A Randomized Open-Label Phase III Study of Single Agent Pembrolizumab Versus Single Agent Chemotherapy Per Physician's Choice for Metastatic Triple Negative Breast Cancer (mTNBC) - (KEYNOTE-119)
Phase: PHASE3
Conditions: Metastatic Triple Negative Breast Cancer
Sponsor: Merck Sharp & Dohme LLC

Offici al Pr ot oc ol Title:  
N C T n u m ber:  
N C T 0 2 5 5 5 6 5 7
1 9- Fe b- 2 0 1 8
D oc u me nt D ate:  
A Ra n d o mize d O pe n- La bel P hase III St u d y of Si n gle A ge nt 
Pe m br oliz u ma b vers us Si n gle A ge nt C he m ot hera p y per 
P h ysicia n’s C h oice f or Metastatic Tri ple Ne gati ve Breast Ca ncer 
( m T N B C) – ( K E Y N O T E- 1 1 9)

Pr o d uct:   M K - 3 4 7 5 
1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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.
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, NJ 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 nvesti gat or Trial File
Bi n der ( or e q ui vale nt).
TI T L E:
A Ra n d o mize d O pe n -La bel P hase III St u d y  of Si n gle A ge nt Pe m br oliz u ma b vers us Si n gle 
A ge nt C he m ot hera p y per P h y sicia n’s C h oice f or Metastatic Tri ple Ne gati ve Breast Ca ncer 
( m T N B C) – ( K E Y N O T E-1 1 9) 
I N D N U M B E R:  1 2 4, 4 4 2
E u dr a C T N U M B E R:   2 0 1 5- 0 0 1 0 2 0- 2 7
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
T A B L E O F C O N T E N T S
S U M M A R Y O F C H A N G E S ................................................................................................ 1 1
1. 0
T RI A L S U M M A R Y .................................................................................................. 1 6
2. 0
T RI A L D E SI G N ........................................................................................................ 1 7
Tri al Desi g n ........................................................................................................... 1 7
2. 1
Tri al Di a gr a m ........................................................................................................ 1 9
2. 2
3. 0
O B J E C TI V E( S) & H Y P O T H E SI S( E S) .................................................................. 2 0
Pri m ar y O bjecti ve(s) & H y p ot hesis(es) .............................................................. 2 0
3. 1
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es) ........................................................... 2 0
3. 2
E x pl or at or y O bjecti ves ......................................................................................... 2 1
3. 3
4. 0
B A C K G R O U N D & R A TI O N A L E .......................................................................... 2 2
B ac k gr o u n d ........................................................................................................... 2 2
4. 1
P har mace utical a n d T hera pe utic Bac k gr o u n d .................................................... 2 2
4. 1. 1
I m m u n ot hera py:  Precli nical St u dies................................................................... 2 3
4. 1. 2
Pe m br oliz u ma b: O n g oi n g Cli nical Trials i n Ot her T u m or T y pes ...................... 2 3
4. 1. 3
I nf or mati o n o n Disease t o be Treate d – m T N B C ............................................... 2 3
4. 1. 4
Pr o of -of -Pri nci ple St u d y  f or Pe m br oliz u ma b use i n m T N B C............................ 2 5
4. 1. 5
R ati o n ale ................................................................................................................ 2 6
4. 2
Rati o nale f or t he Trial a n d Selecte d S u bject P o p ulati o n .................................... 2 6
4. 2. 1
Rati o nale f or D ose Selecti o n/ Re gi me n/ M o dificati o n ......................................... 3 0
4. 2. 2
Rati o nale f or E n d p oi nts ...................................................................................... 3 1
4. 2. 3
4. 2. 3. 1
Efficac y  E n d p oi nts....................................................................................... 3 1
4. 2. 3. 2
Selecti o n of Patie nt Re p orte d O utc o mes I nstr u me nts ................................. 3 1
4. 2. 3. 3
Safet y  E n d p oi nts.......................................................................................... 3 2
4. 2. 3. 4
Pla n ne d E x pl orat or y  Bi o mar ker Researc h................................................... 3 2
4. 2. 3. 5
F ut ure Bi o me dical Researc h ........................................................................ 3 4
Be nefit/ Ris k ........................................................................................................... 3 4
4. 3
5. 0
M E T H O D O L O G Y
................................................................................................... 3 5
E ntr y Criteri a ........................................................................................................ 3 5
5. 1
Dia g n osis/ C o n diti o n f or E ntr y  i nt o t he Trial ...................................................... 3 5
5. 1. 1
S u bject I ncl usi o n Criteria .................................................................................... 3 5
5. 1. 2
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u bject E xcl usi o n Criteria .................................................................................. 3 7
5. 1. 3
Tri al Tre at me nt(s) ................................................................................................ 3 9
5. 2
D ose Selecti o n/ M o dificati o n .............................................................................. 3 9
5. 2. 1
5. 2. 1. 1
D ose Selecti o n ( Pre parati o n) ....................................................................... 3 9
5. 2. 1. 2
D ose M o dificati o n (I nterr u pti o n/ Escalati o n/ Titrati o n/ Ot her) ...................... 4 0
5. 2. 1. 2. 1
Pe m br oliz u ma b D ose M o dificati o ns .................................................... 4 0
5. 2. 1. 2. 2
Ca pecita bi ne .......................................................................................... 4 6
5. 2. 1. 2. 3
Eri b uli n ................................................................................................. 4 6
5. 2. 1. 2. 4
Ge mcita bi ne .......................................................................................... 4 6
5. 2. 1. 2. 5
Vi n orel bi ne ........................................................................................... 4 6
Ti mi n g of D ose A d m i nistrati o n.......................................................................... 4 6
5. 2. 2
5. 2. 2. 1
Pe m br oliz u ma b ............................................................................................ 4 6
5. 2. 2. 2
Ca pecita bi ne ................................................................................................. 4 6
5. 2. 2. 3
Eri b uli n ........................................................................................................ 4 6
5. 2. 2. 4
Ge mcita bi ne ................................................................................................. 4 6
5. 2. 2. 5
Vi n orel bi ne .................................................................................................. 4 7
Trial Bli n di n g/ Mas ki n g ....................................................................................... 4 7
5. 2. 3
R a n d o miz ati o n or Tre at me nt All oc ati o n ............................................................ 4 7
5. 3
Str atific ati o n .......................................................................................................... 4 7
5. 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 7
5. 5
Acce pta ble C o nc o mita nt Me dicati o ns ................................................................ 4 8
5. 5. 1
Pr o hi bite d C o nc o mita nt Me dicati o ns .................................................................. 4 8
5. 5. 2
Resc ue Me dic ati o ns & S u p p orti ve C are ............................................................. 4 9
5. 6
S u p p orti ve Care G ui deli nes f or S u bjects i n Pe m br oliz u ma b Ar m ..................... 4 9
5. 6. 1
S u p p orti ve Care G ui deli nes f or I m m u ne -Relate d A d verse E ve nts .................... 4 9
5. 6. 2
S u p p orti ve Care G ui deli nes f or Ca pecita bi ne ..................................................... 4 9
5. 6. 3
S u p p orti ve Care G ui deli nes f or Eri b uli n ............................................................ 4 9
5. 6. 4
S u p p orti ve Care G ui deli ne f or Ge mcita bi ne ....................................................... 5 0
5. 6. 5
S u p p orti ve Care G ui deli nes f or Vi n orel bi ne ...................................................... 5 0
5. 6. 6
Diet/ Acti vit y/ Ot her C o nsi der ati o ns ..................................................................... 5 0
5. 7
Diet ...................................................................................................................... 5 0
5. 7. 1
C o ntrace pti o n ...................................................................................................... 5 0
5. 7. 2
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Pre g na nc y ............................................................................................................ 5 2
5. 7. 3
N ursi n g W o me n .................................................................................................. 5 2
5. 7. 4
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a ................................................... 5 2
5. 8
Treat me nt After First Ra di ol o gic E vi de nce of Disease Pr o gressi o n .................. 5 3
5. 8. 1
Disc o nti n uati o n of St u d y T hera p y After C o m plete Res p o nse ............................ 5 5
5. 8. 2
S u bject Re pl ace me nt Str ate g y ............................................................................. 5 6
5. 9
Be gi n ni n g a n d E n d of t he Tri al ........................................................................... 5 6
5. 1 0
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n ................................................... 5 6
5. 1 1
6. 0
T RI A L F L O W C H A R T ........................................................................................... 5 7
I niti al Tre at me nt P h ase ........................................................................................ 5 7
6. 1
Pe m br oliz u ma b Treat me nt Ar m .......................................................................... 5 7
6. 1. 1
Sta n dar d Treat me nt Ar m – Ge mcita bi ne or Eri b uli n .......................................... 6 1
6. 1. 2
Sta n dar d Treat me nt Ar m – Ca pecita bi ne ............................................................ 6 6
6. 1. 3
Sta n dar d Treat me nt Ar m – Vi n orel bi ne ............................................................. 7 1
6. 1. 4
Sec o n d C o urse P h ase ( Retre at me nt) f or Pe m br oliz u m a b Ar m O nl y .............. 7 6
6. 2
7. 0
T RI A L P R O C E D U R E S ........................................................................................... 7 9
Tri al Pr oce d ures ................................................................................................... 7 9
7. 1
A d mi nistrati ve Pr oce d ures .................................................................................. 7 9
7. 1. 1
7. 1. 1. 1
I nf or me d C o nse nt......................................................................................... 7 9
7. 1. 1. 2
Ge neral I nf or me d C o nse nt ........................................................................... 7 9
7. 1. 1. 2. 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 ................................................................................................ 8 0
7. 1. 1. 3
I ncl usi o n/ E xcl usi o n Criteria ........................................................................ 8 0
7. 1. 1. 4
S u bject I de ntificati o n Car d .......................................................................... 8 0
7. 1. 1. 5
Me dical Hist or y
........................................................................................... 8 0
7. 1. 1. 5. 1
Disease Details ...................................................................................... 8 0
7. 1. 1. 6
Pri or a n d C o nc o mita nt Me dicati o ns Re vie w ............................................... 8 0
7. 1. 1. 6. 1
Pri or Treat me nt Details f or Breast Ca ncer Dia g n osis .......................... 8 1
7. 1. 1. 6. 2
C o nc o mita nt Me dicati o ns ..................................................................... 8 1
7. 1. 1. 6. 3
S u bse q ue nt A nti -ca ncer T hera py Stat us ............................................... 8 1
7. 1. 1. 7
Assi g n me nt of Scree ni n g N u m ber ............................................................... 8 1
7. 1. 1. 8
Assi g n me nt of Ra n d o mizati o n N u m ber ....................................................... 8 1
7. 1. 1. 9
Trial C o m plia nce ( Me dicati o n/ Diet/ Acti vit y / Ot her) ................................... 8 2
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 1. 1 0 S ur vi val ........................................................................................................ 8 2
Cli nical Pr oce d ures/ Assess me nts ........................................................................ 8 2
7. 1. 2
7. 1. 2. 1
A d verse E ve nt M o nit ori n g ........................................................................... 8 2
7. 1. 2. 2
1 2 -Lea d Electr ocar di o gra m ......................................................................... 8 2
7. 1. 2. 3
P h y sical E xa m.............................................................................................. 8 3
7. 1. 2. 3. 1
F ull P h y sical E xa m ............................................................................... 8 3
7. 1. 2. 3. 2
Directe d P h ys ical E xa m........................................................................ 8 3
7. 1. 2. 4
Vital Si g ns.................................................................................................... 8 3
7. 1. 2. 5
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us......................... 8 3
7. 1. 2. 6
Me n o pa usal Stat us ....................................................................................... 8 3
7. 1. 2. 7
T u m or I ma gi n g a n d Assess me nt of Disease ................................................ 8 4
7. 1. 2. 7. 1
Baseli ne T u m or I ma gi n g ...................................................................... 8 8
7. 1. 2. 7. 2
T u m or I ma gi n g D uri n g t he Trial .......................................................... 8 8
7. 1. 2. 7. 3
E n d of Treat me nt a n d F oll o w -u p T u m or I ma gi n g ................................ 8 9
7. 1. 2. 7. 4
R E CI S T 1. 1 ........................................................................................... 8 9
7. 1. 2. 7. 5
ir R E CIS T .............................................................................................. 8 9
7. 1. 2. 8
T u m or Tiss ue C ollecti o n a n d C orrelati ve Bl o o d Sa m pli n g ......................... 9 2
7. 1. 2. 8. 1
T u m or Tiss ue C ollecti o n ...................................................................... 9 2
7. 1. 2. 8. 2
Bl o o d f or C orrelati ve St u dies ............................................................... 9 3
7. 1. 2. 9
Patie nt -Re p orte d O utc o mes ......................................................................... 9 3
7. 1. 2. 9. 1
T he Patie nt -Re p orte d O utc o mes ........................................................... 9 3
La b orat or y  Pr oce d ures/ Assess me nts .................................................................. 9 4
7. 1. 3
7. 1. 3. 1
La b orat or y  Safet y Eval uati o ns ( He mat ol o g y, C he mistr y , Uri nal ys is, 
a n d Ot her) .................................................................................................... 9 4
7. 1. 3. 2
Pre g na nc y  Test............................................................................................. 9 5
7. 1. 3. 3
P har mac o ki netic/ P har mac o d y na mic E val uati o ns ........................................ 9 6
7. 1. 3. 4
Pla n ne d Ge netic A nal ys is Sa m ple C ollecti o n.............................................. 9 6
7. 1. 3. 5
Bl o o d f or C orrelati ve St u dies ...................................................................... 9 6
7. 1. 3. 6
Bl o o d f or Me n o pa usal Stat us ....................................................................... 9 6
7. 1. 3. 7
F ut ure Bi o me dical Researc h ........................................................................ 9 6
Ot her Pr oce d ures ................................................................................................. 9 7
7. 1. 4
7. 1. 4. 1
Wit h dra wal/ Disc o nti n uati o n ........................................................................ 9 7
7. 1. 4. 1. 1
Wit h dra wal Fr o m F ut ure Bi o me dical Researc h ................................... 9 7
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 4. 2
Bli n di n g/ U n bli n di n g .................................................................................... 9 7
7. 1. 4. 3
Cali brati o n of Critical E q ui p me nt ................................................................ 9 8
Visit Re q uire me nts .............................................................................................. 9 8
7. 1. 5
7. 1. 5. 1
Scree ni n g ...................................................................................................... 9 8
7. 1. 5. 2
Treat me nt Peri o d .......................................................................................... 9 9
7. 1. 5. 2. 1
Sec o n d C o urse P hase ( Retreat me nt Peri o d) ......................................... 9 9
C o n diti o ns of Sec o n d C o urse P hase ............................................... 9 9
7. 1. 5. 2. 1. 1
Visit Re q uire me nts of Sec o n d C o urse P hase ............................... 1 0 0
7. 1. 5. 2. 1. 2
7. 1. 5. 2. 1. 2. 1
Assess me nts/ Pr oce d ures/ Wi n d o ws ....................................... 1 0 0
7. 1. 5. 2. 1. 2. 2
Disc o nti n uati o n D uri n g t he Sec o n d C o urse P hase ................ 1 0 0
7. 1. 5. 2. 1. 2. 3
La b orat or y  Tests D uri n g t he Sec o n d C o urse P hase.............. 1 0 0
7. 1. 5. 2. 1. 2. 4
C o nc o mita nt Me dicati o ns D uri n g t he Sec o n d C o urse P hase 1 0 1
7. 1. 5. 2. 1. 2. 5
Vital Si g ns D uri n g t he Sec o n d C o urse P hase ....................... 1 0 1
7. 1. 5. 2. 1. 2. 6
Pe m br oliz u ma b Restart D uri n g t he Sec o n d C o urse P hase ... 1 0 1
7. 1. 5. 2. 1. 2. 7
T u m or I ma gi n g Sec o n d C o urse P has e .................................. 1 0 1
7. 1. 5. 3
P ost -Treat me nt Visits ................................................................................. 1 0 2
7. 1. 5. 3. 1
Disc o nti n uati o n Visit .......................................................................... 1 0 2
7. 1. 5. 3. 2
Safet y  F oll o w-u p Visit ........................................................................ 1 0 2
7. 1. 5. 3. 3
F oll o w -u p Visits ................................................................................. 1 0 2
7. 1. 5. 3. 4
S ur vi val F oll o w -u p ............................................................................. 1 0 2
7. 1. 5. 3. 5
S ur vi val Stat us .................................................................................... 1 0 3
Assessi n g a n d Rec or di n g A d verse E ve nts ........................................................ 1 0 3
7. 2
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 
7. 2. 1
t he S p o ns or........................................................................................................ 1 0 4
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 ..................................... 1 0 4
7. 2. 2
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 .................................. 1 0 5
7. 2. 3
7. 2. 3. 1
Seri o us A d verse E ve nts ............................................................................. 1 0 5
7. 2. 3. 2
E ve nts of Cli nical I nterest .......................................................................... 1 0 6
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 .......... 1 0 7
E val uati n g A d verse E ve nts ............................................................................... 1 0 7
7. 2. 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 .................................... 1 1 0
7. 2. 5
Tri al G o ver n a nce a n d O versi g ht ....................................................................... 1 1 0
7. 3
Scie ntific A d vis or y  C o m mittee......................................................................... 1 1 0
7. 3. 1
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E xec uti ve O versi g ht C o m mittee ....................................................................... 1 1 0
7. 3. 2
Data M o nit ori n g C o m mittee ............................................................................. 1 1 0
7. 3. 3
8. 0
S T A TI S TI C A L A N A L Y SI S P L A N ...................................................................... 1 1 1
St atistic al A n al ysis Pl a n S u m m ar y ................................................................... 1 1 1
8. 1
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g ............................................... 1 1 3
8. 2
H y p ot heses/ Esti m ati o n....................................................................................... 1 1 3
8. 3
A n al ysis E n d p oi nts ............................................................................................. 1 1 4
8. 4
Efficac y  E n d p oi nts............................................................................................ 1 1 4
8. 4. 1
Safet y  E n d p oi nts............................................................................................... 1 1 5
8. 4. 2
S u bject -Re p orte d O utc o mes E n d p oi nts ............................................................ 1 1 5
8. 4. 3
A n al ysis P o p ul ati o ns ........................................................................................... 1 1 5
8. 5
Efficac y  A nalys is P o p ulati o ns .......................................................................... 1 1 5
8. 5. 1
Safet y A nal ys is P o p ulati o ns ............................................................................. 1 1 5
8. 5. 2
St atistic al Met h o ds .............................................................................................. 1 1 6
8. 6
Statistical Met h o ds f or Efficac y  A nalys es ........................................................ 1 1 6
8. 6. 1
8. 6. 1. 1
O verall S ur vi val ......................................................................................... 1 1 6
8. 6. 1. 2
Pr o gressi o n -Free S ur vi val .......................................................................... 1 1 6
8. 6. 1. 3
O verall Res p o nse Rate a n d Disease C o ntr ol Rate ..................................... 1 1 9
8. 6. 1. 4
D urati o n of Res p o nse................................................................................. 1 1 9
8. 6. 1. 5
S u m mar y  of Statistical Met h o ds f or Efficac y............................................ 1 2 0
Statistical Met h o ds f or Safet y A nal ys es ........................................................... 1 2 1
8. 6. 2
S u m maries of De m o gra p hic a n d Baseli ne C haracteristics ............................... 1 2 4
8. 6. 3
I nteri m A n al yses................................................................................................ . 1 2 4
8. 7
M ulti plicit y
.......................................................................................................... 1 2 5
8. 8
S a m ple Size a n d P o wer C alc ul ati o ns ................................................................ 1 2 7
8. 9
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors ......................................... 1 2 9
8. 1 0
C o m pli a nce ( Me dic ati o n A d here nce) ................................................................ 1 2 9
8. 1 1
E xte nt of E x p os ure .............................................................................................. 1 3 0
8. 1 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 3 0
I n vesti g ati o n al Pr o d uct ...................................................................................... 1 3 0
9. 1
P ac k a gi n g a n d L a beli n g I nf or m ati o n ............................................................... 1 3 0
9. 2
Cli nic al S u p plies Discl os ure ............................................................................... 1 3 0
9. 3
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St or a ge a n d H a n dli n g Re q uire me nts ................................................................ 1 3 1
9. 4
Disc ar d/ Destr ucti o n/ Ret ur ns a n d Rec o ncili ati o n ............................................ 1 3 1
9. 5
St a n d ar d P olicies ................................................................................................. 1 3 1
9. 6
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 3 1
C o nfi de nti alit y ..................................................................................................... 1 3 1
1 0. 1
C o nfi de ntialit y  of Data ..................................................................................... 1 3 1
1 0. 1. 1
C o nfi de ntialit y  of S u bject Rec or ds................................................................... 1 3 1
1 0. 1. 2
C o nfi de ntialit y  of I n vesti gat or I nf or mati o n ...................................................... 1 3 2
1 0. 1. 3
C o nfi de ntialit y  of I R B/I E C Inf or mati o n ........................................................... 1 3 2
1 0. 1. 4
C o m pli a nce wit h Fi n a nci al Discl os ure Re q uire me nts ..................................... 1 3 3
1 0. 2
C o m pl i a nce wit h L a w, A u dit a n d De b ar me nt ................................................. 1 3 3
1 0. 3
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 3 5
1 0. 4
Q u alit y M a n a ge me nt S yste m ............................................................................. 1 3 5
1 0. 5
D at a M a n a ge me nt ............................................................................................... 1 3 5
1 0. 6
P u blic ati o ns ......................................................................................................... 1 3 6
1 0. 7
1 1. 0
LI S T O F R E F E R E N C E S ....................................................................................... 1 3 7
1 2. 0  
A P P E N DI C E S ......................................................................................................... 1 4 5
Merc k C o de of C o n d uct f or Cli nic al Tri als ...................................................... 1 4 5
1 2. 1
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 
1 2. 2
Rese arc h ............................................................................................................... 1 4 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 
1 2. 3
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 5 3
A b bre vi ati o ns ...................................................................................................... 1 6 4
1 2. 4
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us ........................... 1 6 7
1 2. 5
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 .............................. 1 6 8
1 2. 6
Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors 1. 1 Criteri a f or E v al u ati n g 
1 2. 7
Res p o nse i n S oli d T u m ors .................................................................................. 1 6 9
1 3. 0
SI G N A T U R E S ......................................................................................................... 1 7 0
S p o ns or's Re prese nt ati ve ................................................................................... 1 7 0
1 3. 1
I n vesti g at or .......................................................................................................... 1 7 0
1 3. 2
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
LI S T O F T A B L E S
    
Ta ble 1
Efficac y  of C urre ntl y Use d 2 L + M o n ot hera p y Re gi me ns i n m T N B C................... 2 7
Ta ble 2
A de q uate Or ga n F u ncti o n La b orat or y Val ues ........................................................ 3 6
Ta ble 3
Trial Treat me nt ....................................................................................................... 3 9
Ta ble 4
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt G ui deli nes f or I m m u ne-relate d 
A d verse E ve nts Ass ociate d Wit h Pe m br oliz u ma b ................................................. 4 1
Ta ble 5
Pe m br oliz u ma b 
I nf usi o n Reacti o n 
D ose 
m o dificati o n 
a n d 
Treat me nt 
G ui deli n es ............................................................................................................... 4 4
Ta ble 6
I ma gi n g a n d Treat me nt After Site -Assesse d First Ra di ol o gic E vi de nce of 
Pr o gressi ve Disease has Bee n Verifie d b y  the Ce ntral I ma gi n g Ve n d or.  Ta ble 
Re prese nts ir R E CI S T ............................................................................................. 5 4
Ta ble 7
La b orat or y  Tests..................................................................................................... 9 4
Ta ble 8
E val uati n g A d verse E ve nts ................................................................................... 1 0 8
Ta ble 9
Ce ns ori n g R ules f or Pri mar y  an d Se nsiti vit y  Anal y ses of Pr o gressi o n -free 
S ur vi val ................................................................................................................ 1 1 8
Ta ble 1 0
Ce ns ori n g R ules f or D urati o n of Res p o nse .......................................................... 1 1 9
Ta ble 1 1
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts..................................................... 1 2 0
Ta ble 1 2
A nal y sis Strate g y f or Safet y Para meters .............................................................. 1 2 3
Ta b le 1 3 S u m mar y  of Ti mi n g, Sa m ple Size, a n d Decisi o n G ui da nce of I nteri m Efficac y 
A nal y ses a n d Fi nal A nal ysis u n der I nitial Al p ha All ocati o n ............................... 1 2 6
Ta ble 1 4
Pr o d uct Descri pti o ns ............................................................................................. 1 3 0
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9- 0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
LI S T O F FI G U R E S
Fi g ure 1
Trial Desi g n ............................................................................................................ 1 9
Fi g ure 2
Ima gi n g a nd Treat me nt f or Cli nical ly Sta bl e S u bjects After First Ra di ol o gic 
E vi de nce of Pr o gressi ve Disease Assesse d b y t he Site ........................................... 8 6
Fi g ure 3
I ma gi n g Pr ocess f or a Cli nicall y U nsta ble S u bject ................................................. 8 7
Fi g ure 4
M ulti plicit y  Strate g y............................................................................................. 1 2 7
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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
3. 0
8. 0
O bjecti ve(s) & 
H y p ot hesis(es)
Statistical A nal y sis Pla n
Re vise d 
o bjecti ves ,
h y p ot heses , 
a n d 
statistical 
a nal ys is 
pla n
t o 
i ncl u de 
s u bjects wit h P D -L 1  positi ve 
t u m ors wit h a hi g her c o m bi ne d 
p ositi ve sc ore ( C P S) c ut off of 
≥1 0 ( C P S ≥1 0)
D ata fr o m ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g de m o nstrate a n 
e nric he d 
treat me nt 
effect 
wit h 
i ncreasi n g P D -L 1 le vel.  The c ut off 
of C P S ≥1 0 has bee n i ncl u de d t o 
i de ntif y an e nric he d p o p ulati o n of 
patie nts 
t hat 
c o ul d 
p ote ntiall y 
be nefit m ore fr o m pe m br oliz u ma b 
m o n ot hera p y as sec o n d- or t hir d-
li ne i n metastatic 
tri ple ne gati ve 
breast ca ncer .
8. 1
8. 8
Statistical 
A nal y sis 
Pla n 
S u m mar y
M ulti plicit y
U p date d m ulti plicit y  strate g y 
of t he a nal y ses. 
T he u p date d m ulti plicit y  strate g y 
reflects t he u p date d pri mar y  an d 
sec o n dar y 
hy p ot heses 
a n d 
rati o nales. I nitial al p ha is s plit 
bet wee n O S e n d p oi nts i n s u bjects 
wit h 
C P S 
≥1 0 a n d C P S 
≥1 t o 
e ns ure ma xi m u m p o wer t o i de ntif y 
a n e nric he d p o p ulati o n of patie nts 
that c o ul d p ote ntiall y  be nefit m ore 
fr o m pe m br oliz u ma b m o n ot hera p y 
as 
sec o n d-
or 
t hir d-li ne 
i n 
metastatic 
tri ple ne gati ve breast 
ca ncer.
T he 
O S 
i n all s u bjects 
h y p ot hesis ca n be teste d if O S i n 
s u bjects wit h C P S ≥1 is s uccessf ul.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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. 1
8. 7
8. 9
Statistical 
A nal y sis 
Pla n
S u m mar y
I nteri m A nalys es
Sa m ple 
Size 
a n d 
P o wer 
Calc ulati o ns
U p date d t he f oll o wi n g: ti mi n g 
of t he i nteri m/fi nal a nal ysis ; 
t he tar get e ve nts f or fi nal
a nal ys is, a n d sa m ple size a n d 
p o wer calc ulati o n s.
T hese c ha n ges were ma de 
t o be 
c o nsiste nt wit h 
t he a d diti o n of 
pri mar y  
OS e n d p oi nt i n s u bjects 
wit h 
C P S ≥1 0
a n d t he u p date d 
m ulti plicit y  strate g y.
T he u p date d ti mi n g a n d pla n ne d 
n u m ber of e ve nts at I A a n d F A 
were dri ve n b y  the u p date d p o wer /
s uccess H R 
b o u n dar y  calc ulati o n 
base d o n t he u p date d m ulti plicit y  
strate g y to e ns ure a de q uate p o wer 
of eac h pri mar y  en d p oi nt at t he 
ti me of eac h a nal ys is. T he st u d y 
n o w has o nl y  one i nteri m a nal ysis 
as at t he time of I A the i nf or mati o n 
fracti o n 
is 
e x pecte d 
t o 
be 
a p pr o xi matel y
8 5 % 
a n d a d di n g 
a not her I A will 
be little val ue 
a d de d. F or p o wer calc ulati o n, t he 
tr ue hazar d rati o ass u m pti o ns were 
u p date d 
base d 
o n
rece nt data 
o bser ve d fr o m ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g. T he e nr oll me nt 
d urati o n 
a n d 
dr o p -o ut 
rate 
ass u m pti o ns were u p date d base d o n 
rece nt a vaila ble i nf or mati o n.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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. 1
Rati o nale f or t he Trial a n d Selecte d 
S u bject P o p ulati o n
Rati o nale was a d de d f or t he i ncl usi o n 
of C P S ≥1 0.
D ata fr o m 
ot her i n dicati o ns of 
pe m br oliz u ma b m o n ot hera p y i n t he 
sec o n d-li ne setti n g de m o nstrate a n 
e nric he d 
treat me nt 
effect 
wit h 
i ncreasi n g P D -L 1 le vel.  The c ut off 
of C P S ≥1 0 has bee n i ncl u de d t o 
i de ntif y an e nric he d p o p ulati o n of 
patie nts 
wit h 
metastatic 
tri ple 
ne gati ve breast ca ncer t hat c o ul d 
p ote ntiall y  
be nefit 
m ore 
fr o m 
pe m br oliz u ma b m o n ot hera p y.
6. 1. 1
Trial Fl o w C hart – Pe m br oliz u ma b 
M o n ot hera p y
Sa m pli n g f or pe m br oliz u ma b P K a n d 
a nti-dr u g a nti b o dies ( A D A) has bee n 
re m o ve d. Clarifie d t hat P K a nal ys is 
will be perf or me d o nl y if re q uire d.
Base d o n fee d bac k fr o m re g ulat or y 
a ge ncies, s ufficie nt P K/ A D A data 
has 
bee n 
c ollecte d 
f or 
pe m br oliz u ma b a n d sa m ples are n o 
l o n ger nee de d.
7. 1. 3. 3
8. 0
P har mac o ki netic/ P har mac o d y na mic 
E val uati o ns
Statistical A nal y sis Pla n
8. 1
Statistical A nal y sis Pla n S u m mar y
C orrecte d 
t hat
t he 
u nstratifie d 
Mietti ne n a n d N ur mi ne n met h o d will 
be use d f or safet y a nal ys is.
T o be c o nsiste nt wit h Secti o n 8. 6. 2.
8. 2
Res p o nsi bilit y  
for 
A nal y sis/I n-
H o use Bli n di n g
T he i nteri m efficac y to be pr o vi de d b y  
t he e xter nal u n bli n de d statisticia n t o 
e D M C is n ot restricte d t o O S a n d P F S.
U p date d la n g ua ge t o be c o nsiste nt 
wit h 
t he 
u p date d 
h y p ot heses 
(a d diti o n of O R R h yp ot hesis).
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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. 2
Res p o nsi bilit y  
for 
A nal y sis/I n-
H o use Bli n di n g
T he e xter nal u n bli n de d statisticia n will 
n ot 
be 
m o nit ori n g 
O S 
e ve nts i n 
s u bjects wit h P D-L 1  p ositi ve t u m ors t o 
i nf or m t he a nal ys is ti mi n g. I nstea d, 
t he u n bli n de d 
S p o ns or
bi o mar ker 
statisticia n 
will 
ha ve 
t his 
res p o nsi bilit y.
T o all o w m o nit ori n g of n u m ber of 
O S e ve nts t o e ns ure ti mel y a nal ysis.
8. 4. 1
8. 6. 1. 2
Efficac y  E n d p oi nts
P r ogr essi o n- Fr ee S ur vi val
U p date d 
t he ce ns ori n g 
r ules f or 
pri mar y  an d se nsiti vit y a n al yses of 
P F S.
R ecent ch an g es in the th erap eu tic
stan da r d P F S
cens ori n g r ul es; t he
pr i mar y a nal ysi s clos el y f ollo ws
F D A 
g ui d a n ce, a n d
the 
first
se nsitivit y a n al ys is clos el y f ollo ws
t he “i n t ent-t o-tr eat (IT T) c o mplete
f ollo w- u p pri n cip le”.
8. 4. 1
8. 6. 1. 4
Efficac y  E n d p oi nts
D urati o n of Res p o nse
U p date d 
t he
ce ns ori n g 
r ules 
f or 
pri mar y  an d
se nsiti vit y a nal yses of 
D O R.
T o be ali g ne d wit h 
t he u p date d 
ce ns ori n g r ule f or P F S.
8. 4. 1
Efficac y  E n d p oi nts
Clarifie d t he P F S, O R R, 
D O R 
a n d 
D C R e n d p oi nts base d o n ir R E C SIT b y  
In vesti gat or re vie w ma y be perf or me d 
as s u p p orti ve a nal ys is as nee de d.
Clarificati o n.
8. 6. 2
Statistical 
Met h o ds 
f or 
Safet y 
A nal y ses
U p date d t hat safety a nal ysis will be 
perf or me d i n all s u bjects o nl y .
It is e x pecte d t hat t he safet y pr ofile 
f or s u bjects wit h 
P D -L 1 p ositi ve 
t u m ors is si milar as t hat i n all 
s u bjects. As s uc h, safety a nal ys is i n 
all 
s u bjects 
pr o vi des 
m ost 
i nf or mati o n.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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. 1 0
4. 2. 3. 4
S u b gr o u p A nal ys es a n d Effect of 
Baseli ne Fact ors
Pla n ne d 
E x pl orat or y  
Bi o mar ker 
Researc h.
Re m o ve d 
B R C A 1/ 2 
stat us, 
h o m ol o g o us 
rec o m bi nati o n 
defect 
sc ore, 
a n d 
micr osatellite 
sta bilit y 
stat us as cate g ories f or t he s u b gr o u p 
a nal ys is. I nstea d, t hese a nal ys es ma y 
be perf or me d as se parate e x pl orat or y 
bi o mar ker a nal ys es.
T hese 
m a y  
be 
e val uate d 
as 
e x pl orat or y a nal ys es
t o c orrelate 
efficac y/resista nce bi o mar kers wit h 
res p o nse t o pe m br oliz u ma b. All o ws 
fle xi bilit y for
effecti ve 
use 
of 
c ollecte d t u m or sa m ples de pe n di n g 
o n e mer gi n g data re gar di n g t he 
effect of t hese bi o mar kers i n t he 
T N B C p o p ulati o n.
8. 1 0
S u b gr o u p A nal ys es a n d Effect of 
Baseli ne Fact ors
U p date d s u b gr o u p cate g orizati o n f or 
A ge a n d P D -L 1 stat us.
T o 
be ali g ne d wit h 
t he c urre nt 
g ui da nce 
f or a ge cate g or y an d 
u p date d P D -L 1 c ut off. 
Gl o bal  
Gl o bal
C orrecti o ns t o mi n or t yp o gra p hical or 
f or matti n g 
err ors 
ha ve 
bee n 
i nc or p orate d.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
1. 0 T RI A L S U M M A R Y
A b bre viate d Title
A 
Ra n d o mize d 
O pe n -La bel 
P hase 
III St u d y 
of 
Si n gle 
A ge nt 
Pe m br oliz u ma b vers us S i n gle A ge nt
C he m ot hera p y per P h y sicia n’s 
C h oice f or Metastatic 
Tri ple Ne gati ve 
Breast Ca ncer
( mT N B C) –
( K E Y N O T E 1 1 9)
Trial P hase
III
Cli nical I n dicati o n
Metastatic ( Sta ge I V/ M 1) Tri ple Ne gati ve Breast Ca ncer
Trial T y pe
I nter ve nti o nal
T y pe of c o ntr ol
Acti ve C o ntr ol 
R o ute of a d mi nistrati o n
I ntra ve n o us or oral
Trial Bli n di n g
U n bli n de d O pe n -la bel
Treat me nt Gr o u ps
Pe m br oliz u ma b : 2 0 0 m g i ntra ve n o usl y (I V) Q 3 W
Me dicati o ns 
use d as treat me nts of p h ysicia n's c h oice ( T P C) wi ll b e 
ha n dle d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g 
c o u ntries.  Sites ma y c h o ose a n y O N E dr u g fr o m t he f oll o wi n g:
Ca pecita bi ne
Eri b uli n
G e m cita bi ne
Vi n orel bi ne
N u m ber of trial s u bjects
A p pr o x i matel y 6 0 0 s u bjects will be e nr olle d.
Esti mate d d urati o n of trial
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 0 m o nt hs
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 wi ll partici pate i n t he trial fr o m t he ti me he/s he si gn s t he 
I nf or me d C o nse nt F or m  (I C F) u ntil 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 , deat h, or e n d of st u d y.  
After t he scree ni n g p hase, eli gi ble s u bjects will be stratifie d acc or di n g t o 
2 stratificati o n fact ors [ P D-L 1  tu m or stat us ( p ositi ve [ c o mbi ne d p ositi ve 
sc ore ≥1] vs ne gati ve [ c o mbi ne d p ositi ve sc ore < 1] ), a n d hist or y of pri or 
( ne o)
a dj u va nt t hera p y vs . de n o v o metastatic 
disease
at i nitial 
dia g n osis ], a n d t he n ra n d o mize d 1: 1 t o si n gle a ge nt pe m br oliz u ma b or 
si n gle a ge nt c he m ot hera p y per p h ysicia n’s c h oice. St u d y tr e at me nt will 
c o nti n ue u ntil disease pr o gressi o n (verifie d b y  bli n de d ce ntral i ma gi n g 
ve n d or , u nless s u bject is t he n ma na ge d b y  im m u ne -relate d res p o nse 
e val uati o n criteria i n s oli d t u m ors [ir R E CI S T]), 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 ad m i nistrati o n of st u dy 
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 st u d y 
treat me nt, pre g na nc y of t he s u bject, n o nc o m plia nce wit h st u d y treat me nt
or
pr oce d ure 
re q uire me nts, 3 5 
treat me nts
ha ve 
bee n 
c o mplete d 
( pe m br oliz u ma b ar m o nl y), c o nse nt wit h dra w al, bec o mi n g l ost-t o-
f oll o w-u p , deat h or f or a d ministrati ve reas o ns re q uiri n g cessati o n of 
treat me nt. 
After disc o nti n uati o n of st u d y treat me nt, eac h s u bject will be f oll o we d 
f or 3 0 da ys f or a d verse e ve nt ( A E) a n d e ve nts of  cli nical i nterest ( E CI)
m o nit ori n g . S eri o us a d verse e ve nts ( S A Es) will be c ollecte d f or 9 0 da ys 
after t he e n d of st u d y treat me nt. S u bjects w h o 
disc o nti n ue st u dy 
treat me nt f or reas o ns ot her t ha n disease pr o gressi o n will ha ve p ost -
treat me nt f oll o w- u p f or disease status u ntil disease pr o gressi o n (verifie d 
b y bli n de d ce ntral i ma gi n g ve n d or ), start of a n o n -st u d y a ntica ncer 
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
treat me nt, c o nse nt wit h dra w al , bec o mi n g l ost t o f oll o w-u p , deat h or e n d 
of t he st u d y. All s u bjects will be f oll o we d b y  tele p h o ne f or o verall 
s ur vi val u ntil c o nse nt wit h dra wal , b e c o m i n g l ost t o f oll o w-u p , de at h or 
e n d of t he st u d y.
S u bjects w h o st o p p e m br oliz u ma b after ac hie vi n g a C R a n d s u bjects 
w h o , after recei vi n g 3 5 c ycles, st o p pe m br oliz u ma b f or reas o ns ot her 
t ha n disease pr o gressi o n or i nt olera bilit y ma y be eli gi ble f or u p t o o ne 
year of retreat me nt wit h pe m br oliz u ma b u p o n e x perie nci n g disease 
pr o gressi o n. T he decisi o n t o retreat wit h p e m br oliz u ma b will be at t he 
discreti o n of t he I n vesti gat or, o nl y if s u bjects meet t he criteria f or 
retreat me nt a n d t he trial is o n g oi n g. 
S u bjects ma y be tra nsiti o ne d to a n e xte nsi o n st u d y if/ w he n a n e xte nsi o n 
st u d y bec o mes a vaila ble. 
Ra n d o mizati o n Rati o
1: 1
A list of a b bre viati o ns use d i n t his d oc u me nt ca n be f o u n d i n Secti o n 1 2. 4.
2. 0 T RI A L D E SI G N
Tri al Desi g n
2. 1
T his is a ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d, m ultice nter, i nter nati o nal P hase III trial 
of si n gle a ge nt pe m br oliz u ma b vers us si n gle a ge nt c he m ot hera p y per p h y sicia n’s c h oice 
( Treat ment of P h y sicia n’s C h oice , T P C) for s u bjects recei vi n g sec o n d li ne ( 2 L) or t hir d li ne 
( 3 L) treat me nt f or metastatic tri ple ne gati ve breast ca ncer ( m T N B C). T he st u d y will be 
c o n d ucte d i n c o nf or ma nce wit h G o o d Cli nical Practices ( G C Ps).
S u bjects m ust ha ve ce ntrall y c o nfir me d m T N B C, ha ve recei ve d eit her o ne or t w o pri or 
s yste mic treat me nts f or metastatic breast ca ncer , a n d ha ve d oc u me nte d disease pr o gressi o n
o n or after t he m ost rece nt t hera py.   Su bjects m ust ha ve bee n pre vi o usl y  treate d wit h a n 
a nt hrac ycli ne a n d / or a ta xa ne i n t he ( ne o)a dj u va nt or metastatic setti n g. 
All s u bjects i n t his st u d y will be re q uire d t o pr o v i de fres h ne wl y o btai ne d c ore or e xcisi o nal 
bi o ps y  fr o m a metastatic , n ot pre vi o usl y  irra diate d, t u m or lesi o n t o be e val uate d at a ce ntral 
la b orat or y for 1) tri ple-ne gati ve breast ca ncer stat us b y  deter mi nati o n of estr o ge n rece pt or 
( E R), pr o gester o ne rece pt or a n d h u ma n e pi der mal gr o wt h fact or rece pt or-2 ( H E R 2) 
e x pressi o n , 
a n d 
2) 
pr o gra m me d 
deat h -li ga n d 
1 
(P D -L 1 )
e x pressi o n 
b y  
i m m u n o hist oc he mistr y (I H C).  Sa m ples will be se nt t o a ce ntral la b orat or y for real ti me 
e val uati o n t o e ns ure a de q uate t u m or tiss ue is prese nt a n d eli gi bilit y re q uire me nts are 
f ulfille d.   
After t he scree ni n g p hase, eli gi ble su bjects will be first stratifie d acc or di n g t o 2 stratificati o n 
fact ors [ P D-L 1 t u m or stat us ( p ositi ve [c o m bi ne d p ositi ve sc ore ( C P S) ≥1] vs . ne gati ve
[ C P S < 1] ), a n d hist or y  of pri or ( ne o)a dj u va nt treat me nt vs . de n ov o metastatic disease at 
i nitial dia g n osis ].
Su bject s
will 
t he n
be ra n d o mize d
1: 1 t o recei ve si n gle a ge nt 
pe m br oliz u ma b 2 0 0 m g I V o nce e ver y 3 wee ks ( Q 3 W) or si n gle a ge nt c he m ot hera p y per 
p h y sicia n’s c h oice (T P C ): ca pecita bi ne , eri b uli n , ge mcita bi ne , or vi n orel bi ne . F or t he T P C 
ar m , t here is a ma xi m u m e nr oll me nt ca p of 6 0 % of t otal e nr oll me nt f or eac h c he m ot hera p y 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
dr u g .  The T P C d osi n g a n d fre q ue nc y will be ha n dle d acc or di n g t o l ocal re g ulati o ns a n d 
g ui deli nes i n partici pati n g c o u ntries.
St u d y  treat me nt will c o nti n ue u ntil disease pr o gressi o n ( verifie d b y  bli n de d ce ntral i ma gi n g 
ve n d or u nless s u bject is t he n ma na ge d b y ir R E CI S T), u nacce pta ble a d verse e ve nt(s) ( A E[s]), 
i nterc urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of st u d y treat me nt, I nvesti gat or ’s 
decisi o n t o wit h dra w 
t he s u bject fr o m st u d y treat me nt, pre g na nc y of t he s u bject, 
n o nc o m plia nce wit h st u d y treat me nt or pr oce d ure re q uire me nts, 3 5 treat me nts ha ve bee n 
c o m plete d ( pe m br oliz u ma b ar m o nl y ), c o nse nt w it h dra wal, bec o mi n g l ost-t o-f oll o w- u p, 
deat h or f or a d mi nistrati ve reas o ns re q uiri n g cessati o n of treat me nt. 
After disc o nti n uati o n of st u d y treat me nt, eac h s u bject will be f oll o we d f or 3 0 da y s f or A E
a n d e ve nts of cli nical i nterest ( E CIs). S eri o us A E s ( S A Es) will be c ollecte d f or 9 0 d a y s after 
t he e n d of st u dy treat me nt .
S u bjects w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n disease pr o gressi o n will 
ha ve p ost -treat me nt f oll o w- u p f or disease stat us e ver y 3 c ycles (± 7 da y s) u ntil disease 
pr o gressi o n ( verifie d b y  bli n de d ce ntral i ma gi n g ve n d or), start of a n o n -st u d y a ntica ncer 
treat me nt, c o nse nt wit h dra wal, bec o mi n g l ost t o f oll o w-u p, deat h or e n d of t he st u d y . 
All s u bjects will be f oll o we d b y  tele p h o ne e ver y 4 c y cles ( ± 7 da ys) f or o verall s ur vi val ( O S)
u ntil c o nse nt wit h dra w al, bec o mi n g l ost t o f oll o w-u p, deat h or e n d of t he st u d y.
S u bjects ma y  ha ve t he o p p ort u nit y  to tra nsiti o n t o a pe m br oliz u ma b e xte nsi o n st u d y if 
a vaila ble i n t he f ut ure after cl os ure of t his st u d y.
S pecific pr oce d ures t o be perf or me d d uri n g t he trial, as well as t heir prescri be d ti mes a n d 
ass ociate d visit wi n d o ws, are o utli ne d i n t he Trial 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.
I n this trial, pe m br oliz u ma b will be c o m pare d t o T P C as 2 L  or 3 L  mo n ot hera p y  in s u bjects 
wit h ce ntrall y c o nfir me d m T N B C . T he st u d y o bjecti ves are defi ne d i n i n Secti o n 3. 0.
A m ulti plicit y  ap pr oac h will be f oll o we d as descri be d i n Secti o n 8. 0. T he size of t his trial is 
~ 6 0 0 s u bjects. The O S e ve nt s re q uire d i n s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 a n d 
C P S ≥1 0) was esti mate d base d o n t he esti mati o n of t he pre vale nce of P D -L 1 p ositi ve t u m ors
wit h C P S ≥1 ( 6 5%) a n d C P S ≥1 0 ( 3 1%) . T he pre vale nce of P D -L 1 p ositi vit y ( C P S ≥1) i n 
m T N B C was 5 5 % i n t he pr o of -of -pri nci ple st u d y  K N 0 1 2 ( Secti o n 4. 2).
O ne
i nteri m efficac y a nal ysis is pla n ne d i n t his st u d y (Secti o n 8. 7 ).  The i nteri m efficac y 
a nal ys is is t o assess efficac y base d o n O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d i n all s u bjects .
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Tri al Di a gr a m
2. 2
Fi g ure 1
Trial Desi g n
A b bre viati o ns: C P S = c o m bi ne d p ositi ve sc ore; ir R E CI S T = i m m u ne-relate d Res p o nse E val uati o n Criteria i n 
S oli d T u m ors; I V = i ntra ve n o us; P D -L 1 = pr o gra m me d cell deat h li ga n d 1; Q 3 W = e ver y 3 we e ks; 
T P C = c he m ot hera p y pe r p h ysicia n’s c h oice.
* 
I n t he e ve nt t hat treat me nt wit h p e m br oliz u ma b is f o u n d t o be f utile i n s u bjects wit h P D -L 1 ne gati ve 
t u m ors, stratificati o n f or P D-L 1 stat us will be a ba n d o ne d.
* *
Treat me nt ma y be c o nti n ue d be y o n d verifie d 1 st ra di ol o gic e vi de nce of disease pr o gressi o n acc or di n g t o 
ir R E CI S T criteria.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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)
3. 1
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C:
P D -L 1
P ositi ve P o p ul ati o ns : s u bjects wit h P D -L 1  positi ve e x pressi o n defi ne d b y  ≥1 0 
C o m bi ne d P ositi ve Sc ore ( C P S) a n d b y  ≥1 C P S; he ncef ort h a b bre viate d as C P S ≥1 0 a n d 
C P S ≥1 res pecti vel y.
( 1) O bjecti ve: T o c o m pare O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0) .
H y p ot hesis ( H1 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0) . 
( 2) O bjecti ve: T o c o m pare O S i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1) .
H y p ot hesis
( H2 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n s u bjects wit h 
P D -L 1 p ositi ve t u m ors ( C P S ≥1) . 
( 3) O bjecti ve: T o c o m pare O S i n all s u bjects.
H y p ot hes is ( H3 ): Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o T P C i n all s u bjects.
T he st u d y is c o nsi dere d t o ha ve met its pri mar y  objecti ve if pe m br oliz u ma b is s u peri or t o 
T P C i n O S i n eit her s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 [ H 1] or C P S ≥1 [ H 2]) or 
i n all s u bjects ( H 3), at eit her t he i nteri m a nal ysis or t he fi nal a nal ysis.
Sec o n d ar y O bjecti ve(s) & H y p o t hesis(es)
3. 2
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C :
( 1) O bjecti ve:   T o c o m pare pr o gressi o n -free s ur vi val (P F S ) base d o n R E CI S T 1. 1 as 
assesse d b y bli n de d ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hesis ( H 4): Pe m br oliz u ma b pr ol o n gs P F S base d o n R E CI S T 1. 1 as assesse d b y  
bli n de d ce ntral i ma gi n g ve n d or c o m pare d t o T P C i n all s u bjects.
( 2) O bjecti ve:   T o c o m pare o verall res p o nse rate ( O R R) per R E CI S T 1. 1 b y  bli n de d 
ce ntral i ma gi n g ve n d or i n all s u bjects.
H y p ot hes is ( H5 ): Pe m br oliz u ma b i ncreases O R R per R E CI S T 1. 1 b y  bli n de d ce ntral 
i ma gi n g ve n d or c o m pare d t o T P C i n all s u bjects.
( 3) O bjecti ve:   T o e val uate P F S a n d O R R base d o n R E CI S T 1. 1 as assesse d b y  bli n de d 
ce ntral i ma gi n g ve n d or i n s u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 a n d 
C P S ≥1) .
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
( 4) O bjecti ve : T o e val uate d urati o n of res p o nse ( D O R), a n d disease c o ntr ol rate ( D C R) 
base d o n R E CI S T 1. 1 as assesse d b y  bli n de d ce ntral i ma gi n g ve n d or i n s u bjects wit h 
P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d i n all s u bjects.
( 5) O bjecti ve : T o deter mi ne t he safet y a n d t olera bilit y of pe m br oli z u ma b .
T he sec o n dar y hy p ot heses re gar di n g P F S i n all s u bjects ( H 4) a n d O R R i n all s u bjects ( H 5) 
ca n o nl y be f or mall y teste d o nce t he n ull h y p ot hesis re gar di n g t he pri mar y e n d p oi nt O S i n all 
s u bjects ( H3 ) has bee n rejecte d..
E x pl or at or y O bjecti ves
3. 3
Pe m br oliz u m a b will be c o m p are d t o T P C as 2 L or 3 L m o n ot her a py i n s u bjects wit h ce ntr ally 
c o nfir me d m T N B C :
( 1) O bjecti ve:
T o e val uate P F S, O R R, D O R, a n d D C R base d o n ir R E CIS T as assesse d 
b y  bli n de d ce ntral i ma gi n g re vie w i n s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects . 
( 2) O bjecti ve : 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 s u bjects wit h P D -L 1  positi ve t u m ors ( C P S ≥1 0 a n d C P S ≥1) a n d all 
s u bjects usi n g t he E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
(E O R T C ) Q L Q -C 3 0 a n d Q L Q -B R 2 3.
( 3) O bjecti ve: T o c haracterize utilities i n s u bjects wit h P D -L 1  p ositi ve t u m ors ( C P S ≥1 0 
a n d C P S ≥1) a n d all s u bjects usi n g E ur o Q ol (E Q )-5 D .
( 4) O b jecti ve:
T o 
i n vesti gate t he ass ociati o n 
bet wee n 
a ntit u m or 
acti vit y 
of 
pe m br oliz u ma b i n m T N B C a n d efficac y/resista nce bi o mar kers, utilizi n g t u m or a n d 
bl o o d s peci me ns o btai ne d bef ore/ d uri n g treat me nt a n d at disease pr o gressi o n.
( 5) O bjecti ve: T o e x pl ore t he relati o ns hi p bet wee n ge netic variati o n a n d res p o nse t o t he 
treat me nt(s) a d mi nistere d.  Variati o n acr oss t he h u ma n ge n o me will be a nal yze d f or 
ass ociati o n wit h cli nical data c ollecte d i n t his st u d y.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
4. 1
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 p e m br oliz u ma b (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
4. 1. 1
P D -1 c hec k p oi nt i n hi biti o n a n d c a ncer tre at me nt.  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 pr o g n osis i n vari o us mali g na ncies
[ 2-1 4] .  In 
par tic 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 ulator y  T cells see m 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 i n ma n y 
s oli d t u m ors [ 1 0, 1 5-2 1] .
T he P D -1 rece pt or-li ga n d i nteracti o n is a maj or pat h wa y  hijac ke d b y  tu m ors t o s u p press 
im m u ne c o ntr ol [ 2 2].  T he n or mal f u ncti o n of P D-1, w hic h is 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.  PD- 1 (e nc o de d b y  the ge ne P dc d 1) is a
me m ber of t he I g s u perfa mil y relate d t o C D 2 8 a n d c yt ot o xic t-l ym p h oc y te-ass ociate d a nti ge n 
4 (C T L A- 4) , w hic h has bee n s h o w n t o ne gati vel y  re g ulate a nti ge n rece pt or si g nali n g u p o n 
e n ga ge me nt of its li ga n ds ( P D-L 1  an d/ or P D -L 2).  The str uct ures of m uri ne P D -1 al o ne [ 2 3]
a n d i n c o m ple x wit h its li ga n ds were first res ol ve d [ 2 4, 2 5 ]. M ore rece ntl y the N M R -base d 
str uct ure of t he h u ma n P D -1 e xtracell ular re gi o n a n d a nal ys es of its i nteracti o ns wit h its 
li ga n ds were als o re p orte d [ 2 6].  PD- 1 a n d fa mil y me m bers are t ype I tra ns me m bra ne 
gl yc o pr otei ns c o ntai ni n g a n I g Varia ble -t ype ( V-t ype) d o mai n i m p orta nt f or li ga n d bi n di n g 
a n d a c yt o plas mic tail w hic h is res p o nsi ble f or t he acti vati o n of d o w nstrea m si g nali n g 
m olec ules.  The c yt o plas mic tail of P D -1 c o nta i ns 2 t yr osi ne-base d si g nali n g m otifs, a n 
i m m u n orece pt or t yr osi ne-base d i n hi biti o n m otif (I TI M) a n d a n i m m u n orece pt or t yr osi ne-
base d s witc h m otif (IT S M).  Foll o wi n g T
cell sti m ulati o n, P D -1 recr uits t he t yr osi ne 
p h os p hatases S H P -1 a n d S H P -2 t o t he I T S M m ot if wit hi n its c yt o plas mic tail, lea di n g t o t he 
de p h os p h or y lati o n of effect or m olec ules, s uc h as C D 3ζ, P K C θ a n d Z A P 7 0, w hic h are 
i n v ol ve d i n t he C D 3 T cell si g nali n g casca de [ 2 7].  The 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 [ 2 8].  P D -1 was 
s h o w n t o be e x presse d o n acti vate d l ym p h oc y tes, i ncl u di n g peri p heral C D 4 + a n d C D 8 + 
T- cells, B cells, T- re gs a n d Nat ural Killer cells [ 2 9]. E x pressi o n has als o bee n s h o w n d uri n g 
t h ymic de vel o p me nt o n C D 4 -C D 8 - ( d o u ble ne gati ve) T cells [ 3 0], as well as s u bsets of 
macr o p ha ges [ 3 1] a n d de n dritic cells [ 3 2]. T he li ga n ds f or P D -1 ( P D-L 1 a n d P D -L 2 ) are 
c o nstit uti vel y ex presse d or ca n be i n d uce d i n a variet y  of cell t ypes [ 3 3]. 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 ular 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
[ 3 3]. 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 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 2 is 
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
t ho u g ht t o c o ntr ol i m m u ne T cell acti vati o n i n l y mp h oi d or ga ns, w hereas P D -L 1  ser ves t o 
da m pe n u n warra nte d T cell f u ncti o n i n peri p heral tiss ues.  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 [ 3 4, 3 5] , w hic h, via 
its i nteracti o n wit h t he P D -1 rece pt or o n 
t u m or-s pecific T cells, pla y s a critical r ole i n i m m u ne e vasi o n b y  tu m ors [ 3 6].  As a 
c o nse q ue nce, t he P D -1/ P D -L 1 pat h wa y  is a n attracti ve tar get f or t hera pe utic i nter ve nti o n i n 
ca ncer [ 3 7].
I m m u n ot her a p y: Precli nic al S t u dies 
4. 1. 2
P D -1 i m m u ne c hec k p oi nt i n hi biti o n - Precli nic al st u dies. T hera pe utic st u dies i n m o use 
m o dels ha ve s h o w n t hat a d mi nistrati o n of a nti b o dies bl oc ki n g P D -1/ P D- L 1  interacti o n 
e n ha nces i nfiltrati o n of t u m or-s pecific C D 8 + T cells a n d ulti matel y lea ds t o t um or rejecti o n, 
eit her as a m o n o t hera p y or i n c o m bi nati o n wit h 
ot her treat me nt m o dalities
[ 3 8- 4 0].  
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 nstra te d a ntit u m or res p o nses i n 
m o dels 
of s q ua m o us cell carc i n o ma, pa ncreatic carci n o ma, mela n o ma, 
ac ute m y el oi d 
le u ke mia a n d c ol orectal carci n o ma [ 4 1- 4 5].  I n suc h st u dies, t u m or i nfiltrati o n b y C D 8 + 
T- cells a n d i ncrease d I F N-γ, gra nz y m e B a n d perf ori n e x press i o n were o bser ve d , i n dicati n g 
t hat t he mec ha nis m u n derl y i n g t he a ntit u m or acti vit y of PD- 1 c hec k p oi nt i n hi biti 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 viv o [ 42]. E x peri me nts ha ve 
c o nfir me d t he i n viv o effi cac y of a nti -m o use P D -1 a nti b o d y as a m o n o t 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 sy n ge neic m o use t u m or m o dels (see t he I B).
Pe m br oliz u m a b: O n g oi n g C li nic al T ri als i n Ot her T u m or Ty pes
4. 1. 3
Pe m br oliz u m a b –
Cli nic al tri als. P e m br oliz u ma b [Ke y tr u da® ( U S); pre vi o usl y  kn o w n as 
la m br oliz u ma b, M K -3 4 7 5 a n d S C H 9 0 0 0 4 7 5] is a p ote nt a n d hi g hl y selecti ve h u ma nize d 
m o n ocl o nal a nti b o d y (m A b) of t he I g G 4/ ka p pa is ot ype desi g ne d t o directl y  bl oc k t he 
i nteracti o n bet wee n P D -1 a n d its li ga n ds, P D -L 1  an d P D -L 2. Pe m br oliz u ma b was rece ntly 
a p pr o ve d i n t he U S 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, a n d f or use i n mela n o ma s u bjects wit h disease pr o gressi o n after pri or treat me nt 
wit h (a) i pili m u ma b or ( b) a B R A F i n hi bit or , i n t he case of B R A F V 6 0 0-m uta nt disease [4 6 ]. 
It is t he first a nti -P D -1 t hera py t o recei ve re g ulat or y ap pr o val i n t he U S, a n d is c urre ntl y 
u n der re g ulat or y re vie w i n t he E U.
O n g oi n g
cli nical trials of pe m br oliz u ma b are bei n g
c o n d ucte d i n a d va nce d mela n o m a, n o n -s mall cell l u n g ca ncer , a n d a n u m ber of ot h er 
a d va nce d s oli d t u m or i n dicati o ns a n d he mat ol o gic mali g na ncies.
F or st u d y details please
refer t o t he I B.
I nf or m ati o n o n Dise ase t o be T re ate d – m T N B C
4. 1. 4
E xcl u di n g basal cell a n d s q ua m o us cell s ki n ca ncers, breast ca ncer is t he m ost c o m m o nl y 
dia g n ose d mali g na nc y  in w o me n, acc o u nti n g f or 2 9 % of all ne w ca ncers.  It is als o t he 
sec o n d lea di n g ca use of ca ncer deat h (after l u n g ca ncer) a m o n g w o me n.  A b o ut 2 3 2, 6 7 0 ne w 
cases of breast ca ncer a n d 4 0, 0 0 0 deat hs d ue t o breast ca ncer w e re e x pecte d i n w o me n i n t he 
U nite d States i n 2 0 1 4 [4 7 ].  Tri ple -ne gati ve breast ca ncer ( T N B C) is p he n ot y picall y defi ne d 
b y  a lac k of estr o ge n rece pt or ( E R) a n d pr o gester o ne rece pt or e x pressi o n a n d t he a bse nce of 
h u ma n e pi der mal gr o wt h fact or rece pt or-2 ( H E R 2) o vere x pressi o n a n d/ or a m plificati o n [4 8 ].  
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
2 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T N B C re prese nts 1 5- 2 0 % of all breast ca ncers [ 4 9] a n d is o verla p pi n g, b ut n ot s yn o n y m o us, 
wit h t he basal -li ke s u bt y pe defi ne d b y  ge ne e x pressi o n, as a b o ut 7 0 % of T N B Cs ha ve basal -
li ke c haracteristics [5 0, 5 1 ]. 
T N B C is a m olec ularl y heter o ge ne o us disease a n d i ncl u des t u m or s u bsets wit h differe nt 
pr o g n osis.  For e xa m ple, t he cla u di n-l o w s u bty pe, w hic h is c haracterize d b y  lo w e x pressi o n 
of clau di n ge nes a n d ofte n prese nts wit h ste m cell feat ures a n d e pit helial-t o-mese nc h y m al 
tra nsiti o n ( E M T), is ass ociate d wit h p o or pr o g n osis [ 5 2]. Rece nt ge ne e x pressi o n pr ofili n g 
has i de ntifie d u p t o si x disti nct T N B C s u bty pes (t w o basal -li ke, a n i m m u n o m o d ulator y , a 
mese nc h y m al, a mese nc h ymal ste m -li ke a n d a l u mi nal a n dr o ge n rece pt or s u bt ype) [ 5 3 ].
T N B C is ass ociate d wit h y o u n ger a ge at dia g n osis, pre me n o pa usal stat us, Africa n A merica n 
race, m ore a d va nce d disease sta ge, hi g her gra de, hi g h mit otic i n dices, fa mil y hist or y of 
breast ca ncer, Breast Ca ncer 1 ( B R C A 1) m utati o ns, a n d m ore a g gressi ve be ha vi or t ha n ot her 
breast ca ncer s u bty p es [ 4 9].  As re p orte d i n a se mi nal st u d y on T N B C, 3 4 % of all s u bjects 
wit h T N B C e x perie nce dista nt rec urre nce wit h a me dia n dist a nt rec urre nce-free s ur vi val 
( D R F S) of 2. 6 years, c o m pare d t o a dista nt rec urre nce rate of 2 0 % a n d a me dia n D R F S of 5 
ye ars i n ot her breast ca ncer s u bty pes; t he pea k of rec urre nce f or T N B C is wit hi n 1- 3 ye ars 
after i nitial dia g n osis, a n d decreases si g nifica ntl y t hereafter; s u bjects wit h T N B C als o ha ve 
s h orter O S
c o m pare d t o s u bjects wit h n o n- T N B C ( 4. 2 vers us 6. 0 ye ars) [4 8 ].  Fi nall y, 
s u bjects wit h T N B C te n d t o rela pse wit h dista nt metastases rat her t ha n l ocal rec urre nces a n d 
are m ore li kely t o de vel o p visc eral metastases, i ncl u di n g ce ntral ner v o us s yste m ( C N S) 
i n v ol ve me nt [ 5 4].
Treat me nt of T N B C is c halle n gi n g a n d re prese nts a n area of u n met me dical nee d, as t hese 
t u m ors lac k t hera pe utic tar gets, s uc h as E R a n d H E R 2, a n d bec o me ra pi dl y resista nt t o 
c he m ot hera py u p o n l ocal rec urre nce a n d/ or metastasis (e ve n t h o u g h t he y are ofte n se nsiti ve 
t o c yt ot o xic dr u gs at i nitial prese ntati o n) [ 5 5]. T he maj orit y  of s u bjects wit h metastatic 
T N B C ( m T N B C) ha ve e x perie nce d rela pse after ne oa dj u va nt or a dj u va nt t hera py f or ea rl y or 
l ocall y ad va nce d disease.  In a fre q ue ntly refere nce d st u d y, t he O S
of all (at a n y li ne of 
t hera py)  su bjects wit h m T N B C was 1 3. 3 m o nt hs; me dia n d urati o n of first li ne ( 1 L) t hera p y 
f or m T N B C was 1 1. 9 wee ks; 8 0 % of s u bjects recei ve d sec o n d li ne ( 2 L) t hera p y wit h a 
me dia n d urati o n of 9 wee ks, a n d a b o ut 5 0 % recei ve d t hir d li ne ( 3 L) t hera p y wit h a me dia n 
d urati o n of 4 wee ks [ 5 6].
I m m u ne c hec k p oi nt i n hi biti o n f or t he tre at me nt of T N B C. Se veral st u dies ha ve 
de m o nstrate d t hat prese nce of TI Ls has pr o g n ostic si g nifica nce i n T N B C, t h us i m plicati n g 
t he i m m u ne s yste m i n t he pat h o p h y siol o g y  an d p ote ntiall y  the treat me nt of s uc h t u m ors.  
Greater l ym p h oc y tic i nfiltrati o n c o nfers better pr o g n osis i n T N B C, i n de pe n de nt of s yste mic 
t hera py [5 7, 5 8 ].  In a d diti o n, u ns u per vise d ge ne e x pressi o n pr ofili n g of T N B Cs has 
i de ntifie d a ge ne si g nat ure e nric he d f or c yt ot o xic C D 8 + T cell ge nes a n d nat ural killer cell 
( N K C) acti vit y, w hic h is pre dicti ve of g o o d cli nical o utc o me s [ 5 9].  These fi n di n gs s u g gest 
t hat i n hi biti o n of i m m u ne c hec k p oi nts has t he p ote ntial t o i m pr o ve T N B C pr o g n osis b y 
i ncreasi n g t he efficac y of t u m or-ass ociate d i m m u ne res p o nse i n eli mi nati n g breast ca ncer 
cells [ 6 0 ].
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
T ar geti n g t he P D -1 i m m u ne c hec k p oi nt f or t he tre at me nt of T N B C . T he P D -1 li ga n d, 
P D -L 1 , is n ot detecte d i n n or mal breast tiss ue, b ut has bee n re p orte d t o be e x presse d i n a b o ut 
half of all breast ca ncers, partic ularl y i n h or m o ne rece pt or ( H R)-ne gati ve a n d hi g h gra de, 
pr oliferati ve t u m ors [6 1 ].  In a d diti o n, t he prese nce of re g ulat or y T cells, t u m or P D -L 1  
e x pressi o n, a n d P D - 1 – p ositi ve TI Ls has bee n ass ociate d wit h hi g h hist ol o gic gra de, E R 
ne gati vit y , a n d pr o mi ne nt t u m or l ym p h oc y tic i nfiltrati o n [6 2 ].  In a n i n de pe n de nt st u d y, P D -
L 1 was f o u n d e x presse d i n 2 3 % of breast ca ncer s peci me ns a n d it was a gai n ass ociate d wit h 
a ge, t u m or size, A merica n J oi nt C o m mittee o n Ca ncer ( AJ CC) pri mar y  tu m or classificati o n, 
t u m or gra de, l ym p h n o de stat us, a bse nce of E R e x pressi o n, a n d hi g h e x pressi o n of t he 
pr oliferati o n mar ker Ki -6 7 [6 3 ].  A rece nt p u blicati o n re p orte d t hat P D -L 1  messe n ger 
ri b o n ucleic aci d ( m R N A) is e x presse d i n nearl y 6 0 % of breast t u m ors, i n de pe n de ntl y of H R 
stat us, a n d is p ositi vel y  correlate d wit h P D -L 1  pr otei n e x pressi o n a n d i ncrease d TI Ls [6 4 ].  
A n ot her st u d y mi ni n g t he Ca ncer Ge n o me Atlas ( T C G A) R N A se q ue nci n g data s h o we d t hat 
P D -L 1  ge ne e x pressi o n is si g nifica ntly hi g h er i n T N B Cs c o m pare d t o n o n - T N B Cs, a n d is 
ass ociate d wit h P h os p hatase a n d T e nsi n H o m ol o g ( P T E N) l oss; i n t he sa me st u d y, P D -L 1  
was f o u n d e x presse d i n 2 0 % of T N B Cs [6 5 ].  Fi nall y, i n a n a bstract prese nte d i n t he 2 0 1 4 
A merica n S ociet y of Cli nical O nc ol o g y  ( AS C O) A n n ual meeti n g, it was re p orte d t hat P D -L 1  
pr otei n le vels are p ositi vel y  correlate d wit h e x pressi o n of ot her i m m u ne re g ulat ors, s uc h as 
C T L A- 4 a n d I n d olea mi ne 2, 3 -Di O x y ge nase 1 (I D O 1), a n d wit h 
a n dr o ge n rece pt or 
( A R)-ne gati ve a n d B R C A 1 -m uta nt T N B C [1 0 4] .  Des pite t heir disc or da nce i n t he re p orte d 
a bs ol ute P D -L 1 le vels i n breast t u m ors, t he af ore me nti o ne d st u dies clearl y de m o nstrate t hat 
T N B Cs are c haracterize d b y  PD- L 1 p ositi vit y  an d prese nce of TI Ls, a n d t h us s u g gest t hat 
P D -1 i m m u ne c hec k p oi nt i n hi biti o n is a t hera pe utic strate g y wort h y of f urt her i n vesti gati o n 
f or t he treat me nt of t his a g gressi ve breast ca ncer s u bt ype.  
Pr o of -of -Pri nci ple St u d y f or P e m br oliz u m a b use i n m T N B C
4. 1. 5
K N -0 1 2 - Cli nic al d at a s u p p orti n g pe m br oliz u m a b use f or t he tre at me nt of m T N B C . I n 
t he first re p ort of cli nical acti vit y of a n i m m u ne c hec k p oi nt i n hi bit or i n T N B C, a Merc k -
s p o ns ore d m ulti -ce nter, n o n -ra n d o mize d P hase I b trial ( K N-0 1 2) s h o we d t hat si n gle a ge nt 
pe m br oliz u ma b gi ve n at 1 0 m g/ k g I V Q 2 W is a well -t olerate d a n d effecti ve treat me nt wit h 
si g nifica nt t hera pe utic acti vit y i n a s u bset of hea vil y pre-treate d s u bjects wit h m T N B C.  
Met h o ds: P D -L 1  ex pressi o n in ≥1 % t u m or cells or i n str o ma (ie, P D -L 1 p ositi ve m T N B C)
was re q uire d f or st u d y entr y .  PD- L 1  tu m or stat us was deter mi n e d b y  im m u n o hist oc he mical 
a nal ys is of arc hi val t u m or s peci me ns usi n g t he Merc k pr o prietar y  22 C 3 a nti b o d y ( Q ualte k 
assa y).  Pri mar y objecti ves of t his st u d y were t o deter mi ne t he safety,  tolera bilit y , a n d 
a ntit u m or acti vit y of pe m br oliz u ma b i n s u bjects wit h
P D -L 1  positi ve m T N B C. Sec o n dar y 
o bjecti ves i ncl u de d assess me nts of P F S, O S, a n d D O R.  Ad verse e ve nts ( A Es) re p orte d i n 
a n y s u bject recei vi n g at least 1 d ose of st u d y treat me nt were m o nit ore d a n d gra de d usi n g 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts versi o n 4. 0 
(Nati o nal Ca ncer I nstit ute [N CI ] C T C A E v. 4. 0).  T u m or i ma gi n g was o btai ne d e ver y 
8 wee ks a n d e val uate d b y  bot h I n vesti gat or a n d a ce ntral i ma gi n g ve n d or t o assess cli nical 
res p o nses as defi ne d by R E CI S T 1. 1. 
Res ults: A t otal of 3 2 fe male s u bjects wit h a me dia n a ge of 5 0. 5 ye ars (ra n ge 2 9 -7 2 ye ars) 
a n d P D -L 1 p ositi ve m T N B C were e nr olle d i n t he st u d y (t he pre vale nce of P D -L 1 t u m or 
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
2 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
p ositi vit y  in m T N B C was 5 8 %, as deter mi ne d b y  the Q ualte k assa y).  Most of t hese s u bjects 
ha d recei ve d a n d pr o gresse d o n m ulti ple li nes of t hera p y for a d va nce d disease ( 4 7 % of 
s u bjects ha d recei ve d ≥3 pri or treat me nts i n t he metastatic setti n g).  Acc or di n g t o data 
t hr o u g h 0 6 - N o v-2 0 1 4, fi ve s u bjects ( 1 5. 6 %) e x perie nce d at least o ne dr u g-relate d S A E; eac h 
of f o ur s u bjects e x perie nce d o ne of t he f oll o wi n g: Gra de 3 a ne mia, hea dac he, ase ptic 
me ni n gitis or p y re xia, a n d a fift h s u bject e x perie nce d Gra de 5 disse mi nate d i ntra vasc ular 
c oa g ulati o n ( DI C) wit h t hr o m b oc yt o pe nia a n d decrease d bl o o d fi bri n o ge n. Of t he 2 7 s u bjects 
wit h ce ntral l y c o nfir me d meas ura ble disease, o ne s u bject ( 3. 7 %) ha d a c o m plete res p o nse 
( C R), 4 s u bjects ( 1 4. 8 %) ha d a c o nfir me d partial res p o nse ( P R), 2 5. 9 % ha d sta ble disease 
( S D), a n d 4 4. 4 % ha d pr o gr essi ve disease ( P D) base d o n R E CI S T 1. 1 as assesse d b y  ce ntral 
i ma gi n g ve n d or . As of 0 6 - N o v-2 0 1 4, t he me dia n d urati o n of res p o nse ha d n ot bee n reac he d 
(ra n ge 1 5 t o 4 0 + wee ks), a n d t hree s u bjects ( 1 C R; 2 P R) were still o n treat me nt after at l east 
1 1 m o nt hs.
C o ncl usi o ns: T his is t he first re p ort of cli nical acti vit y of a n i m m u ne c hec k p oi nt i n hi bit or i n 
T N B C.   The preli mi nar y  res ults fr o m t his st u d y s u g gest t hat si n gle a ge nt M K -3 4 7 5 is a 
well -t olerate d a n d effecti ve treat me nt wit h si g nifica nt thera pe utic acti vit y i n a s u bset of 
hea vil y  pre-treate d s u bjects wit h rec urre nt/ metastatic tri ple -ne gati ve breast ca ncer .
R ati o n ale
4. 2
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
4. 2. 1
K N -1 1 9: R ati o n ale f or usi n g pe m br oliz u m a b as 2- 3 L m o n ot her a p y 
f or m T N B C . 
S u bject s wit h T N B C w h ose disease has pr o gresse d o n at least o ne s yste mic treat me nt f or 
m T N B C ha ve a dis mal pr o g n osis wit h a P F S of 2- 3 m o nt hs a n d O S of 9- 1 2 m o nt hs [6 6 - 7 1].  
Nearl y all ha ve bee n pre vi o usl y treate d wit h a nt hrac ycli nes(s) a n d ta xa ne(s ), a n d will recei ve 
si n gle a ge nt c he m ot hera p y as a 2 L + re gi me n [7 2 ].  As t here is n o esta blis he d sta n dar d of care 
( S O C) f or m T N B C, a n y dr u g a p pr o ve d f or t he treat me nt of metastatic breast ca ncer, s uc h as
ca pecita bi ne, eri b uli n, ge mcita bi ne, 
or
vi n orel bi ne,
m a y  be use d .  T o
date, n o 
m T N B C -f oc use d cli nical trial has e val uate d t he efficac y of a n y of t he a b o ve me nti o ne d 
a ge nts; hist orical data c o m es fr o m pre -s pecifie d ( 1 st u d y) a n d, m ore c o m m o nl y, retr os pecti ve 
T N B C s u b gr o u p a nal ys is of ra n d o mize d P hase III st u dies i n metastatic breast ca ncer ( M B C;
all s u bt ypes or e xcl u di n g H E R 2 -p ositi ve disease) (Ta ble 1 ). I n a retr os pecti ve T N B C 
s u b gr o u p a nal ys is of t he ra n d o mize d P hase III RI B B O N -2 trial, w hic h i n vesti gate d t he 
c o m bi nati o n of be vaciz u ma b wit h c he m ot hera p y f or M B C 
[7 3 ], si n gle a ge nt ta xa ne, 
ge mcita bi ne, ca pecita bi ne, or vi n orel bi ne as 2 L  mo n ot hera p y  for m T N B C res ulte d i n a n
O R R of 1 8 %, P F S of 2. 7 m o nt hs, a n d O S
of 1 2. 6 m o nt hs [7 4 ]
I n the P hase III st u d y 
c o m pari n g t he c o m bi nati o n of ca pecita bi ne a n d i xa be pilo ne t o si n gle a ge nt ca pecita bi ne as 
2 L + treat me nt f or M B C, ca pecita bi ne s h o we d a n O R R of 9 %, P F S of 2. 1 m o nt hs, a n d O S of 
9 m o nt hs i n m T N B C, acc or di n g t o a pre -s pecifie d s u b gr o u p a nalys is [7 6 ]. I n t he E M B R A C E 
P hase III o pe n -la bel, ra n d o mize d st u d y co m pari n g eri b uli n t o T P C ( T P C, i ncl u di n g si n gle 
a ge nt ta xa ne, ge mcita bi ne, ca pecita bi ne, a n d vi n orel bi ne a m o n g ot hers ) as 3 L + t hera p y for 
M B C, 
eri b uli n s h o we d a n O R R of 1 2 %, P F S of 3. 7 m o nt hs, a n d O S
of 1 3. 1 m o nt hs 
c o m pare d t o O R R of 5 %, P F S of 2. 1 m o nt hs, a n d O S of 1 0. 6 m o nt hs ( H R 0. 8 1; P = 0. 0 4 1) 
f or T P C i n all s u bjects i n de pe n de nt of breast ca ncer s u bt y pe [ 75] ; h o we ver, efficacies of 
eri b uli n a n d T P C i n m T N B C were n ot re p orte d.  Acc or di n g t o a p o ol e d retr os pecti ve 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
2 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
s u b gr o u p a nal ys is of E M B R A C E a n d st u d y # 3 0 1 (eri b uli n vs ca pecita bi ne as 1- 3 L 
m o n ot hera p y f or M B C), eri b uli n e xte n de d O S c o m pare d t o T P C i n s u bjects recei vi n g 1- 3 L +
treat me nt f or m T N B C, as it s h o we d a O S of 1 2. 4 m o nt hs c o m pare d t o 8. 2 m o nt hs f or T P C
( H R 0. 7 4; P = 0. 0 0 6) [ 9 5]; P F S was als o l o n ger f or eri b uli n ( 2. 8 m o nt hs) c o m pare d t o T P C
( 2. 6 m o nt hs), b ut t he differe nce was s mall a n d n ot cli nicall y si gnifica nt, des pite reac hi n g 
statistical si g nifica nce ( H R 0. 7 8; P = 0. 0 1 8). 
Ta ble 1
Efficac y  of C urre ntl y Use d 2 L + M o n ot hera p y Re gi me ns i n m T N B C
St u d y
Li ne T x
Dr u g/ Dr u g c o m b o
O R R %/ P F S m o/ O S m o
Refere nce
RI B B O N -2 P hase III st u d y -
Retr os pecti ve T N B C 
s u b gr o u p a nal ysis
2 L
Ta xa ne or ca pe cita bi ne
or ge m cita bi ne or 
vi n orel bi ne
1 8/ 2. 7/ 1 2. 6
[7 4 ]
P hase III st u d y -pres pecifie d 
T N B C s u b gr o u p a nal ysis
2 L +
Ca pecita bi ne
9/ 2. 1/ 9
[7 6 ]
E M B R A C E a n d # 3 0 1 P hase 
III st u dies-Retr os pecti ve 
T N B C s u b gr o u p a nal ysis
1- 3 L +
Eri b uli n
N R/ 2. 8/ 1 2. 4
[9 5 ]
T P C (ta xa ne, 
ca pecita bi ne , 
ge m cita bi ne, vi n orel bi ne, 
etc.)
N R/ 2. 6/ 8. 2
Gi ve n
( 1) t he p o or o utc o me of s u bjects wit h a d va nce d m T N B C, ( 2) t he lac k of T N B C-
s pecific sta n dar d of care f or t he treat me nt of m T N B C, ( 3) t he pa ucit y  of p u blis he d res ults 
fr o m P hase III cli nical trials pr os pecti vel y e nr olli n g m T N B C s u bjects, a n d ( 4) t he pr o misi n g 
a ntit u m or a n d safety pr ofile of pe m br oliz u ma b i n hea vil y pretreate d m T N B C 
as 
de m o nstrate d b y  the pr o of - of-c o nce pt K N - 0 1 2 st u d y, w hic h s h o we d a n O R R of 1 8. 5 % a n d 
res p o nse d ura bil it y, p ote ntial use of pe m br oliz u ma b as a 2-3 L  m o n ot hera p y for m T N B C will 
be f urt her i n vesti gate d i n a lar ge ra n d o mize d o pe n -la bel P hase 3 st u d y (K N -1 1 9) c o m pari n g 
si n gle a ge nt pe m br oliz u ma b t o T P C m o n ot hera p y. 
K N -1 1 9: R ati o n ale f or c h oice of a ntic a ncer dr u gs i n t he c o m p ar at or ar m . At prese nt 
t here are n o dr u gs s pecificall y ap pr o ve d or c o nsi dere d S O C f or t he treat me nt of m T N B C. 
I nstea d, dr u gs a p pr o ve d f or metastatic 
breast ca ncer are als o use d f or m T N B C. 
T he 
Treat me nt of P h y sicia n’s C h oice ( T P C) is base d o n c o m m o n usa ge of t hese dr u gs f or 
metastatic breast ca ncer, pri or i ncl usi o n of t hese dr u gs as T P C i n P hase III st u dies f or 
metastatic breast ca ncer, a n d i n p ut fr o m scie ntific lea ders.
T he E M B R A C E st u d y, a pi v otal st u d y lea di n g t o t he a p pr o val of eri b uli n f or metastatic 
breast ca ncer, di d n ot restrict t he n u m ber of dr u gs t hat c o ul d be use d as T P C i n t he 
c o m parat or ar m. H o we ver, o ne of t he criticis ms of t he E M B R A C E st u d y desi g n was t hat 
all o wi n g se veral differe nt c he m ot hera pies, eac h wit h t heir o w n t o xicit y pr ofile, precl u de d 
detaile d c o m paris o ns wit h eri b uli n [ 7 5].  KN- 1 1 9 ai ms t o restrict t he T P C t o f o ur fre q ue ntl y 
use d c he m ot hera pies, na mel y  ca pecita bi ne, eri b uli n, ge mcita bi ne, or vi n orel bi ne, base d o n 
ge o gra p hical, i nstit uti o nal a n d p h y sicia n’s prefere nce in or der t o perf or m a m ore detaile d 
c o m paris o n wit h pe m br oliz u ma b. T he a ntica ncer dr u gs i ncl u de d as T P C will be ha n dle d 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
2 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g c o u ntries. F urt her m ore, if a 
T P C is n ot a p pr o ve d i n a partic ular c o u ntr y, t his partic ular a ge nt ca n n ot be use d a n d selecte d 
via i nteracti ve v oice res p o nse s yste m (I V R S) d uri n g ra n d o mizati o n.
Ca pecita bi ne has a re gistere d i n dicati o n f or t he treat me nt of s u bjects wit h metastatic breast 
ca ncer resista nt t o b ot h paclita xel a n d a n a nt hrac ycli ne-c o ntai ni n g c he m ot hera p y re gi me n or 
resista nt t o paclita xel a n d f or w h o m 
f urt her a nt hrac ycli ne t hera p y is n ot i n dicate d.  
Resista nce is defi ne d as pr o gressi ve disease w hile o n treat me nt, wit h or wit h o ut a n i nitial 
res p o nse, or rela pse wit hi n 6 
m o nt hs of c o m pleti n g treat me nt wit h a n a nt hrac ycli ne -
c o ntai ni n g a dj u va nt re gi me n.
Eri b uli n has a re gistere d i n dicati o n f or usa ge as a si n gle a ge nt i n t he treat me nt of metastatic 
breast ca ncer s u bjects w h o ha ve pre vi o usl y  recei ve d at least o ne (i n E U) or t w o (i n U S) 
c he m ot hera pe utic re gi me ns f or t he treat me nt of metastatic disease.  Pri or t hera py m ust als o 
ha ve i ncl u de d a nt hrac y cli ne a n d a ta xa ne i n eit her t he a dj u va nt or metastatic setti n g.  
Ge mcita bi ne has a re gistere d i n dicati o n i n c o m bi nati o n wit h paclit a xel f or first li ne treat me nt 
of metastatic 
breast ca ncer after fail ure of pri or a nt hrac yli ne-c o ntai ni n g a dj u va nt 
c he m ot hera p y u nless a nt hrac y cli nes were cli nicall y c o ntrai n dicate d. 
Vi n orel bi ne has a re gistere d i n dicati o n i n t he U S f or usa ge as a si n gle age nt or i n 
c o m bi nati o n wit h cis plati n f or first li ne treat me nt of s u bjects wit h u nresecta ble, a d va nce d 
n o n- s mall cell l u n g ca ncer ( N S C LC). Alt h o u g h n ot f or mally a p pr o ve d i n t he U S f or t he 
treat me nt of metastatic breast ca ncer, vi n orel bi ne is i ncl u de d i n t he N C C N breast ca ncer 
treat me nt g ui deli nes a n d is c o m m o nl y use d as 2 L + m o n ot hera p y . I n m ost 
E ur o pea n 
c o u ntries, vi n orel bi ne is a p pr o ve d f or metastatic breast ca ncer treat me nt .
R ati o n ale f or i ncl u di n g s u bjects wit h P D -L 1 ne g ati ve t u m ors. T he K N -0 1 2 T N B C pr o of -
of- c o nce pt data was o btai ne d i n s u bjects wit h P D -L 1  p ositi ve t u m ors (ie, P D -L 1  stai ni n g i n 
≥1 % t u m or cells or i n str o ma); n o data is c urre ntl y a vaila ble o n t he perf or ma nce of 
pe m br oliz u ma b i n T N B C s u bjects wit h P D -L 1  ne gati ve t u m ors (ie P D -L 1 stai ni ng i n < 1 % 
t u m or cells a n d n o str o mal stai ni n g).  Due t o t he li mite d efficac y of treat me nt o pti o ns
c urre ntl y a vaila ble i n later ( 2 L +) li ne T N B C, s u bjects wit h P D -L 1  ne gati ve t u m ors ma y  
be nefit fr o m pe m br oliz u ma b.  
K N - 0 8 6: T he perf or ma nce of pe m br oliz u ma b i n s u bjects wit h P D -L 1  ne gati ve t u m ors will 
first be e x pl ore d i n K N - 0 8 6, a t w o-part, n o n-ra n d o mize d, m ulti -site, o pe n -la bel trial of 
pe m br oliz u ma b m o n ot hera p y i n s u bjects wit h m T N B C .  
I n Part 1 , s u bjects will be e nr olle d i n 2 c o h orts, C o h ort A (2 L + m o n ot hera p y f or m T N B C 
i n de pe n de nt of P D -L 1 stat us, ~ 1 6 0 s u bjects) a n d C o h ort B
(1 L m o n ot hera p y  for P D -L 1  
p ositi ve
m T N B C, 
~ 4 0 s u bjects) t o e xa mi ne t he efficac y an d safet y of si n gle a ge nt 
pe m br oliz u ma b i n t he treat me nt of m T N B C.  T he relati o ns hi p bet wee n res p o nse t o treat me nt 
a n d P D- L 1 pr otei n e x pressi o n i n m T N B C will be e x pl ore d i n C o h ort A.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
2 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T w o i nteri m efficac y a nal yses (I A 1 a n d 2) will be perf or me d o n C o h ort A. 
I A 1: Su bjects i n C o h ort A will i nitiall y be e nr olle d i n de pe n de nt of P D -L 1 t u m or stat us.  A 
f utilit y anal y sis (I A 1) will be d o ne o n t he P D -L 1 ne gati ve s u b p o p ulati o n of C o h ort A t o 
e val uate res p o nse i n t his gr o u p.   If treat me nt wit h pe m br oliz u ma b is f o u n d t o be f utile i n 
s u bjects wit h P D -L 1  ne gati ve t u m ors, t he n f urt her e nr oll me nt i n C o h ort A will be li mite d t o 
s u bjects wit h P D-L 1  p ositi ve t u m ors, i ncl u di n g P D-L 1 str o n g p ositi ve t u m ors. 
I A 2 will be d o ne i n C o h ort A t o l o o k at res p o nses i n s u bjects wit h P D -L 1 str o n g p ositi ve
t u m ors.  In t his s u b p o p ulati o n, at least 1 0 s u bjects wit h P D -L 1  str o n g p ositi ve t u m ors nee d t o 
be e nr olle d f or res p o nse assess me nt a n d at least o ne res p o n der is re q uire d t o i nitiate Part 2, 
w hic h will o pe n after e nr oll me nt i n C o h ort A is c o m plete d.  
Part 2 will e xa mi ne w het her hi g her t u m or P D -L 1 e x pressi o n, as deter mi ne d b y  a pr ot ot yp e 
i m m u n o hist oc he mistr y (I H C) assa y, is ass ociate d wit h i ncrease d pr o ba bilit y  of res p o nse t o 
pe m br oliz u ma b i n m T N B C, as it has bee n s h o w n t o be i n ot her t u m or t ypes , s uch a s 
a d va nced N S C L C [ 1 0 3 ].
K N - 1 1 9: R ati o n ale f or I ncl u di n g S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1). T he 
P D -L 1  IH C assa y ( Da k o assa y), w hic h will be use d i n K N -1 1 9, is bei n g de vel o pe d as a 
c o m pa ni o n dia g n ostic a n d will be a vaila ble pri or t o i nitiati o n of K N -1 1 9.  In K N -0 1 2, 
P D -L 1 -p ositi vit y  was defi ne d as ≥1 % t u m or cell stai ni n g or str o mal stai ni n g, a n d was 
deter mi ne d b y  a PD- L 1 pr ot ot y pe I H C assa y ( Q ualte k assa y) t hat is differe nt t ha n t he assa y 
pla n ne d f or K N - 1 1 9 ( Da k o assa y).  The defi niti o n of P D -L 1  positi v it y i n K N -1 1 9 will b e 
ge nerall y e q ui vale nt t o t he defi niti o n use d i n K N - 0 1 2; h o we ver, t he act ual perce nt of 
mi ni m u m p ositi ve stai ni n g re q uire d m a y  be differe nt i n t he ne w assa y. It is als o p ossi ble t hat 
t he pre vale nce of P D -L 1  tu m or p ositi vit y  is differe nt bet wee n t he t w o assa ys, i n w hic h case 
t he sa m ple size a n d statistical c o nsi derati o ns ma y nee d t o be a dj uste d acc or di n gly.
K N - 1 1 9: R ati o n ale f or I ncl u di n g S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0 ).
E val uati o n of O S efficac y b y differe nt C P S c ut offs fr o m ot her i n dicati o ns of pe m br oliz u ma b 
m o n ot hera p y i n t he 2 L + setti n g (ie, hea d a n d nec k s q ua m o us cell carci n o ma [H N S C C ], 
gastric ca ncer, a n d b la d der ca ncer), de m o nstrate a n e nric he d treat me nt effect wit h i ncreasi n g 
P D -L 1  ex pressi o n le vel. Base d o n t hese fi n di n g, a n d t o im pr o v e t he usa ge of bi o mar kers t o 
e n ha nce t he o verall be nefit :ris k pr ofile of pe m br oliz u ma b, C P S ≥1 0 b y  the Da k o assa y is 
i ncl u de d i n or der t o i de ntif y a n e nric he d s u b p o p ulati o n of patie nts wit h m T N B C w h o c o ul d 
p ote ntiall y  be nefit m ore fr o m pe m br oliz u ma b m o n ot hera p y .
K N -1 1 9: R ati o n ale f or re q uiri n g ce ntr al c o nfir m ati o n of T N B C st at us. Se veral st u dies 
ha ve re p orte d disc or da nce i n e val uati o n of E R, pr o gester o ne rece pt or, a n d H E R 2 stat us 
bet wee n l ocal a n d ce ntral la b orat ories, d ue t o b ot h tec h nical iss ues i n I HC testi n g a n d 
i nter pretati o n iss ues i n FI S H testin g [ 7 7- 7 9]. It is, t h us, rec o m me n de d t hat ce ntral testi n g 
s h o ul d be perf or me d t o deter mi ne trial eli gi bilit y, partic ularl y i n lar ge st u dies i n v ol vi n g 
m ulti ple c olla b orati n g i nstit uti o ns i n se veral c o u ntries [7 7].
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
K N -1 1 9: R ati o n ale f or selecti o n of str atific ati o n f act ors. Gi ve n t hat t he pri mar y  o bjecti ves 
of K N -1 1 9 are O S i n s u bjects wit h P D -L 1  positi ve m T N B C a n d i n all s u bjects, stratificati o n 
f or P D -L 1 t u m or stat us ( p ositi ve [ C P S ≥1] vs . ne gati ve [ C P S < 1] ) will be a p plie d t o e ns ure 
e q ual distri b uti o n of s u bjects wit h P D -L 1  positi ve t u m ors a n d ne gati ve t u m ors bet wee n t he 
t w o st u d y ar ms.
Gi ve n t hat s u bjects w h o are dia g n ose d wit h metastatic disease at t he ti me of i nitial breas t 
ca ncer dia g n osis ge nerall y  ha ve m ore a g gressi ve, a n d p oss i bl y of differe nt bi ol o g y , disease 
t ha n s u bjects w h o i nitiall y prese nt wit h earl y or l ocall y ad va nce d T N B C, stratificati o n f or 
pri or ( ne o)a dj u va nt t hera p y  vs de n ov o metastatic disease at i nitial dia g n osis will be a p plie d.
R ati o n ale f or D ose Selecti o n/ Re gi me n / M o dific ati o n
4. 2. 2
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 K e 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 pro 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 : 
•
Cli 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), 
•
Cli nical data s h o wi n g mea ni n gf ul i m pr o ve me nt i n be nefit -ris k i ncl u di n g o 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 ys is) at 2 0 0 m g Q 3 W
A m o n g t he 8
ra n d o mize d d ose -c o m paris o n st u dies, 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). Fi ve st u dies c o m pare d 
2 m g/ k g Q 3 W vs. 1 0 m g/ k g Q 3 W ( K N 0 0 1 B 2, K N 0 0 1 D, K N 0 0 2, K N 0 1 0 a n d K N 0 2 1), a n d 
3 st u dies c o m pare d 1 0 m g/ k g Q 3 W vs. 1 0 m g/ k g Q 2 W ( K N 0 0 1 B 3, K N 0 0 1 F 2 a n d K N 0 0 6). 
All 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 di ffere 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 c a 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 y pe. 
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 sh o w tar get sat urati o n at 2 0 0 m g  Q3 W. First, P K 
data 
i n K N 0 0 1 
e val uati n g 
tar get-me diate d 
dr u g 
dis p ositi o n 
( T M D D) c o ncl usi vel y 
de m o nstrate d sat urati o n of P D -1 i n s yste mic circ u lati o n at d oses m uc h l o wer t ha n 2 0 0 m g  
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 s at 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 osi n g 
pr o vi des si milar c o ntr ol of P K varia bilit y  as w e i 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  Q3 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 va 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 oliz u ma b pr ot oc ols.
R ati o n ale f or E n d p oi nts
4. 2. 3
4. 2. 3. 1
Effic ac y E n d p oi nt s
Pri m ar y:
O S
was
selecte d as t he pri mar y  en d p oi nt f or K N -1 1 9 , beca use O S
has bee n 
rec o g nize d as t he g ol d sta n dar d f or de m o nstrati o n of s u peri orit y of a ne w a nti ne o plastic 
t hera py i n a ra n d o mize d P hase III trial .
Sec o n d ar y :  P F S, O R R, d urati o n of res p o nse (D O R ) a n d D C R base d o n R E CI S T 1. 1 are 
c o m m o nl y use d efficac y e n d p oi nts i n P hase III cli nical trials. T o mi ni mize bias i n ce ntral 
res p o nse assess me nts, i ma gi n g sca ns will be assesse d b y  bli n de d ce ntral i ma gi n g ve n d or . I n 
a d diti o n, ra di ol o gic pr o gressi o n b y  RE CI S T 1. 1 will be base d o n t he ce ntral assess me nt of 
pr o gressi o n, rat her t ha n site assess me nt. 
E x pl or at or y : ir R E CIS T is a n a da ptati o n of R E CI S T 1. 1 t o acc o u nt f or t he u ni q ue t u m or 
res p o nse c haracteristics
t o treat me nt wit h 
ne w i m m u n ot hera pe utic
a ge nts, i ncl u di n g 
pe m br oliz u ma b .
R E CI S T 1. 1 was de vel o pe d base d o n treat me nt wit h c yt ot o xic a ge nts. 
I m mu n ot hera pe utic dr u gs , s uc h as pe m br oliz u ma b,
m a y  pr o d uce a ntit u m or effects b y  
p ote ntiati n g e n d o ge n o us ca ncer -s pecific i m m u ne res p o nses.  T he res p o nse patter ns see n wit h 
s uc h a n a p pr oac h ma y e xte n d be y o n d t he t ypical ti me c o urse of res p o nses see n wit h 
c yt oto xic a ge nts, a n d ca n ma nifest as cli nical res p o nse s after i nitial i ncrease s i n t u m or b ur de n 
or e ve n t he a p peara nce of ne w lesi o ns.  Sta n dar d R E CI S T 1. 1 ma y , t h us, n ot pr o vi de a n 
acc urate assess me nt of res p o nse t o i m m u n ot hera pe utic a ge nts , s uc h as pe m br oliz u ma b, a n d 
will t heref ore be use d wit h t he a da ptati o ns descri be d i n Secti o n 7. 1. 2. 7 a n d referre d t o as 
ir R E CIS T .
4. 2. 3. 2
Selecti o n of P atie nt R e p orte d O utc o mes Instr u me nts
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. It has bee n
tra nslate d a n d vali date d i nt o 8 1 la n g ua ges a n d use d i n m ore t ha n 3, 0 0 0 st u dies w orl d wi de. It
c o ntai ns 5 f u ncti o ni n g scales ( p hys ical, r ole, c o g niti ve, e m oti o nal, a n d s ocial), 3 s ym pt o m
scales (fati g ue, na usea, pai n) a n d a d diti o nal si n gle s ym pt o m ite ms. 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). T he E O R T C Q L Q -C 3 0 i nstr u me nt 
als o c o ntai ns 2 gl o bal scales t hat use 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).
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
3 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
E O R T C Q L Q- B R 2 3 is a q ualit y  of life q uesti o n naire de vel o pe d t o assess t he e xte nt of 
s ym pt o ms or pr o ble ms i n s u bjects recei vi n g treat me nt f or breast ca ncer.  The t o ol is use d i n 
c o nj u ncti o n wit h t he E O R T C Q L Q -C 3 0 a n d f oll o ws t he sa me 4- p oi nt scale descri be d a b o ve.  
T u m or l ocati o n, treat me nt, a n d q ualit y  of life di me nsi o ns are disease -s pecific as pects 
i nc or p orate d i nt o q uesti o n desi g n.  The t o ol c o nsists of 2 3 q uesti o ns a n d is di vi de d i nt o t w o 
secti o ns; o ne secti o n w it h a recall peri o d of o ne wee k a n d o ne secti o n wit h a recall peri o d of 
f o ur weeks.  
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. T he E Q -5 D -3 L will be use d t o calc ulate utilit y  val ues t o i nc or p orate i nt o Q T W i S T 
a n d healt h ec o n o mic m o dels.  T he 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 3- p oi nt scale fr o m 1 (e xtre me pr o ble m) t o 3 ( n o pr o ble m). T he 
e E Q-5 D will 
al wa ys be c o m plete d b y  su bjects first bef ore
co m pleti n g t he e E O R T C 
Q L Q -C 3 0 a n d e E O R T C Q L Q -B R 2 3.
4. 2. 3. 3
S afet y E n d p oi nts
C o m m o nl y  use d safety para meters f or e val uati n g i n vesti gati o nal s yste mic a nti-ca ncer 
treat me nts are i ncl u de d as safet y en d p oi nts f or t he st u d y  i ncl u di n g rate of A E/ S A Es a n d fatal 
S A Es, ca usalit y a n d o utc o me of A E/ S A Es, rate of treat me nt disc o nti n uati o ns a n d reas o ns, 
c ha n ges i n vital si g ns, la b orat or y val ues etc. Gra di n g of A E/ S A Es will be base d o n N CI
C T C A E , Versi o n 4. 0.
4. 2. 3. 4
Pl a n ne d E x pl or at or y Bi o m ar ker Rese arc h
Ne wl y o btai ne d
c ore or e xcisi o nal bi o psies o btai ne d fr o m metastatic, 
n ot pre vi o usl y 
irra diate d, lesi o ns will be use d f or P D -L 1  assess me nt b y  IH C.  Arc hi val t u m or bi o psies will 
als o be o btai ne d, w he n a vaila ble, t o c o m pare t he perf or ma nce of t he P D -L 1 I H C assa y in 
arc hi ve d vers us ne wl y o btai ne d t u m or tiss ues.
A d diti o nal bi o mar ker a n d ot her bi o me dical researc h t o i de ntif y fact ors i m p orta nt f or 
pre dicti n g res p o nsi ve ness or resista nce t o pe m br oliz u ma b t hera p y in m T N B C will als o be 
p urs ue d.  Pre-treat me nt, o n treat me nt, a n d at t he ti me of disease pr o gressi o n t u m or bi o psies 
a n d bl o o d sa m ples (i ncl u di n g ser u m a n d plas ma) will be c ollecte d as descri be d i n Secti o n
6. 0. T u m or a n d bl o o d s peci me ns ma y
be e val uate d b y  hist o pat h ol o gic, tra nscri pti o nal,
ge n o mic [i ncl u di n g tar gete d ne xt ge nerati o n se q ue nci n g ( N G S), w h ole e x o me se q ue nci n g 
( W E S) a n d w h ole ge n o me se q ue nci n g ( W G S)] a n d pr ote o mic a nal ys es, as descri be d bel o w. 
P orti o ns of t u m or a n d bl o o d s peci me ns will be st ore d f or f ut ure a nal ys es.
Assa y s m a y i ncl u de, b ut are n ot be li mite d, t o:
I m m u n o hist oc he mistr y
I n a d diti o n t o deter mi ni n g P D -L 1 e x pressi o n i n t u m or tiss ues b y  IH C as descri be d earlier, 
ot her e x pl orat or y bi o mar kers (e g P D - 1 e x pressi o n, mar kers of T cell p he n ot y pe) ma y  als o be 
e val uate d.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
3 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Tiss ue I nfiltr ati n g L y m p h oc ytes 
Tiss ue i nfiltrati n g l ym p h oc y tes ha ve bee n s h o w n t o pr o vi de pr o g n ostic a n d p ote ntiall y 
pre dicti ve val ue, partic ularl y  in T N B C [6 4, 8 0- 8 2] a n d H E R 2- o vere x pressi n g breast ca ncer 
[ 8 1, 8 3, 8 4]. He mat o x yl i n a n d e osi n ( H & E)-stai ne d breast t u m or secti o ns ca n be e va l uate d 
f or TI Ls, acc or di n g t o a rece ntly p u blis he d sta n dar dize d met h o d ol o g y [ 3].
Tr a nscri pti o n al A n al yses
Messe n ger R N A ( m R N A) e x pressi o n pr ofili n g i n t u m or s peci me ns a n d peri p heral bl o o d will 
be c o m plete d t o assess e x pressi o n eit her b y  RN Ase q or mi d -de ns it y R N A platf or m of 
a p pr o xi matel y 70 0 ge nes a n d atte m pt t o defi ne a ge ne set critical f or cli nical res p o nse t o 
pe m br oliz u ma b.   T he h y p ot hesis t o be teste d is t hat pe m br oliz u ma b i n d uces res p o nses i n 
t u m ors t hat reflect a n i nfla m mat or y/i m m u ne cell-ric h p he n o t ype base d o n ge ne e x pressi o n 
si g nat ures ca pt uri n g P D -L 1 a n d I F N-γ tra nscri pti o nal pr o gra ms.  Gl o bal pr ofili n g m a y
als o 
be p urs ue d.  Ex pressi o n of i n di vi d ual ge nes relate d t o t he i m m u ne s yste m ma y  als o b e 
e val uate d, s uc h as i m m u ne si g nat ures a n d critical c yt o ki nes (e g, I L-1 0).  
Micr o R N A 
pr ofili n g ma y  als o be p urs ue d i n ser u m sa m ples.
Ge n o mic A n al yses
T he a p plicati o n of ne w tec h n ol o gies s uc h as N G S, W E S, 
a n d W G S 
has pr o vi de d t he 
o p p ort u nit y  to defi ne certai n t u m or t ypes at t he ge netic le vel as bei n g ‘ hy per m utate d’ a n d t o 
detect t he prese nce of s pecific T cell cl o nes wit hi n t he t u m or micr oe n vir o n me nt or i n t he 
peri p heral bl o o d [ 8 5- 8 7].  It is p ossi ble t hat t he h y per m utate d state (a n d/ or i ncrease d T cell 
cl o nalit y) or t he h y p o m utate d state (a n d/ or lac k of d o mi na nt T cell cl o nes) m a y  correlate 
wit h res p o nse t o pe m br oliz u ma b i n T N B C.  
I n ad diti o n, u n dersta n di n g s o matic a n d ger mli ne ge netic deter mi na nts of dr u g res p o nse is a n 
i m p orta nt e n dea v or d uri n g me dical researc h.  Tar gete d N G S m a y
b e use d t o e val uate
w het her s o matic ge netic variati o ns, ie, i n t u m ors, circ ulati n g t u m or cells ( C T Cs) a n d 
circ ulati n g t u m or D N A [ 8 8], a n d/ or ger mli ne D N A m utati o ns c orrelate wit h res p onse t o 
pe m br oliz u ma b i n m T N B C. Partic ular e m p hasis will be place d o n t he f oll o wi n g bi ol o gic al 
deter mi na nts/ pat h wa y s: B R C A 1/ 2, PI 3 K, P T E N, E G F R, M E K, 
F G F R, M E T, 
a n d N otc h 
si g nali n g [ 8 9- 9 2].  Micr osatellite 
i nsta bilit y 
ma y als o be e val uate d.
A
h o m ol o g o us 
rec o m bi nati o n defect (H R D ) assa y m a y be use d i n t his st u d y.  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 his data mi g ht i nf or m o pti mal use of pe m br oliz u ma b i n 
f ut ure st u dies e nr olli n g s u bjects wit h T N B C.
Pr ote o mic A n al yses
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  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 [ 9 3].  E nz y me-li n ke d i m m u n oassa y ca n meas ure P D -L 1 i n ser u m a n d c orrelate 
t his e x pressi o n wit h res p o nse t o pe m br oliz u ma b t hera py a n d P D -L 1 pr otei n i n t he t u m or.  
Bl o o d w o ul d be a less i n vasi ve c o m p o ne nt fr o m w hic h t o meas ure P D-L 1  pr otei n bi o mar ker.  
I n a d diti o n t o t his s pecific pr otei n bi o mar ker, b ot h tiss ue a n d bl o o d deri vati ves ca n be 
s u bjecte d t o pr ote o mic pr ofili n g st u dies usi n g a variet y of platf or ms t hat c o ul d i ncl ude, b ut 
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
are n ot li mite d t o, i m m u n oassa y, li q ui d c hr o mat o gra p h y a n d/ or 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 ker(s) t hat c o ul d ai d i n s u bject selecti o n f or 
pe m br oliz u ma b t hera p y i n T N B C.
Pl a n ne d Ge netic A n al ysis
U n dersta n di n g ge netic deter mi na nts of dr u g res p o nse is a n i m p orta nt e n dea v or d uri n g
me dical researc h.  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 s u bject p o p ulati o n. T his researc h c o ntri b utes t o u n dersta n di n g ge netic deter mi na nts of 
efficac y a n d safety ass ociate d wit h t he treat me nts i n t his st u d y. 
4. 2. 3. 5
F ut ure Bi o me dic al Rese arc h
T he S p o ns or 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 h er a nal yt 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. F or i nsta nce, e x pl orat or y 
p har mac o ge netic 
( P Gt) 
st u dies 
ma y 
be 
perf or me d 
if 
si g nifica n t 
P har mac o ki netic/ P har mac o d y na mic ( P K/ P D) relati o ns hi ps are o bser ve d or a d verse e ve nts 
are i de ntifie d.  Ge n o mic mar kers of disease ma y als o be i n vesti gate d.  Suc h retr os pecti ve 
p har mac o ge netic st u dies will be c o n d ucte d wit h a p pr o priate bi ostatistical desi g n a n d a nal y sis 
a n d c o m pare d t o P K/ P D res ults or cli nical o utc o mes. A n y  si g nifica nt P Gt relati o ns hi ps t o 
o utc o me w o ul d re q uire vali dati o n i n f ut ure cli nical trials. 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 / vaccines , 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 d ical 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
4. 3
S u bjects i n cli nical trials ge nerall y  ca n n ot e x pect t o recei ve direct b e nefit fr o m treat me nt 
d uri n g partici pati o n, as cli nical trials are desi g ne d t o pr o vi de i nf or mati o n a b o ut t he safet y 
a n d effecti ve ness of a n i n vesti gati o nal me dici ne.
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 me nts.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A d diti o nal p ote ntial be nefit s are a d dresse d i n S ecti o n 4. 1. 5 , w hic h details res p o nses t o 
pe m br oliz u ma b i n t he T N B C c o h ort of t he m ulti -c o h ort P hase I b st u d y, K N- 0 1 2, w hic h 
e nr olle d s u bjects wit h 
P D -L 1 -p ositi ve (i n ≥1 % of t u m or cells or i n str o ma, b y  
i m m u n o hist oc he mistr y) t u m ors. Si milar t o pe m br oliz u ma b st u dies i n ot her t u m or t ypes, t he 
m ost 
c o m m o n a d verse e ve nts i ncl u de d fati g ue ( 1 7. 9 %), decrease d a p petite ( 1 2. 8 %), 
h y p ot h y r oi dis m ( 1 2. 8 %), a n d art hral gia ( 1 0. 3 %). 
T he safet y an d efficac y data will be s u b mitte d t o a n e xter nal Data M o nit ori n g C o m mittee 
(D M C ) f or re vie w.
5. 0 M E T H O D O L O G Y
E ntr y Criteri a
5. 1
Di a g n osis/ C o n diti o n f or E ntr y i nt o t he Tri al
5. 1. 1
Fe male
a n d male
s u bjects wit h 
Sta ge 
I V/ M 1 m T N B C
w h o 
f ulfill t he f oll o wi n g 
i ncl usi o n/e xcl usi o n criteria will be e nr olle d i n t his trial.
S u bject I n cl usi o n Criteri a
5. 1. 2
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 si g ne d i nf or me d c o nse nt .
2.
Be 1 8 y ears of a ge o n da y  of si g ni n g i nf or me d c o nse nt.
3.
Ha ve recei ve d eit her o ne or t w o pri or s yste mic treat me nts f or metastatic breast ca nce r 
a n d ha ve d oc u me nte d disease pr o gressi o n o n or after t heir m ost rece nt t hera p y .  
4.
Ha ve bee n pre vi o usl y treate d wit h a n a nt hrac ycli ne a n d / or ta xa ne i n t he ( ne o)a dj u va nt or 
metastatic setti n g. 
5.
Ha v e ce ntr al l y c o nfir m e d m T N B C
(deter mi n e d b y
a n e w l y o btai n e d c o r e or 
ex ci si o nal bi o ps y fr o m a metasta tic, n ot pre vi o us ly irra diated, t u mor lesi o n).
6.
Ha ve meas ura ble disease base d o n R E CI S T 1. 1 as assesse d b y  site I n vesti gat or a n d l ocal 
ra di ol o g y re vie w.
7.
Ha ve pr o vi de d a ne wl y  obtai ne d c ore or e xcisi o nal bi o ps y  fr o m a metastatic, n ot 
pre vi o usl y  irra diate d, t u m or lesi o n f or ce ntral deter mi nati o n of tri ple-ne gati ve breast 
ca ncer stat us a n d P D -L 1  bi o mar ker a nal ys is. A de q uac y  of t he bi o ps y s peci me n f or t he 
a b o ve a nal ys es m ust be c o nfir me d b y  the ce ntral la b orat or y. Re peat sa m ples m a y  be 
re q uire d if a de q uate t u m or tiss ue is n ot pr o vi de d. N ote:  S u bjects f or w h o m fres h t u m or 
bi o psies ca n n ot be o btai ne d ( e g i naccessi ble t u m or site or c o ncer n f or s u bject safety) ma y 
s u b mit a n arc hi ve d t u m or s peci me n o nly u p o n a gree me nt fr o m t he S p o ns or .
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
3 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8.
Ha ve a n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1 
assesse d wit hi n 1 0 da y s pri or of treat me nt i nitiati o n.
9.
De m o nstrate a de q uate or ga n f u ncti o n as defi ne d i n Ta ble 2 .
Ta ble 2
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
H e m o gl o bi n
≥9 g/ d L or ≥5. 6 m m ol/ L wit h o ut q ualificati o ns
b
Re n al
Creati ni ne 
C alc ulate d creati ni ne cleara nce ( Cr Cl)a
(Gl o mer ular filtrati o n rate [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
≥3 0 m L/ mi n f or s u bject 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 
wit h t otal bilir u bi n le vels > 1. 5 x U L N
A S T 
(ser u m gl uta mic o xal oacetic tra nsa mi nase
[S G O T ]) a n d 
A L T  (ser u m gl uta mic 
p yr u vic 
tra nsa mi nase [S G P T ])
≤2. 5 x U L N  O R ≤5 X U L N f or s u bjects w it h acti ve 
li ver metastases
Al kali ne P h os p hatase
If > 2. 5x U L N, t he n li ver fracti o n s h o ul d be ≤2. 5 x U L N 
Al b u mi n
≥3. 0 g/ d L
Lactate De h y dr o ge nase ( L D H)
< 2. 5 x U L N
C o a g ul ati o n
I nter nati o nal N or malize d Rati o (I N R) 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)
≤1. 5 x 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 aP T T is wit hi n t hera pe utic 
ra n ge of i nte n de d use of a ntic oa g ula nts
≤1. 5 x 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 aP T T is wi t 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.
b
Criteria m ust be met wit h o ut e r yt hr o p oieti n de pe n de nc y a n d wit h o ut pac ke d re d bl o o d cell ( p R B C) 
tra nsf usi o n wit hi n last 4 we e ks.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
1 0.
Fe male s u bjects of c hil d beari n g p ote ntial s h o ul d 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 a n d 
a gree t o use effecti ve c o ntrace pti o n, as defi ne d i n Secti o n
5. 7. 2 . If t he uri ne test is 
p ositi ve or ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y  test will be re q ui re d.
Male 
s u bjects s h o ul d a gree t o use a n a de q uate met h o d of c o ntrace pti o n starti n g at 
ra n d o mizati o n t hr o u g h at least 1 2 0 d a y s after t he last d ose of pe m br oliz u ma b or T P C, 
acc or di n g t o l ocal sta n dar d of care.
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.
S u bject E xcl usi o n Criteri a
5. 1. 3
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 
partici pate d or is c urre ntl y partici pati n g i n a st u d y of a n i n vesti gati o nal 
a ge nt/ de vice a n d has recei ve d/is recei vi n g t he i n vesti gati o nal a ge nt/ de vice wit hi n 
4 
wee ks of ra n d o mizati o n.
N ote: A su bject w h o ha s e ntere d t he f oll o w-u p p hase of a n i n vesti gati o nal st u d y ma y 
partici pate as l o n g as 4 wee ks h a ve ela pse d si nce t he last d ose of t he i n vesti gati o nal 
a ge nt a n d/ or re m o val of t he de vice .
2.
Has ha d m o n ocl o nal a nti b o d y (m A b) f or direct a nti -ne o plastic treat me nt w it hi n 4 wee ks 
of ra n d o mi zati o n .  
3.
Has ha d c he m ot hera p y,  tar gete d s mall m olec ule t hera py, or ra diati o n t hera p y wit hi n at 
least 2 wee ks of ra n d o mizati o n.
4.
Has n ot rec o vere d fr o m a d verse e ve nts (ie, d o w n gra de d t o ≤ Gra de 1 or t o baseli ne) d ue 
t o a pre vi o usl y a d mi nistere d t hera p y.
N ote:  Su bjects wit h ≤ Gra de 2 ne ur o pat h y  or al o pecia of a n y gra de are a n e xce pti o n
t o t his criteri o n a n d ma y q ualif y f or t he st u d y.
N ote:
If s u bject recei ve d maj or s ur ger y, t he y must ha ve rec o vere d a de q uatel y fr o m
t he t o xicit y a n d/ or c o m plicati o ns fr o m t he s ur ger y pri or t o ra n d o mizati o n.
5.
Has a n a cti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n t he past 2 y ears 
(ie 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). 
N ot e: 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. 
6.
Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g s yste mic st er oi d t hera p y or a n y 
ot her f or m of i m m u n os u p pressi ve t hera p y wit hi n 7 da ys of ra n d o mizati o n.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
3 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7.
Has a k n o w n a d diti o nal mali g na nc y  t hat pr o gress e d or re q uired acti ve treat me nt wit hi n 
t he last 5 ye ars. E xce pti o ns i ncl u de basal cell carci n o ma of t he s ki n, s q ua m ous cell 
carci n o ma of t he s ki n t hat has u n der g o ne p ote ntiall y  curati ve t hera p y , a n d i n sit u cer vical 
ca ncer.
8.
Has k n o w n acti ve brai n metastases a n d/ or carci n o mat o us me ni n gitis. N ote: K n o w n brai n 
metastases are c o nsi dere d acti ve , if a n y of t he f oll o wi n g criteria is a p plica ble:
a.
Brai n i ma gi n g d uri n g scree ni n g de m o nstrates pr o gressi o n of e xisti n g 
metastases a n d/ or a p peara nce of ne w lesi o ns c o m pare d t o brai n i ma gi n g 
perf or me d at least 4 wee ks earlier .
b.
Ne ur ol o gical s ym pt o ms attri b ute d t o brain metastases ha ve n ot ret ur ne d t o 
baseli ne .
c.
Ster oi ds were use d f or brai n metastases wit hi n 2 8 da ys of ra n d o mizati o n 
9.
Has
acti ve/hist or y  of p ne u m o nitis re q uiri n g treat me nt wit h ster oi ds or acti ve/hist or y  of 
i nterstitial l u n g disease.
1 0. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
1 1. Has a hist or y  or c urre nt e vi de nce of a n y c o n diti o n, t hera py, or la b orat or y ab n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere 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 trial, or is n ot i n the 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.  
1 2. Has k n o w n ps yc hiatric or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h c o o perati o n 
wit h t he re q uire me nts of t he trial.
1 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 wit hi n t he 
pr ojecte d d urati o n of t he trial, starti n g wit h t he scree ni n g visit t hr o u g h 1 2 0 d a y s after t he 
last d ose of trial treat me nt as defi ne d i n Secti o n 5. 7. 2.
1 4. Has recei ve d pri or t hera p y  wit h a n a nti-P D -1, a nti -P D -L 1, or a nti-P D -L 2 a ge nt or wit h a n 
a ge nt directe d t o a n ot her c o-i n hi bit or y T cell rece pt or (e g, C T L A - 4, O X -4 0, C D 1 3 7) or 
has pre vi o usl y partici pate d i n Merc k M K-3 4 7 5 cli nical trials.
1 5. Has a k n o w n hist or y  of H u ma n I m m u n o deficie nc y Vir us ( HI V; HI V 1/ 2 a nti b o dies).
1 6. Has a k n o w n acti ve He patitis B (e g, he patitis B s urface a nti ge n [H Bs A g ] reacti ve) or 
He patitis C ( e g, he patitis C vir us [H C V ] R N A [ q ualitati ve] is detecte d).
1 7. Has recei ve d a li ve vacci ne wit hi n 3 0 da ys of ra n d o mizati o n.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
3 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Tri al Tre at me nt(s)
5. 2
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 3 . Me dicati o ns use d as 
treat me nts of p h y sicia n's c h oice ( T P C) will be ha n dle d acc or di n g t o l ocal re g u lati o ns a n d 
g ui deli nes i n partici pati n g c o u ntries. F or a n y  co m merciall y a vaila 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.  The trial site is res p o nsi ble f or rec or di n g t he l ot n u m ber, 
ma n ufact urer, a n d e x pir y date f or a n y l ocall y 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.
Ta ble 3
Trial Treat me nt
Dr u g
D ose
Re gi me n/ Tre at me nt Peri o d
Use
Ca pecita bi ne
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
Eri b uli n
L ocal sta n dar d of care
L ocal sta n dar d of care
T P C
Ge mcita bi ne
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
Pe m br oliz u ma b
2 0 0 m g I V
Da y 1 Q 3 W
E x peri me ntal
Vi n orel bi ne 
L ocal sta n dar d of care 
L ocal sta n dar d of care
T P C
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 wit hi n 3 da y s after t he 
ra n d o mizati o n date.
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.
D ose Selecti o n / M o dific ati o n
5. 2. 1
5. 2. 1. 1
D ose Selecti o n ( Pre p ar ati o n)
T he rati o nale f or selecti o n of d ose of pe m br oliz u ma b t o be use d i n t his trial is pr o vi de d i n 
Secti o n 4. 2. 2 .  Details o n pre parati o n a n d a d mi nistrati o n of pe m br oliz u ma b are pr o vi de d i n 
t he P har mac y Ma n ual. 
T P C dr u gs will be d ose d, pre pare d a n d a d mi nistere d acc or di n g t o l ocal re g ulati o ns a n d 
g ui deli nes. T he b o d y  s urface area ( B S A) i n m2 s h o ul d be calc ulate d per l ocal g ui deli nes.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
5. 2. 1. 2
D ose M o dific ati o n ( I nterr u pti o n/Esc al ati o n/ Titr ati o n/ Ot her)
5. 2. 1. 2. 1
Pe m br oliz u m a b D ose M o dific ati o ns
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt f or i m m u ne -rel ate d A Es (ir A Es) ass oci ate d 
wit h pe m br oliz u m a b
A Es ass ociate d wit h pe m br oliz u ma b e x p os ure ma y  ha ve a n i m m u n ol o gic eti ol o g y.  These 
i m m u ne-relate d A Es (ir A Es) m a y  occ ur s h ortly after t he first d ose or se veral m o nt hs after t he 
last d ose of treat me nt a n d ma y  affect m ore t ha n o n e b o d y  s yste m si m ulta ne o usl y. T h eref ore, 
earl y rec o g niti o n a n d i nitiati o n of treat me nt is critical t o re d uce c o m plicati o ns.  Base d o n 
e xisti n g cli nical st u d y data, m ost 
ir A Es were re versi ble a n d c o ul d be ma na ge d 
wit h 
i nterr u pti o ns of pe m br oliz u ma b, a d mi nistrati o n of c ortic oster oi ds , a n d/or ot her s u p p orti ve 
care. F or s us pecte d ir A Es, e ns ure a de q uate e val uati o n t o c o nfir m eti ol o g y or e xcl u de ot her 
ca uses. A d diti o nal pr oce d ures or tests s uc h as br o nc h osc o p y , e n d osc o p y, or s ki n bi o ps y m a y 
be i ncl u de d as part of t he e val uati o n. 
Base d o n t he se verit y of ir A Es, wit h h ol d or 
per ma ne ntl y disc o nti n ue pe m br oliz u ma b a n d a d mi nister c ortic oster oi ds. D ose m o dificati o n 
a n d t o xicit y ma na ge me nt g ui deli nes f or ir A Es ass ociate d wit h pe m br oliz u ma b are pr o vi de d 
i n Ta ble 4 . 
I n a d diti o n, s u bjects s h o ul d receive 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 nvesti gat or.  Su g geste d s u p p orti ve care meas ures, as descri be d i n 
Secti o n 5. 6. 1, are als o i ncl u de d i n Ta ble 4 .
D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical/s ur gical eve nts or l o gistical reas o ns 
n ot relate d t o trial t hera p y (e g, electi ve s ur ger y, u nrelate d me dical e ve nts, s u bject vacati o n, 
a n d/ or h oli da y s).  Su bjects s h o ul d be place d bac k o n trial t hera py 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 di sc usse d wit h t he S p o ns or.  The 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 s u bject's trial rec or d.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 4
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt G ui deli nes f or I m m u ne-relate d Ad verse E ve nt s 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 wee 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 n d life-t hreate ni n g i m m u ne-relate d a d verse e ve nts (ir A Es), I V c ortic oster oi d s h o ul d be i nitiate d first f oll owe 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 E v 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 s u bjects f or si g ns a n d s y m pt o ms of  
p ne u m o nitis

E val uate 
s u bjects 
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 s u bjects f or si g ns a n d s y m pt o ms of 
e nter oc olitis (ie diarr hea, a b d o mi nal pai n, 
bl o o d or m uc us i n st o ol wit h or wit h o ut 
fe ver) 
a n d 
of 
b o w el 
perf orati o n
(ie
perit o neal si g ns a n d ile us).

S u bjects 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. 

S u bjects 
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 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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 E v 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 
wit h li ver f u ncti o n tests (c o nsi der 
wee kl y 
or 
m o re 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 s u bjects wit h T 1 D M 

A d mi nister a nti -h y per gl yce mic i n 
s u bjects wit h h y per gl yce mia 

M o nit or s u bjects 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 
wit 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. 
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
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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 E v 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
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 
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
Gra de 3, or 
i nt olera ble/ 
persiste nt Gra de 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 or e xcl u de ot her ca uses
Gra de 4 or 
rec urre nt Gra de 3 
Per m a ne ntl y 
disc o nti n ue
N O T E S: 
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.  
2.
F or s u bjects 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 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
D ose m o dific ati o n a n d t o xicit y m a n a ge me nt of i nf usi o n -re acti o ns rel ate d t o 
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 pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. 
D ose 
m o dificati o n 
a n d t o xicit y 
ma na ge me nt g ui deli nes o n pe m br oliz u ma b -ass ociate d 
i nf usi o n reacti o n are pr o vi de d i n Ta ble 5 . 
Ta ble 5
Pe m br oliz u ma b I nf usi o n Reacti o n D ose m o dificati o n a n d Treat me nt G ui deli nes
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at S u bse q ue nt 
D osi n g
Gr a de 1
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n 
n ot i n dicate d
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he 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 ma y be pre me dicate d 
1. 5 h ( ± 3 0 mi n utes) pri or t o 
i nf usi o n of wit h:
Di p he n h y dra mi ne 5 0 m g p o 
( or e q ui vale nt d ose of 
a nti hista mi ne)
Aceta mi n o p he n 5 0 0 -1 0 0 0 
m g p o ( or e q ui vale nt d ose 
of a nal gesic)
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
4 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at S u bse q ue nt 
D osi n g
Gr a des 3 or 4
Gra de 3:
Pr ol o n ge d (i.e., n ot 
ra pi dl y res p o nsi ve t o 
s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of 
i nf usi o n); rec urre nce of 
s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; 
h os pitalizati o n 
i n dicate d f or ot her 
cli nical se q uelae (e. g., 
re nal i m pair me nt, 
p ul m o nar y i nfiltrates)
Gra de 4:
Life -t hreate ni n g; 
press or or ve ntilat or y 
s u p p ort i n dicate d
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y 
i ncl u de b ut is n ot li mite d t o:
E pi ne p hri ne * *
I V fl ui ds
A nti hista mi nes
N S AI Ds
Aceta mi n o p he n
Narc otics
O x y ge n
Press ors
C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as me dicall y 
i n dicate d u ntil t he 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 disc o nti n ue d fr o m 
f urt her st u d y dr u g tre at me nt.
N o s u bse q ue nt d 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 availa 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.c a ncer. g o v
Ot her all o we d d ose i nterr u pti o n s 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 thera p y.  S u bjects s h o ul d 
be place d bac k o n st u d y thera 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 patie nt's st u dy rec or d.
I n case t o xicit y does n ot res ol ve t o Gra de 0- 1 wit hi n 1 2 wee ks after t he last i nf usi o n, 
pe m br oliz u ma b s h o ul d be disc o nti n ue d. S u bjects wit h a la b orat or y a d verse e ve nt still at 
Gra de 2 after 1 2 wee ks p ost last i nf usi o n m a y  restart pe m br oliz u ma b if as ym pt o matic a n d 
o nl y  after c o ns ultati o n wit h t he S p o ns or.
D osi n g i nterr u pti o ns ( pe m br oliz u ma b a n d T P C) are per mitte d i n t he case of me dical/ s ur gical 
e ve nts or l o gistical reas o ns n ot relate d t o st u d y thera p y (e g, electi ve s ur ger y, u nrelate d 
me dical e ve nts, s u bject vacati o n, a n d/ or h oli da y s). S u bjects s h o ul d be place d bac k o n st u d y 
treat me nt wit hi n 3 wee ks of t he sc he d ule d i nterr u pti o n, u nless disc usse d ot her wise wit h t he 
S p o ns or. T he reas o n f or i nterr u pti o n of st u d y treat me nt s h o ul d be d oc u me nte d i n t he 
s u bject's st u dy rec or d.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
4 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
5. 2. 1. 2. 2
C a pecit a bi ne
Refer t o l ocall y iss ue d c a pecita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 3
Eri b uli n
Refer t o l ocally iss ue d e ri b uli n pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 4
Ge mcit a bi ne
Refer t o l ocally iss ue d g e mcita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 1. 2. 5
Vi n orel bi ne
Refer t o l ocally iss ue d vi n orel bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt. 
Ti mi n g of D ose A d mi nistr ati o n
5. 2. 2
C y cle 1 D a y  1 treat me nt wit h pe m br oliz u ma b or T P C s h o ul d be gi n o n t he da y  of 
ra n d o mizati o n (n o later t ha n 3 da y s after ra n d o mizati o n is per mitte d). Trial treat me nts s h o ul d 
be a d mi nistere d as descri be d bel o w a n d acc or di n g t o t he details pr o vi de d i n t he Trial Fl o w 
C harts ( Secti o n 6. 0) .
P e m br oliz u ma b
or
T P C
s h o ul d be a d mi nistere d o n a n o ut patie nt
basis
after all 
pr oce d ures/assess me nts ha ve bee n c o m plete d .
5. 2. 2. 1
Pe m br oliz u m a b
Pe m br oliz u ma b will be a d mi nistere d as a 3 0 -mi n ute
I V inf usi o n Q 3 W
(treat me nt c ycle 
i nter vals ma y  be i ncrease d d ue t o t o xicit y as descri be d i n t he D ose M o dificati o n Secti o n
5. 2. 1. 2. 1 ).  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 
as p ossi ble.  A wi n d o w of -5 mi n / + 1 0 mi n is per mitte d. T he reas o n f or a n y dela y i n i nf usi o n
o utsi de of t he pr ot oc ol s pecifie d wi n d o w
s h o ul d be d oc u me nte d i n t he s u bject’s c hart a n d
rec or de d o n t he electr o nic case re p ort f or ms (e C R Fs ).
T he 
P har mac y
Ma n ual 
c o ntai ns s pecific i nstr ucti o ns f or t he pre parati o n 
of 
t he 
pe m br oliz u ma b i nf usi o n fl ui d a n d a d mi nistrati o n of i nf usi o n s ol uti o n .
5. 2. 2. 2
C a pecit a bi ne
Refer t o l ocall y iss ue d ca peci ta bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 2. 3
Eri b uli n
Refer t o l ocall y iss ue d eri b uli n pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
5. 2. 2. 4
Ge mcit a bi ne
Refer t o l ocall y iss ue d ge mcita bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.  
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
4 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
5. 2. 2. 5
Vi n ore l bi ne
Refer t o l ocall y iss ue d vi n orel bi ne pac ka ge i nsert f or s u bjects recei vi n g t his a ge nt.
Tri al Bli n di n g/ M as ki n g
5. 2. 3
T his is a n o pe n -la bel trial, t heref ore, t he S p o ns or, I n vesti gat or a n d s u bject will k n o w t he 
treat me nt a d mi nistere d.   I ma gi n g data f or t he pri mar y  an al y sis will be re vie we d b y  ce ntral 
i ma gi n g ve n d or bli n de d
t o s u bject’s treat me nt assi g n me nt.
T he s u bject-le vel P D -L 1  
bi o mar ker res ults will be mas ke d i n the data base t o t he st u d y  tea m a n d t he S p o ns or i ncl u di n g 
cli nical, statistical, statistical pr o gra m mi n g, a n d data ma na ge me nt pers o n nel.
Access t o t he 
P D -L 1  su bject -le vel bi o mar ker res ults will be li mite d t o a n u n bli n de d S p o ns or cli nical 
scie ntist, u n bli n de d S p o ns or statisticia n, a n d u n bli n de d S p o ns or statistical pr o gra m mer w h o 
will be res p o nsi ble f or data re vie w b ut w h o will ha ve n o ot her res p o nsi bilities ass ociate d 
wit h t he st u d y .   
Access t o t he all ocati o n sc he d ule a n d t he s u bject -le vel P D -L 1  res ults f or s u m maries or 
a nal ys es will be restricte d t o a n u n bli n de d e xter nal sta tisticia n, a n d, as nee de d, a n e xter nal 
scie ntific pr o gra m mer perf or mi n g t he a nal ys is, w h o will ha ve n o ot her res p o nsi bilities 
ass ociate d wit h t he st u d y.
R a n d o miz ati o n or Tre at me nt All oc ati o n
5. 3
Ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve v oice r es 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.  Su bjects will be assi g ne d 
ra n d o ml y i n a 1: 1 rati o t o pe m br oliz u ma b or T P C after stratificati o n b y  PD- L 1  tu m or stat us 
( p ositi ve [ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d hist or y  of pri or ( ne o)a dj u va nt treat me nt 
v ers u s de n ov o metastatic 
disease at i nitial dia g n osis .  T P C
s h o ul d be i de ntifie d a n d 
d oc u me nte d via I V R S pri or t o ra n d o mizati o n.  S u bject s ra n d o mize d t o T P C w h o disc o nti n ue 
treat me nt are n ot all o we d t o cr oss -o ver t o t he pe m br oliz u ma b ar m .
Str atific ati o n
5. 4
Ra n d o mizati o n will be stratifie d acc or di n g t o t he f oll o wi n g fact ors :

P D -L 1  t u m or stat us ( p ositi ve [ C P S ≥1] vs ne gati ve [ C P S < 1])

Hist or y  of pri or ( ne o)a dj u va nt t hera py vs de n ov o metastatic disease at i nitial dia g n osis
N o stratificati o n base d o n a ge, se x or ot her c haracteristics will be use d i n t his trial .
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 )
5. 5
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
C li 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 
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
4 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
i n vesti gat or a n d/ or t he s u bject's pri mar y  ph 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
5. 5. 1
All treat me nts t hat t he I n vesti gat or c o nsi 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), 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 eC R F s.
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da y s bef ore ra n d o mizati o n a n d 3 0 d a y s after 
t he last d ose of st u d y treat me nt s h o ul d be rec or de d.  Co nc o mita nt me dicati o ns a d mi nistere d 
be y o n d 3 0 d a y s after t he last d ose of trial treat me nt s h o ul d be rec or de d f or S A Es a n d E CIs as 
defi ne d i n Secti o n 7. 2 .
Pr o hi bite d C o nc o mit a nt Me dic ati o ns
5. 5. 2
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 a n d Retreat me nt P hase of t his trial:

A nti ne o plastic s y ste mic c he m ot hera py o r bi ol o gical t hera py 
o
I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol
o
C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol
o
I n vesti gati o nal a ge nts ot her t ha n pe m br oliz u ma b
o
Ra diati o n t hera p y 
N ote:  Ra di ati o n t her a py t o a sy m pt o m atic s olit ary lesi o n or t o t he br ai n m ay be 
all o we d after c o ns ult ati o n wit h S p o ns or (exce pt d uri n g scree ni n g).  

H er bal s u p ple me nts

Li v e vacci nes wit hi n 3 0 da y s pri or t o ra n d o mizati o n a n d w hile partici pati n g i n t he 
trial.  Exa m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g: 
measles, m u m ps, r u bella, varicella , her pes z oster , yell o w fe ver, ra bies, B C G, a n d 
t yp h oi d ( oral) vacci ne s. Seas o nal i nfl ue nza vacci nes f or i njecti o n are ge nerall y kille d 
vir us vacci nes a n d are all o we d .
Ho we ver , i ntra nasal i nfl ue nza vacci nes (e g Fl u -
Mist ®) are li ve atte n uate d vacci nes, a n d are n ot all o we d.

Gl uc oc ortic oi ds f or a n y p ur p ose ot he r t ha n t o m o d ulate s ym pt o ms fr o m a n E CI of 
s us pecte d i m m u n ol o gic eti ol o g y.  The use of p h y si ol o gic d oses of c ortic oster oi ds 
ma y  be a p pr o ve d after c o ns ultati o n wit h t he S p o ns or.
N ote:  For s u bjects r a n d o mize d t o T P C , t he use of syste mic gl uc oc ortic oi ds o n 
tri al tre at me nt is acce pt a ble a n d m ay be re q uire d f or pre me dic ati o n.
N ote:  I n h ale d ster oi ds are all o we d f or m a n a ge me nt of ast h m a.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
4 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
N ote:  Use of pr o p hyl actic c ortic oster oi ds t o av oi d aller gic re acti o ns (e g, t o I V 
c o ntr act dye) is per mitte d.

Maal o x ( or me dic i ne c o ntai ni n g al u mi n u m h y dr o xi de or ma g nesi u m h y dr o xi de)
s h o ul d n ot be a d mi nistere d t o s u bjects w h o are ra n d o mize d t o ca pecita bi ne.
S u bjects w h o, per I n vesti gat or’s assess me nt , re q uire a n y of t he af ore me nti o ne d me dicati o ns
f or cli nical ma na ge me nt s h o ul d be disc o nti n ue d fr o m st u d y treat me nt.  S u 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 d escri be ot her me dicati o ns t hat 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
5. 6
S u p p orti ve C are G ui deli nes f or S u bjects i n Pe m br oliz u m a b Ar m
5. 6. 1
S u bject s s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as d ee me d necessar y  by t he
treati n g I n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of a d verse 
e ve nts ( A Es) wit h p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d i n Secti o n 5. 2. 1. 2, Ta ble 4 ).
W here a p pr o priate, t hese g ui deli nes i ncl u de t he use of oral or I V 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 nistrati o n of 
c ortic oster oi ds. N ote t hat se veral c o urses of ster oi d ta peri n g 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 pr o gressi o n of 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 of t he e ve nt , it is deter mi ne d n ot t o be relate d t o pe m br oliz u ma b, 
t he in vesti gat or d oes n ot nee d t o f oll o w t he treat me nt g ui da nce. 
Refer t o Ta ble 4 i n 
Secti o n 5. 2. 1. 2 f or g ui deli nes re gar di n g d ose m o dificati o n. 
It m a y  be necessar y  to perf or m c o n diti o nal pr oce d ures, s uc h as br o nc h osc o p y , e n d osc o p y, or 
s ki n p h ot o gra p h y, as part of t he e val uati o n of t he e ve nt . 
S u p p orti ve C are G ui deli nes f or I m m u ne-Rel ate d A d verse E ve nt s
5. 6. 2
See Secti o n 5. 2. 1. 2, Ta ble 4 .
S u p p orti ve C are G ui deli nes f or C a pecit a bi ne
5. 6. 3
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
S u p p orti ve C are G ui deli nes f or Eri b uli n
5. 6. 4
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u p p orti ve C are G ui deli ne f or Ge mcit a bi ne
5. 6. 5
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
S u p p orti ve C are G ui deli nes f or Vi n orel bi ne
5. 6. 6
Refer t o l ocal pr o d uct la bel or s u p p orti ve care g ui da nce.
Diet/ Acti vit y/ Ot her C o nsi der ati o ns
5. 7
Diet
5. 7. 1
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
5. 7. 2
Pe m br oliz u ma b ma y  ha ve a d verse effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if 
pe m br oliz u ma b has tra nsie nt a d verse effects o n t he c o m p ositi o n of s per m.  
F or t his trial, male s u bjects will be c o nsi dere d t o be of n o n -re 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 b e 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 ye ars 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 py. 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 my 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 vely, w hile recei vi n g st u d y dru g a n d f or 1 2 0 d a y s (at least 
6 m o nt hs f or s u bjects o n ge mcita bi ne) after t he last d ose of st u d y dr u g b y  co m pl y i n g wit h 
o n e of t he f oll o wi n g:  
( 1) p ractice 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.  
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
5 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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 ac ce 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 nly 
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 n d us ual lifestyl e 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 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 n trace pti o n. 
If 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 dr u g m a 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 v e) fr o m t he d a y  of st u d y dr u g i nitiati o n ( or 1 4 d a y s pri or t o t he i nitiati o n of 
st u d y dr u g 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 d a y s (at least 6 
m o nt hs f or ge mcita bi ne) 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 ntial will 
n ot relia bl y co 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 .
M ale s u bjects s h o ul d als o see k a d vice re gar di n g cr y oc o nser vati o n of
s per m pri or
t o
treat me nt beca use of t he p ossi bilit y of i nfertilit y
N ote: M o nt hl y  pre g na nc y testi n g s h o ul d be c o n d ucte d as per l ocal re g ulati o ns w here 
a p plica ble.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Pre g n a nc y
5. 7. 3
If a s u bject i na d verte ntl y bec o mes pre g na nt w hile o n treat me nt wit h pe m br oliz u ma b or a 
T P C , t he s u bject will be i m me diatel y disc o nti n ue d fr o m treat me nt. T he site will c o ntact t he 
s u bject at least m o nt hl y a n 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 del a 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 I n vesti gat or will ma ke e ver y eff ort t o o btai n per missi o n t o 
f oll o w t he o utc o me of t he pre g na nc y  an 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.   If a male s u bject i m pre g nates his fe male part ner, t he st u d y pers o n nel at t he site 
m ust be i nf or me d i m me diatel y a n d t he pre g na nc y  must be re p orte d t o t he S p o ns or a n d 
f oll o we d as descri be d i n Secti o n 7. 2. 2.
N ursi n g W o me n
5. 7. 4
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
5. 8
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 
discr eti 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.  In 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.  Once a 
s u bject has disc o nti n ue d treat me nt, e ve n t h o u g h he/s he c o nti n ues t o be m o nit ore d i n t he trial, 
he/s he 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 a p pr o priate.
A s u bject m ust be disc o nti n ue d fr o m t he trial f or a n y of 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 treat me nt (b ut s h o ul d c o nti n ue t o be m o nit ore d i n t he 
tri al) f or a ny of 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) re q uests t o 
disc o nti n ue treat me nt
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

C o nfir me d ra di o gra p hic disease pr o gressi o n per t he ter ms o utli ne d i n Secti o n 7. 1. 2. 7
(e xce pti o n if t he S p o ns or a p pr o ves treat me nt c o nti n uati o n). N ote: F or u nc o nfir me d 
ra di o gra p hic disease pr o gressi o n , please see Secti o n 5. 8. 1 .

U nacce pta ble a d verse e x perie nces as descri be d i n Secti o n 7. 2

A n y  pr o gressi o n or rec urre nce of a n y mali g na nc y , or a n y occ urre nce of a n ot her 
mali g na nc y  t hat re q uires acti ve treat me nt

I nterc urre nt ill ness ot her t ha n a n ot her mali g na nc y  as n ote d a b o ve t hat pre ve nts 
f urt her a d mi nistrati o n of treat me nt

Rec urre nt Gra de 2 p ne u m o nitis

I n vesti gat or’s decisi o n t o disc o nti n ue 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

C o m plete d 
3 5 
treat me nts
wit h 
pe m br oliz u ma b . N ote: 
S u bjects 
w h o 
st o p 
pe m br oliz u ma b after 3 5 treat me nts m a y  be eli gi ble f or u p t o 1 7 a d diti o nal st u d y 
treat me nts if t he y pr o gress after st o p pi n g st u d y treat me nt pr o vi de d t he y meet t he 
re q uire me nts detaile d i n Secti o n 7. 1. 5. 2. 1.

A d mi nistrati ve reas o ns
C he m ot hera p y m a y  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 
c ycles per mitte d acc or di n g t o l ocal re g ulati o ns a n d g ui deli nes i n partici pati n g c o u ntries.
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. 0 a n d Sec ti o n
7. 1. 5. 3 . 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 Es an d E CI m o nit ori n g . Seri o us a d verse e ve nt s will be c ollecte d f or 9 0 d a y s after t he 
e n d of treat me nt as descri be d i n Secti o n 7. 2. 3. 1 ). S u bjects w h o dis c o nti n ue f or reas o ns ot her 
t ha n pr o gressi ve disease 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 deat h .  After d oc u me nte d disease pr o gressi o n eac h s u bject will be f oll o we d b y  
tele p h o ne f or o verall s ur vi val 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 .
Tre at me nt A fter First R a di ol o gic E vi de nce of Dise ase Pr o gressi o n
5. 8. 1
I m m u n ot hera pe utic a ge nts s uc h as pe m br oliz u ma b ma y  pr o d uce a ntit u m or effects b y  
p ote ntiati n g e n d o ge n o us ca ncer -s pecific i m m u ne res p o nses.  T he res p o nse patter ns see n wit h 
s uc h a n a p pr oac h ma y e xte n d be y o n d t he t ypical ti me c o urse of res p o nses see n wit h 
c yt ot o xic a ge nts, a n d ca n ma nifest as a cli nical res p o nse after a n i nitial i ncrease i n t u m or 
b ur de n or e ve n t he a p peara nce of ne w lesi o ns.
After t he site has assesse d t he 1 st ra di o gra p hic e vi de nce of P D b y  RE CI S T 1. 1, all i ma ges 
m ust be i m me diatel y su b mitte d t o t he ce ntral i ma gi ng ve n d or f or verificati o n of Pr o gressi ve 
Disease ( P D).  The ce ntral i ma gi n g ve n d or will n otif y  the site a n d t he S p o ns or of t he res ults 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
5 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
of t his ra pi d re vie w. S u bject s s h o ul d re mai n o n treat me nt u ntil ce ntral i ma gi n g assess me nt
of site-assesse d 1 st ra di ol o gic e vi de nce of P D is perf or me d.   If ce ntral i ma gi n g ve n d or
verifies site -assesse d 1 st ra di ol o gic e vi de nce of P D i n eit her treat me nt ar m, t u m or assess me nt 
ma y  be re peate d b y  the site 4 wee ks later i n or der f or t he site t o c o nfir m P D b y  ir R E CIS T
wi t h t he o pti o n of c o nti n ui n g treat me nt per bel o w w hile a waiti n g ra di ol o gic c o nfir mati o n of 
disease pr o gressi o n . 
T he decisi o n t o c o nti n ue st u d y treat me nt after site-assesse d 1 st ra di ol o gic e vi de nce of P D is 
verifie d b y  the ce ntral i ma gi n g ve n d or is at t he I nvesti gat or’s discreti o n base d o n t he cli nical 
stat us of t he s u bject as descri be d i n Ta ble 6 bel o w .  Su bjects ma y  recei ve st u d y treat me nt 
w hile waiti n g f or c o nfir mati o n of P D b y  t he site, if t he y are cli nically sta ble as defi ne d b y  t he 
f oll o wi n g criteria:

A bse nce of si g ns a n d s y m pt o ms (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 gre ssi o n

N o decli ne i n E C O G perf or ma nce stat us

A bse nce of ra pi d pr o gressi o n of disease 

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
Ta ble 6
I ma gi n g a n d Treat me nt 
After 
Site -Assesse d 
Fir st Ra di ol o gic 
E vi de nce 
of 
P r o gressi ve D isease has Bee n Verifie d
b y  the Ce ntral
I ma gi n g Ve n d or.  Ta ble 
R e prese nts ir R E CIS T
Cli nic all y St a ble
Cli nic all y U nst a ble
I m a gi n g
Tre at me nt
I m a gi n g
Tre at me nt
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 w ee ks at site t o 
c o nfir m P D
M a y  c o nti n ue st u d y 
treat me nt at t he 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 mor 
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 w ee 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
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Cli nic all y St a ble
Cli nic all y U nst a ble
I m a gi n g
Tre at me nt
I m a gi n g
Tre at me nt
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 In vesti gat or’s 
discreti o n
C o nti n ue re g ularl y 
sc he d ule d i ma gi n g 
assess me nts 
M a y  restart st u d y 
treat me nt if 
c o n diti o n has 
i mpr o ve d a n d/ or 
cli nicall y sta ble per 
I n vesti gat or’s 
discreti o n . Ne xt 
t u m or i ma gi n g
s h o ul d occ ur 
acc or di n g t o t he 
e ver y 9 wee k ( 6 3 ± 
7 d a ys) i ma gi n g 
sc he d ule f or t he first 
year a n d 1 2 w ee ks 
( 8 4 ± 7 da ys) after 
t he first year
T his all o wa nce t o c o nti n ue treat me nt des pite ce ntrall y v erifie d 1 st ra di ol o gic e vi de nce of 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 m a y ha ve a tra nsie nt t u m or flare i n t he 
first fe w m o nt hs af ter t he start of i m m u n ot hera p y bef ore e x perie nci n g disease res p o nse.  
S u 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 i ma gi n g f or 
c o nfir mati o n of pr o gressi ve disease b y  t he l ocal site.
It must be e m p hasize d t hat cli nicall y sta ble s u bjects m a y  re mai n o n treat me nt after R E CI S T 
1. 1 defi ne d disease pr o gressi o n is verifie d b y  bli n de d ce ntral i ma gi n g ve n d or f or b ot h t he 
e x peri me ntal a n d c o ntr ol ar ms of t he st u d y, a n d t hat t he sc h e d ule of assess me nts be a d here d 
t o. If st u d y t hera p y is disc o nti n ue d f or t o xicit y b ut t he s u bject is ot her wise sta ble, t he s u bject 
s h o ul d c o nti n ue t u m or i ma gi n g as i n dicate d i n t he fl o w c hart u ntil R E CI S T 1. 1 defi ne d 
pr o gressi o n has bee n esta blis he d b y  a bli n de d ce ntral i ma gi n g ve n d or .  
N ote:  If a s u bject wit h c o nfir me d r a di o gr a p hic pr o gressi o n (ie 2 t u m or i m a ges at le ast 2 8 
d ays a p art de m o nstr ati n g pr o gressive dise ase) is cli nic ally st a ble or cli nic ally i m pr ove d, a n d 
t here is n o f urt her i ncre ase i n t he t u m or di me nsi o ns at t he c o nfir m at ory t u m or i m a ge ( as 
assesse d by t he site i nvesti g at or/l oc al r a di ol o gy revie w ), a n exce pti o n m ay be c o nsi dere d t o 
c o nti n ue tre at me nt u p o n c o ns ult ati o n wit h t he S p o ns or.
Disc o nti n u ati o n of St u d y T her a p y After C o m plete R es p o nse
5. 8. 2
Disc o nti n uati o n of treat me nt ma y  be c o nsi dere d f or s u bjects w h o ha ve attai ne d a c o nfir me d 
C R a n d ha ve bee n treate d f or at least 8 c ycles wit h pe m br oliz u ma b a n d ha d at least 2 c ycles 
wit h pe m br oliz u ma b be y o n d t he date w he n t he i nitial C R was declare d.  Su bjects w h o t he n 
e x perie nce ra di o gra p hic disease pr o gressi o n m a y  be eli gi ble f or u p t o 1 7 a d diti o nal 
treat me nts w it h pe m br oliz u ma b
( Sec o n d C o urse P hase or Re -treat me nt P hase) at t he 
discreti o n of t he I n vesti gat or if:

N o ca ncer treat me nt was a d mi nistere d si nce t he last d ose of pe m br oliz u ma b
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

T he s u bject meets t he safet y  para meters liste d i n t he I ncl usi o n/ E xcl usi o n criteria

T he trial is o n g oi n g
S u bjects will res u me t hera p y at t he sa me d ose a n d sc he d ule at t he ti me of i nitial 
disc o nti n uati o n.  Ad diti o nal details are pr o vi de d i n Secti o n
7. 1. 5. 2. 1 .  Res p o nse or 
pr o gressi o n i n t his Sec o n d C o urse P hase will n ot c o u nt t o war ds t he O R R a n d P F S of t he 
pri mar y  e n d p oi nt i n t his trial.
S u bject Re pl ace me nt Str ate g y
5. 9
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
5. 1 0
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)  U p o n st u d y co m pleti o n, partici pa nts are disc o nti n ue d a n d e nr olle d i n a 
pe m br oliz u ma b e xte nsi o n st u d y .
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n
5. 1 1
Earl y trial ter mi nati o n will be t he res ult of t he criteria s pecifie d bel o w:

T he trial m a y  be st o p pe d earl y f or f utilit y or safet y at t he rec o m me n dati o n of t he 
e xter nal Data M o nit ori n g C o m mittee ( eD M C).

Q ualit y  or q ua ntit y  of data rec or di n g is i nacc urate or i nc o m plete as assesse d b y  th e 
S p o ns or

P o or a d here nce t o pr ot oc ol a n d re g ulat or y re q uire me nts

I nci de nce or se verity of a d verse dr u g reacti o n i n t his or ot her st u dies i n dicates a 
p ote ntial healt h hazar d t o s u bjects

Pla ns t o m o dif y  or disc o nti n ue t he de vel o p me nt of t he st u d y me dicati 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 oi 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.
I n t he e ve nt of S p o ns or decisi o n t o n o l o n ger s u p pl y st u d y me d icati o n, a m ple n otificati o n 
will be pr o vi de d s o t hat a p pr o priate a dj ust me nts t o s u bject treat me nt ca n be ma de .
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
5 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
6. 1
Pe m br oliz u m a b Tre at me nt Ar m
6. 1. 1
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -u p 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nistr ati ve Pr oce d ures b
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
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 d
X
Pri or a n d C o nc o mita nt 
Me dicati o n Re vie w
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X z
Trial Treat me nt A d mi nistrati o n 
( Pe m br oliz u ma b)
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer T hera p y 
Stat us
X
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts e
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
1 2 -Lea d E C G ( L ocal) f
X
F ull P h ysical E xa mi nati o n
X
X
Directe d P h ysical E xa mi nati o n
X  
X  
X  
X  
X  
X  
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
5 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -u p 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Vital Si g ns a n d Wei g ht g
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce Stat us
X h
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
i
X
L a b or at or y 
Pr oce d ures/ Assess me nts : 
L O C A L l a b or at or y b, j
Pre g na nc y Test k
X
P T /I N R a n d a P T Tl
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
X
X
X  
X x
X
T 3, F T 4 a n d T S H m,  v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5-3, C E A 
a n d C A 2 7. 2 9) n, v
X
X n
X
X
L a b or at or y 
Pr oce d ures/ Assess me nts:  
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics o
X
C orrelati ve Bl o o d Sa m ples
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, Ser u m)
X
Effic ac y Me as ure me nts b
T u m or I ma gi n gw
X
X x
X
X
Brai n I ma gi n g -if a p plica ble p
X
X p
X
X
B o ne I ma gi n g -if a p plica ble q
X
X q
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
5 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -u p 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Tiss ue C ollecti o n b
Scree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -L 1 
stat us a n d bi o mar ker a nal ysis r
X
O pti o nal tiss ue f or bi o mar ker 
a nal ysis s
X
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker / P D -L 1 a nal ysis t
X
S u bject Re p orte d O utc o mes
b , u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
a.
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 n e. 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).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nts/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m trial
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des all acti ve c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n past 1 0 years c o nsi dere d t o b e cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1.
f.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
g.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d pr i or t o 
treat me nt a d mi nistrati o n.
h.
Scree ni n g E C O G Perf or ma nce Stat us (P S ) s h o ul d be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n.
i.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2.6.
j.
Scree ni n g la b orat or y tests are t o be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n. 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 d ose.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
k.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. 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. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles 
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -u p 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys)
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
l.
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.
m.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
n.
T u m or mar kers ( C A 1 5 -3, C E A , a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote x 
f or details.
o.
Bl o o d f or g e netics are ma n dat or y sa m ples u nless t here 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 .
p.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule (e ver y 9 wee ks [Q 9 W ] f or t he first ye ar, t he n 
Q 1 2 W) a n d will be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
q.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o n e p ai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d. A b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne pai n.
r.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o ps y fr o m a me t ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R
s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6-da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
s.
F or s u bjects o n t h e p e m br oliz u ma b ar m, 2 o pti o nal tiss ue bi o psies ma y be o btai ne d o n or aft er C y cl e 2 , a n d /or at disease pr o gressi o n .  T here are c o nse nt c hec k b o xes i n t h e 
mai n c o nse nt t hat m ust be c o m pl ete d f or e ver y s u bject o n t he pe m br oliz u ma b ar m. 
t.
W he n 
a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
It is str o n gl y rec o m me n de d t hat electr o nic patie nt -re p orte d o utc o mes (e P R Os) are a d mi nistere d 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.
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 - 3, C E A a n d C A 2 7.2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o me et scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt , t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 d a y s) f or t he first ye ar, t he n Q 1 2 W
( +/- 7 d a y s) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d  1st  ra di ol o gic  evi de nce  of disease pr o gressi o n ( PD) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI  deter mi nes t he s u bject w o ul d be nefit fr o m 
c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject per ir R E CI S T), 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 t he e n d of t he st u d y, w hic he ver occ urs 
first.
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( 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 -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C y cle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
6 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – Ge mcit a bi ne or Eri b uli n
6. 1. 2
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
A d mi nistr ati ve 
Pr oce d ures b
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
X
I ncl usi o n/E xcl usi o n 
Criteria
X
S u b ject I de ntificati o n 
Car d
X
De m o gra p hics a n d 
Me dical Hist or y
d
X
Pri or a n d C o nc o mita nt 
Me dicati o n Re vie w
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X z
Ge m cita bi ne or eri b uli n 
A d mi nistrati o n e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P os t-st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
1 2 -Lea d E C G ( L ocal) g
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
F ul l P h ysical E xa mi nati o n
X
X
Dir ecte d P h ysical 
E xa mi nati o n
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vit al Si g ns a n d Wei g ht h
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 i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us j
X
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, k
Pre g na nc y Test l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y Pa nel
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
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) o, v,
X
X o
X
X
L a b or at or y 
Pr oce d ures/ Assess me nts: 
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics p
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
C orrelati ve Bl o o d 
Sa m ples ( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, 
Ser u m)
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g -if 
a p plica ble q
X
X q
X
B o ne I ma gi n g -if 
a p plica ble r
X
X r
T u m or Tiss ue 
C ollecti o n b
Scree ni n g tiss ue f or 
ce ntral c o nfir mati o n of 
T N B C, P D - L 1 stat us a n d 
bi o mar ker a nal ysis s
X
O pti o nal arc hi val tiss ue 
f or bi o mar ker/ P D-L 1 
a nal ysis t
X
S u bject Re p orte d 
O utc o mes b, u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
a.
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 wil l 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).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt s/ pr oce d ures i n Secti o n 7. 0 .  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n di sease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m 
st u d y treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 
wee ks fr o m t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des all acti ve c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1 .
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y t e mperat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G s h o ul d be perf or me d wit h i n 1 0 da ys pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2. 6.
k.
Scree ni n g la b orat or y tests are t o be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n. After C y cle 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 
d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. . 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. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if 
dee me d necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
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.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 15- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote 
w f or details.
p.
Bl o o d f or g e netics are m a n dat or y sa m ples u nless t here 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 the c ollecti o n of 
t he sa m ple f or t hese p ur p oses.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g 
( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Da y
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8 
1 
8
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 t o - 1
-2 8 
t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys 
p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 
1 2 
wee ks
( ± 7 
da ys)
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g
f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first year, t he n Q 1 2 W) a n d will
be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
r.
B o ne sca ns wi ll be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as 
nee de d f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m u sc ul os keletal c o m plai nts or if t he site belie ve s t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has
n o k n o w n metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A b o ne sca n ca n be o btai n e d at f oll o w u p if t here are ne w s y m pt o ms of 
b o ne pai n .
s.
All s u bjects m us t ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o psy fr o m  a met ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n , a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6 - da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
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 E e val uati o n a n d disease stat us n otificati o n.
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 da ys) f or t he first ye ar t he n Q 1 2 W
( +/- 7 da ys) t hereafter. I magi n g s h o ul d c o nti n ue u ntil site-
assesse d 1st ra di ol o gic e vi de nce of P D is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI deter mi nes t he s u bject w o ul d be nefit fr o m c o nti n ue d treat me nt a n d t he n 
f oll o ws t he s u bject per ir R E CI S T), 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 t he e n d of t he st u d y, w hic he ver occ urs first .
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( 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 -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C y cle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt Me dicati o n
Re vie w d uri n g F oll o w -U p Visits is f or n e w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d
(as s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
6 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – C a pecit a bi ne
6. 1. 3
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
Safet y F oll o w -
u p
F oll o w U p 
Visits
S ur vi val 
F oll o w -
u p a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nistr ati ve 
Pr oce d ures b
I nf or me d C o nse nt
X
I nfor me d C o nse nt f or F ut ure 
Bi o me dical Researc h
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 d
X
Pri or a n d C o nc o mita nt 
Me dicati o n Re vie w
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X z
Ca pecita bi ne 
A d mi nistrati o n e
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X  
X  
X  
X  
X  
X
X
X
1 2 -Lea d E C G ( L ocal) g
X
F ull P h ysical E xa mi nati o n
X
X
Directe d P h ysical 
E xa mi nati o n
X  
X  
X  
X  
X  
X  
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
Safet y F oll o w -
u p
F oll o w U p 
Visits
S ur vi val 
F oll o w -
u p a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Vital Si g ns a n d Wei g ht
h
X  
X  
X  
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce Stat us i
X i
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
j
X
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, k h
Pre g na nc y Test Ser u m l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X  
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
X
X
X  
X x
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X
Ser u m Vita mi n D v
X
T u m or 
mar kers 
( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) o, v, w
X
X o
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 
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics p
X
C orrelati ve Bl o o d Sa m ples 
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, Ser u m)
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
Safet y F oll o w -
u p
F oll o w U p 
Visits
S ur vi val 
F oll o w -
u p a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Effic ac y Me as ure me nts
b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g -if 
a p plica ble g q
X
X q
X
X
B o ne I ma gi n g -if a p plica bler
X
X r
T u m or Tiss ue C ollecti o n b
Scree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -
L 1 stat us a n d bi o mar ker 
a nal ysis s
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker/ P D -L 1 a nal ysis t
X
S u bje ct Re p orte d 
O utc o mes b, u
E Q -5 D
X
X
X
X
X y
X
X
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X
X
a.
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 w ee 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 or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nts/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des all acti ve c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If a c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.  
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
6 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
Safet y F oll o w -
u p
F oll o w U p 
Visits
S ur vi val 
F oll o w -
u p a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1 .
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G P S s h o ul d be perf or me d wit hi n 1 0 da y pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2.6.
k.
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 d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tes ts.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. . 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. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
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 tr ial.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote w 
f or details.
p.
Bl o o d f or g e netics are ma n dat or y sa m ples u nless t here 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 o t 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.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first ye ar, t he n Q 1 2 W) a n d will 
be perf or me d i n s u bjects wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
r.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne.
s.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u m or bi o ps y f r o m  a met ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n , a n arc hi val or sa m ple or sli des ma y be s u b mitte d A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt 
i nitiati o n. A n y tiss ue pri or t o t he 5 6- da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n 
arc hi ve d vs . ne wl y o btai ne d t u m or s peci me ns.
u.
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 E e val uati o n a n d disease stat us n otificati o n. 
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Scree ni n g P hase
Treat me nt C ycles
E n d of 
Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n g ( Visit 1)
1 
2 
3 
4 
5 
6
7 a n d 
be y o n d
Disc o n c
Safet y F oll o w -
u p
F oll o w U p 
Visits
S ur vi val 
F oll o w -
u p a
Sc he d uli n g Wi n d o w ( Da ys):
-5 6 t o - 1 
-2 8 t o - 1
+ 3
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of 
disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
w.
T u m or i ma gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W ( +/- 7 da ys) f or t he first ye ar, t he n Q 1 2 W ( +/- 7 da ys) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d  1st  ra di ol o gic  evi de nce  of disease pr o gressi o n ( PD) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site P I deter mi nes t he s u bject w o ul d be nefit fr o m 
c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject per irR E CI S T), t he start of ne w a nti-ca ncer treat me nt, wit h dra wal of  co nse nt, deat h, or t he e n d of t he st u d y, w hic he ver 
occ urs first.
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( 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 -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3
u ntil t he e n d of year 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt Me dicati o n
Re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d
(as s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
7 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St a n d ar d Tre at me nt Ar m – Vi n o rel bi ne
6. 1. 4
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5 
6
7 a n d Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -
u p Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
A d mi nis tr ati ve 
Pr oce d ures b
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
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 d
X
Pri or a n d C o nc o mita nt 
Me dicati o n Re vie w
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X z
Vi n orel bi ne
A d mi nistrati o n e
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P ost -st u d y A ntica ncer 
T hera p y Stat us
X  
X
S ur vi val Stat us a
-------------------------------------------------------------------------------------------------------------------------------------------------

X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -
u p Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts f
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
1 2 -Lea d E C G ( L ocal) g
X
F ull P h ysical E xa mi nati o n
X
X
Directe d P h ysical 
E xa mi nati o n
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vital Si g ns a n d Wei g ht h
X  
X  
X  
X
X
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 i
X  
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Me n o pa usal Stat us
j
X
L a b or at or y 
Pr oce d ures/ Assess me nts:  
L O C A L l a b or at or y b, k
Pre g na nc y Test – Ser u m l
X
P T /I N R a n d a P T Tm
X
C B C wit h Differe ntial
X  
X  
X
X
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C he mistr y Pa nel
X  
X  
X
X
X  
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
X x
X x
X
T 3, F T 4 a n d T S H n, v
X
X
X
X  
X x
X x
X x
X
Ser u m Vita mi n D v
X
T u m or mar kers ( C A 1 5 -3, 
C E A a n d C A 2 7. 2 9) o, v
X
X o
X
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -
u p Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
L a b or at or y 
Pr oce d ures/ Assess me nts:  
C E N T R A L l a b or at or y b
Bl o o d f or Ge netics p
X
C orrelati ve Bl o o d Sa m ples 
( D N A a n d R N A)
X  
X  
X
X
Bl o o d f or E x pl orat or y 
Bi o mar kers ( Plas ma, 
Ser u m) 
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g w
X
X w
X
X
Brai n I ma gi n g –i f 
a p plica ble q
X
X q
X
X
B o ne I ma gi n g -if a p plica bler
X
X r
T u m or Tiss ue C ollecti o n b
S cree ni n g tiss ue f or ce ntral 
c o nfir mati o n of T N B C, P D -
L 1 stat us a n d  bi o mar ker 
a nal ysis s
X
O pti o nal arc hi val tiss ue f or 
bi o mar ker/ P D -L 1 a nal ysis t
X
S u bject Re p orte d 
O utc o me
b, u
E Q -5 D
X
X
X
X
X y
X y
X y
X
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -
u p Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
E O R T C Q L Q -C 3 0
X
X
X
X
X y
X y
X y
X
X
E O R T C Q L Q -B R 2 3
X
X
X
X
X y
X y
X y
X
X
a.
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 w ee 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 n s 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 re c or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt s/ pr oce d ures i n Secti o n 7. 0.  
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n di sease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
Me dical hist or y i ncl u des all active c o n diti o ns a n d a n y c o n diti o n dia g n ose d wit hi n past 1 0 years c o nsi dere d t o be cli nicall y si g nifica nt a n d all a ut oi m m u ne dis or ders, 
re gar dless of o nset date.
e.
If c o u ntr y g ui deli nes s pecif y a n a d diti o nal d osi n g da y (e x. Da y 1 5), t he assess me nts s h o ul d mirr or Da y 8 i n t he fl o w c hart.
f.
G ui da nce o n m o nit ori n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1.
g.
A d diti o nal E C Gs ma y be perf or me d as cli nicall y necessar y.
h.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, b o d y wei g ht, a n d hei g ht ( o nl y at scree ni n g). Vital si g ns s h o ul d be perf or me d 
pri or t o treat me nt a d mi nistrati o n.
i.
Scree ni n g E C O G s h o ul d be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n.
j.
W he n i n dicate d, ser u m F S H a n d estra di ol le vels m ust be assesse d a n d rec or de d i n t he e C R Fs. See S ecti o n 7. 1. 2. 6.
k.
Scree ni n g la b orat or y tests are t o be perf or me d wit hi n 1 0 da ys pri or t o ra n d o mizati o n. Aft er 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 d ose.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
l.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial treat me nt. 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. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if dee me d 
necessar y b y PI or re q uire d b y l ocal g ui deli nes.
m.
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.
n.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
o.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote w 
f or details.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d:
Scree ni n
g P hase
Treat me nt C ycles
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Scree ni n
g ( Visit 
1)
1 
2 
3 
4 
5
6
7 a n d Be y o n d
Disc o n c
Safet y 
F oll o w -u p
F oll o w -
u p Visits
S ur vi val 
F oll o w -
u p a
Treat me nt Visit ( A d mi n wee kl y)
1
2, 3
4 
5 
6 
7 
8 
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6 1 7
1 8 
1 9 
2 0 
2 1
Sc he d uli n g Wi n d o w 
( Da ys):
-5 6 
t o -
1
-2 8 
t o -
1
+ 
3
d
± 3
At ti me 
of 
disc o n
3 0 da ys 
p ost disc o n
( ± 3 da ys)
P ost 
disc o n 
( ± 7 da ys)
E ver y 1 2 
wee ks
( ± 7 da ys)
p.
Bl o o d f or g e netics are m a n dat or y sa m ples u nless t here 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.
q.
D uri n g scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n metastases (s uc h s u bjects als o 
nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier). W hile o n st u d y, brai n i ma gi n g f oll o ws a cale n dar sc he d ule ( Q 9 W f or t he first y ear, t he n Q 1 2 W) a n d will
be perf or me d i n s u bje cts wit h k n o w n brai n metastases a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms .
r.
B o ne sca ns will be perf or me d at scree ni n g f or s u bject wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os ke letal c o m plai nts. O n treat me nt perf or me d as nee de d 
f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject has n o k n o w n 
metastatic disease i n t he b o ne or acti ve s y m pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A bo ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s y m pt o ms of b o ne
metastasis .
s.
All s u bjects m ust ha ve ce ntral c o nfir mati o n of T N B C stat us pri or t o ra n d o mizati o n. A fres h c ore or e xcisi o nal t u mor bi o p s y fr o m a me t ast atic, n ot pre vi o usl y irr a di ate d 
lesi o n will be use d f or c o nfir mati o n of T N B C stat us, P D -L 1 stat us a n d bi o mar ker a nal ysis. If ne w bi o ps y ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical 
c o ntrai n dicati o n a n arc hi val or s a mpl e or sli des ma y be s u b mitted A F T E R s p o ns or a p pr o val. Ne wl y o btai ne d tiss ue ma y be o btai ne d u p t o 5 6 da ys pri or t o treat me nt
wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n. A n y tiss ue pri or t o t he 5 6 -da y wi n d o w ma y be c o nsi dere d wit h S p o ns or c o ns ultati o n.
t.
W he n a vaila ble, arc hi ve d t u m or s peci me ns f or m pri or bi o psies will be c ollecte d f or deter mi nati o n of P D -L 1 stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n arc hi ve d vs .
ne wl y o btai ne d t u m or s peci me ns.
u.
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 E e val uati o n a n d disease stat us n otificati o n. 
v.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
w.
T u m or ima gi n g f oll o ws a cale n dar sc he d ule; it is i n de pe n de nt of c ycles. T o meet scree ni n g criteria, 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 date of 
ra n d o mizati o n. D uri n g treat me nt, t u m or i ma gi n g is perf or me d Q 9 W
( +/- 7 d a y s) f or first ye ar t he n Q 1 2 W
( +/- 7 da ys) t hereafter. I ma gi n g  sh o ul d  co nti n ue   until  site-
assesse d 1st ra di ol o gic e vi de nce of disease pr o gressi o n ( P D) is verifie d b y t he ce ntral i ma gi n g ve n d or ( u nless t he site PI deter mi nes t he s u bject w o ul d be nefit fr om c o nti n ue d 
treat me nt a n d t he n f oll o ws t he s u bject per ir R E CI S T), 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 t he e n d of t he st u d y, w hic he ver occ urs first .
x.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
y.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3 u ntil
t he e n d of ye ar 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
z.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n S ecti o n 7. 1. 2. 1).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
7 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Sec o n d C o urse P h ase ( Retre at me nt) f or Pe m br oliz u m a b Ar m O nl y
6. 2
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
A d mi nistr ati ve Pr oce d ures b
Eli gi bilit y Criteria
X
C o nc o mita nt Me dicati o n & 
Me dical Hist or y
X
X  
X  
X  
X  
X  
X
X
X
X r
Pe m br oliz u ma b A d mi nistrati o n
X  
X  
X  
X  
X  
X
x
P ost -st u d y A ntica ncer T hera p y 
Stat us
X
X
S ur vi val Stat us a
X
Cli nic al 
Pr oce d ures/ Assess me nts b
Re vie w A d verse E ve nts d
X  
X  
X  
X  
X  
X  
X  
X
X
X
X
F ull P h ysical E xa mi nati o n
X
X
Directe d P h ysical E xa mi nati o n
X  
X  
X  
X  
X  
X
Vital Si g ns a n d Wei g ht e
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
L a b or at or y 
Pr oce d ures/ Assess me nts :  
L O C A L l a b or at or y b, f
Pre g na nc y Test – Ser u m g
X
P T /I N R a n d a P T Th
X
C B C wit h Differe ntial
X
X  
X  
X  
X  
X  
X
X
X
C he mistr y Pa nel
X
X  
X  
X  
X  
X  
X
X
X
Uri nal ysis
X
X
X
X  
X p
X
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
T 3, F T 4 a n d T S H i, n
X
X
X  
X p
X
T u m or mar kers ( C A 1 5-3, C E A 
a n d C A 2 7. 2 9) j, n, o
X j
X
X
Effic ac y Me as ure me nts b
T u m or I ma gi n g k, o
X
X o
X
X
Brai n I ma gi n g -if a p plica blel
X
X l
B o ne I ma gi n g -if a p plica blem
X
X m
a.
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 w ee 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 re c or de d).
b.
Re vie w all detaile d i nstr ucti o ns o n assess me nt/ pr oce d ures i n Secti o n 7. 0.
c.
S u bjects w h o disc o nti n ue trial treat me nt f or a n y reas o n ot her t ha n disease pr o gressi o n will m o ve t o t he p ost -treat me nt f oll o w u p p hase. If a s u bject is disc o nti n ue d fr o m st u d y 
treat me nt wit h d oc u me nte d P D, i ma gi n g is n ot perf or me d. T he s u bject will t he n e nter s ur vi val f oll o w u p w here s u bject will be c o ntacte d via a p h o ne call e ver y 1 2 wee ks fr o m 
t he last c o ntact date t o assess f or s ur vi val stat us.
d.
G ui da nce o n rec or di n g A Es a n d E CIs ca n be f o u n d i n Secti o n 7. 1. 2. 1. 
e.
Vital si g ns will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y te m perat ure, p ulse rate, a n d b o d y wei g ht. Vital si g ns s h o ul d be perf or me d pri or t o treat me nt 
a d mi nistrati o n.
f.
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 d ose.  See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests.
g.
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y test s h o ul d be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of trial retreat me nt. . 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. Pre g na nc y tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y s h o ul d be c o m plete d if 
dee me d necessar y b y PI or re q uire d b y l ocal g ui deli nes.
h.
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 h e trial.
i.
T 3 or F T 3 ca n be assa ye d base d o n l ocal sta n dar ds.
j.
T u m or mar kers ( C A 1 5- 3, C E A a n d C A 2 7. 2 9) will f oll o w t he sa me visit sc he d ule as t he t u m or i ma gi n g base d o n a cale n dar sc he d ule a n d n ot treat me nt c ycles. See f o ot n ote o 
f or details.
k.
T u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt. 
l.
Brai n i ma gi n g s h o ul d be perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt i n s u bjects wit h ne w or w orse ni n g ne ur ol o gical s y m pt o ms a n d t h ose wit h k n o w n brai n 
metastases. D ur i n g a s u bject’s first year o n trial, brai n i ma gi n g f oll o ws a Q 9 W cale n dar sc he d ule. After t he first year, brai n i ma gi n g is Q 1 2 W .
m.
B o ne sca ns s h o ul d b e perf or me d wit hi n 2 8 da ys pri or t o restarti n g treat me nt i n s u bjects wit h k n o w n b o ne metastases a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts.  
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
7 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Trial Peri o d :
Treat me nt C ycles 
E n d of Treat me nt
P ost -Treat me nt
Treat me nt C ycle/ Title:
Verifie d 
pri or t o 
treat me nt
1 
2 
3 
4 
5 
6
7 a n d 
Be y o n d
Disc o n c
Safet y F oll o w -u p
F oll o w - up 
Visits
S ur vi val 
F oll o w -u p a
Sc he d uli n g Wi n d o w ( Da ys):
+ 3
± 3 
± 3 
± 3 
± 3 
± 3
At ti me of disc o n
3 0 da ys p ost 
disc o n
( ± 3 da ys)
P ost disc o n 
( ± 7 da ys)
E ver y 1 2 wee ks
( ± 7 da ys)
B o ne sca ns s h o ul d be perf or me d o n treat me nt f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts o r if t he site belie ves t he y ha ve attai ne d a 
C o m plete Res p o nses.  If a s u bject has n o k n o w n metastatic disease i n t he b o ne or acti ve s y m pt o ms, b o ne sca ns are n ot nee de d.  A b o ne sca n ca n be o btai ne d at f oll o w u p wit h 
t here are ne w s y m pt o ms of b o ne pai n.
n.
T 3, F T 4 a n d T S H, ser u m v ita mi n D, a n d tu m or mar kers ( C A 1 5 -3, C E A a n d C A 2 7. 2 9 ) ca n be d o ne ce ntrall y if a site is u na ble t o c o m plete l ocall y.
o.
I ma gi n g f oll o ws a Q 9 W cale n dar sc he d ule, it is i n de pe n de nt of c ycles.
p.
Uri nal ysis, T 3, F T 4, a n d T S H la b orat or y assess me nts after C ycle 6 will b e re peate d o n Treat me nt Da y 1 e ver y 2 C y cles (ie, C y cles 8, 1 0, 1 2, etc.).
q.
S u bject Re p orte d O utc o mes ( E Q-5 D, E O R T C Q L Q -C 3 0, E O R T C Q L Q -B R 2 3) q uesti o n naires will b e a d mi nistere d o n Treat me nt Da y 1 e ver y t hir d c ycle after C ycle 3 u ntil
t he e n d of ye ar 1 ( ie, C ycles 6, 9, 1 2, etc.) a n d e ver y f o urt h c ycle d uri n g year 2 u ntil P D.
r.
C o nc o mita nt m e dicati o n re vie w d uri n g F oll o w -U p Visits is f or ne w a nti-ca ncer treat me nt a n d me dicati o ns a d mi nistere d t o treat a n y A E or E CI re p orte d d uri n g t his peri o d (as
s pecifie d i n Secti o n 7. 1. 2. 1).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
7 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
7. 1
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
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 .
7. 1. 1. 2
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 trial.
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 pro 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 via a re vise d c o nse nt 
f or m or a d de n d u m t o t he ori gi nal c o nse nt f or m t hat ca pt ures t he 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 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 1. 2. 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 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 o ce 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. 3
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. 4
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 partici pa nts i n a 
researc h trial.  The 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.  The i n vesti gat or 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.
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 uati o ns w here t he i n vesti gat or is n ot a vaila ble.
7. 1. 1. 5
Me dic al Hist or y
De m o gra p hic i nf or mati o n a n d me dical hist or y  will be o btai ne d b y  the In 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 c o n diti o n 
dia g n ose d wit hi n t he pri or 1 0 ye ars, t hat are c o nsi dere d t o be cli nicall y si g nifica nt b y  the 
I n vesti gat or. Details re gar di n g t he s u bject’s breast ca ncer hist or y  will be rec or de d se paratel y 
a n d n ot liste d as me dical hist or y .  A n y a ut oi m m u ne dis or ders s h o ul d be rec or de d re gar dless 
of o nset date .
7. 1. 1. 5. 1
Dise ase Det ails
T he I nvesti 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 breast ca ncer dia g n osis .
7. 1. 1. 6
Pri or a n d C o nc o mit a nt Me dic ati o ns Re vie w
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 as s pecifie d i n t he 
Trial Fl o w C h art ( Secti o n 6. 0), i ncl u di n g a n y pr ot oc ol-s pecifie d was h o ut re q uire me nt, a n d 
rec or d pri or me dicati o n ta ke n b y  the s u bject wit hi n 2 8 d a y s bef ore ra n d o mizati o n.  Pri or 
treat me nt f or breast ca ncer will be rec or de d se paratel y a n d n ot liste d as a pri or me dicatio n.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 1. 6. 1
Pri or Tre at me nt Det ails f or Bre ast C a ncer Di a g n osis
T he I n vesti gat or or q ualifie d desi g nee will re vie w all pri or treat me nts f or s u bject’s breast 
ca ncer dia g n osis, i ncl u di n g sys te mic treat me nts, ra diati o n a n d s ur geries.
7. 1. 1. 6. 2
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 s, if a n y, ta ke n b y  the s u bject 
d uri n g t he trial t hr o u g h t he Safet y F oll o w - u p visit , as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0) .  I n a d diti o n, ne w me dicati o ns starte d d uri n g t he Sec o n d C o urse P hase t hr o u g h 
t he Sec o n d C o urse Safet y  Foll o w - u p visit s h o ul d be rec or de d.  All me dicati o ns relate d t o 
re p orta ble A Es, S A Es , a n d E CIs 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. 3
S u bse q ue nt A nti -c a ncer T her a p y St at us
T he I nvesti gat or or q ualifie d desi g ne e will re vie w all ne w a nti-ca ncer t hera py i nitiate d after 
t he last d ose of trial treat me nt.  If a s u bject i nitiates a ne w a nti-ca ncer t hera p y wit hi n 3 0 da ys 
after t he last d ose of trial treat me nt, t he 3 0 d a y  Safet y Foll o w - u p visit m ust occ ur bef ore t he 
first d ose of t he ne w t hera p y.  Once ne w a nti-ca ncer t hera py has bee n i nitiate d t he s u bject 
will m o ve i nt o s ur vi val f oll o w - u p.  
7. 1. 1. 7
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 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. 8
Assi g n me nt of R a n d o miz ati o n N u m ber
All eli gi ble s u bjects will be ra n d o ml y all ocate d a n d will recei ve a ra n d o mizati o n n u m ber.  
T he 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 
ra n d o mizati o n.  Once a 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 ra n d o mizati o n n u m ber.
I n vesti gat ors m ust c h o ose a T P C dr u g (ca pecita bi ne, eri b uli n, ge mcita bi ne or vi n orel bi ne ) 
pri or t o ra n d o mizati o n a n d d oc u me nt t he selecti o n i n t he I V R S a n d trial data base ( See Data 
E ntr y  G ui deli nes).
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
8 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 1. 9
Tri al C o m pli a nce ( Me dic ati o n/ Diet/ Acti vit y/ Ot her)
A n y  inter r u pti o ns greater t ha n 1 2 wee ks bet wee n d oses (pe m br oliz u ma b or T P C ar m s) f or 
n o n dr u g -relate d or a d mi nistrati ve reas o ns re q uire c o ns ultati o n bet wee n t he 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 olla b orati ve decisi o n o n s u bject ma na ge me nt.
A d mi nistrati o n of trial me dicati o n will be wit nesse d b y  t he I n vesti gat or a n d/ or trial staff. T he 
t otal v ol u me of p e m br oliz u ma b or c o m parat or i nf use d will be c o m pare d t o t he t otal v ol u me 
pre pare d t o deter mi ne c o m plia nce wit h 
eac h d ose of pe m br oliz u ma b or c o m parat or 
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.  T P C a ge nts will be pre pare d a n d a d mi nistere d as per l ocal pr o d uct la bel.
Please refer t o Secti o n 5. 2 f or i nstr ucti o ns o n pe m br oliz u ma b a n d T P C.
7. 1. 1. 1 0 S ur vi v al
After t he start of ne w a nti -ca ncer treat me nt or d oc u me nte d disease pr o gressi o n b y t h e c entral 
i ma gi n g ve n d or, t he s u bject s h o ul d be c o ntacte d b y  tele p h o ne e ver y 12 wee ks fr o m t he last 
c o ntact date f or s ur vi val stat us assess me nt .
Cli nic al Pr oce d ures/ Assess me nts
7. 1. 2
7. 1. 2. 1
A d verse E ve nt M o nit ori n g
T he I n vesti gat or or q ualifie d desi g nee will assess eac h s u bject t o e val uate p ote ntial ne w or 
w orse ni n g A Es at eac h visit a n d as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 6. 0) , or m ore 
fre q ue ntly if cli nicall y i n dicate d.  A Es 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 or di n g t o N CI  CT C A E Versi o n 4. 0 ( Secti o n 7. 2 ).  To xicities 
will be c haracterize d i n ter ms re gar 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.  
Please refer t o Secti o n 7 . 2 f or detaile d i nf or mati o n re gar di n g t he assess me nt a n d rec or di n g of 
A Es.  
7. 1. 2. 2
1 2 -Le a d Electr oc ar di o gr a m 
A sta n dar d 1 2 -lea d electr ocar di o gra m (E C G ) will be perf or me d usi n g l ocal sta n dar d 
pr oce d ures o nce 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 ti me p oi nts ma y be perf or me d as cli nically necessar y.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 2. 3
P h ysic al E x a m
7. 1. 2. 3. 1
F ull P h ysic al E x a m
T he I n vesti gat or or cli nical desi g nee will
perf or m a c o m plete p h y si ci an e xa m d uri n g t he 
scree ni n g peri o d. 
Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as me dical 
hist or y. After t he scree ni n g peri o d, a f ull p h y sical e xa m s h o ul d be perf or me d as s pecifie d i n 
t he Trial
Fl o w
C hart
( Secti o n 6. 0).
After
ra n d o mizati o n 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.
7. 1. 2. 3. 2
Directe d P h ysic al E x a m
T he I n vesti gat or or cli nical desi g nee will perf or m direc t e d p h y sical e xa ms at eac h visit w hile 
o n trial treat me nt, as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 6. 0), a n d as nee de d acc or di n g
t o s u bject’s si g ns a n d s ym pt o ms. 
Ne w
cli nicall y si gnifica nt a b n or mal fi n di n gs s h o ul d b e 
rec or de d as A Es.
7. 1. 2. 4
Vit al S i g ns 
T he I n vesti gat or or q ualifie d desi g nee will ta ke vital si g ns at scree ni n g, 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 at treat me nt disc o nti n uati o n , as s pecifie d i n 
t he Trial Fl o w C hart ( Secti o n 6. 0). Vital si g ns s h o uld i ncl u de te m perat ure, p ulse, res pirat ory 
rate, wei g ht a n d bl o o d press ure. Hei g ht will be meas ure d
at scree ni n g o n l y. Vitals s h o ul d
be ta ke n pri or t o treat me nt a d mi nistrati o n.
7. 1. 2. 5
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us
T he I n vesti gat or or q ualifie d desi g nee will assess E C O G stat us ( Secti o n 1 2. 5 ) at scree ni n g, at
eac h treat me nt c ycle a n d at disc o nti n uati o n of trial treat me nt, as s pecifie d i n t he Trial Fl o w 
C hart ( Secti o n 6. 0).
7. 1. 2. 6
Me n o p a us al St at us
T he me n o pa usal stat us ( pre- or p ost -me n o pa u sal) f or all fe male s u bjects less t ha n a ge 6 0 
m ust be deter mi ne d at scree ni n g, acc or di n g t o t he defi niti o ns bel o w. 
T he date of t he 
s u bject’s last me nstr ual peri o d ( L M P) a n d, w he n i n dicate d, ser u m F S H a n d estra di ol le vels 
m ust be assesse d a n d rec or de d i n the e C R Fs.
Pre -me n o pa usal

≤1 2 m o nt hs si nce L M P
O R

Bi oc he mical e vi de nce of pre -me n o pa usal 
stat us, acc or di n g t o ser u m F S H
a n d 
estra di ol le vels a n d l ocal i nstit uti o nal g ui deli nes
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
P ost -me n o pa usal

S u bject has u n der g o ne pri or bilateral o variect o m y/ o o p h orect o m y 
O R

> 1 2 m o nt hs 
si nce L M P
a n d n o h y sterect o m y, h or m o ne re place me nt, estr o ge n 
rece pt or a nta g o nist, c he m ot hera py or o varia n s u p pressi o n at a n y ti me si nce L M P 
O R

Bi oc he mical e vi de nce of p ost -me n o pa usal 
stat us, acc or di n g t o ser u m F S H
a n d 
estra di ol le vels a n d l ocal i nstit uti o nal g ui deli nes.
7. 1. 2. 7
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 u n d i n t he Site I ma gi n g Ma n ual. 
T u m or i ma gi n g m a y b e perf or me d b y co m p ute d 
t o m o gra ph y ( C T) ( preferre d) or ma g netic
res o na nce i ma gi n g ( M RI), b ut t he sa me i ma gi n g 
tec h ni q ue s h o uld be use d i n a s u bject t hr o u g h o ut t he trial. 
A CT is t he m or e c o m m o nl y
us e d m o dalit y a n d is preferre d f or t he maj orit y of s u bjects. A n
M RI
can be utilize d if
cli nicall y a p pr o priate.
D uri n g 
scree ni n g, brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h 
k n o w n brai n 
metastases (s uc h s u bject als o nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks 
earlier) a n d s u bjects wit h w orse ni n g a n d/ or ne w ne ur ol o gical s ym pt o ms . S u bjects wit h 
pre vi o usl y  treate d brai n metastases 
m a y  partici pate pr o vi de d t he y ha ve sta ble brai n 
metastases, ie, wit h o ut e vi de nce of pr o gressi o n b y  ima gi n g (c o nfir me d b y  MRI  if M RI  was 
use d at pri or i ma gi n g, or c o nfir me d b y  CT i ma gi n g if C T was use d at pri or i ma gi n g) f or at 
least 4 wee ks pri or t o t he first d ose of trial treat me nt.  An 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 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 2 8 d a y s pri or t o trial 
i nitiati o n as per l ocal site assess me nt.  This e x ce 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.
W hile
o n st u dy , brai n i ma gi n g s h o ul d be perf or me d i n s u bjects wit h k n o w n brai n metastases 
a n d s u bjects wit h
w orse ni n g
a n d/ or ne w ne ur ol o gical s ym pt o ms. 
If M RI  is me dicall y
c o ntrai n dicate d, C T i ma gi n g will be acce pte d. Brai n i ma gi n g w o ul d be d o ne Q 9 W f or first
ye ar, t he n Q 1 2 W, as s pecif ie d i n t he Trial Fl o w C hart ( Secti o n 6. 0).
If a p plica ble, b o n e sca ns will
be perf or me d as s pecifie d i n t he Trial Fl o w C hart ( Secti o n 
6. 0). B o ne sca ns at scree ni n g f or a n y s u bject wit h
k n o w n b o ne metastases a n d/ or ne w 
b o ne pai n a n d m usc ul os keletal c o m plai nts. D uri n g t he st u dy, b o ne sca ns will be perf or me d
as nee de d f or e val uati o n of w orse ni n g a n d/ or ne w b o ne pai n a n d m usc ul os keletal c o m plai nts 
or if t he site belie ves t he y ha ve attai ne d a C o m plete Res p o nse. If a s u bject h a s n o k n o w n
metastatic disease i n t he b o ne or acti ve s ym pt o ms, a b o ne sca n at baseli ne is n ot nee de d.  A 
b o ne sca n ca n be o btai ne d at f oll o w u p if t here are ne w s ym pt o ms of b o ne pai n.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
All
sc he d ule d i ma ges f or all st u dy s u bjects fr o m 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
( CI V). I n a d diti o n, all u nsc he d ule d i ma ges t hat t he site c o nsi ders 
c o ntri b utes t o pr o gressi o n or res p o nse will
be s u b mitte d t o t he CI V. 
T h e ce ntral i ma gi n g
ve n d or will recei ve all i ma ges fr o m t he sites an d verif y pr o gressi ve disease f oll o wi n g site-
assesse d 1st ra di ol o gic e vi de nce of pr o gressi ve disease usi n g R E C IS T 1. 1. T he verificati o n 
of ra di ol o gic P D will be e x pe dite d b y t he CI V. T he CI V verificati o n of ra di ol o gic P D will
be c o m m u nicate d t o t he site ( Secti o n 7. 1. 2. 7. 3) a n d s p o ns or wit hi n 3- 5 b usi ness da ys after 
recei pt 
of 
all 
re q uire d 
i ma gi n g 
a n d 
res ol uti o n 
of 
all 
q ueries i n 
real-ti me. 
E x pe dite d verificati o n of ra di ol o gic pr o gressi o n as deter mi ne d b y ce ntral i ma gi n g 
ve n d or re vie w (f oll o wi n g site-assesse d 1st ra di ol o gic e vi de nce of pr o gressi ve disease)
will  be c o m m u nicate d t o t he site ( Secti o n 7. 1. 2. 7. 3). T he CI V will perf or m a retr os pecti ve
a nal ysis of s u bject eli gi bilit y (per R E C I S T 1. 1) a n d treat me nt res p o nse b y ( usi n g R E C I S T
1. 1 a n d ir R E CIS T) a nd t he se will
be pr o vi de d t o t he s p o ns or. S p o ns or will
also recei ve
t u m or i ma gi n g f or a retr os pecti ve a nal ysis of s u bject eli gi bilit y a n d treat me nt res p o nse t o be 
perf or me d b y t h e ce ntral ve n d or usi n g R E C I S T 1. 1 a nd ir R E CIS T . Fi g ure 2 s h o ws t he 
pr ocess f or t u m or assess me nt b y site a n d ce ntral i ma gi n g ve n d or f or a cli nicall y sta ble 
s u bject.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
8 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Fi g ure 2
I ma gi n g a nd Treat me nt f or Cli nical l y Sta bl e S u bjects A fter First Ra di ol o gic
E vi de nce of P r o gressi ve Disease Assesse d b y t he Site
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
8 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Fi g ure 3 s h o ws t he pr ocess f or t u m or assess me nt b y  site a n d ce ntral i ma gi n g ve n d or f or a 
cli nicall y u nsta ble s u bject.
* Site m us t se n d all re q uire d i ma gi n g t o CI V a n d res ol ve all i ma gi n g q ueries; t hen t he 3
-5 b usi ness d a y T A T f or n otificati o n be gi ns. A n y
u nsc he d ule d i ma gi n g t hat s u p p orts a
site base d assess me nt of P D s h o ul d als o be se nt t o CI V.
Fi g ure 3
I ma gi n g Pr ocess f or a Cli nicall y U nsta ble S u bject
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 2. 7. 1
B aseli ne T u m or I m a gi n g
T o meet scree ni n g criteria, t u m or i ma gi n g m ust be perf or me d wit hi n 2 8 da y s pri or t o date of 
ra n d o mizati o n.  Eli gi ble s u bjects m ust ha ve meas ura ble disease base d o n R E CI S T 1. 1 as 
assesse d b y site I n vesti gat or a n d l ocal ra di ol o g y re vie w. T u m or i ma gi n g perf or me d as part of 
r o uti ne cli nical ma na ge me nt are acce pta ble f or use as t he 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 , meet t he re q uire me nts s pecifie d i n t he Site I ma gi n g M a n ual ( SIM) , a n d 
were perf or me d wit hi n 2 8 da y s pri or t o ra n d o mizati o n.  
Brai n i ma gi n g at baseli ne s h o ul d be perf or me d i n s u bjects wit h k n o w n brai n metastases 
(s uc h s u bjects als o nee d rec or ds of brai n i ma gi n g perf or me d at least 4 wee ks earlier) a n d 
t h ose wit h w orse ni n g a n d/ or ne w ne ur ol o gical s y m pt o ms.
If a s u bject has a k n o w n hist or y  of b o ne metastases or has ne w b o ne pai n d uri n g scree ni n g, a 
b o ne sca n s h o ul d be o btai ne d pri or t o st u d y entr y .  If a s u bject has n o k n o w n metastatic 
disease i n t he b o ne or acti ve s ym pt o ms, a b o ne scan at baseli ne is n ot nee de d.   A d diti o nall y , 
plai n X- ra y eval uati o n s h o ul d be o btai ne d f or s ym pt o matic s keletal sites wit h ne gati ve b o ne 
sca n e val uati o ns.
7. 1. 2. 7. 2
T u m or I m a gi n g D uri n g t he Tri al
All s u bjects s h o ul d ha ve i ma gi n g assess me nts perf or me d as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0). S u bjects s h o ul d ha ve t u m or i ma gi n g at 9 wee ks ( ± 7 d a y s) fr o m date of 
ra n d o mizati o n u p t o 1 year ( m ore fre q ue ntl y if cli nicall y i n dicate d).  All s u bjects w h o re mai n 
o n treat me nt f or a ye ar will s u bse q ue ntl y ha ve i ma gi n g perf or me d e ver y 1 2 wee ks ( ± 7 da ys). 
I ma 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 co nti n ue t o be perf or me d u ntil site -assesse d 1st ra di ol o gic e vi de nce of 
disease pr o gressi o n ( P D) is verifie d b y  the ce ntral i ma gi ng ve n d or ( u nless t he site PI  
deter mi nes t he s u bject w o ul d be nefit fr o m c o nti n ue d treat me nt a n d t he n f oll o ws t he s u bject 
per 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, deat h, or t he 
e n d of t he st u d y, 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. 
B o n e sca ns will
als o be utilize d to assess osse o us metastases. 
If a s u bject has a k n o w n 
hist or y of b o ne metastases
or has ne w b o ne pai n d uri n g scree ni n g, a b o ne sca n s h o ul d be 
o btai ne d pri or t o st u dy e ntr y. A b o ne sca n at f oll o w u p is re q uire d o nl y if t hey d e vel o p ne w 
or w orse ni n g s ym pt o ms
or if t he site belie ves t hey ha ve attai ne d a C o m plete Res p o nse. If a 
s u bject has n o k n o w n me tastatic disease i n t he b o ne or acti ve s ym pt o ms , a b o ne sca n at 
baseli ne is n ot nee de d. A b o ne
sca n can be o btai ne d at f oll o w u p if t here ar e ne w
s ym pt o ms of
b o ne
pai n.
A d diti o nall y,
plai n
X- ray
e val uati o n
will
be
o btai ne d
f or
s ym pt o matic
sites wit h ne gati ve b o ne sca n e val uati o ns.
Brai n i ma gi n g d uri n g t he trial s h o ul d be perf or me d as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 0) i n s u bjects wit h k n o w n brai n metastases ( Q 9 W f or first ye ar, t he n Q 1 2 W) a n d 
t h ose wit h w orse ni n g a n d/ or ne w ne ur ol o gical s ym pt o ms.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
8 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Per R E CI S T 1. 1, res p o nse ( partial res p o nse (P R) or C R 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 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.  The 
t u m or i ma ge f or c o nfir mati o n of res p o nse ma 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 t u m or i ma gi n g (e g 9 wee ks later) 
w hic he ver is cli nicall y  i n dicate d.
After ce ntral verificati o n of P D b y R E C I S T 1. 1 i n s u p p ort of t he P F S a nal y sis, if t he site PI  
deter mi nes t he s u bject is cli nicall y sta ble a n d w ill be nefit fr o m c o nti n ue d treat me nt, t he 
s u bject will t he n be ma na ge d
b y ir R E CIS T.  P er ir R E CIS T, t hat i nitial P D b y R E C IS T 1. 1 
m ust
be i n cli nicall y sta ble s u bjects, disease pr o gressi o n m a y be c o nfir me d b y t he site 
I n vesti gat or/ l ocal ra di ol o gy re vie w at least 4 wee ks after verificati o n of 1st site-assesse d 1st 
ra di ol o gic e vi de nce of P D . 
Su bjects w h o
ha ve u nc o nfir me d disease pr o gressi o n ( P D)
m a y  c o nti n ue o n treat me nt u ntil pr o gressi o n P D is c o nfir me d pr o vi de d t hey h a ve met
t he 
c o n diti o ns detaile d i n Sec ti o n 7. 1. 2. 7. 4.
7. 1. 2. 7. 3
E n d of Tre at me nt a n d F oll o w -u p T u m or I m a gi n g
I n s u bjects w h o disc o nti n ue st u d y t hera p y, 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 (ie, date of disc o nti n uati o n ± 4 wee k wi n d o w).  If pre vi o us t u m or 
i ma gi n g  was  o btai ne d  wit hi n  4  wee ks  pri or  t o  t he  date  of  disc o nti n uati o n,  t he n  t u m or 
i ma gi n g at treat me nt disc o nti n uati o n is n ot re q uire d. 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 ubjects w h o disc o nti n ue trial treat me nt wit h o ut ce ntrall y verifie 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  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 (Q 9 W i n Year 1 or 1 2 wee ks after 
Year 1) t o m o nit or disease stat us u ntil t he start of a ne w a ntica ncer treat me nt, disease 
pr o gressi o n, deat h, or t he e n d of t he trial, w hic he ver occ urs first.
7. 1. 2. 7. 4
R E CI S T 1. 1
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 wit hi n 3- 5 b usi n ess da y s i n real-
ti me after recei pt of all i ma gi n g a n d res ol uti o n of a n y q ueries t o verif y  site-assesse d 1st 
ra di ol o gic e vi de nce of P D retr os pecti vely as t he pri mar y  meas ure f or assess me nt of t u m or 
res p o nse a n d retr os pecti vel y to deter mi ne s u bject eli gi bilit y.  All sc he d ule d i ma ges f or all 
st u d y su bjects fr o m 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 ( CI V).   In 
a d diti o n, all u nsc he d ule d i ma ges t hat t he site c o nsi ders c o ntri b utes t o pr o gressi o n or res p o nse 
will be s u b mitte d t o t he CI V. All t u m or i ma ges s h o ul d be s u b mitte d t o t he ce ntral ve n d or.
7. 1. 2. 7. 5
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 n 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 ve n t he a p peara nce of ne w lesi o ns.  Sta n dar d R E CI S T 1. 1 m a y , 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
t h us, n ot pr o vi de a n acc urate res p o nse assess me nt of i m m u n ot hera pe utic a ge nts s uc h as 
pe m br oliz u ma b. I mm u ne -relate d R E CI S T (ir R E CI S T) is R E CI S 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 n o-t hera pe utics as descri be d i n secti o n 7. 1. 2. 6. 
ir R E CIS T will be use d b y  local site i n vesti gat ors t o assess t u m or res p o nse a n d pr o gressi o n, 
a n d ma ke treat me nt decisi o ns. 
T heref ore, R E CI S T 1. 1 will be use d wit h t he f oll o wi n g a da ptati o ns:
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.  S u bjects ma y  recei ve st u d 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 sig 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
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   
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 nvesti 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). A n a daptati o n of ir R E CIS T has bee n e m pl o ye d a n d is o utli ne d 
bel o w [ 1 0 2].  
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:

T u m or b ur de n 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 w orse ( q ualitati ve assess me nt)

Ne w lesi o n res ulti n g i n i nitial P D is w orse ( q ualitati ve assess me nt)

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 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 bjects will be 
disc o nti n ue d fr o m st u d y  t hera p y (e xce pti o n n ote d bel o w).
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 
ir R E CIS T: 

T u m or b ur de n 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 i m pr o ve d ( q ualitati ve assess me nt)

Ne w lesi o n res ulti n g i n i nitial P D is sta ble or i m pr o ve d ( q ualitati ve assess me nt)
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial

N o 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 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 b y  ir R E CIS T a n d t he s u bject c o nti n ues t o be 
cli nicall y sta ble, treat me nt ma y c o nti n ue a n d f oll o w t he re g ular i ma gi n g sc he d ule. 
W he n 
feasi ble, su 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  t he 
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 ubjects 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 u nsta 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. 
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 a vaila ble i n C P A C.
A n y  su bject dee me d cli nic all y u nst a ble s h o ul d be disc o nti n ue d fr o m trial treat me nt at 
ce ntral verificati o n of site-assesse d 1 st ra di ol o gic e vi de nce of pr o gressi ve disease 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.
F or a cli nicall y sta ble s u bject wit h site-assesse d 1 st ra di ol o gic e vi de nce of pr o gressi ve disease 
b y  RE CI S T 1. 1 t hat has bee n verifie d b y  ce ntral i ma gi n g ve n d or (ie, u nc o nfir me d 
pr o gressi o n of disease) , it is at t he discreti o n of t he site 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 da y s fr om t h e dat e o f t he t u m or i ma ge first s u g gesti n g P D w hic h was ulti matel y 
verifie d b y  CI V per R E CI S T 1. 1.   If pr o gressi o n b y  ir R E CIS T is n ot c o nfir med b y t he 
s u bse q ue nt t u m or i ma gi n g, t he s u bject s h o ul d c o nti n ue t o recei ve st u dy t herap y a n d ha ve 
t u m or i ma gi n g perf or me d e ver y 9 wee ks ( 6 3 ± 7 da y s) d uri n g t he first ye ar a n d e ver y 12 
wee ks ( 8 4 ± 7 d a y s) after t he first ye ar, or s o o ner if cli nicall y in dicate d, t o m o nit or
disease
stat us. If ra di ol o gic pr o gressi o n is c o nfir me d b y s u bse q ue nt t u m or i ma ge, t he n t he s u bject 
will be disc o nti n ue d fr o m trial treat me nt.  
N O T E : If a s u bject wit h c o nfir me d ra di o gra p hic pr o gressi o n (ie 2 t u m or i ma ges at least 2 8 
da y s a part de m o nstrati n g pr o gressi ve disease) 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 n efit, 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.  In t his 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 ntin ue t o be perf or me d f oll o wi n g t he i nter vals as o utli ne d i n secti o n 
7. 1. 2. 7.   St u d y  Fl o wc hart a n d be s u b mitte d t o t he CI V.
S u bj ects e x hi biti n g t o xicity f r o m
trial t herap y as o utli ne d i n Secti o ns 5. 2. 1 a n d S e cti o n 7. 2 ma y N O T
c o nti n ue t o recei ve
trial t herap y. 
N O T E :  I n su bjects w h o disc o nti n ue st u d y thera p y  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  t u m or i ma gi n g
e ver y 9 wee ks ( ± 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.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T he sa me i ma gi n g tec h ni q ue, ac q uisiti o n, a n d pr ocessi n g para meters 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. A d diti o nal i nf or mati o n is i ncl u de d i n t he Site I ma gi n g Ma n ual.
7. 1. 2. 8
T u m or Tiss ue C ollecti o n a n d C orrel ati ve Bl o o d S a m pli n g
7. 1. 2. 8. 1
T u m or Tiss ue C ollecti o n
All
s u bjects m ust ha ve ce ntral c o nfir mati o n of tri ple-ne gati ve breast ca ncer stat us pri or t o 
ra n d o mizati o n ( Secti o n 5. 1. 2 ). A ne wl y o btai ne d c ore or e xcisi o nal t u m or bi o ps y (fi ne nee dle 
as pirate [F N A ] n ot a de q uate) fr o m a met ast atic lesi o n (or arc hi val bi o ps y , if ne w bi o ps y 
ca n n ot be o btai ne d d ue t o site i naccessi bilit y or a me dical c o ntrai n dicati o n a n d s p o ns or 
a gree me nt is o btai ne d ) will be use d f or c o nfir mati o n of tri ple-ne gati ve breast t u m or stat us.  
Testi n g will be perf or me d b y  a ce ntral ve n d or usi n g c o m merciall y vali date d assa ys a n d 
t u m or stat us f or h or m o ne rece pt or a n d H E R 2 e x pressi o n will be deter mi ne d acc or di n g t o t he 
m ost rece nt A S C O/ C A P g ui de -li nes:
a.
Estr o ge n rece pt or ( E R) ne gati ve stat us is defi ne d as < 1 %
t u m or cells p ositi ve 
f or E R b y  I H C, irres pecti ve of stai ni n g i nte nsity 
b.
Pr o gester o ne rece pt or ne gati ve stat us is defi ne d as < 1 %
t u m or cells p ositi ve 
f or Pr o gester o ne rece pt or b y I H C, irres pecti ve of stai ni n g i nte nsit y
c.
H E R 2 ne gati ve stat us is deter mi ne d b y:  

I H C 1 +,
as defi ne d b y  inc o m plete me m bra ne 
stai ni n g t hat is 
fai nt/ barely pe rce pti ble a n d wit hi n > 1 0 % of i n vasi ve t u m or cells, O R

I H C 0, as defi ne d b y n o stai ni n g o bser ve d or me m bra ne stai ni n g t hat is 
i nc o m plete a n d is fai nt/ barely perce pti ble a n d wit hi n ≤1 0 % of t he 
i n vasi ve t u m or cells, O R

FI S H ne gati ve base d o n s i n gle-pr o be a vera ge H E R 2 c o p y n u m ber < 4. 0 
si g nals/cell, or D ual -pr o be H E R 2 / C E P 1 7 rati o < 2. 0 wit h a n a vera ge 
H E R 2 c o p y  n u m ber < 4. 0 si g nals/cell
A ne wl y o btai ne d c ore or e xcisi o nal t u m or bi o ps y  (fi ne nee dle as pirate is n ot a de q uate) fr o m 
a metastatic lesi o n will als o be use d f or ce ntral deter mi nati o n of P D -L 1 t u m or stat us.
W he n 
a vaila ble, arc hi ve d t u m or s peci me ns fr o m pri or bi o psies will als o be c ollecte d f or 
deter mi nati o n of P D -L 1 t u m or stat us a n d c o m paris o n of bi o mar ker e x pressi o n i n arc hi ve d vs
ne wl y  o btai ne d t u m or s peci me ns.
Ne wl y o btai ne d t u m or tiss ue s h o ul d b e s u b mitte d i n f or mali n ( preferre d) or as f or mali n -fi xe d 
paraffi n e m be d de d t u m or tiss ue bl oc ks.  If after a gree me nt wit h t he S p o ns or u nstai ne d sli des 
are s u b mitte d, t he sli des s h o ul d be fres hl y c ut a n d s u b mitte d t o t he testi n g la b orat or y  wit hi n 7
da y s fr o m site sli de secti o ni n g date ot her wise a ne w s peci me n will be re q ueste d .  
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
T he sa me ne w tiss ue sa m ple ma y  be use d f or b ot h m T N B C stat us a n d P D -L 1 stat us. Ne wl y 
o btai ne d t u m or tiss ue ma y  be o btai ne d u p t o 5 6 da y s pri or t o treat me nt i nitiati o n. T u m o r 
tiss ue o btai ne d rece ntly,  but pri or t o t he 5 6- da y  wi n d o w, ma y  be c o nsi dere d wit h S p o ns or 
c o ns ultati o n .
O nl y  in t he pe m br oliz u ma b ar m, a n opti o nal c ore or e xcisi o nal bi o psies m a y  be o btai ne d 
w hile o n treat me nt , o n or after c y cle 2, a n d/ or at disease pr o g ressi o n, as s pecifie d i n t he Trial 
Fl o w C harts ( Secti o n 6. 0).
N ote: F or all t u m or tiss ue c ollecte d, a fi ne nee dle as pirate, fr oze n sa m ple, plastic e m be d de d 
sa m ple, cell bl oc k, cl ot, b o ne, b o ne marr o w, c yt ol o gic s peci me n, decalcifie d , or f or mali n 
fi xe d sa m ple t hat was fr oze n at a n y p oi nt will n ot be acce pta ble f or a nal ysis.
Detaile d i nstr ucti o ns f or tiss ue c ollecti o n, pr ocessi n g a n d s hi p me nts are pr o vi de d i n t he 
ve n d or’s ma n ual.
7. 1. 2. 8. 2
Bl o o d f or C orrel ati ve St u dies
Bl o o d f or c orrelati ve bi o ma r ker st u dies ( R N A a n d D N A) s h o ul d be c ollecte d pre -d ose at 
C y cle 1, 2, 3 , a n d at treat me nt disc o nti n uati o n .
Detaile d i nstr ucti o ns f or s pecific ti me p oi nts per sa m ple, tiss ue c ollecti o n, pr ocessi n g a n d 
s hi p me nt are pr o vi de d i n t he ve n d or’s m a n ual.
7. 1. 2. 9
P atie nt -Re p orte d O utc o mes
T he eE ur o Q ol ( E Q)-5 D, eE O R T C Q L Q -C 3 0 a n d eE O R T C Q L Q -B R 2 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 E ur o Q ol ( E Q)-5 D first, t he n e E O R T C Q L Q- C 3 0, a n d lastl y the e E O R TC 
Q L Q -B R 2 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. 
7. 1. 2. 9. 1
T he P atie nt - Re p orte d O utc o mes 
T he Patie nt Re p orte d O utc o mes ( P R Os) are assesse d as f oll o ws (as s pecifie d i n t he Trial 
Fl o w C harts ( Secti o n 6. 0):

If a T P C treatme nt has m ore t ha n o ne d ose per c ycle, t he e P R Os will o nl y  be 
a d mi nistere d o n t he first treat me nt da y  of t he c ycle.

A t c yc les 1, 2, a n d 3 

E ver y  3r d c ycle after C ycle 3 u ntil t he e n d of Y ear 1 ( i e, C y cles 6, 9, 1 2, etc.)
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
9 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial

E ver y  4t h c ycle d uri n g Ye ar 2 u ntil P D

At t he Treat me nt Disc o nti n uati o n Visit * 

At t he 3 0 -d a y  Safet y F oll o w-u p Visit *
*I f t he Treat me nt Disc o nti n uati o n Visit occ urs > 3 0 d a y s 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 Foll o w u p Visit, P R Os d o n ot nee d t o be 
re peate d.
L a b or at or y Pr oce d ures/ Assess me nts
7. 1. 3
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 t he 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 v e n d or’s 
m a 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 , Uri n al ysis , a n d 
Ot her )
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 7
Ta ble 7
La b orat or y  Tests
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
H e 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
H e m o gl o bi n
Al kali ne p h os p hatase
Gl uc ose
P T (I N R)
Platelet c o u nt
Ala ni ne a mi n otra nsferase 
( A L T)
Pr otei n
a P T T d
W hite bl o o d cell
(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) or 
Free T 3 e
Re d b l o o d Cell 
C o u nt
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 ( T 4)
A bs ol ute n e utr o p hil 
co u nt g
Calci u m
T h yr oi d sti m ulati n g h or m o ne 
( T S H)
A bs ol ute 
ly m p h oc yte co u nt g
C hl ori de
Bl o o d f or f ut ure bi o me dical 
researc h (F B R )
Creati ni ne
Bl o o d f or c orrelati ve st u dies
Gl uc ose
P K (f or s u bjects o n t he 
pe m br oliz u ma b ar m o nl y)
P h os p h or us
A nti -p e m br oliz u ma b 
A nti b o dies (f or s u bjects o n 
t he pe m br oliz u ma b  ar m o nl y)
Ma g nesi u m
( o nl y 
s u bjects o n Eri b uli n)
F S H, estra di ol f
P otassi u m
Vita mi n D le vels
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
H e m at ol o g y
C he mistr y
Uri n al ysis
Ot her
S o di u m
T u m or mar kers ( C A 1 5 -3, 
C E A , a n d C A 2 7. 2 9)
T otal b ilir u bi n  
Direct b ilir 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 m al
T otal pr otei n
Bl o o d u rea n itr o ge n
Lactate de h y dr o ge nase 
( L D H)
Car b o n di o xi de ( C O 2 or 
bicar b o nate) b
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.  
b.
If c o nsi dere d sta n dar d of care i n y o ur re gi o n.
c.
Bl o o d u rea 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 ( PT/I N R a n d a 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.  An 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.
Bl o o d f or me n o pa usal stat us is o nl y re q uire d f or s o me s u bjects as descri be d i n Secti o n 7. 1. 3. 6
g.
Eit her a bs ol ute or % is acce pta ble as per i nstit uti o nal sta n dar d
La b orat or y  tests will be perf or me d as s pecifie d i n t he Trial Fl o w
C hart ( Secti o n 6. 0). 
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 d a y s pri or t o ra n d o mizati o n.  
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 7 2 h o urs pri or t o 
d osi n g.  Safet y la b orat or y res ults m ust be re vie we d b y  the 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 .
Exce pti o n: T hyr oi d f u ncti o n testi n g ( T 3, F T 4, a n d T S H), Vit a mi n D, a n d t u m or m arker s ( C A 1 5-3, 
C E A a n d C A 2 7. 2 9) res ults c a n be revie we d f oll o wi n g sc he d ule d d osi n g.
7. 1. 3. 2
Pre g n a nc y Test
F or w o m e n of re pr o d ucti ve p ote ntial, a uri ne or 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 t he first d ose of trial treat me nt. 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. If s u bject meets
crit eri a 
f or s e c o n d c o urs e p h as e a uri n e or s er u m pr e g n a n c y  test s h o ul d b e c o m pl et e d pri or t o 
r est arti n g p e m br oli z u m a b. Pre g na nc y  tests (ser u m a n d/ or uri ne tests) d uri n g t he st u d y 
s h o ul d be c o m plete d if dee me d necessar y  by PI  or re q uire d b y  local g ui deli nes .  S u bjects 
m ust be e xcl u de d/ disc o nti n ue d fr o m t he trial i n t he e ve nt of a p ositi ve or b or derli ne -p ositi ve 
test res ult.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
9 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 3. 3
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
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 hara cterizati o n 
of t he cli nical p har mac ol o g y  of p em br oliz u ma b acr oss i n dicati o ns. T heref ore, u p o n a p pr o val 
of A me n d me nt 0 5 eac h site is t o st o p t he c ollecti o n of P K a n d A D A sa m ples f or all s u bjects. 
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 0 5 m a 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. 4
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 ve n d or’s ma n ual . 
T his sa m ple s h o ul d be dra w n f or pla n ne d a nal ys is 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 here 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 RB/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 os es, 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
researc h if t he s u bject si g ns t he F B R c o nse nt.
7. 1. 3. 5
Bl o o d f or C orrel ati ve St u dies
Bl o o d f or c orrelati ve st u dies (i ncl u des bl o o d f or D N A a n d R N A) s h o ul d be c ollecte d pre d ose 
C y cle 1, C ycl e 2, C ycle 3, a n d at treat me nt disc o nti n uati o n. 
Bl o o d f or e x pl orat or y bi o mar kers ( plas ma a n d ser u m), s h o ul d be c ollecte d pre -d ose C y cle 1. 
Detaile 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 ve n d or’s 
ma n ual.
7. 1. 3. 6
Bl o o d f or Me n o p a us al St at us
Bl o o d c ollecti o n at scree ni n g f or bi oc he mical e vi de nce of me n o pa usal stat us ( F S H a n d 
estra di ol) will be c o m plete d if a p plica ble.
7. 1. 3. 7
F ut ure Bi o me dic al Rese arc h
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 Researc h:

Left o ver D N A 

Left o ver mai n st u d y t u m or s peci me ns
If t he s u bject si g ns t he F ut ure Bi o me dical Researc h ( F B R) c o nse nt, a n y left o ver tiss ue t hat 
w o ul d or di naril y  be 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 B R.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
9 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Ot her Pr oce d ures
7. 1. 4
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 st u d y treat ment pri or t o c o m pleti o n of t he trial
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 a n d s ur vi val 
f oll o w-u p c o ntacts.
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 ti me of disc o nti n uati o n.  
A n y  ad verse e ve nts w hic h are pr ese 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 . S u bjects o n t he pe m br oliz u ma b ar m w h o a) attai n a C R or b) 
c o m plete 3 5 treat me nts wit h pe m br oliz u ma b ma 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. 2. 1 .  
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 treat me nts, 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 ( Secti o n 7. 1. 5. 3. 2 ) a n d t he n pr ocee d t o t he 
F oll o w -u p Peri o d of t he st u d y  ( Secti o n 7. 1. 5. 3. 3 ).
7. 1. 4. 1. 1
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 
speci 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 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 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 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 u cti 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 ubject’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.
7. 1. 4. 2
Bli n di n g/ U n bli n di n g
T his is a n o pe n la bel trial; t here is n o bli n di n g f or t his trial.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
9 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 
i nf or mati o n a b o ut i ncl usi o n/e xcl usi o n criteria a n d/ or 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

Dr u g 
a d mi nistrati o n e q ui p me nt –
as re q uire d f or st ora ge, pre parati o n a n d 
a d mi nistrati o n (i nf usi o n) of st u dy dr u g.
See pr ot oc ol -s pecifie d g ui da nce i n t he A d mi nistrati ve Bi n der, ve n d or’s m a n ual , a n d Site 
I ma gi n g Ma n ual.
Visit Re q uire me nts
7. 1. 5
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. 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.
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 d a y s pri or t o ra n d o mizati o n e xce pt f or 
t he f oll o wi n g:

La b orat or y  tests a n d E C O G P S are t o be perf or me d wit hi n 1 0 da ys pri or t o 
ra n d o mizati o n.

F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test will be 
perf or me d wit hi n 7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y me dicati o n.

Ne wl y o btai ne d t u m or tiss ue, a n d arc hi val tiss ue w he n a vaila ble, m a y  be o btai ne d 
wit hi n 5 6 da y s of treat me nt i nitiati o n.
S u bjects ma y  be rescree ne d t wice 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 per i o d are 
acce pta ble i n lie u of a re peat scree ni n g test if perf or me d wit hi n t he s pecifie d ti me fra me a n d 
t he i ncl usi o n/e xcl usi o n criteria is met.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
9 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
7. 1. 5. 2
Tre at me nt Peri o d
Visit ti mi n g re q uire me nts d uri n g t he treat me nt peri o d are as f oll o ws:

A ssess me nts/ pr oce d ures s h o ul d be perf or me d pri or t o d ose f or eac h c ycle u nless 
ot her wise s pecifie d i n t he fl o w c hart.

Treat me nt c ycles are Q 3 W
f or pe m br oliz u ma b a n d acc or di n g t o l ocal la bel or 
g ui deli nes f or T P C ar m.  

T he wi n d o w f or eac h visit is ± 3 da y s u nl ess ot her wise n ote d.  Cycle 1 treat me nt 
s h o ul d be n o m ore t ha n 3 da ys after ra n d o mizati o n.  

O pti o nal c ore or e xcisi o nal bi o psies m a y  be o btai ne d w hile o n treat me nt, o n or after 
c ycle 2 , or at disease pr o gressi o n f or t he pe m br oliz u ma b ar m o nl y.
F or t he f ull list of all visit assess me nts/ pr oce d ures please see 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. 2. 1
Sec o n d C o urse P h ase ( Retre at me nt Peri o d)
C o n diti o ns of Sec o n d C o urse P h ase
7. 1. 5. 2. 1. 1
S u bjects o n t he pe m br oliz u ma b ar m w h o st o p pe m br oliz u ma b wit h S D or better m a y  be 
eli gi ble f or u p t o o ne ye ar of a d diti o nal pe m br oliz u ma b t hera p y if t he y pr o gress after 
st o p pi n g st u d y treat me nt.  This retreat me nt is ter me d t he Sec o n d C o urse P hase of t his s t u d y 
a n d is o nl y  availa ble if t he st u d y re mai ns o pe n a n d t he s u bject meets t he f oll o wi n g 
c o n diti o ns:
Eit her 
o
St o p pe d i nitial treat me nt wit h pe m br oliz u ma b after attai ni n g a n I n vesti gat or-
deter mi ne d c o nfir me d C R acc or di n g t o R E CI S T 1. 1

F oll o wi n g
at 
least 8 
treat me nts
wit h 
pe m br oliz u ma b
bef ore 
disc o nti n ui n g t hera p y , a n d

Recei ve d at least 2 treat me nts wit h pe m br oliz u ma b be y o n d t he date 
w he n t he i nitial C R was declare d
O R
o
H a 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 3 5 treat me nts
of st u d y  t hera p y f or reas o ns ot her t ha n disease pr o gressi o n or i nt olera bilit y
A N D
o
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 after st o p pi n g t heir i nitial treat me nt wit h pe m br oliz u ma b
o
Di d 
n ot 
recei ve a n y 
a nti -ca ncer treat me nt si nce t he
last d ose 
of 
pe m br oliz u ma b
o
Has a perf or ma nce stat us of 0 or 1 o n t he E C O G Perf or ma nce Scale
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
o
De m o nstrate s a de q uate or ga n f u ncti o n as detaile d i n Secti o n 5. 1. 2
o
Fe male s u bject of c hil d beari n g p ote ntial s h o ul d 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 retreat me nt wit h st u d y 
dr u g .  
o
Fe male s u bject of c hil d beari n g p ote ntial s h o ul d be willi n g t o use 2 met h o ds of 
birt h c o ntr ol or be s ur gicall y sterile, or a bstai n fr o m heter ose x ual acti vit y f or 
t he c o urse of t he st u d y thr o u g h 1 2 0 d a y s (at least 6 m o nt hs f or s u bjects o n 
ge mcita bi ne) after t he last d ose of st u d y dr u g ( Secti o n 5. 7. 2 ).  Su bjects of 
c hil d beari n g p ote ntial are t h ose w h o ha ve n ot bee n s ur gically sterilize d or 
ha ve bee n free fr o m me nses f or > 1 y ear. 
o
Male s u bject
s h o ul d a gree t o use a n a de q uate met h o d of c o ntrace pti o n starti n g 
wit h ra n d o mizati o n t hr o u g h 1 2 0 d a y s (at least 6 m o nt hs f or s u bjects o n 
ge mcita bi ne) after t he last d ose of st u d y t hera p y.  
o
D oes n ot ha ve a hist or y  or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or 
la b orat or y ab n or malit y t hat mi g ht i nterfere wit h t he s u bject’s partici pat i o n f or 
t he f ull d urati o n of t he trial or is n ot i n t he best i nterest of t he 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.
Visit R e q uire me nts of Sec o n d C o urse P h ase
7. 1. 5. 2. 1. 2
7. 1. 5. 2. 1. 2. 1 Assess me nts/ P r oce d ures / Wi n d o ws
Assess me nts are p erf or me d o n D a y  1 an d pri or t o ra n d o mizati o n f or eac h c ycle u nless 
ot her wise s pecifie d.  Treat me nt c ycles are 3 wee ks
a n d visit wi n d o ws are ± 3 d a y s u nless 
ot her wise n ote d .  If t o xicit y occ urs , refer t o t he d ose m o dificati o n g ui deli nes pr o vi de d i n 
Secti o n 5. 2. 1. 2. 1.  Ima gi n g s h o ul d al wa ys be perf or me d Q 9 W ( ± 7 d a y s) re gar dless of a n y 
treat me nt dela ys.  
7. 1. 5. 2. 1. 2. 2 Disc o nti n u ati o n D uri n g t he Sec o n d C o urse P h ase
I n s u bjects w h o disc o nti n ue st u d y t hera p y, t u mor 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 (ie, date of disc o nti n uati o n ± 4 wee k wi n d o w).  If a pre vi o us t u m or 
i ma ge was o btai ne d wit hi n 4 wee ks pri or t o t he date of disc o nti n uati o n, t he n a t u m or i ma ge 
at treat me nt disc o nti n uat i o n is n’t ma n dat or y.
F or t h ose s u bjects t hat disc o nti n ue st u d y thera p y 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  tu m or i ma gi n g 
e ver y 9 wee ks ( ± 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.
7. 1. 5. 2. 1. 2. 3 L a b or at or y Tests D uri n g t he Sec o n d C o urse P h ase
La b orat or y  tests f or deter mi ni n g eli gi bilit y for retreat me nt are t o be perf or me d wit hi n 
1 0 da y s pri o r t o t he first retreat me nt d ose of pe m br oliz u ma b.  See Secti o n 7. 1. 3 f or details 
re gar di n g la b orat or y tests.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
F or w o me n of re pr o d ucti ve p ote ntial, a uri ne or ser u m pre g na nc y  test s h o ul d be perf or me d 
wit hi n 7 2 h o urs pri or t o first r e-treat me nt d ose. Pre g na nc y  tests s h o ul d be re peate d if 
re q uire d by l ocal g ui deli nes.
After C y cle 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.  
See Secti o n 7. 1. 3 f or details re gar di n g la b orat or y tests. T 3 or F T 3 ca n be assa ye d base d o n 
l ocal sta n dar ds.
C oa g ulati o n fact ors ( P T/I N R a n d a P T T) s h o ul d be m o nit ore d cl osel y thr o u g h o ut t he trial f or 
a n y s u bject recei vi n g a ntic oa g ula nt t hera p y.
U nres ol ve d la b a b n or malities 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 trial treat me nt if la bs are wit hi n n or mal 
ra n ge.
L a b orat or y safety meas ure me nts will be gra de d per N CI C T C A E versi o n 4. 0.  
7. 1. 5. 2. 1. 2. 4 C o nc o mit a nt Me dic ati o ns D uri n g t he Sec o n d C o urse P h ase
E nter ne w me dicati o ns starte d d uri n g t he trial t hr o u g h t he Safet y Foll o w -u p visit.  Rec or d all 
me dicati o ns ta ke n f or A Es as defi ne d i n Secti o n 7. 2.
7. 1. 5. 2. 1. 2. 5 Vit al Si g ns D uri n g t he Sec o n d C o urse P h ase
Vital si g ns t o 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.    Vitals 
s h o ul d be ta ke n pri or t o treat me nt a d mi nistrati o n.
7. 1. 5. 2. 1. 2. 6 Pe m br oliz u m a b Rest art D uri n g t he Sec o n d C o urse P h ase
S u bjects w h o restart treat me nt s h o ul d res u me pe m br oliz u ma b at t he d ose a n d i nter val 
s pecifie d i n Secti o n 6. 2.
7. 1. 5. 2. 1. 2. 7 T u m or I m a gi n g Sec o n d C o urse P h ase
T u m or i ma gi n g m ust 
be perf or me d wit hi n 2 8 d a y s pri or t o restarti n g treat me nt wit h 
pe m br oliz u ma b.  Ima gi n g s h o ul d c o nti n ue t o be perf or me d Q 9 W ( ± 7 da ys) fr o m first re-
treat me nt d ose or m ore fre q ue ntly if cli nicall y i n dicate d, as s pecifie d i n t he Trial Fl o w C hart 
( Secti o n 6. 2).  Local rea di n g (site I n vesti gat or/l ocal ra di ol o g y re vie w) will be use d t o 
deter mi ne eli gi bilit y an d f or s u bject ma na ge me nt.  The Sites will c ollect a n d se n d t u m or 
i ma gi n g t o t he ce ntral i ma gi n g ve n d or.
T he S p o ns or will c ollect t u m or i ma gi n g f or
retr os pecti ve a nal ys is b y a ce ntral i ma gi n g ve n d or.  The pr ocesses f or i ma ge c ollecti o n a n d 
tra ns missi o n t o t he ce ntral ve n d or are i n t he Site I ma gi n g Ma n ual. 
T he sa me i ma gi n g 
tec h ni q ue, ac q uisiti o n, a n d pr ocessi n g para meters s h o ul d be use d i n a s u bject thr o u g h o ut t he 
trial. 
After t he start of ne w a nti-ca ncer treat me nt or d oc u me nte d disease pr o gressi o n b y t he ce ntral 
i ma gi n g ve n d or, t he s u bject s h o ul d be c o ntacte d b y  tele p h o ne Q 1 2 W t o assess f or s ur vi val 
stat us.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
7. 1. 5. 3
P ost -Tre at me nt Visits
7. 1. 5. 3. 1
Disc o nti n u ati o n Visit
T he Di sc o nti n uati o n Visi t s h o ul d occ ur at t he ti me st u d y treat me nt 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 occ urs 3 0 d a y s fr o m t he last d ose of st u dy 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 b e re peated .  
Visit re q uire me nts are o utli ne d i n Secti o n 6. 0.  Specific pr oce d ure -relate d details are 
pr o vi de d a b o ve i n Secti o n 7. 1.  Ad diti o nal details re gar di n g s u bject wit h dra wal a n d 
disc o nti n uati o n are prese nt e d i n Secti o n 5. 8.
7. 1. 5. 3. 2
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 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 trial treat me nt or bef ore t he i nitiati o n of a ne w a nti-ca ncer treat me nt, w hic he ver 
c o mes first.  All A Es t hat occ ur pri or t o t he Safet y F oll o w -U p Visit s ho 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-ca ncer t hera p y, w hic he ver occ urs first.  Eac h s u bject 
will be f oll o we d f or 3 0 da y s f or A E s a n d E C Is. S eri ous a d verse e ve nts will be c ollecte d f or 
9 0 da y s after t he e n d of trial treat me nt.
S u bjects w h o are eli gi ble f or retreat me nt wit h pe m br oliz u ma b ( Secti o n 7. 1. 5. 2. 1 ) ma 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 Peri o d a n d o ne after t he Sec o n d 
C o urse P hase.
7. 1. 5. 3. 3
F oll o w -u p Visits
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 
m o ve i nt o t he F oll o w -U p P hase a n d s h o ul d be assesse d Q 9 W (± 7 da y s) b y t u m or i ma gi n g t o 
m o nit or disease stat us.  After 1 ye ar, i ma gi n g will be perf or me d Q 1 2 W ( ± 7 da ys).
E ver y  eff ort s h o ul d be ma de t o c ollect i nf or mati o n re gar di n g disease stat us u ntil t he start of 
ne w a nti-ca ncer t hera p y, diseas e pr o gressi o n deter mi ne d b y  ce ntral i ma gi n g ve n d or, deat h, 
e n d of st u d y or if t he s u bject be gi ns retreat me nt wit h pe m br oliz u ma b (Secti o n 7. 1. 5. 2. 1).  
I nf or mati o n re gar di n g p ost -st u d y anti -ca ncer treat me nt will be c ollecte d if ne w treat me nt is 
i nitiate d.
S u bjects w h o are eli gi ble t o recei ve retreat me nt wit h pe m br oliz u ma b acc or di n g t o t he criteria 
i n Secti o n 7. 1. 5. 2. 1 will m o ve fr o m t he F oll o w -U p P hase t o t he Sec o n d C o urse P hase w he n 
t he y ex perie nce disease pr o gressi o n.  Details are pr o vi de d i n Secti o n 6. 0 f or Retreat me nt 
wit h pe m br oliz u ma b.
7. 1. 5. 3. 4
S ur vi v al F oll o w -u p
O nce a s u bject e x perie nces disease pr o gressi o n b y  site assess me nt a n d verifie d b y  ce ntral 
i ma gi n g ve n d or re vie w or starts a ne w a nti-ca ncer 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 at least Q 1 2 W
( m ore 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
fre q ue ntly if nee de d) fr o m t he last c o ntact date 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.
7. 1. 5. 3. 5
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 are a vaila ble at t he ti me of da ta 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 D M C 
re vie w, i nteri m a n d/ or fi nal a nalys is.  U p o n S p o ns or n otificati o n, all s u bjects 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 pre vi o usl y  rec or de d a 
deat h e ve nt i n t he c ollecti o n t o ol ).
Assessi n g a n d Rec or di n g A d verse E ve nts
7. 2
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 u re, 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 dere d a d verse e ve nts.  
E xa m ples of t his ma y  incl u d e, 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 uct, bi ol o gical pr o d uct, de vice, 
dia g n ostic a ge n t 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.
All 
a d verse 
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 
ra n d o mizati o n/treat me nt all ocati o n m ust be rep orte d b y  the 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 di n g b ut n ot li mite d t o was h o ut or disc o nti n uat i o n of us ual t hera p y, diet, place b o 
treat me nt or a pr oce d ure. Fr o m t he ti me of  ra n d o mizati o n /treat me nt all ocati 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, all a d verse e ve nts m ust 
b e
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 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
re p ort f or ms/ w or ks heets.  The 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 with 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 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).
Defi niti o n of a n O ver d ose f or T his Pr ot o c ol a n d Re p orti n g of O ver d ose t o t he 
7. 2. 1
S p o ns or
F or t his trial, a n o ver d ose will be defi ne d as ≥1 0 0 0 m g ( 5 ti mes t he d ose) of pe m br oliz u ma b 
a n d as a n y d ose ≥2 0 % o ver t he prescri be d d ose f or t he c o m parat or a ge nts.
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 t he 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 
f or si g ns of t o xicit y.  Ap pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi de d if cli nicall y 
i n dicate d.
If a n a 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 de ntal 
or i nte nti o nal o ver d ose wit h o ut a d verse effect.”
All re p orts of o ver d ose wit h a n d wit h o ut a n a 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 ne s. 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 o r
7. 2. 2
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.
Pre g na ncies a n d lactati o ns t hat occ ur after t he c o nse nt f or m is si g ne d b ut bef ore 
ra n d o mizati o n/treat me nt all o cati o n m ust be re p orte d b y  the 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 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 o r a pr oce d ure. Pre g na ncies a n d lactati o ns t hat occ ur fr o m t he ti me of 
ra n d o mizati o n t hr o u g h 1 2 0 da y s f oll o wi n g 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 p y, 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  must 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, 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 he r 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 nsor
7. 2. 3
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 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 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 maly/ 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 def i 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 8 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 ra n d o mizati o n /treat me nt 
all ocati 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 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 py, 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 ran d o mizati o n /treat me nt  all ocati 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 
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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 
me dia or pa pe r. 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 nt s are als o k n o w n as E ve nts of Cli nical Interest 
( E CI)  a n d m ust be re p orte d t o 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 ra n d o mizati o n/treat me nt 
all ocati 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, 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 ra n d o mizati o n/treat me nt all ocati 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, 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 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 nvesti gat or Trial File Bi n der ( or 
e q ui vale nt).
E ve nts of cli nical i nterest f or t h is 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 orat or y  res ults. 
2. a n ele vate d A S T or A L T la b val ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n ele vate d t otal bilir u bi n la b val ue t hat is greater t ha n or e q ual t o 2 X t he 
u p per li mit of n or mal a n d, at t he sa me ti me, a n al kali ne p h os p hatase la b val ue t hat is less 
t ha n 2 X t he u p per li mit of n or mal, as deter mi ne d b y  w a y of pr ot oc ol-s pecifie d la b orat or y 
testi ng or u n sc 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 ose of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y  re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. T he trial site g ui da nce f or assess me nt 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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 .
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 ur s 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
7. 2. 4
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.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 8
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 s u bject’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 CH 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); 
or
Is a n o ver d ose ( w het her acci de ntal or i ntenti o nal).  An 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 . An 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 mp 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 dical j u d g me nt, t he e ve nt m a 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 u sl 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. I f 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 k e 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 a n 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 dic all y q ualifie d assess me nt of ca usalit y was d o ne. T his i nitiale d d oc u me nt m ust be retai ne d f or t he re q uire d re g 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 pli a 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 m e 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 k el 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 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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 de s 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. I f 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 de at 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 L I 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 the cli nical/ pat h ol o gical prese ntati o n of t he A E c o nsiste n t 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 by 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 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
7. 2. 5
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 .
Tri al G o ver n a nce a n d O versi g ht
7. 3
Scie ntific A d vis or y C o m mittee
7. 3. 1
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
7. 3. 2
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
Data M o nit ori n g C o m mittee ( D M C) re gar di n g t he trial.
D at a M o nit ori n g C o m mittee
7. 3. 3
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 w a y  (e. g., t he y ca n n ot b e 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 regar 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 descri be d i n t he detaile d D M C c harter. 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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 wil l be a me n de d (c o nsiste nt 
wit h I CH G ui deli ne E- 9).  C ha 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 u n bli n di n g , will 
be d oc u me nte d i n a s u p ple me ntal statistical a nal y sis pla n (s S A P) 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. A se parate P K a nal ys is pla n as well as bi o mar ker 
a nal ys is pla n m a y be pr o vi de d. P ost h oc e x pl orat or y  an al y ses will be clearl y ide ntifie d i n t he 
C S R .  A patie nt -re p orte d o utc o me (P R O ) a nal ys is pla n will be i ncl u de d i n t he s S A P.
I n t his secti o n, “S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 0) ” is a b bre viate d as “ S u bjects 
wit h C P S ≥1 0 ”, a n d “ S u bjects wit h P D -L 1 p ositi ve t u m ors ( C P S ≥1 )” is a b bre viate d as 
“ S u bjects wit h C P S ≥1” .
St atistic al A n al ysis Pl a n S u m m ar y
8. 1
K e y  ele me nts of t he statistical a nal ysis pla n are s u m marize d bel o w; t he c o m pre he nsi ve pla n 
is pr o vi de d i n Secti o n 8. 2 t hr o u g h Secti o n 8. 1 2.
St u d y Desi g n O ver vie w
A P hase III Ra n d o mize d Trial of Si n gle A ge nt P e m br oliz u ma b vers us 
Si n gle A ge nt C he m ot hera p y per P h y sicia n’s C h oice f or Metastatic Tri ple 
Ne gati ve Breast Ca ncer ( m T N B C) 
Treat me nt Assi g n me nt
A p pr o xi matel y 6 0 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o bet w ee n t w o 
treat me nt gr o u ps: ( 1) pe m br oliz u ma b ar m an d ( 2) Treat me nt of P h ysicia n’s 
C h oice ( T P C) ar m. Stratificati o n fact ors are: 1) P D -L 1 t u m or stat us ( p ositi ve
[ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d 2) hist or y of  pri or ( ne o)a dj u va nt 
treat me nt vs de n o v o metastatic disease at i nitial dia g n osis .
A nal ysis P o p ulati o ns
Efficac y: I nte nti o n -t o-treat P o p ulati o n (I T T)
Safet y: All S u bjects as Treate d ( A Sa T)
Pri mar y E n d p oi nt(s)
1 O verall sur vi val ( O S) i n s u bjects wit h C P S ≥1 0
2 O S i n s u bjects wit h C P S ≥1   
3 O S i n all s u bjects 
Statistical Met h o ds 
f or Ke y 
Efficac y A nal yses
T he pri mar y h y p ot heses will be e val uate d b y  co m pari n g pe m br oliz u ma b t o 
T P C o n O S usi n g a stratifie d L o g -ra n k test. Esti mati o n of t he hazar d rati o 
will be perf or me d usi n g a stratifie d C o x re gressi o n m o del. E ve nt rates o ver 
ti me will be esti m ate d wi t hi n eac h treat me nt gr o u p usi n g t he Ka pla n -Meier 
met h o d.
Statistical Met h o ds 
f or Ke y 
Safet y A nal yses
T he a nal ysis of  safet y
res ults will 
f oll o w a tiere d a p pr oac h. Safet y 
para meters or a d verse e x perie nces of  special i nterest t hat are i de ntifie d a 
pri ori c o nstit ute “ T ier 1” safet y 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
( CIs) pr o vi de d f or bet w ee n-gr o u p c o m paris o ns.  Ot her safet y para meters will 
be c o nsi dere d Tier 2 ( wit h 9 5 % c o nfi de nce i nter vals pr o vi de d) or Tier 3 
( wit h p oi nt esti mates b y  treat me nt gr o u p pr o vi de d) T he bet w e e n-treat me nt 
differe n ce 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.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
I nteri m A nal yses
O ne i nteri m efficac y a nal ysis is pla n ne d i n t his st u d y.  Details are pr o vi de d 
i n Secti o n 8. 7.

I nteri m A nal ysis
o
Ti m i n g: a p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is c o mplete d . It 
is esti mate d t hat a p pr o xi matel y 1 3 0 , 2 8 4 a n d 4 4 5 O S e ve nts will be 
accr ue d i n s u bjects wit h C P S ≥1 0 , C P S ≥1 a n d all s u bjects.
o
P ur p ose: i nteri m efficac y a nal ysis f or O S 

Fi nal a nal ysis 
o
Tri g gere d b y d urati o n of f oll o w-u p a n d O S e ve nts i n s u bjects wit h 
C P S ≥1: A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is c o m plete d 
or 3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1, w hic he ver 
occ urs later. A p pr o xi matel y 1 5 4, 3 3 4 a n d 5 2 0 O S e ve nts will b e 
accr ue d i n s u bjects wit h C P S ≥1 0 , C P S ≥1 a n d all s u bject s.
o
If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue sl o wer t ha n e x pecte d 
a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt 
is c o mpl ete d, t he n t he S p o ns or will c o n d uct t he fi nal a n al ysis at 
t hat ti me
o
P ur p ose: fi nal efficac y a nal ysis f or O S 
M ulti plicit y
T he o verall T y pe I err or o ver t he m ulti ple 
e n d p oi nts will be str o n gl y 
c o ntr olle d at 2. 5 % ( o ne-si de d) f or pri mar y h y p ot heses of  OS
e n d p oi nts 
(i nitial α of 1. 7 % i n s u bjects wi t h C P S ≥1 0 a n d 0. 8 % i n s u bjects wit h 
C P S ≥1 ) a n d sec o n dar y h y p ot heses of P F S a n d O R R i n all s u bjects. Usi n g a n 
e xte nsi o n [ 1 0 5] of t he gra p hical a p pr oac h of Ma urer a n d Bretz [9 6 ], al p ha
ca n be re-all ocate d bet w ee n h y p ot heses . G r o u p se q ue ntial met h o ds will be 
use d t o all ocate al p ha bet wee n t he i nteri m a n d fi nal a nal yses f or O S 
e n d p oi nts.
Sa m ple Size a n d P o w er 
T he pla n ne d sa m ple size is a p pr o xi matel y 6 0 0 s u bjects .  Details are pr o vi de d 
i n Secti o n 8. 9.

F or t he pri mar y O S 
e n d p oi nt i n s u bjects wit h 
C P S 
≥1 0 , wit h 
a p pr o xi matel y 1 5 4 O S e ve nts t he trial has ~ 8 5 %
p o w er at a o ne- si de d 
1. 7 % al p ha-le vel, if t he u n derl yi n g H R is 0.6 0 , wit h a H R at b o u n d ar y  
f or s uccess of ~ 0. 7 0 ( ~4. 2 m o nt h i m pr o ve me nt ).

F or t he pri mar y O S 
e n d p oi nt i n s u bjects wi t h C P S 
≥1 , wit h 
a p pr o xi matel y 3 3 4 O S e ve nts t he trial has ~ 8 0 % ( 9 0 %) p o w er at a 
o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel, if t he u n derl yi n g H R is 0. 7 0 , wit h 
a H R at b o u n dar y f or s uccess of  ~0. 7 6 ( 0. 8 0) ( ~3. 1 [ 2. 5] m o nt h 
i mpr o ve me nt).

F or t he pri m ar y O S e n d p oi nt i n all s u bjects, wit h a p pr o xi matel y 5 2 0 
O S e ve nts t he trial has ~ 6 6 % ( 8 0 %) p o w er at a o n e -si de d 0. 8 % ( 2. 5 %) 
al p ha-le vel, if t he u n derl yi n g H R is 0. 7 8 , wit h a H R at b o u n dar y f or 
s uccess of ~ 0. 8 0 ( 0. 8 4) ( ~ 2.4 [ 1. 9] m o nt h i m pr o ve me nt).
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Res p o nsi bilit y f or A n al yses/I n -H o use Bli n di n g
8. 2
T he statistical a nal ys is of t he data o btai ne d fr o m t his st u d y will be the res p o nsi bilit y of t he 
Cli nical Bi ostatistics de part me nt of t he s p o ns or.
T he I V R S ve n d or 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.   
Alt h o u g h t he trial is o pe n la bel, a nal yses or s u m maries ge nerate d b y  ra n d o mize d treat me nt 
assi g n me nt, act ual treat me nt recei ve d, a n d/ or P D -L 1 bi o mar ker stat us will be li mite d a n d 
d oc u me nte d. I n a d diti o n, t he i n de pe n de nt ra di ol o gist(s) will perf or m t he ce ntral i ma gin g 
re vie w wit h o ut k n o wle d ge of treat me nt gr o u p assi g n me nt.
T he st u d y tea m at t he S p o ns or 
c o nsisti n g of cli nical, statistical, statistical pr o gra m mi n g a n d data ma na ge me nt pers o n nel, 
will be bli n de d t o s u bject-le vel P D -L 1 bi o mar ker res ults. A n u n bli n de d S p o ns or cli nical 
scie ntist, u n bli n de d S p o ns or statisticia n a n d u n bli n de d S p o ns or statistical pr o gra m mer will 
ha ve access t o t he s u bject-le vel P D -L 1 res ults f or t he p ur p ose of data re vie w a n d e ve nt 
m o nit ori n g, a n d will ha ve n o ot her res p o nsi bilities ass ociate d wit h t he st u d y. A s u m mar y of 
P D -L 1  bi o mar ker pre vale nce m a y  be pr o vi de d t o t he st u d y tea m at t he S p o ns or b y  the I V R S 
ve n d or or t he u n bl i n de d S p o ns or statisticia n.
Access t o t he all ocati o n sc he d ule a n d t he s u bject -le vel P D -L 1  res ults f or s u m maries or 
a nal ys es will be restricte d t o a n u n bli n de d e xter nal statisticia n, a n d, as nee de d, a n e xter nal 
scie ntific pr o gra m mer perf or mi n g t he a nal ys is, w h o will ha ve n o ot her res p o nsi bilities 
ass ociate d wit h t he st u d y.
Treat me nt -le vel res ults at t he i nteri m efficac y will be pr o vi de d b y  the e xter nal u n bli n de d 
statisticia n t o t he e D M C. T he e xter nal u n bli n de d statisticia n will ha ve access t o all ocati o n 
sc he d ule, treat me nt gr o u p, P D -L 1 stat us f or a n y a n al ysis re q uire d f or e D M C re vie w. Li mite d 
a d diti o nal S P O N S O R pers o n nel m a y  be u n bli n de d t o t he treat me nt le vel a n d/ or P D -L 1  
bi o mar ker res ults of t he efficac y i nteri m a nal yses, 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 or facilitate re g ulat or y fili n g after t he i nteri m efficac y
a nal ys is. T he e xte nt t o w hic h i n di vi d uals are u n bli n de d wit h res pect t o res ults of i nteri m 
a nal ys es will be d oc u me nte d b y t he u n bli n de d statisticia n.
T he e D M C will ser ve as t he pri mar y re vie wer of t he u n bli n de d res ults of t he i nteri m efficac y 
a nal ys es a n d will ma ke rec o m me n dati o ns f or disc o nti n uati o n of t he st u d y or m o dificati o n t o 
a n e xec uti ve o versi g ht c o m mittee of t he S P O N S O R. De pe n di n g o n t he rec o m me n dati o n of 
t he e D M C, t he S p o ns or ma y  pre pare a re g ulat or y su b missi o n.
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 ma 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 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. 
H y p ot heses/ Esti m ati o n
8. 3
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 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A n al ysis E n d p oi nts
8. 4
Effic ac y E n d p oi nts
8. 4. 1
Pri m ar y
O ver all S ur vi v al ( O S)
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 bjects wit h o ut d oc u me nte d deat h at t he ti me of t he fi nal a nal ysis will be ce ns ore d at t he 
date of t he last f oll o w -u p.
Sec o n d ar y a n d E x pl or at or y
Pr o gressi o n- free s ur vi v al ( P F S) – b ase d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntr al 
i m a gi n g ve n d or ( R E CI S T 1. 1 b y  site I n vesti gat or/l ocal ra di ol o g y re vie w as a s u p p orti ve 
a nal ys is).
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 base d o n R E CI S T 1. 1 as assesse d b y bli n de d ce ntral 
i ma gi n g ve n d or ra di ol o g y re vie w or deat h d ue t o a n y ca use, w hic he ver occ urs first. See 
Secti o n 8. 6. 1 f or t he defi niti o n of ce ns ori n g.
O ver all Res p o nse R ate ( O R R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
(R E CI S T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses ; ir R E CIS T b y 
site I nvest i gat or/l ocal ra di ol o g y re vie w m a y  als o be e val uate d).
O verall res p o nse rate is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ys is p o p ulati o n 
w h o ha ve a c o m plete res p o nse ( C R) or partial res p o nse ( P R).
D ur ati o n of O ver all 
Res p o nse ( D O R) –
b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d 
ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or ( R E CIS T 1. 1 b y  
site I nvesti gat or /l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses; ir R E CIS T
b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  als o be e val uate d).
F or s u bjects w h o de m o nstrate d C R or P R, res p o nse d urati o n 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. See Secti o n 8. 6. 1 f or 
t he defi niti o n of ce ns ori n g.
Dise ase C o ntr ol R ate
( D C R) – b ase d o n R E CI S T 1. 1 ( Sec o n d ar y) a n d ir R E CI S T 
( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
( R E CIS T 1. 1 b y  site 
I n vesti gat or/l ocal ra di ol o g y re vie w as t he c orres p o n di n g s u p p orti ve a nal yses ; ir R E CIS T b y 
site I nvesti gat or /l ocal ra di ol o gy re vie w m a y  als o be e val uate d).
Disease c o ntr ol rate ( D C R) is defi ne d as t he pr o p orti o n of t he s u bjects i n t he a nal ysis 
p o p ulati o n w h o ha ve a C R, partial res p o nse ( P R) a n d sta ble disease ( S D), t he latter f or at 
least 8 c y cles .
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
P F S – b ase d o n ir R E CI S T ( E x pl or at or y) as assesse d b y bli n de d ce ntr al i m a gi n g ve n d or
(ir R E CIS T b y  site I n vesti gat or/l ocal ra di ol o g y re vie w m a y  be perf or me d as s u p p orti ve 
a nal ys is).
S afet y E n d p oi nts
8. 4. 2
Safet y  meas ure me nts are descri be d i n Secti o n 7. 0
S u bject -Re p orte d O utc o mes E n d p oi nts
8. 4. 3
Patie nt- re p orte d o utc o me e n d p oi nts are descri be d i n Secti o n 7. 1. 2. 9.
A n al ysis P o p ul ati o ns
8. 5
Effic ac y A n al ysis P o p ul ati o ns
8. 5. 1
T he I T T p o p ulati o n will 
ser ve as t he p o p ulati o n f or pri mar y  efficac y anal y sis. 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. 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.
Details o n t he a p pr oac h t o ha n dli n g missi n g data are pr o vi de d i n Secti o n 8. 6 .
S afet y A n al ysis P o p ul ati o ns
8. 5. 2
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 treat me nt gr o u p c orres p o n di n g 
t o t he st u d y treat me nt t he y act uall y recei ve d f or t he a 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 dr u g f or o ne c ycle, b ut recei ves t he c orrect treat me nt f or all ot her 
c ycles, will be a n al y ze d acc or di n g t o t he c orrect treat me nt gr o u p a n d a narrati ve will be 
pr o vi de d f or a n y e ve nts t hat occ ur d uri n g t he c ycle f or w hic h t he s u bject is i nc orrectl y d ose d. 
At least o ne la b orat or y or vital si g n meas ure me nt o btai ne d s u bse q ue nt t o at least o ne d ose of 
st u d y treat me nt is re q uire d f or i ncl usi o n i n t he a nal ysis of eac h s pecific para meter.  T o assess 
c ha n ge fr o m baseli ne, a baseli ne meas ure me nt is als o re q uire d.
Details o n t he a p pr oac h t o ha n dli n g missi n g data f or safety a nal yses are pr o vi de d i n Sec ti o n 
8. 6 .
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St atistic al Met h o ds
8. 6
St atistic al Met h o ds f or Effic ac y A n al yses
8. 6. 1
T his secti o n descri bes t he statistical met h o ds 
t hat a d dress t he pri mar y  an d sec o n dar y 
o bjecti ves.  Met h o ds relate d t o e x pl orat or y objecti ves (a n d s u p p orti ve a nal yses i ncl u di n g 
P F S 2 ) will be descri be d i n t he s u p ple me ntal 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 . N o mi nal p-val ues will be c o m p ute d 
f or ot her efficac y anal ys es , b ut s h o ul d be i nter prete d wit h ca uti o n d ue t o p ote ntial iss ues of 
m ulti plicit y .
8. 6. 1. 1
O ver all S ur vi v al 
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. 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 (ie, 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 [ P D-L 1  tu m or stat us ( p ositi ve
[ C P S ≥1] vs ne gati ve [ C P S < 1] ), a n d pri or ( ne o)a dj u va nt t hera py vs de n o v o metastatic 
disease at i nitial di a g n osis] will be a p plie d, as stratificati o n fact ors use d f or a nal ys is, 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.
S u bjects i n t he T P C ar m are e x pecte d t o disc o nti n ue treat me nt earlier c o m pare d t o s u bjects i n 
t he pe m br oliz u ma b ar m a n d are n ot all o we d t o cr oss o ver t o t he pe m br oliz u ma b ar m; 
h o we ver, t he y ma y be treate d wit h a n ot her a nti P D -1 dr u g f oll o wi n g t he verificati o n of 
pr o gressi ve disease b y  bli n de d ce ntral i ma gi n g ve n d or. As a n e x pl orat or y anal ys is, t he Ra n k 
Preser vi n g Str uct ura l Fail ure Ti me ( R P S F T) m o del pr o p ose d b y  Ro bi ns a n d Tsiatis ( 1 9 9 1) 
[9 7 ] ma y  be use d t o a dj ust f or t he effect of cr oss o ver t o ot her P D -1 t hera pies o n O S, 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  th e 
met h o ds.
8. 6. 1. 2
Pr o gressi o n- Free S ur vi v al
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. A stratifie d C o x pr o p orti o nal hazar d m o del wi t 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 (ie, 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 d li n g a n d 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 [ P D-L 1  tu m or stat us ( p ositi ve 
[C P S ≥1 ] vs ne gati ve [ C P S < 1] ), a n d Pri or ( ne o)a dj u va nt t hera p y vs de n ov o metastatic 
disease at i nitial dia g n osis ] will be a p plie d, as stratificati o n fact ors use d f or a nal ys is, 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. 
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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 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  doc u me nte d base d o n R E CI S T 1. 1 as assesse d b y  bli n de d ce ntral i ma gi n g 
ve n d or. Deat h is al wa y s c o nsi dere d as a c o nfir me d P D e ve nt. S u bjects w h o d o n ot e x perie nce 
a P F S e ve nt will be ce ns ore d at t he last disease assess me nt ( wit h e xce pti o ns descri be d 
bel o w). Se nsiti vit y  ana l yses will be perf or me d f or c o m paris o n of P F S base d o n I nvesti 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 base d o n R E CI S T 1. 1 as assesse d b y 
bli n de d ce ntral i ma gi n g ve n d or, we will perf or m o ne pri mar y  an d t w o se nsiti vit y ana l yses 
wit h a differe nt set of ce ns ori n g r ules. F or t he pri mar y  anal ys is, if t he e ve nts ( P D or deat h) 
are i m me diatel y after m ore t ha n o ne misse d disease assess me nt, t he data are ce ns ore d at t he 
last disease assess me nt pri or t o missi n g visits.  Als o data after ne w a nti-ca ncer t hera p y are 
ce ns ore d at t he last disease assess me nt pri or t o t he i nitiati o n of ne w a nti-ca ncer t hera p y. T he 
first se nsiti vit y an al y sis f oll o ws t he c o m plete f oll o w u p i nte nti o n-t o-treat pri nci ple. T hat is, 
P Ds/ deat hs are c o u nte d as e ve nts re gar dless of misse d st u d y visits or i nitiati o n of ne w a nti-
ca ncer t hera py.  The sec o n d se nsiti vit y an al y sis 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 h e 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. If a s u bject meets m ulti ple criteria f or ce ns ori n g, t he ce ns ori n g criteri o n t hat occ urs 
earliest will be a p plie d.   T he ce ns ori n g r ules f or pri mar y  an d se nsiti vit y anal y ses are
s u m marize d i n Ta ble 9 .
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 ma y  als o perf or m t he f oll o wi n g t w o a d diti o nal P F S se nsiti vit y 
a nal ys es: 1) a P F S a nal ysis usi n g ti me t o sc he d ule d t u m or assess me nt visit fr o m 
ra n d o mizati o n as o p p ose d t o act ual t u m or assess me nt ti me; 2) Fi n kelstei n ( 1 9 8 6)’s 
li keli h o o d-base d sc ore test [ 9 8] f or i nter val-ce ns ore d data, w hic h 
m o difies 
t he C o x 
pr o p orti o nal hazar d m o del f or i nter val ce ns ore d data, will be use d as a s u p p orti ve a nal ys is 
f or t he P F S e n d p oi nt. T he i nter val will be c o nstr ucte d s o t hat t he left e n d p oi nt is t he date of 
t he last disease assess me nt wit h o ut d oc u me nte d P D a n d t he ri g ht e n d p oi nt is t he date of 
d oc u me nte d P D or deat h, w hic he ver occ urs e arlier.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 9
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of Pr o gressi o n-free S ur vi val
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 
Pr o gresse d at treat me nt 
disc o nti n uati o n d ue t o 
reas o ns ot her t ha n c o m plete 
res p o nse; ot her wise 
ce ns ore d at last disease 
assess me nt if still o n st u d y 
treat me nt or c o m plete d 
st u d y treat me nt.
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 
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 , a n d bef ore 
ne w a nti -ca ncer 
t hera p y, if a n y
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 
i m me diatel y after ≥ 2 
misse d disease 
assess me nts or after 
ne w a nti -ca ncer 
t hera p y, if a n y
Ce ns ore d at last disease 
assess me nt pri or t o t he 
earlier date of  ≥ 2 
c o nsec uti ve misse d 
disease assess me nt a n d 
ne w a nti -ca ncer t hera p y, if 
a n y
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
T he pr o p orti o nal hazar ds ass u m pti o n o n P F S will be e x a mi ne d usi n g b ot h gra p hical a n d 
a nal yt ical met h o ds if warra nte d. T he l o g[-l o g] of t he s ur vi val f u ncti o n v ers us ti me f or P F S 
will be pl otte d f or t he c om paris o n bet wee n p e m br oliz u mab a n d t he T P C ar m. If t he c ur ves 
are n ot parallel, i n dicati n g t hat hazar ds are n ot pr o p orti o nal, s u p p orti ve a nal ys es ma y
b e 
c o n d ucte d 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 ass ociate d wit h 
i m m u n ot hera pies; f or e xa m ple, usi n g Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d
[ 9 9]
a n d para metric met h o d [ 1 0 0] .
O ne ass u m pti o n f or stratifie d C o x pr o p orti o nal hazar d m o del is t hat, t he treat me nt hazar d 
rati o ( H R) is c o nsta nt acr oss t he strata. If str o n g de part ures fr o m t he ass u m pti o n of t he H R 
bei n g t he sa me f or all t he strata o bser ve d ( w hic h ca n res ult i n a n ota bl y biase d a n d/ or less 
p o werf ul a nal ysis), a se nsiti vit y anal ys is m a y  be perf or me d base d o n a t w o-ste p wei g hte d 
C o x m o del a p pr oac h b y  Me hr otra 2 0 1 2 [ 1 0 1 ], i n w hi c h t he treat me nt effect is first esti mate d 
f or eac h strat u m a n d t he n t he strat u m s pecific esti mates are c o m bi ne d f or o verall i nfere nce 
usi n g sa m ple size wei g hts.
F urt her details of se nsiti vit y  a nalys es will be descri be d i n a s u p ple me ntal S A P.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ot her se nsiti vit y anal ys es descri be d f or t he P F S e n d p oi nt will be a p plie d t o O S e n d p oi nt as 
a p pr o priate. F urt her details of se nsiti vit y  a nalys es will be descri be d i n s u p ple me ntal S A P.
8. 6. 1. 3
O ver all Res p o nse R ate a n d Dise ase C o ntr ol R ate
T he stratifie d Mietti ne n a n d N u r mi ne n’s met h o d wit h strata wei g hti n g b y  sa m ple size will be 
use d f or c o m paris o n of t he o verall res p o nse rate ( O R R) a n d disease c o ntr ol rate ( D C R) 
bet wee n t he treat me nt gr o u ps . A 9 5 % c o nfi de nce i nter val f or t he differe nce i n res p o nse rates 
bet wee n t he p e m br oliz u ma b a n d T P C ar m will be pr o vi de d. T he stratificati o n fact ors use d 
f or ra n d o mizati o n will be a p plie d , as stratificati o n fact ors use d f or a nal ys is.
8. 6. 1. 4
D ur ati o n of Res p o nse
If sa m ple size per mits, res p o nse d urati o n will be s u m marize d descri pti vel y  usi n g K a pla n-
Meier me dia ns a n d q uartiles.  Onl y  the s u bset of s u bjects w h o s h o w a c o m plete res p o nse or 
p artial res p o nse will be i ncl u de d i n t his a nal ys is.  See Ta ble 1 0 f or ce ns ori n g r ules f or 
d urati o n of res p o nse.
Ta ble 1 0
Ce ns ori n g R ules f or D urati o n of Res p o nse
Sit u ati o n
D ate of Pr o gressi o n or Ce ns ori n g
O utc o m e
N o pr o gressi o n n or deat h, n o ne w 
a nti -ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt
Ce ns or
( n o n-e ve nt)
N o 
pr o gressi o n n or deat h, ne w 
a nti -ca ncer t hera p y i nitiate d
Last a de q uate disease assess me nt 
bef ore 
ne w  anti -ca ncer t hera p y 
i nitiate d
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n i m me diatel y 
after 
≥ 
2 
c o nsec uti ve 
misse d 
disease assess me nts or after ne w 
a nti -ca ncer t hera p y, if a n y
Earlier date of last a de q uate disease 
assess me nt pri or t o ≥ 2 misse d 
a de q uate disease assess me nts a n d 
ne w a nti -ca ncer t hera p y, if a n y
Ce ns or
( n o n-e ve nt)
Deat h 
or pr o gressi o n after ≤ 1 
misse d 
disease assess me nts a n d 
bef ore ne w a nti -ca ncer t hera p y, if 
a n y
P D or deat h
E n d of res p o nse
( E ve nt)
A misse d disease assess me nt i ncl u des a n y assess me nt t hat is n ot o btai ne d or is c o nsi dere d i na de q uate f or 
e val uati o n of res p o nse.  
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8. 6. 1. 5
S u m m ar y of St atistic al Met h o ds f or E ffic ac y
Ta ble 1 1 s u m marizes t he pri mar y  anal ys is a p pr oac h f or pri mar y a n d 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.
T he strate g y to a d dress m ulti plicit y  iss ues wit h re gar d t o m ulti ple efficac y en d p oi nts,
m ulti ple p o p ulati o n s, a n d i nteri m a nal yses is descri be d i n Secti on 8. 7 a n d i n Secti o n 8. 8.
Ta ble 1 1
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
Pri m ar y E n d p oi nts / H y p ot hesis
Pri m ar y H y p ot hesis # 1
O S i n s u bjects wit h C P S ≥1 0
Test: Stratifie d L o g -ra n k 
test 
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 
I T T
Ce ns ore d at last k n o w n ali ve 
date ( M ore details are i n
Ta ble 9 )
Pri m ar y H y p ot hesis # 2
O S i n s u bjects wit h C P S ≥1
Test: Stratifie d L o g -ra n k 
test 
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 
I T T 
Ce ns ore d at last k n o w n ali ve 
date ( M ore details are i n 
Ta ble 9 )
Pri m ar y H y p ot hesis # 3
O S i n all s u bjects
Test: Stratifie d L o g -ra n k 
test 
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
I T T 
Ce ns ore d at last k n o w n ali ve 
date
Sec o n d ar y E n d p oi nts / H y p ot hesis
Sec o n dar y H y p ot hesis # 4
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Test: Stratifie d L o g -ra n k 
test 
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
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
( M ore details are i n T a ble 9 )
Sec o n dar y H y p ot hesis # 5
O R R base d o n  R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n all s u bjects
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h 
missi n g 
data 
are 
c o nsi dere d 
n o n-
res p o n ders
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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
Sec o n dar y Efficac y O bjecti ves
P F S base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 a n d 
s u bjects wit h C P S ≥1
Test: Stratifie d L o g -ra n k 
test 
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
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
( M ore details are i n T a ble 9 )
O R R base d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 a n d
s u bjects wit h C P S ≥1
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
D C R b ase d o n R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0 , 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
Stratifie d M & N 
met h o d ‡
I T T 
S u bjects wit h missi n g data 
are c o nsi dere d n o n-
res p o n ders
D O R b ase d o n  R E CI S T 1. 1 b y 
bli n de d ce ntral i ma gi n g ve n d or 
i n s u bjects wit h C P S ≥1 0, 
s u bjects wit h C P S ≥1 a n d all 
s u bjects
S u m mar y statistics usi n g 
Ka pla n -Meier met h o d
All 
res p o n ders 
i n I T T 
See Ta ble 1 0
  † 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 will 
be as stratificati o n fact ors f or a nal ysis.
  ‡  Mietti ne n a n d N ur mi ne n met h o d.
Met h o ds relate d t o e x pl orat or y objecti ves (a n d s u p p orti ve a nal ys es i ncl u di n g P F S 2) will be 
descri be d i n t he s u p ple me ntal S A P .
St atistic al Met h o ds f or S afet y A n al yses
8. 6. 2
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 d verse e x perie nces ( A Es), la b orat or y tests, vital si g ns, etc. Of n ote, safet y a nal ys es will be 
c o n d ucte d i n all s u bjects.
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 2 ).  The tiers differ wit h 
res pect t o t he a nal ys es t hat will be perf or me d.  Safet y para meters or a d verse e x perie nces of 
s pecial i nterest t hat are i de ntifie d a pri ori c o nstit ute “ 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.  
Ot her safety par a 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 i nter vals pr 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 b y 
treat me nt gr o u p are pr o vi de d f or Tier 3 safet y para meters.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A d verse e x perie nces (s pecific ter ms as well as s yste m or ga n class ter ms) a n d pre defi ne d 
li mits of c ha n ge i n la b orat or y, vital si g ns, t hat are n ot pre -s pecifie d as Tier - 1 e n d p oi nts will 
be classifie 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 o f e ve nts 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 a n d/ or, vital si g ns, t hat are 
n ot pre -s pecifie d as Tier - 1 e n d p oi nts will be c o nsi dere d Tier 3 safet y p ara meters.  Su 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.    
F or t his pr ot oc ol t here are n o Tier 1 e ve nts. Base d o n t he mec ha nis m 
of acti o n of 
pe m br oliz u ma b a n d safet y data o bser ve d i n hist oric pe m br oliz u ma b trials t o date, t here are 
n o e ve nts of i nterest t hat warra nt classificati o n as Tier I e ve nts. T he br oa d cli nical a n d 
la b orat or y AE cate g ories c o nsisti n g of t he perce nta ge of s u bjects wit h a n y AE, 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 AE w hic h is b ot h dr u g -relate d a n d Gra de 
3- 5, a n y AE w hic h is b ot h seri o us a n d dr u g -relate d, d ose m o dificati o n d ue t o A E , a n d w h o 
disc o nti n ue d 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.  P-val ues ( Tier 1 
o nl y ) a n d 9 5 % c o nfi de nce i nter vals ( Tier 1 a n d 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 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.
T o pr o perl y acc o u nt f or t he p ote ntial differe nce i n f oll o w-u p ti me bet wee n t he st u d y ar ms, 
w hic h is e x pecte d t o be l o n ger i n t he pe m br oliz u ma b ar m, A E i nci de nce de nsit y  adj uste d f or 
treat me nt e x p os ure a nal yses ma y  be perf or me d as a p pr o priate.  Base d o n e mer gi n g e xter nal 
data, t he s u p p orti ve a nal ysis strate g y for safety para meters m a y  be m o difie d t o i m pr o ve t he 
i nte grity a n d efficie nc y of t he desi g n. S h o ul d t his ha p pe n, t he c ha n ge will be d oc u me nte d i n 
s u p ple me ntal S A P, if n ot i n a pr ot oc ol a m e n d me nt, at t he earliest ti me bef ore a n y u n bli n di n g 
of t he data.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 1 2
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 †
p-
V al ue
9 5 % CI f or 
Tre at m e 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
X
X
S pecific A E s, S yste m Or ga n Class, or Pr e-Defi ne d 
Li mit of C ha n ge ‡ (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 yste m Or ga n Class or Pr e-Defi ne d 
Li mit of C ha n ge ‡
‡ (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
†
A d verse E x perie nce refere nces refer t o b ot h Cli nical a n d La b orat or y A Es.
‡
I ncl u des o nl y t h ose e n d p oi nts n ot pre-s pecifie d as Tier 1 or n ot alrea d y pre-s pecifie d as Tier-2 e n d p oi nts.
N ote: X = res ults will be pr o vi de d.
Ti me t o Gr a de 3 -5 A E
I n a d diti o n t o tiere d a p pr oac h, e x pl orat or y an al y sis will be perf or me d o n ti me t o first 
Gra de 3- 5 A E. Ti me t o first Gra de 3- 5 A E is defi ne d as t he ti me fr o m t he first da y  of st u d y 
me dicati o n
t o t he first e ve nt of Gra de 3- 5 A E. T he Ka pla n -Meier met h o d will be use d t o 
esti mate t he c ur ve of ti me t o first Gra de 3- 5 A E.  The treat me nt differe nce i n ti me t o first 
Gra de 3- 5 A E will be assesse d b y  the stratifie d l o g-ra n k test.  A stratifie d C o x pr o p or ti 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).  The 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. See details 
i n s S A P.
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
S u m m aries of De m o gr a p hic a n d B aseli ne C h ar acteristics
8. 6. 3
T he c o m para bilit y  of t he treat me nt gr o u ps f or eac h rele va nt c haracteristic will be assesse d b y 
t he use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n t hese 
c haracteristics.  The n u m ber a n d perce nta ge of s u bjects scree ne d , ra n d o mize d, t he pri mar y 
reas o ns f or scree ni n g fail ure, a n d t he pri mar y  reas o n f or disc o nti n uati o n will be dis pla y e d.  
De m o gra p hic varia bles (e g, a ge), baseli ne c ha racteristics, pri mar y  an d sec o n dar y dia g n oses, 
a n d pri or a n d c o nc o mita nt t hera pies will be s u m marize d b y  treat me nt eit her b y  descri pti ve 
statistics or cate g orical ta bles.
I nteri m A n al yses
8. 7
T here is o ne pla n ne d i nteri m efficac y a nal ys is i n t his trial. Res ults will be re vie we d b y  an 
e xter nal data m o nit ori n g c o m mittee (e D M C). Of n ote, t he b o u n daries f or i nteri m a n d fi nal 
a nal ys es are prese nte d i n S ecti o n 8. 8.
I nteri m A n al ysis
T he p ur p ose of t he i nteri m a nal ysis (IA)
is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d t o T P C i n O S . T he I A is tri g gere d b y  the s pecifie d d urati o n of f oll o w-u p after 
e nr oll me nt is c o m plete d rat her t ha n t he n u m ber of O S e ve nts.   It will be perf or me d
ap pr o xi matel y  1 4
m o nt hs 
after e nr oll me nt is c o m plete d . It is esti mate d at t his ti me 
a p pr o xi matel y 1 3 0 O S e ve nts will be accr ue d i n s u bjects wit h C P S ≥1 0 , a p pr o xi matel y
2 8 4 O S e ve nts i n s u bjects wit h C P S ≥1 , a n d a p pr o xi matel y 4 4 5 O S e ve nts i n all s u bjects.
If t he pe m br oliz u ma b ar m de m o nstrates a s u peri or O S t o T P C i n all s u bjects i n t his i nteri m 
a nal ys is, t he sec o n dar y h yp ot heses f or P F S a n d O R R i n all s u bjects will be teste d at t he sa me 
ti me.  It is esti mate d t hat a p pr o xi matel y 57 5 P F S e ve nts will ha ve acc u m ulate d i n all s u bjects
b y  t hat ti me.
Fi n al A n al ysis
T he p ur p ose o f t he fi nal a nal ys is ( F A) is t o e val uate t he s u peri ority of pe m br oliz u ma b 
c o m pare d t o T P C i n O S.  The fi nal a nal ysis is tri g gere d b y  d urati o n of f oll o w-u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1 : ap pr o xi matel y  24 m o nt hs after e nr oll me nt is c o m plete d or 
3 3 4 O S e ve nts accr ue i n s u bjects wit h C P S ≥1 , w hic he ver occ urs later. It is esti mate d at t his 
ti me a p pr o xi matel y 15 4
O S 
e ve nts will 
be accr ue d i n s u bjects wit h 
C P S ≥1 0 a n d 
a p pr o xi matel y 5 2 0 O S e ve nts i n all s u bjects. If O S e ve nts i n s u bjects wit h C P S ≥1 accr ue 
sl o wer t ha n e x pecte d a n d fe wer t ha n 3 3 4 e ve nts are o bser ve d 2 6 m o nt hs after e nr oll me nt is 
c o m p lete d, t he n t he S p o ns or will c o n d uct t he fi nal a nalys is at t hat ti me.
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
M ulti plicit y
8. 8
T he m ulti plicit y  strate g y specifie d i n t his secti o n will be a p plie d t o t he 3 pri mar y h y p ot heses 
(su peri orit y of pe m br oliz u ma b o n O S i n s u bjects wit h C P S ≥1 0 , wit h C P S ≥1, a n d i n all 
s u bjects) a n d t he 2 sec o n dar y h yp ot heses (s u peri orit y  of pe m br oliz u ma b o n P F S a n d O R R i n 
all s u bjects ).
F or O S
e n d p oi nts , a H wa n g -S hi h -De Ca ni 
al p ha-s pe n di n g f u ncti o n wit h 
t he ga m ma 
para meter (- 4 ) will be use d t o c o nstr uct gr o u p se q ue ntial b o u n daries t o c o ntr ol t he T y p e I 
err or. S pe n di n g ti me will be pl u g ge d i nt o t he pre -s pecifie d al p ha s pe n di n g f u ncti o n t o 
calc ulate al p ha -s pe n di n g. At t he ti me of I A, f or all 3 O S e n d p oi nts t he s pe n di n g ti me will be 
t he mi ni m u m of t he act ual o bser ve d i nf or mati o n fracti o ns a m o n g t hese 3 O S e n d p oi nts , i.e.,
n u m ber of o bser ve d e ve nts at I A/n u m ber of pla n ne d e ve nts at F A. At t he ti me of F A, t he 
s pe n di n g ti me will be 1 f or all 3 O S e n d p oi nts. Of n ote, w hile t he s pe n di n g ti me use d f or 
al p ha-s pe n di n g calc ulati o n will be t he sa me f or t hese 3 O S e n d p oi nts at F A, t he c orrelati o ns 
use d f or c o m p uti n g b o u n ds f or eac h e n d p oi nt will still be fr o m t hat e n d p oi nt de pe n di n g o n 
t he act ual e ve nt c o u nts. T he rati o nale f or t he a b o ve strate g y is t o e ns ure b ot h t hat f ull T y pe I 
err or is s pe nt at t he fi nal a nal ysis wit h o ut o vers pe n di n g at t he i nteri m. J ustificati o n f or t he 
s pe n di n g ti me a p pr oac h ca n be f o u n d i n A n d ers o n et.al. [ 1 0 5 ].
Ta ble 1 3 s u m mariz es t he ti mi n g, pla n ne d n u m ber of e ve nts, sa m ple size a n d decisi o n 
g ui da nce of t he i nteri m efficac y an al y sis a n d fi nal a nal ys is. T hese b o u n daries are calc ulate d
base d o n t he al p ha -s pe n di n g f u ncti o n a n d t he pla n ne d n u m ber of e ve nts . 
T he act ual 
b o u n daries will be deter mi ne d fr o m t he act ual o bser ve d n u m ber of e ve nts, t he pla n ne d 
n u m be r of e ve nts at F A,
t he ti mi n g of t he a nal yses, t he pre -s pecifie d al p ha-s pe n di n g 
f u ncti o n, a n d t he r ules t o deter mi ne s pe n di n g ti me a n d c orrelati o ns as n ote d a b o ve . If t he 
b o u n dar y  is cr osse d at a n i nteri m a nal ysis or at t he fi nal a nal ys is, t he st u d y will be declare d 
t o ha ve met its pri mar y e n d p oi nt. 
Of n ote, t hese calc u lati o ns are base d o n t he ass u m pti o ns t hat t he pre vale nce of P D -L 1  
p o siti vit y i n m T N B C is a p pr o xi matel y 6 5%
f or C P S ≥1 a n d a p pr o xi matel y 3 1 % f or C P S ≥1 0
a n d are s u bject t o m o dificati o n if e mer gi n g data s u g gest t he pre vale nce is differe nt fr o m 
t hese ass u m pti o ns . T hese m o dificati o ns , if ma de, will be d oc u me nte d i n t he s S A P pri or t o 
a n y efficac y a nalys is u n bli n di n g.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
Ta ble 1 3
S u m mar y  of Ti mi n g, Sa m ple Size, a n d Decisi o n G ui da nce of I nteri m Efficac y 
A nal y ses a n d Fi nal A nal y sis u n der I nitial Al p ha All ocati o n
A n al ysis
Criteri a f or C o n d uct of A n al ysis
E n d p o i nt
P ar a meter
V al ue
I nteri m A nal ysis: 
I nteri m O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p: 
A p pr o xi matel y 1 4 m o nt hs after e nr oll me nt is 
c o m plete d .
Pr ojecte d O S e ve nts i n s u bjects wit h C P S
≥1 0 : a p pr o xi matel y 1 3 0
O S i n s u bjects wit h 
C P S ≥1 0
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 8 9
~ H R at b o u n dar y
0. 6 6
Pr ojecte d O S eve nts i n s u bjects wit h C P S ≥1 : 
a p pr o xi matel y 2 8 4
O S i n s u bjects wit h 
C P S ≥1
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 4 3
~ H R at b o u n dar y
0. 7 3
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 4 4 5
O S i n all s u bjects
p val ue ( 1 -si de d) at 
b o u n dar y
n/a
~ H R at b o u n dar y
n/a
Fi nal A nal ysis: 
Fi nal O S 
A nal ysis
Tri g gere d b y d urati o n of f oll o w -u p a n d O S 
e ve nts i n s u bjects wit h C P S ≥1 : 
A p pr o xi matel y 2 4 m o nt hs after e nr oll me nt is 
c o m plete d or 3 3 4 O S e ve nts accr ue i n s u bjects
wit h C P S ≥1 , w hic he ver occ urs later. If O S 
e ve nts i n s u bjects wit h C P S ≥1 accr ue sl o wer 
t ha n e x pecte d a n d fe wer t ha n 3 3 4 e ve nts are 
o bser ve d 2 6 m o nt hs after e nr oll me nt is 
c o m p lete d, t he n t he S p o ns or will c o n d uc t t he 
fi nal a nal ysis at t hat ti me.
Pr ojecte d O S e ve nts i n s u bjects wit h 
C P S ≥1 0 : a p pr o xi matel y 1 5 4
O S i n s u bjects wit h 
C P S ≥1 0
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 1 4 6
~ H R at b o u n dar y
0. 7 0
Pr ojecte d O S e ve nts i n s u bjects wit h C P S ≥1 : 
a p pr o xi matel y 3 3 4
O S i n s u bjects wit h 
C P S ≥1
p val ue ( 1 -si de d) at 
b o u n dar y
0. 0 0 6 6
~ H R at b o u n dar y
0. 7 6
Pr ojecte d O S eve nts i n all s u bjects: 
a p pr o xi matel y 5 2 0
O S i n all s u bjects
p val ue ( 1 -si de d) at 
b o u n dar y
n/a
~ H R at b o u n dar y
n/a
T he trial uses a n e xte nsi o n [ 1 0 5] of t he gra p hical met h o d of Ma urer a n d Bretz [ 9 6] t o pr o vi de 
str o n g m ulti plicit y c o ntr ol f or t he m ulti ple pri mar y a n d sec o n dar y h y p ot heses.
Fi g ure 4
s h o ws t he i nitial o ne- si de d α- all ocati o n f or eac h h y p 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 h y p ot heses.  If H 1 (O S i n s u bjects wit h 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
C P S ≥1 0 ) is s uccessf ul, t he n t he c orres p o n di n g al p ha ca n be reall ocate d t o H 2 ( O S i n 
s u bjects wit h C P S ≥1 ). If H 2 is s uccessf ul, t he al p ha f or t hat h yp ot hesis ca n be reall ocate d t o 
H 3 ( O S i n all s u bjects). If H3 is s uccessf ul, t he al p ha f or t hat h yp ot hesis ca n be reall ocate d ½ 
t o H 4 ( P F S i n all s u bjects) a n d ½ t o H 5 ( O R R i n all s u bjects). T he al p ha f or H 4 a n d H 5 ca n 
als o be reall ocate d t o eac h ot he r, if t he h y p ot hesis was s uccessf ul. Of n ote, H 3 ca n o nl y be 
f or mall y teste d o nce t he n ull h y p ot hesis f or H 2 has bee n rejecte d; H 4 a n d H 5
ca n o nl y  be 
f or mall y teste d o nce t he n ull h y p ot hesis f or H 3
has bee n rejecte d. See Fi g ure 4 f or t he 
m ulti plicit y  strate g y dia gra m of t he st u dy.
H 4 ( P F S i n all s u bjects) will be teste d at I A if H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A 
a d diti o nal al p ha ca n be reall ocate d t o H 4 (e. g., H 3 is n ot s uccessf ul at I A but s uccessf ul at 
F A , or H 1 is n ot s uccessf ul at I A but s uccessf ul at F A a n d H 2/ H 3 are s uccessf ul at b ot h I A 
a n d F A ), t he n t he p-val ue of P F S i n all s u bjects fr o m t he I A will be c o m pare d t o t he u p date d 
al p ha t hres h ol d at t he ti me of F A. Si milarl y , H5 ( O R R i n all s u bjects) will be teste d at I A if 
H 3 ( O S i n all s u bjects) is s uccessf ul. If at F A a d diti o nal al p ha ca n be reall ocate d t o H 5, t he n 
t he p- val ue of O R R i n all s u bjects fr o m t he I A will be c o m pare d t o t he u p date d al p ha 
t hres h ol d at t he ti me of F A.
Fi g ure 4
M ulti plicit y  Strate g y
S a m ple Size a n d P o wer C alc ul ati o ns
8. 9
T he st u d y will ra n d o mize s u bjects i n a 1: 1 rati o bet wee n t he pe m br oliz u ma b ar m a n d t he 
T P C ar m. T he o verall sa m ple size will be u p t o ~ 6 0 0 .
Ra n d o mizati o n will occ ur ce ntrall y usi n g a n i nteracti ve res p o nse s yste m / i nte grate d we b 
res p o nse s yste m (I V R S/I W R S) a n d will be m o nit ore d o n a re g ular basis. W he n I V R S al erts 
t hat t he st u d y is a p pr oac hi n g t he desire d e nr oll me nt, scree ni n g s h o ul d be st o p pe d i n ti me. 
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
H o we ver, s u bjects alrea d y in scree ni n g p hase ma y  be e nr olle d e ve n after we ha ve reac he d 
t he ma xi m u m sa m ple size. T he sa m ple size is dri ve n b y  the O S e ve nts i n s u bjects wit h 
C P S ≥1 0 , s u bjects wit h C P S ≥1 , a n d all s u bjects.
O ver all s ur vi v al a n al ysis i n s u bjects wit h C P S ≥1 0 : F or t he pri mar y  en d p oi nt O S i n 
su bjects wit h C P S ≥1 0 , wit h 1 5 4 O S e ve nts at a o ne -si de d 1. 7 % al p ha-le vel t he trial has 
a p pr o xi matel y 8 5 % p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C , if t he 
u n derl y i n g hazar d rati o of O S is 0. 6 0. S uccess b o u n dar y  f or O S at t he fi nal a nal ysis 
a p pr o xi matel y corres p o n ds t o a n o bser ve d hazar d rati o of ~ 0. 7 0 ( ~ 4. 2 m o nt h i m pr o ve me nt 
o ver O S of 1 0 m o nt hs i n T P C ).
O ver all s ur vi v al a n al ysis i n s u bjects wit h C P S ≥1 : F or t he pri mar y  e n d p oi nt O S i n s u bjects 
wit h C P S ≥1 , wit h 3 3 4 O S e ve nts at a o ne- si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has 
a p pr o xi matel y 80 % ( 9 0 %) p o wer t o de m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C , if 
t he u n derlyi n g hazar d rati o of O S is 0. 7 0. Wit h
a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel, s uccess 
b o u n dar y  f or O S at t he fi nal a nal ysis a p pr o xi matel y corres p o n ds t o a n o bser ve d hazar d rati o 
of ~ 0. 7 6 ( 0. 8 0) ( ~ 3. 1 [ 2. 5] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C ).
O ver all s ur vi v al a n al ysis i n all s u bjects: F or t he pri mar y  en d p oi nt O S i n all s u bjects, wit h 
5 2 0 O S e ve nts a n d a o ne -si de d 0. 8 % ( 2. 5 %) al p ha-le vel t he trial has a p pr o xi matel y 6 6 % 
( 8 0 %) p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C if t he u n derl y i n g hazar d 
rati o of O S is 0. 7 8.
Wit h a o ne-si de d 0. 8 % ( 2. 5 %) al p ha-le vel, s uccess b o u n dar y  f or O S at 
t he fi nal a nal ys is c orres p o n ds a p pr o xi matel y t o a n o bser ve d hazar d rati o of ~ 0. 8 0 ( 0. 8 4)
( ~ 2.4 [ 1. 9] m o nt h i m pr o ve me nt o ver O S of 1 0 m o nt hs i n T P C )
T he sa m ple size a n d p o wer calc ulati o n f or O S e n d p oi nts is base d o n t he f oll o wi n g 
ass u m pti o ns f or all 3 p o p ulati o ns : 1) O S f oll o ws a n e x p o ne ntial distri b uti o n wit h a me dia n of 
1 0 m o nt hs i n t he c o ntr ol ar m; 2) A n e nr oll me nt peri o d of 1 6. 6 m o nt hs a n d a mi ni m u m of 2 4
m o nt hs f oll o w-u p after e nr oll me nt c o m pleti o n; 3) A ye arl y O S dr o p o ut rate of 1 %.   T he 
ass u m pti o n f or O S of 1 0 m o nt hs i n t he T P C ar m is base d o n esti mates of O S fr o m t he trials 
s u m marize d i n Ta ble 1 .
P F S a n al ysis i n all s u bjects: T h is P F S
p o wer is calc ulate d base d o n t he f oll o wi n g 
ass u m pti o ns wit h a p pr o xi matel y 5 7 5 P F S e ve nts:  1) t he h y p ot hesis of O S i n all s u bject is 
s u p p orte d a n d a t otal of 0. 4 % al p ha is all ocate d t o P F S h y p ot hesis ( H 4); 2) P F S f oll o ws a n 
e x p o ne ntial distri b uti o n wit h a me dia n of 3 m o nt hs i n t he T P C ar m; 3) A n e nr oll me nt peri o d 
of 1 6. 6 m o nt hs ; 4 ) A ye arl y P F S dr o p -o ut rate of 8 %.  T he trial has ~ 9 9 % p o wer t o 
d e m o nstrate t hat pe m br oliz u ma b is s u peri or t o T P C o n P F S at a o ne-si de d 0. 4 % al p ha-le vel, 
if t he u n derl yi n g hazar d rati o of P F S is 0. 6 . If t he u n derl yi n g hazar d rati o of P F S is 0. 7, t he n 
t he trial has ~ 9 5 % p o wer.
T he ass u m pti o n f or P F S of 3 m o nt hs i n t he T P C ar m is base d o n esti mate s of P F S fr o m t he 
trials s u m marize d i n Ta ble 1 .
O R R a n al ysis i n all s u bjects: T he O R R p o wer calc ulati o n is base d o n t he f oll o wi n g 
ass u m pti o ns: 1) t he h y p ot hesis of O S i n s u bjects wit h C P S ≥1 is s u p p orte d a n d a t otal of 
0. 4 % al p ha is all ocate d t o O R R h y p ot hesi s (H 5) ; 2) t he u n derl y i n g O R R is 1 0 % i n t he T P C
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
ar m, a n d t here is 1 0 % i ncrease i n pe m br oliz u ma b ar m ( O R R of 2 0 % ) i n all s u bjects. T he trial
has a p pr o xi matel y 8 1 % p o wer t o d e m o nstrate t hat p e m br oliz u ma b is s u peri or t o T P C o n 
O R R i n all s u bjects at a o ne -si de d 0. 4 % al p ha -le vel.
T he a b o ve statistical ass u m pti o n s are base d o n o ur c urre nt u n dersta n di n g of t he pre vale nce of 
t he P D -L 1  bi o mar ker i n T N B C (a p pr o xi matel y 65 % f or C P S ≥1 0 a n d 3 1 % f or C P S ≥1) , a n d 
it is s u bject t o m o dificati o n as nee de d base d o n e mer gi n g e xter nal data o n P D -L 1  pre vale nce 
i n T N B C , or t he c orrelati o n bet wee n P D -L 1  ex pressi o n a n d treat me nt effect. 
A n y 
m o dificati o n if occ urs will be descri be d i n t he s u p ple me ntal S A P.
T he sa m ple size a n d p o wer calc ulati o n s were perf or me d i n t he s oft ware R ( pac ka ge 
“ gs Desi g n”).
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
8. 1 0
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 
esti mate of t he bet wee n -gr o u p treat me nt effect ( wit h a n o mi nal 9 5 % CI ) f or t he pri mar y 
e n d p oi nt 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 classificati o n 
varia bles i n s u bjects wit h C P S ≥1 0 a n d C P S ≥1 a n d i n all s u bjects: 

A ge Cate g or y ( <6 5 vs. ≥6 5 y ears)

Me n o pa usal stat us
(f or fe males o nl y; pre- vs . p ost - me n o pa usal)

Se x ( Fe male vs . Male)

Ge o gra p hic re gi o n (E ur o pe/I srael/ N ort h A merica/ A ustralia vs . Asia vs . Rest of 
W orl d) 

Et h nic ori gi n ( His pa nic vs . N o n-His pa nic)

N u m ber of pri or li nes of treat me nts i n t he metastatic setti n g (ie o ne vs . t w o) 

Ti me t o pr o gressi o n o n first-li ne ( 1 L) t hera p y ( < 6 m o nt hs vs. ≥6 m o nt hs )

T P C

P D -L 1  stat us b y  CP S c ut off ( C P S ≥1 vs C P S
< 1; C P S
≥1 0 vs C P S
< 1 0) . N ote 
s u b gr o u p a nalys is b y P D-L 1  stat us will o nly be c o n d ucte d i n all s u bjects.

Pri or ( ne o)a dj u va nt t hera p y  vs. de n o v o metastatic disease at i nitial dia g n osis .
C o m pli a nce ( Me dic ati o n A d here nce)
8. 1 1
Dr u g acc o u nta bilit y data f or trial treat me nt will be c ollecte d d uri n g t he st u d y. A n y de viati o n 
fr o m pr ot oc ol-directe d a d mi nistrati o n will be re p orte d. 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E xte nt of E x p os ure
8. 1 2
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n c ycles .
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
9. 1
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 to 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 n vesti 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.
C li nical S u p plies will be pr o vi de d by t he S p o ns or as s u m marize d i n Ta ble 1 4 .
Ta ble 1 4
Pr o d uct Descri pti o n s
Pr o d uct N a m e & P ote nc y
D os a ge F or m
C o m me nts
Ca pecita bi ne 1 5 0 m g & 5 0 0 m g
Ta blets
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
Eri b uli n 0. 8 8 m g/ 2 m L
S ol uti o n f or I nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
G e m cita bi ne 1 0 0 0 m g
L y o p hilize d p o w der 
f or I V i nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y 
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
Vi n orel bi ne 5 0 m g/ 5 m L
S ol uti o n f or I nf usi o n
Pr o vi de d ce ntrall y b y  the S p o ns or or 
l ocall y b y t he trial site, s u bsi diar y, 
or desi g nee de pe n di n g o n c o u ntr y
P ac k a gi n g a n d L a beli n g I nf or m ati o n
9. 2
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.
Cli nic al S u p plies Discl os ure
9. 3
T his trial is o pe n -la bel; t heref ore, t he s u bject, t he trial site pers o n nel, t he S p o ns or a n d/ or 
desi g nee are n ot bli n de d. Treat me nt ( na me, stre n gt h or p ote nc y ) is i ncl u de d i n t he la bel te xt; 
ra n d o m c o de/discl os ure e n vel o pes or lists are n ot pr o vi de d.
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
St or a ge a n d H a n dli n g Re q uire me nts
9. 4
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
9. 5
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 plies 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 ntati 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
9. 6
Trial site pers o n nel will 
ha ve access t o a ce ntral electr o nic 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 PIN.  T he y  m ust 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 
m ust n ot s hare t heir assi g ne d PI N wit h a n y o ne .
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
1 0. 1
C o nfi de nti alit y of D at a
1 0. 1. 1
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 oar 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  this 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 o f S u bject Rec or ds
1 0. 1. 2
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.  B y  si gni n g t he c o nse nt f or m, t he s u bject 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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
1 0. 1. 3
B y  si gni n g t his pr ot oc ol, t he i n 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 g e 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 by 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 untries, 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 co nse nts t o t hese uses a n d 
discl os ures.
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 matio n wit h 
ot her partici pati n g 
i n vesti gat ors u p o n re q uest.
C o nfi de nti alit y of I R B/I E C I nf or m ati o n
1 0. 1. 4
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 me m ber t hat 
re vie ws a n d a p pr o ves t his trial.  T he S p o ns or is als o re q uire d t o d oc u me nt t ha t eac h I RB/I E C 
meets re g ulat or y an d I CH 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.
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
C o m pli a nc e wit h Fi n a nci al Discl os ure Re q uire me nts
1 0. 2
Fi na ncial Discl os ure re q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi na ncial Discl os ure b y  Cli nical I n vesti gat ors ( 2 1 C F R Part 5 4).  It is t he 
S p o ns or's res p o nsi bilit y t o deter mi ne, b ase d o n t hese re g ulati o ns, w het her a re q uest f or 
Fi na ncial Discl os ure 
i nf or mati o n is re q uire d.  It is t he i n vesti gat or's/s u bi n vesti gat or's 
res p o nsi bilit y t o c o m pl y wit h a 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 n s 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 os 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 or t hr o u g h a sec ure pass w or d -pr otecte d electr o nic p ortal pr o vi de d b y  the 
S p o ns or.  The 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
1 0. 3
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 nizat i o n of 
Tec h nical 
Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Use G o o d Cli nical Practice: 
C o ns oli date d G ui deli ne a n d ot her ge nerall y  acce pte d sta n dar ds of g o o d cli nical practice); a n d 
all a p plica ble fe deral, state a n d l ocal la ws, r ules a n d re g ulati o ns relati n g t o t he c o n d uct of t he 
cli nical trial.
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 u de 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.
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.
 
 
0 4 V B P K

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.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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/case 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 o n 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 IC 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 de 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 u est, 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 reg 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 best 
of t he i n vesti gat or’s k n o wle d ge, t hreate ne d.
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 di 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 
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
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, a cc 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 of 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 pa ti 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
1 0. 4
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 Act ( 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
1 0. 5
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 n t 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
1 0. 6
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 yi 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 
his/ 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 
ver ifie d as acc urate.
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.
 
 
0 4 V B P K

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.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
P u blic ati o ns
1 0. 7
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 owi 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 ut h 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 
b ec 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 part ies.  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  sect i 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 n e 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 ul ts, 
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 article 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 o f 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 base d o n partici pati o n a n d act ual c o ntri b uti o ns t o 
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.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 3 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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 meet p u blicati o n ti meli nes.
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): p. 4 5 3 1- 8.
2.
Mei, Z., et al., T u m o ur -i nfiltrati n g i nfla m mati o n a n d pr o g n osis i n c ol orectal ca ncer: 
s yste matic re vie w a n d meta-a nal ys is. Br J Ca ncer, 2 0 1 4. 1 1 0( 6): p. 1 5 9 5-6 0 5.
3.
Sal ga d o, R., et al., Har m o nizati o n of t he e val uati o n of t u m or i nfiltrati n g l ym p h oc y tes 
( TI Ls) i n breast ca ncer: rec o m me n dati o ns b y  an i nter nati o nal TI Ls -w or ki n g gr o u p 
2 0 1 4. A n n O nc ol, 2 0 1 4.
4.
Sc hatt o n, T., et al., T u m or -i nfiltrati n g l ym p h oc y tes a n d t heir si g nifica nce i n 
mela n o ma pr o g n osis. Met h o ds M ol Bi ol, 2 0 1 4. 1 1 0 2: p. 2 8 7 - 3 2 4.
5.
G o o de n, M.J., et al., T he pr o g n ostic i nfl ue nce of t u m o ur-i nfiltrati n g l ym p h oc y tes i n 
ca ncer: a s ys te matic re vie w wit h meta-a nal ys is. Br J Ca ncer, 2 0 1 1. 1 0 5( 1): p. 9 3- 1 0 3.
6.
Sc hrei ber, R. D., L.J. Ol d, a n d M.J. 
S m y t h, Ca ncer i m m u n oe diti n g: i nte grati n g 
i m m u nit y's r oles i n ca ncer s u p pressi o n a n d pr o m oti o n. Scie nce, 2 0 1 1. 3 3 1( 6 0 2 4): p. 
1 5 6 5- 7 0.
7.
Bre m nes, R. M., et al., T he r ole of t u m or-i nfiltratin g i m m u ne cells a n d c hr o nic 
i nfla m mati o n at t he t u m or site o n ca ncer de vel o p me nt, pr o gressi o n, a n d pr o g n osis: 
e m p hasis o n n o n -s mall cell l u n g ca ncer. J T h orac O nc ol, 2 0 1 1. 6( 4): p. 8 2 4- 3 3.
8.
Tal ma d ge, 
J. E., I mm u ne 
cell i nfiltrati o n of pri mar y  an d metastatic 
lesi o ns: 
mec ha nis ms a n d cli nical i m pact. Se mi n Ca ncer Bi ol, 2 0 1 1. 2 1( 2): p. 1 3 1 - 8.
9.
S hira be, K., et al., 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: 
pat h ol o g y  a n d cli nical ma na ge me nt. I nt J Cli n O nc ol, 2 0 1 0. 1 5( 6): p. 5 5 2-8.
1 0. N os h o, K., et al., T u m o ur -i nfiltrati n g T- cell s u bsets, m olec ular c ha n ges i n c ol orectal 
ca ncer, a n d pr o g n osis: c o h ort st u d y an d literat ure re vie w. J Pat h ol, 2 0 1 0. 2 2 2( 4): p. 
3 5 0 - 6 6.
1 1. Bellati, F., et al., I mm u n ol o g y  of g y nec ol o gic ne o plas ms: a nal ysis of t he pr o g n ostic 
si g nifica nce of t he i m m u ne stat us. C urr Ca ncer Dr u g Tar gets, 2 0 0 9. 9( 4): p. 5 4 1- 6 5.
1 2. O ble, D. A., et al., 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. 9: p. 3.
1 3. U p pal uri, R., G. P. D u n n, a n d J.S. Le wis, Jr., F oc us o n TI Ls: pr o g n ostic si g nifica nce 
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0 4 V B P K

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

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

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

Pr o d uct:   M K - 3 4 7 5 
1 4 1
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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( P D-L 1) T l ym p h oc y te-i n hi bit or y 
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0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4 2
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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i nfiltrati n g l ym p h oc y tes i n breast ca ncers o vere x pressi n g t he H E R 2/ ne u o nc o ge ne. 
C urr O pi n O nc ol, 2 0 1 4. 2 6( 6): p. 5 6 2- 7.
8 5. Bri g gs, S. a n d I. T o mli ns o n, Ger mli ne a n d s o matic p ol y merase e psil o n a n d delta 
m utati o ns defi ne a ne w class of h y per m utate d c ol orectal a n d e n d ometrial ca ncers. J 
Pat h ol, 2 0 1 3. 2 3 0( 2): p. 1 4 8- 5 3.
8 6. De we y , F. E., et al., Cli nical i nter pretati o n a n d i m plicati o ns of w h ole -ge n o me 
se q ue nci n g. J A M A, 2 0 1 4. 3 1 1( 1 0): p. 1 0 3 5- 4 5.
8 7. V olla n, H. K., et al., A t u m or D N A c o m ple x a berrati o n i n de x is a n i n de pe n de nt 
pre d ict or of s ur vi val i n breast a n d o varia n ca ncer. M ol O nc ol, 2 0 1 4.
8 8. I g natia dis, M. a n d S.J. Da ws o n, Circ ulati n g T u m or Cells a n d Circ ulati n g t u m or D N A 
f or precisi o n me dici ne: Drea m or reality?  A n n O nc ol, 2 0 1 4.
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4 3
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
8 9. Prat, A., et al., Pre dicti n g res p o nse a n d s ur vi val i n c he m ot hera p y-treate d tri ple-
ne gati ve breast ca ncer. Br J Ca ncer, 2 0 1 4. 1 1 1( 8): p. 1 5 3 2- 4 1.
9 0. Krie gs ma n n, M., et al., M utati o nal pr ofiles i n tri ple -ne gati ve breast ca ncer defi ne d b y 
ultra dee p m ulti ge ne se q ue nci n g s h o w hi g h rates of PI 3 K pat h wa y  alterati o ns a n d 
cli nicall y rele va nt e ntit y s u b gr o u p s pecific differe nces. O nc otar get, 2 0 1 4.
9 1. Ba nerji, S., et al., Se q ue nce a nal ysis of m utati o ns a n d tra nsl ocati o ns acr oss breast 
ca ncer s u bt y pes. Nat ure, 2 0 1 2. 4 8 6( 7 4 0 3): p. 4 0 5 - 9.
9 2. Ca ncer Ge n o me Atlas, N., C o m pre he nsi v e m olec ular 
p ortraits of h u ma n breast 
t u m o urs. Nat ure, 2 0 1 2. 4 9 0( 7 4 1 8): p. 6 1-7 0.
9 3. R ossille, D., et al., Hi g h le vel of s ol u ble pr o gra m me d cell deat h li ga n d 1 i n bl o o d 
i m pacts o verall s ur vi val i n a g gressi ve diff use lar ge B- Cell l ym p h o ma: res ults fr o m a 
Fre nc h m ultice nter cli nical trial. Le u ke mia, 2 0 1 4.
9 4. Pic o de C oa na, Y., et al., I pili m u ma b treat me nt res ults i n a n earl y decrease i n t he 
fre q ue nc y of circ ulati n g gra n ul oc y tic m y el oi d-deri ve d s u p press or cells as well as 
t heir Ar gi nase 1 pr o d ucti o n. Ca ncer I m m u n ol Res, 2 0 1 3. 1( 3): p. 1 5 8 - 6 2.
9 5. T wel ves, C., et al., Efficac y  of eri b uli n i n w o me n wit h metastatic breast ca ncer: a
p o ole d a nal ys is of t w o p hase 3 st u dies. Breast Ca ncer Res Treat, 2 0 1 4
9 6. 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 h ical       
A p pr oac hes. Statistics i n Bi o p har mace utical Researc h 2 0 1 3; 5( 4): 3 1 1 - 3 2 0.
9 7. R o bi ns, J. M., Tsiatis, A. A. C orrecti n g f or n o n- c o m plia nce i n ra n d o mize d trials usi n g  
ra n k preser vi n g str uct ural fail ure ti me m o dels. C o m m u nicati o ns i n Statistics -T he or y 
a n d Met h o ds, 1 9 9 1; 2 0 ( 8): 2 6 0 9 - 2 6 3 1.
9 8. Fi n kelstei n D M ( 1 9 8 6). A pr o p orti o nal hazar ds m o del f or i nter val-ce ns ore d fail ure 
ti me data. Bi o metrics 4 2, 8 4 5-5 4.
9 9. U n o, H., et al. M o vi n g Be y o n d t he Hazar d Rati o i n Q ua ntif yi n g t he Bet wee n -Gr o u p 
Differe nce i n S ur vi val A nal y sis. J Cli n O nc ol. 2 0 1 4; 3 2 ( 2 2): 2 3 8 0- 2 3 8 5.
1 0 0. O dell 
P. M., 
A n ders o n 
K. M., 
Ka n nel 
B. W. 
Ne w 
m o dels 
f or pre dicti n g 
car di o vasc ular e ve nts. J o ur nal of Cli nical E pi de mi ol o g y  1 9 9 4; 4 7( 6): 5 8 3-5 9 2.
1 0 1. Me hr otra D., S u S. C., Li X.  An efficie nt alter nati ve t o t he stratifie d C o x m o del 
a nal ys is. Statist. Me d. 2 0 1 2, 3 1 1 8 4 9– 1 8 5 6.
1 0 2. Nis hi n o M, 
Gar ga n o M, 
S u da M, 
Ra mai ya  NH, H o di F S. O pti mizi n g i m m u ne-
relate d t u m or res p o nse assess me nt: d oes re d uci n g t he n u m ber of lesi o ns i m pact 
res p o nse assess me nt i n mela n o ma patie nts treate d wit h i pili m u ma b? J o ur nal f or 
I m m u n ot hera py of Ca ncer. 2 0 1 4; 2: 1 7. d oi: 1 0. 1 1 8 6/ 2 0 5 1 - 1 4 2 6- 2- 1 7.
1 0 3. Gar o n, E. B., et al. A ntit u m or acti vit y of pe m br oliz u ma b a n d c orrelati o n wit h 
pr o gra m me d deat h li ga n d 1 ( P D-L 1) e x pressi o n i n a p o ole d a nal ys is of pre vi o usl y  
treate d a d va nce d N S C L C. 
C orrelati o n 
bet wee n t u m or P D -L 1 e x pressi o n a n d 
i m pr o ve d pe m br o a ntit u m or acti vit y has bee n o bser ve d. A n nals of O nc ol o g y  (2 0 1 4) 
2 5 ( 5): 1 - 4 1. 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
1 0 4. Bas u, G., et al. E x pressi o n of n o vel i m m u n ot hera pe utic tar gets i n tri ple-ne gati ve 
breast ca ncer. J Cli n O nc ol 2 0 1 4; 3 2( 1 5) 1 0 0 1.
1 0 5. A n ders o n, M K 
et al.  Ap plicati o n of gra p hical m ulti plicit y  met h o ds i n c o m ple x 
gr o u p se q ue ntial trials.  2 0 1 7 s u b mitte d
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 4 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
1 2. 1
Merc k *
C o de of C o n d uct f or Cli nic al Tri als
I.
I ntr o d ucti o n
A. P ur p ose
Merc k, t hr o u g h its s u bsi diaries, c o n d ucts cli nical trials w orl d wi de t o e val uate t he safet y a n d effecti ve ness of o ur 
pr o d ucts. As s uc h, we are c o m mitte d t o desi g ni n g, i m ple me nti n g, c o n d ucti n g, a nal yzi n g a n d re p orti n g t hese trials i n 
c o m plia nce wit h t he hi g hest et hical a n d scie ntific sta n dar ds. Pr otecti o n of 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 ula ti 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  the 
part y ( parties) e m pl o y e d f or t heir e xec uti o n (e. g., c o ntract researc h or ga nizati o ns, c olla b orati ve researc h eff orts). T his 
C o de is n ot i nte n de d t o a p pl y t o trials w hic h are o bser vati o nal i n nat ure, or w hic h are retr os pecti ve. F urt her, t his C o de 
d oes n ot a p pl y t o i n vesti gat or -i nitiate d trials w hic h are n ot u n der t he c o ntr ol of Merc k.
II. Scie ntific Iss ues
A. Tri al C o n d uct
1.
Tri al Desi g n
E xce pt f or pil ot or esti mati o n trials, cli nical trial pr ot oc ols will be h y p ot hesis -dri ve n t o assess safet y, efficac y 
a n d/ or p har mac o ki netic or p har mac o d y na mic i n dices of Merc k or c o m parat or pr o d ucts.  Alter nati vel y, Merc k ma y 
c o n d uct o utc o mes researc h trials, trials t o assess or vali date vari o us e n d p oi nt meas ures, or trials t o deter mi ne 
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 the 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 p r 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. I n s uc h cases, p u blicati o n of  
res ults ma y n ot be a p pr o priate si nce t he trial ma y be u n der p o were d a n d t he a nal yses c o m plicate d b y statistical iss ues 
of m ulti 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 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
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 wi ll 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.  S u 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.  S u 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.  Unless 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 gat ors ( or t he s p o ns ori n g 
i nstit uti o n) i n a fair ma n ner f or t he w or k perf or me d i n s u p p ort of Merc k trials.   Merc k d oes n ot pa y i nce nti ves t o 
e nr oll 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 w e 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 di n g 
I nf or me d c o nse nt f or ms will discl ose t hat t he trial is s p o ns ore d b y Merc k, a n d t hat t he i n vesti gat or or s p o ns ori n g 
i nstit uti o n is bei n g pai d or pr o vi de d a gra nt f or perf or mi n g t he trial.  H o we ver, t he l ocal I R B/ 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 o t 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 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 4 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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 2. 2
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 
ma y  be use d t o see 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: T he 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 su 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 y ri 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. 3 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  
Merc k 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  the 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 
i nteract wit h, or ot her as pects of disease.  T he s peci me n(s) m a y  be use d f or f ut ure assa y 
de vel 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 n i 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 dersta 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  Merc k or desi g nees a n d researc h 
will be m o nit ore d a n d re vie we d b y a c o m mittee of o ur scie ntists a n d cli nicia ns.
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 bject s 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 dical 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.  I nf or mati o n c o ntai ne d o n t he c o nse nt f or m al o ne ca n n ot be trace d 
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 4 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
t o a n y speci me ns, test res ults, or me dical i nf or mati o n o nce t he s peci me ns ha ve bee n 
re n dere d de-i de ntifie d
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.  
Eac h i nf or me d c o nse nt a p pr o ve d b y  a n et hics c o m mittee is assi g ne d a u ni q ue trac ki n g 
n u m ber.  The trac ki n g n u m ber o n t his d oc u me nt will be use d t o assi g n s peci me n 
per missi o ns f or eac h s peci me n i nt o t he E ntr uste d Ke yh ol der’s S peci me n Data base.
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 b ot h c o nse nt a n d ac q uisiti o n of F ut ure Bi o me dical Researc h 
s peci me ns will 
be ca pt ure d i n t he electr o nic Case 
Re p ort 
F or ms (e C R Fs). 
Rec o nciliati o n of b ot h f or ms will be perf or me d t o ass ure t hat o nl y a p pr o priatel y-
c o nse nte d s peci me ns are use d f or t his s u b-trial's researc h p ur p oses. A n y s peci me ns 
f or w hic h s uc h a n i nf or me d c o nse nt ca n n ot be verifie d will be destr oye d.
d.
F ut ure Bi o me dic al Researc h S peci me n C ollecti o ns
Bl o o d s peci me ns f or D N A or R N A is olati o n 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. S peci me ns li ke tiss ue a n d 
b o ne marr o w 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 s uc h a 
pr oce d ure f or cli nical p ur p oses.
S peci me ns will be c ollecte d a n d se nt t o t he la b orat or y desi g nate d f or t he trial w here 
t he y will be pr ocesse d (e. g., D N A or R N A e xtracti o n, etc) f oll o wi n g t he Merc k 
a p pr o ve d p olicies a n d pr oce d ures f or s peci me n ha n dli n g a n d pre parati o n.
If s peci me ns are c ollecte d f or a s pecific ge n ot y pe or e x pressi o n a nal ysis as a n 
o bjecti ve t o t he mai n trial, t his a nal ys is is detaile d i n t he mai n b o d y  of t his pr ot oc ol 
(Secti o n 8. 0 – St atistic al A n al ysis Pl a n ).  These s peci me ns will be pr ocesse d, 
a nal yz e d, a n d t he re mai n der of t he s peci me n will be destr o y e d.  The res ults of t hese 
a nal ys es will be re p orte d al o n g wit h t he ot her trial res ults.  A se parate s peci me n will 
be o btai ne d fr o m pr o perl y -c o nse nte d s u bjects i n t his pr ot oc ol f or st ora ge i n t he 
bi ore p osit or y  f or F ut ure Bi o me dical Researc h.
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 h e 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 o m s peci me ns o btai ne d f or F ut ure 
Bi o me dical Researc h, Merc k 
has de vel o pe d sec ure p olicies a n d pr oce d ures.  
All 
s peci me ns will be de-i de ntifie d 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 Rese arc 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 
 
 
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1 9- Fe b- 2 0 1 8
C o nfi de ntial
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.  
T his first c o de will be re place d wit h a sec o n d c o de at a Merc k desi g nate d st ora ge/la b 
facilit y.  The sec o n d c o de is li n ke d t o t he first c o de via a sec o n d k e y . T he s peci me n is 
n o w d o u ble c o de d.  Speci me ns wit h t he sec o n d c o de are s o meti mes referre d t o as d e -
i de ntifie d s peci me ns. T he use of t he sec o n d c o de pr o vi des a d diti o nal c o nfi de ntialit y an d 
pri vac y  pr otecti o n f or s u bjects o ver t he use of a si n gle c o de.  Access t o b ot h k e y s w o ul d 
be nee de d t o li n k a n y  data or s peci me ns bac k t o t he s u bject's i de ntificati o n.
T he sec o n d c o de is st ore d se paratel y fr o m t he first c o de a n d all ass ociate d pers o nal 
s peci me n i de ntifiers.  A sec ure li n k, t he sec o n d ke y , will be utilize d t o matc h t he sec on d 
c o de t o t he first c o de t o all o w cli nical i nf or mati o n c ollecte d d uri n g t he c o urse of t he trial 
t o be ass ociate d wit h t he s peci me n.  This sec o n d k e y  will be tra nsferre d u n der sec ure 
pr oce d ures b y  the Merc k desi g nate d facilit y to a n E ntr uste d Ke y h ol der at Merc k.  The 
sec o n d c o de will be l o g ge d i nt o t he pri mar y  bi ore p osit or y data base at Merc k a n d, i n t his 
data base, t his i de ntifier will n ot ha ve i de ntif yi n g de m o gra p hic data or i de ntif yi n g cli nical 
i nf or mati o n (i.e., race, se x, a ge, dia g n osis, la b val ues) ass ociate d wit h it. T he s peci me n 
will be st ore d i n a desi g nate d bi ore p osit or y  site wit h sec ure p olicies a n d pr oce d ures f or 
s peci me n st ora ge a n d usa ge.
T he sec o n d k e y  ca n be utilize d t o rec o nstr uct t he li n k bet wee n t he res ults of f ut ure 
bi o me dical researc h a n d t he cli nical i nf or mati o n, at t he ti me of a nal ysis.  This li n ka ge 
w o ul d n ot be p ossi ble f or t he scie ntist c o n d ucti n g t he a nal ys is, b ut ca n o nl y  be d o ne b y  
t he Merc k E ntr uste d Ke y h ol der u n der strict sec urit y policies a n d pr oce d ures.  The Merc k 
E ntr uste d Ke y h ol der will li n k t he i nf or mati o n a n d t he n iss ue a de- i de ntifie d data set f or 
a nal ys is.  The o nl y ot her circ u msta nce b y  whic h f ut ure bi o me dical researc h data w o ul d 
be directl y li n ke d t o t he f ull cli nical data set w o ul d be t h ose sit uati o ns ma n date d b y 
re g ulator y  aut h orities (e. g., E M E A, F D A), w here b y  this i nf or mati o n w o ul d be directl y 
tra nsferre d t o t he re g ulat or y a ut h orit y.
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.   H o we ver, e x pl orat or y anal y ses will n ot be c o n d ucte d u n der t he 
hi g hl y vali date d c o n diti o ns us uall y  ass ociate d wit h re g ulat or y ap pr o val of dia g n ostics.  
T he sc o pe of researc h perf or me d o n t hese s peci me ns is li mite d t o t he i n vesti gati o n of t he 
varia bilit y  in bi o mar kers t hat ma y  c orrelate wit h a cli nical p he n oty pe i n s u bjects.
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  
Merc k, 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  Merc k.  
T he i n vesti gat or c o n d ucti n g t he a nal ys is will be pr o vi de d wit h d o u ble c o de d s peci me ns.  
Re -ass ociati o n of a nal ysis res ults wit h c orres p o n di n g cli nical data will o nl y be c o n d ucte d 
b y  the Merc k E ntr uste d K e y h ol der.  An y  co ntracte d t hir d part y a nal ys es will c o nf or m t o 
t he s pecific sc o pe of a nal ysis o utli ne d i n t his s u b-trial.  Fut 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 t he s pecific a nal ysis is perf or me d will be 
ret ur ne d t o t he s p o ns or or destr o ye d a n d d oc u me ntati o n of destr ucti o n will be re p orte d t o 
Merc k.
 
 
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1 9- Fe b- 2 0 1 8
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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 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 Merc k 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  Merc k 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 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 y e d. A letter 
will be se nt fr o m Merc k 
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.
R ete nti o n of S peci 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 ac q uisiti o n.  Speci me ns m a 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 uesti o ns that are bei n g a ns were d.  In 
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 Merc k 
desi g nate d bi ore p osit o r y.  The 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 facility w hic h o perates t o ass ure t he i nte grity of t he 
s peci me ns.  S peci me ns will be destr o ye d acc or di n g t o Merc k 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
Se parate data bases f or s peci me n i nf or mati o n a n d f or res ults fr o m t he F ut ure Bi o me dical 
Researc h s u b-trial will be mai ntai ne d b y  Merc k.  This is d o ne t o se parate t he f ut ure 
e x pl orat or y test res ults ( w hic h i ncl u de ge netic data) fr o m t he cli nical trial data base 
t here by mai ntai ni n g a se parati o n of s u bject n u m ber a n d t hese res ults.  The se parate 
data bases are accessi ble o nl y  to t he a ut h orize d S p o ns or 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 urit y p olicies a n d practices base d i n 
i nter nati o nal sta n dar ds (e. g., I S O 1 7 7 9 9) t o pr otect a gai nst u na ut h orize d access.  The 
Merc k E ntr uste d K e y h ol der mai nt ai ns c o ntr ol o ver access t o all s peci me n data.  These 
data are c ollecte d f or f ut ure bi o me dical researc h p ur p oses o nl y as s pecifie d i n t his s u b-
trial will n ot be use d f or a n y ot her p ur p ose.
 
 
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M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
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
T here is n o defi niti ve re q uire me nt i n eit her a ut h oritati ve et hical g ui deli nes or i n rele va nt 
la ws/re g ulati o ns gl o bally t hat researc h res ults ha ve t o be, i n all circ u msta nces, ret ur ne d t o 
t he trial partici pa nt.  So me g ui deli nes a d v ocate a pr oacti ve ret ur n of data i n certai n 
i nsta nces.  No 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 or fa mil y, a n d t his i nf or mati o n will n ot be e ntere d i nt o t he cli nical data base 
mai ntai ne d b y  Merc k o n s u bjects.  Pri nci ple reas o ns n ot t o i nfor 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, 
c o ncer ns of misi nter pretati o n 
a n d a bse nce of g o o d cli nical practice sta n dar ds i n 
e x pl orat or y researc h ty pi call y use d f or dia g n ostic testi n g.
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 as 
t o h o w t o offer cli nical dia g n ostic  testi n g ( pai d f or b y  Merc k) t o s u bjects e nr olle d a n d 
will be a d vise d t hat c o u nseli n g s h o ul d be ma de a vaila ble f or all w h o c h o ose t o partici pate 
i n t his dia g n ostic testi n g. 
If a n y e x pl orat or y res ults are defi niti vel y ass ociate d wit h cli nical si g nifica nce after 
c o m pleti o n of a cli nical trial, Merc k will p u blis h t he res ults wit h o ut re veali n g s pecific 
s u bject i nf or mati o n, i nf or m all trial sites w h o partici pate d i n t he Merc k cli nical trial a n d 
p ost a n o n y m ize d res ults o n o ur we bsite or ot her accre dite d we bsite(s) t hat all o w f or 
p u blic acces s (e. g., disease s ocieties w h o ha ve pri mar y i nterest i n t he res ults) i n or der t hat 
p h y sicia ns a n d s u bjects ma y p urs ue cli nical dia g n ostic testi n g if t he y wis h t o d o s o.
1 0. Ge n der, Et h nicit y a n d Mi n orities
Alt h o u g h ma n y dia g n oses differ i n ter ms of fre q ue nc y by et h nic p o p ulati o n a n d ge n der, 
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 Merc k cli nical 
trials f or f ut ure bi o me dical researc h.  
Whe n trials wit h s peci me ns are c o n d ucte d a n d 
s u bjects i de ntifie d t o ser ve as c o ntr ols, e ver y eff ort will be ma de t o gr o u p s peci me ns 
fr o m s u bjects a n d c o ntr ols t o re prese nt t he et h nic a n d ge n der p o p ulati o n re prese ntati ve of 
t he disease u n der c urre nt i n vesti gati o n.
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 res earc h, ris ks t o t he s u bject ha ve bee n mi ni mize d. Ris ks i ncl u de 
t h ose ass ociate d wit h ve ni p u nct ure t o o btai n t he w h ole bl o o d s peci me n.  T his s peci me n 
will be o btai ne d at t he ti me of r o uti ne bl o o d s peci me ns dra w n i n t he mai n trial . 
Merc k 
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 on, li ke all me dical i nf or mati o n, ma y  be mis use d.
It is necessar y for s u bject-relate d data (i.e., et h nicit y , dia g n osis, dr u g t hera p y an d d osa ge, 
a ge, t o xicities, etc.) t o be re-ass ociate d t o d o u ble c o de d s peci me ns at t he ti me of data 
a nal ys is.  These s u bject data will be ke pt i n a se parate, sec ure Merc k data base, a n d all 
s peci me ns will be stri p pe d of s u bject i de ntifiers.  No i nf or mati o n c o ncer ni n g res ults 
o btai ne d fr o m f ut ure bi o me dical researc h will be e ntere d i nt o cli nical rec or ds, n or will it 
 
 
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be release d t o o utsi de pers o ns or a ge ncies, i n a n y wa y  that c o ul d be tie d t o a n i n di vi d ual 
s u bject.
1 2. Self -Re p orte d Et h nicit y
S u bjects w h o partici pate i n f ut ure bi o me dical researc h will be as ke d t o pr o vi de self-
re p orte d et h nicit y.  Su bjects w h o d o n ot wis h t o pr o vi d e t his data ma y  still partici pate i n 
f ut ure bi o me dical researc h.
1 3. 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 4. 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
 
 
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1 9 -Fe b -2 0 1 8
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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 
1 2. 3
I R Bs/I E Cs a n d I n vesti g ati o n al Site St aff
 
 
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Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
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Pr o d uct:   M K -3 4 7 5 
1 5 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
 
 
0 4 V B P K

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

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

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

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

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

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

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

Pr o d uct:   M K -3 4 7 5 
1 6 4
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
A b bre vi ati o ns
1 2. 4
A b bre vi ati o n/ Ter m
Defi niti o n
1 L
First li ne
2 L
Sec o n d li ne
3 L
T hir d li ne
A E
A d verse eve nt
A D A
A nti - dr u g anti b o dies
A L T
Ala ni ne a mi n otra nsferase
A N C
A bs ol ute n e utr o p hil co u nt
A P
Al kali ne p h os p hatase
a P T T
Acti vate d partial t hr o m b o plasti n ti me
A Sa T
All s u bjects as treate d
A S C O
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate ami n otra nsferase
ß - hC G
Beta h u ma n ch ori o nic g o na d otr o pi n
B S A
B o d y surface area
C B C
C o m plete b l o o d co u nt
CI
C o nfi de nce i nter val
C N S
Ce ntral n er v o us sys te m
C R
C o m plete res p o nse
Cr Cl
Calc ulate d Creati ni ne C leara nce
C R F
Case r e p ort for m
C S R
Cli nical st u d y re p ort
C T
C o m p ute d to m o gra p h y
C T C A E
C o m m o n to xicit y  criteria f or ad verse eve nts
C T L A- 4
C y t ot o xic t-ly m p h oc y t e- ass ociate d anti ge n 4
D M C
Data M o nit ori n g C o m mittee
D N A
De o x yri b o n ucleic aci d
E CI
E ve nts of cli nical interest
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
e D M C
E xter nal Data M o nit ori n g C o m mittee
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
E O C
E xec uti ve O versi g ht C o m mittee
E O R T C
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer
e P R O
Electr o nic su bject re p orte d o utc o mes
E R C
Et hics Re vie w C o m mittee
F B R
F ut ure b i o me dical researc h
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 6 5
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F D A A A
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act
F D A M A
F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act
F N A
Fi ne n ee dle as pirate
G C P
G o o d Cli nical Practice
G F R
Gl o m er ular filtrati o n rate
H B s A g
He patitis B s urface anti ge n
M B C
Metastatic breast ca ncer
H C V
He patitis C v ir us
HI V
H u ma n im m u n o deficie nc y v ir us
I B
I n vesti gat or’s br oc h ure
I CF
I nf or me d co nse nt for m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I H C
I m m u n o hist oc he mistr y
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 eve nts
ir R E CIS T
I m m u ne-relate d res p o nse eval u ati o n criteria i n soli d tu m ors
I RB
I nstit uti o nal Re vie w B oar d
I TI M
I m m u n orece pt or tyr osi ne -base d in hi biti o n m otif
I T S M
I m m u n orece pt or tyr osi ne -base d switc h m otif
I T T
I nte nti o n-t o-treat
I V
I ntra ve n o us
I V R S
I nteracti ve v oice res p o nse sys te m
I W R S
I nte grate d w e b res p o nse sys te m
K g
K il o gra m
L D H
L actate d e h y dr o ge nase
m A b
M o n ocl o nal anti b o d y
mc L
Micr oliters
M g
Milli gra m
M g/ k g
Milli gra m per k il o gra m
m L
milliliter
M RI
Ma g netic res o na nce ima gi n g
m T N B C
Metastatic tri ple n e gati ve b reast ca ncer
N CI
Nati o nal Ca ncer I nstit ute
N S AI D
N o n -ster oi dal anti -i nfla m mat or y d r u g
N S C L C
N o n -small cell lu n g ca ncer
O R R
O verall res p o nse rate
O S
O verall sur vi val
 
 
0 4 V B P K

Pr o d uct:   M K - 3 4 7 5 
1 6 6
Pr ot oc ol/ A me n d me nt N o.: 1 1 9- 0 5 
M K - 3 4 7 5- 1 1 9-0 5 Fi nal Pr ot oc ol
1 9- Fe b- 2 0 1 8
C o nfi de ntial
A b bre vi ati o n/ Ter m
Defi niti o n
O T C
O ver -t he-c o u nter
P D
Pr o gressi ve d isease
P F S
Pr o gressi o n -free sur vi val
P Gt
P har mac o ge netic
PI N
Pers o nal ide ntificati o n n u m ber
P K
P har mac o ki netic
P K /P D
P har mac o ki netic - phar mac o d y na mic
P O
Oral ad mi nistrati o n
P R
Partial r es p o nse
P R O
Patie nt re p orte d o utc o mes
P T
Pr ot hr o m bi n ti me
P S
Perf or ma nce stat us
R E CI S T
Res p o nse eval u ati o n criteria i n soli d tu m ors
R N A
Ri b o n ucleic aci d
Q 2 W
E ver y  2 w ee ks
Q 3 W
E ver y  3 w ee ks
Q 9 W
E ver y  9 wee ks
S A E
Seri o us ad verse eve nts
S A P
Statistical anal y sis p la n
S G O T
Ser u m g l uta mic o xal oacetic tra nsa mi nase
S G P T
Ser u m g l uta mic p yr u vic tra nsa mi nase
S O C
Sta n dar d of care
S O P
Sta n dar d o perati n g p r oce d ures
TI L
T u m or infiltrati n g ly m p h oc y tes
T N B C
Tri ple n e gati ve b reast ca ncer
T P C
Treat me nt of p h y sicia n’s ch oice
T S H
T h y r oi d sti m ulati n g h or m o ne
U L N
U p per li mit of n or mal
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 6 7
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
E aster n C o o per ati ve O nc ol o g y G r o u p Perf or m a nce St at us
1 2. 5
G R A D E
E C O G P E R F O R M A N C E S T A T U S
0
F ull y  acti ve, a ble t o carr y o n all pre-disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h y sically stre n u o us acti vit y but a m b ulat or y an 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
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 w or k acti vities; 
u p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3
Ca pa ble of o nl y  li mite d self-care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs
4
C o m pletel y  disa ble d; ca n n ot carry o n a n y self-care ; t otall y c o nfi ne d t o be d or c hair
5
Dea d
* O ke n M, 
Creec h R, T or me y  D, et al. T o xicit y  an d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y  Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5: 6 4 9 -6 5 5
htt p://ec o g -acri n. or g/res o urces/ec o g -perf or ma nce -stat us
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 6 8
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
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
1 2. 6
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 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 6 9
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
Res p o nse 
E v al u ati o n Criteri a 
i n S oli d T u m ors 1. 1 Criteri a 
f or E v al u ati n g 
1 2. 7
Res p o nse i n S oli d T u m ors
R E CI S T versi o n 1. 1 * will be use d i n t his st u d y f or assess me nt of t u m or res p o nse. W hile 
eit her C T or M RI  m a y be utilize d, as per R E CIS T 1. 1, C T is t he preferre d i ma gi n g tec h ni q ue 
i n t his st u d y.
* As p u blis he d i n t he E ur o pea n J o ur nal of Ca ncer:
E. A. Eise n ha uer, P. T herasse, J. B o gaerts, L. H. Sc h wartz, D. Sar ge nt, R. F or d, J. Da nce y , S. 
A r b uc k, S. G w y t her, M. 
M o o ne y , L. R u bi nstei n, L.  Sha n kar, L.  Do d d, R. Ka pla n, D. 
Lac o m be, J. Ver weij. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: Re vise d R E CI S T 
g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9 Ja n; 4 5( 2): 2 2 8 -4 7.
 
 
0 4 V B P K

Pr o d uct:   M K -3 4 7 5 
1 7 0
Pr ot oc ol/ A me n d me nt N o.: 1 1 9 -0 5 
M K -3 4 7 5 -1 1 9 -0 5 Fi nal Pr ot oc ol
1 9 -Fe b -2 0 1 8
C o nfi de ntial
1 3. 0 SI G N A T U R E S
S p o ns or's Re pre se nt ati ve
1 3. 1
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
1 3. 2
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 .2 – 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 ma 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 uc 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 bite 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 by 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 4 V B P K