Clinical trial NCT03260894
Conditions: Renal Cell Carcinoma (RCC)
Keywords: Renal cell carcinoma programmed cell death 1 (PD-1) inhibitor indoleamine 2 3-dioxygenase 1 (IDO1) inhibitor
Sponsor: Incyte Corporation
Start date: 2017-12-07; Completion date: 2025-06-04
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of pembrolizumab plus epacadostat compared to sunitinib or pazopanib in participants with locally advanced/metastatic renal cell carcinoma (mRCC) with a clear cell component who have not received prior systemic therapy for their mRCC.

Detailed description:

Arms: arm 1: None arm 2: Standard of care (SoC) (sunitinib or pazopanib monotherapy).
Interventions: intervention 1: Pembrolizumab intervention 2: Epacadostat intervention 3: Sunitinib intervention 4: Pazopanib
Intervention descriptions: intervention 1: Pembrolizumab 200 mg administered intravenously every 3 weeks. intervention 2: Epacadostat 100 mg administered orally twice daily. intervention 3: Sunitinib 50 mg administered orally once daily; 4 weeks on, 2 weeks off for 6-wk cycle. intervention 4: Pazopanib 800 mg administered orally once daily.

Protocol documents:
Prot_SAP_000.pdf: 
P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6 
Title P a ge  
T HI S  PR O T O C O L  A M E N D M E N T  A N D A L L  OF  TH E  IN F O R M A TI O N R E L A TI N G  
T O  IT  A R E C ON F I D E N TI A L A N D P R O P RI E T A R Y P R O P E R T Y O F  ME R C K  
S H A R P  & D OH M E  CO R P.,  A S U B SI DI A R Y  OF  ME R C K  &  C O ., IN C.,  
W HI T E H O U S E  ST A TI O N,  N J, U. S. A. 
Pr ot oc ol  Title:  A R a n d o mize d, O pe n- La bel,  Phase 3  St u d y to  Eval uate Efficac y  a n d Safet y 
of P e m br oliz u ma b ( M K- 3 4 7 5) pl us E paca d ostat v s S ta n dar d of C are (S u niti ni b or 
Paz o pa ni b) as F irst-Li ne  Treat me nt  for  L ocall y  Ad v a nce d or Metastatic Re nal Cell 
Carci n o ma  ( mR C C) ( K E Y N O T E - 6 7 9/ E C H O- 3 0 2) 
Pr ot oc ol  Nu m ber:  6 7 9- 0 6/ E C H O - 30 2 - 0 6 / N C T 0 3 2 6 0 8 9 4
C o m p o u n d N u m ber:  M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
E xec uti o n of St u d y: 
Merc k S har p & D o h m e C or p., a su bsi diar y of M erc k & C o., I nc. 
(Refer e nc e d  her ei n as MS D ) 
O ne Merc k  Dri ve  
P. O. B o x 1 0 0 
W hite h o use S tati o n, Ne w Jerse y, 0 8 8 8 9- 0 1 0 0, U. S. A.  
Gl o b al  S p o ns or of the  St u d y: 
I n c yt e C or p or ati o n ( Refere nce d h erei n as S p o ns or) 
1 8 0 1 A u g usti ne C ut- Off  
Wil mi n gt o n, Dela ware, 1 9 8 0 3, U. S. A.  
R e g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  
I N D N U M B E R:  1 3 3, 7 6 0 
E u dr a C T  N U MB E R:   2 0 1 7- 0 0 2 2 5 9- 2 6  
A p pr o v al D ate:  1 5- J u n- 2 0 1 8 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  


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


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  
A me n d me nt  0 6 
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 (e D M C) a nal ysis  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 trial , a 
P hase  3 st u d y e v al 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 nres ecta ble or m etastatic mel a 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 h er 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 nifi ca 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 y pes. Of n ote, t here were n o ne w safet y c o ncer ns wit h t he pe m br oli z u ma b pl us e paca d ostat c o m bi nati o n c o m pare d t o 
pe m br oliz u ma b m o n ot hera p y. Gi ve n t hat t here is n o c o nfir me d lac k of effi cac y of p e m br oliz u ma b pl us e paca d ostat i n ot her t u m or 
t y pes, t he S p o ns or a n d M S D c o nsi der i nterr u pti o n of st u d y treat me nt u n necessar y i n K E Y N O T E - 6 7 9/ E C H O- 3 0 2. E nr oll me nt t o t his 
st u d y was p er ma n e ntl y st o p pe d o n 0 2-M A Y - 2 0 1 8 as a strate gic d ecisi o n.  F or partici pa nts w h o are c o nsi dere d t o be o btai ni n g o n g oi n g 
cli nical be nefit, c o nti n ue d st u d y treat me nt will be at t he discreti o n of t he i n vesti gat or, after a disc ussi o n wit h t he partic i pa nt of t he 
o bser ve d r es 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  
T hr o u g h o ut  
A d diti o n of n otes t o i nf or m sites t hat 
e nr oll me nt i nt o t he trial is per ma ne ntl y 
st o p pe d a n d t o clarif y t hat after t he first 
i ma gi n g assess me nt, disease m o nit ori n g 
will be perf or me d as per sta n dar d of care 
( S o C). 
Gi ve n t he e xter nal data m o nit ori n g c o m mittee ( D M C) 
re vie w of t h e res ults of K E Y N O T E 2 5 2/ E C H O- 3 0 1, a 
strate gic decisio n was ma de t o per ma n e ntl y st o p e nr oll me nt 
as of 0 2- M A Y - 2 0 1 8.  Partici pa nts will be gi ve n t h e 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 m ai 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 dat a i n t his  R C C 
i n dicati o n. 
All efficac y pr oce d ures a n d e n d p oi nts after Wee k 1 2 are n o 
l o n ger b ei n g assess e 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 h a n ge d a n d a n ote has bee n a d de d.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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  
4. O bjecti ves/ H y p ot heses 
a n d E n d p oi nts 
5. 1. 1 St u d y Dia gr a m 
5. 4. 1. 1 Efficac y E n d p oi nts 
9. 2. 1 T u m or I m a gi n g a n d 
Assess me nt of Diseas e  
8. 1 Disc o nti n uati o n of 
St u d y Treat me nt  
9. 1 0. 3. 3 S ur vi val F oll o w-
u p 
1 0. 1 Statistical A nal ysis 
Pla n S u m mar y  
C ha n ge d pri mar y e n d p oi nt fr o m 
c o m paris o n of P F S (as assesse d b y 
bli n de d, i n de pe n de nt ce ntral re vie w 
([ BI C R]) a n d O S bet w ee n treat me nt ar ms 
t o esti mati o n of O R R (as assesse d per 
R E CI S T 1. 1 b y t he i n vesti gat or)  f or eac h 
treat me nt ar m after last pr ot oc ol- defi ne d 
sca n. P F S, D O R, a n d O S were re m o ve d as 
e n d p oi nts.  i R E CI S T will n o l o n ger be 
use d as a res p o nse ass ess me nt criteri o n.  
O R R is a reas o na ble e n d p oi nt  f or efficac y e val uati o n, gi ve n 
t he re d ucti o n i n t he le n gt h of efficacy d ata c ollecti o n .  
N o c o nfir mati o n of pr o gressi ve disease ( P D) or s ur vi val 
f oll o w- u p will be re q uire 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 
5. 1 O verall D esi g n 
5. 2 N u m ber of 
Partici pa nts  
1 0. 5. 2 Efficac y A nal ysis 
P o p ulati o ns 
1 0. 4. 1. 2 Sec o n dar y  
Re m o ve d all sec o n dar y efficac y e n d p oi nts  
a n d h y p ot h eses. 
P F S, O S, a n d D O R will n o l o n ger be f oll o we d i n t his st u d y.   
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 Tr eat me nt  
 
 
 
 
 
 
 
 
1. S y n o psis  
5. 1 O verall D esi g n 
5. 2 N u m ber of 
Part ici pa nts 
1 0. Statistical A nal ysis 
Pla n S u m mar y  
Re d uce d st u d y p o p ulati o n fr o m 6 3 0 t o 
1 3 0. 
As of 0 2 -M A Y -2 0 1 8 , e nr oll me nt was st o p pe d.  At t hat ti me 
t here were 1 0 1 p artici pa nts ra n d o mize d a n d 4 6 partici pa nts 
i n scree ni n g.  S u bjects i n scree ni n g are all o we d t o  c o nti n ue 
t hr o u g h scree ni n g pr oce d ures. 
1. S y n o psis  
5. 1 O verall D esi g n 
 
O n -st u d y i ma gi n g will o cc ur at t he 
Wee k  1 2 ( ± 7 da ys) visit a n d be assess e d 
b y t he i n vesti gat or rat her t ha n b y t he 
ce ntral ve n d or.  S u bse q u e nt i ma gi n g will 
be perf or me d per Sta n dar d o f Care ( S o C) 
a n d o nl y t he d ate of s u bs e q ue nt sca ns will 
be rec or de d i n t he e C R F.  
C ha n ge i n pri mar y e n d p oi nt t o O R R d oes n ot re q uire 
f oll o wi n g u p patie nts wit h i ma gi n g t o assess P F S, D O R, a n d 
O S e n d p oi nts.   
1. S y n o psis  
A p pe n di x 1, C o m mittee 
Str uct ure, Data 
M o nit ori n g C o m mittee  
Re m o ve d i nteri m a nal yses f or efficac y.  
N o l o n ger a p plica bl e gi ve n t he desi g n c ha n ge. O n l y safet y 
re vie w is n o w pla n n e d f or t he Data M o nit ori n g C o m mittee. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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.  Sc he d ule of A cti vities 
( S o A) 
A dj uste d S o A t o pr o vi de f or t he c ollecti o n  
of st u d y efficac y meas ure me nts u p t o t he 
first o n-st u d y i ma gi n g at Wee k 1 2 (± 7 d ). 
S ur vi val f oll o w u p will n o l o n ger be m o nit ore d .  O nce t he 
Wee k  1 2 ( ± 7 da ys) i ma gi n g is c o m plete d, partici pa nts will 
be f oll o we d u p f or safet y t hr o u g h t he 3 0- da y safet y f o ll o w-
u p usi n g sta n dar d of care pr oce d ures. 
2.  Sc he d ule of A cti vities 
( S o A) 
A dj uste d c ol u m ns a n d si m plifie d ta ble 
la y o ut t o reflect st u d y c h a n ges: 
•  Re m o ve d S ur vi val F oll o w- u p 
C ol u m n a n d R o w 
•  C o ns oli date d visits starti n g after 
Wee k  1 2 ( C ycl e 3 o n war d) 
•  U p date d n otes t o ali g n wit h 
c ha n ges i n t he S o A i n re gar d t o 
ti mi n g of visits a n d pr oce d ures t o 
be d o ne per S o C. 
Si m plifie d S o A t o reflect re d uce d s c o pe of t h e trial.  
2. Sc he d ule of A cti vities  
U p date d n ote f or t he 1 2 -l ea d 
electr ocar di o gra m t o a d d “a n d D C”.  
Clari ficati o n t hat all parti ci pa nts will ha ve a n E C G at 
disc o nti n uati o n. 
2. Sc he d ule of A cti vities  
A d de d t o n ote f or tiss ue sa m ple. “ Ma y use 
arc hi val tiss ue sa m ple t h at was o btai ne d 
pri or t o scree ni n g p eri o d as part of t he 
partici pa nt’s sta n dar d care. ” 
Ali g n me nt wit h ot her Merc k -I n c yt e c olla b orati o n pr ot oc ols. 
3. 2 Bac k gr o u n d  
U p date d refere nce t o t he I n v esti gat or’s 
Br oc h ure (I B) t o refer t o t he c urre nt 
versi o n. 
T he I B is u p d ate d re g ul arl y, s o refere nce t o a s pecific 
versi o n will bec o me o ut d ate d. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 St u d y Desi g n  
7. 8 Sec o n d C o urse P hase 
8. 1 Disc o nti n uati o n of 
St u d y Treat me nt  
9. 1 0. 4 Sec o n d C o urse 
P hase  
A d de d d urati o n f or pe m br oliz u ma b  of 
1 7. 5 c ycles f or I nitial Treat me nt a n d 
8. 5 c ycles f or S ec o n d C o urse 
Clarificati o n.  
5. 3. 1 Cli nical Criteria f or 
Earl y St u d y Ter mi nati o n  
U p date d wit h te m plate la n g ua ge re gar di n g 
earl y ter mi nati o n.  
C orrecti o n of o missi o n.  
7. 1 Treat me nts 
A d mi nistere d  
A d de d “as p az o pa ni b h y dr oc hl ori de” t o 
descri pti o n of treat me nts i n Ta ble 5  
Clarificati o n  
7. 2. 1 D ose M o dificati o n 
f or I m m u ne-r elate d 
A d verse E v e nts: Ta ble 6  
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 d es 
T o ali g n wit h K E Y T R U D A ® S u m mar y of Pr o d u ct 
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. 2. 4 I nterr u pti o ns 
U nrelate d t o A d v erse 
E ve nts 
A d de d b ol de d te xt:  
D osi n g i nterr u pti o ns are per mitte d  f or 
sit u ati o ns ot her t h a n tre at me nt-rel ate d 
A Es, s uc h as  i n t he case of 
me dical/s ur gical e v e nts or l o gistical 
reas o ns n ot rel ate d t o st u d y treat me nt (e g, 
electi ve s ur ger y, u nrelate d me dical e ve nts, 
partici pa nt vacati o n, or h oli da ys). 
Clarificati o n.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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. 2  A d mi nistrati o n a n d 
C o m plia nce of Oral St u d y 
Treat me nt ( E p aca d ost at, 
S u niti ni b, or Paz o pa ni b) 
Re m o v e d te xt s pecif yi n g t hat Sec o n d 
C o urse C 1 D 1 a d mi nistrati o n of 
e paca d ostat bei n g gi ve n at st u d y site.  
Clarificati o n  
7. 7. 2 Pr o hi bite d 
Me dicati o ns a n d Meas ur es  
# 8 - Mefe n a mic aci d,  re m o ve d fr o m liste d 
pr o hi bite d U G T 1 A 9 i n hi bit ors 
Ali g n me nt wit h c urre nt cli nical i nf or mati o n f or e p aca d ostat  
7. 8 Sec o n d C o urse P hase 
( Retreat me nt) 
Re m o ve d “ verifi e d b y BI C R” fr o m t he 
P D cr iteri o n f or e ntr y i nt o sec o n d c o urs e.  
Bli n de d, i n de pe n d e nt ce ntral verificati o n is n o l o n ger t o be 
re q uire d i n t his trial. 
8. 2 Wit h dra wal fr o m t he 
St u d y 
Re m o ve d te xt all o wi n g f or re mai ni n g o n 
st u d y aft er treat me nt disc o nti n uati o n f or 
s ur vi val f oll o w- u p. 
S ur vi val after disc o nti n u ati o n fr o m treat me nt will n o l o n ger 
be trac k e d i n t he st u d y.  
9. 1. 9 Ti mi n g of D ose 
A d mi nistrati o n  
A d de d t hat “fasti n g state” mea ns fasti n g 
f or 8 t o 1 2 h o urs. 
Clarificati o n  
9. 8. 3 Distri b uti o n of 
Partici pa nt Re mi n der 
Car ds a n d/ or Partici pa nt 
Diaries  
C orrecte d D a y 1 5 t o Da y 2 2.  
C orrecti o n t o ali g n wit h S o A.  
9. 1. 9. 1. 2 Ti mi n g of D ose 
A d mi nist rati o n of 
E paca d ostat  
A d de d (ie, 8 -1 2 hr fasti n g)  t o cl arif y 
“fasti n g state”  
Clarificati o n  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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  T u m or I m a gi n g a n d 
Assess me nt of Diseas e  
A p pe n di x 6 
N o i ma gi n g be y o n d t h e Wee k  1 2 sca n will 
be c ollecte d f or t he trial.  B o ne sca ns aft er 
Wee k 1 2 will n ot be c ollecte d. i R E CI S T 
will n o l o n ger be us e d t o assess res p o nse.  
I ma gi n g d o n e aft er Wee k 1 2 will be 
perf or me d p er S o C a n d assesse d l ocall y.  
I n v esti gat ors wis hi n g t o c o nti n ue t o treat 
after P D are t o c o ns ult wit h t he Merc k 
Cli nical Direct or.  Partici pa nts w h o e nter 
t he Sec o n d C o urse o nl y will be f oll o we d 
u p f or safet y. 
Reflects t he c h a n ge i n pri mar y e n d p oi nt t o O R R a n d t he 
re d uce d s c o pe of t h e st u d y. 
9. 1 0. 1 Scree ni n g  
La b orat or y tests are t o be d o ne 1 4 da ys 
pri or ra n d o mizati o n ( n ot first d ose). 
Ali g n me nt wit h sc he d ule of acti vities.  
9. 1 0. 3. 1 Safet y F oll o w -u p 
Visit  
9. 1 0. 3. 2 S ur vi val F oll o w-
u p 
9. 1 0. 3. 3. 1 S ur vi val Stat us 
M o nit ori n g 
U p date d t o i n dicate t hat t his is t he last 
visit, after w hic h t he partici pa nt will ha ve 
c o m plete d t he trial.  
U p date d n o w t hat s ur vi v al f oll o w -u p has bee n o mitte d.  
9. 1 0. 3. 2 F oll o w -u p Visits  
U p date d t o reflect c h a n ge i n t u m or 
i ma gi n g. 
I ma gi n g will be per S o C after t he Wee k 1 2 assess me nt. 
1 0. 1 Statistical A nal ysis 
Pla n S u m mar y  
 
 
 
1 0. 1 Statistical A nal ysis 
Pla n S u m mar y  
1 0. 4. 1 Efficac y E n d p oi nts 
U p date d O R R fr o m a k e y sec o n dar y 
e n d p oi nt t o pri mar y e n d p oi nt; Re m o ve d 
P F S, O S e n d p oi nts. 
O R R is n o w t he pri mar y efficac y e n d p oi nt; t here are n o 
sec o n dar y effi cac y e n d p oi nts. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 0. 1 Statistical A nal ysis 
Pla n S u m mar y  
1 0. 6. 1 Statistical Met h o ds 
f or Efficac y A n al yses 
1 0. 6. 2 Statistical Met h o ds 
f or Safet y A n al ys es  
Re m o ve d stati stical met h o ds f or a nal ysis 
of P F S a n d O S; a n d t o use t he Cl o p per –
Pears o n e x act met h o d t o esti mate O R R.  
Re vise d  a p pr oac h t o a nal yzi n g safet y dat a 
fr o m tiere d a p pr oac h t o s u m marizati o n b y 
descri pti ve statistics wit hi n gr o u p . 
U p date d t o be ali g ne d wit h u p date d o bjecti ves of t he st u d y.  
1 0. 7 I nteri m A nal yses  
U p date d t he I nteri m a n d Fi nal A nal ysis 
Secti o n t o s pecif y n o i nteri m efficac y 
a nal ys es a n d fi n al a nal ysis will be 
perf or me d after all ra n d o mize d 
partici pa nts ha ve h a d a n o p p ort u nit y t o 
ha ve 1 p ost bas eli ne sca n. e D M C will 
perf or m  safet y re vie w per D M C c harter.  
U p date d t o be ali g ne d wit h u p date d o bjecti ves of t he st u d y.  
1 0. 8 M ulti plicit y  
M ulti plicit y a dj ust me nt met h o ds were 
delete d.  
N o l o n ger a p plica bl e.  
1 0. 9 Sa m ple Size a n d 
P o wer Calc ulati o ns  
Sa m ple  size a n d p o wer s ecti o n was 
re vise d t o reflect t he c ha n ge i n e n d p oi nt 
a n d re d uce d sa m ple size.  
U p date d t o be ali g ne d wit h u p date d o bjecti ves of t he st u d y.  
1 0. 1 0 S u b gr o u p A n al ys es  
S u b gr o u p a n al ys es were delete d.  
N o l o n ger nee de d gi ve n t he li mite d sa m ple size. 
2. Sc he d ule of A cti vities  
A p pe n di x 4: Cli nical 
La b orat or y T ests  
Re m o ve d refere n ces t o ce ntral la b orat or y.  
O nl y l ocal la b orat ori es will be use d as of t his a me n d me nt.  
T hr o u g h o ut  
C orrecti o n of t y p o gra p hi cal, e dit orial a n d 
f or matti n g err ors. 
Mi n or e dits, n ot detaile d . 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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  
 
S y n o psis  .......................................................................................................................2 1  
1.
 
Sc he d ule of Acti vities ( S o A)  ......................................................................................2 4  
2.
 
I niti al Tre at me nt P h ase ..........................................................................................2 4  
2. 1
 
Sec o n d C o urse ( Ret re at me nt)  ................................................................................3 0  
2. 2
 
I ntr o d ucti o n ................................................................................................................3 3  
3.
 
St u d y R ati o n ale ....................................................................................................... 3 3  
3. 1
 
B ac k gr o u n d.............................................................................................................. 3 3  
3. 2
 P har mace utical a n d T hera pe utic Bac k gr o u n d  .....................................................3 4  
3. 2. 1
 O n g oi n g St u dies ................................................................................................... 3 6  
3. 2. 2
 
Be nefit/ Ris k Assess me nt  .........................................................................................3 6  
3. 3
 
O bjecti ves/ H y p ot heses a n d E n d p oi nts  .....................................................................3 9  
4.
 
St u d y Desi g n  ...............................................................................................................4 0  
5.
 
O ver all Desi g n  .........................................................................................................4 0  
5. 1
 St u d y Dia gr a m  .....................................................................................................4 2  
5. 1. 1
 
N u m ber of P artici p a nts  ..........................................................................................4 2  
5. 2
 
Be gi n ni n g a n d E n d of St u d y Defi niti o n  ................................................................4 2  
5. 3
 Cli nical Criteria f or Earl y St u d y Ter mi nati o n  .....................................................4 3  
5. 3. 1
 
Scie ntific R ati o n ale f or St u d y Desi g n  ....................................................................4 3  
5. 4
 Rati o nale f or E n d p oi nts ....................................................................................... 4 3  
5. 4. 1
 Efficac y E n d p oi nts ........................................................................................ 4 3  
5. 4. 1. 1
 Res p o nse E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1 ................. 4 3  
5. 4. 1. 1. 1
 M o difie d R E CI S T f or I m m u ne -base d T h era p e utics (i R E CI S T)  ...........4 3  
5. 4. 1. 1. 2
 Safet y E n d p oi nts  ...........................................................................................4 4  
5. 4. 1. 2
 
4 4  
 
4 5  
 
4 5  
 
4 5  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
4 5  
 
4 5  
 
4 6  
 
4 6  
 
4 6  
 
4 7  
 
4 7  
 
4 7  
 
4 7  
 Rati o nale f or t he Us e of C o m parat ors ................................................................. 4 8  
5. 4. 2
 
J ustific ati o n f or D ose  ..............................................................................................4 8  
5. 5
 
4 8  
 Rati o nale f or a Fi x e d D ose of Pe m br ol iz u ma b ....................................................4 9  
5. 5. 2
 Rati o nale f or D ose of S u niti ni b ........................................................................... 5 0  
5. 5. 3
 Rati o nale f or  D ose of Paz o pa ni b .........................................................................5 0  
5. 5. 4
 
St u d y P o p ul ati o n  ........................................................................................................5 0  
6.
 
I ncl usi o n Criteri a ....................................................................................................5 0  
6. 1
 
E xcl usi o n Criteri a  ...................................................................................................5 3  
6. 2
 
Lif est yle Restricti o ns ...............................................................................................5 6  
6. 3
 Meals a n d Dietar y Restri cti o ns  ............................................................................5 6  
6. 3. 1
 Caffei ne, Al c o h ol, a n d T o bacc o Restricti o ns ...................................................... 5 6  
6. 3. 2
 C o ntrace pti o n ....................................................................................................... 5 6  
6. 3. 3
 Pre g n a nc y  .............................................................................................................5 6  
6. 3. 4
 Use i n N ursi n g W o me n ........................................................................................ 5 7  
6. 3. 5
 
Scree n F ail ures  ........................................................................................................5 7  
6. 4
 
P artici p a nt Re pl ace me nt Str ate g y  .........................................................................5 7  
6. 5
 
Tre at me nts  ..................................................................................................................5 7  
7.
 
Tre at me nts A d mi nistere d .......................................................................................5 8  
7. 1
 
D ose M o dific ati o ns ( Esc al ati o n/ Titr ati o n/ Ot her)  ................................................5 9  
7. 2
 D ose M o dificati o n f or I m m u ne- relate d A d vers e E ve nts .....................................5 9  
7. 2. 1
 I nf usi o n Reacti o n D ose M o dificati o ns ................................................................6 9  
7. 2. 2
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 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 .............................. 7 0  
7. 2. 3
 I nterr u pti o ns U nr elate d t o A d verse E v e nts ..........................................................7 2  
7. 2. 4
 D ose M o dificati o ns f or S o C Gr o u p Partici pa nts ................................................. 7 2  
7. 2. 5
 M o dificati o ns f or S u niti ni b ........................................................................... 7 2  
7. 2. 5. 1
 M o dificati o ns f or Paz o pa ni b ......................................................................... 7 2  
7. 2. 5. 2
 
Met h o d of Tre at me nt Assi g n me nt  .........................................................................7 2  
7. 3
 Stratificati o n  .........................................................................................................7 3  
7. 3. 1
 
Bli n di n g  ....................................................................................................................7 3  
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 .................................................... 7 3  
7. 5
 D ose Pre parati o n  ..................................................................................................7 3  
7. 5. 1
 Ha n dli n g, St ora ge a n d A cc o u nta bilit y  .................................................................7 3  
7. 5. 2
 
Tre at me nt C o m pli a nce  ...........................................................................................7 4  
7. 6
 A d mi nistrati o n a n d C o m plia nce of Pe m br oliz u ma b ............................................ 7 4  
7. 6. 1
 A d mi nistrati o n a n d C o m plia nce of Oral St u d y Treat me nt ( E paca d ostat, 
7. 6. 2
S u niti ni b, or Paz o pa ni b) ....................................................................................... 7 4  
 
C o nc o mit a nt T her a p y  .............................................................................................7 4  
7. 7
 Acce pt a ble C o nc o mita nt T hera pies  .....................................................................7 5  
7. 7. 1
 Pr o hi bite d Me dicati o ns or T hera pi es ................................................................... 7 5  
7. 7. 2
 Restricte d Me dicati o ns  .........................................................................................7 7  
7. 7. 3
 Resc ue Me dicati o ns a n d S u p p orti ve Care ........................................................... 7 7  
7. 7. 4
 
Sec o n d C o urse P h ase ( Retre at me nt)  .....................................................................7 8  
7. 8
 
Tre at me nt After t he E n d of t he St u d y  ..................................................................7 8  
7. 9
 Cli nic al S u p plies Discl os ure  ...................................................................................7 8  
7. 1 0
 
Disc o nti n u ati o n/ Wit h dr a w al Criteri a  ......................................................................7 9  
8.
 
Disc o nti n u ati o n of St u d y Tre at me nt  .....................................................................7 9  
8. 1
 
Wit h dr a w al f r o m t he St u d y  ...................................................................................8 0  
8. 2
 
L ost t o F oll o w u p ..................................................................................................... 8 0  
8. 3
 
St u d y Assess me nts a n d Pr o ce d ures  ..........................................................................8 1  
9.
 
A d mi nistr ati ve a n d Ge ner al Pr oce d ures  ..............................................................8 1  
9. 1
 I nf or me d C o nse nt .................................................................................................8 1  
9. 1. 1
 I n cl usi o n/ E x cl usi o n Criteria ................................................................................8 2  
9. 1. 2
 Partici pa nt I de ntificati o n Car d  .............................................................................8 2  
9. 1. 3
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Ser ot o ni n S y n dr o me I nf or mati o n Car d ................................................................ 8 2  
9. 1. 4
 Me dical Hist or y  ...................................................................................................8 2  
9. 1. 5
 Pri or a n d C o nc o mita nt Me dicati o ns Re vie w ....................................................... 8 3  
9. 1. 6
 Pri or Me dicati o ns .......................................................................................... 8 3  
9. 1. 6. 1
 C o nc o mita nt Me dicati o ns ............................................................................. 8 3  
9. 1. 6. 2
 Assi g n me nt of Scr ee ni n g N u m ber ....................................................................... 8 3  
9. 1. 7
 Assi g n me nt of Treat me nt/ Ra n d o mizati o n N u m ber ............................................. 8 3  
9. 1. 8
 Treat me nt A d mi nistrati o n  ....................................................................................8 3  
9. 1. 9
 Ti mi n g of D ose A d mi nistrati o n  ....................................................................8 4  
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 4  
9. 1. 9. 1. 1
 Ti mi n g of D ose A d mi nistrati o n of E paca d ostat  ....................................8 4  
9. 1. 9. 1. 2
 Ti mi n g of D ose A d mi nistrati o n of S u niti ni b  .........................................8 5  
9. 1. 9. 1. 3
 Ti mi n g of D ose A d mi nistrati o n o f Paz o pa ni b ....................................... 8 5  
9. 1. 9. 1. 4
 Wit h dra wal/ Disc o nti n uati o n  ................................................................................8 5  
9. 1. 1 0
 Partici pa nt Bli n di n g/ U n bli n di n g  ..........................................................................8 5  
9. 1. 1 1
 Cali brati o n of Critical E q ui p me nt  ........................................................................8 5  
9. 1. 1 2
 
Effic ac y Assess me nts ...............................................................................................8 6  
9. 2
 T u m or I m a gi n g a n d Assess me nt of Disease ........................................................ 8 6  
9. 2. 1
 I nitial T u m or I m a gi n g ...................................................................................8 6  
9. 2. 1. 1
 T u m or I m a gi n g D uri n g t he St u d y ................................................................. 8 7  
9. 2. 1. 2
 E n d of Treat me nt a n d F oll o w- u p T u m o r I m a gi n g ........................................8 7  
9. 2. 1. 3
 Sec o n d C o urse P hase T u m or I m a gi n g .......................................................... 8 7  
9. 2. 1. 4
 R E CI S T 1. 1 Assess me nt of Disease  .............................................................8 8  
9. 2. 1. 5
 i R E CI S T Assess me nt of Disease ( Gr o u p 1) .................................................8 9  
9. 2. 1. 6
 
A d verse E ve nts, Seri o us A d verse E ve nts a n d Ot her Re p ort a ble S afet y 
9. 3
E ve nts  .......................................................................................................................9 1  
 Ti me Peri o d a n d Fr e q ue n c y f or C ollecti n g A E, S A E a n d Ot her 
9. 3. 1
Re p orta ble Safet y E v e nt I nf or mati o n  ..................................................................9 2  
 Met h o d of Detecti n g A E, S A E a n d Ot her Re p ort a ble Safet y E ve nts .................. 9 4  
9. 3. 2
 F oll o w- u p of A E, S A E a n d Ot her Re p orta ble Safet y E ve nt I nf or mati o n ............ 9 4  
9. 3. 3
 Re g ulat or y Re p orti n g Re q uire me nts f or S A E ..................................................... 9 4  
9. 3. 4
 Disease -Rel ate d E ve nts a n d/ or Disease -R elate d O utc o mes N ot 
9. 3. 5
Q ualif yi n g as A Es or S A Es  ..................................................................................9 4  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Pre g n a nc y a n d E x p os ure D uri n g Breastfee di n g  ..................................................9 5  
9. 3. 6
 E ve nts of Cli nical I nt erest ( E CI)  ..........................................................................9 5  
9. 3. 7
 
Tre at me nt of O ver d ose  ...........................................................................................9 5  
9. 4
 
S af et y  ........................................................................................................................9 6  
9. 5
 P h ysical E x a mi nati o ns  .........................................................................................9 6  
9. 5. 1
 F ull P h ysical E x a mi nati o n  ............................................................................9 6  
9. 5. 1. 1
 Directe d P h ysical E x a mi nati o n  .....................................................................9 6  
9. 5. 1. 2
 Vital Si g ns  ............................................................................................................9 7  
9. 5. 2
 Electr ocar di o gra ms  ..............................................................................................9 7  
9. 5. 3
 Cli nical Safet y La b orat or y Assess me nts ..............................................................9 7  
9. 5. 4
 La b orat or y Safet y E val u ati o ns ( He mat ol o g y , C he mistr y, 
9. 5. 4. 1
Uri nal ysis)  .....................................................................................................9 8  
 Pre g n a nc y T est  ..............................................................................................9 8  
9. 5. 4. 2
 Perf or ma nce Assess me nts  ....................................................................................9 8  
9. 5. 5
 Easter n C o o per ati ve O nc ol o g y Gr o u p Perf or ma n ce Scale ........................... 9 8  
9. 5. 5. 1
 Kar n ofs k y Perf or ma n ce Sc ore  ......................................................................9 8  
9. 5. 5. 2
 
9 8  
 
9 8  
 
9 9  
 
9 9  
 
9 9  
 
1 0 0  
 
1 0 0  
 
1 0 0  
 
1 0 0  
 
1 0 1  
 
1 0 1  
 
1 0 2  
 
1 0 2  
 
1 0 2  
 
1 0 2  
 
1 0 3  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0-3 0 2 - 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
1 0 3  
 Visit Re q uir e me nts  ................................................................................................1 0 3  
9. 1 0
 Scree ni n g  ............................................................................................................1 0 3  
9. 1 0. 1
 Treat me nt Peri o d Visit  .......................................................................................1 0 4  
9. 1 0. 2
 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 4  
9. 1 0. 3
 Safet y F oll o w - u p Visit ................................................................................1 0 4  
9. 1 0. 3. 1
 F oll o w- u p Visits ..........................................................................................1 0 4  
9. 1 0. 3. 2
 S ur vi val F oll o w- u p ..................................................................................... 1 0 5  
9. 1 0. 3. 3
 S ur vi val Stat us M o nit ori n g .................................................................. 1 0 5  
9. 1 0. 3. 3. 1
 U nsc he d ule d Visits ..................................................................................... 1 0 5  
9. 1 0. 3. 4
 Sec o n d C o urse P hase ......................................................................................... 1 0 5  
9. 1 0. 4
 
St atistic al A n al ysis Pl a n  ..........................................................................................1 0 6  
1 0.
 St atistic al A n al ysis Pl a n S u m m a r y  ......................................................................1 0 6  
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 7  
1 0. 2
 H y p ot h eses/ Esti m ati o n  .........................................................................................1 0 7  
1 0. 3
 A n al ysis E n d p oi nts  ................................................................................................1 0 7  
1 0. 4
 Efficac y E n d p o i nts .............................................................................................1 0 7  
1 0. 4. 1
 Pri mar y  ........................................................................................................1 0 7  
1 0. 4. 1. 1
 O bjecti ve  Res p o nse Rat e ( O R R)   – R E CI S T 1. 1  b y 
1 0. 4. 1. 1. 1
I n v esti gat or ..........................................................................................1 0 7  
 Safet y E n d p oi nts  ................................................................................................1 0 7  
1 0. 4. 2
 A n al ysis P o p ul ati o ns ............................................................................................. 1 0 7  
1 0. 5
 Efficac y A nal ysis P o p ulati o n ............................................................................. 1 0 7  
1 0. 5. 1
 Safet y A nal ysis P o p ulati o n ................................................................................ 1 0 7  
1 0. 5. 2
 St atistic al Met h o ds  ................................................................................................1 0 8  
1 0. 6
 Statistical Met h o ds f or Efficac y A nal yses  .........................................................1 0 8  
1 0. 6. 1
 O bjecti ve Res p o nse Rate ( O R R) – R E CI S T 1. 1 b y I n v esti gat or................ 1 0 8  
1 0. 6. 1. 1
 Statistical Met h o ds f or Safet y A nal ys es  ............................................................1 0 8  
1 0. 6. 2
 S u m maries of De m o gra p hic a n d Baseli ne C haract eristics  ................................1 0 9  
1 0. 6. 3
 I nteri m A n al yses ...................................................................................................1 0 9  
1 0. 7
 M ulti plicit y  ............................................................................................................1 0 9  
1 0. 8
 S a m ple Size a n d P o w er C alc ul ati o ns  ..................................................................1 0 9  
1 0. 9
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 S u b gr o u p A n al yses  ................................................................................................1 1 0  
1 0. 1 0
 C o m pli a nce ( Me dic ati o n A d here nce)  ..................................................................1 1 0  
1 0. 1 1
 E xte nt of E x p os ure ................................................................................................ 1 1 0  
1 0. 1 2
 
Ref ere nces  .................................................................................................................1 1 0  
1 1.
 
A p pe n dices  ................................................................................................................1 1 7  
1 2.
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 1 7  
Merc k C o de of C o n d u ct f or Cli nical Trials ................................................................... 1 1 7  
Fi na ncial Discl os ur e  .......................................................................................................1 1 9  
Data Pr otecti o n  ...............................................................................................................1 1 9  
C o nfi de ntialit y of Dat a .................................................................................................. 1 1 9  
C o nfi de ntialit y of Partici pa nt Rec or ds ........................................................................... 1 1 9  
C o nfi de ntialit y of I R B/I E C I nf or mati o n  ........................................................................1 2 0  
C o m mittees Str uct ure  .....................................................................................................1 2 0  
Trial Steeri n g C o m mittee  ...........................................................................................1 2 0  
J oi nt E x ec uti ve O versi g ht C o m mittee .......................................................................1 2 0  
Data M o nit ori n g C o m mittee  ......................................................................................1 2 0  
P u blicati o n P olic y  ..........................................................................................................1 2 1  
C o m plia nce wit h Trial Re gistr ati o n a n d Res ults P osti n g Re q uire me nts  .......................1 2 1  
C o m plia nce wit h La w, A u dit a n d De bar me nt ............................................................... 1 2 1  
Data Q ualit y Ass ur a nce  .................................................................................................1 2 2  
S o urce D oc u m e nts ......................................................................................................... 1 2 3  
St u d y a n d Site Cl os ure ................................................................................................... 1 2 3  
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 4  
Defi niti o ns  ......................................................................................................................1 2 4  
C o ntrace pti o n Re q uire m e nts .......................................................................................... 1 2 4  
Pre g n a nc y T esti n g  ..........................................................................................................1 2 6  
A p pe n di x 3:   A d verse E ve nts:  Defi niti o ns a n d Pr o ce d ures f or R ec or di n g, 
E v al u ati n g, F oll o w- u p, a n d Re p orti n g  ................................................................1 2 7  
Defi niti o n of A E ............................................................................................................ 1 2 7  
Defi niti o n of S A E .......................................................................................................... 1 2 8  
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 2 9  
Rec or di n g A E a n d S A E ................................................................................................. 1 2 9  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 3 3  
A p pe n di x 4:  Cli nic al L a b or at or y Tests  ........................................................................1 3 4  
A p pe n di x 5:  A b bre vi ati o ns a n d Tr a de m ar ks  ..............................................................1 3 6  
A p pe n di x 6:  Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of Dise ase 
Pr o g ressi o n  ............................................................................................................1 4 0  
A p pe n di x 7:  C yt oc hr o me P 4 5 0 I n hi bit ors/I n d ucers ....................................................1 4 4  
A p pe n di x 8:  I M D C Ris k C ate g ories  .............................................................................1 4 5  
A p pe n di x 9:  E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce Sc al e  ...................1 4 6  
A p pe n di x 1 0:  K ar n ofs k y Sc ore ...................................................................................... 1 4 7  
A p pe n di x 1 1:  Ne w Y or k He art Ass oci ati o n ( N Y H A) F u ncti o n al 
Cl assific ati o n ..........................................................................................................1 4 8  
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
LI S T O F T A B L E S  
 
Ta ble 1  
Sc he d ule of St u d y Acti vities f or I nitial Treat me nt P hase  ....................................2 4  
Ta ble 2  
Sc he d ule of St u d y Acti vities f or Sec o n d C o urse ( Retreat me nt) .......................... 3 0  
Ta ble 3  
Efficac y of E paca d ostat i n C o m bi nati o n wit h Pe m br oliz u ma b i n Re nal 
Cell Carci n o ma Patie nts t hat Recei ve d ≤1 Pri or Li nes of T hera p y ...................... 3 7  
Ta ble 4  
A de q u ate Or ga n F u ncti o n La b orat or y Val ues  ......................................................5 2  
Ta ble 5  
St u d y Treat me nts D uri n g Treat me nt P hase  ..........................................................5 8  
Ta ble 6  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne-
relate d A Es Ass o ciate d wit h Pe m br oliz u ma b or E paca d ostat ..............................6 0  
Ta ble 7  
D ose Le vel A dj ust me nts of E paca d ostat .............................................................. 6 9  
Ta ble 8  
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o di ficati o n a n d Treat me nt 
G ui deli nes ............................................................................................................. 6 9  
Ta ble 9  
Si g ns a n d S y m pt o ms of Ser ot o ni n S y n dr o me ...................................................... 7 1  
Ta ble 1 0  I ma gi n g a n d Treat me nt After First Ra di ol o gic E vi de nce of P D ..........................9 0  
Ta ble 1 1  
Re p orti n g Ti me Peri o ds a n d Ti mefra m es f or A d v erse E ve nts a n d Ot her 
Re p orta ble Safet y E v e nts  ......................................................................................9 3  
 
 
 .........................................................................................................9 9  
 
 
 ......................................................................................9 9  
Ta ble 1 4  
A nal ysis Strate g y f or Safet y Para meters  ............................................................1 0 8  
Ta ble 1 5  
9 5 % CIs f or Diff er e nt O bser ve d Res p o nse Rat es............................................... 1 0 9  
Ta ble 1 6  
Hi g hl y Effecti ve C o ntrace pti o n Met h o ds ........................................................... 1 2 5  
Ta ble 1 7  
Pr ot oc ol- Re q uire d Safet y La b orat or y Ass ess me nts  ...........................................1 3 4  
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


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


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
S y n o psis  
1.
Pr ot oc ol Title:   
A Ra n d o mize d, O pe n- La bel, P hase 3 St u d y t o E val uate Efficac y a n d Safet y of 
Pe m br oliz u ma b ( M K- 3 4 7 5) pl us E paca d ostat vs Sta n dar d of Care ( S u niti ni b or Paz o pa ni b) 
as First-Li ne Treat me nt f or L o call y A d va n ce d or Metastatic Re nal Cel l Carci n o ma 
( m R C C) ( K E Y N O T E- 6 7 9/ E C H O- 3 0 2) 
S h ort Title:  
P e m br oliz u ma b  ( M K- 3 4 7 5) pl us Epaca d ostat vs S o C i n m R C C 
O bjecti ves/ H y p ot hes es a n d E n d p oi nts: 
N O T E:  As of A me n d me nt 0 6 , 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 y 
Res p o nse E v al u ati o n Criteri a 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 g at or after c o m pl eti o n of t he first pr ot oc ol- defi ne d effic ac y  i m a gi n g 
assess me nt.  A sec o n d ar y e n d p oi nt will e x a mi ne t he s afet y a n d t oler a bilit y i n 
p artici p a nts tre at e d  wit h  pe m br oliz u m a b pl us e p ac a d os t at a n d i n t h ose tre ate d wit h 
s u niti ni b or p az o p a ni b as st a n d ar d of c are ( S o C).  All ot her effic ac y e n d p oi nts will n o 
l o n ger be a n al yze d.   
T his st u d y will e nr oll partici pa nts wit h l ocall y a d v a nce d/metastatic re nal cell carci n o ma 
( m R C C) wit h a clear cell c o m p o ne nt.  Partici pa nts  m ust n ot ha ve recei ve d pri or s yste mic 
t hera p y f or t h eir m R C C .   
O bjecti ve/ H y p ot hesis  
E n d p oi nt  
Pri m ar y  
•  O bjecti ve:  T o esti mate t he o bjecti ve 
res p o nse r ate ( O R R) as meas ure d p er 
R E CI S T  1. 1 b y i n vesti gat or 
deter mi nati o n of pe m br oliz u ma b 
pl us e paca d ostat a n d sta n dar d of care 
( S o C) (s u niti ni b or paz o pa ni b) 
•  O R R is  defi ne d as t he pr o p orti o n of 
partici pa nts w h o ha v e a b est 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 u ate 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 a n d  S o C 
•  Safet y a n d t olera bilit y of t he treat me nt 
re gi me ns as meas ure d b y t he f oll o wi n g: 
o  N u m ber of partici pa nts e x perie nci n g 
a d verse e ve nts ( A Es)   
o  N u m ber of partici pa nts disc o nti n ui n g 
st u d y treat me nt d ue t o A Es   
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
O ver all Desi g n:  
St u d y P has e  
P hase III  
Cli nical I n dicati o n  
Treat me nt of l ocall y a d v a nce d/metastatic re nal cell 
carci n o ma ( m R C C)  
P o p ulati o n 
Partici pa nt s wit h l ocall y a d va nce d/metastatic re n al cell 
carci n o ma ( m R C C) wit h clear cell c o m p o ne nt.  
Partici pa nts m ust n ot ha ve recei ve d pri or s yste mic t hera p y 
f or t heir m R C C .  
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 , acti ve c o m parat or   
T y pe of C o ntr ol 
Acti ve c o ntr ol wit h o ut place b o 
St u d y Bli n di n g 
U n bli n de d O pe n- la b el 
Esti mate d D urati o n 
of Trial  
T he st u d y is esti mated t o re q uire a p pr o xi matel y 5 years  
fr o m t he ti me t he first partici pa nt si g ns t he i nf or m e d 
c o nse nt u ntil t he last partici pa nt’s last st u d y-relate d p h o ne 
call or visit. 
 
N u m ber of P artici p a nt s: 
A p pr o xi matel y 6 3 0 p arti ci pa nts will be e nr olle d.  
N ote:  Ori gi n all y, a p pr o xi m at el y 6 3 0 p artici p a nts w ere t o be e nr olle d, b ut as of 
A me n d me nt 0 6 o n 0 2- M A Y - 2 0 1 8, e nr oll me nt w as per m a ne ntl y st o p pe d.  It is 
esti m ate d t h at b y t he ti me t he str ate gic d ecisi o n w as m a de t o st o p e nr oll me nt t h at 
1 3 0 p artici p a nts will be r a n d o mize d i n t his st u d y.  
Tre at me nt Gr o u ps a n d D ur ati o n : 
Treat me nt Gr o u ps 
Gr o u p 1:  Pe m br oliz u ma b 2 0 0 m g  i ntra ve n o usl y (I V) e v er y 
t hree wee ks ( Q 3 W) pl us e paca d ostat 1 0 0 m g orall y ( P O)  
t wice dail y (bi d) c o nti n u o usl y 
Gr o u p 2 ( S o C):  S u niti ni b 5 0 m g P O o nce d ail y  ( 6-wee k 
c ycles; 4 wee ks o n treat me nt f oll o we d b y 2 wee ks off  
treat me nt) or p az o pa ni b 8 0 0 m g P O o nce d ail y  
c o nti n u o usl y 
As of A me n d me nt 0 6 , after t he partici pa nt c o m pletes 
Wee k  1 2 i ma gi n g, partici pa nts ca n c h o os e t o disc o nti n ue 
fr o m t he st u d y or c o nti n u e 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 v e cli nical be n efit a n d after 
disc ussi o n wit h t he i n vesti gat or. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 ns e nt f or m t hr o u g h 
t he fi nal c o ntact. 
After a s cree ni n g peri o d of u p t o 2 8 da ys, eac h eli gi ble 
partici pa nt will be assi g n e 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 Es, i nterc urre nt 
ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt, 
I n v esti 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 o ce d ur al  
re q uire me nts, or a d mi nistrati ve reas o ns re q uiri n g cessati o n 
of treat me nt . Partici pa nts i n Gr o u p 1 will recei v e a 
ma xi m u m of  3 5 a d mi nistrati o ns of pe m br oliz u ma b 
(a p pr o xi matel y 2 years). 
Partici pa nts i n Gr o u p 1 w h o st o p st u d y treat me nt (f o r 
reas o ns ot her t h a n diseas e pr o gressi o n or i nt olera bilit y) 
wit h S D or P R after recei vi n g 3 5 i nf usi o ns of 
pe m br oliz u ma b or partici pa nts w h o st o p st u d y treat me nt 
after attai ni n g a C R ( wit h a mi ni m u m of 8 i nf usi o ns of 
pe m br oliz u ma b a n d at least 2 i nf usi o ns be y o n d t h e date 
w he n i nitial C R was declare d) m a y be eli gi ble f or u p t o 1 7 
a d diti o nal i nf usi o ns (a p pr o xi matel y 1 year) of 
pe m br oliz u ma b pl us e paca d ostat u p o n e x perie nci n g 
ra di o gra p hic disease pr o gressi o n. Please refer t o Secti o n 
7. 8 f or c o m plete set of r ules re gar di n g eli gi bilit y f or 
retreat me nt. After t he e n d of treat me nt, eac h partici pa nt 
will be f oll o we d f or t he o cc 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. 
S u bjects w h o disc o nti n ue f or reas o ns ot her t ha n C R or 
c o m pleti o n of 3 5 i nf usi o ns wit h S D or better will 
disc o nti n ue fr o m t he st u d y after S afet y F oll o w- u p V isit 
a n d ha ve p ost treat me nt f oll o w u p i ma gi n g f or dis ease 
stat us m o nit ori n g perf or me d per l ocal sta nd ar ds.   
 
 
St u d y g o v er n a 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 5. 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Sc he d ule of Acti vities ( S o A)  
2.
 
I niti al Tre at me nt P h ase 
2. 1
As of A me n d me nt 0 6 , after Wee k 1 2 assess me nt, 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 p artici p a nt disc ussi o n wit h t he i n vesti g at or a n d if t he y are  recei vi n g cli nic al be nefits.  F or 
t h ose p artici p a nts re m ai ni n g i n t he st u d y, pr oce d ures are si m plifie d.  T he S o A h as bee n a me n de d t o s h o w o nl y t he re q uire d 
assess me nts.   
Ta ble  1  
Sc he d ule of St u d y Acti vities  f or I nitial Treat me nt  P hase  
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
A d mi nistr ati ve Pr oce d ures  
I nf or me d C o nse nt 
X 
 
 
 
 
 
 
 
 
Ma y be o btai ne d u p t o 4 2  da ys pri or t o C 1 D 1. 
P artici pa nts d o n ot nee d t o be rec o nse nte d if c o nse nt 
was o btai ne d greater t ha n 4 2 da ys pri or t o C 1 D 1  
I ncl usi o n/ E xcl usi o n 
Criteria 
X 
 
 
 
 
 
 
 
 
 
P artici pa nt I D Car d 
Iss ue d 
X 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X 
 
 
 
 
 
 
 
 
 
R C C Disease 
Hist or y  
X 
 
 
 
 
 
 
 
 
 
S m o ki n g Hist or y  
X 
 
 
 
 
 
 
 
 
 
Pri or/ C o nc o mita nt 
Me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ra n d o mize 
partici pa nt i n 
I V R S/I W R S 
X 
 
 
 
 
 
 
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
I nter nati o nal 
Metastatic Re nal 
Cell Carci n o ma 
Data base 
C o ns orti u m 
(I M D C) 
X 
 
 
 
 
 
 
 
 
 
Ser ot o ni n 
S y n dr o me 
I nf or mati o n Car d 
 
X 
 
 
 
 
 
 
 
 
P ost -st u d y A nti-
ca ncer T hera p y 
Stat us  
 
 
 
 
 
 
 
X 
X 
 
Cli nic al Ass ess me nts a n d Pr oce d ures  
Re vie w A d verse 
E ve nts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Secti o n 9. 3. 1 f or ti me peri o d a n d fre q ue nc y of 
re p orti n g. 
F ull P h ysical 
E xa mi nati o n  
X 
 
 
 
 
 
 
X 
 
 
Directe d P h ysical 
E xa mi nati o n  
 
X  
X  
X 
X 
X 
X 
 
X 
 
Vital Si g ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hei g ht at Scree ni n g o nl y .  O btai n pre d ose. 
1 2 -Lea d E C G wit h 
Q Tc Meas ure me nt  
X 
X  
 
X 
 
 
 
X 
 
At Scree ni n g a n d D C f or all partici pa nts.  
At sele ct ce nters, perf or m o n C 1 D 1 a n d C 1 D 2 2 pre d ose 
a n d at 2  h ( ± 1 5 mi n) after m or ni n g d ose of e paca d ostat. 
E C O G Stat us  
X 
X 
 
X 
X 
X 
X 
 
X 
P erf or m d uri n g scree ni n g,  wit hi n 1 4  d pri or t o 
ran d o mizati o n  
Kar n ofs k y 
P erf or ma nce Stat us  
( K P S) 
X 
 
 
 
 
 
 
 
 
P erf or m d uri n g scree ni n g, wit hi n 1 4 d pri or t o 
ra n d o mizati o n 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
L a b or at or y Pr oc e d ur es/  Assess me nts – A n al ysis Perf o r me d b y L oc al L a b or at or y  
Pre g na nc y Test – 
Uri ne or Ser u m 
β- H C G  
X 
 
 
 
 
 
 
 
 
W O C B P re q uire ne gati ve test wit hi n 7 2 h pri or t o 
ra n d o mizati o n. Test m o nt hl y (ie, bef ore eac h c ycle) if 
re q uire d b y l ocal re g ulati o ns. 
He patitis B & C   
X 
 
 
 
 
 
 
 
 
At Scree ni n g  wit hi n 1 4  da ys pri or t o ra n d o mizati o n. 
He p atitis B s urface a nti ge n, H B V -D N A, H C V -R N A ( or 
H C V a nti b o d y if H C V -R N A is n ot t he l ocal S o C ). If 
t his testi n g was c o n d ucte d per S o C  wit hi n 4 2  da ys pri or 
t o ra n d o mizati o n, testi n g d oes n ot nee d t o be re peate d. 
HI V Testi n g  
X 
 
 
 
 
 
 
 
 
N ot re q uire d u nless ma n date d b y l ocal healt h a ut h orit y.  
P T/I N R a n d 
a P T T/ P T T  
X 
 
 
 
 
 
 
 
 
At Scree ni n g  wit hi n 1 4  da ys pri or t o ra n d o mizati o n. 
P artici pa nts recei vi n g c o u mari n -base d a ntic oa g ula nts 
s h o ul d ha ve m ore fre q ue nt I N R m o nit ori n g - wee kl y f or 
first 4 we e ks after i nitiati o n of t hera p y or per sta n dar d 
or p er sta n dar d of care a n d u p o n D C of e paca d ostat.  
C B C Wit h 
Differ e ntial  
X 
 
X 
X 
X 
X 
X 
X 
X 
At Scree ni n g wit hi n 1 4  da ys pri or t o ra n d o mizati o n.   
F or Gr o u p  2 o nl y:  Assess as per S o C after t he Wee k  1 2 
i ma gi n g. 
C he mistr y  
X  
 
X 
X 
X 
X 
X 
X 
X 
T 3/ F T 3, F T 4, a n d 
T S H  
X 
 
 
X 
 
X 
X 
X 
X 
At Scree ni n g  wit hi n 1 4  da ys pri or t o ra n d o mizati o n .  
P erf or m Q 6 W fr o m C 1 D 2 2 o n war ds ( C 1 D 2 2, C 2 D 2 2, 
C 3 D 2 2 …) t hr o u g h o ut treat me nt peri o d.   F or Gr o u p  2 
o nl y:  Ass ess as per S o C after t he Wee k  1 2 i ma gi n g.  
Uri nal ysis   
X  
 
 
X 
 
X 
X 
X 
X 
At Scree ni n g  wit hi n 1 4  da ys pri or t o ra n d o mizati o n.  
P erf or m Q 6 W fr o m C 1 D 2 2 t hr o u g h C 4 D 2 2.  
P erf or m Q 1 2 W t hereaft er, starti n g  at C 6 D 2 2 ( C 6 D 2 2, 
C 8 D 2 2, C 1 0 D 2 2 …) t hr o u g h o ut treat me nt .  F or Gr o u p 2 
o nl y:  Ass ess as per S o C after t he Wee k  1 2 i ma gi n g.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
Effic ac y M e as ure me nts  
I ma gi n g –  
c hest, a b d o me n, 
pel vis  
X 
X 
P er S o C  
X c 
 
P erf or m wit hi n 2 8  d pri or t o ra n d o mizati o n  
Baseli ne C A P C T/ M RI t o be perf or me d i n all 
p artici pa nts wit hi n 2 8 da ys pri or t o ra n d o mizati o n. 
I ma gi n g ass ess me nt will be perf or me d at 1 2  wee ks ( ± 7 
d a ys) aft er ra n d o mizati o n. T hereafter i ma gi n g is t o be 
p erf or me d as per S o C f or t he disease a n d l ocal 
g ui del i nes; O nl y t he date of s u bse q ue nt sca ns nee ds t o 
b e e ntere d i nt o t he e C R F  
I ma gi n g –  
b o ne sca n  
X 
X 
P er S o C  
X c 
 
P erf or m wit hi n 2 8 d pri or t o ra n d o mizati o n . After 
ra n d o mizati o n, b o ne sca n will be perf or me d if p ositi ve 
at b aseli ne, at 1 2 wee ks ( ± 7 da ys) t he n as per l ocal S o C.  
Sc h e d ule s h o ul d be f oll o we d re gar dless of treat me nt 
d ela ys. O nl y t he date of s u bse q ue nt sca ns nee ds t o be 
e ntere d i nt o t he e C R F . 
I ma gi n g –  
brai n  
X 
 
P er S o C  
X c 
 
M RI preferre d  
P erf or me d d uri n g scree ni n g f or partici pa nt s wit h brai n 
metastas is t o e ns ure partici pa nt is sta ble (acc or di n g t o 
E xcl usi o n Criteri o n 5). O nl y t he date of s u bse q ue nt 
sca ns nee ds t o be e ntere d i nt o t he e C R F. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
2 9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Scree ni n g  
Tre at me nt C ycles  ( 6-Wee k C ycles)  
E O T  
P ost -Tre at me nt  
S afet y F oll o w -u p b  
N otes  
St u d y Peri o d  
C 1  
C 2  
C 3 o n w ar ds  
D C  
Assess me nts/ pr oce d ures are t o be perf or me d o n 
D a y  1 a n d D a y  2 2 pri or t o t he fi rst d ose of tre at me nt 
f or e ac h c ycle u nl ess ot he r wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y tre at me nt f or 
w h ate ver re as o n will pr oce e d di rectl y t o E O T a n d 
S afet y F oll o w -u p.  
D a ys  
 
1 
8 a 
2 2  
1 
2 2  
 
At D C  
3 0 D a ys P ost -L ast 
D ose  
+ 7  
 
F oll o w -u p  
Sc he d uli n g Wi n d o w 
( D a ys): 
– 2 8  
t o – 1 
± 3  
± 3  
± 3  
± 3  
± 3  
St u d y M e dic ati o n A d mi nistr ati o n a n d/ o r Dis pe nsi n g  
P e m br oliz u ma b 
I nf usi o n 
 
X 
 
X 
X 
X 
X 
 
 
P e m b r oliz u ma b will be a d mi nistere d Q3 W ( D 1 a n d D 2 2 
of eac h c ycl e)  
M or ni n g d ose of e paca d ostat d ose d i n cli nic o n C 1 D 1 
a n d C 2 D 1 pri or t o t he pe m br oliz u ma b i nf usi o n. At all 
ot h er ti mes, e paca d ostat t o be self -a d mi nistere d 
a p pr o xi matel y Q 1 2 H . 
E paca d ostat  
dis pe nse d  
 
X 
 
X 
X 
X 
X 
 
 
S u niti ni b  dis pe nse d  
 
X 
 
 
X 
 
X 
 
 
 
P az o pa ni b 
dis pe nse d  
 
X 
 
 
X 
 
X 
 
 
 
Assess C o m plia n ce  
 
X 
 
X 
X 
X 
X 
 
 
F or oral st u d y me dicati o ns  
N otes:  
a. 
C ycle 1 Da y 8 ( W 2) a p plies O N L Y t o Gr o u p 2/ S o C  ar m.  
b.  
If Disc o nti n u ati o n V isit o cc urs ≥3 0 d a ys fr o m last d ose of st u d y treat me nt, a Safet y F oll o w-u p Visit is n ot re q uire d.  
c. 
O nl y a p plica ble if a p artici p a n t disc o nti n u es st u d y treat me nt b ef ore Wee k 1 2 . 
A b bre viati o ns: A E = a d vers e e ve nt; a P T T = acti vat e p artial t hr o m b o plasti n ti me;  C B C =c o m plete bl o o d c o u n t; C X D X = C ycle X Da y X; d = da ys; D C = disc o nti n uati o n; E C G = 
electr ocar di o gra m; E C O G  = East er n C o o p erati ve O n c ol o g y Gr o u p; 
 E O T = e n d of treat me nt; 
; H B V / H C V = 
he patitis B/ C vir us; HI V = h u ma n i m m u n o d eficie n c y vir us; I C F = i nf or me d c o nse nt f or m; I D = i d e n tificati o n; I N R =i nter nati o nal n or malize d rati o; I V R S/I W R S = I nteracti ve 
v oice/ we b res p o nse s yste m ; mi n = mi n utes; N S A E = n o n -seri o us a d verse e ve nt; P D = pr o gressi ve disease; 
; P T = pr ot hr o m bi n ti me; P T T = partial 
t hr o m b o plasti n ti me; Q = e ver y; 
; S A E = seri o us a d verse e ve nt; S o C = sta n dar d of care; w k = wee ks; W O C B P = w o me n of 
c hil d -beari n g p ote ntial.  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 0  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Sec o n d C o urse ( Ret re at me nt)  
2. 2
As of A me n d me nt 0 6, f or p artici p a nts re m ai ni n g i n t he st u d y w h o are eli gi b le f or t he Sec o n d C o urse P h ase, pr oce d u res are 
si m plifie d. T he S o A h as bee n a me n de d a n d assess me nts n o l o n ger re q uire d h a ve bee n delete d.  Dise ase assess me nts will be 
perf or me d b y t he sites as per S o C f or t he dise ase a n d l oc al g ui deli nes.  
Ta ble 2  
Sc he d ule of St u d y Acti vities  f or Sec o n d C o urse ( Retreat me nt) 
 
Tre at me nt C y cles ( 6 -w ee k c y cles)  
E O T  
P ost -tre at me nt 
N otes  
St u d y Peri o d  
C 1  o n w ar d  
D C  
S afet y 
 F oll o w -u p a 
 
D a ys  
D 1  
D 2 2  
At D C  
3 0 D a ys P ost 
L ast D os e  
Sc he d uli n g Wi n d o w ( D a ys): 
± 3  
± 3  
N A  
+ 7  
A d mi nistr ati ve Pr oce d ures  
Eli gi bilit y Criteria  
X 
 
 
 
 
C o nc o mita nt Me dicati o ns  
X 
X 
X 
X 
 
S u bse q ue nt A nti n e o plastic T h era p y 
Stat us  
 
  
X 
X 
 
Cli nic al Ass ess me nts a n d Pr oce d ures  
Re vie w A d verse E ve nts  
X 
X 
X 
X 
Re p ort all A Es ( N S A Es a n d S A Es) occ urri n g wit hi n 9 0 da ys after 
t h e last d ose of st u d y treat me nt, or 3 0 da ys after t he last d ose of 
st u d y treat me nt if a ne w a nti-ca ncer t hera p y is i nitiate d, 
w hic h e ver is earlier.  
F ull P h ysical E xa mi n ati o n  
X 
 
X 
 
 
Directe d P h ysical E xa mi n ati o n  
X  
X 
 
X 
P erf or m as per S o A e xce pt at C 1 D 1 , w he n a f ull p h ysical e xa m is 
t o b e p erf or me d. 
Vital Si g ns  
X 
X 
X 
X 
O btai n pre d ose.  
1 2 -Lea d E C G wit h Q Tc Meas ure me nt  
X 
 
X 
 
P erf or m wit hi n 1 4 d pri or t o sec o n d c o urse C 1 D 1.  
E C O G Stat us  
X 
X 
X 
X 
B ot h E C O G a n d K P S are perf or me d wit hi n 1 4 d pri or t o sec o n d 
c o urse C 1 D 1. O nl y E C O G is perf or me d  after sec o n d c o urse 
C 1 D 1.  
K ar n ofs k y P erf or m a nc e St at us  
X 
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Tre at me nt C y cles ( 6 -w ee k c y cles)  
E O T  
P ost -tre at me nt 
N otes  
St u d y Peri o d  
C 1  o n w ar d  
D C  
S afet y 
 F oll o w -u p a 
 
D a ys  
D 1  
D 2 2  
At D C  
3 0 D a ys P ost 
L ast D os e  
Sc he d uli n g Wi n d o w ( D a ys): 
± 3  
± 3  
N A  
+ 7  
St u d y M e dic ati o n A d mi nistr ati o n a n d/ o r Dis pe nsi n g  
P e m br oliz u ma b I nf usi o n  
X 
X 
 
 
P e m br oliz u ma b will be a d mi nistere d Q 3 W ( D 1 a n d D 2 2 of eac h 
sec o n d c o urse c ycle) 
E p aca d ostat is d ose d i n cli nic o n  sec o n d c o urse C 1 D 1 pri or t o 
p e m br oliz u ma b i nf usi o n; self -a d mi nistere d t hereafter.  
E paca d ostat  
X 
X 
 
 
Assess C o m plia n ce  
X 
X 
 
 
F or e p aca d ostat  
L a b or at or y Pr oc e d ur es / Assess me nts:  A n al ysis Perf or me d b y L oc al L a b or at or y  
Pre g na nc y Test – Uri n e or Ser u m 
β- H C G  
X 
 
 
 
W O C B P re q uire ne gati ve test wit hi n 7 2 h pri or t o sec o n d c o urse 
C 1 D 1 . Test m o nt hl y if re q uire d b y l ocal re g ulati o ns. 
P T/I N R a n d a P T T / P T T 
X 
 
 
 
Wit hi n 1 4  d pri or t o sec o n d c o urse C 1 D 1 . P artici pa nts recei vi n g 
c o u mari n -base d a ntic oa g ula nts s h o ul d ha ve m ore fr e q ue nt I N R 
m o nit ori n g - wee kl y f or first 4  w k after i nitiati o n of t hera p y a n d 
u p o n D C of e paca d ostat.  
C B C Wit h Differe ntial  
X 
X 
X 
X 
Wit hi n 1 4  d pri or t o sec o n d c o urse C 1 D 1.  
C he mistr y  
X 
X 
X 
X 
T 3/ F T 3, F T 4, a n d T S H  
X 
 
X 
X 
Wit hi n 1 4 d pri or t o sec o n d c o urse C 1 D 1. P erf or m Q 6 W fr o m 
C 2 D 1 o n war ds ( C 2 D 1, C 3 D 1,  
C 4 D 1 …) t hr o u g h t he treat me nt peri o d.  
Uri nal ysis  
X 
 
X 
X 
Wit hi n 1 4 d pri or t o sec o n d c o urse C 1 D 1.  
P erf or m Q 6 W fr o m C 1 D 1 t o C 4 D 1).  
P erf or m Q 1 2 W t hereaft er, starti n g at C 6 D 1 ( C 6 D 1, C 8 D 1, 
C 1 0 D 1 …) t hr o u g h o ut treat me nt peri o d.  
Effic ac y M e as ure me nts  
 
 
 
T u m or I ma gi n g (c h est, a b d o me n a n d 
pel vis [ C A P] C T/ M RI)  
X 
As p er S o C  
P erf or m wit hi n 2 8 d pri or t o s ec o n d c o urs e C 1 D 1. Ima gi n g t o 
b e p erf or me d as per l ocal S o C  f or t he disease a n d l ocal 
g ui d eli n es , o nl y t he date of sca ns perf or me d as per S o C nee ds t o 
b e d o c u me nte d i n t he e C R F.  
B o ne Sca n  
X 
As p er S o C  
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
N otes:  
a. 
If sec o n d c o urse Disc o nti n u ati o n visit o cc urs ≥3 0 d a ys fr o m last d ose of st u d y treat me nt, a sec o n d c o urse Safet y F oll o w -u p Visit is n ot re q uire d.  
A b bre viati o ns: A E =a d verse e v e nt; a P T T =acti v ate p artial t hr o m b o plasti n ti me; C B C =c o m plete bl o o d c o u n t; C X D X = C ycle X Da y X; d = da ys; D C = disc o nti n uati o n; E C G = 
electr ocar di o gra m; E C O G = East er n C o o p erati ve O n c ol o g y Gr o u p;  E C G = electr o car di o gra m;  
; E O T = e n d 
of treat me nt; H  or h = h o urs; H B V / H C V =  h e p atitis B/ C vir us;  HI V = h u ma n i m m u n o d eficie n c y vir us; I C F =i nf or me d c o nse nt f or m; I D = i de ntificati o n; I N R =i nter nati o nal 
n or malize d rati o; mi n = mi n utes; N A = n ot a p plica ble; N S A E = n o n -seri o us a d verse e ve nt; P D = pr o gressi ve diseas e; 
; P T = pr ot hr o m bi n ti me; P T T =partial 
t hr o m b o plasti n ti me; Q = e ver y; S A E = s eri o us a d verse e ve nt; S o C = sta n d ar d of care; w k = we e k (s); W O C B P = w o me n of c hil d-beari n g p ote ntial . 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
I ntr o d ucti o n 
3.
 
St u d y R ati o n ale  
3. 1
Beca use of t o xicities wit h T KIs, a n d i ne vita ble rela pse or diseas e pr o gressi o n wit h c urre nt 
t hera pies, t her e is u n met me dical nee d f or safe a n d effecti ve c o m bi nati o n t hera pies f or clear-
cell R C C.  B ot h i n d olea mi ne 2, 3- de o x y ge nas e 1  (I D O 1) a n d pr o gra m me d cell deat h 1 
( P D- 1) rece pt or h a ve b ee 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 v e bee n s h o w n t o be c o-e x presse d i n m ulti ple ca ncer 
t y pes a n d t o c orr elate wit h p o or pr o g n osis.  C o m bi ne d i n hi biti o n of b ot h pat h wa ys ma y 
t heref or e lea d t o i ncreas e d efficac y.   
Rece ntl y, ni v ol u ma b recei ve d a p pr o v al b y  t h e U S F o o d a n d D r u g A d mi nistrati o n ( F DA) t o 
treat patie nts wit h a d va n ce d R C C w h o ha ve recei ve d pri or a nti- a n gi o ge nic t hera p y. 
Ni v ol u ma b is a n i m m u ne c hec k p oi nt i n hi bit or tar geti n g pr o gra m me d cell deat h pr otei n 1 
(P D - 1). T he a p pr o val w as base d o n data fr o m a ra n d o mize d P hase III o pe n- la bel st u d y i n 
patie nts wit h a d va nce d R C C f oll o wi n g pri or treat me nt wit h tar gete d t hera p y. Ni v ol u ma b 
de m o nstrate d statistical l y si g nifica nt i m pr o ve m e nt i n t he pri mar y e n d p oi nt of O S vers us  
e ver oli m us d uri n g t h e pla n ne d i nteri m a nal ysis ( me dia n 2 5. 0 m o nt hs vers us  2 1. 8 m o nt hs; 
H R: 0. 7 3 ( 9 8. 5 % C o nfi de nce I nt er val [ CI]: 0. 5 7 t o 0. 9 3; P =. 0 0 2 met t he pre -s pecifi e d 
si g nifica n ce P ≤. 0 1 4 8).  T he O R R was 2 5 % f or ni v ol u ma b vers us 5 % f or e v er oli m us ( o d ds 
rati o 5. 9 8; 9 5 % CI: 3. 6 8 t o 9. 7 2; P <. 0 0 1). P F S was n ot si g nifica ntl y i m pr o ve d wit h a me dia n 
P F S 4. 6 m o nt hs f or ni v ol u ma b vers us 4. 4 m o nt hs f or e ver oli m us ( H R: 0. 8 8; 9 5 % CI: 0. 7 5 t o 
1. 0 3; P =. 1 1) [ M otzer, R. J., et al 2 0 1 5]. A d diti o nall y, a P has e 1a o pe n-la bel, si n gle ar m st u d y 
of atez oliz u ma b i n 7 0 s u bjects wit h a d va nce d R C C was c o m plete d i n w hic h 6 1 of t he 
s u bjects ha d recei ve d pre vi o us s yste mic t hera pies.  O verall s ur vi val reac he d a me dia n of 2 8. 9 
m o nt hs ( 9 5 % CI, 2 0. 0 m o nt hs t o n ot reac he d) a n d P F S reac h e d a me dia n of 5. 6 m o nt hs ( 9 5 % 
CI 3. 9 t o 8. 2 m o nt hs) [ Mc Der m ott, D. F., et al 2 0 1 6]. 
Res p o nse data f or partici pa nts  wit h R C C fr o m t he o n g oi n g P hase 2 st u d y (I N C B 2 4 3 6 0-
2 0 2 / KE 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 x cee 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 bas e d o n P hase 1 res p o n ders, t h us warra nti n g a f urt her 
i n vesti gati o n. T he pr ese nt st u d y will e x a mi ne t he c o m bi nati o n of pe m br oliz u ma b pl us 
e paca d ostat vers us S o C (s u niti ni b or paz o pa ni b) i n partici pa nt s wit h c o nfir me d metastatic 
R C C wit h clear -cell hist ol o g y w h o ha v e n ot pre vi o usl y recei ve d s yste mic t h era p y  f or R C C.   
 
B ac k gr o u n d 
3. 2
Pe m br oliz u ma b ( M K- 3 4 7 5) is a p ote nt a n d hi g hl y selecti ve h u ma nize d m o n ocl o nal a nti b o d y 
of t he i m m u n o gl o b uli n (I g) G 4/ ka p pa is ot y pe directe d a gai nst pr o gra m me d cell deat h pr otei n 
1 ( P D  1), t h us i n hi biti n g its i nteracti o n wit h P D -L 1 a n d pr o gra m me d cell d eat h li ga n d 2 ( P D-
L 2). E p aca d ostat (f or m erl y I N C B 0 2 4 3 6 0) re pres e nts a n o vel, p ote nt, a n d s electi ve i n hi bit or 
of t he e nz y me I D O 1 i n b ot h h u ma n t u m or cells a n d h u ma n de n dritic cells. F or a t h or o u g h 
disc ussi o n of t he p har mac ol o g y of pe m br oliz u ma b a n d e paca d ostat, re fer t o t he c urre nt 
e diti o n of t he pe m br oliz u ma b I n v esti gat or's Br oc h ure a n d t he c urre nt e paca d ostat 
I n v esti gat or's Br oc h ur e. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 P h ar m a ce utic al a n d T her a pe utic B ac k gr o u n d  
3. 2. 1
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 n e 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 i m m u ne destr u cti o n des pite 
dis pla yi 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 n ce of hi g h a vi dit y T-
cells t hat are s p ecific f or t hese a nti ge ns [ B o o n, T. 1 9 9 6] [ Erc oli ni, A. M., et al 2 0 0 5]. 
Hist ol o gic e val u ati o n of ma n y h u ma n ca n cers 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 n c y. T hese o bser v ati o ns ha v e 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 he P D - 1 rece pt or is a n i m m u n o gl o b uli n s u perfa mil y m e m ber s h o w n t o n e gati vel y re g ulat e 
a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds P D- L 1 a n d/ or P D- L 2 [ Gree n w al d, 
R. J., et al 2 0 0 5], [ O kaza ki, T., et al 2 0 0 1]. T he P D- 1 pat h wa y re prese nts a maj or i m m u ne 
c o ntr ol s witc h, w hic h ca n be e x pl oite d b y t u m or cells t o o verc o me acti ve T-cell i m m u ne 
s ur veilla nce. E x presse d o n t he s urface of acti vate d T-cells u n der h ealt h y c o n diti o ns, t he 
f u ncti o n of t he P D- 1 r ece pt or is t o d o w n- m o d ulate u n wa nte d or e x cessi ve 
i m m u ne/a ut oi m m u ne res p o nses. A variet y of ca n cers ha ve b ee n d e m o nstrat e d t o e x press 
a b u n da nt le vels of P D- 1 li ga n ds, u nli ke healt h y or ga ns. T h e o bser v e d c orrelati o n of cli nical 
pr o g n osis wit h P D- L 1 e x pressi o n i n m ulti ple ca ncers s u g gests t hat t he P D- 1/ P D- L 1 pat h w a y 
pla ys a critical r ol e i n t u m or e vasi o n a n d is t h us a n attracti ve tar get f or t hera pe utic 
i nter ve nti o n. 
Pe m br oliz u ma b is desi g ne d t o directl y bl oc k t he i nteracti o n bet w ee n P D- 1 a n d its li ga n ds P D 
L 1 a n d P D- L 2. T his bl oc ka de e n h a nces f u ncti o nal acti vit y of t he t ar get l y m p h oc yt es t o 
facilitate t u m or re gressi o n a n d ulti matel y i m m u ne rejecti o n of t he t u m or. 
Rece nt i nterest has f oc us e 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 n c y [ G o di n- Et hier, J., et al 2 0 1 1]. I D 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 yz es 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 meta b olize d s u bse q ue ntl y t hr o u g h a series of 
e nz y matic ste ps t o nic oti na mi de a de ni ne di n u cle oti de. I D O 1 is t he first rat e -li miti n g enz y me 
i n o ne of t he brea k d o w n pat h wa ys of tr y pt o p ha n. I n a n ot her p at h wa y, tr y pt o p ha n 
h y dr o x yl ase catal ysis of tr y pt 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 
d i o x y ge n ase, a n e nz y me pre d o mi na ntl y e x presse d i n li ver t hat catal yz es t he sa me e nz y m atic 
reacti o n as I D O 1 a n d mai ntai ns pr o per tr y pt o p ha n bala nce i n res p o nse t o di etar y u pta ke. I n 
c o ntrast t o tr y pt o p h a n di o x y ge n ase, I D O 1 is e x presse d i n a vari et y of tiss ues, wit h 
partic ularl y hi g h le vels f o u n d i n areas of c o ntact wit h p ote ntial s o urces of i m m u ne c halle n ge 
(e g, g ut, res pir at 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 y pt 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 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]. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I D O 1-dri v e n o xi dati o n of tr y pt o p h a 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- m e diate d r es p o nses b y bl oc ki n g T-cell acti vati o n a n d i n d uci n g T-cell a p o pt osis 
[ Mell or, A. L., et al 2 0 0 3]. B ot h t he re d ucti o n i n l ocal tr y pt o p ha n le vels a n d t he pr o d ucti o n 
of tr y pt o p h a n cat a 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]. I D O 1 acti vit y als o pr o m otes t he 
differe ntiati o n of n ai ve T- cells t o cells wit h a re g ulat or y p h e n ot y p e ( Tre g) [ Fallari n o, F., et al 
2 0 0 6]. Si nce i ncrease d Tre g acti vit y 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 Tre 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 D O 1 e x pa nsi o n of Tre gs ma y pr o vi d e a n a d diti o nal mec ha nis m 
w here b y I D O 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 v a nce of I D O 1 i n hi biti o n t o i m m u ne t olera nce was first de m o nstrate d 
w he n it was s h o w n t hat treati n g mice wit h a s mall m olec ule i n hi bit or of t he I D O 1 pat h w a y, 
1- met h yl -tr y pt o p h a n, c o ul d brea k t he t oler o ge nic state t hat pr otects all o ge n eic c o nce pti o n 
fr o m t he mater n al i m m u ne s yste m [ M u n n, D. H., et al 1 9 9 8]. A critical r ol e 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 gr aft t olera n c e, i nfla m mati o n, a n d ca ncer [ Mell or, A. L. 2 0 0 4]. W hile I D O 1 i n hi biti o n 
ca n e x acer 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], I D 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 nts 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 v eral 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 h a 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 v eral gr o u ps ha ve de m o nstrate d t h at bl oc ka de of I D O 1 acti vit y ca n directl y 
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]. I n a d diti o n, st u dies wit h 1-met h yl -tr y pt o p h a n, de m o nstrate t hat 
I D O 1 i n hi biti o n dra maticall y i ncr eas es t he efficac y of v ari o us c h e m ot hera p e utic a ge nts (e g, 
plati n u m c o m p o u n ds, ta xa ne deri v ati ves c ycl o p h os p ha mi de) wit h o ut i ncrease d t o xicit y 
[ M uller, A. J., et al 2 0 0 5]. Alt h o u g h t he s pecific m ec 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 d ate d, t he effects were n ot o bser ve d i n T-cell-defici e nt a ni mals, 
s u g gesti n g 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 x a 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 p artici pa nts wit h ca n cer, 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 D O 1 has s u bse q ue ntl y 
bee n  f o u n d t o be o v ere x presse d b y a wi de vari et 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 ocali ze t o t he t u m or- drai ni n g l y m p h n o des [ Li u, X., et al 2 0 1 0]. I n crease 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 d e nt pr o g n ostic varia ble 
f or re d u ce d O S i n partici pa nts wit h mela n o ma, o varia n, c ol orectal, a n d p a n creatic ca n cers 
[ O ka m ot o, A., et al 2 0 0 5], [ Bra n dac her, G., et al 2 0 0 6], [I n o, K., et al 2 0 0 6], [ Na ka m ura, T., 
et al 2 0 0 7], [ Wit kie wicz, A., et al 20 0 8] . T o get h er, 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 n a ncies i n c o m bi nati o n wit h c he m ot hera pe utics 
a n d/ or i m m u n ot hera p y- b ase d strate gies.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
As disc usse d a b o ve, t her e are a n u m ber of i n hi bit or y mec ha nis ms t hat ha v e 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 ge nts t hat tar get t hese ne gati ve 
re g ulat or y pat h w a ys a n d t here b y 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 b e be neficial i n t he cli nic. C o m bi ne d i n hi biti o n of b ot h P D- L 1 a n d I D O 1 pat h wa ys ma y 
t heref or e 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.  
 O n g oi n g St u dies  
3. 2. 2
Refer t o t he I n v esti gat or's Br oc h ures (I Bs) f or pe m br oliz u ma b a n d e paca d ostat f or o n g oi n g 
cli nical trials data.  
K E Y N O T E - 2 5 2/ E C H O- 3 0 1: 
K E Y N O T E - 2 5 2/ E C H O- 3 0 1 is a n o n g oi n g P hase 3, ra n d o mize d, d o u ble- bli n d, place b o-
c o ntr olle d st u d y of p e 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 ar e pr o gr essi 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 verall s ur vi val ( 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 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 s ec o n d i nteri m a nal ysis.  T h ere w ere n o safet y 
c o ncer ns f or t he c o m bi nati o n pe m br oliz u ma b pl us e paca d ostat  relati ve t o t h e fi n di n gs o n t he 
p hase 1/ 2 K E Y N O T E- 0 3 7 .  T he st u d y re mai ns o p e 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 Asses s me nt 
3. 3
It ca n n ot be g uara ntee d t hat partici pa nts i n cli nical st u dies will directl y be n efit fr o m 
treat me nt d uri n g partici p ati o n, as cli nical st u dies are desi g n e d t o pr o vi de i nf or mati o n a b o ut 
t he safet y a n d eff ecti ve n ess of a n i n vesti gati o nal me dici ne. 
Gi ve n i nitial data o bser v e 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 i n c o m bi nati o n wit h e paca d ostat a n d a n o verall safet y pr ofile c o m para bl e t o 
a nti-P D - 1 m o n ot hera p y, t he a d diti o n of e paca d ost at t o esta blis he d treat me nts re prese nts a 
rati o nal a n d pr o misi n g first li ne t hera pe utic o pti o n i n patie nts wit h m R C C.  
T he I D O 1 i n hi bit or e paca d ostat has se veral o n g oi n g cli nical st u dies i n c o m bi nati o n wit h 
i m m u ne-tar gete d a ge nts, s uc h as a nti– P D - 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 dy 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 C B 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 BI D, 5 0 m g BI D, a n d 1 0 0 m g BI D wit h pe m br oliz u ma b 
2 m g/ k g I V Q 3 W a n d e p aca 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 nts i ncl u di n g, b ut n ot li mite d t o , Sta ge 3 B, I V or rec urre nt  n o n-small 
cell l u n g ca ncer ( N S C L C ), mela n o ma, ur ot helial carci n o ma ( U C), re n al cell carci n o ma 
( R C C), e n d o metrial a de n ocarci n o ma ( E A), tri ple ne gati ve breast ca n cer ( T N B C), s q ua m o us 
cell car ci n o ma of t he h ea d a n d nec k ( S C C H N), mi cr osatellite -i nsta bilit y ( M SI), col orect al 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
ca ncer ( C R C) , a n d diff us e lar ge B-cell l y m p h o ma ( D L B C L). 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- F E B - 2 0 1 7, a t otal of 2 9 4 partici pa nts were e nr olle d i n P hase 
2 a n d recei ve d ≥ 1 d ose of e paca d ostat a n d p e m br oliz u ma b.  Preli mi nar y d ata s h o w t hat t he 
m ost c o m m o n ( ≥1 0 %) all- gr a de dr u g -rel ate d a d v erse e ve nts ( D R A Es) were fati g u e, ras h, 
na usea, a n d pr urit us.  Gr a de ≥3 D R A Es were o bs er 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 1 treat me nt-relate d d eat h d ue t o res pirat or y fail ure 
w hic h was sec o n dar y t o as pirati o n p ne u m o nia. [ Ha mi d, O., et al 2 0 1 7]. 
As of 2 7- F E B - 2 0 1 7, a vaila ble effi cac y d ata f or p artici pa nts e nr olle d i n t he re nal cell 
carci n o ma 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  (Ta ble 3 ).  A m o n g t h e 
1 9 e val ua ble r e nal cell partici pa nts w h o recei ve d ≤ 1 pri or li nes of t hera p y, t he o bjecti ve 
res p o nse r ate ( O R R) w as 4 7 % a n d diseas e c o ntr ol rate ( D C R) w as 5 8 %, w hic h i ncl u des 1 
c o m plete res p o nse ( C R) per R E CI S T v 1. 1 as deter mi ne d b y i n vesti gat or [ Lara, P. N. Jr., et al 
2 0 1 7] .  T hese preli mi nar y dat a s u g gest i m pr o ve d efficac y of t he e paca d ost at pl us 
pe m br oliz u ma b c o m bi nati o n c o m pare d t o m o n ot hera p y wit h a nti- P D - 1/ P D- L 1 a ge nts i n 
R C C as o bser ve d i n ot her st u dies, a n d t his f or ms t he basis f or i nitiati n g t he pr o p ose d P hase 3 
st u d y.   
Ta ble 3 
Efficac y  of  E paca d ostat  i n  C o m bi nati o n  wit h  Pe m br oliz u ma b  i n  Re nal  Cell 
Carci n o ma Patie nts t hat Recei ve d ≤1 Pri or Li nes of T hera p y 
E v al u a bl e 
p artici p a nt sa 
R e n al  cell c arci n o m a 
(n = 1 9)  
O R R ( C R + P R), n ( %)  
9 ( 4 7)  
C R  
1  
P R  
8  
S D  
2  
D C R ( C R + P R + S D), n ( %)  
1 1 ( 5 8)  
P D  
8  
C R =c o m plete res p o nse; D C R = disease c o ntr ol rate; O R R = o bjecti ve res p o nse rate; 
P D = pr o gressi ve disease; P R = p artial res p o nse; S D =sta ble disease.  
a  E val ua ble p artici p a nt s i n cl u d e d a n y p artici p a nt  wit h ≥ 1 p ost b aseli n e res p o nse assess me nt 
or w h o ha d b ee n disc o nti n u e d fr o m t h e st u d y or die d b ef ore res p o nse c o ul d b e assesse d.  
 
A d diti o nall y, as n ote d i n Ga n ga d har et al ( 2 0 1 7), S mit h et al, ( 2 0 1 7), a n d i n Ha mi d et al 
( 2 0 1 7), res p ecti vel y, i ncr e me ntal i ncreases i n res p o nse rates fr o m t he sa me st u d y ha v e bee n 
o bser ve d w h e n e paca d ost at is c o m bi ne d wit h pe m br oliz u ma b acr oss a ra n ge of t u m or t y p es 
i ncl u di n g N S C L C  (i n b ot h hi g h a n d l o w-e x pressi n g P D - L 1 t u m ors), ur ot helial, a n d hea d a n d 
nec k ca ncer  [ Ga n ga d har, T. C., et al 2 0 1 7] [ S mit h, D. C., et al 2 0 1 7] [ Ha mi d, O., et al 2 0 1 7]. 
T hese i ncr eases i n O R R a n d t otalit y of t he d ata i n cl u di n g t he R C C c o h ort ha ve pr o ve n 
d ura ble i n t he o n g oi n g I N C B 2 4 3 6 0- 2 0 2 st u d y a n d pr o vi de rati o nale f or f urt her st u d y i n 
lar ger p atie nt p o p ulati o ns i n a P hase 3 setti n g. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
T he  use  of M A OIs is pr o hi bite d d uri n g t he st u d y, a n d all partici pa nts will be m o nit ore d f or 
S S s y m pt o ms . Partici pa nts will be pr o vi de d wit h a n i nf or mati ve si m plifie d leaflet des cri bi n g 
t he si g ns a n d p ote ntial 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 hes e si g ns or s y m pt o ms is o bser ve d. 
I n s u m mar y, b ot h I D O 1 a n d P D- 1 ha ve b ee 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 o-e x presse d i n 
m ulti ple ca ncer t y pes a n d t o c orrelat e wit h p o or pr o g n osis.  C o m bi ne d i n hi biti o n of b ot h 
pat h wa ys ma y , t her ef or e, lea d t o i ncrease d efficac y.  Precli nical a n d cli nical data i n dicate 
t hat t hese pat h wa ys are i m p orta nt i n mela n o ma as well as i n ot her ca ncers, i ncl u di n g re n al 
cell car ci n o ma.  
A d diti o nal details re gar di n g s pecific be n efits a n d ris ks f or p artici pa nts parti ci pati n g i n t his 
cli nical trial ma y be f o u n d i n t he c urre nt  I n v esti gat or’s Br o c h ures (I Bs) a n d t he I C F. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
3 9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
O bjecti ves/ H y p ot heses a n d E n d p oi nts  
4.
N O T E: As of A me n d me nt 0 6 , 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  1 2.  T his secti o n h as bee n u p d ate d acc or di n gl y.   
T his st u d y will e nr oll partici pa nts wit h l o call y a d v a nce d/ metastatic re nal cell carci n o ma 
( m R C C) wit h clear cell c o m p o ne nt.  Partici pa nts m ust n ot ha ve recei ve d pri or s yste mic 
t hera p y f or t h eir m R C C. 
O bjecti ve/ H y p ot hesis  
E n d p oi nt  
Pri m ar y  
•  O bjecti ve: T o esti mate t h e o bjecti ve 
res p o nse r ate ( O R R) as meas ure d p er 
R E CI S T  1. 1 b y i n vesti gat or 
deter mi nati o n of pe m br oliz u ma b pl us 
e paca d ostat a n d S o C (s u niti ni b or 
paz o pa ni b)  
•  O R R is defi ne d as t he pr o p orti o n of 
partici pa nts w h o ha v e a b est 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 u ate t h e safet y a n d 
t olera bilit y of p e m br oliz u ma b pl us 
e paca d ostat a n d S o C 
•  Safet y a n d t olera bilit y of t he treat me nt 
re gi me ns as meas ure d b y t he f oll o wi n g: 
o  N u m ber of partici pa nts e x perie nci n g 
a d verse e ve nts ( A Es)  
o  N u m ber of partici pa nts disc o nti n ui n g 
st u d y treat me nt d ue t o A Es  
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 0  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
St u d y D esi g n  
5.
 
O ver all Desi g n  
5. 1
N O T E:  E nr oll me nt w as ter mi n ate d o n 0 2- M A Y - 2 0 1 8.  As of A me n d me nt 0 6 , all 
pr ot oc ol- defi ne d 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 1 2 ( ± 7); t here after p arti ci p a nts will be assesse d  f or effic ac y as per 
S o C f or t he dise ase a n d l oc al g ui deli nes. 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.  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, o pe n-la bel, parallel gr o u p, P hase 3 st u d y t o e v al uate t he efficac y a n d 
safet y of pe m br oliz u ma b pl us e paca d ostat c o m pare d t o s u niti ni b or paz o pa ni b i n partici pa nts 
wit h l ocall y a d v a nce d/ metastatic re n al cell carci n o ma ( m R C C) wit h clea r cell c o m p o ne nt 
w h o ha ve n ot r ecei ve d pri or s yste mic t hera p y f or t heir m R C C. 
A p pr o xi matel y 1 3 0 eli gi ble partici pa nt s will be stratifie d b y t he f oll o wi n g: 1) I nter nati o nal 
Metastatic Re nal Cell Carci n o ma Data b ase C o ns orti u m (I M D C) ris k cate g ories (fa v ora ble 
vers us i nter me diate v ers us p o or [see A p pe n di x 9]) [ K o, J. J., et al 2 0 1 5], 2) I n v esti gat or’s 
i nte n de d c h oice of c o m p arat or (s u niti ni b vers us p az o pa ni b [ deter mi ne d pri or t o 
ra n d o mizati o n]) a n d 3) ge o gra p hical re gi o n [ U S, C A a n d Wester n E U vers us Rest of t he 
W orl d ( R O W)] t he n ra n d o ml y assi g ne d 1: 1 t o o ne of t w o treat me nt gr o u ps.   
•  Gr o u p 1:  Pe m br oliz u ma b 2 0 0 m g i ntra ve n o usl y (I V) e v er y t hree wee ks ( Q 3 W ) 
pl us e paca d ostat 1 0 0 m g orall y ( P O) t wice d ail y ( BI D ) c o nti n u o usl y 
•  Gr o u p 2 ( S o C):  S u niti ni b 5 0 m g P O o nce d ail y ( 6- wee k c ycles; 4 w ee ks o n 
treat me nt f oll o we d b y 2 wee ks off treat me nt) O R paz o pa ni b 8 0 0 m g P O o n ce 
dail y c o nti n u o usl y 
D uri n g t h e treat me nt p eri o d , partici pa nt s will ha ve r o uti ne cli nical visits f or a d mi nistrati o n of 
or o btai ni n g st u d y treat me nt, m o nit ori n g safet y a n d well -bei n g, a n d ass essi n g c h a n ges i n  
disease stat us.  Ke y s afet y ass ess me nts i ncl u de p h ysical e x a mi nati o ns, vital si g ns,  
electr ocar di o gr a p h y ( E C G), saf et y la b orat or y assess me n ts.  Partici pa nts will als o be assesse d 
f or t he occ urr e nce of A Es  a n d s p o nta ne o usl y re p orte d pre g n a nc y.
 
 
 
 
Partici pa nt s are  r e q uire d  t o  s u b mit  a ne wl y  o btai ne d  c ore  or  e x cisi o nal  bi o ps y  or  arc hi val 
tiss ue. T he t u m or tiss ue m ust ha ve bee n o btai ne d pri or t o ra n d o mizati o n a n d after  t he l atest 
s yste mic treat me nt f or R C C.   
Re q uire d i ma gi n g assess me nts  i ncl u de c o m p ute d t o m o gra ph y ( C T)  a n d/ or ma g n etic 
res o na nce i ma gi n g ( M RI) f or c h est, a b d o me n, a n d pel vis ( C A P) a n d b o ne s ca ns.  A C T or 
M RI of C A P will be perf or me d  f or all partici pa nts  at baseli ne a n d o n-st u d y, acc or di n g t o t he 
Sc he d ule of Assess me nts ( S o A) i n Secti o n 2.  B o n e sca ns will be perf or me d f or all 
partici pa nts  at baseli ne. If t he baseli ne b o n e sca n is p ositi ve, o n-st u d y b o ne sca ns will be 
re q uire d acc or di n g t o t he S o A.  Brai n i ma gi n g will be re q uire d acc or di n g t o t he e x cl usi o n 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
criteria i n Secti o n 6. 2 f or partici pa nts, wit h a pri or hist or y of brai n metastas es i n or der t o 
e ns ure t hat t her e is n o e vi de nce of pr o gressi o n  pri or t o ra n d o mizati o n. 
Partici pa nts i n Gr o u p 1 ma y r ecei ve treat me nt f or u p t o 3 5 i nf usi o ns ( 1 7. 5 c ycles) of 
pe m br oliz u ma b pl us e paca d ostat (a p pr o xi matel y 2 years)  if pr ot oc ol-s pecifie d criteri a f or 
disc o nti n uati o n fr o m treat me nt ha ve n ot bee n met.  Partici pa nts i n Gr o u p 2 ma y recei ve 
treat me nt f or a n u nli mite d n u m ber of c ycl es pr o vi de d t hat pr ot oc ol-s pecifie d criteria f or 
disc o nti n uati o n fr o m treat me nt ha ve n ot bee n met. 
After t he e n d of treat me nt, partici pa nts  will  be f oll o we d u p f or s afet y, acc or di n g t o Ta ble 1  
i n t he S o A i n Secti o n 2.  
Partici pa nts w h o disc o nti n u e treat me nt f or a reas o n ot her t ha n disease pr o gressi o n (e g, 
t o xicit y) will disc o nti n ue fr o m t he st u d y after Safet y F oll o w- u ps per t he Sc he d ule of 
Acti vities i n Secti o n 2 a n d Secti o n 9. 3.   
Partici pa nts i n Gr o u p 1 w h o st o p st u d y treat me nt (f or reas o ns ot her t h a n disease pr o gressi o n 
or i nt olera bilit y) wit h S D or P R after recei vi n g 3 5 i nf usi o ns of pe m br oliz u ma b, or 
partici pa nts w h o st o p st u d y treat me nt after attai ni n g a C R ( wit h a mi ni m u m of 8 i nf usi o ns of 
pe m br oliz u ma b a n d at least 2 i nf usi o ns be y o n d t h e date w h e n i nitial C R was declare d) ma y 
be eli gi ble f or u p t o 1 7 a d diti o nal i nf usi o ns of pe m br oliz u ma b (a p pr o xi matel y 1 year) pl us 
e paca d ostat u p o n e x perie nci n g r a di o gra p hi c diseas e pr o gressi o n.  Pleas e refer t o Secti o n 7. 8 
f or c o m plete set of r ules re gar di n g eli gi bilit y f or retreat me nt. 
Partici pa nts w h o disc o nti n ue treat me nt f or a reas o n ot her t ha n attai ni n g a C R or c o m pleti n g 
3 5 i nf usi o ns of pe m br oliz u ma b (e. g. disease pr o gressi o n, t o xicit y, etc) will disc o nti n ue fr o m 
t he st u d y after Saf et y F oll o w- u ps per t he Sc h e d ule of Acti vities i n Secti o n 2 a n d Secti o n 9. 3. 
T here is n o i nteri m a n al ysis i n t his st u d y.  D uri n g t he c o urse of t h e st u d y, Data M o nit ori n g 
C o m mittee ( D M C ) will perf or m o ne s afet y re vie w base d o n t he D M C c h art er .  
S pecific pr oce d ures t o b e 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 d e d i n Secti o n 9 – St u d y Assess me nts a n d Pr oce d ures.  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 St u d y  Di a gr a m 
5. 1. 1
T he o ver all st u d y desi g n is ill ustrate d i n  Fi g ure 1 .  
 
Fi g ure 1 
O verall St u d y Desi g n  
C A = Ca na d a; BI D = t wice a da y; E U = E ur o pea n U ni o n; I M D C = I nter n ati o nal Metastatic 
Re nal Cell Car ci n o ma D ata base C o ns orti u m; I V = i ntra ve n o us; m R C C = metastatic re n al cell 
carci n o ma; P O  =  b y  m o ut h ;  Q 3 W = e ver y  3  w ee ks ; R O W  =  rest  of  w orl d;  U S  =  U nite d 
States  
N ote:  As of A me n d me nt 0 6, pr o gressi o n -free s ur vi v al a nd o ver all s ur vi v al will n ot be 
f oll o w e d u p. 
 
N u m ber of P artici p a nts  
5. 2
As of 0 2- M A Y - 2 0 1 8, e nr oll me nt i n t his trial 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 
a p pr o xi matel y 1 3 0 pa rtici pa nts will be ra n d o mize d i nt o t he st u d y.  
 
Be gi n ni n g a n d E n d of St u d y Defi niti o n  
5. 3
T he o ver all 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 ver all 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 (ie, t he p artici pa nt is u na ble t o be 
c o ntacte d b y t he i n v esti gat or).  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 Cli nic al Criteri a f or E arl y St u d y  Ter mi n ati o n  
5. 3. 1
T he cl i nical st u d y ma y b e ter mi nate d earl y if t he e xte nt (i nci de nce a n d/ or se verit y) of 
e mer gi n g effects/cli nical e n d p oi nts is s uc h t hat t he ris k/ be nefit rati o t o t he st u d y p o p ulati o n 
as a w h ole is u nacce pt a ble.  I n a d diti o n, f urt her recr uit me nt i n t he st u d y or at (a) p artic ular 
st u d y site(s) ma y b e st o p pe d d ue t o i ns ufficie nt c o m plia nce wit h t he pr ot oc ol, G C P a n d/ or 
ot her a p plica ble re g ulat or y re q uire m e nts, pr oce d ure-relate d pr o bl e ms or t he n u m ber of 
disc o nti n uati o ns f or a d mi nistrati ve reas o ns is t o o hi g h. 
 
Scie n tific R ati o n ale f or St u d y Desi g n  
5. 4
 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 gl o b al A me n d me nt 0 6 , t his st u d y will use 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 g es f or ce ntr al re vie w is n o l o n ger 
re q uire d.  All ot her effic ac y e n d p oi nt  assess me nts  will n o l o n ger be c ollecte d .  T his 
secti o n h as bee n a me n de d acc or di n gl y. 
T his st u d y will use a pri mar y e n d p oi nt of O R R , as o utli ne d i n Secti o n 4. 
T his st u d y will use O R R base d o n R E CI S T 1. 1 criteria, as ass esse d b y t he i n vesti gat or.  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 h at de m o nstrates 
s u peri orit y of a ne w a nti ne o plastic t hera p y.  T h e 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 i n vesti gat or/ra di ol o g y assess me nt.   
 Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors, Versi o n 1. 1 
5. 4. 1. 1. 1
R E CI S T 1. 1 will be use d b y t he i n vesti gat or w he n deter mi ni n g eli gi bilit y a n d w he n assessi n g 
i ma ges f or pri mar y effi cac y m eas ures. Alt h o u g h tra diti o nal R E CI S T 1. 1 refere nces a 
ma xi m u m of 5 tar get lesi o ns i n t otal a n d 2 per or ga n, t his pr ot oc ol has i m ple me nte d a 
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 o tal a n d 5 per 
or ga n. T his will be ter me d as R E CI S T 1. 1 t hr o u g h o ut t he pr ot oc ol. F urt her details are f o u n d 
i n Secti o n 9. 2. 1. 5. 
 M o difie d R E CI S T 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 ote: As per A me n d me nt 0 6 , t his secti o n is n o l o n ger a p plic a ble; i R E CI S T dat a will n o 
l o n ger be entere d i nt o t he C R F .  P arti ci 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 tre at me nt a n d be f oll o w e d 
f or s af et 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 s c a ns are re q uire d.  
T he i n vesti g at or s h o ul d c o ns ult wit h t he M S D  Cli nic al Direct or if he/s he c h o oses t o 
c o nti n ue tre at me nt after i niti al r a di o gr a p hic P D.  
R E CI S T 1. 1 will be a da pte d t o acc o u nt f or t he u ni q ue t u m or res p o nse c haracteristics see n 
f oll o wi n g treat me nt wit h pe m br oliz u ma b ( Secti o n 9. 2. 1. 6).  I m m u n ot hera pe utic a ge nts s uc h 
as pe m br oliz u ma b ma y pr o d uce a ntit u m or effects b y p ote ntiati n g e n d o ge n o us ca ncer- s pecific 
i m m u ne res p o nses.  T he res p o nse patter ns see n wit h s uc h a n a p pr o ac h ma y e xte n d be y o n d 
t he t y pical ti me c o urse of res p o nses see n wit h c yt ot o xic a ge nts, a n d patie nts treate d wit h 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
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 p ear a nce of n e w lesi o ns.   
T h us, sta n dar d R E CI S T 1. 1 ma y n ot pr o vi de a n acc urat e res p o ns e assess m e nt of 
i m m u not hera pe utic a ge nts , s uc h as pe m br oliz u ma b.  Base d o n a n a n al ysis 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 ( K N 0 0 1), 7 % of e v al ua ble partici pa nts 
e x perie nce d del a ye d or earl y t u m or ps e u d o- pr o gressi o n.  Of n ote, partici pa nts w h o ha d 
pr o gressi ve disease ( 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 v erall s ur vi val 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 CI S T 1. 1 ma y 
u n deresti mate t he b e 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 CI S T 1. 1 t hat ta kes i nt o acc o u nt t he 
u ni q ue patter n of at y pi cal res p o nses i n i m m u n ot hera p y a n d e na bles treat m e 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 bl e.  
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 CI S 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 CI S 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 o o d a n d Dr u g 
A d mi nistrati o n a n d t he E ur o pea n Me di ci nes A ge n c y [ Se y m our, L., et al 2 0 1 7].  It is a da pte d 
t o acc o u nt f or t h e u ni q ue t u m or res p o nse see n wit h i m m u n ot hera pe utics.  T he 
u ni di me nsi o nal meas ure me nt of tar get lesi o ns, q u alitati 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 CI S T 1 . 1, u ntil pr o gressi o n is see n b y R E CI S T 
1. 1.  H o we ver, if a partici pa nt is cli nicall y sta ble, a d diti o nal i ma gi n g ma y be perf or me d t o 
c o nfir m ra di o gr a p hic pr o gr essi o n.  i R E CI S T will be use d b y I n vesti gat ors t o assess t u m or 
res p o nse a n d pr o gressi o n, a n d ma ke treat me nt decisi o ns, 
 
 
Refer t o Secti o n 9. 2. 1. 6 a n d A p pe n di x 6 f or details o n i R E CI S T. 
 S af et y E n d p oi nts  
5. 4. 1. 2
Safet y p ar a meters c o m m o nl y use d f or e v al uati n g i n vesti gati o nal s yste mic a ntica ncer 
treat ments ar e i ncl u de d as safet y e n d p oi nts. T hese i ncl u de, b ut are n ot li mite d t o, t he 
i nci de nce of ca us alit y, se verit y, o utc o m e of A Es/ S A Es, a n d c ha n ges i n vital si g ns a n d 
la b orat or y val u es. A Es will be assesse d as defi ne d b y N CI C T C A E versi o n 4. 0. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


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


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


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


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 R ati o n ale f or t he Use of C o m p ar at ors 
5. 4. 2
S u niti ni b a n d paz o pa ni b are sel ecte d as refere nce t hera pies i n t his st u d y i n first- li ne treat me nt 
of partici pa nts wit h m R C C.  S u niti ni b is t he m ost fre q ue ntl y  t yr osi ne ki nas e i n hi bit ors (T KI ) 
use d as first-li ne treat me nt f or a d va n ce d R C C a n d has a well c h aracterize d safet y pr ofile; 
t heref or e, s u niti ni b is selecte d as a c o ntr ol f or t he st u d y. S u niti ni b is c urre ntl y t he T KI 
c o m parat or f or se v eral o n g oi n g R C C re gistrati o n st u dies. Paz o pa ni b, as a n a p pr o ve d sta n d ar d 
of car e i n t his sa me setti n g, is warra nte d t o be use d i n t he c o ntr ol ar m. F urt her m ore, i n t he 
first-li ne setti n g, cli nicia ns ofte n prescri be o ne of t he V E G F R- T KIs, s u niti ni b or paz o pa ni b 
[ Mal o uf, G. G., et al 2 0 1 6], wit h s o me variati o n de pe n di n g o n ge o gra p h y a n d a vaila bilit y.    
Paz o pa ni b has bee n de m o nstrate d t o be n o ni nferi or t o s u niti ni b wit h si milar P F S a n d O S 
d urati o ns, b ut wit h a better t o xicit y pr ofile [ M otzer, R. J., et al 2 0 1 3].  T he c h oice of eit her 
paz o pa ni b or s u niti ni b all o ws p h ysicia ns t o d eter mi ne w hic h c o m parat or is t he best treat me nt 
o pti o n f or t heir patie nt a n d p ote ntiall y i m pr o ves c o m plia nce base d u p o n o pti mal 
ma na ge me nt of t he t o xicit y pr ofiles. Stratificati o n will occ ur b y c h oice of c o m parat or dr u g 
(eit her paz o pa ni b or s u niti ni b) s uc h t hat e q ual n u m bers of fa v ora ble-ris k, i nter me diate-ris k, 
a n d p o or-ris k partici pa nts will be ra n d o mize d t o eac h t hera p y o n t he S o C (c o ntr ol) ar m.  T his 
strateg y will hel p i ns ure t hat t here is n ot a n i m bala nce bet w ee n t he 2 c o m p o ne nts of t he S o C 
ar m t hat ma y u nfa v ora bl y bias t he res ults fr o m t h e use of eit her T KI. 
 
J ustific ati o n f or D ose  
5. 5
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
4 9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 R ati o n ale f or a Fi xe d D ose of Pe m br oliz u m a b 
5. 5. 2
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 e ver y 3 wee ks ( Q 3 W). Bas e d 
o n t he t otalit y of data ge nerate d i n t he K e ytr u da d e 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 os e 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. This d ose is j ustifie d b y  t he f oll o wi n g:  
•  
Cli nical data fr o m ei g ht r a n d o mize d st u dies de m o nstrati n g flat d os e- a n d e x p os ure- 
efficac y r elati o ns hi ps fr o m 2 m g/ k g Q 3 W t o 1 0 m g/ k g e v er y 2 w ee ks ( Q 2 W),  
• 
Cli nical data s h o wi n g mea ni n gf ul i m pr o v e me nt i n be nefit -ris k i ncl u di n g o v erall 
s ur vi val at 2 0 0 m g Q 3 W acr oss m ulti ple i n dicati o ns, a n d 
• 
P har mac ol o g y data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati o n 
(i nferr e d fr o m p h ar mac o ki netic [ P K] data) a n d t u m or (i nferre d fr o m p h ysi ol o gicall y 
base d p har m ac o ki netic [ P B P K] a nal ysis) at 2 0 0 m g Q 3 W. 
A m o n g t he 8 ra n d o mize d d ose-c o m paris o n st u dies, a t otal of 2 2 6 2 partici pa nts were e nr olle d 
wit h mela n o ma a n d N S C L C, c o v eri 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 h e d a n d all -c o mers) a n d differe nt treat me nt setti n gs ( m o n ot hera p y a n d i n 
c o m bi nati o n wit h c he m ot hera p y). Fi ve st u dies c o m pare d 2 m g/ k g Q 3 W v ers us 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 vers us 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 rel ati o ns hi ps acr oss t he d os es st u die d 
re pres e nti n g a n a p pr o xi mate 5- t o 7. 5-f ol d differe n ce i n e x p os ure. T he 2 m g/ k g ( or 2 0 0 m g 
fi x e 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 uentl y, flat -
d ose/e x p os ure-res p o nse r elati o ns hi ps were als o o bser ve d i n ot her t u m or t y p es i ncl u di n g hea d 
a n d nec k ca ncer, bla d d er ca ncer, gastric ca n cer a n d classical H o d g ki n L y m p h o ma, 
c o nfir mi n g 2 0 0 m g Q 3 W as t he a p pr o priate d ose i n de pe n de nt of t he t u m or t y pe. T h ese 
fi n di n gs are c o nsiste nt wit h t he mec ha nis m of acti o n of pe m br oliz u ma b, w hic h acts b y 
i nteracti o n wit h i m m u ne cells, a n d n ot via direct bi n di n g t o ca n cer cells. 
A d diti o nall y, p har mac ol o g y dat a clearl y s h o w tar get sat urati o n at 2 0 0 m g Q 3 W. First, P K 
data i n K N 0 0 1 e v al uati n g tar get- me diate d dr u g dis p ositi o n ( T M D D) c o ncl usi vel y 
de m o nstrate d sat ur ati o n of P D- 1 i n s yste mic circ ulati o n at d oses m uc h l o wer t ha n 2 0 0 m g 
Q 3 W. Sec o n dl y, a P B P K a nal ysis w as c o n d u cte d t o pre dict t u m or P D- 1 sat urati o n o ver a 
wi d e ra n ge of t u m or pe n etrati 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 hi e 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 ul ati o n P K a nal ysis of p e m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of 
b o d y w ei g ht a n d ot her partici pa nt c o variat es o n e x p os ure, has s h o w n t hat t h e fi x e 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 x e d d ose a n d 2 m g/ k g Q 3 W d ose. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 0  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
S u p p orte d b y t hes e P K c haract eristics, a n d gi ve n t hat fi x e d- d ose has a d va nt a ges of re d uce d 
d osi n g c o m ple xit y a n d r e d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g Q 3 W fi x e d- d ose was 
selecte d f or e val u ati o n acr oss all pe m br olizu ma b pr ot oc ols. 
 R ati o n ale f or D ose of S u niti ni b  
5. 5. 3
T he d ose f or s u niti ni b is 5 0 m g or all y o nce dail y, wit h or wit h o ut f o o d ( 6- wee k c ycles; 
4 wee ks o n treat me nt f oll o we d b y 2 wee ks off treat me nt) .  T his d ose was selecte d beca use it 
is t he a p pr o ve d d osa ge of s u niti ni b i n a d va nce d R C C.   
 R ati o n ale f or D ose of P az o p a ni b 
5. 5. 4
T he d ose f or p az o pa ni b is 8 0 0 m g orall y o nce dail y wit h o ut f o o d (at least 1  h o ur bef ore or 
2 h o urs after a meal).  T his d ose was select e d beca use it is t he a p pr o ve d d os a ge of paz o pa ni b 
i n a d va nce d R C C. 
 
St u d y P o p ul ati o n 
6.
Male/ fe male p artici pa nts of at least 1 8 years of a ge  wit h hist ol o gicall y c o nfir me d l ocall y 
a d va nce d  / metastatic re n al cell carci n o ma (m R C C ) wit h clear cell c o m p o ne nt will be 
e nr olle d i n t his trial.  
Pr os pecti ve a p pr o v al of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o 
k n o w n as pr ot oc ol wai v ers or e x e m pti o ns, is n ot per mitte d. 
 
I ncl usi o n Criteri a 
6. 1
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:  
T y pe of P artici p a nt a n d Dise ase C h ar a cteristi cs  
1.  Has h ist ol o gic c o nfir mati o n of l ocall y a d va n ce d or metastatic R C C ( Sta ge I V per 
A merica n J oi nt C o m mittee o n Ca ncer ) wit h a clear  cell c o m p o ne nt wit h or wit h o ut 
sarc o mat oi d feat ures. 
2.  M ust n ot ha ve recei ve d a n y pri or s yste mic t h era p y f or t heir m R C C .   
3.  Ha ve meas ura ble disease per  R E CI S T 1. 1 as deter mi ne d b y t he site.  T u m or lesi o ns 
sit uate d i n a pre vi o usl y irra diate d area are c o nsi dere d meas ura ble if pr o gressi o n has 
bee n de m o nstrat e d i n s uc h lesi o ns. 
4.  Ha ve pr o vi de d ar c hi val t u m or tiss ue sa m ple or ne wl y o btai ne d c ore or e x cisi 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. T he t u m or tiss ue m ust ha ve bee n 
o btai ne d pri or t o ra n d o mizati o n a n d after t he latest s yste mic treat me nt f or R C C.    
5.  Ha ve a  Ka r n ofs k y perf or ma nce stat us of ≥ 7 0 wit hi n 1 4 da ys pri or t o ra n d o mizati o n. 
( See A p pe n di x 1 0). 
De m o gr a p hics 
6.  Male/fe male p artici pa nts w h o are at least 1 8 years of a ge o n t he d a y of si g ni n g t he 
i nf or me d c o nse nt. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
Male partici pa nts:  
7.  A male partici pa nt m ust a gree t o us e 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 h e treat me nt peri o d a n d f or at least 1 2 0 da ys after t he last d ose o f 
pe m br oliz u ma b a n d e paca d ostat a n d u p t o 1 8 0 da ys after last d ose of S o C a ge nts a n d 
refr ai n fr o m d o nati n g s per m d uri n g t his peri o d.  
N ote:  A bsti ne nce is acce pta ble if t his is t he us ual lifest yle a n d preferre d 
c o ntrace pti o n f or t he partici pa nt.   
Fe male p artici pa nts:  
8.  A fe male p artici pa nt is eli gi ble t o partici pat e if s he is n ot pre g n a nt (see A p p e 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 plies:  
a) N ot a w o m a 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 n ce i n A p p e 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 ys after t he last d ose of pe m br oli z u ma b 
a n d e paca d ostat a n d u p t o 1 8 0 da ys after last d ose of S o C a ge nts. N ot e:  A bsti ne nce is 
acce pta ble if t his is t he us ual lifest yle a n d preferre d c o ntrace pti o n f or t he p artici pa nt. 
I nf or me d C o nse nt 
9.  T he partici pa nt ( or le gall y acce pta ble re pres e 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 d e q uate or ga n f u n cti o n as defi ne d i n t he f oll o wi n g ta ble (Ta ble 4 ).  S peci me ns 
m ust be c ollecte d wit hi n 1 4 da ys pri or t o ra n d o mi zati o n. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
Ta ble 4 
A de q uate Or ga n F u ncti o n La 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 
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 pri or 
t o ra n d o mizati o n. 
Re nal  
 
Creati ni ne O R   
Meas ure d or calc ulate d creati ni ne cleara nce  
( 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)   
( G F R ma y 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 nt s wit h t otal bilir u bi n le vels 
> 1. 5 × U L N  
(If t here is n o i nstit uti o nal ra n ge f or t he direct 
bilir u bi n, t he 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 s h o ul d t he t otal 
bilir u bi n e xcee d 3 x U L N) 
A S T ( S G O T) a n d A L T ( S G P T)  
≤2. 5 × U L N  
C 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)  O R 
P T T  ( 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)  
≤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 P T T is 
wit hi n t hera pe utic ra n ge of i nte n de d use of 
a ntic oa g ula nts 
A L T ( S G P T) = ala ni n e a mi n otra nsfer ase (ser u m gl uta mic p yr u vic tr a nsa mi n ase); A S T  ( S G O T) =as p artate 
a mi n otra nsferase (s er u m gl uta mi c o xal o acetic tra nsa mi n as e); Cr Cl =creati ni n e cleara n ce; G F R = gl o mer ular filtrati o n rate; 
U L N = u p p er li mit of n or mal.  
N ote: T his ta ble i n cl u d es eli gi bilit y -d efi ni n g la b orat or y val u e re q uire me nts f or treat me nt; la b orat or y val u e re q uire me nts 
s h o ul d be a d a pte d acc or di n g t o l ocal re g ulati o ns a n d g ui d eli n es f or t h e a d mi nistrati o n of s p ecific c h e m ot h era pies. 
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
E xcl usi o n Criteri a  
6. 2
Partici pa nts are e x cl 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 a hist or y of se v ere h y p erse nsiti vit y reacti o n (e g, ge neralize d ras h/er yt he ma, 
h y p ote nsi o n, br o n c h os pas m, a n gi oe d e ma or a na p h yl a xis) t o st u d y treat me nts or t heir 
e x ci pie nts. 
2.  Has a dia g n osis of i m m u n o d eficie nc y or is recei vi n g c hr o nic s yste mic ster oi d t hera p y 
( d oses e x cee di n g 1 0 m g dail y of pre d nis o ne e q ui v ale nt) or a n y ot h er 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. 
C ortic oster oi d use as pre me dicati o n f or I V c o ntrast pr o p h yla xis is per mitte d. 
3.  Has a n acti ve a ut oi m m u ne disease t hat h as re q uire d s yste mic treat me nt i n past 2  years 
(ie, wit h use of diseas e m o dif yi n g a ge nts, c ortic ost er oi ds or i m m u n os u p pressi ve 
dr u gs). Re place me nt t her a p y (e g, t h yr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d 
re place me nt t hera p y f or a dre nal or pit uitar y i ns ufficie nc y, et c.) is n ot c o nsi dere d 
s yste mic treat me nt. 
4.  Has a k n o w n a d diti o nal mali g na n c y t hat has pr o gresse d or h as re q uire d acti ve 
s yste mic treat me nt i n t he last 3 years. N ote: partici pa nts wit h c urati vel y treate d basal 
cell car ci n o ma of t he s ki n, s u perficial bla d d er ca n cer , s q ua m o us cell carci n o ma of t he 
s ki n, c urati vel y res ecte d i n sit u cer vical ca ncer a n d c urati vel y resecte d i n sit u breast 
ca ncer are n ot e x cl u de d.  
5.  Has k n o w n acti ve ce ntr al ner v o us s yst e m  metastas es a n d/ or carci n o mat o us 
me ni n gitis. Partici pa nts wit h pre vi o usl y treate d brai n metastases ma y p arti ci pate 
pr o vi de d t he y ar e 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 g i n g ) ( n ote t hat t he re peat i ma gi n g s h o ul d be p erf or me d 
d uri n g st u d y scr ee ni n g), cli nicall y sta ble, a n d ha v e n ot re q uire d ster oi ds f or at least 
1 4 da ys b ef or e first d ose of st u d y treat me nt.  
6.  Has a hist or y of ( n o n-i nf ecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.  
7.  Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y.  
8.  Has a k n o w n hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  N o HI V 
testi n g is re q uir e d u nless ma n date d b y l ocal h ealt h a ut h orit y. 
9.  Has a k n o w n hist or y of or is p ositi ve f or acti ve H e patitis B ( H Bs A g reacti v e) or has 
acti ve He p atitis C ( H C V R N A). N ote: Testi n g m ust be perf or m e d t o deter mi ne 
eli gi bilit y.  
a)  H B V D N A m ust be u n detecta ble a n d H Bs A g n e gati ve at Scree ni n g  visit.  
b)  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 h ere 
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 nts will be e x cl u de d.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
c)  Partici pa nts w h o ha ve h a d defi niti ve treat me nt f or H C V are p er mitte d if H C V 
R N A is u n detecta ble at Scree ni n g  visit . 
1 0.  Has a n y hist or y of S S  aft er recei vi n g ser ot o n er gic dr u gs.  
1 1.  Has a hist or y of a gastr oi ntesti nal c o n diti o n or pr oce d ure t h at i n t he o pi ni o n of t he 
I n v esti gat or ma y affect oral dr u g a bs or pti o n. 
1 2.  Has a  hist or y of a n y of t h e f oll o wi n g car di o v asc ul ar c o n diti o ns wit hi n 1 2 m o nt hs 
pri or t o ra n d o mizati o n: m y ocar dial i nfarcti o n , u nsta ble a n gi na pect oris, car diac 
a n gi o plast y or ste nti n g, c or o nar y/ peri p h eral arter y b y pass graft,  Class III or I V 
c o n gesti ve heart fail ur e p er Ne w Y or k H eart Ass o ciati o n ( N Y H A), cere br o vasc ular 
acci de nt or tra nsie nt isc h e mic attac k, or N Y H A Class III or I V c o n gesti ve heart 
fail ure (C H F ) (s ee A p p e n di x 1 1).  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. 
1 3.  Has a hist or y of dee p vei n t hr o m b osis or p ul m o nar y e m b olis m wit hi n 6 m o nt hs of 
scree ni n g. 
1 4.  P o orl y c o ntr olle d h y p erte nsi o n ( defi ne d as s yst olic B P ≥ 1 5 0 m m H g or di ast olic B P 
≥ 9 0 m m H g).  I nitiati o n or a dj ust me nt of a nti h y p erte nsi ve me dicati o n(s) is per mitte d 
pri or t o ra n d o mizati o n.  
1 5.  Has a hist or y or pr ese nce of a n a b n or m al electr o car di o gra m ( E C G) t hat, i n t he 
I n v esti gat or's o pi ni o n, is cli nicall y mea ni n gf ul. Scree ni n g Q T c i nter val > 4 8 0 msec is 
e x cl u de d (c orr ecte d b y Fri dericia or Bazett f or m ula). I n t he e ve nt t hat a si n gle Q T c is 
> 4 8 0 msec, t he partici pa nt ma y e nr oll if t he a vera ge Q Tc f or 3 E C Gs is <  4 8 0 msec . 
1 6.  W O C B P w h o has a p ositi ve uri ne pre g n a nc y test wit hi n 7 2 h o urs bef ore t h e first d ose 
of st u d y tr eat me nt. If t he uri ne test is p ositi ve or ca n n ot be c o nfir m e 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 h e e ve nt t hat 7 2 h o urs ha ve el a pse d bet w ee 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 t est ( uri ne or s er u m) 
m ust be perf or me d a n d m ust be ne gati ve i n or der f or partici pa nt t o start recei vi n g 
st u d y treat me nt. 
1 7.  Is pre g na nt or breastfee di n g or e x pecti n g t o c o n cei ve or fat h er c hil dre n wit hi n t he 
pr ojecte d d ur ati o n of t h e st u d y, starti n g wit h t he s cree ni n g visit t hr o u g h 1 2 0  da ys 
after t he l ast d ose of pe m br oliz u ma b a n d e paca d ostat  a n d u p t o 1 8 0 da ys aft er last 
d ose of c he m ot hera pe uti c a ge nts. 
Pri o r/ C o nc o mit a nt T her a p y  
1 8.  Has recei ve d pri or t hera p y wit h a n a nti -P D - 1, a nti -P D - L 1, or a nti P D- L 2 a ge nt, wit h 
e paca d ostat or a n y a nti -I D O 1 a ge nt, or wit h a n a ge nt directe d t o a n ot h er 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).  
1 9.  Has recei ve d pri or t hera p y wit h vas c ular e n d ot h elial gr o wt h fact or ( V E G F)/ V E G F 
rece pt ors ( V E G F R) or m ec ha nistic tar get of ra p a m yci n ( m T O R) t ar geti n g a ge nts i n 
l ocall y a d va nce d/ metastatic setti n g. 
N ote: Pri or ne oa dj u va nt/ a dj u va nt t hera p y f or R C C wit h t h ose a ge nts is acce pta ble if 
c o m plete d > 1 2 m o nt hs pri or t o ra n d o mizati o n. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
2 0.  Has recei ve d pri or s yst e 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 r a n d o mizati o n.  
N ote: Partici pa nts m ust ha ve  rec o vere d fr o m all A Es d ue t o pre vi o us t hera pies t o 
≤Gra de  1 or baseli ne. Partici pa nts wit h ≤Gra de 2 n e ur opat h y ma y be eli gi bl e.  
2 1.  If partici pa nt recei ve d m aj or s ur ger y, t h e y m ust ha ve rec o vere d a d e 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 nti o n pri or t o starti n g st u d y treat me nt. 
2 2.  Has recei ve d li ve v acci n e wit hi n 3 0 da ys b ef ore t he first d ose  of st u d y treat me nt. 
E x a 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, yell o w fe ver, ra bies, Bacill us Cal mette- G u éri n ( 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 ar e all o we d; h o we ver, i ntra nas al i nfl ue nza vacci n es are li ve 
atte n uate d vacci nes a n d are n ot all o we d.  
2 3.  Has recei ve d  t hera p y wit h a m o n oa mi ne o xi dase i n hi bit or ( M A OI) or U G T 1 A 9 
i n hi bit or wit hi n  2 1 da ys pri or t o ra n d o mizati o n, or a ntici pates re q uiri n g o n e of t hese 
pr o hi bite d me dicati o ns d uri n g t he treat me nt p has e. E x a m ples of me dicati o ns i n t hese 
classes ar e f o u n d i n Secti o n 7. 7. 2.  
2 4.  Has c urre nt use ( wit hi n 7 da ys of ra n d o mizati o n) or a ntici pate d nee d f or treat me nt 
wit h dr u gs or f o o ds t hat are k n o w n str o n g c yt oc hr o me P 4 5 0 ( C Y P 3 A 4/ 5) i n hi bit ors 
i ncl u di n g, b ut n ot li mite d t o , ataza na vir, clarit hr o m yci n, i n di na vir, itrac o n az ole, 
ket oc o naz ole, nef az o d o ne, nelfi na vir, rit o na vir, sa q ui na vir, telit hr o m yci n, 
tr olea n d o m yci n, v oric o n az ole, a n d gra pefr uit or gra pefr uit j uice.  N ote: T h e t o pical 
use of t hese me dicati o ns, s uc h as 2 % ket o c o naz ole crea m, is all o we d. 
2 5.  C urre nt use of a n y pr o hi bite d me dicati o n as descri be d i n Secti o n 7. 7. 2 – Pr o hi bite d 
Me dicati o ns or T her a pies.  
Pri o r/ C o nc urre nt Cli nic al St u d y E x perie nce  
2 6.  Is c urr e ntl y p artici pati n g i n or has partici pate d i n a st u d y of a n i n v esti gati o n al a ge nt 
or has use d a n i n v esti 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 nts w h o h a ve e ntere d t he f oll o w- u p p hase of a n i n v esti gati o nal st u d y 
ma y p artici 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 7.  Has k n o w n ps yc hiatri c or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h 
c o o perati n g wit h t he r e q uire me nts of t he st u d y. 
2 8.  Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he r es 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 o f t he st u d y, or is n ot i n t he best i nterest of t he 
partici pa nt  t o partici pate, i n t he o pi ni o n of t he treati n g i n vesti gat or. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Lif est yle Restricti o ns  
6. 3
 Me als a n d Diet ar y Rest ricti o ns  
6. 3. 1
Partici pa n ts s h o ul d mai ntai n a n or mal diet u nless m o dificati ons 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. 
Partici pa nts recei vi n g p az o pa ni b s h o ul d ta ke t heir d ose wit h o ut f o o d ( at least 1 h o ur bef ore 
or 2  h o urs after a meal).   
T here are n o restricti o ns f or pe m br oliz u ma b, e paca d ostat, a n d s u niti ni b wit h res pect t o 
ti mi n g of meals rel ati ve t o d osi n g. 
 C aff ei ne , Alc o h ol, a n d T o b acc o Restri cti o ns 
6. 3. 2
T here  are n o restricti o n s f or partici pa nts i n t his st u d y wit h re gar d t o caffei n e, alc o h ol, or 
t o bacc o. 
 C o ntr ace pti o n  
6. 3. 3
Pe m br oliz u ma b ma y h a v e a d vers e effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if 
pe m br oliz u ma b has tra nsie nt a d verse effects o n t h e 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 h a ve n ot bee n p erf or me d wit h e paca d ostat. 
E paca d ostat s h o ul d n ot b e use d b y pre g n a 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 h e st u d y treat me nt ma y i n v ol ve u n k n o w n ris ks 
t o t he fet us ( u n b or n ba b y) if pre g na n c y were t o occ ur d uri n g t he st u d y. I n or der t o partici p ate 
i n t he st u d y, partici p a 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 nt fr o m t he da y of st u d y treat me nt 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 or al c o ntrace pti o n) t hr o u g h o ut t he st u d y peri o d u p t o 1 2 0 da ys after t h e 
last d ose of pe m br oliz u ma b a nd e p aca d ostat or 1 8 0 da ys after t h e last d ose of S o C . If t here is 
a n y q u esti o n t hat a partici pa nt of c hil d beari n g p ot e 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 ntr ace pti o n, t hat partici pa nt s h o ul d n ot be e ntere d i nt o t he st u d y.  
Defi niti o n s of W O C B P a n d sta n dar ds f or a de q u ate c o ntrace pti o n are o utli ne d i n A p pe n di x 2. 
 Pre g n a nc y  
6. 3. 4
If a partici pa nt bec o m es pre g na nt w hile o n treat m e nt wit h pe m br oliz u ma b or e paca d ostat or 
S o C , 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 m e nt t he partici pa nt’s stat us u ntil t he 
pre g na nc y h as bee n c o m plete d or ter mi nate d. T h e 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 n S A E (e g, deat h, a b orti o n, 
c o n ge nital a n o mal y, or ot her disa bli n g or life- t hreate ni n g c o m plicati o n t o t he m ot her or 
ne w b or n). T h e 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 pr e g na nc y a n d re p ort t he c o n diti o n of t he fet us or n e w b or n t o M S D . If a male 
partici pa nt i m pre g nates his fe male part n er, 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. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 Use i n N ursi n g W o me n  
6. 3. 5
It is u n k n o w n w h et her p e m br oliz u ma b, e paca d ostat , s u niti ni b, or paz o pa ni b are e x crete d i n 
h u ma n mil k. Si nce ma n y dr u gs are e x crete 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 vers e reacti o ns i n t he n ursi n g i nfa nt, p artici 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 f ail 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 u e ntl y r a 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 p are nt re p orti n g of s cree n fail ure parti ci 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, s cree 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 m e 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 fr o m st u d y treat me nt or wit h dra ws fr o m t he st u d y will n ot be 
re place d.  
 
Tre at me nts  
7.
St u d y treat me nt is defi n e d as a n y i n vesti gati o nal treat me nt(s), m ar 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 p artici 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 b y 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 x e d wit h a cli nical la bel i n acc or d a nce wit h 
re g ulat or y r e q uire me nts. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
Tre at me nts A d mi nistere d  
7. 1
T he st u d y tr eat me nts t o b e use d i n t his trial are o utli ne d bel o w i n Ta ble 5 . 
Ta ble 5  
St u d y Treat me nts  D uri n g Treat me nt  P hase  
Dr u g  
D ose / 
P ote nc y  
D ose 
Fre q ue nc y  
R o ute of 
A d mi nistr ati o n  
Re gi me n/ 
Tre at me nt Peri o d  
Use  
S o urci n g  
P e m br oliz u ma b  
2 0 0 m g 
d ose/  
2 5 m g/ m L 
s ol uti o n 
f or 
i nf usi o n 
Q 3 W  
I V i nf usi o n 
Da ys 1 a n d 2 2 of 
eac h 6 -wee k c ycle 
f or u p t o 3 5 
i nf usi o ns  
E x peri me ntal  
( Gr o u p 1) 
Ce ntral  
E paca d ostat  
1 0 0 m g 
d ose/  
1 0 0 m g or 
2 5 m g 
ta blets 
BI D  
Oral  
C o nti n u o us, t wi ce 
dail y d osi n g eac h 
6- wee k c ycle  
E x peri me ntal  
( Gr o u p 1) 
Ce ntral  
S u niti ni b  
(as s u niti ni b 
malate)  a, b  
5 0 m g 
d ose/  
1 2. 5 m g , 
2 5 m g , 
3 7. 5  m g, 
or 5 0  m g , 
ca ps ules  
Q D  
Oral  
6- wee k c ycles ( 4 
wee ks o n 
treat me nt, o nce 
dail y,  f oll o we d b y 
2 wee ks off 
treat me nt) 
Treat me nt of 
ca ncer  
( Gr o u p 2) 
L ocal or 
Ce ntral  
P az o pa ni b b  
(as paz o pa ni b 
h y dr oc hl ori de)  
8 0 0 m g 
d ose/  
2 0 0 m g or 
4 0 0  m g 
ta blets 
Q D  
Oral  
C o nti n u o us o nce 
dail y d osi n g eac h 
6- wee k c ycle  
Treat me nt of 
ca ncer  
( Gr o u p 2) 
L ocal or 
Ce ntral  
a D osi n g o n a 2 -wee k o n, 1 -wee k off s c h e d ule is n ot p er mitte d.  
b Ma y re cei ve tre at me nt f or a n u nli mite d n u m b er of c ycl es pr o vi d e d t h at pr ot o c ol -s p ecifie d criteria f or disc o nti n u ati o n fr o m 
treat me nt h a ve n ot b ee n met.  
 
All pr o d ucts i n dicate d i n  Ta ble 5  will be pr o vi de d ce ntrall y b y M S D or l ocall y b y t he trial 
site, s u bsi diar y, or d esi g n ee, de p e n di n g o n l o cal c o u ntr y o perati o nal or re g ulat or y 
re q uire me nts.  E v er y atte m pt s h o ul d be ma de t o s ource t hes e 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. 8 f or details re gar di n g a d mi nistrati o n of t he st u d y treat me nt. 
Pe m br oliz u ma b will be a d mi nistere d o n a n o ut patie nt basis at t he st u d y site b y st u d y site 
staff.   
E paca d ostat will be dis pe nse d e ver y 3 wee ks a n d will be a d mi nistere d i n t he cli nic o n C ycl e 
1 Da y 1 a n d C ycle 1 Da y 2 2 f oll o wi n g bl o o d dra ws. F or all ot her d os es, e paca d ostat will be 
self-a d mi nistere d b y t he patie nt.  
S u niti ni b  a n d paz o pa ni b will be dis pe nse d e ver y 6 wee ks a n d will be self-a d mi nistere d  b y t he 
partici pa nt.   
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
5 9  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
 
D ose M o dific ati o ns ( Esc al ati o n/ Titr ati o n/ Ot her)  
7. 2
D oses of e p aca d ostat, s u niti ni b , a n d paz o pa ni b ma y n ee d t o be d ecreas e d d ue t o t o xicit y or 
i nterr u pte d a n d r estarte d after r ec o v er y of la b orat or y v al ues or A Es.  
Pe m br oliz u ma b ma y b e i nterr u pte d, a n d n o d os e m o dificati o ns are per mitte d. 
 D ose M o dific ati o n f or I m m u ne- rel ate d A d vers e E ve nts  
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 (ir A Es) ass ociate d wit h 
pe m br oliz u ma b a n d/ or e paca d ostat s h o ul d be ma na ge d as f oll o ws. 
A d verse e ve nts ( b ot h n o n-seri o us a n d seri o us) ass ociate d wit h pe m br oliz u ma b a n d/ or 
e paca d ostat e x p os ure ma y r e pres e nt a n i m m u n ol o gic eti ol o g y. T hes e ir A Es ma y o cc ur 
s h ortl y aft er t he first d ose or se veral m o nt hs after t he last d ose of treat me nt a n d ma y affect 
m ore t ha n o ne b o d y s yste m si m ulta ne o usl y. T h eref ore, earl y rec o g niti o n a n d i nitiati o n of 
treat me nt is critical t o re d uce c o m plicati o ns. Base d o n e xisti n g cli nical st u d y dat a, m ost 
ir A Es were re v ersi 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 pect e 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 x cl u de ot her ca us es. A d diti o nal pr oce d ures or 
tests s uc h as br o nc h osc o p y, e n d os c o p y, or s ki n bi o ps y ma y b e i ncl u de d as part of t he 
e val uati o n. Base d o n t he se verit y of ir A Es, wit h h ol d or per ma ne ntl y disc o nti n ue 
pe m br oliz u ma b a n d e paca d ostat  a n d a d mi nister c ortic oster oi ds.  
Ta ble 6  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. 
Of n ote, partici p a nts w h o re q uire d ose re d u cti o n of e paca d ostat d ue t o A Es will re mai n at t h e 
l o wer d ose, s u m marize d i n Ta ble 7 . Re-es calati o n of e paca d ostat is n ot per mitte d.  
I n cases w her e pe m br oliz u ma b d osi n g is hel d, d osi n g f or e paca d ostat  m ust als o be hel d.  
U p o n i m pr o ve me nt of t h e ir A E t o Gra de 0 or 1, st u d y treat me nt ma n y res u me acc or di n g t o 
Ta ble 6 . T he I n v esti gat or ma y elect t o res u m e bot h pe m br oliz u ma b a n d e paca d ostat or 
pe m br oliz u ma b m o n ot hera p y; h o we ver, e p aca d ost at m o n ot hera p y is n ot per mitte d.   
E x ce pt i n cases of e mer ge nc y, it is rec o m me n d e d t hat t he I n v esti gat or c o ns ult wit h t he 
me dical m o nit or ( or ot her re pr ese ntati ve of M S D) bef ore t e m p oraril y i nterr u pti n g t hera p y f or 
reas o ns ot her t h a n pr ot oc ol-ma n date d treat me nt h ol d.   
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial  
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 0  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
Ta ble 6  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne-relat e d A Es Ass ociate d wit h Pe m br oliz u ma b or 
E paca d ostat  
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
P ne u m o nitis  
Gra de  2 
P e m br oliz u ma b  
Wit h h ol d  u ntil Gra de 0 - 1  
•  A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 
1- 2 m g/ k g 
pre d nis o ne or 
e q ui vale nt)  f oll o we d 
b y ta per  
•  
M o nit or partici pa nts  f or si g ns 
a n d s y m pt o ms of p ne u m o nitis  
•  
E val uate partici pa nts  wit h 
s us pecte d p ne u m o nitis wit h 
ra di o gra p hic i ma gi n g a n d 
i nitiate c ortic oster oi d treat me nt 
•  
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfectio ns . 
E paca d ostat  
Wit h h ol d u ntil Gra de 0 - 1 
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 3 or 4, or 
rec urre nt G ra de 2 
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y  disc o nti n ue  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 1  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
Diarr hea  / c olitis  
Gra de 2 or 3  
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
•  A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 
1- 2 m g/ k g 
pre d nis o ne or 
e q ui vale nt)  f oll o we d 
b y ta per  
•  
M o nit or  partici pa nts f or si g ns 
a n d s y m pt o ms of e nter oc olitis 
(ie diarr hea, a b d o mi nal pai n, 
bl o o d or m uc us i n st o ol wit h or 
wit h o ut fe ver) a n d of b o wel 
perf orati o n ( ie perit o neal si g ns 
a n d ile us).  
•  
P artici pa nts  wit h ≥ Gra de  2 
diarr hea s us pecti n g c olitis 
s h o ul d c o nsi der GI 
c o ns ultati o n a n d perf or mi n g 
e n d osc o p y t o r ule o ut  c olitis.  
•  
P artici pa nts  wit h  
diarr hea/c olitis s h o ul d be 
a d vise d t o dri n k li beral 
q ua ntities of clear fl ui ds. If 
s ufficie nt oral fl ui d i nta ke is 
n ot feasi ble, fl ui d a n d 
electr ol ytes s h o ul d be 
s u bstit ute d via I V i nf usi o n. 
E paca d ostat  
Wit h h ol d u ntil Gra de  0- 1 
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 4 or 
rec urre nt Gra de 3 
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 2  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
A S T  / A L T 
E le vati o n or 
I ncrease d 
Bilir u bi n  
Gra de 2 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
•  A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 
0. 5 - 1 m g/ k g 
pre d nis o ne or 
e q ui vale nt) f oll o we d 
b y ta per  
•  
M o nit or wit h li ver f u ncti o n 
tests (c o nsi der wee kl y or m ore 
fre q ue ntl y u ntil li ver e nz y me 
val ue ret ur ns t o baseli ne or is 
sta ble). 
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 3 or 4  
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
•  A d mi nister  
c ortic oster oi ds 
(i nitial d ose of 
1- 2 m g/ k g 
pre d nis o ne  or 
e q ui vale nt) f oll o we d 
b y  ta per 
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
T y pe 1 dia betes 
mellit us ( T 1 D M ) 
or 
H y per gl yce mia b 
 
Ne wl y  o nset 
T 1 D M  or  
Gra de 3  or 4 
h y per gl yce mia 
ass ociate d wit h 
e vi de nce of β -cell 
fail ure 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
•  I nitiate i ns uli n 
re place me nt t hera p y 
f or partici pa nts  wit h 
T 1 D M  
•  A d mi nister a nti -
h y per gl yce mic i n 
partici pa nts  wit h 
h y per gl yce mia   
•  
M o nit or partici pa nts  f or 
h y per gl yce mia or ot her si g ns 
a n d s y m pt o ms of dia betes . 
 
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 3  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
H y p o p h ysitis  
Gra de 2  
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
•  A d mi nister  
c ortic oster oi ds a n d 
i nitiate h or m o nal 
re place me nts as 
cli nicall y i n dicate d.   
•  
M o nit or f or si g ns a n d 
s y m pt o ms of h y p o p h ysitis 
(i ncl u di n g h y p o pit uitaris m a n d 
a dre nal i ns ufficie nc y)   
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0-1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 3 or 4  
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 -1 or 
per ma ne ntl y disc o nti n ue a  
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1 or 
per ma ne ntl y disc o nti n ue a 
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
H y pert h yr oi dis m b 
Gra de 2  
P e m br oliz u ma b  
C o nti n ue  
•  Treat wit h n o n -
selecti ve beta-
bl oc kers (e g 
pr o pra n ol ol)  or 
t hi oa mi des as 
a p pr o priate  
•  
M o nit or f or si g ns a n d 
s y m pt o ms of t h yr oi d dis or ders.  
E paca d ostat  
C o nti n ue  
Gra de 3 or 4  
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 -1 or 
per ma ne ntl y disc o nti n ue a  
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1 or 
per ma ne ntl y disc o nti n ue a 
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 4  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
H y p ot h yr oi dis m b 
Gra de 2 - 4 
P e m br oliz u ma b  
C o nti n ue  
•  I nitiate t h yr oi d 
re place me nt 
h or m o nes (e g 
le v ot h yr o xi ne or 
li ot h yr o ni ne) per 
sta n dar d of care 
•  
M o nit or f or si g ns a n d 
s y m pt o ms of t h yr oi d dis or ders.  
 
E paca d ostat  
C o nti n ue  
Ne p hritis a n d 
Re nal 
D ysf u ncti o n  
Gra de 2 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
•  A d mi nister  
c ortic oster oi ds  
( pre d nis o ne 
1- 2 m g/ k g  or 
e q ui vale nt)  
f oll o we d b y ta per. 
•  
M o nit or c ha n ges of re nal 
f u ncti o n 
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel. 
Gra de 3 or 4  
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
M y ocar ditis  
Gra de 1 or 2  
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0  
•  
B ase d o n se verit y 
of A E a d mi nister 
c ortic oster oi ds  
•  
E ns ure a de q uate e val uati o n t o 
c o nfir m eti ol o g y a n d/ or 
e xcl u de ot her ca uses  
E paca d ostat  
Wit h h ol d u ntil Gra de 0  
 
O nce res ol ve d t o Gra de 0, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel.  
N ot Relate d: Sa me d ose le vel.  
Gra de 3 or 4  
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 5  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
Ras h  
Gra de 1 or 2  
P e m br oliz u ma b  
C o nti n ue  
•  Ma na ge wit h t o pical 
ster oi ds wit h or 
wit h o ut dr u g 
i nterr u pti o n. 
 
E paca d ostat  
C o nti n ue  
Gra de 3 c 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1 
 
•  A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 
1- 2 m g/ k g 
pre d nis o ne or 
e q ui vale nt) f oll o we d 
b y ta per.  
•  
Restart e paca d ostat at sa me 
d ose if ras h is mil d a n d 
assesse d as Gra de 3 base d o nl y 
o n b o d y s urface area a n d 
res ol ves wit h o ut oral ster oi ds. 
If oral ster oi ds are re q uire d, or 
ras h is se vere, decrease b y 
1 d ose le vel o nce res ol ve d t o 
Gra de  0-1.  
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 4 
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 6  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
As y m pt o matic 
A m ylase or 
Li pase I ncrease d  
Gra de 3 
P e m br oliz u ma b  
Ma y c o nti n ue treat me nt wit h 
M S D Cli nical Direct or a p pr o val 
 
•  
P er ma ne ntl y disc o nti n ue if 
cli nical si g ns a n d s y m pt o ms of 
pa ncreatitis de vel o p 
(a b d o mi nal pai n, na usea, 
v o miti n g).  
•  
If t o xicit y d oes n ot res ol ve 
wit hi n 1 2 wee ks of last d ose 
after a n i nterr u pti o n, m ust 
per ma ne ntl y disc o nti n ue u nless 
a p pr o ve d b y t he M S D Cli nical 
Direct or t o c o nti n ue.  
•  
If Gra de 4 li pase/a m ylase 
ele vati o n is as y m pt o matic a n d 
a b d o mi nal i ma gi n g s u g gests n o 
pat h ol o g y, st u d y dr u g 
a d mi nistrati o n d osi n g ma y 
c o nti n ue wit h M S D Cli nical 
Direct or  a p pr o val. 
E paca d ostat  
Ma y c o nti n ue treat me nt wit h 
M S D Cli nical Direct or  a p pr o val 
Gra de 4 
P e m br oliz u ma b  
Wit h h ol d u ntil t o xicit y res ol ves 
t o Gra de 0- 1 
 
E paca d ostat  
Wit h h ol d u ntil t o xicit y res ol ves 
t o Gra de 0- 1 
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 7  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
All Ot her 
I m m u ne-relate d 
A Es  
I nt olera ble/ 
persiste nt G ra de 
2 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de 0 - 1  
•  B ase d o n se verit y of 
A E a d mi nister  
c ortic oster oi ds   
•  
E ns ure a de q uate e val uati o n t o 
c o nfir m eti ol o g y or e xcl u de 
ot her ca uses  
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1 d ose le vel . 
N ot Relate d: Sa me d ose le vel . 
Gra de 3 
P e m br oliz u ma b  
Wit h h ol d u ntil Gra de  0 -1, or 
disc o nti n ue base d o n t he t y pe of 
e ve nt.  E ve nts t hat re q uire 
disc o nti n uati o n i ncl u de a n d n ot 
li mite d t o: G uillai n-B arre 
S y n dr o me, e nce p halitis  
E paca d ostat  
Wit h h ol d u ntil Gra de 0 -1  
 
O nce res ol ve d t o Gra de 0 -1, ma y 
restart: 
Relate d: Re d uce b y 1  d ose le vel.  
N ot Relate d: Sa me d ose le vel.  
 
E ve nts t hat re q uire 
disc o nti n uati o n i ncl u de a n d n ot 
li mite d t o: G uillai n-B arre 
S y n dr o me, e nce p halitis    
Gra de 4 or 
rec urre nt Gra de 3  
P e m br oliz u ma b  
P er ma ne ntl y disc o nti n ue  
E paca d ostat  
P er ma ne ntl y disc o nti n ue  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 8  
P r ot oc ol/ A me n d me nt N o.:  6 7 9 -0 6/ E C H O -3 0 2 -0 6   
 
 
I m m u ne-rel ate d 
A Es  
T o xicit y G r a de 
or C o n diti o ns 
( C T C A E v 4. 0)  
St u d y Tre at me nt  
Acti o n T a ke n wit h St u d y 
Tre at me nt  
irA E M a n a ge me nt  
wit h C ortic oster oi d 
a n d/ or Ot her 
T her a pies  
M o nit or a n d  Foll o w -u p  
A b bre viati o ns:   A Es = a d vers e e ve 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); C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; GI = gastr oi ntest i nal; ir A E = 
i m m u ne-relate d a d verse e ve nts; I V = i ntra ve n o us; T 1 D M = T y pe 1 dia betes mellit us . 
Ge ner al I nstr ucti o ns:  
1.  C ortic oster oi d ta per  s h o ul d be i nitiate d up o n A E i m pr o vi n g t o Gra de 1 or less  an d c o nti n ue t o ta per o ver at least 4 wee ks . 
2.  F or sit uati o n s w here pe m br oliz u ma b a n d e paca d ostat  ha ve  b ee n wit h h el d, pe m br oliz u ma b a n d e paca d ostat  ca n be res u me d after A E has bee n re d uce d t o 
Gra de 1 or 0  a n d c ortic oster oi d has bee n ta pere d . Pe m br oliz u ma b a n d e paca d ostat s h o ul d be per ma ne ntl y disc o nti n ue d if A E d oes n ot res ol ve wit hi n 
1 2  wee ks of last d ose or c ortic oster oi ds ca n n ot be re d uce d t o ≤ 1 0 m g pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks.  
3.  F or se vere a n d life -t hreate ni n g ir A Es, I V c ortic oster oi d s h o ul d be i nitiate d first f oll o we d b y oral ster oi d. Ot her i m m u n os u p pressi ve treat me nt s h o ul d be 
i nitiate d if ir A Es ca n n ot be c o ntr olle d b y c ortic oster oi ds. 
4.  If t he sa me A E t hat re q uire d e paca d ostat d ose re d ucti o ns t o d ose le vel -2 re -occ urs, re gar dless of t he ca usalit y t o e paca d ostat, e paca d ostat s h o ul d be 
disc o nti n ue d.  If  a  partici pa nt  w h o  is  bei n g  treate d  at  d ose  le vel -2  has  a  differe nt gra de  ≥3 A E  t hat  is c o nsi dere d  u nrelate d  t o  e paca d ostat  b y  t he 
i n vesti gat or, t he partici pa nt ma y res u me st u d y treat me nt at d ose le vel -2 after disc ussi o n wit h M S D Cli nical Direct or . 
N O T E S:  
a. 
W it h h ol d O R  per ma ne ntl y dis c o nti n ue pe m br oliz u ma b or e paca d ostat at t he discreti o n of t he i n vesti gat or.   
b.  F or partici pa nt s wit h Gra de 3 or 4 i m m u ne-relate d e n d ocri n o pat h y w here wit h h ol di n g of pe m br oliz u ma b a n d e paca d ostat is re q uire d, pe m br oliz u ma b 
a n d e paca d ostat ma y be res u me d w he n A E res ol ves t o ≤ Gra de 2 a n d is c o ntr olle d wit h h or m o nal re place me nt t hera p y or ac hie ve d meta b olic c o ntr ol (i n 
case of T 1 D M) . 
c. 
P artici pa nts  wit h Gra de 3 ras h i n t he a bse nce of des q ua mati o n, n o m uc osal i n v ol ve me nt, d oes n ot re q uire s yste mic ster oi ds, a n d res ol ves t o  Gra de 1 
wit hi n 1 4  da ys d oes n ot ha ve t o h ol d st u d y treat me nt.  
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
6 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
W he n i n dicate d b y  T a ble 6  t o miti gate ir A Es, t he d ose of e paca d ostat m ust be re d uce d usi n g 
t he d osi n g le vels o utli ne d i n Ta ble 7 . O nce re d u ce d, re-escal ati o n of e paca d ostat is n ot 
per mitte d.  
Ta ble 7  
D ose Le vel A dj ust me nts of E paca d ostat  
St arti n g D ose of 
E p ac a d ost at  
D ose Le vel - 1 
D ose Le vel - 2 
First re d ucti o n of epaca d ostat  
Sec o n d re d ucti o n of e paca d ostat  
1 0 0 m g BI D 
5 0 m g BI D 
2 5 m g BI D 
 
D ose Le vel - 2 is t he l o west d ose of e p aca d ostat i n t his pr ot oc ol. Refer t o t he ge neral 
i nstr ucti o ns i n Ta ble 6  f or g ui da n ce re gar di n g t h e re- occ urre nce of a n A E w he n a partici pa nt 
has ha d t heir e p aca d ostat d ose re d uce d t o d ose le v el - 2.  
 I nf usi o n Re acti o n D ose M o dific ati o ns 
7. 2. 2
Pe m br oliz u ma b ma y ca use se v er e 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 yl a xis. Si g ns a n d s y m pt o ms us uall y de vel o p d uri n g or s h ortl y after 
dr u g i nf usi o n a n d ge nerall y res ol ve c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. 
D ose m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes o n pe m br oliz u ma b- ass ociate d 
i nf usi o n reacti o n are pr o vi de d i n Ta ble 8 . 
Ta ble 8 
Pe m br oliz u ma b  I nf usi o n Reacti o n D ose Mo dificati o n a n d Treat me nt G ui d eli nes  
N CI C T C A E Gr a de  
Tre at me nt  
Pre me dic ati o n at 
S u bse q ue nt D osi n g  
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 n ts 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 tre at me nt  wit h 
pe m br oliz u m a b.  
P artici 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 m i 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).  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
N CI C T C A E Gr a de  
Tre at me nt  
Pre me dic ati o n at 
S u bse q ue nt D osi n g  
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 ni n g; press or 
or ve ntilat or y s u p p ort 
i n dicate d 
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dica l 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 dicat e 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 m a ne ntl y disc o nti n ue d fr o m f urt her 
tre at me nt wit h pe m br oliz u m a b . 
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 b e a vaila ble at t h e b e dsi d e a n d a p h ysicia n rea dil y a vail a ble d uri n g t h e p eri 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 C T C A E at htt p://cte p.ca n cer. 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 v erse E ve nts; I V = i ntra ve n o us; N CI = Nati o n al Ca n cer 
I nstit ute; N S AI Ds = n o nster oi d al a ntii nfla m mat or y dr u gs; P O = oral. 
 
 Pr o ce d ures f or P artici p a nts E x hi biti n g Ser ot o ni n S y n dr o me  
7. 2. 3
T here is  a rar e c ha n ce t h at e paca d osta t c o ul d ca us e a n i ncrease i n ser ot o ni n le vels i n t he brai n 
t hat mi g ht tri g ger S S [ B o yer E W, S ha n n o n M. 2 0 0 5], w he n a d mi nistere d i n c o m bi nati o n 
wit h ot her ser ot o ner gi c a ge nts.  T his s y n dr o me h as bee n m ost cl osel y ass ociate d wit h t he use 
of M A OIs, me peri di ne, li nez oli d, or met h yl e ne bl u e; all of t hese a ge nts are pr o hi bite d d uri n g 
t he st u d y ( Secti o n 7. 7. 2).   
S electi ve ser ot o ni n re u pt a ke i n hi bit ors ( S S RIs) a n d selecti ve ser ot o ni n/ n ore pi ne p hri ne 
re u pta ke i n hi bit ors (S N RI s) ar e per mitte d i n t he st u d y.  Ser ot o ni n s y n dr o m e us uall y 
ma nifests wit h a ut o n o mic c ha n ges, me ntal stat us c ha n ges, a n d ne ur ol o gical fi n di n gs.  T hese 
mil d, m o derate, a n d se v ere si g ns a n d s y m pt o ms of S S (s u m marize d i n  Ta ble 9 ) s h o ul d be 
e val uate d i n t he c o nte xt of p ossi ble c o m or bi d c o n diti o ns as well.   
T he f oll o wi n g pr oce d ur es will be i m ple me nte d if partici pa nts e x hi bit t he si g ns/s y m pt o ms of 
S S , i ncl u di n g tre m or; h y perrefle xia; s p o nta ne o us, oc ular, or i n d uci ble cl o n us; t o get her wit h 
a gitati o n, f e ver, di a p h oresis, or m uscle ri gi dit y.   
•  I m me diat el y i nterr u pt st u d y treat me nt a d mi nistrati o n.  
•  I m me diat el y i nterr u pt a n y S S RI or S N RI a d mi nistrati o n. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
•  Pr o vi de a p pr o priate m e dical ma na ge me nt of t he p artici pa nt u ntil all si g ns/s y m pt o ms 
are r es ol ve d ( e g, I V fl ui ds a n d/ or s y m p at h o mi metic a mi nes f or h y p ote nsi o n, 
be nz o diaze pi nes f or a gitati o n, a d mi nistrati o n of 5- h y dr o x ytr y pt a mi ne a nta g o nists 
s uc h as c y pr o h e pta di ne). 
•  If eti ol o gi es ot her t ha n S S are e x cl u de d, pe m br oli z u ma b a d mi nistrati o n ma y be 
res u me d u nless ot her A E ma na ge me nt g ui deli nes a p pl y f or t he s pecific e v e nt. 
•  If partici pa nt c h o oses t o r e mai n o n st u d y treat me nt, restart treat me nt wit h e paca d ostat 
after t he S S RI or  S N RI h as bee n disc o nti n ue d, n o s o o ner t ha n 5 half-li ves ha ve 
ela pse d f or t h e s pecifi c S S RI or S N RI i n q uesti o n, a n d after res ol uti o n of 
si g ns/s y m pt o ms of S S. T he S S RI or S N RI d osi n g M A Y N O T be restart e d. 
•  If partici pa nt c h o oses t o wit h dra w fr o m st u d y treatme nt , or m ust restart treat me nt 
wit h S S RI or S N RI, t he p artici pa nt s h o ul d be sc he d ule d f or a f oll o w- u p visit. 
Treat me nt wit h S S RI or S N RI ma y be i nitiate d 2 wee ks after res ol uti o n of si g ns a n d 
s y m pt o ms of S S.  
•  If a partici pa nt ha d e x perie nce d m o derate or se vere u nc o nf o u n d e 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 us a ge, or s er 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 treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d. 
Ta ble 9  
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 -
gr a de f e ver  
I nter mitte nt 
tre m or 
Restless ness  
 
 
Tac h ycar dia  
A kat hisia  
A n xiet y  
 
 
M y driasis  
M y ocl o n us  
 
 
 
Dia p h oresis or 
s hi veri n g 
Mil d 
h y perrefle xia  
 
 
M o der ate  
I n crease d 
Tac h ycar dia  
H y p errefle xia  
Easil y startle d  
R ha b d o m y ol ysis  
 
Fe ver ( u p t o 
4 1  0C)  
I n d u ci ble cl o n us I n crease d 
c o nf usi o n  
Meta b olic 
aci d osis 
 
Diarr hea wit h 
h y peracti ve 
b o wel s o u n ds 
Oc ular cl o n us 
(sl o w 
c o nti n u o us 
lateral e ye 
m o ve me nts)  
A gitati o n a n d 
h y per vi gila n ce  
Re nal Fail ure  
 
Dia p h oresis 
wit h n or mal s ki n 
c ol or 
M y ocl o n us  
 
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)  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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  
Se vere  
Te m perat ur e 
ofte n m ore t ha n 
4 1 0C 
( Sec o n dar y t o 
i ncreas e d t o ne) 
I n crease d 
m uscle t o ne 
(l o wer li m b > 
u p per) 
Deliri u m  
As a b o ve  
 
 
S p o nta ne o us 
cl o n us 
C o ma  
 
 
 
S u bsta ntial 
m y ocl o n us or 
h y perrefle xia  
 
 
B o yer E W, S ha n n o n M. T he s er ot o ni n s y n dr o me. Ne w E n gl J Me d 2 0 0 5; 3 5 2: 1 1 1 2 -1 1 2 0.  
 
 I nterr u pti o ns U nrel ate d t o A d verse E ve nts 
7. 2. 4
D osi n g i nterr u pti o ns are p er mitte d f or sit uati o ns ot her t ha n treat me nt-relat e d A Es, s uc h as i n 
t he case of me dical/s ur gi cal 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 nr elate d me dical e ve nts, partici pa nt vacati o n, or h oli da ys). Partici pa nt s 
s h o ul d be place d bac k o n st u d y treat me nt wit hi n 3 wee ks  of t he s c 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. 
 D ose M o dific ati o ns f or S o C Gr o u p P a rtici p a nt s 
7. 2. 5
 M o dific ati o ns f or S u niti ni b  
7. 2. 5. 1
D ose m o dificati o ns i n 1 2. 5- m g ste ps ma y b e a p pli e d base d o n i n di vi d ual safet y a n d 
t olera bilit y.  D ose i nterr u pti o ns ma y be re q uire d b ase d o n i n di vi d ual safet y a n d t olera bilit y.  
D ose re d u cti o ns are re q uire d wit h c o nc o mita nt us e of C Y P 3 A 4 i n hi bit ors s uc h as 
ket oc o naz ole (see Secti o n 7. 7. 2, Restricte d Me dicati o ns ).  S ee t he f ull pres cri bi n g 
i nf or mati o n or S m P C f or s u niti ni b f or a d diti o nal details o n d ose a dj ust me nts.   
 M o dific ati o ns f or P az o p a ni b  
7. 2. 5. 2
D ose m o dificati o ns i n 2 0 0 m g ste ps ma y be a p plie d base d o n i n di vi d ual safet y a n d 
t olera bilit y.  D ose i nterr u pti o ns ma y be re q uire d b ase d o n i n di vi d ual safet y a n d t olera bilit y.  
D ose re d u cti o ns are re q uire d wit h c o nc o mita nt us e of C Y P 3 A 4 i n hi bit ors s uc h as 
ket oc o naz ole (see Secti o n 7. 7. 2, Restricte d Me dicati o ns).  S ee t he f ull pres cri bi n g 
i nf or mati o n or S m P C f or paz o pa ni b f or a d diti o nal details o n d ose a dj ust me nts. 
 
Met h o d of Tre at me nt Assi g n me nt   
7. 3
All eli gi ble partici p a nts will be ra n d o ml y all ocate d a n d will recei v e 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 aft er 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 n e d t o a p artici pa nt, it ca n ne v er be re-assi g ne d t o 
a n ot her partici pa nt. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A si n gle p artici pa nt ca n n ot be assi g n e d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber. 
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 n teracti ve v oice res p o nse 
s yste m / i nte grate d we b r es p o nse s yst e 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 pl us e paca d ost at or 
sta n dar d of car e (s u niti ni b or paz o pa ni b). 
 Str atifi c 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.  I M D C ris k cate g or y (fa v ora ble vers us i nter me diat e vers us p o or) 
2.  P h ysicia n’s i nte n de d c h oice of c o m parat or dr u g (s u niti ni b vers us paz o pa ni b [ deter mi ne d 
pri or t o ra n d o mizati o n]) 
3.  Ge o gra p hical re gi o n ( U S, C A a n d Wester n E ur o p e vers us R O W)  
N O T E: T he ge o gra p hical re gi o ns are d efi ne d i n d etail b y c o u ntr y i n t he I V R S ma n ual. 
 
 Bli n di n g  
7. 4
T his is a n o pe n-la bel trial; t heref or e, t he S p o ns or, i n vesti gat or, M S D st u d y pers o n nel, a n d 
partici pa nt will k n o w t he treat me nts a d mi nistere d.  
 
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y 
7. 5
 D ose Pre p ar ati o n  
7. 5. 1
Details o n pre parati o n a n d a d mi nistrati o n of I V pe m br oliz u ma b are pr o vi de d i n t he 
P har mac y Ma n u al.  E paca d ostat, s u niti ni b, a n d paz o pa ni b are oral ta blets.   
F or e p aca d ost at, i n s uc h cases w h ere a partici p a 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 ns f or d ose cr us hi n g, a d mi nistrati o n, a n d d ose pre p arati o n are det aile d 
i n t he P har mac y Ma n u al.  I n a d diti o n writte n g ui d a nce f or safe ha n dli n g of t he e paca d ostat 
ta blets will be pr o vi de d t o t he partici pa nt/care gi vers.  
 H a n dli n g, St or a ge a n d Acc o u nt a bilit y 
7. 5. 2
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y treat me nt recei ve d a n d a n y discre pa n cies are re p orte d 
a n d res ol ve d b ef or e use of t he st u d y treat me nt.  
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y treat me nt a n d o nl y a ut h orize d site 
staff ma y s u p pl y or a d mi nister st u d y treat me nt. All st u d y treat me nts m ust b e 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 mat e d) area i n acc or da n ce 
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 ns tit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y 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, r ec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
F or all trial sites, t he l ocal c o u nt r y M S D  pers o n nel or desi g n ee 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 priate.  W here l ocal discar d a n d destr ucti o n is a p pr o priate, t he 
i n vesti gat or is r es p o nsi ble f or e ns uri n g t h at a l ocal discar d/ destr ucti o n pr o ce 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 o call y p urc h ase 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 k e 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 ur e a p pr o priate s u p pl y, st ora ge, h a 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 n ce wit h t he pr ot oc ol a n d a n y a p plica ble la ws a n d re g ulati o ns. 
 
Tre at me nt C o m pli a nce  
7. 6
 A d mi nistr ati o n a n d C o m pli a nce of Pe m br oliz u m a b 
7. 6. 1
A d mi nistrati o n of I V p e m br oliz u ma b will be wit nesse d b y t he i n vesti gat or a n d/ or st u d y staff. 
T he t otal v ol u me of st u d y treat me nt i nf use d will be c o m pare d t o t he t otal v ol u me pre pare d t o 
deter mi ne c o m plia nce wit h eac h d ose a d mi nistere d. Pe m br oliz u ma b will be a d mi nistere d o n 
a n o ut-patie nt basis.  
I nstr u cti o ns f or pr e pari n g a n d a d mi nisteri n g p e 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 Or al St u d y Tre at me nt ( E p ac a d ost at , 
7. 6. 2
S u niti ni b , or P az o p a ni b) 
Partici pa nts will ta ke t heir d ose of e p aca d ost at 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 h e 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. Partici pa nts will self-a d mi nister e p aca d ostat e x ce pt o n C ycle 1 D a y 1 ( C 1 D 1) a n d 
C ycle 1 Da y 2 2 ( C 1 D 2 2), 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 pr i or 
t o t he pe m br oliz u ma b i nf usi o n. 
T he a d mi nistrati o n sc he d ule f or s u niti ni b is dail y f or eac h 6- wee k seri es ( o n treat me nt f or 
4 wee ks, f oll o we d b y 2 wee ks off treat me nt), a n d f or paz o pa ni b is dail y f or eac h 6- wee k 
series). 
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 n el 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. 
I n v esti gat ors a n d t heir st aff s h o ul d e val u ate c o m plia nce at eac h visit, a n d t a 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
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e x cl 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 di cati o n or vacci n ati o n 
s pecificall y pr o hi bite d, disc o nti n uati o n fr o m st u d y t hera p y or v acci n ati o n ma y b e re q uire d.  
T he i n vesti gat or s h o ul d disc uss a n y q u esti o ns re gar di n g t his wit h t he M S D  Cli nical Direct or.  
T he fi nal decisi o n o n a n y s u p p orti ve t hera p y or v acci nati o n rests wit h t he i n vesti gat or a n d/ or 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
t he partici pa nt's pri mar y p h ysicia n.  H o we v er, 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 uir es 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.  
 Acce pt a ble C o nc o mit a nt T her a pies  
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 h a n ge d at t he discreti o n of t he i n vesti gat or i n k ee 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 (s ee secti o n bel o w). All 
c o nc o mita nt me dicati o n will be rec or d e d o n t he case re p ort f or m ( C R F) i ncl u di n g all 
prescri pti o n, o ver-t he- c o u nter, her b al s u p ple me nts, a n d I V me dicati o ns a n d fl ui ds. If c ha n ges 
occ ur d uri n g t he st u d y peri o d, d oc u me ntati o n of dr u g d osa ge fre q ue n c 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 p er mitte d d uri n g t he c o urse of t he st u d y f or u n derl yi n g 
me dical c o n diti o ns a n d ma na ge me nt of s y m pt o ms. S ur ger y f or t u m or c o ntr ol is n ot per mitte d 
d uri n g t he st u d y. Palliati ve ra di ot hera p y ma y be  p er mitte d t o a li mite d n u m ber of lesi o ns if 
c o nsi dere d me di call y necessar y b y t he treati n g p h ysicia n after c o ns ultati o n wit h t he M S D 
Cli nical D irect or.  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 p y 
a n d s h o ul d be res u me d n o earlier t h a 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 r a diati o n treat me nt, i ncl u di n g t he l ocati o n, will be rec o r de d. 
All c o nc o mita nt me dicati o ns recei v e d wit hi n 3 0 da ys b ef ore t he first d ose of st u d y treat me nt 
t hr o u g h t he Safet y F oll o w- u p Visit s h o ul d be rec or de d. After t he Safet y F oll o w- u p Visit, 
rec or d all me dicati o ns ta ke n f or S A Es a n d E CIs. If a partici p a nt e nters i nt o sec o n d c o urs e 
t hera p y, all c o n c o mita nt me dicati o ns recei ve d wit hi n 3 0 da ys b ef 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 s ec o n d c o urs e 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 CIs. 
 Pr o hi bite d Me dic ati o ns or T her a pies  
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 x cl 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 di cati o n or vacci n ati o n 
s pecificall y pr o hi bite d, disc o nti n uati o n fr o m trial t hera p y or v acci n ati o n ma y b e re q uire d.  
T he i n vesti gat or s h o ul d disc uss a n y q u esti o ns re gar di n g t his wit h t he M S D Cli nical Direct or.  
T he fi nal decisi o n o n a n y s u p p orti ve t hera p y or v acci 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 v er, 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 uir es 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 d y partici p a 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 m ust be i nterr u pte d 
or disc o nti n ue d.  E x a m ples of s uc h me dicati o ns i ncl u de M A O i n hi bit ors a n d U G T 1 A 9 
i n hi bit ors.  Partici pa nts ma y c o nti n ue o n treat me nt wit h pe m br oliz u ma b after c o ns ultati o n 
wit h M S D.  
Liste d bel o w are s p ecific restricti o ns f or c o n c o mita nt t hera p y or v acci nati o n:  
Partici pa nts are pr o hi bite d  fr o m recei vi n g t h e 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: 
•  A nti ne o plastic s yste mic c he m ot hera p y or bi ol o gi cal t hera p y n ot s p ecifie d i n t his 
pr ot oc ol. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
o  N ote: de n os u ma b is per mitte d. 
•  I m m u n ot her a p y n ot s pecifie d i n t his pr ot oc ol. 
•  I n v esti gati o nal a ge nts ot her t ha n e p aca d ost at a n d pe m br oliz u ma b. 
•  A n y c hr o nic i m m u n ol o gi cal-s u p pressi v e treat me nt f or a n y reas o n ot her t ha n t he 
ma na ge me nt of a d vers e e ve nts, as descri b e d i n Secti o n 7. 2 ( N ote:  I n hale d or t o pical 
ster oi ds are all o we d, a n d s yste mic ster oi ds or re place me nt d oses of ster oi ds at d oses 
≤ 1 0 m g/ da y pr e d nis o ne or e q ui vale nts are all o we d, a n d i m m u ne s u p pressa nts are 
all o we d as pr o p h yla xis f or c o ntrast aller g y f or i m a gi n g pr o ce d ures.) 
•  O nc ol o gi c s ur ger y f or t u m or c o ntr ol. 
•  Ra diati o n t hera p y f or dis ease c o ntr ol. 
o  N ote: Ra diati o n t hera p y t o a s y m pt o matic s olitar y lesi o n or t o t he brai n ma y 
be all o we d at t he I n vesti gat or’s discreti o n, pr o vi d e d t he lesi o ns were n ot 
pre vi o usl y d efi ne d b y t he site as tar get lesi o ns. 
•  Li ve v acci n es wit hi n 3 0 da ys pri or t o t he first d os e 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.  
o  E x a m pl es 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, yell o w fe ver, nasal seas o n al fl u, nasal 
H 1 N 1 fl u, ra bies, B C G, a n d t y p h oi d. 
•  P artici p a nts i n Gr o u p 1 Recei vi n g pe m br oliz u m a b pl us e p ac a d ost at  
•  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 p aca d ost at has bee n ta k e n.  
o  I n cl u di n g, b ut n ot li mite d t o, h y drazi nes (e x a m ple p he nelzi ne), me peri di ne, 
car o x az o ne, li nez oli d, ec hi n o psi di ne, met h yl e ne bl ue, f uraz oli d o ne, 
tra n yl c y pr o mi ne, br ofar o mi ne, metrali n d ole, mi na pri ne, m ocl o be mi de, 
pirli n d ole, t ol o x at o ne, laza be mi de, parg yli ne, rasa gili ne, sele gili ne.  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
•  A n y U G T 1 A 9 i n hi bit or, i ncl u di n g, b ut n ot li mite d t o acitreti n, a mitri pt yli ne, 
a n dr oster o ne, c ycl os p ori ne, dasati ni b, dicl ofe n ac, difl u nisal, efa vire nz, erl oti ni b, 
fl uta mi de, gefiti ni b, ge mfi br ozil, gl yc yrr h eti nic aci d, gl yc yrr hizi n, i mati ni b, 
i mi pra mi ne, ket oc o naz ole (s yste mic), li n oleic aci d s u p ple me nts, m yc o p h e 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 yt oi n, pr o be n eci d, 
q ui ni di ne, rit o na vir, s oraf e ni b, s ulfi n p yraz o ne, val pr oic aci d, a n d v era pa mil.  
N ote: Ket oc o naz ole 2 % t o pical crea m is all o we d . 
•  P artici p a nts i n Gr o u p 2 Recei vi n g s u niti ni b  
•  Str o n g C Y P 3 A 4 i n hi bit ors s uc h a ket o c o naz ole ma y i n crease s u niti ni b plas ma 
c o nce ntr ati o ns.  Selecti o n of a n alter n ate c o n c o mita nt me dicati o n wit h n o or mi ni mal 
e nz y me i n hi biti o n p ote ntial is rec o m me n de d.  A d ose re d ucti o n f or s u niti ni b t o a 
mi ni m u m of 3 7. 5 m g dail y s h o ul d be c o nsi dere d if str o n g C Y P 3 A 4 i n hi bit ors m ust 
be use d. See A p p e n di x 7 f or listi n gs of C Y P i n hi bit ors/i n d ucers. Refer als o t o t he 
prescri bi n g i nf or mati o n or S P C of s u niti ni b f or c o m plete i nf or mati o n. 
•  P artici p a nts i n Gr o u p 2 Recei vi n g p az o p a ni b 
•  A v oi d use of str o n g C Y P 3 A 4 i n hi bit ors s uc h as ket oc o naz ole wit h paz o pa ni b.  If 
c o-a d mi nistrati o n is warr a nte d re d u ce t he d os e of paz o pa ni b t o 4 0 0 m g. See 
A p pe n di x 7 f or listi n gs of C Y P i n hi bit ors/i n d ucers. Refer als o t o t he prescri bi n g 
i nf or mati o n or S P C of paz o pa ni b f or c o m plete i nf or mati o n.  
•  A ge nts t hat raise gastri c p H s h o ul d be use d wit h ca uti o n wit h paz o pa ni b.  C o nsi der 
s h ort acti n g a ntaci ds i n place of pr ot o n p u m p i n hi bit ors or H 2 rece pt or a nt a g o nists, 
a n d se par ate a nt aci d a d mi nistrati o n fr o m paz o pa ni b d osi n g b y se veral h o urs. 
Partici pa nts w h o, i n t he assess me nt of t he I n vesti gat or, re q uire t he use of a n y of t he 
af ore m e 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 treat me nt 
b ut c o nti n ue i n st u d y f or assess me nt of diseas e stat us a n d s ur vi val. 
T he e x cl usi o n criteria descri be ot her me di cati o ns w hic h are pr o hi bite d i n t his st u d y. 
T here are n o pr o hi bite d t hera pies d uri n g t he P ost- Treat me nt F oll o w - u p P hase.  
 Restricte d Me dic ati o ns  
7. 7. 3
Gr o u p 1 ( pe m br oliz u ma b pl us e paca d ostat o nl y) : Use of c o u mari n- bas e d a ntic oa g ul a nts (e g, 
warf ari n [ C o u ma di n]), Pre visca n (fl ui n di o ne), a n d vita mi n K a nta g o nists are disc o ura ge d. 
L o w - d ose c o u m ari n- bas e d a ntic oa g ula nts, e g, w arfari n 1 m g is acce pta ble; h o we ver, d os es 
t hat i ncreas e t he I N R are disc o ura ge d. If a n alter nati ve ca n n ot be use d, t he I N R s h o ul d be 
m o nit ore d cl osel y ( wee kl y f or t he first 4 w ee ks after i nitiati o n of t hera p y a n d u p o n 
disc o nti n uati o n of e paca d ostat). 
 Resc ue  Me dic ati o ns a n d S u p p orti ve C are  
7. 7. 4
Partici pa nt s s h o ul d recei ve a p pr o pri ate s u p p orti ve care m eas ures as dee me d necessar y b y t he 
treati n g In vesti gat or. S u g geste d s u p p orti ve care m eas ures f or t he ma n a ge m e nt of A Es  wit h 
p ote ntial i m m u n ol o gic eti ol o g y ar e o utli ne d  i n Secti o n 7. 2. 1. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
Sec o n d C o urse P h ase ( Retre at me nt)  
7. 8
All partici pa nt s i n Gr o u p 1 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 i nf usi o ns (a p pr o ximatel y 1 year) of pe m b r oliz u ma b pl us e paca d ostat if 
t he y pr o gress after st o p pi n g st u 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 he st u d y a n d is o nl y a v aila ble if t he st u d y 
re mai ns o pe n a n d t h e partici pa nt  meets t he f oll o wi n g c o n diti o ns: 
Eit her  
o  St o p pe d st u d y treat me nt after attai ni n g a C R b y t h e l ocal i n vesti gat or per R E CI S T 
1. 1, a n d, 
•  Was treate d f or at least  4 c ycles  of st u d y treat me nt (eac h c ycle is 6  w ee ks a n d 
i ncl u des 2 i nf usi o ns of pe m br oliz u ma b) bef ore disc o nti n ui n g t hera p y. 
•  Recei ve d at least 2 i nf usi o ns of pe m br oliz u ma b be y o n d t he d ate w he n t h e i nitial 
C R was declar e d.  
O R  
o  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 i nf usi o ns of 
pe m br oliz u ma b pl us 1 7. 5 c ycles of e paca d ostat  (a p pr o xi matel y 2 years ) f or reas o ns 
ot her t ha n disease pr o gressi o n or i nt olera bilit y. 
•  A N D  
o  E x perie nce d a r a di o gra p hic disease pr o gressi o n p er R E CI S T  1. 1 after st o p pi n g i nitial 
treat me nt, , 
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 m eters liste d i n t he i ncl usi o n criteria a n d 
n o ne of t he safet y par a m eters liste d i n t he e x cl 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 h e Sec o n d C o urse P hase ( Retreat me nt) will be re -treate d at t he s a me 
d ose fre q u e nc y as w he n t he y l ast 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.  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 i nf usi o ns of 
pe m br oliz u ma b (a p pr o xi matel y 1 year) usi n g t he re vise d Sec o n d C o urs e P h ase Sc he d ule of 
Acti vities i n Secti o n 2. 2 . 
 
Tre at me nt After t he E n d of t he St u d y  
7. 9
T here is n o st u d y- s pecifie d treat me nt f oll o wi n g t h e e n d of t he st u d y.  
 Cli nic al S u p plies Discl os ure  
7. 1 0
T his trial is o pe n-la bel; t heref ore, t he p artici pa nt, t he trial site pers o n nel, t h e S p o ns or , M S D 
st u d y pers o n n el, a n d/ or d esi g nee are n ot bli n de d. St u d y treat me nt ( n a me, stre n gt h or 
p ote nc y) is i ncl u de d i n t h e la bel te xt; ra n d o m c o de/ discl os ure e n vel o pes or lists are n ot 
pr o vi de d. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
7 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
Disc o nti n u ati o n/ Wit h dr a w al Criteri a  
8.
 
Disc o n ti 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 pres e nt wit h dra wal fr o m t he st u d y. 
As certai n d ata 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 b e 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 h e p artici pa nt’s last sc he d ul e 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 - Sc he d ule of Acti vities 
( S o A) a n d Secti o n 9. 1 0. 3 – Disc o nti n ue d Partici pa nts C o nti n ui n g t o be M o nit ore d i n t he 
St u d y.  
Partici pa nts ma y disc o nti n ue st u d y treat me nt at a n y ti me f or a n y reas o n or be dr o p pe d fr o m 
t he st u d y treat me nt at t he discreti o n of t he i n vesti gat or s h o ul d a 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 
safet y reas o ns.  S pecific details re gar di n g pr oce d ures t o be perf or me d at st u d y treat me nt 
disc o nti n uati o n are pr o vi de d i n Secti o n 9. 1. 1 0 – Wit h dra wal/ Disc o nti n uati o n. 
A partici pa nt m ust be disc o nti n ue d fr o m st u d y treat me nt b ut c o nti n ue t o be m o nit ore d i n t he 
st u d y f or a n y of t he f oll o wi n g r eas o ns: 
○ T he partici pa nt or p artici pa nt’s le gall y acce pta ble re pres e ntati ve re q uests t o disc o nti n ue 
st u d y treat me nt. 
o  Ra di o gr a p hic diseas e pr o gr essi o n per R E CI S T 1. 1 T he i n vesti gat or s h o ul d c o ns ult wit h 
t he Merc k Cli nical Dir ect or if he/s he c h o oses t o c o nti n ue treat me nt after i nitial 
ra di o gra p hic P D. 
o  U nacce pta ble a d vers e e x perie nce s as des cri be d i n Secti o n 7. 2. 
o  T he partici pa nt has a me dical c o n diti o n or pers o n al circ u msta nce w hic h, i n t he o pi ni o n of 
t he I n v esti 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 tr eat me nt.  
o  T he partici pa nt has a c o nfir me d p ositi ve ser u m pre g n a nc y test. 
o  A n y pr o gressi o n or r ec urre nce of a n y mali g na n c y, or a n y occ urre n ce of a n ot her 
mali g na n c y t hat re q uir es acti ve s yste mic treat me nt.  
o  C o m pleti o n of 3 5 i nf usi o ns of pe m br oliz u ma b (a p pr o xi matel y 2 years)  
o  Disc o nti n uati o n of treat me nt ma y b e c o nsi dere d f or partici pa nts w h o h a ve 
attai ne d a c o nfir me d C R b y l ocal I n vesti gat or ass ess me nt a n d ha ve bee n treate d 
f or at least 8 i nf usi o ns (at least 2 4 wee ks) a n d recei ve d at least 2  i nf usi o ns be y o n d 
t he date w he n t h e i nitial C R was declare d. T hese partici pa nts ma y be e li gi ble f or 
sec o n d c o urs e treat me nt descri be d i n Secti o n 7. 8. 
o  T he st u d y is ter mi nat e d b y t he S p o ns or. 
o  T he st u d y is ter mi nat e d b y t he l ocal healt h a ut h orit y, I R B, or I E C. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
o  T he occ urre n ce of u n acce pta ble t o xicit y n ot ca use d b y t he u n d erl yi n g m ali g na n c y will be 
pres u me d t o be r elate d t o st u d y treat me nt a n d will re q uire t hat all st u d y treat me nt be 
per ma ne ntl y disc o nti n ue d.  U nacce pta ble t o xicit y is defi ne d as f oll o ws: 
o  Occ urre nce of a n A E t hat is relate d t o t he st u d y treat me nt t hat, i n t he j u d g m e nt of 
t he i n vesti gat or or M S D ’s me dical m o nitor, c o m pr o mises t he partici pa nt’ s a bilit y 
t o c o nti n ue st u d y-s pecifi c pr oce d ures or is c o nsi dere d t o n ot be i n t he partici pa nt's 
best i nterest.  
o  A n A E re q uiri n g m or e t ha n 2 d ose re d u cti o ns of e paca d ostat.  Partici p a nts ma y 
c o nti n ue o n pe m br oliz u ma b m o n ot hera p y treat me nt.   
o  Persiste nt A E re q uiri n g a dela y of t hera p y f or m ore t ha n 1 2 wee ks u nless a greater 
dela y has bee n a p pr o v e d b y M S D . 
A partici pa nt  m a y  b e disc o nti n ue d fr o m st u d y treat me nt(s) or refere nce t h era pies as f oll o ws: 
o  If, d uri n g t he c o urse of t h e st u d y, a partici pa nt is f o u n d n ot t o ha ve met eli gi bilit y criteria, 
t he me 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 ar e 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. 
 
W it h dr a w al f r 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 p artici p a nt’s le gall y 
acce pta ble r e pres e ntati ve wit h dra ws c o nse nt fr o m t he st u d y.  
If a partici pa nt wit h dra ws fr o m t he st u d y, t he y will n o l o n ger recei ve st u d y treat me nt or be 
f oll o we d at sc he d ul e d pr ot oc ol visits. 
S pecific details re gar di n g pr oce d ur es t o b e perf or me d at t he ti me of wit h dra wal fr o m t he 
st u d y ar e o utli ne d i n Secti o n 9. 1. 1 0.   T he pr oce d ures t o be perf or me d s h o ul d a partici pa nt 
re peat e 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 bl e t o c o ntact the 
partici pa nt ar e o utl i ne d i n Secti o n 8. 3.   
 
L ost t o F oll o w u p 
8. 3
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 p a nt, t he f oll o wi n g pr o ce d ures are t o be p erf or m e 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 ul e 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 v er y eff ort t o re gai n c o nt act 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 v ale 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 p artici pa nt’s me dical rec or d. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 p ecifie d data ha n dli n g a n d a nal ysis g ui deli nes. 
N O T E: As of A me n d me nt 0 6, t his secti o n is n o l o n ger a p plica bl e.  T here will be n o 
a d diti o nal eff orts t o c o nt act partici pa nts w h o are l ost t o f oll o w- u p.  
 
St u d y Assess me nts a n d Pr oce d ures  
9.
●  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 n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d u ct. 
●  T he I n vesti gat or is r es 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 u alifie d or trai ne d staff.  Dele gati o n of trial sit e 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 v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T h e i n vesti gat or will mai ntai n a scree ni n g l o g 
t o rec or d d etails 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 scr ee ni n g fail ure, as a p plica ble.  
●  Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge m e 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 b e 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 m et t he pr ot oc ol- s pecifi e d criteria a n d were 
perf or me d wit hi n t he ti me fra m e defi ne d i n t he S o A. 
●  A d diti o nal e val uati o ns/testi n g ma y be dee me d necessar y b y t he i n vesti gat or a n d/ or 
M S D  f or reas o ns relate d t o partici pa nt safet y. I n s o me cases, s u c h e val uati o n/testi n g 
ma y b e p ote ntiall y s e nsiti ve i n nat ure (e g, HI V, H e patitis C, etc.), a n d t h us l ocal 
re g ulati o ns ma y re q uir e 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 cas es, s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce 
wit h t h ose re g ulati o ns. 
 
A d mi nistr ati ve 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 n ee 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 p ta ble re pres e ntati ve pri or t o p artici pati n g i n a 
cli nical trial . If t her e 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 r e q uire m e nts), t he i n vesti gat or or q ualifie d desi g n ee m ust e ns ure t he a p pr o priate 
c o nse nt is i n place.  
C o nse nt m ust be d oc u me nte d b y t he p artici pa nt’s date d si g n at ure or b y t h e partici pa nt’s 
le gall y acce pta ble r e pres e 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 ur e 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 p artici pa nt bef ore 
partici pati o n i n t he trial.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
T he i nitial I C F, a n y s u bs e q ue nt re vise d writte n I C F a n d a n y writte n i nf or m ati 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 v al/fa v ora bl e o pi ni o n i n a d va nce of us e.  
T he partici pa nt or his/ her le gall y acce pta ble re pres e 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 v aila ble t hat ma y be rele v a nt t o t he partici pa nt’s 
willi n g ness t o c o nti n ue p artici 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 o c u me nte d via a re vis e d c o nse nt f or m or a d de n d u m t o t h e ori gi n al c o nse nt 
f or m t hat ca pt ur es t he partici pa nt’s date d si g nat ure or b y t he partici pa nt’s l e gall y acce pta ble 
re pres e ntati ve’s dat e 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 ns e 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 m e nts. 
 I ncl usi o n/ E xcl usi o n Criteri a  
9. 1. 2
All i ncl usi o n a n d e x cl usi o n criteria will be re vie w e d b y t h e 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 d e ntificati o n Car d i de ntif yi n g t he m as 
partici pa nts i n a res ear c 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 b ers) t o be utilize d i n t he e ve nt of a n e mer ge nc y. T h e i n vesti gat or or 
q ualifie d desi g nee will pr o vi de t he p artici pa nt wit h a Partici pa nt I de ntificati o n Car d 
i m me diatel y after t he p artici 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 ntifi cati o n Car d.  
T he partici pa nt i de ntificati o n car d als o c o ntai ns c o ntact i nf or mati o n f or t he e mer ge n c y 
u n bli n di n g call ce nter s o t hat a healt h care pr o vi d er ca n o btai n i nf or m ati 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 ycle  1 Da y  1, p artici pa nts i n Gr o u p 1 will be gi ve n a n i nf or mati o n car d listi n g si g ns a n d 
s y m pt o ms of S S. T his i nf or mati o n car d i nstr ucts p artici pa nts t o see k i m me diate me dical care 
if a n y of t he liste d s y m pt o ms are o bser v e 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 h e i n vesti gat or or q ualifie d d esi g n ee.  
C o m pre he nsi ve me dical hist or y pertai ni n g t o R C C will als o be c ollecte d.  T his i ncl u des t he 
dia g n osis, hist o pat h ol o g y, a n d pri or treat me nt (i ncl u di n g ra diati o n a n d s ur ger y). 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Pri o r a n d C o nc o mit a nt Me dic ati o ns Re vie w  
9. 1. 6
 Pri o r Me dic ati o ns  
9. 1. 6. 1
T he i n vesti gat or or q ualifie d desi g n ee will re vi e w pri or me dicati o n use, i ncl u di n g a n y 
pr ot oc ol-s pecifi e 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, i ncl u di n g 
a nti bi otics, b y t he partici pa nt wit hi n  3 0 da ys of t h e first d ose of st u d y treat me nt. 
 C o nc o mit a nt Me dic ati o ns  
9. 1. 6. 2
T he i n vesti gat or or q ualifie d desi g n ee will rec or d me dicati o n, if a n y, t a ke n b y t he p artici pa nt  
d uri n g t he st u d y t hr o u g h t he Safet y F oll o w- u p visit.  After t he  Safet y F oll o w - u p Visit, if 
partici pa nts ar e eli gi ble f or sec o n d c o urse of treat me nt,  rec or d n e w me dicati o ns starte d 
d uri n g t he Sec o n d C o urs e P hase t hr o u g h t he Sec o n d C o urse Safet y F ol l o w- u p Visit. 
 Assi g n me nt of Scree ni n g N u m ber  
9. 1. 7
All c o nse nte d partici p a nts will be gi ve n a u ni q u e s cree ni n g n u m ber t hat will be use d t o 
i de ntif y t he p artici 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 a ssi g ne d o nl y o n e scree ni n g n u m ber.  Scree ni n g n u m bers m ust n ot be re- us e d f or 
differe nt p artici pa nts.  
A n y p artici 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 scr ee ni n g visit.  
S pecific details o n t he scree ni n g visit re q uire m e nts (scree ni n g/rescree ni n g) are pr o vi d e d i n 
Secti o n 9. 1 0. 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 p a nts will be ra n d o ml y all ocate d a n d will recei v e 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 aft er 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 n e d t o a p artici pa nt, it ca n ne v er be re-assi g ne d t o 
a n ot her partici pa nt. 
A si n g le p artici pa nt ca n n ot be assi g n e d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber. 
 Tre at me nt A d mi nistr ati o n  
9. 1. 9
A d mi nistrati o n of pe m br oliz u ma b will be wit nesse d b y t h e i n vesti gat or a n d/ or st u d y staff. 
A d mi nistrati o n of e paca d ostat will be wit nesse d b y t he i n vesti g at or a n d/ or st u d y staff f or t he 
m or ni n g d ose o n C 1 D 1 a n d C 1 D 2 2 (a n d Sec o n d C o urse C 1 D 1 if a p plica ble). All ot her d oses 
of e paca d ostat will be self -a d mi nistere d.  
St u d y treat me nt s h o ul d b e gi n o n t he d a y of treat m e nt all ocati o n/ra n d o mizati o n or as cl ose as 
p ossi ble t o t he date o n w hic h t he partici pa nt is all ocate d/assi g ne d. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Ti mi n g of D ose A d mi nistr ati o n 
9. 1. 9. 1
 Ti mi n g of D ose A d mi nistr ati o n of Pe m br oliz u m a b 
9. 1. 9. 1. 1
St u d y Treat me nt s h o ul d be gi n wit hi n 3 da ys of ra n d o mizati o n.     
St u d y treat me nt wit h pe m br oliz u ma b s h o ul d be a d mi nistere d at eac h treat me nt visit after all 
pr oce d ur es/assess me nts ha ve bee n c o m plete d as detaile d i n t he S o A ( Secti o n 2). At C 1 D 1 
a n d C 1 D 2 2, pe m br oliz u ma b s h o ul d be a d mi nistere d aft er all pr o ce d ures/assess me nts ha ve 
bee n c o m plete d a n d e p aca d ostat d ose has bee n ta k e n i n t he cli nic.   
Pe m br oliz u ma b will be a d mi nistere d o n a n o ut patie nt basis. St u d y treat me nt of 
pe m br oliz u ma b ma y be a d mi nistere d u p t o 3 da ys bef ore or aft er t he sc h e d ule d visit d ue t o 
a d mi nistrati ve reas o ns ( e x ce pt f or C 1 D 1, w here t h e d osi n g wi n d o w is o n t h e date of 
ra n d o mizati o n or u p t o 3 da ys after ra n d o mizati o n). 
Pe m br oliz u ma b will be a d mi nistere d as a d ose of 2 0 0 m g usi n g a 3 0- mi n ut e I V i nf usi o n. 
Sites s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n ti mi n g t o be as cl os e t o 3 0 mi n utes as 
p ossi ble. H o we ver, gi v e n t he varia bilit y of i nf usi o n p u m ps fr o m site t o site, a wi n d o w of -
5 mi n utes a n d + 1 0 mi n utes is per mitte d (ie, i nf usi o n ti me is 3 0 mi n utes -5 mi n/ + 1 0 mi n).  
T he P har mac y M a n ual c o ntai ns s pecific i nstr ucti o ns f or pe m br oliz u ma b rec o nstit uti o n, 
pre par ati o n of t he i nf usi o n fl ui d, a n d a d mi nistrati o n. 
 Ti mi n g of D ose A d mi nistr ati o n of E p ac a d ost at 
9. 1. 9. 1. 2
T he d ose of e paca d ostat i n t his st u d y is 1 0 0 m g t wice dail y. E paca d ostat will be ta ke n t wice 
dail y, o nce i n t he m or ni n g a n d o n ce i n t he e ve ni n g, a p pro xi matel y 1 2  h o urs a part wit h o ut 
re gar d t o f o o d.  
O n C 1 D 1 a n d C 1 D 2 2, t he m or ni n g d os e of e p aca d ostat will be gi ve n at t h e cli nic pri or t o t he 
i nf usi o n of pe m br oliz u ma b a n d aft er all pr o ce d ures/assess me nts ha ve bee n c o m plete d , as 
detaile d i n t he S o A ( Secti o n 2). 
 
 
 
All ot her d oses of e p aca d ostat will be self -a d mi nistere d wit h o ut re gar d t o f o o d. 
If t he m or ni n g or e v e ni n g d ose of e paca d ostat 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 h e 
partici pa nt v o mits after t a ki n g a ta bl et, t he d ose s h o ul d n ot be rea d mi nistere 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. 
T he partici pa nt m ust be i nstr ucte d i n t he ha n dli n g of st u d y treat me nt as f oll o ws: 
•  T o st ore t he st u d y tr eat m e nt at r o o m te m perat ure  a n d ti g htl y cl ose d t o a v oi d m oist ure. 
•  T o o nl y r e 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 h e d ule. 
•  T o re p ort a n y misse d d os es. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
•  If t he partici p a nt v o mits after ta ki n g st u d y 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 pl ace 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.  
 Ti mi n g of D ose A d mi nistr ati o n of S u niti ni b  
9. 1. 9. 1. 3
S u niti ni b will be self-a d mi nistere d  d uri n g eac h 6- wee k treat me nt c ycl e. E ac h 6 -w ee k 
treat me nt c ycl e is br o ke n u p i nt o 4 wee ks o n treat me nt f oll o we d b y 2 wee ks off treat me nt. 
D uri n g t h e 4- wee k treat me nt peri o d, s u niti ni b s h o ul d be ta ke n o nce dail y ( 5 0 m g) wit h o ut 
re gar d t o f o o d. S u niti ni b s h o ul d be ta ke n at a p pr o xi matel y t he sa m e ti me eac h da y. D osi n g 
o n a 2- wee k o n, 1- w ee k off sc he d ule is n ot per mitte d.   
 Ti mi n g of D ose A d mi nistr ati o n of P az o p a ni b 
9. 1. 9. 1. 4
F or eac h 6 -wee k treat me nt c ycl e , paz o pa ni b will be self-a d mi nistere d ( 8 0 0 m g ) o nce dail y 
wit h o ut f o o d (at least 1 h o ur bef or e or 2 h o urs after a meal).   Paz o pa ni b s h o ul d be ta ke n at 
a p pr o xi matel y t he sa me ti me eac h d a y.  
 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 ur a 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 wit h dra ws fr o m p artici pati o n i n t he trial, all a p plica ble acti vities 
sc he d ule d f or t h e disc o nti n uati o n visit  s h o ul d be perf or me d at t he ti me of wit h dra wal.  A n y 
a d verse e ve nts w hic h are prese nt at t he ti me of wit h dra wal s h o ul d be f oll o we d i n acc or da nce 
wit h t he safet y re q uire me nts o utli ne d i n Secti o n 9. 3 - A d vers e E ve nts. 
 P artici p a nt Bli n di n g/ U n bli n di n g  
9. 1. 1 1
T his is a n o pe n la bel trial; t here is n o bli n di n g f or t his trial. 
 C ali br ati o n of Critic al E q ui p me nt  
9. 1. 1 2
T he i n vesti gat or or q ualifie d desi g n ee has t h e res p o nsi bilit y t o e ns ure t hat a n y critical de vice 
or i nstr u me nt use d f or a cli nical e val uati o n/test d uri n g a cli nical trial t hat pr o vi des i m p orta nt 
i nf or mati o n a b o ut i ncl usi o n/e x cl usi o n criteria a n d/ or safet y or effi cac y p ara meters s hall be 
s uita bl y cali br ate d a n d m ai ntai ne d t o e ns ure t h at t he data o btai ne d is relia ble a n d/ or 
re pr o d uci ble.  D oc u me nt ati o n of e q ui p me nt cali brati o n m ust be retai ne d as s o urce 
d oc u me ntati o n at t he trial site.  
Critical E q ui p me nt f or t his trial i ncl u des:  
•  La b orat or y e q ui p me nt – as re q uire d f or i ncl usi o n la b orat orie s a n d s afet y assess me nts 
•  I ma gi n g e q ui p me nt – as r e q uire d f or effi cac y assess me nts  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
Effic ac y Assess me nts  
9. 2
 T u m or I m a gi n g a n d Ass ess me nt of Dise ase  
9. 2. 1
N ote:   As of A me n d me nt 0 6 , t he e n d p oi nt of t he st u d y will be O R R b y Res p o nse 
E v al u ati o n Criteri a 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 g at or after 
c o m pleti o n of t he first pr ot oc ol -defi ne d i m a gi n g assess me nt, w hic h is sc he d ule d at 
Wee k 1 2 ( ± 7 d a ys). T h us, s u b missi o n of i m a ges f or bli n de d i n de pe n de nt ce ntr al re vie w 
( BI C R) is n o l o n ger re q uire d. 
T u m or i ma gi n g is str o n gl y pr eferre d t o b e ac q uire d b y c o m p ute d t o m o gra p h y ( C T).  F or t h e 
c hest, a b d o me n a n d p el vis ( C A P) i ma gi n g, c o ntrast-e n ha nce d ma g netic res o na nce i ma gi n g 
( 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 ma n date d 
b y l ocal practice. M RI is t he str o n gl y preferre d m o dalit y f or i ma gi n g t he brai n.  T he sa me 
i ma gi n g tec h ni q u e re gar di n g m o dalit y (i deall y t he sa me sca n n er) a n d t he us e of c o ntrast 
s h o ul d be use d i n a partici pa nt t hr o u g h o ut t he st u d y t o o pti mize t he re pr o d u ci 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 o cate d at t he site or at a n offsite facilit y. 
Partici pa nt eli gi bilit y will be  deter mi ne d usi n g l ocal assess me nt (I n v esti gat or assess me nt) 
base d o n R E CI S T 1. 1.  Treat me nt s h o ul d c o nti n ue u ntil P D has bee n deter mi ne d per site 
assess me nt.  
 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 6 , all te xt i n t his secti o n rel ati n g t o tr a ns missi o n of i m a ges t o 
t he ce ntr al i m a gi n g ve n d or f or retr os pecti ve re vie w is n o l o n ger a p plic a ble a n d 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 ys 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 s cree ni n g i ma ges t o c o nfir m t he partici pa nt 
has meas ura bl e disease p er 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 ng 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 p erf or m e d wit hi n 2 8 da ys pri or 
t o t he date of r a n d o mizati o n.  
Ma n dat or y t u m or i ma gi n g f or all partici pa nt s at Scree ni n g i ncl u d es C A P i ma gi n g a n d a b o ne 
sca n.  Partici pa nts wit h a hist or y of brai n metast as es ma y p artici pate pr o vi d e d t he y are 
ra di ol o gicall y st a ble acc or di n g t o t he e x cl usi o n criteria d oc u me nte d i n Secti o n 6. 2. 
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.  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 T u m or I m a gi n g D uri n g t he St u d y  
9. 2. 1. 2
N ote: As of A me n d me nt 0 6 , ce ntr al re vie w of i m a g es 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 1 2, f urt her i m a gi n g 
will be perf or me d as per l oc al S o C g ui deli nes h o w e 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 ass ess me nt of C A P s h o ul d be perf or m e d at 1 2 w ee ks ( ± 7  da ys) 
fr o m t he date of ra n d o mi zati o n.  N o f urt her i ma gi n g is ma n date d; a n y f urt h er 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 ass ess me nt as per S o C 
f or t he diseas e a n d l ocal g ui deli nes; o nl y t he date of sca ns perf or me d as per S o C nee ds t o be 
d oc u me nte d i n t he e C R F. 
If t he first b o ne s ca n is p ositi ve at baseli ne, b o ne sca n s s h o ul d be perf or me d  per S o C, 
acc or di n g t o l ocal g ui d eli nes; t he res ults will N O T be c ollecte d. T h e ti mi n g of i ma gi n g 
assess me nts  s h o ul d f oll o w cale n d ar da ys fr o m ra n d o mizati o n a n d s h o ul d n ot be a dj uste d f or 
dela ys i n c ycle starts.   
T he i n vesti gat or s h o ul d c o ns ult wit h t he M S D Cli nical Direct or  if he/s he c h o oses t o c o nti n ue 
treat me nt after i nitial ra di o gra p hi c P D.  
 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 per A me n d me nt 0 6 , t here is n o pr ot oc ol s pecifie d i m a gi n g after t he 
Wee k  1 2 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 h e Wee k 1 2  i ma gi n g ass ess me nt f or 
efficac y a n al ysis , 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 m e nt 
disc o nti n uati o n ( ± 4 wee k wi n d o w).  If a pre vi o us i ma ge was o btai ne d wit hi n 4 wee ks pri or t o 
t he date of disc o nti n uati o n, t he n i ma gi n g at treat m e 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 diseas e pr o gressi o n, t his is 
t he fi nal re q uir e 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 per A me n d me nt 0 6, t his secti o n is n o l o n ger a p plic a ble;  o nl y s afet y 
assess me nts will be perf or me d d uri n g Sec o n d C o urse retre at me nt.  Dis e ase assess me nt 
i n t his peri o d will be perf or me d b y t he i n vesti g at or o nl y per S o C f or t he dise ase a n d 
l oc al g ui deli nes. Dise ase assess me nts will n ot be c ollecte d i n t he C R Fs.  
T u m or i ma gi n g ( C A P a n d b o ne sca n) m ust be p erf or me d wit hi n 2 8 da ys pri or t o restarti n g 
treat me nt wit h pe m br oliz u ma b + e paca d ostat. Bef ore a partici pa nt ma y e nt er Sec o n d C o urse 
P hase, BI C R verificati o n of P D m ust ha ve occ urre d. T he P D i ma gi n g ma y als o be u se d as t he 
Sec o n d C o urse baseli ne i ma gi n g if it is wit hi n 3 0 da ys pri or t o restarti n g treat me nt a n d 
ot her wise meets t he b aseli ne sta n dar ds o utli ne d i n t he Site I ma gi n g Ma n u al.  
L ocal rea di n g (I n v esti gat or assess me nt wit h site ra di ol o g y rea di n g) will be use d  t o deter mi ne 
eli gi bilit y. All sec o n d c o urse i ma gi n g s h o ul d be s u b mitte d t o t he ce ntral i ma gi n g ve n d or f or 
q ualit y c o ntr ol, st ora ge, a n d p ossi ble retr os pecti ve re vie w, t h o u g h BI C R- verificati o n of P D 
will n ot occ ur d uri n g Sec o n d C o urse p hase. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
T he first o n -st u d y i ma gi n g ass ess me nt of C A P s h o ul d be perf or m e d at 1 2 w ee ks ( ± 7 da ys) 
after t he restart of treat m e nt .  S u bse q ue nt t u m or i ma gi n g s h o ul d be perf or me d e ver y 
1 2 wee ks ( ± 7  d a ys), or m ore fr e q ue ntl y if cli nicall y i n dicat e d.     
F or partici pa nts wit h p ositi ve b o ne sca n e nteri n g sec o n d c o urs e, t he first o n-st u d y b o ne s ca n 
s h o ul d be perf or m e d at 2 4  wee ks ( ± 7  d a ys) aft er t he restart of treat me nt .  S u bse q ue nt t u m or 
i ma gi n g s h o ul d be perf or me d e ver y 2 4 wee ks ( ± 7  da ys), at wee ks or m ore fre q ue ntl y if 
cli nicall y i n dicat e d.   
All i ma gi n g s h o ul d be tra ns mitte d t o t he ce ntral i ma gi n g v e n d or, t h o u g h BI C R- verificati o n 
of P D will n ot occ ur d uri n g Sec o n d C o urs e p hase. 
Per iR E CI S T  ( Secti o n 9. 2. 1. 6), if t u m or i ma gi n g s h o ws i nitial P D, t u m or assess me nt s h o ul d 
be re peate d 4 t o 8 wee ks later i n or der t o c o nfir m P D, wit h t he o pti o n of c o nti n ui n g treat me nt 
w hile a waiti n g ra di ol o gic c o nfir mati o n of pr o gressi o n. Partici pa nts w h o o btai n c o nfir mat or y 
i ma gi n g d o n ot nee d t o u n der g o sc he d ul e d t u m or i ma gi n g if it is less t ha n 4 wee ks later a n d 
ma y w ait 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 m e d u ntil disease pr o gressi o n, t he start of ne w a nti-
ca ncer treat me nt, wit h dra wal of c o nse nt, pre g na n c y, deat h, or n otificati o n b y M S D, 
w hic he ver o cc urs first. I n cli nicall y sta ble p artici p a nts, disease pr o gressi o n ma y b e 
c o nfir me d b y t he I n v esti gat or usi n g i R E CI S T 4 t o 8 wee ks after t he first t u m or i ma gi n g 
i n dicati n g P D.  
F or  cli nicall y sta ble p arti ci 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 m e 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 w as 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 ndat or y. I n 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 P D, 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 P D, 
e ver y eff ort s h o ul d be m a de t o c o nti n ue m o nit ori n g diseas e stat us b y ra di ol o gic i ma gi n g 
acc or di n g t o t he s c he d ule t hat t he partici pa nt  was o n d uri n g treat me nt u ntil t he start of ne w 
a ntica ncer treat me nt, disease pr o gressi o n, pre g n a nc y, d eat h, or t he e n d of t he st u d y, 
w hic he ver o cc urs first. F or t hese part ici p a nts, t he ne xt i ma gi n g w o ul d occ ur at t he 
disc o nti n uati o n visit, a n d t he n 1 2 wee ks later. If pre vi o us i ma gi n g w as o btai ne d wit hi n 4 
wee ks pri or t o t he d ate 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. T he ti mi n g of Sec o n d C o urse f oll o w- u p visits ( Secti o n 2. 2) s h o ul d be sc he d ule d 
t o c oi nci de wit h t he parti ci pa nt’s f oll o w- u p i ma gi n g. O n ce i ma gi n g is c o m plete (e g, P D, ne w 
a nti- ne o plastic t her a p y), t he partici pa nt e nters i nt o S ur vi val F oll o w-U p.  
 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 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 gr essi 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 nce s 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, M S D 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 rel e va nt t o e na ble a br oa d er sa m pli n g of t u m or b ur d e n.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
8 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 i R E CI S T Assess me nt of Dise ase ( Gr o u p 1) 
9. 2. 1. 6
N ote: As per A me n d me nt 0 6 , t his secti o n is n o l o n ger a p plic a ble; i R E CI S T will n o 
l o n ger be a p plie d i n t his cli nic al st u d y .  P artici p a nts wit h r a di o gr a p hic dise ase 
pr o gressi o n as deter mi ne d b y R E CI S T 1. 1 b y i n vesti g at or assess me nt will disc o nti n ue 
f r o m t he st u d y tre at ment ; n o c o nfir m at or y s c a ns are re q uire d.  H o w e ver, if t he 
p artici p a nt is ac hie vi n g a cli nic all y me a ni n gf ul be nefit, a n e xce pti o n t o c o nti n ue st u d y 
tre at me nt m a y be c o nsi dere d f oll o wi n g c o ns ult ati o n wit h t he Merc k Cli nic al Direct or.  
T he fi n al st u d y visit wi ll be t he 3 0- d a y S afet y F oll o w-u p Visit.  Assess me nt of A Es will 
be rec o r de d a n d re p ort e d per Secti o n 9. 3.   
i R E CI S 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 CI S T will be use d b y t h e 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 st a ble, partici pa nts 
s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d b y t he I n vesti gat or, w or ki n g wit h 
l ocal ra di ol o g y, acc or di n g t o t he r ules o utli ne d i n A p pe n di x 6. T his all o wa nce t o c o nti n ue 
treat me nt des pite i nitial r a di ol o gic P D ta k es i nt o acc o u nt t he o bser v ati o n t hat s o me 
partici pa nts ca n h a ve a tr a 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 u e nt disease res p o ns e.  T hes e data will be 
ca pt ure d i n t he cli nical d ata base.  
Cli nical sta bilit y is defi n e 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 nifi ca nt pr o gressi o n of 
disease  
•  N o decli ne i n E C O G perf or ma nce stat us  
•  N o re q uire m e nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesi a, 
ra diati o n, or ot her p alliati ve care 
A n y p artici 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 
ce ntral verificati o n of sit e -assess e 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 p eat t u m or i ma gi n g f or c o nfir m ati 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 d y treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m 
P D b y i R E CI S T, p er i n v esti gat or assess me nt. I ma ges s h o ul d c o nti n ue t o b e se nt 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 p eat 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 v esti gat or, a n d t he 
partici pa nt c o nti n ues t o b e cli nicall y st a 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 h e d ule. If P D is c o nfir me d, p artici 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 hi c pr o gressi o n (i C P D) as defi ne d i n A p pe n di x 6, 
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 hi e vi n g a cli nicall y 
mea ni n gf ul be nefit, a n e x ce pti o n t o c o nti n ue st u d y treat me nt ma y be c o nsi dere d f oll o wi n g 
c o ns ultati o n wit h M S D .  I n t his case, if st u d y treat me nt is c o nti n ue d, t u m or i ma gi n g s h o ul d 
c o nti n ue t o be perf or me d f oll o wi n g t he i nter v als 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.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A descri pti o n of t he a d a ptati o ns a n d i R E CI S T pr o cess is pr o vi de d i n A p pe n di x 6, wit h 
a d diti o nal detail i n t he i R E CI S T p u blicati o n [ Se y m o ur, L., et al 2 0 1 7].  A s u m mar y of 
i ma gi n g a n d tr eat me nt re q uire me nts after first ra di ol o gic e vi d e nce of pr o gressi o n is pr o vi de d 
i n Ta ble 1 0  a n d ill ustrate d as a fl o wc h art i n  Fi g ure 2 . 
Ta ble 1 0  I ma gi n g a n d Treat me nt A fter First Ra di ol o gic E vi de nce of P D 
 
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 h as 
bee n verifie d b y BI C R 
Re p eat i ma gi n g at 4 
t o 8 wee ks t o c o nfir m 
P D  
Ma y c o nti n u e st u d y 
treat me nt at t h e 
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 p eat i ma gi n g at 4 
t o 8 wee ks t o c o nfir m 
P D p er I n vesti gat or’s 
discreti o n o nl y  
Disc o nti n u e 
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 p er 
I n vesti gat or assess me nt 
N o a d diti o n al 
i ma gi n g re q uire d 
Disc o nti n u e 
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 n al 
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 p er 
I n vesti gat or assess me nt  
Re p eat i ma gi n g at 4 
t o 8 wee ks t o c o nfir m 
P D. Ma y o cc ur at 
n e xt re g ularl y 
sc h e d ule d i ma gi n g 
visit.  
C o nti n u e st u d y 
treat me nt at t h e 
I n vesti gat or’s 
discreti o n.  
Re p eat i ma gi n g at 4 
t o 8 wee ks t o c o nfir m 
P D p er I n vesti gat or’s 
discreti o n o nl y.  
Disc o nti n u e 
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 p er 
i n vesti gat or assess me nt 
C o nti n u e re g ularl y 
sc h e d ule d i ma gi n g 
assess me nts  
C o nti n u e st u d y 
treat me nt at t h e 
i n vesti gat or’s 
discreti o n  
C o nti n u e re g ularl y 
sc h e d ule d i ma gi n g 
assess me nts  
Ma y r estart st u d y 
treat me nt if c o n diti o n 
h as i m pr o ve d a n d/ or 
cli nicall y sta ble per 
i n vesti gat or’s 
discreti o n. Ne xt 
t u m or i ma ge s h o ul d 
o cc ur acc or di n g t o 
t h e re g ular i ma gi n g 
sc h e d ule 
BI C R = bli n d e d i n d e p e n d e nt ce ntral re vie w; i C P D = i R E CI S T c o nfir me d pr o gressi ve disease; i C R = i R E CI S T c o m plete 
res p o nse; i P R =i R E CI S T p artial res p o nse; i R E CI S T = m o difie d Res p o nse E val u ati o n Criteria i n S oli d T u m ors 1. 1 f or 
im m u ne -b ase d t h era p e utics; i S D  = i R E CI S T sta ble disease; i U P D = i R E CI S T u n c o nfir me d pr o gressi ve disease; 
M S D  = Merc k, S h ar p & D o h me; P D = pr o gressi ve disease; R E CI S T 1. 1 = Res p o nse E val u ati o n Criteria i n S oli d T u m ors 
1. 1.  
N ote:  If pr o gressi o n h as b ee n ce ntrall y verifie d, f urt h er ma n a ge m e nt is b y t h e site, b as e d o n i R E CI S T. A n y f urt h er 
i ma gi n g s h o ul d still b e s u b mitte d t o t h e ce ntral i ma gi n g v e n d or, b ut n o ra pi d re vie w will o cc ur. 
If R E CI S T 1. 1 disease pr o gressi o n h as n ot b ee n ce ntrall y verifie d; i d eall y t h e site s h o ul d c o nti n u e treat me nt. W h et her or 
n ot treat me nt c o nti n u es, i ma gi n g s h o ul d b e c ollecte d a n d s u b mitte d t o t h e ce ntral i ma gi n g ve n d or wit h V O P re q u est u ntil 
R E CI S T 1. 1 pr o gressi o n is verifie d b y BI C R.]  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 
Fi g ure 2 
I ma gi n g  a n d  Tr eat me nt  f or  Cli nicall y  Sta ble Gr o u p  1 Partici pa nts  after  First 
Ra di ol o gic E vi de n ce of P D Assesse d b y t he I n vesti gat or 
 
A d verse E ve nts, Seri o us A d verse E ve nts  a n d Ot her Re p ort a ble S afet y E ve nts  
9. 3
T he defi niti o ns of a n a d v erse e v e 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 safet y e v e nt re p orts ca n b e 
f o u n d i n A p pe n di x 3. 
Pr o gr essi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n a d verse e v e nt as descri be d i n 
Secti o n 9. 3. 5 – Disease -Relate d E ve nts a n d/ or Disease -Rel ate d O utc o mes N ot Q ualif yi n g as 
A Es or S A Es, a n d A p pe n di x 3. 
A E, S A Es, a n d ot her r e p orta ble saf et y e ve nts will be re p ort e d b y t he partici pa nt ( or, w he n 
a p pr o priate, b y a care gi v er, s urr o gate, or t he p arti ci pa nt's le gall y a ut h orize d re pres e ntati ve).  
T he i n vesti gat or, w h o is a q ualifie d p h ysicia n, a n d a n y d esi 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 saf et y e ve nts.  I n v esti gat ors re mai n res p o nsi ble f or f oll o wi n g 
u p o n A E s, S A Es a n d ot her re p orta ble safet y e v e nts f or o utc o me, acc or di n g t o Secti o n 9. 3. 3. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 ar c 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 pecifi e d pr oce d ure or i nter v e 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 p artici pa nt is first re q uire d t o pr o vi de c o nse nt t o t he mai n st u d y a n d 
A Es will be ca pt ure d acc or di n g t o g ui deli nes f or sta n dar d A E re p orti n g. 
 Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E a n d Ot her Re p ort a ble 
9. 3. 1
S af et y E ve nt I nf or m ati o n  
All A Es, S A Es a n d ot her re p orta ble s afet 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 tr eat me nt all o cati o n/ra n d o mizati o n m ust be re p orte d b y t he i n v esti gat or if t he 
partici pa nt is recei vi n g pl ace b o r u n-i n or ot her r u n- i n treat me nt, if t he e v e nt ca use t he 
partici pa nt t o be e x cl u de d fr o m t he trial, or is t he res ult of a pr ot oc ol-s p ecifie 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, di et, or a pr o ce d ure.  
All A Es fr o m t he ti me of treat me nt al l 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 m e nt, or 3 0 da ys f oll o wi n g cessati o n of st u d y treat m e nt if t he 
partici pa nt i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier, m ust be re p orte d b y t he 
i n vesti gat or.  
T he i n vesti gat or m ust re p ort all pre g na n cies 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 oll o wi n g last d ose of pe m br oliz u ma b a n d/ or e paca d ostat O R  
●  1 8 0 da ys after last d ose of c he m ot hera pe utic a ge nts O R  
● 
3 0 da ys f oll o wi n g cessati o n of st u d y treat me nt if t he partici pa nt i nitiates ne w a ntica ncer 
t hera p y. 
A d diti o nall y, a n y S A E br o u g ht t o t he atte nti o n of a n i n vesti gat or at a n y ti me o utsi de of t he 
ti me peri o d s pecifie d a b o ve m ust be re p orte d i m m e diatel y t o M S D if t he e v e nt is c o nsi dere d 
t o be dr u g-rel ate d. 
I n v esti gat ors ar e n ot o bli gat e d t o acti vel y see k A Es, S A E s or ot her re p orta ble safet y e v e nts 
i n f or mer st u d y partici pa nts. H o we ver, if t h e i n vesti gat or lear ns of a n y S A E, i ncl u di n g a 
deat h, at a n y ti me after  a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d t he I n vesti gat or 
c o nsi ders t he e v e nt t o be reas o na bl y relate d t o t he st u d y treat me nt or st u d y partici pati o n, t he 
i n vesti gat or m ust pr o m ptl y n otif y M S D . 
All i nitial a n d f oll o w -u p A Es, S A Es a n d ot her re p orta ble safet y e ve nts will be rec or de d a n d 
re p orte d t o M S D  or desi g nee wit hi n t he ti mefra mes as i n dicate d i n  Ta ble 1 1 . 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Ta ble 1 1 
Re p orti n g  Ti me  Peri o ds  a n d  Ti mefra mes  f or  A d verse  E ve nts  a n d  Ot her 
Re p orta ble Safet y E v e nts  
T y pe of E ve nt  
 
Re p orti n g Ti me 
Peri o d:  
C o nse nt t o 
R a n d o miz ati o n/  
All oc ati o n  
Re p orti n g Ti me 
Peri o d:  
R a n d o miz ati o n/ 
All oc ati o n 
t hr o u g h 
Pr ot oc ol -
S pecifie d 
F oll o w -u p 
Peri o d  
Re p orti n g Ti me 
Peri o d:  
After t he Pr ot oc ol 
S pecifie d F oll o w -u p 
Peri o d  
 
Ti mefr a me 
t o Re p ort 
E ve nt a n d 
F oll o w -u p 
I nf or m ati o n 
t o M S D : 
N o n -Seri o us 
A d verse E ve nt 
( N S A E)  
 
Re p ort if:  
- d ue t o pr ot oc ol -
s pecifie d 
i nter ve nti o n 
- ca uses 
e xcl usi o n  
- partici pa nt  is 
recei vi n g place b o 
r u n-i n or ot her 
r u n-i n treat me nt 
Re p ort all  
N ot re q uire d  
 
P er data 
e ntr y 
g ui deli nes  
Seri o us A d verse 
E ve nt ( S A E)  
i ncl u di n g C a ncer 
a n d O ver d ose  
 
Re p ort if:  
- d ue t o pr ot oc ol -
s pecifie d 
i nter ve nti o n 
- ca uses 
e xcl usi o n  
- partici pa nt  is 
recei vi n g place b o 
r u n-i n or ot her 
r u n-i n treat me nt 
Re p ort all  
Re p ort if:  
- dr u g/ vacci ne rela te d. 
( F oll o w o n g oi n g t o 
o utc o me ) 
 
Wit hi n 2 4 
h o urs of 
lear ni n g of 
e ve nt  
Pre g n a nc y/ L act ati o n 
E x p os ure  
 
Re p ort if:  
- d ue t o 
i nter ve nti o n 
- ca uses 
e xcl usi o n  
Re p ort all  
Pre vi o usl y re p orte d –  
F oll o w t o 
c o m pleti o n/ter mi nati o n; 
re p ort o utc o me 
 
Wit hi n 2 4 
h o urs of 
lear ni n g of 
e ve nt  
E ve nt of Cli nic al 
I nterest (re q uire 
re g ul at or y 
re p orti n g)  
 
Re p ort if:  
- d ue t o 
i nter ve nti o n 
- ca uses 
e xcl usi o n  
Re p ort  
- P ote ntial DI LI  
- Re q uire 
re g ulat or y 
re p orti n g 
N ot re q uire d  
 
Wit hi n 2 4 
h o urs of 
lear ni n g of 
e ve nt  
E ve nt of Cli nic al 
I nterest ( D o n ot 
re q uire re g ul at or y 
re p orti n g)  
 
Re p ort if:  
- d ue t o 
i nter ve nti o n 
- ca uses 
e xcl usi o n  
Re p ort  
- n o n -DI LI E CIs 
a n d t h ose n ot 
re q uiri n g 
re g ulat or y 
re p orti n g 
N ot re q uire d  
 
Wit hi n 5 
cale n dar 
da ys  of 
lear ni n g of 
e ve nt  
  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 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 d etecti n g A E a n d/ or S A E a n d ot her re p ort a ble 
safet y e v e 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 p artici pa nt is t he 
preferre d m et 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 he r Re p ort a ble S afet y E ve nt I nf or m ati o n  
9. 3. 3
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts. All A E s, S A Es a n d ot her re p orta bl e safet y e ve nts 
i ncl u di n g pre g n a nc y a n d e x p os ure d uri n g breastfee di n g, E CI, Ca n cer a n d O ver d ose will be 
f oll o we d u ntil res ol uti o n, sta bilizati o n, u ntil t he e ve nt is ot her wise e x plai ne d, or t he 
partici pa nt is l ost t o f oll o w - u p (as d efi 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 m ati o n o n f oll o w- u p pr oce d ures is gi v e 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 h e 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 safet y of p artici pa nts a n d t he 
safet y of a st u d y tr eat 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 h a ve a le gal res p o nsi bilit y t o n otif y b ot h t he l o cal re g ulat or y 
a ut h orit y a n d ot h er r e g ulat or y a ge n cies a b o ut t he safet y 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 v e nts will be re p orte d t o re g ul at or y a ut h orities, 
I R B/I E Cs a n d i n vesti gat ors i n acc or d a nce wit h all a p plica ble gl o bal laws a n d re g ulati o ns, 
ie, per I nter nati o nal C o nf ere nce o n Har m o nisati o n (I C H) T o pic E 6 ( R 1) G ui deli nes f or 
G o o d Cli nical Practice.  
•  I n v esti gat or saf et y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d s eri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d M S D  p olic y a n d 
f or war de d t o i n vesti gat ors as necess ar 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 an S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A E) fr o m M S D  will file it al o n g 
wit h t he I n v esti gat or’s Br oc h ure a n d will n otif y t h e I R B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uir e me nts. 
 Dise ase -R el ate d E ve nts a n d/ or Dise ase- Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
9. 3. 5
or S A Es  
Efficac y e n d p oi nts, as o utli ne d i n t his secti o n , will n ot be re p orte d t o M S D , as descri be d i n 
Secti o n 9. 3. 1.   
S pecificall y, t he s us pect e d/act ual e ve nts c o v ere d i n t his e x ce pti o n i ncl u de a n y e v e nt t hat is 
disease pr o gr essi o n of t h e ca n cer u n d er st u d y.  
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 dat a t o e ns ure 
t he safet y of t he p artici pa nts i n t he st u d y.  A n y s us pecte d e n d p oi nt w hic h u p o n re vie w is n ot 
pr o gressi o n of t he ca ncer u n der st u d y will be f or w ar de d t o M S D  as an S A E wit hi n 2 4 h o urs 
of deter mi nat i o n t hat t he e ve nt is n ot pr o gressi o n of t he ca n cer u n d er st u d y. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 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 pr e 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 v erse 
e ve nts, a n y pr e g na nc y or i nfa nt e x p os ure d uri n g breastfee di n g i n a partici pa nt (s p o nta ne o usl y 
re p orte d t o t he i n vesti gat or or t heir desi g nee) t hat occ urs d uri n g t he tri al are re p ort a ble t o 
M S D . 
All re p orte d pr e g na nci es 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 n c y. 
Pre g n a nc y o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n h y d ati dif or m m ole, 
bli g hte d o v u m, fetal d eat h, i ntra uteri ne deat h, miscarri a ge a n d still birt h m ust be re p orte d as 
seri o us e ve nts (I m p orta nt Me dical E ve nts). If t he pre g na nc y c o nti n ues t o ter m, t he o utc o me 
( healt h of i nfa nt) m ust als o be re p orte d. 
 E ve nts of Cli nic al I nterest ( E CI)  
9. 3. 7
Selecte d n o n -seri o us a n d seri o us a d vers e e v e nts are als o k n o w n as E v e nts of Cli nical I nterest 
( E CI) a n d m ust be r e p ort e d t o M S D . 
E ve nts of cli nical i nterest f or t his trial i ncl u de:  
1.  a n o ver d ose of st u d y treat me nt, as defi ne d i n Secti o n 9. 4 – Treat me nt of O v er 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 vat e 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 vat e 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 v al 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 h e d ule d la b orat or y testi n g. * 
* N ote:  T hese criteria are base d u p o n a v aila ble re g ulat or y g ui da n ce d o c 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 t ests 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 d a nce f or assess me nt 
a n d f oll o w u p of t hese criteria ca n b e f o u n d i n t he I n v esti gat or Trial File Bi n der ( or 
e q ui vale nt). 
It ma y als o be a p pr o priat e t o c o n d uct a d diti o nal e val uati o n f or a n u n d erl yi n g eti ol o g y i n 
t he setti n g of a b n or malities of li ver bl o o d tests i ncl u di n g A S T, A L T, bilir u bi n, a n d 
al kali ne p h os p hatase t h at d o n ot meet t he criteria n ote d a b o ve.  I n t hes e cases, t he 
decisi o n t o pr ocee d wit h a d diti o nal e val uati o n will be ma de t hr o u g h c o ns ult ati o n bet wee n 
t he st u d y i n vesti gat ors a n d t he M S D Cli nical Direct or.  H o we v er, a b n or malities of li ver 
bl o o d tests t hat d o n ot meet t he criteria n ote d a b o ve are n ot E CIs f or t his st u d y. 
3.  ser ot o ni n s y n dr o m e. T he si g ns a n d s y m pt o ms of S S  are descri be d i n Secti o n 7. 2. 3, 
Ta ble 9 . 
 
Tre at me nt of O ver d ose  
9. 4
I n t his st u d y, a n o ver d os e of pe m br oliz u ma b is defi ne d as a n y d os e hi g h er t ha n ≥1 0 0 0 m g 
( 5 ti mes t he d ose), a n d f or e paca d ostat, a n y d ail y d ose ≥1 0 0 0 m g.  A n o v er d ose of t he S o C 
treat me nts is defi ne d as a d mi nistrati o n of m ore t ha n t he pr ot oc ol-s pecifie d d ose, ie, > 5 0 m g 
f or s u niti ni b, a n d > 8 0 0 m g f or paz o pa ni b.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
I n t he e ve nt of a n o ver d ose, a p pr o priat e 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.  T he i n vesti gat or s h o ul d c o ntact M S D , a n d a d diti o nal m o nit ori n g of t he p artici pa nt  
f or A Es/ S A Es a n d la b or at or y a b n or malities s h o ul d be c o nsi dere d. Decisi o ns re gar di n g d os e 
i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vesti gat or i n c o ns ultati o n wit h MS D  
base d o n t he cli nical e val uati o n of t he partici pa nt . T he partici pa nt  ma y res u me st u d y 
treat me nt at t he discr eti o n of t he i n vesti gat or (refer t o S o C la beli n g f or m ore details). 
I nf or mati o n re gar di n g t h e q ua ntit y of t h e e x cess d ose s h o ul d be d oc u me nte d i n t he e C R F. 
If a n A E is ass o ciate d wit h (“res ults fr o m”) t he o v er d ose of st u d y treat me nt, t he A E is 
re p orte d as a n S A E, e v e n if n o ot her seri o us ness criteria are met. 
If a d ose of st u d y tr eat me nt meeti n g t he pr ot o c 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 os e is re p orte d as a 
n o n-seri o us E CI, usi n g t h e 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 v esti gat or wit hin 
2 4 h o urs t o M S D eit her b y el ectr o nic me di a or pa p er. Electr o ni c re p orti n g  pr oce d ures ca n b e 
f o u n d i n t he electr o ni c data c ollecti o n data e ntr y g ui deli nes. Pa per re p orti n g pr o ce 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 af et y  
9. 5
Details re gar di n g s p ecifi c safet y pr o ce d ures/assess me nts t o be perf or me d i n t his st u d y are 
pr o vi de d bel o w. T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver t he c o urse of 
t he st u d y (fr o m pre-st u d y t o p ost-st u d y visits), i ncl u di n g a p pr o xi mate bl o o d/tiss ue v ol u mes 
dra w n/c ollect e d b y visit a n d b y s a m ple t y p e per p artici pa nt ca n b e f o u n d i n t he Pr oce d ure 
Ma n ual . 
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A. 
 P h ysic al E x a mi n 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 I n vesti gat or or q u alifie d desi g nee will perf or m a f ull p h ysical e x a m i nati o n as per 
i nstit uti o nal sta n dar d d uri n g t he Scree ni n g peri o d. Cli nicall y si g nifica nt a b n or mal fi n di n gs 
s h o ul d be rec or de d as me dical hist or y. T h e ti me p oi nts f or f ull p h ysical e x a mi nati o ns are 
descri be d i n 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 ysical e x a mi nati o n 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 ycl e 1 D a y 1  
a n d Sec o n d C o urse disc o nti n uati o n visit. 
 Direct e d  P h ysic al E x a mi n ati o n 
9. 5. 1. 2
F or c ycl es t hat d o n ot re q uire a f ull p h ysical e x a m i nati o n (as s pecifi e d i n t he S o A), t he 
I n v esti gat or or q ualifie d desi g nee will perf or m a directe d p h ysical e x a mi nati o n as cli nicall y 
i n dicate d pri or t o t he a d mi nistrati o n of t he 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. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Vit al Si g ns  
9. 5. 2
T he I n vesti gat or or q u alifie d desi g nee will ta ke vital si g ns at Scree ni n g , pri or t o t he 
a d mi nistrati o n of eac h d ose of st u d y treat me nt, a n d d uri n g t he F oll o w- u p P eri o d as s pecifie d 
i n t he S o A. Vital si g ns i ncl u de te m perat ure, p ulse, res pirat or y rate, w ei g ht, a n d bl o o d 
press ure. H ei g ht will be meas ure d at Scree ni n g o nl y.  
 Electr oc a r 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 ned at treat me nt 
disc o nti n uati o n a n d as cli nicall y i n dicat e d f or all partici pa nts. At S E L E C T 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 h e first d ose of e paca d ostat, a n d C 1 D 2 2 pre d ose a n d a p pr o xi matel y 
2 h o urs ( ± 1 5 mi n utes) aft er a d mi nistrati o n of e p aca d ostat.  
T he E C G meas ur e me nt s h o ul d al wa ys be perf or m e d pri or
 
 
Cli nicall y si g nifica nt a b n or mal fi n di n gs o bser ve d pri or t o si g ni n g t he I C F 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 o bser v e d after si g ni n g t he I C F 
s h o ul d be rec or de d as a n A E.  A n E C G s h o ul d als o be perf or me d wit hi n 1 4 d pri or t o t he 
sec o n d c o urs e C ycle 1 D a y 1 t o c o nfir m c o nti n ui n g eli gi bilit y. 
T he 1 2- lea d E C Gs will be i nter pret e d b y t he I n vesti gat or at t he site a n d will be use d f or 
i m me diate partici pa nt ma na ge me nt. T he d ecisi o n t o i ncl u de or wit h dra w a partici pa nt fr o m 
t he st u d y bas e 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 M S D me dical m o nit or, as a p pr o priate. T he 
Fri deri cia ( pr eferre d) or Bazett c orrecti o n met h o d f or cal c ulati n g Q Tc will be use d a n d 
rec or d e d i n t he electr o nic case r e p ort f or m (e C R F).  
 Cli nic al S af et y L a b or at or y Assess me nts 
9. 5. 4
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 p erf or me d a n d t o t he S o A f or 
t he ti mi n g a n d fr e q ue n c 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 n y cli nicall y rele v a nt c h a n ges occ urri n g d uri n g t he st u d y i n t he A E s ecti 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 o c 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 v ere t h a n e x pecte d 
f or t he partici p a nt's c o n diti o n. 
•  All pr ot oc ol-re q uir e 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 d a nce wit h t he la b orat or y ma n u al 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 pecifi e 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 n a ge m e nt or 
are c o nsi d ere d cli nicall y si g nifica nt b y t he i n v esti 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 priat e e C R F.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
9 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
•  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 ntl y a b n or mal 
d uri n g partici pati o n i n t he st u d y or wit hi n 3 0 da ys after t he  l ast d ose of st u d y 
treat me nt, e ver y atte m pt s h o ul d be ma de t o perf or m re peat ass ess me nts u ntil t he 
val ues ret ur n t o n or m al or baseli ne or if a ne w b as eli 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 af et 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. 4. 1
La b orat or y tests f or he m at ol o g y, c h e 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 h e ti mi n g of la b orat or y assess m e nts .  F or Gr o u p 2 o nl y, s afet y la b orat or y 
assess me nts ma y be d o ne per S o C after t he Wee k  1 2 i ma gi n g assess me nt.  
 Pre g n a nc y Test  
9. 5. 4. 2
All w o me n w h o ar e 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 t he first d ose of st u d y treat me nt. M o nt hl y pre g na n c y testi n g 
s h o ul d be c o n d ucte d as p er l ocal r e 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 s er u m test will be re q uire d. Partici pa nts m ust be e x cl u de d/ disc o nti n ue d fr o m 
t he st u d y treat me nt i n t he e ve nt of a p ositi ve or b or derli ne- p ositi ve test res ult.  
 Perf or m a nce Ass ess me nts  
9. 5. 5
As b ot h E C O G a n d Kar n ofs k y p erf or ma nce sc ores are c ollecte d at Scree ni n g , it is i m p orta nt 
f or t hese val u es t o n ot c o ntra dict. 
 E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce Sc ale 
9. 5. 5. 1
T he i n vesti gat or or q ualifie d desi g n ee will assess E C O G stat us (see A p p e n di x 9) at 
Scree ni n g , pri or t o t he a d mi nistrati o n of eac h d ose of st u d y treat me nt a n d d uri n g t he f oll o w-
u p peri o d, as s pecifie d i n t he S o A ( Secti o n 2). 
 K ar n ofs k y Perf or m a nce Sc ore  
9. 5. 5. 2
Kar n ofs k y p erf or m a nce s c ores (s ee A p p e n di x 1 0) will be re q uire d at Scree ni n g  t o e val u ate 
eli gi bilit y a n d f or stratifi cati o n p ur p oses.  T he s c ore m ust be assesse d b y a me dicall y 
q ualifie d i n di vi d ual a n d r ec or de d i n t he e C R F. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


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


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


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


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


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 V isit Re q uire me nts 
9. 1 0
Visit re q uire me nts ar e 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 ur e-r elate d d etails are pr o vi d e 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. 1 0. 1
P ote ntial partici pa nts will be e val uate d t o d eter 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 ns 6. 1 a n d 6. 2. Scree ni n g pr o ce d ures ma y be re peate d after c o ns ultati o n 
wit h M S D.  
Writte n c o nse nt m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol-s pecific pr oce d ure. 
Res ults of a test perf or m e d pri or t o t he partici p a nt si g ni n g c o nse nt as p art 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 pr ot oc ol-
s pecifie d ti me fr a me. T h e f oll o wi n g s cree ni n g pr oce d ures m ust be p erf or me d, as s pecifie d : 
•  La b orat 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 x ce pti o n is he patitis testi n g, w hic h ma y b e d o ne u p t o 4 2 da ys pri or t o t he first d ose 
of st u d y tr eat me nt.  
•  E val uati o n of E C O G a n d K P S is t o be perf or me d wit hi n 1 4 da ys pri or t o t h e first d ose 
of st u d y tr eat me nt  bef ore 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 n c 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 n c 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 ( p erf or m e d b y t h e 
l ocal st u d y site la b or at or y). 
•  Arc hi val t u m or sa m ple c ollecti o n is n ot re q uire d t o be o btai ne d wit hi n 2 8 da ys pri or 
t o t he first d ose of st u d y treat me nt, b ut m ust be s u b mitte d pri or t o ra n d o mizati o n. 
Ne wl y o btai ne d t u m or tiss ue m ust be o btai ne d a n d s u b mitte d pri or t o ra n d o mizati o n. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 Tre at me nt Peri o d Visi t 
9. 1 0. 2
Treat me nt visit re q uire m e nts are o utli ne d i n t he S o A ( Secti o n 2).  
Treat me nt wit h pe m br oli z u ma b will occ ur e ver y 2 1 da ys ( Da ys 1 a n d 2 2 of eac h 6- wee k 
c ycle) f or u p t o 3 5 a d mi nistrati o ns (a p pr o xi matel y 2 years).  
E paca d ostat will be d ose d BI D e ver y 1 2 h o urs ( Q 1 2 H) d uri n g t he treat me nt p hase. Treat me nt 
ma y c o nti n ue u ntil t he last da y of t h e last c ycle of pe m br oliz u ma b, u nless a disc o nti n uati o n 
criteri o n is met.  
S u niti ni b a n d Paz o pa ni b will c o nti n ue u ntil pr ot oc ol- s pecifie d criteria f or treat me nt 
disc o nti n uati o n are met. 
 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. 1 0. 3
 S af et y F oll o w- u p Visit  
9. 1 0. 3. 1
N O T E:  As of A me n d me nt 0 6, 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 Saf et y F oll o w - u p Visit s h o ul d be c o n d ucte d a p pr o xi matel y 3 0 da ys after t h e 
last d ose of st u d y tr eat me nt or bef ore t h e i nitiati o n of a ne w a ntica ncer treat me nt, w hic he ver 
c o mes first. If t he p artici pa nt has a disc o nti n uati o n visit ≥3 0 da ys after t he last d ose of st u d y 
treat me nt, t he Saf et y 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 n ce t he y h a 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 d ere d t o ha v e 
c o m plete d t he st u d y; t hes e 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 m e d as per Secti o n 9. 3. 
Partici pa nts w h o e nter Sec o n d C o urse retreat me nt wit h pe m br oliz u ma b pl us e paca d ostat ma y 
ha ve u p t o t w o Safet y F oll o w- u p Visits, o ne after t he I nitial Treat me nt Peri o d a n d o ne aft er 
t he Sec o n d C o urse Tr eat me nt. 
 F oll o w- u p Visits  
9. 1 0. 3. 2
N O T E:  As of A me n d me nt 0 6, 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 dere d t o h a ve c o m plete d t he st u d y o nce 
t he y h a ve atte n de d t he S af et y F oll o w-u p Visit.  Dise ase assess me nt will c o nti n ue as per 
l oc al S o C g ui deli nes; assess me nt a n d rec o r di n g of A Es will be perf or me d as per Secti o n 
9. 3. 
Partici pa nts w h o disc o nti n ue st u d y treat me nt f or a reas o n ot her t h a n P D will ha ve i ma gi n g 
assess me nts  per S o C. E ver y eff ort s h o ul d be ma d e t o c ollect i nf or mati o n re gar di n g diseas e 
stat us u ntil t he start of ne w a nti-ca n cer t h era p y, disease pr o gressi o n, pre g n a nc y, deat h, t he 
e n d of 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. 8.  I nf or mati o n 
re gar di n g p ost-st u d y a nti ca ncer treat me nt will be c ollecte d if ne w treat me nt is i nitiate d.  
Partici pa nts w h o are eli gi ble t o recei v e retreat me nt wit h pe m br oliz u ma b  pl us  e paca d ost at  
(see Secti o n 7. 8) 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 urs e P hase w he n 
t he y e x perie nce disease pr o gressi o n .  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 S ur vi v al F oll o w- u p  
9. 1 0. 3. 3
N O T E:  As of A me n d me nt 0 6, 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 v i v al i nf or m ati o n.  Assess me nt a n d 
rec o r di n g of A Es will c o nti n ue as per Secti o n 9. 3.  
Partici pa nts w h o e x perie nce c o nfir me d diseas e pr o gressi o n or start a n e w a ntica ncer t h era p y, 
will m o ve i nt o t he S ur vi val F oll o w - U p P hase a n d s h o ul d be c o ntacte d b y tele p h o ne 
a p pr o xi matel y e ver y 1 2 wee ks t o assess f or s ur vi val stat us u ntil deat h, wit h dra wal of 
c o nse nt, or t he e n d of t he trial, w hic he ver occ urs first.  
Partici pa nts ma y wit h dra w t heir c o nse nt at a n y ti me fr o m a n y or all p orti o ns of t he st u d y. 
Partici pa nts w h o wit h dra w c o nse nt f or treat me nt a n d/ or i ma gi n g are e n c o ura ge d t o re mai n o n 
t he n o n-i n vasi ve S ur vi val F oll o w- U p p orti o n of t h e st u d y. T h e o nl y pr oce d ures ass ociat e d 
wit h t his p hase are tele p h o ne c o ntacts t o assess s ur vi val stat us a n d t he c urre nt state of t he 
partici pa nt’s m R C C. T he n o n-i n vasi ve nat ure a n d s ocietal be nefit of S ur vi val F oll o w- U p 
s h o ul d be e x plai ne d t o t he partici pa nt b y t he site staff, partic ul arl y w he n disc o nti n ui n g 
treat me nt a n d i ma gi n g. 
 S ur vi v al St at us M o nit ori n g  
9. 1 0. 3. 3. 1
N O T E:  As of A me n d me nt 0 6, t his secti o n is n o l o n ger a p plic a ble; s ur vi v al d at a is n o 
l o n ger bei n g c ollecte d. 
T o e ns ure c urre nt a n d c o m plete s ur vi val data is a v aila ble at t he ti me of dat a base l oc ks, 
u p date d s ur vi val stat us ma y b e re q u este d d uri n g t h e c o urse of t he st u d y b y M S D .  F or 
e x a m ple, u p date d s ur vi val stat us ma y b e re q u este d pri or t o b ut n ot li mite d t o a n e xter nal Data 
M o nit ori n g C o m mittee (e D M C) re vie w a n d/ or fi n al a nal ysis.  U p o n M S D  n otificati o n, all 
partici pa nts w h o d o n ot/ will n ot ha ve a sc he d ule d st u d y visit or st u d y c o nt act d uri n g t he 
M S D  defi ne d ti me peri o d will be c o ntacte d f or t h eir s ur vi val stat us (e x cl u di n g partici p a nts 
w h o  ha ve a pre vi o usl y rec or de d deat h e ve nt i n t he c ollecti o n t o ol). 
 U nsc he d ule d Visits  
9. 1 0. 3. 4
U nsc he d ule d visits ma y be hel d at a n y ti me at t he i n vesti gat or’s discreti o n , a n d a p pr o pri ate 
cli nical a n d la b or at or y meas ure m e nts ma y b e perf or me d base d o n A Es or ot her fi n di n gs. 
U nsc he d ule d visits will be rec or de d i n t he e C R Fs. 
 Sec o n d C o urse P h ase  
9. 1 0. 4
Partici pa nts w h o c o nse nt t o e nter t he Sec o n d C o urse P hase will be ret reate d at t he sa me 
c o m bi nati o n, d ose le vel, a n d fre q u e nc y as w he n t h e y l ast 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.  C he m ot hera p y will n ot be d ose d i n Sec o n d C o urse P hase. 
Pe m br oliz u ma b will be d ose d e ver y 2 1 d a ys ( D a ys 1 a n d 2 2 of eac h 6- w ee k  c ycle) f or u p t o 
1 7 a d mi nistrati o ns of pe m br oliz u ma b  (a p pr o xi matel y 1 year).  E p aca d ostat will be d ose d 
BI D  ( Q 1 2H) d uri n g t h e Sec o n d C o urse P hase.  Treat me nt ma y c o nti n ue u ntil a 
disc o nti n uati o n criteri o n is met.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 St atistic al A n al ysis Pl a n  
1 0.
T his sec ti o n o utli nes t he statistical a nal ysis strate g y a n d pr oce d ures f or t he st u d y. If, after t he 
st u d y has be g u n, c ha n ges are ma d e t o pri mar y a n d/ or ke y s ec o n d ar y h y p ot h eses, or t he 
statistical met h o ds relate d t o t h ose h y p ot heses, t h e n t he pr ot oc ol will be a me nde d (c o nsiste nt 
wit h I nter nati o nal C o nfer e nce o n H ar m o nisati o n G ui deli ne E 9). 
 
 
 
 
 
 
 St atistic al A n al ysis Pl a n S u m m a r y  
1 0. 1
Ke y ele me nts of t h e statistical a nal ysis pla n are s u m marize d bel o w; t he c o m pre he nsi ve pla n 
is pr o vi de d i n Secti o n 1 0. 2 t hr o u g h Secti o n 1 0. 1 2. 
St u d y  Desi g n  O ver vie w  
T his is a ra n d o mize d , o pe n -la bel, m ultice nter P hase III st u d y t o e val uate t he 
efficac y a n d safet y of pe m br oliz u ma b + e paca d ostat  c o m pare d t o  S o C  (s u niti ni b 
or paz o pa ni b m o n ot hera p y ) i n partici pa nt s wit h c o nfir me d u nresecta ble, 
a d va nce d or metastatic R C C wit h a clear -cell c o m p o ne nt w h o  ha ve n ot recei ve d 
pri or s y ste mic t hera p y f or a d va nce d or metastatic R C C .  
Tr e at m e nt Assi g n me nt  
A p pr o xi matel y 1 3 0 partici pa nts will  be ra n d o mize d 1: 1 i nt o t he f oll o wi n g t w o 
treat me nt ar ms: pe m br oliz u ma b 2 0 0 m g I V Q 3 W  + e paca d ostat  1 0 0 m g P O BI D 
or S o C  (s u niti ni b 5 0 m g P O Q D  or paz o pa ni b 8 0 0 m g P O Q D ). 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 nte nti on-t o- Trea t 
Safet y:   All  P artici pa nts  as Treate d  
Pri m ar y E n d p oi nts  
O bj ecti ve Res p o nse Rate ( O R R ) per R E CI S T 1. 1 , as assesse d b y i n vesti gat or 
Ke y Se c o n d a r y E n d p oi nts  
N ot A p plica ble ( N/ A)  
St atistic al  
M et h o ds  
f or 
Ke y  Effic ac y  A n al yses  
O R R will be esti mate d wit hi n eac h treat me nt ar m wit h 9 5 % c o nfi de nce i nter vals 
( CI) usi n g Cl o p per -P ears o n  e xact met h o d  base d  o n  bi n o mial  distri b uti o n  
[ Cl o p per, C. J. a n d P ears o n, E. S. 1 9 3 4]. 
St atistic al  
M et h o ds  
f or 
Ke y  S afet y  A n al yses  
C o u nts a n d perce nta ges of partici pa nts wit h A Es will be pr o vi de d b y treat me nt 
gr o u p.  
I nteri m a n d Fi n al A n al yses  
T h er e is n o  i nt eri m a n al ysis f or effi c a c y.  Fi nal  anal ysis  will be perf or me d 
after all ra n d o mize d partici pa nt s ha d a n o p p ort u nit y t o ha ve o ne p ost-baseli ne 
i ma gi n g sca n.  D uri n g t he c o urse of t he st u d y, D M C s af et y r e vi e w will b e 
c o n d u ct e d p er D M C c h art er.  
M ulti plicit y  
Si nce t his is a n esti mati o n st u d y, t here will be n o m ulti plicit y a dj ust me nt . 
S a m pl e Si z e a n d P o w er  
T he sa m ple size is a p pr o xi mat el y 1 3 0. Wit h a p pr o xi matel y 6 5 partici pa nt s per 
treat me nt ar m, t he 9 5 % CI s f or O R R esti mate are e x pecte d t o be (1 9. 9 % , 
4 3. 4 %) or (2 8. 0 % , 5 2. 9 %) w he n t he O R R rate is a p pr o xi mat el y 3 1 % or 4 0 %, 
res pecti vel y.   
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 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 ysis of t he data o btai ne d fr o m t his st u d y will be t he res p o nsi bilit y of t he 
Cli nical Bi ostatistics de part me nt of t he S p o ns or or desi g nee.  
T he I V R S ve n d or/ S p o ns or will ge n erat e t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y 
treat me nt assi g n me nt f or t his pr ot oc ol, a n d t he ra n d o mizati o n will be i m ple me nte d i n I V R S. 
Alt h o u g h t he st u d y is o pe n la bel, a n al ys es or s u m maries ge nerate d b y ra n d o mize d treat me nt 
assi g n me nt  or act ual tr eat me nt r ecei ve d will be li mite d a n d d oc u me nte d. F urt her 
d oc u me ntati o n will be pr o vi de d i n t he s S A P.  
 H y p ot heses/ Esti m ati o n 
1 0. 3
O bjecti ves a n d h y p ot hes es of t he st u d y are state d i n Secti o n 4 – O bjecti ves/ H y p ot hes es 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 nts 
1 0. 4. 1
 Pri m ar y  
1 0. 4. 1. 1
 O bjecti ve  R es p o nse  R ate ( O R R)   – R E CI S T 1. 1  b y  I n vesti g at or 
1 0. 4. 1. 1. 1
O R R is defi ne d as t he pr o p orti o n of t he partici pa nts i n t he a nal ysis p o p ulati o n w h o ha ve best 
res p o nse of C R or P R. 
 S af et y E n d p oi nts  
1 0. 4. 2
Safet y e n d p oi nts are d escri be d i n Secti o n 5. 4. 1. 2 
 A n al ysis P o p ul ati o ns 
1 0. 5
 Effic ac y A n al ysis P o p ul ati o n 
1 0. 5. 1
T he I nte nti o n -t o- Tr eat (I T T) p o p ulati o n will ser ve as t he p o p ulati o n f or t h e pri mar y efficac y 
a nal ys es. All ra n d o mize d partici pa nt s will be i ncl u de d i n t his p o p ulati o n. Partici pa nt s will be 
a nal yze d i n t he tr eat me nt gr o u p t o w hi c h t he y are ra n d o mize d.  Details o n t he a p pr oac h t o 
ha n dli n g missi n g d ata ar e pr o vi de d i n Secti o n 1 0. 6. 1 – Statistical Met h o ds f or Efficac y 
A nal ys es.  
 S af et y A n al ysis P o p ul ati o n 
1 0. 5. 2
T he All Partici pa nts  as Treate d ( A Pa T) p o p ulati o n will be use d f or t he a n al ysis of safet y data 
i n t his st u dy.  T he A Pa T p o p ulati o n c o nsists of all ra n d o mize d partici pa nt s w h o recei ve d at 
least 1 d ose of st u d y treat me nt. Partici pa nt s 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 d y treat me nt t he y act uall y recei v e d f or t he a nal ysis of safet y dat a 
usi n g t he A Pa T p o p ulati o n.  F or m ost partici pa nt s, 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 nt s 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 h e st u d y treat me nt act uall y 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
recei v e d.  A n y partici pa nt  w h o recei v es t he i nc orrect st u d y treat me nt  f or o ne c ycle b ut 
recei v es t he c orrect treat me nt f or all ot her c ycles will be a nal yze d acc or di n g t o t he c orrect 
treat me nt gr o u p a n d a narrati ve will be pr o vi de d f or a n y e ve nts t hat o cc ur d uri n g t he c ycle 
f or w hic h t he p artici pa nt  is i nc orrectl y d ose d. 
At least o ne  la b or at or y or vital si g n meas ure me nt obtai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter.  T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.  
 St atistic al Met h o ds  
1 0. 6
 St atistic al Met h o ds f or Effic ac y A n al yses 
1 0. 6. 1
T his secti o n descri bes t h e statistical met h o ds t hat a d dress t he pri mar y o bjecti ve  o n O R R.  
 O bjecti ve R es p o nse R at e ( O R R)  – R E CI S T 1. 1 b y I n vesti g at or 
1 0. 6. 1. 1
F or O R R, t he p oi nt esti mate a n d 9 5 % CI will be pr o vi de d usi n g t he e x act bi n o mial met h o d 
pr o p ose d b y Cl o p per a n d Pears o n ( 1 9 3 4). Partici pa nt s i n t he a nal ysis p o p ulati o n wit h o ut 
res p o nse data will be c o u nte d as n o n-res p o n d ers.  
 St atistic al Met h o ds f or S afet y A n al yses 
1 0. 6. 2
Safet y a n d t oler a bilit y will be assesse d b y cli nical re vie w of all rele v a nt para meters i ncl u di n g 
a d verse e x perie nces ( A Es), la b orat or y tests, vital si g ns, a n d E C G meas ure me nts.  
I n di vi d ual e v e 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 relat e 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 d e 3 -5 A E, a dr u g r elate d Gr a 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 4 ).   
Ta ble 1 4 
A nal ysis Strate g y f or Safet y Para meters  
S afet y E n d p oi nt  
Descri pti ve St atistics  
A n y A E   
X  
A n y Seri o us A E  
X  
A n y Gra de 3 -5 A E   
X  
A n y Dr u g -Relate d A E  
X  
A n y Seri o us a n d Dr u g -Relate d A E  
A n y Gra de 3 -5 a n d Dr u g -Relate d A E  
X  
X  
D ose I nterr u pti o n d ue t o A E  
X  
Disc o nti n uati o n d ue t o  A E  
X  
Deat h  
X  
S pecific A Es, S O Cs  
X  
C ha n ge fr o m B aseli ne Res ults ( La b orat or y 
t o xicit y gra de a n d  E C Gs)  
X  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 0 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristi cs  
1 0. 6. 3
T he c o m para bilit y of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d  b y 
t he use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n t hese 
c haracteristics. T he n u m ber a n d perce nta ge of partici pa nts scree ne d a n d ra n d o mize d, a n d t he 
pri mar y reas o ns f or scree ni n g fail ure a n d disc o nti n uati o n will be di s pla ye d. De m o gra p hic 
varia bles (e g, a ge), baseli ne c haracteristics, pri mar y a n d sec o n dar y dia g n oses, a n d pri or a n d 
c o nc o mita nt t hera pies will be s u m marize d b y treat me nt eit her b y descri pti ve statistics or 
cate g orical ta bles. 
 I nteri m A n al yses 
1 0. 7
N O T E:  As of A me n d me nt 0 6, t here will be n o i nteri m effic ac y a n al ysis. T he e D M C will 
c o n d uct s af et 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 6, 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.  
 S a m ple Size a n d P o w er 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 S o C ar ms. T he pri mar y o bjecti ve is t o esti mate O R R f or eac h treat me nt ar m. T he o verall 
sa m ple size of a p pr o xi matel y 1 3 0 is bas e d o n t he pr ojecte d n u m ber of ra n d o mize d 
partici pa nts w he n a strate gic d ecisi o n was ma d e 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 6 5 partici pa nts per treat me nt ar m, t he 9 5 % CI s f or O R R esti ma te are e x pecte d t o be 
( 1 9. 4 %, 4 3. 4 %) or ( 2 8. 0 %, 5 2. 9%) w h e n t he O R R rate is a p pr o xi ma tel y 3 1% or 4 0 %, 
res pecti vel y.  T h e CIs f or differe nt o bs er ve d res p o nse rates are liste d bel o w f or 9 5 % 
c o nfi de nce le vel i n  Ta ble 1 5 .  
Ta ble 1 5  9 5 % CIs f or Diff er e nt O bser ve d Res p o nse Rat es 
Sa m ple Size  
N u m ber of 
Partici pa nts  
wit h a Res p o nse 
O bser ve d  
Res p o nse Rate  
9 5 % CIs 
6 5 
2 0 
~ 3 1 % 
( 1 9. 9 %, 4 3. 4%)  
2 3 
~ 3 5 % 
( 2 3. 9 %, 4 8. 2%)  
2 6 
4 0 % 
( 2 8. 0%,  5 2. 9%)  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 S u b gr o u p A n al yses  
1 0. 1 0
N ote: As  of A me n d me nt 0 6 , 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 dat a f or trial treat me nt will  be c ollecte d d uri n g t he st u d y.  A n y 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 APa T p o p ulati o n. 
 Ref ere nces  
1 1.
[ B o o n, T. 1 9 9 6] 
B o o n T, va n d er Br u g ge n P. H u ma n t u m or a nti ge ns 
rec o g nize d b y T l y m p h o c yt es. J E x p Me d. 1 9 96 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 y n dr o me. N 
E n gl J Me d. 2 0 0 5 Mar 1 7; 3 5 2( 1 1): 1 1 1 2- 2 0. 
0 4 DJ P V  
[ Bra n dac h er, G., et al 
2 0 0 6] 
Bra n d ac h er G, Perat h o ner A, La d ur n er R, 
Sc h nee ber ger S, O brist P, Wi n kler C, et al. Pr o g n ostic 
val ue of i n d olea mi ne 2, 3- di o x y ge nase e x pressi o n i n 
c ol orectal ca ncer: effect o n t u m or -i nfiltrati n g T cells. 
Cli n Ca ncer Res. 2 0 0 6 Fe b 1 5; 1 2( 4): 1 1 4 4- 5 1. 
0 4 9 M F B  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ 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 h e 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  
[ Disis, M. L. 2 0 1 0] 
Disis M L. I m m u ne re g ulati o n of ca ncer. J Cli n O nc ol 
2 0 1 0; 2 8( 2 9): 4 5 3 1- 8. 
0 0 V M NJ  
[ Erc oli ni, A. M., et al 
2 0 0 5] 
Erc oli ni A M, La dle B H, Ma n ni n g E A, Pfa n ne nsti el 
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 Ma y 
1 6; 2 0 1( 1 0): 1 5 9 1- 6 0 2. 
0 4 9 M F L  
[ Fallari n o, F., et al 
2 0 0 6] 
Fallari n o F, Gr o h ma n n U, Y o u S, Mc Grat h B C, 
Ca ve ner D R, V acca C, et al. T he c o m bi ne d effects of 
tr y pt o p ha n star vati o n a n d tr y pt o p ha n cata b olites 
d o w n- re g ulat e T cell rece pt or zeta-c h ai n a n d i n d u ce a 
re g ulat or y p he n ot y p e i n nai ve T cells. J I m m u n ol. 
2 0 0 6 J u n 1; 1 7 6( 1 1): 6 7 5 2- 6 1. 
0 4 9 P T L  
[ 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 v e d cat a b olites 
are r es 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 n ase. 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 p e, 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  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ Ga n ga d h ar, 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 safet y of 
e paca d ostat pl us pe m br oliz u ma b treat me nt of N S C L C: 
preli mi nar y p hase 1/ 2 res ults of E C H O-
2 0 2/ K E Y N O T E - 0 3 7. P oster sessi o n prese nt e 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 nt e 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 p ecti 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  
[ Gree n wal d, R. J., et al 
2 0 0 5] 
Gree n wal d RJ, Free ma n GJ, S har pe A H. T he B 7 
fa mil y r e visite d. A n n u Re v I m m u n ol 2 0 0 5; 2 3: 5 1 5- 4 8. 
0 0 V M Q L  
[ 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 n ce 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 nt e 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  
[ Ha mi d, O., et al 2 0 1 7] 
Ha mi d O, B a uer T M, S pira AI, Olsza ns ki AJ, Patel 
S P, Wasser J S, et al. E paca d ostat Pl us Pe m br oliz u ma b 
i n patie nts wit h S C C H N: Preli mi nar y P hase 1/ 2 
Res ults fr o m E C H O -2 0 2/ K E Y N O T E - 0 3 7 [a bstract]. 
A bstracts of t he 2 0 1 7 A S C O A n n ual Meeti n g; 2 0 1 7 
J u n 2-6; C hica g o, I L: A S C O; 2 0 1 7. p. 1- 1 9. 
0 4 P Q C 6  
[ He n g, D. Y., et al 
2 0 0 9] 
He n g D Y, Xie W, Re ga n M M, Warre n M A, 
G ols ha ya n A R, Sa hi C, et al. Pr o g n ostic fact ors f or 
o verall s ur vi val i n patie nts wit h metastatic re nal cell 
carci n o ma treate d wit h vasc ular e n d ot helial gr o wt h 
fact or-t ar get e d a ge nts: res ults fr o m a lar ge, 
m ultice nter st u d y. J Cli n O nc ol. 2 0 0 9 Dec 
1; 2 7( 3 4): 5 7 9 4- 9. 
0 4 C 3 0 X  
[ H o di, F. S., et al 2 0 1 4] H o di F S, Ri bas A, Da u d A, Ha mi d O, R o bert C, 
keff or d R, et al. E val uati o n of i m m u ne- relate d 
res p o nse criteria (ir R C) i n patie nts ( pts) wit h a d va nce d 
mela n o ma ( M E L) treate d wit h t he a nti -P D - 1 
m o n ocl o nal a nti b o d y M K- 3 4 7 5 [a bstract]. A bstracts 
of t he 2 0 1 4 A S C O A n n u al Meeti n g; 2 0 1 4 M a y 2 9 - 
J u n 2; C hica g o, I L: A S C O; 2 0 1 4. p. 2. 
0 4 6 5 P H  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ 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 n ase 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  
[I n o, K., et al 2 0 0 6] 
I n o K, Y os hi da N, K aji ya ma H, S hi bata K, Y a 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 nas e is 
a n o vel pr o g n ostic i n dicat or f or e n d o metri al ca n cer. 
Br J Ca ncer. 2 0 0 6 D ec 4; 9 5( 1 1): 1 5 5 5- 6 1. 
0 4 9 NJ 5  
[ K o, J. J., et al 2 0 1 5] 
K o JJ, Xie W, Kr oe ger N, Lee J L, Ri ni BI, K n o x JJ, et 
al. T he i nter nati o nal met astatic re n al cell carci n o ma 
data base c o ns orti u m m o del as a pr o g n ostic t o ol i n 
patie nts wit h metastatic re nal cell carci n o ma 
pre v i o usl y treate d wit h first-li ne tar gete d t h era p y: a 
p o p ulati o n- base d st u d y. La n cet O n c ol. 2 0 1 5 
Mar; 1 6( 3): 2 9 3- 3 0 0. 
0 4 N G B K  
[ Lara, P. N. Jr., et al 
2 0 1 7] 
Lara P N Jr, Ba u er T M, H a mi d O, S mit h D C, Gaje ws ki 
T F, Ga n ga d har T C, 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 R C C: 
preli mi nar y p hase 1/ 2 res ults 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 nt e 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 L  
[ Li u, X., et al 2 0 1 0] 
Li u X, S hi n N, K o blis h H K, Ya n g G, Wa n g Q, Wa n g 
K, et al. Selecti ve i n hi biti o n of I D O 1 effecti vel y 
re g ulates me diat ors of a ntit u m or i m m u nit y. Bl o o d. 
2 0 1 0 A pr 2 9; 1 1 5( 1 7): 3 5 2 0- 3 0. 
0 4 Q M 3 8  
[ Mal o uf, G. G., et al 
2 0 1 6] 
Mal o uf G G, Fli p p ot R, K ha yat D. T hera pe utic 
strate gies f or p atie nts wit h metastatic re nal cell 
carci n o ma i n w h o m first- li ne vasc ular e n d ot helial 
gr o wt h fact or rece pt or -directe d t hera pies fail. J O nc ol 
Pract. 2 0 1 6 Ma y; 1 2( 5): 4 1 2- 2 0. 
0 4 N G 8 C  
[ Mc Der m ott, D. F., et 
al 2 0 1 6] 
Mc Der m ott D F, S os ma n J A, Sz n ol M, M assar d C, 
G or d o n M S, Ha mi d O, et al. Atez oliz u ma b, a n A nti-
Pr o gr a m me d Deat h - Li ga n d 1 A nti b o d y, i n Metast atic 
Re nal Cell Carci n o ma: L o n g -T er m Safet y, Cli nical 
Acti vit y, a n d I m m u ne C orrelates Fr o m a P has e Ia 
St u d y. J Cli n O nc ol. 2 0 1 6 Mar 1 0; 3 4( 8): 8 3 3- 4 2. 
0 4 Q M C B  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ Mell or, A. L. 2 0 0 4] 
Mell or A L, M u n n D H. I D O e x pressi o n b y d e n dritic 
cells: t olera nce a n d tr y pt o p ha n cata b olis m. Nat R e v 
I m m u n ol. 2 0 0 4 Oct; 4( 1 0): 7 6 2- 7 4. 
0 4 9 NJ 7  
[ Mell or, A. L., et al 
2 0 0 3] 
Mell or A L, Ba ba n B, C ha n dler P, Mars hall B, J ha ver 
K, Ha nse n A, et al. C utti n g e d ge: i n d uce d i n d olea mi ne 
2, 3 di o x y ge n ase e x pressi o n i n de n dritic cell s u bsets 
s u p presses T cell cl o nal e x pa nsi o n. J I m m u n ol. 2 0 0 3 
A u g 1 5; 1 7 1( 4): 1 6 5 2- 5. 
0 4 9 NJ B  
[ M otzer, R. J., et al 
2 0 1 3] 
M otzer RJ, H uts o n T E, Cella D, Ree ves J, Ha w k i ns R, 
G u o J, et al. Paz o pa ni b vers us s u niti ni b i n metastatic 
re nal- cell carci n o ma. N E n gl J Me d. 2 0 1 3 A u g 
2 2; 3 6 9( 8): 7 2 2- 3 1. 
0 4 C 2 Y 6  
[ M otzer, R. J., et al 
2 0 1 5] 
M otzer RJ, Esc u dier B, Mc Der m ott D F, Ge or ge S, 
Ha m mers HJ, Sri ni vas S, et al. Ni v ol u ma b vers us 
E ver oli m us i n A d va nce d Re nal- Cell Carci n o ma. N 
E n gl J Me d. 2 0 1 5 N o v 5; 3 7 3( 1 9): 1 8 0 3- 1 3. 
0 4 C 3 0 Y  
[ M uller, A. J., et al 
2 0 0 5] 
M uller AJ, D u Ha da wa y J B, D o n o ver P S, S uta nt o -
War d E, Pre n der gast G C. I n hi biti o n of i n d olea mi n e 
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 v est. 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 y pt 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 h i ma T, Sae ki A, Hi da k a T, Na k as 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 n ase 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 n cer. Ca ncer Sci. 2 0 0 7 
J u n; 9 8( 6): 8 7 4- 8 1. 
0 4 9 P W N  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ 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 k a 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 n ase ser ves 
as a mar k er 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 v aria n ca ncer cells. Cli n Ca ncer 
Res. 2 0 0 5 A u g 1 5; 1 1( 1 6): 6 0 3 0- 9. 
0 4 9 P T K  
[ O kaza ki, T., et al 
2 0 0 1] 
O kaza ki T, Mae da A, Nis hi m ura H, K ur osa ki T, 
H o nj o T. P D- 1 i m m u n orece pt or i n hi bits B cell 
rece pt or-me diate d si g n ali n g b y recr uiti n g src 
h o m ol o g y 2- d o mai n-c o ntai ni n g t yr osi ne p h os p hat ase 
2 t o p h os p h ot yr osi ne. Pr oc Natl Aca d Sci U S A 
2 0 0 1; 9 8( 2 4): 1 3 8 6 6- 7 1. 
0 0 V M Q 6  
[ Se y m o ur, L., et al 
2 0 1 7] 
Se y m o ur L, B o gaerts J, Perr o ne A, F or d R, Sc h wartz 
L H, M a n dre k ar S, et al. i R E CI S 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 n cet 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 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 h elial 
carci n o ma: preli mi nar y p hase 1/ 2 res ults of E C H O-
2 0 2/ K E Y N O T E - 0 3 7. P oster sessi o n prese nt e 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  
[ U ytte n h o ve, C., et al 
2 0 0 3] 
U ytte n h o v e C, Pil otte L, T heate I, Str o o ba nt V, C ola u 
D, Par me ntier N, et al. E vi de nce f or a t u m oral 
i m m u ne resista nce mec h a nis m base d o n tr y pt o p ha n 
de gra dati o n b y i n d olea mi ne 2, 3- di o x y ge nas e. Nat 
Me d. 2 0 0 3 Oct; 9( 1 0): 1 2 6 9- 7 4. 
0 4 9 P V 2  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
[ 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 u c h s 
D. Decreas e d ser u m tr y pt o p ha n c o nce ntrati o n pre dicts 
p o or pr o g n osis i n mali g n a 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, Y e o CJ, et al. E x pressi o n of 
i n d olea mi ne 2, 3-di o x y ge nase i n metastatic pa n creatic 
d uctal a de n o carci 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 b é C, et al. G ui deli nes f or t he e v al uati o n of 
i m m u ne t hera p y acti vit y i n s oli d t u m ors: i m m u ne-
relate d res p o nse criteria. Cli n Ca ncer Res 
2 0 0 9; 1 5( 2 3): 7 4 1 2- 2 0. 
0 0 V M N Z  
[ 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. N at Re v I m m u n ol. 2 0 0 6 
A pr; 6( 4): 2 9 5- 3 0 7. 
0 4 9 P V 7  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
 A p pe n dices  
1 2.
A p pe n di x 1:  St u d y G o ver n a nce C o nsi der ati o ns 
Merc k C o de of C o n d uct f or Cli nic al Tri als  
M erc k *  
C o de of C o n d uct f or Cli nic al T ri 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 u cts cli nical trials w orl d wi d e t o e val u ate t h e safet y a n d effecti ve n ess of o ur 
pr o d u cts. As s u c h, we are c o m mitte d t o d esi g ni n g, i m ple me nti n g, c o n d u cti n g, a n al yzi n g a n d re p orti n g t h ese trials i n 
c o m plia n ce wit h t h e hi g h est et hical a n d scie ntific sta n d ar ds. Pr otecti o n of p artici p a nt safet y is t h e o verri di n g c o ncer n 
i n t h e d esi g n of cli nical trials. I n all cases, Merc k cli nical trials will b e c o n d u cte d i n c o m plia n ce wit h l o cal a n d/ or 
nati o n al re g ulati o ns a n d i n acc or da n ce wit h t h e et hical pri n ci ples t hat h a ve t h eir ori gi n i n t h e Declarati o n of Helsi n ki.  
B. Sc o pe  
S uc h sta n d ar ds s h all b e e n d orse d f or all cli nical i nter ve nti o n al i n vesti gati o ns s p o ns ore d b y Merc k irres p ecti ve of t he 
part y ( p arties) e m pl o ye d f or t h eir 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 d e d t o a p pl y t o trials w hic h are o bser vati o n al i n n at ure, or w hic h are retr os p ecti ve. F urt h er, 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 d er 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 o c ols will b e h y p ot h esis -dri ve n t o assess safet y, effic ac y 
a n d/ or p h ar ma c o ki n etic or p h ar mac o d y n a mic i n dices o f Merc k or c o m p arat or pr o d u cts.  Alter n ati vel y, Merc k ma y 
c o n d u ct o utc o mes resear c h trials, trials t o assess or vali d ate vari o us e n d p oi nt meas ures, or trials t o d eter mi ne 
p artici p a nt prefere n ces, etc.   
T h e d esi g n (ie, p artici p a nt p o p ulati o n, d urati o n, sta tistical p o wer) m ust b e a d e q u ate t o a d dress t h e s p ecific p ur p ose 
of t h e trial.  Researc h p artici p a nts m ust meet pr ot o c ol e ntr y criteria t o b e e nr olle d i n t h e trial.  
2.  Site Selecti o n  
Merc k selects i n vesti gati ve sites b ase d o n me dical e x p ertise, ac cess t o a p pr o priate p artici p a nts, a d e q u ac y of 
fa cilities a n d staff, pre vi o us p erf or ma n ce i n Merc k trials, as well as b u d getar y c o nsi d erati o ns.  Pri or t o trial 
i nitiati o n, sites are e val u ate d b y Merc k p ers o n n el t o assess t h e a bilit y t o s u ccessf ull y c o n d u ct t h e trial. 
3.  Site M o nit ori n g/ Scie ntific I nte g rit y  
Trial sites are m o nit ore d t o assess c o m plia n ce wit h t h e trial pr ot o c ol a n d ge n eral pri n ci ples of G o o d Cli nical 
Practice.  Merc k re vie ws cli nical d ata f or acc urac y, c o m plete n ess a n d c o nsiste n c y. Data are v erifi e d vers us s o urce 
d o c u me ntati o n acc or di n g t o sta n dar d o p erati n g pr o ce d ures.  P er Merc k p olicies a n d pr o ce d ures, if fra u d, 
mis c o n d u ct or seri o us G C P -n o n -C o m plia n ce is s us p ecte d, t h e iss ues are pr o m ptl y i n vesti gate d. W h e n n ecessar y, 
t h e cli nical site will b e cl ose d, t h e 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 
d ata 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 h e e xte nt scie ntificall y a p pr o priate, Merc k see ks t o p u blis h t h e res ults of trials it c o n d u cts.  S o me earl y p h ase or 
pil ot trials are i nte n d e d t o b e h y p ot h esis -ge n erati n g rat h er t h a n h y p ot h esis testi n g.  I n s u c h cases, p u blicati o n of 
res ults ma y n ot b e a p pr o priate si nce t h e trial ma y b e u n d er p o were d a n d t h e a n al yses c o m plicate d b y statistical iss ues 
of m ulti plicit y.  
Merc k’s p olic y o n a ut h ors hi p is c o nsiste nt wit h t h e re q uire me nts o utli n e d i n t h e I C H -G o o d Cli nical Practice 
g ui d eli n es. I n s u m mar y, a ut h ors hi p s h o ul d reflect si g nific a nt c o ntri b uti o n t o t h e d esi g n a n d c o n d u ct of t h e trial, 
perf or ma n ce or i nter pretati o n of t h e a n al ysis, a n d/ or writi n g of t h e ma n uscri pt.  All n a me d a ut h ors m ust b e a ble t o 
defe n d t h e trial res ults a n d c o n cl usi o ns.  Merc k f u n di n g of a trial will b e ac k n o wle d ge d i n p u blicati o ns.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 b e re vie we d a n d a p pr o ve d b y a n i n d e p e n d e nt I R B/I E C b ef ore b ei n g i nitiate d at eac h site.  
Si g nifica nt c h a n ges or re visi o ns t o t h e pr ot o c ol will b e a p pr o ve d b y t h e I R B/I E C pri or t o i m ple me nt ati o n, e xce pt t hat 
c ha n ges re q uire d ur ge ntl y t o pr otect p artici p a nt safet y a n d well -b ei n g ma y b e e n acte d i n a ntici p ati o n of I R B/I E C 
a p pr o val. F or eac h site, t h e I R B/I E C a n d Merc k will a p pr o ve t h e partici p a 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 n ci ple i n d ecisi o n -ma ki n g i n cli nical trials is t h at p artici p a nt welfar e is of pri mar y i m p orta n ce.  
P ote ntial p artici p a nts will b e i nf or me d of t h e ris ks a n d b e n efits of, as well as alter n ati ves t o, trial p artici p ati o n. At a 
mi ni m u m, trial d esi g ns will ta ke i nt o acc o u nt t h e l o cal sta n d ar d of care.  P artici p a nts are n e ver d e nie d access t o 
a p pr o priate me dical care b ase d o n p artici p ati o n i n a Merc k cli nical trial.  
All partici p ati o n i n Merc k cli nical trials is v ol u ntar y.  P artici p a 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 p artici p ati o n.  P artici p a 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 u e n ce o n t h eir access t o, 
or recei pt of, me dical care t h at ma y ot h er wise b e a v aila ble t o t h e m.  
C.  C o nfi de nti alit y  
Merc k is c o m mitte d t o safe g u ar di n g p artici p a nt c o nfi d e ntialit y, t o t h e greatest e xte n t p ossi ble.  U nless re q uire d b y 
la w, o nl y t h e 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 h a ve access t o c o nfi d e ntial 
me dical rec or ds t h at mi g ht i d e ntif y t h e rese arc h p artici p a nt b y n a me.   
D.  Ge n o mic R ese arc h  
Ge n o mic Rese a rc h will o nl y b e c o n d u cte d i n acc or d a n ce wit h i nf or me d c o nse nt a n d/ or as s p ecificall 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 de r 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 p e nsate i n vesti g at ors ( or t h e s p o ns ori n g 
i nstit uti o n) i n a fair ma n n er f or t he w or k p erf or me d i n s u p p ort of Merc k trials.  Merc k d o es n ot p a y i n ce nti ves t o 
e nr oll p artici p a nts i n its trials.  H o we v er, w h e n e nr oll me nt is p artic ularl y c h alle n gi n g, a d diti o n al p a y me nts ma y be 
ma d e t o c o m p e nsate f or t h e ti me s p e nt i n e xtra recr uiti n g eff orts.  
Merc k d o es n ot p a y f or p artici p a nt referrals.  H o we v er, Merc k ma y c o m p e nsate referri n g p h ysicia ns f or ti me s pe nt 
o n c h art re vie w t o i d e ntif y p ote ntiall y eli gi ble p artici p a nts.  
B.  Cli nic al Res e a rc h F u n di n g  
I nf or me d c o nse nt f or ms will discl ose t h at t h e trial is s p o ns ore d b y Merc k, a n d t h at t h e i n vesti gat or or s p o ns ori n g 
i nstit uti o n is b ei n g p ai d or pr o vi de d a gra nt f or p erf or mi n g t h e trial.  H o we ver, t h e l o cal I R B/I E C ma y wis h t o alter 
t he w or di n g of t h e discl os ure state me nt t o b e c o nsiste nt wit h fi n a n cial practices at t h at 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 ue sts 
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 ntifi c meeti n gs, i n vesti gat or meeti n gs, etc.) will be 
c o nsiste nt wit h l o cal g ui d eli n es a n d practices i n cl u di n g, i n t h e U. S., t h ose esta blis h e d b y t h e A meric a n Me dical 
Ass o ciati o n ( A M A).  
V. I n vesti g at or C o m mit me nt 
I n vesti gat ors will b e e x p ecte d t o re vie w Merc k’s C o d e of C o n d u ct as a n a p p e n di x t o t h e trial pr ot o c ol, a n d i n si g ni n g 
t he pr ot o c ol, a gree t o s u p p ort t h ese et hical a n d scie ntific sta n d ar ds. 
* I n t his d o c u me nt, " Merc k" refers t o Merc k S h ar p & D o h me C or p. a n d Sc h eri 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 n c.  Merc k is k n o w n as M S D o utsi d e of t h e U nite d States a n d Ca n a d a.  As warra nte d b y 
c o nte xt, Merc k als o i n cl u d es affiliates a n d s u bsi diaries of Merc k & C o., I n c."  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 1 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Fi n a nci al Discl os ure  
Fi na ncial Discl os ur e r e 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 
C o de of Fe d er al Re g ul ati o ns ( C F R), Fi na n cial Dis cl os ure b y Cli nical I n vesti gat ors ( 2 1 C F R 
Part 5 4).  It 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 n cial Discl os ure i nf or mati o n is re q uire d.  It is t he 
i n vesti gat or's/s u bi n vesti gat or’s res p o nsi bilit y t o c o m pl y wit h a n y s uc h re q u est.   
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 d a n ce wit h 2 1 C F R 
Part 5 4, t o pr o vi de his/ her fi na ncial i nterests i n a n d/ or arra n ge me nts wit h t he S p o ns or or 
M S D t o all o w f or t he s u b missi o n of c o m plete a n d acc urate certificati o n a n d discl os ure 
state me nts.  T he i n vesti gat or/s u bi n vesti gat or(s) f urt her a gree t o pr o vi d e 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 n cial 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 p ers o nal data. 
D at a Pr ot ecti 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 n y partici pa nt rec or ds or datasets 
t hat are tr a nsferre d t o M S D  will c o ntai n t he i de ntifier o nl y; p artici 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 p a 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 d ata will be use d by 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 l e 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 x a mi ne d b y Cli nical 
Q ualit y Ass ur a nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y M S D , b y a p pr o priat e 
I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut 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 b y 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 (I R B/I E C) or si milar or e x pert 
c o m mittee; affiliate d i nstit uti o n a n d e m pl o yees, o nl y u n der a n a p pr o priate u n dersta n di n g o f 
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 n erat e 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 x ce pt t o t he e xte nt 
t hat it is i ncl u de d i n a p u blicati o n as pr o vi de d i n t he P u blicati o ns secti o n of t his pr ot oc ol. 
C o nfi de nti alit y of P artici p a nt Rec or ds  
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t h at t he S p o ns or, M S D ( or S p o ns or or M S D 
re pres e ntati ve), I R B/I E C, or re g ulat or y a ut h orit y re prese nt ati ves ma y c o ns ult a n d/ or c o p y 
trial doc u me nts i n or der t o verif y w or ks h eet/cas e re p ort f or m data.  B y si g ni n g t he c o ns e 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 v erif yi n g w or ks heet/case re p ort f or m i nf or mati o n, t he partici pa nt will be i de ntifie d 
b y u ni q ue c o de o 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 . 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 d ata 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 n ce wit h all a p plica ble pri vac y la ws, r ul es 
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 m e 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 m e nts b y 
re q uesti n g a n d mai ntai ni n g r ec 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 mitt ees Str uct ure  
Tri al Steeri n g C o m mitt ee  
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 v esti gat ors partici pati n g i n t he trial  
•  
C o ns ulti n g t hera pe utic-ar ea e x perts a n d cli nical tri alists  
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, 
e val uate r ec o m me n d ati o ns fr o m t he Data M o nit ori n g C o m mittee ( D M C) a n d ma ke 
rec o m me n dati o ns t o t he E x ec uti ve O versi g ht C o m mittee ( E O C).   
S pecific details re gar di n g res p o nsi bilities a n d g o ver na nce of t he Tri al Steeri n g C o m mittee 
will be descri be d i n a s e p arate c hart er.  
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 h e E O C will  recei v e a n d d eci de u p o n a n y rec o m me n dati o ns ma de b y 
t he Data M o nit ori n g C o m mittee ( D M C)  re gar di n g t he trial. 
D at a M o nit ori n g C o m mittee 
T o s u p ple me nt t he r o uti ne trial m o nit ori n g o utli ne d i n t his pr ot oc ol, a n e xter nal Data 
M o nit ori n g C o m mittee ( D M C) will m o nit or t he safet y data fr o m t his trial.  T he v oti n g 
me m bers of t he c o m mittee ar e e xter nal t o t he S p o ns or  a n d M S D.  T he me m bers of t he D M C 
m ust n ot be i n v ol ve d wit h t he trial i n a n y ot h er w a y (e g, t he y ca n n ot be tri al 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 ol es wit h res pect t o t he trial.  
T he D M C will ma ke rec o m me n dati o ns t o t he E O C  re gar di n g ste ps t o e ns ure b ot h partici pa nt 
safet y a n d t he c o nti n ue d et hical i nte grit y of t he tri al. 
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 n ce, 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 ot oc ol tea m ; 
meeti n g f acilitati o n; t he trial g o v er na n ce str u ct ure; a n d re q uire me nts f or a n d pr o per 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
d oc u me ntati o n of D M C r e 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 h at 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.  
P u blic ati o n P olic y  
T he res ults of t his st u d y ma y b e p u blis he d or pres e 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 S p 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 nat e d b y m ut ual a gree me nt.  
If p u blicati o n acti vit y is n ot directe d b y t he S p o ns or or M S D, t he i n vesti gat or a grees t o 
s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or a n d M S D bef ore s u b missi o n.  T his all o ws 
t he S p o ns or a n d M S D t o pr otect pr o priet ar 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 m e nt a n d i n li ne wit h I nt er 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 dici nes A ge nc y ( E M A) cli nical trial Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or 
of t he trial is s olel y r es 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 m e 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 nicaltrialsr e gister.e u or ot her l o cal 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 m e nts. E ntries 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 d ate d trials.  I nf or mati o n p oste d will all o w 
partici pa nts t o i de ntif y p ote ntiall y a p pr o priate trials f or t heir disease c o n diti o ns a n d p urs ue 
partici pati o n b y calli n g a ce ntral c o nt act n u m ber f or f urt her i nf or mati o n o n a p pr o priate tri al 
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 wl e 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 d ate d re gistries are t h at of t he 
S p o ns or a n d a grees n ot t o s u b mit a n y i nf or mati o n a b o ut t his trial or its res ults t o t h ose 
re gistries. 
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt  
B y si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o c o n d uct t he trial i n a n efficie nt a n d 
dili ge nt ma n ner a n d i n c o nf or ma nce wit h t his pr ot oc ol; ge n erall y acce pte d sta n dar ds of G o o d 
Cli nical Practice (e g, I nter nati o nal C o nfere nce o n Har m o nizati o n of Tec h ni cal Re q uire me nts 
f or Re gistrati o n of P har mace uticals f or H u man Use G o o d Cli nical Practi ce: C o ns oli date d 
G ui deli ne a n d ot her ge nerall y acce pte d sta n dar ds of g o o d cli nical practice); a n d all 
a p plica ble f e der al, state a n d l ocal la ws, r ules a n d re g ul ati 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 v er 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 x ec 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 u ct f or Cli nical Trials. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
T he i n vesti gat or a gr ees 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 v er n me nt pr o gra ms f or pr oce d ures i ncl u de d as p art of t he trial 
rei m b urse d t o t he i n vesti gat or b y 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 orit y i ns pecti o n c o n d ucte d 
f or t his trial. 
T he I n vesti gat or a grees t o pr o vi de M S D  wit h rele va nt i nf or mati o n fr o m i ns pecti o n 
o bser vati o ns/fi n di n gs t o all o w M S D  t o assist i n res p o n di n g t o a n y citati o ns res ulti n g fr o m 
re g ulat or y a ut h orit y i ns p ecti 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 ns e 
f or c o ns ultati o n bef or e 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 ud y .  T h e 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 n y pers o n w h o is i n v ol ve d i n c o n d ucti n g t he trial 
is de barre d or if a n y pr ocee di n g f or d e bar me nt is p e 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 u r a nce 
All partici pa nt data r elati 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 dat a). T he i n v esti gat or or 
q ualifie d desi g nee  is r es 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 ni call y si g ni n g t he C R F.  
Detaile d i nf or mati o n r e gar di n g Data M a na ge m e nt pr oce d ures f or t his pr ot o c 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 nt ati o n (s o urce d ata) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e C R F.  
T he i n vesti gat or m ust per mit st u d y -rel ate 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 o c u me nts.  
Trial d oc u me ntati o n will be pr o m ptl y a n d f ull y dis cl ose 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 gr e es t o pr o m ptl y ta ke a n y reas o na ble ste ps t hat are re q u este d b y M S D  or 
a n y re g ulat or y a ut h orities  as a res ult of a n a u dit or i ns pecti o n t o c ure d efici e 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 n ee is res p o nsi ble f or t he data ma n a ge m e nt of t his st u d y , i ncl u di n g q ualit y 
c hec ki n g of t he d ata.  
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 v erificati 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 m e nts; t hat t he safet y a n d ri g hts of partici pa nts are b ei n g pr otecte d; a n d t hat t he 
st u d y is bei n g c o n d uct e d i n acc or d a nce wit h t he c urre ntl y a p pr o v e d pr ot oc ol a n d a n y ot her 
st u d y a gr ee me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Rec or ds a n d d o c u me nts, i ncl u di n g si g n e d I C F, pertai ni n g t o t he c o n d u ct of t his st u d y m ust 
be retai ne d b y t h e i n vesti gat or f or 1 5 years after st u d y c o m pleti o n u nless l o cal 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 d estr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of M S D . N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o M S D .  
S o urce D oc u me nts  
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste nce of t he p artici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he d ata c ollecte d. S o urce d o c 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 m e nts 
m ust be c o nsiste nt wit h t he s o urce d o c u m e nts or t he discre p a ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y n ee d t o re q uest pre vi o us me di cal 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 m e dical, saf et y, re g ulat or y, a d mi nistrati v e, 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  pr e mat urel y t er mi nates a p artic ular trial site, M S D  will pr o m ptl y n otif y 
t hat trial site’s I R B/I E C. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 
Defi niti o ns   
W o m a n of C hil d be ari n g P ot e nti al ( W O C B P)  
A w o ma n is c o nsi der e d f ertile f oll o wi n g m e narc h e a n d u ntil bec o mi n g p ost- me n o pa usal 
u nless per ma ne ntl y steril e (see b el 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 nar c hal  
● 
Pre me n o pa usal f e male wit h o ne of t he f oll o wi n g: 
○  D oc u m e nte d h yster ect o m y 
○ 
D oc u me nte d bilater al sal pi n gect o m y  
○  D oc u me nte d bilater al 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 x a mi nati o n, or me dical hist or y i nter vie w.  
● 
P ost me n o pa usal fe male  
○  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e.  
▪ 
A hi g h f ollicle sti m ulati n g h or m o n e ( F S H) le vel i n t he p ost me n o pa usal ra n ge m a y 
be use d t o c o nfir m a p ost me n o pa usal state i n w o m e n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o n al re place me nt t hera p y ( H R T). H o we v er, i n t he a bse nce 
of 1 2 m o nt hs of a me n orr hea, c o nfir mati o n wit h 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 h e 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 arti ci p a nts  
Male partici pa nts wit h f e 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 n al i nterc o urs e as t heir us ual a n d preferre d lifest yl e 
(a bsti ne nt o n a l o n g ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt. 
● 
Use a male c o n d o m pl us part ner use of a c o ntrace pti ve met h o d wit h a fail ure rat e of < 1 % 
per year as des cri be d  i n Ta ble 1 6  w he n h a vi n g p e nile- va gi nal i nterc o urse wit h a w o ma n 
of c hil d beari n g p ote ntial w h o is n ot c urre ntl y pre g na nt. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
○  N ote: Me n wit h a pre g n a nt or breastfee di n g part n er m ust a gree t o re mai n a bsti ne nt 
fr o m pe nile- va gi n al i nter c o urse or us e a male c o n d o m d uri n g eac h e pis o d e of pe nile 
pe netrati o n . 
Fe m ale P artici p a nts  
Fe male p artici pa nts of c hil d beari n g p ot e ntial are eli gi ble t o partici pate if t h e y  a gree t o use a 
hi g hl y effecti ve m et h o d of c o ntrace pti o n t hat has a l o w user de p e n de n c y c o nsiste ntl y a n d 
c orrectl y as descri be d i n  Ta ble 1 6  d uri n g t he pr ot o c ol- defi ne d  ti me fra me i n Secti o n 6. 1. 
Ta ble 1 6  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 nj ecta ble 
● Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n b, c 
○ 
Oral  
○ 
I nj ecta ble  
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de nc y  
F ail ure r ate of < 1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly.  
● Pr o gest o ge n - o nl y c o ntrace pti ve i m pla nt b, c  
●  I ntra uteri ne h or m o ne- releasi n g s yste m (I U S) b  
● 
I ntra uteri ne de vice (I U D) 
● 
Bilateral t u bal occl usi o n  
● V asect o mize d p art ner  
A vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he 
s ole male se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n 
a d diti o nal hi g hl y effecti ve met h o d of c o ntrace pti o n s h o ul d be u se d.  
● Se x u al a bsti ne nce  
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nt. T he 
relia bilit y of se x ual a bsti ne nce needs 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 m o nal c o ntrace pti o n efficac y is p ote ntiall y decrease d d ue t o i nteracti o n wit h st u d y treat me nt, 
c o n d o ms m ust be use d i n a d diti o n t o t he h or m o nal c o ntrace 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 da ys after t he last d ose of pe m br oliz u ma b  a n d e paca d ostat a n d u p t o 1 8 0 da ys after last d ose 
of c he m ot hera pe utic a ge nts . 
c) If l ocall y re q uire d, i n acc or da nce wit h Cli nical Trial Facilitati o n Gr o u p ( C T F G) g ui deli nes, 
acce pta ble h or m o nal c o ntrace pti ves are li mite d t o t h ose w hic h i n hi bit o v ulati o n.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Pre g n a nc y Testi n g  
W O C B P s h o ul d o nl y b e i ncl u de d after a n e gati ve hi g hl y 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 n c y res ults ca n n ot be c o nfir me d as 
ne gati ve, a ser u m pre g n a nc y t est will be re q uire d.  
F oll o wi n g i nitiati o n of tr eat me nt, p re g n a nc y testi n g will be perf or me d w h e ne ver a n e x pecte d 
me nstr ual c ycle is misse d or w he n pre g na nc y is ot her wise s us pect e d  a n d as re q uire d l ocall y. 
M o nt hl y pre g n a 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.  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 3:  A d verse E ve nts:  Defi niti o ns a n d Pr o ce d ures f or R ec or di n g, E v al u ati n g, 
F oll o w- u p, a n d Re p orti n g  
Defi niti o n  of A E  
A E Defi niti o n  
● 
A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical st u d y p artici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y treat m e nt, w het her or n ot c o nsi dere d 
relate d t o t he st u d y treat me nt. 
● 
N O T E: A n A E ca n t her ef ore be a n y  u nfa v ora ble a n d u ni nte n de d si g n (i n cl u di n g a n 
a b n or mal la b or at or y fi n di n g), s y m pt o m, or diseas e ( ne w or e x acer b ate d) t e m p orall y 
ass ociate d wit h t he use of a st u d y treat me nt.  
● 
N O T E: F or p ur p oses of A E defi niti o n, st u d y treat me nt i ncl u des a n y p har m ace utica l 
pr o d uct, bi ol o gical pr o d u ct, vacci n e, de vice, di a g n ostic a ge nt or pr ot oc ol s p ecifie d 
pr oce d ur e w het h er i n vesti gati o nal (i ncl u di n g acti ve c o m parat or pr o d uct) or mar kete d, 
ma n ufact ur e d b y, lice nse d b y, pr o vi d e d b y or distri b ute d b y t he S p o ns or or M S D  f or 
h u ma n use i n t his st u d y. 
 
E ve nts Meeti n g  t he A E Defi niti o n  
● 
A n y a b n or mal la b or at or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e g, E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, or are c o nsi dere d cli nicall y si g nifica nt i n 
t he me dical a n d sci e ntific j u d g me nt of t h e i n vesti gat or. 
●  E x acer bati o n of a c hr o ni c or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
●  Ne w c o n diti o ns detect e d or dia g n os e d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve b ee n prese nt bef ore t he start of t he st u d y. 
●  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g- dr u g i nteracti o n. 
●  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
treat me nt or a c o nc o mita nt me dicati o n.  
● 
F or all r e p orts of o ver d os e ( w het her acci de ntal or i nte nti o nal) wit h a n ass ociate d 
a d verse e ve nt, t he A E t er m s h o ul d reflect t he cli ni cal s y m pt o ms or a b n or m al test 
res ult.  A n o ver d ose wit h o ut a n y ass ociate d cli nical s y m pt o ms or a b n or m al la b orat or y 
res ults is re p orte d usi n g t he ter mi n ol o g y “acci de nt al or i nte nti o nal o ver d ose wit h o ut 
a d verse eff ect.”  
●  A n y n e w ca ncer (t hat is n ot a c o n diti o n of t he st u d y).  
  
N ote: Pr o gr essi o n of t he ca ncer u n der st u d y is n ot a re p ort a ble e v e nt. Refer t o 
Secti o n 9. 3. 5 f or a d diti o nal details. 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
●  Me dical or s ur gical pr oce d ure ( e g, e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is t he A E. 
●  Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
●  A ntici pate d da y- t o- d a y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d a t t he start of t he st u d y t hat d o n ot w orse n. 
●  S ur ger y pla n ne d pri or t o i nf or me d c o nse nt t o treat a pre-e xisti n g c o n diti o n t hat has 
n ot w orse ne d. 
● 
Refer t o Secti o n 9. 3. 5 f or pr ot oc ol s pecific e x ce pti o ns 
 
Defi niti o n of S A E  
If a n e v e nt is n ot a n A E per defi niti o n a b o ve, t h e n it ca n n ot be a n S A E e v e n if seri o us 
c o n diti o ns are met  
A S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:  
a.  Res ults i n de at h  
b.  Is lif e-t hre ate ni n g 
● 
T he ter m 'life -t hr eate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e v e nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d o es n ot refer t o a n e ve nt, 
w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h, if it were m ore se vere.  
c.  Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xistin g h os pit aliz ati o n  
●  H os pitalizati o n is defi ne d as a n i n patie nt a d missi o n, re gar dl ess of le n gt h of sta y, e ve n 
if t he h os pitalizati o n is a preca uti o nar y meas ure f or c o nti n ue d o bser v ati o n.  ( N ote: 
H os pitalizati o n f or a n electi ve pr oce d ure t o treat a pre -e xisti n g c o n diti o n t hat has n ot 
w orse ne d is n ot a seri o us a d verse e ve nt.  A pre- e xisti n g c o n diti o n is a cli nical c o n diti o n 
t hat is dia g n ose d pri or t o t he use of a M erc k pr o d u ct a n d is d oc u me nte d i n t he patie nt’s 
me dical hist or y.  
d.  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y  
●  T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns. 
●  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie n ces of relati vel y mi n or me dical 
si g nifica n ce s uc h as unc o m plicate d hea dac he, n a usea, v o miti n g, diarr hea, i nfl ue nza, a n d 
acci de nt al tra u ma ( e g, s prai ne d a n kle) w hic h ma y i nterfere wit h or pre v e nt e ver y da y life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 2 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
e. Is a c o n ge nit al a n o m al y/ birt h defect 
● 
i n offs pri n g of partici p a nt ta ki n g t he pr o d u ct re gar dless of ti me t o dia g n osis 
f. Ot her i m p ort a nt me dic al e ve nts:  
●  Me dical or scie ntifi c j u d g me nt s h o ul d be e x ercise d i n deci di n g w h et her S A E 
re p orti n g is a p pr o priat e i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y lif e -t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o p ar dize 
t he partici pa nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts s h o ul d us uall y b e c o nsi dere d 
seri o us. 
E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt 
i n a n e mer ge n c y r o o m or at h o me f or aller gic br o n c h os pas m, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g d e pe n de nc y 
or dr u g a b use.  
 
A d diti o n al E ve nts Re p orte d i n t he S a me M a n ner as S A E  
A d diti o n al E ve nts W hic h R e q uire R e p orti n g i n t he S a me M a n ner as S A E  
● I n a d diti o n t o t he a b o ve criteria, a d verse e ve nts meeti n g eit her of t he bel o w criteria, 
alt h o u g h n ot seri o us per I C H d efi niti o n, are re p orta ble t o M S D  i n t he sa me ti mefra me 
as  S A Es  t o  meet  cert ai n  l ocal  re q uire me nts.  T heref ore,  t hese  e ve nts  are  c o nsi dere d 
seri o us b y M S D  f or c ollecti o n p ur p oses. 
●  Is a ne w ca ncer (t h at is n ot a c o n diti o n of t he st u d y); 
●  Is ass ociate d wit h a n o v er d ose. 
 
Rec or di n g A E a n d S A E  
A E a n d S A E Rec or di n g  
● W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w  all 
d oc u me ntati o n (e g, h os pital pr o gress n otes, la b orat or y, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
●  T he i n vesti gat or will rec or d all rele v a nt A E/ S A E i nf or mati o n o n t he A d verse E ve nt 
case r e p ort f or ms/ w or ks heets at eac h e x a mi nati o n.  
● 
It is n ot  acce pta bl e f or t h e i n vesti gat or t o se n d p h ot oc o pies of t he partici p a nt’s 
me dical rec or ds t o M S D i n lie u of c o m pleti o n of t he A E C R F pa ge. 
● 
T here ma y b e i nsta nces w he n c o pies of m e dical rec or ds f or certai n cas es are 
re q ueste d b y M S D . I n t his case, all partici pa nt i de ntifiers, wit h t he e x ce pti o n of t he 
partici pa nt n u m ber, will be bli n de d o n t he c o pies of t he me dical rec or ds b ef ore 
s u b missi o n t o M S D . 
●  T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. I n s u c h cases, t h e dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Assess me nt of I nte nsit y  
● A n e ve nt is defi ne d as ”s eri o us” w he n it meets at least 1 of t he pre defi n e d o utc o mes 
as descri be d i n t he d efi niti o n of a n S A E, N O T w h e n it is rate d as se v ere.  
●  T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E (a n d 
ot her re p ort a ble saf et y e v e nt) acc or di n g t o t he N CI C o m m o n Ter mi n ol o g y f or 
A d verse E v e nts ( C T C A E), versi o n 4. 0 . A n y a d v erse e ve nt w hic h c ha n ges C T C A E 
gr a de o ver t he c o urse of a gi v e n e pis o de will ha ve eac h c ha n ge of gra d e rec or de d o n 
t he a d vers e e ve nt case re p ort f or ms/ w or ks heets. 
● 
Gra de 1: Mil d; as y m pt o matic or mi d s y m pt o ms; cli nical or dia g n ostic 
o bser vati o ns o nl y; i nter v e nti o n n ot i n dicate d. 
● 
Gra de 2: M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal A D L.  
● 
Gra de 3: Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n or h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care A D L.  
●  Gra de 4: Lif e t hreate ni n g c o nse q ue nces; ur ge nt i nt er ve nti o n i n dicate d. 
● 
Gra de 5: D eat h r elate d t o A E.  
Assess me nt of C a us alit y 
● 
Di d t he st u d y treat me nt ca use t he a d v erse e ve nt?  
●  T he deter mi nati o n of t he li keli h o o d t hat t he st u d y treat me nt ca use d t he a d verse 
e ve nt will be pr o vi de d b y a n i n vesti gat or w h o is a q ualifie d p h ysi cia n.  T he 
i n vesti gat or’s si g ne d/ d ate d i nitials o n t he s o urce d oc u me nt or w or ks h eet t hat 
s u p p orts t he ca usalit y n ote d o n t he A E f or m, e ns ures t hat a me dicall y q ualifie d 
assess me nt of ca usalit y was d o ne.  T his i nitiale d d oc u me nt m ust be retai n e d f or 
t he re q uire d re g ulat or y ti me fra me.  T h e criteria b el o w are i nte n d e d as refere nce 
g ui deli nes t o assist t he i n vesti gat or i n assessi n g t h e li keli h o o d of a rel ati o ns hi p 
bet wee n t he  t est pr o d uct a n d t he a d verse e v e nt bas e d u p o n t he a vaila bl e 
i nf or mati o n 
● 
T he f oll o wi n g c o m p o ne nts are t o be use d t o ass ess t he rel ati o ns hi p bet w ee n 
t he st u d y tre at me nt a n d t he A E;  t he great er t he c orrel ati o n wit h t he c o m p o ne nts 
a n d t heir res p ecti ve el e me nts (i n n u m ber a n d/ or i nte nsit y), t he m ore li kel y t he 
st u d y treat me nt ca use d t h e a d vers e e v e nt:  
● 
E x p os ure:   Is t here e vi d e nce t hat t he p artici pa nt was act uall y e x p ose d t o t he 
st u d y treat me nt s uc h as:  relia ble hist or y, acce pta ble c o m plia nce ass ess me nt 
( pill c o u nt, diar y, etc.), e x pecte d p har mac ol o gic effect, or m eas ure me nt of 
dr u g/ meta b olite i n b o dil y s peci me n? 
● 
Ti me C o urs e:   Di d t he A E f oll o w i n a reas o na bl e te m p oral se q u e 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)? 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
● Li kel y C a use:   Is t he A E n ot reas o na bl y e x plai ne d b y a n ot h er eti ol o g y s uc h 
as u n derl yi n g disease, ot her dr u g(s)/ vacci n e(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 n c 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 d ec 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 tri al); or ( 4) st u d y 
treat me nt(s) is/ar e o nl y use d o ne ti me.) 
● 
Rec h alle n ge:   Was t he p artici 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 n e 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/ar e 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 LI NI C A L DI R E C T O R A S P E R D O S E M O DI FI C A TI O N G UI D E LI N E S I N T H E 
P R O T O C O L, 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 gi cal 
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 v esti gat or w h o is a q ualifie d p h ysicia n acc or di n g t o his/ her best cli nical 
j u d g me nt, i ncl u di n g c o nsi derati o n of t he a b o v e ele me nts.  
● 
Use t he f oll o wi n g scale of criteria as g ui da nce ( n ot all criteria m ust be prese nt t o be 
i n dicati ve of a st u d y treat me nt relati o ns hi p). 
●  Yes, t here is a reas o na ble p ossi bilit y of st u d y treat me nt relati o ns hi p: 
T here is e vi de n ce of e x p os ure t o t he st u d y treat m e nt.  T he te m p oral se q u e nce of 
t he A E o nset relati ve t o t he a d mi nistrati o n of t he st u d y treat me nt is reas o n a ble.  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
T he A E is m ore li kel y e x plai ne d b y t h e st u d y treat me nt t ha n b y a n ot her ca use.  
●  N o, t here is n ot a r eas o na ble p os si bilit y of st u d y treat me nt relati o ns hi p: 
Partici pa nt di d n ot recei v e t he st u d y treat me nt O R te m p oral se q ue n ce of t h e A E 
o nset relati ve t o a d mi nistrati o n of t he st u d y treat m e nt is n ot reas o na ble O R t he 
A E is m ore li kel y e x plai ne d b y a n ot her ca use t h a n t he st u d y treat me nt.  ( Als o 
e ntere d f or a p artici pa nt wit h o ver d ose wit h o ut a n ass ociate d A E.) 
● 
F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie w e d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca us alit y. 
● 
T here ma y b e sit uati o ns i n w hic h a n S A E has occ urre d a n d t h e i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o M S D . H o we ver, it is ver y i m p orta nt 
t hat t he i n vesti gat or al wa ys ma ke a n ass ess me nt of ca usalit y f or e ver y e ve nt bef ore t he 
i nitial tra ns missi o n of t he S A E data t o M S D . 
●  T he i n vesti gat or ma y c h a n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n a n d se n d a n S A E f oll o w- u p re p ort wit h t he u p date d ca us alit y assess me nt. 
● 
T he ca us alit y ass ess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uir e me nts 
●  F or st u dies i n w hic h m ulti ple a ge nts are a d mi nistere d as part of a c o m bi nati o n 
re gi me n, t he i n vesti gat or ma y attri b ute eac h a d verse e ve nt ca usalit y t o t he 
c o m bi nati o n re gi me n or t o a si n gle a ge nt of t he c o m bi nati o n.  I n ge n eral, ca usalit y 
attri b uti o n s h o ul d be assi g ne d t o t he c o m bi nati o n re gi me n ( ie, t o all a ge nts i n t he 
re gi me n). H o w e ver, ca us alit y attri b uti o n ma y be assi g ne d t o a si n gle a ge nt if i n t he 
i n vesti gat or’s o pi ni o n, t h ere is s uffici e nt data t o s u p p ort f ull attri b uti o n of t he a d vers e 
e ve nt t o t he si n gle a ge nt. 
F oll o w- u p of A E a n d S A E  
●  T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d u ct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q uest e d  b y M S D  t o 
el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble. T his ma y 
i ncl u de a d diti o nal la b orat or y tests or i n v esti gati o ns, hist o pat h ol o gical e x a mi nati o ns, 
or c o ns ultati o n wit h ot her healt h care pr ofessi o nals. 
●  Ne w or u p d ate d i nf or mati o n will be rec or d e d i n t he C R F. 
● 
T he i n vesti gat or will s u b mit a n y u p date d S A E d ata t o M S D  wit hi n 2 4 h o urs of recei pt 
of t he i nf or mati o n.  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
Re p orti n g of A E, S A E, a n d Ot her Re p ort a ble S afet y E ve nts t o M S D   
A E, S A E, a n d Ot her Re p ort a ble S afet y E ve nt Re p orti n g t o M S D  vi a Electr o nic 
D at a C ollecti o n T o ol 
●  T he pri mar y mec ha nis m f or re p orti n g t o M S D  will be t he electr o ni c data c ollecti o n 
( E D C) t o ol.   
●  Electr o nic r e p orti n g pr oce d ures ca n be f o u n d i n t he E D C dat a e ntr y g ui d eli nes ( or 
e q ui vale nt). 
●  If t he electr o nic s yste m is u na vaila ble f or m ore t h a n 2 4 h o urs, t he n t he site will 
use t he pa per A E Re p orti n g f or m.   
● 
Refere n ce s ecti o n 9. 3. 1 – Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d 
S A E a n d Ot her Re p ort a ble Safet y E ve nt I nf or mati o n f or re p orti n g ti me 
re q uire me nts  
● 
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes 
a vaila ble.  
● 
Af ter t he st u d y is c o m plete d at a gi ve n site, t he el ectr o nic data c ollecti o n t o ol will be 
ta ke n off-li ne t o pre ve nt t he e ntr y of n e w data or c ha n ges t o e xisti n g data. 
● 
If a site r ecei v es a r e p ort of a ne w S A E fr o m a st u d y partici pa nt or recei v es u p date d 
data o n a pr e vi o usl y r e p orte d S A E after t he electr o nic data c ollecti o n t o ol h as bee n 
ta ke n off-li ne, t h e n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or b y 
tele p h o ne (see ne xt secti o n). 
●  C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he I n vesti gat o r Trial File Bi n d er ( or 
e q ui vale nt).  
S A E Re p orti n g t o M S D  vi a P a per C R F 
● 
If t he electr o nic dat a c oll ecti o n t o ol is n ot o perati o nal, facsi mile tra ns missi o n or 
sec ure e-mail of t he S A E pa per C R F is t he preferre d met h o d t o tra ns mit t his 
i nf or mati o n t o M S D . 
● 
I n rar e cir c u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y 
tele p h o ne is acce pta ble wit h a c o p y of t he S A E d ata c ollecti o n t o ol se nt b y o ver ni g ht 
mail or c o urier s er vice.  
●  I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si g n t he S A E C R F pa ges wit hi n t he desi g n ate d re p orti n g ti me fra mes.  
●  C o ntacts a n d i nstr ucti o ns f or S A E re p orti n g a n d p a 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). 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 4:  Cli nic al L a b or at or y Tests  
N ote:  As of A me n d me nt 0 6 , l oc al l a b or at ories will be use d f or scree ni n g tests a n d all 
ot her st a n d ar d - of-c are cli nic al l a b or at or y tests . 
•  T he tests detaile d i n  Ta bl e 1 7  will be perf or me d b y t he l ocal la b orat or y.  
•  Pr ot oc ol-s pecific r e q uire me nts f or i ncl usi o n or e x cl usi o n of partici pa nts are detaile d 
i n Secti o n 6 of t he pr ot oc ol. 
•  A d diti o nal tests ma y be p erf or me d at a n y ti me d uri n g t he st u d y as d eter mi ne d 
necessar y b y t he i n vesti gat or or re q uire d b y l ocal re g ulati o ns. 
Ta ble 1 7  Pr ot oc ol- Re q uire d Safet y La b orat or y Ass ess me nts  
La b orat or y 
Assess me nts  
P ara meters  
He mat ol o g y / C oa
g ulati o n Fact ors  
Platelet C o u nt  
W B C c o u nt wit h Differe ntial:
a 
Ne utr o p hils  
L y m p h oc ytes  
M o n oc ytes  
E osi n o p hils  
B as o p hils  
R B C I n dices:  
M C V  
M C H  
% Retic ul oc ytes  
R B C C o u nt  
He m o gl o bi n  
He mat ocrit  
P T, I N R , a P T T/ P T T 
( 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) 
C he mistr y  
Bl o o d Urea Nitr o ge n 
( B U N)b 
P otassi u m  
As partate 
A mi n otra nsferase  
( A S T)/ Ser u m 
Gl uta mic -O xal oacetic  
Tra nsa mi nase 
( S G O T) 
T otal bilir u bi n (a n d 
direct bilir u bi n, if t otal 
bilir u bi n is ele vate d 
a b o ve t he u p per li mit 
of n or mal)  
 
Al b u mi n  
Bicar b o nate  or 
car b o n 
di o xi de c 
C hl ori de  
P h os p h or o us  
 
Creati ni ne  
S o di u m  
Ala ni ne 
A mi n otra nsferase  
( A L T)/ Ser u m 
Gl uta mic -P yr u vic 
Tra nsa mi nase ( S G P T)  
T otal p r otei n 
 
Gl uc ose [I n dicate if 
fasti n g, or n o nfasti n g] 
Calci u m  
Al kali ne p h os p hatase  
Lactate de h y dr o ge nase  
 
Uric aci d  
A m ylase  
Li pase  
 
R o uti ne 
Uri nal ysis  
•  
S pecific gra vit y  
•  
p H, gl uc ose, pr otei n, occ ult bl o o d, ket o nes, bilir u bi n, ur o bili n o ge n, nitrite, le u k oc yte s 
•  Micr osc o pic e xa mi nati o n (if bl o o d or pr otei n is a b n or mal)  
Ot her Scree ni n g 
T ests  
( perf or me d 
l ocall y u nless n ot 
feasi ble t o 
perf or m at t he 
site) 
•  
Ser ol o g y   
– He patitis B s urface a nti ge n ( H Bs A g)  
– He patitis B vir us de o x yri b o n ucleic aci d ( H B V D N A)  
– He patitis C a nti b o d y ( H C V)  if H C V R N A is n ot t he l ocal S o C  
– He patitis C a nti b o d y ri b o n ucl e ic aci d (H C V R N A)  
•  
HI V R N A ( o nl y if re q uire d b y l ocal re g ulati o n)  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
La b orat or y 
Assess me nts  
P ara meters  
Ot her tests 
d uri n g st u d y  
•  
C oa g ulati o n pa nel ( 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], I nter nati o nal N or malize d Rati o [I N R])  
•  
E n d ocri n ol o g y ( T 3/ F T 3, F T 4, a n d t h yr oi d sti m ulati n g h or m o ne [ T S H]) 
N O T E S:  
A d diti o nal tests ma y be re q uire d, as a gree d b y t he i n vesti gat or a n d M S D , base d o n e mer gi n g safet y data 
a. 
A bs ol ute val ues m ust be pr o vi de d f or W B C differe ntial la b orat or y res ults f or l y m p h oc ytes a n d ne utr o p hils 
b.  Bl o o d Urea Nitr o ge n is preferre d; if n ot a vaila ble, urea ma y be teste d  
c. 
P erf or m if a vaila ble as S o C  i n y o ur re gi o n. Car b o n di o xi de ma y be eit her a meas ure me nt of C O 2 or bicar b o nate 
as a n electr ol yte . 
 
I n v esti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 5 :  A b bre vi ati o ns a n d Tr a de m ar ks  
A b bre vi ati o n  
Defi niti o n  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A P a T  
All P artici pa nts as Treate d  
a P T T  
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase  
B C G  
B acill us Cal mette -G uéri n  
BI C R  
bli n de d, i n de pe n de nt, ce ntral r e vie w  
BI D  
T wice a da y  
C A  
Ca na da  
C A P  
C hest, a b d o me n, a n d pel vis  
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
C o nfi de nce i nter val  
C R  
C o m plete res p o nse 
Cr Cl  
Creati ni ne cleara nce  
C S R  
Cli nical st u d y re p ort  
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
D C  
Disc o nti n uati o n  
D C R  
Disease c o ntr ol rate  
D N A  
De o x yri b o n ucleic aci d  
D O R  
D urati o n of res p o nse  
eD M C  
E xter nal d ata m o nit ori n g c o m mittee  
 
 
 
E O T  
E n d of treat me nt  
 
 
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 U  
E ur o pea n U ni o n  
F A S  
F ull a nal ysis set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A b bre vi ati o n  
Defi niti o n  
 
 
 
G C P  
G o o d Cli nical Practice  
H B V  
He patitis B vir us  
H C V  
He patitis C vir us  
H R  
Hazar d rati o  
H R Q o L  
Healt h -relate d q ualit y of life 
I B 
I n vesti gat ors Br oc h ure 
I A 
I nteri m a nal ysis 
i C P D 
i R E CI S T C o nfir me d ra di o gra p hic pr o gressi o n 
I C F 
I nf or me d c o nse nt f or m  
I C H 
I nter nati o nal C o nfere nce o n H ar m o nisati o n  
I D 
I de ntificati o n 
I D O 1 
In d olea mi ne 2, 3 -de o x y ge nase 1  
I E C 
I n de pe n de nt et hics c o m mittee 
I H C 
I m m u n o hist oc he mistr y 
I M D C 
I nter nati o nal metastatic re nal cell carci n o ma data base c o ns orti u m 
ir A E 
I m m u ne-relate d a d verse e vent 
I R B 
I nstit uti o nal re vie w b oar d 
i R E CI S T 
M o difie d R E CI S T 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 T T 
I nte nti o n-t o-treat 
i U P D 
i R E CI S T u nc o nfir me d pr o gressi ve disease 
I V 
I ntra ve n o us 
I VR S  
I nteracti ve v oice/ we b res p o ns e s yste m 
K P S  
Kar n ofs k y P erf or ma nce Stat us  
M A OI  
M o n oa mi ne o xi dase i n hi bit ors  
m R C C  
Metastatic Re nal Cell Carci n o ma  
M RI  
Ma g netic res o na nce i ma gi n g  
m R N A  
Messe n ger R N A  
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 CI  
Nati o nal Ca ncer I nstit ute  
N S A E  
N o n -seri o us a d verse e ve nt  
N S C L C  
N o n -s mall cell l u n g ca ncer 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 8  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A b bre vi ati o n  
Defi niti o n  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O R R  
O bj ecti ve res p o nse rate  
O S  
O verall S ur vi val  
P D  
Pr o gressi ve disease  
P D - 1 
P r o gra m me d cell deat h 1 
P D -L 1  
P D -1 li ga n d 
P D -L 2  
P D - 2 li ga nd 
 
 
P F S  
Pr o gressi o n -free s ur vi val 
P F S 2  
Pr o gressi o n after sec o n d li ne of t hera p y  
P R  
P artial Res p o nse  
P K  
P har mac o ki netic  
P O  
P er os ( b y m o ut h)  
P T  
Pr ot hr o m bi n ti me  
P T T  
P artial t hr o m b o plasti n ti me  
Q 3 W  
E ver y 3 wee ks  
 
 
Q o L  
Q ualit y of l ife 
R C C  
Re nal Cell Carci n o ma  
R E CI S T 1. 1  
Res p o nse E val uati o n Criter ia i n S oli d T u m ors, versi o n 1. 1 
R N A  
Ri b o n ucleic aci d  
R O W  
Rest of W orl d  
S A E  
Seri o us ad verse e ve nt  
S D  
Sta ble d isease  
S A P  
Statistical A nal ysis Pla n  
S o A  
Sc he d ule of Acti vities  
S o C  
Sta n dar d of care  
S S  
Ser ot o ni n s y n dr o me  
s S A P 
S u p ple me ntal statistical a nal ysis pla n  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
T 1 D M  
T y pe 1 dia betes mellit us  
T KI  
T yr osi ne -ki nase i n hi bit ors  
Tre g  
T- cells wit h a re g ulat or y p he n ot y pe  
T T D  
Ti me t o deteri orati o n  
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 3 9  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A b bre vi ati o n  
Defi niti o n  
U L N  
U p per li mit of n or mal  
V E G F/  V E G F R  
V asc ular e n d ot helial gr o wt h fact or /V E G F rece pt ors  
W O C B P  
W o ma n of c hil d -beari n g p ote ntial  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 0  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 6 :  Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of Dise ase 
Pr o g ressi o n  
N ote: As per A me n d me nt 0 6, 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 ollect e 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 f r o m t he st u d y a n d be f oll o w e 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 s c a ns are re q uire d.  
U ntil ra di o gr a p hic 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  Gr o u p 1 p artici 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 CI S T 1. 1 as 
deter mi ne d b y t he I n v esti gat or , t h e I n vesti gat or will deci de w het her t o c o nti n ue a partici p a 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 (s ee  Ta bl e 1 0  a n d Fi g ure 2 ).  T his d ecisi 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 ym 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  
•  N o re q uire m e nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesi a, 
ra diati o n, or ot her p alliati ve care  
A n y p artici 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 sit e -assess e 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 p eat t u m or i ma gi n g f or c o nfir m ati o n of P D b y i R E CI S T. 
If t he I n vesti gat or d eci des t o c o nti n ue treat me nt, t he partici pa nt ma y c o nti n ue t o recei ve 
st u d y treat me nt a n d t he t u m or assess me nt s h o ul d be re peate d 4 t o 8 wee ks later t o c o nfir m 
P D b y i R E CI S T, p er I n v esti gat or assess me nt. I ma ges s h o ul d c o nti n ue t o b e se nt i n t o t he 
ce ntral i ma gi n g ve n d or f or p ote ntial retr os pecti ve BI C R.  
T u m or flare m a y ma nifest as a n y fact or ca usi n g ra di o gra p hi c pr o gressi o n per R E CI S T 1. 1, 
i ncl u di n g: 
•  I n crease i n t he s u m of di a 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 m eas 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 n t wit h t he ori gi n al 
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 CI S T defi nes ne w res p o nse cate g ories, i ncl u di n g i U P D ( u n c o nfir me d pr o gressi ve 
disease) a n d i C P D ( c o nfir me d pr o gressi v e disease). F or p ur p oses of i R E CI S T assess me nt, 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 1  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
t he first visit s h o wi n g disease pr o gressi o n acc or di n g t o R E CI S 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 h e 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 CI S T 1. 1 will be 
assesse d as us ual.  
Ne w lesi o ns will be classifie d as meas ura ble or n o n -meas ura bl e, usi n g t h e sa me size 
t hres h ol ds a n d r ules as f or baseli ne lesi o n assess m e nt i n R E CI S T 1. 1. Fr o m meas ura ble n e w 
lesi o ns, u p t o 5 lesi o ns t otal ( u p t o 2 per or ga n), m a y b e selecte d as N e 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 t ar get lesi o ns at baseli ne. All ot her n e 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 disease pr o gressi o n 
c o nfir me d ( wit h a n o v er all res p o nse of i C P D), or as s h o wi n g persiste nt u nc o nf ir me d 
pr o gressi o n ( wit h a n o v erall 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 Dise ase Pr o gressi o n 
Pr o gr essi o n is c o nsi dere d c o nfir me d, a n d t h e 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 w ere t he b asis f or t he i U P D at t he pre vi o us visit s h o w 
w orse ni n g 
o  F or tar get lesi o ns, w orse ni n g is a f urt her i ncreas e 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, 
c o m pare d t o a pri or i U P D ti me p oi nt; t his d oes n ot ha ve t o meet t he 
“ u ne q ui v ocal ” sta n dar d of R E CI S T 1. 1 
o  F or ne w lesi o ns, w orse ni n g is a n y of t h ese: 
 A n i ncreas e i n t he ne w l esi 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 n ce of a d diti o nal ne w lesi o ns 
•  A n y n e w f act or a p p ears t hat w o ul d ha ve tri g gere d P D b y R E CI S T 1. 1 
Persiste nt i U P D  
Pr o gr essi 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 ns e re mai ns i U P D, if: 
•  N o ne of t he pr o gressi o n- c o nfir mi n g fact ors i de ntifie d a b o ve o cc urs A N D 
•  T he tar get lesi o n s u m of dia meters (i nitial tar get l esi o ns) re mai ns a b o v e t he i nitial P D 
t hres h ol d ( b y R E CI S T 1. 1) 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 2  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
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 orr es 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 o cee ds i n a n i de ntical ma n ner, wit h 
p ossi ble o utc o mes of i C P D, i U P D, a n d i S D/i P R/ i C R. 
Res ol uti o n of i U P D 
Pr o gr essi 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 ns e bec o m es 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 o cc urs, A N D 
•  T he tar get lesi o n s u m of dia meters (i nitial tar get l esi 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 m eters 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 ps e u d o- pr o gressi o n, a n d t h e 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 hi c 
pr o gressi o n, w he n e 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 oces s is re peate d b ef ore a res p o ns e of i C P D ca n be assi g n e d. 
M a n a ge me nt F oll o wi n g t he C o nfir m at ory I m a gi n g 
If re p eat 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 v esti gat or, a n d t he 
partici pa nt c o nti n ues t o b e cli nicall y st a ble, st u d y treat me n t 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 h e d ule. If P D is c o nfir me d, p artici pa nts will be disc o nti n ue d fr o m st u d y 
treat me nt. 
N O T E: If a p artici pa nt h as c o nfir me d ra di o gra p hi c pr o gressi o n (i C P D) as defi ne d a b o v e, b ut 
t he partici pa nt is ac hie vi n g a cli nicall y m ea ni n gf ul be nefit, a n e x ce pti o n t o c o nti n ue st u d y 
treat me nt ma y be c o nsi dere d f oll o wi n g c o ns ultati o n wit h M S D. I n t his cas e, 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 r es ol uti o n of pse u d o- pr o gressi o n (ie, ac hie v e 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 ncreas e fr o m 
na dir) eit her f or t he first ti me, or after res ol uti o n of pre vi o us pse u d o-
pr o gressi o n. T he n a dir is al wa ys t he s mallest s u m of dia meters see n d uri n g t he 
e ntire st u d y, eit her bef ore or aft er a n i nsta n ce of pse u d o - pr o gressi o n. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 3  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
•  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 n e q ui v ocal pr o gressi o n, t heir d oi n g s o f or 
t he first ti me res ults i n i U P D. 
o  If n o n-tar get lesi o ns ha ve s h o w n pre vi o us u ne q ui v ocal pr o gressi o n, a n d t his 
pr o gressi o n has n ot res ol ve d, i U P D res ults fr o m a n y si g nifica nt f urt her gr o wt h of 
n o n- tar get lesi o ns, ta ke n as a w h ole. 
•  Ne w lesi o ns  
o  Ne w lesi o ns a p pear f or t he first ti me  
o  A d diti o nal ne w lesi o ns a p pear 
o  Pre vi o usl y i de ntifie d ne w tar get lesi o ns s h o w a n i ncreas e 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 u e 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 n y si g nifica nt gr o wt h 
If a n y of t he e ve nts a b o v e occ ur, t h e 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 I m a gi n g a b o ve) is re peat e d. 
Pr o gr essi o n m ust be c o nfir me d bef ore i C P D ca n o cc 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 h e i nitial P D, wit h 
o ne e x ce 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 d e n of ne w lesi o ns has i ncrease d fr o m its s mallest val ue (f or ne w tar get 
lesi o ns, t he s u m of dia meters is ≥5 m m i ncrease d fr o m its na dir), t he n i U P D ca n n ot res ol ve 
t o i S D or i P R. It will re m ai n i U P D u ntil eit her a decrease i n the n e 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 us es i C P D. 
A d diti o nal details a b o ut i R E CI S T are pr o vi de d i n t he i R E CI S T p u blicati o n [ Se y m o ur, L., et 
al 2 0 1 7]. 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 4  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 7:  C yt oc hr o me P 4 5 0 I n hi bit ors/I n d ucers  
T his a p pe n di x is n ot i ncl usi ve. F or a c o m pre h e nsi ve list please c hec k wit h y o ur p h ar mac y 
pers o n nel.   
U ni versit y of Was hi n gt o n Sc h o ol of P har mace uti cs: Dr u g I nteracti o n Dat a base Pr o gra m. 
2 0 0 2. htt p:// w w w. dr u gi nt eracti o ni nf o. or g. Accesse d Ma y 2 0 1 5.   
P ot e nt C Y P 3 A 4 I n hi bit ors ( yiel di n g s u bstr ate > A U C 5)  
I n hi bit or 
T her a pe utic Cl ass  
A U C R ati o  
Ket oc o naz ole 
A ntif u n gal 
1 5. 9 
Tr olea n d o m yci n 
A nti bi otic  
1 4. 8 
Itr ac o n az ole 
A ntif u n gal 
1 0. 8 
V oric o naz ole 
A ntif u n gal 
9. 6 3 
Mi befra dil  
Calci u m c ha n nel bl oc ker 
8. 8 6 
Clarit hr o m yci n  
A nti bi otic  
8. 3 9 
P osac o naz ole 
A ntif u n gal 
6. 2 3 
Telit hr o m yci n  
A nti bi otics  
6. 2 
Nefaz o d o ne 
A nti de pressa nt 
5. 4 4 
 
M o der ate C Y P 3 A 4 I n hi bit ors ( yiel di n g s u bstr ate ≥ 2 a n d < 5) 
I n hi bit or 
T her a pe utic Cl ass  
A U C R ati o  
Er yt hr o m yci n  
A nti bi otics  
4. 9 9  
Fl uc o naz ole  
A ntif u n gal  
4. 9 3  
Diltiaze m  
Calci u m c ha n nel bl oc ker  
4. 0 6  
A pre pita nt  
A ntie metic  
3. 2 9  
Cas o pita nt  
A ntie metic  
3. 1 3  
Vera p a mil  
Calci u m c ha n nel bl oc ker  
2. 9 2  
Ci pr ofl o x aci n  
A nti bi otics  
2. 1 2  
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 5  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 8 :  I M D C Ris k C ate g ories 
Assess me nts  
Ris k F act or  
B aseli ne Kar n ofs k y P erf or ma nce Stat us  
< 8 0 %  
I nter val bet wee n i nitial dia g n osis of R C C t o start of first-li ne s yste mic treat me nt 
f or a d va nce d disease  
(n ote f or t his st u dy, d ate of r a n d o miz ati o n will be use d as t he st art of first -li ne 
syste mic tre at me nt) 
< 1 year  
B aseli ne He m o gl o bi n  
< L o wer li mit of n or mal  
B aseli ne Platelet C o u nt  
> U p per li mit of n or mal  
B aseli ne C orrecte d Calci u m 1 
> U p per li mit of n or mal  
B aseli ne Ne utr o p hil  
> U p per li mit of n or mal  
T he I M D C ris k gr o u p is deter mi ne d b y t otali n g t he e xisti n g ris k fact ors per s u bj ect.  
I M D C Ris k Gr o u p 
I M D C C ate g or y 
Fa v ora ble  
N o ris k fact ors  
I nter me diate 
1 or 2 ris k fact ors  
P o or  
3 or m ore ris k fact ors 
1.  
C orrecte d calci u m ca n b e calc ulate d b ase d o n t h e f oll o wi n g f or m ul a:  
C orrecte d c alci u m ( m g/ dl) = 0. 8 × [ 4. 0 - s u bject’s al b u mi n ( g/ dl)] + s u bject’s c alci u m ( m g/ dl). 
A s u bject’s c orrecte d calci u m will b e c o m p are d wit h t h e u p p er li mit of n or ma l of i nstit uti o n ser u m c alci u m [ He n g, D. 
Y., et al 2 0 0 9] . 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 6  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 9 :  E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce Sc al e 
E C O G Perf or ma n ce Stat us  
De vel o pe d b y t he Easter n C o o perati ve O nc ol o g y Gr o u p, R o bert L. C o mis, M D, Gr o u p C hair. *  
G R A D E  
E C O G Perf or ma n ce Stat us  
0 
F ull y acti ve, a bl e t o carr y o n all pre -diseas e perf or ma nce wit h o ut restricti o n  
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se d e 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 p a ble of all self -care b ut u n a ble t o carr y o ut a n y w or k 
acti vities; u p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs 
3 
Ca pa ble of o nl y li mite d self -care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs 
4 
C o m pletel y disa ble d; ca n n ot carr y o n a n y self -care; t otall y c o nfi ne d t o be d or 
c hair  
5 
Dea d  
* O ke n M, Creec h R, T or me y D, et al. T o xicit y a n d res p o nse criteria of t he Easter n C o o perati ve O nc ol o g y 
Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5: 6 4 9 -6 5 5.  
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


P r o d uct:  M K -3 4 7 5/I N C B 0 2 4 3 6 0  
1 4 7  
P r ot oc ol/ A me n d me nt N o.:   6 7 9 -0 6/ E C H O -3 0 2 -0 6  
 
 
A p pe n di x 1 0:  K ar n ofs k y Sc ore 
1 0 0 – N or mal; n o c o m plai nts; n o e vi de nce of disease. 
9 0 – A ble t o carr y o n n or mal acti vit y; mi n or si g ns or s y m pt o ms of diseas e. 
8 0 – N or mal acti vit y wit h eff ort; s o me si g ns or s y m pt o ms of disease. 
7 0 – Cares f or s elf; u na bl e t o carr y o n n or mal acti vit y or t o d o acti ve w or k. 
6 0 – Re q uires occasi o nal assista nce, b ut is a ble t o care f or m ost of t heir p ers o nal nee ds.  
5 0 – Re q uires c o nsi der a ble assista nce a n d fre q u e nt me dical care.  
4 0 – Disa ble d; re q uires s pecial care a n d assista nce.  
3 0 – Se verel y disa ble d; h os pital a d missi o n is i n dicate d alt h o u g h deat h n ot i m mi ne nt. 
2 0 – Ver y sic k; h os pital a d missi o n necessar y; acti ve s u p p orti ve treat me nt n ecessar y.  
1 0 – M ori b u n d; fatal pr o cesses pr o gressi n g ra pi dl y.  
0 – Dea d  
Ref ere nces:  
Kar n ofs k y D A, B urc he n al J H, T he cli nical e val uati o n of c he m ot hera p e utic a ge nts i n ca ncer . 
I n: E v al uati o n of C he m ot hera pe utic A ge nts, Macl ea d C M, e d . Ne w Y or k: C ol u m bia 
U ni versit y Pr ess, 1 9 4 9.  
Sc ha g C C , Hei nric h R L , Ga nz P A. Kar n ofs k y perf or ma nce stat us re visite d: relia bilit y, 
vali dit y, a n d g ui deli nes. J Cli n O nc ol 1 9 8 4; 2 ( 3):1 8 7 – 9 3. 
 
 
 
M K - 3 4 7 5- 6 7 9- 0 6 (I N C B 2 4 3 6 0- 3 0 2- 0 6) Fi nal  Pr ot oc ol 
1 5-J u n- 2 0 1 8 
C o nfi de ntial 
 


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


Si g n at ur e M a nif e st
D o c u m e nt N u m b er: I C- D E V- P R O T- A M E N D- 0 3 5 6
R e vi si o n: 0
Titl e: I N C B 2 4 3 6 0- 3 0 2 Pr ot o c ol A m e n d m e nt 6 ( K E Y N O T E- 6 7 9, E C H O- 3 0 2)
All d at e s a n d ti m e s ar e i n E a st er n St a n d ar d Ti m e.
Q ui c k A p pr o v al
A p pr o v e N o w
N a m e/ Si g n at ur e
Titl e
D at e
M e a ni n g/ R e a s o n
1 5 J u n 2 0 1 8, 0 5: 0 9: 5 6 P M
A p pr o v e d