Conditions: Non-small Cell Lung Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 125
Healthy volunteers: no

Brief summary:
In this China extension study, carboplatin and paclitaxel with or without pembrolizumab (MK-3475, KEYTRUDA®) will be administered to Chinese adults with first line metastatic squamous non-small cell lung cancer (NSCLC).

The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS) in Chinese participants.

After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.

Detailed description:
The MK-3475-407-China Extension Study enrolled a total of 125 participants, of which 15 participants have been also previously enrolled in the MK-3475-407 global study (NCT02775435). This China extension study did not include nano particle albumin-bound paclitaxel (nab-paclitaxel) that was an option in the global base study, because nab-paclitaxel it is not yet approved for treatment of NSCLC in China.

Arms:
arm 1: Participants receive pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) PLUS carboplatin Area Under the Curve (AUC) 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles. arm 2: Participants receive normal saline by IV infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS paclitaxel (200 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles.

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Saline placebo for pembrolizumab
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion Carboplatin dose should not exceed 900 mg. intervention 4: IV infusion

Protocol document:
Prot_002.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Randomized, Double-Blind, Phase III Study of Carboplatin-
Paclitaxel/Nab-Paclitaxel Chemotherapy with or without 
Pembrolizumab (MK-3475) in First Line Metastatic Squamous 
Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
30-Oct-2019
NCT03875092


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


Pr o d uct:   M K -3 4 7 5 
4 9
Pr ot oc ol/ A me n d me nt N o.: 4 0 7- 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
A s u bject m ust be disc o nti n ue d fr o m t he trial f or t he f oll o wi n g reas o ns:

T he s u bject or le gal re prese ntati ve (s uc h as a pare nt or le gal g uar dia n) wit h dra ws 
c o nse nt.

T he s u bject is l ost t o f oll o w - u p
A s u bject m ust be disc o nti n ue d fr o m trial treat me nt b ut c o nti n ue t o be f oll o we d f or a n y of 
t he f oll o wi n g reas o ns:

U nacce pta ble a d verse e x perie nces as descri be d i n Secti o n 5. 2. 1. 2.

C o m plete d t otal of 3 5 treat me nts of pe m br oliz u ma b/ sali ne place b o

D oc u me nte d disease pr o gressi o n
N ote: If a s u bject has pr o gressi o n of disease verifie d b y  ce ntral ra di ol o gical re vie w 
usi n g R E CI S T 1. 1, t he s u bject m a y  be u n bli n de d. I f a s u bject was recei vi n g sali ne 
place b o a n d meets all cr oss o ver criteria defi ne d i n Secti o n 7. 1. 5. 5, he/s he will ha ve 
t he o p p ort u nit y  to cr oss o ver t o recei ve o pe n -la bel pe m br oliz u ma b m o n ot hera p y . If a 
s u bject was recei vi n g pe m br oliz u ma b a n d is dee me d t o be cli nicall y be nefiti n g 
des pite ra di ol o gical pr o gressi o n t he y will ha ve t he o p p ort u nit y  t o c o nti n ue o pe n-la bel 
pe m br oliz u ma b m o n ot hera p y. If a s u bject has u nc o nfir me d pr o gress i o n of disease 
a n d is cli nicall y sta ble, it is at t he discreti o n of t he i n vesti gat or t o c o nti n ue treati n g 
t he s u bject wit h t he assi g ne d treat me nt per pr ot oc ol u ntil pr o gressi o n of disease is 
c o nfir me d at least 2 8 d a y s fr o m t he date of t he sca n s u g gesti n g p r o gressi o n of 
disease.
Cli nical Sta bilit y  is defi ne d as:
o
A bse nce of s ym pt o ms a n d si g ns i n dicati n g cli nicall y si g nifica nt pr o gressi o n of 
disease (i ncl u di n g w orse ni n g of la b orat or y  val ues) i n dicati n g disease pr o gressi o n.
o
N o decli ne i n E C O G perf or ma nce stat us .
o
A bse nce 
of ra pi d pr o gressi o n of disease or pr o gressi ve t u m or at critical 
a nat o mical sites (e. g., c or d c o m pressi o n) re q uiri n g ur ge nt alter nati ve me dical 
i nter ve nti o n.

I nterc urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of treat me nt 

I n vesti gat or’s decisi o n t o wit h dra w t he s u bject fr o m treat me nt

T he s u bject has a c o nfir me d p ositi ve ser u m pre g na nc y  test

N o nc o m plia nce wit h trial treat me nt or pr oce d ure re q uire me nts

A d mi nistrati ve reas o ns
If a s u bject attai ns C R verifie d b y  ce ntral ra di ol o gical re vie w, h a s bee n treate d f or at least 
ei g ht c ycles of st u d y  treat me nt, a n d has at least t w o c ycles of st u d y treat me nt be y o n d t he date 
w he n t he i nitial C R was declare d O R t he s u bject has recei ve d t he ma xi m u m a d mi nistrati o ns 
of pe m br oliz u ma b / place b o as o utli ne d a b o ve, t he s u bject a n d I n vesti gat or ma y  co nsi der 
st o p pi n g  
t hera py  
wit h  
pe m br oliz u ma b / place b o.  
S u bjects  
w h o  
disc o nti n ue 
pe m br oliz u ma b / place b o a n d t he n e x perie nce ra di o gra p hic disease pr o gressi o n
b y  local 
 
 
0 5 C 6 H 2


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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




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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


Pr o d uct:  M K -3 4 7 5 
1 1 3
Pr ot oc ol/ A me n d me nt N o.:  4 0 7 - 0 6 
M K -3 4 7 5 -4 0 7 -0 6 Fi nal Pr ot oc ol
3 0 -Oct -2 0 1 9
C o nfi de ntial
[ 2 4]
D u dle y  M E, W u n derlic h 
J R, Ya n g J C, S herr y  RM, T o palia n S L , Restif o 
N P, et al. A d o pti ve cell tra nsfer t hera p y foll o wi n g n o n- m y el oa blati ve b ut 
l ym p h o de pleti n g c he m ot hera p y f or t he treat me nt of patie nts wit h refract or y 
metastatic mela n o ma. J Cli n O nc ol 2 0 0 5; 2 3( 1 0): 2 3 4 6- 5 7.
[ 2 5]
H u n der N N, Walle n H, Ca o J, He n dric ks D W, Reill y  JZ, R o d m y re R, et al. 
Treat me nt of metastatic mela n o ma wit h a ut ol o g o us C D 4 + T cells a gai nst 
N Y -E S O -1. N E n gl J Me d 2 0 0 8; 3 5 8( 2 5): 2 6 9 8 -7 0 3.
[ 2 6]
O kaza ki 
T, 
Mae da 
A, 
Nis hi m ura 
H, 
K ur osa ki 
T, 
H o nj o T. 
P D - 1 
i m m u n orece pt or i n hi bits B cell rece pt or-me diate d si g nali n g b y  recr uiti n g 
src 
h o m ol o g y   
2-d o mai n -c o ntai ni n g 
t yr osi ne 
p h os p hatase  
2  
t o 
p h os p h ot y r osi ne. Pr oc Natl Aca d Sci U S A 2 0 0 1; 9 8( 2 4): 1 3 8 6 6- 7 1.
[ 2 7]
Gree n wal d RJ, Free ma n GJ, S har pe A H. T he B 7 fa mil y re visite d. A n n u 
Re v I m m u n ol 2 0 0 5; 2 3: 5 1 5 - 4 8.
[ 2 8]
K E Y T R U D A ( pe m br oliz u ma b) I n vesti gat or's Br oc h ure, E diti o n N u m ber 
1 0, 3 1- A U G - 2 0 1 5.
[ 2 9]
Gar o n E B, Riz vi N A, H ui R, Lei g hl N, Bal ma n o u kia n A S, E der J P, et al. 
Pe m br oliz u ma b f or t he treat me nt of n o n- s mall-cell l u n g ca ncer. N E n gl J 
Me d. 2 0 1 5 Ma y  2 1; 3 7 2( 2 1): 2 0 1 8- 2 8.
[ 3 0]
Peters S, A djei A A, Gri delli C, Rec k M, Kerr K, Feli p E, et al. Metastatic 
n o n- s mall-cell l u n g ca ncer ( N S C LC): E S M O Cli nical Practice G ui deli nes 
f or dia g n osis, treat me nt a n d f oll o w-u p. A n nals O nc ol 2 0 1 2; 2 3( S u p ple me nt 
7): vii 5 6 -vii 6 4.
[ 3 1]
Sc hiller J H, Harri n gt o n D, Bela ni C P, La n ger C, Sa n dler A, Kr o o k J, et al. 
C o m paris o n of f o ur c he m ot hera p y re gi me ns f or a d va nce d n o n- s mall-cell 
l u n g ca ncer. N E n gl J Me d 2 0 0 2; 3 4 6: 9 2-8.
[ 3 2]
Ar dizz o ni A, B o ni L , Tise o M, F ossella F V, Sc hiller J H, Paes ma ns M, et al. 
Cis plati n - vers us car b o plati n -base d c he m ot hera p y i n first-li ne treat me nt of 
a d va nce d n o n- s mall-cell l u n g ca ncer: a n i n di vi d ual patie nt data meta -
a nal ys is. J Natl Ca ncer I nst. 2 0 0 7 J u n 6; 9 9( 1 1): 8 4 7- 5 7.
[ 3 3]
S oci ns ki M A, B o n dare n k o I, Karase va N A, Ma k hs o n A M, V y n n y c he n k o I, 
O ka m ot o I, et al. Wee kl y  na b -Paclita xel i n C o m bi nati o n Wit h Car b o plati n 
Vers us S ol ve nt -Base d Paclita xel Pl us Car b o plati n as First -Li ne T hera p y i n 
Patie nts Wit h A d va nce d N o n -S mall -Cell L u n g Ca ncer: Fi nal Res ults of a 
P hase III Trial. J Cli n O nc ol 2 0 1 2; 3 0: 2 0 5 5- 6 2.
 
 
0 5 C 6 H 2


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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

SAP_003.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Randomized, Double-Blind, Phase III Study of Carboplatin-
Paclitaxel/Nab-Paclitaxel Chemotherapy with or without 
Pembrolizumab (MK-3475) in First Line Metastatic Squamous 
Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
29-Jan-2018
NCT03875092


M K -3 4 7 5
P A G E 1
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
S u p ple me nt al St atistic al A n al ysis Pl a n (s S A P) 
T A B L E O F C O N T E N T S
Ta ble of C o nte nt … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … ….. 1
1
I NT R O D U C TI O N … … … … … … … … … … … … … … … … … … … … … … … … … … … …... 4
2
S U M M A R Y O F C H A N G E S … … … … … … … … … … … … … … … … … … … … … … … …... 4
3  
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S F O R G L O B A L S T U D Y … … ….. 4
3. 1
Statistical A nal y sis Pla n S u m mar y .................................................................................. 4
3. 2
Res p o nsi bilit y  f or A nalyses/I n- H o use Bli n di n g .............................................................. 6
3. 3
H y p ot heses/ Esti mati o n ..................................................................................................... 6
3. 3. 1
Pri mar y  O bjecti ve(s) & H yp ot hesis(es) .................................................................... 6
3. 3. 2
Sec o n dar y  O bjecti ve(s) & H yp ot hesis(es) ................................................................ 7
3. 3. 3
E x pl orat or y  O bjecti ves ............................................................................................. 7
3. 4
A nal y sis E n d p oi nts........................................................................................................... 8
3. 4. 1
Efficac y  E n d p oi nts.................................................................................................... 8
3. 4. 2
Safet y  E n d p oi nts....................................................................................................... 8
3. 5
A nal y sis P o p ulati o ns ........................................................................................................ 9
3. 5. 1
Efficac y  A nalys is P o p ulati o ns.................................................................................. 9
3. 5. 2
Safet y  A nalys is P o p ulati o ns ..................................................................................... 9
3. 6
Statistical Met h o ds ........................................................................................................... 9
3. 6. 1
Statistical Met h o ds f or Efficac y  A nalys es ................................................................ 9
3. 6. 1. 1
Pr o gressi o n -Free S ur vi val ( P F S) ..................................................................... 1 0
3. 6. 1. 2
O verall S ur vi val ( O S) ...................................................................................... 1 1
3. 6. 1. 3
O bjecti ve Res p o nse Rate ( O R R) a n d D urati o n of Res p o nse ( D O R) .............. 1 2
3. 6. 1. 4
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts................................................ 1 3
3. 6. 1. 5
E x pl orat or y  A nalys es ...................................................................................... 1 4
3. 6. 2
Statistical Met h o ds f or Safet y A nal y ses ................................................................. 1 5
3. 6. 3
S u m maries of Baseli ne C haracteristics, De m o gra p hics, a n d Ot her A nal ys es ........ 1 6
3. 7
I nteri m A nalys is............................................................................................................. 1 6
3. 8
M ult i plicit y..................................................................................................................... 1 7
3. 8. 1
O bjecti ve Res p o nse Rate ........................................................................................ 1 8
3. 8. 2
Pr o gressi o n -free S ur vi val........................................................................................ 1 9
3. 8. 3
O verall S ur vi val ...................................................................................................... 1 9
3. 9
Sa m ple Size a n d P o wer Calc ulati o ns................................ ............................................. 2 0
 
 
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0 6 D V Z Q


M K -3 4 7 5
P A G E 2
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 1 0
S u b gr o u p A nal y ses a n d Effect of Baseli ne Fact ors.................................................... 2 1
3. 1 1
E xte nt of E x p os ure ..................................................................................................... 2 2
4
St atistical A nal ysis Pla n f or E xte nsi o n … … … … … … … … … … … … … … … … … … … ….. 2 2
4. 1
I ntr o d ucti o n .................................................................................................................... 2 2
4. 2
Res p o nsi bilit y  f or A nalyses/I n- H o use Bli n di n g ............................................................ 2 2
4. 3
H y p ot heses/ Esti mati o n ................................................................................................... 2 3
4. 4
T he A nal ys is E n d p oi nts ................................................................................................. 2 3
4. 4. 1
Efficac y  E n d p oi nts.................................................................................................. 2 3
4. 4. 2
Safet y  E n d p oi nts..................................................................................................... 2 3
4. 5
A nal y sis P o p ulati o ns ...................................................................................................... 2 3
4. 5. 1
Efficac y  A nalys is P o p ulati o ns................................................................................ 2 3
4. 5. 2
Safet y  A nalys is P o p ulati o ns ................................................................................... 2 4
4. 6
Statistical Met h o ds ......................................................................................................... 2 4
4. 6. 1
Statistical Met h o ds f or Efficac y  A nalys es .............................................................. 2 4
4. 6. 1. 1
O verall S ur vi val ( O S) ...................................................................................... 2 4
4. 6. 1. 2
Pr o gressi o n -Free S ur vi val ( P F S) ..................................................................... 2 5
4. 6. 1. 3
O bjecti ve Res p o nse Rate ( O R R) a n d D urati o n of Res p o nse ( D O R) .............. 2 5
4. 6. 1. 4
E x pl orat or y  A nalys es ...................................................................................... 2 5
4. 6. 2
Statistical Met h o ds f or Safet y A nal ys es ................................................................. 2 5
4. 6. 3
S u m maries of Baseli ne C haracteristics, De m o gra p hics, a n d Ot her A nal ys es ........ 2 5
4. 7
I nteri m A nalys is & Fi nal a nalys is.................................................................................. 2 6
4. 8
M ulti plicit y ..................................................................................................................... 2 6
4. 9 
Sa m ple Size a n d P o wer Calc ulati o ns................................ ............................................. 2 6
4. 1 0
S u b gr o u p A nal y ses a n d Effect of Baseli ne Fact ors.................................................... 2 6
5
R E F E R E N C E S … … … … … … … … … … … … … … … … … … … … … … … … … … … … ….. 2 6
 
 
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0 6 D V Z Q


M K -3 4 7 5
P A G E 3
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Listi n g of Ta bles
Ta ble 1
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S.................................. 1 1
Ta ble 2
Ce ns ori n g R ules f or D O R........................................................................................... 1 3
Ta ble 3
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts........................................................... 1 4
Ta ble 4
A nal y sis Strate g y f or Safet y Para meters.................................................................... 1 6
Ta ble 5
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y ...................................................... 1 7
Ta ble 6
P ossi ble Al p ha- le vels a n d A p pr o xi mate O R R differe nce Re q uire d t o De m o nstrate 
Efficac y  f or O R R at I A 1............................................................................................................... 1 8
Ta ble 7
Efficac y  B o u n daries a n d Pr o perties f or Pr o gressi o n-free S ur vi val A nalys es ............ 1 9
Ta ble 8
Efficac y  B o u n daries a n d Pr o perties f or O verall S ur vi val A nal ys es ........................... 2 0
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 4
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
1
I N T R O D U C TI O N
T his s u p ple me ntal S A P (s S A P) is a c o m pa ni o n d oc u me nt t o t he pr ot oc ol. I n ad diti o n t o t he 
i nf or mati o n prese nte d i n t he pr ot oc ol S A P w hic h pr o vi des t he pri nci pal feat ures of c o nfir mat or y 
a nal ys es f or t his trial, t his s u p ple me ntal S A P pr o vi des a d diti o nal statistical a nal ys is details/ data 
deri vati o ns a n d d oc u me nts m o dificati o ns or a d diti o ns t o t he a nal ys is pla n t hat are n ot “ pri nci pal” 
i n nat ure a n d res ult fr o m i nf or mati o n t hat was n ot a vaila ble at t he ti me of pr ot oc ol fi nalizati o n.  
Se parate a nal ys is pla ns (i.e., se parate d oc u me nts fr o m t his s S A P) ma y
be de vel o pe d f or 
P K/ m o deli n g a nal ys is, bi o mar ker a nalys is, a n d ge netic data a nal ysis.   
2 
S U M M A R Y O F C H A N G E S
T his s S A P ali g ns wit h t he pr ot oc ol a me n d me nt v 0 4 f or t he C hi na e xte nsi o n st u d y wit h re gar d t o 
statistical a nal ysis pla n.
3
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S F O R G L O B A L S T U D Y
3. 1
St atistic al A n al ysis Pl a n S u m m ar y
T his secti o n c o ntai ns a brief s u m mar y  of t he statistical a nal yses f or gl o bal st u d y of t his trial. F ull 
detail is pr o vi de d i n Secti o ns 3. 2 -3. 1 1 .  
St u d y Desi g n
O ver vie w
A P hase III St u d y of Car b o plati n -Paclita xel/ Na b -Paclita xel C he m ot hera p y
wit h or wit h o ut Pe m br oliz u ma b ( M K -3 4 7 5) i n First Li ne Metastatic
S q ua m o us N o n -s mall Cell L u n g Ca ncer S u bjects ( K E Y N O T E-4 0 7)
Tre at m e nt Assi g n me nt
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o recei ve pe m br oliz u ma b or sali ne place b o 
i n c o mbi nati o n wit h car b o plati n a n d a ta xa ne (i n vesti gat ors c h oice of paclita xel or na b -
paclita xel). Stratificati o n fact ors are i n Secti o n 5. 4 of t he pr ot oc ol . T his is a ra n d o mize d 
d o u ble -bli n de d st u d y.
A n al ysis P o p ul ati o ns
Efficac y: I nt e nt t o Trea t (I TT)
Safet y: All S u bjects as Treate d ( A Sa T)
Pri m ar y E n d p oi nts
1.
Pr o gressi o n -free S ur vi val 
( P FS)
per R E CI S T 
1. 1 assesse d b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or 
2.
O verall S ur vi val ( O S )
St atistic al Met h o ds
f or
Ke y Effic ac y A n al yses
T he d ual pri mar y h y p ot heses o n P F S a n d O S 
will b e e val uate d b y
c o mpari n g 
pe m br oliz u ma b t o sali ne place b o i n c o m bi nati o n wit h car b o plati n a n d a ta xa ne usi n g a 
stratifie d L o g -ra n k test. T he hazar d rati o will be esti mate 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 mate d wit hi n eac h treat me nt gr o u p 
u si n g t he Ka pla n -Meier met h o d. T he stratifie d M & N me t h o d wit h sa m ple size wei g hts 
will be use d f or a nal ysis of O R R.
St atistic al Met h o ds
f or
Ke y S afet y A n al yses
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h. T here are n o Tier 1 safet y 
para met ers i n t his trial. All safet y para meters are c o nsi dere d eit her Tier 2 or Tier 3. Tier 
2 para meters will be assesse d via p oi nt esti mates wit h 9 5 % c o nfi de nce i nter vals 
pr o vi de d f or bet w ee n -gr o u p c o m paris o ns; o nl y  poi nt esti mates b y  treat me nt gr o u p are 
pr o vi de d f or Tier 3 safet y para meters. T he bet w e e n -treat me nt differe nce will be
a nal yze d usi n g t he Mietti ne n a n d N ur mi ne n met h o d.
I n t he pri m ar y safet y c o mparis o n, s u bjects w h o cr oss o ver t o p e m br oliz u ma b ar e 
ce ns ore d at ti me of cr oss o ver (i.e., A Es occ ur ri n g d uri n g treat me nt wit h pe m br oliz u ma b 
are e xcl u de d f or c o ntr ol -ar m s u bjects). A n e x pl orat or y safet y a nal ysis will be c o n d ucte d 
 
 
0 5 G W B G
0 6 D V Z Q


M K- 3 4 7 5
P A G E 5
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
      2 9J A N 2 0 1 8 –  A M E N D M E N T # 0 4
f or t he cr oss o ver p o p ulati o n i ncl u di n g all safet y e ve nts starti n g fr o m t he date of t he first 
d ose of pe m br oliz u ma b.
I nteri m  A n al yses
T here are f o ur a nal yses pla n ne d f or t his st u d y: t hree i nteri m a nal yses a n d o ne fi nal a nal ysis. 
Res ults fr o m t he first t hree i nteri m a nal yses will be re vie we d b y a n e xter nal data m o nit ori n g 
c o m mittee. Details are pr o vi de d i n Secti o n 3. 7 .
I nteri m a nal ysis (I A) 1
o 
Ti mi n g: T o be perf or me d after ~ 2 0 0  s u bjects  ha ve  ~ 2 8  wee ks  of  
f oll o w- u p
o 
P ur p ose: T o de m o nstrate s u peri orit y of p e m br oliz u ma b i n c o m bi nati o n 
wit h car b o plati n a n d a ta xa ne i n O R R
I nteri m a nal ysis (I A) 2
o 
Ti mi n g: T o be perf or me d after a t ar g et n u m b er of P F S e ve nts ( ~ 3 3 2) 
is o bser ve d
o 
P ur p ose:  1)  T o  de m o nstrate  s u peri orit y  of  p e m br oliz u ma b i n  
c o m bi nati o n wit h car b o plati n a n d a ta xa ne i n P F S; 2) T o de m o nstrate 
s u peri orit y of pe m br oliz u ma b i n c o m bi nati o n wit h car b o plati n a n d a 
ta xa ne i n O S
I nteri m a nal ysis (I A) 3
o 
Ti mi n g: T o be perf or me d aft er a t ar g et n u m b er of P F S e ve nts ( ~ 4 1 5) 
is o bser ve d
o 
P ur p ose: 1)  T o  de m o nstrate  s u peri orit y  of  p e m br oliz u ma b i n  
c o m bi nati o n wit h car b o plati n a n d a ta xa ne i n P F S; 2) T o de m o nstrate 
s u peri orit y of p e m br oliz u ma b i n c o m bi nati o n wit h car b o plati n a n d a 
ta xa ne i n O S
M ulti plicit y
T he st u d y uses t he gra p hical  met h o d of Ma urer a n d Bretz [ 2 ] t o c o ntr ol  m ulti plicit y f or 
m ulti ple  h y p ot heses  as  well  as i nteri m  a nal yses.  Acc or di n g  t o  t his a p pr oac h, st u d y  
h y p ot heses ma y be teste d m ore t ha n o nce, a n d w he n a partic ular n ull h y p ot hesis is
rejecte d, t he al p ha all ocate d t o t hat h y p ot hesis ca n be reall ocate d t o ot her h y p ot hesis 
tests. T he  o verall  t y pe  I  err or  is  c o ntr olle d  at  0. 0 2 5  ( o ne-si de d)  f or  t he  h y p ot hesis  
testi n g of O R R, P F S a n d O S. T he pre-all ocate d al p ha is 0. 0 0 5, 0. 0 1 a n d 0. 0 1 f or O R R, 
P F S a n d O S, res pecti vel y. O R R ma y be teste d at 0. 0 0 5 or at 0. 0 2 5 (if b ot h P F S a n d O S 
are p ositi ve, usi n g t he p- val ue fr o m I A 1). P F S ma y be teste d at 0. 0 1 or at 0. 0 1 5 (if O R R 
is p ositi ve b ut O S n ot p ositi ve), or at 0. 0 2 (if O S is p ositi ve b ut  O R R n ot p ositi ve) or at 
0. 0 2 5 (if b ot h O S a n d O R R are p ositi ve). O S ma y be teste d at 0. 0 1 or at 0. 0 2 (if P F S is 
p ositi ve b ut O R R n ot p ositi ve) or 0. 0 2 5 (if b ot h P F S a n d O R R are p ositi ve).  A La n-
De Mets  O' Brie n- Fle mi n g  a p pr o xi mati o n  s pe n di n g  f u ncti o n  will  be  use d  f or  t he  
calc ulati o n of efficac y b o u n ds f or P F S a n d O S.
S a m ple 
Size 
a n d
P o w e r
T he fi nal a nal ysis occ urs after ~ 3 6 1 deat hs are o bser ve d u nless t he trial is ter mi nate d 
earl y. Wit h 3 6 1 deat hs, t he st u d y has ~ 9 2 % p o wer f or detecti n g a hazar d rati o ( H R) of 
0. 7 at 0. 0 2 5 ( o ne-si de d), ~ 9 0 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 ( o ne-si de d) a n d 
~ 8 5 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 1 ( o ne-si de d).
T he pla n ne d sa m ple size is a p pr o xi matel y 5 6 0 s u bjects ass u mi n g ~ 1 5. 5  m o nt hs of 
e nr oll me nt.
3. 2  
Res p o nsi bilit y f or A n al yses/I n- H o use Bli n di n g
T he statistical a nal ysis of t he data o btai ne d fr o m t his st u d y will be t he res p o nsi bilit y of t he 
Cli nical Bi ostatistics de part me nt of t he S p o ns or.


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T he S P O N S O R
will 
ge nerate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y treat me nt 
assi g n me nt f or t his pr ot oc ol, a n d t he ra n d o mizati o n will be i m ple me nte d i n I V R S. 
T his trial is d o u ble bli n de d wit h a cr oss o ver p hase. At t he ti me of d oc u me nte d pr o gressi o n,
s u bjects will ha ve treat me nt assi g n me nt u n bli n de d a n d be a ble t o c o nti n ue t hera py i n t he 
Cr oss o ver P hase ( please refer t o pr ot oc ol secti o n 2. 1 Trial Desi g n f or details). I n ad diti o n, 
i n de pe n de nt ce ntral ra di ol o gist(s) will perf or m t he ce ntral i ma gi n g re view wit h o ut k n o wle d ge of 
treat me nt assi g n me nt.
A n e xter nal data m o nit ori n g c o m mittee (e D M C) will be c o n ve ne d t o re vie w acc u m ulati n g safet y  
t o pr o vi de a n o p p ort u nit y  to ter mi nate t he st u d y earl y if t here are c o ncer ns re gar di n g safety. T he 
e D M C will als o re view t he u n bli n de d efficac y res ults at t he pla n ne d i nteri m a nal ys es. T he 
e D M C res p o nsi bilities a n d re vie w sc he d ules will be o utli ne d i n t he e D M C c harter. T he 
rec o m me n dati o n of t he e D M C will be c o m m u nicate d t o a n e xec uti ve o versi g ht c o m mittee of t he 
S p o ns or. I n t he e ve nt of a rec o m me n dati o n t o halt t he trial earl y due t o safet y co ncer ns, t he 
S p o ns or will c o m m u nicate t his t o t he a p pr o priate re g ulat or y age ncies. If t he e D M C rec o m me n ds 
m o dificati o ns t o t he desi g n of t he pr ot oc ol or disc o nti n uati o n of t he st u d y, t his e xec uti ve 
o versi g ht c o m mittee 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 li mite d n u m ber of 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, if re q uire d, i n or der t o 
act o n t he rec o m me n dati o ns of t he e D M C . T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o t he 
res ults will be d oc u me nte d. A d diti o nal l o gistical details, re visi o ns t o t he a b o ve pla n a n d data 
m o nit ori n g g ui da nce will be pr o vi de d i n t he e D M C C harter.
3. 3
H y p ot heses/ Esti m ati o n
3. 3. 1
Pri m ar y O bjecti ve(s) & H y p ot hesis(es)
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1.
O bjecti ve:
T o e val uate pr o gressi o n free s ur vi val ( P F S) per R E CI S T 1. 1 as assesse d b y  a 
ce ntral i ma gi n g ve n d or i n s u bjects treate d wit h Pe m br oliz u ma b c o m pare d t o place b o .
H y p ot hesis: P e m br oliz u ma b pr ol o n gs P F S b y  RE CI S T 1. 1 as assesse d b y  a ce ntral i ma gi n g 
ve n d or c o m pare d t o place b o.
2.
O bjecti ve: T o eval uate o verall s ur vi val ( O S) i n s u bjects treate d wit h Pe m br oliz u ma b 
c o m pare d t o place b o.
H y p ot hesis: Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o place b o .
3. 3. 2
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es)
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
 
 
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1.
O bjecti ve: T o e val uate t he o bjecti ve res p o nse rate ( O R R) a n d d urati o n of res p o nse ( D O R) 
per R E CI S T 1. 1 as assesse d b y  a ce ntral i ma gi n g ve n d or i n s u bjects treate d wit h 
Pe m br oliz u ma b c o m pare d t o place b o.
H y p ot hesis:
Pe m br oliz u ma b i m pr o ves O R R per R E CI S T 1. 1 as assesse d b y  a ce ntral 
i ma gi n g ve n d or c o m pare d t o place b o. 
2.
O bjecti ve: T o e val uate t he safet y a n d t olera bilit y pr ofile of Pem br oliz u ma b. 
3. 3. 3
E x pl or at or y O bjecti ves
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1) O bjecti ve: E val uate pe m br oliz u ma b c o m pare d t o place b o wit h res pect t o:
a.
P F S per R E CI S T 1. 1 as assesse d b y  in vesti gat or re vie w i n t he ne xt li ne of t hera py 
( P F S 2). 
b.
P F S per ir R E CI S T as assesse d b y  site i n vesti gat or.
c.
O R R a n d D urati o n of Res p o nse ( D O R) per ir R E CI S T as assesse d b y site i n vesti gat or.
d.
P F S a n d O R R per R E CI S T 1. 1 as assesse d b y ce ntral i ma gi n g ve n d or a n d O S b y  P D-
L 1 stat us ( ≥1 % vs. < 1 %) a n d b y  ta xa ne (i n vesti gat ors c h oice of paclita xel or na b -
paclita xel).
2) T o i n vesti gate t he relati o ns hi p bet wee n pe m br oliz u ma b treat me nt a n d bi o mar kers pre dicti n g 
res p o nse (e. g., P D -L 2, ge netic variati o n, ser u m s P D-L 1 ) utilizi n g ne wl y o btai ne d or arc hi val 
F F P E t u m or tiss ue a n d bl o o d, i ncl u di n g ser u m a n d plas ma.
3) T o e val uate c ha n ges i n healt h -relate d q ualit y- of- life assess me nts fr o m baseli ne i n t he o verall 
st u d y p o p ulati o n a n d b y P D-L 1  e x pressi o n le vel usi n g t he E O R T C Q L Q- C 3 0 a n d E O R T C Q LQ-
L C 1 3.
4) T o c haracterize utilities i n s u bjects treate d wit h pe m br oliz u ma b a n d c he m ot hera p y c o m pare d 
t o sali ne place b o a n d c he m ot hera py usi n g t he E ur o Q o L( E Q) -5 D.
5) T o c haracterize t he p har mac o ki netic c haracteristics of car b o plati n, paclita xel/ na b -paclita xel
treat me nt, a n d pe m br oliz u ma b.
6) T o i de ntif y 
molec ular ( ge n o mic, meta b olic 
a n d/ or pr ote o mic) bi o mar kers t hat m a y  be
i n dicati ve of cli nical res p o nse/resista nce, safet y, p har mac o d y na mic acti vit y, a nd/ or
t he 
mec ha nis m of acti o n of pe m br oliz u ma b a n d ot her treat me nts.
 
 
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3. 4
A n al ysis E n d p oi nts
3. 4. 1
Effic ac y E n d p oi nts
D u al Pri m ar y 
Pr o gressi o n -Free S ur vi v al –
R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or 
Pr o gressi o n -free-s ur vi val ( P F S) is def i ne d as t he ti me fr o m ra n d o mizati o n t o t he first
d oc u me nte d disease pr o gressi o n per R E CI S T 1. 1 base d o n bli n de d i n de pe n de nt ce ntral i ma gi n g 
ve n d or re vie w or deat h d ue t o a n y ca use, w hic he ver occ urs first. See Secti o n 3. 6. 1 f or t he 
ce ns ori n g r ules.
O ver all S ur vi v al
O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o deat h d ue t o a n y ca use. 
S u bjects wit h o ut d oc u me nte d deat h at t he ti me of t he a nal ys is will be ce ns ore d at t he date of t he 
last k n o w n c o ntact .
Sec o n d ar y
O bjecti ve Res p o nse R ate – R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al i ma gi n g 
ve n d or
O bjecti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of t he s u bjects w h o ha ve a c o nfir me d 
c o m plete res p o nse ( C R) or partial res p o nse ( P R). Res p o nses are base d o n c o nfir me d assess me nts
b y  t he bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or per R E CIS T 1. 1. 
D ur ati o n of Res p o nse ( D O R) - R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or
F or s u bjects w h o de m o nstrate d C R or P R, d urati o n of res p o nse ( D O R) is defi ne d as t he ti me
fr o m first d oc u me nte d e vi de nce of C R or P R u ntil disease pr o gressi o n or deat h. Res p o nse
d urati o n f or s u bjects w h o ha ve n ot pr o gresse d or die d at t he ti me of a nal ysis will be ce ns ore d at 
t he date of t heir last t u m or assess me nt. Res p o nse d urati o n will be calc ulate d f or R E CI S T 1. 1 
base d o n bli n de d i n de pe n de nt ra di ol o gists ’ re vie w.
3. 4. 2
S afet y E n d p oi nts
Safet y  meas ure me nts are descri be d i n Pr ot oc ol Secti o n 4. 2. 3. 4.
 
 
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3. 5
A n al ysis P o p ul ati o ns
3. 5. 1 
Effic ac y A n al ysis P o p ul ati o ns
T he i nte nti o n -t o-treat (I T T) p o p ulati o n will ser ve as t he p o p ulati o n f or pri mar y  efficac y a nal ysis. 
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.
A p pr o xi matel y  20 0 ra n d o mize d s u bjects are pla n ne d t o be i ncl u de d i n t he first i nteri m a nal ysis. 
Base d o n act ual e nr oll me nt, 2 0 4 s u bjects w h o were ra n d o mize d o n or pri or t o A pril 1 1 2 0 1 7 will 
be i ncl u de d i n t he I T T p o p ulati o n i n t he first i nteri m a nal ys is. Se ve nt y s u bjects w h o faile d 
scree ni n g o n or pri or t o A pr 1 1 2 0 1 7 i n a d ditio n t o t he 2 0 4 ra n d o mize d s u bjects will be i ncl u de d 
i n t he Scree ni n g P o p ulati o n.
3. 5. 2
S afet y A n al ysis P o p ul ati o ns
T he All S u bjects as Treate d ( A Sa T) p o p ulati o n will be use d f or t he a nal y sis of safet y data i n t his 
st u d y. T he A Sa T p o p ulati o n c o nsists of all ra n d omize 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 s u bject w h o recei ves t he i nc orrect 
st u d y me dicati o n f or o ne c ycle b ut recei ves t he c orrect treat me nt f or all ot her c ycles will be 
a nal yz e d acc or di n g t o t he s u bject’s ra n d o mize d treat me nt gr o u p a n d a narrati ve will be pr o vi de d 
f or a ny e ve nts t hat occ ur d uri n g t he c y cle f or w hic h t he s u bject was 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.
F or t he first i nteri m a nal ysis, a m o n g t he I T T p o p ulati o n of 2 0 4 s u bjects, 2 0 3 of t he m recei ve d at 
least o ne d ose of st u dy treat me nt a n d t h us will be i ncl u de d i n t he A Sa T p o p ulati o n.
3. 6
St atistic al Met h o ds
3. 6. 1
St atistic al Met h o ds f or Effic ac y A n al yses
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 3. 8 , M ulti plicit y . N o mi nal p - val ues will be 
c o m p ute d f or ot her efficac y 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.
All statistical tests, u nless ot her wise s pecifie d, will be stratifie d f or treat me nt a n d stratificati o n 
fact ors.
 
 
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3. 6. 1. 1
Pr o gressi o n -Free S ur vi v al ( P F S)
T he n o n- para metric Ka pla n -Meier 
met h o d will be use d t o esti mate t he P F S c ur ve i n eac h 
treat me nt gr o u p. T he treat me nt differe nce i n P F S will be assesse d b y  the stratifie d l o g-ra n k test
( base d o n t he stratificati o n fact ors defi ne d i n Pr ot oc ol Secti o n 5. 4). A stratifie d C o x pr o p orti o nal 
hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he ma g nit u de of t he 
treat me nt differe nce (i.e., hazar d rati o) bet wee n t he treat me nt ar ms. T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h Efr o n's met h o d of tie ha n dli n g a n d wit h a 
si n gle treat me nt c o variate will 
be re p orte d. T he 
sa me stratificati o n fact ors use d f or 
ra n d o mizati o n will be a p plie d t o b ot h t he stratifie d l o g-ra n k test a n d t he stratifie d C o x m o del. 
F or t he first i nteri m a nal y sis, d ue t o t he s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b-
paclita xel a n d East Asia, t his strat u m will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d 
paclita xel a n d E ast Asia i n stratifie d a nal ys es. 
Si nce disease pr o gressi o n is assesse d peri o dicall y , pr o gressi ve disease ( P D) ca n occ ur a n y ti me 
i n t he ti me i nter val bet wee n t he last assess me nt w here P D was n ot d oc u me nte d a n d t he 
assess me nt w he n P D is d oc u me nte d. F or t he pri mar y an al y sis, f or t he s u bjects w h o ha ve P D, t he 
tr ue date of disease pr o gressi o n will be a p pr o xi mate d b y t he date of t he first assess me nt at w hic h 
P D is o bjecti vel y  d oc u me nte d per R E CI S T 1. 1 b y  a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or, 
re gar dless of disc o nti n uati o n of st u d y dr u g. Deat h is al wa ys c o nsi dere d as a c o nfir me d P D e ve nt. 
Se nsiti vit y  anal ys es will 
be perf or me d f or c o m paris o n of P F S base d o n i n vesti gat or’s 
assess me nt. 
I n or der t o e val uate t he r o b ust ness of t he P F S e n d p oi nt per R E CI S T 1. 1 b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or, we will perf or m t w o se nsiti vit y a nal yses wit h a differe nt set 
of ce ns ori n g r ules. T he first se nsiti vit y anal y sis is t he sa me as t he pri mar y  anal ys is e xce pt t hat it 
ce ns ors at t he last disease assess me nt wit h o ut P D w he n P D or deat h is d oc u me nte d after m ore 
t ha n o ne misse d disease assess me nt. T he sec o n d se nsiti vit y anal ys is is t he sa me as t he pri mar y 
a nal ys is e xce pt t hat it c o nsi ders disc o nti n uati o n of treat me nt or i nitiati o n of ne w a ntica ncer 
treatme nt, w hic he ver occ urs later, t o be a P D e ve nt f or s u bjects wit h o ut d oc u me nte d P D or 
deat h. T he ce ns ori n g r ules f or pri mar y  an d se nsiti vit y anal ys es are s u m marize d i n Ta ble 1 . I n 
case t here is a n i m bala nce bet wee n t he treat me nt gr o u ps o n disease assess me nt sc he d ules or 
ce ns ori n g patter ns, we will 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 nalys es: 1) 
a P F S a nal y sis usi n g ti me t o sc he d ule d t u m or assess ment 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’s li keli h o o d-base d sc ore test f or i nter val-ce ns ore d 
data [4 ] 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 ysis 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 ght 
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 earlier. I n case t he 
pr o p orti o nal hazar ds ass u m pti o n d oes n’t h ol d, Fle mi n g a n d Harri n gt o n’s wei g hte d l o g-ra n k test, 
Restricte d Mea n 
S ur vi val Ti me ( R M S T) met h o d or ot her met h o ds, as a p pr o priate, m a y  be 
c o n d ucte d.
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 1
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 1
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S
Sit uati o n
Pri mar y A nal ysis
Se nsiti vit y
A nal ysis 1
Se nsiti vit y
A nal ysis 2
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is n ot 
i nitiate d
Ce ns ore d at last 
disease 
assess me nt 
Ce ns ore d at last 
disease assess me nt 
Ce ns ore d at last disease 
assess me nt if still o n 
st u d y t hera p y; pr o gresse d 
at treat me nt 
disc o nti n uati o n ot her wise
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is i nitiate d
Ce ns ore d at last 
disease 
assess me nt bef ore 
ne w a ntica ncer 
treat me nt
Ce ns ore d at last 
disease assess me nt 
bef ore ne w  
a ntica ncer treat me nt
Pr o gresse d at date of ne w  
a ntica ncer treat me nt
N o P D a n d n o deat h; 
≥ 2 c o nsec uti ve 
misse d disease 
assess me nts
Ce ns ore d at last 
disease 
assess me nt
Ce ns ore d at last 
disease assess me nt 
pri or t o ≥2 
c o nsec uti ve misse d 
visits
Ce ns ore d at last disease 
assess me nt
P D or deat h 
d oc u me nte d after ≤1 
misse d disease 
assess me nt
Pr o gresse d at date 
of d oc u me nte d 
P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or 
deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
P D or deat h 
d oc u me nte d after ≥2 
misse d disease 
assess me nts
Pr o gresse d at date 
of d oc u me nte d 
P D or deat h
Ce ns ore d at last 
disease assess me nt 
pri or t o t he  ≥2 
misse d disease 
assess me nt
Pr o g resse d at date of 
d oc u me nte d P D or deat h
3. 6. 1. 2
O ver all S ur vi v al ( O S)
T he n o n- para metric Ka pla n -Meier met h o d will be use d t o esti mate t he s ur vi val c ur ves. T he 
treat me nt differe nce i n s ur vi val will be assesse d b y  the stratifie d l o g-ra n k test. A stratifie d C o x 
pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d f or ra n d o mizati o n will be a p plie d t o b ot h t he 
stratifie d l o g-ra n k test a n d t he stratifie d C o x m o del.
F or t he first i nteri m a nal ysis, d ue t o t he 
s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b -paclita xel a n d East Asia, t his strat u m 
will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d paclita xel a n d East Asia i n stratifie d 
a nal ys es. T he Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d ma y  be c o n d ucte d f or O S t o 
acc o u nt f or t he p ossi ble n o n- pr o p orti o nal hazar ds effect a n d t o esti mate t he a bs ol ute be nefit of 
e x peri me ntal treat me nt. A c ure rate m o del ma y  be a p plie d t o esti mate t he l o n g-ter m effect.
Si nce s u bjects i n t he c o ntr ol ar m are all o we d t o s witc h t o t he pe m br oliz u ma b treat me nt after
pr o gres si ve disease, a dj ust me nt f or t he effect of cr oss o ver o n O S m a y  be perf or me d base d o n 
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 2
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
rec o g nize d met h o ds, e. g., a t w o-sta ge met h o d or t he Ra n k Preser vi n g Str uct ural 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 [3 ], base d o n a n e xa mi nati o n of t he 
a p pr o priate ness of t he data t o t he ass u m pti o ns re q uire d b y t he met h o ds.
3. 6. 1. 3
O bjecti ve Res p o nse R ate ( O R R) a n d D ur ati o n of Res p o nse ( D O R)
T he stratifie d Mietti ne n a n d N ur mi ne n’s met h o d [5 ] wit h wei g hts pr o p orti o nal t o t he strat u m 
size will be use d f or c o m paris o n of t he O R R bet wee n t he treat me nt ar ms. T he differe nce i n O R R 
a n d its 9 5 % c o nfi de nce i nter val fr o m t he stratifie d Mie tti ne n a n d N ur mi ne n met h o d wit h strata 
wei g hti n g b y  sa m ple size wit h
a si n gle treat me nt c o variate will be re p orte d. T he stratificati o n 
fact ors use d f or ra n d o mizati o n ( See Pr ot oc ol Secti o n 5. 4) will be a p plie d t o t he a nal ys is. F or t he 
first i nteri m a nal ysis, d ue t o t he s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b -
paclita xel a n d East Asia, t his strat u m will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d 
paclita xel a n d East Asia i n stratifie d a nal ys es.
If sa m ple size per mits, D O R will be s u m marize d d escri pti vel y usi n g Ka pla n -Meier me dia ns a n d 
q uartiles. O nl y  the s u bset of patie nts w h o s h o w a c o m plete res p o nse or partial res p o nse will be 
i ncl u de d i n t his a nal ysis.
F or eac h D O R a nal ys is, a c orres p o n di n g s u m mar y of t he reas o ns res p o n di n g s u bjects are 
cens ore d will als o be pr o vi de d.  Res p o n di n g s u bjects w h o are ali ve, ha ve n ot pr o gresse d, ha ve 
n ot i nitiate d ne w a nti-ca ncer treat me nt, ha ve n ot bee n deter mi ne d t o be l ost t o f oll o w- u p, a n d 
ha ve ha d a disease assess me nt wit hi n ~ 5 m o nt hs of t he data c ut off dat e are c o nsi dere d o n g oi n g 
res p o n ders at t he ti me of a nal ys is.  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.
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 3
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 2 
Ce ns ori n g R ules f or D O R
Sit uati o n
Date 
of 
Pr o gressi o n 
or 
Ce ns ori n g
O utc o me
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 a nti-
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 after ≥ 2 
c o nsec uti ve 
misse d 
disease 
assess me nts
Last 
a de q uate 
disease 
assess me nt pri or t o ≥ 2 misse d 
a de q uate disease assess me nts
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n after ≤ 1 
miss e d disease assess me nts
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.  
3. 6. 1. 4
A n al ysis Str ate g y f or Ke y Effic ac y E n d p oi nts
Ta ble 3 s u m marizes t he pri mar y  anal ys is a p pr oac h f or pri mar y  an d ke y  sec o n dar y efficac y 
e n d p oi nts. Se nsiti vit y a nal ysis met h o ds are descri be d a b o ve f or eac h e n d p oi nt a s a p plica ble.
T he strate g y  t o 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, a n d i nteri m 
a nal ys es is descri be d i n Secti o n 3. 7 I nteri m A naly ses a n d i n Secti o n 3. 8 M ulti plicit y .
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 4
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 3
A nal y sis Strate g y  f or Ke y Efficac y E n d p oi nts
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
A n al ysis 
P o p ul ati o n
Missi n g D at a A p pr o ac h
D u al Pri m ar y E n d p oi nt s
P F S per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T

Pri mar y ce ns ori n g r ule

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
O S
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T
M o del base d
(ce ns ore d at t he last date t he 
s u bject was k n o w n t o be 
ali ve)
Ke y S ec o n d ar y E n d p oi nt s
O R R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test a n d Esti mati o n : 
Stratifie d M & N met h o d wit h 
sa m ple size wei g hts † †
I T T
S u bjects wit h o ut assess me nts 
are c o nsi dere d n o n-
res p o n ders a n d 
c o nser vati vel y i ncl u de d i n 
de n o mi nat or
D O R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Descri pti ve statistics f or 
ra n ge a n d  Ka pla n-Meier 
esti mate of me dia n
Patie nts i n I T T 
p o p ulati o n wit h 
a n o bjecti ve 
res p o nse
  †
Statistical m o dels are descri be d i n f urt her detail i n t he te xt. F or stratifie d a nal yses, t he stratificati o n fact ors 
use d f or ra n d o mizati o n (Secti o n 5. 4) will be a p plie d t o t he a nal ysis. 
† †
Mietti ne n a n d N ur mi ne n met h o d
3. 6. 1. 5 
E x pl or at or y A n al yses
A n e x pl orat or y anal ys is of P F S 2, defi ne d as t he ti me fr o m ra n d o mizati o n t o s u bse q ue nt disease 
pr o gressi o n after i nitiati o n of ne w a nti-ca ncer t hera p y, o r deat h fr o m a n y ca use, w hic he ver first, 
ma y  be carrie d o ut. Patie nts ali ve a n d f or w h o m a disease pr o gressi o n f oll o wi n g i nitiati o n of ne w 
a nti-ca ncer treat me nt has n ot bee n o bser ve d will be ce ns ore d at t he last ti me t he s u bject was 
k n o w n t o be ali ve a n d wit h o ut disease pr o gressi o n
 
 
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0 6 D V Z Q


M K -3 4 7 5
P A G E 1 5
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 6. 2
St atistic al Met h o ds f or S afet y A n al yses
Safet y  an d t olera bilit y will be assesse d b y  cli nical re vie w of all rele va nt para meters i ncl u di n g 
a d verse e x perie nces ( A Es), la b orat or y tests a n d vital si g ns.
A d verse E ve nts
A d verse e ve nts ( A Es) will be c o de d usi n g t he sta n dar d Me d D R A a n d gr o u pe d s yste m or ga n 
class. A d verse e ve nts ( A Es) will be gra de d b y  the i n vesti gat or acc or di n g t o t he C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E), versi o n 4. 0.
Tiere d A p pr o ac h
T he a nal y sis of safet y res ults will f oll o w a tiere d a p pr oac h (Ta ble 4 ). T he tiers differ wit h res pect 
t o t he a nal yses t hat will be perf or me d. “ Tier 1” safet y en d p oi nts will be s u bject t o i nfere ntial 
testi n g f or statistical si g nifica nce wit h p- val ues a n d 9 5 % c o nfi de nce i nter vals pr o vi de d f or 
bet wee n -gr o u p c o m paris o ns. F or t his pr ot oc ol, t here are n o Tier 1 A Es. Ot her safety para meters 
will be c o nsi dere d Tier 2 or Tier 3. Tier 2 para meters w ill 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  poi 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.
A d verse e x perie nces (s pecific ter ms as well as s yste m or ga n class ter ms) t hat are n ot pre -
s pecifie d as Tier 1 e n d p oi nts will be 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 of 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  95 % c o nfi de nce i nter vals m a y  be pr o vi de d 
wit h o ut a dj ust me nt f or m ulti plicit y , t he c o nfi de nce i nter vals s h o ul d be re gar de d as a hel pf ul 
descri pti ve meas ure t o be use d i n re vie w, n ot a f or mal met h o d f or assessi n g t he statistical 
si g nifica nce of t he bet wee n -gr o u p differe nces i n a d verse e x perie nces a n d pre defi ne d li mits of 
c ha n ge.
C o nti n u o us meas ures s uc h as c ha n ges fr o m baseli ne i n la b orat or y val ues a n d vital si g ns, a n d 
E C G para meters will be c o nsi dere d Tier 3 safet y para meters. S u m mar y  statistics f or baseli ne, 
o n- treat me nt, a n d c ha n ge fr o m baseli ne val ues will be pr o vi de d b y  treat me nt gr o u p i n ta ble 
f or mat. 
T o pr o pe rly 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 n a nal ysis of Gra de 3- 5 A Es will be base d 
o n t he ti me t o first e ve nt usi n g t he ti me-t o-e ve nt a nal ys is met h o ds (i.e., t he l o g-ra n k test will be 
use d f or testi n g t he ti me t o A Es, a n d t he C o x m o del wit h Efr o n's tie ha n dli n g met h o d will be 
use d f or esti mati n g t he hazar d rati o a n d its 9 5 % c o nfi de nce i nter val). F or ot her A Es wit h 
p ote ntiall y  differe ntial f oll o w- u p ti me, s uc h a nal ysis ma y  als o be e x pl ore d.
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 6
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
I n ad diti o n, 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 A E, a n y dr u g-relate d A E, a n y Gra de 3- 5 A E, a n y seri o us A E, a n y A E w hic h 
is b ot h dr u g relate d a n d Gra de 3- 5, a n y A E w hic h is b ot h seri o us a n d dr u g -relate d, 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. 9 5 % c o nfi de nce i nter vals ( Tier 2) will be pr o vi de d f or bet wee n -treat me nt 
differe nces i n t he perce nta ge of s u bjects wit h e ve nts; t hese a nal y ses will be perf or me d usi n g t he 
u nstratifie d Mietti ne n a n d N ur mi ne n met h o d
[5 ], a n u nc o n diti o nal, asy m pt otic met h o d . 
Ta ble 4
A nal y sis Strate g y  f or Safet y Para meters
Safet y Tier
Safet y E n d p oi nt
p -Val ue
9 5 % CI f or 
Treat me nt 
C o m paris o n
Descri pti ve 
Statistics
Tier 2
A n y A E
X
X
A n y Gra de 3 -5 A E
X
X
A n y Seri o us A E
X
X
O nset of First 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 Es, S O Cs (i ncl u di n g ≥4 of s u bjects i n o ne 
of t he treat me nt gr o u ps)
X
X
Tier 3
S pecific A Es, S O Cs (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
T here are n o Tier 1 A Es pre- s pecifie d i n t his pr ot oc ol.
3. 6. 3
S u m m aries of B aseli ne C h ar acteristics, De m o gr a p hics, a n d Ot her A n al yses
T he c o m para bilit y of t he treat me nt gr o u ps f or eac h rele va nt baseli ne c haracteristic will b e 
assesse d b y  the use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n 
t hese c haracteristics. T he n u m ber a n d perce nta ge of s u bjects ra n d o mize d 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 (s uc h as a ge) a n d baseli ne 
c haracteristics will be s u m marize d b y  treat me nt eit her b y  descri pti ve statistics or cate g orical 
ta bles.
3. 7
I nteri m A n al ysis
T here are t hree pla n ne d i nteri m a nal yses (I A) i n a d diti o n t o t he fi nal a nal ysis f or t his st u d y. 
Details o n t he b o u n daries f or esta blis hi n g statistical si g nifica nce wit h re gar d t o efficac y are 
disc usse d f urt her i n Secti o n 3. 8 .  T he trial will c o nti n ue u ntil t he n u m ber of deat hs ( See Secti o n 
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 7
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 9 ) is a p pr o xi matel y eq ual t o t he tar gete d n u m ber f or t he fi nal a nal ysis , irres pecti ve of t he 
o utc o me fr o m t he i nteri m a nal ys es. T he a nal ys es pla n ne d, e n d p oi nts e val uate d, a n d dri vers of 
ti mi n g are s u m marize d i n Ta ble 5 .
Ta ble 5
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y
A n al yses 
Ke y 
E n d p oi nts 
Ti mi n g
Esti m ate d Ti me after 
First P artici p a nt 
R a n d o mize d 
Pri m ar y P ur p ose of A n al ysis
I A 1
O R R
~ 2 0 0 s u bjects are f oll o w e d 
f or ~ 2 8 wee ks s o t hat eac h 
patie nt has at least 4 t u m or 
assess me nts
~ 1 5 m o nt hs 
De m o nstrate O R R 
s u peri orit y
I A 2
P F S
O S
~ 3 3 2 P F S e ve nts ha ve bee n 
o bser ve d.
~ 2 0 m o nt hs 
De m o nstrate P F S s u peri orit y
De m o nstrate O S  s u peri orit y
I A 3
P F S
O S
~ 4 1 5 P F S e ve nts ha ve bee n 
o bser ve d 
~ 2 5 m o nt hs
De m o nstrate P F S s u peri orit y
De m o nstrate O S  s u peri orit y
Fi nal 
A nal ysis
O S
~ 3 6 1 deat hs ha ve occ urre d . 
~ 3 1 m o nt hs 
De m o nstrate O S  s u peri orit y
3. 8
M ulti plicit y
T he st u d y uses t he gra p hical met h o d of Ma urer a n d Bretz [2 ] t o c o ntr ol m ulti plicit y  for m ulti ple 
h y p ot heses as well as i nteri m a nal yses. Acc or di n g t o t his a p pr oac h, st u d y hy p ot heses m a y  be 
teste d m ore t ha n o nce, a n d w he n a partic ular n ull h y p ot hesis is rejecte d, t he al p ha all ocate d t o 
t hat h y p ot hesis ca n be reall ocate d t o ot her h y p ot hesis tests. Fi g ure 1 s h o ws t he i nitial o ne- si de d 
al p ha all ocati o n f or eac h h 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.
 
 
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P A G E 1 8
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
      2 9J A N 2 0 1 8 –  A M E N D M E N T # 0 4
N ote: If b ot h P F S a n d O S n ull h y p ot heses are rejecte d, t he reall ocati o n strate g y all o ws re-testi n g of O R R at al p ha = 0. 0 2 5 base d o n t he p- val ue at 
I A 1
O R R = o bjecti ve res p o nse rate; O S = o verall s ur vi val; P F S = pr o gressi o n-free s ur vi val
Fi g ure 1 
T y pe I Err or Reall ocati o n Strate g y F oll o wi n g Cl ose d Testi n g Pri nci ple
3. 8. 1  
O bjecti ve Res p o nse R ate
T he st u d y all ocates al p ha = 0. 0 0 5, o ne-si de d, t o tes t O R R, a n d O R R is teste d o nl y at t he first 
i nteri m a nal ysis (I A 1). H o we ver, if t he test d oes n ot reac h statistical si g nifica nce at I A 1, t he p-
val ue fr o m I A 1 ca n be c o m pare d t o a n u p date d al p ha-le vel if t he n ull h y p ot heses f or b ot h P F S 
a n d O S are rejecte d at a later ti me. P o wer at t he p ossi ble al p ha-le vels as well as t he a p pr o xi mate 
treat me nt  differe nce  re q uire d  t o  reac h  t he  b o u n d  ( O R R differe nce)  are  s h o w n  i n Ta ble  6 , 
ass u mi n g  u n derl yi n g  2 5 %  a n d  5 0 %  res p o nse  rates  i n  t he  c o ntr ol  a n d  e x peri me ntal  gr o u ps,  
res pecti vel y. 
Ta ble 6 
P ossi ble Al p ha-le vels a n d A p pr o xi mate O R R differe nce Re q uire d t o De m o nstrate 
Efficac y f or O R R at I A 1
Al p h a
O R R differe nce
P o wer
0. 0 0 5
~ 0. 1 8
0. 8 4
0. 0 2 5
~ 0. 1 3
0. 9 4


M K -3 4 7 5
P A G E 1 9
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 8. 2
Pr o gressi o n -free S ur vi v al
T he i nitial al p ha -le vel f or testi n g P F S is 0. 0 1. If t he n ull h yp ot hesis f or O R R is rejecte d, Fi g ure 1
s h o ws t hat its al p ha = 0. 0 0 5 is f ull y reall ocate d t o P F S h y p ot hesis testi n g. If t he n ull h y p ot hesis 
f or O S is rejecte d, t he n al p ha = 0. 0 1 is esse ntiall y full y reall ocate d t o P F S h y p ot hesis testi ng. 
T h us, t he P F S n ull h y p ot hesis ma y  be teste d at al p ha = 0. 0 1, al p ha = 0. 0 1 5 (if t he O R R n ull 
h y p ot hesis is rejecte d b ut n ot t he O S n ull h y p ot hesis), al p ha = 0. 0 2 (if t he O S n ull h y p ot hesis is 
rejecte d b ut n ot t he O R R n ull h y p ot hesis), or al p ha = 0. 0 2 5 (if b ot h the O R R a n d O S n ull 
h y p ot heses are rejecte d). Ta ble 7 s h o ws t he b o u n dar y pr o perties f or eac h of t hese al p ha -le vels 
f or t he i nteri m a nal ys es, w hic h were deri ve d usi n g a La n -De Mets O' Brie n -Fle mi n g s pe n di n g 
f u ncti o n. N ote t hat t he fi nal r o w i n dicates the t otal p o wer t o reject t he n ull h y p ot hesis f or P F S at 
eac h al p ha -le vel. If t he act ual n u m ber of e ve nts at t he P F S a nal yses differ fr o m t h ose s pecifie d i n 
t he ta ble, t he b o u n ds will be a dj uste d usi n g t he La n -De Mets O' Brie n -Fle mi n g s pe n di n g f u ncti o n 
acc or di n gl y. Als o n ote t hat if t he O S n ull h y p ot hesis is rejecte d at a n i nteri m or fi nal a nal ysis, 
eac h P F S i nteri m a n d fi nal a nal ysis test ma y  be c o m pare d t o its u p date d b o u n ds c o nsi deri n g t he 
al p ha reall ocati o n fr o m t he O S h y p ot hesis .
Ta ble 7
Efficac y  B o u n daries a n d Pr o perties f or Pr o gressi o n-free S ur vi val A nalys es
A n al ysis
V al ue
= 0. 0 1
= 0. 0 1 5
= 0. 0 2
= 0. 0 2 5
I A 2 : 8 0 % *
N: 5 6 0
E ve nts: 3 3 2
M o nt h: 2 0
Z
-2. 6 5 3 9
-2. 4 8 1 7
-2. 3 5 3 6
-2. 2 5 0 4
p ( 1 -si de d) §
0. 0 0 4
0. 0 0 6 5
0. 0 0 9 3
0. 0 1 2 2
H R at b o u n d 
0. 7 4 7 3
0. 7 6 1 6
0. 7 7 2 3
0. 7 8 1 1
P( Cr oss) if H R = 1 †
0. 0 0 4
0. 0 0 6 5
0. 0 0 9 3
0. 0 1 2 2
P( Cr oss) if H R = 0. 7 #
0. 7 2 4 3
0. 7 7 8 7
0 . 8 1 4 8
0. 8 4 1 1
I A 3 : 1 0 0 % *
N: 5 6 0
E ve nts: 4 1 5
M o nt h: 2 5
Z
-2. 3 7 3 7
-2. 2 2 4 4
-2. 1 1 3 8
-2. 0 2 5
p ( 1 -si de d) §
0. 0 0 8 8
0. 0 1 3 1
0. 0 1 7 3
0. 0 2 1 4
H R at b o u n d 
0. 7 9 2 1
0. 8 0 3 8
0. 8 1 2 6
0. 8 1 9 7
P( Cr oss) if H R = 1 †
0. 0 1
0. 0 1 5
0. 0 2
0. 0 2 5
P( Cr oss) if H R = 0. 7 #
0. 9
0. 9 2 4 3
0. 9 3 9 2
0. 9 4 9 4
* P e rce nta ge of e x pecte d nu m ber of e ve nts at fi nal a nal ysis re q uire d at i nteri m a nal ysis
§p ( 1 -si de d) is t he n o mi nal al p ha f or testi n g.
H R at b o u n d is t he a p pr o xi mate H R re q uire d t o reac h a n efficac y b o u n d
†P( Cr oss if H R = 1) is t he c u m ulati ve pr o ba bil it y of cr ossi n g a b o u n d u n der t he n ull h y p ot hesis
#P( Cr oss if H R = 0. 7) is t he c u m ulati ve pr o ba bil it y of cr ossi n g a b o u n d u n der t he alter nati ve h y p ot hesis
3. 8. 3
O ver all S ur vi v al
T he O S h y p ot hesis ma y  be teste d at al p ha = 0. 0 1 (i nitiall y all ocate d al p ha), al p ha= 0. 0 2 (if t he P F S 
b ut n ot t he O R R n u ll h y p ot hesis is rejecte d), or al p ha= 0. 0 2 5 (if b ot h t he O R R a n d P F S n ull 
h y p ot heses are rejecte d). Ta ble 8 de m o nstrates t he b o u n ds a n d b o u n dar y  pr o perties f or O S 
h y p ot h esis testi n g deri ve d usi n g a La n -De Mets O' Brie n - Fle mi n g s pe n di n g f u ncti o n. If t he act ual 
n u m ber of O S e ve nts at t he i nteri m a n d fi nal a nal yses differs fr o m t h ose s pecifie d i n t he ta ble, 
the b o u n ds
will 
be a dj uste d usi n g t he La n -De Mets 
O' Brie n -Fle mi n g s pe n di n g f u ncti o n 
acc or di n gl y.
 
 
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P A G E 2 0
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 8
Efficac y  B o u n daries a n d Pr o perties f or O verall S ur vi val A nalys es
A n al ysis
V al ue
= 0. 0 1
= 0. 0 2
= 0. 0 2 5
I A 2 : 5 9 % *
N: 5 6 0
E ve nts: 2 1 2
M o nt h: 2 0
Z 
-3. 1 6 4 8
-2. 8 2 0 2
-2. 7 0 2
p ( 1 -si de d) §
0. 0 0 0 8
0. 0 0 2 4
0. 0 0 3 4
H R at b o u n d 
0. 6 4 7 4
0. 6 7 8 8
0. 6 8 9 9
P( Cr oss) if H R = 1 †
0. 0 0 0 8
0. 0 0 2 4
0. 0 0 3 4
P( Cr oss) if H R = 0. 7 #
0. 2 8 4 9
0. 4 1 1 5
0. 4 5 8
I A 3 : 7 9 % *
N: 5 6 0
E ve nts: 2 8 6
M o nt h: 2 5
Z 
-2. 6 9 1 4
-2. 3 9 9 2
-2. 2 9 9 5
p ( 1 -si de d) §
0. 0 0 3 6
0. 0 0 8 2
0. 0 1 0 7
H R at b o u n d 
0. 7 2 7 4
0. 7 5 3 0
0. 7 6 1 9
P( Cr oss) if H R = 1 †
0. 0 0 3 8
0. 0 0 9
0. 0 1 1 7
P( Cr oss) if H R = 0. 7 #
0. 6 3 1 2
0. 7 3 6 2
0. 7 6 8 4
Fi nal 
N: 5 6 0
E ve nts: 3 6 1
M o nt h: 3 1
Z 
-2. 3 7 4 2
-2. 1 1 6
-2. 0 2 8
p ( 1 -si de d) §
0. 0 0 8 8
0. 0 1 7 2
0. 0 2 1 3
H R at b o u n d 
0. 7 7 8 9
0. 8 0 0 3
0. 8 0 7 8
P( Cr oss) if H R = 1 †
0. 0 1
0. 0 2
0. 0 2 5
P( Cr oss) if H R = 0. 7 #
0. 8 5
0. 9 0 3 4
0. 9 1 8 1
* Perce nta ge of e x pecte d n u m ber of e ve nts at fi nal a nal ysis re q uire d at i nteri m a nal ysis
§p ( 1 -si de d) is t he n o mi nal α f or testi n g.
H R at b o u n d is t he a p pr o xi mate H R re q uire d t o reac h a n efficac y b o u n d
†P( Cr oss if H R = 1) is t he c u m ulati ve pr o ba bili t y of cr ossi n g a b o u n d u n der t he n ull h y p ot hesis
#P( Cr oss if H R = 0. 7) is t he c u m ulati ve pr o ba bili t y of cr ossi n g a b o u n d u n der t he alter nati ve h y p ot hesis
3. 9
S a m ple Size a n d P o wer C alc ul ati o ns
Wit h ~ 2 0 0 s u bjects, the st u d y h as ~ 8 4 % p o wer f or detecti n g a 2 5 % differe nce i n O R R ( 5 0 % vs 
2 5 %) or ~ 9 7 % p o wer f or detecti n g a 3 0 % differe nce i n O R R ( 5 0 % vs. 2 0 %) at i nitiall y assi g ne d 
0. 0 0 5 ( o ne-si de d) si g nifica nce le vel. T he st u d y has ~ 9 4 % p o wer f or detecti n g a 2 5 % differe nce 
i n O R R ( 5 0 % vs 2 5 %) or ~ 9 9 % p o wer f or detecti n g a 3 0 % differe nce i n O R R ( 5 0 % vs 2 0 % ) at 
0. 0 2 5 ( o ne -si de d) si g nifica nce le vel. 
Wit h
4 1 5 P F S e ve nts, t he st u d y has ~ 9 0 % p o wer f or detecti n g a H R of 0. 7 at i nitiall y assi g ne d 
0. 0 1 ( o ne-si de d) si g nifica nce le vel, ~ 9 2 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 1 5 ( o ne-si de d)
si g nifica nce le vel, ~ 9 4 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 ( o ne-si de d) si g nifica nce le vel, 
a n d ~ 9 5 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 5 ( o ne-si de d) si g nifica nce le vel. 
Wit h
3 6 1 deat hs, t he st u d y has ~ 8 5 % p o wer f or detecti n g a hazar d rati o ( H R) of 0. 7 at 0. 0 1
( o ne-si de d) si g nifica nce le vel, ~ 9 0 % p o wer f or detecti n g a H R of 0. 7 at 0. 0 2 ( o ne-si de d) 
 
 
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P A G E 2 1
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S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
si g nifica nce le vel, a n d ~ 9 2 % p o wer f or det ecti n g a H R of 0. 7 at 0. 0 2 5 ( o ne-si de d) si g nifica nce 
le vel.
T he pla n ne d sa m ple size is a p pr o xi matel y 56 0 s u bjects ass u mi n g: ( 1) t he e nr oll me nt peri o d is 
1 5. 5 m o nt hs a n d t he ra m p- u p peri o d of e nr oll me nt is 7 m o nt hs; ( 2) me dia n P F S is 6 m o nt hs i n 
t he c o ntr ol gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 3) me dia n O S is 1 2 m o nt hs i n t he c o ntr ol 
gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 4) t he a n n ual dr o p o ut rate is 3 % f or P F S a n d 1 % f or O S; 
( 5) t he n u m ber of e ve nts a n d al p ha le vels of i nteri m a nal yses a n d fi nal a nal ys is are as s pecifie d 
i n Secti o n 3. 7 a n d Secti o n 3. 8 .
3. 1 0
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
T o deter mi ne w het her t he treat me nt effect is c o nsiste nt acr oss vari o us s u b gr o u ps, t he bet wee n -
gr o u p treat me nt effect ( wit h a n o mi nal 9 5 % CI) will be esti mate d a n d pl otte d wit hi n eac h 
cate g or y of t he f oll o wi n g classificati o n varia bles:

A ge cate g or y  (< 6 5 vs. ≥6 5 y ears, a n d < 6 5 vs. 6 5 -7 4 vs. 7 5 -8 4 vs. ≥8 5 y ears)

Se x (fe male vs. male)

Race ( w hite vs. n o n -w hite)

E C O G stat us ( 0 vs. 1)

Ge o gra p hic re gi o n of e nr olli n g site (East Asia vs. N o n- East Asia ; U S vs. E x -U S; E U vs. 
N o n -E U )

S m o ki n g stat us ( ne ver vs. f or mer /c urre nt)

Brai n metastasis stat us at baseli ne ( y es vs. n o)

P D -L 1  stat us (T P S < 1 % vs. T P S ≥1 %, T P S < 5 0 % vs. T P S ≥5 0 % , TP S < 1 % vs. T P S 1 
– 4 9 % vs .T P S ≥5 0 %)

Ta xa ne c he m ot hera p y (paclita xel vs. na b -paclita xel )
A d diti o nal s u b gr o u p a nal yses s uc h as C hi na vs. n o n- C hi na ma y  be c o n d ucte d per C hi na l ocal 
re g ulat or y nee ds. T he c o nsiste nc y of t he treat me nt effect will be assesse d descri pti vel y  via 
s u m mar y statistics b y  cate g or y for t he classificati o n varia bles liste d a bo ve. If a n y le vel of a 
s u b gr o u p varia ble has fe wer t ha n 1 0 % of t he I T T p o p ulati o n , a b o ve a nal ys is will n ot be 
perf or me d f or t his le vel of t he s u b gr o u p varia ble. If a s u b gr o u p varia ble has t w o le vels a n d o ne 
le vel of t he s u b gr o u p varia ble has fe wer t ha n 1 0 % of t he I T T p o p ulati o n , t he n t his s u b gr o u p will 
n ot be dis pla y e d i n t he f orest pl ot. F or t he first i nteri m a nal ysis, t he s u b gr o u p a nal ysis f or O R R 
will be c o n d ucte d usi n g u nstratifie d Mietti ne n a n d N ur mi ne n met h o d .
T he E U re gi o n i ncl u des c o u ntries fr o m b ot h E U me m ber states ( 2 0 1 6) a n d E F T A me m bers.
3. 1 1
E xte nt of E x p os ure
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n c y cles. 
 
 
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P A G E 2 2
P R O T O C O L N O. 4 0 7 v 0 4
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     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
4
S T A TI S TI C A L A N A L Y SI S P L A N F O R E X T E N SI O N
4. 1 
I ntr o d ucti o n
Af ter t he gl o bal st u d y enr oll me nt is cl ose d, s u bjects fr o m C hi na will c o nti n ue t o be e nr olle d i n 
a n e xte nsi o n st u d y desi g ne d t o meet C hi na l ocal re gistrati o n nee ds .  The e xte nsi o n st u d y will be 
i de ntical t o t he gl o bal st u d y (e. g., i ncl usi o n a n d e xcl usi o n criteria, pri mar y  an d sec o n dar y 
e n d p oi nts, st u d y pr oce d ures) i n ge neral, wit h t he a d diti o nal statistical a nal ys is pla n f or t he 
C hi nese s u b p o p ulati o n.  The p ur p ose of t his e xte nsi o n st u d y is t o e val uate t he c o nsiste nc y of 
efficac y a n d safet y i n t he C hi nese s u bp o p ulati o n t o t he gl o bal p o p ulati o n.  C o u ntr y -s pecific 
a nal ys is ma y als o be c o n d ucte d per l ocal re g ulat or y re q uire me nt.
After t he e nr oll me nt f or t he gl o bal st u d y is c o m plete d, s u bjects i n C hi na will c o nti n ue t o be
e nr olle d i n a 1: 1 rati o i nt o t he pe m br oliz u ma b ar m a n d t he S O C ar m u ntil t he sa m ple size f or t he 
o verall C hi nese s u b p o p ulati o n reac hes a p pr o xi matel y 1 2 0.  
After t he c ut-off date f or t he pri mar y  a nal ys es of t he gl o bal st u d y (i ncl u di n g i nteri m a n d fi nal 
a nal ys es), all C hi nese s u bjects, i ncl u di n g s u bjects e nr olle d i n t he gl o bal st u d y a n d t he e xte nsi o n 
st u d y , will c o nti n ue t heir ra n d o mize d treat me nt a n d c o nti n ue t o be f oll o we d u p f or P F S a n d O S 
e ve nts f or C hi na re gistrati o n p ur p ose. T he e xte nsi o n st u d y will be c o m plete d after tar get n u m ber 
of deat hs has bee n o bser ve d bet wee n t he t w o ar ms i n t he C hi nese s u b p o p ulati o n. T he e x pecte d 
ti mi n g of t he a nal ys is f or t he s u b p o p ulati o n is ar o u n d 3. 3 years fr o m t he ti me w he n t he first 
s u bject fr o m C hi na is e nr olle d i n t he gl o bal st u d y.  Ho we ver, if t he tar get n u m ber of P F S e ve nts 
or deat hs i n t he C hi nese s u b p o p ulati o n is reac he d bef ore a n I A for t he gl o bal st u d y, t he 
c orres p o n di n g a nal ysis f or C hi nese s u b p o p ulati o n will occ ur at t he sa me ti me as t he gl o bal I A or 
t he fi nal a nalys is ( gl o bal st u d y). 
4. 2  
Res p o nsi bilit y f or A n al yses/I n- H o use Bli n di n g
T he trial is d o u ble -bli n de d, a nal ys es or s u m maries ge nerate d b y  ra n d o mize d treat me nt 
assi g n me nt a n d act ual treat me nt recei ve d will be li mite d a n d d oc u me nte d. S u bjects ra n d o mize d 
i n t he e xte nsi o n st u d y will n ot be i ncl u de d i n t he data base l oc k a n d pri mar y  anal ys is f or t he 
gl o bal st u d y. 
F or all C hi nese s u bjects, i ncl u di n g s u bjects ra n d o mize d i n t he gl o bal st u d y an d t he e xte nsi o n 
st u d y, pat ie nt le vel treat me nt ra n d o mizati o n 
i nf or mati o n will 
be 
bli n de d 
t o t he 
statisticia n(s)/ pr o gra m mer(s) res p o nsi ble f or t he a nal ysis of C hi na e xte nsi o n st u d y until t he 
e xte nsi o n st u d y data base l oc k is ac hie ve d. T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o t he 
res ults will be li mite d. Bli n de d a n d u n bli n de d me m bers will be clearly d oc u me nte d wit h bli n di n g 
stat us al o n g wit h ti me i nf or mati o n. 
4. 3
H y p ot heses/ Esti m ati o n
N o h y p ot hesis testi n g is pla n ne d f or t he C hi na e xte nsi o n st u d y.
After s uccee di n g i n t he gl o bal st u d y, t he c o nsiste nc y of efficac y an d safety i n t he C hi nese 
s u b p o p ulati o n t o t he gl o bal p o p ulati o n will be e val uate d. C o nsiste nc y of efficac y will be 
 
 
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M K -3 4 7 5
P A G E 2 3
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
e val uate d usi n g t he perce nta ge of ris k re d ucti o n preser ve d i n t he C hi nese s u b p o p ulati o n fr o m t he 
e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y efficac y anal ys es ( base d o n p oi nt esti mates). 
Sa m ple size is desi g ne d t o pr o vi de a b o ut 8 0 % c ha nce of o bser vi n g t he p oi nt esti mate of C hi nese 
s u b p o p ulati o n preser ves ≥a p pr o xi matel y 50 % of e m pirical ris k re d ucti o n fr om t he gl o bal 
pri mar y  efficac y anal ys is ass u mi n g t he sa me hazar d rati o use d i n t he sa m ple size a n d p o wer 
calc ulati o n f or t he gl o bal st u d y .  
4. 4
T he A n al ysis E n d p oi nts
4. 4. 1
Effic ac y E n d p oi nts
D u al Pri m ar y 
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, t he 
sa me as descri be d i n Secti o n 3. 4. 1 .
Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first 
d oc u me nte d disease pr o gressi o n per R E CI S T 1. 1 base d o n bli n de d i n de pe n de nt ra di ol o gists’ 
assess me nt or deat h d ue t o a n y ca use, w hic he ver occ urs first, t he sa me as descri be d i n Secti o n 
3. 4. 1 .
Sec o n d ar y
O bjecti ve res p o nse rate ( O R R) base d u p o n bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or ’s
assesse d R E CIS T 1. 1 as descri be d i n Secti o n 3. 4. 1 .
D urati o n of res p o nse ( D O R) base d u p o n bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or ’s assesse d 
R E CI S T 1. 1 as descri be d i n Secti o n 3. 4. 1 .
4. 4. 2
S afet y E n d p oi nts
Safet y  e n d p oi nts are t he sa me as descri be d i n Secti o n 3. 4. 2 .
4. 5
A n al ysis P o p ul ati o ns
4. 5. 1
Effic ac y A n al ysis P o p ul ati o ns
Efficac y  anal y sis will be carrie d o ut i n t he e ntire i nte nti o n-t o-treat (I T T) p o p ulati o n . T his 
p o p ulati o n will i ncl u de all s u bjects w h o are ra n d o mize d i n t he gl o bal st u d y a n d all s u bjects w h o 
are ra n d o mize d i n t he e xte nsi o n st u d y. C hi nese s u b p o p ulati o n will i ncl u de all C hi nese s u bjects 
i n t his p o p ulati o n. 
4. 5. 2
S afet y A n al ysis P o p ul ati o ns
Safet y  an a l ysis will be carrie d o ut i n t he e ntire All S u bjects as Treate d ( A Sa T) p o p ulati o n, i.e., 
all ra n d o mize d s u bjects (i n t he gl o bal st u d y an d e xte nsi o n st u d y) w h o recei ve d at least 1 d ose of 
st u d y treat me nt.  C hi nese s u b p o p ulati o n will i ncl u de all C hi nese s u bjects i n t his p o p ulati o n. 
 
 
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4. 6
St atistic al Met h o ds
Re gar di n g t he a nal ys is f or e xte nsi o n, n o h y p ot hesis testi n g is pla n ne d. T here is n o pla n of 
i nteri m a nal ysis. N o m ulti plicit y a dj ust me nt will be a p plie d t o t he a nal ysis f or e xte nsi o n.
4. 6. 1
St atistic al Met h o ds f or Effic ac y A n al yses
4. 6. 1. 1
O ver all S ur vi v al ( O S)
A nal y sis of O S f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y if a p plica ble. 
I n detail, t he 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. F or t he w h ole 
p o p ulati o n, stratifie d l o g-ra n k wil l be use d t o assess t he treat me nt differe nce a n d stratifie d C o x 
pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese 
s u b gr o u p a nal ys is, t he stratifie d met h o d will o nl y be use d if a p plica ble. T he fact or of Ge o gra p h y 
( East Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ysis f or t he C hi nese 
s u b gr o u p a nalys is.
As a n e x pl orat or y anal ysis, rec o g nize d met h o ds, e. g., t he Ra n k Preser vi n g Str uct ural Fail ure 
Ti me ( R P S F T) m o del, t w o-sta ge met h o d, etc., will be use d t o a dj ust f or t he effect of cr oss o ver 
o n O S base d u p o n t he a p pr o priate ness of t he data t o t he ass u m pti o n re q uire d b y  the met h o ds. 
T he R P S F T m o del 
pr o vi des a ra n d o mizati o n-base d esti mate of treat me nt effect ( R B E E) 
c orrecte d f or t he bias i n d uce d b y cr oss o ver. T he 9 5 % c o nfi de nce i nter vals of t he hazar d rati o f or 
O S after a dj ust me nt of t he effect of cr oss o ver will be pr o vi de d. T o f urt her acc o u nt f or t he 
p ossi ble c o nf o u n di n g effect, a se nsiti vit y anal ys is of O S t hat ce ns ors s u bjects at t he ti me of 
i nitiati o n of ne w t hera p y will be perf or me d a n d a n O S a nal ysis t hat treats i nitiati o n of ne w 
t hera py as a ti me -de pe n de nt bi nar y  c o variate will als o be c o n d ucte d.
C o nsiste nc y  of efficac y will be e val uate d usi n g t he perce nta ge of ris k re d ucti on preser ve d i n t he 
C hi nese s u b p o p ulati o n fr o m t he e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y  efficac y 
a nal ys es ( base d o n p oi nt esti mates). Sa m ple size is desi g ne d t o pr o vi de a b o ut 8 0 % c ha nce of 
o bser vi n g t he p oi nt esti mate of C hi nese s u b p o p ulati o n pr eser ves ≥ a p pr o xi matel y 50 % of 
e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y  efficac y a nal ys is ass u mi n g t he sa me hazar d 
rati o use d i n t he sa m ple size a n d p o wer calc ulati o n f or t he gl o bal st u d y.
I n a d diti o n, s u p p orti ve a nal ys es o n t he e ntire I T T p o p ulati o n will be pr o vi de d wit h t he data 
p o ol i n g gl o bal st u d y (pri or t o data c ut off f or t he pri mar y  anal ys is) a n d C hi na e xte nsi o n st u d y 
t o get her. Acc or di n gl y, n o n -C hi nese s u bjects will be ce ns ore d at last k n o w n ali ve date (t his ca n 
be c ut off date if s o me assess ment ha p pe n s t o be o n t hat da y  or t here’s assess me nt be y o n d t he 
c ut off date) w hic h is c o nsiste nt wit h t he pri mar y  a nal ys is i n t he gl o bal st u d y if s u bjects are still 
ali ve at pri mar y  an al y sis ti me f or gl o bal st u d y. T he pri mar y anal y sis f or O S will be c o n d uct e d i n 
t he C hi nese s u b p o p ulati o n w he n a p pr o xi matel y 7 5 O S e ve nts ha ve bee n c ollecte d.
 
 
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4. 6. 1. 2
Pr o gressi o n -Free S ur vi v al ( P F S)
A nal y sis of P F S f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y if a p plica ble. 
I n detail, t he 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. F or t he w h ole 
p o p ulati o n, stratifie d l o g-ra n k test will be use d t o assess t he treat me nt differe nce a n d stratifie d 
C o x pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese 
s u b gr o u p a nal ys is, t he stratifie d met h o d will o nl y be use d if a p plica ble. T he fact or of Ge o gra p h y 
( East Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ysis f or C hi nese s u b gr o u p 
a nal ys is. I n case t he pr o p orti o nal hazar ds ass u m pti o n d oes n’t h ol d, Fle mi n g a n d Harri n gt o n’s 
wei g hte d l o g-ra n k test, Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d or ot her met h o ds, as 
a p pr o priate, ma y be c o n d ucte d.
C o nsiste nc y  in P F S will be e val uate d si milarly as t hat i n O S.  The pri mar y a nal ys is f or P F S wil l 
be c o n d ucte d i n t he C hi nese s u b p o p ulati o n w he n a p pr o xi matel y 75 P F S e ve nts ha ve bee n 
c ollecte d.
4. 6. 1. 3
O bjecti ve Res p o nse R ate ( O R R) a n d D ur ati o n of Res p o nse ( D O R)
Stratifie d Mietti ne n a n d N ur mi ne n’ s met h o d wit h wei g hts pr o p orti o nal t o t he strat u m size will be
use d f or c o m paris o n of t he O R R bet wee n t he treat me nt ar ms. A 9 5 % CI f or t he differe nce i n 
res p o nse rates bet wee n t he pe m br oliz u ma b ar m a n d t he c o ntr ol ar m will b e pr o vi de d. T he sa me 
stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese s u b p o p ulati o n 
a nal ys is, t he stratifie d met h o d will o nl y  be use d if a p plica ble. T he fact or of Ge o gra p h y ( East 
Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ys is f or C hi nese s u b gr o u p 
a nal ys is.
F or t he C hi nese s u b gr o u p a nal ys is, D O R will be s u m marize d descri pti vel y usi n g Ka pla n -Meier 
me dia ns
a n d q uartiles if sa m ple size per mits. O nl y t he s u bset of patie nts w h o s h o w a c o m plete 
res p o nse or partial res p o nse will be i ncl u de d i n t his a nal y sis.
4. 6. 1. 4
E x pl or at or y A n al yses
E x pl orat or y  A nalys es f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y (if a p plica ble).
4. 6. 2
St atistic al Met h o ds f or S afet y A n al yses
Safet y  anal ys es f or e xte nsi o n are t he sa me t o t hat f or t he gl o bal st u d y as descri be d i n Secti o n 
3. 6. 2 .  
4. 6. 3
S u m m aries of B aseli ne C h ar acteristics, De m o gr a p hics, a n d Ot her A n al yses
T he y  are t he sa me f or e xte nsi o n t o t hat f or t he gl o bal st u d y as descri be d i n Secti o n 3. 1 0 . 
 
 
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4. 7
I nteri m A n al ysis & Fi n al a n al ysis 
T he pri mar y  anal y sis f or P F S will 
be c o n d ucte d i n t he C hi nese 
s u b p o p ulati o n w he n 
a p pr o xi matel y 7 5 P F S e ve nts ha ve bee n c ollecte d. O S w ill als o be a nal yze d .
T he 
pri mar y  anal ys is f or O S 
will 
be c o n d ucte d i n t he C hi nese 
s u b p o p ulati o n w he n 
a p pr o xi matel y 7 5 O S e ve nts ha ve bee n c ollecte d.
4. 8
M ulti plicit y
N o m ulti plicit y  a dj ust me nt will be a p plie d t o t he a nal ysis of C hi na. 
4. 9
S a m ple Size a n d P o wer C alc ul ati o ns
After t he e nr oll me nt of gl o bal st u d y co m pletes , t he e xte nsi o n st u d y will c o nti n ue t o ra n d o mize 
s u bjects i n a 1: 1 rati o i nt o t he pe m br oliz u ma b ar m a n d t he place b o ar m i n C hi na u ntil t he sa m ple 
size f or t he o verall C hi nese s u bjects (i ncl u di n g th ose e nr olle d i n t he gl o bal st u d y) reac hes 
a p pr o xi matel y 12 0. T he e xte nsi o n st u d y  p o p ulati o n, i.e., t h ose C hi nese s u bjects ra n d o mize d after 
t he cl ose of e nr oll me nt f or t he gl o bal st u d y, will n ot be i ncl u de d i n t he gl o bal pri mar y a nal ysis. 
T he e xte nsi o n st u d y will c o m plete after ≥a p pr o xi matel y 75 deat hs ha ve bee n o bser ve d bet wee n 
t he t w o ar ms i n t he C hi nese s u b p o p ulati o n ass u mi n g t he u n derl yi n g hazar d rati o f or O S is 0. 7 0. 
Wit h 7 5
deat hs a n d a tr ue hazar d rati o of 0. 7 0 , t he e xte nsi o n st u d y has > 9 0 % c ha nce t o o bser ve a 
hazar d rati o o n O S < 1 a n d ~ 8 0 %  cha nce t o o bser ve a p oi nt esti mate t hat preser v es ≥
a p pr o xi matel y 50 % of t he e m pirical ris k re d ucti o n fr o m t he gl o bal a nal ysis i n t he C hi nese 
s u b p o p ulati o n ass u mi n g t he u n derl yi n g hazar d rati o is 0. 7 0. T he sa me c o nsi derati o n a p plies t o 
P F S. 
T he a b o ve calc ulati o ns f or t he c o nsiste nc y eval uati o n i n P F S a n d O S are base d o n t he sa me 
ass u m pti o ns o n t he c orres p o n di n g me dia n O S/ P F S a n d t he tr ue hazar d rati o res pecti vely.
4. 1 0
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
All s u b gr o u p a nal ys is defi ne d i n S ecti o n 3. 1 0 will be re peate d f or t he e ntire p o p ulati o n a n d 
C hi nese s u b p o p ulati o n if a p plica ble. I n a d diti o n, res ults f or C hi nese s u b p o p ulati o n vs. n o n-
C hi nese s u b p o p ulati o n will be pr o vi de d. C o u ntr y -s pecific a nal ys is m a y  als o be c o n d ucte d per 
l ocal re g ulat or y re q uire me nt.
 
 
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5
R E F E R E N C E S
1.
A n ders o n K M, Clar k J B. Fitti n g s pe n di n g f u ncti o ns. Stat Me d 2 0 1 0; 2 9( 3): 3 2 1 - 7.
2.
Ma urer 
W, 
Bretz 
F. M ulti ple 
testi n g i n gr o u p se q ue ntial trials usi n g gra p hical 
a p pr oac hes. Stat Bi o p har m Res 2 0 1 3; 5( 4): 3 1 1 - 2 0.
3.
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 n Stat - T he or M 1 9 9 1; 2 0( 8): 2 6 0 9-3 1.
4.
Fi n kelstei n D M. 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 1 9 8 6; 4 2: 8 4 5 - 5 4.
5.
Mietti ne n O, N ur mi ne n M. C o m parati ve a nal ys is of t w o rates. Stat Me d 1 9 8 5; 4: 2 1 3- 2 6.
 
 
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Re visi o n Hist or y
D ate
S u m m ar y of C h a n ge
0 9 J U N2 0 1 7
Ori gi nal D oc u me nt
2 3 O C T 2 0 1 7
Versi o n 0 2
1 5 N O V 2 0 1 7
Versi o n 0 3
2 9 J A N 2 0 1 8
Versi o n 0 4
 
 
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M K -3 4 7 5
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S u p ple me nt al St atistic al A n al ysis Pl a n (s S A P) 
T A B L E O F C O N T E N T S
Ta ble of C o nte nt … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … ….. 1
1
I NT R O D U C TI O N … … … … … … … … … … … … … … … … … … … … … … … … … … … …... 4
2
S U M M A R Y O F C H A N G E S … … … … … … … … … … … … … … … … … … … … … … … …... 4
3
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S F O R G L O B A L S T U D Y … … ….. 4
3. 1
Statistical A nal y sis Pla n S u m mar y .................................................................................. 4
3. 2
Res p o nsi bilit y  f or A nalyses/I n -H o use Bli n di n g .............................................................. 6
3. 3
H y p ot heses/ Esti mati o n ..................................................................................................... 6
3. 3. 1
Pri mar y  O bjecti ve(s) & H yp ot hesis(es) .................................................................... 6
3. 3. 2
Sec o n dar y  O bjecti ve(s) & H yp ot hesis(es) ................................................................ 7
3. 3. 3
E x pl orat or y  O bjecti ves ............................................................................................. 7
3. 4
A nal y sis E n d p oi nts........................................................................................................... 8
3. 4. 1
Efficac y  E n d p oi nts.................................................................................................... 8
3. 4. 2
Safet y  E n d p oi nts....................................................................................................... 8
3. 5
A nal y sis P o p ulati o ns ........................................................................................................ 9
3. 5. 1
Efficac y  A nalys is P o p ulati o ns.................................................................................. 9
3. 5. 2
Safet y  A nalys is P o p ulati o ns ..................................................................................... 9
3. 6
Statistical Met h o ds ........................................................................................................... 9
3. 6. 1
Statistical Met h o ds f or Efficac y  A nalys es ................................................................ 9
3. 6. 1. 1
Pr o gressi o n -Free S ur vi val ( P F S) ..................................................................... 1 0
3. 6. 1. 2
O verall S ur vi val ( O S) ...................................................................................... 1 1
3. 6. 1. 3
O bjecti ve Res p o nse Rate ( O R R) a n d D urati o n of Res p o nse ( D O R) .............. 1 2
3. 6. 1. 4
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts................................................ 1 3
3. 6. 1. 5
E x pl orat or y  A nalys es ...................................................................................... 1 4
3. 6. 2
Statistical Met h o ds f or Safet y A nal y ses ................................................................. 1 5
3. 6. 3
S u m maries of Baseli ne C haracteristics, De m o gra p hics, a n d Ot her A nal ys es ........ 1 6
3. 7
I nteri m A nalys is............................................................................................................. 1 6
3. 8
M ult i plicit y..................................................................................................................... 1 7
3. 8. 1
O bjecti ve Res p o nse Rate ........................................................................................ 1 8
3. 8. 2
Pr o gressi o n -free S ur vi val........................................................................................ 1 9
3. 8. 3
O verall S ur vi val ...................................................................................................... 1 9
3. 9
Sa m ple Size a n d P o wer Calc ulati o ns ............................................................................. 2 0
 
 
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3. 1 0
S u b gr o u p A nal y ses a n d Effect of Baseli ne Fact ors.................................................... 2 1
3. 1 1
E xte nt of E x p os ure ..................................................................................................... 2 2
4
St atistical A nal ysis Pla n f or E xte nsi o n… … … … … … … … … … … … … … … … … … … ….. 2 2
4. 1
I ntr o d ucti o n .................................................................................................................... 2 2
4. 2
Res p o nsi bilit y  f or A nalyses/I n -H o use Bli n di n g ............................................................ 2 2
4. 3
H y p ot heses/ Esti mati o n ................................................................................................... 2 3
4. 4
T he A nal ys is E n d p oi nts ................................................................................................. 2 3
4. 4. 1
Efficac y  E n d p oi nts.................................................................................................. 2 3
4. 4. 2
Safet y  E n d p oi nts..................................................................................................... 2 3
4. 5
A nal y sis P o p ulati o ns ...................................................................................................... 2 3
4. 5. 1
Efficac y  A nalys is P o p ulati o ns................................................................................ 2 3
4. 5. 2
Safet y  A nalys is P o p ulati o ns ................................................................................... 2 4
4. 6
Statistical Met h o ds ......................................................................................................... 2 4
4. 6. 1
Statistical Met h o ds f or Efficac y  A nalys es .............................................................. 2 4
4. 6. 1. 1
O verall S ur vi val ( O S) ...................................................................................... 2 4
4. 6. 1. 2
Pr o gressi o n -Free S ur vi val ( P F S) ..................................................................... 2 5
4. 6. 1. 3
O bjecti ve Res p o nse Rate ( O R R) a n d D urati o n of Res p o nse ( D O R) .............. 2 5
4. 6. 1. 4
E x pl orat or y  A nalys es ...................................................................................... 2 5
4. 6. 2
Statistical Met h o ds f or Safet y A nal ys es ................................................................. 2 5
4. 6. 3
S u m maries of Baseli ne C haracteristics, De m o gra p hics, a n d Ot her A nal ys es ........ 2 5
4. 7
I nteri m A nalys is & Fi nal a nalys is.................................................................................. 2 6
4. 8
M ulti plicit y ..................................................................................................................... 2 6
4. 9
Sa m ple Size a n d P o wer Calc ulati o ns................................ ............................................. 2 6
4. 1 0
S u b gr o u p A nal y ses a n d Effect of Baseli ne Fact ors.................................................... 2 6
5
R E F E R E N C E S … … … … … … … … … … … … … … … … … … … … … … … … … … … … ….. 2 6
 
 
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Listi n g of Ta bles
Ta ble 1
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S.................................. 1 1
Ta ble 2
Ce ns ori n g R ules f or D O R........................................................................................... 1 3
Ta ble 3
A nal y sis Strate g y f or Ke y Efficac y E n d p oi nts........................................................... 1 4
Ta ble 4
A nal y sis Strate g y f or Safet y Para meters.................................................................... 1 6
Ta ble 5
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y ...................................................... 1 7
Ta ble 6
P ossi ble Al p ha -le vels a n d A p pr o xi mate O R R differe nce Re q uire d t o De m o nstrate 
Efficac y  f or O R R at I A 1............................................................................................................... 1 8
Ta ble 7
Efficac y  B o u n daries a n d Pr o perties f or Pr o gressi o n-free S ur vi val A nalys es ............ 1 9
Ta ble 8
Efficac y  B o u n daries a n d Pr o perties f or O verall S ur vi val A nal ys es ........................... 2 0
 
 
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     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
1
I N T R O D U C TI O N
T his s u p ple me ntal S A P (s S A P) is a c o m pa ni o n d oc u me nt t o t he pr ot oc ol. I n ad diti o n t o t he 
i nf or mati o n prese nte d i n t he pr ot oc ol S A P w hic h pr o vi des t he pri nci pal feat ures of c o nfir mat or y 
a nal ys es f or t his trial, t his s u p ple me ntal S A P pr o vi des a d diti o nal statistical a nal ys is details/ data 
deri vati o ns a n d d oc u me nts m o dificati o ns or a d diti o ns t o t he a nal ys is pla n t hat are n ot “ pri nci pal” 
i n nat ure a n d res ult fr o m i nf or mati o n t hat was n ot a vaila ble at t he ti me of pr ot oc ol fi nalizati o n.  
Se parate a nal ys is pla ns (i.e., se parate d oc u me nts fr o m t his s S A P) ma y
be de vel o pe d f or 
P K/ m o deli n g a nal ys is, bi o mar ker a nalys is, a n d ge netic data a nal ysis.   
2 
S U M M A R Y O F C H A N G E S
T his s S A P ali g ns wit h t he pr ot oc ol a me n d me nt v 0 4 f or t he C hi na e xte nsi o n st u d y wit h re gar d t o 
statistical a nal ysis pla n.
3
A N A L Y TI C A L A N D M E T H O D O L O GI C A L D E T AI L S F O R G L O B A L S T U D Y
3. 1
St atistic al A n al ysis Pl a n S u m m ar y
T his secti o n c o ntai ns a brief s u m mar y  of t he statistical a nal yses f or gl o bal st u d y of t his trial. F ull 
detail is pr o vi de d i n Secti o ns 3. 2 -3. 1 1 .  
St u d y Desi g n
O ver vie w
A P hase III St u d y of Car b o plati n -Paclita xel/ Na b -Paclita xel C he m ot hera p y
wit h or wit h o ut Pe m br oliz u ma b ( M K -3 4 7 5) i n First Li ne Metastatic
S q ua m o us N o n -s mall Cell L u n g Ca ncer S u bjects ( K E Y N O T E-4 0 7)
Tre at m e nt Assi g n me nt
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o recei ve pe m br oliz u ma b or sali ne place b o 
i n c o mbi nati o n wit h car b o plati n a n d a ta xa ne (i n vesti gat ors c h oice of paclita xel or na b -
paclita xel). Stratificati o n fact ors are i n Secti o n 5. 4 of t he pr ot oc ol . T his is a ra n d o mize d 
d o u ble -bli n de d st u d y.
A n al ysis P o p ul ati o ns
Efficac y: I nt e nt t o Trea t (I TT)
Safet y: All S u bjects as Treate d ( A Sa T)
Pri m ar y E n d p oi nts
1.
Pr o gressi o n -free S ur vi val 
( P FS)
per R E CI S T 
1. 1 assesse d b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or 
2.
O verall S ur vi val ( O S )
St atistic al Met h o ds
f or
Ke y Effic ac y A n al yses
T he d ual pri mar y h y p ot heses o n P F S a n d O S 
will b e e val uate d b y
c o mpari n g 
pe m br oliz u ma b t o sali ne place b o i n c o m bi nati o n wit h car b o plati n a n d a ta xa ne usi n g a 
stratifie d L o g -ra n k test. T he hazar d rati o will be esti mate 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 mate d wit hi n eac h treat me nt gr o u p 
u si n g t he Ka pla n -Meier met h o d. T he stratifie d M & N me t h o d wit h sa m ple size wei g hts 
will be use d f or a nal ysis of O R R.
St atistic al Met h o ds
f or
Ke y S afet y A n al yses
T he a nal ysis of safet y res ults will f oll o w a tiere d a p pr oac h. T here are n o Tier 1 safet y 
para met ers i n t his trial. All safet y para meters are c o nsi dere d eit her Tier 2 or Tier 3. Tier 
2 para meters will be assesse d via p oi nt esti mates wit h 9 5 % c o nfi de nce i nter vals 
pr o vi de d f or bet w ee n -gr o u p c o m paris o ns; o nl y  poi nt esti mates b y  treat me nt gr o u p are 
pr o vi de d f or Tier 3 safet y para meters. T he bet w e e n -treat me nt differe nce will be
a nal yze d usi n g t he Mietti ne n a n d N ur mi ne n met h o d.
I n t he pri m ar y safet y c o mparis o n, s u bjects w h o cr oss o ver t o p e m br oliz u ma b ar e 
ce ns ore d at ti me of cr oss o ver (i.e., A Es occ ur ri n g d uri n g treat me nt wit h pe m br oliz u ma b 
are e xcl u de d f or c o ntr ol -ar m s u bjects). A n e x pl orat or y safet y a nal ysis will be c o n d ucte d 
 
 
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T he S P O N S O R
will 
ge nerate t he ra n d o mize d all ocati o n sc he d ule(s) f or st u d y treat me nt 
assi g n me nt f or t his pr ot oc ol, a n d t he ra n d o mizati o n will be i m ple me nte d i n I V R S. 
T his trial is d o u ble bli n de d wit h a cr oss o ver p hase. At t he ti me of d oc u me nte d pr o gressi o n,
s u bjects will ha ve treat me nt assi g n me nt u n bli n de d a n d be a ble t o c o nti n ue t hera py i n t he 
Cr oss o ver P hase ( please refer t o pr ot oc ol secti o n 2. 1 Trial Desi g n f or details). I n ad diti o n, 
i n de pe n de nt ce ntral ra di ol o gist(s) will perf or m t he ce ntral i ma gi n g re view wit h o ut k n o wle d ge of 
treat me nt assi g n me nt.
A n e xter nal data m o nit ori n g c o m mittee (e D M C) will be c o n ve ne d t o re vie w acc u m ulati n g safet y  
t o pr o vi de a n o p p ort u nit y  to ter mi nate t he st u d y earl y if t here are c o ncer ns re gar di n g safety. T he 
e D M C will als o re view t he u n bli n de d efficac y res ults at t he pla n ne d i nteri m a nal ys es. T he 
e D M C res p o nsi bilities a n d re vie w sc he d ules will be o utli ne d i n t he e D M C c harter. T he 
rec o m me n dati o n of t he e D M C will be c o m m u nicate d t o a n e xec uti ve o versi g ht c o m mittee of t he 
S p o ns or. I n t he e ve nt of a rec o m me n dati o n t o halt t he trial earl y due t o safet y co ncer ns, t he 
S p o ns or will c o m m u nicate t his t o t he a p pr o priate re g ulat or y age ncies. If t he e D M C rec o m me n ds 
m o dificati o ns t o t he desi g n of t he pr ot oc ol or disc o nti n uati o n of t he st u d y, t his e xec uti ve 
o versi g ht c o m mittee 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 li mite d n u m ber of 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, if re q uire d, i n or der t o 
act o n t he rec o m me n dati o ns of t he e D M C . T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o t he 
res ults will be d oc u me nte d. A d diti o nal l o gistical details, re visi o ns t o t he a b o ve pla n a n d data 
m o nit ori n g g ui da nce will be pr o vi de d i n t he e D M C C harter.
3. 3
H y p ot heses/ Esti m ati o n
3. 3. 1
Pri m ar y O bjecti ve(s) & H y p ot hesis(es)
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1.
O bjecti ve:
T o e val uate pr o gressi o n free s ur vi val ( P F S) per R E CI S T 1. 1 as assesse d b y  a 
ce ntral i ma gi n g ve n d or i n s u bjects treate d wit h Pe m br oliz u ma b c o m pare d t o place b o .
H y p ot hesis: P e m br oliz u ma b pr ol o n gs P F S b y  RE CI S T 1. 1 as assesse d b y  a ce ntral i ma gi n g 
ve n d or c o m pare d t o place b o.
2.
O bjecti ve: T o eval uate o verall s ur vi val ( O S) i n s u bjects treate d wit h Pe m br oliz u ma b 
c o m pare d t o place b o.
H y p ot hesis: Pe m br oliz u ma b pr ol o n gs O S c o m pare d t o place b o .
3. 3. 2 
Sec o n d ar y O bjecti ve(s) & H y p ot hesis(es)
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
 
 
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1.
O bjecti ve: T o e val uate t he o bjecti ve res p o nse rate ( O R R) a n d d urati o n of res p o nse ( D O R) 
per R E CI S T 1. 1 as assesse d b y  a ce ntral i ma gi n g ve n d or i n s u bjects treate d wit h 
Pe m br oliz u ma b c o m pare d t o place b o.
H y p ot hesis:
Pe m br oliz u ma b i m pr o ves O R R per R E CI S T 1. 1 as assesse d b y  a ce ntral 
i ma gi n g ve n d or c o m pare d t o place b o. 
2.
O bjecti ve: T o e val uate t he safet y a n d t olera bilit y pr ofile of Pem br oliz u ma b. 
3. 3. 3
E x pl or at or y O bjecti ves
I n 1 L  su bjects wit h metastatic 
s q ua m o us n o n-s mall cell l u n g ca ncer ( N S C LC) recei vi n g
i n vesti gat or’s c h oice of sta n dar d of care c he m ot hera py (i.e. car b o plati n a n d a ta xa ne):
1) O bjecti ve: E val uate pe m br oliz u ma b c o m pare d t o place b o wit h res pect t o:
a.
P F S per R E CI S T 1. 1 as assesse d b y  in vesti gat or re vie w i n t he ne xt li ne of t hera py 
( P F S 2). 
b.
P F S per ir R E CI S T as assesse d b y  site i n vesti gat or.
c.
O R R a n d D urati o n of Res p o nse ( D O R) per ir R E CI S T as assesse d b y site i n vesti gat or.
d.
P F S a n d O R R per R E CI S T 1. 1 as assesse d b y ce ntral i ma gi n g ve n d or a n d O S b y  P D-
L 1 stat us ( ≥1 % vs. < 1 %) a n d b y  ta xa ne (i n vesti gat ors c h oice of paclita xel or na b -
paclita xel).
2) T o i n vesti gate t he relati o ns hi p bet wee n pe m br oliz u ma b treat me nt a n d bi o mar kers pre dicti n g 
res p o nse (e. g., P D -L 2, ge netic variati o n, ser u m s P D-L 1 ) utilizi n g ne wl y o btai ne d or arc hi val 
F F P E t u m or tiss ue a n d bl o o d, i ncl u di n g ser u m a n d plas ma.
3) T o e val uate c ha n ges i n healt h -relate d q ualit y- of- life assess me nts fr o m baseli ne i n t he o verall 
st u d y p o p ulati o n a n d b y P D-L 1  e x pressi o n le vel usi n g t he E O R T C Q L Q- C 3 0 a n d E O R T C Q LQ-
L C 1 3.
4) T o c haracterize utilities i n s u bjects treate d wit h pe m br oliz u ma b a n d c he m ot hera p y c o m pare d 
t o sali ne place b o a n d c he m ot hera py usi n g t he E ur o Q o L( E Q) -5 D.
5) T o c haracterize t he p har mac o ki netic c haracteristics of car b o plati n, paclita xel/ na b -paclita xel
treat me nt, a n d pe m br oliz u ma b.
6) T o i de ntif y 
molec ular ( ge n o mic, meta b olic 
a n d/ or pr ote o mic) bi o mar kers t hat m a y  be
i n dicati ve of cli nical res p o nse/resista nce, safet y, p har mac o d y na mic acti vit y, a nd/ or
t he 
mec ha nis m of acti o n of pe m br oliz u ma b a n d ot her treat me nts.
 
 
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3. 4
A n al ysis E n d p oi nts
3. 4. 1
Effic ac y E n d p oi nts
D u al Pri m ar y 
Pr o gressi o n -Free S ur vi v al –
R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or 
Pr o gressi o n -free-s ur vi val ( P F S) is def i ne d as t he ti me fr o m ra n d o mizati o n t o t he first
d oc u me nte d disease pr o gressi o n per R E CI S T 1. 1 base d o n bli n de d i n de pe n de nt ce ntral i ma gi n g 
ve n d or re vie w or deat h d ue t o a n y ca use, w hic he ver occ urs first. See Secti o n 3. 6. 1 f or t he 
ce ns ori n g r ules.
O ver all S ur vi v al
O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o deat h d ue t o a n y ca use. 
S u bjects wit h o ut d oc u me nte d deat h at t he ti me of t he a nal ys is will be ce ns ore d at t he date of t he 
last k n o w n c o ntact .
Sec o n d ar y
O bjecti ve Res p o nse R ate – R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al i ma gi n g 
ve n d or
O bjecti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of t he s u bjects w h o ha ve a c o nfir me d 
c o m plete res p o nse ( C R) or partial res p o nse ( P R). Res p o nses are base d o n c o nfir me d assess me nts
b y  t he bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or per R E CIS T 1. 1. 
D ur ati o n of Res p o nse ( D O R) - R E CI S T 1. 1 assesse d b y a bli n de d i n de pe n de nt ce ntr al 
i m a gi n g ve n d or
F or s u bjects w h o de m o nstrate d C R or P R, d urati o n of res p o nse ( D O R) is defi ne d as t he ti me
fr o m first d oc u me nte d e vi de nce of C R or P R u ntil disease pr o gressi o n or deat h. Res p o nse
d urati o n f or s u bjects w h o ha ve n ot pr o gresse d or die d at t he ti me of a nal ysis will be ce ns ore d at 
t he date of t heir last t u m or assess me nt. Res p o nse d urati o n will be calc ulate d f or R E CI S T 1. 1 
base d o n bli n de d i n de pe n de nt ra di ol o gists ’ re vie w.
3. 4. 2
S afet y E n d p oi nts
Safet y  meas ure me nts are descri be d i n Pr ot oc ol Secti o n 4. 2. 3. 4.
 
 
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3. 5
A n al ysis P o p ul ati o ns
3. 5. 1 
Effic ac y A n al ysis P o p ul ati o ns
T he i nte nti o n -t o-treat (I T T) p o p ulati o n will ser ve as t he p o p ulati o n f or pri mar y  efficac y a nal ysis. 
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.
A p pr o xi matel y  20 0 ra n d o mize d s u bjects are pla n ne d t o be i ncl u de d i n t he first i nteri m a nal ysis. 
Base d o n act ual e nr oll me nt, 2 0 4 s u bjects w h o were ra n d o mize d o n or pri or t o A pril 1 1 2 0 1 7 will 
be i ncl u de d i n t he I T T p o p ulati o n i n t he first i nteri m a nal ys is. Se ve nt y s u bjects w h o faile d 
scree ni n g o n or pri or t o A pr 1 1 2 0 1 7 i n a d ditio n t o t he 2 0 4 ra n d o mize d s u bjects will be i ncl u de d 
i n t he Scree ni n g P o p ulati o n.
3. 5. 2
S afet y A n al ysis P o p ul ati o ns
T he All S u bjects as Treate d ( A Sa T) p o p ulati o n will be use d f or t he a nal y sis of safet y data i n t his 
st u d y. T he A Sa T p o p ulati o n c o nsists of all ra n d omize 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 s u bject w h o recei ves t he i nc orrect 
st u d y me dicati o n f or o ne c ycle b ut recei ves t he c orrect treat me nt f or all ot her c ycles will be 
a nal yz e d acc or di n g t o t he s u bject’s ra n d o mize d treat me nt gr o u p a n d a narrati ve will be pr o vi de d 
f or a ny e ve nts t hat occ ur d uri n g t he c y cle f or w hic h t he s u bject was 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.
F or t he first i nteri m a nal ysis, a m o n g t he I T T p o p ulati o n of 2 0 4 s u bjects, 2 0 3 of t he m recei ve d at 
least o ne d ose of st u dy treat me nt a n d t h us will be i ncl u de d i n t he A Sa T p o p ulati o n.
3. 6
St atistic al Met h o ds
3. 6. 1
St atistic al Met h o ds f or Effic ac y A n al yses
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 3. 8 , M ulti plicit y . N o mi nal p -val ues will be 
c o m p ute d f or ot her efficac y 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.
All statistical tests, u nless ot her wise s pecifie d, will be stratifie d f or treat me nt a n d stratificati o n 
fact ors.
 
 
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3. 6. 1. 1
Pr o gressi o n -Free S ur vi v al ( P F S)
T he n o n- para metric Ka pla n -Meier 
met h o d will be use d t o esti mate t he P F S c ur ve i n eac h 
treat me nt gr o u p. T he treat me nt differe nce i n P F S will be assesse d b y  the stratifie d l o g-ra n k test
( base d o n t he stratificati o n fact ors defi ne d i n Pr ot oc ol Secti o n 5. 4). A stratifie d C o x pr o p orti o nal 
hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he ma g nit u de of t he 
treat me nt differe nce (i.e., hazar d rati o) bet wee n t he treat me nt ar ms. T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h Efr o n's met h o d of tie ha n dli n g a n d wit h a 
si n gle treat me nt c o variate will 
be re p orte d. T he 
sa me stratificati o n fact ors use d f or 
ra n d o mizati o n will be a p plie d t o b ot h t he stratifie d l o g-ra n k test a n d t he stratifie d C o x m o del. 
F or t he first i nteri m a nal y sis, d ue t o t he s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b-
paclita xel a n d East Asia, t his strat u m will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d 
paclita xel a n d E ast Asia i n stratifie d a nal ys es. 
Si nce disease pr o gressi o n is assesse d peri o dicall y , pr o gressi ve disease ( P D) ca n occ ur a n y ti me 
i n t he ti me i nter val bet wee n t he last assess me nt w here P D was n ot d oc u me nte d a n d t he 
assess me nt w he n P D is d oc u me nte d. F or t he pri mar y an al y sis, f or t he s u bjects w h o ha ve P D, t he 
tr ue date of disease pr o gressi o n will be a p pr o xi mate d b y t he date of t he first assess me nt at w hic h 
P D is o bjecti vel y  d oc u me nte d per R E CI S T 1. 1 b y  a bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or, 
re gar dless of disc o nti n uati o n of st u d y dr u g. Deat h is al wa ys c o nsi dere d as a c o nfir me d P D e ve nt. 
Se nsiti vit y  anal ys es will 
be perf or me d f or c o m paris o n of P F S base d o n i n vesti gat or’s 
assess me nt. 
I n or der t o e val uate t he r o b ust ness of t he P F S e n d p oi nt per R E CI S T 1. 1 b y  a bli n de d 
i n de pe n de nt ce ntral i ma gi n g ve n d or, we will perf or m t w o se nsiti vit y a nal yses wit h a differe nt set 
of ce ns ori n g r ules. T he first se nsiti vit y anal y sis is t he sa me as t he pri mar y  anal ys is e xce pt t hat it 
ce ns ors at t he last disease assess me nt wit h o ut P D w he n P D or deat h is d oc u me nte d after m ore 
t ha n o ne misse d disease assess me nt. T he sec o n d se nsiti vit y anal ys is is t he sa me as t he pri mar y 
a nal ys is e xce pt t hat it c o nsi ders disc o nti n uati o n of treat me nt or i nitiati o n of ne w a ntica ncer 
treatme nt, w hic he ver occ urs later, t o be a P D e ve nt f or s u bjects wit h o ut d oc u me nte d P D or 
deat h. T he ce ns ori n g r ules f or pri mar y  an d se nsiti vit y anal ys es are s u m marize d i n Ta ble 1 . I n 
case t here is a n i m bala nce bet wee n t he treat me nt gr o u ps o n disease assess me nt sc he d ules or 
ce ns ori n g patter ns, we will 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 nalys es: 1) 
a P F S a nal y sis usi n g ti me t o sc he d ule d t u m or assess ment 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’s li keli h o o d-base d sc ore test f or i nter val-ce ns ore d 
data [4 ] w hic h m o difies the 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 ysis 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 ght 
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 earlier. I n case t he 
pr o p orti o nal hazar ds ass u m pti o n d oes n’t h ol d, Fle mi n g a n d Harri n gt o n’s wei g hte d l o g-ra n k test, 
Restricte d Mea n 
S ur vi val Ti me ( R M S T) met h o d or ot her met h o ds, as a p pr o priate, m a y  be 
c o n d ucte d.
 
 
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M K -3 4 7 5
P A G E 1 1
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 1
Ce ns ori n g R ules f or Pri mar y  a n d Se nsiti vit y A nal yses of P F S
Sit uati o n
Pri mar y A nal ysis
Se nsiti vit y
A nal ysis 1
Se nsiti vit y
A nal ysis 2
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is n ot 
i nitiate d
Ce ns ore d at last 
disease 
assess me nt 
Ce ns ore d at last 
disease assess me nt 
Ce ns ore d at last disease 
assess me nt if still o n 
st u d y t hera p y; pr o gresse d 
at treat me nt 
disc o nti n uati o n ot her wise
N o P D a n d n o deat h; 
ne w a ntica ncer 
treat me nt is i nitiate d
Ce ns ore d at last 
disease 
assess me nt bef ore 
ne w a ntica ncer 
treat me nt
Ce ns ore d at last 
disease assess me nt 
bef ore ne w  
a ntica ncer treat me nt
Pr o gresse d at date of ne w  
a ntica ncer treat me nt
N o P D a n d n o deat h; 
≥ 2 c o nsec uti ve 
misse d disease 
assess me nts
Ce ns ore d at last 
disease 
assess me nt
Ce ns ore d at last 
disease assess me nt 
pri or t o ≥2 
c o nsec uti ve misse d 
visits
Ce ns ore d at last disease 
assess me nt
P D or deat h 
d oc u me nte d after ≤1 
misse d disease 
assess me nt
Pr o gresse d at date 
of d oc u me nte d 
P D or deat h
Pr o gresse d at date of 
d oc u me nte d P D or 
deat h
Pr o gresse d at date of 
d oc u me nte d P D or deat h
P D or deat h 
d oc u me nte d after ≥2 
misse d disease 
assess me nts
Pr o gresse d at date 
of d oc u me nte d 
P D or deat h
Ce ns ore d at last 
disease assess me nt 
pri or t o t he  ≥2 
misse d disease 
assess me nt
Pr o g resse d at date of 
d oc u me nte d P D or deat h
3. 6. 1. 2
O ver all S ur vi v al ( O S)
T he n o n- para metric Ka pla n -Meier met h o d will be use d t o esti mate t he s ur vi val c ur ves. T he 
treat me nt differe nce i n s ur vi val will be assesse d b y  the stratifie d l o g-ra n k test. A stratifie d C o x 
pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d f or ra n d o mizati o n will be a p plie d t o b ot h t he 
stratifie d l o g-ra n k test a n d t he stratifie d C o x m o del.
F or t he first i nteri m a nal ysis, d ue t o t he 
s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b -paclita xel a n d East Asia, t his strat u m 
will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d paclita xel a n d East Asia i n stratifie d 
a nal ys es. T he Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d ma y  be c o n d ucte d f or O S t o 
acc o u nt f or t he p ossi ble n o n- pr o p orti o nal hazar ds effect a n d t o esti mate t he a bs ol ute be nefit of 
e x peri me ntal treat me nt. A c ure rate m o del ma y  be a p plie d t o esti mate t he l o n g-ter m effect.
Si nce s u bjects i n t he c o ntr ol ar m are all o we d t o s witc h t o t he pe m br oliz u ma b treat me nt after
pr o gres si ve disease, a dj ust me nt f or t he effect of cr oss o ver o n O S m a y  be perf or me d base d o n 
 
 
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M K -3 4 7 5
P A G E 1 2
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
rec o g nize d met h o ds, e. g., a t w o-sta ge met h o d or t he Ra n k Preser vi n g Str uct ural 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 [3 ], base d o n a n e xa mi nati o n of t he 
a p pr o priate ness of t he data t o t he ass u m pti o ns re q uire d b y t he met h o ds.
3. 6. 1. 3
O bjecti ve Res p o nse R ate ( O R R) a n d D ur ati o n of Res p o nse ( D O R)
T he stratifie d Mietti ne n a n d N ur mi ne n’s met h o d [5 ] wit h wei g hts pr o p orti o nal t o t he strat u m 
size will be use d f or c o m paris o n of t he O R R bet wee n t he treat me nt ar ms. T he differe nce i n O R R 
a n d its 9 5 % c o nfi de nce i nter val fr o m t he stratifie d Mie tti ne n a n d N ur mi ne n met h o d wit h strata 
wei g hti n g b y  sa m ple size wit h
a si n gle treat me nt c o variate will be re p orte d. T he stratificati o n 
fact ors use d f or ra n d o mizati o n ( See Pr ot oc ol Secti o n 5. 4) will be a p plie d t o t he a nal ys is. F or t he 
first i nteri m a nal ysis, d ue t o t he s mall sa m ple size i n t he strat u m wit h T P S < 1 % a n d na b -
paclita xel a n d East Asia, t his strat u m will be c o m bi ne d wit h t he strat u m wit h T P S < 1 % a n d 
paclita xel a n d East Asia i n stratifie d a nal ys es.
If sa m ple size per mits, D O R will be s u m marize d d escri pti vel y usi n g Ka pla n -Meier me dia ns a n d 
q uartiles. O nl y  the s u bset of patie nts w h o s h o w a c o m plete res p o nse or partial res p o nse will be 
i ncl u de d i n t his a nal ysis.
F or eac h D O R a nal ys is, a c orres p o n di n g s u m mar y of t he reas o ns res p o n di n g s u bjects are 
cens ore d will als o be pr o vi de d.  Res p o n di n g s u bjects w h o are ali ve, ha ve n ot pr o gresse d, ha ve 
n ot i nitiate d ne w a nti-ca ncer treat me nt, ha ve n ot bee n deter mi ne d t o be l ost t o f oll o w- u p, a n d 
ha ve ha d a disease assess me nt wit hi n ~ 5 m o nt hs of t he data c ut off dat e are c o nsi dere d o n g oi n g 
res p o n ders at t he ti me of a nal ys is.  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.
 
 
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0 6 D V Z Q


M K -3 4 7 5
P A G E 1 3
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 2 
Ce ns ori n g R ules f or D O R
Sit uati o n
Date 
of 
Pr o gressi o n 
or 
Ce ns ori n g
O utc o me
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 a nti-
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 after ≥ 2 
c o nsec uti ve 
misse d 
disease 
assess me nts
Last 
a de q uate 
disease 
assess me nt pri or t o ≥ 2 misse d 
a de q uate disease assess me nts
Ce ns or
( n o n-e ve nt)
Deat h or pr o gressi o n after ≤ 1 
miss e d disease assess me nts
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.  
3. 6. 1. 4
A n al ysis Str ate g y f or Ke y Effic ac y E n d p oi nts
Ta ble 3 s u m marizes t he pri mar y  anal ys is a p pr oac h f or pri mar y  an d ke y  sec o n dar y efficac y 
e n d p oi nts. Se nsiti vit y a nal ysis met h o ds are descri be d a b o ve f or eac h e n d p oi nt a s a p plica ble.
T he strate g y  t o 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, a n d i nteri m 
a nal ys es is descri be d i n Secti o n 3. 7 I nteri m A naly ses a n d i n Secti o n 3. 8 M ulti plicit y .
 
 
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M K -3 4 7 5
P A G E 1 4
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
Ta ble 3
A nal y sis Strate g y  f or Ke y Efficac y E n d p oi nts
E n d p oi nt/ V ari a ble
( Descri pti o n, Ti me P oi nt)
St atistic al Met h o d †
A n al ysis 
P o p ul ati o n
Missi n g D at a A p pr o ac h
D u al Pri m ar y E n d p oi nt s
P F S per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T

Pri mar y ce ns ori n g r ule

Se nsiti vit y a nal ysis 1

Se nsiti vit y a nal ysis 2
O S
Test : Stratifie d L o g-ra n k test 
t o assess t he treat me nt 
differe nce
Esti mati o n : Stratifie d C o x 
m o del wit h Efr o n’s tie 
ha n dli n g met h o d t o assess 
t he ma g nit u de of treat me nt 
differe nce
I T T
M o del base d
(ce ns ore d at t he last date t he 
s u bject was k n o w n t o be 
ali ve)
Ke y S ec o n d ar y E n d p oi nt s
O R R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Test a n d Esti mati o n : 
Stratifie d M & N met h o d wit h 
sa m ple size wei g hts † †
I T T
S u bjects wit h o ut assess me nts 
are c o nsi dere d n o n-
res p o n ders a n d 
c o nser vati vel y i ncl u de d i n 
de n o mi nat or
D O R per R E CI S T 1. 1 b y 
bli n de d i n de pe n de nt ce ntral 
i ma gi n g ve n d or
Descri pti ve statistics f or 
ra n ge a n d  Ka pla n-Meier 
esti mate of me dia n
Patie nts i n I T T 
p o p ulati o n wit h 
a n o bjecti ve 
res p o nse
  †
Statistical m o dels are descri be d i n f urt her detail i n t he te xt. F or stratifie d a nal yses, t he stratificati o n fact ors 
use d f or ra n d o mizati o n (Secti o n 5. 4) will be a p plie d t o t he a nal ysis. 
† †
Mietti ne n a n d N ur mi ne n met h o d
3. 6. 1. 5 
E x pl or at or y A n al yses
A n e x pl orat or y anal ys is of P F S 2, defi ne d as t he ti me fr o m ra n d o mizati o n t o s u bse q ue nt disease 
pr o gressi o n after i nitiati o n of ne w a nti-ca ncer t hera p y, o r deat h fr o m a n y ca use, w hic he ver first, 
ma y  be carrie d o ut. Patie nts ali ve a n d f or w h o m a disease pr o gressi o n f oll o wi n g i nitiati o n of ne w 
a nti-ca ncer treat me nt has n ot bee n o bser ve d will be ce ns ore d at t he last ti me t he s u bject was 
k n o w n t o be ali ve a n d wit h o ut disease pr o gressi o n
 
 
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M K -3 4 7 5
P A G E 1 5
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 6. 2
St atistic al Met h o ds f or S afet y A n al yses
Safet y  an d t olera bilit y will be assesse d b y  cli nical re vie w of all rele va nt para meters i ncl u di n g 
a d verse e x perie nces ( A Es), la b orat or y tests a n d vital si g ns.
A d verse E ve nts
A d verse e ve nts ( A Es) will be c o de d usi n g t he sta n dar d Me d D R A a n d gr o u pe d s yste m or ga n 
class. A d verse e ve nts ( A Es) will be gra de d b y  the i n vesti gat or acc or di n g t o t he C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E), versi o n 4. 0.
Tiere d A p pr o ac h
T he a nal y sis of safet y res ults will f oll o w a tiere d a p pr oac h (Ta ble 4 ). T he tiers differ wit h res pect 
t o t he a nal yses t hat will be perf or me d. “ Tier 1” safet y en d p oi nts will be s u bject t o i nfere ntial 
testi n g f or statistical si g nifica nce wit h p- val ues a n d 9 5 % c o nfi de nce i nter vals pr o vi de d f or 
bet wee n -gr o u p c o m paris o ns. F or t his pr ot oc ol, t here are n o Tier 1 A Es. Ot her safety para meters 
will be c o nsi dere d Tier 2 or Tier 3. Tier 2 para meters w ill 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  poi 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.
A d verse e x perie nces (s pecific ter ms as well as s yste m or ga n class ter ms) t hat are n ot pre -
s pecifie d as Tier 1 e n d p oi nts will be 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 of 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  95 % c o nfi de nce i nter vals m a y  be pr o vi de d 
wit h o ut a dj ust me nt f or m ulti plicit y , t he c o nfi de nce i nter vals s h o ul d be re gar de d as a hel pf ul 
descri pti ve meas ure t o be use d i n re vie w, n ot a f or mal met h o d f or assessi n g t he statistical 
si g nifica nce of t he bet wee n -gr o u p differe nces i n a d verse e x perie nces a n d pre defi ne d li mits of 
c ha n ge.
C o nti n u o us meas ures s uc h as c ha n ges fr o m baseli ne i n la b orat or y val ues a n d vital si g ns, a n d 
E C G para meters will be c o nsi dere d Tier 3 safet y para meters. S u m mar y  statistics f or baseli ne, 
o n- treat me nt, a n d c ha n ge fr o m baseli ne val ues will be pr o vi de d b y  treat me nt gr o u p i n ta ble 
f or mat. 
T o pr o pe rly 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 n a nal ysis of Gra de 3- 5 A Es will be base d 
o n t he ti me t o first e ve nt usi n g t he ti me-t o-e ve nt a nal ys is met h o ds (i.e., t he l o g-ra n k test will be 
use d f or testi n g t he ti me t o A Es, a n d t he C o x m o del wit h Efr o n's tie ha n dli n g met h o d will be 
use d f or esti mati n g t he hazar d rati o a n d its 9 5 % c o nfi de nce i nter val). F or ot her A Es wit h 
p ote ntiall y  differe ntial f oll o w- u p ti me, s uc h a nal ysis ma y  als o be e x pl ore d.
 
 
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0 6 D V Z Q


M K -3 4 7 5
P A G E 1 6
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
I n ad diti o n, 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 A E, a n y dr u g-relate d A E, a n y Gra de 3- 5 A E, a n y seri o us A E, a n y A E w hic h 
is b ot h dr u g relate d a n d Gra de 3- 5, a n y A E w hic h is b ot h seri o us a n d dr u g -relate d, 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. 9 5 % c o nfi de nce i nter vals ( Tier 2) will be pr o vi de d f or bet wee n -treat me nt 
differe nces i n t he perce nta ge of s u bjects wit h e ve nts; t hese a nal y ses will be perf or me d usi n g t he 
u nstratifie d Mietti ne n a n d N ur mi ne n met h o d
[5 ], a n u nc o n diti o nal, asy m pt otic met h o d . 
Ta ble 4
A nal y sis Strate g y  f or Safet y Para meters
Safet y Tier
Safet y E n d p oi nt
p -Val ue
9 5 % CI f or 
Treat me nt 
C o m paris o n
Descri pti ve 
Statistics
Tier 2
A n y A E
X
X
A n y Gra de 3 -5 A E
X
X
A n y Seri o us A E
X
X
O nset of First 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 Es, S O Cs (i ncl u di n g ≥4 of s u bjects i n o ne 
of t he treat me nt gr o u ps)
X
X
Tier 3
S pecific A Es, S O Cs (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
T here are n o Tier 1 A Es pre- s pecifie d i n t his pr ot oc ol.
3. 6. 3
S u m m aries of B aseli ne C h ar acteristics, De m o gr a p hics, a n d Ot her A n al yses
T he c o m para bilit y of t he treat me nt gr o u ps f or eac h rele va nt baseli ne c haracteristic will b e 
assesse d b y  the use of ta bles a n d/ or gra p hs. N o statistical h y p ot hesis tests will be perf or me d o n 
t hese c haracteristics. T he n u m ber a n d perce nta ge of s u bjects ra n d o mize d 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 (s uc h as a ge) a n d baseli ne 
c haracteristics will be s u m marize d b y  treat me nt eit her b y  descri pti ve statistics or cate g orical 
ta bles.
3. 7
I nteri m A n al ysis
T here are t hree pla n ne d i nteri m a nal yses (I A) i n a d diti o n t o t he fi nal a nal ysis f or t his st u d y. 
Details o n t he b o u n daries f or esta blis hi n g statistical si g nifica nce wit h re gar d t o efficac y are 
disc usse d f urt her i n Secti o n 3. 8 .  T he trial will c o nti n ue u ntil t he n u m ber of deat hs ( See Secti o n 
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 7
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
3. 9 ) is a p pr o xi matel y eq ual t o t he tar gete d n u m ber f or t he fi nal a nal ysis , irres pecti ve of t he 
o utc o me fr o m t he i nteri m a nal ys es. T he a nal ys es pla n ne d, e n d p oi nts e val uate d, a n d dri vers of 
ti mi n g are s u m marize d i n Ta ble 5 .
Ta ble 5
S u m mar y  of I nteri m a n d Fi nal A nalys es Strate g y
A n al yses 
Ke y 
E n d p oi nts 
Ti mi n g
Esti m ate d Ti me after 
First P artici p a nt 
R a n d o mize d 
Pri m ar y P ur p ose of A n al ysis
I A 1
O R R
~ 2 0 0 s u bjects are f oll o w e d 
f or ~ 2 8 wee ks s o t hat eac h 
patie nt has at least 4 t u m or 
assess me nts
~ 1 5 m o nt hs 
De m o nstrate O R R 
s u peri orit y
I A 2
P F S
O S
~ 3 3 2 P F S e ve nts ha ve bee n 
o bser ve d.
~ 2 0 m o nt hs 
De m o nstrate P F S s u peri orit y
De m o nstrate O S  s u peri orit y
I A 3
P F S
O S
~ 4 1 5 P F S e ve nts ha ve bee n 
o bser ve d 
~ 2 5 m o nt hs
De m o nstrate P F S s u peri orit y
De m o nstrate O S  s u peri orit y
Fi nal 
A nal ysis
O S
~ 3 6 1 deat hs ha ve occ urre d . 
~ 3 1 m o nt hs 
De m o nstrate O S  s u peri orit y
3. 8
M ulti plicit y
T he st u d y uses t he gra p hical met h o d of Ma urer a n d Bretz [2 ] t o c o ntr ol m ulti plicit y  for m ulti ple 
h y p ot heses as well as i nteri m a nal yses. Acc or di n g t o t his a p pr oac h, st u d y hy p ot heses m a y  be 
teste d m ore t ha n o nce, a n d w he n a partic ular n ull h y p ot hesis is rejecte d, t he al p ha all ocate d t o 
t hat h y p ot hesis ca n be reall ocate d t o ot her h y p ot hesis tests. Fi g ure 1 s h o ws t he i nitial o ne- si de d 
al p ha all ocati o n f or eac h h 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.
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 1 8
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
N ote: If b ot h P F S a n d O S n ull h y p ot heses are rejecte d, t he reall ocati o n strate g y all o ws re -testi n g of O R R at al p ha = 0. 0 2 5 base d o n t he p-val ue at 
I A 1
O R R = o bjecti ve res p o nse rate; O S = o verall s ur vi val; P F S = pr o gressi o n-free s ur vi val
Fi g ure 1
T y pe I Err or Reall ocati o n Strate g y F oll o wi n g Cl ose d Testi n g Pri nci ple
3. 8. 1
O bjecti ve Res p o nse R ate
T he st u d y all ocates al p ha = 0. 0 0 5 , o ne-si de d, t o test O R R, a n d O R R is teste d o nl y  at t he first 
i nteri m a nal ys is (I A 1). H o we ver, if t he test d oes n ot reac h statistical si g nifica nce at I A 1, t he p-
val ue fr o m I A1 ca n be c o m pare d t o a n u p date d al p ha-le vel if t he n ull h y p ot heses f or b ot h P F S 
a nd O S are rejecte d at a later ti me. P o wer at t he p ossi ble al p ha-le vels as well as t he a p pr o xi mate 
treat me nt differe nce re q uire d t o reac h t he b o u n d ( O R R differe nce ) are s h o w n i n Ta ble 6 , 
ass u mi n g u n derl yi n g 2 5 % a n d 5 0 % res p o nse rates i n t he c o ntr ol a n d e x peri me ntal gr o u ps, 
res pecti vely. 
Ta ble 6
P ossi ble Al p ha -le vels a n d A p pr o xi mate O R R differe nce Re q uire d t o De m o nstrate 
Efficac y  f or O R R at I A 1
Al p h a
O R R differe nce
P o w er
0. 0 0 5
~ 0. 1 8
0. 8 4
0. 0 2 5
~ 0. 1 3
0. 9 4
 
 
0 5 G W B G
0 6 D V Z Q


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


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


M K -3 4 7 5
P A G E 2 1
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
si g nifica nce le vel, a n d ~ 9 2 % p o wer f or det ecti n g a H R of 0. 7 at 0. 0 2 5 ( o ne-si de d) si g nifica nce 
le vel.
T he pla n ne d sa m ple size is a p pr o xi matel y 56 0 s u bjects ass u mi n g: ( 1) t he e nr oll me nt peri o d is 
1 5. 5 m o nt hs a n d t he ra m p- u p peri o d of e nr oll me nt is 7 m o nt hs; ( 2) me dia n P F S is 6 m o nt hs i n 
t he c o ntr ol gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 3) me dia n O S is 1 2 m o nt hs i n t he c o ntr ol 
gr o u p a n d t he tr ue hazar d rati o is 0. 7; ( 4) t he a n n ual dr o p o ut rate is 3 % f or P F S a n d 1 % f or O S; 
( 5) t he n u m ber of e ve nts a n d al p ha le vels of i nteri m a nal yses a n d fi nal a nal ys is are as s pecifie d 
i n Secti o n 3. 7 a n d Secti o n 3. 8 .
3. 1 0
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
T o deter mi ne w het her t he treat me nt effect is c o nsiste nt acr oss vari o us s u b gr o u ps, t he bet wee n -
gr o u p treat me nt effect ( wit h a n o mi nal 9 5 % CI) will be esti mate d a n d pl otte d wit hi n eac h 
cate g or y of t he f oll o wi n g classificati o n varia bles:

A ge cate g or y  (< 6 5 vs. ≥6 5 y ears, a n d < 6 5 vs. 6 5 -7 4 vs. 7 5 -8 4 vs. ≥8 5 y ears)

Se x (fe male vs. male)

Race ( w hite vs. n o n -w hite)

E C O G stat us ( 0 vs. 1)

Ge o gra p hic re gi o n of e nr olli n g site (East Asia vs. N o n- East Asia ; U S vs. E x -U S; E U vs. 
N o n -E U )

S m o ki n g stat us ( ne ver vs. f or mer /c urre nt)

Brai n metastasis stat us at baseli ne ( y es vs. n o)

P D -L 1  stat us (T P S < 1 % vs. T P S ≥1 %, T P S < 5 0 % vs. T P S ≥5 0 % , TP S < 1 % vs . T P S 1 
– 4 9 % vs .T P S ≥5 0 %)

Ta xa ne c he m ot hera p y (paclita xel vs. na b -paclita xel )
A d diti o nal s u b gr o u p a nal yses s uc h as C hi na vs. n o n- C hi na ma y  be c o n d ucte d per C hi na l ocal 
re g ulat or y nee ds. T he c o nsiste nc y of t he treat me nt effect will be assesse d descri pti vel y  via 
s u m mar y statistics b y  cate g or y for t he classificati o n varia bles liste d a bo ve. If a n y le vel of a 
s u b gr o u p varia ble has fe wer t ha n 1 0 % of t he I T T p o p ulati o n , a b o ve a nal ys is will n ot be 
perf or me d f or t his le vel of t he s u b gr o u p varia ble. If a s u b gr o u p varia ble has t w o le vels a n d o ne 
le vel of t he s u b gr o u p varia ble has fe wer t ha n 1 0 % of t he I T T p o p ulati o n , t he n t his s u b gr o u p will 
n ot be dis pla y e d i n t he f orest pl ot. F or t he first i nteri m a nal ysis, t he s u b gr o u p a nal ysis f or O R R 
will be c o n d ucte d usi n g u nstratifie d Mietti ne n a n d N ur mi ne n met h o d .
T he E U re gi o n i ncl u des c o u ntries fr o m b ot h E U me m ber states ( 2 0 1 6) a n d E F T A me m bers.
3. 1 1
E xte nt of E x p os ure
T he e xte nt of e x p os ure will be s u m marize d as d urati o n of treat me nt i n c y cles. 
 
 
0 5 G W B G
0 6 D V Z Q


M K -3 4 7 5
P A G E 2 2
P R O T O C O L N O. 4 0 7 v 0 4
S u p ple me ntal S A P
     2 9J A N 2 0 1 8 – A M E N D M E N T # 0 4
4
S T A TI S TI C A L A N A L Y SI S P L A N F O R E X T E N SI O N
4. 1 
I ntr o d ucti o n
Af ter t he gl o bal st u d y enr oll me nt is cl ose d, s u bjects fr o m C hi na will c o nti n ue t o be e nr olle d i n 
a n e xte nsi o n st u d y desi g ne d t o meet C hi na l ocal re gistrati o n nee ds .  The e xte nsi o n st u d y will be 
i de ntical t o t he gl o bal st u d y (e. g., i ncl usi o n a n d e xcl usi o n criteria, pri mar y  an d sec o n dar y 
e n d p oi nts, st u d y pr oce d ures) i n ge neral, wit h t he a d diti o nal statistical a nal ys is pla n f or t he 
C hi nese s u b p o p ulati o n.  The p ur p ose of t his e xte nsi o n st u d y is t o e val uate t he c o nsiste nc y of 
efficac y a n d safet y i n t he C hi nese s u bp o p ulati o n t o t he gl o bal p o p ulati o n.  C o u ntr y -s pecific 
a nal ys is ma y als o be c o n d ucte d per l ocal re g ulat or y re q uire me nt.
After t he e nr oll me nt f or t he gl o bal st u d y is c o m plete d, s u bjects i n C hi na will c o nti n ue t o be
e nr olle d i n a 1: 1 rati o i nt o t he pe m br oliz u ma b ar m a n d t he S O C ar m u ntil t he sa m ple size f or t he 
o verall C hi nese s u b p o p ulati o n reac hes a p pr o xi matel y 1 2 0.  
After t he c ut-off date f or t he pri mar y  a nal ys es of t he gl o bal st u d y (i ncl u di n g i nteri m a n d fi nal 
a nal ys es), all C hi nese s u bjects, i ncl u di n g s u bjects e nr olle d i n t he gl o bal st u d y a n d t he e xte nsi o n 
st u d y , will c o nti n ue t heir ra n d o mize d treat me nt a n d c o nti n ue t o be f oll o we d u p f or P F S a n d O S 
e ve nts f or C hi na re gistrati o n p ur p ose. T he e xte nsi o n st u d y will be c o m plete d after tar get n u m ber 
of deat hs has bee n o bser ve d bet wee n t he t w o ar ms i n t he C hi nese s u b p o p ulati o n. T he e x pecte d 
ti mi n g of t he a nal ys is f or t he s u b p o p ulati o n is ar o u n d 3. 3 years fr o m t he ti me w he n t he first 
s u bject fr o m C hi na is e nr olle d i n t he gl o bal st u d y.  Ho we ver, if t he tar get n u m ber of P F S e ve nts 
or deat hs i n t he C hi nese s u b p o p ulati o n is reac he d bef ore a n I A for t he gl o bal st u d y, t he 
c orres p o n di n g a nal ysis f or C hi nese s u b p o p ulati o n will occ ur at t he sa me ti me as t he gl o bal I A or 
t he fi nal a nalys is ( gl o bal st u d y). 
4. 2
Res p o nsi bilit y f or A n al yses/I n- H o use Bli n di n g
T he trial is d o u ble - bli n de d, a nal ys es or s u m maries ge nerate d b y  ra n d o mize d treat me nt 
assi g n me nt a n d act ual treat me nt recei ve d will be li mite d a n d d oc u me nte d. S u bjects ra n d o mize d 
i n t he e xte nsi o n st u d y will n ot be i ncl u de d i n t he data base l oc k a n d pri mar y  anal ys is f or t he 
gl o bal st u d y. 
F or all C hi nese s u bjects, i ncl u di n g s u bjects ra n d o mize d i n t he gl o bal st u d y an d t he e xte nsi o n 
st u d y, pat ie nt le vel treat me nt ra n d o mizati o n 
i nf or mati o n will 
be 
bli n de d 
t o t he 
statisticia n(s)/ pr o gra m mer(s) res p o nsi ble f or t he a nal ysis of C hi na e xte nsi o n st u d y until t he 
e xte nsi o n st u d y data base l oc k is ac hie ve d. T he e xte nt t o w hic h i n di vi d uals are u n bli n de d t o t he 
res ults will be li mite d. Bli n de d a n d u n bli n de d me m bers will be clearly d oc u me nte d wit h bli n di n g 
stat us al o n g wit h ti me i nf or mati o n. 
4. 3
H y p ot heses/ Esti m ati o n
N o h y p ot hesis testi n g is pla n ne d f or t he C hi na e xte nsi o n st u d y.
After s uccee di n g i n t he gl o bal st u d y, t he c o nsiste nc y of efficac y an d safety i n t he C hi nese 
s u b p o p ulati o n t o t he gl o bal p o p ulati o n will be e val uate d. C o nsiste nc y of efficac y will be 
 
 
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e val uate d usi n g t he perce nta ge of ris k re d ucti o n preser ve d i n t he C hi nese s u b p o p ulati o n fr o m t he 
e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y efficac y anal ys es ( base d o n p oi nt esti mates). 
Sa m ple size is desi g ne d t o pr o vi de a b o ut 8 0 % c ha nce of o bser vi n g t he p oi nt esti mate of C hi nese 
s u b p o p ulati o n preser ves ≥a p pr o xi matel y 50 % of e m pirical ris k re d ucti o n fr om t he gl o bal 
pri mar y  efficac y anal ys is ass u mi n g t he sa me hazar d rati o use d i n t he sa m ple size a n d p o wer 
calc ulati o n f or t he gl o bal st u d y .  
4. 4
T he A n al ysis E n d p oi nts
4. 4. 1
Effic ac y E n d p oi nts
D u al Pri m ar y 
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, t he 
sa me as descri be d i n Secti o n 3. 4. 1 .
Pr o gressi o n -free s ur vi val ( P F S) is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first 
d oc u me nte d disease pr o gressi o n per R E CI S T 1. 1 base d o n bli n de d i n de pe n de nt ra di ol o gists’ 
assess me nt or deat h d ue t o a n y ca use, w hic he ver occ urs first, t he sa me as descri be d i n Secti o n 
3. 4. 1 .
Sec o n d ar y
O bjecti ve res p o nse rate ( O R R) base d u p o n bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or ’s
assesse d R E CIS T 1. 1 as descri be d i n Secti o n 3. 4. 1 .
D urati o n of res p o nse ( D O R) base d u p o n bli n de d i n de pe n de nt ce ntral i ma gi n g ve n d or ’s assesse d 
R E CI S T 1. 1 as descri be d i n Secti o n 3. 4. 1 .
4. 4. 2
S afet y E n d p oi nts
Safet y  e n d p oi nts are t he sa me as descri be d i n Secti o n 3. 4. 2 .
4. 5
A n al ysis P o p ul ati o ns
4. 5. 1
Effic ac y A n al ysis P o p ul ati o ns
Efficac y  anal y sis will be carrie d o ut i n t he e ntire i nte nti o n-t o-treat (I T T) p o p ulati o n . T his 
p o p ulati o n will i ncl u de all s u bjects w h o are ra n d o mize d i n t he gl o bal st u d y a n d all s u bjects w h o 
are ra n d o mize d i n t he e xte nsi o n st u d y. C hi nese s u b p o p ulati o n will i ncl u de all C hi nese s u bjects 
i n t his p o p ulati o n. 
4. 5. 2
S afet y A n al ysis P o p ul ati o ns
Safet y  an a l ysis will be carrie d o ut i n t he e ntire All S u bjects as Treate d ( A Sa T) p o p ulati o n, i.e., 
all ra n d o mize d s u bjects (i n t he gl o bal st u d y an d e xte nsi o n st u d y) w h o recei ve d at least 1 d ose of 
st u d y treat me nt.  C hi nese s u b p o p ulati o n will i ncl u de all C hi nese s u bjects i n t his p o p ulati o n. 
 
 
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4. 6
St atistic al Met h o ds
Re gar di n g t he a nal ys is f or e xte nsi o n, n o h y p ot hesis testi n g is pla n ne d. T here is n o pla n of 
i nteri m a nal ysis. N o m ulti plicit y a dj ust me nt will be a p plie d t o t he a nal ysis f or e xte nsi o n.
4. 6. 1
St atistic al Met h o ds f or Effic ac y A n al yses
4. 6. 1. 1
O ver all S ur vi v al ( O S)
A nal y sis of O S f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y if a p plica ble. 
I n detail, t he 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. F or t he w h ole 
p o p ulati o n, stratifie d l o g-ra n k wil l be use d t o assess t he treat me nt differe nce a n d stratifie d C o x 
pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese 
s u b gr o u p a nal ys is, t he stratifie d met h o d will o nl y be use d if a p plica ble. T he fact or of Ge o gra p h y 
( East Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ysis f or t he C hi nese 
s u b gr o u p a nalys is.
As a n e x pl orat or y anal ysis, rec o g nize d met h o ds, e. g., t he Ra n k Preser vi n g Str uct ural Fail ure 
Ti me ( R P S F T) m o del, t w o-sta ge met h o d, etc., will be use d t o a dj ust f or t he effect of cr oss o ver 
o n O S base d u p o n t he a p pr o priate ness of t he data t o t he ass u m pti o n re q uire d b y  the met h o ds. 
T he R P S F T m o del 
pr o vi des a ra n d o mizati o n-base d esti mate of treat me nt effect ( R B E E) 
c orrecte d f or t he bias i n d uce d b y cr oss o ver. T he 9 5 % c o nfi de nce i nter vals of t he hazar d rati o f or 
O S after a dj ust me nt of t he effect of cr oss o ver will be pr o vi de d. T o f urt her acc o u nt f or t he 
p ossi ble c o nf o u n di n g effect, a se nsiti vit y anal ys is of O S t hat ce ns ors s u bjects at t he ti me of 
i nitiati o n of ne w t hera p y will be perf or me d a n d a n O S a nal ysis t hat treats i nitiati o n of ne w 
t hera py as a ti me -de pe n de nt bi nar y  c o variate will als o be c o n d ucte d.
C o nsiste nc y  of efficac y will be e val uate d usi n g t he perce nta ge of ris k re d ucti on preser ve d i n t he 
C hi nese s u b p o p ulati o n fr o m t he e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y  efficac y 
a nal ys es ( base d o n p oi nt esti mates). Sa m ple size is desi g ne d t o pr o vi de a b o ut 8 0 % c ha nce of 
o bser vi n g t he p oi nt esti mate of C hi nese s u b p o p ulati o n pr eser ves ≥ a p pr o xi matel y 50 % of 
e m pirical ris k re d ucti o n fr o m t he gl o bal pri mar y  efficac y a nal ys is ass u mi n g t he sa me hazar d 
rati o use d i n t he sa m ple size a n d p o wer calc ulati o n f or t he gl o bal st u d y.
I n a d diti o n, s u p p orti ve a nal ys es o n t he e ntire I T T p o p ulati o n will be pr o vi de d wit h t he data 
p o ol i n g gl o bal st u d y (pri or t o data c ut off f or t he pri mar y  anal ys is) a n d C hi na e xte nsi o n st u d y 
t o get her. Acc or di n gl y, n o n -C hi nese s u bjects will be ce ns ore d at last k n o w n ali ve date (t his ca n 
be c ut off date if s o me assess ment ha p pe n s t o be o n t hat da y  or t here’s assess me nt be y o n d t he 
c ut off date) w hic h is c o nsiste nt wit h t he pri mar y  a nal ys is i n t he gl o bal st u d y if s u bjects are still 
ali ve at pri mar y  an al y sis ti me f or gl o bal st u d y. T he pri mar y anal y sis f or O S will be c o n d uct e d i n 
t he C hi nese s u b p o p ulati o n w he n a p pr o xi matel y 7 5 O S e ve nts ha ve bee n c ollecte d.
 
 
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4. 6. 1. 2
Pr o gressi o n -Free S ur vi v al ( P F S)
A nal y sis of P F S f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y if a p plica ble. 
I n detail, t he 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. F or t he w h ole 
p o p ulati o n, stratifie d l o g-ra n k test will be use d t o assess t he treat me nt differe nce a n d stratifie d 
C o x pr o p orti o nal hazar d m o del wit h Efr o n's met h o d of tie ha n dli n g will be use d t o assess t he 
ma g nit u de of t he treat me nt differe nce (i.e., t he hazar d rati o). T he hazar d rati o a n d its 9 5 % 
c o nfi de nce i nter val fr o m t he stratifie d C o x m o del wit h a si n gle treat me nt c o variate will be 
re p orte d. T he sa me stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese 
s u b gr o u p a nal ys is, t he stratifie d met h o d will o nl y be use d if a p plica ble. T he fact or of Ge o gra p h y 
( East Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ysis f or C hi nese s u b gr o u p 
a nal ys is. I n case t he pr o p orti o nal hazar ds ass u m pti o n d oes n’t h ol d, Fle mi n g a n d Harri n gt o n’s 
wei g hte d l o g-ra n k test, Restricte d Mea n S ur vi val Ti me ( R M S T) met h o d or ot her met h o ds, as 
a p pr o priate, ma y be c o n d ucte d.
C o nsiste nc y  in P F S will be e val uate d si milarly as t hat i n O S.  The pri mar y a nal ys is f or P F S wil l 
be c o n d ucte d i n t he C hi nese s u b p o p ulati o n w he n a p pr o xi matel y 75 P F S e ve nts ha ve bee n 
c ollecte d.
4. 6. 1. 3
O bjecti ve Res p o nse R ate ( O R R) a n d D ur ati o n of Res p o nse ( D O R)
Stratifie d Mietti ne n a n d N ur mi ne n’ s met h o d wit h wei g hts pr o p orti o nal t o t he strat u m size will be
use d f or c o m paris o n of t he O R R bet wee n t he treat me nt ar ms. A 9 5 % CI f or t he differe nce i n 
res p o nse rates bet wee n t he pe m br oliz u ma b ar m a n d t he c o ntr ol ar m will b e pr o vi de d. T he sa me 
stratificati o n fact ors use d i n t he gl o bal st u d y will be use d. F or t he C hi nese s u b p o p ulati o n 
a nal ys is, t he stratifie d met h o d will o nl y  be use d if a p plica ble. T he fact or of Ge o gra p h y ( East 
Asia vs. n o n- East Asia) will n ot be i ncl u de d i n t he stratifie d a nal ys is f or C hi nese s u b gr o u p 
a nal ys is.
F or t he C hi nese s u b gr o u p a nal ys is, D O R will be s u m marize d descri pti vel y usi n g Ka pla n -Meier 
me dia ns
a n d q uartiles if sa m ple size per mits. O nl y t he s u bset of patie nts w h o s h o w a c o m plete 
res p o nse or partial res p o nse will be i ncl u de d i n t his a nal y sis.
4. 6. 1. 4
E x pl or at or y A n al yses
E x pl orat or y  A nalys es f or e xte nsi o n is t he sa me t o t hat f or t he gl o bal st u d y (if a p plica ble).
4. 6. 2
St atistic al Met h o ds f or S afet y A n al yses
Safet y  anal ys es f or e xte nsi o n are t he sa me t o t hat f or t he gl o bal st u d y as descri be d i n Secti o n 
3. 6. 2 .  
4. 6. 3
S u m m aries of B aseli ne C h ar acteristics, De m o gr a p hics, a n d Ot her A n al yses
T he y  are t he sa me f or e xte nsi o n t o t hat f or t he gl o bal st u d y as descri be d i n Secti o n 3. 1 0 . 
 
 
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4. 7
I nteri m A n al ysis & Fi n al a n al ysis 
T he pri mar y  anal y sis f or P F S will 
be c o n d ucte d i n t he C hi nese 
s u b p o p ulati o n w he n 
a p pr o xi matel y 7 5 P F S e ve nts ha ve bee n c ollecte d. O S w ill als o be a nal yze d .
T he 
pri mar y  anal ys is f or O S 
will 
be c o n d ucte d i n t he C hi nese 
s u b p o p ulati o n w he n 
a p pr o xi matel y 7 5 O S e ve nts ha ve bee n c ollecte d.
4. 8
M ulti plicit y
N o m ulti plicit y  a dj ust me nt will be a p plie d t o t he a nal ysis of C hi na. 
4. 9
S a m ple Size a n d P o wer C alc ul ati o ns
After t he e nr oll me nt of gl o bal st u d y co m pletes , t he e xte nsi o n st u d y will c o nti n ue t o ra n d o mize 
s u bjects i n a 1: 1 rati o i nt o t he pe m br oliz u ma b ar m a n d t he place b o ar m i n C hi na u ntil t he sa m ple 
size f or t he o verall C hi nese s u bjects (i ncl u di n g th ose e nr olle d i n t he gl o bal st u d y) reac hes 
a p pr o xi matel y 12 0. T he e xte nsi o n st u d y  p o p ulati o n, i.e., t h ose C hi nese s u bjects ra n d o mize d after 
t he cl ose of e nr oll me nt f or t he gl o bal st u d y, will n ot be i ncl u de d i n t he gl o bal pri mar y a nal ysis. 
T he e xte nsi o n st u d y will c o m plete after ≥a p pr o xi matel y 75 deat hs ha ve bee n o bser ve d bet wee n 
t he t w o ar ms i n t he C hi nese s u b p o p ulati o n ass u mi n g t he u n derl yi n g hazar d rati o f or O S is 0. 7 0. 
Wit h 7 5
deat hs a n d a tr ue hazar d rati o of 0. 7 0 , t he e xte nsi o n st u d y has > 9 0 % c ha nce t o o bser ve a 
hazar d rati o o n O S < 1 a n d ~ 8 0 %  cha nce t o o bser ve a p oi nt esti mate t hat preser v es ≥
a p pr o xi matel y 50 % of t he e m pirical ris k re d ucti o n fr o m t he gl o bal a nal ysis i n t he C hi nese 
s u b p o p ulati o n ass u mi n g t he u n derl yi n g hazar d rati o is 0. 7 0. T he sa me c o nsi derati o n a p plies t o 
P F S. 
T he a b o ve calc ulati o ns f or t he c o nsiste nc y eval uati o n i n P F S a n d O S are base d o n t he sa me 
ass u m pti o ns o n t he c orres p o n di n g me dia n O S/ P F S a n d t he tr ue hazar d rati o res pecti vely.
4. 1 0
S u b gr o u p A n al yses a n d Effect of B aseli ne F act ors
All s u b gr o u p a nal ys is defi ne d i n S ecti o n 3. 1 0 will be re peate d f or t he e ntire p o p ulati o n a n d 
C hi nese s u b p o p ulati o n if a p plica ble. I n a d diti o n, res ults f or C hi nese s u b p o p ulati o n vs. n o n-
C hi nese s u b p o p ulati o n will be pr o vi de d. C o u ntr y -s pecific a nal ys is m a y  als o be c o n d ucte d per 
l ocal re g ulat or y re q uire me nt.
 
 
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5
R E F E R E N C E S
1.
A n ders o n K M, Clar k J B. Fitti n g s pe n di n g f u ncti o ns. Stat Me d 2 0 1 0; 2 9( 3): 3 2 1 - 7.
2.
Ma urer 
W, 
Bretz 
F. M ulti ple 
testi n g i n gr o u p se q ue ntial trials usi n g gra p hical 
a p pr oac hes. Stat Bi o p har m Res 2 0 1 3; 5( 4): 3 1 1 - 2 0.
3.
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 n Stat - T he or M 1 9 9 1; 2 0( 8): 2 6 0 9- 3 1.
4.
Fi n kelstei n D M. 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 1 9 8 6; 4 2: 8 4 5 -5 4.
5.
Mietti ne n O, N ur mi ne n M. C o m parati ve a nal ys is of t w o rates. Stat Me d 1 9 8 5; 4: 2 1 3- 2 6.
 
 
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Re visi o n Hist or y
D ate
S u m m ar y of C h a n ge
0 9 J U N2 0 1 7
Ori gi nal D oc u me nt
2 3 O C T 2 0 1 7
Versi o n 0 2
1 5 N O V 2 0 1 7
Versi o n 0 3
2 9 J A N 2 0 1 8
Versi o n 0 4
 
 
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