Clinical trial NCT03374488
Conditions: UC (Urothelial Cancer)
Keywords: Urothelial carcinoma programmed cell death protein 1 (PD-1) inhibitor indoleamine 2,3-dioxygenase (IDO) inhibitor
Sponsor: Incyte Corporation
Start date: 2017-12-22; Completion date: 2020-07-23
Enrollment: 84 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 as a treatment for recurrent or progressive metastatic urothelial carcinoma in patients who have failed a first-line platinum-containing chemotherapy regimen for advanced/metastatic disease.

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 Day 1 of each cycle 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 
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Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
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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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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 3
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 mela n o ma bli n de d cli nical st u d y, a 
P hase 3 st u d y eval 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 hese 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 ypes.  Of n ote, t here were n o ne w safet y co ncer ns wit h t he pe m br oliz u ma b pl u s 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 lac 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  in 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- M A 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 discr eti 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 last partici pa nt c o m pletes 
first i ma gi n g assess me nt f or efficac y 
a nal ys 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 dy treat me nt as per 
pr ot oc ol. 
Gi ve n t he results f or pe m br oliz u ma b + e paca d ostat 
treat me nt fr o m t he mela n o ma st u d y  K E Y N O T E-
2 5 2/ E C H O - 3 0 1, as of 02 - MA 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 YN O T E 6 9 8 / E C H O- 3 0 7.  
P artici 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 d y treat me nt.  T he st u d y will 
re mai n 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 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 ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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, So 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. All efficac y pr oced ures will 
disc o nti n ue after Wee k 9 ; t hereafter 
perf or me d as per l ocal sta n dar d of care 
(S o C ). 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 heir Wee k 
9 i ma gi n g assess me nt f or efficac y  
a nal ys is.
5. 1. 1 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 nts 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 ose t o disc o nti n ue 
fr o m t he st u d y or c o nti n ue treat me nt as 
per pr ot oc ol afte r 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 Safet y F U visit.
 
 
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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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 nts was st o p pe d a n d t hat 
8 5 partici pa nts will be ra n d o mize 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 t hat 
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 a s of A me n d me nt 
0 3, 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 nts fr o m 
c o nfir me d t o e val uate d b y i n vesti gat or. 
Delete 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 py. 
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 ysis 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 n ee will be i nf or me d 
of t he st u d y treat me nt t he y recei ve
 
 
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Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
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Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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. 9 Cli nical S u p plies 
Discl os ure
A d diti o nal of te xt t hat the 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).  
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 y i 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.
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 ote t hat ce ntral re vie w of 
i ma gi n g a n d i R ECI S T is n o l o n ger 
a p plica ble.  S ecti o n u p date d acc or di n gl y.
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.  S ecti 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 Wee k 9 i ma gi n g 
assess me nt f or efficac y  anal y sis. Secti o n 
u p date d acc or di n gl y.
 
 
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Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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
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 nal ysis.  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 CI S 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 ysis
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.  
 
 
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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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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. 8. 1 T u m or Tiss ue 
C ollecti o n
A d diti o n of te xt t o clarif y  t hat a 
partici pa nt’s P D -L 1 stat us will n ot be 
discl ose d t o i n vesti gati ve sites or st u d y  
partici pa nts after t he st u d y  is u n bli n de d
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 CI S 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; safety 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 ot her 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 h is 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 ; 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 f o ot n otes re gar di n g f oll o w - u p 
visits.
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 tu m or 
ima 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.
 
 
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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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 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 E CI 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.
5. 4. 1. 3 Rati o nale f or Patie nt 
Re p orte d O utc o mes
9. 2. 2
Pa tie nt Re p orte d 
O utc o mes
A d diti o n of n ote t hat 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 ma gi n g assess me nt at Wee k 9.
 
 
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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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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. 6 i R E CIS T Assess me nt 
of Disease
A p pe n di x 7
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 CI 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.
1 0 . Statistical A nal y sis Pla n
W h ole s ecti 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 . 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 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 .  H o we ver, 
sta n dar d safety re p orti n g s h o ul d c o nti n ue, a s 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.
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 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.
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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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
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 me 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.
9. 2. 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.  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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 ntly 
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 ntly 
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. 5. 4 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.
5. 1 O verall Desi g n
Re place d te xt relati n g t o i nteri m a nal ysis 
wit h te xt t hat t here is n o i nteri m a nal ys is 
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 d uce sc o pe 
of t he st u d y . eD M C will c o n d uct a safet y re vie w as pe r t he 
D M C c harter.
Secti o n 1 2, A p pe n di x 1
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 ysis of data.
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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
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.  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 as 
per pr ot oc ol a n d are c o nsi dere d t o 
recei ve cli nical be nefit w ill 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
9. 9. 1 Scree ni n g
Scree ni n g p hase wi n d o w of u p t o 4 2 d a y  
c ha n ge d t o a p pr oxi m ately 4 2 d a y s
Ali g n me nt wit h ot her o n g oi n g pe m br oliz u ma b + 
e paca d ostat st u dies
9. 3. 7 E ve nts of Cli nical 
I nterest ( E CI)
I nserti o n of a d diti o nal te xt f or re p orti n g 
re q uire me nts of E CIs “or 3 0 da y s 
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”.
2. 1 I nitial Treat me nt P hase 
I n S o A t u m or i ma gi n g n otes: c ha n ge d 
“ Baseli ne C A P C T/ M RI t o be perf or me d 
i n all partici pa nts wit hi n 2 8 da ys of 
ra n d o mizati o n” t o “ wit hi n 2 8 da ys pri or 
t o ra n d o mizati o n”
1 2 lea d E C G r o w: cr oss refere nce t o 
n otes
N ote a d de d f or T 3/ F T 3, F T 4, a n d T S H 
r o w: T otal T 3 is preferre d b ut free T 3 is 
acce pta ble. Sites o nl y nee d t o re p ort 
eit her T otal T 3 or free T 3.
N ote a d de d t o S o A f or arc hi val tiss ue.
C orrecti o n a n d clarificati o n of ti mi n g of pr oce d ures
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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. 2 Sec o n d C o urse 
Retreat me nt
Inserte d f o ot n ote cr oss refere nce i nt o 
hea der r o ws
U p date d n otes f or all la bs t o i n dicate t hat 
pretreat me nt la bs s h o ul d be ta ke n 1 4 
da y s pri or t o sec o n d c o urse C ycle 1
I nserte d r o w f or 1 2-Lea d E C G wit h Q Tc 
Meas ure me nt
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 will be d ose d
t wice daily (a p pr o xi matel y  Q 1 2 H)
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
3. 3. 1 Be nefit/ Ris ks f or 
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 ncer n of I D O 1 
i n hi biti o n.
6. 2 E xcl usi o n Criteria
Criteria # 2 1 - n ote re m o ve d.
Melat o ni n a n d pr o p of ol re m o ve d fr o m 
e xcl usi o n criteria.
7. 7. 2 Pr o hi bite d C o nc o mita nt 
Me dicati o ns
# 7 - melat o ni n s u p ple me nts re m o ve d .
# 8 - m efe na mic aci d a n d pr o p of ol 
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.
N ote relati n g t o Pr o p of ol delete d .
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5
Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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. 2. 1. 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)
A d diti o n of f oll o wi n g pr oce d ure of
partici pa nts e x hi biti n g si g ns/s y m pt o ms 
of S S: I f 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 i n 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.
9. 3. 7 E ve nts of Cli nical 
I nterest ( E CI)
Ser ot o ni n s y n dr o me a d de d as a n E CI
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
Ta ble 3 - n ote # 4 – i nserte d clarificati o n 
o n gra de of A E t o w hic h n ote a p plies
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 nc y  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
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 
 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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. 6. 1 A d mi nistrati o n a n d 
C o m plia nce of 
Pe m br oliz u ma b
Re m o val of te xt re q uiri n g c o ns ultati o n 
wit h S p o ns or f or i nterr u pti o ns fr o m t he 
pr ot oc ol -s pecifie d treat me nt pla n f or 
m ore t ha n 1 2 wee ks bet wee n 
pe m br oliz u ma b d oses f or n o n dr u g -
relate d or a d mi nistrati ve reas o ns
C o nsiste nc y  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
7. 2. 1. 3 D ose I nterr u pti o ns 
U nrelate d t o A d verse E ve nts
A d de d t hat d ose 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.”
Clarificati o n
7. 6. 2 A d mi nistrati o n a n d 
C o m plia nce of E paca d ostat 
or Matc hi n g Place b o
Re m o val te xt s pecif yi n g t hat of Sec o n d 
C o urse C 1 D 1 a d mi nistrati o n of 
e paca d ostat / place b o bei n g gi ve n at st u d y  
site.
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 nce 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 7
2. 
Sc he d ule of Acti vities ( S o A) ......................................................................................3 0
I niti al Tre at me nt P h ase ..........................................................................................3 0
2. 1
Sec o n d C o urse P h ase ( Retre at me nt) .....................................................................3 5
2. 2
3.
I ntr o d ucti o n ................................................................................................................3 7
St u d y R ati o n ale .......................................................................................................3 7
3. 1
B ac k gr o u n d ..............................................................................................................3 7
3. 2
P har mace utical a n d T hera pe utic Bac k gr o u n d .....................................................3 7
3. 2. 1
O ver vie w of Ur ot helial Carci n o ma ...............................................................3 8
3. 2. 1. 1
Treat me nt f or Rec urre nt or Pr o gressi ve Metastatic Ur ot helial 
3. 2. 1. 2
Carci n o ma .....................................................................................................3 8
I m m u ne S ur veilla nce a n d Ne o plastic Tra nsf or mati o n .................................3 9
3. 2. 1. 3
I n hi biti o n of P D-1 as a Tar get f or Ca ncer ....................................................3 9
3. 2. 1. 4
Acti vit y  of P D -1/ P D -L 1 I n hi bit ors i n Ur ot helial Carci n o ma .......................4 0
3. 2. 1. 5
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 ............4 1
3. 2. 1. 6
C o m bi ne d I m m u ne C hec k p oi nt I n hi biti o n ...................................................4 3
3. 2. 1. 7
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 biti o n ........................4 3
3. 2. 1. 8
Pre -cli nical a n d Cli nical St u dies..........................................................................4 4
3. 2. 2
O n g oi n g Cli nical St u dies .....................................................................................4 4
3. 2. 3
Be nefit/ Ris k Assess me nt .........................................................................................4 4
3. 3
Be nefit/ Ris ks f or E paca d ostat ..............................................................................4 4
3. 3. 1
Be nefit/ Ris ks fr o m Pe m br oliz u ma b .....................................................................4 5
3. 3. 2
Be nefit/ Ris ks f or t he C o m bi nati o n of E paca d ostat a n d Pe m br oliz u ma b .............4 5
3. 3. 3
4.
O bjecti ves/ H y p ot heses a n d E n d p oi nts .....................................................................4 6
5.
St u d y Desi g n ...............................................................................................................4 7
O ver all Desi g n .........................................................................................................4 7
5. 1
St u d y  Dia gra m .....................................................................................................4 8
5. 1. 1
 
 
0 4 Y C 7 6




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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Pre g na nc y .............................................................................................................6 3
6. 3. 3
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 3
Tre at me nts A d mi nistere d .......................................................................................6 3
7. 1
D ose M o dific ati o n ( Esc al ati o n/ Titr ati o n/ Ot her) ..................................................6 4
7. 2
D ose M o dificati o n f or I m m u ne-relate d A Es .......................................................6 4
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 3
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 4
I nterr u pti o ns U nrelate d t o A d verse E ve nts...................................................7 8
7. 2. 1. 3
Sec o n d C o urse P hase ( Retreat me nt) ....................................................................7 8
7. 2. 2
Met h o d of Tre at me nt Assi g n me nt .........................................................................7 9
7. 3
Stratificati o n .........................................................................................................7 9
7. 3. 1
Bli n di n g ....................................................................................................................7 9
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 0
7. 5
D ose Pre parati o n ..................................................................................................8 0
7. 5. 1
Ha n dli n g, St ora ge a n d Acc o u nta bilit y .................................................................8 0
7. 5. 2
Tre at me nt C o m pli a nce ...........................................................................................8 0
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 0
7. 6. 1
A d mi nistrati o n a n d C o m plia nce of E paca d ostat or Matc hi n g Place b o
...............8 1
7. 6. 2
C o nc o mit a nt T her a p y .............................................................................................8 1
7. 7
Acce pta ble C o nc o mita nt Me dicati o ns .................................................................8 1
7. 7. 1
Pr o hi bite d C o nc o mita nt Me dicati o ns ...................................................................8 1
7. 7. 2
Restricte d C o nc o mita nt Me dicati o ns ...................................................................8 3
7. 7. 3
Resc ue Me dicati o ns a n d S u p p orti ve Care ...........................................................8 3
7. 7. 4
Tre at me nt After t he E n d of t he St u d y ..................................................................8 4
7. 8
Cli nic al S u p plies Discl os ure ...................................................................................8 4
7. 9
St a n d ar d P olicies .....................................................................................................8 4
7. 1 0
8.
Disc o nti n u ati o n/ Wit h dr a w al Criteri a ......................................................................8 4
Disc o nti n u ati o n of St u d y Tre at me nt..................................................................... 8 4
8. 1
 
 
0 4 Y C 7 6


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


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


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


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


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 4 2
A p pe n di x 4: Cli nic al L a b or at or y Tests ...............................................................1 4 3
1 2. 4
A p pe n di x 5: E C O G Perf or m a nc e St at us ............................................................1 4 5
1 2. 5
A p pe n di x 6: A b bre vi ati o ns a n d Tr a de m ar ks .....................................................1 4 6
1 2. 6
A p pe n di x 7: Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of 
1 2. 7
Dise ase Pr o gressi o n ...............................................................................................1 5 0
 
 
0 4 Y C 7 6




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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 8
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
1.
S y n o psis
Pr ot oc ol Title:
A P hase 3 Ra n d o mize d, D o u ble- Bli n d Cli nical St u d y  of Pe m br oliz u ma b + E paca d ostat vs 
Pe m br oliz u ma b + Place b o as a Treat me nt f or Rec urre nt or Pr o gressi ve Metastatic Ur ot helial 
Carci n o ma i n Patie nts w h o ha ve Faile d a First -Li ne Plati n u m -c o ntai ni n g C he m ot hera p y 
Re gi me n f or A d va nce d/ Metastatic Disease ( K E Y N O T E -6 9 8/ E C H O -3 0 3)
S h ort Title: 
P h ase 3 St u d y  of Pe m br o wit h/ wit h o ut E paca d ostat i n 2 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 nts 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) t hat has rec urre d or pr o gresse d 
f oll o wi n g o ne p ri or li ne of plati n u m-c o ntai ni n g c he m ot hera p y f or a d va nce d/ metastatic disease :
N O T E: As of A me n d me nt 0 3, 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 CI S 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 safety a n d t olera bilit y of partici pa nts 
treate 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, wil l 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 safet y 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 C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 8
Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
O ver all Desi g n:
St u d y P hase
P hase III
Cli nical I n dicati o n
A sec o n d-li ne (2 L ) treat me nt of pa tie nts wit h 
a d va nce d/ u nresecta ble or metastatic ur ot helial carci n o ma
P o p ulati o n
A d ult partici pa nts wit h a d va nce d/ u nresecta ble or metastatic 
ur ot helial carci n o ma
St u d y T y pe
I nter ve nti o nal
T y pe of Desi g n
Ra n d o mize d , parallel-gr o u p, m ulti -site, d o u ble-bli n d 
As of A me n d me nt 0 3, 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 nalys is.
T y pe of C o ntr ol
Acti ve C o ntr ol
St u d y Bli n di n g  
D o u ble- bli n d
N ote: As of A me n d me nt 0 3, t he st u d y  will be u n bli n de d 
w he n t he last partici pa nts 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 Trial
T he stu d y  is esti mated 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 -relate d visit.
N u m ber of P artici p a nt s:
Ori gi nall y, a p pr o xi matel y  6 4 8 partici pa nts were t o be e nr olle d, b ut as of A me n d me nt 0 3, 
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 8 5 partici pa nts will be ra n d o mize d i n 
t his st u d y.
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 9
Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Tre at me nt Gr o u ps a n d D ur ati o n :
Treat me nt Gr o u ps
1.
Pe m br oliz u ma b 2 0 0 m g i ntra ve n o us (I V) e ver y 3 wee ks 
( Q 3 W) + e paca d ostat 1 0 0 m g P O BI D c o nti n u o usl y
2.
Pe 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 3, 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
Eac h partici pa nt will partici pate i n t he st u d y fr o m t he ti me 
t he partici pa nt si g ns t he i nf or me d 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 a p pr o xi matel y 4 2 d a y s, eac h 
partici pa nt will be assi g ne d t o recei ve st u d y treat me nt u ntil 
disease pr o gressi o n , u nacce pta ble a d verse e ve nt(s) ( 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 st u d y treat me nt or 
pr oce d ure re q uire me nts , 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 st u d y treat me nt after 
recei vi n g 3 5 a d mi nistrati o ns of pe m br oliz u ma b f or reaso 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 
st u d y 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 (a p pr o xi matel y 1 year) of pe m br oliz u ma b 
wit h e paca d ostat/ matc hi n g pla ce b o u p o n e x perie nci n g 
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 
Secti o n 9. 3.  
St u d y  g o ver na nce c o nsi derati o ns are o utli ne d i n A p pe n di x 1. 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 6.
 
 
0 4 Y C 7 6
















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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 he g oal of ca ncer i m m u n ot hera p y is t o i nitiate or rei nitiate a self- s ustai ni n g c ycle of ca ncer 
i m m u nit y, e na bli n g it t o a m plif y a n d pr o pa gate.  Ca ncer i m m u n ot hera pies m ust o verc o me t he 
ne gati ve fee d bac k mec ha nis ms t hat are i n here nt i n m ost ca ncers t o e va d e i m m u ne s ur veilla nce.  
Bla d der ca ncer was t he first i n dicati o n f or w hic h a n i m m u n ot hera p y was gra nte d a p pr o val b y t he 
F o o d a n d Dr u g A d mi nistrati o n ( F D A ) i n 1 9 9 0. Bacill us Cal mette -G u éri n ( B C G) has bee n 
s h o w n t o be a n effecti ve a ge nt f or t he treat me nt of s u perficial bla d der ca ncer si nce its a p pr o val 
i n 1 9 9 0. A u g me ntati o n of B C G i m m u n ot hera p y wit h i nterfer o n- α 2 b a n d ot her a ge nts ha ve 
e mer ge d si nce t he n f or patie nts w h o fail i nitial treat me nt [ Kass o uf, W. 2 0 0 4] s u g gesti n g t hat 
bla d der ca ncer ma y  be a t u m or t ype res p o nsi ve t o i m m u n ot hera p y .
T here is a n u n met nee d i n t he a d va nce d disease setti n g, si nce c urre nt c he m ot hera p y re gi me ns are 
t o xic a n d pr o vi de li mite d be nefit.  T here 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 pr o gra m me d cell deat h ( P D -1) i n hi bit or, pe m br oliz u ma b ( M K -3 4 7 5) m o n ot hera p y, 
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 1 4] [ Ki m, J. 
W., et al 2 0 1 5] .  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  tar geti n g P D-1 wit h pe m br oliz u ma b, a n d t he tr y pt 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) wit h e paca d ostat (f or merl y 
I N CB 0 2 4 3 6 0) .  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 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.  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 ys 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 nt s wit h pr o gressi ve metastatic ur ot helial 
carci n o ma ( U C) fr o m t he o n g oi n g P hase 1/ 2 st u d y I N 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 py 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 (see Secti o n 3. 2. 1. 8), t h us warra nti n g a f urt her caref ully 
c o ntr olle d ra n d o mize d st u d y.  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 pl us place b o i n partici pa nt s wit h 
a d va nce d/ metastatic disease w h o ha ve ha d pr o gressi o n or rec urre nce f oll o wi n g a plati n u m -
c o ntai ni n g c he m ot hera p y re gi me n.  
B ac k gr o u n d
3. 2
Refer t o t he c urre nt In vesti gat or’s Br oc h ure (I B)/a p pr o ve d la beli n g f or detaile d bac k gr o u n d 
i nf or mati o n o n pe m br oliz u ma b ( M K -3 4 7 5 ) a n d e paca d ostat.  
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 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 yme I D O 1 i n b ot h h u ma n t u m o r 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 
c urre nt pe m br oliz u ma b I B a n d t he c urre nt e paca d ostat I B.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
O ver vie w of Ur ot heli al C arci n o m a
3. 2. 1. 1
Ur ot helial carci n o ma , als o k n o w n as tra nsiti o nal c ell carci n o ma ( 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 y pe 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 percent of bla d der ca ncers.
Tre at me nt f or Rec urre nt or Pr o gressi ve Met ast atic Ur ot heli al C arci n o m a
3. 2. 1. 2
T he maj orit y  of patie nts wit h T C C de vel o p l ocalize d, n o n-i n vasi ve disease.  H o we ver, 
a p pr o xi matel y 2 5 % of patie nts will ha ve m uscle-i n vasi ve disease a n d eit her prese nt wit h or later 
de vel o p metastases.  S ys te 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 c o m bi nati o n 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 py re gi me ns, t he 5 -year s ur vi val rate is a p pr o xi matel y  
1 5 % wit h c o nte m p orar y  c he m ot hera p y re gi me ns.  Sec o n d-li ne c he m ot hera p y, us ually as a si n gle 
a ge nt, has ha d o nl y a li mite d r ole, wit h a m o dest i ncrease i n me dia n o verall s ur vi val ( O S) was at 
best 6. 9 m o nt hs c om pare d t o best s u p p orti ve care [ Bell m u nt, J., et al 2 0 0 9]. 
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.  P o or 
perf or ma nce stat us 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.  T his was ill ustrate d b y  a n i nter gr o u p st u d y t hat 
c o m pare d cis plati n al o ne wit h met h otre xate, vi n blasti ne, d o x or u bici n, a n d cis plati n i n patie nts 
wit h metastatic disease [ L oe 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 p o or perf or ma nce stat us were m ost pre dicti ve of p o or res p o nse a n d s ur vi val.  T he prese nce 
of t hese u nfa v ora ble feat ures was ass ociate d wit h me dia n s u r vi val of 4 m o nt hs, c o m pare d wit h 
1 8 m o nt hs i n t h ose patie nts wit h o ut t hese feat ures. N o patie nts wit h li ver or b o ne metastases a n d 
o nl y  o ne patie nt wit h a Kar n ofs ky P S < 8 0 perce nt s ur vi ve d past 6 years [ 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 perf or ma nce stat us or t he prese nce of visceral metastases.  I n t he sec o n d -li ne setti n g 
( patie nts wit h plati n u m-refract or y T C C), m ulti variate a nal ysis i de ntifie d E C O G P S > 1, 
he m o gl o bi n le vel less t ha n 1 0 g/ d L a n d t he prese nce of li ver metastasis as t he mai n a d verse 
pr o g n ostic fact ors f or O S [ Bell m u nt, J., et al 2 0 1 0].  T hese fact ors ill ustrate t hat si nce bla d der 
ca ncer is m ore ofte n a disease of t he el derl y a n d i nfir m, ma n y patie nts ca n n ot be nefit fr o m 
m o der n cis plati n -base d c he m ot hera p y re gi me ns, a n d ot her treat me nt o pti o ns are nee de d f or t his 
lar ge p o p ulati o n of patie nts.
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.  Treat me nt f or bla d der ca ncer has e v ol ve d o ver ti me t o e nc o m pass n ot o nl y tra diti o nal 
c he m ot hera p y, b ut has bee n partic ularl y i m pacte d b y t he use of i m m u n ot hera p y [ Bell m u nt, J., et 
al 2 0 1 7] .  T he P D -1/ P D -L 1 i n hi bit ors s uc h as atez oliz u ma b, pe m br oliz u ma b, ni v ol u ma b a n d 
d ur val 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 st u dies i n patie nts wit h U C .  T hese i ncl u de st u dies as first - a n d 
sec o n d-li ne t hera py a n d as well as i n t he a dj u va nt setti n g. Atez oliz u ma b ni v ol u ma b, 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
d ur val u ma b, a n d a vel u ma b rece ntl y 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 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 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.
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 were n ot eli gi ble f or cis p lati n-c o ntai ni n g c he m ot hera p y, 
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.  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 E Y N O T E -0 4 5.  Patie nts were ra n d o mize d t o recei v e eit her 
pe m br oliz u ma b 2 0 0 m g e ver y 3 wee ks (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 [ Bell m u nt, J., et al 2 0 1 7] [ Ke ytr u da® U nite d States Pac ka ge I nsert 
[ U S PI], 2 0 1 7].
I m m u ne S ur veill a nce a n d Ne o pl astic Tr a nsf or m ati o n
3. 2. 1. 3
T he i m p orta nce of i ntact i m m u ne s ur veilla nce i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des [ 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 t he i m m u ne s yste m by e x pl oiti n g t he i m m u ne 
c hec k p oi nt pat h wa ys t hat d o w nre g ulate t he i m m u ne res p o ns e t o a v oi d healt h y tiss ue da ma ge 
[ Da vies, M. 2 0 1 4].  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 dity T cells 
t hat are s pecific f or t hese a nti ge ns [ B o on, 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 i nfla 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 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 vel y res p o n d i n a wa y t hat c o nsiste ntl y res ults i n rejecti o n.
T here 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 n ce of t he tr ypt o p ha n -cata b olizi 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 ypt o p ha n meta b olites; a n d i nfiltrati o n wit h F o x P 3 + re g ulat or y T cells ( T -re g), 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. 4
T he P D -1 rece pt or -li ga nd 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 din 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 C D 2 8 a n d c yt ot o xic T-l ym p h oc y te-ass ociate d a nti ge n -4 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
(C T L A- 4) , w hic h has bee n s h o w n t o ne gati vely re g ulate a nti ge n rece pt or si g nali n g u p o n 
e nga 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 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, 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 
[ Hira o ka, N. 2 0 1 0] [N o bili, C., et al 2 0 0 8] .  P D-1 has bee n s h o w n t o be e x presse d o n acti vate d 
l ym p h oc y tes i ncl u di n g peri p heral C D 4 + a n d C D 8 + T -cells, B-cells, T -re gs, a n d nat ural killer 
cells [ H o di, F. S. a n d Dra n off, G. 2 0 1 0] [ Kl o or, M. 2 0 0 9] .  E x pressi o n has als o bee n s h o w n 
d uri n g t h y 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 y pes, i ncl u d i n g 
n o n he mat o p oietic tiss ues as well as i n vari o us t u m ors [ Lee, H. E., et al 2 0 0 8] [ Leffers, N., et al 
2 0 0 9] [ Nis hi m ura, H., et al 2 0 0 0] [ N o bili, C., et al 2 0 0 8] . Bi n di n g of eit her P D -1 li g a 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 y m 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 u ncti 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 h y  or ga ns e x press little (if a ny) 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 partici pa 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.
Acti vit y of P D -1/ P D -L 1 I n hi bit ors i n Ur ot heli al C arci n o m a
3. 2. 1. 5
Se veral P D -1/ P D -L 1 c hec k p oi nt i n hi bit ors ha ve de m o nstrate d acti vit y  i n refract or y U C .  
Atez oliz u ma b ( T E C E N T RI Q ® ) is a n Fc-e n gi neere d, h u ma nize d, m A b t hat bi n ds t o P D -L 1  a n d 
bl oc ks i nteracti o ns wit h t he P D -1 a n d B 7. 1 rece pt ors ( T E C E N T RI Q ® U S PI, 2 0 1 6).  
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 i n Ma y 2 0 1 6 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, eit her 
f or metastatic disease or f or pr o gressi ve disease ( P D) less t ha n 1 2 m o nt hs after a dj u va nt or 
ne oa dj u va nt c he m ot hera p y . A n ur ot helial e x pa nsi o n c o h ort i n a P hase I st u d y  pr o vi de d i nitial 
e vi de nce of t he safet y a n d efficac y [ P o wles, T., et al 2 0 1 4].  S u bse q ue ntl y, I M vi g or 2 1 0, a n o pe n 
la bel P hase 2 st u d y e nr olle d 3 1 0 partici pa nt s wit h a d va nce d ur ot helial ca ncer w h o were 
pre vi o usl y  treate d wit h plati n u m-base d c he m ot hera p y .  Accelerate d a p pr o val was base d u p o n a n 
O R R of 1 4. 8 % ( 9 5 % co nfi de nce inter val [ C I] 1 1. 1, 1 9. 3) a n d pr ol o n ge d d urati o n of res p o nse 
( me dia n D OR n ot reac he d) [ R ose n ber g, J. E., et al 2 0 1 6].
Ni v ol u ma b ( M D X-1 1 0 6; O P DI V O) is a f ull y h u ma n I g G 4 mA b t hat bi n ds t o P D-1 a n d bl oc ks 
i nteracti o n wit h P D-L 1 a n d P D -L 2  a n d rest ores T-cell a ntit u m or f u ncti o n [ Bra h mer, J. R., et al 
2 0 1 0] . Ni v ol u ma b recei ve d accelerate d a p pr o val fr o m t he U S F D A i n Fe br uar y  2 0 1 7 f or t he 
treat me nt of partici pa nt s wit h l ocall y a d va nce d or metastatic U C w h o ha ve disease pr o gressi o n 
d uri n g or f oll o wi n g plati n u m -c o ntai ni n g c he m ot hera p y or ha ve disease pr o gressi o n wit hi n 1 2 
m o nt hs of ne oa dj u va nt or a dj u va nt treat me nt wit h a plati n u m -c o ntai ni n g c he m ot hera p y 
( O P DI V O® , 2 0 1 7).  I n a P hase 1/ 2 st u d y ( C hec k Mate 0 3 2); t he U C part of t he st u d y c o nsiste d of 
t w o treat me nt re gi me ns: ni v ol u ma b m o n ot hera p y a n d ni v ol u ma b i n c o m bi nati o n wit h 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
i pili m u ma b. T he st u d y p o p ulati o n is partici p a nts wit h a d va nce d ur ot helial ca ncer w h o ha ve 
pr o gresse d after ≥1 pri or li ne of plati n u m -base d c he m ot hera p y.  A t otal of 8 6 partici pa nt s wit h 
U C were e nr olle d a n d 7 8 partici pa nt s were treate d wit h ni v ol u ma b 3 m g/ k g as a m o n ot hera py.  
Wit h a mi ni m u m f oll o w u p of 9 m o nt hs, t he i n vesti gat or -assesse d O R R i n t he m o n ot hera p y 
gr o u p was 2 4. 4 % ( 9 5 % CI  1 5. 3-3 5. 4). Me dia n O S was 9. 7 m o nt hs ( 9 5 % CI  7. 3-1 6. 2) [ S har ma, 
P., et al 2 0 1 6] I n t he Ni v ol u ma b 1 m g/ k g + I pili m u ma b 3 m g/ k g gr o u p, t here were 1 0 4 
partici pa nt s treate d a n d me dia n O S was 1 0. 2 m o nt hs ( 9 5 % CI 4. 5-N R). I n t he Ni v ol u ma b 3 
m g/ k g + I pili m u ma b 1 m g/ k g gr o u p, t here were 2 6 partici pa nt s treate d a n d me dia n O S was 7. 3 
m o nt hs ( 9 5 % CI  5. 6-1 1. 4). 
Pe m br oliz u ma b is a h u ma nize d I g G 4 -ka p pa m A b t hat als o bi n ds t o P D- 1 a n d is a p pr o ve d f or 
m ulti ple i n dicati o ns . A d diti o nall y , pe m br oliz u ma b was gra nte d brea kt hr o u g h t hera p y 
desi g nati o n i n t he U S f or t he sec o n d li ne treat me nt of partici pa nt s 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. T his 
a p plicati o n is base d o n a p hase 3 st u d y ( K E Y N O T E-0 4 5) w here partici pa nts wit h a d va nce d U C
recei ve eit her pe m br oliz u ma b or i n vesti gat or’s c h oice of sec o n d-li ne c he m ot hera py f oll o wi n g 
pr o gressi o n o n a plati n u m -c o ntai ni n g re gi me n. T he res ults de m o nstrate a statisticall y si g nifica nt 
O S a d va nta ge of p e m br oliz u ma b o ver c he m ot hera p y a n d a l o wer rate of treat me nt -relate d 
a d verse e ve nts ( A Es) t ha n c he m ot hera p y [ Bell m u nt, J., et al 2 0 1 7] [ Baj ori n, D. F., et al 2 0 1 7] .
D ur val u ma b (IM FI N ZI ™) is a P D-L 1 c hec k p oi nt i n hi bit or t hat recei ve d accelerate d a p pr o val o n 
0 1 -M a y -2 0 1 7 f or t he treat me nt of patie nts wit h l ocall y  a d va nce d or metastatic U C w h o ha ve 
disease pr o gressi o n d uri n g or f oll o wi n g plati n u m -c o ntai ni n g c he m ot hera p y o r w h o ha ve disease 
pr o gressi o n wit hi n 1 2 m o nt hs of ne oa dj u va nt or a dj u va nt treat me nt wit h plati n u m -c o ntai ni n g 
c he m ot hera p y.  T hese st u dies i n dicate t hat i m m u n ot hera pies are acti ve a n d ma y offer i m pr o ve d 
efficac y o ver tra diti o nal c he m ot hera py i n a d va nce d U C . T hese data s u p p ort t he use of P D -1/ P D -
L 1 i n hi bit ors i n t his setti n g. H o we ver, t he maj orit y  of partici pa nt s d o n ot deri ve a be nefit as 
e vi de nce d b y t he relati vel y l o w res p o nse rates ( R R), a n d t here re mai ns a hi g h u n met me dical 
nee d f or m ore efficaci o us t hera pies. 
A vel u ma b ( B A V E N CI O ® ) ( is als o a P D-L 1 c hec k p oi nt i n hi bit or t hat recei ve d accelerate d 
a p pr o val o n 0 9 -M a y -2 0 1 7 f or patie nts wit h l ocall y  a d va nce d or metastatic U C w h ose disease 
pr o gresse d d uri n g or f oll o wi n g plati n u m -c o ntai ni n g c he m ot hera p y o r wit hi n 1 2 m o nt hs of 
ne oa dj u va nt or a dj u va nt plati n u m -c o ntai ni n g c he m ot hera p y.
I n hi biti o 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. 6
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 first 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 y pt o p ha n di o xy 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 nc e 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 variet y of tiss ues, wit h partic ularl y hi g h le vels f o u n d i n 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
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 me 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 cells a n d macr o p ha ges at l ocalize 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 ypt 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 u me 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-
regs [ 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 -re g 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], I DO 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.
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 ma ll 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 f r o m t he mater nal 
i m m u ne s yste 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 graft t oler a nce, 
i nfla m mati o n, a n d ca ncer [ Mell or, A. L. 2 0 0 4].  W hile ID O 1 i n hi biti o n ca n e xacer bate disease i n 
m o dels of a ut oi m m u ne dis or ders [ Mell or, A. L. 2 0 0 4], ID O 1 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 i n 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 y cl 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 ull y 
el uci date d, t he effects 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 vate 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] .  I DO 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 
de n dritic cells t hat l ocalize t o t he t u m or drai ni n g l ym p h n o des [ U ytte n h o ve, C., et al 2 0 0 3].  
I ncrease 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, pancreatic, a n d 
bla d der ca ncers [ 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] 
[ O ka m ot o, A., et al 2 0 0 5] [ Wit kie wicz, A., et al 2 0 0 8].  
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 her a 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. 7
Bl oc ka 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 nt s wit h a d va nce d mela n o ma [ H o di, F. S. a n d Dra n off, G. 2 0 1 0].  Ni v ol u ma b, a 
f ull y h u ma n I g G 4 a nti b o d y 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 nt s 
wit h mela n o ma, re nal cell ca ncer, a n d n o n -s mall cell l u n g ca ncer (N S C L C) [ Ha mi d, O., et al
2 0 1 3] [ 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. 2 0 1 2] a n d [ W olc h o k, J. D., 
et al 2 0 1 3] .  Alt h o u g h t hese si n gle a ge nts ha ve a ntit u m or acti vit y, m ulti ple i m m u ne i n hi bit or y 
mec ha nis ms are prese n t c o nc urre ntl y wit hi n t he 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 xa 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 hi 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]. T his was de m o nstrate d i n cli nical st u dies 
e val uati n g partici pa nt s wit h metastatic mela n o ma, a n d t he c o m bi nati o n of ni v ol u ma b a n d 
i pili m u ma b has si nce bee n a p pr o ve d by re g ulat or y a ut h orities f or mela n o ma, a n d t his 
c o m bi nati o n c o nti n ues t o be i n vesti gate d i n a n u m ber of a d diti o nal t u m or t y pes.
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 biti o n
3. 2. 1. 8
A s descri be d a b o ve, 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, I D O 1 i n hi biti o n has bee n s h o w n t o 
s yner gize 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 n g t um 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 ucti 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 here are se veral o n g oi n g cli nical st u dies wit h t he I D O 1 i n hi bit or e paca d ostat 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 -1, 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 (B I 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 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 S C LC, mela 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 ).  I n 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 t he P hase 2 p orti o n , a n d recei ve d ≥ 1 d ose of e paca d ostat a n d 
pe m br oliz u ma b . T he m ost c o m m o n ( ≥1 0 %) all -gra de treat me nt-relate d a d verse e ve nts (T R A Es )
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
were fati g ue, ras h, na usea a n d pr urit us [ Ha mi d, O., et al 2 0 1 7]. 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.
As of 2 7 -Fe b -2 0 1 7 , availa ble efficac y data f or partici pa nt s e nr olle d i n t he U 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 [ S mit h, D. C., et al 2 0 1 7].  T here were 4 0 e val ua ble 
partici pa nt s wit h a n O R R of 3 5 % (1 4 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 utoff all 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, partial r es p o nse ( P R ), or sta ble disease (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 o ne pri or treat me nt 
re gi me n.  T hese res ults c o m pare fa v ora bl y t o sec o n d-li ne t hera py wit h pe m br oliz u ma b
m o n ot hera p y i n t his setti n g, w hic h has a n O R R of 2 1. 1% [ Bell m u nt, J., et al 2 0 1 7].
Pre -cli nic al a n d Cli nic al St u dies
3. 2. 2
Refer t o t he I Bs 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 mab a n d e paca d ostat f or o n g oi n g cli nical st u dies 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 n d 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 
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
Be nefit /Ris ks f or 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 olid 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 ).  T he data s h o wi n g t he li mite d efficac y  i n s oli d 
t u m ors s u p p ort t hat a n e paca d ostat m o n ot hera py ar m is n ot warra nte d.
A p ote ntial c o ncer n of I D O 1 i n hi biti o n is a n i ncrease i n ser ot o ni n le vel s t hat c o ul d preci pitate a 
cl uster of A Es ter me d ser ot o ni n s yn dr o me ( S S) w he n a d mi nistere d al o ne or i n c o m bi nati o n wit h 
ot her ser ot o ner gic a ge nts. T his rare s y n dr o me has bee n ass ociate d wit h s o me m o n oa mi ne 
o xi dase i n hi bit ors ( M A OIs) a n d c o m bi nati o ns of se r ot o ner gic dr u gs [ 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 O i n hi bit ors 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 treated 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.  
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 partici pa nt s will be assesse d f or S S s y m pt o ms at a n a p pr o priate ti mefra me after d osi n g.  
Partici pa nt s 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.
A d diti o n al details re gar di n g s pecific be nefits a n d ris ks of e paca d ostat f or partici pa nts i n t his 
cli nical st u d y ma y be f o u n d i n t he acc o m pa nyi n g c urre nt I B a n d I C F.
B e nefit/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 ns as detaile d i n t he I B.
I n t he Phase 3 st u d y , K E Y N O T E-0 4 5, pe m br oliz u ma b vers us c he m ot hera p y , as sec o n d -li ne 
t hera py f or plati n u m -refract or y a d va nce d U C , was ass ociate d wit h si g nifica ntl y  l o n ger O S (1 0. 3 
m o nt hs vers us 7. 4 m o nt hs, res pecti vel y) a n d a l o wer rate of treat me nt -relate d A Es [ Bell m u nt, J., 
et al 2 0 1 7] [ Baj ori n, D. F., et al 2 0 1 7] .
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 -relate d A Es (ir A Es) 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 irA Es were mil d t o 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 p y.  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 irA 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] .  In 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 nts i n t his cli nical 
st u d y m a y  be f o u n d i n t he acc o m pa nyi n g c urre nt I B a n d I nf or me d C o nse nt F or m .
Be nefit /Ris ks f or t he C o m bi n ati o n of E p ac a d ost at a n d Pe m br oliz u m a b
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 vere, 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 .  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 w h o ha ve disease pr o gressi o n o n at least 1 li ne of 
t hera py 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, T C C 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, Diff use Lar ge B -Cell L y 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 m icr osatellite 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 t he P hase 2 p orti o n of I N C B 2 4 3 6 0 -2 0 2 
( K E Y N O T E-0 3 7) 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.  T he m ost fre q ue ntl y  re p orte d (≥ 1 0 %) treat me nt -relate d 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.  
Treat m e nt -relate d 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 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
treat me nt-relate d 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 um o nia.
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 safety pr ofile c o m para ble t o a nti-P D - 1 m o n ot hera p y,  this 
c o m bi nati o n re prese nts a rati o nale a n d pr o misi n g o pti o n i n partici pa nts wit h metastatic U C.
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 3, 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 or di n gl y.
I n male/fe male partici pa nts of at least 1 8 years 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 t hat has rec urre d or pr o gresse d f oll o wi n g o ne pri or li ne 
of plati n u m- c o ntai ni n g c he m ot hera p y f or a d va nce d/ metastatic disease:
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 safet y 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 3, 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 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 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 nefits).  
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, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p , m ulti-site, st u d y of 
pe m br oliz u ma b pl us e paca d ostat c o m pare d t o pe m br oliz u ma b pl us p lace b o, i n partici pa nts wit h 
c o nfir me d metastatic or l ocall y a d va nce d/ u nresecta ble U C (tra nsiti o nal cell or pre d o mi na ntly 
tra nsiti o nal cell hist ol o g y) of t he bla d der, re nal pel vis, ureter, or uret hra t hat has rec urre d or 
pr o gresse d f oll o wi n g o ne pri or li ne of plati n u m-c o ntai ni n g c he m ot hera p y f or 
a d va nce d/ metastatic disease .  N o a d diti o nal li nes of s yste mic treat me nt are all o we d.
A p pr o xi matel y  6 4 8 eli gi ble partici pa nt s were t o be ra n d o mize d i nt o t he st u d y b ut as of 
A me n d me nt 0 3, 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 8 5 
partici pa nts will be ra n d o mize d i n t his st u d y .
Partici pa nts will be ce ntrall y  ra n d o mize d i n a 1: 1 rati o t o recei ve eit her pe m br oliz u ma b 2 0 0 m g 
I V Q 3 W pl us e paca d ostat 1 0 0 m g BI D c o nti n u o us d osi n g or pe m br oliz u ma b 2 0 0 m g I V Q 3 W 
pl us matc hi n g e paca d ostat place b o.  Pri or t o r a n d o mizati o n , eli gi ble partici pa nts will be stratifie d 
b y  t he f oll o wi n g 2 stratificati o n fact ors: 1) Bell m u nt sc ore ( 0, vs 1 vs ≥2) a n d 2) P D -L 1 
e x pressi o n fr o m t u m or tiss ue sa m ples, base d o n C P S ≥1 0 vers us C P S < 1 0 per I H C , as assesse d 
b y  t he desi g nate d ce ntral la b orat or y. 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 PD- 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.  Partici pa nts wit h n o n -
e val ua ble t u m or tiss ue sa m ple will be e xcl u de d.
St u d y  treat me nt is defi ne d as pe m br oliz u ma b + e paca d ostat or pe m br oliz u ma b + matc hi n g 
e paca d ostat place b o, a n d will be gi ve n f or u p t o 3 5 c ycles or u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , or In vesti gat or decisi o n.  Partici pa nts w h o disc o nti n ue treat me nt will 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
disc o nti n ue fr o m t he st u d y after Safet y F oll o w -u p . I nvesti gat ors will assess t he i ma ges usi n g 
R E CI S T 1. 1 (see Secti o n 9. 2. 1. 5) t o deter mi ne eli gi bilit y  at scree ni n g as well as O R R after t he 
first o n -st u d y i ma gi n g at Wee k
9 . T u m or i ma gi n g will be site -assesse d f or P D a n d treat me nt 
disc o nti n uati o n.
S pecific pr oce d ures t o be perf or me d d uri n g t he tri al, 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.
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 co urse of t he st u d y , t he e xter nal Data 
M o n it 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 .
St u d y Di a gr a m
5. 1. 1
T he st u d y  desi g n is de picte d i n Fi g ure 1 .  
Fi g ure 1
St u d y  Desi g n
N O T E : As of A m e n d me nt 0 3, 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 mpletes t he Wee k 
9 
i ma 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 m i 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 P S = Easter n C o o perati ve O nc ol o g y Gr o u p; Perf or ma nce Stat us; I V = 
i ntra ve n o us; P O = orall y; Q 3 W = e ver y 3 wee ks
N u m ber of P artici p a nts
5. 2
Ori gi nall y, a p pr o xi matel y  6 4 8 partici pa nts were t o be ra n d o mize d i n t his st u d y b ut as of 
A me n d me nt 0 3, 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 t hat 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 8 5 
partici pa nts will be ra n d o mize d i n t his st u d y .  
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 st u d y 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 st u d y e n ds w he n t he last partici pa nt c o m pletes t he last st u d y -relate d p h o ne-call or visit, 
wit h dra ws fr o m t he st u d y or is l ost t o f oll o w -u p (i e, t he partici pa nt is u na ble t o be c o ntacte d by 
t he i n vesti gat or).
Cli nic al Criteri a f or E arl y St u d y Ter mi n ati o n
5. 3. 1
Earl y st u d y 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
T he g oal of ca ncer i m m u n ot hera p y is t o i nitiate or rei nitiate a self-s ustai ni n g c ycle of ca ncer 
i m m u nit y, e na bli n g it t o a m plif y a n d pr o pa gate.  Ca ncer i m m u n ot hera pies m ust o verc o me t he 
ne gati ve fee d bac k mec ha nis ms t hat are i n here nt i n m ost ca ncers t o e va de i m m u ne s ur veilla nce.  
Bla d der ca ncer was t he first i n dicati o n f or w hic h a n i m m u n ot hera p y was gra nte d a p pr o val b y t he 
F D A i n 1 9 9 0. B C G has bee n s h o w n t o be a n effecti ve a ge nt f or t he treat me nt of s u perficial 
bla d der ca ncer si nce its a p pr o val i n 1 9 9 0. A u g me ntati o n of B C G i m m u n o t hera py wit h 
i nterfer o n-α 2 b a n d ot her a ge nts ha ve e mer ge d si nce t he n f or partici pa nt s w h o fail i nitial 
treat me nt [ Kass o uf, W. 2 0 0 4] s u g gesti n g t hat bla d der ca ncer ma y be a t u m or t y pe res p o nsi ve t o 
i m m u 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 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 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 nt s wit h pr o gressi ve metastatic U C fr o m t he o n g oi n g P hase 2 st u d y (IN C B 
2 4 3 6 0 -2 0 2), 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 1 res p o n ders, t h us warra nti n g a f urt her caref ull y c o ntr olle d 
ra n d o mize d st u d y.  
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 were n ot eli gi ble f or cis plati n -c o ntai n i n g c he m ot hera py 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 nal ysis s h o we d a n O R R of 2 9 % ( 9 5 % CI: 2 4, 3 4), wit h a c o m plete 
res p o nse ( 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 7. 8 m o nt hs (Ke ytr u da ® U S PI, 2 0 1 7 ). 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 . T his 
ap pr o val is base d o n a p hase 3 S t u d y K E Y N O T E -0 4 5 w here partici pa nt s recei ve eit her 
pe m br oliz u ma b or i n vesti gat or’s c h oice sec o n d -li ne c he m ot hera p y f oll o wi n g pr o gressi o n o n a 
plati n u m -c o ntai ni n g re gi me n. 
I n K E Y N O T E -0 4 5 , 5 4 2 partici pa nts ( pe m br oliz u ma b, n = 2 7 0; c he m ot hera p y, n = 2 7 2) were 
e nr olle d a s of t he 1 8 -Ja n-2 0 1 7 data c ut -off f or a pla n ne d s ur vi val a nal ys is.  The me dia n f oll o w -
u p was 1 8. 5 m o nt hs (ra n ge, 1 4. 2-2 6. 5) [ Baj ori n, D. F., et al 2 0 1 7]. T he m e dia n O S was 
si g nifica ntly l o n ger wit h pe m br o liz u ma b vs c he m o t hera py ( 1 0. 3 vs 7. 4 m o nt hs ; H R, 0. 7 0; P < 
0. 0 0 1), a n d si g nifica nce was mai ntai ne d re gar dless of P D -L 1  e x pressi o n as meas ure d by 
c o m bi ne d p ositi ve sc ore ([ C P S]; H azar d R ati o [ H R]: C P S < 1, 0. 8 4; C P S ≥1, 0. 5 9; C P S < 1 0, 
0. 7 6; C P S ≥1 0 , 0. 5 7). O S be nefit wit h pe m br o liz u ma b vs c he m o t hera p y was see n re gar dless of 
a ge, E C O G P S, pri or t hera p y, li ver metastases, hist ol o g y, a n d c h oice of c he m o. T he 1 8- m o nt h
O S rate ( 9 5 % CI) was 3 6. 1 % ( 3 0. 1 % -4 2. 0 %) wit h pe m br o liz u ma b vs 2 0. 5 % ( 1 5. 2 % -2 5. 8 %) 
wit h c he m o t hera p y ( Ka pla n - Meier esti mate). P F S was n ot differe nt bet wee n ar ms. O R R was 
hi g her wit h pe m br o liz u ma b v c he m o ( 2 1. 1 % v s 1 1. 0 %), a n d me dia n (ra n ge) D O R was l o n ger 
( n ot reac he d [ 1. 6 + t o 2 0. 7 + m o nt h] vs 4. 4 m o nt hs [ 1. 4 + t o 2 0. 3]). Re s p o nses laste d ≥1 2 m o nt hs
i n 6 9 % of partici pa nts treate d wit h pe m br oliz u ma b vs 3 6 % i n partici pa nts treate d wit h 
c he m ot hera p y . Fe wer partici pa nts e x perie nce d a treat me nt -relate d A E wit h pe m br oliz u ma b vs
c he m o t hera py treat me nt (a ny G ra de, 6 1. 3 % vs 9 0. 2 %; G ra de ≥3, 1 6. 5 % v s 4 9. 8 %).
I n 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 uati n g t he efficac y a n d safety 
of pe m br oliz u ma b ( 2 0 0 m g Q 3 W) i n first -li ne cis plati n-i neli gi ble partici pa nts wit h u nresecta ble 
or metastatic U C, 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.  
I n data prese nte d at A S C O 2 0 1 7, as of a 0 9-Mar -2 0 1 7 data c ut off, s u bjects wit h P D -L 1  C P S ≥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 t ha n partici pa nts
wit h C P S < 1 0 ( O R R of 2 3 % i n C P S < 1 0 s u bjects a n d 5 1 % i n s u bjects wit h C P S ≥1 0) 
[ O' D o n nell, P. H., et al 2 0 1 7].  M ore o ver, c o m plete res p o nses were see n i n 3 % of C P S < 1 0 
s u bjects a n d 1 8 % of t h ose wit h C P S ≥1 0.
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 pl us place b o i n partici pa nt s wit h a d va nce d/ metastatic U C w h o ha ve ha d 
pr o gressi o n or rec urre nce f oll o wi n g a plati n u m -c o ntai ni n g c he m ot hera p y re gi me n.  O S, a n d P F S 
will be t he o bjecti ve e n d p oi nts. T here is a n u n met nee d i n t his setti n g, si nce c urre nt 
c he m ot hera p y re gi me ns are t o xic a n d pr o vi de li mite d be nefit. 
W hile t he c urre nt m o n ot hera py 
P D -1 t hera pies ha ve s h o w n pr o misi n g acti vit y , t he y ha ve li mite d be nefit gi ve n t hat t he R R is l o w 
a n d o nl y a s mall pr o p orti o n of partici pa nt s deri ve l o n g ter m be nefit. 
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: As of A me n d me nt 0 3, 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. After i m a gi n g at Wee k 9, a ll 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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 .  I ma ges will be rea d by I n vesti gat ors
bli n de d t o treat me nt assi g n me nt t o mi ni mize bias i n t he res p o nse assess me nts.  T he fi nal 
deter mi nati o n of ra di ol o gic pr o gressi o n will be base d o n t he l ocal site In vesti gat or/ra di ol o g y  
assess me nt .  
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 nvesti gat or w he n assessi n g i ma ges f or pri mar y  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 (Secti o n 9. 1. 2. 5) . Alt h o u g h 
tra diti o nal R E CIS T 1. 1 re fere 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 m o dificati 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 .
Refer t o Secti o n 9. 2. 1. 5 f or details o n R E CI S T 1. 1 .
M o difie d R E CI S T 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 3, 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 r es 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 (Secti o n 9. 2. 1. 6) . 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 by 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 wi t h s uc h a n a p pr oac h ma y e xte n d be yo n d t he 
t ypical ti me c o urse of res p o nses see n wit h c y t 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 lesio 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 pical res p o nses i n i m m u n ot hera p y 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 pe a 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 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
i ma gi n g ma y be perf or me d t o c o nfir m ra di o gra p hic pr o gressi o n. i R E CIS T will be use d b y  
In 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 d ecisi o ns.
Refer t o Secti o n 9. 2. 1. 6 f or details o n i R E CI S 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 us alit 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 Es will be assesse d as defi ne d b y Nati o nal Ca ncer I nstit ute ( N CI ) C T C A E, Versi o n 4. 0.
R ati o n ale f or 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 3, 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.
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 ur o Q ol-5 D ( E Q -5 D) 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 L Q -C 3 0. T hese P R O assess me nts are n ot p ure efficac y  or safet y e n d p oi nts beca use t he y are 
affecte d b y b ot h disease pr o gressi o n a n d treat me nt t olera bilit y.
E O R T C Q L Q - C 3 0
5. 4. 1. 3. 1
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 s y m pt o m ite ms (fati g ue, na us ea/ v o miti n g, a n d pai n), 6 si n gle ite ms ( dys 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 ualit y  of life 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.  M ea n c ha n ge fr o m baseli ne i n gl o bal healt h stat us / q ualit y of life scale of t he E O R T C 
Q L Q -C 3 0 will be e val uate d as a tertiar y o bjecti ve.
E ur o Q ol -5 D -5 L ( E Q -5 D -5 L)
5. 4. 1. 3. 2
T he electr o nic E Q -5 D -5 L (e E Q-5 D -5 L ) is a sta n dar dize d i nstr u me nt f or use as a meas ure of 
healt h o utc o me a n d will pr o vi de data t o de vel o p healt h utilities f or use i n healt h ec o n o mic 
a nal ys 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 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 ncer st u dies a n d p u blis he d res ults fr o m t hese st u dies s u p p ort its vali dit y 
a n d relia bilit y [ Pic kar d, A. S., et al 2 0 0 7].
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
R ati o n ale f or the Use of C o m p ar at or/ Pl ace b o
5. 4. 2
I n a p hase 3 trial ( K E Y N O T E -0 4 5) w here partici pa nt s recei ve eit her pe m br oliz u ma b or 
i n vesti gat or’s c h oice sec o n d-li ne c he m ot hera py f oll o wi n g pr o gressi o n o n a plati n u m -c o ntai ni n g 
re gi me n, t here was a statisticall y si g nifica nt O S a d va nta ge of pe m br oliz u ma b o ver c he m ot hera p y 
( 1 0. 3 vs 7. 4 m o nt hs; H R, 0. 7 0; P < 0. 0 0 1) i n 5 4 2 partici pa nts ( pe m br oliz u ma b, n = 2 7 0; 
c he m ot hera p y, n = 2 7 2) e nr olle d as of t he 1 8 -Ja n-2 0 1 7 data c ut -off f or a pla n ne d s ur vi val a nal ys is
[ Baj ori n, D. F., et al 2 0 1 7].  T he 1 8-m o nt h O S rate ( 9 5 % CI) was 3 6. 1 % ( 3 0. 1 % -4 2. 0 %) wit h 
pe m br oliz u ma b vs 2 0. 5 % ( 1 5. 2 % -2 5. 8 %) wit h c he m ot hera p y  ( K M esti mate).  P F S was n ot 
differe nt bet wee n ar ms.  O R R was hi g her wit h pe m br o liz u ma b vs c he m o t hera py ( 2 1. 1 % vs
1 1. 0 %), a n d me dia n (ra n ge) D O R was l o n ger ( n ot reac he d [ 1. 6 + t o 2 0. 7 + m o nt h] vs 4. 4 m o nt hs 
[ 1. 4 + t o 2 0. 3]). Res p o nses laste d ≥1 2 m o nt hs i n 6 9 % of partici pa nts treate d wit h 
pe m br oliz u ma b vs 3 6 % i n partici pa nts treate d wit h c he m ot hera p y.  Fe wer partici pa nts 
e x perie nce d a treat me nt -relate d A E wit h pe m br oliz u ma b vs che m ot hera p y treat me nt (a ny gra de, 
6 1. 3 % vs 9 0. 2 %; G ra de ≥3, 1 6. 5 % vs 4 9. 8 %). 
I n t his st u dy, pe m br oliz u ma b pl us e paca d ostat will be c o m pare d t o pe m br oliz u ma b pl us place b o.  
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 3, 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 heir Wee k 9
i m a gi n g assess me nt.  
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 otality of data 
ge nerate d i n t he Ke y tr u da® de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he a p 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
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial

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 
( K N 0 0 1 B 2, K N 0 0 1 D, K N 0 0 2, K N 0 1 0 a n d K N 0 2 1), a n d 3 st u dies c o m pare d 1 0 m g/ k g Q 3 W vs 
1 0 m g/ k g Q 2 W ( K N 0 0 1 B 3, K N 0 0 1 F 2 a n d K N 0 0 6). All of t hese st u dies de m o nstrate d flat 
d ose - a n d e x p os ure -res p o nse relati o ns hi ps acr oss t he d oses st u die d re prese nti n g a n a p pr o xi mate 
5 t o 7. 5 f ol d differe nce i n e x p os ure. T he 2 m g/ k g ( or 2 0 0 m g fi xe d -d ose) Q 3 W pr o vi de d si milar 
res p o nses t o t he hi g hest d oses st u die d. S u bse q ue ntl y, flat d ose-/e x p os ure-res p o nse relati o ns hi ps 
were als o o bser ve d i n ot her t u m or t y pes i ncl u di n g h ea 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 hese fi n di n gs are c o nsiste nt wit h t he mec ha nis m of acti o n of 
pe m br oliz u ma b, w hic h acts b y  i nteracti o n wit h i m m u ne cells, a n d n ot via direct bi n di n g t o 
ca ncer cells.
A d diti o nall y , p har mac ol o g y data 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 N 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 y ste 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 sat urati o n o ver a wi de 
ra n ge of t u m or pe netrati o n a n d P D-1 e x pressi o n. T his e val uati o n c o ncl u de d t hat pe m br oliz u ma b 
at 2 0 0 m g Q 3 W ac hie ves f ull P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.
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 n ta 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 dy 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 ma b, a r o b ust 
o bjecti ve res p o nse rate ( O R R), d ura ble D C R s, as well as pr o vi di n g o pti mal tar get i n hi biti o n of 
I DO 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 
ha ve bee n well t olerate d.
D oses of 2 5 m g BI D t o 3 0 0 m g BI D of e paca d ostat 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 a n d 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 
 
 
0 4 Y C 7 6




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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
a.
If partici pa nt s ha ve o nly 1 meas ura ble lesi o n per R E CI S T 1. 1, a n y bi o ps y s peci me n 
s h o ul d be o btai ne d fr o m t he n o n-tar get lesi o n or arc hi val tiss ue.
b.
If partici pa nt s ha ve o nly 1 meas ura ble lesi o n per R E CI S T 1. 1, t his lesi o n s h o ul d n ot 
ha ve bee n i n t he fiel d of pri or irra diati o n u nless t here is d oc u me nte d pr o gressi o n of 
t he lesi o n(s).
4.
Ha ve pr o vi de d a n arc hi val t u m or 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 f or P D-L 1 a nal y sis.  A ne wl y o btai ne d 
bi o ps y  is str o n gly 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 hly 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 res ol uti o n of all t o xicities a n d a n y t o xic ef fect(s) of t he m ost rece nt pri or t hera py t o 
Gra de 1 or less (e xce pt al o pecia). Partici pa nt s wit h ≤Gra de 2 ne ur o pat h y are a n e xce pti o n 
a n d ma y e nr oll.
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.
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us of 0- 1 wit hi n 1 4 da y s 
pri or t o ra n d o mizati o n .
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 2 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:

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 2 ), 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 plie s: 
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 2
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 2 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 (c orres p o n di n g t o ti me nee de d t o 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.
I nf or me d C o nse nt
9.
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 0. Ha ve a de q uate o r ga n f u ncti o n as defi ne d in t he f oll o wi n g ta ble ( Ta ble 1 ).  S peci me ns 
m us t be c ollecte d wit hi n 1 4 da y s pri or t o ra n d o mizati o n.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 mat ol o gical
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 nal
Creati ni ne O R
Meas ure d or calc ulate d
b creati ni ne cleara nce
( G F R ca n als o be use d i n place of creati ni ne or 
Cr Cl)
≤1. 5 × U L N O R
≥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 L N
He patic
T otal bilir u bi n
≤1. 5 × U L N O R direct bilir u bi n ≤U L N f or 
partici pa nts wit h t otal bilir u bi n le vels 
> 1. 5 × U L N .  
If t here is n o i nstit uti o nal U L N , t hen direct 
bilir u bi n s h o ul d be < 4 0 % of t he t otal bilir u bi n.  
I n n o case ca n t otal bilir u bi n e xcee d 3. 0 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 oa g ulati 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.
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 ur ot helial carci n o ma t hat is s uita ble f or l ocal t hera p y wit h c urati ve i nte nt.
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
2.
Has prese nce of a gastr oi ntesti nal c o n diti o n t hat i n t he o pi ni o n of t he I n vesti gat or m a y  
affect dr u g a bs or pti o n.
3.
Has cli nicall y si g nifica nt car diac disease, i ncl u di n g u nsta ble a n gi na, ac ute m y ocar dial 
i nfarcti o n wit hi n 6 m o nt hs fr o m Da y 1 of st u d y dr u g a d mi nistrati o n, or Ne w Y or k Heart 
Ass ociati o n Class III or I V c o n gesti ve heart fail ure.  Me dicall y c o ntr olle d arr h yt h mia
sta ble o n me dicati o n is per mitte d.
4.
Has a hist or y  or prese nce 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 msec is e xcl u de d (c orrecte d by Fr ideric ia f or m ula or Bazett f or m ula ).  I n 
t he 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.
5.
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 st u d y, i nterfere wit h t he partici pa nt's partici pati o n 
f or t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he pa rtici 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.
6.
Has a dia g n osis of i m m u n o deficie nc y  or is recei vi n g c hr o nic 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.
7.
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 y ears.  

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 
earl y 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 ge n ( 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 y ear pri or t o st u d y all ocati o n.
8.
Has k n o w n acti ve ce ntral ner v o us s ys t em ( C N S ) metastases a n d/ or carci n o mat o us 
me ni n gitis.  Partici 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 pea t i ma gi n g s h o ul d be perf or me d d uri n g t he st u d y 
scree ni n g), cli nically 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.
9.
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.
1 0. 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.
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
1 1. Has k n o w n hist or y  of or is p ositi ve f or acti ve He patitis B ( 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 partici pa nt s will 
be e xcl u de d.  

Partici pa nts 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 Scree ni n g V isit.
1 2. Has a hist or y  of ( n o n-i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
1 3. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
1 4. 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.  HI V testi n g is 
n ot re q uire d u nless ma n date d by l ocal healt h a ut h orit y.
1 5. Has k n o w n ps yc hiatric or s u bsta nce a b us e 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 6. 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 2).  If t he uri ne test is p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m 
pre g na nc y  test will be re q uire d.

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 d y treat me nt, a n ot her pre g na nc y  test ( uri ne or ser u m) m ust be 
perf or me d a n d m ust be ne gati ve i n or der f or s u bject t o start recei vi n g st u d y treat me nt .  
Pri or/ C o nc o mit a nt T her a p y
1 7. Has recei ve d pri or t hera p y wit h a n a nti -P D -1, a nti -P D -L 1, a nti P D -L 2 a ge nt, I D 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 rece pt 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 8. Has recei ve d pri or s ys te 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 fro 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 o m t he i nter ve ntio n pri or t o starti n g st u d y
treat me nt.
1 9. Has recei ve d pri or ra di ot hera p y wit hi n 2 wee ks of ra n d o mizati o n.  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 (t o Gra de ≤1) , 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 py)  t o n o n-C N S disease.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
2 0. 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 st u d y treat me nt.  
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 be lla, varicella/z oster (c hic ke n p o x), yell o w fe ver, ra bies, B C G, a n d t y p h oi d 
vacci ne.  Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d vir us vacci nes a n d 
are all o we d; h o we ver, i ntra nasal i nfl ue nza vacci nes are li ve atte n uate d vacci nes a n d are
n ot all o we d.
2 1. 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. 2.
2 2. Has a n y hist or y  of SS after recei vi n g ser ot o ner gic dr u gs.
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 st u d y of a n i n vesti gati o nal a ge nt or 
has use d a n i n vesti gati o nal de vice wit hi n 4 wee ks pri or t o t he first d ose of st u d y
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 st u d y m a y  
partici pate as l o n g as it has bee n 4 wee ks after t he last d ose of t he pre vi o us 
i n vesti gati o nal a ge nt.
Ot her E xcl usi o ns
2 4. 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 st u d y, starti n g wit h t he scree ni n g visit t hr o u g h 1 2 0 da ys after 
t he last d ose of st u d y treat me 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 b r 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 nts s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks t o 
t he fet us ( u n b or n ba 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 nts 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 nts 
fr o m t he da y of st u dy me dicati o n i nitiati o n ( or 1 4 da ys 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 dy peri o d u p t o 1 2 0 da ys after t he last d ose of st u d y 
me dicati o n. If t here is a n y questi o n t hat a partici pa nt of c hil d beari n g p ote ntial will n ot relia bl y  
c o m pl y wit h t he re q uire me nts f or c o ntrace pti o n, t hat partici pa nt s h o ul d n ot be e ntere d i nt o t he 
st u d y. 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 p e n di x 2.
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 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 parti ci 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 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 S A E (e g, deat h, a b orti o n, c o n ge nital a n o maly, 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 nts 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 data 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 nt w h o disc o nti n ues f r 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.
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 re 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 nt(s) t o be use d i n t his trial are o utli ne d bel o w i n Ta ble 2 .
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Ta ble 2
St u d y  Treat me nt(s)
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 
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 
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 miti gate i m m u ne -
relate d A Es (ir A Es), if i n dicate d i n Ta ble 3 .
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 s u p plies i n dicate d i n Ta ble 2 will be pr o vi de d per t he ‘ S o urci n g’ c ol u m n de pe n di n g u p o n 
l ocal c o u ntr y o perati o nal re q uire me nts.  E ver 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 secti 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 3, 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.
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
f or I m m u ne-rel ate d A Es
7. 2. 1
D ose m o dificati o n a n d t o xicit y  ma na ge me nt f or i m m u ne-relate d A Es ass ociate d wit h 
pe m br oliz u ma b a n d 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 ( b ot h n o n-seri o us a n d seri o us) ass ociate d wit h pe m br oli z u ma b 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 ma y occ ur s h ortl y after t he first d ose or se veral m o nt hs after 
t he last d ose of pe m br oliz u ma b treat me nt a n d ma y affect m ore t ha n o n b o d y sys te m 
si m ulta ne o usl y.  T heref ore, early 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 pe m br oliz u ma b -ass ociate d ir A Es were 
re versi ble a n d c o ul d be ma na ge d wit h i nterr u pti o ns of pe m br oliz u ma b, a d mi nistrati o n of 
c ortic oster oi ds a n d/ or ot her s u p p orti ve care.  F or s us pecte d ir A Es, e ns ure a de q uate e val uati o n t o 
c o nfir m eti ol o g y or e xcl u de ot her ca uses.  A d diti o nal pr oce d ures or tests s uc h as br o nc h osc o py, 
e n d osc o p y, s ki n bi o ps y ma y be i ncl u de d as part of t he e val uati o n. 
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. 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
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 is res u me d. Partici pa nts are all o we d, h o we ver, t o recei ve 
pe m br o liz 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 p y 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 dicati o n h ol d.
 
 
0 4 Y C 7 6


















Pr o d uct:   M K -3 4 7 5 /IN C B 0 2 4 3 6 0 
7 4
Pr ot oc ol/ A me n d me nt N o.: 6 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial

If a partici pa n t 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 
i n 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 pt o ms of Ser ot o ni n S y n 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
o 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
o 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]
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
Pe m br oliz u m a b
Pe m br oliz u ma b ma y  ca use se vere or life t hreate ni n g i nf usi o n-reacti o ns i ncl u di n g se vere 
h y perse nsiti vit y  or a na p h yla xis.  Si g ns a n d sy m pt o ms us uall y  de vel o p duri 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 
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5 /IN C B 0 2 4 3 6 0 
7 5
Pr ot oc ol/ A me n d me nt N o.: 6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
m o dificati o n a n d t o xicit y  ma na ge me nt g ui deli nes o n pe m br oliz u ma b ass ociate d i nf usi o n reacti o n 
are pr o vi de d i n Ta ble 6 .
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 dicate d 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 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 pe 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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3-0 3) Fi nal Pr ot oc ol
1 2- 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 (ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms 
f oll o wi n g i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or 
ot her cli nical se q uelae (e. g., 
re nal i m pair me nt, p ul m o nar y 
i nfiltrates)
Gra de 4:
Life -t hreate nin g; press or or 
ve ntilat or y s u p p ort i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de b ut is 
n ot li mite d t o:
E pi ne p hri ne * *
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d 
u ntil t he 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 tre at me nt.
N o s u bse q ue nt d osi n g
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y 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
A b bre viati o ns: 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; I V = i ntra ve n o us; N CI = Nati o nal Ca ncer I nstit ute; N S A I Ds = n o nster oi dal a nti-i nfla m mat or y 
dr u gs; P O = oral.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
I nterr u pti o ns 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 vents, partici pa nt vacati o n, or h oli da y s). Partici pa nt s s h o ul d be 
place d bac k o n st u d y  t hera p y wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless ot her wise 
disc usse d wit h 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 partici 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 3, 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; 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 ycles (a p pr o xi matel y 1 year) of 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 stu d y 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 st u d y a n d 
is o nl y a vaila ble if t he st u d y re mai ns o pe n a n d t he partici pa nt meets t he f oll o wi n g c o n diti o ns:
Eit her

St o p pe d i nitial treat me nt wit h st u dy 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 ycles of st u d y 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 y o n d t he date w he n t he i nitial 
C R was declare d
O R

Ha d S D, P R, or C R a n d st o p pe d st u d y treat me nt after c o m pleti o n of 3 5 c ycles 
(a p pr o xi matel y 2 years) of st u d y 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  I n 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 st u d y 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 st u d y is o n g oi n g.
Partici pa nts w h o e nter t he Sec o n d C o urse P hase will be retreate 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 oli z 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 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 bjecti ve res p o nse or disease pr o gressi o n t hat occ urs d uri n g t he Sec o n d C o urse P hase f or a 
partici pa nt will n ot be c o u nte d as a n e ve nt f or t he pri mar y a nal ys is i n 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 + 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.
Bell m u nt ris k sc ore of 0 vs 1 vs ≥2.
T he Bell m u nt ris k sc ore f or eac h partici pa nt is calc ulate d b y t he prese nce of t he t otal n u m ber 
of t he f oll o wi n g ris k fact ors (eac h c o u nts a sc ore of 1) at baseli ne: 

E C O G P S ≥ 1

Prese nce of li ver metastases 

He m o gl o bi n le vel < 1 0 g/ d L

Ti me fr o m last c he m ot hera p y d ose ( < 3 m o nt hs [ N ote: 9 0 da ys will be use d] fr o m 
ra n d o mizati o n)
2.
P D -L 1  e x pressi o n fr o m t u m or tiss ue sa m ples, base d o n C P S ≥1 0 vs C P S < 1 0 per I H C assa y , 
as assesse d b y t he desi g nate d ce ntral la b orat or y
Bli n di n g 
7. 4
T he st u d y is d o u ble -bli n de d usi n g e paca d ostat a n d matc hi n g place b o, s uc h t hat t he partici pa nt, 
t he st u d y site pers o n nel, a n d t he S p o ns or a n d M S D or desi g nee d o n ot k n o w t he i de ntit y of t he 
treat me nt ar m. 
N ote: As of A me n d me nt 0 3, 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 ma gi n g assess me nt f or effic ac y a n al ysis.  After u n bli n di n g, for 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 c o nti n ue st u d y tre at me nt after 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 treat me nt ar ms, will n ot be 
bli n de d.
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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 blets 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 ministrati 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 ne e 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 stu 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 ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce wit h t he 
la bele d st ora ge c o n 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 nta 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 p riate.  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 ocall y 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.
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 ultat i 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 pe m br oli z u ma b will be wit nesse d b y t he i n vesti gat or a n d/ or trial staff.  T he 
t otal v ol u me of trial me dicati o n i nf use d will be c o m pare d wit h t he t otal v ol u me pre pare d t o 
deter mi ne c o m plia nce wit h eac h d ose a d mi nistere d.  
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Pe m br oliz u ma b will be a d mi nistere d o n a n o ut -patie nt basis.  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 sh 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 site 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 visits i n or der 
f or site pers o n nel t o c o n d uct ta blet c o u nts t o assess st u d y treat me nt acc o u nta bilit y. In vesti gat ors 
a n d t heir staff s h o ul d e val u ate 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, 
he r 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 dy 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 ym 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 ra 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 ysicia n as l o n g as t he lesi o ns are N O T a R E CIS 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 hera py 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 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 CI s 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 py, all c o nc o mita nt me dicati o ns recei ve d wit hi n 3 0 da y s 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 nica l Direct or.  T he 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
fi nal decisi o n o n a ny 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.
If a st u dy partici pa nt m ust recei ve 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 
d uri n g t he st u d y treat me nt peri o d, treat me nt wit h e paca d ostat ( or place b o) m ust be i nterr u pte d or 
disc o nti n ue d.  E xa m ples o f 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 ma 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 b ite 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. I n vesti 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 n y  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 py 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 CI or f or use as a pre-me dicati o n f or 
c he m ot hera p y 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 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 S O C (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.
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 n f 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 y m 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 dy 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 p y or s ur ger y), t he 
partic ipa 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 oll o wi 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 nes a n d ar e 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 ys 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. 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial

I ncl u di n g, b ut n o t 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 psidi ne, met h y le ne bl ue, f uraz oli d o n, tra n yl c ypr 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 y li ne, 
rasa gili ne, selegili 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, difl 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 yl 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.
N ote: Ket oc o naz ole 2 % t o pical crea m is all o we d.
P artici 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 m a y  be 
a d mi nistere d at t he discreti o n of t he I n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care.  All c o nc o mita nt me dicati o n will be rec or de d o n t he electr o nic case re p ort f or m 
(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 y s after t he 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 ys 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 ve nts of cli nical i nterest ( E CIs) as defi ne d i n Secti o n 9. 3. 7
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-base 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; h o we ver, ot her hi g her d oses are disc o ura ge d.  If a n alter na ti 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 nter nati o nal n or malize d rati o (I N R) s h o ul d 
be m o nit ore d cl osel y ( wee kl y f or t he first 4 wee ks after i nitiati o n of t hera py 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 a n d S u p p orti ve C are
7. 7. 4
Partici pa nts s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of A Es 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 u i 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 sy m pt o ms d o n ot i m pr o ve 
wit h a d mi nistrati o n of c ortic oster oi ds.  N ote t hat se veral c o urses of ster oi d ta peri n g ma y be 
necessar y  as sy m pt o ms ma y  w orse n w he n t he ster oi d d ose is decrease d.  F or eac h dis or der, 
atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastatic disease or bacterial or viral 
i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care.  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 nvesti gat or deter mi nes t he e ve nts t o be relate d t o pe m br oliz u ma b. 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 gar di n g d ose m o dificati o n a n d s u p p orti ve care. 
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o py, or s ki n 
p h ot o gra p h y as part of e val uati o n of t he e ve nt.
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 ac ti o n be warra nte d.
St a n d ar d P olicies
7. 1 0
At t he cl ose of t he trial 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 place 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 par tici pate d i n a trial c o n d ucte d b y t he S p o ns or. T his is t o a d vise y o 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 o d 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 - S o 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 or e 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 n y u nt o war d effect occ ur.  I n 
a d diti o n, a partici pa nt ma y be disc o nti n ue d fr o m st u d y  treat me nt b y t he 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 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 d e 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 
In 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 nfir me d p ositi ve ser u m pre g na nc y  test.
o
Partici pa nt c h o oses t o disc o nti n ue st u d y treat me nt a n d re mai ns i n t he st u d y t o be f oll o we d 
f or pr o gressi o n a n d s ur vi val.
o
Partici pa nt has recei ve d 3 5 c ycles (a p pr o xi matel y 2 years) of treat me nt wit h pe m br oliz u ma b.
o
T he st u d y  is ter mi nate d b y t he s p o ns or.
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 ble a d verse e x perie nces n ot ca use d b y a n u n derl y in g mali g na nc y
as descri be d i n Secti o n 7. 2. 1.
o
Persiste 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 .
A partici pa nt m a y be disc o nti n ue d fr o m st u d y  treat me nt as f oll o ws:
If, d uri n g t he c o urse of t 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 
trial, all visits a n d pr oce d ures, as o utli ne d i n t he S o A , s h o ul d be c o m plete d.
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 ma y 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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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.
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 the 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 3, 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 ort s 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:
o
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit.  If t he 
partici pa nt is c o ntacte d, t he partici pa nt s h o ul d be c o u nsele d o n t he i m p orta nce of 
mai ntai ni n g t he pr ot oc ol -s pecifie d visit sc he d ule.
o
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 re c or d.
o
N ote:  A partici pa nt is n ot c o nsi dere d l ost t o f oll o w -u p u ntil t he last sc he d ule d visit f or 
t he i 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.
●
T he I n vesti gat or is res p o nsi ble f or ass uri n g t hat pr oce d ures are c o n d ucte d b y 
a p pr o priatel y q ualifie d or trai ne d staff.  Dele gati o n of trial site pers o n nel res p o nsi bilities 
will be d oc u me nte d i n t he I n vesti gat or Trial File Bi n der ( or e q ui vale nt).
●
All scree ni n g e val uati o ns m ust be c o m p lete 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 pplica 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 nd were perf or me d 
wit hi n t he ti me fra me defi ne d i n t he S o A.
●
A d diti o nal e val uati o ns/testi n g ma y  be dee me d necessar y by t he i n vesti gat or a n d/ or M S D
f or reas o ns relate d t o partici pa nt safety. I n s o me cases, s uc h e val uati o n/testi n g ma y be 
p ote ntiall y  se nsiti ve i n nat ure (e g, HI V, He patitis C, etc.), a n d t h us l ocal re g ulati o ns ma y 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
re q uire t hat a d diti o nal i nf or me d c o nse nt be o btai ne d fr o m t he partici pa nt .  I n t hese cases, 
s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce wit h t h ose re g ulati o ns.
A d mi nistr a ti ve a n d Ge ner al Pr oce d ures
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 ni o 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 he c o m m u nicati o n of t his i nf or mati o n will be pr o vi de d a n d 
d oc u me nte d via a re vise d c o nse nt f or m or a d de n d u m t o t he ori gi nal c o nse nt f or m t hat ca pt ures 
t he partici pa nt’s date d si g nat ure or by t he partici pa nt’s le gall y acce pta ble re prese ntati ve’s date d 
si g nat ure.
S pecifics a b o ut a trial a n d t he trial p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate at t he 
pr ot oc ol le vel.  
T he i nf or me d c o nse nt will a d here t o I 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 usio 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 y i n g t he m as partici pa nts i n 
a researc h st u d y. T he car d will c o ntai n 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 partic i 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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.
Ser 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 als o be gi ve n a 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 are 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 n y c o n diti o n dia g n ose d wit hi n t he pri or 1 0 years t hat t he 
I n vesti gat or c o nsi ders t o be cli nicall y si g nifica nt. Detai ls 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 parately 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 by t he partici pa nt wit hi n 2 8 
da y s bef ore 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 partici pa nt has 
e nr olle d i n t his st u d y will be rec or de d se paratel y a n d n ot liste d as a pri or me dicati o n .
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 t hr o u g h t he Safety F oll o w -u p visit.  I n a d diti o n, ne w me dicati o ns starte d d uri n g 
t he Sec o n d C o 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 o mizati 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.  
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 b e 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 ne d t o a partici pa nt, it ca n ne ver be re-assi g ne d t o a n ot her partici pa nt.
 
 
0 4 Y C 7 6




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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial

T o st ore t he st u d y  treat me nt at r o o m te m perature a n d ti g htl y cl ose d t o a v oi d m oist ure .

T o o nl y  re m o ve fr o m t he st u d y treat me nt b ottle/ kit t he n u m ber of ta blets nee de d at t he ti me 
of a d mi nistrati o n.

T o ma ke e ver y  eff ort t o ta ke d oses o n sc he d ule.

T o re p ort a n y misse d d oses.

If t he partici pa nt v o mits after ta ki n g st u dy treat me nt, t he partici pa nt s h o ul d n ot ta ke a n ot her 
d ose.

T o kee p st u d y treat me nt i n a safe place a n d o ut of reac h of c hil dre n.

T o bri n g all use d a n d u n use d st u d y  treat me nt kits t o t he site at eac h visit.

If a d ose of e paca d ostat/ matc hi n g place b o 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 a d mi nistere d at t he us ual ti me.
Wit h dr a w al/ Disc o nti n u ati o n
9. 1. 1 0
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 treat me nt peri o d s h o ul d 
be e nc o ura ge d t o c o nti n ue t o be f oll o we d f or all re mai ni n g st u d y visits.
W he n a partici pa nt disc o nti n ues/ wit h dra ws fr o m partici pati o n i n t he trial, all a p plica ble acti vities 
sc he d ule d f or t he fi nal st u d y visit s h o ul d be perf or med at t he ti me of disc o nti n uati o n .  A n y 
a d verse e ve nts w hic h are prese nt at t he ti me of disc o nti n uati o n/ wit h dra wal s h o ul d be f oll o we d i n 
acc or da nce wit h t he safet y re q uire me nts o utli ne d i n Secti o n 9. 3 - A d verse E ve nts .
P artici p a nt Bli n di n g/ U n bli n di n g
9. 1. 1 1
Partici pa nts w h ose trea t 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 hys icia 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 yste m a n d perf or m t he u n bli n d i n t he IV R S 
s yste 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, IV R S/I W 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 safety.
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.
As of A me n d me nt 0 3, 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 plete s t he 
Wee k
9 i ma gi n g assess me nt f or efficac y  a nal ysis.  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 t he 
pa rtici pa nt’s treat me nt assi g n me nt.  T he site s h o ul d e ns ure i ma gi n g data is e ntere d i n t he 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
data base pri or t o u n bli n di n g.  Please refer t o t he C R F g ui deli nes a n d c o ntact t he site m o nit or f or 
o perati o nal details.  
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 ote: As of A me n d me nt 0 3 , ce ntr al re vie w of i m a gi n g a n d i R E CI S T is 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 M RI
ma 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 l ocal practice ma n dates it. M RI  is t he 
str o n gly pre ferre 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 deally 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 dy t o o pti mize t he re pr o d uci bilit y of t he assess me nt of e xisti n g a n d ne w t u m or 
b ur de n a n d i m pr o ve t he acc urac y  of t he assess me nt of res p o nse or pr o gressi o n base d o n i ma gi n g.  
N ote: f or t he p ur p oses of assessi n g t u m or i ma gi n g, t he ter m “I n vesti gat or” refers t o t he l ocal 
i n vesti gat or at t he site a n d/ or t he ra di ol o gical re vie wer l ocate d at t he site or at a n offsite facility.
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 partici 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 sy 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 n ti 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 ote: As of A me n d me nt 0 3, ce ntr al re vie w of i m a gi n g is 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.
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 participa 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 are acce pta ble f or use as 
scree ni n g t u m or i ma gi n g if t he y are of dia g n ostic q ualit y 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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 dicall y  c o ntrai n dicate d, C T wit h c o ntrast is a n acce pta ble 
alter nati ve.   
T u m or I ma gi n g D uri n g t he St u d y
9. 2. 1. 2
N ote: As of A me n d me nt 0 3, 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 ne s 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 or me 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; an y  f urt her i ma gi n g f or disease 
assess me nts will be perf or m e 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.  
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.  
If t he b o ne sca n is p ositi ve 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 , 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.  
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 ote : As of A me n d me nt 0 3, 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 nts 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 .  F or partici pa nts 
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 P h ase T u m or I m a gi n g
9. 2. 1. 4
N ote: As of A me n d me nt 0 3, t h e 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 (i ncl u di n g b o ne sca n) m ust be perf or me d wit hi n 2 8 d a y s pri or t o restarti n g 
treat me nt wit h pe m br oliz u ma b + e paca d ostat/ matc hi n g place b o .  L ocal rea di n g (I n vesti gat or 
assess me nt wit h site ra di ol o g y rea di n g) will be use d t o deter mi ne eli gi bilit y.  Sec o n d C o urse 
i ma gi n g ca n be s u b mitte d t o t he ce ntral i ma g i 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 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 
ra n d o mizati o n.  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
da y s) or m ore fre q ue ntl y if cli nicall y i n dicate d.
Per R E CI S T 1. 1 ( Secti o n 9. 2. 1. 5) i f 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 
 
 
0 4 Y C 7 6


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 3
Pr ot oc ol/ A me n d me nt N o.:   6 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
w hile a wai ti n g ra di ol o gic c o nfir mati o n of pr o gressi o n.  Partici pa nts 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 n4 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 t he M S D , w hic he ver occ urs first. I n 
cli nicall y 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 CIS 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 nts 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 v i 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 or partici pa nts 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 nts 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 ma de t o c o nti n ue m o nit ori n g 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 d a y s) u ntil eit her t he start of a ne w a ntica ncer treat me nt, 
disease pr o gressi o n, deat h, or t he e n d of t he st u d y, w hic he ver occ urs first.  
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  t he I n vesti gat or 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 treat me 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 ons 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 R E CI S T Assess me nt of Dise ase
9. 2. 1. 6
N ote: As of A me n d me nt 0 3, t his secti o n is n o l o n g er 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 n s 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 by 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 7 . 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 partici 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 perf or ma nce stat us 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial

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 u nsta ble s h o ul d be disc o nti n ue d fr o m st u d y treat me nt at 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 CI S 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 dy 
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. 
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 7 , 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 nefit, 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 S p o ns or.  In 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 h e 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 CI S T pr ocess is pr o vi de d i n A p pe n di x 7 , 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 i ma 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 .
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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
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 w hic h has 
bee n verifie d b y 
I n vesti gat or
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 we e ks t o 
co nfir m P D. Ma 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 we e 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 i S D, i P R or 
i C 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 mpr o ve d a n d/ or 
cli nicall y sta ble per 
i n vesti gat or’s 
discreti o n. Ne xt 
t u m or i ma gi n g 
s h o ul d occ ur 
acc or di n g t o t he 
re g ular i ma gi n g 
sc he d ule
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 = 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.
N ote:  If pr o gress i o n has bee n verifie d b y t he I n vesti gat or , f urt her ma na ge me nt b y t he site s h o ul d be 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, f or p ossi ble retr os pecti ve re vie w.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 ote: As of A me n d me nt 0 3, 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 nicall y  by partici pa nts 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 ycle 
1- 4, t he n e ver y  3r d c ycle t hr o u g h 1 2 m o nt hs (ie, C ycles 7, 1 0, 1 3, 1 6), t he n e ver y 4t h c ycle after 
1 2 m o nt hs u ntil E O T (ie, C y cles 2 0, 2 4, 2 8, 3 2), at Disc o nti n uati o n, 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 P R O (e P R Os) are a d mi nistere d t o 
ra n d o mize d partici pa nts pri or t o dr u g a d mi nistrati o n, A E e val uati o n, a n d disease stat us 
n otificati o n.  If t he 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 
MI S S _ M O D E f or m m ust be c o m plete d t o ca pt ure t he reas o n t he assess me nt was n ot perf or me d.
S ur vi v al F oll o w -u p
9. 2. 3
N O T E:  As of A me n d me nt 0 3, 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 
c o nti n ue as per S ecti o n 9. 3.
O nce a partici pa nt e x perie nces I n vesti gat or -c o nfir me d P D or starts a ne w a nti -ca ncer t hera p y, 
t he partici pa nt m o ves i nt o t he S ur vi val F oll o w-U p P hase a n d s h o ul d be c o ntacte d b y tele p h o ne 
a p pr o xi matel y e ver y 1 2 wee ks ± 7 d a y s t o assess 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. P ost -st u d y treat me nts a n d t he 
partici pa nt’s res p o nse t o t he m will als o be c ollecte d.
If a partici pa nt wit h dra ws c o nse nt f or treat me nt a n d/ or i ma gi n g, t he partici pant s h o ul d still be 
f oll o we d f or s ur vi val u nless t he y s pecificall y wit h dra w t heir c o nse nt f or s ur vi val f oll o w-u p .  
Partici pa nts s h o ul d be e nc o ura ge d t o re mai n i n t he S ur vi val F oll o w -U p P hase a n d sites s h o ul d 
e ns ure t he partici pa nt u n dersta n ds t he n o n -i n vasive nat ure of t his p hase.
M S D will re q uest s ur vi val stat us t o be assesse d at a d diti o nal ti me p oi nts d uri n g t he c o urse of t he 
st u d y. F or e xa m ple, s ur vi val stat us ma y  be re q ueste d pri or t o a n e xter nal D M C safet y re vie w, 
efficac y i nteri m a nal yses, a n d fi nal a nalys is. All partici pa nts w h o are i n t he F oll o w -U p a n d 
S ur vi val F oll o w -U p P hases a n d n ot k n o w n t o ha ve die d pri or t o t he re q uest f o r t hese a d diti o nal 
s ur vi val stat us ti me p oi nts will be c o ntacte d at t hat ti me.
A d verse E ve nts ( A E), Seri o us A d verse E ve nts ( S A E) a n d Ot her Re p ort a ble S afet y 
9. 3
E ve nts 
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 3 .  Pr o gressi o n of ca ncer u n der st u dy is n ot c o nsi dere d a n a d v erse e ve nt as descri be d 
i n A p pe n di x 3.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 as 
ot her re p orta ble safet y e ve nts. I nvesti 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 (f or 
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 o rti n g.
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E a n d Ot her Re p ort a ble S afet y 
9. 3. 1
E ve nt I nf or m ati o n 
All A Es, S A Es a n d ot her re p orta ble safet y e ve nts t hat occ ur after t he 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 ort e 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 p y, 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 n e 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 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 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 uri 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 ol l 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 M S D
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 vely 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 ve nt t o 
be reas o na bl y re late 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 mefra mes as i n dicate d i n Ta ble 8 .
 
 
0 4 Y C 7 6




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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 uire 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 ve sti gat or is re q uire d t o pr oacti vely 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 ble safet y e ve nts i ncl u di n g 
pre g na nc y  a n d e x p os ure d uri n g breastfee di n g, 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, stabilizati 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 3.
Re g ul at or y Re p orti n g Re q uire me nts f or S A E
9. 3. 4

Pr o m pt n otificati o n ( wit hi n 2 4 h o urs) b y  t he i n vesti gat or t o 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 safety of a st u d y treat me nt u n der cli nical i n vesti gati o n are met. 

T he S p o ns or a n d M S D ha 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 vesti gat ors i n acc or da nce wit h all a p plica ble gl o bal la w s a n d 
re g ulati o ns, ie, per I CH T o pic E 6 ( R 1) G ui deli nes f or G o o d Cli nical Practice.

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 warde d t o i n vesti gat ors as necessar y .

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific 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 n vesti gat or’s Br oc h ure 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 or 
9. 3. 5
S A Es
Pr o gressi o n of 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 ny 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 an 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 ca ncer u n der st u d y.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 ncy 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 or m m ole, 
bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, miscarria ge a n d still birt h m ust be re p orte d as 
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 n ti 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 Interest 
( E CI) a n d m ust be re p orte d t o M S D .
E ve nts of cli nical i nte rest 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 me nt a n d 
f oll o w u p of t hese criteria ca n be f o u n d i n t he I n vesti gat or 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 y s 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 treat me nt if t he partici pa nt 
i nitiates ne w a ntica ncer t hera py, w hic he ver i s 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.
Tre at me nt of O ver d ose
9. 4
F or t his st u d y, a n o ver d ose is defi ne d as 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.  
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 orte d b y 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 trial are 
pr o vi de d bel o w. T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver t he c o urse of t he 
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 St u d y Pr oce d ures 
Ma n ual .
Pla n n e 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 ati 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 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 disc o nti n uati o n visit.  Cli nicall y  si g nifica nt a b n or mal fi n di n gs 
s h o ul d be rec or de d as me dical hist or y.  A d diti o nal f ull p h ysical e xa ms s h o ul d be perf or me d as 
s pecifie d i n t he So A ( Secti o n 2).  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 s h o ul d als o be perf or me d at t he 
disc o nti n uati o n visit a n d, if a p plica ble, 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 ha t d o n ot re q uire a f ull p hys ical e xa m per t he S o A ( Secti o n 2), 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 cli nicall 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.
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 as s pecifie d i n t he S o A.  Vital si g ns i ncl u de 
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 par tici pa nts. At select ce nters o nl y , 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 urs ( ± 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 urs ( ± 1 5 mi n utes) after a d mi nistrati o n of 
e paca d o stat.  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.
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 s u bject ma na ge me nt.  T he decisi o n t o i ncl u de or wit h dra w a s u bject 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 Fr idericia ( preferre d) 
or Bazett c orrecti o n met h o d f or calc ulati n g Q T c 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 S t 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 pri 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 s cale is descri be d i n 
A p pe n di x 5 . 
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 4 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he S o A f or t he 
ti mi n g a n d fre q ue nc y. 
●
T he i n vesti gat or 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 ny 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y  si g nifica nt 
a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g 
disease, u nless j u d ge d b y t he i n vesti gat or t o be m ore se vere  t ha n e x pecte d f or t he 
partici pa nt's c o n diti o n.
●
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 4 , m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he S o A.
●
If la b orat or y val ues fr 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 ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or (e g, S A E or A E or d ose 
m o dificati o n), t he n t he res ults m ust be rec or de d i n t he a p pr o p riate C R F (e g, S LA 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 or mal d uri n g 
partici pati o n i n t he st u d y  or wit hi n 3 0 da y s after t he last d ose of st u d y treat me nt, e ver y 
 
 
0 4 Y C 7 6


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 3
Pr ot oc ol/ A me n d me nt N o.:   6 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
atte m pt s h o ul d be ma de t o perf or m re peat assess me nts u ntil t he val ues ret ur n t o n or mal or 
baseli ne or if a ne w baseli ne is esta blis he d as deter mi ne d b y t he i n vesti gat or. 
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 4 .  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 2), m ust be teste d f or pre g na nc y wit hi n 7 2 
h o urs of 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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
After a scree ni n g p hase of a p pr o xi matel y 4 2 d a y s pri or t o treat me nt ra n d o mizati o n, p ote ntial 
partici pa nts 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 m e 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 bef ore 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 n t as part of r o uti ne cli nical ma na ge me nt 
are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti me fra me.   Scree ni n g 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 ra n d o mizati o n e x ce pt f or 
t he f oll o wi n g:

La b ora t or y tests are 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 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 by 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 pri or t o ra n d o mizati o n.
Partici pa nt s 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 pecifie d ti me fra me a n d t he c orres p o n di n g 
i ncl usi o n/e xcl usi o n criteria is met.  Partici pa 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.
Tre at me nt Peri o d
9. 9. 2
Visit re q uire me nts are o u tli 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 . 9.
Treat 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 o se d BI D (a p pr o xi matel y e ver y 1 2 h o urs [Q 1 2 H] ) 
d uri n g t he treat me nt p hase , u ntil C 3 5 D 2 1.  Treat me nt will 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 urs e 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 treat me nt, t he 
Disc o nti n ua tio 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 dy visit, t he E O T e val uati o ns will s u perse de t h ose of t hat sc he d ule d visit.  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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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
9. 9. 5. 1
N O T E:  As of A me n d me nt 0 3, 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 occ ur 3 0 da ys ( + 7 da y s) 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 Visit 
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 p y .  If t he partici pa nt 
has a disc o nti n uati o n visit ≥3 0 da y s after t he last d ose of st u d y treat me nt, t he Safety F oll o w -u p 
visit is n ot re q uire d.
A partici pa nt 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 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 .  
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 o r pe m br oliz u ma b (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 visits, 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).  
F oll o w -U p Visits
9. 9. 5. 2
N O T E:  As of A me n d me nt 0 3, 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 p ost-tre at me nt f oll o w-u p are c o nsi d ere 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 d e d t he S afet y 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.
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 disease pr o gressi o n will 
m o ve i n t o f oll o w-u p a n d s h o ul d be assesse d e ver y  9 wee ks ( 6 3  ± 7 d a y s) f or t he first 12 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 the n e ver y  1 2 wee ks ( 8 4 da ys ± 7
da y s) t hereafter. 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 p y, disease pr o gressi o n, 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 retreat me nt as detaile d i n Secti o n 7. 2. 2 .  Inf or mati o n re gar di n g p ost-
st u d y a nti ne o plastic treat me nt will be c ollecte d if ne w treat me nt is i nitiate d.
Partici pa nts w h o are eli gi ble t o recei ve retreat me nt 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 ( R etreat me nt) w he n t he y e x perie nce 
disease pr o gressi o n.  
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 3, 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.
 
 
0 4 Y C 7 6




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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
St u d y Desi g n O ver vie w
T his is a ra n d o mize d, d o u ble -bli n d, m ultice nter P hase III trial t o e val uate t he 
efficac y a n d safet y of p e m br oliz u ma b pl us e paca d ostat c o m pare d t o 
p e m br oliz u ma b pl us place b o i n partici pa nts wit h U C of t he re nal pel vis, ureter, 
bla d der, or uret hra t hat is tra nsiti o nal cell t y pe or mi xe d hist ol o g y 
( pre d o mi na ntl y tra nsiti o nal cell) t y pe ( K E Y N O T E-6 9 8/ E C H O -3 0 3) .
Tre at m e nt Assi g n me nt
A p pr o xi matel y 8 5 partici pa nts will be ra n d o mize d 1: 1 t o recei ve 
pe m br oliz u ma b + e paca d ostat or pe m br oliz u ma b + place b o. Stratificati o n 
fact ors are pr o vi de d i n Secti o n 7. 3. 1.  
A n al ysis P o p ul ati o ns
Efficac y: I nt e nti on-t o- Tr e a t (I T T)
Safet y:   All Partici pa nt s as Treate d ( A Pa T)
Pri m ar y E n d p oi nts
O bjecti ve Res p o nse Rate ( O R R) per R E CI S T 1. 1 assesse d b y i n vesti gat or 
deter mi nati o n
St atistic al Met h o ds
f or
Ke y Effic ac y A n al yses
O R R will be esti mate d b y treat me nt gr o u p wit h 9 5 % CI calc ulate d b y t he 
Cl o p per -Pears o n e xact me t h o d [ Cl o p per, C. J. a n d Pears o n, E. S. 1 9 3 4]
St atistic al Met h o ds
f or
Ke y S afet y A n al yses
P oi nt esti mates (c o u nt a n d perce nta ge) b y treat me nt gr o u p will be pr o vi de d f or 
safet y e n d p oi nts.
I nteri m a n d Fi n al A n al yses
T here wi ll be n o i nteri m a nal ysis. D uri n g t he c o urse of t he st u d y, D M C will 
perf or m 1 safet y re vie w base d o n t he D M C c harter.
T he fi nal a nal ysis will be perf or m e d after t he last partici pa nt c o mplete s t he 
W ee k 9 i m a gi n g assess me nt.
M ulti plicit y
T here w ill be n o m ulti plicit y a dj ust me nt. 
S a m pl e Siz e a n d P o w e r
T otal sa m ple size is a p pr o xi matel y 8 5 .
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 ns or . 
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 s t u d y will be c o n d ucte d as a d o u ble-bli n d st u d y  u n der i n-h o use bli n di n g pr oce d ures.  T he 
official, fi nal data base will n ot be u n bli n de d u ntil me dical/scie ntific re vie w has bee n perf or me d, 
pr ot oc ol de viati o ns ha ve bee n i de ntifie d, a n d data ha ve bee n declare d fi nal a n d c o m plete. 
A n e D M C will be c o n ve ne d t o re vie w acc u m ulati n g safety 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.
Bli 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 anal ys is. 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 ysis, 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.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 gar di 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. – 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 nts
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 in vesti g at or deter mi n ati o n
O bjecti ve Res p o nse Rate is defi ne d as t he 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 o m plete res p o nse ( C R ) or partial res p o nse ( 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 .
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 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 A Pa T p o p ulati o n will be use d f or t he a nal ys is of safety data i n t his st u d 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 d y 
treat me nt.  Partici pa nts will be a nal yze 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 dy 
treat me nt t he y act uall y recei ve d f or t he a nal ysis 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 ually 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 y cles will be a nal yze d acc or di n g t o t he c orrect treat me nt gr o u p a n d a narrati ve will be 
pr o vi de d f or a 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 orrectl y d ose d.
At least o ne la b orat or y  or vital si g n meas ure me nt o btai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter. T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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
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 nt s 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) 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 me t h o d.
St atistic al Met h o d f or S afet y A n al ysis
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 ).  
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Ta ble 1 1
A nal y sis Strate g y f or Safet y E n d p oi nts
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
Cli nic al L a b or at or y Tests
1 0. 6. 3
T he cli nical la b orat or y  data will be a nalyz e d usi n g s u m mar y statistics (e g, mea ns a n d 
fre q ue ncies), a n d n o f or mal statistical c o m paris o ns a m o n g t he treat me nts are pla n ne d.  I n 
a d diti o n, distri b uti o ns of ke y la b orat or y para meters (i ncl u di n g he m o gl o bi n, ne utr o p hils, a n d 
platelets) will be pl otte d o ver ti me; t hese val ues will als o be classifie d i nt o C T C A E t o xicit y 
gra des a n d ta b ulate d.  Descri pti ve statistics a n d mea n c ha n ge fr o m baseli ne will be deter mi ne d 
f or vital si g ns at eac h assess me nt ti me.  Vital si g n res ults will be re vie we d f or cli nicall y n ota ble 
a b n or malities.
S u m m aries of B aseli ne C h ar acteristics a n d De m o gr a p hics
1 0. 6. 4
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 g ra p hs.  N o statistical h yp 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 nts scree ne d, ra n d o mize d, a n d t he 
pri mar y  reas o n f or scree ni n g fail ure, a n d t he pri mar y reas o n f or disc o nti n uati o n will be 
dis pla y e d.   De m o gra p hic varia bles (e. g., a ge, race, etc.) a n d baseli ne c haracteristics will be 
s u m marize d b y treat me nt eit her by descri pti ve statistics or cate g orical ta bles.
I nteri m A n al yses
1 0. 7
N O T E:  As of A me n d me nt 0 3 , t here will be n o i nteri m effic ac y a n al ysis. T h e 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 3 , 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -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 pl us e paca d ostat a n d 
pe m br oliz u ma b pl us 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  8 5 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 n d p oi nt. 
Wit h esti mate d 4 2 partici pa nts per treat me nt ar m, Ta ble 1 2 gi ves exa m ples of O R R esti mate a n d
9 5 % CI , wit h differe nt n u m bers of o bser ve d res p o n ders.
Ta ble 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
4 2
9
2 1. 4 %
( 1 0. 3 %, 3 6. 8 %)
2 6. 5 %
4 2
1 0
2 3. 8 %
( 1 2. 0 %, 3 9. 4 %)
2 7. 4 %
4 2
1 1
2 6. 2 %
( 1 3. 9 %, 4 2. 0 %)
2 8. 2 %
4 2
1 2
2 8. 6 %
( 1 5. 7 %, 4 4. 6 %)
2 8. 9 %
S u b gr o u p A n al yses
1 0. 1 0
N O T E:  As of A me n d me nt 0 3, 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 ny d e viati o n 
fr o m pr ot oc ol-directe d a d mi nistrati 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 A P a T p o p ulati o n.
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 4
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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 ume 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 2 0 1 7]
Baj ori n D F, Wit R D, Va u g h n DJ, Fra det Y, Lee 
J L, F o n g L, et al. Pla n ne d s ur vi val a nal ys is fr o m 
K E Y N O T E -0 4 5: P hase 3, o pe n -la bel st u d y of 
pe m br oliz u ma b 
( pe m br o) vers us 
paclita xel, 
d oceta xel, or vi nfl u ni ne i n rec urre nt, 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 B
[ Bell m u nt, J., et al 2 0 0 9]
Bell m u nt J, T he o d ore C, De m k o v T, K o m ya k o v 
B, Se n gel o v L,  Da u gaar d G, et al. P hase III trial 
of vi nfl u ni ne pl us best s u p p orti ve care c o m pare d 
wit h best s u p p orti ve care al o ne after a plati n u m-
c o ntai ni n g re gi me n i n patie nts wit h a d va nce d 
tra nsiti o nal cell carci n o ma of t he ur ot helial tract. 
J Cli n O nc ol 2 0 0 9; 2 7( 2 7): 4 4 5 4- 6 1.
0 3 X L P K
[ Bell m u nt, J., et al 2 0 1 0]
Bell m u nt J, C h o ueiri T K, F o u gera y  R, Sc h utz 
F A, Sal hi Y, 
Wi n q uist 
E. et al. Pr o g n ostic
fact ors i n patie nts wit h a d va nce d tra nsiti o nal cell 
carci n o ma of t he ur ot helial tract e x perie nci n g 
treat me nt 
fail ure 
wit h 
plati n u m -c o ntai ni n g 
re gi me ns. 
J 
Cli n 
O nc ol. 
2 0 1 0 
A pr 
1 0; 2 8( 1 1): 1 8 5 0 - 5.
0 4 Q 3J Q
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ Bell m u nt, J., et al 2 0 1 7]
Bell m u nt J, de Wit R, Va u g h n DJ, Fra det Y, Lee 
J L, F o n g L, et al. Pe m br oliz u ma b as Sec o n d -
Li ne 
T hera p y 
f or 
A d va nce d 
Ur ot helial 
Carci n o ma. 
N 
E n gl 
J 
Me d. 
2 0 1 7 
Mar 
1 6; 3 7 6( 1 1): 1 0 1 5 - 1 0 2 6.
0 4 N Z L S
[ 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 ly 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
[ Bra h mer, J. R., et al 2 0 1 0]
Bra h mer J R, Dra ke C G, W oll ner 
I, Po w derl y 
J D, Pic us J, S harf ma n W H, et al. P hase I st u d y 
of 
si n gle-a ge nt 
a nti-pr o gra m me d 
deat h -1 
( M D X-1 1 0 6) i n refract or y soli d t u m ors: safet y, 
cli nical 
acti vit y, 
p har mac o d y n a mics, 
a n d 
i m m u n ol o gic c orrelates. J Cli n O nc ol. 2 0 1 0 J ul 
1; 2 8( 1 9): 3 1 6 7 - 7 5.
0 4 M B Y Q
[ 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 orect al 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
[ 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 an d m y el oi d cells wit hi n 
B 1 6 
mela n o ma t u m ors. Pr oc Natl Aca d Sc i 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
[ Da vies, M. 2 0 1 4]
Da vies M. Ne w m o dalities of ca ncer treat me nt 
f or N S C L C: f oc us o n i m m u n ot hera p y. Ca ncer 
Ma na g Res. 2 0 1 4 Fe b 3; 6: 6 3 - 7 5.
0 4 Q 3J R
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ 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 n c 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 mstr 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
M a 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 phe n ot y pe 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
[ 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 res p 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, Kiril o vs k y 
A, Mlec ni k 
B, La g orce -Pa gès C, et al. T y pe, 
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.
0 0 V M P S
[ 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 py 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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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  phase 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 ma 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  an 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. 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
[ 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. Le u k oc y te 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  cuta 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
[ Hira o ka, N. 2 0 1 0]
Hira o ka N. T u m or -i nfiltrati n g l ym p h oc y tes a n d 
he pat ocell ular carci n o ma: m olec ular bi ol o g y . I nt 
J Cli n O nc ol 2 0 1 0; 1 5( 6): 5 4 4- 5 1.
0 0 V M P T
[ 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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ 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 
MK- 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 
M a y  29 - 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 nd 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 herap y  tar geti n g 
C T L A - 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 5 2 0 1 7]
K E Y T R U D A 
( pe m br oliz u ma b) I nvesti 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 y a 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.  Gl o bal Ca ncer Statistics. C A Ca ncer 
J Cli n 20 1 1; 6 1( 2): 6 9 - 9 0.
0 3 S T K B
[ Kass o uf, W. 2 0 0 4]
Kass o uf 
W, 
Ka mat 
A M. 
C urre nt 
state of 
i m m u n ot hera p y for bla d der ca ncer. E x pert Re v 
A ntica ncer T her. 2 0 0 4 Dec; 4( 6): 1 0 3 7 - 4 6.
0 4 Q 3 K 4
[ Ki m, J. W., et al 2 0 1 5]
Ki m 
J W, T o mita Y, 
Tre pel J, A p ol o 
A B. 
E mer gi n g i m m u n ot hera pies f or bla d der ca ncer. 
C urr O pi n O nc ol. 2 0 1 5 Ma y ; 2 7( 3): 1 9 1- 2 0 0.
0 4 H 2J Q
[ Kl o or, M. 2 0 0 9]
Kl o or M. L y m p h oc yte i nfiltrati o n a n d pr o g n osis 
i n c ol orectal 
ca ncer. 
La n cet 
O nc ol. 
2 0 0 9 
Se p; 1 0( 9): 8 4 0 - 1.
0 0 V M P Y
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ Lee, H. E., et al 2 0 0 8]
Lee H E, C hae S W, Lee YJ, Ki m M A, Lee H S, 
Lee B L, et al. Pr o g n ostic i m plicati o ns of t yp e 
a n d de nsit y of t u m o ur-i nfiltrati n g l ym p h oc y tes 
i n gastric ca ncer. Br J Ca ncer 2 0 0 8; 9 9( 1 0): 1 7 0 4-
1 1.
0 0 V M Q 2
[ Leffers, N., et al 2 0 0 9]
Leffers 
N, 
G o o de n 
MJ M, 
de 
J o n g R A, 
H o o ge b o o m B- N, te n H o or K A, H olle ma H, et 
al. Pr o g n ostic si g nifica nce of t u m or-i nfiltrati n g 
T- l ym p h oc y tes i n pri mar y an d metastatic lesi o ns 
of 
a d va nce d sta ge o varia n ca ncer. 
Ca ncer 
I m m u n ol I m m u n ot her 2 0 0 9; 5 8( 3): 4 4 9- 5 9.
0 0 V M Q 3
[ 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 ym p h oc y tes 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
[ Mell or, A. L. 2 0 0 4]
Mell or 
A L , M u n n 
D H. 
I DO 
e x pressi o n b y 
de n dritic 
cells: 
t olera nce 
a n d 
tr ypt o p ha n 
cata b olis m. 
Nat 
Re v 
I mm 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 n d 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 mm 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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ M uller, A. J., et al 2 0 0 5]
M uller 
AJ, 
D u Ha da wa y  JB, 
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 olera nce. J Cli n 
I n 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
[ Nis hi m ura, H., et al 2 0 0 0]
Nis hi m ura H, H o nj o T, Mi nat o N. Facilit ati o n of 
beta selecti o n a n d m o dificati o n 
of p ositi ve 
selecti o n i n t he t hy m us of P D - 1-deficie nt mice. J 
E x p Me d. 2 0 0 0 Mar 6; 1 9 1( 5): 8 9 1 - 8.
0 0 V M Q 4
[ 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, 
Le o ne B E, Trezzi R, et al. Pr ol o n ge d s urvi val of 
a patie nt affecte d b y  pa ncreatic a de n ocarci n o ma 
wit h 
massi ve 
l ym 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 n ical 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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ O ka m ot o, A., et al 2 0 0 5]
O ka 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
[ Pic kar d, A. S., et al 2 0 0 7]
Pic kar d A S, Wil ke 
C T, Li n H- W, 
Ll o y d 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 o wles, T., et al 2 0 1 4]
P o wles T, E der J P, Fi ne G D, Braite h F S, L o ri ot 
Y, Cr uz C, et al. M P D L 3 2 8 0 A (a nti-P D -L 1) 
treat me nt lea ds t o cli nical acti vit y in metastatic 
bla d der 
ca ncer. 
Nat ure. 
2 0 1 4 
N o v 
2 7; 5 1 5( 7 5 2 8): 5 5 8 - 6 2.
0 4 C Z 7 R
[ 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
[ R ose n ber g, J. E., et al 2 0 1 6]
R ose n ber g J E, H off ma n -Ce nsits J, P o wles T, 
va n der Heij de n M S, Balar A V, Necc hi A, et al. 
Atez oliz u ma b i n patie nts wit h l ocall y ad va nce d 
a n d metastatic ur ot helial carci n o ma w h o ha ve 
pr o gresse d f oll o wi ng treat me nt wit h plati n u m -
base d c he m ot hera p y:  a si n gle-ar m, m ultice ntre, 
p hase 2 trial. La ncet. 2 0 1 6 Mar 4. [ E p u b a hea d 
of pri nt].
0 4 C Z H 6
[ 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. L o n g -ter m 
foll 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 
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 7 
J ul; 1 5( 7): 2 5 6 4- 9.
0 4 C R R W
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ 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,  Bo 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 har ma, P., et al 2 0 1 6]
S har ma P, Calla ha n 
M K, 
B o n o 
P, Ki m 
J, 
S pili o p o ul o u P, Cal v o 
E. et al. Ni v ol u ma b 
m o n ot hera p y i n rec urre nt metastatic ur ot helial 
carci n o ma ( C hec k Mate 0 3 2): a m ultice ntre, 
o pe n -la bel, t w o-sta ge, m ulti-ar m, p hase 1/ 2 trial. 
La ncet O nc ol. 2 0 1 6 N o v; 1 7( 1 1): 1 5 9 0 -1 5 9 8.
0 4 Q 3 K 7
[ S mit h, D. C., et al 2 0 1 7]
S mit h D C, Gaje ws ki T F, Ha mi d O, Wasser J S, 
Olsza ns ki AJ , Patel S P, et al. E paca d ostat pl us 
pe m br oliz u ma b 
i n patie nts 
wit h 
a d va nce d 
ur ot helial carci n o ma: preli mi nar y  phase 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: 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 N
[ S pra n ger, S., et al 2 0 1 3]
S pra n ger S, S paa pe n R M, Z h a 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, 
I DO, 
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  CD 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
[ 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 y de. 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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
[ 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. 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 
in 
ca ncer. 
N 
E n gl 
J 
Me d 
2 0 1 2; 3 6 6( 2 6): 2 4 4 3 - 5 4.
0 3 T G B 4
[ 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
[ U ytte n h o ve, C., et al 2 0 0 3]
U y tte n h o ve C, Pil otte L,  Theate 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 ypt o p ha n de gra dati o n b y  in 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 5]
v o n der Maase H, Se n gel o v L,  Ro 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 nlic h, 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 ncentrati 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
[ Wit kie wicz, A., et al 2 0 0 8]
Wit kie wicz 
A, 
Willia 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 in 
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 py acti vit y in 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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ W olc h o k, J. D., et al 2 0 1 3]
W olc h o k 
J D, Kl u ger H, Calla ha n M K, P ost o w 
M A, Riz vi N A, Les o k hi n A M. Ni v ol u ma b pl us 
i pili m u ma b i n a d va nce d mela n o ma. N E n gl J 
Me d 2 0 1 3; 3 6 9: 1 2 2 - 3 3.
0 3 T 0 K Y
[ 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 mm 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 C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
1 2.
A p pe n dice s
A p pe n di x 1 : St u d y G o ver n a nce C o nsi der ati o ns
1 2. 1
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 an 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 o se 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 pretatio 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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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 tria ls 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, tr ial 
desi 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 Re se 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 its trials.  H o we ver, w he n e nr oll me nt is partic ularl y c hall e 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 o vi de d a gra nt f or perf or mi n g t he trial.  H o we ver, t he l ocal I R B/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 dicate Merc k as a s o urce of f u n di n g.
C.
F u n di n g f or Tr a vel a n d Ot her Re q uests
F u n di n g of tra vel b y 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 o ciati 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 et hical a n d scie ntific sta n dar ds.
* I n t his d oc u me nt, " Merc k" refers t o Merc k S har p & D o h me C or p. a n d Sc heri n g C or p orati o n, eac h of w hic h is a 
s u bsi diar y of Merc k & C o., I nc.  Merc k is k n o w n as M S D o utsi de of t he U nite d States a n d Ca na da.  As warra nte d b y 
c o nte xt, Merc k als o i ncl u des affiliates a n d s u bsi diari es of Merc k & C o., I nc."
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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 agree 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 other 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 will be c o nsi dere d c o nfi de ntial b y t he i n vesti gat or, e xce pt t o t he e xte nt 
t hat it is i ncl u de d i n a p u blicati o n as pr o vi de d i n t he P u blicati ons 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 t his pr ocess.  If trial d oc u me nts will be p h ot oc o pie d d uri n g t he pr ocess of 
verif y i n g w or ks heet/case re p ort f or m i nf or mati o n, t he partici pant will be i de ntifie d b y  u ni q ue 
c o de o nl y;  f ull na mes/i nitials will be mas ke d pri or t o tra ns missi o n t o M S D .
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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 n d a d dress of eac h I R B/I E C t hat re vie ws a n d a p pr o ves t his 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 
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 MC 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 vesti gat ors) a n d m ust ha ve n o 
c o m peti n g i nterests t hat c o ul d affect t heir r oles wit h res pect t o t he trial. 
T he D M C will ma ke rec o m me n dati o ns t o t he E O C re gar di n g ste ps t o ens 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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
P u blic ati o n P olic y
T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie ntific meeti n gs. T he S p o ns or 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. I n acc or da nce wit h 
sta n dar d e dit orial a n d et hical practice, t he Sp o ns or a n d M S D will ge n erall 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 in 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 I nter 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 dicines 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.  Inf or mati o n p oste d will all o w partici pa nts t o i de ntif y  p ote ntially 
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 th 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 
Practi ce (e g, I nter nati o nal C o nfere nce o n Har m o nizati o n of Tec h nical Re q uire me nts f or 
Re gistrati o n of P har mace uticals f or H u ma n Use G o o d Cli nical Practice: C o ns oli date d G ui deli ne 
a n d ot her ge nerall y acce pte d sta n dar ds of g o o d cli nical practice); a n d all a p plica b le 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 xec 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.
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.
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 pecti 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 n d 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 n y pr ocee di n g f or de bar me nt is pe n di n g or, t o t he best of t he i n vesti gat or’s 
k n o wle d ge, t hreate ne d.
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 ysicall y or 
electr o nicall y si g ni n g t he C R F. 
Detaile d i nf or mati o n re gar di n g Data Ma na ge me nt pr oce d ures f or t his pr ot oc ol will be pr o vi de d 
se paratel y.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F. 
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
Trial d oc u me ntati o n will be pr o m ptl y  a n d f ull y disclose d t o M S D
b y  t he i n vesti gat or u p o n 
re q uest a n d als o s hall be ma de a vaila ble at t he 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 that are re q ueste d b y  M S D or a n d 
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 m a na ge me nt of t his st u d y, i ncl u di n g q uality 
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, IC H G C P, a n d all a p plica ble re g ulat or y  re q uire me nts. 
Re c 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 by 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 y e 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 party wit h o ut writte n n otificati o n t o M S D . 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 part ici 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 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  n otif y t hat 
trial site’s IR B/I E C.
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 2 : 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. 2
Defi niti o ns 
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w) 
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 n te d hys 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 us al 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 vel i n t he p ost me n o pa usal ra n ge ma y be 
use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n 
or h or m o nal re place me nt t hera p y ( H R T). H o we ver, i n t he a bse nce of 1 2 m o nt hs of 
a me n orr hea, c o nfir mati o n wit h t w o F S H meas ure me nts i n t he p ost me n o pa usal ra n ge 
is re q uire d. 
○
Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of 
t he n o n-h or m o nal hi g hl y  effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir 
H R T d uri n g t he st u d y. Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of 
p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
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 o wi 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 yle (a bsti ne nt 
o n a l o n g ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt.
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
●
Use a male c o n d o m pl us part ner use of a n a d diti o nal c o ntrace pti ve met h o d w he n ha vi n g 
pe nile -va gi nal i nterc o urse wit h a W O C B P w h o is n ot c urre ntl y pre g na nt.
o
T he f oll o wi n g are n ot acce pta ble met h o ds of c o ntrace pti o n:
▪
Peri o dic a bsti ne nce (cale n dar, sy m pt ot her mal, p ost -o v ulati o n met h o ds), wit h dra wal 
(c oit us i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d ( L A M).
▪
Male c o n d o m wit h ca p, dia p hra g m or s p o n ge wit h s per mici de .
▪
Male a n d fe male c o n d o m ca n n ot be use d t o get her.
○
N ote: Me n wit h a pre g na nt or breastfee di n g part ner m ust a gree t o re mai n a bsti ne nt fr o m 
pe nile - va gi nal i nterc o urse or use a male c o n d o m duri 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 3
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 C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
Ta ble 1 3
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 nly 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 nly c o ntrace pti ve i m pla nt b, c 
●
I ntra uteri ne h or m o ne-releasi n g sys te m (I U S) b
●
I ntra uteri ne de vice (I U D)
●
Bilateral t u bal occl usi o n
●
Vasect o mize d part 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 h i g hly effecti ve met h o d of c o ntrace pti o n s h o ul d be use d. 
●
Se x ual 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 relati o 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 rates are hi g her t ha n perfect-use fail ure rates (ie, w he n use d c o nsiste ntl y  
a n d c orrectl y). 
b) If h or mo 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 pti o n 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 t o eli mi nate stu d y  
treat me nt pl us 3 0 da ys f or st u d y treat me nts wit h ge n ot o xic p ote ntial  after the last d ose of 
st u d y treat me nt.
c) If l ocally 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. 
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 gna nc y  test will be re q uire d. M o nt hly 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.
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 C 7 6










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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
●
Ti me C o urse:   Di d t he A E f oll o w i n a reas o na ble te m p oral se q ue nce fr o m 
a d mi nistrati o n of t he st u d y treat me nt? Is t he ti me of o nset of t he A E 
c o m pati ble wit h a dr u g-i n d uce d effect (a p plies t o trials wit h i n vesti gati o nal 
me dici nal pr o d uct)?
●
Li 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 D I R E C T O R A S P E R D O S E M O DI FI C A TI O N G UI D E LI N E S I N T H E 
P R O T O C O L , A N D I F R E Q UI R E D, T H E I 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.
 
 
0 4 Y C 7 6










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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 5 : E C O G Perf or m a nce S t at us
1 2. 5
G R A D E
E C O G P E R F O R M A N C E S T A T U S
0
F ull y  acti ve, a ble t o carr y o n all pre-disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h y 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 A m. J. Cli n. O nc ol.: 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.
T he Easter n C o o p erati ve O nc ol o g y Gr o u p, R o bert C o mis M. D., Gr o u p C hair.
 
 
0 4 Y C 7 6


Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 6
Pr ot oc ol/ A me n d me nt N o.:   6 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 6 : A b bre vi ati o ns a n d Tr a de m ar ks
1 2. 6
A b bre vi ati o n/ Ter m
Defi niti o n
2 L
sec o n d li ne
A E
ad verse eve nt
A L T
ala ni ne ami n otra nsferase
A N C
abs ol ute n e utr o p hil co u nt
A Pa T
All Partici pa nt s as Treate d
a P T T
acti vate d p artial thr o m b o plasti n ti me
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 re vie w
BI D
twice d ail y
C 1 D 1
C y cle 1 Da y 1
C A P
c hest, a b d o me n a n d pel vis
C 2 D 1
C y cle 2 Da y 1
CI
co nfi de nce inter val
c L D A
c o nstrai ne d l o n git u di nal data a nal ys is
C ma x
p las ma m a xi m u m c o nce ntrati o n
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
C tr o u g h
p las ma mi ni m u m c o nce ntrati o n
D C
Disc o nti n uati o n
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 D M C
e xter nal Data M o nit ori n g C o m mittee
E M A
E ur o pea n Me dici nes A ge nc y
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 7
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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 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
eE Q - 5 D
electr o nic E ur o Q ol -5 Di me nsi o ns
E Q - 5 D
E ur o Q ol -5 Di me nsi o ns
E O T
E n d of Treat me nt
e P R O
electr o nic p a tie nt-re p orte d o utc o me
E U
E ur o pea n U ni o n
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
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
F S H
follicle sti m ulati n g h or m o ne
F W E R
fa mil ywise T y p e I err or rate
G C P
G o o d Cli nical Practice
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 B V
He patitis B vir us
H C G
h u ma n ch ori o nic g o na d otr o pi 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
h azar d rati o
H R Q o L
Healt h Relate d Q ualit y  of L ife
H R T
h or m o nal re place me nt thera p y
I B
I n vesti gat or’s Br oc h ure
i C P D
i R E CIS T c o nfir me d pr o gressi ve disease
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 nizati o n
i C R
i R E CIS T c o m plete res p o nse
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
i m m u n o gl o b uli n
I H C
im m u n o hist oc he mistr y
I N R
inter nati o nal n or malize d r ati o
I RB
I nstit uti o nal Re vie w B oar d
ir A E
im m u ne -relate d a d verse eve nt
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 U S
intra uteri ne h or m o ne -releasi n g sys te m
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 8
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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
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
L A M
lactati o nal ame n orr h oea m et h o d
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 in hi bit or
m g
m illi gra m
m g/ k g
m illi gra m per k il o gra m
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 CI
( U S) Nati o nal Ca ncer I nstit ute
N S AI D
n o nster oi dal anti -i nfla m mat or y d r u gs
N S C L C
n o n-s mall cell lu n g ca ncer
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-C o 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
P D - L 2
p r o gra m me d cell d eat h-li ga n d 2
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
pr o p orti o nal hazar d
PI
Pri nci pal I n vesti gat or
P K
p har mac o ki netic(s)
P R
p artial res p o nse
P R O
patie nt -re p orte d o utc o me 
P S
Perf 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
p erf or ma nce stat us
P S A
p r ostate-s pecific A nti ge n
Q 1 2 H
e ver y 1 2 h o urs
Q 2 W
ever y  2 Wee ks
Q 3 W
ever y  3 Wee ks
Q L Q
Q ualit y  of Life Q uesti o n naire
Q o L
Q ualit y  of Life
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 9
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- 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
Q Tc
correcte 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 D
sta ble d isease
S G O T
ser u m g l uta mic o xal oacetic tra nsa mi nase
S G P T
ser u m g l uta mic- pyr u vic tra nsa mi nase
SI M
Site I ma gi n g Ma n ual
S N RI
ser ot o ni n- nore pi ne p hri ne re u pta ke in hi bit or
S o A
Sc he d ule of Acti vities
S O C
sta n dar d of care
S O P
Sta n dar d O perati n g Pr oce d ure
S S
ser ot o ni n sy n dr o me
s S A P
su p ple me ntal Statistical A nal y sis Pla n
S S RI
Selecti ve ser ot o ni n re u pta ke in hi bit or
T 1 D M
T y pe 1 d ia betes m ellit us
T C C
tra nsiti o nal cell carci n o ma
T R A Es
treat me nt-relate d ad verse eve nts
T- re g
re g ulat or y T-cell
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 L N
u p per li mit of n or mal
U S
U nite d States
U S PI
U nite d States Pac ka ge I nsert
W O C B P
w o ma n of chil d b eari n g p ote ntial
 
 
0 4 Y C 7 6


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 9 8 - 0 3/ E C H O-3 0 3 -0 3 
M K -3 4 7 5 -6 9 8 -0 3 (IN C B 2 4 3 6 0 -3 0 3 -0 3) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 7 : 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. 7
Pr o gressi o n
N ote: As of A me n d me nt 0 3, 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.
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 nts 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 treat me 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 ).  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 nt 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 gi c 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 dy 
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 we e 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 re vie w. 
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)
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 g ressi ve disease). F or p ur p oses of i R E CIS T assess me nt, t he first visit 
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 1
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 ne 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 b y R E CIS 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 CI S 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 gressi 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 nitial i U P D 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 of 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, 
co 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 lesi o ns, w orse ni n g is a n y 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 CIS 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 nfi r 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)
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.
 
 
0 4 Y C 7 6


Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 2
Pr ot oc ol/ A me n d me nt N o.:   6 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 o ns 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 CI S 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 repeat i ma gi n g d oes n ot c o nfir m P D per i R E CI S 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 ued 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, 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. In 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.
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 n y of t he f oll o wi n g e ve nts:

Tar get lesi o ns
o
S u m of dia meters reac 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 na 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.

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
 
 
0 4 Y C 7 6


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 9 8- 0 3/ E C H O - 3 0 3- 0 3 
M K - 3 4 7 5- 6 9 8- 0 3 (IN C B 2 4 3 6 0 - 3 0 3- 0 3) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
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 nts 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 ons, 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. I t 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 na l details a b o ut i R E CIS T are pr o vi de d i n t he i R E CI S T p u blicati o n [ Se ym o ur, L., et al 
2 0 1 7].
 
 
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