A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
Phase: PHASE3
Conditions: Non-small Cell Lung Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Randomized, Double-Blind, Phase III Study of Carboplatin-
Paclitaxel/Nab-Paclitaxel Chemotherapy with or without 
Pembrolizumab (MK-3475) in First Line Metastatic Squamous 
Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
30-Oct-2019
NCT03875092

Pr o d uct:   M K -3 4 7 5 
1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T HI S P R O T O C O L A M E N D M E N T A N D A L L O F T H E I N F O R M A TI O N R E L A TI N G 
T O I T A R E C O N FI D E N TI A L A N D P R O P RI E T A R Y P R O P E R T Y O F 
M E R C K 
S H A R P 
& 
D O H M E 
C O R P., 
A 
S U B SI DI A R Y 
O F 
M E R C K  
& 
C O., 
I N C., 
W HI T E H O U S E S T A TI O N, N J, U. S. A.
T his pr ot oc ol a me n d me nt is a p plic a ble o nl y t o C hi n a
S P O N S O R:
Merc k S har p & D o h me C or p., a s u bsi diar y  of Merc k & C o., I nc. 
( hereafter referre d t o as t he S p o ns or or Merc k)
O ne Merc k Dri ve
P. O. B o x 1 0 0
W hite h o use Stati o n , Ne w Jerse y, 0 8 8 8 9- 0 1 0 0, U. S. A.
Pr ot oc ol -s pecific S p o ns or C o ntact i nf or mati o n ca n be f o u n d i n t he I n vesti gat or Trial File 
Bi n der ( or e q ui vale nt).
TI T L E:
A Ra n d o mize d, D o u ble- Bli n d, P hase III St u d y of Car b o plati n -Paclita xel/ Na b -Paclita xel 
C he m ot hera p y wit h 
or wit h o ut 
Pe m br oliz u ma b ( M K-3 4 7 5) i n First Li ne Metastatic 
S q ua m o us N o n- s mall Cell Lu n g Ca ncer S u bjects ( K E Y N O T E -4 0 7)
I N D N U M B E R:  1 1 6, 8 3 3
E u dr a C T N U M B E R:   2 0 1 6- 0 0 0 2 2 9- 3 8
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T A B L E O F C O N T E N T S
D O C U M E N T HI S T O R Y ..................................................................................................... 1 1
S U M M A R Y O F C H A N G E S ................................................................................................ 1 2
1. 0 
T RI A L S U M M A R Y .................................................................................................. 1 4
2. 0 
T RI A L D E SI G N ........................................................................................................ 1 5
Tri al Desi g n ........................................................................................................... 1 5
Tri al Di a gr a m ........................................................................................................ 1 8
3. 0 
O B J E C TI V E( S) & H Y P O T H E SI S( E S) .................................................................. 1 8
Pri m ar y O bjecti ve(s) & H y p ot hesis(es) .............................................................. 1 8
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es) ........................................................... 1 9
E x pl or at or y O bjecti ves ......................................................................................... 1 9
4. 0 
B A C K G R O U N D & R A TI O N A L E .......................................................................... 2 0
B ac k gr o u n d ........................................................................................................... 2 0
P har mace utical a n d T hera pe utic Bac k gr o u n d .................................................... 2 0
Pre -cli nical a n d Cli nical Trials ........................................................................... 2 1
O n g oi n g Cli nical Trials ....................................................................................... 2 2
I nf or mati o n o n Ot her Trial-Relate d T hera p y ...................................................... 2 3
R ati o n ale ................................................................................................................ 2 4
Rati o nale f or t he Trial a n d Selecte d S u bject P o p ulati o n .................................... 2 4
Rati o nale f or D ose Selecti o n/ R e gi me n/ M o dificati o n ......................................... 2 5
4. 2. 2. 1 
Rati o nale f or t he Use of Place b o ................................................................. 2 6
Rati o nale f or E n d p oi nts ...................................................................................... 2 6
4. 2. 3. 1 
Efficac y  E n d p oi nts....................................................................................... 2 6
4. 2. 3. 2 
I m m u ne-relate d R E CIS T (ir R E CI S T) ......................................................... 2 7
4. 2. 3. 3 
Patie nt Re p orte d O utc o mes .......................................................................... 2 7
E O R T C Q L Q- C 3 0 a n d E O R T C Q L Q L C 1 3 ......................................... 2 7
E ur o Q ol ( E Q)- 5 D ................................................................................. 2 8
4. 2. 3. 4 
Safet y  E n d p oi nts.......................................................................................... 2 8
4. 2. 3. 5 
Pla n ne d E x pl orat or y  Bi o mar ker Researc h................................................... 2 9
4. 2. 3. 6 
F ut ure Bi o me dical Researc h ........................................................................ 3 0
Be nefit/ Ris k ........................................................................................................... 3 0
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
5. 0 
M E T H O D O L O G Y
................................................................................................... 3 1
E ntr y Criteri a ........................................................................................................ 3 1
Dia g n osis/ C o n diti o n f or E ntr y  i nt o t he Trial...................................................... 3 1
S u bject I ncl usi o n Criteria .................................................................................... 3 1
S u bject E xcl usi o n Criteria .................................................................................. 3 3
Tri al Tre at me nt(s) ................................................................................................ 3 5
D ose Selecti o n/ M o dificati o n .............................................................................. 3 6
5. 2. 1. 1 
D ose Selecti o n ( Pre parati o n) ....................................................................... 3 6
5. 2. 1. 2 
D ose M o dificati o n ....................................................................................... 3 6
Car b o plati n 
a n d Paclita xel 
or 
Na b -paclita xel 
C he m ot hera p y 
Re gi me n ................................................................................................ 3 7
Pe m br oliz u ma b ..................................................................................... 3 7
Ti mi n g of D ose A d mi nistrati o n .......................................................................... 4 2
5. 2. 2. 1 
Pe m br oliz u ma b/ sali ne place b o ................................................................... 4 3
5. 2. 2. 2 
Paclita xel ...................................................................................................... 4 3
5. 2. 2. 3 
Na b -paclita xel .............................................................................................. 4 3
5. 2. 2. 4 
Car b o plati n ................................................................................................... 4 3
5. 2. 2. 5 
A ntie metic T hera p y ..................................................................................... 4 4
Trial Bli n di n g...................................................................................................... 4 4
R a n d o miz ati o n or Tre at me nt All oc ati o n ............................................................ 4 4
Str atific ati o n .......................................................................................................... 4 4
C o nc o mit a nt Me dic ati o ns/ V acci n ati o ns ( All o we d & Pr o hi bite d) .................... 4 5
Acce pta ble C o nc o mita nt Me dicati o ns ................................................................ 4 5
Pr o hi bite d C o nc o mita nt Me dicati o ns .................................................................. 4 5
Resc ue Me dic ati o ns & S u p p orti ve C are ............................................................. 4 6
Diet/ Acti vit y/ Ot her C o nsi der ati o ns ..................................................................... 4 6
Diet ...................................................................................................................... 4 6
C o ntrace pti o n ...................................................................................................... 4 6
Use i n Pre g na nc y ................................................................................................ 4 8
Use i n N ursi n g W o me n ....................................................................................... 4 8
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a ................................................... 4 8
S u bject Re pl ace me nt Str ate g y ............................................................................. 5 0
Be gi n ni n g a n d E n d of t he Tri al ........................................................................... 5 0
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n ................................................... 5 0
6. 0 
T RI A L F L O W C H A R T ........................................................................................... 5 1
I niti al Tre at me nt P h ase ........................................................................................ 5 1
I nitial Treat me nt P hase – C y cles 1 - 4 .................................................................. 5 1
I nitial Treat me nt P hase – C y cles 5 a n d Be yo n d ................................................. 5 4
Sec o n d C o urse P h ase ( Retre at me nt) ................................................................... 5 6
Cr oss o ver P h ase .................................................................................................... 5 8
7. 0 
T RI A L P R O C E D U R E S ........................................................................................... 6 1
Tri al Pr oce d ures ................................................................................................... 6 1
A d mi nistrati ve Pr oce d ures .................................................................................. 6 1
7. 1. 1. 1 
I nf or me d C o nse nt......................................................................................... 6 1
Ge neral I nf or me d C o nse nt .................................................................... 6 1
C o nse nt a n d C ollecti o n of S peci me ns f or F ut ure Bi o me dical 
Researc h ................................................................................................ 6 2
7. 1. 1. 2 
I ncl usi o n/ E xcl usi on Criteria ........................................................................ 6 2
7. 1. 1. 3 
S u bject I de ntificati o n Car d .......................................................................... 6 2
7. 1. 1. 4 
Me dical Hist or y
........................................................................................... 6 2
7. 1. 1. 5 
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w ............................................... 6 2
Pri or Me dicati o ns .................................................................................. 6 2
C o nc o mita nt Me dicati o ns ..................................................................... 6 3
7. 1. 1. 6 
Assi g n me nt of Scree ni n g N u m ber ............................................................... 6 3
7. 1. 1. 7 
Assi g n me nt of Treat me nt/ Ra n d o mizati o n N u m ber ..................................... 6 3
7. 1. 1. 8 
Trial C o m plia nce ( Me dicati o n/ Diet/ Acti vit y / Ot her) ................................... 6 3
Cli nical Pr oce d ures/ Assess me nts ........................................................................ 6 3
7. 1. 2. 1 
A d verse E ve nt ( A E) M o nit ori n g .................................................................. 6 3
7. 1. 2. 2 
P h y sical E xa m.............................................................................................. 6 4
F ull P h y sical E xa m ............................................................................... 6 4
Directe d P h ys ical E xa m........................................................................ 6 4
7. 1. 2. 3 
Vital Si g ns.................................................................................................... 6 4
7. 1. 2. 4 
1 2 -Lea d Electr ocar di o gra m ( E C G) .............................................................. 6 4
7. 1. 2. 5 
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Scale ........... 6 4
7. 1. 2. 6 
T u m or I ma gi n g a n d Assess me nt of Disease ................................................ 6 5
I nitial T u m or I ma gi n g........................................................................... 6 5
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T u m or I ma gi n g D uri n g t he Trial .......................................................... 6 6
E n d of Treat me nt a n d F oll o w -u p of T u m or I ma gi n g ........................... 6 6
Sec o n d C o urse ( Retreat me nt) T u m or I ma gi n g ..................................... 6 7
R E CI S T 1. 1 Assess me nt of Disease ..................................................... 6 7
ir R E CIS T Assess me nt of Disease ......................................................... 6 8
7. 1. 2. 7 
T u m or Tiss ue C ollecti o n: P D -L 1  Stat us...................................................... 7 1
La b orat or y  Pr oce d ures/ Assess me nts .................................................................. 7 2
7. 1. 3. 1 
La b orat or y  Safety E val uati o ns ( He mat ol o g y, C he mistr y  a n d Uri nal ysis) .. 7 2
7. 1. 3. 2 
P har mac o ki netic/ P har mac o d y na mic E val uati o ns ........................................ 7 4
7. 1. 3. 3 
Patie nt Re p orte d O utc o mes ( P R Os) ............................................................. 7 4
7. 1. 3. 4 
Bl o o d f or R N A A nal ys es a n d Bi o mar ker A nal yses ( plas ma, ser u m) .......... 7 4
7. 1. 3. 5 
Pla n ne d Ge netic A nal ys is Sa m ple C ollecti o n.............................................. 7 4
7. 1. 3. 6 
F ut ure Bi o me dical Researc h Sa m ple C oll ecti o n ......................................... 7 5
Ot her Pr oce d ures ................................................................................................. 7 5
7. 1. 4. 1 
Wit h dra wal/ Disc o nti n uati o n ........................................................................ 7 5
Wit h dra wal Fr o m F ut ure Bi o me dical Researc h
................................... 7 5
7. 1. 4. 2 
Bli n di n g/ U n bli n di n g .................................................................................... 7 6
7. 1. 4. 3 
Cali brati o n of Critical E q ui p me n t................................................................ 7 6
Visit Re q uire me nts .............................................................................................. 7 6
7. 1. 5. 1 
Scree ni n g ...................................................................................................... 7 7
7. 1. 5. 2 
Treat me nt Peri o d Visit................................................................................. 7 7
7. 1. 5. 3 
P ost -Trial ...................................................................................................... 7 7
Safet y  F oll o w-u p Visit .......................................................................... 7 8
F oll o w -u p Visits ................................................................................... 7 8
S ur vi val F oll o w -u p ............................................................................... 7 8
7. 1. 5. 4 
S ur vi val Stat us ............................................................................................. 7 8
7. 1. 5. 5 
Sec o n d C o urse P hase ................................................................................... 7 8
7. 1. 5. 6 
Cr oss o ver P hase ........................................................................................... 7 9
7. 1. 5. 7 
Cr oss o ver Assess me nts a n d Pr oce d ures ...................................................... 8 0
Assessi n g a n d Rec or di n g A d verse E ve nts .......................................................... 8 0
Defi niti o n of a n O ver d ose f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o 
t he S p o ns or.......................................................................................................... 8 1
Re p orti n g of Pre g na nc y  a n d Lactati o n t o t he S p o ns or ....................................... 8 1
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I m me diate Re p orti n g of A d verse E ve nts t o t he S p o ns or.................................... 8 2
7. 2. 3. 1 
Seri o us A d verse E ve nts ............................................................................... 8 2
7. 2. 3. 2 
E ve nts of Cli nical I nterest ............................................................................ 8 3
7. 2. 3. 3 
Pr ot oc ol -S pecific E xce pti o ns t o Seri o us A d verse E ve nt Re p orti n g ............ 8 3
E val uati n g A d verse E ve nts ................................................................................. 8 4
S p o ns or Res p o nsi bilit y  f or Re p orti n g A d verse E ve nts ...................................... 8 7
T RI A L G O V E R N A N C E A N D O V E R SI G H T ................................................... 8 7
Scie ntific A d vis or y  C o m mittee........................................................................... 8 7
E xec uti ve O versi g ht C o m mittee ......................................................................... 8 7
Data M o nit ori n g C o m mittee ............................................................................... 8 7
8. 0 
S T A TI S TI C A L A N A L Y SI S P L A N ........................................................................ 8 8
St atistic al A n al ysis Pl a n S u m m ar y ..................................................................... 8 8
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g ................................................. 9 0
H y p ot heses/ Esti m ati o n......................................................................................... 9 0
A n al ysis E n d p oi nts ............................................................................................... 9 1
Efficac y  E n d p oi nts.............................................................................................. 9 1
Safet y  E n d p oi nts................................................................................................. 9 1
A n al ysis P o p ul ati o ns ............................................................................................. 9 1
Efficac y  A nalys is P o p ulati o ns ............................................................................ 9 1
Safet y A nal ys is P o p ulati o ns ............................................................................... 9 2
St atistic al Met h o ds ................................................................................................ 9 2
Statistical Met h o ds f or Efficac y  A nalys es .......................................................... 9 2
8. 6. 1. 1 
Pr o gressi o n -Free S ur vi val ( P F S) ................................................................. 9 3
8. 6. 1. 2 
O verall S ur vi val ( O S) .................................................................................. 9 4
8. 6. 1. 3 
O bjecti ve res p o nse rate ( O R R) a n d D urati o n of Res p o nse ( D O R) ............. 9 5
8. 6. 1. 4 
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts............................................ 9 5
Statistical Met h o ds f or Safet y A nal ys es ............................................................. 9 6
S u m maries of De m o gra p hic 
a n d Baseli ne 
C haracteristics 
a n d Ot her 
A nal y ses .............................................................................................................. 9 7
I nteri m A n al yses ................................................................................................... 9 7
M ulti plicit y
............................................................................................................ 9 8
O bjecti ve Res p o nse Rate .................................................................................... 9 9
Pr o gressi o n -free S ur vi val.................................................................................... 9 9
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
O verall S ur vi val ................................................................................................ 1 0 0
S a m ple Size a n d P o wer C alc ul ati o ns ................................................................ 1 0 1
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors ......................................... 1 0 2
E xte nt of E x p os ure .............................................................................................. 1 0 2
9. 0 
L A B E LI N G, P A C K A GI N G, S T O R A G E A N D R E T U R N O F  CLI NI C A L 
S U P P LI E S ............................................................................................................... 1 0 2
I n vesti g ati o n al Pr o d uct ...................................................................................... 1 0 2
P ac k a gi n g a n d L a beli n g I nf or m ati o n ............................................................... 1 0 3
Cli nic al S u p plies Discl os ure ............................................................................... 1 0 3
St or a ge a n d H a n dli n g Re q uire me nts ................................................................ 1 0 4
Disc ar d/ Destr ucti o n/ Ret ur ns a n d Rec o ncili ati o n ............................................ 1 0 4
St a n d ar d P olicies ................................................................................................. 1 0 4
1 0. 0 
A D MI NI S T R A TI V E A N D R E G U L A T O R Y D E T AI L S ..................................... 1 0 5
C o nfi de nti alit y ..................................................................................................... 1 0 5
C o nfi de ntialit y  of Data ..................................................................................... 1 0 5
C o nfi de ntialit y  of S u bject Rec or ds................................................................... 1 0 5
C o nfi de ntialit y  of I n vesti gat or I nf or mati o n...................................................... 1 0 5
C o nfi de ntialit y  of I R B/I E C Inf or mati o n ........................................................... 1 0 6
C o m pli a nce wit h Fi n a nci al Discl os ure Re q uire me nts ..................................... 1 0 6
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt ................................................. 1 0 6
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P osti n g Re q uire me nts ...... 1 0 8
Q u alit y M a n a ge me nt S yste m ............................................................................. 1 0 8
D at a M a n a ge me nt ............................................................................................... 1 0 8
P u blic ati o ns ......................................................................................................... 1 0 9
1 1. 0 
LI S T O F R E F E R E N C E S ....................................................................................... 1 1 1
1 2. 0   
A P P E N DI C E S ......................................................................................................... 1 1 5
Merc k C o de of C o n d uct f or Cli nic al Tri als ...................................................... 1 1 5
C ollecti o n 
a n d M a n a ge me nt  
of S peci me ns 
f or F ut ure 
Bi o me dic al 
Rese arc h ............................................................................................................... 1 1 7
U n derst a n di n g 
t he I nte nt, Sc o pe 
a n d 
P u blic 
He alt h 
Be nefits 
of 
E x pl or at or y 
Bi o m ar ker 
Rese arc h: 
A 
G ui de 
f or I R Bs/I E Cs a n d 
I n vesti g ati o n al Site St aff .................................................................................... 1 2 1
List of A b bre vi ati o ns .......................................................................................... 1 3 2
C o m m o n Ter mi n ol o g y Criteri a f or A d verse E ve nts V 4. 0 ( C T C A E) ............. 1 3 4
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
E C O G Perf or m a nce St at us ................................................................................ 1 3 5
1 3. 0 
SI G N A T U R E S ......................................................................................................... 1 3 6
S p o ns or's Re prese nt ati ve ................................................................................... 1 3 6
I n vesti g at or .......................................................................................................... 1 3 6
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
LI S T O F T A B L E S
Ta ble 1 
A de q uate Or ga n F u ncti o n L a b orat or y Val ues...................................................... 3 2
Ta ble 2 
Trial Treat me nt ..................................................................................................... 3 5
Ta ble 3 
D ose M o dificati o ns 
a n d T o xicit y  
Ma na ge me nt G ui deli nes f or I mm u ne -
relate d A Es Ass ociate d wit h Pe m br oliz u ma b....................................................... 3 8
Ta ble 4 
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 ............................................................................................................. 4 1
Ta ble 5 
I ma gi n g a n d Treat me nt after First Ra di ol o gic E vi de nce of P D ........................... 7 0
Ta ble 6 
La b orat or y  Tests ................................................................................................... 7 3
Ta ble 7 
E val uati n g A d verse E ve nts ................................................................................... 8 5
Ta ble 8 
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S ............................ 9 4
Ta ble 9 
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts..................................................... 9 5
Ta ble 1 0
A nal y sis Strate g y f or Safet y Para meters............................................................... 9 7
Ta ble 1 1
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y ................................................ 9 8
Ta ble 1 2
P ossi ble Al p ha- le vels a n d A p pr o xi mate 
O R R 
Differe nce 
Re q uire d 
t o 
De m o nstrate Efficac y  f or O R R at IA 1 .................................................................. 9 9
Ta ble 1 3
Efficac y  B o u n daries a n d Pr o perties f or Pr o gressi o n-free S ur vi val A nalys es .... 1 0 0
Ta ble 1 4
Efficac y  B o u n daries a n d Pr o perties f or O verall S ur vi val A nalys es ................... 1 0 1
Ta ble 1 5
Pr o d uct Descr i pti o ns........................................................................................... 1 0 3
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
LI S T O F FI G U R E S
Fi g ure 1 
St u d y  Sc he ma...................................................................................................... 1 8
Fi g ure 2 
I ma gi n g a n d Treat me nt f or Cli nicall y  Sta ble S u bjects After First Ra di ol o gic 
E vi de nce of P D Assesse d b y  t he Site.................................................................. 7 1
Fi g ure 3 
T y pe I Err or Reall ocati o n Strate g y F oll o wi n g Cl ose d Testi n g Pri nci ple ........... 9 9
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
D O C U M E N T HI S T O R Y
D oc u me nt
D ate of Iss ue
O ver all R ati o n ale
3 4 7 5 - 4 0 7- 0 0
2 4 -Mar - 2 0 1 6
Ori gi nal pr ot oc ol
3 4 7 5 - 4 0 7- 0 1
2 7 -J ul- 2 0 1 7
C hi na a me n d me nt: T o e xte n d t he e nr oll me nt peri o d be y o n d 
t he gl o bal st u dy t o ac hie ve re q uire d n u m ber of C hi nese 
s u bjects a n d e ve nts t o i n vesti gate efficac y a n d safet y i n 
C hi nese N S C L C s u bjects.
3 4 7 5 - 4 0 7- 0 2
2 6 -Oct - 2 0 1 7
T he statistical desi g n was u p date d t o o pti mize t he st u d y  f or 
t he i de ntificati o n of l o n g ter m treat me nt effect i n O S a n d 
P F S.
3 4 7 5 - 4 0 7- 0 3
1 3 -N o v - 2 0 1 7  
T he statistical desi g n was u p date d t o o pti mize t he st u d y f or 
t he i de ntificati o n of l o n g ter m treat me nt effect i n O S a n d 
P F S.
3 4 7 5 - 4 0 7- 0 4
2 0 -N o v - 2 0 1 7
C hi na a me n d me nt: T he statistical desi g n was u p date d t o 
o pti mize t he st u d y  f or t he i de ntificati o n of l o n g ter m 
treat me nt effect i n O S a n d P F S.
3 4 7 5 - 4 0 7- 0 5
2 8 -J u n- 2 0 1 8
Gl o bal a me n d me nt: I nteri m res ults were p ositi ve a n d 
t heref ore s u bjects are t o be gi ve n t he o pti o n of disc o nti n ui n g 
place b o treat me nt.
3 4 7 5 - 4 0 7- 0 6
3 0 -Oct - 2 0 1 9
C hi na a me n d me nt: I nteri m res ults were p ositi ve a n d 
t heref ore s u bjects are t o be gi ve n t he o pti o n of disc o nti n ui n g 
place b o treat me nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S U M M A R Y O F C H A N G E S
P RI M A R Y R E A S O N ( S) F O R T HI S A M E N D M E N T:
Secti o n N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s) 
R ati o n ale
2. 1
4. 2. 2. 1
5. 2. 2
5. 2. 3
6. 1. 1
6. 1. 2
7. 1. 5. 6
Trial Desi g n
Rati o nale f or t he Use of 
Place b o
Ti mi n g of D ose A d mi nistrati o n
Trial Bli n di n g
I nitial Treat me nt P hase –
C y cles 1- 4
I nitial Treatme nt P hase –
C y cles 5 a n d Be yo n d
Cr oss o ver P hase
T o all o w f or u n bli n di n g s o t hat 
s u bjects fr o m t he C hi na 
e xte nsi o n i n t he place bo ar m 
( Ar m 2) ha ve t he o pti o n of 
disc o nti n ui n g n or mal sali ne 
( place b o) treat me nt a n d 
s witc hi n g t o pe m br oliz u ma b i n 
t he e ve nt of d oc u me nte d 
pr o gressi ve disease b y ce ntral 
re vie w. 
I nteri m res ults were p ositi ve 
a n d t heref ore s u bjects are t o be 
gi ve n t he o pti o n of 
disc o nti n ui n g place b o 
treat me nt.
8. 1
Statistical A nal y sis Pla n 
S u m mar y
T o clarif y  s u bse q ue nt a nal ysis 
ti mi n g after o bser vi n g p ositi ve 
P F S a n d O S res ults i n t he 
i nteri m a nal ysis of t he C hi na 
e xte nsi o n.
After o bser vi n g p ositi ve P F S 
a n d O S i n t he interi m a nal y sis, 
al p ha c o ntr olle d statistical 
a nal ys is has bee n c o m plete d f or 
t he st u d y.
8. 2
Res p o nsi bilit y  f or A nalyses/I n-
H o use Bli n di n g
T o clarif y i n -h o use u n bli n di n g 
after o bser vi n g p ositi ve P F S 
a n d O S res ults i n t he i nteri m 
a nal ys is of t he C hi na e xte nsi o n.
I n-h o use u n bli n di n g has bee n 
gra nte d t o a li mite d n u m ber of 
pers o n nel fr o m S p o ns or after 
t he i nteri m a nalys is of t he 
C hi na e xte nsi o n was a nal yze d 
a n d d oc u me nte d.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Secti o n N u m ber (s)
Secti o n Title (s)
Descri pti o n of C h a n ge (s) 
R ati o n ale
8. 7
I nteri m A nalys es
T o clarif y  s u bse q ue nt a nal ysis 
ti mi n g after o bser vi n g p ositi ve 
P F S a n d O S res ults i n t he 
i nteri m a nal ysis of t he C hi na 
e xte nsi o n.
After o bser vi n g p ositi ve P F S 
a n d O S i n t he i nteri m a nal ysis, 
al p ha c o ntr olle d statistical 
a nal ys is has bee n c o m plete d f or 
t he st u d y.
A D DI TI O N A L C H A N G E ( S) F O R T HI S A M E N D M E N T:
Secti o n N u m ber (s) 
Secti o n Title (s)
Descri pti o n of C h a n ge (s) 
R ati o n ale
4. 2. 3. 5
6. 1. 1
6. 1. 2
P har mac o ki netic E n d p oi nts
I nitial Treat me nt P hase – C y cles 1 -
4
I nitial Treat me nt P hase – C y cles 5 
a n d Be yo n d
Re m o ve d t he P K e x pl orat or y  
e n d p oi nt a n d c ollecti o n of 
bl o o d sa m ples f or P K a n d 
A D A a nal ys es.
T he acc u m ulati o n of r o b ust 
P K a n d A D A data has 
all o we d f or t he a de q uate 
c haracterizati o n of t he cli nical 
p har mac ol o g y  of 
pe m br oliz u ma b acr oss 
i n dicati o ns. T heref ore, t he 
c ollecti o n of P K a n d A D A 
sa m ples f or pe m br oliz u ma b 
are bei n g disc o nti n ue d f or 
s u bjects e nr olle d u n der 
A me n d me nt 6
7. 1. 3. 2
P har mac o ki netic/ P har mac o d y na mic 
E val uati o ns
A d de d la n g ua ge f or P K 
disc o nti n uati o n .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1. 0 T RI A L S U M M A R Y
A b bre viate d Title
P hase III st u d y of car b o plati n a n d paclita xel or na n o particle al b u mi n-
b o u n d paclita xel ( na b-paclita xel) wit h or wit h o ut p e m br oliz u ma b i n 
first li ne metastatic s q ua m o us N S C L C.
S p o ns or Pr o d uct I de ntifiers 
M K -3 4 7 5
pe m br oliz u ma b
Trial P hase
P hase III
Cli nical I n dicati o n
Treat me nt of metastatic s q ua m o us n o n- s mall cell l u n g ca ncer
Trial T y pe
I nter ve nti o nal
T y pe of c o ntr ol
Place b o -c o ntr ol
R o ute of a d mi nistrati o n 
I ntra ve n o us
Trial Bli n di n g
D o u ble -bli n d
( Select Gr o u ps)
T here are 2 treat me nt ar ms:
 
Pe m br oliz u ma b pl us car b o plati n a n d paclita xel or na b -
paclita xel
 
Sali ne
place b o pl us car b o plati n a n d paclita xel or na b -
paclita xel
N u m ber of trial s u bjects
Gl o bal st u d y: A p pr o x i matel y 5 6 0 s u bjects will be e nr olle d.
E xte nsi o n St u d y i n C hi na: A p pr o xi matel y 
1 2 0
C hi nese s u bjects 
o verall will be e nr olle d i n t he g l o bal st u d y a n d t he exte nsi o n st u d y. 
Esti mate d d urati o n of trial
Gl o bal 
st u d y: T he S p o ns or esti mates t hat t he trial will 
re q uire 
a p pr o xi matel y 4 year s fr o m t he ti me t he first s u bject si g ns t he 
i nf or me d c o nse nt u ntil t he last s u bject’s last st u d y-relate d p h o ne call 
or visit.
E xte nsi o n St u d y i n C hi na: T he S p o ns or esti mates t hat t he trial wi ll 
re q uire a p pr o xi matel y a n a d diti o nal 1 5 m o nt hs ( be yo n d t he g l o bal 
st u d y’s last s u bject last st u d y-relate d p h o ne call) fr o m t he ti me t he 
first s u bject si g ns t he i nf or me d c o nse nt u ntil t he last s u bject’s last 
st u d y-relate d p h o ne call or visit.
D urati o n of Partici pati o n 
Eac h s u bject w ill partici pate i n t he trial fr o m t he ti me t he s u bject si g ns 
t he I nf or me d C o nse nt F or m (I C F) t hr o u g h t he fi nal c o ntact.  After a 
scree ni n g p hase of u p t o 2 8 da ys, eli gi ble s u bjects will recei ve 
assi g ne d treat me nt o n Da y 1 of eac h 3- wee k ( Q 3 W) d osi n g c ycle. All 
s u bjects will recei ve u p t o a ma xi m u m of 4 c ycles of car b o plati n, 
paclita xel or na b -paclita xel a n d p e m br oliz u ma b or sali ne place b o. 
Treat me nt wit h p e m br oliz u ma b or sali ne place b o will c o nti n ue u ntil 
t otal of 3 5 treat me nt a d mi nistrati o ns of p e m br oliz u ma b
or sali ne 
place b o 
t hera p y ha ve 
bee n 
a d mi nistere d, d oc u me nte d 
disease 
pr o gressi o n, u nacce pta ble a d verse e ve nt(s), i nterc urre nt ill ness t hat 
pre ve nts f urt her 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 s u bject, s u bject wit h dra ws c o nse nt, pre g na nc y of  the 
s u bject, n o nc o m plia nce 
wit h  t he trial treat me nt or 
pr oce d ure 
re q uire me nts or a d mi nistrati ve reas o ns. S u bjects fr o m C hi na w h o are 
still o n me dicati o n wi ll be u n bli n de d after Ame n d me nt 6 a n d will be 
all o we d t o disc o nti n ue treat me nt wit h sali ne place b o. 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S u bjects w h o e x perie nce d oc u me nte d disease pr o gressi o n verifie d b y 
ce ntral i ma gi n g ve n d or will ha ve treat me nt assi g n me nt u n bli n de d a n d 
be a ble t o c o nti n ue o n o pe n -la bel pe m br oliz u ma b m o n ot hera p y i n t he 
Cr oss o ver P hase. T he details are o utli ne d i n S ecti o n 7. 1. 5. 5 .
S u bjects w h o attai n a c o mplete res p o nse verifie d b y  ce ntral i ma gi n g 
ve n d or a n d ha ve bee n o n p e m br oliz u ma b / t hera p y f or ≥ 8 c ycles, ma y
c o nsi der st o p pi n g trial treat me nt. T hese s u bjects, as we ll as t h ose 
s u bjects assi g ne d t o t he pe m br oliz u ma b ar m that st o p trial t hera p y 
after 3 5 treat me nt a d mi nistrati o ns f or reas o ns ot her t ha n disease 
pr o gressi o n or i nt olera bilit y, ma y be eli gi ble f or re-treat me nt wit h 
pe m br oliz u ma b i n t he Sec o n d 
C o urse 
P hase 
after t he y ha ve 
e x perie nce d ra di o gra p hic disease pr o gressi o n at t he discreti o n of t he 
i n vesti gat or acc or di n g t o t he criteria i n Secti o n 7. 1. 5. 4.
After t he e n d of treat me nt, eac h s u bject will be f oll owe d f or a 
mi ni m u m of 3 0 da ys f or a d verse e ve nt m o nit ori n g e ve n if t he s u bject
starte d ne w a nti ne o plastic treat me nt (seri o us a d verse e ve nts will be 
c ollecte d f or u p t o 9 0 da ys f oll o wi n g cessati o n of S p o ns or’s pr o d uct, 
or 3 0 da ys f oll o wi n g cessati o n of treatme nt if t he s u bject i nitiates ne w 
a ntica ncer t hera p y, w hic he ver is earlier ). S u bjects will ha ve p ost -
treat me nt f oll o w-u p f or disease stat us, i ncl u di n g ra di o gra p hic i ma gi n g 
e ver y 1 2 we e ks, u ntil i nitiati n g a n o n -st u d y ca ncer treat me nt, 
e x perie nci n g disease pr o gressi o n, deat h, wit h dra wi n g 
c o nse nt, or 
bec o mi n g l ost t o f oll o w -u p .
All s u bjects wi ll be f oll o we d f or o verall s ur vi val u ntil deat h , l ost t o 
f oll o w u p or w it h dra wal of c o nse nt.
A list of a b bre viati o ns use d i n t his d oc u me nt ca n be f o u n d i n Secti o n 1 2.4.
2. 0 T RI A L D E SI G N
Tri al Desi g n
T his is a w orl d wi de, ra n d o mize d, place b o -c o ntr olle d
wit h acti ve treat me nt, parallel -gr o u p, 
m ulti -site, d o u ble -bli n d trial of i ntra ve n o us (IV) pe m br oliz u ma b (als o k n o w n as M K -3 4 7 5) 
c o m bi ne d wit h car b o plati n-paclita xel/ na b -paclita xel c he m ot hera p y vers us sali ne place b o 
c o m bi ne d 
wit h 
car b o plati n- paclita xel/ na b-paclita xel
c he m ot herap y  in 
s u bjects 
wit h 
metastatic s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) w h o ha ve n ot pre vi o usl y  recei ve d 
s yste mic thera p y f or  metastatic disease ( 1 L).  
A p pr o xi matel y  5 6 0 eli gi ble s u bjects will be e nr olle d i nt o t his trial t o e xa mi ne t he efficac y of 
pe m br oliz u ma b c o m bi ne d wit h c he m ot hera p y c o m pare d t o c he m ot hera p y al o ne. S u bjects 
w ill be ra n d o mize d 1: 1 as i n dicate d bel o w:
• 
Ar m 1: Pe m br oliz u ma b 2 0 0 m g
( Da y 1) + car b o plati n A U C 6 ( D 1) + paclita xel 2 0 0
m g/ m 2 ( D 1) O R na b -paclita xel 1 0 0 m g/ m 2 ( D 1, D 8, D 1 5)
Q 3 W f or 4 c ycles f oll o we d b y  
pe m br oliz u ma b 2 0 0 m g ( D 1)  Q 3 W u ntil pr o gressi o n.
Ra n d o mizati o n Rati o
Ra n d o mize d 1 : 1 t o eit her recei ve p e m br oliz u ma b c o m bi ne d wit h 
car b o plati n a n d i n vesti gat ors c h oice of paclita xel or na b -paclita xel , or 
sali ne place b o c o mbi ne d wit h car b o plati n a n d i n vesti gat ors c h oice of 
paclita xel or na b -paclita xel .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
•
Ar m 2: Sali ne place b o + car b o plati n A U C 6 ( D 1) + paclita xel 2 0 0 m g/ m 2 ( D 1) O R na b -
paclita xel 1 0 0 m g/ m 2 ( D 1, D 8, D 1 5) Q 3 W f or 4 c y cles f oll o we d b y  sali ne place b o ( D 1) Q 3 W
u ntil pr o gressi o n.
Beca use of p ositi ve res ults o bser ve d at t he i nteri m a nal ysis i n t he C hi na e xte nsi o n, t his st u d y 
will be u n bli n de d s o t hat s u bjects assi g ne d t o t he place b o ar m ( Ar m 2) ma y  disc o nti n ue 
treat me nt wit h n or mal sali ne place b o a n d ha ve t he o p ti o n of recei vi n g pe m br oliz u ma b if 
t here is d oc u me nte d pr o gressi ve disease b y ce ntral ra di ol o gical re vie w. 
S u bjects will recei ve u p t o 4 c ycles of pe m br oliz u ma b or sali ne place b o wit h c he m ot hera p y 
f oll o we d b y pe m br oliz u ma b or sali ne place b o Q 3 w eeks as ma i nte na nce t hera p y. Please refer 
t o Fi g ure 1 f or detaile d st u d y desi g n.
S u bjects will be stratifie d b y  paclita xel vs. na b -paclita xel , P D -L 1  stat us ( T u m or Pr o p orti o n 
Sc ore ( T P S) ≥1 % vs . < 1 %; P D -L 1 i ne val ua ble s u bjects will be i ncl u de d wit h t he T P S < 1 %
gr o u p) a n d g e o gra p hic re gi o n of t he e nr olli n g site ( East Asia vs. n o n- East Asia)
pri or t o 
ra n d o mizati o n. 
After ra n d o mizati o n, su bjects will be e val uate d wit h ra di o gra p hic i ma gi n g t o assess res p o nse 
t o treat me nt wit h t he sc he d ul e o utli ne d i n secti o n 7. 1. 2. 6. 2 ; treat me nt-base d decisi o ns s h o ul d 
be base d o n t he i m m u ne-relate d R E CI S T criteria (ir R E CIS T) ( details are pr o vi de d i n secti o n 
7. 1. 2. 6. 6 a n d t he TI P S heet).  All i ma gi ng o btai ne d o n st u d y  will  be  s u b mitte d  t o  a bli n de d 
i n de pe n de nt ce ntral  ima gi n g ve n d or w h o  will  assess  the  ima ges  usi n g Res p o nse 
E val uati o n Criteria i n S oli d T u m ors ( R E CIS T 1. 1) f or deter mi nati o n of o bjecti ve res p o nse 
rate ( O R R) a n d pr o gressi o n -free s ur vi val ( P F S) b y  RE CI S T 1. 1. A d verse E ve nt ( A E) 
m o nit ori n g will be o n g oi n g t hr o u g h o ut t he trial a n d gra de d i n se verit y acc or di n g t o t he 
g ui deli nes o utli ne d i n t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( C T C A E) ve rsi o n 4. 0. 
Treat me nt wit h pe m br oliz u ma b or sali ne place b o will c o nti n ue u ntil t otal of 3 5 treat me nts 
ha ve bee n a d mi nistere d or s u bject wit h dra wal or disc o nti n uati o n criteria is met as o utli ne d i n 
secti o n 5. 8. 
Treat me nt -base d decisi o ns will be ma de b y  l ocal ra di ol o gical re vie w base d o n i m m u ne-
relate d R E CI S T criteria (ir R E CIS T) a n d t he disease pr o gressi o n will be verifie d b y  ce ntral 
ra di ol o gical re vie w. At 
t he ti me of d oc u me nte d pr o gressi o n verifie d
b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or re vie w per R E CI S T 1. 1, s u bjects will ha ve treat me nt 
assi g n me nt u n bli n de d a n d be a ble t o c o nti n ue t hera p y in t he Cr oss o ver P hase as i n dicate d 
bel o w:
1.
S u bjects w h o ha d recei ve d sali ne place b o will be a ble t o recei ve o pe n -la bel 
pe m br oliz u ma b m o n ot hera p y f or a t otal o f 3 5 treat me nts.
2.
S u bjects w h o
ha d recei ve d pe m br oliz u ma b , b ut are dee me d t o be be nefiti n g 
cli nicall y des pite pr o gressi o n, will be a ble t o recei ve o pe n -la bel pe m br oliz u ma b 
m o n ot hera p y t o c o m plete a t otal of 3 5 treat me nts.
T he details re gar di n g Cr oss o ver P hase is o utli ne d i n secti o n 7. 1. 5. 5.
S u bjects w h o attai n a c o m plete res p o nse ( C R) verifie d b y  ce ntral ra di ol o gical re vie w ma y 
c o nsi der st o p pi n g trial treat me nt. T hese s u bjects, as well as t h ose s u bjects assi g ne d t o t he 
pe m br oliz u ma b ar m t hat st o p trial t hera p y after 3 5 treat me nt a d mi nistrati o ns f or reas o ns 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
ot her t ha n disease pr o gressi o n or i nt olera bilit y, ma y  be eli gi ble f or re-treat me nt wit h o pe n -
la bel pe m br oliz u ma b m o n ot hera p y after t he y ha ve e x perie nce d ra di o gra p hic disease 
pr o gressi o n at t he discreti o n of t he i n vesti gat or acc or di n g t o defi ne d criteria i n Secti o n 
7. 1. 5. 4. T his re-treat me nt will be t he Sec o n d C o urse P hase. Res p o nse or pr o gressi o n i n t he 
Sec o n d C o urse P hase will n ot c o u nt t o war d t he O R R a n d P F S e n d p oi nts i n t his trial.
After t he e n d of treat me nt, eac h s u bject will be f oll o we d f or a mi ni m u m of 3 0 da y s f or A E 
m o nit ori n g. Seri o us a d verse e ve nts ( S A Es) will be c ollecte d f or u p t o 9 0 da y s after t he e n d of 
treat me nt or 3 0 da y s f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w ca ncer 
thera p y, w hic he ver is earlier. S u bjects will ha ve p ost -treat me nt f oll o w-u p f or disease stat us, 
u ntil i nitiati n g a n o n- st u d y ca ncer treat me nt, e x perie nci n g disease pr o gressi o n, deat h, 
wit h dra wi n g c o nse nt, or bec o mi n g l ost t o f oll o w -u p.
T his trial has d ual pr i mar y e n d p oi nts: 1) pr o gressi o n free s ur vi val (P F S ) per R E CI S T 1. 1 b y 
a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or re vie w a n d 2) o verall s ur vi val ( O S). T he trial 
will be c o nsi dere d p ositi ve if h y p ot hesis test f or eit her o ne of t hese pri mar y  en d p oi nts is 
s uccessf ul. Ot her sec o n dar y e n d p oi nts i ncl u de o bjecti ve res p o nse rate (O R R ) a n d res p o nse 
d urati o n ( D O R) per R E CI S T 1. 1 b y  a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or re vie w
a n d safety as assesse d b y  a variet y of para meters of A Es. E x pl orat or y  anal y ses i ncl u de P F S 
b y  in vesti gat or- assesse d ir R E CIS T, O R R b y  in vesti gat or -assesse d ir R E CI S T, P F S, O S a n d 
O R R i n differe nt P D -L 1 s u b gr o u ps a n d P F S, O S a n d O R R i n s u b gr o u ps base d o n t he c h oice 
of ta xa ne t hera p y. Dr u g -dr u g i nteracti o n st u dies a n d q ualit y of life assessme nts are f urt her 
e x pl orat or y e n d p oi nts. 
Partici pati o n i n t his trial will be de pe n de nt u p o n s u p pl yi n g t u m or tiss ue f or P D -L 1 testi n g. 
T he details of t u m or tiss ue re q uire me nts are o utli ne d i n secti o n 7. 1. 2. 7. T he s peci me n will be 
e val uate d at a ce ntral la borat or y  facilit y for e x pressi o n stat us of P D -L 1  in a pr os pecti ve 
ma n ner t o e na ble stratificati o n. I n ter ms of stratificati o n, P D -L 1 n o n- e val ua ble s u bjects wi ll 
be gr o u pe d wit h t he T P S < 1 % gr o u p.
T here are f o ur a nal yses pla n ne d f or t his st u d y: t hree i nteri m a nal ys es a n d t he fi nal a nal ysis. 
Res ults fr o m t he t hree i nteri m a nal yses will be re vie we d b y  an e xter nal data m o nit ori n g 
c o m mittee. T he details re gar di n g t he ti mi n g a n d p ur p ose of eac h a nal ys is are pr o vi de d i n 
Secti o n 8. 7.
E xte nsi o n St u d y i n C hi n a
After the e nr oll me nt peri o d of t he gl o bal st u d y is c o m plete d , s u bjects fr o m C hi na
will 
c o nti n ue t o be e nr olle d i n t he e xte nsi o n st u d y, u ntil t he tar get n u m ber of 1 2 0 C hi nese 
s u bjects is reac he d, t o c ollect a d diti o nal efficac y an d safet y data i n C hi nese s u bjects i n or der 
t o s u p p ort f ut ure l ocal re gistrati o n i n C hi na .  T he e xte nsi o n st u d y will be i de ntical t o t he 
gl o bal st u d y (e. g., i ncl usi o n a n d e xcl usi o n criteria, st u d y en d p oi nts, pri mar y  an d sec o n dar y 
o bjecti ves, st u d y pr oce d ures), wit h t he e xce pti o n of a n a d diti o nal s u p ple me ntal Statistical 
A nal y sis Pla n (sS A P) f or C hi nese s u bjects. T he e xte nsi o n st u d y will be u n bli n de d s o t hat 
s u bjects assi g ne d t o t he place b o ar m ( Ar m 2) ma y disc o nti n ue treat me nt wit h n or mal sali ne 
place b o a n d ha ve t he o pti o n of recei vi n g pe m br oliz u ma b if t here is d oc u me nte d pr o gressi ve 
disease b y ce ntral ra di ol o gical re vie w. 
Details of t he a nal ysis will be pr o vi de d i n a se parate C hi na -s pecific sS A P d oc u me nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S pecific pr oce d ures t o be perf or me d d uri n g t he trial, as well as t heir prescri be d ti mes a n d 
ass ociate d visit wi n d o ws, are o utli ne d i n t he Tri al Fl o w C hart - Secti o n 6 . 0. Details of eac h 
pr oce d ure are pr o vi de d i n Secti o n 7 . 0 – Trial Pr oce d ures.
Tri al Di a gr a m
T he trial desi g n is de picte d i n Fi g ure 1 :
Fi g ure 1 
St u d y  Sc he ma
3. 0 O B J E C TI V E( S) & H Y P O T H E SI S( E S)
Pr i m ar y O bjecti ve(s) & H y p ot hesis(es)
I n 1 L  su bjects wit h metastatic s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g 
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1.
O bjecti ve: E val uate p r o gressi o n free sur vi val ( P F S) per R E CI S T 1. 1 as assesse d b y  a 
ce ntral i ma gi n g ve n d or i n s u bjects treate d wit h p e m br oliz u ma b c o m pare d t o place b o .
H y p ot hesis: Pe m br oliz u ma b pr ol o n gs P F S b y  RE CI S T 1. 1 as assesse d b y a ce ntral 
i ma gi n g ve n d or c o m pare d t o place b o.
2.
O bjecti ve: E val uate o verall sur vi val ( O S) i n s u bjects treate d wit h p e m br oliz u ma b 
c o m pare d t o place b o .
H y p ot hesis: Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o place b o.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Sec o n d ar y O bjecti ve(s) & H y p o t hesis(es)
I n 1 L  su bjects wit h metastatic s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g 
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1.
O bjecti ve: E val uate t he o bjecti ve res p o nse rate ( O R R) a n d d urati o n of res p o nse
( D O R) per R E CI S T 1. 1 as assesse d b y  a ce ntral i ma gi n g ve n d or i n s u bjects treate d 
wit h Pe m br oliz u ma b c o m pare d t o place b o .
H y p ot hesis: Pe m br oliz u ma b i m pr o ves O R R per R E CI S T 1. 1 as assesse d b y  a ce ntral
i ma gi n g ve n d or c o m pare d t o place b o
2.
O bjecti ve: E val uate t he safet y a n d t olera bilit y pr ofile of Pe m br oliz u ma b .
E x pl or at or y O bjecti ves 
I n 1 L  s u bjects wit h metastatic s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g 
i n vesti gat or’s c h oice of sta n dar d of care of c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1)
O b jecti ve: E val uate pe m br oliz u ma b c o m pare d t o place b o wit h res pect t o:
a.
P F S per R E CI S T 1. 1 as assesse d b y  in vesti gat or re vie w i n t he ne xt li ne of 
t hera py ( P F S 2).
b.
P F S per ir R E CI S T as assesse d b y site i n vesti gat or .
c.
O R R a n d D urati o n of Res p o nse (D O R ) per ir R E CIS T as assesse d b y  site 
i n vesti gat or.
d.
P F S a n d O R R per R E CI S T 1. 1 as assesse d b y  ce ntral i ma gi n g ve n d or a n d O S
b y  PD- L 1 stat us (≥1 % vs < 1 % ) a n d b y  ta xa ne (i n vesti gat ors c h oice of 
paclita xel or na b -paclita xel) . 
2)
T o i n vesti gate t he relati o ns hi p bet w ee n pe m br oliz u ma b treat me nt a n d bi o mar kers 
pre dicti n g res p o nse (e. g., P D -L 2 , ge netic variati o n, ser u m s P D-L 1 ) utilizi n g ne wl y 
o btai ne d or arc hi val F F P E t u m or tiss ue a n d bl o o d, i ncl u di n g ser u m a n d plas ma.
3)
T o e val uate c ha n ges i n healt h -relate d q ualit y -of -life assess me nts fr o m baseli ne i n t he 
o verall st u d y po p ulati o n a n d b y  PD- L 1 e x pressi o n le vel usi n g t he E O R T C Q L Q- C 3 0 
a n d E O R T C Q L Q-L C 1 3.
4)
T o c haracterize utilities i n s u bjects treate d wit h pe m br oliz u ma b a n d c he m ot hera p y 
c o m pare d t o sali ne place b o a n d c he m ot her a p y usi n g t he E ur o Q o L( E Q) -5 D.
5)
T o c haracterize t he p har mac o ki netic c haracteristics of car b o plati n, paclita xel/ na b -
paclita xel treat me nt, a n d pe m br oliz u ma b.
6)
T o i de ntif y  m olec ular ( ge n o mic, meta b olic a n d/ or pr ote o mic) bi o mar kers t hat ma y  b e 
i n dicati ve of cli nical res p o nse/resista nce, safety,  phar mac o d y na mic acti vit y, a n d/ or 
t he mec ha nis m of acti o n of pe m br oliz u ma b a n d ot her treat me nts .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
4. 0 B A C K G R O U N D & R A TI O N A L E
B ac k gr o u n d
Refer t o t he I n vesti gat or’s Br oc h ure (I B)/a p pr o ve d la beli n g f or detaile d bac k gr o u n d 
i nf or mati o n o n M K -3 4 7 5 .
P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d
T he i m p orta nce of i ntact i m m u ne s ur veilla nce i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des [ 1]. Acc u m ulati n g e vi de nce s h o ws a c orrelati o n 
bet wee n t u m or-i nfiltrati n g l ym p h oc y tes ( TI Ls) i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n 
vari o us mali g na ncies [ 2] [ 3] [ 4] [ 5] [ 6] [ 7] [ 8]. 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 see ms t o c orrelate wit h 
i m pr o ve d pr o g n osis a n d l o n g -ter m s ur vi val  in  soli d  mali g na ncies suc h  as  ovaria n,  
c ol orectal a n d  pa ncreatic  ca ncer, he pat ocell ular carci n o ma, mali g na nt mela n o ma a n d re nal 
cell carci n o ma ( R C C). TI Ls  ca n be e x pa n de d e x vi v o a n d re-i nf use d, i n d uci n g d ura ble 
o bjecti ve t u m or res p o nses i n ca ncers s uc h as mela n o ma [ 9] [ 1 0].
T he P D -1 rece pt or-li ga n d i nteracti o n is a maj or pat h wa y  hijac ke d b y  tu m ors t o s u p press 
i m m u ne c o ntr ol. T he n or mal f u ncti o n of P D -1, e x presse d o n t he cell s urface of acti vate d T -
cells u n der healt h y c o n diti o ns, is t o d o w n -m o d ulate 
u n wa nte d or e xcessi ve i m m u ne 
res p o nses, i ncl u di n g a ut oi m m u ne reacti o ns. P D -1 (e nc o de d b y  the ge ne P dc d 1) is a n I g 
s u perfa mily me m ber relate d t o C D 2 8 a n d C T L A -4 w hic h has bee n s h o w n t o ne gat i vel y 
re g ulate a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds ( P D-L 1  an d/ or P D -L 2)
[ 1 1] [ 1 2]. T he mec ha nis m b y  whic h P D -1 d o w n m o d ulates T- cell res p o nses is si milar t o, b ut 
disti nct fr o m t hat of C T L A -4 as b ot h m olec ules re g ulate a n o verla p pi n g set of si g nali n g 
pr otei ns [ 1 3] [ 1 4]. P D -1 was s h o w n t o be e x presse d o n acti va te d l ym p h oc y tes i ncl u di n g 
peri p heral C D 4 + a n d C D 8 + T- cells, B- cells, T re gs a n d Nat ural Killer cells [ 1 5] [ 1 6]. T he 
li ga n ds f or P D -1 ( P D-L 1 a n d P D -L 2) are c o nstit uti v el y ex presse d or ca n be i n d uce d i n a 
variet y of cell t ypes, i ncl u di n g n o n -he mat o p oietic tiss ues as well as i n vari o us t u m ors. B ot h 
li ga n ds are t ype I tra ns me m bra ne rece pt ors c o ntai ni n g b ot h I g V- a n d I g C-li ke d o mai ns i n t he 
e xtracell ular re gi o n a n d c o ntai n s h ort c yt o plas mic re gi o ns wit h n o k n o w n si g nali n g m otifs. 
Bi n di n g of eit her P D -1 li ga n d t o P D -1 i n hi bits T- cell acti vati o n tri g gere d t hr o u g h t he T- cell 
rece pt or. P D -L 1 is e x presse d at l o w le vels o n vari o us n o n - he mat o p oietic tiss ues, m ost 
n ota bl y  on vasc ul ar e n d ot heli u m, w hereas P D -L 2 pr otei n is o nl y  detecta bl y ex presse d o n 
a nti ge n -prese nti n g cells f o u n d i n l ym p h oi d tiss ue or c hr o nic i nfla m mat or y en vir o n me nts. 
P D -L 2  is t h o u g ht t o c o ntr ol i m m u ne T- cell acti vati o n i n l ym p h oi d or ga ns, w hereas P D -L 1 
ser ves t o d a m pe n u n warra nte d T- cell f u ncti o n i n peri p heral tiss ues [ 1 7]. Alt h o u g h healt h y 
or ga ns e x press little (if a n y) P D -L 1, a variet y of ca ncers were de m o nstrate d t o e x press 
a b u n da nt le vels of t his T- cell i n hi bit or. Hi g h e x pressi o n of P D -L 1 o n t u m or cells (a n d t o a 
lesser e xte nt of P D -L 2 ) has bee n f o u n d t o c orrelate wit h p o or pr o g n osis a n d s ur vi val i n 
vari o us ca ncer t ypes, i ncl u di n g R C C 1 7 [ 1 8], pa ncreatic carci n o ma [ 1 9], he pat ocell ular 
carci n o ma [ 2 0], a n d o varia n carci n o ma . [ 2 1] F urt her m ore, P D -1 has bee n s u g geste d t o 
re g ulate t u m or-s pecific T- cell e x pa nsi o n i n s u bjects wit h mela n o ma [ 2 2].
P D -1/ P D -L 1  pat h wa y pla ys a critical r ole i n t u m or i m m u ne e vasi o n a n d s h o ul d be 
c o nsi dere d as a n attracti ve tar get f or t hera pe utic i nter ve nti o n. T he pr o g n ostic i m plicati o ns of 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
P D -L 1  ex pressi o n i n N S C L C are c urre ntl y bei n g i n vesti gate d i n o n g oi n g e pi de mi ol o gic 
st u dies as well 
as K E Y N O T E -0 0 1 a n d K E Y N O T E -0 1 0, t he p hase II/III trial of 
pe m br oliz u ma b vs. d oceta xel i n pre vi o usl y  treate d s u bjects wit h a d va nce d or metastati c 
N S C L C.
Pre -cli nic al a n d Cli nic al Tri als
A nti -m o use P D -1 or a nti -m o use P D -L 1 a nti b o dies ha ve de m o nstrate d a nti -t u m or res p o nses 
as a m o n o -t hera p y in m o dels of s q ua m o us cell carci n o ma, pa ncreatic carci n o ma, mela n o ma 
a n d c ol orectal carci n o ma. Bl oc ka de of t he P D -1 pat h wa y  effecti vel y pr o m ote d C D 8 + T- cell 
i nfiltrati o n i nt o t he t u m or a n d t he prese nce of I F N-ga m ma, gra nz y m e B a n d perf ori n, 
i n dicati n g t hat t he mec ha nis m of acti o n i n v ol ve d l ocal i nfiltrati o n a n d acti vati o n of effect or 
T- cell f u ncti o n i n vi v o [ 2 1] [ 2 3] [ 2 4] [ 2 5] [ 2 6] [ 2 7]. I n-h o use e x peri me nts ha ve c o nfir me d 
t he i n vi v o efficac y of P D -1 bl oc ka de as a m o n ot hera p y  as well as i n c o m bi nati o n wit h 
c he m ot hera p y i n s y n ge neic m o use t u m or m o dels (see t he I B).
Pe m br oliz u ma b is a hi g hl y  selecti ve h u ma nize d m o n ocl o nal a nti b o d y  (m A b) t hat bi n ds t o t he 
P D -1 rece pt or a n d directl y bl oc ks t he i nteracti o n bet wee n P D -1 a n d its li ga n ds, t here b y 
e n ha nci n g t u m or re gressi o n a n d ulti matel y  im m u ne rejecti o n (see t he I B).  Pe m br oliz u ma b 
is bei n g i n vesti gate d i n vari o us o nc ol o g y i n dicati o ns i ncl u di n g mela n o ma, N S C LC, re nal cell 
carci n o ma ( R C C), breast ca ncer, m ulti ple m y el o ma ( M M), micr osatellite u nsta ble t u m ors, 
a n d hea d a n d nec k ca ncer.  Pe m br oliz u ma b [ Ke ytr u da ( U S)], is a p pr o ve d f or treat me nt of 
mela n o ma i n se veral c o u ntries; i n t he U S it is i n dicate d f or t he treat me nt of a d va nce d, 
u nresecta ble or metastatic mali g na nt mela n o ma i n s u bjects wit h disease pr o gressi o n after 
pri or treat me nt wit h i pili m u ma b a n d, f or B R A F V 6 0 0 m utati o n -p ositi ve patie nts, a B R A F 
i n hi bit or, w hile i n t he E U it is a p pr o ve d f or t he treat me nt of a d va nce d ( u nresecta ble or 
metastatic) mela n o ma i n a d ults. Pe m br oliz u ma b has als o bee n gra nte d a p pr o val i n t he U S f or 
t he treat me nt of s u bjects wit h metastatic N S C LC w h ose t u m ors e x press P D - L 1 as deter mi ne d 
b y  an F D A -a p pr o ve d test a n d w h o ha ve disease pr o gressi o n o n or after plati n u m -c o ntai ni n g 
c he m ot hera p y.
A n o pe n -la bel p hase 1 trial ( Ke yn ote 0 0 1) is bei n g c o n d ucte d t o e val uate t he safet y an d 
cli nical acti v it y of si n gle a ge nt pe m br oliz u ma b. T he d ose escalati o n p orti o n of t his trial 
e val uate d t hree d ose le vels, 1 m g/ k g, 3 m g/ k g, a n d 1 0 m g/ k g, a d mi nistere d e ver y 2 wee ks, i n 
s u bjects wit h a d va nce d s oli d t u m ors. All 3 d ose le vels were well t olerate d a n d n o d ose -
li miti n g t o xicities ( D LTs) were o bser ve d. Base d o n P K data s h o wi n g a half -life of 2 1 d a y s, 
t he d osi n g fre q ue nc y i n t he e x pa nsi o n c o h ort has bee n c ha n ge d t o e ver y 3 wee ks [ 2 8].
I n t he sa me o pe n -la bel m ulti -c o h ort p hase 1 trial ( K E Y N O T E-0 0 1), a t otal of 5 5 0 N S C L C 
s u bjects were 
treate d i n se veral d ose e x pa nsi o n c o h orts wit h 
at least 1 d ose of 
pe m br oliz u ma b. T he i nitial data fr o m 4 9 5 N S C L C s u bjects were p u blis he d a n d re p orte d. T he 
o bjecti ve res p o nse rate was 1 9. 4 % ( 18. 0 % i n t he 3 9 4 pre vi o usl y treate d s u bjects a n d 2 4. 8 % 
i n t he 1 0 1 pre vi o usl y  untreate d s u bjects). T he res p o nse rate was si milar re gar dless of d ose, 
sc he d ule, a n d hist ol o gic a nalys is. C urre nt or f or mer s m o kers ha d a res p o nse rate of 2 2. 5 %, as 
c o m pare d wit h 1 0. 3 % a m o n g s u bjects w h o ha d ne ver s m o ke d ci garettes.
S u bjects were re q uire d t o s u b mit a ne wl y  obtai ne d t u m or bi o ps y  pri or t o i nitiati n g t hera p y 
wit h pe m br oliz u ma b t o e val uate t he t u m ors f or e x pressi o n of P D -L 1 . After e val uati o n of 
se veral met h o ds 
f or pat h ol o gical assess me nt, i n a trai ni n g set, me m bra n o us 
P D -L 1 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
e x pressi o n i n at least 5 0 % of t u m or cells (t u m or pr o p orti o n sc ore, ≥5 0 %) was selecte d as t he 
c ut off p oi nt defi ni n g P D -L 1  hi gh. I n a vali dati o n set of 3 1 3 s u bjects, t he res p o nse rate was 
4 5. 2 % i n t he 7 3 s u bjects wit h a t u m or pr o p orti o n sc ore of at least 5 0 %, i ncl u di n g 4 3. 9 % i n 
pre vi o usl y  treate d s u bjects a n d 5 0. 0 % i n pre vi o usl y  untreate d s u bjects, val ues t hat 
n u mericall y e xcee de d t he res p o nse rate i n t he trai ni n g gr o u p [ 2 9].
Pe m br oliz u ma b has bee n ge nerall y  well -t olerate d.  The m ost c o m m o n treat me nt relate d 
a d verse e ve nts were fati g ue ( 1 9. 4 %), pr urit us ( 1 0. 7 %), a n d decrease d a p petite ( 1 0. 5 %). 
A d verse e ve nts of gra de 3 or hi g her were re p orte d i n 4 7 of 4 9 5 s u bjects ( 9. 5 %). T he o nl y 
treat me nt-relate d a d verse e ve nts of a n i nfla m mat or y or i m m u ne-me diate d 
nat ure t hat 
occ urre d i n m ore t ha n 2 % of patie nts were i nf usi o n-relate d reacti o ns (i n 1 5 patie nts [ 3. 0 %]), 
h y p ot h y r oi dis m (i n 3 4 patie nts [ 6. 9 %]), a n d p ne u m o nit is (i n 1 8 patie nts [ 3. 6 %]). O ne 
i nf usi o n reacti o n le d t o treat me nt disc o nti n uati o n. All t he patie nts wit h h y p ot h y r oi dis m were 
s uccessf ully treate d wit h me dical t hera p y [ 2 8].
O n g oi n g Cli nic al Tri als
A n u m ber of c li nical trials are e x pl ori n g t he val ue of pe m br oliz u ma b m o n ot hera p y co m pare d 
t o sta n dar d c he m ot hera p y in a P D -L 1 -e nric he d p o p ulati o n, b ot h as sec o n d-li ne t hera p y 
( K E Y N O T E-0 1 0) a n d first-li ne t hera py ( K E Y N O T E-0 2 4 a n d K E Y N O T E -0 4 2) wit h res ults 
e x pecte d i n 2 0 1 5 -2 0 1 6. Pe m br oliz u ma b m o n ot hera p y c o m pare d t o place b o is als o bei n g 
e val uate d i n patie nts wit h earl y sta ge N S C L C after resecti o n a n d c o m pleti o n of sta n dar d 
a dj u va nt t hera p y ( K E Y N O T E-0 9 1).
Se veral o n g oi n g trials are e x pl ori n g differe nt c o m bi nati o ns of pe m br oliz u ma b wit h 
c he m ot hera p y, tar gete d t hera py a n d ot her i m m u n ot hera p y. O n g oi n g
p hase
I b/II st u d y 
( K E Y N O T E-0 2 1)
e x pl ore d differe nt c he m ot hera p y  co m bi nati o ns 
wit h pe m br oliz u ma b ; 
preli mi nar y  data prese nte d at A S C O 2 0 1 5 s u g gest a ma na gea ble t o xicit y pr ofile. I n c o h ort A 
of K E Y N O T E -0 2 1, 2 5 s u bjects wit h N S C L C were treate d wit h 4 c ycles of car b o plati n, 
paclita xel a n d pe m br oliz u ma b f oll o we d b y  mai nte na nce pe m br oliz u ma b e ver y 3 wee ks. 
T here was n o d ose -li miti n g t o xicit y (D L Ts ) a n d n o treat me nt-relate d deat h re p orte d i n c o h ort 
A. A p pr o xi matel y  9 6 % of patie nts e x perie nce d ≥1 treat me nt-relate d A E of a n y gra de wit h 
t he m ost c o m m o n treat me nt-relate d A Es bei n g al o pecia, fati g ue, a n d na usea . O verall, t he 
t o xicit y pr ofile fr o m t he c o m bi nati o n is c o m pati ble wit h w hat w o ul d be e x pecte d fr o m 
c he m ot hera p y al o ne . T he preli mi nar y  data base d o n i n vesti gat or-assesse d r es p o nse rate base d 
o n R E CI S T 1. 1 was 2 5 %
i n all c o mers a n d t he res p o nses were d ura ble. I n the e x pl orat or y 
a nal ys is of 9 s u bjects wit h s q ua m o us cell N S C L C, t he o bjective res p o nse rate was 5 5. 6 % 
( 9 5 % CI : 2 1. 2 -8 6. 3) wit h disease c o ntr ol rate of 1 0 0 %; t he me dia n pr o gressi o n free s ur vi val 
a n d d urati o n of res p o nse is n ot reac he d. Res p o nses were see n i n b ot h P D -L 1  positi ve a n d 
P D -L 1  ne gati ve patie nts. A n o n g oi n g p hase 1 B/ 2 st u d y (K E Y N O T E -0 2 6) is e x pl ori n g t he 
c o m bi nati o n of pe m br oliz u ma b wit h car b o plati n a n d na b -paclita xel. T he preli mi nar y  safet y 
res ults fr o m t his trial s h o we d t hat t he c o m bi nati o n of car b o plati n/ na b -paclita xel a n d 
pe m br oliz u ma b was safe a n d t olera ble a n d t he m ost 
c o m m o n A Es were he mat ol o gic 
t o xicities. T w o o ut of i nitial 1 2 s u bjects treate d o n p hase I p orti o n of t he st u d y ha d d ose 
li miti n g t o xicities ( D L T): o ne gra de 4 h y per gl yc e mia a n d o ne gra de 3 fe brile ne utr o pe nia. 
T he p hase 2 p orti o n of t he st u d y  is o n g oin g.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I nf or m ati o n o n Ot her Tri al-Rel ate d T her a p y
Plati n u m d o u blet c he m ot hera p y is t he sta n dar d of care f or t he treat me nt of patie nts wit h g o o d 
perf or ma nce stat us ( E C O G 0 or 1), a d va nce d or metastatic, pre vi o usl y u ntreate d s q ua m o us 
N S C L C . Treat me nts i ncl u de c is plati n or car b o plati n i n c o m bi nati o n wit h 
paclita xel , 
ge mcita bi ne, or d oceta xel [ 3 0]. M ulti ple p hase III st u dies ha ve de m o nstrate d si milar efficac y 
f or m ost plati n u m d o u blets i n N S C LC patie nts; st u d y  E C O G 1 5 9 4 bei n g t he m ost cite d [ 3 1].
A meta -a nal ys is of ra n d o mize d c o ntr olle d cli nical trials c o m pare d c he m ot hera p y re gi me ns 
c o ntai ni n g eit her cis plati n or car b o plati n i n c o m bi nati o n wit h t hir d ge nerati o n a nti ne o plastic 
a ge nts i ncl u di n g d oceta xel, paclita xel, a n d ge mcita bi ne. Cis plati n c o ntai ni n g re gi me ns were 
ass ociate d wit h a me dia n s ur vi val of 9. 1 m o nt hs a n d a 1- ye ar s ur vi val pr o ba bilit y  of 3 7 %, 
w hile car b o plati n c o ntai ni n g re gi me ns were ass ociate d wit h a me dia n s ur vi val of 8. 4 m o nt hs 
a n d a 1- ye ar s ur vi val pr o ba bilit y  of 3 4 %. T he ris k of deat h was hi g her wit h car b o plati n 
c o m pare d wit h cis plati n, alt h o u g h t he differe nce was n ot statisticall y si g nifica nt ( H R = 1. 0 7, 
9 5 perce nt CI : 0. 9 9 - 1. 1 5, P = . 1 0 0. T hese data s u p p ort t he i nterc ha n gea ble use of 
car b o plati n or cis plati n i n c o m bi nati o n wit h sta n dar d of care a nti ne o plastic a ge nts [ 3 2].
A ra n d o mize d p hase III trial c o m pare d t he efficac y an d safet y of al b u mi n -b o u n d paclita xel 
( na b-paclita xel)
pl us 
car b o plati n 
wit h 
s ol ve nt-base d 
paclita xel 
(s b-paclita xel) 
pl us 
car b o plati n i n a d va nce d N S C L C. A total of 1, 0 5 2 u ntreate d s u bjects wit h sta ge III B t o I V 
N S C L C were ra n d o ml y assi g ne d 1: 1 t o recei ve 1 0 0 m g/ m 2 na b -paclita xel wee kl y  an d 
car b o plati n at A U C of 6 Q 3 W ( na b-paclita xel ) or 2 0 0 m g/ m 2 s b- paclita xel pl us car b o plati n 
A U C 6 Q 3 W (s b- paclita xel ). T he pri mar y  en d p oi nt was o bjecti ve res p o nse rate ( O R R). T he 
O R R i n na b -paclita xel ar m a n d s b-paclita xel ar m were 3 3 % v 2 5 % res pecti vely (res p o nse 
rate rati o, 1. 3 1 3; 9 5 % CI, 1. 0 8 2 t o 1. 5 9 3). In s u bjects wit h s q ua m o us hist ol o g y , t he O R R was 
4 1 % v 2 4 % (res p o nse rate rati o, 1. 6 8 0; 9 5 % CI, 1. 2 7 1 t o 2. 2 2 1 ). H o we ver, t here were n o 
si g nifica nt differe nces i n pr o gressi o n -free s ur vi val ( me dia n, 6. 3 v 5. 8 m o nt hs; hazar d rati o 
[ H R], 0. 9 0 2; 9 5 % CI , 0. 7 6 7 t o 1. 0 6 0; P . 2 1 4) a n d o verall s ur vi val ( O S; me dia n, 1 2. 1 v 1 1. 2 
m o nt hs; H R, 0. 9 2 2; 9 5 % CI , 0. 7 9 7 t o 1. 0 6 6; P . 2 7 1) i n t he na b -P C ar m vers us t he s b-
paclita xel ar m, res pecti vel y. Si g nifica ntl y less gra de -3 n e ur o pat h y, ne utr o pe nia, art hral gia, 
a n d m y al gia occ urre d i n t he na b -paclita xel ar m, a n d less t hr o m b oc yt o pe nia a n d a ne mia 
occ urre d i n t he s b -paclita xel ar m [ 3 3].
Rece ntl y , a n o pe n -la bel, ra n d o mize d, a cti ve c o ntr ol le d p hase II trial e val uate d na b -paclita xel
a n d car b o plati n c o m pare d wit h ge mcita bi ne a n d car b o plati n as first-li ne t hera py i n l ocall y 
a d va nce d or metastatic s q ua m o us cell carci n o ma of l u n g. A t otal of 1 2 0 u ntreate d a d va nce d 
s q ua m o us l u n g ca ncer s u bjects were ra n d o mize d at a 1: 1 rati o t o recei ve na b -paclita xel ( 1 3 5 
m g/ m 2, D 1, D 8, Q 3 W) pl us car b o plati n ( A U C 5, D 1, Q 3 W ) or ge mcita bi ne ( 1, 2 5 0 m g / m2, 
D 1, 8, Q 3 W ) a n d car b o plati n ( A U C 5, D 1, Q 3 W ). T he pri mar y  en d p oi nt was
o bjecti ve 
res p o nse rate a n d t he sec o n d e n d p oi nts were
pr o gressi o n free s ur vi val, o verall s ur vi val,
safety a n d bi o mar kers ass ociate d wit h na b -paclita xel. T he preli mi nar y  res ults fr o m t his trial 
were prese nte d at A S C O 2 0 1 4. T here were 1 1 0 cases e val ua ble f or O R R ( na b-P C, 5 4; G C, 
5 6), 1 1 9 e val ua ble f or s ur vi val ( na b-P C, 5 7; G C, 6 2) a n d 1 2 4 e val ua ble f or safety ( na b-P C, 
5 9; G C, 6 5), res pecti vel y. O R R was 4 6. 3 % ( 2 5/ 5 4) f or t he na b -P C ar m a n d 3 0. 4 % ( 1 7/ 5 6) 
f or t he G C arm res pecti vel y, P = 0. 0 8 5. T he me dia n pr o gressi o n -free s ur vi val was 5. 7 v 4. 8 
m o nt hs
( hazar d rati o [ H R], 0. 9 0 7; 9 5 % CI , 0. 5 8 8 t o 1. 3 9 9; P = 0. 6 5 7) i n t he na b -P C ar m 
vers us t he G C ar m. O verall s ur vi val was n ot mat ure [ 3 4].
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Rece ntl y , a lar ge ra n d o mize d trial e val uate d n ecit u m u ma b, a sec o n d-ge nerati o n, m o n ocl o nal 
a nti b o d y agai nst e pi der mal gr o wt h fact or rece pt or ( E G F R) i n s u bjects wit h pre vi o usl y 
u ntreate d sta ge I V s q u a m o us N S C LC. I n t his st u d y, 1 0 9 3 s u bjects were ra n d o ml y  assi g ne d t o 
recei ve necit u m u ma b pl us ge mcita bi ne a n d cis plati n ( n = 5 4 5) or ge mcita bi ne a n d cis plati n 
( n = 5 4 8). T he O R R was 3 1 % i n necit u m u ma b pl us c he m ot hera p y a n d 2 9 % i n c he m ot hera p y 
al o ne ar ms res pecti vely. T he me dia n P F S was 5. 7 m o nt hs ( 5. 6- 6. 0) a n d 5. 5 m o nt hs ( 4. 8- 5. 6) 
i n necit u m u ma b pl us c he m ot hera p y vs c he m ot her a p y al o ne. H o we ver, 
t here was 
a 
statisticall y si gnifica nt i m pr o ve me nt i n o verall s ur vi val wit h me dia n o verall s ur vi val was
1 1· 5 m o nt hs ( 9 5 % CI  10· 4 – 1 2· 6 ) vs 9· 9 m o nt hs ( 8· 9– 1 1· 1); stratifie d hazar d rati o 0· 8 4 
[ 9 5 % CI 0· 7 4 – 0· 9 6; p = 0· 0 1]). I n the necit u m u ma b pl us ge mcita bi ne a n d cis plati n gr o u p, t he 
n u m ber of s u bjects wit h at least o ne gra de 3 or w orse a d verse e ve nt was hi g her ( 3 8 8 [ 7 2 %] 
of 5 3 8 s u bjects) t ha n i n t he ge mcita bi ne a n d cis plati n gr o u p ( 3 3 3 [ 6 2 %] of 5 4 1), as was t he 
i nci de nce of S A Es ( 2 5 7 [ 4 8 %] of 5 3 8 s u bjects vs 2 0 3 [ 3 8 %] of 5 4 1). M ore
s u bjects i n t he 
necit u m u ma b pl us ge mcita bi ne a n d cis plati n gr o u p ha d G ra de 3 – 4 h y p o ma g nesae mia ( 4 7 
[ 9 %] of 5 3 8 s u bjects i n t he necit u m u ma b pl us ge mcita bi ne a n d cis plati n gr o u p vs si x [ 1 %] of 
5 4 1 i n t he ge mcita bi ne a n d cis plati n gr o u p) a n d G ra de 3 ras h ( 2 0 [ 4 %] vs o ne [ < 1 %]) [ 3 5].
R ati o n ale
R ati o n ale f or t he Tri al a n d Selecte d S u bject P o p ul ati o n
L u n g ca ncer acc o u nte d f or a n esti mate d 1 3 % of t otal ca ncer dia g n oses, re prese nti n g 1. 8 
milli o n ne w cases i n 2 0 1 2. M ortalit y  fr o m l u n g ca ncer i n 2 0 1 2 a m o u nte d t o 1. 6 milli o n 
deat hs gl o ball y:  the lea di n g ca use of ca ncer deat h i n me n a n d t he sec o n d lea di n g ca use i n 
w o me n [ 3 6]. N S C L C acc o u nts f or a p pr o xi matel y 8 5 % of all l u n g ca ncer cases, wit h 2 5 % of 
t hese bei n g s q ua m o us cell N S C LC.
Pr o gress has bee n ma de i n t he cli nical ma na ge me nt of earl y sta ge N S C L C b y  esta blis hi n g 
c o m pre he nsi ve, m ulti -m o dalit y  treat me nt re gi me ns; h o we ver, t he pr o g n osis f or a d va nce d 
disease has n ot i m pr o ve d s u bsta ntiall y. Wit h a n o verall 5- ye ar s ur vi val rate of 9 % t o 1 3 %
[ 3 7]
t he treat me nt of N S C L C 
re mai ns a hi g hl y u n met me dical 
nee d. C y t ot o xic 
c he m ot hera pies as si n gle a g e nts or i n c o m bi nati o n ha ve ser ve d as t he mai nsta y  of treat me nt 
f or deca des wit h plati n u m c o ntai ni n g d o u blets c o nferri n g t he greatest a d va nces i n o verall 
s ur vi val gai ns.  
M olec ular pr ofili n g has, h o we ver, esta blis he d a defi nite r ole f or E G F R a n d A L K direc te d 
t hera py i n a s u bset of n o n -s q ua m o us N S C L C patie nts. T he E G F R t yr osi ne ki nase i n hi bit ors 
gefiti ni b, erl oti ni b a n d afati ni b ha ve de m o nstrate d mar ke d s u peri orit y over c he m ot hera p y i n 
patie nts wit h acti vati n g E G F R m utati o ns. I n ad diti o n, a ge nts w hic h o verc o me resista nce t o 
i nitial t hera p y are als o i n de vel o p me nt. Si milarl y, A L K i n hi bit ors criz oti ni b a n d ceriti ni b 
ha ve s h o w n si g nifica nt acti vit y in A L K -rearra n ge d N S C L C 
wit h 
m ore 
a ge nts i n 
de vel o p me nt. I nteresti n gl y, t he A L K i n hi bit ors are als o acti ve i n a rare s u b gr o u p of R O S -1 
rearra n ge d N S C L C patie nts. H o we ver, t hese m olec ular a berrati o ns are ver y  unc o m m o n i n 
patie nt wit h s q ua m o us cell N S C L C. C urre nt g ui deli nes d o n ot rec o m me n d r o uti ne testi n g f or 
E G F R a n d A L K i n s q ua m o us cell N S C L C patie nts.
C o m pare d t o n o n- s q ua m o us N S C L C, t he first li ne treat me nt o pti o ns f or patie nts wit h 
s q ua m o us cell N S C L C are s o me w hat li mite d. Ne wer a nti -meta b olite s li ke pe metre xe d ha v e
little or n o acti vit y in s q ua m o us cell pati e nts a n d a nti -a n gi o ge nic t hera pies li ke be vaciz u ma b 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
are n o t use d d ue t o t o xicit y co ncer ns i ncl u di n g maj or p ul m o nar y  he m orr ha ge.  A plati n u m 
base d d o u blet wit h eit her a ta xa ne or ge mcita bi ne re mai ns t he mai nsta y  first li ne t hera py f or 
c he m o-naï ve 
a n d rec urre nt patie nts. 
Rece ntl y , necit u m u ma b 
i n c o m bi nati o n wit h 
ge mcita bi ne a n d cis plati n was a p pr o ve d b y  Fo o d a n d Dr u g A d mi nistrati o n ( F D A) base d o n 
t he trial o utli ne d i n secti o n 4. 1. 4. T he a bs ol ute be nefit fr o m a d diti o n of necit u m u ma b t o 
plati n u m d o u blet re mai ns s mall a n d is n ot wi del y use d yet  d ue t o t o xicit y co ncer ns as well as 
t he nee d t o use cis plati n base d t hera p y . Ne wer c he m ot hera p y  c o mbi nati o n o pti o ns wit h better 
efficac y res ults a n d i m pr o ve d safet y an d t olera bilit y outc o me are nee de d i n first li ne t hera py 
f or sta ge I V s q ua m o us cell N S C LC.
T he c urre nt st u d y will i ncl u de patie nts wit h sta ge I V s q ua m o us cell N S C L C as o utli ne d i n 
detail i n t he secti o n 5. 1.
A plati n u m d o u blet wit h a ta xa ne or ge mcita bi ne is t he m ost c o m m o nl y use d first li ne 
t hera py f or c he m o -naï ve metastatic s q ua m o us N S C L C patie nts. Car b o plati n wit h eit her 
paclita xel or na b -paclita xel is o ne of t he acce pte d sta n dar d o pti o ns f or t hese patie nts. Base d 
o n preli mi nar y  safet y a n d efficac y data fr o m c o m bi nati o n st u dies wit h pe m br oliz u ma b a n d 
ot her P D -L 1 i n hi bit ors, t he c urre nt st u d y  will utilize t he car b o plati n a n d i n vesti gat or’s c h oice 
of eit her paclita xel or na b -paclita xel at a p pr o ve d d oses as t he c he m o -bac k b o ne i n b ot h ar m of 
t he st u d y.
R ati o n ale f or D ose Selecti o n/ Re gi me n / M o dific ati o n
T he pla n ne d d ose of pe m br oliz u ma b f or t his trial is 2 0 0 m g e ver y 3 wee ks ( Q 3 W). Base d o n 
t he t otalit y of data ge nerate d i n t he Ke y tr u da de vel o p me nt pr o gra m, 2 0 0 m g Q 3 W is t he 
a p pr o priate d ose of pe m br oliz u ma b acr oss all i n dicati o ns a n d re gar dless of t u m or t ype. As 
o utli ne d bel o w, t his d ose is j ustifie d b y : 
 
C li nical data fr o m ei g ht ra n d o mize d st u dies de m o nstrati n g flat d ose - a n d e x p os ure -
efficac y relati o ns hi ps fr o m 2 m g/ k g Q 3 W t o 1 0 m g/ k g e ver y t w o wee ks (Q 2 W ), 
 
C li nical data s h o wi n g mea ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g o verall 
s ur vi val at 2 0 0 m g Q 3 W acr oss m ulti ple i n dicati o ns, a n d
 
P har mac ol o g y  data s h o wi n g f ull tar get sat urati o n i n b ot h s yste mic circ ulati o n 
(i nferre d fr o m p har mac o ki netic [ P K] data) a n d t u m or (i nferre d fr o m p h y si ol o gically 
base d p har mac o ki netic [ P B P K] a nal y sis) at 2 0 0 m g Q 3 W
A m o n g t he ei g ht 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 s u bjects were e nr olle d 
wit h mela n o ma a n d n o n -s mall cell l u n g ca ncer ( N S C LC), c o veri n g differe nt disease setti n gs 
(treat me nt naï ve, pre vi o usl y  treate d, P D -L 1 e nric he d a n d all -c o mers) a n d differe nt treat me nt 
setti n gs ( m o n ot hera py a n d i n c o m bi nati o n wit h c he m ot hera p y) . T hree st u dies co m pare d 2 
m g/ k g Q 3 W vs. 1 0 m g/ k g Q 2 W ( K N 0 0 1 B 2, K N 0 0 1 D, a n d K N 0 2 1), a n d t hree st u dies 
c o m pare d 1 0 m g / k g Q 3 W vs. 1 0 m g/ k g Q 2 W ( K N 0 0 1 B 3, K N 0 0 1 F 2 , a n d K N 0 0 6). All of 
t hese st u dies de m o nstrate d flat d ose - a n d e x p os ure -res p o nse relati o ns hi ps acr oss t he d oses
st u die d re prese nti n g a n a p pr o xi mate 5 t o 7. 5 f ol d differe nce i n e x p os ure. T he 2 m g/ k g ( or 
2 0 0 m g 
fi xe d-d ose) Q 3 W 
pr o vi de d si milar res p o nses t o t he hi g hest d oses st u die d. 
S u bse q ue ntl y , flat d ose -/e x p os ure-res p o nse relati o ns hi ps were als o o bser ve d i n ot her t u m or 
t ypes 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. 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T hese fi n di n gs are c o nsiste nt wit h t he mec ha nis m of acti o n of pe m br oliz u ma b, w hic h acts b y 
i nteracti o n wit h i m m u ne cells, a n d n ot via direct bi n di n g t o ca ncer cells.
A d diti o nall y , p har mac ol o g y  data clearl y s h o w tar get sat urati o n at 2 0 0 m g  Q3 W. F irst, P K 
data 
i n K N 0 0 1 
e val uati n g
tar get-me diate d 
dr u g 
dis p ositi o n 
( T M D D) c o ncl usi v el y 
de m o nstrate d sat urati o n of P D -1 i n s yste mic circ ulati o n at d oses m uc h l o wer t ha n 2 0 0 m g  
Q 3 W. Sec o n dl y , a P B P K a nal ys is was c o n d ucte d t o pre dict t u m or P D -1 sat urati o n o ver a 
wi de ra n ge of t u m or pe netrati o n a n d P D -1 e x pressi o n. T his e val uati o n c o ncl u de d t hat 
pe m br oliz u ma b at 2 0 0 m g Q 3 W ac hie ves f ull P D -1 sat urati o n i n b ot h bl o o d a n d t u m or.
Fi nall y , p o p ulati o n P K a nal ys is of pe m br oliz u ma b, w hic h c haracterize d t he i nfl ue nce of 
b o d y  wei g ht a n d ot her s u bject c o variates o n e x p os ure, has s h o w n t hat t he fi xe d-d o si 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  these P K c haracteristics, a n d gi ve n t hat fi xe d-d ose has a d v a nta ges of re d uce d 
d osi n g c o m ple xit y an d re d uce d p ote ntial of d osi n g err ors, t he 2 0 0 m g  Q3 W fi xe d-d ose was 
selecte d f or e val uati o n acr oss all pe m br olizu ma b pr ot oc ols.
4. 2. 2. 1
R ati o n ale f or the U se o f Pl ace b o
T he use of sali ne place b o i n c o m bi nati o n wit h sta n dar d c he m ot hera p y will e ns ure t he 
o bjecti vit y  
of 
i n vesti gat or-assesse d 
pr o gressi o n 
as 
well  
as 
a n y 
decisi o ns 
t o 
i nterr u pt/ disc o nti n ue t hera py. Si nce ra n d o mizati o n a n d place b o use ca n be a percei ve d 
barrier to s u bject e nr oll me nt, cr oss o ver is all o we d at ti me of d oc u me nte d disease 
pr o gressi o n . D ue t o p ositi ve res ults fr o m t he i nteri m a nal ysis i n t he C hi na e xte nsi o n, s u bjects 
w h o are still o n st u d y me dicati o n will be all o we d t o be u n bli n de d , a n d s u bjects in t he sali ne 
place b o ar m will be all o we d t o disc o nti n ue sali ne place b o treat me nt after A me n d me nt 6.
R ati o n ale f or E n d p oi nts
4. 2. 3. 1
Effic ac y E n d p oi nts
Pri mar y : T his trial has d ual pri mar y  en d p oi nts of P F S a n d O S. T he trials will be c o nsi dere d 
p ositi ve if h y p ot hesis test f or eit her o ne of t hese pri mar y e n d p oi nts is s uccessf ul. 
P F S is a n acce pta ble meas ure of cli nical be nefit f or a ra n d o mize d p hase III trial t hat 
de m o nstrates s u peri ority of a ne w a nti ne o plastic t hera py, es peciall y if t he ma g nit u de of 
effect is lar ge a n d t he t hera py has a n acce pta ble ris k-be nefit pr ofile. F urt her m ore, it is a n 
e n d orse d re g ulat or y en d p oi nt f or first-li ne N S C L C trials wit h rece nt F D A a n d E M A 
a p pr o vals i ncl u di n g t he E G F R i n hi bit ors afati ni b a n d erl oti ni b. P F S will be assesse d pe r 
R E CI S T 1. 1 b y  a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or t hat will be bli n de d t o t he 
treat me nt assi g n me nt t o mi ni mize a n y bias i n t he res p o nse assess me nts.  In a d diti o n, fi nal 
deter mi nati o n of ra di ol o gic pr o gressi ve disease ( P D) will 
be base d o n t he bl i n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or assess me nt of pr o gressi o n, rat her t ha n l ocal site 
i n vesti gat or/ra di ol o g y assess me nt.  Ex pe dite d assess me nt b y  the bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or i n i nsta nces of s us pecte d ra di ol o gical pr o gressi o n i de ntif ie d at t he site 
( verificati o n of P D) will be c o m m u nicate d t o t he st u d y tea m. T he cr oss o ver ar m as well as 
t he ap pr o val of ni v ol u ma b a n d pe m b roliz u ma b i n t he sec o n d li ne setti n g will ma ke s u bject 
cr oss o ver t o a P D -1/ P D -L 1  age nt fr o m t he c o ntr ol gr o u p al m os t certai n a n d ma y  ma ke it 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
c halle n gi n g t he abilit y  to meas ure o verall s ur vi val relia bl y. H o we ver, t he o verall s ur vi val is 
a n i m p orta nt e n d p oi nt i n t he treat me nt of metastatic N S C L C a n d t his trial will e val uate b ot h 
P F S a n d O S as d ual pri mar y  e n d p oi nts as o utli ne d i n detail i n Secti o n 8. 0 Statistical A nal y sis 
Pla n . 
Sec o n dar y : O R R b y  RE CI S T 1. 1 criteria as assesse d b y  bli n de d i n de pe n de nt ce ntral 
ra di ol o g y re vie w a n d t he d urati o n of res p o nse b y  RE CI S T 1. 1 as assesse d b y  bli n de d ce ntral 
ra di ol o gists’ re vie w wil l ser ve as a d diti o nal meas ures of effica c y. I n a rece nt e x pl orat or y 
a nal ys is of best R E CIS T res p o nse a n d s ur vi val i n patie nts wit h metastatic s q ua m o us N S C L C 
treate d wit h a P D-1 i n hi bit or, t here was c orrelati o n bet wee n res p o nse a n d o verall s ur vi val.
4. 2. 3. 2
I m m u ne-rel ate d R E CI S T (ir R E CI S T)
R E CI S T 1. 1 will be a da pte d t o acc o u nt f or t he u ni q ue t u m or res p o nse c haracteristics see n 
wit h treat me nt of pe m br oliz u ma b.  Im m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b ma y 
pr o d uce a ntit u m or effects b y  pote ntiati n g e n d o ge n o us ca ncer-s pecific i m m u ne res p o nses.  
T he res p o nse patter ns see n wit h s uc h a n a p pr oac h ma y  e xte n d be yo n d t he t y pical ti me c o urse 
of res p o nses see m wit h c yt ot o xic a ge nts, a n d ca n ma nifest a cli nical res p o nse after a n i nitial 
i ncrease i n t u m or b ur de n or e ven t he a p peara nce of ne w lesi o ns.
Sta n dar d R E CI S T 1. 1 ma y , t h us, n ot pr o vi de a c o m plete 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 ysis of patie 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 s u bjects e x perie nce d dela y e d or 
earl y t u m or pse u d o -pr o gressi o n.  Of n ote, s u bjects w h o ha d pr o gressi ve disease b y  RE CI S T 
1. 1 b ut n ot b y  im m u ne -relate d Res p o nse Criteria ha d l o n ger O S t ha n s u bjects wit h 
pr o gressi ve disease b y  bot h criteria.  Ad diti o nall y , t he data su g gest t hat R E CI S 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 15 % of s u bjects.  These 
fi n di n gs s u p p ort t he nee d t o a p pl y a mo dificati o n t o R E CI S T 1. 1 t hat ta kes i nt o acc o u nt t he 
u ni q ue patter ns of at y pical res p o nse i n i m m u n ot hera py a n d e na ble treat me nt b e y o n d i nitial 
ra di o gra p hic pr o gressi o n. H o we ver, it is n ot clear w het her t he sa me patter n will be o bser ve d 
i n c o m bi nati o n wit h c he m ot hera p y, he nce R E CI S T 1. 1 will re mai n t he pri mar y  assess me nt 
met h o d.
I m m u ne-relate d R E CIS T (ir R E CI S T) is R E CIS T 1. 1 a da pte d t o acc o u nt f or t he u ni q ue t u m or 
res p o nse see n wit h 
i m m u ne-t hera pe utics as descri be d i n [ 3 8]. T he 
assess me nt of 
u ni di me nsi o nal tar get lesi o ns a n d res p o nse cate g ories per ir R E CIS T are i de ntical t o R E CI S T 
1. 1.  Ho we ver, Merc k has i m ple me nte d a n a da ptati o n relate d t o ne w lesi o ns, n o n -tar get a n d 
t u m or b ur de n assess me nt i n or der t o c o nfir m ra di o gra p hic pr o gressi o n.  ir R E CIS T will be 
use d b y  l ocal site i n vesti gat ors t o assess t u m or res p o nse a n d pro gressi o n, a n d ma ke treat me nt 
decisi o ns.   ( See Secti o n 7. 1. 2. 6. 6 f or details)
4. 2. 3. 3
P atie nt Re p orte d O utc o mes
E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q L C 1 3
T he E O R T C Q L Q -C 3 0 was de vel o pe d t o assess t he q ualit y  of life of ca ncer s u bjects a n d is 
t he m ost wi del y use d ca ncer -s pecific H R Q o L i nstr u me nt.  It co ntai ns 3 0 ite ms a n d meas ures 
fi ve f u ncti o nal di me nsi o ns ( p h ysical, r ole, e m oti o nal, c o g niti ve, a n d s ocial), t hree s ym pt o m 
ite ms (fati g ue, na usea/ v o miti n g, a n d pai n), si x si n gle ite ms ( d ys p nea, slee p dist ur ba nce, 
a p petite l oss, c o nsti pati o n, diarr hea, a n d fi na ncial i m pact) a n d gl o bal healt h a n d q ualit y  of 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
life.  The gl o bal healt h a n d q ualit y  of life scale uses a 7 p oi nt scale sc ori n g wit h a nc h ors 
( 1 = ver y p o or a n d 7 =e xcelle nt); t he ot her ite ms are sc ore d o n a 4 p oi nt scale ( 1 = n ot at all, 2 =a 
little, 3 = q uite a bit, 4 = ver y m uc h).
T he E O R T C Q L Q -L C 1 3, a s u p ple me ntal l u n g ca ncer -s pecific m o d ule use d i n c o m bi nati o n 
wit h Q L Q -C 3 0, c o m prises m ulti -ite m a n d si n gle-ite m meas ures of l u n g ca ncer -ass ociate d 
s ym pt o ms 
(c o u g h, he m o pt y sis, d y s p nea, a n d site s pecific pai n) a n d treat me nt-relate d 
s ym pt o ms (s ore m o ut h, d y s p ha gia, peri p heral ne ur o pat h y an d al o pecia) [ 3 9]. It is sc ore d o n a 
4 p oi nt scale ( 1 = n ot at all, 2 =a little, 3 = q uite a bit, 4 = ver y m uc h) a n d has bee n tra nslate d a n d 
vali date d i nt o m ore t ha n 6 0 la n g ua ges.
T he E O R T C Q L Q -C 3 0 a n d Q L Q -L C 1 3 are t he m ost fre q ue ntl y  utilize d a n d re p orte d patie nt-
re p orte d o utc o me meas ures 
i n l u n g ca ncer cli nical trials. T he relia bilit y, vali dit y a n d 
practicalit y of t hese i nstr u me nts ha ve bee n re p orte d [ 3 9] [ 4 0].
E ur o Q ol ( E Q) -5 D
T he E ur o Q ol- 5 D ( E Q-5 D ) is a sta n dar dize d i nstr u me nt f or use as a meas ure of healt h 
o utc o me.  The E Q -5 D will pr o vi de data f or use i n ec o n o mic m o dels a n d a nal ys es i ncl u di n g 
de vel o pi n g healt h utilities or Q A L Ys.  The fi ve healt h state di me nsi o ns i n t his i nstr u me nt 
i ncl u de t he f oll o wi n g: m o bilit y , 
self-care, 
us ual 
acti vities, 
pai n/ disc o mf ort, 
a n d 
a n xiet y/ de pressi o n.  Eac h di me nsi o n is rate d o n a t hree p oi nt scale fr o m 1 (e xtre me pr o ble m) 
t o 3 ( n o pr o ble m).  The 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 s u bject rates his or her ge neral state of healt h at t he ti me of t he as sess me nt.  T he 
E Q - 5 D will al wa ys be c o m plete d b y  su bjects first bef ore c o m pleti n g t he E O R T C Q L Q- C 3 0 
a n d E O R T C Q L Q-L C 1 3.
4. 2. 3. 4
S afet y E n d p oi nts
T he safety o bjecti ve of t his st u d y is t o c haracterize t he safety a n d t olera bilit y of 
pe m br oliz u ma b
i n c o m bi nati o n 
wit h 
car b o plati n 
a n d 
paclita xel 
or 
na b -paclita xel 
c he m ot hera p y i n s u bjects n ot pre vi o usl y  sys te micall y treate d f or s q ua m o us N S C L C.  The 
safety a nal ysis will be base d o n s u bjects w h o ha ve t o xicities as defi ne d b y C T C A E v 4. 0.  
T he attri b uti o n t o dr u g, ti me-of -o n set, d urati o n of t he e ve nt, its res ol uti o n, a n d a n y 
c o nc o mita nt me dicati o ns a d mi nistere d will be rec or de d.  AEs will be a nal y ze 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 cha n ges.  Furt her m ore, s pecific 
e ve nts will be c ollecte d a n d desi g nate d as e ve nts of cli nical i nterest ( E CIs) as descri be d i n 
Secti o n 7. 2. 3. 2.
T he ma n dat or y  Safet y F oll o w -u p Visit s h o ul d be c o n d ucte d a p pr o xi matel y 30 d a y s after t he 
last d ose of st u d y treat me nt or bef ore t he i nitiati o n of ne w a nti -ne o plastic treat me nt, 
w hic he ver occ urs first.  All A Es t hat occ ur pri or t o t he Safet y F oll o w -u p Visit s h o ul d be 
rec or de d.  S u bjects wit h a n A E of Gra de > 1 will be f oll o we d u ntil t he res ol uti o n of t he A E t o 
Gra de 0- 1 or u ntil t he be gi n ni n g of a ne w a nti -ne o plastic t herap y , w hic he ver occ urs first.  
S A Es t hat occ ur wit hi n 9 0 d a y s f oll o wi n g cessati o n of treat me nt or 3 0 d a y s f oll o wi n g 
cessati o n of treat me nt if t he s u bject i nitiate d ne w a nti -ne o plastic t hera p y, w hic he ver is 
earlier, s h o ul d be f oll o we d a n d rec or de d. 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
2 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
4. 2. 3. 5
Pl a n ne d E x pl or at or y Bi o m ar ker Rese arc h
I ntr o d ucti o n: Ca ncer i m m u n ot hera pies re prese nt a n i m p orta nt a n d n o vel class of a nti-t u m or 
a ge nts.  Ho we ver, t he mec ha nis m of acti o n of t hese e xciti n g ne w t hera pies is n ot c o m pletel y 
u n derst o o d a n d m uc h re mai ns t o be lear ne d regar di n g h o w best t o le vera ge t hese ne w dr u gs 
i n treati n g patie nts. T h us, t o ai d f ut ure patie nts, it is i m p orta nt t o i n vesti gate t he deter mi na nts 
of res p o nse or resista nce t o ca ncer i m m u n ot hera p y as well as de ter mi na nts of a d verse e ve nts 
i n 
t he 
c o urse 
of 
o ur 
cli nical 
trials. 
T hese  
eff orts 
will  
i de ntif y 
no vel 
pre dicti ve/ p har mac o d y na mic bi o mar kers a n d ge nerate i nf or mati o n t hat will better g ui de 
si n gle-a ge nt a n d c o m bi nati o n t hera p y wit h i m m u n o-o nc ol o g y  dr u gs. T o i de ntif y no vel 
bi o mar kers, we will c o llect bi os peci me ns ( bl o o d c o m p o ne nts, t u m or material, etc.) t o s u p p ort 
a nal ys es of cell ular c o m p o ne nts (e. g., pr otei n, D N A, R N A, meta b olites) a n d ot her circ ulati n g 
m olec ules.   I n vesti gati o ns ma y  i ncl u de b ut are n ot li mite d t o:
Ger mli ne ( bl o o d) ge netic a nal yses (e.g., S N P a nal yses, w h ole e x o me se q ue nci n g, w h ole 
ge n o me se q ue nci n g):   T his researc h will e val uate w het her ge netic variati o n wit hi n a cli nical 
trial p o p ulati o n c orrelates wit h res p o nse t o t he treat me nt(s) u n der e val uati o n. If ge netic 
variati o n is f o u n d t o pre dict efficac y or a d verse e ve nts, t he data mi g ht i nf or m o pti mal use of 
t hera pies i n t he patie nt p o p ulati o n. F urt her m ore, it is i m p orta nt t o e val uate ger mli ne D N A 
variati o n acr oss t he ge n o me i n or der t o i nter pret t u m or-s pecific D N A m utati o ns . Fi na ll y, 
micr osatellite i nsta bilit y (M SI ) m a y  be e val uate d as t his is a n i m p orta nt bi o mar ker f or s o me 
ca ncers (i .e., c ol orectal ca ncer).
Ge netic ( D N A) anal y ses fr o m t u m or:  The a p plicati o n of ne w tec h n ol o gies, s uc h as ne xt 
ge nerati o n se q ue nci n g, has pr o vi de d scie ntists t he o p p ort u nit y  to i de ntif y tu m or -s pecific 
D N A 
c ha n ges (i.e., m utati o ns, 
met h y lati o n stat us, micr osatellite 
i nsta bilit y etc.). K e y  
m olec ular c ha n ges of i nterest t o i m m u ne-o nc ol o g y  dr u g de vel o p me nt i ncl u de (f or e xa m ple) 
t he m utati o nal b ur de n of t um ors a n d t he cl o nalit y of T- cells i n t he t u m or micr oe n vir o n me nt. 
I ncrease d m utati o nal b ur de n (s o meti mes referre d t o as a ‘ h yper -m utate d’ state) ma y  ge nerate 
ne o -a nti ge n prese ntati o n i n t he t u m or micr oe n vir o n me nt.  T o c o n d uct t his t y pe of researc h, it 
is i mp orta nt t o i de ntif y tu m or -s pecific m utati o ns t hat occ ur acr oss all ge nes i n t he t u m or 
ge n o me.  Th us, ge n o me wi de a p pr oac hes m a y  be use d f or t his eff ort. N ote t hat i n or der t o 
u n dersta n d t u m or-s pecific m utati o ns; it is necessar y  to c o m pare t he t u m or ge n o me wit h t he 
ger mli ne ge n o me.  
Micr osatellite i nsta bilit y (M SI ) m a y  als o be e val uate d as t his is a n 
i m p orta nt bi o mar ker f or s o me ca ncers (i.e., c ol orectal ca ncer).
T u m or a n d bl o o d R N A a nal yses: B ot h ge n o me -wi de a n d tar gete d messe n ger R N A ( m R N A) 
e x pressi o n pr of ili n g a n d se q ue nci n g i n t u m or tiss ue a n d i n bl o o d ma y be perf or me d t o defi ne 
ge ne si g nat ures t hat c orrelate t o cli nical res p o nse t o treat me nt wit h pe m br oliz u ma b or ot her 
i m m u n ot hera pies. Pe m br oliz u ma b i n d uces a res p o nse i n t u m ors t hat li kel y reflects a n 
infla me d/ i m m u ne p he n ot y pe. S pecific i m m u ne-relate d ge ne sets (s uc h as t h ose ca pt uri n g 
i nterfer o n-ga m ma tra nscri pti o nal pat h wa y s) ma y be e val uate d a n d ne w si g nat ures ma y  be 
i de ntifie d.   In di vi d ual ge nes relate d t o t he i m m u ne s yste m m a y  als o be e val uate d (e. g., I L-
1 0).  Micr o R N A pr ofili n g ma y  als o be p urs ue d.
Pr ote o mics a n d i m m u n o hist oc he mistr y (I H C) usi n g bl o o d or tu m or :  Tu m or a n d bl o o d 
sa m ples fr o m t his st u d y ma y un der g o pr ote o mic a nal ys es (e.g., P D -L 1  IH C).  P D -L 1 pr otei n 
le vel i n t u m or secti o ns, assesse d b y  IH C , has bee n s h o w n t o c orrelate wit h res p o nse t o 
pe m br oliz u ma b i n patie nts wit h N S C L C, a n d a n I V D de vice has bee n de vel o pe d f or use wit h 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
pe m br oliz u ma b i n N S C L C.   Preli mi nar y  data i n dicates t hat t his ass ociati o n ma y als o be tr ue
i n a d diti o nal ca ncer t ypes (ie, T N B C, H & N a n d gastric). A d diti o nal t u m or or bl o o d -deri ve d 
pr otei ns ma y  als o c orrelate wit h res p o nse t o pe m br oliz u ma b.  T heref ore, t u m or tiss ue ma y  be 
s u bjecte d t o pr ote o mic a nal yses usi n g a variet y of platf or ms t hat c o ul d i ncl u de b ut ar e n ot 
li mite d t o i m m u n oassa ys, li q ui d c hr o mat o gra p h y/ mass s pectr o metr y.  This a p pr oac h c o ul d 
i de ntif y n o vel pr otei n bi o mar kers t hat c o ul d ai d i n patie nt selecti o n f or pe m br oliz u ma b ( M K-
3 4 7 5) t hera p y.
Ot her bl o o d deri ve d bi o mar kers: 
I n a d diti o n t o e x pressi o n o n t he t u m or tiss ue, P D -L 1 a n d ot her t u m or deri ve d pr otei ns ca n be 
s he d fr o m t u m or a n d release d i nt o t he bl o o d.  Assa ys s uc h as e nz ym e -li n ke d i m m u n oassa y 
meas ure s uc h pr otei ns i n ser u m. C orrelati o n of e x pressi o n wit h res p o nse t o pe m br oliz u ma b 
t hera py ma y i de ntif y ne w a p pr oac hes f or pre dicti ve bi o mar kers i n bl o o d, re prese nti n g a 
maj or a d va nce fr o m t o da y’s relia nce o n assessi n g t u m or bi o mar kers.  This researc h w o ul d 
ser ve t o de vel o p s uc h assa ys f or f ut ure cli nical use.
4. 2. 3. 6
F ut ure Bi o me dic al Rese arc h
T he S p o ns o r will c o n d uct F ut ure Bi o me dical Researc h o n s peci me ns c ollecte d f or f ut ure 
bi o me dical researc h d uri n g t his cli nical trial.  This researc h m a y  incl u de ge netic a nal ys es 
( D N A), ge ne e x pressi o n pr ofili n g ( R N A), pr ote o mics, meta b ol o mics (ser u m, plas ma) a n d/ or 
t he meas ure me nt of ot her a nalyt es.
S uc h researc h is f or bi o mar ker testi n g t o a d dress e mer ge nt q uesti o ns n ot descri be d else w here 
i n t he pr ot oc ol (as part of t he mai n trial) a n d will o nl y  be c o n d ucte d o n s peci me ns fr o m 
a p pr o priatel y c o nse nte d s u bjects. T he 
o bjecti ve of c ollecti n g s peci me ns f or F ut ure 
Bi o me dical Researc h is t o e x pl ore a n d i de ntif y bi o mar kers t hat i nf or m t he scie ntific 
u n dersta n di n g of diseases a n d/ or t heir t hera pe utic treat me nts. T he o verarc hi n g g oal is t o use 
s uc h i nf or mati o n t o de vel o p safer, m ore effecti ve dr u gs / vacci nes, a n d/ or t o e ns ure t hat 
s u bjects recei ve t he c orrect d ose of t he c orrect dr u g / vacci ne at t he c orrect ti me.  The details 
of t his F ut ure Bi o me dical Researc h s u b-trial are prese nte d i n Secti o n 1 2. 2 - C ollecti o n a n d 
Ma na ge me nt 
of S peci me ns f or F ut ure Bi o me dical Researc h.  Ad diti o nal i nf or mati o nal 
material f or i nstit uti o nal re vie w b oar ds/et hics c o m mittees (IR Bs/ E R Cs) a n d i n vesti gati o nal 
site staff is pr o vi de d i n Secti o n 1 2. 3.
Be nefit/ Ris k
S u bjects i n cli nical trials ge nerall y  ca n n ot e x pect t o recei ve direct be nefit fr o m 
treat me nt/ vacci nati o n d uri n g partici pati o n, as cli nical trials are desi g ne d t o pr o vi de 
i nf or mati o n a b o ut t he safet y a n d effecti ve ness of a n i n vesti gati o nal me dici ne.
As descri be d i n Secti o n 4. 1. 2. a n d 4. 1. 3 ( preli mi nar y) st u d y res ults s h o w t hat pe m br oliz u ma b
i n c o m bi nati o n wit h c he m ot hera py ha ve si g nifica nt cli nical acti vit y as t he first li ne t hera p y i n 
patie nts wit h a d va nce d N S C L C . C o nsi deri n g t he hi g h u n met me dical nee d f or ne w a n d 
t olera ble treat me nt o pti o ns i n patie nts wit h sta ge I V s q ua m o us N S C L C , t he a nti-t u m or 
acti vit y a n d t he fa v ora ble safety p r ofiles, t he e xisti n g data s u g gests t hat a c o m bi nati o n of P D-
1 bl oc ka de wit h c he m ot hera p y is a pr o misi n g t hera pe utic strate g y an d t he be nefit ris k 
assess me nt f or pat ie nts i ncl u de d i nt o t his trial is c o nsi dere d t o be fa v ora ble.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A d diti o nal details re gar di n g s pecific be nefits a n d ris ks f or s u bjects partici pati n g i n t his 
cli nical trial ma y  be f o u n d i n t he acc o m pa n yi n g I nvesti gat ors Br oc h ure (I B) a n d I nf or me d 
C o nse nt d oc u m e nts.
5. 0 M E T H O D O L O G Y
E ntr y Criteri a
Di a g n osis/ C o n diti o n f or E ntr y i nt o t he Tri al
Male/ Fe male 
s u bjects wit h 
s q ua m o us N S C L C 
w h o 
ha ve n ot recei ve d pri or s yste mic 
c he m ot hera p y treat me nt f or t heir metastatic N S C L C, w h o are at least 1 8 ye ars of a ge , will 
be e nr olle d i n t his trial.
S u bject I ncl usi o n Criteri a
I n or der t o be eli gi ble f or partici pati o n i n t his trial, t he s u bject m ust:
1.
Ha ve a hist ol o gicall y  or c yt ol o gicall y c o nfir me d dia g n osis of sta ge I V ( M 1a or M 1 b -
AJ C C 7t h e diti o n) s q ua m o us N S C L C.
Patie nts wit h mi xe d 
hist ol o g y (e xa m ple 
a de n os q ua m o us) are all o we d if t here is s q ua m o us c o m p o ne nt i n t he s peci me n.
2.
Ha ve meas ura ble disease base d o n R E CI S T 1. 1 as deter mi ne d b y  the l ocal site 
i n vesti gat or/ra di ol o g y assess me nt.  Tar get lesi o ns sit uate d i n a pre v i 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 .
3.
Ha ve n ot recei ve d pri or s y ste mic treat me nt f or t heir metastatic N S C LC. S u bjects w h o 
recei ve d a dj u va nt or ne oa dj u va nt t hera py are eli gi ble if t he a dj u va nt / ne oa dj u va nt 
t hera py was c o m plete d at least 1 2 m o nt hs pri or t o t he de vel o p me nt of metastatic 
disease.
4.
Ha ve pr o vi de d t u m or tiss ue fr o m l ocati o ns n ot ra diate d pri or t o bi o ps y ; f or mali n-
fi xe d s peci me ns after t he s u bject has bee n dia g n ose d wit h metastatic dise ase will be 
preferre d f or deter mi nati o n of P D -L 1 stat us pri or t o ra n d o mizati o n. Bi o psies o btai ne d 
pri or t o recei pt of a dj u va nt/ ne oa dj u va nt c he m ot hera p y will be per mitte d if rece nt 
bi o ps y  is n ot feasi ble.
5.
Be ≥1 8 y ears of a ge o n da y of si g ni n g i nf or me d c o nsent.
6.
Ha ve a life e x pecta nc y  of at least 3 m o nt hs.
7.
Ha ve a perf or ma nce stat us of 0 or 1 o n t he Easter n C o o perati ve O nc ol o g y  Gr o u p 
( E C O G) Perf or ma nce Stat us.
8.
Ha ve a de q uate or ga n f u ncti o n as i n dicate d b y  t he f oll o wi n g la b orat or y val ues (Ta ble 1 ):
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 1 
A de q uate Or ga n F u ncti o n L a b orat or y Val ues
S yste m
L a b or at or y V al ue
H e m at ol o gic al
A bs ol ute ne utr o p hil c o u nt ( A N C)
≥1, 5 0 0 / mc L
Platelets
≥1 0 0, 0 0 0 / mc L
He m o gl o bi n
≥9 . 0 g/ d L or ≥5. 6 m m ol/ L – 4 wee ks wit h o ut tra nsf usi o ns
Re n al
Creati ni ne  O R
calc ulate d creati ni ne cleara nce ( Cr Cl) a
( G F R ca n als o be use d i n place of 
creati ni ne or Cr Cl)
≤1. 5 X u p per li mit of n or mal ( U L N) O R
≥6 0 m L/ mi n f or s u bjects wit h creati ni ne le vels > 1. 5 X 
i nstit uti o nal U L N
He p atic
Ser u m t otal bilir u bi n
≤1. 5 x U L N O R
Direct bilir u bi n ≤U L N f or s u bjects w it h t otal bilir u bi n le vels 
> 1. 5 x U L N
A S T ( S G O T) a n d A L T ( S G P T)
≤2. 5 x U L N  O R
≤5 x U L N f or s u bjects 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) or 
Pr ot hr o m bi n Ti me ( P T)
Acti vate d Partial T hr o m b o plasti n Ti me 
(a P T T) or Partial T hr o m b o plasti n Ti me 
( P T T)
≤1. 5 × U L N u nless s u bject is recei vi n g a ntic oa g ula nt t hera p y 
as l o n g as P T or a 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. Creati ni ne Cleara nce s h o ul d be calc ulate d per i nstit uti o nal sta n dar d
9.
If fe male of c hil d beari n g p ote ntial ( Secti o n 5. 7. 2), ha ve a ne gati ve uri ne or ser u m 
pre g na nc y  test wit hi n 7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y me dicati o n.  
If t he uri ne test is p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test 
will be re q uire d .
1 0. If fe male of c hil d beari n g p ote ntial ( Secti o n 5. 7. 2), be willi n g t o use a n a de q uate 
met h o d of c o ntrace pti o n as o utli ne d i n Secti o n 5. 7. 2 -C o ntrace pti o n, f or t he c o urse of 
t he st u d y t hr o u g h 1 2 0 da ys after t he last d ose of st u d y me dicati o 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 s u bject.
1 1. If male s u bject wit h a fe male part ner(s) of c hil d-beari n g p ote ntial, m ust a gree t o use 
a n a de q uate met h o d of c o ntrace pti o n as o utli ne d i n Secti o n 5. 7. 2- C o ntrace pti o n, 
starti n g wit h t he first d ose of st u d y thera p y t hr o u g h 1 2 0 da y s after t he last d ose of 
st u d y thera p y . Males 
wit h pre g na nt part ners m ust 
a gree t o use a c o n d o m; n o 
a d diti o nal met h o d of c o ntrace pti o n is re q uire d f or t he pre g na nt part ner.
N ote: A bsti ne nce is acc e pta ble if t his is t he us ual lifest y le a n d preferre d c o ntrace pti o n 
f or t he s u bject.
1 2. S u bject 
has 
v ol u ntaril y 
a gree d t o partici pate 
b y  
gi vi n g writte n 
i nf or me d 
c o nse nt/asse nt f or t he trial. T he s u bject ma y  als o pr o vi de c o nse nt/asse nt f or F ut ure 
Bi o me dical Res earc h. H o we ver, t he s u bject m a y  partici pate i n t he mai n trial wit h o ut 
partici pati n g i n F ut ure Bi o me dical Researc h.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S u bject E xcl usi o n Criteri a
T he s u bject m ust be e xcl u de d fr o m partici pati n g i n t he trial if t he s u bject:
1.
Has n o n -s q ua m o us hist ol o g y  NS C L C. Mi x e d t u m ors will be cate g orize d b y  th e 
pre d o mi na nt cell t ype; if s mall cell ele me nts are prese nt, t he s u bject is i neli gi ble; f or 
n o n -s mall cell hist ol o g y  if t here is a n y s q ua m o us ele me nt is prese nt (e xa m ple 
a de n os q ua m o us), t he s u bject is eli gi ble; t he s q ua m ous ele me nt d oes n ot ha ve t o be 
pre d o mi na nt .
2.
Is curre ntl y  partici pati n g a n d recei vi n g st u d y thera p y  or has partici pate d i n a st u d y of 
a n i n vesti gati o nal a ge nt a n d recei ve d st u d y thera p y  or use d a n i n vesti gati o nal de vice 
wit hi n 4 wee ks pri or t o a d mi nistrati o n of pe m br oliz u ma b .
3.
Bef ore t he first d ose of trial treat me nt:
a)
Has recei ve d pri or s ys te mic c yt ot o xic c he m ot hera p y f or metastatic disease
b)
Has recei ve d ot her tar gete d or bi ol o gical a nti ne o plastic t hera py (e. g., erl oti ni b, 
criz oti ni b, cet u xi ma b) f or metastatic disease
c)
Ha d maj or s ur ger y  ( < 3 wee ks pri or t o first d ose)
4.
Recei ve d ra diati o n t hera p y to t he l u n g t hat is > 3 0 G y  wit hi n 6 m o nt hs of t he first 
d ose of trial treat me nt .
5.
C o m plete d palliati ve ra di ot hera p y wit hi n 7 da ys of t he first d ose of tr ial treat me nt.
6.
Is e x pecte d t o re q uire a n y ot her f or m of a nti ne o plastic t hera py w hile o n st u d y.
7.
Has recei ve d a li ve-vir us vacci nati o n wit hi n 3 0 d a y s of pla n ne d treat me nt start. 
Seas o nal fl u vacci nes t hat d o n ot c o ntai n li ve vir us are per mitte d .
8.
Has a k n o w n hist or y  of pri or mali g na nc y  exce pt if t he s u bject has u n der g o ne 
p ote ntiall y  curati ve t hera p y wit h n o e vi de nce of t hat disease rec urre nce f or 5 ye ars 
si nce i nitiati o n of t hat t hera py.  
N ote: T he ti me re q uire me nt f or n o e vi de nce of disease f or 5 ye ars d oes n ot a p pl y to 
t he N S C L C t u m or f or w hic h a s u bject is e nr olle d i n t he st u d y.  The ti me re q uire me nt 
als o d oes n ot a p pl y t o s u bjects w h o u n der we nt s uccessf ul defi niti ve resecti o n of basal 
cell carci n o ma of t he s ki n, s u perficial bla d der ca ncer, s q ua m o us cell ca rci n o ma of t he 
s ki n, i n sit u cer vical ca ncer, or ot her i n sit u ca ncers.
9.
Has k n o w n acti ve ce ntral ner v o us s yste m ( C N S) metastases a n d/ or carci n o mat o us 
me ni n gitis. 
 Su bjects 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 cli nicall y sta ble f or at least 2 wee ks a n d, ha ve n o e vi de nce of ne w 
or e nlar gi n g brai n metastases a n d als o are off ster oi ds 3 d a y s pri or t o d osi n g wit h 
st u d y me dicati o n.  Sta ble brai n metastases b y  this defi niti o n s h o ul d be esta blis he d 
pri or t o t he first d ose of stu d y  
me dicati o n. S u bjects wit h as ym pt o matic 
brai n 
metastases (i.e., n o ne ur ol o gical s ym pt o ms, n o re q uire me nts f or c ortic oster oi ds, a n d 
n o lesi o n > 1. 5 c m) m a y  partici pate b ut will re q uire re g ular i ma gi n g of t he brai n as a 
site of disease.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1 0. Has p re-e xisti n g p e ri p heral ne ur o pat h y  that is ≥ Gra de 2 b y C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts (C T C A E ) versi o n 4 criteria.
1 1. Pre vi o usl y  ha d a se vere h y perse nsiti vit y  reacti o n t o treat me nt wit h 
a n ot her 
m o n ocl o nal a nti b o d y .
1 2. Has a k n o w n se nsiti vit y to a n y c o m p o ne nt of car b o plati n or paclita xel or na b -
paclita xel .
1 3. Has acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n past 2 years 
(i.e. wit h use of disease m o dif y i n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve 
dr u gs).  Re place me nt t hera p y (e. g., t h yr o xi ne, i ns uli n, or p h y si ol o gic c ortic oster oi d 
re place me nt t hera py f or a dre nal or pit uitar y  ins ufficie nc y , etc.) is n ot c o nsi dere d a 
f or m of sys te mic treat me nt.
1 4. Is on c hr o nic s yste mic ster oi ds. S u bjects wit h ast h ma t hat re q uire i nter mitte nt use of 
br o nc h o dilat ors , i n hale d ster oi ds, or l ocal ster oi d i njecti o ns w o ul d n ot be e xcl u de d 
fr o m t he st u d y.
1 5. Ha d pri or treat me nt wit h a n y  ot her a nti-P D - 1, or P D -L 1  or P D -L 2 a ge nt or a n 
a nti b o d y
or a s mall m olec ule
tar geti n g ot her i m m u n o-re g ulat or y rece pt ors or 
mec ha nis ms.  Has p artici pate d i n a n y ot her pe m br oliz u ma b trial a n d has bee n treate d 
wit h pe m br oliz u ma b .
E xa m ples of s uc h a nti b o dies i ncl u de ( b ut are n ot li mite d t o) a nti b o dies a gai nst I D O, 
P D -L 1 , I L-2 R, GI T R .
1 6. Has a n acti ve i nfecti o n re q uiri n g t hera p y.
1 7. Has 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) ( k n o w n HI V 1/ 2 
a nti b o dies p ositi ve).
1 8. Has k n o w n acti ve He patitis B or C. Acti ve He patitis B is defi ne d as a k n o w n p ositi ve 
H Bs A g res ult. Acti ve He patitis C is defi ne d b y  a k n o w n p ositi ve He p C A b res ult a n d 
k n o w n q ua ntitat i ve H C V R N A res ults greater t ha n t he l o wer li mits of detecti o n of t he 
assa y.
1 9. Has a hist or y or c urre nt e vi de nce of a n y  co n diti o n, t hera p y , or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he s u bject’s partici pati o n 
f or t he f ull d urati o n of t he st u d y, or is n ot i n t he best i nterest of t he s u bject t o 
partici pate, i n t he o pi ni o n of t he treati n g I n vesti gat or.
2 0. Has 
k n o w n ps yc hiatric or s u bsta nce a b use dis or der t hat w o ul d 
i nterfere wit h 
c o o perati o n wit h t he re q uire me nts of t he trial.
2 1. Is, at t he ti me of si g ni n g i nf or me d c o nse nt, a re g ular user (i ncl u di n g “recreati o nal 
use”) of a n y illicit dr u gs or ha d a rece nt hist or y  (wit hi n t he last ye ar) of s u bsta nce 
a b use (i ncl u di n g alc o h ol) .
2 2. Has i nterstitial l u n g disease or a hist or y  of p ne u m o nitis t hat re q uire d oral or 
i ntra ve n o us gl uc oc ortic oi ds t o assist wit h ma na ge me nt.
L y m p ha n gitic s prea d of t he 
N S C L C is n ot e xcl usi o nar y .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
2 3. Is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve or fat her c hil dre n w hile o n 
st u d y me dicati o n a n d f or t he re q uire d d urati o n of c o ntrace pti o n after t he last d ose of 
st u d y me dicati o n.
Tri al Tre at me nt(s)
Trial treat me nt s h o ul d be gi n o n t he d a y  of ra n d o mizati o n or as cl ose as p ossi ble t o t he date 
o n w hic h treat me nt is all ocate d.  T he treat me nts t o be use d in t his trial are o utli ne d bel o w i n 
Ta ble 2 a n d secti o n 5. 2. 2 .
Ta ble 2 
Trial Treat me nt
Dr u g 
D ose/ P ote nc y
D ose 
Fre q ue nc y
R o ute of 
A d mi nistr ati o n
Re gi m e n/
Tre at m e nt Peri o d 
Use
Pe m br oliz u ma b 1
2 0 0 m g 
Q 3 W 
I V i nf usi o n
Da y  1 of eac h 2 1 
da y c ycle f or u p t o 
3 5 c ycles
E x peri me ntal
N or mal sali ne 1
N/ A
Q 3 W 
I V i nf usi o n
Da y  1 of eac h 2 1 
da y c ycle f or u p t o 
3 5 c ycles
Place b o
Paclita xel 2
2 0 0 m g/ m 2 
Q 3 W 
I V i nf usi o n
Da y  1 of eac h 2 1 
da y c ycle f or 4 
c ycles
Treat me nt of 
ca ncer 
Na b -paclita xel 2
1 0 0 m g/ m 2
Q 1 W 
I V i nf usi o n
Da y  1, 8, 1 5 of eac h 
2 1 da y c ycle f or 4 
c ycles
Treat me nt of 
ca ncer 
Car b o plati n 
A U C 6 
Q 3 W 
I V i nf usi o n
Da y  1 of eac h 2 1 
da y c ycle f or 4 
c ycles
Treat me nt of 
ca ncer 
1Pe m br oliz u ma b t o be a d mi nistere d pri or t o c he m ot hera p y.
2 I n vesti gat or’s c h oice of eit her paclita xel or na b-paclita xel.
3Car b o plati n d ose s h o ul d n ot t o e xcee d 9 0 0 m g.
All s u p plies i n dicate d i n Ta ble 2 a b o ve will be pr o vi de d ce ntrall y b y  the S p o ns or or l ocall y 
b y  the 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 operati o nal or re g ulat or y 
re q uire me nts.
F or a n y c o m merciall y availa ble pr o d uct t hat is pr o vi de d b y  the trial site, s u bsi diar y or 
desi g nee e ver y atte m pt will be ma de t o s o urce t hese s u p plies fr o m a si n gle l ot/ batc h n u m ber. 
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 locall y  purc hase d pr o d uct as per l ocal g ui deli nes u nless ot her wise i nstr ucte d b y  the 
S p o ns or .
T he i n vesti gat or s hall ta ke res p o nsi bilit y for a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p ply, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of trial 
treat me nts i n acc or da nce wit h t he pr ot oc ol a n d a ny a p plica ble la ws a n d re g ulati o ns.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
D ose Selecti o n/ M o dific ati o n
5. 2. 1. 1
D ose Selecti o n ( Pre p ar ati o n)
Pe m br oliz u ma b: t he d ose a m o u nt re q uire d t o pre pare t he pe m br oliz u ma b i nf usi o n s ol uti o n 
will be base d o n a fi xe d d ose of 2 0 0 m g .  Details o n t he d ose calc ulati o n, pre parati o n a n d 
a d mi nistrati o n are pr o vi de d i n t he P har mac y Ma n ual.
Sta n dar d c he m ot hera pe utic a ge nts (car b o plati n a n d paclita xel or na b -paclita xel) will be 
pre pa re d a n d a d mi nistere d as per t he a p pr o ve d pr o d uct la bel.
5. 2. 1. 2
D ose M o dific at i o n
If a p pr o priate, t he in vesti gat or m a y  attri b ute eac h t o xicit y eve nt t o car b o plati n, p aclita xel or 
na b -paclita xel or pe m br oliz u ma b al o ne or t o t he c o m bi nati o n a n d use a ste p wise d ose 
re d ucti o n. Dose m o dificati o ns m ust be base d o n t he ma xi m u m t o xicit y ex perie nce d d uri n g a 
c ycle. Treat me nt relate d t o xicit y must res ol ve t o gra de ≤1 or baseli ne pri or t o res u mi n g t he 
s u bse q ue nt c ycle, wit h t he e xce pti o n of al o pecia, gra de 2 fati g ue, e n d ocri ne -relate d A Es 
re q uiri n g treat me nt or h or m o ne re place me nt, w hic h ma y  be gra de ≤2. D ose m o dificati o ns 
a n d t o xicit y ma na ge me nt g ui deli nes f or i m m u ne-relate d A Es ass ociate d wit h pe m br oliz u ma b 
are o utli ne d i n secti o n 5. 2. 1. 2. 2 a n d Ta ble 3 bel o w. 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 m a y  not be re-escalate d. S u bjects ca n ha ve a ma xi m u m of 2 d ose 
m o dificati o ns (if a p plica ble) t o eac h of t he c o m p o ne nts of st u d y thera p y  thr o u g h o ut t he 
c o urse of t he st u d y for t o xicities.  If a s u bject 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, t he m ost c o nser vati ve d ose a dj ust me nt rec o m me n de d s h o ul d 
be f oll o we d ( d ose re d ucti o n a p pr o priate t o t he m ost se vere t o xicit y).  Su bjects w h o re q uire a 
3r d d ose m o dificati o n t o a n y partic ular c o m p o ne nt will ha ve t hat a ge nt disc o nti n ue d.
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 m a y  not be re-escalate d. 
S u bjects ca n ha ve a ma xi m u m of 2 d ose m o dificati o ns (if a p plica ble) t o eac h of t he 
c o m p o ne nts of st u d y thera p y  thr o u g h o ut t he c o urse of t he st u d y for t o xicities.  If a s u bject 
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, t he m ost 
c o nser vati ve d ose a dj u st me nt rec o m me n de d s h o ul d be f oll o we d ( d ose re d ucti o n a p pr o priate 
t o t he m ost se vere t o xicit y).  Su bjects w h o re q uire a 3r d d ose m o dificati o n t o a n y partic ular 
c o m p o ne nt will ha ve t hat a ge nt disc o nti n ue d.
Pe m br oliz u ma b d ose re d ucti o ns are n ot per mitte d. Pe m br oliz u ma b 
treat me nt ma y  be 
i nterr u pte d or disc o nti n ue d d ue t o t o xicit y. 
Re d ucti o n of o ne c he m ot hera p y  a ge nt a n d n ot t he ot her a ge nt is a p pr o priate if, i n t he o pi ni o n 
of t he I nvesti gat or, t he t o xicit y  is clearl y relate d t o o ne of t he treat me nts. If, i n the o pi ni o n of 
t he I nvesti gat or, t he t o xicit y is relate d t o t he c o m bi nati o n of b ot h c he m ot hera p y a ge nts, b ot h 
dr u gs s h o ul d be re d uce 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 t hree a ge nts, all t hree a ge nt s s h o ul d be re d uce d (if a p plica ble), 
i nterr u pte d or disc o nti n ue d acc or di n g t o t he rec o m me n de d d ose m o dificati o ns. 
S u bjects ma y  ha ve c he m ot hera p y disc o nti n ue d a n d c o nti n ue o n pe m br oliz u ma b/sali ne 
place b o al o ne. Si milarl y  su bjects m a y  disc o nti n ue pe m br oliz u ma b/sali ne 
place b o a n d 
c o nti n ue o n c he m ot hera p y al o ne d uri n g t he first f o ur c ycles if a p pr o priate.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
C he m ot hera p y m a y  be i nterr u pte d f or a ma xi m u m of 6 wee ks; pe m br oliz u ma b ma y  be 
i nterr u pte d f or a ma xi m u m of 1 2 wee ks.
T he C o m m o n Ter mi n ol o g y  Criteria f or A d v erse E ve nts versi o n 4. 0 ( C T C A E 4. 0) m ust be 
use d t o gra de t he se verit y of a d verse e ve nts. All d ose m o dificati o ns s h o ul d be base d o n t he 
A E re q uiri n g t he greatest d ose m o dificati o n. 
C ar b o pl ati n a n d P aclit a xel or N a b -p aclit a xel C he m ot her a p y Re gi me n
Refer t o a p pr o ve d pr o d uct la bels f or d ose m o dificati o ns re gar di n g t his re gi me n.
Pe m br oliz u m a b
Pe m br oliz u ma b d ose
re d ucti o ns are n ot per mitte d. Pe m br oliz u ma b treat me nt ma y  be 
i nterr u pte d or disc o nti n ue d d ue t o t o xicit y. 
A d verse e ve nts ( b ot h n o n-seri o us a n d seri o us) ass ociate d wit h pe m br oliz u ma b 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 a d verse e ve nts 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. 
Pe m br oliz u ma b m ust be wit h hel d f or dr u g -relate d t o xicities a n d se vere or life-t hreate ni n g 
A Es as per Ta ble 3 bel o w.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 3 
D ose M o dificati o ns a n d T o xicit y Ma na ge me nt G ui deli nes f or I m m u ne-relate d A Es Ass ociate d wit h Pe m br oliz u ma b
Ge ner al i nstr ucti o ns:
1. 
C ortic oster oi d ta per s h o ul d be i nitiate d u p o n A E i m pr o vi n g t o Gra de 1 or less a n d c o nti n ue t o ta per o ver at least 4 w ee ks.
2. 
F or sit uati o ns w here p e m br oliz u ma b has bee n wit h hel d, pe m br oliz u ma b ca n be res u me d after A E has bee n re d uce d t o Gra de 1 or 0 a n d 
c ortic oster oi d has bee n ta pere d. Pe m br oliz u ma b s h o ul d be per ma ne ntl y disc o nti n ue d if A E d oes n ot res ol ve wi t hi n 1 2 we e ks of last d ose or 
c ortic oster oi ds ca n n ot be re d uce d t o ≤ 1 0 m g pre d nis o ne or e q ui vale nt per da y wit hi n 1 2 wee ks. 
3. 
F or se vere a nd life-t hreate ni n g ir A Es, I V c ortic oster oi d s h o ul d be i nitiate d first f oll o we d b y oral ster oi d. Ot her i m m u n os u p pressi ve treat me nt 
s h o ul d be i nitiate d if ir A Es ca n n ot be c o ntr olle d b y c ortic oster oi ds.
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A Ev 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or a n d f oll o w -u p
P ne u m o nitis 
Gra de 2
Wit h h ol d
 A d mi nister c ortic oster oi ds (i nitial 
d ose of 1 -2 m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d b y ta per
 
M o nit or partici pa nts f or si g ns a n d 
s y m pt o ms of p ne u m o nitis
 
E val uate partici pa nts wit h s us pecte d 
p ne u m o nitis wit h ra di o gra p hic i ma gi n g a n d 
i nitiate c ortic oster oi d treat me nt
 
A d d pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns
Gra de 3 or 4, or 
rec urre nt gra de 2
Per m a ne ntl y 
disc o nti n ue
Diarr hea / c olitis  
Gra de 2 or 3 
Wit h h ol d
 A d mi nister c ortic oster oi ds (i nitial 
d ose of 1 -2 m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d b y ta per
 
M o nit or partici pa nts f or si g ns a n d s y m pt o ms 
of e nter oc olitis (i.e. diarr hea, a b d o mi nal
pai n, bl o o d or m uc us i n st o ol wit h or 
wit h o ut fe ver) a n d of b o w el perf orati o n (i.e. 
perit o neal si g ns a n d ile us).
 
Partici pa nts wit h ≥ Gra de 2 diarr hea 
s us pecti n g c olitis s h o ul d c o nsi der GI 
c o ns ultati o n a n d perf or mi n g e n d osc o p y t o 
r ule o ut c olitis. 
 
Partici pa nts wit h diarr hea/c olitis s h o ul d be 
a d vise d t o dri n k li beral q ua ntities of clear 
fl ui ds.  If s ufficie nt oral fl ui d i nta ke is n ot 
feasi ble, fl ui d a n d electr ol ytes s h o ul d be 
s u bstit ute d via I V i nf usi o n.
Gra de 4
Per m a ne ntl y 
disc o nti n ue
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
3 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A Ev 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or a n d f oll o w -u p
A S T / A L T
ele vati o n or 
I ncrease d 
Bilir u bi n
Gra de 2
Wit h h ol d

A d mi nister c ortic oster oi ds (i nitial 
d ose of 0. 5 - 1 m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d b y ta per
 
M o nit or w it h li ver f u ncti o n tests (c o nsi der 
wee kl y or m ore fre q ue ntl y u ntil li ver 
e nz y me val ue ret ur ne d t o baseli ne or is 
sta ble
Gra de 3 or 4  
Per m a ne ntl y 
disc o nti n ue

A d mi nister c ortic oster oi ds (i nitial 
d ose of 1 -2 m g/ k g pre d nis o ne or 
e q ui vale nt) f oll o we d b y ta per
T y pe 1 dia betes 
mellit us ( T 1 D M) 
or 
H y per gl yce mia
Ne wl y o nset 
T 1 D M or 
Gra de 3 or 4 
h y per gl yce mia 
ass ociate d wit h 
e vi de nce of -cell 
fail ure
Wit h h ol d

I nitiate i ns uli n re place me nt 
t hera p y f or partici pa nts wit h 
T 1 D M 

A d mi nister a nti -h y per gl yce mic i n 
partici pa nts wit h h y per gl yce mia 
 
M o nit or partici pa nts f or h y per gl yce mia or 
ot her si g ns a n d s y m pt o ms of dia betes.
H y p o p h ysitis 
Gra de 2
Wit h h ol d
 
A d mi nister c ortic oster oi ds a n d 
i nitiate h or m o nal re place me nts as 
cli nicall y i n dicate d.  
 
M o nit or f or si g ns a n d s y m pt o ms of 
h y p o p h ysitis (i ncl u di n g h y p o pit uitaris m a n d 
a dre nal i ns ufficie nc y)
Gra de 3 or 4 
Wit h h ol d or 
per ma ne ntl y 
disc o nti n ue 1
H y pert h yr oi dis m  
Gra de 2
C o nti n ue 

Treat w it h n o n-selecti ve beta-
bl oc kers (e. g. pr o pra n ol ol) or 
t hi o na mi des as a p pr o priate 
 
M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d 
dis or ders. 
Gra de 3 or 4  
Wit h h ol d or 
Per m a ne ntl y 
disc o nti n ue 1
H y p ot h yr oi dis m 
Gra de 2 - 4 
C o nti n ue 
 
I nitiate t h yr oi d re place me nt 
h or m o nes (e. g. le v ot h yr o xi ne or 
li ot h yr o ni ne) per sta n dar d of care
 
M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d 
dis or ders. 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I m m u ne-rel ate d 
A Es
T o xicit y gr a de or 
c o n diti o ns 
( C T C A Ev 4. 0)
Acti o n t a ke n t o 
pe m br oliz u m a b
ir A E m a n a ge me nt wit h 
c ortic oster oi d a n d/ or ot her 
t her a pies
M o nit or a n d f oll o w -u p
Ne p hritis a n d 
re nal d ysf u ncti o n
Gra de 2
Wit h h ol d 
 
A d mi nister c ortic oster oi ds 
( pre d nis o ne 1-2 m g/ k g or 
e q ui vale nt) f oll o we d b y ta per.
 
M o nit or c ha n ges of re nal f u ncti o n
Gra de 3 or 4  
Per m a ne ntl y 
disc o nti n ue
M y ocar ditis 
Gra de 1 or 2 
Wit h h ol d
 
Base d o n se verit y of A E 
a d mi nister c ortic oster oi ds
 
E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 3 or 4 
Per m a ne ntl y 
disc o nti n ue
All Ot her 
i m m u ne-relate d 
A E s
I nt olera ble/ 
persiste nt Gra de 2
Wit h h ol d
 
Base d o n t y pe a n d se verit y of A E 
a d mi nister c ortic oster oi ds 
 
E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 3
Wit h h ol d or 
disc o nti n ue base d 
o n t he t y pe of 
e ve nt.  E ve nts t hat 
re q uire 
disc o nti n uati o n 
i ncl u de a n d n ot 
li mite d t o:  
G uillai n -Barre 
S y n dr o me, 
e nce p halitis
Gra de 4 or 
rec urre nt Gra de 3 
Per m a ne ntl y 
disc o nti n ue
1. 
Wit h h ol d or per ma ne ntl y disc o nti n ue pe m br oliz u ma b is at t he discreti o n of t he i n vesti gat or or treati n g p h ysicia n.  
N O T E: 
F or partici pa nts wit h Gra de 3 or 4 i m m u ne-relate d e n d ocri n o pat h y w here wit h h ol d of p e m br oliz u ma b is re q uire d, pe m br oliz u ma b ma y be res u me d 
w he n A E res ol ves t o ≤ Gra de 2 a n d is c o ntr olle d w it h h or m o nal re place me nt t hera p y or ac hie ve d meta b olic c o ntr ol (i n case of T 1 D M).  
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt of i nf usi o n -re acti o ns rel ate d t o 
pe m br oliz u m a b
Pe m br oliz u ma b ma y  ca use se vere or life t hreate ni n g i nf usi o n-reacti o ns i ncl u di n g se vere 
h y perse nsiti vit y  or a na p h yla xis. Si g ns a n d s ym pt o ms us uall y  de vel o p d uri n g or s h ortl y after 
dr u g i nf usi o n a n d ge nerall y  res ol ve c o m 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 4 . 
Ta ble 4 
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d Treat me nt G ui deli nes
N CI C T C A E Gr a de 
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
Gr a de 1
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n 
n ot i n dicate d
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bject is dee me d me dicall y 
sta ble i n t he o pi ni o n of t he i n vesti gat or.
N o ne
Gr a de 2
Re q uires t hera p y or 
i nf usi o n i nterr u pti o n b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt 
(e. g., a nti hista mi nes, 
N S AI Ds, narc otics, I V 
fl ui ds); pr o p h ylactic 
me dicati o ns i n dicate d 
f or ≤2 4 hrs
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y 
i ncl u de b ut is n ot li mite d t o:
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bject is dee me d me dicall y 
sta ble i n t he o pi ni o n of t he i n vesti gat or.
If s y m pt o ms res ol ve wit hi n 1 h o ur of st o p pi n g 
dr u g i nf usi o n, t he i nf usi o n ma y be restarte d at 
5 0 % of t he ori gi nal i nf usi o n rate (e. g. fr o m 1 0 0 
m L/ hr t o 5 0 m L/ hr).  Ot her wise d osi n g will be 
hel d u ntil s y m pt o ms res ol ve a n d t he s u bject 
s h o ul d be pre me dicate d f or t he ne xt sc he d ule d 
d ose.
S u bjects w h o de vel o p Gra de 2 t o xicit y des pite 
a de q uate pre me dicati o n s h o ul d be per ma ne ntl y 
disc o nti n ue d fr o m f urt her st u d y dr u g treat me nt
S u bject m a y be pre me dicate d 
1. 5 h ( ± 3 0 mi n utes) pri or t o 
i nf usi o n of p e m br oliz u ma b 
wit h:
Di p he n h y dra mi ne 5 0 m g p o 
( or e q ui vale nt d ose of 
a nti hista mi ne).
Aceta mi n o p he n 5 0 0 -1 0 0 0 m g 
p o ( or e q ui vale nt d ose of 
a nal gesic).
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
N CI C T C A E Gr a de 
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt D osi n g
Gr a des 3 or 4
Gra de 3:
Pr ol o n ge d (i.e., n ot 
ra pi dl y res p o nsi ve t o 
s y m pt o matic me dicati o n 
a n d/ or brief i nterr u pti o n 
of i nf usi o n); rec urre nce 
of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d 
f or ot her cli nical 
se q uelae (e. g., re nal 
i mpair me nt, p ul m o nar y 
i nfiltrates)
Gra de 4:
Li fe-t hreate ni n g; 
press or or ve ntilat or y 
s u p p ort i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y 
i ncl u de b ut is n ot li mite d t o:
E pi ne p hri ne * *
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he s u bject is dee me d me dicall y 
sta ble i n t he o pi ni o n of t he i n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla xis, e pi ne p hri ne s h o ul d be 
use d i m me diatel y.
S u bject is per m a ne ntl y d isc o nti n ue d fr o m 
f urt her st u d y dr u g tre at me nt.
N o s u bse q ue nt d osi n g
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble d uri n g 
t he peri o d of dr u g a d mi nistrati o n.
F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 4. 0 ( C T C A E) at 
htt p://cte p.ca ncer. g o v
Ot her all o we d d ose i nterr u pti o n f or pe m br oliz u m a b 
Pe m br oliz u ma b ma y  be i nterr u pte d f or sit uati o ns ot her t ha n treat me nt-relate d A Es s uc h as 
me dical / s ur gical e ve nts or l o gistical reas o ns n ot relate d t o st u d y t hera p y. S u bjects s h o ul d be 
place d bac k o n st u d y  t hera p y wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless ot her wise 
disc usse d wit h t he S p o ns or. T he reas o n f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he pa tie nt's 
st u d y rec or d.
Ti mi n g of D ose A d mi nistr ati o n
S u bjects will recei ve bli n de d pe m br oliz u ma b 2 0 0 m g ( D 1) or sali ne place b o ( D 1) t o get her 
wit h paclita xel 2 0 0 m g/ m 2 (D 1) O R na b -paclita xel 1 0 0 m g / m2 ( D 1, D 8, D 1 5) + car b o plati n 
A U C 6 ( D1) Q 3 W f or 4 c ycles f oll o we d b y  bli n de d pe m br oliz u ma b 2 0 0 m g ( D 1) or sali ne 
place b o ( D 1) Q 3 W u ntil pr o gressi o n/c o m pleti o n. S u bjects fr o m C hi na w h o are still o n 
me dicati o n 
will be u n bli n de d after A me n d me nt 
6 a n d will be all o we d t o disc o nti n ue 
treat me nt wit h sali ne place b o.
P e m br oliz u ma b or sali ne will be a d mi nistere d pri or t o c he m ot hera p y .
Trial treat me nt s h o ul d be a d mi nistere d o n Da y  1 of eac h c ycle after all pr oce d ures / 
assess me nts ha ve bee n c o m plete d. Trial treat me nt ca n be a d mi nistere d +/ - 3 d a y s of t he 
tar gete d Da y  1 for eac h c ycle, e xce pt C ycl e 1 w here treat me nt ca n o nl y  be a d mi nistere d + 3 
da y s of t he tar gete d da y 1.
All trial treat me nts will be a d mi nistere d o n a n o ut -patie nt basis.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
F or s u bjects w h o e x perie nce disease pr o gressi o n, i n vesti gat ors m a y  elect t o i nterr u pt 
treat me nt b y  deferri n g t he decisi o n t o c o nti n ue/ disc o nti n ue treat me nt i n t he trial u ntil 
c o nfir mati o n of disease pr o gressi o n per R E CI S T 1. 1 at least 2 8 da ys fr o m t he date of 
i ma gi n g de m o nstrati n g disease pr o gressi o n c o nfir me d t hr o u g h bli n de d i n de pe n de nt ce ntral
i ma gi n g ve n d or re vie w.  S u bjects f or w h o m P D is n ot c o nfir me d o n s u bse q ue nt i ma gi n g ma y 
res u me treat me nt.  Please see Secti o n 5. 8 f or ot her e xce pti o ns.
5. 2. 2. 1
Pe m br oliz u m a b/ s ali ne pl ace b o
Pe m br oliz u ma b/sali ne place b o will be a d mi nistere d as a 3 0- mi n ute 
I V i nf usi o n Q 3 W. 
Pe m br oliz u ma b /sali ne place b o will
be a d mi nistere d pri or t o c he m ot hera p y. Sites s h o ul d 
ma ke e ver y eff ort t o tar get i nf usi o n ti mi n g t o be as cl ose t o 3 0- mi n ut es as p ossi ble.  
H o we ver, gi ve n t he varia bilit y  of i nf usi o n p u m ps fr o m site t o site, a wi n d o w of - 5 mi n utes 
a n d + 1 0 mi n utes is per mitte d (i.e., i nf usi o n ti me is 3 0- mi n utes: -5 mi n/ + 1 0 mi n).  
T he P har mac y  
Ma n ual c o ntai ns s pecific i nstr ucti o ns f or pe m br oliz u ma b rec o nstit uti o n, 
pre parati o n of t he i nf usi o n fl ui d, a n d a d mi nistrati o n .
5. 2. 2. 2
P aclit a xel
Paclita xel 2 0 0 m g/ m 2 will be a d mi nistere d as a n I V i nf usi o n o ver 3 h o urs Q 3 W f or 4 c ycles
as per l ocal practice a n d la bels. All s u bjects s h o ul d be pre -me dicate d wit h ora l or i ntra ve n o us 
ster oi d a n d a nti-hista mi nes acc or di n g t o t he a p pr o ve d pr o d uct la bel a n d/ or sta n dar d practice. 
A d diti o nal pre -me dicati o ns 
s h o ul d be a d mi nistere d as per sta n dar d practice. P aclita xel 
s h o ul d be c o m pletel y a d mi nistere d bef ore i nitiati n g car b o plati n d ose.
5. 2. 2. 3 
N a b- p aclit a xel
Na b -paclita xel will be a d mi nistere d at 1 0 0 m g/ m 2 as a n I V inf usi o n o ver 3 0 mi n utes f or 4 
c ycles as per l ocal practice a n d la bels. S u bjects will be d ose d o n D a y  1, 8 a n d 1 5 of eac h 
Q 3 W c ycle.   Na b-paclita xel s h o ul d be c o m pletel y a d mi nistere d bef ore i nitiati n g car b o plati n 
d ose.
5. 2. 2. 4
C ar b o pl ati n
Car b o plati n A U C 6 m g/ m L / mi n will be a d mi nistere d as a n I V inf usi o n o ver 1 5- 6 0 mi n utes 
Q 3 W f or 4 c ycles i m me diately after paclita xel or na b -paclita xel as per l ocal practice a n d 
la bels. T he car b o plati n d ose s h o ul d be calc ulate d u si n g Cal vert f or m ula (see bel o w ). 
Car b o plat i n d ose s h o ul d n ot t o e xcee d 9 0 0 m g
Cal vert F or m ula
T otal D ose ( m g) = (tar get A U C) x ( Cr Cl + 2 5)
T he esti mate d G F R use d i n t he Cal vert f or m ula s h o ul d n ot e xcee d 1 2 5 m L / mi n
Ma xi m u m car b o plati n d ose ( m g) = tar get A U C 6 ( m g• mi n/ m L ) x ( 1 2 5 + 2 5) = 6 x
1 5 0 m L / mi n = 9 0 0 m g
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
5. 2. 2. 5
A ntie metic T her a p y
A ntie metic t hera py s h o ul d f oll o w M A S C C 
g ui deli nes ( htt p:// w w w. mascc. or g/a ntie metic-
g ui deli nes/) a n d s h o ul d, f or t he first f o ur c ycles, i ncl u de a 5- H T 3 rece pt or a nta g o nist, 
de xa met has o ne ( or e q ui vale nt) a n d / or a pre pita nt as pe r t he M A S C C g ui deli nes. If a pre pita nt 
is n ot l ocall y a vaila ble, t he S p o ns or will pr o vi de s u p plies.
Tri al Bli n di n g 
T his is a d o u ble -bli n de d trial; t heref ore, t he s u bject, t he i n vesti gat or a n d S p o ns or pers o n nel 
or dele gate(s) w h o are i n v ol ve d i n t he treat ment a d mi nistrati o n or cli nical e val uati o n of t he 
s u bjects are u na ware of t he gr o u p assi g n me nts. T he c he m ot hera p y a ge nts will be o pe n -la bel.  
T he S p o ns or, i n vesti gat or a n d s u bject will n ot k n o w w het her t he treat me nt a d mi nistere d 
c o ntai ns pe m br oliz u ma b or sal i ne place b o.  T he st u d y site’s u n bli n de d p har macist will o btai n 
eac h s u bject’s st u d y ide ntificati o n n u m ber a n d st u d y dr u g assi g n me nt fr o m t he i nteracti ve 
v oice res p o nse s yste m (I V R S)/i nteracti ve we b res p o nse s yste m (IW R S) 
a n d pre pa re t he 
s ol uti o ns f or i nf usi o n. T he u n bli n de d p har macist will pr o vi de t he i n vesti gati ve staff wit h 
rea dy- t o-use bli n de d pe m br oliz u ma b/sali ne i nf usi o n s ol uti o ns, pac ka ge d i de ntically i n or der 
t o mai ntai n t he bli n di n g, f or a d mi nistrati o n at sc he d ule d i nf usi o n visits.
Beca use of p osit i ve res ults o bser ve d at t he i nteri m a nal ysis i n t he C hi na e xte nsi o n , t his st u d y 
will be u n bli n de d s o t hat s u bjects assi g ne d t o t he place b o ar m ( Ar m 2) ma y  disc o nti n ue 
treat me nt wit h n or mal sali ne place b o a n d ha ve t he o pti o n of recei vi n g pe m br oliz u ma b if 
t here is d oc u me nte d pr o gressi ve disease b y  ce ntral ra di ol o gical re view. T h us, t he s u bject, 
i n vesti gat or, a n d S p o ns or pers o n nel or dele gate(s) w h o are i n v ol ve d i n t he treat me nt 
a d mi nistrati o n or cli nical e val uati o n of t he s u bjects will be ma de a ware of t he gr o u p 
assi g n me nts after A me n d me nt 6.
See Secti o n 7. 1. 4. 2, Bli n di n g/ U n bli n di n g, f or a descri pti o n of t he met h o d of u n bli n di n g a 
s u bject d uri n g t he trial, s h o ul d s uc h acti o n be warra nte d.
R a n d o miz ati o n o r Tre at me nt All oc ati o n
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 s yste m (I V R S/IW R S). 
T here are 2 treat me nt ar ms.  
S u bjects will be assi g ne d ra n d o mly i n a 1: 1 rati o t o t o pe m br oliz u ma b a n d c he m ot hera p y or
sali ne place b o a n d c he m ot hera p y , res pecti vely. T he c h oice of paclita xel or na b -paclita xel
treat me nt will be deter mi ne d pri or t o ra n d o mizati o n a n d d oc u me nte d i n t he I V R S/IW R S.  
Str atific ati o n
Treat me nt all ocati o n/r a 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)
P D -L 1  ex pressi o n: T u m or Pr o p orti o n Sc ore ≥1 % 
vs .
< 1%. 
 PD- L 1  ine val ua ble 
s u bjects will be i ncl u de d wit h t he T P S <1 % gr o u p.
2)
C h oice of ta xa ne c he m ot hera p y:  paclita xel vs. na b -paclita xel
3)
Ge o gra p hic re gi o n of t he e nr olli n g site ( East Asia vs. n o n -East Asia)
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
C o nc o mit a nt Me dic ati o ns / V acci n ati o ns ( All o we d & Pr o hi bite d)
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e xcl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g trial.  If t here is a cli nical i n dicati o n f or a n y me dicati o n or vacci nati o n 
s pecifically pr o hi bite d d uri n g t he trial, disc o nti n uati o n fr o m trial t hera p y or vacci nati o n ma y 
be re q uire d.  The i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his wit h t he S p o ns or 
Cli nical Direct or.  The fi nal decisi o n o n a n y s u p p orti ve t hera py or vacci nati o n rests wit h t he 
i n vesti gat or a n d/ or t he s u bject's pri mar y p h y sicia n.  Ho we ver, t he decisi o n t o c o nti n ue t he 
s u bject o n trial t hera p y or vacci nati o n sc he d ule re q uires t he m ut ual a gree me nt of t he 
i n vesti gat or, t he S p o ns or a n d t he s u bject.
Acce pt a ble C o nc o mit a nt Me dic ati o ns
All treat me nts t hat t he i n vesti gat or c o n si ders necessar y  for a s u bject’s welfare m a y  be 
a d mi nistere d at t he discreti o n of t he i n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care.  All c o nc o mita nt me dicati o n will be rec or de d o n t he case re p ort f or m ( C R F) 
i ncl u di n g all prescri pti o n, o ver -t he-c o u nter ( O T C), her bal s u p ple me nts, a n d I V me dicati o ns 
a n d fl ui ds.  If c ha n ges occ ur d uri n g t he trial peri o d, d oc u me ntati o n of dr u g d osa ge, 
fre q ue nc y, r o ute, a n d date will als o be i ncl u de d o n t he C R F.
Palliati ve a n d s u p p orti ve care is per mitte d d uri n g t he c o urse of t he trial f or u n derl yi n g 
me dical c o n diti o ns a n d ma na ge me nt of s ym pt o ms. S ur ger y  or ra di ot hera p y for t u m or c o ntr ol 
is n ot per mitte d d uri n g t he st u d y; h o we ver, ra di ot hera py or pr oce d ures f or s ym pt o m 
ma na ge me nt is all o we d.
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 trial treat me nt 
t hr o u g h t he Safet y F oll o w -u p Visit s h o ul d be rec or de d.  After t he Safet y  Foll o w -u p Visit 
rec or d all me dicati o ns ta ke n f or S A Es a n d E CIs as defi ne d i n Secti o n 7. 2.
C ol o n y -Sti m ul at i n g F act ors
R o uti ne use of c ol o n y-sti m ulati n g fact ors ( C S Fs) is n ot per mitte d. A merica n S ociet y of 
Cli nical O nc ol o g y  g ui deli nes f or use of C S Fs s h o ul d be f oll o we d [ 4 1].
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
S u bjects are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pies d uri n g t he Scree ni n g, 
Treat me nt, Cr oss o ver a n d Sec o n d C o urse P hases of t his trial:
 
A nti ne o plastic s yste mic c he m ot hera p y or bi ol o gical t hera py n ot s pecifie d i n t his 
pr ot oc ol.
 
I m m u n ot hera py 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.
 
I n vesti gati o nal a ge nts ot her t ha n pe m br oliz u ma b.
 
Ra diati o n t hera p y ; ra di ot hera py f or s ym pt o m ma na ge me nt is all o we d wit h s p o ns or’s 
a p pr o val .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
 
Li ve vacci nes wit hi n 3 0 da y s pri or t o t he first d ose of trial treat me nt a n d w hile 
partici pati n g i n t he trial.  E xa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: measles, m u m ps, r u bella, c hic ke n p o x, ye ll o w fe ver, nasal seas o nal fl u, 
nasal H 1 N 1 fl u, ra bies, B C G, a n d t y p h oi d.
 
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 ym pt o ms fr o m a n 
i m m u ne-relate d a d verse E ve nt (as liste d i n Secti o n 5. 6) or f or use as a pre -me dicati o n 
f or c he m ot hera pe utic a ge nts s pecifie d i n t he pr ot oc ol or as a pre -me dicati o n pri or t o a 
C T sca n f or s u bjects wit h c o ntrast aller g y or f or use f or C O P D e xacer bati o n re q uiri n g 
ster oi d f or rec o ver y. Re place me nt d oses of ster oi ds (f or e xa m ple, pre d nis o ne 1 0 m g 
dail y ) are per mitte d w hile o n st u d y.
S u bjects w h o, i n t he assess me nt b y  the i n vesti gat or, re q uire t he use of a n y of t he 
af ore me nti o ne d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he trial
treat me nt.  Su bjects ma y recei ve ot her me dicati o ns t hat t he i n vesti gat or dee ms t o be 
me dicall y  necessar y.  
T he E xcl usi o n Criteria descri bes o t her me dicati o ns w hic h are pr o hi bite d i n t his trial.
T here are n o pr o hi bite d t hera pies d uri n g t he P ost -Treat me nt F oll o w -u p P hase .
Resc ue Me dic ati o ns & S u p p orti ve C are
S u bjects s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y  by t he 
treati n g i n vesti gat or.  Su g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of a d verse 
e ve nts wit h p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d bel o w. W here 
a p pr o priat e, these 
g ui deli nes i ncl u de t he use of oral or i ntra ve n o us 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 age nts if s ym pt o ms d o n ot i m pr o ve wit h a d mi n istrati o n of 
c ortic oster oi ds. N ote t hat se veral c o urses of ster oi d ta peri n g m a y  be necessar y  as s ym pt o ms 
ma y  worse n w he n t he ster oi d d ose is decrease d. F or eac h dis or der, atte m pts s h o ul d be ma de 
t o r ule o ut ot her ca uses s uc h as metastatic disease or bacterial or viral i nfecti o n, w hic h mi g ht 
re q uire a d diti o nal s u p p orti ve care. T he treat me nt g ui deli nes are i nte n de d t o be a p plie d w he n 
t he i n vesti gat or deter mi nes t he e ve nts t o be relate d t o pe m br oliz u ma b. 
N ote: if after t he e val uati o n t he e ve nt is deter mi ne d n ot t o be relate d, t he i n vesti gat or d oes 
n ot nee d t o f oll o w t he treat me nt g ui da nce
(as o utli ne d bel o w) . Refer t o Ta ble 3
i n 
Secti o n 5. 2. 1 f or g ui deli nes re gar di n g d ose m o dificati o n a n d s u p p orti ve care . 
Diet/ Acti vit y/ Ot her C o nsi der ati o ns
Diet
S u bjects s h o ul d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n A E 
s uc h as diarr hea, na usea or v o miti n g.
C o ntr ace pti o n
Pe m br oliz u ma b ma y  ha ve a d verse effects o n a fet us i n uter o. F urt her m ore, it is n ot k n o w n if 
pe m br oliz u ma b has tra ns ie nt a d verse effects o n t he c o m p ositi o n of s per m.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
F or t his trial, male s u bjects will be c o nsi dere d t o be of n o n -pr o d ucti ve p ote ntial if t he y ha ve 
az o os per mia ( w het her d ue t o ha vi n g ha d a vasect o m y  or d ue t o a n u n derl y i n g me dical 
c o n diti o n).
Fe male s u bjects will be c o nsi dere d of n o n -re pr o d ucti ve p ote ntial if t he y are eit her: 
( 1) p ost me n o pa usal ( defi ne d as at least 1 2 m o nt hs wit h n o me nses wit h o ut a n alter nati ve 
me dical ca use; i n w o me n < 4 5 y ears of a ge a hi g h f ollicle sti m ulati n g h or m o ne ( F S H) 
le vel i n t he p ost me n o pa usal ra n ge m a y  be use d t o c o nfir m a p ost -me n o pa usal state i n 
w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y. I n t he 
a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.); 
O R 
( 2) ha ve ha d a h y sterect o m y an d/ or bilateral o o p h orect o m y, bilateral sal pi n gect o m y or 
bilateral t u bal li gati o n/ occl usi o n, at least 6 wee ks pri or t o scree ni n g; 
O R 
( 3) has a c o n ge nital or ac q uire d c o n diti o n t hat pre ve nts c hil d beari n g.
Fe male a n d male s u bjects of re pr o d ucti ve p ote ntial m ust a gree t o a v oi d bec o mi n g pre g na nt 
or i m pre g nati n g a part ner, res pecti vel y, w hile recei vi n g st u d y dr u g a n d f or 1 2 0 da ys after t he 
last d ose of st u d y dr u g b y c o m plyi n g wit h o ne of t he f oll o wi n g:  
( 1) practice a bsti ne nce† fr o m heter ose x ual acti vit y; 
O R 
( 2) use ( or ha ve t heir part ner use) acce pta ble c o ntrace pti o n d uri n g heter ose x ual acti vit y.  
Acce pta ble met h o ds of c o ntrace pti o n are ‡:
Si n gle met h o d ( o ne of t he f oll o wi n g is acce pta ble):
•
i ntra uteri ne de vice (I U D)
•
vasect o m y of a fe male s u bject ’s male part ner 
•
c o ntrace pti ve r o d i m pla nte d i nt o t he s ki n
C o m bi nati o n met h o d (re q uires use of t w o of t he f oll o wi n g):
•
dia p hra g m wit h 
s per mici de (ca n n ot be use d i n c o nj u ncti o n wit h 
cer vical 
ca p/s per mici de)
•
cer vical ca p wit h s per mici de ( n ulli par o us w o me n o nl y )  
•
c o ntrace pti ve s p o n ge ( n ulli par o us w o me n o nl y ) 
•
male c o n d o m or fe male c o n d o m (ca n n ot be use d t o get her)
•
h or m o nal c o ntrace pti ve: oral c o ntrace pti ve pill (estr o ge n/ pr o gesti n pill or 
pr o gesti n -o nl y  pill), c o ntrace pti ve s ki n patc h, va gi nal c o ntrace pti ve ri n g, or 
s u bc uta ne o us c o ntrace pti ve i njecti o n
† A bsti ne nce (relati ve t o heter ose x ual acti vit y) ca n be use d as t he s ole met h o d 
of 
c o ntrace pti o n if it is c o nsiste ntl y em pl o y e d as t he s u bject’s preferre d a nd us ual lifest yle 
a n d if c o nsi dere d acce pta ble b y  local re g ulat or y age ncies a n d E R Cs/I R Bs.  Peri o dic 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
a bsti ne nce (e. g., cale n dar, o v ulati o n, s ym pt o -t her mal, p ost -o v ulati o n met h o ds, etc.) a n d 
wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n. 
‡I f a c o ntrace pti ve met h o d liste d a b o ve is restricte d b y  local re g ulati o ns/ g ui deli nes, t he n 
it d oes n ot q ualif y  as a n acce pta ble met h o d of c o ntrace pti o n f or s u bjects partici pati n g at 
sites i n t his c o u ntr y/re gi o n.
S u bjects s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y  in v ol ve u n k n o w n ris ks t o 
t he fet us ( u n b or n ba b y)  if pre g na nc y  were t o occ ur d uri n g t he st u d y.  In or der t o partici pate 
i n t he st u d y, s u bjects of c hil d beari n g p ote ntial m ust a d here t o t he c o ntrace pti o n re q uire me nt 
( descri be d a b o ve) fr o m t he d a y of st u d y me dicati o n 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 me dicati o n f or oral c o ntrace pti o n) t hr o u g h o ut t he st u d y peri o d u p t o 1 2 0 
da y s after t he last d ose of trial t hera py. If t here is a n y questi o n t hat a s u bject of c hil d beari n g 
p ote nti al 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 s u bject s h o ul d 
n ot be e ntere d i nt o t he st u d y .
Use i n Pre g n a nc y
If a fe male s u bject i na d verte ntl y bec o mes pre g na nt w hile o n treat me nt i n t his st u d y, t he 
s u bject will i m me diatel y  be rem o ve d fr o m t he st u d y . T he site will c o ntact t he s u bject at least 
m o nt hl y  an d d oc u me nt t he s u bject’s stat us u ntil t he pre g na nc y  has bee n c o m plete d or 
ter mi nate d. T he o utc o me of t he pre g na nc y  will be re p orte d t o t he S p o ns or wit h o ut dela y  an d 
wit hi n 2 4 h o urs if t he o utc o me is a seri o us a d verse e x perie nce (e. g., deat h, a b orti o n, 
c o n ge nital a n o mal y,  or ot her disa bli n g or life-t hreate ni n g c o m plicati o n t o t he m ot her or 
ne w b or n). T he st u d y in 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 t he S p o ns or. 
Use i n N ursi n g W o me n
It is u n k n o w n w het her pe m br oliz u ma b is e xcrete d i n h u ma n mil k. Si nce ma n y dr u gs are 
e xcrete d i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d verse reacti o ns i n t he 
n ursi n g i nfa nt, s u bjects w h o are breast -fee di n g are n ot eli gi ble f or e nr oll me nt.
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a
S u bjects ma y  wit h dra w c o nse nt at a n y ti me f or a n y reas o n or be dr o p pe d fr o m t he trial at t he 
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 s u bject ma y b e 
wit h dra w n b y  the i n vesti gat or or t he S p o ns or if e nr oll me nt i nt o t he trial is i na p pr o priate, t he 
trial pla n is vi olate d, or f or a d mi nistrati ve a n d/ or ot her safety reas o ns.  Specific details 
re gar di n g disc o nti n uati o n or wit h dra wal pr oce d ures ; i ncl u di n g s pecific details re gar di n g 
wit h dra wal fr o m F ut ure Bi o me dical Researc h,
are pr o vi de d i n Secti o n 7. 1. 4 –
Ot her 
Pr oce d ures.
I n t his trial, a s u bject ma y  disc o nti n ue fr o m treat me nt b ut c o nti n ue t o partici pate i n t he 
re g ularly sc he d ule d acti vities, as l o n g as t he s u bject d oes n ot wit h dra w c o nse nt. T he 
disc o nti n uati o n fr o m t he treat me nt is per ma ne nt e xce pt 1) a s u bject w h o
disc o nti n ue d 
treat me nt f or C R or 2) a s u bject w h o disc o nti n ue d after recei vi n g t he ma xi m u m 
3 5 
pe m br oliz u ma b/ sali ne place b o treat me nt. T hese last t w o cate g ories of s u bjects m a y  be 
all o we d t o be gi n treat me nt a gai n if dee me d me dicall y ap pr o priate i n t he sec o n d c o urse p hase 
(re-treat me nt).
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
4 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A s u bject m ust be disc o nti n ue d fr o m t he trial f or t he f oll o wi n g reas o ns:

T he s u bject or le gal re prese ntati ve (s uc h as a pare nt or le gal g uar dia n) wit h dra ws 
c o nse nt.

T he s u bject is l ost t o f oll o w - u p
A s u bject m ust be disc o nti n ue d fr o m trial treat me nt b ut c o nti n ue t o be f oll o we d f or a n y of 
t he f oll o wi n g reas o ns:

U nacce pta ble a d verse e x perie nces as descri be d i n Secti o n 5. 2. 1. 2.

C o m plete d t otal of 3 5 treat me nts of pe m br oliz u ma b/ sali ne place b o

D oc u me nte d disease pr o gressi o n
N ote: If a s u bject has pr o gressi o n of disease verifie d b y  ce ntral ra di ol o gical re vie w 
usi n g R E CI S T 1. 1, t he s u bject m a y  be u n bli n de d. I f a s u bject was recei vi n g sali ne 
place b o a n d meets all cr oss o ver criteria defi ne d i n Secti o n 7. 1. 5. 5, he/s he will ha ve 
t he o p p ort u nit y  to cr oss o ver t o recei ve o pe n -la bel pe m br oliz u ma b m o n ot hera p y . If a 
s u bject was recei vi n g pe m br oliz u ma b a n d is dee me d t o be cli nicall y be nefiti n g 
des pite ra di ol o gical pr o gressi o n t he y will ha ve t he o p p ort u nit y  t o c o nti n ue o pe n-la bel 
pe m br oliz u ma b m o n ot hera p y. If a s u bject has u nc o nfir me d pr o gress i o n of disease 
a n d is cli nicall y sta ble, it is at t he discreti o n of t he i n vesti gat or t o c o nti n ue treati n g 
t he s u bject wit h t he assi g ne d treat me nt per pr ot oc ol u ntil pr o gressi o n of disease is 
c o nfir me d at least 2 8 d a y s fr o m t he date of t he sca n s u g gesti n g p r o gressi o n of 
disease.
Cli nical Sta bilit y  is defi ne d as:
o
A bse nce of s ym pt o ms a n d si g ns i n dicati n g cli nicall y si g nifica nt pr o gressi o n of 
disease (i ncl u di n g w orse ni n g of la b orat or y  val ues) i n dicati n g disease pr o gressi o n.
o
N o decli ne i n E C O G perf or ma nce stat us .
o
A bse nce 
of ra pi d pr o gressi o n of disease or pr o gressi ve t u m or at critical 
a nat o mical sites (e. g., c or d c o m pressi o n) re q uiri n g ur ge nt alter nati ve me dical 
i nter ve nti o n.

I 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 s u bject fr o m treat me nt

T he s u bject has a c o nfir me d p ositi ve ser u m pre g na nc y  test

N o nc o m plia nce wit h trial treat me nt or pr oce d ure re q uire me nts

A d mi nistrati ve reas o ns
If a s u bject attai ns C R verifie d b y  ce ntral ra di ol o gical re vie w, h a s bee n treate d f or at least 
ei g ht c ycles of st u d y  treat me nt, a n d has at least t w o c ycles of st u d y treat me nt be y o n d t he date 
w he n t he i nitial C R was declare d O R t he s u bject has recei ve d t he ma xi m u m a d mi nistrati o ns 
of pe m br oliz u ma b / place b o as o utli ne d a b o ve, t he s u bject a n d I n vesti gat or ma y  co nsi der 
st o p pi n g  
t hera py  
wit h  
pe m br oliz u ma b / place b o.  
S u bjects  
w h o  
disc o nti n ue 
pe m br oliz u ma b / place b o a n d t he n e x perie nce ra di o gra p hic disease pr o gressi o n
b y  local 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
i n vesti gat or’s assess me nt acc or di n g t o ir R E CI S T m a y  be eli g i ble f or re-treat me nt wit h 
pe m br oliz u ma b i n t he Sec o n d C o urse P hase at t he discreti o n of t he I nvesti gat or as descri be d 
i n Secti o n 7. 1. 5. 4.
C he m ot hera p y will be disc o nti n ue d w he n a s u bject has recei ve d t he ma xi m u m n u m ber of 4 
c ycles as o utli ne d i n t he pr ot oc ol.
T he E n d of Treat me nt a n d F oll o w -u p visit pr oce d ures are liste d i n Secti o n 6 - Trial Fl o w 
C hart a n d Secti o n 7. 1. 5 - Visit Re q uire me nts.  After t he e n d of treat me nt, eac h s u bject will 
be f oll o we d f or a mi ni m u m of 3 0 da y s f or a d verse e ve nt m o nit ori n g e ve n if t he s u bject 
starte d ne w a nti ne o plastic treat me nt (seri o us a d verse e ve nts will be c ollecte d f or u p t o 9 0 
da y s f oll o wi n g cessati o n of S p o ns or’s pr o d uct, or 3 0 da y s f oll o wi n g cessati o n of treat me nt if 
t he s u bject i nitiates ne w a ntica ncer t hera py,  wh ic he ver is earlier as descri be d i n Secti o n 
7. 2. 3. 1). S u bjects will 
ha ve p ost -treat me nt f oll o w-u p f or disease stat us u ntil disease 
pr o gressi o n, i nitiati n g a n o n -st u d y ca ncer treat me nt, wit h dra wi n g c o nse nt, bec o mi n g l ost t o 
f oll o w-u p or e nteri n g t he Sec o n d C o urse P hase.  
T his st u d y will be c o nsi dere d c o m plete i n ter ms of pri mar y  en d p oi nt f oll o wi n g t he fi nal 
a nal ys is of P F S a n d O S , after t he pre-s pecifie d n u m ber of P F S a n d O S e ve nts.
S u bject Re pl ace me nt Str ate g y
A s u bject w h o disc o nti n ues fr o m t he trial will n ot be re place d.
Be gi n ni n g a n d E n d of t he Tri al
T he o verall trial be gi ns w he n t he first s u bject si g ns t he i nf or me d c o nse nt f or m.  The o verall 
trial e n ds w he n t he last s u bject c o m pletes t he last st u d y-relate d p h o ne -call or visit,
disc o nti n ues fr o m t he trial or is l ost t o f oll o w-u p (i.e. t he s u bject is u na ble t o be c o ntacte d b y  
t he i n vesti gat or).
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n
T he cli nical trial ma y  be ter mi nate d earl y if t he e xte nt (i nci de nce a n d/ or se verit y) of 
e mer gi n g effects/cli nical e n d p o i nts is s uc h t hat t he ris k/ be nefit rati o t o t he trial p o p ulati o n as 
a w h ole is u nacce pta ble.  In a d diti o n, f urt her recr uit me nt i n t he trial or at (a) partic ular trial 
site(s) ma y  be st o p pe d d ue t o i ns ufficie nt c o m plia nce wit h t he pr ot oc ol, G C P a n d/ or ot her
a p plica ble re g ulat or y re q uire me nts, pr oce d ure -relate d pr o ble ms 
or 
t he 
n u m ber of 
disc o nti n uati o ns f or a d mi nistrati ve reas o ns is t o o hi g h.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
6. 0 T RI A L F L O W C H A R T
I niti al Tre at me nt P h ase
I niti al Tre at me nt P h ase – C ycles 1 - 4
Details re gar di n g pr oce d ures liste d i n t his ta ble are o utli ne d i n Secti o n 7.
Scree ni n g 
P h ase
Tre at me nt C ycles   ( 3-Wee k C ycles)
Tre at me nt C ycle
Scree ni n g 
( Visit 1)
1  
1  
1  
2  
2  
2  
3  
3  
3  
4  
4  
4
D a y (i n C ycle)
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5
Sc he d uli n g Wi n d o w ( D a ys): 1
-2 8 t o - 1 
+ 3 
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1
A d mi nistr ati ve Pr oce d ures
I nf or me d C o nse nt 
X
I nf or me d C o nse nt f or F ut ure Bi o me dical Researc h 
( o pti o nal)
X
I ncl usi o n/ E xcl usi o n Criteria
X
S u bject I de ntificati o n Car d
X
De m o gra p hics a n d Me dical Hist or y
X
Pri or a n d C o nc o mita nt Me dicati o ns
X
X
X
X
X
N S C L C Disease Details a n d Pri or Treat me nt
X
Call I V R S
X   
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
Cli nic al Pr oce d ures / Assess me nts
Re vie w A d verse E ve nts 
X   
X 3
X 3
X   
X 3
X 3
X   
X 3
X 3
X   
X 3
X 3
F ull P h ysical E xa mi nati o n
X
Directe d P h ysical E xa mi nati o n
X
X
X
X
Vital Si g ns a n d Wei g ht 
X 4
X   
X 3
X 3
X   
X 3
X 3
X   
X 3
X 3
X   
X 3
X 3
1 2 -Lea d E C G
X
E C O G Perf or ma nce Stat us
X 5
X
X
X
X
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Scree ni n g 
P h ase
Tre at me nt C ycles   ( 3-Wee k C ycles)
Tre at me nt C ycle
Scree ni n g 
( Visit 1)
1  
1  
1  
2  
2  
2  
3  
3  
3  
4  
4  
4
D a y (i n C ycle)
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5
Sc he d uli n g Wi n d o w ( D a ys): 1
-2 8 t o - 1 
+ 3 
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1
L a b or at or y Pr oce d ures / Assess me nts: A n al ysis Perf or me d b y L oc al L a b or at or y
Pre g na nc y Test - Uri ne or Ser u m β -H C G 6
X
P T /I N R a n d a P T T/ P T T 
X 5
C B C wit h Differe ntial
7
X 5
X 3, 8
X 2, 8
X   
X 3, 8
X 3 , 8
X   
X 3, 8
X 3, 8
X 
X 3, 8
X 3, 8
C o m pre he nsi ve C he mistr y Pa nel 5, 7
X 5
X
X
X
Uri nal ysis 7
X 5
T 3 or F T 3, F T 4 a n d T S H 7, 9
X 5
X
X
A n al ysis Perf or me d b y Ce ntr al L a b or at or y
Bl o o d f or Ge netic A nal ysis 1 0
X
Bl o o d f or R N A A nal yses
X
X
Bl o o d f or Plas ma Bi o mar ker A nal yses
X
X
Bl o o d f or Ser u m Bi o mar ker A nal yses
X
X
T u m or Tiss ue C ollecti o n
T u m or Tiss ue C ollecti o n 
X
Effic ac y Me as ure me nts
T u m or I ma gi n g 
X
X 1 1
St u d y Dr u g A d mi nistr ati o n
Car b o plati n
X
X
X
X
Paclita xel 
X
X
X
X
Na b -paclita xel 1 2
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
Pe m br oliz u ma b or Sali ne Place b o 1 3
X
X
X
X
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Scree ni n g 
P h ase
Tre at me nt C ycles   ( 3-Wee k C ycles)
Tre at me nt C ycle
Scree ni n g 
( Visit 1)
1  
1  
1  
2  
2  
2  
3  
3  
3  
4  
4  
4
D a y (i n C ycle)
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5 
1  
8 
1 5
Sc he d uli n g Wi n d o w ( D a ys): 1
-2 8 t o - 1 
+ 3 
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1  
± 3  
± 1  
± 1
P atie nt Re p orte d O utc o mes ( P R O) 1 4
E ur o Q ol ( E Q) -5 D 1
X
X
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
E O R T C Q L Q -L C 1 3
X
X
X
X
1. 
I n ge neral, t he wi n d o w f or eac h visit is ± 3 da ys u nless ot her wise n ote d. If treat me nt c ycles are a dj uste d all pr oce d ures e xce pt i ma gi n g will be c o m plete d acc or di n g t o t he 
C y cle n u m ber a n d n ot wee ks o n treat me nt, i ma gi n g will n ot be a dj uste d f or dela ys i n treat me nt c ycles a n d will be perf or me d per cale n dar sc he d ule .
2. 
O n C ycle 1, Da y 1, call t o o btai n all ocati o n n u m ber .  At s u bse q ue nt visits, call t o e ns ure visits are ca pt ure d i n t he I V R S s yste m.
3. 
Visit D a y 8 a n d D a y 1 5 pr oce d ures o nl y a p pl y t o s u bjects recei vi n g na b-paclita xel.
4. 
Hei g ht will be meas ure d o nl y at Visit 1.
5. 
E C O G a n d la b orat or y tests f or scree ni n g 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 trial treat me nt.
6. 
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o first d ose of trial treat me nt. A ser u m test ca n be c o nsi der e d if uri ne is 
n ot a p pr o priate. 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.
7. 
After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 3 da ys pri or t o Da y 1 of s u bse q ue nt c ycles.
8. 
If s u bject recei ve d na b-paclita xel, la bs are dra w n i n c o nj u ncti o n wit h eac h d ose of na b -paclita xel o n Da y 8 a n d Da y 1 5 of eac h Q 3 W c ycle.
9. 
S u bjects ma y be d ose d i n s u bse q ue nt c ycles after C ycl e 1 , D a y 1 w hile t h yr oi d f u ncti o n tests are pe n di n g.
1 0. T his sa m ple s h o ul d be dra w n f or pla n ne d a nal ysis of t he ass ociati o n bet wee n ge netic varia nts i n D N A a n d dr u g res p o nse. If t he re is eit her a d oc u me nte d la w or re g ulati o n
pr o hi biti n g c ollecti o n, or if t he I R B/I E C d oes n ot a p pr o ve t he c ollecti o n of t he sa m ple f or t hese p ur p oses, t he n t his sa m ple will n ot be c ollecte d at t hat site. If t he sa m ple is 
c ollecte d, left o ver e xtracte d D N A will be st ore d f or f ut ure bi o me dical resear c h if t he s u bject si g ns t he F B R c o nse nt. If t he pla n ne d ge netic a nal ysis is n ot a p pr o ve d, b ut F B R is 
a p pr o ve d a n d c o nse nt is gi ve n, t his sa m ple will be c ollecte d f or t he p ur p ose of F B .
1 1 .  I ma gi n g is perf or me d at wee k 6 ( ± 7 da ys) a n d wee k 1 2 ( ± 7 da ys) an d wee k 1 8 ( ± 7 da ys) t he n e ver y 9 wee ks ( 6 3 da ys ± 7 da ys) f or t he first 4 5 wee ks i n t he treat me nt peri o d.  
Refer t o i ma gi n g ma n ual f or a d diti o nal details. 
1 2 . D osi n g f or na b -paclita xel is o n Da y 1, Da y 8 a n d Da y 1 5 of eac h Q 3 W.
1 3. S u bjects assi g ne d t o t he place b o ar m ( Ar m 2) ma y disc o nti n ue treat me nt wit h sali ne place b o a n d ha ve t he o pti o n of recei vi n g pe m br oliz u ma b if t here is d oc u me nte d 
pr o gressi ve disease b y ce ntral ra di ol o gical re vie w.
1 4. P R Os ( 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-L C 1 3) are c o m plet e d at C ycles 1 t hr o u g h 7 a n d t he n e ver y 3r d c ycle (e ver y 9 wee ks) w hile o n treat me nt u p t o 4 8 wee ks.  
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I niti al Tre at me nt P h ase – C ycles 5 a n d Be y o n d
Details re gar di n g pr oce d ures liste d i n t his ta ble are o utli ne d i n Secti o n 7.
Tre at me nt C ycles   ( 3-Wee k C ycles)
E n d of Tre at me nt 
P ost Tre at me nt
Tre at me nt C ycle
5 
6 t o 1 7 
1 8 t o 3 5 
Disc o n
S afet y F oll o w -
u p
F oll o w -u p Visits 
S ur vi v al F oll o w -u p 1
Sc he d uli n g Wi n d o w ( D a ys): 2
± 3  
± 3  
± 3
At Ti me of 
Disc o n ± 3 
d a ys
3 0 D a ys P ost 
D ose + 7 d a ys
6 Wee ks P ost 
S afet y F oll o w -u p ± 
3 d a ys
E ver y 1 2 Wee ks ± 7 
d a ys
Pri or a n d C o nc o mita nt Me dicati o ns
X   
X   
X
X
X
X
X
S u bse q ue nt a nti ne o plastic t hera p y stat us
X
X
X
X
S ur vi val Stat us 3
X
Cli nic al Pr oce d ures / Assess me nts
Re vie w A d verse E ve nts 
X   
X   
X
X
X
X 4
F ull P h ysical E xa m
X
Directe d P h ysical E xa mi nati o n
X   
X   
X
Vital Si g ns a n d Wei g ht 5
X   
X   
X
X
X
E C O G Perf or ma nce Stat us
X   
X   
X
X
X
L a b or at or y Pr oce d ures / Assess me nts: A n al ysis Perf or me d b y L oc al L a b or at or y
Pre g na nc y Test - Uri ne or Ser u m β -H C G 
X 6
C B C wit h Differe ntial
7
X   
X   
X
X
X
C o m pre he nsi ve C he mistr y Pa nel 7
X   
X   
X
X
X
Uri nal ysis 7
X 8
X 8
X
T 3 or F T 3, F T 4 a n d T S H 7, 9
X 1 0
X 1 0
X
A n al ysis Perf or me d b y Ce ntr al L a b or at or y
Bl o o d f or R N A A nal yses
X
X
Bl o o d f or Plas ma Bi o mar ker A nal yses
X
Bl o o d f or Ser u m Bi o mar ker A nal yses
X
Effic ac y Me as ure me nts
T u m or I ma gi n g 
X 1 1
X 1 1 
X 1 2
X 1 3
X 1 3 ,1 4
St u d y Dr u g A d mi nistr ati o n
Pe m br oliz u ma b or Sali ne Place b o 1 5
X   
X   
X
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Tre at me nt C ycles   ( 3-Wee k C ycles)
E n d of Tre at me nt 
P ost Tre at me nt
Tre at me nt C ycle
5  
6 t o 1 7 
1 8 t o 3 5 
Disc o n
S afet y F oll o w -
u p
F oll o w -u p Visits 
S ur vi v al F oll o w -u p 1
Sc he d uli n g Wi n d o w ( D a ys): 2
± 3  
± 3  
± 3
At Ti me of 
Disc o n ± 3 
d a ys
3 0 D a ys P ost 
D ose + 7 d a ys
6 Wee ks P ost 
S afet y F oll o w -u p ± 
3 d a ys
E ver y 1 2 Wee ks ± 7 
d a ys
P atie nt Re p orte d O utc o mes ( P R O) 1 6
E ur o Q ol ( E Q)-5 D
X   
X
X
X
E O R T C Q L Q -C 3 0
X   
X
X
X
E O R T C Q L Q -L C 1 3
X   
X
X
X
1. 
After d oc u me nte d disease pr o gressi o n, or t he start of ne w a nti -ca ncer treat me nt; c o ntacts are e ver y 1 2 wee ks b y tele p h o ne
2. 
I n ge neral, t he wi n d o w f or eac h visit is ± 3 da ys u nless ot her wise n ote d. 
3. 
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 wee ks b y tele p h o ne. U p date d s ur vi val 
status ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o ns or n otificati o n, all partici pa nts w h o d o n ot/ will n ot ha ve a sc he d ule d st u d y visit 
or st u d y c o ntact d uri n g t he S p o ns or defi ne d ti me peri o d will be c o ntacte d f or t heir s ur vi val stat us (e xcl u di n g partici pa nts t hat ha ve a deat h e ve nt pre vi o usl y rec or de d).
4. 
Seri o us a d verse e ve nts m ust be re p orte d u p t o 9 0 da ys f oll o wi n g cessati o n of treat me nt or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w a ntica ncer 
t hera p y, w hic he ver is earlier.
5. 
Hei g ht will be meas ure d o nl y at Visit 1.
6. 
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o u rs pri or t o first d ose of trial treat me nt. A ser u m test ca n be c o nsi dere d if uri ne is 
n ot a p pr o priate. 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.
7. 
After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 3 da ys pri o r t o Da y 1 of s u bse q ue nt c ycles.
8. 
T o be re peate d e ver y 6 c ycles be gi n ni n g wit h C ycle 6.
9. 
S u bjects ma y be d ose d i n s u bse q ue nt c ycles after C ycl e 1, D a y 1 w hile t h yr oi d f u ncti o n tests are pe n di n g.
1 0. T o be re peate d e ver y ot her C ycle be gi n ni n g wit h C ycl e 6.
1 1. I ma gi n g is perf or me d at wee k 6 ( ± 7 da ys), wee k 1 2 ( ± 7 da ys) a n d wee k 1 8 ( ± 7 da ys) t he n e ver y 9 wee ks ( 6 3 da ys ± 7 da ys) f or t he first 4 5 wee ks i n t he treat me nt peri o d. 
Refer t o i ma gi n g ma n ual f or a d diti o nal details.
1 2 . I ma gi n g perf or me d e ver y 1 2 wee ks ( 8 4 da ys ± 7 da ys) s u bse q ue ntl y. Refer t o i ma gi n g ma n ual f or a d diti o nal details.
1 3 . If a pre vi o us sca n was o btai ne d wit hi n 4 wee ks pri or t o t he date of disc o nti n uati o n, t he n a sca n at treat me nt disc o nti n uati o n is n ot ma n dat or y. F oll o w u p sca ns t o be perf or me d 
e ver y 1 2 wee ks ( 8 4 ± 7 da ys), refer t o secti o n 7. 1. 2. 6. 3. 
1 4 . I n s u bjects w h o disc o nti n ue trial treat me nt, t u m or i ma gi n g s h o ul d be perf or me d at t he ti me of treat me nt disc o nti n uati o n ( ± 4 wee k wi n d o w).
1 5. S u bjects assi g ne d t o t he place b o ar m ( Ar m 2) ma y disc o nti n ue treat me nt wit h sali ne place b o a n d ha ve t he o pti o n of recei vi n g pe m br oliz u ma b if t here is d oc u me nt e d 
pr o gressi ve disease b y ce ntral ra di ol o gical re vie w.
1 6. P R Os ( 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-L C 1 3) are c o m plete d at C ycles 1 t hr o u g h 7 a n d t he n e ver y 3r d c ycle (e ver y 9 wee ks) w hile o n treat me nt u p t o 4 8 
wee ks.  All P R Os are als o c o m plete d at treat me nt disc o nti n uati o n visit a n d 3 0 -da y safet y f oll o w -u p visit .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Sec o n d C o urse P h ase ( Retre at me nt)
Details re gar di n g t he pr oce d ures liste d i n t his ta ble are o utli ne d i n Secti o n 7. 0.  Sec o n d c o urse retreat me nt s u bjects m a y  recei ve u p t o 
1 7 c y cles (a p pr o xi matel y 1 y ear) of pe m br oliz u ma b t hera p y.
Tri al Peri o d:
Tre at me nt C ycles ( 3 -Wee k C ycles)
E n d of 
Treat me nt
P ost -Tre at me nt
Tre at me nt C ycle/ Title:
1  
2  
3  
4
T o be Re pe ate d 
Be y o n d 6 C ycles 
Disc o n
S afet y 
F oll o w -u p 1
F oll o w 
U p Visits
S ur vi v al 
F oll o w -
u p 1
5  
6
Sc he d uli n g Wi n d o w ( D a ys) 2:
+ 3 
± 3  
± 3  
± 3  
± 3 
± 3
At T i me 
of 
Disc o n ± 3 
d a ys
3 0 D a ys 
P ost 
Disc o n + 7 
d a ys
6 Wee ks 
P ost 
S afet y 
F oll o w 
u p ± 3 
d a ys
E ver y 
1 2 
W e e ks± 
7 d a ys
A d mi nistr ati ve Pr oce d ures
Eli gi bilit y Criteria
X
C o nc o mita nt Me dicati o n Re vie w
X 
X 
X 
X 
X 
X 
X 
X
S u bse q ue nt a nti ne o plastic t hera p y stat us
X 
X 
X 
X
S ur vi val Stat us 3
X
Cli nic al Pr oce d ures/ Assess me nts
Re vie w A d verse E ve nts
X 
X 
X 
X 
X 
X 
X 
X 
X
F ull P h ysical E xa mi nati o n
X
Directe d P h ysical E xa mi nati o n
X 
X 
X 
X 
X 
X
Vital Si g ns
X 
X 
X 
X 
X 
X 
X
E C O G Perf or ma nce Stat us
X 
X 
X 
X 
X 
X 
X 
X
L a b or at or y Pr oce d ures/ Assess me nts:  a n al ysis perf or me d 
b y L O C A L l a b or at or y
Pre g na nc y Test – Ser u m or Uri ne
X 4
He mat ol o g y 5
X 6
X 
X 
X 
X 
X 
X 
X
C he mistr y Pa nel 5
X 6
X 
X 
X 
X 
X 
X 
X
Uri nal ysis 5
X 6
X
X 8
T 3 or F T 3, F T 4, T S H 5, 7
X 6
X
X 9
X
Effic ac y Me as ure me nts
T u m or I ma gi n g
X 1 0
X 1 1
X 1 1
X
X 1 1
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Tri al Peri o d:
Tre at me nt C ycles ( 3 -Wee k C ycles)
E n d of 
Treat me nt
P ost -Tre at me nt
Tre at me nt C ycle/ Title:
1  
2  
3  
4
T o be Re pe ate d 
Be y o n d 6 C ycles 
Disc o n
S afet y 
F oll o w -u p 1
F oll o w 
U p Visits
S ur vi v al 
F oll o w -
u p 1
5  
6
Sc he d uli n g Wi n d o w ( D a ys) 2:
+ 3 
± 3  
± 3  
± 3  
± 3  
± 3
At T i me 
of 
Disc o n ± 3 
d a ys
3 0 D a ys 
P ost 
Disc o n + 7 
d a ys
6 Wee ks 
P ost 
S afet y 
F oll o w 
u p ± 3 
d a ys
E ver y 
1 2 
W e e ks± 
7 d a ys
St u d y Dr u g A d mi nistr ati o n
Pe m br oliz u ma b 
X 
X 
X 
X 
X 
X
1. After d oc u me nte d disease pr o gressi o n, or t he start of ne w a nti-ca ncer treat me nt ; c o ntacts are e ver y 1 2 wee ks b y tele p h o ne.
2. I n ge neral, t he wi n d o w f or eac h visit is ± 3 da ys u nless ot her wise n ote d.
3. After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 wee ks b y tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o ns or n otificati o n, all partici pa nts w h o d o n ot/ will n ot ha ve a sc he d ule d st u d y visit 
or st u d y c o ntact d uri n g t he S p o ns or defi ne d ti me peri o d will be c o ntacte d f or t heir s ur vi val stat us (e xcl u di n g partici pa nts t hat ha ve a deat h e ve nt pre vi o usl y rec o r de d).
4. F o r w o me n of re pr o d ucti ve p ote ntial, a ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o first d ose of trial treat me nt. A uri ne test ca n be c o nsi dere d if ser u m 
is n ot a p pr o priate.
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.
5. After C ycle 1, la b sa m ple s ca n be c ollecte d u p t o 3 da ys pri or t o t he sc he d ule d ti me p oi nt.  
6. La b orat or y tests f or deter mi ni n g eli gi bilit y f or retreat me nt are t o be perf or me d wit hi n 1 0 da ys pri or t o t he first retreat me nt d ose of pe m br oliz u ma b.  
7. S u bjects ma y be d ose d i n s u bse q ue nt c ycles after C ycl e 1, D a y 1 w hile t h yr oi d f u ncti o n tests are pe n di n g. 6
8. T o be re peate d e ver y 6 c ycles be gi n ni n g wit h c ycle 6.
9. T o be re peate d e ver y ot her c ycle be gi n ni n g wit h c ycle 6.
1 0 . A sca n 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.
1 1. I ma gi n g perf or me d e ver y 1 2 wee ks ( 8 4 ± 7 da ys) fr o m t he date of re-treat me nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Cr oss o ver P h ase
A p plica ble f or s u bjects w h o are u n bli n de d after verificati o n f or P D b y  bli n de d i n de pe n de nt ce ntral ra di ol o gical re vie w a n d eli gi ble 
a n d q ualifie d f or t he cr oss o ver p hase . Details re gar di n g t he pr oce d ures liste d i n t his ta ble are o utli ne d i n Secti o n 7. 0.  Cr oss o ver 
s u bjects ma y recei ve u p t o 3 5 c ycles (a p pr o xi matel y 2 ye ars) of pe m br oliz u ma b t hera p y.
Scr  
P h ase
Tre at me nt C ycles 1
E n d of Tre at me nt P h ase
F oll o w 
u p 
P h ase 2
S ur vi v al 
F oll o w 
u p 3
Tre at me nt C ycle / Sc he d ule d 
Ti m e
Scr  
( Visit 
1)
1 4
2  
3  
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3
1 4 
t hr o u g h 
3 5
Disc o nti n u ati o n 
Visit 5
S afet y 
F oll o w u p 
Visit 6
F oll o w 
u p Visit 
3 a n d 
B e y o n d
S ur vi v al 
F oll o w 
u p Visit 
1 a n d 
B e y o n d
Sc he d uli n g Wi n d o w ( D a ys):
-2 8 t o 
- 1
+ 3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3 
± 3 
± 3  
± 3  
± 3  
± 3  
± 3
At St u d y Dr u g 
Disco nti n uatio n ± 3
3 0 Days 
Fro m Last 
Dose + 7
E ver y 3 
Mo nt hs 
A fter Visit 
2 ± 3
E ver y 3 
M o nt hs     
± 7
A d m i nistr ati ve Pr oce d ures
Pri or a n d C o nc o mita nt 
Me dicati o ns
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
X
X
S u bse q ue nt a nti ne o plastic 
t hera p y stat us
X
X   
X   
X
S ur vi val Stat us 7
X
Cli nic al Pr oce d ures / Assess me nts
Re vie w A d verse E ve nts
8
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
X
X   
X
F ull P h ysical E xa mi nati o n 
X 
X
X
X
Directe d P h ysical E xa mi nati o n 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
Vital Si g ns a n d Wei g ht
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
E C O G Perf or ma nce Stat us 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
L a b or at or y Pr oce d ures / Assess me nts: a n al ysis perf or me d b y l oc al l a b or at or y 9
C B C  wit h Differe ntial
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
P T/ I N R a n d a P T T/ P T T 
X 
X
C o m pre he nsi ve C he mistr y 
Pa nel
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
X
X
Uri nal ysis
X 
X
X
X
X 
X 1 0
X
X
T 3 or F T 3, F T 4 a n d T S H 1 1
X 
X 
X
X
X
X
X
X
X
X
X
Pre g na nc y Test – Ser u m or 
Uri ne
X
X 1 2
Effic ac y Me as ure me nts
T u m or I ma gi n g 1 3
X   
X
X
X
X   
X
X
X
X 1 4
St u d y Dr u g A d mi nistr ati o n
Pe m br oliz u ma b 1 5
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
5 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Scr  
P h ase
Tre at me nt C ycles 1
E n d of Tre at me nt P h ase
F oll o w 
u p 
P h ase 2
S ur vi v al 
F oll o w 
u p 3
Tre at me nt C ycle / Sc he d ule d 
Ti m e
Scr  
( Visit 
1)
1 4
2  
3  
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3
1 4 
t hr o u g h 
3 5
Disc o nti n u ati o n 
Visit 5
S afet y 
F oll o w u p 
Visit 6
F oll o w 
u p Visit 
3 a n d 
Be y o n d
S ur vi v al 
F oll o w 
u p Visit 
1 a n d 
B e y o n d
Sc he d uli n g Wi n d o w ( D a ys):
-2 8 t o 
- 1
+ 3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3
± 3
± 3  
± 3  
± 3  
± 3  
± 3
At St u d y Dr u g 
Disco nti n uatio n ± 3
3 0 Days 
Fro m Last 
Dose + 7
E ver y 3 
Mo nt hs 
A fter Visit 
2 ± 3
E ver y 3 
M o nt hs     
± 7
1. 
I n ge neral, 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 trial treat me nt f or eac h c ycle u nless ot her wise s pecifie d.   Treat me nt c ycles are 3 
wee ks ( 2 1 da ys ± 3 da ys).  If treat me nt c ycles are a dj uste d all pr oce d ures e xce pt i ma gi n g will be c o m plete d acc or di n g t o t he C ycle n u m ber a n d n ot wee ks o n treat me nt, i ma gi n g 
will be perf or me d e ver y 1 2 wee ks ( 8 4 da ys ± 7 da ys) fr o m t he first d ose of trial treat me nt re gar dless of a n y treat me nt dela ys.
2. 
S u bjects w h o st o p pe m br oliz u ma b after 3 5 trial treat me nts a n d ha ve ac hie ve d P R a n d/ or S D O R ha ve ac hie ve d a C R (see secti o n 5. 8 ) will m o ve t o t he F oll o w u p P hase of t he 
st u d y. F oll o w u p visit 1 s h o ul d ta ke place 3 m o nt hs after t he last d ose of trial treat me nt. F oll o w u p visit 2 s h o ul d ta ke pla ce 6 m o nt hs after last d ose of trial treat me nt a n d 
a d diti o nal F oll o w u p visits s h o ul d ta ke place e ver y 3 m o nt hs t hereafter. S u bjects w h o e x perie nce disease pr o gressi o n (a n d d o n ot c o nti n ue i nt o t he Sec o n d C o urse P hase) or start a 
ne w a nti ne o plastic t hera p y will m o ve directl y i nt o S ur vi val F oll o w u p. F or s u bject c o n ve nie nce, all F oll o w u p assess me n ts ma y occ ur d uri n g t he sa me visit as t he i ma gi n g st u dies 
are o btai ne d.  S u bjects wit h a n A E of Gra de > 1 will be f urt her f oll o we d u ntil t he res ol uti o n of t he A E t o Gra de 0 -1 or u ntil be gi n ni n g of a ne w a nti ne o plastic t hera p y, w hic he ver 
occ urs first
3. 
O nce t h e s u bject st o ps t he i ma gi n g assess me nts f or t his pr ot oc ol (e. g. f or P D or starti n g a ne w a nti ne o plastic t hera p y), t he s u bject m o ves i nt o t he S ur vi val F oll o w -u p P hase a n d 
s h o ul d be c o ntacte d b y tele p h o ne e ver y 3 m o nt hs t o assess f or s ur vi val stat us.  P ost -st u d y treat me nts a n d t he s u bject’s res p o nse t o t he m will als o be c ollecte d.
4. 
Scree ni n g pr oce d ures ma y be c o m plete d d uri n g t hese 3 0 da ys.  All pr oce d ures a n d assess me nts c o m plete d at t he ti me of wit h dra w al fr o m t he mai n st u d y ma y be use d as 
a p pr o priate f or t h e start of t he Cr oss o ver P hase of t he st u d y. 
If s u bjects c o nti n ue i nt o t he Cr oss o ver p hase, Safet y f oll o w- u p is n ot re q uire d ,
5. 
T he Disc o nti n uati o n Visit s h o ul d occ ur at t he ti me st u d y dr u g is disc o nti n ue d f or a n y reas o n. If t he Disc o nti n uati o n Visit oc c urs 3 0 da ys fr o m t he last d ose of st u d y treat me nt, at 
t he ti me of t he ma n dat or y Safet y F oll o w u p Visit, pr oce d ures d o n ot nee d t o be re peate d.
6. 
T he ma n dat or y Safet y F oll o w -u p Visit f or all s u bjects 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 trial treat me nt or bef ore t he i nitiati o n of ne w a nti ne o plastic 
treat me nt, w hic he ver c o mes first. S u bjects wit h a n A E of Gra de > 1 will be f urt her f oll o we d u ntil t he res ol uti o n of t he A E t o Gra de 0 - 1 or u ntil be gi n ni n g of a ne w a nti ne o plastic 
t hera p y, w hic he ver occ urs first. S u bjects w h o are eli gi ble f or treat me nt wit h pe m br oliz u ma b d uri n g t he Sec o n d C o urse P hase ma y ha ve u p to t hree Safet y F oll o w -u p Visits, o ne 
after t he Treat me nt P hase, Cr oss o ver P hase a n d t he Sec o n d C o urse P hase. If t he Disc o nti n uati o n Visit occ urs a p pr o xi matel y 3 0 da ys ( +/- 3 da ys) fr o m last d ose trial treat me nt t he 
sa me pr oce d ures d o n ot nee d t o be re peate d f or t he Safet y F oll o w-u p Visit.
7. 
After d oc u me nte d l ocal site assesse d disease pr o gressi o n, or t he start of ne w a ntica ncer treat me nt; c o ntacts are a p pr o xi matel y e ver y 1 2 wee ks b y tele p h o ne. U p date d s ur vi val 
stat us ma y be re q ueste d b y t he S p o ns or at a n y ti me d uri n g t he c o urse of t he st u d y. U p o n S p o ns or n otificati o n, all partici pa nt s w h o d o n ot/ will n ot ha ve a sc he d ule d st u d y visit or 
st u d y c o ntact d uri n g t he S p o ns or defi ne d ti me peri o d will be c o ntacte d f or t heir s ur vi val stat us (e xcl u di n g partici pa nts t hat ha ve a deat h e ve nt pre vi o usl y rec or de d).
8. 
O nce a s u bject disc o nti n ues st u d y treat me nt, re p ort all S A Es (relate d a n d u nrelate d t o tr ial treat me nt), occ urri n g wit hi n 9 0 da ys f oll o wi n g cessati o n of treat me nt or 3 0 da ys 
f oll o wi n g cessati o n of treat me nt if t he s u bject i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier.  After t his ti me, re port o nl y S A Es t hat are c o nsi dere d relate d t o t rial treat me nt.
9. 
La b orat or y tests f or scree ni n g 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 trial treat me nt. After C ycle 1, la b sa m ples ca n be c ollecte d u p t o 7 2 h o urs pri or t o t he 
sc he d ule d ti me p oi nt. La b orat or y res ults m ust be k n o w n prior t o d osi n g. Uri nal ysis: perf or m e ver y 6 c ycles after C ycle 1 4. T 3 or F T 3, F T 4, a n d T S H: perf or m e ver y 2 c ycles after 
C y cle 1 4; t h yr oi d f u ncti o n tests will be perf or me d b y a ce ntral la b o nl y if t he l ocal la b orat or y is u na ble t o perf or m t his se r vice. See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y 
tests.  
1 0. Uri nal ysis is perf or me d e ver y 6 c ycles after C ycle 1 3. Uri nal ysis is n ot re q uire d wit h C ycle 1 4.
1 1. S u bjects ma y be d ose d i n s u bse q ue nt c ycles after C ycle 1, Da y 1 w hile t h yr oi d f u ncti o n tests are pe n di n g.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
`
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Scr  
P h ase
Tre at me nt C ycles 1
E n d of Tre at me nt P h ase
F oll o w 
u p 
P h ase 2
S ur vi v al 
F oll o w 
u p 3
Tre at me nt C ycle / Sc he d ule d 
Ti m e
Scr  
( Visit 
1)
1 4
2  
3  
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3
1 4 
t hr o u g h 
3 5
Disc o nti n u ati o n 
Visit 5
S afet y 
F oll o w u p 
Visit 6
F oll o w 
u p Visit 
3 a n d 
Be y o n d
S ur vi v al 
F oll o w 
u p Visit 
1 a n d 
B e y o n d
Sc he d uli n g Wi n d o w ( D a ys):
-2 8 t o 
- 1
+ 3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3
± 3
± 3  
± 3  
± 3  
± 3  
± 3
At St u d y Dr u g 
Disco nti n uatio n ± 3
3 0 Days 
Fro m Last 
Dose + 7
E ver y 3 
Mo nt hs 
A fter Visit 
2 ± 3
E ver y 3 
M o nt hs     
± 7
1 2. F or w o me n of re pr o d ucti ve p ote ntial, a ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o first d ose of trial treat me nt. A uri ne test ca n be c o nsi dere d if ser u m is 
n ot a p pr o priate. 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 pe r l ocal re g ulati o ns w here a p plica ble.
1 3. Bli n de d i n de pe n de nt ce ntral re vie w verif yi n g pr o gressi ve disease is: 1) re q uire d f or cr oss o ver, wit h o ut e xce pti o n, a n d 2) is base d o n R E CI S T 1. 1. T u m or res p o nse assess me nt is 
re q uire d e ver y 1 2 wee ks ( 8 4 da ys ± 7 da ys) u ntil t he s u bject starts a n ot her a nti-ca ncer treat me nt. Refer t o i ma gi n g ma n ual f or a d diti o nal details. Assess me nt of disease res p o nse or 
pr o gressi o n will be deter mi ne d b y t he i n vesti gat or.  T he treati n g p h ysicia n will rec or d a p h ysicia n assesse d t u m or res p o nse a n d t he criteria use d, i.e., i m m u ne -relate d R E CI S T or 
sta n dar d R E CI S T v 1. 1 o n t he disc o nti n uati o n f or m. 
1 4. T u m or i ma gi n g is n ot nee de d f or s u bjects w h o start a n ot her a nti- ca ncer treat me nt re gi me n.
1 5. Pe m br oliz u ma b ca n be a d mi nistere d f or u p t o 3 5 c ycles.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 0 T RI A L P R O C E D U R E S
Tri al Pr oce d ures
T he Trial Fl o w C hart - Secti o n 6 . 0 s u m marizes t he trial pr oce d ures t o be perf or me d at eac h 
visit.  In di vi d ual trial pr oce d ures are descri be d i n detail bel o w.  It ma y  be necessar y  to 
perf or m t hese pr oce d ures at u nsc he d ule d ti me p oi nts if dee me d cli nicall y necessar y  by t he 
i n vesti gat or.
F urt her m ore, a d diti o nal e val uati o ns/testi n g ma y  be dee me d necessar y b y t he i n vesti gat or a n d 
or t he S p o ns or f or reas o ns relate d t o s u bject safet y. I n s o me cases, s uc h e val uati o n/testi n g 
ma y  be p ote ntiall y se nsiti ve i n nat ure (e. g., HI V, He patitis C, etc.), a n d t h us l ocal re g ulati o ns 
ma y  re q uire t hat a d diti o nal i nf or me d c o nse nt be o btai ne d fr o m t he s u bject.  In t hese cases, 
s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce wit h t h ose re g ulati o ns.
A d mi nistr ati ve Pr oce d ures
7. 1. 1. 1
I nf or me d C o nse nt
T he i n vesti gat or or q ualifie d desi g nee m ust o btai n d oc u me nte d c o nse nt fr o m eac h p ote ntial 
s u bject or eac h s u bject’s le gall y acce pta ble re prese ntati ve pri or t o partici pati n g i n a cli nical 
trial or F ut ure Bi o me dical Researc h . If t here are c ha n ges t o t he s u bject’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
C o nse nt m ust be d oc u me nte d b y  the s u bject’s date d si g nat ure or b y  the s u bject’s le gall y 
acce pta ble re prese ntati ve’s date d si g nat ure o n a c o nse nt f or m al o n g wit h t he date d si g nat ure 
of t he pers o n c o n d ucti n g t he c o nse nt disc ussi o n. 
A c o p y of t he si g ne d a n d date d c o nse nt f or m s h o ul d be gi ve n t o t he s u bject bef ore 
partici pati o n i n t he tri al.
T he i nitial i nf or me d c o nse nt f or m, a n y s u bse q ue nt re vise d writte n i nf or me d c o nse nt f or m 
a n d a n y writte n 
i nf or mati o n pr o vi de d t o t he s u bject m ust 
recei ve t he I RB/ E R C’s 
a p pr o val/fa v ora ble o pi ni o n i n a d va nce of use.  The s u bject or his/ her le gall y acce pta ble 
re prese ntati ve s h o ul d be i nf or me d i n a ti mely ma n ner if ne w i nf or mati o n bec o mes a vaila ble 
t hat m a y  be rele va nt t o t he s u bject’s willi n g ness t o c o nti n ue partici pati o n i n t he trial.  Th e 
c o m m u nicati o n of t his i nf or mati o n will be pr o vi de d a n d d oc u me nte d v ia a re vise d c o nse nt 
f or m or a d de n d u m t o t he ori gi nal c o nse nt f or m t hat ca pt ures t he s u bject’s date d si g nat ure or 
b y  t he s u bject’s le gally acce pta ble re prese ntati ve’s date d si g nat ure.
S pecifics a b o ut a trial a n d t he trial p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate at 
t he pr ot oc ol le vel.  
T he i nf or me d c o nse nt will a d here t o I RB/ E R C re q uire me nts, a p plica ble la ws a n d re g ulati o ns 
a n d S p o ns or re q uire me nts.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
C o nse nt a n d C ollecti o n of S peci me ns f or F ut ure Bi o me dic al Rese arc h
T he i n vesti gat or or q ualifie d desi g nee will e x plai n t he F ut ure Bi o me dical Researc h c o nse nt 
t o t he s u bject, a ns wer all of his/ her q uesti o ns, a n d o btai n writte n i nf or me d c o nse nt bef ore 
perf or mi n g a n y pr oce d ure relate d t o t he F ut ure Bi o me dical Researc h s u b -trial.  A c o p y of t he 
i nf or me d c o nse nt will be gi ve n t o t he s u bject.
7. 1. 1. 2
I ncl usi o n/ E xcl usi o n Criteri a
All i ncl usi o n a n d e xcl usi o n criteria will be re vie we d b y  t he i n vesti gat or or q ualifie d desi g nee 
t o e ns ure t hat t he s u bject q ualifies f or t he trial.
7. 1. 1. 3
S u bject I de ntific ati o n C ar d
All s u bjects will be gi ve n a S u bject I de ntificati o n Car d i de ntif yi n g t he m as par tici pa nts i n a 
researc h trial. T he car d will c o ntai n trial site c o ntact i nf or mati o n (i ncl u di n g direct tele p h o ne 
n u m bers) t o be utilize d i n t he e ve nt of a n e mer ge nc y. T he i n vesti gator or q ualifie d desi g nee 
will pr o vi de t he s u bject wit h a S u bject I de ntificati o n Car d i m me diatel y after t he s u bject 
pr o vi des writte n i nf or me d c o nse nt. At t he ti me of treat me nt all ocati o n/ra n d o mizati o n, site 
pers o n nel will a d d t he treat me nt/ra n d o mizati o n n u m ber t o t he S u bject I de ntificati o n Car d.
T he s u bject i de ntificati o n car d als o c o ntai ns c o ntact i nf or mati o n f or t he e mer ge nc y 
u n bli n di n g call ce nter s o t hat a healt h care pr o vi der ca n o btai n i nf or mati o n a b o ut trial 
me dicati o n/ vacci nati o n i n e mer ge nc y  sit uatio ns w here t h e i n vesti gat or is n ot a vaila ble.
7. 1. 1. 4
Me dic al Hist or y
A me dical hist or y  will be o btai ne d b y t he i n vesti gat or or q ualifie d desi g nee.  Me dical hist or y  
will i ncl u de all acti ve c o n diti o ns, a n d a n y co n diti o n dia g n ose d wit hi n t he pri or 1 0 years t hat 
are co nsi dere d t o be cli nicall y sig nifica nt b y  the I n vesti gat or. Details re gar di n g t he s u bject’s 
l u n g ca ncer will be rec or de d se parately a n d n ot liste d as me dical hist or y.
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 
s u bject’s l u n g ca ncer.
7. 1. 1. 5
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
Pri or Me dic ati o ns
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 dica ti o n ta ke n b y  the s u bject 
d uri n g t he scree ni n g peri o d ( Da y  -3 0 t hr o u g h Da y -1 of trial treat me nt start). Pri or a ntica ncer
treat me nt f or N S C L C will be rec or de d se paratel y a n d n ot liste d as a pri or me dicati o n.
T he i n vesti gat or or q ualifie d desi g nee will re vi e w a n d rec or d all pri or a nti -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, re gar dless of t he ti me pri or t o first
d ose of trial treat me nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
C o nc o mit a nt Me dic ati o ns
T he i n vesti gat or or q ualifie d desi g nee will rec or d me dicati o n, if a n y, ta ke n b y  the s u bject 
d uri n g t he trial.  All me dicati o ns relate d t o re p orta ble S A Es s h o ul d be rec or de d as defi ne d i n 
Secti o n 7. 2.
7. 1. 1. 6
Assi g n me nt of Scree ni n g N u m ber
All c o nse nte d s u bjects will be gi ve n a u ni q ue scree ni n g n u m ber t hat will be use d t o i de ntif y 
t he s u bject f or all pr oce d ures t hat occ ur pri or t o ra n d o mizati o n or treat me nt all ocati o n.  Eac h 
s u bject will be assi g ne d o nl y  o ne scree ni n g n u m ber.  Scree ni n g n u m bers m ust n ot be re -use d 
f or differe nt s u bjects.
A n y  su bject w h o is scree ne d m ulti ple ti mes will retai n t he ori gi nal scree ni n g n u m ber 
assi g ne d at t he i nitial scree ni n g visit.
S pecific details o n t he scree ni n g visit re q uire me nts (scree ni n g/rescree ni n g) are pr o vi de d i n 
Secti o n 7. 1. 5. 1.  
7. 1. 1. 7
Assi g n me nt of Tre at me nt/ R a n d o miz ati o n N u m ber
All eli gi ble su bjects will be ra n d o mly all ocate d a n d will recei ve a treat me nt/ra n d o mizati o n 
n u m ber.  The treat me nt/ra n d o mizati o n n u m ber i de ntifies t he s u bject f or all pr oce d ures 
occ urri n g after treat me nt all ocati o n/ ra n d o mizati o n.  Once a treat me nt/ra n d o mizati o n n u m ber 
is assi g ne d t o a s u bject, it ca n ne ver be re-assi g ne d t o a n ot her s u bject.
A si n gle s u bject ca n n ot be assi g ne d m ore t ha n 1 treat me nt/ra n d o mizati o n n u m ber.
7. 1. 1. 8
Tri al C o m pli a nce ( Me dic ati o n/ Diet/ Acti vit y/ Ot her)
I nterr u pti o ns fr o m t he pr ot oc ol s pecifie d treat me nt pla n f or greater t ha n 1 2 wee ks bet wee n
pe m br oliz u ma b d oses f or n o n -dr u g -relate d or a d mi nistrati ve reas o ns (see Secti o n 5. 2. 1. 2 f or
dr u g -relate d m o dificati o ns)
re q uire c o ns ultati o n bet wee n t he i n vesti gat or a n d t he S p o ns or 
a n d writte n d oc u me ntati o n of t he c o lla b orati ve decisi o n o n s u bject ma na ge me nt.
Trial me dicati o n s will be a d mi nistere d b y  site a n d/ or i nstit uti o n staff per l ocal S O Ps a n d
g ui deli nes. T he t otal v ol 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 n ce t o eac h d ose of pe m br oliz u ma b a d mi nistere d.
T he i nstr ucti o ns f or pre pari n g a n d a d mi nisteri n g pe m br oliz u ma b will be pr o vi de d i n t he
P har mac y  Ma n ual.
Cli nic al Pr oce d ures/ Assess me nts
7. 1. 2. 1
A d verse E ve nt ( A E) M o nit ori n g
T he I n vesti gat or or q ualifie d desi g nee wil l assess eac h s u bject t o e val uate f or p ote ntial ne w 
or w orse ni n g A Es as s pecifie d i n t he Trial Fl o w C hart a n d m ore fre q ue ntl y if cli nicall y 
i n dicate d. A d verse e x perie nces will be gra de d a n d rec or de d t hr o u g h o ut t he st u d y an d d uri n g 
t he f oll o w-u p peri o d acc o r di n g t o N CI C T C A E Versi o n 4. 0 (see Secti o n 1 2. 5 ). T o xicities 
will be c haracterize d i n ter ms i ncl u di n g seri o us ness, ca usalit y, t o xicit y gra di n g, a n d acti o n 
ta ke n wit h re gar d t o trial treat me nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A n i m m u ne relate d a d verse e ve nt (ir A E) m a y  be defi ne d as a n a d verse e ve nt of u n k n o w n 
eti ol o g y, ass ociate d wit h dr u g e x p os ure a n d is c o nsiste nt wit h a n i m m u ne p he n o me n o n. 
Eff orts s h o ul d be ma de t o r ule o ut ne o plastic, i nfecti o us, meta b olic, t o xi n or ot her e ti ol o gic 
ca uses pri or t o la beli n g a n a d verse e ve nt i m m u ne relate d.  Im m u n ol o gical, ser ol o gical a n d 
hist ol o gical ( bi o psy) data s h o ul d be use d t o s u p p ort t he dia g n osis of a n i m m u ne-relate d 
t o xicit y.  
Please refer t o Secti o n 7. 2 f or detaile d i nf or mati o n re ga r di n g t he assess me nt a n d rec or di n g of 
A Es.
7. 1. 2. 2
P h ysic al E x a m
F ull P h ysic al E x a m
T he I n vesti gat or or q ualifie d desi g nee will perf or m a c o m plete p h y sical e xa m d uri n g t he 
scree ni n g peri o d. Cli nicall y  si gnifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical 
his t or y. T he ti me p oi nts f or f ull p h y sical e xa m are descri be d i n Secti o n 6 - Trial Fl o w C hart.
After t he first d ose of trial treat me nt ne w cli nicall y si gnifica nt a b n or mal fi n di n gs s h o ul d be 
rec or de d as A Es.
Directe d P h ysic al E x a m
F or c ycles t hat d o n ot re q uire d a f ull p h ysical e xa m per t he Trial Fl o w C hart, t he I n vesti gat or 
or q ualifie d desi g nee will perf or m a directe d p h y sical e xa m as cli nicall y i n dicate d pri or t o 
trial treat me nt a d mi nistrati o n. 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.
7. 1. 2. 3
Vit al Si g ns
T he I nvesti gat or or q ualifie d desi g nee will ta ke vital si g ns at scree ni n g, pri or t o t he 
a d mi nistrati o n of eac h d ose of trial treat me nt a n d d uri n g t he F oll o w -u p peri o d as s pecifie d i n 
t he Trial Fl o w C hart.   Vital si g ns i ncl u de te m perat ure, p ulse, res pirat or y rate, wei g ht a n d 
bl o o d press ure. Hei g ht will be meas ure d at Visit 1 o nl y .
7. 1. 2. 4
1 2 -Le a d Electr oc ar di o gr a m ( E C G)
A sta n dar d  12- lea d  EC G  will  be  perf or me d  usi n g  local  sta n dar d  pr oce d ures  once  at 
scree ni n g. Cli nicall y  si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical hist or y .  
A d diti o nal E C Gs ma y  be perf or me d as cli nically n ecessar y. 
7. 1. 2. 5
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce Sc ale
T he I n vesti gat or or q ualifie d desi g nee will asse ss E C O G stat us (see Secti o n 1 2. 6 ) at 
scree ni n g, pri or t o eac h c ycle of trial treat me nt a n d d uri n g t he F oll o w -u p peri o d as s pecifie d 
i n t he Trial Fl o w C hart.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 1. 2. 6
T u m or I m a gi n g a n d Assess me nt of Dise ase
T he pr ocess f or i ma ge c ollecti o n a n d tra ns missi o n t o t he ce ntral i ma gi n g ve n d or ca n be 
f o un d i n t he Site I ma gi n g Ma n ual ( SIM).  Tu m or i ma gi n g s h o ul d be ac q uire d b y  co m p ute d 
t o m ogra p h y ( C T, str o n gl y preferre d) a n d s h o ul d i ncl u de t he c hest, a b d o me n a n d pel vis.
Ma g netic 
res o na nce i ma gi n g ( M RI) s h o ul d be use d w he n C T is c o ntrai n dicate d or f or 
i ma gin g i n t he brai n. T he sa me i ma gi n g tec h ni q ue re gar di n g m o dalit y a n d use of c o ntrast 
s h o ul d be use d i n a s u bject t hr o u g h o ut t he trial t o o pti mize t he vis ualizati o n of e xisti n g a n d 
ne w t u m or b ur de n.
L ocal site i n vesti gat or/ra di ol o g y assess me nt base d o n R E CI S T 1. 1 will be use d t o deter mi ne 
s u bject eli gi bilit y.  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, Merc k all o ws 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.  All 
sc he d ule d i ma ges f or all st u d y su bjects fr om t he sites will be s u b mitte d t o t he ce ntral 
i ma gi n g ve n d or. I n a d diti o n, a d diti o nal i ma gi n g (i ncl u di n g ot her m o dalities) 
t hat are 
o btai ne d at u nsc he d ule d ti me p oi nts t o deter mi ne disease pr o gressi o n, as well as i ma gi n g 
o btai ne d f or ot her reas o ns b ut ca pt u res ra di ol o gic pr o gressi o n, s h o ul d be s u b mitte d t o t he 
ce ntral i ma gi n g ve n d or.
T he ce ntral i ma gi n g ve n d or will verif y  pr o gressi ve disease ( P D) f oll o wi n g l ocal site 
i n vesti gat or-assesse d 1st ra di ol o gic e vi de nce of P D.  Ex pe dite d verificati o n of ra di ol o gic P D 
b y  the ce ntral i ma gi n g ve n d or will be c o m m u nicate d t o t he st u d y site a n d s p o ns or ( See 
Secti o n 7. 1. 2. 6. 3). T he e x pe dite d ce ntral verificati o n of P D s h o ul d be re q ueste d o nl y  whe n 
t he s u bject is a ca n di date f or cr oss o ver a n d ma y occ ur eit her at t he first i nsta nce of P D b y 
R E CI S T 1. 1 or t he c o nfir mati o n sca n ≥ 4 wee ks later t o c o nfir m P D b y ir R E CI S T.
I niti al T u m or I m a gi n g
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 d a y s pri or t o t he date of 
ra n d o mizati o n.  T he site st u d y tea m m ust re vie w scree ni n g i ma ges t o c o nfir m t he s u bject has 
meas ura ble disease per R E CI S T 1. 1. T he scree ni n g i ma ges m ust be s u b mitte d t o t he ce ntral 
i ma gi n g ve n d or f or retr os pecti ve c o nfir mati o n of eli gi bilit y.
Sca ns perf or me d as part of r o uti ne cli nical ma na ge me nt are ac ce pta ble f or use as scree ni n g 
t u m or i ma gi n g if t he y are of dia g n ostic q ualit y  an d perf or me d wit hi n 2 8 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. 
S u bjects wit h pre vi o usl y treate d brai n metastases ma y  partici p ate pr o vi de d t he y ha ve sta ble 
brai n metastases, 
i.e. wit h o ut 
e vi de nce of pr o gressi o n b y  ima gi n g 
d uri n g scree ni n g; 
[c o nfir me d b y  ma g netic res o na nce i ma gi n g ( M RI) if M RI  was use d at pri or i ma gi n g, or 
c o nfir me d b y  co m p ute d t o m o gra p hy ( C T) i ma gi n g if C T use d a t pri or i ma gi n g]. A n y 
ne ur ol o gic s ym pt o ms m ust ha ve ret ur ne d t o baseli ne a n d s u bjects m ust ha ve n o cli nical 
e vi de nce of ne w or e nlar gi n g brai n metastases, 
a n d ha ve n ot use d ster oi ds f or brai n 
metastases f or at least 3 da y s pri or t o trial i nitiati o n as per l ocal site assess me nt. T his 
e xce pti o n d oes n ot i ncl u de carci n o mat o us me ni n gitis, 
as s u bjects wit h carci n o mat o us 
me ni n gitis are e xcl u de d re gar dless of cli nical sta bilit y .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T u m or I m a gi n g D uri n g t he Tri al
T he i ma gi n g assess me nt s h o ul d be perf or me d at Wee k 6 ( 42 ± 7 da y s), Wee k 1 2 ( 8 4 ± 7 
da y s) a n d Wee k 
1 8 ( 1 2 6 ± 7 da y s) fr o m t he date of ra n d o mizati o n. S u bse q ue nt t u m or 
i ma gi n g s h o ul d be perf or me d e ver y 9 wee ks ( 6 3 da y s ± 7 d a y s) or m ore fre q ue ntl y if 
cli nicall y in dicate d.  After 4 5 wee ks, s u bjects w h o re mai n o n treat me nt will ha ve i ma gi n g 
perf or me d e ver y 12 wee ks ( 8 4 d a y s ± 7 d a y s).  Ima gi n g ti mi n g s h o ul d f oll o w cale n dar d a y s 
a n d s h o ul d n ot be a dj uste d f or dela y s i n c ycle starts. I ma gi n g s h o ul d c o nti n ue t o be 
perf or me d u ntil disease pr o gressi o n verifie d b y  ce ntral i ma gi n g ve n d or ( u nless site PI  elects 
t o c o nti n ue treat me nt a n d f oll o w ir R E CIS T), t he start of ne w a nti -ca ncer treat me nt, 
wit h dra wal of c o nse nt, or deat h, w hic he ver occ urs first. All s u p ple me ntal i ma gi n g m ust be 
s u b mitte d t o t he ce ntral i ma gi n g ve n d or. 
Pe r R E CI S T 1. 1, partial a n d c o m plete res p o nse s h o ul d be c o nfir me d b y a re peat t u m or 
i ma gi n g assess me nt n ot less t ha n 4 wee ks fr o m t he date t he res p o nse was first d oc u me nte d.  
T he t u m or i ma gi n g f or c o nfir mati o n of res p o nse m a y  be perf or me d at t he earliest 4 w ee ks 
after t he first i n dicati o n of res p o nse, or at t he ne xt sc he d ule d sca n (i.e. 6, 9 or 1 2 wee ks 
later), w hic he ver is cli nicall y in dicate d.  Su bjects will t he n ret ur n t o re g ular sc he d ule d 
i ma gi n g, starti n g wit h t he ne xt sc he d ule d i ma gi n g ti me p oi nt. S u bje cts w h o o btai n a 
c o nfir mati o n sca n d o n ot nee d t o u n der g o t he ne xt sc he d ule d t u m or i ma gi n g if it is < 4 wee ks 
later; t u m or i ma gi n g ma y res u me at t he s u bse q ue nt sc he d ule d i ma gi n g ti me p oi nt.
Per ir R E CI S T (secti o n 7. 1. 2. 6. 6), disease pr o gressi o n s h o ul d be c o nfir me d b y  t he site at least 
4 wee ks after ce ntral verificati o n of site-assesse d 1st ra di ol o gic e vi de nce of P D i n cli nicall y 
sta ble s u bjects.  Su bjects w h o ha ve u nc o nfir me d disease pr o gressi o n ma y  co nti n ue o n 
treat me nt at t he discreti o n of t he site i n vestigat or u ntil pr o gressi o n is c o nfir me d b y  the site 
pr o vi de d t he y ha ve met t he c o n diti o ns detaile d i n Secti o n 7. 1. 2. 6. 6. S u bjects w h o o btai n a 
c o nfir mati o n sca n d o n ot nee d t o u n der g o t he ne xt sc he d ule d t u m or i ma gi n g if it is < 4 wee ks 
later; t u m or i ma gi n g may res u me at t he s u bse q ue nt sc he d ule d i ma gi n g ti me p oi nt if cli nicall y  
sta ble. S u bjects w h o ha ve c o nfir me d disease pr o gressi o n as assesse d b y  the site will 
disc o nti n ue t he treat me nt. E xce pti o n is detaile d i n Secti o n 7. 1. 2. 6. 6.
E n d of Tre at me nt a n d F oll o w -u p of T u m or I m a gi n g
I n s u bjects w h o disc o nti n ue trial treat me nt, t u m or i ma gi n g s h o ul d be perf or me d at t he ti me 
of treat me nt disc o nti n uati o n ( ± 4 wee k wi n d o w).  If a pre vi o us sca n was o btai ne d wit hi n 4 
wee ks pri or t o t he date of disc o nti n uati o n, t he n a sca n a t treat me nt disc o nti n uati o n is n ot 
ma n dat or y . I n s u bjects w h o 
disc o nti n ue trial treat me nt d ue t o d oc u me nte d disease 
pr o gressi o n, t his is t he fi nal re q uire d t u m or i ma gi n g.
I n s u bjects w h o disc o nti n ue trial treat me nt wit h o ut d oc u me nte d disease pr o gressi o n, tu m or 
i ma gi n g usi n g t he sa me i ma gi n g sc he d ule use d w hile o n treat me nt (e ver y 9 wee ks i n ye ar 1 
or 1 2 wee ks after ye ar 1) t o m o nit or disease stat us u ntil ( 1) t he start of ne w a nti -ca ncer 
treat me nt, ( 2) disease pr o gressi o n, ( 3) deat h, or ( 4) t he e n d of t he stu d y , w hic he ver occ urs 
first, s h o ul d be use d.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Sec o n d C o urse ( Retre at me nt) T u m or I m a gi n g
A sca n m ust be perf or me d wit hi n 2 8 da y s pri or t o restarti n g treat me nt wit h pe m br oliz u ma b.  
L ocal rea di n g (i n vesti gat or assess me nt wit h site ra di ol o g y rea di n g) will be us e d t o deter mi ne 
eli gi bilit y.  Ima gi n g s h o ul d be s u b mitte d t o t he ce ntral i ma gi n g ve n d or f or retr os pecti ve 
verificati o n.
T he first o n st u d y ima gi n g assess me nt s h o ul d be perf or me d at 1 2 wee ks ( 8 4 d a y s ± 7 d a y s) 
after t he restart of treat me nt. S u bse q ue nt t u m or i ma gi n g s h o ul d be perf or me d e ver y 1 2 wee ks 
( 8 4 da ys ± 7 da ys) or m ore fre q ue ntl y if cli nically i n dicate d.
Per R E CI S T 1. 1, partial or c o m plete res p o nse s h o ul d be c o nfir me d b y  a re peat t u m or 
i ma gi n g assess me nt n ot less t ha n 4 wee ks fr o m t he date t he res p o nse was first d oc u me nte d.  
T he t u m or i ma gi n g f or c o nfir mati o n of res p o nse m a y  be perf or me d at t he earliest 4 wee ks 
after t he first i n dicati o n of res p o nse, or at t he ne xt sc he d ule d sca n, w hic he ver is cli nicall y 
i n dicate d. S u bjects will t he n ret ur n t o re g ular s c he d ule d i ma gi n g e ver y 1 2 wee ks ( 8 4 da ys ± 7 
da y s), starti n g wit h 
t he ne xt sc he d ule d i ma gi n g ti me p oi nt. S u bjects w h o 
o btai n a 
c o nfir mati o n sca n d o n ot nee d t o u n der g o sc he d ule d t u m or i ma gi n g if it is < 4 wee ks later 
a n d ma y wait u ntil t he ne xt sc he d ule d i ma gi n g ti me p oi nt.
Per ir R E CIS T (secti o n 7. 1. 2. 6. 6), if t u m or i ma gi n g s h o ws i nitial P D, t u m or assess me nt 
s h o ul d be re peate d ≥ 4 wee ks later i n or der t o c o nfir m P D wit h t he o pti o n of c o nti n ui n g 
treat me nt w hile a waiti n g ra di ol o gic c o nfir mati o n of pr o gressi o n. S u bjects w h o o btai n a 
c o nfir mati o n sca n d o n ot nee d t o u n der g o sc he d ule d t u m or i ma gi n g if it is < 4 wee ks later 
a n d ma y wait u ntil t he ne xt sc he d ule d i ma gi n g ti me p oi nt if cli nicall y sta ble.
I ma gi n g s h o ul d c o nti n ue t o be perf or me d u ntil disease pr o gressi o n, t he start of ne w a nti -
ca ncer treat me nt, wit h dra wal of c o nse nt, deat h, or n otificati o n b y  the S p o ns or, w hic he ver 
occ urs first.  Disease pr o gressi o n m a y  be c o nfir me d at least 4 wee ks after t he first t u m or 
i ma gi n g i n dicati n g pr o gressi ve disease i n cli nicall y sta ble s u bjects.
I n s u bjects w h o disc o nti n ue trial treat me nt, t u m or i ma gi n g s h o ul d be perf or me d at t he ti me 
of treat me nt disc o nti n uati o n ( ± 4 wee k wi n d o w).  If a pre vi o us sca n was o btai ne d wit hi n 4 
wee ks pri or t o t he date of disc o nti n uati o n, t he n a sca n at treat me nt disc o nti n uati o n is n’t 
ma n dat or y . I n s u bjects w h o 
disc o nti n ue trial treat me nt d ue t o d oc u me nte d disease 
pr o gressi o n, t his is t he fi nal re q uire d t u m or i ma gi n g.
I n s u bjects w h o disc o nti n ue trial treat me nt wit h o ut d oc u me nte d disease pr o gressi o n, e ver y 
eff ort s h o ul d be ma de t o c o nti n ue m o nit ori n g t heir disease stat us b y ra di ol o gic i ma gi n g e ver y 
1 2 wee ks ( 8 4 da y s ± 7 da y s) u ntil ( 1) t he start of ne w a nti -ca ncer treat me nt, ( 2) disease 
pr o gressi o n, ( 3) deat h, or ( 4) t he e n d of t he st u d y, w hic he ver occ urs first.
R E CI S T 1. 1 Assess me nt of Dise ase
R E CI S T 1. 1 will be a p plie d b y  the ce ntral i ma gi n g ve n d or as t he pri mar y  meas ure f or 
assess me nt of t u m or res p o nse, date of disease pr o gressi o n, a n d as a basis f or all pr ot oc ol 
g ui deli nes relate d t o disease stat us (e. g., disc o nti n uati o n of st u d y thera p y ). I nitial t u m or 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
i ma gi n g s h o wi n g site-assesse d P D s h o ul d be s u b mitte d t o t he ce ntral i ma gi n g ve n d or 
i m me diatel y. T he site will be n otifie d via e mail if t he ce ntral i ma gi n g ve n d or verifies 
pr o gressi ve disease ( P D) usi n g R E CI S T 1. 1. Fi g ure 2 ill ustrates t he i ma gi n g fl o w i n v ol vi n g 
verificati o n of P D f or cli nicall y  sta ble s u bjects.
ir R E CI S T Assess me nt of Dise ase
ir R E CIS T is R E CI S T 1. 1 a da pte d as descri be d bel o w t o acc o u nt f or t he u ni q ue t u m or 
res p o nse see n wit h 
i m m u n ot hera pe utic dr u gs. 
ir R E CI S T will 
be 
use d 
b y  site 
i n vesti gat or/l ocal ra di ol o g y re vie w 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 his data will be c ollecte d i n t he cli nical data base. Treat me nt efficac y 
base d o n ir R E CI S T as assesse d b y  ce ntral i ma gi n g ve n d or re vie w will be e val uate d 
retr os pecti vely.
W he n 
feasi ble, s u bjects s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n is c o nfir me d b y  the 
l ocal site i n vesti gat or/ra di ol o g y assess me nt.  This all o wa nce t o c o nti n ue treat me nt des pite 
i nitial ra di ol o gic pr o gressi ve disease ( P D) ta kes i nt o acc o u nt t he o bser vati o n t hat s o me 
s u bjects ca n ha ve a tra nsie nt t u m or flare i n t he first fe w m o nt hs 
after t he start of 
i m m u n ot hera p y, an d t he n e x perie nce s u bse q ue nt disease res p o nse.  Su bjects t hat are dee me d 
cli nicall y unsta ble are n ot re q uire d t o ha ve re peat t u m or i ma gi n g f or c o nfir mati o n of P D.  
T u m or flare i ncl u des a n y of t he f oll o wi n g sce nari os:
• 
W orse ni n g of e xisti n g tar get lesi o n(s)
• 
W orse ni n g of e xisti n g n o n -tar get lesi o n(s)
• 
De vel o p me nt of ne w lesi o ns(s)
I n s u bjects w h o ha ve i nitial e vi de nce of ra di ol o gical P D b y  RE CI S T 1. 1 as verifie d b y  
ce ntral i ma gi n g ve n d or, it is at t he discreti o n of t he PI  whet her t o c o nti n ue a s u bject o n st u d y  
treat me nt u ntil re peat i ma gi n g is o btai ne d ( usi n g ir R E CI S T f or s u bject ma na ge me nt, see
Ta ble 5 a n d Fi g ure 2 ).  This cli nical j u d g me nt decisi o n b y  the site s h o ul d be base d o n t he 
s u bject’s o verall cli nical c o n diti o n, i ncl u di n g perf or ma nce stat us, cli nical s ym pt o ms, a n d 
la b orat or y data.  Su bjects ma y  recei ve st ud y  treat me nt a n d t u m or assess me nt s h o ul d be 
re peate d ≥ 4 wee ks later i n or der t o c o nfir m P D b y  ir R E CIS T per site assess me nt.  Cli nical 
sta bilit y is defi ne d as t he f oll o wi n g: 
1) A bse nce of s ym pt o ms a n d si g ns i n dicati n g cli nicall y si gnifica nt pr o gressi o n of disease, 
i ncl u di n g w orse ni n g of la b orat or y val ues
2) N o decli ne i n E C O G perf or ma nce stat us 
3) A bse nce of ra pi d pr o gressi o n of disease 
4) A bse nce of pr o gressi ve t u m or at critical a nat o mical sites (e. g., c or d c o m pressi o n) 
re q uiri n g ur ge nt alter nati ve me dical i nter ve nti o n
A n y  su bject dee me d cli nicall y unsta ble s h o ul d be disc o nti n ue d fr o m trial treat me nt at site -
assesse d first ra di ol o gic e vi de nce of P D a n d is n ot re q uire d t o ha ve re peat i ma gi n g f or P D 
c o nfir mati o n.  
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
6 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I n deter mi ni n g w het her or n ot t he t u m or b ur de n has i ncrease d or decrease d per ir R E CIS T, 
t he l ocal site i n vesti gat or s h o ul d c o nsi der all tar get a n d n o n- tar get lesi o ns as well as a n y 
i ncre me ntal ne w lesi o n(s).
Sce nari os w here P D is n ot c o nfir me d at re peat i ma gi n g if A L L of t he f oll o wi n g occ ur b y 
irR E CI S T:
•
Tar get lesi o n s u m of dia meters is < 2 0 % or < 5 m m a bs ol ute i ncrease c o m pare d t o na dir
•
N o n -tar get disease res ulti n g i n i nitial P D is sta ble or q ualitati vel y i m pr o ve d
•
Ne w lesi o n res ulti n g i n i nitial P D is sta ble or q ualitati vel y  i m pr o ve d
•
N o ne w i ncre me ntal ne w lesi o n(s) si nce last e val uati o n
•
N o i ncre me ntal ne w n o n -tar get lesi o n pr o gressi o n si nce last e val uati o n
If re peat i ma gi n g d oes n ot c o nfir m P D per ir R E CIS T as assesse d b y  the l ocal site 
i n vesti gat or a n d t he s u bject c o nti n ues t o be cli nicall y sta ble, st u d y treat me nt a n d t u m or 
i ma gi n g ma y c o nti n ue per st u d y sc he d ule. 
Sce nari os w here P D is c o nfir me d at re peat i ma gi n g if A N Y of t he f oll o wi n g occ ur b y  
ir R E CIS T: 
•
Tar get lesi o n s u m of dia meters re mai ns ≥2 0 % a n d at least 5 m m a bs ol ute i ncrease 
c o m pare d t o na dir
•
N o n -tar get disease res ulti n g i n i nitial P D is q ualitati vel y w orse
•
Ne w lesi o n res ulti n g i n i nitial P D is q ualitati vel y  w orse
•
A d diti o nal ne w lesi o n(s) si nce last e val uati o n
•
A d diti o nal ne w n o n -tar get lesi o n pr o gressi o n si nce last e val uati o n
If re peat i ma gi n g c o nfir ms P D d ue t o a n y of t he sce nari os liste d a b o ve, s u bject will be 
disc o nti n ue d fr o m st u d y  t hera p y.
N O T E: If a s u bject has c o nfir me d ra di o gra p hic pr o gressi o n (i.e. 2 sca ns at least 4 wee ks 
a part de m o nstrati n g pr o gressi ve dis ease) per ir R E CIS T, b ut t he s u bject is ac hie vi n g a 
cli nicall y mea ni n gf ul be nefit, a n d t here is n o f urt her i ncrease i n t he t u m or b ur de n at t he 
c o nfir mat or y tu m or i ma gi n g, a n e xce pti o n t o c o nti n ue treat me nt m a y  be c o nsi dere d 
f oll o wi n g c o ns ultati o n wit h t he S p o ns or. I n this case, if treat me nt is c o nti n ue d, t u m or 
i ma gi n g s h o ul d c o 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 ns 6. 0 
St u d y  Fl o wc hart 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 d diti o nal details a b o ut ir R E CIS T are refere nce d i n Merc k TI P S heet f or R E CI S T 1 1 a n d 
ir R E CIS T.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 5 
I ma gi n g a n d Treat me nt after First Ra di ol o gic E vi de nce of P D
Cli nic all y St a ble
Cli nic all y U nst a ble
I m a gi n g 
Tre at m e nt
I m a gi n g
Tre at m e nt
1st ra di ol o gic 
e vi de nce of P D 
b y R E CI S T 1. 1 
w hic h has bee n 
verifie d b y t he 
ce ntral i ma gi n g 
ve n d or
Re peat i ma gi n g at 
> 4 wee ks at site 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 l ocal 
site I n vesti gat or’s 
discreti o n w hile 
a waiti n g c o nfir mat or y 
t u m or i ma gi n g b y site
b y ir R E CI S T.
Re peat i ma gi n g at >
4 wee ks t o c o nfir m 
P D per p h ysicia n 
discreti o n o nl y
Disc o nti n ue treat me nt
Re peat t u m or 
i ma gi n g c o nfir ms 
P D b y ir R E CI S T 
at t he l ocal site
N o a d diti o nal 
i ma gi n g re q uire d
Disc o nti n ue treat me nt
(e xce pti o n is p ossi ble 
u p o n c o ns ultati o n 
wit h s p o ns or)
N o a d diti o nal 
i ma gi n g re q uire d
N/ A
Re peat t u m or 
i ma gi n g s h o ws 
S D, P R or C R b y 
ir R E CI S T b y t he 
l ocal site
C o nti n ue re g ularl y 
sc he d ule d i ma gi n g 
assess me nts 
C o nti n ue st u d y 
treat me nt at t he l ocal 
site I n vesti gat or’s 
discreti o n
C o nti n ue re g ularl y 
sche 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 o utli ne d i n 
t he pr ot oc ol
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Fi g ure 2 
I ma gi n g a n d Treat me nt f or Cli nicall y Sta ble S u bjects After First Ra di ol o gic 
E vi de nce of P D Assesse d b y  t he Site
7. 1. 2. 7
T u m or Tiss ue C ollecti o n: P D -L 1 St at us
Partici pati o n i n t his trial will be de pe n de nt u p o n s u p pl yi n g t u m or tiss ue f or P D- L 1 testi n g 
fr o m l ocati o ns n ot ra diate d pri or t o bi o ps y ; f or mali n-fi xe d s peci me ns after t he s u bject has 
bee n dia g n ose d wit h metastatic disease will be preferre d f or deter mi nati o n of P D -L 1  stat us 
pri or t o ra n d o mizati o n. Bi o psies 
o btai ne d pri or t o recei pt o f a dj u va nt/ ne oa dj u va nt 
c he m ot hera p y will be per mitte d if rece nt bi o ps y is n ot feasi ble. S u bjects w h ose s u b mitte d 
tiss ue is i ne val ua ble f or P D-L 1  stat us ca n still be eli gi ble t o partici pate i n t he st u d y. 
All s u bjects s h o ul d s u b mit eit her a ne wl y  obtai ne d core or e xcisi o nal bi o ps y  or arc hi val 
tiss ue ( F N A is n ot a de q uate f or b ot h arc hi val a n d ne w tiss ue sa m ples) t o a ce ntral la b f or 
c haracterizati o n of P D -L 1 stat us pri or t o treat me nt all ocati o n.
N ote: S u b missi o n of f or mali n-fi xe d paraffi n e m be d de d t u m or tiss ue sa m ple bl oc ks are 
preferre d; if s u b mitti n g u nstai ne d sli des, t he sli des s h o ul d be fres hl y cut a n d s u b mitte d t o t he 
testi n g la b orat or y wit hi n 1 4 d a y s fr o m t he site sli de secti o n date, ot her wise a ne w s peci me n 
will be re q ueste d.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
If t he sa m ple is deter mi ne d t o be n o n -e val ua ble pri or t o testi n g b y  the ce ntral la b orat or y, a 
ne w sa m ple s h o ul d be s u b mitte d if a vaila ble.  This ma y  incl u de a d diti o nal c ut sli des t hat are 
o utsi de of t he 1 4 da y  wi n d o w n ote d a b o ve.
I n di vi d ual s u bject P D-L 1  stat us will n ot be discl ose d t o i n vesti gati ve sites a n d st ud y  s u bjects. 
A nal y ses b y P D-L 1 bi o mar ker stat us will be li mite d a n d d oc u me nte d.
If t he s u bject si g ns t he F ut ure Bi o me dical Researc h c o nse nt, a n y left o ver sa m ples t hat w o ul d 
be or di naril y discar de d at t he e n d of t he mai n st u d y will be retai ne d f or F ut ure Bi o me dical 
Researc h.
L a b or at or y Pr oce d ures/ Assess me nts
Details re gar di n g s pecific la b orat or y pr oce d ures/assess me nts t o be perf or me d i n t his trial are 
pr o vi de d bel o w. T he t otal a m o u nt of bl o o d/tiss ue t o be dra w n/c ollecte d o ver the c o urse of 
t he trial (fr o m pre -trial t o p ost -trial visits), i ncl u di n g a p pr o xi mate bl o o d/tiss ue v ol u mes 
dra w n/c ollecte d b y  visit a n d b y  sa m ple t ype per s u bject ca n be f o u n d i n t he Pr oce d ure 
Ma n ual .
7. 1. 3. 1
L a b or at or y S afet y E v al u ati o ns ( He m at ol o g y, C he mistr y a n d Uri n al ysis)
La b orat or y  tests f or he mat ol o g y, c he mistr y a n d uri nal ysis are s pecifie d i n Ta ble 6 .
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 6 
La b orat or y  Tests
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
He m at ocrit 
Al b u mi n
Bl o o d
Ser u m β -h u ma n c h ori o nic 
g o na d otr o pi n ( β -h C G) a
He m o gl o bi n 
Al kali ne p h os p hatase
Gl uc ose
P T (I N R) d
Platelet c o u nt 
Ala ni ne a mi n otra nsferase ( A L T) 
Pr otei n
a P T T/ P T T d
W hite Bl o o d Cell 
- W B C (t otal a n d 
differe ntial)
As partate a mi n otra nsferase 
( A S T)
S pecific gra vit y  
T otal trii o d ot h yr o ni ne ( T 3) e
Re d Bl o o d Cell 
C o u nt
Car b o n di o xi de ( C O 2 or 
Bicar b o nate)
b
Micr osc o pic 
e xa m, if a b n or mal 
res ults are n ote d 
Free t h yr o xi ne ( F T 4)
A bs ol ute 
Ne utr o p hil C o u nt
Calci u m
Uri ne pre g na nc y 
testa
T h yr oi d sti m ulati n g h or m o ne 
( T S H)
A bs ol ute 
L y m p h oc yte 
C o u nt
C hl ori de
F ollicle Sti m ulati n g H or m o ne 
( F S H)f
Creati ni ne
Bl o o d f or c orrelati ve st u dies
Gl uc ose
Bl o o d f or ge netics
Lactate De h y dr o ge nase
P h os p h or us
P otassi u m
S o di u m
T otal Bilir u bi n
Direct Bilir u bi n, if t otal bilir u bi n 
is ele vate d a b o ve t he u p per li mit 
of n or mal
T otal pr otei n
Bl o o d Urea Nitr o ge n
Uric aci d
Urea c
a.
Perf or m o n w o me n of c hil d beari n g p ote ntial o nl y. Uri ne pre g na nc y test is preferre d. If t he uri ne test 
is p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d. 
b.
If t hese tests are n ot d o ne as part of sta n dar d of care i n y o ur re gi o n t he n t hese tests d o n ot nee d t o be 
perf or me d.
c.
Bl o o d Urea Nitr o ge n is preferre d; if n ot a vaila ble urea ma y be teste d.
d.
C oa g ulati o n fact ors ( P T/I N R a n d a P T T/ P T T) s h o ul d be teste d as part of t he scree ni n g pr oce d ures f or 
all s u bjects. A n y s u bject recei vi n g a ntic oa g ula nt t hera p y s h o ul d ha ve c oa g ulati o n fact ors m o nit ore d 
cl osel y t hr o u g h o ut t he trial.
e.
T otal T 3 is preferre d; if n ot a vaila ble free T 3 ma y be teste d.
f. As nee de d, F S H t o be perf or me d at Scree ni n g t o c o nfir m p ost -me n o pa usal stat us. 
La b orat or y  tests f or scree ni n g s h o ul d be perf or me d wit hi n 1 0 da y s pri or t o t he first d ose of 
trial treat me nt.  After C y cle 1, pre -d ose la b orat or y pr oce d ures ca n be c o n d ucte d u p t o 3 da y s 
pri or t o Da y  1 of s u bse q ue nt c ycles.  
Res ults m ust 
be re vie we d b y  th e i n vesti gat or or q ualifie d desi g nee a n d f o u n d t o be 
acce pta ble pri or t o eac h d ose of trial treat me nt. U nres ol ve d a b n or mal la bs t hat are dr u g 
relate d A Es s h o ul d be f oll o we d u ntil res ol uti o n. La bs d o n ot nee d t o be re peate d after t he e n d 
of treat me nt if la b s are wit hi n n or mal ra n ge. 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 1. 3. 2
P h ar m ac o ki netic/ P h ar m ac o d y n a mic E v al u ati o ns
Pe m br oliz u m a b 
T he acc u m ulati o n of r o b ust P K a n d A D A data has all o we d f or t he a de q uate c haracterizati o n 
of t he cli nical p har mac ol o g y  of pe m br oliz u ma b acr oss i n dicati o ns. T heref ore, t he c ollecti o n 
of P K a n d A D A sa m ples f or pe m br oliz u ma b are bei n g disc o nti n ue d f or s ubjects e nr olle d 
u n der A me n d me nt 6. Bl o o d sa m ples f or P K a n d A D A c ollecte d pri or t o A me n d me nt 6 m a y  
be st ore d. A nal ys is will be perf or me d o nly if re q uire d.
E x pl or at or y dr u g -dr u g i nter acti o n a n al ysis 
T he p ote ntial of dr u g i nteracti o n bet wee n bi ol o gics s uc h as pe m br oliz u ma b a n d s mall 
m olec ule dr u gs is ne gli gi ble. T heref ore, c ollecti o n of sa m ples f or t he assess me nt of P K of 
paclita xel a n d na b -paclita xel is bei n g disc o nti n ue d u n der A me n d me nt 6. Bl o o d sa m ples f or 
P K c ollecte d pri or t o A me n d me nt 6 ma y  be st ore d. A nal ys is will be perf or me d o nl y if 
re q uire d.
7. 1. 3. 3
P atie nt Re p orte d O utc o mes ( P R Os)
T he E ur o Q ol ( 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- L C 1 3 q uesti o n naires will be 
a d mi nistere d b y  trai ne d st u d y site pers o n nel a n d c o m plete d electr o nicall y by t he s u bjects 
t he msel ves.  
It is str o n gl y rec o m me n de d t hat e P R Os are a d mi nistere d pri or t o dr u g a d mi nistrati o n, 
a d verse e ve nt e val uati o n a n d disease stat us n otificati o n. T he e P R Os are c o m plete d i n t he 
f oll o wi n g or der: E ur o Q ol e( E Q)-5 D first, t he n E O R T C e Q L Q-C 3 0, a n d lastl y the E O R T C 
e Q L Q-L C 1 3 at t he ti me p oi nts s pecifie d i n t he Trial Fl o w C harts a n d briefl y s u m marize d 
bel o w. 
P R Os ( 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- L C 1 3) are c o m plete d at C y cles 1 
t hr o u g h 7 a n d t he n e ver y 3r d c ycle (e ver y 9 wee ks) w hile o n treat me nt u p t o 4 8 wee ks.  All 
P R Os are als o c o m plete d at treat me nt disc o nti n uati o n visit a n d 3 0 -da y  safet y f oll o w-u p visit .
7. 1. 3. 4
Bl o o d f or R N A A n al yses a n d Bi o m ar ker A n al yses ( pl as m a , ser u m)
Bl o o d f or R N A A nal y ses s h o ul d be c ollecte d pre -d ose o n Da y  1 of C y cle 1, 2, a n d 5, or at 
ti me of disc o nti n uati o n.   Bl o o d f or Bi o mar ker A nal y ses ( plas ma, ser u m) s h o ul d be c ollecte d 
pre -d ose o n D a y  1 of C y cle 1, 2 or at ti me of disc o nti n uati o n. Deta ile d i nstr ucti o ns wit h 
s pecific ti me p oi nts per sa m ple are pr o vi de d i n t he Pr oce d ures Ma n ual. A n y left o ver sa m ples 
will be st ore d f or f ut ure bi o me dical researc h if t he s u bject si g ns t he F B R c o nse nt.
7. 1. 3. 5
Pl a n ne d Ge netic A n al ysis S a m ple C ollecti o n
Sa m ple c ollecti o n, st ora ge a n d s hi p me nt i nstr ucti o ns f or Pla n ne d Ge netic A nal ys is sa m ples 
will be pr o vi de d i n t he Pr oce d ure Ma n ual.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 1. 3. 6
F ut ure Bi o me dic al Rese arc h S a m ple C ollecti o n
T he f oll o wi n g s peci me ns are t o be o btai ne d as part of F ut ure Bi o me dical Resear c h:
D N A f or f ut ure researc h.
• 
Left o ver R N A
• 
Left o ver plas ma a n d ser u m fr o m bi o mar ker a nal ys es
• 
Left o ver mai n st u d y t u m or
Ot her Pr oce d ures
7. 1. 4. 1
Wit h dr a w al/ Disc o nti n u ati o n
S u bjects w h o disc o nti n ue/ wit h dra w fr o m treat me nt pri or t o c o m pleti o n of t he treat me nt
re gi me n 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 s u bject disc o nti n ues/ wit h dra ws fr o m partici pati o n i n t he trial, all a p plica ble acti vities 
sc he d ule d f or t he e n d of treat me nt visit s h o ul d be perf or me d at t he time of disc o nti n uati o n.  
A n y  ad verse e ve nts w hic h are prese nt at t he ti me of disc o nti n uati o n/ wit h dra wal s h o ul d be 
f oll o we d i n acc or da nce wit h t he safet y re q uire me nts o utli ne d i n Secti o n 7. 2 - Assessi n g a n d 
Rec or di n g A d verse E ve nts . Su bjects w h o a) attai n a C R or b) c o m plete 3 5 a d mi nistrati o ns of 
pe m br oliz u ma b (a p pr o xi matel y 2 years) m a y  disc o nti n ue treat me nt wit h t he o pti o n of 
restarti n g treat me nt if t he y meet t he criteria s pecifie d i n Secti o n 7. 1. 5. 4.  After disc o nti n ui n g 
treat me nt f oll o wi n g assess me nt of C R or 3 5 a d mi nistrati o ns of pe m br oliz u ma b, t hese 
s u bjects s h o ul d ret ur n t o t he site f or a Safet y  Foll o w -u p Visit ( descri be d i n Secti o n 7. 1. 5. 3) 
a n d t he n pr ocee d wit h assess me nts ( descri be d i n Secti o n 7. 1. 5. 3) .
Wit h dr a w al Fr o m F ut ure Bi o me dic al Rese arc h
S u bj ects ma y  wit h dra w t heir c o nse nt f or F ut ure Bi o me dical Researc h a n d ha ve t heir 
s peci me ns a n d all deri vati ves destr o ye d.   Su bjects m a y  wit h dra w c o nse nt at a n y ti me b y  
c o ntacti n g t he pri nci pal i n vesti gat or f or t he mai n trial.  If me dical rec or ds f or t he mai n
trial 
are still a vaila ble, t he i n vesti gat or will c o ntact t he S p o ns or usi n g t he desi g nate d mail b o x 
(cli nical.s peci me n. ma na ge me nt @ merc k.c o m), a n d a f or m will be pr o vi de d b y  t he S p o ns or t o 
o btai n a p pr o priate i nf or mati o n t o c o m plete s peci me n wit h dra wal. 
 Su bs e q ue ntl y, t he 
s u bject's s peci me ns will be re m o ve d fr o m t he bi ore p osit or y  an d be destr o y e d.  A letter will 
be se nt fr o m t he S p o ns or t o t he i n vesti gat or c o nfir mi n g t he destr ucti o n. It is t he 
res p o nsi bilit y of t he i n vesti gat or t o i nf or m t he s u bject of c o m plet i o n of destr ucti o n.  An y  
a nal ys es i n pr o gress at t he ti me of re q uest f or destr ucti o n or alrea d y perf or me d pri or t o t he 
re q uest bei n g recei ve d b y t he S p o ns or will c o nti n ue t o be use d as part of t he o verall researc h 
trial data a n d res ults.   N o ne w a nalys es w o ul d be ge nerate d after t he re q uest is recei ve d.
I n t he e ve nt t hat t he me dical rec or ds f or t he mai n trial are n o l o n ger a vaila ble (e. g., if t he 
i n vesti gat or is n o l o n ger re q uire d b y  re g ulat or y aut h orities t o retai n t he mai n trial rec or ds) or 
t he s peci me ns ha ve bee n c o m pletel y an o n y mize d, t here will n o l o n ger be a li n k bet wee n t he 
s u bject’s pers o nal i nf or mati o n a n d t heir s peci me ns.  In t his sit uati o n, t he re q uest f or 
s peci me n destr ucti o n ca n n ot be pr ocesse d.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 1. 4. 2
Bli n di n g/ U n bli n di n g
W he n t he i n vesti gat or or s u b -i n vesti gat or nee ds t o i de ntif y t he dr u g use d b y a s u bject a n d t he 
d osa ge a d mi nistere d i n case of e mer ge nc y e. g., t he occ urre nce of seri o us a d verse 
e x perie nces, he/s he will c o ntact t he e mer ge nc y  u n bli n di n g call ce nter b y tele p h o ne a n d ma ke 
a re q uest f or e me r ge nc y un bli n di n g.  As re q ueste d b y  the i n vesti gat or or s u b-i n vesti gat or t he 
e mer ge nc y un bli n di n g call ce nter will pr o vi de t he i nf or mati o n t o hi m/ her pr o m ptl y  an d 
re p ort u n bli n di n g t o t he s p o ns or.  The e mer ge nc y un bli n di n g call ce nter will ma ke a rec or d 
pr o m ptl y  ho we ver, t he i n vesti gat or or s u b-i n vesti gat or m ust e nter t he t o xicit y gra de of t he 
a d verse e x perie nces o bser ve d,   their relati o n t o st u d y dr u g, t he reas o n t here of, etc., i n t he 
me dical c hart etc., bef ore u n bli n di n g is perf or me d. S u bjects w h ose treat me nt assi g n me nt has 
bee n u n bli n de d m ust be disc o nti n ue d fr o m st u d y  dr u g.
A d diti o nall y , t he i n vesti gat or m ust g o i nt o t he I V R S s yste m a n d perf or m t he u n bli n d i n t he 
I V R S s yste m t o u p date dr u g dis p ositi o n.  In t he e ve nt t hat t he e mer ge nc y un bli n di n g call 
ce nter is n ot a vaila ble f or a gi ve n site i n t his trial, I V R S/IW R S s h o ul d be use d f or e mer ge nc y 
u n bli n di n g i n t he e ve nt t hat t his is re q uire d f or s u bject safet y.
I n t he e ve nt t hat u n bli n di n g has occ urre d, t he circ u msta nces ar o u n d t he u n bli n di n g (e. g., 
date, reas o n a n d pers o n perf or mi n g t he u n bli n di n g ) m ust be d oc u me nte d pr o m ptl y , a n d t he 
S p o ns or Cli nical Direct or n otifie d as s o o n as p ossi ble. O nl y  the pri nci pal i n vesti gat or or 
dele gate a n d t he res pecti ve s u bject’s c o de s h o ul d be u n bli n de d. Trial site pers o n n el a n d 
S p o ns or pers o n nel directl y  ass ociate d wit h t he c o n d uct of t he trial s h o ul d n ot be u n bli n de d.
S u bjects w h ose treat me nt assi g n me nt has bee n u n bli n de d ( by t he i n vesti gat or, Merc k 
s u bsi diar y, or t hr o u g h t he e mer ge nc y un bli n di n g call ce nter) m ust be disc o nti n ue d fr o m 
st u d y dr u g.
7. 1. 4. 3
C ali br ati o n of Critic al E q ui p me nt
T he i n vesti gat or or q ualifie d desi g nee has t he res p o nsi bilit y to e ns ure t hat a n y critical de vice
or i nstr u me nt use d f or a cli nical e val uati o n/test d uri n g a cli nical trial t hat pr o vi des i m p orta nt 
inf or mati o n a b o ut i ncl usi o n/e xcl usi o n criteria a n d/ or safety or efficac y para meters s hall be 
s uita bl y cali brate d a n d mai ntai ne d 
t o e ns ure t hat t he data o btai ne d is relia ble a n d/ or 
re pr o d uci ble.  D oc u me ntati o n 
of e q ui p me nt cali brati o n m ust 
be retai ne d as s o urce 
d oc u me ntati o n at t he trial site.
Critical E q ui p me nt f or t his trial i ncl u des:
• 
La b orat or y e q ui p me nt – as re q uire d f or i ncl usi o n la bs a n d trial assess me nts
• 
I ma gi n g e q ui p me nt – as re q uire d f or st u d y o bjecti ves
See pr ot oc ol -s pecifie d g ui da nce i n t he A d m i nistrati ve Bi n der, Pr oce d ures Ma n ual a n d Site 
I ma gi n g Ma n ual.
Visit Re q uire me nts
Visit re q uire me nts are o utli ne d i n Secti o n 6 . 0 - Trial Fl o w C hart.   S pecific pr oce d ure -relate d 
details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 7
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
7. 1. 5. 1
Scree ni n g
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0 - Trial Fl o w C hart. S pecific pr oce d ure relate d
details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures.
A p pr o xi matel y  28 d a y s pri or t o ra n d o mizati o n, p ote ntial s u bjects will be e val uate d t o
deter mi ne t hat t he y f ulfill t he e ntr y re q uire me nts as set f ort h i n Secti o n 5. 1. Scree ni n g
pr oce d ures ma y  be re peate d after c o ns ultati o n wit h t he S p o ns or.
Writte n 
c o nse nt m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol s pecific pr oce d ure.
Res ults of a test perf or me d pri or t o t he s u bject si g ni n g c o nse nt as part of r o uti ne cli nical 
ma na ge me nt are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti me 
fra me. Scree ni n g pr oce d ures are t o be c o m plete d wit hi n 2 8 da ys pri or t o t he first d ose of trial 
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 y s pri or t o t he first d ose of trial 
treat me nt.

F or w o me n of re pr o d ucti ve p ote ntial, a uri ne pre g na nc y  test will be perf or me d wit hi n 
7 2 h o urs pri or t o first d ose of trial 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, perf or me d b y  the l ocal st u d y site 
la b orat or y, will be re q uire d.

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 ra n d o mizati o n.
S u bjects 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 perf or me d d uri n g t he i nitial scree ni n g peri o d are acce pta ble i n lie u
of re peati n g a 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 res ults meet
t he i ncl usi o n/e xcl usi o n criteria.
7. 1. 5. 2
Tre at me nt Peri o d Visit
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0 - Trial Fl o w C hart. S pecific pr oce d ure -relate d
details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures.
7. 1. 5. 3
P ost -Tri al
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0 - Trial Fl o w C hart. S pecific pr oce d ure -relate d
details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures. S u bjects will be f oll o we d f or u p
t o 2 years. If t he s u bject e x perie nce d a C R, P R, or S D d uri n g t he Treat me nt P hase o n
pe m br oliz u ma b, a nd t he n e x perie nces P D at a n y ti me d uri n g t hat t w o ye ar f oll o w- u p peri o d,
he/s he will be eli gi ble t o recei ve u p t o 1 2 m o nt hs of t hera py wit h pe m br oliz u ma b i n t he
Sec o n d C o urse P hase acc or di n g t o t he criteria i n Secti o n 7. 1. 5. 4. After t he Sec o n d C o urse
P hase , s u bjects s h o ul d be f oll o we d f or u p t o t w o years, wit h n o o pti o n f or retreat me nt wit h
pe m br oliz u ma b o n st u d y .
S u bjects w h o disc o nti n ue trial treat me nt f or a reas o n ot her t ha n disease pr o gressi o n will still 
be c o nsi dere d as o n st u d y an d s h o ul d c o nti n ue wit h re g ularl y  sc he d ule d assess me nts (als o 
refer t o secti o n 7. 1. 2. 6. 3), i ncl u di n g c ollecti n g s u bject i nf or mati o n o n t he start of ne w 
a nti ne o plastic t hera p y, disease pr o gressi o n, a n d deat h.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 8
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S afet y F oll o w -u p Visit
T he ma n dat or y  S afety F oll o w - U p Visit s h o ul d b e c o n d ucte d a p pr o xi matel y 30 d a y s after t he
last d ose of trial treat me nt or bef ore t he i nitiati o n of a ne w a nti ne o plastic treat me nt,
w hic he ver c o mes first. S u bjects wit h a n A E of Gra de > 1 will be f urt her f oll o we d u ntil t he 
res ol uti o n of t he A E t o Gra de 0- 1 or u ntil be gi n ni n g of a ne w a nti ne o plastic t hera py,
w hic he ver occ urs first. S u bjects w h o are eli gi ble per t he re q uire me nts i n Secti o n 7. 1. 5. 4 f or
treat me nt wit h pe m br oliz u ma b d uri n g t he Sec o n d C o urse P hase m a y  ha ve u p t o t w o safety
f oll o w- u p visits, o ne after t he Treat me nt P hase a n d t he sec o n d after t he Sec o n d C o urse
P hase.
F oll o w -u p Visits
F oll o w u p visit re q uire me nts are o utli ne d i n Secti o n 6. 0 - Trial Fl o w C hart.
S ur vi v al F oll o w -u p
S u bjects w h o e x perie nce c o nfir me d disease pr o gressi o n or start a ne w a nt ica ncer t hera py,  
will 
m o ve 
i nt o S ur vi val F oll o w -U p 
P hase a n d s h o ul d be c o ntacte d b y  tele p h o ne 
a p pr o xi matel y ever y  12 wee ks t o assess f or s ur vi val stat us u ntil deat h, wit h dra wal of 
c o nse nt, or t he e n d of t he st u d y, w hic he ver occ urs first. P ost -st u d y treat ments a n d t he 
s u bject’s res p o nse t o t he m will als o be c ollecte d.
7. 1. 5. 4
S ur vi v al St at us
T o e ns ure c urre nt a n d c o m plete s ur vi val data is a vaila ble at t he ti me of data base l oc ks, 
u p date d s ur vi val stat us ma y  be re q ueste d d uri n g t he c o urse of t he st u d y by t he S p o ns or.  For 
e xa m ple, u p date d s ur vi val stat us ma y be re q ueste d pri or t o b ut n ot li mite d t o a n e xter nal Data 
M o nit ori n g 
C o m mittee (e D M C) re vie w, i nteri m a n d/ or fi nal a nal ys is.  Up o n S p o ns or 
n otificati o n, all partici pa nts w h o d o n ot/ will n ot ha ve a sc he d ule d st u d y  visit or st u d y co ntact 
d uri n g t he S p o ns or defi ne d ti me peri o d will be c o ntacte d f or t heir s ur vi val stat us (e xcl u di n g 
partici pa nts t hat ha ve a pre vi o usl y rec or de d deat h e ve nt i n t he c ollecti o n t o ol). 
7. 1. 5. 5
Sec o n d C o urse P h ase
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0 - Trial Fl o w C hart. 
S pecific pr oce d ure -relate d details are pr o vi de d a b o ve i n Secti o n 7. 1 - Trial Pr oce d ures. 
S u bjects w h o were ra n d o mize d t o recei ve pe m br oliz u ma b ma y  be eli gi ble t o recei ve 
pe m br oliz u m ab i n t he Sec o n d C o urse P hase of t his st u d y  f or u p t o 1 7 c y cles if t he s u bject:
 
St o p pe d t heir i nitial treat ment wit h 
pe m br oliz u ma b / place b o after attai ni n g a 
c o nfir me d C R b y  ce ntral re vie w, were 
treate d f or at
least ei g ht c ycles wit h 
pe m br oliz u ma b / place b o, 
a n d  
recei ve d 
at  
least 
t w o 
treat me nts 
wit h
pe m br oliz u ma b / place b o be y o n d t he date w he n t he i nitial C R was declare d. 
O R
 
Ha d S D, P R or C R a n d st o p pe d pe m br oliz u ma b treat me nt after 1 7 c ycles f or reas o ns 
ot her t ha n disease pr o gressi o n or i nt olera bilit y.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
7 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A N D

E x perie nce d a n i n vesti gat or-deter mi ne d c o nfir me d ra di o gra p hic disease pr o gressi o n 
acc or di n g t o ir R E CI S T after st o p pi n g t heir i nitial treat me nt wit h pe m br oliz u ma b d ue 
t o ac hie ve me nt of a c o nfir me d C R.

Di d n ot recei ve a n y ot her s yste mic a nti-ca ncer treat me nt si nce t he last d ose of 
pe m br oliz u ma b. ( Local treat me nt s uc h as ra diati o n or s ur ger y as a nti-ca ncer t hera py 
is all o we d; S p o ns or c o ns ultati o n m ust 
be o btai ne d a n d s u bjects s h o ul d ha ve 
rec o vere d c o m pletel y fr o m si de effects of l ocal pr oce d ures. I n patie nts wit h brai n 
metastases,  
ne ur ol o gical 
sta bilit y  
must 
be 
d oc u me nte d 
bef ore 
i nitiati n g 
pe m br oliz u ma b.)

C o nti n ues t o meet i ncl usi o n criteria 7, 8 a n d 9.

D oes n ot meet e xcl usi o n criteria 2, 3, 4, 6 -8, 1 1, 1 3, 1 4 a n d/ or 2 2.
A n o bjecti ve res p o nse or pr o gressi o n of disease t hat occ urs d uri n g t he Sec o n d C o urse P hase 
f or a s u bject will n ot be c o u nte d as a n e ve nt f or t he pri mary a nal ys is of eit her e n d p oi nt i n t his 
trial.
7. 1. 5. 6
Cr oss o ver P h ase 
S u bjects w h o are u n bli n de d after verificati o n f or P D b y  bli n de d i n de pe n de nt ce ntral 
ra di ol o gical re vie w, will ha ve t he o p p ort u nit y  to recei ve pe m br oliz u ma b m o n ot hera p y i n t he 
cr oss o ver p hase . S u bjects w h o per ma ne ntl y disc o nti n ue c he m ot hera p y d ue t o a n a d verse 
e ve nt, wit h dra w c o nse nt, or f or a n y reas o n ot her t ha n pr o gressi ve disease, will n ot be eli gi ble 
f or cr oss o ver. S u bjects w h o are u n bli n de d after A me n d me nt 6 will be all o we d t o cr oss o ver 
after d oc u me nte d P D b y  bli n de d i n de pe n de nt ce ntral ra di ol o gical re vie w. Cr oss o ver s u bjects 
m ust n ot i nitiate treat me nt wit h pe m br oliz u ma b a n y earlier t ha n 2 1 da y s after t heir last d ose 
of c he m ot hera p y re gar dless of t he ti me of pr o gressi o n.
Cr oss o ver Q ualificat i o ns:
S u bjects w h o recei ve d place b o will be c o nsi dere d f or cr oss o ver t o pe m br oliz u ma b after
d oc u me nte d, pr o gressi ve disease assesse d base d o n R E CI S T 1. 1. verifie d b y  ce ntral i ma gi n g 
ve n d or re vie w. Cr oss o ver is o pti o nal a n d is at t he discreti o n of t he I n vesti gat or ( wit h t he
S p o ns or s a gree me nt). S u bjects w h o meet t he f oll o wi n g criteria are eli gi ble f or cr oss o ver:

D oc u me ntati o n of pr o gressi ve disease will be defi ne d as ce ntral i ma gi n g ve n d or
assess me nt

A d verse e ve nts (e xce pt al o pecia a n d peri p heral ne ur o p at h y) d ue t o t hera p y must ha ve 
i m pr o ve d t o C T C A E ( Versi o n 4. 0) ≤Gra de 1

If a s u bject is u nsta ble as a res ult of a ne w or pr o gressi n g brai n metastasis(es), t he
s u bject will n ot be eli gi ble f or cr oss o ver.

E C O G Perf or ma nce Stat us 0 - 1

S u bject has n ot recei ve d a n y ot her s yste mic a nti-ca ncer t hera pies ot her t ha n t he
c he m ot hera p y a d mi nistere d d uri n g t he treat me nt p hase.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 0
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
 
If re q uire d, c o m plete d palliati ve ra di ot hera py (3 0 G y  or less) ≥ 7 d a y s bef ore t he first
d ose of cr oss o ver trial treat me nt.
 
Patie nt has a de q uate or ga n f u ncti o n as i n dicate d b y  the la b orat or y val ues i n Secti o n
5. 1. 2.
7. 1. 5. 7 
Cr oss o ver Assess me nts a n d Pr oce d ures
Cr oss o ver s u bjects m ust n ot i nitiate treat me nt wit h pe m br oliz u ma b a n y earlier t ha n 2 1 d a y s
after t heir last d ose of c he m ot hera p y re gar dless of t he ti me of pr o gressi o n. T he s u bject will
t he n start t he cr oss o ver p hase as o utli ne d i n Cr oss o ver Fl o w C hart i n Secti o n 6. 3. Scree ni n g
pr oce d ures nee d t o be c o m plete d wit hi n 2 8 da y s of c o nfir me d pr o gressi ve disease ( or u p t o 
4 2 d a y s fr o m last d ose if rec o veri n g fr o m a n a d verse e ve nt) . All pr oce d ures a n d assess me nts 
c o m plete d at t he ti me of wit h dra wal fr o m t he mai n st u d y ma y be use d as a p pr o priate f or t he 
start of t he Cr oss o ver P hase of t he st u d y. T he t u m or i ma ge use d t o deter mi ne pr o gressi ve 
disease ca n be use d as t he ne w baseli ne i ma ge f or t he Cr oss o ver p hase if 1) 3 0 d a y s pri or t o 
recei vi n g t he first d ose of pe m br oliz u ma b m o n ot hera p y a n d 2) N o st u d y treat me nt bet wee n 
t he i ma ge a n d first d ose of pe m br oliz u ma b m o n ot h era p y, ot her wise a ne w baseli ne i ma ge 
m ust be perf or me d pri or t o pe m br oliz u ma b m o n ot hera p y treat me nt. S u bjects w h o cr oss o ver 
a n d t he n ac hie ve a C R per R E CI S T 1. 1 ha ve t he o pti o n t o h ol d pe m br oliz u ma b w hile 
c o nti n ui n g i n t he trial. A d diti o nal details are pr o vi de d i n Sec o n d C o urse P hase Secti o n 
7. 1. 5. 4.
Assessi n g a n d Rec or di n g A d verse E ve nts
A n a d verse e ve nt is defi ne d as a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y 
ha ve t o ha ve a ca usal relati o ns hi p wit h t his treat me nt. A n a d verse e ve nt ca n t heref ore be a n y 
u nfa v o ura ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e xa m ple), 
s ym pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure.  An y  worse ni n g (i.e., a n y cli nicall y si gnifica nt a d verse c ha n ge i n 
fre q ue nc y an d/ or i nte nsit y) of a pree xisti n g c o n diti o n t hat is te m p orall y ass ociate d wit h t he 
use of t he S p o ns or’s pr o d uct, is als o a n a d verse e ve nt.
C ha n ges res ulti n g fr o m n or mal gr o wt h a n d de vel o p me nt t hat d o n ot var y si g nifica ntly i n 
fre q ue nc y or se verity fr o m e x pecte d le vels are n ot t o be c o nsi der e d a d verse e ve nts.  
E xa m ples of t his ma y  incl u de, b ut are n ot li mite d t o, teet hi n g, t ypical cr yi n g in i nfa nts a n d 
c hil dre n a n d o nset of me nses or me n o pa use occ urri n g at a p hys i ol o gicall y a p pr o priate ti me.
S p o ns or's pr o d uct i ncl u des a n y p har mace utical pr o d u ct, bi ol o gical pr o d uct, de vice, 
dia g n ostic a ge nt or pr ot oc ol -s pecifie d pr oce d ure, w het her i n vesti gati o nal (i ncl u di n g place b o 
or acti ve c o m parat or me dicati o n) or mar kete d, ma n ufact ure d b y , lice nse d b y , pr o vi de d b y  or 
distri b ute d b y  t he S p o ns or f or h u ma n use.
A d verse e ve nts m a y  occ ur d uri n g cli nical trials, or as prescri be d i n cli nical practice, fr o m 
o ver d ose ( w het her acci de ntal or i nte nti o nal), fr o m a b use a n d fr o m wit h dra wal.
Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n a d verse e ve nt
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
All a d vers e 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  th e i n vesti gat or if t he y ca use t he s u bject t o be 
e xcl u de d fr o m t he trial, or are t he res ult of a pr ot oc ol -s pecifie d i nter ve nti o n, i ncl u din g b ut 
n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera py, diet, place b o treat me nt or a 
pr oce d ure. 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 d a y s f oll o wi n g 
cessati o n of treat me nt, all a d verse e ve nts m ust be re p orte d b y  the i n vesti gat or. S uc h e ve nts 
will be rec or de d at eac h e xa mi nati o n o n t he A d verse E ve nt case re p ort f or ms/ w or ks heets.  
T he re p orti n g ti mefra me f or a d verse e ve nts meeti n g a n y seri o us criteria is descri be d i n 
secti o n 7. 2. 3. 1. T he i n vesti gat or will ma ke e ver y atte m pt t o f oll o w all s u bjects wit h n o n -
seri o us a d verse e ve nts f or o utc o me.
Electr o nic re p orti n g pr oce d ures ca n be f o u n d i n t he Electr o nic Data Ca pt ure (E D C ) data 
e ntr y gui deli nes. Pa per re p orti n g pr oce d ures ca n be f o u n d i n t he I n vesti gat or Trial File 
Bi n der ( or e q ui vale nt).
A d verse e ve nts will n ot be c ollecte d f or s u bjects d uri n g t he pre -scree ni n g peri o d (f or 
deter mi nati o n of arc hi val tiss ue stat us) as l o n g as t hat s u bject has n ot u n der g o ne a n y 
pr ot oc ol -s pecifie d pr oce d ure or i nter ve nti o n.  If t he s u bject re q uires a bl o o d dra w, fres h 
t u m or bi o ps y  etc., t he s u bject is first re q uire d t o pr o vi de c o nse nt t o t he mai n st u d y an d A Es 
will be ca pt ure d acc or di n g t o g ui deli nes f or sta n dar d A E re p orti n g.
Defi niti o n of a n O ver d ose f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he 
S p o ns or
F or p ur p oses of t his trial, a n o ver d ose will be defi ne d as a n y d ose e xcee di n g t he prescri be d 
d ose f or pe m br oliz u ma b b y  ≥1 0 0 0 m g  (5 ti mes t he d ose) . N o s pecific i nf or mati o n is 
a vaila ble o n t he treat me nt of o ver d ose of
pe m br oliz u ma b . I n the e ve nt of o ver d ose, 
pe m br oliz u ma b s h o ul d be disc o nti n ue d a n d t he s u bject s h o ul d be o bser ve d cl osel y for 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 ded if cli nicall y  i n dicate d.
If a n a d verse e ve nt(s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of S p o ns or's pr o d uct or 
vacci ne, t he a d verse e ve nt(s) is re p orte d as a seri o us a d verse e ve nt, e ve n if n o ot her 
seri o us ness criteria are met.
If a d ose of S p o ns or's pr o d uct or vacci ne meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n 
wit h o ut a n y ass ociate d cli nical s ym pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is 
re p orte d as a n o n -seri o us E ve nt of Cli nical I nterest ( E CI), usi n g t he ter mi n ol o g y “acci d e ntal 
or i nte nti o nal o ver d ose wit h o ut a d verse effect.”
All re p orts of o ver d ose wit h a n d wit h o ut a n a d verse e ve nt m ust 
be re p orte d b y  the 
i n vesti gat or wit hi n 2 4 h o urs t o t he S p o ns or eit her b y  electr o nic me dia or pa per. Electr o nic 
re p orti n g pr oce d ures ca n be f o u n d i n t he E D C data e ntr y gui deli nes. Pa per re p orti n g 
pr oce d ures ca n be f o u n d i n t he In vesti gat or Trial File Bi n der ( or e q ui vale nt).
Re p orti n g of Pre g n a nc y a n d L act ati o n t o t he S p o ns or
Alt h o u g h pre g na nc y  a n d lactati o n are n ot c o nsi dere d a d verse e ve nts, it is t he res p o nsi bilit y of 
i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g na nc y or lactati o n i n a s u bject 
(s p o nta ne o usly re p orte d t o t he m) t hat occ urs d uri n g t he trial.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Pre g na ncies a n d lactati o ns t hat occ ur 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 d a y s f oll o wi n g cessati o n of S p o ns or’s pr o d uct, or 3 0 da ys f oll o wi n g cessati o n of 
treat me nt if t he s u bject i nitiates ne w a ntica ncer t hera py, w hic he ver is earlier, m ust be 
re p orte d b y  the i n vesti gat or.  
All re p orte d pre g na ncies
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  outc o mes of s p o nta ne o us a b orti o n, 
misse d a b orti o n, be ni g n h y dati dif or m m ole, bli g hte d o v u m, fetal deat h, i ntra uteri ne deat h, 
miscarria ge a n d still birt h m ust be re p orte d as seri o us e ve nts (Im p orta nt Me dical E ve nts). If 
t he pre g na nc y c o nti n ues t o ter m, t he o utc o me ( healt h of i nfa nt) m ust als o be re p orte d.
S uc h e ve nts m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or eit her b y  electr o nic me dia or 
pa per. Electr o nic re p orti n g pr oce d ures ca n be f o u n d i n t he E D C data e ntr y g ui deli nes. Pa per 
re p orti n g pr oce d ures ca n be f o u n d i n t he I n vesti gat or Trial File Bi n der ( or e q ui vale nt).
I m me di ate Re p orti n g of A d verse E ve nts t o t he S p o ns or
7. 2. 3. 1
Seri o us A d verse E ve nts
A seri o us a d verse e ve nt is a n y ad verse e ve nt occ urr i n g at a n y d ose or d uri n g a n y use of 
S p o ns or's pr o d uct t hat:
●
Res ults i n deat h;
●
Is life t hreate ni n g;
●
Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y;
●
Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n;
●
Is a c o n ge nital a n o mal y/ birt h defect;
●
Is a n ot her i m p orta nt me dical e ve nt.
N ote: I n a d diti o n t o t he a b o ve criteria, a d verse e ve nts meeti n g eit her of t he bel o w criteria, 
alt h o u g h n ot seri o us per I C H defi niti o n, are re p orta ble t o t he S p o ns or i n t he sa me ti mefra me 
as S A Es t o meet certai n l ocal re q uire me nts. T heref ore, t hese e ve nts are c o nsi dere d seri o us b y 
t he S p o ns or f or c ollecti o n p ur p oses.
●
Is a ne w ca ncer (t hat is n ot a c o n diti o n of t he st u d y);
●
Is ass ociate d wit h a n o ver d ose.
Refer t o Ta ble 7 f or a d diti o nal details re gar di n g eac h of t he a b o ve criteria.
F or t he ti me peri o d be gi n ni n g w he n 
t he c o nse nt f or m is si g ne d u ntil treat me nt 
all ocati o n/ra n d o mizati o n, a n y seri o us a d verse e ve nt, or f oll o w u p t o a seri o us a d verse e ve nt, 
i ncl u di n g deat h d ue t o a n y ca use ot her t ha n pr o gressi o n of t he ca ncer u n der st u d y (refere nce 
Secti o n 7. 2. 3. 3 f or a d diti o nal details), t hat occ urs t o a n y su bject m ust be re p orte d wit hi n 2 4 
h o urs t o t he S p o ns or if it ca uses t he s u bject t o be e xcl u de d fr o m t he trial, or is t he res ult of a 
pr ot oc ol -s pecifie d i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or disc o nti n uati o n of 
us ual t hera p y, diet, place b o treat me nt or a pr oce d ure.
F or t he ti me peri o d be gi n ni n g at treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 9 0 d a y s 
f oll o wi n g cessati o n of treat me nt, or 3 0 d a y s f oll o wi n g cessati o n of treat me nt if t he s u bject 
i nitiates ne w a ntica ncer t hera p y, w hic he ver is earlier, a n y seri o us a d verse e ve nt, or f oll o w u p 
t o a seri o us a d verse e ve nt, i ncl u di n g deat h d ue t o a n y ca use ot her t ha n pr o gressi o n of t he 
ca ncer u n der st u d y (refere nce Secti o n 7. 2. 3. 3 f or a d diti o nal details), w het her or n ot relate d t o 
t he S p o ns or's pr o d uct, m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or eit her b y  electr o nic 
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
me dia or pa per. Electr o nic re p orti n g pr oce d ures ca n be f o u n d i n t he E D C data e ntr y 
g ui deli nes. Pa per re p orti n g pr oce d ures ca n be f o u n d i n t he I nvesti gat or Trial File Bi n der ( or 
e q ui vale nt)
A d diti o nall y , a n y seri o us a d verse e ve nt, c o nsi dere d b y  an i n vesti gat or w h o is a q ualifie d 
p h y sicia n t o be relate d t o t he S p o ns or's pr o d uct t hat is br o u g ht t o t he atte nti o n of t he 
i n vesti gat or at a n y ti me f oll o wi n g c o nse nt t hr o u g h t he e n d of t he s pecifie d safet y foll o w - u p 
peri o d s pecifie d i n t he para gra p h a b o ve, or at a n y ti me o utsi de of t he ti me peri o d s pecifie d i n 
t he pre vi o us para gra p h als o m ust be re p orte d i m me diately t o t he S p o ns or.
All s u bjects wit h seri o us a d verse e ve nts m ust be f oll o we d u p f or o utc o me.
7. 2. 3. 2
E ve nts of Cli nic al I nterest
Selecte d n o n- seri o us a n d seri o us a d verse e ve nts are als o k n o w n as E ve nts of Cli nical I nterest 
( E CI)  a n d m ust be re p orte d t o t he S p o ns or.
F or t he ti me peri o d be gi n ni n g w he n 
t he c o nse nt f or m is si g ne d u ntil treat me nt 
all ocati o n/ra n d o mizati o n, a n y E CI, or f oll o w u p t o a n E CI, t hat occ urs t o a n y s u bject m ust be 
re p orte d wit hi n 2 4 h o urs t o t he S p o ns or if it ca uses t he s u bject t o be e xcl u de d fr o m t he trial, 
or is t he res ult of a pr ot oc ol -s pecifie d i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or 
disc o nti n uati o n of us ual t hera p y, di et, place b o treat me nt or a pr oce d ure.
F or t he ti me peri o d be gi n ni n g at treat me nt all ocati o n/ra n d o mizati o n t hr o u g h 3 0
da y s 
f oll o wi n g cessati o n of treat me nt, a n y E CI, or f oll o w u p t o a n E CI , w het her or n ot relate d t o 
t he S p o ns or’s pr o d uct, m ust be re p orte d w it hi n 2 4 h o urs t o t he S p o ns or, eit her b y  electr o nic 
me dia or pa per.  Electr o nic re p orti n g pr oce d ures ca n be f o u n d i n t he E D C data e ntr y 
g ui deli nes.  Pa per re p orti n g pr oce d ures ca n be f o u n d i n t he I n vesti gat or Trial File Bi n der ( or 
e q ui vale nt).
E ve nts of cl i nical i nterest f or t his trial i ncl u de:
1. a n o ver d ose of S p o ns or's pr o d uct, as defi ne d i n Secti o n 7. 2. 1 - Defi niti o n of a n O ver d ose 
f or T his Pr ot oc ol a n d Re p orti n g of O ver d ose t o t he S p o ns or, t hat is n ot ass ociate d wit h 
cli nical s ym pt o ms or a b n or mal la b o rat or y res ults. 
2. a n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n al kali ne p h os p hatase la b val ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y  w a y of pr ot oc ol-s pecifie d la b orat or y 
testi n g or u nsc he d ule d la b orat or y testi n g. *
* N ote:  These criteria are base d u p o n a vaila ble re g ulat or y gui da nce d oc u me nts. T he 
p ur p o se 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 nvesti gat or Trial File Bi n der ( or 
e q ui vale nt).
7. 2. 3. 3
Pr ot oc ol -S pecific E xce pti o ns t o Seri o us A d verse E ve nt Re p orti n g
Efficac y  en d p oi nts as o utli ne d i n t his secti o n will n ot be re p orte d t o t he S p o ns or as descri be d 
i n Secti o n 7. 2. 3 - I mme diate Re p orti n g of A d verse E ve nts t o t he S p o ns or.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 4
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
S pecificall y, t he s us pecte d/act ual e ve nts c o vere d i n t his e x ce pti o n i ncl u de a n y eve nt t hat is 
disease pr o gressi o n of t he ca ncer u n der st u d y.
T he S p o ns or will m o nit or u n bli n de d a g gre gate d efficac y en d p oi nt e ve nts a n d safety data t o 
e ns ure t he safet y of t he s u bjects i n t he trial. A n y  sus pecte d e n d p oi nt w hic h u p o n re vie w is 
n ot pr o gressi o n of t he ca ncer u n der st u d y will be f or war de d t o gl o bal safet y as a S A E wit hi n 
2 4 h o 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 .
E v al u ati n g A d verse E ve nts
A n i n vesti gat or w h o is a q ualifie d p h y sicia n will e val uate all a d verse e ve nts acc or di n g t o t he 
N CI  Co m m o n Ter mi n ol o g y  for A d verse E ve nts ( C T C A E), versi o n 4 . 0. A n y  ad verse e ve nt 
w hic h c ha n ges C T C A E gra de o ver t he c o urse of a gi ve n e pis o de will ha ve eac h c ha n ge of 
gra de rec or de d o n t he a d verse e ve nt case re p ort f or ms/ w or ks heets.
All a d verse e ve nts re gar dless of C T C A E gra de m ust als o be e val uate d f or seri o us ness.
F or st u dies i n w hic h m ulti ple a ge nts are a d mi nistere d as part of a c o m bi nati o n re gi me n, t he 
i n vesti gat or m a y  attri b ute eac h a d verse e ve nt ca usalit y to t he c o m bi nati o n re gi me n or t o a 
si n gle a ge nt of t he c o m bi nati o n.  In ge neral, ca usalit y attri b uti o n s h o ul d be assi g ne d t o t he 
c o m bi nati o n re gi me n (i.e., t o all a ge nts i n t he re gi me n). H o we ver, ca usalit y attri b uti o n ma y  
be assi g ne d t o a si n gle a ge nt if i n t he i n vesti gat or’s o pi ni o n, t here is s ufficie nt data t o s u p p ort 
f ull attri b uti o n of t he a d verse e x perie nce t o t he si n gle a ge nt.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 7 
E val uati n g A d verse E ve nts
A n i n vesti gat or w h o is a q ualifie d p h ysicia n, will e val uate all a d verse e ve nts as t o:
V 4. 0 C T C A E 
Gr a di n g
Gr a de 1 
Mil d; as y m pt o m atic or mi d s y m pt o ms; cli nic al or di a g n ostic o bser v ati o ns o nl y; i nter ve nti o n n ot i n dic ate d.
Gr a de 2 
M o der ate; mi ni m al, l oc al or n o ni n v asi ve i nter ve nti o n i n dic ate d; li miti n g a ge -a p pr o pri ate i nstr u me nt al A D L.
Gr a de 3  
Se vere or 
me dic all y 
si g nific a nt b ut n ot i m me di atel y life-t hre ate ni n g; h os pit aliz ati o n or pr ol o n g ati o n or h os pit aliz ati o n i n dic ate d; 
dis a bli n g; li miti n g self -c are A D L.
Gr a de 4 
Life t hre ate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dic ate d.
Gr a de 5 
De at h rel ate d t o A E
Seri o us ness 
A seri o us a d verse e ve nt is a n y a d verse e ve nt occ urri n g at a n y d ose or d uri n g a n y use of S p o ns or’s pr o d uct t hat:
† Res ults i n de at h ; or
† Is life t hre ate ni n g; or places t he s u bject, i n t he vie w of t he i n vesti gat or, at i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d ( N ote: T his d oe s n ot i ncl u de a n 
a d verse e ve nt t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.); or
† Res ults i n a persiste nt or si g nific a nt dis a bilit y/i nc a p acit y (s u bsta ntial disr u pti o n of o ne’s a bilit y t o c o n d uct n or mal life f u ncti o ns); or
† Res ults i n or pr ol o n gs a n e xisti n g i n p atie nt h os pit aliz ati o n ( h os pitalizati o n is defi ne d as a n i n patie nt a d missi o n, re gar dless of le n gt h of sta y, e ve n if t he 
h os pitalizati o n is a preca uti o nar y meas ure f or c o nti n ue d o bser vati o n. ( N ote: H os pitalizati o n f or a n electi ve pr oce d ure t o treat a pre -e xisti n g c o n diti o n t hat has n ot 
w orse ne d is n ot a seri o us a d verse e ve nt.  A pre-e xisti n g c o n diti o n is a cli nical c o n diti o n t hat is dia g n ose d pri or t o t he use of a Merc k pr o d uct a n d is d oc u me nte d i n 
t he patie nt’s me dical hist or y.); or
† Is a c o n ge nit al a n o m al y/ birt h defect (i n offs pri n g of s u bject ta ki n g t he pr o d uct re gar dless of ti me t o dia g n osis); or
Is a ne w c a ncer (t hat is n ot a c o n diti o n of t he st u d y) (alt h o u g h n ot seri o us per I C H defi niti o n, is re p orta ble t o t he S p o ns or wit hi n 2 4 h o urs t o meet certai n l ocal 
re q uire me nts); o r
Is a n o ver d ose ( w het her acci de ntal or i nte nti o nal).  A n y a d verse e ve nt ass ociate d wit h a n o ver d ose is c o nsi dere d a seri o us a d verse e ve nt f or c ollecti o n p ur p oses . A n 
o ver d ose t hat is n ot ass ociate d wit h a n a d verse e ve nt is c o nsi dere d a n o n -seri o us e ve nt of cli nical i nterest a n d m ust be re p orte d wit hi n 2 4 h o urs.
Ot her i m p ort a nt me dic al e ve nts t hat ma y n ot res ult i n deat h, n ot be life t hreate ni n g, or n ot re q uire h os pitalizati o n ma y be c o nsi dere d a seri o us a d verse e vent w he n, 
base d u p o n a p pr o priate me dica l j u d g me nt, t he e ve nt ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes 
liste d pre vi o usl y ( desi g nate d a b o ve b y a †).
D ur ati o n 
Rec or d t he start a n d st o p dates of t he a d verse e ve nt. If less t ha n 1 da y, i n dicate t he a p pr o priate le n gt h of ti me a n d u nits
Acti o n t a ke n  
Di d t he a d verse e ve nt ca use t he S p o ns or’s pr o d uct t o be disc o nti n ue d?
Rel ati o ns hi p t o 
S p o ns or’s 
Pr o d uct
Di d t he S p o ns or’s pr o d uct ca use t he a d verse e ve nt? T he deter mi nati o n of t he li keli h o o d t hat t he S p o ns or’s pr o d uct ca use d t he a d verse e ve nt will be pr o vi de d b y  an 
i n vesti gat or w h o is a q ualifie d p h ysicia n. T he i n vesti gat or’s si g ne d/ date d i nitials o n t he s o urce d oc u me nt or w or ks heet t hat s u p p orts t he ca usalit y n ote d o n t he A E 
f or m, e ns ures t hat a me dicall y q ualifie d assess me nt of ca usalit y was d o ne. T his i nitiale d d oc u me nt m us t be retai ne d f or t he re q uire d reg ulat or y ti me fra me. T he 
criteria bel o w are i nte n de d as refere nce g ui deli nes t o assist t he i n vesti gat or i n assessi n g t he li keli h o o d of a relati o ns hi p bet wee n t he test dr u g a n d t he a d verse e ve nt 
base d u p o n t he a vaila ble i nf or mati o n.
T he f oll o wi n g c o m p o ne nts are t o be use d t o assess t he rel ati o ns hi p bet wee n t he S p o ns or’s pr o d uct a n d t he A E ; t he greater t he c orrelati o n wit h t he c o m p o ne nts 
a n d t heir res pecti ve ele me nts (i n n u m ber a n d/ or i nte nsit y), t he m ore li kel y t he S p o ns or’s pr o d uct ca use d t he a d verse e ve nt ( A E):
E x p os ure 
Is t here e vi de nce t hat t he s u bject was act uall y e x p ose d t o t he S p o ns or’s pr o d uct s uc h as: relia ble hist or y, acce pta ble c o m plia nce assess me nt ( pill 
c o u nt, diar y, etc.), e x pecte d p har mac ol o gic effect, or meas ure me nt of dr u g/ meta b olite i n b o dil y s peci me n?
Ti me C o urse 
Di d  
t he  
A E  
f oll o w  
i n  
a  
reas o na ble  
te m p oral  
se q ue nce  
fr o m  
a d mi nistrati o n  
of  
t he  
S p o ns or’s  
pr o d uct? 
Is t he ti me of o nset of t he A E c o m pati ble wit h a dr u g-i n d uce d effect (a p plies t o trials wit h i n vesti gati o nal me dici nal pr o d uct)?
Li kel y C a use 
Is t he A E n ot reas o na bl y e x plai ne d b y a n ot her eti ol o g y s uc h as u n derl yi n g disease, ot her dr u g(s)/ vacci ne(s), or ot her h ost or e n vir o n me ntal fact ors
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
8 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Rel ati o ns hi p 
T he f oll o wi n g c o m p o ne nts are t o be use d t o assess t he rel ati o ns hi p bet wee n t he test dr u g a n d t he A E: (c o nti n ue d)
t o S p o ns or's 
Pr o d uct
(c o nti n ue d) 
Dec h alle n ge 
Was t he S p o ns or’s pr o d uct disc o nti n ue d or d ose/e x p os ure/fre q ue nc y re d uce d?
If yes, di d t he A E res ol ve or i m pr o ve?
If yes, t his is a p ositi ve dec halle n ge. If n o, t his is a ne gati ve dec halle n ge.
( N ote: T his criteri o n is n ot a p plica ble if: ( 1) t he A E res ulte d i n deat h or per ma ne nt disa bilit y; ( 2) t he A E res ol ve d/i m pr o ved des pite c o nti n uati o n of 
t he S p o ns or’s pr o d uct; or ( 3) t he trial is a si n gle-d ose dr u g trial); or ( 4) S p o ns or’s pr o d uct(s) is/are o nl y use d o ne ti me.)
Rec h alle n ge 
Was t he s u bject re- e x p ose d t o t he S p o ns or’s pr o d uct i n t his st u d y?
If yes, di d t he A E rec ur or w orse n?
If yes, t his is a p ositi ve rec halle n ge. 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) S p o ns or’s pr o d uct(s) is/are use d o nl y o ne ti me).
N O T E: I F A R E C H A L L E N G E I S P L A N N E D F O R A N A D V E R S E E V E N T W HI C H 
W A S 
S E RI O U S A N D W HI C H 
M A Y H A V E B E E N 
C A U S E D B Y T H E S P O N S O R' S P R O D U C T, O R I F R E E X P O S U R E T O T H E S P O N S O R' S P R O D U C T P O S E S A D DI TI O N A L P O T E N TI A L 
SI G NI FI C A N T RI S K T O T H E S U BJ E C T, T H E N T H E R E C H A L L E N G E M U S T  B E A P P R O V E D I N A D V A N C E B Y T H E S P O N S O R 
C LI NI C A L DI R E C T O R A S P E R D O S E M O DI FI C A TI O N G UI D E LI N E S I N T H E P R O T O C O L.
C o nsiste nc y 
wit h Tri al 
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 S p o ns or’s pr o d uct or dr u g class p har mac ol o g y 
or t o xic ol o g y?
T he assess me nt of relati o ns hi p will be re p orte d o n t he case re p ort f or ms / w or ks heets b y a n i n vesti gat or w h o is a q ualifie d p h ysicia n acc or di n g t o his/ her best cli nical j u d g me nt, i ncl u di n g 
c o nsi derati o n of t he a b o ve ele me nts.
Rec or d o ne of t he f oll o wi n g 
Use t he f oll o wi n g sc ale of criteri a as g ui d a nce ( n ot all criteri a m ust be prese nt t o be i n dic ati ve of a S p o ns or’s pr o d uct rel ati o ns hi p).
Yes, t here is a re as o n a ble 
p ossi bilit y of S p o ns or's pr o d uct 
rel ati o ns hi p.
T here is e vi de nce of e x p os ure t o t he S p o ns or's pr o d uct.  The te m p oral se q ue nce of t he A E o nset relati ve t o t he a d mi nistrati o n of t he S p o ns or's 
pr o d uct is reas o na ble.  T he A E is m ore li kel y e x plai ne d b y t he S p o ns or's pr o d uct t ha n b y a n ot her ca use.
N o, t here is n ot a re as o n a ble 
p ossi bilit y of S p o ns or's pr o d uct 
rel ati o ns hi p
S u bject di d n ot recei ve t he S p o ns or's pr o d uct O R te m p oral se q ue nce of t he A E o nset relati ve t o a d mi nistrati o n of t he S p o ns or' s pr o d uct is n ot 
reas o na ble O R t he A E is m ore li kel y e x plai ne d b y a n ot her ca use t ha n t he S p o ns or’s pr o d uct .  ( Als o e ntere d f or a s u bject wit h o ver d ose wit h o ut a n 
ass ociate d A E.)
 
 
0 5 C 6 H 2

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

Pr o d uct:  M K -3 4 7 5 
8 8
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
8. 0 S T A TI S TI C A L A N A L Y SI S P L A N
T his secti o n o utli nes t he statistical a nal ys is strate g y an d pr oce d ures f or t he st u d y.  If, after 
t he st u d y has be g u n, c ha n ges are ma de t o pri mar y  an d/ or k e y  sec o n dar y hy p ot heses, or t he 
statistical met h o ds relate d t o t h ose h y p ot heses, t he n t he pr ot oc ol will be a me n de d (c o nsiste nt 
wit h I CH G ui deli ne E- 9).  Cha n ges t o e x pl orat or y or ot her n o n -c o nfir mat or y anal ys es ma de 
after t he pr ot oc ol has bee n fi nalize d, b ut pri or t o t he c o n d uct of a n y  anal ys is, will be 
d oc u me nte d i n a s u p ple me ntal S A P (s S A P) as nee de d a n d refere nce d i n t he Cli nical St u d y  
Re p ort ( C S R) f or t he st u d y . Se parate a nal ys is pla ns (i.e., se parate d oc u me nts fr o m t he s S A P) 
ma y  be de vel o pe d f or P K/ m o deli n g a nal ys is, bi o mar ker a n al ysis, a n d ge netic data a nal ys is.
P ost h oc e x pl orat or y  a nal yses will be clearly i de ntifie d i n t he C S R .
St atistic al A n al ysis Pl a n S u m m ar y
Ke y  ele me nts of t he statistical a nalys is pla n are s u m marize d bel o w; t he c o m pre he nsi ve pla n 
is pr o vi de d i n Secti o ns 8. 2 t hr o u g h 8. 11.
St u d y Desi g n O ver vie w
A P hase III St u d y of Car b o plati n - Paclita xel/ Na b -Paclita xel C he m ot hera p y 
wit h or wit h o ut Pe m br o liz u ma b ( M K-3 4 7 5) i n First Li ne Metastatic 
S q ua m o us N o n -s mall Cell Lu n g Ca ncer S u bjects ( K E Y N O T E -4 0 7 )
Tre at m e nt Assi g n me nt
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o recei ve pe m br oliz u ma b or 
sali ne place b o i n c o m bi nati o n wit h car b o plati n a n d a ta xa ne (i n vesti gat ors 
c h oice of paclita xel or na b -paclita xel) . Stratificati o n fact ors are i n Secti o n 
5. 4 . T his is a ra n d o mize d d o u ble-bli n de d st u d y. 
A n al ysis P o p ul ati o ns
Efficac y: I nte nti on t o Trea t (I TT)
Safet y: All S u bjects as Treate d (A Sa T)
D u al P ri m ar y
E n d p oi nts/ H y p ot heses
1) 
Pr o gressi o n- free S ur vi val ( P F S) pe r R E CI S T 1. 1 assesse d b y
a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or 
2) 
O verall s ur vi val ( O S)
St atistic al Met h o ds
f or
Ke y
Effic ac y A n al yses
T he d ual pri mar y h y p ot heses o n P F S a n d O S wil l b e e val uate d b y  
c o m pari n g p e m br oliz u ma b t o sali ne place b o i n c o m bi nati o n wit h 
car b o plati n a n d a ta xa ne usi n g a stratifie d L o g- ra n k test. T he hazar d rati o
wil l be esti mate d usi n g a stratifie d C o x re gressi o n m o d el . E ve nt rates o ver
ti me wil l be esti mate d wit hi n eac h treat me nt gr o u p usi n g t he Ka pla n -
Meier
me t h o d. T he s tratifie d M & N met h o d wit h sa m ple size we i g hts will 
be use d f or a nal ysis of O R R.
St atistic al Met h o ds
f or
Ke y S afet y A n al yses
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h. T here are n o 
Tier 1 safet y para meters i n t his trial. All safet y para meters are c o nsi dere d 
eit her Tier 2 or Tier 3.  Tier 2 para meters will be assesse d via p oi nt 
esti mates wit h 9 5 % c o nfi de nce i nter vals pr o vi de d f or bet we e n -gr o u p 
c o m paris o ns; o nl y p oi nt esti mates b y treat me nt gr o u p are pr o vi de d f or 
Tier 3 safet y para meters. T he bet w e e n -treat me nt differe nce will be 
a nal yze d usi n g t he Mietti ne n a n d N ur mi ne n met h o d.
I n t he pri mar y safet y c o m paris o n, s u bjects w h o cr oss o ver t o 
pe m br oliz u ma b are ce ns ore d at ti me of cr oss o ver (i.e., A Es occ urri n g 
d uri n g treat me nt wit h pe m br oliz u ma b are e xcl u de d f or c o ntr ol -ar m 
s u bjects). A n e x pl orat or y safet y a nal ysis will be c o n d ucte d f o r t he 
cr oss o ver p o p ulati o n i ncl u di n g all safet y e ve nts starti n g fr o m t he date of 
t he first d ose of pe m br oliz u ma b.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 0
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g
T he statistical a nal ys is of t he data o btai ne d fr o m t his st u d y will be t he res p o nsi bilit y of t he 
Cli nical Bi ostatistics de part me nt of t he S p o ns or .
T he S p o ns or
will ge nerate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y treat me nt 
assi g n me nt f or t his pr ot oc ol, a n d t he ra n d o mizati o n will be i m ple me nte d i n I V R S.
T his trial is d o u ble bli n de d wit h a cr oss o ver p hase.  At t he ti me of d oc u me nte d pr o gressi o n, 
s u bjects will ha ve treat me nt assi g n me nt u n bli n de d a n d be a ble t o c o nti n ue t hera py i n t he 
Cr oss o ver P hase 
(please refer t o secti o n 2. 1 Trial Desi g n 
f or details ). I n ad diti o n, 
i n de pe n de nt ce ntral ra di ol o gist(s) will 
perf or m t he ce ntral i ma gi n g re vie w wit h o ut 
k n o wle d ge of treat me nt assi g n me nt .
A n e xter nal data m o nit ori n g c o m mittee (e D M C) will be c o n ve ne d t o re vie w acc u m ulati n g 
safety t o pr o vi de a n o p p ort u nit y  to ter mi nate t he st u d y earl y if t here are c o ncer ns re gar di n g 
safety. T he e D M C will als o re vie w t he u n bli n de d efficac y res ults at t he pla n ne d i nteri m 
a nal ys es. T he e D M C res p o nsi bilities a n d re vie w sc he d ules will be o utli ne d i n t he e D M C 
c harter. T he rec o m me n dati o n of t he e D M C will be c o m m u nicate d t o a n e xec uti ve o versi g ht 
c o m mittee of t he S p o ns or . In t he e ve nt of a rec o m me n dati o n t o halt t he trial early d ue t o 
safety c o ncer ns, t he S p o ns or will c o m m u nicate t his t o t he a p pr o priate re g ulat or y age ncies. If 
t he e D M C rec o m me n ds m o dificati o ns t o t he desi g n of t he pr ot oc ol or disc o nti n uati o n of t he 
st u d y, t his e xec uti ve o versi g ht c o m mittee m a y  be u n bli n de d t o res ults at t he treat me nt le vel 
i n or der t o act o n t hese rec o m me n dati o ns.
A li mite d n u m ber of a d diti o nal S p o ns or pers o n nel ma y  be u n bli n de d, if re q uire d, i n or der t o 
act o n t he rec o m me n dati o ns of t he e D M C . T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o 
t he res ults will be d oc u me nte d. A d diti o nal l o gistical details, re visi o ns t o t he a b o ve pla n a n d 
data m o nit ori n g g ui da nce will be pr o vi de d i n t he e D M C C harter .
P ositi ve res ults f or b ot h P F S a n d O S were o bser ve d at t he i nteri m a nal ysis i n t he C hi na 
e xte nsi o n. T h us , a li mite d n u m ber of S p o ns or pers o n nel ha ve bee n u n bli n de d t o s u p p ort 
re g ulat or y fili n g. T he e xte nt t o w hic h i n di vi d uals were
u n bli n de d t o t he res ults has bee n
d oc u me nte d.
E xte nsi o n S t u d y i n C hi n a
F or all C hi nese s u bjects, i ncl u di n g s u bjects ra n d o mize d i n t he gl o bal st u d y a n d t he e xte nsi o n 
st u d y, patie nt 
le vel treat me nt ra n d o mizati o n i nf or mati o n will 
b e 
bli n de d 
t o t he 
statisticia n(s)/ pr o gra m mer(s) res p o nsi ble f or t he C hi na e xte nsi o n st u d y anal y sis u n til t he 
e xte nsi o n st u d y data base l oc k is ac hie ve d . T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o 
t he res ults will be li mite d. Bli n de d a n d u n bli n de d me m bers will be clearl y d oc u me nte d.
H y p ot heses/ Esti m ati o n
O bjecti ves a n d h y p ot heses of t he st u d y are state d i n Secti o n 3. 0.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 1
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A n al ysis E n d p oi nts
Effic ac y E n d p oi nts
D u al Pri m ar y
Pr o gressi o n- free s ur vi v al ( P F S) – R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt
ce ntr al i ma gi n g ve n d or
Pr o gressi o n -free-s ur vi val ( P F S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first 
d oc u me nte d disease pr o gressi o n per R E CI S T
1. 1 base d o n bli n de d i n de pe n de nt ce ntral
i ma gi n g ve n d or re vie w or deat h d ue t o a n y ca use, w hic he ver occ urs first. Se e Secti o n 8. 6. 1
f or t he ce ns ori n g r ules.
O ver all S ur vi v al
O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o deat h d ue t o a n y ca use.  
S u bjec ts wit h o ut d oc u me nte d deat h at t he ti me of a nal y sis will be ce ns ore d at t he date of last 
k n o w n c o ntact. 
Sec o n d ar y
O bjecti ve res p o nse r ate ( O R R) – R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or 
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 s u bjects w h o ha ve a c o m plete 
res p o nse ( C R) or a partial res p o nse ( P R). Res p o nses are base d o n c o nfir me d assess me nts b y 
t he bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or re vie w per R E CI S T 1. 1.
D ur ati o n of Res p o nse ( D O R) – R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or
F or s u bjects w h o de m o nstrate d C R or P R, d urati o n of res p o nse ( D O R) is defi ne d as t he ti me 
fr o m first d oc u me nte d e vi de nce of C R or P R u ntil disease pr o gressi o n or deat h. Res p o nse 
d urati o n f or s u bjects w h o ha ve n ot pr o gresse d or die d at t he ti me of a nal ysis will be ce ns ore d 
at t he date of t heir last t u m or assess me nt. Res p o nse d urati o n will be calc ulate d f or R E CI S T 
1. 1 base d o n bli n de d i n de pe n de nt ra di ol o gists’ re vie w .
S afet y E n d p oi nts
Safet y  meas ure me nts are descri be d i n Secti o n 4. 2. 3. 4 .
A n al ysis P o p ul ati o ns
Effic ac y A n al ysis P o p ul ati o ns
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 pri mar y  efficac y 
a nal ys is. All ra n d o mize d s u bjects will be i ncl u de d i n t his p o p ulati o n. H o we ver, a n y patie nt 
e nr olle d i n t he exte nsi o n st u d y in C hi na after t he gl o bal e nr oll me nt is c o m plete d, will be 
e xcl u de d fr o m t he I TT p o p ulati o n (see bel o w) . S u bjects will be i ncl u de d i n t he treat me nt 
gr o u p t o w hic h t he y  are ra n d o mize d. 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 2
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
E xte nsi o n St u d y i n C hi n a
After t he e nr oll me nt f or t he gl o bal st u d y is c o m plete d , t he st u d y will c o nti n ue t o ra n d o mize 
s u bjects i n C hi na u ntil t he sa m ple size f or t he C hi nese s u bjects reac hes a p pr o xi matel y 
1 2 0 C hi nese s u bjects.  The C hi nese s u bjects ra n d o mize d i n t he e xte nsi o n st u d y will n ot be 
i ncl u de d i n t he a b o ve pri mar y  efficac y anal y sis p o p ulati o n.  The I TT C hi nese s u bjects as 
well as t he e ntire I T T p o p ulati o n c o nsisti n g of t he pri mar y  efficac y po p ulati o n a n d s u bjects 
ra n d o mize d i n t he e xte nsi o n will be a nal yze d se paratel y per l ocal re g ulat or y re q uire me nt.
S afet y A n al ysis P o p ul ati o ns
T he All S u bjects as Treate d ( A Sa T) p o p ulati o n will be use d f or t he a nal ysis of safety data i n 
t his st u d y.  The A Sa T p o p ulati o n c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least 
o ne d ose of st u d y treat me nt. S u bjects will be i ncl u de d i n t he treatme nt gr o u p c orres p o n di n g 
t o t he st u d y treat me nt t he y act uall y recei ve d f or t he a nal ys is of safety data usi n g t he A Sa T 
p o p ulati o n.  F or m ost s u bjects t his will be t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d.  
S u bjects w h o ta ke i nc orrect st u d y  treat me nt f or t he e ntire treat me nt peri o d will be i ncl u de d i n 
t he treat me nt gr o u p c orres p o n di n g t o t he st u d y treat me nt act uall y recei ve d. A n y  su bject w h o 
recei ves t he i nc orrect st u d y me dicati o n f or o ne c ycle b ut recei ves t he c orrect treat me nt f or all 
ot her c ycles w ill be a nal yze d acc or di n g t o t he s u bject’s ra n d o mize d treat me nt gr o u p a n d a 
narrati ve will be pr o vi de d f or a n y e ve nts t hat occ ur d uri n g t he c ycle f or w hic h t he s u bject 
was i nc orrectly d ose d. 
At least o ne la b orat or y or vital si g n meas ure me nt o btai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter.  T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.
E xte nsi o n St u d y
T he C hi nese s u bjects ra n d o mize d a n d treate d in t he e xte nsi o n st u d y will n ot be i ncl u de d i n 
t he a b o ve pri mar y  safet y anal ys is p o p ulati o n.  The A Sa T C hi nese s u bjects as well as t he 
e ntire A Sa T p o p ulati o n c o nsisti n g of t he pri mar y  safet y p o p ulati o n a n d s u bjects ra n d o mize d 
a n d treate d will be a nal yze d pe r l ocal re g ulat or y re q uire me nts.
St atistic al Met h o ds
St atistic al Met h o ds f or Effic ac y A n al yses
T his secti o n descri bes t he statistical met h o ds 
t hat a d dress t he pri mar y  an d sec o n dar y 
o bjecti ves.  Met h o ds relate d t o e x pl orat or y o bjecti ves will be descri be d i n t he s S A P.
Efficac y  res ults t hat will be dee me d t o be statisticall y si gnifica nt after c o nsi derati o n of t he 
T y pe I err or c o ntr ol strate g y are descri be d i n Secti o n 8. 8, M ulti plicit y. N o mi nal p-val ues will 
be c o m p ute d f or ot her efficac y an al y ses, b ut s h o ul d b e i nter prete d wit h ca uti o n d ue t o 
p ote ntial iss ues of m ulti plicit y .
All 
statistical tests, u nless ot her wise s pecifie d, 
will be stratifie d f or treat me nt a n d 
stratificati o n fact ors.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 3
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
8. 6. 1. 1
Pr o gressi o n -Free S ur vi v al ( P F S)
T he n o n- para metric Ka pla n -Meier met h o d will be use d t o esti mate t he P F S c ur ve i n eac h 
treat me nt gr o u p. T he treat me nt differe nce i n P F S will be assesse d b y  the stratifie d l o g-ra n k 
test ( base d o n t he stratificati o n fact ors defi ne d i n secti o n 5. 4). A stratifie d C o x pr o p orti o nal 
hazar d m o del wit h Efr o n' s met h o d of tie ha n dli n g will be use d t o assess t he ma g nit u de of t he 
treat me nt differe nce (i.e., hazar d rati o) bet wee n t he treat me nt ar ms. T he hazar d rati o a n d its 
9 5 % c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h Efr o n's met h o d of tie ha n dli n g 
a nd wit h a si n gle treat me nt c o variate will be re p orte d. T he stratificati o n fact ors use d f or 
ra n d o mizati o n (See Secti o n 5. 4) will be a p plie d t o b ot h t he stratifie d l o g-ra n k test a n d t he 
stratifie d C o x m o del. 
Si nce disease pr o gressi o n is assesse d peri o dicall y , pr o gressi ve disease ( P D) ca n occ ur a n y 
ti me i n t he ti me i nter val bet wee n t he last assess me nt w here P D was n ot d oc u me nte d a n d t he 
assess me nt w he n P D is d oc u me nte d. F or t he pri mar y anal y sis, f or t he s u bjects w h o ha ve P D, 
t he tr ue date of disease pr o gressi o n will be a p pr o xi mate d b y  the date of t he first assess me nt 
at w hic h P D is o bjecti vel y d oc u me nte d per R E CI S T 1. 1 b y  a bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or, re gar dless of disc o nti n uati o n of st u d y dr u g. Deat h is al wa ys co nsi dere d as a 
c o nfir me d P D e ve nt. Se nsiti vit y  anal y ses will be perf or me d f or c o m paris o n of P F S base d o n 
i n vesti gat or's assess me nt.
I n or der t o e val uate t he r o b ust ness of t he P F S e n d p oi nt per R E CI S T 1. 1 b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or, we will perf or m t w o se nsiti vit y anal y ses wit h a 
differe nt set of ce ns ori n g r ules. T he first se nsiti vit y anal y sis is t he sa me as t he pri mar y  
a nal ys is e xce pt t hat it ce ns ors at t he last disease assess me nt wit h o ut P D w he n P D or deat h is 
d oc u me nte d after m ore t ha n o ne misse d disease assess me nt. T he sec o n d se nsiti vit y anal ys is 
is t he sa me as t he pri mar y  anal ys is e xce pt t hat it c o nsi ders disc o nti n uati o n of treat me nt or 
i nitiati o n of a n a ntica ncer treat me nt s u bse q ue nt t o disc o nti n uati o n of st u d y-s pecifie d 
treat me nts, w hic he ver occ urs later, t o be a P D e ve nt f or s u bjects wit h o ut d oc u me nte d P D or 
deat h. T he ce ns ori n g r ules f or pri mar y  a n d se nsiti vit y a nal yses are s u m marize d i n Ta ble 8 . I n 
case t here is a n i m bala nce bet wee n t he treat me nt gr o u ps o n disease assess me nt sc he d ules or 
ce ns ori n g patter ns, we will perf or m a n a d diti o nal P F S se nsiti vit y anal y sis usi n g ti me fr o m 
ra n d o mizati o n t o sc he d ule d t u m or assess me nt ti me i nstea d of act ual t u m or assess me nt.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 4
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 8 
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S
Sit u ati o n
Pri m ar y A n al ysis 
Se nsiti vit y A n al ysis 1 
Se nsiti vit y A n al ysis 2
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is n ot 
i nitiate d
Ce ns ore d at last disease 
assess me nt 
Ce ns ore d at last 
disease assess me nt 
Ce ns ore d at last disease 
assess me nt if still o n 
st u d y t hera p y; pr o gresse d 
at treat me nt 
disc o nti n uati o n ot her wise
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is i nitiate d
Ce ns ore d at last disease 
assess me nt bef ore ne w 
a ntica ncer treat me nt
Ce ns ore d at last 
disease assess me nt 
bef ore ne w a ntica ncer 
treat me nt
Pr o gresse d at date of ne w  
a ntica ncer treat me nt
P D or deat h 
d oc u me nte d after ≤ 1 
misse d disease 
assess me nt
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or 
deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
P D or deat h 
d oc u me nte d after ≥ 2 
misse d disease 
assess me nts
Pr o gresse d at date of 
d oc u me nte d P D or deat h
Ce ns ore d at last 
disease ass ess me nt 
pri or t o t he  ≥ 2 misse d 
disease assess me nt
Pr o gresse d at date of 
d oc u me nte d P D or deat h
I n case t he pr o p orti o nal hazar ds ass u m pti o n is n ot vali d, s u p p orti ve a nalys es usi n g Restricte d 
Mea n S ur vi val Ti me ( R M S T) met h o d ma y  be c o n d ucte d f or P F S t o acc o u nt f or t he p ossi ble 
n o n- pr o p orti o nal hazar ds effect.
A n e x pl orat or y anal ys is of P F S 2, defi ne d as t he ti me fr o m ra n d o mizati o n t o s u bse q ue nt 
disease pr o gressi o n after i nitiati o n of ne w a nti-ca ncer t hera p y, or deat h fr o m a n y ca use, 
w hic he ver first, m a y
be carrie d o ut. Patie nts ali ve a n d f or w h o m a disease pr o gressi o n 
f oll o wi n g i nitiati o n of ne w a nti-ca ncer treat me nt has n ot bee n o bser ve d will be ce ns ore d at 
t he last ti me t he s u bject was k n o w n t o be ali ve a n d wit h o ut disease pr o gressi o n .
F urt her details o f se nsiti vit y a nalys es will be descri be d i n s S A P as nee de d.
8. 6. 1. 2
O ver all S ur vi v al ( O S)
T he n o n- para metric Ka pla n -Meier met h o d will be use d t o esti mate t he s ur vi val c ur ves. T he 
treat me nt differe nce i n s ur vi val will be assesse d b y  the stratifie d l o g-ra n k test ( base d o n t he 
stratificati o n fact or defi ne d i n secti o n 5. 4). A stratifie d C o x pr o p orti o nal hazar d m o del wit h 
Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he ma g nit u de of t he treat me nt 
differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % c o nfi de nce i nter val fr o m t he 
stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be re p orte d. T he stratificati o n 
fact ors use d f or ra n d o mizati o n (See Secti o n 5. 4 ) will be a p plie d t o b ot h t he stratifie d l o g-
ra n k test a n d t he stratifie d C o x m o del. T he Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d 
ma y  be c o n d ucte d f or O S t o acc o u nt f or t he p ossi ble n o n- pr o p orti o nal hazar ds effect a n d t o 
esti mate t he a bs ol ute be nefit of e x peri me ntal treat me nt.  A c ure rate m o del ma y be a p plie d t o 
esti mate t he l o n g-ter m effect .
Si nce s u bjects i n t he c o ntr ol ar m are all o we d t o s witc h t o t he pe m br oliz u ma b treat me nt after 
pr o gressi ve disease, a dj ust me nt f or t he effect of cr oss o ver o n O S ma y  be perf or me d base d o n 
rec o g nize d met h o ds, e. g., a t w o-sta ge met h o d or t he Ra n k Preservi n g Str uct ural Fail ure Ti me 
( R P S F T) m o del, 
base d o n a n e xa mi nati o n of t he a p pr o priate ness of t he data t o t he 
ass u m pti o ns re q uire d b y t he met h o ds.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 5
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
F urt her details of se nsiti vit y a nal ys es will be descri be d i n s S A P as nee de d.
8. 6. 1. 3
O bjecti ve res p o nse r ate ( O R R) a nd D ur ati o n of Res p o nse ( D O R)
T he stratifie d Mietti ne n a n d N ur mi ne n met h o d will be use d f or t he c o m paris o n of t he O R R 
bet wee n t he t w o treat me nt gr o u ps. T he differe nce i n O R R a n d its 9 5 % c o nfi de nce i nter val 
fr o m t he stratifie d Mietti ne n a n d N ur mi ne n met h o d wit h strata wei g hti n g b y sa m ple size wit h 
a si n gle treat me nt c o variate will be re p orte d. T he stratificati o n fact ors use d f or ra n d o mizati o n 
(See Secti o n 5. 4 ) will be a p plie d t o t he a nal ys is.
If sa m ple size per mits, D O R will be s u m marize d descri pti vel y usi n g Ka pla n -Meier me dia ns 
a n d q uartiles. O nl y t he s u bset of patie nts w h o s h o w a c o m plete res p o nse or partial res p o nse 
will be i ncl u de d i n t his a nal y sis.
8. 6. 1. 4
A n al ysis Str ate g y f or Ke y Effic ac y E n d p oi nts
Ta ble 9 s u m marizes t he pri mar y  anal ys is a p pr oac h f or pri mar y  an d ke y  sec o n dar y efficac y 
e n d p oi nts. Se nsiti vit y a nal ysis met h o ds are descri be d a b o ve f or eac h e n d p oi nt as a p plica ble.
T he strate g y to a d dress m ulti pli cit y iss ues wit h re gar d t o m ulti ple efficac y en d p oi nts, a n d 
i nteri m a nal yses is descri be d i n Secti o n 8. 7 Interi m A nal y ses a n d i n Secti o n 8. 8 M ulti plicit y.
Ta ble 9 
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)  
St atistic al Met h o d †
A n al ysis 
P o p ul ati o n 
Missi n g D at a A p pr o ac h
D u al Pri m ar y E n d p oi nt s
P F S per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T
Pri mar y ce ns ori n g r ule
Se nsiti vit y a nal ysis 1
Se nsiti vit y a nal ysis 2
O S
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T
M o del base d
(ce ns ore d at t he last date
t he s u bject was k n o w n t o 
be ali ve)
Ke y S ec o n d ar y E n d p oi nt s
O R R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test a n d Esti mati o n : 
Stratifie d M & N met h o d wit h 
sa m ple size wei g hts† †
I T T
S u bjects wit h o ut assess me nts 
are c o nsi dere d n o n-
res p o n ders a n d 
c o nser vati vel y i ncl u de d i n 
de n o mi nat or
D O R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
D escri pti ve statistics f or 
ra n ge a n d Ka pla n -Meier 
esti mate of me dia n
Patie nts i n I T T
p o p ulati o n wit h 
a n o bjecti ve 
res p o nse
  † Statistical m o dels are descri be d i n f urt her detail i n t he te xt. F or stratifie d a nal yses, t he stratificati o n fact ors use d 
f or ra n d o mizati o n ( Secti o n 5. 4) will be a p plie d t o t he a nal ysis.
† † Mietti ne n a n d N ur mi ne n met h o d
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 6
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
St atistic al Met h o ds f or S afet y A n al yses
Safet y  an d t olera bilit y  will be assesse d b y cli nical re vie w of all rele va nt para meters i ncl u di n g 
A Es, la b orat or y  tests, a n d vital si g ns.
A d verse E ve nts
A d verse e ve nts ( A Es) will be c o de d usi n g t he sta n dar d Me d D R A a n d gr o u pe d s yste m or ga n 
class. A d verse e ve nts ( A Es) will be gra de d b y  the i n vesti gat or acc or di n g t o t he C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E), versi o n 4. 0.
Tiere d A p pr o ac h
T he a nal ys is of safety res ults will f oll o w a tiere d a p pr oac h (Ta ble 1 0 ).  The tiers differ wit h 
res pect t o t he a nal ys es t hat will be perf or me d. “ Tier 1” safety e n d p oi nts t hat will be s u bject 
t o i nfere ntial testi n g f or statistical si g nifica nce wit h p - val ues a n d 9 5 % c o nfi de nce i nter vals 
pr o vi de d f or bet wee n -gr o u p c o m paris o ns. F or t his pr ot oc ol, t here are n o Tier 1 e ve nts. Ot her 
safety para meters will be c o nsi dere d Tier 2 or Tier 3. Tier 2 para meters will be assesse d via 
p oi nt esti mates wit h 9 5 % c o nfi de nce  inter vals p r o vi de d f or bet wee n -gr o u p c o m paris o ns; 
o nl y  p oi nt esti mates by treat me nt gr o u p are pr o vi de d f or Tier 3 safet y para meters. 
A d verse e x perie nces (s pecific ter ms as well as s yste m or ga n class ter ms) t hat are n ot pre -
s pecifie d as Tier -1 e n d p oi nts will be class ifie d as bel o n gi n g t o " Tier 2" or " Tier 3", base d o n 
t he n u m ber of e ve nt s o bser ve d. Me m bers hi p i n Tier 2 re q uires t hat at least 4 s u bjects i n a n y 
treat me nt gr o u p e x hi bit t he e ve nt; all ot her a d verse e x perie nces a n d pre defi ne d li mits of 
c ha n ge will bel o n g t o Tier 3.
T he t hres h ol d of at least 4 e ve nts was c h ose n beca use t he 9 5 % c o nfi de nce i nter val f or t he 
bet wee n -gr o u p differe nce i n perce nt i nci de nce will al wa ys i ncl u de zer o w he n treat me nt 
gr o u ps of e q ual size eac h ha ve less t ha n 4 e ve nts a n d t h us w o ul d a d d little t o t he 
i nter pretati o n of p ote ntiall y  mea ni n gf ul differe nces. Beca use ma n y 9 5 % c o nfi de nce i nter vals 
ma y  be pr o vi de d wit h o ut a dj ust me nt f or m ulti plicit y , t he c o nfi de nce i nter vals s h o ul d be 
re gar de d as a hel pf ul descri pti ve meas ure t o be use d i n re vie w, n ot a f or mal met h o d f or 
assessi n g t he statistical si g nifica nce of t he bet wee n -gr o u p differe nces i n a d verse e x perie nces 
a n d pre defi ne d li mits of c ha n ge.
C o nti n u o us meas ures s uc h as c ha n ges fr o m baseli ne i n la b orat or y val ues a n d vital si g ns, t hat 
are n ot p re-s pecifie d as Tier- 1 e n d p oi nts will be c o nsi dere d Tier 3 safety para meters.  
S u m mar y  statistics f or baseli ne, o n -treat me nt, a n d c ha n ge fr o m baseli ne val ues will be 
pr o vi de d b y treat me nt gr o u p i n ta ble f or mat.
I n a d diti o n, t he br oa d cli nical a n d la b orat ory A E cate g ories c o nsisti n g of t he perce nta ge of 
s u bjects wit h a n y A E, a n y dr u g relate d A E, a n y Gra de 3- 5 A E, a n y seri o us A E, a n y A E 
w hic h is b ot h dr u g -relate d a n d Gra de 3- 5, a n y A E w hic h is b ot h seri o us a n d dr u g -relate d, a 
d ose m o dificati o n d ue t o A E, a disc o nti n uati o n d ue t o a n A E, a n d deat h will be c o nsi dere d 
Tier 2 e n d p oi nts. T he 9 5 % c o nfi de nce i nter vals ( Tier 2) will be pr o vi de d f or bet wee n -
treat me nt differe nces i n t he perce nta ge of s u bjects wit h e ve nts; t hese a nal yses will be 
perf or me d usi n g t he u n stratifie d Mietti ne n a n d N ur mi ne n met h o d ( 1 9 8 5), a n u nc o n diti o nal, 
as ym pt otic met h o d .
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 7
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 1 0
A nal y sis Strate g y f or Safet y Para meters
S afet y Tier
S afet y E n d p oi nt †
9 5 %  CI f or 
Tre at me nt 
C o m p aris o n
Descri pti ve 
St atistics
Tier 2
A n y A E
X
X
A n y Seri o us A E 
X
X
A n y Gra de 3 -5 A E
X
X
A n y Dr u g -Relate d A E
X
X
A n y Seri o us a n d Dr u g -Relate d A E
X
X
A n y Gra de 3 -5 a n d Dr u g -Relate d A E
X
X 
D ose M o dificati o n d ue t o A E
X
X
Disc o nti n uati o n d ue t o A E
X
X
Deat h
S pecific A Es, S O Cs, or P D L Cs ‡ (i nci de nce ≥4 of s u bjects 
i n o ne of t he treat me nt gr o u ps)
X
X
Tier 3
S pecific A Es, S O Cs or P D L Cs ‡ (i nci de nce < 4 of s u bjects 
i n all of t he treat me nt gr o u ps)
X
C ha n ge fr o m Baseli ne Res ults ( La bs, E C Gs, Vital Si g ns)
X
S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristics a n d Ot her A n al yses
T he c o m para bilit y of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d b y 
t he use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n t hese 
c haracteristics.  The n u m ber a n d perce nta ge of s u bjects ra n d o mize d, a n d t he pri mar y reas o ns 
f or disc o nti n uati o n will be dis pla ye d.  De m o gra p hic varia bles (e. g., a ge, ge n der) a n d baseli ne 
c haracteristics will be s u m marize d b y  treat me nt eit her b y  descri pti ve statistics or cate g o rical 
ta bles.
I nteri m A n al yses
T here are t hree pla n ne d i nteri m a nal yses i n a d diti o n t o t he fi nal a nal ysis f or t his st u d y. 
Details o n t he b o u n daries f or esta blis hi n g statistical si g nifica nce wit h re gar d t o efficac y are 
disc usse d f urt her i n Secti o n 8. 8.   T he trial will c o nti n ue u ntil t he n u m ber of deat hs ( See 
Secti o n 8. 9) is a p pr o xi matel y eq ual t o t he tar gete d n u m ber f or t he fi nal a nal ysis irres pecti ve 
of t he o utc o me fr o m t he i nteri m a nalys es .
T he a nal ys es pla n ne d, e n d p oi nts e val uate d, a n d dri vers of ti mi n g a re s u m marize d i n Ta ble 1 1 .
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 8
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 1 1
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y
A n al yses 
Ke y 
E n d p oi nts   
Ti mi n g
Esti m ate d Ti me after 
First P artici p a nt 
R a n d o mize d 
Pri m ar y P ur p ose of 
A n al ysis
I A 1 
O R R 
~ 2 0 0 s u bjects are 
f oll o we d f or ~ 2 8 wee ks s o 
t hat eac h patie nt has at 
least 4 t u m or assess me nts
~ 1 5 m o nt hs 
De m o nstrate O R R 
s u peri orit y
I A 2 
P F S
O S
~ 3 3 2 P F S e ve nts ha ve 
bee n o bser ve d.
~ 2 0 m o nt hs 
De m o nstrate P F S 
s u peri orit y
De m o nstrate O S  
s u peri orit y
I A 3 
P F S
O S
~ 4 1 5 P F S e ve nts ha ve 
bee n o bser ve d 
~ 2 5 m o nt hs
De m o nstrate P F S 
s u peri orit y
De m o nstrate O S  
s u peri orit y
Fi nal 
A nal ysis
O S 
~ 3 6 1 deat hs ha ve 
occ urre d .
~ 3 1 m o nt hs 
De m o nstrate O S  
s u peri orit y
Beca use of p ositi ve res ults i n t he C hi na e xte nsi o n f or b ot h P F S a n d O S o bser ve d at t he 
i nteri m a nal ysis, s u bse q ue nt a nalys es ma y be perf or me d at t he pla n ne d ti me of fi nal a nalys is,
or as nee de d.
M ulti plicit y
T he st u d y uses t he gra p hical met h o d of Ma urer a n d Bretz [ 4 2] t o c o ntr ol m ulti plicit y  for 
m ulti ple 
h y p ot heses as well 
as i nteri m a nal yses.
Acc or di n g 
t o t his a p pr oac h, st u d y 
h y p ot heses m a y  be teste d m ore t ha n o nce, a n d w he n a partic ular n ull h y p ot hesis is rejecte d, 
t he al p ha all ocate d t o t hat h y p ot hesis ca n be reall ocate d t o ot her h y p ot hesis tests. Fi g ure 3
s h o ws t he i nitial o ne-si de d al p ha all ocati o n f or eac h h yp ot hesis i n t he elli pse re prese nti n g t he 
h y p ot hesis. T he wei g hts f or reall ocati o n fr o m eac h h y p ot hesis t o t he ot hers are re prese nte d i n 
t he b o xes o n t he li nes c o n necti n g hy p ot heses.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
9 9
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
N ote: If b ot h P F S a n d O S n ull h y p ot heses are rejecte d, t he reall ocati o n strate g y all o ws re -testi n g of O R R at al p ha = 0. 0 2 5 base d o n t he p-
val ue at I A 1
O R R = o bjecti ve res p o nse rate; O S = o verall s ur vi val; P F S = pr o gressi o n -free s ur vi val
Fi g ure 3 
T y pe I Err or Reall ocati o n Strate g y F oll o wi n g Cl ose d Testi n g Pri nci ple
O bjecti ve Res p o nse R ate
T he st u d y all ocates al p ha = 0. 0 0 5, o ne -si de d, t o test O R R, a n d O R R is teste d o nl y  at t he first 
i nteri m a nal ysis (I A 1). H o we ver, if t he test d oes n ot reac h statistical si g nifica nc e at I A 1, t he 
p- val ue fr o m I A 1 ca n be c o m pare d t o a n u p date d al p ha-le vel if t he n ull h y p ot heses f or b ot h 
P F S a n d O S are rejecte d at a later ti me. P o wer at t he p ossi ble al p ha-le vels as well as t he 
a p pr o xi mate treat me nt differe nce re q uire d t o reac h t he b o u n d ( O R R differe nce ) are s h o w n i n
Ta ble 1 2 , ass u mi n g u n derl y i n g 2 5 % a n d 5 0 % res p o nse rates i n t he c o ntr ol a n d e x peri me ntal 
gr o u ps, res pecti vel y . 
Ta ble 1 2
P ossi ble Al p ha -le vels a n d A p pr o xi mate O R R Differe nce Re q uire d t o 
De m o nstrate Efficac y  f or O R R at IA 1
Al p ha
O R R differe nce
P o w er
0. 0 0 5
~ 0. 1 8
0. 8 4
0. 0 2 5
~ 0. 1 3
0. 9 4
Pr o gressi o n- free S ur vi v al
T he i nitial al p ha -le vel f or testi n g P F S is 0. 0 1. If t he n ull h y p ot hesis f or O R R is rejecte d, 
Ta ble 1 2 s h o ws t hat its al p ha = 0. 0 0 5 is f ull y reall ocate d t o P F S h y p ot hesis testi n g. If t he n ull 
h y p ot hesis f or O S is rejecte d, t he n al p ha = 0. 0 1 is esse ntiall y f ully reall ocate d t o P F S 
h y p ot hesis testi n g. T h us, t he P F S n ull h y p ot hesis ma y  be teste d at al p ha = 0. 0 1, al p ha = 0. 0 1 5 
(if t he O R R n ull h yp ot hesis is rejecte d b ut n ot t he O S n ull h y p ot hesis), al p ha = 0. 0 2 (if t he O S 
n ull h y p ot hesis is rejecte d b ut n ot t he O R R n ull h y p ot hesis), or al p ha = 0. 0 2 5 (if b ot h t he O R R 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 0
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
a n d O S n ull h y p ot heses are rejecte d). Ta ble 1 3 s h o ws t he b o u n dar y pr o perties f or eac h of 
t hese al p ha-le vels f or t he i nteri m a nal ys es, w hic h were deri ve d usi n g a La n - De Mets O' Brie n -
Fle mi n g s pe n di n g f u ncti o n. N ote t hat t he fi nal r o w i n dicates the t otal p o wer t o reject t he n ull 
h y p ot hesis f or P F S at eac h al p ha-le vel. If t he act ual n u m ber of e ve nts at t he P F S a nal ys es 
differ fr o m t h ose s pecifie d i n t he ta ble, t he b o u n ds will be a dj uste d usi n g t he La n -De Mets 
O' Brie n -Fle mi n g s pe n di n g f u ncti o n acc or di n gl y. Als o n ote t hat if t he O S n ull h y p ot hesis is 
rejecte d at a n i nteri m or fi nal a nal ys is, eac h P F S i nteri m a n d fi nal a nal ysis test ma y  be 
c o m pare d t o its u p date d b o u n ds c o nsi deri n g t he al p ha reall ocati o n fr o m t he O S h y p ot hesis .
Ta ble 1 3
Efficac y  B o u n daries a n d Pr o perties f or Pr o gressi o n-free S ur vi val A nalys es
A n al ysis 
V al ue
= 0. 0 1 
= 0. 0 1 5 
= 0. 0 2
= 0. 0 2 5
I A 2 : 8 0 % *
N: 5 6 0
E ve nts: 3 3 2
M o nt h: 2 0
Z
-2. 6 5 3 9 
-2. 4 8 1 7 
-2. 3 5 3 6 
-2. 2 5 0 4
p ( 1 -si de d) §
0. 0 0 4 
0. 0 0 6 5 
0. 0 0 9 3 
0. 0 1 2 2
H R at b o u n d 
0. 7 4 7 3 
0. 7 6 1 6 
0. 7 7 2 3 
0. 7 8 1 1
P( Cr oss) if H R = 1 †
0. 0 0 4 
0. 0 0 6 5 
0. 0 0 9 3 
0. 0 1 2 2
P( Cr oss) if H R = 0. 7 #
0. 7 2 4 3 
0. 7 7 8 7 
0 . 8 1 4 8 
0. 8 4 1 1
I A 3 : 1 0 0 % *
N: 5 6 0
E ve nts: 4 1 5
M o nt h: 2 5
Z
-2. 3 7 3 7 
-2. 2 2 4 4 
-2. 1 1 3 8 
-2. 0 2 5
p ( 1 -si de d) §
0. 0 0 8 8 
0. 0 1 3 1 
0. 0 1 7 3 
0. 0 2 1 4
H R at b o u n d 
0. 7 9 2 1 
0. 8 0 3 8 
0. 8 1 2 6 
0. 8 1 9 7
P( Cr oss) if H R = 1†
0. 0 1 
0. 0 1 5 
0. 0 2 
0. 0 2 5
P( Cr oss) if H R = 0. 7 #
0. 9 
0. 9 2 4 3 
0. 9 3 9 2 
0. 9 4 9 4
* P e rce nta ge of e x pecte d nu m ber of e ve nts at fi nal a nal ysis re q uire d at i nteri m a nal ysis
§p ( 1 -si de d) is t he n o mi nal al p ha f or testi n g.
H R at b o u n d is t he a p pr o xi mate H R re q uire d t o reac h a n efficac y b o u n d
†P( Cr oss if H R = 1) is t he c u m ulati ve pr o ba bil it y of cr ossi n g a b o u n d u n der t he n ull h y p ot hesis
#P( Cr oss if H R = 0. 7) is t he c u m ulati ve pr o ba bil it y of cr ossi n g a b o u n d u n der t he alter nati ve h y p ot hesis
O ver all S ur vi v al
T he O S h y p ot hesis m a y  be teste d a t al p ha = 0. 0 1 (i nitiall y all ocate d al p ha ), al p ha= 0. 0 2 (if t he 
P F S b ut n ot t he O R R n u ll h y p ot hesis is rejecte d), or al p ha = 0. 0 2 5 (if b ot h t he O R R a n d P F S 
n ull h y p ot heses are rejecte d). Ta ble 1 4 de m o nstrates t he b o u n ds a n d b o u n dar y  pr o perties f or 
O S h y p ot hesis testi n g deri ve d usi n g a La n -De Mets O' Brie n - Fle mi n g s pe n di n g f u ncti o n. If 
t he act ual n u m ber of O S e ve nts at t he i nteri m a n d final a nal ys es differs fr o m t h ose s pecifie d 
i n t he ta ble, the b o u n ds will be a dj uste d usi n g t he La n -De Mets O' Brie n -Fle mi n g s pe n di n g 
f u ncti o n acc or di n gl y.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 1
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Ta ble 1 4
Efficac y  B o u n daries a n d Pr o perties f or O verall S ur vi val A nalys es
A n al ys is 
V al ue
= 0. 0 1 
= 0. 0 2 
= 0. 0 2 5
I A 2 : 5 9 % *
N: 5 6 0
E ve nts: 2 1 2
M o nt h: 2 0
Z 
-3. 1 6 4 8 
-2. 8 2 0 2 
-2. 7 0 2
p ( 1 -si de d) §
0. 0 0 0 8
0. 0 0 2 4
0. 0 0 3 4
H R at b o u n d 
0. 6 4 7 4
0. 6 7 8 8
0. 6 8 9 9
P( Cr oss) if H R = 1 †
0. 0 0 0 8
0. 0 0 2 4
0. 0 0 3 4
P( Cr oss) if H R = 0. 7 #
0. 2 8 4 9
0. 4 1 1 5
0. 4 5 8
I A 3 : 7 9 % *
N: 5 6 0
E ve nts: 2 8 6
M o nt h: 2 5
Z 
-2. 6 9 1 4 
-2. 3 9 9 2 
-2. 2 9 9 5
p ( 1 -si de d) §
0. 0 0 3 6
0. 0 0 8 2
0. 0 1 0 7
H R at b o u n d 
0. 7 2 7 4
0. 7 5 3 0
0. 7 6 1 9
P( Cr oss) if H R = 1 †
0. 0 0 3 8
0. 0 0 9
0. 0 1 1 7
P( Cr oss) if H R = 0. 7 #
0. 6 3 1 2
0. 7 3 6 2
0. 7 6 8 4
Fi nal 
N: 5 6 0
E ve nts: 3 6 1
M o nt h: 3 1
Z 
-2. 3 7 4 2 
-2. 1 1 6
-2. 0 2 8
p ( 1 -si de d) §
0. 0 0 8 8
0. 0 1 7 2
0. 0 2 1 3
H R at b o u n d 
0. 7 7 8 9
0. 8 0 0 3
0. 8 0 7 8
P( Cr oss) if H R = 1 †
0. 0 1
0. 0 2
0. 0 2 5
P( Cr oss) if H R = 0. 7 #
0. 8 5
0. 9 0 3 4
0. 9 1 8 1
* Perce nta ge of e x pecte d n u m ber of e ve nts at fi nal a nal ysis re q uire d at i nteri m a nal ysis
§p ( 1 -si de d) is t he n o mi nal α f or testi n g.
H R at b o u n d is t he a p pr o xi mate H R re q uire d t o reac h a n efficac y b o u n d
†P( Cr oss if H R = 1) is t he c u m ulati ve pr o ba bili t y of cr ossi n g a b o u n d u n der t he n ull h y p ot hesis
#P( Cr oss if H R = 0. 7) is t he c u m ulati ve pr o ba bili t y of cr ossi n g a b o u n d u n der t he alter nati ve h y p ot hesis
S a m ple Size a n d P o wer C alc ul ati o ns
Wit h ~ 2 0 0 s u bjects, the st u d y has ~ 8 4 % p o wer f or detecti n g a 2 5 % differe nce i n O R R ( 5 0 % 
vs 2 5 %) or ~ 9 7 % p o wer f or detecti n g a 3 0 % differe nce i n O R R ( 5 0 % vs . 2 0 %) at i nitiall y 
assi g ne d 0. 0 0 5 ( o ne-si de d) si g nifica nce le vel. T he st u d y has ~ 9 4 % p o wer f or detecti n g a 
2 5 % differe nce i n O R R ( 5 0 % vs 2 5 %) or ~ 9 9 % p o wer f or detecti n g a 3 0 % differe nce i n 
O R R ( 5 0 % vs 2 0 % ) at 0. 0 2 5 ( o ne -si de d) si g nifica nce le vel. 
Wit h
4 1 5 P F S e ve nts, t he st u d y has ~ 9 0 % p o wer f or detecti n g a H R of 0. 7 at i nitiall y 
assi g ne d 0. 0 1 ( o ne-si de d) si g nifica nce le vel, ~9 2 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 1 5
( o ne-si de d) si g nifica nce le vel, ~ 9 4 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 ( o ne-si de d) 
si g nifica nce le vel a n d ~ 9 5 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 5 ( o ne-si de d) 
si g nifica nce le vel. 
Wit h
3 6 1 deat hs, t he st u d y has ~ 8 5 % p o wer f or detecti n g a hazar d rati o ( H R) of 0. 7 at 0. 0 1
( o ne-side d) si g nifica nce le vel, ~9 0 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 ( o ne-si de d)
si g nifica nce le vel, a n d ~ 9 2 % 
p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 5
( o ne-si de d)
si g nifica nce le vel.
T he pla n ne d sa m ple size is a p pr o xi matel y 56 0 s u bjects ass u mi n g : ( 1) t he e nr oll me nt peri o d 
is 1 5. 5 m o nt hs a n d t he ra m p-u p peri o d of e nr oll me nt is 7 m o nt hs; ( 2) me dia n P F S is 6 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 2
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
m o nt hs i n t he c o ntr ol gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 3) me dia n O S is 1 2 m o nt hs i n 
t he c o ntr ol gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 4) t he a n n ual dr o p o ut rate is 3 % f or P F S 
a n d 1 % f or O S; ( 5) t he n u m ber of e ve nts a n d al p ha le vels of i nteri m a nal ys es a n d fi nal 
a nal ys is are as s pecifie d i n S ecti o n 8. 7 a n d S ecti o n 8. 8.
E xte nsi o n St u d y i n C hi n a
After t he e n r oll me nt f or t he gl o bal st u d y is c o m plete d, t he st u d y will c o nti n ue t o ra n d o mize 
s u bjects i n a 1: 1 rati o i nt o t he pe m br oliz u ma b + c he m ot hera p y ar m or sali ne place b o +
che m ot hera p y ar m i n C hi na u ntil t he sa m ple size f or t he C hi nese s u bjects reac hes 
a p pr o xi matel y 12 0 , t o e val uate t he c o ns iste nc y of efficac y an d safet y in t he C hi nese 
s u b p o p ulati o n c o m pare d t o t he gl o bal p o p ulati o n .  Chi nese s u bjects ra n d o mize d after 
c o m pleti o n of e nr oll me nt i n t he gl o bal st u d y will n ot be i ncl u de d i n t he a nal ysis of t he gl o bal 
st u d y.
S u b gr o u p A n al yses a n d E ffect of B aseli ne F act ors
T o deter mi ne w het her t he treat me nt effect is c o nsiste nt acr oss vari o us s u b gr o u ps, t he 
bet wee n -gr o u p treat me nt effect f or O S, P F S a n d O R R ( wit h a n o mi nal 9 5 % CI) will be 
esti mate d a n d pl otte d wit hi n eac h cate g or y of t he f oll o wi n g c lassificati o n varia bles: 
• 
A ge cate g or y  ( <6 5, ≥6 5 years)
• 
E C O G Perf or ma nce Scale ( 0, 1)
• 
Se x (fe male, male)
• 
Race ( w hite, n o n -w hite)
• 
Ge o gra p hic re gi o n of e nr olli n g site ( East Asia, n o n -East Asia)
• 
S m o ki n g stat us ( ne ver, f or mer/ c urre nt)
• 
Brai n metastasis stat us at baseli ne ( y es, n o)
• 
P D -L 1  e x pressi o n ( T P S < 1 %, 5 0 % > T P S ≥1 % , or T P S ≥5 0 % ) 
• 
Ta xa ne c he m ot hera p y ( paclita xel , na b- paclita xel)
E xte nt of E x p os ure
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n c ycles.
9. 0 L A B E LI N G, 
P A C K A GI N G, 
S T O R A G E 
A N D 
R E T U R N 
O F  
C LI NI C A L 
S U P P LI E S
I n vesti g ati o n al Pr o d uct
T he i n vesti gat or s hall ta ke res p o nsi bilit y for a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p ply, st ora ge, ha n dli n g, distri b uti o n a n d usa ge of 
i nvesti gati o nal pr o d uct i n acc or da nce wit h t he pr ot oc ol a n d a n y ap plica ble la ws a n d 
re g ulati o ns.
Cli nical S u p plies will be pr o vi de d b y t he S p o ns or as s u m marize d i n Ta ble 1 5 .
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 3
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
Cli nical s u p plies will be pac ka ge d t o s u p p ort e nr oll me nt a n d re place me nt s u bjects as 
re q uire d.  
Whe n a re place me nt s u bject is re q uire d, t he S p o ns or or desi g nee nee ds t o be 
c o ntacte d pri or t o d osi n g t he re place me nt s u p plies.
Ta ble 1 5
Pr o d uct Descri pti o n s
Pr o d uct N a me & 
P ote nc y
D os a ge F or m 
S o urce/ A d diti o n al I nf or m ati o n
Pe m br oliz u ma b 
( M K-
3 4 7 5) 1 0 0 m g / 4 m L
S ol uti o n f or I nf usi o n 
Pr o vi de d ce ntrall y b y t he S p o ns or.
Na b - Paclita xel  
1 0 0 m g
vial
P o w der f or Inf usi o n 
Pr o vi de d ce ntrall y by t he S p o ns or 
or 
l ocall y 
by 
t he trial site, 
s u bsi diar y, or desi g nee. 
Car b o plati n 
1 0
m g/ m L , 
6 0 m L
S ol uti o n f or I nf usi o n 
Pr o vi de d ce ntrall y by t he S p o ns or 
or 
l ocall y 
by 
t he trial site, 
s u bsi diar y, or desi g nee. 
Paclita xel 6 m g/ m L , 1 6. 7
m L
S ol uti o n f or I nf usi o n 
Pr o vi de d ce ntrall y by t he S p o ns or 
or 
l ocall y 
by 
t he trial site, 
s u bsi diar y, or desi g nee. 
All s u p plies i n dicate d i n Ta ble 1 5 will be pr o vi de d per t he “ S o urce/ A d diti o nal I nf or mati o n” 
c ol u m n de pe n di n g o n l ocal c o u ntr y  o perati o nal re q uire me nts.
A n y  co m merciall y  availa ble pr o d uct n ot i ncl u de d i n Ta ble 1 5 will be pr o vi de d b y  the trial 
site, s u bsi diar y or desi g nee . E ver y  atte m pt 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. T he trial site is res p o nsi ble f or rec or di n g the l ot n u m ber, 
ma n ufact urer, a n d e x pir y date f or a n y l ocall y purc hase d pr o d uct as per l ocal g ui deli nes 
u nless ot her wise i nstr ucte d b y  t he S p o ns or.
P ac k a gi n g a n d L a beli n g I nf or m ati o n
Cli nical s u p plies will be affi xe d wit h a cli nical la bel i n acc or da nce wit h
re g ulat ory 
re q uire me nts.
All s u p plies will be pr o vi de d o pe n la bel. Pe m br oliz u ma b will be pr o vi de d as n o n -kitte d 
si n gle vials or as si n gle/ m ulti vials i n a kit b o x.  The ot her pr o d ucts will be pr o vi de d as a kit 
wit h a si n gle vial.
Cli nic al S u p plies Discl os ure
T his trial is bli n de d b ut pr o vi de d o pe n la bel; t heref ore, a n u n bli n de d p har macist or q ualifie d 
trial site pers o n nel will be use d t o bli n d s u p plies. Treat me nt i de ntit y (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.
T he e mer ge nc y un bli n di n g call ce nter will use t he treat me nt/ra n d o mizati o n sc he d ule f or t he 
trial t o u n bli n d s u bjects a n d t o u n mas k treat me nt i de ntit y. I n t he e ve nt t hat t he e mer ge nc y 
u n bli n di n g call ce nter is n ot a v aila ble f or a gi ve n site i n t his trial, t he ce ntral electr o nic 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 4
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
treat me nt all ocati o n/ ra n d o mizati o n s yste m (I V R S/IW R S) s h o ul d be use d i n or der to u n bli n d 
s u bjects a n d t o u n mas k treat me nt/ vacci ne i de ntit y. T he S p o ns or will
n ot pr o vi de ra n d o m 
c o de/ discl os ure e n vel o pes or lists wit h t he cli nical s u p plies .
Treat me nt i de ntificati o n i nf or mati o n is t o be u n mas ke d O N L Y if necessar y  for t he welfare 
of t he s u bject.  E ver y  eff ort s h o ul d be ma de n ot t o u n bli n d t he s u bject u nless necessary . 
I n t he e ve nt t hat u n bli n di n g has occ urre d, t he circ u msta nces ar o u n d t he u n bli n di n g (e. g., 
date , reas o n a n d pers o n perf or mi n g t he u n bli n di n g ) m ust be d oc u me nte d pr o m ptl y , a n d t he 
S p o ns or Cli nical Direct or n otifie d as s o o n as p ossi ble.  Onl y  the pri nci pa l i n vesti gat or or 
dele gate a n d t he res pecti ve s u bject’s c o de s h o ul d be u n bli n de d.  Trial site pers o n nel a n d 
S p o ns or pers o n nel directl y  ass ociate d wit h t he c o n d uct of t he trial s h o ul d n ot be u n bli n de d t o 
treat me nt assi g n me nt . S u bjects w h ose treat me nt assi g n me nt has bee n u n bli n de d ( b y the 
i n vesti gat or, Merc k s u bsi diar y, or t hr o u g h t he e mer ge nc y un bli n di n g call ce nter) m ust be 
disc o nti n ue d fr o m st u d y  dr u g.
Secti o n 5. 8 o utli nes t he criteria f or all o wi n g s u bjects w h o are disc o nti n ue d fr o m treat me nt t o 
c o nti n ue t o be m o nit ore d i n t he trial.
St or a ge a n d H a n dli n g Re q uire me nts
Cli nical s u p plies m ust be st ore d i n a sec ure, li mite d-access l ocati o n u n der t he st ora ge 
c o n diti o ns s pecifie d o n t he la bel.  
Recei pt a n d dis pe nsi n g of trial me dicati o n m ust be rec or de d b y  an a ut h orize d pers o n at t he 
trial site.
Cli nical s u p plies ma y  n ot be use d f or a ny p ur p ose ot her t ha n t hat state d i n t he pr ot oc ol.
Disc ar d/ Destr ucti o n/ Ret ur ns a n d Rec o ncili ati o n
T he i n vesti gat or is res p o nsi ble f or kee pi n g acc urate rec or ds of t he cli nical s u p pli es recei ve d 
fr o m t he S p o ns or or desi g nee, t he a m o u nt dis pe nse d t o a n d ret ur ne d b y  the s u bjects a n d t he 
a m o u nt re mai ni n g at t he c o ncl usi o n of t he trial. F or all trial sites, t he l ocal c o u ntr y Sp o ns or 
pers o n nel or desi g nee will pr o vi de a p pr o priate d oc u me ntat i o n t hat m ust be c o m plete d f or 
dr u g acc o u nta bilit y an d ret ur n, or l ocal discar d a n d destr ucti o n if a p pr o priate.   Where l ocal 
discar d a n d destr ucti o n is a p pr o priate, t he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat a l ocal 
discar d/ destr ucti o n pr oce d ure is d oc u me nte d .
St a n d ar d P olicies
Trial  
site 
pers o n nel  
will  
ha ve  
access 
t o 
a 
ce ntral 
electr o nic  
treat me nt 
all ocati o n/ ra n d o mizati o n s yste m (I V R S/IW R S 
s yste m) t o all ocate s u bjects, t o assi g n 
treat me nt t o s u bjects a n d t o ma na ge t he distri b uti o n of cli nical s u p plies. Eac h pers o n 
accessi n g t he I V R S s yste m m ust be assi g ne d a n i n di vi d ual u ni q ue PI N.  The y  must use o nl y  
t heir assi g ne d PI N t o access t he s yste m, a n d t he y must n ot s hare t heir assi g ne d PI N wit h 
a n yo ne.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 5
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1 0. 0 A D MI NI S T R A TI V E A N D R E G U L A T O R Y D E T AI L S
C o nfi de nti alit y
C o nfi de nti alit y of D at a
B y  si gni n g t his pr ot oc ol, t he i n vesti gat or affir ms t o t he S p o ns or t hat i nf or mati o n f ur nis he d t o 
t he i n vesti gat or b y  the S p o ns or will be mai ntai ne d i n c o nfi de nce, a n d s uc h i nf or mati o n will 
be di v ul ge d t o t he i nstit uti o nal re vie w b oa r d, et hics re vie w c o m mittee (I R B/ E R C) or si milar 
or e x pert c o m mittee; affiliate d i nstit uti o n a n d e m pl o yees, o nl y  un der a n a p pr o priate 
u n dersta n di n g of c o nfi de ntialit y wit h s uc h b oar d or c o m mittee, affiliate d i nstit uti o n a n d 
e m pl o yees.  Data ge nerate d b y  th is trial will be c o nsi dere d c o nfi de ntial b y  the i n vesti gat or, 
e xce pt t o t he e xte nt t hat it is i ncl u de d i n a p u blicati o n as pr o vi de d i n t he P u blicati o ns secti o n 
of t his pr ot oc ol.
C o nfi de nti alit y of S u bject 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 ( or S p o ns or re prese ntati ve), 
I RB/ E R C, or re g ulat or y  aut h orit y  re prese ntati ves ma y  co ns ult a n d/ or c o p y  trial d oc u me nts i n 
or der t o verif y  wor ks heet/case re p ort f or m data.  By si g ni n g t he c o nse nt f or m, t he s u bject 
a grees t o t his pr ocess.  If trial d oc u me nts will be p h ot oc o pie d d uri n g t he pr ocess of verif y i n g 
w or ks heet/case re p ort f or m i nf or mati o n, t he s u bject will be i de ntifie d b y  uni q ue c o de o nl y ; 
f ull na mes/i nitials will be mas ke d pri or t o tra ns missi o n t o t he S p o ns or.
B y  si g ni n g t his pr ot oc ol, t he i n vesti gat or a grees t o treat all s u bject data use d a n d discl ose d i n 
c o n necti o n wit h 
t his trial i n acc or da nce wit h 
all a p plica ble pri vac y la ws, r ules a n d 
re g ulati o ns.
C o nfi de nti alit y of I n vesti g at or I nf or m ati o n
B y  si gni n g t his pr ot oc ol, t he in vesti gat or rec o g nizes t hat certai n pers o nal i de ntif yi n g 
i nf or mati o n wit h res pect t o t he i n vesti gat or, a n d all s u bi n vesti gat ors a n d trial site pers o n nel, 
ma y  be use d a n d discl ose d f or trial ma na ge me nt 
p ur p oses, as part of a re g ulat or y 
s u b missi o ns, a n d as re q uire d b y la w.  T his i nf or mati o n ma y i ncl u de:
1.
na me, a d dress, tele p h o ne n u m ber a n d e -mail a d dress;
2.
h os pital or cli nic a d dress a n d tele p h o ne n u m ber;
3.
c urric ul u m vitae or ot her s u m mar y of q ualificati o ns a n d cre de ntials; a n d
4.
ot her pr ofessi o nal d oc u me ntati o n.
C o nsiste nt wit h t he p ur p oses descri be d a b o ve, t his i nf or mati o n ma y  be tra ns mitte d t o t he 
S p o ns or, a n d s u bsi diaries, affiliates a n d a ge nts of t he S p o ns or, i n y o ur c o u ntr y an d ot her 
c o u ntries, i ncl u di n g c o u ntries t hat d o n ot ha ve la ws pr otecti n g s uc h i nf or mati o n.  
A d diti o nall y , t he i n vesti gat or’s na me a n d b usi ness c o ntact i nf or mati o n ma y  be i ncl u de d 
w he n 
re p orti n g certai n seri o us a d verse e ve nts t o re g ulat or y aut h orities or t o ot her 
i n vesti gat ors.  By si g ni n g t his pr ot oc ol, t he i n vesti gat or e x pressl y c o nse nts t o t hese uses a n d 
discl os ures.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 6
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
If t his is a m ultice nter trial, i n or der t o facilitate c o ntact bet wee n i n vesti gat ors, t he S p o ns or 
ma y  share a n i n vesti gat or’s na me a n d c o ntact i nf or mati o n wit h 
ot her partici pati n g 
i n vesti gat ors u p o n re q uest.
C o nfi d e nti alit y of I R B/I E C I nf or m ati o n
T he S p o ns or is re q uire d t o rec or d t he na me a n d a d dress of eac h I RB/I E C t hat re vie ws a n d 
a p pr o ves t his trial.  The S p o ns or is als o re q uire d t o d oc u me nt t hat eac h I R B/I E C meets 
re g ulat or y an 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 RB/I E C me m bers 
a n d t o ma ke 
t hese rec or ds a vaila ble f or 
re g ulat or y a ge nc y re vie w u p o n re q uest by t h ose a ge ncies.
C o m pli a nce wit h Fi n a nci al Discl os ure Re q uire me nts
Fi na ncial Discl os ur e re q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi na ncial Discl os ure b y  Cli nical I n vesti gat ors ( 2 1 C F R Part 5 4).  It is t he 
S p o ns or's res p o nsi bilit y t o deter mi ne, base d o n t hese re g ulati o ns, w het her a re q uest f or 
Fi na ncial D iscl os ure i nf or mati o n is re q uire d.  It is t he i n vesti gat or's/s u bi n vesti gat or's 
res p o nsi bilit y t o c o m pl y wit h a n y s uc h re q uest.  
T he i n vesti gat or/s u bi n vesti gat or(s) a gree, if re q ueste d b y  the S p o ns or i n acc or da nce wit h 2 1 
C F R Part 5 4, t o pr o vi de his/ her fi na ncial i nterests i n a n d/ or arra n ge me nts wit h t he S p o ns or t o 
all o w f or t he s u b missi o n of c o m plete a n d acc urate certificati o n a n d discl os ure state me nts.  
T he 
i n vesti gat or/s u bi n vesti gat or(s) f urt her a gree t o pr o vi de t his i nf or mati o n o n a 
Certificati o n/ Discl o s ure F or m, c o m m o nl y kn o w n as a fi na ncial discl os ure f or m, pr o vi de d b y  
t he S p o ns or . 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 i n t he U nite d States f or t hese p ur p oses.  This ma y  in v ol ve t he 
tra ns missi o n of i nf or mati o n t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g pers o nal data.
C o m pli a nce wit h L a w, A u dit a n d De b ar me nt
B y  si gni n g t his pr ot oc ol, t he i n vesti gat or a grees t o c o n d uct t he trial i n a n efficie nt a n d 
dili ge nt ma n ner a n d i n c o nf or ma nce wit h t his pr ot oc ol; ge nerall y acce pte d sta n dar ds of G o o d 
Cli nical 
Practice 
(e. g., I nter nati o nal C o nfere nce 
o n 
Har m o 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 ner all y acce pte d sta n dar ds of g o o d cli nical practice); a n d 
all a p plica ble fe deral, state a n d l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he 
cli nical trial.
T he C o de of C o n d uct, a c ollecti o n of g oals a n d c o nsi derati o ns t hat g o ver n t he et hical a n d 
scie ntific c o n d uct of cli nical i n vesti gati o ns s p o ns ore d b y Merc k, is pr o vi de d i n Secti o n 1 2. 1 -
Merc k C o de of C o n d uct f or Cli nical Trials .
T he i n vesti gat or als o a grees t o all o w m o nit ori n g, a u dits, I RB/ E R C re vie w a n d re g ulat or y 
a ut h orit y ins pecti o n of trial-relate d d oc u me nts a n d pr oce d ures a n d pr o vi de f or direct access 
t o all trial-relate d s o urce data a n d d oc u me nts.
T he i n vesti gat or a grees n ot t o see k rei m b urse me nt fr o m s u bjects, t heir i ns ura nce pr o vi ders or 
fr o m g o ver n me nt pr o gra ms f or pr oce d ures i ncl ude d as part of t he trial rei m b urse d t o t he 
i n vesti gat or by t he S p o ns or.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 7
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
T he i n vesti gat or s hall pre pare a n d mai ntai n c o m plete a n d acc urate trial d oc u me ntati o n i n 
c o m plia nce wit h G o o d Cli nical Practice sta n dar ds a n d a p plica ble fe deral, state a n d l ocal 
la ws, r ules a n d re g ulati o ns; a n d, f or eac h s u bject partici pati n g i n t he trial, pr o vi de all data, 
a n d, u p o n c o m pleti o n or ter mi nati o n of t he cli nical trial, s u b mit a n y ot her re p orts t o t he 
S p o ns or as re q uire d b y  t his pr ot oc ol or as ot her wise re q uire d p urs ua nt t o a n y a gree me nt wit h 
t he S p o ns or.
Trial d oc u me ntati o n will be pr o m ptl y  an d f ully discl ose d t o t he S p o ns or b y  the i n vesti gat or 
u p o n re q uest a n d als o s hall be ma de a vaila ble at t he trial site u p o n re q uest f or i ns pecti o n, 
c o p yi n g, re vie w a n d a u dit at reas o na ble ti mes b y  re prese ntati ves of t he S p o ns or or a n y 
re g ulat or y aut h orities.  T he i n vesti gat or a grees t o pr o m ptl y  ta ke a n y reas o na ble ste ps t hat are 
re q ueste d by t he S p o ns or as a res ult of a n a u dit t o c ure deficie ncies i n t he trial d oc u me ntati o n 
a n d w or ks heets/ case re p ort f or ms.
T he i n vesti gat or m ust mai ntai n c o pies of all d oc u me ntati o n a n d rec or ds relati n g t o t he 
c o n d uct of t he trial i n c o m plia nce wit h all a p plica ble le gal a n d re g ulat or y re q uire me nts.  T his 
d oc u me ntati o n i ncl u des, b ut is n ot li mite d t o, t he pr ot oc ol, w or ks heets/c ase re p ort f or ms, 
a d vertisi n g 
f or s u bject partici pati o n, 
a d verse 
e ve nt 
re p orts, s u bject s o urce data, 
c orres p o n de nce wit h re g ulat or y aut h orities a n d I RBs/ E R Cs, c o nse nt f or ms, i n vesti gat or’s 
c urric ula vitae, m o nit or visit l o gs, la b orat or y refere nce ra n ges, la b orat or y certificati o n or 
q ualit y  c o ntr ol pr oce d ures a n d la b orat or y direct or c urric ul u m vitae.  B y si g ni n g t his pr ot oc ol, 
t he i n vesti gat or a grees t hat d oc u me ntati o n s hall be retai ne d u ntil at least 2 ye ars after t he last 
a p pr o val of a mar keti n g a p plicati on i n a n I CH re gi o n or u ntil t here are n o pe n di n g or 
c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or u ntil at least 2 ye ars ha ve ela pse d 
si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct.  
Beca use t he cli nical d e vel o p me nt a n d mar keti n g 
a p plicati o n pr ocess is varia ble, it is 
a ntici pate d t hat t he rete nti o n peri o d ca n be u p t o 1 5 years or l o n ger after pr ot oc ol data base 
l oc k. T he S p o ns or will deter mi ne t he mi ni m u m rete nti o n peri o d a n d n otif y  the i n vesti gat or 
w he n d oc u me nts m a y  be destr o ye d.  T he S p o ns or will deter mi ne t he mi ni m u m rete nti o n 
peri o d a n d u p o n re q uest, will pr o vi de g ui da nce t o t he i n vesti gat or w he n d oc u me nts n o l o n ger 
nee d t o be retai ne d.  T he s p o ns or als o rec o g nizes t hat d oc u me nts ma y nee d t o be retai ne d f or 
a l o n ger peri o d if re q uire d b y  local re g ulat or y re q uire me nts. All trial d oc u me nts s hall be 
ma de a vaila ble if re q uire d b y  rele va nt re g ulat or y aut h orities. T he i n vesti gat or m ust c o ns ult 
wit h a n d o btai n writte n a p pr o val b y t he S p o ns or pri or t o destr o yi n g trial a n d/ or s u bject files.  
I C H G o o d Cli nical Practice g ui deli nes rec o m me n d t hat t he i n vesti gat or i nf or m t he s u bject’s 
pri mar y  ph y sicia n a b o ut t he s u bject’s partici pati o n i n t he trial if t he s u bject has a pri mar y  
p h y sicia n a n d if t he s u bject a grees t o t he pri mar y p h ysicia n bei n g i nf or me d.
T he i n vesti gat or will pr o m ptl y  inf or m t he S p o ns or of a n y re g ulat or y aut h orit y  ins pecti o n 
c o n d ucte d f or t his trial.
Pers o ns de barre d fr o m c o n d ucti n g or w or ki n g o n cli nical trials b y  an y  co urt or re g ulat or y 
a ut h orit y will n ot be all o we d t o c o n d uct or w or k o n t his S p o ns or’s trials.  The i n vesti gat or 
will i m me diatel y discl ose i n writi n g t o t he S p o ns or if a n y pers o n w h o is i n v ol ve d i n 
c o n d ucti n g t he trial is de barre d or if a n y pr ocee di n g f or de bar me nt is pe n di n g or, t o t he bes t 
of t he i n vesti gat or’s k n o wle d ge, t hreate ne d.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 0 8
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
I n t he e ve nt t he S p o ns or pre mat urel y ter mi nates a partic ular trial site, t he S p o ns or will 
pr o m ptl y  n otif y t hat trial site’s IR B/I E C.
Acc or di n g t o E ur o pea n le gislati o n, a S p o ns or m ust 
desi g nate a n o verall c o or d i nati n g 
i n vesti gat or f or a m ulti -ce nter trial (i ncl u di n g m ulti nati o nal).  Whe n m ore t ha n o ne trial site 
is o pe n i n a n E U c o u ntr y, Merc k, as t he S p o ns or, will desi g nate, per c o u ntr y, a nati o nal 
pri nci pal c o or di nat or ( Pr ot oc ol CI ), res p o nsi ble f or c o or di nati n g t he w or k of t he pri nci pal 
i n vesti gat ors at t he differe nt trial sites i n t hat Me m ber 
State, acc or di n g t o nati o nal 
re g ulati o ns.  For a si n gle-ce nter trial, t he Pr ot oc ol CI  is t he pri nci pal i n vesti gat or.  In 
a d diti o n, t he S p o ns or m ust desi g nate a pri nci pal or c o or di nati n g i n vesti gat or t o re vie w t he 
trial re p ort t hat s u m marizes t he trial res ults a n d c o nfir m t hat, t o t he best of his/ her 
k n o wle d ge, t he re p ort acc urately descri bes t he c o n d uct a n d res ults of t he trial [ Cli nical St u d y  
Re p ort ( C S R) CI ].  The S p o ns or ma y  co nsi der o ne or m ore fact ors i n t he selecti o n of t he 
i n di vi d ual t o ser ve as t he Pr ot oc ol CI  an d or C S R CI  (e. g., a vaila bilit y of t he CI  duri n g t he 
a ntici pate d re vie w pr ocess, t h or o u g h u n dersta n di n g of cli nical trial met h o ds, a p pr o priate 
e nr oll me nt o f s u bject c o h ort, ti mel y ac hie ve me nt of trial milest o nes).  The Pr ot oc ol CI  must 
be a partici pati n g trial i n vesti gat or.
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P osti n g Re q uire me nts
U n der t he ter ms of t he F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Ac t ( F D A M A) a n d t he 
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act ( F D A A A), t he S p o ns or of t he trial is s olel y 
res p o nsi ble f or deter mi ni n g w het her t he trial a n d its res ults are s u bject t o t he re q uire me nts 
f or s u b missi o n t o t he Cli nical Trials Data Ba n k, htt p:// w w w.cli nicaltrials. g o v.  Merc k, as 
S p o ns or of t his trial, will re vie w t his pr ot oc ol a n d s u b mit t he i nf or mati o n necessar y  to f ulfill 
t hese re q uire me nts.  
Merc k e ntries are n ot li mite d t o F D A M A/ F D A A A ma n date d trials. 
I nf or mati o n p oste d will all o w s u bjects t o i de ntif y pote ntiall y a p pr o priate trials f or t heir 
disease c o n diti o ns a n d p urs ue partici pati o n b y  calli n g a ce ntral c o ntact n u m ber f or f urt her 
i nf or mati o n o n a p pr o priate trial l ocati o ns a n d trial site c o ntact i nf or mati o n.    
B y  si gni n g t his pr ot oc ol, t he i n vesti gat or ac k n o wle d ges t hat t he stat ut or y obli gati o ns u n der 
F D A M A/ F D A A A are t hat of t he S p o ns or a n d a grees n ot t o s u b mit a n y  i nf or mati o n a b o ut t his 
trial or its res ults t o t he Cli nical Trials Data Ba n k.
Q u alit y M a n a ge me nt S yste m
B y  si gni n g t his pr ot oc ol , t he S p o ns or a grees t o be res p o nsi ble f or i m ple me nti n g a n d 
mai ntai ni n g 
a q ualit y  
ma na ge me nt s yste m wit h 
writte n 
de vel o p me nt pr oce d ures a n d 
f u ncti o nal area sta n dar d o perati n g pr oce d ures ( S O Ps) t o e ns ure t hat trials are c o n d ucte d a n d 
data are ge nerate d, d oc u me nte d, a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, acce pte d 
sta n dar ds of G o o d Cli nical Practice, a n d all a p plica ble fe deral, state, a n d l ocal la ws, r ules a n d 
re g ulati o ns relati n g t o t he c o n d uct of t he cli nical trial.
D at a M a n a ge me nt
T he i n vesti gat or or q ualifie d desi g nee is res p o nsi ble f or rec or di n g a n d verif y i n g t he acc urac y 
of s u bject data.  By si g ni n g t his pr ot oc ol, t he i n vesti gat or ac k n o wle d ges t hat his/ her 
electr o nic si g nat ure is t he le gally bi n di n g e q ui vale nt of a writte n si g nat ure.  By e nteri n g 
h is/ her electr o nic si g nat ure, t he i n vesti gat or c o nfir ms t hat all rec or de d data ha ve bee n 
verifie d as acc urate.
 
 
0 5 C 6 H 2

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

Pr o d uct:  M K -3 4 7 5 
1 1 0
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
t he trial a n d writi n g, as disc usse d a b o ve. T he first a ut h or is res p o nsi ble f or defe n di n g t he 
i nte grity of t he data, met h o d(s) of data a nal ys is a n d t he scie ntific c o nte nt of t he ma n uscri pt.
T he S p o ns or m ust ha ve t he o p p ort u nit y  to re vie w all pr o p ose d a bstracts, ma n uscri pts or 
prese ntati o ns re gar di n g t his trial 4 5 da y s pri or t o s u b missi o n f or p u blicati o n/ prese ntati o n. 
A n y  inf or mati o n i de ntifie d b y  the S p o ns or as c o nfi de ntial m ust 
be delete d pri or t o 
s u b missi o n; t his c o nfi de ntialit y does n ot i ncl u de efficac y an d safet y res ults. S p o ns or re vie w 
ca n be e x pe dite d t o mee t p u blicati o n ti meli nes.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 1
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1 1. 0 LI S T O F R E F E R E N C E S
[ 1]
Disis M L . I m m u ne re g ulati o n of ca ncer. J Cli n O nc ol 2 0 1 0; 2 8( 2 9): 4 5 3 1-8.
[ 2]
D o n g H, Str o me S E, Sal o ma o D R, Ta m ura H, Hira n o F, Flies D B, et al. 
T u m or -ass ociate d B 7 -H 1 pr o m otes T- cell a p o pt osis: a p ote ntial mec ha nis m 
of i m m u ne e vasi o n. Nat Me d 2 0 0 2; 8( 8): 7 9 3 - 8 0 0.
[ 3]
Hi n o R, Ka bas hi ma K, Kat o Y, Ya gi H, Na ka m ura M, 
H o nj o T, et al. 
T u m or cell e x pressi o n of pr o gra m me d cell deat h - 1 li ga n d 1 is a pr o g n ostic 
fact or f or mali g na nt mela n o ma. Ca ncer 2 0 1 0; 1 1 6: 1 7 5 7- 6 6.
[ 4]
T o palia n S L , H o di F S, Bra h mer J R, Getti n ger S N, S mit h D C, Mc Der m ott 
D F, et al. Safet y, acti vit y, a n d i m m u ne c orrelates of a nti-P D -1 a nti b o d y in 
ca ncer. N E n gl J Me d 2 0 1 2; 3 6 6( 2 6): 2 4 4 3 - 5 4.
[ 5]
Pat nai k A, Ka n g S P, T olc her A W, Rasc o D W, Pa pa d o p o ul os K P, Beera m 
M, et al.  20 1 2 A S C O A n n ual Meeti n g:  Phase I st u d y of M K - 3 4 7 5 (a nti-
P D -1 m o n ocl o nal a nti b o d y ) i n patie nts wit h a d va nce d s oli d t u m ors.
[ 6]
H o di F S, O' Da y  SJ, Mc Der m ott D F, We ber R W, S os ma n J A, Haa ne n J B, et 
al. I mpr o ve d s ur vi val wit h 
i pili m u ma b i n patie nts wit h 
metastatic 
mela n o ma. N E n gl J Me d 2 0 1 0; 3 6 3( 8): 7 1 1- 2 3.
[ 7]
C ha p ma n P B, Ha usc hil d A, R o bert C, Ha n ne n J B, Asciert o P, Lar ki n J, et 
al. I mpr o ve d s ur vi val wit h ve m urafe ni b i n mela n o ma wit h B R A F V 6 0 0 E 
m utati o n. N E n gl J Me d 2 0 1 1; 3 6 4( 2 6): 2 5 0 7- 1 6.
[ 8]
R o bert C, T h o mas L,  Bo n dare n k o I, O' Da y  S, We ber 
J, Gar be C, et al. 
I pili m u ma b pl us dacar bazi ne f or pre vi o usl y  untreate d metastatic mela n o ma. 
N E n gl J Me d 2 0 1 1; 3 6 4( 2 6): 2 5 1 7 - 2 6.
[ 9]
Sasa ki A, Ta na ka F, Mi m ori K, I n o ue H, Kai S, S hi bata K, et al. Pr o g n ostic 
val ue of t u m or-i nfiltrati n g F O X P 3 + re g ulat or y T cells i n patie nts wit h 
he pat ocell ular carci n o ma. EJ S O 2 0 0 8; 3 4: 1 7 3 - 9.
[ 1 0]
S he n Z, Z h o u S, Wa n g 
Y, Li R, Z h o n g C, Li a n g C, et al. Hi g her 
i ntrat u m oral i nfiltrate d F o x p 3 + Tre g n u m bers a n d F o x p 3 +/ C D 8 + rati o are 
ass ociate d wit h a d verse pr o g n osis i n resecta ble gastric ca ncer. J Ca ncer Res 
Cli n O nc ol 2 0 1 0; 1 3 6: 1 5 8 5 - 9 5.
[ 1 1]
Tal ma d ge J E, D o n k or M, 
Sc h olar E. I nfla m mat or y cell i nfiltrati o n of 
t u m ors: Je k yll or H yde. Ca ncer Metastasis Re v 2 0 0 7; 2 6( 3- 4): 3 7 3 - 4 0 0.
[ 1 2]
Us u b üt ü n A, A y ha n A, U y g ur M C, Öze n H, T o kl u C, R uaca n S. Pr o g n ostic 
fact ors i n re nal cell carci n o ma. J E x p Cli n Ca ncer Res 1 9 9 8; 1 7( 1): 7 7- 8 1.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 2
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
[ 1 3]
N o bili C, De grate L, Ca pr otti R, Fra nci osi C, Le o ne B E, Trezzi R, et al. 
Pr ol o n ge d s ur vi val of a pa tie nt affecte d b y  pa ncreatic a de n ocarci n o ma wit h 
massi ve 
l ym p h oc y te a n d de n dritic cell i nfiltrati o n after i nterle u ki n- 2 
i m m u n ot hera p y. Re p ort of a case. T u m ori 2 0 0 8; 9 4( 3): 4 2 6- 3 0.
[ 1 4]
Hira o ka N. T u m or -i nfiltrati n g l ym p h oc y tes a n d he pat ocell ular carci n o ma:
m olec ular bi ol o g y . Int J Cli n O nc ol 2 0 1 0; 1 5( 6): 5 4 4 - 5 1.
[ 1 5]
H o di 
F S, Dra n off 
G. 
T he 
bi ol o gic i m p orta nce of t u m or-i nfiltrati n g 
l ym p h oc y tes. J C uta n Pat h ol 2 0 1 0; 3 7( S u p pl 1): 4 8- 5 3.
[ 1 6]
Kl o or M. 
L y m p h oc y t e i nfiltrati o n a n d pr o g n osis i n c ol orectal ca ncer. 
L a ncet O nc ol. 2 0 0 9 Se p; 1 0( 9): 8 4 0 - 1.
[ 1 7]
Lee H E, C hae S W, Le e YJ, Ki m M A, Lee H S, Lee B L, et al. Pr o g n ostic 
i m plicati o ns of t ype a n d de nsit y  of t u m o ur-i nfiltrati n g l ym p h oc y tes i n 
gastric ca ncer. Br J Ca ncer 2 0 0 8; 9 9( 1 0): 1 7 0 4 - 1 1.
[ 1 8]
Li otta F, Gacci M, Fr osali F, Q uerci V, Vitt ori G, La pi ni A, et al. Fre q ue nc y 
of re g ulat or y T cells i n peri p heral bl o o d a n d i n t u m o ur-i nfiltrati n g 
l ym p h oc y tes c orrelates wit h p o or pr o g n osis i n re nal cell carci n o ma. BJ U I nt 
2 0 1 1; 1 0 7( 9): 1 5 0 0 - 6.
[ 1 9]
S uz u ki H, C hi kaza wa N, Tas a ka T, Wa da J, Ya masa ki A, Kita ura Y, et al. 
I ntrat u m oral C D 8 + T/ F O X P 3 + cell rati o is a pre dicti ve mar ker f or s ur vi val 
i n patie nts 
wit h 
c ol orectal 
ca ncer. 
Ca ncer 
I mm u n ol 
I mm u n ot her 
2 0 1 0; 5 9: 6 5 3 - 6 1.
[ 2 0]
C he w V, T o w C, Te o M, W o n g H L, C ha n J, Ge hri n g A, et al. I nfla m mat or y 
t u m or micr oe n vir o n me nt  
is ass ociate d 
wit h 
s u peri or 
s ur vi val 
i n 
he pat ocell ular carci n o ma patie nts. J He pat ol 2 0 1 0; 5 2: 3 7 0- 9.
[ 2 1]
P ölc her M, Bra u n M, Frie dric hs N, R u dl o ws ki C, Berc ht E, Fi m mers R, et 
al. F o x p 3( +) cell i nfiltrati o n a n d gra n z yme B( +)/ F o x p 3( +) cell rati o are 
ass ociate d wit h 
o utc o me i n ne oa dj u va nt c he m ot hera p y-treate d o varia n 
carci n o ma. Ca ncer I m m u n ol Im m u n ot her 2 0 1 0; 5 9( 6): 9 0 9 - 1 9.
[ 2 2]
O ble D A, L o e we R, Y u P, Mi h m 
M C 
Jr. F oc us o n TI Ls: pr o g n ostic 
si g nifica nce of t u m or i nfiltrati n g l ym p h oc y tes i n h u ma n mela n o ma. Ca ncer 
I m m u n. 2 0 0 9 A pr 2; 9: 3.
[ 2 3]
R o p p o ne n K M, Es keli ne n MJ, 
Li p p o ne n P K, Al ha va E, K os ma V- M. 
Pr o g n ostic val ue of t u m o ur-i nfiltrati n g l ym p h oc y tes ( TI Ls) i n c ol orectal 
ca ncer. J Pat h ol 1 9 9 7; 1 8 2( 3): 3 1 8 - 2 4.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 3
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
[ 2 4]
D u dle y  M E, W u n derlic h 
J R, Ya n g J C, S herr y  RM, T o palia n S L , Restif o 
N P, et al. A d o pti ve cell tra nsfer t hera p y foll o wi n g n o n- m y el oa blati ve b ut 
l ym p h o de pleti n g c he m ot hera p y f or t he treat me nt of patie nts wit h refract or y 
metastatic mela n o ma. J Cli n O nc ol 2 0 0 5; 2 3( 1 0): 2 3 4 6- 5 7.
[ 2 5]
H u n der N N, Walle n H, Ca o J, He n dric ks D W, Reill y  JZ, R o d m y re R, et al. 
Treat me nt of metastatic mela n o ma wit h a ut ol o g o us C D 4 + T cells a gai nst 
N Y -E S O -1. N E n gl J Me d 2 0 0 8; 3 5 8( 2 5): 2 6 9 8 -7 0 3.
[ 2 6]
O kaza ki 
T, 
Mae da 
A, 
Nis hi m ura 
H, 
K ur osa ki 
T, 
H o nj o T. 
P D - 1 
i m m u n orece pt or i n hi bits B cell rece pt or-me diate d si g nali n g b y  recr uiti n g 
src 
h o m ol o g y   
2-d o mai n -c o ntai ni n g 
t yr osi ne 
p h os p hatase  
2  
t o 
p h os p h ot y r osi ne. Pr oc Natl Aca d Sci U S A 2 0 0 1; 9 8( 2 4): 1 3 8 6 6- 7 1.
[ 2 7]
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.
[ 2 8]
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 0, 3 1- A U G - 2 0 1 5.
[ 2 9]
Gar o n E B, Riz vi N A, H ui R, Lei g hl N, Bal ma n o u kia n A S, E der J P, et al. 
Pe m br oliz u ma b f or t he treat me nt of n o n- s mall-cell l u n g ca ncer. N E n gl J 
Me d. 2 0 1 5 Ma y  2 1; 3 7 2( 2 1): 2 0 1 8- 2 8.
[ 3 0]
Peters S, A djei A A, Gri delli C, Rec k M, Kerr K, Feli p E, et al. Metastatic 
n o n- s mall-cell l u n g ca ncer ( N S C LC): E S M 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 nals O nc ol 2 0 1 2; 2 3( S u p ple me nt 
7): vii 5 6 -vii 6 4.
[ 3 1]
Sc hiller J H, Harri n gt o n D, Bela ni C P, La n ger C, Sa n dler A, Kr o o k J, et al. 
C o m paris o n of f o ur c he m ot hera p y re gi me ns f or a d va nce d n o n- s mall-cell 
l u n g ca ncer. N E n gl J Me d 2 0 0 2; 3 4 6: 9 2-8.
[ 3 2]
Ar dizz o ni A, B o ni L , Tise o M, F ossella F V, Sc hiller J H, Paes ma ns M, et al. 
Cis plati n - vers us car b o plati n -base d c he m ot hera p y i n first-li ne treat me nt of 
a d va nce d n o n- s mall-cell l u n g ca ncer: a n i n di vi d ual patie nt data meta -
a nal ys is. J Natl Ca ncer I nst. 2 0 0 7 J u n 6; 9 9( 1 1): 8 4 7- 5 7.
[ 3 3]
S oci ns ki M A, B o n dare n k o I, Karase va N A, Ma k hs o n A M, V y n n y c he n k o I, 
O ka m ot o I, et al. Wee kl y  na b -Paclita xel i n C o m bi nati o n Wit h Car b o plati n 
Vers us S ol ve nt -Base d Paclita xel Pl us Car b o plati n as First -Li ne T hera p y i n 
Patie nts Wit h A d va nce d N o n -S mall -Cell L u n g Ca ncer: Fi nal Res ults of a 
P hase III Trial. J Cli n O nc ol 2 0 1 2; 3 0: 2 0 5 5- 6 2.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 4
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
[ 3 4]
Ya n g JJ, H ua n g C, C he n G Y, S o n g Y, C he n g Y, Ya n H H, et al. A 
ra n d o mize d p hase II cli nical trial of na b -paclita xel a n d car b o plati n 
c o m pare d wit h ge mcita bi ne a n d car b o plati n as first-li ne t hera p y in l ocall y 
a d va nce d or metastatic s q ua m o us cell carci n o ma of l u n g. B M C Ca ncer. 
2 0 1 4 Se p 2 0; 1 4: 6 8 4.
[ 3 5]
T hatc her N, Hirsc h F R, L uft A V, Szczes na A, Ci ulea n u T E, De di u M, et al. 
Necit u m u ma b 
pl us ge mcita bi ne a n d cis plati n v ers us ge mcita bi ne a n d 
cis plati n al o ne as first-li ne t hera py i n patie nts wit h sta ge I V s q ua m o us n o n -
s mall-cell l u n g ca ncer ( S Q UIR E): a n o pe n -la bel, ra n d o mise d, c o ntr olle d 
p hase 3 trial. La ncet O nc ol. 2 0 1 5 J ul; 1 6( 7): 7 6 3 - 7 4.
[ 3 6]
T orre L A, Bra y F, Sie gel R L , Ferla y  J, L o rtet-Tie ule nt J, Je mal A. Gl o bal 
ca ncer statistics, 2 0 1 2. C A Ca ncer J Cli n. 2 0 1 5 Mar; 6 5( 2): 8 7- 1 0 8.
[ 3 7]
G ol dstra w P, Cr o wle y  J, C ha ns k y  K, Gir o u x DJ , Gr o o me P A, Ra mi -P orta 
R, 
et al. I nter nati o nal Ass ociati o n 
f or t he St u d y  of L u n g 
Ca ncer 
I nternati o nal Sta gi n g C o m mittee; Partici pati n g I nstit uti o ns. T he I A SL C 
L u n g Ca ncer Sta gi n g Pr oject: pr o p osals f or t he re visi o n of t he T N M sta ge 
gr o u pi n gs i n  the f ort hc o mi n g (se ve nt h) e diti o n of t he T N M Classificati o n 
of mali g na nt t u m o urs. J T h orac O nc ol. 2 0 0 7 A u g; 2( 8): 7 0 6 -1 4. Errat u m i n: J 
T h orac O nc ol. 2 0 0 7 Oct; 2( 1 0): 9 8 5.
[ 3 8]
Nis hi n o M, Gi o b bie -H ur der A, Gar ga n o M, S u da M, Ra mai y a N H, H o di 
F S. De vel o pi n g a c o m m o n la n g ua ge f or t u m or res p o nse t o i m m u n ot hera p y: 
i m m u ne-relate d res p o nse criteria usi n g u ni di me nsi o nal meas ure me nts. Cli n 
Ca ncer Res. 2 0 1 3 J ul 1 5; 1 9( 1 4): 3 9 3 6- 4 3.
[ 3 9]
Ber g ma n B, Aar o ns o n N K, A h me dzai S, Kaasa S, S ulli va n M. T he E O R T C 
Q L Q -L C 1 3: a m o d ular s u p ple me nt t o t he E O R T C c ore q ualit y  of life 
q uesti o n naire ( Q L Q-C 3 0) f or use i n l u n g ca nc er cli nical trials. E ur J Ca ncer 
1 9 9 4; 3 0 A( 5): 6 3 5 - 4 2.
[ 4 0]
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.
[ 4 1]
S mit h TJ , K hatc heressia n J, L y ma n G H, Ozer H, Ar mita ge J O, Bal d ucci L, 
et al. 2 0 0 6 u p date of rec o m me n dati o ns f or t he use of w hite bl o o d cell 
gr o wt h fact ors: a n e vi de nce-base d cli nical practice g ui deli ne. J Cli n O nc ol 
2 0 0 6; 2 4( 1 9): 3 1 8 7 - 2 0 5.
[ 4 2]
Ma urer 
W, 
Bretz F. M ulti ple 
testi n g i n gr o u p se q ue ntial trials usi n g 
gra p hical a p pr oac hes. Stat Bi o p har m Res 2 0 1 3; 5( 4): 3 1 1 - 2 0.
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 5
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1 2. 0
A P P E N DI C E S
Merc k C o de of C o n d uct f or Cli nic al Tri als
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 h est et hical a n d scie ntific sta n dar ds. Pr otecti o n of s u bject safet y is t he o verri di n g c o ncer n i n 
t he desi g n of cli nical trials. I n all cases, Merc k cli nical trials will be c o n d ucte d i n c o m plia nce wit h l ocal a n d/ or 
nati o nal re g 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 not u n der t he c o ntr ol of Merc k.
II. Scie ntific Iss ues
A. Tri al C o n d uct
1. Tri al Desi g n
E xce pt f or pil ot or esti mati o n trials, cli nical trial pr ot oc ols will be h y p ot hesis -dri ve n t o assess safet y, efficac y 
a n d/ or p har mac o ki netic or p har mac o d y na mic i n dices of Merc k or c o m parat or pr o d ucts.  Alter nati vel y, Merc k ma y 
c o n d uct o utc o mes researc h trials, trials t o assess or vali date vari o us e n d p oi nt meas ures, or trials t o deter mi ne 
s u bject prefere nces, etc.  
T he desi g n (i.e., s u bject p o p ulati o n, d urati o n, statistical p o wer) m ust be a de q uate t o a d dress t he s pecific p ur p ose 
of t he trial.  Researc h s u bjects m ust meet pr ot oc ol e ntr y criteria t o be e nr olle d i n t he trial. 
2. Site Selecti o n
Merc k selects i n vesti gati ve sites base d o n me dical e x pertise, access t o a p pr o priate s u bjects, a de q uac y of facilities 
a n d staff, pre vi o us perf or ma nce i n Merc k trials, as well as b u d getar y c o nsi derati o ns.  Prior t o trial i nitiati o n, sites 
are e val uate d b y Merc k pers o n nel t o assess t he a bilit y t o s uccessf ull y c o n d uct t he trial.
3. Site M o nit ori n g/ Scie ntific I nte grit y
Trial sites are m o nit ore d t o assess c o m plia nce wit h 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 co nsiste nc y. Data are verifie d vers us s o urce 
d oc u me ntati o n acc or di n g t o sta n dar d o perati n g pr oce d ures.  Per  Merc k p olicies a n d 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.  So me earl y p hase or 
pil ot trials are i nte n de d t o be h y p ot hesis - ge nerati n g rat her t ha n h y p ot hesis testi n g.  In s uc h cases, p u blicati o n of  
res ults ma y n ot be a p pr o priate si nce t he trial ma y be u n der p o were d a n d t he a nal yses c o m plicate d b y statistical iss ues 
of m ulti plicit y.
Merc k’s 
p olic y o n a ut h ors hi p is c o nsiste nt wit h t he re q uire me nts o utli ne d i n t he I C H-G o o d Cli nical Practice 
g ui deli nes. I n s u m mar y, a ut h ors hi p s h o ul d reflect si g nifica nt c o ntri b uti o n t o t he desi g n a n d c o n d uct of t he trial, 
perf or ma nce or i nter pretati o n of t he a nal ysis, a n d/ or writi n g of t he ma n uscri pt.  All na me d a ut h ors m ust be a ble t o 
defe n d t he trial res ults a n d c o ncl usi o ns.  Merc k f u n di n g of a trial will be ac k n o wle d ge d i n p u blicati o ns. 
 
 
0 5 C 6 H 2

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

Pr o d uct:  M K -3 4 7 5 
1 1 7
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
C ollecti o n a n d M a n a ge me nt of S peci me ns f or F ut ure Bi o me dic al Rese arc h
1.
D efi niti o ns
a.
Bi o mar ker:  A bi ol o gical m olec ule f o u n d i n bl o o d, ot her b o d y  fl ui ds, or tiss ues t hat is a 
si g n of a n or mal or a b n or mal pr ocess or of a c o n diti o n or disease.  A bi o mar ker m a y  be 
use d t o se e h o w well t he b o d y res p o n ds t o a treat me nt f or a disease or c o n diti o n.1
b.
P har mac o ge n o mics:  The i n vesti gati o n of variati o ns of D N A a n d R N A c haracteristics as 
relate d t o dr u g/ vacci ne res p o nse.2
c.
P har mac o ge netics:  A s u bset of p har mac o ge n o mics, p har mac o ge netics is t he i nfl ue nce of 
variati o ns i n D N A se q ue nce o n dr u g / vacci ne res p o nse.2
d.
D N A:  De o x yri b o n ucleic aci d.
e.
R N A:  Ri b o n ucleic aci d.
2.
Sc o pe of F ut ure Bi o me dic al Rese arc h
T he s peci me ns c ollecte d i n t his trial as o utli ne d i n Secti o n 7. 1. 3. 6 – F ut ure Bi o me dical 
Researc h Sa m ple C ollecti o n will be use d t o st u d y vari o us ca uses f or h o w s u bjects ma y  
res p o n d t o a dr u g / vacci ne.  Fut ure bi o me dical researc h s peci me n(s) will be st ore d t o 
pr o vi de a res o urce f or f ut ure trials c o n d ucte d b y  t he S p o ns or f oc use d o n t he st u d y of 
bi o mar kers res p o nsi ble f or h o w a dr u g/ vacci ne e nters a n d is re m o ve d b y  t h e b o d y, h o w a 
dr u g / vacci ne w or ks, ot her pat h wa y s a dr u g / vacci ne ma y  interact wit h , or ot her as pects of 
disease. T he s peci me n(s) ma y  be use d f or f ut ure assa y de ve l o p me nt a n d/ or dr u g/ vacci ne 
de vel o p me nt.
It is n o w well rec o g nize d t hat i nf or mati o n o btai ne d fr o m st u d yi n g a n d testi n g cli nical 
s peci me ns offers u ni q ue o p p ort u nities t o e n ha nce o ur u n dersta n di n g of h o w i n di vi d uals 
res p o n d t o dr u gs / vacci nes, e n ha nce o ur u n d ersta n di n g of h u ma n disease a n d ulti matel y 
i m pr o ve p u blic healt h t hr o u g h de vel o p me nt of n o vel treat me nts tar gete d t o p o p ulati o ns 
wit h t he greatest nee d.  All s peci me ns will be use d b y  t he S p o ns or or t h ose w or ki n g f or 
or wit h t he S p o ns or.
3.
S u m m ar y of Pr oce d ures f or F ut ure Bi o me dic al Rese arc h
a.
S u bjects f or E nr oll me nt
All s u bjects e nr olle d i n t he cli nical trial will be c o nsi dere d f or e nr oll me nt i n t he 
F ut ure Bi o me dical Researc h s u b -trial.
b.
I nf or me d C o nse nt
I nf or me d c o nse nt f or s peci me ns (i.e., D N A, R N A, pr otei n, etc.) will be o btai ne d 
d uri n g scree ni n g f or pr ot oc ol e nr oll me nt fr o m all s u bjects or le gal g uar dia ns, at a trial 
visit b y  the i n vesti gat or or his or her desi g nate.  Inf or me d c o nse nt f or F ut ure 
Bi o me d ical Researc h s h o ul d be prese nte d t o t he s u bjects o n Visit 1.  If dela y e d, 
prese nt c o nse nt at ne xt p ossi ble S u bject Visit. I nf or me d c o nse nt m ust be o btai ne d 
pri or t o c ollecti o n of all F ut ure Bi o me dical Researc h s peci me ns.   C o nse nt f or ms 
si g ne d b y  the s u bject will be ke pt at t he cli nical trial site u n der sec ure st ora ge f or 
re g ulat or y reas o ns.  
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 8
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A te m plate of eac h trial site’s a p pr o ve d i nf or me d c o nse nt will be st ore d i n t he 
S p o ns or’s cli nical d oc u me nt re p osit or y. Eac h c o nse nt will be assesse d f or a p pr o priate 
s peci me n per missi o ns.  
c.
e C R F D oc u me ntati o n f or F ut ure Bi o me dical Researc h S peci me ns
D oc u me ntati o n of s u bject c o nse nt f or F ut ure Bi o me dical Researc h will be ca pt ure d i n 
t he electr o nic Case Re p ort F or ms (e C R Fs). A n y  speci me ns f or w hic h s uc h a n 
i nf or me d c onse nt ca n n ot be verifie d will be destr o y e d.
d.
F ut ure Bi o me dical Researc h S peci me n C ollecti o ns
C oll ecti o n of s peci me ns f or F ut ure B i o me dical Researc h will be perf or me d as 
o utli ne d i n t he trial fl o w c hart. I n ge neral, if a d diti o nal bl o o d s peci me ns are bei n g
c ollecte d f or F ut ure Bi o me dical Researc h, t hese will us uall y  be o btai ne d at a ti me 
w he n t he s u bject is ha vi n g bl o o d dra w n f or ot her trial p ur p oses.
4.
C o nfi de nti al S u bject I nf or m ati o n f or F ut ure Bi o me dic al Rese arc h 
I n or der t o o pti mize t he researc h t hat ca n be c o n d ucte d wit h F ut ure Bi o me dical Researc h 
s peci me ns, it is critical t o li n k s u bject' cli nical i nf or mati o n wit h f ut ure test res ults. I n fact 
little or n o researc h ca n be c o n d ucte d wit h o ut c o n necti n g t he cli nical trial data t o t he 
s peci me n. T he cli nical data all o w s pecific a nal yses t o be c o n d ucte d. K n o wi n g s u bject 
c haracteristics li ke ge n der, a ge, me dical hist or y  an d treat me nt o utc o mes are critical t o 
u n dersta n di n g cli nical c o nte xt of a nal y tical res ults.
T o mai ntai n 
pri vac y  of i nf or mati o n c ollecte d fr om 
s peci me ns o btai ne d f or F ut ure 
Bi o me dical Researc h, t he S p o ns or has de vel o pe d sec ure p olicies a n d pr oce d ures. All 
s peci me ns will be si n gle-c o de d per I CH E 1 5 g ui deli nes as descri be d bel o w . 
At t he cli nical trial site, u ni q ue c o des will be place d o n t he F ut ure Bi o me dical Researc h 
s peci me ns f or tra nsfer t o t he st ora ge facilit y.  This first c o de is a ra n d o m n u m ber w hic h 
d oes n ot c o ntai n a n y pers o nall y  ide ntif y i n g i nf or mati o n e m be d de d wit hi n it. T he li n k ( or 
ke y ) bet wee n s u bject i de ntifiers a n d t his first u ni q ue c o de will be hel d at t he trial site.  N o 
pers o nal i de ntifiers will a p pear o n t he s peci me n t u be.  
5.
Bi ore p osit or y S peci me n Us a ge
S peci me ns o btai ne d f or t he Merc k Bi ore p osit or y will be use d f or a nal ys es usi n g g o o d 
scie ntific practices.  A nal y ses utilizi n g t he F ut ure Bi o me dical Researc h s peci me ns m a y  
be perf or me d b y  t he S p o ns or , or a n a d diti o nal t hir d part y (e. g., a u ni versit y  in vesti gat or) 
desi g nate d b y  t he S p o ns or . T he i n vesti gat or c o n d ucti n g t he a nal ysis will f oll o w t he 
S p o ns or’s pri vac y  an d c o nfi de ntia lit y re q uire me nts. A n y  co ntracte d t hir d part y  an al y ses 
will c o nf or m t o t he s pecific sc o pe of a nal ys is o utli ne d i n t his s u b-trial. F ut ure Bi o me dical 
Researc h s peci me ns re mai ni n g wit h t he t hir d part y  after s pecific a nal ysis is perf or me d 
will be re p orte d t o the S p o ns or .
6. 
Wit h dr a w al Fr o m F ut ure Bi o me dic al Rese arc h 
S u bjects ma y  wit h dra w t heir c o nse nt f or F ut ure Bi o me dical Researc h a n d ha ve t heir 
s peci me ns a n d all deri vati ves destr o ye d.   Su bjects m a y  wit h dra w c o nse nt at a n y ti me b y  
c o ntacti n g t he pri nci pal i nvesti gat or f or t he mai n trial. If me dical rec or ds f or t he mai n 
trial are still a vaila ble, t he i n vesti gat or will c o ntact t he S p o ns or usi n g t he desi g nate d 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 1 9
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
mail b o x (cli nical.s peci me n. ma na ge me nt @ merc k.c o m) a n d a f or m will be pr o vi de d t o 
o btai n a p pr o priate i nf or mati o n t o c o m plete s peci me n wit h dra wal.
S u bse q ue ntl y , t he 
s u bject's s peci me ns will 
be re m o ve d fr o m t he bi ore p osit or y  an d be destr o ye d . 
D oc u me ntati o n
will be se nt t o t he i n vesti gat or c o nfir mi n g t he destr ucti o n. It is t he 
res p o nsi bilit y of t he i n vesti gat or t o i nf or m t he s u bject of c o m pleti o n of destr ucti o n.  An y  
a nal ys es i n pr o gress at t he ti me of re q uest f or destr ucti o n or alrea d y perf or me d pri or t o 
t he re q uest bei n g recei ve d b y  the S p o ns or will c o nti n ue t o be use d as part of t he o verall 
researc h trial data a n d res ults. N o ne w a nal yses w o ul d be ge nerate d after t he re q uest is 
recei ve d.
I n t he e ve nt t hat t he me dical rec or ds f or t he mai n trial are n o l o n ger a vaila ble (e. g., if t he 
i n vesti gat or is n o l o n ger re q uire d b y  re g ulat or y aut h orities t o retai n t he mai n trial 
rec or ds) or t he s peci me ns ha ve bee n c o m pletel y a n o n ymize d, t here will n o l o n ger be a 
li n k bet wee n t he s u bject’s pers o nal i nf or mati o n a n d t heir s peci me ns. I n t his sit uati o n, t he 
re q uest f or s peci me n destr ucti o n ca n n ot be pr ocesse d. 
7.
Rete nti o n of S p eci me ns 
F ut ure Bi o me dical Researc h s peci me ns will be st ore d i n t he bi ore p osit or y  for p ote ntial 
a nal ys is f or u p t o 2 0 ye ars fr o m t he e n d of t he mai n st u d y. S peci me ns ma y be st ore d f or 
l o n ger if a re g ulat or y or g o ver n me ntal a ut h orit y has acti ve q ue sti o ns t hat are bei n g  
a ns were d. I n t his s pecial circ u msta nce, s peci me ns will be st ore d u ntil t hese q uesti o ns 
ha ve bee n a de q uatel y a d dresse d.
S peci me ns fr o m t he trial site will be s hi p pe d t o a ce ntral la b orat or y an d t he n s hi p pe d t o 
t he S p o ns or -desi g nate d bi ore p osit or y . If a ce ntral la b orat or y is n ot utilize d i n a partic ular 
trial, t he trial site will s hi p directl y  to t he S p o ns or -desi g nate d bi ore p osit or y . T he 
s peci me ns will be st ore d u n der strict s u per visi o n i n a li mite d access facilit y whic h 
o pe rates t o ass ure t he i nte grit y of the s peci me ns.  Speci me ns will be destr o y e d acc or di n g 
t o S p o ns or p olicies a n d pr oce d ures a n d t his destr ucti o n will be d oc u me nte d i n t he 
bi ore p osit or y  data base.
8.
D at a Sec urit y
Data bases c o ntai ni n g s peci me n i nf or mati o n a n d test res ults are accessi ble o nl y  to t he 
a ut h orize d S p o ns or re prese ntati ves a n d t he desi g nate d trial a d mi nistrat or researc h 
pers o n nel a n d/ or c olla b orat ors . Data base user a ut he nticati o n is hi g hl y sec ure, a n d is 
acc o m plis he d usi n g net w or k sec urity p olicies a nd practices base d o n i nter nati o nal 
sta n dar ds (e. g., I SO 1 7 7 9 9) t o pr otect a gai nst u na ut h orize d access.
9.
Re p orti n g of F ut ure Bi o me dic al Rese arc h D at a t o S u bjects
N o i nf or mati o n o btai ne d fr o m e x pl orat or y la b orat or y st u dies will be re p orte d t o t he 
s u bject, fa mil y, or p h y sicia ns. Pri nci ple reas o ns n ot t o i nf or m or ret ur n res ults t o t he 
s u bject i ncl u de: Lac k of rele va nce t o s u bject healt h, li mitati o ns of pre dicti ve ca pa bilit y, 
a n d c o ncer ns re gar di n g misi nter pretati o n.
If a ny e x pl orat or y res ults are defi niti vel y ass ociate d wit h cli nical si g nifica nce f or s u bjects 
w hile t he cli nical trial is still o n g oi n g, i n vesti gat ors will be c o ntacte d wit h i nf or mati o n. 
After t he cli nical trial has c o m plete d, if a n y  e x pl orat or y res ults are defi niti vel y ass ociate d 
wit h cli nical sig nifica nce, t he S p o ns or will e n dea v or t o ma ke s uc h res ults a vaila ble 
 
 
0 5 C 6 H 2

Pr o d uct:  M K -3 4 7 5 
1 2 0
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
t hr o u g h a p pr o priate mec ha nis ms 
(e. g., scie ntific p u blicati o ns a n d/ or prese ntati o ns). 
S u bjects will n ot be i de ntifie d b y  na me i n a n y p u blis he d re p orts a b o ut t his st u d y or i n a n y 
ot her scie ntific p u blicati o n or prese ntati o n.
1 0. F ut ure Bi o me dic al Rese arc h St u d y P o p ul ati o n
E ver y  eff ort will be ma de t o recr uit all s u bjects dia g n ose d a n d treate d o n S p o ns or cli nical 
trials f or F ut ure Bi o me dical Researc h.
1 1. Ris ks Vers us Be nefits of F ut ure Bi o me dic al Rese arc h 
F or f ut ure bi o me dical researc h, ris ks t o t he s u bject ha ve bee n mi ni mize d. N o a d diti o nal 
ris ks t o t he s u bject ha ve bee n i de ntifie d as n o a d diti o nal s peci me ns are bei n g c ollecte d 
f or F ut ure Bi o me dical Researc h (i.e., o nl y left o ver sa m ples are bei n g retai ne d). 
T he S p o ns or has de vel o pe d strict sec urit y, p olicies a n d pr oce d ures t o a d dress s u bject data 
pri vac y  co ncer ns.  Data pri vac y  ris ks are lar gel y li mite d t o rare sit uati o ns i n v ol vi n g 
p ossi ble breac h of c o nfi de ntialit y.  In t his hi g hl y u nli kel y  sit uati o n t here is ris k t hat t he 
i nf or mati o n, li ke all me dical i nf or mati o n, ma y be mis use d.
1 2. Q uesti o ns
A n y  questi o ns relate d t o t he f ut ure bi o me dical researc h s h o ul d be e-maile d directl y t o 
cli nical.s peci me n. ma na ge me nt @ merc k.c o m.
1 3. Refere nces
1.
Nati o nal Ca ncer I nstit ute: htt p:// w w w.ca ncer. g o v/ dicti o nar y /?searc h T xt = bi o mar ker
2.
I nter nati o nal C o nfere nce 
o n Har m o nizati o n: 
D E FI N I TI ON S 
F O R G E N O MI C 
BI O M A R K E R S, P H A R M A C O G E N O MI C S, P H A R M A C O G E N E TI C S, G E N O MI C 
D A T A  
A N D  
S A M P L E 
C O DI N G  
C A T E G O RI E S  
- 
E 1 5; 
htt p:// w w w.ic h. or g/ L O B/ me dia/ M E DI A 3 3 8 3. p df
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 2 1
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
U n derst a n di n g t he I nte nt, Sc o pe a n d P u blic He alt h Be nefits of E x pl or at or y Bi o m ar ker Rese arc h: A G ui de 
f or 
I R Bs/I E Cs a n d I n vesti g ati o n al Site St aff
 
 
0 5 C 6 H 2

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

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

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

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

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

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

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

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

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

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

Pr o d uct:   M K -3 4 7 5 
1 3 2
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
List of A b bre vi ati o ns
A b bre viati o n/ Ter m
Defi niti o n
1 L
First Li ne
A E
A d verse e ve nt
A D A
A nti -Dr u g A nti b o dies
A L T
Ala ni ne a mi n otra nsferase
A L K
a na plastic l y m p h o ma ki nase
A N C
A bs ol ute ne utr o p hil c o u nt
a P T T
Acti vate d partial t hr o m b o plasti n ti me
A U C
Area U n der C ur ve
A S T
As partate a mi n otra nsferase
β -H C G
Beta h u ma n c h ori o nic g o na d otr o pi n
B S C
best s u p p orti ve care
C B C
C o m plete bl o o d c o u nt
CI
c o nfi de nce i nter val
C N S
Ce ntral ner v o us s yste m
C R
C o m plete res p o nse
Cr Cl
Calc ulate d creati ni ne cleara nce
C R F
Case re p ort f or m
C S R
Cli nical st u d y re p ort
C T
C o m p ute d t o m o gra p h y
C T C A E
C o m m o n T o xicit y Criteria f or A d verse E ve nts
D L T
D ose Li miti n g T o xicit y
D N A
De o x yri b o n ucleic aci d
D M C
Data M o nit ori n g C o m mittee D M C
D O R
D urati o n of res p o nse
E CI
E ve nts of cli nical i nterest
E C G
Electr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
E 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 R C
Et hics re vie w c o m mittee
F B R
F ut ure Bi o me dical Researc h
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
G F R
Gl o m er ular filtrati o n rate
H b
He m o gl o bi n
H B V
He patitis B
H C V
He patitis C
HI V
H u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s br oc h ure
I C F
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
I H C
I m m u n o hist oc he mistr y
ir R C
i m m u ne-relate d res p o nse criteria
I N R
I nter nati o nal n or malize d rati o
ir A Es
I m m u ne-relate d a d verse e ve nts
I R B
I nstit uti o nal Re vie w B oar d
I T T
i nte nt-t o-treat 
I V
I ntra ve n o us
K g
Kil o gra m
L D H
lactate de h y dr o ge nase
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 3 3
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A b bre viati o n/ Ter m
Defi niti o n
mc L
Milli meters
M E L
Mela n o ma 
M G
Milli gra m
M g/ k g
Milli gra m per kil o gra m
M M
M ulti ple m yel o ma
M RI
Ma g netic res o na nce i ma gi n g
M S D
Merc k S har p & D o h me C or p., a s u bsi diar y of Merc k 
& C o., I nc.
M T D
Ma xi m u m t olerate d d ose
N A or N/ A 
N ot A p plica ble
N a b -paclita xel 
N a n o particle al b u mi n -b o u n d paclita xel 
N C C N
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
Nati o nal Ca ncer I nstit ute
N S C L C
n o n -s mall cell l u n g ca ncer ( N S C L C)
O R R
O verall 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 D
Pr o gressi ve disease
P E T
P ositr o n e missi o n t o m o gra p h y
P F S
Pr o gressi o n free s ur vi val
P F S 2
ne xt li ne of t hera p y P F S 2
P Gt
P har m ac o ge netic
P K
P har m ac o ki netic
P K -P D
P har m ac o ki netic -P har m ac o d y na mic
P R O
patie nt re p orte d o utc o me 
P R
Partial res p o nse
P T
Pr ot hr o m bi n ti me
R C C
re nal cell carci n o ma 
R N A
Ri b o n ucleic aci d
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors 
R E CI S T 1. 1
R R
Res p o nse rate
Q 3 W
E ver y 3 wee ks
S A E
Seri o us a d verse e ve nts
S A P
Statistical A nal ysis Pla n
S F U
S ur vi val f oll o w -u p
S G O T
Ser u m gl uta mic o xal oacetic tra nsa mi nase
S G P T
Ser u m gl uta mic p yr u vic tra nsa mi nase
S O C
Sta n dar d of Care
TI L
T u m or -i nfiltrati n g l y m p h oc ytes
T S H
T h yr oi d sti m ulati n g h or m o ne
T T P
Ti m e T o Pr o gressi o n
U L N
U p per li mit of n or mal
W H O
W orl d Healt h Or ga nizati o n
 
 
0 5 C 6 H 2

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

Pr o d uct:   M K -3 4 7 5 
1 3 5
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
E C O G Perf or m a nce St at us
Gra de
Descri pti o n
0
N or mal acti vit y. F ull y acti ve, a ble t o carr y o n all pre -disease 
perf or ma nce wit h o ut restricti o n.
1
S y m pt o ms, 
b ut a m b ulat or y. Restricte d 
i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble t o carr y out w or k of a li g ht or 
se de ntar y nat ure (e. g., li g ht h o use w or k, office w or k).
2
I n be d < 5 0 % of t he ti me. A m b ulat or y  an d ca pa ble of all self-care, 
b ut u na ble t o carr y out a n y wor k acti vities. U p a n d a b o ut m ore t ha n 
5 0 % of wa ki n g h o urs.
3
I n be d > 5 0 % of t he ti me. Ca pa ble of o nl y  li mite d self-care, c o nfi ne d 
t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs.
4
1 0 0 % be dri d de n. C o m pletel y  disa ble d. Ca n n ot carr y o n a n y self-
care. T otall y c o nfi ne d t o be d or c hair.
5 
Dea d.
* As p u blis he d i n A m. J. Cli n. O nc ol.:  Oke n, M. M., Creec h, R. H., T or mey, D. C., H ort o n, J., D avis, T. E., 
Mc F a d de n, 
E. T., C ar b o ne, P. P.: T oxicity A n d Res p o nse Criteri a Of T he E aster n C o o per ative 
O nc ol o gy Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2. T h e Easter n C o o perati ve O nc ol o g y Gr o u p, 
R o bert C o mis M. D., Gr o u p C hair.
 
 
0 5 C 6 H 2

Pr o d uct:   M K -3 4 7 5 
1 3 6
Pr ot oc ol/ A me n d me nt N o.: 4 0 7 -0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
1 3. 0 SI G N A T U R E S
S p o ns or's Re prese nt ati ve
T Y P E D N A M E
TI T L E
SI G N A T U R E
D A T E SI G N E D
I n vesti g at or
I a gree t o c o n d uct t his cli nical trial i n acc or da nce wit h t he desi g n o utli ne d i n t his pr ot oc ol 
a n d t o a bi de b y  all pr o visi o ns of t his pr ot oc ol (i ncl u di n g ot her ma n uals a n d d oc u me nts 
refere nce d fr o m t his pr ot oc ol).  I agree t o c o n d uct t he trial i n acc or da nce wit h ge nerall y 
acce pte d sta n dar ds of G o o d Cli nical Practice.  I als o a gree t o re p ort all i nf or mati o n or data i n 
acc or da nce wit h t he pr ot oc ol a n d, i n partic ular, I a gree t o re p ort a n y seri o us a d verse e ve nts 
as defi ne d i n Secti o n 7 . 0 – T RI A L P R O C E D U R E S (Assessi n g a n d Rec or di n g A d verse 
E ve nts ).  I als o a gree t o ha n dle all cli nical s u p plies pr o vi de d b y  the S p o ns or a n d c ollect a n d 
ha n dle all cli nical s peci me ns i n acc or da nce wit h t he pr ot oc ol.  I un dersta n d t hat i nf or mati o n 
t hat i de ntifies me will be use d a n d discl ose d as descri be d i n t he pr ot oc ol, a n d t hat s uc h 
i nf or mati o n m a y  be tra nsferre d t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g s u c h 
i nf or mati o n.  Si nce t he i nf or mati o n i n t his pr ot oc ol a n d t he refere nce d I n vesti gat or’s 
Br oc h ure is c o nfi de ntial, I u n dersta n d t hat its discl os ure t o a n y t hir d parties, ot her t ha n t h ose 
i n v ol ve d i n a p pr o val, s u per visi o n, or c o n d uct of t he trial is pr o hi b ite d.  I will e ns ure t hat t he 
necessar y  preca uti o ns are ta ke n t o pr otect s uc h i nf or mati o n fr o m l oss, i na d verte nt discl os ure 
or access b y t hir d parties.
T Y P E D N A M E
TI T L E
SI G N A T U R E
D A T E SI G N E D
 
 
0 5 C 6 H 2