Clinical trial NCT02555657
Conditions: Metastatic Triple Negative Breast Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-10-13; Completion date: 2020-11-10
Enrollment: 622 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, participants with metastatic triple negative breast cancer (mTNBC) will be randomly assigned to receive either single agent pembrolizumab or single agent chemotherapy chosen by the treating physician (Treatment of Physician's Choice, TPC) in accordance with local regulations and guidelines, consisting of either capecitabine, eribulin, gemcitabine, or vinorelbine. The primary study hypothesis is that pembrolizumab extends overall survival compared to TPC.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (up to \~2 years). Qualified participants who receive first course of pembrolizumab but continue to experience disease progression may, at investigator's discretion, initiate a second course of pembrolizumab at 200 mg IV Q3W for up to 17 administrations (up to \~1 year). arm 2: Participants receive capecitabine, eribulin, gemcitabine, or vinorelbine as TPC in accordance with local regulations and guidelines.
Interventions: intervention 1: pembrolizumab intervention 2: capecitabine intervention 3: eribulin intervention 4: gemcitabine intervention 5: vinorelbine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
SAP_002.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Study of Navarixin (MK-7123) in Combination 
with Pembrolizumab (MK-3475) in Participants with Selected 
Advanced/Metastatic Solid Tumors
23-Apr-2019
NCT02054806


M K -3 4 7 5
P A G E 1
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
S u p ple me nt al St atistic al A n al ysis Pl a n (sS A P )
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ................................................................................................................... 4
LI S T O F FI G U R E S ................................................................................................................. 5
1
I N T R O D U C TI O N............................................................................................................ 6
2
S U M M A R Y O F C H A N G E S........................................................................................... 6
3
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S ........................................... 6
3. 1
St atistic al A n al ysis Pl a n S u m m ar y ....................................................................... 6
3. 2
Res p o nsi bilit y f or A n al yses/I n- H o use Bli n di n g .................................................. 8
3. 3
H y p ot heses/ Esti m ati o n .......................................................................................... 9
3. 3. 1
Pri mar y  O bjecti ve(s) & H yp ot hesis(es) ......................................................... 9
3. 3. 2
Sec o n dar y  O bjecti ve(s) & H yp ot hesis(es) ..................................................... 9
3. 3. 3
E x pl orat or y  O bjecti ves ................................................................................ 1 0
3. 4
A n al ysis E n d p oi nts ...............................................................................................1 0
3. 4. 1
Efficac y  E n d p oi nts....................................................................................... 1 1
3. 4. 2
Safet y  E n d p oi nts.......................................................................................... 1 2
3. 5
A n al ysis P o p ul ati o ns ............................................................................................ 1 2
3. 5. 1
Efficac y A nal ys is P o p ulati o ns..................................................................... 1 2
3. 5. 2
Safet y  A nalys is P o p ulati o ns ........................................................................ 1 2
3. 6
St atistic al Met h o ds ...............................................................................................1 2
3. 6. 1
Statisti cal Met h o ds f or Efficac y A nalys es ................................................... 1 2
3. 6. 1. 1
O verall S ur vi val ( O S) ........................................................................ 1 3
3. 6. 1. 2
Pr o gressi o n -Free S ur vi val ( P F S) ....................................................... 1 4
3. 6. 1. 3
O bjecti ve Res p o nse Rate ( O R R) ....................................................... 1 7
3. 6. 1. 4
Disease C o ntr ol Rate ( D C R) ..............................................................1 7
3. 6. 1. 5
D urati o n of Res p o nse ( D O R) ............................................................. 1 8
3. 6. 1. 6
S u m mar y  of Statistical Met h o ds f or Efficac y.................................... 1 8
3. 6. 2
Statistical C o nsi derati o ns f or Patie nt -Re p orte d O utc o mes ( P R O) .............. 2 0
3. 6. 2. 1
Patie nt Re p orte d O utc o me ( P R O) E n d p oi nts ....................................2 0
3. 6. 2. 2
Patie nt Re p orte d O utc o me ( P R O) A nal ys is P o p ulati o n ....................2 2
3. 6. 2. 3
A nal y sis A p pr oac hes ......................................................................... 2 2
3. 6. 2. 3. 1
Sc ori n g Al g orit h m ...................................................................2 2
3. 6. 2. 3. 2 
Patie nt Re p orte d O utc o me ( P R O) Sc ore A nal ys is................... 2 4
3. 6. 2. 3. 3
A nal y sis of t he Ti me t o Deteri orati o n ( T T D) ..........................2 4
3. 6. 2. 3. 4
A nal y sis of O verall Im pr o ve me nt ............................................2 5
3. 6. 2. 3. 5
S u m mar y  of C o m pleti o n a n d C o m plia nce...............................2 5
3. 6. 3
Statistical Met h o ds f or Safet y A nal ys es ......................................................2 5
3. 6. 4
S u m maries of De m o gra p hic a n d Baseli ne C haracteristics ..........................2 7
 
 
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M K -3 4 7 5
P A G E 3
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 6. 5
Statistical Met h o ds f or E x pl orat or y  A nalys es .............................................2 8
3. 7
I nteri m A n al yses .................................................................................................. 2 8
3. 8
M ulti plicit y
........................................................................................................... 3 0
3. 9
S a m ple Size a n d P o wer C alc ul ati o ns ................................................................. 3 2
3. 1 0
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors .......................................... 3 3
3. 1 1
C o m pli a nce ( Me dic ati o n A d here nce) ................................................................. 3 4
3. 1 2
E xte nt of E x p os ure ...............................................................................................3 4
4
R E F E R E N C E S ............................................................................................................... 3 4
 
 
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M K -3 4 7 5
P A G E 4
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
LI S T O F T A B L E S
Ta ble 1
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of Pr o gressi o n-
free S ur vi val................................................................................................................. 1 6
Ta ble 2
Ce ns ori n g R ules f or D O R............................................................................ 1 8
Ta bl e 3
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts............................................ 1 9
Ta ble 4
P R O Assess me nt Sc he d ule.......................................................................... 2 1
Ta ble 5
A nal y sis Strate g y f or Safet y Para meters...................................................... 2 7
Ta ble 6
S u m mar y  of Ti mi n g, Sa m ple Size, a n d Decisi o n G ui da nce of I nteri m 
Efficac y  A nalys es a n d Fi nal A nal ys is u n der I nitial Al p ha All ocati o n........................ 2 9
Ta ble 7
S u m mar y  of Alter nati ve Efficac y Decisi o n G ui da nce................................. 3 0
 
 
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M K -3 4 7 5
P A G E 5
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
LI S T O F FI G U R E S
Fi g ure 1
M ulti plicit y  Strate g y.................................................................................... 3 2
 
 
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P A G E 6
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
1
I N T R O D U C TI O N
T his s u p ple me ntal S A P (s S A P) is a c o m pa ni o n d oc u me nt t o t he pr ot oc ol. I n a d diti o n t o t he 
i nf or mati o n prese nte d i n t he pr ot oc ol S A P w hic h pr o vi de s t he pri nci pal feat ures of 
c o nfir mat or y a nalys es f or t his trial , t his s u p ple me ntal S A P pr o vi des a d diti o nal statistical 
a nal ys is details/ data deri vati o ns a n d d oc u me nt s m o dificati o ns or a d diti o ns t o t he a nal ys is 
pla n t hat are n ot “ pri nci p al” i n nat ure a n d res ult fr o m i nf or mati o n t hat was n ot a vaila ble at 
t he ti me of pr ot oc ol fi nalizati o n.
2 
S U M M A R Y O F C H A N G E S
T he f oll o wi n g c ha n ges ma de t o t he s S A P c o m pare d t o t he pre vi o us versi o n:
•
A d de d ma x -c o m b o test as a se nsiti vit y a nalys is f or o verall s ur vi val ( O S) ( Sect i o n 3. 6. 1. 1)
•
U p date d d etails of a nal ys is of patie nt re p orte d o utc o me ( P R O) data ( Secti o n 3. 6. 2).
All ot her c ha n ges are t o e ns ure c o nsiste nc y  wit h c ha n ges ma de t o t he pr ot oc ol ( M K-3 4 7 5-
1 1 9- 0 5).
3
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S
3. 1
St atistic al A n al ysis Pl a n S u m m ar y
K e y  ele me nts of t he statistical a nalys is pla n are s u m marize d bel o w; t he c o m pre he nsi ve 
pla n is pr o vi de d i n Secti o ns 3. 2 – Res p o nsi bilit y  f or A nalys es/I n-H o use Bli n di n g t hr o u g h 
3. 1 2 – E xte nt of E x p os ure.
St u d y Desi g n O ver vie w
A P hase III Ra n d o mize d Trial of Si n gle A ge nt Pe m br oliz u ma b vers us Si n gle 
A ge nt C he m ot hera p y per P h ysicia n’s C h oice f or Metastatic Tri ple Ne gati ve 
Breast Ca ncer ( m T N B C) 
Treat me nt Assi g n me nt
A p pr o xi matel y 6 0 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o bet w ee n t w o 
treat me nt gr o u ps: ( 1) pe m br oliz u ma b ar m a n d ( 2) Treat me nt of P h ysicia n’s 
C h oice ( T P C) ar m. Stratificati o n fact ors are: 1) P D -L 1 t u m or stat us ( p ositi ve 
[ C P S ≥1] vs ne gati ve [ C P S < 1]), a n d 2) hist or y of pri or ( ne o)a dj u va nt 
treat me nt vs de n o v o metastatic disease at i nitial dia g n osis.
A nal ysis P o p ulati o ns 
Efficac y: I nte nti o n -t o-treat P o p ulati o n (I T T)
Safet y: All S u bjects as Treate d ( A Sa T)
Pri mar y E n d p oi nt(s)
1 O verall sur vi val ( O S) i n s u bjects wit h C P S ≥1 0
2 O S i n s u bjects w it h C P S ≥1   
3 O S i n all s u bjects 
Statistical Met h o ds f or Ke y 
Efficac y A nal 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 t o 
T P C o n O S usi n g a s tratifie d L o g-ra n k test. Esti mati o n of t he hazar d rati o 
will be perf or me d usi n g a stratifie d C o x re gr essi 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.
 
 
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P A G E 7
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
Statistical Met h o ds f or Ke y 
Safet y A nal yses
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h. Safet y para meters 
or a d verse e x perie nces of s pecial i nterest t hat are i de ntifie d a pri ori
c o nstit ute “ Tier 1” safet y e n d p oi nts t hat will be s u bject t o i nfere ntial testi n g 
f or statistical si g nifica nce wit h p-val ues a n d 9 5 % c o nfi de nce i nter vals ( CIs) 
pr o vi de d f or bet w e e n-gr o u p c o m paris o ns.  Ot her safet y para meters will be 
c o nsi dere d Tier 2 ( wit h 9 5 % c o nfi de nce i nter vals pr o vi de d) or Tier 3 ( wit h 
p oi nt esti mates b y treat me nt gr o u p pr o vi de d) T he bet w ee n -treat me nt 
differe nce will be a nal yze d usi n g t he Mietti ne n a n d N ur mi ne n met h o d.
I nteri m A nal yses
O ne i nteri m efficac y a nal ysis is pla n ne d i n t his st u d y.  Details are pr o vi de d i n 
Secti o n 8. 7.
•
I nteri m A nal ysis 
o
Ti m i n g: a p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is c o m plete d. It 
is esti mate d t hat a p pr o xi matel y 1 3 0, 2 8 4 a n d 4 4 5 O S e ve nts will be 
accr ue d i n s u bjects wit h C P S ≥1 0, C P S ≥1 a n d all s u bjects.
o
P ur p ose: i nteri m efficac y a nal ysis f or O S
•
Fi nal a nal ysis
o
Tri g ger e d b y d urati o n of f oll o w-u p a n d O S e ve nts i n s u bjects wit h 
C P S ≥1: A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is c o m plete d or 
3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1, w hic he ver occ urs 
later. A p pr o xi matel y 1 5 4, 3 3 4 a n d 5 2 0 O S e ve nts will be accr ue d i n 
s ubjects wit h C P S ≥1 0, C P S ≥1 a n d all s u bjects.
o
If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue sl o w er t ha n e x pecte d 
a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt 
is c o m plete d, t he n t he S p o ns or will c o n d uct t he fi nal a nal ysis at t hat 
ti me
o
P ur p ose: fi nal efficac y a nal ysis f or O S
M ulti plicit y
T he o verall T y pe I err or o ver t he m ulti ple e n d p oi nts will be str o n gl y 
c o ntr olle d at 2. 5 % ( o ne -si de d) f or pri mar y h y p ot heses of O S e n d p oi nts 
(i nitial α of 1. 7% i n s u bjects wi t h C P S ≥1 0 a n d 0. 8 % i n s u bjects wit h 
C P S ≥1 ) a n d sec o n dar y h y p ot heses of P F S a n d O R R i n all s u bjects . Usi n g a n 
e xte nsi o n of t he gra p hical a p pr oac h of Ma urer a n d Bretz , al p ha ca n be re -
all ocate d bet w ee n h y p ot heses. G r o u p se q ue ntial met h o ds will be use d t o 
all ocate al p ha bet wee n t he i nteri m a n d fi nal a nal yses f or O S e n d p oi nts.
Sa m ple Size a n d P o w er
T he pla n ne d sa m ple size is a p pr o xi matel y 6 0 0 s u bjects.  Details are pr o vi de d 
i n Secti o n 3 . 9.
•
F or t he pri mar y O S e n d p oi nt i n s u bjects wit h C P S ≥1 0, wit h 
a p pr o xi matel y 1 5 4 O S e ve nts t he trial has ~ 8 5 % p o w er at a o ne -si de d 
1. 7 % al p ha -le vel, if t he u n derl yi n g H R is 0.6 0, wit h a H R at b o u n dar y
f or s uccess of ~ 0. 70 ( ~4. 2 m o nt h i m pr o ve me nt ).
•
F or t he pri mar y O S e n d p oi nt i n s u bjects w it h C P S ≥1, wi t h 
a p pr o xi matel y 3 3 4 O S e ve nts t he trial has ~ 8 0 % ( 9 0 %) p o wer at a o ne -
si de d 0. 8% ( 2. 5 %) al p ha-le vel, if t he u n derl yi n g H R is 0.7 0, wit h a H R 
at b o u n dar y f or s uccess of ~ 0. 7 6 ( 0. 8 0) ( ~3. 1 [ 2. 5] m o nt h i m pr o ve me nt).
•
F or t he pri mar y O S e n d p oi nt i n all s u bjects, w it h a p pr o xi matel y 5 2 0 O S 
e ve nts t he trial has ~ 6 6 % ( 8 0 %) p o w er at a o ne-si de d 0. 8 % ( 2. 5 %) 
al p ha-le vel, if t he u n derl yi n g H R is 0. 7 8, wit h a H R at b o u n dar y f or 
s uccess of ~ 0. 8 0 ( 0. 8 4) ( ~ 2. 4 [ 1. 9] m o nt h i m pr o ve me nt).
 
 
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P A G E 8
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 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 ys is 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 he I V R S ve n d or will ge nerate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y  treat me nt 
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 n te d i n I V R S.
Alt h o u g h t he trial is o pe n la bel, a nal ys es or s u m maries ge nerate d b y ra n d o mize d treat me nt 
assi g n me nt, act ual treat me nt recei ve d, a n d/ or P D -L 1 bi o mar ker stat us will be li mite d a n d 
d oc u me nte d. I n a d diti o n, t he i n de pe n de nt ra di ol o gist(s) will perf or m t he ce ntral i ma gi n g 
re vie w wit h o ut k n o wle d ge of treat me nt gr o u p assi g n me nt. T he st u d y tea m at t he S p o ns or 
c o nsisti n g of cli nical, statistical, statistical pr o gra m mi n g a n d data ma na ge me nt pers o n nel, 
will be bli n de d t o s u bject-le vel P D- L 1 bi o mar ker res u lts. A n u n bli n de d S p o ns or cli nical 
scie ntist, u n bli n de d S p o ns or statisticia n a n d u n bli n de d S p o ns or statistical pr o gra m mer will 
ha ve access t o t he s u bject -le vel P D- L 1 res ults f or t he p ur p ose of data re vie w a n d e ve nt 
m o nit ori n g, a n d will ha ve n o ot her res p o n si bilities ass ociate d wit h t he st u d y. A s u m mar y of 
P D -L 1  bi o mar ker pre vale nce ma y be pr o vi de d t o t he st u d y tea m at t he S p o ns or b y t he I V R S 
ve n d or or t he u n bli n de d S p o ns or statisticia n.
Access t o t he all ocati o n sc he d ule a n d t he s u bject -le vel P D-L 1 res ults f or s u m maries or 
a nal ys es will be restricte d t o a n u n bli n de d e xter nal statisticia n, a n d, as nee de d, a n e xter nal 
scie ntific pr o gra m mer perf or mi n g t he a nalys is, w h o will ha ve n o ot her res p o nsi bilities 
ass ociate d wit h t he st u d y.
Treat me nt -le vel res ults at t he i nteri m efficac y will be pr o vi de d b y  t he e xter nal u n bli n de d 
statisticia n t o t he e D M C. T he e xter nal u n bli n de d statisticia n will ha ve access t o all ocati o n 
sc he d ule, treat me nt gr o u p, P D-L 1  stat us f or a n y a nal ysis re q uire d f or e D M C re vie w. Li mite d 
a d diti o nal S P O N S O R pers o n nel m a y  be u n bli n de d t o t he treat me nt le vel a n d/ or P D-L 1  
bi o mar ker res ults of t he efficac y i nteri m a nalys es, if re q uire d, i n or der t o act o n t he 
rec o m me n dati o ns of t he e D M C or facilitate re g ulat or y fili n g after t he i nteri m efficac y 
a nal ys is. The e xte nt t o w hic h i n di vi d uals are u n bli n de d wit h res pect t o res ults of i nteri m 
a nal ys es will be d oc u me nte d b y t he u n bli n de d statisticia n.
T he e D M C will ser ve as t he pri mar y  re vie wer of t he u n bli n de d res ults of t he i nteri m efficac y 
a nal ys es a n d will ma ke r ec o m me n dati o ns f or disc o nti n uati o n of t he st u d y  or m o dificati o n t o 
a n e xec uti ve o versi g ht c o m mittee of t he S P O N S O R. De pe n di n g o n t he rec o m me n dati o n of 
t he e D M C, t he S p o ns or ma y pre pare a re g ulat or y s u b missi o n. If t he e D M C rec o m me n ds 
m o dificati o ns t o t he de si g n of t he pr ot oc ol or disc o nti n uati o n of t he st u d y, t his e xec uti ve 
o versi g ht c o m mittee ma y be u n bli n de d t o res ults at t he treat me nt le vel i n or der t o act o n 
t hese rec o m me n dati o ns. A d diti o nal l o gistical details, re visi o ns t o t he a b o ve pla n a n d data 
m o nit o ri n g g ui da nce will be pr o vi de d i n t he e D M C C harter.
 
 
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M K -3 4 7 5
P A G E 9
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 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 Pr ot oc ol Secti o n 3. 0 – O bjecti ve(s) & 
H y p ot hesis(es) a n d are liste d i n t his secti o n.
3. 3. 1
Pri m ar y O bjecti ve(s) & H y p ot hesis(es)
Pe m br o liz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C:
P D -L 1 P ositi ve P o p ul ati o ns : s u bjects wit h P D-L 1 p ositi ve e x pressi o n defi ne d b y ≥1 0 
C o m bi ne d P ositi ve Sc ore ( C P S) a n d b y  ≥1 C P S; he ncef ort h a b bre viate d as C P S ≥1 0 a n d 
C P S ≥1 res pecti vel y.
( 1) O bjecti ve: T o c o m pare O S i n s u bjects wit h P D - L 1 p ositi ve t u m ors ( C P S ≥1 0).
H y p ot hesis ( H 1 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0) . 
( 2) O bjecti ve: T o c o m pare O S i n s u bjects w it h P D -L 1 p ositi ve t u m ors ( C P S ≥1).
H y p ot hesis ( H 2 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1) . 
( 3) O bjecti ve: T o c o m pare O S i n all s u bjects.
H y p ot hesis ( H 3): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n all s u bjects.
T he st u d y  is c o nsi dere d t o ha ve met its pri mar y o bjecti ve if pe m br oliz u ma b is s u peri or t o 
T P C i n O S i n eit her s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 [ H 1] or C P S ≥1 [ H 2]) or 
i n all s u bjects (H 3), at eit her t he i nteri m a nal y sis or t he fi nal a nal ysis.
3. 3. 2 
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es)
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C:
( 1) O bjecti ve:   T o c o m pare pr o gressi o n -free s ur vi val ( P F S) base d o n R E CI S T 1. 1 as 
assesse d b y bli n de d ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hesis ( H 4): Pe m br oliz u ma b pr ol o n gs P F S base d o n R E CI S T 1. 1 as assesse d b y  
bli n de d ce ntral i ma gi n g ve n d or c o m pare d t o T P C i n all s u bjects.
( 2) O bjecti ve:   T o c o m pare o verall res p o nse rate ( O R R) per R E CI S T 1. 1 b y  bli n de d 
ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hesis ( H 5): Pe m br oliz u ma b i ncreases O R R per R E CI S T 1. 1 b y  bli n de d ce ntral 
i ma gi n g ve n d or c o m pare d t o T P C i n all s u bject s.
 
 
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( 3) O bjecti ve:   T o e val uate P F S a n d O R R base d o n R E CI S T 1. 1 as assesse d b y  bli n de d 
ce ntral i ma gi n g ve n d or i n s u bjects wit h P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 a n d 
C P S ≥1) .
( 4) O bjecti ve: T o e val uate d urati o n of res p o nse ( D O R), a n d disease c o ntr ol rate ( D C R) 
base d o n R E CI S T 1. 1 as assesse d b y  bli n de d ce ntral i ma gi n g ve n d or i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d i n all s u bjects.
( 5) O bjecti ve: T o deter mi ne t he safet y a n d t olera bilit y  of pe m br oliz u ma b.
T he sec o n dar y  h yp ot heses re gar di n g P F S i n all s u bjects ( H 4) a n d O R R i n all s u bjects ( H 5) 
ca n o nl y be f or mall y teste d o nce t he n ull h y p ot hesis re gar di n g t he pri mar y  e n d p oi nt O S i n all 
s u bjects ( H 3) has bee n rejecte d.
3. 3. 3
E x pl o r at or y O bjecti ves
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C:
( 1) O bjecti ve: T o e val uate P F S, O R R, D O R, a n d D C R base d o n ir R E CI S T as assesse d 
b y  bli n de d ce ntral i ma gi n g re vie w i n s u bjects wit h P D-L 1 p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects.
( 2) O bjecti ve: T o e val uate c ha n ges i n healt h -relate d q ualit y- of-life assess me nts fr o m 
baseli ne i n s u bjects wit h P D-L 1  p ositi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d all 
s u bjects usi n g t he E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
(E O R T C ) Q L Q -C 3 0 a n d Q L Q -B R 2 3.
( 3) O bjecti ve: T o c haracterize utilities i n s u bjects wit h P D-L 1  p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects usi n g E ur o Q ol ( E Q )-5 D.
( 4) O bjecti ve : T o i n vesti gate t he ass ociati o n bet wee n a n tit u m or acti vit y of 
pe m br oliz u ma b i n m T N B C a n d efficac y /resista nce bi o mar kers, utilizi n g t u m or a n d 
bl o o d s peci me ns o btai ne d bef ore/ d uri n g treat me nt a n d at disease pr o gressi o n.
( 5) O bjecti ve: T o e x pl ore t he relati o ns hi p bet wee n ge netic variati o n a n d res p o nse t o t he 
treat me nt(s) a d mi nistere d.  Variati o n acr oss t he h u ma n ge n o me will be a nal yze d f or 
ass ociati o n wit h cli nical data c ollecte d i n t his st u d y.
3. 4
A n al ysis E n d p oi nts
Efficac y  a n d safety e n d p oi nts t hat will be e val uate d are liste d bel o w.
 
 
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3. 4. 1
Effic ac y E n d p oi nts
Pri m ar y
O ver all S ur vi v al ( O S)
O verall s ur vi val 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. 
S u bjects wit h o ut d oc u me nte d deat h at t he ti me of t he a nal ys is will be ce ns ore d at t he date of 
t he last f oll o w- u p.
Sec o n d ar y/ E x pl or at or y
Pr o gressi o n -free s ur vi val ( P F S) – base d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntral 
i ma gi n g ve n d or ( R E CIS T 1. 1 b y  site I n vesti gat or/l ocal ra di ol o g y re vie w as a s u p p orti ve 
a nal ys is).
Pr o gressi o n -free-s ur vi val ( P F S) 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 base d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntral 
i ma gi n g ve n d or ra di ol o g y re vie w or deat h d ue t o a n y  ca use, w hic he ver occ urs first. See 
Secti o n 3 . 6. 1 f or t he defi niti o n of ce ns ori n g.
O ver all Res p o nse R ate ( O R R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or ( R E CIS T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nalys es; ir R E CIS T b y  
site I nvesti gat or /l ocal ra di ol o g y revie w m a y  als o be e val uate d).
O verall res p o nse rate is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ysis p o p ulati o n 
w h o ha ve a c o m plete res p o nse ( C R) or partial res p o nse ( P R).
D ur ati o n of O ver all Res p o nse ( D O R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d 
ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or ( R E CIS T 1. 1 b y  
site I nvesti gat or/l ocal ra di ol o g y  re vie w as t he c orres p o n di n g s u p p orti ve a nal yses; ir R E CIS T
b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  als o be e val uate d).
F or s u bjects w h o de m o nstrate d C R or P R, res p o nse d urati o n is defi ne d as t he ti me fr o m first 
d oc u me nte d e vi de nce of C R or P R u ntil disease pr o gressi o n or deat h. See Secti o n 3 . 6. 1 f or 
t he defi niti o n of ce ns ori n g.
Dise ase C o ntr ol R ate ( D C R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or ( R E CIS T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nalys es; ir R E CIS T b y  
site I nvesti gat or /l ocal ra di ol o g y re vie w m a y  als o be e val uated ).
Disease c o ntr ol rate ( D C R) is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ys is 
p o p ulati o n w h o ha ve a C R, partial res p o nse ( P R) a n d sta ble disease ( S D), t he latter f or at 
least 8 c ycles.
 
 
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2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
P F S – b ase d o n ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or 
(ir R E CIS T b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  be perf or me d as s u p p orti ve 
a nal ys is).
3. 4. 2
S afet y E n d p oi nts
Safet y  meas ure me nts are descri be d i n Pr ot oc ol Secti o n 4. 2. 3 – Rati o nale f or E n d p oi nts a n d 
Pr ot oc ol Secti o n 7. 0 – Trial Pr oce d ures.
3. 5
A n al ysis P o p ul ati o ns
3. 5. 1 
Effic ac y A n al ysis P o p ul ati o ns
T he I T T p o p ulati o n will ser ve as t he p o p ulati o n f or pri mar y  efficac y a nal ysis. All 
ra n d o mize d s u bjects will be i ncl u de d i n t his p o p ulati o n. S u bjects will be i ncl u de d i n t he 
treat me nt gr o u p t o w hic h t he y  are ra n d o mize d.
Details o n t he a p pr oac h t o ha n dli n g missi n g data are pr o vi de d i n Secti o n 3. 6 – Statistical 
Met h o ds.
3. 5. 2
S afet y A n al ysis P o p ul ati o ns
T he All S u bjects as Treate d ( A Sa T) p o p ulati o n will be use d f or t he a nal ys is of safety data i n 
t his stu d y .  T he A Sa T p o p ulati o n c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt. S u bjects will be i ncl u de d i n t he treat me nt gr o u p c orres p o n di n g 
t o t he st u d y treat me nt t he y act ually recei ve d f or t he a nal ys is of safety data us i n g t he A Sa T 
p o p ulati o n.  F or m ost s u bjects t his will be t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d.  
S u bjects w h o ta ke i nc orrect st u d y  treat me nt f or t he e ntire treat me nt peri o d will be i ncl u de d i n 
t he treat me nt gr o u p c orres p o n di n g t o t he st u d y treatme nt act uall y recei ve d. A n y s u bject w h o 
recei ves t he i nc orrect st u d y dr u g f or o ne c ycle, b ut recei ves t he c orrect treat me nt f or all ot her 
c ycles, will be a nal yze d acc or di n g t o t he c orrect treat me nt gr o u p a n d a narrati ve will be 
pr o vi de d f or a n y e ve nts t hat occ ur d uri n g t he c y cle f or w hic h t he s u bject is i nc orrectl y  d ose d.
At least o ne la b orat or y  or vital si g n meas ure me nt o btai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter.  T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.
Details o n t he a p pr oac h t o ha n dli n g missi n g data f or safet y a nal ys es are pr o vi de d i n Secti o n 
3. 6 – Statistical Met h o ds.
3. 6
St atistic al Met h o ds
3. 6. 1
St atistic al Met h o ds f or Effic ac y A n al yses
Efficac y res ults t hat will be dee me d t o be statisticall y si g nifica nt after c o nsi derati o n of t he 
T y pe I err or c o ntr ol strate g y are descri be d i n Secti o n 3. 8 – M ulti plicit y .  N o mi nal p-val ues 
will be c o m p ute d f or ot her efficac y a nalys es, b ut s h o ul d be i nter prete d wit h ca uti o n d ue t o 
p ote ntial iss ues of m ulti plicit y . Of n ote, f or t he stratifie d a nalys es perf or me d i n all s u bject s, 
 
 
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b ot h stratificati o n fact ors [ P D -L 1  t u m or stat us ( p ositi ve [ C P S ≥1] vs ne gati ve [ C P S < 1]), a n d 
pri or ( ne o)a dj u va nt t hera p y  vs de n o v o metastatic disease at i nitial dia g n osis] will be 
i ncl u de d. F or efficac y a nal yses perf or me d i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1), o nl y  t he stratificati o n fact or of pri or ( ne o)a dj u va nt t hera p y vs de n o v o
metastatic disease at i nitial dia g n o sis will be c o nsi dere d i n t he a nalys is m o dels, i.e., n ot 
c o nsi deri n g t he stratificati o n fact or of P D-L 1 t u m or stat us. If t here is t o o s mall n u m ber ( < 1 0) 
of s u bjects i n s pecific strat u m f or a nalys es i n all s u bjects or s u bjects wit h P D -L 1 p ositi ve 
t u m ors (C P S ≥1 0 a n d C P S ≥1) base d o n bli n de d data re vie w, t he n strata will be c o m bi ne d
wit h t he nei g h b ori n g strata. If t he mis -stratificati o n rate at ra n d o mizati o n is greater t ha n 1 0 %
base d o n re vie w of bli n de d data , a d diti o nal se nsiti vit y a nal ys es ma y be perf or me d f or 
pri mar y  efficac y a n d ke y sec o n dar y efficac y e n d p oi nts acc or di n g t o eac h s u bject’s strat u m 
base d o n act ual data o bser ve d/c ollecte d .
3. 6. 1. 1
O ver all S ur vi v al ( O S)
T he n o n -para metric Ka pla n - Meier met h o d will be use d t o esti mate t he s ur vi val c ur ves. T he 
treat me nt differe nce i n s ur vi val will be assesse d b y t he stratifie d l o g-ra n k test. A stratifie d 
C o x pr o p orti o nal hazar d m o del wit h Efr o n’s met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce ( i e, t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n [ P D-L 1  t u m or stat us ( p ositi ve
[ C P S ≥1] vs ne gati ve [ C P S < 1]), a n d pri or ( ne o)a dj u va nt t hera p y vs de n o v o metastatic 
disease at i nitial dia g n osis] will be a p plie d, as stratificati o n fact ors use d f or a nal ys is, 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.
S u bjects i n t he T P C ar m are e x pecte d t o disc o nti n ue treat me nt earlier c o m pare d t o s u bjects i n 
t he pe m br oliz u ma b ar m a n d are n ot all o we d t o cr oss o ver t o t he pe m br oliz u ma b ar m; 
h o we ver, t he y  m a y be treate d wit h a n ot her a nti P D-1 dr u g f oll o wi n g t he verificati o n of 
pr o gressi ve disease b y bli n de d ce ntral i ma gi n g ve n d or. As a n e x pl orat or y  a nal ysis, t he Ra n k 
Preser vi n g Str uct ural Fail ure Ti me ( R P S F T) m o del pr o p ose d b y  R o bi ns a n d Tsiatis (1 9 9 1)
[ 1] a n d t w o sta ge-m o del [ 2] ma y  be use d t o a dj ust f or t he effect of cr oss o ver t o ot her P D- 1 
t hera pies o n O S, base d o n a n e xa mi nati o n of t he a p pr o priate ness of t he data t o t he 
ass u m pti o ns re q uire d b y t he met h o ds.
T he R P S F T m o del pr o vi des a ra n d o mizati o n -base d esti mate of t he treat me nt effect c orrecte d 
f or bias i ntr o d uce d by cr oss o ver fr o m t he c o ntr ol ar m t o t he e x peri me ntal treat me nt. T his 
met h o d is ra n k - preser vi n g i n t he se nse t hat it ass u mes t hat gi ve n t w o s u bjects i a n d j, if 
s u bject i faile d bef ore s u bject j w he n b ot h were o n o ne treat me nt, t he n s u bject i w o ul d als o 
fail bef ore s u bject j if b ot h s u bjects t o o k a n y ot her alter nati ve treat me nt. T he met h o d is 
str uct ural i n t he se nse t hat it ass u mes a defi ne d relati o ns hi p bet wee n t he o bser ve d s ur vi val 
ti me a n d t he s ur vi val ti me t hat w o ul d ha ve bee n o bser ve d if cr oss o ver ha d n ot occ urre d. It is
als o ass u me d t hat t he treat me nt effect is t he sa me bef ore a n d after pr o gressi o n. M ore 
s pecifically, t he R P S F T met h o d first relates t he o bser ve d s ur vi val ti me t o a late nt s ur vi val 
ti me (e x peri me ntal treat me nt-free s ur vi val ti me if t he patie nt was ne ver t o recei ve t he 
e x peri me ntal treat me nt) t hr o u g h a n accelerate d fail ure ti me m o del. T he treat me nt effect will 
t he n be esti mate d u n der t he ass u m pti o n t hat t he late nt s ur vi val c ur ves are i de ntical bet wee n 
 
 
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2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
t he c o ntr ol a n d e x peri me ntal treat me nt ar ms. Re -ce ns ori n g of t he late nt s ur vi val ti me usi n g 
t he treat me nt effect will be a p plie d i n or der t o preser ve t he i n de pe n de nt ce ns ori n g 
ass u m pti o n. T he O S a nal ysis will t he n be a p plie d t o t he “c orrecte d” s ur vi val dataset, w hic h 
i ncl u des t he a dj uste d s ur vi val ti me f or s u bjects i n t he c o ntr ol ar m s o t hat it reflects t he O S 
ha d t he y  n ot recei ve d t he e x peri me ntal treat me nt as well as t he o bser ve d s ur vi val ti me f or 
s u bjects i n t he e x peri me ntal treat me nt ar m. T he H R a n d t he ass ociate d 9 5 % CI f or O S after 
a dj ust me nt of t he cr oss o ver effect usi n g t he R P S F T met h o d will be pr o vi de d.
U n der t he ass u m pti o ns of n o u n meas ure d c o nf o u n ders at t he sec o n dar y  baseli ne ti me-p oi nt 
( disease pr o gressi o n), treat me nt s witc hi n g o nly ha p pe ns after pr o gressi o n, a n d ha p pe ns s o o n 
after pr o gressi o n, t he “t w o- sta ge” a p pr oac h ma y be a p pr o priate. At Sta ge 1, t he date of 
disease pr o gressi o n is use d as a sec o n dar y  baseli ne f or s u bjects w h o ha ve a d oc u me nte d 
pr o gressi o n i n t he c o ntr ol ar m a n d data fr o m t hese s u bjects be y o n d t his ti me -p oi nt are 
c o nsi dere d as a n o bs er vati o nal dataset.  A n accelerate d fail ure ti me m o del i ncl u di n g 
c o variates f or cr oss o ver a n d ot her pr o g n ostic c o variates meas ure d at t he sec o n dar y  baseli ne 
will be a p plie d t o t his o bser vati o nal dataset t o esti mate a n accelerati o n fact or.  At Sta ge 2, a 
c ou nterfact ual s ur vi val dataset will be c o nstr ucte d s uc h t hat s ur vi val ti me of s u bjects wit h 
treat me nt s witc hi n g will be s hr u n k by t he i n verse of t he accelerati o n fact or, w hile n o 
s hri n ka ge is perf or me d f or t he s ur vi val ti me of s u bjects i n t he c o ntr ol gr o u p wit h o ut 
treat me nt s witc hi n g or s u bjects i n t he e x peri me ntal ar m. T he O S a nalys is will t he n be a p plie d 
t o t his c o u nterfact ual s ur vi val dataset t o esti mate t he H R fr o m t his t w o-sta ge met h o d.
It is ver y i m p orta nt t o assess trial data, cr oss o ver mec ha nis m, a n d treat me nt effect t o 
deter mi ne w hic h met h o d is li kel y  t o be m ost a p pr o priate t o e val uate t he cr oss o ver effect.  
A d diti o nal s u p p orti ve u nstratifie d a nal ys es ma y als o be pr o vi de d.
D ue t o m ulti ple occ urre nces of dela y e d se parati o n p he n o me na o bser ve d i n m o n ot h era p y 
I m m u n o-O nc ol o g y  (I/ O) R C Ts, an ot her se nsiti vit y  a nalys is, w hic h e val uates t he treat me nt 
differe nce f or O S usi n g t he stratifie d ma x -c o m b o test, will be c o n d ucte d at t he fi nal a nal ys is. 
T he ma x -c o m b o test statistic is t he ma xi m u m of t he l o g-ra n k test statistic a n d wei g hte d l o g-
ra n k variati o n of t he Fle mi n g-Harri n gt o n test statistic s; Zm = ma x ( Z 1, Z2, Z3), w here Z1, Z2
a n d Z 3 are t he test statistics fr o m t he F H ( 0, 0), F H ( 1, 1) a n d F H ( 0, 1) fa mil y  of test 
statistics, res pecti vely. F H ( 0, 0) c orres p o n d s t o t he l o g-ra n k test, w hile F H ( 1, 1) a n d F H ( 0, 
1) are m ore se nsiti ve t o mi d dle a n d late-differe nce alter nati ves, res pecti vel y . T he a dj uste d 
n o mi nal p- val ue, w hic h ca n be deri ve d b y i nte grati n g u n der t he m ulti variate n or mal de nsit y
[ 3] will be re p orte d. N o f or mal h y p ot hesis test will be c o n d ucte d.
3. 6. 1. 2
Pr o gressi o n -Free S ur vi v al ( P F S)
T he n o n -para metric Ka pla n -Meier met h o d will be use d t o esti mate t he P F S c ur ve i n eac h 
treat me nt gr o u p. T he treat me nt differe nce i n P F S will be assesse d b y t he stratifie d l o g -ra n k 
test. A stratifie d C o x pr o p orti o nal hazar d m o del wit h Efr o n’s met h o d of tie ha n dli n g will be 
use d t o assess t he ma g nit u de of t he treat me nt differe nce (i .e. hazar d rati o) bet wee n t he 
treat me nt ar ms. T he hazar d rati o a n d its 9 5 % c o nfi de nce i nter val fr o m t he stratifie d C o x 
m o del wit h Efr o n’s met h o d of tie ha n dli n g a n d wit h a si n gle treat me nt c o variate will be 
re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n (see Pr ot oc ol Secti o n 5. 4 –
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 1 5
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
Stratificati o n) will be a p pli e d, as stratificati o n fact ors use d f or a nal ys is, 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.
Si nce disease pr o gressi o n is assesse d peri o dicall y, pr o gressi ve disease ( P D) ca n occ ur a n y  
ti me i n t he ti me i nter val bet wee n t he last assessme nt w here P D was n ot d oc u me nte d a n d t he 
assess me nt w he n P D is d oc u me nte d. F or t he s u bjects w h o ha ve P D, t he tr ue date of disease 
pr o gressi o n will be a p pr o xi mate d b y  t he date of t he first assess me nt at w hic h P D is 
o bjecti vel y  d oc u me nte d base d o n R E CIS T 1. 1 as assesse d b y bli n de d ce ntral i ma gi n g 
ve n d or. Deat h is al wa y s c o nsi dere d as a c o nfir me d P D e ve nt. S u bjects w h o d o n ot e x perie nce 
a P F S e ve nt will be ce ns ore d at t he last disease assess me nt ( wit h e xce pti o ns descri be d 
bel o w). Se nsiti vit y  a nalyses will be p erf or me d f or c o m paris o n of P F S base d o n I n vesti gat or's 
assess me nt.
I n or der t o e val uate t he r o b ust ness of t he P F S e n d p oi nt base d o n R E CIS T 1. 1 as assesse d b y  
bli n de d ce ntral i ma gi n g ve n d or, we will perf or m o ne pri mar y  a n d t w o se nsiti vit y a nal yses 
wit h a di ffere nt set of ce ns ori n g r ules. F or t he pri mar y  a nalys is, if t he e ve nts ( P D or deat h) 
are i m me diatel y after m ore t ha n o ne misse d disease assess me nt, t he data are ce ns ore d at t he 
last disease assess me nt pri or t o missi n g visits.  Als o data after ne w a nti-ca ncer t hera p y are 
ce ns ore d at t he last disease assess me nt pri or t o t he i nitiati o n of ne w a nti -ca ncer t hera p y. T he 
first se nsiti vit y a nalys is f oll o ws t he c o m plete f oll o w u p i nte nti o n-t o-treat pri nci ple. T hat is, 
P Ds/ deat hs are c o u nte d as e ve nts re gar dless of misse d st u d y  visits or i nitiati o n of ne w a nti-
ca ncer t hera p y.  T he sec o n d se nsiti vit y  a nalys is c o nsi ders disc o nti n uati o n of treat me nt or 
i nitiati o n of a n a ntica ncer treat me nt s u bse q ue nt t o disc o nti n uati o n of st u d y-s pecifie d 
treat me nts, w hic he ver occ urs later, t o be a P D e ve nt f or s u bjects wit h o ut d oc u me nte d P D or 
deat h. If a s u bject meets m ulti ple criteria f or ce ns ori n g, t he ce ns ori n g criteri o n t hat occ urs 
earliest will be a p plie d.  T he ce ns ori n g r ules f or pri mar y  a n d se nsiti vit y a nal yses are 
s u m marize d i n Ta ble 1 .
 
 
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0 6 D W 2 6


M K -3 4 7 5
P A G E 1 6
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
T a ble 1  
Ce ns ori n g R ules f or Pri m ar y a n d Se nsiti vit y A n al yses of Pr o gressi o n- free 
S ur vi v al
Sit u ati o n
Pri m ar y A n al ysis
Se nsiti vit y
A n al ysis 1
Se nsiti vit y
A n al ysis 2
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is n ot 
i nitiate d
Ce ns ore d at last disease 
assess me nt 
Ce ns ore d at last disease 
assess me nt 
Pr o gresse d at treat me nt 
disc o nti n uati o n d ue t o 
reas o ns ot her t ha n 
c o m plete res p o nse; 
ot her wise ce ns ore d at last 
disease assess me nt if still 
o n st u d y treat me nt or 
c o m plete d st u d y treat me nt.
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is i nitiate d
Ce ns ore d at last disease 
assess me nt bef ore ne w 
a ntica ncer treat me nt
Ce ns ore d at last disease 
assess me nt 
Pr o gresse d at date of ne w  
a ntica ncer treat me nt
P D or deat h 
d oc u me nte d after ≤ 1 
misse d disease 
assess me nt, a n d 
bef ore ne w a nti -
ca ncer t hera p y, if a n y
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
P D or deat h 
d oc u me nte d 
i m me diatel y after ≥ 2 
misse d disease 
assess me nts or after 
ne w a nti -ca ncer 
t hera p y, if a n y
Ce ns ore d at last disease 
assess me nt pri or t o t he 
earlier date of ≥ 2 
c o nsec uti ve misse d 
disease assess me nt a n d 
ne w a nti -ca ncer t hera p y, 
if a n y
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
T he pr o p orti o nal hazar ds ass u m pti o n o n P F S will be e xa mi ne d usi n g b ot h gra p hical a n d 
a nal yt ical met h o ds if warra nte d.  T he l o g[- l o g] of t he s ur vi val f u ncti o n vs ti me f or P F S ma y 
be pl otte d f or t he c o m paris o n bet wee n p e m br oliz u mab a n d t he T P C ar m.  If t he c ur ves are 
n ot parallel, i n dicati n g t hat hazar ds are n ot pr o p orti o nal, s u p p orti ve a nalys es ma y be
c o n d ucte d t o acc o u nt f or t he p ossi ble n o n - pr o p orti o nal hazar ds effect ass ociate d wit h 
i m m u n ot hera pies; f or e xa m ple, usi n g Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d [ 4]
a n d para metric met h o d [ 5]. T he R M S T is si m pl y  t he p o p ulati o n a vera ge of t he a m o u nt of 
e ve nt-free s ur vi val ti me e x perie nce d d uri n g a fi xe d st u d y f oll o w-u p ti me. T his q ua ntit y  ca n 
be esti mate d b y t he area u n der t he Ka pla n -Meier
c ur ve u p t o t he f oll o w-u p ti me.  T he cli nical 
rele va nce an d feasi bilit y  s h o ul d be ta ke n i nt o acc o u nt i n t he c h oice of f oll o w-u p ti me t o 
defi ne R M S T (e. g., near t he last o bser ve d e ve nt ti me ass u mi n g t hat t he peri o d of cli nical 
i nterest i n t he s ur vi val e x perie nce is t he w h ole o bser ve d f oll o w-u p ti me f or t he trial, b ut 
a v oi di n g t he ver y e n d of t he tail w here varia bilit y ma y be hi g h); a descri pti o n of t he R M S T 
as a f u ncti o n of t he c ut off ti me ma y  be of i nterest. T he differe nce bet wee n t w o R M S Ts f or 
t he t w o treat me nt gr o u ps will be esti mate d a n d 9 5 % CI will be pr o vi ded.
O ne ass u m pti o n f or stratifie d C o x pr o p orti o nal hazar d m o del is t hat t he treat me nt H R is 
c o nsta nt acr oss t he strata.  If str o n g de part ures fr o m t he ass u m pti o n of t he H R bei n g t he sa me 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 1 7
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
f or all t he strata o bser ve d ( w hic h ca n res ult i n a n ota bl y biase d a n d/ or less p o werf ul 
a nal ys is), a se nsiti vit y a nal ysis ma y be perf or me d base d o n a t w o-ste p wei g hte d C o x m o del 
a p pr oac h b y  Me hr otra et al., 2 0 1 2 [ 6], i n w hic h t he treat me nt effect is first esti mate d f or eac h 
strat u m, a n d t he n t he strat u m s pecific esti mates are c o m bi ne d f or o verall i nfere nce usi n g 
sa m ple size wei g hts. T he R M S T met h o d a n d t w o -ste p wei g hte d C o x m o del ma y als o be 
a p plie d t o O S e n d p oi nts as a p pr o priate as se nsiti vit y  a nalys es.
I n case t here is a n i m bala nce bet wee n t he treat me nt gr o u ps o n disease assess me nt sc he d ules 
or ce ns ori n g patter ns, we ma y  als o perf or m o ne a d diti o nal P F S s u p p orti ve a nal ysis usi n g 
Fi n kelstei n ( 1 9 8 6)’s li keli h o o d- base d sc ore test [ 7] f or i nter val-ce ns ore d data, w hic h 
m o difies t he C o x pr o p orti o nal hazar d m o del f or i nter val -ce ns ore d data. T he i nter val will be 
c o nstr ucte d s o t hat t he left e n d p oi nt is t he date of t he last disease assess me nt wit h o ut
d oc u me nte d P D a n d t he ri g ht e n d p oi nt is t he date of d oc u me nte d P D or deat h, w hic he ver 
occ urs earlier.
A d diti o nal P F S s u p p orti ve a nal ys es ma y be perf or me d as a p pr o priate, i ncl u di n g a P F S 
a nal ys is usi n g ti me t o sc he d ule d t u m or assess me nt visit fr o m ra n d o mizati o n as o p p ose d t o 
t he act ual t u m or assess me nt ti me.  A d diti o nal s u p p orti ve unstratifie d a nal yses ma y  als o be 
pr o vi de d.
3. 6. 1. 3
O bjecti ve Res p o nse R ate ( O R R)
Stratifie d Mietti ne n a n d N ur mi ne n’s met h o d will be use d f or t he c o m paris o n of O R R 
bet wee n 2 treat me nt ar ms. T he differe nce i n O R R a n d its 9 5 % CI fr o m t he stratifie d 
Mietti ne n a n d N ur m i ne n’s met h o d wit h strata wei g hti n g b y sa m ple size will be re p orte d.  
T he stratificati o n fact ors use d f or ra n d o mizati o n (see Pr ot oc ol Secti o n 5. 4 – Stratificati o n) 
will be a p plie d t o t he a nal ysis.
T he O R R h y p ot heses will be teste d acc or di n g t o t he h y p ot hes es testi n g pla n as descri be d i n 
Secti o n 3. 8 – M ulti plicit y .
Se nsiti vit y  a nal yses will be perf or me d f or O R R base d o n site i n vesti gat or/l ocal ra di ol o g y 
re vie w.  A d diti o nal s u p p orti ve u nstratifie d a nal y ses ma y als o be pr o vi de d.
3. 6. 1. 4
Dise ase C o ntr ol R ate ( D C R)
Stra tifie d Mietti ne n a n d N ur mi ne n’s met h o d will be use d f or t he c o m paris o n of D C R 
bet wee n 2 treat me nt ar ms.  T he differe nce i n D C R a n d its 9 5 % CI fr o m t he stratifie d 
Mietti ne n a n d N ur mi ne n’s met h o d wit h strata wei g hti n g b y  sa m ple size will be re p orte d.  
T he st ratificati o n fact ors use d f or ra n d o mizati o n (see Pr ot oc ol Secti o n 5. 4 – Stratificati o n) 
will be a p plie d t o t he a nal y sis.
Se nsiti vit y  a nal yses will be perf or me d f or D C R base d o n site i n vesti gat or/l ocal ra di ol o g y 
re vie w.
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 1 8
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 6. 1. 5  
D ur ati o n of Res p o nse ( D O R)
If sa m ple size per mits, D O R will be s u m marize d descri pti vely usi n g t he n o n -para metric 
Ka pla n -Meier met h o d.  O nl y  t he s u bset of s u bjects w h o ac hie ve d C R or P R will be i ncl u de d 
i n t his a nal ysis.
Ce ns ori n g r ules f or D O R are s u m marize d i n Ta ble 2 . If a s u bject meets m ulti ple criteria f or 
ce ns ori n g, t he ce ns ori n g criteri o n t hat occ urs earliest will be a p plie d.
F or eac h D O R a nal ys is, a c orres p o n di n g s u m mar y of t he reas o ns res p o n di n g s u bjects are 
ce ns ore d will als o be pr o vi de d. Res p o n di n g s u bjects w h o are ali ve, ha ve n ot pr o gresse d, ha ve 
n ot i nitiate d ne w a nti -ca ncer treat me nt, ha ve n ot bee n deter mi ne d t o be l ost t o f oll o w-u p, a n d 
ha ve ha d a disease assess me nt wit hi n ~ 5 m o nt hs of t he data c ut off date are c o nsi dere d 
o n g oi n g res p o n ders at t he ti me of a nal ys is. If a s u bject meets m ulti ple criteria f or ce ns ori n g, 
t he ce ns ori n g criteri o n t hat occ urs earliest will be a p plie d.
T a ble 2  
Ce ns ori n g R ules f or D O R
Sit u ati o n
D ate of Pr o gressi o n or Ce ns ori n g
O utc o m e
N o pr o gressi o n n or deat h, n o ne w a nti -
ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt
Ce ns or
( n o n-e ve nt)
N o pr o gressi o n n or deat h, ne w a nti -
ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt 
bef ore ne w  a nti-ca ncer t hera p y i nitiate d
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n i m me diatel y after 
≥ 2 c o nsec uti ve misse d disease 
assess me nts or after ne w a nti -ca ncer 
t hera p y, if a n y
Earlier date of last a de q uate disease 
assess me nt pri or t o ≥ 2 misse d 
a de q uate d isease assess me nts a n d ne w 
a nti -ca ncer t hera p y, if a n y
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n after ≤ 1 misse d 
disease assess me nts a n d bef ore ne w 
a nti -ca ncer t hera p y, if a n y
P D or deat h
E n d of res p o nse
( E ve nt)
A misse d disease assess me nt i ncl u des a n y as sess me nt t hat is n ot o btai ne d or is c o nsi dere d i na de q uate f or 
e val uati o n of res p o nse.
3. 6. 1. 6
S u m m ar y of St atistic al Met h o ds f or Effic ac y
Ta ble 3 s u m marizes t he pri mar y a nalys is a p pr oac h f or pri mar y a n d sec o n dar y efficac y 
e n d p oi nts of Part 2.  Se nsiti vit y a nalys is met h o ds are descri be d a b o ve f or eac h e n d p oi nt as 
a p plica ble.
T he strate g y  t o a d dress m ulti plicit y iss ues wit h re gar d t o m ulti ple efficac y e n d p oi nts, 
m ulti ple p o p ulati o ns, a n d i nteri m a nal y ses is descri be d i n Secti o n 3. 7 – I nteri m A nal yses a n d 
i n Secti o n 3. 8 – M ulti plicit y .
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 1 9
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
T a ble 3  
A n al ysis St r ate g y f or Ke y Effic ac y E n d p oi nts
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
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 E n d p oi nts/ H y p ot hesis
Pri m ar y H y p ot hesis # 1
O S i n s u bjects wit h C P S ≥1 0
Test: 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
Pri m ar y H y p ot hesis # 2
O S i n s u bjects wit h C P S ≥1
Test: 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
Pri m ar y H y p ot hesis # 3
O S i n all s u bjects
Test: 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
Sec o n d ar y E n d p oi nts/ H y p ot hesis
Sec o n d ar y H y p ot hesis # 4
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Test: 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

Pri mar y ce ns ori n g r ule

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
( M ore details are i n T a ble 1 )
Sec o n d ar y H y p ot hesis # 5
O R R base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Stratifie d M & N 
met h o d ‡
I T T
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
Sec o n d ar y Effic ac y O bjecti ves
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or
i n s u bjects wit h C P S ≥1 0 a n d 
s u bjects wit h C P S ≥1
Test: 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

Pri mar y ce ns ori n g r ule

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
( M ore details are i n T a ble 1 )
O R R base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or
i n s u bjects wit h C P S ≥1 0 a n d 
s u bjects wit h C P S ≥1
Stratifie d M & N 
met h o d ‡
I T T
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
 
 
0 5 7 5 T 4
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M K -3 4 7 5
P A G E 2 0
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
A n al ysis 
P o p ul ati o n
Missi n g D at a A p pr o ac h
D C R b ase d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0, 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
Stratifie d M & N 
met h o d ‡
I T T
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
D O R b ase d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0, 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
S u m mar y statistics usi n g 
Ka pla n -Meier met h o d
All 
res p o n ders i n 
I T T
See Ta ble 2
  † 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 stratificati o n fact ors 
use d f or ra n d o mizati o n will be as stratificati o n fact ors f or a nal ysis.
  ‡  Mietti ne n a n d N ur mi ne n met h o d.
3. 6. 2
St atistic al C o nsi der ati o ns f or P atie nt - Re p orte d O utc o mes ( P R O)
3. 6. 2. 1
P atie nt Re p orte d O utc o me ( P R O) E n d p oi nts
T he P R O e n d p oi nts i ncl u de res ults fr o m t he E O R T C Q L Q- C 3 0, E O R T C Q L Q -B R 2 3, a n d 
E Q - 5 D ™ q uesti o n naires.
T he E O R T C Q L Q C 3 0 is a self- re p orte d 3 0-ite m ca ncer s pecific i nstr u me nt t hat assesses 1 5 
d o mai ns: 5 f u ncti o nal scales ( p h ys ical, r ole, e m oti o nal, c o g niti ve a n d s ocial f u ncti o ni n g), 9 
s ym pt o m scales or si n gle ite ms (fati g ue, na usea a n d v o miti n g, pai n, d y s p nea, i ns o m nia, 
a p petite l oss, c o nsti pati o n, diarr hea a n d fi na ncial diffic ulties), a n d a gl o bal healt h stat us / 
Q o L .
T he E O R T C Q L Q -B R 2 3 is a breast -s pecific m o d ule of t he E O R T C Q L Q. It i ncl u des 2 3 
ite ms c o m p ose d of 4 f u ncti o nal scales (i.e., b o dy i ma ge, se x ual f u ncti o ni n g, se x ual 
e nj o yme nt a n d f ut ure pers pecti ve) a n d 4 s y m pt o m scales (s ys te mic t hera p y si de effects, 
breast s y m pt o ms, ar m s y m pt o ms a n d u pset b y  hair l oss).
E Q -5 D is a sta n dar dize d meas ure of healt h stat us de vel o pe d b y t he E ur o Q ol Gr o u p i n or der 
t o pr o vi de a si m ple, ge neric meas ure of healt h f or cli nical a n d ec o n o mic a p praisal [ 8].  E Q-
5 D c o m prises t w o se parate ele me nts. Utilit y  sc ore ( or descri pti ve s yste m), t he first of t hese 
ca pt ures healt h state acr oss fi ve di me nsi o ns: m o bilit y , self-care, us ual acti vities, pai n / 
disc o mf ort, a n xiet y / de pressi o n. U ni q ue healt h states are defi ne d by c o m bi ni n g res p o nse 
le vels fr o m eac h of t he fi ve di me nsi o ns. T he sec o n d E Q-5 D ele me nt is base d o n a ver tical 
vis ual a nal o g ue scale ( V A S).  T he V A S rec or ds t he res p o n de nt’s self -rate d healt h o n a
vertical, vis ual a nal o g ue scale ra n gi n g fr o m 0 t o 1 0 0 w here t he e n d p oi nts are la belle d ‘ Best 
i ma gi na ble healt h state’ ( 1 0 0) a n d ‘ W orst i ma gi na ble healt h state’ ( 0).  T his i nf or mati o n ca n 
be use d as a q ua ntitati ve meas ure of healt h o utc o me as j u d ge d b y  t he i n di vi d ual res p o n de nts.
I n t his trial, t he P R Os will be assesse d acc or di n g t o t he f oll owi n g sc he d ule ( Ta ble 4 ). F or t he 
a nal ys is, P R Os assesse d at visits of “ E n d of Treat me nt” a n d “ Safety F oll o w -u p” will be 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 1
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
ma p pe d i nt o differe nt ti me p oi nts acc or di n g t o t he act ual visit ti me.  If t here are m ulti ple 
P R O c ollecti o ns wit hi n t he ti me wi n d o w of a s pecific visit, t he c ollecti o n cl osest t o t he tar get 
da y  will be use d i n t he a nal ysis.
T a ble 4
P R O Assess me nt Sc he d ule
Wee k
1
E n d of 
Treat me nt
Safet y 
F oll o w -u p 3
Baseli ne ( 0)
3
6
1 5
2 4
3 3
4 2
5 1 2
Treat me nt 
C y cle ( C)
C 1 
C 2 
C 3 
C 6 
C 9
C 1 2 
C 1 5 
C 1 8 2
X  
X
1P R O c ollecti o ns are sc he d ule d o n t he 1st da y of a c ycle, a n d Wee k is c o u nte d as n u m ber of w ee ks ela pse d 
si nce t he start of treat me nt. E. g, t he first da y of C 2 is ma p pe d t o Wee k 3.
2After t he 3r d c ycle a n d u ntil t he e n d of Year 1, P R Os will be c ollecte d e ver y 3r d c ycle (e ver y 9 wee ks) u ntil 
P D, w hile t he s u bject is recei vi n g st u d y treat me nt. D uri n g Year 2, t he y will occ ur e ver y 4t h c ycle (e ver y 1 2 
wee ks) u ntil P D, w hile t he s u bject is recei vi n g st u d y tre at me nt.
3If t he E n d of Treat me nt Visit occ urs 3 0 da ys fr o m t he last d ose of st u d y treat me nt, at t he ti me of t he 
ma n dat or y Safet y F oll o w u p Visit, P R Os d o n ot nee d t o be re peate d.
Ke y P R O E n d p oi nt
Pri m ar y a n al ysis ti me p oi nt:   t he pri mar y e P R O a nalys is ti me p oi nt is defi ne d as t he latest 
ti me p oi nt w here t he c o m pleti o n a n d c o m plia nce rates are still hi g h e n o u g h base d o n bli n de d 
data re vie w ( ~ 6 0 % c o m pleti o n rate a n d ~ 8 0 % c o m plia nce rate). T he ke y  P R O e n d p oi nt is:
•
T he mea n sc ore c ha n ges fr o m baseli ne t o t he pri mar y  a nalys is ti me p oi nt i n E O R T C 
Q L Q -C 3 0 gl o bal healt h stat us/ Q o L  sc ore.
S u p p orti ve P R O E n d p oi nts
T he f oll o wi n g are s u p p orti ve P R O e n d p oi nts a n d ma y be a nal yz e d as a p pr o priate.
1.
T he mea n sc ore c ha n ges fr o m baseli ne t o t he pri mar y  a nalys is ti me p oi nt i n V A S as 
meas ure d b y E Q - 5 D.
2.
T he mea n sc ore c ha n ges fr o m baseli ne t o t he pri mar y  a nalys is ti me p oi nt f or:
o
T he Q L Q -C 3 0 s y m pt o m scale Na usea a n d V o mi ti n g.
o
T he Q L Q -C 3 0 s y m pt o m scale Diarr h ea.
o
T he Q L Q -C 3 0 s y m pt o m scale P h y sical F u nc ti o ni n g.
o
T he Q L Q -B R 2 3 s y m pt o m scale S y ste mic T hera p y Si de Effects.
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 2
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3.
Ti me t o deteri orati o n ( T T D), defi ne d as ti me fr o m start of treat me nt t o first o nset of 
1 0 p oi nts or m ore w orse ni n g fr o m baseli ne , f or
o
T he Q L Q -C 3 0 s y m pt o m scale Na usea a n d V o mi ti n g.
o
T he Q L Q -C 3 0 s y m pt o m scale Diarr h ea.
o
T he Q L Q -C 3 0 s y m pt o m scale P h y sical F u ncti o ni n g.
o
T he Q L Q -B R 2 3 s y m pt o m scale S y ste mic T hera p y Si de Effects.
4.
O verall i m pr o ve me nt rate, w here im pr o ve me nt is defi ne d as a 1 0 p oi nts or m ore 
i m pr o ve me nt fr o m baseli ne at a ny ti me d uri n g t he trial, f or 
o
T he Q L Q -C 3 0 s y m pt o m scale Na usea a n d V o mi ti n g.
o
T he Q L Q -C 3 0 s y m pt o m scale Diarr h ea.
o
T he Q L Q -C 3 0 s y m pt o m scale P h y sical F u ncti o ni n g.
o
T he Q L Q -B R 2 3 s y m pt o m scale S y ste mic T hera p y Si de Effects.
3. 6. 2. 2
P atie nt Re p orte d O utc o me ( P R O) A n al ysi s P o p ul ati o n
T he P R O F ull A nal ys is Set ( F A S) p o p ulati o n will be use d f or P R O a nal yses. T he P R O F A S 
p o p ulati o n c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of st u d y  
me dicati o n a n d c o m plete d at least o ne P R O assess me nt.
T he a nal ys is will be c o n d ucte d i n all s u bjects a n d i n s u bjects wit h C P S ≥1 0 , a n d s u bjects 
wit h C P S ≥1 .
3. 6. 2. 3
A n al ysis A p pr o ac hes
T he P R Os are e x pl orat or y o bjecti ves i n t his st u d y , t h us n o f or mal h y p ot heses are f or m ulate d. 
N o mi nal p- val ues wit h o ut m ulti plicit y  a dj ust me nt will be pr o vi de d a n d s h o ul d be i nter prete d 
wit h ca uti o n.
3. 6. 2. 3. 1
Sc ori n g Al g orit h m
Q L Q - C 3 0 Sc ori n g
T he Q L Q -C 3 0 is c o m p ose d of b ot h m ulti -ite m scales a n d si n gle-ite m meas ures. T hese 
i ncl u de a gl o bal healt h stat us / Q o L scale, fi ve f u ncti o nal scales, t hree sy m pt o m s cales, a n d 
si x si n gle ite ms. Eac h of t he m ulti-ite m scales i ncl u des a differe nt set of ite ms - n o ite m 
occ urs i n m ore t ha n o ne scale.
All of t he scales a n d si n gle-ite m meas ures will f oll o w a sta n dar dizati o n pr oce d ure pri or t o 
a nal ys is s o t hat sc ores ra n ge fr o m 0 t o 1 0 0. A hi g h scale sc ore re prese nts a hi g her res p o nse 
le vel. T h us a hi g h sc ore f or a f u ncti o nal scale re prese nts a hi g h / healt hy le vel of f u ncti o ni n g; 
a hi g h sc ore f or t he gl o bal healt h stat us / Q o L  re prese nts a hi g h Q o L; b ut a hi g h sc ore f or a 
sy m pt o m scale / ite m re prese nts a hi g h le vel of s y m pt o mat ol o g y  / pr o ble ms.
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 3
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
Acc or di n g t o t he E O R T C Q L Q- C 3 0 Sc ori n g Ma n ual [ 9], t he pri nci ple f or sc ori n g t hese 
scales is t he sa me i n all cases:
1.
Esti mate t he a vera ge of t he ite ms t hat c o ntri b ute t o t he scale; t his is t he ra w sc ore.
2.
Use a li near tra nsf or mati o n t o sta n dar dize t he ra w sc ore, s o t hat sc ores ra n ge fr o m 0 t o 
1 0 0; a hi g her sc ore re prese nts a hi g her (" better") le vel of f u ncti o ni n g, or a hi g her 
(" w orse") le vel of sy m pt o m s.
S pecificall y, if ite ms I1, I2, …,In are i ncl u de d i n a scale, t he sc ori n g pr oce d ure is as f oll o ws:
1.
C o m p ute t he ra w sc ore:
2.
Li near tra nsf or mati o n t o o btai n t he sc ore S :
F u ncti o n scales: 
S y m pt o m scales / ite ms: 
Gl o bal healt h stat us / Q o L:
R a n ge is t he differe nce bet wee n t he ma xi m u m p ossi ble val ue of R S a n d t he mi ni m u m 
p ossi ble val ue. T he Q L Q -C 3 0 has bee n desi g ne d s o t hat all ite ms i n a n y  scale ta ke t he sa me 
ra n ge of val ues. T heref ore, t he ra n ge of R S e q uals t he ra n ge of t he ite m val ues. If m ore t ha n 
half of t he ite ms wit hi n o ne scale are missi n g, t he n t he scale is c o nsi dere d missi n g, 
ot her wise, t he sc ore will be calc ulate d as t he a vera ge sc ore of t h ose a vaila ble ite ms.
Q L Q -B R 2 3 Sc ori n g
T he sc ori n g a p pr oac h f or t he Q L Q -B R 2 3 is i de ntical i n pri nci p le t o t hat f or t he f u ncti o n a n d 
s ym pt o m scales / si n gle ite ms of t he Q L Q -C 3 0. A li near tra nsf or mati o n will be a p plie d t o 
sta n dar dize t he sc ores bet wee n 0 a n d 1 0 0 as descri be d a b o ve f or t he E O R T C Q LQ- C 3 0 
sc ori n g.
E Q - 5 D Sc ori n g
T he E Q -5 D utilit y  sc ore will be calc ulate d base d o n t he E ur o pea n al g orit h m [ 8] base d o n 
res p o nses o n t he fi ve healt h state di me nsi o ns, i ncl u di 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.
n
I
I
I
R S
n /)
...
(
2
1




1 0 0
1
1










R a n ge
R S
S
1 0 0
1 

R a n ge
R S
S
1 0 0
1 

R a n ge
R S
S
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 4
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 6. 2. 3. 2 
P atie nt Re p orte d O utc o me ( P R O) Sc ore A n al ysis
T o assess t he treat me nt effect o n t he P R Os, f or eac h c o nti n u o us P R O e n d p oi nt defi ne d, a 
c o nstrai ne d l o n git u di nal data a nal ys is (c L D A) m o del will be use d as t he pri mar y a nalys is 
met h o d, wit h t he P R O sc ore as t he res p o nse varia ble [ 1 0].  Onl y  P R O data u p t o t he pri mar y  
a nal ys is ti me p oi nt will be i ncl u de d i n t his a nal ys is m o del.
T he c L D A m o del is s pecifie d as f oll o ws:
W here Y ijt is t he P R O sc ore f or s u bject i, wit h treat me nt j, at visit t, γ0 is t he baseli ne mea n 
f or all treat me nt gr o u ps, γ jt is t he mea n c ha n ge fr o m baseli ne f or treat me nt gr o u p j at ti me t,
X i is t he vect or of stratificati o n val ues ( Pr ot oc ol Secti o n 5. 4) f or s u bject i, a n d β is t he 
c orres p o n di n g c oefficie nt f or strata.
T he treat me nt effect o n P R O sc ore c ha n ge fr o m baseli ne will be e val uate d at t he pri mar y 
a nal ys is ti me p oi nt. Bet wee n-gr o u p c o m paris o n will be perf or me d a n d t he differe nces i n t he 
least-s q uares mea n c ha n ge fr o m baseli ne at t he pri mar y a nalys is ti me p oi nt wi ll be re p orte d, 
t o get her wit h 9 5 % CI a n d n o mi nal p-val ue. I n a d diti o n, m o del -base d least -s q uares mea n 
sc ore wit h c orres p o n di n g 9 5 % CI will be pr o vi de d b y treat me nt gr o u p at t he pri mar y  a nalys is 
ti me p oi nt.
Patie nts wit h disease pr o gressi o n c o nfir me d or fee li n g w orse d ue t o dr u g-relate d A E ma y 
ha ve missi n g P R O assess me nts. T he missi n g data m ust be ha n dle d acc or di n gl y t o o btai n 
vali d statistical a nal y sis res ults. T he c L D A m o del i m plicitl y treats missi n g data as missi n g at 
ra n d o m ( M A R). Se nsiti vit y a nalys es ma y be c o n d ucte d i n case t he r o b ust ness of M A R 
ass u m pti o n is q uesti o na ble.
Descri pti ve statistics ( mea n, S E) of c ha n ge fr o m baseli ne n o i m p utati o n f or missi n g data o n 
t he f oll o wi n g sc ore/scales will be pl otte d f or Q L Q-C 3 0 gl o bal healt h stat us/ Q o L , sy m pt o m 
scales na usea a n d v o miti n g, diarr hea, t he Q L Q -B R 2 3 s y m pt o m scale s ys te mic t hera p y si de 
effects , a n d t he Q L Q -C 3 0 p h y sical f u ncti o ni n g.
3. 6. 2. 3. 3
A n al ysis of t he Ti me t o Deteri or ati o n ( T T D)
T he n o n -para metric Ka pla n -Meier met h o d
will be use d t o esti mate t he deteri orati o n c ur ve i n 
eac h gr o u p. T he treat me nt differe nce i n ti me- t o-deteri orati o n will be assesse d b y  t he 
stratifie d l o g-ra n k test. A stratifie d C o x pr o p orti o nal hazar d m o del wit h Efr o n ’s met h o d of tie 
ha n dli n g will be use d t o assess t he ma g nit u de of t he treat me nt differe nce ( hazar d rati o) 
bet wee n treat me nt ar ms. T he stratificati o n fact ors use d f or ra n d o mizati o n (see Pr ot oc ol 
Secti o n 5. 4 – Stratificati o n) will be a p plie d t o t he a nal y sis. T his a nal y sis will be c o n d ucte d 
f or Q L Q- C 3 0 gl o bal healt h stat us/ Q o L, s ym pt o m scale s na usea a n d v o miti n g, diarr hea, 
p h y sical f u ncti o ni n g, a n d t he Q L Q -B R 2 3 s y m pt o m scale sys te mic thera p y  si de effects.
    =  0 +   ( > 0 ) +   ,
 = 1 ,2 ,  = 0 ,1 ,…  
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 5
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3. 6. 2. 3. 4
A n al ysis of O ver all I m pr o ve me nt
Stratifie d Mietti ne n a n d N ur mi ne n’s met h o d will be use d f or t he c o m paris o n of o verall 
i m pr o ve me nt rates bet wee n 2 treat me nt ar ms.  T he differe nce i n o verall i m pr o ve me nt rates
a n d its 9 5 % CI fr o m t he stratifie d Mietti ne n a n d N ur mi ne n’s met h o d wit h strata wei g hti n g b y 
sa m ple size will be re p orte d.   T he stratificati o n fact ors use d f or ra n d o mizati o n (see Pr ot oc ol 
Secti o n 5. 4 – Stratificati o n) will be a p plie d t o t he a nal y sis. T his a nal y sis will be c o n d ucte d 
f or Q L Q- C 3 0 gl o bal healt h stat us/ Q o L, s ym pt o m scale s na usea a n d v o miti n g, diarr hea, 
p h y sical f u ncti o ni n g, a n d t he Q L Q -B R 2 3 s y m pt o m scale sys te mic thera p y  si de effects.
Of n ote, f or all a b o ve e P R O a nal ysis ( Secti o n 3. 6. 2.3. 2 t o Secti o n 3. 6. 2. 3. 5) i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors (C P S ≥1 0 a n d C P S ≥1 ), o nl y  t he stratificati o n fact or of pri or 
( ne o)a dj u va nt t hera py vs de n o v o metastatic dis ease at i nitial dia g n osis will be c o nsi dere d i n 
t he a nalys is m o dels, i.e., n ot c o nsi deri n g t he stratificati o n fact or of P D-L 1 t u m or stat us.
3. 6. 2. 3. 5
S u m m ar y of C o m pleti o n a n d C o m pli a nce
C o m pleti o n a n d c o m plia nce of Q L Q - C 3 0, Q L Q-B R 2 3 a n d E Q -5 D b y  treat me nt a n d visit will 
be descri be d base d o n t he P R O F A S p o p ulati o n.
C o m pleti o n Rate is defi ne d as t he perce nta ge of s u bjects w h o c o m pletes at least o ne 
sc ore/ite m o ver t he n u m ber of s u bjects i n t he P R O F A S p o p ulati o n at eac h ti me p oi nt.
T he c o m pleti o n rate is e x pecte d t o s hri n k i n t he later visits d uri n g d ue t o earl y 
disc o nti n uati o ns. T heref ore, a n ot her meas ure me nt, C o m plia nce Rate, defi ne d as t he 
perce nta ge of s u bjects w h o c o m pletes at least o ne sc ore/ite m o ver t he n u m ber of eli gi ble 
s u bjects w h o are e x pecte d t o c o m plete t he P R O assess me nt ( n ot i ncl u di n g t he s u bjects 
missi n g b y  desi g n (s uc h as deat h, disc o nti n uati o n, tra nslati o n n ot a vaila ble, etc.), will be 
e m pl o ye d as a s u p p orti ve meas ure.
T he reas o ns of n o n -c o m pleti o n a n d n o n -c o m plia nce will als o be s u m marize d.
3. 6. 3
St atisti c 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 perie nces , la b orat or y tests, vital si g ns, etc. Of n ote, safet y a nal yses will be 
c o n d ucte d i n all s u bjects.
T he a nal ys is of safety res ults will f oll o w a tiere d a p pr oac h ( Ta ble 5 ).  T he tiers differ wit h 
res pect t o t he a nalys es t hat will be perf or me d.  F or t his pr ot oc ol, t here are n o Tier 1 safet y  
e n d p oi nts.  Tier 2 para meters will be assesse d via p oi nt esti mates wit h 9 5 % CI s pr o vi de d f or 
bet wee n -gr o u p c o m paris o ns; o nl y  p oi nt esti mates b y treat me nt gr o u p will be pr o vi de d f or 
Tier 3 safet y  para meters.
A d verse e x peri e nces (s pecific ter ms as well as s ys te m or ga n class ter ms) a n d pre defi ne d 
li mits of c ha n ge will be classifie d as bel o n gi n g t o “ Tier 2” or “ Tier 3”, base d o n t he n u m ber 
of e ve nts o bser ve d.  Me m bers hi p i n Tier 2 re q uires t hat at least 4 s u bjects i n a n y treatme nt 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 6
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
gr o u p e x hi bit t he e ve nt; all ot her a d verse e x perie nces a n d pre defi ne d li mits of c ha n ge will 
bel o n g t o Tier 3.
T he t hres h ol d of at least 4 e ve nts was c h ose n beca use t he 9 5 % CI f or t he bet wee n -gr o u p 
differe nce i n perce nt i nci de nce will al wa y s i ncl u de zer o w he n treat me nt gr o u ps of e q ual size 
eac h ha ve less t ha n 4 e ve nts a n d t h us w o ul d a d d little t o t he i nter pretati o n of p ote ntiall y  
mea ni n gf ul differe nces.  Beca use ma n y 9 5 % CIs ma y  be pr o vi de d wit h o ut a dj ust me nt f or 
m ulti plicit y , t he CIs s h o ul d be re gar de d as a hel pf ul descri pti ve meas ure t o be use d i n 
re vie w, n ot a f or mal met h o d f or assessi n g t he statistical si g nifica nce of t he bet wee n-gr o u p 
differe nces i n a d verse e x perie nces a n d pre defi ne d li mits of c ha n ge.
C o nti n u o us meas ures s uc h as c ha n ges fr o m baseli n e i n la b orat or y a n d vital si g ns will be 
c o nsi dere d Tier 3 safet y para meters.  S u m mar y  statistics f or baseli ne, o n-treat me nt, a n d 
c ha n ge fr o m baseli ne val ues will be pr o vi de d b y t reat me nt gr o u p.
T he br oa d cli nical a n d la b orat or y  A E cate g ories c o nsisti n g of t he perce nta ge of s u bjects wit h 
a n y A E, a n y dr u g relate d A E, a n y Gra de 3-5 A E, a n y  seri o us A E, a n y A E w hic h is b ot h 
dr u g -relate d a n d Gra de 3-5, a n y A E w hic h is b ot h seri o us a n d dr u g -relate d, d ose 
m o dificati o n d ue t o A E , a n d w h o disc o nti n ue d d ue t o a n A E, a n d deat h will be c o nsi dere d 
Tier 2 e n d p oi nts.  F or Tier 2 e n d p oi nts, p oi nt esti mates a n d 9 5 % CIs will be pr o vi de d f or 
bet wee n -treat me nt differe nces i n t he perce nta ge of s u bjects wit h e ve nts; t hese a nalys es will 
be perf or me d usi n g t he Mietti ne n a n d N ur mi ne n met h o d [ 1 1].
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 7
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
T a ble 5  
A n al ysis Str ate g y f or S afet y P ar a meters
Safet y 
Tier
Safet y E n d p oi nt †
p- Val ue
9 5 % CI f or 
Treat me nt 
C o m paris o n
Descri pti ve 
Statistics
Tier 2
A n y A E
X
X
A n y Seri o us A E 
X
X
A n y Gra de 3 -5 A E
X
X
A n y Dr u g -Relate d A E
X
X
A n y Seri o us a n d Dr u g -Relate d A E
X
X
A n y Gra de 3 -5 a n d Dr u g -Relate d A E
X
X 
D ose M o dificati o n d ue t o A E
X
X
Disc o nti n uati o n d ue t o A E
X
X
Deat h
X
X
S pecific A Es, S yste m Or ga n Class, or Pre -Defi ne d 
Li mit of C ha n ge
‡ (i nci de nce ≥4 of s u bjects i n o ne of 
t he treat me nt gr o u ps)
X
X
Tier 3
S pecific A Es, S yste m Or ga n Class or Pre -Defi ne d 
Li mit of C ha n ge
‡ (i nci de nce < 4 of s u bjects i n all of 
t he treat me nt gr o u ps)
X
C ha n ge fr o m Baseli ne Res ults ( La bs, E C Gs, Vital 
Si g ns)
X
†
A d verse E x perie nce refere nces refer t o b ot h Cli nical a n d La b orat or y A Es.
‡
I ncl u des o nl y t h ose e n d p oi nts n ot pre-s pecifie d as Tier 1 or n ot alrea d y pre-s pecifie d as Tier-2 e n d p oi nts.
N ote: X = res ults will be pr o vi de d.
T o pr o perl y acc o u nt f or t he p ote ntial differe nce i n f oll o w -u p ti me bet wee n treat me nt ar ms, 
w hic h is e x pecte d t o be l o n ger i n t he pe m br oliz u ma b ar m, A E i nci de nce de nsit y  a dj uste d f or 
treat me nt e x p os ure a nalyses ma y be perf or me d as a p pr o priate.
I n a d diti o n t o t he tiere d a p pr oac h, e x pl orat or y a nal ysis ma y be perf or me d o n ti me t o first 
Gra de 3 -5 A E. Ti me t o first Gra de 3 -5 A E is defi ne d as t he ti me fr o m t he first da y  of st u d y 
me dicati o n t o t he first e ve nt of Gra de 3-5 A E. T he Ka pla n -Meier met h o d wi ll be use d t o 
esti mate t he c ur ve of ti me t o first Gra de 3 -5 A E.  T he treat me nt differe nce i n ti me t o first 
Gra de 3 - 5 A E will be assesse d by t he l o g -ra n k test.  A C o x pr o p orti o nal hazar d m o del wit h 
Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he m a g nit u de of t he treat me nt 
differe nce (i.e., t he H R). T he H R a n d its 9 5 % CI fr o m t he C o x m o del wit h a si n gle treat me nt 
c o variate will be re p orte d.
3. 6. 4
S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristics
T he c o m para bilit y  of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d b y  
t he use of ta bles a n d/ or gra p hs.  N o statistical h yp ot hesis testi n g will be perf or me d o n t hese 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 8
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
c haracteristics.  T he n u m ber a n d perce nta ge of s u bjects scree ne d, ra n d o mize d, t he pri mar y  
reas o ns f or scree ni n g fail ure, an d t he pri mar y  reas o n f or disc o nti n uati o n will be dis pla ye d.  
De m o gra p hic varia bles (e. g., a ge) a n d baseli ne c haracteristics will be s u m marize d b y  
treat me nt eit her by descri pti ve statistics or cate g orical ta bles.
3. 6. 5 
St atistic al Met h o ds f or E x pl or at or y A n al yses
E x pl orat or y  a nalys es relate d t o P F S, O R R, D O R, a n d D C R base d o n ir R E CI S T will be 
c o n d ucte d usi n g t he sa me pri mar y  statistical met h o ds as t h ose f or R E CI S T 1. 1 base d P F S, 
O R R, D O R a n d D C R, res pecti vel y .
T he a nal ys es pla n f or t he e x pl orat or y o bjecti ves re gar di n g bi o mar kers will be pr o vi de d i n 
se parate S A P(s) as a p pr o priate.
A n e x pl orat or y  a nalys is of P F S 2, defi ne d as t he ti me fr o m ra n d o mizati o n t o s u bse q ue nt 
disease pr o gressi o n after i nitiati o n of ne w a nti- ca ncer t hera p y, or deat h fr o m a n y ca use, 
w hic he v er occ urs first, ma y be carrie d o ut. S u bjects ali ve a n d f or w h o m a P F S e ve nt has n ot 
bee n o bser ve d s h o ul d be ce ns ore d at t he last ti me t he s u bject was k n o w n ali ve a n d wit h o ut 
disease pr o gressi o n.
3. 7
I nteri m A n al yses
T here is o ne pla n ne d i nteri m efficac y  a nal ysis i n t his trial. Res ults will be re vie we d b y a n 
e xter nal data m o nit ori n g c o m mittee (e D M C).   Res ults will be re vie we d b y  t he e xter nal 
D M C.
I nteri m A n al ysis
T he p ur p ose of t he i nteri m a nal y sis (I A) is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d to T P C i n O S. T he I A is tri g gere d b y  t he s pecifie d d urati o n of f oll o w-u p after 
e nr oll me nt is c o m plete d rat her t ha n t he n u m ber of O S e ve nts.  I t will be perf or me d 
a p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is c o m plete d. It is esti mate d at t his ti me 
a p pr o xi mate l y 1 3 0 O S e ve nts will be accr ue d i n s u bjects wit h C P S ≥1 0 , a p pr o xi matel y
2 8 4 O S e ve nts i n s u bjects wit h C P S ≥1, a n d a p pr o xi matel y 4 4 5 O S e ve nts i n all s u bjects.
If t he pe m br oliz u ma b ar m de m o nstrates a s u peri or O S t o T P C i n all s u bjects i n t his i nteri m 
a nal ys is, t he sec o n dar y h yp ot heses f or P F S a n d O R R i n all s u bjects will be teste d at t he sa me 
ti me.  It is esti mate d t hat a p pr o xi matel y 5 7 5 P F S e ve nts will ha ve acc u m ulate d i n all s u bjects 
b y  t hat ti me.
T he esti mate d b o u n daries f or O S e n d p oi nts at I A are pr o vi de d i n Ta ble 6 , ass u mi n g t he 
pla n ne d n u m bers of e ve nts are a nal y ze d.
Fi n al A n al ysis
T he p ur p ose of t he fi nal a nal ys is ( F A) is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d t o T P C i n O S.  T he fi nal a nal y sis is tri g gere d b y d urati o n of f oll o w-u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1: a p pr o xi matel y  2 4 m o nt hs after e nr oll me nt is c o m plete d or 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 2 9
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1, w hic he ver occ urs later. It is esti mate d at t his 
ti me a p pr o xi matel y 15 4 O S e ve nts will be accr ue d i n s u bjects wit h C P S ≥1 0 a n d 
a p pr o xi matel y 5 2 0 O S e ve nts i n all s u bjects. If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue 
sl o wer t ha n e x pecte d a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt is 
c o m plete d, t he n t he S p o ns or will c o n d uct t he fi nal a nal ys is at t hat ti me.
Ta ble 6 s u m marizes t he ti mi n g, sa m ple size a n d decisi o n g ui da nce of t he i nteri m a nal ys is 
a n d F A, ass u mi n g t here is n o al p ha re-all ocati o n bet wee n h y p ot heses.  B o u n daries are base d 
o n esti mate d n u m ber of e ve nts a n d ma y  be u p date d at ti mes of t he a nalys es usi n g t he act ual 
o bser ve d n u m ber of e ve nts a n d s pe n di n g f u ncti o ns as n ote d a b o ve.
T a ble 6 
S u m m ar y of Ti mi n g, S a m ple Size, a n d Decisi o n G ui d a nce of I nteri m 
Effic ac y A n al yses a n d Fi n al A n al ysis u n der I niti al Al p h a All oc ati o n
A n al ysis
Criteri a f or C o n d uct of A n al ysis
E n d p oi nt
P ar a meter
V al ue
I nteri m 
A nal ysis: 
I nteri m O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p: 
A p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is 
c o m plete d.
Pr ojecte d O S e ve nts i n s u bjects wit h C P S 
≥1 0: a p pr o xi matel y 1 3 0
O S i n s u bjects 
wit h C P S ≥1 0
p val ue ( 1 -si de d) 
at b o u n dar y
0. 0 0 8 9
~ H R at b o u n dar y
0. 6 6
Pr ojecte d O S e ve nts i n s u bjects wit h 
C P S ≥1 : a p pr o xi matel y 2 8 4
O S i n s u bjects 
wit h C P S ≥1
p val ue ( 1 -si de d) 
at b o u n dar y
0. 0 0 4 3
~ H R at b o u n dar y
0. 7 3
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 4 4 5
O S i n all 
s u bjects
p val ue ( 1 -si de d) 
at b o u n dar y
n/a
~ H R at b o u n dar y
n/a
Fi nal A nal ysis: 
Fi nal O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1 : 
A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is 
c o m plete d or 3 3 4 O S e ve nts accr ue i n 
s u bjects wit h C P S ≥1, w hic he ver occ urs 
later. If O S e ve nts i n s u bjects wit h C P S ≥1 
accr ue sl o wer t ha n e x pecte d a n d fe wer t ha n 
3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after 
e nr oll me nt is c o m plete d, t he n t he S p o ns or 
will c o n d uct t he fi nal a nal ysis at t hat ti me.
Pr ojecte d O S eve nts i n s u bjects wit h 
C P S ≥1 0 : a p pr o xi matel y 1 5 4
O S i n s u bjects 
wit h C P S ≥1 0
p val ue ( 1 -si de d) 
at b o u n dar y
0. 0 1 4 6
~ H R at b o u n dar y
0. 7 0
Pr ojecte d O S e ve nts i n s u bjects wit h 
C P S ≥1 : a p pr o xi matel y 3 3 4
O S i n s u bjects 
wit h C P S ≥1
p val ue ( 1 -si de d) 
at b o u n dar y
0. 0 0 6 6
~ H R at b o u n dar y
0. 7 6
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 5 2 0
O S i n all 
s u bjects
p val ue ( 1 -si de d) 
at b o u n dar y
n/a
~ H R at b o u n dar y
n/a
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 3 0
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
If a hy p ot hesis is s u p p orte d, t he al p ha ca n be re -all ocate d t o a n ot her h y p ot hesis f oll o wi n g t he 
pre -s pecifie d r ules i n Secti o n 3. 8 – M ulti plicit y .  T he alter nati ve efficac y decisi o n g ui da nce 
f or O S wit h res pect t o t he re-all ocate d al p ha fr o m t he s u p p ort of ot her h y p ot hesis(es) is 
s u m marize d i n Ta ble 7 bel o w, ass u mi n g t he sa me n u m bers of e ve nts s pecifie d i n Ta ble 7
a vaila ble f or a nal ys es at eac h ti me p oi nt.  Please n ote t hat t h e act ual b o u n daries will be 
a dj uste d base d o n t he act ual n u m ber of e ve nts o bser ve d at t he ti me of t he c orres p o n di n g 
a nal ys is base d o n t he s pe n di n g f u ncti o ns s pecifie d i n t his secti o n.
If a n efficac y b o u n dar y is cr osse d at I A or F A f or O S i n s u bjects wit h CP S ≥1 0, wit h C P S ≥1 
or all s u bjects, t he st u d y will be declare d t o ha ve met its pri mar y  o bjecti ve. T he st u d y ma y 
c o nti n ue till c o m pleti o n re gar dless of t he res ults of t he i nteri m a nal ys es i n or der t o o btai n 
mat ure O S data.
Of n ote, t hese calc ulati o ns are base d o n t he ass u m pti o ns t hat t he pre vale nce of P D -L 1 
p ositi vit y  i n m T N B C is a p pr o xi matel y 6 5 % f or C P S ≥1 a n d a p pr o xi matel y  3 1 % f or 
C P S ≥1 0.
T a ble 7
S u m m ar y of Alter n ati ve Effic ac y Decisi o n G ui d a nce
E n d p oi nt
Sce n ari o
T ot al 
Al p h a 
All oc ate d
A n al ysis
U p d ate d Effic ac y B o u n d ar y ( After 
al p h a Re -All oc ati o n)
p- v al ue ( 1 -si de d) 
at B o u n d ar y
A p pr o x. H R at 
B o u n d ar y
O S i n S u bjects 
wit h C P S ≥ 1
H 1 s u p p orte d
0. 0 2 5
I A
0. 0 1 3 5
0. 7 7
F A
0. 0 2 1 7
0. 8 0
O S i n All 
S u bjects
H 1 a n d H 2 s u p p orte d
0. 0 2 5
I A
0. 0 1 3 8
0. 8 1
F A
0. 0 2 1 7
0. 8 4
O S i n All 
S u bjects
H 1 is n ot s u p p orte d a n d 
0. 0 0 8
I A
0. 0 0 4 4
0. 7 8
H 2 s u p p orte d
F A
0. 0 0 6 6
0. 8 0
3. 8
M ulti plicit y
T he m ulti plicit y  strate g y s pecifie d i n t his secti o n will be a p plie d t o t he 3 pri mar y h yp ot heses 
(s u peri ority of pe m br oliz u ma b o n O S i n s u bjects wit h C P S ≥1 0, wit h C P S ≥1, a n d i n all 
s u bjects), a n d t he 2 sec o n dar y h yp ot heses (s u peri orit y  of pe m br oliz u ma b o n P F S a n d O R R i n 
all s u bjects).
F or O S e n d p oi nts, a H wa n g -S hi h -De Ca ni al p ha- s pe n di n g f u ncti o n wit h t he ga m ma 
para meter ( -4) will be use d t o c o nstr uct gr o u p se q ue ntial b o u n daries t o c o ntr ol t he T y p e I 
err or. S pe n di n g ti me will be pl u g ge d i nt o t he pre- s pecifie d al p ha s pe n di n g f u ncti o n t o 
calc ulate al p ha-s pe n di n g.  At t he ti me of I A, f or all 3 O S e n d p oi nts t he s pe n di n g ti me will be 
t he mi ni m u m of t he act ual o bser ve d i nf or mati o n fracti o ns a m o n g t hese 3 O S e n d p oi nts, i.e., 
n u m ber of o bser ve d e ve nts at I A/ n u m ber of pla n ne d e ve nts at F A. At t he ti me of F A, t he 
s pe n di n g ti me will be 1 f or all 3 O S e n d p oi nts. Of n ote, w hile t he s pe n di n g ti me use d f or 
al p ha-s pe n di n g calc ulati o n will be t he sa me f or t hese 3 O S e n d p oi nts at F A, t he c orrelati o ns 
 
 
0 5 7 5 T 4
0 6 D W 2 6


M K -3 4 7 5
P A G E 3 1
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
use d f or c o m p uti n g b o u n ds f or eac h e n d p oi nt will still be fr o m t hat e n d p oi nt de pe n di n g o n 
t he actual e ve nt c o u nts. T he rati o nale f or t he a b o ve strate g y  is t o e ns ure b ot h t hat f ull T ype I 
err or is s pe nt at t he fi nal a nal ys is wit h o ut o vers pe n di n g at t he i nteri m. J ustificati o n f or t he 
s pe n di n g ti me a p pr oac h ca n be f o u n d i n A n ders o n et.al [ 1 2].
T he trial uses a n e xte nsi o n of t he gra p hical met h o d of Ma urer a n d Bretz [ 1 3] t o pr o vi de 
str o n g m ulti plicit y c o ntr ol f or t he m ulti ple pri mar y a n d sec o n dar y h yp ot heses.
Fi g ure 1 s h o ws t he i nitial o ne-si de d α- all ocati o n f or eac h h y p ot hesis i n t he elli pse
re prese nti n g t he hy p ot hesis. T he wei g hts f or reall ocati o n fr o m eac h h y p ot hesis t o t he ot hers 
are re prese nte d i n t he b o xes o n t he li nes c o n necti n g h yp ot heses.  If H 1 (O S i n s u bjects wit h 
C P S ≥1 0 ) is s uccessf ul, t he n t he c orres p o n di n g al p ha ca n be reall ocate d t o H 2 ( O S i n 
s u bjects wit h C P S ≥1 ). If H 2 is s uccessf ul, t he al p ha f or t hat hy p ot hesis ca n be reall ocate d t o 
H 3 ( O S i n all s u bjects). If H3 is s uccessf ul, t he al p ha f or t hat h yp ot hesis ca n be reall ocate d ½ 
t o H4 ( P F S i n all s u bjects) a n d ½ t o H 5 ( O R R i n all s u bjects). T he al p ha f or H 4 a n d H 5 ca n 
als o be reall ocate d t o eac h ot her, if t he h y p ot hesis was s uccess f ul.  Of n ote, H 3 ca n o nl y be 
f or mall y teste d o nce t he n ull h yp ot hesis f or H 2 has bee n rejecte d ; H 4 a n d H 5 ca n o nl y be 
f or mall y teste d o nce t he n ull h yp ot hesis f or H 3 has bee n rejecte d. See Fi g ure 1 f or t he 
m ulti plicit y  strate g y dia gra m of t he st u d y.
H 4 ( P F S i n all s u bjects) will be teste d at I A if H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A 
a d diti o nal al p ha ca n be reall ocate d t o H 4 (e. g., H 3 is n ot s uccessf ul at I A b ut s uccessf ul at 
F A, or H 1 is n ot s uccessf ul at I A b ut s uccessf ul at F A a n d H 2/ H 3 are s uccessf ul at b ot h I A 
a n d F A), t he n t he p- val ue of P F S i n all s u bjects fr o m t he I A will be c o m pare d t o t he u p date d 
al p ha t hres h ol d at t he ti me of F A.  Si milarl y , H 5 ( O R R i n all s u bjects) will be teste d at I A if 
H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A a d diti o nal al p ha ca n be reall ocate d t o H 5, t he n 
t he p-val ue of O R R i n all s u bjec ts fr o m t he I A will be c o m pare d t o t he u p date d al p ha 
t hres h ol d at t he ti me of F A.
 
 
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M K -3 4 7 5
P A G E 3 2
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
Fi g ure 1  
M u lti plicit y Str ate g y
3. 9
S a m ple Size a n d P o wer C alc ul ati o ns
T he st u d y  will ra n d o mize s u bjects i n a 1: 1 rati o bet wee n t he pe m br oliz u ma b ar m a n d t he 
T P C ar m. T he o verall sa m ple size will be u p t o ~ 6 0 0.
Ra n d o mizati o n will occ ur ce ntrall y  usi n g a n i nteracti ve res p o nse sys te m / i nte grate d we b 
res p o nse sys te m (I V R S/I W R S) a n d will be m o nit ore d o n a re g ular basis. W he n IV R S alerts 
t hat t he st u d y is a p pr oac hi n g t he desire d e nr oll me nt, scree ni n g s h o ul d be st o p ped i n ti me. 
H o we ver, s u bjects alrea d y i n scree ni n g p hase ma y be e nr olle d e ve n after we ha ve reac he d 
t he ma xi m u m sa m ple size. T he sa m ple size is dri ve n b y t he O S e ve nts i n s u bjects wit h 
C P S ≥1 0, s u bjects wit h C P S ≥1, a n d all s u bjects .
O ver all s ur vi v al a n al ys is i n s u bjects wit h C P S ≥1 0 : F or t he pri mar y  e n d p oi nt O S i n 
s u bjects wit h C P S ≥1 0 , wit h 1 5 4 O S e ve nts at a o ne- si de d 1. 7 % al p ha -le vel t he trial has 
a p pr o xi matel y 8 5% p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or
t o T P C , if t he 
u n derl y i n g hazar d rati o of O S is 0. 6 0. S uccess b o u n dar y  f or O S at t he fi nal a nalys is 
a p pr o xi matel y c orres p o n ds t o a n o bser ve d hazar d rati o of ~ 0. 7 0 ( ~ 4. 2 m o nt h i m pr o ve me nt 
o ver O S of 1 0 m o nt hs i n T P C ).
O ver all s ur vi v al a n al ysis i n s u bjects wit h C P S ≥1 : F or t he pri mar y  e n d p oi nt O S i n s u bjects 
wit h C P S ≥1 , wit h 3 3 4 O S e ve nts at a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has 
a p pr o xi matel y 8 0% ( 9 0 %) p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C , if 
t he u n derlyi n g hazar d rati o of O S is 0. 7 0. Wit h
a o ne- si de d 0. 8 % ( 2. 5 %) al p ha-le vel, s uccess 
b o u n dar y  f or O S at t he fi nal a nalys is a p pr o xi matel y c orres p o n ds t o a n o bser ve d hazar d rati o 
of ~ 0. 7 6 ( 0. 8 0) ( ~ 3. 1 [ 2. 5] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C ).
 
 
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M K -3 4 7 5
P A G E 3 3
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
O ver all s ur vi v al a n al ysis i n all s u bjects: F or t he pri mar y  e n d p oi nt O S i n all s u bjects, wit h 
5 2 0 O S e ve nts a n d a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has a p pr o xi matel y 6 6 % 
( 8 0 %) p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C if t he u n derl yi n g hazar d 
rati o of O S is 0. 7 8 . Wit h a
o ne- si de d 0. 8 % ( 2. 5 %) al p ha-le vel, success b o u n dar y  f or O S at 
t he fi nal a nalys is c orres p o n ds a p pr o xi matel y t o a n o bser ve d hazar d rati o of ~ 0. 8 0 ( 0. 8 4)
(~ 2. 4 [ 1. 9] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C ).
T he sa m ple size a n d p o wer calc ulati o n f or O S e n d p oi nts is base d o n t he f oll o wi n g 
ass u m pti o ns f or all 3 p o p ulati o ns : 1) O S f oll o ws a n e x p o ne ntial distri b uti o n wit h a me dia n of 
1 0 m o nt hs i n t he c o ntr ol ar m ; 2) A n e nr oll me nt peri o d of 1 6. 6 m o nt hs a n d a mi ni m u m of 2 4
m o nt hs f oll o w - u p after e nr oll me nt c o m pleti o n; 3) A ye arl y O S dr o p o ut rate of 1 %.
P F S a n al ysis i n all s u bjects: T h is P F S p o wer is calc ulate d base d o n t he f oll o wi n g 
ass u m pti o ns wit h a p pr o xi matel y 5 7 5 P F S e ve nts :  1) t he h yp ot hesis of O S i n all s u bject is 
s u p p orte d a n d a t otal of 0. 4 % al p ha is all ocate d t o P F S h yp ot hesis ( H 4); 2) P F S f oll o ws a n 
e x p o ne ntial distri b uti o n wit h a me dia n of 3 m o nt hs i n t he T P C ar m; 3) A n e nr oll me nt peri o d 
of 1 6. 6 m o nt hs; 4) A y earl y PF S dr o p - o ut rate of 8%.  T he trial has ~ 9 9 % p o wer t o 
d e m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C o n P F S at a o ne- si de d 0. 4 % al p ha -le vel, 
if t he u n derlyi n g hazar d rati o of P F S is 0.6. If t he u n derl yi n g hazar d rati o of P F S is 0. 7, t he n 
t he trial has ~ 9 5 % p o wer.
O R R a n al ysis i n all s u bjects: T he O R R p o wer calc ulati o n is base d o n t he f oll o wi n g 
ass u m pti o ns: 1) t he h yp ot hesis of O S i n s u bjects wit h C P S ≥1 is s u p p orte d a n d a t otal of 
0. 4 % al p ha is all ocate d t o O R R h y p ot hesis ( H 5) ; 2) t he u n derl yi n g O R R is 1 0 % i n t he T P C 
ar m, a n d t here is 1 0 % i ncrease i n pe m br oliz u ma b ar m ( O R R of 2 0 %) i n all s u bjects. T he trial
has a p pr o xi matel y 8 1 % p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C o n 
O R R i n all s u bjects at a o ne- si de d 0. 4 % al p ha -le vel.
T he a b o ve statistical ass u m pti o ns are base d o n o ur c urre nt u n dersta n di n g of t he pre vale nce of 
t he P D-L 1  bi o mar ker i n T N B C (a p pr o xi matel y 6 5% f or C P S ≥1 0 a n d 3 1 % f or C P S ≥1 ), a n d 
it is s u bject t o m o dificati o n as nee de d base d o n e mer gi n g e xter nal data o n P D-L 1  pre vale nce 
i n T N B C, or t he c orrelati o n bet wee n P D-L 1 e x pressi o n a n d treat me nt effect. A n y  
m o dificati o n if occ urs will be descri be d i n t he s u p ple me ntal S A P.
T he sa m ple size a n d p o wer calc ulati o n s were perf or me d i n t he s oft ware R ( pac ka ge 
“ gs Desi g n”).
3. 1 0 
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
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 nt 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 s u bjects wit h C P S ≥1 0 a n d C P S ≥1 a n d i n all s u bjects:
•
A ge Cate g or y ( < 6 5 vs. ≥6 5 y ears)
•
Me n o pa usal stat us
(f or fe males o nl y; pre- vs. p ost-me n o pa usal )
 
 
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M K -3 4 7 5
P A G E 3 4
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
•
Ge o gra p hic re gi o n ( E ur o pe/I srael/ N ort h A merica/ A ustralia vs. Asia vs. Rest of 
W orl d)
•
Et h nic ori gi n ( His pa nic vs. N o n -His pa nic)
•
N u m ber of pri or li nes of treat me nts i n t he metastatic setti n g (ie o ne vs . t w o)
•
Ti me t o pr o gressi o n o n first -li ne ( 1 L) t hera p y ( < 6 m o nt hs vs. ≥6 m o nt hs )
•
T P C
•
P D -L 1  stat us b y  C P S c ut off ( C P S ≥1 vs C P S < 1; C P S ≥1 0 vs C P S < 1 0) . N ote 
s u b gr o u p a nalys is b y P D-L 1  stat us will o nly be c o n d ucte d i n all s u bjects.
•
Pri or ( ne o)a dj u va nt t hera p y  vs. de n o v o metastatic disease at i nitial dia g n osis.
3. 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 treat me nt will be c ollecte d d uri n g t he st u d y.  A ny 
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.
3. 1 2
E xte nt of E x p os ure
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n n u m ber of c ycles or
a d mi nistrati o ns as a p pr o priate.
4
R E F E R E N C E S
[ 1] 
J. R. Tsiatis a n d A. Tsiatis, " 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 nic ati o ns i n St atistics -T he ory 
a n d Met h o ds, v ol. 2 0, n o. 8, p p. 2 6 0 9 - 0 6 3 1, 1 9 9 1. 
[ 2] 
N. R. L ati mer a n d K. R. A bra ms, " NI C E D S U Tec h nical S u p p ort D oc u me nt 1 6: 
A dj usti n g S ur vi val Ti me Esti mates i n t he Prese nce of Treat me nt S witc hi n g," 2 0 1 4.
[ 3] 
T. G. Karris o n, " Versatile tests f or c o m pari n g s ur vi val c ur ves base d o n wei g hte d l o g -
ra n k statistics," T he St at a J o ur n al, v ol. 1 6, n o. 3, p. 6 7 8 – 6 9 0, 2 0 1 6. 
[ 4] 
H. U n o, B. Cla g gett, L. Tia n, E. I n o ue, P. Gall o a n d T. Mi y ata, " M o vi n g be yo n d t he 
hazar d rati o i n q ua ntif y i n g t he bet wee n-gr o u p differe nce i n s ur vi val a nal ysis," J o ur nal 
of Cli nic al O nc ol o gy, v ol. 3 2, n o. 2 2, p p. 2 3 8 0- 2 3 8 5, 2 0 1 4. 
[ 5] 
P. O dell, K. A n ders o n a n d W. Ka n nel, " Ne w m o dels f or pre dicti n g car di o vasc ular 
e ve nts," J o ur nal of Cli nic al E pi de mi ol o gy, v ol. 4 7, n o. 6, p p. 5 8 3- 5 9 2, 1 9 9 4. 
[ 6] 
D. Me hr otra, S. S u a n d X. L i, " A n efficie nt alter nati ve t o t he stratifie d C o x m o del 
a nal ys is," Statistics i n Me dici ne, v ol. 3 1, n o. 1 7, p p. 1 8 4 9 - 1 8 5 6, 2 0 1 2. 
 
 
0 5 7 5 T 4
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M K -3 4 7 5
P A G E 3 5
P R O T O C O L N O. 1 1 9- 0 5
S U P P L E M E N T A L S A P
2 3 A P R 2 0 1 9 – A M E N D M E N T 0 2
[ 7] 
D. Fi n kelstei n, " A pr o p orti o nal hazar ds m o del f or i nter val -ce ns ore d fail ure ti me data," 
Bi o metrics, v ol. 4 2, p p. 8 4 5 - 8 5 4, 1 9 8 6. 
[ 8] 
M. va n Ree ne n a n d M. O p pe, E Q- 5 D- 3 L  User G ui de V 5. 1, 2 0 1 5. 
[ 9] 
P. Fa y ers, N. Aar o ns o n, K. Bj or dal, M. Gr oe n v ol d, D. C urra n a n d A. B ott o mle y , 
E O R T C Q L Q- C 3 0 Sc ori n g Ma n ual ( 3r d e diti o n), Br ussels: E O R T C, 2 0 0 1. 
[ 1 0] K. L ia n g a n d S. Ze ger, " L o n git u di nal data a nal ys is of c o nti n u o us a n d discrete 
res p o nses f or pre-p ost desi g ns," S a nk hy ā: T he I n di a n J o ur n al of St atistics, n o. 6 2 
( Series B), p p. 1 3 4-1 4 8, 2 0 0 0. 
[ 1 1] O. Mietti ne n a n d M. N ur mi ne n, " C o m parati ve a nal y sis of t w o rates," Statistics i n 
Me dici ne, n o. 4, p p. 2 1 3- 2 2 6, 1 9 8 5. 
[ 1 2] M. A n ders o n, " A p plicati o n of gra p hical m ulti plicit y met h o ds i n c o m ple x gr o u p 
se q ue ntial trials," 2 0 1 7 S u b mitte d.
[ 1 3] W. Ma urer a n d F. Bretz, " 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," Stati stics i n Bi o p h ar m ace utic al Rese arc h, v ol. 5, n o. 4, p p. 3 1 1 - 3 2 0, 
2 0 1 3. 
 
 
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Prot_001.pdf: 
Offici al Pr ot oc ol Title:  
N C T n u m ber:  
N C T 0 2 5 5 5 6 5 7
1 9- Fe b- 2 0 1 8
D oc u me nt D ate:  
A Ra n d o mize d O pe n- La bel P hase III St u d y of Si n gle A ge nt 
Pe m br oliz u ma b vers us Si n gle A ge nt C he m ot hera p y per 
P h ysicia n’s C h oice f or Metastatic Tri ple Ne gati ve Breast Ca ncer 
( m T N B C) – ( K E Y N O T E- 1 1 9)


Pr o d uct:   M K - 3 4 7 5 
1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T HI S P R O T O C O L A M E N D M E N T 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 
C O R P., 
A 
S U B SI DI A R Y 
O F 
M E R C K 
&
C O., 
I N C., 
W HI T E H O U S E S T A TI O N, N J, U. S. A.
S P O N S O R:
Merc k S har p & D o h me C or p., a s u bsi diar y  of Merc k & C o., I nc. 
( hereafter referre d t o as t he S p o ns or or Merc k )
O ne Merc k Dri ve
P. O. B o x 1 0 0
W hite h o use Stati o n, NJ 0 8 8 8 9- 0 1 0 0, U. S. A.
Pr ot oc ol -s pecific S p o ns or C o ntact i nf or mati o n ca n be f o u n d i n t he I nvesti gat or Trial File
Bi n der ( or e q ui vale nt).
TI T L E:
A Ra n d o mize d O pe n -La bel P hase III St u d y  of Si n gle A ge nt Pe m br oliz u ma b vers us Si n gle 
A ge nt C he m ot hera p y per P h y sicia n’s C h oice f or Metastatic Tri ple Ne gati ve Breast Ca ncer 
( m T N B C) – ( K E Y N O T E-1 1 9) 
I N D N U M B E R:  1 2 4, 4 4 2
E u dr a C T N U M B E R:   2 0 1 5- 0 0 1 0 2 0- 2 7
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
T A B L E O F C O N T E N T S
S U M M A R Y O F C H A N G E S ................................................................................................ 1 1
1. 0
T RI A L S U M M A R Y .................................................................................................. 1 6
2. 0
T RI A L D E SI G N ........................................................................................................ 1 7
Tri al Desi g n ........................................................................................................... 1 7
2. 1
Tri al Di a gr a m ........................................................................................................ 1 9
2. 2
3. 0
O B J E C TI V E( S) & H Y P O T H E SI S( E S) .................................................................. 2 0
Pri m ar y O bjecti ve(s) & H y p ot hesis(es) .............................................................. 2 0
3. 1
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es) ........................................................... 2 0
3. 2
E x pl or at or y O bjecti ves ......................................................................................... 2 1
3. 3
4. 0
B A C K G R O U N D & R A TI O N A L E .......................................................................... 2 2
B ac k gr o u n d ........................................................................................................... 2 2
4. 1
P har mace utical a n d T hera pe utic Bac k gr o u n d .................................................... 2 2
4. 1. 1
I m m u n ot hera py:  Precli nical St u dies................................................................... 2 3
4. 1. 2
Pe m br oliz u ma b: O n g oi n g Cli nical Trials i n Ot her T u m or T y pes ...................... 2 3
4. 1. 3
I nf or mati o n o n Disease t o be Treate d – m T N B C ............................................... 2 3
4. 1. 4
Pr o of -of -Pri nci ple St u d y  f or Pe m br oliz u ma b use i n m T N B C............................ 2 5
4. 1. 5
R ati o n ale ................................................................................................................ 2 6
4. 2
Rati o nale f or t he Trial a n d Selecte d S u bject P o p ulati o n .................................... 2 6
4. 2. 1
Rati o nale f or D ose Selecti o n/ Re gi me n/ M o dificati o n ......................................... 3 0
4. 2. 2
Rati o nale f or E n d p oi nts ...................................................................................... 3 1
4. 2. 3
4. 2. 3. 1
Efficac y  E n d p oi nts....................................................................................... 3 1
4. 2. 3. 2
Selecti o n of Patie nt Re p orte d O utc o mes I nstr u me nts ................................. 3 1
4. 2. 3. 3
Safet y  E n d p oi nts.......................................................................................... 3 2
4. 2. 3. 4
Pla n ne d E x pl orat or y  Bi o mar ker Researc h................................................... 3 2
4. 2. 3. 5
F ut ure Bi o me dical Researc h ........................................................................ 3 4
Be nefit/ Ris k ........................................................................................................... 3 4
4. 3
5. 0
M E T H O D O L O G Y
................................................................................................... 3 5
E ntr y Criteri a ........................................................................................................ 3 5
5. 1
Dia g n osis/ C o n diti o n f or E ntr y  i nt o t he Trial ...................................................... 3 5
5. 1. 1
S u bject I ncl usi o n Criteria .................................................................................... 3 5
5. 1. 2
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u bject E xcl usi o n Criteria .................................................................................. 3 7
5. 1. 3
Tri al Tre at me nt(s) ................................................................................................ 3 9
5. 2
D ose Selecti o n/ M o dificati o n .............................................................................. 3 9
5. 2. 1
5. 2. 1. 1
D ose Selecti o n ( Pre parati o n) ....................................................................... 3 9
5. 2. 1. 2
D ose M o dificati o n (I nterr u pti o n/ Escalati o n/ Titrati o n/ Ot her) ...................... 4 0
5. 2. 1. 2. 1
Pe m br oliz u ma b D ose M o dificati o ns .................................................... 4 0
5. 2. 1. 2. 2
Ca pecita bi ne .......................................................................................... 4 6
5. 2. 1. 2. 3
Eri b uli n ................................................................................................. 4 6
5. 2. 1. 2. 4
Ge mcita bi ne .......................................................................................... 4 6
5. 2. 1. 2. 5
Vi n orel bi ne ........................................................................................... 4 6
Ti mi n g of D ose A d m i nistrati o n.......................................................................... 4 6
5. 2. 2
5. 2. 2. 1
Pe m br oliz u ma b ............................................................................................ 4 6
5. 2. 2. 2
Ca pecita bi ne ................................................................................................. 4 6
5. 2. 2. 3
Eri b uli n ........................................................................................................ 4 6
5. 2. 2. 4
Ge mcita bi ne ................................................................................................. 4 6
5. 2. 2. 5
Vi n orel bi ne .................................................................................................. 4 7
Trial Bli n di n g/ Mas ki n g ....................................................................................... 4 7
5. 2. 3
R a n d o miz ati o n or Tre at me nt All oc ati o n ............................................................ 4 7
5. 3
Str atific ati o n .......................................................................................................... 4 7
5. 4
C o nc o mit a nt Me dic ati o ns/ V acci n ati o ns (All o we d & Pr o hi bite d ) ...................... 4 7
5. 5
Acce pta ble C o nc o mita nt Me dicati o ns ................................................................ 4 8
5. 5. 1
Pr o hi bite d C o nc o mita nt Me dicati o ns .................................................................. 4 8
5. 5. 2
Resc ue Me dic ati o ns & S u p p orti ve C are ............................................................. 4 9
5. 6
S u p p orti ve Care G ui deli nes f or S u bjects i n Pe m br oliz u ma b Ar m ..................... 4 9
5. 6. 1
S u p p orti ve Care G ui deli nes f or I m m u ne -Relate d A d verse E ve nts .................... 4 9
5. 6. 2
S u p p orti ve Care G ui deli nes f or Ca pecita bi ne ..................................................... 4 9
5. 6. 3
S u p p orti ve Care G ui deli nes f or Eri b uli n ............................................................ 4 9
5. 6. 4
S u p p orti ve Care G ui deli ne f or Ge mcita bi ne ....................................................... 5 0
5. 6. 5
S u p p orti ve Care G ui deli nes f or Vi n orel bi ne ...................................................... 5 0
5. 6. 6
Diet/ Acti vit y/ Ot her C o nsi der ati o ns ..................................................................... 5 0
5. 7
Diet ...................................................................................................................... 5 0
5. 7. 1
C o ntrace pti o n ...................................................................................................... 5 0
5. 7. 2
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Pre g na nc y ............................................................................................................ 5 2
5. 7. 3
N ursi n g W o me n .................................................................................................. 5 2
5. 7. 4
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a ................................................... 5 2
5. 8
Treat me nt After First Ra di ol o gic E vi de nce of Disease Pr o gressi o n .................. 5 3
5. 8. 1
Disc o nti n uati o n of St u d y T hera p y After C o m plete Res p o nse ............................ 5 5
5. 8. 2
S u bject Re pl ace me nt Str ate g y ............................................................................. 5 6
5. 9
Be gi n ni n g a n d E n d of t he Tri al ........................................................................... 5 6
5. 1 0
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n ................................................... 5 6
5. 1 1
6. 0
T RI A L F L O W C H A R T ........................................................................................... 5 7
I niti al Tre at me nt P h ase ........................................................................................ 5 7
6. 1
Pe m br oliz u ma b Treat me nt Ar m .......................................................................... 5 7
6. 1. 1
Sta n dar d Treat me nt Ar m – Ge mcita bi ne or Eri b uli n .......................................... 6 1
6. 1. 2
Sta n dar d Treat me nt Ar m – Ca pecita bi ne ............................................................ 6 6
6. 1. 3
Sta n dar d Treat me nt Ar m – Vi n orel bi ne ............................................................. 7 1
6. 1. 4
Sec o n d C o urse P h ase ( Retre at me nt) f or Pe m br oliz u m a b Ar m O nl y .............. 7 6
6. 2
7. 0
T RI A L P R O C E D U R E S ........................................................................................... 7 9
Tri al Pr oce d ures ................................................................................................... 7 9
7. 1
A d mi nistrati ve Pr oce d ures .................................................................................. 7 9
7. 1. 1
7. 1. 1. 1
I nf or me d C o nse nt......................................................................................... 7 9
7. 1. 1. 2
Ge neral I nf or me d C o nse nt ........................................................................... 7 9
7. 1. 1. 2. 1
C o nse nt a n d C ollecti o n of S peci me ns f or F ut ure Bi o me dical 
Researc h ................................................................................................ 8 0
7. 1. 1. 3
I ncl usi o n/ E xcl usi o n Criteria ........................................................................ 8 0
7. 1. 1. 4
S u bject I de ntificati o n Car d .......................................................................... 8 0
7. 1. 1. 5
Me dical Hist or y
........................................................................................... 8 0
7. 1. 1. 5. 1
Disease Details ...................................................................................... 8 0
7. 1. 1. 6
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w ............................................... 8 0
7. 1. 1. 6. 1
Pri or Treat me nt Details f or Breast Ca ncer Dia g n osis .......................... 8 1
7. 1. 1. 6. 2
C o nc o mita nt Me dicati o ns ..................................................................... 8 1
7. 1. 1. 6. 3
S u bse q ue nt A nti -ca ncer T hera py Stat us ............................................... 8 1
7. 1. 1. 7
Assi g n me nt of Scree ni n g N u m ber ............................................................... 8 1
7. 1. 1. 8
Assi g n me nt of Ra n d o mizati o n N u m ber ....................................................... 8 1
7. 1. 1. 9
Trial C o m plia nce ( Me dicati o n/ Diet/ Acti vit y / Ot her) ................................... 8 2
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 1. 1 0 S ur vi val ........................................................................................................ 8 2
Cli nical Pr oce d ures/ Assess me nts ........................................................................ 8 2
7. 1. 2
7. 1. 2. 1
A d verse E ve nt M o nit ori n g ........................................................................... 8 2
7. 1. 2. 2
1 2 -Lea d Electr ocar di o gra m ......................................................................... 8 2
7. 1. 2. 3
P h y sical E xa m.............................................................................................. 8 3
7. 1. 2. 3. 1
F ull P h y sical E xa m ............................................................................... 8 3
7. 1. 2. 3. 2
Directe d P h ys ical E xa m........................................................................ 8 3
7. 1. 2. 4
Vital Si g ns.................................................................................................... 8 3
7. 1. 2. 5
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us......................... 8 3
7. 1. 2. 6
Me n o pa usal Stat us ....................................................................................... 8 3
7. 1. 2. 7
T u m or I ma gi n g a n d Assess me nt of Disease ................................................ 8 4
7. 1. 2. 7. 1
Baseli ne T u m or I ma gi n g ...................................................................... 8 8
7. 1. 2. 7. 2
T u m or I ma gi n g D uri n g t he Trial .......................................................... 8 8
7. 1. 2. 7. 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 ................................ 8 9
7. 1. 2. 7. 4
R E CI S T 1. 1 ........................................................................................... 8 9
7. 1. 2. 7. 5
ir R E CIS T .............................................................................................. 8 9
7. 1. 2. 8
T u m or Tiss ue C ollecti o n a n d C orrelati ve Bl o o d Sa m pli n g ......................... 9 2
7. 1. 2. 8. 1
T u m or Tiss ue C ollecti o n ...................................................................... 9 2
7. 1. 2. 8. 2
Bl o o d f or C orrelati ve St u dies ............................................................... 9 3
7. 1. 2. 9
Patie nt -Re p orte d O utc o mes ......................................................................... 9 3
7. 1. 2. 9. 1
T he Patie nt -Re p orte d O utc o mes ........................................................... 9 3
La b orat or y  Pr oce d ures/ Assess me nts .................................................................. 9 4
7. 1. 3
7. 1. 3. 1
La b orat or y  Safet y Eval uati o ns ( He mat ol o g y, C he mistr y , Uri nal ys is, 
a n d Ot her) .................................................................................................... 9 4
7. 1. 3. 2
Pre g na nc y  Test............................................................................................. 9 5
7. 1. 3. 3
P har mac o ki netic/ P har mac o d y na mic E val uati o ns ........................................ 9 6
7. 1. 3. 4
Pla n ne d Ge netic A nal ys is Sa m ple C ollecti o n.............................................. 9 6
7. 1. 3. 5
Bl o o d f or C orrelati ve St u dies ...................................................................... 9 6
7. 1. 3. 6
Bl o o d f or Me n o pa usal Stat us ....................................................................... 9 6
7. 1. 3. 7
F ut ure Bi o me dical Researc h ........................................................................ 9 6
Ot her Pr oce d ures ................................................................................................. 9 7
7. 1. 4
7. 1. 4. 1
Wit h dra wal/ Disc o nti n uati o n ........................................................................ 9 7
7. 1. 4. 1. 1
Wit h dra wal Fr o m F ut ure Bi o me dical Researc h ................................... 9 7
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 4. 2
Bli n di n g/ U n bli n di n g .................................................................................... 9 7
7. 1. 4. 3
Cali brati o n of Critical E q ui p me nt ................................................................ 9 8
Visit Re q uire me nts .............................................................................................. 9 8
7. 1. 5
7. 1. 5. 1
Scree ni n g ...................................................................................................... 9 8
7. 1. 5. 2
Treat me nt Peri o d .......................................................................................... 9 9
7. 1. 5. 2. 1
Sec o n d C o urse P hase ( Retreat me nt Peri o d) ......................................... 9 9
C o n diti o ns of Sec o n d C o urse P hase ............................................... 9 9
7. 1. 5. 2. 1. 1
Visit Re q uire me nts of Sec o n d C o urse P hase ............................... 1 0 0
7. 1. 5. 2. 1. 2
7. 1. 5. 2. 1. 2. 1
Assess me nts/ Pr oce d ures/ Wi n d o ws ....................................... 1 0 0
7. 1. 5. 2. 1. 2. 2
Disc o nti n uati o n D uri n g t he Sec o n d C o urse P hase ................ 1 0 0
7. 1. 5. 2. 1. 2. 3
La b orat or y  Tests D uri n g t he Sec o n d C o urse P hase.............. 1 0 0
7. 1. 5. 2. 1. 2. 4
C o nc o mita nt Me dicati o ns D uri n g t he Sec o n d C o urse P hase 1 0 1
7. 1. 5. 2. 1. 2. 5
Vital Si g ns D uri n g t he Sec o n d C o urse P hase ....................... 1 0 1
7. 1. 5. 2. 1. 2. 6
Pe m br oliz u ma b Restart D uri n g t he Sec o n d C o urse P hase ... 1 0 1
7. 1. 5. 2. 1. 2. 7
T u m or I ma gi n g Sec o n d C o urse P has e .................................. 1 0 1
7. 1. 5. 3
P ost -Treat me nt Visits ................................................................................. 1 0 2
7. 1. 5. 3. 1
Disc o nti n uati o n Visit .......................................................................... 1 0 2
7. 1. 5. 3. 2
Safet y  F oll o w-u p Visit ........................................................................ 1 0 2
7. 1. 5. 3. 3
F oll o w -u p Visits ................................................................................. 1 0 2
7. 1. 5. 3. 4
S ur vi val F oll o w -u p ............................................................................. 1 0 2
7. 1. 5. 3. 5
S ur vi val Stat us .................................................................................... 1 0 3
Assessi n g a n d Rec or di n g A d verse E ve nts ........................................................ 1 0 3
7. 2
Defi niti o n of a n O ver d ose f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o 
7. 2. 1
t he S p o ns or........................................................................................................ 1 0 4
Re p orti n g of Pre g na nc y  a n d Lactati o n t o t he S p o ns or ..................................... 1 0 4
7. 2. 2
I m me diate Re p orti n g of A d verse E ve nts t o t he S p o ns or .................................. 1 0 5
7. 2. 3
7. 2. 3. 1
Seri o us A d verse E ve nts ............................................................................. 1 0 5
7. 2. 3. 2
E ve nts of Cli nical I nterest .......................................................................... 1 0 6
7. 2. 3. 3
Pr ot oc ol -S pecific E xce pti o ns t o Seri o us A d verse E ve nt Re p orti n g .......... 1 0 7
E val uati n g A d verse E ve nts ............................................................................... 1 0 7
7. 2. 4
S p o ns or Res p o nsi bilit y  f or Re p orti n g A d verse E ve nts .................................... 1 1 0
7. 2. 5
Tri al G o ver n a nce a n d O versi g ht ....................................................................... 1 1 0
7. 3
Scie ntific A d vis or y  C o m mittee......................................................................... 1 1 0
7. 3. 1
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E xec uti ve O versi g ht C o m mittee ....................................................................... 1 1 0
7. 3. 2
Data M o nit ori n g C o m mittee ............................................................................. 1 1 0
7. 3. 3
8. 0
S T A TI S TI C A L A N A L Y SI S P L A N ...................................................................... 1 1 1
St atistic al A n al ysis Pl a n S u m m ar y ................................................................... 1 1 1
8. 1
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g ............................................... 1 1 3
8. 2
H y p ot heses/ Esti m ati o n....................................................................................... 1 1 3
8. 3
A n al ysis E n d p oi nts ............................................................................................. 1 1 4
8. 4
Efficac y  E n d p oi nts............................................................................................ 1 1 4
8. 4. 1
Safet y  E n d p oi nts............................................................................................... 1 1 5
8. 4. 2
S u bject -Re p orte d O utc o mes E n d p oi nts ............................................................ 1 1 5
8. 4. 3
A n al ysis P o p ul ati o ns ........................................................................................... 1 1 5
8. 5
Efficac y  A nalys is P o p ulati o ns .......................................................................... 1 1 5
8. 5. 1
Safet y A nal ys is P o p ulati o ns ............................................................................. 1 1 5
8. 5. 2
St atistic al Met h o ds .............................................................................................. 1 1 6
8. 6
Statistical Met h o ds f or Efficac y  A nalys es ........................................................ 1 1 6
8. 6. 1
8. 6. 1. 1
O verall S ur vi val ......................................................................................... 1 1 6
8. 6. 1. 2
Pr o gressi o n -Free S ur vi val .......................................................................... 1 1 6
8. 6. 1. 3
O verall Res p o nse Rate a n d Disease C o ntr ol Rate ..................................... 1 1 9
8. 6. 1. 4
D urati o n of Res p o nse................................................................................. 1 1 9
8. 6. 1. 5
S u m mar y  of Statistical Met h o ds f or Efficac y............................................ 1 2 0
Statistical Met h o ds f or Safet y A nal ys es ........................................................... 1 2 1
8. 6. 2
S u m maries of De m o gra p hic a n d Baseli ne C haracteristics ............................... 1 2 4
8. 6. 3
I nteri m A n al yses................................................................................................ . 1 2 4
8. 7
M ulti plicit y
.......................................................................................................... 1 2 5
8. 8
S a m ple Size a n d P o wer C alc ul ati o ns ................................................................ 1 2 7
8. 9
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors ......................................... 1 2 9
8. 1 0
C o m pli a nce ( Me dic ati o n A d here nce) ................................................................ 1 2 9
8. 1 1
E xte nt of E x p os ure .............................................................................................. 1 3 0
8. 1 2
9. 0
L A B E LI N G, P A C K A GI N G, S T O R A G E A N D R E T U R N O F  CLI NI C A L 
S U P P LI E S ............................................................................................................... 1 3 0
I n vesti g ati o n al Pr o d uct ...................................................................................... 1 3 0
9. 1
P ac k a gi n g a n d L a beli n g I nf or m ati o n ............................................................... 1 3 0
9. 2
Cli nic al S u p plies Discl os ure ............................................................................... 1 3 0
9. 3
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St or a ge a n d H a n dli n g Re q uire me nts ................................................................ 1 3 1
9. 4
Disc ar d/ Destr ucti o n/ Ret ur ns a n d Rec o ncili ati o n ............................................ 1 3 1
9. 5
St a n d ar d P olicies ................................................................................................. 1 3 1
9. 6
1 0. 0
A D MI NI S T R A TI V E A N D R E G U L A T O R Y D E T AI L S ..................................... 1 3 1
C o nfi de nti alit y ..................................................................................................... 1 3 1
1 0. 1
C o nfi de ntialit y  of Data ..................................................................................... 1 3 1
1 0. 1. 1
C o nfi de ntialit y  of S u bject Rec or ds................................................................... 1 3 1
1 0. 1. 2
C o nfi de ntialit y  of I n vesti gat or I nf or mati o n ...................................................... 1 3 2
1 0. 1. 3
C o nfi de ntialit y  of I R B/I E C Inf or mati o n ........................................................... 1 3 2
1 0. 1. 4
C o m pli a nce wit h Fi n a nci al Discl os ure Re q uire me nts ..................................... 1 3 3
1 0. 2
C o m pl i a nce wit h L a w, A u dit a n d De b ar me nt ................................................. 1 3 3
1 0. 3
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P osti n g Re q uire me nts ...... 1 3 5
1 0. 4
Q u alit y M a n a ge me nt S yste m ............................................................................. 1 3 5
1 0. 5
D at a M a n a ge me nt ............................................................................................... 1 3 5
1 0. 6
P u blic ati o ns ......................................................................................................... 1 3 6
1 0. 7
1 1. 0
LI S T O F R E F E R E N C E S ....................................................................................... 1 3 7
1 2. 0  
A P P E N DI C E S ......................................................................................................... 1 4 5
Merc k C o de of C o n d uct f or Cli nic al Tri als ...................................................... 1 4 5
1 2. 1
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 
1 2. 2
Rese arc h ............................................................................................................... 1 4 7
U n derst a n di n g 
t he I nte nt, Sc o pe 
a n d 
P u blic 
He alt h 
Be nefits 
of 
1 2. 3
E x pl or at or y 
Bi o m ar ker 
Rese arc h: 
A 
G ui de 
f or I R Bs/I E Cs a n d 
I n vesti g ati o n al Site St aff .................................................................................... 1 5 3
A b bre vi ati o ns ...................................................................................................... 1 6 4
1 2. 4
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 6 7
1 2. 5
C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts V 4. 0 .............................. 1 6 8
1 2. 6
Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors 1. 1 Criteri a f or E v al u ati n g 
1 2. 7
Res p o nse i n S oli d T u m ors .................................................................................. 1 6 9
1 3. 0
SI G N A T U R E S ......................................................................................................... 1 7 0
S p o ns or's Re prese nt ati ve ................................................................................... 1 7 0
1 3. 1
I n vesti g at or .......................................................................................................... 1 7 0
1 3. 2
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
LI S T O F T A B L E S
    
Ta ble 1
Efficac y  of C urre ntl y Use d 2 L + M o n ot hera p y Re gi me ns i n m T N B C................... 2 7
Ta ble 2
A de q uate Or ga n F u ncti o n La b orat or y Val ues ........................................................ 3 6
Ta ble 3
Trial Treat me nt ....................................................................................................... 3 9
Ta ble 4
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 ................................................. 4 1
Ta ble 5
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 n es ............................................................................................................... 4 4
Ta ble 6
I ma gi n g a n d Treat me nt After Site -Assesse d First Ra di ol o gic E vi de nce of 
Pr o gressi ve Disease has Bee n Verifie d b y  the Ce ntral I ma gi n g Ve n d or.  Ta ble 
Re prese nts ir R E CI S T ............................................................................................. 5 4
Ta ble 7
La b orat or y  Tests..................................................................................................... 9 4
Ta ble 8
E val uati n g A d verse E ve nts ................................................................................... 1 0 8
Ta ble 9
Ce ns ori n g R ules f or Pri mar y  an d Se nsiti vit y  Anal y ses of Pr o gressi o n -free 
S ur vi val ................................................................................................................ 1 1 8
Ta ble 1 0
Ce ns ori n g R ules f or D urati o n of Res p o nse .......................................................... 1 1 9
Ta ble 1 1
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts..................................................... 1 2 0
Ta ble 1 2
A nal y sis Strate g y f or Safet y Para meters .............................................................. 1 2 3
Ta b le 1 3 S u m mar y  of Ti mi n g, Sa m ple Size, a n d Decisi o n G ui da nce of I nteri m Efficac y 
A nal y ses a n d Fi nal A nal ysis u n der I nitial Al p ha All ocati o n ............................... 1 2 6
Ta ble 1 4
Pr o d uct Descri pti o ns ............................................................................................. 1 3 0
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
LI S T O F FI G U R E S
Fi g ure 1
Trial Desi g n ............................................................................................................ 1 9
Fi g ure 2
Ima gi n g a nd Treat me nt f or Cli nical ly Sta bl e S u bjects After First Ra di ol o gic 
E vi de nce of Pr o gressi ve Disease Assesse d b y t he Site ........................................... 8 6
Fi g ure 3
I ma gi n g Pr ocess f or a Cli nicall y U nsta ble S u bject ................................................. 8 7
Fi g ure 4
M ulti plicit y  Strate g y............................................................................................. 1 2 7
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
S U M M A R Y O F C H A N G E S
P RI M A R Y R E A S O N ( S) F O R T HI S A M E N D M E N T:
Secti o n N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s)
R ati o n ale
3. 0
8. 0
O bjecti ve(s) & 
H y p ot hesis(es)
Statistical A nal y sis Pla n
Re vise d 
o bjecti ves ,
h y p ot heses , 
a n d 
statistical 
a nal ys is 
pla n
t o 
i ncl u de 
s u bjects wit h P D -L 1  positi ve 
t u m ors wit h a hi g her c o m bi ne d 
p ositi ve sc ore ( C P S) c ut off of 
≥1 0 ( C P S ≥1 0)
D ata fr o m ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g de m o nstrate a n 
e nric he d 
treat me nt 
effect 
wit h 
i ncreasi n g P D -L 1 le vel.  The c ut off 
of C P S ≥1 0 has bee n i ncl u de d t o 
i de ntif y an e nric he d p o p ulati o n of 
patie nts 
t hat 
c o ul d 
p ote ntiall y 
be nefit m ore fr o m pe m br oliz u ma b 
m o n ot hera p y as sec o n d- or t hir d-
li ne i n metastatic 
tri ple ne gati ve 
breast ca ncer .
8. 1
8. 8
Statistical 
A nal y sis 
Pla n 
S u m mar y
M ulti plicit y
U p date d m ulti plicit y  strate g y 
of t he a nal y ses. 
T he u p date d m ulti plicit y  strate g y 
reflects t he u p date d pri mar y  an d 
sec o n dar y 
hy p ot heses 
a n d 
rati o nales. I nitial al p ha is s plit 
bet wee n O S e n d p oi nts i n s u bjects 
wit h 
C P S 
≥1 0 a n d C P S 
≥1 t o 
e ns ure ma xi m u m p o wer t o i de ntif y 
a n e nric he d p o p ulati o n of patie nts 
that c o ul d p ote ntiall y  be nefit m ore 
fr o m pe m br oliz u ma b m o n ot hera p y 
as 
sec o n d-
or 
t hir d-li ne 
i n 
metastatic 
tri ple ne gati ve breast 
ca ncer.
T he 
O S 
i n all s u bjects 
h y p ot hesis ca n be teste d if O S i n 
s u bjects wit h C P S ≥1 is s uccessf ul.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Secti o n N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s)
R ati o n ale
8. 1
8. 7
8. 9
Statistical 
A nal y sis 
Pla n
S u m mar y
I nteri m A nalys es
Sa m ple 
Size 
a n d 
P o wer 
Calc ulati o ns
U p date d t he f oll o wi n g: ti mi n g 
of t he i nteri m/fi nal a nal ysis ; 
t he tar get e ve nts f or fi nal
a nal ys is, a n d sa m ple size a n d 
p o wer calc ulati o n s.
T hese c ha n ges were ma de 
t o be 
c o nsiste nt wit h 
t he a d diti o n of 
pri mar y  
OS e n d p oi nt i n s u bjects 
wit h 
C P S ≥1 0
a n d t he u p date d 
m ulti plicit y  strate g y.
T he u p date d ti mi n g a n d pla n ne d 
n u m ber of e ve nts at I A a n d F A 
were dri ve n b y  the u p date d p o wer /
s uccess H R 
b o u n dar y  calc ulati o n 
base d o n t he u p date d m ulti plicit y  
strate g y to e ns ure a de q uate p o wer 
of eac h pri mar y  en d p oi nt at t he 
ti me of eac h a nal ys is. T he st u d y 
n o w has o nl y  one i nteri m a nal ysis 
as at t he time of I A the i nf or mati o n 
fracti o n 
is 
e x pecte d 
t o 
be 
a p pr o xi matel y
8 5 % 
a n d a d di n g 
a not her I A will 
be little val ue 
a d de d. F or p o wer calc ulati o n, t he 
tr ue hazar d rati o ass u m pti o ns were 
u p date d 
base d 
o n
rece nt data 
o bser ve d fr o m ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g. T he e nr oll me nt 
d urati o n 
a n d 
dr o p -o ut 
rate 
ass u m pti o ns were u p date d base d o n 
rece nt a vaila ble i nf or mati o n.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A D DI TI O N A L C H A N G E ( S) F O R T HI S A M E N D M E N T:
Secti o n 
N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s)
R ati o n ale
4. 2. 1
Rati o nale f or t he Trial a n d Selecte d 
S u bject P o p ulati o n
Rati o nale was a d de d f or t he i ncl usi o n 
of C P S ≥1 0.
D ata fr o m 
ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g de m o nstrate a n 
e nric he d 
treat me nt 
effect 
wit h 
i ncreasi n g P D -L 1 le vel.  The c ut off 
of C P S ≥1 0 has bee n i ncl u de d t o 
i de ntif y an e nric he d p o p ulati o n of 
patie nts 
wit h 
metastatic 
tri ple 
ne gati ve breast ca ncer t hat c o ul d 
p ote ntiall y  
be nefit 
m ore 
fr o m 
pe m br oliz u ma b m o n ot hera p y.
6. 1. 1
Trial Fl o w C hart – Pe m br oliz u ma b 
M o n ot hera p y
Sa m pli n g f or pe m br oliz u ma b P K a n d 
a nti-dr u g a nti b o dies ( A D A) has bee n 
re m o ve d. Clarifie d t hat P K a nal ys is 
will be perf or me d o nl y if re q uire d.
Base d o n fee d bac k fr o m re g ulat or y 
a ge ncies, s ufficie nt P K/ A D A data 
has 
bee n 
c ollecte d 
f or 
pe m br oliz u ma b a n d sa m ples are n o 
l o n ger nee de d.
7. 1. 3. 3
8. 0
P har mac o ki netic/ P har mac o d y na mic 
E val uati o ns
Statistical A nal y sis Pla n
8. 1
Statistical A nal y sis Pla n S u m mar y
C orrecte d 
t hat
t he 
u nstratifie d 
Mietti ne n a n d N ur mi ne n met h o d will 
be use d f or safet y a nal ys is.
T o be c o nsiste nt wit h Secti o n 8. 6. 2.
8. 2
Res p o nsi bilit y  
for 
A nal y sis/I n-
H o use Bli n di n g
T he i nteri m efficac y to be pr o vi de d b y  
t he e xter nal u n bli n de d statisticia n t o 
e D M C is n ot restricte d t o O S a n d P F S.
U p date d la n g ua ge t o be c o nsiste nt 
wit h 
t he 
u p date d 
h y p ot heses 
(a d diti o n of O R R h yp ot hesis).
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Secti o n 
N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s)
R ati o n ale
8. 2
Res p o nsi bilit y  
for 
A nal y sis/I n-
H o use Bli n di n g
T he e xter nal u n bli n de d statisticia n will 
n ot 
be 
m o nit ori n g 
O S 
e ve nts i n 
s u bjects wit h P D-L 1  p ositi ve t u m ors t o 
i nf or m t he a nal ys is ti mi n g. I nstea d, 
t he u n bli n de d 
S p o ns or
bi o mar ker 
statisticia n 
will 
ha ve 
t his 
res p o nsi bilit y.
T o all o w m o nit ori n g of n u m ber of 
O S e ve nts t o e ns ure ti mel y a nal ysis.
8. 4. 1
8. 6. 1. 2
Efficac y  E n d p oi nts
P r ogr essi o n- Fr ee S ur vi val
U p date d 
t he ce ns ori n g 
r ules f or 
pri mar y  an d se nsiti vit y a n al yses of 
P F S.
R ecent ch an g es in the th erap eu tic
stan da r d P F S
cens ori n g r ul es; t he
pr i mar y a nal ysi s clos el y f ollo ws
F D A 
g ui d a n ce, a n d
the 
first
se nsitivit y a n al ys is clos el y f ollo ws
t he “i n t ent-t o-tr eat (IT T) c o mplete
f ollo w- u p pri n cip le”.
8. 4. 1
8. 6. 1. 4
Efficac y  E n d p oi nts
D urati o n of Res p o nse
U p date d 
t he
ce ns ori n g 
r ules 
f or 
pri mar y  an d
se nsiti vit y a nal yses of 
D O R.
T o be ali g ne d wit h 
t he u p date d 
ce ns ori n g r ule f or P F S.
8. 4. 1
Efficac y  E n d p oi nts
Clarifie d t he P F S, O R R, 
D O R 
a n d 
D C R e n d p oi nts base d o n ir R E C SIT b y  
In vesti gat or re vie w ma y be perf or me d 
as s u p p orti ve a nal ys is as nee de d.
Clarificati o n.
8. 6. 2
Statistical 
Met h o ds 
f or 
Safet y 
A nal y ses
U p date d t hat safety a nal ysis will be 
perf or me d i n all s u bjects o nl y .
It is e x pecte d t hat t he safet y pr ofile 
f or s u bjects wit h 
P D -L 1 p ositi ve 
t u m ors is si milar as t hat i n all 
s u bjects. As s uc h, safety a nal ys is i n 
all 
s u bjects 
pr o vi des 
m ost 
i nf or mati o n.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Secti o n 
N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s)
R ati o n ale
8. 1 0
4. 2. 3. 4
S u b gr o u p A nal ys es a n d Effect of 
Baseli ne Fact ors
Pla n ne d 
E x pl orat or y  
Bi o mar ker 
Researc h.
Re m o ve d 
B R C A 1/ 2 
stat us, 
h o m ol o g o us 
rec o m bi nati o n 
defect 
sc ore, 
a n d 
micr osatellite 
sta bilit y 
stat us as cate g ories f or t he s u b gr o u p 
a nal ys is. I nstea d, t hese a nal ys es ma y 
be perf or me d as se parate e x pl orat or y 
bi o mar ker a nal ys es.
T hese 
m a y  
be 
e val uate d 
as 
e x pl orat or y a nal ys es
t o c orrelate 
efficac y/resista nce bi o mar kers wit h 
res p o nse t o pe m br oliz u ma b. All o ws 
fle xi bilit y for
effecti ve 
use 
of 
c ollecte d t u m or sa m ples de pe n di n g 
o n e mer gi n g data re gar di n g t he 
effect of t hese bi o mar kers i n t he 
T N B C p o p ulati o n.
8. 1 0
S u b gr o u p A nal ys es a n d Effect of 
Baseli ne Fact ors
U p date d s u b gr o u p cate g orizati o n f or 
A ge a n d P D -L 1 stat us.
T o 
be ali g ne d wit h 
t he c urre nt 
g ui da nce 
f or a ge cate g or y an d 
u p date d P D -L 1 c ut off. 
Gl o bal  
Gl o bal
C orrecti o ns t o mi n or t yp o gra p hical or 
f or matti n g 
err ors 
ha ve 
bee n 
i nc or p orate d.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
1. 0 T RI A L S U M M A R Y
A b bre viate d Title
A 
Ra n d o mize d 
O pe n -La bel 
P hase 
III St u d y 
of 
Si n gle 
A ge nt 
Pe m br oliz u ma b vers us S i n gle A ge nt
C he m ot hera p y per P h y sicia n’s 
C h oice f or Metastatic 
Tri ple Ne gati ve 
Breast Ca ncer
( mT N B C) –
( K E Y N O T E 1 1 9)
Trial P hase
III
Cli nical I n dicati o n
Metastatic ( Sta ge I V/ M 1) Tri ple Ne gati ve Breast Ca ncer
Trial T y pe
I nter ve nti o nal
T y pe of c o ntr ol
Acti ve C o ntr ol 
R o ute of a d mi nistrati o n
I ntra ve n o us or oral
Trial Bli n di n g
U n bli n de d O pe n -la bel
Treat me nt Gr o u ps
Pe m br oliz u ma b : 2 0 0 m g i ntra ve n o usl y (I V) Q 3 W
Me dicati o ns 
use d as treat me nts of p h ysicia n's c h oice ( T P C) wi ll b e 
ha n dle d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g 
c o u ntries.  Sites ma y c h o ose a n y O N E dr u g fr o m t he f oll o wi n g:
Ca pecita bi ne
Eri b uli n
G e m cita bi ne
Vi n orel bi ne
N u m ber of trial s u bjects
A p pr o x i matel y 6 0 0 s u bjects will be e nr olle d.
Esti mate d d urati o n of trial
T he s p o ns or esti mates t hat t he trial will re q uire a p pr o xi matel y 4 0 m o nt hs
fr o m t he ti me t he first s u bject si g ns t he i nf or me d c o nse nt u ntil t he last 
s u bject’s last st u d y-relate d p h o ne call or visit.
D urati o n of Partici pati o n
Eac h s u bject wi ll partici pate i n t he trial fr o m t he ti me he/s he si gn s t he 
I nf or me d C o nse nt F or m  (I C F) u ntil wit h dra wi n g c o nse nt , bec o mi n g l ost -
t o-f oll o w-u p , deat h, or e n d of st u d y.  
After t he scree ni n g p hase, eli gi ble s u bjects will be stratifie d acc or di n g t o 
2 stratificati o n fact ors [ P D-L 1  tu m or stat us ( p ositi ve [ c o mbi ne d p ositi ve 
sc ore ≥1] vs ne gati ve [ c o mbi ne d p ositi ve sc ore < 1] ), a n d hist or y of pri or 
( ne o)
a dj u va nt t hera p y vs . de n o v o metastatic 
disease
at i nitial 
dia g n osis ], a n d t he n ra n d o mize d 1: 1 t o si n gle a ge nt pe m br oliz u ma b or 
si n gle a ge nt c he m ot hera p y per p h ysicia n’s c h oice. St u d y tr e at me nt will 
c o nti n ue u ntil disease pr o gressi o n (verifie d b y  bli n de d ce ntral i ma gi n g 
ve n d or , u nless s u bject is t he n ma na ge d b y  im m u ne -relate d res p o nse 
e val uati o n criteria i n s oli d t u m ors [ir R E CI S T]), u nacce pta ble a d verse 
e ve nt(s), i nterc urre nt ill ness t hat pre ve nts f urt her ad m i nistrati o n of st u dy 
treat me nt, I n vesti gat or’s decisi o n t o wit h dra w t he s u bject fr o m st u d y 
treat me nt, pre g na nc y of t he s u bject, n o nc o m plia nce wit h st u d y treat me nt
or
pr oce d ure 
re q uire me nts, 3 5 
treat me nts
ha ve 
bee n 
c o mplete d 
( pe m br oliz u ma b ar m o nl y), c o nse nt wit h dra w al, bec o mi n g l ost-t o-
f oll o w-u p , deat h or f or a d ministrati ve reas o ns re q uiri n g cessati o n of 
treat me nt. 
After disc o nti n uati o n of st u d y treat me nt, eac h s u bject will be f oll o we d 
f or 3 0 da ys f or a d verse e ve nt ( A E) a n d e ve nts of  cli nical i nterest ( E CI)
m o nit ori n g . S eri 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 st u d y treat me nt. S u bjects w h o 
disc o nti n ue st u dy 
treat me nt f or reas o ns ot her t ha n disease pr o gressi o n will ha ve p ost -
treat me nt f oll o w- u p f or disease status u ntil disease pr o gressi o n (verifie d 
b y bli n de d ce ntral i ma gi n g ve n d or ), start of a n o n -st u d y a ntica ncer 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
treat me nt, c o nse nt wit h dra w al , bec o mi n g l ost t o f oll o w-u p , deat h or e n d 
of t he st u d y. All s u bjects will be f oll o we d b y  tele p h o ne f or o verall 
s ur vi val u ntil c o nse nt wit h dra wal , b e c o m i n g l ost t o f oll o w-u p , de at h or 
e n d of t he st u d y.
S u bjects w h o st o p p e m br oliz u ma b after ac hie vi n g a C R a n d s u bjects 
w h o , after recei vi n g 3 5 c ycles, st o p pe m br oliz u ma b f or reas o ns ot her 
t ha n disease pr o gressi o n or i nt olera bilit y ma y be eli gi ble f or u p t o o ne 
year of retreat me nt wit h pe m br oliz u ma b u p o n e x perie nci n g disease 
pr o gressi o n. T he decisi o n t o retreat wit h p e m br oliz u ma b will be at t he 
discreti o n of t he I n vesti gat or, o nl y if s u bjects meet t he criteria f or 
retreat me nt a n d t he trial is o n g oi n g. 
S u bjects ma y be tra nsiti o ne d to a n e xte nsi o n st u d y if/ w he n a n e xte nsi o n 
st u d y bec o mes a vaila ble. 
Ra n d o mizati o n Rati o
1: 1
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 Secti o n 1 2. 4.
2. 0 T RI A L D E SI G N
Tri al Desi g n
2. 1
T his is a ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d, m ultice nter, i nter nati o nal P hase III trial 
of si n gle a ge nt pe m br oliz u ma b vers us si n gle a ge nt c he m ot hera p y per p h y sicia n’s c h oice 
( Treat ment of P h y sicia n’s C h oice , T P C) for s u bjects recei vi n g sec o n d li ne ( 2 L) or t hir d li ne 
( 3 L) treat me nt f or metastatic tri ple ne gati ve breast ca ncer ( m T N B C). T he st u d y will be 
c o n d ucte d i n c o nf or ma nce wit h G o o d Cli nical Practices ( G C Ps).
S u bjects m ust ha ve ce ntrall y c o nfir me d m T N B C, ha ve recei ve d eit her o ne or t w o pri or 
s yste mic treat me nts f or metastatic breast ca ncer , a n d ha ve d oc u me nte d disease pr o gressi o n
o n or after t he m ost rece nt t hera py.   Su bjects m ust ha ve bee n pre vi o usl y  treate d wit h a n 
a nt hrac ycli ne a n d / or a ta xa ne i n t he ( ne o)a dj u va nt or metastatic setti n g. 
All s u bjects i n t his st u d y will be re q uire d t o pr o v i de fres h ne wl y o btai ne d c ore or e xcisi o nal 
bi o ps y  fr o m a metastatic , n ot pre vi o usl y  irra diate d, t u m or lesi o n t o be e val uate d at a ce ntral 
la b orat or y for 1) tri ple-ne gati ve breast ca ncer stat us b y  deter mi nati o n of estr o ge n rece pt or 
( E R), pr o gester o ne rece pt or a n d h u ma n e pi der mal gr o wt h fact or rece pt or-2 ( H E R 2) 
e x pressi o n , 
a n d 
2) 
pr o gra m me d 
deat h -li ga n d 
1 
(P D -L 1 )
e x pressi o n 
b y  
i m m u n o hist oc he mistr y (I H C).  Sa m ples will be se nt t o a ce ntral la b orat or y for real ti me 
e val uati o n t o e ns ure a de q uate t u m or tiss ue is prese nt a n d eli gi bilit y re q uire me nts are 
f ulfille d.   
After t he scree ni n g p hase, eli gi ble su bjects will be first stratifie d acc or di n g t o 2 stratificati o n 
fact ors [ P D-L 1 t u m or stat us ( p ositi ve [c o m bi ne d p ositi ve sc ore ( C P S) ≥1] vs . ne gati ve
[ C P S < 1] ), a n d hist or y  of pri or ( ne o)a dj u va nt treat me nt vs . de n ov o metastatic disease at 
i nitial dia g n osis ].
Su bject s
will 
t he n
be ra n d o mize d
1: 1 t o recei ve si n gle a ge nt 
pe m br oliz u ma b 2 0 0 m g I V o nce e ver y 3 wee ks ( Q 3 W) or si n gle a ge nt c he m ot hera p y per 
p h y sicia n’s c h oice (T P C ): ca pecita bi ne , eri b uli n , ge mcita bi ne , or vi n orel bi ne . F or t he T P C 
ar m , t here is a ma xi m u m e nr oll me nt ca p of 6 0 % of t otal e nr oll me nt f or eac h c he m ot hera p y 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
dr u g .  The T P C d osi n g a n d fre q ue nc y will be ha n dle d acc or di n g t o l ocal re g ulati o ns a n d 
g ui deli nes i n partici pati n g c o u ntries.
St u d y  treat me nt will c o nti n ue u ntil disease pr o gressi o n ( verifie d b y  bli n de d ce ntral i ma gi n g 
ve n d or u nless s u bject is t he n ma na ge d b y ir R E CI S T), u nacce pta ble a d verse e ve nt(s) ( A E[s]), 
i nterc urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of st u d y treat me nt, I nvesti gat or ’s 
decisi o n t o wit h dra w 
t he s u bject fr o m st u d y treat me nt, pre g na nc y of t he s u bject, 
n o nc o m plia nce wit h st u d y treat me nt or pr oce d ure re q uire me nts, 3 5 treat me nts ha ve bee n 
c o m plete d ( pe m br oliz u ma b ar m o nl y ), c o nse nt w it h dra wal, bec o mi n g l ost-t o-f oll o w- u p, 
deat h or f or a d mi nistrati ve reas o ns re q uiri n g cessati o n of treat me nt. 
After disc o nti n uati o n of st u d y treat me nt, eac h s u bject will be f oll o we d f or 3 0 da y s f or A E
a n d e ve nts of cli nical i nterest ( E CIs). S eri o us A E s ( S A Es) will be c ollecte d f or 9 0 d a y s after 
t he e n d of st u dy treat me nt .
S u bjects w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n will 
ha ve p ost -treat me nt f oll o w- u p f or disease stat us e ver y 3 c ycles (± 7 da y s) u ntil disease 
pr o gressi o n ( verifie d b y  bli n de d ce ntral i ma gi n g ve n d or), start of a n o n -st u d y a ntica ncer 
treat me nt, c o nse nt wit h dra wal, bec o mi n g l ost t o f oll o w-u p, deat h or e n d of t he st u d y . 
All s u bjects will be f oll o we d b y  tele p h o ne e ver y 4 c y cles ( ± 7 da ys) f or o verall s ur vi val ( O S)
u ntil c o nse nt wit h dra w al, bec o mi n g l ost t o f oll o w-u p, deat h or e n d of t he st u d y.
S u bjects ma y  ha ve t he o p p ort u nit y  to tra nsiti o n t o a pe m br oliz u ma b e xte nsi o n st u d y if 
a vaila ble i n t he f ut ure after cl os ure of t his st u d y.
S pecific pr oce d ures t o be perf or me d d uri n g t he trial, 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 Trial Fl o w C hart - Secti o n 6. 0. Details of eac h 
pr oce d ure are pr o vi de d i n Secti o n 7. 0 – Trial Pr oce d ures.
I n this trial, pe m br oliz u ma b will be c o m pare d t o T P C as 2 L  or 3 L  mo n ot hera p y  in s u bjects 
wit h ce ntrall y c o nfir me d m T N B C . T he st u d y o bjecti ves are defi ne d i n i n Secti o n 3. 0.
A m ulti plicit y  ap pr oac h will be f oll o we d as descri be d i n Secti o n 8. 0. T he size of t his trial is 
~ 6 0 0 s u bjects. The O S e ve nt s re q uire d i n s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 a n d 
C P S ≥1 0) was esti mate d base d o n t he esti mati o n of t he pre vale nce of P D -L 1 p ositi ve t u m ors
wit h C P S ≥1 ( 6 5%) a n d C P S ≥1 0 ( 3 1%) . T he pre vale nce of P D -L 1 p ositi vit y ( C P S ≥1) i n 
m T N B C was 5 5 % i n t he pr o of -of -pri nci ple st u d y  K N 0 1 2 ( Secti o n 4. 2).
O ne
i nteri m efficac y a nal ysis is pla n ne d i n t his st u d y (Secti o n 8. 7 ).  The i nteri m efficac y 
a nal ys is is t o assess efficac y base d o n O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d i n all s u bjects .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Tri al Di a gr a m
2. 2
Fi g ure 1
Trial Desi g n
A b bre viati o ns: C P S = c o m bi ne d p ositi ve sc ore; ir R E CI S T = i m m u ne-relate d Res p o nse E val uati o n Criteria i n 
S oli d T u m ors; I V = i ntra ve n o us; P D -L 1 = pr o gra m me d cell deat h li ga n d 1; Q 3 W = e ver y 3 we e ks; 
T P C = c he m ot hera p y pe r p h ysicia n’s c h oice.
* 
I n t he e ve nt t hat treat me nt wit h p e m br oliz u ma b is f o u n d t o be f utile i n s u bjects wit h P D -L 1 ne gati ve 
t u m ors, stratificati o n f or P D-L 1 stat us will be a ba n d o ne d.
* *
Treat me nt ma y be c o nti n ue d be y o n d verifie d 1 st ra di ol o gic e vi de nce of disease pr o gressi o n acc or di n g t o 
ir R E CI S T criteria.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
3. 0 O B J E C TI V E( S) & H Y P O T H E SI S( E S)
Pr i m ar y O bjecti ve(s) & H y p ot hesis(es)
3. 1
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C:
P D -L 1
P ositi ve P o p ul ati o ns : s u bjects wit h P D -L 1  positi ve e x pressi o n defi ne d b y  ≥1 0 
C o m bi ne d P ositi ve Sc ore ( C P S) a n d b y  ≥1 C P S; he ncef ort h a b bre viate d as C P S ≥1 0 a n d 
C P S ≥1 res pecti vel y.
( 1) O bjecti ve: T o c o m pare O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0) .
H y p ot hesis ( H1 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0) . 
( 2) O bjecti ve: T o c o m pare O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1) .
H y p ot hesis
( H2 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1 p ositi ve t u m ors ( C P S ≥1) . 
( 3) O bjecti ve: T o c o m pare O S i n all s u bjects.
H y p ot hes is ( H3 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n all s u bjects.
T he st u d y is c o nsi dere d t o ha ve met its pri mar y  objecti ve if pe m br oliz u ma b is s u peri or t o 
T P C i n O S i n eit her s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 [ H 1] or C P S ≥1 [ H 2]) or 
i n all s u bjects ( H 3), at eit her t he i nteri m a nal ysis or t he fi nal a nal ysis.
Sec o n d ar y O bjecti ve(s) & H y p o t hesis(es)
3. 2
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C :
( 1) O bjecti ve:   T o c o m pare pr o gressi o n -free s ur vi val (P F S ) base d o n R E CI S T 1. 1 as 
assesse d b y bli n de d ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hesis ( H 4): Pe m br oliz u ma b pr ol o n gs P F S base d o n R E CI S T 1. 1 as assesse d b y  
bli n de d ce ntral i ma gi n g ve n d or c o m pare d t o T P C i n all s u bjects.
( 2) O bjecti ve:   T o c o m pare o verall res p o nse rate ( O R R) per R E CI S T 1. 1 b y  bli n de d 
ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hes is ( H5 ): Pe m br oliz u ma b i ncreases O R R per R E CI S T 1. 1 b y  bli n de d ce ntral 
i ma gi n g ve n d or c o m pare d t o T P C i n all s u bjects.
( 3) O bjecti ve:   T o e val uate P F S a n d O R R base d o n R E CI S T 1. 1 as assesse d b y  bli n de d 
ce ntral i ma gi n g ve n d or i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 a n d 
C P S ≥1) .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
( 4) O bjecti ve : T o e val uate d urati o n of res p o nse ( D O R), a n d disease c o ntr ol rate ( D C R) 
base d o n R E CI S T 1. 1 as assesse d b y  bli n de d ce ntral i ma gi n g ve n d or i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d i n all s u bjects.
( 5) O bjecti ve : T o deter mi ne t he safet y a n d t olera bilit y of pe m br oli z u ma b .
T he sec o n dar y hy p ot heses re gar di n g P F S i n all s u bjects ( H 4) a n d O R R i n all s u bjects ( H 5) 
ca n o nl y be f or mall y teste d o nce t he n ull h y p ot hesis re gar di n g t he pri mar y e n d p oi nt O S i n all 
s u bjects ( H3 ) has bee n rejecte d..
E x pl or at or y O bjecti ves
3. 3
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C :
( 1) O bjecti ve:
T o e val uate P F S, O R R, D O R, a n d D C R base d o n ir R E CIS T as assesse d 
b y  bli n de d ce ntral i ma gi n g re vie w i n s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects . 
( 2) O bjecti ve : T o e val uate c ha n ges i n healt h- relate d q ualit y -of -life assess me nts fr o m 
baseli ne i n s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d all 
s u bjects usi n g t he E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
(E O R T C ) Q L Q -C 3 0 a n d Q L Q -B R 2 3.
( 3) O bjecti ve: T o c haracterize utilities i n s u bjects wit h P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects usi n g E ur o Q ol (E Q )-5 D .
( 4) O b jecti ve:
T o 
i n vesti gate t he ass ociati o n 
bet wee n 
a ntit u m or 
acti vit y 
of 
pe m br oliz u ma b i n m T N B C a n d efficac y/resista nce bi o mar kers, utilizi n g t u m or a n d 
bl o o d s peci me ns o btai ne d bef ore/ d uri n g treat me nt a n d at disease pr o gressi o n.
( 5) O bjecti ve: T o e x pl ore t he relati o ns hi p bet wee n ge netic variati o n a n d res p o nse t o t he 
treat me nt(s) a d mi nistere d.  Variati o n acr oss t he h u ma n ge n o me will be a nal yze d f or 
ass ociati o n wit h cli nical data c ollecte d i n t his st u d y.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
4. 0 B A C K G R O U N D & R A TI O N A L E
B ac k gr o u n d
4. 1
Refer t o t he I n vesti gat or’s Br oc h ure (I B)/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 p e m br oliz u ma b (M K -3 4 7 5 ).
P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d
4. 1. 1
P D -1 c hec k p oi nt i n hi biti o n a n d c a ncer tre at me nt.  T he i m p orta nce of i ntact i m m u ne 
s ur veilla nce i n c o ntr olli n g o ut gr o wt h of ne o plastic tra nsf or mati o n has bee n k n o w n f or 
deca des [ 1].  
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 ym p h oc y tes ( TI Ls) i n ca ncer tiss ue a n d pr o g n osis i n vari o us mali g na ncies
[ 2-1 4] .  In 
par tic 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 + 
re g ulator y  T cells see m t o c orrelate wit h i m pr o ve d pr o g n osis a n d l o n g-ter m s ur vi val i n ma n y 
s oli d t u m ors [ 1 0, 1 5-2 1] .
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  tu m ors t o s u p press 
im m u ne c o ntr ol [ 2 2].  T he n or mal f u ncti o n of P D-1, w hic h is 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.  PD- 1 (e nc o de d b y  the ge ne P dc d 1) is a
me m ber of t he I g s u perfa mil y relate d t o C D 2 8 a n d c yt ot o xic t-l ym p h oc y te-ass ociate d a nti ge n 
4 (C T L A- 4) , w hic h 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  an d/ or P D -L 2).  The str uct ures of m uri ne P D -1 al o ne [ 2 3]
a n d i n c o m ple x wit h its li ga n ds were first res ol ve d [ 2 4, 2 5 ]. M ore rece ntl y the N M R -base d 
str uct ure of t he h u ma n P D -1 e xtracell ular re gi o n a n d a nal ys es of its i nteracti o ns wit h its 
li ga n ds were als o re p orte d [ 2 6].  PD- 1 a n d fa mil y me m bers are t ype I tra ns me m bra ne 
gl yc o pr otei ns c o ntai ni n g a n I g Varia ble -t ype ( V-t ype) d o mai n i m p orta nt f or li ga n d bi n di n g 
a n d a c yt o plas mic tail w hic h is res p o nsi ble f or t he acti vati o n of d o w nstrea m si g nali n g 
m olec ules.  The c yt o plas mic tail of P D -1 c o nta i 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 (I TI M) a n d a n i m m u n orece pt or t yr osi ne-
base d s witc h m otif (IT S M).  Foll 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 T S M m ot if 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 y lati 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 [ 2 7].  The mec ha nis m b y  whic 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 [ 2 8].  P D -1 was 
s h o w n t o be e x presse d o n acti vate d l ym p h oc y tes, i ncl u di n g peri p heral C D 4 + a n d C D 8 + 
T- cells, B cells, T- re gs a n d Nat ural Killer cells [ 2 9]. E x pressi o n has als o bee n s h o w n d uri n g 
t h ymic de vel o p me nt o n C D 4 -C D 8 - ( d o u ble ne gati ve) T cells [ 3 0], as well as s u bsets of 
macr o p ha ges [ 3 1] a n d de n dritic cells [ 3 2]. T he li ga n ds f or P D -1 ( P D-L 1 a n d P D -L 2 ) are 
c o nstit uti vel y ex presse d or ca n be i n d uce d i n a variet y  of cell t ypes [ 3 3]. P D -L 1 is e x presse d 
at l o w le vels o n vari o us n o n -he mat o p oietic tiss ues, m ost n ota bl y  on vasc ular e n d ot heli u m, 
w hereas P D -L 2  pr otei n is o nl y  detecta bl y ex presse d o n a nti ge n -prese nti n g cells f o u n d i n 
l ym p h oi d 
tiss ue or c hr o nic i nfla m mat or y en vir o n me nts
[ 3 3]. B ot h li ga n ds are t ype I 
tra ns me m bra ne rece pt ors c o ntai ni n g b ot h I g V- a n d I g C-li ke d o mai ns i n t he e xtracell ular 
re gi o n a n d s h ort c yt o plas mic re gi o ns wit h n o k n o w n si g nali n g m otifs.  Bi n di n g of eit her P D -
1 li ga n d t o P D -1 i n hi bits T cell acti vati o n tri g gere d t hr o u g h t he T cell rece pt or. P D -L 2 is 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
t ho u g ht t o c o ntr ol i m m u ne T cell acti vati o n i n l y mp h oi d or ga ns, w hereas P D -L 1  ser ves t o 
da m pe n u n warra nte d T cell f u ncti o n i n peri p heral tiss ues.  Alt h o u g h healt h y  or ga ns e x press 
little (if a n y) P D -L 1 , a variet y of ca ncers were de m o nstrate d t o e x press a b u n da nt le vels of 
t his T
cell i n hi bit or [ 3 4, 3 5] , w hic h, via 
its i nteracti o n wit h t he P D -1 rece pt or o n 
t u m or-s pecific T cells, pla y s a critical r ole i n i m m u ne e vasi o n b y  tu m ors [ 3 6].  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 
ca ncer [ 3 7].
I m m u n ot her a p y: Precli nic al S t u dies 
4. 1. 2
P D -1 i m m u ne c hec k p oi nt i n hi biti o n - Precli nic al st u dies. T hera pe utic st u dies i n m o use 
m o dels ha ve s h o w n t hat a d mi nistrati o n of a nti b o dies bl oc ki n g P D -1/ P D- L 1  interacti o n 
e n ha nces i nfiltrati o n of t u m or-s pecific C D 8 + T cells a n d ulti matel y lea ds t o t um or rejecti o n, 
eit her as a m o n o t hera p y or i n c o m bi nati o n wit h 
ot her treat me nt m o dalities
[ 3 8- 4 0].  
A nti -m o use P D -1 or a nti -m o use P D -L 1 a nti b o dies ha ve de m o nstra te d a ntit u m or res p o nses i n 
m o dels 
of s q ua m o us cell carc i n o ma, pa ncreatic carci n o ma, mela n o ma, 
ac ute m y el oi d 
le u ke mia a n d c ol orectal carci n o ma [ 4 1- 4 5].  I n suc h st u dies, t u m or i nfiltrati o n b y C D 8 + 
T- cells a n d i ncrease d I F N-γ, gra nz y m e B a n d perf ori n e x press i o n were o bser ve d , i n dicati n g 
t hat t he mec ha nis m u n derl y i n g t he a ntit u m or acti vit y of PD- 1 c hec k p oi nt i n hi biti o n i n v ol ve d 
l ocal i nfiltrati o n a n d acti vati o n of effect or T cell f u ncti o n i n viv o [ 42]. E x peri me nts ha ve 
c o nfir me d t he i n viv o effi cac y of a nti -m o use P D -1 a nti b o d y as a m o n o t hera p y, as well as i n 
c o m bi nati o n wit h c he m ot hera p y, i n sy n ge neic m o use t u m or m o dels (see t he I B).
Pe m br oliz u m a b: O n g oi n g C li nic al T ri als i n Ot her T u m or Ty pes
4. 1. 3
Pe m br oliz u m a b –
Cli nic al tri als. P e m br oliz u ma b [Ke y tr u da® ( U S); pre vi o usl y  kn o w n as 
la m br oliz u ma b, M K -3 4 7 5 a n d S C H 9 0 0 0 4 7 5] is a p ote nt a n d hi g hl y selecti ve h u ma nize d 
m o n ocl o nal a nti b o d y (m A b) of t he I g G 4/ ka p pa is ot ype desi g ne d t o directl y  bl oc k t he 
i nteracti o n bet wee n P D -1 a n d its li ga n ds, P D -L 1  an d P D -L 2. Pe m br oliz u ma b was rece ntly 
a p pr o ve d i n t he U S f or t he treat me nt of a d va nce d, u nresecta ble or metastatic mali g na nt 
mela n o ma, a n d f or use i n mela n o ma s u bjects wit h disease pr o gressi o n after pri or treat me nt 
wit h (a) i pili m u ma b or ( b) a B R A F i n hi bit or , i n t he case of B R A F V 6 0 0-m uta nt disease [4 6 ]. 
It is t he first a nti -P D -1 t hera py t o recei ve re g ulat or y ap pr o val i n t he U S, a n d is c urre ntl y 
u n der re g ulat or y re vie w i n t he E U.
O n g oi n g
cli nical trials of pe m br oliz u ma b are bei n g
c o n d ucte d i n a d va nce d mela n o m a, n o n -s mall cell l u n g ca ncer , a n d a n u m ber of ot h er 
a d va nce d s oli d t u m or i n dicati o ns a n d he mat ol o gic mali g na ncies.
F or st u d y details please
refer t o t he I B.
I nf or m ati o n o n Dise ase t o be T re ate d – m T N B C
4. 1. 4
E xcl u di n g basal cell a n d s q ua m o us cell s ki n ca ncers, breast ca ncer is t he m ost c o m m o nl y 
dia g n ose d mali g na nc y  in w o me n, acc o u nti n g f or 2 9 % of all ne w ca ncers.  It is als o t he 
sec o n d lea di n g ca use of ca ncer deat h (after l u n g ca ncer) a m o n g w o me n.  A b o ut 2 3 2, 6 7 0 ne w 
cases of breast ca ncer a n d 4 0, 0 0 0 deat hs d ue t o breast ca ncer w e re e x pecte d i n w o me n i n t he 
U nite d States i n 2 0 1 4 [4 7 ].  Tri ple -ne gati ve breast ca ncer ( T N B C) is p he n ot y picall y defi ne d 
b y  a lac k of estr o ge n rece pt or ( E R) a n d pr o gester o ne rece pt or e x pressi o n a n d t he a bse nce of 
h u ma n e pi der mal gr o wt h fact or rece pt or-2 ( H E R 2) o vere x pressi o n a n d/ or a m plificati o n [4 8 ].  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
2 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T N B C re prese nts 1 5- 2 0 % of all breast ca ncers [ 4 9] a n d is o verla p pi n g, b ut n ot s yn o n y m o us, 
wit h t he basal -li ke s u bt y pe defi ne d b y  ge ne e x pressi o n, as a b o ut 7 0 % of T N B Cs ha ve basal -
li ke c haracteristics [5 0, 5 1 ]. 
T N B C is a m olec ularl y heter o ge ne o us disease a n d i ncl u des t u m or s u bsets wit h differe nt 
pr o g n osis.  For e xa m ple, t he cla u di n-l o w s u bty pe, w hic h is c haracterize d b y  lo w e x pressi o n 
of clau di n ge nes a n d ofte n prese nts wit h ste m cell feat ures a n d e pit helial-t o-mese nc h y m al 
tra nsiti o n ( E M T), is ass ociate d wit h p o or pr o g n osis [ 5 2]. Rece nt ge ne e x pressi o n pr ofili n g 
has i de ntifie d u p t o si x disti nct T N B C s u bty pes (t w o basal -li ke, a n i m m u n o m o d ulator y , a 
mese nc h y m al, a mese nc h ymal ste m -li ke a n d a l u mi nal a n dr o ge n rece pt or s u bt ype) [ 5 3 ].
T N B C is ass ociate d wit h y o u n ger a ge at dia g n osis, pre me n o pa usal stat us, Africa n A merica n 
race, m ore a d va nce d disease sta ge, hi g her gra de, hi g h mit otic i n dices, fa mil y hist or y of 
breast ca ncer, Breast Ca ncer 1 ( B R C A 1) m utati o ns, a n d m ore a g gressi ve be ha vi or t ha n ot her 
breast ca ncer s u bty p es [ 4 9].  As re p orte d i n a se mi nal st u d y on T N B C, 3 4 % of all s u bjects 
wit h T N B C e x perie nce dista nt rec urre nce wit h a me dia n dist a nt rec urre nce-free s ur vi val 
( D R F S) of 2. 6 years, c o m pare d t o a dista nt rec urre nce rate of 2 0 % a n d a me dia n D R F S of 5 
ye ars i n ot her breast ca ncer s u bty pes; t he pea k of rec urre nce f or T N B C is wit hi n 1- 3 ye ars 
after i nitial dia g n osis, a n d decreases si g nifica ntl y t hereafter; s u bjects wit h T N B C als o ha ve 
s h orter O S
c o m pare d t o s u bjects wit h n o n- T N B C ( 4. 2 vers us 6. 0 ye ars) [4 8 ].  Fi nall y, 
s u bjects wit h T N B C te n d t o rela pse wit h dista nt metastases rat her t ha n l ocal rec urre nces a n d 
are m ore li kely t o de vel o p visc eral metastases, i ncl u di n g ce ntral ner v o us s yste m ( C N S) 
i n v ol ve me nt [ 5 4].
Treat me nt of T N B C is c halle n gi n g a n d re prese nts a n area of u n met me dical nee d, as t hese 
t u m ors lac k t hera pe utic tar gets, s uc h as E R a n d H E R 2, a n d bec o me ra pi dl y resista nt t o 
c he m ot hera py u p o n l ocal rec urre nce a n d/ or metastasis (e ve n t h o u g h t he y are ofte n se nsiti ve 
t o c yt ot o xic dr u gs at i nitial prese ntati o n) [ 5 5]. T he maj orit y  of s u bjects wit h metastatic 
T N B C ( m T N B C) ha ve e x perie nce d rela pse after ne oa dj u va nt or a dj u va nt t hera py f or ea rl y or 
l ocall y ad va nce d disease.  In a fre q ue ntly refere nce d st u d y, t he O S
of all (at a n y li ne of 
t hera py)  su bjects wit h m T N B C was 1 3. 3 m o nt hs; me dia n d urati o n of first li ne ( 1 L) t hera p y 
f or m T N B C was 1 1. 9 wee ks; 8 0 % of s u bjects recei ve d sec o n d li ne ( 2 L) t hera p y wit h a 
me dia n d urati o n of 9 wee ks, a n d a b o ut 5 0 % recei ve d t hir d li ne ( 3 L) t hera p y wit h a me dia n 
d urati o n of 4 wee ks [ 5 6].
I m m u ne c hec k p oi nt i n hi biti o n f or t he tre at me nt of T N B C. Se veral st u dies ha ve 
de m o nstrate d t hat prese nce of TI Ls has pr o g n ostic si g nifica nce i n T N B C, t h us i m plicati n g 
t he i m m u ne s yste m i n t he pat h o p h y siol o g y  an d p ote ntiall y  the treat me nt of s uc h t u m ors.  
Greater l ym p h oc y tic i nfiltrati o n c o nfers better pr o g n osis i n T N B C, i n de pe n de nt of s yste mic 
t hera py [5 7, 5 8 ].  In a d diti o n, u ns u per vise d ge ne e x pressi o n pr ofili n g of T N B Cs has 
i de ntifie d a ge ne si g nat ure e nric he d f or c yt ot o xic C D 8 + T cell ge nes a n d nat ural killer cell 
( N K C) acti vit y, w hic h is pre dicti ve of g o o d cli nical o utc o me s [ 5 9].  These fi n di n gs s u g gest 
t hat i n hi biti o n of i m m u ne c hec k p oi nts has t he p ote ntial t o i m pr o ve T N B C pr o g n osis b y 
i ncreasi n g t he efficac y of t u m or-ass ociate d i m m u ne res p o nse i n eli mi nati n g breast ca ncer 
cells [ 6 0 ].
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
T ar geti n g t he P D -1 i m m u ne c hec k p oi nt f or t he tre at me nt of T N B C . T he P D -1 li ga n d, 
P D -L 1 , is n ot detecte d i n n or mal breast tiss ue, b ut has bee n re p orte d t o be e x presse d i n a b o ut 
half of all breast ca ncers, partic ularl y i n h or m o ne rece pt or ( H R)-ne gati ve a n d hi g h gra de, 
pr oliferati ve t u m ors [6 1 ].  In a d diti o n, t he prese nce of re g ulat or y T cells, t u m or P D -L 1  
e x pressi o n, a n d P D - 1 – p ositi ve TI Ls has bee n ass ociate d wit h hi g h hist ol o gic gra de, E R 
ne gati vit y , a n d pr o mi ne nt t u m or l ym p h oc y tic i nfiltrati o n [6 2 ].  In a n i n de pe n de nt st u d y, P D -
L 1 was f o u n d e x presse d i n 2 3 % of breast ca ncer s peci me ns a n d it was a gai n ass ociate d wit h 
a ge, t u m or size, A merica n J oi nt C o m mittee o n Ca ncer ( AJ CC) pri mar y  tu m or classificati o n, 
t u m or gra de, l ym p h n o de stat us, a bse nce of E R e x pressi o n, a n d hi g h e x pressi o n of t he 
pr oliferati o n mar ker Ki -6 7 [6 3 ].  A rece nt p u blicati o n re p orte d t hat P D -L 1  messe n ger 
ri b o n ucleic aci d ( m R N A) is e x presse d i n nearl y 6 0 % of breast t u m ors, i n de pe n de ntl y of H R 
stat us, a n d is p ositi vel y  correlate d wit h P D -L 1  pr otei n e x pressi o n a n d i ncrease d TI Ls [6 4 ].  
A n ot her st u d y mi ni n g t he Ca ncer Ge n o me Atlas ( T C G A) R N A se q ue nci n g data s h o we d t hat 
P D -L 1  ge ne e x pressi o n is si g nifica ntly hi g h er i n T N B Cs c o m pare d t o n o n - T N B Cs, a n d is 
ass ociate d wit h P h os p hatase a n d T e nsi n H o m ol o g ( P T E N) l oss; i n t he sa me st u d y, P D -L 1  
was f o u n d e x presse d i n 2 0 % of T N B Cs [6 5 ].  Fi nall y, i n a n a bstract prese nte d i n t he 2 0 1 4 
A merica n S ociet y of Cli nical O nc ol o g y  ( AS C O) A n n ual meeti n g, it was re p orte d t hat P D -L 1  
pr otei n le vels are p ositi vel y  correlate d wit h e x pressi o n of ot her i m m u ne re g ulat ors, s uc h as 
C T L A- 4 a n d I n d olea mi ne 2, 3 -Di O x y ge nase 1 (I D O 1), a n d wit h 
a n dr o ge n rece pt or 
( A R)-ne gati ve a n d B R C A 1 -m uta nt T N B C [1 0 4] .  Des pite t heir disc or da nce i n t he re p orte d 
a bs ol ute P D -L 1 le vels i n breast t u m ors, t he af ore me nti o ne d st u dies clearl y de m o nstrate t hat 
T N B Cs are c haracterize d b y  PD- L 1 p ositi vit y  an d prese nce of TI Ls, a n d t h us s u g gest t hat 
P D -1 i m m u ne c hec k p oi nt i n hi biti o n is a t hera pe utic strate g y wort h y of f urt her i n vesti gati o n 
f or t he treat me nt of t his a g gressi ve breast ca ncer s u bt ype.  
Pr o of -of -Pri nci ple St u d y f or P e m br oliz u m a b use i n m T N B C
4. 1. 5
K N -0 1 2 - Cli nic al d at a s u p p orti n g pe m br oliz u m a b use f or t he tre at me nt of m T N B C . I n 
t he first re p ort of cli nical acti vit y of a n i m m u ne c hec k p oi nt i n hi bit or i n T N B C, a Merc k -
s p o ns ore d m ulti -ce nter, n o n -ra n d o mize d P hase I b trial ( K N-0 1 2) s h o we d t hat si n gle a ge nt 
pe m br oliz u ma b gi ve n at 1 0 m g/ k g I V Q 2 W is a well -t olerate d a n d effecti ve treat me nt wit h 
si g nifica nt t hera pe utic acti vit y i n a s u bset of hea vil y pre-treate d s u bjects wit h m T N B C.  
Met h o ds: P D -L 1  ex pressi o n in ≥1 % t u m or cells or i n str o ma (ie, P D -L 1 p ositi ve m T N B C)
was re q uire d f or st u d y entr y .  PD- L 1  tu m or stat us was deter mi n e d b y  im m u n o hist oc he mical 
a nal ys is of arc hi val t u m or s peci me ns usi n g t he Merc k pr o prietar y  22 C 3 a nti b o d y ( Q ualte k 
assa y).  Pri mar y objecti ves of t his st u d y were t o deter mi ne t he safety,  tolera bilit y , a n d 
a ntit u m or acti vit y of pe m br oliz u ma b i n s u bjects wit h
P D -L 1  positi ve m T N B C. Sec o n dar y 
o bjecti ves i ncl u de d assess me nts of P F S, O S, a n d D O R.  Ad verse e ve nts ( A Es) re p orte d i n 
a n y s u bject recei vi n g at least 1 d ose of st u d y treat me nt were m o nit ore d a n d gra de d usi n g 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts versi o n 4. 0 
(Nati o nal Ca ncer I nstit ute [N CI ] C T C A E v. 4. 0).  T u m or i ma gi n g was o btai ne d e ver y 
8 wee ks a n d e val uate d b y  bot h I n vesti gat or a n d a ce ntral i ma gi n g ve n d or t o assess cli nical 
res p o nses as defi ne d by R E CI S T 1. 1. 
Res ults: A t otal of 3 2 fe male s u bjects wit h a me dia n a ge of 5 0. 5 ye ars (ra n ge 2 9 -7 2 ye ars) 
a n d P D -L 1 p ositi ve m T N B C were e nr olle d i n t he st u d y (t he pre vale nce of P D -L 1 t u m or 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
2 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
p ositi vit y  in m T N B C was 5 8 %, as deter mi ne d b y  the Q ualte k assa y).  Most of t hese s u bjects 
ha d recei ve d a n d pr o gresse d o n m ulti ple li nes of t hera p y for a d va nce d disease ( 4 7 % of 
s u bjects ha d recei ve d ≥3 pri or treat me nts i n t he metastatic setti n g).  Acc or di n g t o data 
t hr o u g h 0 6 - N o v-2 0 1 4, fi ve s u bjects ( 1 5. 6 %) e x perie nce d at least o ne dr u g-relate d S A E; eac h 
of f o ur s u bjects e x perie nce d o ne of t he f oll o wi n g: Gra de 3 a ne mia, hea dac he, ase ptic 
me ni n gitis or p y re xia, a n d a fift h s u bject e x perie nce d Gra de 5 disse mi nate d i ntra vasc ular 
c oa g ulati o n ( DI C) wit h t hr o m b oc yt o pe nia a n d decrease d bl o o d fi bri n o ge n. Of t he 2 7 s u bjects 
wit h ce ntral l y c o nfir me d meas ura ble disease, o ne s u bject ( 3. 7 %) ha d a c o m plete res p o nse 
( C R), 4 s u bjects ( 1 4. 8 %) ha d a c o nfir me d partial res p o nse ( P R), 2 5. 9 % ha d sta ble disease 
( S D), a n d 4 4. 4 % ha d pr o gr essi ve disease ( P D) base d o n R E CI S T 1. 1 as assesse d b y  ce ntral 
i ma gi n g ve n d or . As of 0 6 - N o v-2 0 1 4, t he me dia n d urati o n of res p o nse ha d n ot bee n reac he d 
(ra n ge 1 5 t o 4 0 + wee ks), a n d t hree s u bjects ( 1 C R; 2 P R) were still o n treat me nt after at l east 
1 1 m o nt hs.
C o ncl usi o ns: T his is t he first re p ort of cli nical acti vit y of a n i m m u ne c hec k p oi nt i n hi bit or i n 
T N B C.   The preli mi nar y  res ults fr o m t his st u d y s u g gest t hat si n gle a ge nt M K -3 4 7 5 is a 
well -t olerate d a n d effecti ve treat me nt wit h si g nifica nt thera pe utic acti vit y i n a s u bset of 
hea vil y  pre-treate d s u bjects wit h rec urre nt/ metastatic tri ple -ne gati ve breast ca ncer .
R ati o n ale
4. 2
R ati o n ale f or t he Tri al a n d Selecte d S u bject P o p ul ati o n
4. 2. 1
K N -1 1 9: R ati o n ale f or usi n g pe m br oliz u m a b as 2- 3 L m o n ot her a p y 
f or m T N B C . 
S u bject s wit h T N B C w h ose disease has pr o gresse d o n at least o ne s yste mic treat me nt f or 
m T N B C ha ve a dis mal pr o g n osis wit h a P F S of 2- 3 m o nt hs a n d O S of 9- 1 2 m o nt hs [6 6 - 7 1].  
Nearl y all ha ve bee n pre vi o usl y treate d wit h a nt hrac ycli nes(s) a n d ta xa ne(s ), a n d will recei ve 
si n gle a ge nt c he m ot hera p y as a 2 L + re gi me n [7 2 ].  As t here is n o esta blis he d sta n dar d of care 
( S O C) f or m T N B C, a n y dr u g a p pr o ve d f or t he treat me nt of metastatic breast ca ncer, s uc h as
ca pecita bi ne, eri b uli n, ge mcita bi ne, 
or
vi n orel bi ne,
m a y  be use d .  T o
date, n o 
m T N B C -f oc use d cli nical trial has e val uate d t he efficac y of a n y of t he a b o ve me nti o ne d 
a ge nts; hist orical data c o m es fr o m pre -s pecifie d ( 1 st u d y) a n d, m ore c o m m o nl y, retr os pecti ve 
T N B C s u b gr o u p a nal ys is of ra n d o mize d P hase III st u dies i n metastatic breast ca ncer ( M B C;
all s u bt ypes or e xcl u di n g H E R 2 -p ositi ve disease) (Ta ble 1 ). I n a retr os pecti ve T N B C 
s u b gr o u p a nal ys is of t he ra n d o mize d P hase III RI B B O N -2 trial, w hic h i n vesti gate d t he 
c o m bi nati o n of be vaciz u ma b wit h c he m ot hera p y f or M B C 
[7 3 ], si n gle a ge nt ta xa ne, 
ge mcita bi ne, ca pecita bi ne, or vi n orel bi ne as 2 L  mo n ot hera p y  for m T N B C res ulte d i n a n
O R R of 1 8 %, P F S of 2. 7 m o nt hs, a n d O S
of 1 2. 6 m o nt hs [7 4 ]
I n the P hase III st u d y 
c o m pari n g t he c o m bi nati o n of ca pecita bi ne a n d i xa be pilo ne t o si n gle a ge nt ca pecita bi ne as 
2 L + treat me nt f or M B C, ca pecita bi ne s h o we d a n O R R of 9 %, P F S of 2. 1 m o nt hs, a n d O S of 
9 m o nt hs i n m T N B C, acc or di n g t o a pre -s pecifie d s u b gr o u p a nalys is [7 6 ]. I n t he E M B R A C E 
P hase III o pe n -la bel, ra n d o mize d st u d y co m pari n g eri b uli n t o T P C ( T P C, i ncl u di n g si n gle 
a ge nt ta xa ne, ge mcita bi ne, ca pecita bi ne, a n d vi n orel bi ne a m o n g ot hers ) as 3 L + t hera p y for 
M B C, 
eri b uli n s h o we d a n O R R of 1 2 %, P F S of 3. 7 m o nt hs, a n d O S
of 1 3. 1 m o nt hs 
c o m pare d t o O R R of 5 %, P F S of 2. 1 m o nt hs, a n d O S of 1 0. 6 m o nt hs ( H R 0. 8 1; P = 0. 0 4 1) 
f or T P C i n all s u bjects i n de pe n de nt of breast ca ncer s u bt y pe [ 75] ; h o we ver, efficacies of 
eri b uli n a n d T P C i n m T N B C were n ot re p orte d.  Acc or di n g t o a p o ol e d retr os pecti ve 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
2 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
s u b gr o u p a nal ys is of E M B R A C E a n d st u d y # 3 0 1 (eri b uli n vs ca pecita bi ne as 1- 3 L 
m o n ot hera p y f or M B C), eri b uli n e xte n de d O S c o m pare d t o T P C i n s u bjects recei vi n g 1- 3 L +
treat me nt f or m T N B C, as it s h o we d a O S of 1 2. 4 m o nt hs c o m pare d t o 8. 2 m o nt hs f or T P C
( H R 0. 7 4; P = 0. 0 0 6) [ 9 5]; P F S was als o l o n ger f or eri b uli n ( 2. 8 m o nt hs) c o m pare d t o T P C
( 2. 6 m o nt hs), b ut t he differe nce was s mall a n d n ot cli nicall y si gnifica nt, des pite reac hi n g 
statistical si g nifica nce ( H R 0. 7 8; P = 0. 0 1 8). 
Ta ble 1
Efficac y  of C urre ntl y Use d 2 L + M o n ot hera p y Re gi me ns i n m T N B C
St u d y
Li ne T x
Dr u g/ Dr u g c o m b o
O R R %/ P F S m o/ O S m o
Refere nce
RI B B O N -2 P hase III st u d y -
Retr os pecti ve T N B C 
s u b gr o u p a nal ysis
2 L
Ta xa ne or ca pe cita bi ne
or ge m cita bi ne or 
vi n orel bi ne
1 8/ 2. 7/ 1 2. 6
[7 4 ]
P hase III st u d y -pres pecifie d 
T N B C s u b gr o u p a nal ysis
2 L +
Ca pecita bi ne
9/ 2. 1/ 9
[7 6 ]
E M B R A C E a n d # 3 0 1 P hase 
III st u dies-Retr os pecti ve 
T N B C s u b gr o u p a nal ysis
1- 3 L +
Eri b uli n
N R/ 2. 8/ 1 2. 4
[9 5 ]
T P C (ta xa ne, 
ca pecita bi ne , 
ge m cita bi ne, vi n orel bi ne, 
etc.)
N R/ 2. 6/ 8. 2
Gi ve n
( 1) t he p o or o utc o me of s u bjects wit h a d va nce d m T N B C, ( 2) t he lac k of T N B C-
s pecific sta n dar d of care f or t he treat me nt of m T N B C, ( 3) t he pa ucit y  of p u blis he d res ults 
fr o m P hase III cli nical trials pr os pecti vel y e nr olli n g m T N B C s u bjects, a n d ( 4) t he pr o misi n g 
a ntit u m or a n d safety pr ofile of pe m br oliz u ma b i n hea vil y pretreate d m T N B C 
as 
de m o nstrate d b y  the pr o of - of-c o nce pt K N - 0 1 2 st u d y, w hic h s h o we d a n O R R of 1 8. 5 % a n d 
res p o nse d ura bil it y, p ote ntial use of pe m br oliz u ma b as a 2-3 L  m o n ot hera p y for m T N B C will 
be f urt her i n vesti gate d i n a lar ge ra n d o mize d o pe n -la bel P hase 3 st u d y (K N -1 1 9) c o m pari n g 
si n gle a ge nt pe m br oliz u ma b t o T P C m o n ot hera p y. 
K N -1 1 9: R ati o n ale f or c h oice of a ntic a ncer dr u gs i n t he c o m p ar at or ar m . At prese nt 
t here are n o dr u gs s pecificall y ap pr o ve d or c o nsi dere d S O C f or t he treat me nt of m T N B C. 
I nstea d, dr u gs a p pr o ve d f or metastatic 
breast ca ncer are als o use d f or m T N B C. 
T he 
Treat me nt of P h y sicia n’s C h oice ( T P C) is base d o n c o m m o n usa ge of t hese dr u gs f or 
metastatic breast ca ncer, pri or i ncl usi o n of t hese dr u gs as T P C i n P hase III st u dies f or 
metastatic breast ca ncer, a n d i n p ut fr o m scie ntific lea ders.
T he E M B R A C E st u d y, a pi v otal st u d y lea di n g t o t he a p pr o val of eri b uli n f or metastatic 
breast ca ncer, di d n ot restrict t he n u m ber of dr u gs t hat c o ul d be use d as T P C i n t he 
c o m parat or ar m. H o we ver, o ne of t he criticis ms of t he E M B R A C E st u d y desi g n was t hat 
all o wi n g se veral differe nt c he m ot hera pies, eac h wit h t heir o w n t o xicit y pr ofile, precl u de d 
detaile d c o m paris o ns wit h eri b uli n [ 7 5].  KN- 1 1 9 ai ms t o restrict t he T P C t o f o ur fre q ue ntl y 
use d c he m ot hera pies, na mel y  ca pecita bi ne, eri b uli n, ge mcita bi ne, or vi n orel bi ne, base d o n 
ge o gra p hical, i nstit uti o nal a n d p h y sicia n’s prefere nce in or der t o perf or m a m ore detaile d 
c o m paris o n wit h pe m br oliz u ma b. T he a ntica ncer dr u gs i ncl u de d as T P C will be ha n dle d 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
2 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g c o u ntries. F urt her m ore, if a 
T P C is n ot a p pr o ve d i n a partic ular c o u ntr y, t his partic ular a ge nt ca n n ot be use d a n d selecte d 
via i nteracti ve v oice res p o nse s yste m (I V R S) d uri n g ra n d o mizati o n.
Ca pecita bi ne has a re gistere d i n dicati o n f or t he treat me nt of s u bjects wit h metastatic breast 
ca ncer resista nt t o b ot h paclita xel a n d a n a nt hrac ycli ne-c o ntai ni n g c he m ot hera p y re gi me n or 
resista nt t o paclita xel a n d f or w h o m 
f urt her a nt hrac ycli ne t hera p y is n ot i n dicate d.  
Resista nce is defi ne d as pr o gressi ve disease w hile o n treat me nt, wit h or wit h o ut a n i nitial 
res p o nse, or rela pse wit hi n 6 
m o nt hs of c o m pleti n g treat me nt wit h a n a nt hrac ycli ne -
c o ntai ni n g a dj u va nt re gi me n.
Eri b uli n has a re gistere d i n dicati o n f or usa ge as a si n gle a ge nt i n t he treat me nt of metastatic 
breast ca ncer s u bjects w h o ha ve pre vi o usl y  recei ve d at least o ne (i n E U) or t w o (i n U S) 
c he m ot hera pe utic re gi me ns f or t he treat me nt of metastatic disease.  Pri or t hera py m ust als o 
ha ve i ncl u de d a nt hrac y cli ne a n d a ta xa ne i n eit her t he a dj u va nt or metastatic setti n g.  
Ge mcita bi ne has a re gistere d i n dicati o n i n c o m bi nati o n wit h paclit a xel f or first li ne treat me nt 
of metastatic 
breast ca ncer after fail ure of pri or a nt hrac yli ne-c o ntai ni n g a dj u va nt 
c he m ot hera p y u nless a nt hrac y cli nes were cli nicall y c o ntrai n dicate d. 
Vi n orel bi ne has a re gistere d i n dicati o n i n t he U S f or usa ge as a si n gle age nt or i n 
c o m bi nati o n wit h cis plati n f or first li ne treat me nt of s u bjects wit h u nresecta ble, a d va nce d 
n o n- s mall cell l u n g ca ncer ( N S C LC). Alt h o u g h n ot f or mally a p pr o ve d i n t he U S f or t he 
treat me nt of metastatic breast ca ncer, vi n orel bi ne is i ncl u de d i n t he N C C N breast ca ncer 
treat me nt g ui deli nes a n d is c o m m o nl y use d as 2 L + m o n ot hera p y . I n m ost 
E ur o pea n 
c o u ntries, vi n orel bi ne is a p pr o ve d f or metastatic breast ca ncer treat me nt .
R ati o n ale f or i ncl u di n g s u bjects wit h P D -L 1 ne g ati ve t u m ors. T he K N -0 1 2 T N B C pr o of -
of- c o nce pt data was o btai ne d i n s u bjects wit h P D -L 1  p ositi ve t u m ors (ie, P D -L 1  stai ni n g i n 
≥1 % t u m or cells or i n str o ma); n o data is c urre ntl y a vaila ble o n t he perf or ma nce of 
pe m br oliz u ma b i n T N B C s u bjects wit h P D -L 1  ne gati ve t u m ors (ie P D -L 1 stai ni ng i n < 1 % 
t u m or cells a n d n o str o mal stai ni n g).  Due t o t he li mite d efficac y of treat me nt o pti o ns
c urre ntl y a vaila ble i n later ( 2 L +) li ne T N B C, s u bjects wit h P D -L 1  ne gati ve t u m ors ma y  
be nefit fr o m pe m br oliz u ma b.  
K N - 0 8 6: T he perf or ma nce of pe m br oliz u ma b i n s u bjects wit h P D -L 1  ne gati ve t u m ors will 
first be e x pl ore d i n K N - 0 8 6, a t w o-part, n o n-ra n d o mize d, m ulti -site, o pe n -la bel trial of 
pe m br oliz u ma b m o n ot hera p y i n s u bjects wit h m T N B C .  
I n Part 1 , s u bjects will be e nr olle d i n 2 c o h orts, C o h ort A (2 L + m o n ot hera p y f or m T N B C 
i n de pe n de nt of P D -L 1 stat us, ~ 1 6 0 s u bjects) a n d C o h ort B
(1 L m o n ot hera p y  for P D -L 1  
p ositi ve
m T N B C, 
~ 4 0 s u bjects) t o e xa mi ne t he efficac y an d safet y of si n gle a ge nt 
pe m br oliz u ma b i n t he treat me nt of m T N B C.  T he relati o ns hi p bet wee n res p o nse t o treat me nt 
a n d P D- L 1 pr otei n e x pressi o n i n m T N B C will be e x pl ore d i n C o h ort A.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
2 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T w o i nteri m efficac y a nal yses (I A 1 a n d 2) will be perf or me d o n C o h ort A. 
I A 1: Su bjects i n C o h ort A will i nitiall y be e nr olle d i n de pe n de nt of P D -L 1 t u m or stat us.  A 
f utilit y anal y sis (I A 1) will be d o ne o n t he P D -L 1 ne gati ve s u b p o p ulati o n of C o h ort A t o 
e val uate res p o nse i n t his gr o u p.   If treat me nt wit h pe m br oliz u ma b is f o u n d t o be f utile i n 
s u bjects wit h P D -L 1  ne gati ve t u m ors, t he n f urt her e nr oll me nt i n C o h ort A will be li mite d t o 
s u bjects wit h P D-L 1  p ositi ve t u m ors, i ncl u di n g P D-L 1 str o n g p ositi ve t u m ors. 
I A 2 will be d o ne i n C o h ort A t o l o o k at res p o nses i n s u bjects wit h P D -L 1 str o n g p ositi ve
t u m ors.  In t his s u b p o p ulati o n, at least 1 0 s u bjects wit h P D -L 1  str o n g p ositi ve t u m ors nee d t o 
be e nr olle d f or res p o nse assess me nt a n d at least o ne res p o n der is re q uire d t o i nitiate Part 2, 
w hic h will o pe n after e nr oll me nt i n C o h ort A is c o m plete d.  
Part 2 will e xa mi ne w het her hi g her t u m or P D -L 1 e x pressi o n, as deter mi ne d b y  a pr ot ot yp e 
i m m u n o hist oc he mistr y (I H C) assa y, is ass ociate d wit h i ncrease d pr o ba bilit y  of res p o nse t o 
pe m br oliz u ma b i n m T N B C, as it has bee n s h o w n t o be i n ot her t u m or t ypes , s uch a s 
a d va nced N S C L C [ 1 0 3 ].
K N - 1 1 9: R ati o n ale f or I ncl u di n g S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1). T he 
P D -L 1  IH C assa y ( Da k o assa y), w hic h will be use d i n K N -1 1 9, is bei n g de vel o pe d as a 
c o m pa ni o n dia g n ostic a n d will be a vaila ble pri or t o i nitiati o n of K N -1 1 9.  In K N -0 1 2, 
P D -L 1 -p ositi vit y  was defi ne d as ≥1 % t u m or cell stai ni n g or str o mal stai ni n g, a n d was 
deter mi ne d b y  a PD- L 1 pr ot ot y pe I H C assa y ( Q ualte k assa y) t hat is differe nt t ha n t he assa y 
pla n ne d f or K N - 1 1 9 ( Da k o assa y).  The defi niti o n of P D -L 1  positi v it y i n K N -1 1 9 will b e 
ge nerall y e q ui vale nt t o t he defi niti o n use d i n K N - 0 1 2; h o we ver, t he act ual perce nt of 
mi ni m u m p ositi ve stai ni n g re q uire d m a y  be differe nt i n t he ne w assa y. It is als o p ossi ble t hat 
t he pre vale nce of P D -L 1  tu m or p ositi vit y  is differe nt bet wee n t he t w o assa ys, i n w hic h case 
t he sa m ple size a n d statistical c o nsi derati o ns ma y nee d t o be a dj uste d acc or di n gly.
K N - 1 1 9: R ati o n ale f or I ncl u di n g S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 ).
E val uati o n of O S efficac y b y differe nt C P S c ut offs fr o m ot her i n dicati o ns of pe m br oliz u ma b 
m o n ot hera p y i n t he 2 L + setti n g (ie, hea d a n d nec k s q ua m o us cell carci n o ma [H N S C C ], 
gastric ca ncer, a n d b la d der ca ncer), de m o nstrate a n e nric he d treat me nt effect wit h i ncreasi n g 
P D -L 1  ex pressi o n le vel. Base d o n t hese fi n di n g, a n d t o im pr o v e t he usa ge of bi o mar kers t o 
e n ha nce t he o verall be nefit :ris k pr ofile of pe m br oliz u ma b, C P S ≥1 0 b y  the Da k o assa y is 
i ncl u de d i n or der t o i de ntif y a n e nric he d s u b p o p ulati o n of patie nts wit h m T N B C w h o c o ul d 
p ote ntiall y  be nefit m ore fr o m pe m br oliz u ma b m o n ot hera p y .
K N -1 1 9: R ati o n ale f or re q uiri n g ce ntr al c o nfir m ati o n of T N B C st at us. Se veral st u dies 
ha ve re p orte d disc or da nce i n e val uati o n of E R, pr o gester o ne rece pt or, a n d H E R 2 stat us 
bet wee n l ocal a n d ce ntral la b orat ories, d ue t o b ot h tec h nical iss ues i n I HC testi n g a n d 
i nter pretati o n iss ues i n FI S H testin g [ 7 7- 7 9]. It is, t h us, rec o m me n de d t hat ce ntral testi n g 
s h o ul d be perf or me d t o deter mi ne trial eli gi bilit y, partic ularl y i n lar ge st u dies i n v ol vi n g 
m ulti ple c olla b orati n g i nstit uti o ns i n se veral c o u ntries [7 7].
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
K N -1 1 9: R ati o n ale f or selecti o n of str atific ati o n f act ors. Gi ve n t hat t he pri mar y  o bjecti ves 
of K N -1 1 9 are O S i n s u bjects wit h P D -L 1  positi ve m T N B C a n d i n all s u bjects, stratificati o n 
f or P D -L 1 t u m or stat us ( p ositi ve [ C P S ≥1] vs . ne gati ve [ C P S < 1] ) will be a p plie d t o e ns ure 
e q ual distri b uti o n of s u bjects wit h P D -L 1  positi ve t u m ors a n d ne gati ve t u m ors bet wee n t he 
t w o st u d y ar ms.
Gi ve n t hat s u bjects w h o are dia g n ose d wit h metastatic disease at t he ti me of i nitial breas t 
ca ncer dia g n osis ge nerall y  ha ve m ore a g gressi ve, a n d p oss i bl y of differe nt bi ol o g y , disease 
t ha n s u bjects w h o i nitiall y prese nt wit h earl y or l ocall y ad va nce d T N B C, stratificati o n f or 
pri or ( ne o)a dj u va nt t hera p y  vs de n ov o metastatic disease at i nitial dia g n osis will be a p plie d.
R ati o n ale f or D ose Selecti o n/ Re gi me n / M o dific ati o n
4. 2. 2
T he pla n ne d d ose of pe m br oliz u ma b f or t his trial is 2 0 0 m g e ver y 3 wee ks ( Q 3 W). Base d o n 
t he t otalit y of data ge nerate d i n t he K e y tr 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 pro priate d ose of pe m br oliz u ma b acr oss all i n dicati o ns a n d re gar dless of t u m or t ype. As 
o utli ne d bel o w, t his d ose is j ustifie d b y : 
•
Cli nical 
data fr o m ei g ht 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 e ver y t w o wee ks 
( 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 har mac o ki netic [ P K] data) a n d t u m or (i nferre d fr o m p h y si ol o gically 
base d p har mac o ki netic (P B P K ) a nal ys is) 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, 2 2 6 2 s u bjects were e nr olle d wit h 
mela n o ma a n d n o n -s mall cell l u n g ca ncer ( N S C LC), 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 py 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 vs. 1 0 m g/ k g Q 3 W ( K N 0 0 1 B 2, K N 0 0 1 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 vs. 1 0 m g/ k g Q 2 W ( K N 0 0 1 B 3, K N 0 0 1 F 2 a n d K N 0 0 6). 
All 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 di ffere 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 ypes i ncl u di n g hea d a n d nec k ca ncer, bla d der c a 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 m or 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 sh o w tar get sat urati o n at 2 0 0 m g  Q3 W. First, P K 
data 
i n K N 0 0 1 
e val uati n g 
tar get-me diate d 
dr u g 
dis p ositi o n 
( 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 u lati o n at d oses m uc h l o wer t ha n 2 0 0 m g  
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Q 3 W. Sec o n dl y , a P B P K a nal ys is 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 s at urati o n i n b ot h bl o o d a n d t u m or.
Fi nall y , p o p ulati o n P K a nal ys is 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 s u bject 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 w e i 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  Q3 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  these 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 an d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g  Q3 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.
R ati o n ale f or E n d p oi nts
4. 2. 3
4. 2. 3. 1
Effic ac y E n d p oi nt s
Pri m ar y:
O S
was
selecte d as t he pri mar y  en d p oi nt f or K N -1 1 9 , beca use O S
has bee n 
rec o g nize d as t he g ol d sta n dar d f or de m o nstrati o n of s u peri orit y of a ne w a nti ne o plastic 
t hera py i n a ra n d o mize d P hase III trial .
Sec o n d ar y :  P F S, O R R, d urati o n of res p o nse (D O R ) a n d D C R base d o n R E CI S T 1. 1 are 
c o m m o nl y use d efficac y e n d p oi nts i n P hase III cli nical trials. T o mi ni mize bias i n ce ntral 
res p o nse assess me nts, i ma gi n g sca ns will be assesse d b y  bli n de d ce ntral i ma gi n g ve n d or . I n 
a d diti o n, ra di ol o gic pr o gressi o n b y  RE CI S T 1. 1 will be base d o n t he ce ntral assess me nt of 
pr o gressi o n, rat her t ha n site assess me nt. 
E x pl or at or y : ir R E CIS T is a n a da ptati o n of R E CI S T 1. 1 t o acc o u nt f or t he u ni q ue t u m or 
res p o nse c haracteristics
t o treat me nt wit h 
ne w i m m u n ot hera pe utic
a ge nts, i ncl u di n g 
pe m br oliz u ma b .
R E CI S T 1. 1 was de vel o pe d base d o n treat me nt wit h c yt ot o xic a ge nts. 
I m mu n ot hera pe utic dr u gs , s uc h as pe m br oliz u ma b,
m a y  pr o d uce a ntit u m or effects b y  
p ote ntiati n g e n d o ge n o us ca ncer -s pecific i m m u ne res p o nses.  T he res p o nse patter ns see n wit h 
s uc h a n a p pr oac h ma y e xte n d be y o n d t he t ypical ti me c o urse of res p o nses see n wit h 
c yt oto xic a ge nts, a n d ca n ma nifest as cli nical res p o nse s after i nitial i ncrease s i n t u m or b ur de n 
or e ve n t he a p peara nce of ne w lesi o ns.  Sta n dar d R E CI S T 1. 1 ma y , t h us, n ot pr o vi de a n 
acc urate assess me nt of res p o nse t o i m m u n ot hera pe utic a ge nts , s uc h as pe m br oliz u ma b, a n d 
will t heref ore be use d wit h t he a da ptati o ns descri be d i n Secti o n 7. 1. 2. 7 a n d referre d t o as 
ir R E CIS T .
4. 2. 3. 2
Selecti o n of P atie nt R e p orte d O utc o mes Instr u me nts
E O R T C Q L Q- C 3 0 was de vel o pe d t o assess t he q ualit y  of life of ca ncer s u bjects. It has bee n
tra nslate d a n d vali date d i nt o 8 1 la n g ua ges a n d use d i n m ore t ha n 3, 0 0 0 st u dies w orl d wi de. It
c o ntai ns 5 f u ncti o ni n g scales ( p hys ical, r ole, c o g niti ve, e m oti o nal, a n d s ocial), 3 s ym pt o m
scales (fati g ue, na usea, pai n) a n d a d diti o nal si n gle s ym pt o m ite ms. It is sc ore d o n a 4 p oi nt
scale ( 1 = n ot at all, 2 =a little, 3 = q uite a bit, 4 = ver y m uc h). T he E O R T C Q L Q -C 3 0 i nstr u me nt 
als o c o ntai ns 2 gl o bal scales t hat use 7 p oi nt scale sc ori n g wit h a nc h ors ( 1 = ver y p o or a n d 
7 =e xcelle nt).
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
3 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
E O R T C Q L Q- B R 2 3 is a q ualit y  of life q uesti o n naire de vel o pe d t o assess t he e xte nt of 
s ym pt o ms or pr o ble ms i n s u bjects recei vi n g treat me nt f or breast ca ncer.  The t o ol is use d i n 
c o nj u ncti o n wit h t he E O R T C Q L Q -C 3 0 a n d f oll o ws t he sa me 4- p oi nt scale descri be d a b o ve.  
T u m or l ocati o n, treat me nt, a n d q ualit y  of life di me nsi o ns are disease -s pecific as pects 
i nc or p orate d i nt o q uesti o n desi g n.  The t o ol c o nsists of 2 3 q uesti o ns a n d is di vi de d i nt o t w o 
secti o ns; o ne secti o n w it h a recall peri o d of o ne wee k a n d o ne secti o n wit h a recall peri o d of 
f o ur weeks.  
T he E ur o Q ol -5 D ( E Q-5 D) 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. T he E Q -5 D -3 L will be use d t o calc ulate utilit y  val ues t o i nc or p orate i nt o Q T W i S T 
a n d healt h ec o n o mic m o dels.  T he fi ve healt h state di me nsi o ns i n t his i nstr u me nt 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 3- p oi nt scale fr o m 1 (e xtre me pr o ble m) t o 3 ( n o pr o ble m). T he 
e E Q-5 D will 
al wa ys be c o m plete d b y  su bjects first bef ore
co m pleti n g t he e E O R T C 
Q L Q -C 3 0 a n d e E O R T C Q L Q -B R 2 3.
4. 2. 3. 3
S afet y E n d p oi nts
C o m m o nl y  use d safety para meters f or e val uati n g i n vesti gati o nal s yste mic a nti-ca ncer 
treat me nts are i ncl u de d as safet y en d p oi nts f or t he st u d y  i ncl u di n g rate of A E/ S A Es a n d fatal 
S A Es, ca usalit y a n d o utc o me of A E/ S A Es, rate of treat me nt disc o nti n uati o ns a n d reas o ns, 
c ha n ges i n vital si g ns, la b orat or y val ues etc. Gra di n g of A E/ S A Es will be base d o n N CI
C T C A E , Versi o n 4. 0.
4. 2. 3. 4
Pl a n ne d E x pl or at or y Bi o m ar ker Rese arc h
Ne wl y o btai ne d
c ore or e xcisi o nal bi o psies o btai ne d fr o m metastatic, 
n ot pre vi o usl y 
irra diate d, lesi o ns will be use d f or P D -L 1  assess me nt b y  IH C.  Arc hi val t u m or bi o psies will 
als o be o btai ne d, w he n a vaila ble, t o c o m pare t he perf or ma nce of t he P D -L 1 I H C assa y in 
arc hi ve d vers us ne wl y o btai ne d t u m or tiss ues.
A d diti o nal bi o mar ker a n d ot her bi o me dical researc h t o i de ntif y fact ors i m p orta nt f or 
pre dicti n g res p o nsi ve ness or resista nce t o pe m br oliz u ma b t hera p y in m T N B C will als o be 
p urs ue d.  Pre-treat me nt, o n treat me nt, a n d at t he ti me of disease pr o gressi o n t u m or bi o psies 
a n d bl o o d sa m ples (i ncl u di n g ser u m a n d plas ma) will be c ollecte d as descri be d i n Secti o n
6. 0. T u m or a n d bl o o d s peci me ns ma y
be e val uate d b y  hist o pat h ol o gic, tra nscri pti o nal,
ge n o mic [i ncl u di n g tar gete d ne xt ge nerati o n se q ue nci n g ( N G S), w h ole e x o me se q ue nci n g 
( W E S) a n d w h ole ge n o me se q ue nci n g ( W G S)] a n d pr ote o mic a nal ys es, as descri be d bel o w. 
P orti o ns of t u m or a n d bl o o d s peci me ns will be st ore d f or f ut ure a nal ys es.
Assa y s m a y i ncl u de, b ut are n ot be li mite d, t o:
I m m u n o hist oc he mistr y
I n a d diti o n t o deter mi ni n g P D -L 1 e x pressi o n i n t u m or tiss ues b y  IH C as descri be d earlier, 
ot her e x pl orat or y bi o mar kers (e g P D - 1 e x pressi o n, mar kers of T cell p he n ot y pe) ma y  als o be 
e val uate d.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
3 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Tiss ue I nfiltr ati n g L y m p h oc ytes 
Tiss ue i nfiltrati n g l ym p h oc y tes ha ve bee n s h o w n t o pr o vi de pr o g n ostic a n d p ote ntiall y 
pre dicti ve val ue, partic ularl y  in T N B C [6 4, 8 0- 8 2] a n d H E R 2- o vere x pressi n g breast ca ncer 
[ 8 1, 8 3, 8 4]. He mat o x yl i n a n d e osi n ( H & E)-stai ne d breast t u m or secti o ns ca n be e va l uate d 
f or TI Ls, acc or di n g t o a rece ntly p u blis he d sta n dar dize d met h o d ol o g y [ 3].
Tr a nscri pti o n al A n al yses
Messe n ger R N A ( m R N A) e x pressi o n pr ofili n g i n t u m or s peci me ns a n d peri p heral bl o o d will 
be c o m plete d t o assess e x pressi o n eit her b y  RN Ase q or mi d -de ns it y R N A platf or m of 
a p pr o xi matel y 70 0 ge nes a n d atte m pt t o defi ne a ge ne set critical f or cli nical res p o nse t o 
pe m br oliz u ma b.   T he h y p ot hesis t o be teste d is t hat pe m br oliz u ma b i n d uces res p o nses i n 
t u m ors t hat reflect a n i nfla m mat or y/i m m u ne cell-ric h p he n o t ype base d o n ge ne e x pressi o n 
si g nat ures ca pt uri n g P D -L 1 a n d I F N-γ tra nscri pti o nal pr o gra ms.  Gl o bal pr ofili n g m a y
als o 
be p urs ue d.  Ex pressi o n of i n di vi d ual ge nes relate d t o t he i m m u ne s yste m ma y  als o b e 
e val uate d, s uc h as i m m u ne si g nat ures a n d critical c yt o ki nes (e g, I L-1 0).  
Micr o R N A 
pr ofili n g ma y  als o be p urs ue d i n ser u m sa m ples.
Ge n o mic A n al yses
T he a p plicati o n of ne w tec h n ol o gies s uc h as N G S, W E S, 
a n d W G S 
has pr o vi de d t he 
o p p ort u nit y  to defi ne certai n t u m or t ypes at t he ge netic le vel as bei n g ‘ hy per m utate d’ a n d t o 
detect t he prese nce of s pecific T cell cl o nes wit hi n t he t u m or micr oe n vir o n me nt or i n t he 
peri p heral bl o o d [ 8 5- 8 7].  It is p ossi ble t hat t he h y per m utate d state (a n d/ or i ncrease d T cell 
cl o nalit y) or t he h y p o m utate d state (a n d/ or lac k of d o mi na nt T cell cl o nes) m a y  correlate 
wit h res p o nse t o pe m br oliz u ma b i n T N B C.  
I n ad diti o n, u n dersta n di n g s o matic a n d ger mli ne ge netic deter mi na nts of dr u g res p o nse is a n 
i m p orta nt e n dea v or d uri n g me dical researc h.  Tar gete d N G S m a y
b e use d t o e val uate
w het her s o matic ge netic variati o ns, ie, i n t u m ors, circ ulati n g t u m or cells ( C T Cs) a n d 
circ ulati n g t u m or D N A [ 8 8], a n d/ or ger mli ne D N A m utati o ns c orrelate wit h res p onse t o 
pe m br oliz u ma b i n m T N B C. Partic ular e m p hasis will be place d o n t he f oll o wi n g bi ol o gic al 
deter mi na nts/ pat h wa y s: B R C A 1/ 2, PI 3 K, P T E N, E G F R, M E K, 
F G F R, M E T, 
a n d N otc h 
si g nali n g [ 8 9- 9 2].  Micr osatellite 
i nsta bilit y 
ma y als o be e val uate d.
A
h o m ol o g o us 
rec o m bi nati o n defect (H R D ) assa y m a y be use d i n t his st u d y.  If ge netic variati o n is f o u n d t o 
pre dict efficac y or a d verse e ve nts, t his data mi g ht i nf or m o pti mal use of pe m br oliz u ma b i n 
f ut ure st u dies e nr olli n g s u bjects wit h T N B C.
Pr ote o mic A n al yses
I n a d diti o n t o e x pressi o n o n t he t u m or tiss ue, P D -L 1  ca n be s he d fr o m t u m or a n d release d
i nt o t he bl o o d [ 9 3].  E nz y me-li n ke d i m m u n oassa y ca n meas ure P D -L 1 i n ser u m a n d c orrelate 
t his e x pressi o n wit h res p o nse t o pe m br oliz u ma b t hera py a n d P D -L 1 pr otei n i n t he t u m or.  
Bl o o d w o ul d be a less i n vasi ve c o m p o ne nt fr o m w hic h t o meas ure P D-L 1  pr otei n bi o mar ker.  
I n a d diti o n t o t his s pecific pr otei n bi o mar ker, b ot h tiss ue a n d bl o o d deri vati ves ca n be 
s u bjecte d t o pr ote o mic pr ofili n g st u dies usi n g a variet y of platf or ms t hat c o ul d i ncl ude, b ut 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
are n ot li mite d t o, i m m u n oassa y, li q ui d c hr o mat o gra p h y a n d/ or mass s pectr o metr y.  This 
a p pr oac h c o ul d i de ntif y n o vel pr otei n bi o mar ker(s) t hat c o ul d ai d i n s u bject selecti o n f or 
pe m br oliz u ma b t hera p y i n T N B C.
Pl a n ne d Ge netic A n al ysis
U n dersta n di n g ge netic deter mi na nts of dr u g res p o nse is a n i m p orta nt e n dea v or d uri n g
me dical researc h.  T his researc h will e val uate w het her ge netic variati o n wit hi n a cli nical trial 
p o p ulati o n c orrelates wit h res p o nse t o t he treat me nt(s) u n der e val uati o n.  If ge netic variati o n 
is f o u n d t o pre dict efficac y or a d verse e ve nts, t he data mi g ht
i nf or m o pti mal use of t hera pies 
i n t he s u bject p o p ulati o n. T his researc h c o ntri b utes t o u n dersta n di n g ge netic deter mi na nts of 
efficac y a n d safety ass ociate d wit h t he treat me nts i n t his st u d y. 
4. 2. 3. 5
F ut ure Bi o me dic al Rese arc h
T he S p o ns or will c o n d uct F ut ure Bi o me dical Researc h o n s peci me ns c ollecte d f or f ut ure 
bi o me dical researc h d uri n g t his cli nical trial.  This researc h m a y  incl u de ge netic a nal ys es 
( D N A), ge ne e x pressi o n pr ofili n g ( R N A), pr ote o mics, meta b ol o mics (ser u m, plas ma) a n d/ or 
t he meas ure me nt of ot h er a nal yt es .
S uc h researc h is f or bi o mar ker testi n g t o a d dress e mer ge nt q uesti o ns n ot descri be d else w here 
i n t he pr ot oc ol (as part of t he mai n trial) a n d will o nl y  be c o n d ucte d o n s peci me ns fr o m 
a p pr o priatel y c o nse nte d s u bjects. T he 
o bjecti ve of c ollecti n g
s peci me ns f or F ut ure 
Bi o me dical Researc h is t o e x pl ore a n d i de ntif y bi o mar kers t hat i nf or m t he scie ntific 
u n dersta n di n g of diseases a n d/ or t heir t hera pe utic treat me nts. F or i nsta nce, e x pl orat or y 
p har mac o ge netic 
( P Gt) 
st u dies 
ma y 
be 
perf or me d 
if 
si g nifica n t 
P har mac o ki netic/ P har mac o d y na mic ( P K/ P D) relati o ns hi ps are o bser ve d or a d verse e ve nts 
are i de ntifie d.  Ge n o mic mar kers of disease ma y als o be i n vesti gate d.  Suc h retr os pecti ve 
p har mac o ge netic st u dies will be c o n d ucte d wit h a p pr o priate bi ostatistical desi g n a n d a nal y sis 
a n d c o m pare d t o P K/ P D res ults or cli nical o utc o mes. A n y  si g nifica nt P Gt relati o ns hi ps t o 
o utc o me w o ul d re q uire vali dati o n i n f ut ure cli nical trials. T he o verarc hi n g g oal is t o use s uc h 
i nf or mati o n t o de vel o p safer, m ore effecti ve dr u gs / vaccines , a n d/ or t o e ns ure t hat s u bjects 
recei ve t he c orrect d ose of t he c orrect dr u g / vacci ne at t he c orrect ti me.  The details of t his 
F ut ure Bi o me dical Researc h s u b-trial are prese nte d i n Secti o n 1 2. 2 - C ollecti o n a n d 
Ma na ge me nt 
of S peci me ns f or F ut ure Bi o me d ical Researc h.  Ad diti o nal i nf or mati o nal 
material f or i nstit uti o nal re vie w b oar ds/et hics c o m mittees (IR Bs/ E R Cs) a n d i n vesti gati o nal 
site staff is pr o vi de d i n Secti o n 1 2. 3.
Be nefit/ Ris k
4. 3
S u bjects i n cli nical trials ge nerall y  ca n n ot e x pect t o recei ve direct b e nefit fr o m treat me nt 
d uri n g partici pati o n, as cli nical trials 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.
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or s u bjects partici pati n g i n t his 
cli nical trial ma y  be f o u n d i n t he acc o m pa n yi n g I nvesti gat ors Br oc h ure (I B) a n d I nf or me d 
C o nse nt d oc u me nts.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A d diti o nal p ote ntial be nefit s are a d dresse d i n S ecti o n 4. 1. 5 , w hic h details res p o nses t o 
pe m br oliz u ma b i n t he T N B C c o h ort of t he m ulti -c o h ort P hase I b st u d y, K N- 0 1 2, w hic h 
e nr olle d s u bjects wit h 
P D -L 1 -p ositi ve (i n ≥1 % of t u m or cells or i n str o ma, b y  
i m m u n o hist oc he mistr y) t u m ors. Si milar t o pe m br oliz u ma b st u dies i n ot her t u m or t ypes, t he 
m ost 
c o m m o n a d verse e ve nts i ncl u de d fati g ue ( 1 7. 9 %), decrease d a p petite ( 1 2. 8 %), 
h y p ot h y r oi dis m ( 1 2. 8 %), a n d art hral gia ( 1 0. 3 %). 
T he safet y an d efficac y data will be s u b mitte d t o a n e xter nal Data M o nit ori n g C o m mittee 
(D M C ) f or re vie w.
5. 0 M E T H O D O L O G Y
E ntr y Criteri a
5. 1
Di a g n osis/ C o n diti o n f or E ntr y i nt o t he Tri al
5. 1. 1
Fe male
a n d male
s u bjects wit h 
Sta ge 
I V/ M 1 m T N B C
w h o 
f ulfill t he f oll o wi n g 
i ncl usi o n/e xcl usi o n criteria will be e nr olle d i n t his trial.
S u bject I n cl usi o n Criteri a
5. 1. 2
I n or der t o be eli gi ble f or partici pati o n i n t his trial, t he s u bject m ust:
1.
Ha ve si g ne d i nf or me d c o nse nt .
2.
Be 1 8 y ears of a ge o n da y  of si g ni n g i nf or me d c o nse nt.
3.
Ha ve recei ve d eit her o ne or t w o pri or s yste mic treat me nts f or metastatic breast ca nce r 
a n d ha ve d oc u me nte d disease pr o gressi o n o n or after t heir m ost rece nt t hera p y .  
4.
Ha ve bee n pre vi o usl y treate d wit h a n a nt hrac ycli ne a n d / or ta xa ne i n t he ( ne o)a dj u va nt or 
metastatic setti n g. 
5.
Ha v e ce ntr al l y c o nfir m e d m T N B C
(deter mi n e d b y
a n e w l y o btai n e d c o r e or 
ex ci si o nal bi o ps y fr o m a metasta tic, n ot pre vi o us ly irra diated, t u mor lesi o n).
6.
Ha ve meas ura ble disease base d o n R E CI S T 1. 1 as assesse d b y  site I n vesti gat or a n d l ocal 
ra di ol o g y re vie w.
7.
Ha ve pr o vi de d a ne wl y  obtai ne d c ore or e xcisi o nal bi o ps y  fr o m a metastatic, n ot 
pre vi o usl y  irra diate d, t u m or lesi o n f or ce ntral deter mi nati o n of tri ple-ne gati ve breast 
ca ncer stat us a n d P D -L 1  bi o mar ker a nal ys is. A de q uac y  of t he bi o ps y s peci me n f or t he 
a b o ve a nal ys es m ust be c o nfir me d b y  the ce ntral la b orat or y. Re peat sa m ples m a y  be 
re q uire d if a de q uate t u m or tiss ue is n ot pr o vi de d. N ote:  S u bjects f or w h o m fres h t u m or 
bi o psies ca n n ot be o btai ne d ( e g i naccessi ble t u m or site or c o ncer n f or s u bject safety) ma y 
s u b mit a n arc hi ve d t u m or s peci me n o nly u p o n a gree me nt fr o m t he S p o ns or .
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
3 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8.
Ha ve a n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1 
assesse d wit hi n 1 0 da y s pri or of treat me nt i nitiati o n.
9.
De m o nstrate a de q uate or ga n f u ncti o n as defi ne d i n Ta ble 2 .
Ta ble 2
A de q uate Or ga n F u ncti o n L a b orat or y Val ues
S yste m
L a b or at or y V al ue
H e m at ol o gic al
A bs ol ute ne utr o p hil c o u nt ( A N C)
≥1, 5 0 0/ mc L
Platelets
≥1 0 0, 0 0 0/ mc L
H e m o gl o bi n
≥9 g/ d L or ≥5. 6 m m ol/ L wit h o ut q ualificati o ns
b
Re n al
Creati ni ne 
C alc ulate d creati ni ne cleara nce ( Cr Cl)a
(Gl o mer ular filtrati o n rate [G F R ] ca n als o be use d 
i n place of creati ni ne or Cr Cl)
≤1. 5 x u p per li mit of n or mal ( U L )N O R
≥3 0 m L/ mi n f or s u bject wit h creati ni ne le vels > 1. 5 x 
i nstit uti o nal U L N
He p atic
Ser u m t otal bilir u bi n
≤1. 5 x U L N O R Direct bilir u bi n ≤U L N f or s u bjects 
wit h t otal bilir u bi n le vels > 1. 5 x U L N
A S T 
(ser u m gl uta mic o xal oacetic tra nsa mi nase
[S G O T ]) a n d 
A L T  (ser u m gl uta mic 
p yr u vic 
tra nsa mi nase [S G P T ])
≤2. 5 x U L N  O R ≤5 X U L N f or s u bjects w it h acti ve 
li ver metastases
Al kali ne P h os p hatase
If > 2. 5x U L N, t he n li ver fracti o n s h o ul d be ≤2. 5 x U L N 
Al b u mi n
≥3. 0 g/ d L
Lactate De h y dr o ge nase ( L D H)
< 2. 5 x U L N
C o a g ul ati o n
I nter nati o nal N or malize d Rati o (I N R) or 
Pr ot hr o m bi n Ti me ( P T)
Acti vate d Partial T hr o m b o plasti n Ti me (a P T T)
≤1. 5 x U L N u nless s u bject is recei vi n g a ntic oa g ula nt 
t hera p y as l o n g as P T or aP 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
≤1. 5 x U L N u nless s u bject is recei vi n g a ntic oa g ula nt 
t hera p y as l o n g as P T or aP T T is wi t hi n t hera pe utic 
ra n ge of i nte n de d use of a ntic oa g ula nts
a
Creati ni ne cleara nce s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.
b
Criteria m ust be met wit h o ut e r yt hr o p oieti n de pe n de nc y a n d wit h o ut pac ke d re d bl o o d cell ( p R B C) 
tra nsf usi o n wit hi n last 4 we e ks.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
1 0.
Fe male s u bjects of c hil d beari n g p ote ntial s h o ul d ha ve a ne gati ve uri ne or ser u m 
pre g na nc y  test wit hi n 7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y me dicati o n a n d 
a gree t o use effecti ve c o ntrace pti o n, as defi ne d i n Secti o n
5. 7. 2 . If t he uri ne test is 
p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y  test will be re q ui re d.
Male 
s u bjects s h o ul d a gree t o use a n a de q uate met h o d of c o ntrace pti o n starti n g at 
ra n d o mizati o n t hr o u g h at least 1 2 0 d a y s after t he last d ose of pe m br oliz u ma b or T P C, 
acc or di n g t o l ocal sta n dar d of care.
N ote: A bsti ne nce is acce pta ble if t his is t he us ual lifest yle a n d preferre d c o ntrace pti o n 
f or t he s u bject.
S u bject E xcl usi o n Criteri a
5. 1. 3
T he s u bject m ust be e xcl u de d fr o m partici pati n g i n t he trial if t he s u bject :
1.
Has 
partici pate d or is c urre ntl y partici pati n g i n a st u d y of a n i n vesti gati o nal 
a ge nt/ de vice a n d has recei ve d/is recei vi n g t he i n vesti gati o nal a ge nt/ de vice wit hi n 
4 
wee ks of ra n d o mizati o n.
N ote: A su bject w h o ha s e ntere d t he 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 4 wee ks h a ve ela pse d si nce t he last d ose of t he i n vesti gati o nal 
a ge nt a n d/ or re m o val of t he de vice .
2.
Has ha d m o n ocl o nal a nti b o d y (m A b) f or direct a nti -ne o plastic treat me nt w it hi n 4 wee ks 
of ra n d o mi zati o n .  
3.
Has ha d c he m ot hera p y,  tar gete d s mall m olec ule t hera py, or ra diati o n t hera p y wit hi n at 
least 2 wee ks of ra n d o mizati o n.
4.
Has n ot rec o vere d fr o m a d verse e ve nts (ie, d o w n gra de d t o ≤ Gra de 1 or t o baseli ne) d ue 
t o a pre vi o usl y a d mi nistere d t hera p y.
N ote:  Su bjects wit h ≤ Gra de 2 ne ur o pat h y  or al o pecia of a n y gra de are a n e xce pti o n
t o t his criteri o n a n d ma y q ualif y f or t he st u d y.
N ote:
If s u bject recei ve d maj or s ur ger y, t he y must ha ve rec o vere d a de q uatel y fr o m
t he t o xicit y a n d/ or c o m plicati o ns fr o m t he s ur ger y pri or t o ra n d o mizati o n.
5.
Has a n a cti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n t he past 2 y ears 
(ie wit h use of disease m o dif y i n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve dr u gs). 
N ot e: Re place me nt t hera p y (e g, t h yr o xi ne, i ns uli n, or p h y si ol o gic c ortic oster oi d 
re place me nt t hera py f or a dre nal or pit uitar y  ins ufficie nc y , etc.) is n ot c o nsi dere d a 
f or m of sys te mic treat me nt. 
6.
Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g s yste mic st er oi d t hera p y 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 of ra n d o mizati o n.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
3 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7.
Has a k n o w n a d diti o nal mali g na nc y  t hat pr o gress e d or re q uired acti ve treat me nt wit hi n 
t he last 5 ye ars. E xce pti o ns i ncl u de basal cell carci n o ma of t he s ki n, s q ua m ous cell 
carci n o ma of t he s ki n t hat has u n der g o ne p ote ntiall y  curati ve t hera p y , a n d i n sit u cer vical 
ca ncer.
8.
Has k n o w n acti ve brai n metastases a n d/ or carci n o mat o us me ni n gitis. N ote: K n o w n brai n 
metastases are c o nsi dere d acti ve , if a n y of t he f oll o wi n g criteria is a p plica ble:
a.
Brai n i ma gi n g d uri n g scree ni n g de m o nstrates pr o gressi o n of e xisti n g 
metastases a n d/ or a p peara nce of ne w lesi o ns c o m pare d t o brai n i ma gi n g 
perf or me d at least 4 wee ks earlier .
b.
Ne ur ol o gical s ym pt o ms attri b ute d t o brain metastases ha ve n ot ret ur ne d t o 
baseli ne .
c.
Ster oi ds were use d f or brai n metastases wit hi n 2 8 da ys of ra n d o mizati o n 
9.
Has
acti ve/hist or y  of p ne u m o nitis re q uiri n g treat me nt wit h ster oi ds or acti ve/hist or y  of 
i nterstitial l u n g disease.
1 0. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
1 1. 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 py, or la b orat or y ab n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he trial, 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 the 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 treati n g I n vesti gat or.  
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 trial.
1 3. Is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve or fat her c hil dre n wit hi n t he 
pr ojecte d d urati o n of t he trial, starti n g wit h t he scree ni n g visit t hr o u g h 1 2 0 d a y s after t he 
last d ose of trial treat me nt as defi ne d i n Secti o n 5. 7. 2.
1 4. Has 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 c o-i 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) or 
has pre vi o usl y partici pate d i n Merc k M K-3 4 7 5 cli nical trials.
1 5. Has a k n o w n hist or y  of H u ma n I m m u n o deficie nc y Vir us ( HI V; HI V 1/ 2 a nti b o dies).
1 6. Has a k n o w n acti ve He patitis B (e g, he patitis B s urface a nti ge n [H Bs A g ] reacti ve) or 
He patitis C ( e g, he patitis C vir us [H C V ] R N A [ q ualitati ve] is detecte d).
1 7. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys of ra n d o mizati o n.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
3 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Tri al Tre at me nt(s)
5. 2
T he treat me nts t o be use d in t his trial are o utli ne d bel o w i n Ta ble 3 . Me dicati o ns use d as 
treat me nts of p h y sicia n's c h oice ( T P C) will be ha n dle d acc or di n g t o l ocal re g u lati o ns a n d 
g ui deli nes i n partici pati n g c o u ntries. F or a n y  co m merciall y a vaila ble pr o d uct t hat is pr o vi de d 
b y  the trial site, s u bsi diar y, or desi g nee, e ver y atte m pt will be ma de t o s o urce t hese s u p plies 
fr o m a si n gle l ot/ batc h n u m ber.  The trial 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 pir y date f or a n y l ocall y purc hase d pr o d uct 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.
Ta ble 3
Trial Treat me nt
Dr u g
D ose
Re gi me n/ Tre at me nt Peri o d
Use
Ca pecita bi ne
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
Eri b uli n
L ocal sta n dar d of care
L ocal sta n dar d of care
T P C
Ge mcita bi ne
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
Pe m br oliz u ma b
2 0 0 m g I V
Da y 1 Q 3 W
E x peri me ntal
Vi n orel bi ne 
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
Trial treat me nt s h o ul d be gi n o n t he d a y  of ra n d o mizati o n or wit hi n 3 da y s after t he 
ra n d o mizati o n date.
T he i n vesti gat or s hall ta ke res p o nsi bilit y for 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 u p ply, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of trial 
treat me nts i n acc or da nce wit h t he pr ot oc ol a n d a ny a p plica ble la ws a n d re g ulati o ns.
D ose Selecti o n / M o dific ati o n
5. 2. 1
5. 2. 1. 1
D ose Selecti o n ( Pre p ar ati o n)
T he rati o nale f or selecti o n of d ose of pe m br oliz u ma b t o be use d i n t his trial is pr o vi de d i n 
Secti o n 4. 2. 2 .  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. 
T P C dr u gs will be d ose d, pre pare d a n d a d mi nistere d acc or di n g t o l ocal re g ulati o ns a n d 
g ui deli nes. T he b o d y  s urface area ( B S A) i n m2 s h o ul d be calc ulate d per l ocal g ui deli nes.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
5. 2. 1. 2
D ose M o dific ati o n ( I nterr u pti o n/Esc al ati o n/ Titr ati o n/ Ot her)
5. 2. 1. 2. 1
Pe m br oliz u m a b D ose M o dific ati o ns
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 (ir 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  ha ve a n i m m u n ol o gic eti ol o g y.  These 
i m m u ne-relate d A Es (ir A Es) m a y  occ ur s h ortly after t he first d ose or se veral m o nt hs after t he 
last d ose of treat me nt a n d ma y  affect m ore t ha n o n e 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, or s ki n bi o ps y m a y 
be i ncl u de d as part of t he e val uati o n. 
Base d o n t he se verit y of ir A Es, wit h h ol d or 
per ma ne ntl y disc o nti n ue pe m br oliz u ma b a n d a d mi nister c ortic oster oi ds. 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 are pr o vi de d 
i n Ta ble 4 . 
I n a d diti o n, s u bjects s h o ul d receive a p pr o priate s u p p orti ve care meas ures 
as dee me d 
necessar y  by t he treati n g I nvesti gat or.  Su g geste d s u p p orti ve care meas ures, as descri be d i n 
Secti o n 5. 6. 1, are als o i ncl u de d i n Ta ble 4 .
D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical/s ur gical eve nts or l o gistical reas o ns 
n ot relate d t o trial t hera p y (e g, electi ve s ur ger y, u nrelate d me dical e ve nts, s u bject vacati o n, 
a n d/ or h oli da y s).  Su bjects s h o ul d be place d bac k o n trial t hera py 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 di sc usse d wit h t he S p o ns or.  The 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 s u bject's trial rec or d.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 4
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 Ad verse E ve nt s Ass ociate d Wit h 
Pe m br oliz u ma b
Ge ner al i nstr ucti o ns:
1.
C ortic oster oi d ta per s h o ul d be i nitiate d u p o n A E i m pr o vi n g t o Gra de 1 or less a n d c o nti n ue t o ta per o ver at least 4 wee ks.
2.
F or sit uati o ns w here p e m br oliz u ma b has bee n wit h hel d, pe m br oliz u ma b ca n be res u me d after A E has bee n re d uce d t o Gra de 1 or 0 a n d 
c ortic oster oi d has bee n ta pere d. Pe m br oliz u ma b s h o ul d be per ma ne ntl y disc o nti n ue d if A E d oes n ot res ol ve wi t hi n 1 2 we e ks of last d ose or 
c ortic oster oi ds ca n n ot be re d uce d t o ≤ 1 0 m g pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks. 
3.
F or se vere a n d life-t hreate ni n g i m m u ne-relate d a d verse e ve nts (ir A Es), I V c ortic oster oi d s h o ul d be i nitiate d first f oll owe d b y oral ster oi d. Ot her 
i m m u n os u p pressi ve treat me nt s h o ul d be i nitiate d if ir A Es ca n n ot be c o ntr olle d b y c ortic oster oi ds.
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A E v 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or 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- 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 s u bjects f or si g ns a n d s y m pt o ms of  
p ne u m o nitis

E val uate 
s u bjects 
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

A d d 
pr o p h ylactic 
a nti bi otics 
f or 
o p p ort u nistic i nfecti o ns
Gra de 3 or 4, or 
rec urre nt gra de 2
Per m a 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- 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 s u bjects 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 w el 
perf orati o n
(ie
perit o neal si g ns a n d ile us).

S u bjects wit h ≥ Gra de 2 diarr 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. 

S u bjects 
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.
Gra de 4
Per m a ne ntl y 
disc o nti n ue
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A E v 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or a n d f oll o w -u p
A S T / A L T 
ele vati o n or 
I ncrease d 
Bilir u bi n
Gra de 2
Wit h h ol d

A d mi nister c ortic oster oi ds (i nitial 
d ose of 0. 5 - 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 o re 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 or 4 
Per m a ne ntl y 
disc o nti n ue

A d mi nister c ortic oster oi ds (i nitial 
d ose of 1- 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 y pe 1 dia betes 
mellit us ( T 1 D M) 
or 
H y per gl yce mia
Ne wl y 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

I nitiate 
i ns uli n 
re place me nt 
t hera p y f or s u bjects wit h T 1 D M 

A d mi nister a nti -h y per gl yce mic i n 
s u bjects wit h h y per gl yce mia 

M o nit or s u bjects 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 1 
H y pert h yr oi dis m 
Gra de 2
C o nti n ue 

Treat 
wit h 
n o n- selecti 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 m a ne ntl y 
disc o nti n ue 1
H y p ot h yr oi dis m
Gra de 2- 4
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. 
Ne p hritis a n d 
re nal d ysf u ncti o n
Gra de 2
Wit h h ol d 

A d mi nister 
c ortic oster oi ds 
( pre d nis o ne 
1- 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 m a ne ntl y 
disc o nti n ue
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A E v 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or a n d f oll o w -u p
M y ocar ditis
Gra de 1 or 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 or 4
Per m a ne ntl y 
disc o nti n ue
All Ot her 
i m m u ne-relate d 
A E s
Gra de 3, or 
i nt olera ble/ 
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 4 or 
rec urre nt Gra de 3 
Per m a ne ntl y 
disc o nti n ue
N O T E S: 
1.
Wit h h ol d or per ma ne ntl y disc o nti n ue pe m br oliz u ma b is at t he discreti o n of t he I n vesti gat or or treati n g p h ysicia n.  
2.
F or s u bjects wit h Gra de 3 or 4 i m m u ne -relate d e n d ocri n o pat h y w here wit h h ol d of p e m br oliz u ma b is re q uire d, pe m br oliz u ma b ma y be res u me d w he n 
A E res ol ves t o ≤ Gra de 2 a n d is c o ntr olle d w it h h or m o nal re place me nt t hera p y or ac hie ve d meta b olic c o ntr ol (i n case of T 1 D M).  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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 ym 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 usi 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 5 . 
Ta ble 5
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 m e nt
Pre m e dic ati o n at S u bse q ue nt 
D osi n g
Gr a 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 s u bject 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
Gr a 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 s u bject 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 s u bject 
s h o ul d be pre me dicate d f or t he ne xt sc he d ule d 
d ose.
S u bjects 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 treat me nt .
S u bject 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 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 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
4 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at S u bse q ue nt 
D osi n g
Gr a des 3 or 4
Gra de 3:
Pr ol o n ge d (i.e., 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 hri 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 s u bject 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.
S u bject is per m a ne ntl y disc o nti n ue d fr o m 
f urt her st u d y dr u g tre at me nt.
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 availa 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 4. 0 ( C T C A E) at 
htt p://cte p.c a ncer. g o v
Ot her all o we d d ose i nterr u pti o n s 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 thera p y.  S u bjects s h o ul d 
be place d bac k o n st u d y thera 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 patie nt's st u dy rec or d.
I n case t o xicit y does n ot res ol ve t o Gra de 0- 1 wit hi n 1 2 wee ks after t he last i nf usi o n, 
pe m br oliz u ma b s h o ul d be disc o nti n ue d. S u bjects wit h a la b orat or y a d verse e ve nt still at 
Gra de 2 after 1 2 wee ks p ost last i nf usi o n m a y  restart pe m br oliz u ma b if as ym pt o matic a n d 
o nl y  after c o ns ultati o n wit h t he S p o ns or.
D osi n g i nterr u pti o ns ( pe m br oliz u ma b a n d T P C) are per mitte d i n t he case of 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 thera p y (e g, electi ve s ur ger y, u nrelate d 
me dical e ve nts, s u bject vacati o n, a n d/ or h oli da y s). S u bjects s h o ul d be place d bac k o n st u d y 
treat me nt wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless disc usse d ot her wise wit h t he 
S p o ns or. T he reas o n f or i nterr u pti o n of st u d y treat me nt s h o ul d be d oc u me nte d i n t he 
s u bject's st u dy rec or d.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
4 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
5. 2. 1. 2. 2
C a pecit a bi ne
Refer t o l ocall y iss ue d c a pecita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 3
Eri b uli n
Refer t o l ocally iss ue d e ri b uli n pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 4
Ge mcit a bi ne
Refer t o l ocally iss ue d g e mcita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 5
Vi n orel bi ne
Refer t o l ocally iss ue d vi n orel bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt. 
Ti mi n g of D ose A d mi nistr ati o n
5. 2. 2
C y cle 1 D a y  1 treat me nt wit h pe m br oliz u ma b or T P C s h o ul d be gi n o n t he da y  of 
ra n d o mizati o n (n o later t ha n 3 da y s after ra n d o mizati o n is per mitte d). Trial treat me nts s h o ul d 
be a d mi nistere d as descri be d bel o w a n d acc or di n g t o t he details pr o vi de d i n t he Trial Fl o w 
C harts ( Secti o n 6. 0) .
P e m br oliz u ma b
or
T P C
s h o ul d be a d mi nistere d o n a n o ut patie nt
basis
after all 
pr oce d ures/assess me nts ha ve bee n c o m plete d .
5. 2. 2. 1
Pe m br oliz u m a b
Pe m br oliz u ma b will be a d mi nistere d as a 3 0 -mi n ute
I V inf usi o n Q 3 W
(treat me nt c ycle 
i nter vals ma y  be i ncrease d d ue t o t o xicit y as descri be d i n t he D ose M o dificati o n Secti o n
5. 2. 1. 2. 1 ).  Sites s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n ti mi n g t o be as cl ose t o 3 0 mi n 
as p ossi ble.  A wi n d o w of -5 mi n / + 1 0 mi n is per mitte d. T he reas o n f or a n y dela y i n i nf usi o n
o utsi de of t he pr ot oc ol s pecifie d wi n d o w
s h o ul d be d oc u me nte d i n t he s u bject’s c hart a n d
rec or de d o n t he electr o nic case re p ort f or ms (e C R Fs ).
T he 
P har mac y
Ma n ual 
c o ntai ns s pecific i nstr ucti o ns f or t he pre parati o n 
of 
t he 
pe m br oliz u ma b i nf usi o n fl ui d a n d a d mi nistrati o n of i nf usi o n s ol uti o n .
5. 2. 2. 2
C a pecit a bi ne
Refer t o l ocall y iss ue d ca peci ta bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 2. 3
Eri b uli n
Refer t o l ocall y iss ue d eri b uli n pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 2. 4
Ge mcit a bi ne
Refer t o l ocall y iss ue d ge mcita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
4 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
5. 2. 2. 5
Vi n ore l bi ne
Refer t o l ocall y iss ue d vi n orel bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.
Tri al Bli n di n g/ M as ki n g
5. 2. 3
T his is a n o pe n -la bel trial, t heref ore, t he S p o ns or, I n vesti gat or a n d s u bject will k n o w t he 
treat me nt a d mi nistere d.   I ma gi n g data f or t he pri mar y  an al y sis will be re vie we d b y  ce ntral 
i ma gi n g ve n d or bli n de d
t o s u bject’s treat me nt assi g n me nt.
T he s u bject-le vel P D -L 1  
bi o mar ker res ults will be mas ke d i n the data base t o t he st u d y  tea m a n d t he S p o ns or i ncl u di n g 
cli nical, statistical, statistical pr o gra m mi n g, a n d data ma na ge me nt pers o n nel.
Access t o t he 
P D -L 1  su bject -le vel bi o mar ker res ults will be li mite d t o a n u n bli n de d S p o ns or cli nical 
scie ntist, u n bli n de d S p o ns or statisticia n, a n d u n bli n de d S p o ns or statistical pr o gra m mer w h o 
will be res p o nsi ble f or data re vie w b ut w h o will ha ve n o ot her res p o nsi bilities ass ociate d 
wit h t he st u d y .   
Access t o t he all ocati o n sc he d ule a n d t he s u bject -le vel P D -L 1  res ults f or s u m maries or 
a nal ys es will be restricte d t o a n u n bli n de d e xter nal sta tisticia n, a n d, as nee de d, a n e xter nal 
scie ntific pr o gra m mer perf or mi n g t he a nal ys is, w h o will ha ve n o ot her res p o nsi bilities 
ass ociate d wit h t he st u d y.
R a n d o miz ati o n or Tre at me nt All oc ati o n
5. 3
Ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve v oice r es p o nse s yste m / i nte grate d 
we b res p o nse s yste m (I V R S/IW R S).
T here are 2 treat me nt ar ms.  Su bjects will be assi g ne d 
ra n d o ml y i n a 1: 1 rati o t o pe m br oliz u ma b or T P C after stratificati o n b y  PD- L 1  tu m or stat us 
( p ositi ve [ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d hist or y  of pri or ( ne o)a dj u va nt treat me nt 
v ers u s de n ov o metastatic 
disease at i nitial dia g n osis .  T P C
s h o ul d be i de ntifie d a n d 
d oc u me nte d via I V R S pri or t o ra n d o mizati o n.  S u bject s ra n d o mize d t o T P C w h o disc o nti n ue 
treat me nt are n ot all o we d t o cr oss -o ver t o t he pe m br oliz u ma b ar m .
Str atific ati o n
5. 4
Ra 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 :

P D -L 1  t u m or stat us ( p ositi ve [ C P S ≥1] vs ne gati ve [ C P S < 1])

Hist or y  of pri or ( ne o)a dj u va nt t hera py vs de n ov o metastatic disease at i nitial dia g n osis
N o stratificati o n base d o n a ge, se x or ot her c haracteristics will be use d i n t his trial .
C o nc o mit a nt Me dic ati o ns / V acci n ati o ns (All o we d & Pr o hi bite d )
5. 5
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 trial.  If t here is a cli nical i n dicati o n f or a n y me dicati o n
or vacci nati o n
s pecifically pr o hi bite d d uri n g t he trial, disc o nti n uati o n fr o m trial t hera p y or vacci nati o n ma y 
be re q uire d.  The 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
C li nical Direct or .  The fi nal decisi o n o n a n y s u p p orti ve t hera py or vacci nati o n rests wit h t he 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
4 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
i n vesti gat or a n d/ or t he s u bject's pri mar y  ph y sicia n.  Ho we ver, t he decisi o n t o c o nti n ue t he 
s u bject o n trial t hera p y or vacci nati o n sc he d ule 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 s u bject.
Acce pt a ble C o nc o mit a nt Me dic ati o ns
5. 5. 1
All treat me nts t hat t he I n vesti gat or c o nsi ders necessar y  for a s u bject’s welfare m a y  be 
a d mi nistere d at t he discreti o n of t he I n 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 case re p ort f or m ( C R F) 
i ncl u di n g all prescri pti o n, o ver -t he-c o u nter ( O T C), 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 trial 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 will als o be i ncl u de d o n t he eC R F s.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da y s bef ore ra n d o mizati o n a n d 3 0 d a y s after 
t he last d ose of st u d y treat me nt s h o ul d be rec or de d.  Co nc o mita nt me dicati o ns a d mi nistere d 
be y o n d 3 0 d a y s after t he last d ose of trial treat me nt s h o ul d be rec or de d f or S A Es a n d E CIs as 
defi ne d i n Secti o n 7. 2 .
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
5. 5. 2
S u bjects are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he Scree ni n g ,
Treat me nt a n d Retreat me nt P hase of t his trial:

A nti ne o plastic s y ste mic c he m ot hera py o r bi ol o gical t hera py 
o
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol
o
C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol
o
I n vesti gati o nal a ge nts ot her t ha n pe m br oliz u ma b
o
Ra diati o n t hera p y 
N ote:  Ra di ati o n t her a py t o a sy m pt o m atic s olit ary lesi o n or t o t he br ai n m ay be 
all o we d after c o ns ult ati o n wit h S p o ns or (exce pt d uri n g scree ni n g).  

H er bal s u p ple me nts

Li v e vacci nes wit hi n 3 0 da y s pri or t o ra n d o mizati o n a n d w hile partici pati n g i n t he 
trial.  Exa 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 , her pes z oster , yell o w fe ver, ra bies, B C G, a n d 
t yp h oi d ( oral) vacci ne s. 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 .
Ho 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.

Gl uc oc ortic oi ds f or a n y p ur p ose ot he r t ha n t o m o d ulate s ym pt o ms fr o m a n E CI of 
s us pecte d i m m u n ol o gic eti ol o g y.  The use of p h y si 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:  For s u bjects r a n d o mize d t o T P C , t he use of syste mic gl uc oc ortic oi ds o n 
tri al tre at me nt is acce pt a ble a n d m ay be re q uire d f or pre me dic ati o n.
N ote:  I n h ale d ster oi ds are all o we d f or m a n a ge me nt of ast h m a.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
4 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
N ote:  Use of pr o p hyl actic c ortic oster oi ds t o av oi d aller gic re acti o ns (e g, t o I V 
c o ntr act dye) is per mitte d.

Maal o x ( or me dic i ne c o ntai ni n g al u mi n u m h y dr o xi de or ma g nesi u m h y dr o xi de)
s h o ul d n ot be a d mi nistere d t o s u bjects w h o are ra n d o mize d t o ca pecita bi ne.
S u bjects w h o, per I n vesti gat or’s assess me nt , re q uire a n y of t he af ore me nti o ne d me dicati o ns
f or cli nical ma na ge me nt s h o ul d be disc o nti n ue d fr o m st u d y treat me nt.  S u bjects ma y  recei ve 
ot her me dicati o ns t hat t he I n vesti gat or dee ms t o be me dicall y necessar y.
T he E xcl usi o n Criteria d escri be ot her me dicati o ns t hat are pr o hi bite d i n t his trial.
T here are n o pr o hi bite d t hera pies d uri n g t he P ost -Treat me nt F oll o w -u p P hase.
Resc ue Me dic ati o ns & S u p p orti ve C are
5. 6
S u p p orti ve C are G ui deli nes f or S u bjects i n Pe m br oliz u m a b Ar m
5. 6. 1
S u bject s s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as d ee me d necessar y  by 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 d verse 
e ve nts ( A Es) wit h p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d i n Secti o n 5. 2. 1. 2, Ta ble 4 ).
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 c ortic oster oi ds , as well as 
a d diti o nal a nti -i nfla m mat or y age nts if s ym 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 m a y  be necessar y  as s ym pt o ms 
ma y  worse n w he n t he ster oi d d ose is decrease d. F or eac h dis or der , atte m pts s h o ul d be ma de 
t o r ule o ut ot her ca uses , s uc h as pr o gressi o n of 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. T he 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 in 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 4 i n 
Secti o n 5. 2. 1. 2 f or g ui deli nes re gar di n g d ose m o dificati o n. 
It m a y  be necessar y  to 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 t he e val uati o n of t he e ve nt . 
S u p p orti ve C are G ui deli nes f or I m m u ne-Rel ate d A d verse E ve nt s
5. 6. 2
See Secti o n 5. 2. 1. 2, Ta ble 4 .
S u p p orti ve C are G ui deli nes f or C a pecit a bi ne
5. 6. 3
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
S u p p orti ve C are G ui deli nes f or Eri b uli n
5. 6. 4
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u p p orti ve C are G ui deli ne f or Ge mcit a bi ne
5. 6. 5
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
S u p p orti ve C are G ui deli nes f or Vi n orel bi ne
5. 6. 6
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
Diet/ Acti vit y/ Ot her C o nsi der ati o ns
5. 7
Diet
5. 7. 1
S u bjects 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.
C o ntr ace pti o n
5. 7. 2
Pe m br oliz u ma b ma y  ha ve a d verse effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if 
pe m br oliz u ma b has tra nsie nt a d verse effects o n t he c o m p ositi o n of s per m.  
F or t his trial, male s u bjects will be c o nsi dere d t o be of n o n -re pr o d ucti ve p ote ntial if t he y 
ha ve az o os per mia ( w het her d ue t o ha vi n g ha d a vasect o m y or d ue t o a n u n derl y i n g me dical 
c o n diti o n).  
Fe male s u bjects will b e c o nsi dere d of n o n -re pr o d ucti ve p ote ntial if t he y are eit her: 
( 1) p ost me n o pa usal ( defi ne d as at least 1 2 m o nt hs wit h n o me nses wit h o ut a n alter nati ve 
me dical ca use; i n w o me n < 4 5 ye ars of a ge a hi g h f ollicle sti m ulati n g h or m o ne ( F S H) 
le vel i n t he p ost me n o pa usal ra n ge m a 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 or m o nal re place me nt t hera py. I n t he 
a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.); 
O R 
( 2) ha ve ha d a h y sterect o m y an d/ or bilateral o o p h orect o m y, bilateral sal pi n gect o my or 
bilateral t u bal li gati o n/ occl usi o n, at least 6 wee ks pri or t o scree ni n g; 
O R 
( 3) has a c o n ge nital or ac q uire d c o n diti o n t hat pre ve nts c hil d beari n g.
Fe male a n d male s u bjects of re pr o d ucti ve p ote ntial m ust a gree t o a v oi d bec o mi n g pre g na nt 
or i m pre g nati n g a part ner, res pecti vely, w hile recei vi n g st u d y dru g a n d f or 1 2 0 d a y s (at least 
6 m o nt hs f or s u bjects o n ge mcita bi ne) after t he last d ose of st u d y dr u g b y  co m pl y i n g wit h 
o n e of t he f oll o wi n g:  
( 1) p ractice a bsti ne nce † fr o m heter ose x ual acti vit y; 
O R 
( 2) use ( or ha ve t heir part ner use) acce pta ble c o ntrace pti o n d uri n g heter ose x ual acti vit y.  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
5 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Acce pta ble met h o ds of c o ntrace pti o n are ‡:
Si n gle met h o d ( o ne of t he f oll o wi n g is ac ce pta ble):
•
i ntra uteri ne de vice (I U D)
•
vasect o m y of a fe male s u bject’s male part ner 
•
c o ntrace pti ve r o d i m pla nte d i nt o t he s ki n
C o m bi nati o n met h o d (re q uires use of t w o of t he f oll o wi n g):
•
dia p hra g m wit h s per mici de (ca n n ot be use d i n c o nj u ncti o n wit h cer vical ca p/s per mici de)
•
cer vical ca p wit h s per mici de ( n ulli par o us w o me n o nl y )  
•
c o ntrace pti ve s p o n ge ( n ulli par o us w o me n o nl y ) 
•
male c o n d o m or fe male c o n d o m (ca n n ot be use d t o get her)
•
h or m o nal c o ntrace pti ve: oral c o ntrace pti ve pill (estr o ge n/ pr o gesti n pill or pr o gesti n - o nly 
pill), c o ntrace pti ve s ki n patc h, va gi nal c o ntrace pti ve ri n g, or s u bc uta ne o us c o ntrace pti ve 
i njecti o n
A bsti ne nce (relati ve t o heter ose x ual acti vit y ) ca n be use d as t he s ole met h o d of c o ntrace pti o n 
if it is c o nsiste ntl y em pl o y e d as t he s u bject’s preferre d a n d us ual lifestyl e a n d if c o nsi dere d 
acce pta ble b y  local re g ulat or y age ncies a n d E R Cs/I R Bs.  Peri o dic a bsti ne nce (e g, cale n dar, 
o v ulati o n, s ym pt o -t her mal, p ost -o v ulati o n met h o ds, etc.) a n d wit h dra wal are n ot acce pta ble 
met h o ds of c o n trace pti o n. 
If a c o ntrace pti ve met h o d liste d a b o ve is restricte d b y  local re g ulati o ns/ g ui deli nes, t he n it 
d oes n ot q ualif y  as a n acce pta ble met h o d of c o ntrace pti o n f or s u bjects partici pati n g at sites i n 
t his c o u ntr y/re gi o n.
S u bjects s h o ul d be i nf or me d t hat ta ki n g t he st u d y dr u g m a y  in 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  were t o occ ur d uri n g t he st u d y.  In or der t o partici pate i n 
t he st u d y, s u bjects of c hil d beari n g p ote ntial m ust a d here t o t he c o ntrace pti o n re q uire me nt 
( descri be d a b o v e) fr o m t he d a y  of st u d y dr u g i nitiati o n ( or 1 4 d a y s pri or t o t he i nitiati o n of 
st u d y dr u g 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 d a y s (at least 6 
m o nt hs f or ge mcita bi ne) after t he last d ose of trial t hera py.  If t here is a n y questi o n t hat a 
s u bject of c hil d beari n g p ote ntial will 
n ot relia bl y co m pl y  
wit h t he re q uire me nts f or 
c o ntrace pti o n, t hat s u bject s h o ul d n ot be e ntere d i nt o t he st u d y .
M ale s u bjects s h o ul d als o see k a d vice re gar di n g cr y oc o nser vati o n of
s per m pri or
t o
treat me nt beca use of t he p ossi bilit y of i nfertilit y
N ote: M o nt hl y  pre g na nc y testi n g s h o ul d be c o n d ucte d as per l ocal re g ulati o ns w here 
a p plica ble.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Pre g n a nc y
5. 7. 3
If a s u bject i na d verte ntl y bec o mes pre g na nt w hile o n treat me nt wit h pe m br oliz u ma b or a 
T P C , t he s u bject will be i m me diatel y disc o nti n ue d fr o m treat me nt. T he site will c o ntact t he 
s u bject at least m o nt hl y a n d d oc u me nt t he s u bject’s stat us u ntil t he pre g na nc y  has bee n 
c o m plete d or ter mi nate d. T he o utc o me of t he pre g na nc y will be re p orte d t o t he S p o ns or 
wit h o ut del a y an d wit hi n 2 4 h o urs if t he o utc o me is a seri o us a d verse e x perie nce (e g, deat h, 
a b orti o n, c o n ge nital a n o mal y, or ot her disa bli n g or life-t hreate ni n g c o m plicati o n t o t he 
m ot her or ne w b or n).
T he st u d y I n vesti gat or will ma ke e ver y eff ort t o o btai n per missi o n t o 
f oll o w t he o utc o me of t he pre g na nc y  an d re p ort t he c o n diti o n of t he fet us or ne w b or n t o t he 
S p o ns or.   If a male s u bject 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  must 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 7. 2. 2.
N ursi n g W o me n
5. 7. 4
It is u n k n o w n w het her pe m br oliz u ma b is e xcrete d i n h u ma n mil k.  Si nce ma n y dr u gs are 
e xcrete d i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d verse reacti o ns i n t he 
n ursi n g i nfa nt, s u bjects w h o are breast -fee di n g are n ot eli gi ble f or e nr oll me nt.
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a
5. 8
S u bjects ma y  wit h dra w c o nse nt at a n y ti me f or a n y reas o n or be dr o p pe d fr o m t he trial at t he 
discr eti 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.  In a d diti o n, a s u bject ma y  b e 
wit h dra w n b y  the i n vesti gat or or t he S p o ns or if e nr oll me nt i nt o t he trial is i na p pr o priate, t he 
trial pla n is vi olate d, or f or a d mi nistrati ve a n d/ or ot her safety reas o ns.  Specific details 
re gar di n g disc o nti n uati o n or wit h dra wal pr oce d ures ; i ncl u di n g s pecific details re gar di n g 
wit h dra wal fr o m F ut ure Bi o me dical Researc h,
are pr o vi de d i n Secti o n 7. 1. 4 –
Ot her 
Pr oce d ures.
I n t his trial, a s u bject ma y  disc o nti n ue fr o m treat me nt b ut c o nti n ue t o partici pate i n t he 
re g ularly sc he d ule d acti vities, as l o n g as t he s u bject d oes n ot wit h dra w c o nse nt.  Once a 
s u bject has disc o nti n ue d treat me nt, e ve n t h o u g h he/s he c o nti n ues t o be m o nit ore d i n t he trial, 
he/s he m a y  be all o we d t o be gi n treat me nt a gai n if dee me d me dicall y a p pr o priate.
A s u bject m ust be disc o nti n ue d fr o m t he trial f or a n y of t he f oll o wi n g reas o ns:
●
T he s u bject or le gal re prese ntati ve (s uc h as a pare nt or le gal g uar dia n) wit h dra ws 
c o nse nt.

T he s u bject is l ost t o f oll o w - u p
A s u bject m ust be disc o nti n ue d fr o m treat me nt (b ut s h o ul d c o nti n ue t o be m o nit ore d i n t he 
tri al) f or a ny of t he f oll o wi n g reas o ns :

T he s u bject or le gal re prese ntati ve (s uc h as a pare nt or le gal g uar dia n) re q uests t o 
disc o nti n ue treat me nt
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

C o nfir me d ra di o gra p hic disease pr o gressi o n per t he ter ms o utli ne d i n Secti o n 7. 1. 2. 7
(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). N ote: F or u nc o nfir me d 
ra di o gra p hic disease pr o gressi o n , please see Secti o n 5. 8. 1 .

U nacce pta ble a d verse e x perie nces as descri be d i n Secti o n 7. 2

A n y  pr o gressi o n or rec urre nce of a n 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

I nterc urre nt ill ness ot her t ha n a n ot her mali g na nc y  as n ote d a b o ve t hat pre ve nts 
f urt her a d mi nistrati o n of treat me nt

Rec urre nt Gra de 2 p ne u m o nitis

I n vesti gat or’s decisi o n t o disc o nti n ue treat me nt

T he s u bject has a c o nfir me d p ositi ve ser u m pre g na nc y  test

N o nc o m plia nce wit h trial treat me nt or pr oce d ure re q uire me nts

C o m plete d 
3 5 
treat me nts
wit h 
pe m br oliz u ma b . N ote: 
S u bjects 
w h o 
st o p 
pe m br oliz u ma b after 3 5 treat me nts m a y  be eli gi ble f or u p t o 1 7 a d diti o nal st u d y 
treat me nts if t he y pr o gress after st o p pi n g st u d y treat me nt pr o vi de d t he y meet t he 
re q uire me nts detaile d i n Secti o n 7. 1. 5. 2. 1.

A d mi nistrati ve reas o ns
C he m ot hera p y m a y  be disc o nti n ue d w he n a s u bject has recei ve d t he ma xi m u m n u m ber of 
c ycles per mitte d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g c o u ntries.
T he E n d of Treat me nt a n d F oll o w -u p visit pr oce d ures are liste d i n Secti o n 6. 0 a n d Sec ti o n
7. 1. 5. 3 . After t he e n d of treat me nt, eac h s u bject will be f oll o we d f or a mi ni m u m of 3 0 da y s
f or A Es an d E CI m o nit ori n g . Seri o us a d verse e ve nt s will be c ollecte d f or 9 0 d a y s after t he 
e n d of treat me nt as descri be d i n Secti o n 7. 2. 3. 1 ). S u bjects w h o dis c o nti n ue f or reas o ns ot her 
t ha n pr o gressi ve disease will ha ve p ost -treat me nt f oll o w-u p f or disease stat us u ntil disease 
pr o gressi o n, i nitiati n g a n o n -st u d y ca ncer treat me nt, wit h dra wi n g c o nse nt , bec o mi n g l ost t o 
f oll o w-u p or deat h .  After d oc u me nte d disease pr o gressi o n eac h s u bject 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, 
w hic he ver occ urs first .
Tre at me nt A fter First R a di ol o gic E vi de nce of Dise ase Pr o gressi o n
5. 8. 1
I m m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b ma y  pr o d uce a ntit u m or effects b y  
p ote ntiati n g e n d o ge n o us ca ncer -s pecific i m m u ne res p o nses.  T he res p o nse patter ns see n wit h 
s uc h a n a p pr oac h ma y e xte n d be y o n d t he t ypical ti me c o urse of res p o nses see n wit h 
c yt ot o xic a ge nts, a n d ca n ma nifest as a cli nical res p o nse after a n i nitial i ncrease i n t u m or 
b ur de n or e ve n t he a p peara nce of ne w lesi o ns.
After t he site has assesse d t he 1 st ra di o gra p hic e vi de nce of P D b y  RE CI S T 1. 1, all i ma ges 
m ust be i m me diatel y su b mitte d t o t he ce ntral i ma gi ng ve n d or f or verificati o n of Pr o gressi ve 
Disease ( P D).  The ce ntral i ma gi n g ve n d or will n otif y  the site a n d t he S p o ns or of t he res ults 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
5 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
of t his ra pi d re vie w. S u bject s s h o ul d re mai n o n treat me nt u ntil ce ntral i ma gi n g assess me nt
of site-assesse d 1 st ra di ol o gic e vi de nce of P D is perf or me d.   If ce ntral i ma gi n g ve n d or
verifies site -assesse d 1 st ra di ol o gic e vi de nce of P D i n eit her treat me nt ar m, t u m or assess me nt 
ma y  be re peate d b y  the site 4 wee ks later i n or der f or t he site t o c o nfir m P D b y  ir R E CIS T
wi t h t he o pti o n of c o nti n ui n g treat me nt per bel o w w hile a waiti n g ra di ol o gic c o nfir mati o n of 
disease pr o gressi o n . 
T he decisi o n t o c o nti n ue st u d y treat me nt after site-assesse d 1 st ra di ol o gic e vi de nce of P D is 
verifie d b y  the ce ntral i ma gi n g ve n d or is at t he I nvesti gat or’s discreti o n base d o n t he cli nical 
stat us of t he s u bject as descri be d i n Ta ble 6 bel o w .  Su bjects ma y  recei ve st u d y treat me nt 
w hile waiti n g f or c o nfir mati o n of P D b y  t he site, if t he y are cli nically sta ble as defi ne d b y  t he 
f oll o wi n g criteria:

A bse nce of si g ns a n d s y m pt o ms (i ncl u di n g w orse ni n g of la b orat or y val ues) i n dicati n g 
disease pr o gre ssi o n

N o decli ne i n E C O G perf or ma nce stat us

A bse nce of ra pi d pr o gressi o n of disease 

A bse nce of pr o gressi ve t u m or at critical a nat o mical sites (e g, 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
Ta ble 6
I ma gi n g a n d Treat me nt 
After 
Site -Assesse d 
Fir st Ra di ol o gic 
E vi de nce 
of 
P r o gressi ve D isease has Bee n Verifie d
b y  the Ce ntral
I ma gi n g Ve n d or.  Ta ble 
R e prese nts ir R E CIS T
Cli nic all y St a ble
Cli nic all y U nst a ble
I m a gi n g
Tre at me nt
I m a gi n g
Tre at me nt
1st ra di ol o gic 
e vi de nce of P D b y 
R E CI S T 1. 1 
w hic h has bee n 
verifie d b y t he 
ce ntral i ma gi n g 
ve n d or
Re peat i ma gi n g at 
> 4 w ee ks at site t o 
c o nfir m P D
M a y  c o nti n ue st u d y 
treat me nt at t he l ocal 
site I n vesti gat or’s 
discreti o n w hile 
a waiti n g 
c o nfir mat or y t u mor 
i ma gi n g b y  site b y  
ir R E CI S T.
Re peat i ma gi n g at 
> 4 w ee ks t o 
c o nfir m P D per 
p h ysicia n 
discreti o n o nl y
Disc o nti n ue 
treat me nt
Re peat t u m or 
i ma gi n g c o nfir ms 
P D b y ir R E CI S T 
at t he l ocal site
N o a d diti o nal 
i ma gi n g re q uire d
Disc o nti n ue 
treat me nt (e xce pti o n 
is p ossi ble u p o n 
c o ns ultati o n wit h 
s p o ns or)
N o a d diti o nal 
i ma gi n g re q uire d
N/ A
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Cli nic all y St a ble
Cli nic all y U nst a ble
I m a gi n g
Tre at me nt
I m a gi n g
Tre at me nt
Re peat t u m or 
i ma gi n g s h o ws 
S D, P R or C R b y  
ir R E CI S T b y t he 
l ocal site
C o nti n ue re g ularl y 
sc he d ule d i ma gi n g 
assess me nts 
C o nti n ue st u d y 
treat me nt at t he l ocal 
site In vesti gat or’s 
discreti o n
C o nti n ue re g ularl y 
sc he d ule d i ma gi n g 
assess me nts 
M a y  restart st u d y 
treat me nt if 
c o n diti o n has 
i mpr o ve d a n d/ or 
cli nicall y sta ble per 
I n vesti gat or’s 
discreti o n . Ne xt 
t u m or i ma gi n g
s h o ul d occ ur 
acc or di n g t o t he 
e ver y 9 wee k ( 6 3 ± 
7 d a ys) i ma gi n g 
sc he d ule f or t he first 
year a n d 1 2 w ee ks 
( 8 4 ± 7 da ys) after 
t he first year
T his all o wa nce t o c o nti n ue treat me nt des pite ce ntrall y v erifie d 1 st ra di ol o gic e vi de nce of P D
ta kes i nt o acc o u nt t he o bser vati o n t hat s o me s u bjects m a y ha ve a tra nsie nt t u m or flare i n t he 
first fe w m o nt hs af ter t he start of i m m u n ot hera p y bef ore e x perie nci n g disease res p o nse.  
S u bjects t hat are dee me d cli nicall y unsta ble are n ot re q uire d t o ha ve re peat i ma gi n g f or 
c o nfir mati o n of pr o gressi ve disease b y  t he l ocal site.
It must be e m p hasize d t hat cli nicall y sta ble s u bjects m a y  re mai n o n treat me nt after R E CI S T 
1. 1 defi ne d disease pr o gressi o n is verifie d b y  bli n de d ce ntral i ma gi n g ve n d or f or b ot h t he 
e x peri me ntal a n d c o ntr ol ar ms of t he st u d y, a n d t hat t he sc h e d ule of assess me nts be a d here d 
t o. If st u d y t hera p y is disc o nti n ue d f or t o xicit y b ut t he s u bject is ot her wise sta ble, t he s u bject 
s h o ul d c o nti n ue t u m or i ma gi n g as i n dicate d i n t he fl o w c hart u ntil R E CI S T 1. 1 defi ne d 
pr o gressi o n has bee n esta blis he d b y  a bli n de d ce ntral i ma gi n g ve n d or .  
N ote:  If a s u bject wit h c o nfir me d r a di o gr a p hic pr o gressi o n (ie 2 t u m or i m a ges at le ast 2 8 
d ays a p art de m o nstr ati n g pr o gressive dise ase) is cli nic ally st a ble or cli nic ally i m pr ove d, a n d 
t here is n o f urt her i ncre ase i n t he t u m or di me nsi o ns at t he c o nfir m at ory t u m or i m a ge ( as 
assesse d by t he site i nvesti g at or/l oc al r a di ol o gy revie w ), a n exce pti o n m ay be c o nsi dere d t o 
c o nti n ue tre at me nt u p o n c o ns ult ati o n wit h t he S p o ns or.
Disc o nti n u ati o n of St u d y T her a p y After C o m plete R es p o nse
5. 8. 2
Disc o nti n uati o n of treat me nt ma y  be c o nsi dere d f or s u bjects 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 wit h pe m br oliz u ma b a n d ha d at least 2 c ycles 
wit h pe m br oliz u ma b be y o n d t he date w he n t he i nitial C R was declare d.  Su bjects w h o t he n 
e x perie nce ra di o gra p hic disease pr o gressi o n m a y  be eli gi ble f or u p t o 1 7 a d diti o nal 
treat me nts w it h pe m br oliz u ma b
( Sec o n d C o urse P hase or Re -treat me nt P hase) at t he 
discreti o n of t he I n vesti gat or if:

N o ca ncer treat me nt was a d mi nistere d si nce t he last d ose of pe m br oliz u ma b
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

T he s u bject meets t he safet y  para meters liste d i n t he I ncl usi o n/ E xcl usi o n criteria

T he trial is o n g oi n g
S u bjects will res u me t hera p y at t he sa me d ose a n d sc he d ule at t he ti me of i nitial 
disc o nti n uati o n.  Ad diti o nal details are pr o vi de d i n Secti o n
7. 1. 5. 2. 1 .  Res p o nse or 
pr o gressi o n i n t his Sec o n d C o urse P hase will n ot c o u nt t o war ds t he O R R a n d P F S of t he 
pri mar y  e n d p oi nt i n t his trial.
S u bject Re pl ace me nt Str ate g y
5. 9
A s u bject w h o disc o nti n ues fr o m t he trial will n ot be re place d.
Be gi n ni n g a n d E n d of t he Tri al
5. 1 0
T he o verall trial be gi ns w he n t he first s u bject si g ns t he i nf or me d c o nse nt f or m.  The o verall 
trial e n ds w he n t he last s u bject c o m pletes t he last st u d y-relate d p h o ne -call or visit,
disc o nti n ues fr o m t he trial or is l ost t o f oll o w -u p (i.e. t he s u bject is u na ble t o be c o ntacte d b y  
t he i n vesti gat or)  U p o n st u d y co m pleti o n, partici pa nts are disc o nti n ue d a n d e nr olle d i n a 
pe m br oliz u ma b e xte nsi o n st u d y .
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n
5. 1 1
Earl y trial ter mi nati o n will be t he res ult of t he criteria s pecifie d bel o w:

T he trial m a y  be st o p pe d earl y f or f utilit y or safet y at t he rec o m me n dati o n of t he 
e xter nal Data M o nit ori n g C o m mittee ( eD M C).

Q ualit y  or q ua ntit y  of data rec or di n g is i nacc urate or i nc o m plete as assesse d b y  th e 
S p o ns or

P o or a d here nce t o pr ot oc ol a n d re g ulat or y re q uire me nts

I nci de nce or se verity of a d verse dr u g reacti o n i n t his or ot her st u dies i n dicates a 
p ote ntial healt h hazar d t o s u bjects

Pla ns t o m o dif y  or disc o nti n ue t he de vel o p me nt of t he st u d y me dicati o n
T he cli nical trial 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 trial p o p ulati o n as 
a w h ole is u nacce pta ble.  In a d diti o n, f urt her recr uit me nt i n t he trial or at (a) partic ular trial 
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 t he n u m ber of 
disc o nti n uati o ns f or a d mi nistrati ve reas o ns is t o o hi g h.
I n t he e ve nt of S p o ns or decisi o n t o n o l o n ger s u p pl y st u d y me d icati o n, 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 s u bject treat me nt ca n be ma de .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
5 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
6. 0
T RI A L F L O W C H A R T
I niti al Tre at me nt P h ase
6. 1
Pe m br oliz u m a b Tre at me nt Ar m
6. 1. 1
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nistr ati ve Pr oce d ures b
I nf or me d C o nse nt
X
I nf or me d C o nse nt f or F ut ure 
Bi o me dical Researc h
X
I ncl usi o n/ E xcl usi o n Criteria
X
S u bject I de ntificati o n Car d
X
De m o gra p hics a n d Me dical 
Hist or y d
X
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
X
X z
Trial Treat me nt A d mi nistrati o n 
( Pe m br oliz u ma b)
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer T hera p y 
Stat us
X
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts e
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
1 2 -Lea d E C G ( L ocal) f
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
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
5 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Vital Si g ns a n d Wei g ht g
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce Stat us
X h
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
i
X
L a b or at or y 
Pr oce d ures/ Assess me nts : 
L O C A L l a b or at or y b, j
Pre g na nc y Test k
X
P T /I N R a n d a P T Tl
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
X
X
X  
X x
X
T 3, F T 4 a n d T S H m,  v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5-3, C E A 
a n d C A 2 7. 2 9) n, v
X
X n
X
X
L a b or at or y 
Pr oce d ures/ Assess me nts:  
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics o
X
C orrelati ve Bl o o d Sa m ples
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, Ser u m)
X
Effic ac y Me as ure me nts b
T u m or I ma gi n gw
X
X x
X
X
Brai n I ma gi n g -if a p plica ble p
X
X p
X
X
B o ne I ma gi n g -if a p plica ble q
X
X q
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
5 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Tiss ue C ollecti o n b
Scree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -L 1 
stat us a n d bi o mar ker a nal ysis r
X
O pti o nal tiss ue f or bi o mar ker 
a nal ysis s
X
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker / P D -L 1 a nal ysis t
X
S u bject Re p orte d O utc o mes
b , u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
a.
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 wee ks b y  tele p h o n e. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o ns or n otificati o n, all partici pa nt s 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 deat h e ve nt pre vi o usl y rec or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nts/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m trial
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des 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 past 1 0 years c o nsi dere d t o b e cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1.
f.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
g.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d pr i or t o 
treat me nt a d mi nistrati o n.
h.
Scree ni n g E C O G Perf or ma nce Stat us (P S ) s h o ul d be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n.
i.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2.6.
j.
Scree ni 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 ra n d o mizati o n. After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d d ose.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
k.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. If t he uri ne test is p ositi ve 
or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
l.
A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial.
m.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
n.
T u m or mar kers ( C A 1 5 -3, C E A , a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote x 
f or details.
o.
Bl o o d f or g e netics are ma n dat or y sa m ples u nless t here is eit her a d oc u me nte d la w or re g ulati o n pr o hi biti n g c ollecti o n, or if t he I R B/I E C d oes n ot a p pr o ve t he c ollecti o n of 
t he sa m ple f or t hese p ur p oses .
p.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule (e ver y 9 wee ks [Q 9 W ] f or t he first ye ar, t he n 
Q 1 2 W) a n d will be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
q.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o n e p ai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d. A b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne pai n.
r.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o ps y fr o m a me t ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R
s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6-da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
s.
F or s u bjects o n t h e p e m br oliz u ma b ar m, 2 o pti o nal tiss ue bi o psies ma y be o btai ne d o n or aft er C y cl e 2 , a n d /or at disease pr o gressi o n .  T here are c o nse nt c hec k b o xes i n t h e 
mai n c o nse nt t hat m ust be c o m pl ete d f or e ver y s u bject o n t he pe m br oliz u ma b ar m. 
t.
W he n 
a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
It is str o n gl y rec o m me n de d t hat electr o nic patie nt -re p orte d o utc o mes (e P R Os) are a d mi nistere d pri or t o dr u g a d mi nistrati o n, a d verse e ve nt e val uati o n a n d disease stat us 
n otificati o n.
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 - 3, C E A a n d C A 2 7.2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o me et scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt , t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 d a y s) f or t he first ye ar, t he n Q 1 2 W
( +/- 7 d a y s) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d  1st  ra di ol o gic  evi de nce  of disease pr o gressi o n ( PD) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI  deter mi nes t he s u bject w o ul d be nefit fr o m 
c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject per ir R E CI S T), t he start of ne w a nti -ca ncer treat me nt, wit h dra wal of c o nse nt, deat h, or t he e n d of t he st u d y, w hic he ver occ urs 
first.
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, a n d E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C y cle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
6 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – Ge mcit a bi ne or Eri b uli n
6. 1. 2
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
A d mi nistr ati ve 
Pr oce d ures b
I nf or me d C o nse nt
X
I nf or me d C o nse nt f or 
F ut ure Bi o me dical 
Researc h
X
I ncl usi o n/E xcl usi o n 
Criteria
X
S u b ject I de ntificati o n 
Car d
X
De m o gra p hics a n d 
Me dical Hist or y
d
X
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  
X  
X  
X  
X  
X  
X  
X  
X  
X z
Ge m cita bi ne or eri b uli n 
A d mi nistrati o n e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P os t-st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
1 2 -Lea d E C G ( L ocal) g
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
F ul l P h ysical E xa mi nati o n
X
X
Dir ecte d P h ysical 
E xa mi nati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vit al Si g ns a n d Wei g ht h
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce 
Stat us
X i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us j
X
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, k
Pre g na nc y Test l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Uri nal ysis
X
X
X
X  
X x
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) o, v,
X
X o
X
X
L a b or at or y 
Pr oce d ures/ Assess me nts: 
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics p
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
C orrelati ve Bl o o d 
Sa m ples ( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, 
Ser u m)
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g -if 
a p plica ble q
X
X q
X
B o ne I ma gi n g -if 
a p plica ble r
X
X r
T u m or Tiss ue 
C ollecti o n b
Scree ni n g tiss ue f or 
ce ntral c o nfir mati o n of 
T N B C, P D - L 1 stat us a n d 
bi o mar ker a nal ysis s
X
O pti o nal arc hi val tiss ue 
f or bi o mar ker/ P D-L 1 
a nal ysis t
X
S u bject Re p orte d 
O utc o mes b, u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
a.
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 wee ks b y tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o ns or n otificati o n, all partici pa nt s 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 wil l 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 deat h e ve nt pre vi o usl y rec or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt s/ pr oce d ures i n Secti o n 7. 0 .  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n di sease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m 
st u d y treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 
wee ks fr o m t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des 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 past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1 .
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y t e mperat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G s h o ul d be perf or me d wit h i n 1 0 da ys pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2. 6.
k.
Scree ni 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 ra n d o mizati o n. After C y cle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d 
d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. . If t he uri ne test is 
p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if 
dee me d necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 15- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote 
w f or details.
p.
Bl o o d f or g e netics are m a n dat or y sa m ples u nless t here is eit her a d oc u me nte d la w or re g ulati o n pr o hi biti n g c ollecti o n, or if t he I R B/I E C d oes n ot a p pr o ve the c ollecti o n of 
t he sa m ple f or t hese p ur p oses.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g
f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first year, t he n Q 1 2 W) a n d will
be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
r.
B o ne sca ns wi ll be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as 
nee de d f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m u sc ul os keletal c o m plai nts or if t he site belie ve s t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has
n o k n o w n metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A b o ne sca n ca n be o btai n e d at f oll o w u p if t here are ne w s y m pt o ms of 
b o ne pai n .
s.
All s u bjects m us t ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o psy fr o m  a met ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n , a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6 - da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
It is str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d 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.
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 da ys) f or t he first ye ar t he n Q 1 2 W
( +/- 7 da ys) t hereafter. I magi n g s h o ul d c o nti n ue u ntil site-
assesse d 1st ra di ol o gic e vi de nce of P D is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI deter mi nes t he s u bject w o ul d be nefit fr o m c o nti n ue d treat me nt a n d t he n 
f oll o ws t he s u bject per ir R E CI S T), t he start of ne w a nti-ca ncer treat me nt, wit h dra wal of c o nse nt, deat h, or t he e n d of t he st u d y, w hic he ver occ urs first .
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, a n d E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C y cle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt Me dicati o n
Re vie w d uri n g F oll o w -U p Visits is f or n e w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d
(as s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
6 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – C a pecit a bi ne
6. 1. 3
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nistr ati ve 
Pr oce d ures b
I nf or me d C o nse nt
X
I nfor me d C o nse nt f or F ut ure 
Bi o me dical Researc h
X
I ncl usi o n/ E xcl usi o n Criteria
X
S u bject I de ntificati o n Car d
X
De m o gra p hics a n d Me dical 
Hist or y d
X
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
X
X z
Ca pecita bi ne 
A d mi nistrati o n e
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
1 2 -Lea d E C G ( L ocal) g
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
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Vital Si g ns a n d Wei g ht
h
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce Stat us i
X i
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
j
X
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, k h
Pre g na nc y Test Ser u m l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
X
X
X  
X x
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or 
mar kers 
( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) o, v, w
X
X o
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 b
Bl o o d f or Ge netics p
X
C orrelati ve Bl o o d Sa m ples 
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, Ser u m)
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Effic ac y Me as ure me nts
b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g -if 
a p plica ble g q
X
X q
X
X
B o ne I ma gi n g -if a p plica bler
X
X r
T u m or Tiss ue C ollecti o n b
Scree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -
L 1 stat us a n d bi o mar ker 
a nal ysis s
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker/ P D -L 1 a nal ysis t
X
S u bje ct Re p orte d 
O utc o mes b, u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
a.
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 w ee ks b y  tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. 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 deat h e ve nt pre vi o usl y rec or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nts/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des 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 past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If a c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
6 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1 .
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G P S s h o ul d be perf or me d wit hi n 1 0 da y pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2.6.
k.
After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tes ts.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. . If t he uri ne test is p ositi ve 
or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he tr ial.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote w 
f or details.
p.
Bl o o d f or g e netics are ma n dat or y sa m ples u nless t here is eit her a d oc u me nte d la w or re g ulati o n pr o hi biti n g c ollecti o n, or if t he I R B/I E C d oes n o t a p pr o ve t he c ollecti o n of 
t he sa m ple f or t hese p ur p oses.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first ye ar, t he n Q 1 2 W) a n d will 
be perf or me d i n s u bjects wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
r.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne.
s.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o ps y f r o m  a met ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n , a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6- da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
It is str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d 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. 
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
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 a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
w.
T u m or i ma gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W ( +/- 7 da ys) f or t he first ye ar, t he n Q 1 2 W ( +/- 7 da ys) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d  1st  ra di ol o gic  evi de nce  of disease pr o gressi o n ( PD) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site P I deter mi nes t he s u bject w o ul d be nefit fr o m 
c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject per irR E CI S T), t he start of ne w a nti-ca ncer treat me nt, wit h dra wal of  co nse nt, deat h, or t he e n d of t he st u d y, w hic he ver 
occ urs first.
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, a n d E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt Me dicati o n
Re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d
(as s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
7 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – Vi n o rel bi ne
6. 1. 4
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5 
6
7 a n d Be y o n d
Disc o n c
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 a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nis tr ati ve 
Pr oce d ures b
I nf or me d C o nse nt
X
I nf or me d C o nse nt f or 
F ut ure Bi o me dical 
Researc h
X
I ncl usi o n/ E xcl usi o n 
Criteria
X
S u bject I de ntificati o n Car d
X
De m o gra p hics a n d Me dical 
Hist or y d
X
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  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X z
Vi n orel bi ne
A d mi nistrati o n e
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
-------------------------------------------------------------------------------------------------------------------------------------------------

X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
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 a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
1 2 -Lea d E C G ( L ocal) g
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
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vital Si g ns a n d Wei g ht h
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce Stat us i
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
j
X
L a b or at or y 
Pr oce d ures/ Assess me nts:  
L O C A L l a b or at or y b, k
Pre g na nc y Test – Ser u m l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y Pa nel
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Uri nal ysis
X
X
X
X  
X x
X x
X x
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X x
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5 -3, 
C E A a n d C A 2 7. 2 9) o, v
X
X o
X
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
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 a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
L a b or at or y 
Pr oce d ures/ Assess me nts:  
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics p
X
C orrelati ve Bl o o d Sa m ples 
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, 
Ser u m) 
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g –i f 
a p plica ble q
X
X q
X
X
B o ne I ma gi n g -if a p plica bler
X
X r
T u m or Tiss ue C ollecti o n b
S cree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -
L 1 stat us a n d  bi o mar ker 
a nal ysis s
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker/ P D -L 1 a nal ysis t
X
S u bject Re p orte d 
O utc o me
b, u
E Q -5 D
X
X
X
X
X y
X y
X y
X
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
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 a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X y
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X y
X y
X
X
a.
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 w ee ks b y  tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o n s 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 deat h e ve nt pre vi o usl y re c or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt s/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n di sease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des all active 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 past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1.
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G s h o ul d be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2. 6.
k.
Scree ni 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 ra n d o mizati o n. Aft er C ycle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d d ose.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. If t he uri ne test is p ositi ve 
or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote w 
f or details.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
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 a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
p.
Bl o o d f or g e netics are m a n dat or y sa m ples u nless t here is eit her a d oc u me nte d la w or re g ulati o n pr o hi biti n g c ollecti o n, or if t he I R B/I E C d oes n ot a p pr o ve t he c ollecti o n of 
t he sa m ple f or t hese p ur p oses.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first y ear, t he n Q 1 2 W) a n d will
be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms .
r.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os ke letal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A bo ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne
metastasis .
s.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u mor bi o p s y fr o m a me t ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n a n arc hi val or s a mpl e or sli des ma y be s u b mitted A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt
wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n. A n y tiss ue pri or t o t he 5 6 -da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns f or m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n arc hi ve d vs .
ne wl y o btai ne d t u m or s peci me ns.
u.
It is str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d 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. 
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 d a y s) f or first ye ar t he n Q 1 2 W
( +/- 7 da ys) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d 1st ra di ol o gic e vi de nce of disease pr o gressi o n ( P D) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI deter mi nes t he s u bject w o ul d be nefit fr om c o nti n ue d 
treat me nt a n d t he n f oll o ws t he s u bject per ir R E CI S T), t he start of ne w a nti-ca ncer treat me nt, wit h dra wal of c o nse nt, deat h, or t he e n d of t he st u d y, w hic he ver occ urs first .
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3 u ntil
t he e n d of ye ar 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n S ecti o n 7. 1. 2. 1).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
7 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Sec o n d C o urse P h ase ( Retre at me nt) f or Pe m br oliz u m a b Ar m O nl y
6. 2
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
A d mi nistr ati ve Pr oce d ures b
Eli gi bilit y Criteria
X
C o nc o mita nt Me dicati o n & 
Me dical Hist or y
X
X  
X  
X  
X  
X  
X
X
X
X r
Pe m br oliz u ma b A d mi nistrati o n
X  
X  
X  
X  
X  
X
x
P ost -st u d y A ntica ncer T hera p y 
Stat us
X
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts d
X  
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
Vital Si g ns a n d Wei g ht e
X
X  
X  
X  
X  
X  
X
X
E C O G Perf or ma nce Stat us
X  
X  
X  
X  
X  
X  
X  
X
X
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, f
Pre g na nc y Test – Ser u m g
X
P T /I N R a n d a P T Th
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X
X
X
Uri nal ysis
X
X
X
X  
X p
X
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
T 3, F T 4 a n d T S H i, n
X
X
X  
X p
X
T u m or mar kers ( C A 1 5-3, C E A 
a n d C A 2 7. 2 9) j, n, o
X j
X
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g k, o
X
X o
X
X
Brai n I ma gi n g -if a p plica blel
X
X l
B o ne I ma gi n g -if a p plica blem
X
X m
a.
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 w ee ks b y  tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. 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 deat h e ve nt pre vi o usl y re c or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt/ pr oce d ures i n Secti o n 7. 0.
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
G ui da nce o n rec or di n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1. 
e.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, a n d b o d y wei g ht. Vital si g ns s h o ul d be perf or me d pri or t o treat me nt 
a d mi nistrati o n.
f.
After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
g.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial retreat me nt. . If t he uri ne test is 
p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if 
dee me d necessar y b y PI or re q uire d b y l ocal g ui deli nes.
h.
A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t h e trial.
i.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
j.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote o 
f or details.
k.
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. 
l.
Brai n i ma gi n g s h o ul d be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n 
metastases. D ur i n g a s u bject’s first year o n trial, brai n i ma gi n g f oll o ws a Q 9 W cale n dar sc he d ule. After t he first year, brai n i ma gi n g is Q 1 2 W .
m.
B o ne sca ns s h o ul d b e perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt i n s u bjects wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts.  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
7 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
B o ne sca ns s h o ul d be perf or me d o n treat me nt f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts o r if t he site belie ves t he y ha ve attai ne d a 
C o m plete Res p o nses.  If a s u bject has n o k n o w n metastatic disease i n t he b o ne or acti ve s y m pt o ms, b o ne sca ns are n ot nee de d.  A b o ne sca n ca n be o btai ne d at f oll o w u p wit h 
t here are ne w s y m pt o ms of b o ne pai n.
n.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
o.
I ma gi n g f oll o ws a Q 9 W cale n dar sc he d ule, it is i n de pe n de nt of c ycles.
p.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
q.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3 u ntil
t he e n d of ye ar 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
r.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
7 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 0 T RI A L P R O C E D U R E S
Tri al Pr oce d ures
7. 1
T he Trial Fl o w C hart - Secti o n 6 . 0 s u m marizes t he trial pr oce d ures t o be perf or me d at eac h 
visit.  In di vi d ual trial pr oce d ures are descri be d i n detail bel o w.  It ma y  be necessar y  to 
perf or m t hese pr oce d ures at u nsc he d ule d ti me p oi nts if dee me d cli nicall y necessar y  by t he 
i n vesti gat or.
F urt her m ore, 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 reas o ns relate d t o s u bject 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, He patitis C, etc.), 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 s u bject.  In 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.
A d mi nistr ati ve Pr oce d ures
7. 1. 1
7. 1. 1. 1
I nf or me d C o nse nt
T he i n vesti gat or or q ualifie d desi g nee m ust o btai n d oc u me nte d c o nse nt fr o m eac h p ote ntial 
s u bject or eac h s u bject’s le gall y acce pta ble re prese ntati ve pri or t o partici pati n g i n a cli nical 
trial or F ut ure Bi o me dical Researc h .
7. 1. 1. 2
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  the s u bject’s date d si g nat ure or b y  the s u bject’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 s u bject bef ore 
partici pati o n i n t he trial.
T he i nitial i nf or me d c o nse nt f or m, a n y s u bse q ue nt re vise d writte n i nf or me d c o nse nt f or m 
a n d a n y writte n 
i nf or mati o n pr o vi de d t o t he s u bject m ust 
recei ve t he I RB/ E R C’s 
a p pro val/fa v ora ble o pi ni o n i n a d va nce of use.  The s u bject or his/ her le gall y acce pta ble 
re prese ntati ve s h o ul d be i nf or me d i n a ti mely ma n ner if ne w i nf or mati o n bec o mes a vaila ble 
t hat m a y  be rele va nt t o t he s u bject’s willi n g ness t o c o nti n ue partici pati o n i n t he trial.  Th e 
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 s u bject’s date d si g nat ure or 
b y  t he s u bject’s le gally acce pta ble re prese ntati ve’s date d si g nat ure.
S pecifics a b o ut a trial a n d t he trial 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 RB/ E R 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.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 1. 2. 1
C o nse nt a n d C ollecti o n of S peci me ns f or F ut ure Bi o me dic al Rese arc h
T he i n vesti gat or or q ualifie d desi g nee will e x plai n t he F ut ure Bi o me dical Researc h c o nse nt 
t o t he s u bject, a ns wer all of his/ her q uesti o ns, a n d o btai n writte n i nf or me d c o nse nt bef ore 
perf or mi n g a n y pr o ce d ure relate d t o t he F ut ure Bi o me dical Researc h s u b -trial.  A c o p y of t he 
i nf or me d c o nse nt will be gi ve n t o t he s u bject.
7. 1. 1. 3
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 or q ualifie d 
desi g nee t o e ns ure t hat t he s u bject q ualifies f or t he trial.
7. 1. 1. 4
S u bject I de ntific ati o n C ar d
All s u bjects will be gi ve n a S u bject 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 trial.  The car d will c o ntai n trial 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 utilize d i n t he e ve nt of a n e mer ge nc y.  The i n vesti gat or or q ualifie d desi g nee 
will pr o vi de t he s u bject wit h a S u bject I de ntificati o n Car d i m me diatel y after t he s u bject 
pr o vi des writte n i nf or me d c o nse nt.
T he s u bject 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 h care pr o vi der ca n o btai n i nf or mati o n a b o ut trial 
me dicati o n/ vacci nati 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.
7. 1. 1. 5
Me dic al Hist or y
De m o gra p hic i nf or mati o n a n d me dical hist or y  will be o btai ne d b y  the In vesti gat or or 
q ualifie d desi g nee.   Me dical hist or y  will i ncl u de 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 ye ars, t hat are c o nsi dere d t o be cli nicall y si g nifica nt b y  the 
I n vesti gat or. Details re gar di n g t he s u bject’s breast ca ncer hist or y  will be rec or de d se paratel y 
a n d n ot liste d as me dical hist or y .  A n y a ut oi m m u ne dis or ders s h o ul d be rec or de d re gar dless 
of o nset date .
7. 1. 1. 5. 1
Dise ase Det ails
T he I nvesti gat or or q ualifie d desi g nee will o btai n pri or a n d c urre nt details re gar di n g t he 
s u bject’s breast ca ncer dia g n osis .
7. 1. 1. 6
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
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 as s pecifie d i n t he 
Trial Fl o w C h art ( Secti o n 6. 0), 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  the s u bject wit hi n 2 8 d a y s bef ore ra n d o mizati o n.  Pri or 
treat me nt f or breast ca ncer will be rec or de d se paratel y a n d n ot liste d as a pri or me dicatio n.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 1. 6. 1
Pri or Tre at me nt Det ails f or Bre ast C a ncer Di a g n osis
T he I n vesti gat or or q ualifie d desi g nee will re vie w all pri or treat me nts f or s u bject’s breast 
ca ncer dia g n osis, i ncl u di n g sys te mic treat me nts, ra diati o n a n d s ur geries.
7. 1. 1. 6. 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 s, if a n y, ta ke n b y  the s u bject 
d uri n g t he trial t hr o u g h t he Safet y F oll o w - u p visit , as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0) .  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 urse P hase t hr o u g h 
t he Sec o n d C o urse Safet y  Foll o w - u p visit s h o ul d be rec or de d.  All me dicati o ns relate d t o 
re p orta ble A Es, S A Es , a n d E CIs s h o ul d be rec or de d as defi ne d i n Secti o n 7. 2.
7. 1. 1. 6. 3
S u bse q ue nt A nti -c a ncer T her a p y St at us
T he I nvesti gat or or q ualifie d desi g ne e will re vie w all ne w a nti-ca ncer t hera py i nitiate d after 
t he last d ose of trial treat me nt.  If a s u bject i nitiates a ne w a nti-ca ncer t hera p y wit hi n 3 0 da ys 
after t he last d ose of trial treat me nt, t he 3 0 d a y  Safet y Foll o w - u p visit m ust occ ur bef ore t he 
first d ose of t he ne w t hera p y.  Once ne w a nti-ca ncer t hera py has bee n i nitiate d t he s u bject 
will m o ve i nt o s ur vi val f oll o w - u p.  
7. 1. 1. 7
Assi g n me nt of Scree ni n g N u m ber
All c o nse nte d s u bjects 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 s u bject f or all pr oce d ures t hat occ ur pri or t o ra n d o mizati o n or all ocati o n.  Eac h s u bject 
will be assi g ne d o nl y o ne 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 or 
differe nt s u bjects.
A n y  su bject 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.
S pecific details o n t he scree ni n g visit re q uire me nts (scree ni n g/rescree ni n g) are pr o vi de d i n 
Secti o n 7. 1. 5. 1.  
7. 1. 1. 8
Assi g n me nt of R a n d o miz ati o n N u m ber
All eli gi ble s u bjects will be ra n d o ml y all ocate d a n d will recei ve a ra n d o mizati o n n u m ber.  
T he ra n d o mizati o n n u m ber i de ntifies t he s u bject f or all pr oce d ures occ urri n g after 
ra n d o mizati o n.  Once a ra n d o mizati o n n u m ber is assi g ne d t o a s u bject, it ca n ne ver be re-
assi g ne d t o a n ot her s u bject.
A si n gle s u bject ca n n ot be assi g ne d m ore t ha n 1 ra n d o mizati o n n u m ber.
I n vesti gat ors m ust c h o ose a T P C dr u g (ca pecita bi ne, eri b uli n, ge mcita bi ne or vi n orel bi ne ) 
pri or t o ra n d o mizati o n a n d d oc u me nt t he selecti o n i n t he I V R S a n d trial data base ( See Data 
E ntr y  G ui deli nes).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
8 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 1. 9
Tri al C o m pli a nce ( Me dic ati o n/ Diet/ Acti vit y/ Ot her)
A n y  inter r u pti o ns greater t ha n 1 2 wee ks bet wee n d oses (pe m br oliz u ma b or T P C ar m s) 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 s u bject ma na ge me nt.
A d mi nistrati o n of trial me dicati o n will be wit nesse d b y  t he I n vesti gat or a n d/ or trial staff. T he 
t otal v ol u me of p e m br oliz u ma b or c o m parat or i nf use d will be c o m pare d t o 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 of pe m br oliz u ma b or c o m parat or 
a d mi nistere d.
T he i nstr ucti o ns f or pre pari n g a n d a d mi nisteri n g pe m br oliz u ma b will be pr o vi de d i n t he 
P har mac y  Ma n ual.  T P C a ge nts will be pre pare d a n d a d mi nistere d as per l ocal pr o d uct la bel.
Please refer t o Secti o n 5. 2 f or i nstr ucti o ns o n pe m br oliz u ma b a n d T P C.
7. 1. 1. 1 0 S ur vi v al
After t he start of ne w a nti -ca ncer treat me nt or d oc u me nte d disease pr o gressi o n b y t h e c entral 
i ma gi n g ve n d or, t he s u bject s h o ul d be c o ntacte d b y  tele p h o ne e ver y 12 wee ks fr o m t he last 
c o ntact date f or s ur vi val stat us assess me nt .
Cli nic al Pr oce d ures/ Assess me nts
7. 1. 2
7. 1. 2. 1
A d verse E ve nt M o nit ori n g
T he I n vesti gat or or q ualifie d desi g nee will assess eac h s u bject t o e val uate p ote ntial ne w or 
w orse ni n g A Es at eac h visit a n d as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 6. 0) , or m ore 
fre q ue ntly if cli nicall y i n dicate d.  A Es will be gra de d a n d rec or de d t hr o u g h o ut t he st u d y  an d 
d uri n g t he f oll o w-u p peri o d acc or di n g t o N CI  CT C A E Versi o n 4. 0 ( Secti o n 7. 2 ).  To xicities 
will be c haracterize d i n ter ms re gar di n g seri o us ness, ca usalit y, t o xicit y gra di n g, a n d acti o n 
ta ke n wit h re gar d t o trial treat me nt.  
Please refer t o Secti o n 7 . 2 f or detaile d i nf or mati o n re gar di n g t he assess me nt a n d rec or di n g of 
A Es.  
7. 1. 2. 2
1 2 -Le a d Electr oc ar di o gr a m 
A sta n dar d 1 2 -lea d electr ocar di o gra m (E C G ) will be perf or me d usi n g l ocal sta n dar d 
pr oce d ures o nce at scree ni n g.  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 . A d diti o nal ti me p oi nts ma y be perf or me d as cli nically necessar y.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 2. 3
P h ysic al E x a m
7. 1. 2. 3. 1
F ull P h ysic al E x a m
T he I n vesti gat or or cli nical desi g nee will
perf or m a c o m plete p h y si ci an 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. After t he scree ni n g peri o d, a f ull p h y sical e xa m s h o ul d be perf or me d as s pecifie d i n 
t he Trial
Fl o w
C hart
( Secti o n 6. 0).
After
ra n d o mizati o n ne w
cli nicall y
si gnifica nt
a b n or mal fi n di n gs s h o ul d be rec or de d as A Es.
7. 1. 2. 3. 2
Directe d P h ysic al E x a m
T he I n vesti gat or or cli nical desi g nee will perf or m direc t e d p h y sical e xa ms at eac h visit w hile 
o n trial treat me nt, as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 6. 0), a n d as nee de d acc or di n g
t o s u bject’s si g ns a n d s ym pt o ms. 
Ne w
cli nicall y si gnifica nt a b n or mal fi n di n gs s h o ul d b e 
rec or de d as A Es.
7. 1. 2. 4
Vit al S i g ns 
T he I n vesti gat or or q ualifie d desi g nee will ta ke vital si g ns at scree ni n g, pri or t o t he 
a d mi nistrati o n of eac h d ose of trial treat me nt a n d at treat me nt disc o nti n uati o n , as s pecifie d i n 
t he Trial Fl o w C hart ( Secti o n 6. 0). Vital si g ns s h o uld i ncl u de te m perat ure, p ulse, res pirat ory 
rate, wei g ht a n d bl o o d press ure. Hei g ht will be meas ure d
at scree ni n g o n l y. Vitals s h o ul d
be ta ke n pri or t o treat me nt a d mi nistrati o n.
7. 1. 2. 5
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
T he I n vesti gat or or q ualifie d desi g nee will assess E C O G stat us ( Secti o n 1 2. 5 ) at scree ni n g, at
eac h treat me nt c ycle a n d at disc o nti n uati o n of trial treat me nt, as s pecifie d i n t he Trial Fl o w 
C hart ( Secti o n 6. 0).
7. 1. 2. 6
Me n o p a us al St at us
T he me n o pa usal stat us ( pre- or p ost -me n o pa u sal) f or all fe male s u bjects less t ha n a ge 6 0 
m ust be deter mi ne d at scree ni n g, acc or di n g t o t he defi niti o ns bel o w. 
T he date of t he 
s u bject’s last me nstr ual peri o d ( L M P) a n d, w he n i n dicate d, ser u m F S H a n d estra di ol le vels 
m ust be assesse d a n d rec or de d i n the e C R Fs.
Pre -me n o pa usal

≤1 2 m o nt hs si nce L M P
O R

Bi oc he mical e vi de nce of pre -me n o pa usal 
stat us, acc or di n g t o ser u m F S H
a n d 
estra di ol le vels a n d l ocal i nstit uti o nal g ui deli nes
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
P ost -me n o pa usal

S u bject has u n der g o ne pri or bilateral o variect o m y/ o o p h orect o m y 
O R

> 1 2 m o nt hs 
si nce L M P
a n d n o h y sterect o m y, h or m o ne re place me nt, estr o ge n 
rece pt or a nta g o nist, c he m ot hera py or o varia n s u p pressi o n at a n y ti me si nce L M P 
O R

Bi oc he mical e vi de nce of p ost -me n o pa usal 
stat us, acc or di n g t o ser u m F S H
a n d 
estra di ol le vels a n d l ocal i nstit uti o nal g ui deli nes.
7. 1. 2. 7
T u m or I m a gi n g a n d Assess me nt of Dise ase
T he
pr ocess 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 Site I ma gi n g Ma n ual. 
T u m or i ma gi n g m a y b e perf or me d b y co m p ute d 
t o m o gra ph y ( C T) ( preferre d) or ma g netic
res o na nce i ma gi n g ( M RI), b ut t he sa me i ma gi n g 
tec h ni q ue s h o uld be use d i n a s u bject t hr o u g h o ut t he trial. 
A CT is t he m or e c o m m o nl y
us e d m o dalit y a n d is preferre d f or t he maj orit y of s u bjects. A n
M RI
can be utilize d if
cli nicall y a p pr o priate.
D uri n g 
scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h 
k n o w n brai n 
metastases (s uc h s u bject als o nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks 
earlier) a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s ym pt o ms . S u bjects wit h 
pre vi o usl y  treate d brai n metastases 
m a y  partici pate pr o vi de d t he y ha ve sta ble brai n 
metastases, ie, wit h o ut e vi de nce of pr o gressi o n b y  ima gi n g (c o nfir me d b y  MRI  if M RI  was 
use d at pri or i ma gi n g, or c o nfir me d b y  CT i ma gi n g if C T was use d at pri or i ma gi n g) f or at 
least 4 wee ks pri or t o t he first d ose of trial treat me nt.  An y  ne ur ol o gic s ym pt o ms m ust ha ve 
ret ur ne d t o baseli ne a n d s u bjects m ust 
ha ve n o e vi de nce of ne w or e nlar gi n g brai n 
metastases, a n d ha ve n ot use d ster oi ds f or brai n metastases f or at least 2 8 d a y s pri or t o trial 
i nitiati o n as per l ocal site assess me nt.  This e x ce pti o n d oes n ot i ncl u de carci n o mat o us 
me ni n gitis, as s u bjects wit h carci n o mat o us me ni n gitis are e xcl u de d re gar dless of cli nical 
sta bilit y.
W hile
o n st u dy , brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h k n o w n brai n metastases 
a n d s u bjects wit h
w orse ni n g
a n d/ or ne w ne ur ol o gical s ym pt o ms. 
If M RI  is me dicall y
c o ntrai n dicate d, C T i ma gi n g will be acce pte d. Brai n i ma gi n g w o ul d be d o ne Q 9 W f or first
ye ar, t he n Q 1 2 W, as s pecif ie d i n t he Trial Fl o w C hart ( Secti o n 6. 0).
If a p plica ble, b o n e sca ns will
be perf or me d as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 
6. 0). B o ne sca ns at scree ni n g f or a n y s u bject wit h
k n o w n b o ne metastases a n d/ or ne w 
b o ne pai n a n d m usc ul os keletal c o m plai nts. D uri n g t he st u dy, b o ne sca ns will be perf or me d
as nee de d f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts 
or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject h a s n o k n o w n
metastatic disease i n t he b o ne or acti ve s ym pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A 
b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s ym pt o ms of b o ne pai n.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
All
sc he d ule d i ma ges f or all st u dy s u bjects fr o m t he sites will
be s u b mitte d t o t he ce ntral 
i ma gi n g ve n d or
( CI V). I n a d diti o n, all u nsc he d ule d i ma ges t hat t he site c o nsi ders 
c o ntri b utes t o pr o gressi o n or res p o nse will
be s u b mitte d t o t he CI V. 
T h e ce ntral i ma gi n g
ve n d or will recei ve all i ma ges fr o m t he sites an d verif y pr o gressi ve disease f oll o wi n g site-
assesse d 1st ra di ol o gic e vi de nce of pr o gressi ve disease usi n g R E C IS T 1. 1. T he verificati o n 
of ra di ol o gic P D will be e x pe dite d b y t he CI V. T he CI V verificati o n of ra di ol o gic P D will
be c o m m u nicate d t o t he site ( Secti o n 7. 1. 2. 7. 3) a n d s p o ns or wit hi n 3- 5 b usi ness da ys after 
recei pt 
of 
all 
re q uire d 
i ma gi n g 
a n d 
res ol uti o n 
of 
all 
q ueries i n 
real-ti me. 
E x pe dite d verificati o n of ra di ol o gic pr o gressi o n as deter mi ne d b y ce ntral i ma gi n g 
ve n d or re vie w (f oll o wi n g site-assesse d 1st ra di ol o gic e vi de nce of pr o gressi ve disease)
will  be c o m m u nicate d t o t he site ( Secti o n 7. 1. 2. 7. 3). T he CI V will perf or m a retr os pecti ve
a nal ysis of s u bject eli gi bilit y (per R E C I S T 1. 1) a n d treat me nt res p o nse b y ( usi n g R E C I S T
1. 1 a n d ir R E CIS T) a nd t he se will
be pr o vi de d t o t he s p o ns or. S p o ns or will
also recei ve
t u m or i ma gi n g f or a retr os pecti ve a nal ysis of s u bject eli gi bilit y a n d treat me nt res p o nse t o be 
perf or me d b y t h e ce ntral ve n d or usi n g R E C I S T 1. 1 a nd ir R E CIS T . Fi g ure 2 s h o ws t he 
pr ocess f or t u m or assess me nt b y site a n d ce ntral i ma gi n g ve n d or f or a cli nicall y sta ble 
s u bject.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
8 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Fi g ure 2
I ma gi n g a nd Treat me nt f or Cli nical l y Sta bl e S u bjects A fter First Ra di ol o gic
E vi de nce of P r o gressi ve Disease Assesse d b y t he Site
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
8 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Fi g ure 3 s h o ws t he pr ocess f or t u m or assess me nt b y  site a n d ce ntral i ma gi n g ve n d or f or a 
cli nicall y u nsta ble s u bject.
* Site m us t se n d all re q uire d i ma gi n g t o CI V a n d res ol ve all i ma gi n g q ueries; t hen t he 3
-5 b usi ness d a y T A T f or n otificati o n be gi ns. A n y
u nsc he d ule d i ma gi n g t hat s u p p orts a
site base d assess me nt of P D s h o ul d als o be se nt t o CI V.
Fi g ure 3
I ma gi n g Pr ocess f or a Cli nicall y U nsta ble S u bject
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 2. 7. 1
B aseli ne T u m or I m a gi n g
T o meet scree ni n g criteria, t u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da y s pri or t o date of 
ra n d o mizati o n.  Eli gi ble s u bjects m ust ha ve meas ura ble disease base d o n R E CI S T 1. 1 as 
assesse d b y site I n vesti gat or a n d l ocal ra di ol o g y re vie w. T u m or i ma gi n g 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 t u m or i ma gi n g if t he y are 
of dia g n ostic q ualit y , meet t he re q uire me nts s pecifie d i n t he Site I ma gi n g M a n ual ( SIM) , a n d 
were perf or me d wit hi n 2 8 da y s pri or t o ra n d o mizati o n.  
Brai n i ma gi n g at baseli ne s h o ul d be perf or me d i n s u bjects wit h k n o w n brai n metastases 
(s uc h s u bjects als o nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier) a n d 
t h ose wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
If a s u bject has a k n o w n hist or y  of b o ne metastases or has ne w b o ne pai n d uri n g scree ni n g, a 
b o ne sca n s h o ul d be o btai ne d pri or t o st u d y entr y .  If a s u bject has n o k n o w n metastatic 
disease i n t he b o ne or acti ve s ym pt o ms, a b o ne scan at baseli ne is n ot nee de d.   A d diti o nall y , 
plai n X- ra y eval uati o n s h o ul d be o btai ne d f or s ym pt o matic s keletal sites wit h ne gati ve b o ne 
sca n e val uati o ns.
7. 1. 2. 7. 2
T u m or I m a gi n g D uri n g t he Tri al
All s u bjects s h o ul d ha ve i ma gi n g assess me nts perf or me d as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0). S u bjects s h o ul d ha ve t u m or i ma gi n g at 9 wee ks ( ± 7 d a y s) fr o m date of 
ra n d o mizati o n u p t o 1 year ( m ore fre q ue ntl y if cli nicall y i n dicate d).  All s u bjects w h o re mai n 
o n treat me nt f or a ye ar will s u bse q ue ntl y ha ve i ma gi n g perf or me d e ver y 1 2 wee ks ( ± 7 da ys). 
I ma gi n g ti mi n g s h o ul d f oll o w cale n dar d a y s a n d s h o ul d n ot be a dj uste d f or dela y s i n c ycle 
starts. I ma gi n g s h o ul d co nti n ue t o be perf or me d u ntil site -assesse d 1st ra di ol o gic e vi de nce of 
disease pr o gressi o n ( P D) is verifie d b y  the ce ntral i ma gi ng ve n d or ( u nless t he site PI  
deter mi nes t he s u bject w o ul d be nefit fr o m c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject 
per ir R E CIS T), t he start of ne w a nti-ca ncer treat me nt, wit h dra wal of c o nse nt, deat h, or t he 
e n d of t he st u d y, w hic he ver occ urs first. 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. 
B o n e sca ns will
als o be utilize d to assess osse o us metastases. 
If a s u bject has a k n o w n 
hist or y of b o ne metastases
or has ne w b o ne pai n d uri n g scree ni n g, a b o ne sca n s h o ul d be 
o btai ne d pri or t o st u dy e ntr y. A b o ne sca n at f oll o w u p is re q uire d o nl y if t hey d e vel o p ne w 
or w orse ni n g s ym pt o ms
or if t he site belie ves t hey ha ve attai ne d a C o m plete Res p o nse. If a 
s u bject has n o k n o w n me tastatic disease i n t he b o ne or acti ve s ym pt o ms , a b o ne sca n at 
baseli ne is n ot nee de d. A b o ne
sca n can be o btai ne d at f oll o w u p if t here ar e ne w
s ym pt o ms of
b o ne
pai n.
A d diti o nall y,
plai n
X- ray
e val uati o n
will
be
o btai ne d
f or
s ym pt o matic
sites wit h ne gati ve b o ne sca n e val uati o ns.
Brai n i ma gi n g d uri n g t he trial s h o ul d be perf or me d as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0) i n s u bjects wit h k n o w n brai n metastases ( Q 9 W f or first ye ar, t he n Q 1 2 W) a n d 
t h ose wit h w orse ni n g a n d/ or ne w ne ur ol o gical s ym pt o ms.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
8 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Per R E CI S T 1. 1, res p o nse ( partial res p o nse (P R) or C R s h o ul d be c o nfir me d b y  a re peat 
t u m or i ma gi n g n ot less t ha n 4 wee ks fr o m t he date t he res p o nse was first d oc u me nte d.  The 
t u m or i ma ge f or c o nfir mati o n of res p o nse ma y  be perf or me d at t he earliest 4 wee ks after t he 
first i n dicati o n of res p o nse, or at t he ne xt sc he d ule d t u m or i ma gi n g (e g 9 wee ks later) 
w hic he ver is cli nicall y  i n dicate d.
After ce ntral verificati o n of P D b y R E C I S T 1. 1 i n s u p p ort of t he P F S a nal y sis, if t he site PI  
deter mi nes t he s u bject is cli nicall y sta ble a n d w ill be nefit fr o m c o nti n ue d treat me nt, t he 
s u bject will t he n be ma na ge d
b y ir R E CIS T.  P er ir R E CIS T, t hat i nitial P D b y R E C IS T 1. 1 
m ust
be i n cli nicall y sta ble s u bjects, disease pr o gressi o n m a y be c o nfir me d b y t he site 
I n vesti gat or/ l ocal ra di ol o gy re vie w at least 4 wee ks after verificati o n of 1st site-assesse d 1st 
ra di ol o gic e vi de nce of P D . 
Su bjects w h o
ha ve u nc o nfir me d disease pr o gressi o n ( P D)
m a y  c o nti n ue o n treat me nt u ntil pr o gressi o n P D is c o nfir me d pr o vi de d t hey h a ve met
t he 
c o n diti o ns detaile d i n Sec ti o n 7. 1. 2. 7. 4.
7. 1. 2. 7. 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
I n s u bjects w h o disc o nti n ue st u d y t hera p y, 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 (ie, date of disc o nti n uati o n ± 4 wee k wi n d o w).  If pre vi o us t u m or 
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  t u m or 
i ma gi n g at treat me nt disc o nti n uati o n is n ot re q uire d. I n s u bjects w h o disc o nti n ue trial 
treat me nt 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.
I n s ubjects w h o disc o nti n ue trial treat me nt wit h o ut ce ntrall y verifie 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  tu m or i ma gi n g 
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 (Q 9 W i n Year 1 or 1 2 wee ks after 
Year 1) t o m o nit or disease stat us u ntil 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 trial, w hic he ver occ urs first.
7. 1. 2. 7. 4
R E CI S T 1. 1
R E CI S T 1. 1 will be a p plie d b y  the ce ntral i ma gi n g ve n d or wit hi n 3- 5 b usi n ess da y s i n real-
ti me after recei pt of all i ma gi n g a n d res ol uti o n of a n y q ueries t o verif y  site-assesse d 1st 
ra di ol o gic e vi de nce of P D retr os pecti vely as t he pri mar y  meas ure f or assess me nt of t u m or 
res p o nse a n d retr os pecti vel y to deter mi ne s u bject eli gi bilit y.  All sc he d ule d i ma ges f or all 
st u d y su bjects fr o m t he sites will be s u b mitte d t o t he ce ntral i ma gi n g ve n d or ( CI V).   In 
a d diti o n, all u nsc he d ule d i ma ges t hat t he site c o nsi ders c o ntri b utes t o pr o gressi o n or res p o nse 
will be s u b mitte d t o t he CI V. All t u m or i ma ges s h o ul d be s u b mitte d t o t he ce ntral ve n d or.
7. 1. 2. 7. 5
ir R E CI S T
R E CI S T 1. 1 will be a da pte d t o acc o u nt f or t he u ni q ue t u m or res p o nse c haracteristics see n 
wit h treat me nt of pe m br oliz u ma b.  Im m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b ma y 
pr o d uce a ntit u m or effects b y  pote ntiati n g e n d o ge n o us ca ncer-s pecific i m m u ne res p o nses.  
T he res p o nse patter ns see n wit h s uc h a n a p pr oac h ma y  e xte n d be yo n d t he t y pical ti me c o urse 
of res p o nses see n wit h c yt ot o xic a ge nts, a n d ca n ma nifest a cli nical res p o nse after a n i nitial 
i ncrease i n t u m or b ur de n or e ve n t he a p peara nce of ne w lesi o ns.  Sta n dar d R E CI S T 1. 1 m a y , 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
t h us, n ot pr o vi de a n acc urate res p o nse assess me nt of i m m u n ot hera pe utic a ge nts s uc h as 
pe m br oliz u ma b. I mm u ne -relate d R E CI S T (ir R E CI S T) is R E CI S T 1. 1 a da pte d t o acc o u nt f or 
t he u ni q ue t u m or res p o nse see n wit h i m m u n o-t hera pe utics as descri be d i n secti o n 7. 1. 2. 6. 
ir R E CIS T will be use d b y  local site i n vesti gat ors t o assess t u m or res p o nse a n d pr o gressi o n, 
a n d ma ke treat me nt decisi o ns. 
T heref ore, R E CI S T 1. 1 will be use d wit h t he f oll o wi n g a da ptati o ns:
I n s u bjects w h o ha ve i nitial e vi de nce of ra di ol o gical P D b y  RE CI S T 1. 1 as verifie d b y  
ce ntral i ma gi n g ve n d or, it is at t he discreti o n of t he PI  whet her t o c o nti n ue a s u bject o n st u d y  
treat me nt u ntil re peat i ma gi n g is o btai ne d.  S u bjects ma y  recei ve st u d y treat me nt a n d t u m or 
assess me nt s h o ul d be re peate d ≥ 4 wee ks later i n or der t o c o nfir m P D b y ir R E CIS T per site 
assess me nt.  Cli nical sta bilit y is defi ne d as t he f oll o wi n g: 
1)  
A bse nce of s ym pt o ms a n d si g ns i n dicati n g cli nicall y sig nifica nt pr o gressi o n of disease, 
i ncl u di n g w orse ni n g of la b orat or y val ues
2)
N o decli ne i n E C O G perf or ma nce stat us 
3)  
A bse nce of ra pi d pr o gressi o n of disease 
4)  
A bse nce of pr o gressi ve t u m or at critical a nat o mical sites (e g, 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   
I n deter mi ni n g w het her or n ot t he t u m or b ur de n has i ncrease d or decrease d per ir R E CIS T, 
t he l ocal site I nvesti gat or s h o ul d c o nsi der all tar get a n d n o n- tar get lesi o ns as well as a n y 
i ncre me ntal ne w lesi o n(s). A n a daptati o n of ir R E CIS T has bee n e m pl o ye d a n d is o utli ne d 
bel o w [ 1 0 2].  
Sce nari os w here P D is c o nfir me d at re peat i ma gi n g if A N Y of t he f oll o wi n g occ ur b y  
ir R E CIS T:

T u m or b ur de n re mai ns ≥ 2 0 % a n d at least 5 m m a bs ol ute i ncrease c o m pare d t o na dir

N o n -tar get disease res ulti n g i n i nitial P D is w orse ( q ualitati ve assess me nt)

Ne w lesi o n res ulti n g i n i nitial P D is w orse ( q ualitati ve assess me nt)

A d diti o nal ne w lesi o n(s) si nce last e val uati o n

A d diti o nal ne w n o n -tar get pr o gressi o n si nce last e val uati o n
If re peat i ma gi n g c o nfir ms P D d ue t o a n y of t he sce nari os liste d a b o ve, s u bjects will be 
disc o nti n ue d fr o m st u d y  t hera p y (e xce pti o n n ote d bel o w).
Sce nari os w here P D is n ot c o nfir me d at re peat i ma gi n g if A L L of t he f oll o wi n g occ ur b y 
ir R E CIS T: 

T u m or b ur de n is < 2 0 % or < 5 m m a bs ol ute i ncrease c o m pare d t o na dir

N o n -tar get disease res ulti n g i n i nitial P D is sta ble or i m pr o ve d ( q ualitati ve assess me nt)

Ne w lesi o n res ulti n g i n i nitial P D is sta ble or i m pr o ve d ( q ualitati ve assess me nt)
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial

N o i ncre me ntal ne w lesi o n(s) si nce last e val uati o n

N o i ncre me ntal ne w n o n -tar get pr o gressi o n si nce last e val uati o n
If re peat i ma gi n g d oes n ot c o nfir m P D b y  ir R E CIS T a n d t he s u bject c o nti n ues t o be 
cli nicall y sta ble, treat me nt ma y c o nti n ue a n d f oll o w t he re g ular i ma gi n g sc he d ule. 
W he n 
feasi ble, su bjects s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d b y  t he 
l ocal site I n vesti gat or/ra di ol o g y assess me nt.  This all o wa nce t o c o nti n ue treat me nt des pite 
i nitial ra di ol o gic pr o gressi ve disease ( P D) ta kes i nt o acc o u nt t he o bser vati o n t hat s o me 
s ubjects ca n ha ve a tra nsie nt t u m or flare i n t he first fe w m o nt hs 
after t he start of 
i m m u n ot hera p y, an d t he n e x perie nce s u bse q ue nt disease res p o nse.  Su bjects t hat are dee me d 
cli nicall y u nsta ble are n ot re q uire d t o ha ve re peat t u m or i ma gi n g f or c o nfir mati o n of P D. 
A d diti o nal details a b o ut ir R E CIS T are refere nce d i n Merc k TI P S heet f or R E CI S T 1. 1 a n d 
ir R E CIS T a vaila ble i n C P A C.
A n y  su bject dee me d cli nic all y u nst a ble s h o ul d be disc o nti n ue d fr o m trial treat me nt at 
ce ntral verificati o n of site-assesse d 1 st ra di ol o gic e vi de nce of pr o gressi ve disease a n d is n ot 
re q uire d t o ha ve re peat i ma gi n g f or P D c o nfir mati o n.
F or a cli nicall y sta ble s u bject wit h site-assesse d 1 st ra di ol o gic e vi de nce of pr o gressi ve disease 
b y  RE CI S T 1. 1 t hat has bee n verifie d b y  ce ntral i ma gi n g ve n d or (ie, u nc o nfir me d 
pr o gressi o n of disease) , it is at t he discreti o n of t he site I n vesti gat or t o c o nti n ue treati n g t he
s u bject wit h t he assi g ne d treat me nt per pr ot oc ol u ntil pr o gressi o n of disease is c o nfir me d at 
least 2 8 da y s fr om t h e dat e o f t he t u m or i ma ge first s u g gesti n g P D w hic h was ulti matel y 
verifie d b y  CI V per R E CI S T 1. 1.   If pr o gressi o n b y  ir R E CIS T is n ot c o nfir med b y t he 
s u bse q ue nt t u m or i ma gi n g, t he s u bject s h o ul d c o nti n ue t o recei ve st u dy t herap y a n d ha ve 
t u m or i ma gi n g perf or me d e ver y 9 wee ks ( 6 3 ± 7 da y s) d uri n g t he first ye ar a n d e ver y 12 
wee ks ( 8 4 ± 7 d a y s) after t he first ye ar, or s o o ner if cli nicall y in dicate d, t o m o nit or
disease
stat us. If ra di ol o gic pr o gressi o n is c o nfir me d b y s u bse q ue nt t u m or i ma ge, t he n t he s u bject 
will be disc o nti n ue d fr o m trial treat me nt.  
N O T E : If a s u bject wit h c o nfir me d ra di o gra p hic pr o gressi o n (ie 2 t u m or i ma ges at least 2 8 
da y s a part de m o nstrati n g pr o gressi ve disease) per ir R E CIS T, b ut t he s u bject is ac hie vi n g a 
cli nicall y mea ni n gf ul be n efit, a n d t here is n o f urt her i ncrease i n t he t u m or b ur de n at t he 
c o nfir mat or y tu m or i ma gi n g, a n e xce pti o n t o c o nti n ue treat me nt m a 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.  In t his case, if treat me nt is c o nti n ue d, t u m or 
i ma gi n g s h o ul d c o ntin ue t o be perf or me d f oll o wi n g t he i nter vals as o utli ne d i n secti o n 
7. 1. 2. 7.   St u d y  Fl o wc hart a n d be s u b mitte d t o t he CI V.
S u bj ects e x hi biti n g t o xicity f r o m
trial t herap y as o utli ne d i n Secti o ns 5. 2. 1 a n d S e cti o n 7. 2 ma y N O T
c o nti n ue t o recei ve
trial t herap y. 
N O T E :  I n su bjects w h o disc o nti n ue st u d y thera p y  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  t u m or i ma gi n g
e ver y 9 wee ks ( ± 7 da y s) u ntil ( 1) t he start of ne w a nti-ca ncer treat me nt, ( 2) 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.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T he sa me i ma gi n g tec h ni q ue, ac q uisiti o n, a n d pr ocessi n g para meters s h o ul d be use d i n a 
s u bject t hr o u g h o ut t he trial. A d diti o nal i nf or mati o n is i ncl u de d i n t he Site I ma gi n g Ma n ual.
7. 1. 2. 8
T u m or Tiss ue C ollecti o n a n d C orrel ati ve Bl o o d S a m pli n g
7. 1. 2. 8. 1
T u m or Tiss ue C ollecti o n
All
s u bjects m ust ha ve ce ntral c o nfir mati o n of tri ple-ne gati ve breast ca ncer stat us pri or t o 
ra n d o mizati o n ( Secti o n 5. 1. 2 ). A ne wl y o btai ne d c ore or e xcisi o nal t u m or bi o ps y (fi ne nee dle 
as pirate [F N A ] n ot a de q uate) fr o m a met ast atic lesi o n (or arc hi val bi o ps y , if ne w bi o ps y 
ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical c o ntrai n dicati o n a n d s p o ns or 
a gree me nt is o btai ne d ) will be use d f or c o nfir mati o n of tri ple-ne gati ve breast t u m or stat us.  
Testi n g will be perf or me d b y  a ce ntral ve n d or usi n g c o m merciall y vali date d assa ys a n d 
t u m or stat us f or h or m o ne rece pt or a n d H E R 2 e x pressi o n will be deter mi ne d acc or di n g t o t he 
m ost rece nt A S C O/ C A P g ui de -li nes:
a.
Estr o ge n rece pt or ( E R) ne gati ve stat us is defi ne d as < 1 %
t u m or cells p ositi ve 
f or E R b y  I H C, irres pecti ve of stai ni n g i nte nsity 
b.
Pr o gester o ne rece pt or ne gati ve stat us is defi ne d as < 1 %
t u m or cells p ositi ve 
f or Pr o gester o ne rece pt or b y I H C, irres pecti ve of stai ni n g i nte nsit y
c.
H E R 2 ne gati ve stat us is deter mi ne d b y:  

I H C 1 +,
as defi ne d b y  inc o m plete me m bra ne 
stai ni n g t hat is 
fai nt/ barely pe rce pti ble a n d wit hi n > 1 0 % of i n vasi ve t u m or cells, O R

I H C 0, as defi ne d b y n o stai ni n g o bser ve d or me m bra ne stai ni n g t hat is 
i nc o m plete a n d is fai nt/ barely perce pti ble a n d wit hi n ≤1 0 % of t he 
i n vasi ve t u m or cells, O R

FI S H ne gati ve base d o n s i n gle-pr o be a vera ge H E R 2 c o p y n u m ber < 4. 0 
si g nals/cell, or D ual -pr o be H E R 2 / C E P 1 7 rati o < 2. 0 wit h a n a vera ge 
H E R 2 c o p y  n u m ber < 4. 0 si g nals/cell
A ne wl y o btai ne d c ore or e xcisi o nal t u m or bi o ps y  (fi ne nee dle as pirate is n ot a de q uate) fr o m 
a metastatic lesi o n will als o be use d f or ce ntral deter mi nati o n of P D -L 1 t u m or stat us.
W he n 
a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will als o be c ollecte d f or 
deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n arc hi ve d vs
ne wl y  o btai ne d t u m or s peci me ns.
Ne wl y o btai ne d t u m or tiss ue s h o ul d b e s u b mitte d i n f or mali n ( preferre d) or as f or mali n -fi xe d 
paraffi n e m be d de d t u m or tiss ue bl oc ks.  If after a gree me nt wit h t he S p o ns or u nstai ne d sli des 
are s u b mitte d, t he sli des s h o ul d be fres hl y c ut a n d s u b mitte d t o t he testi n g la b orat or y  wit hi n 7
da y s fr o m site sli de secti o ni n g date ot her wise a ne w s peci me n will be re q ueste d .  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T he sa me ne w tiss ue sa m ple ma y  be use d f or b ot h m T N B C stat us a n d P D -L 1 stat us. Ne wl y 
o btai ne d t u m or tiss ue ma y  be o btai ne d u p t o 5 6 da y s pri or t o treat me nt i nitiati o n. T u m o r 
tiss ue o btai ne d rece ntly,  but pri or t o t he 5 6- da y  wi n d o w, ma y  be c o nsi dere d wit h S p o ns or 
c o ns ultati o n .
O nl y  in t he pe m br oliz u ma b ar m, a n opti o nal c ore or e xcisi o nal bi o psies m a y  be o btai ne d 
w hile o n treat me nt , o n or after c y cle 2, a n d/ or at disease pr o g ressi o n, as s pecifie d i n t he Trial 
Fl o w C harts ( Secti o n 6. 0).
N ote: F or all t u m or tiss ue c ollecte d, a fi ne nee dle as pirate, fr oze n sa m ple, plastic e m be d de d 
sa m ple, cell bl oc k, cl ot, b o ne, b o ne marr o w, c yt ol o gic s peci me n, decalcifie d , or f or mali n 
fi xe d sa m ple t hat was fr oze n at a n y p oi nt will n ot be acce pta ble f or a nal ysis.
Detaile d i nstr ucti o ns f or tiss ue c ollecti o n, pr ocessi n g a n d s hi p me nts are pr o vi de d i n t he 
ve n d or’s ma n ual.
7. 1. 2. 8. 2
Bl o o d f or C orrel ati ve St u dies
Bl o o d f or c orrelati ve bi o ma r ker st u dies ( R N A a n d D N A) s h o ul d be c ollecte d pre -d ose at 
C y cle 1, 2, 3 , a n d at treat me nt disc o nti n uati o n .
Detaile d i nstr ucti o ns f or s pecific ti me p oi nts per sa m ple, tiss ue c ollecti o n, pr ocessi n g a n d 
s hi p me nt are pr o vi de d i n t he ve n d or’s m a n ual.
7. 1. 2. 9
P atie nt -Re p orte d O utc o mes
T he eE ur o Q ol ( E Q)-5 D, eE O R T C Q L Q -C 3 0 a n d eE O R T C Q L Q -B R 2 3 q uesti o n naires will 
be a d mi nistere d b y  trai ne d st u d y site pers o n nel a n d c o m plete d electr o nicall y by t he s u bjects 
t he msel ves.
It is str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d pri or t o dr u g a d mi nistrati o n, 
a d verse e ve nt e val uati o n a n d disease stat us n otificati o n. T he e P R Os are c o m plete d i n t he 
f oll o wi n g or der: e E ur o Q ol ( E Q)-5 D first, t he n e E O R T C Q L Q- C 3 0, a n d lastl y the e E O R TC 
Q L Q -B R 2 3 at t he ti me p oi nts s pecifie d i n t he Trial Fl o w C harts a n d briefl y s u m marize d 
bel o w. 
7. 1. 2. 9. 1
T he P atie nt - Re p orte d O utc o mes 
T he Patie nt Re p orte d O utc o mes ( P R Os) are assesse d as f oll o ws (as s pecifie d i n t he Trial 
Fl o w C harts ( Secti o n 6. 0):

If a T P C treatme nt has m ore t ha n o ne d ose per c ycle, t he e P R Os will o nl y  be 
a d mi nistere d o n t he first treat me nt da y  of t he c ycle.

A t c yc les 1, 2, a n d 3 

E ver y  3r d c ycle after C ycle 3 u ntil t he e n d of Y ear 1 ( i e, C y cles 6, 9, 1 2, etc.)
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
9 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

E ver y  4t h c ycle d uri n g Ye ar 2 u ntil P D

At t he Treat me nt Disc o nti n uati o n Visit * 

At t he 3 0 -d a y  Safet y F oll o w-u p Visit *
*I f t he Treat me nt Disc o nti n uati o n Visit occ urs > 3 0 d a y s fr o m t he last d ose of st u d y 
treat me nt, at t he ti me of t he ma n dat or y  Safet y Foll o w u p Visit, P R Os d o n ot nee d t o be 
re peate d.
L a b or at or y Pr oce d ures/ Assess me nts
7. 1. 3
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 trial 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 trial (fr o m pre -trial t o p ost -trial 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 ype per s u bject, ca n be f o u n d i n t he v e n d or’s 
m a n ual .
7. 1. 3. 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 , Uri n al ysis , a n d 
Ot her )
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 Ta ble 7
Ta ble 7
La b orat or y  Tests
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
H e m at ocrit
Al b u mi n
Bl o o d
Ser u m β -h u ma n c h ori o nic 
g o na d otr o pi n ( β -h C G) a
H e m o gl o bi n
Al kali ne p h os p hatase
Gl uc ose
P T (I N R)
Platelet c o u nt
Ala ni ne a mi n otra nsferase 
( A L T)
Pr otei n
a P T T d
W hite bl o o d cell
(t otal a n d 
differe ntial)
As partate 
a mi n otra nsferase ( A S T)
S pecific gra vit y 
T otal trii o d ot h yr o ni ne ( T 3) or 
Free T 3 e
Re d b l o o d Cell 
C o u nt
Bicar b o nate b
Micr osc o pic e xa m, if 
a b n or mal res ults are n ote d
Free t h yr o xi ne ( T 4)
A bs ol ute n e utr o p hil 
co u nt g
Calci u m
T h yr oi d sti m ulati n g h or m o ne 
( T S H)
A bs ol ute 
ly m p h oc yte co u nt g
C hl ori de
Bl o o d f or f ut ure bi o me dical 
researc h (F B R )
Creati ni ne
Bl o o d f or c orrelati ve st u dies
Gl uc ose
P K (f or s u bjects o n t he 
pe m br oliz u ma b ar m o nl y)
P h os p h or us
A nti -p e m br oliz u ma b 
A nti b o dies (f or s u bjects o n 
t he pe m br oliz u ma b  ar m o nl y)
Ma g nesi u m
( o nl y 
s u bjects o n Eri b uli n)
F S H, estra di ol f
P otassi u m
Vita mi n D le vels
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
S o di u m
T u m or mar kers ( C A 1 5 -3, 
C E A , a n d C A 2 7. 2 9)
T otal b ilir u bi n  
Direct b ilir 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 m al
T otal pr otei n
Bl o o d u rea n itr o ge n
Lactate de h y dr o ge nase 
( L D H)
Car b o n di o xi de ( C O 2 or 
bicar b o nate) b
Uric aci d
Urea c
a.
Perf or m o n w o me n of c hil d beari n g p ote ntial o nl y.  
b.
If c o nsi dere d sta n dar d of care i n y o ur re gi o n.
c.
Bl o o d u rea nitr o ge n is preferre d; if n ot a vaila ble urea ma y be teste d.
d.
C oa g ulati o n fact ors ( PT/I N R a n d a P T T) s h o ul d be teste d as part of t he scree ni n g pr oce d ures f or all s u bjects.  An y 
s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut t he trial.
e.
T otal T 3 is preferre d; if n ot a vaila ble free T 3 ma y be teste d.
f.
Bl o o d f or me n o pa usal stat us is o nl y re q uire d f or s o me s u bjects as descri be d i n Secti o n 7. 1. 3. 6
g.
Eit her a bs ol ute or % is acce pta ble as per i nstit uti o nal sta n dar d
La b orat or y  tests will be perf or me d as s pecifie d i n t he Trial Fl o w
C hart ( Secti o n 6. 0). 
La b orat or y  tests f or scree ni n g s h o ul d be perf or me d wit hi n 1 0 d a y s pri or t o ra n d o mizati o n.  
After C y cle 1, pre -d ose la b orat or y pr oce d ures ca n be c o n d ucte d u p t o 7 2 h o urs pri or t o 
d osi n g.  Safet y la b orat or y res ults m ust be re vie we d b y  the 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 trial treat me nt .
Exce pti o n: T hyr oi d f u ncti o n testi n g ( T 3, F T 4, a n d T S H), Vit a mi n D, a n d t u m or m arker s ( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) res ults c a n be revie we d f oll o wi n g sc he d ule d d osi n g.
7. 1. 3. 2
Pre g n a nc y Test
F or w o m e n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test s h o ul d be perf or me d 
wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. If t he uri ne test is p ositi ve or ca n n ot 
be c o nfir me d as ne gati ve, a ser u m pre g na nc y  test will be re q uire d. If s u bject meets
crit eri a 
f or s e c o n d c o urs e p h as e a uri n e or s er u m pr e g n a n c y  test s h o ul d b e c o m pl et e d pri or t o 
r est arti n g p e m br oli z u m a b. Pre g na nc y  tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y 
s h o ul d be c o m plete d if dee me d necessar y  by PI  or re q uire d b y  local g ui deli nes .  S u bjects 
m ust be e xcl u de d/ disc o nti n ue d fr o m t he trial i n t he e ve nt of a p ositi ve or b or derli ne -p ositi ve 
test res ult.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
9 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 3. 3
P h ar m ac o ki netic/ P h ar m ac o d y n a mic E v al u ati o ns
T he acc u m ulati o n of r o b ust P K a n d A D A data has all o we d f or t he a de q uate c hara cterizati o n 
of t he cli nical p har mac ol o g y  of p em br oliz u ma b acr oss i n dicati o ns. T heref ore, u p o n a p pr o val 
of A me n d me nt 0 5 eac h site is t o st o p t he c ollecti o n of P K a n d A D A sa m ples f or all s u bjects. 
Bl o o d sa m ples f or P K a n d A D A c ollecte d pri or t o A me n d me nt 0 5 m a y  be st ore d. A nal ys is 
will be perf or me d o nl y if re q uire d.
7. 1. 3. 4
Pl a n ne d Ge netic A n al ysis S a m ple C ollecti o n
Sa m ple c ollecti o n, st ora ge a n d s hi p me nt i nstr ucti o ns f or Pla n ne d Ge netic A nal ys is sa m ples 
will be pr o vi de d i n t he ve n d or’s ma n ual . 
T his sa m ple s h o ul d be dra w n f or pla n ne d a nal ys is of t he ass ociati o n bet wee n ge netic varia nts
i n D N A a n d dr u g res p o nse.  
If t here is eit her a d oc u me nte d la w or re g ulati o n pr o hi biti n g c ollecti o n, or if t he I RB/I E C
d oes n ot a p pr o ve t he c ollecti o n of t he sa m ple f or t hese p ur p os es, t he n t his sa m ple will n ot be
c ollecte d at t hat site.
If t he sa m ple is c ollecte d, left o ver e xtracte d D N A
will
be st ore d f or f ut ure bi o me dical
researc h if t he s u bject si g ns t he F B R c o nse nt.
7. 1. 3. 5
Bl o o d f or C orrel ati ve St u dies
Bl o o d f or c orrelati ve st u dies (i ncl u des bl o o d f or D N A a n d R N A) s h o ul d be c ollecte d pre d ose 
C y cle 1, C ycl e 2, C ycle 3, a n d at treat me nt disc o nti n uati o n. 
Bl o o d f or e x pl orat or y bi o mar kers ( plas ma a n d ser u m), s h o ul d be c ollecte d pre -d ose C y cle 1. 
Detaile d i nstr ucti o ns wit h s pecific ti me p oi nts per sa m ple are pr o vi de d i n t he ve n d or’s 
ma n ual.
7. 1. 3. 6
Bl o o d f or Me n o p a us al St at us
Bl o o d c ollecti o n at scree ni n g f or bi oc he mical e vi de nce of me n o pa usal stat us ( F S H a n d 
estra di ol) will be c o m plete d if a p plica ble.
7. 1. 3. 7
F ut ure Bi o me dic al Rese arc h
T he f oll o wi n g s peci me ns are t o be o btai ne d as part of F ut ure Bi o me dical Researc h:

Left o ver D N A 

Left o ver mai n st u d y t u m or s peci me ns
If t he s u bject si g ns t he F ut ure Bi o me dical Researc h ( F B R) c o nse nt, a n y left o ver tiss ue t hat 
w o ul d or di naril y  be discar de d at t he e n d of t he mai n st u d y will be retai ne d f or F B R.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
9 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Ot her Pr oce d ures
7. 1. 4
7. 1. 4. 1
Wit h dr a w al/ Disc o nti n u ati o n
S u bjects w h o disc o nti n ue/ wit h dra w fr o m st u d y treat ment pri or t o c o m pleti o n of t he trial
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 a n d s ur vi val 
f oll o w-u p c o ntacts.
W he n a s u bject disc o nti n ues/ wit h dra ws fr o m partici pati o n i n t he trial, all a p plica ble acti vities 
sc he d ule d f or t he e n d -of -treat me nt visit s h o ul d be perf or me d at t he ti me of disc o nti n uati o n.  
A n y  ad verse e ve nts w hic h are pr ese nt at t he ti me of disc o nti n uati o n/ 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 7. 2 - Assessi n g a n d 
Rec or di n g A d verse E ve nts . S u bjects o n t he pe m br oliz u ma b ar m w h o a) attai n a C R or b) 
c o m plete 3 5 treat me nts wit h pe m br oliz u ma b ma y  disc o nti n ue treat me nt wit h t he o pti o n of 
restarti n g treat me nt if t he y 
meet t he criteria s pecifie d i n Secti o n 
7. 1. 5. 2. 1 .  
After 
disc o nti n ui n g treat me nt f oll o wi n g assess me nt of C R or 3 5 treat me nts, t hese s u bjects s h o ul d 
ret ur n t o t he site f or a Safet y  Foll o w -u p Visit ( Secti o n 7. 1. 5. 3. 2 ) a n d t he n pr ocee d t o t he 
F oll o w -u p Peri o d of t he st u d y  ( Secti o n 7. 1. 5. 3. 3 ).
7. 1. 4. 1. 1
Wit h dr a w al Fr o m F ut ure Bi o me dic al Rese arc h
S u bjects ma y  wit h dra w t heir c o nse nt f or F ut ure Bi o me dical Researc h a n d ha ve t heir 
speci me ns a n d all deri vati ves destr o ye d.   Su bjects m a y  wit h dra w c o nse nt at a n y ti me b y  
c o ntacti n g t he pri nci pal i n vesti gat or f or t he mai n trial.  If me dical rec or ds f or t he mai n trial 
are still a vaila ble, t he i n vesti gat or will c o ntact t he S p o ns or usi n g t he desi g nate d mail b o x 
(cli nical.s peci me n. ma na ge me nt @ merc k.c o m ), a n d a f or m will be pr o vi de d b y  t he S p o ns or t o 
o btai n a p pr o priate i nf or mati o n t o c o m plete s peci me n wit h dra wal. 
 Su bse q ue ntl y , t he 
s u bject's s peci me ns will be re m o ve d fr o m t he bi ore p osit or y  an d be destr o y e d.  A letter will 
be se nt fr o m t he S p o ns or t o t he i n vesti gat or c o nfir mi n g t he destr ucti o n. It is t he 
res p o nsi bilit y of t he i n vesti gat or t o i nf or m t he s u bject of c o m pleti o n of destr ucti o n.  An y  
a nal ys es i n pr o gress at t he ti me of re q uest f or destr u cti o n or alrea d y perf or me d pri or t o t he 
re q uest bei n g recei ve d b y t he S p o ns or will c o nti n ue t o be use d as part of t he o verall researc h 
trial data a n d res ults.   N o ne w a nalys es w o ul d be ge nerate d after t he re q uest is recei ve d.
I n t he e ve nt t hat t he me dical
rec or ds f or t he mai n trial are n o l o n ger a vaila ble (e. g., if t he 
i n vesti gat or is n o l o n ger re q uire d b y  re g ulat or y aut h orities t o retai n t he mai n trial rec or ds) or 
t he s peci me ns ha ve bee n c o m pletel y an o n y mize d, t here will n o l o n ger be a li n k bet wee n t he 
s ubject’s pers o nal i nf or mati o n a n d t heir s peci me ns.  In t his sit uati o n, t he re q uest f or 
s peci me n destr ucti o n ca n n ot be pr ocesse d.
7. 1. 4. 2
Bli n di n g/ U n bli n di n g
T his is a n o pe n la bel trial; t here is n o bli n di n g f or t his trial.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
9 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 4. 3
C ali br ati o n of Critic al 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 to e ns ure t hat a n y critical 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 trial t hat pr o vi des i m p orta nt 
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 safety or efficac y para meters s hall be 
s uita bl y cali brate d a n d mai ntai ne d 
t o e ns ure t hat t he data o btai ne d is 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 trial site.
Critical E q ui p me nt f or t his trial i ncl u des:

La b orat or y e q ui p me nt – as re q uire d f or i ncl usi o n la bs a n d trial assess me nts

I ma gi n g e q ui p me nt – as re q uire d f or st u d y o bjecti ves

Dr u g 
a d mi nistrati o n e q ui p me nt –
as re q uire d f or st ora ge, pre parati o n a n d 
a d mi nistrati o n (i nf usi o n) of st u dy dr u g.
See pr ot oc ol -s pecifie d g ui da nce i n t he A d mi nistrati ve Bi n der, ve n d or’s m a n ual , a n d Site 
I ma gi n g Ma n ual.
Visit Re q uire me nts
7. 1. 5
Visit re q uire me nts are o utli ne d i n Secti o n 6 . 0 - Trial Fl o w C hart.   S pecific pr oce d ure -relate d 
details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures.
7. 1. 5. 1
Scree ni n g
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0 – Trial Fl o w C hart.
Res ults of a test perf or me d pri or t o t he s u bject 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 2 8 d a y s pri or t o ra n d o mizati o n e xce pt f or 
t he f oll o wi n g:

La b orat or y  tests a n d E C O G P S are t o be perf or me d wit hi n 1 0 da ys pri or t o 
ra n d o mizati o n.

F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test will be 
perf or me d wit hi n 7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y me dicati o n.

Ne wl y o btai ne d t u m or tiss ue, a n d arc hi val tiss ue w he n a vaila ble, m a y  be o btai ne d 
wit hi n 5 6 da y s of treat me nt i nitiati o n.
S u bjects ma y  be rescree ne d t wice 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 perf or me d d uri n g t he i nitial scree ni n g per i 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 i ncl usi o n/e xcl usi o n criteria is met.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
9 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 5. 2
Tre at me nt Peri o d
Visit ti mi n g re q uire me nts d uri n g t he treat me nt peri o d are as f oll o ws:

A ssess me nts/ pr oce d ures s h o ul d be perf or me d pri or t o d ose f or eac h c ycle u nless 
ot her wise s pecifie d i n t he fl o w c hart.

Treat me nt c ycles are Q 3 W
f or pe m br oliz u ma b a n d acc or di n g t o l ocal la bel or 
g ui deli nes f or T P C ar m.  

T he wi n d o w f or eac h visit is ± 3 da y s u nl ess ot her wise n ote d.  Cycle 1 treat me nt 
s h o ul d be n o m ore t ha n 3 da ys after ra n d o mizati o n.  

O pti o nal c ore or e xcisi o nal bi o psies m a y  be o btai ne d w hile o n treat me nt, o n or after 
c ycle 2 , or at disease pr o gressi o n f or t he pe m br oliz u ma b ar m o nl y.
F or t he f ull list of all visit assess me nts/ pr oce d ures please see Secti o n 6. 0 – Trial Fl o w C hart.  
S pecific pr oce d ure -relate d details are pr o vi de d a b o ve i n Secti o n 7. 1 – Trial Pr oce d ures.  
7. 1. 5. 2. 1
Sec o n d C o urse P h ase ( Retre at me nt Peri o d)
C o n diti o ns of Sec o n d C o urse P h ase
7. 1. 5. 2. 1. 1
S u bjects o n t he pe m br oliz u ma b ar m w h o st o p pe m br oliz u ma b wit h S D or better m a y  be 
eli gi ble f or u p t o o ne ye ar of a d diti o nal pe m br oliz u ma b t hera p y if t he y pr o gress after 
st o p pi n g st u d y treat me nt.  This retreat me nt is ter me d t he Sec o n d C o urse P hase of t his s t u d y 
a n d is o nl y  availa ble if t he st u d y re mai ns o pe n a n d t he s u bject meets t he f oll o wi n g 
c o n diti o ns:
Eit her 
o
St o p pe d i nitial treat me nt wit h pe m br oliz u ma b after attai ni n g a n I n vesti gat or-
deter mi ne d c o nfir me d C R acc or di n g t o R E CI S T 1. 1

F oll o wi n g
at 
least 8 
treat me nts
wit h 
pe m br oliz u ma b
bef ore 
disc o nti n ui n g t hera p y , a n d

Recei ve d at least 2 treat me nts wit h pe m br oliz u ma b be y o n d t he date 
w he n t he i nitial C R was declare d
O R
o
H a d S D, P R or C R a n d st o p pe d pe m br oliz u ma b treat me nt after 3 5 treat me nts
of st u d y  t hera p y 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
o
E x perie nce d 
a n I n vesti gat or-deter mi ne d c o nfir me d ra di o gra p hic disease 
pr o gressi o n after st o p pi n g t heir i nitial treat me nt wit h pe m br oliz u ma b
o
Di d 
n ot 
recei ve a n y 
a nti -ca ncer treat me nt si nce t he
last d ose 
of 
pe m br oliz u ma b
o
Has a perf or ma nce stat us of 0 or 1 o n t he E C O G Perf or ma nce Scale
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 0 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
o
De m o nstrate s a de q uate or ga n f u ncti o n as detaile d i n Secti o n 5. 1. 2
o
Fe male s u bject of c hil d beari n g p ote ntial s h o ul d ha ve a ne gati ve uri ne or 
ser u m pre g na nc y  test wit hi n 7 2 h o urs pri or t o recei vi n g retreat me nt wit h st u d y 
dr u g .  
o
Fe male s u bject of c hil d beari n g p ote ntial s h o ul d be willi n g t o use 2 met h o ds of 
birt h c o ntr ol or be s ur gicall y sterile, or a bstai n fr o m heter ose x ual acti vit y f or 
t he c o urse of t he st u d y thr o u g h 1 2 0 d a y s (at least 6 m o nt hs f or s u bjects o n 
ge mcita bi ne) after t he last d ose of st u d y dr u g ( Secti o n 5. 7. 2 ).  Su bjects of 
c hil d beari n g p ote ntial are t h ose w h o ha ve n ot bee n s ur gically sterilize d or 
ha ve bee n free fr o m me nses f or > 1 y ear. 
o
Male s u bject
s h o ul d a gree t o use a n a de q uate met h o d of c o ntrace pti o n starti n g 
wit h ra n d o mizati o n t hr o u g h 1 2 0 d a y s (at least 6 m o nt hs f or s u bjects o n 
ge mcita bi ne) after t he last d ose of st u d y t hera p y.  
o
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 ab n or malit y t hat mi g ht i nterfere wit h t he s u bject’s partici pat i 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 treati n g I n vesti gat or.
Visit R e q uire me nts of Sec o n d C o urse P h ase
7. 1. 5. 2. 1. 2
7. 1. 5. 2. 1. 2. 1 Assess me nts/ P r oce d ures / Wi n d o ws
Assess me nts are p erf or me d o n D a y  1 an d pri or t o ra n d o mizati o n f or eac h c ycle u nless 
ot her wise s pecifie d.  Treat me nt c ycles are 3 wee ks
a n d visit wi n d o ws are ± 3 d a y s u nless 
ot her wise n ote d .  If t o xicit y occ urs , refer t o t he d ose m o dificati o n g ui deli nes pr o vi de d i n 
Secti o n 5. 2. 1. 2. 1.  Ima gi n g s h o ul d al wa ys be perf or me d Q 9 W ( ± 7 d a y s) re gar dless of a n y 
treat me nt dela ys.  
7. 1. 5. 2. 1. 2. 2 Disc o nti n u ati o n D uri n g t he Sec o n d C o urse P h ase
I n s u bjects w h o disc o nti n ue st u d y t hera p y, t u mor 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 (ie, date of disc o nti n uati o n ± 4 wee k wi n d o w).  If a pre vi o us t u m or 
i ma ge 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 a t u m or i ma ge 
at treat me nt disc o nti n uat i o n is n’t ma n dat or y.
F or t h ose s u bjects t hat disc o nti n ue st u d y thera p y 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  tu m or i ma gi n g 
e ver y 9 wee ks ( ± 7 da y s) u ntil ( 1) t he start of ne w a nti -ca ncer treat me nt, ( 2) 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.
7. 1. 5. 2. 1. 2. 3 L a b or at or y Tests D uri n g t he Sec o n d C o urse P h ase
La b orat or y  tests f or deter mi ni n g eli gi bilit y for retreat me nt are t o be perf or me d wit hi n 
1 0 da y s pri o r t o t he first retreat me nt d ose of pe m br oliz u ma b.  See Secti o n 7. 1. 3 f or details 
re gar di n g la b orat or y tests.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test s h o ul d be perf or me d 
wit hi n 7 2 h o urs pri or t o first r e-treat me nt d ose. Pre g na nc y  tests s h o ul d be re peate d if 
re q uire d by l ocal g ui deli nes.
After C y cle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he sc he d ule d ti me p oi nt.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests. T 3 or F T 3 ca n be assa ye d base d o n 
l ocal sta n dar ds.
C oa g ulati o n fact ors ( P T/I N R a n d a P T T) s h o ul d be m o nit ore d cl osel y thr o u g h o ut t he trial f or 
a n y s u bject recei vi n g a ntic oa g ula nt t hera p y.
U nres ol ve d la b a b n or malities t hat are dr u g relate d A Es s h o ul d be f oll o we d u ntil res ol uti o n.  
La bs d o n ot nee d t o be re peate d after t he e n d of trial treat me nt if la bs are wit hi n n or mal 
ra n ge.
L a b orat or y safety meas ure me nts will be gra de d per N CI C T C A E versi o n 4. 0.  
7. 1. 5. 2. 1. 2. 4 C o nc o mit a nt Me dic ati o ns D uri n g t he Sec o n d C o urse P h ase
E nter ne w me dicati o ns starte d d uri n g t he trial t hr o u g h t he Safet y Foll o w -u p visit.  Rec or d all 
me dicati o ns ta ke n f or A Es as defi ne d i n Secti o n 7. 2.
7. 1. 5. 2. 1. 2. 5 Vit al Si g ns D uri n g t he Sec o n d C o urse P h ase
Vital si g ns t o i ncl u de te m perat ure, p ulse, res pirat or y  rate, wei g ht a n d bl o o d press ure.    Vitals 
s h o ul d be ta ke n pri or t o treat me nt a d mi nistrati o n.
7. 1. 5. 2. 1. 2. 6 Pe m br oliz u m a b Rest art D uri n g t he Sec o n d C o urse P h ase
S u bjects w h o restart treat me nt s h o ul d res u me pe m br oliz u ma b at t he d ose a n d i nter val 
s pecifie d i n Secti o n 6. 2.
7. 1. 5. 2. 1. 2. 7 T u m or I m a gi n g Sec o n d C o urse P h ase
T u m or i ma gi n g m ust 
be perf or me d wit hi n 2 8 d a y s pri or t o restarti n g treat me nt wit h 
pe m br oliz u ma b.  Ima gi n g s h o ul d c o nti n ue t o be perf or me d Q 9 W ( ± 7 da ys) fr o m first re-
treat me nt d ose or m ore fre q ue ntly if cli nicall y i n dicate d, as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 2).  Local rea di n g (site I n vesti gat or/l ocal ra di ol o g y re vie w) will be use d t o 
deter mi ne eli gi bilit y an d f or s u bject ma na ge me nt.  The Sites will c ollect a n d se n d t u m or 
i ma gi n g t o t he ce ntral i ma gi n g ve n d or.
T he S p o ns or will c ollect t u m or i ma gi n g f or
retr os pecti ve a nal ys is b y a ce ntral i ma gi n g ve n d or.  The pr ocesses f or i ma ge c ollecti o n a n d 
tra ns missi o n t o t he ce ntral ve n d or are i n t he Site I ma gi n g Ma n ual. 
T he sa me i ma gi n g 
tec h ni q ue, ac q uisiti o n, a n d pr ocessi n g para meters s h o ul d be use d i n a s u bject thr o u g h o ut t he 
trial. 
After t he start of ne w a nti-ca ncer treat me nt or d oc u me nte d disease pr o gressi o n b y t he ce ntral 
i ma gi n g ve n d or, t he s u bject s h o ul d be c o ntacte d b y  tele p h o ne Q 1 2 W t o assess f or s ur vi val 
stat us.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 5. 3
P ost -Tre at me nt Visits
7. 1. 5. 3. 1
Disc o nti n u ati o n Visit
T he Di sc o nti n uati o n Visi t s h o ul d occ ur at t he ti me st u d y treat me nt is disc o nti n ue d f or a n y
reas o n.  If t he Disc o nti n uati o n Visit occ urs 3 0 d a y s fr o m t he last d ose of st u dy treat me nt, at
t he ti me of t he ma n dat or y
Safet y F oll o w u p Visit, pr oce d ures d o n ot nee d t o b e re peated .  
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0.  Specific pr oce d ure -relate d details are 
pr o vi de d a b o ve i n Secti o n 7. 1.  Ad diti o nal details re gar di n g s u bject wit h dra wal a n d 
disc o nti n uati o n are prese nt e d i n Secti o n 5. 8.
7. 1. 5. 3. 2
S afet y F oll o w -u p Visit
T he ma n dat or y  S afety 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 30 d a y s after t he 
last d ose of trial treat me nt or bef ore t he i nitiati o n of a ne w a nti-ca ncer treat me nt, w hic he ver 
c o mes first.  All A Es t hat occ ur pri or t o t he Safet y F oll o w -U p Visit s ho ul d be rec or de d.  
S u bjects wit h a n A E of Gra de > 1 will be f oll o we d u ntil t he res ol uti o n of t he A E t o Gra de 0-
1 or u ntil t he be gi n ni n g of a ne w a nti-ca ncer t hera p y, w hic he ver occ urs first.  Eac h s u bject 
will be f oll o we d f or 3 0 da y s f or A E s a n d E C Is. S eri ous a d verse e ve nts will be c ollecte d f or 
9 0 da y s after t he e n d of trial treat me nt.
S u bjects w h o are eli gi ble f or retreat me nt wit h pe m br oliz u ma b ( Secti o n 7. 1. 5. 2. 1 ) ma y  ha ve 
u p t o t w o safety f oll o w- u p visits, o ne after t he Treat me nt Peri o d a n d o ne after t he Sec o n d 
C o urse P hase.
7. 1. 5. 3. 3
F oll o w -u p Visits
S u bjects w h o disc o nti n ue trial treat me nt f or a reas o n ot her t ha n disease pr o gressi o n will 
m o ve i nt o t he F oll o w -U p P hase a n d s h o ul d be assesse d Q 9 W (± 7 da y s) b y t u m or i ma gi n g t o 
m o nit or disease stat us.  After 1 ye ar, i ma gi n g will be perf or me d Q 1 2 W ( ± 7 da ys).
E ver y  eff ort s h o ul d be ma de t o c ollect i nf or mati o n re gar di n g disease stat us u ntil t he start of 
ne w a nti-ca ncer t hera p y, diseas e pr o gressi o n deter mi ne d b y  ce ntral i ma gi n g ve n d or, deat h, 
e n d of st u d y or if t he s u bject be gi ns retreat me nt wit h pe m br oliz u ma b (Secti o n 7. 1. 5. 2. 1).  
I nf or mati o n re gar di n g p ost -st u d y anti -ca ncer treat me nt will be c ollecte d if ne w treat me nt is 
i nitiate d.
S u bjects 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 7. 1. 5. 2. 1 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 ex perie nce disease pr o gressi o n.  Details are pr o vi de d i n Secti o n 6. 0 f or Retreat me nt 
wit h pe m br oliz u ma b.
7. 1. 5. 3. 4
S ur vi v al F oll o w -u p
O nce a s u bject e x perie nces disease pr o gressi o n b y  site assess me nt a n d verifie d b y  ce ntral 
i ma gi n g ve n d or re vie w or starts a ne w a nti-ca ncer t hera p y, t he s u bject m o ves i nt o t he 
S ur vi val F oll o w -U p P hase a n d s h o ul d be c o ntacte d b y  tele p h o ne at least Q 1 2 W
( m ore 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 0 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
fre q ue ntly if nee de d) fr o m t he last c o ntact date 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.
7. 1. 5. 3. 5
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 are a vaila ble at t he ti me of da ta 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 by t he S p o ns or.  For 
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 nalys is.  U p o n S p o ns or n otificati o n, all s u bjects 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 co 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 pre vi o usl y  rec or de d a 
deat h e ve nt i n t he c ollecti o n t o ol ).
Assessi n g a n d Rec or di n g A d verse E ve nts
7. 2
A n a d verse e ve nt is defi ne d as a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y 
ha ve t o ha ve a ca usal relati o ns hi p wit h t his treat me nt. A n a d verse e ve nt ca n t heref ore be a n y 
u nfa v o ura 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, f or e xa m ple), 
s ym pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d u re, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure.  An y  worse ni n g (i.e., a n y cli nicall y si gnifica nt a d verse c ha n ge i n 
fre q ue nc y an d/ or i nte nsit y) of a pree xisti n g c o n diti o n t hat is te m p orall y ass ociate d wit h t he
use of t he S p o ns or’s pr o d uct, is als o a n a d verse e ve nt.
C ha n ges res ulti n g fr o m n or mal gr o wt h a n d de vel o p me nt t hat d o n ot var y si g nifica ntly i n 
fre q ue nc y or se verity fr o m e x pecte d le vels are n ot t o be c o nsi dere d a d verse e ve nts.  
E xa m ples of t his ma y  incl u d e, b ut are n ot li mite d t o, teet hi n g, t ypical cr yi n g in i nfa nts a n d 
c hil dre n a n d o nset of me nses or me n o pa use occ urri n g at a p hys i ol o gicall y a p pr o priate ti me.
S p o ns or's pr o d uct i ncl u des a n y p har mace utical pr o d uct, bi ol o gical pr o d uct, de vice, 
dia g n ostic a ge n t or pr ot oc ol -s pecifie d pr oce d ure, w het her i n vesti gati o nal (i ncl u di n g place b o 
or acti ve c o m parat or me dicati o n) or mar kete d, 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.
A d verse e ve nts m a y  occ ur d uri n g  cli nical trials, or as prescri be d i n cli nical practice, fr o m 
o ver d ose ( w het her acci de ntal or i nte nti o nal), fr o m a b use a n d fr o m wit h dra wal.
Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n a d verse e ve nt.
All 
a d verse 
e ve nts 
t hat occ ur 
after 
t he c o nse nt 
f or m is
si g ne d 
b ut 
bef ore 
ra n d o mizati o n/treat me nt all ocati o n m ust be rep orte d b y  the i n vesti gat or if t he y ca use t he 
s u bject t o be e xcl u de d fr o m t he trial, or are 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 uat i o n of us ual t hera p y, diet, place b o 
treat me nt or a pr oce d ure. Fr o m t he ti me of  ra n d o mizati o n /treat me nt all ocati o n t hr o u g h 3 0
da y s f oll o wi n g cessati o n of treat me nt, all a d verse e ve nts m ust 
b e
re p orte d b y  the 
i n vesti gat or. S uc h e ve nts will be rec or de d at eac h e xa mi nati o n o n t he A d verse E ve nt case 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 0 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
re p ort f or ms/ w or ks heets.  The re p orti n g ti mefra me f or a d verse e ve nts meeti n g a n y seri o us 
criteria is descri be d i n secti o n 7. 2. 3. 1. T he i n vesti gat or will ma ke e ver y atte m pt t o f oll o w all 
s u bjects with n o n -seri o us a d verse e ve nts f or o utc o me.
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 gui deli nes. 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 Trial File Bi n der ( or e q ui vale nt).
Defi niti o n of a n O ver d ose f or T his Pr ot o c ol a n d Re p orti n g of O ver d ose t o t he 
7. 2. 1
S p o ns or
F or t his trial, a n o ver d ose will be defi ne d as ≥1 0 0 0 m g ( 5 ti mes t he d ose) of pe m br oliz u ma b 
a n d as a n y d ose ≥2 0 % o ver t he prescri be d d ose f or t he c o m parat or a ge nts.
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, pe m br oliz u ma b s h o ul d be disc o nti n ue d a n d t he s u bject s h o ul d be o bser ve d cl osel y 
f or si g ns of t o xicit y.  Ap 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.
If a n a d verse e ve nt(s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of S p o ns or's pr o d uct or 
vacci ne, t he a d verse e ve nt(s) is re p orte d as a seri o us a d verse e ve nt, e ve n if n o ot her 
seri o us ness criteria are met.
If a d ose of S p o ns or's pr o d uct or vacci ne meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n 
wit h o ut a n y ass ociate d cli nical s ym pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is 
re p orte d as a n o n -seri o us E ve nt of Cli nical I nterest ( E CI), 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.”
All re p orts of o ver d ose wit h a n d wit h o ut a n a d verse e ve nt m ust 
be re p orte d b y  the 
i n vesti gat or wit hi n 2 4 h o urs t o t he S p o ns or eit her b y  electr o nic me dia or pa per. 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 gui deli ne s. Pa per re p orti n g 
pr oce d ures ca n be f o u n d i n t he In vesti gat or Trial File Bi n der ( or e q ui vale nt).
Re p orti n g of Pre g n a nc y a n d L act ati o n t o t he S p o ns o r
7. 2. 2
Alt h o u g h pre g na nc y  a n d lactati o n are n ot c o nsi dere d a d verse e ve nts, it is t he res p o nsi bilit y of 
i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g na nc y or lactati o n i n a s u bject 
(s p o nta ne o usly re p orte d t o t he m) t hat occ urs d uri n g t he trial.
Pre g na ncies a n d lactati o ns t hat occ ur after t he c o nse nt f or m is si g ne d b ut bef ore 
ra n d o mizati o n/treat me nt all o cati o n m ust be re p orte d b y  the i n vesti gat or if t he y ca use t he 
s u bject t o be e xcl u de d fr o m t he trial, or are 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, place b o 
treat me nt o r a pr oce d ure. Pre g na ncies a n d lactati o ns t hat occ ur fr o m t he ti me of 
ra n d o mizati o n t hr o u g h 1 2 0 da y s f oll o wi n g cessati o n of S p o ns or’s pr o d uct , or 3 0 da ys 
f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w a ntica ncer t hera p y, w hic he ver is 
earlier, m ust be re p orte d b y  the i n vesti gat or.  All re p orte d pre g na ncies  must 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  outc 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, 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 0 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
miscarria ge a n d still birt h m ust be re p orte d as seri o us e ve nts (Im 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.
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or eit he r b y  electr o nic me dia or
pa per. 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. 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 Trial File Bi n der ( or e q ui vale nt).
I m me di ate Re p orti n g of A d verse E ve nts t o t he S p o nsor
7. 2. 3
7. 2. 3. 1
Seri o us A d verse E ve nts
A seri o us a d verse e ve nt is a n y ad verse e ve nt occ urri n g at a n y d ose or d uri n g a n y use of 
S p o ns or's pr o d uct t hat:
●
Res ults i n deat h;
●
Is life t hreate ni n g;
●
Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y;
●
Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n;
●
Is a c o n ge nital a n o maly/ birt h defect;
●
Is a n ot her i m p orta nt me dical e ve nt 
N ote: I n a d diti o n t o t he a b o ve criteria, a d verse e ve nts 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 def i niti o n, are re p orta ble t o t he S p o ns or i n t he sa me ti mefra me 
as S A Es t o meet certai n l ocal re q uire me nts. T heref ore, t hese e ve nts are c o nsi dere d seri o us b y 
t he S p o ns or f or c ollecti o n p ur p oses.
●
Is a ne w ca ncer (t hat is n ot a c o n diti o n of t he st u d y);
●
Is ass ociate d wit h a n o ver d ose.
Refer t o Ta ble 8 f or a d diti o nal details re gar di n g eac h of t he a b o ve criteria.
F or t he ti me peri o d be gi n ni n g w he n t he c o nse nt f or m is si g ne d u ntil ra n d o mizati o n /treat me nt 
all ocati o n , a n y seri o us a d verse e ve nt, or f oll o w u p t o a seri o us a d verse e ve nt, i ncl u di n g deat h 
d ue t o a n y ca use ot her t ha n pr o gressi o n of t he ca ncer u n der st u d y (refere nce Secti o n 7. 2. 3. 3 
f or a d diti o nal details) , t hat occ urs t o a n y s u bject m ust be re p orte d wit hi n 2 4 h o urs t o t he 
S p o ns or if it ca uses t he s u bject t o be e xcl u de d fr o m t he trial, 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 py, diet, place b o treat me nt or a pr oce d ure.
F or t he ti me peri o d be gi n ni n g at ran d o mizati o n /treat me nt  all ocati o n t hr o u g h 9 0 d a y s 
f oll o wi n g cessati o n of treat me nt, or 3 0 d a y s f oll o wi n g cessati o n of treat me nt if t he s u bject 
i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier, a n y seri o us a d verse e ve nt, or f oll o w u p 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
t o a seri o us a d verse e ve nt, i ncl u di n g deat h d ue t o a n y ca use ot her t ha n pr o gressi o n of t he 
ca ncer u n der st u d y (refere nce Secti o n 7. 2. 3. 3 f or a d diti o nal details), w het her or n ot relate d t o 
t he S p o ns or's pr o d uct, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or eit her b y  electr o nic 
me dia or pa pe r. 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. Pa per re p orti n g pr oce d ures ca n be f o u n d i n t he I nvesti gat or Trial File Bi n der ( or 
e q ui vale nt).
A d diti o nall y , a n y seri o us a d verse e ve nt, c o nsi dere d b y  an i n vesti gat or w h o is a q ualifie d 
p h y sicia n t o be relate d t o t he S p o ns or's pr o d uct t hat is br o u g ht t o t he atte nti o n of t he 
i n vesti gat or at a n y ti me f oll o wi n g c o nse nt t hr o u g h t he e n d of t he s pecifie d safet y foll o w - u p 
peri o d s pecifie d i n t he para gra p h a b o ve, or at a n y ti me o utsi de of t he ti me peri o d s pecifie d i n 
t he pre vi o us para gra p h als o m ust be re p orte d i m me diately t o t he S p o ns or.  
All s u bjects wit h seri o us a d verse e ve nts m ust be f oll o we d u p f or o utc o me.
7. 2. 3. 2
E ve nts of Cli nic al I nterest
Selecte d n o n- seri o us a n d seri o us a d verse e ve nt s are als o k n o w n as E ve nts of Cli nical Interest 
( E CI)  a n d m ust be re p orte d t o t he S p o ns or.
F or t he ti me peri o d be gi n ni n g w he n t he c o nse nt f or m is si g ne d u ntil ra n d o mizati o n/treat me nt 
all ocati o n, a n y E CI, or f oll o w u p t o a n E CI, t hat occ urs t o a n y s u bject m ust be re p orte d 
wit hi n 2 4 h o urs t o t he S p o ns or if it ca uses t he s u bject t o be e xcl u de d fr o m t he trial, 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, place b o treat me nt or a pr oce d ure.
F or t he ti me peri o d be gi n ni n g at ra n d o mizati o n/treat me nt all ocati o n t hr o u g h 3 0 d a y s 
f oll o wi n g cessati o n of treat me nt, a n y E CI, or f oll o w u p t o a n E CI , w het her or n ot relate d t o 
t he S p o ns or’s pr o d uct, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or, eit her b y  electr o nic 
me dia or pa per.  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. Pa per re p orti n g pr oce d ures ca n be f o u n d i n t he I nvesti gat or Trial File Bi n der ( or 
e q ui vale nt).
E ve nts of cli nical i nterest f or t h is trial 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 7. 2. 1 - Defi niti o n of a n O ver d ose 
f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he S p o ns or, t hat is n ot ass ociate d wit h 
cli nical s ym 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 vate 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  w a y of pr ot oc ol-s pecifie d la b orat or y 
testi ng or u n sc he d ule d la b orat or y testi n g. *
* N ote:  These criteria are base d u p o n a vaila ble re g ulat or y gui 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 trial site g ui da nce f or assess me nt 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 0 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 nvesti gat or Trial File Bi n der ( or 
e q ui vale nt).
7. 2. 3. 3
Pr ot oc ol -S pecific E xce pti o ns t o Seri o us A d verse E ve nt Re p orti n g
Efficac y  en 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 7. 2. 3 - I mme diate Re p orti n g of A d verse E ve nts t o t he S p o ns or .
S pecificall y, t he s us pecte d/act ual e ve nts c o vere d i n t his e x ce pti o n i ncl u de a n y eve 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 en d p oi nt e ve nts a n d safety data t o 
e ns ure t he safet y of t he s u bjects i n t he trial. A n y  sus pecte d e n d p oi nt w hic h 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 safet y as a S A E wit hi n 
2 4 h o ur s 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
E v al u ati n g A d verse E ve nts
7. 2. 4
A n i n vesti gat or w h o is a q ualifie d p h y sicia n will e val uate all a d verse e ve nts acc or di n g t o t he 
N CI  Co m m o n Ter mi n ol o g y  for A d verse E ve nts ( C T C A E), versi o n 4. 0 . A n y  ad verse e ve nt 
w hic h 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 d verse e ve nt case re p ort f or ms/ w or ks heets.
All a d verse e ve nts re gar dless of C T C A E gra de m ust als o be e val uate d f or seri o us ness.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 8
E val uati n g A d verse E ve nts
A n i n vesti gat or w h o is a q ualifie d p h ysicia n, will e val uate all a d verse e ve nts as t o:
V 4. 0 C T C A E 
Gr a di n g
Gr a de 1
Mil d; as y m pt o m atic or mi d s y m pt o ms; cli nic al or di a g n ostic o bser v ati o ns o nl y; i nter ve nti o n n ot i n dic ate d.
Gr a de 2
M o der ate; mi ni m al, l oc al or n o ni n v asi ve i nter ve nti o n i n dic ate d; li miti n g a ge -a p pr o pri ate i nstr u me nt al A D L.
Gr a de 3
Se vere or me dic all y si g nific a nt b ut n ot i m me di atel y life-t hre ate ni n g; h os pit aliz ati o n or pr ol o n g ati o n or h os pit aliz ati o n i n dic ate d; dis a bli n g; 
li miti n g self-c are A D L.
Gr a de 4
Life t hre ate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dic ate d.
Gr a de 5
De at h rel ate d t o A E
Seri o us ness
A seri o us a d verse e ve nt is a n y a d verse e ve nt occ urri n g at a n y d ose or d uri n g a n y use of S p o ns or’s pr o d uct t hat:
† Res ults i n de at h ; or
† Is life t hre ate ni n g; or places t he s u bject, i n t he vie w of t he i n vesti gat or, at i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d ( N ote: T his d oe s n ot i ncl u de a n a d verse e ve nt 
t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.); or
† Res ults i n a persiste nt or si g nific a nt dis a bilit y/i nc a p acit y (s u bsta ntial disr u pti o n of o ne’s a bilit y t o c o n d uct n or mal life f u ncti o ns); or
† Res ults i n or pr ol o n gs a n e xisti n g i n p atie nt h os pit aliz ati 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 pre -e xisti n g c o n diti o n t hat has n ot w orse ne d is n ot a seri o us a d verse 
e ve nt.  A pre-e 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 Merc k pr o d uct a n d is d oc u me nte d i n t he s u bject’s me dical hist or y.); or
† Is a c o n ge nit al a n o m al y/ birt h defect (i n offs pri n g of s u bject ta ki n g t he pr o d uct re gar dless of ti me t o dia g n osis); or
Is a ne w c a ncer (t hat is n ot a c o n diti o n of t he st u d y) (alt h o u g h n ot seri o us per I CH defi niti o n, is re p orta ble t o t he S p o ns or wit hi n 2 4 h o urs t o meet certai n l ocal re q uire me nts); 
or
Is a n o ver d ose ( w het her acci de ntal or i ntenti o nal).  An y a d verse e ve nt ass ociate d wit h a n o ver d ose is c o nsi dere d a seri o us a d verse e ve nt f or c ollecti o n p ur p oses . An o ver d ose 
t hat is n ot ass ociate d wit h a n a d verse e ve nt is c o nsi dere d a n o n-seri o us e ve nt of cli nical i nterest a n d m ust be re p orte d wit hi n 2 4 h o urs.
Ot her i mp ort a nt me dic al e ve nts t hat ma y n ot res ult i n deat h, n ot be life t hreate ni n g, or n ot re q uire h os pitalizati o n ma y be c o nsi dere d a seri o us a d verse e vent w he n, base d 
u p o n a p pr o priate me dical j u d g me nt, t he e ve nt m a y  je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d pre vi o u sl y 
( desi g nate d a b o ve b y a †).
D ur ati o n
Rec or d t he start a n d st o p dates of t he a d verse e ve nt. I f less t ha n 1 da y, i n dicate t he a p pr o priate le n gt h of ti me a n d u nits
Acti o n t a k e n 
Di d t he a d verse e ve nt ca use t he S p o ns or’s pr o d uct t o be disc o nti n ue d?
Rel ati o ns hi p 
t o 
S p o ns or’s 
Pr o d uct
Di d t he S p o ns or’s pr o d uct ca use t he a d verse e ve nt? T he deter mi nati o n of t he li keli h o o d t hat t he S p o ns or’s pr o d uct ca use d t he a d verse e ve nt 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 dic all 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 dr u g a n d t he a d verse e ve nt base d u p o n t he a vaila ble i nf or mati o n.
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 he rel ati o ns hi p bet wee n t he S p o ns or’s pr o d uct a n d t he A E ; t he greater t he c orrelati 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 S p o ns or’s pr o d uct ca use d t he a d verse e ve nt ( A E):
E x p os ure
Is t here e vi de nce t hat t he s u bject was act uall y e x p ose d t o t he S p o ns or’s pr o d uct s uc h as: relia ble hist or y, acce pta ble c o m pli a 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 m e 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 S p o ns or’s pr o d uct?
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 trials wit h i n vesti gati o nal me dici nal pr o d uct)?
Li k el 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
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 0 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Rel ati o ns hi p
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 he rel ati o ns hi p bet wee n t he test dr u g a n d t he A E: (c o nti n ue d)
t o S p o ns or's 
Pr o d uct
(c o nti n ue d) 
Dec h alle n ge
Was t he S p o ns or’s pr o d uct 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 ved de s pite c o nti n uati o n of t he 
S p o ns or’s pr o d uct; or ( 3) t he trial is a si n gle -d ose dr u g trial); or ( 4) S p o ns or’s pr o d uct(s) is/are o nl y use d o ne ti me.)
Rec h alle n ge
Was t he s u bject re -e x p ose d t o t he S p o ns or’s pr o d uct 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. I f 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 de at h or per ma ne nt disa bilit y, or ( 2) t he trial is a si n gle-d ose dr u g trial); or ( 3) 
S p o ns or’ s pr o d uct(s) is/are use d o nl y o ne 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 D V E R S E E V E N T W HI C H W A S S E RI O U S A N D W HI C H M A Y H A V E B E E N C A U S E D B Y 
T H E S P O N S O R' S P R O D U C T, O R I F R E E X P O S U R E T O T H E S P O N S O R' S P R O D U C T 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 S U BJ E C 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 L I NI C A L DI 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.
C o nsiste nc y 
wit h 
Tri al 
Tre at me nt 
Pr ofile
Is the cli nical/ pat h ol o gical prese ntati o n of t he A E c o nsiste n t wit h pre vi o us k n o wle d ge re gar di n g t he S p o ns or’s pr o d uct or dr u g class p har mac ol o g y or 
t o xic ol o g y?
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 his/ her 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.
Rec or d o ne of t he f oll o wi n g
Use t he f oll o wi n g sc ale of criteri a as g ui d a nce ( n ot all criteri a m ust be prese nt t o be i n dic ati ve of a S p o ns or’s pr o d uct rel ati o ns hi p).
Yes, t here is a re as o n a ble 
p ossi bilit y of S p o ns or's pr o d uct 
rel ati o ns hi p.
T here is e vi de nce of e x p os ure t o t he S p o ns or's pr o d uct.  The 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 S p o ns or's pr o d uct is 
reas o na ble.  T he A E is m ore li kel y e x plai ne d by t he S p o ns or's pr o d uct t ha n b y a n ot her ca use.
N o, t here is n ot a re as o n a ble 
p ossi bilit y of S p o ns or's pr o d uct 
rel ati o ns hi p
S u bject di d n ot recei ve t he S p o ns or's pr o d uct 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 S p o ns or' s pr o d uct 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 S p o ns or’s pr o d uct.  ( Als o e ntere d f or a s u bject wit h o ver d ose wit h o ut a n ass ociate d A E.)
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S p o ns or Res p o nsi bilit y f or Re p orti n g A d verse E ve nts
7. 2. 5
All A d verse E ve nts will be re p orte d t o re g ulat or y a ut h orities, I RB/I E Cs a n d i n vesti gat ors i n 
acc or da nce wit h all a p plica ble gl o bal la ws a n d re g ulati o ns, i.e., per I C H T o pic E 6 ( R 1) 
G ui deli nes f or G o o d Cli nical Practice .
Tri al G o ver n a nce a n d O versi g ht
7. 3
Scie ntific A d vis or y C o m mittee
7. 3. 1
T his trial was de vel o pe d i n c olla b orati o n wit h a Scie ntific A d vis or y  Co m mittee ( S A C).  The 
S A C c o m prises b ot h S p o ns or a n d n o n -S p o ns or scie ntific e x perts w h o pr o vi de i n p ut wit h 
res pect t o trial desi g n, i nter pretati o n of trial res ults a n d s u bse q ue nt peer -re vie we d scie ntific 
p u blicati o ns.
E xec uti ve O versi g ht C o m mittee
7. 3. 2
T he E xec uti ve O versi g ht 
C o m mittee 
( E O C) c o m prises
me m bers of S p o ns or Se ni or 
Ma na ge me nt.  The E O C will recei ve a n d deci de u p o n a n y rec o m me n dati o ns ma de b y  the
Data M o nit ori n g C o m mittee ( D M C) re gar di n g t he trial.
D at a M o nit ori n g C o m mittee
7. 3. 3
T o s u p ple me nt t he r o uti ne trial m o nit ori n g o utli ne d i n t his pr ot oc ol , a n e xter nal Data 
M o nit ori n g C o m mittee ( D M C) will m o nit or t he i nteri m data fr o m t his trial.  The 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.  The me m bers of t he D M C m ust n ot 
be i n v ol ve d wit h t he trial i n a n y ot her w a y  (e. g., t he y ca n n ot b e trial 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 res pect t o t he trial. 
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 s u bject 
safety a n d t he c o nti n ue d et hical i nte grit y of t he trial.  Als o, t he D M C will re vie w i nteri m trial 
res ults, c o nsi der t he o verall ris k a n d be nefit t o trial partici pa nts (see Secti o n 8. 7 - I nteri m 
A nal y ses) a n d rec o m me n d t o t he E O C if t he trial 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 regar 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 trial 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 a se parate c harter t hat is 
re vie we d a n d a p pr o ve d b y  the D M C.  The D M C will m o nit or t he trial at a n a p pr o priate 
fre q ue nc y, as descri be d i n t he detaile d D M C c harter. 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
8. 0 S T A TI S TI C A L A N A L Y SI S P L A N
T his secti o n o utli nes t he statistical a nal ys is strate g y an d pr oce d ures f or t he st u d y. If, after 
t he st u d y has be g u n, c ha n ges are ma de t o pri mar y  an d/ or k e y  sec o n dar y hy p ot heses, or t he 
statistical met h o ds relate d t o t h ose h y p ot heses, t he n t he pr ot oc ol wil l be a me n de d (c o nsiste nt 
wit h I CH G ui deli ne E- 9).  C ha n ges t o e x pl orat or y or ot her n o n -c o nfir mat or y anal ys es ma de 
after t he pr ot oc ol has bee n fi nalize d, b ut pri or t o t he c o n d uct of a n y anal ys is u n bli n di n g , will 
be d oc u me nte d i n a s u p ple me ntal statistical a nal y sis pla n (s S A P) a n d refere nce d i n t he 
Cli nical St u d y  Re p ort ( C S R) f or t he st u d y. A se parate P K a nal ys is pla n as well as bi o mar ker 
a nal ys is pla n m a y be pr o vi de d. P ost h oc e x pl orat or y  an al y ses will be clearl y ide ntifie d i n t he 
C S R .  A patie nt -re p orte d o utc o me (P R O ) a nal ys is pla n will be i ncl u de d i n t he s S A P.
I n t his secti o n, “S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0) ” is a b bre viate d as “ S u bjects 
wit h C P S ≥1 0 ”, a n d “ S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 )” is a b bre viate d as 
“ S u bjects wit h C P S ≥1” .
St atistic al A n al ysis Pl a n S u m m ar y
8. 1
K e y  ele me nts of t he statistical a nal ysis pla n are s u m marize d bel o w; t he c o m pre he nsi ve pla n 
is pr o vi de d i n Secti o n 8. 2 t hr o u g h Secti o n 8. 1 2.
St u d y Desi g n O ver vie w
A P hase III Ra n d o mize d Trial of Si n gle A ge nt P e m br oliz u ma b vers us 
Si n gle A ge nt C he m ot hera p y per P h y sicia n’s C h oice f or Metastatic Tri ple 
Ne gati ve Breast Ca ncer ( m T N B C) 
Treat me nt Assi g n me nt
A p pr o xi matel y 6 0 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o bet w ee n t w o 
treat me nt gr o u ps: ( 1) pe m br oliz u ma b ar m an d ( 2) Treat me nt of P h ysicia n’s 
C h oice ( T P C) ar m. Stratificati o n fact ors are: 1) P D -L 1 t u m or stat us ( p ositi ve
[ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d 2) hist or y of  pri or ( ne o)a dj u va nt 
treat me nt vs de n o v o metastatic disease at i nitial dia g n osis .
A nal ysis P o p ulati o ns
Efficac y: I nte nti o n -t o-treat P o p ulati o n (I T T)
Safet y: All S u bjects as Treate d ( A Sa T)
Pri mar y E n d p oi nt(s)
1 O verall sur vi val ( O S) i n s u bjects wit h C P S ≥1 0
2 O S i n s u bjects wit h C P S ≥1   
3 O S i n all s u bjects 
Statistical Met h o ds 
f or Ke y 
Efficac y A nal yses
T he pri mar y h y p ot heses will be e val uate d b y  co m pari n g pe m br oliz u ma b t o 
T P C o n O S usi n g a stratifie d L o g -ra n k test. Esti mati o n of t he hazar d rati o 
will be perf or me d usi n g a stratifie d C o x re gressi o n m o del. E ve nt rates o ver 
ti me will be esti m ate d wi t hi n eac h treat me nt gr o u p usi n g t he Ka pla n -Meier 
met h o d.
Statistical Met h o ds 
f or Ke y 
Safet y A nal yses
T he a nal ysis of  safet y
res ults will 
f oll o w a tiere d a p pr oac h. Safet y 
para meters or a d verse e x perie nces of  special i nterest t hat are i de ntifie d a 
pri ori c o nstit ute “ T ier 1” safet y e n d p oi nts t hat will be s u bject t o i nfere ntial 
testi n g f or statistical si g nifica nce wit h p -val ues a n d 9 5 % c o nfi de nce i nter vals
( CIs) pr o vi de d f or bet w ee n-gr o u p c o m paris o ns.  Ot her safet y para meters will 
be c o nsi dere d Tier 2 ( wit h 9 5 % c o nfi de nce i nter vals pr o vi de d) or Tier 3 
( wit h p oi nt esti mates b y  treat me nt gr o u p pr o vi de d) T he bet w e e n-treat me nt 
differe n ce will be a nal yze d usi n g t he Mietti ne n a n d N ur mi ne n met h o d.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 1 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
I nteri m A nal yses
O ne i nteri m efficac y a nal ysis is pla n ne d i n t his st u d y.  Details are pr o vi de d 
i n Secti o n 8. 7.

I nteri m A nal ysis
o
Ti m i n g: a p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is c o mplete d . It 
is esti mate d t hat a p pr o xi matel y 1 3 0 , 2 8 4 a n d 4 4 5 O S e ve nts will be 
accr ue d i n s u bjects wit h C P S ≥1 0 , C P S ≥1 a n d all s u bjects.
o
P ur p ose: i nteri m efficac y a nal ysis f or O S 

Fi nal a nal ysis 
o
Tri g gere d b y d urati o n of f oll o w-u p a n d O S e ve nts i n s u bjects wit h 
C P S ≥1: A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is c o m plete d 
or 3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1, w hic he ver 
occ urs later. A p pr o xi matel y 1 5 4, 3 3 4 a n d 5 2 0 O S e ve nts will b e 
accr ue d i n s u bjects wit h C P S ≥1 0 , C P S ≥1 a n d all s u bject s.
o
If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue sl o wer t ha n e x pecte d 
a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt 
is c o mpl ete d, t he n t he S p o ns or will c o n d uct t he fi nal a n al ysis at 
t hat ti me
o
P ur p ose: fi nal efficac y a nal ysis f or O S 
M ulti plicit y
T he o verall T y pe I err or o ver t he m ulti ple 
e n d p oi nts will be str o n gl y 
c o ntr olle d at 2. 5 % ( o ne-si de d) f or pri mar y h y p ot heses of  OS
e n d p oi nts 
(i nitial α of 1. 7 % i n s u bjects wi t h C P S ≥1 0 a n d 0. 8 % i n s u bjects wit h 
C P S ≥1 ) a n d sec o n dar y h y p ot heses of P F S a n d O R R i n all s u bjects. Usi n g a n 
e xte nsi o n [ 1 0 5] of t he gra p hical a p pr oac h of Ma urer a n d Bretz [9 6 ], al p ha
ca n be re-all ocate d bet w ee n h y p ot heses . G r o u p se q ue ntial met h o ds will be 
use d t o all ocate al p ha bet wee n t he i nteri m a n d fi nal a nal yses f or O S 
e n d p oi nts.
Sa m ple Size a n d P o w er 
T he pla n ne d sa m ple size is a p pr o xi matel y 6 0 0 s u bjects .  Details are pr o vi de d 
i n Secti o n 8. 9.

F or t he pri mar y O S 
e n d p oi nt i n s u bjects wit h 
C P S 
≥1 0 , wit h 
a p pr o xi matel y 1 5 4 O S e ve nts t he trial has ~ 8 5 %
p o w er at a o ne- si de d 
1. 7 % al p ha-le vel, if t he u n derl yi n g H R is 0.6 0 , wit h a H R at b o u n d ar y  
f or s uccess of ~ 0. 7 0 ( ~4. 2 m o nt h i m pr o ve me nt ).

F or t he pri mar y O S 
e n d p oi nt i n s u bjects wi t h C P S 
≥1 , wit h 
a p pr o xi matel y 3 3 4 O S e ve nts t he trial has ~ 8 0 % ( 9 0 %) p o w er at a 
o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel, if t he u n derl yi n g H R is 0. 7 0 , wit h 
a H R at b o u n dar y f or s uccess of  ~0. 7 6 ( 0. 8 0) ( ~3. 1 [ 2. 5] m o nt h 
i mpr o ve me nt).

F or t he pri m ar y O S e n d p oi nt i n all s u bjects, wit h a p pr o xi matel y 5 2 0 
O S e ve nts t he trial has ~ 6 6 % ( 8 0 %) p o w er at a o n e -si de d 0. 8 % ( 2. 5 %) 
al p ha-le vel, if t he u n derl yi n g H R is 0. 7 8 , wit h a H R at b o u n dar y f or 
s uccess of ~ 0. 8 0 ( 0. 8 4) ( ~ 2.4 [ 1. 9] m o nt h i m pr o ve me nt).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g
8. 2
T he statistical a nal ys is of t he data o btai ne d fr o m t his st u d y will be the 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 he I V R S ve n d or will ge nerate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y treat me nt 
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 I V R S.   
Alt h o u g h t he trial is o pe n la bel, a nal yses or s u m maries ge nerate d b y  ra n d o mize d treat me nt 
assi g n me nt, act ual treat me nt recei ve d, a n d/ or P D -L 1 bi o mar ker stat us will be li mite d a n d 
d oc u me nte d. I n a d diti o n, t he i n de pe n de nt ra di ol o gist(s) will perf or m t he ce ntral i ma gin g 
re vie w wit h o ut k n o wle d ge of treat me nt gr o u p assi g n me nt.
T he st u d y tea m at t he S p o ns or 
c o nsisti n g of cli nical, statistical, statistical pr o gra m mi n g a n d data ma na ge me nt pers o n nel, 
will be bli n de d t o s u bject-le vel P D -L 1 bi o mar ker res ults. A n u n bli n de d S p o ns or cli nical 
scie ntist, u n bli n de d S p o ns or statisticia n a n d u n bli n de d S p o ns or statistical pr o gra m mer will 
ha ve access t o t he s u bject-le vel P D -L 1 res ults f or t he p ur p ose of data re vie w a n d e ve nt 
m o nit ori n g, a n d will ha ve n o ot her res p o nsi bilities ass ociate d wit h t he st u d y. A s u m mar y of 
P D -L 1  bi o mar ker pre vale nce m a y  be pr o vi de d t o t he st u d y tea m at t he S p o ns or b y  the I V R S 
ve n d or or t he u n bl i n de d S p o ns or statisticia n.
Access t o t he all ocati o n sc he d ule a n d t he s u bject -le vel P D -L 1  res ults f or s u m maries or 
a nal ys es will be restricte d t o a n u n bli n de d e xter nal statisticia n, a n d, as nee de d, a n e xter nal 
scie ntific pr o gra m mer perf or mi n g t he a nal ys is, w h o will ha ve n o ot her res p o nsi bilities 
ass ociate d wit h t he st u d y.
Treat me nt -le vel res ults at t he i nteri m efficac y will be pr o vi de d b y  the e xter nal u n bli n de d 
statisticia n t o t he e D M C. T he e xter nal u n bli n de d statisticia n will ha ve access t o all ocati o n 
sc he d ule, treat me nt gr o u p, P D -L 1 stat us f or a n y a n al ysis re q uire d f or e D M C re vie w. Li mite d 
a d diti o nal S P O N S O R pers o n nel m a y  be u n bli n de d t o t he treat me nt le vel a n d/ or P D -L 1  
bi o mar ker res ults of t he efficac y i nteri m a nal yses, if re q uire d, i n or der t o act o n t he 
rec o m me n dati o ns of t he e D M C or facilitate re g ulat or y fili n g after t he i nteri m efficac y
a nal ys is. T he e xte nt t o w hic h i n di vi d uals are u n bli n de d wit h res pect t o res ults of i nteri m 
a nal ys es will be d oc u me nte d b y t he u n bli n de d statisticia n.
T he e D M C will ser ve as t he pri mar y re vie wer of t he u n bli n de d res ults of t he i nteri m efficac y 
a nal ys es a n d will ma ke rec o m me n dati o ns f or disc o nti n uati o n of t he st u d y or m o dificati o n t o 
a n e xec uti ve o versi g ht c o m mittee of t he S P O N S O R. De pe n di n g o n t he rec o m me n dati o n of 
t he e D M C, t he S p o ns or ma y  pre pare a re g ulat or y su b missi o n.
If t he e D M C rec o m me n ds 
m o dificati o ns t o t he desi g n of t he pr ot oc ol or disc o nti n uati o n of t he st u d y, t his e xec uti ve 
o versi g ht c o m mittee ma y  be u n bli n de d t o res ults at t he treat me nt le vel i n or der t o act o n 
t hese rec o m me n dati o ns. A d diti o nal l o gistical details, re visi o ns t o t he a b o ve pla n a n d data 
m o nit ori n g g ui da nce will be pr o vi de d i n t he e D M C C harter. 
H y p ot heses/ Esti m ati o n
8. 3
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. 0 .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A n al ysis E n d p oi nts
8. 4
Effic ac y E n d p oi nts
8. 4. 1
Pri m ar y
O ver all S ur vi v al ( O S)
O verall S ur vi val ( O S) 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. 
S u bjects wit h o ut d oc u me nte d deat h at t he ti me of t he fi nal a nal ysis will be ce ns ore d at t he 
date of t he last f oll o w -u p.
Sec o n d ar y a n d E x pl or at or y
Pr o gressi o n- free s ur vi v al ( P F S) – b ase d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntr al 
i m a gi n g ve n d or ( R E CI S T 1. 1 b y  site I n vesti gat or/l ocal ra di ol o g y re vie w as a s u p p orti ve 
a nal ys is).
Pr o gressi o n -free-s ur vi val ( P F S) 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 base d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntral 
i ma gi n g ve n d or ra di ol o g y re vie w or deat h d ue t o a n y ca use, w hic he ver occ urs first. See 
Secti o n 8. 6. 1 f or t he defi niti o n of ce ns ori n g.
O ver all Res p o nse R ate ( O R R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
(R E CI S T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses ; ir R E CIS T b y 
site I nvest i gat or/l ocal ra di ol o g y re vie w m a y  als o be e val uate d).
O verall res p o nse rate is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ys is p o p ulati o n 
w h o ha ve a c o m plete res p o nse ( C R) or partial res p o nse ( P R).
D ur ati o n of O ver all 
Res p o nse ( D O R) –
b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d 
ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or ( R E CIS T 1. 1 b y  
site I nvesti gat or /l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses; ir R E CIS T
b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  als o be e val uate d).
F or s u bjects w h o de m o nstrate d C R or P R, res p o nse d urati o n is defi ne d as t he ti me fr o m first 
d oc u me nte d e vi de nce of C R or P R u ntil disease pr o gressi o n or deat h. See Secti o n 8. 6. 1 f or 
t he defi niti o n of ce ns ori n g.
Dise ase C o ntr ol R ate
( D C R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
( R E CIS T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses ; ir R E CIS T b y 
site I nvesti gat or /l ocal ra di ol o gy re vie w m a y  als o be e val uate d).
Disease c o ntr ol rate ( D C R) is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ysis 
p o p ulati o n w h o ha ve a C R, partial res p o nse ( P R) a n d sta ble disease ( S D), t he latter f or at 
least 8 c y cles .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
P F S – b ase d o n ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
(ir R E CIS T b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  be perf or me d as s u p p orti ve 
a nal ys is).
S afet y E n d p oi nts
8. 4. 2
Safet y  meas ure me nts are descri be d i n Secti o n 7. 0
S u bject -Re p orte d O utc o mes E n d p oi nts
8. 4. 3
Patie nt- re p orte d o utc o me e n d p oi nts are descri be d i n Secti o n 7. 1. 2. 9.
A n al ysis P o p ul ati o ns
8. 5
Effic ac y A n al ysis P o p ul ati o ns
8. 5. 1
T he I T T p o p ulati o n will 
ser ve as t he p o p ulati o n f or pri mar y  efficac y anal y sis. All 
ra n d o mize d s u bjects will be i ncl u de d i n t his p o p ulati o n. S u bjects will be i ncl u de d i n t he 
treat me nt gr o u p t o w hic h t he y are ra n d o mize d.
Details o n t he a p pr oac h t o ha n dli n g missi n g data are pr o vi de d i n Secti o n 8. 6 .
S afet y A n al ysis P o p ul ati o ns
8. 5. 2
T he All S u bjects as Treate d ( A Sa T) p o p ulati o n will be use d f or t he a nal ysis of safety data i n 
t his st u d y.  The A Sa T p o p ulati o n c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt. S u bjects will be i ncl u de d i n t he treat me nt gr o u p c orres p o n di n g 
t o t he st u d y treat me nt t he y act uall y recei ve d f or t he a nal ys is of safety data usi n g t he A Sa T 
p o p ulati o n.  F or m ost s u bjects t his will be t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d.  
S u bjects w h o ta ke i nc orrect st u d y  treat me nt f or t he e ntire treat me nt peri o d will be i ncl u de d i n 
t he treat me nt gr o u p c orres p o n di n g t o t he st u d y treat me nt act uall y recei ve d. A n y  su bject w h o 
recei ves t he i nc orrect st u d y dr u g f or o ne c ycle, b ut recei ves t he c orrect treat me nt f or all ot her 
c ycles, will be a n al y ze d acc or di n g t o t he c orrect treat me nt gr o u p a n d a narrati ve will be 
pr o vi de d f or a n y e ve nts t hat occ ur d uri n g t he c ycle f or w hic h t he s u bject is i nc orrectl y d ose d. 
At least o ne la b orat or y or vital si g n meas ure me nt o btai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter.  T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.
Details o n t he a p pr oac h t o ha n dli n g missi n g data f or safety a nal yses are pr o vi de d i n Sec ti o n 
8. 6 .
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 1 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St atistic al Met h o ds
8. 6
St atistic al Met h o ds f or Effic ac y A n al yses
8. 6. 1
T his secti o n descri bes t he statistical met h o ds 
t hat a d dress t he pri mar y  an d sec o n dar y 
o bjecti ves.  Met h o ds relate d t o e x pl orat or y objecti ves (a n d s u p p orti ve a nal yses i ncl u di n g 
P F S 2 ) will be descri be d i n t he s u p ple me ntal S A P.
Efficac y  res ults t hat will be dee me d t o be statisticall y si gnifica nt after c o nsi derati o n of t he 
T y pe I err or c o ntr ol strate g y  are descri be d i n Secti o n 8. 8 . N o mi nal p-val ues will be c o m p ute d 
f or ot her efficac y anal ys es , b ut s h o ul d be i nter prete d wit h ca uti o n d ue t o p ote ntial iss ues of 
m ulti plicit y .
8. 6. 1. 1
O ver all S ur vi v al 
T he n o n -para metric Ka pla n -Meier met h o d will be use d t o esti mate t he s ur vi val c ur ves. T he 
treat me nt differe nce i n s ur vi val will be assesse d b y  the stratifie d l o g-ra n k test. A stratifie d 
C o x pr o p orti o nal hazar d m o del wit h Efr o n ’s met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (ie, t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n [ P D-L 1  tu m or stat us ( p ositi ve
[ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d pri or ( ne o)a dj u va nt t hera py vs de n o v o metastatic 
disease at i nitial di a g n osis] will be a p plie d, as stratificati o n fact ors use d f or a nal ys is, 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.
S u bjects i n t he T P C ar m are e x pecte d t o disc o nti n ue treat me nt earlier c o m pare d t o s u bjects i n 
t he pe m br oliz u ma b ar m a n d are n ot all o we d t o cr oss o ver t o t he pe m br oliz u ma b ar m; 
h o we ver, t he y ma y be treate d wit h a n ot her a nti P D -1 dr u g f oll o wi n g t he verificati o n of 
pr o gressi ve disease b y  bli n de d ce ntral i ma gi n g ve n d or. As a n e x pl orat or y anal ys is, t he Ra n k 
Preser vi n g Str uct ura l Fail ure Ti me ( R P S F T) m o del pr o p ose d b y  Ro bi ns a n d Tsiatis ( 1 9 9 1) 
[9 7 ] ma y  be use d t o a dj ust f or t he effect of cr oss o ver t o ot her P D -1 t hera pies o n O S, base d 
o n a n e xa mi nati o n of t he a p pr o priate ness of t he data t o t he ass u m pti o ns re q uire d b y  th e 
met h o ds.
8. 6. 1. 2
Pr o gressi o n- Free S ur vi v al
T he n o n -para metric Ka pla n -Meier met h o d will be use d t o esti mate t he P F S c ur ve i n eac h 
treat me nt gr o u p. T he treat me nt differe nce i n P F S will be assesse d b y  the stratifie d l o g-ra n k 
test. A stratifie d C o x pr o p orti o nal hazar d m o del wi t h Efr o n ’s met h o d of tie ha n dli n g will be 
use d t o assess t he ma g nit u de of t he treat me nt differe nce (ie, hazar d rati o) bet wee n t he 
treat me nt ar ms. T he hazar d rati o a n d its 9 5 % c o nfi de nce i nter val fr o m t he stratifie d C o x 
m o del wit h Efr o n ’s met h o d of tie ha n d li n g a n d wit h a si n gle treat me nt c o variate will be 
re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n [ P D-L 1  tu m or stat us ( p ositi ve 
[C P S ≥1 ] vs ne gati ve [ C P S < 1] ), a n d Pri or ( ne o)a dj u va nt t hera p y vs de n ov o metastatic 
disease at i nitial dia g n osis ] will be a p plie d, as stratificati o n fact ors use d f or a nal ys is, 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 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 1 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Si nce disease pr o gressi o n is assesse d peri o dicall y, pr o gressi ve disease ( P D) ca n occ ur a n y 
ti me i n t he ti me i nter val bet wee n t he last assess me nt w here P D was n ot d oc u me nte d a n d t he 
assess me nt w he n P D is d oc u me nte d. F or t he s u bjects w h o ha ve P D, t he tr ue date of disease 
pr o gressi o n will be a p pr o xi mate d b y  the date of t he first assess me nt at w hic h P D is 
o bjecti vel y  doc u me nte d base d o n R E CI S T 1. 1 as assesse d b y  bli n de d ce ntral i ma gi n g 
ve n d or. Deat h is al wa y s c o nsi dere d as a c o nfir me d P D e ve nt. S u bjects w h o d o n ot e x perie nce 
a P F S e ve nt will be ce ns ore d at t he last disease assess me nt ( wit h e xce pti o ns descri be d 
bel o w). Se nsiti vit y  ana l yses will be perf or me d f or c o m paris o n of P F S base d o n I nvesti gat or 's 
assess me nt.
I n or der t o e val uate t he r o b ust ness of t he P F S e n d p oi nt base d o n R E CI S T 1. 1 as assesse d b y 
bli n de d ce ntral i ma gi n g ve n d or, we will perf or m o ne pri mar y  an d t w o se nsiti vit y ana l yses 
wit h a differe nt set of ce ns ori n g r ules. F or t he pri mar y  anal ys is, if t he e ve nts ( P D or deat h) 
are i m me diatel y after m ore t ha n o ne misse d disease assess me nt, t he data are ce ns ore d at t he 
last disease assess me nt pri or t o missi n g visits.  Als o data after ne w a nti-ca ncer t hera p y are 
ce ns ore d at t he last disease assess me nt pri or t o t he i nitiati o n of ne w a nti-ca ncer t hera p y. T he 
first se nsiti vit y an al y sis f oll o ws t he c o m plete f oll o w u p i nte nti o n-t o-treat pri nci ple. T hat is, 
P Ds/ deat hs are c o u nte d as e ve nts re gar dless of misse d st u d y visits or i nitiati o n of ne w a nti-
ca ncer t hera py.  The sec o n d se nsiti vit y an al y sis c o nsi ders disc o nti n uati o n of treat me nt or 
i nitiati o n of a n a ntica ncer treat me nt s u bse q ue nt t o disc o nti n uati o n of st u d y-s pecifie d 
treat me nts, w hic h e ver occ urs later, t o be a P D e ve nt f or s u bjects wit h o ut d oc u me nte d P D or 
deat h. If a s u bject meets m ulti ple criteria f or ce ns ori n g, t he ce ns ori n g criteri o n t hat occ urs 
earliest will be a p plie d.   T he ce ns ori n g r ules f or pri mar y  an d se nsiti vit y anal y ses are
s u m marize d i n Ta ble 9 .
I n case t here is a n i m bala nce bet wee n t he treat me nt gr o u ps o n disease assess me nt sc he d ules 
or ce ns ori n g patter ns, we ma y  als o perf or m t he f oll o wi n g t w o a d diti o nal P F S se nsiti vit y 
a nal ys es: 1) a P F S a nal ysis usi n g ti me t o sc he d ule d t u m or assess me nt visit fr o m 
ra n d o mizati o n as o p p ose d t o act ual t u m or assess me nt ti me; 2) Fi n kelstei n ( 1 9 8 6)’s 
li keli h o o d-base d sc ore test [ 9 8] f or i nter val-ce ns ore d data, w hic h 
m o difies 
t he C o x 
pr o p orti o nal hazar d m o del f or i nter val ce ns ore d data, will be use d as a s u p p orti ve a nal ys is 
f or t he P F S e n d p oi nt. T he i nter val will be c o nstr ucte d s o t hat t he left e n d p oi nt is t he date of 
t he last disease assess me nt wit h o ut d oc u me nte d P D a n d t he ri g ht e n d p oi nt is t he date of 
d oc u me nte d P D or deat h, w hic he ver occ urs e arlier.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 1 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 9
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of Pr o gressi o n-free S ur vi val
Sit u ati o n
Pri m ar y A n al ysis
Se nsiti vit y
A n al ysis 1
Se nsiti vit y
A n al ysis 2
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is n ot 
i nitiate d
Ce ns ore d at last disease 
assess me nt 
Ce ns ore d at last disease 
assess me nt 
Pr o gresse d at treat me nt 
disc o nti n uati o n d ue t o 
reas o ns ot her t ha n c o m plete 
res p o nse; ot her wise 
ce ns ore d at last disease 
assess me nt if still o n st u d y 
treat me nt or c o m plete d 
st u d y treat me nt.
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is i nitiate d
Ce ns ore d at last disease 
assess me nt bef ore ne w 
a ntica ncer treat me nt
Ce ns ore d at last disease 
assess me nt 
Pr o gresse d at date of ne w  
a ntica ncer treat me nt
P D or deat h 
d oc u me nte d after ≤ 1 
misse d disease 
assess me nt , a n d bef ore 
ne w a nti -ca ncer 
t hera p y, if a n y
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
P D or deat h 
d oc u me nte d 
i m me diatel y after ≥ 2 
misse d disease 
assess me nts or after 
ne w a nti -ca ncer 
t hera p y, if a n y
Ce ns ore d at last disease 
assess me nt pri or t o t he 
earlier date of  ≥ 2 
c o nsec uti ve misse d 
disease assess me nt a n d 
ne w a nti -ca ncer t hera p y, if 
a n y
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
T he pr o p orti o nal hazar ds ass u m pti o n o n P F S will be e x a mi ne d usi n g b ot h gra p hical a n d 
a nal yt ical met h o ds if warra nte d. T he l o g[-l o g] of t he s ur vi val f u ncti o n v ers us ti me f or P F S 
will be pl otte d f or t he c om paris o n bet wee n p e m br oliz u mab a n d t he T P C ar m. If t he c ur ves 
are n ot parallel, i n dicati n g t hat hazar ds are n ot pr o p orti o nal, s u p p orti ve a nal ys es ma y
b e 
c o n d ucte d t o acc o u nt f or t he p ossi ble n o n- pr o p orti o nal hazar ds effect ass ociate d wit h 
i m m u n ot hera pies; f or e xa m ple, usi n g Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d
[ 9 9]
a n d para metric met h o d [ 1 0 0] .
O ne ass u m pti o n f or stratifie d C o x pr o p orti o nal hazar d m o del is t hat, t he treat me nt hazar d 
rati o ( H R) is c o nsta nt acr oss t he strata. If str o n g de part ures fr o m t he ass u m pti o n of t he H R 
bei n g t he sa me f or all t he strata o bser ve d ( w hic h ca n res ult i n a n ota bl y biase d a n d/ or less 
p o werf ul a nal ysis), a se nsiti vit y anal ys is m a y  be perf or me d base d o n a t w o-ste p wei g hte d 
C o x m o del a p pr oac h b y  Me hr otra 2 0 1 2 [ 1 0 1 ], i n w hi c h t he treat me nt effect is first esti mate d 
f or eac h strat u m a n d t he n t he strat u m s pecific esti mates are c o m bi ne d f or o verall i nfere nce 
usi n g sa m ple size wei g hts.
F urt her details of se nsiti vit y  a nalys es will be descri be d i n a s u p ple me ntal S A P.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 1 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ot her se nsiti vit y anal ys es descri be d f or t he P F S e n d p oi nt will be a p plie d t o O S e n d p oi nt as 
a p pr o priate. F urt her details of se nsiti vit y  a nalys es will be descri be d i n s u p ple me ntal S A P.
8. 6. 1. 3
O ver all Res p o nse R ate a n d Dise ase C o ntr ol R ate
T he stratifie d Mietti ne n a n d N u r mi ne n’s met h o d wit h strata wei g hti n g b y  sa m ple size will be 
use d f or c o m paris o n of t he o verall res p o nse rate ( O R R) a n d disease c o ntr ol rate ( D C R) 
bet wee n t he treat me nt gr o u ps . A 9 5 % c o nfi de nce i nter val f or t he differe nce i n res p o nse rates 
bet wee n t he p e m br oliz u ma b a n d T P C ar m will be pr o vi de 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 , as stratificati o n fact ors use d f or a nal ys is.
8. 6. 1. 4
D ur ati o n of Res p o nse
If sa m ple size per mits, res p o nse d urati o n will be s u m marize d descri pti vel y  usi n g K a pla n-
Meier me dia ns a n d q uartiles.  Onl y  the s u bset of s u bjects w h o s h o w a c o m plete res p o nse or 
p artial res p o nse will be i ncl u de d i n t his a nal ys is.  See Ta ble 1 0 f or ce ns ori n g r ules f or 
d urati o n of res p o nse.
Ta ble 1 0
Ce ns ori n g R ules f or D urati o n of Res p o nse
Sit u ati o n
D ate of Pr o gressi o n or Ce ns ori n g
O utc o m e
N o pr o gressi o n n or deat h, n o ne w 
a nti -ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt
Ce ns or
( n o n-e ve nt)
N o 
pr o gressi o n n or deat h, ne w 
a nti -ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt 
bef ore 
ne w  anti -ca ncer t hera p y 
i nitiate d
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n i m me diatel y 
after 
≥ 
2 
c o nsec uti ve 
misse d 
disease assess me nts or after ne w 
a nti -ca ncer t hera p y, if a n y
Earlier date of last a de q uate disease 
assess me nt pri or t o ≥ 2 misse d 
a de q uate disease assess me nts a n d 
ne w a nti -ca ncer t hera p y, if a n y
Ce ns or
( n o n-e ve nt)
Deat h 
or pr o gressi o n after ≤ 1 
misse d 
disease assess me nts a n d 
bef ore ne w a nti -ca ncer t hera p y, if 
a n y
P D or deat h
E n d of res p o nse
( E ve nt)
A misse d disease assess me nt i ncl u des a n y assess me nt t hat is n ot o btai ne d or is c o nsi dere d i na de q uate f or 
e val uati o n of res p o nse.  
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8. 6. 1. 5
S u m m ar y of St atistic al Met h o ds f or E ffic ac y
Ta ble 1 1 s u m marizes t he pri mar y  anal ys is a p pr oac h f or pri mar y a n d sec o n dar y efficac y 
e n d p oi nts. Se nsiti vit y a nal ysis met h o ds are descri be d a b o ve f or eac h e n d p oi nt.
T he strate g y to a d dress m ulti plicit y  iss ues wit h re gar d t o m ulti ple efficac y en d p oi nts,
m ulti ple p o p ulati o n s, a n d i nteri m a nal yses is descri be d i n Secti on 8. 7 a n d i n Secti o n 8. 8.
Ta ble 1 1
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
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 E n d p oi nts / H y p ot hesis
Pri m ar y H y p ot hesis # 1
O S i n s u bjects wit h C P S ≥1 0
Test: 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 ( M ore details are i n
Ta ble 9 )
Pri m ar y H y p ot hesis # 2
O S i n s u bjects wit h C P S ≥1
Test: 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 ( M ore details are i n 
Ta ble 9 )
Pri m ar y H y p ot hesis # 3
O S i n all s u bjects
Test: 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
Sec o n d ar y E n d p oi nts / H y p ot hesis
Sec o n dar y H y p ot hesis # 4
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Test: 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

Pri mar y ce ns ori n g r ule 

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
( M ore details are i n T a ble 9 )
Sec o n dar y H y p ot hesis # 5
O R R base d o n  R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h 
missi n g 
data 
are 
c o nsi dere d 
n o n-
res p o n ders
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 2 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
A n al ysis 
P o p ul ati o n
Missi n g D at a A p pr o ac h
Sec o n dar y Efficac y O bjecti ves
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 a n d 
s u bjects wit h C P S ≥1
Test: 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

Pri mar y ce ns ori n g r ule 

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
( M ore details are i n T a ble 9 )
O R R base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 a n d
s u bjects wit h C P S ≥1
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
D C R b ase d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 , 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
D O R b ase d o n  R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0, 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
S u m mar y statistics usi n g 
Ka pla n -Meier met h o d
All 
res p o n ders 
i n I T T 
See Ta ble 1 0
  † 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 stratificati o n fact ors use d f or ra n d o mizati o n will 
be as stratificati o n fact ors f or a nal ysis.
  ‡  Mietti ne n a n d N ur mi ne n met h o d.
Met h o ds relate d t o e x pl orat or y objecti ves (a n d s u p p orti ve a nal ys es i ncl u di n g P F S 2) will be 
descri be d i n t he s u p ple me ntal S A P .
St atistic al Met h o ds f or S afet y A n al yses
8. 6. 2
Safet y  an 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 perie nces ( A Es), la b orat or y tests, vital si g ns, etc. Of n ote, safet y a nal ys es will be 
c o n d ucte d i n all s u bjects.
Tiere d A p pr o ac h 
T he a nal ys is of safety res ults will f oll o w a tiere d a p pr oac h (Ta ble 1 2 ).  The tiers differ wit h 
res pect t o t he a nal ys es t hat will be perf or me d.  Safet y para meters or a d verse e x perie nces of 
s pecial i nterest t hat are i de ntifie d a pri ori c o nstit ute “ Tier 1” safety e n d p oi nts t hat will be 
s u bject t o i nfere ntial testi n g f or statistical si g nifica nce wit h p- val ues a n d 9 5 % c o nfi de nce 
i nter vals pr o vi de d f or bet wee n -gr o u p c o m paris o ns.  
Ot her safety par a meters will 
be 
c o nsi dere d Tier 2 or Tier 3.  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 vals pr o vi de d f or bet wee n -gr o u p c o m paris o ns; 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.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A d verse e x perie nces (s pecific ter ms as well as s yste m or ga n class ter ms) a n d pre defi ne d 
li mits of c ha n ge i n la b orat or y, vital si g ns, t hat are n ot pre -s pecifie d as Tier - 1 e n d p oi nts will 
be classifie d as bel o n gi n g t o " Tier 2" or " Tier 3", base d o n t he n u m ber o f e ve nts o bser ve d.  
Me m bers hi p i n Tier 2 re q uires t hat at least 4 s u bjects i n a n y treat me nt gr o u p e x hi bit t he 
e ve nt; all ot her a d verse e x perie nces a n d pre defi ne d li mits of c ha n ge will bel o n g t o Tier 3.
T he t hres h ol d of at least 4 e ve nts was c h ose n beca use t he 9 5 % c o nfi de nce i nter val f or t he 
bet wee n -gr o u p differe nce i n perce nt i nci de nce will al wa ys i ncl u de zer o w he n treat me nt 
gr o u ps of e q ual size eac h ha ve less t ha n 4 e ve nts a n d t h us w o ul d a d d little t o t he 
i nter pretati o n of p ote ntiall y mea ni n gf ul differe nces.  Beca use ma n y 9 5 % c o nfi de nce i nter vals 
ma y  be pr o vi de d wit h o ut a dj ust me nt f or m ulti plicit y , t he c o nfi de nce i nter vals s h o ul d be 
re gar de d as a hel pf ul descri pti ve meas ure t o be use d i n re vie w, n ot a f or mal met h o d f or 
assessi n g t he statistical si g nifica nce of t he bet wee n -gr o u p differe nces i n a d verse e x perie nces 
a n d pre defi ne d li mits of c ha n ge.
C o nti n u o us meas ures s uc h as c ha n ges fr o m baseli ne i n la b orat or y a n d/ or, vital si g ns, t hat are 
n ot pre -s pecifie d as Tier - 1 e n d p oi nts will be c o nsi dere d Tier 3 safet y p ara meters.  Su m mar y 
statistics f or baseli ne, o n- treat me nt, a n d c ha n ge fr o m baseli ne val ues will be pr o vi de d b y 
treat me nt gr o u p i n ta ble f or mat.    
F or t his pr ot oc ol t here are n o Tier 1 e ve nts. Base d o n t he mec ha nis m 
of acti o n of 
pe m br oliz u ma b a n d safet y data o bser ve d i n hist oric pe m br oliz u ma b trials t o date, t here are 
n o e ve nts of i nterest t hat warra nt classificati o n as Tier I e ve nts. T he br oa d cli nical a n d 
la b orat or y AE cate g ories c o nsisti n g of t he perce nta ge of s u bjects wit h a n y AE, a n y dr u g 
relate d A E, a n y Gra de 3 -5 A E, a n y  seri o us A E, a n y AE w hic h is b ot h dr u g -relate d a n d Gra de 
3- 5, a n y AE w hic h is b ot h seri o us a n d dr u g -relate d, d ose m o dificati o n d ue t o A E , a n d w h o 
disc o nti n ue d d ue t o a n A E, a n d deat h will be c o nsi dere d Tier 2 e n d p oi nts.  P-val ues ( Tier 1 
o nl y ) a n d 9 5 % c o nfi de nce i nter vals ( Tier 1 a n d Tier 2) will be pr o vi de d f or bet wee n -
treat me nt differe nces i n t he perce nta ge of s u bjects wit h e ve nts; t hese a nal yses will be 
perf or me d usi n g t he Mietti ne n a n d N ur mi ne n met h o d ( 1 9 8 5), a n u nc o n diti o nal, as ym pt otic 
met h o d.
T o pr o perl y acc o u nt f or t he p ote ntial differe nce i n f oll o w-u p ti me bet wee n t he st u d y ar ms, 
w hic h is e x pecte d t o be l o n ger i n t he pe m br oliz u ma b ar m, A E i nci de nce de nsit y  adj uste d f or 
treat me nt e x p os ure a nal yses ma y  be perf or me d as a p pr o priate.  Base d o n e mer gi n g e xter nal 
data, t he s u p p orti ve a nal ysis strate g y for safety para meters m a y  be m o difie d t o i m pr o ve t he 
i nte grity a n d efficie nc y of t he desi g n. S h o ul d t his ha p pe n, t he c ha n ge will be d oc u me nte d i n 
s u p ple me ntal S A P, if n ot i n a pr ot oc ol a m e n d me nt, at t he earliest ti me bef ore a n y u n bli n di n g 
of t he data.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 1 2
A nal y sis Strate g y f or Safet y Para meters
S afet y 
Tier
S afet y E n d p oi nt †
p-
V al ue
9 5 % CI f or 
Tre at m e nt 
C o m p aris o n
Descri pti ve 
St atistics
Tier 2
A n y A E
X
X
A n y Seri o us A E 
X
X
A n y Gra de 3 -5 A E
X
X
A n y Dr u g -Relate d A E
X
X
A n y Seri o us a n d Dr u g -Relate d A E
X
X
A n y Gra de 3 -5 a n d Dr u g -Relate d A E
X
X 
D ose M o dificati o n d ue t o A E
X
X
Disc o nti n uati o n d ue t o A E
X
X
Deat h
X
X
S pecific A E s, S yste m Or ga n Class, or Pr e-Defi ne d 
Li mit of C ha n ge ‡ (i nci de nce ≥4 of s u bjects i n 
o ne of t he treat me nt gr o u ps)
X
X
Tier 3
S pecific A Es, S yste m Or ga n Class or Pr e-Defi ne d 
Li mit of C ha n ge ‡
‡ (i nci de nce < 4 of s u bjects i n 
all of t he treat me nt gr o u ps)
X
C ha n ge fr o m Baseli ne Res ults ( La bs, E C Gs, Vital 
Si g ns)
X
†
A d verse E x perie nce refere nces refer t o b ot h Cli nical a n d La b orat or y A Es.
‡
I ncl u des o nl y t h ose e n d p oi nts n ot pre-s pecifie d as Tier 1 or n ot alrea d y pre-s pecifie d as Tier-2 e n d p oi nts.
N ote: X = res ults will be pr o vi de d.
Ti me t o Gr a de 3 -5 A E
I n a d diti o n t o tiere d a p pr oac h, e x pl orat or y an al y sis will be perf or me d o n ti me t o first 
Gra de 3- 5 A E. Ti me t o first Gra de 3- 5 A E is defi ne d as t he ti me fr o m t he first da y  of st u d y 
me dicati o n
t o t he first e ve nt of Gra de 3- 5 A E. T he Ka pla n -Meier met h o d will be use d t o 
esti mate t he c ur ve of ti me t o first Gra de 3- 5 A E.  The treat me nt differe nce i n ti me t o first 
Gra de 3- 5 A E will be assesse d b y  the stratifie d l o g-ra n k test.  A stratifie d C o x pr o p or ti o nal 
hazar d m o del wit h Efr o n ’s met h o d of tie ha n dli n g will be use d t o assess t he ma g nit u de of t he 
treat me nt differe nce (i e, t he hazar d rati o).  The hazar d rati o a n d its 9 5 % c o nfi de nce i nter val 
fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be re p orte d. See details 
i n s S A P.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 2 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristics
8. 6. 3
T he c o m para bilit y  of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d b y 
t he use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n t hese 
c haracteristics.  The n u m ber a n d perce nta ge of s u bjects scree ne d , ra n d o mize d, t he pri mar y 
reas o ns f or scree ni n g fail ure, a n d t he pri mar y  reas o n f or disc o nti n uati o n will be dis pla y e d.  
De m o gra p hic varia bles (e g, a ge), baseli ne c ha racteristics, pri mar y  an d sec o n dar y dia g n oses, 
a n d pri or a n d c o nc o mita nt t hera pies will be s u m marize d b y  treat me nt eit her b y  descri pti ve 
statistics or cate g orical ta bles.
I nteri m A n al yses
8. 7
T here is o ne pla n ne d i nteri m efficac y a nal ys is i n t his trial. Res ults will be re vie we d b y  an 
e xter nal data m o nit ori n g c o m mittee (e D M C). Of n ote, t he b o u n daries f or i nteri m a n d fi nal 
a nal ys es are prese nte d i n S ecti o n 8. 8.
I nteri m A n al ysis
T he p ur p ose of t he i nteri m a nal ysis (IA)
is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d t o T P C i n O S . T he I A is tri g gere d b y  the s pecifie d d urati o n of f oll o w-u p after 
e nr oll me nt is c o m plete d rat her t ha n t he n u m ber of O S e ve nts.   It will be perf or me d
ap pr o xi matel y  1 4
m o nt hs 
after e nr oll me nt is c o m plete d . It is esti mate d at t his ti me 
a p pr o xi matel y 1 3 0 O S e ve nts will be accr ue d i n s u bjects wit h C P S ≥1 0 , a p pr o xi matel y
2 8 4 O S e ve nts i n s u bjects wit h C P S ≥1 , a n d a p pr o xi matel y 4 4 5 O S e ve nts i n all s u bjects.
If t he pe m br oliz u ma b ar m de m o nstrates a s u peri or O S t o T P C i n all s u bjects i n t his i nteri m 
a nal ys is, t he sec o n dar y h yp ot heses f or P F S a n d O R R i n all s u bjects will be teste d at t he sa me 
ti me.  It is esti mate d t hat a p pr o xi matel y 57 5 P F S e ve nts will ha ve acc u m ulate d i n all s u bjects
b y  t hat ti me.
Fi n al A n al ysis
T he p ur p ose o f t he fi nal a nal ys is ( F A) is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d t o T P C i n O S.  The fi nal a nal ysis is tri g gere d b y  d urati o n of f oll o w-u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1 : ap pr o xi matel y  24 m o nt hs after e nr oll me nt is c o m plete d or 
3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1 , w hic he ver occ urs later. It is esti mate d at t his 
ti me a p pr o xi matel y 15 4
O S 
e ve nts will 
be accr ue d i n s u bjects wit h 
C P S ≥1 0 a n d 
a p pr o xi matel y 5 2 0 O S e ve nts i n all s u bjects. If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue 
sl o wer t ha n e x pecte d a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt is 
c o m p lete d, t he n t he S p o ns or will c o n d uct t he fi nal a nalys is at t hat ti me.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 2 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
M ulti plicit y
8. 8
T he m ulti plicit y  strate g y specifie d i n t his secti o n will be a p plie d t o t he 3 pri mar y h y p ot heses 
(su peri orit y of pe m br oliz u ma b o n O S i n s u bjects wit h C P S ≥1 0 , wit h C P S ≥1, a n d i n all 
s u bjects) a n d t he 2 sec o n dar y h yp ot heses (s u peri orit y  of pe m br oliz u ma b o n P F S a n d O R R i n 
all s u bjects ).
F or O S
e n d p oi nts , a H wa n g -S hi h -De Ca ni 
al p ha-s pe n di n g f u ncti o n wit h 
t he ga m ma 
para meter (- 4 ) will be use d t o c o nstr uct gr o u p se q ue ntial b o u n daries t o c o ntr ol t he T y p e I 
err or. S pe n di n g ti me will be pl u g ge d i nt o t he pre -s pecifie d al p ha s pe n di n g f u ncti o n t o 
calc ulate al p ha -s pe n di n g. At t he ti me of I A, f or all 3 O S e n d p oi nts t he s pe n di n g ti me will be 
t he mi ni m u m of t he act ual o bser ve d i nf or mati o n fracti o ns a m o n g t hese 3 O S e n d p oi nts , i.e.,
n u m ber of o bser ve d e ve nts at I A/n u m ber of pla n ne d e ve nts at F A. At t he ti me of F A, t he 
s pe n di n g ti me will be 1 f or all 3 O S e n d p oi nts. Of n ote, w hile t he s pe n di n g ti me use d f or 
al p ha-s pe n di n g calc ulati o n will be t he sa me f or t hese 3 O S e n d p oi nts at F A, t he c orrelati o ns 
use d f or c o m p uti n g b o u n ds f or eac h e n d p oi nt will still be fr o m t hat e n d p oi nt de pe n di n g o n 
t he act ual e ve nt c o u nts. T he rati o nale f or t he a b o ve strate g y is t o e ns ure b ot h t hat f ull T y pe I 
err or is s pe nt at t he fi nal a nal ysis wit h o ut o vers pe n di n g at t he i nteri m. J ustificati o n f or t he 
s pe n di n g ti me a p pr oac h ca n be f o u n d i n A n d ers o n et.al. [ 1 0 5 ].
Ta ble 1 3 s u m mariz es t he ti mi n g, pla n ne d n u m ber of e ve nts, sa m ple size a n d decisi o n 
g ui da nce of t he i nteri m efficac y an al y sis a n d fi nal a nal ys is. T hese b o u n daries are calc ulate d
base d o n t he al p ha -s pe n di n g f u ncti o n a n d t he pla n ne d n u m ber of e ve nts . 
T he act ual 
b o u n daries will be deter mi ne d fr o m t he act ual o bser ve d n u m ber of e ve nts, t he pla n ne d 
n u m be r of e ve nts at F A,
t he ti mi n g of t he a nal yses, t he pre -s pecifie d al p ha-s pe n di n g 
f u ncti o n, a n d t he r ules t o deter mi ne s pe n di n g ti me a n d c orrelati o ns as n ote d a b o ve . If t he 
b o u n dar y  is cr osse d at a n i nteri m a nal ysis or at t he fi nal a nal ys is, t he st u d y will be declare d 
t o ha ve met its pri mar y e n d p oi nt. 
Of n ote, t hese calc u lati o ns are base d o n t he ass u m pti o ns t hat t he pre vale nce of P D -L 1  
p o siti vit y i n m T N B C is a p pr o xi matel y 6 5%
f or C P S ≥1 a n d a p pr o xi matel y 3 1 % f or C P S ≥1 0
a n d are s u bject t o m o dificati o n if e mer gi n g data s u g gest t he pre vale nce is differe nt fr o m 
t hese ass u m pti o ns . T hese m o dificati o ns , if ma de, will be d oc u me nte d i n t he s S A P pri or t o 
a n y efficac y a nalys is u n bli n di n g.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 1 3
S u m mar y  of Ti mi n g, Sa m ple Size, a n d Decisi o n G ui da nce of I nteri m Efficac y 
A nal y ses a n d Fi nal A nal y sis u n der I nitial Al p ha All ocati o n
A n al ysis
Criteri a f or C o n d uct of A n al ysis
E n d p o i nt
P ar a meter
V al ue
I nteri m A nal ysis: 
I nteri m O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p: 
A p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is 
c o m plete d .
Pr ojecte d O S e ve nts i n s u bjects wit h C P S
≥1 0 : a p pr o xi matel y 1 3 0
O S i n s u bjects wit h 
C P S ≥1 0
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 8 9
~ H R at b o u n dar y
0. 6 6
Pr ojecte d O S eve nts i n s u bjects wit h C P S ≥1 : 
a p pr o xi matel y 2 8 4
O S i n s u bjects wit h 
C P S ≥1
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 4 3
~ H R at b o u n dar y
0. 7 3
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 4 4 5
O S i n all s u bjects
p val ue ( 1 -si de d) at 
b o u n dar y
n/a
~ H R at b o u n dar y
n/a
Fi nal A nal ysis: 
Fi nal O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1 : 
A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is 
c o m plete d or 3 3 4 O S e ve nts accr ue i n s u bjects
wit h C P S ≥1 , w hic he ver occ urs later. If O S 
e ve nts i n s u bjects wit h C P S ≥1 accr ue sl o wer 
t ha n e x pecte d a n d fe wer t ha n 3 3 4 e ve nts are 
o bser ve d 2 6 m o nt hs after e nr oll me nt is 
c o m p lete d, t he n t he S p o ns or will c o n d uc t t he 
fi nal a nal ysis at t hat ti me.
Pr ojecte d O S e ve nts i n s u bjects wit h 
C P S ≥1 0 : a p pr o xi matel y 1 5 4
O S i n s u bjects wit h 
C P S ≥1 0
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 1 4 6
~ H R at b o u n dar y
0. 7 0
Pr ojecte d O S e ve nts i n s u bjects wit h C P S ≥1 : 
a p pr o xi matel y 3 3 4
O S i n s u bjects wit h 
C P S ≥1
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 6 6
~ H R at b o u n dar y
0. 7 6
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 5 2 0
O S i n all s u bjects
p val ue ( 1 -si de d) at 
b o u n dar y
n/a
~ H R at b o u n dar y
n/a
T he trial uses a n e xte nsi o n [ 1 0 5] of t he gra p hical met h o d of Ma urer a n d Bretz [ 9 6] t o pr o vi de 
str o n g m ulti plicit y c o ntr ol f or t he m ulti ple pri mar y a n d sec o n dar y h y p ot heses.
Fi g ure 4
s h o ws t he i nitial o ne- si de d α- all ocati o n f or eac h h y p ot hesis i n t he elli pse
re prese nti n g t he h y p ot hesis. T he wei g hts f or reall ocati o n fr o m eac h h y p ot hesis t o t he ot hers 
are re prese nte d i n t he b o xes o n t he li nes c o n necti n g h y p ot heses.  If H 1 (O S i n s u bjects wit h 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 2 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
C P S ≥1 0 ) is s uccessf ul, t he n t he c orres p o n di n g al p ha ca n be reall ocate d t o H 2 ( O S i n 
s u bjects wit h C P S ≥1 ). If H 2 is s uccessf ul, t he al p ha f or t hat h yp ot hesis ca n be reall ocate d t o 
H 3 ( O S i n all s u bjects). If H3 is s uccessf ul, t he al p ha f or t hat h yp ot hesis ca n be reall ocate d ½ 
t o H 4 ( P F S i n all s u bjects) a n d ½ t o H 5 ( O R R i n all s u bjects). T he al p ha f or H 4 a n d H 5 ca n 
als o be reall ocate d t o eac h ot he r, if t he h y p ot hesis was s uccessf ul. Of n ote, H 3 ca n o nl y be 
f or mall y teste d o nce t he n ull h y p ot hesis f or H 2 has bee n rejecte d; H 4 a n d H 5
ca n o nl y  be 
f or mall y teste d o nce t he n ull h y p ot hesis f or H 3
has bee n rejecte d. See Fi g ure 4 f or t he 
m ulti plicit y  strate g y dia gra m of t he st u dy.
H 4 ( P F S i n all s u bjects) will be teste d at I A if H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A 
a d diti o nal al p ha ca n be reall ocate d t o H 4 (e. g., H 3 is n ot s uccessf ul at I A but s uccessf ul at 
F A , or H 1 is n ot s uccessf ul at I A but s uccessf ul at F A a n d H 2/ H 3 are s uccessf ul at b ot h I A 
a n d F A ), t he n t he p-val ue of P F S i n all s u bjects fr o m t he I A will be c o m pare d t o t he u p date d 
al p ha t hres h ol d at t he ti me of F A. Si milarl y , H5 ( O R R i n all s u bjects) will be teste d at I A if 
H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A a d diti o nal al p ha ca n be reall ocate d t o H 5, t he n 
t he p- val ue of O R R i n all s u bjects fr o m t he I A will be c o m pare d t o t he u p date d al p ha 
t hres h ol d at t he ti me of F A.
Fi g ure 4
M ulti plicit y  Strate g y
S a m ple Size a n d P o wer C alc ul ati o ns
8. 9
T he st u d y will ra n d o mize s u bjects i n a 1: 1 rati o bet wee n t he pe m br oliz u ma b ar m a n d t he 
T P C ar m. T he o verall sa m ple size will be u p t o ~ 6 0 0 .
Ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve res p o nse s yste m / i nte grate d we b 
res p o nse s yste m (I V R S/I W R S) a n d will be m o nit ore d o n a re g ular basis. W he n I V R S al erts 
t hat t he st u d y is a p pr oac hi n g t he desire d e nr oll me nt, scree ni n g s h o ul d be st o p pe d i n ti me. 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 2 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
H o we ver, s u bjects alrea d y in scree ni n g p hase ma y  be e nr olle d e ve n after we ha ve reac he d 
t he ma xi m u m sa m ple size. T he sa m ple size is dri ve n b y  the O S e ve nts i n s u bjects wit h 
C P S ≥1 0 , s u bjects wit h C P S ≥1 , a n d all s u bjects.
O ver all s ur vi v al a n al ysis i n s u bjects wit h C P S ≥1 0 : F or t he pri mar y  en d p oi nt O S i n 
su bjects wit h C P S ≥1 0 , wit h 1 5 4 O S e ve nts at a o ne -si de d 1. 7 % al p ha-le vel t he trial has 
a p pr o xi matel y 8 5 % p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C , if t he 
u n derl y i n g hazar d rati o of O S is 0. 6 0. S uccess b o u n dar y  f or O S at t he fi nal a nal ysis 
a p pr o xi matel y corres p o n ds t o a n o bser ve d hazar d rati o of ~ 0. 7 0 ( ~ 4. 2 m o nt h i m pr o ve me nt 
o ver O S of 1 0 m o nt hs i n T P C ).
O ver all s ur vi v al a n al ysis i n s u bjects wit h C P S ≥1 : F or t he pri mar y  e n d p oi nt O S i n s u bjects 
wit h C P S ≥1 , wit h 3 3 4 O S e ve nts at a o ne- si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has 
a p pr o xi matel y 80 % ( 9 0 %) p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C , if 
t he u n derlyi n g hazar d rati o of O S is 0. 7 0. Wit h
a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel, s uccess 
b o u n dar y  f or O S at t he fi nal a nal ysis a p pr o xi matel y corres p o n ds t o a n o bser ve d hazar d rati o 
of ~ 0. 7 6 ( 0. 8 0) ( ~ 3. 1 [ 2. 5] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C ).
O ver all s ur vi v al a n al ysis i n all s u bjects: F or t he pri mar y  en d p oi nt O S i n all s u bjects, wit h 
5 2 0 O S e ve nts a n d a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has a p pr o xi matel y 6 6 % 
( 8 0 %) p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C if t he u n derl y i n g hazar d 
rati o of O S is 0. 7 8.
Wit h a o ne-si de d 0. 8 % ( 2. 5 %) al p ha-le vel, s uccess b o u n dar y  f or O S at 
t he fi nal a nal ys is c orres p o n ds a p pr o xi matel y t o a n o bser ve d hazar d rati o of ~ 0. 8 0 ( 0. 8 4)
( ~ 2.4 [ 1. 9] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C )
T he sa m ple size a n d p o wer calc ulati o n f or O S e n d p oi nts is base d o n t he f oll o wi n g 
ass u m pti o ns f or all 3 p o p ulati o ns : 1) O S f oll o ws a n e x p o ne ntial distri b uti o n wit h a me dia n of 
1 0 m o nt hs i n t he c o ntr ol ar m; 2) A n e nr oll me nt peri o d of 1 6. 6 m o nt hs a n d a mi ni m u m of 2 4
m o nt hs f oll o w-u p after e nr oll me nt c o m pleti o n; 3) A ye arl y O S dr o p o ut rate of 1 %.   T he 
ass u m pti o n f or O S of 1 0 m o nt hs i n t he T P C ar m is base d o n esti mates of O S fr o m t he trials 
s u m marize d i n Ta ble 1 .
P F S a n al ysis i n all s u bjects: T h is P F S
p o wer is calc ulate d base d o n t he f oll o wi n g 
ass u m pti o ns wit h a p pr o xi matel y 5 7 5 P F S e ve nts:  1) t he h y p ot hesis of O S i n all s u bject is 
s u p p orte d a n d a t otal of 0. 4 % al p ha is all ocate d t o P F S h y p ot hesis ( H 4); 2) P F S f oll o ws a n 
e x p o ne ntial distri b uti o n wit h a me dia n of 3 m o nt hs i n t he T P C ar m; 3) A n e nr oll me nt peri o d 
of 1 6. 6 m o nt hs ; 4 ) A ye arl y P F S dr o p -o ut rate of 8 %.  T he trial has ~ 9 9 % p o wer t o 
d e m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C o n P F S at a o ne-si de d 0. 4 % al p ha-le vel, 
if t he u n derl yi n g hazar d rati o of P F S is 0. 6 . If t he u n derl yi n g hazar d rati o of P F S is 0. 7, t he n 
t he trial has ~ 9 5 % p o wer.
T he ass u m pti o n f or P F S of 3 m o nt hs i n t he T P C ar m is base d o n esti mate s of P F S fr o m t he 
trials s u m marize d i n Ta ble 1 .
O R R a n al ysis i n all s u bjects: T he O R R p o wer calc ulati o n is base d o n t he f oll o wi n g 
ass u m pti o ns: 1) t he h y p ot hesis of O S i n s u bjects wit h C P S ≥1 is s u p p orte d a n d a t otal of 
0. 4 % al p ha is all ocate d t o O R R h y p ot hesi s (H 5) ; 2) t he u n derl y i n g O R R is 1 0 % i n t he T P C
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 2 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
ar m, a n d t here is 1 0 % i ncrease i n pe m br oliz u ma b ar m ( O R R of 2 0 % ) i n all s u bjects. T he trial
has a p pr o xi matel y 8 1 % p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C o n 
O R R i n all s u bjects at a o ne -si de d 0. 4 % al p ha -le vel.
T he a b o ve statistical ass u m pti o n s are base d o n o ur c urre nt u n dersta n di n g of t he pre vale nce of 
t he P D -L 1  bi o mar ker i n T N B C (a p pr o xi matel y 65 % f or C P S ≥1 0 a n d 3 1 % f or C P S ≥1) , a n d 
it is s u bject t o m o dificati o n as nee de d base d o n e mer gi n g e xter nal data o n P D -L 1  pre vale nce 
i n T N B C , or t he c orrelati o n bet wee n P D -L 1  ex pressi o n a n d treat me nt effect. 
A n y 
m o dificati o n if occ urs will be descri be d i n t he s u p ple me ntal S A P.
T he sa m ple size a n d p o wer calc ulati o n s were perf or me d i n t he s oft ware R ( pac ka ge 
“ gs Desi g n”).
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
8. 1 0
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 nt 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 s u bjects wit h C P S ≥1 0 a n d C P S ≥1 a n d i n all s u bjects: 

A ge Cate g or y ( <6 5 vs. ≥6 5 y ears)

Me n o pa usal stat us
(f or fe males o nl y; pre- vs . p ost - me n o pa usal)

Se x ( Fe male vs . Male)

Ge o gra p hic re gi o n (E ur o pe/I srael/ N ort h A merica/ A ustralia vs . Asia vs . Rest of 
W orl d) 

Et h nic ori gi n ( His pa nic vs . N o n-His pa nic)

N u m ber of pri or li nes of treat me nts i n t he metastatic setti n g (ie o ne vs . t w o) 

Ti me t o pr o gressi o n o n first-li ne ( 1 L) t hera p y ( < 6 m o nt hs vs. ≥6 m o nt hs )

T P C

P D -L 1  stat us b y  CP S c ut off ( C P S ≥1 vs C P S
< 1; C P S
≥1 0 vs C P S
< 1 0) . N ote 
s u b gr o u p a nalys is b y P D-L 1  stat us will o nly be c o n d ucte d i n all s u bjects.

Pri or ( ne o)a dj u va nt t hera p y  vs. de n o v o metastatic disease at i nitial dia g n osis .
C o m pli a nce ( Me dic ati o n A d here nce)
8. 1 1
Dr u g acc o u nta bilit y data f or trial treat me nt 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. 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E xte nt of E x p os ure
8. 1 2
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n c ycles .
9. 0 L A B E LI N G, 
P A C K A GI N G,
S T O R A G E 
A N D 
R E T U R N 
O F 
C LI NI C A L 
S U P P LI E S
I n vesti g ati o n al Pr o d uct
9. 1
T he i n vesti gat or s hall ta ke res p o nsi bilit y for a n d s hall ta ke all ste ps to mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p ply, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of 
i n vesti gati o nal pr o d uct i n acc or da nce wit h t he pr ot oc ol a n d a n y ap plica ble la ws a n d 
re g ulati o ns.
C li nical S u p plies will be pr o vi de d by t he S p o ns or as s u m marize d i n Ta ble 1 4 .
Ta ble 1 4
Pr o d uct Descri pti o n s
Pr o d uct N a m e & P ote nc y
D os a ge F or m
C o m me nts
Ca pecita bi ne 1 5 0 m g & 5 0 0 m g
Ta blets
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
Eri b uli n 0. 8 8 m g/ 2 m L
S ol uti o n f or I nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
G e m cita bi ne 1 0 0 0 m g
L y o p hilize d p o w der 
f or I V i nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y 
Pe m br oliz u ma b ( M K -3 4 7 5) 1 0 0 m g / 4 m L
S ol uti o n f or I nf usi o n
Pr o vi de d ce ntrall y b y t he S p o ns or
Vi n orel bi ne 5 0 m g/ 5 m L
S ol uti o n f or I nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
P ac k a gi n g a n d L a beli n g I nf or m ati o n
9. 2
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 ory 
re q uire me nts.
Cli nic al S u p plies Discl os ure
9. 3
T his trial is o pe n -la bel; t heref ore, t he s u bject, t he trial site pers o n nel, t he S p o ns or a n d/ or 
desi g nee are n ot bli n de d. Treat me nt ( na me, stre n gt h or p ote nc y ) is i ncl u de d i n t he la bel te xt; 
ra n d o m c o de/discl os ure e n vel o pes or lists are n ot pr o vi de d.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St or a ge a n d H a n dli n g Re q uire me nts
9. 4
Cli nical s u p plies m ust be st ore d i n a sec ure, li mite d-access l ocati o n u n der t he st ora ge 
c o n diti o ns s pecifie d o n t he la bel.  
Recei pt a n d dis pe nsi n g of trial me dicati o n m ust be rec or de d b y  an a ut h orize d pers o n at t he 
trial site.
Cli nical s u p plies ma y  n ot be use d f or a ny p ur p ose ot her t ha n t hat state d i n t he pr ot oc ol.
Disc ar d/ Destr ucti o n/ Ret ur ns a n d Rec o ncili ati o n
9. 5
T he i n vesti gat or is res p o nsi ble f or kee pi n g acc urate rec or ds of t he cli nical s u p plies recei ve d 
fr o m t he S p o ns or or desi g nee, t he a m o u nt dis pe nse d t o a n d ret ur ne d b y  the s u bjects a n d t he 
a m o u nt re mai ni n g at t he c o ncl usi o n of t he trial. F or all trial sites, t he l ocal c o u ntr y Sp 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 an d ret ur n, or l ocal discar d a n d destr ucti o n if a p pr o priate.   Where 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 .
St a n d ar d P olicies
9. 6
Trial site pers o n nel will 
ha ve access t o a ce ntral electr o nic ra n d o mizati o n s yste m 
(I V R S/IW R S s yste m) t o all ocate s u bjects, t o assi g n treat me nt t o s u bjects 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 V R S s yste m m ust be assi g ne d a n 
i n di vi d ual u ni q ue PIN.  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 .
1 0. 0 A D MI NI S T R A TI V E A N D R E G U L A T O R Y D E T AI L S
C o nfi de nti alit y
1 0. 1
C o nfi de nti alit y of D at a
1 0. 1. 1
B y  si gni 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  the 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 nstit uti o nal re vie w b oar d, et hics re vie w c o m mittee (I R B/ E R 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  un 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  this trial will be c o nsi dere d c o nfi de ntial b y  the 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.
C o nfi de nti alit y o f S u bject Rec or ds
1 0. 1. 2
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 RB/ E R C, or re g ulat or y  aut h orit y  re prese ntati ves ma y  co ns ult a n d/ or c o p y  trial d oc u me nts i n 
or der t o verif y  wor ks heet/case re p ort f or m data.  B y  si gni n g t he c o nse nt f or m, t he s u bject 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
a grees t o t his pr ocess.  If trial d oc u me nts will be p h ot oc o pie d d uri n g t he pr ocess of verif y i n g 
w or ks heet/case re p ort f or m i nf or mati o n, t he s u bject will be i de ntifie d b y  uni q ue c o de o nl y ; 
f ull na mes/i nitials will be mas ke d pri or t o tra ns missi o n t o t he S p o ns or.
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 s u bject data use d a n d discl ose d i n 
c o n necti o n wit h 
t his trial 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.
C o nfi de nti alit y of I n vesti g at or I nf or m ati o n
1 0. 1. 3
B y  si gni n g t his pr ot oc ol, t he i n vesti gat or rec o g nizes t hat certai n pers o nal i de ntif yi n g 
i nf or mati o n wit h res pect t o t he i n vesti gat or, a n d all s u bi n vesti gat ors a n d trial site pers o n nel, 
ma y  be use d a n d discl ose d f or trial ma na g e me nt p ur p oses, as part of a re g ulat or y 
s u b missi o ns, a n d as re q uire d by la w.  T his i nf or mati o n ma y i ncl u de:
1.
na me, a d dress, tele p h o ne n u m ber a n d e -mail a d dress;
2.
h os pital or cli nic a d dress a n d tele p h o ne n u m ber;
3.
c urric ul u m vitae or ot her s u m mar y of q ualificati o ns a n d cre de ntials; a n d
4.
ot her pr ofessi o nal d oc u me ntati o n.
C o nsiste nt wit h t he p ur p oses descri be d a b o ve, t his i nf or mati o n ma y  be tra ns mitte d t o t he 
S p o ns or, a n d s u bsi diaries, affiliates a n d a ge nts of t he S p o ns or, i n y o ur c o u ntr y an d ot her 
c o untries, i ncl u di n g c o u ntries t hat d o n ot ha ve la ws pr otecti n g s uc h i nf or mati o n.  
A d diti o nall y , t he i n vesti gat or’s na me a n d b usi ness c o ntact i nf or mati o n ma y  be i ncl u de d 
w he n 
re p orti n g certai n seri o us a d verse e ve nts t o re g ulat or y aut h orities or t o ot her 
i n vesti gat ors.  By si g ni n g t his pr ot oc ol, t he i n vesti gat or e x pressl y co nse nts t o t hese uses a n d 
discl os ures.
If t his is a m ultice nter trial, i n or der t o facilitate c o ntact bet wee n i n vesti gat ors, t he S p o ns or 
ma y  share a n i n vesti gat or’s na me a n d c o ntact i nf or matio n wit h 
ot her partici pati n g 
i n vesti gat ors u p o n re q uest.
C o nfi de nti alit y of I R B/I E C I nf or m ati o n
1 0. 1. 4
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 RB/I E C me m ber t hat 
re vie ws a n d a p pr o ves t his trial.  T he S p o ns or is als o re q uire d t o d oc u me nt t ha t eac h I RB/I E C 
meets re g ulat or y an d I CH 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 RB/I E C me m bers a n d t o ma ke t hese rec or ds a vaila ble f or 
re g ulat or y a ge nc y re vie w u p o n re q uest by t h ose a ge ncies.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
C o m pli a nc e wit h Fi n a nci al Discl os ure Re q uire me nts
1 0. 2
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, b ase d o n t hese re g ulati o ns, w het her a re q uest f or 
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 gat or(s) a gree, if re q ueste d b y  the S p o n s 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, c o m m o nl y kn 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 or t hr o u g h a sec ure pass w or d -pr otecte d electr o nic p ortal pr o vi de d b y  the 
S p o ns or.  The 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.  This ma y  in 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.
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt
1 0. 3
B y  si gni 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 trial 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 o o d 
Cli nical 
Practice 
(e. g., I nter nati o nal C o nfere nce 
o n 
Har m o nizat i o n of 
Tec h nical 
Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Use G o o d Cli nical Practice: 
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 o o d cli nical practice); 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 trial.
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 Merc k, is pr o vi de d i n Secti o n 1 2. 1 -
Merc k C o de of
C o n d uct f or Cli nical Trials .
T he i n vesti gat or als o a grees t o all o w m o nit ori n g, a u dits, I RB/ E R C re vie w a n d re g ulat or y 
a ut h orit y ins pecti o n of trial-relate d d oc u me nts a n d pr oce d ures a n d pr o vi de f or direct access 
t o all trial-relate d s o urce data a n d d oc u me nts.
T he i n vesti gat or a grees n ot t o see k rei m b urse me nt fr o m s u bjects, 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 trial rei m b urse d t o t he 
i n vesti gat or by t he S p o ns or.
T he i n vesti gat or s hall pre pare a n d mai ntai n c o m plete a n d acc urate trial d oc u me ntati o n i n 
c o m plia nce wit h G o o d Cli nical Practice sta n dar ds a n d a p plica ble fe deral, state a n d l ocal 
la ws, r ules a n d re g ulati o ns; a n d, f or eac h s u bject partici pati n g i n t he trial, pr o vi de all data, 
a n d, u p o n c o m pleti o n or ter mi nati o n of t he cli nical trial, s u b mit a n y ot her re p orts t o t he 
S p o ns or as re q uire d b y t his pr ot oc ol or as ot her wise re q uire d p urs ua nt t o a n y  a gree me nt wit h 
t he S p o ns or.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 3 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial d oc u me ntati o n will be pr o m ptl y  an d f ully discl ose d t o t he S p o ns or b y  the 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 trial 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 aut 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 by t he S p o ns or as a res ult of a n a u dit t o c ure deficie ncies i n t he trial d oc u me ntati o n 
a n d w or ks heets/case re p ort f or ms.
T he i n vesti gat or m ust mai ntai n c o pies of all d oc u me ntati o n a n d rec or ds relati n g t o t he 
c o n d uct of t he trial i n c o m plia nce wit h all a p plica ble le gal a n d re g ulat or y  re q uire me nts.  T his 
d oc u me ntati o n i ncl u des, b ut is n ot li mite d t o, t he pr ot oc ol, w or ks heets/case re p ort f or ms, 
a d vertisi n g 
f or s u bject partici pati o n, 
a d verse 
e ve nt 
re p orts, s u bject s o urce data, 
c orres p o n de nce wit h re g ulat or y aut h orities a n d I RBs/ E R Cs, c o nse nt f or ms, i n vesti gat or’s 
c urric ula vitae, m o nit or visit l o gs, la b orat or y refere nce ra n ges, la b orat or y certificati o n or 
q ualit y  c o ntr ol pr oce d ures a n d la b orat or y direct or c urric ul u m vitae.  B y  si g ni n g t his pr ot oc ol, 
t he i n vesti gat or a grees t hat d oc u me ntati o n s hall be retai ne d u ntil at least 2 ye ars after t he last 
a p pr o val of a mar keti n g a p plicati o n i n a n I CH re gi o n or u ntil t here are n o pe n di n g or 
c o nte m plate d mar keti n g a p plicati o ns i n a n IC H re gi o n or u ntil at least 2 ye ars ha ve ela pse d 
si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct.  
Beca use t he cli nical de vel o p me nt a n d mar keti n g 
a p plicati o n pr ocess is varia ble, it is 
a ntici pate d t hat t he rete nti o n peri o d ca n be u p t o 1 5 years or l o n ger after pr ot oc ol data base 
l oc k. T he S p o ns or will deter mi ne t he mi ni m u m rete nti o n peri o d a n d n otif y  the i n vesti gat or 
w he n d oc u me nts m a y  be destr o ye d.  T he S p o ns or will deter mi ne t he mi ni m u m rete nti o n 
peri o d a n d u p o n re q u est, will pr o vi de g ui da nce t o t he i n vesti gat or w he n d oc u me nts n o l o n ger 
nee d t o be retai ne d.  T he s p o ns or als o rec o g nizes t hat d oc u me nts ma y nee d t o be retai ne d f or 
a l o n ger peri o d if re q uire d b y  local re g ulat or y re q uire me nts. All trial d oc u me nts s hall be 
ma de a vaila ble if re q uire d b y  rele va nt re g ulat or y aut h orities. T he i n vesti gat or m ust c o ns ult 
wit h a n d o btai n writte n a p pr o val b y t he S p o ns or pri or t o destr o yi n g trial a n d/ or s u bject files.  
I C H G o o d Cli nical Practice g ui deli nes rec o m me n d t hat t he i n vesti gat or i nf or m t he s u bject’s 
pri mar y  ph y sicia n a b o ut t he s u bject’s partici pati o n i n t he trial if t he s u bject has a pri mar y  
p h y sicia n a n d if t he s u bject a grees t o t he pri mar y p h ysicia n bei n g i nf or me d.
T he i n vesti gat or will pr o m ptl y  inf or m t he S p o ns or of a n y reg ulat or y  aut h orit y  ins pecti o n 
c o n d ucte d f or t his trial.
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 trials b y  an y  co 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 trials.  The 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 trial 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.
I n t he e ve nt t he S p o ns or pre mat urel y ter mi nates a partic ular trial site, t he S p o ns or will 
pr o m ptl y  n otif y t hat trial site’s IR B/I E C.
Acc or di n g t o E ur o pea n le gislati o n, a S p o ns or m ust 
desi g nate a n o verall c o or di nati n g 
i n vesti gat or f or a m ulti -ce nter trial (i ncl u di n g m ulti nati o nal).  Whe n m ore t ha n o ne trial site 
is o pe n i n a n E U c o u ntr y, Merc k, as t he S p o ns or, will desi g nate, per c o u ntr y, a nati o nal 
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
pri nci pal c o or di nat or ( Pr ot oc ol CI ), res p o nsi ble f or c o or di nati n g t he w or k of t he pri nci pal 
i n vesti gat ors at t he differe nt trial sites i n t hat Me m ber 
State, a cc or di n g t o nati o nal 
re g ulati o ns.  For a si n gle-ce nter trial, t he Pr ot oc ol CI  is t he pri nci pal i n vesti gat or.  In 
a d diti o n, t he S p o ns or m ust desi g nate a pri nci pal or c o or di nati n g i n vesti gat or t o re vie w t he 
trial re p ort t hat s u m marizes t he trial res ults a n d c o nfir m t hat, t o t he best of his/ her 
k n o wle d ge, t he re p ort acc urately descri bes t he c o n d uct a n d res ults of t he trial [ Cli nical St u d y  
Re p ort ( C S R) CI ].  The S p o ns or ma y  co nsi der o ne or m ore fact ors i n t he selecti o n of t he 
i n di vi d ual t o ser ve as t he Pr ot oc ol CI  an d or C S R CI  (e. g., a vaila bilit y of t he CI  duri n g t he 
a ntici pate d re vie w pr ocess, t h or o u g h u n dersta n di n g of cli nical trial met h o ds, a p pr o priate 
e nr oll me nt of s u bject c o h ort, ti mel y ac hie ve me nt of trial milest o nes).  The Pr ot oc ol CI  must 
be a partici pa ti n g trial i n vesti gat or.
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P osti n g Re q uire me nts
1 0. 4
U n der t he ter ms of t he F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act ( F D A M A) a n d t he 
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 A A A), t he S p o ns or of t he trial
is s olel y 
res p o nsi ble f or deter mi ni n g w het her t he trial 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 t he Cli nical Trials Data Ba n k, htt p:// w w w.cli nicaltrials. g o v.  Merc k, as 
S p o ns or of t his trial, will re vie w t his pr ot oc ol a n d s u b mit t he i nf or mati o n necessar y  to f ulfill 
t hese re q uire me nts.  
Merc k e ntries are n ot li mite d t o F D A M A/ F D A A A ma n date d trials. 
I nf or mati o n p oste d will all o w s u bjects t o i de ntif y pote ntiall y a p pr o priate trials 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 trial l ocati o ns a n d trial site c o ntact i nf or mati o n.    
B y  si gni 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 obli gati o ns u n der 
F D A M A/ F D A A A 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 
trial or its res ults t o t he Cli nical Trials Data Ba n k.
Q u alit y M a n a ge me nt S yste m
1 0. 5
B y  si gni n g t his pr ot oc ol, t he S p o ns or a grees t o be res p o nsi ble f or i m ple me nti n g a n d 
mai ntai ni n g 
a q ualit y  
ma na ge me n t s yste m wit h 
writte n 
de vel o p me nt pr oce d ures a n d 
f u ncti o nal area sta n dar d o perati n g pr oce d ures ( S O Ps) t o e ns ure t hat trials are c o n d ucte d a n d 
data are ge nerate d, d oc u me nte d, a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, acce pte d 
sta n dar ds of G o o d Cli nical Practice, 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 trial.
D at a M a n a ge me nt
1 0. 6
T he i n vesti gat or or q ualifie d desi g nee is res p o nsi ble f or rec or di n g a n d verif yi n g t he acc urac y 
of s u bject data .  By 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 his/ her 
electr o nic si g nat ure is t he le gally bi n di n g e q ui vale nt of a writte n si g nat ure.  By e nteri n g 
his/ her electr o nic si g nat ure, t he i n vesti gat or c o nfir ms t hat all rec or de d data ha ve bee n 
ver ifie d as acc urate.
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 parately.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 3 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
P u blic ati o ns
1 0. 7
T his trial is i nte n de d f or p u blicati o n, e ve n if ter mi nate d pre mat urel y. P u blicati o n ma y i ncl u de 
a n y or all of t he f oll owi n g: p osti n g of a s yn o psis o nli ne, a bstract a n d/ or prese ntati o n at a 
scie ntific c o nfere nce, or p u blicati o n of a f ull ma n uscri pt.  The S p o ns or will w or k wit h t he 
a ut h ors t o s u b mit a ma n uscri pt descri bi n g trial res ults wit hi n 1 2 m o nt hs after t he last data 
b ec o me a vaila ble, w hic h ma y  ta ke u p t o se veral m o nt hs after t he last s u bject visit i n s o me 
cases s uc h as vacci ne trials.  Ho we ver, ma n uscri pt s u b missi o n ti meli nes ma y be e xte n de d o n 
O T C trials.  F or trials i nte n de d f or pe diatric -relate d re g ulat or y fili n gs, t he i n vesti gat or a grees 
t o dela y  pu blicati o n of t he trial res ults u ntil t he S p o ns or n otifies t he i n vesti gat or t hat all 
rele va nt re g ulat or y aut h orit y  decisi o ns o n t he trial dr u g ha ve bee n ma de wit h re gar d t o 
pe diatric -relate d re g ulat or y fili n gs. Merc k will p ost a s yn o psis of trial res ults f or a p pr o ve d 
pr o d ucts o n w w w.cli nicaltrials. g o v b y  12 m o nt hs after t he last s u bject's last visit f or t he 
pri mar y  outc o me, 1 2 m o nt hs after t he decisi o n t o disc o nti n ue de vel o p me nt, or pr o d uct 
mar keti n g ( dis pe nse d, a d mi nistere d, deli vere d or pr o m ote d), w hic he ver is later.
T hese ti meli nes ma y  be e xte n de d f or pr o d ucts t hat are n ot ye t mar kete d, if a d diti o nal ti me is 
nee de d f or a nal ys is, t o pr otect i ntellect ual pr o pert y , or t o c o m pl y wit h c o nfi de ntialit y 
a gree me nts wit h ot her part ies.  Aut h ors of t he pri mar y  res ults ma n uscri pt will be pr o vi de d 
t he c o m plete res ults fr o m t he Cli nical St u d y R ep ort, s u bject t o t he c o nfi de ntialit y  a gree me nt. 
W he n 
a ma n uscri pt is s u b mitte d t o a bi o me dical j o ur nal, t he S p o ns or's p olic y  is t o als o 
i ncl u de t he pr ot oc ol a n d statistical a nal ysis pla n t o facilitate t he peer a n d e dit orial re vie w of 
t he ma n uscri pt.  If t he ma n uscri pt is s u bse q ue ntl y acce pte d f or p u blicati o n, t he S p o ns or will 
all o w t he j o ur nal, if it s o desires, t o p ost o n its we bsite t he ke y  sect i o ns of t he pr ot oc ol t hat 
are rele va nt t o e val uati n g t he trial, s pecificall y th ose secti o ns descri bi n g t he trial o bjecti ves 
a n d h y p ot heses, t he s u bject i ncl usi o n a n d e xcl usi o n criteria, t he trial desi g n a n d pr oce d ures, 
t he efficac y a n d safety m eas ures, t he statistical a nal ysis pla n, a n d a n y a me n d me nts relati n g t o 
t h ose secti o ns.  T he S p o ns or reser ves t he ri g ht t o re dact pr o prietar y i nf or mati o n.
F or m ultice nter trials, s u bse q ue nt t o t he m ultice nter p u blicati o n ( or after p u blic discl os ure of 
t he res ults o nli n e at w w w.cli nicaltrials. g o v if a m ultice nter ma n uscri pt is n ot pla n ne d), a n 
i n vesti gat or a n d his/ her c ollea g ues m a y  pu blis h t heir data i n de pe n de ntly.  In m ost cases, 
p u blicati o n of i n di vi d ual trial site data d oes n ot a d d val ue t o c o m plete m ultice nter res ul ts, 
d ue t o statistical c o ncer ns.  I n rare cases, p u blicati o n of si n gle trial site data pri or t o t he mai n 
pa per m a y  be of val ue.  Li mitati o ns of si n gle trial site o bser vati o ns i n a m ultice nter trial 
s h o ul d al wa ys be descri be d i n s uc h a ma n uscri pt.
A ut h ors hi p cre dit s h o ul d be base d o n 1) s u bsta ntial c o ntri b uti o ns t o c o nce pti o n a n d desi g n, 
or ac q uisiti o n of data, or a nal ys is a n d i nter pretati o n of data; 2) drafti n g t he article or re visi n g 
it criticall y for i m p orta nt i ntellect ual c o nte nt; a n d 3) fi nal a p pr o val o f t he versi o n t o be 
p u blis he d. A ut h ors m ust meet c o n diti o ns 1, 2 a n d 3.  Si g nifica nt c o ntri b uti o ns t o trial 
e xec uti o n ma y  als o be ta ke n i nt o acc o u nt t o deter mi ne a ut h ors hi p, pr o vi de d t hat 
c o ntri b uti o ns ha ve als o bee n ma de t o all t hree of t he prece di n g a ut h ors hi p criteria.  Alt h o u g h 
p u blicati o n pla n ni n g ma y  b e gi n bef ore c o n d ucti n g t he trial, fi nal decisi o ns o n a ut h ors hi p a n d 
t he or der of a ut h ors’ na mes will be ma de base d o n partici pati o n a n d act ual c o ntri b uti o ns t o 
t he trial a n d writi n g, as disc usse d a b o ve. T he first a ut h or is res p o nsi ble f or defe n di n g t he 
i nte grity of t he data, met h o d(s) of data a nal ys is a n d t he scie ntific c o nte nt of t he ma n uscri pt.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 3 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T he S p o ns or m ust ha ve t he o p p ort u nit y  to re vie w all pr o p ose d a bstracts, ma n uscri pts or 
prese ntati o ns re gar di n g t his trial 4 5 da y s pri or t o s u b missi o n f or p u blicati o n/ prese ntati o n. 
A n y  inf or mati o n i de ntifie d b y  the S p o ns or as c o nfi de ntial m ust 
be delete d pri or t o 
s u b missi o n; t his c o nfi de ntialit y does n ot i ncl u de efficac y an d safet y res ults. S p o ns or re vie w 
ca n be e x pe dite d t o meet p u blicati o n ti meli nes.
1 1. 0 LI S T O F R E F E R E N C E S
1.
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): p. 4 5 3 1- 8.
2.
Mei, Z., et al., T u m o ur -i nfiltrati n g i nfla m mati o n a n d pr o g n osis i n c ol orectal ca ncer: 
s yste matic re vie w a n d meta-a nal ys is. Br J Ca ncer, 2 0 1 4. 1 1 0( 6): p. 1 5 9 5-6 0 5.
3.
Sal ga d o, R., et al., Har m o nizati o n of t he e val uati o n of t u m or i nfiltrati n g l ym p h oc y tes 
( TI Ls) i n breast ca ncer: rec o m me n dati o ns b y  an i nter nati o nal TI Ls -w or ki n g gr o u p 
2 0 1 4. A n n O nc ol, 2 0 1 4.
4.
Sc hatt o n, T., et al., T u m or -i nfiltrati n g l ym p h oc y tes a n d t heir si g nifica nce i n 
mela n o ma pr o g n osis. Met h o ds M ol Bi ol, 2 0 1 4. 1 1 0 2: p. 2 8 7 - 3 2 4.
5.
G o o de n, M.J., et al., T he pr o g n ostic i nfl ue nce of t u m o ur-i nfiltrati n g l ym p h oc y tes i n 
ca ncer: a s ys te matic re vie w wit h meta-a nal ys is. Br J Ca ncer, 2 0 1 1. 1 0 5( 1): p. 9 3- 1 0 3.
6.
Sc hrei ber, R. D., L.J. Ol d, a n d M.J. 
S m y t h, Ca ncer i m m u n oe diti n g: i nte grati n g 
i m m u nit y's r oles i n ca ncer s u p pressi o n a n d pr o m oti o n. Scie nce, 2 0 1 1. 3 3 1( 6 0 2 4): p. 
1 5 6 5- 7 0.
7.
Bre m nes, R. M., et al., T he r ole of t u m or-i nfiltratin g i m m u ne cells a n d c hr o nic 
i nfla m mati o n at t he t u m or site o n ca ncer de vel o p me nt, pr o gressi o n, a n d pr o g n osis: 
e m p hasis o n n o n -s mall cell l u n g ca ncer. J T h orac O nc ol, 2 0 1 1. 6( 4): p. 8 2 4- 3 3.
8.
Tal ma d ge, 
J. E., I mm u ne 
cell i nfiltrati o n of pri mar y  an d metastatic 
lesi o ns: 
mec ha nis ms a n d cli nical i m pact. Se mi n Ca ncer Bi ol, 2 0 1 1. 2 1( 2): p. 1 3 1 - 8.
9.
S hira be, K., et al., T u m or -i nfiltrati n g l ym p h oc y tes a n d he pat ocell ular carci n o ma: 
pat h ol o g y  a n d cli nical ma na ge me nt. I nt J Cli n O nc ol, 2 0 1 0. 1 5( 6): p. 5 5 2-8.
1 0. N os h o, K., et al., T u m o ur -i nfiltrati n g T- cell s u bsets, m olec ular c ha n ges i n c ol orectal 
ca ncer, a n d pr o g n osis: c o h ort st u d y an d literat ure re vie w. J Pat h ol, 2 0 1 0. 2 2 2( 4): p. 
3 5 0 - 6 6.
1 1. Bellati, F., et al., I mm u n ol o g y  of g y nec ol o gic ne o plas ms: a nal ysis of t he pr o g n ostic 
si g nifica nce of t he i m m u ne stat us. C urr Ca ncer Dr u g Tar gets, 2 0 0 9. 9( 4): p. 5 4 1- 6 5.
1 2. O ble, D. A., et al., F oc us o n TI Ls: pr o g n ostic si g nifica nce of t u m or i nfiltrati n g 
l ym p h oc y tes i n h u ma n mela n o ma. Ca ncer I m m u n, 2 0 0 9. 9: p. 3.
1 3. U p pal uri, R., G. P. D u n n, a n d J.S. Le wis, Jr., F oc us o n TI Ls: pr o g n ostic si g nifica nce 
of t u m or i nfiltrati n g l ym p h oc y tes i n hea d a n d nec k ca ncers. Ca ncer I m m u n, 2 0 0 8. 8: 
p. 1 6.
1 4. D u n n, G. P., I.F. D u n n, a n d W. T. C urr y , F oc us o n TI Ls: Pr o g n ostic si g nifica nce of 
t u m or i nfiltrati n g l ym p h oc y tes i n h u ma n gli o ma. Ca ncer I m m u n, 2 0 0 7. 7: p. 1 2.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 3 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
1 5. C ha n g, W.J., 
et al., I nfla m mati o n-relate d fact ors pre dicti n g pr o g n osis of gastric 
ca ncer. W orl d J Gastr oe nter ol, 2 0 1 4. 2 0( 1 6): p. 4 5 8 6- 9 6.
1 6. Prest o n, C. C., et al., T he rati os of C D 8 + T cells t o C D 4 + C D 2 5 + F O X P 3 + a n d
F O X P 3 - T cells c orrelate wit h p o or cli nical o utc o me i n h u ma n ser o us o varia n ca ncer. 
P L o S O ne, 2 0 1 3. 8( 1 1): p. e 8 0 0 6 3.
1 7. Y o o n, H. H., et al., Pr o g n ostic i m pact of F o x P 3 + re g ulat or y T cells i n relati o n t o 
C D 8 + T l ym p h oc y te de nsit y  in h u ma n c ol o n carci n o mas. P L o S O ne, 2 0 1 2. 7( 8): p. 
e 4 2 2 7 4.
1 8. Ki m, 
S. T., et al., T u m or -i nfiltrati n g l ym p h oc y tes, t u m or c haracteristics, a n d 
rec urre nce i n s u bjects wit h earl y breast ca ncer. A m J Cli n O nc ol, 2 0 1 3. 3 6( 3): p. 2 2 4-
3 1.
1 9. Mat hai, A. M., et al., R ole of F o x p 3 -p ositi ve t u m or-i nfiltrati n g l ym p h oc y tes i n t he 
hist ol o gic feat ures a n d cli nical o utc o mes of he pat ocell ular carci n o ma. A m J S ur g 
Pat h ol, 2 0 1 2. 3 6( 7): p. 9 8 0- 6.
2 0. Li u, F., et al., C D 8( +) c yt ot o xic T cell a n d F O X P 3( +) re g ulat or y T cell i nfiltrati o n i n 
relati o n t o breast ca ncer s ur vi val a n d m olec ular s u bt ypes. Breast Ca ncer Res Treat, 
2 0 1 1. 1 3 0( 2): p. 6 4 5 - 5 5.
2 1. Kir k, R., Ris k fact ors. C D 8 +: F O X P 3 + cell rati o is a n o vel s ur vi val mar ker f or 
c ol orectal ca ncer. Nat Re v Cli n O nc ol, 2 0 1 0. 7( 6): p. 2 9 9.
2 2. Pe d oee m, A., et al., Pr o gra m me d deat h -1 pat h wa y  in ca ncer a n d a ut oi m m u nit y. Cli n 
I m m u n ol, 2 0 1 4. 1 5 3( 1): p. 1 4 5- 5 2.
2 3. Z ha n g, X., 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): p. 3 3 7- 4 7.
2 4. Lazar -M ol nar, E., et al., Cr y stal str uct ure of t he c o m ple x bet wee n pr o gra m me d deat h -
1 ( P D -1) a n d its li ga n d P D -L 2. Pr oc Natl Aca d Sci U S A, 2 0 0 8. 1 0 5( 3 0): p. 1 0 4 8 3 - 8.
2 5. Li n, D. Y., et al., T he P D -1/ P D -L 1  co m ple x rese m bles t he a nti ge n-bi n di n g F v 
d o mai ns of a nti b o dies a n d T cell rece pt ors. Pr oc Natl Aca d Sci U S A, 2 0 0 8. 1 0 5( 8): 
p. 3 0 1 1- 6.
2 6. C he n g, X., et al., Str uct ure a n d i nteracti o ns of t he h u ma n pr o gra m me d cell deat h 1 
rece pt or. J Bi ol C he m, 2 0 1 3. 2 8 8( 1 7): p. 1 1 7 7 1-8 5.
2 7. S he p par d, K. A., 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 y lati 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( 1 -3): p. 3 7 - 4 1.
2 8. Ott, P. A., F. S. H o di, a n d C. R o bert, C T L A -4 a n d P D -1/ P D -L 1  bl oc ka de: ne w 
i m m u n ot hera pe utic m o dalities wit h d ura ble cli nical be nefit i n mela n o ma s u bjects. 
Cli n Ca ncer Res, 2 0 1 3. 1 9( 1 9): p. 5 3 0 0 - 9.
2 9. Ya o, S. a n d L. C he n, P D -1 as a n i m m u ne m o d ulat or y  rece pt or. Ca ncer J, 2 0 1 4. 2 0( 4): 
p. 2 6 2- 4.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 3 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
3 0. Nis hi m ura, H., et al., De vel o p me ntall y re g ulate d e x pressi o n of t he P D - 1 pr otei n o n 
t he s urface of d o u ble -ne g ati ve ( C D 4 -C D 8 -) t h ym oc y tes. I nt I m m u n ol, 1 9 9 6. 8( 5): p. 
7 7 3- 8 0.
3 1. H ua n g, X., et al., P D - 1 e x pressi o n b y  macr o p ha ges pla y s a pat h ol o gic r ole i n alteri n g 
micr o bial cleara nce a n d t he i n nate i nfla m mat or y res p o nse t o se psis. Pr oc Natl Aca d 
Sci U S A, 2 0 0 9. 1 0 6( 1 5): p. 6 3 0 3 -8.
3 2. Pe na- Cr uz, V., et al., P D - 1 o n i m mat ure a n d P D - 1 li ga n ds o n mi grat or y  hu ma n 
La n ger ha ns cells re g ulate a nti ge n-prese nti n g cell acti vit y. J I nvest Der mat ol, 2 0 1 0. 
1 3 0( 9): p. 2 2 2 2 - 3 0.
3 3. Keir, M. E., 
et al., P D - 1 a n d its li ga n ds i n t olera nce a n d i mm u nit y . A n n u Re v 
I m m u n ol, 2 0 0 8. 2 6: p. 6 7 7- 7 0 4.
3 4. Kari m, R., et al., T u m or -e x presse d B 7 -H 1 a n d B 7 -D C i n relati o n t o P D -1 + T- cell 
i nfiltrati o n a n d s ur vi val of s u bjects wit h cer vical carci n o ma. Cli n Ca ncer Res, 2 0 0 9. 
1 5( 2 0): p. 6 3 4 1 - 7.
3 5. Ta u be, J. M., et al., C ol ocalizati o n of i nfla m mat or y  res p o nse wit h B 7-h 1 e x pressi o n i n 
h u ma n mela n oc y tic lesi o ns s u p p orts a n a da pti ve resista nce mec ha nis m of i m m u ne 
esca pe. Sci Tra nsl Me d, 2 0 1 2. 4( 1 2 7): p. 1 2 7ra 3 7.
3 6. Sa n ma me d, M. F. 
a n d L. C he n, I n d uci ble e x pressi o n of B 7 -H 1 ( P D-L 1) a n d its 
selecti ve r ole i n t u m or site i m m u ne m o d ulati o n. Ca ncer J, 2 0 1 4. 2 0( 4): p. 2 5 6- 6 1.
3 7. T o palia n, S. L ., C. G. Dra ke, a n d D. M. Par d oll, Tar geti n g t he P D -1/ B 7 -H 1( P D -L 1 ) 
pat h wa y  to acti vate a nti-t u m or i m m u nit y. C urr O pi n I mm u n ol, 2 0 1 2. 2 4( 2): p. 2 0 7-
1 2.
3 8. Hira n o, F., et al., Bl oc ka de of B 7 -H 1 a n d P D - 1 b y m o n ocl o nal a nti b o dies p ote ntiates 
ca ncer t hera pe utic i m m u nit y. Ca ncer Res, 2 0 0 5. 6 5( 3): p. 1 0 8 9- 9 6.
3 9. Bla n k, C., et al., P D -L 1/ B 7 H -1 i n hi bits t he effect or p hase of t u m or rejecti o n b y  T cell 
rece pt or ( T C R) tra ns genic C D 8 + T cells. Ca ncer Res, 2 0 0 4. 6 4( 3): p. 1 1 4 0 - 5.
4 0. We ber, 
J., I mm u ne c hec k p oi nt pr otei ns: a ne w t hera pe utic para di g m f or ca ncer --
precli nical bac k gr o u n d: C T L A -4 a n d P D - 1 bl oc ka de. Se mi n O nc ol, 2 0 1 0. 3 7( 5): p. 
4 3 0- 9.
4 1. Str o me, S. E., et al., B 7 -H 1 bl oc ka de a u g me nts a d o pti ve T- cell i m m u n ot hera py f or 
s q ua m o us cell carci n o ma. Ca ncer Res, 2 0 0 3. 6 3( 1 9): p. 6 5 0 1- 5.
4 2. C urra n, M. A., et al., P D -1 a n d C T L A- 4 c o m bi nati o n bl oc ka de e x pa n ds i nfiltrati n g T 
cells a n d re d uces re g ulat or y T an d m y el oi d cells wit hi n B 1 6 mela n o ma t u m ors. Pr oc 
Natl Aca d Sci U S A, 2 0 1 0. 1 0 7( 9): p. 4 2 7 5 - 8 0.
4 3. Pil o n -T h o mas, S., et al., Bl oc ka de of pr o gra m me d deat h li ga n d 1 e n ha nces t he 
t hera pe utic efficac y of c o m bi nati o n i m m u n ot hera p y a gai nst mela n o ma. J I mm u n ol, 
2 0 1 0. 1 8 4( 7): p. 3 4 4 2 - 9.
4 4. N o mi, T., et al., Cli nical si g nifica nce a n d t hera pe utic p ote ntial of t he pr o gra m me d 
deat h - 1 li ga n d/ pr o gra m me d deat h - 1 pat h wa y  in h u ma n pa ncreatic ca ncer. Cli n 
Ca ncer Res, 2 0 0 7. 1 3( 7): p. 2 1 5 1 - 7.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
4 5. Z ha n g, L., T. F. Gaje ws ki, a n d J. Kli ne, P D -1/ P D -L 1 i nteracti o ns i n hi bit a ntit u m or 
i m m u ne res p o nses i n a m uri ne ac ute m y el oi d le u ke mia m o del. Bl o o d, 2 0 0 9. 1 1 4( 8): 
p. 1 5 4 5- 5 2.
4 6. P o ole, R. M., Pe m br oliz u ma b: First Gl o bal A p pr o val. Dr u gs, 2 0 1 4.
4 7. Sie gel, R., et al., Ca ncer statistics, 2 0 1 4. C A Ca ncer J Cli n, 2 0 1 4. 6 4( 1): p. 9- 2 9.
4 8. De nt, R.,
et al., Tri ple -ne gati ve breast ca ncer: cli nical feat ures a n d patter ns of 
rec urre nce. Cli n Ca ncer Res, 2 0 0 7. 1 3( 1 5 Pt 1): p. 4 4 2 9- 3 4.
4 9. Ba uer, 
K. R., 
et al., Descri pti ve 
a nal ys is of estr o ge n rece pt or ( E R)-ne gati ve, 
pr o gester o ne rece pt or ( P R)-ne gati ve, a n d H E R 2- ne gati ve i n vasi ve breast ca ncer, t he 
s o-calle d tri ple-ne gati ve p he n ot y pe: a p o p ulati o n -base d st u d y fr o m t he Calif or nia 
ca ncer Re gistr y. Ca ncer, 2 0 0 7. 1 0 9( 9): p. 1 7 2 1- 8.
5 0. S orlie, T., et al., Ge ne e x pressi o n patter ns of breast carci n o mas disti n g uis h t u m or 
su bclasses wit h cli nical i m plicati o ns. Pr oc Natl Aca d Sci U S A, 2 0 0 1. 9 8( 1 9): p. 
1 0 8 6 9- 7 4.
5 1. Ra k ha, 
E. A. 
a n d I.O. 
Ellis, 
Tri ple -ne gati ve/ basal -li ke breast ca ncer: re vie w. 
Pat h ol o g y , 2 0 0 9. 4 1( 1): p. 4 0-7.
5 2. Per o u, C. M., M olec ular stratificati o n of tri ple-ne gati ve breast ca ncers. O nc ol o gist, 
2 0 1 1. 1 6 S u p pl 1: p. 6 1 -7 0.
5 3. Le h ma n n, B. D., et al., I de ntificati o n of h u ma n tri ple-ne gati ve breast ca ncer s u bt ypes 
a n d precli nical m o dels f or selecti o n of tar gete d t hera pies. J Cli n I nvest, 2 0 1 1. 1 2 1( 7): 
p. 2 7 5 0- 6 7.
5 4. Li n, N. U.,
et al., Sites of dista nt rec urre nce a n d cli nical o utc o mes i n s u bjects wit h 
metastatic tri ple-ne gati ve breast ca ncer: hi g h i nci de nce of ce ntral ner v o us s yste m 
metastases. Ca ncer, 2 0 0 8. 1 1 3( 1 0): p. 2 6 3 8- 4 5.
5 5. Ar ne d os, M., et al., Tri ple -ne gati ve breast ca ncer : are we ma ki n g hea d wa y  at least? 
T her A d v Me d O nc ol, 2 0 1 2. 4( 4): p. 1 9 5 - 2 1 0.
5 6. Kassa m, F., et al., S ur vi val o utc o mes f or s u bjects wit h metastatic tri ple-ne gati ve 
breast ca ncer: i m plicati o ns f or cli nical practice a n d trial desi g n. Cli n Breast Ca ncer, 
2 0 0 9. 9 ( 1): p. 2 9- 3 3.
5 7. Ma h m o u d, 
S. M., et al., T u m or -i nfiltrati n g C D 8 + l ym p h oc y tes pre dict cli nical 
o utc o me i n breast ca ncer. J Cli n O nc ol, 2 0 1 1. 2 9( 1 5): p. 1 9 4 9- 5 5.
5 8. De n kert, C., et al., T u m or -ass ociate d l ym p h oc y tes as a n i n de pe n de nt pre dict or of 
res p o nse t o ne oa dj u va nt c he m ot hera p y i n breast ca ncer. J Cli n O nc ol, 2 0 1 0. 2 8( 1): p. 
1 0 5- 1 3.
5 9. Fi na k, G., et al., Str o mal ge ne e x pressi o n pre dicts cli nical o utc o me i n breast ca ncer. 
Nat Me d, 2 0 0 8. 1 4( 5): p. 5 1 8- 2 7.
6 0. Sta g g, J. a n d B. Allar d, I mm u n ot hera pe utic a p pr oac hes i n tri ple-ne gati ve breast 
ca ncer: latest researc h a n d cli nical pr os pects. T her A d v Me d O nc ol, 2 0 1 3. 5( 3): p. 
1 6 9- 8 1.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
6 1. G he be h, 
H., 
et al., T he B 7 -H 1 
( P D-L 1) T l ym p h oc y te-i n hi bit or y 
molec ule is 
e x presse d i n breast ca ncer s u bjects wit h i nfiltrati n g d uctal carci n o ma: c orrelati o n wit h 
i m p orta nt hi g h-ris k pr o g n ostic fact ors. Ne o plasia, 2 0 0 6. 8( 3): p. 1 9 0- 8.
6 2. G he be h, H., et al., F O X P 3 + Tre gs a n d B 7 -H 1 +/ P D -1 + T l ym p h oc y tes c o-i nfiltrate 
t he t u m or tiss ues of hi g h -ris k breast ca ncer s u bjects: I mplicati o n f or i m m u n ot hera p y. 
B M C Ca ncer, 2 0 0 8. 8: p. 5 7.
6 3. M ue nst, S., et al., E x pressi o n of pr o gra m me d deat h li ga n d 1 ( P D-L 1) is ass ociate d 
wit h p o or pr o g n osis i n h u ma n breast ca ncer. Breast Ca ncer Res Treat, 2 0 1 4. 1 4 6( 1): 
p. 1 5- 2 4.
6 4. Sc hal per, K., et al., I n Sit u T u m or P D -L 1  mR N A E x pressi o n Is Ass ociate d wit h 
I ncrease d TI Ls a n d Better O utc o me i n Breast Carci n o mas Cli n Ca ncer Res, 2 0 1 4. 2 0: 
p. 2 7 7 3.
6 5. Mitte n d orf, E. A., et al., P D -L 1  ex pressi o n i n tri ple-ne gati ve breast ca ncer. Ca ncer 
I m m u n ol Res, 2 0 1 4. 2( 4): p. 3 6 1- 7 0.
6 6. Miles, D. W., et al., Bi o mar ker res ults fr o m t he A V A D O p hase 3 trial of first-li ne 
be vaciz u ma b pl us d oceta xel f or H E R 2 -ne gati ve metastatic breast ca ncer. Br J Ca ncer, 
2 0 1 3. 1 0 8( 5): p. 1 0 5 2 -6 0.
6 7. Lia o, Y., et al., Acce pta ble b ut li mite d efficac y of ca pecita bi ne-base d d o u blets i n t he
first-li ne treat me nt of metastatic 
tri ple-ne gati ve breast ca ncer: a pil ot st u d y. 
C he m ot hera p y, 2 0 1 3. 5 9( 3): p. 2 0 7 -1 3.
6 8. Sta u dac her, L., et al., Plati n u m -base d c he m ot hera p y i n metastatic tri ple-ne gati ve 
breast ca ncer: t he I nstit ut C urie e x perie nce. A n n O nc o l, 2 0 1 1. 2 2( 4): p. 8 4 8- 5 6.
6 9. U h m, J. E., et al., Treat me nt o utc o mes a n d cli nic o pat h ol o gic c haracteristics of tri ple-
ne gati ve breast ca ncer s u bjects w h o recei ve d plati n u m-c o ntai ni n g c he m ot hera p y. I nt J 
Ca ncer, 2 0 0 9. 1 2 4( 6): p. 1 4 5 7 - 6 2.
7 0. O' S ha u g h ness y , J., et al., I ni pari b pl us c he m ot hera p y i n metastatic tri ple-ne gati ve 
breast ca ncer. N E n gl J Me d, 2 0 1 1. 3 6 4( 3): p. 2 0 5 - 1 4.
7 1. Si n g h, J., et al., P hase 2 trial of e ver oli m us a n d car b o plati n c o m bi nati o n i n s u bjects 
wit h tri ple ne gati ve metastatic breast ca ncer. Breast Ca ncer Res, 2 0 1 4. 1 6( 2): p. R 3 2.
7 2. A n dre, F. a n d C. C. Zieli ns ki, O pti mal strate gies f or t he treat me nt of metastatic tri ple-
ne gati ve breast ca ncer wit h c urre ntl y ap pr o ve d a ge nts. A n n O nc ol, 2 0 1 2. 2 3 S u p pl 6: 
p. vi 4 6 - 5 1.
7 3. Br ufs k y,  A. M., et al., RI B B O N -2: a ra nd o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
p hase III trial e val uati n g t he efficac y an d safet y of be vaciz u ma b i n c o m bi nati o n wit h 
c he m ot hera p y f or sec o n d-li ne treat me nt of h u ma n e pi der mal gr o wt h fact or rece pt or 
2- ne gati ve metastatic breast ca ncer. J Cli n O n c ol, 2 0 1 1. 2 9( 3 2): p. 4 2 8 6 -9 3.
7 4. Br ufs k y, A., et al., Sec o n d -li ne be vaciz u ma b -c o ntai ni n g t hera py i n s u bjects wit h 
tri ple-ne gati ve breast ca ncer: s u b gr o u p a nal y sis of t he RI B B O N-2 trial. Breast Ca ncer 
Res Treat, 2 0 1 2. 1 3 3( 3): p. 1 0 6 7 - 7 5.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7 5. C ortes, J., et al., E ri b uli n m o n ot hera p y vers us treat me nt of p h y sicia n's c h oice i n 
s u bjects wit h metastatic breast ca ncer ( E M B R A C E): a p hase 3 o pe n-la bel ra n d o mise d 
st u d y. La ncet, 2 0 1 1. 3 7 7(9 76 9): p. 9 1 4 - 2 3.
7 6. Pi v ot, X. B., et al., Acti vit y  of i xa be pil o ne i n oestr o ge n rece pt or-n e gati ve a n d 
oestr o ge n rece pt or-pr o gester o ne rece pt or-h u ma n e pi der mal gr o wt h fact or rece pt or 2-
ne gati ve metastatic breast ca ncer. E ur J Ca ncer, 2 0 0 9. 4 5( 1 7): p. 2 9 4 0 -6.
7 7. Mc C ull o u g h, A. E., et al., Ce ntral pat h ol o g y  la b orat or y re vie w of H E R 2 a n d E R i n 
earl y bre ast ca ncer: a n A L T T O trial [ BI G 2- 0 6/ N C C T G N 0 6 3 D ( Allia nce)] ri n g 
st u d y. Breast Ca ncer Res Treat, 2 0 1 4. 1 4 3( 3): p. 4 8 5- 9 2.
7 8. G oss, P. E., et al., A dj u va nt la pati ni b f or w o me n wit h earl y- sta ge H E R 2 -p ositi ve 
breast ca ncer: a ra n d o mise d, c o ntr olle d, p hase 3 trial. La n cet O nc ol, 2 0 1 3. 1 4( 1): p. 
8 8- 9 6.
7 9. Perez, E. A., et al., H E R 2 testi n g b y  local, ce ntral, a n d refere nce la b orat ories i n 
s peci me ns fr o m t he N ort h Ce ntral Ca ncer Treat me nt Gr o u p N 9 8 3 1 i nter gr o u p 
a dj u va nt trial. J Cli n O nc ol, 2 0 0 6. 2 4( 1 9): p. 3 0 3 2- 8.
8 0. A da ms , S., et al., Pr o g n ostic Val ue of T u m or -I nfiltrati n g L y m p h oc y tes i n Tri ple -
Ne gati ve Breast Ca ncers Fr o m T w o P hase III Ra n d o mize d A dj u va nt Breast Ca ncer 
Trials: E C O G 2 1 9 7 a n d E C O G 1 1 9 9. J Cli n O nc ol, 2 0 1 4.
8 1. L oi, S., et al., T u m or i nfiltrati n g l ym p h oc y tes are pr o g n ostic i n tri ple ne gati ve breast 
ca ncer a n d pre dicti ve f or trast uz u ma b be nefit i n earl y breast ca ncer: res ults fr o m t he 
Fi n H E R trial. A n n O nc ol, 2 0 1 4. 2 5( 8): p. 1 5 4 4 -5 0.
8 2. Ci mi n o -Mat he ws, A., et al., Metastatic tri ple-ne gati ve breast ca ncers at first rela pse 
ha ve fe wer t u m or-i nfiltrati n g l ym p h oc y tes t ha n t heir matc he d pri mar y  breast t u m ors: 
a pil ot st u d y. H u m Pat h ol, 2 0 1 3. 4 4( 1 0): p. 2 0 5 5- 6 3.
8 3. Li u, S., et al., Pr o g n ostic si g nifica nce of F O X P 3 + t u m or i nfiltrati n g l ym p h oc y tes i n 
breast ca ncer de pe n ds o n estr o ge n rece pt or a n d h u ma n e pi der mal gr o wt h fact or 
rece pt or- 2 e x pressi o n stat us a n d c o nc urre nt c yt ot o xic T- cell i nfiltrati o n. Breast 
Ca ncer Res, 2 0 1 4. 1 6( 5): p. 4 3 2.
8 4. Sa vas, P., et al., O nc o ge ne a d dicti o n a n d i m m u nit y: cli nical i m plicati o ns of t u m o ur 
i nfiltrati n g l ym p h oc y tes i n breast ca ncers o vere x pressi n g t he H E R 2/ ne u o nc o ge ne. 
C urr O pi n O nc ol, 2 0 1 4. 2 6( 6): p. 5 6 2- 7.
8 5. Bri g gs, S. a n d I. T o mli ns o n, Ger mli ne a n d s o matic p ol y merase e psil o n a n d delta 
m utati o ns defi ne a ne w class of h y per m utate d c ol orectal a n d e n d ometrial ca ncers. J 
Pat h ol, 2 0 1 3. 2 3 0( 2): p. 1 4 8- 5 3.
8 6. De we y , F. E., et al., Cli nical i nter pretati o n a n d i m plicati o ns of w h ole -ge n o me 
se q ue nci n g. J A M A, 2 0 1 4. 3 1 1( 1 0): p. 1 0 3 5- 4 5.
8 7. V olla n, H. K., et al., A t u m or D N A c o m ple x a berrati o n i n de x is a n i n de pe n de nt 
pre d ict or of s ur vi val i n breast a n d o varia n ca ncer. M ol O nc ol, 2 0 1 4.
8 8. I g natia dis, M. a n d S.J. Da ws o n, Circ ulati n g T u m or Cells a n d Circ ulati n g t u m or D N A 
f or precisi o n me dici ne: Drea m or reality?  A n n O nc ol, 2 0 1 4.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8 9. Prat, A., et al., Pre dicti n g res p o nse a n d s ur vi val i n c he m ot hera p y-treate d tri ple-
ne gati ve breast ca ncer. Br J Ca ncer, 2 0 1 4. 1 1 1( 8): p. 1 5 3 2- 4 1.
9 0. Krie gs ma n n, M., et al., M utati o nal pr ofiles i n tri ple -ne gati ve breast ca ncer defi ne d b y 
ultra dee p m ulti ge ne se q ue nci n g s h o w hi g h rates of PI 3 K pat h wa y  alterati o ns a n d 
cli nicall y rele va nt e ntit y s u b gr o u p s pecific differe nces. O nc otar get, 2 0 1 4.
9 1. Ba nerji, S., et al., Se q ue nce a nal ysis of m utati o ns a n d tra nsl ocati o ns acr oss breast 
ca ncer s u bt y pes. Nat ure, 2 0 1 2. 4 8 6( 7 4 0 3): p. 4 0 5 - 9.
9 2. Ca ncer Ge n o me Atlas, N., C o m pre he nsi v e m olec ular 
p ortraits of h u ma n breast 
t u m o urs. Nat ure, 2 0 1 2. 4 9 0( 7 4 1 8): p. 6 1-7 0.
9 3. R ossille, D., et al., Hi g h le vel of s ol u ble pr o gra m me d cell deat h li ga n d 1 i n bl o o d 
i m pacts o verall s ur vi val i n a g gressi ve diff use lar ge B- Cell l ym p h o ma: res ults fr o m a 
Fre nc h m ultice nter cli nical trial. Le u ke mia, 2 0 1 4.
9 4. Pic o de C oa na, Y., et al., I pili m u ma b treat me nt res ults i n a n earl y decrease i n t he 
fre q ue nc y of circ ulati n g gra n ul oc y tic m y el oi d-deri ve d s u p press or cells as well as 
t heir Ar gi nase 1 pr o d ucti o n. Ca ncer I m m u n ol Res, 2 0 1 3. 1( 3): p. 1 5 8 - 6 2.
9 5. T wel ves, C., et al., Efficac y  of eri b uli n i n w o me n wit h metastatic breast ca ncer: a
p o ole d a nal ys is of t w o p hase 3 st u dies. Breast Ca ncer Res Treat, 2 0 1 4
9 6. Ma urer W, 
Bretz F. M ulti ple Testi n g i n Gr o u p Se q ue ntial Trials usi n g Gra p h ical       
A p pr oac hes. Statistics i n Bi o p har mace utical Researc h 2 0 1 3; 5( 4): 3 1 1 - 3 2 0.
9 7. 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 nicati o ns i n Statistics -T he or y 
a n d Met h o ds, 1 9 9 1; 2 0 ( 8): 2 6 0 9 - 2 6 3 1.
9 8. Fi n kelstei n D M ( 1 9 8 6). A pr o p orti o nal hazar ds m o del f or i nter val-ce ns ore d fail ure 
ti me data. Bi o metrics 4 2, 8 4 5-5 4.
9 9. U n o, H., 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 y sis. J Cli n O nc ol. 2 0 1 4; 3 2 ( 2 2): 2 3 8 0- 2 3 8 5.
1 0 0. O dell 
P. M., 
A n ders o n 
K. M., 
Ka n nel 
B. W. 
Ne w 
m o dels 
f or pre dicti n g 
car di o vasc ular e ve nts. J o ur nal of Cli nical E pi de mi ol o g y  1 9 9 4; 4 7( 6): 5 8 3-5 9 2.
1 0 1. Me hr otra D., S u S. C., Li X.  An efficie nt alter nati ve t o t he stratifie d C o x m o del 
a nal ys is. Statist. Me d. 2 0 1 2, 3 1 1 8 4 9– 1 8 5 6.
1 0 2. Nis hi n o M, 
Gar ga n o M, 
S u da M, 
Ra mai ya  NH, H o di F S. O pti mizi n g i m m u ne-
relate d t u m or res p o nse assess me nt: d oes re d uci n g t he n u m ber of lesi o ns i m pact 
res p o nse assess me nt i n mela n o ma patie nts treate d wit h i pili m u ma b? J o ur nal f or 
I m m u n ot hera py of Ca ncer. 2 0 1 4; 2: 1 7. d oi: 1 0. 1 1 8 6/ 2 0 5 1 - 1 4 2 6- 2- 1 7.
1 0 3. Gar o n, E. B., et al. A ntit u m or acti vit y of pe m br oliz u ma b a n d c orrelati o n wit h 
pr o gra m me d deat h li ga n d 1 ( P D-L 1) e x pressi o n i n a p o ole d a nal ys is of pre vi o usl y  
treate d a d va nce d N S C L C. 
C orrelati o n 
bet wee n t u m or P D -L 1 e x pressi o n a n d 
i m pr o ve d pe m br o a ntit u m or acti vit y has bee n o bser ve d. A n nals of O nc ol o g y  (2 0 1 4) 
2 5 ( 5): 1 - 4 1. 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
1 0 4. Bas u, G., et al. E x pressi o n of n o vel i m m u n ot hera pe utic tar gets i n tri ple-ne gati ve 
breast ca ncer. J Cli n O nc ol 2 0 1 4; 3 2( 1 5) 1 0 0 1.
1 0 5. A n ders o n, M K 
et al.  Ap plicati o n of gra p hical m ulti plicit y  met h o ds i n c o m ple x 
gr o u p se q ue ntial trials.  2 0 1 7 s u b mitte d
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 4 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
1 2. 0
A P P E N DI C E S
Merc k C o de of C o n d uct f or Cli nic al Tri als
1 2. 1
Merc k *
C o de of C o n d uct f or Cli nic al Tri als
I.
I ntr o d ucti o n
A. P ur p ose
Merc k, 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, i m ple me nti 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 s u bject safet y is t he o verri di n g c o ncer n i n 
t he desi g n of cli nical trials. I n all cases, Merc k cli nical trials will be c o n d ucte d i n c o m plia nce wit h l ocal a n d/ or 
nati o nal re g ula ti o ns 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
S uc h 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 Merc k irres pecti ve of  the 
part y ( parties) e m pl o y e 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 w hic h 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 c o ntr ol of Merc k.
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 Merc k or c o m parat or pr o d ucts.  Alter nati vel y, Merc k ma y 
c o n d uct o utc 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 
s u bject prefere nces, etc.  
T he desi g n (i.e., s u bject 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.  Researc h s u bjects 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
Merc k selects i n vesti gati ve sites base d o n me dical e x pertise, access t o a p pr o priate s u bjects, a de q uac y of facilities 
a n d staff, pre vi o us perf or ma nce i n Merc k trials, as well as b u d getar y c o nsi derati o ns.  Prior t o trial i nitiati o n, sites 
are e val uate d b y Merc k pers o n nel t o assess t he a bilit y t o s uccessf ull y c o n d uct t he trial.
3.
Site M o nit ori n g/ Scie ntific I nte grit y
Trial sites are m o nit ore d t o assess c o m plia nce wit h the trial pr ot oc ol a n d ge neral pri nci ples of G o o d Cli nical 
Practice.  Merc k re vie ws cli nical data f or acc urac y, c o m plete ness a n d co 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 
Merc k p olicies a n d p r oce d ures, if fra u d, 
misc o n d uct or seri o us G C P -n o n -C o m plia nce are s us pecte d, t he iss ues are pr o m ptl y i n vesti gate d. W he n necessar y, 
t he cli nical site will be cl ose d, t he res p o nsi ble re g ulat or y a ut h orities a n d et hics re vie w c o m mittees n otifie d a n d 
data discl ose d acc or di n gl y. 
B. P u blic ati o n a n d A ut h ors hi p
T o t he e xte nt scie ntificall y a p pr o priate, Merc k see ks t o p u blis h t he res ults of trials it c o n d ucts.  So me earl y p hase or 
pil ot trials are i nte n 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 
of m ulti plicit y.
Merc k’s 
p olic y o n a ut h ors hi p is c o nsiste nt wit h t he re q uire me nts o utli ne d i n t he I C H-G o o d Cli nical Practice 
g ui deli nes. 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.  Merc k 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. 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
III. S u bject Pr otecti o n
A.
I R B/ E R C re vie w
All cli nical trials will be re vie we d a n d a p pr o ve d b y a n i n de pe n de nt I R B/ E R C bef ore bei n g i nitiate d at eac h site.  
Si g nifica nt c ha n ges or re visi o ns t o t he pr ot oc ol will be a p pr o ve d b y t he I R B/ E R C pri or t o i m ple me ntati o n, e xce pt t hat 
c ha n ges re q uire d ur ge ntl y t o pr otect s u bject safet y a n d well -bei n g ma y be e nacte d i n a ntici pati o n of I R B/ E R C 
a p pr o val. F or eac h site, t he I R B/ E R C a n d Merc k will a p pr o ve t he s u bject i nf or me d c o nse nt f or m. 
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 s u bject welfare is of  pri mar y i mp orta nce.  P ote ntial 
s u bjects 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 wi ll ta ke i nt o acc o u nt t he l ocal sta n dar d of care.  S u bjects are ne ver de nie d access t o a p pr o priate me dical care 
base d o n partici pati o n i n a Merc k cli nical trial . 
All partici pati o n i n Merc k cli nical trials is v ol u ntar y.  S u bjects are e nr olle d o nl y after pr o vi di n g i nf or me d c o nse nt f or 
partici pati o n.  S u bjects ma y wit h dra w fr o m a Merc k 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.
C.
C o nfi de nti alit y
Merc k is c o m mitte d t o safe g uar di n g s u bject c o nfi de ntialit y, t o t he greatest e xte nt p ossi ble.  Unless re q uire d b y la w, 
o nl y t he i n vesti gat or, s p o ns or ( or re prese ntati ve) 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 researc h s u bject b y na me.  
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 i nf or me d c o nse nt a n d/ or as s pecificall y a ut h orize d b y 
a n Et hics C o m mittee.
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 Merc k’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 or me d i n s u p p ort of Merc k trials.   Merc k d oes n ot pa y i nce nti ves t o 
e nr oll s u bjects 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.
Merc k d oes n ot pa y f or s u bject referrals.  Ho w e ver, Merc k ma y c o m pe nsate referri n g p h ysicia ns f or ti me s pe nt o n 
c hart re vie w t o i de ntif y p ote ntiall y eli gi ble s u bjects.
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 Merc k, 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 I R B/ E R C 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 nsiste nt wit h fi na ncial practices at t hat i nstit uti o n.  As n ote d a b o ve, 
p u blicati o ns res ulti n g fr o m Merc k trials will i n dicate Merc k 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  in vesti gat ors a n d s u p p ort staff (e. g., t o scie ntific meeti n gs, i n vesti gat or me eti n gs, etc.) will be 
c o nsiste nt wit h l ocal g ui deli nes a n d practices i ncl u di n g, i n t he U. S., t h ose esta blis he d b y t he A merica n Me dical 
Ass ociati o n ( A M A). 
V. I n vesti g at or C o m mitme nt
I n vesti gat ors will be e x pecte d t o re vie w Merc k’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 o t 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.
* I n t his d oc u me nt, " Merc k" refers t o Merc k S har p & D o h me C or p. a n d Sc heri n g C or p orati o n, eac h of w hic h is a 
s u bsi diar y of Merc k & C o., I nc.  Merc k is k n o w n as M S D o utsi de of t he U nite d States a n d Ca na da.  As warra nte d b y 
c o nte xt, Merc k als o i ncl u des affiliates a n d s u bsi diaries of Merc k & C o., I nc."
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 4 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 2. 2
1.
D efi niti o ns
a.
Bi o mar ker:  A bi ol o gical m olec ule f o u n d i n bl o o d, ot her b o d y  fl ui ds, or tiss ues t hat 
is a si g n of a n or mal or a b n or mal pr ocess or of a c o n diti o n or disease.  A bi o mar ker 
ma y  be use d t o see h o w well t he b o d y  res p o n ds t o a treat me nt f or a disease or 
c o n diti o n. 1
b.
P har mac o ge n o mics: T he i n vesti gati o n of variati o ns of D N A a n d R N A c haracteristics 
as relate d t o dr u g / vacci ne res p o nse.2
c.
P har mac o ge netics:  
A su bset of p har mac o ge n o mics, p har mac o ge netics is t he 
i nfl ue nce of variati o ns i n D N A se q ue nce o n dr u g/ vacci ne res p o nse.2
d.
D N A:  De o x y ri b o n ucleic aci d.
e.
R N A:  Ri b o n ucleic aci d.
2.
Sc o pe of F ut ure Bi o me dic al Rese arc h
T he s peci me ns c ollecte d i n t his trial as o utli ne d i n Secti o n 7. 1. 3. 3 will be use d t o st u d y 
vari o us ca uses f or h o w s u bjects ma y  res p o n d t o a dr u g / vacci ne.  Fut ure bi o me dical 
researc h s peci me n(s) will be st ore d t o pr o vi de a res o urce f or f ut ure trials c o n d ucte d b y  
Merc k f oc use d o n t he st u d y of bi o mar kers res p o nsi ble f or h o w a dr u g / vacci ne e nters a n d 
is re m o ve d b y  the b o d y , h o w a dr u g / vacci ne w or ks, ot her pat h wa y s a dr u g / vacci ne ma y 
i nteract wit h, or ot her as pects of disease.  T he s peci me n(s) m a y  be use d f or f ut ure assa y 
de vel o p me nt a n d/ or dr u g/ vacci ne de vel o p me nt.
It is n o w well rec o g nize d t hat i nf or mati o n o btai ne d fr o m st u d yi n g a n d testi n g cli nical 
s peci me ns offers u n i q ue o p p ort u nities t o e n ha nce o ur u n dersta n di n g of h o w i n di vi d uals 
res p o n d t o dr u gs / vacci nes, e n ha nce o ur u n dersta n di n g of h u ma n disease a n d ulti matel y 
i m pr o ve p u blic healt h t hr o u g h de vel o p me nt of n o vel treat me nts tar gete d t o p o p ulati o ns 
wit h t he greatest nee d.  All s peci me ns will be use d b y  Merc k or desi g nees a n d researc h 
will be m o nit ore d a n d re vie we d b y a c o m mittee of o ur scie ntists a n d cli nicia ns.
3.
S u m m ar y of Pr oce d ures f or F ut ure Bi o me dic al Rese arc h
a.
S u bjects f or E nr oll me nt
All s u bjects e nr olle d i n t he cli nical trial will be c o nsi dere d f or e nr oll me nt i n t he 
F ut ure Bi o me dical Researc h s u b -trial.
b.
I nf or me d C o nse nt
I nf or me d c o nse nt f or s peci me ns (i.e., D N A, R N A, pr otei n, etc.) will be o btai ne d 
d uri n g scree ni n g f or pr ot oc ol e nr oll me nt fr o m all s u bject s or le gal g uar dia ns, at a trial 
visit b y  the i n vesti gat or or his or her desi g nate.  Inf or me d c o nse nt f or F ut ure 
Bi o me dical Researc h s h o ul d be prese nte d t o t he s u bjects o n Visit 1.  If dela y e d, 
prese nt c o nse nt at ne xt p ossi ble S u bject Visit. I nf or me d c o nse nt m ust be o btai ne d 
pri or t o c ollecti o n of all F ut ure Bi o me dical Researc h s peci me ns.   C o nse nt f or ms 
si g ne d b y  the s u bject will be ke pt at t he cli nical trial site u n der sec ure st ora ge f or 
re g ulat or y reas o ns.  I nf or mati o n c o ntai ne d o n t he c o nse nt f or m al o ne ca n n ot be trace d 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
t o a n y speci me ns, test res ults, or me dical i nf or mati o n o nce t he s peci me ns ha ve bee n 
re n dere d de-i de ntifie d
A te m plate of eac h trial site’s a p pr o ve d i nf or me d c o nse nt will be st ore d i n t he 
S p o ns or’s cli nical d oc u me nt re p osit or y.  Eac h c o nse nt will 
be assesse d f or 
a p pr o priate s peci me n per missi o ns.  
Eac h i nf or me d c o nse nt a p pr o ve d b y  a n et hics c o m mittee is assi g ne d a u ni q ue trac ki n g 
n u m ber.  The trac ki n g n u m ber o n t his d oc u me nt will be use d t o assi g n s peci me n 
per missi o ns f or eac h s peci me n i nt o t he E ntr uste d Ke yh ol der’s S peci me n Data base.
c.
e C R F D oc u me ntati o n f or F ut ure Bi o me dical Researc h S peci me ns
D oc u me ntati o n of b ot h c o nse nt a n d ac q uisiti o n of F ut ure Bi o me dical Researc h 
s peci me ns will 
be ca pt ure d i n t he electr o nic Case 
Re p ort 
F or ms (e C R Fs). 
Rec o nciliati o n of b ot h f or ms will be perf or me d t o ass ure t hat o nl y a p pr o priatel y-
c o nse nte d s peci me ns are use d f or t his s u b-trial's researc h p ur p oses. A n y s peci me ns 
f or w hic h s uc h a n i nf or me d c o nse nt ca n n ot be verifie d will be destr oye d.
d.
F ut ure Bi o me dic al Researc h S peci me n C ollecti o ns
Bl o o d s peci me ns f or D N A or R N A is olati o n will us uall y  be o btai ne d at a ti me w he n 
t he s u bject is ha vi n g bl o o d dra w n f or ot her trial p ur p oses. S peci me ns li ke tiss ue a n d 
b o ne marr o w will us uall y  be o btai ne d at a ti me w he n t he s u bject is ha vi n g s uc h a 
pr oce d ure f or cli nical p ur p oses.
S peci me ns will be c ollecte d a n d se nt t o t he la b orat or y desi g nate d f or t he trial w here 
t he y will be pr ocesse d (e. g., D N A or R N A e xtracti o n, etc) f oll o wi n g t he Merc k 
a p pr o ve d p olicies a n d pr oce d ures f or s peci me n ha n dli n g a n d pre parati o n.
If s peci me ns are c ollecte d f or a s pecific ge n ot y pe or e x pressi o n a nal ysis as a n 
o bjecti ve t o t he mai n trial, t his a nal ys is is detaile d i n t he mai n b o d y  of t his pr ot oc ol 
(Secti o n 8. 0 – St atistic al A n al ysis Pl a n ).  These s peci me ns will be pr ocesse d, 
a nal yz e d, a n d t he re mai n der of t he s peci me n will be destr o y e d.  The res ults of t hese 
a nal ys es will be re p orte d al o n g wit h t he ot her trial res ults.  A se parate s peci me n will 
be o btai ne d fr o m pr o perl y -c o nse nte d s u bjects i n t his pr ot oc ol f or st ora ge i n t he 
bi ore p osit or y  f or F ut ure Bi o me dical Researc h.
4.
C o nfi de nti al S u bject I nf or m ati o n f or F ut ure Bi o me dic al Rese arc h 
I n or der t o o pti mize t he researc h t hat ca n be c o n d ucte d wit h F ut ure Bi o me dical Researc h 
s peci me ns, it is critical t o li n k s u bject' cli nical i nf or mati o n wit h f ut ure test res ults. I n fact 
little or n o researc h ca n be c o n d ucte d wit h o ut c o n necti n g t he cli nical trial data t o t he 
s peci me n. T h e cli nical data all o w s pecific a nal yses t o be c o n d ucte d. K n o wi n g s u bject 
c haracteristics li ke ge n der, a ge, me dical hist or y  an d treat me nt o utc o mes are critical t o 
u n dersta n di n g cli nical c o nte xt of a nal y tical res ults.
T o mai ntai n 
pri vac y  of i nf or mati o n c ollecte d fr o m s peci me ns o btai ne d f or F ut ure 
Bi o me dical Researc h, Merc k 
has de vel o pe d sec ure p olicies a n d pr oce d ures.  
All 
s peci me ns will be de-i de ntifie d as descri be d bel o w. 
At t he cli nical trial site, u ni q ue c o des will be place d o n t he F ut ure Bi o me dical Rese arc h 
s peci me ns f or tra nsfer t o t he st ora ge facilit y.  This first c o de is a ra n d o m n u m ber w hic h 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 4 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
d oes n ot c o ntai n a n y pers o nall y  ide ntif y i n g i nf or mati o n e m be d de d wit hi n it. T he li n k ( or 
ke y ) bet wee n s u bject i de ntifiers a n d t his first u ni q ue c o de will be hel d at t he trial site.  N o 
pers o nal i de ntifiers will a p pear o n t he s peci me n t u be.  
T his first c o de will be re place d wit h a sec o n d c o de at a Merc k desi g nate d st ora ge/la b 
facilit y.  The sec o n d c o de is li n ke d t o t he first c o de via a sec o n d k e y . T he s peci me n is 
n o w d o u ble c o de d.  Speci me ns wit h t he sec o n d c o de are s o meti mes referre d t o as d e -
i de ntifie d s peci me ns. T he use of t he sec o n d c o de pr o vi des a d diti o nal c o nfi de ntialit y an d 
pri vac y  pr otecti o n f or s u bjects o ver t he use of a si n gle c o de.  Access t o b ot h k e y s w o ul d 
be nee de d t o li n k a n y  data or s peci me ns bac k t o t he s u bject's i de ntificati o n.
T he sec o n d c o de is st ore d se paratel y fr o m t he first c o de a n d all ass ociate d pers o nal 
s peci me n i de ntifiers.  A sec ure li n k, t he sec o n d ke y , will be utilize d t o matc h t he sec on d 
c o de t o t he first c o de t o all o w cli nical i nf or mati o n c ollecte d d uri n g t he c o urse of t he trial 
t o be ass ociate d wit h t he s peci me n.  This sec o n d k e y  will be tra nsferre d u n der sec ure 
pr oce d ures b y  the Merc k desi g nate d facilit y to a n E ntr uste d Ke y h ol der at Merc k.  The 
sec o n d c o de will be l o g ge d i nt o t he pri mar y  bi ore p osit or y data base at Merc k a n d, i n t his 
data base, t his i de ntifier will n ot ha ve i de ntif yi n g de m o gra p hic data or i de ntif yi n g cli nical 
i nf or mati o n (i.e., race, se x, a ge, dia g n osis, la b val ues) ass ociate d wit h it. T he s peci me n 
will be st ore d i n a desi g nate d bi ore p osit or y  site wit h sec ure p olicies a n d pr oce d ures f or 
s peci me n st ora ge a n d usa ge.
T he sec o n d k e y  ca n be utilize d t o rec o nstr uct t he li n k bet wee n t he res ults of f ut ure 
bi o me dical researc h a n d t he cli nical i nf or mati o n, at t he ti me of a nal ysis.  This li n ka ge 
w o ul d n ot be p ossi ble f or t he scie ntist c o n d ucti n g t he a nal ys is, b ut ca n o nl y  be d o ne b y  
t he Merc k E ntr uste d Ke y h ol der u n der strict sec urit y policies a n d pr oce d ures.  The Merc k 
E ntr uste d Ke y h ol der will li n k t he i nf or mati o n a n d t he n iss ue a de- i de ntifie d data set f or 
a nal ys is.  The o nl y ot her circ u msta nce b y  whic h f ut ure bi o me dical researc h data w o ul d 
be directl y li n ke d t o t he f ull cli nical data set w o ul d be t h ose sit uati o ns ma n date d b y 
re g ulator y  aut h orities (e. g., E M E A, F D A), w here b y  this i nf or mati o n w o ul d be directl y 
tra nsferre d t o t he re g ulat or y a ut h orit y.
5.
Bi ore p osit or y S peci me n Us a ge
S peci me ns o btai ne d f or t he Merc k Bi ore p osit or y will be use d f or a nal ys es usi n g g o o d 
scie ntific practices.   H o we ver, e x pl orat or y anal y ses will n ot be c o n d ucte d u n der t he 
hi g hl y vali date d c o n diti o ns us uall y  ass ociate d wit h re g ulat or y ap pr o val of dia g n ostics.  
T he sc o pe of researc h perf or me d o n t hese s peci me ns is li mite d t o t he i n vesti gati o n of t he 
varia bilit y  in bi o mar kers t hat ma y  c orrelate wit h a cli nical p he n oty pe i n s u bjects.
A nal y ses utilizi n g t he F ut ure Bi o me dical Researc h s peci me ns m a y  be perf or me d b y  
Merc k, or a n a d diti o nal t hir d part y (e. g., a u ni versit y  in vesti gat or) desi g nate d b y  Merc k.  
T he i n vesti gat or c o n d ucti n g t he a nal ys is will be pr o vi de d wit h d o u ble c o de d s peci me ns.  
Re -ass ociati o n of a nal ysis res ults wit h c orres p o n di n g cli nical data will o nl y be c o n d ucte d 
b y  the Merc k E ntr uste d K e y h ol der.  An y  co ntracte d t hir d part y a nal ys es will c o nf or m t o 
t he s pecific sc o pe of a nal ysis o utli ne d i n t his s u b-trial.  Fut ure Bi o me dical Researc h 
s peci me ns re mai ni n g wit h t he t hir d part y  after t he s pecific a nal ysis is perf or me d will be 
ret ur ne d t o t he s p o ns or or destr o ye d a n d d oc u me ntati o n of destr ucti o n will be re p orte d t o 
Merc k.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 5 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
6.
Wit h dr a w al Fr o m F ut ure Bi o me dic al Rese arc h 
S u bjects ma y  wit h dra w t heir c o nse nt f or F ut ure Bi o me dical Researc h a n d ha ve t heir 
s peci me ns a n d all deri vati ves destr o ye d.   Su bjects m a y  wit h dra w c o nse nt at a n y ti me b y  
c o ntacti n g t he pri nci pal i n vesti gat or f or t he mai n trial.  If me dical rec or ds f or t he mai n 
trial are still a vaila ble, t he i n vesti gat or will c o ntact Merc k usi n g t he desi g nate d mail b o x 
(cli nical.s peci me n. ma na ge me nt @ merc k.c o m ) a n d a f or m will be pr o vi de d b y  Merc k t o 
o btai n a p pr o priate i nf or mati o n t o c o m plete s peci me n wit h dra wal.  Su bse q ue ntl y , t he 
s u bject's s peci me ns will be re m o ve d fr o m t he bi ore p osit or y  an d be destr o y e d. A letter 
will be se nt fr o m Merc k 
t o t he i n vesti gat or c o nfir mi n g t he destr ucti o n. It is t he 
res p o nsi bilit y of t he i n vesti gat or t o i nf or m t he s u bject of c o m pleti o n of destr ucti o n.  An y  
a nal ys es i n pr o gress at t he ti me of re q uest f or destr ucti o n or alrea d y perf or me d pri or t o 
t he re q uest bei n g recei ve d b y  the S p o ns or will c o nti n ue t o be use d as part of t he o verall 
researc h trial data a n d res ults. N o ne w a nal yses w o ul d be ge nerate d after t he re q uest is 
recei ve d.
I n t he e ve nt t hat t he me dical rec or ds f or t he mai n trial are n o l o n ger a vaila ble (e. g., if t he 
i n vesti gat or is n o l o n ger re q uire d b y  re g ulat or y aut h orities t o retai n t he mai n trial 
rec or ds) or t he s peci me ns ha ve bee n c o m pletel y a n o n ymize d, t here will n o l o n ger be a 
li n k bet wee n t he s u bject’s pers o nal i nf or mati o n a n d t heir s peci me ns. I n t his sit uati o n, t he 
re q uest f or s peci me n destr ucti o n ca n n ot be pr ocesse d. 
7.
R ete nti o n of S peci me ns 
F ut ure Bi o me dical Researc h s peci me ns will be st ore d i n t he bi ore p osit or y  for p ote ntial 
a nal ys is f or u p t o 2 0 ye ars fr o m ac q uisiti o n.  Speci me ns m a y  be st ore d f or l o n ger if a 
re g ulat or y or g o ver n me ntal a ut h orit y has acti ve q uesti o ns that are bei n g a ns were d.  In 
t his s pecial circ u msta nce, s peci me ns will be st ore d u ntil t hese q uesti o ns ha ve bee n 
a de q uatel y a d dresse d.
S peci me ns fr o m t he trial site will be s hi p pe d t o a ce ntral la b orat or y an d t he n s hi p pe d t o 
t he Merc k 
desi g nate d bi ore p osit o r y.  The s peci me ns will 
be st ore d u n der strict 
s u per visi o n i n a li mite d access facility w hic h o perates t o ass ure t he i nte grity of t he 
s peci me ns.  S peci me ns will be destr o ye d acc or di n g t o Merc k p olicies a n d pr oce d ures a n d 
t his destr ucti o n will be d oc u me nte d i n t he bi ore p osit or y data base.
8.
D at a Sec urit y
Se parate data bases f or s peci me n i nf or mati o n a n d f or res ults fr o m t he F ut ure Bi o me dical 
Researc h s u b-trial will be mai ntai ne d b y  Merc k.  This is d o ne t o se parate t he f ut ure 
e x pl orat or y test res ults ( w hic h i ncl u de ge netic data) fr o m t he cli nical trial data base 
t here by mai ntai ni n g a se parati o n of s u bject n u m ber a n d t hese res ults.  The se parate 
data bases are accessi ble o nl y  to t he a ut h orize d S p o ns or a n d t he desi g nate d trial 
a d mi nistrat or researc h pers o n nel a n d/ or c olla b orat ors.  Data base user a ut he nticati o n is 
hi g hl y sec ure, a n d is acc o m plis he d usi n g net w or k sec urit y p olicies a n d practices base d i n 
i nter nati o nal sta n dar ds (e. g., I S O 1 7 7 9 9) t o pr otect a gai nst u na ut h orize d access.  The 
Merc k E ntr uste d K e y h ol der mai nt ai ns c o ntr ol o ver access t o all s peci me n data.  These 
data are c ollecte d f or f ut ure bi o me dical researc h p ur p oses o nl y as s pecifie d i n t his s u b-
trial will n ot be use d f or a n y ot her p ur p ose.
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 5 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
9.
Re p orti n g of F ut ure Bi o me dic al Rese arc h D at a t o S u bjects
T here is n o defi niti ve re q uire me nt i n eit her a ut h oritati ve et hical g ui deli nes or i n rele va nt 
la ws/re g ulati o ns gl o bally t hat researc h res ults ha ve t o be, i n all circ u msta nces, ret ur ne d t o 
t he trial partici pa nt.  So me g ui deli nes a d v ocate a pr oacti ve ret ur n of data i n certai n 
i nsta nces.  No i nf or mati o n o btai ne d fr o m e x pl orat or y la b orat or y st u dies will be re p orte d 
t o t he s u bject or fa mil y, a n d t his i nf or mati o n will n ot be e ntere d i nt o t he cli nical data base 
mai ntai ne d b y  Merc k o n s u bjects.  Pri nci ple reas o ns n ot t o i nfor m or ret ur n res ults t o t he 
s u bject i ncl u de: lac k of rele va nce t o s u bject healt h, li mitati o ns of pre dicti ve ca pa bilit y, 
c o ncer ns of misi nter pretati o n 
a n d a bse nce of g o o d cli nical practice sta n dar ds i n 
e x pl orat or y researc h ty pi call y use d f or dia g n ostic testi n g.
If a ny e x pl orat or y res ults are defi niti vel y ass ociate d wit h cli nical si g nifica nce f or s u bjects 
w hile t he cli nical trial is still o n g oi n g, i n vesti gat ors will be c o ntacte d wit h i nf or mati o n as 
t o h o w t o offer cli nical dia g n ostic  testi n g ( pai d f or b y  Merc k) t o s u bjects e nr olle d a n d 
will be a d vise d t hat c o u nseli n g s h o ul d be ma de a vaila ble f or all w h o c h o ose t o partici pate 
i n t his dia g n ostic testi n g. 
If a n y e x pl orat or y res ults are defi niti vel y ass ociate d wit h cli nical si g nifica nce after 
c o m pleti o n of a cli nical trial, Merc k will p u blis h t he res ults wit h o ut re veali n g s pecific 
s u bject i nf or mati o n, i nf or m all trial sites w h o partici pate d i n t he Merc k cli nical trial a n d 
p ost a n o n y m ize d res ults o n o ur we bsite or ot her accre dite d we bsite(s) t hat all o w f or 
p u blic acces s (e. g., disease s ocieties w h o ha ve pri mar y i nterest i n t he res ults) i n or der t hat 
p h y sicia ns a n d s u bjects ma y p urs ue cli nical dia g n ostic testi n g if t he y wis h t o d o s o.
1 0. Ge n der, Et h nicit y a n d Mi n orities
Alt h o u g h ma n y dia g n oses differ i n ter ms of fre q ue nc y by et h nic p o p ulati o n a n d ge n der, 
e ver y eff ort will be ma de t o recr uit all s u bjects dia g n ose d a n d treate d o n Merc k cli nical 
trials f or f ut ure bi o me dical researc h.  
Whe n trials wit h s peci me ns are c o n d ucte d a n d 
s u bjects i de ntifie d t o ser ve as c o ntr ols, e ver y eff ort will be ma de t o gr o u p s peci me ns 
fr o m s u bjects a n d c o ntr ols t o re prese nt t he et h nic a n d ge n der p o p ulati o n re prese ntati ve of 
t he disease u n der c urre nt i n vesti gati o n.
1 1. Ris ks Vers us Be nefits of F ut ure Bi o me dic al Rese arc h 
F or f ut ure bi o me dical res earc h, ris ks t o t he s u bject ha ve bee n mi ni mize d. Ris ks i ncl u de 
t h ose ass ociate d wit h ve ni p u nct ure t o o btai n t he w h ole bl o o d s peci me n.  T his s peci me n 
will be o btai ne d at t he ti me of r o uti ne bl o o d s peci me ns dra w n i n t he mai n trial . 
Merc k 
has de vel o pe d strict sec urit y, p olicies a n d pr oce d ures t o a d dress s u bject data 
pri vac y  co ncer ns.  Data pri vac y  ris ks are lar gel y li mite d t o rare sit uati o ns i n v ol vi n g 
p ossi ble breac h of c o nfi de ntialit y.  In t his hi g hl y u nli kel y  sit uati o n t here is ris k t hat t he 
i nf or mati on, li ke all me dical i nf or mati o n, ma y  be mis use d.
It is necessar y for s u bject-relate d data (i.e., et h nicit y , dia g n osis, dr u g t hera p y an d d osa ge, 
a ge, t o xicities, etc.) t o be re-ass ociate d t o d o u ble c o de d s peci me ns at t he ti me of data 
a nal ys is.  These s u bject data will be ke pt i n a se parate, sec ure Merc k data base, a n d all 
s peci me ns will be stri p pe d of s u bject i de ntifiers.  No i nf or mati o n c o ncer ni n g res ults 
o btai ne d fr o m f ut ure bi o me dical researc h will be e ntere d i nt o cli nical rec or ds, n or will it 
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 5 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
be release d t o o utsi de pers o ns or a ge ncies, i n a n y wa y  that c o ul d be tie d t o a n i n di vi d ual 
s u bject.
1 2. Self -Re p orte d Et h nicit y
S u bjects w h o partici pate i n f ut ure bi o me dical researc h will be as ke d t o pr o vi de self-
re p orte d et h nicit y.  Su bjects w h o d o n ot wis h t o pr o vi d e t his data ma y  still partici pate i n 
f ut ure bi o me dical researc h.
1 3. Q uesti o ns
A n y  questi o ns relate d t o t he f ut ure bi o me dical researc h s h o ul d be e-maile d directl y t o 
cli nical.s peci me n. ma na ge me nt @ merc k.c o m.
1 4. Refere nces
1.
Nati o nal Ca ncer I nstit ute: htt p: // w w w.ca ncer. g o v/ dicti o nar y/?searc h T xt = bi o mar ker
2.
I nter nati o nal
C o nfere nce 
o n Har m o nizati o n: 
D E FI N I TI ON S 
F O R G E N O MI C 
BI O M A R K E R S, P H A R M A C O G E N O MI C S, P H A R M A C O G E N E TI C S, G E N O MI C 
D A T A 
A N D 
S A M P L E 
C O DI N G 
C A T E G O RI E S 
-
E 1 5; 
htt p:// w w w.ic h. or g/ L O B/ me dia/ M E DI A 3 3 8 3. p df
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
U n derst a n di n g t he I nte nt, Sc o pe a n d P u blic He alt h 
Be nefits of E x pl or at or y Bi o m ar ker Rese arc h: A G ui de 
f or 
1 2. 3
I R Bs/I E Cs a n d I n vesti g ati o n al Site St aff
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 5 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A b bre vi ati o ns
1 2. 4
A b bre vi ati o n/ Ter m
Defi niti o n
1 L
First li ne
2 L
Sec o n d li ne
3 L
T hir d li ne
A E
A d verse eve nt
A D A
A nti - dr u g anti b o dies
A L T
Ala ni ne a mi n otra nsferase
A N C
A bs ol ute n e utr o p hil co u nt
A P
Al kali ne p h os p hatase
a P T T
Acti vate d partial t hr o m b o plasti n ti me
A Sa T
All s u bjects as treate d
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate ami n otra nsferase
ß - hC G
Beta h u ma n ch ori o nic g o na d otr o pi n
B S A
B o d y surface area
C B C
C o m plete b l o o d co u nt
CI
C o nfi de nce i nter val
C N S
Ce ntral n er v o us sys te m
C R
C o m plete res p o nse
Cr Cl
Calc ulate d Creati ni ne C leara nce
C R F
Case r e p ort for m
C S R
Cli nical st u d y re p ort
C T
C o m p ute d to m o gra p h y
C T C A E
C o m m o n to xicit y  criteria f or ad verse eve nts
C T L A- 4
C y t ot o xic t-ly m p h oc y t e- ass ociate d anti ge n 4
D M C
Data M o nit ori n g C o m mittee
D N A
De o x yri b o n ucleic aci d
E CI
E ve nts of cli nical interest
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
e D M C
E xter nal Data M o nit ori n g C o m mittee
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
E O C
E xec uti ve O versi g ht C o m mittee
E O R T C
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer
e P R O
Electr o nic su bject re p orte d o utc o mes
E R C
Et hics Re vie w C o m mittee
F B R
F ut ure b i o me dical researc h
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 6 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
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 A M A
F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act
F N A
Fi ne n ee dle as pirate
G C P
G o o d Cli nical Practice
G F R
Gl o m er ular filtrati o n rate
H B s A g
He patitis B s urface anti ge n
M B C
Metastatic breast ca ncer
H C V
He patitis C v ir us
HI V
H u ma n im m u n o deficie nc y v ir us
I B
I n vesti gat or’s br oc h ure
I CF
I nf or me d co nse nt for m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I H C
I m m u n o hist oc he mistr y
I N R
I nter nati o nal n or malize d rati o
ir A Es
I m m u ne-relate d a d verse eve nts
ir R E CIS T
I m m u ne-relate d res p o nse eval u ati o n criteria i n soli d tu m ors
I RB
I nstit uti o nal Re vie w B oar d
I TI M
I m m u n orece pt or tyr osi ne -base d in hi biti o n m otif
I T S M
I m m u n orece pt or tyr osi ne -base d switc h m otif
I T T
I nte nti o n-t o-treat
I V
I ntra ve n o us
I V R S
I nteracti ve v oice res p o nse sys te m
I W R S
I nte grate d w e b res p o nse sys te m
K g
K il o gra m
L D H
L actate d e h y dr o ge nase
m A b
M o n ocl o nal anti b o d y
mc L
Micr oliters
M g
Milli gra m
M g/ k g
Milli gra m per k il o gra m
m L
milliliter
M RI
Ma g netic res o na nce ima gi n g
m T N B C
Metastatic tri ple n e gati ve b reast ca ncer
N CI
Nati o nal Ca ncer I nstit ute
N S AI D
N o n -ster oi dal anti -i nfla m mat or y d r u g
N S C L C
N o n -small cell lu n g ca ncer
O R R
O verall res p o nse rate
O S
O verall sur vi val
 
 
0 4 V B P K


Pr o d uct:   M K - 3 4 7 5 
1 6 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
O T C
O ver -t he-c o u nter
P D
Pr o gressi ve d isease
P F S
Pr o gressi o n -free sur vi val
P Gt
P har mac o ge netic
PI N
Pers o nal ide ntificati o n n u m ber
P K
P har mac o ki netic
P K /P D
P har mac o ki netic - phar mac o d y na mic
P O
Oral ad mi nistrati o n
P R
Partial r es p o nse
P R O
Patie nt re p orte d o utc o mes
P T
Pr ot hr o m bi n ti me
P S
Perf or ma nce stat us
R E CI S T
Res p o nse eval u ati o n criteria i n soli d tu m ors
R N A
Ri b o n ucleic aci d
Q 2 W
E ver y  2 w ee ks
Q 3 W
E ver y  3 w ee ks
Q 9 W
E ver y  9 wee ks
S A E
Seri o us ad verse eve nts
S A P
Statistical anal y sis p la n
S G O T
Ser u m g l uta mic o xal oacetic tra nsa mi nase
S G P T
Ser u m g l uta mic p yr u vic tra nsa mi nase
S O C
Sta n dar d of care
S O P
Sta n dar d o perati n g p r oce d ures
TI L
T u m or infiltrati n g ly m p h oc y tes
T N B C
Tri ple n e gati ve b reast ca ncer
T P C
Treat me nt of p h y sicia n’s ch oice
T S H
T h y r oi d sti m ulati n g h or m o ne
U L N
U p per li mit of n or mal
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E aster n C o o per ati ve O nc ol o g y G r o u p Perf or m a nce St at us
1 2. 5
G R A D E
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 y sically stre n u o us acti vit y but a m b ulat or y an d a ble t o carr y out 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  an d ca pa ble of all self-care b ut u na ble t o carr y out 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 carry 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
* O ke n M, 
Creec h R, T or me y  D, et al. T o xicit y  an d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y  Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5: 6 4 9 -6 5 5
htt p://ec o g -acri n. or g/res o urces/ec o g -perf or ma nce -stat us
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts V 4. 0
1 2. 6
T he descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d N CI C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) versi o n 4. 0 will be utilize d f or a d verse e ve nt re p orti n g. 
( htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml).
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 6 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Res p o nse 
E v al u ati o n Criteri a 
i n S oli d T u m ors 1. 1 Criteri a 
f or E v al u ati n g 
1 2. 7
Res p o nse i n S oli d T u m ors
R E CI S T versi o n 1. 1 * will be use d i n t his st u d y f or assess me nt of t u m or res p o nse. W hile 
eit her C T or M RI  m a y be utilize d, as per R E CIS T 1. 1, C T is t he preferre d i ma gi n g tec h ni q ue 
i n t his st u d y.
* As p u blis he d i n t he E ur o pea n J o ur nal of Ca ncer:
E. A. Eise n ha uer, P. T herasse, J. B o gaerts, L. H. Sc h wartz, D. Sar ge nt, R. F or d, J. Da nce y , S. 
A r b uc k, S. G w y t her, M. 
M o o ne y , L. R u bi nstei n, L.  Sha n kar, L.  Do d d, R. Ka pla n, D. 
Lac o m be, J. Ver weij. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: Re vise d R E CI S T 
g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9 Ja n; 4 5( 2): 2 2 8 -4 7.
 
 
0 4 V B P K


Pr o d uct:   M K -3 4 7 5 
1 7 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
1 3. 0 SI G N A T U R E S
S p o ns or's Re pre se nt ati ve
1 3. 1
T Y P E D N A M E
TI T L E
SI G N A T U R E
D A T E SI G N E D
I n vesti g at or
1 3. 2
I a gree t o c o n d uct t his cli nical trial 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 (i ncl u di n g ot her ma n uals a n d d oc u me nts 
refere nce d fr o m t his pr ot oc ol).  I agree t o c o n d uct t he trial i n acc or da nce wit h ge nerall y 
acce pte d sta n dar ds of G o o d Cli nical Practice.  I als o a gree t o re p ort all i nf or mati o n or data i n 
acc or da nce wit h t he pr ot oc ol a n d, i n partic ular, I a gree t o re p ort a n y  seri o us a d verse e ve nts 
as defi ne d i n Secti o n 7 .2 – Assessi n g a n d Rec or di n g A d verse E ve nts.  I als o a gree t o ha n dle 
all cli nical s u p plies pr o vi de d b y  the S p o ns or a n d c ollect a n d ha n dle all cli nical s peci me ns i n 
acc or da nce wit h t he pr ot oc ol.  I un dersta n d t hat i nf or mati o n t hat i de ntifies me will be use d 
a n d discl ose d as descri be d i n t he pr ot oc ol, a n d t hat s uc h i nf or mati o n ma y  be tra nsferre d t o 
c o u ntries t hat d o n ot ha ve la ws pr otecti n g s uc h i nf or mati o n.  Si nce t he i nf or mati o n i n t his 
pr ot oc ol a n d t he refere nce d I n vesti gat or’s Br oc h ure is c o nfi de ntial, I u n dersta n d t hat its 
discl os ure t o a n y t hir d parties, ot her t ha n t h ose i n v ol ve d i n a p pr o val, s u per visi o n, or c o n d uct 
of t he trial is pr o hi bite d.  I will e ns ure t hat t he necessar y  preca uti o ns are ta ke n t o pr otect s uc h 
i nf or mati o n fr o m l oss, i na d verte nt discl os ure or access by t hir d parties.
T Y P E D N A M E
TI T L E
SI G N A T U R E
D A T E SI G N E D
 
 
0 4 V B P K