Clinical trial NCT03361865
Conditions: UC (Urothelial Cancer)
Keywords: Urothelial cancer, programmed cell death 1 (PD-1) inhibitor indoleamine 2,3-dioxygenase (IDO) inhibitor
Sponsor: Incyte Corporation
Start date: 2017-12-04; Completion date: 2020-08-04
Enrollment: 93 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of pembrolizumab + epacadostat vs pembrolizumab + placebo in participants with cisplatin-ineligible urothelial carcinoma.

Detailed description:

Arms: arm 1: Pembrolizumab + epacadostat arm 2: Pembrolizumab + placebo
Interventions: intervention 1: Pembrolizumab intervention 2: Epacadostat intervention 3: Placebo
Intervention descriptions: intervention 1: Pembrolizumab administered intravenously every 3 weeks. intervention 2: Epacadostat administered orally twice daily. intervention 3: Matching placebo administered orally twice daily.

Protocol documents:
Prot_SAP_000.pdf: 


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
M S D
Si g n at or y
T y pe d Na me:
Title:
Date
Pr ot oc ol -s pecific M S D c o nt act i nf or m ati o n c a n be f o u n d i n t he I n vesti g at or Tri al File 
Bi n der ( or e q ui v ale nt). 
I n vesti g at or Si g n at or y
I a gree t o c o n d uct t his cli nical 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.
T y pe d Na me:
Title:
Date
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S
A m e n d me nt 0 4
O ver all R ati o n ale f or t he A me n d me nt:
T he e xter nal data m o nit ori n g c o m mittee ( eD M C) a nal ys is of t he K E Y N O T E- 2 5 2/ E C H O- 3 0 1 bli n de d cli nical st u d y , a Phase 3 st u d y  
e val uati n g e paca d ostat i n c o m bi nati o n wit h pe m br oliz u ma b i n partici pa nts wit h u nresecta ble or metastatic mela n o ma, deter mi ne d t hat 
t he st u d y di d n ot meet t he pre-s pecifie d e n d p oi nt of i m pr o ve me nt i n pr o gressi o n-free s ur vi val f or t he c o m bi nati o n of pe m br oliz u ma b 
a n d e paca d ostat c o m pare d t o pe m br oliz u ma b a n d place b o. T he e D M C f urt her deter mi ne d t hat t he o verall s ur vi val e n d p oi nt is n ot 
e x pecte d t o reac h statistical si g nifica nce. T hes e res ults are s pecific t o mela n o ma, a n d ca n n ot be e xtra p olate d t o ot her t u m or t y pes.  Of 
n ote, t here were n o ne w safet y c o ncer ns wit h t he pe m br oliz u ma b pl us e paca d ostat c o m bi nati o n c o m pare d t o pe m br oliz u ma b 
m o n ot hera p y.  Gi ve n t hat t here is n o c o nfir me d la c k of efficac y of pe m br oliz u ma b pl us e paca d ostat i n ot her t u m or t ypes, t he S p o ns or 
a n d M S D c o nsi der i nterr u pti o n of st u d y  treat me nt u n necessar y i n K E Y N O T E-6 7 2/ E C H O -3 0 7 a n d K E Y N O T E -6 9 8/ E C H O - 3 0 3.  
E nr oll me nt i n b ot h st u dies was per ma ne ntl y st o p pe d o n 0 2 - MA Y -2 0 1 8 as a strate gic decisi o n. F or partici pa nts w h o are c o nsi dere d t o 
be o btai ni n g o n g oi n g cli nical be nefit, c o nti n ue d st u d y  treat me nt will be at t he discreti o n of t he i n vesti gat or after a disc ussi o n wit h t he 
partici pa nt of t he res ults fr o m K E Y N O T E-2 5 2/ E C H O- 3 0 1.
S u m m ar y of C h a n ges T a ble:
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1 S y n o psis
2. 1 I nitial Treat me nt P hase 
S o A
A d diti o n of n otes t hat t he st u d y  will be 
u n bli n de d after t he last partici pa nt c o m pletes 
first i ma gi n g assess me nt f or efficac y a nalys is; 
partici pa nts ma y  c h o ose t o disc o nti n ue fr o m 
t he st u d y or c o nti n ue o pe n-la bel st u d y 
treat me nt as per pr ot oc ol. 
Gi ve n t he res ults f or pe m br oliz u ma b + 
e paca d ostat treat me nt fr o m mela n o ma i n 
K E Y N O T E -2 5 2/ E C H O -3 0 1, as of 0 2-M A Y -
2 0 1 8 e nr oll me nt was per ma ne ntl y  st o p pe d i n 
K E Y N O T E 6 7 2/ E C H O -3 0 7 .  Partici pa nts will 
be gi ve n t he o pti o n t o disc o nti n ue fr o m t he 
st u d y or c o nti n ue st u dy treat me nt.  T he st u d y 
will re mai n o pe n s o t hat partici pa nts st ill o n 
st u d y will ha ve c o nti n ue d access t o st u d y 
treat me nt a n d t o all o w c ollecti o n of preli mi nar y 
efficac y data i n t his U C i n dicati o n.
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Efficac y pr oce d ures after Wee k 9 are n o l o n ger 
bei n g ma n date d .  W here deleti o n of te xt c o ul d 
ca use c o nf usi o n, d ue t o t he desi g n of t he st u d y 
t o date, t he te xt has bee n left u nc ha n ge d a n d a 
n ote has bee n a d de d.
2. 2 Sec o n d C o urse P hase 
( Retreat me nt) S o A
A d diti o n of n ote t hat pr oce d ures are si m plifie d, 
S o A u p date d acc or di n gl y; disease assess me nt 
will be perf or me d b y t he i n vesti gat or per l ocal 
S o C g ui deli nes.
3. 2. 3 O n -g oi n g Cli nical 
St u dies
K E Y N O T E -2 5 2/ E C H O - 3 0 1 relate d te xt 
i nserte d
5. 1 O verall Desi g n
I nserte d n ote t hat e nr oll me nt was st o p pe d; 
st u d y treat me nt will be u n bli n de d after last 
partici pa nt c o m pletes Wee k 9
i ma gi n g
assess me nt f or efficac y  a nal ysis; t hereafter all 
st u d y efficac y pr oce d ures will st o p after Wee k 
9 a n d t hereafter will be perf or me d as per l ocal 
S o C. 
5. 1. 2 St u d y  Dia gra m
Fi g ure 1 – A d diti o n of f o ot n ote t hat t he st u d y  
will be u n bli n de d after t he last partici pa nt 
c o m pletes t he Wee k 9 i ma gi n g assess me nt f or 
efficac y a nalys is, t hat partici pa nts ca n c h o ose 
t o c o nti n ue treat me nt as per pr ot oc ol after 
disc ussi o n wit h t he i n vesti gat or , a n d t hat n o 
place b o will be a d mi nistere d after u n bli n di n g. 
T he last st u d y  visit will be t he Safety F U visit.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 2 N u m ber of Partici pa nts
A d diti o n of n ote t hat as of 0 2 -M A Y - 2 0 1 8 
e nr oll me nt was st o p pe d a n d t hat a p pr o xi matel y 
1 0 0 partici pa nts will be ra n d o m ize d i n t he 
st u d y
7. 1 Treat me nts A d mi nistere d
A d diti o n of n ote t hat partici pa nts w h o c o nti n ue 
st u d y treat me nt after u n bli n di n g will n o l o n ger 
be dis pe nse d e paca d ostat place b o
7. 2. 2 Sec o n d C o urse P hase 
( Retreat me nt)
A d diti o n of n ote t hat as of A me n d me nt 0 4, 
disease assess me nt will be perf or me d b y t he 
i n vesti gat or per l ocal S o C g ui deli nes; place b o 
will n ot be a d mi nistere d after u n bli n di n g. T his 
secti o n has bee n u p date d acc or di n gly. C ha n ge d 
i ma gi n g re q uire me nt fr o m c o nfir me d t o 
e val uate d b y i n vesti gat or. D elete d refere nce t o 
place b o, a n d s pecifie d pe m br oliz u ma b 
m o n ot hera p y. 
7. 4 Bli n di n g
A d diti o n of te xt t hat t he st u d y  will be 
u n bli n de d after t he last partici pa nt c o m pletes 
t he Wee k 9 i ma gi n g assess me nt f or efficac y 
a nal ys is, a n d t hat after u n bli n di n g f or 
partici pa nts c o nti n ui n g st u d y  treat me nt t he 
partici pa nt, st u d y site pers o n nel, S p o ns or a n d 
M S D or desi g nee will be i nf or me d of 
t he 
st u d y treat me nt t he y recei ve.
9. 2. 1
T u m or I ma gi n g a n d 
Assess me nt of Disease
A d diti o n of n ot e t hat ce ntral re vie w of i ma gi n g 
a n d i R E CIS T is n o l o n ger a p plica ble.  Secti o n 
u p date d acc or di n gl y.
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
9. 2. 1. 1 I nitial T u m or I ma gi n g
A d diti o n of n ote t hat ce ntral re vie w of i ma gi n g 
is n o l o n ger a p plica ble.  Secti o n u p date d 
acc or di n gl y.
9. 2. 1. 2 T u m or I ma gi n g D uri n g 
t he St u d y
A d diti o n of n ote t hat ce ntral re vie w of i ma gi n g 
a n d i R E CIS T is n o l o n ger a p plica ble.  N o 
f urt her i ma gi n g will be re q uire d after t he first 
o n -st u d y i ma gi n g assess me nt at Wee k 9. 
Secti o n u p date d acc or di n gl y 
I nserte d te xt t hat a n y f urt her i ma gi n g f or 
disease assess me nts will be perf or me d per 
l ocal S o C g ui deli nes a n y f urt her i ma gi n g f or 
disease assess me nts will be perf or me d b y site 
i n vesti gat or/ra di ol o g y assess me nt as per l ocal 
S o C g ui deli nes; o nl y  t he date of sca ns 
perf or me d as per S o C nee ds t o be d oc u me nte d 
i n t he e C R F  
9. 2. 1. 3 E n d of Treat me nt a n d 
F oll o w -u p T u m or I ma gi n g
A d diti o n of n ote t hat t here is n o pr ot oc ol 
s pecifie d i ma gi n g after t he Wee k 9 assess me nt
f or efficac y a nalys is.  Secti o n u p date d 
acc or di n gl y.
Re m o val of refere nce t o i R E CIS T
A d diti o n of clarificati o n t hat e n d- of-treat me nt 
(E O T ) sca n will be perf or me d f or partici pa nts 
w h o disc o nti n ue st u d y  treat me nt bef ore t he 
first sc he d uled o n- st u d y i ma gi n g f or efficac y 
a nal ys is
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
9. 2. 1. 4 Sec o n d C o urse P hase 
T u m or I ma gi n g
A d diti o n of n ote t hat t he te xt i n t his secti o n is 
n o l o n ger a p plica ble; disease assess me nt will 
be perf or me d b y t he i n vesti gat or per l ocal S o C 
g ui deli nes; res ults will n ot be c ollecte d, o nl y 
t he date of sca ns perf or me d as per S o C nee ds 
t o be d oc u me nte d i n t he e C R F
1. S y n o psis
4. O bjecti ves/ H y p ot heses a n d 
E n d p oi nts
A d diti o n of n otes t o clarif y  t he sec o n dar y 
efficac y e n d p oi nt of O R R base d o n R E CIS T 
1. 1 b y  i n vesti gat or deter mi nati o n will bec o me 
t he pri mar y e n d p oi nt; safet y e n d p oi nt u p date d 
t o ali g n wit h c urre nt g ui da nce ; all ot her 
efficac y e n d p oi nts will n o l o n ger be c ollecte d 
after Wee k 9.
O R R a n d safet y o bjecti ves a n d e n d p oi nts 
re w or de d. All efficac y o bjecti ves/e n d p oi nts 
delete d.
T he st u d y  sc o pe has bee n re d uce d t o c ollect 
preli mi nar y  efficac y data f or c o m bi nati o n 
treat me nt i n t his U C i n dicati o n.
W here deleti o n of te xt c o ul d ca use c o nf usi o n, 
d ue t o t he desi g n of t he st u d y  t o date, t he te xt 
has bee n left u nc ha n ge d a n d a n ote has bee n 
a d de d
2. 1 I nitial Treat me nt P hase
I ma gi n g/ b o ne sca n assess me nts after Wee k 9 
c ha n ge d t o as per S o C
2. 2 Sec o n d C o urse P hase
C ha n ge d c ollecti o n ti mi n g of t u m or i ma gi n g, 
b o ne sca ns t o as per S o C ; o nl y t he date of 
sca ns perf or me d as per S o C nee ds t o be 
d oc u me nte d i n t he e C R F
Delete d r o w f or P R Os a n d f o ot n otes re gar di n g 
f oll o w-u p visits
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1 O verall Desi g n
I nserte d n ote t hat t he pri mar y o bjecti ve will 
e val uate t he e n d p oi nt of O R R base d o n 
R E CI S T 1. 1, as assesse d b y  t he i n vesti gat or; 
all ot her efficac y e n d p oi nts will n o l o n ger be 
c ollecte d.
Delete d refere nce s t o BI C R P F S, D C R, D O R 
a n d i R E CIS T.
5. 4. 1. 1 Efficac y  E n d p oi nts  
A d diti o n of n ote t hat t he pri mar y e n d p oi nt will 
be O R R base d o n R E CI S T 1. 1 as assesse d b y  
t he i n vesti gat or; tra ns missi o n of i ma ges f or 
ce ntral re vie w is n o l o n ger re q uire d.  After t he 
Wee k 9 i ma gi n g,
all ot her efficac y e n d p oi nts 
will n o l o n ger be c ollecte d or perf or me d.  
Deleti o n of all te xt relati n g t o P F S, O S, D C R, 
D O R
5. 4. 1. 1. 2
M o difie d R E CI S T 
f or I m m u ne-base d 
T hera pe utics (i R E CI S T)
A d diti o n of n ote t hat t his secti o n is n o l o n ger 
a p plica ble; i R ECI S T data will n o l o n ger be 
c ollecte d.  Partici pa nts wit h ra di o gra p hic 
disease pr o gressi o n as deter mi ne d b y  R E CI S T 
1. 1 will disc o nti n ue fr o m t he st u d y a n d be 
f oll o we d f or safety m o nit ori n g, as detaile d i n 
Secti o n 9. 3; n o c o nfir mat or y  sca ns are 
re q uire d.
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 4. 1. 3 Rati o nale f or Patie nt 
Re p orte d O utc o mes
9. 2. 2
Patie nt Re p orte d 
O utc o mes
A d diti o n of n ote t hat P R O assess me nts will n o 
l o n ger be c ollecte d after t he first o n -st u d y 
i ma gi n g assess me nt at Wee k 9
9. 2. 1. 6 i R E CIS T Assess me nt 
of Disease &
A p pe n di x 8
A d diti o n of n ote t hat t his secti o n is n o l o n ger 
a p plica ble; i R E CIS T data will n o l o n ger be 
c ollecte d.  Partici pa nts wit h ra di o gra p hic 
disease pr o gressi o n as deter mi ne d b y  R E CI S T 
1. 1 will disc o nti n ue fr o m t he st u d y a n d be 
f oll o we d f or safety m o nit ori n g, a s detaile d i n 
Secti o n 9. 3; n o c o nfir mat or y  sca ns are 
re q uire d.
1 0 Statistical A nal y sis Pla n
W h ole secti o n re vise d t o reflect c ha n ges i n 
o bjecti ves a n d e n d p oi nts
1. 0 S y n o psis
Deleti o n of t e xt relati n g t o f oll o w -u p of 
partici pa nts t hat disc o nti n ue treat me nt f or 
reas o ns ot her t ha n disease pr o gressi o n.
T he fi nal visit i n t he st u d y  will be t he Safety 
F oll o w -u p Visit.  T here will be n o f oll o w -u p f or 
s ur vi val stat us.  Partici pa nts c urre ntly i n f oll o w -
u p or i n s ur vi val f oll o w- u p are c o nsi dere d t o 
ha ve c o m plete d t he st u d y.  H o we ver, sta n dar d 
safety re p orti n g s h o ul d c o nti n ue, as a p plica ble.
2. 1 I nitial Treat me nt P hase & 
2. 2 Sec o n d C o urse P hase 
( Retreat me nt) S o As
Deleti o n of c ol u m ns f or F oll o w -u p a n d 
S ur vi val F oll o w- u p.  Deleti o n of r o w f or 
s ur vi val stat us assess me nt.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1 O verall Desi g n
A d diti o n of n ote t hat t he last st u d y  visit is t he 
Safet y  F oll o w-u p Visit. Deleti o n of te xt 
relati n g t o f oll o w- u p i ma gi n g f or partici pa nt 
w h o disc o nti n ue treat me nt f or reas o ns ot her 
t ha n disease pr o gressi o n
8. 2
Wit h dra wal fr o m t he St u d y
Deleti o n of te xt i n dicati n g t hat partici pa nts
w h o disc o nti n ue/ wit h dra w 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 
S ur vi val stat us
8. 3 L ost t o F oll o w - u p
A d diti o n of a n ote t hat t his is n o l o n ger 
a p plica ble.  T here will be n o a d diti o nal eff orts 
t o c o ntact partici pa nts w h o are l ost t o f oll o w -
u p.
9. 2. 1. 3 E n d of Treat me nt a n d 
F oll o w -u p T u m or I ma gi n g
Deleti o n of te xt relati n g t o i ma gi n g f oll o w - u p 
after treat m e nt disc o nti n uati o n f or reas o ns 
ot her t ha n disease pr o gressi o n.
9. 9. 5. 1 Safet y F oll o w -u p Visit
A d diti o n of n ote t hat t he last st u d y  visit is t he 
Safet y  F oll o w-u p Visit.
A d de d te xt t hat partici pa nts c urre ntl y i n 
f oll o w-u p or i n s ur vi val f oll o w -u p are 
c o nsi dere d t o ha ve c o m plete d t he st u d y; t hese 
partici pa nts are n ot re q uire d t o atte n d a n y 
f urt her visits.  Assess me nt a n d rec or di n g of 
A Es will be perf or me d as per Secti o n 9. 3.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
9. 9. 5. 2 F oll o w -U p Visits
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble.  Partici pa nts c urre ntl y i n p ost -
treat me nt f oll o w- u p are c o nsi dere d t o ha ve 
c o m plete d t he st u d y o nce t he y ha ve atte n de d 
t he Safety F oll o w -u p Visit.  Assess me nt a n d 
rec or di n g of A Es will be perf or me d as per 
Secti o n 9. 3.
9. 9. 5. 3 S ur vi val F oll o w - u p
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble.  Partici pa nts c urre ntl y i n S ur vi val 
F oll o w -u p are c o nsi dere d t o ha ve c o m plete d 
t he st u d y; t hese partici pa nts will n o l o n ger be 
c o ntacte d f or s ur vi val i nf or mati o n.  
Assess me nt a n d rec or di n g of A Es will c o nti n ue 
as per Secti o n 9. 3.
9. 9. 6 S ur vi val Stat us
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble; s ur vi val data is n o l o n ger bei n g 
c ollecte d.
1. S y n o psis
5. 4. 2
Rati o nale f or t he Use 
of C o m parat or/ Place b o
A d diti o n of n ote t hat t he st u d y will be 
u n bli n de d after t he last partici pa nt c o m pletes 
Wee k 9 i ma gi n g assess me nt f or efficac y  
a nal ys is.  Partici pa nts o n t he pe m br oliz u ma b 
pl us place b o ar m w h o wa nt t o c o nti n ue st u d y  
treat me nt s per pr ot oc ol a n d are c o nsi der e d t o 
recei ve cli nical be nefit will n o l o n ger recei ve 
place b o.
N o l o n ger necessar y  t o c o nti n ue wit h place b o 
after u n bli n di n g a n d c ollecti o n of efficac y  data.
1. S y n o psis - Esti mate d 
D urati o n of St u d y
C ha n ge d t o 3 6 m o nt hs f or esti mate d d urati o n 
of st u d y
T o ali g n wit h st u d y K E Y N O T E - 6 9 8
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
2. 1 I nitial Treat me nt P hase
2. 2 Sec o n d C o urse P hase 
( Retreat me nt P hase)
9. 9. 2 Treat me nt Peri o d
A d de d t hat e paca d ostat wil be d ose d t wice 
dail y  (a p pr o xi matel y Q 1 2 H)
T o ali g n wit h c urre nt cli nical i nf or mati o n of 
e paca d ostat I B
2. 1 I nitial Treat me nt P hase
2. 2 Sec o n d C o urse P hase 
( Retreat me nt P hase)
A d diti o n of se nte nce t hat T otal T 3 is preferre d 
o ver Free T 3, b ut b ot h are acce pte d a n d sites 
are t o o nl y re p ort o ne T 3 la b.
Clarificati o n a b o ut t h y r oi d la b assess me nts
3. 3. 1 Be nefit / Ris ks fr o m 
E paca d ostat
C ha n ge a n u nc o m m o n ris k of I D O 1 i n hi biti o n 
t o a p ote ntial c o ncern of I D O 1 i n hi biti o n 
Ali g n me nt wit h c urre nt cli nical i nf or mati o n f or 
c urre nt e paca d ostat I B
5. 1 O verall Desi g n
5. 1. 1 Data M o nit ori n g 
C o m mittee a n d I nteri m 
A nal y ses 
Re place te xt relati n g t o i nteri m a nal ys is wit h 
te xt t hat t here is n o i nteri m a nal ysis a n d eD M C 
will perf or m o ne safet y re vie w base d o n t he 
D M C c harter
T here is n o f or mal efficac y  IA f oll o wi n g t he 
re duce d sc o pe of t he st u d y . e D M C will c o n d uct 
a safet y re vie w as per t he D M C c harter.
Secti o n 1 2, A p pe n di x 3
Data M o nit ori n g C o m mittee – te xt refere nci n g 
i nteri m data re place d wit h safety data. Deleti o n 
of te xt re gar di n g i nteri m a nal ys is of data. 
7. 2. 1 D ose M o dificati o n f or 
I m m u ne-relate d A Es
Ta ble 3 – A d de d t hat, i n case of rec urre nt 
Gra de 3 c olitis, partici pa nts will per ma ne ntl y  
disc o nti n ue treat me nt a n d ma na ge me nt wit h 
c ortic oster oi d te xt a p plie d t o all t o xicit y 
gra des .
T o ali g n wit h K E Y T R U D A ® S u m mar y  of 
Pr o d uct C haracteristics ( S m P C) a n d C o m pa n y  
C ore Data S heet ( C C D S)
C o nsiste n cy a n d ali g n me nt wit h c urre nt cli nical 
i nf or mati o n f or pe m br oliz u ma b a n d e paca d ostat
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
7. 5. 1 D ose Pre parati o n
A d diti o n of refere nce t o p har mac y  ma n ual f or 
pre parati o n of e paca d ostat i n cases w here a 
partici pa nt is u na ble t o s wall o w or has a 
fee di n g t u be
Re q uest 
7. 7. 2 Pr o hi bite d Me dicati o ns 
# 8 – mefe na mic aci d re m o ve d fr o m liste d 
pr o hi bite d U G T 1 A 9 i n hi bit ors
Ali g n me nt wit h c urre nt cli nical i nf or mati o n f or 
c urre nt e paca d ostat I B
7. 9 Cli nical S u p plies 
Discl os ure
9. 1. 1 1 Partici pa nt 
Bli n di n g/ U n bli n di n g
Re visi o n of te xt f or e mer ge nc y  u n bli n di n g 
s pecif yi n g pri nci pal i n vesti gat or, site 
pers o n nel, a n d S p o ns or pers o n nel ma y  be 
u n bli n de d s o t hat t he a p pr o priate f oll o w - u p 
me dical care ca n be pr o vi de d t o t he partici pa nt. 
A d diti o n of te xt t hat t he st u d y  will be 
u n bli n de d after t he last partici pa nt c o m pletes 
t he Wee k 9 i ma gi n g assess me nt f or efficac y 
a nal ys is a n d t hat at t he ti me of u n bli n di n g 
e ver y eff ort will be ma de t o ha ve all pe n di n g 
data e ntere d i nt o t he e C R Fs bef ore t he site is 
u n bli n de d.
T o ali g n wit h c urre nt u p date d u n bli n di n g te xt i n 
pe m br oliz u ma b
9. 1. 1 2 Cali brati o n of 
E q ui p me nt
U p date d e q ui p me nt cali brati o n la n g ua ge.
Te xt ual re visi o ns were a p plie d t o clarif y  
i n vesti gat or res p o nsi bilit y f or cali brati o n a n d 
mai nte na nc e of st u d y e q ui p me nt.
9. 9. 5. 1 Safet y F oll o w -u p Visit
U p date d Safet y F oll o w -u p Visit la n g ua ge.
T o re m o ve c o nflict f or re p orti n g A Es/ S A Es 
T hr o u g h o ut 
C orrecti o n of t y p o gra p hical, e dit orial a n d 
f or matti n g err ors.
C orrecti o n a n d c o nsiste nc y
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
T a ble of C o nte nts
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ...............................................3
1.
S y n o psis .......................................................................................................................2 4
2. 
Sc he d ule of Acti vities ( S o A) ......................................................................................2 8
I niti al Tre at me nt P h ase ..........................................................................................2 8
2. 1
Sec o n d C o urse P h ase ( Retre at me nt) .....................................................................3 3
2. 2
3.
I ntr o d ucti o n ................................................................................................................3 6
St u d y R ati o n ale .......................................................................................................3 6
3. 1
B ac k gr o u n d ..............................................................................................................3 6
3. 2
P har mace utical a n d T hera pe utic Bac k gr o u n d .....................................................3 6
3. 2. 1
I n hi biti o n of P D-1 as a Tar get f or Ca nc er ....................................................3 7
3. 2. 1. 1
I n hi biti o n of I n d olea mi ne 2, 3– Di o x y ge nase as a Tar get f or Ca ncer ............3 8
3. 2. 1. 2
C o m bi ne d I m m u ne C hec k p oi nt I n hi biti o n ...................................................3 9
3. 2. 1. 3
C o m bi nati o n of I D O 1 I nhi bit or wit h C hec k p oi nt I n hi bit or ..........................4 0
3. 2. 1. 4
O ver vie w of Ur ot helial Carci n o ma ...............................................................4 1
3. 2. 1. 5
Treat me nt f or A d va nce d/ Metastatic Ur ot helial Carci n o ma ..........................4 1
3. 2. 1. 6
Pre -cli nical a n d Cli nical St u dies ..........................................................................4 2
3. 2. 2
O n g oi n g Cli nical St u dies .....................................................................................4 2
3. 2. 3
Be nefit/ Ris k Assess me nt .........................................................................................4 3
3. 3
Be nefits/ Ris ks fr o m E paca d ostat......................................................................... 4 3
3. 3. 1
Be nefits/ Ris ks fr o m Pe m br oliz u ma b ...................................................................4 3
3. 3. 2
Be nefits/ Ris ks f or t he C o m bi nati o n of Pe m br oliz u ma b a n d E paca d ostat ...........4 4
3. 3. 3
4.
O bjecti ves/ H y p ot he ses a n d E n d p oi nts .....................................................................4 5
5.
St u d y Desi g n ...............................................................................................................4 6
O ver all Desi g n .........................................................................................................4 6
5. 1
Data M o nit ori n g C o m mittee a n d I nteri m A nal ys es .............................................4 7
5. 1. 1
St u d y  Dia gra m .....................................................................................................4 7
5. 1. 2
N u m ber of P artici p a nts ..........................................................................................4 8
5. 2
Be gi n ni n g a n d E n d of St u d y Defi niti o n ................................................................4 8
5. 3
 
 
0 4 Y B Q D




Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Use i n N ursi n g W o me n ........................................................................................6 3
6. 3. 4
Scree n F ail ures ........................................................................................................6 3
6. 4
P artici p a nt Re pl ace me nt Str ate g y .........................................................................6 3
6. 5
7.
Tre at me nts ..................................................................................................................6 4
Tre at me nts A d mi nistere d .......................................................................................6 4
7. 1
D ose M o dific ati o n ( Esc al ati o n/ Titr ati o n/ Ot her) ..................................................6 5
7. 2
D ose M o dificati o n ............................................................................................... 6 5
7. 2. 1
Pr oce d ures f or Partici pa nts E x hi biti n g Ser ot o ni n S y n dr o me ( S S) ...............7 5
7. 2. 1. 1
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt of I nf usi o n-reacti o ns 
7. 2. 1. 2
Relate d t o Pe m br oliz u ma b ............................................................................7 7
I nterr u pti o ns U nrelate d t o A d verse E ve nts...................................................8 0
7. 2. 1. 3
Sec o n d C o urse P hase ( Retreat me nt) ....................................................................8 0
7. 2. 2
Met h o d of Tre at me nt Assi g n me nt .........................................................................8 1
7. 3
Stratificati o n .........................................................................................................8 1
7. 3. 1
Bli n di n g ....................................................................................................................8 1
7. 4
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y ....................................................8 2
7. 5
D ose Pre parati o n ..................................................................................................8 2
7. 5. 1
Ha n dli n g, St ora ge a n d Acc o u nta bilit y .................................................................8 2
7. 5. 2
Tre at me nt C o m pli a nce ...........................................................................................8 3
7. 6
A d mi nistrati o n a n d C o m plia nce of Pe m br oliz u ma b ............................................8 3
7. 6. 1
A d mi nistrati o n a n d C o m plia nce of E p aca d ostat or Matc hi n g Place b o ...............8 3
7. 6. 2
C o nc o mit a nt T her a p y .............................................................................................8 3
7. 7
Acce pta ble C o nc o mita nt Me dicati o ns .................................................................8 3
7. 7. 1
Pr o hi bite d C o nc o mita nt Me dicati o ns ...................................................................8 4
7. 7. 2
Restricte d C o nc o mita nt Me dicati o ns ...................................................................8 6
7. 7. 3
Resc ue Me dicati o ns & S u p p orti ve Care ..............................................................8 6
7. 7. 4
Tre at me nt After t he E n d of t he St u d y ..................................................................8 6
7. 8
Cli nic al S u p plies Discl os ure ...................................................................................8 6
7. 9
St a n d ar d P olicies .....................................................................................................8 7
7. 1 0
8.
Disc o nti n u ati o n/ Wit h dr a w al Criteri a ......................................................................8 7
Disc o nti n u ati o n of St u d y Tre at me nt..................................................................... 8 7
8. 1
Wit h dr a w al fr o m t he St u d y
...................................................................................8 8
8. 2
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
L ost t o F oll o w U p ....................................................................................................8 9
8. 3
9.
St u d y Assess me nts a n d Pr oce d ures.......................................................................... 8 9
A d mi nistr ati ve a n d Ge ner al Pr oce d ures ..............................................................9 0
9. 1
I nf or me d C o nse nt.................................................................................................9 0
9. 1. 1
Ge neral I nf or me d C o nse nt ............................................................................9 0
9. 1. 1. 1
I ncl usi o n/ E xcl usi o n Criteria ................................................................................9 0
9. 1. 2
Partici pa nt I de ntificati o n Car d .............................................................................9 0
9. 1. 3
Ser ot o ni n S y n dr o me I nf or mati o n Car d ................................................................9 1
9. 1. 4
Me dical Hist or y
...................................................................................................9 1
9. 1. 5
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w .......................................................9 1
9. 1. 6
Pri or Me dicati o ns ..........................................................................................9 1
9. 1. 6. 1
C o nc o mita nt Me dicati o ns .............................................................................9 1
9. 1. 6. 2
Assi g n me nt of Scree ni n g N u m ber .......................................................................9 1
9. 1. 7
Assi g n me nt of Treat me nt/ R a n d o mizati o n N u m ber .............................................9 2
9. 1. 8
Treat me nt A d mi nistrati o n ....................................................................................9 2
9. 1. 9
Ti mi n g of D ose A d mi nistrati o n ....................................................................9 2
9. 1. 9. 1
Ti mi n g of D ose A d mi nistrati o n of Pe m br oliz u ma b ..............................9 2
9. 1. 9. 1. 1
Ti mi n g of D ose A d mi nistrati o n of E paca d ostat ....................................9 2
9. 1. 9. 1. 2
Wit h dra wal/ Disc o nti n uati o n
................................................................................9 3
9. 1. 1 0
Partici pa nt Bli n di n g/ U n bli n di n g ..........................................................................9 3
9. 1. 1 1
Cali brati o n of E q ui p me nt .....................................................................................9 4
9. 1. 1 2
Effic ac y Assess me nts............................................................................................... 9 4
9. 2
T u m or I ma gi n g a n d Assess me nt of Disease ........................................................9 4
9. 2. 1
I nitial T u m or I ma gi n g...................................................................................9 5
9. 2. 1. 1
T u m or I ma gi n g D uri n g t he St u d y .................................................................9 5
9. 2. 1. 2
E n d of Treat me nt a n d F oll o w -u p T u m o r Ima gi n g ........................................9 6
9. 2. 1. 3
Sec o n d C o urse ( Retreat me nt) T u m or I ma gi n g .............................................9 6
9. 2. 1. 4
R E CI S T 1. 1 Assess me nt of Disease .............................................................9 7
9. 2. 1. 5
i R E CIS T Assess me nt of Disease ..................................................................9 7
9. 2. 1. 6
Patie nt Re p orte d O utc o mes ................................................................................1 0 1
9. 2. 2
Healt h Care Res o urce Utilizati o n ......................................................................1 0 1
9. 2. 3
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A d verse E ve nts, Seri o us A d verse E ve nts a n d Ot her Re p ort a ble S afet y 
9. 3
E ve nts .....................................................................................................................1 0 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E, S A E a n d Ot her 
9. 3. 1
Re p orta ble Safet y E ve nt I nf or mati o n ................................................................1 0 2
Met h o d of Detecti n g A E, S A E a n d Ot her Re p orta ble Safet y E ve nts ................1 0 4
9. 3. 2
F oll o w -u p of A E, S A E a n d Ot her Re p orta ble Safet y  E ve nt I nf or mati o n..........1 0 4
9. 3. 3
Re g ulat or y  Re p orti n g Re q uire me nts f or S A E ...................................................1 0 4
9. 3. 4
Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
9. 3. 5
Q ualif yi n g as A Es or S A Es ................................................................................1 0 4
Pre g na nc y  a n d E x p os ure D uri n g Breastfee di n g ................................................1 0 5
9. 3. 6
E ve nts of Cli nical I nterest ( E CI )........................................................................1 0 5
9. 3. 7
Tre at me nt of O ver d ose .........................................................................................1 0 6
9. 4
S afet y ......................................................................................................................1 0 6
9. 5
P h y sical E xa mi nati o ns .......................................................................................1 0 6
9. 5. 1
F ull P h y sical E xa mi nati o n ..........................................................................1 0 6
9. 5. 1. 1
Directe d P h ys ical E xa mi nati o n...................................................................1 0 6
9. 5. 1. 2
Vital Si g ns.......................................................................................................... 1 0 7
9. 5. 2
Electr ocar di o gra ms ............................................................................................1 0 7
9. 5. 3
Perf or ma nce Assess me nts ..................................................................................1 0 7
9. 5. 4
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 .........1 0 7
9. 5. 4. 1
Kar n ofs k y Perf or ma nce Stat us ( K P S) ........................................................1 0 7
9. 5. 4. 2
Cli nical Safet y  La b orat or y Assess me nts............................................................1 0 8
9. 5. 5
La b orat or y  Safety E val uati o ns ( He mat ol o g y, C he mistr y , 
9. 5. 5. 1
Uri nal y sis)...................................................................................................1 0 8
Pre g na nc y  Test............................................................................................1 0 8
9. 5. 5. 2
1 0 8
1 0 8
1 0 9
1 0 9
1 1 0
1 1 0
1 1 0
1 1 0
1 1 0
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
1 1 1
Visit Re q uire me nts ................................................................................................1 1 1
9. 9
Scree ni n g ............................................................................................................1 1 1
9. 9. 1
Treat me nt Peri o d ................................................................................................1 1 2
9. 9. 2
Sec o n d C o urse P hase ( Retreat me nt) ..................................................................1 1 2
9. 9. 3
Disc o nti n uati o n Visit .........................................................................................1 1 2
9. 9. 4
Disc o nti n ue d Partici pa nts C o nti n ui n g t o be M o nit ore d i n t he St u d y ................1 1 2
9. 9. 5
Safet y  F oll o w-U p Visit ...............................................................................1 1 2
9. 9. 5. 1
F oll o w -U p Visits .........................................................................................1 1 3
9. 9. 5. 2
S ur vi val F oll o w -U p ....................................................................................1 1 3
9. 9. 5. 3
U nsc he d ule d Visits ..................................................................................... 1 1 3
9. 9. 5. 4
S ur vi val Stat us ...................................................................................................1 1 3
9. 9. 6
1 0.
St atistic al A n al ysis Pl a n ..........................................................................................1 1 4
St atistic al A n al ysis Pl a n S u m m ar y...................................................................... 1 1 4
1 0. 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 5
1 0. 2
H y p ot h eses/ Esti m ati o n .........................................................................................1 1 5
1 0. 3
A n al ysis E n d p oi nts ................................................................................................1 1 5
1 0. 4
Efficac y  E n d p oi nt ..............................................................................................1 1 5
1 0. 4. 1
Pri mar y  E n d p oi nt........................................................................................1 1 5
1 0. 4. 1. 1
Safet y  E n d p oi nts................................................................................................1 1 5
1 0. 4. 2
A n al ysis P o p ul ati o ns .............................................................................................1 1 6
1 0. 5
Efficac y  A nalys is P o p ulati o n.............................................................................1 1 6
1 0. 5. 1
Safet y A nal ys is P o p ulati o n ................................................................................1 1 6
1 0. 5. 2
1 1 6
St atistic al Met h o ds ................................................................................................1 1 6
1 0. 6
Statistical Met h o ds f or Efficac y  A nalys es .........................................................1 1 6
1 0. 6. 1
O bjecti ve Res p o nse Rate ( O R R) ................................................................1 1 6
1 0. 6. 1. 1
Statistical Met h o ds f or Safet y A nal ys es ............................................................1 1 7
1 0. 6. 2
S u m maries of D e m o gra p hic a n d Baseli ne C haracteristics ................................1 1 7
1 0. 6. 3
I nteri m A n al yses ................................................................................................... 1 1 7
1 0. 7
M ulti plicit y
............................................................................................................1 1 7
1 0. 8
S a m ple Size a n d P o wer C alc ul ati o ns ..................................................................1 1 8
1 0. 9
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
2 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
S u b gr o u p A n al yses ................................................................................................1 1 8
1 0. 1 0
C o m pli a nce ( Me dic ati o n A d here nce) ..................................................................1 1 8
1 0. 1 1
E xte nt of E x p os ure ................................................................................................1 1 8
1 0. 1 2
1 1.
Refere nces .................................................................................................................1 1 9
1 2.
A p pe n dices ................................................................................................................1 3 3
A p pe n di x 1: A b bre vi ati o ns a n d Tr a de m ar ks .....................................................1 3 3
1 2. 1
A p pe n di x 2: Cli nic al L a b or at or y Tests ...............................................................1 3 7
1 2. 2
A p pe n di x 3: St u d y G o ver n a nce C o nsi der ati o ns ................................................1 3 9
1 2. 3
Merc k C o de of C o n d uct f or Cli nical Trials
...................................................................1 3 9
Fi na ncial Discl os ure .......................................................................................................1 4 1
Data Pr otecti o n ...............................................................................................................1 4 1
C o nfi de ntialit y  of Data ..................................................................................................1 4 1
C o nfi de ntialit y  of Partici pa nt Rec or ds...........................................................................1 4 1
C o nfi de ntialit y  of I R B/I E C Inf or mati o n ........................................................................1 4 2
C o m mittees Str uct ure .....................................................................................................1 4 2
Trial Steeri n g C o m mittee ...........................................................................................1 4 2
J oi nt E xec uti ve O versi g ht C o m mittee .......................................................................1 4 2
Data M o nit ori n g C o m mittee ......................................................................................1 4 2
P u blicati o n P olic y ......................................................................................................1 4 3
C o m plia nce wit h Trial Re gistrati o n a n d Res ults P osti n g Re q uire me nts .......................1 4 3
C o m plia nce wit h La w, A u di t a n d De bar me nt ...............................................................1 4 3
Data Q ualit y Ass ura nce .................................................................................................1 4 4
S o urce D oc u me nts .........................................................................................................1 4 5
St u d y  a n d Site Cl os ure...................................................................................................1 4 5
A p pe n di x 4: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or 
1 2. 4
Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g ............................................1 4 6
Defi niti o n of A E ............................................................................................................1 4 6
Defi niti o n of S A E ..........................................................................................................1 4 7
A d diti o nal E ve nts re p orte d i n t he sa me ma n ner as S A E ...............................................1 4 8
Rec or di n g A E a n d S A E .................................................................................................1 4 8
Re p orti n g of A E, S A E, a n d Ot her Re p orta ble Safet y  E ve nts t o M S D ..........................1 5 1
A p pe n di x 5: C o ntr ace pti ve G ui d a nce a n d Pre g n a nc y Testi n g .........................1 5 3
1 2. 5
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
2 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
C o ntrace pti o n Re q uire me nts ..........................................................................................1 5 4
Pre g na nc y  Testi n g..........................................................................................................1 5 5
A p pe n di x 6:  Ne w Y or k He art Ass oci ati o n ( N Y H A) F u ncti o n al 
1 2. 6
Cl assific ati o n ..........................................................................................................1 5 6
A p pe n di x 7: E C O G a n d K ar n ofs k y Perf or m a nce Assess me nts .......................1 5 7
1 2. 7
A p pe n di x 8: Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of 
1 2. 8
Dise ase Pr o gressi o n ...............................................................................................1 5 9
 
 
0 4 Y B Q D




Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
LI S T O F FI G U R E S
Fi g ure 1
St u d y  Desi g n.........................................................................................................4 7
Fi g ure 2
Best C ha n ge Fr o m Baseli ne i n T u m or Size, K E Y N O T E -0 5 2 ............................. 4 9
Fi g ure 3
I ma gi n g a n d Treat me nt f or Cli nicall y Sta ble Partici pa nts after First 
Ra di ol o gic E vi de nce of P D Assesse d b y t he I n vesti gat or ..................................1 0 0
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
1.
S y n o psis
Pr ot oc ol Title:  
P h ase 3 R a n d o mize d, D o u ble -bli n d Tri al of Pe m br oliz u m a b ( M K -3 4 7 5) i n 
C o m bi n ati o n wit h E p ac a d ost at (I N C B 0 2 4 3 6 0) or Pl ace b o i n P artici p a nts wit h 
Cis pl ati n -i neli gi ble Ur ot heli al C arci n o m a ( K E Y N O T E-6 7 2/ E C H O - 3 0 7)
S h ort Title: 
P h ase 3 St u d y of Pe m br o liz u ma b wit h /wit h o ut E paca d ostat i n 1 L Ur ot helial Carci n o ma
O bjecti ves/ H y p ot hes es a n d E n d p oi nts:
I n male/fe male partici pa nt s of at least 1 8 y ears of a ge wit h hist ol o gicall y c o nfir me d 
dia g n osis of a d va nce d/ u nresecta ble or metastatic ur ot helial carci n o ma ( U C):
N O T E: As of A me n d me nt 0 4 , t he pri mar y e n d p oi nt of t he st u d y will be o bjecti ve res p o nse 
rate ( O R R) base d o n Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CIS T 1. 1) as 
assesse d b y t he i n vesti gat or. A sec o n dar y  e n d p oi nt will e val uate t he safet y a n d t olera bilit y 
of partici pa nts trea te d wit h pe m br oliz u ma b pl us e paca d ostat vers us t h ose treate d wit h 
pe m br oliz u ma b pl us place b o. All ot her e n d p oi nts , i ncl u di n g i ma gi n g, will n o l o n ger be 
c ollecte d or perf or me d after t he i ma gi n g assess me nt at Wee k 9 . T his secti o n has bee n 
a me n de d acc or di n gl y . 
O bjecti ve/ H y p ot hesis
E n d p oi nt
Pri m ar y

O bjecti ve: T o esti mate t he O R R of 
pe m br oliz u ma b pl us e paca d ostat 
a n d pe m br oliz u ma b pl us place b o
base d o n R E CI S T 1. 1 b y  
i n vesti gat or deter mi nati o n.

O R R - defi ne d as t he pr o p orti o n of 
partici pa nts i n t he a nalys is p o p ulati o n 
w h o ha ve a best res p o nse of c o m plete 
res p o nse ( C R) or partial res p o nse ( P R).
Sec o n d ar y

O bjecti ve: T o e val uate t he safety 
a n d t olera bilit y of pe m br oliz u ma b 
pl us e paca d ostat vers us 
pe m br oliz u ma b pl us place b o .

A d verse e ve nts ( A Es)

St u d y  dr u g disc o nti n uati o ns d ue t o A Es
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
O ver all Desi g n:
Trial P hase
P hase III
Cli nical I n dicati o n
T he
treat me nt of partici pa nts
wit h 
cis plati n-i neli gi ble
a d va nce d/ u nresecta ble or metastatic ur ot helial c arci n o ma
P o p ulati o n
A d ult partici pa nts wit h cis plati n-i neli gi ble 
a d va nce d/ u nresecta ble or metastatic ur ot helial c arci n o ma
Trial T y p e
I nter ve nti o nal
T y pe of Desi g n
Ra n d o mize d, place b o -c o ntr olle d, m ulti-site, d o u ble-bli n d
As of A me n d me nt 0 4, t he st u d y will be un bli n de d after 
t he last partici pa nt c o m pletes Wee k 9 i ma gi n g 
assess me nt f or efficac y  a nal ysis.
T y pe of C o ntr ol
Acti ve C o ntr ol
Trial Bli n di n g
D o u ble- bli n d
N ote: As of A me n d me nt 0 4, t he st u d y  will be u n bli n de d 
w he n t he last partici pa nt c o m pletes Wee k 9 i ma gi n g; a n y 
c o nti n uati o n of st u d y  treat me nt will be u n bli n de d/o pe n -
la bel a n d as per pr ot oc ol.
Esti mate d D urati o n 
of St u d y
T he st u d y is esti mate d t o re q uire a p pr o xi matel y 3 6
m o nt hs fr o m t he ti me t he first partici pa nt si g ns t he 
i nf or me d c o nse nt u ntil t he last partici pa nt’s last st u d y-
related visit.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
N u m ber of P artici p a nt s:
A p pr o xi matel y 6 5 0 partici pa nts will be e nr olle d.
Ori gi nall y, a p pr o xi matel y 6 5 0 partici pa nts were t o be e nr olle d, b ut as of A me n d me nt 
0 4, o n 0 2- M A Y -2 0 1 8 e nr oll me nt was per ma ne ntl y  st o p pe d.  It is esti mate d t hat b y t he 
ti me t he strate gic decisi o n was ma de t o st o p e nr oll me nt t hat 1 0 0 partici pa nts will be 
ra n d o mize d i n t his st u d y.
Tre at me nt Gr o u ps a n d D ur ati o n :
Treat me nt Gr o u ps
1.
P e m br oliz u ma b 2 0 0 m g I V e very 3 wee ks ( Q 3 W)
+ e paca d ostat 1 0 0 m g P O t wice daily ( BI D )
c o nti n u o usl y
2.
P e m br oliz u ma b 2 0 0 m g I V Q 3 W + place b o P O 
BI D c o nti n u o usl y
As of A me n d me nt 0 4, t he st u d y will be u n bli n de d 
after t he last partici pa nt c o m pletes Wee k 9 
i ma gi n g. Partici pa nts ca n c h o ose t o disc o nti n ue 
fr o m t he st u d y or c o nti n ue st u d y treat me nt as per 
pr ot oc ol , if t he y are c o nsi dere d t o recei ve cli nical 
be nefit a n d after disc ussi o n wit h t he i n vesti gat or.  
N ote: Partici pa nts assi g ne d t o t he pe m br oliz u ma b 
pl us place b o ar m will recei ve pe m br oliz u ma b 
wit h o ut place b o after u n bli n di n g ..
D urati o n of 
Partici pati o n
E ac h partici pa nt will partici pate i n t he trial fr o m t he ti me 
t he partici pa nt si g ns t he i nf or me d c o nse nt f or m (I C F) 
t hr o u g h t he fi nal pr ot oc ol-s pecifie d c o ntact.  
After a scree ni n g p hase of u p t o or a p pr o xi matel y
4 2 da ys , eac h partici pa nt will be assi g ne d t o recei ve trial 
treat me nt u ntil disease pr o gressi o n, u nacce pta ble A Es, 
i nterc urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of 
treat me nt, i n vesti gat or’s decisi o n t o wit h dra w t he 
partici pa nt, n o nc o m plia nce wit h trial treat me nt or 
pr oce d u re re q uire me nts or a d mi nistrati ve reas o ns 
re q uiri n g cessati o n of treat me nt, or u ntil t he partici pa nt 
has recei ve d 3 5 a d mi nistrati o ns of pe m br oliz u ma b 
(a p pr o xi matel y 2 ye ars).  Partici pa nts w h o st o p trial 
treat me nt after recei vi n g 3 5 a d mi nistrati o ns of 
pe m b r 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 , or partici pa nts w h o attai n a 
c o m plete res p o nse ( C R) a n d st o p trial treat me nt ma y  be 
eli gi ble f or u p t o 1 7 a d diti o nal a d mi nistrati o ns of 
pe m br oliz u ma b wit h e paca d ostat or place b o
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
(a p pr o xi matel y 1 year) u p o n e x perie nci n g ra di o gra p hic 
disease pr o gressi o n.  
After t he e n d of treat me nt, eac h partici pa nt will pr ocee d 
t o Safet y F oll o w-u p a n d be f oll o we d f or t he occ urre nce 
of A Es a n d s p o nta ne o usl y re p orte d pre g na nc y as 
descri be d u n der Sect i o n 9. 3.  
A list of a b bre viati o ns use d i n t his d oc u me nt ca n be f o u n d i n A p pe n di x 1.
 
 
0 4 Y B Q D


















Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
3.
I ntr o d ucti o n
St u d y R ati o n ale 
3. 1
T here is relati vel y  li mite d be nefit fr o m first-li ne c yt ot o xic c he m ot hera p y i n partici pa nt s wit h 
a d va nce d/ u nresecta ble (i n o pera ble) or metastatic ur ot helial carci n o ma ( U C) w h o ca n n ot recei ve 
cis plati n .  Th ere are re p orts of pr o misi n g res ults wit h t he i m m u ne c hec k p oi nt i n hi bit or, 
pr o gra m me d cell deat h ( P D-1) , pe m br oliz u ma b ( M K -3 4 7 5) , a n d ot her a nti -P D -1 pat h wa y  a ge nts 
i n t his patie nt p o p ulati o n [ P o wles, T., et al 2 0 14] .  T he c urre nt a p pr oac h will atte m pt t o e xte n d 
t he n u m ber of partici pa nts w h o de vel o p a n i m m u ne res p o nse b y t ar geti n g P D - 1 wit h 
pe m br oliz u ma b ( M K -3 4 7 5), a n d t he tr ypt o p ha n -cata b olizi n g e nz yme i n d olea mi ne 2, 3 
di o x y ge nase - 1 (I D O 1) i n hi bit or, e paca d ostat (f or merl y IN C B 0 2 4 3 6 0) .  B ot h ID O 1 a n d P D -1 
ha ve bee n s h o w n t o s u p press T- cell -me diate d a ntit u m or i m m u nit y ; a n d I DO 1 a n d t he P D -1 
li ga n d, P D-L 1, ha ve bee n s h o w n t o be c oe x presse d i n m ulti ple ca ncer t y pes a n d t o c orrelate wit h 
p o or pr o g n osis.  P D -L 1 a n d I D O 1 are ga m ma -i nterfer o n res p o nsi ve ge nes t hat are ofte n 
s u b verte d i n ta n de m by t u m or cells.  F urt her, tri g geri n g a n a nti -t u m or i m m u ne res p o nse wit h 
pe m br oliz u ma b ma y  be li mite d b y t he i n d ucti o n of t he n or mal c o u nter re g ulat or y pat h wa y I DO 1.  
C o m bi ne d i n hi biti o n of b ot h pat h wa y s ma y t heref ore lea d t o greater i n d ucti o n of a ntit u m or 
i m m u nit y a n d t o i ncrease d efficac y.  Res p o nse data f or partici pa nt s wit h a d va nce d or metastatic 
U C fr o m t he o n g oi n g Phase 1/ 2 st u d y  IN C B 2 4 3 6 0 -2 0 2 ( K E Y N O T E -0 3 7) , is e nc o ura gi n g wit h a 
hi g h O R R t hat e xcee ds m o n ot hera p y wit h P D -1 i n hi bit ors a n d a p pears d ura ble base d o n P hase 2
res p o n ders.  T he prese nt st u d y will e xa mi ne t he c o m bi nati o n of pe m br oliz u ma b a n d e paca d ostat 
vers us pe m br oliz u ma b a n d place b o as first-li ne t hera py i n cis plati n -i neli gi ble partici pa nts wit h 
a d va nce d or metastatic U C .
B ac k gr o u n d
3. 2
Refer t o t he res pecti ve I nvesti 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 pe m br oliz u ma b [I B E diti o n 1 5 2 0 1 7] a n d e paca d ostat [IB E diti o n 1 0, 2 0 1 7 ] .
P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d
3. 2. 1
Pe m br oliz u ma b is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y  ( m A b) 
wit h hi g h s pecificit y  of bi n di n g t o t he P D-1 rece pt or, t h us i n hi biti n g its i nteracti o n wit h 
pr o gra m me d cell deat h li ga n d 1 ( P D -L 1) a n d pr o gra m me d cell deat h li ga n d 2 ( P D -L 2).   
E paca d ostat re prese nts a n o vel, p ote nt, a n d selecti ve i n hi bit or of t he e nz y me (I D O 1 i n b ot h 
h u ma n t u m or cells a n d h u ma n de n dritic cells.  F or a t h or o u g h disc ussi o n of t he p har mac ol o g y  of 
pe m br oliz u ma b a n d e paca d ostat, refer t o t he pe m br oliz u ma b I B [IB E diti o n 1 5 2 0 1 7] a n d t he 
e paca d ostat I B [IB E diti o n 1 0, 2 0 1 7 ] .
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 on has bee n k n o w n f or deca des [ Disis, M. L. 2 0 1 0].  T he i na bilit y of t he i m m u ne 
s yste m t o c o ntr ol t u m or gr o wt h d oes n ot a p pear t o res ult fr o m a n i na bilit y t o rec o g nize t he t u m or 
as f orei g n.  T u m or cells ha ve bee n s h o w n t o e va de i m m u ne destr ucti o n des pite dis pla y i n g 
rec o g niza ble a nti ge ns o n t heir s urface a n d des pite t he prese nce of hi g h a vi dit y T cells t hat are
s pecific f or t hese a nti ge ns [ B o o n, T. 1 9 9 6] [Erc oli ni, A. M., et al 2 0 0 5].  Hist ol o gic e val uati o n of 
ma n y  h u ma n ca ncers s h o ws e xte nsi ve i nfiltrati o n b y infla m mat or y  a n d i m m u ne cells [ Gal o n, J., 
et al 2 0 0 6] , s u g gesti n g t hat t he i m m u ne s yste m res p o n ds less effecti vel y t o mali g na nc y.  T hese 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
o bser vati o ns ha ve le d t o t he h y p ot hesis t hat d o mi na nt mec ha nis ms of i m m u ne t olera nce or 
i m m u ne s u p pressi o n are res p o nsi ble f or t he i m m u ne s yste m's i na bilit y t o effecti vely res p o n d i n a 
w a y  t hat c o nsiste ntl y res ults i n rejecti o n.
T her e are a n u m ber of i n hi bit or y mec ha nis ms t hat ha ve bee n i de ntifie d t o be i n v ol ve d i n t u m or 
me diate d i m m u ne s u p pressi o n a n d i ncl u de e x pressi o n of P D -L 1 , w hic h ca n e n ga ge t he i n hi bit or y 
rece pt or P D-1 o n acti vate d T cells; t he prese nce of t he tr y pt o p ha n -cata b o lizi n g e nz yme I D O 1, 
w hic h e x p oses t he e x q uisite se nsiti vit y  of T cells t o tr ypt o p ha n de pleti o n a n d tr y pt o p ha n 
meta b olites; a n d i nfiltrati o n wit h F o x P 3 + T -re gs, w hic h ca n me diate e xtri nsic s u p pressi o n of 
effect or T -cell f u ncti o n. T heref ore, a ge nts t hat tar get t hese ne gati ve re g ulat or y  pat h wa ys a n d 
t here by all o w t he e x pa nsi o n of effect or T cells prese nt i n t he t u m or ma y be be neficial i n t he 
cli nic.
I n hi biti o n of P D-1 as a T ar get f or C a ncer
3. 2. 1. 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 sti m ulate d b y t u m ors t o s u p press 
i m m u ne c o ntr ol.  T he n or mal f u ncti o n of P D-1, e x presse d o n t he cell s urface of acti vate d T cells 
u n der healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or e xcessi ve i m m u ne res p o nses, 
i ncl u di n g a ut oi m m u ne reacti o ns.  P D-1 (e nc o de d b y  t he ge ne P dc d 1) is a n i m m u n o gl o b uli n (I g) 
s u perfa mily me m ber relate d t o cl uster of differe ntiati o n 2 8 (C D 2 8 ) a n d c yt ot o xic 
T- l ym p h oc y t e-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 a n d/ or P D -L 2) [ Tal ma d ge, J. 
E., et al 2 0 0 7] [ Us u b üt ü n, A., et al 1 9 9 8] .  T he 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 LA- 4, as b ot h m olec ules re g ulate a n 
o verla p pi n g set of si g nali n g pr otei ns [ Parr y, R. V., et al 2 0 0 5] [ Fra ncisc o, L. M., et al 2 0 1 0] .  
P D -1 has bee n s h o w n t o be e x presse d o n acti vate d l y m 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 -regs, a n d nat ural killer cells [ H o di, F. S. a n d Dra n off, G. 2 0 1 0].  
E x pressi o n ha s als o bee n s h o w n d uri n g t hy m ic de vel o p me nt o n C D 4-C D 8 - ( d o u ble ne gati ve) 
T- cells as well as s u bsets of macr o p ha ges a n d de n dritic cells [ Hille n, F., et al 2 0 0 8].  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 e x presse d or ca n be i n d uce d i n a variety of cell 
t ypes, i ncl u di n g n o n he mat o p oietic tiss ues as well as i n vari o us t u m ors [IB E diti o n 1 5 2 0 1 7] .  
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 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 o n 
vasc ular e n d ot heli u m, w hereas P D -L 2 pr otei n is o nl y  detecta bly e x 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 e n vir o n me nts.  P D -L 2 is t h o u g ht t o 
c o ntr ol i m m u ne T -cell acti vati o n i n l ym p 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 uncti o n i n peri p heral tiss ues [ N o bili, C., et al 2 0 0 8].  Alt h o u g h healt hy 
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.  P D -1 has bee n s u g geste d t o re g ulate t u m or-s pecific T-cell 
e x pa nsi o n i n partic ipa nt s wit h mela n o ma [ Li otta, F., et al 2 0 1 1].  T his s u g gests t hat t he P D-
1/ P D -L 1  pat h wa y pla ys a critical r ole i n t u m or i m m u ne e vasi o n a n d s h o ul d be c o nsi dere d as a n 
attracti ve tar get f or t hera pe utic i nter ve nti o n.
T he str uct ure of m uri ne P D -1 has bee n res ol ve d [ Z ha n g, X., et al 2 0 0 4].  P D-1 a n d its fa mil y  
me m bers are t y pe I tra ns me m bra ne gl yc o pr otei ns c o ntai ni n g a n I m m u n o gl o b ul i n (Ig)- varia ble –
t ype (I g V t y pe) d o mai n res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic tail res p o nsi ble f or t he 
bi n di n g of si g nali n g m olec ules.  T he c y t o plas mic tail of P D-1 c o ntai ns 2 t yr osi ne -base d 
si g nali n g m otifs, a n i m m u n orece pt or t yr osi ne-base d i n hi biti o n m otif, a n d a n i m m u n orece pt or 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
t yr osi ne-base d s witc h m otif.  F oll o wi n g T -cell sti m ulati o n, P D -1 recr uits t he t yr osi ne 
p h os p hatases, S H P -1 a n d S H P -2, t o t he i m m u n orece pt or t yr osi ne -base d s witc h m otif wit hi n its 
c yt o plas mic tail, lea di n g t o t he de p h os p h or ylati o n of effect or m olec ules s uc h as C D 3 zeta 
( C D 3ζ), pr otei n ki nase C-t heta ( P K C θ), a n d zeta-c hai n -ass ociate d pr otei n ki nase ( Z A P 7 0), 
w hic h are i n v ol ve d i n t h e C D 3 T -cell si g nali n g casca de [ O kazaki, T., et al 2 0 0 1] [ C he m nitz, J. 
M., et al 2 0 0 4] [ S he p par d, K -A, et al 2 0 0 4] [ Rile y, J. L . 2 0 0 9].  T he mec ha nis m b y w hic h P D-1 
d o w n -m o d ulates T cell res p o nses is si milar t o, b ut disti nct fr o m, t hat of C T L A - 4, beca use b ot h 
m olec ules re g ulate a n o verla p p i n g set of si g nali n g pr otei ns [ Parr y, R. V., et al 2 0 0 5] [ Fra ncisc o, 
L. M., et al 2 0 1 0] .  As a c o nse q ue nce, t he P D-1/ P D -L 1 pat h wa y  is a n attracti ve tar get f or 
t hera pe utic i nter venti o n i n U C .
Base d o n prec li nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or bl oc ki n g 
acti vit y f or P D-1.  Pe m br oliz u ma b has a n acce pta ble precli nical safet y pr ofile a n d is i n cli nical 
de vel o p me nt as a n i ntra ve n o us (I V) i m m u n ot hera p y  f or a d va nce d mali g na ncies.  K E Y T R U D A ®
( pe m br oliz u ma b) is i n dicate d f or t he treat me nt of partici pa nt s acr oss a n u m ber of mali g na ncies .  
F or m ore details o n s pecific i n dicati o ns refer t o t he I B [IB E diti o n 1 5 2 0 1 7] .
I n hi bitio n of I n d ole a mi ne 2, 3– Di o x y ge n ase as a T ar get f or C a ncer
3. 2. 1. 2
Rece nt i nterest has f oc use d o n t he r ole of I D O 1 as a mec ha nis m of i n d ucti o n of t olera nce t o 
mali g na nc y  [ G o di n-Et hier, J., et al 2 0 1 1] .  ID O 1 is a he me -c o ntai ni n g, m o n o meric 
o xi d ore d uctase t hat catal yzes t he de gra dati o n of t he esse ntial a mi n o aci d tr y pt o p ha n t o N -
f or m yl-k y n ure ni ne.  K y n ure ni ne ca n be s u bse q ue ntl y  meta b olize d t hr o u g h a series of e nz ymatic 
ste ps t o nic oti na mi de a de ni ne di n ucle oti de.  I D O 1 is t he fir st rate-li miti n g e nz yme i n o ne of t he 
brea k d o w n pat h wa y s of tr ypt o p ha n.  I n a n ot her pat h wa y , tr ypt o p ha n h y dr o x y lase catalys is of 
tr ypt o p ha n lea ds t o t he f or mati o n of ser ot o ni n a n d melat o ni n.  
T he e x pressi o n a n d acti vit y  pr ofiles of I D O 1 are disti nct fr o m t h ose of tr ypt o p ha n di o x y ge nase, 
a n e nz yme pre d o mi na ntl y  e x presse d i n li ver t hat catalyz es t he sa me e nz y matic reacti o n as I D O 1 
a n d mai ntai ns pr o per tr y pt o p ha n bala nce i n res p o nse t o dietar y u pta ke.  I n c o ntrast t o tr y pt o p ha n 
di o x y ge nase, I D O 1 is e x presse d i n a variety of tiss ues, wit h partic ularl y hi g h le vels f o u n d i n 
areas of c o ntact wit h p ote ntial s o urces of i m m u ne c halle n ge (e g, g ut, res pirat or y tract, place nta, 
s plee n), c o nsiste nt wit h a r ole f or re g ulati n g tr ypt o p ha n meta b olis m i n a l ocal micr oe n vir o n m e nt 
[ Mell or, A. L. 2 0 0 4].  Wit hi n t he i m m u ne s yste m, I D O 1 acti vit y is s pecificall y i n d uce d i n cells 
s uc h as de n dritic cell s a n d macr o p ha ges at l oc alize d sites of i nfla m mati o n [ M u n n, D. H. 2 0 0 7].  
I DO 1 dri ve n o xi dati o n of tr y pt o p ha n res ults i n a str o n g i n hi bit or y  effect o n t he de vel o p me nt of 
T- cell me diate d res p o nses b y  bl oc ki n g T-cell acti vati o n a n d i n d uci n g T -cell a p o pt osis [ Mell or, 
A. L ., et al 2 0 0 3].  B ot h t he re d ucti o n i n l ocal tr y pt o p ha n le vels a n d t he pr o d ucti o n of tr y pt o p ha n 
cata b olites t hat are i n hi bit or y t o cell pr oliferati o n c o ntri b ute t o t he i m m u n os u p pressi ve effects 
[ Fr ume nt o, G., et al 2 0 0 2] .  ID O 1 acti vit y  als o pr o m otes t he differe ntiati o n of nai ve T cells t o T-
re gs [ Fallari n o, F., et al 2 0 0 6].  Si nce i ncrease d T-re g acti vity has bee n s h o w n t o pr o m ote t u m or 
gr o wt h a n d T -r eg de pleti o n has bee n s h o w n t o all o w a n ot her wise i neffect ual a ntit u m or i m m u ne 
res p o nse t o occ ur [ Z o u, W. 2 0 0 6], ID O 1 e x pa nsi o n of T -re gs ma y pr o vi de a n a d diti o nal 
mec ha nis m w here b y I DO 1 c o ul d pr o m ote a n i m m u n os u p pressi ve e n vir o n me nt.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
T he bi ol o gical rele va nce of I D O 1 i n hi biti o n t o i m m u ne t olera nce was first de m o nstrate d w he n it 
was s h o w n t hat treati n g mice wit h a s mall m olec ule i n hi bit or of t he I D O 1 pat h wa y , 
1- met h y l-tr ypt o p ha n, c o ul d brea k t he t oler o ge nic state t hat pr otects all o ge neic c o nce pti fr o m t he 
mater nal i m m u ne s ys te m [ M u n n, D. H., et al 1 9 9 8].  A critical r ole f or I D O 1 i n 
i m m u n o m o d ulati o n has bee n c o nfir me d i n n u mer o us a ni mal m o dels, i ncl u di n g m o dels of 
all o gra ft t olera nce, i nfla m mati o n, a n d ca ncer [ Mell or, A. L. 2 0 0 4].  W hile I D O 1 i n hi biti o n ca n 
e xacer bate disease i n m o d els of a ut oi m m u ne dis or ders [ Mell or, A. L. 2 0 0 4], I D O1 n ull mice 
s h o w n o e vi de nce of s usce pti bilit y t o de vel o pi n g s p o nta ne o us a ut oi m m u nit y or alterati o ns in 
i m m u ne s yste m de vel o p me nt [ Mell or, A. L., et al 2 0 0 3], s u g gesti n g t hat I D O 1 i n hi biti o n, i n a 
t hera pe utic setti n g, ma y pr o d uce mi ni mal si de effects i n partici pa nt s wit h o ut pre-e xisti n g 
a ut oi m m u ne c o n diti o ns.
Wit hi n t he c o nte xt of ca ncer, t here are se veral li nes of e vi de nce t o s u g gest t hat I D O 1 is a ke y 
re g ulat or of t he i m m u n os u p pressi ve mec ha nis ms res p o nsi ble f or t u m or esca pe fr o m i m m u ne 
s ur veilla nce.  Se veral gr o u ps ha ve de m o nstrate d t hat bl oc ka de of I D O 1 acti vit y ca n directly 
i nfl ue nce t he a bilit y of t u m or-beari n g a ni mals t o reject t u m ors [ U ytte n h o ve, C., et al 2 0 0 3] 
[ M uller, A. J., et al 2 0 0 5].  In a d diti o n, st u dies wit h 1 -met h y l-tr ypt o p ha n, de m o nstrate t hat I D O 1 
i n hi biti o n dra maticall y i ncreases t he efficac y of vari o us c he m ot hera pe utic a ge nts (e g, plati n u m 
c o m p o u n ds, ta xa ne deri vati ves, c ycl o p h os p ha mi de) wit h o ut i ncrease d t o xicit y  [ M uller, A. J., et 
al 2 0 0 5] .  Alt h o u g h t he s pecific mec ha nis ms res p o nsi ble f or t his p ote ntiati o n re mai n t o be f ully 
el uci date d, t he effe cts were n ot o bser ve d i n T -cell deficie nt a ni mals, s u g gesti n g t hat t he res ults 
ma y  be t he c o nse q ue nce of t he disa ble me nt of i m m u n os u p pressi ve mec ha nis ms t hat e xist wit hi n 
t he t u m or micr oe n vir o n me nt.
Base d o n st u dies e xa mi ni n g ser u m le vels of tr y pt o p ha n a n d k y n ure ni ne, I D O 1 a p pears t o be 
c hr o nicall y acti vat e d i n partici pa nt s wit h ca ncer, a n d I D O 1 acti vati o n c orrelates wit h m ore 
e xte nsi ve disease [ H ua n g, L., et al 2 0 1 0], [ Wei nlic h, G., et al 2 0 0 7].  ID O 1 has s u bse q ue ntl y
bee n f o u n d t o be o vere x presse d b y a wi de variet y of h u ma n t u m or cell t y pes as well as b y t he 
D Cs t hat l ocalize t o t he t u m or drai ni n g ly m p h n o des [ U ytte n h o ve, C., et al 2 0 0 3].  Increase d 
e x pressi o n of I D O 1 i n t u m or cells has bee n s h o w n t o be a n i n de pe n de nt pr o g n ostic varia ble f or 
re d uce d O S i n partici pa nt s wit h mela n o ma, o varia n, c ol orectal, a n d pa ncreatic ca ncers 
[ O ka m ot o, A., et al 2 0 0 5] [ Bra n dac her, G., et al 2 0 0 6] [I n o, K., et al 2 0 0 6] [ Na ka m ura, T., et al 
2 0 0 7] [ Wit kie wicz, A., et al 2 0 0 8] .  T o get her, t hese res ults s u g gest t hat t he I D O 1 pat h wa y is a 
ke y  re g ulat or y ele me nt res p o nsi ble f or t he i n d ucti o n a n d mai nte na nce of t u m or i m m u ne 
t olera nce.  S mall m olec ule i n hi bit ors of I D O 1 ma y pr o vi de a n i n n o vati ve a n d tracta ble met h o d t o 
treat a d va nce d mali g na ncies eit her al o ne or i n c o m bi nati o n wit h c he m ot hera pe utics a n d/ or 
i m m u n ot hera p y-base d strate gies.
C o m bi ne d I m m u ne C hec k p oi nt I n hi biti o n
3. 2. 1. 3
Bl oc k a de of i m m u ne i n hi bit or y pat h wa ys is e mer gi n g as a n i m p orta nt t hera pe utic m o dalit y f or 
t he treat me nt of ca ncer as e vi de nce d by t he cli nical res p o nses o bser ve d wit h a nti b o dies t o 
C T L A- 4 a n d P D -1/ P D -L 1.  I pili m u ma b, a f ull y h u ma n, I g G 1 m A b bl oc ki n g C T L A -4, i m pr o ve d 
O S i n partici pa nts wit h a d va nc e d mela n o ma [ H o di, F. S. a n d Dra n off, G. 2 0 1 0] [ R o bert, C., et al 
2 0 1 1] .  Ni v ol u ma b, a f ull y h u ma n I g G 4 a nti b o dy bl oc ki n g P D -1, pr o d uce d d ura ble o verall 
res p o nses i n partici pa nts wit h mela n o ma, r e nal cell ca ncer, a n d N S C LC [ T o palia n, S. L., et al 
2 0 1 2] [ Ha mi d, O., et al 2 0 1 3] [ W olc h o k, J. D., et al 2 0 1 0] .  Alt h o u g h t hese si n gle a ge nts ha ve 
a ntit u m or acti vit y, multi ple i m m u ne i n hi bit or y  mec ha nis ms are prese nt c o nc urre ntly wit hi n t he 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
t u m or micr oe n vir o n me nt, s u g gesti n g t hat c o m bi nati o n t hera pies ma y be re q uire d f or o pti mal 
t hera pe utic effect [ Q ueza da, S. A. 2 0 1 3].
F or e x a m ple, C T L A -4 a n d P D -1 a p pear t o pla y  c o m ple me ntar y r oles i n re g ulati n g a da pti ve 
i m m u nit y.  W hereas P D-1 c o ntri b utes t o T -cell e x ha usti o n i n peri p heral tiss ues, C T LA- 4 i n h i bits 
at earlier p oi nts i n T -cell acti vati o n.  I n precli nical m o dels, c o m bi ne d bl oc ka de of P D -1 a n d 
C T L A- 4 ac hie ve d m ore pr o n o u nce d a ntit u m or acti vit y  t ha n bl oc ka de of eit her pat h wa y al o ne 
[ C urra n, M. A., et al 2 0 1 0] [ Sel b y, M, et al 2 0 1 3].
O n t he basis of t hese o bser vati o ns, a P hase 3 st u d y  was c o n d ucte d t o i n vesti gate t he safety a n d 
efficac y of c o m bi ne d C T L A-4 a n d P D -1 bl oc ka de ( wit h t he use of i pili m u ma b a n d ni v ol u ma b, 
res pecti vely) i n pa rtici pa nts wit h a d va nce d mela n o ma.  T he o bjecti ve res p o nse rate ( O R R; 
acc or di n g t o m o difie d W orl d He alt h Or ga nizati o n criteria) f or all partici pa nt s i n t he 
c o nc urre nt- re gi me n gr o u p was 6 1 % a m o n g partici pa nt s wit h B R A F wil d-t ype t u m ors vers us 
1 1 % i n t he i pili m u ma b al o ne gr o u p. Me dia n d urati o n of res p o nse ( D O R) ha d n ot bee n reac he d 
i n eit her gr o u p. Me dia n pr o gressi o n free -s ur vi val (P F S ) ha d n ot bee n reac he d wit h t he 
c o m bi nati o n t hera p y a n d was 4. 4 m o nt hs f or i pili m u ma b m o n ot hera p y.  Gra de 3 or 4 A Es 
occ urre d i n 5 4 % of partici pa nt s i n t he c o nc urre nt-re gi me n gr o u p a n d were 2 4 % i n t he 
ipili m u ma b m o n ot he ra p y gr o u p [ P ost o w, M. A., et al 2 0 1 5].  C o m m o n Gra de 3 or 4 selecte d 
A Es t hat were relate d t o t he c o m bi nati o n t hera p y i ncl u de d c olitis ( 1 7 %), diarr hea ( 1 1 %), a n d a n 
ele vate d ala ni ne a mi n otra nsferase le vel ( 1 1 %) .  Diarr hea ( 1 1 %) was t he m ost fre q ue ntly re p orte d 
Gra de 3 or 4 A E ass ociate d wit h i pili m u ma b m o n ot hera p y , f oll o we d by c olitis ( 7 %).  In b ot h 
re gi me n gr o u ps, treat me nt-relate d a d verse e ve nt s ( T R A E) were ma na gea ble a n d ge nerall y 
re versi ble wit h t he use of im m u n os u p pressa nts ( or h or m o ne -re place me nt t hera py f or 
e n d ocri n o pat hies) acc or di n g t o pre vi o usl y esta blis he d al g orit h ms [ P ost o w, M. A., et al 2 0 1 5].
C o m bi n ati o n of I D O 1 I n hi bit or wit h C hec k p oi nt I n hi bit or
3. 2. 1. 4
As descri be d pre vi o usl y, I D O 1 is a n ot her ne gati ve re g ulat or y mec ha nis m t hat c o ntri b utes t o 
t u m or deri ve d i m m u ne s u p pressi o n.  I n precli nical m o dels, ID O 1 i n hi biti o n has bee n s h o w n t o 
s yner gi ze wit h bl oc ka de of eit her a nti C T L A -4 or a nti P D -1/ P D -L 1  i n dela yi ng t u m or gr o wt h 
a n d i ncreasi n g O S [ H ol m gaar d, R. B., et al 2 0 1 3] [ S pra n ger, S., et al 2 0 1 3].  T his effect was 
s h o w n t o be T cell de pe n de nt, lea di n g t o e n ha nce d T -cell pr oliferati o n a n d i nterle u ki n -2 
pr o d uc ti o n wit hi n t he t u m or a n d t o a mar ke d i ncrease i n t he effect or-t o-re g ulat or y T cell rati os i n 
t he t u m ors. 
T he I D O 1 i n hi bit or e paca d ostat has se veral o n g oi n g cli nical st u dies i n c o m bi nati o n wit h 
i m m u ne-tar gete d a ge nts, s uc h as a nti– P D -, a n d a nti – P D -L 1 . A st u d y wit h e paca d ostat a n d a n 
a nti – C T L A- 4 a nti b o d y  has rece ntl y c o m plete d (I N C B 2 4 3 6 0-2 0 1).   I n a n o n g oi n g P hase 1/ 2 
st u d y I N CB 2 4 3 6 0 -2 0 2 (K E Y N O T E -0 3 7 ), t he safet y, efficac y, a n d t olera bilit y of t he 
c o m bi nati o ns of e paca d ostat 2 5 m g t wice dail y (BI D ), 5 0 m g BI D, a n d 1 0 0 m g BI D wit h 
pe m br oliz u ma b 2 m g/ k g I V e ver y 3 wee ks ( Q 3 W) a n d e paca d ostat 3 0 0 m g BI D wit h 
pe m br oliz u ma b 2 0 0 m g I V Q 3 W were e val uate d i n partici pa nt s wit h Sta ge 3 B, I V or rec urre nt 
n o n -s mall cell l u n g ca ncer (N S C L C) , mela n o ma, tra nsiti o nal cell carci n o ma (T C C ), re nal cell 
carci n o ma , e n d o metrial a de n ocarci n o ma or s q ua m o us cell carci n o ma of t he hea d a n d nec k 
(S C C H N ).  In t he P hase 1 d ose -escalati o n part, e paca d ostat 5 0 m g  BI D, 1 0 0 m g BI D, a n d 
3 0 0 m g BI D wit h pe m br oliz u ma b 2 0 0 m g I V Q 3 W was e val uate d.  As of 2 7 -Fe b -2 0 1 7 a t otal of 
2 9 4 partici pa nt s were e nr olle d i n P hase 2 , a n d recei ve d ≥1 d ose of e paca d ostat a n d 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
pe m br oliz u ma b . T he m ost c o m m o n ( ≥1 0 %) all -gra de T R A Es were fati g ue, ras h, na usea , a n d 
pr urit us. Gra de ≥3 T R A Es were o bser ve d i n 1 8 % ( m ost c o m m o n: i ncrease d li pase [ 4 %] a n d 
ras h [3 %]). T here was o ne treat me nt-relate d deat h d ue t o res pirat or y fail ure, w hic h was 
sec o n dar y t o as pirati o n p ne u m o nia [ Ha mi d, O., et al 2 0 1 7].
As of 2 7 -Fe b -2 0 1 7 , a vaila ble efficac y data f or partici pa nt s e nr olle d i n t he T C C c o h ort (I N C B 
2 4 3 6 0 -2 0 2 / K E Y N O T E-0 3 7 ) was re vie we d.  T here were 4 0 e val ua ble partici pa nt s wit h a n O R R 
of 3 5 % ( 14 of 4 0 ). Of t hese, t here were 1 1 P Rs a n d 3 C Rs. At t he ti me of t he data c ut off 1 0 of 
1 4 res p o nses were still o n g oi n g.  T he disease c o ntr ol rate ( D C R) was 5 3 %, wit h 2 1 of 
4 0 partici pa nt s wit h C R, P R, or S D as t heir best o bjecti ve res p o nse.  T wel ve of t he 1 4 res p o n ders 
ha d recei ve d 1 pri or treat me nt re gi me n .  T hese res ults c o m pare fa v ora b l y t o sec o n d-li ne t hera py 
wit h pe m br oliz u ma b i n U C ( K E Y N O T E-0 4 5) , w hic h has a n O R R of 2 1. 1%.   
I n s u m mar y, b ot h I D O 1 a n d P D-1 ha v e bee n s h o w n t o s u p press T- cell me diate d a ntit u m or 
i m m u nit y, a n d I D O 1 a n d t he P D-1 li ga n d P D -L 1 ha ve bee n s h o w n t o be c oe x presse d i n m ulti ple 
ca ncer t y pes a n d t o c orrelate wit h p o or pr o g n osis.  C o m bi ne d i n hi biti o n of b ot h pat h wa ys ma y 
t heref ore lea d t o i ncrease d efficac y.  Precli nical a nd cli nical data i n dicate t hat t hese pat h wa ys are 
i m p orta nt i n mela n o ma as well as i n ot her ca ncers, i ncl u di n g U C .
O ver vie w of Ur ot heli al C arci n o m a
3. 2. 1. 5
Ur ot helial carci n o ma, als o referre d t o as T C C , descri bes a ra n ge of t u m ors t hat arise fr o m t he 
ur ot helial e n d ot heli u m, w hic h i ncl u des t he bla d der, re nal pel vis, ureter, a n d uret hra.  T he 
w orl d wi de i nci de nce of bla d der ca ncer e xcee ds 3 0 0, 0 0 0 cases a n n uall y [Je mal A, Bra y F, Ce nter 
M M, Ferla y  J, War d E, F or ma n D 2 0 1 1].  Ur ot helial carci n o ma is t he pre d o mi na nt hist ol o gic 
t ype of bla d der ca ncer i n t he U nite d States a n d Wester n E ur o pe, w here it acc o u nts f or 
a p pr o xi matel y 9 0% of bla d der ca ncers.
Tre at me nt f or A d v a nce d/ Met ast atic Ur ot heli al C arci n o m a
3. 2. 1. 6
A p pr o xi matel y  2 5 % of patie nts wit h m uscle -i n vasi ve disease eit her prese nt wit h or later de vel o p 
metastases. S y ste mic c he m ot hera p y is t he sta n dar d a p pr oac h f or t he i nitial treat me nt of patie nts
wit h i n o pera ble l ocall y a d va nce d or metastatic ur ot helial mali g na ncies. T he me dia n s ur vi val 
wit h m ulti -a ge nt c he m ot hera p y is a p pr o xi matel y  1 4 t o 1 5 m o nt hs [ v o n der Maase, H., et al 
2 0 0 5] . W hile t his is s u peri or t o t he esti mate d 6 -m o nt h s ur vi val wit h metastatic disease pri or t o 
t he de vel o p me nt of m o der n c he m ot hera p y  re gi me ns, t he 5-ye ar s ur vi val rate is a p pr o xi matel y 
1 5 % wit h c o nte m p orar y  re gi me ns.
M ore effecti ve a n d less t o xic treat me nts are greatl y nee de d i n t his patie nt p o p ulati o n, a n d 
i m m u n ot hera p y offers a d diti o nal o pti o ns f or patie nts pr o gressi n g after t heir i nitial s yste mic 
t hera py.  T he P D -1/ P D -L 1 i n hi bit ors atez oliz u ma b, pe m br oliz u ma b, ni v ol u ma b , d ur val u ma b ,
a n d a vel u ma b ha ve de m o nstrate d s o me acti vit y i n earl y cli nical st u dies a n d are c urre ntl y bei n g 
e val uate d i n ra n d o mize d cli nical trials i n patie nts wit h U C .  T hese i ncl u de trials as first- a n d 
sec o n d-li ne t hera py a n d i n t he a dj u va nt setti n g.  Atez oliz u ma b, ni v ol u ma b, d ur val u ma b, a n d 
a vel u ma b ha v e rece ntl y recei ve d accelerate d a p pr o val fr o m t he U. S. F o o d a n d Dr u g 
A d mi n istrati o n (F D A ) f or t he treat me nt of a d va nce d U C t hat has pr o gresse d d uri n g or after 
pre vi o us plati n u m -base d c he m ot hera p y.   I n a d diti o n, atez oliz u ma b recei ve d accelerate d a p pr o val 
fr o m t he U S F D A f or t he treat me nt of a d va nce d U C i n patie nts w h o are n ot eli gi ble f or 
cis p lati n-c o ntai ni n g c he m ot hera p y.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
O n 1 8 -M a y -2 0 1 7 , t he F D A gra nte d accelerate d a p pr o val t o pe m br oliz u ma b f or patie nts wit h 
l ocall y a d va nce d or metastatic U C w h o are n ot eli gi ble f or cis plati n -c o ntai ni n g c he m ot hera p y.  
A p pr o val was base d o n data fr o m a m ultice nter, o pe n -la bel, si n gle-ar m trial, K E Y N O T E -0 5 2, 
i n vesti gati n g pe m br oliz u ma b i n 3 7 0 patie nts.  T he efficac y a nalys is s h o we d a n O R R of 2 9%
( 9 5 % co nfi de nce inter val [ CI ]: 24 , 3 4), wit h a c o m plete res p o nse rate of 7% a n d a partial 
res p o nse ( P R) rate of 2 2%.
T he me dia n D O R ha d n ot bee n reac he d (ra n ge: 1. 4 + t o 1 7. 8 + 
m o nt hs). T he me dia n f oll o w -u p ti me was 7. 8 m o nt hs [ U. S. Prescri bi n g I nf or mati o n 2 0 1 7]. 
Als o o n 1 8 -M a y -2 0 1 7, t he F D A gra nte d re g ular a p pr o val t o pe m br oliz u ma b f or patie nts wit h 
l ocall y a d va nce d or metastatic U C wit h disease pr o gressi o n o n or after plati n u m -c o ntai ni n g 
c he m ot hera p y.  A p pr o val was base d o n data fr o m a m ultice nter, ra n d o mize d, acti ve -c o ntr olle d 
trial, K EY N O T E -0 4 5.  Patie nts were ra n d o mize d t o recei ve eit her pe m br oliz u ma b 2 0 0 m g Q 3 W
( n = 2 7 0) or I n vesti gat or’s c h oice of paclita xel , d oceta xel , or vi nfl u ni ne ( K E Y T R U D A ® U nite d 
States Pac ka ge I nsert , 2 0 1 7). 
A n u m ber of cli nical a n d m olec ular c haracteristics ha ve bee n s h o w n t o c orrelate wit h O S.  A 
p o or Kar n ofs k y  perf or ma nce stat us ( K P S) a n d t he prese nce of visceral (ie, p ul m o nar y, li ver, 
b o ne) metastases c orrelate wit h s h orte ne d s ur vi val i n cli nical trials. I n a retr os pecti ve 
m ulti variate re gressi o n a nal ysis of a data base
of 2 0 3 partici pa nt s wit h u nresecta ble or metastatic 
T C C, t he me dia n s ur vi val ti mes f or partici pa nt s w h o ha d 0, 1, or 2 of t hese ris k fact ors were 3 3, 
1 3. 4, a n d 9. 3 m o nt hs, res pecti vel y ( P = 0 . 0 0 0 1) [ Baj ori n, D. F., et al 1 9 9 9].  T his was als o 
ill ustrate d b y a n I nter gr o u p st u d y t hat c o m pare d t hese ris k fact ors i n partici pa nts wit h metastatic 
disease treate d wit h cis plati n al o ne vers us met h otre xate, vi n blasti ne, d o x or u bici n, a n d cis plati n 
[ Loe hrer, P. J. Sr., et al 1 9 9 2] . T he prese nce of b o ne or li ver metastases a n d a p o or K P S were 
m ost pre dicti ve of p o or res p o nse a n d s ur vi val.
T he me dia n s ur vi val was 4 m o nt hs i n partici pa nts 
wit h t hese ris k fact ors, c o m pare d wit h 1 8 m o nt hs i n t h ose partici pa nt s wit h o ut t hese fact ors.  N o 
partici pa nt s wit h li ver or b o ne metastases a n d o nl y 1 partici pa nt wit h a K P S < 8 0 % s ur vi ve d past 
6 ye ars [ Sa x ma n, S. B., et al 1 9 9 7].  Se veral s u bse q ue nt re p orts c o nfir me d t he relati o ns hi p 
bet wee n s h orte ne d s ur vi val a n d p o or K P S or t he prese nce of visceral metastases. T he Baj ori n 
ris k sc ore is a pr o g n ostic m o del t hat pre dicts O S i n metas tatic ur ot helial ca ncer partici pa nt s
base d o n t he prese nce of 0, 1, or 2 of t hese ris k fact ors ; it will be use d a stratificati o n fact or i n 
t his st u d y.
Pre -cli nic al a n d Cli nic al St u dies
3. 2. 2
Refer t o t he I B f or pe m br oliz u ma b a n d e paca d ostat f or precli nical a n d cli nical st u d y data.
O n g oi n g Cli nic al St u dies
3. 2. 3
Refer t o t he I B f or pe m br oliz u ma b a n d e paca d ostat f or o n g oi n g cli nical trials data .
K E Y N O T E -2 5 2/ E C H O -3 0 1:
K E Y N O T E -2 5 2/ E C H O -3 0 1 is a n o n g oi n g P hase 3, ra n d o mize d, d o u ble -bli n d, place b o -
c o ntr olle d st u d y of pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat or place b o i n partici pa nts 
wit h u nresecta ble or metastatic mela n o ma.  T he d ual pri mar y  e nd p oi nts of t he st u d y  are 
pr o gressi o n free s ur vi val ( P F S) per R E CI S T 1. 1 as assesse d b y ce ntral i ma gi n g a n d O S. T he
e xter nal data m o nit ori n g c o m mittee (e D M C) c o ncl u de d t hat t he st u d y di d n ot meet t he pri mar y 
o bjecti ve of i m pr o vi n g P F S i n t he c o m bi nati o n c o m pare d t o pe m br oliz u ma b m o n ot hera p y d uri n g 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
a sec o n d i nteri m a nal ys is. T here were n o ne w safet y  c o ncer ns.  T he st u d y re mai ns o pe n s o t hat 
partici pa nts still o n st u d y  will ha ve c o nti n ue d access t o o pe n-la bel pe m br oliz u ma b.
Be nefit/ Ris k Assess me nt
3. 3
It ca n n ot be g uara ntee d t hat partici pa nts i n cli nical trials will directl y be 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.
Gi ve n i nitial data o bser ve d i n K E Y N O T E -0 3 7 s u g gesti n g i m pr o ve d efficac y  of pe m br oliz u ma b 
wit h e paca d ostat a n d a n o verall safet y pr ofile c o m p ara ble t o a nti -P D -1 m o n ot hera p y , t his 
c o m bi nati o n re prese nts a rati o nale a n d pr o misi n g first -li ne t hera pe utic o pti o n i n partici pa nts wit h 
metastatic U C.
Be nefits/ Ris ks fr o m E p ac a d ost at
3. 3. 1
E paca d ostat, as a si n gle t hera p y, ha d a pre dicta ble p har mac o ki netic ( P K) pr ofile a n d acce pta ble 
safety pr ofile, b ut li mite d si n gle- a ge nt efficac y i n partici pa nts wit h s oli d t u m ors i n t he P hase 1 
st u d y of 5 2 partici pa nts (I N C B 2 4 3 6 0 -1 0 1).  
A p ote ntial c o nc er n of I D O1 i n h ibi ti o n is an i nc rease i n serot o n in le v els t hat co ul d pr eci pitate a 
cl uster of A E s te r med s er ot o n in s yn dr o me ( SS ) w he n ad m inis tered al on e o r i n co m b i natio n wit h 
ot her ser ot o ner g ic a gents.  T h is rare s yn dr o m e has b een ass oci ate d wit h s o me m o n oa mi ne 
o x i dase i n hibi t ors (M A OIs ) an d co m b inati o ns of s er ot o ner gic dr u g s [ B o yer, E. W. 2 0 0 5] .  T he 
cli nical ma nifestati o ns of S S ra n ge fr o m barely perce pti ble t o let hal; o nset is ra pi d ( wit hi n 1 2 
h o urs of dr u g[s] a d mi nistrati o n). N o ncli nical data s u g gest t hat S S is u nli kel y  f oll o wi n g 
treat me nt wit h eit her e paca d ostat al o ne or i n c o m bi nati o n wit h M A OI s s uc h as li nez oli d [ Z ha n g, 
Y., et al 2 0 1 6] . As of 2 7 -Fe b -2 0 1 7, 2 of 9 5 8 partici pa nts treate d acr oss t he e paca d ostat pr o gra m 
ha ve re p orte d S S or s y m pt o ms of S S a n d b ot h were mil d i n t heir se verit y  a n d res ol ve d.  
Alt h o u g h t he i nci de nce of S S is u nc o m m o n, use of M A OIs are pr o hi bite d d uri n g t he st u d y , a n d 
all parti ci pa nts will be assesse d f or S S s ym pt o ms at a n a p pr o priate ti mefra me after d osi n g.  
Partici pa nts will be pr o vi de d wit h a n i nf or mati ve car d descri bi n g t he si g ns a n d s y m pt o ms of S S 
al o n g wit h i nstr ucti o ns t o see k i m me diate me dical care if a n y of t hese si g ns or s y m pt o ms are 
o bser ve d.
Be nefits/ Ris ks fr o m Pe m br oliz u m a b
3. 3. 2
Pe m br oliz u ma b m o n ot hera p y has a p ositi ve be nefit -ris k pr ofile a n d is well t olerate d i n m ulti ple 
a p pr o ve d i n dicati o n s as detaile d i n t he I B.  T he be nefits i n first-li ne cis plati n-i neli gi ble 
partici pa nts wit h u nresecta ble or metastatic U C were de m o nstrate d i n K E Y N O T E -0 5 2.  
Pe m br oliz u ma b was well t olerate d a n d t he O R R at i nteri m a nal ysis (IA) was 2 9 %.   I n 
cis plati n -i neli gi ble partici pa nts, res ults fr o m K E Y N O T E -0 5 2 de m o nstrate d t hat m ore t ha n half 
of pe m br oliz u ma b -treate d patie nts e x perie nce d t u m or s hri nka ge wit h ver y  li mite d t o xicit y.  
See Secti o n 5. 4 f or a d dit i o nal details o n K E Y N O T E-0 5 2 .  T he res ults of t his st u d y  lea d t o t he 
accelerate d a p pr o val of pe m br oliz u ma b i n patie nts wit h l ocall y a d va nce d or metastatic U C w h o 
were n ot eli gi ble f or cis plati n -c o ntai ni n g c he m ot hera p y.
D ue t o t he mec ha nis m of acti o n of pe m br oliz u ma b, i m m u ne -me diate d a d verse reacti o ns ha ve 
bee n see n w he n use d as m o n ot hera p y.  T he maj orit y of t he i m m u ne- me diate d A Es were mil d t o 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
m o derate i n se verit y, ma na gea ble wit h a p pr o priate care, a n d rarel y re q uire d disc o nti n uati o n of 
t hera py.  I nf usi o n -relate d reacti o ns are als o p ossi ble f oll o wi n g a d mi nistrati o n of pe m br oliz u ma b. 
G ui da nce f or t he ma na ge me nt of i m m u ne -relate d A Es a n d i nf usi o n-relate d reacti o ns is i n t he 
pr ot oc ol.
T he Refere nce Safet y Dataset ( N = 2 7 9 9) c o m prises t he l oc ke d safet y  data fr o m St u dies 
K E Y N O T E -0 0 1, -0 0 2, -0 0 6, a n d -0 1 0 [IB E diti o n 1 5 2 0 1 7] .  I n t hat dataset, a d verse e ve nts ( A Es) 
were ge nerall y  ma na gea ble a n d i nfre q ue ntl y re q uire d disc o nti n uati o n of pe m br oliz u ma b
treat me nt.
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or partici pa nt s 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 nyi n g I B [IB E diti o n 1 5 2 0 1 7] a n d Inf or me d C o nse nt.
Be nefits/ Ris ks f or t he C o m bi n ati o n of Pe m br oliz u m a b a n d E p ac a d ost at
3. 3. 3
T he c o m bi nati o n of pe m br oliz u ma b a n d e paca d ostat has t he p ote ntial t o ca use m ore fre q ue nt, 
m ore se ve re, a n d/ or ne w i m m u ne-relate d t o xicities as c o m pare d wit h eac h a ge nt i n di vi d uall y.  
St u d y  IN C B 2 4 3 6 0 -2 0 2 (K E Y N O T E -0 3 7 ) is a n o n g oi n g P hase 1/ 2 st u dy o f e paca d ostat 
a d mi nistere d i n c o m bi nati o n wit h pe m br oliz u ma b, wit h P hase 1 bei n g a d ose -escalati o n p hase 
a n d P hase 2 bei n g a n o pe n -la bel, si n gle ar m, c o h ort e x pa nsi o n p hase.  P hase 1 is bei n g 
c o n d ucte d i n partici pa nt s wit h a d va nce d or metastatic s oli d t u m ors i ncl u di n g Sta ge 3 B, Sta ge I V, 
or rec urre nt N S C L C, mela n o ma, T C C of t he ge nit o uri nar y  tract, re nal cell ca ncer, tri ple ne gati ve 
breast ca ncer, a de n ocarci n o ma of t he e n d o metri u m, or S C C H N w h o ha ve disease pr o gressi o n o n 
at least 1 li ne of t hera p y f or a d va nce d or metastatic ca ncer (e xce pt mela n o ma).  P hase 2 is 
c o n d ucte d i n partici pa nt s wit h N S C LC, mela n o ma, tra nsiti o nal cell carci n o ma of t he 
ge nit o uri nar y  tract, tri ple ne gati ve breast ca ncer, S C C H N, o varia n ca ncer, d iff use lar ge B -Cell 
ly m p h o ma , clear cell re nal cell ca ncer, gastric ca ncer, he pat ocell ular carci n o ma, a n d 
micr osatell ite i nsta bilit y (M SI ) hi g h c ol orectal ca ncer.  
Safet y  data is a vaila ble o n 2 9 4 partici pa nts fr o m P hase 2 treate d wit h t he rec o m me n de d P hase 2 
d ose of e paca d ostat 1 0 0 m g BI D a n d pe m br oliz u ma b 2 0 0 m g Q 3 W [ Ha mi d, O., et al 2 0 1 7].  T he 
m ost f re q ue ntl y re p orte d (≥ 1 0 %) T R A Es of a n y  gra de were fati g ue ( 2 9 %), ras h ( 1 7 %), na usea 
( 1 1 %), a n d pr urit us ( 1 0 %).  Ras h i ncl u des t he preferre d ter ms ras h, ras h ge neralize d, ras h 
mac ular, ras h mac ul o pa p ular, a n d ras h pr uritic.  T R A Es Gra de ≥3 were o bser ve d i n 1 8 % of 
partici pa nts.  T he m ost c o m m o n T R A Es Gra de ≥3 were i ncrease d li pase ( 4 %) a n d ras h ( 3 %).  
T here was o ne treat me nt-relate d deat h d ue t o res pirat or y fail ure w hic h was sec o n dar y t o 
as pirati o n p ne u m o nia.  
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or partici pa nts partici pati n g i n t his 
cli nical trial ma y be f o u n d i n Secti o n 3. 2. 1. 4 a n d t he acc o m pa nyi n g I B a n d I nf or me d C o nse nt 
d oc u me nts.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
4.
O bjecti ves/ H y p ot heses a n d E n d p oi nts
N O T E: As of A me n d me nt 0 4, t he pri m ar y e n d p oi nt of t he st u d y will be O R R b ase d o n 
R E CI S T 1. 1 as assesse d b y t he i n vesti g at or.  All ot her effic ac y e n d p oi nts , i ncl u di n g 
i m a gi n g, will n o l o n ger be c ollecte d or perf or me d after t he first i m a gi n g assess me nt at 
Wee k 9 .  T his secti o n h as bee n u p d ate d acc ordi n gl y.
I n male/fe male partici pa nt s of at least 1 8 y ears of a ge wit h hist ol o gicall y c o nfir me d dia g n osis of 
a d va nce d/ u nresecta ble or metastatic U C :
O bjecti ve/ H y p ot hesis
E n d p oi nt
Pri m ar y    

O bjecti ve: T o esti mate t he o bjecti ve 
res p o nse rate (O R R ) of pe m br oliz u ma b 
pl us e paca d ostat a n d pe m br oliz u ma b 
pl us place b o base d o n R E CI S T 1. 1 b y  
i n vesti gat or deter mi nati o n.

O R R - defi ne d as t he pr o p orti o n of 
partici pa nts i n t he a nalys is p o p ulati o n 
w h o ha ve a best res p o nse of c o m plete 
res p o nse ( C R) or partial res p o nse ( P R).
Sec o n d ar y

O bjecti ve: T o e val uate t he safety a n d 
t olera bilit y of pe m br oliz u ma b pl us
e paca d ostat vers us pe m br oliz u ma b pl us
place b o .

A d verse e ve nts ( A Es)

St u d y  dr u g disc o nti n uati o ns d ue t o A Es
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
5.
St u d y Desi g n 
O ver all Desi g n 
5. 1
N ote: E nr oll me nt w as st o p pe d str ate gic all y o n 0 2 – M A Y -2 0 1 8.   As of A me n d me nt 0 4, a ll 
st u d y effic ac y pr oce d ures will disc o nti n ue after t he first o n -st u d y i m a gi n g at Wee k 9 ( ± 7 
d a ys) ; t here after p artici p a nts will be tre ate d as per S o C f or t he dise ase a n d l oc al 
g ui deli nes.  T he s t u d y will be u n bli n de d after t he l ast p artici p a nt c o m pletes t heir Wee k 9 
i m a gi n g assess me nt f or effic ac y a n al ysis. S afet y pr oce d ures will c o nti n ue as per pr ot oc ol 
f or all p artici p a nts c o nti n ui n g st u d y tre at me nt (e g, wit h eit her o pe n l a bel pe m br oliz u m a b
or pe m br oliz u m a b a n d e p ac a d ost at if t he y are c o nsi dere d t o be deri vi n g cli nic al be nefit) .  
T he l ast st u d y visit is t he S afet y F oll o w -u p Visit. T his secti o n h as bee n u p d ate d 
acc or di n gl y.   
T his is a ra n d o mize d, acti ve-c o ntr olle d, parallel -gr o u p , m ulti - site, d o u ble -bli n d st u d y of 
pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat or place b o i n partici pa nts wit h U C w h o ha ve 
n ot recei ve d pri or s ys te mic c he m ot hera p y (ie, first li ne, 1 L) a n d w h o are n ot eli gi ble t o recei ve 
cis plati n .
A p pr o xi matel y  6 5 0 partici pa nt s were t o be e nr olle d . As of A me n d me nt 0 4, o n 0 2 -M A Y -2 0 1 8 
e nr oll me nt i n t he st u d y was st o p pe d. It is esti mate d b y t he ti me t he strate gic decisi o n was ma de 
o n 0 2 -M A Y -2 0 1 8 t o per ma ne ntl y  st o p e nr oll me nt t hat 1 0 0 partici pa nts will be ra n d o mize d i n 
t his st u d y. 
Partici pa nts will be stratifie d b y  Baj ori n ris k sc ore ( 0, 1, 2) a n d P D-L 1 e x pressi o n , assesse d b y 
ce ntral la b orat or y , C P S ≥1 0 vers us C P S < 1 0 , a n d t he n ra n d o mize d 1: 1 t o eit her pe m br oliz u ma b 
+ e paca d ostat or pe m br oliz u ma b + place b o.  Pri or t o ra n d o mizati o n , eac h partici pa nt m ust 
pr o vi de a ne wl y o btai ne d or arc hi val f or mali n -fi xe d paraffi n-e m be d de d ( F F P E) t u m or bi o ps y f or 
P D -L 1  deter mi nati o n b y i m m u n o hist oc he mistr y (I H C) b y a ce ntral la b orat or y.  All partici pa nt s 
will recei ve pe m br oliz u ma b re gar dless of P D - L1 e x pressi o n (C P S ≥1 0 vers us C P S < 1 0 ) at 
baseli ne; partici pa nts wit h n o n -e val ua ble res ults are e xcl u de d .
Treat me nt wit h t he c o m bi nati o n t hera p y will i ncl u de pe m br oliz u ma b bei n g a d mi nistere d e ver y 
2 1 da y s f or u p t o 3 5 a d mi nistrati o ns (a p pr o xi matel y 2 years) wit h e paca d ostat or matc hi n g 
place b o d ose d BI D .  T he treat me nt peri o d will c o nti n ue as l o n g as partici pa nt s are recei vi n g 
be nefit fr o m treat me nt a n d ha ve n ot ha d disease pr o gressi o n or met a n y criteria f or st u d y 
wit h dra wal ( Secti o n 8. 1).   Partici pa nts w h o disc o nti n ue treat me nt will disc o nti n ue fr o m t he st u d y 
after Safet y F oll o w -u p.  T he st u d y has n o pla n ne d treat me nt cr oss o ver.
Partici pa nts w h o st o p st u d y treat me nt after at least 8 c y cles , wit h i n vesti gat or- deter mi ne d 
c o nfir me d C R or c o m ple te 3 5 c y cles (a p pr o xi matel y 2 years) wit h S D, P R, or C R, ma y  be 
eli gi ble f or u p t o 1 year ( 1 7 c ycles) of a d diti o nal c o m bi nati o n t hera p y if t he y e x perie nce disease 
pr o gressi o n.  T his retreat me nt is ter me d t he Sec o n d C o urse P hase ( Retreat me nt) of t his st u d y  a n d 
is o nl y a vaila ble if t he st u d y re mai ns o pe n a n d t he partici pa nt meets t he criteria i n Secti o n 7. 2. 2.
T here is n o i nteri m a nal ysis i n t his st u d y . D uri n g t he c o urse of t he st u dy, t he e xter nal Data 
M o nit ori n g C o m mittee ( eD M C) will perf or m 1 safet y re vie w base d o n t he eD M C c harter.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
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 S o A - Secti o n 2. Details of eac h pr oce d ure are 
pr o vi de d i n Secti o n 9 – St u d y  Assess me nts a n d Pr oce d ures.
D at a M o nit ori n g C o m mittee a n d I nteri m A n al yses
5. 1. 1
T here is n o i nteri m efficac y a nal ys is i n t his st u d y. D uri n g t he c o urse of t he st u d y, D M C will 
perf or m 1 safety re vie w as descri be d i n t he eD M C c harter.
St u d y Di a gr a m
5. 1. 2
T he st u dy desi g n is de picte d i n Fi g ure 1 .
N O T E: As of A me n d me nt 0 4, t he st u d y will be u n bli n de d after t he l ast p artici p a nt 
c o m pletes t he Wee k 9 i m a gi n g assess me nt f or effic ac y a n al ysis; p artici p a nts c a n c h o ose t o 
disc o nti n ue fr o m t he st u d y or c o nti n ue st u d y tre at me nt as per pr ot oc ol after disc ussi o n 
wit h t he i n vesti g at or a n d if t he y are deri vi n g cli nic al be nefits .  N o pl ace b o will be 
a d mi nistere d after u n bli n di n g.  T he l ast st u d y visit is t he S afet y F oll o w -u p Visit.
BI D = t wice dail y; C P S = c o m bi ne d p ositi ve sc ore; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; I V = i ntra ve n o us; P O = orall y; 
P S = Perf or ma nce Stat us; Q 3 W = e ver y 3 wee ks
Fi g ure 1
St u d y  Desi g n
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
N u m ber of P artici p a nts
5. 2
A p pr o xi matel y  6 5 0 partici pa nts were t o be ra n d o mize d i nt o t he st u d y. As of A me n d me nt 0 4, o n 
0 2 -M A Y -2 0 1 8 e nr oll me nt i n t he st u d y  was st o p pe d. It is esti mate d b y t he ti me t he strate gic 
decisi o n was ma de o n 0 2 - MA Y -2 0 1 8 t o per ma ne ntl y  st o p e nr oll me nt t hat 1 0 0 partici pa nts will 
be ra n d o mize d i n t his st u d y .
Be gi n ni n g a n d E n d of St u d y Defi niti o n
5. 3
T he o verall trial be gi ns w he n t he first partici pa nt si g ns t he i nf or me d c o nse nt f or m (I C F).  T he 
o verall trial e n ds w he n t he last partici pa nt c o m pletes t he last st u d y -relate d p h o ne-call or visit, 
wit h dra ws fr o m t he trial or is l ost t o f oll o w -u p (i.e. t he partici pa nt is u na ble t o be c o ntacte d b y 
t he i n vesti gat or).
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n
5. 3. 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 i n vesti gat or retai ns t he ri g ht t o ter mi nate st u d y partici pati o n at a n y ti me, acc or di n g t o t he 
ter ms s pecifie d i n t he st u d y c o ntract.  T he i n vesti gat or is t o n otif y t he I nstit uti o nal Re vie w B oar d 
(I RB) or i n de pe n de nt et hics c o m mittee (I E C) i n writi n g of t he st u dy's c o m pleti o n or earl y 
ter mi nati o n, a n d se n d a c o p y of t he n otificati o n t o t he M S D or M S D desi g nee a n d retai n 1 c o p y 
f or t he site st u d y re g ulat or y file.
T he st u d y  ma y be ter mi nate d earl y if re q uire d b y re g ulat or y decisi o n, or u p o n a d vice of t he 
D M C.  I f t he st u d y is ter mi nate d pre mat urel y, t he i n vesti gat ors, t he IR Bs a n d I E Cs, a n d 
re g ulat or y b o dies will be n otifie d of t he decisi o n a n d reas o n f or ter mi nati o n of t he st u d y.  
Scie ntific R ati o n ale f or St u d y Desi g n 
5. 4
Partici pa nt s wit h a d va nce d or metastatic U C prese nt u ni q ue c halle n ges. Alt h o u g h a variet y of 
c he m ot hera pe utic a ge nts are use d i n t his setti n g a n d i nitiall y are ass ociate d wit h res p o nse, t he 
pr o g n osis f or partici pa nt s is p o or – me dia n s ur vi val fr o m st u dies i n t hese setti n g ra n ges fr o m 8 t o 
1 5 m o nt hs, a n d t he maj orit y  of partici pa nt s die fr o m c o m plicati o ns relate d t o disease [ v o n der 
Maase, H.,
et al 2 0 0 0] [ De Sa ntis, M., et al 2 0 1 2] . T he a d va nce d/ metastatic setti n g re prese nts a 
cli nical are a i n nee d of n o vel t hera pe utic a p pr oac hes s uc h as wit h c hec k p oi nt i n hi bit or t hera p y .  
T he c urre nt a p pr oac h will atte m pt t o e xte n d t he n u m ber of partici pa nts w h o de vel o p a n i m m u ne 
res p o nse by a d mi nisteri n g t he I D O 1 e nz y m e i n hi bit or, e paca d ostat, i n c o m bi nati o n wit h t he P D -
1 c hec k p oi nt i n hi bit or, pe m br oliz u ma b i n a first -li ne setti n g.  
Cis plati n -base d c o m bi nati o n c he m ot hera p y is sta n dar d first -li ne treat me nt f or partici pa nt s wit h 
a d va nce d bla d der ca ncer base d o n ra n d o mize d trials [ Lo g ot hetis, C. J., et al 1 9 9 0] [ v o n der 
Maase, H., et al 2 0 0 0] [ Sa x ma n, S. B., et al 1 9 9 7] [ L oe hrer, P. J . Sr., et al 1 9 9 2] [ Ster n ber g, C. 
N., et al 2 0 0 6] [ v o n der Maase, H., et al 2 0 0 5] . T he me dia n s ur vi val wit h t hese re gi me ns is 1 3 t o 
1 5 m o nt hs, a n d 5 % t o 1 5 % of partici pa nt s attai n l o n g-ter m s ur vi val. H o we ver, cis plati n 
i neli gi bilit y is c o m m o n beca use of re nal d y sf u ncti o n (creati ni ne cleara nce [ Cr Cl] < 6 0 m L / mi n) 
or E C O G P S of 2, or b ot h. F urt her m ore, heari n g l oss, Gra de 2 ne ur o pat h y, heart fail ure, a n d 
a ge-ass ociate d di mi nis he d re nal f u ncti o n ma y als o c o nfer cis plati n i neli gi bilit y [ Gals k y, M. D., 
et al 2 0 1 1] [ Gals k y, M. D., et al 2 0 1 1] [ Das h, A., et al 2 0 0 6].
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Car b o plati n is ofte n s u bstit ute d f or cis plati n i n s uc h partici pa nt s, b ut it is ass ociate d wit h i nferi or 
o utc o mes, as de m o nstrate d i n a meta -a nal ys is of ra n d o mize d P hase 2 st u dies [ Gals k y, M. D., et 
al 2 0 1 1] [ Gals k y, M. D., et al 2 0 1 2].
A P hase 3 st u dy c o m pari n g ge mcita bi ne ( G E M)/car b o plati n wit h M C A VI 
( met h otre xate/car b oplati n/ vi n blasti ne) i n cis plati n -i neli gi ble partici pa nt s de m o nstrate d a me dia n 
s ur vi val of o nl y 8 t o 9 m o nt hs wit h b ot h re gi me ns [ De Sa ntis, M., et al 2 0 1 2]. N ota bl y , t h ose 
wit h b ot h p o or re nal f u ncti o n a n d p o o r perf or ma nce stat us ( P S) fare d es peciall y p o orly wit h 
c o m bi nati o n c he m ot hera p y i n t his st u d y.  T h us, t here re mai ns a si g nifica nt u n met me dical nee d 
f or well-t olerate d acti ve t hera pies i n t his p o p ulati o n.  Acc or di n g t o t he Nati o nal C o m pre he nsi ve 
Ca ncer Net w or k ( N C C N) g ui deli nes, cli nical st u dies of p ote ntiall y less t o xic t hera pies are 
rec o m me n de d f or t his p o p ulati o n of partici pa nt s.
K E Y N O T E -0 5 2, a n o pe n -la bel, m ultice nter, P hase 2 st u d y , e val uate d t he efficac y a n d safet y of 
pe m br oliz u ma b ( 2 0 0 m g Q 3 W) i n fir st-li ne cis plati n-i neli gi ble partici pa nts wit h u nresecta ble or 
metastatic U C .  I n data prese nte d at T he A merica n S ociet y  of Cli nical O nc ol o g y ( A S C O) 
C o nfere nce i n 2 0 1 7, o f t he 3 7 0 partici pa nts e nr olle d, 8 5 % ha d visceral metastases, i ncl u di n g 
2 1 % wit h li ver metastases [ O' D o n nell, P. H., et al 2 0 1 7]. Reas o ns f or cis plati n i neli gi bilit y  
i ncl u de d: 5 0 % wit h baseli ne Cr Cl of < 6 0 m L / mi n, 3 2 % wit h E C O G P S of 2, 9 % wit h E C O G 2 
a n d baseli ne Cr Cl of < 6 0 m L / mi n, a n d 9 % wit h ot her reas o ns ( Class III heart fail ure, Gra de 2 or 
greater peri p heral ne ur o pat h y , a n d Gra de 2 or greater heari n g l oss). Ni net y  perce nt of patie nts 
were treat me nt naï ve, a n d 1 0 % recei ve d pri or a dj u va nt or ne oa dj u va nt plati n u m -base d 
c he m ot hera p y.
Res ults f r o m K E Y N O T E- 0 5 2 i n Fi g ure 2 de m o nstrate d t hat m ore t ha n half of partici pa nts
a nal yz e d, w h o recei ve d ≥1 d ose of pe m br oliz u ma b, ha d a baseli ne sca n wit h meas ura ble disease 
per R E CI S T 1. 1, a n d a p ost baseli ne assess me nt ( n = 3 3 2) , e x perie nce d t u m or s hri n ka ge ( data 
c ut-off 0 9 -Mar -2 0 1 7) .
Fi g ure 2
Best C ha n ge Fr o m Baseli ne i n T u m or Size, K E Y N O T E - 0 5 2
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
T he efficac y  a nalys is s h o we d a n O R R o f 2 9% ( 9 5 % CI : 25 , 3 4), wit h a C R rate of 7 % a n d a P R
rate of 2 2 %. T he me dia n D O R ha d n ot bee n reac he d (ra n ge: 1. 4 + t o 1 7. 8 + m o nt hs).  T he 
me dia n f oll o w -u p ti me was 9. 5 m o nt hs [ O' D o n nell, P. H., et al 2 0 1 7].
I n K E Y N O T E-0 5 2, t here was ver y  little t o xicit y. T R A Es were e x perie nce d b y  66 % of 
partici pa nts.  T he m ost c o m m o n T R A E s were fati g ue (1 8 %) , pr urit us ( 1 7 %), ras h ( 1 2 %), 
decrease d a p petite ( 1 0 %), a n d h y p ot h y r oi dis m ( 1 0 %).  Gra de 3- 5 T R A E s were e x perie nce d b y 
1 9 % of partici pa nts , 7 % disc o nti n ue d t hera p y beca use of a T R A E , a n d t here was 1 deat h d ue t o a 
T R A E ( m y ositis) .  It was c o ncl u de d fr o m a nalys is of K E Y N O T E-0 5 2 t hat pe m br oliz u ma b 
2 0 0 m g Q 3 W de m o nstrates s u bsta ntial a ntit u m or acti vit y  a n d has a ma na gea ble t o xicit y pr ofile 
i n cis plati n-i neli gi ble partici pa nts wit h u nresecta ble or metastatic U C .
I n K E Y N O T E-0 5 2 t he P D -L 1 C P S -hi g h c ut p oi nt was deter mi ne d t o be ≥1 0 P D -L 1  e x pressi o n.  
S u bjects wit h P D -L 1  C P S stai ni n g ≥1 0 de m o nstrate d hi g her res p o nse rates ( R R) wit h 
pe m br oliz u ma b m o n ot hera p y.  
B ot h I D O 1 a n d P D -1 ha ve bee n s h o w n t o s u p press T -cell-me diate d a ntit u m or i m m u nit y ; a n d 
I DO 1 a n d t he P D-1 li ga n d, P D -L 1 , ha ve bee n s h o w n t o be c oe x presse d i n m ulti ple ca ncer ty pes 
a n d t o c orrelate wit h p o or pr o g n osis.  P D -L 1  a n d I D O 1 are ga m ma-i nterfer o n res p o nsi ve ge nes 
t hat are ofte n s u b verte d i n ta n de m b y t u m or cells.  C o m bi ne d i n hi biti o n of b ot h pat h wa y s ma y 
t heref ore lea d t o greater s u p pressi o n of a ntit u m or i m m u nit y a n d t o i ncrease d efficac y.  Res p o nse 
data f or partici pa nts wit h a d va nce d metastatic U C fr o m t he o n g oi n g P hase 1/ 2 st u d y 
I N CB 2 4 3 6 0 -2 0 2 ( K E Y N O T E -0 3 7), is e nc o ura gi n g wit h a hi g h O R R t h at e xcee ds m o n ot hera p y 
wit h P D -1 i n hi bit ors a n d a p pears d ura b le base d o n P hase 1 res p o n ders.  See Secti o n 3. 2. 1. 4 f or 
a d diti o nal details.  
I n li g ht of t he relati vely l i mite d be nefit fr o m c yt ot o xic c he m ot hera p y i n partici pa nt s wit h 
a d vance d/ u nresecta ble (i n o pera ble) or metastatic ur ot helial ca ncer w h o are cis plati n -i neli gi ble, 
a n d t he pr o misi n g res ult s wit h pe m br oliz u ma b a n d I D O 1, pe m br oliz u ma b a n d e paca d ostat 
vers us pe m br oli z u ma b pl us place b o will be c o m pare d i n t his partici pa nt p o p ulati o n .
R ati o n ale f or E n d p oi nts
5. 4. 1
Effic ac y E n d p oi nts
5. 4. 1. 1
N O T E : A s of A me n d me nt 0 4, t he pri m ar y e n d p oi nt of t he st u d y will be O R R b ase d o n 
R E CI S T 1. 1 as assesse d b y t he i n vesti g at or ; tr a ns missi o n of i m a ges f or ce ntr al re vie w is n o 
l o n ger re q uire d. All ot her effic ac y e n d p oi nts , i ncl u di n g i m a gi n g after t he first o n st u d y 
sc a n at Wee k 9, will n o l o n ger be c ollecte d or perf or me d. T his secti o n h as bee n a me n de d 
acc or di n gl y.
T his st u d y will use O R R base d o n R E CI S T 1. 1 criteria as assesse d b y  t he i n vesti gat or as t he 
pri mar y e n d p oi nt.  O R R is a n acce pta ble meas ure of cli nical be nefit f or a late sta ge st u d y t hat 
de m o nstrates s u peri orit y of a ne w a nti ne o plastic t hera p y.
R E CI S T 1. 1
5. 4. 1. 1. 1
R E CI S T 1. 1 will be use d b y  t he i n vesti gat or w he n assessi n g i ma ges f or efficac y  meas ures a n d b y 
t he l ocal site w he n deter mi ni n g eli gi bilit y. Alt h o u g h tra diti o nal R E CI S T 1. 1 refere nces a 
ma xi m u m of 5 tar get lesi o ns i n t otal a n d 2 per or ga n, t his pr ot oc ol has i m ple me nte d a 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
m o difi cati o n t o R E CI S T 1. 1 t o all o w a ma xi m u m of 1 0 tar get lesi o ns i n t otal a n d 5 per or ga n. 
T his will be ter me d as R E CI S T 1. 1 t hr o u g h o ut t he pr ot oc ol. F urt her details are f o u n d i n Secti o n 
9. 2. 1. 5.
M o difie d R E CI S T 1. 1 f or I m m u ne-b ase d T her a pe utics (i R E CI S T)
5. 4. 1. 1. 2
N O T E : As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble; i R E CI S T d at a will n o 
l o n ger be c ollecte d. P a rtici p a nts wit h r a di o gr a p hic dise ase pr o gressi o n as deter mi ne d b y 
R E CI S T 1. 1 will disc o nti n ue fr o m t he st u d y a n d be f oll o we d f or s afet y m o nit ori n g, as 
det aile d i n Secti o n 9. 3; n o c o nfir m at or y sc a ns are re q uire d.
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 
f oll o wi n g treat me nt wit h pe m br oliz u ma b. I mm 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 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 partici pa nts treate d wit h pe m br oliz u ma b ma y 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.
T h us, sta n dar d R E CI S T 1. 1 ma y  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. Base d o n a n a nal y sis of partici pa nts wit h 
mela n o ma e nr olle d i n K E Y N O T E -0 0 1, 7 % of e val ua ble partici pa nts e x perie nce d dela y e d or 
earl y t u m or pse u d o -pr o gressi o n. Of n ote, partici pa nts w h o ha d P D b y R E CI S T 1. 1 b ut n ot b y  
t he i m m u ne-relate d res p o nse criteria [ W olc h o k, J. D., et al 2 0 0 9] ha d l o n ger O S t ha n partici pa nts 
wit h P D b y  b ot h criteria [ H o di, F. S., et al 2 0 1 4]. A d diti o nall y , t he data s u g gest t hat R E CIS T 
1. 1 ma y  u n deresti mate t he be nefit of pe m br oliz u ma b i n a p pr o xi matel y 1 5 % of partici pa nts. 
T hese fi n di n gs s u p p ort t he nee d t o a p pl y a m o dificati o n t o R E CIS T 1. 1 t hat ta kes i nt o acc o u nt 
t he u ni q ue patter n of aty pica l res p o nses i n i m m u n ot hera py a n d e na bles treat me nt be y o n d i nitial 
ra di o gra p hic pr o gressi o n, if t he partici pa nt is cli nicall y sta ble.
M o difie d R E CI S T 1. 1 f or i m m u ne -base d t hera pe utics ( i R E CIS T ) assess me nt has bee n de vel o pe d 
a n d p u blis he d b y t he R E CIS T W or ki n g Gr o u p, wit h i n p ut fr o m lea di n g e x perts fr o m i n d ustr y  
a n d aca de mia, al o n g wit h partici pati o n fr o m t he U S F D A a n d t he E ur o pea n Me dici nes A ge nc y 
[ E M A] [ Se ym o ur, L., et al 2 0 1 7] . T he u ni di me nsi o nal meas ure me nt of tar get lesi o ns, q ualitati ve 
assess me nt of n o n -tar get lesi o ns, a n d res p o nse cate g ories are i de ntical t o R E CIS T 1. 1, u ntil 
pr o gressi o n is see n b y R E CI S T 1. 1. H o we ver, if a partici pa nt is cli nicall y sta ble, a d diti o nal 
i ma gi n g ma y be perf or me d t o c o nfir m radi o gra p hic pr o gressi o n. i R E CIS T will be use d b y  
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
 
Refer t o Secti o n 9. 2. 1. 6 f or details o n i R E CIS T.
S afet y E n d p oi nts
5. 4. 1. 2
Safet y  para meters c o m m o nl y use d f or e val uati n g i n vesti gati o nal sys te mic a ntica ncer treat me nts 
are i ncl u de d as safet y e n d p oi nts i ncl u di n g, b ut n ot li mite d t o, t he i nci de nce of, ca usalit y, a n d 
o utc o me of A Es /seri o us a d verse e ve nts ( S A Es); a n d c ha n ges i n vital si g ns a n d la b orat or y val ues. 
A d verse e ve nts will be assesse d as defi ne d b y 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.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
P atie nt Re p orte d O utc o mes
5. 4. 1. 3
N O T E : As of A me n d me nt 0 4, P R O will n o l o n ger be c ollecte d after t he first o n -st u d y 
i m a gi n g assess me nt at Wee k 9.
As part of t he a nal ys es f or t his st u d y, partici pa nts will pr o vi de i nf or mati o n re gar di n g t heir 
H R Q o L  usi n g t he E O R T C Q LQ- C 3 0 P R O i nstr u me nts.  Healt h utilities will be e val uate d usi n g 
t he E Q -5 D -5 L P R O i nstr u me nt.  E Q -5 D -5 L  will be a d mi nistere d first, t he n E O R T C Q LQ- C 3 0 .  
T hese P R O assess me nts are n ot p ure efficac y  or safety e n d p oi nts beca use t he y are affecte d b y 
b ot h disease pr o gressi o n a n d treat me nt t olera bilit y.
E O R T C Q L Q - C 3 0
5. 4. 1. 3. 1
T he E O R T C Q L Q -C 3 0 is t he m ost wi del y  use d ca ncer s pecific H R Q o L i nstr u me nt, w hic h 
c o ntai ns 3 0 ite ms a n d meas ures 5 f u ncti o nal di me nsi o ns ( p h ysical, r ole, e m oti o nal, c o g niti ve a n d 
s ocial), 3 sy m pt o m ite ms (fati g ue, na usea/ v o miti n g, a n d pai n), 6 si n gle ite ms ( d ys p nea, slee p 
dist ur ba nce, a p petite l oss, c o nsti pati o n, diarr hea, a n d fi na ncial i m pact), a n d a gl o bal healt h a n d 
Q o L scale [ Aar o ns o n, N. K., et al 1 9 9 3].
F or t he gl o bal healt h stat us/ q ualit y  of life a n d f u ncti o n scales, a hi g her val ue i n dicates a better 
le vel of f u ncti o n; f or sy m pt o m scales a n d ite ms, a hi g her val ue i n dicates i ncrease d se verit y of 
s ym pt o ms.  T T D a n d mea n c ha n ge fr o m baseli ne i n gl o bal healt h stat us/ Q o L scale of t he 
E O R T C Q L Q- C 3 0, will be e val uate d as sec o n dar y o bjecti ves.
E ur o Q o L -5 D -5 L ( E Q -5 D -5 L)
5. 4. 1. 3. 2
T he E Q -5 D -5 L is a sta n dar dize d i nstr u me nt f or use as a meas ure of healt h o utc o me a n d will 
pr o vi de data t o de vel o p healt h utilities f or use i n heal t h ec o n o mic a nalys es [ Ra bi n, R. 2 0 0 1].  
T he 5 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 fi ve p oi nt scale 
fr o m 1 (n o pr o ble m) t o 5 ( u na ble t o/e xtre me pr o ble ms).  T he E Q -5 D -5 L als o i ncl u des a gra de d 
( 0 t o 1 0 0) vertical vis ual a nal o g scale o n w hic h t he partici pa nt rates his or her ge neral state of 
healt h at t he ti me of t he assess me nt.  T his i nstr u me nt has bee n use d e xte nsi vel y i n ca n cer st u dies 
a n d p u blis he d res ults fr o m t hese st u dies s u p p ort its vali dit y a n d relia bilit y [ Pic kar d, A. S., et al 
2 0 0 7] .
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
R ati o n ale f or t he Use of C o m p ar at or/ Pl ace b o
5. 4. 2
Data fr o m I A of K E Y N O T E -0 5 2 de m o nstrates t hat pe m br oliz u ma b m o n ot hera py at 2 0 0 m g 
Q 3 W has s u bsta ntial a ntit u m or acti vit y  a n d a ma na gea ble t o xicit y pr ofile i n cis plati n-i neli gi ble 
partici pa nts wit h u nresecta ble or metastatic U C [ O'D o n nell, P. H., et al 2 0 1 7] . I n data prese nte d 
at A S C O i n 2 0 1 7 fr o m I A, C R rate was 7 % a n d O R R was 2 9 % i n all partici pa nts ( N =3 7 0 ).  A
T R A E was e x perie nce d i n 6 6 % of partici pa nts , m ost c o m m o nl y fati g ue ( 1 8 %), pr urit us ( 1 7 %), 
ras h ( 1 2 %), decrease d a p petite ( 1 0 %), a n d h y p ot h yr oi dis m ( 1 0 %). G ra de 3/ 4 T R A E were 
e x perie nce d i n 1 9 % of partici pa nts a n d 7 % disc o nti n ue d t hera p y beca use of a T R A E . T here was 
1 treat me nt-relate d deat h.
T he use of a n e paca d ostat matc hi n g place b o i n c o m bi nati o n wit h pe m br oliz u ma b will e ns ure t he 
o bjecti vit y  of i n vesti gat or-assesse d pr o gressi o n f or t he pe m br oliz u ma b pl us e paca d ostat 
c o m bi nati o n vers us pe m br oliz u ma b m o n ot hera p y, as well as a ny d ecisi o ns t o 
i nterr u pt/ disc o nti n ue t hera p y.
N O T E : As of A me n d me nt 0 4, t he st u d y will be u n bli n de d after t he l ast p artici p a nt 
c o m pletes Wee k 9 i m a gi n g assess me nt f or effic ac y a n al ysis..
J ustific ati o n f or D ose 
5. 5
R ati o n ale f or D ose a n d Re gi me n of Pe m br oliz u m a b
5. 5. 1
T he pla n ne d d ose of pe m br oliz u ma b f or t his st u d y  is 2 0 0 m g Q 3 W. Base d o n t he t otalit y of data 
ge nerate d i n t he K E Y T R U D A ® de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he a p pr o priate d ose of 
pe m br oliz u ma b f or a d ults acr oss all i n dicati o ns a n d re gar dless of t u m or t y pe. As o utli ne d bel o w, 
t his d ose is j ustifie d b y: 

Cli nical data fr o m 8 ra n d o mize d st udies 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 2 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 S at 2 0 0 m g 
Q 3 W acr oss m ulti ple i n dicati o ns, a n d

P har mac ol o g y  data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati o n (i nferre d 
fr o m P K data) a n d t u m or (i nferre d fr o m p hys i ol o gicall y-base d 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, a t otal of 2 2 6 2 partici pa nts were e nr olle d 
wit h mela n o ma a n d N S C L C, c o veri n g differe nt disease setti n gs (treat me nt naï ve, pre vi o usl y 
treate d, P D-L 1 e nric he d a n d all -c o mers) a n d differe nt treat me nt setti n gs ( m o n ot hera 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 2 W 
( KE Y N O T E -0 0 1 B 2, -0 0 1 D, -0 0 2, -0 1 0 a n d -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 E Y N O T E -0 0 1 B 3, -0 0 1 F 2 a n d -0 0 6). All of t hese st u dies de m o nstra te d flat 
d ose - a n d e x p os ure -res p o nse relati o ns hi ps acr oss t he d oses st u die d re prese nti n g a n a p pr o xi mate 
5 t o 7. 5 f ol d differe nce i n e x p os ure. T he 2 m g/ k g ( or 2 0 0 m g fi xe d -d ose) Q 3 W pr o vi de d si milar 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
res p o nses t o t he hi g hest d oses st u die d. S u bse q ue ntl y , flat d ose-/e x p os ure-res p o nse relati o ns hi ps 
were als o o bser ve d i n ot her t u m or t y pes i ncl u di n g hea d a n d nec k ca ncer, bla d der ca ncer, gastric 
ca ncer a n d classical H o d g ki n L y m p h o ma, c o nfir mi n g 2 0 0 m g Q 3 W as t he a p pr o priate d ose 
i n de pe n de nt of t he t u m or t ype. T h ese 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 clearly s h o w tar get sat urati o n at 2 0 0 m g Q 3 W. First, P K data 
i n K E Y N O T E -0 0 1 e val uati n g tar get -me diate d dr u g dis p ositi o n c o ncl usi vel y  de m o nstrate d 
sat urati o n of P D-1 i n s ys te mic circ ulati o n at d oses m uc h l o wer t ha n 2 0 0 m g Q 3 W. Sec o n dl y , a 
p h y si ol o gically- base d P K a nal ys is was c o n d ucte d t o pre dict t u m or P D- 1 saturati o n o ver a wi de 
ra n ge of t u m or pe netrati o n a n d P D-1 e x pressi o n. T his e val uati o n c o ncl u de d t hat pe m br oliz u ma b 
at 2 0 0 m g Q 3 W ac hie ves f ull P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.
Fi nall y , p o p ulati o n P K a nal ysis of pe m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of b o dy 
wei g ht a n d ot her partici pa nt c o variates o n e x p os ure, has s h o w n t hat t he fi xe d -d osi n g pr o vi des 
si milar c o ntr ol of P K varia bilit y as wei g ht base d d osi n g, wit h c o nsi dera ble o verla p i n t he 
distri b uti o n of e x p os ures fr o m t he 2 0 0 m g Q 3 W fi xe d d ose a n d 2 m g/ k g Q 3 W d ose. S u p p orte d 
b y  t hese P K c haracteristics, a n d gi ve n t hat fi xe d-d ose has a d va nta ges of re d uce d d osi n g 
c o m ple xit y a n d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g Q 3 W fi xe d-d ose was selecte d f or 
e val uati o n acr oss all pe m br oliz u ma b pr ot oc ols.
R ati o n ale f or D ose a n d Re gi me n of E p ac a d ost at i n C o m bi n ati o n wit h 
5. 5. 2
Pe m br oliz u m a b
T he d ose f or e paca d ostat f or t he c urre nt st u d y was selecte d o n t he basis of ha vi n g a well -
t olerate d safet y pr ofile as m o n ot hera py a n d i n c o m bi nati o n wit h pe m br oliz u m a b, a r o b ust O R R , 
d ura ble D C R , as well as pr o vi di n g o pti mal tar get i n hi biti o n of ID O 1 base d o n n o ncli nical 
m o dels.  D oses of e paca d ostat of u p t o 7 0 0 m g BI D as m o n ot hera p y h a ve bee n well t olerate d.
D oses of e paca d ostat 2 5 m g BI D t o 3 0 0 m g BI D i n c o m bi nati o n wit h pe m br oliz u ma b, 
ni v ol u ma b, d ur val u ma b a n d atez oliz u ma b are c urre ntl y bei n g e val uate d i n se veral o n g oi n g 
P hase 2 st u dies.  D oses of pe m br oliz u ma b 2 m g/ k g or a 2 0 0 m g flat d ose ha ve bee n st u die d i n 
t he o n g oi n g P hase 1/ 2 st u d y  of pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat.  Re d ucti o ns i n 
t u m or b ur de n were see n i n 1 4 of 1 9 e val ua ble partici pa nts acr oss d oses of 2 5 m g BI D t o 1 0 0 m g 
BI D i n c o m bi nati o n wit h pe m br oliz u ma b 2 m g/ k g a n d 2 0 0 m g flat d osi n g [ Ga n ga d har, T. C., et 
al 2 0 1 5] .  O bjecti ve res p o nses were o bser ve d i n all t u m or t y pes a n d t he maj orit y  are d ura ble; t his 
c o m bi nati o n has bee n well t olerate d wit h rates of i m m u ne-relate d a d verse e ve nts (ir A Es) t hat are 
si milar t o pe m br oliz u ma b m o n ot hera p y a n d l o w rates of treat me nt disc o nti n uati o n d ue t o ir A Es 
[ Ga n ga d har, T. C., et al 2 0 1 7] [ Ha mi d, O., et al 2 0 1 7] . 
 
 
0 4 Y B Q D




Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
5 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
4.
Ha ve pr o vi de d tiss ue f or P D -L 1 a nal ys is fr o m a n arc hi val tiss ue sa m ple or ne wl y 
o btai ne d c ore or e xcisi o nal bi o ps y of a t u m or lesi o n n ot pre vi o usl y irra diate d.  A ne wly 
o btai ne d bi o ps y  is str o n gl y preferre d b ut n ot re q uire d if arc hi val tiss ue is a de q uate f or 
a nal ys is.  If s u b mitti n g u nstai ne d c ut sli des, fres hl y c ut sli des s h o ul d be s u b mitte d t o t he 
ce ntral la b orat or y wit hi n 1 4 da ys fr o m w he n t he sli des are c ut.  Refer t o Secti o n 9. 8. 1 i n 
t he pr ot oc ol f or a n e x pla nati o n.  P D -L 1  stat us (C P S ≥1 0 or C P S < 1 0 ) m ust be deter mi ne d 
b y  t he ce ntral la b orat or y pri or t o ra n d o mizati o n. Partici pa nts will be e xcl u de d if P D -L 1 
stat us ca n n ot be deter mi ne d.
5.
Ha ve recei ve d n o pri or s yste mic c he m ot hera p y f or a d va nce d/ u nresecta ble (i n o pera ble) or 
metastatic ur ot helial ca ncer
a.
A dj u va nt plati n u m base d c he m ot hera p y, f oll o wi n g ra di cal c ystect o my, wit h 
rec urre nce > 1 2 m ont hs fr o m c o m pleti o n of t hera p y  is per mitte d.
O R
b.
Ne oa dj u va nt plati n u m base d c he m ot hera p y, wit h rec urre nce > 1 2 m o nt hs si nce 
c o m pleti o n of t hera p y is per mitte d.
N ote: L o w -d ose c he m ot hera p y (e g, l o w d ose cis plati n, cis plati n + f l u or o uracil ( 5-F U ), 
mi t o m yci n + 5- F U, or cis plati n + paclita xel) gi ve n c o nc urre nt wit h ra diati o n t o t he 
pri mar y  t u m or site is n ot c o nsi dere d as s yste mic t hera p y.  I n t he cli nical setti n g, 
c he m ot hera p y is gi ve n wit h t he s ole p ur p ose of se nsitizi n g t he t u m or t o l ocal ra diati o n.  It 
is n ot a d mi nistere d at d oses wit h a ny s ys te mic efficac y. S ur ger y  is n ot c o nsi dere d first-
li ne t hera py f oll o wi n g dia g n osis of a d va nce d/ metastatic disease.
De m o gr a p hics
6.
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.
7.
Ha ve a P S of 0, 1 or 2 wit hi n 1 4 da y s pri or t o ra n d o mizati o n o n t he E C O G Perf or ma nce 
Scale .
Male partici pa nts:
8.
A male partici pa nt m ust a gree t o use a c o ntrace pti o n as detaile d i n A p pe n di x 5 of t his 
pr ot oc ol d uri n g t he treat me nt peri o d a n d f or at least 1 2 0 da y s after t he last d ose of st u d y 
treat me nt a n d refrai n fr o m d o nati n g s per m d uri n g t his peri o d.
Fe male partici pa nts:
9.
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt (see A p pe n di x 5 ), n ot 
breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies: 
a.) N ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P) as defi ne d i n A p pe n di x 5
O R 
b.) A W O C B P w h o a grees t o f oll o w t he c o ntrace pti ve g ui da nce i n A p pe n di x 5 d uri n g t he 
treat me nt peri o d a n d f or at least 1 2 0 d a y s (c orres p o n di n g t o ti me nee de d to eli mi nate a n y  
st u d y treat me nts ( M K-3 4 7 5 a n d e paca d ostat ) after t he last d ose of st u d y treat me nt.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
5 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
I nf or me d C o nse nt
1 0. T he partici pa nt ( or le gall y  acce pta ble re prese ntati ve if a p plica ble) pr o vi des writte n 
i nf or me d c o nse nt f or t he trial.
L a b or at or y V al ues
1 1. De m o nstrate a de q uat e or ga n f u ncti o n as defi ne d i n Ta ble 1 . All scree ni n g la bs m ust be 
c ollecte d wit hi n 1 4 da y s pri or t o ra n d o mizati o n.
Ta ble 1
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
He 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/ µ L
Platelets
≥1 0 0 0 0 0/ µ L
He m o gl o bi n
≥9. 0 g/ d L or ≥5. 6 m m ol/ L a
Re n al
Creati ni ne O R
Meas ure d or calc ulate d
b creati ni ne cleara nce
( G F R ca n als o be use d i n place of creati ni ne 
or Cr Cl)
≤1. 5 × U L N O R
≥3 0 m L / mi n f or partici pa nt wit h creati ni ne 
le vels > 1. 5 × i nstit uti o nal U LN
He p atic
T otal bilir u bi n
≤1. 5 × U L N O R direct bilir u bi n ≤U L N f or 
partici pa nt s wit h t otal bilir u bi n le vels 
> 1. 5 × U L N .  
If t here is n o i nstit uti o nal U L N, t he n direct 
bilir u bi n m ust be < 4 0 % of t otal bilir u bi n t o 
be eli gi ble. N ote: I n n o case ca n t he t otal 
bilir u bi n e xcee d 3 x U L N
A S T ( S G O T) a n d A L T ( S G P T)
≤2. 5 × U L N
C o a g ul ati o n
I nter nati o nal n or malize d rati o (I N R) O R
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)
or partial t hr o m b o plasti n ti me ( P T T) c
≤1. 5 × U L N u nless partici pa nt is recei vi n g 
a ntic oa g ula nt t hera p y as l o n g as P T or 
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
A L T ( S G P T) = ala ni ne a mi n otra nsferase (ser u m gl uta mic p yr u vic tra nsa mi nase); A S T ( S G O T) = as partate 
a mi n otra nsferase (ser u m gl uta mic o xal oacetic tra nsa mi nase); Cr Cl = creati ni ne cleara nce; G F R = gl o mer ular filtrati o n 
rate; U L N = u p per li mit of n or mal
a Criteria m ust be met wit h o ut er 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 2 wee ks.
b Creati ni ne cleara nce ( Cr Cl) s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.
c P T T ma y be perf or me d if t he l ocal la b is u na ble t o perf or m a P T T .
N ote: T his ta ble i ncl u des eli gi bilit y- defi ni n g la b orat or y val ue re q uire me nts f or treat me nt; la b orat or y val ue re q uire me nts 
s h o ul d be a da pte d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes f or t he a d mi nistrati o n of s pecific c he m ot hera pies.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
E xcl usi o n Criteri a 
6. 2
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Has disease t hat is s uita ble f or l ocal t hera p y a d mi nistere d wit h c urati ve i nte nt.
2.
Has a k n o w n a d diti o nal mali g na nc y  t hat is pr o gressi n g or has re q uire d acti ve treat me nt 
wit hi n t he past 3 ye ars.  
N ote:  Partici pa nt s wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he 
s ki n, or carci n o ma i n sit u (e g, breast carci n o ma, cer vical ca ncer i n sit u) t hat ha ve 
u n der g o ne p ote ntiall y c urati ve t hera p y are n ot e xcl u de d.   Partici pa nt s wit h l o w-ris k early 
sta ge pr ostate ca ncer defi ne d as f oll o ws are n ot e xcl u de d; Sta ge T 1c or T 2a wit h a 
Gleas o n sc ore ≤ 6 a n d pr ostatic -s pecific a nti gen ( P S A) < 1 0 n g/ m L eit her treate d wit h 
defi niti ve i nte nt or u ntreate d i n acti ve s ur veilla nce t hat has bee n sta ble f or t he past year 
pri or t o st u d y all ocati o n.
3.
Has k n o w n acti ve ce ntral ner v o us s ys te m (C N S ) metastases a n d/ or carci n o mat o us 
me ni n gitis.  Parti ci pa nt s wit h pre vi o usl y treate d brai n metastases ma y partici pate 
pr o vi de d t he y  are ra di ol o gicall y sta ble, ie, wit h o ut e vi de nce of pr o gressi o n f or at least 4 
wee ks b y re peat i ma gi n g, ( n ote t hat re peat i ma gi n g s h o ul d be perf or me d d uri n g t he st u dy 
scree ni n g), cli nicall y sta ble a n d wit h o ut re q uire me nt of ster oi d treat me nt f or at least 1 4 
da y s pri or t o first d ose of st u d y treat me nt.
4.
Has a n acti ve a ut oi m m u ne disease t hat has re q uire d s y ste mic treat me nt i n past 2 years 
(ie, wit h use of disease m o dif yi n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve dr u gs).  
Re place me nt t hera p y (e g, t h y r o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d re place me nt 
t hera py f or a dre nal or pit uitar y i ns ufficie nc y) is n ot c o nsi dere d a f or m of s yste mic 
treat me nt a n d is all o we d.
5.
Has a dia g n osi s of i m m u n o deficie nc y or is recei vi n g c hr o nic sys te mic ster oi d t hera py (i n 
d osi n g e xcee di n g 1 0 m g dail y  of pre d nis o ne e q ui vale nt) or a ny ot her f or m of 
i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t he first d ose of st u d y treat me nt.
6.
Has a hist or y  of ( n o n-i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
7.
Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera py.
8.
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) i nfecti o n.  N o HI V testi n g 
is re q uire d u nless ma n date d b y l ocal healt h a ut h orit y.
9.
Has k n o w n hist or y  of or is p ositi ve f or acti ve He patitis B ( He patitis B s urface a nti ge n 
[H Bs A g ] reacti ve) or has acti ve He patitis C ( H C V R N A). N ote: Testi n g m ust be 
perf or me d t o deter mi ne eli gi bilit y . 

H B V D N A m ust be u n detecta ble a n d H Bs A g ne gati ve at scree ni n g visit.

He patitis C A b testi n g is all o we d f or scree ni n g p ur p oses i n c o u ntries w here H C V 
R N A is n ot part of S O C.  I n t hese cases, H C V a nti b o d y  p ositi ve pa rtici pa nts will 
be e xcl u de d.  
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial

Partici pa nt s w h o ha ve ha d defi niti ve treat me nt f or H C V are per mitte d if H C V 
R N A u n detecta ble at S cree ni n g V isit.
1 0. Has a hist or y  of a gastr oi ntesti nal c o n diti o n or pr oce d ure t hat i n t he o pi ni o n of t he 
I n vesti gat or ma y affect oral dr u g a bs or pti o n.
1 1. Has a hist or y  or presence of a n a b n or mal electr ocar di o gra m ( E C G) t hat, i n t he 
i n vesti gat or's o pi ni o n, is cli nicall y mea ni n gf ul.  Scree ni n g c orrecte d Q T i nter val (Q Tc )
i nter val > 4 8 0 millisec o n ds is e xcl u de d (c orrecte d b y Fr idericia or Bazett f or m ula ).  I n the 
e ve nt t hat a si n gle Q Tc is > 4 8 0 millisec o n ds, t he partici pa nt m a y  e nr oll if t he a vera ge 
Q Tc f or t he 3 E C Gs is < 4 8 0 millisec o n ds.
1 2. 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 a b 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 with t he partici pa nt 's partici pati o n 
f or t he f ull d urati o n of t he trial, or is n ot i n t he best i nterest of t he partici pa nt t o 
partici pate, i n t he o pi ni o n of t he treati n g i n vesti gat or.
1 3. 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 n g 
wit h t he re q uire me nts of t he st u d y.
1 4. A W O C B P w h o has a p ositi ve uri ne pre g na nc y  test wit hi n 7 2 h o urs bef ore ra n d o mizati o n 
(see A p pe n di x 5).  If t he uri ne test ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y 
test is re q uire d.  I n s uc h cases, t he partici pa nt m ust be e xcl u de d fr o m partici pati o n if t he 
ser u m pre g na nc y res ult is p ositi ve.
N ote: I n t he e ve nt t hat > 7 2 h o urs ha ve ela pse d bet wee n t he scree ni n g pre g na nc y  test a n d 
t he first d ose of st u dy treat me nt, a n ot her pre g na nc y test ( uri ne or ser um) m ust be 
perf or me d a n d m ust be ne gati ve i n or der f or partici pa nt t o start recei vi n g st u d y  treat me nt.
1 5. 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 h r o u g h 1 2 0 da ys after t he 
last d ose of pe m br oliz u ma b a n d e paca d ostat/ matc hi n g place b o.
Pri or/ C o nc o mit a nt T her a p y
1 6. Has recei ve d pri or t hera p y wit h a n a n ti-P D -1, a nti -P D -L 1, a nti P D-L 2 a ge nt , ID O 1 
i n hi bit or, or wit h a n a ge nt directe d t o a n ot her sti m ulat or y  or c o-i n hi bit or y T-cell recept or 
(e g, C T L A-4, O X 4 0, C D 1 3 7), or a n y ot her a nti b o d y  or dr u g tar geti n g T-cell c o-
sti m ulat or y pat h wa ys i n t he a dj u va nt or a d va nce d/ metastatic setti n g.
1 7. Has recei ve d pri or s yste mic a nti-ca ncer t hera p y i ncl u di n g i n vesti gati o nal a ge nts wit hi n 4 
wee ks pri or t o ra n d o mizati o n.
N ote: Partici pa nt s m ust ha ve rec o vere d fr o m all A Es d ue t o pre vi o us t hera pies t o ≤Gra de 
1 or baseli ne. Partici pa nt s wit h ≤Gra de 2 ne ur o pat h y  ma y be eli gi ble.
N ote: If partici pa nt recei ve d maj or s ur ger y, t he y m ust 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 om t he i nter ve nti o n pri or t o starti n g st u d y treat me nt.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
1 8. Has recei ve d pri or ra di ot hera p y wit hi n 2 wee ks of start of trial treat me nt.   Partici pa nt s 
m ust ha ve rec o vere d fr o m all ra diati o n -relate d t o xicities, a n d n ot re q uire c ortic oster oi ds.  
A 1 -wee k was h o ut is per mitte d f or palliati ve ra diati o n ( ≤2 wee ks of ra di ot hera p y) t o n o n -
C N S disease.
1 9. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys pri or t o t he first d ose of trial dr u g.  E xa m ples 
of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  measles, m u m ps, r u bella, 
varicella/z oster (c hic ke n p o x), y ell o w fe ver, ra bies, Bacill us Cal mette – G uéri n ( B C G), 
a n d t yp h oi d vacci ne.  Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d vir us 
vacci nes a n d are all o we d; h o we ver, i ntra nasal i nfl ue nza vacci nes are li ve atte n uate d 
vacci nes a n d are n ot all o we d.
2 0. Has recei ve d t hera p y wit h a M A OI, or U G T 1 A 9 i n hi bit or wit hi n 2 1 da y s pri or t o starti n g 
treat me nt, or a ntici pates re q uiri n g o ne of t hese pr o hi bite d me dicati o ns d uri n g t he 
treat me nt p hase. E xa m ples of me dicati o ns i n t hese classes are f o u n d i n Secti o n 7. 7 –
C o nc o mita nt T hera p y.
2 1. Has a n y hist or y  of Ser ot o ni n S y n dr o me after recei vi n g ser ot o ner gic dr u gs.
2 2. Has se vere h y perse nsiti vit y ( ≥Gra de 3) t o st u d y treat me nt (pe m br oliz u ma b a n d 
e paca d ostat) a n d/ or a n y of its e xci pie nts.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 3. Is c urre ntl y partici pati n g i n or has partici pate d i n a trial of a n i n vesti gati o nal a ge nt or has 
use d a n i n vesti gati o nal de vice wit hi n 4 wee ks pri or t o t he first d ose of trial treat me nt.
N ote:  Partici pa nt s w h o ha ve e ntere d t he F oll o w -u p P hase of a n i n vesti gati o nal trial ma y  
partici pate as l o n g as it has bee n 4 wee ks after t he last d ose of t he pre vi o us 
i n vesti gati o nal a ge nt.
Lifest yle Restricti o ns
6. 3
Me als a n d Diet ar y Restricti o ns
6. 3. 1
Partici pa nts s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n A E 
s uc h as diarr hea, na usea, or v o miti n g.
C o ntr ace pti o n
6. 3. 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.
De vel o p me ntal a n d re pr o d ucti ve t o xicit y  st u dies ha ve n ot bee n perf or me d wit h e paca d ostat . 
E paca d ostat s h o ul d n ot be use d b y pre g na nt w o me n.
Partici pa nt s s h o ul d be i nf or me d t hat ta ki n g t he st u d y treat me nt m a y  i n v ol ve u n k n o w n ris ks t o t he 
fet us ( u n b or n ba by)  if pre g na nc y were t o occ ur d uri n g t he st u d y.  I n or der t o partici pate i n t he 
st u d y, partici pa nt s 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 ve i n Secti o n 6. 1 Incl usi o n Criteria ) fr o m t he da y of st u d y treat me nt i nitiati o n ( or 
1 4 da y s pri or t o t he i nitiati o n of st u d y treat me nt f or oral c o ntrace pti o n) t hr o u g h o ut t he st u d y
peri o d u p t o 1 2 0 da y s after t he last d ose of st u d y treat me nt.  If t here is a ny q uesti o n t hat a 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
partici pa nt of c hil d beari n g p ote ntial will n ot relia bl y  c o m ply wit h t he re q uire me nts f or 
c o ntrace pti o n, t hat partici pa nt s h o ul d n ot be e ntere d i nt o t he st u d y.
Defi niti o ns of W O C B P a n d sta n dar ds f or a de q uate c o ntrace pti o n are o utli ne d i n A p pe n di x 5.
Pre g n a nc y
6. 3. 3
If a partici pa nt bec o mes pre g na nt w hile o n treat me nt wit h pe m br oliz u ma b a n d/ or e paca d ostat , 
t he partici pa nt will be i m me diatel y  disc o nti n ue d fr o m st u d y treat me nt.  T he site will c o ntact t he 
partici pa nt at least m o nt hl y a n d d oc u me nt t he partici pa nt ’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 M S D
wit h o ut 
dela y  a n 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 a n 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 M S D .  If a male 
partici pa nt i m pre g nates his fe male part ner, t he st u d y pers o n nel at t he site m ust be i nf or me d
i m me diatel y a n d t he pre g na nc y m ust be re p orte d t o M S D
a n d f oll o we d as descri be d i n 
Secti o n 9. 3. 6 .
Use i n N ursi n g W o me n
6. 3. 4
It is u n k n o w n w het her pe m br oliz u ma b or e paca d ostat 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, partici pa nt s w h o are breastfee di n g are n ot eli gi ble f or e nr oll me nt.
Scree n F ail ures
6. 4
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y  ra n d o mize d.  A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o e ns ure 
tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet t he C o ns oli date d Sta n dar ds of 
Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y  
a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, eli gi bilit y criteria, 
a n d a n y A Es or S A E s meeti n g re p orti n g re q uire me nts as o utli ne d i n t he e ntr y g ui deli nes.
P artici p a nt Re pl ace me nt Str ate g y
6. 5
A partici pa n t w h o disc o nti n ues fr o m st u d y treat me nt or wit h dra ws fr o m t he st u d y will n ot be 
re place d.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
7.
Tre at me nts
St u d y  treat me nt is defi ne d as a ny i n vesti gati o nal treat me nt(s), mar kete d pr o d uct(s), place b o, or 
me dical de vice (s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u d y 
pr ot oc ol.
Cli nical s u p plies [st u d y  treat me nt(s) pr o vi de d by M S D ] will be pac ka ge d t o s u p p ort e nr oll me nt.
Cli nical s u p plies will be affi xe d wit h a cli nical la bel i n acc or da nce wit h r e g ulat or y re q uire me nts.
Tre at me nts A d mi nistere d
7. 1
T he st u d y  treat me nts t o be use d i n t his trial are o utli ne d bel o w i n Ta ble 2 .
Ta ble 2
St u d y  Treat me nts
St u d y 
Tre at m e nt 
N a m e
D os a ge 
F o r m ul ati o n
U nit D ose 
Stre n gt h(s)
D os a ge Le vel
R o ute of 
A d mi nistr ati o n
S o urci n g
Pe m br oliz u ma b
S ol uti o n f or 
I V i nf usi o n
2 5 m g/ m L
2 0 0 m g Q 3 W
D a y  1 of eac h 
c ycle f or u p t o 
3 5 c ycles 
I V i nf usi o n
Pr o vi de d ce ntrall y 
E paca d ostat or 
E paca d ostat 
Place b o
Ta blet
1 0 0 m g
1 0 0 m g BI D 
c o nti n u o usl y f or 
u p t o 3 5 c ycles
Oral
Pr o vi de d ce ntrall y 
E paca d ostat or 
E paca d ostat 
Place b o
Ta blet
2 5 m g
2 5 m g or 
5 0 m g * BI D 
c o nti n u o usl y f or 
u p t o 3 5 c ycles
Oral
Pr o vi de d ce ntrall y 
* E paca d ostat or matc hi n g place b o ma y be re d uce d t o 5 0 m g BI D ( Le vel -1) or 2 5 m g BI D ( Le vel -2) t o m iti gate i m m u ne-relate d 
A Es (ir A Es), if i n dicate d i n Ta ble 3 .
A b bre viati o ns: BI D = t wice dail y; I V = i ntra ve n o us; Q 3 W = e ver y 3 wee ks.
All place b os were create d b y  t he S p o ns or t o matc h t he acti ve pr o d uct.
All pr o d ucts i n dicate d i n Ta ble 2 will be pr o vi de d ce ntrall y b y  M S D or l ocall y by t he trial site, 
s u bsi diar y, or desi g nee, de pe n di n g o n l ocal c o u ntr y o perati o nal or re g ulat or y  re q uire me nts.  
E v er y atte m pt s h o ul d 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.
Refer t o S ecti o n 9. 1. 9 f or details re gar di n g a d mi nistrati o n of t he st u d y treat me nt.
As of A me n d me nt 0 4, partici pa nts w h o c o nti n ue st u d y treat me nt after u n bli n di n g will n o lo n ger 
be dis pe nse d e paca d ostat place b o.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
D ose M o dific ati o n ( Esc al ati o n/ Titr ati o n/ Ot her) 
7. 2
D ose M o dific ati o n
7. 2. 1
D ose m o dificati o n a n d t o xicit y  ma nage me nt f or i m m u ne -relate d A Es (ir A Es) ass ociate d wit h 
pe m br oliz u ma b a n d/ or e paca d ostat or matc hi n g place b o s h o ul d be ma na ge d as f oll o ws. 
A Es ass ociate d wit h pe m br oliz u ma b a n d e paca d ostat e x p os ure ma y re prese nt a n i m m u n ol o gic 
eti ol o g y. T hese ir A Es m a y  occ ur s h ortl y after t he first d ose or se veral m o nt hs after t he last d ose 
of treat me nt a n d ma y  affect m ore t ha n o n b o dy s yste m si m ulta ne o usl y . T heref 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 trial data, m ost ir A Es wer e 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 t ests s uc h as br o nc h osc o p y, e n d osc o p y , s ki n bi o ps y 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 e paca d ostat/ matc hi n g place b o a n d a d mi nister c ortic oster oi ds.
Ta ble 3 s u m marizes t he ir A E d ose m o dificati o n acti o ns f or pe m br oliz u ma b a n d 
e paca d ostat/ matc hi n g place b o. Of n ote, partici pa nts w h o re q uire d ose re d ucti o n of 
e paca d ostat/ matc hi n g place b o d ue t o A Es will re mai n at t he l o wer d ose, s u m marize d i n Ta ble 4 .
Re -escalati o n of e paca d ostat or matc hi n g place b o is n ot per mitte d.
I n cases w here pe m br oliz u ma b d osi n g is hel d, d osi n g f or e paca d ostat/ matc hi n g place b o m ust 
als o be hel d u ntil pe m br oliz u ma b ma y res u me. Partici pa nts are all o we d, h o we ver, t o recei ve 
pe m br oliz u ma b m o n ot hera p y at t he I n vesti gat or’s discreti o n u p o n i m pr o ve me nt of t he ir A E t o 
Gra de 0 or 1, u nless disc o nti n uati o n of b ot h st u d y  treat me nts is s pecifie d i n Ta ble 3 (e g, if t he 
t o xicit y was c o nsi dere d relate d t o t he c o m bi nati o n t hera py a n d n ot pe m br oliz u ma b 
m o n ot hera p y).
E xce pt i n cases of e mer ge nc y , it is rec o m me n de d t hat t he In vesti gat or c o ns ult wit h t he me dical 
m o nit or ( or ot her re prese ntati ve of M S D) bef ore te m p oraril y i nterr u pti n g t hera p y f or reas o ns 
ot her t ha n pr ot oc ol -ma n date d me dicat i o n h ol d.
 
 
0 4 Y B Q D






















Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
7 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial

If partici pa nt c h o oses t o wit h dra w fr o m t he st u d y,  or m ust restart treat me nt wit h S S RI or 
S N RI , t he partici pa nt s h o ul d be sc he d ule d f or a f oll o w-u p visit.  Treat me nt wit h S S RI  or 
S N RI  ma y be i nitiate d 2 wee ks after res ol uti o n of si g ns a n d sy m pt o ms of S S.

If a partici pa nt ha d e x perie nce d m o derate or se vere u nc o nf o u n de d S S i n t he o pi ni o n of 
t he in vesti gat or, wit h o ut c o nc o mita nt S S RI  or S N RI usa ge, or ser ot o ner gic c o nc o mita nt 
me dicati o ns, o nl y  pe m br oliz u ma b a d mi nistrati o n ma y be res u me d; e paca d ostat/ place b o 
treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d.
Ta ble 5
Si g ns a n d S y m p t o ms of Ser ot o ni n S yn dr o me
Seri o us ness
A ut o n o mic 
si g ns 
Ne ur ol o gic al 
si g ns 
Me nt al st at us 
Ot her
Mil d
Afe brile or l o w -
gra de fe ver
Tac h yc ar dia
M y driasis
Dia p h oresis or 
s hi veri n g
I nter mitte nt 
tre m or
A kat hisia
M y ocl o n us
Mil d 
h y perrefle xia
Restless ness
A n xiet y
M o der ate
I ncrease d 
Tac h yc ar dia
Fe ver ( u p t o 
4 1 C)
Diarr hea wit h 
h y peracti ve 
b o wel s o u n ds
Dia p h oresis wit h 
n or mal s ki n c ol or
H y perrefle xia
I n d uci ble cl o n us
Oc ular cl o n us 
(sl o w c o nti n u o us 
lateral e ye 
m o ve me nts)
M y ocl o n us
Easil y  startle d
I ncrease d 
c o nf usi o n
A gitati o n a n d 
h y per vi gila nce
R ha b d o m y ol ys is
Meta b olic 
aci d osis
Re nal Fail ure
Disse mi nate d 
i ntra vasc ular 
c oa g ul o pat h y 
(sec o n dar y t o 
h y pert her mia)
Se vere
Te m perat ure 
ofte n m ore t ha n 
4 1 C ( Sec o n dar y  
t o i ncrease d 
t o ne)
I ncrease d m uscle 
t o ne (l o wer li m b 
> u p per)
S p o nta ne o us 
cl o n us
S u bsta ntial 
m y ocl o n us or 
h y perrefle xia
Deliri u m
C o ma
As a b o ve
S o urce: [ B o yer, E. W. 2 0 0 5]
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
7 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-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 
7. 2. 1. 2
P e m br oliz u m a b
Pe m br oliz u ma b ma y  ca use se vere or life t hreate ni n g i nf usi o n-reacti o ns i ncl u di n g se vere 
h y perse nsiti vit y  or a na p h yla xis. Si g ns a n d s y m pt o ms us uall y  de vel o p d uri n g or s h ortl y after 
dr u g i nf usi o n a n d ge nerall y  res ol ve c o m pletely 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 ovi de d i n Ta ble 6 .
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
7 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Ta ble 6
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 partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
N o ne
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 partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
If s y m pt o ms res ol ve wit hi n 1 h o ur of st o p pi n g dr u g 
i nf usi o n, t he i nf usi o n ma y be restarte d at 5 0 % of t he 
ori gi nal i nf usi o n rate (e g fr o m 1 0 0 m L/ hr t o 5 0 m L/ hr).  
Ot her wise d osi n g will be hel d u ntil s y m pt o ms res ol ve a n d 
t he partici pa nt s h o ul d be pre me dicated f or t he ne xt 
sc he d ule d d ose.
P artici p a nt s w h o de vel o p Gr a de 2 t o xicit y des pite 
a de q u ate pre me dic ati o n s h o ul d be 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
Partici pa nt ma y be pre me dicate d 1. 5 h ( ± 3 0 mi n utes) pri or 
t o i nf usi o n of p e m br oliz u ma b 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 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
7 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 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 mpair m e 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 dit i 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 partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla xis, e pi ne p hri ne s h o ul d be use d 
i m me diatel y.
P artici p a nt is per ma ne ntl y disc o nti n ue d fr o m  f urt her 
st u d y dr u g tre at me nt.
N o s u bse q ue nt d o si n g
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g t he peri o d of dr u g a d mi nistrati o n.
F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 4. 0 ( C T C A E ) at htt p://cte p.ca ncer. g o v.
C T C A E = C o m m o n Ter mi n ol o g y C riteria f or A d verse E ve nts; I V =i ntra ve n o us; N CI =Nat i o nal Ca ncer I nstit ute; N S AI Ds =n o nster oi dal a nti-i nfla m mat or y dr u gs; P O = oral .
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Interr u pti o n s U nrel ate d t o A d verse E ve nts
7. 2. 1. 3
D osi n g i nterr u pti o ns are per mitte d f or sit uati o ns ot her t ha n treat me nt-relate d A Es, s uc h as 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 treat me nt (e g, 
electi ve s ur ger y, u nrelate d me dical e ve nts, partici pa nt vacati o n, or h oli da ys). Partici pa nt s
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 ot her wise disc usse d wit h M S D . 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 p artici pa nt’s st u d y rec or d.
Sec o n d C o urse P h ase ( Retre at me nt)
7. 2. 2
N O T E: As of A me n d me nt 0 4, dise ase assess me nt will be p erf or me d b y t he i n vesti g at or 
per l oc al S o C g ui deli nes; pl ace b o will n ot be a d mi nistere d after u n bli n di n g. T his 
secti o n h as bee n u p d ate d acc or di n gl y.
All partici pa nts w h o st o p st u d y treat me nt wit h S D or better ma y be eli gi ble f or u p t o a n 
a d diti o nal 1 7 c yc les (a p pr o xi matel y 1 year) o f c o m bi nati o n treat me nt of pe m br oliz u ma b pl us 
e paca d ostat or pe m br oliz u ma b m o n ot hera p y if t he y pr o gress after st o p pi n g trial treat me nt 
fr o m t he i nitial treat me nt p hase. T his retreat me nt is ter me d t he Sec o n d C o urse P hase of t his
trial a n d is o nl y a vaila ble if t he trial re mai ns o pe n a n d t he partici pa nt meets t he f oll o wi n g 
c o n diti o ns:
Eit her

St o p pe d i nitial treat me nt wit h trial treat me nt after attai ni n g C R e val uate d b y  t he l ocal 
i n vesti gat or base d o n R E CIS T 1. 1, a n d
o
Was treate d wit h at least 8 c y cles of trial treat me nt bef ore disc o nti n ui n g 
treat me nt, a n d
o
Recei ve d at least 2 treat me nts wit h pe m br oliz u ma b be yo n d t he date w he n t he 
i nitial C R was declare d
O R

Ha d S D, P R, or C R a n d st o p pe d trial treat me nt after c o m pleti o n of 3 5 c ycles 
(a ppr o xi matel y  2 years) of trial treat me nt
A N D

E x perie nce d ra di o gra p hic disease pr o gressi o n verifie d b y in vesti gat or assess me nt
base d o n R E CI S T 1. 1 after st o p pi n g i nitial treat me nt, a n d
o
N o ne w a ntica ncer treat me nt was a d mi nistere d after t he last d ose of trial
treat me nt, a n d
o
T he partici pa nt meets all of t he safet y p ara meters liste d i n t he i ncl usi o n criteria 
a n d n o ne of t he safet y para meters liste d i n t he e xcl usi o n criteria, a n d
o
T he trial is o n g oi n g.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Partici pa nts w h o e nter t he Sec o n d C o urse P hase will be retreat e d wit h t he sa me c o m bi nati o n
a n d e paca d ostat d ose le vel as w he n t he y  last recei ve d t he c o m bi nati o n of pe m br oliz u ma b 
pl us e paca d ostat or pe m br oliz u ma b m o n ot hera p y i n t he i nitial treat me nt p hase, u nless a 
st u d y-wi de decisi o n is ot her wise a n n o u nce d b y t he D M C or S p o ns or via a n a d mi nistrati ve 
me m o .  N ote :  If e paca d ostat was disc o nti n ue d it s h o ul d n ot be restarte d.
Treat me nt will be 
a d mi nistere d f or u p t o a n a d diti o nal 1 7 c ycles (a p pr o xi matel y 1 year) usi n g t he Sec o n d 
C o urse P hase S o A i n Secti o n 2. 2.
A n o bject i ve res p o nse or disease pr o gressi o n t hat occ urs d uri n g t he Sec o n d C o urse P hase f or 
a partici pa nt will n ot be c o u nte d as a n e ve nt f or t he pri mar y  a nalys is of t his st u d y.
Met h o d of Tre at me nt Assi g n me nt 
7. 3
Treat me nt all ocati o n/ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve v oice res p o nse 
s yste m / i nte grate d we b res p o nse sys te m (I V R S/I W R S).  T here are 2 st u d y treat me nt ar ms.  
Partici pa nts 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 + e paca d ostat or 
pe m br oliz u ma b + e paca d ostat matc hi n g place b o.
Str atific ati o n
7. 3. 1
Treat me nt all ocati o n/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:
1.
Baj or i n ris k sc ore; base d o n t he prese nce of visceral (l u n g, li ver, or b o ne) metastasis a n d/ 
or K P S < 8 0 %.
a.
0 ( neit her criteri o n)
b.
1 (e xactl y  1 criteri o n)
c.
2 ( b ot h criteri o n)
2.
P D -L 1  E x pressi o n 
d.
C P S ≥1 0 per I HC assa y
e.
C P S < 1 0 per I H C assa y
Bli n di n g 
7. 4
A d o u ble -bli n di n g tec h ni q ue wit h i n -h o use bli n di n g will be use d.  E paca d ostat a n d matc hi n g 
place b o will be pac ka ge d i de ntica ll y s o t hat t he bli n d is mai ntai ne d.   T he partici pa nt, t he 
i n vesti gat or, t he S p o ns or , M S D st u d y pers o n nel , or dele gate(s) w h o are i n v ol ve d i n t he st u d y  
treat me nt a d mi nistrati o n or cli nical e val uati o n of t he partici pa nts are u na ware of t he gr o u p 
assi g n me nts.
N O T E: As of A me n d me nt 0 4, t he st u d y will be u n bli n de d after t he l ast p artici p a nt 
c o m pletes Wee k 9 i m a gi n g assess me nt f or effic ac y a n al ysis. After u n bli n di n g, f or 
p artici p a nts w h o are be nefiti n g fr o m st u d y tre at me nt a n d u p o n disc ussi o n wit h t he 
i n vesti g at or, t he p artici p a nt, st u d y site pers o n nel, S p o ns or, a n d M S D or desi g nee will 
be i nf or me d of t he st u d y tre at me nt t he y recei ve (e g, pe m br oliz u m a b, or 
pe m br oliz u m a b i n c o m bi n ati o n wit h e p ac a d ost at) .
Pe m br oliz u ma b, w hic h will be d ose d t o all partici pa nts i n b ot h trea t me nt ar ms, will n ot be 
bli n de d.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
See Secti o n 9. 1. 1 1 f or a descri pti o n of t he met h o d of u n bli n di n g a partici pa nt d uri n g t he trial, 
s h o ul d s uc h acti o n be warra nte d.
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y
7. 5
D ose Pre p ar ati o n
7. 5. 1
Details o n pre parati o n a n d a d mi nistrati o n of I V pe m br oliz u ma b are pr o vi de d i n t he 
P har mac y  Ma n ual.  E paca d ostat a n d matc hi n g place b o are oral ta blets a n d d o n ot re q uire 
pre parati o n.
F or e paca d ostat i n s uc h cases w here a partici pa nt is u na ble t o s wall o w ta b lets or has a 
fee di n g t u be i nstr ucti o n f or d ose cr us hi n g, a d mi nistrati o n a n d d ose pre parati o n are detaile d i n 
t he P har mac y Ma n ual.  I n a d diti o n writte n g ui da nce f or safe ha n dli n g of t he e paca d ostat 
ta blets will be pr o vi de d t o t he partici pa nt/care gi vers.
H a n dli n g, St or a ge a n d Acc o u nt a bilit y
7. 5. 2
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y treat me nt recei ve d a n d a n y discre pa ncies are re p orte d 
a n d res ol ve d bef ore use of t he st u d y treat me nt.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nl y a ut h orize d site 
staff ma y s u p ply or a d mi nister st u d y treat me nt. All st u d y treat me nts m ust be st ore d i n a 
sec ure, e n vir o n me ntally c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o m ate d) area i n acc or da nce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d site 
staff.
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u dy treat me nt acc o u nta bilit y , rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
F or all trial sites, t he l ocal c o u ntr y M S D
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 nt a bilit y a n d ret ur n, or l ocal discar d 
a n d destr ucti o n if a p pr o priate.  W here l ocal discar d a n d destr ucti o n is a p pr o priate, t he 
i n vesti gat or is res p o nsi ble f or e ns uri n g t hat a l ocal discar d/ destr ucti o n pr oce d ure is 
d oc u me nte d.
T he 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 ocally p urc 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 M S D .
T he i n vesti gat or s hall ta ke res p o nsi bilit y  f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p pl y, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of st u d y 
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.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 3
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Tre at me nt C o m pli a nce
7. 6
I nterr u pti o ns fr o m t he pr ot oc ol-s pecifie d treat me nt pla n f or greater t ha n 1 2 wee ks fr o m t he 
last d ose re q uire c o ns ultati o n bet wee n t he I n vesti gat or a n d M S D
a n d writte n d oc u me ntati o n 
of t he c olla b orati ve decisi o n o n partici pa nt ma na ge me nt.
A d mi nistr ati o n a n d C o m pli a nce of Pe m br oliz u m a b
7. 6. 1
A d mi nistrati o n of I V pe m br oliz u ma b wil l be wit nesse d by t he I n vesti gat or a n d/ or st u d y staff.  
T he t otal v ol u me of st u d y treat me nt i nf use d will be c o m pare d wit h t he t otal v ol u me pre pare d 
t o deter mi ne c o m plia nce wit h eac h d ose a d mi nistere d.  Pe m br oliz u ma b will be a d mi nistere d 
o n a n o ut patie nt ba sis.  
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 are pr o vi de d i n t he P har mac y 
Ma n ual.
A d mi nistr ati o n a n d C o m pli a nce of E p ac a d ost at or M atc hi n g Pl ace b o
7. 6. 2
Partici pa nts will ta ke t heir d ose of e paca d ostat or matc hi n g place b o i n t he m or ni n g a n d 
e ve ni n g, a p pr o xi matel y 1 2 h o urs a part wit h o ut re gar d t o f o o d. If t he m or ni n g or e ve ni n g 
d ose is misse d b y  m ore t ha n 4 h o urs, t hat d ose s h o ul d be s ki p pe d a n d t he ne xt sc he d ule d 
d ose s h o ul d be ta ke n at t he us ual ti me. If t he partici pa nt v o mits after ta ki n g a ta blet, t he d ose 
s h o ul d n ot be re-a d mi nistere d u ntil t he ne xt sc he d ule d d ose.   Partici pa nts will self -a d mi nister 
e paca d ostat or matc hi n g place b o e xce pt o n C y cle 1 Da y 1 (C 1 D 1 ), a n d C y cle 2 Da y 1 
(C 2 D 1 ), w he n t he m or ni n g d ose will be gi ve n at t he st u d y s ite cli nic pri or t o t he 
pe m br oliz u ma b i nf usi o n.
Partici pa nts will be i nstr ucte d t o bri n g all st u d y treat me nts wit h t he m t o t he st u d y visit s i n 
or der f or site pers o n nel t o c o n d uct ta blet c o u nts t o assess st u d y treat me nt acc o u nta bilit y .  
In vesti gat ors a n d t h eir staff s h o ul d e val uate c o m plia nce at eac h visit, a n d ta ke a p pr o priate 
ste ps t o o pti mize c o m plia nce.
C o nc o mit a nt T her a p y
7. 7
Acce pt a ble C o nc o mit a nt Me dic ati o ns
7. 7. 1
All treat me nts t hat t he i n vesti gat or c o nsi ders necessar y f or a partici pa nt’s welfare ma y be 
a d mi nistere d or c ha n ge 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 a n d pr o hi bite d me dicati o ns i n t his st u d y .  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, her bal s u p ple me nts, a n d I V me dicati o ns a n d fl ui ds. If c ha n ges occ ur d uri n g t he 
st u d y peri o d, d oc u me ntati o n of dr u g d osa ge fre q ue nc y, r o ute, a n d date will als o be i ncl u de d 
o n t he C R F.
Palliati ve a n d s u p p orti ve care is per mitte d d uri n g t he c o urse of t he st u d y f or u n derl yi n g 
me dical c o n diti o ns a n d ma na ge me nt of s y m pt o ms. S ur ger y  f or t u m or c o ntr ol is n ot 
per mitte d d uri n g t he st u d y. Palliati ve r a di ot hera p y is per mitte d t o a li mite d n u m ber of 
lesi o ns if c o nsi dere d me dicall y necessar y by t he treati n g p h ys icia n as l o n g as t he lesi o ns are 
N O T a R E CI S T 1. 1 -defi ne d tar get lesi o n. St u d y  treat me nt s h o ul d be hel d d uri n g t he c o urse 
of palliati ve ra di ot her a p y a n d s h o ul d be res u me d n o earlier t ha n t he ne xt sc he d ule d 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
a d mi nistrati o n of st u d y treat me nt. T he s pecifics of t he ra diati o n treat me nt, i ncl u di n g t he 
l ocati o n, will be rec or de d.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da y s bef ore t he first d ose of st u d y treat me nt 
t hr o u g h t he Safety F oll o w -u p Visit s h o ul d be rec or de d. After t he Safet y  F oll o w-u p Visit, 
rec or d all me dicati o ns ta ke n f or S A Es a n d E CIs as defi ne d i n Secti o n 9. 3 . If a partici pa nt 
e nters i nt o sec o n d c o urse t hera p y, all c o nc o mita nt me dic ati o ns recei ve d wit hi n 3 0 da ys 
bef ore t he first d ose of sec o n d c o urse treat me nt s h o ul d be rec or de d. F oll o wi n g sec o n d 
c o urse t hera p y Safet y F oll o w -u p Visit, rec or d all me dicati o ns ta ke n f or S A Es a n d E CI s as 
defi ne d i n Secti o n 9. 3.
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
7. 7. 2
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e xcl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g st u d y.  If t here is a cli nical i n dicati o n f or a n y me dicati o n or vacci nati o n 
s pecifically pr o hi bite d, 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.  
T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he M S D Cli nical Direct or.  
T he fi nal decisi o n o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h t he i n vesti gat or a n d/ or 
t he partici pa nt's pri mar y p h ysicia n.  H o we ver, t he decisi o n t o c o nti n ue t he partici pa nt o n 
st u d y treat me nt re q uires t he m ut ual a gree me nt of t he i n vesti gat or, M S D, a n d t he partici pa nt.
St u d y  partici pa nts w h o m ust be gi n treat me nt wit h a me dicati o n pr o hi bite d f or c o nc o mita nt 
use wit h e paca d ostat ma y be treate d as cli nicall y i n dicate d; h o we ver, treat me nt wit h 
e paca d ostat ( or place b o) m ust be disc o nti n ue d.  E xa m ples of s uc h me dicati o ns i ncl u de M A O 
i n hi bit ors, a n d U G T 1 A 9 i n hi bit ors.  Partici pa nts ma y  c o nti n ue o n treat me nt wit h 
pe m br oliz u m a b after c o ns ultati o n wit h M S D.
Liste d bel o w are s pecific restricti o ns f or c o nc o mita nt t hera p y or vacci nati o n:
Partici pa nts 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 Sec o n d C o urse P hases of t his st u d y:
1.
In ves ti gati o nal a ge nts ot her t ha n pe m br oliz u ma b a n d e paca d ostat .
2.
A nti -ca ncer me dicati o ns, i ncl u di n g c he m ot hera p y or bi ol o gic t hera p y ot her t ha n t he 
st u d y treat me nts.
3.
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol.
4.
Pr ol o n ge d t hera p y wit h s yste mic gl uc oc ortic oi ds ( > 7 da y s) f or a ny p ur p ose ot her t ha n t o 
m o d ulate s y m pt o ms fr o m a n A E, S A E, or e ve nt of cli nical i nterest ( E CI ) or f or use as a 
pre -me dicati o n f or c he m ot hera py or i n partici pa n ts wit h a k n o w n hist or y of a n I V 
c o ntrast aller g y a d mi nistere d as part of c o m p ute d t o m o gra p h y ( C T) ra di o gra p h y. Brief, 
li mite d use of s yste mic c ortic oster oi ds (≤7 da y s) are per mitte d w here s uc h use is 
c o nsi dere d sta n dar d of care (e g , f or C O P D e xacer bati o n). 
Re place me nt d oses of ster oi ds (f or e xa m ple, pre d nis o ne 5 t o 7. 5 m g dail y) are per mitte d 
w hile o n st u d y , as is t he use of l ocal ster oi ds.
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
5.
Ra diati o n t hera p y or s ur ger y .
N ote:  R a diati o n t hera p y or s ur ger y  t o a sy m pt o matic s olitar y  lesi o n is all o we d.  N o 
pe m br oliz u ma b i nf usi o ns are per mitte d d uri n g ra diati o n t hera py or pr oce d ure a n d 
e paca d ostat or matc hi n g place b o s h o ul d be st o p pe d t he da y  treat me nt be gi ns.  St u d y 
treat me nt ma y be res u me d as early as 1 wee k after treat me nt if t he partici pa nt ’s 
s ym pt o ms are i m pr o vi n g a n d n ot re q uiri n g c ortic oster oi ds f or ma na ge me nt. M S D 
c o ns ultati o n is re q uire d f or st u d y  treat me nt restart after ra diati o n t hera p y or s ur ger y.  If 
st u d y treat me nt is n ot res u me d wit hi n 1 2 wee ks of c o m pleti n g treat me nt (ra diati o n 
t hera py or s ur g er y), t he partici pa nt s h o ul d disc o nti n ue st u d y treat me nt per ma ne ntl y.
6.
Li ve atte n uate d vacci ne wit hi n 3 0 da y s bef ore t he first d ose of st u d y treat me nt a n d w hile 
partici pati n g i n t he st u d y.   

E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f ol l owi n g:  measles, 
m u m ps, r u bella, c hic ke n p o x, y ell o w fe ver, ra bies, B C G, a n d t y p h oi d vacci ne.  
Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y  kille d vir us vacci nes a n d are 
all o we d; h o we ver, i ntra nasal i nfl ue nza vacci nes are li ve atte n uate d vacci n es a n d are 
n ot all o we d.
7.
A n y  M A OI or dr u g ass ociate d wit h si g nifica nt M A O i n hi bit or y acti vit y a ge nts is 
pr o hi bite d fr o m 2 1 da y s bef ore starti n g st u d y treat me nt t hr o u g h 2 wee ks after t he fi nal 
d ose of e paca d ostat or matc hi n g place b o has bee n ta ke n. 

I ncl u di n g, b ut n ot li mite d t o, h ydrazi nes (e xa m ple p he nelzi ne), me peri di ne, 
car o xaz o ne, li nez oli d, ec hi n o psi di ne met h y le ne bl ue, f uraz oli d o n, tra n ylc y pr o mi ne, 
br ofar o mi ne, metrali n d ole, mi na pri ne, m ocl o be mi de, pirli n d ole, t ol o xat o ne, 
laz be mi de, par g yli ne, rasa gili ne, sele gili ne.
8.
A n y  U G T 1 A 9 i n hi bit or, i ncl u di n g: acitreti n, a mitri pt yli ne, a n dr oster o ne, c ycl os p ori ne, 
dasati ni b, dicl ofe nac, di fl u nisal, efa vire nz, erl oti ni b, fl uta mi de, gefiti ni b, ge mfi br ozil, 
gl yc yr r heti nic aci d, gl yc yrr hizi n, i mati ni b, i mi pra mi ne, ket oc o naz ole, li n oleic aci d 
s u p ple me nts, m yc o p he n olic aci d, nifl u mic aci d, nil oti ni b, p he n o bar bital, p he n y l b utaz o ne, 
p he n y t oi n, pr o be neci d, q ui ni di ne, rit o na vir, s orafe ni b, s ulfi n p yraz o ne, val pr oic aci d, a n d 
vera pa mil. 
Partici pa nts w h o, i n t he assess me nt of t he I n vesti gat or, re q uire t he use of a n y  of t he 
af ore me nti o ne d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he trial.  
All treat me nts t hat t he I n vesti gat or c o nsi ders necessar y  f or a partici pa nt’s welfare ma 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 e 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) pr o d ucts, her bal s u p ple me nts, a n d I V me dicati o ns a n d 
fl ui ds.  If c ha n ges occ ur d uri n g t he 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 s h o ul d als o be i ncl u de d o n t he e C R F.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da y s pri or t o t he first d ose of trial treat me nt 
a n d u p t o 3 0 da ys after the last d ose of trial treat me nt s h o ul d be rec or de d.  C o nc o mita nt 
me dicati o ns a d mi nistere d 3 0 da 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 CI s as defi ne d i n Secti o n 9. 3. 7
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Restricte d C o nc o mit a nt Me dic ati o ns
7. 7. 3
U se of c o u mari n-bas e d a ntic oa g ula nts (e g, warfari n) wit h e paca d ostat is disc o ura ge d.  L o w -
d ose warfari n ( 1 m g) is acce pta ble.  If a n alter nati ve t o c o u mari n -base d a ntic oa g ula nts ca n n ot 
be use d, t he I N R s h o ul d be m o nit ore d cl osel y per S o A w he n e paca d ostat is starte d ( wee kly 
for t he first 4 wee ks after i nitiati o n of t hera p y  a n d u p o n disc o nti n uati o n of e paca d ostat or 
matc hi n g place b o ).
Resc ue Me dic ati o ns & S u p p orti ve C are
7. 7. 4
Partici pa nt s s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y 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 Es wit h 
p ote ntial i m m u n ol o gic eti ol o g y  are o utli ne d al o n g wit h t he d ose m o dificati o n g ui deli nes i n 
Secti o n 7. 2, Ta ble 3 .  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 
treat me nt wit h c ortic oster oi ds, as well as a d diti o nal a nti-i nfla m mat or y a ge nts if s 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 ma y be necessar y as s ym pt o ms ma y  w orse n w he n t he ster oi d d ose is decrease d.  F or 
eac h dis or der, atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastatic disease or 
bacterial or viral i nfecti o n, w hi c 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
or e paca d ostat , t he I n vesti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce.  Refer t o 
Ta ble 3 i n Secti o n 7. 2. 1 f or g ui deli nes re gardi n g d ose m o dificati o n a n d s u p p orti ve care. 
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o p y, or 
s ki n p h ot o gra p hy as part of e val uati o n of t he e ve nt.
Tre at me nt After t he E n d of t he St u d y 
7. 8
T here is n o st u d y- s pecifie d treat me nt f oll o wi n g t he e n d of t he st u dy.
Cli nic al S u p plies Discl os ure
7. 9
T he e mer ge nc y  u n bli n di n g call ce nter will use t he treat me nt/ra n d o mizati o n sc he d ule f or t he 
trial t o u n bli n d partici pa nts a n d t o u n mas k st u d y treat me nt i de ntit y. T he e mer ge nc y  
u n bli n di n g call ce nter s h o ul d o nl y  be use d i n cases of e mer ge nc y (see Secti o n 9. 1. 1 1 ). I n t he 
e ve nt t hat t he e mer ge nc y u n bli n di n g call ce nter is n ot a vaila ble f or a gi ve n site i n t his trial, 
t he ce ntral electr o nic treat me nt all ocati o n/ra n d o mizati o n s yste m (I V R S/IW R S) s h o ul d be 
use d i n or der t o u n bli n d partici pa nts a n d t o u n mas k st u d y treat me nt i de ntit y.  M S D
will n ot 
pr o vi de ra n d o m c o de/ discl os ure e n vel o pes or lists wit h t he cli nical s u p plies.
See Secti o n 9. 1. 1 0, Partici pa nt Bli n di n g/ U n bli n di n g, f or a descri pti o n of t he met h o d of 
u n bli n di n g a partici pa nt d uri n g t he trial, s h o ul d s uc h acti o n be warra nte d.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
St a n d ar d P olicies
7. 1 0
At t he cl ose of t he st u d y after u n bli n di n g, a letter is t o be se nt b y t he i n vesti gat or t o t h ose 
partici pa nts w h o recei ve d pl ace b os i n t he i ma ge of t he c o m petit or’s pr o d uct t o pr o vi de t he 
f oll o wi n g a d vice: 
“ Y o u ha ve partici pate d i n a st u d y c o n d ucte d b y M S D u n der t he s p o ns ors hi p if In c y t e. T his is 
t o a d vise yo u t hat y o u were a m o n g t h ose w h o recei ve d a l o o k -ali ke ta blet create d b y t he 
S p o ns or t o rese m ble t he dr u g e paca d ostat as m uc h as p ossi ble. Y o u di d n ot recei ve t he acti ve 
dr u g e paca d ostat as ma n ufact ure d b y I ncyt e C or p orati o n .”
8.
Disc o nti n u ati o n/ Wit h dr a w al Criteri a 
Disc o nti n u ati o n of St u d y Tre at me nt 
8. 1
Disc o nti n uati o n of st u d y  treat me nt d oes n ot re prese nt wit h dra wal fr o m t he st u d y.
As certai n data o n cli nical e ve nts be y o n d st u d y  treat me nt disc o nti n uati o n ma y be i m p orta nt 
t o t he st u d y, t he y m ust be c ollecte d t hr o u g h t he partici pa nt’s last sc he d ule d f oll o w-u p, e ve n 
if t he partici pa nt has disc o nti n ue d st u d y treat me nt.  T heref ore, all partici pa nts w h o 
disc o nti n ue st u d y  treat me nt pri or t o c o m pleti o n of t he pr ot oc ol-s pecifie d treat me nt peri od
will still c o nti n ue t o partici pate i n t he st u d y as s pecifie d i n Secti o n 2 - So A a n d Secti o n 9. 9. 5
– Disc o nti n ue d Partici pa nts C o nti n ui n g t o be M o nit ore d i n t he St u d y .
Partici pa nts ma y  disc o nti n ue st u d y treat me 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 st u d y treat me nt at t he discreti o n of t he i n vesti gat or s h o ul d a ny u nt o war d effect occ ur.  I n 
a d diti o n, a partici pa nt ma y be disc o nti n ue d fr o m st u d y treat me nt b y the i n vesti gat or or M S D
if st u d y treat me nt 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.  S pecific details re gar di n g pr oce d ures t o be perf or me d at st u d y treat me nt 
disc o nti n uati o n are pr o vi de d i n Secti o n 9. 1 .1 0 – Wit h dra wal/ Disc o nti n uati o n.
A partici pa nt m ust be disc o nti n ue d fr o m st u d y treat me nt b ut c o nti n ue t o be m o nit ore d i n t he 
st u d y f or a ny of t he f oll o wi n g reas o ns:
○
T he partici pa nt or partici pa nt’s le gall y acce pta ble re prese ntati ve re q uests t o disc o nti n ue
st u d y treat me nt.
o
T he partici pa nt has a me dical c o n diti o n or pers o nal circ u msta nce w hic h, i n t he o pi ni o n of 
t he i n vesti gat or a n d/ or M S D , place d t he partici pa nt at u n necessar y ris k fr o m c o nti n ue d 
a d mi nistrati o n of st u d y treat me nt.
o
T he partici pa nt has a c o nf ir me d p ositi ve ser u m pre g na nc y test.
o
C o m plete d 3 5 tre at me nt cycles ( a p pr oxi m ately 2 ye ars) wit h pe m br oliz u m a b.  
N ote: T he n u m ber of treat me nts is calc ulate d starti n g wit h t he first d ose.  Partici pa nt s 
w h o st o p t he c o m bi nati o n or pe m br oliz u ma b after recei vi n g 3 5 d oses ma y be eli gi ble f or 
retreat me nt if t he y pr o gress after st o p pi n g 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 9.9 . 3. Partici pa nt s ma y be retreate d i n t he Sec o n d
C o urse P hase ( Retreat me nt) f or u p t o a n a d diti o nal 1 7 c ycles (a p pr o xi matel y 1 ye ar).
o
T he st u d y  is ter mi nate d b y t he s p o ns or.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
o
T he st u d y  is ter mi nate d b y t he l ocal healt h a ut h orit y, IR B, or I E C.
o
A n y  pr o gressi o n or rec urre nce of a ny 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.
N ote: S ur gical e xcisi o n of n o n -ur ot helial ca ncer is all o we d.  Refer t o Secti o n 7. 7 –
C o nc o mita nt T hera p y f or ra diati o n a n d s ur ger y all o we d f or ur ot helial ca ncer.
o
T he occ urre nce of u nacce pta bl e t o xicit y n ot ca use d b y t he u n derlyi n g mali g na nc y  will be 
pres u me d t o be relate d t o st u d y  treat me nt a n d will re q uire t hat all st u d y treat me nt be 
per ma ne ntl y disc o nti n ue d.  U nacce pta ble t o xicit y is defi ne d as f oll o ws:

Occ urre nce of a n A E t hat is relate d t o treat me nt wit h t he st u d y treat me nt t hat, i n t he 
j u d g me nt of t he i n vesti gat or or t he s p o ns or's me dical m o nit or, c o m pr o mises t he 
partici pa nt 's a bilit y t o c o nti n ue st u d y-s pecific pr oce d ures or is c o nsi dere d t o n ot be i n 
t he partici pa nt 's best i nterest.

Persi ste nt A E re q uiri n g a dela y of t hera py f or m ore t ha n 1 2 wee ks u nless a greater 
dela y  has bee n a p pr o ve d b y M S D .
o
Rec urre nt Gra de 2 p ne u m o nitis .
o
Disc o nti n uati o n of treat me nt ma y  be c o nsi dere d f or partici pa nts w h o ha ve attai ne d a 
c o nfir me d c o m plete res p o nse ( C R) a n d ha ve bee n treate d f or at least 8 c ycles (at least 
2 4 wee ks), recei vi n g 2 c ycles of t he c o m bi nati o n i ncl u di n g 2 d oses of pe m br oliz u ma b 
a n d at least 8 0 % of t he pla n ne d d oses of e paca d ostat or matc hi n g place b o be y o n d t he 
date w he n t he i nitial C R was declare d. T hese partici pa nts ma y  be eli gi ble f or sec o n d 
c o urse treat me nt descri be d i n Secti o n 7. 2. 2.
A partici pa nt m a y be disc o nti n ue d fr o m st u d y  treat me nt as f oll o ws:
o
If, d uri n g t he c o urse of t he st u d y, a partici pa nt is f o u n d n ot t o ha ve met eli gi bilit y criteria, 
t he me dical m o nit or, i n c olla b orati o n wit h t he i n vesti gat or, will deter mi ne w het her t he 
partici pa nt s h o ul d be wit h dra w n fr o m t he st u d y.
F or partici pa nts w h o are disc o nti n ue d fr o m st u d y treat me nt b ut c o nti n ue t o be m o nit ore d i n 
t he st u d y, see Sectio n 2 a n d Secti o n 9. 9. 5 f or t h ose pr oce d ures t o be c o m plete d at eac h 
s pecifie d visit.
Partici pa nts ma y  be all o we d t o be gi n st u d y treat me nt a gai n if dee me d me dicall y a p pr o priate ,
f oll o wi n g c o ns ultati o n wit h M S D.  F oll o wi n g u n bli n di n g ( necessar y o nly i n tr ue me dical 
e mer ge ncies) partici pa nts will be treate d wit h pe m br oliz u ma b m o n ot hera p y , treat me nt wit h 
e paca d ostat/ place b o is n ot all o we d .
Wit h dr a w al fr o m t he St u d y
8. 2
A partici pa nt m ust be wit h dra w n fr o m t he st u d y  if t he partici pa nt or partici pa nt’s le gally 
acce pta ble re prese ntati ve wit h dra ws c o nse nt fr o m t he st u d y.
If a partici pa nt wit h dra ws fr o m t he st u d y, t he y will n o l o n ger recei ve st u d y treat me nt or be 
f oll o we d at sc he d ule d pr ot oc ol visits.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
S pecific details re gar di n g pr oce d ures t o be perf or me d at t he ti me of wit h dra wal fr o m t he 
st u d y; are o utli ne d i n Secti o n 9. 1. 1 0 – Wit h dra wal/ Disc o nti n uati o n.
T he pr oce d ures t o be 
perf or me d s h o ul d a partici pa nt re peate dl y fail t o ret ur n f or sc he d ule d visits a n d/ or if t he 
st u d y site is u na ble t o c o ntact t he partici pa nt are o utli ne d i n Secti o n 8. 3.
L ost t o F oll o w U p
8. 3
N O T E: As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble.  T here will be n o 
a d diti o n al eff orts t o c o nt act p artici p a nts w h o are l ost t o f oll o w u p .
If a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y visit a n d/ or if t he site is u na ble 
t o c o ntact t he partici pa nt, t he f oll o wi n g pr oce d ures are t o be perf or me d:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit.  I f t he 
partici pa nt is c o ntacte d , t he partici pa nt s h o ul d be c o u nsele d o n t he i m p orta nce of 
mai ntai ni n g t he pr ot oc ol -s pecifie d visit sc he d ule.

T he i n vesti gat or or desi g nee m ust ma ke e ver y  eff ort t o re gai n c o ntact wit h t he 
partici pa nt at eac h misse d visit (e g, p h o ne calls a n d/ or a certifie d letter t o t he 
partici pa nt’s last k n o w n maili n g a d dress or l ocall y e q ui vale nt met h o ds). T hese 
c o ntact atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.

N ote:  A partici pa nt is n ot c o nsi dere d l ost t o f oll o w -u p u ntil t he last sc he d ule d visi t 
f or t he i n di vi d ual partici pa nt.  T he a m o u nt of missi n g data f or t he partici pa nt will be 
ma na ge d via t he pre -s pecifie d data ha n dli n g a n d a nal ysis g ui deli nes.
9.
St u d y Assess me nts a n d Pr oce d ures

St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. 

A d here nce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d uct.

All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y  criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g 
t o rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d 
reas o ns f or scree ni n g fail ure, as a p plica ble. 

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g,
bl o o d c o u nt) a n d o btai ne d bef ore si g ni n g of I C F ma y  be utilize d f or scree ni n g or 
baseli ne p ur p oses pr o vi de d t he pr oce d ure met t he pr ot oc ol -s pecifie d criteria a n d were 
perf or me d wit hi n t he ti me fra me defi ne d i n t he S o A.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 0
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A d mi nistr ati ve a n d Ge ner al Pr oce d ure s
9. 1
I nf or me d C o nse nt
9. 1. 1
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 
partici pa nt or eac h partici pa nt’s le gall y acce pta ble re prese ntati ve pri or t o partici pati n g i n a 
cli nical trial . If t here are c ha n ges t o t he partici pa nt’s stat us d uri n g t he trial (e g, healt h or a ge 
of maj orit y  re q uire me nts), t he i n vesti gat or or q ualifie d desi g nee m ust e ns ure t he a p pr o priate 
c o nse nt is i n place. 
Ge ner al I nf or me d C o nse nt
9. 1. 1. 1
C o nse nt m ust be d oc u me nte d b y  t he partici pa nt’s date d si g nat ure or by t he partici pa nt’s 
le gall y acce pta ble re prese ntati ve’s date d si g nat ure o n a c o nse nt f or m al o n g wit h t he date d 
si g nat ure of t he pers o n c o n d ucti n g t he c o nse nt disc ussi o n. 
A c o p y of t he si g ne d a n d date d c o nse nt f or m s h o ul d be gi ve n t o t he partici pa nt bef ore 
partici pati o n i n t he trial.
T he i nitial I C F, a n y  s u bse q ue nt re vise d writte n I C F a n d a ny writte n i nf or mati o n pr o vi de d t o 
t he partici pa nt m ust recei ve t he I R B/I E C’s a p pr o val/fa v ora ble o pi nio n i n a d va nce of use.  
T he partici pa nt 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 mel y  
ma n ner if ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o t he partici pa nt’s 
willi n g ness t o c o nti n ue partici pati o n i n t he trial.  T h 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 partici pa nt’s date d si g nat ure or by t he partici pa nt’s le gall y acce pta ble 
re prese ntati ve’s date d si g nature.
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 R B/I E C re q uire me nts, a p plica ble la ws a n d re g ulati o ns 
a n d M S D
re q uire me nts.
I ncl usi o n/ E xcl usi o n Criteri a
9. 1. 2
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 partici pa nt q ualifies f or t he st u d y.
P artici p a nt I de ntific ati o n C ar d
9. 1. 3
All partici pa nts will be gi ve n a Partici pa nt I de ntificati o n Car d i de ntif yi n g t he m as 
partici pa nts i n a researc h trial. T he 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. T he i n vesti gat or or 
q ualifie d desi g nee will pr o vi de t he partici pa nt wit h a Partici pa nt I de ntificati o n Car d 
i m me diatel y after t he partici pa nt pr o vi des writte n i nf or me d c o nse nt. At t he ti me of treat me nt 
all ocati o n/ra n d o mizati o n, site pers o n nel will a d d t he treat me nt/ra n d o mizati o n n u m ber t o t he 
Partici pa nt I de ntificati o n Car d.
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 1
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
T he partici pa nt i de ntificati o n car d als o c o ntai ns c o ntact i nf or mati o n f or t he e mer ge nc y 
u n bli n di n g call ce nter s o t hat a healt h care pr o vi der ca n o btai n i nf or mati o n a b o ut st u d y 
treat me nt 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.
S er ot o ni n S y n dr o me I nf or m ati o n C ar d
9. 1. 4
O n C 1 D 1 , partici pa nts will be gi ve n a ser ot o ni n s y n dr o me ( S S) i nf or mati o n car d listi n g si g ns 
a n d s ym pt o ms of S S.  T his i nf or mati o n car d als o i nstr ucts partici pa nts t o see k i m me diate 
me dical care if a n y o f t hese s ym pt o ms a re o bser ve d.
Me dic al Hist or y
9. 1. 5
A me dical hist or y  will be o btai ne d b y t he i n vesti gat or or q ualifie d desi g nee. T he me dical 
hist or y  will c ollect all acti ve c o n diti o ns a n d a ny c o n diti o n dia g n ose d wit hi n t he pri or 
1 0 ye ars t hat t he I n vesti gat or c o nsi ders t o be c li nicall y si g nifica nt. Details re gar di n g t he 
disease f or w hic h t he partici pa nt has e nr olle d i n t his st u d y  will be rec or de d se paratel y a n d 
n ot liste d as me dical hist or y .
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
9. 1. 6
Pri or Me dic ati o ns
9. 1. 6. 1
T he In vesti gat or or q ualifie d desi g nee will re vie w pri or me dicati o n use, i ncl u di n g a n y 
pr ot oc ol -s pecifie d was h o ut re q uire me nt, a n d rec or d pri or me dicati o n ta ke n b y  t he partici pa nt 
wit hi n 2 8 da y s bef or e first d ose of st u d y treat me nt. Treat me nt f or t he disease f or w hic h t he 
pa rtici pa nt has e nr olle d i n t his st u d y will be rec or de d se parately a n d n ot liste d as a pri or 
me dicati o n .
C o nc o mit a nt Me dic ati o ns
9. 1. 6. 2
T he In vesti gat or or q ualifie d desi g nee will rec or d me dicati o n, if a n y, ta ke n b y t he partici pa nt 
d uri n g t he st u d y.  I n a d diti o n, n e 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 Safety F oll o w -u p visit s h o ul d be rec or de d.
Assi g n me nt of Scree ni n g N u m ber
9. 1. 7
All c o nse nte d partici pa nts will be gi ve n a u ni q ue scree ni n g n u m ber t hat will be use d t o 
i de ntif y t he partici pa nt f or all pr oce d ures t hat occ ur pri or t o ra n d omizati o n .  Eac h partici pa nt 
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 partici pa nts.
A n y  partici pa nt w h o is scree ne d m ulti ple ti mes will retai n t he ori gi nal scree ni n g n u m ber 
assi g ne d at t he i nitial scree ni n g visit.
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 9. 9 . 1.  
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 2
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Assi g n me nt of Tre at me nt/ R a n d o miz ati o n N u m ber
9. 1. 8
All eli gi ble partici pa nts will be ra n d o ml y  all ocate d a n d will recei ve a 
treat me nt/ra n d o mizati o n n u m ber.  T he treat me nt/ra n d o mizati o n n u m ber i de ntifies t he 
partici pa nt f or all pr oce d ures occ urri n g after treat me nt all ocati o n/ra n d o mizati o n.  O nce a 
treat me nt/ra n d o mizati o n n u m ber is assi g ned t o a partici pa nt, it ca n ne ver be re -assi g ne d t o 
a n ot her partici pa nt.
A si n gle partici pa nt ca n n ot be assi g ne d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber.
Tre at me nt A d mi nistr ati o n
9. 1. 9
A d mi nistrati o n of pe m br oliz u ma b will be wit nesse d b y t he i n vesti gat or a n d/ o r st u d y staff.  
A d mi nistrati o n of e paca d ostat or matc hi n g place b o will be wit nesse d b y t he i n vesti gat or 
a n d/ or st u d y staff f or t he m or ni n g d ose o n C 1 D 1 a n d C 2 D 1, b ut ot her wise self-a d mi nistere d.
St u d y  treat me nt s h o ul d be gi n wit hi n t hree da y s of a n d as cl os e as p ossi ble t o t he date o n 
w hic h t he partici pa nt is all ocate d/assi g ne d.   
Ti mi n g of D ose A d mi nistr ati o n
9. 1. 9. 1
Ti mi n g of D ose A d mi nistr ati o n of Pe m br oliz u m a b
9. 1. 9. 1. 1
St u d y  treat me nt wit h pe m br oliz u ma b s h o ul d be a d mi nistere d o n Da y 1 of eac h c ycle after all 
pr oce d ures/assess me nts ha ve bee n c o m plete d as detaile d i n t he S o A ( Secti o n 2) .  All st u d y 
treat me nts will be a d mi nistere d o n a n o ut patie nt basis.
St u d y  treat me nt of pe m br oliz u ma b ma y  be a d mi nistere d u p t o 3 da ys bef ore or after t he 
sc he d ule d Da y 1 of eac h c ycle d ue t o a d mi nistrati ve reas o ns e xce pt f or C 1 D 1 , w here t he 
wi n d o w is + 3 da y s fr o m ra n d o mizati o n.
Pe m br oliz u ma b will be a d mi nistere d as a d ose of 2 0 0 m g usi n g a 3 0 -mi n ute I V i nf usi o n.  
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 utes as 
p ossi ble.  H o we ver, gi ve n t he varia bilit y  of i nf usi o n p u m ps fr o m site t o site, a wi n d o w of -5 
mi n utes a n d + 1 0 mi n utes is per mitte d (i.e., i nf us i o n ti me is 3 0 mi n utes -5 mi n/ + 1 0 mi n). 
T he P har mac y  Ma n ual c o ntai ns s pecific i nstr ucti o ns f or pe m br oliz u ma b d ose calc ulati o n, 
rec o nstit uti o n, pre parati o n of t he i nf usi o n fl ui d, a n d a d mi nistrati o n.
Ti mi n g of D ose A d mi nistr ati o n of E p ac a d ost at
9. 1. 9. 1. 2
E paca d ostat/ matc hi n g place b o will be s u p plie d as 1 0 0 m g ta blets pac ka ge d i n hi g h -de nsit y 
p ol y et h yl e ne b ottles. All ta blet e xci pie nts c o m pl y wit h t he re q uire me nts of t he a p plica ble 
c o m pe n dial m o n o gra p hs ( P h E ur, U S P/ N F; refer t o I B). E paca d ostat/ matc hi n g place b o 
2 5 m g ta blets are als o a vaila ble. B ottles of ta blets s h o ul d be st ore d at r o o m te m perat ure 
( 1 5° C t o 3 0° C/ 5 9° F t o 8 6° F).
Partici pa nts will ta ke t heir d ose of e paca d ostat or matc hi n g place b o i n t he m or ni n g a n d 
e ve ni n g, a p pr o xi matel y 1 2 h o urs a part wit h o ut re gar d t o f o o d. Partici pa nts will self -
a d mi nister e paca d ostat or matc hi n g place b o e xce pt o n C 1 D 1 a n d C 2 D 1, w he n t he m or ni n g 
d ose will be gi ve n at t he st u d y  site cli nic pri or t o t he i nf usi o n of pe m br oliz u ma b. 
 
 
 
0 4 Y B Q D




Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 4
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
u n bli n di n g call ce nter b y tele p h o ne a n d ma ke a re q uest f or e mer ge nc y u n bli n di n g.  As 
re q ueste d by t he i n vesti gat or or dele gate t he e mer ge nc y u n bli n di n g call ce nter will pr o vi de 
t he i nf or mati o n t o hi m/ her pr o m ptl y a n d re p ort u n bli n di n g t o M S D .  Pri or t o c o ntacti n g t he 
e mer ge nc y u n bli n di n g call ce nter t o re q uest u n bli n di n g of a partici pa nt’s treat me nt 
assi g n me nt, t he i n vesti gat or or dele gate m ust e nter t he t o xicit y gra de of t he a d verse e ve nts 
o bser ve d, t he relati o n t o st u d y  dr ug, t he reas o n t here of, etc., i n t he me dical c hart etc.
Partici pa nts w h ose treat me nt assi g n me nt has bee n u n bli n de d b y t he i n vesti gat or/ dele gate 
a n d/ or n o n -st u d y treati n g p h ysicia n s h o ul d c o nti n ue t o be m o nit ore d i n t he trial.
A d diti o nall y , t he i n vesti gat or m ust g o i nt o t he I V R S s y ste m a n d perf or m t he u n bli n d i n t he 
I V R S sys te m t o u p date dr u g dis p ositi o n.  I n t he e ve nt t hat t he e mer ge nc y u n bli n di n g call 
ce nter is n ot a vaila ble f or a gi ve n site i n t his trial, I V R S/IW R S s h o ul d be use d f or e mer ge nc y  
u n bli n di n g i n t he e ve nt t hat t his is re q uire d f or partici pa nt safet y.
St u d y  treat me nt i de ntificati o n i nf or mati o n is t o be u n mas ke d O N L Y if necessar y f or t he 
welfare of t he partici pa nt.  E ver y  eff ort s h o ul d be ma de n ot t o u n bli n d t he partici pa nt u nless 
necessar y . 
I n t he e ve nt t hat u n bli n di n g has occ urre d, t he circ u msta nces ar o u n d t he u n bli n di n g (e g, date, 
reas o n a n d pers o n perf or mi n g t he u n bli n di n g) m ust be d oc u me nte d pr o m ptl y, a n d t he M S D
Cli nical Direct or n otifie d as s o o n as p ossi ble. O nce a n e mer ge nc y  u n bli n di n g has ta ke n 
place, t he pri nci pal i n vesti gat or, site pers o n nel, a n d S p o ns or pers o n nel ma y be u n bli n de d s o 
t hat t he a p pr o priate f oll o w-u p me dical care ca n be pr o vi de d t o t he partici pa nt .
C ali br ati o n of E q ui p me nt
9. 1. 1 2
T he i n vesti gat or or q ualifie d desi g nee has t he res p o nsi bilit y t o e ns ure t hat a n y de vice or 
i nstr u me nt use d f or a cli nical e val uati o n/test d uri n g a cli nical st u d y t hat pr o vi des i nf or mati o n 
a b o ut i ncl usi o n/e xcl usi o n criteria a n d/ or safet y or efficac y para meters s hall be s uita bl y 
cali brate d a n d/ or mai ntai ne d t o e ns ure t hat t he data o btai 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 
st u d y site.
Effic ac y Assess me nts 
9. 2
T u m or I m a gi n g a n d Assess me nt of Dise ase
9. 2. 1
N O T E :  As of A me n d me nt 0 4, ce ntr al re vie w i m a gi n g a n d i R E CI S T are n o l o n ger 
a p plic a ble. T his secti o n h as bee n u p d ate d acc or di n gl y .
T u m or i ma gi n g is str o n gl y preferre d t o be ac q uire d b y C T ; i ma gi n g s h o ul d i ncl u de t he c hest, 
a b d o me n, a n d pel vis .  F or t he a b d o me n a n d pel vis, c o ntrast -e n ha nce d ma g netic res o na nce 
i ma gi n g ( MRI ) m a y be use d w he n C T wit h i o di nate d c o ntrast is c o ntrai n dicate d, or w he n
ma n date d b y l ocal practice. M RI  is t he str o n gl y preferre d m o dalit y f or i ma gi n g of t he brai n.  
T he sa me i ma gi n g tec h ni q ue re gar di n g m o dalit y , i deall y t he sa me sca n ner, a n d t he use of 
c o ntrast s h o ul d be use d i n a partici pa nt t hr o u g h o ut t he st u d y t o o pti mize t he re pr o d uci bilit y 
of t he assess me nt of e xisti n g a n d ne w t u m or b ur de n a n d i m pr o ve t he acc urac y of t he 
assess me nt of res p o nse or pr o gressi o n base d o n i ma gi n g. N ote: f or t he p ur p oses of assessi n g 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 5
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
t u m or i ma gi n g, t he ter m “I n vesti gat or” refers t o t he l ocal i n vesti gat or at t he site a n d/ or t he 
ra di ol o gical re vie wer l ocate d at t he site or at a n offsite facilit y.
All partici pa nts will ha ve a baseli ne b o ne sca n perf or me d at scree ni n g. F or p artici pa nts wit h 
p ositi ve b o ne sca ns at baseli ne , b o ne sca ns s h o ul d be perf or me d as per l ocal S o C g ui deli nes ; 
t he res ults will n ot be m o nit ore d .  F or p artici pa nts wit h ne w s y m pt o ms s u g gesti ve of osse o us 
metastasis, a b o ne sca n s h o ul d be o btai ne d. 
A d diti o nall y , plai n X-ra y e val uati o n s h o ul d be 
o btai ne d f or s y m pt o matic sites wit h ne gati ve b o ne sca n e val uati o ns.  
Partici pa nt eli gi bilit y will be deter mi ne d usi n g l ocal assess me nt (I n vesti gat or assess me nt) 
base d o n R E CI S T 1. 1.  
Treat me nt s h o ul d c o nti n ue u ntil P D has bee n deter mi ne d b y  In vesti gat or assesse d disease 
pr o gressi o n b y R E CI S T 1. 1 . 
I niti al T u m or I m a gi n g
9. 2. 1. 1
N O T E :  As of A me n d me nt 0 4, ce ntr al re vie w i m a gi n g is n o l o n ger a p plic a ble. T his 
secti on h as bee n u p d ate d acc or di n gl y .
I nitial t u m or i ma gi n g at Scree ni n g m ust be perf or me d wit hi n 2 8 da y s pri or t o t he date of 
ra n d o mizati o n.  T he site st u d y tea m m ust re vie w scree ni n g i ma ges t o c o nfir m t he partici pa nt
has meas ura ble disease per R E CI S T 1. 1.
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 is acce pta ble f or use as 
scree ni n g t u m or i ma gi n g if it is of dia g n ostic q ualit y  a n d perf or me d wit hi n 2 8 da y s pri or t o 
t he date of ra n d o mizati o n. 
If brai n i ma gi n g is perf or me d t o d oc u me nt t he sta bilit y of e xisti n g metastases, M RI s h o ul d 
be use d if p ossi ble. If M RI  is me dically c o ntrai n dicate d, C T wit h c o ntrast is a n acce pta ble 
alter nati ve.   N ote: f or partici pa nts wit h sta ble brai n metastases at ra n d o mizati o n, re peat brai n 
i ma gi n g m ust be perf or me d t o d oc u me nt c o m plete res p o nse. B o ne sca ns m ust be perf or me d 
t o c o nfir m C R if p ositi ve at baseli ne.  
T u m or I m a gi n g D uri n g t he St u d y
9. 2. 1. 2
N O T E :  As of A me n d me nt 0 4, ce ntr al re vie w of i m a ges a n d i R E CI S T are n o l o n ger 
a p plic a ble.  After t he first o n -st u d y i m a gi n g assess me nt at Wee k 9, f urt her i m a gi n g will 
be perf or me d as per l oc al S o C g ui deli nes ; h o we ver t he d at a will n ot be c ollecte d.  T his 
secti o n h as bee n u p d ate d acc or di n gl y.
T he first o n -st u d y i ma gi n g assess me nt s h o ul d be perf orme d at 9 wee ks ( 6 3 da y s ±7 d a y s) 
fr o m t he date of ra n d o mizati o n.  N o f urt her i ma gi n g is ma n date d; a n y f urt her i ma gi n g f or 
disease assess me nts will be perf or me d b y site i n vesti gat or/ra di ol o g y assess me nt as per S o C 
f or t he disease a n d l ocal g ui deli nes; o nl y t he date of sca ns perf or me d as per S o C nee ds t o be 
d oc u me nte d i n t he e C R F .  I ma gi n g ti mi n g s h o ul d f oll o w cale n dar da ys a n d s h o ul d n ot be
a dj uste d f or dela ys i n c ycle starts. 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 6
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
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
9. 2. 1. 3
N O T E : As per A me n d me nt 0 4, there is n o pr ot oc ol -s pecifie d i m a gi n g after t he Wee k 9 
assess me nt f or effic ac y a n al ysis. T his secti o n h as bee n u p d ate d acc or di n gl y.
F or partici pa nt s w h o disc o nti n ue st u d y treat me nt bef ore t he Wee k 9 i ma gi n g assess me nt f or 
efficac y a nalys is, t u m or i ma gi n g s h o ul d be perf or me d at t he ti me of treat me nt 
disc o nti n uati o n ( ± 4 wee k wi n d o w). If pre vi o us i ma gi n g was o btai ne d wit hi n 4 wee ks pri or 
t o t he date of disc o nti n uati o n, t he n i ma gi n g at treat me nt disc o nti n uati o n is n ot ma n dat or y.  I n 
partici pa nt s w h o disc o nti n ue st u d y 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.
Sec o n d C o urse ( Retre at me nt) T u m or I m a gi n g
9. 2. 1. 4
N O T E : As per A me n d me nt 0 4, the te xt i n t his secti o n is n o l o n ger a p plic a ble; dise ase 
assess me nt will be perf or me d b y t he i n vesti g at or per l oc al S o C g ui deli nes; res ults will 
n ot be c ollecte d, o nl y t he d ate of sc a ns perf or me d as per S o C nee ds t o be d oc u me nte d i n 
t he e C R F.
T u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt wit h 
pe m br oliz u ma b + e pac a d ostat or matc hi n g place b o. L o cal rea di n g (I n vesti gat or assess me nt 
wit h site ra di ol o g y  rea di n g) will be use d t o deter mi ne eli gi bilit y. All Sec o n d C o urse i ma gi n g 
s h o ul d be s u b mitte d t o t he ce ntral i ma gi n g ve n d or f or q ualit y  c o ntr ol, st ora ge, a n d p ossi ble
retr os pecti ve re vie w t h o u g h BI C R-verificati o n of P D will n ot occ ur d uri n g Sec o n d C o urse 
P hase .
T he first o n -st u d y i ma gi n g assess me nt s h o ul d be perf or me d at 1 2 wee ks ( 8 4 da y s ± 7 d a y s) 
after t he restart of treat me nt. S u bse q ue nt t u m or i ma gi n g s h o ul d be perf or me d e ver y 1 2
wee ks ( 8 4 d a y s ± 7 d a y s) or m ore fre q ue ntly if cli nicall y i n dicate d.
Per iR E CI S T ( Secti o n 9. 2. 1. 6 ), if t u m or i ma gi n g s h o ws i nitial P D, t u m or assess me nt s h o ul d 
be re peate d 4 t o 8 wee ks later i n or der t o c o nfir m P D , wit h t he o pti o n of c o nti n ui n g treat me nt 
w hile a waiti n g ra di ol o gic c o nfir mati o n of pr o gressi o n.
Partici pa nt s w h o o btai n c o nfir mator y  
i ma gi n g d o n ot nee d t o u n der g o sc he d ule d t u m or i ma gi n g if it is less t ha n 4 wee ks later a n d 
ma y  wait u ntil t he ne xt sc he d ule d i ma gi n g ti me p oi nt , if cli nicall y sta ble.
I ma gi n g s h o ul d c o nti n ue t o be perf or me d u ntil disease pr o gressi o n, t he start of a ne w 
a ntica ncer treat me nt, wit h dra wal of c o nse nt, deat h, or n otificati o n b y M S D , w hic he ver 
occ urs first. I n cli nically sta ble partici pa nts, disease pr o gressi o n ma y  be c o nfir me d b y  t he 
I n vesti gat or usi n g i R E CI S T 4 t o 8 wee ks after t he first t u m or i ma gi n g i n dicati n g P D.  
F or partici pa nt s w h o disc o nti n ue Sec o n d C o urse st u d y treat me nt, t u m or i ma gi n g s h o ul d be 
perf or me d at t he ti me of treat me nt disc o nti n uati o n ( ± 4 wee k wi n d o w). If pre vi o us i ma gi n g
was o btai ne d wit hi n 4 wee ks pri or t o t he date of disc o nti n uati o n, t he n i ma gi n g at treat me nt 
disc o nti n uati o n is n ot ma n dat or y. F o r partici pa nt s w h o disc o nti n ue st u d y 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.
F or partici pa nt s w h o disc o nti n ue Sec o n d C o urse st u d y treat me nt 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 made t o c o nti n ue m o nit ori n g t heir disease stat us b y  
ra di ol o gic i ma gi n g e ver y 1 2 wee ks ( 8 4 d a y s ± 7 da y s) u ntil eit her t he start of a ne w 
 
 
0 4 Y B Q D


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 7
Pr ot oc ol/ A me n d me nt N o.: 6 7 2 -0 4 / E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
a ntica ncer treat me nt, disease pr o gressi o n, 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.
R E CI S T 1. 1 Assess me nt of Dise ase
9. 2. 1. 5
R E CI S T 1. 1 will be use d b y  BI C R as t he pri mar y meas ure f or assess me nt of t u m or res p o nse, 
date of disease pr o gressi o n, a n d as a basis f or all pr ot oc ol g ui deli nes relate d t o disease stat us 
(e g, disc o nti n uati o n of st u d y treatme nt ).  Alt h o u g h R E CI S T 1. 1 refere nces a ma xi m u m of 5 
tar get lesi o ns i n t otal a n d 2 per or ga n, t his pr ot oc ol all o ws a ma xi m u m of 1 0 tar get lesi o ns i n 
t otal a n d 5 per or ga n, if cli nicall y rele va nt t o e na ble a br oa der sa m pli n g of t u m or b ur de n.  
I nitial t u m or i ma gi n g s h o wi n g site-assesse d P D s h o ul d be s u b mitte d t o t he BI C R
i m me diatel y f or verificati o n.  T he site will be n otifie d if t he BI C R verifies P D usi n g R E CI S T 
1. 1.  Fi g ure 3 ill ustrates t he i ma gi n g fl o w i n v ol vi n g verificati o n of P D f or cli nicall y sta ble 
partici pa nt s.
i R E CI S T Assess me nt of Dise ase
9. 2. 1. 6
N O T E : As per A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble; i R E CI S T d at a will 
n o l o n ger be c ollecte d. P artici p a nts wit h r a di o gr a p hic dise ase pr o gressi o n as 
deter mi ne d b y R E CI S T 1. 1 will disc o nti n ue fr o m t he st u d y a n d be f oll o we d f or s afet y 
m o nit ori n g, as det aile d i n Secti o n 9. 3; n o c o nfir m at or y sc a ns are re q uire d. 
i R E CIS T is base d o n R E CI S T 1. 1, b ut 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 ot hera pe utic dr u gs i R E CIS T will be use d b y  t he I n vesti gat or 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. W he n cli nicall y  sta ble, partici pa nt s 
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 I n vesti gat or , w or ki n g wit h 
l ocal ra di ol o g y, acc or di n g t o t he r ules o utli ne d i n A p pe n di x 8. T his all o wa nce t o c o nti n ue 
treat me nt des pite i nitial ra di ol o gic P D ta kes i nt o acc o u nt t he o bser vati o n t hat s o me 
p artici pa nt s 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, a n d t he n e x perie nce s u bse q ue nt disease res p o nse. T his data will be 
ca pt ure d i n t he cli nical data base.
Cli nical sta bilit y  is defi ne d as t he f oll o wi n g: 

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y  si g nifica nt pr o gressi o n of 
disease

N o decli ne i n E C O G P S

N o re q uire me nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesia, 
ra diati o n, or ot her palliati ve care
A n y  partici pa nt dee me d cli nicall y unsta ble s h o ul d be disc o nti n ue d fr o m st u d y  treat me nt at 
ce ntral verificati o n of site -assesse d first ra di ol o gic e vi de nce of P D, a n d is 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 b y  i R E CIS T.
If t he I n vesti gat or deci des t o c o nti n ue treat me nt, t he partici pa nt ma y c o nti n ue t o recei ve 
st u d y treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m 
P D b y  i R E CIS T, per I n vesti gat or assess me nt.  I ma ges s h o ul d c o nti n ue t o be se nt i n t o t he 
ce ntral i ma gi n g ve n d or f or p ote n tial retr os pecti ve BI C R. 
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
9 8
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
If re peat i ma gi n g d oes n ot c o nfir m P D per i R E CIS T, as assesse d b y  t he I n vesti gat or, a n d t he 
partici pa nt c o nti n ues t o be cli nicall y  sta ble, st u d y 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.  If P D is c o nfir me d, partici pa nts will be disc o nti n ue d fr o m st u d y  
treat me nt.
If a partici pa nt has c o nfir me d ra di o gra p hic pr o gressi o n (i C P D) as defi ne d i n A p pe n di x 8, 
st u d y treat me nt s h o ul d be disc o nti n ue d; h o we ver, if t he partici pa nt is ac hie vi n g a cli nicall y 
mea ni n gf ul be nefi t, a n e xce pti o n t o c o nti n ue st u d y treat me nt ma y be c o nsi dere d f oll o wi n g 
c o ns ultati o n wit h t he M S D .  In t his case, if st u dy t reat 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 nti n 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 2 a n d 
s u b mitte d t o t he ce ntral i ma gi n g ve n d or.
A descri pti o n of t he i R E CIS T pr ocess is pr o vi de d i n A p pe n di x 8 , wit h a d diti o nal details i n 
t he i R E CIS T p u blicati o n [ Se ym o ur, L., et al 2 0 1 7] . A s u m mar y  of ima gi n g a n d treat me nt 
re q uire me nts after first ra di ol o gic e vi de nce of pr o gressi o n is pr o vi de d i n Ta ble 7 a n d 
ill ustrate d as a fl o wc hart i n Fi g ure 3 . 
 
 
0 4 Y B Q D


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
9 9
Pr ot oc ol/ A me n d me nt N o.: 6 7 2- 0 4 / E C H O- 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 -3 0 7- 0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Ta ble 7
I ma gi n g a n d Treat me nt after First Ra di ol o gic E vi de nce of Pr o gressi ve Disease
E ve nt
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
First ra di ol o gic 
e vi de nce of P D b y 
R E CI S T 1. 1 t hat has 
bee n verifie d b y BI C R
Re peat i ma gi n g at 4 t o 8 
wee ks 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 I n vesti gat or’s discreti o n 
w hile a waiti n g c o nfir mat or y 
t u m or i ma gi n g b y site b y 
i R E CI S T.
Re peat i ma gi n g at 4 t o 8
wee ks t o c o nfir m P D per 
I n vesti gat or’s 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 (i C P D) 
b y i R E CI S T per 
I n vesti gat or 
assess me nt
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 M S D)
N o a d diti o nal i ma gi n g 
re q uire d
N ot a p plica ble
Re peat t u m or i ma gi n g 
s h o ws i U P D b y 
i R E CI S T per 
I n vesti gat or 
assess me nt
Re peat i ma gi n g at 4 t o 8 
wee ks t o c o nfir m P D. 
M a y  occ ur at ne xt 
re g ularl y sc he d ule d 
i ma gi n g visit.
C o nti n ue st u d y treat me nt at 
t he I n vesti gat or’s discreti o n.
Re peat i ma gi n g at 4 t o 8 
wee ks t o c o nfir m P D per 
I n vesti gat or’s 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 
s h o ws iS D, iP R or iC R 
b y i R E CI S T per 
I n vesti gat or 
assess me nt
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 I n 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 m pr 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 
re g ular i ma gi n g sc he d ule
A b bre viati o ns: BI C R = bli n de d i n de pe n de nt ce ntral re vie w; i C P D = i R E CI S T c o nfir me d pr o gressi ve disease; i C R = i R E CI S T c o m plete res p o nse; i R E CI S T partial res p o nse; 
i R E CI S T = m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors 1. 1 f or i m m u ne -base d t hera pe utics; i S D = i R E CI S T sta ble disease; i U P D = i R E CI S T u nc o nfir me d 
pr o gressi ve disease; P D = pr o gressi ve disease; R E CI S T 1. 1 = Res p o nse E val uati o n Criteria i n S oli d T u m ors 1. 1 ; V O P = verificati o n of pr o gressi o n.
N ote:  If pr o gressi o n has bee n ce ntrall y verifie d, f urt her ma na ge me nt is b y t he site, base d o n i R E CI S T. A n y f urt her i ma gi n g s h o ul d still be s u b mitte d t o t he ce ntral i ma gi n g 
ve n d or, b ut n o ra pi d re vie w will occ ur.   If R E CI ST 1. 1 disease pr o gressi o n has n ot bee n ce ntrall y verifie d, i deall y t he site s h o ul d c o nti n ue treat me nt. W het her or n ot treat me nt 
c o nti n ues, i ma gi n g s h o ul d be c ollecte d a n d s u b mitte d t o t he ce ntral i ma gi n g ve n d or wit h V O P re q uest u ntil R E CI S T 1. 1 pr o gress i o n is verifie d b y BI C R.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Fi g ure 3
I ma gi n g a n d Treat me nt f or Cli nicall y Sta ble Partici pa nts after First Ra di ol o gic 
E vi de nce of P D Assesse d b y  t he I n vesti gat or
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
P atie nt Re p orte d O utc o mes
9. 2. 2
N O T E : As of A me n d me nt 0 4, P R Os will n o l o n ger be c ollecte d after t he first o n -st u d y 
i m a gi n g assess me nt at Wee k 9.
T he E ur o Q o L E Q -5 D a n d E O R T C Q L Q- C 3 0 q uesti o n naires will be a d mi nistere d b y trai ne d 
site pers o n nel a n d c o m plete d electr o nically b y s u bjects i n t he f oll o wi n g or der: E ur o Q o L E Q -
5 D first, t he n E O R T C Q L Q -C 3 0. T he q uesti o n naires s h o ul d be a d mi nistere d pri or t o d osi n g 
at C y cle 1 -4, t he n e ver y  3r d c ycle t hr o u g h Year 1 (ie, C ycles 7, 1 0, 1 3, 1 6), t he n e ver y 4t h 
c ycle after Year 1 f or u p t o 2 years fr o m treat me nt i nitiati o n or u ntil E O T (ie, C ycles 2 0, 2 4, 
2 8, 3 2), w hic he ver c o mes first , a n d at t he 3 0-d a y  Safet y F oll o w-u p Visit.
It is best practice a n d str o n gly 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 t o ra n d o mize d s u bjects pri or t o dr u g a d mi nistrati o n, A E
e val uati o n, a n d disease stat us n otificati o n.  If t he s u bject d oes n ot c o m plete t he e P R Os at a 
sc he d ule d ti me p oi nt, t he MIS S _ M O D E f or m m ust be c o m plete d t o ca pt ure t he reas o n t he 
assess me nt was n ot perf or me d.
He alt h C are Res o urce Utiliz ati o n
9. 2. 3
All -ca use h os pitalizati o ns a n d e mer ge n c y  r o o m visits m ust be re p orte d i n t he e C R F, fr o m t he 
ti me of treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 da ys f oll o wi n g cessati o n of st u d y 
treat me nt, or 3 0 da ys f oll o wi n g cessati o n of st u d y treat me nt, if t he partici pa nt i nitiates ne w 
a ntica ncer t hera p y , w hic he ver is earlier.
A d verse E ve nts, Seri o us A d verse E ve nts a n d Ot her Re p ort a ble S afet y E ve nts 
9. 3
T he defi niti o ns of a n a d verse e ve nt ( A E) or seri o us a d verse e ve nt ( S A E), as well as t he 
met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A E a n d S A E a n d t he pr oce d ures 
f or c o m pleti n g a n d tra ns mitti n g A E, S A E a n d ot her re p orta ble safety e ve nt re p orts ca n be 
f o u n d i n A p pe n di x 4.
A E, S A Es, a n d ot her re p orta ble safet y  e ve nts will be re p orte d b y t he partici pa nt ( or, w he n 
a p pr o priate, b y a care gi ver, s urr o gate, or t he partici pa nt's le gall y  a ut h orize d re prese ntati ve). 
T he i n vesti gat or, w h o is a q ualifie d p h ys icia n, a n d a n y desi g nees are res p o nsi ble f or 
detecti n g, assessi n g, d oc u me nti n g, a n d re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or 
S A E as well a s ot her re p orta ble safet y e ve nts. I n vesti gat ors re mai n res p o nsi ble f or f oll o wi n g 
u p A E, S A Es a n d ot her re p orta ble safet y e ve nts f or o utc o me acc or di n g t o Secti o n 9. 3. 3.
A d verse e ve nts will n ot be c ollecte d f or partici pa nts d uri n g t he pre -scree ni n g peri o d (for 
deter mi nati o n of arc hi val tiss ue stat us) as l o n g as t hat partici pa nt has n ot u n der g o ne a n y 
pr ot oc ol -s pecifie d pr oce d ure or i nter ve nti o n.  If t he partici pa nt re q uires a bl o o d dra w, fres h 
t u m or bi o ps y etc., t he partici pa nt is first re q uire d t o pr o vi de c o nse nt t o t he mai n st u d y a n d 
A Es will be ca pt ure d acc or di n g t o g ui deli nes f or sta n dar d A E re p orti n g.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E a n d Ot her Re p ort a ble 
9. 3. 1
S afet y E ve nt I nf or m ati o n 
All A Es, S A Es a n d ot her re p orta ble safet y e ve nts t hat occ ur a fter t he c o nse nt f or m is si g ne d 
b ut bef ore treat me nt all ocati o n/ra n d o mizati o n m ust be re p orte d b y t he i n vesti gat or if t he 
partici pa nt is recei vi n g place b o r u n -i n or ot her r u n-i n treat me nt, if t he e ve nt ca uses t he 
partici pa nt 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, or a pr oce d ure. 

All A Es fr o m t he ti me of treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 da y s f oll o wi n g 
cessati o n of st u d y treat me nt, or 3 0 da ys f oll o wi n g cessati o n of st u d y treat me nt if t he 
partici pa nt i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier, m ust be re p orte d b y t he 
i n vesti gat or. 

All A Es meeti n g seri o us criteria, fr o m t he ti me of treat me nt all ocati o n/ra n d o miz ati o n 
t hr o u g h 9 0 da ys f oll o wi n g cessati o n of st u d y treat me nt, or 3 0 da ys f oll o wi n g cessati o n of 
st u d y treat me nt if t he partici pa nt i nitiates ne w a ntica ncer t hera py, w hic he ver is earlier 
m ust be re p orte d b y t he i n vesti gat or. 

All pre g na ncies a n d e x p os ure d u ri n g breastfee di n g, fr o m t he ti me of treat me nt 
all ocati o n/ra n d o mizati o n t hr o u g h 1 2 0 da ys f oll o wi n g cessati o n of st u d y treat me nt, or 3 0 
da y s f oll o wi n g cessati o n of st u d y treat me nt if t he partici pa nt i nitiates ne w a ntica ncer 
t hera py  m ust be re p orte d b y t he i n vesti gat or. 

A d diti o nall y , a ny S A E br o u g ht t o t he atte nti o n of a n i n vesti gat or at a n y ti me o utsi de of 
t he ti me peri o d s pecifie d a b o ve m ust be re p orte d i m me diatel y t o t he S p o ns or if t he e ve nt 
is c o nsi dere d t o be dr u g-relate d.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A E or S A E or ot her re p orta ble safet y e ve nts 
i n f or mer st u dy partici pa nts. H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he 
c o nsi ders t he e v e nt t o be reas o na bl y relate d t o t he st u d y treat me nt or st u d y partici pati o n, t he 
i n vesti gat or m ust pr o m ptl y n otif y M S D .
All i nitial a n d f oll o w -u p A Es, S A Es a n d ot her re p orta ble safet y  e ve nts will be rec or de d a n d 
re p orte d t o M S D
or desi g nee wit hi n t he ti mefr a mes as i n dicate d i n Ta ble 8 .
 
 
0 4 Y B Q D




Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 4
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Met h o d of Detecti n g A E, S A E a n d Ot her Re p ort a ble S afet y E ve nts
9. 3. 2
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A E a n d/ or S A E a n d ot her re p orta ble 
safety e ve nts. O pe n -e n de d a n d n o n -lea di n g ver bal q uesti o ni n g of t he partici pa nt is t he 
preferre d met h o d t o i n q ui re a b o ut A E occ urre nce.
F oll o w -u p of A E, S A E a n d Ot her Re p ort a ble S afet y E ve nt I nf or m ati o n 
9. 3. 3
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All A E, S A E a n d ot her re p orta bl e safet y e ve nts 
i ncl u di n g pre g na nc y a n d e x p os ure d uri n g breastfee di n g, E CI, Ca ncer a n d O ver d ose will be 
f oll o we d u ntil res ol uti o n, sta bilizati o n, u ntil t he e ve nt is ot her wise e x plai ne d, or t he 
partici pa nt is l ost t o f oll o w -u p (as defi ne d i n Secti o n 8. 3). I n a d diti o n, t he i n vesti gat or will 
ma ke e ver y  atte m pt t o f oll o w all n o n-seri o us A Es t hat occ ur i n ra n d o mize d partici pa nts f or 
o utc o me.  F urt her i nf or mati o n o n f oll o w -u p pr oce d ures is gi ve n i n A p pe n di x 4.
Re g ul at or y Re p orti n g Re q uire me nts f or S A E
9. 3. 4
a.
Pr o m pt n ot ificati o n ( wit hi n 2 4 h o urs) b y t he i n vesti gat or t o M S D
of S A E is esse ntial s o 
t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safety of partici pa nts a n d t he 
safet y of a st u dy treat me nt u n der cli nical i n vesti gati o n are met. 
b.
T he S p o ns or a n d M S D h a ve a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y 
a ut h orit y a n d ot her re g ulat or y a ge ncies a b o ut t he safety of a st u d y treat me nt u n der 
cli nical i n vesti gati o n. 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 v esti 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, 
ie, per I nter nati o nal C o nfere nce o n Har m o nisati 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 (I C H) T o pic E 6 ( R 1) G ui deli nes f or 
G o o d Cli nical Practic e.
c.
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d M S D
p olic y  a n d 
f or war de d t o i n vesti gat ors as necessar y.
d.
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her 
s pecific safety i nf or mati o n (e g, s u m mar y or listi n g of S A E) fr o m M S D
will file it al o n g 
wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
9. 3. 5
or S A Es
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 re p orta ble e ve nt. 
M S D
will m o nit or u n bli n de d a g gre gate d efficac y  e n d p oi nt e ve nts a n d safet y data t o e ns ure
t he safety of t he partici pa nts i n t he st u d y.  A n y s us pecte d e n d p oi nt 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 M S D gl o bal safet y as a S A E 
wit hi n 2 4 h o urs of deter mi nati o n t hat t he e ve nt is n ot pr o gressi o n of t he c a ncer u n der st u d y.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Pre g n a nc y a n d E x p os ure D uri n g Bre astfee di n g
9. 3. 6
Alt h o u g h pre g na nc y  a n d i nfa nt e x p os ure d uri n g breastfee di n g are n ot c o nsi dere d a d verse 
e ve nts, a n y pre g na nc y or i nfa nt e x p os ure d uri n g breastfee di n g i n a partici pa nt (s p o nta ne o usl y 
re p orte d t o t he i n vesti gat or or t heir desi g nee) t hat occ urs d uri n g t he trial are re p orta ble t o 
M S D .
All re p orte d pre g na ncies m ust be f oll o we d t o t he c o m pleti o n/ter mi nati o n of t he pre g na nc y . 
Pre g na nc y  o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n hy d ati dif o r m m ole, 
bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, miscarria ge a n d still birt h m ust be re p orte d as 
seri o us e ve nts (I m p orta nt Me dical E ve nts). If t he pre g na nc y c o nti n ues t o ter m, t he o utc o me 
( healt h of i nfa nt) m ust als o be re p orte d.
E ve nts of Cli nic al I nterest ( E CI)
9. 3. 7
Selecte d n o n -seri o us a n d seri o us a d verse e ve nts are als o k n o w n as E ve nts of Cli nical 
I nterest ( E CI) a n d m ust be re p orte d t o M S D .
E ve nts of cli nical i nterest f or t his trial i ncl u de: 
1.
a n o ver d ose of st u d y treat me nt, as defi ne d i n Secti o n 9. 4 – Treat me nt of O ver d ose, 
t hat is n ot ass ociate d wit h cli nical s y m pt o ms or a b n or mal la b orat or y res ults.
2.
a n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit 
of n or mal a n d a n ele 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 n g or u nsc he d ule d la b orat or y testi n g. *
* N ote:  T hese criteria are base d u p o n a vaila ble re g ulat or y g ui da nce d oc u me nts. T he 
p ur p ose of t he criteria is t o s pecif y  a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. T he trial site g ui da nce f or assess m e nt 
a n d f oll o w u p of t hese criteria ca n be f o u n d i n t he I n vesti gat or Trial File Bi n der ( or 
e q ui vale nt).
3.
ser ot o ni n s yn dr o me.  T he si g ns a n d s y m pt o ms of ser ot o ni n s y n dr o me are descri be d i n 
Secti o n 7. 2. 1. 1 .
E CI s t hat occ ur after t he c o nse nt f or m is si g ne d b ut bef ore treat me nt ra n d o mizati o n m ust be 
re p orte d by t he I n vesti gat or t o M S D if t he e ve nt ca use d t he partici pa nt t o be e xcl u de d fr o m 
t he st u d y or is t he res ult of a pr ot oc ol-s pecifie d i nter ve nti o n. 
All E CI s t hat occ ur fr o m t he ti me of treat me nt ra n d o mizati o n t hr o u g h 9 0 da ys f oll o wi n g 
cessati o n of st u d y treat me nt , or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he partici pa nt 
i nitiates ne w a ntica ncer t hera py, w hic he ver is earlier, m ust be re p orte d b y t he i n vesti gat or t o 
M S D wit hi n 2 4 h o urs of lear ni n g of t he e ve nt .
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 6
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Tre at me nt of O ver d ose
9. 4
I n t his st u d y, a n o ver d ose is a n y d ose hi g her t ha n ≥1 0 0 0 m g ( 5 ti mes t he d ose) of 
pe m br oliz u ma b or ≥1 0 0 0 m g of e paca d ostat dail y . 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 or e paca d ostat. I n t he e ve nt of o ver d ose, t he 
partici pa nt s h o ul d be o bser ve d cl osel y  f or si g ns of t o xicit y. A p pr o priate s u p p orti ve 
treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d.
If a n A E is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of st u d y treat me nt, t he A E is 
re p orte d as a S A E , e ve n if n o ot her seri o us ness criteria are met.
If a d ose of st u d y treat me nt 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 y m 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 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 E m ust be re p o rte d by t he i n vesti gat or wit hi n 
2 4 h o urs t o M S D 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 electr o nic data ca pt ure (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).
S afet y 
9. 5
Details re gar di n g s pecific safet y pr oce d ures/assess me nts t o be perf or me d i n t his st u d y are 
pr o vi de d bel o w. T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver t he c o urse of 
t he st u d y (fr o m pre-st u d y t o p ost-st u d y visits), i ncl u di n g a p pr o xi mate bl o o d/tiss ue v ol u mes 
dra w n/c ollecte d b y visit a n d b y sa m ple t y pe per partici pa nt ca n be f o u n d i n t he 
Pr oce d ures/ La b orat or y Ma n ual .
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A.
P h ysic al E x a mi n a ti o ns
9. 5. 1
F ull P h ysic al E x a mi n ati o n
9. 5. 1. 1
T he In vesti gat or or cli nical desi g nee will perf or m a f ull p h y sical e xa m as per i nstit uti o nal 
sta n dar d, d uri n g t he scree ni n g peri o d, a n d t he disc o nti n uati o n visit, as s pecifie d i n t he S o A
( Secti o n 2. 0).  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 first d ose of st u d y treat me nt ne w cli nicall y si g nifica nt a b n or mal fi n di n gs 
s h o ul d be rec or de d as A Es.  A f ull p h y sical e xa mi nati o n s h o ul d als o be perf o rme d at t he
Sec o n d C o urse C ycle 1 a n d Sec o n d C o urse disc o nti n uati o n visit.
Directe d P h ysic al E x a mi n ati o n
9. 5. 1. 2
F or c y cles t hat d o n ot re q uire a f ull p h ys ical e xa m per t he S o A ( Secti o n 2. 0), t he In vesti gat or 
or q ualifie d desi g nee will perf or m a directe d p h ys ical e xa m as clinicall y i n dicate d pri or t o 
d osi n g o n Da y  1 of eac h treat me nt c ycle.  Ne w cli nicall y si g nifica nt a b n or mal fi n di n gs 
s h o ul d be rec or de d as A Es.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 7
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Vit al Si g ns
9. 5. 2
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 a n d pri or t o t he 
a d mi nistrati o n of eac h d ose of st u d y treat me nt a n d at E O T as s pecifie d i n t he S o A. Vital 
si g ns 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. Hei g ht will be 
meas ure d at Scree ni n g Visit o nl y .
Electr oc ar di o gr a ms
9. 5. 3
Baseli ne E C Gs will be o btai ne d at scree ni n g, wit h a d diti o nal E C Gs o btai ne d at E O T, a n d as 
cli nicall y i n dicate d f or all partici pa nt s. At select ce nters, a d diti o nal E C Gs will als o be 
o btai ne d at C 1 D 1 pre d ose a n d a p pr o xi matel y  2 h o u r (± 1 5 mi n utes) after t he first d ose of 
e paca d ostat, a n d C 2 D 1 pre d ose a n d a p pr o xi matel y  2 h o u r (± 1 5 mi n utes) after a d mi nistrati o n 
of e paca d ostat as s pecifie d i n t he S o A . T he E C G meas ure me nt s h o ul d al wa ys be perf or me d 
pri or t o t he P K sa m ple bl o o d dra w if b ot h are sc he d ule d at t he sa me n o mi nal pla n ne d ti me 
p oi nt.  Cli nicall y  si g nifica nt a b n or mal fi n di n gs pri or t o si g ni n g c o nse nt s h o ul d be rec or de d as 
me dical hist or y .  Cli nicall y si g nifica nt a b n or mal fi n di n gs after si g ni n g c o nse nt s h o ul d be 
rec or de d as a n A E. A n E C G s h o ul d als o be perf or me d at t he Sec o n d C o urse C y cle 1 Da y 1 
a n d Sec o n d C o urse disc o nti n uati o n visit as o utli ne d i n t he S o A .
T he 1 2- lea d E C Gs will be i nter prete d by t he i n vesti gat or at t he site a n d will be use d f or 
i m me diate partici pa nt ma na ge me nt.  T he decisi o n t o i ncl u d e or wit h dra w a partici pa nt fr o m 
t he st u d y base d o n a n E C G fla g ge d as " A b n or mal, Cli nicall y Si g nifica nt" is t he res p o nsi bilit y 
of t he i n vesti gat or, i n c o ns ultati o n wit h t he me dical m o nit or, as a p pr o priate.  T he Fri dericia 
( preferre d) or Bazett c orrecti o n met h o d use d f or calc ulati n g Q Tc will be use d a n d rec or de d i n 
t he e C R F.
Perf or m a nce Assess me nts
9. 5. 4
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us
9. 5. 4. 1
T he I n vesti gat or or q ualifie d desi g nee will assess E C O G P S at scree ni n g ( wit hi n 1 4 da y s 
p ri or t o ra n d o mizati o n); o n Da y  1 of eac h c ycle, pri or t o t he a d mi nistrati o n of eac h d ose of 
pe m br oliz u ma b; a n d at E O T, as s pecifie d i n t he S o A.  T he E C O G P S scale is descri be d i n 
A p pe n di x 7.
K ar n ofs k y Perf or m a nce St at us ( K P S)
9. 5. 4. 2
T he K P S is a sta n dar d wa y  of meas uri n g t he a bilit y of ca ncer patie nts t o perf or m or di nar y 
tas ks, wit h sc ores ra n gi n g fr o m 0 t o 1 0 0 %.  A hi g her sc ore mea ns t he patie nt is better a ble t o 
carr y o ut dail y acti vities.  See A p pe n di x 7 f or a descri pti o n of t he f ull scale.  T he K P S will be 
ass esse d as s pecifie d i n t he S o A ( Secti o n 2) at scree ni n g o nl y ( wit hi n 1 4 da y s pri or t o 
ra n d o mizati o n), a n d will be use d f or stratificati o n b y t he Baj ori n ris k sc ore.  T he Baj ori n ris k 
sc ore is base d o n t he prese nce of visceral (l u n g, li ver, or b o ne) metastasis a n d/ or K P S < 8 0 %
as detaile d i n 7. 3. 1 .
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 8
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Cli nic al S afet y L a b or at or y Assess me nts
9. 5. 5
Refer t o A p pe n di x 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he S o A f or 
t he ti mi n g a n d fre q ue nc y. 
●
T he In vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he 
C R F. T he la b orat or y  re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y  
si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he 
u n derl y i n g disease, u nless j u d ge d by t he i n vesti gat or t o be m ore se vere t ha n e x pecte d 
f or t he partici pa nt's c o n diti o n.
●
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be 
c o n d ucte d i n acc or da nce wit h t he Pr oce d ures/ L a b orat or y Ma n ual a n d t he S o A.
●
If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifie d la b orat or y  assess me nts perf or me d at 
t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n st u d y partici pa nt mana ge me nt or 
are c o nsi dere d cli nicall y si g nifica nt by t he In vesti gat or (e g, S A E or A E or d ose 
m o dificati o n), t he n t he res ults m ust be rec or de d i n t he a p pr o priate C R F (e g, S L A B).
●
F or a n y l a b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntly a b n o r mal 
d uri n g partici pati o n i n t he st u d y  or wit hi n 3 0 da y s after t he last d ose of st u d y 
treat me nt, e ver y atte m pt s h o ul d be ma de t o perf or m re peat assess me nts u ntil t he 
val ues ret ur n t o n or mal or baseli ne or if a ne w baseli ne is esta blis he d as deter mi ne d 
b y  the i n vesti gat or. 
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)
9. 5. 5. 1
La b orat or y  tests f or he mat ol o g y, c he mistr y, a n d uri nal ysis are s pecifie d i n A p pe n di x 2.  
Refer t o S o A f or t he ti mi n g of la b orat or y  assess me nts.
Pre g n a nc y Test
9. 5. 5. 2
All w o me n w h o are bei n g c o nsi dere d f or partici pati o n i n t he st u d y, a n d w h o are n ot 
s ur gicall y sterilize d or p ost me n o pa usal (as defi ne d i n A p pe n di x 5), m ust be teste d f or 
pre g na nc y  wit hi n 7 2 h o urs pri or t o ra n d o mizati o n.  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.  If a uri ne test is p ositi ve or n ot 
e val ua ble, a ser u m test will be re q uire d.  Partici pa nts m ust be e xcl u de d/ disc o nti n ue d fr o m t he 
st u d y 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 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 9
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Visit Re q uire me nts
9. 9
Visit re q uire me nts are o utli ne d i n Secti o n 2 – Sc he d ule of Acti vities ( S o A).  S pecific 
pr oce d ure -relate d details are pr o vi de d a b o ve i n Secti o n 9 – St u d y  Assess me nts a n d 
Pr oce d ures.
Scree ni n g
9. 9. 1
A p pr o xi matel y  4 2 d a y s pri or t o treat me nt all ocati o n/ra n d o mizati o n, p ote ntial partici pa nt will 
be e val uate d t o deter mi ne t hat t he y f ulfill t he e ntr y re q uire me nts as set f ort h i n Secti o n 6. 0.  
Scree ni n g pr oce d ures ma y be re peate d after c o ns ultati o n wit h M S D.  
Writte n c o nse nt m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol -s pecific pr oce d ures.  
Res ults of a test perf or me d pri or t o t he partici pa nt si g ni n g c o nse nt as part of r o uti ne cli nical 
ma na ge me nt are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti me 
fra me. Res ults fr o m t he scree ni n g visit e val uati o ns will be re vie w e d t o c o nfir m partici pa nt
eli gi bilit y bef ore ra n d o mizati o n or t he a d mi nistrati o n of st u d y dr u g.  Scree ni n g pr oce d ures 
are t o be c o m plete d wit hi n a p pr o xi matel y 4 2 d a y s pri or t o t he first d ose of st u d y treat me nt 
e xce pt f or t he f oll o wi n g:

La b orat or y tests ar e t o be perf or me d wit hi n 1 4 da ys pri or t o ra n d o mizati o n. A n 
e xce pti o n is he patitis testi n g, w hic h ma y be d o ne u p t o 4 2 da y s pri or t o 
ra n d o mizati o n.

E val uati o n of E C O G is t o be perf or me d wit hi n 1 4 da y s 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 t he ra n d o mizati o n. If uri ne pre g na nc y res ults 
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 ( perf or me d 
b y  t he l ocal st u d y site la b orat or y).  

I nitial t u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da y s of ra n d o mizati o n.
Partici pa nts ma y  be rescree ne d after i nitiall y faili n g t o meet t he i ncl usi o n/e xcl usi o n criteria.  
Res ults fr o m assess me nts d uri n g t he i nitial scree ni n g peri o d are acce pta ble i n lie u of a re peat 
scree ni n g test if perf or me d wit hi n t he s pecific ti me fra me a n d t he c orres p o n di n g 
i ncl usi o n/e xcl usi o n criteria are met.  Partici pa nt s w h o are rescree ne d will retai n t heir ori gi nal 
scree ni n g n u m ber.
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
Tre at me nt Peri o d
9. 9. 2
Visit re q uire me nts are o utli ne d i n t he S o A ( Secti o n 2. 0).  S pecific pr oce d ure-relate d details 
are pr o vi de d i n Secti o n 9.   
T reat me nt wit h pe m br oliz u ma b will occ ur e ver y 2 1 da ys ( 1 c ycle) f or a ma xi m u m of 
3 5 c ycles (a p pr o xi matel y 2 years) .
E paca d ostat or matc hi n g place b o will be d ose d t wice daily ( a p pr o xi matel y Q 1 2 H) d uri n g t he 
treat me nt p hase.  Treat me nt ma y c o nti n ue u ntil C 3 5 D 2 1, u nless a disc o nti n uati o n criteri o n is 
met ( Secti o n 8. 1) .
Sec o n d C o urse P h ase ( Retre at me nt)
9. 9. 3
Visit re q uire me nts f or t he Sec o n d C o urse P hase ( Retreat me nt) are o utli ne d i n t he Sec o n d 
C o urse P hase ( Retreat me nt) S o A ( Secti o n 2. 0). 
Disc o nti n u ati o n Visit
9. 9. 4
If a decisi o n is ma de t hat t he partici pa nt will per ma ne ntl y  disc o nti n ue st u dy dr u g, t he 
Disc o nti n uati o n V isit s h o ul d be c o n d ucte d at E O T .  If t he Disc o nti n uati o n V isit c oi nci des 
wit h a re g ular st u d y visit, t he Disc o nti n uati o n Visit e val uati o ns will s u perse de t h ose of t hat 
sc he d ule d visit.  T he partici pa nt s h o ul d be e nc o ura ge d t o ret ur n f or t he Safet y Foll o w -u p 
visit.
Disc o nti n ue d P artici p a nts C o nti n ui n g t o be M o nit ore d i n t he St u d y
9. 9. 5
S afet y F oll o w -U p Visit
9. 9. 5. 1
N O T E: As of A me n d me nt 0 4, t he S afet y F oll o w -u p Visit will be t he l ast visit i n t he 
st u d y. T his secti o n h as bee n a me n de d acc or di n gl y .
T he ma n dat or y  Safet y F oll o w - U p Visit s h o ul d be c o n d ucte d 3 0 da y s ( + 7 d a y s) da ys after t he 
last d ose of st u d y treat me nt or bef ore t he i nitiati o n of a ne w a ntica ncer treat me nt, w hic he ver 
c o mes first .  Reas o na ble eff orts s h o ul d be ma de t o ha ve t he partici pa nt ret ur n f or t he Safet y 
F oll o w -u p V isit a n d re p ort a n y A Es t hat ma y occ ur pri or t o i nitiati n g ne w a ntica ncer t hera py.   
If t he partici pa nt has a disc o nti n uati o n visit ≥3 0 da ys after t he last d ose of st u d y treat me nt, 
t he Safety F oll o w -u p V isit is n ot re q uire d. Partici pa nts will be c o nsi dere d t o ha ve c o m plete d 
t his st u d y o nce t he y ha ve atte n de d t his visit. Partici pa nts c urre ntl y i n F oll o w -u p or i n 
S ur vi val F oll o w -u p are c o nsi dere d t o ha ve c o m plete d t he st u d y; t hese partici pa nts are n ot 
re q uire d t o atte n d a ny f urt her visits. Assess me nt a n d rec or di n g of A Es will be perf or me d as 
per Secti o n 9. 3.
Partici pa nt s w h o are eli gi ble f or retreat me nt wit h t he c o m bi nati o n t hera py (as descri be d i n 
Secti o n 7. 2. 2 ) ma y ha ve u p t o 2 Safet y F oll o w- up V isits, 1 after t he treat me nt peri o d a n d 
1 after t he Sec o n d C o urse P hase ( Retreat me nt).   
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 3
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
F oll o w -U p Visits
9. 9. 5. 2
N O T E : As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble. P artic ip a nts 
c urre ntl y i n p ost -tre at me nt f oll o w-u p are c o nsi dere d t o h a ve c o m plete d t he st u d y o nce 
t he y h a ve atte n de d t he S afet y F oll o w-u p Visit; a ssess me nt a n d recor di n g of A Es will be 
perf o r me d as per Secti o n 9. 3 .
Partici pa nt s w h o disc o nti n ue st u d y treat me nt f or a reas o n ot her t ha n BI C R -verifie d dise ase 
pr o gressi o n will m o ve i nt o t he F oll o w -u p P hase.  F oll o w - up V isits ma y be sc he d ule d t o 
c oi nci de wit h F oll o w - up i ma gi n g a n d s h o ul d be assesse d e ver y 9 wee ks ( 6 3 ± 7 da y s) fr o m 
t he date of ra n d o mizati o n, f or t he first 1 2 m o nt hs ( 5 4 wee ks) b y  ra di ol o gic i ma gi n g t o 
m o nit or disease stat us ; t he n e ver y 1 2 wee ks ( 8 4 da ys ± 7 d a y s) t hereafter d uri n g st u d y 
partici pati o n . T he i ma gi n g assess me nt sc he d ule c o nti n ues if a partici pa nt disc o nti n ues 
treat me nt; if a partici pa nt has starte d t he 1 2 wee k i ma gi n g, t he y will c o nti n ue t o be assesse d 
e ver y 1 2 wee ks.  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 ne o plastic t hera py, BI C R -verifie d disease pr o gressi o n, wit h dra wal 
of c o nse nt, pre g na nc y , deat h, a n d e n d of t he st u d y , or if t he partici pa nt be gi ns Sec o n d C o urse 
P hase ( R etreat me n t) as detaile d i n Secti o n 7. 2. 2.  I nf or mati o n re gar di n g p ost -st u d y 
a nti ne o plas tic treat me nt will be c ollecte d if ne w treat me nt is i nitiate d.
Partici pa nt s w h o are eli gi ble t o recei ve retreat me nt acc or di n g t o t he criteria i n Secti o n 7. 2. 2 
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 ( Retreat me nt) w he n t he y 
e x perie nce disease pr o gressi o n verifie d b y BI C R .
S ur vi v al F oll o w -U p
9. 9. 5. 3
N O T E : As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble. P artici p a nts 
c urre ntl y i n S ur vi v al F oll o w -u p are c o nsi dere d t o h a ve c o m plete d t he st u d y; t hese 
p artici p a nts will n o l o n ger be c o nt acte d f or s ur vi v al i nf or m ati o n. Assess me nt a n d 
rec or di n g of A Es will be perf or me d as per Secti o n 9. 3.
Partici pa nt s w h o e x perie nce c o nfir me d disease pr o gressi o n b y  BI C R or start a ne w a nti -
ca ncer t hera p y will m o ve i nt o t he S ur vi val F oll o w - up P hase a n d s h o ul d be c o ntacte d by 
tele p h o ne a p pr o xi matel y e ver y 1 2 wee ks ( ± 7 da y s) 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.   
U nsc he d ule d Visits
9. 9. 5. 4
U nsc he d ule d st u d y visits ma y occ ur at a n y ti me if me dicall y warra nte d.  A n y assess me nts 
perf or me d at t h ose visits s h o ul d be rec or de d i n t he e C R F.
S ur vi v al St at us
9. 9. 6
N O T E : As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble; s ur vi v al d at a is n o 
l o n ger bei n g c ollecte d. 
T o e ns ure c urre nt a n d c o m plete s ur vi val data is a vaila ble at t he ti me of data base l oc ks, 
u p date d s ur vi val stat us ma y be re q ueste d d uri n g t he c o urse of t he st u dy b y M S D.  F or 
e xa m ple, u p date d s ur vi val stat us ma y be re q ueste d pri or t o b ut n ot li mite d t o a n e xter nal Data 
M o nit ori n g C o m mittee (e D M C) re vie w, i nteri m a n d/ or fi nal a nal ys is.  U p o n M S D 
n otificati o n, all partici pa nts w h o d o n ot/ will n ot ha ve a sc h e d ule d st u d y visit or st u d y c o ntact 
 
 
0 4 Y B Q D




Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-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
1 0. 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 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 N S O R. 
T he I V R S ve n d or/ S p o ns 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.
T his st u d y  will be c o n d ucte d as a d o u ble-bli n d st u d y  u n der i n-h o use bli n di n g pr oce d ures. 
T he official, fi nal data base will n ot be u n bli n de d u ntil me dical/scie ntific re vie w has bee n 
pe rf or me d, pr ot oc ol de viati o ns ha ve bee n i de ntifie d, a n d data ha ve bee n declare d fi nal a n d 
c o m plete. 
A n e xter nal D M C will be c o n ve ne d t o re vie w acc u m ulati n g safet y data. T he eD M C 
res p o nsi bilities a n d re vie w sc he d ules will be o utli ne d i n t he D M C c harter.
Bl i n di n g t o treat me nt assi g n me nt will be mai ntai ne d at all i n vesti gati o nal sites u ntil t he last 
partici pa nt c o m pletes t he first sc he d ule d i ma gi n g (ie, Wee k 9) f or efficac y a nal ysis. 
Partici pa nt -le vel u n bli n di n g will be restricte d t o a n e xter nal u n bli n de d statisticia n a n d 
e xter nal u n bli n de d 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. 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 t he res ults will be d oc u me nte d. 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 D M C C harter.
Pri or t o fi nal st u d y  u n bli n di n g, t he u n bli n de d statisticia n a n d u n bli n de d scie ntific 
pr o gra m mer will n ot be i n v ol ve d i n a n y  disc ussi o ns re gardi n g m o dificati o ns t o t he pr ot oc ol, 
statistical met h o ds, i de ntificati o n of pr ot oc ol de viati o ns, or data vali dati o n eff orts.
H y p ot heses/ Esti m ati o n
1 0. 3
O bjecti ves of t he st u d y are state d i n Secti o n 4. 4 – O bjecti ves a n d h y p ot heses a n d E n d p oi nts .
A n al ysis E n d p oi nt s
1 0. 4
Effic ac y E n d p oi nt
1 0. 4. 1
Pri m ar y E n d p oi nt
1 0. 4. 1. 1
O bjecti ve Res p o nse R ate ( O R R) – R E CI S T 1. 1 assesse d b y i n vesti g at or
O bjecti ve Res p o nse Rate is defi ne d as t he pr o p orti o n of partici pa nts i n t he a nal ysis 
p o p ulati o n w h o ha ve a best res p o nse of C R or P R base d o n R E CI S T 1. 1 b y  i n vesti gat or 
deter mi nati o n .
S afet y E n d p oi nts
1 0. 4. 2
Safet y  a n d t olera bilit y will be assesse d by cli nical re vie w of all rele va nt para meters i ncl u di n g 
A Es, S A Es, fatal A Es, la b orat or y  tests, a n d vital si g ns as descri be d i n Secti o n 9. 5 . 
F urt her m ore, s pecific e ve nts will be c ollecte d a n d desi g nate d as E CIs as descri be d i n 
Secti o n 9. 3. 7 .
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 6
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A n al ysis P o p ul ati o ns
1 0. 5
Effic ac y A n al ysis P o p ul ati o n
1 0. 5. 1
T he I nte nti o n -t o-Treat (I T T) p o p ulati o n will ser ve as t he p o p ulati o n f or t he efficac y a nal ys is. 
All ra n d o mize d partici pa nts will be i ncl u de d i n t his p o p ulati o n. Partici pa nts will be a nal yz e 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. 
S afet y A n al ysis P o p ul ati o n
1 0. 5. 2
T he All Pa rtici pa nts as Treate d ( A Pa 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 ud y . T he A Pa T p o p ulati o n c o nsists of all ra n d o mize d partici pa nts w h o recei ve d at 
least 1 d ose of st u dy treat me nt. Partici pa nts will be a nal yz e 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 nalys is of safety data 
usi n g t he A Pa T p o p ulati o n. F or m ost partici pa nts 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. Partici pa nts 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 partici pa nt w h o recei ves t he i nc orrect st u d y  treat me nt 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 yz e 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 ny e ve nts t hat occ ur d uri n g t he c ycle 
f or w hic h t he partici pa nt is i nc orrectly 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.
St atistic al Met h o ds
1 0. 6
St atistic al Met h o ds f or Effic ac y A n al yses
1 0. 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 o bjecti ve .  
O bjecti ve Res p o nse R ate ( O R R)
1 0. 6. 1. 1
T he pri mar y  efficac y e n d p oi nt O R R is defi ne d as t he pr o p orti o n of partici pa nts i n t he 
a nal ys is p o p ulati o n w h o ha ve a best res p o nse of C R or P R at t he first sca n base d o n 
R E CI S T 1. 1 b y i n vesti gat or deter mi nati o n.
O R R will be esti mate d b y treat me nt gr o u p. 9 5 % CI  f or O R R will be pr o vi de d usi n g t he 
Cl o p per -Pears o n (e xact ) met h o d.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 7
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
St atistic al Met h o ds f or S afet y A n al yses
1 0. 6. 2
Safet y  a n d t olera bilit y will be assesse d by 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, a n d vital si g ns. 
I n di vi d ual e ve nts a n d t he br oa d A E cate g ories c o nsisti n g of t he pr o p orti o n of partici pa nts 
wit h a n y  A E, a dr u g relate d A E, a seri o us A E, a n A E w hic h is b ot h dr u g-relate d a n d seri o us, 
a Gra de 3-5 A E, a dr u g relate d Gra de 3 -5 A E, a fatal A E, d ose i nterr u pti o n d ue t o a n A E a n d 
disc o nti n uati o n d ue t o a n A E, will be s u m marize d b y c o u nts a n d perce nta ges b y treat me nt 
gr o u p ( Ta ble 1 1 ).  
Ta ble 1 1
A nal y sis Strate g y f or Safet y Para meters
S afet y E n d p oi nt
Descri pti ve St atistics
A n y A E
X
A n y Seri o us A E 
X
A n y Gra de 3 -5 A E 
X
A n y Dr u g -Relate d A E
X
A n y Seri o us a n d Dr u g -Relate d A E
A n y Gra de 3 -5 a n d Dr u g -Relate d A E
X
X
D ose I nterr u pti o n d ue t o A E
X
Disc o nti n uati o n d ue t o A E
X
Deat h
X
S pecific A Es, S O Cs 
X
C ha n ge fr o m Baseli ne Res ults ( La b orat or y t o xicit y gra de)
X
S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristics
1 0. 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 by 
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. T he n u m ber a n d perce nta ge of partici pa nt s scree ne d a n d ra n d o mize d, a n d t he 
pri mar y  reas o ns f or scree ni n g fail ure a n d 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 haracteristics, pri mar y a n 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
1 0. 7
N O T E:  As of A me n d me nt 0 4 , t here will be n o i nteri m effic ac y a n al ysis. T he e D M C will 
c o n d uct s afet y re vie w b ase d o n D M C c h arter. 
M ulti plicit y
1 0. 8
N O T E:  As of A me n d me nt 0 4 , n o h y p ot hesis testi n g will be perf or me d i n t his st u d y. 
T heref ore, n o m ulti plicit y a dj ust me nt is nee de d.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 8
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
S a m ple Size a n d P o wer C alc ul ati o ns
1 0. 9
T he st u d y  will ra n d o mize partici pa nts i n a 1: 1 rati o i nt o t he pe m br oliz u ma b + e pa ca d ostat
a n d pe m br oliz u ma b + place b o ar ms. T he pri mar y  o bjecti ve is t o esti mate O R R f or eac h 
treat me nt ar m. T he o verall sa m ple size of a p pr o xi matel y  1 0 0 is base d o n t he pr ojecte d 
ra n d o mize d partici pa nts w he n a strate gic decisi o n was ma de t o re desi g n t he st u d y base d o n 
O R R as t he pri mar y  e nd p oi nt. 
Wit h a n esti mate d 5 0 partici pa nts per treat me nt ar m, Ta b le 1 2 gi ves e xa m ples of O R R 
esti mates a n d 9 5 % CI , wit h differe nce n u m bers of o bser ve d res p o n ders.
Ta b le 1 2
O R R esti mate a n d 9 5 % CI
# of p artici p a nt
# of res p o n der
O R R
9 5 % CI
CI Wi dt h
5 0
1 4
2 8 % 
( 1 6. 2 %, 4 2. 5 %)
2 6. 3 %
5 0
1 5
3 0 %
( 1 7. 9 %, 4 4. 6 %)
2 6. 7 %
5 0
1 6
3 2 %
( 1 9. 5 %, 4 6. 7 %)
2 7. 2 %
5 0
1 7
3 4 % 
( 2 1. 2 %, 4 8. 8 %) 
2 7. 6 %
5 0
1 8
3 6 %
( 2 2. 9 %, 5 0. 8 %)
2 7. 9 %
S u b gr o u p A n al yses
1 0. 1 0
N ote: As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble.
C o m pli a nce ( Me dic ati o n A d here nce)
1 0. 1 1
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 n y 
de viati o n fr o m pr ot oc ol -directe d a d mi nis trati o n will be re p orte d.
E xte nt of E x p os ure
1 0. 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.  S u m mar y 
statistics will be pr o vi de d o n E xte nt of E x p os ure f or t he AP a T p o p ulati o n.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 9
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
1 1. Refere nces
[ Aar o ns o n, N. K., et al 1 9 9 3]
Aar o ns o n N K, A h me dzai S, Ber g ma n B, 
B ulli n ger M, C ull A, D uez NJ, et al. T he 
E ur o pea n Or ga nizati o n f or Researc h a n d 
Treat me nt of Ca ncer Q L Q -C 3 0: a q ualit y -
of- life i nstr u me nt f or use i n i nter nati o nal 
cli nical trials i n o nc ol o g y. J Natl Ca ncer 
I nst 1 9 9 3; 8 5( 5): 3 6 5- 7 6.
0 3 Q 3 Q L
[ Baj ori n, D. F., et al 1 9 9 9]
Baj ori n D F, D o d d P M, Maz u m dar M, 
Fazzari M, Mc Caffre y  J A, Sc her HI, et al. 
L o n g -ter m s ur vi val i n metastatic 
tra nsiti o nal-cell carci n o ma a n d pr o g n ostic 
fact ors pre dicti n g o utc o me of t hera py. J 
Cli n O nc ol. 1 9 9 9 Oct; 1 7( 1 0): 3 1 7 3 - 8 1.
0 4 Q 3 N 9
[ B o o n, T. 1 9 9 6]
B o o n T, va n der Br u g ge n P. H u ma n t u m or 
a nti ge ns rec o g nize d b y T l y m p h oc y tes. J 
E x p Me d. 1 9 9 6 Mar 1; 1 8 3( 3): 7 2 5- 9.
0 4 9 M F 6
[ B o yer E W, S ha n n o n M 2 0 0 5]
B o yer E W, S ha n n o n M. T he ser ot o ni n 
s yn dr o me. N E n gl J Me d 
2 0 0 5; 3 5 2( 1 1): 1 1 1 2 - 2 0.
0 3 T F 4 X
[ B o yer, E. W. 2 0 0 5]
B o yer E W, S ha n n o n M. T he Ser ot o ni n 
S y n dr o me. N E n gl J Me d 2 0 0 5; 3 5 2: 1 1 1 2 -
2 0
0 4 F R Y Y
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Bra n dac her, G., et al 2 0 0 6]
Bra n dac her G, Perat h o ner A, La d ur ner R, 
Sc h nee ber ger S, O brist P, Wi n kler C, et al. 
Pr o g n ostic val ue of i n d olea mi ne 2, 3 -
di o x y ge nase e x pressi o n i n c ol orectal 
ca ncer: effect o n t u m or-i nfiltrati n g T cells. 
Cli n Ca ncer Res. 2 0 0 6 Fe b 1 5; 1 2( 4): 1 1 4 4 -
5 1.
0 4 9 M F B
[ C he m nitz, J. M., et al 2 0 0 4]
C he m nitz J M , Parr y R V, Nic h ols K E, J u ne 
C H, Rile y  JL.  S H P-1 a n d S H P -2 ass ociate 
wit h i m m u n orece pt or t yr osi ne -base d 
s witc h m otif of pr o gra m me d deat h 1 u p o n 
pri mar y  h u ma n T cell sti m ulati o n, b ut o nl y 
rece pt or li gati o n pre ve nts T cell acti vati o n. 
J Im m u n ol 2 0 0 4; 1 7 3: 9 4 5 - 5 4.
0 0 V M P N
[ Cl o p per, C. J. a n d Pears o n, E. 
S. 1 9 3 4]
Cl o p per CJ, Pears o n E S. T he use of 
c o nfi de nce or fi d ucial li mits ill ustrate d i n 
t he case of t he bi n o mial. Bi o metri ka 
1 9 3 4; X X VI: 4 0 4 - 1 3.
0 3 P H D N
[ C urra n, M. A., et al 2 0 1 0]
C urra n M A, M o ntal v o W, Ya gita H,
Allis o n J P. 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 a n 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 
Mar 2; 1 0 7( 9): 4 2 7 5 - 8 0.
0 4 2 2 D 9
[ Das h, A., et al 2 0 0 6]
Das h A, Gals k y M D, Vic kers AJ, Seri o 
A M, K o p pie T M, Dal ba g ni G, et al. 
I m pact of re nal i m pair me nt o n eli gi bilit y 
f or a dj u va nt cis plati n- base d c he m ot hera py 
i n patie nts wit h ur ot helial carci n o ma of t he 
bla d der. Ca ncer. 2 0 0 6 A u g 1; 1 0 7( 3): 5 0 6 -
1 3.
0 4 C R R S
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ De Sa ntis, M., et al 2 0 1 2]
De Sa ntis M, Bell m u nt J, Mea d G, Kerst 
J M, Lea h y M, Mar ot o P, et al. 
Ra n d o mize d p hase II/III trial assessi n g 
ge mcita bi ne/car b o plati n a n d 
met h otre xate/car b o plati n/ vi n blasti ne i n 
patie nts wit h a d va nce d ur ot helial ca ncer 
w h o are u nfit f or cis plati n -base d 
c hem ot hera p y:  E O R T C st u d y 3 0 9 8 6. J 
Cli n O nc ol 2 0 1 2; 3 0( 2): 1 9 1- 9.
0 3 Y 8 8 N
[ Disis, M. L. 2 0 1 0]
Disis M L . I m m u ne re g ulati o n of ca ncer. J 
Cli n O nc ol 2 0 1 0; 2 8( 2 9): 4 5 3 1- 8.
0 0 V M NJ
[ Erc oli ni, A. M., et al 2 0 0 5]
Erc oli ni A M, La dle B H, Ma n ni n g E A, 
Pfa n ne nstiel L W, Ar mst r o n g T D, Mac hiels 
J P, et al. Recr uit me nt of late nt p o ols of 
hi g h -a vi dit y C D 8( +) T cells t o t he 
a ntit u m or i m m u ne res p o nse. J E x p Me d. 
2 0 0 5 Ma y  1 6; 2 0 1( 1 0): 1 5 9 1- 6 0 2.
0 4 9 M F L
[ Fallari n o, F., et al 2 0 0 6] 
Fallari n o F, Gr o h ma n n U, Y o u S, Mc Grat h 
B C, Ca ve ner D R, Vacca C, et al. T he 
c o m bi ne d effects of tr ypt o p ha n star vati o n 
a n d tr ypt o p ha n cata b olites d o w n -re g ulate 
T cell rece pt or zeta -c hai n a n d i n d uce a 
re g ulat or y p he n oty p e i n nai ve T cells. J 
I m m u n ol. 2 0 0 6 J u n 1; 1 7 6( 1 1): 6 7 5 2- 6 1.
0 4 9 P T L
[ Fra ncisc o, L. M., et al 2 01 0]
Fra ncisc o L M, Sa ge P T, S har pe A H. T he 
P D -1 pat h wa y  i n t olera nce a n d 
a ut oi m m u nit y. I m m u n ol Re v 
2 0 1 0; 2 3 6: 2 1 9 - 4 2.
0 0 V M N M
[ Fr u me nt o, G., et al 2 0 0 2]
Fr u me nt o G, R ot o n d o R, T o netti M, 
Da m o nte G, Be natti U, Ferrara G B. 
Tr y pt o p ha n -deri ve d cata b olites are 
resp o nsi ble f or i n hi biti o n of T a n d nat ural 
killer cell pr oliferati o n i n d uce d b y 
i n d olea mi ne 2, 3-di o x y ge nase. J E x p Me d. 
2 0 0 2 A u g 1 9; 1 9 6( 4): 4 5 9 - 6 8.
0 4 9 P S Y
[ Gal o n, J., et al 2 0 0 6]  
Gal o n J, C ostes A, Sa nc hez-Ca b o F, 
0 0 V M P S
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Kiril o vs k y  A, Mlec ni k B, La g orce-Pa gès 
C, et al. T ype, de nsit y , a n d l ocati o n of 
i m m u ne cells wit hi n h u ma n c ol orectal 
t u m ors pre dict cli nical o utc o me. Scie nce 
2 0 0 6; 3 1 3( 5 7 9 5): 1 9 6 0 -4.
[ Gals k y, M. D., et al 2 0 1 1]
Gals k y  M D, Ha h n N M, R ose n ber g J, 
S o n pa v de G, H uts o n T, O h W K, et al. A 
c o nse ns us defi niti o n of patie nts wit h 
metastatic ur ot helial carci n o ma w h o are 
u nfit f or cis plati n -base d c he m ot hera p y. 
La ncet O nc ol. 2 0 1 1 Mar; 1 2( 3): 2 1 1- 4.
0 4 C R R Y
[ Gals k y, M. D., et al 2 0 1 1]
Gals k y  M D, Ha h n N M, R ose n ber g J, 
S o n pa v de G, H uts o n T, O h W K, et al. 
Treat me nt of patie nts wit h metastatic 
ur ot helial ca ncer " u nfit" f or cis plati n- base d 
c he m ot hera p y. J Cli n O nc ol 
2 0 1 1; 2 9( 1 7): 2 4 3 2 - 8.
0 3 Y 8 8 2
[ Gals k y, M. D., et al 2 0 1 2]
Gals k y  M D, C he n GJ, O h W K, Bell m u nt 
J, R ot h BJ, Petri oli R, et al. C o m parati ve 
effecti ve ness of ci s plati n-base d a n d 
car b o plati n - base d c he m ot hera py f or 
treat me nt of a d va nce d ur ot helial 
carci n o ma. A n n O nc ol 2 0 1 2; 2 3( 2): 4 0 6- 1 0.
0 3 Y 8 B 4
[ Ga n ga d har, T. C., et al 2 0 1 5]
Ga n ga d har T C, Ha mi d O, S mit h D C, 
Ba uer T M, Wasser J S, L u ke JJ, et al. 
Preli mi nar y  res ults fr o m a p hase 1/ 2 st u d y 
of e paca d ostat (I N C B 0 2 4 3 6 0) i n 
c o m bi nati o n wit h pe m br oliz u ma b i n 
patie nts wit h selecte d a d va nce d ca ncers. 
P oster sessi o n prese nte d at: 3 0t h A n n ual 
Meeti n g of t he S ociet y f or I m m u n ot hera p y  
of Ca ncer; 2 0 1 5 N o v 4 -8; Nati o nal Har b or, 
M D.
0 4 9 K Y R
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 3
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Ga n ga d har, T. C., et al 2 0 1 7]
Ga n ga d har T C, Sc h nei der BJ, Ba uer T M, 
Wasser J S, S pira AI , Patel S P, et al. 
Efficac y  a n d safety of e paca d ostat pl us 
pe m br oliz u ma b treat me nt of N S C L C: 
preli mi nar y  p hase 1/ 2 res ults of E C H O-
2 0 2/ K E Y N O T E -0 3 7. P oster sessi o n 
prese nte d at: 5 3r d A n n ual Meeti n g of t he 
A merica n S ociet y of Cli nical O nc ol o g y  
( A S C O), 2 0 1 7 J u ne 2-6; C hica g o, I L.
0 4 P V G H
[ G o di n-Et hier, J., et al 2 0 1 1]
G o di n- Et hier J, Ha nafi L A, Piccirill o C A, 
La p oi nte R. I n d olea mi ne 2, 3 -di o x y ge nase 
e x pressi o n i n h u m a n ca ncers: cli nical a n d 
i m m u n ol o gic pers pecti ves. Cli n Ca ncer 
Res. 2 0 1 1 N o v 1 5; 1 7( 2 2): 6 9 8 5 - 9 1.
0 4 9 P S S
[ Ha mi d, O., et al 2 0 1 3]
Ha mi d O, R o bert C, Da u d A, H o di F S, 
H w u WJ, Keff or d R, et al. Safet y  a n d 
t u m or res p o nses wit h la m br oliz u ma b (a nti-
P D -1) i n mela n o ma. N E n gl J Me d. 2 0 1 3 
J ul 1 1; 3 6 9( 2): 1 3 4- 4 4.
0 4J Q G 5
[ Ha mi d, O., et al 2 0 1 7]
Ha mi d O, Ba uer T M, S pira AI, S mit h D C, 
Olsza ns ki AJ, Tar hi ni A A, et al. Safet y of 
E paca d ostat 1 0 0 m g BI D Pl us 
Pe m br oliz u ma b 2 0 0 m g Q 3 W i n a d va nce d 
s oli d t u m ors: P hase 2 data fr o m E C H O-
2 0 2/ K E Y N O T E -0 3 7 [a bstract]. A bstracts 
of t he 2 0 1 7 A S C O A n n ual Meeti n g; 2 0 1 7 
J u n 2 - 6; C hica g o, I L : A S C O; 2 0 1 7. P. 2.
0 4 Q 3 K 9
[ Ha mi d, O., et al 2 0 1 7]
Ha mi d O, Ba uer T M, S pira AI, S mit h D C, 
Olsza ns ki AJ, Tar hi ni A A, et al. Safet y of 
E paca d ostat 1 0 0 m g BI D Pl us 
Pe m br oliz u ma b 2 0 0 m g Q 3 W i n a d va nce d 
s oli d t u m ors: P hase 2 data fr o m E C H O-
2 0 2/ K E Y N O T E -0 3 7. P oster sessi o n 
prese nte d at: 5 3r d A n n ual Meeti n g of t he 
A merica n S ociet y of Cli nical O nc ol o g y ; 
2 0 1 7 J u ne 2 – 6; C hica g o, I L.
0 4 P Q B R
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 4
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Hille n, F., et al 2 0 0 8]
Hille n F, Baete n CI M, va n de Wi n kel A, 
Cre y te ns D, va n der Sc haft D WJ, 
Wi n ne pe n ni nc k x V, et al. L e u k oc yte 
i nfiltrati o n a n d t u m or cell plasticit y are 
para meters of a g gressi ve ness i n pri mar y  
c uta ne o us mela n o ma. Ca ncer I m m u n ol 
I m m u n ot her 2 0 0 8; 5 7( 1): 9 7-1 0 6.
0 0 V M P 5
[ H o di, F. S. a n d Dra n off, G. 
2 0 1 0]
H o di F S, Dra n off G. T he bi ol o gic 
i m p orta nce of t u m or-i nfiltrati n g 
l ym p h oc y tes. J C uta n Pat h ol 
2 0 1 0; 3 7( S u p pl 1): 4 8 - 5 3.
0 0 V M P W
[ H o di, F. S., et al 2 0 1 4]
H o di F S, Ri bas A, Da u d A, Ha mi d O, 
R o bert C, keff or d R, et al. E val uati o n of 
i m m u ne-relate d res p o nse criteria (ir R C) i n 
patie nts ( pts) wit h a d va nce d mela n o ma 
( M E L) treate d wit h t he a nti-P D - 1 
m o n ocl o nal a nti b o d y  M K-3 4 7 5 [a bstract]. 
A bstracts of t he 2 0 1 4 A S C O A n n ual 
Meeti n g; 2 0 1 4 Ma y  2 9 - J u n 2; C hica g o, 
I L: A S C O; 2 0 1 4. p. 2.
0 4 6 5 P H
[ H ol m gaar d, R. B., et al 2 0 1 3]
H ol m gaar d R B, Za mari n D, M u n n D H, 
W olc h o k J D, Allis o n J P. I n d olea mi ne 2, 3 -
di o x y ge nase is a critical resista nce 
mec ha nis m i n a ntit u m or T cell 
i m m u n ot hera p y tar geti n g C T LA- 4. J E x p 
Me d. 2 0 1 3 J ul 1; 2 1 0( 7): 1 3 8 9- 4 0 2.
0 4 9 NJ 4
[ H ua n g, L., et al 2 0 1 0]
H ua n g L, Ba ba n B, J o h ns o n B A 3r d, 
Mell or A L. De n dritic cells, i n d olea mi ne 
2, 3 di o x y ge nase a n d ac q uire d i m m u ne 
pri vile ge. I nt Re v I m m u n ol. 2 0 1 0 
A pr; 2 9( 2): 1 3 3 -5 5.
0 4 B 5 F M
[IB E diti o n 1 0, 2 0 1 7 ]
E P A C A D O S T A T (I N C B 0 2 4 3 6 0 ) –
I n vesti gat ors Br oc h ure v 1 0, 1 1-Dec - 2 0 1 7.
0 4 T 9 P C
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[IB E diti o n 1 5 2 0 1 7]  
K E Y T R U D A ( pe m br oliz u ma b) 
I n vesti gat or’s Br oc h ure, E diti o n N u m ber 
1 5, 1 8- Se p- 2 0 1 7.
0 4 R 9 W 6
[In o, K., et al 2 0 0 6]
I n o K, Y os hi da N, Kaji ya ma H, S hi bata K, 
Ya ma m ot o E, Ki d o k or o K, et al. 
I n d olea mi ne 2, 3-di o x y ge nase is a n o vel 
pr o g n ostic i n dicat or f or e n d o metrial 
ca ncer. Br J Ca ncer. 2 0 0 6 Dec 
4; 9 5( 1 1): 1 5 5 5 -6 1.
0 4 9 NJ 5
[Je mal A, Bra y F, Ce nter M M, 
Ferla y  J, War d E, F or ma n D 
2 0 1 1]
Je mal A, Bra y F, Ce nter M M, Ferla y J, 
War d E, F or ma n D.  G l o bal Ca ncer 
Statistics. C A Ca ncer J Cli n 
2 0 1 1; 6 1( 2): 6 9 - 9 0.
0 3 S T K B
[ Li otta, F., et al 2 0 1 1]
Li otta F, Gacci M, Fr osali F, Q uerci V, 
Vitt ori G, La pi ni A, et al. Fre q ue nc y  of 
re g ulat or y T cells i n peri p heral bl o o d a n d 
i n t u m o ur-i nfiltrati n g l y m p h oc ytes 
c orrelates wit h p o or pr o g n osis i n re nal cell 
carci n o ma. BJ U I nt 2 0 1 1; 1 0 7( 9): 1 5 0 0 - 6.
0 0 V M Q M
[ Loe hrer, P. J. Sr., et al 1 9 9 2]
L oe hrer PJ Sr, Ei n h or n L H, Els o n PJ, 
Cra wf or d E D, K ue bler P, Ta n n oc k I, et al. 
A ra n d o mize d c o m paris o n of cis plati n 
al o ne or i n c o m bi nati o n wit h met h otre xate, 
vi n blasti ne, a n d d o x or u bici n i n patie nts 
wit h metastatic ur ot helial carci n o ma: a 
c o o perati ve gr o u p st u d y. J Cli n O nc ol. 
1 9 9 2 J ul; 1 0( 7): 1 0 6 6 -7 3. Errat u m i n: J Cli n 
O nc ol 1 9 9 3 Fe b; 1 1( 2): 3 8 4.
0 4 C V G 6
[ Lo g ot hetis, C. J., et al 1 9 9 0]
L o g ot hetis CJ, De xe us F H, Fi n n L, Sella 
A, A mat o RJ, A y ala A G, et al. A 
pr os pecti ve ra n d o mize d trial c o m pari n g 
M V A C a n d CI S C A c he m ot hera p y  f or 
patie nts wit h metastatic ur ot helial t u m ors. 
J Cli n O nc ol. 1 9 9 0 J u n; 8( 6): 1 0 5 0- 5.
0 4 C R R T
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 6
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Mell or, A. L. 2 0 0 4]
Mell or A L, M u n n D H. I D O e x pressi o n b y  
de n dritic cells: t olera nce a n d tr y pt o p ha n 
cata b olis m. Nat Re v I m m u n ol. 2 0 0 4 
Oct; 4( 1 0): 7 6 2 -7 4.
0 4 9 NJ 7
[ Mell or, A. L., et al 2 0 0 3]
Mell or A L, Ba ba n B, C ha n dler P, Mars hall 
B, J ha ver K, Ha nse n A, et al. C utti n g e d ge: 
i n d uce d i nd olea mi ne 2, 3 di o x y ge nase 
e x pressi o n i n de n dritic cell s u bsets 
s u p presses T cell cl o nal e x pa nsi o n. J 
I m m u n ol. 2 0 0 3 A u g 1 5; 1 7 1( 4): 1 6 5 2- 5.
0 4 9 NJ B
[ M uller, A. J., et al 2 0 0 5]
M uller AJ, D u Ha da wa y  J B, D o n o ver P S, 
S uta nt o -War d E, Pre n der gast G C. 
I n hi biti o n of i n d olea mi ne 2, 3-di o x y ge nase, 
a n i m m u n ore g ulat or y tar get of t he ca ncer 
s u p pressi o n ge ne Bi n 1, p ote ntiates ca ncer 
c he m ot hera p y. Nat Me d. 2 0 0 5 
Mar; 1 1( 3): 3 1 2 - 9.
0 4 9 P W 6
[ M u n n, D. H. 2 0 0 7]
M u n n D H, Mell or A L. I n d olea mi ne 2, 3 -
di o x y ge nase a n d t u m or -i n d uce d t olerance. 
J Cli n In vest. 2 0 0 7 Ma y ; 1 1 7( 5): 1 1 4 7- 5 4.
0 4 9 P W D
[ M u n n, D. H., et al 1 9 9 8]
M u n n D H, Z h o u M, Att w o o d J T, 
B o n dare v I, C o n wa y SJ, Mars hall B, et al. 
Pre ve nti o n of all o ge neic fetal rejecti o n b y  
tr ypt o p ha n cata b olis m. Scie nce. 1 9 9 8 A u g 
2 1; 2 8 1( 5 3 8 0): 1 1 9 1 - 3.
0 4 9 P W F
[ Na ka m ura, T., et al 2 0 0 7]
Na ka m ura T, S hi ma T, Sae ki A, Hi da ka T, 
Na kas hi ma A, Ta ki ka wa O, et al. 
E x pressi o n of i n d olea mi ne 2, 3-
di o x y ge nase a n d t he recr uit me nt of F o x p 3 -
e x pressi n g re g ulat or y T cells i n t he 
de vel o p me nt a n d pr o gressi o n of uteri ne 
cer vical ca ncer. Ca ncer Sci. 2 0 0 7 
J u n; 9 8( 6): 8 7 4- 8 1.
0 4 9 P W N
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 7
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ N o bili, C., et al 2 0 0 8]
N o bili C, De grate L, Ca pr otti R, Fra nci osi 
C, L e o ne B E, Trezzi R, et al. Pr ol o n ge d 
s ur vi val of a patie nt affecte d b y pa ncreatic 
a de n ocarci n o ma wit h massi ve l y m p h oc y te 
a n d de n dritic cell i nfiltrati o n after 
i nterle u ki n-2 i m m u n ot hera p y. Re p ort of a 
case. T u m ori 2 0 0 8; 9 4( 3): 4 2 6- 3 0.
0 0 V M P 9
[ O' D o n nell, P. H., et al 2 0 1 7]
O' D o n nell P H, Gri vas P, Balar A V, 
Bell m u nt J, V u k y  J, P o wles T, et al. 
Bi o mar ker fi n di n gs a n d mat ure cli nical 
res ults fr o m K E Y N O T E-0 5 2: First -li ne 
pe m br oliz u ma b ( pe m br o) i n cis plati n -
i neli gi ble a d va nce d ur ot helial ca ncer ( U C). 
P oster sessi o n prese nte d at: A merica n 
S ociet y  of Cli nical O nc ol o g y ( A S C O), 
2 0 1 7 J u ne 2 -6; C hica g o, I L.
0 4 Q 3 N D
[ O ka m ot o, A., et al 2 0 0 5]
O k a m ot o A, Ni kai d o T, Oc hiai K, 
Ta ka k ura S, Sait o M, A o ki Y, et al. 
I n d olea mi ne 2, 3-di o x y ge nase ser ves as a 
mar ker of p o or pr o g n osis i n ge ne 
e x pressi o n pr ofiles of ser o us o varia n 
ca ncer cells. Cli n Ca ncer Res. 2 0 0 5 A u g 
1 5; 1 1( 1 6): 6 0 3 0 - 9.
0 4 9 P T K
[ O kaza ki, T., et al 2 0 0 1]
O kaza ki T, Mae da A, Nis hi m ura H, 
K ur osa ki T, H o nj o T. P D - 1 
i m m u n orece pt or i n hi bits B cell rece pt or-
me diate d si g nali n g b y recr uiti n g src 
h o m ol o g y  2-d o mai n -c o ntai ni n g t yr osi ne 
p h os p hatase 2 t o p h os p h ot y r osi ne. Pr oc 
Natl Aca d Sci U S A 2 0 0 1; 9 8( 2 4 ): 1 3 8 6 6-
7 1.
0 0 V M Q 6
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 8
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Parr y, R. V., et al 2 0 0 5]
Parr y  R V, C he m nitz J M, Fra u wirt h K A, 
La nfra nc o A R, Bra u nstei n I , K o ba yas hi 
S V, et al. C T L A- 4 a n d P D -1 rece pt ors 
i n hi bit T-cell acti vati o n b y disti nct 
mec ha nis ms. M ol Cell Bi ol 
2 0 0 5; 2 5( 2 1): 9 5 4 3 -5 3.
0 0 V M Q 7
[ Pic kar d, A. S., et al 2 0 0 7]
Pic kar d A S, Wil ke C T, Li n H -W, L l o yd A. 
Healt h utilities usi n g t he E Q -5 D i n st u dies 
of ca ncer. P har mac oec o n o mics 
2 0 0 7; 2 5( 5): 3 6 5 - 8 4.
0 3 R L H G
[ P ost o w, M. A., et al 2 0 1 5]
P ost o w M A, C hes ne y  J, Pa vlic k A C, 
R o bert C, Gr oss ma n n K, Mc Der m ott D, et 
al. Ni v ol u ma b a n d i pili m u ma b vers us 
i pili m u ma b i n u ntreate d mela n o ma. N 
E n gl J Me d. 2 0 1 5 Ma y  2 1; 3 7 2( 2 1): 2 0 0 6-
1 7.
0 4 9 P T M
[ P o wles, T., et al 2 0 1 4]
P o wles T, V o gelza n g NJ, Fi ne G D, E der 
J P, Braite h F S, Lori ot Y, et al. I n hi biti o n 
of P D -L 1 b y M P D L 3 2 8 0 A a n d cli nical 
acti vit y i n pts wit h metastatic Ur ot helial 
Bla d der Ca ncer ( U B C) [a bstract]. 
A bstracts of t he 2 0 1 4 A S C O A n n ual 
Meeti n g; 2 0 1 4 Ma y  2 9 - J u n 2; C hica g o, 
I L: A S C O; 2 0 1 4. p. 2.
0 4 C 7 2 K
[ Q ueza da, S. A. 2 0 1 3]
Q ueza da S A, Pe g gs K S. E x pl oiti n g C T L A-
4, P D - 1 a n d P D-L 1 t o reacti vate t he h ost 
i m m u ne res p o nse a gai nst ca ncer. Br J 
Ca ncer. 2 0 1 3 A pr 3 0; 1 0 8( 8): 1 5 6 0- 5.
0 4 9 P T R
[ Ra bi n, R. 2 0 0 1]
Ra bi n R, de C harr o F. E Q -5 D: a meas ure 
of healt h stat us fr o m t he E ur o Q ol Gr o u p. 
A n n Me d 2 0 0 1; 3 3: 3 3 7- 4 3.
0 3 X L S 2
[Rile y , J. L. 2 0 0 9]
Rile y  JL.  P D-1 si g nali n g i n pri mar y  T 
cells. Im m u n ol Re v 2 0 0 9; 2 2 9: 1 1 4 - 2 5.
0 0 V M Q 9
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 9
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ R o bert, C., et al 2 0 1 1]
R o bert C, T h o mas L , B o n dare n k o I, O' Da y 
S, We ber J, Gar be C, et al. I pili m u ma b 
pl us dacar bazi ne f or pre vi o usl y  u ntreate d 
metastati c mela n o ma. N E n gl J Me d 
2 0 1 1; 3 6 4( 2 6): 2 5 1 7 - 2 6.
0 0 V M Q B
[ Sa x ma n, S. B., et al 1 9 9 7]
Sa x ma n S B, Pr o pert KJ, Ei n h or n L H, 
Cra wf or d E D, Ta n n oc k I, Ra g ha va n D, et 
al. Lo n g -ter m f oll o w-u p of a p hase III 
i nter gr o u p st u d y of cis plati n al o ne or i n 
c o m bi nati o n wit h m et h otre xate, 
vi n blasti ne, a n d d o x or u bici n i n patie nts 
wit h metastatic ur ot helial carci n o ma: a 
c o o perati ve gr o u p st u d y. J Cli n O nc ol. 
1 9 9 7 J ul; 1 5( 7): 2 5 6 4 - 9.
0 4 C R R W
[ Sel b y, M, et al 2 0 1 3]
Sel b y  M, E n gel har dt J, L u LS, Q ui gle y  M, 
Wa n g C, C he n B, et al. A ntit u m or acti vit y  
of c o nc urre nt bl oc ka de of i m m u ne 
c hec k p oi nt m olec ules C T L A - 4 a n d P D- 1 
i n precli nical m o dels. [ A bstract 3 0 6 1]. 
2 0 1 3 A S C O A n n ual Meeti n g, Ge neral 
P oster Sessi o n, De vel o p me ntal 
T hera p utics - I mm u n ot hera p y ; 2 0 1 3 Ma y 
3 1 - J u n 3. C hica g o, I L, 2 0 1 3.
0 3 T 0J P
[ Se ym o ur, L., et al 2 0 1 7]
Se y m o ur L, B o gaerts J, Perr o ne A, F or d R, 
Sc h wartz L H, Ma n dre kar S, et al. 
i R E CIS T: g ui deli nes f or res p o nse criteria 
f or use i n trials testi n g 
i m m u n ot hera pe utics. La ncet O nc ol. 2 0 1 7 
Mar; 1 8( 3):e 1 4 3 -e 1 5 2.
0 4 P 9 R V
[ S he ppar d, K -A, et al 2 0 0 4]
S he p par d K -A, Fitz L J, Lee J M, Be na n der 
C, Ge or ge J A, W o oters J, et al. P D- 1 
i n hi bits T-cell rece pt or i n d uce d 
p h os p h or 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: 3 7 -4 1.
0 0 V M Q C
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[S pra n ger, S., et al 2 0 1 3]
S pra n ger S, S paa pe n R M, Z ha Y, Willia ms 
J, Me n g Y, Ha T T, et al. U p-re g ulati o n of 
P D -L 1 , ID O, a n d T(re gs) i n t he mela n o ma 
t u m or micr oe n vir o n me nt is dri ve n b y 
C D 8( +) T cells. Sci Tra nsl Me d. 2 0 1 3 A u g 
2 8; 5( 2 0 0): 2 0 0ra 1 1 6.
0 4 9 P T Z
[ Ster n ber g, C. N., et al 2 0 0 6]
Ster n ber g C N, de M ul der P, Sc h or na gel 
J H, T he o d ore C, F ossa S D, va n O oster o m 
A T, et al. Se ve n ye ar u p date of a n E O R T C 
p hase III trial of hi g h -d ose i nte nsit y  M-
V A C c he m ot hera p y a n d G -C S F vers us 
classic M -V A C i n a d va nce d ur ot helia l 
tract t u m o urs. E ur J Ca ncer 2 0 0 6; 4 2: 5 0- 4.
0 3 Y K 9 S
[ Tal ma d ge, J. E., et al 2 0 0 7]
Tal ma d ge J E, D o n k or M, Sc h olar E. 
I nfla m mat or y cell i nfiltrati o n of t u m ors: 
Je k yll or H yde. Ca ncer Metastasis Re v 
2 0 0 7; 2 6( 3 -4): 3 7 3 - 4 0 0.
0 0 V M P H
[ T o palia n, S. L., et al 2 0 1 2]
T o palia n S L , H o di F S, Bra h mer J R, 
Getti n ger S N, S mit h D C, Mc Der m ott D F, 
et al. Safet y, acti vit y , a n d i m m u ne 
c orrelates of a nti -P D -1 a nti b o d y  i n ca ncer. 
N E n gl J Me d. 2 0 1 2 J u n 2 8; 3 6 6( 2 6): 2 4 4 3 -
5 4.
0 4 C 0 L K
[ U. S. Prescri bi n g I nf or mati o n 
2 0 1 7]
U. S. Prescri bi n g I nf or mati o n: 
K E Y T R U D A - pe m br oliz u ma b f or 
i njecti o n, f or i ntra ve n o us use: 
K E Y T R U D A pe m br oliz u ma b i njecti o n, 
2 0 1 7.
0 4 R F X M
[ Us u b üt ü n, A., et al 1 9 9 8]
Us u b üt ü n A, A y ha n A, U y g ur M C, Öze n 
H, T o kl u C, R uaca n S. Pr o g n ostic fact ors 
i n re nal cell carci n o ma. J E x p Cli n Ca ncer 
Res 1 9 9 8; 1 7( 1): 7 7 - 8 1.
0 0 V M PJ
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ U ytte n h o ve, C., et al 2 0 0 3]
U y tte n h o ve C, Pil otte L, T heate I, 
Str o o ba nt V, C ola u D, Par me ntier N, et al. 
E vi de nce f or a t u m oral i m m u ne resista nce 
mec ha nis m base d o n tr y pt o p ha n 
de gra dati o n b y i n d olea mi ne 2, 3 -
di o x y ge nase. Nat Me d. 2 0 0 3 
Oct; 9( 1 0): 1 2 6 9 -7 4.
0 4 9 P V 2
[ v o n der Maase, H., et al 
2 0 0 0]
v o n der Maase H, Ha nse n S W, R o berts J T, 
D o gli otti L , Oli ver T, M o ore MJ, et al. 
Ge mcita bi ne a n d cis plati n vers us 
met h otre xate, vi n blasti ne, d o x or u bici n, 
a n d cis plati n i n a d va nce d or metastatic 
bla d der ca ncer: res ults of a lar ge, 
ra n d o mize d, m ulti nati o nal, m ultice nter, 
p hase III st u d y . J Cli n O nc ol. 2 0 0 0 
Se p; 1 8( 1 7): 3 0 6 8 - 7 7.
0 4 C R R X
[ v o n der Maase, H., et al 
2 0 0 5]
v o n der Maase H, Se n gel o v L , R o berts J T, 
Ricci S, D o gli otti L , Oli ver T, et al. L o n g-
ter m s ur vi val res ults of a ra n d o mize d trial 
c o m pari n g ge mcita bi ne pl us cis plati n, wit h 
met h otre xate, vi n blasti ne, d o x or u bici n, 
pl us cis plati n i n patie nts wit h bla d der 
ca ncer. J Cli n O nc ol. 2 0 0 5 J ul 
2 0; 2 3( 2 1): 4 6 0 2 - 8.
0 4 C T 2 2
[ Wei nlich, G., et al 2 0 0 7]  
Wei nlic h G, M urr C, Ric har dse n L, 
Wi n kler C, F uc hs D. Decrease d ser u m 
tr ypt o p ha n c o nce ntrati o n pre dicts p o or 
pr o g n osis i n mali g na nt mela n o ma patie nts. 
Der mat ol o g y . 2 0 0 7; 2 1 4( 1): 8- 1 4.
0 4 9 P V 3
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
[ Wit kie wicz, A., et al 2 0 0 8]
Wit kie wicz A, Will ia ms T K, C ozzit ort o J, 
D ur ka n B, S h o walter S L, Ye o CJ, et al. 
E x pressi o n of i n d olea mi ne 2, 3-
di o x y ge nase i n metastatic pa ncreatic 
d uctal a de n ocarci n o ma recr uits re g ulat or y  
T cells t o a v oi d i m m u ne detecti o n. J A m 
C oll S ur g. 2 0 0 8 Ma y ; 2 0 6( 5): 8 4 9-5 4; 
disc ussi o n 8 5 4- 6.
0 4 9 P V 5
[ W olc h o k, J. D., et al 2 0 0 9]
W olc h o k J D, H o os A, O' Da y  S, We ber J S, 
Ha mi d O, Le b bé C, et al. G ui deli nes f or t he 
e val uati o n of i m m u ne t hera p y acti vit y  i n 
s oli d t u m ors: i m m u ne-relate d res p o nse 
criteria. Cli n Ca ncer Res 
2 0 0 9; 1 5( 2 3): 7 4 1 2 -2 0.
0 0 V M N Z
[ W olc h o k, J. D., et al 2 0 1 0]
W olc h o k J D, Ne y ns B, Li nette G, Ne grier 
S, L utz k y  J, T h o mas L, et al. Ipili m u ma b 
m o n ot hera p y i n patie nts wit h pretreate d 
a d va nce d mela n o ma: a ra n d o mise d, 
d o u ble -bli n d, m ultice ntre, p hase 2, d ose -
ra n gi n g st u dy. La ncet O n c ol 2 0 1 0; 1 1: 1 5 5 -
6 4.
0 3 Y K 4 R
[ Z ha n g, X., et al 2 0 0 4]
Z ha n g X, Sc h wartz J -C D, G u o X, B hatia 
S, Ca o E, C he n L , et al. Str uct ural a n d 
f u ncti o nal a nalys is of t he c osti m ulat or y 
rece pt or pr o gra m me d deat h-1. I m m u nit y  
2 0 0 4; 2 0: 3 3 7 - 4 7.
0 0 V M QJ
[ Z o u, W. 2 0 0 6]
Z o u W. Re g ulat or y  T cells, t u m o ur 
i m m u nit y a n d i m m u n ot hera p y. Nat Re v 
I m m u n ol. 2 0 0 6 A pr; 6( 4): 2 9 5- 3 0 7.
0 4 9 P V 7
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 3
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
1 2. A p pe n dices
A p pe n di x 1: A b bre vi ati o ns a n d Tr a de m ar ks
1 2. 1
A b bre vi ati o n/ Ter m
Defi niti o n
1 L
first-li ne (t hera py)
5 -F U
fl u or o uracil
A E
ad verse eve nt
A L T
ala ni ne ami n otra nsferase
A Pa T
A ll Partici pa nts as treate d
a P T T
acti vate d p artial thr o m b o plasti n ti me
A S C O
T he A merica n S ociet y of Cli nical O nc ol o g y
A S T
as partate ami n otra nsferase
B C G
Bacill us Cal mette -G u éri n (tu berc ul osis vacci ne)
BI C R
b li n de d i n de pe n de nt ce ntral i ma gi n g re vie w(er)
C 1 D 1
C y cle 1 Da y 1
C 2 D 1
C y cle 2 Da y 1
C D 3 ζ
C D 3 zeta
CI
co nfi de nce inter val
c L D A
co nstrai ne d lo n git u di nal d ata anal ys is
C N S
ce ntral n er v o us sys te m
C P S
C o m bi ne d 
P ositi ve 
Sc ore 
f or P D -L 1 
p ositi vit y  (c o m bi ne d 
e x pressi o n of t u m or cells a n d i nfla m mat or y mar kers)
C R
co m plete res p o nse
Cr Cl
creati ni ne cleara nce
C R F
case re p ort for m
C S R
Cli nical St u d y  Re p ort
C T
co m p ute d to m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C T L A- 4
c yt ot o xic T -ly m p h oc y t e- ass ociate d a nti ge n - 4
D C R
d isease co ntr ol rate  ( C R, P R, a n d S D)
D M C
Data M o nit ori n g C o m mittee
D N A
d e o x yri b o n ucleic aci d
D O R
d urati o n of res p o nse
E CI
eve nts of cli nical interest
E C G
electr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
e C R F
electr o nic case re p ort f or m
E D C
electr o nic d ata c a pt ure
E M A
E ur o pea n Me dici nes A ge nc y
E O C
E xec uti ve O versi g ht C o m mittee
E 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 O R T C Q L Q- C 3 0
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire
e P R O
electr o nic patie nt -re p orte d o utc o mes
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 4
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
E Q - 5 D
E ur o Q ol -5 Di me nsi o ns , 5-le vel Q uesti o n naire
e P R O
electr o nic p atie nt-re p orte d o utc o me
E R C
Et hics Re vie w C o m mittee
E ur o Q ol
E ur o pea n Q ualit y  of Li fe
F A S
F ull A nal ys is Set
F D A
U. S. 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 F P E
f or mali n-fi xe d p araffi n-em be d de d
G C P
G o o d Cli nical Practice
G E M
g e mcita bi ne
H 1
H y p ot hesis 1
H 2
H y p ot hesis 2
H Bs A g
He patitis B s urface a nti ge n
H C V
He patitis C vir us
HI V
h u ma n im m u n o deficie nc y v ir us
H R Q o L
Healt h Relate d Q ualit y  of Life
I A
i nteri m a nal ysis
I B
I n vesti gat or’s Br oc h ure
I CF
inf 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 ni sati 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
i C P D
c o nfir me d ra di o gra p hic pr o gressi o n
I DO 1
in d olea mi ne 2, 3 -di o x y ge nase
I E C
I n de pe n de nt Et hics C o m mittee
I g G
i m m u n o gl o b uli n G
I g V
i m m u n o gl o b uli n varia ble
I H C
im m u n o hist oc he mistr y
I RB
I nstit uti o nal Re vie w B oar d
ir A E
i m m u ne-relate d a d verse e ve nts
iR E CI S T
im m u ne -base d t hera pe utics R E CI S T
I T T
I nte nti o n-t o-Treat 
I UD
intra uteri ne d e vice
I V
intra ve n o us
I V R S
interacti ve v oice res p o nse sys te m
I W R S
inte grate d w e b res p o nse sys te m
K P S
Kar n ofs k y perf or ma nce stat us
m A b
m o n ocl o nal anti b o d y
M A OI
M o n oa mi ne o xi dase i n hi bit or
M C A VI
M et h otre xate pl us car b o plati n pl us vi n blasti ne 
m g
m illi gra m
m g/ k g
m illi gra m per k il o gra m
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
M K - 3 4 7 5 (f or merly 
S C H 9 0 0 4 5)
Merc k desi g nati o n f or pe m br oliz u ma b
m L
milliliter
M RI
m a g netic res o na nce ima gi n g
m R N A
messe n ger ri b o n ucleic aci d
M SI
m icr osatellite i nsta bilit y
M S D
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.
N A or N/ A
n ot ap plica ble
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
( U S) Nati o nal Ca ncer I nstit ute
N S C L C
n o n- s mall cell l u n g ca ncer
N Y H A
Ne w Y or k Heart Ass ociati o n
O R R
o bjecti ve res p o nse rate 
O S
o verall sur vi val
O T C
o ver -t he-co u nter ( n o n -prescri pti o n)
P D
p r o gressi ve d isease
P D - 1
p r o gra m me d cell d eat h 1
P D -L 1
p r o gra m me d cell d eat h-li ga n d 1
Pe m br o
Pe m br oliz u ma b
P F S
p r o gressi o n-free sur vi val
P H
p r o p orti o nal h azar d
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
P K C θ
pr otei n ki nase C -t heta
P R
p artial res p o nse
P R O
p atie nt-re p orte d o utc o me 
P S
p erf or ma nce stat us
P T
p r ot hr o m bi n ti me
P T T
p artial thr o m b o plasti n ti me
P S A
p r ostatic-s pecific anti ge n
Q 2 W
e ver y 2 wee ks
Q 3 W
ever y  3 w ee ks
Q L Q
Q ualit y  of Life Q uesti o n naire
Q o L
Q ualit y  of Life
Q Tc
c orrecte d Q T i nter val
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R N A
ri b o n ucleic aci d
R R
res p o nse rate
S A E
seri o us a d verse eve nt(s)
S A P
Statistical A nal y sis Pla n
S C C H N
s q ua m o us cell carci n o ma of t he hea d a n d nec k
S D
sta ble d isease
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 6
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
S G O T
Ser u m Gl uta mic O xal oacetic Tra nsa mi nase
S G P T
Ser u m Gl uta mic -P y r u vic Tra nsami nase
S o A
Sc he d ule of Acti vities
S O C
sta n dar d of care
S S
sero t o ni n s yn dr o me
s S A P
su p ple me ntal Statistical A nal y sis Pla n
S N RI
ser ot o ni n/ n ore pi ne p hri ne re u pta ke i n hi bit or
S S RI
Ser ot o ni n re u pta ke i n hi bit or
T 1 D M
T y pe 1 d ia betes m ellit us
T 1 D M
T y pe 1 d ia betes m ellit us
T B
t u berc ul osis
T- re gs
re g ulat or y T-cell
T R A E
treat me nt-relate d ad verse eve nt
T S H
th y r oi d-sti m ulati n g h or m o ne
T T D
ti me t o tr ue d eteri orati o n
U C
u r ot helial carci n o ma
U S
U nite d States
W O C B P
w o ma n of c hil d beari n g p ote ntial
Z A P 7 0
zeta-c hai n ass ociate d pr otei n ki nase
 
 
0 4 Y B Q D






Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 9
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 3: St u d y G o ver n a nce C o nsi der ati o ns
1 2. 3
Merc k C o de of C o n d uct f or Cli nic al Tri als
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 partici pa nt 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 ulati 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 t he 
part y ( parties) e m pl o ye d f or t heir e xec uti o n (e g, c o ntract researc h or ga nizati o ns, c olla b orati ve researc h eff orts). T his 
C o de is n ot i nte n de d t o a p pl y t o trials 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 
partici pa nt prefere nces, etc.  
T he desi g n (ie, partici pa nt p o p ulati o n, d urati o n, sta tistical 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 partici pa nts m ust meet pr ot oc ol e ntr y criteria t o be e nr olle d i n t he trial. 
2.
Site Selecti o n
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 partici pa nts, 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.  Pri or 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 t he 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 c o nsiste nc y. Data are verifie d v ers 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 pr 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.  S o 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 pli cit 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 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
III. P artici p a nt Pr otecti o n
A.
I R B/I E 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/I E 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/I E 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 partici pa nt 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/I E C 
a p pr o val. F or eac h site, t he I R B/I E C a n d Merc k will a p pr o ve t he partici pa nt 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 partici pa nt welfare is of pri mar y i m p orta nce.  
P ote ntial partici pa nts will be i nf or me d of t he ris ks a n d be nefits of, as well as alter nati ves t o, trial partici pati o n. At a 
mi ni m u m, trial de si g ns will ta ke i nt o acc o u nt t he l ocal sta n dar d of care.  Partici pa nts 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.  Partici pa nts 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.  Partici pa nts 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 partici pa nt c o nfi de ntialit y, t o t he greatest e xte nt p ossi ble.  U nless re q uire d b y 
la w, o nl y t he i n vesti gat or, s p o ns or ( or 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 partici pa nt 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 partici pa nts i n it s 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 partici pa nt referrals.  H o we 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 partici pa nts.
B.
Cli nic al Rese arc h F u n di n g 
I nf or me d c o nse nt f or ms will discl ose t hat t he trial is s p o ns ore d b y 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 ovi 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/I E 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 di cate 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 i n 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 meeti 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 ot oc ol, a n d i n si g ni n g 
t he pr ot oc ol, a gree t o s u p p ort t hese ethical 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 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Fi n a nci al Discl os ure
Fi na ncial Discl os ure re q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi na ncial Discl os ure b y Cli nical I n vesti gat ors ( 2 1 C F R Part 5 4).  I t is M S D’s
res p o nsi bilit y t o deter mi ne, base d o n t hese re g ulati o ns, w het her a re q uest f or 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 ny 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  M S D
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 or 
M S D 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  k n o w n as a fi na ncial discl os ure f or m, pr o vi de d b y 
M S D . T he i n vesti gat or/s u bi n vesti gat or(s) als o c o nse nt t o t he tra ns missi o n of t his i nf or mati o n 
t o t he S p o ns or a n d M S D i n t he U nite d States f or t hese p ur p oses.  T his ma y i n v ol ve t he 
tra ns missi o n of i nf or mati o n t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g pers o nal data.
D at a Pr otecti o n
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y  M S D . A ny partici pa nt rec or ds or datasets 
t hat are tra nsferre d t o M S D
will c o ntai n t he i de ntifier o nl y ; partici pa nt na mes or a n y 
i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d. 
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
S p o ns or a n d M S D i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust 
als o be e x plai ne d t o t he partici pa nt. 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y M S D , b y a p pr o priate 
I RB/I E C me m bers, a n d b y  i ns pect ors fr o m re g ulat or y a ut h orities.
C o nfi de nti alit y of D at a
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or affir ms t o M S D
t hat i nf or mati o n f ur nis he d t o t he 
i n vesti gat or by M S D
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 (IR B/I E C) or si milar or e x pert 
c o m mittee; affiliate d i nstit uti o n a n d e m pl o y ees, o nl y u n der a n a p pr o priate u n dersta n di n g of 
c o nfi de ntialit y wit h s uc h b oar d or c o m mittee, affiliate d i nstit uti o n a n d e m pl o yees.  Data 
ge nerate d b y t his trial wi ll be c o nsi dere d c o nfi de ntial b y t he i n vesti gat or, e xce pt t o t he e xte nt 
t hat it is i ncl u de d i n a p u blicati o n as pr o vi de d i n t he P u blicati o ns secti o n of t his pr ot oc ol.
C o nfi de nti alit y of P artici p a nt Rec or ds
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t hat t he S p o ns or, M S D ( or S p o ns or or M S D
re prese ntati ve), I R B/I E C, or re g ulat or y a ut h orit y re prese ntati ves ma y c o ns ult a n d/ or c o p y 
trial d oc u me nts i n or der t o verif y w or ks heet/case re p ort f or m data.  B y si g ni n g t he c o nse nt 
f or m, t he partici pa nt a grees t o this 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 partici pa nt will be i de ntifie d 
b y  u ni q ue c o de o nly;  f ull na mes/i nitials will be mas ke d pri or t o tra ns missi o n t o M S D .
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o treat all partici pa nt data use d a n d 
discl ose d i n c o n necti o n wit h t his 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 R B/I E C I nf or m ati o n
M S D will
rec or d t he na me a nd a d dress of eac h I R B/I E C t hat re vie ws a n d a p pr o ves t his trial.  
M S D will
d oc u me nt t hat eac h I R B/I E C meets re g ulat or y  a n d I C H G C P re q uire me nts b y 
re q uesti n g a n d mai ntai ni n g rec or ds of t he na mes a n d q ualificati o ns of t he I R B/I E C me m bers 
a n d t o ma ke t hese rec or ds a vaila ble f or re g ulat or y a ge nc y  re vie w u p o n re q uest b y t h ose 
a ge ncies.
C o m mittees Str uct ure
Tri al Steeri n g C o m mittee
T his trial will be c o n d ucte d i n c o ns ultati o n wit h a Trial Steeri n g C o m mittee.  T he Trial 
Steeri n g C o m mittee c o m prises:
•
S p o ns or a n d M S D pers o n nel 
•
I n vesti gat ors partici pati n g i n t he trial 
•
C o ns ulti n g t hera pe utic -area e x perts a n d cli nical trialists 
T he Trial Steeri n g C o m mittee will pr o vi de g ui da nce o n t he o perati o nal as pects of t he trial .
S pecific details re gar di n g res p o nsi bilities a n d g o ver na nce of t he Trial Steeri n g C o m mittee 
will be descri be d i n a se parate c harter.
J oi nt E xec uti ve O versi g ht C o m mittee
T he J oi nt E x ec 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 a n d M S D 
Se ni or Ma na ge me nt.  T he 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 
t he 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
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 safety data fr o m t his trial.  T he v oti n g 
me m bers of t he c o m mittee are e xter nal t o t he S p o ns or a n d M S D.  T he me m bers of t he D M C 
m ust n ot be i n v ol ve d wit h t he trial i n a n y  ot her wa y (e g, t he y ca n n ot be trial i n vestigat 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 partici pa nt 
safety a n d t he c o nti n ue d et hical i nte grit y of t he trial.
S pecific details re gar di n g c o m p ositi o n, res p o nsi bilities, a n d g o ver na nce, i ncl u di n g t he r oles 
a n d res p o nsi bilities of t he vari o us me m bers a n d t he S p o ns or a n d M S D pr o t 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 t he 
D M C c harter t hat is re vie we d a n d a p pr o ve d b y all t he D M C me m bers.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 3
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
A D M C rec o m me n dati o n will be c o m m u nicate d t o t he J oi nt E O C as a gree d t o i n t he D M C 
C harter
P u blic ati o n P oli c y
T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie ntific meeti n gs. T he S p o ns or 
a n d M S D will c o m pl y  wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. In acc or da nce 
wit h sta n dar d e dit orial a n d et hical practice, t he S p o ns or a n d M S D will ge nerall y s u p p ort 
p u blicati o n of m ultice nter st u dies o nl y  i n t heir e ntiret y a n d n ot as i n di vi d ual site data. I n t his 
case, a c o or di nati n g i n vesti gat or will be desi g nate d b y  m ut ual a gree me nt.
If p u blicati o n acti vit y is n ot directe d b y t he S p o ns or or M S D , t he i n vesti gat or a grees t o 
s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or a n d M S D bef ore s u b missi o n.  T his all o ws 
t he S p o ns or a n d M S D t o pr otect pr o prietar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
A ut h ors hi p will be deter mi ne d b y  m ut ual a gree me nt a n d i n li ne wit h Inter nati o nal C o m mittee 
of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
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
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 A me n d me nts Act ( F D A A A) of 2 0 0 7 
a n d t he E ur o pea n Me d ici nes A ge nc y ( E M A) cli nical trial Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or 
of t he 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 htt p:// w w w.cli nicaltrials. g o v, 
w w w.cli nicaltrialsre gister.e u or ot her l ocal re gistries.  T he S p o ns or 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  t o f ulfill t hese re q uire me nts. Entries are n ot li mite d t o 
F D A A A or t he E M A cli nical trial directi ve ma n date d trials.  I nf or mati o n p oste d will all o w 
partici pa nts t o i de ntif y  p ote ntiall y a p pr o priate 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 g ni n g t his pr ot oc ol, t he i n vesti gat or ac k n o wle d ges t hat t he stat ut or y o bli gati o ns u n der 
F D A A A, t he E M A cli nical trials directi ve or ot her l ocall y  ma n date d re gistries are t hat of t he 
S p o ns or a n d a grees n ot t o s u b mit a n y  i nf or mati o n a b o ut t his trial or its res ults t o t h ose 
re gistries.
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o c o n d uct t he 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 CH 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 or e xe c ute d b y  M S D , is pr o vi de d i n 
t his a p pe n di x u n der t he Merc k C o de of C o n d uct f or Cli nical Trials.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 4
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
T he i n vesti gat or a grees n ot t o see k rei m b urse me nt fr o m partici pa nts, t heir i ns ura nce 
pr o vi ders or fr o m g o ver n me nt pr o gra ms f or pr oce d ures i ncl u de d as part of t he trial 
rei m b urse d t o t he i n vesti gat or by M S D .
T he i n vesti gat or will pr o m ptl y  i nf or m M S D
of a n y  re g ulat or y a ut h ority i ns pecti o n c o n d ucte d 
f or t his trial.
T he I n vesti gat or a grees t o pr o vi de M S D
wit h rele va nt i nf or mati o n fr o m i ns pecti o n 
o bser vati o ns/fi n di n gs t o all o w M S D
t o assist i n res p o n di n g t o a ny citati o ns res ulti n g fr o m 
re g ulat or y a ut h ority i ns pe cti o n, a n d will pr o vi de M S D
wit h a c o p y  of t he pr o p ose d res p o nse 
f or c o ns ultati o n bef ore s u b missi o n t o t he re g ulat or y a ut h orit y. 
Pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical trials b y  a n y c o urt or re g ulat or y 
a ut h orit y will n ot be all o we d t o c o nd uct or w or k o n t his st u d y. T he i n vesti gat or will 
i m me diatel y discl ose i n writi n g t o M S D
if a ny 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 ny 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 hrea te ne d.
D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o M S D
or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or or 
q ualifie d desi g nee is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
p h y sically or electr o nicall y  si g ni n g t he C R F. 
Detaile d i nf or mati o n re gar di n g Data Ma na ge me nt pr oce d ures f or t his pr ot oc ol will be 
pr o vi de d se paratel y.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F. 
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
Trial d oc u me ntati o n wi ll be pr o m ptl y  an d f ully discl ose d t o M S D
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 M S D
or a n y  re g ulat or y a ut h orities.  
T he i n vesti gat or a grees t o pr o m ptl y  ta ke a n y reas o na ble ste ps t hat are re q ueste d b y  M S D
or 
a n y re g ulat or y a ut h orities as a res ult of a n a u dit or i ns pecti o n t o c ure deficie ncies i n t he trial 
d oc u me ntati o n a n d w or ks heets/case re p ort f or ms.
M S D
or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y 
c hec ki n g of t he data. 
St u d y  m o nit ors will perf or m o n g oi n g s o urce data re vie w a n d verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m 
s o urce d oc u me nts; t hat t he safety a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he 
st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntly a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts. 
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C F, pertai ni n g t o t he c o n d uct of t his st u d y  m ust 
be retai ne d b y t he i n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of M S D . N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o M S D . 
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
Data re p orte d o n t he C R F or e ntere d i n t he electr o nic case re p ort f or m (e C R F) t hat are 
tra nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he 
discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma y nee d t o re q uest pre vi o us me dical 
rec or ds or tra nsfer rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical rec or ds m ust be 
a vaila ble.
St u d y a n d Site Cl os ure
M S D, i n c olla b orati o n wit h t he S p o ns or , ma y  st o p t he st u d y or st u d y site partici pati o n i n t he 
st u d y f or me dical, safety,  re g ulat or y, a d mi nistrati ve, or ot her reas o ns c o nsiste nt wit h 
a p plica ble la ws, re g ulati o ns, a n d G C P. 
I n t he e ve nt M S D
pre mat urel y ter mi nates a partic ular trial site, M S D
will pr o m ptl y  notif y 
t hat trial site’s IR B/I E C.
 
 
0 4 Y B Q D










Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
me dici nal pr o d uct)?
●
Li kel y C a use:   Is t he A E n ot reas o na bly 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 diseas e, ot her dr u g(s)/ vacci ne(s), or ot her h ost or e n vir o n me ntal 
fact ors
●
Dec h alle n ge: Was t he st u d y treat me nt disc o nti n ue d or 
d ose/e x p os ure/fre q ue nc y re d uce d?
●
If yes, di d t he A E res ol ve or i m pr o ve?
●
If yes, t his is a p ositi ve dec halle n ge. 
●
If n o, t his is a ne gati ve dec halle n ge.
( N ote:  T his criteri o n is n ot a p plica ble if:  ( 1) t he A E res ulte d i n deat h or 
per ma ne nt disa bilit y ; ( 2) t he A E res ol ve d/i m pr o ve d des pite c o nti n uati o n of 
t he st u d y treat me nt; ( 3) t he trial is a si n gle-d ose dr u g trial); or ( 4) st u d y 
treat me nt(s) is/are o nly use d o ne ti me.)
●
Rec h alle n ge:   Was t he partici pa nt re -e x p ose d t o t he st u d y treat me nt i n t his 
trial?
●
If yes, di d t he A E rec ur or w orse n?
●
If yes, t his is a p ositi ve rec halle n ge. 
●
If n o, t his is a ne gati ve rec halle n ge.
( N ote:  T his criteri o n is n ot a p plica ble if:  ( 1) t he i nitial A E res ulte d i n deat h 
or per ma ne nt disa bilit y , or ( 2) t he trial is a si n gle-d ose dr u g trial); or ( 3) st u d y 
treat me nt(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 T U D Y 
T R E A T M E N T , O R I F R E-E X P O S U R E T O T H E S T U D Y T R E A T M E N 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 P A R TI CI P A N T T H E N 
T H E R E C H A L L E N G E M U S T B E A P P R O V E D I N A D V A N C E B Y T H E M S D
C L I NI CA 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 , A N D I F R E Q UI R E D, T H E I N S TI T U TI O N A L R E VI E W 
B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E.
●
C o nsiste nc y wit h St u d y tre at me nt Pr ofile: Is t he cli nical/ pat h ol o gical 
prese ntati o n of t he A E c o nsiste nt wit h pre vi o us k n o wle d ge re gar di n g t he 
st u d y treat me nt 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 hys icia 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.
●
Use t he f oll o wi n g scale of criteria as g ui da nce ( n ot all criteria m ust be prese nt t o be 
i n dicati ve of a st u d y treat me nt relati o ns hi p).
●
Yes, t here is a reas o na ble p ossi bilit y  of st u d y treat me nt relati o ns hi p:
T here is e vi de nce of e x p os ure t o t he st u d y treat me nt.  T he te m p oral se q ue nce of 
 
 
0 4 Y B Q D






Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 3
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 5: C o ntr ace pti ve G ui d a nce a n d Pre g n a nc y Testi n g
1 2. 5
W o ma n of C hil d beari n g P ote ntial ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal 
u nless per ma ne ntl y sterile (see bel o w) 
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
●
Pre me narc hal
●
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
○
D oc u me nte d h ys terect o m y
○
D oc u me nte d bilateral sal pi n gect o m y
○
D oc u me nte d bilateral o o p h orect o m y
N ote:  D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he partici pa nt’s 
me dical rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w.
●
P ost me n o pa usal fe male
○
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. 
▪
A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) le ve l i n t he p ost me n o pa usal ra n ge ma y 
be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o nal re place me nt t hera py ( H R T). H o we ver, i n t he a bse nce 
of 1 2 m o nt hs of a me n orr hea, c o nfir mati o n wit h t w o F S H meas ure me nts i n t he 
p ost me n o pa usal ra n ge is re q uire d . 
○
Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne 
of t he n o n -h or m o nal hi g hl y  effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue 
t heir H R T d uri n g t he st u d y. Ot her wise, t he y m ust disco nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 4
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
C o ntr ace pti o n Re q uire me nts
M ale P artici p a nts:
Male partici pa nts wit h fe male part ners of c hil d beari n g p ote ntial are eli gi ble t o partici pate if 
t he y a gree t o o ne of t he f oll owi n g d uri n g t he pr ot oc ol defi ne d ti me fra me i n secti o n 6. 1: 
●
Be a bsti ne nt fr o m pe nile -va gi nal i nterc o urse as t heir us ual a n d preferre d lifest y le 
(a bsti ne nt o n a l o n g ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt
●
Use a male c o n d o m pl us part ner use of a c o ntrace pti ve met h o d wit h a fail ure rate of < 1 % 
per year as descri be d i n Ta ble 1 4 w he n ha vi n g pe nile -va gi nal i nterc o urse wit h a w o ma n of 
c hil d beari n g p ote nt ial w h o is n ot c urre ntl y pre g na nt.
○
N ote: Me n wit h a pre g na nt or breastfee di n g part ner m ust a gree t o re mai n a bsti ne n t 
fr o m pe nile va gi nal i nterc o urse or use a male c o n d o m d uri n g eac h e pis o de of pe nile 
pe netrati o n .
Fe m ale P artici p a nts:
Fe male partici pa nts of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o use a 
hi g hl y effecti ve met h o d of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as descri be d i n Ta ble 1 4
d uri n g t he pr ot oc ol -defi ne d ti me fra me i n Secti o n 6. 1 . 
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 5
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
Ta ble 1 4
Hi g hl y Effecti ve C o ntrace pti o n Met h o ds
Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds T h at Are User De pe n de nt 
a
F ail ure r ate of < 1 %  per ye ar w he n use d c o nsiste ntly a n d c orrectly.
●
C o m bi ne d (estr o ge n - a n d pr o gest o ge n - c o ntai ni n g ) h or m o nal c o ntrace pti o n b, c
○
Oral 
○
I ntra va gi nal 
○
Tra ns der mal 
○
I njecta ble
●
Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n b, c
○
Oral 
○
I njecta ble 
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de nc y 
F ail ure r ate of < 1 %  per ye ar w he n use d c o nsiste ntly a n d c orrectly.
●
Pr o gest o ge n - o nl y c o ntrace pti ve i m pla nt b, c
●
I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) b
●
I ntra uteri ne de vice (I U D)
●
Bilateral t u bal occl usi o n
●
V asect o mize d p art ner 
A vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he s ole 
male se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal 
hi g hl y effecti ve met h o d of c o ntrace pti o n s h o ul d be u se d. 
●
Se x u al a bsti ne nce 
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nt. T he 
relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relatio n t o t he d urati o n of t he st u d y a n d t he 
preferre d a n d us ual lifest yle of t he partici pa nt.) 
N otes: 
Use s h o ul d be c o nsiste nt wit h l ocal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or 
partici pa nts of cli nical st u dies. 
a) T y pical use fail ure r ates are hi g her t ha n perfect-use fail ure rates (i.e. w he n use d c o nsiste ntl y a n d 
c orrectl y). 
b) If h or m o nal c o ntrace pti o n efficac y is p ote ntiall y decrease d d ue t o i nteracti o n wit h st u d y treat me nt, 
c o n d o ms m ust be use d i n a d diti o n t o t he h or m o nal c o ntrace pt i o n d uri n g t he treat me nt peri o d a n d f or at 
least 1 2 0 da ys after t he last d ose of st u d y treat me nt.
c) If l ocall y re q uire d, i n acc or da nce wit h Cli nical Trial Facilitati o n Gr o u p ( C T F G) g ui deli nes, 
acce pta ble h or m o nal c o ntrace pti ves are li mite d t o t h ose w hic h i n hi bit o v ulati o n. 
Pre g n a nc y Testi n g
W O C B P s h o ul d o nl y  be i ncl u de d after a ne gati ve hi g hly se nsiti ve uri ne or ser u m pre g na nc y 
test wit hi n 7 2 h o urs of ra n d o mizati o n. If uri ne pre g na nc y res ults 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. 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 pl ica ble.
F oll o wi n g i nitiati o n of treat me nt , pre g na nc y  testi n g will be perf or me d w he ne ver a n e x pecte d 
me nstr ual c y cle is misse d or w he n pre g na nc y  is ot her wise s us pecte d a n d as re q uire d l ocall y.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 6
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 6:  Ne w Y or k He art Ass oci ati o n ( N Y H A) F u ncti o n al Cl assi fic ati o n
1 2. 6
Cl ass
F u ncti o n al C a p acit y: H o w a p atie nt wit h c ar di ac dise ase feels 
d uri n g p h ysic al acti vit y
I
Partici pa nt s wit h car diac disease b ut res ulti n g i n n o li mitati o n of 
p h y sical acti vit y. Or di nar y  ph y sical acti vit y does n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea or a n gi nal pai n. 
II
Partici pa nt s wit h car diac disease res ulti n g i n sli g ht li mitati o n of 
p h y sical acti vit y. T h e y  are c o mf orta ble at rest. Or di nar y  ph y sical 
acti vit y res ults i n fati g ue, pal pitati o n, d ys p nea or a n gi nal pai n. 
III
Partici pa nt s wit h car diac disease res ulti n g i n mar ke d li mitati o n of 
p h y sical acti vit y. T h e y  are c o mf orta ble at rest. Less t ha n or di nar y 
acti vit y ca uses fati g ue, pal pitati o n, d ys p nea or a n gi nal pai n. 
I V
Partici pa nt s wit h car diac disease res ulti n g i n i na bilit y to carr y on 
a n y ph y sical acti vit y 
wit h o ut disc o mf ort. S y m pt o ms 
of heart 
fail ure or t he a n gi nal s yn dr o me ma y  be prese nt e ve n at rest.  If a n y 
p h y sical acti vit y is u n derta ke n, disc o mf ort i ncreases.
* As p u blis he d i n: T he Criteri a C o m mittee of t he Ne w Y ork He art Ass oci ati o n. ( 1 9 9 4). 
N o me ncl at ure a n d Criteri a f o r Di a g n osis of Dise ases of t he He art a n d Gre at Vessels. ( 9t h e d.). 
B ost o n: Little, Br o w n &  C o. p p. 2 5 3– 2 5 6.
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 7
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 7: E C O G a n d K ar n ofs k y Perf or m a nce Assess me nts
1 2. 7
E C O G Perf or m a nce St at us
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 sicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y 
o ut w or k of a li g ht or se de ntar y  nat ure, e g, li g ht h o use w or k, office w or k
2
A m b ulat or y  a n d ca pa ble of all self-care b ut u na ble t o carr y o ut a ny w or k 
acti vities; u p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3
Ca pa ble of o nl y li mite d self -care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs
4
C o m pletel y  disa ble d; ca n n ot carr y o n a n y self-care; t otall y c o nfi ne d t o be d or 
c hair
5
Dea d
* As p u blis he d i n:  Oke n, M. M., Creec h, R. H., T or mey, D. C., H ort o n, J., D avis, T. E., Mc F a d de n, 
E. T., C ar b o ne, P. P.: T oxicity A n d Res p o nse Criteri a Of T he E aster n C o o per ative O nc ol o gy 
Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 8
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
K ar n ofs k y Perf or m a nce St at us ( K P S)
G R A D E
K A R N O F S K Y P E R F O R M A N C E S T A T U S
1 0 0
N or mal; n o c o m plai nts; n o e vi de nce of disease.
9 0
A ble t o carr y  o n n or mal acti vit y; mi n or si g ns or s ym pt o ms of disease.
8 0
N or mal acti vit y  wit h eff ort; s o me si g ns or sy m pt o ms of disease.
7 0
Cares f or self; u na ble t o carr y  o n n or mal acti vity or t o d o acti ve w or k.
6 0
Re q uires occasi o nal assista nce, b ut is a ble t o care f or m ost of t heir pers o nal nee ds.
5 0
Re q uires c o nsi dera ble assista nce a n d fre q ue nt me dical care.
4 0
Disa ble d; re q uires s pecial care a n d assista nce.
3 0
Se verel y disa ble d; h os pital a d missi o n is i n dicate d alt h o u g h deat h n ot i m mi ne nt.
2 0
Ver y  sic k; h os pital a d missi o n necessar y; acti ve s u p p orti ve treat me nt necessar y.
1 0
M ori b u n d; fatal pr ocesses pr o gressi n g ra pi dl y.
0
Dea d
As p u blis he d i n:
K ar n ofsky D A, B urc he n al J H, T he cli nic al ev al u ati o n of c he m ot her a pe utic a ge nts i n c a ncer. 
I n: Ev al u ati o n of C he m ot her a pe utic A ge nts, M acle a d C M, e d. Ne w Y ork: C ol u m bi a U niversity Press, 
1 9 4 9. 
Sc h a g C C, Hei nric h R L, G a nz P A. K ar n ofsky perf or m a nce st at us revisite d: reli a bility, v ali dity, a n d 
g ui deli nes. J Cli n O nc ol 1 9 8 4; 2( 3): 1 8 7 – 9 3 .
 
 
0 4 Y B Q D


Pr o d uct:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 9
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 - 0 4/ E C H O-3 0 7 -0 4
M K -3 4 7 5 -6 7 2 -0 4 (I N C B 2 4 3 6 0 -3 0 7 -0 4) Fi nal Pr ot oc ol
1 3 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 8: Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of Dise ase 
1 2. 8
Pr o gressi o n
N ote: As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble; i R E CI S T d at a will n o 
l o n ger be c ollecte d. P artici p a nts wit h r a di o gr a p hic dise ase pr o gressi o n as deter mi ne d 
b y R E CI S T 1. 1 will disc o nti n ue fr o m t he st u d y a n d be f oll o we d f or s afet y m o nit ori n g, 
as det aile d i n Secti o n 9. 3; n o c o nfir m at or y sc a ns are re q uire d. 
Assess me nt at Scree ni n g a n d Pri or t o R E CI S T 1. 1 Pr o gressi o n
U ntil ra di o gra p hic disease pr o gressi o n base d o n R E CI S T 1. 1, t here is n o disti nct i R E CI S T 
assess me nt.
Assess me nt a n d Decisi o n at R E CI S T 1. 1 Pr o gressi o n
F or partici pa nt s w h o s h o w e vi de nce of ra di ol o gical P D b y R E CIS T 1. 1 as deter mi ne d b y t he 
I n vesti gat or, t he I n vesti gat or will deci de w het her t o c o nti n ue a partici pa nt o n st u d y treatme nt
u ntil re peat i ma gi n g is o btai ne d ( usi n g i R E CI S T f or partici pa nt ma na ge me nt (see Ta ble 7
a n d Fi g ure 3 ).  T his decisi o n b y t he I n vesti gat or s h o ul d be base d o n t he partici pa nt ’s o verall 
cli nical c o n diti o n   
Cli nical sta bilit y  is defi ne d as t he f oll o wi n g: 

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y  si g 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

N o decli ne i n E C O G perf or ma nce stat us 

N o re q uire me nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesia, 
ra diati o n, or ot her palliati ve care.
A n y  partici pa n t 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 st u d y treat me nt at 
ce ntral verificati o n of site -assesse d first ra di ol o gic e vi de nce of P D , a n d is 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 P D b y  i R E CIS T .
If t he I n vesti gat or deci des t o c o nti n ue treat me nt, t he partici pa nt ma y c o nti n ue t o recei ve 
st u d y treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m 
P D b y  i R E CIS T, per I n vesti gat or assess me nt. I ma ges s h o ul d c o nti n ue t o be se nt i n t o t he 
ce ntral i ma gi n g ve n d or f or p ote ntial retr os pecti ve BI C R.
T u m or flare ma y  ma nifest as a n y fact or ca usi n g ra di o gra p hic pr o gressi o n per R E CIS T 1. 1, 
i ncl u di n g:

I ncrease i n t he s u m of dia meters of tar get lesi o n(s) i de ntifie d at baseli ne t o ≥2 0 % a n d 
≥5 m m fr o m na dir
o
N ote: t he i R E CI S T p u blicati o n uses t he ter mi n ol o g y  “s u m of meas ure me nts”, 
b ut “s u m of dia meters” will be use d i n t his pr ot oc ol, c o nsiste nt wit h t he 
ori gi nal R E CI S T 1. 1 ter mi n ol o g y .

U ne q ui v ocal pr o gressi o n of n o n -tar get lesi o n(s) i de ntifie d at baseli ne

De vel o p me nt of ne w lesi o n(s)
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 0
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
i R E CIS T defi nes ne w res p o nse cate g ories, i ncl u di n g i U P D ( u nc o nfir me d pr o gressi ve 
disease) a n d i C P D (c o nfir me d pr o gressi ve disease). F or p ur p oses of i R E CI S T assess me nt, 
t he first visit s h o wi n g pr o gressi o n acc or di n g t o R E CIS T 1. 1 will be assi g n e d a visit ( o verall) 
res p o nse of i U P D, re gar dless of w hic h fact ors ca use d t he pr o gressi o n.
At t his visit, tar get a n d n o n- tar get lesi o ns i de ntifie d at baseli ne by R E CI S T 1. 1 will be 
assesse d as us ual.
Ne w lesi o ns will be classifie d as meas ura ble or n o n -meas ura ble, usi n g t he sa me size 
t hres h ol ds a n d r ules as f or baseli ne lesi o n assess me nt i n R E CIS T 1. 1. Fr o m meas ura ble ne w 
lesi o ns, u p t o 5 lesi o ns t otal ( u p t o 2 per or ga n), ma y be selecte d as Ne w Lesi o ns – Tar get. 
T he s u m of dia meters of t hese lesi o ns will be calc ulate d, a n d ke pt disti nct fr o m t he s u m of 
dia meters f or tar get lesi o ns at baseli ne. All ot her ne w lesi o ns will be f oll o we d q ualitati vel y  
as Ne w Lesi o ns – N o n -tar get.
Assess me nt at t he C o nfir m at ory I m a gi n g
O n t he c o nfir mat or y  i ma gi n g, t he partici pa nt will be classifie d as pr o gressi o n c o nfir me d 
( wit h a n o verall res p o nse of i C P D), or as s h o wi n g persiste nt u nc o nfir me d pr o gressi o n ( wit h 
a n o verall res p o nse of i U P D), or as s h o wi n g disease sta bilit y  or res p o nse (i S D/i P R/i C R).
C o nfir m ati o n of Pr o gressi o n
Pr o gr essi o n is c o nsi dere d c o nfir me d, a n d t he o verall res p o nse will be i C P D, if A N Y of t he 
f oll o wi n g occ urs:

A n y  of t he fact ors t hat were t he basis f or t he i U P D at t he pre vi o us visit s h o w 
w orse ni n g
o
F or tar get lesi o ns, w orse ni n g is a f urt her i ncrease i n t he s u m o f dia meters of 
≥5 m m, c o m pare d t o a n y pri or i U P D ti me p oi nt
o
F or n o n -tar get lesi o ns, w orse ni n g is a n y si g nifica nt gr o wt h i n lesi o ns o verall, 
c o m pare d t o a pri or i U P D ti me p oi nt; t his d oes n ot ha ve t o meet t he 
“ u ne q ui v ocal” sta n dar d of R E CI S T 1. 1
o
F or ne w les i o ns, w orse ni n g is a ny of t hese:

A n i ncrease i n t he ne w lesi o n s u m of dia meters b y ≥5 m m fr o m a pri or 
i U P D ti me p oi nt 

Visi ble gr o wt h of ne w n o n- tar get lesi o ns 

T he a p peara nce of a d diti o nal ne w lesi o ns

A n y  ne w fact or a p pears t hat w o ul d ha ve tri g gere d P D b y R E CI S T 1. 1
Persiste nt i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o verall res p o nse re mai ns i U P D, if:

N o ne of t he pr o gressi o n -c o nfir mi n g fact ors i de ntifie d a b o ve occ urs A N D

T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) re mai ns a b o ve t he i nitial P D 
t hres h ol d ( by R E CI S T 1. 1)
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 1
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial
A d diti o nal i ma gi n g f or c o nfir mati o n s h o ul d be sc he d ule d 4 t o 8 wee ks fr o m t he i ma gi n g o n 
w hic h i U P D is see n. T his ma y  c orres p o n d t o t he ne xt visit i n t he ori gi nal visit sc he d ule. T he 
assess me nt of t he s u bse q ue nt c o nfir mati o n i ma gi n g pr ocee ds i n a n i de ntical ma n ner, wit h 
p ossi ble o utc o mes of i C P D, i U P D, a n d i S D/i P R/i C R.
Res ol uti o n of i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o verall res p o nse bec o mes i S D/i P R/i C R, if:

N o ne of t he pr o gressi o n -c o nfir mi n g fact ors i de ntifie d a b o ve occ urs, A N D

T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) is n ot a b o ve t he i nitial P D 
t hres h ol d. 
T he res p o nse is classifie d as i S D or i P R ( de pe n di n g o n t he s u m of dia meters of t he tar get 
lesi o ns), or i C R if all lesi ons res ol ve.
I n t his case, t he i nitial i U P D is c o nsi dere d t o be pse u d o- pr o gressi o n, a n d t he le vel of 
s us pici o n f or pr o gressi o n is “reset”. T his mea ns t hat t he ne xt visit t hat s h o ws ra di o gra p hic 
pr o gressi o n, w he ne ver it occ urs, is a gai n classifie d as i U P D b y i R E CIS T, a n d t he 
c o nfir mati o n pr ocess is re peate d bef ore a res p o nse of i C P D ca n be assi g ne d.
M a n a ge me nt F oll o wi n g t he C o nfir m at ory I m a gi n g
If re peat i ma gi n g d oes n ot c o nfir m P D per i R E CIS T, as assesse d b y  t he I n vesti gat or, a n d t he 
partici pa nt c o nti n ues t o be cli nicall y  sta ble, st u d y 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. If P D is c o nfir me d, partici pa nts will be disc o nti n ue d fr o m st u d y 
treat me nt.
N O T E: If a partici pa nt has c o nfir me d ra di o gra p hic pr o gressi o n (i C P D) as defi ne d a b o ve, b ut 
t he partici pa nt is ac hie vi n g a cli nicall y mea ni n gf ul be nefit, or if R E CI S T 1. 1 P D has n ot bee n 
verifie d ce ntrall y , a n e xce pti o n t o c o nti n ue st u d y treat me nt ma y be c o nsi dere d f oll o wi n g 
c o ns ultati o n wit h M S D. I n t his case, if st u d y  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 nti n 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 2 a n d s u b mitte d t o t he 
ce ntral i ma gi n g ve n d or.
Detecti o n of Pr o gressi o n at Visits After Pse u d o -pr o gressi o n Res olves
After res ol uti o n of pse u d o - pr o gressi o n (ie, ac hie ve me nt of i S D/i P R/i C R), i U P D is i n dicate d 
b y  a ny of t he f oll o wi n g e ve nts:

Tar get lesi o ns
o
S u m of dia meters r eac hes t he P D t hres h ol d ( ≥2 0 % a n d ≥5 m m i ncrease fr o m 
na dir) eit her f or t he first ti me, or after res ol uti o n of pre vi o us pse u d o -
pr o gressi o n. T he n a dir is al wa ys t he s mallest s u m of dia meters see n d uri n g t he 
e ntire st u d y, eit her bef ore or after a n i nsta nce of pse u d o-pr o gressi o n.
 
 
0 4 Y B Q D


Pr o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 2
Pr ot oc ol/ A me n d me nt N o.:  6 7 2 -0 4/ E C H O - 3 0 7- 0 4
M K - 3 4 7 5- 6 7 2-0 4 (I N C B 2 4 3 6 0 - 3 0 7-0 4) Fi nal Pr ot oc ol
1 3- J u n- 2 0 1 8
C o nfi de ntial

N o n -tar get lesi o ns
o
If n o n-tar get lesi o ns ha ve ne ver s h o w n u ne q ui v ocal pr o gressi o n, t heir d oi n g 
s o f or t he first ti me res ults i n i U P D.
o
If n o n-tar get lesi o ns ha ve s h o w n pre vi o us u ne q ui v ocal pr o gressi o n, a n d t his 
pr o gressi o n has n ot res ol ve d, i U P D res ults fr o m a n y  si g nifica nt f urt her gr o wt h 
of n o n -tar get lesi o ns, ta ke n as a w h ole.

Ne w lesi o ns
o
Ne w lesi o ns a p pear f or t he first ti me
o
A d diti o nal ne w lesi o ns a p pear
o
Pre vi o usl y  i de ntifie d ne w tar get lesi o ns s h o w a n i ncrease of ≥5 m m i n t he 
ne w lesi o n s u m of dia meters, fr o m t he na dir val ue of t hat s u m
o
Pre vi o usl y  i de ntifie d n o n-tar get lesi o ns s h o w a ny si g nifica nt gr o wt h
If a ny of t he e ve nt s a b o ve occ ur, t he o verall res p o nse f or t hat visit is i U P D, a n d t he i U P D 
e val uati o n pr ocess (see Assess me nt at t he C o nfir mat or y  Ima gi n g a b o ve) is re peate d.  
Pr o gressi o n m ust be c o nfir me d bef ore i C P D ca n occ ur.
T he decisi o n pr ocess is i de ntical t o t he i U P D c o nfir mati o n pr ocess f or t he i nitial P D, wit h 
o ne e xce pti o n: if ne w lesi o ns occ urre d at a pri or i nsta nce of i U P D, a n d at t he c o nfir mat or y  
i ma gi n g t he b ur de n of ne w lesi o ns has i ncrease d fr o m its s mallest val ue (f or ne w tar get 
lesi o ns, t he s u m of dia meters is ≥5 m m i ncrease d fr o m its na dir), t he n i U P D ca n n ot res ol ve 
t o i S D or i P R. It will re mai n i U P D u ntil eit her a decrease i n t he ne w lesi o n b ur de n all o ws 
res ol uti o n t o i S D or i P R, or u ntil a c o nfir mat or y fact or ca uses i C P D.
A d diti o nal details a b o ut i R E CIS T are pr o vi de d i n t he i R E CIS T p u blicati o n [ Se ym o ur, L., et 
al 2 0 1 7] .
 
 
0 4 Y B Q D