u d y pers o n nel at t he site m ust be 
i nf or me d i m me diatel y a n d t he pre g na nc y m ust be re p orte d t o t he S p o ns or a n d f oll o we d as 
descri be d i n Secti o n 8. 4 .
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 ra n d o mize d i n t he st u d y. A mi ni mal set of scree n-fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n-fail ure partici pa nts t o meet t he C O N S O R T 
p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal 
i nf or mati o n i ncl u des de m o gra p h y, scree n-fail ure details, eli gi bilit y criteria, a n d a n y A Es or 
S A Es meeti n g re p orti n g re q uire me nts as o utli ne d i n t he data e ntr y g ui deli nes.
Partici pa nts ma y be rescree ne d u p t o t w o ti mes after i nitiall y faili n g t o meet t he 
i ncl usi o n/e xcl usi o n criteria (refer t o Secti o n 8. 1 0. 1).
5. 5
P artici p a nt Re pl ace me nt Str ate g y
A partici pa nt w h o disc o nti n ues fr o m st u d y i nter ve nti o n O R wit h dra ws fr o m t he st u d y will 
n ot be re place d.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
6
S T U D Y I N T E R V E N TI O N
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), 
place b o, or me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o 
t he st u d y pr ot oc ol.
Cli nical s u p plies (st u d y i nter ve nti o ns pr o vi de d b y t he S p o ns or) will be pac ka ge d t o s u p p ort 
e nr oll me nt . Cli nical s u p plies will be affi xe d wit h a cli nical la bel i n acc or da nce wit h 
re g ulat or y re q uire me nts.
6. 1
St u d y I nter ve nti o n(s) A d mi nistere d
N O T E: I n ali g n me nt wit h t he st u d y u p d ate me m o se nt t o I n vesti g at ors o n 2 5 - J A N-
2 0 2 3, all st u d y p artici p a nts s h o ul d st o p o n g oi n g tre at me nt wit h 
pe m br oliz u m a b/ pl ace b o. E xce pti o ns m a y be re q ueste d f or st u d y p artici p a nts w h o, i n 
t he assess me nt of t heir st u d y p hysici a n, are be nefitti n g fr o m t he c o m bi n ati o n of 
e nz al ut a mi de a n d pe m br oliz u m a b, after c o ns ulti n g wit h t he S p o ns or. All ot her st u d y 
p artici p a nts s h o ul d be disc o nti n ue d fr o m st u d y a n d be offere d S O C tre at me nt as 
dee me d necess ar y b y t he I n vesti g at or. If e nz al ut a mi de as S O C is n ot acces si ble off 
st u d y t o t he p artici p a nt, ce ntr al s o urci n g m a y c o nti n ue. 
T he st u d y i nter ve nti o n(s) t o be use d i n t his st u d y are o utli ne d i n Ta ble 5 .
C o u ntr y -s pecific re q uire me nts are n ote d i n A p pe n di x 7 .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 5
St u d y I nter ve nti o ns
Ar m 
N a me
Ar m T y pe
I nter ve nti o n 
N a me
I nter ve nti o n 
T y pe
D ose 
F or m ul ati o n
U nit D ose 
Stre n gt h(s)
D os a ge 
Le vel(s)
R o ute of 
A d mi nistr ati o n
Re gi me n/
Tre at me nt 
Peri o d/
V acci n ati o n 
Re gi me n
Use 
I M P 
or 
NI M P/
A x M P
S o urci n g
Ar m 1
E x peri me ntal
Pe m br oliz u ma b
Bi ol o gical/ Vacci ne
S ol uti o n
2 5 m g/ m L
2 0 0 m g
I V I nf usi o n
Da y 1 of 
eac h 2 1 -da y 
c ycle
Test 
Pr o d uct
I M P
Ce ntral
Ar m 1
E x peri me ntal
E nzal uta mi de
Dr u g
Ca ps ule
4 0 m g/ 
8 0 m g
1 6 0 m g
Oral
F o ur 4 0 -m g 
ca ps ules/ 
ta blets 
orall y per 
da y/t w o 8 0 
m g ta blets 
orall y per 
da y
Test 
Pr o d uct
I M P
Ce ntral
Ar m 2
Acti ve 
C o m parat or
E nzal uta mi de
Dr u g
Ca ps ule
4 0 m g/ 
8 0 m g
1 6 0 m g
Oral
F o ur 4 0 -m g 
ca ps ules/ 
ta blets 
orall y per 
da y/t w o 8 0 
m g ta blets 
orall y per 
da y
Test 
Pr o d uct
I M P
Ce ntral
Ar m 2
Acti ve 
C o m parat or
Place b o
Dr u g
S ol uti o n
N A  
N A
I V I nf usi o n
Da y 1 of 
eac h 2 1 -da y 
c ycle
Place b o
I M P
L ocal
E E A
E ur o pea n Ec o n o mic Area; I M P i n vesti gati o nal me dici nal pr o d uct; I V  i ntra ve n o us; N A n ot a p plica ble; NI M P / A x M P n o ni n vesti gati o nal /a u xiliar y me dici nal pr o d uct.
T he classificati o n of I M P a n d NI M P / A x M P i n t his ta ble is base d o n g ui da nce iss ue d b y t he E ur o pea n C o m missi o n a n d a p plies t o c o u ntries i n t he E E A. C o u ntr y differe nces wit h res pect t o t he 
defi niti o n/classificati o n of I M P a n d NI M P / A x M P ma y e xist. I n t hese circ u msta nces, l ocal le gislati o n is f oll o we d.
I n t his pr ot oc ol, place b o f or pe m br oliz u ma b is dil uent al o ne ( n or mal sali ne a n d/ or de xtr ose); dil ue nt is use d f or bli n di n g p ur p oses a n d d oes n ot c o ntai n acti ve i n gre die nts. N or mal sali ne is t he pri mar y 
dil ue nt/ place b o f or pe m br oliz u ma b; use de xtr ose o nl y if sali ne is n ot a vaila ble.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
All st u d y i nter ve nti o ns will be a d mi nistere d o n a n o ut patie nt basis.
All pr o d ucts i n dicate d i n Ta ble 5 w ill be pr o vi de d ce ntrall y b y t he S p o ns or wit h t he 
e xce pti o n of place b o w hic h will be pr o vi de d l ocall y .
All partici pa nts will als o recei ve a n d re mai n o n a sta ble re gi me n of A D T ( L H R H a g o nist or 
a nta g o nist) or ha ve s ur gical castrati o n. D ose a n d fre q ue nc y of a d mi nistrati o n will be 
c o nsiste nt wit h l ocal pr o d uct la bel a n d s h o ul d n ot c ha n ge d uri n g t he st u d y.
Refer t o Secti o n 8. 1. 8 f or details re gar di n g a d mi nistrati o n of t he st u d y i nter ve nti o n.
6. 2
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
6. 2. 1
D ose Pre p ar ati o n
Details o n pre parati o n a n d a d mi nistrati o n of pe m br oliz u ma b are pr o vi de d i n t he P har mac y 
Ma n ual.
6. 2. 2
H a n dli n g, St or a ge, a n d Acc o u nt a bilit y
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei ve d, a n d a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y i nter ve nti o n.
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n, 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 i nter ve nti o n. All st u d y i nter ve nti o ns 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 ual or a ut o mate d) area i n 
acc or da nce wit h t he la bele d st ora ge c o n dit i o ns wit h access li mite d t o t he i n vesti gat or a n d 
a ut h orize d site staff.
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
F or all st u d y sites, t he l ocal c o u ntr y S p o ns or pers o n nel or desi g nee will pr o vi de a p pr o priate 
d oc u me ntati o n t hat m ust be c o m plete d f or dr u g acc o u nta bilit y a n d ret ur n, or l ocal discar d 
a n d destr uct i o n if a p pr o priate. W here l ocal discar d a n d destr ucti o n is a p pr o priate, t he 
i n vesti gat or is res p o nsi ble f or e ns uri n g t hat a l ocal discar d/ destr ucti o n pr oce d ure is 
d oc u me nte d.
T he st u d y site is res p o nsi ble f or rec or di n g t he l ot n u m ber, ma n ufact urer, a n d e x p ir y date f or 
a n y l ocall y p urc hase d pr o d uct (if a p plica ble) as per l ocal g ui deli nes u nless ot her wise 
i nstr ucte d b y t he S p o ns or.
T he i n vesti gat or s hall ta ke res p o nsi bilit y f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s up pl y, st ora ge, ha n dli n g, distri b uti o n, a n d usa ge of st u d y 
i nter ve nti o ns i n acc or da nce wit h t he pr ot oc ol a n d a n y a p plica ble la ws a n d re g ulati o ns.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
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
6. 3. 1
I nter ve nti o n Assi g n me nt
I nter ve nti o n ra n d o mizati o n will o cc ur ce ntrall y usi n g a n I R T s yste m. T here are 2 st u d y 
i nter ve nti o n ar ms. Partici pa nts will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o pe m br oliz u ma b + 
e nzal uta mi de + A D T or place b o + e nzal uta mi de + A D T , res pecti vel y.
6. 3. 2
Str atific ati o n
R a n d o mizati o n will be stratifie d acc or di n g t o t he f oll o wi n g fact ors:
•
Pri or d oceta xel f or m H S P C: Yes vs N o
N O T E: U p t o 6 c ycles of d oceta xel t hera p y f or m H S P C is per mitte d as l o n g as fi nal 
treat me nt a d mi nistrati o n is c o m plete d wit hi n 2 m o nt hs of ra n d o mizati o n a n d n o e vi de nce 
of disease pr o gressi o n d uri n g or after c o m pleti o n of t hera p y.
•
Prese nce of hi g h -v ol u me disease: Yes vs N o
N O T E: Hi g h -v ol u me disease is defi ne d as prese nce of visceral metastases O R ≥4 b o ne 
lesi o ns wit h ≥1 be y o n d t he verte bral b o dies a n d pel vis.
6. 3. 3
Bli n di n g
As of I A 1, t he st u d y w as u n bli n de d. T he s u bsecti o n bel o w is ret ai ne d f or refere nce. 
A d o u ble -bli n di n g tec h ni q ue wit h i n -h o use bli n di n g will be use d. Pe m br oliz u ma b a n d 
place b o will be pre pare d a n d/ or dis pe nse d i n a bli n de d fas hi o n b y a n u n bli n de d p har macist or 
q ualifie d site pers o n nel s o t hat t he bli n d is mai ntai ne d . T he partici pa nt, t he i n vesti gat or, a n d 
S p o ns or pers o n nel or dele gate(s) w h o are i n v ol ve d i n t he st u d y i nter ve nti o n a d mi nistrati o n or 
cli nical e val uati o n of t he partici pa nts are u na ware of t he i nter ve nti o n assi g n me nts.
T he treat me nt i de ntit y of e nzal uta mi de will be o pe n -la bel; t he i de ntit y of t h ose treat me nts will 
be k n o w n b y t he partici pa nt, t he i n vesti gat or, t he S p o ns or, a n d dele gate(s) w h o are i n v ol ve d 
i n st u d y i nter ve nti o n a d mi nistrati o n or t he clinical e val uati o n of partici pa nts.
See Secti o n 8. 1. 1 0 f or a descri pti o n of t he met h o d of u n bli n di n g a partici pa nt d uri n g t he 
st u d y s h o ul d s uc h acti o n be warra nte d.
P D -L 1 a n d P S A res ults are n ot re p orte d bac k t o sites t o pre ve nt earl y wit h dra wal of 
partici pa nts fr o m st u d y i nter ve nti o n.
6. 4
St u d y I nter ve nti o n C o m pli a nce
Refer t o Secti o n 6. 6. 3 f or D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or ir A Es 
ass ociate d wit h pe m br oliz u ma b m o n ot hera p y, c of or m ulati o ns, or I O c o m bi nati o ns a n d f or 
ot her all o we d d ose i nterr u pti o ns.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A d mi nistrati o n of pe m br oliz u ma b/ place b o will be m o nit ore d b y t he i n vesti gat or a n d/ or st u d y 
staff. T he t otal v ol u me of st u d y me dicati o n i nf use d will be c o m pare d wit h t he t otal v ol u me 
pre pare d t o deter mi ne c o m plia nce wit h eac h d ose a d mi nistere d.
I nterr u pti o ns fr o m t he pr ot oc ol-s pecifie d treat me nt pla n f or m ore t ha n 1 2 wee ks bet wee n 
pe m br oliz u ma b d oses f or n o n dr u g -relate d or a d mi nistrati ve reas o ns re q uire c o ns ultati o n 
bet wee n t he i n vesti gat or a n d t he S p o ns or a n d writte n d oc u me ntati o n of t he c olla b orati ve 
decisi o n o n partici pa nt ma na ge me nt. 
F or e nzal uta mi de, t he site will vali date c o m plia nce wit h st u d y i nter ve nti o n at eac h site visit 
acc or di n g t o t heir sta n dar d o perati n g pr oce d ure. If d oses are misse d or v o mite d, t his m ust be 
i n dicate d i n t he s o urce d oc u me nts a n d C R Fs.
6. 5
C o nc o mit a nt T her a p y
6. 5. 1
Pr o hi bite d C o nc o mit a nt T her a p y
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e xcl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g st u d y. If t here is a cli nical i n dicati o n f or a n y me dicati o n o r vacci nati o n 
s pecificall y pr o hi bite d, disc o nti n uati o n fr o m st u d y t hera p y or vacci nati o n ma y be re q uire d. 
T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he S p o ns or's Cli nical 
Direct or. T he fi nal decisi o n o n a n y s u p p orti ve t hera p y or vac ci nati o n rests wit h t he 
i n vesti gat or a n d/ or t he partici pa nt's pri mar y p h ysicia n. H o we ver, t he decisi o n t o c o nti n ue t he 
partici pa nt o n st u d y i nter ve nti o n re q uires t he m ut ual a gree me nt of t he i n vesti gat or, t he 
S p o ns or, a n d t he partici pa nt.
Partici pa nts are p r o hi bite d fr o m recei vi n g t he f oll o wi n g c o nc o mita nt t hera pies d uri n g t he 
Treat me nt P hase of t his st u d y:
•
A nti ne o plastic s yste mic c he m ot hera p y, tar gete d or bi ol o gical t hera p y n ot s pecifie d i n t his 
pr ot oc ol (e xce pt de n os u ma b a n d bi p h os p h o nate f or b o ne metastas es as sta n dar d of care if 
o n sta ble d oses > 4 wee ks pri or t o ra n d o mizati o n)
•
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol
•
I n vesti gati o nal a ge nts n ot s pecifie d i n t his pr ot oc ol
•
I nitiati o n of b o ne res or pti ve t hera p y i ncl u di n g b ut n ot li mite d t o de n os u ma b ( u nless 
a p pr o ve d b y S p o ns or c o ns ultati o n)
•
Ra diati o n t hera p y
N ote: Palliati ve l ocalize d ra diati o n t hera p y t o a site of pre -e xisti n g disease ma y be 
per mitte d w hile o n st u d y after c o ns ultati o n wit h S p o ns or. T he ra diati o n treat me nt fiel d 
ma y n ot i ncl u de a tar get lesi o n b y R E CI S T 1. 1.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
Li ve vacci nes wit hi n 3 0 da ys pri or t o t he first d ose of st u d y i nter ve nti o n a n d w hile 
partici pati n g i n t he st u d y. E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: measles, m u m ps, r u bella, varicella/z oster, yell o w fe ver, ra bies, B C G, a n d 
t y p h oi d vacci ne. Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d vir us 
vacci nes a n d are all o we d; h o we ver, i ntra nasal i nfl ue nza vacci nes (e g, Fl u Mist ®) are li ve 
atte n uate d vacci nes a n d are n ot all o we d.  
N ote: If prec l u de d b y l ocal re g ulati o ns, li ve vacci nes s h o ul d n ot be gi ve n f or 1 2 0 da ys 
after t he last d ose of pe m br oliz u ma b is a d mi nistere d.
A n y lice nse d C O VI D-1 9 vacci ne (i ncl u di n g f or E mer ge nc y Use) i n a partic ular c o u ntr y 
is all o we d i n t he st u d y as l o n g as t he y are m R N A vacci nes, re plicati o n -i nc o m pete nt 
a de n o viral vacci nes, or i nacti vate d vacci nes. T hese vacci nes will be treate d j ust as a n y 
ot her c o nc o mita nt t hera p y.
I n vesti gati o nal vacci nes (i.e., t h ose n ot lice nse d or a p pr o ve d f or E mer ge nc y Use) are n ot 
all o we d.
•
S yste mic gl uc oc ortic oi ds f or a n y p ur p ose ot her t ha n t o m o d ulate s y m pt o ms fr o m a n A E
t hat is s us pecte d t o ha ve a n i m m u n ol o gic eti ol o g y. T he use of p h ysi ol o gic d oses of 
c ortic oster oi ds ma y be a p pr o ve d after c o ns ultati o n wit h t he S p o ns or.
N ote: T he f oll o wi n g uses of c ortic oster oi ds are per mitte d wit h o ut S p o ns or c o ns ultati o n:
-
I n hale d ster oi ds f or ma na ge me nt of ast h ma
-
Pr o p h ylactic c ortic oster oi ds t o a v oi d aller gic reacti o ns (e g, I V c o ntract d ye)
-
Palliati ve pre d nis o ne u p t o 1 0 m g dail y or c ortic oster oi d e q ui vale nt i n t he ma n ner 
use d t o treat me n wit h pr ostate ca ncer
-
P h ysi ol o gic d oses of c ortic o ster oi ds f or a dre nal i ns ufficie nc y
-
I ntra nasal ster oi ds f or aller gies
•
5- α re d uctase i n hi bit ors (e g, fi nasteri de, d utasteri de), estr o ge ns, a n d/ or c y pr oter o ne
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
Str o n g C Y P 2 C 8 i n hi bit ors or str o n g C Y P 3 A 4 i n d ucers s h o ul d be a v oi de d. H o we ver, if 
t hese me dicati o ns are necessar y a n d ca n n ot be a v oi de d t he n e nzal uta mi de d ose s h o ul d be 
a dj uste d as i n dicate d i n t he a p pr o ve d pr o d uct la bel. E nzal uta mi de is a str o n g C Y P 3 A 4 
i n d ucer a n d a m o derate C Y P 2 C 9 a n d C Y P 2 C 1 9 i n d ucer. C o nc o mita nt use of 
e nzal uta mi de wit h narr o w t hera pe utic i n de x dr u gs t hat are meta b olize d b y C Y P 3 A 4 (e g, 
alfe nta nil, c ycl os p ori ne, di h y dr oer g ota mi ne, er g ota mi ne, fe nta n yl, pi m ozi de, q ui ni di ne, 
sir oli m us, tacr oli m us), C Y P 2 C 9 (e g, p he n yt oi n, warfari n), a n d C Y P 2 C 1 9 (e g, 
S- me p he n yt oi n, cl o pi d o grel) s h o ul d be a v oi de d if p ossi ble as e nzal uta mi de ma y decrease 
t heir e x p os ure. If c oa d mi nistrati o n wit h warfari n ca n n ot be a v oi de d, c o n d uct a d diti o nal 
I N R m o nit ori n g.
N ote: a list of str o n g/ m o derate i n d ucers of C Y P 3 A 4 ca n be f o u n d at t he f oll o wi n g 
we bsite: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/
De vel o p me nt Res o urces/ Dr u gI nteracti o ns La beli n g/ uc m 0 9 3 6 6 4. ht m #ta ble 2 - 2.
I n a d diti o n t o t he me dicati o ns liste d here, site staff s h o ul d refer t o t he l ocal a p pr o ve d pr o d uct 
la bel f or per mitte d a n d pr o hi bite d me dicati o ns, as well as dr u g- dr u g i nteracti o ns f or 
e nzal uta mi de. Ca uti o n s h o ul d be use d if partici pa nts are recei vi n g c o nc o mita nt me dicati o ns 
t hat ma y l o wer t he seiz ure t hres h ol d.
T he E xcl usi o n Criteria descri be ot her me dicati o ns w hic h are pr o hi bite d i n t his st u d y.
Al l treat me nts t hat t he in vesti gat or c o nsi ders necessar y f or a partici pa nt’s welfare ma y be 
a d mi nis tere d at t he discreti o n of t he in vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care. All c o nc o mita nt me dicati o n will be rec or de d o n t he e C R F i n cl u di n g all 
prescri pti o n, O T C pr o d ucts, her bal s u p ple me nts, a n d I V me dicati o ns a n d fl ui ds. If c ha n ges 
occ ur d uri n g t he st u d y peri o d, d oc u me ntati o n of dr u g d osa ge, fre q ue nc y, r o ute, a n d date 
s h o ul d als o be i ncl u de d o n t he e C R F.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da ys pri or t o t he first d ose of st u d y 
i nter ve nti o n a n d u p t o 3 0 da ys after t he last d ose of st u d y i nter ve nti o n s h o ul d be rec or de d. 
All c o nc o mita nt me dicati o ns a d mi nistere d d uri n g S A Es or E CIs are t o be rec or de d. S A Es 
a n d E CIs are defi ne d i n Secti o n 8. 4 .
6. 5. 2
Resc ue Me dic ati o ns a n d S u p p orti ve C are
Partici pa nts s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.
S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of A Es wi t h p ote ntial i m m u n ol o gic
eti ol o g y are o utli ne d al o n g wit h t he d ose m o dificati o n g ui deli n es i n Ta ble 7 . W here 
a p pr o priate, t hese g ui deli nes i ncl u de t he use of oral or I V tre at me nt wit h c ortic oster oi ds, as 
well as a d diti o nal a nti -i nfla m mat or y a ge nts if s y m pt o ms d o n ot i m pr o ve wit h a d mi nistrati o n 
of c ortic oster oi ds. N ote t hat se veral c o urses of ster oi d ta peri n g ma y be necessar y as 
s y m pt o ms ma y w orse n w he n t he ster oi d d ose is decrease d. F or eac h dis or der, atte m pts 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastatic disease or bacterial or viral 
i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care. The treat me nt g ui deli nes are 
i nte n de d t o be a p plie d w he n t he i n vesti gat or deter mi nes t he e ve nts t o be relate d t o 
pe m br oliz u ma b.
N ote: If after t he e val uati o n of t he e ve nt, it is deter mi ne d n ot t o be relate d t o pe m br oliz u ma b, 
t he i n vesti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce. Refer t o Ta ble 7 i n 
Secti o n 6. 6. 3 f or g ui deli nes re gar di n g d ose m o dificati o n a n d s u p p orti ve  care.
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o p y, or 
s ki n p h ot o gra p h y as part of e val uati o n of t he e ve nt.
6. 6
D ose M o dific ati o n (Esc al ati o n/ Titr ati o n/ Ot her)
6. 6. 1
C o nc o mit a nt C o m bi n ati o n T her a p y
If eit her pe m br oliz u ma b/ place b o is i nterr u pte d f or > 1 2 wee ks (i m m u ne-relate d A E) or 
> 3 c o nsec uti ve wee ks f or a d mi nistrati ve reas o ns or e nzal uta mi de is i nterr u pte d f or 
2 8 c o nsec uti ve da ys, t he site m ust gai n a p pr o val fr o m t he S p o ns or t o c o nti n ue t he ot her 
part ner dr u g. Partici pa nts w h o m ust disc o nti n ue 1 of t he 2 dr u gs i n t he c o m bi nati o n d ue t o 
dr u g -relate d A Es ma y c o nti n ue wit h t he ot her c o m bi nati o n part ner f oll o wi n g c o ns ultati o n 
wit h t he S p o ns or u ntil criteria f or disc o nti n uati o n of treat me nt are met. 
All partici pa nts s h o ul d re mai n o n a sta ble re gi me n of A D T c o nsiste nt wit h prescri bi n g 
i nf or mati o n a n d o nl y a dj uste d if cli nicall y i n dicate d t o ac hie ve or mai ntai n s u b-castrate 
le vels of test oster o ne ( < 5 0 n g/ d L).
6. 6. 2
D ose M o dific ati o n f or E nz al ut a mi de
If a partici pa nt e x perie nces a n y Gra de ≥3 t o xicit y relate d t o e nzal uta mi de treat me nt, t he dr u g 
s h o ul d be wit h hel d u ntil t he t o xicit y decreases t o Gra de ≤2. E nzal uta mi de ca n t he n be 
res u me d at t he re d uce d d ose of 1 2 0 m g dail y. F or re peat Gra de ≥3 t o xicit y, it ca n a gai n be 
hel d u ntil t o xicit y decrease t o Gra de ≤2 a n d res u me d at t he re d uce d d ose of 8 0 m g dail y. 
Re d ucti o n bel o w 8 0 m g is n ot all o we d ( Ta ble 6 ).
O nce t he d ose has bee n re d uce d, it ma y n ot be escalate d u p t o a pre vi o us d ose le vel. 
E nzal uta mi de s h o ul d be per ma ne ntl y disc o nti n ue d i n partici pa nts w h o de vel o p a seiz ure 
w hile o n treat me nt. 
P osteri or re versi ble e nce p hal o pat h y s y n dr o me ( P R E S) has bee n o bser ve d i n partici pa nts 
treate d wit h e nzal uta mi de. T his ma y prese nt wit h ra pi dl y e v ol vi n g s y m pt o ms of seiz ure, 
let har g y, hea dac he, c o nf usi o n, bli n d ness or vis ual dist ur ba nces, or ot her ne ur ol o gic 
s y m pt o ms. H y perte nsi o n ma y or ma y n ot be prese nt. P osteri or re versi ble e nce p hal o pat h y 
s y n dr o me is dia g n ose d b y brai n i ma gi n g ( prefera bl y M RI). E nzal uta mi de s h o ul d be wit h hel d 
if P R E S is s us pecte d a n d t he n disc o nti n ue d if a P R E S dia g n osis is c o nfir me d. 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Pe m br oliz u ma b/ place b o s h o ul d be i nterr u pte d if P R E S or seiz ure is o bser ve d a n d ma y be 
res u me d i n t hese partici pa nts after c o ns ultati o n wit h t he S p o ns or.
Partici pa nts s h o ul d be directe d t o re p ort t he de vel o p me nt of ras h re gar dless of se verit y 
pr o m ptl y t o i n vesti gat ors. Partici pa nts wit h ras h s h o ul d be treate d pr o m ptl y wit h ster oi ds a n d 
d ose i nterr u pti o n per pr ot oc ol a n d m o nit ore d cl osel y f or w orse ni n g of ras h w hic h ma y 
re q uire a d diti o nal treat me nt. 
I n cases w here b ot h e nzal uta mi de a n d pe m br oliz u ma b are i nterr u pte d, after res ol uti o n of t he 
t o xicit y, t he partici pa nt s h o ul d first res u me treat me nt wit h e nzal uta mi de, a n d if t olerate d, 
t he n pe m br oliz u ma b i nf usi o ns ca n res u me.
Ta ble 6
E nzal uta mi de D ose M o dificati o n G ui deli nes f or Dr u g -Relate d A d verse 
E ve nts
Dr u g
D ose/ P ote nc y
D ose 
Fre q ue nc y
Re gi me n
I nitial e nzal uta mi de 
d ose
1 6 0 m g
Q D
F o ur 4 0 -m g ca ps ules/ta blets or t w o 8 0 -m g 
ta blets
First d ose re d ucti o n
1 2 0 m g
Q D
T hree 4 0 -m g ca ps ules/ta blets
Sec o n d d ose re d ucti o n
8 0 m g
Q D
T w o 4 0 -m g ca ps ules/ta blets or o ne 8 0 -m g 
ta blet
A b bre viati o ns: Q D e ver y da y
6. 6. 3
I m m u ne-Rel ate d E ve nts a n d D ose M o dific ati o n ( Wit h h ol d, Tre at, 
Disc o nti n ue)
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt f or I m m u ne -rel ate d A Es Ass oci ate d Wit h 
Pe m br oliz u m a b
A Es ass ociate d wit h pe m br oliz u ma b e x p os ure ma y re prese nt a n i m m u ne -relate d res p o nse. 
T hese ir A Es ma y occ ur s h ortl y after t he first d ose or se veral m o nt hs after t he last d ose of 
pe m br oliz u ma b treat me nt a n d ma y affect m ore t ha n o ne b o d y s yste m si m ulta ne o usl y. 
T h eref ore, earl y rec o g niti o n a n d i nitiati o n of treat me nt is critical t o re d uce c o m plicati o ns. 
Base d o n e xisti n g cli nical st u d y data, m ost ir A Es were re versi ble a n d c o ul d be ma na ge d wit h 
i nterr u pti o ns of pe m br oliz u ma b, a d mi nistrati o n of c ortic oster oi ds, a n d/ or ot her s u p p orti ve 
care. F or s us pecte d ir A Es, e ns ure a de q uate e val uati o n t o c o nfir m eti ol o g y or e xcl u de ot her 
ca uses. A d diti o nal pr oce d ures or tests s uc h as br o nc h osc o p y, e n d osc o p y, s ki n bi o ps y ma y be 
i ncl u de d as part of t he e val uati o n.
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or ir A Es ass ociate d w it h 
p e m br oliz u ma b m o n ot hera p y, cof or m ulati o ns, or I O co m bi nati o ns are pr o vi de d i n Ta ble 7 .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
7 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 7
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne -relate d A d verse E ve nts Ass ociate d W it h 
Pe m br oliz u ma b M o n ot hera p y, C of or m ulati o ns , or I O C o m bi nati o ns
Ge neral i nstr ucti o ns:
1. Se vere a n d life -t hreate ni n g ir A Es s h o ul d be treate d wit h I V c ortic oster oi ds f oll o we d b y oral ster oi ds. Ot her i m m u n os u p pressi ve treat me nt s h o ul d be gi n if 
t he ir A Es are n ot c o ntr olle d b y c ortic oster oi ds.
2. Pe m br oliz u ma b m o n ot hera p y, c of or m ulati o ns, or I O c o m bi nati o ns m ust be per ma ne ntl y dis c o nti n ue d if t he ir A E d oes n ot res ol ve or t he c ortic oster oi d 
d ose is n ot ≤1 0 m g/ da y wit hi n 1 2 wee ks of t he last treat me nt.
3. T he c ortic oster oi d ta per s h o ul d be gi n w he n t he ir A E is ≤ Gra de 1 a n d c o nti n ue at least 4 wee ks.
4. If pe m br oliz u ma b m o n ot hera p y, cof or m ulati o ns, or I O c o m bi nati o ns ha ve bee n wit h hel d, treat me nt ma y res u me after t he ir A E decrease d t o ≤Gra de 1 
after c ortic oster oi d ta per.
ir A Es
T o xicit y Gr a de 
( C T C A E v 5. 0)
Acti o n Wit h 
Pe m br oliz u m a b
M o n ot her a p y, 
C of or m ul ati o ns, or I O 
C o m bi n ati o ns
C ortic oster oi d a n d/ or Ot her 
T her a pies
M o nit ori n g a n d F oll o w -u p
P ne u m o nitis
Gra de 2
Wit h h ol d

A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2 m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per

A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns

M o nit or partici pa nts f or si g ns a n d 
s y m pt o ms of p ne u m o nitis

E val uate partici pa nts wit h s us pecte d 
p ne u m o nitis wit h ra di o gra p hic 
i ma gi n g a n d i nitiate c ortic oster oi d 
treat me nt
Rec urre nt Gra de 2 , or
Gra de 3 or 4
Per ma ne ntl y 
disc o nti n ue
Diarr hea/ C olitis
Gra de 2 or 3
Wit h h ol d

A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2 m g/ k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per

M o nit or partici pa nts f or si g ns a n d 
s y m pt o ms of e nter oc olitis (ie, 
diarr hea, a b d o mi nal pai n, bl o o d or 
m uc us i n st o ol wit h or wit h o ut fe ver) 
a n d of b o wel perf orati o n (ie, 
perit o neal si g ns a n d ile us)

Partici pa nts wit h ≥Gra de 2 di arr hea 
s us pecti n g c olitis s h o ul d c o nsi der GI 
c o ns ultati o n a n d perf or mi n g 
e n d osc o p y t o r ule o ut c olitis

Partici pa nts wit h diarr hea/c olitis 
s h o ul d be a d vise d t o dri n k li beral 
q ua ntities of clear fl ui ds. If s ufficie nt 
oral fl ui d i nta ke is n ot feasi ble, fl ui d 
a n d electr ol ytes s h o ul d be s u bstit ute d 
via I V i nf usi o n
Rec urre nt Gra de 3 or 
Gra de 4
Per ma ne ntl y 
disc o nti n ue
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
ir A Es
T o xicit y Gr a de 
( C T C A E v 5. 0)
Acti o n Wit h 
Pe m br oliz u m a b
M o n ot her a p y, 
C of or m ul ati o ns, or I O 
C o m bi n ati o ns
C ortic oster oi d a n d/ or Ot her 
T her a pies
M o nit ori n g a n d F oll o w -u p
A S T or A L T Ele vati o n 
or I ncrease d Bilir u bi n
Gra de 2 a
Wit h h ol d

A d mi nister c ortic oster oi ds 
(i nitial d ose of 0. 5 t o 
1 m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d b y 
ta per

M o nit or wit h li ver f u ncti o n tests 
(c o nsi der wee kl y or m ore fre q ue ntl y 
u ntil li ver e nz y me val ue ret ur ne d t o 
baseli ne or is sta ble)
Gra de 3 b or 4 c
Per ma ne ntl y 
disc o nti n ue

A d mi nister c ortic oster oi ds 
(i nitial d ose of 1 t o 2 m g / k g 
pre d nis o ne or e q ui vale nt) 
f oll o we d b y ta per
T 1 D M or 
H y per gl yce mia
Ne w o nset T 1 D M or 
Gra de 3 or 4 
h y per gl yce mia 
ass ociate d wit h 
e vi de nce of -cell 
fail ure
Wit h h ol d
d

I nitiate i ns uli n re place me nt 
t hera p y f or partici pa nts wit h 
T 1 D M

A d mi nister 
a nti h y per gl yce mic i n 
partici pa nts wit h 
h y per gl yce mia

M o nit or partici pa nts f or 
h y per gl yce mia or ot her si g ns a n d 
s y m pt o ms of dia betes
H y p o p h ysitis
Gra de 2
Wit h h ol d

A d mi nister c ortic oster oi ds 
a n d i nitiate h or m o nal 
re place me nts as cli nicall y 
i n dicate d

M o nit or
f or si g ns a n d s y m pt o ms of 
h y p o p h ysitis (i ncl u di n g 
h y p o pit uitaris m a n d a dre nal 
i ns ufficie nc y)
Gra de 3 or 4
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d
H y pert h yr oi dis m
Gra de 2
C o nti n ue

Treat wit h n o nselecti ve 
beta -bl oc kers (e g, 
pr o pra n ol ol) or t hi o na mi des 
as a p pr o priate

M o nit or f or si g ns a n d s y m pt o ms of 
t h yr oi d dis or ders
Gra de 3 or 4
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
ir A Es
T o xicit y Gr a de 
( C T C A E v 5. 0)
Acti o n Wit h 
Pe m br oliz u m a b
M o n ot her a p y, 
C of or m ul ati o ns, or I O 
C o m bi n ati o ns
C ortic oster oi d a n d/ or Ot her 
T her a pies
M o nit ori n g a n d F oll o w -u p
H y p ot h yr oi dis m
Gra de 2
C o nti n ue

I nitiate t h yr oi d re place me nt 
h or m o nes (e g, 
le v ot h yr o xi ne or 
li ot h yr o ni ne) per sta n dar d of 
care

M o nit or f or si g ns a n d s y m pt o ms of 
t h yr oi d dis or ders
Gr a de 3 or 4
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue d
Ne p hritis:
gra di n g acc or di n g t o 
i ncrease d creati ni ne or 
ac ute ki d ne y i nj ur y
Gra de 2
Wit h h ol d

A d mi nister c ortic oster oi ds 
( pre d nis o ne 1 t o 2 m g/ k g or 
e q ui vale nt) f oll o we d b y 
ta per

M o nit or c ha n ges of re nal f u ncti o n
Gra de 3 or 4
Per ma ne ntl y 
disc o nti n ue
Ne ur ol o gical T o xicities
Gra de 2
Wit h h ol d

Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 3 or 4
Per ma ne ntl y 
disc o nti n ue
M y ocar ditis
As y m pt o matic 
car diac e nz y me 
ele vati o n wit h 
cli nical s us pici o n of 
m y ocar ditis ( w hic h 
was pre vi o usl y 
m y ocar ditis Gra de 1 
usi n g C T C A E v 4. 0)
Wit h h ol d

Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 2, 3 or 4
Per ma ne ntl y 
disc o nti n ue
E xf oliati ve 
Der mat ol o gic 
C o n diti o ns
S us pecte d SJ S, T E N, 
or D R E S S
Wit h h ol d

Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y or e xcl u de ot her ca uses
C o nfir me d SJ S, 
T E N, or D R E S S
Per ma ne ntl y 
disc o nti n ue
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
ir A Es
T o xicit y Gr a de 
( C T C A E v 5. 0)
Acti o n Wit h 
Pe m br oliz u m a b
M o n ot her a p y, 
C of or m ul ati o ns, or I O 
C o m bi n ati o ns
C ortic oster oi d a n d/ or Ot her 
T her a pies
M o nit ori n g a n d F oll o w -u p
All Ot her ir A Es
Persiste nt Gra de 2
Wit h h ol d

Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y or e xcl u de ot her ca uses
Gra de 3
Wit h h ol d or disc o nti n ue 
base d o n t he e ve nt e
Rec urre nt Gra de 3 or 
Gra de 4
Per ma ne ntl y 
disc o nti n ue
A E(s) a d verse e ve nt(s); A L T ala ni ne a mi n otra nsferase; A S T as partate a mi n otra nsferase; 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; D R E S S
Dr u g 
Ras h wit h E osi n o p hilia a n d S yste mic S y m pt o m; GI gastr oi ntesti nal; I O i m m u n o o nc ol o g y; ir i m m u ne relate d; I V i ntra ve n o us ; SJ S
Ste ve ns J o h ns o n S y n dr o me; 
T 1 D M t y pe 1 dia betes mellit us; T E N
T o xic E pi der mal Necr ol ysis; U L N u p per li mit of n or mal.
N ote: N o n -ir A E will be m a n a ge d as a p pr o pri ate, f oll o wi n g cli nic al pr actice rec o m me n d ati o ns.
a
A S T/ A L T: > 3. 0 t o 5. 0 × U L N if baseli ne n or mal; > 3. 0 t o 5. 0 × baseli ne, if baseli ne a b n or mal;
bilir u bi n: > 1. 5 t o 3. 0 × U L N if baseli ne n or mal; > 1. 5 t o 3. 0 × baseli ne if baseli ne a b n or mal
b
A S T/ A L T: > 5. 0 t o 2 0. 0 × U L N, if baseli ne n or mal; > 5. 0 t o 2 0. 0 × baseli ne, if baseli ne a b n or mal; bilir u bi n: > 3. 0 t o 1 0. 0 × U L N if baseli ne n or mal; > 3. 0 t o 1 0. 0 × baseli ne 
if baseli ne a b n or mal
c
A S T/ A L T: > 2 0. 0 × U L N, if baseli ne n or mal; > 2 0. 0 × baseli ne, if baseli ne a b n or mal; 
bilir u bi n: > 1 0. 0 × U L N if baseli ne n or mal; > 1 0. 0 × baseli ne if baseli ne a b n or mal
d
T he decisi o n t o wit h h ol d or per ma ne ntl y disc o nti n ue pe m br oliz u ma b m o n ot hera p y, c of or m ulati o ns, or I O c o m bi nati o ns is at t he discreti o n of t he i n vesti gat or or treati n g 
p h ysicia n. If c o ntr ol ac hie ve d or ≤Gra de 2, pe m br oliz u ma b m o n ot hera p y, c of or m ulati o ns, or I O c o m bi nati o ns ma y be res u me d.
e
E ve nts t hat re q uire disc o nti n uati o n i ncl u de, b ut are n ot li mite d t o e nce p halitis a n d ot her cli nicall y i m p orta nt ir A Es (e g, vasc ulitis a n d scler osi n g c h ola n gitis)
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt of I nf usi o n Re acti o ns Rel ate d t o 
Pe m br oliz u m a b
Pe m br oliz u ma b ma y ca use se vere or life -t hreate ni n g i nf usi o n-reacti o ns i ncl u di n g se vere 
h y perse nsiti vit y or a na p h yla xis. Si g ns a n d s y m pt o ms us uall y de vel o p d uri n g or s h ortl y after 
dr u g i nf us i o n a n d ge nerall y res ol ve c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. 
D ose m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes o n pe m br oliz u ma b ass ociate d 
i nf usi o n reacti o n are pr o vi de d i n Ta ble 8 .
Ta ble 8
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d Treat me nt 
G ui deli nes
N CI C T C A E Gr a de
Tre at me nt
Pre me dic ati o n at 
S u bse q ue nt D osi n g
Gra de 1
Mil d reacti o n; i nf usi o n i nterr u pti o n 
n ot i n dicate d; i nter ve nti o n n ot 
i n dicate d
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he partici pa nt 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or
N o ne
Gra de 2
Re q uires t hera p y or i nf usi o n 
i nterr u pti o n b ut res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt (e g, 
a nti hista mi nes, N S AI Ds, narc otics, 
I V fl ui ds); pr o p h ylactic me dicati o ns 
i n dicate d f or ≤2 4 hrs
St o p I nf usi o n
A d diti o nal a p pr o priate me dical t hera p y 
ma y i ncl u de b ut is n ot li mite d t o:
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he partici pa nt 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
If s y m pt o ms res ol ve wit hi n 1 h o ur of 
st o p pi n g dr u g i nf usi o n, t he i nf usi o n ma y 
be restarte d at 5 0 % of t he ori gi nal 
i nf usi o n rate (e g, fr o m 1 0 0 m L/ hr t o 5 0 
m L/ hr). Ot her wise d osi n g will be hel d 
u ntil s y m pt o ms res ol ve a n d t he 
partici pa nt s h o ul d be pre me dicate d f or 
t he ne xt sc he d ule d d ose.
Partici pa nts w h o de vel o p Gra de 2 
t o xicit y des pite a de q uate pre me dicati o n 
s h o ul d be per ma ne ntl y disc o nti n ue d 
fr o m f urt her st u d y dr u g i nter ve nti o n.
Partici pa nt ma y be 
pre me dicate d 1. 5 h ( ± 3 0 
mi n utes) pri or t o 
i nf usi o n of st u d y 
i nter ve nti o n wit h:
Di p he n h y dra mi ne 5 0 m g 
P O ( or e q ui vale nt d ose 
of a nti hista mi ne) .
Aceta mi n o p he n 5 0 0 -
1 0 0 0 m g P O ( or 
e q ui vale nt d ose of 
a nal gesic).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
N CI C T C A E Gr a de
Tre at me nt
Pre me dic ati o n at 
S u bse q ue nt D osi n g
Gra des 3 or 4
Gra de 3:
Pr ol o n ge d (ie, n ot ra pi dl y res p o nsi ve 
t o s y m pt o matic me dicati o n a n d/ or 
brief i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; h os pitalizati o n 
i n dicate d f or ot her cli nical se q uelae 
(e g, re nal i m pair me nt, p ul m o nar y 
i nfiltrates)
Gra de 4:
Life -t hreate ni n g; press or or 
ve ntilat or y s u p p ort i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y 
ma y i ncl u de b ut is n ot li mite d t o:
E pi ne p h ri ne * *
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he partici pa nt 
is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla xis, e pi ne p hri ne 
s h o ul d be use d i m me diatel y.
Partici pa nt is per ma ne ntl y disc o nti n ue d 
fr o m f urt her st u d y dr u g i nter ve nti o n.
N o s u bse q ue nt d osi n g
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g t he 
peri o d of dr u g a d mi nistrati o n.
F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 5. 0 ( C T C A E) at 
htt p://cte p.ca ncer. g o v
Ot her All o we d D ose I nterr u pti o n f or Pe m br oliz u m a b
Pe m br oliz u ma b ma y be i nterr u pte d f or sit uati o ns ot her t ha n treat me nt -relate d A Es s uc h as 
me dical / s ur gical e ve nts or l o gistical reas o ns n ot relate d t o st u d y t hera p y. Partici pa nts s h o ul d 
be place d bac k o n st u d y t hera p y wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless 
ot her wise disc usse d wit h t he S p o ns or. T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n 
t he partici pa nt's st u d y rec or d.
6. 6. 4
M a n a ge me nt of O verl a p pi n g T o xicities
Base d o n t he k n o w n t o xicit y pr ofiles of pe m br oliz u ma b a n d e nzal uta mi de, certai n treat me nt -
relate d A Es are u ni q uel y ass ociate d wit h o ne dr u g vers us t he ot her. F or e xa m ple, seiz ure is a 
k n o w n ris k f or e nzal uta mi de treat me nt, w hile i m m u ne -relate d A Es are ris ks f or 
pe m br oliz u ma b treat me nt. H o we ver, certai n A Es, s uc h as diarr hea, ma y be i nitiall y 
c o nsi dere d attri b uta ble t o eit her st u d y i nter ve nti o n. T heref ore, e val uati o n of attri b uti o n is 
i m p orta nt f or deter mi ni n g t he st u d y i nter ve nti o n m ost li kel y relate d t o t he A E, or a n 
alter nati ve eti ol o g y, a n d s u bse q ue ntl y pr o per cli nical ma na ge me nt. T he f oll o wi n g as pects 
s h o ul d be c o nsi dere d: 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1.
Ti mi n g of A E o nset: 
Si nce e nzal uta mi de is d ose d dail y a n d c o nti n u o usl y d ue t o a relati vel y s h ort half -life ( 5. 8 
da ys), a n d pe m br oli z u ma b is d ose d Q 3 W d ue t o a l o n g half -life, e nzal uta mi de ca n be 
i nterr u pte d t o assess w het her a n A E i m pr o ves/res ol ves wit h dec halle n ge (ie, i nterr u pti o n 
of treat me nt) base d o n t he f oll o wi n g 2 sce nari os:
•
If a n A E is i de ntifie d d uri n g a treat me nt c ycle (ie, bet wee n 2 pe m br oliz u ma b d oses), 
c o nsi der w het her o nl y e nzal uta mi de d ose i nterr u pti o n is nee de d. 
•
If a n A E is i de ntifie d at t he be gi n ni n g of a treat me nt c ycle, pe m br oliz u ma b s h o ul d be 
hel d, a n d e nzal uta mi de i nterr u pte d base d o n se verit y a n d ca usalit y assess me nt.
If t he partici pa nt rec o vers fr o m a n A E i n res p o nse t o e nzal uta mi de i nterr u pti o n (ie, 
p ositi ve dec halle n ge), t he e ve nt is m ore li kel y t o be relate d t o e nzal uta mi de. 
Ot her wise, after e xcl u di n g ot her alter nati ve e x pla nati o ns, a n i m m u ne -relate d A E 
s h o ul d be c o nsi dere d. I n cases w here b ot h e nzal uta mi de a n d pe m br oliz u ma b are 
i nterr u pte d d ue t o t o xicit y, e nzal uta mi de s h o ul d be res u me d first, a n d if t olerate d, 
t he n pe m br oliz u ma b i nf usi o ns ca n res u me.  
2.
Se verit y of A E:
If a n A E is s us pecte d t o be treat me nt-relate d a n d is se vere/life -t hreate ni n g at t he ti me of 
o nset or is ra pi dl y w orse ne d, acti o n i ncl u di n g i nterr u pti n g b ot h dr u gs a n d i nitiati n g 
treat me nt wit h a c ortic oster oi d ( wit h e xce pti o n of h y p ot h yr oi dis m, T y pe 1 dia betes 
mellit us) a n d ot her s u p p orti ve care s h o ul d be ta ke n pr o m ptl y.
6. 7
I nter ve nti o n After t he E n d of t he St u d y
T here is n o st u d y -s pecifie d i nter ve nti o n f oll o wi n g t he e n d of t he st u d y.
6. 8
Cli nic al S u p plies Discl os ure
T he e mer ge nc y u n bli n di n g call ce nter will use t he i nter ve nti o n/ra n d o mizati o n sc he d ule f or 
t he st u d y t o u n bli n d partici pa nts a n d t o u n mas k st u d y i nter ve nti o n i de ntit y. T he e mer ge nc y 
u n bli n di n g call ce nter s h o ul d o nl y be use d i n cases of e mer ge nc y (see Secti o n 8. 1. 1 0 ). In t he 
e ve nt t hat t he e mer ge nc y u n bli ndi n g call ce nter is n ot a vaila ble f or a gi ve n site i n t his st u d y, 
t he ce ntral electr o nic (IR T) s h o ul d be use d t o u n bli n d partici pa nts a n d t o u n mas k st u d y 
i nter ve nti o n i de ntit y. T he S p o ns or will n ot pr o vi de ra n d o m c o de/ discl os ure e n vel o pes or lists 
wit h t he cli nical s u p plies.
6. 9
St a n d ar d P olicies
Trial site pers o n nel will ha ve access t o t he I R T s yste m t o all ocate partici pa nts, t o assi g n 
i nter ve nti o n t o partici pa nts a n d t o ma na ge t he distri b uti o n of cli nical s u p plies. Eac h pers o n 
accessi n g t he I R T s yste m m ust be assi g ne d a n i n di vi d ual u ni q ue PI N. T he y m ust use o nl y 
t heir assi g ne d PI N t o access t he s yste m, a n d t he y m ust n ot s hare t heir assi g ne d PI N wit h 
a n y o ne.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
7
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N 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 I nter ve nti o n
D isc o nti n uati o n of st u d y i nter ve nti o n d oes n ot re prese nt wit h dra wal fr o m t he st u d y.
As certai n data o n cli nical e ve nts be y o n d st u d y i nter ve nti o n disc o nti n uati o n ma y be 
i m p orta nt t o t he st u d y, t he y m ust be c ollecte d t hr o u g h t he partici pa nt’s last sc he d ule d f oll o w-
u p, e ve n if t he partici pa nt has disc o nti n ue d st u d y i nter ve nti o n. T heref ore, a ll partici pa nts 
w h o disc o nti n ue st u d y i nter ve nti o n pri or t o c o m pleti o n of t he pr ot oc ol-s pecifie d treat me nt 
peri o d/ vacci nati o n re gi me n will still c o nti n ue t o partici pate i n t he st u d y as s pecifie d i n
Secti o n 1. 3 a n d Secti o n 8. 1 0 . 3.
Partici pa nts ma y disc o nti n ue st u d y i nter ve nti o n at a n y ti me f or a n y reas o n or be d r o p pe d
fr o m t he st u d y i nter ve nti o n at t he discreti o n of t he i n vesti gat or s h o ul d a n y u nt o war d effect 
occ ur. I n a d diti o n, a partici pa nt ma y be disc o nti n ue d fr o m st u d y i nter ve nti o n b y t he 
i n vesti gat or or t he S p o ns or if st u d y i nter ve nti o n is i na p pr o priate, t he st u d y pla n is vi olate d, or 
f or a d mi nistrati ve a n d/ or ot her safet y reas o ns. S pecific details re gar di n g pr oce d ures t o be 
perf or me d at st u d y i nter ve nti o n disc o nti n uati o n are pr o vi de d i n Secti o n 8. 1 0. 2. 2 .
A partici pa nt m ust be disc o nti n ue d fr o m st u d y i nter ve nti o n, b ut c o nti n ue t o be m o nit ore d i n 
t he st u d y f or a n y of t he f oll o wi n g reas o ns:
•
T he partici pa nt or partici pa nt’s le gall y acce pta ble re prese ntati ve re q uests t o disc o nti n ue 
st u d y i nter ve nti o n.
•
T he par tici pa nt i nterr u pts pe m br oliz u ma b or place b o a d mi nistrati o n f or m ore t ha n 1 2 
c o nsec uti ve wee ks f or a n ir A E wit h o ut S p o ns or c o ns ultati o n. 
•
T he partici pa nt has misse d 2 8 c o nsec uti ve da ys of e nzal uta mi de wit h o ut S p o ns or 
c o ns ultati o n.
•
T he partici pa nt has a me d ical c o n diti o n or pers o nal circ u msta nce w hic h, i n t he o pi ni o n of 
t he i n vesti gat or a n d/ or S p o ns or, place d t he partici pa nt at u n necessar y ris k fr o m c o nti n ue d 
a d mi nistrati o n of st u d y i nter ve nti o n.
•
T he partici pa nt re q uires a n y me dicati o n or vacci nati o n s pecifi call y pr o hi bite d i n t his 
st u d y ( Secti o n 6. 5. 1).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
BI C R -verifie d r a di o gra p hic disease pr o gressi o n o utli ne d i n Secti o n 8. 2. 1 (e xce pti o n if t he 
S p o ns or a p pr o ves treat me nt c o nti n uati o n f oll o wi n g P D).
-
As of A me n d me nt 0 4, ce ntr al t u m or res p o nse assess me nts will n o l o n ger be 
perf or me d. P artici p a nts o n st u d y tre at me nt will be assesse d l oc all y b y t he 
i n vesti g at or f or dise ase pr o gressi o n per S O C sc he d ule. P artici p a nts wit h P D per 
l oc al i n vesti g at or assess me nt s h o ul d be disc o nti n ue d (e xce pti o n if t he S p o ns or 
a p pr o ves tr e at me nt c o nti n u ati o n f oll o wi n g P D).
•
A n y pr o gressi o n or rec urre nce of a n y sec o n dar y mali g na nc y, or a n y occ urre nce of 
a n ot her mali g na nc y t hat re q uires acti ve treat me nt.
•
Disc o nti n uati o n of pe m br oliz u ma b/ place b o ma y be c o nsi dere d f or partici pa nts w h o ha ve 
attai ne d a c o nfir me d C R a n d ha ve bee n treate d f or at least 8 c ycles (at least 2 4 wee ks), 
recei vi n g 2 c ycles of pe m br oliz u ma b/ place b o be y o n d t he date w he n t he i nitial C R was 
declare d ( d oes n ot a p pl y t o e nzal uta mi de). T hese partici pa nts ma y be eli gi ble f or s ec o n d 
c o urse treat me nt descri be d i n Secti o n 8. 1 0. 2. 3.
•
C o m pleti o n of 3 5 c ycles (a p pr o xi matel y 2 years) wit h pe m br oliz u ma b/ place b o ( d oes n ot 
a p pl y t o e nzal uta mi de).
N ote: T he n u m ber of treat me nts is calc ulate d starti n g wit h t he first d ose. Partici pa nts w h o 
st o p pe m br oliz u ma b after recei vi n g 3 5 d oses ma y be eli gi ble f or retreat me nt if t he y 
pr o gress after st o p pi n g pe m br oliz u ma b pr o vi de d t he y meet t he re q uire me nts detaile d i n 
Secti o n 8. 1 0. 2. 3. Partici pa nts ma y be retreate d i n t he Sec o n d C o urse P hase ( Retreat me nt ) 
f or u p t o a n a d diti o nal 1 7 c ycles (a p pr o xi matel y 1 year).
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 m ust be wit h dra w n fr o m t he st u d y if t he partici pa nt or partici pa nt’s le gall y 
acce pta ble re prese ntati ve wit h dra ws c o nse nt fr o m t he st u d y.
If a partici pa nt wit h dra ws fr o m t he st u d y, t he y will n o l o n ger recei ve st u d y i nter ve nti o n or be 
f oll o we d at sc he d ule d pr ot oc ol visits.
S pecific details re gar di n g pr oce d ures t o be perf or me d at t he ti me of wit h dra wal fr o m t he 
st u d y, are o utli ne d i n Secti o n 8. 1. 9 . The pr oce d ures t o be perf or me d s h o ul d a partici pa nt 
re peate dl y fail t o ret ur n f or sc he d ule d visits a n d/ or if t he st u d y site is u na ble t o c o ntact t he 
partici pa nt are o utli ne d i n Secti o n 7. 3 .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
7. 3
L ost t o F oll o w -u p
If a partici 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 a n d/ or if t he site is u na ble 
t o c o ntact t he partici pa nt, t he f oll o wi n g pr oce d ures are t o be perf or me d:
•
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit. If t he 
partici pa nt is c o ntacte d, t he partici pa nt s h o ul d be c o u nsele d o n t he i m p orta nce of 
mai ntai ni n g t he pr ot oc ol -s pecifie d visit sc he d ule.
•
T he i n vesti gat or or desi g nee m ust ma ke e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt 
at eac h misse d visit (e g, tele p h o ne calls a n d/ or a certifie d letter t o t he partici pa nt’s last 
k n o w n maili n g a d dress or l ocall y e q ui vale nt met h o ds). T hese c o ntact 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 rec or d.
N ote: A partici pa nt is n ot c o nsi dere d l ost t o f oll o w -u p u ntil t he last sc he d ule d visit f or t he 
i ndi vi d ual partici pa nt. T he missi n g data f or t he partici pa nt will be ma na ge d via t he 
pres pecifie d statistical data ha n dli n g a n d a nal ysis g ui deli nes .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
8 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 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
•
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A.
•
A d here nce t o t he st u d y desi 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 uire d f or st u d y c o n d uct.
•
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat pr oce d ures are c o n d ucte d b y 
a p pr o priatel y q ualifie d ( b y e d ucati o n, trai ni n g, a n d e x perie nce) staff. Dele gati o n of 
st u d y-site pers o n nel res p o nsi bilities will be d oc u me nte d i n t he I n vesti gat or Trial File 
Bi n der ( or e q ui vale nt).
•
All st u d y -relate d me dical decisi o ns m ust be ma de b y a n i n vesti gat or w h o is a q ualifie d 
p h ysicia n .
•
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns for 
scree ni n g fail ure, as a p plica ble.
•
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 me nt (e g, bl o o d 
c o u nt) a n d o btai ne d bef ore si g ni n g of I C F ma y be u tilize d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ure met t he pr ot oc ol-s pecifie d criteria a n d were perf or me d 
wit hi n t he ti me fra me defi ne d i n t he S o A.
•
A d diti o nal e val uati o ns/testi n g ma y be dee me d necessar y b y t he i n vesti gat or a n d or t he 
S p o ns or f or re as o ns relate d t o partici pa nt safet y. I n s o me cases, s uc h e val uati o n/testi n g 
ma y be p ote ntiall y se nsiti ve i n nat ure (e g, HI V, H e patitis C), a n d t h us l ocal re g ulati o ns 
ma y re q uire t hat a d diti o nal i nf or me d c o nse nt be o btai ne d fr o m t he partici pa nt. I n t hese 
cases, s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce wit h t h ose re g ulati o ns.
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h partici pa nt o ver t he d urati o n of t he st u d y 
is pr o vi de d i n t he Pr oce d ures Ma n ual.
Re peat or u nsc he d ule d sa m ples ma y be ta k e n f or safet y reas o ns or f or tec h nical iss ues wit h 
t he sa m ples.
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
T he i n vesti gat or or me dicall y q ualifie d desi g nee (c o nsiste nt wit h l ocal re q uire me nts) m ust 
o btai n d oc u me nte d co nse nt fr o m eac h p ote ntial partici pa nt ( or eac h partici pa nt’s le gall y 
acce pta ble re prese ntati ve) pri or t o partici pati n g i n a cli nical st u d y. If t here are c ha n ges t o t he 
partici pa nt’s stat us d uri n g t he st u d y (e g, healt h or a ge of maj orit y re q uire me nts), t he 
i n vesti gat or or me dicall y q ualifie d desi g nee m ust e ns ure t he a p pr o priate c o nse nt is i n place.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1. 1. 1
Ge ner al I nf or me d C o nse nt
C o nse nt m ust be d oc u me nte d b y t he partici pa nt’s date d si g nat ure or b y t he partici pa nt’s 
le gall y acce pta ble re prese ntati ve’s date d si g nat ure o n a c o nse nt f or m al o n g wit h t he date d 
si g nat ure of t he pers o n c o n d ucti n g t he c o nse nt disc ussi o n.
A c o p y of t he si g ne d a n d date d c o nse nt f or m s h o ul d be gi ve n t o t he partici pa nt bef ore 
partici pati o n i n t he st u d y.
T he i nitial I C F, a n y s u bse q ue nt re vise d writte n I C F, a n d a n y writte n i nf or mati o n pr o vi de d t o 
t he partici pa nt m ust recei ve t he I R B/I E C’s a p pr o val/fa v ora ble o pi ni o n i n a d va nce of use. T he 
partici pa nt or t heir le gall y acce pta ble re prese ntati ve s h o ul d be i nf orme d i n a ti mel y ma n ner if 
ne w i nf or mati o n bec o mes a vaila ble t hat ma y be rele va nt t o t he partici pa nt’s willi n g ness t o 
c o nti n ue partici pati o n i n t he st u d y. T he c o m m u nicati o n of t his i nf or mati o n will be pr o vi de d 
a n d d oc u me nte d via a re vise d c o nse nt f or m or a d de n d u m t o t he ori gi nal c o nse nt f or m t hat 
ca pt ures t he partici pa nt’s date d si g nat ure or b y t he partici pa nt’s le gall y acce pta ble 
re prese ntati ve’s date d si g nat ure.
T he partici pa nt or t heir le gall y acce pta ble re prese ntati ve will be as ke d t o si g n c o nse nt after 
BI C R -verifie d disease pr o gressi o n if c o nti n ui n g o n st u d y treat me nt. As of A me n d me nt 0 4, 
dise ase pr o gressi o n will n o l o n ger be ce ntr all y verifie d, p artici p a nts will o nl y be 
assesse d l oc all y.
S pecifics a b o ut a st u d y a n d t he st u d y p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate 
at t he pr ot oc ol le vel.
T he i nf or me d c o nse nt will a d here t o I R B/I E C re q uire me nts, a p plica ble la ws a n d re g ulati o ns, 
a n d S p o ns or re q uire me nts .
8. 1. 2
I ncl usi o n/ E xcl usi o n Criteri a
All i ncl usi o n a n d e xcl usi o n criteria will be re vie we d b y t he i n vesti gat or, w h o is a q ualifie d 
p h ysicia n, t o e ns ure t hat t he partici pa nt q ualifies f or t he st u d y.
8. 1. 3
P artici p a nt I de ntific ati o n C ar d
All partici pa nts will be gi ve n a partici pa nt i de ntificati o n car d i de ntif yi n g t he m as partici pa nts 
i n a researc h st u d y. T he car d will c o ntai n st u d y-site c o ntact i nf or mati o n (i ncl u di n g direct 
tele p h o ne n u m bers) t o be use d i n t he e ve nt of a n e mer ge nc y. T he i n vesti gat or or q ualifie d 
desi g nee will pr o vi de t he partici pa nt wit h a partici pa nt i de ntificati o n car d i m me diatel y after 
t he partici pa nt pr o vi des writte n i nf or me d c o nse nt. At t he ti me of i nter ve nti o n ra n d o mizati o n,
site pers o n nel will a d d t he treat me nt/ra n d o mizati o n n u m ber t o t he partici pa nt i de ntificati o n 
car d.
T he partici pa nt i de ntificati o n car d als o c o ntai ns c o ntact i nf or mati o n f or t he e mer ge nc y 
u n bli n di n g call ce nter s o t hat a healt hcare pr o vi der ca n o btai n i nf or mati o n a b o ut st u d y 
i nter ve nti o n i n e mer ge nc y sit uati o ns w here t he i n vesti gat or is n ot a vaila ble.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1. 4
Me dic al Hist or y
A me dical hist or y will be o btai ne d b y t he i n vesti gat or or q ualifie d desi g nee. T he me dical 
hist or y will c ollect all acti ve c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n t he pri or 
1 0 years t hat t he i n vesti gat or c o nsi ders t o be cli nicall y si g nifica nt. Details re gar di n g t he 
disease f or w hic h t he partici pa nt has e nr olle d i n t his st u d y will be rec or de d se paratel y a n d 
n ot liste d as me dical hist or y.
8. 1. 5
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
8. 1. 5. 1
Pri or Me dic ati o ns
T he i n vesti gat or or q ualifie d desi g nee will re vie w pri or me dicati o n use, i ncl u di n g a n y 
pr ot oc ol -s pecifie d was h o ut re q uire me nt, a n d rec or d pri or me dicati o n ta ke n b y t he partici pa nt 
wit hi n 2 8 da ys bef ore starti n g t he st u d y. Treat me nt f or t he disease f or w hic h t he partici pa nt 
has e nr olle d i n t his st u d y will be rec or de d se paratel y a n d n ot liste d as a pri or me dicati o n.
8. 1. 5. 2
C o nc o mit a nt Me dic ati o ns
T he i n vesti gat or or q ualifie d desi g nee will rec or d me dicati o n, if a n y, ta ke n b y t he partici pa nt 
d uri n g t he st u d y t hr o u g h t he Safet y F oll o w -u p Visit. I n a d diti o n, ne w me dicati o ns starte d 
d uri n g t he Sec o n d C o ur se P hase t hr o u g h t he Sec o n d C o urse Safet y F oll o w-u p Visit s h o ul d 
be rec or de d.
8. 1. 6
Assi g n me nt of Scree ni n g N u m ber
All c o nse nte d partici pa nts will be gi ve n a u ni q ue scree ni n g n u m ber t hat will be use d t o 
i de ntif y t he partici pa nt f or all pr oce d ures t hat occ ur pri o r t o ra n d o mizati o n. Eac h partici pa nt 
will be assi g ne d o nl y 1 scree ni n g n u m ber. Scree ni n g n u m bers m ust n ot be re -use d f o r 
differe nt partici pa nts.
A n y partici pa nt w h o is scree ne d m ulti ple ti mes will retai n t he ori gi nal scree ni n g n u m ber 
assi g ne d at t he i nitial Scree ni n g Visit. Partici pa nts ma y be rescree ne d u p t o t w o ti mes after 
i nitiall y faili n g t o meet t he i ncl usi o n/e xcl usi o n criteria. S pecific details o n t he 
scree ni n g/rescree ni n g visit re q uire me nts are pr o vi de d i n Secti o n 8. 1 0 . 1.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1. 7
Assi g n me nt of Tre at me nt/ R a n d o miz ati o n N u m ber
All eli gi ble partici pa nts will be ra n d o ml y all ocate d a n d will recei ve a 
treat me nt/ra n d o mizati o n n u m ber. T he treat me nt/ra n d o mizati o n n u m ber i de ntifies t he 
partici pa nt f or all pr oce d ures occ urri n g after treat me nt ra n d o mizati o n. O nce a 
treat me nt/ra n d o mizati o n n u m ber is assi g ne d t o a partici pa nt, it ca n ne ver be re-assi g ne d t o 
a n ot her partici pa nt.
A si n gle partici pa nt ca n n ot be assi g ne d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber.
8. 1. 8 
St u d y I nter ve nti o n A d mi nistr ati o n
A d mi nistrati o n of pe m br oliz u ma b/ place b o will be m o nit ore d b y t he i n vesti gat or a n d/ or st u d y 
staff.
O n Da y 1 of eac h c ycle, st u d y i nter ve nti o n s h o ul d be a d mi nistere d after all pr oce d ures a n d 
assess me nts ha ve bee n c o m plete d. St u d y i nter ve nti o n ca n be a d mi nistere d ± 3 da ys of t he 
tar gete d Da y 1 f or eac h c ycle, e xce pt C ycle 1 w here treat me nt ca n o nl y be a d mi nistere d + 3 
da ys of t he tar gete d Da y 1.
8. 1. 8. 1
Ti mi n g of D ose A d mi nistr ati o n
8. 1. 8. 1. 1
Pe m br oliz u m a b/ Pl ace b o
Pe m br oliz u ma b/ place b o treat me nts will be gi n o n Da y 1 of eac h c ycle after all pre d ose st u d y 
pr oce d ures a n d assess me nts ha ve bee n c o m plete d as detaile d i n t he S o A. 
Pe m br oliz u ma b will be a d mi nistere d as a fi xe d -d ose of 2 0 0 m g usi n g a 3 0 -mi n ute I V 
i nf usi o n Q 3 W. Sites s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n ti mi ng t o be as cl ose t o 
3 0 mi n utes as p ossi ble. H o we ver, gi ve n t he varia bilit y of i nf usi o n p u m ps fr o m site t o site, a 
wi n d o w of -5 mi n utes a n d + 1 0 mi n utes is per mitte d (ie, i nf usi o n ti me is 
3 0 mi n utes - 5 mi n/ + 1 0 mi n).
8. 1. 8. 1. 2
E nz al ut a mi de
E nzal uta mi de will be a d mi nist ere d at a d ose of 1 6 0 m g (f o ur 4 0 -m g ca ps ules/ta blets or t w o 
8 0 -m g ta blets) orall y Q D. E nzal uta mi de treat me nt s h o ul d be gi n o n t he sa me da y as C ycle 1, 
Da y 1 of pe m br oliz u ma b/ place b o treat me nt, wit h t he first d ose a d mi nistere d after t he e n d of 
t he pe m br olizu ma b/ place b o I V i nf usi o n.
S u bse q ue nt e nzal uta mi de treat me nts will be ta ke n P O Q D at a p pr o xi matel y t he sa me ti me 
eac h da y o n a c o nti n u o us dail y d osi n g sc he d ule. Ca ps ules/ta blets ca n be ta ke n wit h or 
wit h o ut f o o d. Ca ps ules/ta blets m ust be s wall o we d w h ole a n d s h o ul d n ot be c he we d, 
diss ol ve d, or o pe ne d.
Partici pa nts m ust be i nstr ucte d t hat if t he y miss a d ose, or v o mit at a n y ti me after ta ki n g a 
d ose, t he y s h o ul d ta ke t heir ne xt d ose at its sc he d ule d ti me. T he site will vali date c o m plia nce 
wit h st u d y i nter ve nti o n (i ncl u di n g misse d or v o mite d d oses) at eac h site visit acc or di n g t o 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
t heir sta n dar d o perati n g pr oce d ure. If d oses are misse d or v o mite d, t his m ust be i n dicate d i n 
t he s o urce d oc u me nts a n d C R Fs.
8. 1. 8. 1. 3
A D T
All partici pa nts will recei ve a n d re mai n o n a s ta ble re gi me n of A D T ( L H R H a g o nist or 
a nta g o nist) or ha ve s ur gical castrati o n. D ose a n d fre q ue nc y of a d mi nistrati o n will be 
c o nsiste nt wit h l ocal pr o d uct la bel a n d s h o ul d n ot c ha n ge d uri n g t he st u d y.
8. 1. 9
Disc o nti n u ati o n a n d Wit h dr a w al
Partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n pri or t o c o m pleti o n of t he treat me nt peri o d
s h o ul d be e nc o ura ge d t o c o nti n ue t o be f oll o we d f or all re mai ni n g st u d y visits as o utli ne d i n 
t he S o A a n d Secti o n 8. 1 0 . 3.
W he n a partici pa nt wit h dra ws fr o m partici pati o n i n t he st u d y all a p plica ble acti vities 
sc he d ule d f or t he fi nal st u d y visit s h o ul d be perf or me d (at t he ti me of wit h dra wal). A n y A Es 
t hat are prese nt at t he ti me of wit h dra wal s h o ul d be f oll o we d i n acc or da nce wit h t he safet y 
re q uire me nts o utli ne d i n Secti o n 8 . 4.
8. 1. 1 0
P artici p a nt Bli n di n g/ U n bli n di n g
As of I A 1, t he st u d y w as u n bli n de d. T he s u bsecti o ns bel o w are ret ai ne d f or refere nce.
S T U D Y I N T E R V E N TI O N I D E N TI FI C A TI O N I N F O R M A TI O N I S T O B E U N B LI N D E D
O N L Y I F N E C E S S A R Y F O R T H E W E L F A R E O F T H E P A R TI CI P A N T. E V E R Y 
E F F O R T S H O U L D B E M A D E N O T T O U N B LI N D.
F or e mer ge nc y sit uati o ns w here t he i n vesti gat or or me dicall y q ualifie d desi g nee (c o nsiste nt 
wit h l ocal re q uire me nts) nee ds t o i de ntif y t he i nter ve nti o n use d b y a partici pa nt a n d/ or t he 
d osa ge a d mi nistere d, t he i n vesti gat or will c o ntact t he e mer ge nc y u n bli n di n g call ce nter b y 
tele p h o ne a n d ma ke a re q uest f or e mer ge nc y u n bli n di n g. As re q ueste d b y t he i n vesti gat or or 
me dicall y q ualifie d desi g nee, t he e mer ge nc y u n bli n di n g call ce nter will pr o vi de t he 
i nf or mati o n t o t he m pr o m ptl y a n d re p ort u n bli n di n g t o t he S p o ns or. Pri or t o c o ntacti n g t he 
e mer ge nc y u n bli n di n g call ce nter t o re q uest u n bli n di n g of a partici pa nt’s i nter ve nti o n 
assi g n me nt, t he i n vesti gat or w h o is a q ualifie d p h ysicia n s h o ul d ma ke reas o na ble atte m pts t o 
e nter t he t o xicity gra de of t he A Es o bser ve d, t he relati o n t o st u d y dr u g , t he reas o n t here of, 
etc, i n t he me dical c hart. If it is n ot p ossi ble t o rec or d t his assess me nt i n t he c hart pri or t o t he 
u n bli n di n g, t he u n bli n di n g s h o ul d n ot be dela ye d.
In t he e ve nt t hat u n bli n di n g has occ urre d, t he circ u msta nces ar o u n d t he u n bli n di n g (e g, date, 
reas o n, a n d pers o n perf or mi n g t he u n bli n di n g) m ust be d oc u me nte d pr o m ptl y, a n d t he 
S p o ns or Cli nical Direct o r n otifie d as s o o n as p ossi ble.
O nce a n e mer ge nc y u n bli n di n g has ta ke n place, t he pri nci pal i n vesti gat or, site pers o n nel, a n d 
S p o ns or pers o n nel ma y be u n bli n de d s o t hat t he a p pr o priate f oll o w -u p me dical care ca n be 
pr o vi de d t o t he partici pa nt.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Partici pa nts w h ose treat me nt assi g n me nt has bee n u n bli n de d b y t he i n vesti gat or or me dicall y 
q ualifie d desi g n ee a n d/ or n o nst u d y treati n g p h ysicia n m ust be disc o nti n ue d fr o m st u d y 
i nter ve nti o n b ut s h o ul d c o nti n ue t o be m o nit ore d i n t he st u d y.
8. 1. 1 0. 1
N o n- e mer ge nc y U n bli n di n g
I n t he e ve nt of P D, t here ma y be a nee d t o u n bli n d t he partici pa nt’s treat me nt assi g n me nt 
pri or t o i nitiati n g Sec o n d C o urse Treat me nt ( Secti o n 8. 1 0. 2. 3). I n t his circ u msta nce, 
u n bli n di n g t o pe m br oliz u ma b vers us place b o a d mi nistrati o n ma y occ ur o n a n i n di vi d u al 
basis a n d o nl y after c o ns ultati o n wit h t he S p o ns or Cli nical Direct or. E ver y eff ort s h o ul d be 
ma de n ot t o u n bli n d t he partici pa nt u nless necessar y.
8. 1. 1 1
C ali br ati o n of E q ui p me nt
T he i n vesti gat or or q ualifie d desi g nee has t he res p o nsi bilit y t o e ns ure t hat a n y de vice or 
i nstr u me nt use d f or a cli nical e val uati o n/test d uri n g a cli nical st u d y t hat pr o vi des i nf or mati o n 
a b o ut i ncl usi o n/e xcl usi o n criteria a n d/ or safet y or efficac y para meters s hall be s uita bl y 
cali brate d a n d/ or mai ntai ne d t o e ns ure t hat t he data o btai n e d are relia ble a n d/ or re pr o d uci ble. 
D oc u me ntati o n of e q ui p me nt cali brati o n m ust be retai ne d as s o urce d oc u me ntati o n at t he 
st u d y site.
8. 2 
Effic ac y/I m m u n o ge nicit y Assess me nts
8. 2. 1
T u m or I m a gi n g a n d Assess me nt of Dise ase
As of A me n d me nt 0 4 : Ce ntr al t u m or res p o nse assess me nts will be disc o nti n ue d. 
I m a gi n g sc a ns will n o l o n ger be s u b mitte d t o i C R O n or re a d b y BI C R. L oc al t u m or 
i m a gi n g s h o ul d c o nti n ue per S O C sc he d ule f or p artici p a nts still o n st u d y tre at me nt.
T he s u bsecti o ns bel o w are ret ai ne d f or refere nce.
T he pr oce ss f or i ma ge c ollecti o n a n d tra ns missi o n t o t he ce ntral i ma gi n g ve n d or ca n be 
f o u n d i n t he SI M. T u m or i ma gi n g is as f oll o ws: 
•
C hest, a b d o me n, a n d pel vis sca ns are re q uire d f or all partici pa nts at Scree ni n g a n d o n 
st u d y. C T wit h I V a n d oral c o ntrast is preferre d or n o n-c o ntrast C T of t he c hest a n d M RI 
of t he a b d o me n a n d pel vis wit h I V ga d oli ni u m f or partici pa nts i n w h o m i o di nate d 
c o ntrast is c o ntrai n dicate d, or w he n ma n date d b y l ocal practice. 
•
B o ne sca n ( b o ne sci nti gra p h y, ra di o n ucli de b o ne sca n, etc.) of t he w h ole b o d y is re q uire d 
f or all partici pa nts at Scree ni n g a n d o n st u d y f or all sc he d ule d i ma gi n g visits. 
◦
Ot her b o ne i ma gi n g m o dalities (ie, F D G -P E T, P S M A P E T, M RI, S P E C T, etc.) 
ca n n ot be a s u bstit ute f or t he b o ne sca n ( A p pe n di x 8, Secti o n 1 0. 8. 1). 
•
Brai n i ma gi n g is o nl y as cli nicall y i n dicate d at baseli ne a n d o n st u d y. M RI (str o n gl y 
preferre d) or C T wit h c o ntrast of t he brai n.
•
A d diti o nal i ma gi n g ac q uire d as per sta n dar d of care or as cli nicall y i n dicate d, use d t o 
s u p p ort ra di o gra p hic disease pr o gressi o n or efficac y assess me nts, s h o ul d be se nt t o t he 
i C R O.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
T he sa me i ma gi n g tec h ni q ue re gar di n g m o dalit y, i deall y t he sa me sca n ner, a n d t he use of 
c o ntrast s h o ul d be use d i n a partici pa nt t hr o u g h o ut t he st u d y t o o pti mize t he re pr o d uci bilit y 
of t he assess me nt of e xisti n g a n d ne w t u m or b ur de n a n d i m pr o ve t he acc urac y of t he 
assess me nt of res p o nse or pr o gressi o n base d o n i ma gi n g. 
N ote: F or t he p ur p oses of assessi n g t u m or i ma gi n g, t he ter m “i n vesti gat or” refers t o t he 
l ocal i n vesti gat or at t he site a n d/ or t he ra di ol o gical re vie wer at t he site or at a n offsite 
facilit y.
At Scree ni n g, partici pa nt eli gi bilit y will re q uire ra di o gra p hic d oc u me n tati o n usi n g l ocal 
assess me nt (i n vesti gat or assess me nt) t hat is verifie d b y t he BI C R. W he n t he i n vesti gat or 
i de ntifies baseli ne metastatic disease, t he ce ntral i ma gi n g ve n d or will perf or m a n e x pe dite d 
verificati o n of eli gi bilit y t hat t he partici pa nt’s i ma g i n g s h o ws at least 2 b o ne lesi o ns o n b o ne 
sca n a n d/ or visceral disease (e g, l u n g or li ver) b y C T/ M RI per P C W G-m o difie d R E CI S T 1. 1 
a n d will c o m m u nicate t he res ults t o t he st u d y site a n d s p o ns or w hic h is re q uire d pri or t o 
partici pa nt ra n d o mizati o n. Partici pa nts w h ose metastatic disease is li mite d t o l y m p h n o des 
are n ot eli gi ble.
U p o n i n vesti gat or -assesse d disease pr o gressi o n, t he i n dicati ve sca ns are t o be s u b mitte d 
i m me diatel y t o i C R O f or BI C R verificati o n of pr o gressi o n. After s u b missi o n of sca ns, t he 
i C R O will e mail t he assess me nt t o t he site a n d S p o ns or.
•
If disease pr o gressi o n is n ot verifie d, t he pr ocess c o nti n ues as f oll o ws: If partici pa nt is 
cli nicall y sta ble, c o nti n ue st u d y i nter ve nti o n per pr ot oc ol
-
Res u me i ma gi n g per pr ot oc ol sc he d ule 
-
Se n d sca ns t o i C R O
-
C o nti n ue l ocal assess me nt
-
D o n ot c ha n ge i n vesti gat or assess me nt of pr o gressi o n
-
If s u bse q ue nt sca n(s) i n dicate pr o gressi o n, s u b mit sca ns t o i C R O t o re q uest 
verificati o n
•
If t he partici pa nt is n ot cli nicall y sta ble, best me dical practice is t o be a p plie d
Bef ore st o p pi n g st u d y i nter ve nti o n or i m a gi n g or st arti n g ne w a ntic a ncer t her a p y i n a 
p artici p a nt w h o is cli nic all y st a ble, c o m m u nic ati o n wit h t he S p o ns or is re q uire d.
If disease pr o gressi o n is verifie d, t he pr ocess c o nti n ues as f oll o ws:
•
I n vesti gat or j u d gme nt will deter mi ne acti o n
•
If t he partici pa nt is cli nicall y sta ble a n d st u d y i nter ve nti o n is t o c o nti n ue, c o m m u nicati o n 
wit h t he S p o ns or is re q uire d a n d a c o nse nt a d de n d u m m ust be si g ne d
N ote: t he c o nse nt a d de n d u m m ust be si g ne d pri or t o starti n g st u d y i nt er ve nti o n after 
verificati o n of disease pr o gressi o n is pr o vi de d b y t he i C R O.
•
O btai n sca ns l ocall y per ori gi nal pr ot oc ol sc he d ule
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
D o n ot se n d sca ns t o i C R O
•
F or t he p ur p ose of t his decisi o n pr ocess, lac k of cli nical sta bilit y is defi ne d as:
-
U nacce pta ble t o xicit y
-
Cli nical si g ns or s y m pt o ms i n dicati n g cli nicall y si g nifica nt disease pr o gressi o n
-
Decli ne i n perf or ma nce stat us
-
Ra pi d disease pr o gressi o n or t hreat t o vital or ga ns or critical a nat o mical sites (e g, 
C N S metastasis, res pirat or y fail ure d ue t o t u m or c o m pressi o n, s pi nal c or d 
c o m pressi o n) re q uiri n g ur ge nt alter nati ve me dical i nter ve nti o n.
T he pri mar y meas ure use d b y BI C R f or assess me nt of t u m or res p o nse, date of disease 
pr o gressi o n, a n d as a basis f or all pr ot oc ol g ui deli nes relate d t o disea se stat us (e g, 
disc o nti n uati o n of st u d y i nter ve nti o n) will be P C W G -m o difie d R E CI S T 1. 1. P C W G P D u is 
n ot c o nsi dere d ra di o gra p hic P D.
Assess me nt of treat me nt res p o nse i n t he s oft tiss ues will be acc or di n g t o s oft tiss ue r ules of 
P C W G -m o difie d R E CI S T 1. 1, m o d ifie d t o f oll o w a ma xi m u m of 1 0 tar get s oft tiss ue lesi o ns 
a n d a ma xi m u m of 5 tar get lesi o ns per or ga n. Assess me nt of treat me nt res p o nse i n b o ne will 
be acc or di n g t o t he b o ne lesi o n r ules of P C W G -m o difie d R E CI S T 1. 1, as descri be d i n 
A p pe n di x 8.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
S oft tiss ue a n d b o ne res p o nse assess me nts will be c o m bi ne d t o pr o d uce a n o verall 
ra di o gra p hic res p o nse, as f oll o ws:
S oft Tiss ue Res p o nse
B o ne Sc a n Res ult
P C W G -m o difie d R E CI S T 1. 1 Ti me 
P oi nt Res p o nse E ntere d I nt o C R F
P D
A n y
P D
A n y
P D
P D
A n y (e xce pt P D)
P D u
P D u
N E
N o n -P D, N E D or N E
N E
N E D
N E
N E
N E D
N o n -P D
N o n -C R/ N o n -P D
N E D
N E D
N E D
S D
N o n -P D, N E D, or N E *
S D
N o n -C R/ N o n -P D 
N o n -P D, N E D, or N E *
N o n -C R/ N o n -P D
P R
N o n -P D, N E D or N E *
P R
C R
N o n -P D or N E *
P R 
(if tar get lesi o ns were prese nt at 
baseli ne)
N o n -C R/ N o n -P D 
(if n o tar get lesi o ns at baseli ne)
C R
N E D
C R
A b bre viati o ns: C R  c o m plete res p o nse; C R F  case re p ort f or m; N E  n o n e val ua ble; N E D  n o e vi de nce of disease; 
P C W G  Pr ostate Ca ncer W or ki n g Gr o u p; P D  pr o gressi ve disease; P D u  pr o gressi ve disease u nc o nfir me d; P R  
partial res p o nse; R E CI S T 1. 1  Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1. 
* If t he b o ne sca n is e ntirel y missi n g or was n ot d o ne, a n d b o ne lesi o ns were prese nt at baseli ne, t he n t he o verall 
res p o nse is n o n e val ua ble.
8. 2. 1. 1
I niti al T u m or I m a gi n g
I nitial t u m or i ma gi n g at Scree ni n g m ust be perf or me d wit hi n 4 2 da ys pri or t o t he date of 
ra n d o mizati o n. T u m or i ma gi n g b y C T ( or M RI) a n d ra di o n ucli de b o ne sca n is re q uire d at 
Scree ni n g.
Sca ns perf or me d as part of r o uti ne cli nical ma na ge me nt are acce pta ble f or use as t he 
scree ni n g sca ns if t he y are of dia g n ostic q ualit y a n d perf or me d wit hi n 4 2 da ys pri or t o t he 
date of ra n d o mizati o n. Sca ns are re q uire d t o be se nt t o t he ce ntral i ma gi ni n g v e n d or a n d 
verifie d f or eli gi bilit y pri or t o ra n d o mizati o n. 
At Scree ni n g, all s oft tiss ue lesi o ns see n b y C T ( or M RI) a n d all b o ne lesi o ns see n b y 
ra di o n ucli de b o ne sca n will be d oc u me nte d. I n deter mi ni n g res p o nse t o treat me nt or 
pr o gressi o n, i n vesti gat ors m ust e val uate all tar get a n d n o n -tar get lesi o ns a n d searc h f or ne w 
lesi o ns at eac h i ma gi n g ti me p oi nt.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 2. 1. 2
T u m or I m a gi n g D uri n g t he St u d y
O n st u d y i ma gi n g assess me nts m ust be perf or me d e ver y 1 2 wee ks ( 8 4 da ys ± 7 da ys) fr o m 
t he date of ra n d o mizati o n. All s u p ple me ntal i ma gi n g m ust be s u b mitte d t o t he ce ntral 
i ma gi n g ve n d or.
Ti mi n g of i ma gi n g s h o ul d f oll o w cale n dar da ys fr o m date of ra n d o mizati o n a n d s h o ul d n ot 
be a dj uste d f or dela ys i n c ycle starts. Res p o nse m ust be c o nfir me d at least 4 wee ks later t o be 
c o nsi dere d f or best o verall res p o nse.  
Ra di o gra p hic pr o gressi o n will be deter mi ne d acc or di n g t o P C W G -m o difie d R E CI S T 1. 1. 
Disease pr o gressi o n i n b o ne lesi o ns s h o ul d be c o nfir me d b y a n ot her b o ne sca n ≥6 wee ks 
after site assesse d first ra di o gra p hic e vi de nce of di sease pr o gressi o n.
8. 2. 1. 3
E n d -of - Tre at me nt a n d F oll o w -u p T u m or I m a gi n g
F or partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n, t u m or i ma gi n g s h o ul d be perf or me d at 
t he ti me of treat me nt disc o nti n uati o n ( ± 4 wee k wi n d o w). If pre vi o us i ma gi n g was o btai ne d 
wit hi n 4 wee k s pri or t o t he date of disc o nti n uati o n, t he n i ma gi n g at treat me nt disc o nti n uati o n 
is n ot ma n dat or y. F or partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n d ue t o BI C R-verifie d 
disease pr o gressi o n, t his is t he fi nal re q uire d t u m or i ma gi n g.
If partici pa nts disco nti n ue st u d y i nter ve nti o n wit h o ut d oc u me nte d disease pr o gressi o n, e ver y 
eff ort is t o be ma de t o m o nit or disease stat us b y ac q uiri n g t u m or sca ns usi n g t he sa me 
sc he d ule (e ver y 1 2 wee ks) calc ulate d fr o m t he date of ra n d o mizati o n (see Secti o n 8. 2. 1. 2 ).
Sca ns are t o be c o nti n ue d u ntil o ne of t he f oll o wi n g c o n diti o ns are met:
•
disease pr o gressi o n as defi ne d b y P C W G M o difie d R E CI S T 1. 1 v erifie d b y BI C R
•
t he start of a ne w a ntica ncer treat me nt
•
deat h
•
wit h dra wal of c o nse nt
•
t he e n d of t he st u d y
8. 2. 1. 4
Sec o n d C o urse ( Ret re at me nt) T u m or I m a gi n g
T u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt wit h 
pe m br oliz u ma b . L ocal rea di n g (i n vesti gat or assess me nt wit h site ra di ol o g y rea di n g) will be 
use d t o deter mi ne eli gi bilit y.
Res p o nse assess me nts a n d pr o gressi ve disease are deter mi ne d b y i n vesti gat or assess me nt.
T he o nl y Sec o n d C o urse sca n t o be pr o vi de d t o t he i C R O is t he baseli ne sca n if it is t he fi nal 
sca n f or t he I nitial Treat me nt P hase or E xte nsi o n First C o urse.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
9 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
T he first o n -st u d y i ma gi n g assess me nt s h o ul d be perf or me d at 1 2 wee ks ( 8 4 da ys ± 7 da ys) 
after t he restart of treat me nt. S u bse q ue nt t u m or i ma gi n g s h o ul d be perf or me d e ver y 1 2 wee ks 
( 8 4 da ys ± 7 da ys) or m ore fre q ue ntl y, if cli nicall y i n dicate d.
F or partici pa nts w h o disc o nti n ue Sec o n d C o urse st u d y i nter ve nti o n, t u m or i ma gi n g s h o ul d be 
perf or me d at t he ti me of i nter ve nti o n disc o nti n uati o n ( ± 4 wee k wi n d o w). If pre vi o us i ma gi n g 
was o btai ne d wit hi n 4 wee ks pri or t o t he date of disc o nti n uati o n, t he n i ma gi n g at i nter ve nti o n 
disc o nti n uati o n is n ot ma n dat or y. F or partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n d ue t o 
d oc u me nte d disease pr o gressi o n, t his is t he fi nal re q uire d t u m or i ma gi n g.
F or partici pa nts w h o disc o nti n ue Sec o n d C o urse st u d y i nter ve nti o n wit h o ut d oc u me nte d 
disease pr o gressi o n, e ver y eff ort s h o ul d be ma de t o c o nti n ue m o nit ori n g t heir disease stat us 
b y ra di ol o gic i ma gi n g e ver y 1 2 wee ks ( 8 4 da ys ± 7 da ys) u ntil eit her t he start of a ne w 
a ntica ncer treat me nt, disease pr o gressi o n, deat h, or t he e n d of t he st u d y, w hic he ver occ urs 
first.
8. 2. 1. 5
S y m pt o m atic S kelet al -Rel ate d E ve nt ( S S R E) Assess me nt
As of A me n d me nt 0 4: S S R E assess me nts will be disc o nti n ue d. T he secti o n bel o w is
ret ai ne d f or refere nce.
Partici pa nts will be assesse d f or S S R E as detaile d i n t he S o A ( Secti o n 1. 3). Ti me fr o m 
ra n d o mizati o n t o first S S R E is defi ne d b y a n y of t he f oll o wi n g or a c o m bi nati o n: 
•
Use of E B R T t o pre ve nt or relie ve s keletal s y m pt o ms. 
•
Occ urre nce of ne w s y m pt o matic pat h ol o gic b o ne fract ure ( verte bral or n o n -verte bral). 
Ra di ol o gic d oc u me ntati o n is re q uire d. 
•
Occ urre nce of s pi nal c or d c o m pressi o n. Ra di ol o gic d oc u me ntati o n is re q uire d.
•
Or t u m or -relate d ort h o pe dic s ur gical i nter ve nti o n, w hic he ver occ urs first.
Partici pa nts wit h ne w s y m pt o matic pat h ol o gical b o ne fract ures a n d s pi nal c or d c o m pressi o n 
will re q uire ra di ol o gic d oc u me ntati o n. I ma gi n g m o dalit y use d t o assess t he S S R E is at t he 
discreti o n of t he I n vesti gat or. All S S R E -relate d i ma gi n g s h o ul d be s u b mitte d t o t he i C R O f or 
q ualit y c o ntr ol, st ora ge, a n d p ossi ble retr os pecti ve re vie w.
8. 2. 2
Pr ost ate -s pecific A nti ge n Assess me nts
As of A me n d me nt 0 4: Pr ost ate -s pecific a nti ge n assess me nts will be disc o nti n ue d. T he 
secti o n bel o w is ret ai ne d f or refere nce.
Ce ntral la b orat or y P S A asse ss me nt m ust occ ur acc or di n g t o t he S o A ( Secti o n 1. 3 S o A 
ta bles). P S A ti mi n g s h o ul d f oll o w cale n dar da ys a n d s h o ul d n ot be a dj uste d f or dela ys i n 
c ycle starts.
I n partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n wit h o ut BI C R-verifie d disease 
pr o gressi o n, e ve r y eff ort s h o ul d be ma de t o c o nti n ue m o nit ori n g t heir disease stat us b y P S A 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
assess me nts u ntil: 1) t he start of ne w a ntica ncer treat me nt, 2) ra di o gra p hic disease 
pr o gressi o n, 3) deat h or 4) t he e n d of t he st u d y, w hic he ver occ urs first. I n t hese partici pa nts , 
P S A will be meas ure d b y a ce ntral la b orat or y.
Sa m ple c ollecti o n, st ora ge, a n d s hi p me nt i nstr ucti o ns will be i n t he Pr oce d ures Ma n ual. T he 
wi n d o w f or P S A c ollecti o ns is ± 7 da ys.
8. 2. 3
T u m or Tiss ue C ollecti o n
Partici pa nts m ust pr o vi de a t u m or tiss ue fr o m a ne wl y o btai ne d c ore or e xcisi o nal bi o ps y 
( o btai ne d wit hi n 1 2 m o nt hs of Scree ni n g) fr o m s oft tiss ue n ot pre vi o usl y irra diate d (sa m ples 
fr o m t u m ors pr o gressi n g i n a pri or site of ra diati o n are all o we d; ot her e xce pti o ns ma y be 
c o nsi dere d after S p o ns or c o ns ultati o n ). Partici pa nts wit h b o ne o nl y or b o ne pre d o mi na nt 
disease ma y pr o vi de a b o ne bi o ps y sa m ple ( decalcificati o n n ot all o we d). H o we ver, if 
o btai ni n g a ne w bi o ps y is n ot feasi ble, t he n partici pa nts ma y pr o vi de a n arc hi val t u m or tiss ue 
sa m ple after S p o ns or c o ns ultati o n. F F P E tiss ue bl oc ks are preferre d t o sli des. Ne wl y 
o btai ne d bi o psies are preferre d t o arc hi ve tiss ue. 
A de q uac y of t hese s peci me ns f or P D -L 1 bi o mar ker a nal ysis will be re q uire d b y a ce ntral 
la b orat or y pri or t o ra n d o mizati o n.
8. 2. 4
P atie nt -re p orte d O utc o m es a n d Q u alit y of Life Assess me nts
As of A me n d me nt 0 4: P R Os a n d Q u alit y of Life assess me nts will be disc o nti n ue d. T he 
s u bsecti o ns bel o w are ret ai ne d f or refere nce.
T he B PI -S F , F A C T-P, a n d E Q -5 D -5 L q uesti o n naires s h o ul d be a d mi nistere d at t he site per 
t he So A i n Secti o n 1. 3. Partici pa nts m ust c o m plete t he P R O q uesti o n naires i n t he f oll o wi n g 
or der: B PI -S F, F A C T -P, E Q -5 D -5 L.
It is best practice a n d str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d t o ra n d o mize d 
partici pa nts pri or t o dr u g a d mi nistrati o n, A E e val uati o n, a n d disease stat us n otificati o n. If t he 
partici pa nt d oes n ot c o m plete t he e P R Os at a sc he d ule d ti me p oi nt, t he MI S S _ M O D E f or m 
m ust be c o m plete d t o ca pt ure t he reas o n t he assess me nt was n ot perf or me d.
Site staff m ust n ot rea d, a d mi nister or c o m plete t he P R O q uesti o n naires o n be half of t he 
partici pa nt. If t he partici pa nt is u na ble t o rea d t he q uesti o n naire (e g, is bli n d or illiterate), t hat 
partici pa nt ma y still partici pate i n t he st u d y, b ut is e xe m pt fr o m c o m pleti n g P R O 
q uesti o n naires. Partici pa nts e xe m pt i n t his re gar d s h o ul d be fla g ge d a p pr o priatel y b y t he site 
staff.
8. 2. 4. 1
B PI -S F 
T he B PI -S F  is pr o vi de d o n a n e P R O de vice at t he site a n d will be c o m plete d b y t he 
partici pa nt at t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3) . 
T he B PI -S F  has 1 5 ite ms t hat are rate d o n a 0 t o 1 0 n u meric rati n g scale, wit h 0 N o Pai n a n d 
1 0
W orst Pai n I ma gi na ble. T his i nstr u me nt c o nsists of 2 d o mai ns: pai n se verit y a n d pai n 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 3. 1
P h ysic al E x a mi n ati o ns
T he i n vesti gat or or q ualifie d desi g nee will perf or m a c o m plete p h ysical e xa m d uri n g t he 
Scree ni n g peri o d. Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical 
hist or y. T he ti me p oi nts f or f ull p h ysical e xa ms are descri be d i n Secti o n 1. 3. Aft er t he first 
d ose of st u d y i nter ve nti o n, ne w cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d 
as A Es.
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
8. 3. 1. 1 
F ull P h ysic al E x a mi n ati o n
T he i n vesti gat or or q ualifie d desi g nee will perf or m a c o m plete p h ysical e xa m d uri n g t he 
Scree ni n g peri o d. Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical 
hist or y. T he ti me p oi nts f or f ull p h ysical e xa ms are descri be d i n Secti o n 1. 3 . After t he first 
d ose of st u d y i nter ve nti o n, ne w cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d 
as A Es.
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
8. 3. 1. 2
Directe d P h ysic al E x a mi n ati o n
F or c ycles t hat d o n ot re q uire a f ull p h ysical e xa m as defi ne d i n Secti o n 1. 3, t he i n vesti gat or 
or q ualifie d desi g nee will perf or m a directe d p h ysical e xa m as cli nicall y i n dicate d pri or t o 
st u d y i nter ve nti o n a d mi nistrati o n. Ne w cli nicall y si g nifica nt a b n or mal fi n di ngs s h o ul d be 
rec or de d as A Es.
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
8. 3. 2
Vit al Si g ns
Vital si g ns will be meas ure d i n a sitti n g, se mi -rec u m be nt or s u pi ne p ositi o n after 5 mi n utes 
rest a n d will i ncl u de wei g ht, te m perat ure, s yst olic a n d diast olic bl o o d press ure, heart, a n d 
res pirat or y rate. Rec or d vital si g ns pri or t o st u d y i nter ve nti o n a d mi nistrati o n at treat me nt 
visits. Hei g ht will be meas ure d at Scree ni n g o nl y.
8. 3. 3
Electr oc ar di o gr a ms
A sta n dar d 1 2- lea d E CG will be perf or me d o nce at t he Scree ni n g Visit usi n g l ocal sta n dar d 
pr oce d ures. Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical hist or y.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 3. 4
Cli nic al S afet y L a b or at or y Assess me nts
Refer t o A p pe n di x 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he S o A f or 
t he ti mi n g a n d fre q ue nc y.
•
T he i n vesti gat or or me dicall y q ualifie d desi g nee (c o nsiste nt wit h l ocal re q uire me nts) 
m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y cli nicall y 
rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. T he la b orat or y 
re p orts m ust be file d wit h t he s o urce d oc u me nts. 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 w hic h 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 vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n.
•
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he S o A.
•
If la b orat or y val ues fr om n o n pr ot oc ol -s pecifie d la b orat or y assess me nts perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n st u d y partici pa nt ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or (e g, S A E or A E or d ose 
m o dificati o n), t he n t he res u lts m ust be rec or de d i n t he a p pr o priate C R F (e g, S L A B).
•
F or a n y 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 pati o n i n t he st u d y or wit hi n 3 0 da ys after t he last d ose of st u d y i nter ve nti o n, e ver y 
atte m pt s h o ul d be ma de t o perf or m re peat assess me nts u ntil t he val ues ret ur n t o n or mal or 
baseli ne or if a ne w baseli ne is esta blis he d as deter mi ne d b y t he i n vesti gat or .
Details re gar di n g s pecific la b orat or y pr oce d ures/assess me nts t o be perf or me d i n t his st u d y 
are pr o vi de d bel o w. T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver t he c o urse 
of t he st u d y (fr o m prest u d y t o p ostst u d y visits), i ncl u di n g a p pr o xi mate bl o o d/tiss ue v ol u mes 
dra w n/c ollecte d b y visit a n d b y sa m ple t y pe per partici pa nt ca n be f o u n d i n t he St u d y 
Pr oce d ures Ma n ual. Refer t o t he Secti o n 1. 3 f or t he ti mi n g of la b orat or y assess me nts.
8. 3. 4. 1
L a b or at or y S afet y E v al u ati o ns ( He m at ol o g y, C he mistr y a n d Uri n al ysis)
La b orat or y tests f or he mat ol o g y, c he mistr y, a n d uri nal ysis are s pecifie d i n A p pe n di x 2 .
8. 3. 5
Perf or m a nce Assess me nts
8. 3. 5. 1
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce Sc ale
T he i n vesti gat or or q ualifie d desi g nee will assess E C O G stat us (see A p pe n di x 1 1 ) at 
S cree ni n g a n d pri or t o t he a d mi nistrati o n of eac h d ose of st u d y i nter ve nti o n as s pecifie d i n 
t he S o A ( Secti o n 1. 3 ).
8. 4
A d verse E ve nts, Seri o us A d verse E ve nts, a n d Ot her Re p ort a ble S afet y E ve nts
T he defi niti o ns of a n A E or S A E, as well as t he met h o d of rec or di n g, e val uati n g, a n d 
assessi n g ca usalit y of A E a n d S A E a n d t he pr oce d ures f or c o m pleti n g a n d tra ns mitti n g A E, 
S A E, a n d ot her re p orta ble safet y e ve nt re p orts ca n be f o u n d i n A p pe n di x 3 .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A d verse e ve nts, S A Es, a n d ot her re p orta ble safet y e ve nts will be re p orte d b y t he part ici pa nt 
( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he partici pa nt’s le gall y a ut h orize d 
re prese ntati ve).
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E as well as ot her re p orta ble safet y e ve nts. 
I n vesti gat ors nee d t o d oc u me nt if a n S A E was ass ociate d wit h a me dicati o n err or, mis use, or 
a b use.
I n vesti gat ors re mai n res p o nsi ble f or f oll o wi n g u p A Es, S A Es, a n d ot her re p orta ble safet y 
e ve nts f or o utc o me acc or d i n g t o Secti o n 8. 4. 3 . T he i n vesti gat or, w h o is a q ualifie d p h ysicia n, 
will assess e ve nts t hat meet t he defi niti o n of a n A E or S A E as well as ot her re p orta ble safet y 
e ve nts wit h res pect t o seri o us ness, i nte nsit y/t o xicit y , a n d ca usalit y.
8. 4. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E, a n d Ot her Re p ort a ble 
S afet y E ve nt I nf or m ati o n
All A Es, S A Es, a n d ot her re p orta ble safet y e ve nts t hat occ ur after t he i nf or me d c o nse nt f orm
is si g ne d, b ut bef ore i nter ve nti o n ra n d o mizati o n, m ust be re p orte d b y t he i n vesti gat or if t he 
partici pa nt is recei vi n g place b o r u n -i n or ot her r u n-i n treat me nt, if t he e ve nt ca use t he 
partici pa nt t o be e xcl u de d fr o m t he st u d y, or is t he res ult of a pr ot oc ol -s pecifie d i nter ve nti o n, 
i ncl u di n g, b ut n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, diet, or a pr oce d ure.
•
All A Es fr o m t he ti me of i nter ve nti o n ra n d o mizati o n t hr o u g h 3 0 da ys f oll o wi n g cessati o n 
of st u d y i nter ve nti o n m ust be re p orte d b y t he i n vesti gat or.
•
All A Es meeti n g seri o us criteria, fr o m t he ti me of i nter ve nti o n all ocati o n/ ra n d o mizati o n 
t hr o u g h 9 0 da ys f oll o wi n g cessati o n of st u d y i nter ve nti o n or 3 0 da ys f oll o wi n g cessati o n 
of st u d y i nter ve nti o n if t he partici pa nt i nitiates ne w a ntica ncer t hera p y, w hi c he ver is 
earlier, m ust be re p orte d b y t he i n vesti gat or.
•
All pre g na ncies a n d e x p os ure d uri n g breastfee di n g of partici pa nt's fe male part ner, fr o m 
t he ti me of i nter ve nti o n ra n d o mizati o n t hr o u g h 1 2 0 da ys f oll o wi n g cessati o n of st u d y 
i nter ve nti o n, or 3 0 da ys foll o wi n g cessati o n of st u d y i nter ve nti o n if t he partici pa nt 
i nitiates ne w a ntica ncer t hera p y m ust be re p orte d b y t he i n vesti gat or.
•
A d diti o nall y, a n y S A E br o u g ht t o t he atte nti o n of a n i n vesti gat or at a n y ti me o utsi de t he 
ti me peri o d s pecifie d a b o ve m ust be re p orte d i m me diatel y t o t he S p o ns or if t he e ve nt is 
c o nsi dere d relate d t o st u d y i nter ve nti o n.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A Es or S A Es or ot her re p orta ble safet y e ve nts 
i n f or mer st u d y partici pa nts. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d t he i n vesti gat or 
c o nsi ders t he e ve nt t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, 
t he i n vesti gat or m ust pr o m ptl y n otif y t he S p o ns or.
All i nitial a n d f oll o w -u p A Es, S A Es, a n d ot her re p orta ble safet y e ve nts will be rec or d e d a n d 
re p orte d t o t he S p o nso r or desi g nee wit hi n t he ti me fra mes as i n dicate d i n Ta ble 9 .
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 9
Re p orti n g Ti me Peri o ds a n d Ti me Fra mes f or A d verse E ve nts a n d Ot her 
Re p orta ble Safet y E ve nts
T y pe of E ve nt
Re p orti n g Peri o d:
C o nse nt t o 
R a n d o miz ati o n/
All oc ati o n
Re p orti n g Peri o d:
R a n d o miz ati o n/
All oc ati o n 
T hr o u g h 
Pr ot oc ol -s pecifie d 
F oll o w -u p Peri o d
Re p orti n g 
Peri o d:
After t he 
Pr ot oc ol -
s pecifie d F oll o w-
u p Peri o d
Ti me Fr a m e 
t o Re p ort 
E ve nt a n d 
F oll o w -u p 
I nf or m ati o n t o 
S p o ns or
N S A E
Re p ort if:
– d ue t o pr ot oc ol -
s pecifie d 
i nter ve nti o n
– ca uses e xcl usi o n
– partici pa nt is 
recei vi n g place b o 
r u n-i n or ot her r u n-
i n treat me nt
Re p ort all
N ot re q uire d
Per data e ntr y 
g ui deli nes
S A E
Re p ort if:
– d ue t o pr ot oc ol -
s pecifie d 
i nter ve nti o n
– ca uses e xcl usi o n
– partici pa nt is 
recei vi n g place b o 
r u n-i n or ot her r u n-
i n treat me nt
Re p ort all
Re p ort if:
– dr u g/ vacci ne 
relate d.
( F oll o w 
o n g oi n g t o 
o utc o me)
Wit hi n 
2 4 h o urs of 
lear ni n g of 
e ve nt
Pre g na nc y/ Lactati o n 
E x p os ure
Re p ort if:
– partici pa nt has bee n 
e x p ose d t o a n y 
pr ot oc ol -s pecifie d 
i nter ve nti o n (e g, 
pr oce d ure, was h o ut ,
or r u n -i n treat me nt 
i ncl u di n g place b o 
r u n-i n)
E xce pti o n: A p ositi ve 
pre g na nc y test at t he 
ti me of i nitial 
scree ni n g is n ot a 
re p orta ble e ve nt.
Re p ort all
Pre vi o usl y 
re p orte d – F oll o w 
t o c o m pleti o n/
ter mi nati o n; 
re p ort o utc o me
Wit hi n 
2 4 h o urs of 
lear ni n g of 
e ve nt
E CI (re q uire 
re g ulat or y re p orti n g)
Re p ort if:
– d ue t o i nter ve nti o n
– ca uses e xcl usi o n
Re p ort
– p ote ntial DI LI
– re q uire re g ulat or y 
re p orti n g
N ot re q uire d
Wit hi n 
2 4 h o urs of 
lear ni n g of 
e ve nt
E CI ( d o n ot re q uire 
re g ulat or y re p orti n g)
Re p ort if:
– d ue t o i nter ve nti o n
– ca uses e xcl usi o n
Re p ort
– n o n -DI LI E CIs 
a n d t h ose n ot 
re q uiri n g 
re g ulat or y 
re p orti n g
N ot re q uire d
Wit hi n 
5 cale n dar da ys 
of lear ni n g of 
e ve nt
DI LI dr u g i n d uce d li ver i nj ur y; E CI e ve nt of cli nical i nterest; N S A E n o nseri o us a d verse e ve nt; S A E seri o us a d verse 
e ve nt.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 4. 2
Met h o d of Detecti n g A Es, S A Es, a n d Ot her Re p ort a ble S afet y E ve nts
Care will be ta 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 a n d ot her 
re p orta ble safet y e ve nts. O pe n-e n de d a n d n o nlea di n g ver bal q uesti o ni n g of t he partici pa nt is 
t he preferre d met h o d t o i n q uire a b o ut A E occ urre nce.
8. 4. 3
F oll o w -u p of A E, S A E, a n d Ot her Re p ort a ble S afet y E ve nt I nf or m ati o n
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 oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All A Es, S A Es, a n d ot her re p orta ble safet y e ve nts, 
i ncl u di n g pre g na nc y a n d e x p os ure d uri n g breastfee di n g of partici pa nt’s fe male part ner, E CIs, 
ca ncer, a n d o ver d ose will be f oll o we d u ntil res ol uti o n, sta bilizati o n, u ntil 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 ). I n 
a d diti o n, t he i n vesti gat or will ma ke e ver y atte m pt t o f oll o w all n o nseri o us A Es t hat occ ur i n 
ra n d o mize d partici pa nts f or o utc o me. F urt her i nf or mati o n o n f oll o w - u p pr oce d ures is gi ve n 
i n A p pe n di x 3.
8. 4. 4  
Re g ul at or y Re p orti n g Re q uire me nts f or S A E
Pr o m pt n otificati o n ( wit hi n 2 4 h o urs ) b y t he i n vesti gat or t o t he S p o ns or of 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 ds t he safet y of partici pa nts a n d t he 
safet y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.
T he S p o ns or has a le gal res 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 ge ncies a b o ut t he safet y of a st u d y i nter ve nti o n 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 a n d gl o bal la ws a n d 
re g ulati o ns relati n g t o safet y re p orti n g t o re g ulat or y a ut h orities, I R B/I E Cs, a n d i n vesti gat ors.
I n vesti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y 
re q uire me 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 E) fr o m t he S p o ns or will 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 uire me nts.
8. 4. 5
Pre g n a nc y a n d E x p os ure D uri n g Bre astfee di n g
Alt h o u g h pre g na nc y a n d i nfa nt e x p os ure d uri n g breastfee di n g are n ot c o nsi dere d A Es, a n y 
pre g na nc y or i nfa nt e x p os ure d uri n g breastfee di n g i n a partici pa nt ’s fe male part ner
(s p o nta ne o usl y re p orte d t o t he i n vesti gat or or t heir desi g nee), t hat occ urs d uri n g t he st u d y are
re p orta ble t o t he S p o ns or.
All re p orte d pre g na ncies of partici pa nt’s fe male part ner m ust be f oll o we d t o t he 
c o m pleti o n/ter mi nati o n of t he pre g na nc y.
Pre g na nc y o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n h y dati dif or m m ole, 
bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, miscarria ge, a n d still birt h m ust be re p orte d as 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
seri o us e ve nts (I m p orta nt Me dical E ve nts). If t he pre g na nc y c o nti n ues t o ter m, t he o utc o me 
( healt h of i nfa nt) m ust als o be re p orte d.
8. 4. 6
Dise ase -rel ate d E ve nts a n d/ or Dise ase -rel ate d O utc o mes N ot Q u alif yi n g as 
A Es or S A Es
Efficac y e n d p oi nts as o utli ne d i n t his secti o n will n ot be re p orte d t o t he S p o ns or as descri be d 
i n Secti o n 8. 4. 1 .
S pecificall y, t he s us pecte d/act ual e ve nts c o vere d i n t his e xce pti o n i ncl u de a n y e ve nt t hat is 
disease pr o gressi o n of t he ca ncer u n der st u d y.
T he S p o ns or will m o nit or u n bli n de d a g gre gate d efficac y e n d p oi nt e ve nts a n d safet y data t o 
e ns ure t he safet y of t he partici pa nts i n t he st u d y.
A n y s us pecte d e n d p oi nt t hat u p o n re vie w is n ot pr o gressi o n of t he ca ncer u n der st u d y will be 
f or war de d t o Gl o bal P har mac o vi gila nce as a n SA E wit hi n 2 4 h o urs of deter mi nati o n t hat t he 
e ve nt is n ot pr o gressi o n of t he ca ncer u n der st u d y.
8. 4. 7
E ve nts of Cli nic al I nterest
Selecte d n o nseri o us a n d S A Es are als o k n o w n as E CIs a n d m ust be re p orte d t o t he S p o ns or.
E ve nts of cli nical i nterest f or t his st u d y i ncl u de:
1.
A n o ver d ose of S p o ns or's pr o d uct, as defi ne d i n Secti o n 8. 5, t hat is n ot ass ociate d wit h 
cli nical s y m pt o ms or a b n or mal la b orat or y res ults. 
2.
A n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n ele v ate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n al kali ne p h os p hatase la b val ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y wa y of pr ot oc ol-s pecifie d la b orat or y 
testi n g or u nsc he d ule d la b orat or y testi n g. * 
* N ote: T hese criteria are base d u p o n a vaila ble re g ulat or y g ui da nce d oc u me nts. T he 
p ur p ose of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. T he st u d y site g ui da nce f or 
assess me nt a n d f oll o w u p of t hese criteria ca n be f o u n d i n t he I n vesti gat or St u d y File 
Bi n der ( or e q ui vale nt). 
8. 5
Tre at me nt of O ver d ose
F or t his st u d y, a n o ver d ose of pe m br oliz u ma b will be defi ne d as a n y d ose of 1 0 0 0 m g or 
greater ( > 5 ti mes t he i n dicate d d ose).
N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o ver d ose of pe m br oliz u ma b. I n t he 
e ve nt of o ver d ose, t he partici pa nt s h o ul d be o bser ve d cl osel y f or si g ns of t o xicit y. 
A p pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A n e nzal uta mi de o ver d ose is defi ne d as at least 2 dail y d oses of st u d y i nter ve nti o n ta ke n t he 
sa me cale n dar da y. I n t he e ve nt of a n o ver d ose, treat me nt wit h st u d y dr u g s h o ul d be 
i nterr u pte d a n d ge neral s u p p orti ve meas ures i nitiate d, ta ki n g i nt o c o nsi derati o n t he half-life 
is 5. 8 da ys f or e nzal uta mi de. Partici pa nts ma y be at i ncrease d ris k of seiz ures f oll o wi n g a n 
o ver d ose of e nzal uta mi de. Neit her t he effects of o ver d ose of e nzal uta mi de n or a n a nti d ote t o 
o ver d o se are k n o w n.
T he me dical m o nit or m ust be c o ntacte d i n t he e ve nt of a st u d y dr u g o ver d ose.
8. 6
P h ar m ac o ki netics
P K para meters will n ot be e val uate d i n t his st u d y.
8. 7
P h ar m ac o d y n a mics
P har mac o d y na mic para meters will n ot be e val uate d i n t his st u d y.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 0 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1 0
Visit Re q uire me nts
Visit re q uire me nts are o utli ne d i n Secti o n 1. 3 . S pecific pr oce d ure -relate d details are pr o vi de d 
i n Secti o n 8.
8. 1 0. 1
Scree ni n g
Writte n c o nse nt m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol -s pecific pr oce d ure. 
Res ults of a test perf or me d pri or t o t he partici pa nt si g ni n g c o nse nt as part of r o uti ne cli nical 
ma na ge me nt are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti me 
fra me.
Scree ni n g pr oce d ures are t o be c o m plete d wit hi n 4 2 da ys pri or t o t he first d ose of st u d y 
i nter ve nti o n. e xce pt f or t he f oll o wi n g:
•
La b orat or y tests are t o be perf or me d wit hi n 1 0 da ys pri or t o t he first d ose of st u d y 
i nter ve nti o n. A n e xce pti o n is HI V a n d he patitis testi n g w hic h ma y be do ne u p t o 4 2 da ys 
pri or t o t he first d ose of ra n d o mizati o n if re q uire d b y l ocal re g ulati o ns.
•
E val uati o n of E C O G is t o be perf or me d wit hi n 1 0 da ys pri or t o t he first d ose of st u d y 
i nter ve nti o n.
•
T u m or tiss ue fr o m a ne wl y o btai ne d c ore or e xcisi o nal bi o ps y o b tai ne d wit hi n 1 2 m o nt hs 
of Scree ni n g. Arc hi val t u m or tiss ue sa m ple ( > 1 2 m o nt hs) ca n be s u b mitte d after S p o ns or 
c o ns ultati o n.
Partici pa nts ma y be rescree ne d u p t o t w o ti mes after i nitiall y faili n g t o meet t he 
i ncl usi o n/e xcl usi o n criteria. Res ults fr o m assess me nts d uri n g t he i nitial scree ni n g peri o d are 
acce pta ble i n lie u of a re peat scree ni n g test if perf or me d wit hi n t he s pecifie d ti me fra me a n d 
t he c orres p o n di n g i ncl usi o n/e xcl usi o n criteria is met. Partici pa nts w h o are rescree ne d will 
retai n t heir ori gi nal scree ni n g n u m ber.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
8. 1 0. 2
Tre at me nt Peri o d
Visit re q uire me nts are o utli ne d i n t he S o A ( Secti o n 1. 3). S pecific pr oce d ure -relate d details 
are pr o vi de d i n Secti o n 8. 1 .
8. 1 0. 2. 1
E xte nsi o n First C o urse
If pe m br oliz u ma b/ place b o is c o m plete d or disc o nti n ue d f or reas o ns ot her t ha n pr o gressi ve 
disease, partici pa nts still recei vi n g e nzal uta mi de will c o nti n ue t o recei ve e nzal uta mi de + 
A D T a n d tra nsiti o n i nt o E xte nsi o n First C o urse. F or t hese partici pa nts, tra nsiti o ni n g i nt o 
E xte nsi o n First C o urse will all o w f or less fre q ue nt cli nic visits b y i ncreasi n g t he c ycle le n gt h 
t o 8 4 da ys (Ta ble 2 ). Tra nsiti o n i nt o E xte nsi o n First C o urse s h o ul d occ ur wit hi n 2 1 da ys ( ± 7 
da ys) of t he last c ycle rec ei ve d i n t he I nitial Treat me nt C o urse. P S A a n d i ma gi n g 
assess me nts will c o nti n ue per ori gi nal cale n dar -base d sc he d ule calc ulate d fr o m 
ra n d o mizati o n. Treat me nt wit h e nzal uta mi de/ A D T will t he n c o nti n ue u ntil criteria f or 
disc o nti n uati o n is met (e g, disease p r o gressi o n). 
P ost -treat me nt assess me nts liste d i n t he S o A (Ta ble 1 ) will n ot be re q uire d if partici pa nts 
tra nsiti o n i nt o E xte nsi o n First C o urse. P ost-treat me nt visits will occ ur o nce all st u d y 
me dicati o n ( pe m br oliz u ma b/ place b o/e nzal uta mi de) is disc o nti n ue d. 
S pecific pr oce d ures t o be perf or me d d uri n g E xte nsi o n First C o urse, as well as t heir 
prescri be d ti mes a n d ass ociate d visit wi n d o ws, are o utli ne d i n t he S o A i n Secti o n 1. 3.
8. 1 0. 2. 2
E n d of Tre at me nt Visit
T he E n d of Treat me nt Visit s h o ul d occ ur at t he ti me st u d y i nter ve nti o n is disc o nti n ue d. If t he 
E n d of Treat me nt Visit occ urs 3 0 da ys after t he last d ose of st u d y i nter ve nti o n, at t he ti me of 
t he ma n dat or y Safet y F oll o w-u p Vis it, pr oce d ures d o n ot nee d t o be re peate d. Visit 
re q uire me nts are o utli ne d i n t he S o A ( Secti o n 1. 3). S pecific pr oce d ure-relate d details are 
pr o vi de d a b o ve i n Secti o n 8 
St u d y Assess me nts a n d Pr oce d ures. Pri or t o disc o nti n ui n g 
partici pa nts fr o m t hera p y, s u b mit t he Treat me nt Ter mi nati o n & Disease Assess me nt 
Ter mi nati o n F or m.
8. 1 0. 2. 3
Sec o n d C o urse 
N O T E: As of A me n d me nt 0 4, S ec o n d C o urse tre at me nt is n ot a n o pti o n f or 
p artici p a nts. T here are c urre ntl y n o p artici p a nts i n t he Sec o n d C o urse P h ase. T he 
s u bsecti o n bel o w is ret ai ne d f or refere nce.
All partici pa nts w h o st o p pe m br oliz u ma b wit h S D or better ma y be eli gi ble f or u p t o 1 7 
a d diti o nal c ycles (a p pr o xi matel y 1 year) of pe m br oliz u ma b treat me nt if t he y ha ve BI C R -
verifie d pr o gressi o n after st o p pi n g st u d y i nter ve nti o n fr o m t he I nitial Treat me nt P hase. I n 
t his circ u msta nce, u n bli n di n g t o pe m br oliz u ma b vers us place b o a d mi nistrati o n ma y occ ur o n 
a n i n di vi d ual basis a n d o nl y after c o ns ultati o n wit h S p o ns or Cli nical Direct or as o utli ne d i n 
Secti o n 8. 1. 1 0. 1. Partici pa nts s h o ul d c o nti n ue treat me nt wit h A D T. E nzal uta mi de ma y be 
c o nti n ue d at t he i n vesti gat or’s discreti o n d uri n g t he Sec o n d C o urse treat me nt. T his 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
retreat me nt is ter me d t he Sec o n d C o urse P hase of t his st u d y a n d is o nl y a vaila ble if t he st u d y 
re mai ns o pe n a n d t he partici pa nt meets t he f oll o wi n g c o n diti o ns:
EI T H E R
•
st o p pe d i nitial pe m br oliz u ma b/ place b o after attai ni n g a n i n vesti gat or-deter mi ne d 
c o nfir me d C R base d o n P C W G -m o difie d R E CI S T 1. 1; a n d
•
was treate d wit h at least 8 c ycles of pe m br oliz u ma b/ place b o bef ore disc o nti n ui n g 
treat me nt; a n d
•
recei ve d at least 2 treat me nts wit h pe m br oliz u ma b/ place b o be y o n d t he date w he n t he 
i nitial C R was declare d.
O R
•
ha d S D, P R, or C R a n d st o p pe d pe m br oliz u ma b/ place b o after c o m pleti o n of 3 5 c ycles 
(a p pr o xi matel y 2 years) of pe m br oliz u ma b/ place b o f or reas o ns ot her t ha n disease 
pr o gressi o n or i nt olera bilit y
A N D
•
e x perie nce d BI C R -verifie d ra di o gra p hic disease pr o gressi o n per P C W G -m o difie d 
R E CI S T 1. 1 after st o p pi n g pe m br oliz u ma b/ place b o; a n d
•
u p o n u n bli n di n g at t he ti me of ce ntrall y verifie d disease pr o gressi o n, were f o u n d t o ha ve 
recei ve d pe m br oliz u ma b (refer t o Secti o n 8. 1. 1 0); a n d
•
n o ne w a ntica ncer treat me nt was a d mi nistere d after t he last d ose of st u d y i nter ve nti o n; 
a n d
•
de m o nstrate a de q uate or ga n f u ncti o n as detaile d i n Secti o n 5. 1; a n d 
•
d oes n ot ha ve a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y 
a b n or malit y t hat mi g ht i nterfere wit h t he s u bject’s partici pati o n f or t he f ull d urati o n of 
t he trial or is n ot i n t he best i nterest of t he s u bject t o partici pate, i n t he o pi ni o n of t he 
treat me nt i n vesti gat or; a n d 
•
t he st u d y is o n g oi n g.
A n o bjecti ve res p o nse or disease pr o gressi o n t hat occ urs d uri n g t he Sec o n d C o urse P hase f or 
a partici pa nt will n ot be c o u nte d as a n e ve nt f or t he pri mar y a nal ysis of eit her e n d p oi nt i n t his 
st u d y.
8. 1 0. 3
P ost -tre at me nt Visits
P ost -treat me nt visits are o utli ne d i n eac h S o A s pecifie d i n Secti o n 1. 3. P ost -treat me nt 
assess me nts liste d i n t he I nitial Treat me nt P hase ( Ta ble 1 ) will n ot be re q uire d if partici pa nts 
tra nsiti o n i nt o E xte nsi o n First C o urse (Ta ble 2 ). P ost-treat me nt visits will occ ur o nce all 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
st u d y me dicati o n ( pe m br oliz u ma b/ place b o a n d e nzal uta mi de) is disc o nti n ue d (ie, d o n ot 
c o nti n ue wit h e nzal uta mi de i n E xte nsi o n First C o urse).   
8. 1 0. 3. 1
S afet y F oll o w -u p Visit
T he ma n dat or y Safet y F oll o w -u p Visit s h o ul d be c o n d ucte d a p pr o xi matel y 3 0 da ys after t he 
last d ose of st u d y i nter ve nti o n or bef ore t he i nitiati o n of a ne w a ntica ncer treat me nt, 
w hic he ver c o mes first.
Partici pa nts w h o are eli gi ble f or retreat me nt wit h pe m br oliz u ma b ma y ha ve u p t o 2 Safet y 
F oll o w -u p Visits, 1 after t he I nitial/ E xte nsi o n Treat me nt P hase a n d 1 after t he Sec o n d C o urse 
Treat me nt.
8. 1 0. 3. 2
F oll o w -u p Visits
As of A me n d me nt 0 4: F oll o w -U p Visits will be disc o nti n ue d. T his secti o n bel o w is 
ret ai ne d f or refere nce.
Partici pa nts w h o disc o nti n ue all st u d y i nter ve nti o n ( pe m br oliz u ma b/ place b o a n d 
e nzal uta mi de) f or a reas o n ot her t ha n BI C R -verifie d ra di o gra p hic disease pr o gressi o n will 
m o ve i nt o t he F oll o w -u p P hase. F oll o w -u p visits will be sc he d ule d e ver y 1 2 wee ks ( 8 4 da ys 
± 7 da ys) . F or partici pa nts w h o disc o nti n ue st u d y i nter ve nti o n wit h o ut d oc u me nte d BI C R -
veri fie d disease pr o gressi o n, e ver y eff ort s h o ul d be ma de t o c o nti n ue m o nit ori n g disease 
stat us b y P S A a n d ra di ol o gic i ma gi n g ( C T/ M RI a n d b o ne sca ns) usi n g t he sa me i ma gi n g 
sc he d ule use d w hile o n treat me nt (e ver y 1 2 wee ks) calc ulate d fr o m t he date of ra n d o mizati o n 
(see Secti o n 8. 2. 1. 2 ) u ntil t he start of a ne w a ntica ncer treat me nt, BI C R -verifie d disease 
pr o gressi o n, 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 ( or 
if t he partici pa nt be gi ns retreat me nt wit h pe m br oliz u ma b as detaile d i n Secti o n 8. 1 0. 2. 3). 
I nf or mati o n re gar di n g p ostst u d y a ntica ncer treat me nt will be c ollecte d if ne w treat me nt is 
i nitiate d.
Partici pa nts w h o are eli gi ble t o recei ve retreat me nt wit h pe m br oliz u ma b acc or di n g t o t he 
criteria i n Secti o n 8. 1 0. 2. 3 will m o ve fr o m t he F oll o w -u p P hase t o t he Sec o n d C o urse P hase 
w he n t he y e x perie nce disease pr o gressi o n. Details are pr o vi de d i n t he S o A ( Secti o n 1. 3) f or 
retreat me nt wit h pe m br oliz u ma b.
Pri or t o d isc o nti n ui n g partici pa nts fr o m f oll o w-u p , s u b mit t he Treat me nt Ter mi nati o n & 
Disease Assess me nt Ter mi nati o n F or m. 
8. 1 0. 3. 3
S ur vi v al F oll o w -u p
As of A me n d me nt 0 4: S ur vi v al F oll o w -u p visit will be disc o nti n ue d. T h ose p artici p a nts 
re m ai ni n g o n st u d y tre at me nt at t he ti me of A me n d me nt 0 4, s h o ul d c o nti n ue t o be 
m o nit ore d i n t he st u d y t hr o u g h t he A E re p orti n g Peri o d (secti o n 8. 4). T he secti o n bel o w 
is ret ai ne d f or refere nce.
Partici pa nts w h o e x perie nce BI C R -verifie d ra di o gra p hic pr o gressi o n or start a ne w 
a ntica ncer t her a p y, will m o ve i nt o t he S ur vi val F oll o w -u p P hase a n d s h o ul d be c o ntacte d b y 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
tele p h o ne a p pr o xi matel y e ver y 1 2 wee ks 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.
8. 1 0. 4
S ur vi v al St at us
T o e ns ure c urre nt a n d c o m plete s ur vi val data is a vaila ble at t he ti me of data base l oc ks, 
u p date d s ur vi val stat us ma y be re q ueste d d uri n g t he c o urse of t he st u d y b y t he S p o ns or. F or 
e xa m ple, u p date d s ur vi val stat us ma y be re q ueste d pri or t o b ut n ot li mite d t o a n e D M C
re vie w, i nteri m a n d/ or fi nal a nal ysis. U p o n S p o ns or n otificati o n, all partici pa nts w h o d o 
n ot/ will n ot ha ve a sc he d ule d st u d y visit or st u d y c o ntact d uri n g t he S p o ns or defi ne d ti me 
peri o d will be c o ntacte d f or t heir s ur vi val stat us (e xcl u di n g partici pa nts t hat ha ve a 
pre vi o usl y rec or de d deat h e ve nt i n t he c ollecti o n t o ol).
0 8 9 V 4 C
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
St u d y Desi g n O ver vie w
A P hase 3, Ra n d o mize d, D o u ble -bli n d Trial of Pe m br oliz u ma b 
( M K-3 4 7 5) Pl us E nzal uta mi de Pl us A D T Vers us Place b o Pl us 
E nzal uta mi de Pl us A D T i n Partici pa nts Wit h Metastatic H or m o ne -
Se nsiti ve Pr ostate Ca ncer ( m H S P C)
Tre at me nt Assi g n me nt
A p pr o xi matel y 1 2 3 2 eli gi ble partici pa nts will be ra n d o mize d i n a 1: 1 rati o 
t o o ne of t he f oll o wi n g 2 treat me nt ar ms:
•
Ar m 1: pe m br oliz u ma b pl us e nzal uta mi de pl us A D T
•
Ar m 2: place b o pl us e nzal uta mi de pl us A D T
Ra n d o mizati o n stratificati o n fact ors are:
•
Pri or d oceta xel f or m H S P C: Yes vs N o
•
Hi g h -v ol u me disease: Yes vs N o .
A n al ysis P o p ul ati o ns
Efficac y: I T T
Safet y: A Pa T
Pri m ar y E n d p oi nt(s)
1.
r P F S
2.
O S
Ke y Sec o n d ar y E n d p oi nts
1.
T F S T
3.
T T S S R E
St atistic al Met h o ds f or Ke y 
Effic ac y A n al yses
T he pri mar y h y p ot heses will be e val uate d b y c o m pari n g pe m br oliz u ma b 
pl us e nzal uta mi de pl us A D T ar m t o place b o pl us e nzal uta mi de pl us A D T 
ar m wit h res pect t o r P F S, O S, T F S T, a n d T T S S R E usi n g a stratifie d l o g -
ra n k test. T he hazar d rati o will be esti mate d usin g a C o x re gressi o n m o del. 
E ve nt rates o ver ti me will be esti mate d wit hi n eac h treat me nt gr o u p usi n g 
t he Ka pla n-Meier met h o d. 
St atistic al Met h o ds f or Ke y 
S afet y A n al yses
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h. T he tiers differ 
wit h res pect t o t he a nal yses t hat will be perf or me d. T here are n o e ve nts of 
i nterest t hat warra nt ele vati o n t o Tier 1 e ve nts i n t his st u d y. Tier 2 
para meters will be assesse d via p oi nt esti mates wit h 9 5 % c o nfi de nce 
i nter val ( CIs) pr o vi de d f or bet wee n-gr o u p c o m paris o n; o nl y p oi nt 
esti mates b y treat me nt gr o u p are pr o vi de d f or Tier 3 safet y para meters. 
T he 9 5 % CIs f or t he bet wee n -treat me nt differe nces i n perce nta ges will be 
pr o vi de d usi n g t he Mietti ne n & N ur mi ne n met h o d.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
I nteri m A n al yses
M ulti plicit y
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
S a m ple Size a n d P o wer 
9. 2
Res p o nsi bilit y f or A n al yses/I n -h o use Bli n di n g 
T he statistical a nal ysis of t he data o btai ne d fr o m t his st u d y will be t he res p o nsi bilit y of t he 
Cli nical Bi ostatistics de part me nt of t he S p o ns or.
T his st u d y will be c o n d ucte d as a d o u ble -bli n d st u d y u n der i n -h o use bli n di n g pr oce d ures. 
T he official, fi nal data base will n ot be u n bli n de d u ntil me dical/scie ntific re vie w has bee n 
perf or me d, pr ot oc ol de viati o ns ha ve bee n i de ntifie d, a n d data ha ve bee n declare d fi nal a n d 
c o m plete.
T he Cli nical Bi ostatistics de part me nt of t he S p o ns or will ge nerate t he ra n d o mize d all ocati o n 
sc he d ule f or st u d y i nter ve nti o n assi g n me nt f or t his pr ot oc ol, a n d t he ra n d o mizati o n will be 
i m ple me nte d i n a n I R T b y a st u d y ve n d or.
Bli n di n g pr oce d ure relate d t o t he pla n ne d i nteri m a nal yses is descri be d i n Secti o n 9. 7.
E xte nsi o n P orti o n i n C hi n a:
F or all partici pa nts i n C hi na, i ncl u di n g partici pa nts ra n d o mize d i n t he gl o bal p orti o n a n d t he 
e xte nsi o n p orti o n, partici pa nt -le vel treat me nt ra n d o mizati o n i nf or mati o n will be bli n de d t o 
t he statisticia n(s)/ pr o gra m mer(s) res p o nsi ble f or t he a nal ysis of t he E xte nsi o n P orti o n i n 
C hi na u ntil t he e xte nsi o n p orti o n data base l o c k is ac hie ve d. T he e xte nt t o w hic h i n di vi d uals 
are u n bli n de d t o t he res ults will be li mite d. Bli n de d a n d u n bli n de d me m bers will be clearl y 
d oc u me nte d.
9. 3
H y p ot heses/ Esti m ati o n 
O bjecti ves a n d h y p ot heses of t he st u d y are state d i n Secti o n 3.
9. 4
A n al ysis E n d p oi nts 
Efficac y a n d safet y e n d p oi nts t hat will be e val uate d f or wit hi n - a n d bet wee n -treat me nt 
differe nces are liste d bel o w, f oll o we d b y t he descri pti o ns of t he deri vati o ns of selecte d 
e n d p oi nts.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 4. 1
Effic ac y E n d p oi nts
9. 4. 1. 1
Pri m ar y
R a di o gr a p hic Pr o gressi o n -free S ur vi v al
P C W G -m o difie d R E CI S T 1. 1 b y BI C R is 
defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first d oc u me nte d disease pr o gressi o n or deat h 
d ue t o a n y ca use, w hic he ver occ urs first. 
O ver all S ur vi v al is defi ne d as t he ti me fr o m ra n d o mizati o n t o deat h d ue t o a n y ca use.
9. 4. 1. 2
Ke y Sec o n d ar y
T F S T is defi ne d as t he ti me fr o m ra n d o mizati o n t o i nitiati o n of t he first s u bse q ue nt 
a ntica ncer t hera p y or deat h, w hic he ver occ urs first. A n y s yste mic treat me nt f or pr ostate 
ca ncer t hat is i nte n de d t o pr ol o n g s ur vi val is i ncl u de d. Ra di o p har mace utical t hera p y w it h t he 
p ur p ose of ca ncer treat me nt is als o i ncl u de d, f or e xa m ple, b ut n ot li mite d t o, Ra di u m 2 2 3. 
E xcl u de d fr o m t he defi niti o n are palliati ve treat me nts i nte n de d f or s u p p orti ve care o nl y, e g, 
pre d nis o ne prescri be d f or pai n, s ur ger y f or s keletal -relate d e ve nt s uc h as c or d c o m pressi o n or 
pat h ol o gic fract ure, a n d l ocalize d ra di ot hera p y f or pai n ma na ge me nt o nl y.
T T S S R E is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first s y m pt o matic s keletal-relate d 
e ve nt, defi ne d as: 
•
first use of E B R T t o pre ve nt or relie ve s keletal s y m pt o ms, 
•
occ urre nce of ne w s y m pt o matic pat h ol o gic b o ne fract ure ( verte bral or n o n -verte bral), 
•
occ urre nce of s pi nal c or d c o m pressi o n,
•
or t u m or -relate d ort h o pe dic s ur gical i nter ve nti o n,
w hic he ver occ urs first. 
9. 4. 1. 3
Sec o n d ar y
P S A res p o nse r ate is defi ne d as t he pr o p orti o n of partici pa nts i n t he a nal ysis p o p ulati o n 
wit h P S A decli ne of ≥5 0 % fr o m baseli ne meas ure d t wice at least 3 wee ks a part. 
O bjecti ve res p o nse r ate
P C W G -m o difie d R E CI S T 1. 1 b y BI C R is defi ne d as t he 
pr o p orti o n of partici pa nts i n t he a nal ysis p o p ulati o n w h o ha ve a best o verall res p o nse of 
eit her c o nfir me d C R or P R. 
D ur ati o n of res p o nse
P C W G -m o difie d R E CI S T 1. 1 b y BI C R is defi ne d as t he ti me fr o m 
t he earliest date of first d oc u me nte d e vi de nce of c o nfir me d C R or P R u ntil earliest date of 
disease pr o gressi o n or deat h fr o m a n y ca use, w hic he ver occ urs first.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 1 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ti me t o P S A pr o gressi o n is defi ne d as t he ti me fr o m ra n d o mizati o n t o P S A pr o gressi o n. 
Partici pa nts wit h o ut P S A pr o gressi o n will be ce ns ore d at t he last P S A assess me nt date. T he 
P S A pr o gressi o n date is defi ne d as t he date t hat 1) ≥2 5 % i ncrease a n d ≥2 n g/ m L a b o ve t he 
na dir, a n d w hic h is c o nfir me d b y a sec o n d val ue ≥3 wee ks later if t here is P S A decli ne fr o m 
baseli ne 2) or ≥2 5 % i ncrease a n d ≥2 n g/ m L i ncrease fr o m baseli ne be y o n d 1 2 wee ks if t here 
is n o P S A decli ne fr o m baseli ne.
P S A u n detect a ble r ate is defi ne d as t he pr o p orti o n of partici pa nts i n t he a nal ysis p o p ulati o n 
wit h P S A < 0. 2 n g/ m L d uri n g st u d y i nter ve nti o n. 
Ti me t o r a di o gr a p hic s oft tiss ue pr o gressi o n per s oft tiss ue r ule of P C W G- m o difie d 
R E CI S T 1. 1 b y BI C R is defi ne d as t he ti me fr o m ra n d o mizati o n t o ra di o gra p hic s oft tiss ue 
pr o gressi o n.
P F S 2 defi ne d as t he ti me fr o m ra n d o mizati o n t o disease pr o gressi o n as deter mi ne d b y 
i n vesti gat or assess me nt after ne xt-li ne of t hera p y or deat h fr o m a n y ca use, w hic he ver occ urs 
first. 
9. 4. 1. 4 
E x pl or at or y
9. 4. 2
S afet y E n d p oi nts
Safet y meas ure me nts are descri be d i n Secti o n 4. 2. 1. 2.
Safet y a n d t olera bilit y will be assesse d b y cli nical re vie w of all rele va nt para meters i ncl u di n g 
a d verse e ve nts, la b orat or y val ues a n d vital si g ns.
9. 4. 3
P R O E n d p oi nts
9. 4. 3. 1
Ti me t o P ai n Pr o gressi o n
Ti me t o pai n pr o gressi o n is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he earliest date of 
pai n pr o gressi o n base d o n t he B PI -S F Ite m # 3 “ w orst pai n i n 2 4 h o urs” a n d o piate use.
9. 4. 3. 2
F A C T - P
F A C T -P was de vel o pe d as a disease -s pecific a dj u nct t o t he F A C T meas ure me nt s yste m a n d 
c o nsists of F A C T -G ( ge neral) w hic h c o ntai ns a 2 7 -ite m self-re p ort q uesti o n naire meas uri n g 
ge neral healt h -relate d q ualit y of life i n 4 d o mai ns ( p h ysical, s ocial, e m oti o nal, a n d f u ncti o nal 
well -bei n g) a n d 1 2 p r ostate ca ncer-s pecific ite ms. 
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
P R O e n d p oi nts relate d t o F A C T -P i ncl u de 
•
T he c ha n ge fr o m baseli ne at t he latest ti me p oi nt w he n pres pecifie d criteria are met wit h 
re gar ds t o P R O c o m pleti o n a n d c o m plia nce rates 
•
Pr o p orti o n of partici pa nts wit h best sc ore of “i m pr o ve d”
•
Pr o p orti o n of partici pa nts wit h best sc ore of “ w orse ne d”
•
Pr o p orti o n of partici pa nts wit h best sc ore of “ n o c ha n ge”
f or eac h of t he f oll o wi n g F A C T-P sc ores/scales
•
F A C T -P t ot al sc ore: F A C T -G sc ore + pr ostate ca ncer s u bsc ore
•
F A C T -G t ot al sc ore: p h y sical well-bei n g + s ocial/fa mil y well -bei n g + e m oti o nal well -
bei n g + f u ncti o nal well -bei n g
•
P C S: pr ostate ca ncer s u bsc ore
•
P W B: p h ysical well -bei n g
•
S W B: s ocial/fa mil y well-bei n g 
•
E W B: e m oti o nal well-bei n g 
•
F W B: f u ncti o nal well-bei n g 
•
T OI (trial o utc o me i n de x): p h ysical well-bei n g + f u ncti o nal well -bei n g + pr ostate ca ncer 
s u bsc ore
•
F A P SI - 6 ( F A C T a d va nce d pr ostate s y m pt o m i n de x 6): a s y m pt o m sc ore ma de u p of 6 
ite ms fr o m wit hi n t he F A C T P ( 3 pai n ite ms, 1 fati g ue ite m, 1 wei g ht l oss ite m, a nd 1 
c o n diti o n getti n g w orse ite m) 
•
P C S p ai n -rel ate d sc ore: Calc ulate d fr o m t he f o ur q uesti o ns o n pai n i n t he F A C T - P
A best res p o nse of “I m pr o ve d”, “ N o C ha n ge”, a n d “ W orse ne d”, defi ne d acc or di n g t o 
Ta ble 1 0 a n d Ta ble 1 1 will be calc ulate d f or eac h partici pa nt f or eac h F A C T - P sc ore.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 1 0
Defi niti o n of Visit Res p o nse f or F A C T -P sc ore
Mi ni m u m i m p ort a nt differe nce ( MI D)
F A C T - P-T ot al
1 0
F A C T -G T ot al
7
F A P SI - 6
3
T OI
9
P C S
3
P C S p ai n -rel ate d sc ore
2
F W B, P W B, S W B, E W B
3
A b bre viati o ns: E W B e m oti o nal well bei n g; F A C T G  F u ncti o nal Assess me nt of Ca ncer T hera p y
Ge neral; F A C T P  
F u ncti o nal Assess me nt of Ca ncer T hera p y
Pr ostate Ca ncer; F A P SI 6  F u ncti o nal Assess me nt of Pr ostate Ca ncer 
S y m pt o ms I n de x 6; F W B  f u ncti o nal well bei n g; P C S  Pr ostate Ca ncer S y m pt o ms; P W B  p h ysical well bei n g; 
S W B s ocial/fa mil y well bei n g; T OI  Trial O utc o me I n de x.
Ta ble 1 1
Defi niti o n of Best Sc ore f or F A C T -P sc ore
O ver all Sc ore Res p o nse
Criteri a
I m pr o ve d
T w o c o nsec uti ve visit res p o nses of “i m pr o ve d”.
N o c ha n ge
D oes n ot q ualif y f or o verall sc ore res p o nse of “i m pr o ve d”. T w o c o nsec uti ve 
visit res p o nses of eit her “ n o c ha n ge” or “i m pr o ve d” a n d “ n o c ha n ge”.
W orse ne d
D oes n ot q ualif y f or o verall sc ore res p o nse of “i m pr o ve d” or “ n o c ha n ge”. A 
visit res p o nse of “ w orse ne d”.
Ot her
D oes n ot q ualif y f or 1 of t he a b o ve.
9. 4. 3. 3
B PI -S F
A vali date d q uesti o n naire c o m m o nl y use d i n ca ncer trials t h at i ncl u des se veral i n di vi d ual 
ite ms meas ure d o n a scale of 0 t o 1 0, wit h l o wer sc ores re prese nti n g l o wer le vels of pai n 
i nte nsit y or less i nterfere nce of pai n wit h acti vities of dail y li vi n g (e g, slee p, m o o d, a n d 
acti vit y).
I n a d diti o n t o ti me t o pai n pr ogressi o n, P R O e n d p oi nts relate d t o B PI -S F  i ncl u de b ut n ot 
li mite d t o 
•
ti me t o pai n se verit y pr o gressi o n 
•
t he c ha n ge fr o m baseli ne i n pai n i nterfere nce at t he latest ti me p oi nt w he n pres pecifie d 
criteria are met wit h re gar ds t o P R O c o m pleti o n a n d c o m plia nce rates
Details of P R O e n d p oi nts will be pr o vi de d i n s S A P. 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 4. 3. 4
E Q -5 D -5 L
T he 5 healt h state di me nsi o ns i n t he E Q -5 D -5 L i ncl u de t he f oll o wi n g: m o bilit y, self -care, 
us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n. Eac h di me nsi o n is rate d o n a 5 -
p oi nt scale fr o m 1 ( n o pr o ble m) t o 5 ( u na ble t o/e xtre me pr o ble ms). T he E Q -5 D -5 L als o 
i ncl u des a gra de d ( 0 t o 1 0 0) vertical vis ual a nal o g scale o n w hic h t he partici pa nt rates his or 
her ge neral state of healt h at t he ti me of t he assess me nt. 
P R O e n d p oi nts relate d t o E Q -5 D -5 L i ncl u de b ut are n ot li mite d t o t he c ha n ge fr o m baseli ne 
in E Q -5 D -5 L V A S at t he latest ti me p oi nt w he n pres pecifie d criteria are met wit h re gar ds t o 
P R O c o m pleti o n a n d c o m plia nce rates. 
0 8 9 V 4 C
C CI
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n will be a p plie d t o b ot h t he 
stratifie d l o g-ra n k test a n d t he stratifie d C o x m o del.  
0 8 9 V 4 C
C CI
0 8 C V S X

0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 2 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 1 3 
Efficac y A nal ysis Met h o ds f or Ke y Efficac y E n d p oi nts
E n d p oi nt/ V ari a ble
St atistic al Met h o d a
A n al ysis 
P o p ul ati o n
Missi n g D at a A p pr o ac h
Pri m ar y A n al ysis:
r P F S per P C W G-m o difie d 
R E CI S T 1. 1 as assesse d b y 
BI C R
Testi n g: Stratifie d l o g -ra n k 
Test Esti mati o n: Stratifie d 
C o x m o del wit h Efr o n’s tie 
ha n dli n g met h o d.
I T T
Ce ns ore d acc or di n g t o r ules 
i n Ta bl e 1 2
O S
Testi n g: Stratifie d l o g -ra n k 
Test Esti mati o n: Stratifie d 
C o x m o del wit h Efr o n’s tie 
ha n dli n g met h o d.
I T T
Ce ns ore d at last k n o w n 
ali ve date
Ke y Sec o n d ar y A n al ysis ：
T F S T
Testi n g: Stratifie d L o g -ra n k 
Test Esti mati o n: Stratifie d 
C o x m o del wit h Efr o n’s tie 
ha n dli n g met h o d.
I T T
Ce ns ore d at t he last k n o w n 
ti me t o ha ve n ot recei ve d 
s u bse q ue nt ne w a ntica ncer 
t hera p y
T T S S R E
Testi n g: Stratifie d L o g -ra n k 
Test Esti mati o n: Stratifie d 
C o x m o del wit h Efr o n’s tie 
ha n dli n g met h o d.
I T T
Ce ns ore d at t he last k n o w n 
ti me t o be free of 
s y m pt o matic s keletal-
relate d e ve nt 
A b bre viati o ns: BI C R  bli n de d i n de pe n de nt ce ntral re vie w; I T T  i nte nti o n t o treat; O S  o verall s ur vi val; P C W G  
Pr ostate Ca ncer W or ki n g Gr o u p; m o difie d R E CI S T 1. 1  m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors 
Versi o n 1. 1; r P F S  ra di o gra p hic pr o gressi o n free s ur vi val; T F S T  ti me t o i nitiati o n of t he first s u bse q ue nt a ntica ncer 
t hera p y or deat h; T T S S R E ti me t o s y m pt o matic s keletal relate d e ve nt 
a.
Statistical m o dels are descri be d i n f urt her detail i n t he te xt. F or stratifie d a nal yses, t he stratifi cati o n fact ors use d f or 
ra n d o mizati o n will be a p plie d t o t he a nal ysis. S mall strata will be c o m bi ne d i n a wa y s pecifie d b y a bli n de d 
statisticia n pri or t o t he a nal ysis.
9. 6. 2
St atistic al Met h o ds f or S afet y A n al yses
Safet y a n d t olera bilit y will be assesse d b y cli nical re vie w of all rele va nt para meters i ncl u di n g 
a d verse e x periences, la b orat or y tests, vital si g ns, a n d E C G meas ure me nts. 
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h ( Ta ble 1 4 ). T he tiers differ wit h 
res pect t o t he a nal yses t hat will be perf or me d. A d verse e x periences (s pecific ter ms as well as 
s yste m or ga n class ter ms) a n d e ve nts t hat meet pre defi ne d li mits of c ha nge i n la b orat or y a n d 
vital si g ns, a n d E C G para meters are eit her pres pecifie d as Tier -1 e n d p oi nts or will be 
classifie d as bel o n gi n g t o “ Tier 2” or “ Tier 3,” base d o n o bser ve d pr o p orti o ns of partici pa nts 
wit h a n e ve nt.  
0 8 9 V 4 C
C CI
0 8 C V S X

0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 7. 1
Effic ac y I nteri m A n al yses
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 7. 2
S afet y I nteri m A n al yses
T he e D M C c o n d ucte d re g ular safet y i nteri m a nal yses. T he ti mi n g of t hese safet y i nteri m 
a nal yses was s pecifie d i n t he e D M C c harter.
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 8
M ulti plicit y 
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 8. 2
O ver all S ur vi v al
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 3 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
9. 9
S a m ple Size a n d P o wer C alc ul ati o ns 
N O T E: As of A me n d me nt 0 4 , all t he pres pecifie d i nteri m a nal yses after I A 1 a n d fi nal 
a nal ysis of t he st u d y descri be d i n t he S A P will n ot be perf or me d. T his secti o n is retai ne d f or 
refere nce.
T he sa m ple size is esti mate d base d o n t he pri mar y e n d p oi nts of r P F S. 
A t otal of a p pr o xi matel y 1 2 3 2 partici pa nts will be ra n d o mize d i n a 1: 1 rati o t o t he 
pe m br oliz u ma b pl us e nzal uta mi de pl us A D T gr o u p a n d t he place b o pl us e nzal uta mi de pl us 
A D T gr o u p, (a p pr o xi matel y 6 1 6 partici pa nts per gr o u p) res pecti vel y.
0 8 9 V 4 C
C CI
C CI
0 8 C V S X

0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
E xte nsi o n P orti o n i n C hi n a:
T o e val uate t he c o nsiste nc y of efficac y a n d safet y i n t he p o p ulati o n i n C hi na c o m pare d wit h 
t he gl o bal p o p ulati o n, after c o m pleti o n of gl o bal p orti o n e nr oll me nt, partici pa nts i n C hi na 
will c o nti n ue t o be ra n d o mize d i n a 1: 1 rati o i nt o t he pe m br oliz u ma b pl us e nzal uta mi de pl us 
A D T ar m a n d place b o pl us e nzal uta mi de pl us A D T ar m u ntil t he pla n ne d sa m ple size of 
a p pr o xi matel y 1 8 6 partici pa nts i n C hi na is reac he d. Partic i pa nts i n C hi na ra n d o mize d after 
c o m pleti o n of e nr oll me nt i n t he gl o bal p orti o n will n ot be i ncl u de d i n t he a nal ysis of t he 
gl o bal p orti o n.
9. 1 0
S u b gr o u p A n al yses 
T o deter mi ne w het her t he treat me nt effect is c o nsiste nt acr oss vari o us s u b gr o u ps, t he 
esti mate of t he bet wee n-gr o u p treat me nt effect ( wit h a n o mi nal 9 5 % CI) f or t he pri mar y 
e n d p oi nts will be esti mate d a n d pl otte d wit hi n eac h cate g or y of t he f oll o wi n g classificati o n 
varia bles:
I n a d diti o n, a F orest pl ot will be pr o d uce d, w hic h pr o vi des t he esti mate d p oi nt esti mates a n d 
c o nfi de nce i nter vals f or t he treat me nt effect acr oss t he cate g ories of s u b gr o u ps liste d a b o ve.
I n t he e ve nt t hat t here are a s mall n u m ber of res p o nses/e ve nts i n o ne or m ore strata, f or t he 
p ur p ose of a nal ysis strata will be c o m bi ne d t o e ns ure s ufficie nt n u m ber of res p o nses/e ve nts 
i n eac h strat u m. Details re gar di n g t he c o m bi ni n g of strata will be s pecifie d i n t he s S A P pri or 
t o data base l oc k base d o n a bli n de d re vie w of res p o nse c o u nts b y strat u m.
C o u ntr y -s pecific or re gi o n-s pecific p o p ulati o ns ma y als o be a nal yze d per l ocal re g ulat or y 
re q uire me nt. 
9. 1 1
C o m pli a nce ( Me dic ati o n A d here nce) 
Dr u g acc o u nta bilit y data f or st u d y i nter ve nti o n will be c ollecte d d uri n g t he st u d y. A n y 
de viati o n fr o m pr ot oc ol -directe d a d mi nistrati o n will be re p orte d.
9. 1 2
E xte nt of E x p os ure 
T he e xte nt of e x p os ure f or e nzal ut a mi de will be s u m marize d as d urati o n of treat me nt i n da ys. 
T he e xte nt of e x p os ure f or pe m br oliz u ma b/ place b o will be s u m marize d as d urati o n of 
treat me nt i n c ycles. D ose i nterr u pti o n f or eac h dr u g, d ose re d ucti o n or d ose i ncrease f or 
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
e nzal uta mi de will be s u m marize d. S u m mar y statistics will be pr o vi de d o n E xte nt of 
E x p os ure f or t he A Pa T p o p ulati o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S
1 0. 1
A p pe n di x 1 : Re g ul at or y, Et hic al, a n d St u d y O versi g ht C o nsi der ati o ns
1 0. 1. 1
C o de of C o n d uct f or I nter ve nti o n al Cli nic al Tri als
Merc k S h ar p & D o h me L L C, R a h w a y, N J, U S A ( M S D)
I.
I ntr o d ucti o n
A.
P ur p ose
Merc k S har p & D o h me L L C, Ra h wa y, NJ, U S A ( M S D), t hr o u g h its s u bsi diaries, 
c o n d ucts cli nical trials w orl d wi de t o e val uate t he safet y a n d effecti ve ness of o ur 
pr o d ucts. As s uc h, we are c o m mitte d t o desi g ni n g, pla n ni n g, c o n d ucti n g, a nal yzi n g, 
a n d re p orti n g t hese trials i n c o m plia nce wit h t he hi g hest et hical a n d scie ntific 
sta n dar ds. Pr otecti o n of partici pa nts i n cli nical trials is t he o verri di n g c o ncer n i n t he 
desi g n a n d c o n d uct of cli nical trials. I n all cases, M S D cli nical trials will be 
c o n d ucte d i n c o m plia nce wit h M S D’s gl o bal sta n dar ds, l ocal a n d/ or nati o nal 
re g ulati o ns (i ncl u di n g all a p plica ble data pr otecti o n la ws a n d re g ulati o ns), a n d 
I nter nati o nal C o u ncil f or Har m o nisati o n G o o d Cli nical Practice (I C H G C P) E 6 a n d 
I C H Ge neral C o nsi derati o ns f or Cli nical St u dies E 8, a n d i n acc or da nce wit h t he 
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.
B.
Sc o pe
Hi g hest et hical a n d scie ntific sta n dar ds s hall be e n d orse d f or all cli nical 
i nter ve nti o nal i n vesti gati o ns s p o ns ore d b y M S D irres pecti ve of t he part y ( parties) 
e m pl o ye d f or t heir e xec uti o n (e. g., c o ntract researc h or ga nizati o ns, c olla b orati ve 
researc h eff orts). T his C o de is n ot i nte n de d t o a p pl y t o trials t hat are o bser vati o nal i n 
nat ure, or w hic h are retr os pecti ve. F urt her, t his C o de d oes n ot a p pl y t o i n vesti gat or -
i nitiate d trials, w hic h are n ot u n der t he f ull c o ntr ol of M S D.
II. Scie ntific Iss ues
A.
Tri al C o n d uct
1.
Tri al Desi g n
E xce pt f or pil ot or esti mati o n trials, cli nical trial pr ot oc ols will be h y p ot hesis -
dri ve n t o assess safet y, efficac y, a n d/ or p har mac o ki netic or p har mac o d y na mic 
i n dices of M S D or c o m parat or pr o d ucts. Alter nati vel y, M S D ma y c o n d uct 
o u tc o mes researc h trials, trials t o assess or vali date vari o us e n d p oi nt meas ures, or 
trials t o deter mi ne patie nt prefere nces, etc.
T he desi g n (i.e., partici pa nt p o p ulati o n, d urati o n, statistical p o wer) m ust be 
a de q uate t o a d dress t he s pecific p ur p ose of t he trial a n d s hall res pect t he data 
pr otecti o n ri g hts of all partici pa nts, trial site staff a n d, w here a p plica ble, t hir d 
parties. I n p ut ma y be c o nsi dere d fr o m a br oa d ra n ge of sta ke h ol ders, i ncl u di n g 
patie nt a d v ocac y gr o u ps/ patie nts re prese nti n g t he trial p o p ulati o n, care gi vers, a n d 
healt hcare pr o vi ders t o e ns ure o perati o nal feasi bilit y. Trial desi g n als o i ncl u des 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
pr oacti ve i de ntificati o n of critical t o q ualit y fact ors utilizi n g a ris k -base d 
a p pr oac h. Pla ns are t he n de vel o pe d t o assess a n d miti gate ris ks t o t h ose fact ors as 
a p pr o priate d uri n g t he trial. All trial pr ot oc ols are a n d will be assesse d f or t he 
nee d a n d ca pa bilit y t o e nr oll u n derre prese nte d gr o u ps. Partici pa nts m ust meet 
pr ot oc ol e ntr y criteria t o be e nr olle d i n t he trial.
2.
Site Selecti o n
M S D’s cli nical trials are c o n d ucte d gl o ball y i n ma n y differe nt c o u ntries a n d i n 
di verse p o p ulati o ns, i ncl u di n g pe o ple of var yi n g a ge, race, et h nicit y, ge n der, a n d 
acc o u nti n g f or ot her p ote ntial disease relate d fact ors. M S D selects i n vesti gati ve 
sites base d o n me dical e x pertise, access t o a p pr o priate partici pa nts, a de q uac y of 
facilities a n d staff, pre vi o us perf or ma nce i n cli nical trials, as well as b u d getar y 
c o nsi derati o ns. Pri or t o trial i nitiati o n, sites are e val uate d b y M S D pers o n nel ( or 
i n di vi d uals acti n g o n be half of M S D) t o assess t he a bilit y t o s uccessf ull y c o n d uct 
t he trial. I n di vi d uals i n v ol ve d i n trial c o n d uct recei ve trai ni n g c o m me ns urate wit h 
t heir r ole pri or t o t heir bec o mi n g i n v ol ve d i n t he trial.
W here a p pr o priate, a n d i n acc or da nce wit h re g ulat or y a ut h orit y g ui da nce, M S D 
will ma ke c o ncerte d eff orts t o raise a ware ness of cli nical trial o p p ort u nities i n 
vari o us c o m m u nities. M S D will see k t o e n ga ge u n derre prese nte d gr o u ps a n d 
t h ose dis pr o p orti o natel y i m pacte d b y t he disease u n der st u d y. M S D will s u p p ort 
cli nical trial i n vesti gat ors t o e nr oll u n derre prese nte d gr o u ps a n d e x pa n d access t o 
t h ose w h o will ulti matel y use t he pr o d ucts u n der i n vesti gati o n.
3.
Site M o nit ori n g/ Scie ntific I nte grit y
I n vesti gati ve trial sites are m o nit ore d t o assess c o m plia nce wit h t he trial pr ot oc ol 
a n d G o o d Cli nical Practice ( G C P). M S D re vie ws cli nical data f or acc urac y, 
c o m plete ness, a n d c o nsiste nc y. Data are verifie d vers us s o urce d oc u me ntati o n 
acc or di n g t o sta n dar d o perati n g pr oce d ures. Per M S D p olicies a n d pr oce d ures, if 
p ote ntial fra u d, scie ntific/researc h misc o n d uct, pri vac y i nci de nts/ breac hes or 
Cli nical Trial -relate d Si g nifica nt Q ualit y Iss ues are re p orte d, s uc h matters are 
i n vesti gate d. W he n necessar y, a p pr o priate c orrecti ve a n d/ or pre ve ntati ve acti o ns 
are defi ne d a n d re g ulat or y a ut h orities a n d/ or et hics re vie w c o m mittees are 
n otifie d.
B.
P u blic ati o n a n d A ut h ors hi p
Re gar dless of trial o utc o me, M S D c o m mits t o p u blis h t he pri mar y a n d sec o n dar y 
res ults of its re gistere d trials of mar kete d pr o d ucts i n w hic h treat me nt is assi g ne d, 
acc or di n g t o t he pre-s pecifie d pla ns f or data a nal ysis. T o t he e xte nt scie ntificall y 
a p pr o priate, M S D see ks t o p u blis h t he res ults of ot her a nal yses it c o n d ucts t hat are 
i m p orta nt t o patie nts, p h ysicia ns, a n d pa yers. S o me earl y p hase or pil ot trials are 
i nten de d t o be h y p ot hesis ge nerati n g rat her t ha n h y p ot hesis testi n g; i n s uc h cases, 
p u blicati o n of res ults ma y n ot be a p pr o priate si nce t he trial ma y be u n der p o were d a n d 
t he a nal yses c o m plicate d b y statistical iss ues s uc h as m ulti plicit y.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
M S D’s p olic y o n a ut h o rs hi p is c o nsiste nt wit h t he rec o m me n dati o ns p u blis he d b y t he 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E). I n s u m mar y, 
a ut h ors hi p s h o ul d reflect si g nifica nt c o ntri b uti o n t o t he desi g n a n d c o n d uct of t he 
trial, perf or ma nce or i nter pretati o n of t he a nal ysis, a n d/ or writi n g of t he ma n uscri pt. 
All na me d a ut h ors m ust be a ble t o defe n d t he trial res ults a n d c o ncl usi o ns. M S D 
f u n di n g of a trial will be ac k n o wle d ge d i n p u blicati o ns.
III. P artici p a nt Pr otecti o n
A.
Re g ul at or y A ut h orit y a n d Et hics C o m mit tee Re vie w (I nstit uti o n al Re vie w B o ar d 
[I R B]/I n de pe n de nt Et hics C o m mittee [I E C])
All pr ot oc ols a n d pr ot oc ol a me n d me nts will be s u b mitte d b y M S D f or re g ulat or y 
a ut h orit y acce pta nce/a ut h orizati o n pri or t o i m ple me ntati o n of t he trial or a me n d me nt, 
i n c o m plia nce wit h l ocal a n d/ or nati o nal re g ulati o ns.
T he pr ot oc ol, pr ot oc ol a me n d me nt(s), i nf or me d c o nse nt f or m, i n vesti gat or’s 
br oc h ure, a n d ot her rele va nt trial d oc u me nts m ust be re vie we d a n d a p pr o ve d b y a n 
I R B/I E C bef ore bei n g i m ple me nte d at eac h site, i n c o m pliance wit h l ocal a n d/ or 
nati o nal re g ulati o ns a n d I C H G ui deli nes. C ha n ges t o t he pr ot oc ol t hat are re q uire d 
ur ge ntl y t o eli mi nate a n i m me diate hazar d a n d t o pr otect partici pa nt safet y ma y be 
e nacte d i n a ntici pati o n of et hics c o m mittee a p pr o val. M S D will i nf or m re g ulat or y 
a ut h orities of s uc h ne w meas ures t o pr otect partici pa nt safet y, i n c o m plia nce wit h 
l ocal a n d/ or nati o nal re g ulati o ns.
B.
S afet y
T he g ui di n g pri nci ple i n decisi o n -ma ki n g i n cli nical trials is t hat partici pa nt welfare is 
of pri mar y i m p orta nce. P ote ntial partici pa nts will be i nf or me d of t he ris ks a n d 
be nefits of, as well as alter nati ves t o, trial partici pati o n. At a mi ni m u m, trial desi g ns 
will ta ke i nt o acc o u nt t he l ocal sta n dar d of care.
All partici pati o n i n M S D cli nical trials is v ol u ntar y. Partici pa nts e nter t he trial o nl y 
after i nf or me d c o nse nt is o btai ne d. Trial desi g ns i ncl u de pr oce d ures a n d s yste ms f or 
t he i de ntificati o n, m o nit ori n g, a n d re p orti n g of safet y c o ncer ns. Partici pa nts ma y 
wit h dra w fr o m a n M S D trial at a n y ti me, wit h o ut a n y i nfl ue nce o n t heir access t o, or 
recei pt of, me dical care t hat ma y ot her wise be a vaila ble t o t he m.
D uri n g trial pla n ni n g, t he nee d f or a n i n de pe n de nt Data M o nit ori n g C o m mittee 
( D M C) is assesse d. D M C re vie w of data acc u m ulate d d uri n g t he c o n d uct of t he trial 
is inte gral t o t he well -bei n g of trial partici pa nts.
C.
C o nfi de nti alit y
M S D is c o m mitte d t o safe g uar di n g partici pa nt c o nfi de ntialit y, t o t he greatest e xte nt 
p ossi ble, as well as all a p plica ble data pr otecti o n ri g hts. U nless re q uire d b y la w, o nl y 
t he i n vesti gat or, S p o ns or ( or i n di vi d uals acti n g o n be half of M S D), et hics c o m mittee, 
a n d/ or re g ulat or y a ut h orities will ha ve access t o c o nfi de ntial me dical rec or ds t hat 
mi g ht i de ntif y t he partici pa nt b y na me.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
D.
Ge n o mic Rese arc h
Ge n o mic researc h will o nl y be c o n d ucte d i n acc or da nce wit h a pr ot oc ol a n d i nf or me d 
c o nse nt a ut h orize d b y a n et hics c o m mittee.
E.
Tri al Res ults
At t he ti me of pr o vi di n g i nf or me d c o nse nt a n d i n acc or da nce wit h l ocal la ws a n d 
re g ulati o ns, partici pa nts s h o ul d be i nf or me d a b o ut t he pla ns f or a vaila bilit y of trial 
res ults.
I V. Fi n a nci al C o nsi der ati o ns
A.
P a y me nts t o I n vesti g at ors
Cli nical trials are ti me - a n d la b or-i nte nsi ve. It is M S D’s p olic y t o c o m pe nsate 
i n vesti gat ors ( or t he s p o ns ori n g i nstit uti o n) i n a fair ma n ner f or t he w or k perf orme d 
i n s u p p ort of M S D trials. M S D d oes n ot pa y i nce nti ves t o e nr oll partici pa nts i n its 
trials. H o we ver, w he n e nr oll me nt is partic ularl y c halle n gi n g, a d diti o nal pa y me nts 
ma y be ma de t o c o m pe nsate f or t he ti me s pe nt i n e xtra recr uiti n g eff orts.
M S D d oes n ot
pa y f or partici pa nt referrals. H o we ver, M S D ma y c o m pe nsate 
referri n g p h ysicia ns f or ti me s pe nt o n me dical rec or d re vie w a n d me dical e val uati o n 
t o i de ntif y p ote ntiall y eli gi ble partici pa nts.
B.
Cli nic al Rese arc h F u n di n g
I nf or me d c o nse nt f or ms will discl ose t hat t he trial is s p o ns ore d b y M S D, a n d t hat t he 
i n vesti gat or or s p o ns ori n g i nstit uti o n is bei n g pai d or pr o vi de d a gra nt f or perf or mi n g 
t he trial. H o we ver, t he l ocal et hics c o m mittee ma y wis h t o alter t he w or di n g of t he 
discl os ure state me nt t o be c o nsist e nt wit h fi na ncial practices at t hat i nstit uti o n. As 
n ote d a b o ve, all p u blicati o ns res ulti n g fr o m M S D trials will i n dicate M S D as a s o urce 
of f u n di n g.
C.
F u n di n g f or Tr a vel a n d Ot her Re q uests
F u n di n g of tra vel b y i n vesti gat ors a n d s u p p ort staff (e. g., t o s cie ntific meeti n gs, 
i n vesti gat or meeti n gs, etc) will be c o nsiste nt wit h l ocal g ui deli nes a n d practices.
V.
I n vesti g at or C o m mit me nt
I n vesti gat ors will be e x pecte d t o re vie w M S D’s C o de of C o n d uct as a n a p pe n di x t o t he 
trial pr ot oc ol, a n d i n si g ni n g t he pr ot oc ol, a gree t o s u p p ort t hese et hical a n d scie ntific 
sta n dar ds.
1 0. 1. 2
Fi n a nci al Discl os ure
Fi na ncial discl os ure re q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi na ncial Discl os ure b y Cli nical I n vesti gat ors ( 2 1 C F R Part 5 4). It is t he
S p o ns or’s res p o nsi bilit y t o deter mi ne, base d o n t hese re g ulati o ns, w het her a re q uest f or 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
fi na ncial discl os ure i nf or mati o n is re q uire d. It is t he i n vesti gat or’s/s u bi n vesti gat or’s 
res p o nsi bilit y t o c o m pl y wit h a n y s uc h re q uest.
T he i n vesti gat or/s u bi n vesti ga t or(s) a gree, if re q ueste d b y t he S p o ns or i n acc or da nce wit h 2 1 
C F R Part 5 4, t o pr o vi de his/ her fi na ncial i nterests i n a n d/ or arra n ge me nts wit h t he S p o ns or t o 
all o w f or t he s u b missi o n of c o m plete a n d acc urate certificati o n a n d discl os ure state me nts. 
T he i n vesti gat or/s u bi n vesti gat or(s) f urt her a gree t o pr o vi de t his i nf or mati o n o n a 
Certificati o n/ Discl os ure F or m, fre q ue ntl y k n o w n as a fi na ncial discl os ure f or m, pr o vi de d b y 
t he S p o ns or. T he i n vesti gat or/s u bi n vesti gat or(s) als o c o nse nt t o t he tra ns missi o n of t his 
i nf or mati o n t o t he S p o ns or i n t he U nite d States f or t hese p ur p oses. T his ma y i n v ol ve t he 
tra ns missi o n of i nf or mati o n t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g pers o nal data.
1 0. 1. 3
D at a Pr otecti o n
T he S p o ns or will c o n d uct t his st u d y i n c o m plia nce wit h all a p plica ble data pr otecti o n 
re g ulati o ns.
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he S p o ns or. A n y partici pa nt rec or ds or 
datasets t hat are tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt na mes 
or a n y inf or mati o n t hat w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d.
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 data will be use d b y t he 
S p o ns or i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ned 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 priate 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 h orities.
1 0. 1. 3. 1
C o nfi de nti alit y of D at a
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or affir ms t o t he S p o ns or t hat i nf or mati o n f ur nis he d t o 
t he i n vesti gat or b y t he S p o ns or will be mai ntai ne d i n c o nfi de nce, a n d s uc h i nf or mati o n will 
be di v ul ge d t o t he I R B, I E C, or si milar or e x pert c o m mittee , affiliate d i nstit uti o n , a n d 
e m pl o yees, o nl y u n der a n a p pr o priate u n dersta n di n g of c o nfi de ntialit y wit h s uc h b oar d or 
c o m mittee, affiliate d i nstit uti o n , a n d e m pl o yees. Data ge nerate d b y t his st u d y will be 
c o nsi dere d c o nfi de ntial b y t he i n vesti gat or, e xce pt t o t he e xte nt t hat it is i ncl u de d i n a 
p u blicati o n as pr o vi de d i n t he P u blicati o ns secti o n of t his pr ot oc ol.
1 0. 1. 3. 2
C o nfi de nti alit y of P artici p a nt Rec or ds
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t hat t he S p o ns or ( or S p o ns or re prese ntati ve), 
I R B/I E C, or re g ulat or y a ut h orit y re prese ntati ves ma y c o ns ult a n d/ or c o p y st u d y d oc u me nts t o 
verif y w or ks heet/ C R F data. B y si g ni n g t he c o nse nt f or m, t he partici pa nt a grees t o t his 
pr ocess. If st u d y d oc u me nts will be p h ot oc o pie d d uri n g t he pr ocess of verif yi n g 
w or ks heet/ C R F i nf or mati o n, t he partici pa nt will be i de ntifie d b y u ni q ue c o de o nl y; f ull 
na mes/i nitials will be mas ke d bef ore tra ns missi o n t o t he S p o ns or.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o treat all partici pa nt data use d a n d 
discl ose d i n c o n necti o n wit h t his st u d y i n acc or da nce wit h all a p plica ble pri vac y la ws, r ules ,
a n d re g ulati o ns.
1 0. 1. 3. 3
C o nfi de nti alit y of I R B/I E C I nf or m ati o n
T he S p o ns or is re q uire d t o rec or d t he na me a n d a d dress of eac h I R B/I E C t hat re vie ws a n d 
a p pr o ves t his st u d y. T he S p o ns or is als o re q uire d t o d oc u me nt t hat eac h I R B/I E C meets 
re g ulat or y a n d I C H G C P re q uire me nts b y re q uesti n g a n d mai ntai ni n g rec or ds of t he na mes 
a n d q ualificati o ns of t he I R B/I E C me m bers a n d t o ma ke t hese rec or ds a va ila ble f or 
re g ulat or y a ge nc y re vie w u p o n re q uest b y t h ose a ge ncies.
1 0. 1. 4
C o m mittees Str uct ure
1 0. 1. 4. 1
E xter n al D at a M o nit ori n g C o m mittee
T o s u p ple me nt t he r o uti ne st u d y m o nit ori n g o utli ne d i n t his pr ot oc ol, a n e xter nal D M C will 
m o nit or t he i nteri m data fr o m t his st u d y. T he v oti n g me m bers of t he c o m mittee are e xter nal 
t o t he S p o ns or. T he me m bers of t he D M C m ust n ot be i n v ol ve d wit h t he st u d y i n a n y ot her 
wa y (e g, t he y ca n n ot be st u d y i n vesti gat ors) a n d m ust ha ve n o c o m peti n g i nterests t hat c o ul d 
affect t heir r oles wit h r es pect t o t he st u d y.
T he D M C will ma ke rec o m me n dati o ns t o t he E O C re gar di n g ste ps t o e ns ure b ot h partici pa nt 
safet y a n d t he c o nti n ue d et hical i nte grit y of t he st u d y. Als o, t he D M C will re vie w i nteri m 
st u d y res ults, c o nsi der t he o verall ris k a n d be nefit t o st u d y partici pa nts (Secti o n 9. 7 I nteri m
A nal ysis ) a n d rec o m me n d t o t he E O C w het her t he st u d y s h o ul d c o nti n ue i n acc or da nce wit h 
t he pr ot oc ol.
S pecific details re gar di n g c o m p ositi o n, res p o nsi bilities, a n d g o ver na nce, i ncl u di n g t he r oles 
a n d res p o nsi bilities of t he vari o us me m bers a n d t he S p o ns or pr ot oc ol tea m ; meeti n g 
facilitati o n; t he st u d y g o ver na nce str uct ure; a n d re q uire me nts f or a n d pr o per d oc u me ntati o n 
of D M C re p orts, mi n utes, a n d rec o m me n dati o ns will be descri be d i n t he D M C c harter t hat is 
re vie we d a nd a p pr o ve d b y all t he D M C me m bers.
1 0. 1. 5
P u blic ati o n P olic y
T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. 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 me nt.
If p u blicati o n acti vit y is n ot directe d b y t he S p o ns or, 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 prietar y i nf or mati o n a n d t o pr o vi de c o m me nts.
A ut h ors hi p will be deter mi ne d b y m ut ual a gree me nt a n d i n li ne wit h I C MJ E a ut h ors hi p 
re q uire me nts.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 1. 6
C o m pli a nce wit h St u d y Re gistr ati o n a n d Res ults P osti n g Re q uire me nts
U n der t he ter ms of t he F D A A A of 2 0 0 7 a n d t he E M A cli nical trial Directi ve 2 0 0 1/ 2 0/ E C, t he 
S p o ns or of t he st u d y is s olel y res p o nsi ble f or de ter mi ni n g w het her t he st u d y a n d its res ults 
are s u bject t o t he re q uire me nts f or s u b missi o n t o htt p:// w w w.cli nicaltrials. g o v, 
w w w.cli nicaltrialsre gister.e u , or ot her l ocal re gistries. M S D, as S p o ns or of t his st u d y, will 
re vie w t his pr ot oc ol a n d s u b mit t he inf or mati o n necessar y t o f ulfill t hese re q uire me nts. M S D 
e ntries are n ot li mite d t o F D A A A or t he E M A cli nical trials directi ve ma n date d trials. 
I nf or mati o n p oste d will all o w partici pa nts t o i de ntif y p ote ntiall y a p pr o priate st u dies f or t heir 
disease c o n diti o ns a n d p urs ue partici pati o n b y calli n g a ce ntral c o ntact n u m ber f or f urt her 
i nf or mati o n o n a p pr o priate st u d y l ocati o ns a n d st u d y-site c o ntact i nf or mati o n.
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or ac k n o wle d ges t hat t he stat ut or y o bli gati o ns u n der 
F D A A A, t he E M A cli nical trials directi ve, or ot her l ocall y ma n date d re gistries are t hat of t he 
S p o ns or a n d a grees n ot t o s u b mit a n y i nf or mati o n a b o ut t his st u d y or its res ults t o t h ose 
re gistries.
1 0. 1. 7
C o m pli a nce wit h L a w, A u dit, a n d De b ar me nt
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o c o n d uct t he st u d y i n a n efficie nt a n d 
dili ge nt ma n ner a n d i n c o nf or ma nce wit h t his pr ot oc ol , ge nerall y acce pte d sta n dar ds of G C P 
(e g, I C H G C P: C o ns oli date d G ui deli ne a n d ot her ge nerall y acce pte d sta n dar ds of G C P), a n d 
all a p plica ble fe deral, state , a n d l ocal la ws, r ules , a n d re g ulati o ns relati n g t o t he c o n d uct of 
t he cli nical st u d y.
T he C o de of C o n d uct, a c ollecti o n of g oals a n d c o nsi derati o ns t hat g o ver n t he et hical a n d 
scie ntific c o n d uct of cli nical i n vesti gati o ns s p o ns ore d b y M S D, is pr o vi de d i n t his a p pe n di x 
u n der t he C o de of C o n d uct f or Cli nical Trials.
T he i n vesti gat or a grees n ot t o see k rei m b urse me nt fr o m partici pa nts, t heir i ns ura nce 
pr o vi ders, or fr o m g o ver n me nt pr o gra ms f or pr oce d ures i ncl u de d as part of t he st u d y 
rei m b urse d t o t he i n vesti gat or b y t he S p o ns or.
T he i n vesti gat or will pr o m ptl y i nf or m t he S p o ns or of a n y re g ulat or y a ut h orit y i ns pecti o n 
c o n d ucte d f or t his st u d y.
T he i n vesti gat or a grees t o pr o vi de t he S p o ns or wit h rele va nt i nf or mati o n fr o m i ns pecti o n 
o bser vati o ns/fi n di n gs t o all o w t he S p o ns or t o assist i n res p o n di n g t o a n y citati o ns res ulti n g 
fr o m re g ulat or y a ut h orit y i ns pecti o n a n d will pr o vi de t he S p o ns or wit h a c o p y of t he 
pr o p ose d res p o nse f or c o ns ultati o n bef ore s u b missi o n t o t he re g ula t or y a ut h orit y.
Pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical st u dies b y a n y c o urt or re g ulat or y 
a ut h orit y will n ot be all o we d t o c o n d uct or w or k o n t his S p o ns or’s st u dies. T he i n vesti gat or 
will i m me diatel y discl ose i n writi n g t o t he S p o ns or if a n y pers o n w h o is i n v ol ve d i n 
c o n d ucti n g t he st u d y is de barre d or if a n y pr ocee di n g f or de bar me nt is pe n di n g or, t o t he best 
of t he i n vesti gat or’s k n o wle d ge, t hreate ne d.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 4 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
F or i n vesti gat ors l ocate d i n c o u ntries wit h seri o us breac h re p orti n g re q uire me nts, i n ve sti gat or 
will pr o m ptl y re p ort t o t he S p o ns or a n y seri o us breac h or s us pecte d seri o us breac h t hat 
occ urs i n c o m plia nce wit h t h ose re q uire me nts. U nless m ore s pecificall y defi ne d i n t he 
a p plica ble re q uire me nts, a seri o us breac h is a n y breac h of t he a p plica ble cli nical trial 
re g ulati o n or of t he cli nical trial pr ot oc ol w hic h is li kel y t o affect t o a si g nifica nt de gree: (i) 
t he safet y or ri g hts of a trial partici pa nt, or (ii) t he relia bilit y a n d r o b ust ness of t he data 
ge nerate d i n t he cli nical trial .
1 0. 1. 8
D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or 
or q ualifie d desi g nee is res p o nsi ble f or 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 nicall y si g ni n g t he C R F.
Detaile d i nf or mati o n re gar di n g Data Ma na ge me nt pr oce d ures f or t his pr ot oc ol will be 
pr o vi de d se paratel y.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F.
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.
St u d y d oc u me ntati o n will be pr o m ptl y a n d f ull y discl ose d t o t he S p o ns or b y t he i n vesti gat or 
u p o n re q uest a n d als o s hall be ma de a vaila ble at t he st u d y site u p o n re q uest f or i ns pecti o n, 
c o p yi n g, re vie w, a n d a u dit at reas o na ble ti mes b y re prese ntati ves of t he S p o ns or or a n y 
re g ulat or y a ut h orities. T he i n vesti gat or a grees t o pr o m ptl y ta ke a n y reas o na ble ste ps t hat are 
re q ueste d b y t he S p o ns or or a n y re g ulat or y a ut h orities as a res ult of a n a u dit or i ns pecti o n t o 
c ure deficie ncies i n t he st u d y d oc u me ntati o n a n d w or ks heets/ C R Fs.
T he S p o ns or or de si 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.
St u d y m o nit ors will perf or m o n g oi n g s o urce data re vie w a n d verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he 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 oc 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.
Rec or ds a n d d oc u me nts, i ncl u di n g partici pa nts’ d oc u me nte d i nf or me d c o nse nt, pertai ni n g t o 
t he c o n d uct of t his st u d y m ust be retai ne d b y t he i n vesti gat or f or 1 5 years after st u d y 
c o m pleti o n u nless l ocal re g ulati o ns or i nstit ut i o nal p olicies re q uire a l o n ger rete nti o n peri o d. 
N o rec or ds ma y be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he 
S p o ns or. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n 
n otificati o n t o t he S p o ns or.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 1. 9
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. T he i n vesti gat or/i nstit uti o n s h o ul d mai ntai n a de q uate a n d 
acc urate s o urce d oc u me nts a n d st u d y rec or ds t hat i ncl u de all perti ne nt o bser vati o ns o n eac h 
of t he site’s partici pa nts. S o urce d oc u me nts a n d data s h o ul d be attri b uta ble, le gi ble, 
c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete. C ha n ges t o s o urce data s h o ul d be 
tracea ble, s h 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 d oc u me nts are file d at t he i n vesti gat or’s site.
Data re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me 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 ne d. T he 
i n vesti gat or/i nstit uti o n 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. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
1 0. 1. 1 0
St u d y a n d Site Cl os ure
T he S p o ns or or its desi g nee ma y st o p t he st u d y or st u d y -site partici pati o n i n t he st u d y f or 
me dical, safet y, re g ulat or y, a d mi nistrati ve, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, 
re g ulati o ns, a n d G C P.
I n t he e ve nt t he S p o ns or pre mat urel y ter mi nates a partic ular st u d y site, the S p o ns or or 
desi g nee will pr o m ptl y n otif y t hat st u d y site’s I R B/I E C as s pecifie d b y a p plica ble re g ulat or y 
re q uire me nt(s).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 2
A p pe n di x 2 : Cli nic al L a b or at or y Tests
T he tests detaile d i n Ta ble 2 0 will be perf or me d b y t he ce ntral la b orat or y.
Res ults of pre d ose la b orat or y pr oce d ures m ust be re vie we d b y t he i n vesti gat or or q ualifie d 
desi g nee a n d f o u n d t o be acce pta ble pri or t o eac h d ose of pe m br oliz u ma b/ place b o. After 
ra n d o mizati o n, l ocal la b orat or y res ults are per mitte d i n t he e ve nt t hat t he ce ntral la b orat or y 
res ults are n ot a vaila ble i n ti me f or eit her st u d y i nter ve nti o n a d mi nistrati o n a n d/ or res p o nse 
e val uati o n. If a l ocal sa m ple is u se d, it is i m p orta nt t hat t he sa m ple f or ce ntral a nal ysis is 
o btai ne d i n parallel. A d diti o nall y, if t he use of l ocal la b orat or y test res ults i n a c ha n ge i n 
st u d y partici pa nt ma na ge me nt, or are c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or (e g, 
S A E or A E or d ose m o dificati o n), t he n t he res ults m ust be rec or de d i n t he a p pr o priate C R F. 
Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e xcl usi o n of partici pa nts are detaile d i n 
Secti o n 5. 1 a n d Secti o n 5. 2 of t he pr ot oc ol, res pecti vel y .
A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d necessar y b y 
t he i n vesti gat or or re q uire d b y l ocal re g ulati o ns.
P D -L 1 a n d P S A res ults are n ot re p orte d bac k t o sites t o pre ve nt earl y wit h dra wal of 
partici pa nts fr o m st u d y i nter ve nti o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
Ta ble 2 0
Pr ot oc ol -re q uire d Safet y La b orat or y Assess me nts
L a b or at or y 
Assess me nts
P ar a meters
He mat ol o g y
Platelet C o u nt 
R B C I n dices:
M C V
M C H
Retic ul oc ytes
W B C c o u nt wit h 
Differe ntial:
A bs ol ute Ne utr o p hil C o u nt 
( A N C)
L y m p h oc ytes
M o n oc ytes
E osi n o p hils
Bas o p hils
R B C C o u nt
He m o gl o bi n
He mat ocrit
C he mistr y
Bl o o d Urea Nitr o ge n 
( B U N)
P otassi u m
As partate 
A mi n otra nsferase
( A S T)/ Ser u m Gl uta mic-
O xal oacetic 
Tra nsa mi nase ( S G O T)
T otal bilir u bi n 
(a n d direct 
bilir u bi n, if t otal 
bilir u bi n is 
ele vate d a b o ve 
t he u p per li mit of 
n or mal)
Al b u mi n
Bicar b o nate
C hl ori de
P h os p h or o us
Creati ni ne
S o di u m
Ala ni ne 
A mi n otra nsferase
( A L T)/ Ser u m Gl uta mic-
P yr u vic Tra nsa mi nase 
( S G P T)
T otal Pr otei n
Gl uc ose ( n o nfasti n g)
Calci u m
Al kali ne p h os p hatase
R o uti ne Uri nal ysis
•
S pecific gra vit y
•
p H, gl uc ose, pr otei n, bl o o d, ket o nes, bilir u bi n, ur o bili n o ge n, nitrite, le u k oc yte 
esterase 
•
Micr osc o pic e xa mi nati o n (if bl o o d or pr otei n is a b n or mal)
Ot her Tests
•
Test oster o ne ( n ot re q uire d t o be re vie we d pre d ose)
•
T h yr oi d f u ncti o n tests
•
P T or I N R a n d P T T/a P T T
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 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 U N bl o o d urea nitr o ge n; I N R i nter nati o nal n or maliz e d rati o; M C H
mea n c or p usc ular 
he m o gl o bi n; M C V
mea n c or p usc ular v ol u me; P T pr ot hr o m bi n ti me; P T T partial t hr o m b o plasti n ti me; R B C re d bl o o d 
cell; S G O T ser u m gl uta mic o xal oacetic tra nsa mi nase; S G P T ser u m gl uta mic p yr u vic tra nsa mi nase; W B C
w hite bl o o d 
cell.
T he i n vesti gat or ( or me dicall y q ualifie d desi g nee) m ust d oc u me nt t heir re vie w of eac h 
la b orat or y safet y re p ort.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 3
A p pe n di x 3 : A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
1 0. 3. 1
Defi niti o ns of Me dic ati o n Err or, Mis use, a n d A b use
Me dic ati o n Err or
T his is a n u ni nte n de d fail ure i n t he dr u g treat me nt pr ocess t hat lea ds t o or has t he p ote ntial t o 
lea d t o har m t o t he patie nt.
Mis use
T his refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y a n d i na p pr o priatel y use d 
n ot i n acc or da nce wit h t he ter ms of t he pr o d uct i nf or mati o n.
A b use
T his c orres p o n ds t o t he persiste nt or s p ora dic i nte nti o nal , e xcessi ve use of a me dici nal 
pr o d uct f or a percei ve d ps yc h ol o gical or p h ysi ol o gical re war d or desire d n o n t hera pe utic 
effect.
1 0. 3. 2
Defi niti o n of A E
A E defi niti o n
•
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical st u d y partici pa nt, te m p orall y 
ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot c o nsi dere d relate d t o t he 
st u d y i nter ve nti o n.
•
N ote: A n A E ca n t heref ore be a n y u nfa v ora ble a n d 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 a st u d y i nter ve nti o n.
•
N ote: F or p ur p oses of A E defi niti o n, st u d y i nter ve nti o n i ncl u des a n y p har mace utical 
pr o d uct, bi ol o gical pr o d uct, vacci ne, dia g n ostic a ge nt, me dical de vice, c o m bi nati o n 
pr o d uct, or pr ot oc ol -s pecifie d pr oce d ure w het her i n vesti gati o nal or mar kete d (i ncl u di n g 
place b o, acti ve c o m parat or pr o d uct, or r u n -i n i nter ve nti o n), ma n ufact ure d b y, lice nse d 
b y, pr o vi de d b y, or distri b ute d b y t he S p o ns or f or h u ma n use i n t his st u d y.
E ve nts meeti n g t he A E defi niti o n
•
A n y a b n or ma l la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e g, E C G, ra di ol o gical sca ns, 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.
•
E xacer bati o n of a c hr o nic or i nter mitte nt pree xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
Ne w c o n diti o ns detecte d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of t he st u d y.
•
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.
•
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o nc o mita nt me dicati o n.
•
F or all re p orts of o ver d ose ( w het her acci de ntal or i nte nti o nal) wit h a n ass ociate d A E, t he 
A E ter m s h o ul d reflect t he cli nical s y m pt o ms or a b n or mal test res ult. A n o ver d ose 
wit h o ut a n y ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y r es ults is re p orte d usi n g 
t he ter mi n ol o g y “acci de ntal or i nte nti o nal o ver d ose wit h o ut a d verse effect.”
E ve nts N O T meeti n g t he A E defi niti o n
•
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): t he c o n diti o n t hat lea ds t o 
t he pr oce d ure is t he A E.
•
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).
•
A ntici pate d da y -t o-da y fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t he st u d y t hat d o n ot w o rse n.
•
S ur gical pr oce d ure(s) pla n ne d pri or t o i nf or me d c o nse nt t o treat a pree xisti n g c o n diti o n 
t hat has n ot w orse ne d.
•
Refer t o Secti o n 8. 4. 6 f or pr ot oc ol -s pecific e xce pti o ns.
1 0. 3. 3
Defi niti o n of S A E
If a n e ve nt is n ot a n A E per 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.
A n S A E 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 deat h
b.
Is life-t hreate 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 e ve nt i n w hic h 
t he partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d deat h, if it were m ore se vere.
c.
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
-
H os pitalizati o n is defi ne d as a n i n patie nt a d missi o n, re gar dless of le n gt h of sta y, e ve n 
if t he h os pitalizati o n is a preca uti o nar y meas ure f or c o nti n ue d o bser vati o n. ( N ote: 
H os pitalizati o n f or a n electi ve pr oce d ure t o treat a pree xisti n g c o n diti o n t hat has n ot 
w orse ne d is n ot a n S A E.) A pree xisti n g c o n diti o n is a cli nical c o n diti o n t hat is 
dia g n ose d pri or t o t he use of a n M S D pr o d uct a n d is d oc u me nte d i n t he partici pa nt’s 
me dical hist or y.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
d.
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit 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 nital a n o mal y/ birt h defect
-
I n offs pri n g of partici pa nt ta ki n g t he pr o d uct re gar dless of ti me t o dia g n osis.
f.
Ot her i m p orta nt me dical e ve nts
-
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y 
n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y 
je o par dize t he partici pa nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 1 
of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y be 
c o nsi dere d seri o us.
-
E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n 
a n e mer ge nc y r o o m 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.
1 0. 3. 4
A d diti o n al E ve nts Re p orte d
A d diti o n al e ve nts t h at re q uire re p orti n g
I n a d diti o n t o t he a b o ve criteria, A Es meeti n g eit her of t he bel o w criteria, alt h o u g h n ot 
seri o us per I C H defi niti o n, are re p orta ble t o t he S p o ns or.
•
Is a ne w ca ncer (t hat is n ot t he ca ncer u n der st ud y ) as n ote d i n Secti o n 8. 4. 1 .
•
Is ass ociate d wit h a n o ver d ose.
1 0. 3. 5
Rec or di n g A E a n d S A E
A E a n d S A E rec or di n g
•
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, a n d dia g n ostics re p orts) relate d t o 
t he e ve nt.
•
T he i n vesti gat or will rec or d all rele va nt A E/ S A E i nf or mati o n o n t he A E 
C R Fs/ w or ks heets at eac h e xa mi nati o n.
•
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 t o t he S p o ns or i n lie u of c o m pleti o n of t he A E C R F pa ge.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
T here ma y be 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 b y 
t he S p o ns or. 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 bli n de d o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n t o t he 
S p o ns or.
•
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. I n s uc h cases, 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.
Assess me nt of i nte nsit y /t o xicit y
•
A n e ve nt is defi ne d as “seri o us” w he n it meets at least 1 of t he pre defi ne d o utc o mes as 
descri be d i n t he defi niti o n of a n S A E, n ot w he n it is rate d as se vere.
•
T he i n vesti gat or w ill ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E (a n d ot her 
re p orta ble safet y e ve nt) acc or di n g t o t he N CI C T C A E, versi o n 5. 0. A n y A E t hat c ha n ges 
C T C A E gra de o ver t he c o urse of a gi ve n e pis o de will ha ve eac h c ha n ge of gra de 
rec or de d o n t he A E C R Fs/ wor ks heets.
-
Gra de 1: Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d.
-
Gra de 2: M o derate; mi ni mal, l ocal , or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal A D L.
-
Gra de 3: Se v ere 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 A D L.
-
Gra de 4: Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d.
-
Gra de 5: Deat h relate d t o A E.
Assess me nt of c a us alit y
•
Di d t he st u d y i nter ve nti o n ca use t he A E?
•
T he deter mi nati o n of t he li keli h o o d t hat t he st u d y i nter ve nti o n ca use d t he A E will be 
pr o vi de d b y a n i n vesti gat or w h o is a q ualifie d p h ysicia n. T he i n vesti gat or’s si g ne d/ date d 
i nitials o n t he s o urce d oc u me nt or w or ks heet t hat s u p p orts t he ca usalit y n ote d o n t he A E 
f or m e ns ures t hat a me dicall y q ualifie d assess me nt of ca usalit y was d o ne. T his i nitiale d 
d oc u me nt m ust be retai ne d f or t he re q uire d re g ulat or y ti me fra me. T he criteria bel o w are 
i nte n de d as refere nce g ui deli nes t o assist t he i n vesti gat or i n assessi n g t he li keli h o o d of a 
relati o ns hi p bet wee n t he test pr o d uct a n d t he A E base d u p o n t he a vaila ble i nf or mati o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
T he f oll o wi n g c o m p o ne nts are t o be use d t o assess t h e rel ati o ns hi p bet wee n t he 
st u d y i nter ve nti o n a n d t he A E; t he gre ater t he c orrel ati o n wit h t he c o m p o ne nts a n d 
t heir res pecti ve ele me nts (i n n u m ber a n d/ or i nte nsit y), t he m ore li kel y t he st u d y 
i nter ve nti o n c a use d t he A E:
-
E x p os ure: Is t here e vi de nce t hat t he partici pa nt was act uall y e x p ose d t o t he st u d y 
i nter ve nti o n s uc h as: relia ble hist or y, acce pta ble c o m plia nce assess me nt ( pill c o u nt, 
diar y, etc), e x pecte d p har mac ol o gic effect, or meas ure me nt of dr u g/ meta b olite i n 
b o dil y s peci me n?
-
Ti me C o urse: Di d t he A E f oll o w i n a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he st u d y i nter ve nti o n? Is t he ti me of o nset of t he A E c o m pati ble 
wit h a dr u g -i n d uce d effect (a p plies t o st u dies wit h I M P)?
-
Li kel y C a use: Is t he A E n ot reas o na bl y e x plai ne d b y a n ot her eti ol o g y s uc h as 
u n derl yi n g disease, ot her dr u g(s)/ vacci ne(s), or ot her h ost or e n vir o n me ntal fact ors.
-
Dec h alle n ge: Was t he st u d y i nter ve nti o n disc o nti n ue d or d ose/e x p os ure/fre q ue nc y 
re d uce d?
◦
If yes, di d t he A E res ol ve or i m pr o ve?
◦
If yes, t his is a p ositi ve dec halle n ge.
◦
If n o, t his is a ne gati ve dec halle n ge.
( N ote: T his criteri o n is n ot a p plica ble if: ( 1) t he A E res ulte d i n deat h or per ma ne nt 
disa bilit y; ( 2) t he A E res ol ve d/i m pr o ve d des pite c o nti n uati o n of t he st u d y 
i nter ve nti o n; ( 3) t he st u d y is a si n gle-d ose dr u g st u d y; or ( 4) st u d y i nter ve nti o n (s) 
is/are o nl y use d 1 ti me.)
-
Rec h alle n ge: Was t he partici pa nt ree x p ose d t o t he st u d y i nter ve nti o n i n t his st u d y?
◦
If yes, di d t he A E rec ur or w orse n?
◦
If yes, t his is a p ositi ve rec halle n ge.
◦
If n o, t his is a ne gati ve rec halle n ge.
( N ote: T his criteri o n is n ot a p plica ble if: ( 1) t he i nitial A E res ulte d i n deat h or 
per ma ne nt disa bilit y; ( 2) t he st u d y is a si n gle-d ose dr u g st u d y; or ( 3) st u d y 
i nter ve nti o n (s) is/are use d o nl y 1 ti me.)
N O T E: I F A R E C H A L L E N G E I S P L A N N E D F O R A N A E T H A T W A S S E RI O U S A N D 
M A Y H A V E B E E N C A U S E D B Y T H E S T U D Y I N T E R V E N TI O N , O R I F R E E X P O S U R E 
T O T H E S T U D Y I N T E R V E N TI O N P O S E S A D DI TI O N A L P O T E N TI A L SI G NI FI C A N T 
RI S K T O T H E P A R TI CI P A N T T H E N T H E R E C H A L L E N G E M U S T B E A P P R O V E D I N 
A D V A N C E B Y T H E S P O N S O R C LI NI C A L D I R E C T O R A S P E R D O S E 
M O DI FI C A TI O N G UI D E LI N E S I N T H E P R O T O C O L, A N D I F R E Q UI R E D, T H E 
I R B/I E C.
•
C o nsiste nc y wit h st u d y i nter ve nti o n pr ofile: Is t he cli nical/ pat h ol o gical prese ntati o n of 
t he A E c o nsiste nt wit h pre vi o us k n o wle d ge re gar di n g t he st u d y i nter ve nti o n or dr u g class 
p har mac ol o g y or t o xic ol o g y?
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
•
T he assess me nt of relati o ns hi p will be re p orte d o n t he case re p ort f or ms/ w or ks heets b y 
a n i n vesti gat or w h o is a q ualifie d p h ysicia n acc or di n g t o t heir best cli nical j u d g me nt, 
i ncl u di n g c o nsi derati o n of t he a b o ve ele me nts.
•
Use t he f oll o wi n g scale of criteria as g ui da nce ( n ot all criteria m ust be prese nt t o be 
i n dicati ve of a st u d y i nter ve nti o n relati o ns hi p).
-
Yes, t here is a reas o na ble p ossi bilit y of st u d y i nter ve nti o n relati o ns hi p:
◦
T here is e vi de nce of e x p os ure t o t he st u d y i nter ve nti o n. T he te m p oral se q ue nce of 
t he A E o nset relati ve t o t he a d mi nistrati o n of t he st u d y i nter ve nti o n is reas o na ble. 
T he A E is m ore li kel y e x plai ne d b y t he st u d y i nter ve nti o n t ha n b y a n ot her ca use.
-
N o, t her e is n ot a reas o na ble p ossi bilit y of st u d y i nter ve nti o n relati o ns hi p:
◦
Partici pa nt di d n ot recei ve t he st u d y i nter ve nti o n O R te m p oral se q ue nce of t he A E 
o nset relati ve t o a d mi nistrati o n of t he st u d y i nter ve nti o n is n ot reas o na ble O R t he 
A E is m ore li kel y e x plai ne d b y a n ot her ca use t ha n t he st u d y i nter ve nti o n. ( Als o 
e ntere d f or a partici pa nt wit h o ver d ose wit h o ut a n ass ociate d A E.)
•
T he i n vesti gat or m ust re vie w a n d pr o vi de a n assess me nt of ca usalit y f or eac h A E/ S A E 
a n d d oc u me nt t his i n t he me dical n otes.
•
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 t o t he S p o ns or. H o we ver, it is ver y i m p orta nt 
t hat t he i n vesti gat or al wa ys ma ke a n assess me nt of ca usalit y f or e ver y e ve nt bef ore t he 
i nitial tra ns missi o n of t he S A E data t o t he S p o ns or.
•
T he i n vesti gat or ma y c ha n ge t heir 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 se n d a n S A E f oll o w -u p re p ort wit h t he u p date d ca usalit y assess me nt.
•
T he ca usalit y assess me nt is 1 of t he c riteria 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.
•
F or st u dies i n w hic h m ulti ple a ge nts are a d mi nistere d as part of a c o m bi nati o n re gi me n, 
t he i n vesti gat or ma y attri b ute eac h A E ca usalit y t o t he c o m bi nati o n re gi me n or t o a si n gle 
a ge nt of t he c o m bi nati o n. I n ge neral, ca usalit y attri b uti o n s h o ul d be assi g ne d t o t he 
c o m bi nati o n re gi me n (ie, t o all a ge nts i n t he re gi me n). H o we ver, ca usalit y attri b uti o n 
ma y be assi g ne d t o a si n gle a ge nt if i n t he i n vesti gat or’s o pi ni o n, t here is s ufficie nt data 
t o s u p p ort f ull attri b uti o n of t he A E t o t he si n gle a ge nt.
F oll o w -u p of A E a n d S A E
•
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 S p o ns or t o 
el ucidate 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 nal 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.
•
Ne w or u p date d i nf or mati o n will be rec or de d i n t he C R F.
•
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 
recei pt of t he i nf or mati o n.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 5 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 3. 6
Re p orti n g of A Es, S A Es, a n d Ot her Re p ort a ble S afet y E ve nts t o t he S p o ns or
A E, S A E, a n d ot her re p ort a ble s afet y e ve nt re p orti n g t o S p o ns or vi a electr o nic d at a 
c ollecti o n t o ol
•
T he pri mar y mec ha nis m f or re p orti n g t o t he S p o ns or will be t he E D C t o ol.
-
Electr o nic re p orti n g pr oce d ures ca n be f o u n d i n t he E D C data e ntr y g ui deli nes ( or 
e q ui vale nt).
-
If t he electr o nic s yste m is u na vaila ble f or m ore t ha n 2 4 h o urs, t he n t he site will use 
t he pa per A E Re p orti n g f or m.
-
Refere nce Secti o n 8. 4. 1 f or re p orti n g ti me re q uire me nts.
•
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes 
a vaila ble.
•
After t he st u d y is c o m plete d at a gi ve n site, t he E D C t o ol will be ta ke n off -li ne t o pre ve nt 
t he e ntr y of ne w data or c ha n ges t o e xisti n g data.
•
If a site recei ves a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei ves u p date d data 
o n a pre vi o usl y re p orte d S A E after t he E D C t o ol has bee n ta ke n off-li ne, t he n t he site ca n 
re p ort t his i nf or mati o n o n a pa per S A E f or m or b y tele p h o ne (see ne xt secti o n).
•
C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he I n vesti gat or St u d y File Bi n der ( or 
e q ui vale nt).
S A E re p orti n g t o t he S p o ns or vi a p a per C R F
•
If t he E D C t o ol is n ot o perati o nal, facsi mile tra ns missi o n or sec ure e mail of t he S A E 
pa per C R F is t he preferre d met h o d t o tra ns mit t his i nf or mati o n t o t he S p o ns or.
•
I n rare circ u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y 
tele p h o ne is acce pta ble wit h a c o p y of t he S A E data c ollecti o n t o ol se nt b y o ver ni g ht 
mail or c o urier ser vice.
•
I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si g n t he S A E C R F pa ges wit hi n t he d esi g nate d re p orti n g ti me fra mes.
•
C o ntacts a n d i nstr ucti o ns f or S A E re p orti n g a n d pa per re p orti n g pr oce d ures ca n be f o u n d 
i n t he I n vesti gat or St u d y File Bi n der ( or e q ui vale nt).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 4
A p pe n di x 4 : Me dic al De vice a n d Dr u g– D e vice C o m bi n ati o n Pr o d ucts: Pr o d uct 
Q u alit y C o m pl ai nts/ M alf u ncti o ns: Defi niti o ns, Rec or di n g, a n d F oll o w -u p
N ot a p plica ble.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 5
A p pe n di x 5 : C o ntr ace pti ve G ui d a nce
1 0. 5. 1
Defi niti o ns
W o me n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n 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 ne ntl y sterile (see bel o w):
If fertilit y is u nclear (e g, a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot 
be c o nfir me d bef ore first d ose of st u d y i nter ve nti o n, a d di ti o nal e val uati o n s h o ul d be 
c o nsi dere d.
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 narc hal
•
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
-
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
F or i n di vi d uals wit h per ma ne nt i nfertilit y d ue t o a n alter nate me dical ca use ot her t ha n 
t he a b o ve (e g, M ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y), i n vesti gat or discreti o n 
s h o ul d be a p plie d t o deter mi ni n g st u d y e ntr y.
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he partici pa nt’s 
me dical rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w.
•
P ost me n o pa usal fe male
-
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.
◦
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 ver, 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 t w o 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 o ne 
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 her 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.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 5. 2
C o ntr ace pti ve Re q uire me nts
Male partici pa nts are eli gi ble t o partici pate if t he y a gree t o t he f oll o wi n g d uri n g t he 
i nter ve nti o n peri o d a n d f or at least 1 2 0 da ys after t he last d ose of st u d y i nter ve nti o n:
•
Refrai n fr o m d o nati n g s per m
P L U S eit her:
•
Be a bsti ne nt fr o m heter ose x ual i nterc o urse as t heir preferre d a n d us ual lifest yle (a bsti ne nt 
o n a l o n g -ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt
O R
•
M ust a gree t o use c o ntrace pti o n, u nless c o nfir me d t o be az o os p er mic ( vasect o mize d or 
sec o n dar y t o me dical ca use [ A p pe n di x 5]), as detaile d bel o w:
•
A gree t o use 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 O C B P) w h o is n ot c urre ntl y pre g na nt. 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 -va gi nal pe netrati o n.
Male partici pa nts m ust a gree t o use male c o n d o m w he n e n ga gi n g i n a n y acti vit y t hat all o ws 
f or passa ge of ejac ulate t o a n ot her pers o n of a n y se x.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 6
A p pe n di x 6 : C ollecti o n a n d M a n a ge me nt of S peci me ns f or F ut ure Bi o me dic al 
Rese arc h
N ot a p plica ble.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 7
A p pe n di x 7 : C o u ntr y-s pecific Re q uire me nts
1 0. 7. 1 
L a b or at or y Testi n g
HI V St at us
W hile t he pr ot oc ol d oes n ot re q uire s pecific testi n g f or HI V at Scree ni n g, it d oes re q uire 
testi n g if re q uire d b y t he l ocal healt h a ut h orit y. Sites s h o ul d c hec k wit h t heir l ocal healt h 
a ut h orit y t o i n q uire if c o u ntr y -s pecific g ui da nce re gar di n g ma n dat or y HI V testi n g at 
Scree ni n g is re q uire d. T his ca n als o be perf or me d per t he discreti o n of t he i n vesti gat or, if 
desire d. Perf or m l ocall y if re q uire d.
He p atitis B/ C St at us
W hile t he pr ot oc ol d oes n ot re q uire s pecific testi n g f or he patitis B/ C at Scree ni n g, it d oes 
re q uire testi n g if re q uire d b y t he l ocal healt h a ut h orit y. Sites s h o ul d c hec k wit h t heir l ocal 
healt h a ut h orit y t o i n q uire if c o u ntr y -s pecific g ui da nce re gar di n g ma n dat or y he patitis B/ C 
testi n g at Scree ni n g is re q uire d. T his ca n als o be perf or me d per t he discreti o n of t he 
i n vesti gat or, if desire d. Perf or m l ocall y if re q uire d. 
1 0. 7. 2  
C o u ntr y -s pecific I nf or m ati o n
0 8 9 V 4 C
C CI
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 8
A p pe n di x 8: Descri pti o n of t he Pr ost ate C a ncer W or ki n g Gr o u p ( P C W G) 
Pr ocess f or Assess me nt of B o ne Lesi o ns 
T he r ules f or e val uati o n of res p o nse a n d pr o gressi o n base d o n b o ne lesi o ns were create d b y 
t he P C W G a n d p u blis he d as part of P C W G 3 [ Sc her, H. I., et al 2 0 1 6]. All b o ne lesi o ns are 
e val uate d acc or di n g t o t hese r ules, i ncl u di n g assess me nt at scree ni n g/ baseli ne a n d e val uati o n 
of res p o nse.
1 0. 8. 1
I m a gi n g Met h o ds 
T he P C W G r ules were desi g ne d base d o n t he ra di o n ucli de ( Tc-9 9 m) b o ne sci nti gra p h y. 
Ot her m o dalities, i ncl u di n g F D G -P E T, s o di u m fl u ori de P E T, b o ne M RI, etc. ma y ha ve 
i n di vi d ual a d va nta ges, b ut t he P C W G r ules were n ot create d wit h t he perf or ma nce 
c haracteristics of t hese met h o ds i n mi n d a n d s h o ul d n ot be use d i nstea d of ra di o n ucli de b o ne 
sca n.
O nl y b o ne lesi o ns see n b y b o ne sca n ma y be f oll o we d f or assess me nt of t u m or treat me nt 
res p o nse. B o ne disease see n b y C T o nl y ( n ot visi ble o n b o ne sca n) is pres u me d n ot t o 
re prese nt acti ve disease a n d s h o uld n ot be d oc u me nte d as a b o ne lesi o n (scler otic lesi o ns 
see n o n C T ma y re prese nt heale d disease or n o n-mali g na nt c o nf o u n ders s uc h as b o ne i nfarcts 
or ot her be ni g n fi n di n gs).
1 0. 8. 2
D oc u me nt ati o n of B o ne Lesi o ns at B aseli ne
At baseli ne, i n di vi d ual b o ne lesi o ns ma y be rec or de d as n o n -tar get lesi o ns o nl y, a n d t he 
n u m ber of b o ne lesi o ns s h o ul d be n ote d.
1 0. 8. 3
Assess me nt of B o ne Res p o nse at S u bse q ue nt I m a gi n g Ti me P oi nts
At all f oll o w -u p ti me p oi nts, b o ne disease will be classifie d as P D ( pr o gressi ve disease), P D u 
( pr o gressi ve disease u nc o nfir me d), N o n -P D ( n o pr o gressi ve disease), N E D ( n o e vi de nce of 
disease), or N E ( n o n -e val ua ble). T he defi niti o ns are s u m marize d i n t he f oll o wi n g ta ble a n d 
descri be d i n m ore detail bel o w.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
B o ne Res p o nse
Defi niti o n
P D
Pr o gressi ve dise ase: 
2 ne w lesi o ns, n ot flare, persiste nt
P D u
Pr o gressi ve dise ase u nc o nfir me d: 
Te m p orar y mar ker of p ossi ble P D, t o be u p date d t o P D or n o n -P D 
o nce a s u bse q ue nt sca n is a vaila ble. 
If t his is t he fi nal visit, t he visit res p o nse will re main P D u
N o n- P D
N o n- pr o gressi ve dise ase: 
At least o ne b o ne lesi o n prese nt, b ut n ot e n o u g h t o tri g ger P D
N E
N o n- e v al u a ble: 
Stat us of b o ne lesi o ns ca n n ot be deter mi ne d (sca n q ualit y, sca n 
missi n g, etc.)
N E D
N o e vi de nce of dise ase: 
N o lesi o ns see n o n b o ne sca n
1 0. 8. 4
Descri pti o ns of B o ne Res p o nse C ate g ories
1 0. 8. 4. 1
N o E vi de nce of Dise ase
N o lesi o ns see n o n b o ne sca n at t his visit. Eit her n o ne were see n at baseli ne, or all 
c o m pletel y res ol ve d o n s u bse q ue nt i ma gi n g. 
1 0. 8. 4. 2
N o n- pr o gressi o n ( N o n -P D)
At least o ne b o ne lesi o n is prese nt o n t he sca n at t his visit, b ut t he c o n diti o ns f or pr o gressi o n 
ha v e n ot bee n met, beca use t here are n ot at least t w o ne w lesi o ns prese nt.
1 0. 8. 4. 3
U nc o nfir me d Pr o gressi ve Dise ase ( P D u)
At least t w o ne w b o ne lesi o ns are prese nt, b ut a n a d diti o nal sca n is re q uire d f or c o nfir mati o n. 
T his res p o nse cate g or y is mea nt as a place h ol der t hat reflects te m p orar y u ncertai nt y a n d is 
u p date d t o P D or n o n -P D o nce a s u bse q ue nt b o ne sca n is a vaila ble.
1 0. 8. 4. 4
Pr o gressi ve Dise ase ( P D)
At least t w o ne w b o ne lesi o ns are prese nt, w hic h ha ve bee n c o nfir me d t o n ot re prese nt flare 
or a n y ot her c o nf o u n der (see be l o w), a n d w hic h are persiste nt f or at least 6 wee ks. T he ne w 
b o ne lesi o ns d o n ot all ha ve t o a p pear at t he sa me ti me. T h us, if o ne ne w lesi o n a p pears at 
visit N, a n d a n ot her ne w lesi o n at visit N + 1, visit N + 1 is c o nsi dere d t o re prese nt pr o gressi ve 
disease.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 8. 4. 5
C o nfir m ati o n of Pr o gressi o n
Ra di o gra p hic pr o gressi o n of b o ne lesi o ns is defi ne d as t he a p peara nce of ≥2 ne w b o ne 
lesi o ns o n ra di o n ucli de b o ne sca n. W he n ≥2 ne w b o ne lesi o ns are first o bser ve d, t his is 
classifie d as P D u, w hic h mar ks t he p ossi bilit y of pr o gressi o n t hat will be res ol ve d b y t he ne xt 
sca n.
1 0. 8. 4. 5. 1 
F or Ne w Lesi o ns Wit hi n t he Fl are Wi n d o w ( < 1 2 wee ks)
After a sca n classifie d as P D u wit hi n t he first 1 2 wee ks of treat me nt, if t he ne xt b o ne sca n 
o utsi de t he flare wi n d o w s h o ws at least t w o a d diti o nal ne w b o ne lesi o ns (i n a d diti o n t o t he 
ne w lesi o ns see n o n t he pri or sca n), t he i nitial pr o gressi o n is c o nsi dere d c o nfir me d, a n d t he 
b o ne sca n res p o nse u p date d t o P D. Beca use t his re q uires at least 2 ne w lesi o ns, f oll o we d b y 
a n ot her 2 ne w lesi o ns, t his is k n o w n as t he “ 2 + 2 r ule”.
If t he ne xt b o ne sca n o utsi de t he flare wi n d o w d oes n ot s h o w at least t w o a d diti o nal ne w 
b o ne lesi o ns, t he lesi o ns see n o n t he pri or sca n wit hi n t he flare wi n d o w are c o nsi dere d t o be 
pre -e xisti n g lesi o ns t hat beca me m ore v isi ble beca use of t he t u m or flare p he n o me n o n.
•
T he b o ne res p o nse at t he pri or visit is u p date d t o n o n -P D
•
T he b o ne lesi o ns see n wit hi n t he flare wi n d o w are i g n ore d f or t he p ur p oses of c o u nti n g 
ne w lesi o ns at later ti me p oi nts, si nce t he y were n ot ne w. T his ma y be referre d t o as “re -
baseli ni n g”.
1 0. 8. 4. 5. 2
F or Ne w Lesi o ns O utsi de t he Fl are Wi n d o w ( > 1 2 wee ks)
After a sca n classifie d as P D u after t he first 1 2 wee ks of treat me nt, if at least 2 of t he ne w 
lesi o ns see n o n t hat sca n persist o n t he ne xt b o ne sca n perf or me d at least 6 wee ks later, t his 
c o nfir ms t he i nitial pr o gressi o n. T he pri or res p o nse is t he n u p date d t o P D. If t he ne w lesi o ns 
ha ve disa p peare d o n t his later sca n, t he pri or res p o nse is u p date d t o n o n -P D beca use t hese 
lesi o ns are pres u me d t o be n o n-mali g na nt i n n at ure. N o re -baseli ni n g of lesi o ns will occ ur i n 
t his sce nari o.
1 0. 8. 4. 6
S u persc a n
A “s u persca n” occ urs w he n t here is diff use s keletal i n v ol ve me nt b y t u m or, s uc h t hat 
i n di vi d ual b o ne lesi o ns are n ot disti n g uis ha ble. T he b o ne sca n ma y i nitiall y a p pear n or mal, 
beca use t he i ncrease b o ne u pta ke ma y be u nif or m, b ut ca n be disti n g uis he d b y t he fai nt or 
a bse nt acti vit y i n t he ki d ne ys a n d uri nar y tract.
If t here is a tr ue s u persca n at baseli ne, i de ntif yi n g i n di vi d ual ne w b o ne lesi o ns, a n d 
deter mi ni n g pr o gressi o n base d o n b o ne lesi o ns, ma y be i m p ossi ble. 
If a s u persca n occ urs after baseli ne, t he patie nt’s b o ne res p o nse will be rec or de d as P D. N o 
s u bse q ue nt i ma gi n g will be re q uire d f or c o nfir mati o n, beca use a s u persca n is e xtre mel y 
u nli kel y t o be ca use d b y be ni g n c o n dit i o ns or t u m or flare. 
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 8. 4. 7
M a n a ge me nt F oll o wi n g C o nfir me d P D
If re peat i ma gi n g d oes c o nfir m P D, partici pa nts will be disc o nti n ue d fr o m st u d y i nter ve nti o n.
N ote: If a partici pa nt has c o nfir me d ra di o gra p hic pr o gressi o n as defi ne d a b o ve, b ut t he 
partici pa nt is ac h ie vi n g a cli nicall y mea ni n gf ul be nefit, a n e xce pti o n t o c o nti n ue st u d y 
i nter ve nti o n ma y be c o nsi dere d f oll o wi n g c o ns ultati o n wit h t he S p o ns or. I n t his case, if st u d y 
i nter ve nti o n is c o nti n ue d, t u m or i ma gi n g s h o ul d c o nti n ue (refere nce t he efficac y secti o n of 
t he pr ot oc ol).
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 6 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 9
A p pe n di x 9 : Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of Dise ase 
Pr o gressi o n
N ot a p plica ble.
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 1 0
A p pe n di x 1 0 : A b bre vi ati o ns
A b bre vi ati o n
E x p a n de d Ter m
A D L
acti vities of dail y li vi n g
A D T
a n dr o ge n de pri vati o n t hera p y
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 P T T
acti vate d partial t hr o m b o plasti n ti me
A Pa T
All -Partici pa nts -as-Treate d
A S T
as partate a mi n otra nsferase
B C G
Bacill us Cal mette
G uéri n
BI C R
bli n de d i n de pe n de nt ce ntral re vie w
B PI -S F
Brief Pai n I n ve nt or y S h ort F or m
C D 2 8
cl uster of differe ntiati o n 2 8
C D 3ζ
cl uster of differe ntiati o n 3 zeta
C F R
C o de of Fe deral Re g ulati o ns
c H L
classical H o d g ki n L y m p h o ma 
CI
c o nfi de nce i nter val
C N S
ce ntral ner v o us s yste m 
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C R
c o m plete res p o nse
Cr Cl
Creati ni ne cleara nce
C R F
case re p ort f or m 
C R P C
castrati o n-resista nt pr ostate ca ncer
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
ct D N A
circ ulati n g t u m or de o x yri b o n ucleic aci d
C T L A - 4
c yt ot o xic T-l y m p h oc yte-ass ociate d pr otei n 4
D C R
disease c o ntr ol rate
D O R
d urati o n of res p o nse
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A b bre vi ati o n
E x p a n de d Ter m
D N A
de o x yri b o n ucleic aci d 
E B R T
e xter nal -bea m ra diati o n t hera p y
E C G
electr ocar di o gra m 
E CI
e ve nt of cli nical i nterest
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
electr o nic Case Re p ort F or m
E D C
electr o nic data c ollecti o n
e D M C
e xter nal Data M o nit ori n g C o m mittee
E LI S A
e nz y me-li n ke d i m m u n oassa y
E M A
E ur o pea n Me dici nes A ge nc y
E O C
e xec uti ve o versi g ht c o m mittee
E S M O
E ur o pea n S ociet y f or Me dical O nc ol o g y
E W B
e m oti o nal well-bei n g
F A C T - G
F u ncti o nal Assess me nt of Ca ncer T hera p y -Ge neral
F A C T - P 
F u ncti o nal Assess me nt of Ca ncer T hera p y -Pr ostate
F A P SI 6
F A C T A d va nce d Pr ostate S y m pt o m I n de x 6
F A S
f ull a nal ysis set
F D A
F o o d a n d Dr u g A d mi nistrati o n
F D A A A 
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act
F D G -P E T
fl ur o de o x y gl uc ose-p ositr o n e missi o n t o m o gra p h y
F F P E
f or mali n-fi xe d, paraffi n e m be d de d
F S H
f ollicle sti m ulati n g h or m o ne
F T 3
free trii o d ot h yr o ni ne
F T 4
free t h yr o xi ne
F W B
f u ncti o nal well-bei n g
G C P
G o o d Cli nical Practice 
G F R
gl o mer ular filtrati o n rate
H
H y p ot hesis
H C C
he patic cell carci n o ma
H C V
He patitis C vir us
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A b bre vi ati o n
E x p a n de d Ter m
H G R A C
H u ma n Ge netic Res o urces A d mi nistrati o n of C hi na
HI V
h u ma n i m m u n o deficie nc y vir us
H N S C C
hea d a n d nec k s q ua m o us cell carci n o ma
H R
hazar d rati o
H R Q o L
healt h- relate d q ualit y of life
H R T
h or m o ne re place me nt t hera p y
I A
i nteri m a nal ysis
I B
I n vesti gat or’s Br oc h ure 
I CF
I nf or me d C o nse nt F or m 
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
i C R O
I ma gi n g C o ntract Researc h Or ga nizati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g
i m m u n o gl o b uli n
I H C
i m m u n o hist oc he mistr y
I L
i nterle u ki n
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
ir A E
i m m u ne-relate d a d verse e ve nt
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
I T T
I nte nt-t o-Treat
I V
i ntra ve n o us
I V D
i n vitr o dia g n ostic
K N
K E Y N O T E
L H R H
l utei nizi n g-h or m o ne releasi n g h or m o ne
m A b
m o n ocl o nal a nti b o d y
m C R P C
metastatic castrati o n -resista nt pr ostate ca ncer
m H S P C
metastatic h or m o ne -se nsiti ve pr ostate ca ncer
M RI
ma g netic res o na nce i ma gi n g
m R N A
messe n ger ri b o n ucleic aci d
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 3
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A b bre vi ati o n
E x p a n de d Ter m
M SI
micr osatellite i nsta bilit y
N
n u m ber
N A
N ot A p plica ble
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
Nati o nal Ca ncer I nstit ute
N E
n o n -e val ua ble
N E D
n o e vi de nce of disease
N H A
ne xt ge nerati o n h or m o nal a ge nts
NI M P
N o n- I n vesti gati o nal Me dici nal Pr o d uct
N o n- P D
n o n -pr o gressi o n
N S AI D
n o n -ster oi dal a nti-i nfla m mat or y dr u g
N S C L C
n o n -s mall cell l u n g ca ncer
O R R
o bjecti ve res p o nse rate
O R
o bjecti ve res p o nse
O S
o verall s ur vi val
O T C
o ver -t he-c o u nter
P B P K
p h ysi ol o gicall y -base d p har mac o ki netic
P C S
Pr ostate Ca ncer S y m pt o ms
P C W G
Pr ostate Ca ncer W or ki n g Gr o u p
P D
pr o gressi ve disease
P D - 1
pr o gra m me d cell deat h 1
P D -L 1
pr o gra m me d cell deat h li ga n d 1
P D -L 2
pr o gra m me d cell deat h li ga n d 2
P D L C
pre defi ne d li mit of c ha n ge
P D u
u nc o nfir me d pr o gressi ve disease 
P F S
pr o gressi o n -free s ur vi val
P F S 2
Ti me fr o m ra n d o mizati o n t o disease pr o gressi o n as deter mi ne d b y 
i n vesti gat or assess me nt after ne xt-li ne of t hera p y or deat h fr o m a n y 
ca use, w hic he ver occ urs first.
PI N
pers o nal i de ntificati o n n u m ber
P K
p har mac o ki netic
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 4
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A b bre vi ati o n
E x p a n de d Ter m
P K C θ
pr otei n ki nase C -t heta
P M B C L
pri mar y me diasti nal B -cell l y m p h o ma
P O
Per oral ( b y m o ut h)
P R
partial res p o nse
P R E S
p osteri or re versi ble e nce p hal o pat h y s y n dr o me
P R O
patie nt -re p orte d o utc o me
P S A
pr ostate -s pecific a nti ge n
P S M A -P E T
Pr ostate S pecific Me m bra ne A nti ge n -P ositr o n E missi o n T o m o gra p h y
P T
pr ot hr o m bi n ti me
P T T
partial t hr o m b o plasti n ti me
P W B
p h ysical well -bei n g
Q 2 W
e ver y 2 wee ks
Q 3 W
e ver y 3 wee ks
Q D
e ver y da y
R E CI S T 1. 1
Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1
R M S T
restricte d mea n s ur vi val ti me
R N A
ri b o n ucleic aci d
r P F S
ra di o gra p hic pr o gressi o n-free s ur vi val
R P S F T
ra n k preser vi n g str uct ural fail ure ti me
S A E
seri o us a d verse e ve nt 
S C F
S p o ns or C o m m u nicati o n F or m
S D
sta ble disease
SI M
Site I ma gi n g Ma n ual
S L A B
s u p ple me ntal la b orat or y
S N P
si n gle n ucle oti de p ol y m or p his m
S o A
sc he d ule of acti vities
S O C
sta n dar d of care
S P E C T
Si n gle P h ot o n E missi o n C o m p uter T o m o gra p h y
s S A P
s u p ple me ntal Statistical A nal ysis Pla n
S S R E
s y m pt o matic s keletal-relate d e ve nt
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 5
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
A b bre vi ati o n
E x p a n de d Ter m
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
S W B
s ocial/fa mil y well-bei n g
T 3
t otal trii o d ot h yr o ni ne
T E A
Treat me nt Eli gi bilit y Assess me nt
T F S T
ti me t o i nitiati o n of t he first s u bse q ue nt a ntica ncer t hera p y
T M D D
tar get-me diate d dr u g dis p ositi o n
T OI
Trial O utc o me I n de x
T R A E
treat me nt-relate d a d verse e ve nt
T T B P
ti me t o b o ne pr o gressi o n
T T P P
ti me t o pai n pr o gressi o n
T T S S R E
ti me t o s y m pt o matic s keletal-relate d e ve nt 
U C
ur ot helial carci n o ma
U L N
u p per li mit of n or mal
U S
U nite d States
V A S
vis ual a nal o g scale
W O C B P
w o ma n/ w o me n of c hil d beari n g p ote ntial 
Z A P 7 0
zeta-c hai n-ass ociate d pr otei n ki nase
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 6
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 0. 1 1
A p pe n di x 1 1 : E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us
Gr a de
E C O G P E R F O R M A N C E S T A T U S
0
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e g, li g ht h o use w or k, office w or k
2
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities; u p a n d 
a b o ut m ore t ha n 5 0 of wa ki n g h o urs
3
Ca pa ble of o nl y li mite d self-care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 of wa ki n g h o urs
4
C o m pletel y disa ble d; ca n n ot carr y o n a n y self -care; t otall y c o nfi ne d t o be d or c hair
5
Dea d
S o urce: [ O ke n, M. M., et al 1 9 8 2]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 7
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
1 1
R E F E R E N C E S
[ Ar mstr o n g, A. J., et 
al 2 0 1 9]
Ar mstr o n g AJ, Sz m ule witz R Z, Petr yla k D P, 
Villers A, Aza d A, Alcaraz A, et al. P hase 3 
st u d y of a n dr o ge n de pri vati o n t hera p y ( A D T) 
wit h e nzal uta mi de ( E N Z A) or place b o ( P B O) i n 
metastatic h or m o ne -se nsiti ve pr ostate ca ncer 
( m H S P C): T he A R C H E S trial [a bstract]. 
Prese nte d at: A merica n S ociet y of Cli nical 
O nc ol o g y ( A S C O) 2 0 1 9 Ge nit o uri nar y Ca ncers 
S y m p osi u m; 2 0 1 9 Fe b 1 4 -1 6; Sa n Fra ncisc o, 
C A. J Cli n O nc ol. 2 0 1 9; 3 7( 7 s u p pl). A bstract n o. 
6 8 7.
[ 0 5 8 K P 0]
[ Bis h o p, J. L., et al 
2 0 1 5]
Bis h o p J L, Si o A, A n geles A, R o berts M E, Aza d 
A A, C hi K N, et al. P D -L 1 is hi g hl y e x presse d i n 
E nzal uta mi de resista nt pr ostate ca ncer. 
O nc otar get. 2 0 1 5 Ja n 1; 6( 1): 2 3 4 -4 2.
[ 0 4 9 Y S Q]
[ Ca ncer re gistrati o n 
c o m mittee of t he 
Ja pa nese Ur ol o gical 
Ass ocia 2 0 0 5]
Ca ncer re gistrati o n c o m mittee of t he Ja pa nese 
Ur ol o gical Ass ociati o n. Cli nic o pat h ol o gical 
statistics o n re gistere d pr ostate ca ncer patie nts i n 
Ja pa n: 2 0 0 0 re p ort fr o m t he Ja pa nese Ur ol o gical 
Ass ociati o n. I nt J Ur ol. 2 0 0 5; 1 2: 4 6 -6 1.
[ 0 5 8 M Y M]
[ C he m nitz, J. M., et 
al 2 0 0 4]
C he m nitz J M, Parr y R V, Nic h ols K E, J u ne C H, 
Rile y J L. S H P -1 a n d S H P -2 ass ociate wit h 
i m m u n orece pt or t yr osi ne-base d s witc h m otif of 
pr o gra m me d deat h 1 u p o n pri mar y h u ma n T cell 
sti m ulati o n, b ut o nl y rece pt or li gati o n pre ve nts T 
cell activati o n. J I m m u n ol 2 0 0 4; 1 7 3: 9 4 5 -5 4.
[ 0 0 V M P N]
[ C hi, K. N., et al 
2 0 1 9]
C hi K N, A gar wal N, Bjartell A, C h u n g B H, 
Pereira de Sa nta na G o mes AJ, Gi ve n R W, et al. 
First res ults fr o m TI T A N: a p hase III d o u ble -
bli n d, ra n d o mize d st u d y of a pal uta mi de ( A P A) 
vers us pl ace b o ( P B O) i n patie nts ( pts) wit h 
metastatic castrati o n -se nsiti ve pr ostate ca ncer 
( m C S P C) recei vi n g a n dr o ge n de pri vati o n 
t hera p y ( A D T) [a bstract]. Prese nte d at: 2 0 1 9 
A merica n S ociet y of Cli nical O nc ol o g y ( A S C O) 
A n n ual Meeti n g; 2 0 1 9 Ma y 3 1 -J u n 4; C hica g o, 
I L. J Cli n O nc ol. 2 0 1 9; 3 7( 1 5 s u p pl). A bstract 
n o. 5 0 0 6.
[ 0 5 8 K P 7]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 8
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
[ Cleela n d, C. S. 
2 0 0 9a]
Cleela n d C S. T he brief pai n i n ve nt or y: user 
g ui de. [ H o ust o n ( T X)]: C harles S. Cleela n d; 
c 2 0 0 9. 6 3 p.
[ 0 5 0 C D N]
[ Da vis, I. D., et al 
2 0 1 9]
Da vis I D, Marti n AJ, St oc kler M R, Be g bie S, 
C hi K N, C h o w d h ur y S, et al. E nzal uta mi de wit h 
sta n dar d first-Li ne t hera p y i n metastatic pr ostate 
ca ncer. N E n gl J Me d. I n press 2 0 1 9.
[ 0 5 8J M Q]
[ Disis, M. L. 2 0 1 0]
Disis M L. I m m u ne re g ulati o n of ca ncer. J Cli n 
O nc ol 2 0 1 0; 2 8( 2 9): 4 5 3 1 -8.
[ 0 5 8 S Q L]
[ D u dle y, M. E., et al 
2 0 0 5]
D u dle y M E, W u n derlic h J R, Ya n g J C, S herr y 
R M, T o palia n S L, Restif o N P, et al. A d o pti ve 
cell tra nsfer t hera p y f oll o wi n g n o n -
m yel oa blati ve b ut l y m p h o de pleti n g 
c he m ot hera p y f or t he treat me nt of patie nts wit h 
refract or y metastatic mela n o ma. J Cli n O nc ol 
2 0 0 5; 2 3( 1 0): 2 3 4 6 -5 7.
[ 0 0 V M P R]
[ D w or ki n, R. H., et al 
2 0 0 5]
D w or ki n R H, T ur k D C, Farrar J T, 
Ha yt h or nt h waite J A, Je nse n M P, Katz N P, et al. 
C ore o utc o me meas ures f or c hr o nic pai n cli nical 
trials: I M M P A C T rec o m me n dati o ns. Pai n 
2 0 0 5; 1 1 3: 9 -1 9.
[ 0 3 Q 4 N P]
[ D w or ki n, R. H., et al 
2 0 0 8]
D w or ki n R H, T ur k D C, W yr wic h K W, Beat o n 
D, Cleela n d C S, Farrar J T, et al. I nter preti n g t he 
Cli nical I m p orta nce of Treat me nt O utc o mes i n 
C hr o nic Pai n Cli nical Trials: I M M P A C T 
Rec o m me n dati o ns. J Pai n 2 0 0 8; 9( 2): 1 0 5 -2 1.
[ 0 3 Q S W B]
[ Es per, P., et al 1 9 9 7]
Es per P, M o F, C h o da k G, Si n ner M, Cella D, 
Pie nta KJ. Meas uri n g q ualit y of life i n me n wit h 
pr ostate ca ncer usi n g t he f u ncti o nal assess me nt 
of ca ncer t hera p y -pr ostate i nstr u me nt. Ur ol o g y. 
1 9 9 7 Dec; 5 0( 6): 9 2 0 -8.
[ 0 4 8 7 7 L]
[ Ferla y, J., et al 2 0 1 5]
Ferla y J, S oerj o matara m I, Di ks hit R, Eser S, 
Mat hers C, Re bel o M, et al. Ca ncer i nci de nce 
a n d m ortalit y w orl d wi de: s o urces, met h o ds a n d 
maj or patter ns i n G L O B O C A N 2 0 1 2. I nt J 
Ca ncer. 2 0 1 5 M ar 1; 1 3 6( 5): E 3 5 9 -8 6.
[ 0 4 3 H C 4]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 7 9
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
[ F o o d a n d Dr u g 
A d mi nistrati o n 
2 0 0 9 b]
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 o n patie nt-re p orte d o utc o me meas ures: 
use i n me dical pr o d uct de vel o p me nt t o s u p p ort 
la beli n g clai ms; a vaila bilit y. Fe d Re gist. 2 0 0 9 
Dec 9; 7 4( 2 3 5): 6 5 1 3 2 -3.
[ 0 5 0 C D Q]
[ Fra ncisc o, L. M., et 
al 2 0 1 0]
Fra ncisc o L M, Sa ge P T, S har pe A H. T he P D -1 
pat h wa y i n t olera nce a n d a ut oi m m u nit y. 
I m m u n ol Re v 2 0 1 0; 2 3 6: 2 1 9-4 2.
[ 0 5 8 S Q P]
[ Graff, J. N., et al 
2 0 1 6]
Graff J N, Al u m kal JJ, Dra ke C G, T h o mas G V, 
Re d m o n d W L, Far ha d M, et al. Earl y e vi de nce 
of a nti- P D -1 acti vit y i n e nzal uta mi de -resista nt 
pr ostate ca ncer. O nc otar get. 2 0 1 6 J ul 1 2. [ E p u b 
a hea d of pri nt].
[ 0 4 H 4 F 2]
[ Graff, J. N., et al 
2 0 1 8]
Graff J N, Al u m kal JJ, T h o m ps o n R F, M ora n A, 
T h o mas G V, W o o d M A, et al. Pe m br oliz u ma b 
( Pe m br o) pl us e nzal uta mi de ( E nz) i n metastatic 
castrati o n resista nt pr ostate ca ncer ( m C R P C): 
e xte n de d f oll o w u p [a bstract]. Prese nte d at: 2 0 1 8 
A merica n S ociet y of Cli nical O nc ol o g y ( A S C O) 
A n n ual Meeti n g; 2 0 1 8 J u n 1 -5; C hica g o, I L. J 
Cl i n O nc ol. 2 0 1 8; 3 6( 1 5 s u p pl). A bstract n o. 
5 0 4 7.
[ 0 5 0 C F 3]
[ Gree n wal d, R. J., et 
al 2 0 0 5]
Gree n wal d RJ, Free ma n GJ, S har pe A H. T he B 7 
fa mil y re visite d. A n n u Re v I m m u n ol 
2 0 0 5; 2 3: 5 1 5 -4 8.
[ 0 0 V M Q L]
[ H u n der, N. N., et al 
2 0 0 8]
H u n der N N, Walle n H, Ca o J, He n dri c ks D W, 
Reill y J Z, R o d m yre R, et al. Treat me nt of 
metastatic mela n o ma wit h a ut ol o g o us C D 4 + T 
cells a gai nst N Y -E S O -1. N E n gl J Me d 
2 0 0 8; 3 5 8( 2 5): 2 6 9 8 -7 0 3.
[ 0 0 V M P X]
[Jac k, R. H., et al 
2 0 1 0]
Jac k R H, Da vies E A, M oller H. Pr ostate ca ncer 
i nci de nce, sta ge at dia g n osis, treat me nt a n d 
s ur vi val i n et h nic gr o u ps i n S o ut h-East E n gla n d. 
BJ U I nt. 2 0 1 0; 1 0 5: 1 2 2 6 -3 0.
[ 0 5 8 M Y W]
[ Kell y, S. P., et al 
2 0 1 8]
Kell y S P, A n ders o n W F, R ose n ber g P S, C o o k 
M B. Past, c urre nt, a n d f ut ure i nci de nce rates a n d 
b ur de n of metastatic pr osta te ca ncer i n t he 
U nite d States. E ur Ur ol F oc us. 2 0 1 8; 4: 1 2 1 -7.
[ 0 5 8 L 4 F]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 8 0
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
[ K w o n, E. D., et al 
2 0 1 4]
K w o n E D, Dra ke C G, Sc her HI, Fizazi K, B ossi 
A, va n de n Eert we g h AJ M, et al. I pili m u ma b 
vers us place b o after ra di ot hera p y i n patie nts wit h 
metastatic castrati o n -resista nt pr ostate ca ncer 
t hat ha d pr o gresse d after d oceta xel 
c he m ot hera p y ( C A 1 8 4 -0 4 3): a m ultice ntre, 
ra n d o mise d, d o u ble-bli n d, p hase 3 trial. La ncet 
O nc ol. 2 0 1 4 J u n; 1 5: 7 0 0 -1 2.
[ 0 5 0 0 W H]
[ Ma urer, W. a n d 
Bretz, F. 2 0 1 3]
Ma urer W a n d B retz F. M ulti ple testi n g i n gr o u p 
se q ue ntial trials usi n g gra p hical a p pr oac hes. Stat 
Bi o p har m Res 2 0 1 3; 5( 4): 3 1 1 -2 0.
[ 0 3 X Q V B]
[ Mietti ne n, O. a n d 
N ur mi ne n, M. 1 9 8 5]
Mietti ne n O a n d N ur mi ne n M. C o m parati ve 
a nal ysis of t w o rates. Stat Me d 1 9 8 5; 4: 2 1 3 -2 6.
[ 0 0 V MQ Y]
[ Nati o nal Ca ncer 
I nstit ute 2 0 1 9]
T he S ur veilla nce, E pi de mi ol o g y, a n d E n d 
Res ults Pr o gra m [I nter net]. Bet hes da ( M D): 
Nati o nal Ca ncer I nstit ute ( N CI). S E E R Ca ncer 
Statistics Re vie w ( C S R) 1 9 7 5 -2 0 1 6; 2 0 1 9 A pr 
1 5 [cite d 2 0 1 9 J u n 2 8]; [a b o ut 2 scree ns]. 
A va ila ble fr o m: 
htt ps://seer.ca ncer. g o v/csr/ 1 9 7 5 _ 2 0 1 6/.
[ 0 5 8 N 5 Z]
[ O kaza ki, T., et al 
2 0 0 1]
O kaza ki T, Mae da A, Nis hi m ura H, K ur osa ki T, 
H o nj o T. P D -1 i m m u n orece pt or i n hi bits B cell 
rece pt or-me diate d si g nali n g b y recr uiti n g src 
h o m ol o g y 2 -d o mai n -c o ntai ni n g t yr osi ne 
p h os p hatase 2 t o p h os p h ot yr osi ne. Pr oc Natl 
Aca d Sci U S A 2 0 0 1; 9 8( 2 4): 1 3 8 6 6 -7 1.
[ 0 0 V M Q 6]
[ O ke n, M. M., et al 
1 9 8 2]
O ke n M M, Creec h R H, T or me y D C, H ort o n J, 
Da vis T E, Mc Fa d de n E T, et al. T o xicit y a n d 
res p o nse criteria of t he Easter n C o o perati ve 
O nc ol o g y Gr o u p. A m J Cli n O nc ol 
1 9 8 2; 5( 6): 6 4 9 -5 5.
[ 0 3 Q 3 F 0]
[ Parr y, R. V., et al 
2 0 0 5]
Parr y R V, C he m nitz J M, Fra u wirt h K A, 
La nfra nc o A R, Bra u nstei n I, K o ba yas hi S V, et 
al. C T L A-4 a n d P D -1 rece pt ors i n hi bit T -cell 
acti vati o n b y disti nct mec ha nis ms. M ol Cell Bi ol 
2 0 0 5; 2 5( 2 1): 9 5 4 3 -5 3.
[ 0 0 V M Q 7]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 8 1
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
[ Pic kar d, A. S., et al 
2 0 0 7]
Pic kar d A S, Near y M P, Cella D. Esti mati o n of 
mi ni mall y i m p orta nt differe nces i n E Q - 5 D 
utilit y a n d V A S sc ores i n ca ncer. Healt h Q ual 
Life O utc o mes 2 0 0 7; 5: 1 -8.
[ 0 0 W 0 F M]
[ Ra bi n, R. a n d de 
C harr o, F. 2 0 0 1]
Ra bi n R, de C harr o F. E Q -5 D: a meas ure of 
healt h stat us fr o m t he E ur o Q ol gr o u p. A n n Me d 
2 0 0 1; 3 3: 3 3 7 -4 3.
[ 0 3 Q M 4 6]
[ Rile y, J. L. 2 0 0 9]
Rile y J L. P D -1 si g nali n g i n pri mar y T cells. 
I m m u n ol Re v 2 0 0 9; 2 2 9: 1 1 4-2 5.
[ 0 0 V M Q 9]
[ R o bi ns, J. M. a n d 
Ts iatis, A. A. 1 9 9 1]
R o bi ns J M, Tsiatis A A. C orrecti n g f or n o n -
c o m plia nce i n ra n d o mize d trials usi n g ra n k 
preser vi n g str uct ural fail ure ti me m o dels. 
C o m m u n Stat -T he or M 1 9 9 1; 2 0( 8): 2 6 0 9 -3 1.
[ 0 2 3 V W F]
[ Sc her, H. I., et al 
2 0 1 5]
Sc her HI, S ol o K, Vala nt J, T o d d M B, Me hra M. 
Pre vale nce of pr ostate ca ncer cli nical states a n d 
m ortalit y i n t he U nite d States: esti mates usi n g a 
d y na mic pr o gressi o n m o del. P L o S O ne. 2 0 1 5 
Oct 1 3; 1 0( 1 0):e 0 1 3 9 4 4 0.
[ 0 5 8 M Z 7]
[ Sc her, H. I., et al 
2 0 1 6]
Sc her HI, M orris MJ, Sta dler W M, Hi ga n o C, 
Basc h E, Fizazi K, et al. Trial Desi g n a n d 
O bjecti ves f or Castrati o n -Resista nt Pr ostate 
Ca ncer: U p date d Rec o m me n dati o ns Fr o m t he 
Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p 
3. J Cli n O nc ol. 2 0 1 6 A pr 2 0; 3 4( 1 2): 1 4 0 2 -1 8.
[ 0 4 F K V M]
[ S he p par d, K-A, et al 
2 0 0 4]
S he p par d K- A, Fitz LJ, Lee J M, Be na n der C, 
Ge or ge J A, W o oters J, et al. P D -1 i n hi bits T -cell 
rece pt or i n d uce d p h os p h or ylati o n of t he 
Z A P 7 0/ C D 3zeta si g nal os o me a n d d o w nstrea m 
si g nali n g t o P K Ct heta. F E B S Lett. 2 0 0 4; 5 7 4: 3 7-
4 1.
[ 0 0 V M Q C]
[ Sie gel, R. L., et al 
2 0 1 8]
Sie gel R L, Miller K D, Je mal A. Ca ncer 
statistics, 2 0 1 8. C A Ca ncer J Cli n. 2 0 1 8 Ja n-
Fe b; 6 8( 1): 7 -3 0.
[ 0 5 0 2 Z R]
[ S mit h, S. 2 0 1 8]
S mit h S, W ola ns ki P. Metastatic pr ostate ca ncer 
i nci de nce i n A ustralia after a me n d me nt t o 
pr ostate s pecific a nti ge n scree ni n g g ui deli nes 
[a bstract]. A N Z J S ur g. 2 0 1 8; 8 8( 7-8): E 5 8 9 -9 3.
[ 0 5 8 N 4 Q]
0 8 9 V 4 C
0 8 C V S X

P R O D U C T: M K
3 4 7 5
1 8 2
P R O T O C O L/ A M E N D M E N T N O.: 9 9 1 0 4
M K
3 4 7 5 9 9 1 0 4 FI N A L P R O T O C O L
1 5 M A Y
2 0 2 3
[ T o palia n, S. L., et al 
2 0 1 2]
T o palia n S L, H o di F S, Bra h mer J R, Getti n ger 
S N, S mit h D C, Mc Der m ott D F, et al. Safet y, 
acti vit y, a n d i m m u ne c orrelates of a nti -P D -1 
a nti b o d y i n ca ncer. N E n gl J Me d. 2 0 1 2 J u n 
2 8; 3 6 6( 2 6): 2 4 4 3 -5 4.
[ 0 5 0 2 S W]
[ T orre, L. A., et al 
2 0 1 6]
T orre L A, Sie gel R L, War d E M, Je mal A. 
Gl o bal ca ncer i nci de nce a n d m ortalit y rates a n d 
tre n ds - a n u p date. Ca ncer E pi de mi ol 
Bi o mar kers Pre v. 2 0 1 6 Ja n; 2 5( 1): 1 6 -2 7.
[ 0 4 Z V D R]
[ U n o, H., et al 2 0 1 4]
U n o H, Cla g gett B, Tia n L, I n o ue E, Gall o P, 
Mi yata T, et al. M o vi n g be y o n d t he hazar d rati o 
i n q ua ntif yi n g t he bet wee n-gr o u p differe nce i n 
s ur vi val a nal ysis. J Cli n O nc ol. 2 0 1 4 A u g 
1; 3 2( 2 2): 2 3 8 0 -5.
[ 0 4 5 X 5 X]
[ Wei ner, A. B., et al 
2 0 1 6]
Wei ner A B, Mat ule wicz R S, E g ge ner S E, 
Sc haeffer E M. I ncreasi n g i nci de nce of metastatic 
pr ostate ca ncer i n t he U nite d States ( 2 0 0 4 -2 0 1 3). 
Pr ostate Ca ncer Pr ostatic Dis. 2 0 1 6; 1 9: 3 9 5 -9 7.
[ 0 5 8 M Z V]
[ Z ha n g, X., et al 
2 0 0 4]
Z ha n g X, Sc h wartz J-C D, G u o X, B hatia S, Ca o 
E, C he n L, et al. Str uct ural a n d f u ncti o nal 
a nal ysis of t he c osti m ulat or y rece pt or 
pr o gra m me d deat h -1. I m m u nit y 2 0 0 4; 2 0: 3 3 7 -4 7.
[ 0 0 V M QJ]
0 8 9 V 4 C
0 8 C V S X