A Phase 3 Randomized, Open-Label Clinical Study to Evaluate the Efficacy and Safety of Pembrolizumab Plus Epacadostat, Pembrolizumab Monotherapy, and the EXTREME Regimen as First Line Treatment for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE-669/ECHO-304)
Phase: PHASE3
Conditions: Head and Neck Cancer
Sponsor: Incyte Corporation



Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
M S D
Si g n at or y
T y pe d Na me:
Title:
Date
Pr ot oc ol -s pecific M S D c o nt act i nf or m ati o n c a n be f o u n d i n t he I n vesti g at or Tri al File 
Bi n der ( or e q ui v ale nt). 
I n vesti g at or Si g n at or y
I a gree t o c o n d uct t his cli nical trial i n acc or da nce wit h t he desi g n o utli ne d i n t his pr ot oc ol 
a n d t o a bi de b y all pr o visi o ns of t his pr ot oc ol.
T y pe d Na me:
Title:
Date
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S
A m e n d me nt 0 4
O ver all R ati o n ale f or t he A me n d me nt:
T he e xter nal data m o nit ori n g c o m mittee ( eD M C) a nal ys is of t he K E Y N O T E -2 5 2/ E C H O - 3 0 1 bli n de d cli nical st u d y , a P hase 3 st u d y 
e val uati n g e paca d ostat i n c o m bi nati o n wit h pe m br oliz u ma b i n partici pa nts wit h u nresecta ble or metastatic mela n o ma, deter mi ne d t hat 
t he st u d y di d n ot meet t he pre-s pecifie d e n d p oi nt of i m pr o ve me nt i n pr o gressi o n-free s ur vi val f or t he c o m bi nati o n of pe m br oliz u ma b 
a n d e paca d ostat c o m pare d t o pe m br oliz u ma b a n d place b o.   T he e D M C f urt her deter mi ne d t hat t he o verall s ur vi val e n d p oi nt is n ot 
e x pecte d t o reac h statistical si g nifica nce. T hese res ults are s pecific t o mela n o ma, a n d ca n n ot be e xtra p olate d t o ot her t u m or t ypes.  Of 
n ote t here were n o ne w safety c o ncer ns wit h t he pe m br oliz u ma b + e paca d ostat c o m bi nati o n c o m pare d t o pe m br oliz u ma b 
m o n ot hera p y.  Gi ve n t hat t here is n o c o nfir me d lac k of efficac y of pe m br oliz u ma b + e paca d ostat i n ot her t u m or t y pes, t he S p o n s 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 6 9 / E C H O-3 0 4 .  E nr oll me nt i n t his st u d y was 
per ma ne ntl y st o p pe d o n 0 2- M A Y -2 0 1 8 as a strate gic decisi o n.  F or partici pa nts w h o are c o nsi dere d t o be o btai ni n g o n g oi n g cli nical 
be nefit, c o nti n ue d st u d y t reat me nt will be at t he discreti o n of t he in vesti gat or, after a disc ussi o n wit h t he partici pa nt of t he o bser ve d 
res ults fr o m K E Y N O T E- 2 5 2/ E C H O - 3 0 1.
S u m m ar y of C h a n ges T a ble:
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
1 S y n o psis
2. Sc he d ule of Acti vities
(S o A )
A d diti o n of n otes t o clarif y  t hat after t he first 
i ma gi n g assess me nt f or efficac y a nalys is, 
partici pa nts ma y  c h o ose t o disc o nti n ue fr o m t he 
st u d y or c o nti n ue st u dy treat me nt as per pr ot oc ol
after partici pa nt disc ussi o n wit h t he i n vesti gat or .
Gi ve n t he lat est res ults f or pe m br oliz u ma b pl us
e paca d ostat treat me nt fr o m mela n o ma st u d y E C H O-
3 0 1/ K E Y N O T E - 2 5 2, as of 0 2- M A Y -2 0 1 8 e nr oll me nt 
was per ma ne ntl y st o p pe d i n K E Y N O T E-6 6 9/ E C H O -
3 0 4. 8 9 partici pa nts were ra n d o mize d i nt o t he st u d y. 
P artici pa nts will be gi ve n t he o pti o n t o disc o nti n ue 
fr o m t he st u d y or c o nti n ue st u d y treat me nt.  T he st u d y 
will re mai n o pe n t o all o w partici pa nts access t o st u d y 
treat me nt a n d t o all o w c ollecti o n of preli mi nar y  
efficac y data i n t his H N S C C i n dicati o n.
E fficac y pr oce d ures after Wee k 9 are n o l o n ger bei n g 
ma n date d . 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
W here deleti o n of te xt c o ul d ca use c o nf usi o n, d ue t o 
t he desi g n of t he st u d y t o date, t he te xt has bee n left 
u nc ha n ge d a n d a n ote has bee n a d de d.
3. 2. 3 O n g oi n g Cli nical 
St u dies
5. 1 O verall Desi g n
K E Y N O T E 2 5 2/ E C H O -3 0 1 relate d te xt i nserte d.
I nserte d n ote t hat e nr oll me nt was st o p pe d; after 
t he first i ma gi n g assess me nt at Wee k 9 ( ± 
7 da y s), partici pa nts ha ve t he o pti o n t o c o nti n ue 
o n t he s t u d y after partici pa nt disc ussi o n wit h t he 
i n vesti gat or, all st u d y efficac y pr oce d ures will 
st o p after Wee k 9 a n d t hereafter will be 
perf or me d as per l ocal sta n dar d of care (S o C ).
Clarifie d safet y pr oce d ures f or Gr o u ps 1, 2, a n d 
3.
1. S y n o psis
5. 2 N u m ber of 
Partici pa nts
A d diti o n of te xt stati n g t hat as of 0 2-M A Y - 2 0 1 8 
e nr oll me nt was st o p pe d a n d 8 9 partici pa nts were 
e nr olle d i n t he st u d y.
7. 2. 6 Sec o n d C o urse 
P hase
7. 4 Bli n di n g
A d diti o n of n ote, a n d relate d c ha n ges, t hat 
i ma gi n g assess me nts will n o l o n ger be ma de by 
bli n de d i n de pe n de nt ce ntral re vie w ( BI C R); all 
disease pr o gressi o n will be assesse d b y t he 
in vesti gat or base d o n R E CI S T 1. 1.
1. S y n o psis
2. Sc he d ule of Acti vities 
(S o A)
4. O bjecti ves/ H y p ot heses 
a n d E n d p oi nts
5. 1 O verall Desi g n
5. 4. 1 Rati o nale f or 
E n d p oi nts
Re m o ve d refere nces t o BI C R assess me nt of 
disease pr o gressi o n.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
8. 1 Disc o nti n uati o n of 
St u d y  Treat me nt
9. 1. 9. 1. 3 Gr o u p 3 
E X T R E M E Re gi me nt 
D ose A d mi nistrati o ns
9. 2. 1. 3 E n d of Treat me nt 
a n d F oll o w -u p T u m or 
I ma gi n g
9. 2. 1. 4 Sec o n d C o urse 
P hase T u m or I ma gi n g
9. 2. 1. 5 R E CI S T 1. 1 
Assess me nt of Disease
9. 9. 2 Treat me nt P hase
9. 2. 1 T u m or I ma gi n g a n d 
Assess me nt 
of 
Disease
9. 2. 1. 1
I nitial 
T u m or 
I ma gi n g
A d diti o n of n ote t hat ce ntral re vie w of i ma gi n g 
a n d i R ECI S T is n o l o n ger a p plica ble.  Secti o n 
u p date d acc or di n gl y.
2. Sc he d ule of Acti vities 
( S o A)
9. 2. 1. 2
T u m or 
I ma gi n g 
D uri n g 
t he 
St u d y
9. 2. 1. 4 
Sec o n d 
C o urse 
P hase T u m or I ma gi n g
A d diti o n of n ote t hat ce ntral re vie w of i ma gi n g 
a n d i R ECI S T is n o l o n ger a p plica ble.  After t he 
first o n- st u d y ima gi n g 
assess me nt at Wee k 
9, 
f urt her i ma gi n g will be perf or me d as per l ocal 
S o C g ui deli nes . Secti o n u p date d acc or di n gl y .
I nserte d te xt t hat i ma gi n g f or disease assess me nts 
will be perf or me d as per l ocal S o C g ui deli nes; 
o nl y  the date of sca ns perf or me d as per S o C 
nee ds t o be d oc u me nte d i n t he e C R F.   
9. 2. 1. 3 E n d of Treat me nt 
a n d 
F oll o w - u p 
T u m or 
I ma gi n g
A d diti o n 
of n ote t hat t here is n o pr ot oc ol 
s pecifie d i ma gi n g after t he Wee k 
9 assess me nt
f or 
efficac y 
anal y sis. 
 
Secti o n 
u p date d 
acc or di n gl y.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
Re m o val of refere nce t o i R E CI S T .
A d diti o n of clarificati o n t hat e n d of treat me nt 
( E O T) sca n will be perf or me d f or partici pa nts 
w h o disc o nti n ue st u d y treat me nt bef ore t he first 
sc he d uled o n- st u d y i ma gi n g f or efficac y a nalys is.
1. 
S y n o psis
4.
O bjecti ves/
H y p ot heses 
a n d 
E n d p oi nts
A d diti o n 
of n otes t o clarif y the sec o n dar y 
efficac y en d p oi nt of O R R base d o n R E CI S T 1. 1 
b y  i n vesti gat or deter mi nati o n will bec o me t he 
pri mar y  en d p oi nt; safet y en d p oi nts will re mai n 
u nc ha n ge d; all ot her efficac y en d p oi nts will n o 
l o n ger be c ollecte d after Wee k 9.
O R R 
a n d 
safet y 
objecti ves 
a n d 
e n d p oi nts 
re w or de d. 
All 
efficac y 
objecti ves/e n d p oi nts 
delete d.
T he 
st u d y sc o pe 
has 
bee n 
re d uce d t o c ollect 
preli mi nar y  efficac y data f or c o m bi nati o n treat me nt i n 
rec urre nt or metastatic hea d a n d nec k s q ua m o us cell 
carci n o ma.
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 to date, t he te xt has bee n left 
u nc ha n ge d a n d a n ote has bee n a d de d .
1. S y n o psis
T he esti mate d d urati o n of t he trial was decrease d 
fr o m 5 0 t o 4 1 m o nt hs.
2 . Sc he d ule of Acti vities 
( S o A)
Delete d n ote t hat all p ost -st u d y a ntica ncer t hera p y 
nee ds t o be rec or de d.
Clarifie d 
t hat m o nt hl y 
pre g na nc y  test s h o ul d 
occ ur bef ore eac h c y cle.
Re m o ve d te xt a b o ut re peati n g la bs after t he e n d 
of treat me nt a n d i n re gar d t o u nres ol ve d a b n or mal 
la bs d uri n g Safet y F oll o w -U p ; a d de d la bs s h o ul d 
be f oll o we d u p as per sites’ practices.
2. 1. 2 
E X T R E M E 
Re gi me n Ar m ( Gr o u p 3)
Safet y  Pr oce d ures/ Assess me nts after Wee k 
9 
c ha n ge d t o as per S o C.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 1 O verall Desi g n
I nserte d n ote t hat the pri mar y  objecti ve will 
e val uate t he e n d p oi nt of O R R base d o n R E CI S T 
1. 1, 
as assesse d b y  the 
i n vesti gat or, after 
c o m pleti o n of t he first i ma gi n g assess me nt; all 
ot her efficac y en d p oi nts will 
n o l o n ger be 
c ollecte d.
5. 1. 1 
Data 
M o nit ori n g 
C o m mittee
1 2. 3 A p pe n di x 3: St u d y 
G o ver na nce 
C o nsi derati o ns, 
Data 
M o nit ori n g C o m mittee
Re m o ve d te xt referri n g t o a n i nteri m a nal ys is.
5. 4 Scie ntific 
Rati o nale 
for St u d y  Desi g n
Re m o ve d te xt referri n g t o P F S a n d O S e n d p oi nts 
s u p p orti n g re g ulat or y ap pr o val of pe m br oliz u ma b 
pl us e paca d ostat f or patie nts wit h R/ M H N S C C.
5. 4. 1. 1
Efficac y 
E n d p oi nts
5. 4. 1. 1. 1 R E CI S T 1. 1
A d diti o n of n ote t hat t he pri mar y e n d p oi nt will be 
O R R base d o n R E CI S T 1. 1 as assesse d b y  the 
in vesti gat or; tra ns missi o n of i ma ges f or ce ntral 
re vie w of i ma gi n g is n o l o n ger re q uire d.  After 
t he Wee k 9 i ma gi n g, all ot her efficac y en d p oi nts 
will n o l o n ger be c ollecte d or perf or m e d.  
Deleti o n of all te xt relati n g t o P F S, O S, D O R .
5. 4. 1. 1. 1 R E CI S T 1. 1
A d diti o n 
of n ote t hat R E CI S T 1. 1 will 
be 
assesse d b y  the i n vesti gat or a n d tra ns missi o n of 
i ma ges t o t he ce ntral re vie w of i ma gi n g is n o 
l o n ger re q uire d.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
5. 4. 1. 1. 2 
M o difie d 
R E CI S T
f or 
I m m u ne-
base d 
T hera pe utics 
(i R E CIS T )
9. 2. 1. 6
i R E CIS T 
Assess me nt 
of 
Disease
A p pe n di x 8
A d diti o n of n ote t hat t his secti o n is n o l o n ger 
a p plica ble; i R E CIS T data will 
n o l o n ger be 
c ollecte d.  Partici pa nts wit h ra di o gra p hic disease 
pr o gressi o n as deter mi ne d b y  RE CI S T 1. 1 will 
disc o nti n ue fr o m t he st u d y an d be f oll o we d f or 
safety m o nit ori n g, as detaile d i n Secti o n 9. 3; n o 
c o nfir mat or y sca ns are re q uire d.
2. 1 
I nitial 
Treat me nt 
P hase
5. 4. 1. 5 
Rati o nale 
f or 
Patie nt 
Re p orte d 
O utc o mes
9. 2. 2
Patie nt 
Re p orte d 
O utc o mes
P R Os will
n o l o n ger be c ollecte d after C y cle 4
a n d t he S o As were re vise d acc or di n gl y an d n otes 
were a d de d w here a p plica ble .
7. 2. 6 
Sec o n d 
C o urse 
P hase
Re m o ve d te xt referri n g t o a d diti o nal pri mar y  
e n d p oi nts.
1 2. 2 A p pe n di x 2: Cli nical 
La b orat or y  Tests
Re vise d te xt t o i n dicate t hat all la b orat or y tests 
will be perf or me d b y t he l ocal la b orat or y .
1 0. 
Statistical 
A nal y sis 
Pla n
E ntire 
secti o n re vise d t o reflect c ha n ges i n 
o bjecti ves a n d e n d p oi nts, as well as re m o ve d all 
refere nces t o BI C R 
assess me nt 
of 
disease 
pr o gressi o n.
1. S y n o psis
Te xt relati n g t o f oll o w- u p of partici pa nts t hat 
disc o nti n ue treat me nt f or reas o ns ot her t ha n 
disease 
pr o gressi o n 
a n d re place d wit h 
te xt 
relati n g t o disc o nti n uati o n fr o m t he st u d y after 
t he Safety F oll o w -u p Visit.
T he fi nal visit i n t he st u d y will be t he Safet y F oll o w- u p 
Visit.  There will be n o f oll o w-u p f or s ur vi val stat us.  
Partici pa nts c urre ntl y in f oll o w- u p or i n s ur vi val 
f oll o w-u p are c o nsi dere d t o ha ve c o m plete d t he st u d y.  
H o we ver, sta n dar d safet y re p orti n g s h o ul d c o nti n ue, as 
a p plica ble.
 
 
0 4 Y B M H

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

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
9. 9. 4 . 2 F oll o w -U p Visits
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble. 
 
Partici pa nts c urre ntl y in 
p ost -
treat me nt f oll o w-u p are c o nsi dere d t o ha ve 
c o m plete d t he st u d y once t he y ha ve atte n de d t he 
Safet y  
Foll o w - u p Visit. 
 
Assess me nt 
a n d 
rec or di n g of A Es 
will 
be perf or me d as per 
Secti o n 9. 3.
9. 9. 4 . 3 S ur vi val F oll o w -
u p
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble.  Partici pa nts c urre ntl y i n S ur vi val 
F oll o w - u p are c o nsi dere d t o ha ve c o m plete d t he 
st u d y; t hese partici pa nts will 
n o l o n ger be 
c o ntacte d f or s ur vi val i nf or mati o n.  Assess me nt 
a n d rec or di n g of A Es will c o nti n ue as per Secti o n 
9. 3.
9. 9. 7 S ur vi val Stat us
A d diti o n of a n ote t hat t his secti o n is n o l o n ger 
a p plica ble; s ur vi val data is n o l o n ger bei n g 
c ollecte d.
5. 1 O verall Desi g n
C ha n ge d car b o plati n i nf usi o n ti me fr o m 3 0 t o 6 0 
mi n utes.
C orrecti o n
7. 2. 1 D ose M o dificati o n 
f or I m m u ne-relate d A Es
Ta ble 4 – 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.
Ta ble n ote # 4 – i nserte d clarificati o n o n gra de of 
A E t o w hic h t he n ote a p plies.
T o ali g n wit h K E Y T R U D A ® S u m mar y of Pr o d uct 
C haracteristics ( S m P C) a n d C o m pa n y C ore Data S heet 
( C C D S).
C o nsiste nc y  a n d ali g n me nt wit h c urre nt cli nical 
i nf or mati o n f or pe m br oliz u ma b a n d e paca d ostat.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
7. 2. 1. 2 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
A d de d g ui da nce f or partici pa nts e x perie nci n g 
m o derate or se vere u nc o nf o u n de d S S, wit h o ut 
c o nc o mita nt S S RI or S N RI usa ge, or ser ot o ner gic 
c o nc o mita nt me dicati o ns.
Ali g n me nt wit h c urre nt cli nical i nf or mati o n f or 
e paca d ostat.
7. 2. 5 D ose I nterr u pti o ns 
U nrelat e d t o A d verse 
E ve nts
A d de d t hat d ose i nterr u pti o ns are per mitte d f or 
sit uati o ns ot her t ha n treat me nt-relate d A Es.
Clarificati o n
7. 2. 6 Sec o n d C o urse 
P hase
Re m o ve d a n ote a b o ut partici pa nts’ i nitial 
treat me nt.
Clarificati o n
7. 5. 1 D ose Pre parati o n
A d diti o n of refere nce t o t he P har mac y Ma n ual f or 
pre parati o n of e paca d ostat i n cases w here a 
partici pa nt is u na ble t o s wall o w or has fee di n g 
t u be.
Clarificati o n 
7. 7. 3 Pr o hi bite d 
Me dicati o ns a n d 
Meas ures
Re m o ve d mefe na mic aci d fr o m t he list of 
pr o hi bite d U G T 1 A 9 i n hi bit ors.
T his c ha n ge was ma de t o ali g n wit h t he c urre nt 
e paca d ostat I B.
Delete d a n ote t hat ra diati o n t hera py ma y be 
c o nsi dere d t o a s olitar y lesi o n or t o t he brai n.
Clarificati o n
9. 1. 9. 1 Ti mi n g of D ose 
A d mi nistrati o n
Delete d te xt fr o m t he se nte nce a b o ut C ycle 1 Da y 
1 re gar di n g si g ni n g t he I C F.
C orrecti o n
9. 1. 1 2 Cali brati o n of 
E q ui p me nt
U p date d e q ui p me nt cali brati o n la n g ua ge.
Te xt ual re visi o ns were a p plie d t o clarif y  i n vesti gat or 
res p o nsi bilit y f or cali brati o n a n d mai nte na nce of st u d y 
e q ui p me nt.
9. 9. 4. 1 Safet y F oll o w - u p 
Visit
U p date d Safet y F oll o w -u p Visit la n g ua ge.
T o re m o ve c o nflict f or re p orti n g A Es/ S A Es 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
6. 2 E xcl usi o n Criteria
7. 1 Treat me nts 
A d mi nistere d
7. 7. 4. 3 S u p p orti ve Care 
G ui deli nes f or Cis plati n 
a n d Car b o plati n
1 2. 9 A p pe n di x 9
Re m o ve d A p pe n di x 9: Cis plati n Mar ket 
A ut h orizati o n ( o nl y  f or sites c o n d ucti n g t he st u dy 
i n Fra nce) a n d all refere nces t o t his A p pe n di x.
T he i nf or mati o n i n t his a p pe n di x is u n necessar y  as n o 
partici pa nts were e nr olle d i n Fra nce a n d e nr oll me nt is 
st o p pe d.
T hr o u g h o u t 
C orrecti o n of t y p o gra p hical, e dit orial a n d 
f or matti n g err ors.
Re visi o ns were a p plie d f or c o nsiste nc y  a n d as 
c orrecti o ns.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
T a ble of C o nte nts
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ...............................................3
1.
S y n o psis .......................................................................................................................2 3
2. 
Sc he d ule of Acti vities ( S o A) ......................................................................................2 6
I niti al Tre at me nt P h ase ..........................................................................................2 6
2. 1
Pe m br oliz u ma b pl us E paca d ostat a n d Pe m br oliz u ma b M o n ot hera p y 
2. 1. 1
Ar ms ( Gr o u p 1 a n d 2) ..........................................................................................2 6
E X T R E M E Re gi me n Ar m ( Gr o u p 3) ..................................................................3 1
2. 1. 2
Sec o n d C o urse P h ase ( Retre at me nt, Gr o u p 1 a n d 2 o nl y) ..................................3 6
2. 2
3.
I ntr o d ucti o n ................................................................................................................3 8
St u d y R ati o n ale .......................................................................................................3 8
3. 1
B ac k gr o u n d ..............................................................................................................3 8
3. 2
P har mace utical a n d T hera pe utic Bac k gr o u n d .....................................................3 9
3. 2. 1
I n hi biti o n of P D-1 as a Tar get f or Ca ncer ....................................................3 9
3. 2. 1. 1
I n hi biti o n of I n d olea mi ne 2, 3– Di o x y ge nase as a Tar get f or Ca ncer ............3 9
3. 2. 1. 2
C o m bi nati o n I m m u n ot hera p y .......................................................................4 1
3. 2. 1. 3
C o m plete d Cli nical St u dies ..................................................................................4 1
3 . 2. 2
O n g oi n g Cli nical St u dies .....................................................................................4 1
3. 2. 3
I nf or mati o n o n Ot her St u d y-Relate d T hera p y .....................................................4 4
3. 2. 4
Be nefit/ Ris k Assess me nt .........................................................................................4 5
3. 3
Be nefit/ Ris k of Pe m br oliz u ma b ...........................................................................4 5
3. 3. 1
4 5
Be nefit/ Ris k of Pe m br oliz u ma b pl us E paca d ostat ...............................................4 5
3. 3. 3
Be nefit/ Ris k of E X T R E M E .................................................................................4 6
3. 3. 4
4.
O bjecti ves/ H y p ot heses a n d E n d p oi nts .....................................................................4 6
5.
St u d y Desi g n ...............................................................................................................4 7
O ver all Desi g n .........................................................................................................4 7
5. 1
Data M o nit ori n g C o m mittee ................................................................................4 8
5. 1. 1
St u d y  Dia gra m .....................................................................................................4 9
5. 1. 2
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
N u m ber of P artici p a nts ..........................................................................................4 9
5. 2
Be gi n ni n g a n d E n d of St u d y Defi niti o n ................................................................4 9
5. 3
Cli nical Criteria f or Earl y St u d y Ter mi nati o n .....................................................5 0
5. 3. 1
Scie ntific R ati o n ale f or St u d y Desi g n ....................................................................5 0
5. 4
Rati o nale f or E n d p oi nts .......................................................................................5 2
5. 4. 1
Efficac y  E n d p oi nts........................................................................................5 2
5. 4. 1. 1
R E CI S T 1. 1 ............................................................................................5 2
5. 4. 1. 1. 1
M o difie d R E CI S T f or I mm u ne -base d T hera pe utics (i R E CI S T) ...........5 2
5. 4. 1. 1. 2
Safet y  E n d p oi nts...........................................................................................5 3
5. 4. 1. 2
5 3
5 4
Patie nt Re p orte d O utc o mes ...........................................................................5 4
5. 4. 1. 5
E O R T C Q L Q- C 3 0 a n d E O R T C Q L Q- H & N 3 5 .....................................5 4
5. 4. 1. 5. 1
E ur o Q o L -5 D ..........................................................................................5 5
5. 4. 1. 5. 2
5 5
Rati o nale f or t he Use of C o m parat or ...................................................................5 7
5. 4. 2
J ustific ati o n f or D ose ..............................................................................................5 7
5. 5
Rati o nale f or Pe m br oliz u ma b D osi n g Re gi me ns .................................................5 7
5. 5. 1
5 8
6.
St u d y P o p ul ati o n ........................................................................................................5 9
I ncl usi o n Criteri a ....................................................................................................5 9
6. 1
E xcl usi o n Criteri a ...................................................................................................6 1
6. 2
Lifest yle Restricti o ns............................................................................................... 6 5
6. 3
Meals a n d Dietar y Restricti o ns ............................................................................6 5
6. 3. 1
C o ntrace pti o n .......................................................................................................6 5
6. 3. 2
Pre g na nc y .............................................................................................................6 5
6. 3. 3
Use i n N ursi n g W o me n ........................................................................................6 5
6. 3. 4
Pe m br oliz u ma b .............................................................................................6 6
6. 3. 4. 1
E paca d ostat ...................................................................................................6 6
6. 3. 4. 2
Cet u xi ma b .....................................................................................................6 6
6. 3. 4. 3
Cis plati n ........................................................................................................6 6
6. 3. 4. 4
Car b o plati n ....................................................................................................6 6
6. 3. 4. 5
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
5- fl u or o uracil ................................................................................................6 6
6. 3. 4. 6
Scree n F ail ures ........................................................................................................6 6
6. 4
P artici p a nt Re pl ace me nt Str ate g y .........................................................................6 6
6. 5
7.
Tre at me nts ..................................................................................................................6 6
Tre at me nts A d mi nistere d .......................................................................................6 7
7. 1
D ose M o dific ati o n ...................................................................................................6 7
7. 2
D ose M o dificati o n f or Pe m br oliz u ma b a n d E paca d ostat ....................................6 9
7. 2. 1
D ose m o dificati o n a n d t o xicit y  ma na ge me nt of i nf usi o n-reacti o ns 
7. 2. 1. 1
relate d t o pe m br oliz u ma b .............................................................................7 8
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 9
7. 2. 1. 2
D ose M o dificati o ns f or Cet u xi ma b ......................................................................8 1
7. 2. 2
I nf usi o n Reacti o ns ........................................................................................8 3
7. 2. 2. 1
Der mat ol o gic T o xi cit y ..................................................................................8 3
7. 2. 2. 2
D ose M o dificati o ns f or Cis plati n or Car b o plati n .................................................8 4
7. 2. 3
D ose M o dificati o ns f or 5 -fl u or o uracil .................................................................8 6
7. 2. 4
D ose I nterr u pti o ns U nrelate d t o A d verse E ve nt s.................................................8 8
7. 2. 5
Sec o n d C o urse P hase ...........................................................................................8 8
7. 2. 6
Met h o d of Tre at me nt Assi g n me nt .........................................................................8 9
7. 3
Stratificati o n .........................................................................................................8 9
7. 3. 1
Bli n di n g ....................................................................................................................8 9
7. 4
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y ....................................................8 9
7. 5
D ose Pre parati o n ..................................................................................................8 9
7. 5. 1
Ha n dli n g, St ora ge a n d Acc o u nta bilit y .................................................................9 0
7. 5. 2
Tre at me nt C o m pli a nce ...........................................................................................9 1
7. 6
C o m plia nce of Pe m br oliz u ma b ............................................................................9 1
7. 6. 1
C o m plia nce of E paca d ostat ..................................................................................9 1
7. 6. 2
C o m plia nce of E X T R E M E Re gi me n ...................................................................9 1
7. 6. 3
C o nc o mit a nt T her a p y .............................................................................................9 1
7. 7
Per mitte d Me dicati o ns .........................................................................................9 1
7. 7. 1
Restricte d Me dicati o ns .........................................................................................9 2
7. 7. 2
Pr o hi bite d Me dicati o ns a n d Meas ures .................................................................9 2
7. 7. 3
Resc ue Me dicati o ns & S u p p orti ve Care ..............................................................9 3
7. 7. 4
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
S u p p orti ve Care G ui deli nes f or Pe m br oliz u ma b ..........................................9 3
7. 7. 4. 1
S u p p orti ve Care G ui deli nes f or E paca d ostat ................................................9 4
7. 7. 4. 2
S u p p orti ve Care G ui deli nes f or Cis plati n a n d Car b o plati n ..........................9 4
7. 7. 4. 3
S u p p orti ve Care G ui deli nes f or 5 -fl u or o uracil .............................................9 4
7. 7. 4. 4
S u p p orti ve Care G ui deli nes f or Cet u xi ma b ..................................................9 4
7. 7. 4. 5
Tre at me nt After t he E n d of t he St u d y ..................................................................9 4
7. 8
Cli nic al S u p plies Discl os ure ...................................................................................9 4
7. 9
8.
Disc o nti n u ati o n/ Wit h dr a w al Criteri a ......................................................................9 5
Disc o nti n u ati o n of St u d y Tre at me nt..................................................................... 9 5
8. 1
Wit h dr a w al fr o m t he St u d y
...................................................................................9 6
8. 2
L ost t o F oll o w -u p ....................................................................................................9 6
8. 3
9.
St u d y Assess me nts a n d Pr oce d ures.......................................................................... 9 7
A d mi nistr ati ve a n d Ge ner al Pr oce d ures ..............................................................9 7
9. 1
I nf or me d C o nse nt.................................................................................................9 7
9. 1. 1
Ge neral I nf or me d C o nse nt ............................................................................9 7
9. 1. 1. 1
I ncl usi o n/ E xcl usi o n Criteria ................................................................................9 8
9. 1. 2
Partici pa nt I de ntificati o n Car d .............................................................................9 8
9. 1. 3
Ser ot o ni n S y n dr o me I nf or mati o n Car d ................................................................9 8
9. 1. 4
Me dical Hist or y
...................................................................................................9 8
9. 1. 5
Disease Details ..............................................................................................9 8
9. 1. 5. 1
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w .......................................................9 9
9. 1. 6
Pri or Me dicati o ns ..........................................................................................9 9
9. 1. 6. 1
Pri or O nc ol o gical Treat me nt Details f or Hea d a n d Nec k 
9. 1. 6. 1. 1
Ca ncer ....................................................................................................9 9
C o nc o mita nt Me dicati o ns .............................................................................9 9
9. 1. 6. 2
Assi g n me nt of Scree ni n g N u m ber .......................................................................9 9
9. 1. 7
Assi g n me nt of Treat me nt/ Ra n d o mizati o n N u m ber .............................................9 9
9. 1. 8
Treat me nt A d mi nistrati o n ....................................................................................9 9
9. 1. 9
Ti mi n g of D ose A d mi nistrati o n ..................................................................1 0 0
9. 1. 9. 1
Gr o u p 1 D ose A d mi nistrati o ns ............................................................1 0 0
9. 1. 9. 1. 1
Gr o u p 2 D ose A d mi nistrati o ns ............................................................1 0 1
9. 1. 9. 1. 2
Gr o u p 3 E X T R E M E Re gi me n D ose A d mi nistrati o ns .........................1 0 1
9. 1. 9. 1. 3
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Wit h dra wal/ Disc o nti n uati o n
..............................................................................1 0 1
9. 1. 1 0
Partici pa nt Bli n di n g/ U n bli n di n g ........................................................................1 0 1
9. 1. 1 1
Cali brati o n of E q ui p me nt ...................................................................................1 0 1
9. 1. 1 2
Effic ac y Assess me nts............................................................................................. 1 0 2
9. 2
T u m or I ma gi n g a n d Assess me nt of Disease ......................................................1 0 2
9. 2. 1
I nitial T u m or I ma gi n g.................................................................................1 0 2
9. 2. 1. 1
T u m or I ma gi n g D uri n g t he St u d y ...............................................................1 0 3
9. 2. 1. 2
E n d of Treat me nt a n d F oll o w -u p T u m or I ma gi n g ......................................1 0 3
9. 2. 1. 3
Sec o n d C o urse P hase T u m or I ma gi n g ........................................................1 0 3
9. 2. 1. 4
R E CI S T 1. 1 Assess me nt of Disease ...........................................................1 0 3
9. 2. 1. 5
i R E CIS T Assess me nt of Disease ( Gr o u p 1 a n d 2) .....................................1 0 4
9. 2. 1. 6
Patie nt Re p orte d O utc o mes ................................................................................1 0 7
9. 2. 2
Healt h Care Res o urce Utilizati o n ......................................................................1 0 8
9. 2. 3
A d verse E ve nts, Seri o us A d verse E ve nts a n d Ot her Re p ort a ble S afet y 
9. 3
E ve nts .....................................................................................................................1 0 8
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E, S A E a n d Ot her 
9. 3. 1
Re p orta ble Safet y E ve nt I nf or mati o n ................................................................1 0 8
Met h o d of Detecti n g A E, S A E a n d Ot her Re p orta ble Safet y E ve nts ................1 1 0
9. 3. 2
F oll o w -u p of A E, S A E a n d Ot her Re p orta ble Safet y  E ve nt I nf or mati o n..........1 1 0
9. 3. 3
Re g ulat or y  Re p orti n g Re q uire me nts f or S A E ...................................................1 1 0
9. 3. 4
Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
9. 3. 5
Q ualif yi n g as A Es or S A Es ................................................................................1 1 1
Pre g na nc y  a n d E x p os ure D uri n g Breastfee di n g ................................................1 1 1
9. 3. 6
E ve nts of Cli nical I nterest ( E CI )........................................................................1 1 1
9. 3. 7
Tre at me nt of O ver d ose .........................................................................................1 1 2
9. 4
S afet y ......................................................................................................................1 1 3
9. 5
P h y sical E xa mi nati o ns .......................................................................................1 1 3
9. 5. 1
F ull P h y sical E xa m .....................................................................................1 1 3
9. 5. 1. 1
Directe d P h ys ical E xa m..............................................................................1 1 3
9. 5. 1. 2
Vital Si g ns.......................................................................................................... 1 1 3
9. 5. 2
Electr ocar di o gra ms ............................................................................................1 1 3
9. 5. 3
Cli nical Safet y  La b orat or y Assess me nts............................................................1 1 4
9. 5. 4
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
La b orat or y  Safety E val uati o ns ( He mat ol o g y , C he mistr y, 
9. 5. 4. 1
C oa g ulati o n, a n d Uri nal ysis) ......................................................................1 1 5
Pre g na nc y  Test............................................................................................1 1 5
9. 5. 4. 2
He patitis B a n d C Ser ol o g y .........................................................................1 1 5
9. 5. 4. 3
Perf or ma nce Assess me nts ..................................................................................1 1 5
9. 5. 5
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Scale.........................1 1 5
9. 5. 5. 1
1 1 5
1 1 5
1 1 6
1 1 6
1 1 6
1 1 6
1 1 7
1 1 7
Visit Re q uire me nts ................................................................................................1 1 7
9. 9
Scree ni n g ............................................................................................................1 1 7
9. 9. 1
Treat me nt P hase .................................................................................................1 1 8
9. 9. 2
E n d of Treat me nt ...............................................................................................1 1 9
9. 9. 3
P ost -treat me nt Visits..........................................................................................1 1 9
9. 9. 4
Safet y  F oll o w-u p Visit ................................................................................1 1 9
9. 9. 4. 1
F oll o w -u p Visits ..........................................................................................1 1 9
9. 9. 4. 2
S ur vi val F oll o w -u p .....................................................................................1 2 0
9. 9. 4. 3
Sec o n d C o urse P hase .........................................................................................1 2 0
9. 9. 5
U nsc he d ule d Visits ............................................................................................ 1 2 0
9. 9. 6
S ur vi val Stat us ...................................................................................................1 2 0
9. 9. 7
1 0.
St atistic al A n al ysis Pl a n ..........................................................................................1 2 0
St atistic al A n al ysis Pl a n S u m m ar y...................................................................... 1 2 1
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 2 1
1 0. 2
H y p ot heses/ Esti m ati o n ......................................................................................... 1 2 2
1 0. 3
A n al ysis E n d p oi nts ................................................................................................1 2 2
1 0. 4
Efficac y  E n d p oi nt ..............................................................................................1 2 2
1 0. 4. 1
Safet y  E n d p oi nts................................................................................................1 2 2
1 0. 4. 2
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A n al ysis P o p ul ati o ns .............................................................................................1 2 2
1 0. 5
Efficac y  A nalys is P o p ulati o n.............................................................................1 2 2
1 0. 5. 1
Safet y A nal ys is P o p ulati o n ................................................................................1 2 2
1 0. 5. 2
St atistic al Met h o ds ................................................................................................1 2 3
1 0. 6
Statistical Met h o ds f or Efficac y  A nalys es .........................................................1 2 3
1 0. 6. 1
Statistical Met h o ds f or Safet y A nal ys es ............................................................1 2 3
1 0. 6. 2
S u m maries of Baseli ne C haracteristics a n d De m o gra p hics ...............................1 2 4
1 0. 6. 3
I nteri m A n al ysis ....................................................................................................1 2 4
1 0. 7
M ulti plicit y
............................................................................................................1 2 4
1 0. 8
S a m ple Size a n d P o wer C alc ul ati o ns ..................................................................1 2 4
1 0. 9
S u b gr o u p A n al yses ................................................................................................1 2 5
1 0. 1 0
C o m pli a nce ( Me dic ati o n A d here nce) ..................................................................1 2 5
1 0. 1 1
E xte nt of E x p os ure ................................................................................................1 2 5
1 0. 1 2
1 1.
Refere nces .................................................................................................................1 2 5
1 2.
A p pe n dices ................................................................................................................1 3 3
A p pe n di x 1: A b bre vi ati o ns a n d Tr a de m ar ks .....................................................1 3 3
1 2. 1
A p pe n di x 2: Cli nic al L a b or at or y Tests ...............................................................1 3 7
1 2. 2
A p pe n di x 3: St u d y G o ver n a nce C o nsi der ati o ns ................................................1 3 9
1 2. 3
Merc k C o de of C o n d uct f or Cli nical Trials
...................................................................1 3 9
Fi na ncial Discl os ure .......................................................................................................1 4 1
Data Pr otecti o n ...............................................................................................................1 4 1
C o nfi de ntialit y  of Data ..................................................................................................1 4 1
C o nfi de ntialit y  of Partici pa nt Rec or ds...........................................................................1 4 1
C o nfi de ntialit y  of I R B/I E C Inf or mati o n ........................................................................1 4 2
C o m mittees Str uct ure .....................................................................................................1 4 2
Scie ntific A d vis or y  C o m mittee..................................................................................1 4 2
Trial Steeri n g C o m mittee ...........................................................................................1 4 2
J oi nt E xec uti ve O versi g ht C o m mittee .......................................................................1 4 2
Data M o nit ori n g C o m mittee ......................................................................................1 4 2
P u blicati o n P olic y ......................................................................................................1 4 3
C o m plia nce wit h Trial Re gistrati o n a n d Res ults P osti n g Re q uire me nts .......................1 4 3
C o m plia nce wit h La w, A u dit a n d De bar me nt ...............................................................1 4 3
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
2 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Data Q ualit y Ass ura nce .................................................................................................1 4 4
S o urce D oc u me nts .........................................................................................................1 4 5
St u d y  a n d Site Cl os ure...................................................................................................1 4 5
A p pe n di x 4: A d verse E ve nts: Defi ni ti o ns a n d Pr oce d ures f or 
1 2. 4
Rec or di n g, E v al u ati n g, F oll o w -u p, a n d Re p orti n g ............................................1 4 6
Defi niti o n of A E ............................................................................................................1 4 6
Defi niti o n of S A E ..........................................................................................................1 4 7
Rec or di n g A E a n d S A E .................................................................................................1 4 8
Re p orti n g of A E, S A E, a n d Ot her Re p orta ble Safet y  E ve nts t o M S D ..........................1 5 2
A p pe n di x 5: C o ntr ace pti ve G ui d a nce a n d Pre g n a nc y Testi n g .........................1 5 3
1 2. 5
C o ntrace pti o n Re q uire me nts ..........................................................................................1 5 3
Pre g na nc y  Testi n g..........................................................................................................1 5 6
A p pe n di x 6 : E C O G Perf or m a nce St at us Sc ale ..................................................1 5 7
1 2. 6
A p pe n di x 7: Pr o hi bite d M o n o a mi ne O xi d ase ( M A O) I n hi bit ors a n d 
1 2. 7
Dr u gs Ass oci ate d wit h Si g nific a nt M o n o a mi ne O xi d ase I n hi bit o r y 
Acti vit y ...................................................................................................................1 5 8
A p pe n di x 8: Descri pti o n of t he i R E CI S T Pr ocess f or Assess me nt of 
1 2. 8
Dise ase Pr o gressi o n ...............................................................................................1 5 9
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
LI S T O F FI G U R E S
          
Fi g ure 1
St u d y  Desi g n.........................................................................................................4 9
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 a n d 2 Partici pa nts 
after First Ra di ol o gic E vi de nce of Disease Pr o gressi o n Assesse d b y  t he 
I n vesti gat or .........................................................................................................1 0 7
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
1.
S y n o psis
Pr ot oc ol Title:  
A P h ase 3 R a n d o mize d, O pe n- L a bel Cli nic al St u d y t o E v al u ate t he Effic ac y a n d 
S afet y of Pe m br oliz u m a b pl us E p ac a d ost at, Pe m br oliz u m a b M o n ot her a p y, a n d t he 
E X T R E M E Re gi me n as First li ne Tre at me nt f or Rec urre nt or Met ast atic He a d a n d 
Nec k S q u a m o us Cell C arci n o m a ( K E Y N O T E- 6 6 9/ E C H O -3 0 4)
S h ort Title: 
Pe m br oliz u ma b pl us epaca d ostat , pe m br oliz u ma b m o n ot hera p y , a n d t he E X T R E M E 
re gi me n as first li ne treat me nt f or R/ M H N S C C ( K E Y N O T E - 6 6 9/ E C H O- 3 0 4)
O bjecti ves/ H y p ot hese s a n d E n d p oi nts:
All o bjecti ves a p pl y  t o all ra n d o mize d partici pa nts wit h rec urre nt or metastatic ( R/ M) 
hea d a n d nec k s q ua m o us cell carci n o ma ( H N S C C) . 
N O T E: As of A me n d me nt 0 4, t he pri m ar y e n d p oi nt of t he st u d y will be o bjecti ve 
res p o nse r ate ( O R R) b ase d o n 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. A sec o n d ar y e n d p oi nt will o nl y 
e x a mi ne t he s afet y a n d t oler a bilit y of p artici p a nts tre ate d wit h pe m br oliz u m a b pl us 
e p ac a d ost at, pe m br oliz u m a b m o n ot her a p y, a n d t he E X T R E M E re gi me n 
(cet u xi m a b + pl ati n u m [cis pl ati n or c ar b o pl ati n] + 5-fl u or o ur acil). All ot her 
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 
i m a gi n g assess me nt at Wee k 9.  T his secti o n h as bee n a me n de d acc or di n gl y.
O bjecti ve/ H y p ot hesis
E n d p oi nt
Pri m ar y
O bjecti ve: T o esti mate t he o bjecti ve 
res p o nse rate ( O R R) of 
pe m br oliz u ma b + e paca d ostat , 
pe m br oliz u ma b m o n ot hera p y, a n d
t he E X T R E M E re gi me n base d o n
R E CI S T 1. 1 b y i n vesti gat or 
deter mi nati o n.

O R R is defi ne d as t he pr o p orti o n of 
partici pa nts i n t he a nalys is p o p ulati o n 
w h o ha ve a best res p o nse of c o m plete
res p o nse (C R ) or partial res p o nse ( P R ).
Sec o n d ar y

O bjecti ve: T o e val uate t he safet y 
a n d t olera bilit y of t he 3 treat me nt 
gr o u ps.

A d verse e ve nts ( A Es)

S t u d y treat me nt disc o nti n uati o ns d ue t o 
A Es .
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
O ver all Desi g n:
St u d y P hase
P hase 3
Cli nical I n dicati o n
T he treat me nt of partici pa nts wit h ( R/ M) H N S C C .
P o p ulati o n
Partici pa nts wit h R/ M H N S C C i n t he first li ne setti n g.
St u d y T y pe
I nter ve nti o nal
T y pe of Desi g n
M ulti -site, ra n d o mize d a n d o pe n-la bel
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 bel
Esti mate d D urati o n 
of Trial
T he trial is esti mated t o re q uire a p pr o xi matel y 4 1 m o nt hs
fr o m t he ti me t he first partici pa nt si g ns t he i nf or me d 
c o nse nt u ntil t he last partici pa nt’s last st u d y -relate d 
p h o ne call or visit.
N u m ber of P artici p a nt s:
Ori gi nall y, a p pr o xi matel y 6 2 5 partici pa nts were t o be ra n d o mize d i n t his st u d y , b ut as
of A me n d me nt 0 4, o n 0 2 -M A Y - 2 0 1 8, e nr oll me nt i n t he st u d y was st o p pe d. B y t he ti me 
t he strate gic decisi o n was ma de t o st o p e nr oll me nt, 8 9 partici pa nts were ra n d o mize d i n 
t his st u d y.
Tre at me nt Gr o u ps a n d D ur ati o n :
Treat me nt Gr o u ps
Partici pa nts will be ra n d o mize d i n a 2: 1: 2 rati o i n 
3 treat me nt gr o u ps:
Gr o u p 1:
P e m br oliz u ma b 2 0 0 m g I V i nf usi o n e ver y 3 wee ks 
(Q 3 W ) < 3 5 c ycles; A N D
E paca d ostat 1 0 0 m g P O t wice daily ( BI D ) < 3 5 c ycles.
Gr o u p 2 :
P e m br oliz u ma b 2 0 0 m g I V i nf usi o n Q 3 W ≤3 5 c ycles.
Gr o u p 3: ( E X T R E M E re gi me n):
C et u xi ma b 4 0 0 m g/ m 2 I V i nf usi o n C y cle 1 Da y 1; 
f oll o we d by cet u xi ma b 2 5 0 m g/ m 2 I V i nf usi o n e ver y 
wee k ( Q W ) u ntil disease pr o gres si o n or u nacce pta ble 
t o xicit y; A N D
C is plati n 1 0 0 m g/ m 2 I V i nf usi o n O R Car b o plati n area 
u n der t he c ur ve 5 ( A U C 5) I V i nf usi o n Q 3 W < 6 c y cles; 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
A N D
5-fl u or o uracil ( 5-F U) 1 0 0 0 m g/ m 2/ da y c onti n u o us I V 
i nf usi o n o ver Da y s 1 t o 4 Q 3 W < 6 c ycles.
As of A me n d me nt 0 4 , after t he partici pa nt c o m pletes 
Wee k 9 i ma gi n g, partici pa nts ca n c h o ose t o disc o nti n ue 
fr o m t he st u d y or c o nti n ue st u d y treat me nt as per pr ot oc ol
after partici pa nt disc ussi o n wit h t he in vesti gat or a n d if 
t he y are recei vi n g cli nical be nefits.
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 inf or me d co nse nt for m 
(IC F) t hr o u g h t he fi nal pr ot oc ol -s pecifie d c o ntact.  
After a S cree ni n g P hase of 2 8 d a y s, eac h partici pa nt will 
be assi g ne d t o recei ve st u d y treat me nt u ntil disease 
pr o gressi o n , u nacce pta ble A Es, i nterc urre nt ill ness t hat 
pre ve nts f urt her a d mi nistrati o n of treat me nt, 
i n vesti gat or’s decisi o n t o wit h dra w t he partici pa nt, 
n o nc o m plia nce wit h st u d y treat me nt or pr oce d ure 
re q uire me nts or a d mi nistrati ve reas o ns re q uiri n g 
cessati o n of treat me nt, or u ntil t he partici pa nt has 
recei ve d 3 5 a d mi nistrati o ns of pe m br oliz u ma b pl us 
e paca d ostat or pe m br oliz u ma b m o n ot hera p y
(a p pr o xi matel y 2 ye ars).  P artici pa nt s w h o st o p st u d y 
treat me nt after recei vi n g 3 5 a d mi nistrati o ns of 
pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b
m o n ot hera p y, f or reas o ns ot her t ha n disease pr o gressi o n 
or i nt olera bilit y , or partici pa nt s w h o attai n a C R a n d st o p 
st u d y treat me nt ma y be eli gi ble f or u p t o 1 7 a d diti o nal 
c ycles (a p pr o xi matel y 1 ye ar) of pe m br oliz u ma b pl us 
e paca d ostat or pe m br oliz u ma b m o n ot hera p y u p o n 
e x perie nci n g disease pr o gressi o n.  
After t he e n d of treat me nt ( E O T), eac h partici pa nt will 
pr ocee d t o safet y f oll o w -u p a n d will be f oll o we d f or t he 
occ urre nce of A Es a n d s p o nta ne o usl y  re p orte d pre g na nc y 
as descri be d u n der Secti o n 9. 3. 3.
A list of a b bre viati o ns use d i n t his d oc u me nt ca n be f o u n d i n A p pe n di x 1. St u d y  g o ver na nce 
c o nsi derati o ns are o utli ne d i n A p pe n di x 3.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
2 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
St u d y Peri o d
Scree n
Tre at me nt ( 3 -w e e k c ycles)
E O T
P ost -tre at me nt
N otes
Assess me nts/ pr oce d ures are t o be 
perf or me d o n Da y 1 a n d pri or t o 
t he first d ose of treat me nt f or eac h 
c ycle u nless ot her 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 w ill pr ocee d directl y t o 
E O T a n d S afet y F oll o w -u p.
Tre at me nt C ycle/ Title
Scree n
( V 1)
1 
2 
3 
4
C ycle 5 t o 
C ycle 3 5
Disc o n
S afet y F U
Sc he d ule d W i n d o w 
( D a ys):
-2 8 
t o - 1
+ 5
± 3 
± 3 
± 3 
± 3
At tre at me nt disc o n
3 0 d a ys after 
l ast d ose 
( + 7 d a ys)
He mat ol o g y
X
X
X
X
X
X
X
Uri nal ysis a n d t h yr oi d pa nel 
s h o ul d be re peate d e ver y 2 c ycles .
U nres ol ve d a b n or mal la bs d uri n g 
t he Safet y F oll o w - u p Visit t hat are 
T R A Es s h o ul d be f oll o we d u p as
per sites’ practices. . 
Uri nal ysis
X
X
X
X
X
X
C he mistr y
X
X
X
X
X
X
X
T 3 (t otal or free), F T 4 
a n d T S H
X
X
X
X
X
X
He patitis B a n d C 
Ser ol o g y
X
Testi n g ma y be perf or me d u p t o 4 0
da y s pri or t o ra n d o mizati o n if 
perf or me d as part of t he sta n dar d 
d oc u me nte d cli nical acti vities.
A E/ S A E Re vie w
X
X
X
X
X
X
X
X
Re p ort n o n -seri o us A Es occ urri n g 
wit hi n 3 0 da ys after t he last d ose 
of st u d y treat me nt. Re p ort S A Es 
occ urri n g wit hi n 9 0 da ys after t he 
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 ntica ncer 
t hera p y is i nitiate d, w hic he ver is 
first.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
3 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
St u d y 
Peri o d
Scree n
Tre at me nt ( 3 -w e e k c ycles)
E O T
P ost -
tre atme nt
N otes
Assess me nts/ pr oce d ures are t o be perf or me d o n 
Da y 1 a n d pri or t o t he first d ose of treat me nt f or 
eac h c ycle u nless ot her wise s pecifie d. 
P artici p a nts w h o disc o nti n ue st u d y 
tre atme nt f or w h ate ver re as o n will pr ocee d 
directl y t o E O T a n d S afet y F oll o w -u p.
Tre at me nt 
C ycle/ Title
Scree n
( V 1)
1
2
3
4
C ycle 5 
O n w ar ds
Disc o n
S afet y F U
Tre at me nt 
D a y
1
8
1 5
1
8
1 5
1
8
1 5
1
8
1 5
1
8
1 5
Sc he d ule d 
Wi n d o w  
( D a ys):
-2 8 t o
- 1
+ 5
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Per St a n d ar d 
of C are
At 
tre atme nt 
disc o n
3 0 d a ys 
after l ast 
d ose + 7
Vital Si g ns
a n d Wei g ht
X
X
X
X
X
X
X
X
X
X
X
X
X
Per St a n d ar d of C are
Vital si g ns t o i ncl u de te m perat ure, p ulse, 
res pirat or y rate a n d bl o o d press ure. Wei g ht is 
o nl y re q uire d o n Da y 1 of e ver y c ycle.
E C O G P S
X
X
X
X
X
Per St a n d ar d of C are
E C O G P S is t o be perf or me d wit hi n 7 da ys of 
ra n d o mizati o n a n d m ust be 0 or 1 o n t he first 
da y of d osi n g .
1 2 -lea d 
E C G ( L ocal)
X 
Per St a n d ar d of C are
E C Gs s h o ul d als o be d o ne w he n cli nicall y 
i n dicate d.
He mat ol o g y
X
X
X
X
X
X
X
X
X
X
X
X
Per St a n d ar d of C are
U nres ol ve d a b n or mal la bs d uri n g t he Safet y 
F oll o w -u p Visit t hat are T R A Es s h o ul d be 
f oll o we d u p as per sites’ practices.
Uri nal ysis 
X
X
X
Per St a n d ar d of C are
C he mistr y
X
X
X
X
X
X
X
X
X
X
X
X
Per St a n d ar d of C are
T 3 (t otal or 
free), F T 4 
a n d T S H
X
X
X
Per St a n d ar d of C are
Pre g na nc y 
Test Ser u m 
or Uri ne 
(W O C B P 
o nl y)
X
W O C B P re q uire ne gati ve test wit hi n 7 2
h o urs 
pri or t o C ycle 1 Da y 1. M o nt hl y (ie, bef ore 
eac h c ycle) pre g na nc y testi n g s h o ul d be 
c o n d ucte d as per l ocal re g ulati o ns w here 
a p plica ble.
C oa g ulati o n
X
A n y partici pa nt recei vi n g a ntic oa g ula nt t hera p y 
s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d 
cl osel y t hr o u g h o ut t he st u d y.
He patitis B 
a n d C 
Ser ol o g y
X
Testi n g ma y be perf or me d u p t o 4 0 da y s pri or 
t o ra n d o mizati o n if perf or me d as part of t he 
sta n dar d d oc u me nte d cli nical acti vities.
A E/ S A E 
Re vie w
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Re p ort n o n -seri o us A Es occ urri n g wit hi n 
3 0 da ys after t he last d ose of st u d y treat me nt.
Re p ort S A Es occ urri n g wit hi n 9 0 da ys after t he 
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 ntica ncer 
t hera p y is i nitiate d, w hic he ver is first.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
3 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
A b bre viati o ns: 5- F U = 5 -fl u or o uracil A E = ad verse e ve nts; C = c ycle; D = da y ; Disc o n = Disc o nti n uati o n Visit; D N A = de o x yri b o n ucleic aci d; E C G = e lectr ocar di o gra ms; E C O G
P S = Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us ; E O R T C Q L Q -C 3 0 = E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life q uesti o n naire
C ore 3 0 ; E O R T C Q L Q-H & N 3 5 = E O R T C Hea d a n d Nec k S pecific Q o L q uesti o n naire; E O T = e n d of treat me nt; e P R O = electr o nic patie nt re p orte d o utc o mes; E Q -5 D = E ur o Q ol 
5 di me nsi o ns q uesti o n naire; F T 4 = f ree t h yr o xi ne; F U = f oll o w -u p;  H N S C C = h ea d a n d nec k s q ua m o us cell carci n o ma; H P V = H u ma n Pa pill o ma Vir us; I E C = I nstit uti o nal 
E t hics C o m mittee; I R B = I nstit uti o nal R e vie w B oar d; P D = disease pr o gressi o n; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors ;
; S A E = s eri o us 
a d verse e ve nts ; S o A = sc he d ule of acti vities; T 3 = t rii o d ot h yr o ni ne; T R A E = treat me nt-relate d A E; T S H = t h yr oi d -sti m ulati n g h or m o ne; Visit = visit; W O C B P
= w o me n of 
chil d beari n g p ote ntial .
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
3 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
St u d y Peri o d
Tre at me nt ( 3-w e e k c ycles)
E O T
P ost -tre at me nt
N otes
Assess me nts/ pr oce d ures are t o be perf or me d o n Da y 1 
a n d pri or t o t he first d ose of treat me nt f or eac h c ycle 
u nless ot her wise s pecifie d.
Tre at me nt C ycle/ Title
1
C ycle 2 t o 1 7
Disc o n
S afet y F U
Sc he d ule d Wi n d o w ( D a ys):
+ 3
+ 3
At 2 n d C o urse 
Tre at me nt Disc o n
3 0 d a ys after l ast 
d ose
( + 7 d a ys)
E C O G P S 
X
X
X
X
E C O G P S is t o be perf or me d wit hi n 7 da ys of 
ra n d o mizati o n a n d m ust be 0 or 1 o n t he first da y of 
d osi n g .
1 2 -lea d E C G ( L ocal) 
X
X
E C Gs s h o ul d als o be d o ne w he n cli nicall y i n dicate d.
Pre g na nc y Test Ser u m or Uri ne 
(W O C B P o nl y)
X
W O C B P re q uire ne gati ve test wit hi n 7 2
h o urs pri or t o 
C y cle 1 Da y 1. M o nt hl y (ie, bef ore eac h c ycle)
pre g na nc y testi n g s h o ul d be c o n d ucte d as per l ocal 
re g ulati o ns w here a p plica ble.
C oa g ulati o n
X
A n y partici pa nt recei vi n g a ntic oa g ula nt t hera p y s h o ul d 
ha ve c oa g ulati o n fact ors m o nit ore d cl osel y t hr o u g h o ut 
t he st u d y.
He mat ol o g y
X
X
X
X
Uri nal ysis a n d t h yr oi d pa nel s h o ul d be re peate d e ver y 
2 c ycles. U nres ol ve d a b n or mal la bs d uri n g t he Safet y 
F oll o w - u p Visit t hat are T R A Es s h o ul d be f oll o we d
u ntil res ol uti o n as per sites’ practices
Uri nal ysis
X
X
X
X
C he mistr y
X
X
X
X
T 3 (t otal or free), F T 4 a n d T S H
X
X
X
X
A E/ S A E re vie w
X
X
X
X
Re p ort n o n -seri o us A Es occ urri n g wit hi n 3 0 da ys after 
t he last d ose of st u d y treat me nt. Re p ort S A Es 
occ urri n g wit hi n 9 0 da ys after t he 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 ntica ncer t hera p y is i nitiate d, 
w hic he ver is first.
A b bre viati o ns: A E = a d verse e ve nts; C = c ycle; D = d a y ; Disc o n = Disc o nti n uati o n Visit; E C G = e lectr ocar di o gra ms; E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p
perf or ma nce stat us ; E O T = e n d of treat me nt ; F T 4 = f ree t h yr o xi ne; F U = f oll o w -u p; R E CI S T = Res p o nse E val uati o n Criteria in S oli d T u m ors ; S A E = s eri o us a d verse e ve nts ;
T 3 = t rii o d ot h yr o ni ne; T R A E = treat me nt-relate d A E; T S H = t h yr oi d -sti m ulati n g h or m o ne; W O C B P
= w o m e n of chil d beari n g p ote ntial .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
3.
I ntr o d ucti o n
T he efficac y  a n d safety o f co m bi nati o n t hera p y of pe m br oliz u ma b pl us e paca d ostat , 
pe m br oliz u ma b m o n ot hera p y, a n d E X T R E M E re gi me n is bei n g i n vesti gate d as a first li ne 
treat me nt f or partici pa nts wit h rec urre nt or metastatic ( R/ M) hea d a n d nec k s q ua m o us cell 
ca ncers ( H N S C C) i n t his ra n d o mize d, o pe n -la bel, P hase 3 st u d y.
St u d y R ati o n ale 
3. 1
C o m bi ni n g i m m u n ot hera pies wit h differi n g mec ha nis ms of acti o n has t he p ote ntial t o f urt her 
e n ha nce t he ir cli nical be nefits c o m pare d wit h usi n g si n gle a ge nt i m m u n ot hera py.
Preli mi nar y  data as of 2 7 -Fe b -2 0 1 7 data c ut off fr o m K E Y N O T E -0 3 7 /E C H O -2 0 2 , s u g geste d
a 3 9 % o bjecti ve res p o nse rate ( O R R) i n 3 1 partici pa nts wit h H N S C C w h o recei ve d 1 t o 
2 pri or li nes of t hera p y w he n treate d wit h pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat
[ Ha mi d, O., et al 2 0 1 7]. T his O R R c o m pares fa v ora bl y t o t he O R R fr o m pe m br oliz u ma b 
m o n ot hera p y ( O R R of 1 6 %) (see Secti o n 5. 4 f or details).  Gi ve n t he c o m para bilit y i n O R R 
of t he c o m bi nati o n of pe m br oliz u ma b a n d e paca d ostat (i n pre vi o usl y treate d H N S C C 
partici pa nts) wit h t he E X T R E M E re gi me n (i n first li ne H N S C C partici pa nts), t he pr o mise of 
m ore d ura ble res p o nses wit h i m m u n ot hera p y, a n d a fa v ora ble o verall t olera bilit y  pr ofile,
f urt her i n vesti gati o n of t he c o m bi nati o n i n a lar ger st u d y t o c o m pare efficac y, safety, a n d 
t olera bilit y wit h sta n dar d of care ( S o C) f or partici pa nt s wit h R/ M H N S C C i n t he first li ne 
setti n g is warra nte d.
B ac k gr o u n d
3. 2
Pe m br oliz u ma b (M K -3 4 7 5; tra de na me K E Y T R U D A® ) is a p ote nt h u ma nize d 
i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y ( m A b) wit h hi g h s pecificit y of bi n di n g t o 
t he pr o gra m me d cell deat h 1 ( P D -1) rece pt or, t h us i n hi biti n g its i nteracti o n wit h pr o gra m me d 
cell deat h li ga n d 1 ( P D -L 1) a n d pr o gra m me d cell deat h li ga n d 2 ( P D -L 2).  Pe m br oliz u ma b
has a n acce pta ble precli nical safet y pr ofile a n d is i n cli nical de vel o p me nt as a n i ntra ve n o us 
(I V) i m m u n ot hera py f or a d va nce d mali g na ncies .  K E Y T R U D A ® is i n dicate d f or t he 
treat me nt of patie nts acr oss a n u m ber of i n dicati o ns .   Accelerate d a p pr o val was recei ve d f or 
patie nts wit h R/ M H N S C C wit h disease pr o gressi o n o n or after plati n u m -c o ntai ni n g 
c he m ot hera p y.  F or m ore details o n s pecific i n dicati o ns refer t o t he pe m br oliz u ma b
I n vesti gat or B r oc h ure (I B) [IB E diti o n 1 5 2 0 1 7] .
E paca d ostat is a n o vel, p ote nt, a n d selecti ve i n hi bit or of t he i n d olea mi ne 2, 3 di o x y ge n ase 1 
(I D O 1) e nz yme 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 ( D Cs).  Beca use I D O 1 
cata b olis m of tr y pt o p ha n i n hi bits T-cell– me diate d i m m u ne res p o nses a n d I D O 1 e x pressi o n 
has bee n s h o w n t o be ele vate d i n ma n y h u ma n ca ncers, I D O 1 i n hi biti o n ma y rest ore a n
effecti ve a ntit u m or i m m u ne res p o nse a n d ma y pr o vi de a met h o d t o treat mali g na nt diseases 
eit her al o ne or i n c o m bi nati o n wit h c he m ot hera pe utics a n d/ or i m m u n ot hera p y -base d 
strate gies.  Pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat is i n cli nical de vel o p me nt f or 
se veral a d va nce d mali g na ncies.  F or m ore details o n s pecific i n dicati o ns refer t o t he 
epaca d ostat I B [IB E diti o n 1 0, 2 0 1 7 ] .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
3 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d
3. 2. 1
I n hi biti o n of P D-1 as a T ar get f or C a ncer
3. 2. 1. 1
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o ns has bee n k n o w n f or deca des [ Disis, M. L. 2 0 1 0].  Acc u m ulati n g e vi de nce 
s h o ws a c orrelati o n bet wee n t u m or -i nfiltrati n g l y m p h oc ytes i n ca ncer tiss ue a n d fa v ora ble 
pr o g n osis i n vari o us mali g na ncies.  I n partic ular, t he prese nce of C D 8 + T -cells a n d t he rati o 
of C D 8 + effect or T cells/ F o x P 3 + re g ulat or y T cells ( Tre gs) c orrelates wit h i m pr o ve d 
pr o g n osis a n d l o n g -ter m s ur vi val i n ma n y  s oli d t u m ors.  
T he P D -1 rece pt or -li ga n d i nteracti o n is a maj or pat h wa y hijac ke d b y t u m ors t o s u p press 
i m m u ne c o ntr ol.  T he n or mal f u ncti o n of P D-1, e x presse d o n t he cell s urfa ce of acti vate d 
T cells u n der healt h y c o n diti o ns, is t o d o w n-m o d ulate u n wa nte d or e xcessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns. P D -1 (e nc o de d b y t he ge ne P dc d 1) is a n 
i m m u n o gl o b uli n (I g) s u perfa mily me m ber relate d t o cl uster of differe ntiati o n 2 8 ( C D 2 8) a n d 
c yt ot o xic T-l ym p h oc y t e-ass ociate d pr otei n 4 ( C T L A -4) t hat has bee n s h o w n t o ne gati vel y 
re g ulate a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds ( P D-L 1 a n d/ or P D -L 2 ) 
[ Gree n wal d, R. J., et al 2 0 0 5] [ O kaza ki, T., et al 2 0 0 1] .
T he str uct ure of m uri ne P D -1 has bee n res ol ve d [ Z ha n g, X., et al 2 0 0 4].  P D-1 a n d its fa mil y  
me m bers are t y pe I tra ns me m bra ne gl yc o pr otei ns c o ntai ni n g a n I g -varia ble – t ype (I g V t y pe) 
d o mai n res p o nsi ble f or li ga n d bi n di n g a n d a c y t o plas mic tail res p o nsi ble f or t he bi n di n g of 
si g nali n g m olec ules.  T he c yt o plas mic tail of P D-1 c o ntai ns 2 t y r osi ne-base d si g nali n g 
m otifs, a n i m m u n orece pt or t y r osi ne-base d i n hi biti o n m otif, a n d a n i m m u n orece pt or t y r osi ne-
base d s witc h m otif.  F oll o wi n g T -cell sti m ulati o n, P D -1 recr uits t he t y r osi ne p h os p hatases, 
Src h o m ol o g y  re gi o n 2 d o mai n -c o ntai ni n g p h os p hatase ( S H P )-1 a n d S H P -2, t o t he 
i m m u n orece pt or tyr osi ne -base d s witc h m otif wit hi n its c yt o plas mic tail, lea di n g t o t he 
de p h os p h or y lati o n of effect or m olec ules s uc h as C D 3 zeta ( C D 3ζ), pr otei n ki nase C-t heta 
( P K C θ), a n d zeta-c hai n -ass ociate d pr otei n ki nase ( Z A P 7 0), w hic h are i n v ol ve d i n t he C D 3 
T- cell si g nali n g casca de [ O kaza ki, T., et al 2 0 0 1] [ C he m nitz, J. M., et al 2 0 0 4] [ S he p par d, K -
A, et al 2 0 0 4] [ Rile y , J. L. 2 0 0 9].  T he mec ha nis m b y w hic h P D1 d o w n -m o d ulates T cell 
res p o nses is si milar t o, b ut disti nct fr o m, t hat of C T LA- 4, beca use b ot h m olec ules re g ulate a n 
o verla p pi n g set of si g nali n g pr otei ns [ Parr y, R. V., et al 2 0 0 5] [ Fra ncisc o, L. M., et al 2 0 1 0] .  
As a c o nse q ue nce, t he P D -1/ P D -L 1 pat h wa y  is a n attracti ve tar get f or t hera pe utic 
i nter ve nti o n i n m ulti ple t u m or t y pes i ncl u di n g H N S C C.
I n hi biti o n of I n d ole a mi ne 2, 3– Di o x y ge n ase as a T ar get f or C a ncer
3. 2. 1. 2
Rece nt i nterest has f oc use d o n t he r ole of I D O1 as a mec ha nis m of i n d ucti o n of t olera nce t o 
mali g na nc y  [ G o di n-Et hier, J., et al 2 0 1 1] .  ID O 1 is a he me c o ntai ni n g, m o n o meric 
o xi d ore d uctase t hat catal yzes t he de gra dati o n of t he esse ntial a mi n o aci d tr y pt o p ha n t o 
N -f or myl -k y n ure ni ne.  K y n ure ni ne ca n be s u bse q ue ntl y  meta b olize d t hr o u g h a series of 
e nz ymatic ste ps t o nic oti na mi de a de ni ne di n ucle oti de.  I D O 1 is t he first rate li miti n g e nz y me 
i n o ne of t he cata b olic pat h wa ys of tr ypt o p ha n.  I n a n ot her pat h wa y , catal ysis of tr ypt o p ha n 
b y  t he e nz yme tr y pt o p ha n h y dr o x yl ase lea ds t o t he f or mat i o n of ser ot o ni n a n d melat o ni n.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
T he e x pressi o n a n d acti vit y  pr ofiles of I D O 1 are disti nct fr o m t h ose of tr y pt o p ha n 
di o x y ge nase, a n e nz y me pre d o mi na ntl y  e x presse d i n li ver t hat catalyz es t he sa me e nz y m atic 
reacti o n as I D O 1 a n d mai ntai ns pr o per tr ypt o p ha n bala nce i n res p o nse t o dietar y  u pta ke.  I n 
c o ntrast t o tr ypt o p ha n di o x y ge nase, I D O 1 is e x presse d i n a variet y  of tiss ues, wit h 
partic ularl y hi g h le vels f o u n d i n areas of c o ntact wit h p ote ntial s o urces of i m m u ne c halle n ge 
(e g, g ut, res pirat or y tract, place nta, s plee n), c o nsiste nt wit h a r ole f or re g ulati n g tr ypt o p ha n 
meta b olis m i n a l ocal micr oe n vir o n me nt [ Mell or, A. L. 2 0 0 4].  Wit hi n t he i m m u ne s yste m, 
I DO 1 acti vit y  is s pecificall y i n d uce d i n cells s uc h as D Cs a n d macr o p ha ges at l ocalize d sites 
of i nfla m mati o n [ M u n n, D. H. 2 0 0 7].
I DO 1 -dri ve n o xi dati o n of tr y pt o p ha n res ults i n a str o n g i n hi bit or y  effect o n t he de vel o p me nt 
of T -cell– me diate d res p o nses b y  bl oc ki n g T-cell acti vati o n a n d i n d uci n g T -cell a p o pt osis 
[ Mell or, A. L., et al 2 0 0 3].  B ot h t he re d ucti o n i n l ocal tr ypt o p ha n le vels a n d t he pr o d ucti o n 
of tr y pt o p ha n cata b olites t hat are i n hi bit or y  t o cell pr oliferati o n c o ntri b ute t o t he 
i m m u n os u p pressi ve effects [ Fr u me nt o, G., et al 2 0 0 2] s uc h as D C mat urati o n a n d T -cell 
gr o wt h arrest a n d cell deat h [ Mell or, A. L. 1 9 9 9].  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 he n oty pe ( Tre g; [ Fallari n o, F., et al 
2 0 0 6] ).  Beca use 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 w ise 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 g ma y pr o vi de 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.
Wit hi n t he c o nte xt of ca ncer, t here are se veral li nes of e vi de nce t o s u g gest t hat I D O 1 is a ke y 
re g ulat or of t he i m m u n os u p pressi ve mec ha nis ms res p o nsi ble f or t u m or esca pe fr o m i m m u ne 
s ur veilla nce.  Se veral gr o u ps ha ve de m o nstrate d t hat bl oc ka de of I D O 1 acti vit y ca n directly 
i nfl ue nce t he a bilit y of t u m or-beari n g a ni mals t o reject t u m ors [ U ytte n h o ve, C., et al 2 0 0 3] 
[ M uller, A. J., et al 2 0 0 5].  In a d diti o n, st u dies wit h 1 -met h y l-tr ypt o p ha n de m o nstrate t hat 
I DO 1 i n hi biti o n dra mati call y i ncreases t he efficac y of vari o us c he m ot hera pe utic a ge nts (e g, 
plati n u m c o m p o u n ds, ta xa ne deri vati ves, c y cl o p h os p ha mi de) wit h o ut i ncrease d t o xicit y 
[ M uller, A. J., et al 2 0 0 5].  Alt h o u g h t he s pecific mec hanis ms res p o nsi ble f or t his 
p ote ntiati o n re mai n t o be f ull y  el uci date d, t he effects were n ot o bser ve d i n T-cell– deficie nt 
a ni mals, s u g gesti n g t hat t he res ults ma y  be t he c o nse q ue nce of t he disa ble me nt of 
i m m u n os u p pressi ve mec ha nis ms t hat e xist wit hi n t he t um or micr oe n vir o n me nt.
Base d o n st u dies e xa mi ni n g ser u m le vels of tr y pt o p ha n a n d k y n ure ni ne, I D O 1 a p pears t o be 
c hr o nicall y acti vate d i n partici pa nt s wit h ca ncer, a n d I D O 1 acti vati o n c orrelates wit h m ore 
e xte nsi ve disease [ H ua n g, L., et al 2 0 1 0] [ Wei nlic h, G., et al 2 0 0 7] .  ID O 1 has s u bse q ue ntl y 
bee n f o u n d t o be o vere x presse d b y a wi de variet y of h u ma n t u m or cell t y pes, as well as b y 
t he D Cs t hat l ocalize t o t he t u m or-drai ni n g l y m p h n o des [ U ytte n h o ve, C., et al 2 0 0 3] [ M u n n, 
D. H., et al 2 0 0 4] .  Increase d e x pressi o n of I D O 1 i n t u m or cells has bee n s h o w n t o be a n 
i n de pe n de nt pr o g n ostic varia ble f or re d uce d o verall s ur vi val (O S) i n partici pa n ts wit h 
mela n o ma, o varia n, c ol orectal, a n d pa ncreatic ca ncers [ O ka m ot o, A., et al 2 0 0 5] 
[ Bra n dac her, G., et al 2 0 0 6] [In o, K., et al 2 0 0 6] [ Na ka m ura, T., et al 2 0 0 7] [ Wi t kie wicz, A., 
et al 2 0 0 8] .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
C o m bi n ati o n I m m u n ot her a p y
3. 2. 1. 3
Alt h o u g h pe m br oliz u ma b has de m o nstrate d a ntit u m or acti vit y  i n patie nts wit h H N S C C w he n 
a d mi nistere d as m o n ot hera p y, m ulti ple i m m u ne i n hi bit or y mec ha nis ms are prese nt 
c o nc urre ntl y wit hi n t he t u m or micr oe n vir o n me nt, s u g gesti n g t hat c o m bi nati o n t hera pies ma y 
be re q uire d f or o pti mal t hera pe utic effect [ Q ueza da, S. A. 2 0 1 3].  Gi ve n t he e vi de nce 
de m o nstrati n g 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 nsible 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 mali g na ncies i n c o m bi nati o n wit h ot her 
i m m u n ot hera p y-base d strate gies s uc h as i n hi bit ors of t he P D -1/ P D -L 1 a xis. 
C o m plete d Cli nic al St u dies
3. 2. 2
F urt her d etails of ot her c o m plete d cli nical st u dies are pr o vi de d i n t he pe m br oliz u ma b I B [IB 
E diti o n 1 5 2 0 1 7] a n d epaca d ostat I B [IB E diti o n 1 0, 2 0 1 7 ] .
O n g oi n g Cli nic al St u dies
3. 2. 3
O n g oi n g pe m br oliz u ma b cli nical st u dies are bei n g c o n d ucte d i n a d va nce d mela n o ma, n o n -
s mall cell l u n g ca ncer (N S C L C) , a n u m ber of a d va nce d s oli d t u m or i n dicati o ns (i ncl u di n g 
hea d a n d nec k ca ncer) a n d he mat ol o gic mali g na ncies.  F or st u d y details please refer t o t he 
pe m br oliz u ma b I B [IB E diti o n 1 5 2 0 1 7] .
K E Y N O T E -0 1 2 a n d K E Y N O T E -0 5 5 are o n g oi n g cli nical st u dies e val uati n g pe m br oliz u ma b
m o n ot hera p y i n hea d a n d nec k ca ncer t hat ha ve de m o nstrate d cli nical acti vit y  i n partici pa nts
wit h R/ M disease. 
K E Y N O T E -0 1 2 is a P hase 1 b, m ulti -c o h ort st u d y e val uati n g t he acti vit y of pe m br oliz u ma b 
i n vari o us s oli d t u m ors, i ncl u di n g 2 c o h orts of partici pa nts ( C o h ort s B a n d B 2) wit h R/ M
H N S C C.  C o h ort B c o nsiste d of 6 0 partici pa nts wit h P D -L 1  p ositi ve H N S C C w h o recei ve d 
pe m br oliz u ma b 1 0 m g/ k g e ver y 2 wee ks (Q 2 W) .  C o h ort B 2 c o nsiste d of 1 3 2 partici pa nts 
re gar dless of P D-L 1 stat us, w h o recei ve d pe m br oliz u ma b 2 0 0 m g e ver y 3 wee ks (Q 3 W) .  
Res p o nses were see n i n b ot h h u ma n pa pill o ma vir us (H P V )-p ositi ve a n d H P V -ne gati ve 
partici pa nts.  T his was t he first i m m u n ot hera p y de m o nstrati n g cli nicall y mea ni n gf ul 
a nti -t u m or acti vit y i n a hea vil y pretreate d i nc ura ble H N S C C p o p ulati on wit h R/ M disease
[ Me hra, R., et al 2 0 1 6]. 
T he efficac y  a n d safety res ults after l o n g ter m f oll o w -u p base d o n p o ole d data fr o m 
C o h orts B a n d B 2 were prese nte d at A S C O 2 0 1 6.  T he last partici pa nt was e nr olle d o n 0 8 -
O C T -2 0 1 4 a n d 3 2 ( 1 7 %) partici pa nts were still o n treat me nt as of t he 0 1 -S E P -2 0 1 5 data 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
c ut off.  Me dia n a ge was 6 0 ye ars; 8 3 % of partici pa nts were male; 7 0 % ha d Easter n 
C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us (E C O G P S ) 1; a n d 6 1 % ha d recei ve d 
≥2 t hera pies f or rec urre nt disease. T he O R R (c o nfir me d) was 1 7. 7 % ( 9 5 % CI , 
1 2. 6 %- 2 3. 9 %; 7 C Rs, 2 7 P Rs). Me dia n f oll o w -u p d urati o n i n res p o n ders was 1 2. 5 m o nt hs 
(ra n ge, 8. 4-2 4. 4). As of t he data c ut off, me dia n d urati o n of res p o nse ( D O R ) was n ot y et 
reac he d (ra n ge, 1. 8 + t o 2 1. 8 + m o nt hs) a n d res p o nses were o n g oi n g i n 2 2 ( 7 6 %) partici pa nts . 
Res p o nses of ≥6 m o nt hs a n d ≥1 2 m o nt hs were n ote d i n 2 5 partici pa nts a n d 4 partici pa nts , 
res pecti vely. T hirt y- t hree ( 1 7 %) partici pa nts ac hie ve d S D .  T he O R R was 2 1. 9 % ( 9 5 % 
c o nfi de nce i nter val [ CI ], 1 2. 5 %-3 4. 0 %) i n H P V -p ositi ve partici pa nts a n d 1 5. 9 % ( 9 5 % CI ,
1 0. 0 %- 2 3. 4 %) i n H P V -ne gati ve partici pa nts).  T he O R R see n wit h pe m br oliz u ma b treat me nt 
is greater t ha n t he e xisti n g sta n dar d si n gle a ge nt c yt ot o xic c he m ot hera pies s uc h as 
met h otre xate, w hic h i n t he setti n g of sec o n d li ne R/ M disease has a n O R R of a p pr o xi matel y  
4 %.  Me dia n O S was 8. 5 m o nt hs ( 9 5 % CI , 6. 5 m o nt hs - 1 0. 5 m o nt hs ), c o m pare d t o t he 
hist orical O S rate of 6 m o nt hs f or partici pa nts w h o pr o gress f o ll o wi n g first li ne treat me nt.  
T he 6 -m o nt h pr o gressi o n -free s ur vi val (P F S ) rate was 2 4. 9 %. T he perce nta ge of res p o n ders 
w h o were i n res p o nse f or at least 6 m o nt hs was 8 5 % a n d 7 1. 0 % of res p o n ders ha d o n g oi n g 
res p o nses at t he data c ut off .  T hese res ults de mo nstrate t he c o nsiste nt d ura bilit y  of res p o nses 
see n wit h pe m br oliz u ma b treat me nt a n d c o m pare fa v ora bly t o S o C c he m ot hera p y or 
e pi der mal gr o wt h fact or rece pt or ( E G F R) i n hi bit ors, w hic h ha ve re p orte d me dia n D O R of 
4 t o 6 m o nt hs. 
Treat me nt -relate d A Es ( T R A Es) occ urre d i n 1 2 2 ( 6 4 %) partici pa nts , a n d 
2 3 ( 1 2 %) partici pa nts ha d a Gra de 3 t o 4 T R A E. N o partici pa nts die d d ue t o a T R A E. 
Ala ni ne a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase ( A S T) i ncreases were t he 
o nl y  Gra de 3 t o 4 T R A Es o bser ve d i n > 2 partici pa nts .
K E Y N O T E - 0 5 5 is a P hase 2 , n o nra n d o mize d, si n gle c o h ort st u d y of pe m br oliz u ma b 
( 2 0 0 m g Q 3 W) m o n ot hera p y  i n a hea vily pretreate d p o p ulati o n of partici pa nts wit h R/ M
H N S C C w h o ha ve pr o gresse d o n pri or plati n u m a n d cet u xi ma b t hera p y .  Partici pa nt s 
recei ve d pe m br oliz u ma b 2 0 0 m g ( Q 3 W). A m o n g 1 7 1 partici pa nts treate d, 7 5 % recei ve d 2 or 
m ore pri or li nes of t hera p y  f or metastatic disease, 8 2 % were P D-L 1 p ositi ve, a n d 2 2 % were 
H P V p ositi ve. At t he ti me of a nal ys is, 1 0 9 partici pa nts ( 6 4 %) e x perie nce d a T R A E; 
2 6 partici pa nts ( 1 5 %) e x perie nce d a G ra de ≥3 e ve nt [ Ba u ml, J., et al 2 0 1 7].
Se ve n partici pa nts ( 4 %) disc o nti n ue d treat me nt, a n d 1 die d of T R A Es .  O verall res p o nse rate 
was 1 6 % ( 9 5 % CI, 1 1 % t o 2 3 %), wit h a me dia n d urati o n of res p o nse of 8 m o nt hs (ra n ge, 2 + 
t o 1 2 + m o nt hs); 7 5 % of res p o nses were o n g oi n g at t he ti me of a nalys is. Res p o nse rates were 
si milar i n all H P V a n d P D-L 1 s u b gr o u ps. Me dia n P F S was 2. 1 m o nt hs, a n d me dia n O S was 
8 m o nt hs [ Ba u ml, J., et al 2 0 1 7].  T he se res ults prese nte d c o nfir m fi n di n gs fr o m K E Y N O T E-
0 1 2 i n t he R/ M H N S C C p o p ulati o n; pe m br oliz u ma b m o n ot hera p y de m o nstrates c o nsiste nt 
a n d cli nicall y mea ni n gf ul acti vit y of pe m br oliz u ma b 2 0 0 m g Q 3 W wi t h a n acce pta ble safety 
pr ofile i n hea vily pretreate d partici pa nts wit h H N S C C.
K E Y N O T E -0 4 8 is a n o n g oi n g P hase 3, ra n d o mize d, acti ve-c o ntr olle d, m ulti-site, o pe n-la bel 
st u d y of pe m br oliz u ma b, or pe m br oliz u ma b pl us plati n u m pl us 5 -fl u or o uracil (5- F U )
c he m ot hera pies vers us plati n u m pl us 5 -F U pl us cet u xi ma b ( E X T R E M E re gi me n) i n 
partici pa nt s wit h a d va nce d hea d a n d nec k ca ncer.  Ap pr o xi matel y  8 2 5 partici pa nts wit h first 
li ne R/ M H N S C C were pla n ne d t o be ra n d o mize d 1: 1: 1 bet w ee n t he 3 ar ms of t he st u d y t o 
e xa mi ne t he efficac y a n d safety of pe m br oliz u ma b , pe m br oliz u ma b pl us c he m ot hera p y 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
4 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
vers us S o C wit h cet u xi ma b a n d c he m ot hera p y.  Pri or t o ra n d o mizati o n, partici pa nts were
stratifie d b y P D-L 1 t u m or e x pressi o n (str o n gl y p ositi ve vers us n ot str o n gl y p ositi ve), H P V 
stat us ( p ositi ve vers us ne gati ve), a n d E C O G P S ( 0 vs. 1).  T he pri mar y  e n d p oi nts of t he st u d y
are P F S, per R E CIS T 1. 1 as assesse d b y BI C R , a n d O S. E nr oll me nt has bee n c o m plete d.
K E Y N O T E -0 3 7/ E C H O -2 0 2 is a n o n g oi n g P hase 1/ 2 cli nical st u dy e val uati n g pe m br oliz u ma b 
i n c o m bi nati o n wit h e paca d ostat t hat has s h o w n cli nical acti vit y i n vari o us t u m or t ypes 
i ncl u di n g partici pa nts wit h R/ M H N S C C.  I n P hase 1 (a d ose -escalati o n p hase) , e paca d ostat 
d oses of 2 5 m g, 5 0 m g , a n d 1 0 0 m g orall y  (P O ) BI D i n c o m bi nati o n wit h pe m br oliz u ma b 
2 m g/ k g I V Q 3 W a n d e paca d ostat 3 0 0 m g  BI D i n c o m bi nati o n wit h t he fi xe d d ose of 
pe m br oliz u ma b 2 0 0 m g I V Q 3 W were e val uate d.  Safet y e x pa nsi o n c o h orts als o e val uate d 
e paca d ostat d oses of 5 0 m g, 1 0 0 m g , a n d 3 0 0 m g wit h t he fi xe d d ose of pe m br oliz u ma b 
2 0 0 m g I V Q 3 W. 
T he c o m bi nati o n of e paca d ostat 1 0 0 m g BI D a n d pe m br oliz u ma b 2 0 0 m g I V Q 3 W was 
selecte d f or f urt her e val uati o n i n P hase 2 (a n o pe n-la bel, si n gle ar m, c o h ort e x pa nsi o n 
p hase) . A t otal of 3 8 partici pa nts wit h m etastatic H N S C C a n d ≥1 pri or c he m ot hera p y 
re gi me n wit h plati n u m were e nr olle d: 2 partici pa nts i n P hase 1 a n d 3 6 partici pa nts i n 
P hase 2. 
Preli mi nar y  efficac y data as of 2 7 - FE B - 2 0 1 7 data c ut off s u g gest e n ha nce d res p o nse rates as 
c o mpare d t o hist orical O R Rs o bser ve d wit h pe m br oliz u ma b m o n ot hera p y .  A m o n g t he 
3 1 partici pa nts wit h H N S C C w h o recei ve d 1 t o 2 pri or li nes of t hera p y, t he O R R was 3 9 % 
a n d disease c o ntr ol rate ( D C R) was 6 5 %, w hic h i ncl u des 3 c o m plete res p o nses ( C R).  
Res p o nses were o bser ve d re gar dless of H P V ass ociati o n stat us or P D -L 1  stat us. A m o n g 
7 partici pa nts wit h H N S C C w h o recei ve d ≥3 pri or li ne of t hera p y, t he O R R was 1 4 % ( 1 P R) 
wit h D C R of 4 3 % ( 2 S D).  T his c o m pares fa v ora bl y  t o hist orical O R Rs f or ot her a ntit u m or 
a ge nts i n t his hea vil y treate d p o p ulati o n [ Ha mi d, O., et al 2 0 1 7]. Si milar d ura ble res p o nses 
were o bser ve d i n ot her t u m or t y pes e nr olle d i n t his st u d y  ( mela n o ma, re nal cell carci n o ma, 
ur ot helial ca ncer, a n d N S C L C ).  
Safet y  data as of 2 7- Fe b -2 0 1 7 data c ut off , is a vaila ble f or a t otal of 2 9 4 -partici pa nts i n 
vari o us t u m or t y pes t hat ha ve bee n treate d i n t he P hase 2 part of K E Y N O T E - 0 3 7/ E C H O- 2 0 2
wit h e paca d ostat 1 0 0 m g  P O BI D a n d pe m br oliz u ma b 2 0 0 m g I V Q 3 W [ Ha mi d, O., et al 
2 0 1 7] .  Treat me nt-relate d A Es occ urri n g i n > 1 0 % of partici pa nts were fati g ue ( 2 9%) , ras h 
(1 7 %) , na usea ( 1 1 %) , a n d pr urit us ( 1 0 %) .  A t otal of 5 2 partici pa nts ( 1 8 %) ha d Gra de ≥3 
T R A Es a n d t he m ost c o m m o n Gra de ≥3 T R A Es were as y m pt o matic i ncreases i n li pase ( 4 %)
a n d ras h ( 3 %).  Treat me nt-relate d A Es le d t o treat me nt disc o nti n uati o n i n 5 % of partici pa nts . 
T here was 1 treat me nt-relate d deat h d ue t o res pirat or y fail ure (sec o n dar y t o aspirati o n 
p ne u m o nia; p ne u m o nitis c o ul d n ot be r ule d o ut).
E paca d ostat is c urre ntl y bei n g e val uate d i n c o m bi nati o n wit h P D - 1 i n hi bit ors, P D-L 1  
i n hi bit ors, a n d a Ja n us ki nase (J A K) i n hi bit or wit h J A K 1 selecti vit y. F urt her details of 
o n g oi n g cli nical st u dies of t hese c o m bi nati o ns are pr o vi de d i n t he e paca d ostat I B [IB E diti o n 
1 0, 2 0 1 7 ].
A n u nc o m m o n c o ncer n of I D O 1 i n hi biti o n is a n i ncrease i n ser ot o ni n le vels t hat c o ul d 
preci pitate a cl uster of A Es ter me d ser ot o ni n s y n dr o me, w he n a d mi nistere d al o ne or i n 
c o m bi nati o n wit h ot her ser ot o ner gic a ge nts.  T his rare s y n dr o me has bee n ass ociate d wit h 
s o me m o n oa mi ne o xi dase i n hi bit ors ( M A OIs) a n d c o m bi nati o ns of ser ot o ner gic dr u gs 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
[ B o yer E W, S ha n n o n M. 2 0 0 5] .  N o ncli nical data s u g gest t hat ser ot o ni n s y n dr o me is u nli kel y 
f oll o wi n g treat me nt wit h eit her e paca d ostat al o ne or wit h c o m bi nati o n wit h M A OIs s uc h as 
li nez oli d [ Z ha n g, Y., et al 2 0 1 6].  
As of 2 7 - FE B -2 0 1 7 data c ut off , 2 partici pa nts recei vi n g e paca d ostat i n c o m bi nati o n wit h 
P D -1/ P D -L 1 i n hi bit ors acr oss t he e paca d ostat pr o gra m ( 9 5 8 partici pa nts treate d) ha ve 
re p orte d ser ot o ni n s yn dr o me or s y m pt o ms of ser ot o ni n s y n dr o me a n d b ot h were mil d i n t heir 
se verity a n d res ol ve d ( Data o n File).  Alt h o u g h t he i nci de nce of ser ot o ni n s yn dr o me is 
u nc o m m o n, use of M A OIs will be pr o hi bite d d uri n g t he st u d y, a n d all partici pa nts s h o ul d be 
assesse d f or ser ot o ni n s y n dr o me s y m pt o ms at a n a p pr o priate ti mefra me after d osi n g.  
Partici pa nts will be pr o vi de d wit h a leaflet descri bi n g t he si g ns a n d s y m pt o ms of t he 
s yn dr o me al o n g wit h i nstr ucti o ns t o see k i m me diate me dical care if a n y of t hese si g ns or 
s ym pt o ms is o bser v e d.
K E Y N O T E -2 5 2/ E C H O -3 0 1 is a n o n g oi n g P hase 3, ra n d o mize d, d o u ble -bli n d, place b o -
c o ntr olle d st u d y of pe m br oliz u ma b i n c o m bi nati o n wit h e paca d ostat or place b o i n 
partici pa nts wit h u nresecta ble or metastatic mela n o ma.  T he d ual pri mar y  e n d p oi nts of t he 
st u d y are P F S per R E CI S T 1. 1 as assesse d by ce ntral i ma gi n g a n d O S.  T he e D M C 
c o ncl u de d t hat t he st u d y di d n ot meet t he pri mar y o bjecti ve of i m pr o vi n g P F S i n t he 
c o m bi nati o n c o m pare d t o pe m br oliz u ma b m o n ot hera py d uri n g a s ec o n d i nteri m a nal ys is.  
T here were n o ne w safet y c o ncer ns.  T h is st u d y re mai ns o pe n s o t hat partici pa nts still o n 
st u d y will ha ve c o nti n ue d access t o o pe n-la bel pe m br oliz u ma b.
I nf or m ati o n o n Ot her St u d y -Rel ate d T her a p y
3. 2. 4
A variet y of c he m ot hera pies are use d f or patie nts wit h R/ M, first li ne H N S C C.  Earl y  st u dies 
de m o nstrate d s mall s ur vi val be nefits after treat me nt wit h cis plati n or met h otre xate or 
c he m ot hera p y c o m bi nati o ns [ Li ver p o ol Hea d a n d Nec k O nc ol o g y Gr o u p 1 9 9 0].  In t he 1 8 
ye ars f oll o wi n g t his earl y re p ort fr o m T he Li ver p o ol Hea d a n d Nec k O nc ol o g y  Gr o u p, 
cis plati n, car b o plati n, met h otre xate, paclita xel, 5 -F U , a n d t heir vari o us c o m bi nati o ns ha ve 
bee n e val uate d i n se veral P hase 3 st u dies [ F orastiere, A. A., et al 2 0 0 1] [ F orastiere, A. A., et 
al 1 9 9 2] [ Gi bs o n, M. K., et al 2 0 0 5] [Jac o bs, C., et al 1 9 9 2] [ Sc h or na gel, J. H., et al 1 9 9 5] 
[ Sc hrij vers, D., et al 1 9 9 8].  T he c o m bi nati o n of cis plati n a n d 5- F U s h o we d ge nerally better 
res ults t ha n ot her re gi me ns wit h o verall res p o nse rates ra n gi n g fr o m 1 1 t o 3 7 % a n d O S 
ra n gi n g fr o m 2 3 t o 3 6 wee ks.  A d diti o n of cet u xi ma b t o plati n u m - 5-F U de m o nstrate d t he 
first si g nifica nt increase i n O S i n first li ne hea d a n d nec k ca ncer i n t he E X T R E M E st u d y
[ Ver m or ke n, J. B., et al 2 0 0 8].  O verall s ur vi val was i ncrease d fr o m 7. 4 m o nt hs f or 
plati n u m - 5-F U t o 1 0. 1 m o nt hs wit h t he plati n u m/ 5- F U /cet u xi ma b re gi me n.  In t he
E X T R E M E gr o u p , t he c orres p o n di n g O R R i ncrease d fr o m 2 0 t o 3 6 % a n d t he P F S i ncrease d 
fr o m 3. 3 t o 5. 6 m o nt hs .  H o we ver, t he E X T R E M E re gi me n is ass ociate d wit h a n 8 2 % 
fre q ue nc y of Gra de 3 or 4 t o xicities.  
Si nce R/ M first li ne H N S C C patie nts ha ve s o me w hat heter o ge ne o us c haracteristics, Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k ( N C C N) g ui deli nes ge nerall y hi g hli g ht t he i m p orta nce of 
c o nsi deri n g i n di vi d ualize d s yste mic t hera pies base d o n patie nt c haracteristics, gi ve n t he 
t o xicit y of t he EX T R E M E re gi me n.  N C C N g ui deli nes offer c o nsi derati o n of t he use of 
alter nati ve c o m bi nati o n re gi me ns i ncl u di n g plati n u m pl us ta xa ne, cis plati n pl us cet u xi ma b 
a n d cis plati n pl us 5- F U , or t he use of t hese a ge nts as m o n ot hera pies.  Paclita xel or d oceta xel -
base d re gi me ns are use d b y  ma ny cli nicia ns, b ut ta xa ne -c o ntai ni n g re gi me ns ha ve yet t o be 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
directl y  c o m pare d wit h t he E X T R E M E re gi me n i n a ra n d o mize d P hase 3 st u d y.  T he 
E X T R E M E re gi me n is t he o nl y  Cate g or y 1 e vi de nce -s u p p orte d c o m bi nati o n re gi me n 
rec o m me n de d by N C C N [ Nati o nal C o m pre he nsi ve Ca ncer Net w or k 2 0 1 6].
Be nefit/ Ris k Assess me nt
3. 3
It ca n n ot be g uara ntee d t hat partici pa nts i n cli nical st u dies will directl y  be nefit fr o m 
treat me nt d uri n g partici pati o n, as cli nical st u dies are desi g ne d t o pr o vi de i nf or mati o n a b o ut 
t he safety a n d effecti ve ness of a n i n vesti gati o nal me dici ne.
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or partici pa nts partici pati n g i n t his 
cli nica l st u d y m a y  be f o u n d i n t he acc o m pa nyi n g I Bs [IB E diti o n 1 5 2 0 1 7] [ I B E diti o n 1 0, 
2 0 1 7 ] , Prescri bi n g I nf or mati o n a n d Inf or me d C o nse nt d oc u me nts.
Be nefit/ Ris k of Pe m br oliz u m a b
3. 3. 1
Pe m br oliz u ma b m o n ot hera p y ha s a p ositi ve be nefit-ris k pr ofile a n d is well t olerate d i n t he 
a p pr o ve d i n dicati o ns.  P u blicati o ns of a si g nifica ntl y p ositi ve be nefit/ris k rati o ha ve bee n 
re p orte d f or mela n o ma i n a si n gle ar m st u d y e nc o m passi n g nearly 1 0 0 0 partici pa nts 
( K E Y N O T E-0 0 1), w hic h le d t o U S F o o d a n d Dr u g A d mi nistrati o n ( F D A ) a p pr o val i n 
Se pte m ber 2 0 1 4.  Pe m br oliz u ma b has s u bse q ue ntl y  recei ve d a p pr o val f or se veral i n dicati o ns. 
T he I B pr o vi des a d diti o nal details a b o ut t hese a p pr o vals [IB E diti o n 1 5 2 0 1 7] .  T he U S F D A 
a p pr o val t o treat patie nts wit h R/ M H N S C C wit h disease pr o gressi o n o n or after 
plati n u m -c o ntai ni n g c he m ot hera p y was base d o n t he efficac y o bser ve d i n K E Y N O T E-0 1 2 
a n d K E Y N O T E -0 5 5.  T he p ote ntial be nefits f or patie nts wit h H N S C C are a d dresse d i n 
Secti o n 3. 2. 3 , w hic h details res p o nses of partici pa nts wit h H N S C C i n K E Y N O T E-0 1 2 a n d 
K E Y N O T E -0 5 5.
M ost c o m m o n a d verse reacti o ns (re p orte d i n ≥2 0 % of patie nts) were fati g ue, pr urit us, 
diarr hea, decrease d a p petite, ras h, d ys p nea, c o nsti pati o n, a n d na usea .  I n t he pe m br oliz u ma b 
m o n ot hera p y st u dies, t he i nci de nce of Gra de 3 t o 5 dr u g -relate d A Es acr oss st u dies is 1 3. 8 %.  
Pe m br oliz u ma b i m m u ne -me diate d A d verse E ve nts of S pecial I nterest ( A E O SI s) are 
relati vely u nc o m m o n.  T he m ost fre q ue ntl y re p orte d A E O SI is h y p ot h yr oi dis m, wit h a n 
o verall i nci de nce of 8. 5 %.  F urt her m ore, m ost A E O SI s are mil d t o m o derate i n se verity, a n d 
are ge nerall y rea dily ma na gea ble wit h a p pr o priate care i n t he cli nical setti n g [IB E diti o n 1 5 
2 0 1 7] .
Be nefit/ Ris k of Pe m br oliz u m a b pl us E p ac a d ost at
3. 3. 3
S afet y data as of 2 7 -Fe b -2 0 1 7 data c ut off , f or t he 2 9 4 partici pa nts t hat ha ve bee n treate d i n 
t he P hase 2 part of K E Y N O T E -0 3 7 /E C H O -2 0 2 wit h e paca d ostat 1 0 0 m g  P O BI D a n d 
pe m br oliz u ma b 2 0 0 m g I V Q 3 W i n dicates a safet y/t olera bilit y pr ofile of pe m br oliz u ma b 
pl us e paca d ostat t hat is acce pta ble a n d ma na gea ble. O verall, 1 8 % of partici pa nts ha d 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Gra de ≥3 T R A Es a n d T R A Es le d t o disc o nti n uati o n i n 5 % of partici pa nts . See Secti o n 3. 2. 3
f or f urt her details.
P reli mi nar y data, as of 2 7 -Fe b -2 0 1 7 data c ut off , s u g gest e n ha nce d res p o nse rates as 
c o m pare d t o hist orical O R Rs o bser ve d wit h pe m br oliz u ma b m o n ot hera p y i n H N S C C.  F or 
f urt her details refer t o Secti o n 3. 2. 3 .
T he o bser ve d i m m u n ot hera pe utic res p o nses, t o get her wit h t he t olera bilit y  of pe m br oliz u ma b 
pl us e paca d ostat ar g ues str o n gl y f or a c o m paris o n wit h t he E X T R E M E re gi me n i n t he 
first li ne i n partici pa nts wit h H N S C C as pr o p ose d i n t his st u d y.
Be nefit/ Ris k of E X T R E M E
3. 3. 4
Be nefits a n d ris ks of t he E X T R E M E re gi me n are s u m marize d i n Secti o n 3. 2. 4 .  T he 
E X T R E M E re gi me n de m o nstrate d t he si g nifica nt i ncrease i n P F S a n d O S i n first li ne hea d 
a n d nec k ca ncer c o m pare d wit h c h e m ot hera p y ( plati n u m + 5-F U).  A t otal of 8 2 % of patie nts 
e x perie nce d a Gra de 3 or 4 A E i ncl u di n g ne ut r o pe nia ( 2 2 %), a ne mia ( 1 3 %), a n d 
t hr o m b oc yt o pe nia ( 1 1 %).  T hese A Es occ urre d i n si milar fre q ue ncies t o 
plati n u m - 5-F U -treate d partici pa nts [ Ver m or ke n, J. B., et al 2 0 0 8].  A d diti o nal details 
re gar di n g s pecific be nefits a n d ris ks f or E X T R E M E-treate d partici pa nts ma y be f o u n d i n t he 
prescri bi n g i nf or mati o n f or t hese S o C treat me nts.
4.
O bjecti ves/ H y p ot heses a n d E n d p oi nts
N O T E: As of A me n d me nt 0 4, t he pri m ar y e n d p oi nt of t he st u d y will be O R R b ase d o n 
R E CI S T 1. 1 as assesse d b y t he i n vesti g at or. All ot her effic ac y e n d p oi nts , i ncl u di n g 
i m a gi n g, will n o l o n ger be c ollecte d or perf or me d after t he first i m a gi n g assess me nt at 
Wee k 9 .  T his secti o n h as bee n u p d ate d acc or di n gl y.
As assess e d i n eac h of 3 treat me nt gr o u ps of partici pa nts wit h R/ M H N S C C recei vi n g 
pe m br oliz u ma b pl us e paca d ostat , pe m br oliz u ma b a n d E X T R E M E re gi me n .
O bjecti ve
E n d p oi nt
Pri m ar y

O bjecti ve : T o esti mate O R R of 
p e m br oliz u ma b + e paca d ostat, 
p e m br oliz u ma b m o n ot hera p y, a n d t he 
E X T R E M E re gi me n base d o n
R E CI S T 1. 1 b y i n vesti gat or 
deter mi nati o n .

O R R is defi ne d as t he pr o p orti o n of 
partici pa nts i n t he a nalys is p o p ulati o n
w h o ha ve a best res p o nse of C R or P R.
Sec o n d ar y

O bjecti ve: T o e val uate t he safet y a n d 
t olera bilit y of t he 3 treat me nt gr o u ps.

A Es; 

S t u d y treat me nt disc o nti n uati o ns d ue t o 
A Es .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
O bjecti ve
E n d p oi nt
5.
St u d y Desi g n 
O ver all Desi g n 
5. 1
N ote :  E nr oll me nt w as st o p pe d str ate gic all y o n 0 2 -M A Y -2 0 1 8 . 89 p artici p a nts were 
r a n d o mize d i n t he st u d y.  As of A me n d me nt 0 4, all st u d y effic ac y pr oce d ures will 
disc o nti n ue after first o n -st u d y i m a gi n g at Wee k 9 ( ± 7 d a ys) ; t here after p artici p a nts 
will be tre ate d as per S o C f or t he dise ase a n d l oc al g ui deli nes.  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 i n Gr o u p 1 a n d 2 c o nti n u i n g st u d y 
tre at me nt. F or Gr o u p 3 p artici p a nts c o nti n ui n g st u d y tre at me nt after firs t o n-st u d y 
i m a gi n g at Wee k 9 ( ± 7 d a ys) , s afet y pr oce d ures will c o nti n ue as per S o C .  T he l ast 
st u d y visit is t he S afet y F oll o w -u p Visit.  T his secti o n h as bee n u p d ate d acc or di n gl y.
T his is a ra n d o mize d, acti ve-c o ntr olle d, 3 parallel -gr o u p s, m ulti-site, o pe n -la bel P hase 3 
st u d y e val uati n g pe m br oliz u ma b pl us e paca d ostat , pe m br oliz u ma b m o n ot hera py, a n d t he 
E X T R E M E re gi me n i n partici pa nt s wit h R/ M H N S C C w h o ha ve n ot recei ve d pri or s ys te mic 
t hera py f or R/ M disease . T he E X T R E M E ar m was selecte d as a c o m parat or si nce it is t he 
S o C per N C C N g ui deli ne , w hile t he pe m br oliz u ma b m o n ot hera py ar m was i ncl u de d t o 
i de ntif y t he c o ntri b uti o n of t he i n di vi d ual c o m p o ne nts of t he pe m br oliz u ma b pl us 
e paca d ostat ar m. T he st u d y has a pri mar y  e n d p oi nt of O R R . T he st u d y will be c o n d ucte d i n 
c o nf or ma nce wit h G o o d Cli nical Practices ( G C P).
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
T he st u d y  i ncl u des a S cree ni n g p eri o d, a T reat me nt p eri o d, a n d a P ost -treat me nt Safet y  
F oll o w - up peri o d. After si g ni n g t he i nf or me d c o nse nt, ca n di date partici pa n ts will be 
scree ne d a gai nst all t he eli gi bilit y criteria.  Eli gi ble partici pa n ts will be ce ntrall y ra n d o mize d 
i n a 2: 1: 2 rati o a n d will be stratifie d base d o n:

E C O G P S ( 0 vs. 1)

H P V p 1 6 e x pressi o n stat us (eit her or o p har yn x -p 1 6 p ositi ve vs. or o p har y n x -p 1 6 
n e gati ve or lar yn x/ h y p o p har y n x/ oral ca vit y  H N S C C); a n d 

Pri or s y ste mic o nc ol o gical t hera py (as part of t he defi niti ve treat me nt f or l ocall y 
a d va nce d disease ) ( yes vs. n o).
Ori gi nall y, ap pr o xi matel y  6 2 5 eli gi ble partici pa nt s wit h R/ M H N S C C w h o meet t he 
i ncl usi o n/e xcl usi o n criteria were t o be e nr olle d i n t he st u d y a n d ce ntrall y ra n d o mize d i n a 
2: 1: 2 rati o i n 3 treat me nt gr o u ps:

Gr o u p 1: Pe m br oliz u ma b 2 0 0 m g 3 0 -mi n ute I V i nf usi o n Q 3 W ≤3 5 c ycles pl us 
e paca d ostat 1 0 0 m g P O BI D ≤3 5 c ycles

Gr o u p 2: Pe m br oliz u ma b 2 0 0 m g 3 0 -mi n ute I V i nf usi o n Q 3 W ≤3 5 c ycles

Gr o u p 3 : E X T R E M E re gi me n:
o
C et u xi ma b 4 0 0 m g/ m 2 1 2 0 -mi n ute I V i nf usi o n C y cle 1 Da y 1; f oll o we d b y 
cet u xi ma b 2 5 0 m g/ m 2 6 0 -mi n ute I V i nf usi o n Q W u ntil ra di o gra p hic P D or 
u nacce pta ble t o xicit y ; A N D
o
C is plati n 1 0 0 m g/ m2 6 0 -mi n ute I V i nf usi o n Q 3 W O R 
Car b o plati n A U C 5 6 0 -mi n ute I V i nf usi o n Q 3 W ≤6 c ycles; A N D
o
5- F U 1 0 0 0 m g/ m 2/ da y c o nti n u o us I V i nf usi o n o ver Da y s 1 t o 4 Q 3 W 
≤6 c ycles
S pecific pr oce d ures t o be perf or me d d uri n g t he trial, as well as t heir prescri be d ti mes a n d 
ass ociate d visit wi n d o ws, are o utli ne d i n t he Trial S o A - Secti o n 2. Details of eac h pr oce d ure 
are pr o vi de d i n Secti o n 9 – St u d y  Assess me nts a n d Pr oce d ures.
D at a M o nit ori n g C o m mittee 
5. 1. 1
T his st u d y will use a n i n de pe n de nt, e xter nal Data M o nit ori n g C o m mittee ( eD M C) t o m o nit or 
safety.  Details are descri be d i n Secti o n 1 0. 7 .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
4 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
St u d y Di a gr a m
5. 1. 2
T he st u d y desi g n is de picte d i n Fi g ure 1 .
A b bre viati o ns: 5- F U = 5 -fl u or o uracil; A U C = area u n der t he c ur ve; C = C ycle; D = da y; E C O G P S = Easter n 
C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us ; H N S C C = hea d a n d nec k s q ua m o us cell carci n o ma ; I V = 
i ntra ve n o usl y; Q 3 W = e ver y 3 we e ks; R/ M = rec urre nt or metastatic.
1.
Stratificati o n b y E C O G P S , H P V p 1 6 stat us (or o p har y n x -p 1 6 p ositi ve vs. or o p har y n x -p 1 6 ne gati ve or 
lar y n x/ h y p o p har y n x/ oral ca vit y H N S C C) a n d pri or s yste mic o nc ol o gical t hera p y (as part of t he defi niti ve 
treat me nt i n t he l ocall y a d va nce d disease) ( yes vs. n o). 
2.
Pri mar y t u m or l ocati o n i n t he oral ca vit y, or o p har y n x, h y p o p har y n x, a n d lar y n x.
3.
S y ste mic t hera p y c o m plete d > 6 m o nt hs pri or t o si g ni n g c o nse nt if gi ve n as part of m ulti m o dal treat me nt f or 
l ocall y a d va nce d disease is all o we d.
4. 
2 1 -da y c ycle f or a ma xi m u m of 6 c ycles f oll o w e d b y mai nte na nce t hera p y wit h cet u xi ma b 2 5 0 m g/ m 2
wee kl y u ntil disease pr o gressi o n or u nacce pta ble t o xicit y.
Fi g ure 1
St u d y Desi g n
N u m ber of P artici p a nts
5. 2
As of A me n d me nt 0 4, o n 0 2 -M A Y -2 0 1 8 e nr oll me nt i n t he st u d y was st o p pe d a n d 8 9
partici pa nts were e nr olle d i n 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 verall st u d y be gi ns w he n t he first partici pa nt si g ns t he i nf or me d c o nse nt f or m (I C F).  
T he o verall st u d y e n ds w he n t he last partici pa nt c o m pletes t he last st u d y -relate d p h o ne-call 
or visit, wit h dra ws fr o m t he st u d y or is l ost t o f oll o w -u p (i.e. t he partici pa nt is u na ble t o be 
c o ntacte d b y t he i n vesti gat or).
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 cli nical st u d y m a y  be ter mi nate d earl y if t he e xte nt (i nci de nce a n d/ or se verit y) of
e mer gi n g effects/cli nical e n d p oi nts is s uc h t hat t he ris k/ be nefit rati o t o t he st u d y p o p ulati o n 
as a w h ole is u nacce pta ble. I n a d diti o n, f urt her recr uit me nt i n t he st u d y or at a partic ular 
st u d y site(s) ma y be st o p pe d d ue t o i ns ufficie nt c o m plia nce wit h t he pr ot oc ol, G C P a n d/ or 
ot her a p plica ble re g ulat or y re q uire me nts, pr oce d ure-relate d pr o ble ms or 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.
T he i n vesti gat or retai ns t he ri g ht t o ter mi nate st u d y partici pati o n at a n y ti me, acc or di n g t o t he 
ter ms s pecifie d i n t he st u d y c o ntract. T he i n vesti gat or is t o n otif y  t he I R B or In de pe n de nt 
E t hics C o m mittee (I E C) i n writi n g of t he st u d y’ s c o m pleti o n or early ter mi nati o n, a n d se n d a 
c o p y of t he n otificati o n t o t he M S D or M S D desi g nee a n d retai n 1 c o p y f or t he site st u d y 
re g ulat or y file.
T he st u d y  m a y  be ter mi nate d earl y if re q uire d b y re g ulat or y decisi o n, or u p o n a d vice of t he
D M C. If t he st u d y is ter mi nate d pre mat urel y, t he i n vesti gat ors, t he IR Bs a n d I E Cs, a n d 
re g ulat or y b o dies will be n otifie d of t he decisi o n a n d reas o n f or ter mi nati o n of t he st u d y. 
T he D M C will rec o m me n d ter mi nati o n of t he st u d y if warra nte d, as descri be d i n 
Secti o n 1 0. 2 .
Scie ntific R a ti o n ale f or St u d y Desi g n 
5. 4
Hea d a n d nec k s q ua m o us cell ca ncers arise fr o m t he e pit helial cells t hat li ne t he oral ca vit y, 
p har y n x, a n d lar y n x a n d c o m prise t he vast maj orit y  of hea d a n d nec k ca ncers.  Pre d o mi na nt 
ris k fact ors f or n o n-nas o p har y n geal H N S C C ( oral ca vit y, or o p har yn x, h y p o p har y n x, a n d 
lar yn x) i ncl u de pri or alc o h ol c o ns u m pti o n a n d t o bacc o use [ Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k 2 0 1 6] .  I n de vel o pe d c o u ntries, i nfecti o n wit h H P V, i n partic ular H P V 1 6, is a n 
acce pte d ris k fact or f or t u m ors s pecificall y i n t he or o p har y n x [ Gillis o n, M. L., et al 2 0 1 5].  
A nal y ses fr o m cli nical st u dies ha ve s h o w n i m pr o ve d pr o g n osis a n d res p o nse t o treat me nt i n 
partici pa nts wit h H P V -p ositi ve t u m ors c o m pare d wit h t h ose wit h H P V -ne gati ve t u m ors 
[ Fa k hr y, C., et al 2 0 0 8] [ A n g, K. K., et al 2 0 1 0] .  Des pite a s hare d cell ular ori gi n, H N S C C of 
t he nas o p har yn x , h o we ver, is relati vely u nc o m m o n a n d has differi n g ris k fact ors (e g, 
E pstei n -Barr vir us i nfecti o n, ge netic s usce pti bilit y, a n d diet) c o m pare d wit h n o n -
nas o p har y n geal H N S C C; t heref ore, it is c o nsi dere d a se parate cli nical e ntit y [ Ar giris, A., et 
al 2 0 0 8] [ C h ua, M. L ., et al 2 0 1 6].  
Rec urre nt/ metastatic H N S C C has p ote ntiall y  de vastati n g effects o n basic f u ncti o ns s uc h as 
eati n g, s wall o wi n g, s pea ki n g a n d breat hi n g.  I n a d diti o n t he pai n ass ociate d wit h rec urre nce, 
a n d t he s ocial is olat i o n as well as p ote ntial disfi g ure me nt fr o m t he disease i n t he hea d/ nec k 
re gi o n, all p oi nt t o t he val ue of pre ve nti n g pr o gressi o n i n t his patie nt p o p ulati o n .  T here is 
t h us a n u n met me dical nee d t o s u p p ort t he de vel o p me nt of ne w treat me nt strate gies t o 
i m pr o ve t he o utc o me of patie nts.
A lar ge n u m ber of patie nts wit h H N S C C i nitiall y  prese nt wit h l ocally a d va nce d, Sta ge III/I V 
disease t hat is i nitiall y  treate d wit h c o m bi nati o ns of c he m ot hera py, ra diati o n a n d/ or s ur ger y.  
T his i nitial treat me nt is ge nerall y de si g nate d as “ defi niti ve” t hera py,  w hic h t ypicall y 
c o m bi nes c he m o -ra diati o n a n d s ur ger y a n d ca n res ult i n D C R s ra n gi n g bet wee n 3 3 a n d 8 6 % 
of patie nts.  Patie nts w h o pr o gress after i nitial defi niti ve t hera p y re q uire s u bse q ue nt 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
5 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
treat me nt f or rec urre nt ( R) disease.  Patie nts w h o i nitiall y prese nt wit h metastatic ( M)
disease 
ge nerall y recei ve t he sa me t hera p y as t h ose wit h rec urre nt disease after defi niti ve treat me nt.  
I nitial treat me nt o pti o ns f or patie nts wit h R/ M disease i ncl u de vari o us c he m ot hera p y a ge nts 
( plati n u m [cis plati n or car b o plati n], 5-F U, or ta xa nes), eit her al o ne or i n c o m bi nati o n, a n d 
t he bi ol o gic a ge nt cet u xi ma b [ Nati o nal C o m pre he nsi ve Ca ncer Net w or k 2 0 1 6] [ Gre g oire, V., 
et al 2 0 1 0] .  In partici pa nts wit h n o n -nas o p har n y g eal H N S C C, t he a d diti o n of cet u xi ma b t o 
plati n u m [cis plati n or car b o plati n] a n d 5 -F U ( E X T R E M E re gi me n) pr ol o n ge d me dia n O S 
fr o m 7. 4 m o nt hs t o 1 0. 1 m o nt hs ( hazar d rati o [ H R] = 0. 8 0; P = 0. 0 4) a n d me d ia n P F S fr o m 
3. 3 m o nt hs t o 5. 6 m o nt hs ( H R = 0. 5 4; P < 0. 0 0 1) c o m pare d wit h plati n u m −5 -F U d o u blet.  
A d diti o nall y , O R R i ncrease d fr o m 2 0 % wit h plati n u m/ 5-F U t o 3 6 % wit h t he E X T R E M E 
re gi me n ( P < 0. 0 0 1; [ Ver m or ke n, J. B., et al 2 0 0 8]).  Base d o n t hese res ults, t he E X T R E M E 
re gi me n is n o w t he S o C f or patie nts wit h n o n-nas o p har y n geal R/ M H N S C C [ Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k 2 0 1 6] [ Gre g oire, V., et al 2 0 1 0].
W hile
A Es of Gra de ≥3 were c o m para ble bet wee n t he treat me nt gr o u ps ( E X T R E M E: 8 2 %; 
plati n u m/ 5 -F U: 7 6 %), t he m ost c o m m o n A Es o bser ve d wit h E X T R E M E (a ne mia, 
ne utr o pe nia, t hr o m b oc y t o pe nia) a n d cet u xi ma b-s pecific A Es ( Gra de 3 s ki n t o xicities, 
Gra de 3 or 4 i nf usi o n -relate d reacti o ns) li mit t he use of t his re gi me n t o yo u n ger partici pa nts 
wit h g o o d perf or ma nce stat us.  I n t h ose w h o are eli gi ble t o recei ve t his re gi me n, ma n y  will 
st o p t hera py pre mat urel y d ue t o t o xicit y , as de m o nstrate d b y a 2 0 % disc o nti n uati o n rate f or
A Es i n t he pi v otal P hase 3 st u d y  [ Ver m or ke n, J. B., et al 2 0 0 8].  C o m m o n c o m or bi dities i n 
partici pa nts wit h H N S C C s uc h as di mi nis he d he patic, car diac, a n d p ul m o nar y  f u ncti o n fr o m 
pre vi o us alc o h ol a n d t o bacc o us e a n d p o or n utriti o nal stat us fr o m t he cli nical ma nifestati o ns 
of t he ca ncer a n d/ or pre vi o us ra diati o n ca n f urt her li mit t he use of t he E X T R E M E re gi me n.  
Sec o n d li ne treat me nt re gi me ns are li mite d a n d pri maril y palliati ve res ulti n g i n ver y p o or 
l o n g-ter m sur vi val rates f or t his patie nt p o p ulati o n.
Gi ve n t he li mite d t olera bilit y  pr ofile of E X T R E M E a n d p o or o utc o mes wit h sec o n d li ne 
t hera pies, t here is a critical nee d f or effecti ve a n d well t olerate d alter nati ve re gi me n t hat 
offer s s ustai ne d res p o nses a n d prol o n ge d s ur vi val c o m pare d wit h t he E X T R E M E re gi me n i n 
t he first li ne setti n g f or R/ M H N S C C.
Pe m br oliz u ma b m o n ot hera p y i n R/ M H N S C C i n partici pa nts w h o ha d disease pr o gressi o n o n 
or after plati n u m -c o ntai ni n g c he m ot hera p y de m o nstrate d c o nfir me d O R R of 1 6 % wit h a C R 
rate of 5 % (refer t o t he K E Y T R U D A® U S prescri bi n g i nf or mati o n ).  A p e m br oliz u ma b 
m o n ot hera p y ar m has bee n i ncl u de d i n t his c urre nt st u d y t o deter mi ne t he c o ntri b uti o n of 
e paca d ostat t o t he treat me nt effect of pe m br oliz u ma b pl us e paca d ostat c o m bi nati o n t hera p y.  
Pe m br oliz u ma b m o n ot hera p y i n t he first li ne setti n g is bei n g st u die d i n K E Y N O T E - 0 4 8 (see 
Secti o n 3. 2. 3 )  T heref ore t he pe m br oliz u ma b m o n ot hera p y ar m i n t his st u d y will i ncl u de a 
mi ni mal n u m ber of partici pa nts as a c o nc urre nt c o ntr ol. 
Base d o n t he res ults detaile d i n Secti o n 3. 2. 3 f or K E Y N O T E - 0 3 7/ E C H O-2 0 2 , c o m bi nati o n 
t hera py wit h pe m br oliz u ma b a n d e paca d ostat de m o nstrate d a n acce pta ble safety pr ofile wit h 
pr o misi n g a nti -t u m or acti vit y i n patie nts wit h R/ M H N S C C.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
R ati o n ale f or E n d p oi nts
5. 4. 1
Effic ac y E n d p oi nts
5. 4. 1. 1
N O T E: As of A me n d me nt 0 4, t he pri m ar y e n d p oi nt will be O R R b ase d o n R E CI S T 1. 1 
as assesse d b y t he in vesti g at or ; tr a ns missi o n of i m a ges f or ce ntr al re vie w of i m a gi n g is 
n o l o n ger re q uire d .
After i m a gi n g at Wee k 9, all ot her effic ac y e n d p oi nts , i ncl u di n g 
i m a gi n g after t he first o n st u d y sc a n at Wee k 9, will n o l o n ger be c ollecte d or 
perf or me d .  T his secti o n h as bee n a me n de d acc or di n gl y.
O bjec ti ve res p o nse rate, base d o n R E CI S T 1. 1 as assess e d b y  t he in vesti gat or , will ser ve as 
t he pri mar y meas ure of efficac y .  O R R is a n acce pta ble meas ure of cli nical be nefit f or a late 
sta ge st u dy t hat de m o nstrates safet y a n d efficac y of a ne w a nti ne o plastic t hera py.
R E CI S T 1. 1
5. 4. 1. 1. 1
N ote: As of A me n d me nt 0 4, R E CI S T 1. 1 will be assess e d b y t he i n vesti g at or; 
tr a ns missi o n of i m a ges for ce ntr al re vie w of i m a gi n g is n o l o n ger re q uire d. 
R E CI S T 1. 1 will be use d b y  t he l ocal site w he n deter mi ni n g eli gi bilit y an d c o n d ucti n g site 
disease assess me nt . 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 otal a n d 5 per or ga n.  T his will be ter me d as 
R E CI S T 1. 1 t hr o u g h o ut t he pr ot oc ol. F urt her details are f o u n d i n Secti o n 9. 2. 1. 5 . 
M o difie d R E CI S T
f or I m m u ne-b ase d T her a pe utics (i R E CI S T )
5. 4. 1. 1. 2
N O T E: As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble; i R E CI S T d at a will 
n o l o n ger be c ollecte d.
P artici p a nts wit h r a di o gr a p hic dise ase pr o gressi o n as 
deter mi ne d b y R E CI S T 1. 1 will disc o nti n ue fr o m t he st u d y a n d f oll o we d f or s afet y 
m o nit ori n g, as det aile d i n Secti o n 9. 3 ; n o c o nfir m at or y sc a ns are re q uire d.
R E CI S T 1. 1 will be a da pte d t o acc o u nt f or t he u ni q ue t u m or res p o nse c haracteristics see n
f oll o wi n g treat me nt wit h i m m u n ot hera pe utic a ge nts.  Im m u n ot h era pe utic a ge nts s uc h as 
pe m br oliz u ma b ma y  pr o d uce a ntit u m or effects by p ote ntiati n g e n d o ge n o us ca ncer -s pecific 
i m m u ne res p o nses.  T he res p o nse patter ns see n wit h s uc h a n a p pr oac h ma y e xte n d be y o n d 
t he t ypical ti me c o urse of res p o nses see n wit h c y t ot o xic age nts, a n d partici pa nts treate d wit h 
pe m br oliz u ma b ma y  ma nifest a cli nical res p o nse after a n i nitial i ncrease i n t u m or b ur de n or 
e ve n t he a p peara nce of ne w lesi o ns.  
T h us, sta n dar d R E CIS T 1. 1 ma y n ot pr o vi de a n acc urate res p o nse assess me nt of 
i m m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b.  Base d o n a n a nal y sis of partici pa nts wit h 
mela n o ma e nr olle d i n K E Y N O T E -0 0 1, 7 % of e val ua ble pa rtici pa nts e x perie nce d dela ye d or 
earl y t u m or pse u d o -pr o gressi o n. Of n ote, pa rtici pa nts w h o ha d P D b y  R E CIS T 1. 1 b ut n ot 
b y  t he i m m u ne-relate d res p o nse criteria [ W olc h o k, J. D., et al 2 0 0 9] ha d l o n ger O S t ha n 
pa rtici pa nts wit h P D b y  b ot h criteria [ H o di, F. S., et al 2 0 1 4].  A d diti o nall y, t he data s u g gest 
t hat R E CIS T 1. 1 ma y  u n deresti mate t he be nefit of pe m br oliz u ma b i n a p pr o xi matel y 1 5 % of 
pa rtici pa nts [ H o di, F. S., et al 2 0 1 6].  T hese fin di n gs s u p p ort t he nee d t o a p pl y  a m o dificati o n 
t o R E CIS T 1. 1 t hat ta kes i nt o acc o u nt t he u ni q ue patter n of at y pical res p o nse s i n 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
i m m u n ot hera p y a n d e na bles treat me nt be yo n d i nitial ra di o gra p hic pr o gressi o n , if t he 
partici pa nt is cli nicall y sta ble . 
iR 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 dici nes A ge nc y [ Se ym o ur, L., et 
al 2 0 1 7] . T he u ni di me nsi o nal meas ure me nt of tar get lesi o ns, q ualitati ve assess me nt of n o n-
tar get lesi o ns, a n d res p o nse cate g ories are i de ntical t o R E CIS T 1. 1 , u ntil pr o gressi o n is see n 
b y  R E CIS 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 gra p hic pr o gressi o n. i R E CIS T will be use d b y i n vesti gat ors t o 
assess t u m or res p o nse a n d pr o gressi o n, a n d ma ke treat me nt decisi o ns
 
T he O R R, D O R, a n d P F S will als o be e val uate d per i R E CI S T b y  i n vesti gat or assess me nt.
Refer t o Secti o n 9. 2. 1. 5 a n d Secti o n 9. 2. 1. 6 f or details o n R E CIS T 1. 1 a n d i R E CI S T , 
res pecti vely.
S afet y E n d p oi nts
5. 4. 1. 2
Safet y  para meters c o m m o nl y use d f or e val uati n g i n vesti gati o nal sys te mic a ntica ncer 
treat me nts are i ncl u de d as safety e n d p oi nts i ncl u di n g, b ut n ot li mite d t o, t he i nci de nce of, 
ca usalit y, a n d o utc o me of A Es/ S A Es; a n d c ha n ges i n vital si g ns a n d la b orat or y val ues. 
A d verse e ve nts will be assesse d as defi ne d b y N CI C o m m o n T o xicit y  Criteria f or A d verse 
E ve nts ( C T C A E ), v ersi o n 4. 0. 
T he o bjecti ve i s t o c haracterize t he safet y a n d t olera bilit y of t he 3 treat me nt gr o u ps.  
T he pri mar y  safety a nal ysis will be base d o n partici pa nts w h o e x perie nce d t o xicities as 
defi ne d b y C T C A E. Safet y  will be assesse d by q ua ntif y i n g t he t o xicities a n d gra des 
e x perie nce d b y partici pa nts w h o ha ve recei ve d st u d y treat me nt, i ncl u di n g S A Es a n d e ve nts 
of cli nical i nterest ( E CIs). Safet y  will be assesse d b y  re p orte d a d verse e x perie nces usi n g 
C T C A E, v ersi o n 4. 0. T he attri b uti o n t o dr u g, ti me -of -o nset, d urati o n of t he e ve nt, its 
res ol uti o n, a n d a ny c o nc o mita nt me dicati o ns a d mi nistere d will be rec or de d. A d verse e ve nt s 
will be a nal yz e d i ncl u di n g b ut n ot li mite d t o all A Es, S A Es, fatal A Es, a n d la b orat or y 
c ha n ges. F urt her m ore, E CI will be c ollecte d a n d a nal yz e d as descri be d i n Secti o n 9. 3. 7 .  
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
E ur o Q o L -5 D
5. 4. 1. 5. 2
T he E Q -5 D is a sta n d ar dize d i nstr u me nt f or use as a meas ure of healt h o utc o me a n d will 
pr o vi de data t o de vel o p healt h utilities f or use i n healt h ec o n o mic a nal ys es [ Ra bi n, R. 2 0 0 1].  
T he 5 healt h state di me nsi o ns i n t his i nstr u me nt i ncl u de t he f oll o wi n g: m o bilit y , self-care, 
us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n.  Eac h di me nsi o n is rate d o n a 
5- p oi nt scale fr o m 1 (n o pr o ble m ) t o 5 ( u na ble t o/e xtre me pr o ble ms).  T he E Q- 5 D als o 
i ncl u des a gra de d ( 0 t o 1 0 0) vertical vis ual a nal o g scale o n w hic h t he partici pa nt rates his or 
her ge neral state of healt h at t he ti me of t he assess me nt.  T his i nstr u me nt has bee n use d 
e xte nsi vel y i n ca ncer st u dies a n d p u blis he d res ults fr o m t hese stu dies s u p p ort its vali dit y  a n d 
relia bilit y [ Pic kar d, A. S., et al 2 0 0 7].
 
 
0 4 Y B M H

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

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
R ati o n ale f or t he Use of C o m p ar at or
5. 4. 2
T he E X T R E M E ar m was i ncl u de d beca use t his re gi me n is a Cate g or y 1 e vi de nce -s u p p orte d 
c o m bi nati o n re gi me n rec o m me n de d b y N C C N (see S ecti o n 3. 2. 4 ).
A pe m br oliz u ma b m o n ot hera p y ar m is a d de d i n t his st u d y  i n or der t o esta blis h t he ma g nit u de 
of be nefit fr o m e paca d ostat i n t he pe m br oliz u ma b pl us e paca d ostat c o m bi nati o n re gi me n (see 
Secti o n 5. 4).  
J ustific ati o n f or D ose 
5. 5
R ati o n ale f or Pe m br oliz u m a b D osi n g Re gi me ns
5. 5. 1
T he pla n ne d d ose of pe m br oliz u ma b f or t his st u d y is 2 0 0 m g Q 3 W.  Base d o n t he t otalit y  of 
data ge nerate d i n t he K E Y T R U D A ® de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he a p pr o priate 
d ose of pe m br oliz u ma b f or a d ults acr oss all i n dicati o ns a n d re gar dless of t u m or t y pe. As 
o utli ne d bel o w, t his d ose is j ustifie d b y : 

Cli nical data fr o m 8 ra n d o mize d st u dies de m o nstrati n g flat d ose- a n d 
e x p os ure - efficac y relati o ns hi ps fr o m 2 m g/ k g Q 3 W t o 1 0 m g/ k g Q 2 W, 

Cli nical data s h o wi n g mea ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g O S at 
2 0 0 m g Q 3 W acr oss m ulti ple i n dicati o ns, a n d

P har mac ol o g y  data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati o n 
(i nferre d fr o m P K data) a n d t u m or (i nferre d fr o m p h ysi ol o gically base d P K [ P B P K] 
a nal ys is) at 2 0 0 m g Q 3 W.
A m o n g t he 8 ra n d o mize d d ose-c o m paris o n st u dies, a t otal of 2 2 6 2 partici p a nts were e nr olle d 
wit h mela n o ma a n d N S C L C, c o veri n g differe nt disease setti n gs (treat me nt naï ve, pre vi o usl y 
treate d, P D-L 1 e nric he d a n d all -c o mers) a n d differe nt treat me nt setti n gs ( m o n ot hera py a n d i n 
c o m bi nati o n wit h c he m ot hera p y). Fi ve st u dies c o m pare d 2 m g / k g Q 3 W vers us 1 0 m g/ k g 
Q 2 W ( K E Y N O T E -0 0 1 B 2, K E Y N O T E -0 0 1 D, K E Y N O T E -0 0 2, K E Y N O T E -0 1 0 a n d 
K E Y N O T E -0 2 1), a n d 3 st u dies c o m pare d 1 0 m g / k g Q 3 W vs. 1 0 m g/ k g Q 2 W 
( KE Y N O T E -0 0 1 B 3, K E Y N O T E -0 0 1 F 2 a n d K E Y N O T E -0 0 6). All of t hese st u dies 
de m o nstrate d flat d ose - a n d e x p os ure -res p o nse relati o ns hi ps acr oss t he d oses st u die d 
re prese nti n g a n a p pr o xi mate 5 t o 7. 5-f ol d differe nce i n e x p os ure. T he 2 m g / k g ( or 2 0 0 m g  
fi xe d d ose) Q 3 W pr o vi de d si milar res p o nses t o t he hi g hest d oses st u die d. S u bse q ue ntl y , flat 
d ose -/e x p osure -res p o nse relati o ns hi ps were als o o bser ve d i n ot her t u m or ty pes i ncl u di n g 
hea d a n d nec k ca ncer, bla d der ca ncer, gastric ca ncer a n d classical H o d g ki n L y m p h o ma, 
c o nfir mi n g 2 0 0 m g Q 3 W as t he a p pr o priate d ose i n de pe n de nt of t he t u m or t ype. T hese 
fi n di n gs are c o nsiste nt wit h t he mec ha nis m of acti o n of pe m br oliz u ma b, w hic h acts by 
i nteracti o n wit h i m m u ne cells, a n d n ot via direct bi n di n g t o ca ncer cells.
A d diti o nall y , p har mac ol o g y data clearly s h o w tar get sat urati o n at 2 0 0 m g  Q 3 W. First, P K 
data i n K E Y N O T E -0 0 1 e val uati n g tar get -me diate d dr u g dis p ositi o n c o ncl usi vel y  
de m o nstrate d sat urati o n of P D -1 i n s y ste mic circ ulati o n at d oses m uc h l o wer t ha n 2 0 0 m g  
Q 3 W. Sec o n dl y , a P B P K a nalys is was c o n d ucte d t o pre dict t u m or P D-1 sat urati o n o ver a 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
wi de ra n ge of t u m or p e netrati o n a n d P D -1 e x pressi o n. T his e val uati o n c o ncl u de d t hat 
pe m br oliz u ma b at 2 0 0 m g Q 3 W ac hie ves f ull P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.
Fi nall y , p o p ulati o n P K a nal ysis of pe m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of 
b o d y  wei g ht a n d ot her partici pa nt c o variates o n e x p os ure, has s h o w n t hat t he fi xe d -d osi n g 
pr o vi des si milar c o ntr ol of P K varia bilit y as wei g ht base d d osi n g, wit h c o nsi dera ble o verla p 
i n t he distri b uti o n of e x p os ures fr o m t he 2 0 0 m g  Q 3 W fi xe d d ose a n d 2 m g/ k g Q 3 W d ose. 
S u p p orte d b y  t hese P K c haracteristics, a n d gi ve n t hat fi xe d-d ose has a d va nta ges of re d uce d 
d osi n g c o m ple xit y  a n d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g  Q 3 W fi xe d-d ose was 
selecte d f or e val uati o n acr oss all pe m br olizu ma b pr ot oc ols.
     
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
5 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
6.
St u d y P o p ul ati o n
Male a n d f e male partici pa nts wit h R/ M H N S C C of at least 1 8 ye ars of a ge wit h o ut pri or
s yste mic treat me nt f or R/ M H N S C C will be e nr olle d i n t his trial.
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o 
k n o w n as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
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 acteristics
1.
Male/fe male partici pa n ts w h o are at least 1 8 years of a ge o n t he da y of si g ni n g 
i nf or me d c o nse nt wit h hist ol o gically or c y t ol o gicall y-c o nfir me d R/ M H N S C C t hat is 
c o nsi dere d i nc ura ble b y l ocal t hera pies will be e nr olle d i n t his st u d y.  
N ote:  T he eli gi ble pri mar y  t u m or l ocati o ns are or o p har yn x, oral ca vit y, 
h y p o p har y n x, a n d lar y n x.
Male partici pa nts:
2.
A male partici pa nt m ust a gree t o use c o ntrace pti o n as detaile d i n A p pe n di x 5 of t his 
pr ot oc ol d uri n g t he treat me nt peri o d a n d f or at least 1 2 0 d a y s after t he last d ose of 
pe m br oliz u ma b a n d e paca d ostat , or pe m br oliz u ma b al o ne, a n d f or at least 1 8 0 da y s 
after t he last d ose of t he E X T R E M E re gi me n.  He m ust als o refrai 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 pr eferre d c o ntrace pti o n f or t he partici pa nt.
Fe male partici pa nts:
3.
A fe male partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt (see A p pe n di x 5 ), 
n ot breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies: 
a.) N ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P) as defi ne d i n A p pe n di x 5 O R 
b.) A W O C B P w h o a grees t o f oll o w t he c o ntrace pti ve g ui da nce i n A p pe n di x 5 d uri n g 
t he treat me nt peri o d a n d f or at least 1 2 0 d a y s after t he last d ose of pe m br oliz u ma b
a n d e paca d os tat, or pe m br oliz u ma b al o ne, a n d f or at least 1 8 0 d a y s after last d ose of 
t he E X T R E M E re gi me n.  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.
I nf or me d C o nse nt
4.
T he partici pa nt ( or le gall y acce pta ble re prese ntati ve if a p plica ble) pr o vi des writte n 
i nf or me d c o nse nt f or t he st u d y.  
Di a g n ostic Assess me nts
5.
Ha ve meas ura ble disease b y  C T or M RI base d o n R E CIS T 1. 1 as deter mi ne d b y  site 
ra di ol o g y.  L esi 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 nstrate d i n s uc h lesi o ns f oll o wi n g ra diati o n t hera py.
6.
Ha ve a n E C O G P S of 0 or 1 wit hi n 7 da y s pri or t o ra n d o mizati o n .
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
7.
Ha ve a de q uate or ga n f u ncti o n as defi ne d i n t he f oll o wi n g ta ble (Ta ble 1 ).  S peci me ns 
m ust be c ollecte d wit hi n ≤1 0 da y s pri or t o t he start of st u d y treat me nt. ( Partici pa nts 
ma y  be e nr olle d base d o n l ocal la b orat or y res ults pe n di n g ce ntral la b orat or y res ults).
Ta ble 1
A de q uate Or ga n F u ncti o n L a b orat or y Val ues
S yste m
L a b or at or y V al ue
He m at ol o gic al
A bs ol ute ne utr o p hil c o u nt ( A N C)
≥1 5 0 0/ µ L
Platelets
≥1 0 0 0 0 0/ µ L
He m o gl o bi n
≥9. 0 g/ d L or ≥5. 6 m m ol/ L a
Re n al
Creati ni ne O R
Meas ure d or calc ulate d
b creati ni ne 
cleara nce
( G F R ca n als o be use d i n place of 
creati ni ne or Cr Cl)
≤1. 5 × U L N O R
≥3 0 m L/ mi n f or partici pa nt wit h creati ni ne 
le vels > 1. 5 × i nstit uti o nal U L N
N ote:  Cis plati n s h o ul d n ot be use d if 
creati ni ne cleara nce is l o wer t ha n 
6 0 m L/ mi n .
He p atic
T otal bilir u bi n
≤1. 5 × U L N O R direct bilir u bi n ≤U L N f or 
partici pa nt s wit h t otal bilir u bi n le vels 
> 1. 5 × U L N c
A S T ( S G O T) a n d A L T ( S G P T)
≤2. 5 × U L N ( ≤5 × U L N f or partici pa nt s wit h 
li ver metastases)
C o a g ul ati o n
I nter nati o nal n or malize d rati o (I N R) O R 
pr ot hr o m bi n ti me ( P T)
Acti vate d partial t hr o m b o plasti n ti me 
(a P T T) or partial t hr o m b o plasti n ti me 
(P T T )d
≤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 e 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 b bre viati o ns: A L T ( S G P T) = ala ni ne a mi n otra nsferase (ser u m gl uta mic p yr u vic tra nsa mi nase); A S T ( S G O T) =
as partate a mi n otra nsferase (ser u m gl uta mic o xal oacetic tra nsa mi nase); Cr Cl = creati ni ne cleara nce; G F R =
gl o mer ular filtrati o n rate; U L N = u p per li mit of n or mal.
a Criteria m ust be met wit h o ut er yt hr o p oieti n de pe n de nc y a n d wit h o ut pac ke d re d bl o o d cell ( p R B C) tra nsf usi o n 
wit hi n last 2 wee ks of t he scree ni n g test .
b Creati ni ne cleara nce ( Cr Cl) s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.
c If t here is n o i nstit uti o nal n or mal ra n ge a vaila ble 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 otal bilir u bi n e xcee d 3. 0 × U L N.
d 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.
e Use of c o u mari n - base d a ntic oa g ula nts (e g, warfari n ) wit h e paca d ostat is disc o ura ge d.  L o w-d ose warfari n ( 1 m g) 
is acce pta ble; h o we ver, ot her hi g her d oses are disc o ura ge d.  If a n alter nati ve t o c o u mari n -base d a ntic oa g ula nts 
ca n n ot be use d, t he I N R s h o ul d be m o nit ore d cl osel y per S o C w he n e paca d ostat is starte d.
N ote: T his ta ble i ncl u des eli gi bilit y -defi ni n g la b orat or y val ue re q uire me nts f or treat me nt; la b orat or y val ue 
re q uire me nts s h o ul d be a da pte d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes f or t he a d mi nistrati o n of s pecific 
c he m ot hera pies.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
8.
Ha ve d oc u me ntati o n of res ults fr o m testi n g of H P V stat us f or or o p h ar y n geal ca ncer 
defi ne d as p 1 6 I H C testi n g usi n g CI Ntec ® p 1 6 Hist ol o g y assa y a n d a 7 0 % c ut off 
p oi nt.  I f H P V stat us was pre vi o usl y teste d usi n g t his met h o d, n o a d diti o nal testi n g is 
re q uire d. 
N ote:  T u m or p 1 6 e x pressi o n m ust be e val uate d b y assess me nt of I H C a nal ysis wit h 
CI Ntec ® p 1 6 Hist ol o g y  assa y ( Ve nta na Me dical S yste ms I nc., T ucs o n A Z) usi n g 
‘ Be nc h mar k Ultra’ a ut ostai ner ( Ve nta na, T ucs o n, A Z) a n d sta n dar d pr ot oc ol.  
P ositi ve p 1 6 e x pressi o n is defi ne d as str o n g a n d diff use n uclear a n d c yt o plas mic 
staini n g i n 7 0 % or m ore of t he t u m or cells. 
N ote:  H P V stratificati o n i n t his st u d y will be perf or me d usi n g l ocal testi n g of H P V 
stat us i n partici pa nts wit h or o p har y n x ca ncer usi n g t he s pecifie d met h o d.
N ote:  If l ocal p 1 6 testi n g res ults are n ot a vaila ble, o r ca n n ot be assesse d b y t he 
s pecifie d met h o d, a t u m or tiss ue sa m ple ma y be s u b mitte d f or p 1 6 testi n g at t he 
desi g nate d ce ntral la b orat or y . 
N ote:  Oral ca vit y , hy p o p har y n x, a n d lar y n x ca ncer are n ot re q uire d t o u n der g o H P V 
testi n g by p 1 6 I H C as b y c o n ve nti o n t hese t u m or l ocati o ns are ass u me d t o be H P V 
ne gati ve.   
9.
Ha ve a baseli ne arc hi val t u m or s peci me n a vaila ble or is willi n g t o u n der g o a 
pre -st u dy treat me nt t u m or c ore or e xcisi o nal bi o ps y of a t u m or lesi o n n ot pre vi o usl y  
irra diate d, t o o btai n t he s peci me n. Fi ne nee dle as pirate ( F N A) a n d b o ne metastases 
sa m ples are n ot acce pta ble.
N ote:  A ne wl y o btai ne d bi o ps y is str o n gl y preferre d, b ut a n arc hi val sa m ple is 
acce pta ble. T u m or lesi o ns use d f or ne wl y o btai ne d bi o psies s h o ul d n ot be t he sa me 
lesi o ns use d as R E CIS T tar get lesi o ns, u nless t here are n o ot her lesi o ns s uita ble f or 
bi o ps y , i n w hic h case c o ns ultati o n wit h t he M S D
Cli nical Direct or is re q uire d.
E xcl usi o n Criteri a 
6. 2
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Has c arci n o ma of t he nas o p har yn x, sali var y  gla n d, u n k n o w n pri mar y ori gi n, or 
n o ns q ua m o us hist ol o gies as pri mar y t u m ors. 
2.
Has disease pr o gressi o n wit hi n 6 m o nt hs of c o m pleti o n of c urati vel y i nte n de d 
s yste mic treat me nt f or l oc ore gi o nally a d va nce d H N S C C.  
3.
Has a life e x pecta nc y  of less t ha n 3 m o nt hs a n d/ or has ra pi dly pr o gressi n g disease (e g 
t u m or blee di n g, u nc o ntr olle d t u m or pai n) i n t he o pi ni o n of t he treati n g i n vesti gat or.
4.
Has a hist or y  of blee di n g re q uiri n g a me dical i nt er ve nti o n (e g, e m b olizati o n 
pr oce d ure, R B C tra nsf usi o n, or h os pitalizati o n) wit hi n 3 0 da y s of st u d y e nr oll me nt .
5.
Has a h ist or y of peri p heral ne ur o pat hy ≥ Gra de 2 f or partici pa nts w h o ma y recei ve
cis plati n.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
6.
Has a hist or y  of di h y dr o p y ri mi di ne de h ydr o ge nase ( D P D) deficie nc y  ( h o m oz yg o us or 
heter oz y g o us m utati o ns). 
7.
Has a hist or y  of an y  c o ntrai n dicati o n or has a se vere h y perse nsiti vit y  t o a n y 
c o m p o ne nts of e paca d ostat, pe m br oliz u ma b ( ≥Gra de 3) , cis plati n or car b o plati n, 
cet u xi mab, a n d 5- F U .
N ote: Sites are i nstr ucte d t o refer t o t he a p pr o ve d pr o d uct la beli n g f or t hese t hera pies 
f or i nf or mati o n o n c o ntrai n dicati o ns or preca uti o ns f or use.
8.
Ha d a n all o ge neic tiss ue/s oli d or ga n tra ns pla nt.
9.
Has a hist or y  of gastr oi ntesti nal c o n diti o n or pr oce d ure t hat ma y affect dr u g 
a bs or pti o n.
N ote: Partici pa nts wit h fee di n g t u bes are eli gi ble.
1 0. A n y  hist or y of Ser ot o ni n S yn dr o me after recei vi n g ser ot o ner gic dr u gs.
1 1. A W O C B P w h o has a p ositi ve uri ne pre g na nc y  test wit hi n 7 2 h o urs bef ore t he first 
d ose of st u d y  treat me nt (see A p pe n di x 5).  If t he uri ne test ca n n ot be c o nfir me d as 
ne gati ve, a ser u m pre g na nc y  test is re q uire d.  I n s uc h cases, t he partici pa nt m ust be 
e xcl u de d fr o m partici pati o n if t he ser u m pre g na nc y res ult is p ositi ve.
N ote: I n t he e ve nt t hat 7 2 h o urs ha ve ela pse d bet wee n t he scree ni n g pre g na nc y test 
a n d t he first d ose of st u d y treat me nt, a n ot her pre g na nc y  test ( uri ne or ser u m) m ust be 
perf or me d a n d m ust be ne gati ve i n or der f or t he partici pa nt t o start recei vi n g st u d y 
treat me nt.
Pri or/ C o nc o mit a nt T her a p y
1 2. Has recei ve d pri or s ys te mic t hera p y (as part of m ulti m o dal treat me nt) f or H N S C C 
a d mi nistere d i n t he rec urre nt a n d/ or metastatic setti n g f or i nc ura ble disease.
N ote:  S y ste mic t hera p y (as part of m ulti m o dal treat me nt) w hic h was c o m plete d m ore 
t ha n 6 m o nt hs pri or t o si g ni n g c o nse nt if gi ve n as part of m ulti m o dal treat me nt f or 
l ocall y a d va nce d disease is all o we d.
1 3. Has n ot f ull y  rec o vere d (ie, ≤Gra de 1 or at baseli ne) fr o m A E s d ue t o a pre vi o usl y 
a d mi nistere d treat me nt.
N ote:
Partici pa nts wit h ≤Gra de 2 al o pecia are a n e xce pti o n t o t his criteri o n a n d ma y  
q ualif y  f or t he st u d y. 
N ote: If partici pa nts ha ve recei ve d maj or s ur ger y, t he y m ust ha ve rec o vere d 
a de q uatel y fr o m t he t o xicit y a n d/ or c o m plicati o ns fr o m t he i nter ve nti o n pri or t o 
starti n g st u d y treat me nt.
1 4. Has recei ve d pri or palliati ve ra di ot hera py wit hi n 2 wee ks of start of st u d y treat me nt.  
Partici pa n ts m ust ha ve rec o vere d fr o m all ra diati o n-relate d t o xicities, n ot re q uire 
c ortic oster oi ds, a n d n ot ha ve ha d ra diati o n p ne u m o nitis.  
1 5. Has recei ve d pri or t hera p y wit h e paca d ostat or a n y I D O 1 i n hi bit or, a n a nti-P D - 1, 
a nti-P D -L 1, or a nti P D -L 2 a ge nt , or a n y a gent directe d t o a n ot her sti m ulat or y  or c o-
i n hi bit or y T-cell rece pt or (e g, C T L A -4, O X -4 0, C D 1 3 7).
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
1 6. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys pri or t o t he first d ose of st u d y treat me nt.  
E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g :  measles, 
m u m ps, r u bella, varicella/z oster (c hic ke n p o x), y ell o w fe ver, ra bies, Bacill us 
Cal mette – G uéri n ( B C G), a n d t y p h oi d vacci ne.  Seas o nal i nfl ue nza vacci nes f or 
i njecti o n are ge nerally kille d vir us vacci nes a n d are all o we d; h o we ver, i ntra nasal 
i nfl ue nza vacci nes are li ve atte n uate d vacci nes a n d are n ot all o we d.
1 7. Has recei ve d t hera p y wit h a n M A OI, or U G T 1 A 9 i n hi bit or wit hi n 2 1 da y s pri or t o 
starti n g treat me nt, or a ntici pates re q uiri n g o ne of t hese pr o hi bite d me dicati o ns d uri n g 
t he treat me nt p hase. E xa m ples of me dicati o ns i n t hese classes are f o u n d i n 
Secti o n 7. 7. 3.
1 8. C urre nt use of a n y pr o hi bit e d me dicati o n as descri be d i n Secti o n 7. 7. 3.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 9. Is c urre ntl y partici pati n g i n or has partici pate d i n a st u d y of a n i n vesti gati o nal a ge nt 
or has use d a n i n vesti gati o nal de vice wit hi n 4 wee ks pri or t o t he first d ose of st u d y
treat me nt.
N ote:  Partici pa nts w h o ha ve e ntere d t he P ost -treat me nt Foll o w - u p Phase of a n 
i n vesti gati o nal st u d y ma y  partici pate as l o n g as it has bee n 4 wee ks after t he last d ose 
of t he pre vi o us i n vesti gati o nal a ge nt.
Di a g n ostic A ssess me nts
2 0. Has a dia g n osis of i m m u n o deficie nc y  or is recei vi n g c hr o nic sys te mic ster oi d t hera py 
(i n d osi n g e xcee di n g 1 0 m g daily of pre d nis o ne or e q ui vale nt) or a n y ot her f or m of 
i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t o t he first d ose of st u d y treat me nt.  
C or tic oster oi d use as pre-me dicati o n f or aller gic reacti o ns (e g I V c o ntrast) is 
per mitte d .  
2 1. Has a k n o w n a d diti o nal mali g na nc y  t hat is pr o gressi n g or has re q uired acti ve 
s yste mic treat me nt wit hi n t he past 3 ye ars.  
N ot e:  Partici pa nts wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of 
t he s ki n, or carci n o ma i n sit u (e g, breast carci n o ma, cer vical ca ncer i n sit u) t hat ha ve 
u n der g o ne p ote ntiall y c urati ve t hera p y are n ot e xcl u de d. Partici pa nts wit h l o w -ris k 
earl y sta ge pr ostate ca ncer defi ne d as f oll o ws are n ot e xcl u de d; Sta ge T 1c or T 2a wit h 
a Gleas o n sc ore ≤ 6 a n d pr ostatic -s pecific a nti ge n ( P S A) < 1 0 n g/ m L eit her treate d 
wit h defi niti ve i nte nt or u ntreate d i n acti ve s ur veilla nce t hat has bee n sta ble f or t he 
past y ear pri or t o st u d y e nr oll me nt. Ot her e xce pti o ns ma y  be c o nsi dere d after 
c o ns ultati o n wit h t he M S D Cli nical Direct or.
2 2. Has k n o w n acti ve ce ntral ner v o us s ys te m metastases 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 partici pate 
pr o vi de d t he y  are ra di ol o gicall y sta ble, ie, wit h o ut e vi de nce of pr o gressi o n f or at least 
4 wee ks b y re peat i ma gi n g ( n ote t hat t he re peat i ma gi n g s h o ul d be perf or me d d uri n g 
st u d y scree ni n g), cli nicall y sta ble a n d wit h o ut re q uire me nt of ster oi d treat me nt f or at 
least 1 4 d a ys pri or t o first d ose of st u d y treat me nt. 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
2 3. Has a n acti ve a ut oi m m u ne disease t hat has re q uire d s y ste mic treat me nt i n past 2 ye ars 
(ie, wit h use of disease m o dif yi n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve 
dr u gs). Re place me nt t hera p y  (e g, t hyr o xi ne, i ns uli n, or p h ysi ol o gic c ortic oster oi d 
re place me nt t hera py f or a dre nal or pit uitar y i ns ufficie nc y, etc.) is n ot c o nsi dere d a 
f or m of sys te mic treat me nt a n d is all o we d .
2 4. Has a h ist or y of ( n o n-i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis.
2 5. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
2 6. Has a k n o w n hist or y  of h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n.  N o HI V 
testi n g is re q uire d u nless ma n date d by l ocal healt h a ut h orit y.
2 7. Has a k n o w n hist or y  of or is p ositi ve f or acti ve he patitis B ( defi ne d as h e patitis B 
s urface a nti ge n [H Bs A g ] reacti ve) or h e patitis C ( defi ne d as H C V R N A [ q ualitati ve] 
is detecte d).  N ote:
Testi n g m ust be perf or me 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 ne gati ve at Scree ni n g V isit.
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 here 
H C V R N A is n ot part of S o C.  I n t hese cases, H C V a nti b o d y  p ositi ve patie nts 
will be e xcl u de d.
c.
Partici pa nt s w h o ha ve ha d defi niti ve treat me nt f or H C V are per mitte d if H C V 
R N A is u n detecta ble at Scree ni n g V isit.
2 8. Has k n o w n ps yc hiatric or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h 
c o o perati n g wit h t he re q uire me nts of t he st u d y.
2 9. Has a hist or y  or c urre nt e vi de nce of a n y c o n diti o n, t hera py or la b orat or y a b n or malit y  
t hat mi g ht c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he partici pa nt’s 
partici pati o n f or t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he 
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.
3 0. Is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve or fat her c hil dre n wit hi n t he 
pr ojecte d d urati o n of t he st u d y, starti n g wit h t he Scree ni n g V isit t hr o u g h 1 2 0 da y s 
after t he last d ose of 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
a n d u p t o 1 8 0 d a y s after t he last d ose of E X T R E M E re gi me n.
Ot her E xcl usi o ns
3 1. Scree ni n g c orrecte d Q T ( Q Tc ) i nter val > 4 8 0 m illiseco n ds is e xcl u de d (Fr idericia 
f or m ula is t he preferre d met h o d. Bazett f or m ula is acce pta ble).  I n t he e ve nt t hat a 
si n gle Q Tc is >4 8 0 millisec o n ds, t he partici pa nt ma y  e nr oll if t he a vera ge Q Tc f or t he 
3 electr ocar di o gra ms ( E C Gs ) is < 4 8 0 millisec o n ds.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Lifest yle Restricti o ns
6. 3
Me als a n d Diet ar y Restricti o ns
6. 3. 1
Partici pa nts s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n 
A E s uc h as diarr hea, na usea, or v o miti n g.
O n C y cle 1 Da y 1 a n d C ycle 2 Da y 1 t he partici pa nt s h o ul d arri ve t o t he cli nic i n a fasti n g 
state t o c oi nci de wit h t he sc he d ule d bl o o d dra w .
C o ntr ace pti o n
6. 3. 2
Pe m br oliz u ma b , e paca d ostat, cet u xi ma b, cis plati n, car b o plati n a n d 5- F U m a y  ha ve a d verse 
effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if pe m br oliz u ma b , e paca d ostat, 
cet u xi ma b, cis plati n, car b o plati n a n d 5- F U h a ve tra nsie nt a d verse effects o n t he c o m p ositi o n 
of s per m.  
De vel o p me ntal a n d re pr o d ucti ve t o xicit y  st u dies ha ve n ot bee n perf or me d wit h e paca d ostat. 
E paca d ostat s h o ul d n ot be use d b y pre g na nt w o me n.
Partici pa nts s h o ul d be i nf or me d t hat ta ki n g t he st u d y treat me nt m a y  i n v ol ve u n k n o w n ris ks 
t o t he fet us ( u n b or n ba by) if pre g na nc y were t o occ ur d uri n g t he st u dy. I n or der t o 
partici pate i n t he st u d y, partici pa nts of c hil d beari n g p ote ntial m ust a d here t o t he 
c o ntrace pti o n re q uire me nt fr o m t he da y of st u dy treat me nt i nitiati o n ( or 1 4 da y s pri or t o t he 
i nitiati o n of st u d y treat me nt f or oral c o ntrace pti o n) t hr o u g h o ut t he st u dy peri o d a n d f or at 
least 1 2 0 d a y s after t he last d ose of 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, a n d f or at least 1 8 0 d a y s after t he last d ose of t he E X T R E M E re gi me n. If 
t here is a n y q uesti o n t hat a partici pa nt of c hil d beari n g p ote ntial will n ot relia bl y c o m pl y wit h 
t he re q uire me nts f or c o ntrace pti o n, t hat partici pa nt s h o ul d n ot be e ntere d i nt o t he st u d y. 
Defi niti o ns of W O C B P a n d sta n dar ds f or a de q uate c o ntrace pti o n are o utli ne d i n A p pe n di x 5.
Pre g n a nc y
6. 3. 3
If a partici pa nt bec o mes pre g na nt w hile o n treat me nt o n a ny ar m of t his st u d y, t he partici pa nt 
will be i m me diatel y  disc o nti n ue d fr o m st u d y treat me nt.  T he site will c o ntact t he partici pa nt 
at least m o nt hl y a n d d oc u me nt t he partici pa nt’s stat us u ntil t he pre g na nc y has bee n 
c o m plete d or ter mi nate d.  T he o utc o me of t he pre g na nc y will be re p orte d t o M S D
wit h o ut 
dela y  a n d wit hi n 2 4 h o urs if t he outc o me is a seri o us a d verse e x perie nce (e g, deat h, a b orti o n, 
c o n ge nital a n o mal y, or ot her disa bli n g or life -t hreate ni n g c o m plicati o n t o t he m ot her or 
ne w b or n).  T he st u d y i n vesti gat or will ma ke e ver y eff ort t o o btai n per missi o n t o f oll o w t he 
o utc o me of t he pre g na nc y  a n d re p ort t he c o n diti o n of t he fet us or ne w b or n t o M S D.   If a 
male partici pa nt i m pre g nates his fe male part ner, t he st u d y pers o n nel at t he site m ust be 
i nf or me d i m me diatel y a n d t he pre g na nc y m ust be re p orte d t o M S D a n d f oll o we d as 
descri be d i n S ecti o n 9. 3 . 6.
Use i n N ursi n g W o me n
6. 3. 4
Si nce ma n y  dr u gs are e xcrete d i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us 
a d verse reacti o ns i n t he n ursi n g i nfa nt, partici pa nts w h o are breastfee di n g are n ot eli gi ble f or 
e nr oll me nt.  S pecific a d diti o nal i nf or mati o n f oll o ws f or i n di vi d ual a ge nts use d i n t his st u d y.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
P e m br oliz u m a b
6. 3. 4. 1
It is u n k n o w n w het her pe m br oliz u ma b is e x crete d i n h u ma n mil k.  
E p ac a d ost at
6. 3. 4. 2
It is u n k n o w n w het her e paca d ostat is e xcrete d i n h u ma n mil k.
C et u xi m a b
6. 3. 4. 3
It is n ot k n o w n w het her cet u xi ma b is secrete d i n h u ma n mil k. I g G a nti b o dies, s uc h as 
cet u xi ma b, ca n be e xcrete d i n h u ma n mil k.
Cis pl ati n
6. 3. 4. 4
Cis plati n has bee n re p orte d t o be f o u n d i n h u ma n mil k; partici pa nts recei vi n g cis plati n 
i njecti o n s h o ul d n ot breast-fee d.
C ar b o pl ati n
6. 3. 4. 5
It is n ot k n o w n w het her car b o plati n is e xcrete d i n h u ma n mil k.  Beca use t here is a p ossi bilit y 
of t o xicit y  i n n ursi n g i nfa nts sec o n dar y t o car b o plati n treat me nt of t he m ot her, it is 
rec o m me n de d t hat breastfee di n g be disc o nti n ue d if t he m ot her is treate d wit h car b o plati n 
i njectio n.
5-f l u or o ur acil
6. 3. 4. 6
It is n ot k n o w n w het her 5- F U is e xcrete d i n h u ma n mil k.  Beca use 5- F U i n hi bits D N A, R N A 
a n d pr otei n s y nt hesis, m ot hers s h o ul d n ot n urse w hile recei vi n g t his dr u g.
Scree n F ail ures
6. 4
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y  b ut 
are n ot s u bse q ue ntl y ra n d o mize d i n t he st u d y.  A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Tri als ( 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 hy, 
scree n fail ure details, eli gi bilit y criteria, a n d a ny A Es or S A E s meeti n g re p orti n g 
re q uire me nts as o utli ne d i n t he e ntr y g ui deli nes.
P artici p a nt Re pl ace me nt Str ate g y
6. 5
A partici pa nt w h o disc o nti n ue s 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.
7.
Tre at me nts
St u d y  treat me nt is defi ne d as a ny i n vesti gati o nal treat me nt(s), mar kete d pr o d uct(s), place b o,
or me dical de vice (s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u dy 
pr ot oc ol.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Cli nical s u p plies [st u d y  treat me nt(s) pr o vi de d by M S D ] will be pac ka ge d t o s u p p ort 
e nr oll me nt. Cli nical s u p plies will be affi xe d wit h a cli nical la be l i n acc or da nce wit h 
re g ulat or y re q uire me nts.
Tre at me nts A d mi nistere d
7. 1
T he st u d y  treat me nt(s) t o be use d i n t his trial are o utli ne d bel o w i n Ta ble 2 .
Ta ble 2
St u d y  Treat me nts
St u d y 
Tre at m e nt 
N a m e
D os a ge 
F o r m ul ati o n
U nit D ose 
Stre n gt h(s)
D os a ge Le vel(s)
R o ute of 
A d mi nistr ati o n
S o urci n g
Pe m br oliz u ma b
S ol uti o n
2 5 m g/ m L
2 0 0 m g Q 3 W
I V i nf usi o n
Ce ntral
E paca d ostat
Ta blet 
1 0 0 m g
1 0 0 m g BI D
Oral
Ce ntral
E paca d ostat
Ta blet
2 5 m g
2 5 m g 1 BI D
Oral
Ce ntral
Cet u xi ma b
S ol uti o n
5 m g/ m L 3
4 0 0 m g/ m 2 o n 
C y cle 1, Da y 1 
t he n 2 5 0 m g/ m 2
Q W
I V i nf usi o n
Ce ntral or L ocal 2
Car b o plati n
S ol uti o n
1 0 m g/ m L 3
A U C 5 Q 3 W
I V i nf usi o n
Ce ntral or L ocal 2
Cis plati n
S ol uti o n
1 m g/ m L 3
1 0 0 m g/ m 2 Q 3 W
I V i nf usi o n
Ce ntral or L ocal 2,
5-f l u or o uracil
S ol uti o n
5 0 m g/ m L 3
1 0 0 0 m g/ m 2/ da y 
o ver Da ys 1 t o 4, 
Q 3 W
I V i nf usi o n
Ce ntral or L ocal 2
A b bre viati o ns:  A U C = area u n der t he c ur ve; BI D = t wice dail y; I V = i ntra ve n o us; Q 3 W = e ver y 3 wee ks; Q W = o nce 
wee kl y
1 I n case of pla n ne d d ose re d ucti o ns.
2 Will be pr o vi de d l ocall y i n s o me c o u ntries b y t he trial site, s u bsi diar y or desi g nee, de pe n di n g o n l ocal c o u ntr y o per ati o nal 
or re g ulat or y re q uire me nts.
3 Or e q ui vale nt f or m ulati o n 
St u d y  treat me nt s h o ul d be gi n o n t he da y  of ra n d o mizati o n or wit hi n 5 da ys of t he date o n 
w hic h t he partici pa n t is all ocate d/assi g ne d.
All pr o d ucts i n dicate d i n Ta ble 2 will be pr o vi de d ce ntrall y b y M S D or l ocall y b y t he trial 
site, s u bsi diar y, or desi g nee, de pe n di n g o n l ocal c o u ntr y o perati o nal or re g ulat or y  
re q uire me nts. E ver y  atte m pt s h o ul d be ma de t o s o urce t hese s u p plies fr o m a si n gle l ot/ batc h 
n u m ber.
Refer t o S ecti o n 9. 1. 9 f or details re gar di n g a d mi nistrati o n of t he st u d y treat me nt.
D ose M o dific ati o n
7. 2
T he C T C A E versi o n 4. 0 m ust be use d t o gra de t he se verit y of A Es.  If a p pr o priate, t he 
in vesti gat or m a y  attri b ute eac h t o xicit y e ve nt t o pe m br oliz u ma b or e paca d ostat or t he 
c o m bi nati o n i n Gr o u p 1 a n d use a ste p wise d ose re d ucti o n f or e paca d ostat acc or di n g t o 
Ta bl e 3 .  F or Gr o u p 3 ( E X T R E M E re gi me n), t he in vesti gat or ma y  attri b ute eac h t o xicit y 
e ve nt t o cis plati n or car b o plati n, 5- F U , or cet u xi ma b al o ne o r i n c o m bi nati o n of 2 or 3, a n d 
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
6 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
use a ste p wise d ose re d ucti o n acc or di n g t o Ta bl e 3 .  If a d ose re d ucti o n f or t o xicit y occ urs 
wit h a n y  a ge nt, t he d ose ma y n ot be re-escalate d. D ose m o dificati o ns are al wa y s base d o n 
t he pre vi o us c ycle.
Partici pa nts ca n ha ve 2 le vels of d ose re d ucti o ns per a ge nt t o e paca d ostat , cis plati n, 
car b o plati n, 5- F U , a n d cet u xi ma b t hr o u g h o ut t he c o urse of t he st u d y f or t o xicities as 
descri be d i n Ta bl e 3 . Refer t o t he ge neral i nstr ucti o ns i n Ta ble 4 f or g ui da nce re gar di n g t he 
re- occ urre nce of a n A E w he n a partici pa nt has ha d t heir e paca d ostat d ose re d uce d t o d ose 
le vel - 2.  D ose re d ucti o ns of p e m br oliz u ma b are n ot per mitte d. If f urt her t o xicit y occ urs or 
t he criteria f or res u mi n g treat me nt are n ot met, t he partici pa nt m ust be disc o nti n ue d fr o m t hat 
dr u g a n d m a y  c o nti n ue t o partici pate i n t he st u d y.  
F or plati n u m t o xic ities refer t o Ta ble 1 0 a n d Ta ble 1 1 , 5-F U t o xicities refer t o Ta ble 1 2 a n d
Ta ble 1 3 , a n d cet u xi ma b t o xicities refer t o Ta ble 7 , Ta ble 8 , a n d Ta ble 9 .  If a partici pa nt
e x perie nces se veral t o xicities a n d t here are c o nflicti n g rec o m me n dati o ns, f oll o w t he m ost 
c o nser vati ve d ose a dj ust me nt rec o m me n de d ( d ose re d ucti o n a p pr o priate t o t he m ost s e vere 
t o xicit y).
F or t he E X T R E M E re gi me n, re d ucti o n or h ol di n g of o ne a ge nt a n d n ot t he ot her a ge nts is 
a p pr o priate if, i n t he o pi ni o n of t he in vesti gat or, t he t o xicit y  is clearly relate d t o o ne of t he 
st u d y treat me nts. If, i n t he o pi ni o n of t he in vesti ga t or, t he t o xicit y is relate d t o t he 
c o m bi nati o n of 2 a ge nts, b ot h dr u gs s h o ul d be re d uce d or hel d acc or di n g t o rec o m me n de d 
d ose m o dificati o ns. If t he t o xicit y is relate d t o t he c o m bi nati o n of 3 a ge nts, all 3 a ge nts 
s h o ul d be re d uce d or hel d acc or di n g t o the rec o m me n de d d ose m o dificati o ns. If o ne or m ore 
st u d y a ge nt(s) are hel d f or t o xicit y, t he sc he d ule f or restarti n g t he a ge nt(s) s h o ul d c orres p o n d 
wit h t he ne xt treat me nt c ycle o nce t he t o xicit y  has res ol ve d acc or di n g t o t he rec o m me n de d 
g ui deli nes. 
Ta bl e 3
D ose M o dificati o ns f or St u d y  Treat me nts
D ose le vel 0
D ose le vel - 1
D ose le vel - 2
D ose le vel - 3
E p ac a d ost at
1 0 0 m g BI D
5 0 m g BI D 
2 5 m g BI D
Disc o nti n ue
Cis pl ati n
1 0 0 m g/ m 2
8 0 m g/ m 2
( 2 0 % decrease)
6 4 m g/ m 2
( 2 0 % decrease)
Disc o nti n ue
C ar b o pl ati n
A U C 5  
A U C 4
( 2 0 % decrease)
A U C 3
( 2 0 % decrease)
Disc o nti n ue
5 -fl u or o ur acil
1 0 0 0 m g/ m 2/ da y
8 0 0 m g/ m 2/ da y
( 2 0 % decrease)
6 4 0 m g/ m 2/ da y
( 2 0 % decrease)
Disc o nti n ue
Cet u xi m a b
4 0 0 m g/ m 2 t he n 
2 5 0 m g/ m 2
2 0 0 m g/ m 2
( 2 0 % decrease)
1 5 0 m g/ m 2
( 2 0 % decrease)
Disc o nti n ue
A b bre viati o ns:
A U C = area u n der t he c ur ve ; BI D = t wice dail y.
N ote: Pe m br oliz u ma b d ose s h o ul d n ot be m o difie d f or t o xicit y.  See Ta ble 4 f or m o dificati o n of 
p e m br oliz u ma b or epaca d ostat d osi n g sc he d ule f or dr u g -relate d A Es.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
6 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
I n vesti gat ors ma y f oll o w t he l ocal prescri bi n g i nf or mati on f or d ose m o dificati o ns of 
E X T R E M E re gi me n .  If a t o xicit y is n ot ot her wise s pecifie d, i n vesti gat ors s h o ul d refer t o t he 
la bel or l ocal S o C f or d ose a dj ust me nts.  D ose m o dificati o n acc or di n g t o Ta bl e 3 is all o wa ble 
f or i nt olera ble Gra de 2 or 3 t o xicities n ot s pecifie d i n t he ta bles bel o w at t he in vesti gat or’s 
discreti o n.  T hese d ose m o dificati o n decisi o ns m ust be d oc u me nte d i n t he partici pa nt ’s st u dy 
rec or ds a n d i n t he electr o nic case re p ort f or m ( e C R F).
E xce pti o nal circ u msta nces t o f oll o wi n g t he d ose m o dificati o n ta bles bel o w ma y be 
c o nsi dere d after c o ns ultati o n wit h M S D .
D ose M o dific ati o n f or Pe m br oliz u m a b a n d E p ac a d ost at
7. 2. 1
P e m br oliz u ma b pl us e paca d ostat m ust be wit h hel d f or dr u g -relate d se vere or life-t hreate ni n g 
A Es. T he treat me nt g ui deli nes o utli ne d i n t his secti o n are i nte n de d t o be a p plie d w he n t he 
i n vesti gat or deter mi nes if t he e ve nts are relate d t o pe m br oliz u ma b, e paca d ostat, or t he 
c o m bi nati o n.
I n all cases w here pe m br oliz u ma b d osi n g is wit h hel d, d osi n g f or e paca d ostat s h o ul d als o be 
wit h hel d u ntil pe m br oliz u ma b is res u med .  Partici pa nts are all o we d, h o we ver, t o recei ve 
pe m br oliz u ma b m o n ot hera p y if e paca d ostat is disc o nti n ue d d ue t o dr u g -relate d A Es.
E xce pt i n cases of e mer ge nc y , it is rec o m me n de d t hat t he i n vesti gat or c o ns ult wit h t he M S D 
Cli nical Direct or bef ore te m p oraril y i nterr u pti n g t hera p y or per ma ne ntl y  disc o nti n ui n g a ny 
st u d y treat me nt f or reas o ns ot her t ha n pr ot oc ol-ma n dat e d me dicati o n h ol d or disc o nti n uati o n .
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt f or i m m u ne -rel ate d A Es ass oci ate d wit h 
pe m br oliz u m a b a n d/ or e p ac a d ost at
A d verse e ve nts 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 re prese nt 
a n i m m u n ol o gic eti ol o g y.  T hese i m m u ne -relate d A Es (ir A Es) ma y occ ur s h ortl y after t he 
first d ose or se veral m o nt hs after t he last d ose of treat me nt a n d ma y affect m ore t ha n o ne
b o d y  sys te m si m ulta ne o usl y.  T heref ore, early rec o g niti o n a n d i nitiati o n of treat me nt is 
crit ical t o re d uce c o m plicati o ns.  Base d o n e xisti n g cli nical st u d y data, m ost ir A Es were 
re versi ble a n d c o ul d be ma na ge d wit h i nterr u pti o ns of pe m br oliz u ma b a n d/ or e paca d ostat , 
a d mi nistrati o n of c ortic oster oi ds a n d/ or ot her s u p p orti ve care.  F or s us pecte d ir A Es, e ns ure 
a de q uate e val uati o n t o c o nfir m eti ol o g y or e xcl u de ot her ca uses.  A d diti o nal pr oce d ures or 
tests s uc h as br o nc h osc o p y, e n d osc o p y, s ki n bi o ps y ma y be i ncl u de d as part of t he 
e val uati o n. Base d o n t he se verit y of ir A Es, wit h h ol d or per ma ne ntl y dis c o nti n ue 
pe m br oliz u ma b a n d/ or e paca d ostat a n d a d mi nister c ortic oster oi ds. Partici pa nts w h o 
e x perie nce a n u nacce pta ble t o xicit y t hat is attri b ute d t o e paca d ostat a n d n ot pe m br oliz u ma b 
i n t he o pi ni o n of t he i n vesti gat or a n d M S D ma y per ma ne ntly disc o nti n ue e paca d ostat b ut 
c o nti n ue wit h pe m br oliz u ma b as m o n ot hera py, u p o n i m pr o ve me nt of t o xicit y as per t he 
rec o m me n dati o ns i n Ta ble 4 .
D ose m o dificati o n a n d t o xicit y  ma na ge me nt g ui deli nes f or ir A Es ass ociate d wit h 
pe m br oliz u ma b or e paca d ostat are pr o vi de d i n Ta ble 4 .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
7 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt of i nf usi o n -re acti o ns rel ate d t o 
7. 2. 1. 1
pe m br oliz u m a b
Pe m br oliz u ma b ma y  ca use se vere or life t hreate ni n g i nf usi o n-reacti o ns i ncl u di n g se vere 
h y perse nsiti vit y  or a na p h yla xis.  Si g ns a n d sy m pt o ms us uall y  de vel o p d uri n g or s h ortl y after 
dr u g i nf usi o n a n d ge nerall y  res ol ve c o m pletely wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n.  
D ose m o dificati o n a n d t o xicit y  ma na ge me nt g ui deli nes o n pe m br oliz u ma b ass ociate d 
i nf usi o n reacti o n are pr o vi de d i n Ta ble 5 .  
Ta ble 5
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d Treat me nt G ui deli nes
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
Gr a de 1
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot i n dicate d; 
i nter ve nti o n n ot i n dicate d
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he 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 n al 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 w ise 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 nts w h o de vel o p Gr a de 2 t o xicit y 
des pite a de q u ate pre me dic ati o n s h o ul d be
per m a ne ntl y disc o nti n ue d fr o m  f urt her st u d y 
tre at me nt
Partici pa nt ma y be 
pre me dicate d 1. 5 h 
( ± 3 0 mi n utes) pri or t o 
i nf usi o n of pe m br oliz u ma b 
wit h:
Di p he n h y dra mi ne 5 0 m g p o 
( or e q ui vale nt d ose of 
a nti hista mi ne).
Aceta mi n o p he n 5 0 0 -1 0 0 0 m g 
p o ( or e q ui vale nt d ose of 
a nal gesic).
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
7 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
Gr a des 3 or 4
Gra de 3:
Pr ol o n ge d (ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms 
f oll o wi n g i nitial 
i mpr o ve me nt; 
h os pitalizati o n i n dicate d 
f or ot her cli nical se q uelae 
(e g, re nal i m pair me nt, 
p ul m o nar y i nfiltrates)
Gra de 4:
Life -t hreate ni n g; press or 
or ve ntilat or y s u p p ort 
i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y 
i ncl u de b ut is n ot li mite d t o:
E pi ne p hri ne * *
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he partici pa nt is dee me d me dicall y 
sta ble i n t he o pi ni o n of t he i n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla x is, e pi ne p hri ne s h o ul d be 
use d i m me diatel y.
P artici p a nt is per ma ne ntl y disc o nti n ue d fr o m  
f urt her st u d y tre at me nt.
N o s u bse q ue nt d osi n g
A b bre viati o ns: I V = i ntra ve n o us; C T C A E – C o m m o n Ter mi n ol o g y Criteria f or A Es; N S AI Ds = n o nster oi dal a nti -i nfla m mat or y 
dr u gs; N CI = Nati o nal Ca ncer I nstit ute
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g t he peri o d of
dr u g a d mi nistrati o n.
F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criter ia f or A d verse E ve nts v 4. 0 ( C T C A E) at 
htt p://cte p.ca ncer. g o v
Pr oce d ures f or P artici p a nt s E x hi biti n g Ser ot o ni n S y n dr o me
7. 2. 1. 2

T here is a rare c ha nce t hat e paca d ostat c o ul d ca use 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 ser ot o ni n sy n dr o me [ 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 gic a ge nts.  T his s y n dr o me has bee n 
m ost cl osel y  ass ociate d wit h use of M A OIs, me peri di ne, li nez oli d, or met h yle ne bl ue; 
all of t hese a ge nts are pr o hi bite d d uri n g t he st u dy (see A p pe n di x 7 ).  Selecti ve
ser ot o ni n re u pta 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 RIs) are per mitte d i n t he st u d y.  Ser ot o ni n s y n dr o me 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 vere si g ns a n d s y m pt o ms of ser ot o ni n s yn dr o me (s u m marize d 
i n Ta ble 6 ) 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 h e f oll o wi n g pr oce d ures will be i m ple me nte d if partici pa nt s i n Gr o u p 1 e x hi bit t he 
si g ns/s ym pt o ms of ser ot o ni n s yn dr o me descri be d i n Ta ble 6 , 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, fe ver, 
dia p h oresis, or m uscle ri gi dit y:

I m me diatel y i nterr u pt e paca d ostat a n d pe m br oliz u ma b a d mi nistrati o n.  

I m me diatel y i nterr u pt a n y S S RI or S N RI a d mi nistrati o n.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial

Pr o vi de a p pr o priate me dical ma na ge me nt of t he partici pa nt u ntil all si g ns/s y m pt o ms 
are res ol ve d (e g, I V fl ui ds a n d/ or s y m pat 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 gi tati o n, a d mi nistrati o n of 5-h y dr o x yt r ypta mi ne a nta g o nists 
s uc h as c ypr o he pta di ne).

If eti ol o gies ot her t ha n ser ot o ni n s yn dr o me are e xcl u de d, pe m br oliz 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 ve nt.

If partici pa nt c h o oses t o re mai n i n t he st u d y , restart treat me nt wit h e paca d ostat after 
t he S S RI or S N RI has bee n disc o nti n ue d, n o s o o ner t ha n after 5 half -li ves ha ve 
ela pse d f or t he s pecific 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 ym pt o ms of ser ot o ni n s yn dr o me .  T he S S RI or S N RI d osi n g M A Y N O T be 
restarte d.

If partici pa nt c h o oses t o wit h dra w fr o m t he st u d y,  or m ust restart treat me nt wit h S S RI 
or S N RI , t he partici pa nt s h o ul d be sc he d ule d f or a F oll o w -u p V isit.  Treat me nt wit h 
S S RI  or S N RI m a 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 
ser ot o ni n s yn dr o me .

If a partici pa nt ha d e x perie nce d m o derate or se vere u nc o nf o u n de d S S i n t he o pi ni o n 
of t he i n vesti gat or, wit h o ut c o nc o mita nt S S RI  or S N RI usa ge, or ser ot o ner gic 
c o nc o mita nt m e 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 6
Si g ns a n d S y m pt o ms of Ser ot o ni n S y n dr o me
Seri o us ness
A ut o n o mic si g ns
Ne ur ol o gic al si g ns
Me nt al st at us  
Ot her
Mil d
Afe brile or l o w -gra de 
fe ver
Tac h ycar dia
M y driasis
Dia p h oresis or s hi veri n g
I nter mitte nt tre m or
A kat hisia
M y ocl o n us
Mil d h y perrefle xia
Restless ness
A n xiet y
M o der ate
I ncrease d tac h ycar dia
Fe ver ( u p t o 4 1 °C)
Diarr hea wit h h y peracti ve 
b o w el s o u n ds
Dia p h oresis wit h n or mal 
s ki n c ol or
H y perrefle xia
I n d uci ble cl o n us
Oc ular cl o n us (sl o w 
c o nti n u o us lateral e ye 
m o ve me nts)
M y ocl o n us
Easil y startle d
I ncrease d 
c o nf usi o n
A gitati o n a n d 
h y per vi gila nce
R ha b d o m y ol ysis
Meta b olic aci d osis
Re nal fail ure
Disse mi nate d 
i ntra vasc ular 
c oa g ul o pat h y 
(sec o n dar y t o 
h y pert her mia)
Se vere
T e m perat ure ofte n m ore 
t ha n 4 1°C ( Sec o n dar y t o 
i ncrease d t o ne)
I ncrease d m uscle t o ne 
(l o wer li m b > u p per)
S p o nta ne o us cl o n us
S u bsta ntial m y ocl o n us 
or h y perrefle xia
Deliri u m
C o m a
As a b o ve
S o urce: [ Bo yer E W, S ha n n o n M. 2 0 0 5]
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
D ose M o dific ati o ns f or Cet u xi m a b
7. 2. 2
F or a n y d ela ye d cet u xi ma b treat me nt, d o n ot re peat t he i nitial d ose of 4 0 0 m g/ m².  At t he 
restart of cet u xi ma b treat me nt, all s u bse q ue nt i nf usi o ns will be at t he a p pr o priate d ose le vel 
acc or di n g t o Ta ble 7 , Ta ble 8 , a n d Ta ble 9 .  If a partici pa nt de vel o ps a t o xicit y  t hat ma n dates 
i nterr u pti o n of t hera py, t he t o xicit y m ust res ol ve wit hi n 1 2 wee ks fr o m t he last d ose of 
cet u xi ma b or t he dr u g s h o ul d be disc o nti n ue d wit h t he e xce pti o n of a partici pa nt w h o is 
cli nicall y sta ble a n d cli nicall y be nefiti n g fr o m cet u xi ma b treat me nt.  In t his case, t he 
in vesti gat or ma y  re q uest that M S D all o w t he partici pa nt t o c o nti n ue t o recei ve cet u xi ma b.
Cet u xi ma b t hera p y will n ot be dela ye d f or c he m ot hera p y- relate d t o xicit y.  If c he m ot hera py 
a d mi nistrati o n is dela ye d, t he partici pa nt m a y  c o nti n ue t o recei ve wee kl y i nf usi o ns of 
cet u xi ma b. Aft er res ol uti o n of t o xicit y, plati n u m a n d/ or 5- F U m a y  be restarte d at a ny 
wee kl y visit w he n cet u xi ma b is gi ve n (ie Da y 8 or Da y 1 5 of a c ycle) as l o n g as t here are 
≥3 wee ks d urati o n bet wee n c o nsec uti ve c he m ot hera p y c ycl es .  T he i nter val bet wee n 
plati n u m a n d/ or 5- F U i nf usi o ns will c o nti n ue as Q 3 W fr o m t he ti me of t he restart. If 
partici pa nt o n t he cet u xi ma b + plati n u m + 5- F U ar m are re q uire d t o ha ve t he plati n u m a n d/ or 
5- F U disc o nti n ue d f or t o xicit y , t he partici pa nt ma y  c onti n ue t o recei ve cet u xi ma b al o ne.  I n 
t he case of cet u xi ma b t o xicit y, partici pa nt m a y  c o nti n ue o n c he m ot hera py al o ne.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
Ta ble 7  
D ose M o dificati o n G ui deli nes f or Cet u xi ma b Dr u g- Relate d A d verse E ve nts
C ate g or y
T o xicit y
H ol d 
Cet u xi m a b
Tre at m e nt f or 
Gr a de
Ti mi n g f or Rest arti n g 
Cet u xi m a b Tre at me nt
D ose f or Rest arti n g Cet u xi m a b
Tre at m e nt
Disc o nti n ue Cet u xi m a b
N o n he mat ol o gic
I nf usi o n reacti o n
2- 4
See Secti o n 7. 2. 2 . 1 a n d Ta ble 8
Ras h
3- 4
See Secti o n 7. 2. 2 . 2 a n d Ta ble 9
All ot her 
n o n he mat ol o gic 
t o xicities1
3- 4
T o xicit y res ol ves t o 
Gra de 0 - 1
Re d uce b y 1 d ose le vel
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
La b orat or y A E 2
4
T o xicit y res ol ves t o 
Gra de 2 or less
A b bre viati o ns: A E = a d verse e ve nt
N ote:  Per ma ne nt disc o nti n uati o n s h o ul d be c o nsi dere d f or a n y se vere or life -t hreate ni n g e ve nt. C o ns ult M S D
bef ore restarti n g treat me nt after Gra de 4 dr u g -relate d A E.
1
Partici pa nts wit h i nt olera ble or persiste nt Gra de 2 dr u g- relate d A E ma y h ol d at p h ysicia n discreti o n.  Per ma ne ntl y disc o nti n ue fr o m a ge nt f or persiste nt Gra de 2 a d verse 
reacti o ns f or w hic h treat me nt has bee n hel d, a n d di d n ot rec o ver t o Gra de 0-1 wit hi n 1 2 wee ks of t he last d ose.  
2
Wit h in vesti gat or a n d M S D
a gree me nt, partici pa nt s wit h a la b orat or y A E still at Gra de 2 after 1 2 wee ks ma y c o nti n ue i n t he st u d y o nl y if as y m pt o matic a n d c o ntr olle d.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
I nf usi o n Re acti o ns
7. 2. 2. 1
Partici pa nts w h o e x perie nce cet u xi ma b -relate d i nf usi o n reacti o ns s h o ul d ha ve cet u xi ma b 
re d uce d acc or di n g t o Ta ble 8 a n d c o nti n ue t o recei ve a nti hista mi ne pre me dicati o n pri or t o 
a d mi nistrati o n.  O nce t he cet u xi ma b i nf usi o n rate has bee n decrease d d ue t o a n 
aller gic/ h y perse nsiti vit y  reacti o n, it s h o ul d re main decrease d f or all s u bse q ue nt i nf usi o ns.
If t he partici pa nt e x perie nces a sec o n d i nf usi o n reacti o n at t he decrease d rate, cet u xi ma b 
m ust be disc o nti n ue d.  If a n y  Gra de 3 or 4 i nf usi o n reacti o n occ urs, cet u xi ma b treat me nt 
m ust be disc o nti n ue d i m me diatel y . Partici pa nts w h o e x perie nce seri o us i nf usi o n reacti o ns 
will be disc o nti n ue d fr o m cet u xi ma b. T he partici pa nt ma y  c o nti n ue t o recei ve c he m ot hera py 
as sc he d ule d.
Ta ble 8
Cet u xi ma b D ose M o dificati o n f or I nf usi o n Reacti o ns
N CI 
C T C A E 
Gr a de
H ol d Tre at me nt 
( Yes/ No)
D ose f or Rest arti n g Tre at me nt
1
N o
Decrease t he cet u xi ma b i nf usi o n rate b y 5 0 % a n d 
m o nit or cl osel y f or a n y w orse ni n g. 
N ote: T he t otal i nf usi o n ti me f or cet u xi ma b s h o ul d n ot 
e xcee d 4 h o urs.
2
Y es
St o p cet u xi ma b i nf usi o n a n d 
a d mi nister br o nc h o dilat ors, 
o x y ge n, etc. as me dicall y 
i n dicate d.
Res u me i nf usi o n at 5 0 % of pre vi o us rate o nce 
aller gic/ h y perse nsiti vit y reacti o n has res ol ve d or 
decrease d t o Gra de 1 i n se verit y, a n d m o nit or cl osel y f or 
a n y w orse ni n g .
3 - 4
Y es
St o p t he cet u xi ma b i nf usi o n 
i m me diatel y a n d disc o n nect 
i nf usi o n t u bi n g fr o m t he 
partici pa nt
St o p t he cet u xi ma b i nf usi o n i m me diatel y a n d disc o n nect 
i nf usi o n t u bi n g fr o m t he partici pa nt . A d mi nister 
e pi ne p hri ne, br o nc h o dilat ors, a nti hista mi nes, 
gl uc oc ortic oi ds, i ntra ve n o us fl ui ds, vas o press or a ge nts, 
o x y ge n, etc., as me dicall y i n dicate d.
P artici p a nt m ust disc o nti n ue tre at me nt wit h 
cet u xi m a b per m a ne ntl y .
A b bre viati o ns:  N CI C T C A E = Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
Der m at ol o gic T o xicit y
7. 2. 2. 2
T he d osi n g of cet u xi ma b will be o mitte d 1 t o 2 wee ks i n t he case of se vere ( Gra de 3 or 4) 
ac neif or m ras h.  If ac neif or m ras h i m pr o ves d uri n g t his ti me, t he n t he d ose of cet u xi ma b 
s h o ul d be re d uce d as i n dicate d i n Ta ble 9 .  T he d ose m o dificati o n g ui deli nes i n Ta ble 7
s h o ul d be f oll o we d f or der mat ol o gic t o xicities ot her t ha n ac neif or m ras h.
If ac neif or m ras h d oes n ot i m pr o ve d uri n g t his ti me, cet u xi ma b will be disc o nti n ue d.  
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Partici pa nts w h o ha ve hel d cet u xi ma b t hera p y  f or m ore t ha n 2 c o nsec uti ve i nf usi o ns d ue t o 
ac neif or m ras h, a n d u p o n res ol uti o n of t he t o xicit y are still felt t o be be nefiti n g fr o m 
cet u xi ma b treat me nt ma y res u me cet u xi ma b wit h M S D
a p pr o val.  
Ta ble 9
Cet u xi ma b D ose M o dificati o n f or Se vere Ac neif or m Ras h
Se vere Ac neif or m 
R as h ( Gr a de 3)
D ose 
I nterr u pti o n
O utc o me
D ose M o dific ati o n
1 st occ urre nce
O m it 1-2 d oses
I m pr o ve da
N o ne, c o nti n ue at sa me d ose
2 n d occ urre nce
O m it 1-2 wee ks
I m pr o ve da
Per ma ne ntl y re d uce b y 1 d ose le vel b
3 r d occ urre nce
O m it 1-2 wee ks
I m pr o ve da
Per ma ne ntl y re d uce b y a n ot her d ose 
le vel b
4 t h occ urre nce
Disc o nti n ue
N/ A  
N/ A
A b bre viati o ns: N/ A = n ot a p plica ble
a
If ras h d oes n ot i m pr o ve, t he n disc o nti n ue cet u xi ma b.
b
Disc o nti n ue cet u xi ma b if d ose is less t ha n 1 5 0 m g/ m 2
D ose M o dific ati o ns f or Cis pl ati n or C ar b o pl ati n
7. 2. 3
I n vesti gat ors ma y s witc h partici pa nts fr o m cis plati n t o car b o plati n d uri n g t he c o urse of t he 
st u d y if t o xicities occ ur.  If t he cis plati n d ose was m o difie d pri or t o s witc hi n g, t he part ici pa nt 
ma y  start at a car b o plati n d ose of A U C 5 a n d will be eli gi ble t o recei ve a n a d diti o nal 2 d ose 
m o dificati o ns of car b o plati n.  
Ta ble 1 0
D ose M o dificati o n G ui deli nes f or Fe brile Ne utr o pe nia or D oc u me nte d I nfecti o n
A d verse E ve nt
N u m ber of 
Occ urre nces
Tre at me nt M o dific ati o n
Fe brile ne utr o pe nia a
D oc u me nte d i nfecti o n
1
Re d uce b y 1 d ose le vel
T he use of gr o wt h fact ors a n d a nti bi otics s h o ul d be 
c o nsi dere d per l ocal sta n dar ds
2 
Re d uce b y  1 d ose le vel
C o nsi der pr o p h y lactic a nti bi otics f or s u bse q ue nt 
c ycles.
T he use of gr o wt h fact ors s h o ul d be str o n gl y 
c o nsi dere d per l ocal sta n dar ds
3
Disc o nti n ue plati n u m
a
A N C < 1 0 0 0/ m m 3 ( 1. 0 × 1 09/ L) a n d a si n gle te m perat ure > 3 8. 3° C or s ustai ne d te m perat ure ≥3 8° C 
f or > 1 h o ur.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Ta ble 1 1
D ose M o dificati o n G ui deli nes f or Plati n u m Dr u g -Relate d A d verse E ve nts
C ate g or y
T o xicit y
H ol d Pl ati n u m  
Tre at m e nt f or 
Gr a de
Ti mi n g f or Rest arti n g 
Pl ati n u m Tre at me nt
D ose f or Rest arti n g Pl ati n u m 
Tre at m e nt
Disc o nti n ue Pl ati n u m
H e m at ol o gic
Ne utr o pe nia
3 1
Ne utr o p hil c o u nt res ol ves t o 
> 1, 0 0 0/ m m 3
( 1. 0 × 1 0 9/ L)
N o re d ucti o n
*c o nsi der G -C S F
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
4 1
Re d uce b y 1 d ose le vel
*c o nsi der G -C S F
T hr o m b oc yt o pe nia
2
Platelet c o u nt res ol ves t o 
≥7 5, 0 0 0/ m m 3
( 7 5 × 1 0 9/ L) or baseli ne
N o re d ucti o n
3- 4 1
Re d uce b y 1 d ose le vel
N o n he mat ol o gic
Creati ni ne i ncrease d
2- 4 1
T o xicit y res ol ves t o 
Gra de 0 - 1
F or partici pa nts ta ki n g 
Car b o plati n, re d uce b y 1 d ose le vel
F or partici pa nts ta ki n g Cis plati n, 
c ha n ge Cis plati n t o Car b o plati n
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
Ot ot o xicit y or 
se ns or y ne ur o pat h y
2
C ha n ge Cis plati n t o Car b o plati n
M a y  c o nti n ue treat me nt wit h Car b o plati n
3- 4
M a y  s witc h Cis plati n t o Car b o plati n if res ol ve d t o Gra de ≤ 2 w it hi n 1 2 wee ks of last i nf usi o n
If alrea d y usi n g car b o plati n, t he n disc o nti n ue
All ot her 
n o n he mat ol o gic 
t o xicities2
3- 4 1
T o xicit y res ol ves t o 
Gra de 0 - 1
Re d uce b y 1 d ose le vel
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
La b orat or y A E 2
4
T o xicit y res ol ves t o 
Gra de 2 or less
A b bre viati o ns:  A E = a d verse e ve nt; G- C S F = gra n u loc yte - c ol o n y sti m ulati n g fact or.
1 Per ma ne nt disc o nti n uati o n s h o ul d be c o nsi dere d f or a n y se vere or life -t hreate ni n g e ve nt. C o ns ult M S D
bef ore restarti n g treat me nt after Gra de 4 dr u g -relate d A E.
2 Partici pa nts wit h i nt olera ble or persiste nt Gra de 2 dr u g -relate d A E ma y h ol d at p h ysicia n discreti o n.  Per ma ne ntl y disc o nti n ue fr o m a ge nt f or persiste nt Gra de 2 a d verse reacti o ns 
f or w hic h treat me nt has bee n hel d, a n d di d n ot rec o ver t o Gra de 0-1 wit hi n 1 2 wee ks of t he last d ose.  Wit h in vesti gat or a n d M S D
a gree me nt, partici pa nts wit h a la b orat or y A E
still at Gra de 2 after 1 2 wee ks ma y c o nti n ue i n t he st u d y o nl y if as y m pt o matic a n d c o ntr olle d.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
D ose M o dific ati o ns f or 5 -fl u or o ur acil
7. 2. 4
Ta ble 1 2
D ose M o dificati o n G ui deli nes f or Fe brile Ne utr o pe nia or D oc u me nte d I nfecti o n
A d verse E ve nt
N u m ber of 
Occ urre nces
Tre at me nt M o dific ati o n
Fe brile ne utr o pe nia a
D oc u me nte d i nfecti o n
1
Re d uce b y 1 d ose le vel
T he use of gr o wt h fact ors a n d a nti bi otics s h o ul d be 
c o nsi dere d per l ocal sta n dar ds
2
Re d uce b y 1 d ose le vel
C o nsi der pr o p h y lactic a nti bi otics f or s u bse q ue nt 
c ycles.
T he use of gr o wt h fact ors s h o ul d be str o n gly 
c o nsi dere d per l ocal sta n dar ds
3
Disc o nti n ue 5 -fl u or o uracil
a
A N C < 1 0 0 0/ m m 3 ( 1. 0 × 1 09/ L) a n d a si n gle te m perat ure > 3 8. 3° C or s ustai ne d te m perat ure ≥3 8° C 
f or > 1 h o ur.
 
 
0 4 Y B M H

Pr o d uct:   M K -3 4 7 5/I N C B 0 2 4 3 6 0 
8 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9- 0 4 / E C H O- 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n-2 0 1 8
C o nfi de ntial
Ta ble 1 3
D ose M o dificati o n G ui deli nes f or 5 -fl u or o uracil Dr u g-Relate d A d verse E ve nts
C ate g or y
T o xicit y
H ol d 
5- fl u or o ur acil 
Tre at m e nt f or 
Gr a de
Ti mi n g f or Rest arti n g 
5-f l u or o ur acil Tre at m e nt
D ose f or Rest arti n g 
5-f l u or o ur acil Tre at m e nt
Disc o nti n ue 5-f l u or o ur acil
H e m at ol o gic
Ne utr o pe nia
3 1
Ne utr o p hil c o u nt res ol ves t o 
> 1, 0 0 0/ m m 3
( 1. 0 × 1 0 9/ L)
N o re d ucti o n
*c o nsi der G -C S F
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
4 1
Re d uce b y 1 d ose le vel
*c o nsi der G -C S F
T hr o m b oc yt o pe nia
2
Platelet c o u nt res ol ves t o 
≥7 5, 0 0 0/ m m 3
( 7 5 × 1 0 9/ L) or baseli ne
N o re d ucti o n
3- 4 1
Re d uce b y 1 d ose le vel
N o n he mat ol o gic
Creati ni ne i ncrease d
2- 4 1
T o xicit y res ol ves t o 
Gra de 0 - 1
N o re d ucti o n
T o xicit y d oes n ot res ol ve 
wit hi n 1 2 w ee ks of last 
i nf usi o n or if > 2 d ose le vel 
re d ucti o ns e xcee de d
M uc ositis
Diarr hea
2- 4 1
Re d uce b y 1 d ose le vel
Ha n d -f o ot s y n dr o me
2
N o re d ucti o n
3- 4 1
Re d uce b y 1 d ose le vel
All ot her 
n o n he mat ol o gic 
t o xicities2
3- 4 1
La b orat or y A E 2
4
T o xicit y res ol ves t o 
Gra de 2 or less
A b bre viati o ns:  A E = a d verse e ve nt; G- C S F = gra n ul oc yte - c ol o n y sti m ulati n g fact or.
1
Per ma ne nt disc o nti n uati o n s h o ul d be c o nsi dere d f or a n y se vere or life -t hreate ni n g e ve nt. C o ns ult M S D
bef ore restarti n g treat me nt after Gra de 4 dr u g -relate d A E.
2
Partici pa nts wit h i nt olera ble or persiste nt Gra d e 2 dr u g-relate d A E ma y h ol d at p h ysicia n discreti o n.  Per ma ne ntl y disc o nti n ue fr o m a ge nt f or persiste nt Gra de 2 a d verse 
reacti o ns f or w hic h treat me nt has bee n hel d, a n d di d n ot rec o ver t o Gra de 0-1 wit hi n 1 2 wee ks of t he last d ose.  Wit h in vesti gat or a n d M S D
a gree me nt, partici pa nt s wit h a 
la b orat or y A E still at Gra de 2 after 1 2 wee ks ma y c o nti n ue i n t he st u d y o nl y if as y m pt o matic a n d c o ntr olle d.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
D ose Interr u pti o n s U nrel ate d t o A d verse E ve nts
7. 2. 5
D osi n g i nterr u pti o ns are per mitte d f or sit uati o ns ot her t ha n treat me nt-relate d A Es, s uc h as i n 
t he case of me dical /s ur gical e ve nts or l o gistical reas o ns n ot relate d t o st u dy treat me nt (e g, 
electi ve s ur ger y, u nrelate d me dical e ve nts, partici pa nt vacati o n, or h oli da ys).  Partici pa nts 
s h o ul d be place d bac k o n st u d y treat me nt wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, 
u nless ot her wise disc usse d wit h M S D .  T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n 
t he partici pa nt’s st u dy rec or d.
Sec o n d C o urse P h ase
7. 2. 6
N ote: As of A me n d me nt 0 4, i m a gi n g assess me nts will be n o l o n ger be m a de b y BI C R; 
all dise ase pr o gressi o n will be assesse d b y t he in vesti g at or b ase d o n R E CI S T 1. 1. T his 
secti o n h as bee n u p d ate d acc or di n gl y.
Gr o u p 1 a n d 2 partici pa nts w h o st o p pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b
m o n ot hera p y, wit h S D or better ma y  be eli gi ble f or u p t o a n a d diti o nal 1 7 c ycles 
(a p pr o xi matel y 1 year) of pe m br oliz u ma b pl us e paca d ostat , or pe m br oliz u ma b m o n ot hera p y
if t he y pr o gress a n d ha ve a ra di o gra p hic disease pr o gressi o n after st o p pi n g pe m br oliz u ma b 
pl us e paca d ostat , or pe m br oliz u ma b m o n ot hera p y fr o m t he i nitial Treat me n t Phase.  T his 
retreat me nt is ter me d t he Sec o n d C o urse P hase of t his st u d y a n d is o nl y a vaila ble if t he st u d y
re mai ns o pe n a n d t he partici pa nt meets t he f oll o wi n g c o n diti o ns:
Eit her

St o p pe d i nitial treat me nt of pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b
m o n ot hera p y after attai ni n g a C R e val uate d b y  t he l ocal i n vesti gat or base d o n 
R E CI S T 1. 1, a n d
o
Was treate d wit h at least 2 4 wee ks (at least 8 i nf usi o ns of pe m br oliz u ma b) bef ore 
disc o nti n ui n g treat me nt, a n d
o
Recei ve d at least 2 c ycles of t he pe m br oliz u ma b pl us e paca d ostat or 
pe m br oliz u ma b m o n ot hera p y b e y o n d t he date w he n t he i nitial C R was declare d
O R

Ha d S D, P R, or C R a n d st o p pe d st u d y treat me nt after c o m pleti o n of 3 5 c ycles of 
pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b m o n ot hera p y (a p pro xi matel y  
2 ye ars) f or reas o ns ot her t ha n ra di o gra p hic disease pr o gressi o n or i nt olera bilit y
A N D

E x perie nce d a n i n vesti gat or -deter mi ne d ra di o gra p hic disease pr o gressi o n b y 
R E CI S T 1. 1 after st o p pi n g i nitial treat me nt wit h pe m br oliz u ma b pl us e paca d ostat or 
pe m br oliz u ma b m o n ot hera p y , a n d
o
N o ne w a ntica ncer treat me nt was a d mi nistere d after t he last d ose of
pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b m o n ot hera p y , a n d
o
C o nti n ues t o m eet all of t he safet y p ara meters liste d i n t he i ncl usi o n criteria a n d 
n o ne of t he safet y para meters liste d i n t he e xcl usi o n criteria, a n d
o
T he st u d y is o n g oi n g
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
8 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Partici pa nts w h o e nter t he Sec o n d C o urse P hase will be retreate d at t he sa me c o m bi nati o n,
d ose le vel, a n d fre q ue nc y as w he n t he y last recei ve d pe m br oliz u ma b pl us e paca d ostat o r 
pe m br oliz u ma b m o n ot hera p y.   Treat me nt will be a d mi nistere d f or u p t o a n a d diti o nal 
1 7 c ycles (a p pr o xi matel y 1 year) usi n g t he Sec o n d C o urse P hase S o A i n Secti o n 2. 2 .
Met h o d of Tre at me nt Assi g n me nt 
7. 3
Treat me nt all ocati o n/ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve v oice res p o nse 
s yste m / i nte grate d we b res p o nse sys te m (I V R S/I W R S).  T here are 3 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 2: 1: 2 rati o t o pe m br oliz u ma b pl us e paca d ostat , 
pe m br oliz u ma b m o n ot hera p y, a n d E X T R E M E re gi me n, res pecti vely.
In vesti gat ors m ust c h o ose w hic h plati n u m dr u g will be use d (car b o plati n or cis plati n) pri or t o 
ra n d o mizati o n. T he selecti o n will be d oc u me nte d i n t he st u d y data base via I V R S/I W R S 
( See Data E ntr y  G ui deli nes).
Str atific ati o n
7. 3. 1
Treat me nt all ocati o n/ra n d o mizati o n will be stratifie d acc or di n g t o t he f oll o wi n g fact ors:
1.
E C O G P S ( 0 vs. 1).
2.
H P V p 1 6 stat us ( o r o p har y n x-p 1 6 p ositi ve vs. o r o p har yn x -p 1 6 ne gati ve or 
lar yn x/ h y p o p har y n x/ oral ca vit y  H N S C C).
3.
Pri or s y ste mic o nc ol o gical t hera py (as t he part of t he defi niti ve treat me nt f or t he 
l ocall y a d va nce d disease) ( yes vs. n o).   
Bli n di n g 
7. 4
T his is a n o pe n -la bel st u d y; t heref ore, 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 st u d y treat me nt a d mi nistere d.
N ote: As of A me n d me nt 0 4, i m a gi n g assess me nts will be n o l o n ger be m a de b y BI C R; 
all dise ase pr o gressi o n will be assesse d b y t he in vesti g at or b ase d o n R E CI S T 1. 1.
 
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
T he rati o nale f or selecti o n of d oses t o be use d i n t his st u d y is pr o vi de d i n Secti o n 5. 5 .
Details o n pre parati o n a n d a d mi nistrati o n of I V pe m br oliz u ma b are pr o vi de d i n t he 
P har mac y  Ma n ual. E paca d ostat is a n oral ta blet a n d d oes n ot re q uire pre parati o n.
F or e paca d ostat i n s uc h cases w here a partici pa nt is u na ble t o s wall o w ta blets or has a 
fee di n g t u be i nstr ucti o n f or d ose cr us hi n g, a d mi nistrati o n a n d d ose pre parati o n are detaile d i n 
t he P har mac y Ma n ual.  I n a d diti o n writte n g ui da nce f or safe ha n dli n g of t he e paca d ostat 
ta blets will be pr o vi de d t o t he partici pa nt/care gi vers.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 0
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Gr o u p 3 ( E X T R E M E re gi me n) treat me nts will be pre pare d a n d a d mi nistere d as per t he 
a p pr o ve d pr o d uc t la bel.  T he b o d y s urface area i n m2 s h o ul d be calc ulate d per l ocal g ui da nce.
Cet u xi ma b will be a d mi nistere d at a d ose of 4 0 0 m g / m2 as a n I V i nf usi o n o n Da y 1 of t he 
st u d y f oll o we d by s u bse q ue nt wee kl y d oses of 2 5 0 m g / m2 as I V i nf usi o ns.
Car b o plati n will be a d mi nistere d at a n A U C of 5 m g/ m L per mi n ute as a n I V i nf usi o n o n 
D a y 1 of a 3 -wee k c y cle.  P urs ua nt t o t he C T E P I nf or mati o n Letter Re gar di n g t he A U C 
Base d D osi n g of Car b o plati n, t he ma xi m u m car b o plati n d ose s h o ul d n ot e xcee d t he tar get 
A U C ( m g * mi n/ m L) * 1 5 0 m L / mi n, b ut it ma y be less. As well, t he gl o mer ular filtrati o n rate 
( G F R) use d i n t he Cal vert f or m ula t o A U C-base d d osi n g s h o ul d n ot e xcee d 1 2 5 m L / mi n. 
F or t his st u d y, t he ma xi m u m d ose of car b o plati n ca n n ot e xcee d a t otal d ose of 7 5 0 m g . 
Alterati o ns i n re nal f u ncti o n ma y  re q uire a recalc ulati o n of t he car b o plati n d ose.
Cis plati n will be a d mi nistere d at a d ose of 1 0 0 m g / m2 as a n IV i nf usi o n o n Da y 1 of a 
3- wee k c y cle.   
5- F U will be a d mi nistere d at a d ose of 1 0 0 0 m g / m2/da y  as a c o nti n u o us I V i nf usi o n f or 
4 da y s o n Da ys 1 t o 4 of a 3 -wee k c y cle.
Pre parati o n of st u d y treat me nts s h o ul d f oll o w t he l ocal pr o d uct la bel.
H a n dli n g, St or a ge a n d Acc o u nt a bilit y
7. 5. 2
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y treat me nt recei ve d a n d a n y discre pa ncies are re p orte d 
a n d res ol ve d bef ore use of t he st u d y treat me nt.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nl y a ut h orize d site 
staff ma y s u p ply or a d mi nister st u d y  treat me nt. All st u d y treat me nts m ust be st ore d i n a 
sec ure, e n vir o n me ntally c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d site 
staff.
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u dy treat me nt acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
F or all t rial sites, t he l ocal c o u ntr y M S D
pers o n nel or desi g nee will pr o vi de a p pr o priate 
d oc u me ntati o n t hat m ust be c o m plete d f or dr u g acc o u nta bilit y  a n d ret ur n, or l ocal discar d 
a n d destr ucti o n if a p pr o priate.  W here l ocal discar d a n d destr ucti o n is a p pr o priate, t he 
i n vesti gat or is res p o nsi ble f or e ns uri n g t hat a l ocal discar d/ destr ucti o n pr oce d ure is 
d oc u me nte d.
T he trial site is res p o nsi ble f or rec or di n g t he l ot n u m ber, ma n ufact urer, a n d e x pir y  date f or 
a n y l ocally p urc hase d pr o d uct as per l ocal g ui deli nes u nles s ot her wise i nstr ucte d by M S D .
T he i n vesti gat or s hall ta ke res p o nsi bilit y  f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p pl y, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of st u dy 
treat me nts i n acc or da nce wit h t he pr ot oc ol a n d a n y a p plica ble la ws a n d re g ulati o ns.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Tre at me nt C o m pli a nce
7. 6
C o m plia nce wit h st u d y treat me nts s h o ul d be e m p hasize d t o t he partici pa nt s b y t he site 
pers o n nel, a n d a p pr o priate ste ps s h o ul d be ta ke n t o o pti mize c o m plia nce d uri n g t he st u d y.  
I nterr u pti o ns fr o m t he pr ot oc ol-s pecifie d treat me nt pla n f or m ore t ha n 3 wee ks f or n o n dr u g-
relate d or a d mi nistrati ve reas o ns re q uire c o ns ultati o n bet wee n t he in vesti gat or a n d M S D
a n d 
writte n d oc u me ntati o n of t he c olla b orati ve decisi o n o n partici pa nt ma na ge me nt. 
C o m pli a nce of Pe m br oliz u m a b
7. 6. 1
A d mi nistrati o n of pe m br 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 o l u me of pe m br oliz u ma b 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 nister e d. 
C o m pli a nce of E p ac a d ost at
7. 6. 2
Partici pa nts will self -a d mi nister e paca d ostat e xce pt o n C ycle 1 Da y 1 a n d C ycle 2 Da y 1, 
w he n t he m or ni n g d ose will be gi ve n at t he st u d y site cli nic.
Partici pa nts will be i nstr ucte d t o 
bri n g all re mai ni n g e paca d ostat ta blets wit h t he m t o t he st u d y  visits i n or der f or site 
pers o n nel t o c o n d uct ta blet c o u nts t o assess st u d y treat me nt acc o u nta bilit y.  
C o m pli a nce of E X T R E M E Re gi me n
7. 6. 3
A d mi nistrati o n of cis plati n/ car b o plati n, 5 -F U, a n d cet u xi 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. C o m plia nce wit h t hese refere nce t hera pies will be 
d oc u me nte d i n t he me di cal rec or d a n d m o nit ore d b y M S D or its desi g nee.  
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 xcl usi o n criteria are n o t all o we d 
d uri n g t he st u d y.  If t here is a cli nical i n dicati o n f or a ny me dicati o n or vacci nati o n 
s pecifically pr o hi bite d, disc o n ti n uati o n fr o m st u d y treat me nt m a y  be re q uire d.  T he 
i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he M S D
Cli nical Direct or .  T he 
fi nal decisi o n o n a ny s u p p orti ve t hera p y or vacci nati o n rests wit h t he i n vesti gat or a n d/ or t he 
partici pa nt's pri mar y  p hysicia n.  H o we ver, t he decisi o n t o c o nti n ue t he partici pa nt o n st u d y 
treat me nt re q uires t he m ut ual a gree me nt of the i n vesti gat or, M S D , a n d t he partici pa nt.
Per mitte d Me dic ati o ns
7. 7. 1
All treat me nts t hat t he in vesti gat or c o nsi ders necessar y  f or a partici pa nt’s welfare ma y be 
a d mi nistere d at t he discreti o n of t he in vesti gat or i n kee pi n g wit h t he c o m m u nit y  sta n dar ds of 
me dical care.  All c o nc o mita nt me dicati o n will be rec or de d o n t he e C R F i ncl u di n g all 
prescri pti o n, o ver -t he-c o u nter ( O T C) pr o d ucts, her bal s u p ple me nts, a n d I V me dicati o ns a n d 
fl ui ds.  If c ha n ges occ ur d uri n g t he st u d y peri o d, d oc u me ntati o n of dr u g d osa ge, fre q ue nc y , 
r o ute, a n d date s h o ul d als o be i ncl u de d o n t he e C R F.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da y s pri or t o t he first d ose of st u d y treat me nt
a n d u p t o 3 0 da ys after t he last d ose of st u d y treat me nt s h o ul d be rec or de d.  C o nc o mita nt 
me dicati o ns a d mi nistere d 3 0 da y s after t he last d ose of st u d y treat me nt s h o ul d be rec or de d 
f or S A Es a n d e ve nts of E CIs as defi ne d i n Secti o n 9. 3 . If a partici pa nt e nters i nt o S ec o n d 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
C o urse P hase, all c o nc o mita nt me dicati o ns recei ve d wit hi n 3 0 da y s bef ore t he first d ose of 
S ec o n d C o urse st u d y 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 urse P hase Safet y  
F oll o w -u p Visit, rec or d all me dicati o ns ta ke n f or S A Es a n d E CI s as defi ne d i n Secti o n 9. 3.
Restricte d Me d ic ati o ns
7. 7. 2
Liste d bel o w are s pecific restricti o ns f or c o nc o mita nt t hera p y d uri n g t he c o urse of t he st u d y:

Use of c o u mari n -base d a ntic oa g ula nts (e g, warfari n ) wit h e paca d ostat is disc o ura ge d.  
L o w -d ose warfari n ( 1 m g) is acce pta ble; h o we ver, ot her hi g her d oses are 
disc o ura ge d.  If a n alter nati ve t o c o u mari n-base d a ntic oa g ula nts ca n n ot be use d, t he 
I N R s h o ul d be m o nit ore d cl osel y per S o C w he n e paca d ostat is starte d.
N ote:   F or partici pa nts ra n d o mize d t o eit her t he E X T R E M E ar m or pe m br oliz u ma b 
m o n ot hera p y ar m, t he use of c o u mari n -base d a ntic oa g ula nts is n ot restricte d.

Use of a n y restricte d me dicati o ns as descri be d i n l ocal pac ka ge i nserts or prescri bi n g 
i nf or mati o n f or pe m br oliz u ma b, cet u xi ma b, cis plati n, car b o plati n, a n d/ or 5- F U .
Pr o hi bite d Me dic ati o ns a n d Me as ures
7. 7. 3
Partici pa nts are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he Scree ni n g a n d 
T reat me nt P hase of t his st u d y  u nless ot her wise n ote d bel o w:

A n y  i n vesti gati o nal me dicati o n ot her t ha n t he st u d y treat me nts

A nti ne o plastic s y ste mic c hem ot hera p y o r bi ol o gical t hera py

I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol

C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol

S y ste mic gl uc oc ortic oi ds f or a n y p ur p ose ot her t ha n t o m o d ulate s y m pt o ms fr o m a n 
A E. T he use of p h ys i ol o gic d oses of c ortic oster oi ds ma y be a p pr o ve d after 
c o ns ultati o n wit h M S D . A d diti o nall y , a s h ort, li mite d c o urse of ster oi ds ma y be use d 
t o treat me dical c o n diti o ns a n d/ or A Es d uri n g t he st u d y after M S D
n otificati o n a n d 
c o ns ultati o n.
N ote: F or partici pa n ts ra n d o mize d t o t he E X T R E M E ar m t he use of s ys te mic 
gl uc oc ortic oi ds o n st u d y treat me nt is acce pta ble a n d ma y be re q uire d f or 
pre me dicati o n.
N ote:  I n hale d ster oi ds are all o we d f or ma na ge me nt of ast h ma/ c hr o nic o bstr ucti ve 
p ul m o nar y  disease.
N ote: Use of pr o p h yl actic c ortic oster oi ds t o a v oi d aller gic reacti o ns (e g, t o I V 
c o ntrast d y e) is per mitte d.

O nc ol o gic s ur ger y f or t u m or c o ntr ol.

Ra diati o n t hera p y 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial

A d mi nistrati o n of a li ve atte n uate d vacci ne wit hi n 3 0 da ys bef ore t he first d ose of 
st u d y treat me nt a n d w hile partici pati n g i n t he st u d y.  E xa m ples of li ve vacci nes 
i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  measles, m u m ps, r u bella, 
varicella/z oster , yell o w fe ver, ra bies, B C G, a n d ty p h oi d vacci ne.  Seas o nal i nfl ue nza 
vacci nes f or i njecti o n are ge nerall y kille d vir us vacci nes a n d are all o we d; h o we ver, 
i ntra nasal i nfl ue nza vacci nes are li ve atte n uate d vacci nes a n d are n ot all o we d.
N ote:  F or partici pa nt s ra n d o mize d t o t he E X T R E M E ar m t he use of li ve vacci nes is 
acce pta ble d uri n g t he st u d y.

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 is pr o hi bite d 
fr o m 2 1 da ys bef ore starti n g st u d y treat me nt t hr o u g h 2 wee ks after t he fi nal d ose of 
e paca d ostat has bee n ta ke n.  See A p pe n di x 7 f or pr o hi bite d a ge nts. 
N ote:  F or partici pa nts ra n d o mize d t o eit her t he E X T R E M E ar m or pe m br oliz u ma b 
m o n ot hera p y ar m, t he use of M O AI or dr u g ass ociate d wit h si g nifica nt M A O 
i n hibit or y  acti vit y is acce pta ble d uri n g t he st u d y .

A n y  U G T 1 A 9 i n hi bit or, i ncl u di n g: acitreti n, a mitri pt yli ne, a n dr oster o ne, 
c ycl os p ori ne, dasati ni b, dicl ofe nac, difl u nisal, efa vire nz, erl oti ni b, fl uta mi de, 
gefiti ni b, ge mfi br ozil, gl yc yrr heti nic aci d, gl yc yr r hizi n, i mati ni b, i mi pra mi ne, 
ket oc o naz ole, li n oleic aci d s u p ple me nts, m y c o p he n olic aci d, nifl u mic aci d, nil oti ni b, 
p he n o bar bital, p he n yl b utaz o ne, p he n y t oi n, pr o be neci d, q ui ni di ne, rit o na vir, s orafe ni b, 
s ulfi n p yraz o ne, val pr oic aci d, a n d vera pa mil. 
N ote:  F or partici pa nts ra n d o mize d t o t he E X T R E M E ar m or pe m br oliz u ma b 
m o n ot hera p y ar m, t he use of U G T 1 A 9 i n hi bit or s is acce pta ble.
T he excl us i o n criteria descri be ot her me dicati o ns t hat 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.
Partici pa nts w h o, i n t he assess me nt b y  t he i n vesti gat or, re q uire t he use of a n y of t he 
af ore me nti o ne d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he st u d y.
Resc ue Me dic ati o ns & S u p p orti ve C are
7. 7. 4
S u p p orti ve C are G ui deli nes f or Pe m br oliz u m a b
7. 7. 4. 1
Partici pa nts s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of A Es wit h 
p ote ntial i m m u n ol o gic eti ol o g y  are o utli ne d al o n g wit h t he d ose m o dificati o n g ui deli nes i n 
Secti o n 7. 2. 1.  W here a p pr o priate, t hese g ui deli nes i ncl u de t he use of oral or I V treat me nt 
wit h c ortic oster oi ds, as well as a d diti o nal a nti -i nfla m mat or y a ge nts if sy m pt o ms d o n ot 
i m pr o ve wit h a d mi nistrati o n of c ortic oster oi ds.  N ote t hat se veral c o urses of ster oi d ta peri n g 
ma y  be necessar y as s ym pt o ms ma y  w orse n w he n t he ster oi d d ose is decrease d.  F or eac h 
dis or der, atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses s uc h as metastatic disease or 
bacterial or vir al i nfecti o n, w hic h mi g ht re q uire a d diti o nal s u p p orti ve care.  T he treat me nt 
g ui deli nes are i nte n de d t o be a p plie d w he n t he in vesti gat or deter mi nes t he e ve nts t o be 
relate d t o pe m br oliz u ma b. 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
N ote: If after t he e val uati o n of t he e ve nt, it is deter mi ne d n ot t o be relate d t o pe m br oliz u ma b, 
t he in vesti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce.  Refer t o Ta ble 4 a n d Ta ble 5
i n Secti o n 7. 2 f or g ui deli nes re gar di n g d ose m o dificati o n a n d s u p p orti ve care. 
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d osc o p y, or 
s ki n p h ot o gra p hy as p art of e val uati o n of t he e ve nt.
S u p p orti ve C are G ui deli nes f or E p ac a d ost at
7. 7. 4. 2
S u p p orti ve care g ui deli nes liste d a b o ve i n Secti o n 7. 7. 4. 1 are a p plica ble t o e paca d ostat as 
well. 
A d diti o nall y, t he pr oce d ures i n Secti o n 7. 2. 1. 2 will be i m ple me nte d if partici pa nt s
e x hi bit t he si g ns/s ym pt o ms of ser ot o ni n s yn dr o me descri be d i n Ta ble 6 .
S u p p orti ve C are G ui deli nes f or Cis pl ati n a n d C ar b o pl ati n
7. 7. 4. 3
F or partici pa nt s ra n d o mize d t o Gr o u p 3 ( E X T R E M E re gi me n) t he use of s yste mic 
gl uc oc ortic oi ds d uri n g st u d y treat me nt is acce pta ble a n d m a y  be re q uire d f or pre me dicati o n.
Please refer t o t he pr o d uct la bel or l ocal sta n dar ds of care f or a d diti o nal cis plati n a n d 
car b o plati n s u p p orti ve meas ures a n d A E ma na ge me nt .
S u p p orti ve C are G ui deli nes f or 5 -fl uor o ur acil
7. 7. 4. 4
Please refer t o t he pr o d uct la bel or l ocal sta n dar ds of care f or 5- F U s u p p orti ve meas ures a n d 
A E ma na ge me nt .
S u p p orti ve C are G ui deli nes f or Cet u xi m a b
7. 7. 4. 5
Partici pa nts recei vi n g cet u xi ma b s h o ul d be pre -me dicate d wit h a n H 1 a nta g o nist (e g, 5 0
m g  
of di p he n h y dra mi ne) i ntra ve n o usl y 3 0 t o 6 0 mi n utes pri or t o t he first d ose.  Pre me dicati o n 
f or s u bse q ue nt d oses of cet u xi ma b s h o ul d be gi ve n per me dical j u d g me nt a n d hist or y of pri or 
i nf usi o n reacti o ns.
G ui deli nes f or me dical t hera p y f or i nf usi o n reacti o ns detaile d i n Ta ble 5 are als o 
rec o m me n de d f or reacti o ns d ue t o cet u xi ma b.
Refer t o t he a p pr o ve d pr o d uct la bel f or a d diti o nal s u p p orti ve care g ui da nce a n d A E 
ma na ge me nt . 
Tre at me nt After t he E n d of t he St u d y 
7. 8
T here is n o st u d y- s pecifie d treat me nt f oll o wi n g t he e n d of t he st u dy.
Cli nic al S u p plies Discl os ure
7. 9
T his trial is o pe n-la bel; t heref ore, t he partici pa nt, t he trial site pers o n nel, t he S p o ns or, M S D 
st u d y pers o n nel, a n d/ or desi g nee are n ot bli n de d. St u d y treat me nt ( na me, stre n gt h or 
p ote nc y ) is i ncl u de d i n t he la bel te xt; ra n d o m c o de/ discl os ure e n vel o pes or lists are 
n ot pr o vi de d.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 5
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
8.
Disc o nti n u ati o n/ Wit h dr a w al Criteri a 
Disc o nti n u ati o n of St u d y Tre at me nt 
8. 1
Disc o nti n uati o n of st u d y treat me nt d oes n ot re prese nt wit h dra wal fr o m t he st u d y .
As certai n data o n cli nical e ve nts be y o n d st u d y  treat me nt disc o nti n uati o n ma y be i m p orta nt 
t o t he st u d y, t he y m ust be c ollecte d t hr o u g h t he partici pa nt’s last sc he d ule d f oll o w-u p, e ve n 
if t he partici pa nt has disc o nti n ue d st u d y treat me nt.  T heref ore, all partici pa nts w h o 
disc o nti n ue st u d y  treat me nt pri or t o c o m pleti o n of t he pr ot oc ol-s pecifie d i ma gi n g 
re q uire me nts (ie, bef ore Wee k 9 efficac y  assess me nt, P D or i nitiati o n of a ne w a ntica ncer 
treat me nt) 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 a n d Secti o n
9. 9. 4 .
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 
safety reas o ns.  S pecific details re gar di n g pr oce d ures t o be perf or me d at st u d y treat me nt 
disc o nti n uati o n are pr o vi de d i n Secti o n 9. 1. 1 0 .
A partici pa nt m ust be disc o nti n ue d fr o m st u d y treat me nt b ut c o nti n ue t o be m o nit ore d i n t he 
st u d y f or a ny of t he f oll o wi n g reas o ns:
○
T he partici pa nt or partici pa nt’s le gall y acce pta ble re prese ntati ve re q uests t o disc o nti n ue 
st u d y treat me nt.
o
R a di o gra p hic disease pr o gressi o n per R E CI S T 1. 1 .
o
U nacce pta ble A Es as descri be d i n Secti o n 7. 2. 1 wit h a re q uire me nt t o per ma ne ntl y  
disc o nti n ue.
o
T he partici pa nt i nterr u pts st u d y  treat me nt a d mi nistrati o n f or a n y T R A E f or m ore t ha n 
1 2 c o nsec uti ve wee ks or m ore t ha n 3 wee ks f or i nterr u pti o ns u nrelate d t o A Es , u nless 
a p pr o ve d wit h writte n d oc u me ntati o n fr o m M S D.
o
T he partici pa nt has a me dical c o n diti o n or pers o nal circ u msta nce w hic h, i n t he o pi ni o n of 
t he i n vesti gat or a n d/ or M S D , place d t he partici pa nt at u n necessar y ris k fr o m c o nti n ue d 
a d mi nistrati o n of st u d y treat me nt.
o
T he partici pa nt has a c o nfir me d p ositi ve ser u m pre g na nc y  test.
o
A d mi nistrati ve reas o ns.
o
A n y  pr o gressi o n or rec urre nce of a ny mali g na nc y , or a n y occ urre nce of a n ot her 
mali g na nc y  t hat re q uires acti ve s yste mic treat me nt. 
o
N o nc o m plia nce wit h st u d y treat me nt or pr oce d ure re q uire me nts.
o
Rec urre nt Gra de 2 p ne u m o nitis .
o
C o m pleti o n of 3 5 treat me nt c ycles (a p pr o xi matel y 2 years) wit h pe m br oliz u ma b pl us 
e paca d ostat or pe m br oliz u ma b m o n ot hera p y.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 6
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
o
Disc o nti n uati o n of treat me nt ma y  be c o nsi dere d f or partici pa nts w h o ha ve attai ne d a C R 
a n d ha ve bee n treate d f or at lea st 8 c ycles (at least 2 4 wee ks), a n d recei ve d at least
2 c ycles of pe m br oliz u ma b pl us e paca d ostat or pe m br oliz u ma b m o n ot hera p y b e y o n d t he 
date w he n t he i nitial C R was declare d.  T hese partici pa nts ma y be eli gi ble f or S ec o n d 
C o urse T reat me nt descri be d i n Secti o n 7. 2. 6.
F or partici pa nts w h o are disc o nti n ue d fr o m st u d y treat me nt b ut c o nti n ue t o be m o nit ore d i n 
t he trial, see Secti o n 2 a n d Secti o n 9. 9. 4 f or t h ose pr oce d ures t o be c o m plete d at eac h 
s pecifie d visit.
Partici pa nts ma y  be all o we d t o be gi n st u d y treat me nt a gai n if dee me d me dicall y a p pr o priate
f oll o wi n g c o ns ultati o n wit h M S D .
Wit h dr a w al fr o m t he St u d y
8. 2
A partici pa nt m ust be wit h dra w n fr o m t he st u d y  if t he partici pa nt or partici pa nt’s le gally 
acce pta ble re prese ntati ve wit h dra ws c o nse nt fr o m t he st u d y.
If a partici pa nt wit h dra ws fr o m t he st u d y, t he y will n o l o n ger recei ve st u d y treat me nt or be 
f oll o we d at sc he d ule d pr ot oc ol visits.
S pecific details re gar di n g pr oce d ures t o be perf or me d at t he ti me of wit h dra wal fr o m t he 
st u d y are o utli ne d i n Secti o n 9. 1. 1 0.
L ost t o F oll o w - u p
8. 3
N O T E: As of A me n d me nt 0 4, t his secti o n is n o l o n ger a p plic a ble.  T here will be n o 
a d diti o n al eff orts t o c o nt act p artici p a nts w h o are l ost t o f oll o w -u p.
If a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y visit a n d/ or if t he site is u na ble 
t o c o ntact t he partici pa nt, t he f oll o wi n g pr oce d ures are t o be perf or me d:
o
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit.  I f t he 
partici pa nt is c o ntacte d, t he partici pa nt s h o ul d be c o u nsele d o n t he i m p orta nce of 
mai ntai ni n g t he pr ot oc ol -s pecifie d visit sc he d ule.
o
T he i n vesti gat or or desi g nee m ust ma ke e ver y  eff ort t o re gai n c o ntact wit h t he 
partici pa nt at eac h misse d visit (e g, p h o ne calls a n d/ or a certifie d letter t o t he 
partici pa nt’s last k n o w n m aili n g a d dress or l ocall y e q ui vale nt met h o ds). T hese 
c o ntact atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.
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 am o u nt of missi n g data f or t he partici pa nt will be 
ma na ge d via t he pre -s pecifie d data ha n dli n g a n d a nal ysis g ui deli nes.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 7
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
9.
St u d y Assess me nts a n d Pr oce d ures
●
St u d y  pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A. 
●
A d here nce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is 
esse ntial a n d re q uire d f or st u d y c o n d uct.
●
T he I n vesti gat or is res p o nsi ble f or ass uri n g t hat pr oce d ures are c o n d ucte d b y 
a p pr o priatel y q ualifie d or trai ne d staff.  Dele gati o n of trial site pers o n nel 
res p o nsi bilities will be d oc u me nte d i n t he I n vesti gat or Trial File Bi n der ( or 
e q ui vale nt).
●
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y  criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g 
t o rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d 
reas o ns f or scree ni n g fail ure, as a p plica ble. 
●
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, 
bl o o d c o u nt) a n d o btai ne d bef o re si g ni n g of I CF ma y  be utilize d f or scree ni n g or 
baseli ne p ur p oses pr o vi de d t he pr oce d ure met t he pr ot oc ol -s pecifie d criteria a n d were 
perf or me d wit hi n t he ti me fra me defi ne d i n t he S o A.
●
A d diti o nal e val uati o ns/testi n g ma y  be dee me d necessar y by t he i n v esti gat or a n d /or 
M S D
f or reas o ns relate d t o partici pa nt safety. I n s o me cases, s uc h e val uati o n/testi n g 
ma y  be p ote ntiall y se nsiti ve i n nat ure (e. g., HI V, He patitis C, etc.), a n d t h us l ocal 
re g ulati o ns ma y re q uire t hat a d diti o nal i nf or me d c o nse nt be o btai ned fr o m t he 
partici pa nt .  I n t hese cases, s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce 
wit h t h ose re g ulati o ns.
A d mi nistr 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 nee m ust o btai n d oc u me nte d c o nse nt fr o m eac h p ote ntial 
partici pa nt or eac h partici pa nt’s le gall y acce pta ble re prese ntati ve pri or t o partici pati n g i n a 
cli nical trial . If t here are c ha n ges t o t he partici pa nt’s stat us d uri n g t he trial (e g, healt h or a ge 
of maj orit y  re q uire me nts), t he i n vesti gat or or q ualifie d desi g nee m ust e ns ure t he a p pr o priate 
c o nse nt is i n place. 
Ge ner al I nf or me d C o nse nt
9. 1. 1. 1
C o nse nt m ust be d oc u me nte d b y t he partici pa nt’s date d si g nat ure or b y t he partici pa nt’s 
le gall y acce pta ble re prese ntati ve’s date d si g nat ure o n a c o nse nt f or m al o n g wit h t he date d 
si g nat ure of t he pers o n c o n d ucti n g t he c o nse nt disc ussi o n. 
A c o p y of t he si g ne d a n d date d c o nse nt f or m s h o ul d be gi ve n t o t he partici pa nt bef ore 
partici pati o n i n t he trial.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 8
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
T he i nitial I C F, a n y  s u bse q ue nt re vise d writte n I C F a n d a ny writte n i nf or mati o n pr o vi de d t o 
t he partici pa nt m ust recei ve t he I R B/I E C’s a p pr o val/fa v ora ble o pi ni o n i n a d va nce of use.  
T he p artici pa nt or his/ her le gall y acce pta ble re prese ntati ve s h o ul d be i nf or me d i n a ti mel y 
ma n ner if ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o t he partici pa nt’s 
willi n g ness t o c o nti n ue partici pati o n i n t he trial.  T he c o m m u nicati o n of t his i nf o r mati o n will 
be pr o vi de d a n d d oc u me nte d via a re vise d c o nse nt f or m or a d de n d u m t o t he ori gi nal c o nse nt 
f or m t hat ca pt ures t he partici pa nt’s date d si g nat ure or by t he partici pa nt’s le gall y acce pta ble 
re prese ntati ve’s date d si g nat ure.
S pecifics a b o ut a trial a n d t he trial p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate at 
t he pr ot oc ol le vel.  
T he i nf or me d c o nse nt will a d here t o I R B/I E C re q uire me nts, a p plica ble la ws a n d re g ulati o ns 
a n d M S D
re q uire me nts.
I ncl usi o n/ E xcl usi o n Criteri a
9. 1. 2
All i ncl usi o n a n d e xc l usi o n criteria will be re vie we d b y t he i n vesti gat or or q ualifie d desi g nee 
t o e ns ure t hat t he partici pa nt q ualifies f or t he st u d y.
P artici p a nt I de ntific ati o n C ar d
9. 1. 3
All partici pa nts will be gi ve n a Partici pa nt I de ntificati o n Car d i de ntif yi n g t he m as 
partici pa nts i n a researc h st u d y. T he car d will c o ntai n trial site c o ntact i nf or mati o n (i ncl u di n g 
direct tele p h o ne n u m bers) t o be utilize d i n t he e ve nt of a n e mer ge nc y. T h e i n vesti gat or or 
q ualifie d desi g nee will pr o vi de t he partici pa nt wit h a Partici pa nt I de ntificati o n Car d 
i m me diatel y after t he partici pa nt pr o vi des writte n i nf or me d c o nse nt. At t he ti me of treat me nt 
all ocati o n/ra n d o mizati o n, site pers o n nel will a d d t he tre at me nt/ra n d o mizati o n n u m ber t o t he 
Partici pa nt I de ntificati o n Car d.
T he partici pa nt i de ntificati o n car d als o c o ntai ns c o ntact i nf or mati o n f or t he e mer ge nc y 
u n bli n di n g call ce nter s o t hat a healt h care pr o vi der ca n o btai n i nf or mati o n a b o ut st u d y 
treat me nt in 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 y cle 1 D a y 1, Gr o u p 1 partici pa nts will als o be gi ve n a ser ot o ni n s yn dr o me i nf or mati o n 
car d listi n g si g ns a n d s ym pt o ms of ser ot o ni n s yn dr o me.  T his i nf or mati o n car d als o i nstr ucts 
partici pa nts t o see k i m me diate me dical care if a n y of t hese sy m pt o ms are o bser ve d.
Me dic al Hist or y
9. 1. 5
A me dical hist or y  will be o btai ne d b y t he in vesti gat or or q ualifie d desi g nee.  M e dical hist or y 
will c ollect all acti ve c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n t he pri or 1 0 ye ars t hat 
t he in vesti gat or c o nsi ders t o be cli nicall y si g nifica nt. Details re gar di n g t he partici pa nt’s 
H N S C C will be rec or de d se paratel y a n d n ot liste d as me dical hist or y .
Dise ase Det ails
9. 1. 5. 1
T he i n vesti gat or or q ualifie d desi g nee will o btai n pri or a n d c urre nt details re gar di n g t he 
partici pa nt’s hea d a n d nec k ca ncer .
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
9 9
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
9. 1. 6
Pri or Me dic ati o ns
9. 1. 6. 1
T he i n vesti gat or or q ualifie d desi g nee will re vie w pri or me dicati o n use, i ncl u di n g a n y 
pr ot oc ol -s pecifie d was h o ut re q uire me nt, a n d rec or d pri or me dicati o n ta ke n b y t he partici pa nt 
wit hi n 2 8 da y s bef ore t he first d ose of st u d y treat me nt.  Pri or o nc ol o gical treat me nt f or hea d 
a n d nec k ca ncer will be rec or de d se paratel y a n d n ot liste d as a pri or me dicati o n.
Pri or O nc ol o gic al Tre at me nt Det ails f or He a d a n d Nec k C a ncer
9. 1. 6. 1. 1
T he i n vesti gat or or q ualifie d desi g nee will re vie w all pri or ca ncer treat me nts i ncl u di n g 
s yste mic treat me nts, ra diati o n a n d s ur geries.
C o nc o mit a nt Me dic ati o ns
9. 1. 6. 2
As s pecifie d i n S ecti o n 7. 7 , the i n vesti gat or or q ualifie d desi g nee will rec or d me dicati o n, if 
a n y, ta ke n b y t he partici pa nt d uri n g t he st u d y t hr o u g h t he Safety F oll o w -u p V isit.  In 
a d diti o n, ne w me dicati o ns starte d d uri n g t he Sec o n d C o urse P hase t hr o u g h t he Sec o n d 
C o urse Safet y F oll o w -u p V isit s h o ul d be rec or de d.
Assi g n me nt of Scree ni n g N u m ber
9. 1. 7
All c o nse nte d partici pa nts will be gi ve n a u ni q ue scree ni n g n u m ber t hat will be use d t o 
i de ntif y t he partici pa nt f or all pr oce d ures t hat occ ur pri or t o ra n d o mizati o n.  Eac h partici pa nt 
will be assi g ne d o nl y o ne scree ni n g n u m ber.  Scree ni n g n u m bers m ust n ot be re -use d f or 
differe nt partici pa nts.
A n y  partici pa nt w h o is scree ne d m ulti ple ti mes will retai n t he ori gi nal scree ni n g n u m ber 
assi g ne d at t he i nitial S cree ni n g V isit.
S pe cific details o n t he Scree ni n g Visit re q uire me nts (scree ni n g/rescree ni n g) are pr o vi de d i n 
Secti o n 9. 9. 1 .  
Assi g n me nt of Tre at me nt/ R a n d o miz ati o n N u m ber
9. 1. 8
All eli gi ble partici pa nts will be ra n d o ml y all ocate d a n d will recei ve a 
treat me nt/ra n d o mizati o n n u m ber. T he treat me nt/ra n d o mizati o n n u m ber i de ntifies t he 
partici pa nt f or all pr oce d ures occ urri n g after treat me nt all ocati o n/ra n d o mizati o n.  O nce a 
treat me nt/ra n d o mizati o n n u m ber is assi g ne d t o a partici pa nt, it ca n ne ver be re-assi g ne d t o 
a n ot her partici pa nt.
A si n gle partici pa nt ca n n ot be assi g ne d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber.
Tre at me nt A d mi nistr ati o n
9. 1. 9
St u d y  Treat me nt s h o ul d be gi n wit hi n 5 d a y s of ra n d o mizati o n.
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 1
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Gr o u p 2 D ose A d mi nistr ati o ns
9. 1. 9. 1. 2
Pe m br oliz u ma b will be a d mi nistere d as detaile d f or Gr o u p 1 a b o ve.
Gr o u p 3 E X T R E M E Re gi me n D ose A d mi nistr ati o n s
9. 1. 9. 1. 3
1)
Cet u xi ma b A d mi nistrati o n 
Cet u xi ma b s h o ul d be a d mi nistere d o n Da y s 1, 8, a n d 1 5 of eac h 2 1 d a y  c ycle.  Cet u xi ma b 
will be a d mi nistere d as a n i nitial l oa di n g d ose of 4 0 0 m g/ m 2 as a 1 2 0 -mi n ute I V i nf usi o n o n 
C y cle 1, Da y 1.  F or all s u bse q ue nt i nf usi o ns, t he cet u xi ma b d ose is 2 5 0 m g/ m 2 as a 
6 0 -mi n ute I V i nf usi o n o nce wee kl y.  T he cet u xi ma b i nf usi o n m ust be c o m plete d 1 h o ur 
bef ore a d mi nistrati o n of t he plati n u m a n d 5- F U .  After plati n u m a n d 5- F U are c o m plete d , f or 
partici pa nts wit h at least S D , cet u xi ma b m o n ot hera p y m a y c o nti n ue u ntil ra di o gra p hic 
disease pr o gressi o n or u nacce pta ble t o xicit y  occ urs.
2)
Cis plati n A d mi nistrati o n
Cis plati n will be a d mi nistere d at 1 0 0 m g/ m 2 as a 6 0 -mi n ute I V i nf usi o n ( or i nf usi o n d urati o n 
acc or di n g t o l ocal practice) o n Da y  1 of eac h 2 1-d a y  c ycle.  
3)
Car b o plati n A d mi nist rati o n 
Car b o plati n will be a d mi nistere d at a d ose of A U C 5 as a 6 0 -mi n ute I V i nf usi o n ( or i nf usi o n 
d urati o n acc or di n g t o l ocal practice) o n Da y  1 of eac h 2 1-d a y  c ycle.
4)
5-f l u or o uracil A d mi nistrati o n 
5- fl u or o uracil will be a d mi nistere d at 1 0 0 0 m g/ m2/ da y as a c o nti n u o us I V i nf usi o n o ver 
D a y s 1 t hr o u g h 4 of eac h 2 1 -d a y  c ycle.  
Sites are i nstr ucte d t o c o ns ult l ocal prescri bi n g i nf or mati o n f or a d diti o nal i nf or mati o n a n d 
i nstr ucti o ns f or pre parati o n a n d a d mi nistrati o n of t he E X T R E M E re gi me n .
Wit h dr a w al/ Disc o nti n u ati o n
9. 1. 1 0
Partici pa nts w h o disc o nti n ue st u d y  treat me nt pri or t o c o m pleti o n of t he treat me nt peri o d
s h o ul d be e nc o ura ge d t o c o nti n ue t o be f oll o we d f or all re mai ni n g st u d y visits.
W he n a partici pa nt wit h dra ws fr o m partici pati o n i n t he st u d y, all a p plica ble acti vities 
sc he d ule d f or t he fi nal st u d y visit s h o ul d be perf or me d at t he ti me of wit h dra wal.  A n y A Es
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 .
P arti ci 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 st u d y; t here is n o bli n di n g f or t his st u d y.
C ali br ati o n of E q ui p me nt
9. 1. 1 2
T he i n vesti gat or or q ualifie d desi g nee has t he res p o nsi bilit y  t o e ns ure t hat a n y de vice or 
i nstr u me nt use d f or a cli nical e val uati o n/test d uri n g a cli nical st u d y t hat pr o vi des i nf or mati o n 
a b o ut i ncl usi o n/e xcl usi o n criteria a n d/ or safet y or efficac y para meters s hall be s uita bl y 
cali brate d a n d/ or mai ntai ne d t o e ns ure t hat t he data o btai ne d is relia ble a n d/ or re pr o d uci ble. 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 2
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
D oc u me ntati o n of e q ui p me nt cali brati o n m ust be retai ne d as s o urce d oc u me ntati o n at t he 
st u d y site.
Effic ac y Assess me nts 
9. 2
T u m or I m a gi n g a n d Assess me nt of Dise ase
9. 2. 1
N ote: As of A me n d me nt 0 4 , ce ntr al re vie w of i m a gi n g a n d i R E CI S T is n o l o n ger 
a p plic a ble .  T his secti o n h as bee n u p d ate d acc or di n gl y.
T u m or i ma gi n g is str o n gl y preferre d t o be ac q uire d b y c o m p ute d t o m o gra p h y ( C T).  F or 
hea d a n d nec k, a b d o me n a n d pel vis, m a g netic res o na nce i ma gi n g ( M RI) m a y  be use d w he n 
C T wit h i o di nate d c o ntrast is c o ntrai n dicate d, or w he n ma n date d b y l ocal practice.  Ma g netic 
res o na nce i ma gi n g is t he str o n gly preferre d m o dalit y f or i ma gi n g t he brai n (f or brai n 
metasta ses).  T he sa me i ma gi n g tec h ni q ue, i ncl u di n g m o dalit y  (i deally t he sa me sca n ner) a n d 
t he use of c o ntrast, s h o ul d be use d i n a partici pa nt t hr o u g h o ut t he st u d y t o o pti mize t he 
re pr o d uci bilit y of t he assess me nt of e xisti n g a n d ne w t u m or b ur de n a n d i m pr o ve t h e 
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 “ in vesti gat or” refers t o t he l ocal i n vesti gat or 
at t he site a n d/ or t he ra di ol o gical re vie wer l ocate d at t he site or at a n offsite facilit y.
I ma gi n g s h o ul d i ncl u de t he hea d a n d nec k, c hest, a n d a b d o me n at all ti me p oi nts s pecifie d i n 
Secti o n 2 - S o A.  I ma gi n g of t he brai n a n d pel vis are o pti o nal (if cli nicall y i n dicate d).  F or a n 
i n di vi d ual partici pa nt , i ma gi n g s h o ul d be c o nsiste nt at all ti me p oi nts, (ie, f oll o w- u p sca ns 
s h o ul d i ma ge t he sa me areas as t he baseli ne area, usi n g t he sa me i ma gi n g m o dalit y).
Partici pa nt eli gi bilit y will be deter mi ne d usi n g l ocal assess me nt (i n vesti gat or assess me nt ) 
base d o n R E CI S T 1. 1.
Treat me nt s h o ul d c o nti n ue u ntil P D has bee n deter mi ne d per i n vesti gat or 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 4, ce ntr al re vie w of i m a gi n g is n o l o n ger a p plic a ble. T his 
secti o n h as bee n u p d ate d acc or di n gl y .
I nitial t u m or i ma gi n g at scree ni n g m ust be perf or me d wit hi n -2 8 t o -1 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 scree ni n g i ma ges t o c o nfir m t he 
parti cipa nt has meas ura ble disease per R E CI S T 1. 1. 
T u m or i ma gi n g perf or me d as part of r o uti ne cli nical ma na ge me nt is acce pta ble f or use as 
scree ni n g t u m or i ma gi n g if it is of dia g n osti c q ualit y a n d perf or me d wit hi n -2 8 t o -1 d a y s 
pri or t o t he date of ra n d o mizati o n a n d ca n be assesse d b y t he ce ntral i ma gi n g ve n d or .
If brai n i ma gi n g is perf or me d t o d oc u me nt t he sta bilit y of e xisti n g metastases, M RI s h o ul d 
be use d if p ossi ble.  If M RI  is me dically c o ntrai n dicate d, C T wit h c o ntrast is a n acce pta ble 
alter nati ve.  
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 3
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 4 , ce ntr al re vie w of i m a ges a n d i R E CI S T is n o l o n ger 
a p plic a ble.  A fter t he first o n-st u d y i m a gi n g assess me nt at Wee k
9 , f urt her i m a gi n g will 
be perf or me d as per l oc al S o C g ui deli nes h o we ver t hese d at a will n ot be c ollecte d .  T his 
secti o n h as bee n u p d ate d acc or di n gl y .
T he first o n -st u d y i ma gi n g assess me nt s h o ul d be perf or me d at Wee k 9
(6 3 da y s ± 7 d a y s)
fr o m t he date of ra n d o mizati o n.  N o f urt her i ma gi n g is ma n date d; a n y  f urt her i ma gi n g f or 
disease assess me nts will be perf or me d b y site i n vesti gat or/ra di ol o g y assess me nt as per S o C 
f or t he disease a n d l ocal g ui deli nes; o nl y t he date of sca ns perf or me d as per S o C nee ds t o be 
d oc u me nte d i n t he e C R F .
E n d of Tre at me nt a n d F ol l 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 4 , t here is n o pr ot oc ol s pecifie d i m a gi n g after t he 
Wee k
9 assess me nt.  T his secti o n h as bee n u p d ate d acc or di n gl y .  
F or partici pa nt s w h o disc o nti n ue st u d y treat me nt bef ore t he Wee k 9 i ma gi n g assess me nt f or 
efficac y a nalys is, t u m or i ma gi n g s h o ul d be perf or me d at t he ti me of treat me nt 
disc o nti n uati o n ( ± 4 wee k wi n d o w).  If pre v i o us i ma gi n g was o btai ne d wit hi n 4 wee ks pri or 
t o t he date of disc o nti n uati o n, t he n i ma gi n g at treat me nt disc o nti n uati o n is n ot ma n dat or y.  
F or partici pa nt s w h o disc o nti n ue st u d y treat me nt d ue t o ra di o gra p hic disease pr o gressi o n, 
t his is t he fi nal re q uire d t u m or i ma gi n g.
Sec o n d C o urse P h ase T u m or I m a gi n g
9. 2. 1. 4
N ote: As of A me n d me nt 0 4 , Sec o n d C o urse i m a gi n g will be assesse d b y t he i n vesti g ator
a n d i R E CI S T is n o l o n ger a p plic a ble ; tr a ns missi o n of i m a ges t o t he ce ntr al re vie w of 
i m a gi n g is n o l o n ger re q uire d.  Dise ase assess me nt will be perf or me d b y t he i n vesti g at or 
per S o C f or t he dise ase a n d l oc al g uideli nes.   T his secti o n h as bee n u p d ate d 
acc or di n gl y .
T u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt wit h 
pe m br oliz u ma b pl us e paca d ostat, or pe m br oliz u ma b m o n ot hera p y .  Bef ore a partici pa nt ma y  
e nter Sec o n d C o urse P hase, ra di o gra p hic P D m ust ha ve occ urre d.  T he P D i ma gi n g m a y  als o 
be use d as t he Sec o n d C o urse baseli ne i ma gi n g if it is wit hi n 2 8 da y s pri or t o restarti n g 
treat me nt. 
L ocal rea di n g (i n vesti gat or assess me nt w it 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.  Ima gi n g f or disease assess me nts will be perf or me d b y  site i n vesti gat or/ra di ol o g y 
assess me nt as per S o C f or t he disease a n d l ocal g ui deli nes; o nl y  t he date of sca ns perf or me d 
as per S o C nee ds t o be d oc u me nte d i n t he e C R F .
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 gressi o n, a n d as a basis f or all pr ot oc ol g ui deli nes relate d t o disease stat us (e g, 
disc o n ti n uati o n of st u d y treat me nt). Alt h o u g h R E CI S T 1. 1 refere nces a ma xi m u m of 5 tar get 
lesi o ns i n t otal a n d 2 per or ga n, t his pr ot oc ol all o ws a ma xi m u m of 1 0 tar get lesi o ns i n t otal 
a n d 5 per or ga n, if cli nicall y rele va nt t o e na ble a br oa der sa m pli n g of t u m or b ur de n. 
 
 
0 4 Y B M H

Pr o d uct:   M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 4
Pr ot oc ol/ A me n d me nt N o.: 6 6 9 -0 4 / E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
i R E CI S T Assess me nt of Dise ase ( Gr o u p 1 a n d 2)
9. 2. 1. 6
N O T E: As of A me n d me nt 0 4 , t his secti o n is n o l o n ger a p plic a ble; i R E CI S T d at a will n o 
l o n ger be c ollecte d. P a rtici p a nts wit h r a di o gr a p hic dise ase pr o gressi o n as deter mi ne d 
b y R E CI S T 1. 1 will disc o nti n ue fr o m t he st u d y a n d be f oll o we d f or s afet y m o nit ori n g, 
as det aile d i n Secti o n 9. 3 ; n o c o nfir m at or y sc a ns are re q uire d . 
i R E CIS T is base d o n R E CI S T 1. 1 , b ut a da pte d t o acc o u n t 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 a ge nts a n d t heref ore is o nl y re q uire d f or partici pa nts i n Gr o u p 1 a n d 
Gr o u p 2 .  i R E CIS T will be use d b y t he in 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 h e n cli nicall y sta ble, Gr o u p 1 a n d 2
partici pa nt s s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d by t he in vesti gat or , 
w or ki n g wit h l ocal ra di ol o g y, acc or di n g t o t he r ules o utli ne d i n A p pe n di x 8 . T his all o wa nce 
t o c o nti n ue treat me nt des pite i nitial ra di ol o gic P D ta kes i nt o acc o u nt t he o bser vati o n t hat 
s o me partici pa nts ca n ha ve a tra nsie nt t u m or flare i n t he first fe w m o nt hs after t he start of 
i m m u n ot hera p y, a n d t he n e x perie nce s u bse q ue nt disease res p o nse.  T h ese data will be 
ca pt ure d i n t he cli nical data base.  
Cli nical sta bilit y  is defi ne d as t he f oll o wi n g: 

A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y  si g nifica nt pr o gressi o n of 
disease

N o decli ne i n E C O G P S

N o re q uire me nts f or i nte nsifie d ma na ge me nt, i ncl u di n g i ncrease d a nal gesia, 
ra diati o n, or ot her palliati ve care. 
A n y  partici pa nt dee me d cli nic all y u nst a ble s h o ul d be disc o nti n ue d fr o m st u d y treat me nt at
ce ntral verificati o n of site-assesse d first ra di ol o gic e vi de nce of P D a n d is n ot re q uire d t o ha ve 
re peat t u m or i ma gi n g f or c o nfir mati o n of P D b y  i R E CIS T .
If t he in 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 to c o nfir m 
P D b y  i R E CIS T, per in vesti gat or assess me nt. I ma ges s h o ul d c o nti n ue t o be se nt i n t o t he 
ce ntral i ma gi n g ve n d or f or p ote ntial retr os pecti ve BI C R.
If re peat i ma gi n g d oes n ot c o nfir m P D per i R E CI S T, as assesse d b y t he in vesti gat or, a n d t he 
partici p a nt c o nti n ues t o be cli nicall y sta ble, st u d y treat me nt ma y c o nti n ue a n d f oll o w t he 
re g ular i ma gi n g sc he d ule. If P D is c o nfir me d, partici pa nts will be disc o nti n ue d fr o m st u dy 
treat me nt.
 
 
0 4 Y B M H

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

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

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 7
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A b bre viati o ns: i R E CI S T = m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors 1. 1 f or 
i m m u ne-base d t hera pe utics; P D = pr o gressi ve disease ; R E CIS T 1. 1 = Res p o nse E val uati o n 
Criteria i n S oli d T u m ors 1. 1.
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 a n d 2 Partici pa nts after First 
Ra di ol o gic E vi de nce of Disease Pr o gressi o n Assesse d b y t he I n vesti gat or
P atie nt Re p orte d O utc o mes
9. 2. 2
N ote: As of A me n d me nt 0 4 , P R Os will n o l o n ger be c ollecte d after t he first o n -st u d y 
i m a gi n g assess me nt at Wee k 9.
T he E Q - 5 D, E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -H & N 3 5 q uesti o n naires will be 
a d mi nistere d b y trai ne d site pers o n nel a n d c o m plete d electr o nicall y b y partici pa n ts i n t he 
f oll o wi n g or der: E Q-5 D first, t h e n E O R T C Q L Q -C 3 0 , f oll o we d b y E O R T C Q LQ- H & N 3 5 . 
T he q uesti o n naires s h o ul d be a d mi nistere d pri or t o d osi n g at C ycle 1, C ycl e 2, C y cle 3 , a n d 
C y cle 4.
It is best practice a n d str o n gly rec o m me n de d t hat electr o nic patie nt -re p orte d o utc o mes 
(e P R Os) are a d mi nistere d t o ra n d o mize d partici pa n ts pri or t o dr u g a d mi nistrati o n, A E
e val uati o n, a n d disease stat us n otificati o n.  If t he partici pa n t d oes n ot c o m plete t he e P R Os at 
a sc he d ule d ti me p oi nt, t he MIS S _ M O D E f or m m ust be c o m plete d t o ca pt ure t he reas o n t he 
assess me nt was n ot perf or me d.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 0 8
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
He alt h C are Res o urce Utiliz ati o n
9. 2. 3
All -ca use h os pitalizati o ns a n d e mer ge nc y r o o m visits m ust be re p orte d i n t he e C R F, fr o m t he 
ti me of treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 da y s f oll o wi n g cessati o n of st u d y 
treat me nt, or 3 0 d a y s f oll o wi n g cessati o n of st u d y treat me nt, if t he partici pa nt i nitiates ne w 
a ntica nce r t hera py, w hic he ver is earlier .
A d verse E ve nts, Seri o us A d verse E ve nts a n d Ot her Re p ort a ble S afet y E ve nts 
9. 3
T he defi niti o ns of a n a d verse e ve nt ( A E) or seri o us a d verse e ve nt ( S A E), as well as t he 
met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A E a n d S A E a n d t he pr oce d ures 
f or c o m pleti n g a n d tra ns mitti n g A E, S A E a n d ot her re p orta ble safety e ve nt re p orts ca n be 
f o u n d i n A p pe n di x 4.
Pr o gressi o n of t he ca ncer u n der st u d y  is n ot c o nsi dere d a n a d verse e ve nt as descri be d i n 
Secti o n 9. 3. 5 – Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot Q ualif y i n g as 
A Es or S A Es, a n d A p pe n di x 4.
A E, S A Es, a n d ot her re p orta ble safet y  e ve nts will be re p orte d b y t he partici pa nt ( or, w he n 
a p pr o priate, b y a care gi ver, s urr o gate, or t he partici pa nt's le gall y a ut h orize d re prese ntati ve). 
T he i n vesti gat or, w h o is a q ualifie d p h ys icia n, a n d a n y desi g nees are res p o nsi ble f or 
detecti n g, assessi n g, d oc u me nti n g, a n d re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or 
S A E as well as ot her re p orta ble safet y e ve nts. I n vesti gat ors re mai n res p o nsi ble f or f oll o wi n g 
u p A E, S A Es a n d ot her re p orta ble safet y e ve nts f or o utc o me acc or di n g t o Secti o n 9. 3. 3.
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E, S A E a n d Ot her Re p ort a ble 
9. 3. 1
S afet y E ve nt I nf or m ati o n 
All A Es, S A Es a n d ot her re p orta ble safet y e ve nts t hat occ ur after t he c o nse nt f or m is si g ne d 
b ut bef ore treat me nt all ocati o n/ra n d o mizati o n m ust be re p orte d b y t he i n vesti gat or if t he 
parti ci pa nt is recei vi n g place b o r u n -i n or ot her r u n-i n treat me nt, if t he e ve nt ca use t he 
partici pa nt t o be e xcl u de d fr o m t he trial, or is t he res ult of a pr ot oc ol -s pecifie d i nter ve nti o n, 
i ncl u di n g b ut n ot li mite d t o was h o ut or disc onti n uati o n of us ual t hera p y, diet, or a pr oce d ure. 
○
All A Es fr o m t he ti me of treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 3 0 da ys f oll o wi n g 
cessati o n of st u d y treat me nt m ust be re p orte d b y t he i n vesti gat or. 
○
All A Es meeti n g seri o us criteria, fr o m t he ti m e of treat me nt all ocati o n/ra n d o mizati o n 
t hr o u g h 9 0 da y s f oll o wi n g cessati o n of st u d y treat me nt, or 3 0 da ys f oll o wi n g cessati o n of 
st u d y treat me nt if t he partici pa nt i nitiates ne w a ntica ncer t hera py, 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 ncies a n d e x p os ure d uri n g breastfee di n g fr o m t he ti me 
of treat me nt all ocati o n/ra n d o mizati o n t hr o u g h
○
1 2 0 da y s 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 y s after last d ose of c he m ot hera pe ut ic a ge nts O R 
○
3 0 da y s f oll o wi n g cessati o n of st u d y treat me nt if t he partici pa nt i nitiates ne w a ntica ncer 
t hera py.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 1
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
○
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d M S D
p olic y  a n d 
f or war de d t o i n vesti gat ors as necessar y.
○
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safety i nf or mati o n (e g, s u m mar y or listi n g of S A E) fr o m M S D
will file it al o n g 
wit h t he I n vesti gat or’s Br oc h ure a n d will n otif y  t he IR B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uire me nts.
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
9. 3. 5
or S A Es
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 pecte d/act ual e ve nts c o vere d i n t his e xce pti o n i ncl u de a ny 
e ve nt t hat is disease pr o gressi o n of t he ca ncer u n der 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 data t o e ns ure 
t he safety of t he partici pa nts i n t he st u d y.  A n y s us pecte d e n d p oi nt w hic h, u p o n re vie w , is n ot 
pr o gressi o n of t he ca ncer u n der st u d y will be f or war de d t o M S D gl o bal safet y as a S A E 
wit hi n 2 4 h o urs of deter mi nati o n t hat t he e ve nt is n ot pr o gressi o n of t he ca ncer u n der st u d y.
Pre g n a nc y a n d E x p os ure D uri n g Bre astfee di n g
9. 3. 6
Alt h o u g h pre g na nc y  a n d i nfa nt e x p os ure d uri n g breastfee di n g are n ot c o nsi dere d a d verse 
e ve nts, a n y pre g na nc y o r 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 usly 
re p orte d t o t he i n vesti gat or or t heir desi g nee) t hat occ urs d uri n g t he trial are re p orta ble t o 
M S D .
All re p orte d pre g na ncies m ust be f oll o we d t o t he c o m pleti o n/ter mi nati o n of t he pre g na nc y . 
Pre g na nc y  o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n hy d ati dif or m m ole, 
bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, miscarria ge a n d still birt h m ust be re p orte d as 
seri o us e ve nts (I m p orta nt Me dical E ve nts). If t he pre g na nc y c o nti n ues t o ter m, t he o utc o me 
( healt h of i nfa nt) m ust als o be re p orte d.
E ve nts of Cli nic al I nterest ( E CI)
9. 3. 7
Selecte d n o n -seri o us a n d seri o us a d verse e ve nts are als o k n o w n as E ve nts of Cli nical Interest 
( E CI) a n d m ust be re p orte d t o M S D .
E ve nts of cli nical i nteres t f or t his trial i ncl u de: 
1.
a n o ver d ose of st u d y treat me nt, as defi ne d i n Secti o n 9. 4 – Treat me nt of O ver d ose, 
t hat is n ot ass ociate d wit h cli nical s y m pt o ms or a b n or mal la b orat or y res ults.
2 . a n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ua l t o 3 X t he u p per li mit 
of n or mal a n d a n ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n al kali ne p h os p hatase la b val ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y  w a y of pr ot oc ol-s pecifie d la b orat or y 
testi n g or u nsc he d ule d la b orat or y testi n g. *
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 2
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
* N ote:  T hese criteria are base d u p o n a vaila ble re g ulat or y g ui da nce d oc u me nts. T he 
p ur p ose of t he criteria is t o s pecif y  a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. T he trial site g ui da nce f or assess me nt 
a n d f oll o w u p of t hese criteria ca n be f o u n d i n t he I n vesti gat or Trial File Bi n der ( or 
e q ui vale nt).
It ma y als o be a p pr o priate t o c o n d uct 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  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 hat d o n ot meet t he criteria n ote d a b o ve.  I n t hese 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 ultati 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 ver, 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 yn dr o me. T he si g ns a n d s y m pt o ms of ser ot o ni n s y n dr o me are descri be d i n
Secti o n 7. 2. 1. 2 .
Tre at me nt of O ver d ose
9. 4
Pe m br oliz u m a b or E p ac a d ost at O ver d ose
F or t his st u d y, a n o ver d ose will be defi ne d as ≥1 0 0 0 m g ( ≥5 ti mes t he d ose) of 
pe m br oliz u ma b , ≥1 0 0 0 m g of e paca d ostat dail y , or as a n y d ose ≥2 0 % o ver t he prescri be d 
d ose f or t he E X T R E M E re gi me n.  N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of a n 
o ver d ose of pe m br oliz u ma b or e paca d ostat. I n t he e ve nt of o ver d ose, t he partici pa nt s h o ul d 
be o bser ve d cl osel y f or si g ns of t o xicit y .  A p pr o priate s u p p orti ve treat me nt s h o ul d be 
pr o vi de d if cli nicall y i n dicate d.
Cet u xi m a b O ver d ose
T here is n o a vaila ble i nf or mati o n f or t he treat me nt of a cet u xi ma b o ver d ose. I n cases of 
greater t ha n rec o m me n de d d oses, t he A Es were si milar t o t he k n o w n safet y pr ofile. 
A p pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d. 
Ot her wise, o ver d ose s h o ul d be ma na ge d acc or di n g t o l ocal la bel a n d practice.
C ar b o pl ati n O ver d ose
T here is n o k n o w n a nti d ote f or car b o plati n o ver d ose. T he a ntici pate d c o m plicati o ns of 
o ver d ose ma y  i ncl u de m yel os u p pressi o n a n d i m pair me nt of he patic a n d re nal f u ncti o n. 
Ot her wise, o ver d ose s h o ul d be ma na ge d acc or di n g t o l ocal la bel a n d practice.
Cis pl ati n O ver d ose
T here is n o s pecific a nti d ote f or cis plati n o v er d ose. O ver d ose ma y res ult i n t he si de effects 
ass ociate d wit h t he dr u g occ urri n g i n a n e xcessi ve ma n ner. 
Ot her wise, o ver d ose s h o ul d be ma na ge d acc or di n g t o l ocal la bel a n d practice.
5-fl u or o ur acil O ver d ose
Si g ns a n d s y m pt o ms of 5 -F U o ver d ose are si milar t o t he a d verse reacti o ns ass ociate d wit h 
t he dr u g a n d s h o ul d be ma na ge d acc or di n g t o l ocal la bel a n d practice. Partici pa nt s w h o ha ve 
a 5-F U o ver d ose s h o ul d be cl osel y m o nit ore d f or 4 wee ks.
Ot her wise, o ver d ose s h o ul d be ma na ge d acc or di n g t o l ocal la bel a n d practice.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 3
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
If a n A E (s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of st u d y treat me nt, t he A E (s) is 
re p orte d as a S A E , e ve n if n o ot her seri o us ness criteria are met.
If a d ose of st u d y treat me nt meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n wit h o ut a n y 
ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y  res ults, t he o ver d ose is re p orte d as a 
n o n -seri o us E CI, usi n g t he ter mi n ol o g y “acci de ntal or i nte nti o nal o ver d ose wit h o ut a d verse 
effect.”
All re p orts of o ver d ose wit h a n d wit h o ut a n A E m ust be re p orte d wit hi n 2 4 h o urs t o M S D 
eit her b y electr o nic me dia or pa per.  M S D
C o ntact i nf or mati o n ca n be f o u n d i n t he 
I n vesti gat or Trial File Bi n der ( or e q ui vale nt).
S afet y 
9. 5
Pla n ne d ti me p oi nts f or all sa fet 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 m
9. 5. 1. 1
T he in vesti gat or or q ualifie d desi g nee will perf or m a f ull p h y sical e xa m as per i nstit uti o nal 
sta n dar d d uri n g t he scree ni n g peri o d.  Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be 
rec or de d as me dical hist or y.  T he ti me p oi nts f or f ull p h ysical e xa ms are descri be d i n 
Secti o n 2 - S o A .  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.  
Directe d P h ysic al E x a m
9. 5. 1. 2
F or c y cles t hat d o n ot re q uire a f ull p h ys ical e xa m, as s pecifie d i n Secti o n 2 - S o A , t he 
in vesti gat or or q ualifie d desi g nee will perf or m a directe d p h ys ical e xa m as cli nicall y 
i n dicate d pri or t o 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.
Vit al Si g ns
9. 5. 2
T he i n vesti gat or or q ualifie d desi g nee will ta ke wei g ht a n d vital si g ns at scree ni n g a n d as 
s pecifie d i n Secti o n 2 - S o A . Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d by 
at least 5 mi n utes of rest f or t he partici pa nt i n a q uiet setti n g wit h o ut distracti o ns.
Hei g ht will 
be meas ure d at scree ni n g o nl y . 
Electr oc ar di o gr a ms
9. 5. 3
Baseli ne E C Gs will be o btai ne d at scree ni n g wit h a d diti o nal E C Gs o btai ne d at E O T, a n d as 
cli nicall y i n dicate d f or all partici pa nts . At select ce nters o nl y , a d diti o nal E C Gs will als o be 
o btai ne d fr o m Gr o u p 1 partici pa nts at C ycle 1 Da y 1 pre d ose a n d 2 h o urs ( ± 1 5 mi n utes) 
after t he first d ose of e paca d ostat a n d C y cle 2 D a y 1 pre d ose a n d 2 h o urs ( ± 1 5 mi n utes) after 
a d mi nistrati o n of e paca d ostat. T he E C G meas ure me nt s h o ul d al wa ys be perf or me d pri or t o 
t he P K sa m ple bl o o d dra w if b ot h are sc he d ule d at t he sa me n o mi nal pla n ne d ti me p oi nt. 
Cli nicall y  si g nifica nt a b nor mal fi n di n gs pri or t o si g ni n g c o nse nt s h o ul d be rec or de d as 
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 4
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
me dical hist or y . Cli nicall y  si g nifica nt a b n or mal fi n di n gs after si g ni n g c o nse nt s h o ul d be 
rec or de d as a n A E.
T he E C Gs will be i nter prete 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 decisi 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 
base d o n a n E C G fla g ge d as " A b n or mal, Cli nicall y Si g nifica nt" is t he res p o nsi bilit y  of t he 
i n vesti gat or, i n c o ns ultati o n wit h t he M S D
Cli nical Direct or , as a p pr o priate. T he Fri dericia 
( preferre d) or Bazett c orrecti o n met h o d f or calc ulati n g Q Tc will be use d a n d rec or de d i n t he 
e C R F.
Cli nic al S afet y L a b or at or y Assess me nts
9. 5. 4
Refer t o A p pe n di x 2 f or t he list of cli nical la b orat or y tests t o be perf or me d a n d t o t he S o A f or 
t he ti mi n g a n d fre q ue nc y. 
●
T he i n vesti gat or m ust re vie w t he la b orat or y  re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he 
C R F. T he la b orat or y  re p orts m ust be file d wit h t he s o urce d oc u me nts. Cli nicall y  
si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he 
u n derl y i n g disease, u nless j u d ge d by t he i n vesti gat or t o be m ore se vere  t ha n e x pecte d 
f or t he partici pa nt's c o n diti o n.
●
All pr ot oc ol -re q uire d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 , m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he S o A.
●
If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifie d la b orat or y assess me nts perf or me d at 
t he i nstit uti o n’s l ocal la b orat or y re q uire a c ha n ge i n st u d y partici pa nt ma na ge me nt or 
are c o nsi dere d cli nicall y si g nifica nt by t he i n vesti gat or (e g, S A E or A E or d ose 
m o dificati o n), t he n t he res ults m ust be rec or de d i n t he a p pr o p riate C R F.
●
F or a n y l a b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntly a b n or mal 
d uri n g partici pati o n i n t he st u d y  or wit hi n 3 0 da y s f or all A Es a n d 9 0 d a y s f or all 
S A Es (or 3 0 da y s f oll o wi n g cessati o n of treat me nt if t he partici pa nt i nitiates ne w 
a ntica ncer t hera p y, w hic he ver occ urs first) after t he last d ose of st u d y treat me nt, 
e ver y atte m pt s h o ul d be ma de t o perf or m re peat assess me nts u ntil t he val ues ret ur n t o 
n or mal or baseli ne or if a ne w baseli ne is esta blis he d as deter mi ne d b y t he 
i n vesti gat or. 
La b orat or y  tests f or scree ni n g or e ntr y i nt o t he Sec o n d C o urse P hase ( Retreat me nt) s h o ul d be 
perf or me d wit hi n 1 0 da ys pri or t o t he first d ose of st u d y treat me nt. Scree ni n g la bs s h o ul d be 
c ollecte d a n d assesse d pri or t o ra n d o mizi n g t he partici pa nt. After C ycl e 1, pre -d ose 
la b orat or y pr oce d ures ca n be c o n d ucte d u p t o 7 2 h o urs pri or t o d osi n g.  Res ults f or s pecific
la b orat or y tests (ie, c o m plete bl o o d c o u nt wit h c o m plete differe ntial, ser u m creati ni ne, 
electr ol yt es, a n d uri nal ys is) m ust b e a vaila ble a n d re vie we d by t he i n vesti gat or or q ualifie d 
desi g nee a n d f o u n d t o be acce pta ble pri or t o a d mi nistrati o n of eac h d ose of st u d y treat me nt.
Details re gar di n g s pecific la b orat or y pr oce d ures/assess me nts t o be perf or me d i n t his st u d y
are pr o vi de d bel o w.  T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver t he c o urse 
of t he st u d y (fr o m pre-st u d y t o p ost-st u d y visits), i ncl u di n g a p pr o xi mate bl o o d/tiss ue 
v ol u mes dra w n/c ollecte d b y  visit a n d b y sa m ple t ype per partici pa nt ca n be f o u n d i n t he 
La b orat or y Ma n ual.  
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 5
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
L a b or at or y S afet y E v al u ati o ns ( He m at ol o g y, C he mistr y, C o a g ul ati o n, a n d 
9. 5. 4. 1
Uri n al ysis)
La b orat or y  tests f or he mat ol o g y, c he mistr y, c oa g ulati o n, a n d uri nal ysis are s pecifie d i n 
A p pe n di x 2.
Pre g n a nc y Test
9. 5. 4. 2
All w o me n w h o are bei n g c o nsi dere d f or partici pati o n i n t he st u d y, a n d w h o are n ot 
s ur gicall y sterilize d or p ost me n o pa usal (as defi ne d i n A p pe n di x 5), m ust be teste d f or 
pre g na nc y  wit hi n 7 2 h o urs of first d ose of st u d y treat me nt. If a uri ne test is p ositi ve or n ot 
e val ua ble, a ser u m test will be re q uire d.  Partici pa nts m ust be e xcl u de d/ disc o nti n ue d fr o m t he 
st u d y i n t he e ve nt of a p ositi ve test res ult. Re peate d Pre g na nc y test (s uc h as m o nt hl y  test) 
ma y  be c o n d ucte d if re q uire d b y l ocal re g ulati o ns.  
He p atitis B a n d C Ser ol o g y
9. 5. 4. 3
Ser ol o g y f or He patitis B a n d He patitis C will be perf or me d f or all partici pa nts . Re q uire d 
tests are i n dicate d i n Ta ble 2 1 i n A p pe n di x 2.
Perf or m a nce Assess me nts
9. 5. 5
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce Sc ale
9. 5. 5. 1
T he i n vesti gat or or q ualifie d desi g nee will assess E C O G P S (see A p pe n di x 6 ) at scree ni n g
( wit hi n 7 da y s of ra n d o mizati o n), 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 P ost -treat me nt F oll o w - up P hase as s pecifie d i n Secti o n 2 - S o A . E C O G P S 
m ust be 0 or 1 o n t he first da y  of d osi n g. 
 
 
0 4 Y B M H

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

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 7
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Visit Re q uire me nts
9. 9
Visit re q uire me nts are o utli ne d i n Secti o n 2 – Sc he d ule of Acti vities ( S o A).  S pecific 
pr oce d ure -relate d details are pr o vi de d a b o ve i n Secti o n 9 – St u d y  Assess me nts a n d 
Pr oce d ures.
Scree ni n g
9. 9. 1
A p pr o xi matel y  2 8 da ys pri or t o treat me nt ra n d o mizati o n, p ote ntial partici pa nts will be 
e val uate d t o deter mi ne t hat t he y f ulfill t he e ntr y re q uire me nts as set f ort h i n Secti o ns 6. 1 a n d 
6. 2 . Scree ni n g pr oce d ures ma y be re pe ate d after c o ns ultati o n wit h M S D .
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 8
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
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 p r ot oc ol-s pecific pr oce d ure. 
Res ults of a test perf or me d pri or t o t he partici pa nt si g ni n g c o nse nt as part of r o uti ne cli nical 
ma na ge me nt are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti me 
fra me. Scree ni n g pr oce d ures are t o be c o m plete d wit hi n a p pr o xi matel y  2 8 da y s pri or t o t he 
first d ose of st u d y treat me nt e xce pt f or t he f oll o wi n g:

La b orat or y  tests are t o be perf or me d wit hi n 1 0 da ys pri or t o t he first d ose of st u d y 
treat me nt.  A n e xce pti o n is he patitis testi n g w hic h ma y be d o ne u p t o 4 0 da y s pri or t o 
ra n d o mizati o n if d o ne as part of sta n dar d d oc u me nte d cli nical acti vities.  Scree ni n g
la bs s h o ul d be c ollecte d a n d assesse d pri or t o ra n d o mizi n g t he partici pa nt.  

E val uati o n of E C O G P S is t o be perf or me d wit hi n 7 da y s pri or t o date of 
ra n d o mizati o n. 

F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test will be 
perf or me d wi t hi n 7 2 h o urs pri or t o t he first d ose of st u d y treat me nt. If uri ne 
pre g na nc y  res ults ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be 
re q uire d ( perf or me d by t he l ocal st u d y site la b orat or y).

T u m or tiss ue 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 y s pri or t o 
t he first d ose of st u d y treat me nt. T u m or s peci me n m ust be recei ve d b y t he ce ntral 
ve n d or bef ore a partici pa nt is ra n d o mize d.
Partici pa nts ma y  be rescree ne d after i nitiall y faili n g t o meet t he i ncl usi o n/e xcl usi o n criteria. 
Res ults fr o m assess me nts d uri n g t he i nit ial scree ni n g p eri o d are acce pta ble i n lie u of a re peat 
scree ni n g test if perf or me d wit hi n t he s pecifie d ti me fra me a n d t he c orres p o n di n g 
i ncl usi o n/e xcl usi o n criteria are met.
Partici pa nts w h o are rescree ne d will retai n t heir ori gi nal 
scree ni n g n u m ber.
Tre at me nt P h ase 
9. 9. 2
Visit re q uire me nts are o utli ne d i n Secti o n 2 - S o A . S pecific pr oce d ure -relate d details are 
pr o vi de d i n Secti o n 9. 1. At C y cle 1 Da y 1, res ults fr o m Scree ni n g Visit e val uati o ns s h o ul d 
be re vie we d t o deter mi ne w het her t he partici pa nt c o nti n ues t o meet t he eli gi bilit y
re q uire me nts, as s pecifie d i n Secti o n 6.
Treat me nt wit h pe m br oliz u ma b will occ ur e ver y  2 1 da ys ( 1 c ycle) f or u p t o 3 5 c ycles 
(a p pr o xi matel y 2 years) . T he ma xi m u m d urati o n of t he i nitial T reat me nt P hase is s pecifie d 
as 3 5 c ycles of treat me nt (a p pr o xi matel y 2 years) u nless a disc o nti n uati o n criteri o n is met 
( Secti o n 8. 1).
E paca d ostat will be d ose d BI D d uri n g t he T reat me nt P hase. Treat me nt ma y  c o nti n ue u ntil 
C ycle 3 5 D a y 2 1, u nless a disc o nti n uati o n criteri o n is met ( Secti o n 8. 1).
T he E X T R E M E re gi me n treat me nts will occ ur e ver y  2 1 d a y s ( 1 c ycle) f or u p t o 6 c ycles f or 
5- F U a n d cis plati n/car b o plati n. Cet u xi ma b will be a d mi nistere d wee kl y u ntil ra di o gra p hic 
P D or u nacce pta ble t o xicit y .
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 1 9
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
E n d of Tre at me nt
9. 9. 3
W he n t he partici pa nt per ma ne ntl y disc o nti n ues st u d y  treat me nts, t he E O T V isit s h o ul d be 
c o n d ucte d. If t he E O T V isit c oi nci des wit h a re g ular st u d y visit, t he E O T e val uati o ns will 
s u perse de t h ose of t hat sc he d ule d visit. T he partici pa nt s h o ul d be e nc o ura ge d t o ret ur n f or 
t he P ost -treat me nt Safet y F oll o w - up V isit.
P ost -tre at me nt Visits
9. 9. 4
S afet y F oll o w -u p Visit
9. 9. 4. 1
N O T E:  As of A me n d me n t 0 4, t he S afet y F oll o w-u p Visit will be t he l ast visit i n t he 
st u d y.  T his secti o n h as bee n a me n de d acc or di n gl y .
T he ma n dat or y  Safety F oll o w -u p Visit s h o ul d be c o n d ucte d a p pr o xi matel y  3 0 da ys after t he 
last d ose of st u d y treat me nt or bef ore t he i nitiati o n of a ne w a ntica ncer treat me nt, w hic he ver 
c o mes first.  
A partici pa nt will be c o nsi dere d t o ha ve c o m plete d t his st u d y  o nce t he y ha ve atte n de d t his 
visit.  Partici pa nts c urre ntl y i n F oll o w -u p or i n S ur vi val F oll o w -u p are c o nsi dere d t o ha ve 
c o m plete d t he st u d y; t hese partici pa nts are n ot re q uire d t o atte n d a n y f urt her visits.  
Assess me nt a n d rec or di n g of A Es will be perf or me d as per Secti o n 9. 3 .
Partici pa nts w h o are eli gi ble t 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 or pe m br oliz u ma b m o n ot hera p y m a y  ha ve u p t o 2 S afet y F oll o w - up V isits;
1 after t he initial treat me nt p eri o d a n d 1 after t he Sec o n d C o urse st u d y treat me nt.
F oll o w -u p Visits
9. 9. 4. 2
N O T E:  As of A me n d me nt 0 4 , t his secti o n is n o l o n ger a p plic a ble.  P 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 afet y F oll o w-u p Visit; a ssess me nt a n d rec or di n g of A Es will be 
perf or me d as per Secti o n 9. 3.
Partici pa nts w h o disc o nti n u e st u d y treat me nt f or a reas o n ot her t ha n BI C R -verifie d 
ra di o gra p hic disease pr o gressi o n will m o ve i nt o t he P ost -treat me nt F oll o w - up P hase a n d 
s h o ul d be assesse d b y  ra di ol o gic i ma gi n g e ver y 6 wee ks ( 4 2 da ys ± 7 da y s) f or t he first year 
a n d e ver y 9 wee ks ( 6 3 da ys ± 7 da ys) t hereafter t o m o nit or disease stat us. E ver y  eff ort 
s h o ul d be ma de t o c ollect i ma gi n g u ntil BI C R -verifie d ra di o gra p hic disease pr o gressi o n , t he 
start of a ne w a ntica ncer t hera p y, wit h dra wal of c o nse nt f or i ma gi n g, pre g na nc y, deat h, or t he 
e n d of t he st u d y. I nf or mati o n re gar di n g p ost-st u d y a ntica ncer treat me nt will be c ollecte d if 
ne w treat me nt is i nitiate d.
Partici pa nts w h o are eli gi ble t o recei ve retreat me nt wit h pe m br oliz u ma b pl us e paca d ostat or 
pe m br oliz u ma b m o n ot hera p y acc or di n g t o t he criteria i n Secti o n 7. 2. 6 will m o ve fr o m t he 
P ost -treat me nt F oll o w - up P hase t o t he Sec o n d C o urse P hase w he n t he y  e x perie nce disease 
pr o gressi o n. 
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 1
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
St atistic al A n al ysis Pl a n S u m m ar y
1 0. 1
K e y  ele me nts of t he statistical a nalys is pla n are s u m marize d bel o w; t he c o m pre he nsi v e pla n 
is pr o vi de d i n Secti o ns 1 0. 2 t hr o u g h 1 0. 1 2.
St u d y Desi g n O ver vie w
A P hase 3 Ra n d o mize d, O pe n -La bel Cli nical 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 pl us E paca d ostat , 
Pe m br oliz u ma b m o n ot hera p y a n d t he E X T R E M E Re gi me n as First 
li ne Treat me nt f or Rec urre nt or Metastatic Hea d a n d Nec k S q ua m o us 
Cell Carci n o ma ( K E Y N O T E -6 6 9)
Tre at me nt Assi g n me nt
A p pr o xi matel y 9 0 partici pa nt s will be ra n d o mize d 2: 1: 2 i nt o 
3 treat me nt ar ms, stratifie d b y E C O G P S, H P V p 1 6 stat us a n d pri or 
s yste mic t hera p y (see Secti o n 7. 3. 1 f or details).  T he treat me nt ar ms 
are as f oll o ws:

pe m br oliz u ma b 2 0 0 m g Q 3 W + e paca d ostat;

pe m br oliz u ma b 2 0 0 m g Q 3 W

cet u xi ma b + plati n u m + 5 -F U ( E X T R E M E)
T his st u d y will be c o n d ucte d as a n o pe n -la bel st u d y.
A n al ysis P o p ul ati o ns
Efficac y: I nte nti o n t o Treat (I T T)
Safet y: All Partici pa nt s as Treate d ( A Pa T)
Pri m ar y E n d p oi nt(s)
O bjecti ve Res p o nse Rate ( O R R) per R E CI S T 1. 1 assesse d b y 
i n vesti gat or deter mi nati o n
St atistic al Met h o ds f or 
Ke y Effic ac y A n al yses
O R R will be esti mate d b y treat me nt gr o u p wit h 9 5 % CI calc ulate d b y 
Cl o p per a n d Pears o n e xact met h o d [ Cl o p per, C. J. a n d Pears o n, E. S. 
1 9 3 4] .
St atistic al Met h o ds f or 
Ke y S afet y A n al yses
P oi nt esti mates (c o u nt a n d perce nta ge) b y treat me nt gr o u p will be 
pr o vi de d f or safet y e n d p oi nts. 
I nteri m A n al yses
Effic ac y

Fi nal a nal ysis 
Ti mi n g: W he n all ra n d o mize d partici pa nts ha ve o ne p ost -baseli ne
i ma gi n g sca n or disc o nti n ue t he st u d y. 
S afet y:
O ne safet y re vie w will be c o n d ucte d at ~ 4 m o nt h after first partici pa nt 
is ra n d o mize d.
M ulti plicit y
T here will be n o m ulti plicit y a dj ust me nt. 
S a m ple Size a n d P o wer 
T he sa m ple size is a p pr o xi matel y 9 0 partici pa nts wit h 3 6 partici pa nts 
i n eac h of t he pe m br oliz u ma b + e paca d ostat a n d E X T R E M E ar ms, 
a n d 1 8 partici pa nts i n t he pe m br oliz u ma b m o n ot hera p y ar m.  Se cti o n 
1 0 . 9 pr o vi des t he precisi o n of t he O R R esti mates. 
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g
1 0. 2
T he statistical a nal ys is of t he data o btai ne d fr o m t his st u d y will be t he res p o nsi bilit y of t he 
M S D Cli nical Bi ostatistics de part me nt .
M S D
will ge ne rate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u dy 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 mizatio n will be i m ple me nte d i n I V R S.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 2
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
Alt h o u g h t he st u d y is o pe n-la bel, a nalys 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 a n d act ual treat me nt recei ve d will be li mite d a n d d oc u me nte d.
T he e D M C will ser ve as t he pri mar y  re vie wer of t he u n bli n de d safety d ata .  A d diti o nal 
l o gistical details will be pr o vi de d i n t he e D M C C harter.
H y p ot heses/ Esti m ati o n
1 0. 3
O bjecti ves of t he st u d y are state d i n Secti o n 4 . 0.
A n al ysis E n d p oi nts
1 0. 4
Effic ac y E n d p oi nt
1 0. 4. 1
O bjecti ve Res p o nse R ate ( O R R) – R E CI S T 1. 1 b y in vesti g at or deter mi n ati o n
O bjecti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of t he partici pa nt s i n t he a nal ysis 
p o p ulati o n w h o ha ve a best res p o nse of c o m plete res p o nse ( C R) or partial res p o nse ( P R). 
Res p o nses are base d o n R E CI S T 1. 1 b y  in vesti gat or deter mi nati o n .
S afet y E n d p oi nts
1 0. 4. 2
Safet y meas ure me nts are descri be d i n Secti o n 5. 4. 1. 2 a n d Secti o n 9. 
A n al ysis P o p ul ati o ns
1 0. 5
Effic ac y A n al ysis P o p ul ati o n
1 0. 5. 1
T he I nte nti o n -t o-Treat (I T T) p o p ulati o n will ser ve as t he p o p ulati o n f or efficac y  a nalys 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 nalyz e d 
i n t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d.  
S afet y A n al ysi s P o p ul ati o n
1 0. 5. 2
T he All Partici pa nt s as Treate d (A P a T) p o p ulati o n will be use d f or t he a nal y sis of safety data 
i n t his st u d y.  T he A Pa T p o p ulati o n c o nsists of all ra n d o mize d partici pa nt s w h o recei ve d at 
least 1 d ose of st u dy treat me nt. Partici pa nt s will be a nal yz e d i n t he treat me nt gr o u p 
c orres p o n di n g t o t he st u d y treat me nt t he y act uall y recei ve f or t he a nalys is of safety data 
usi n g t he A Pa T p o p ulati o n.  F or m ost partici pa 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 dy treat me nt f or t he e ntire treat me nt 
peri o d will be i ncl u de d i n t he treat me nt gr o u p c orres p o n di n g t o t he st u d y treat me nt act uall y 
recei ve.  A ny partici pa nt w h o recei ves t he i nc orrect st u d y  treat me nt f or 1 c ycle b ut recei ves 
t he c orrect treat me nt f or all ot her c ycles will be a nal yze d acc or di n g t o t he c orrect treat me nt 
gr o u p a n d a narrati ve will be pr o vi de d f or a n y e ve nts t hat occ ur d uri n g t he c ycle f or w hic h 
t he partici pa nt is i nc orrectl y d ose d.
At least 1 l a b orat or y val ue o btai ne d s u bse q ue nt t o at least 1 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 nalys is of eac h s pecific para meter.  T o assess c ha n ge fr o m 
baseli ne, a baseli ne meas ure me nt is als o re q uire d.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 3
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
St atistic al Met h o ds
1 0. 6
St atistic al Met h o d s f or Effic ac y A n al yses
1 0. 6. 1
T his secti o n descri bes t he statistical met h o ds t hat a d dress t he pri mar y o bjecti ve .
O R R will be esti mate d b y treat me nt gr o u p. 9 5 % CI  f or O R R will be pr o vi de d usi n g Cl o p per
a n d Pears o n e xact met h o d [ Cl o p per, C. J. a n d Pears o n, E. S. 1 9 3 4].
St atistic al Met h o ds f or S afet y A n al yses
1 0. 6. 2
Safet y  a n d t olera bilit y will be assesse d by cli nical re vie w of all rele va nt para meters i ncl u di n g 
A 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 ve nts a n d t he br oa d A E cate g ories c o nsisti n g of t he pr o p orti o n of partici pa nts 
wit h a n y  A E, a dr u g relate d A E, a seri o us A E, a n A E w hic h is b ot h dr u g-relate d a n d seri o us, 
a Gra de 3-5 A E, a dr u g relate d Gra de 3 -5 A E, a fatal A E, d ose i nterr u pti o n d ue t o a n A E a n d 
disc o nti n uati o n d ue t o a n A E , will be s u m marize d b y c o u nts a n d perce nta ges b y  treat me nt 
gr o u p (Ta ble 1 8 ).
Ta ble 1 8
A nal y sis Strate g y  f or Safet y E n d p oi nts
S afet y E n d p oi nt
Descri pti ve 
St atistics
A n y  A E 
X
A n y  Seri o us A E 
X
A n y  Gra de 3-5 A E
X
A n y  Dr u g-Relate d A E
X
A n y  Seri o us a n d Dr u g-Relate d A E
A n y  Gra de 3-5 a n d Dr u g -Relate d A E
X
X
D ose I nterr u pti o n d ue t o A E
X
Disc o nti n uati o n d ue t o A E
X
Deat h
X
S pecific A Es, S O Cs 
X
C ha n ge fr o m Baseli ne Res ults ( la b t o xicit y gra de)
X
A b bre viati o ns: A E = a d verse e ve nt; 
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 4
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
S u m m aries of B aseli ne C h ar acteristics a n d De m o gr a p hics
1 0. 6. 3
T he c o m para bilit y  of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d by 
t he use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n t hese 
c haracteristics. T he n u m ber a n d perce nta ge of partici pa nt s scree ne d, ra n d o mize d, a n d t he 
pri mar y  reas o n f or scree ni n g fail ure, a n d t he pri mar y reas o n f or disc o nti n uati o n will be 
dis pla y e d. De m o gra p hic varia bles ( e g, a ge, race, etc.) a n d baseli ne c haracteristics will be 
s u m marize d b y treat me nt eit her by descri pt i ve statistics or cate g orical ta bles. 
I nteri m A n al ysis
1 0. 7
N o efficac y  i nteri m a nal ysis will be c o n d ucte d. O ne safet y  re vie w b y  D M C is pla n ne d at ~ 4 
m o nt hs after t he first pa rtici pa nt is ra n d o mize d.
M ulti plicit y
1 0. 8
T here is n o h y p ot hesis testi n g 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 wer C alc ul ati o ns
1 0. 9
T he st u d y  wil l ra n d o mize a p pr o xi matel y 9 0 partici pa nts i n a 2: 1: 2 rati o i nt o p e m br oliz u ma b 
pl us epaca d ostat, p e m br oliz u ma b m o n ot hera p y a n d E X T R E M E ar ms , wit h 3 6 partici pa nts
eac h i n t he pe m br oliz u ma b pl us e paca d ostat a n d E X T R E M E ar ms res pecti ve l y, a n d 1 8 
partici pa nts i n t he pe m br oliz u ma b m o n ot hera p y  ar m. T w o -si de d 9 5 % CI f or O R R are s h o w n 
i n Ta ble 1 9 a n d Ta ble 2 0 .
Ta ble 1 9
T w o -si de d 9 5 % CI f or O R R wit h 3 6 p artici pa nts
N u m ber of 
Res p o n ders
O R R Esti m ate ( %)
9 5 % CI † of O R R ( %)
1 1
~ 3 0
( 1 6. 4, 4 8. 1)
1 3
~ 3 5
( 2 0. 8, 5 3. 8)
1 4
~ 4 0
( 2 3. 1, 5 6. 5)
1 6
~ 4 5
( 2 7. 9, 6 1. 9)
1 8
5 0
( 3 2. 9, 6 7. 1)
† Base d o n t he t w o- taile d e xact CI of a bi n o mial pr o p orti o n ( Cl o p per a n d Pears o n, 
1 9 3 4).
Ta ble 2 0
T w o -si de d 9 5 % CI f or O R R wit h 1 8 p artici pa nts
N u m ber of 
Res p o n ders
O R R Esti m ate ( %)
9 5 % CI † of O R R ( %)
5
~ 3 0
( 9. 7, 5 3. 5)
6
~ 3 5
( 1 3. 3, 5 9. 0)
7
~ 4 0
( 1 7. 3, 6 4. 3)
8
~ 4 5
( 2 1. 5, 6 9. 2)
9
5 0
( 2 6. 0, 7 4. 0)
† Base d o n t he t w o- taile d e xact CI of a bi n o mial pr o p orti o n ( Cl o p per a n d Pears o n, 
1 9 3 4).
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 5
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
S u b gr o u p A n al yses
1 0. 1 0
N o s u b gr o u p a nal ys is is nee de d.
C o m pli a nce ( Me dic ati o n A d here nce)
1 0. 1 1
Dr u g acc o u nta bilit y  data f or st u d y treat me nt will be c ollecte d d uri n g t he st u d y.  A ny 
de viati o n fr o m pr ot oc o l-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
E xte nt of E x p os ure f or a partici pa nt is defi ne d as n u m ber of c ycles i n w hic h t he partici pa nt
recei ves t he st u d y treat me nt i nf usi o n. 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 o r A Pa T p o p ulati o n.
1 1.
Refere nces
[ Aar o ns o n, N. K., 
et al 1 9 9 3]
Aar o ns o n N K, A h me dzai S, Ber g ma n B, B ulli n ger M, C ull 
A, D uez NJ, et al. T he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer Q L Q -C 3 0: a q ualit y -of -life 
i nstr u me nt f or use i n i nter nati o nal cli nical trials i n 
o nc ol o g y . J Natl Ca ncer I nst 1 9 9 3; 8 5( 5): 3 6 5-7 6.
0 3 Q 3 Q L
[ A n g, K. K., et al 
2 0 1 0]
A n g K K, Harris J, W heeler R, We ber R, R ose nt hal DI , 
N g u ye n- Ta n P F, et al. H u ma n pa pill o ma vir us a n d s ur vi val 
of patie nts wit h or o p har y n geal ca ncer. N E n gl J Me d. 2 0 1 0 
J ul 1; 3 6 3( 1): 2 4-3 5.
0 4 F P 0 Y
[ Ar giris, A., et al 
2 0 0 8]
Ar giris A, Kara m o uzis M V, Ra be n D, Ferris R L. Hea d a n d 
nec k ca ncer. La ncet. 2 0 0 8 Ma y  1 7; 3 7 1( 9 6 2 5): 1 6 9 5-7 0 9.
0 4 N 0 C F
[ Ba u ml, J., et al 
2 0 1 7]
Ba u ml J, Sei wert T Y, Pfister D G, W o r de n F, Li u S V, 
Gil bert J, et al. Pe m br oliz u ma b f or Plati n u m - a n d 
Cet u xi ma b -Refract or y  Hea d a n d Nec k Ca ncer: Res ults 
Fr o m a Si n gle -Ar m, P hase II St u d y . J Cli n O nc ol. 2 0 1 7 
Ma y  1 0; 3 5( 1 4): 1 5 4 2-1 5 4 9.
0 4 Q T G 6
[ Bj or dal, K., et al 
1 9 9 4]
Bj or dal K, A hl ner -El m q vist M, T olless o n E, Je nse n A B, 
Raza vi D, Ma her EJ, et al. De vel o p me nt of a E ur o pea n 
Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer 
( E O R T C) q uesti o n naire m o d ule t o be use d i n q ualit y of life 
assess me n ts i n  hea d a n d nec k ca ncer patie nts. Acta O nc ol 
1 9 9 4; 3 3( 8): 8 7 9 -8 5.
0 3 W N B B
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 6
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ Bj or dal, K., et al 
2 0 0 0]
Bj or dal K, de Graeff A, Fa y ers P M, Ha m merli d E, va n 
P ottels ber g he C, C urra n D, et al. A 1 2 c o u ntr y  fiel d st u d y of 
t he E O R T C Q L Q-C 3 0 ( versi o n 3. 0) a n d t he hea d a n d nec k 
ca ncer s pecific m o d ule ( E O R T C Q L Q- H & N 3 5) i n hea d a n d 
nec k patie nts. E O R T C Q ualit y  of Life Gr o u p. E ur J Ca ncer. 
2 0 0 0 Se p; 3 6( 1 4): 1 7 9 6 -8 0 7.
0 4 0 V G M
[ 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 her, G., et 
al 2 0 0 6]
Bra n dac her G, Perat h o ner A, La d ur ner R, Sc h nee ber ger S, 
O brist P, Wi n kler C, et al. Pr o g n ostic val ue of i n d olea mi ne 
2, 3- di o x y ge nase e x pressi o n i n c ol orectal ca ncer: effect o n 
t u m or-i nfiltrati n g T cells. Cli n Ca ncer Res. 2 0 0 6 Fe b 
1 5; 1 2( 4): 1 1 4 4 - 5 1.
0 4 9 M F B
[ C he m nitz, J. M., 
et al 2 0 0 4]
C he m nitz J M, Parr y  R V, Nic h ols K E, J u ne C H, Rile y JL.  
S H P -1 a n d S H P -2 ass ociate wit h i m m u n orece pt or t y r osi ne-
base d s witc h m otif of pr o gra m me d deat h 1 u p o n pri mar y  
h u ma n T cell sti m ulati o n, b ut o nl y rece pt or li gati o n 
pre ve nts T cell acti vati o n. J I m m u n ol 2 0 0 4; 1 7 3: 9 4 5 - 5 4.
0 0 V M P N
[ C hera, B. S., et al 
2 0 1 4]
C hera B S, Eis br uc h A, M ur p h y  B A, Ri d ge J A, Ga vi n P, 
Ree ve B B, et al. Rec o m me n de d patie nt -re p orte d c ore set of 
s ym pt o ms t o meas ure i n hea d a n d nec k ca ncer treat me nt 
trials. J Natl Ca ncer I nst. 2 0 1 4 J ul 8; 1 0 6( 7):[ 4 p.].
0 4 0 W H F
[ C h ua, M. L., et al 
2 0 1 6]
C h ua M L , Wee J T, H ui E P, C ha n A T. Nas o p har y n geal 
carci n o ma. La ncet. 2 0 1 6 Mar 5; 3 8 7( 1 0 0 2 2): 1 0 1 2 - 2 4.
0 4 N 0 C L
[ Cl o p per, C. J. a n d 
Pears o n, E. S. 
1 9 3 4]
Cl o p per CJ, Pears o n E S. T he use of c o nfi de nce or fi d ucial 
li mits ill ustrate d i n t he case of t he bi n o mial. Bi o metri ka 
1 9 3 4; X X VI: 4 0 4 - 1 3.
0 3 P H D N
[ 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
[ Fa k hr y, C., et al 
2 0 0 8]
Fa k hr y  C, Westra W H, Li S, C mela k A, Ri d ge J A, Pi nt o H, 
et al. Im pr o ve d s ur vi val of patie nts wit h h u ma n 
pa pill o ma vir us- p ositi ve hea d a n d nec k s q ua m o us cell 
carci n o ma i n a pr os pecti ve cli nical trial. J Natl Ca ncer I nst 
2 0 0 8; 1 0 0( 4): 2 6 1 -9.
0 3 W Q 6 Y
[ Fallari n o, F., et al 
2 0 0 6]
Fallari n o F, Gr o h ma n n U, Y o u S, Mc Grat h B C, Ca ve ner 
D R, Vacca C, et al. T he c o m bi ne d effects of tr y pt o p ha n 
star vati o n a n d tr ypt o p ha n cata b olites d o w n- re g ulate T cell 
rece pt or zeta-c hai n a n d i n d uce a re gulat or y  p he n ot ype 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 N 0 C M
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 7
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ F orastiere, A. A., 
et al 1 9 9 2]
F orastiere A A, Metc h B, Sc h uller D E, E nsle y  J F, H utc hi ns 
L F, Tri ozzi P, et al. Ra n d o mize d c o m paris o n of cis plati n 
pl us fl u or o uracil a n d car b o plati n pl us fl u or o uracil vers us 
met h otre xate i n a d va nce d s q ua m o us -cell carci n o ma of t he 
hea d a n d nec k: a S o ut h west O nc ol o g y  Gr o u p st u d y. J Cli n 
O nc ol 1 9 9 2; 1 0( 8): 1 2 4 5 - 5 1.
0 3 W N 8 M
[ F orastiere, A. A., 
et al 2 0 0 1]
F orastiere A A, Le o n g T, R o wi ns k y  E, M ur p hy B A, Vl oc k 
D R, De C o nti R C, et al. P hase III c o m paris o n of hi g h -d ose 
paclita xel + cis plati n + gra n ul oc y te c ol o ny- sti m ulati n g 
fact or vers us l o w-d ose paclita xel + cis plati n i n a d va nce d 
hea d a n d nec k ca ncer: Easter n C o o perati ve O nc ol o g y  
Gr o u p St u d y  E 1 3 9 3. J Cli n O nc ol. 2 0 0 1 Fe b 1 5; 1 9( 4): 1 0 8 8-
9 5.
0 3 Y X NJ
[ Fra ncisc o, L. M., 
et al 2 0 1 0]
Fra ncisc o L M, Sa ge P T, S har pe A H. T he P D- 1 pat h wa y  i n 
t olera nce a n d a ut oi m m u nit y. I m m u n ol Re v 2 0 1 0; 2 3 6: 2 1 9-
4 2.
0 0 V M N M
[ Fr u me nt o, G., et 
al 2 0 0 2]
Fr u me nt o G, R ot o n d o R, T o netti M, Da m o nte G, Be natti U, 
Ferrara G B. Tr y pt o p ha n -deri ve d cata b olites are res p o nsi ble 
f or i n hi biti o n of T a n d nat ural killer cell pr oliferati o n 
i n d uce d by i n d olea mi ne 2, 3 -di o x y ge nase. J E x p Me d. 2 0 0 2 
A u g 1 9; 1 9 6( 4): 4 5 9 - 6 8.
0 4 9 P S Y
[ Gi bs o n, M. K., et 
al 2 0 0 5]
Gi bs o n M K, L i Y, M ur p h y B, H ussai n M H, De C o nti R C, 
E nsle y  J, et al. Ra n d o mize d p hase III e val uati o n of cis plati n 
pl us fl u or o uracil vers us cis plati n pl us paclita xel i n a d va nce d 
hea d a n d nec k ca ncer ( E 1 3 9 5): a n i nter gr o u p trial of t he 
Easter n C o o perati ve O nc ol o g y Gr o u p. J Cli n O nc ol. 2 0 0 5 
Ma y  2 0; 23( 1 5): 3 5 6 2 - 7.
0 4 8 D V 8
[ Gillis o n, M. L., et 
al 2 0 1 5]
Gillis o n M L , C hat ur ve di A K, A n ders o n W F, Fa k hr y C. 
E pi de mi ol o g y  of H u ma n Pa pill o ma vir us-P ositi ve Hea d a n d 
Nec k S q ua m o us Cell Carci n o ma. J Cli n O nc ol. 2 0 1 5 Oct 
1 0; 3 3( 2 9): 3 2 3 5 - 4 2.
0 4 D G D Y
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 8
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ 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, L a p oi nte R. 
I n d olea mi ne 2, 3-di o x y ge nase e x pressi o n i n h u ma n ca ncers: 
cli nical a n d i m m u n ol o gic pers pecti ves. Cli n Ca ncer Res. 
2 0 1 1 N o v 1 5; 1 7( 2 2): 6 9 8 5 - 9 1.
0 4 9 P S S
[ Gree n wal d, R. J., 
et al 2 0 0 5]
Gree n wal d RJ, Free ma n GJ, S har pe A H. T he B 7 fa mil y  
re visite d. A n n u Re v I m m u n ol 2 0 0 5; 2 3: 5 1 5- 4 8.
0 0 V M Q L
[ Gre g oire, V., et al 
2 0 1 0]
Gre g oire V, Lefe b vre J L,  Licitra L, Feli p E; E H N S-E S M O -
E S T R O G ui deli nes W or ki n g Gr o u p. S q ua m o us cell 
carci n o ma of t he hea d a n d nec k: E H N S -E S M O -E S T R O 
Cli nical Practice G ui deli nes f or dia g n osis, treat me nt a n d 
f oll o w-u p. A n n O nc ol. 2 0 1 0 Ma y ; 2 1 S u p pl 5: v 1 8 4- 6.
0 4 D 2 F 5
[ Ha mi d, O., et al 
2 0 1 7]
Ha mi d O, Ba 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
[ 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, O lsza ns ki AJ, 
Tar hi ni A A, et al. Safet y of E paca d ostat 1 0 0 m g BI D Pl us 
Pe m br oliz u ma b 2 0 0 m g Q 3 W i n a d va nce d s oli d t u m ors: 
P hase 2 data fr o m E C H O -2 0 2/ K E Y N O T E - 0 3 7. P oster 
sessi o n prese nte d at: 5 3r d A n n ual Meeti n g of t he A merica n 
S ociet y  of Cli nical O nc ol o g y; 2 0 1 7 J u ne 2 – 6; C hica g o, I L.
0 4 P Q B R
[ 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. Patter ns of res p o nse i n patie nts wit h a d va nce d 
mela n o ma treate d wit h Pe m br oliz u ma b ( M K- 3 4 7 5) a n d 
e val uati o n of i m m u ne-relate d res p onse criteria (ir R C). J 
I m m u n ot her Ca ncer. 2 0 1 4; 2( S u p pl 3): P 1 0 3.
0 4 6 5 R W
[ H o di, F. S., et al 
2 0 1 6]
H o di F S, H w u WJ, Keff or d R, We ber J S, Da u d A, Ha mi d 
O, et al. E val uati o n of i m m u ne -relate d res p o nse criteria a n d 
R E CI S T v 1. 1 i n patie nts wit h a d va nce d mela n o ma treate d 
wit h pe m br oliz u ma b. J Cli n O nc ol. 2 0 1 6 Ma y  
1; 3 4( 1 3): 1 5 1 0 - 7.
0 4 H 0 R Y
[ 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
[IB E diti o n 1 0, 
2 0 1 7 ]
E P A C A D O S T A T (I N C B 0 2 4 3 6 0) – I n vesti gat ors Br oc h ure 
v 1 0, 1 1- Dec -2 0 1 7.
0 4 T 9 P C
[IB E diti o n 1 5 
2 0 1 7]
K E Y T R U D A ( pe m br oliz u ma b) I n vesti gat or’s Br oc h ure, 
E diti o n N u m ber 1 5, 1 8- Se p- 2 0 1 7.
0 4 R 9 W 6
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 2 9
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[In o, K., et al 
2 0 0 6]
I n o K, Y os hi da N, Kaji ya ma H, S hi bata K, Ya ma m ot o E, 
Ki d o k or o K, et al. I n d olea mi ne 2, 3 -di o x y ge nase is a n o vel 
pr o g n ostic i n dicat or f or e n d o metrial ca ncer. Br J Ca ncer. 
2 0 0 6 Dec 4; 9 5( 1 1): 1 5 5 5 - 6 1.
0 4 9 NJ 5
[Jac o bs, C., et al 
1 9 9 2]
Jac o bs C, L yma n G, Velez -Ga rcia E, Sri d har K S, K ni g ht 
W, H oc hster H, et al. A p hase III ra n d o mize d st u d y 
c o m pari n g cis plati n a n d fl u or o uracil as si n gle a ge nts a n d i n 
c o m bi nati o n f or a d va nce d s q ua m o us cell carci n o ma of t he 
hea d a n d nec k. J Cli n O nc ol. 1 9 9 2 Fe b; 1 0( 2): 2 5 7 - 6 3.
0 3 Y X N 5
[Li ver p o ol Hea d 
a n d Nec k 
O nc ol o g y  Gr o u p 
1 9 9 0]
Li ver p o ol Hea d a n d Nec k O nc ol o g y  Gr o u p. A p hase III 
ra n d o mise d trial of cist plati n u m, met h otre xtate, cis plati n u m 
+ met h otre xate a n d cis plati n u m + 5 -F U i n e n d sta ge 
s q ua m o us carci n o ma of t he hea d a n d nec k. Br J Ca ncer. Fe b 
1 9 9 0; 6 1( 2): 3 1 1 – 3 1 5.
0 3 Y X P F
[ Mac hiels, J. P., et 
al 2 0 1 5]
Mac hiels J P, Ha d da d RI , Fa yette J, Licitra L F, Ta hara M, 
Ver m or ke n J B, et al. Afati ni b vers us met h otre xate as 
sec o n d-li ne treat me nt i n patie nts wit h rec urre nt or 
metastatic s q ua m o us -cell carci n o ma of t he hea d a n d nec k 
pr o gressi n g o n or after plati n u m- base d t hera p y ( L U X - Hea d 
& Nec k 1): a n o pe n -la bel, ra n d o mise d p hase 3 trial. La ncet 
O nc ol. 2 0 1 5 Ma y; 1 6( 5): 5 8 3 - 9 4.
0 4 8 8 Y Q
[ Me hra, R., et al 
2 0 1 6]
Me hra R, Sei wert T Y, Ma hi pal A, Weiss J, Ber ger R, Pa ul 
E der J et al. Efficac y  a n d safety of pe m br oliz u ma b i n 
rec urre nt/ metastatic hea d a n d nec k s q ua m o us cell 
carci n o ma ( R/ M H N S C C): P o ole d a nal yses after l o n gter m 
f oll o w u p i n K E Y N O T E 0 1 2 [a bstract]. J Cli n O nc ol. 
2 0 1 6; 3 4(s u p pl). A bstract n o. 6 0 1 2.
0 4 G Z 3 C
[ Mell or, A. L. 
1 9 9 9]
Mell or A L, M u n n D H. Tr y pt o p ha n cata b olis m a n d T -cell 
t olera nce: i m m u n os u p pressi o n b y star vati o n? Im m u n ol 
T o da y . 1 9 9 9 Oct; 2 0( 1 0): 4 6 9- 7 3.
0 4 N 0 C P
[ Mell or, A. L. 
2 0 0 4]
Mell or A L, M u n n D H. I D O e x pressi o n b y  de n dritic cells: 
t olera nce a n d tr ypt o p ha n cata b olis m. Nat Re v I m m u n ol. 
2 0 0 4 Oct; 4( 1 0): 7 6 2 - 7 4.
0 4 9 NJ 7
[ Mell or, A. L., et 
al 2 0 0 3]
Mell or A L, Ba ba n B, C ha n dler P, Mars hall B, J ha ver K, 
Ha nse n A, et al. C utti n g e d ge: i n d uce d i n d olea mi ne 2, 3 
di o x y ge nase e x pressi o n i n de n dritic cell s u bsets s u p presses 
T cell cl o nal e x pa nsi o n. J I 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
[ Mesia, R., et al 
2 0 1 0]
Mesia R, Ri vera F, Ka wec ki A, R otte y  S, Hitt R, Kie nzer H, 
et al. Q ualit y of life of patie nts recei vi n g plati n u m-base d 
c he m ot hera p y pl us cet u x i ma b first li ne f or rec urre nt a n d/ or 
metastatic s q ua m o us cell carci n o ma of t he hea d a n d nec k. 
A n n O nc ol. 2 0 1 0 Oct; 2 1( 1 0): 1 9 6 7- 7 3.
0 4 0 W NJ
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 0
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ M uller, A. J., et al 
2 0 0 5]
M uller AJ, D u Ha da wa y  J B, D o n o ver P S, S uta nt o-War d E, 
Pre n der gast G C. I n hi biti o n of i n d olea mi ne 2, 3-di o x y ge nase, 
a n i m m u n ore g ulat or y tar get of t he ca ncer s u p pressi o n ge ne 
Bi n 1, p ote ntiates ca ncer c he m ot hera p y. Nat Me d. 2 0 0 5 
Mar; 1 1( 3): 3 1 2 -9.
0 4 9 P W 6
[ M u n n, D. H. 
2 0 0 7]
M u n n D H, Mell or A L. I n d olea mi ne 2, 3 -di o x y ge nase a n d 
t u m or-i n d uce d t olerance. J Cli n I n vest. 2 0 0 7 
Ma y ; 1 1 7( 5): 1 1 4 7- 5 4.
0 4 9 P W D
[ M u n n, D. H., et al 
2 0 0 4]
M u n n D H, S har ma M D, H o u D, Ba ba n B, Lee J R, A nt o nia 
SJ, et al. E x pressi o n of i n d olea mi ne 2, 3 -di o x y ge nase b y  
plas mac y t oi d de n dritic cells i n t u m or-drai ni n g l y m p h n o des. 
J Cli n In vest. 2 0 0 4 J ul; 1 1 4( 2): 2 8 0 -9 0. Errat u m i n: J Cli n 
I n vest. 2 0 0 4 A u g; 1 1 4( 4): 5 9 9.
0 4 9 P W C
[ Na ka m ura, T., et 
al 2 0 0 7]
Na ka m ura T, S hi ma T, Sae ki A, Hi da ka T, Na kas hi ma A, 
Ta ki ka wa O, et al. E x pressi o n of i n d olea mi ne 2, 3-
di o x y ge nase a n d t he recr uit me nt of F o x p 3 -e x pressi n g 
re g ulat or y T cells i n t he de vel o p me nt a n d pr o gressi o n of 
uteri ne cer vical ca ncer. Ca ncer Sci. 2 0 0 7 J u n; 9 8( 6): 8 7 4 - 8 1.
0 4 9 P W N
[ Nati o nal 
C o m pre he nsi ve 
Ca ncer Net w or k 
2 0 1 6]
Nati o nal C o m pre he nsi ve Ca ncer Net w or k. N C C N cli nical 
practice g ui deli nes i n o nc ol o g y  ( N C C N G ui deli nes): hea d 
a n d nec k ca ncers. F ort Was hi n gt o n, P A: Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k; 2 0 1 6.
0 4 F Q D C
[ O ka m ot o, A., et al 
2 0 0 5]
O ka m ot o A, Ni kai d o T, Oc hiai K, Ta ka k ura S, Sait o M, 
A o ki Y, et al. I n d olea mi ne 2, 3 -di o x y ge nase ser ves as a 
mar ker of p o or pr o g n osis i n ge ne e x pressi o n pr ofiles of 
ser o us o varia n ca ncer cells. Cli n Ca ncer Res. 2 0 0 5 A u g 
1 5; 1 1( 1 6): 6 0 3 0 - 9.
0 4 9 P T K
[ 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 cel l rece pt or-me diate d 
si g nali n g by recr uiti n g src h o m ol o g y 2- d o mai n -c o ntai ni n g 
t yr osi ne p h os p hatase 2 t o p h os p h ot yr osi ne. Pr oc Natl Aca d 
Sci U S A 2 0 0 1; 9 8( 2 4): 1 3 8 6 6- 7 1.
0 0 V M Q 6
[ Parr y, R. V., et al 
2 0 0 5]
Parr y  R V, C he m nitz J M, Fra u wirt h K A, La nfra nc o A R, 
Bra u nstei n I, K o ba y as hi S V, et al. C T LA -4 a n d P D - 1 
rece pt ors i n hi bit T-cell acti vati o n b y disti nct mec ha nis ms. 
M ol Cell Bi ol 2 0 0 5; 2 5( 2 1): 9 5 4 3- 5 3.
0 0 V M Q 7
[ Pic kar d, A. S., et 
al 2 0 0 7]
Pic kar d A S, Wil ke C T, Li n H -W, L l o yd A. Healt h utilities 
usi n g t he E Q - 5 D i n st u dies of ca ncer. P har mac oec o n o mics 
2 0 0 7; 2 5( 5): 3 6 5 -8 4.
0 3 R L H G
[ Q ueza da, S. A. 
2 0 1 3]
Q ueza da S A, Pe g gs K S. E x pl oiti n g C T L A- 4, P D - 1 a n d P D-
L 1 t o reacti vate t he h ost i m m u ne res p o nse a gai nst ca ncer. 
Br J Ca ncer. 2 0 1 3 A pr 3 0; 1 0 8( 8): 1 5 6 0- 5.
0 4 9 P T R
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 1
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ Ra bi n, R. 2 0 0 1]
Ra bi n R, de C harr o F. E Q -5 D: a meas ure of healt h stat us 
fr o m t he E ur o Q ol Gr o u p. A n n Me d 2 0 0 1; 3 3: 3 3 7- 4 3.
0 3 X L S 2
[ Rile y, J. L. 2 0 0 9]
Rile y  JL.  P D-1 si g nali n g i n pri mar y  T cells. I m m u n ol Re v 
2 0 0 9; 2 2 9: 1 1 4 - 2 5.
0 0 V M Q 9
[ Sc h or na gel, J. H., 
et al 1 9 9 5]
Sc h o r na gel J H, Ver weij J, de M ul der P H M, C o g netti F, 
Ver m or ke n J B, Ca p pelaere P, et al. Ra n d o mize d p hase III 
trial of e datre xate vers us met h otre xate i n patie nts wit h 
metastatic a n d/ or rec urre nt s q ua m o us cell carci n o ma of t he 
hea d a n d nec k: a E ur o pea n Or ga nizat i o n f or Researc h a n d 
Treat me nt of Ca ncer Hea d a n d Nec k Ca ncer C o o perati ve 
Gr o u p st u d y . J Cli n O nc ol 1 9 9 5; 1 3( 7): 1 6 4 9-5 5.
0 3 W N 7 G
[ Sc hrij vers, D., et 
al 1 9 9 8]
Sc hrij vers D, J o h ns o n J, Ji mi nez U, G ore M, K os mi dis P, 
Sz pir glas H, et al. P hase III trial of m o d u lati o n of 
cis plati n/fl u or o uracil c he m ot hera p y b y i nterfer o n alfa -2 b i n 
patie nts wit h rec urre nt or metastatic hea d a n d nec k ca ncer. J 
Cli n O nc ol.  1 9 9 8 Mar; 1 6( 3): 1 0 5 4 - 9.
0 3 Y X N C
[ Se ym o ur, L., et al 
2 0 1 7]
Se y m o ur L, B o gaerts J, Perr o ne A, F or d R, Sc h wartz L H, 
Ma n dre kar S, et al. i R E 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. L a ncet 
O nc ol. 2 0 1 7 Mar; 1 8( 3):e 1 4 3 -e 1 5 2.
0 4 P 9 R V
[ S he p par d, K-A, et 
al 2 0 0 4]
S he p par d K -A, Fitz L J, Lee J M, Be na n der C, Ge or ge J A, 
W o oters J, et al. P D- 1 i n hi bits T-cell rece pt or i n d uce d 
p h os p h or y lati o n of t he Z A P 7 0/ C D 3zeta si g nal os o me a n d 
d o w nstrea m si g nali n g t o P K Ct heta. F E B S Lett. 
2 0 0 4; 5 7 4: 3 7 - 4 1.
0 0 V M Q C
[ U ytte n h o ve, C., et 
al 2 0 0 3]
U y tte n h o ve C, Pil otte L, T heate I, Str o o ba nt V, C ola u D, 
Par me n tier N, et al. E vi de nce f or a t u m oral i m m u ne 
resista nce mec ha nis m base d o n tr ypt o p ha n de gra dati o n b y  
i n d olea mi ne 2, 3-di o x y ge nase. Nat Me d. 2 0 0 3 
Oct; 9( 1 0): 1 2 6 9 - 7 4.
0 4 9 P V 2
[ Ver m or ke n, J. B., 
et al 2 0 0 8]
Ver m or ke n J B, Mesia R, Ri vera F, Re me nar E, Ka wec ki A,
R otte y  S, et al. Plati n u m-base d c he m ot hera p y pl us 
cet u xi ma b i n hea d a n d nec k ca ncer. N E n gl J Me d. 2 0 0 8 
Se p 1 1; 3 5 9( 1 1): 1 1 1 6 - 2 7.
0 3 Y X RJ
[ Wei nlic h, G., et al 
2 0 0 7]
Wei nlic h G, M urr C, Ric har dse n L, Wi n kler C, F uc hs D. 
Decrease d ser u m tr 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 na nt mela n o ma patie nts. Der mat ol o g y . 
2 0 0 7; 2 1 4( 1): 8 - 1 4.
0 4 9 P V 3
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 2
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
[ Wit kie wicz, A., et 
al 2 0 0 8]
Wit kie wicz A, Willia ms T K, C ozzit ort o J, D ur ka n B, 
S h o walter S L , Ye o CJ, et al. E x pressi o n of i n d olea mi ne 2, 3-
di o x y ge nase i n meta static pa ncreatic d uctal a de n ocarci n o ma 
recr uits re g ulat or y T cells t o a v oi d i m m u ne detecti o n. J A m 
C oll S ur g. 2 0 0 8 Ma y ; 2 0 6( 5): 8 4 9-5 4; disc ussi o n 8 5 4 -6.
0 4 9 P V 5
[ W olc h o k, J. D., et 
al 2 0 0 9]
W olc h o k J D, H o os A, O' Da y  S, We ber J S, Ha mi d O, 
Le b bé C, et al. G ui deli nes f or t he e val uati o n of i m m u ne 
t hera py acti vit y  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 ha n g, X., et al 
2 0 0 4]
Z ha n g X, Sc h wartz J - C D, G u o X, B hatia S, Ca o E, C he n L, 
et al. Str uct ural a n d fu ncti o nal a nal ys is of t he c osti m ulat or y 
rece pt or pr o gra m me d deat h-1. I m m u nit y  2 0 0 4; 2 0: 3 3 7- 4 7.
0 0 V M QJ
[ Z ha n g, Y., et al 
2 0 1 6]
Z ha n g Y, B o w ma n K, Dia m o n d S, Yeles wara m S. Effects 
of E paca d ostat wit h c o -a d mi nistrati o n of Li nez oli d o n brai n 
e xtracell ular fl uid c o nce ntrati o ns of Ser ot o ni n. P oster 
sessi o n prese nte d at: 2 0 1 6 A A P S A n n ual Meeti n g A n d 
E x p ositi o n; 2 0 1 6 N o v 1 3 - 1 7; De n ver, U S.
0 4 P C M R
[ Z o u, W. 2 0 0 6]
Z o u W. Re g ulat or y  T cells, t u m o ur i m m u nit y a n d 
i m m u n ot hera p y. Nat Re v Im m u n ol. 2 0 0 6 A pr; 6( 4): 2 9 5 - 3 0 7.
0 4 9 P V 7
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 3
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
1 2.
A p pe n dices
A p pe n di x 1: A b bre vi ati o ns a n d Tr a de m ar ks
1 2. 1
A b bre vi ati o n/ Ter m
Defi niti o n
5 -F U
5-f l u or o uracil
A E
ad verse e ve nt
A E O SI
ad verse eve nts of special interest
A L T ( S G P T)
ala ni ne a mi n otra nsferase (ser u m gl uta mic pyr u vic 
tra nsa mi nase)
A N C
abs ol ute ne utr o p hil c o u nt
A Pa T
All Partici 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 ( S G O T)
as partate a mi n otra nsferase (ser u m gl uta mic o xal oacetic 
tra nsa mi nase)
A U C
area u n der t he c ur ve
B C G
Bacill us Cal mette – G uéri n
BI D
twice dail y
BI C R
b li n de d i n de pe n de nt ce ntral re vie w
C D 2 8
cl uster of differe ntiati o n 2 8
C D 3ζ
C D 3 zeta
CI
co nfi de nce i nter vals
c L D A
co nstrai ne d l o n git u di nal data a nal ys is
C ma x
ma xi m u m c o nce ntrati o n
C O N S O R T
C o ns oli date d Sta n dar ds of Re p orti n g Trials
C R
co m plete res p o nse
C S R
Cli nical St u d y  Re p ort
C T
co m p ute d t o m o gra p h y
C T C A E
C o m m o n T o xicit y  Criteria f or A d verse E ve nts
C T L A- 4
c yt ot o xic T l y m p h oc y te ass ociate d pr otei n 4
C tr o u g h
mi ni m u m c o nce ntrati o n
D C R
d isease c o ntr ol rate
D Cs
d e n dritic cells
D L T
d ose -li miti n g t o xicit y
D M C
Data M o nit ori n g C o m mittee
D N A
de o x yri b o n ucleic aci d
D O R
d urati o n of res p o nse
D P D
d i h ydr o p yri mi di ne de h y d r o ge nase
E C Gs
electr ocar di o gra ms
E CI
eve nts of cli nical i nterest
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 4
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us
e C R F
electr o nic case re p ort f or m
e D M C
E xter nal Data M o nit ori n g C o m mittee
E G F R
e pi der mal gr o wt h fact or rece pt or
E M A
E ur o pea n Me dici nes A ge nc y
E O C
J oi nt E xec uti ve O versi g ht C o m mittee
E O R T C
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of 
Ca ncer
E O R T C Q L Q- C 3 0
E O R T C Q o L  q uesti o n naire C ore 3 0
E O R T C Q L Q- H & N 3 5
E O R T C Hea d a n d Nec k S pecific Q o L q uesti o n naire
E O T
en d of treat me nt
e P R Os
electr o nic patie nt re p orte d o utc o mes
E Q - 5 D
E ur o Q ol 5 di me nsi o ns q uesti o n naire
F A S
F ull A nal ys is S et
F D A
F o o d a n d Dr u g A d mi nistrati o n
F D A A
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act
F N A
fi ne nee dle as pirate
F T 4
free t hyr o xi ne
G C P
G o o d Cli nical Practices
G F R
g l o mer ular filtrati o n rate
H 1
h y p ot hesis 1
H 2
h y p ot hesis 2
H 3
h y p ot hesis 3
H Bs A g
He patitis B s urface a nti ge n
HI V
h u ma n i m m u n o deficie nc y vir us
H N S C C
h ea d a n d nec k s q ua m o us cell carci n o ma
H P V
H u ma n Pa pill o ma Vir us
H R Q o L
H ealt h- Relate d Q o L
H S D
H wa n g -S hi h -Deca ni
I A
interi m a nal y sis
I As
i nteri m a nal yses
I B
I n vesti gat or Br oc h ure
I CF
inf or me d co nse nt for m
i C P D
c o nfir me d pr o gressi ve disease
i C R
i m m u ne c o nfir me d res p o nse
I DO 1
in d olea mi ne 2, 3 di o x y ge nase 1
I E C
I nstit uti o nal E t hics C o m mittee
I g
i m m u n o gl o b uli n
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 5
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
I g G 4
im m u n o gl o b uli n G 4
I g V t yp e
I g-varia ble – t yp e
I H C
im m u n o hist oc he mistr y
I N R
inter nati o nal n or malize d rati o
i P R
i m m u ne partial res p o nse
ir A E
im m u ne -relate d a d verse e ve nt
I RB
I nstit uti o nal R e vie w B oar d
i S D
i m m u ne sta ble disease
i R E CIS T
m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors
f or i m m u ne- base d t hera pe utics
I T T
I nte nti o n-t o-Tr eat
i U P D
i R E CIS T u nc o nfir me d pr o gressi ve disease
I V
i ntra ve n o us
I VD
in vitr o dia g n ostic
I V R S
interacti ve v oice res p o nse s y ste m
I W R S
inte grate d we b res p o nse s y ste m
J A K
Ja n us ki nase
m A b
m o n ocl o nal a nti b o d y
M A O
m o n oa mi ne o xi dase
M A OI
m o n oa mi ne o xi dase i n hi bit ors
M RI
ma g netic res o na nce i ma gi n g
m R N A
messe n ger ri b o n ucleic aci d
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
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
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
O T C
o ver -t he-c o u nter
P B P K
p h y si ol o gically base d P K
P D
pr o gressi ve disease
P D - 1
pr o gra m me d cell deat h 1
P D -L 1
p r o gra m me d cell deat h li ga n d 1
P D -L 2
pr o gra m me d cell deat h li ga n d 2
P F S
p r o gressi o n-free s ur vi val
P H
pr o p orti o nal hazar d
P K
p har mac o ki netics
P K C θ
p r otei n ki nase C-t heta
P O
orall y
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 6
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
P R
partial res p o nse
p R B C
pac ke d re d bl o o d cell
P R O
p atie nt-re p orte d o utc o mes
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 2 W
e ver y 2 wee ks
Q 3 W
ever y  3 wee ks
Q W
e ver y wee k
Q o L
Q ualit y  of L ife
Q L Q
Q o L  q uesti o n naire
Q Tc
c orrecte d Q T i nter val
R E CI S T
Res p o nse E val uati o n Criteria in S oli d T u m ors
R/ M
rec urre nt or metastatic
R N A
ri b o n ucleic aci d
R P S F T
Ra n k Preser vi n g Str uct ural Fail ure Ti me
S A E
seri o us a d verse e ve nts
S D
sta ble disease
S H P - 1
Src h o m ol o g y  re gi o n 2 d o mai n-c o ntai ni n g p h os p hatase- 1
S H P - 2
Src h o m ol o g y  re gi o n 2 d o mai n-c o ntai ni n g p h os p hatase- 2
S N RI
selecti ve ser ot o ni n/ n ore pi ne p hri ne re u pta ke i n hi bit ors
S o A
Sc he d ule of Acti vities
S o C
sta n dar d of care
s S A P
su p ple me ntal Statistical A nal y sis Pla n
S S RI
selecti ve ser ot o ni n re u pta ke i n hi bit ors
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o ns
T 1 D M
T y pe 1 dia betes mellit us
T 3
trii o d ot h yr o ni ne
T R A E
treat me nt-relate d a d verse e ve nt
Tre gs
re g ulat or y T cells
T S H
th y r oi d-sti m ulati n g h or m o ne
T T D
ti me t o deteri orati o n
U L N
u p per li mit of n or mal
W O C B P
w o me n of chil d beari n g p ote ntial
Z A P 7 0
z eta-c hai n-ass ociate d pr otei n ki nase
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 3 9
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 3: St u d y G o ver n a nce C o nsi der ati o ns
1 2. 3
Merc k C o de of C o n d uct f or Cli nic al Tri als
Merc k *
C o de of C o n d uct f or Cli nic al Tri als
I.
I ntr o d ucti o n
A. P ur p ose
Merc k, t hr o u g h its s u bsi diaries, c o n d ucts cli nical trials w orl d wi de t o e val uate t he safet y a n d effecti ve ness of o ur 
pr o d ucts. As s uc h, we are c o m mitte d t o desi g ni n g, i m ple me nti n g, c o n d ucti n g, a nal yzi n g a n d re p orti n g t hese trials i n 
c o m plia nce wit h t he hi g hest et hical a n d scie ntific sta n dar ds. Pr otecti o n of partici pa nt safet y is t he o verri di n g c o ncer n 
i n t he desi g n of cli nical trials. I n all cases, Merc k cli nical trials will be c o n d ucte d i n c o m plia nce wit h l ocal a n d/ or 
nati o nal re g ulati o ns a n d i n acc or da nce wit h t he et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki. 
B. Sc o pe
S uc h sta n dar ds s hall be e n d orse d f or all cli nical i nter ve nti o nal i n vesti gati o ns s p o ns ore d b y Merc k irres pecti ve of t he 
part y ( parties) e m pl o ye d f or t heir e xec uti o n (e g, c o ntract researc h or ga nizati o ns, c olla b orati ve researc h eff orts). T his 
C o de is n ot i nte n de d t o a p pl y t o trials w hic h are o bser vati o nal i n nat ure, or w hic h are retr os pecti ve. F urt her, t his C o de 
d oes n ot a p pl y t o i n vesti gat or -i nitiate d trials w hic h are n ot u n der t he c o ntr ol of Merc k.
II. Scie ntific Iss ues
A. Tri al C o n d uct
1.
Tri al Desi g n
E xce pt f or pil ot or esti mati o n trials, cli nical trial pr ot oc ols will be h y p ot hesis - dri ve n t o assess safet y, efficac y 
a n d/ or p har mac o ki netic or p har mac o d y na mic i n dices of Merc k or c o m parat or pr o d ucts.  Alter nati vel y, Merc k ma y 
c o n d uct o utc o mes researc h trials, trials t o assess or vali date vari o us e n d p oi nt meas ures, or trials t o deter mi ne 
partici pa nt prefere nces, etc.  
T he desi g n (ie, partici pa nt p o p ulati o n, d urati o n, sta tistical p o wer) m ust be a de q uate t o a d dress t he s pecific p ur p ose 
of t he trial.  Researc h partici pa nts m ust meet pr ot oc ol e ntr y criteria t o be e nr olle d i n t he trial. 
2.
Site Selecti o n
Merc k selects i n vesti gati ve sites base d o n me dical e x pertise, access t o a p pr o priate partici pa nts, a de q uac y of 
facilities a n d staff, pre vi o us perf or ma nce i n Merc k trials, as well as b u d getar y c o nsi derati o ns.  Pri or t o trial 
i nitiati o n, sites are e val uate d b y Merc k pers o n nel t o assess t he a bilit y t o s uccessf ull y c o n d uct t he trial.
3.
Site M o nit ori n g/ Scie ntific I nte grit y
Trial sites are m o nit ore d t o assess c o m plia nce wit h t he trial pr ot oc ol a n d ge neral pri nci ples of G o o d Cli nical 
Practice.  Merc k re vie ws cli nical data f or acc urac y, c o m plete ness a n d c o nsiste nc y. Data are verifie d v ers us s o urce 
d oc u me ntati o n acc or di n g t o sta n dar d o perati n g pr oce d ures.  Per Merc k p olicies a n d pr oce d ures, if fra u d, 
misc o n d uct or seri o us G C P -n o n -C o m plia nce are s us pecte d, t he iss ues are pr o m ptl y i n vesti gate d. W he n necessar y, 
t he cli nical site will be cl ose d, t he res p o nsi ble re g ulat or y a ut h orities a n d et hics re vie w c o m mittees n otifie d a n d 
data discl ose d acc or di n gl y. 
B. P u blic ati o n a n d A ut h ors hi p
T o t he e xte nt scie ntificall y a p pr o priate, Merc k see ks t o p u blis h t he res ults of trials it c o n d ucts.  S o me earl y p hase or 
pil ot trials are i nte n de d t o be h y p ot hesis -ge nerati n g rat her t ha n h y p ot hesis testi n g.  I n s uc h cases, p u blicati o n of 
res ults ma y n ot be a p pr o priate si nce t he trial ma y be u n der p o were d a n d t he a nal yses c o m plicate d b y statistical iss ues 
of m ulti pli cit y.
Merc k’s p olic y o n a ut h ors hi p is c o nsiste nt wit h t he re q uire me nts o utli ne d i n t he I C H - G o o d Cli nical Practice 
g ui deli nes. I n s u m mar y, a ut h ors hi p s h o ul d reflect si g nifica nt c o ntri b uti o n t o t he desi g n a n d c o n d uct of t he trial, 
perf or ma nce or i nter pretati o n of t he a nal ysis, a n d/ or writi n g of t he ma n uscri pt.  All na me d a ut h ors m ust be a ble t o 
defe n d t he trial res ults a n d c o ncl usi o ns.  Merc k f u n di n g of a trial will be ac k n o wle d ge d i n p u blicati o ns. 
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 0
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
III. P artici p a nt Pr otecti o n
A.
I R B/I E C re vie w
All cli nical t rials will be re vie we d a n d a p pr o ve d b y a n i n de pe n de nt I R B/I E C bef ore bei n g i nitiate d at eac h site.  
Si g nifica nt c ha n ges or re visi o ns t o t he pr ot oc ol will be a p pr o ve d b y t he I R B/I E C pri or t o i m ple me ntati o n, e xce pt t hat 
c ha n ges re q uire d ur ge ntl y t o pr otect p artici pa nt safet y a n d well -bei n g ma y be e nacte d i n a ntici pati o n of I R B/I E C 
a p pr o val. F or eac h site, t he I R B/I E C a n d Merc k will a p pr o ve t he partici pa nt i nf or me d c o nse nt f or m. 
B.
S afet y
T he g ui di n g pri nci ple i n decisi o n - ma ki n g i n cli nical trials is t hat partici pa nt welfare is of pri mar y i m p orta nce.  
P ote ntial partici pa nts will be i nf or me d of t he ris ks a n d be nefits of, as well as alter nati ves t o, trial partici pati o n. At a 
mi ni m u m, trial desi g ns will ta ke i nt o acc o u nt t he l ocal sta n dar d of care.  Partici pa nts are ne ver de nie d access t o 
a p pr o priate me dical care base d o n partici pati o n i n a Merc k cli nical trial. 
All partici pati o n i n Merc k cli nical trials is v ol u ntar y.  Partici pa nts are e nr olle d o nl y after pr o vi di n g i nf or me d c o nse nt 
f or partici pati o n.  Partici pa nts ma y wit h dra w fr o m a Merc k trial at a n y ti me, wit h o ut a n y i nfl ue nce o n t heir access t o, 
or recei pt of, me dical care t hat ma y ot her wise be a vaila ble t o t he m.
C.
C o nfi de nti alit y
Merc k is c o m mitte d t o safe g uar di n g partici pa nt c o nfi de ntialit y, t o t he greatest
e xte nt p ossi ble.  U nless re q uire d b y 
la w, o nl y t he i n vesti gat or, s p o ns or ( or re prese ntati ve) a n d/ or re g ulat or y a ut h orities will ha ve access t o c o nfi de ntial 
me dical rec or ds t hat mi g ht i de ntif y t he researc h partici pa nt b y na me.  
D.
Ge n o mic Rese arc h
Ge n o mic Researc h will o nl y be c o n d ucte d i n acc or da nce wit h i nf or me d c o nse nt a n d/ or as s pecificall y a ut h orize d b y 
a n Et hics C o m mittee.
I V. Fi n a nci al C o nsi der ati o ns
A.
P a y me nts t o I n vesti g at ors
Cli nical trials are ti me - a n d la b or -i nte nsi ve.  It is Merc k’s p olic y t o c o m pe nsate i n vesti gat ors ( or t he s p o ns ori n g 
i nstit uti o n) i n a fair ma n ner f or t he w or k perf or me d i n s u p p ort of Merc k trials.  Merc k d oes n ot pa y i nce nti ves t o 
e nr oll partici pa nts i n its trials.  H o we ver, w he n e nr oll me nt is partic ularl y c halle n gi n g, a d diti o nal pa y me nts ma y be 
ma de t o c o m pe nsate f or t he ti me s pe nt i n e xtra recr uiti n g eff orts.
Merc k d oes n ot pa y f or partici pa nt referrals.  H o we ver, Merc k ma y c o m pe nsate referri n g p h ysicia ns f or ti me s pe nt 
o n c hart re vie w t o i de ntif y p ote ntiall y eli gi ble partici pa nts.
B.
Cli nic al Rese arc h F u n di n g 
I nf or me d c o nse nt f or ms will discl ose t hat t he trial is s p o ns ore d b y Merc k, a n d t hat t he i n vesti gat or or s p o ns ori n g 
i nstit uti o n is bei n g pai d or pr o vi de d a gra nt f or perf or mi n g t he trial.  H o we ver, t he l ocal I R B/IE C ma y wis h t o alter 
t he w or di n g of t he discl os ure state me nt t o be c o nsiste nt wit h fi na ncial practices at t hat i nstit uti o n.  As n ote d a b o ve, 
p u blicati o ns res ulti n g fr o m Merc k trials will i n dicate Merc k as a s o urce of f u n di n g.
C.
F u n di n g f or Tr a vel a n d Ot her Re q uests
F u n di n g of tra vel b y i n vesti gat ors a n d s u p p ort staff (e g, t o scie ntific meeti n gs, i n vesti gat or meeti n gs, etc.) will be 
c o nsiste nt wit h l ocal g ui deli nes a n d practices i ncl u di n g, i n t he U. S., t h ose esta blis he d b y t he A merica n Me dical 
Ass ociati o n ( A M A). 
V. I n vesti g at or C o m mitme nt
I n vesti gat ors will be e x pecte d t o re vie w Merc k’s C o de of C o n d uct as a n a p pe n di x t o t he trial pr ot oc ol, a n d i n si g ni n g 
t he pr ot oc ol, a gree t o s u p p ort t hese et hical a n d scie ntific sta n dar ds.
* I n t his d oc u me nt, " Merc k" r efers t o Merc k S har p & D o h me C or p. a n d Sc heri n g C or p orati o n, eac h of w hic h is a 
s u bsi diar y of Merc k & C o., I nc.  Merc k is k n o w n as M S D o utsi de of t he U nite d States a n d Ca na da.  As warra nte d b y 
c o nte xt, Merc k als o i ncl u des affiliates a n d s u bsi diaries of Mer c k & C o., I nc."
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 1
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Fi n a nci al Discl os ure
Fi na ncial Discl os ure re q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi na ncial Discl os ure b y Cli nical I n vesti gat ors ( 2 1 C F R Part 5 4).  I t is M S D’s
res p o nsi bilit y t o deter mi ne, base d o n t hese re g ulati o ns, w het her a re q uest f or Fi na ncial 
Discl os ure i nf or mati o n is re q uire d.  It is t he i n vesti gat or's/s u bi n vesti gat or's res p o nsi bilit y  t o 
c o m pl y wit h a ny s uc h re q uest.  
T he i n vesti gat or/s u bi n vesti gat or(s) a gree, if re q ueste d b y  M S D
i n acc or da nce wit h 2 1 C F R 
Part 5 4, t o pr o vi de his/ her fi na ncial i nterests i n a n d/ or arra n ge me nts wit h t he S p o ns or or 
M S D
t o all o w f or t he s u b missi o n of c o m plete a n d acc urate certificati o n a n d discl os ure 
state me nts.  T he i n vesti gat or/s u bi n vesti gat or(s) f urt her a gree t o pr o vi de t his i nf or mati o n o n a 
Certificati o n/ Discl os ure F or m, c o m m o nl y  k n o w n as a fi na ncial discl os ure f or m, pr o vi de d b y 
M S D . T he i n vesti gat or/s u bi n vesti gat or(s) als o c o nse nt t o t he tra ns missi o n of t his i nf or mati o n 
t o t he S p o ns or a n d M S D i n t he U nite d States f or t hese p ur p oses.  T his ma y i n v ol ve t he 
tra ns missi o n of i nf or mati o n t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g pers o nal data.
D at a Pr otecti o n
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y  M S D . A ny partici pa nt rec or ds or datasets 
t hat are tra nsferre d t o M S D
will c o ntai n t he i de ntifier o nl y ; partici pa nt na mes or a n y 
i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d. 
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d data will be use d b y t he 
S p o ns or a n d M S D i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust 
als o be e x plai ne d t o t he partici pa nt. 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y M S D , b y a p pr o priate 
I RB/I E C me m bers, a n d b y  i ns pect ors fr o m re g ulat or y a ut h orities.
C o nfi de nti alit y of D at a
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or affir ms t o M S D
t hat i nf or mati o n f ur nis he d t o t he 
i n vesti gat or by M S D
will be mai ntai ne d i n c o nfi de nce, a n d s uc h i nf or mati o n will be di v ul ge d 
t o t he i nstit uti o nal re vie w b oar d, et hics re vie w c o m mittee (IR B/I E C) or si milar or e x pert 
c o m mittee; affiliate d i nstit uti o n a n d e m pl o y ees, o nl y u n der a n a p pr o priate u n dersta n di n g of 
co nfi de ntialit y  wit h s uc h b oar d or c o m mittee, affiliate d i nstit uti o n a n d e m pl o yees.  Data 
ge nerate d b y t his trial will be c o nsi dere d c o nfi de ntial b y t he i n vesti gat or, e xce pt t o t he e xte nt 
t hat it is i ncl u de d i n a p u blicati o n as pr o vi de d i n t he P u blicati o ns secti o n of t his pr ot oc ol.
C o nfi de nti alit y of P artici p a nt Rec or ds
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t hat t he S p o ns or, M S D ( or S p o ns or or M S D
re prese ntati ve), I R B/I E C, or re g ulat or y a ut h orit y re prese ntati ves ma y c o ns ult a n d/ or c o p y 
trial d oc ume nts i n or der t o verif y  w or ks heet/case re p ort f or m data.  B y si g ni n g t he c o nse nt 
f or m, t he partici pa nt a grees t o t his pr ocess.  If trial d oc u me nts will be p h ot oc o pie d d uri n g t he 
pr ocess of verif y i n g w or ks heet/case re p ort f or m i nf or mati o n, t he partici pa nt will be i de ntifie d 
b y  u ni q ue c o de o nly;  f ull na mes/i nitials will be mas ke d pri or t o tra ns missi o n t o M S D .
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 2
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o treat all partici pa nt data use d a n d 
discl ose d i n c o n necti o n wit h t his trial i n acc or da nce wit h all a p plica ble pri vac y la ws, r ules 
a n d re g ulati o ns.
C o nfi de nti alit y of I R B/I E C I nf or m ati o n
M S D will
rec or d t he na me a n d a d dress of eac h I R B/I E C t hat re vie ws a n d a p pr o ves t his trial.  
M S D will
d oc u me nt t hat eac h I R B/I E C meets re g ulat or y  a n d I C H G C P re q uire me nts b y 
re q uesti n g a n d mai ntai ni n g rec or ds of t he na mes a n d q ualificati o ns of t he I R B/I E C me m bers 
a n d t o ma ke t hese rec or ds a vaila ble f or re g ulat or y a ge nc y  re vie w u p o n re q uest b y t h ose 
a ge ncies.
C o m mittees Str uct ure
Scie ntific A d vis or y C o m mittee
T his trial was de vel o pe d i n c olla b orati o n wit h a Scie ntific A d vis or y  C o m mittee ( S A C). T he 
S A C c o m prises S p o ns or , M S D, a n d n o n -S p o ns or scie ntific e x perts w h o pr o vi de i n p ut wit h 
res pect t o trial desi g n, i nter pretati o n of trial res ults a n d s u bse q ue nt peer-re vie we d scie ntific 
p u blicati o ns.
Tri al Steeri n g C o m mittee
T his trial will be c o n d ucte d i n c o ns ultati o n wit h a Trial Steeri n g C o m mittee.  T he Trial 
Steeri n g C o m mittee c o m prises:
•
S p o ns or a n d M S D pers o n ne l 
•
I n vesti gat ors partici pati n g i n t he trial 
•
C o ns ulti n g t hera pe utic -area e x perts a n d cli nical trialists 
T he Trial Steeri n g C o m mittee will pr o vi de g ui da nce o n t he o perati o nal as pects of t he trial.  
S pecific details re gar di n g res p o nsi bilities a n d g o ver na nce of t he Trial Steeri n g C o m mittee 
will be descri be d i n a se parate c harter.
J oi nt E xec uti ve O versi g ht C o m mittee
T he J oi nt E x ec uti ve O versi g ht C o m mittee ( E O C) c o m prises me m bers of S p o ns or a n d M S D 
Se ni or Ma na ge me nt.  T he E O C will recei ve a n d deci de u p o n a n y rec o m me n dati o ns ma de b y 
t he Data M o nit ori n g C o m mittee ( D M C)
re gar di n g t he trial.
D at a M o nit ori n g C o m mittee
T o s u p ple me nt t he r o uti ne trial m o nit ori n g o utli ne d i n t his pr ot oc ol, a n e xter nal Data 
M o nit ori n g C o m mittee ( D M C) will m o nit or t he safety data fr o m t his trial.  T he v oti n g 
me m bers of t he c o m mittee are e xter nal t o t he S p o ns or a n d M S D.  T he me m bers of t he D M C 
m ust n ot be i n v ol ve d wit h t he trial i n a n y  ot her wa y (e g, t he y ca n n ot be trial i n vesti gat ors) 
a n d m ust ha ve n o c o m peti n g i nterests t hat c o ul d affect t heir r oles wit h res pect t o t he trial. 
T he D M C will ma ke rec o m me n dati o ns t o t he E O C re gar di n g ste ps t o e ns ure b ot h partici pa nt 
safety a n d t he c o nti n ue d et hical i nte grit y of t he trial.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 3
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
S pecific details re gar di n g c o m p ositi o n, res p o nsi bilities, a n d g o ver na nce, i ncl u di n g t he r oles 
a n d res p o nsi bilities of t he vari o us me m bers a n d t he S p o ns or a n d M S D pr ot oc ol tea m ; 
meeti n g facilitati o n; t he trial g o ver na nce str uct ure; a n d re q uire me nts f or a n d pr o per 
d oc u me ntati o n of D M C re p orts, mi n utes, a n d rec o m me n da ti o ns will be descri be d i n t he 
D M C c harter t hat is re vie we d a n d a p pr o ve d b y all t he D M C me m bers.
P u blic ati o n P olic y
T he res ults of t his st u d y  ma y be p u blis he d or prese nte d at scie ntific meeti n gs. T he S p o ns or 
a n d M S D will c o m pl y  wit h t he re q uire me nts f or p ublicati o n of st u d y  res ults. In acc or da nce 
wit h sta n dar d e dit orial a n d et hical practice, t he S p o ns or a n d M S D will ge nerall y s u p p ort 
p u blicati o n of m ultice nter st u dies o nl y  i n t heir e ntiret y a n d n ot as i n di vi d ual site data. I n t his 
case, a c o or di nati n g i n vesti gat or will be desi g nate d b y  m ut ual a gree me nt.
If p u blicati o n acti vit y is n ot directe d b y t he S p o ns or or M S D , t he i n vesti gat or a grees t o 
s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or a n d M S D bef ore s u b missi o n.  T his all o ws 
t he S p o ns or a n d M S D t o pr otect pr o prietar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
A ut h ors hi p will be deter mi ne d b y  m ut ual a gree me nt a nd i n li ne wit h I nter nati o nal C o m mittee 
of Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P osti n g Re q uire me nts
U n der t he ter ms of t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act ( F D A A A) of 2 0 0 7 
a n d t he E ur o pe a 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  res p o nsi ble f or deter mi ni n g w het her t he trial a n d its res ults are s u bject t o 
t he re q uire me nts f or s u b missi o n t o htt p:// w w w.cli nicaltrials. g o v, 
w w w.cli nicaltri alsre gister.e u or ot her l ocal re gistries.  T he S p o ns or will re vie w t his pr ot oc ol 
a n d s u b mit t he i nf or mati o n necessar y  t o f ulfill t hese re q uire me nts. Entries are n ot li mite d t o 
F D A A A or t he E M A cli nical trial directi ve ma n date d trials.  I nf or mati o n p oste d w ill all o w 
partici pa nts t o i de ntif y  p ote ntiall y a p pr o priate trials f or t heir disease c o n diti o ns a n d p urs ue 
partici pati o n b y  calli n g a ce ntral c o ntact n u m ber f or f urt her i nf or mati o n o n a p pr o priate trial 
l ocati o ns a n d trial site c o ntact i nf or mati o n.  
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or ac k n o wle d ges t hat t he stat ut or y o bli gati o ns u n der 
F D A A A, t he E M A cli nical trials directi ve or ot her l ocall y  ma n date d re gistries are t hat of t he 
S p o ns or a n d a grees n ot t o s u b mit a n y  i nf or mati o n a b o ut t his trial or its res ults t o t h ose 
re gistries.
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o c o n d uct t he trial i n a n efficie nt a n d 
dili ge nt ma n ner a n d i n c o nf or ma nce wit h t his pr ot oc ol; ge nerall y acce pte d sta n dar ds of G o o d 
Cl i nical Practice (e g, I nter nati o nal C o nfere nce o n Har m o nizati o n of Tec h nical Re q uire me nts 
f or Re gistrati o n of P har mace uticals f or H u ma n Use G o o d Cli nical Practice: C o ns oli date d 
G ui deli ne a n d ot her ge nerall y  acce pte d sta n dar ds of g o o d cli nical practice); a n d all 
a p plica ble fe deral, state a n d l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he 
cli nical trial.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 4
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
T he C o de of C o n d uct, a c ollecti o n of g oals a n d c o nsi derati o ns t hat g o ver n t he et hical a n d 
scie ntific c o n d uct of cli nical i n vesti gati o ns s p o ns ore d or e xec ute d b y  M S D , is pr o vi de d i n 
t his a p pe n di x u n der t he Merc k C o de of C o n d uct f or Cli nical Trials.
T he i n vesti gat or a grees n ot t o see k rei m b urse me nt fr o m partici pa nts, t heir i ns ura nce 
pr o vi ders or fr o m g o ver n me nt pr o gra ms f or pr oce d ures i ncl u de d a s part of t he trial 
rei m b urse d t o t he i n vesti gat or by M S D .
T he i n vesti gat or will pr o m ptl y  i nf or m M S D
of a n y  re g ulat or y a ut h ority i ns pecti o n c o n d ucte d 
f or t his trial.
T he in vesti gat or a grees t o pr o vi de M S D
wit h rele va nt i nf or mati o n fr o m i ns pecti o n 
o bser vati o ns/fi n di n gs t o all o w M S D
t o assist i n res p o n di n g t o a ny citati o ns res ulti n g fr o m 
re g ulat or y a ut h ority i ns pecti o n, a n d will pr o vi de M S D
wit h a c o p y  of t he pr o p ose d res p o nse 
f or c o ns ultati o n bef ore s u b missi o n t o t he re g ulat or y a ut h orit y. 
Pers o ns de barre d f r o m c o n d ucti n g or w or ki n g o n cli nical trials b y a n y c o urt or re g ulat or y 
a ut h orit y will n ot be all o we d t o c o n d uct or w or k o n t his st u d y. T he i n vesti gat or will 
i m me diatel y discl ose i n writi n g t o M S D
if a ny pers o n w h o is i n v ol ve d i n c o n d ucti n g t he trial 
is de barre d or if a n y pr ocee di n g f or de bar me nt is pe n di n g or, t o t he best of t he i n vesti gat or’s 
k n o wle d ge, t hreate ne d.
D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic C R F u nless 
tra ns mitte d t o M S D
or desi g nee electr o nicall y (e g, la b orat or y data). T he i n vesti gat or or 
q ualifie d desi g nee is res p o nsi ble f or verif y i n g t hat data e ntries are acc urate a n d c orrect b y 
p h y sically or electr o nicall y  si g ni n g t he C R F. 
Detaile d i nf or mati o n re gar di n g Data Ma na ge me nt pr oce d ures f or t his pr ot oc ol will be 
pr o vi de d se paratel y.
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F. 
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts. 
Trial d oc u me ntati o n will be pr o m ptl y  a n d f ull y discl 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 grees t o pr o m ptl y  ta ke a n y reas o na ble ste ps t hat are re q ueste d b y M S D
or 
a n y re g ulat or y a ut h orities as a res ult of a n a u dit or i ns pecti o n t o c ure deficie ncies i n t he trial 
d oc u me ntati o n a n d w or ks heets/case re p ort f or ms.
M S D
or desi g nee is res p o nsi ble f or t he data ma na ge me nt of t his st u d y , i ncl u di n g q uality 
c hec ki n g of t he data. 
St u d y  m o nit ors will perf or m o n g oi n g s o urce data re vie w a n d verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m 
s o urce d oc u me nts; t hat t he safety a n d ri g hts of partici pa nts are bei n g pr otecte d; a n d t hat t he 
st u d y is bei n g c o n d ucte d in acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts. 
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 4 5
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C F, pertai ni n g t o t he c o n d uct of t his st u d y  m ust 
be retai ne d b y t he i n vesti gat o r f or 1 5 years after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstit uti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y be destr o ye d d uri n g 
t he rete nti o n peri o d wit h o ut t he writte n a p pr o val of M S D . N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or party wit h o ut writte n n otificati o n t o M S D . 
S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or’s site.
D ata re p orte d o n t he C R F or e ntere d i n t he e C R F t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.
St u d y a n d Site Cl os ure
M S D, i n c olla b orati o n wit h t he S p o ns or ma y  st o p t he st u d y or st u d y site partici pati o n i n t he 
st u d y f or me dical, safety,  re g ulat or y, a d mi nistrati ve, or ot her reas o ns c o nsiste nt wit h 
a p plica ble la ws, re g ulati o ns, a n d G C P. 
I n t he e ve nt M S D
pre mat urel y  ter mi nates a partic ular trial site, M S D
will pr o m ptl y  n otif y 
t hat trial site’s IR B/I E C.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 0
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
●
Li kel y C a use:   Is t he A E n ot reas o na bly e x plai ne d b y  a n ot her eti ol o g y s uc h 
as u n derl y i n g disease, ot her dr u g(s)/ vacci ne(s), or ot her h ost or e n vir o n me ntal 
fact ors
●
Dec h alle n ge: Was t he st u d y treat me nt disc o nti n ue d or 
d ose/e x p os ure/fre q ue nc y re d uce d?
●
If yes, di d t he A E res ol ve or i m pr o ve?
●
If yes, t his is a p ositi ve dec halle n ge. 
●
If no, t his is a ne gati ve dec halle n ge.
( N ote:  T his criteri o n is n ot a p plica ble if:  ( 1) t he A E res ulte d i n deat h or 
per ma ne nt disa bilit y ; ( 2) t he A E res ol ve d/i m pr o ve d des pite c o nti n uati o n of 
t he st u d y treat me nt; ( 3) t he trial is a si n gle- d ose dr u g trial); or ( 4) st u d y 
treat me nt(s) is/are o nly use d o ne ti me.)
●
Rec h alle n ge:   Was t he partici pa nt re -e x p ose d t o t he st u d y treat me nt i n t his 
trial?
●
If yes, di d t he A E rec ur or w orse n?
●
If yes, t his is a p ositi ve rec halle n ge. 
●
If n o, t his is a ne gati ve rec halle n ge.
( N ote:  T his criteri o n is n ot a p plica ble if:  ( 1) t he i nitial A E res ulte d i n deat h 
or per ma ne nt disa bilit y , or ( 2) t he trial is a si n gle-d ose dr u g trial); or ( 3) st u d y 
treat me nt(s) is/are use d o nl y o ne ti me.)
N O T E:  I F A R E C H A L L E N G E I S P L A N N E D F O R A N A D V E R S E E V E N T W HI C H 
W A S S E RI O U S A N D W HI C H M A Y H A V E B E E N C A U S E D B Y T H E S T U D Y 
T R E A T M E N T , O R I F R E-E X P O S U R E T O T H E S T U D Y T R E A T M E N T P O S E S 
A D DI TI O N A L P O T E N TI A L SI G NI FI C A N T RI S K T O T H E P A R TI CI P A N T T H E N 
T H E R E C H A L L E N G E M U S T B E A P P R O V E D I N A D V A N C E B Y T H E M S D
C L I NI CA L DI R E C T O R A S P E R D O S E M O DI FI C A TI O N G UI D E LI N E S I N T H E 
P R O T O C O L , A N D I F R E Q UI R E D, T H E I N S TI T U TI O N A L R E VI E W 
B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E.
●
C o nsiste nc y wit h St u d y tre at me nt Pr ofile: Is t he cli nical/ pat h ol o gical 
prese ntati o n of t he A E c o nsiste nt wit h pre vi o us k n o wle d ge re gar di n g t he 
st u d y treat me nt or dr u g class p har mac ol o g y  or t o xic ol o g y?
●
T he assess me nt of relati o ns hi p will be re p orte d o n t he case re p ort f or ms / w or ks heets 
b y  a n i n vesti gat or w h o is a q ualifie d p hys icia n acc or di n g t o his/ her best cli nical 
j u d g me nt, i ncl u di n g c o nsi derati o n of t he a b o ve ele me nts.
●
Use t he f oll o wi n g scale of criteria as g ui da nce ( n ot all criteria m ust be prese nt t o be 
i n dicati ve of a st u d y treat me nt relati o ns hi p).
●
Yes, t here is a reas o na ble p ossi bilit y  of st u d y treat me nt relati o ns hi p:
T here is e vi de nce of e x p os ure t o t he st u d y treat me nt.  T he te m p oral se q ue nce of 
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 na ble.  
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 3
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 5: C o ntr ace pti ve G ui d a nce a n d Pre g n a nc y Testi n g
1 2. 5
Defi niti o ns 
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal 
u nless per ma ne ntl y sterile (see bel o w) 
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:
●
Pre me narc hal
●
Pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
○
D oc u me nte d h ys terect o m y
○
D oc u me nte d bilateral sal pi n gect o m y
○
D oc u me nte d bilateral o o p h orect o m y
N ote:  D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he partici pa nt’s 
me dical rec or ds, me dical e xa mi nati o n, or me dical hist or y  i nter vie w.
●
P ost me n o pa usal fe male
○
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use. 
▪
A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y 
be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o nal re place me nt t hera py ( H R T). H o we ver, i n t he a bse nce 
of 1 2 m o nt hs of a me n orr hea, co 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 HR T d uri n g t he st u d y . Ot her wise, t he y m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.
C o ntr ace pti o n Re q uire me nts
M a le P artici p a nts
Male partici pa nts wit h fe male part ners of c hil d beari n g p ote ntial are eli gi ble t o partici pate if 
t he y a gree t o o ne of t he f oll o wi n g d uri n g t he pr ot oc ol defi ne d ti me fra me i n secti o n 6. 1: 
●
Be a bsti ne nt fr o m pe nile -va gi nal i nterc o urse as t heir us ual a n d preferre d lifest y le 
(a bsti ne nt o n a l o n g ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 4
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
●
Use a male c o n d o m pl us part ner use of a n a d diti o nal c o ntrace pti ve met h o d w he n ha vi n g 
pe nile - va gi nal i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial w h o is n ot c urre ntly 
pre g na nt.
o
T he f oll o wi n g are n ot acce pta ble met h o ds of c o ntrace pti o n:
▪
Peri o dic a bsti ne nce (cale n dar, sy m pt ot her mal, p ost -o v ulati o n met h o ds), 
wit h dra wal (c oit us i nterr u pt us), s per mici des o nl y , a n d lactati o nal a me n orr h oea 
met h o d ( L A M).
▪
Male c o n d o m wit h ca p, dia p hra g m or s p o n ge wit h s per mici de .
▪
Male a n d fe male c o n d o m ca n n ot be use d t o get her.
○
N ote: Me n wit h a pre g na nt or breastfee di n g part ner m ust a gree t o re mai n a bsti ne nt 
fr o m pe nile va gi nal i nterc o urse or use a male c o n d o m d uri n g eac h e pis o de of pe nile 
pe netrati o n .
Fe m ale P artici p a nts
Fe male partici pa nts of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o use a 
hi g hl y effecti ve met h o d of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as descri be d i n 
Ta ble 2 2 d uri n g t he pr ot oc ol -defi ne d ti me fra me i n Secti o n 6. 1 a n d Secti o n 6. 3. 2.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 5
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Ta ble 2 2
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 g e n- a n d pr o gest o ge n - c o ntai ni n g) h or m o nal c o ntrace pti o n b, c
○
Oral 
○
I ntra va gi nal 
○
Tra ns der mal 
○
I njecta ble
●
Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n b, c
○
Oral 
○
I njecta ble 
Hi g hl y Effecti ve Met h o ds T h at H a ve L o w User De pe n de nc y 
F ail ure r ate of < 1 %  per ye ar w he n use d c o nsiste ntly a n d c orrectly.
●
Pr o gest o ge n - o nl y c o ntrace pti ve i m pla nt b, c
●
I ntra uteri ne h or m o ne-releasi n g s yste m (I U S) b
●
I ntra uteri ne de vice (I U D)
●
Bilateral t u bal occl usi o n
●
V asect o mize d p art ner 
A vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he 
s ole male se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n 
a d diti o nal hi g hl y effecti ve met h o d of c o ntrace pti o n s h o ul d be u se d. 
●
Se x u al a bsti ne nce 
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nt. T he 
relia bilit y of se x ual a bsti ne nce 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 (i.e. w he n use d c o nsiste ntl y a n d 
c orrectl y). 
b) If h or m o nal c o ntrace pti o n efficac y is p ote ntiall y decrease d d ue t o i nteracti o n wit h st u d y treat me nt, 
c o n d o ms m ust be use d i n a d diti o n t o t he h or m o nal c o ntrace 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 , or pe m br oliz u ma b 
m o n ot hera p y , a n d f or at least 1 8 0 da ys after t he last d ose of t he E X T R E M E re gi me n.
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. 
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 6
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
Pre g n a nc y Testi n g
W O C B P s h o ul d o nl y  be i ncl u de d after a ne gati ve hi g hly se nsiti ve uri ne or ser u m pre g na nc y 
test. 
F oll o wi n g i nitiati o n of treat me nt , pre g na nc y testi n g will be perf or me d w he ne ver a n e x pecte d 
me nstr ual c y cle is misse d or w he n pre g na nc y  is ot her wise s us pecte d; after t he last d ose of 
st u d y treat me nt; a n d as re q uire d l ocall y. M o nt hl y pre g na nc y testi n g s h o ul d be c o n d ucte d as 
per l ocal re g ulati o ns w here a p plica ble.
 
 
0 4 Y B M H

Pr o d uct: M K - 3 4 7 5/I N C B 0 2 4 3 6 0 
1 5 8
Pr ot oc ol/ A me n d me nt N o.:   6 6 9 - 0 4/ E C H O-3 0 4 -0 4
M K -3 4 7 5 -6 6 9 -0 4 (I N C B 2 4 3 6 0 -3 0 4 -0 4) Fi nal Pr ot oc ol
1 2 -J u n-2 0 1 8
C o nfi de ntial
A p pe n di x 7 : Pr o hi bite d M o n o a mi ne O xi d ase ( M A O) I n hi bit ors a n d Dr u gs 
1 2. 7
Ass oci ate d wit h Si g nific a nt M o n o a mi ne O xi d ase I n hi bit or y Acti vit y
M o n o a mi ne O xi d ase I n hi bit ors
Dr u gs Ass oci ate d Wit h Si g nific a nt M o n o a mi ne 
O xi d ase I n hi bit or y Acti vit y
H y drazi nes (e xa m ple p he nelzi ne)
Me peri di ne
Car o xaz o ne
Li nez oli d
Ec hi n o psi di ne
Met h yle ne bl ue
F uraz oli d o ne
Tra n ylc y pr o mi ne
Br ofar o mi ne
Metrali n d ole
Mi na pri ne
M ocl o be mi de
Pirli n d ole
T ol o xat o ne
Laz be mi de
Par g yli ne
Rasa gili ne
Sele gili ne
 
 
0 4 Y B M H

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

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 0
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
i R E CIS T defi nes ne w res p o nse cate g ories, i ncl u di n g u nc o nfir me d pr o gressi ve disease
(i U P D) a n d c o nfir me d pr o gressi ve disease (i C P D).  F or p ur p oses of i R E CI S T assess me nt, 
t he first visit s h o wi n g pr o gressi o n acc or di n g t o R E CIS T 1. 1 will be assi g ne d a visit ( o verall) 
res p o nse of i U P D, re gar dless of w hic h fact ors ca use d t he pr o gressi o n.
At t his visit, tar get a n d n o n- tar get lesi o ns i de ntifie d at baseli ne by R E CI S T 1. 1 will be 
assesse d as us ual.
Ne w lesi o ns will be classifie d as meas ura ble or n o n - meas ura ble, usi n g t he sa me size 
t hres h ol ds a n d r ules as for baseli ne lesi o n assess me nt i n R E CI S T 1. 1.  F or meas ura ble ne w 
lesi o ns, u p t o 5 lesi o ns t otal ( u p t o 2 per or ga n), ma y be selecte d as Ne w Lesi o ns – Tar get. 
T he s u m of dia meters of t hese lesi o ns will be calc ulate d, a n d ke pt disti nct fr o m t he s u m of 
dia met ers f or tar get lesi o ns at baseli ne.  All ot her ne w lesi o ns will be f oll o we d q ualitati vel y 
as Ne w Lesi o ns – N o n -tar get.
Assess me nt at t he C o nfir m at ory I m a gi n g
O n t he c o nfir mat or y  i ma gi n g, t he partici pa nt will be classifie d as pr o gressi o n c o nfir me d 
( wit h a n o verall res p o nse of i C P D), persiste nt u nc o nfir me d pr o gressi o n ( wit h a n o verall 
res p o nse of i U P D), or as s h o wi n g disease sta bilit y or res p o nse (i S D/i P R/i C R).
C o nfir m ati o n of Pr o gressi o n
Pr o gressi o n is c o nsi dere d c o nfir me d, a n d t he o verall res p o nse will be i C P D, if A N Y of t he 
f oll o wi n g occ urs:

A n y  of t he fact ors t hat were t he basis f or t he i U P D at t he pre vi o us visit s h o w 
w orse ni n g
o
F or tar get lesi o ns, w orse ni n g is a f urt her i ncrease i n t he s u m 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 hese:

A n i ncrease i n t he ne w lesi o n s u m of dia meters b y ≥5 m m fr o m a pri or 
i U P D ti me p oi nt 

Visi ble gr o wt h of ne w n o n- tar get lesi o ns 

T he a p peara nce of a d diti o nal ne w lesi o ns

A n y  ne w fact or a p pears t hat w o ul d ha ve tri g gere d P D b y  R E CI S T 1. 1
Persiste nt i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o verall res p o nse re mai ns i U P D, if:

N o ne of t he pr o gressi o n -c o nfir mi n g fact ors i de ntifie d a b o ve occ urs , A N D

T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) re mai ns a b o ve t he i nitial 
disease pr o gressi o n t hres h ol d ( b y  R E CI S T 1. 1)
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 1
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
A d diti o nal i ma gi n g f or c o nfir mati o n s h o ul d be sc he d ule d 4 t o 8 wee ks fr o m t he sca n o n 
w hic h i U P D is see n.  T his ma y  c orres p o n d t o t he ne xt visit i n t he ori gi nal visit sc he d ule.  T he 
assess me n t of t he s u bse q ue nt c o nfir mati o n sca n pr ocee ds i n a n i de ntical ma n ner, wit h 
p ossi ble o utc o mes of i C P D, i U P D, a n d i S D/i P R/i C R.
Res ol uti o n of i U P D
Pr o gressi o n is c o nsi dere d n ot c o nfir me d, a n d t he o verall res p o nse bec o mes i S D/i P R/i C R, if:

N o ne of t he pr o gress i o n-c o nfir mi n g fact ors i de ntifie d a b o ve occ urs, A N D

T he tar get lesi o n s u m of dia meters (i nitial tar get lesi o ns) is n ot a b o ve t he i nitial P D 
t hres h ol d. 
T he res p o nse is classifie d as i S D or i P R ( de pe n di n g o n t he s u m of dia meters of t he tar get 
lesi o ns), or iC R if all lesi o ns res ol ve.
I n t his case, t he i nitial i U P D is c o nsi dere d t o be pse u d o- pr o gressi o n, a n d t he le vel of 
s us pici o n f or pr o gressi o n is “reset”.  T his mea ns t hat t he ne xt visit t hat s h o ws ra di o gra p hic 
pr o gressi o n, w he ne ver it occ urs, is a gai n class ifie d as i U P D b y i R E CIS T, a n d t he 
c o nfir mati o n pr ocess is re peate d bef ore a res p o nse of i C P D ca n be assi g ne d.
M a n a ge me nt F oll o wi n g t he C o nfir m at ory I m a gi n g
If re peat i ma gi n g d oes n ot c o nfir m P D per i R E CIS T, as assesse d b y  t he i n vesti gat or, a n d t he 
partici p a nt c o nti n ues t o be cli nicall y  sta ble, st u d y treat me nt ma y c o nti n ue a n d f oll o w t he 
re g ular i ma gi n g sc he d ule.  If P D is c o nfir me d, partici pa nts will be disc o nti n ue d fr o m st u dy 
treat me nt.
N O T E: If a partici pa nt has c o nfir me d ra di o gra p hic pr o gressi o n (i C P D) as defi ne d a b o ve, b ut 
t he partici pa nt is ac hie vi n g a cli nicall y mea ni n gf ul be nefit or if R E CI S T 1. 1 P D has n ot bee n 
verifie d ce ntrall y , a n e xce pti o n t o c o nti n ue st u d y treat me nt ma y be c o nsi dere d f oll o wi n g 
c o ns ultati o n wit h M S D.  I n t his case, if st u d y treat me nt is c o nti n ue d, t u m or i ma gi n g s h o ul d 
c o nti n ue t o be perf or me d f oll o wi n g t he i nter vals as o utli ne d i n Secti o n 2 a n d s u b mitte d t o t he 
ce ntral i ma gi n g ve n d or.
Detecti o n of Pr o gressi o n at Visits after Pse u d o- pr o gressi o n Res olves
After res ol uti o n of pse u d o - pr o gressi o n (ie, ac hie ve me nt of i S D/i P R/i C R), i U P D is i n dicate d 
b y  a ny of t he f oll o wi n g e ve nts:

Tar get lesi o ns
o
S u m of dia meters reac hes t he P D t hres h ol d ( ≥2 0 % a n d ≥5 m m i ncrease fr o m 
na dir) eit her f or t he first ti me, or after res ol uti o n of pre vi o us 
pse u d o -pr o gressi o n.  T he na dir is al wa y s t he s mallest s u m of dia meters see n 
d uri n g t he e ntire st u d y, eit her bef ore or after a n i nsta nce of 
pse u d o -pr o gressi o n.

N o n -tar get lesi o ns
o
If n o n-tar get lesi o ns ha ve ne ver s h o w n u ne q ui v ocal pr o gressi o n, t heir d oi n g 
s o f or t he first ti me res ults i n i U P D.
 
 
0 4 Y B M H

Pr o d uct: M K -3 4 7 5/I N C B 0 2 4 3 6 0 
1 6 2
Pr ot oc ol/ A me n d me nt N o.:   6 6 9- 0 4/ E C H O - 3 0 4- 0 4
M K - 3 4 7 5- 6 6 9-0 4 (I N C B 2 4 3 6 0 - 3 0 4-0 4) Fi nal Pr ot oc ol
1 2- J u n- 2 0 1 8
C o nfi de ntial
o
If n o n-tar get lesi o ns ha d s h o w n pre vi o us u ne q ui v ocal pr o gressi o n, a n d t his 
pr o gressi o n has n ot res ol ve d, i U P D res ults fr o m a n y  si g nifica nt f urt her gr o wt h 
of n o n -tar get lesi o ns, ta ke n as a w h ole.

Ne w lesi o ns
o
Ne w lesi o ns a p pear f or t he first ti me
o
A d diti o nal ne w lesi o ns a p pear
o
Pre vi o usl y  i de ntifie d ne w tar get lesi o ns s h o w a n i ncrease of ≥5 m m i n t he 
ne w lesi o n s u m of dia meters, fr o m t he na dir val ue of t hat s u m
o
Pre vi o usl y  i de ntifie d n o n-tar get lesi o ns s h o w a ny si g nifica nt gr o wt h
If a ny of t he e ve nts a b o ve occ ur, t he o verall res p o nse f or t hat visit is i U P D, a n d t he i U P D 
e val uati o n pr ocess (see Assess me nt at t he C o nfir mat or y  Ima gi n g a b o ve) is re peate d. 
Pr o gressi o n m ust be c o nfir me d bef ore i C P D ca n occ ur.
T he decisi o n pr ocess i s i de ntical t o t he i U P D c o nfir mati o n pr ocess f or t he i nitial P D, wit h 
o ne e xce pti o n:  if ne w lesi o ns occ urre d at a pri or i nsta nce of i U P D, a n d at t he c o nfir mat or y  
i ma gi n g t he b ur de n of ne w lesi o ns has i ncrease d fr o m its s mallest val ue (f or ne w tar get 
lesi ons, t he s u m of dia meters is ≥5 m m i ncrease d fr o m its na dir), t he n i U P D ca n n ot res ol ve 
t o i S D or i P R. It will re mai n i U P D u ntil eit her a decrease i n t he ne w lesi o n b ur de n all o ws 
res ol uti o n t o i S D or i P R, or u ntil a c o nfir mat or y fact or ca uses i C P D.
A d diti o nal details a b o ut i R E 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 ym o ur, L., et 
al 2 0 1 7] .
 
 
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