Clinical trial NCT02325557
Conditions: Cancer Prostate Cancer
Sponsor: Advaxis, Inc.
Start date: 2015-06-04; Completion date: 2020-01-22
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1/2 multicenter, dose determining, open-label study of ADXS31-142 monotherapy and a combination of ADXS31-142 and pembrolizumab (MK-3475) in participants with metastatic castration-resistant prostate cancer. Part A will be dose-determining part of ADXS31-142 monotherapy. Part B will be dose-determining part of ADXS31-142 and pembrolizumab (MK-3475) in combination. Part B expansion will treat additional participants with the recommended dose from Part B.

Detailed description:
Part A of the study will be an open-label, Phase 1, multicenter, non-randomized, dose-determining trial of ADXS31-142 monotherapy in participants with mCRPC. The dose determining phase is intended to select a recommended Phase 2 dose (RP2D) for Part B.

Part B of the study will be an open-label, Phase 1-2, multicenter, non-randomized dose-determining trial of ADXS31-142 in combination with pembrolizumab (MK-3475) in participants with mCRPC. Part B will consist of a dose-determination phase followed by an expansion cohort phase. The dose-determining phase is intended to select an RP2D for the combination.

Dose escalation/de-escalation for this study will be explored by applying the modified toxicity probability interval design.

Arms: arm 1: Participants received ADXS31-142 1 × 10\^9 colony-forming units (CFU), 5 × 10\^9 CFU, or

1 × 10\^10 CFU intravenously (IV) every 3 weeks (Q3W) in a 12-week cycle for up to 24 months or until disease progression or discontinuation. arm 2: Participants received ADXS31-142 1 × 10\^9 CFU) IV Q3W (in a 12-week cycle) in combination with 200 mg pembrolizumab IV Q3W for three times, with a fourth pembrolizumab dose 3 weeks later (in 12 week-cycles) for up to 24 months or until disease progression or discontinuation.
Interventions: intervention 1: ADXS31-142 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: ADXS31-142 IV infusion intervention 2: Pembrolizumab IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1  of 9 4  
P R O T O C O L A D X S 1 4 2 -0 3  
A P H A S E 1 -2 D O S E - E S CA L A TI O N A N D S A F E T Y S T U D Y O F 
A D X S 3 1 -1 4 2 A L O N E A N D  O F A D X S 3 1 -1 4 2 I N C O M BI N A TI O N WI T H 
P E M B R O LI Z U M A B ( M K -3 4 7 5) I N P A TI E N T S WI T H  P R E VI O U S L Y 
T R E A T E D M E T A S T A TI C C A S T R A TI O N -R E SI S T A N T P R O S T A T E 
C A N C E R  
S P O N S O R: 
A D V A XI S, I N C.  
3 0 5 C O L L E G E R O A D E A S T 
P RI N C E T O N, N J 0 8 5 4 0  
6 0 9 -4 5 2 -9 8 1 3 ( O F FI C E )
6 0 9 -4 5 2 -9 8 1 8 ( F A X)
I N D N U M B E RS:   
A D X S 3 1- 1 4 2:  1 6 2 3 7  
P E M B R O LI Z U M A B ( M K -3 4 7 5):  1 1 0 0 8 0  
Versi o n 1. 0: 
A u g ust 1 9, 2 0 1 4 
A me n d me nt 1:   
Oct o ber 1 9, 2 0 1 4 
A me n d me nt 2:  
N o ve m ber 1 2, 2 0 1 4 
A me n d me nt 3:   
Dece m b er 1 9, 2 0 1 4 
A me n d me nt 4:   
A pril 3 0, 2 0 1 5 
A me n d me nt 5:  
A u g ust 1 3, 2 0 1 5 
A me n d me nt 6:  
Dece m b er 2, 2 0 1 5 
A me n d me nt 7: 
Dece m b er 3 0, 2 0 1 5 
A me n d me nt 8:  
A u g ust 5, 2 0 1 6 
A me n d me nt 9:  
A pril  2 1, 2 0 1 7 




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3  of 9 4  
 
 
 
 
 
 
 
 
I N V E S TI G A T O R SI G N A T UR E  PA G E  
Pr ot oc ol  N o.:    
 
A D X S 1 4 2 - 0 3 
Title:  
A P hase 1 - 2 D ose- Escal ati o n a n d Safet y St u d y of A D X S 3 1- 1 4 2 
Al o ne a n d of A D X S 3 1- 1 4 2 i n C o m bi nati o n wit h Pe m br oliz u ma b 
( M K-3 4 7 5) i n Patie nts wit h Pre vi o usl y Treate d M etastatic 
Castrati o n -Resista nt Pr ostate Ca ncer  
A me n d me nt 9 :  
 
A pril  2 1, 2 0 1 7 
 
B y si g ni n g b el o w, t he I n vesti gat or a grees t o a d here t o t he pr ot oc ol as o utli ne d a n d a grees t hat 
a n y c ha n ges t o t he pr ot oc ol m ust be a p pr o ve d b y A d va xis, I nc. pri or t o s ee ki n g a p pr o val fr o m 
t he a p pr o vi n g I nstit uti o nal Re vie w B o ar d (I R B)/ Et hical Re vie w C o m mittee ( E R C). 
T his  st u d y will  be c o n d ucte d i n acc or da nce wit h  G o o d Cli nical  Practices  ( G C Ps), I nter n ati o nal 
C o u ncil o n  Har m o nisati o n, f or merl y I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
G ui deli nes, t he Declarati o n  of Helsi n ki,  a n d l ocal et hical a n d le gal re q uire me nts. 
 
I n vesti g at or N a me:  
 
 
  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g nat ure 
Date  
 
  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
PI N a me ( Pri nte d) 
Site #  
 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4  of 9 4  
 
 
 
 
 
 
 
 
T A B L E O F C O N T E N T S  
Pr ot oc ol A D X S 1 4 2- 0 3 ........................................................................................................ 1  
Pr ot oc ol A p pr o v al .............................................................................................................. 2  
I n vesti g at or Si g n at ure P a ge .............................................................................................. 3 
T a ble Of C o nte nts  .............................................................................................................. 4 
List of T a bles  ...................................................................................................................... 7 
1  
Tri al S u m m ar y ............................................................................................................ 8  
2  
Tri al Desi g n  ................................................................................................................. 8 
2. 1  
Tri al Desi g n  ............................................................................................................ 8 
2. 1. 1  
P art A  – A D X S 3 1 -1 4 2 M o n ot her a p y .............................................................. 8 
2. 1. 2  
P art B – A D X S 3 1 - 1 4 2 + Pe m b r oliz u m a b ( M K- 3 4 7 5) C o m bi n ati o n 
T her a p y  ............................................................................................................. 9 
2. 2  
Tri al Desi g n  .......................................................................................................... 1 0 
3  
O bjecti ves  & H y p ot hes es  ......................................................................................... 1 0 
3. 1  
Pri m ar y O bjecti ves & H y p ot heses  ..................................................................... 1 0 
3. 2  
Sec o n d ar y O bjecti ves ........................................................................................... 1 0 
3. 3  
E x pl or at or y O bjecti ve ......................................................................................... 1 1  
4  
B ac k gr o u n d & R ati o n ale ......................................................................................... 1 1  
4. 1  
B ac k gr o u n d .......................................................................................................... 1 1  
4. 1. 1  
P h ar m a ce utic al a n d T her a pe utic B ac k gr o u n d  ........................................... 1 1 
4. 1. 1. 1  
A D X S 3 1 - 1 4 2 I m m u n ot her a p y ................................................................ 1 1 
4. 1. 1. 2  
A nti -P D - 1 A nti b o d y Pe m br oliz u m a b ( M K- 3 4 7 5) ................................. 1 2 
4. 1. 2  
Precli nic al a n d Cli nic al Tri al D at a ............................................................... 1 3  
4. 1. 3  
S u m m ar y of S af et y of A D X S 3 1- 1 4 2 b ase d o n A D X S 1 1- 0 0 1 ...................... 1 3  
4. 1. 4  
Del a ye d/ L ate Listeri a I nf ecti o n  .................................................................... 1 6 
4. 2  
R ati o n ale ............................................................................................................... 1 6  
4. 2. 1  
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  ........................... 1 6 
4. 2. 2  
R ati o n ale f or D ose Selecti o n/ Re gi me n/ M o dific ati o n .................................. 1 9  
4. 2. 2. 1  
A D X S 3 1 - 1 4 2 D ose Selecti o n .................................................................... 1 9 
4. 2. 2. 2  
Pe m b r oliz u m a b ( M K - 3 4 7 5) D ose Selecti o n ........................................... 2 0 
4. 2. 3  
R ati o n ale f or E n d p oi nts ................................................................................ 2 1  
4. 2. 3. 1  
Effic ac y E n d p oi nts ................................................................................... 2 1  
4. 2. 3. 2  
S af et y  E n d p oi nts  ...................................................................................... 2 1 
 
 
5  
Met h o d ol o g y .............................................................................................................. 2 2  
5. 1  
E ntr y Criteri a  ....................................................................................................... 2 2 
5. 1. 1  
Di a g n osis/ C o n diti o n f or E ntr y i nt o t he Tri al .............................................. 2 2  
5. 1. 2  
S u bject I ncl usi o n Criteri a  ............................................................................. 2 2 
5. 1. 3  
S u bject E xcl usi o n Criteri a  ............................................................................ 2 4 
5. 2  
Tri al Tre at me nts  .................................................................................................. 2 6 
5. 2. 1  
D ose Selecti o n/ M o dific ati o n  .......................................................................... 2 6 
5. 2. 1. 1  
D ose Selecti o n  ........................................................................................... 2 6 
5. 2. 1. 2  
Tre at me nt Del a ys a n d M o dific ati o ns ..................................................... 3 1  
5. 2. 2  
Ti mi n g of D ose A d mi nistr ati o n .................................................................... 3 4  
5. 2. 3  
A d mi nistr ati o n of A D X S 3 1- 1 4 2 .................................................................... 3 5  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5  of 9 4  
 
 
 
 
 
 
 
 
5. 2. 4  
Pret re at me nt Pr o p h yl a xis Re gi me n  ............................................................. 3 5 
5. 2. 5  
P ost -Tre at me nt M o nit o ri n g  .......................................................................... 3 6 
5. 2. 6  
Tri al Bli n di n g/ M as ki n g  ................................................................................. 3 6 
5. 3  
Tre at me nt All oc ati o n  ........................................................................................... 3 6 
5. 4  
Str atific ati o n  ......................................................................................................... 3 6 
5. 5  
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)  ................... 3 6 
5. 5. 1  
Acce pt a ble C o nc o mit a nt Me dic ati o n  ........................................................... 3 7 
5. 5. 2  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  .......................................................... 3 7 
5. 6  
Resc ue Me dic ati o ns & S u p p orti ve C are  ............................................................ 3 8 
5. 6. 1  
S u p p orti ve C are G ui deli nes  .......................................................................... 3 8 
5. 6. 1. 1  
P ne u m o nitis:  ............................................................................................. 3 9 
5. 6. 1. 2  
Di arr he a:  ................................................................................................... 3 9 
5. 6. 1. 3  
Di a betes: .................................................................................................... 3 9 
5. 6. 1. 4  
H y p o p h ysitis: ............................................................................................ 4 0  
5. 6. 1. 5  
H y pert h yr oi dis m or H y p ot h yr oi dis m: ................................................... 4 0  
5. 6. 1. 6  
He p atic:  ..................................................................................................... 4 0 
5. 6. 1. 7  
Re n al F ail ure or Ne p hritis:  ..................................................................... 4 1 
5. 6. 1. 8  
C yt o ki ne Rele ase S y m pt o ms:  .................................................................. 4 1 
5. 6. 1. 9  
Listeri osis a n d Listeri a I nfecti o n – I de ntific ati o n a n d M a n a ge me nt .. 4 4 
5. 6. 1. 1 0  
M a n a ge me nt a n d S ur veill a nce of Listeri a d uri n g St u d y P artici p at i o n 4 4 
5. 6. 1. 1 1  
N a use a/ v o miti n g ....................................................................................... 4 5  
5. 6. 1. 1 2  
M a n a ge me nt of I nf usi o n Re acti o ns ........................................................ 4 5  
5. 6. 2  
Diet  .................................................................................................................. 4 7 
5. 6. 3  
Use i n Pre g n a nc y  ............................................................................................ 4 7 
5. 7  
S u bject St u d y P artici p ati o n  ................................................................................ 4 7 
5. 8  
M aj or a n d Mi n or S ur ger ies a n d A D X S 3 1-1 4 2 Tre at me nt  .............................. 4 7 
5. 9  
S u bject Wit h dr a w al/ Disc o nti n u ati o n Criteri a  .................................................. 4 7 
5. 1 0  
S u bject Re pl ace me nt St r ate g y  ............................................................................ 4 8 
5. 1 1  
Cli nic al Criteri a f or E arl y Tri al Ter mi n ati o n ................................................... 4 8 
6  
Tri al Fl o w C h art ....................................................................................................... 5 0  
6. 1  
P art A Fl o w C h art – A D X S 3 1 - 1 4 2 M o n ot her a p y ............................................. 5 0 
6. 2  
P art B Fl o w C h art – A D X S 3 1 - 1 4 2 M o n ot her a p y + Pe m br oliz u m a b ( M K-
3 4 7 5) C o m bi n ati o n T her a p y ............................................................................... 5 2  
7  
Tri al Pr o ce d ures  ....................................................................................................... 5 4 
7. 1  
Tri al Pr o ce d ures ................................................................................................... 5 4 
7. 1. 1  
A d mi nistr ati ve Pr oce d ures  ........................................................................... 5 4 
7. 1. 1. 1  
I nf or me d C o nse nt .................................................................................... 5 4 
7. 1. 1. 2  
I ncl usi o n/ E xcl usi o n Criteri a ................................................................... 5 5 
7. 1. 1. 3  
S u bject I de ntific ati o n C ar d  ..................................................................... 5 5 
7. 1. 1. 4  
Me dic al Hist or y  ........................................................................................ 5 5 
7. 1. 1. 5  
S ur gic al Hist or y  ....................................................................................... 5 5 
7. 1. 1. 6  
Pri o r a n d C o nc o mit a nt Me dic ati o ns Re vie w  ........................................ 5 5 
7. 1. 1. 7  
Dise ase Det ails a n d Tre at me nts  .............................................................. 5 6 
7. 1. 1. 8  
Assi g n me nt of S u bject I de ntific ati o n N u m ber  ...................................... 5 6 
7. 1. 2  
Cli nic al Pr oce d ures/ Assess me nts  .................................................................. 5 6 




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7  of 9 4  
 
 
 
 
 
 
 
 
1 0. 3  
C o m pli a nce wit h l a w, A u dit a n d De b ar me nt  .................................................... 8 4 
1 0. 4  
C o m pli a nce wit h Tri al Re gistr ati o n a n d Res ults P o sti n g Re q uire me nts ....... 8 5 
1 0. 5  
Q u alit y M a n a ge me nt S yste m .............................................................................. 8 5  
1 0. 6  
D at a M a n a ge me nt ................................................................................................ 8 5  
1 1  List of Ref ere nce  ....................................................................................................... 8 6 
1 1. 1  
E C O G Perf or m a nce St at us  ................................................................................. 9 1 
1 1. 2  
C o m m o n Ter mi n ol o g y Criteri a f or A d verse E v e nts V 4. 0 3 ( C T C A E) ............ 9 1  
1 1. 3  
I m m u ne R es p o nse M o dific ati o n t o Res p o nse E v al u ati o n Criteri a i n S oli d 
T u m ors (ir R E CI S T) f or E v al u ati n g Res p o nse i n S oli d T u m ors  ..................... 9 1 
1 2  List of A b bre vi ati o ns ................................................................................................ 9 2  
LI S T O F T A B L E S 
T a ble 1  
N u m ber ( %) of S u bjects wit h A d verse E ve nts > 5 % I nci de nce  
( S af et y P o p ul ati o n, N = 2 3 0) .......................................................................... 1 4 
T a ble 2  
N u m ber ( %) of S u bjects wit h A d verse E ve nts > 5 % wit h Res pect  
t o Rel ati o ns hi p ( P ossi bl y rel ate d, Pr o b a bl y Rel ate d a n d Rel ate d)  
( S af et y P o p ul ati o n, N = 2 3 0) .......................................................................... 1 5 
T a ble 3   
A de q u ate Or g a n F u ncti o n L a b or at or y V al ues .......................................... 2 3 
T a ble 4  
Tri al Tre at me nts  ........................................................................................... 2 6 
T a ble 5  
D ose Decisi o ns f or A D X S 3 1 - 1 4 2 M o n ot her a p y  
( T ar gete d D L T R at e = 2 5 %) ....................................................................... 2 7 
T a ble 6  
A D X S 3 1 - 1 4 2 M o n ot her a p y D oses t o be use d i n P art A ............................ 3 0 
T a ble 7  
A D X S 3 1 - 1 4 2 a n d Pe m b r oliz u m a b ( M K- 3 4 7 5) C o m bi n ati o n T her a p y  
D oses t o be use d i n Tri al P art B  .................................................................. 3 1 
T a ble 8  
D ose M o dific ati o n G ui deli nes f or Dr u g -Rel ate d A d verse E ve nts  
wit h Pe m br oliz u m a b ( M K - 3 4 7 5) ................................................................ 3 2 
T a ble 9  
Tre at me nt Del a y/ Disc o nti n u ati o n G ui deli nes f or Dr u g -R el ate d  
A d verse E ve nts -A D X S 3 1 - 1 4 2 ...................................................................... 3 4 
T a ble 1 0 
Rec o m me n de d M a n a ge me nt G ui deli nes f or A d verse E ve nts  
Ass oci ate d wit h C yt o ki ne Rele ase  ............................................................... 4 2 
T a ble 1 1 
A D X S 3 1 - 1 4 2 or Pe m b r oliz u m a b ( M K- 3 4 7 5) I nf usi o n Re acti o n  
Tre at me nt G ui deli nes  ................................................................................... 4 6 
T a ble 1 2  
T u m or R es p o nse E v al u ati o n: C o m p aris o n of R E CI S T 1. 1 a n d  
ir R E CI S T ...................................................................................................... 6 1 
T a ble 1 3 
Best O ver all Res p o nse ( R E CI S T 1. 1) ......................................................... 6 2  
T a ble 1 4 
I m m u ne-Rel at e d Best O ver all Res p o nse (ir B O R)  ..................................... 6 3 
T a ble 1 5  
L a b or at or y Tests .......................................................................................... 6 5  
T a ble 1 6  
E v al u ati n g A d verse E ve nts  .......................................................................... 7 5 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8  of 9 4  
 
 
 
 
 
 
 
 
1 
T RI A L S U M M A R Y  
 
A b bre viate d Title  
P hase 1 - 2 D ose-Escalati o n a n d Safet y St u d y of A D X S 3 1 -
1 4 2 Al o ne a n d A D X S 3 1 - 1 4 2 + Pe m br oliz u ma b (M K - 3 4 7 5) 
C o m bi nati o n T hera p y i n Patie nts wit h Pre vi o usl y Tre ate d 
Metastatic Castrati o n -Resista nt Pr ostate Ca ncer ( m C R P C)  
Trial P hase  
1- 2 
Cli nical I n dicati o n  
Pre vi o usl y treate d m C R P C 
Trial T y p e  
D ose deter mi ni n g wit h e x pa nsi o n  
T y pe of c o ntr ol  
N o ne  
R o ute of a d mi nistrati o n  
A D X S 3 1 - 1 4 2 – I V; pe m br oliz u ma b ( M K- 3 4 7 5) - I V 
Trial Bli n di n g  
O pe n -la bel 
Treat me nt Gr o u ps  
A D X S 3 1 -1 4 2 m o n ot hera p y; A D X S 3 1 -1 4 2 + pe m br oliz u ma b 
( M K- 3 4 7 5) c o m bi nati o n t hera p y 
N u m ber of trial s u bjects  
A p pr o xi matel y 5 1  
Esti mate d d urati o n of trial  A p pr o xi matel y 7 years  
D urati o n of Partici pati o n  
A p pr o xi matel y 5 years  
2 
T RI A L D E SI G N  
2. 1  
Tri al D e si g n  
T his is a P hase 1 - 2, o pe n-la bel, m ultice nter, d ose-deter mi ni n g s afet y a n d t olera bilit y st u d y wit h a 
P hase 2 e x pa nsi o n c o h ort. 
2. 1. 1  
P art A – A D X S 3 1 -1 4 2 M o n ot h er a p y  
Part A of t he st u d y will be a n o pe n- l a bel, P hase 1, m ultice nter, n o n-ra n d o mi ze d, d ose-
deter mi ni n g tri al of A D X S 3 1- 1 4 2 m o n ot hera p y i n s u bjects wit h metastatic castrati o n -resista nt 
pr ostate ca n cer ( m C R P C).  T he d ose- d eter mi ni n g p hase was  i nte n d e d t o select a rec o m me n de d 
P hase 2 d ose ( R P 2 D) of A D X S 3 1 - 1 4 2 f or Part B.  T he starti n g d os e le vel of A D X S 3 1- 1 4 2 
m o n ot hera p y is 1 x 1 0 9 c ol o n y f or mi n g u nits (cf u ) ( D L 1) (T a ble 6 ).  T h e st u d y w as ori gi nall y 
desi g ne d t o e val uate hi g h er d ose c o h orts as well d ose 5 x 1 0 9 cf u, 1 x 1 01 0 cf u. Base d o n safet y 
data fr o m ot her A d va xis trials t hat use si milar c o nstr ucts, it was deci de d t h at escalati o n t o 5 x 1 0 9 
cf u or 1 x 1 0 1 0 cf u w o ul d n o l o n ger be i ncl u de d i n t his st u d y d esi g n. T his is base d o n o verall 
re vie w of t h e saf et y d ata acr oss t he L m -b ase d pr o gra m of cli nical trials, w hi c h esta blis he d t hat 
t he starti n g d ose of 1 x 1 09 cf u is m ore t olera ble t ha n hi g h er d oses. U p t o 2 1 s u bjects will be 
e ntere d ( wit h a mi ni m u m of 6 s u bjects treat e d at t he rec o m me n d e d d ose b ef ore pr o cee di n g t o t he 
ne xt p hase).  After c o ns ultati o n wit h t he S p o ns or a n d i n vesti gat or, t he R P 2 D of A D X S 3 1- 1 4 2 
will be selecte d.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9  of 9 4  
 
 
 
 
 
 
 
 
2. 1. 2  
P art B – A D X S 3 1 -1 4 2 + P e m br oli z u m a b  ( M K-3 4 7 5) C o m bi n ati o n T h er a p y  
Part B of t he st u d y will b e a n o pe n- l a bel, P hase 1- 2, m ultice nter, n o n-ra n d o mize d d ose-
deter mi ni n g tri al of A D X S 3 1 - 1 4 2 i n c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) i n s u bjects 
wit h m C R P C.  Part B will c o nsist of a d ose -deter mi nati o n p hase f oll o we d b y a n e x pa nsi o n 
c o h ort p hase.  T h e d ose- deter mi ni n g p h ase is i nte n de d t o select a R P 2 D f or t he c o m bi nati o n.  A 
m o difie d 3 + 3 desi g n will be use d t o deter mi ne t h e d ose of A D X S 3 1- 1 4 2 i n c o m bi nati o n wit h 
pe m br oliz u ma b ( M K- 3 4 7 5). 
D uri n g t h e d ose- d eter mi ni n g sta ge, s u bjects will be e ntere d at  a d os e of 1 x 1 09 of A D X S 3 1 - 1 4 2 
(see Ta bl e 7 ) i n c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) at 2 0 0 m g .  If t his d ose 
c o m bi nati o n is n ot t olera ble, t he n D ose L e v el - 1 at a d ose of 0. 5 x 1 0 9 of A D X S 3 1 - 1 4 2 i n 
c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) at a d ose of 2 0 0 m g will be e val uate d.  D os e-
deter mi nati o n will c o nti n ue u ntil i de ntificati o n of a rec o m me n d e d R P 2 D f or t he c o m bi nati o n t o 
be use d i n t he e x pa nsi o n c o h ort.  A mi ni m u m of 6 s u bjects will be  treate d at t he R P 2 D bef ore 
i nitiati n g t he e x pa nsi o n c o h ort.  
T he e x pa nsi o n c o h ort will be o pe n f or e nr oll me nt o nce t he R P 2 D of A D X S 3 1- 1 4 2 i n 
c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) is selecte d i n t he Part B d ose- deter mi nati o n p hase.  
F urt her assess me nt of t he R P 2 D will be e x pl ore d i n u p t o 3 0 s u bjects wit h m C R P C t o e val uate 
t he safet y a n d cli nical acti vit y of A D X S 3 1- 1 4 2 i n c o m bi nati o n wit h pe m br oliz u mab ( M K - 3 4 7 5). 
A d verse e ve nts will be m o nit ore d fr o m t he ti me i nf or me d c o nse nt is o btai ne d a n d gra d e 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 Criteri a f or A d verse E v e nts ( C T C A E) Versi o n  ( v) 4. 0 3. 
Treat me n t wit h A D X S 3 1- 1 4 2 or A D X S 3 1- 1 4 2 i n c o m bi nati o n wit h pe m br oliz u ma b ( M K-3 4 7 5) 
will  c o nti n ue u ntil d oc u me nte d disease pr o gressi o n, u nacce pta ble a d v erse e ve nt(s) ( A E(s), 
i nterc urr e nt ill ness t hat pre ve nts f urt h er 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 ns e nt, s u bject e x perie nces a c o m plete res p o nse a n d 
recei v es o ne a d diti o nal c ycl e of treat me nt, n o nc o m plia nce wit h trial treat me nt or pr oce d ure 
re q uire me nts, c o m pleti o n of 2 4 m o nt hs of treat me nt wit h A D X S 3 1-1 4 2 a n d pe m br oliz u ma b 
( M K- 3 4 7 5), or a d mi nistrati ve reas o ns.  S u bjects w h o attai n a n i n vesti gat or-c o nfir m e d ir C R, after 
recei vi n g at least 2 c ycles of t hera p y, ma y c o nsi der st o p pi n g p e m br oliz u ma b ( M K-3 4 7 5) a n d 
c o nti n ue treat me nt wit h A D X S 3 1 - 1 4 2 o nl y.  I n a d diti o n, all s u bjects will partici pate i n a 3- year 
L m  Sur veilla nce M o nit ori n g peri o d.  S u bjects w h o disc o nti n ue treat me nt f or reas o ns ot her t ha n 
disease pr o gr essi o n 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 ot her a nti-ca ncer treat me nt, wit h dra wi n g c o nse nt, b ec o mi n g l ost t o 
f oll o w- u p, or u ntil t he S p o ns or e n ds t he st u d y ( Refer t o Secti o n 7. 1. 5. 3 ).  T he p ri mar y o bjecti ves 
of t he trial ar e t o esta blis h a  ma xi m u m t olerate d d ose  (M T D ) or m a xi m u m all o wa ble d ose 
(M A D ) a n d t o d eter mi ne safet y a n d t olera bilit y of A D X S 3 1- 1 4 2 i n c o m bi nati o n wit h 
pe m br oliz u ma b ( M K- 3 4 7 5) i n s u bjects wit h m C R P C. 






 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1 2  of 9 4  
 
 
 
 
 
 
 
 
a dapti ve cell ular i m m u ne res p o nse [2 ].  T he a bilit y t o deli ver a nti ge n t o t he c yt os olic 
c o m part me nt of A P Cs i n or der t o de v el o p h u ma n le u k oc yte a nti ge n Class I prese ntati o n t o 
i n d uce C D 8 + c yt ot o xic T-cell res p o ns es a p pears t o be a n i m p orta nt as pect of de vel o pi n g a n 
effecti ve t her a pe utic a nti -t u m or t hera p y.  Pe pti des deri ve d fr o m L m  i n t he p ha g ol ys os o me a n d 
t he c yt os ol ca n be prese nte d b y b ot h t he maj or hist oc o m pati bilit y c o m ple x ( M H C) Class  I a n d 
Class II m olec ules, i n d uci n g b ot h C D 4 + a n d C D 8 + T cell res p o nses.  T here is e vi de nce t h at L m  
als o gets i nt o t u m ors, pr o ba bl y carrie d b y i nfecte d macr o p ha ges a n d ne utr o p hils.  O ne p ote nt ial 
c o nse q ue nce of t his is t he o bser ve d a bilit y of li ve Listeri a  vect or s t hat secrete a n L L O-a nti ge n 
f usi o n, b ut n ot t h ose t hat secret e o nl y a n a nti ge n, t o di mi nis h re g ulat or y T-cells ( Tre gs) wit hi n 
t he t u m or, b ut n ot i n t he s plee n or n or mal peri p heral tiss ues [3 , 4 ]. 
4. 1. 1. 2  
A nti -P D -1 A nti b o d y P e m br oli z u m a b ( M K -3 4 7 5)  
Pe m br oliz u ma b  is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y ( m A b) 
wit h hi g h s pecifi cit y of bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D - 1) rece pt or, t h us i n hi biti n g 
its i nteracti o n wit h pr o gr a m me d cell deat h li ga n d 1 ( P D- L 1) a n d pr o gra m me d cell deat h li ga n d 2 
( P D-L 2) .  Base d o n precli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y a n d p ote nt rece pt or 
bl oc ki n g acti vit y f or P D- 1.  Pe m br oliz u ma b has a n acce pta b le precli nical s afet y pr ofile a n d is i n 
cli nical de vel o p me nt as a n i ntra ve n o us (I V) i m m u n ot hera p y f or a d va n ce d mali g na n cies.  
Ke ytr u da ™ ( p e m br oliz u ma b) is i n dicate d f or t h e treat me nt of patie nts acr oss a n u m ber of 
i n dicati o ns.  F or m ore d etails o n s pecific  i n dicati o ns refer t o t he I n vesti gat or br oc h ure. 
T he i m p orta nce of i ntact i m m u ne s ur veilla nce i n c o ntr olli n g o ut gr o wt h of n e o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des [3 9 ].  Acc u m ulati n g e vi de n ce s h o ws a c orrelati o n 
bet wee n t u m or-i nfiltr ati n g l y m p h oc ytes ( TI Ls) i n ca ncer tiss ue a n d pr o g n osis i n vari o us 
mali g na n cies [4 0- 5 2 ].  I n partic ular, t he prese n ce 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 ul at or y T cells see m t o c orrelat e wit h i m pr o ve d pr o g n osis a n d l o n g- ter m 
s ur vi val i n ma n y s oli d t u m ors [4 8 , 5 3- 6 1 ]. 
T he P D - 1 rece pt or-li ga n d i nteracti o n is a maj or p at h wa y hijac k e d b y t u m ors t o s u p press i m m u ne 
c o ntr ol [ 6 0 ].  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 x cessi 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 n c o de d b y t he ge ne P dc d 1) is a n I g s u p erfa mil y 
me m ber rel ate d t o C D 2 8 a n d C T L A- 4 w hic h h as b ee n s h o w n t o ne gati vel y re g ulate a nti ge n 
rece pt or si g n ali n g u p o n e n ga ge me nt of its li ga n ds ( P D- L 1 a n d/ or P D L 2) .  T he str uct ure of 
m uri ne P D- 1 al o ne a n d i n c o m ple x wit h its li ga n d were first  res ol ve d [6 1 ], a n d m ore rece ntl y 
t he N M R- base d str uct ure of t he h u ma n P D-1 e xtracell ular re gi o n a n d a nal ysis of its i nteracti o ns 
wit h its li ga n ds were als o re p orte d [6 2 ].  P D -1 a n d fa mil y me m bers are t y pe I tra ns me m bra n e 
gl yc o pr ot ei ns c o ntai ni n g a n I g Varia ble -t y pe ( V-t y pe) d o mai n res p o nsi ble f or li ga n d bi n di n g a n d 
a c yt o plas mic tail , w hic h is res p o nsi ble f or t he bi n di n g of si g nali n g m olec ules.  T he c yt o plas mic 
tail of P D- 1 c o ntai ns 2 t yr osi ne- base d si g n ali n g m otifs, a n i m m u n orece pt or t yr osi ne-base d 
i n hi biti o n m otif (I TI M) a n d a n i m m u n orece pt or t yr osi ne-base d s witc h m otif (I T S M).  F oll o wi n g 
T- cell sti m ulati o n, P D - 1 recr uits t he t yr osi ne p h os p hatases S H P- 1 a n d S H P- 2 t o t he I T SM m otif 
wit hi n its c yt o plas mic tail, lea di n g t o t he d e p h os p h or ylati o n of effect or m olec ules s uc h as C D 3ζ, 
P K C θ a n d Z A P 7 0, w hic h are i n v ol ve d i n t he C D 3 T- cell si g n ali n g cas ca de  6 3].  T he mec ha nis m 
b y w hic 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 
6 4].  P D- 1 was s h o w n t o be e x presse d o n acti vate d l y m p h oc ytes i ncl u di n g peri p heral C D 4 + a n d 




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1 4  of 9 4  
 
 
 
 
 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1 5  of 9 4  
 
 
 
 
 
 
 




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1 7  of 9 4  
 
 
 
 
 
 
 
 
pr ostate is a dis pe nsa ble or ga n.  T her ef ore, eli mi nati o n of all pr ostate cells w o ul d n ot i nterfere 
si g nifica ntl y wit h maj or or ga n f u ncti o n or ge neral q ualit y of life ( p ost-castrati o n) a n d a n y 
p ote ntial a ut oi m m u nit y t o pr ostate cells ge n erat e d fr o m i m m u n ot hera p y w o ul d n ot i m pact 
patie nt safet y.  T hir d, t here is e vi de nce t hat pr ostat e ca n cer is a n i m m u n ol o gicall y “ visi ble” 
disease.  S p o nta ne o us a ut oa nti b o dies, as s h o w n b y p ha ge pr otei n micr o arra ys, i n dicate t h at a 
nasce nt i m m u ne res p o ns e ma y be alr ea d y prese nt, wit h t he p ote ntial t o be a m plifie d [2 6 ].  It has 
bee n re p orte d t hat i nitiati o n of c he mical castrati o n ma y res ult i n l y m p h oc yt e i nfiltrati o n i nt o 
pr ostate tiss ue.  Si p ule ucel T, a n i m m u n ot hera p y directe d a gai nst P S M A has rece ntl y b ee n 
s h o w n t o i m pr o ve t he s ur vi val of me n wit h pr ostate ca n cer.  E u ge ne K w o n a n d ot hers ha v e 
re p orte d a nec d ot al o bser vati o n of a d o w nsta gi n g of pr ostate ca ncer i n me n wit h l ocall y a d v a nce d 
n o n- resecta ble disease tr eate d wit h i pili m u ma b [2 7 ].  Lastl y, pr ostate ca ncer te n ds t o be a sl o w-
gr o wi n g disease.  Si nce i m m u n ot hera p y relies o n t he ge nerati o n, pr oliferati o n, a n d i nfiltrati o n of 
effect or cells a n d is n ot directl y c yt ot o xic t o t u m ors, it ta kes ti me t o be gi n t o see t u m or s hri n ka ge 
i n res p o nse t o i m m u n ot hera p y.  A m o d est rate of disease pr o gressi o n c o ul d all o w m ore ti me t o 
ge n erat e a n a ntit u m or i m m u ne res p o nse a n d re d u ce i m m u n os u p pressi ve fact ors bef ore t h e 
t u m ors ca use cli nical d eteri orati o n of t he p atie nt [3 , 2 8 ]. 
I m m u n ol o gic c h ec k p oi nts are i n v ol ve d i n li miti n g ( or s h utti n g d o w n) t h e ma g nit u de of a n 
i m m u ne res p o nse b y c o ntr olli n g t he n u m bers a n d acti vati o n state of l y m p h oc yt es i n v ol ve d i n a n 
i m m u ne res p o nse.  Si g nali n g t hr o u g h bi n di n g of t he P D- 1 rece pt or t o P D-L 1 ca uses deacti vati o n 
of l y m p h oc ytes, i n cl u di n g C D 8 + T- cells.  P D- 1 t o P D- L 1 bi n di n g is a si g nifica nt c o m p o ne nt of 
peri p her al t olera nce a n d n or mall y f u n cti o ns t o pr otect tiss ues fr o m “ b ysta n der” da m a ge d uri n g 
a n i nfla m mat or y e v e nt.  H o we ver, w he n P D- L 1 is e x presse d b y t u m or cells, it ca n pre ve nt 
t u m or-s pecific T-cells fr o m killi n g mali g na nt cells b y s h utti n g d o w n t h eir acti vit y a n d s o meti mes 
tri g geri n g a p o pt osis of t he C T Ls. 
W hile P D - 1 bloc ki n g strate gies ha ve s h o w n g o o d cli nical pr o mise, t here are still s o me 
s h ortc o mi n gs.  I n c urr e nt P D-1 cli nical trials, t here is n o st u d y w here m ore t ha n 5 0 % of patie nts 
can be n efit fr o m P D - 1 bi n di n g i n hi biti o n, a n d i n diseases w here it w or ks best, m ost res p o nse 
rates ar e t he r a n ge of 2 0- 4 0 %, missi n g t he maj orit y of p atie nts.  O ne p ote ntial reas o n t hat P D-1 
bi n di n g bl oc ka d e mi g ht n ot be eff ecti ve f or a lar ger pr o p orti o n of p atie nts is t hat t he nee de d 
t u m or-s pecific c yt ot o xic cells wer e n ot ge nerate d i n t he first place.  I n t his case, “ o pe ni n g u p ” 
t he c hec k p oi nt will ha ve n o effect beca use t here are n o effect or cells hel d- u p at t hat c hec k p oi nt.  
A n ot her, a n d p ote ntiall y less “ s ol va ble”, reas o n is t hat peri p heral t olera nce me diate d b y i m m u ne 
c hec k p oi nts is n ot t he o nl y mec ha nis m of i m m u n ol o gic t olera nce t h at ca n pr otect t u m ors fr o m 
cell ular i m m u nit y.  Ma n y s oli d t u m ors are als o pr otecte d b y me diat ors of ce ntral t olera nce w hic h 
i ncl u de Tre gs a n d m yel oi d deri ve d s u p press or cells ( M D S Cs).  I n t his case, acti vate d T-cells t hat 
ma ke it past P D - L 1 o n t h e s urface of t u m ors t he n i nfiltrate t he t u m or micr o e n vir o n me nt o nl y t o 
be s h ut d o w n b y i n hi bit or y e x ocri ne fact ors fr o m Tre gs a n d M D S Cs w hic h i ncl u de I L- 1 0, I L - 9, 
T G F beta, ar gi nas e, a n d i n d uci ble nitric o xi de s y nt hase, res p ecti vel y.  T hes e fact ors res ult i n 
a ner g y of t h e acti vate d T -cells wit hi n t he t u m or micr oe n vir o n me nt.  
Esse ntia ll y, t he li mite d effecti ve ness of P D-1 treat me nt i n t he maj orit y of ca ncer p atie nts ca n b e 
attri b ute d t o eit her t he i n a bilit y t o ge nerate t u m or s pecific C T Ls t hat d o n ot alrea d y e xist, a n d/ or 
t he i na bilit y f or P D- 1 bl o c ka de t o ha v e a n y i m pact o n Tre gs a n d M D S Cs t hat resi de wit hi n a n d 
pr otect t he t u m or micr oe n vir o n me nt.  H o we ver, if o ne c o ul d c o m bi ne P D- 1 bl oc ka de wit h a 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 1 8  of 9 4  
 
 
 
 
 
 
 
 
treat me nt t hat e ns ur es t u m or reacti ve T-cells are ge n erat e d a n d prese nt, a n d als o re d uce or 
eli mi nate t he eff ects of ce ntral t olera n ce me diat e d b y Tre gs a n d M D S Cs i n t he t u m or 
micr oe n vir o n me nt, a si g nifica ntl y lar ger pr o p orti o n of patie nts c o ul d be effecti vel y treate d i n 
diseases w here P D - 1 bl o c ka de h as s h o w n wea k or little acti vit y.  A d diti o nall y, b y c o m bi ni n g 
s y ner gisticall y wit h a n a ge nt t hat r e d uces Tre gs a n d M D S Cs wit hi n t u m ors, P D- 1 bl oc ka de c o ul d 
als o c o ntri b ute t o acti vit y i n diseases w hic h are c urre ntl y pr otect e d s olel y b y ce ntral t olera nce 
a n d w her e P D - 1 has n ot hist oricall y bee n acti ve.  T hese diseas es ma y i ncl u de pr ostate ca ncer, 
o varia n ca ncer a n d ot hers.  T his c o m bi nati o n c o ul d i m pr o ve t he acti vit y of P D-1 w here it has 
acti vit y, a n d als o cr eate a d diti o nal utilit y i n diseas es w here P D -1 bl oc ka d e a p pears t o h a ve little 
effect as a m o n ot hera p y.  
T he A d va xis L m - L L O i m m u n ot hera p y v ect ors are a u ni q ue tec h n ol o g y t h at is pr o vi n g t o be 
effecti ve as m o n ot her a p y i n s o me n ot ori o usl y resista nt mali g na nci es.  F urt her m ore, t his s yste m 
is tr ul y a platf or m a n d o v er 2 0 differe nt t u m or a nti ge n-s pecifi c vect ors ha ve alrea d y b ee n 
creat e d.  U nli ke m ost t hera pe utic vacci nes, t his s yste m ge n erat es a p o werf ul a n d al m ost 
e x cl usi ve cell ular i m m u nit y a gai nst t he t u m or tar get of i nterest i n t he setti n g of a s yste mic 
i m m u ne res p o nse t o a p ote ntial pat h o ge n.  T his res p o nse has bee n s h o w n t o i ncreas e t he 
e x pressi o n of P D- L 1 o n t u m ors as well as P D- 1 e x pressi o n o n T- cells.  T hese vect ors s hift t he 
i m m u n ot o pe t o a T H- 1 p he n ot y p e a n d are ass o ciate d wit h u pre g ulati o n of c he m o ki nes a n d 
c he m o ki ne rece pt ors t her e b y facilitati n g e xtra vasati o n a n d i nfiltrati o n of C D 8 + T -cells i nt o 
t u m ors.  Per ha ps t he m ost si g nifica nt as p ect of AD X S 3 1 -1 4 2 treat me nt is t he t u m or 
micr oe n vir o n me nt s pecific d o w n-re g ul ati o n of t he relati ve n u m ber a n d f u n cti o n of b ot h Tre gs 
a n d M D S Cs t hat me diat e ce ntral t oler a nce, pr otecti n g t he t u m or micr o e n vir o n me nt t here b y 
all o wi n g i nfiltrati n g C D 8 + T -cells t o kill t u m or a nti ge n e x pressi n g tar get cells i n t he t u m ors.  
Si m pl y state d, t he A d va xis vect or ca n e ns ure t h ere is a fres h s u p pl y of t u m or s pecific C T Ls a n d 
at t he sa me ti me, ne utrali ze Tre gs a n d M D S Cs i n t he t u m or micr oe n vir o n m e nt, e na bli n g T-cells 
t o kill t u m or cells wit h o ut restricti o n. 
A rece nt p u blicati o n fr o m of t he la b orat or y of Sa mir K hleif has de m o nstrate d, i n a n a ni mal 
m o del, t he s y ner gistic acti vit y of c o m bi nati o n A d v a xis L m -L L O -T A A treat me nt wit h a P D - 1 
bl oc ki n g a nti b o d y acti ve i n b ot h m o use a n d ma n [2 9 ].  His data de m o nstrate t hat t hese 2 
treat me nts ar e c o m ple me ntar y t ec h n ol o gies.  T he A d va xis L m -L L O i m m u n ot hera p y ge n erat es 
T A A s pecific T -cells a n d ne utralizes Tre gs a n d M D S Cs i n t he t u m or micr oe n vir o n me nt, a n d 
P D - 1 a nti b o d y o v er-ri d es t he i n hi bit or y effects of P D- 1 li ga n d bi n di n g w hi c h res ults i n a 
si g nifica ntl y lar ger n u m b er of t u m or a nti ge n s p ecific T-cells t o fi g ht a gai nst t he ca ncer.  T his 
c o m bi nati o n si g nifica ntl y i m pr o ves t he effi cac y of t he treat me nt o v er eit her m o n ot hera p y, 
res ulti n g i n si g nifica nt i m pr o ve me nt i n s ur vi val. 
Treat me nt of pr ostate ca ncer wit h a d e n dritic -cell base d i m m u n ot hera p y, Pr o ve n ge ( De n dre o n) 
has bee n de m o nstr ate d t o i m pr o ve l o n g-t er m s ur vi val i n me n wit h C R P C a n d has bee n a p pr o ve d 
b y t he U nite d States ( U S) F o o d a n d Dr u g A d mi nistrati o n ( F D A).  T his s u g g ests t hat 
i m m u n ot hera p y ca n be effecti ve a gai nst C R P C.  U nf ort u natel y, Pr o ve n ge h as n ot bee n 
ass ociate d wit h a n o bjecti ve t u m or res p o nse a n d a p pears t o sl o w pr o gressi o n of C R P C i n s o me 
patie nts.  A D X S 3 1- 1 4 2 h as de m o nstrate d si g nifica nt P S A- s pecific a ntit u m or acti vit y i n a ni mal 
m o dels i ncl u di n g t he cleara nce of e xisti n g t u m ors a n d pre ve nti n g t he pr o gressi o n of i m pla nte d 






 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 1  of 9 4  
 
 
 
 
 
 
 
 
A p o p ulati o n p har mac o ki netic ( P K) m o del, w hic h c haracterize d t he i nfl ue n ce of b o d y w ei g ht 
a n d ot her patie nt c o v ariat es o n e x p os ure, has bee n de vel o pe d.  T he P K pr ofile of pe m br oliz u ma b 
is c o nsiste nt wit h t hat of ot her h u ma nize d m o n ocl o nal a nti b o dies, w hic h t y picall y h a ve a l o w 
clear a nce a n d a li mite d  v ol u me of distri b uti o n.  T he distri b uti o n of e x p os ures fr o m t he 2 0 0 m g 
fi x e d d ose are pr e dicte d t o c o nsi dera bl y o verla p t h ose o btai ne d wit h t he 2 m g/ k g d ose a n d 
i m p orta ntl y will mai ntai n i n di vi d ual patie nt e x p os ures wit hi n t he e x p os ure ra n ge est a blis he d i n 
mela n o ma as ass oci ate d wit h ma xi mal cli nical res p o nse.   P har mac o ki netic pr o perties of 
pe m br oliz u ma b, a n d s pecificall y t he wei g ht- d e pe n de nc y i n cleara n ce a n d v ol u me of distri b uti o n 
are c o nsiste nt wit h n o mea ni n gf ul a d va nta ge t o wei g ht- bas e d d osi n g relati v e t o fi x e d d osi n g.    
 
I n tr a nslati n g t o ot her t u m or i n dicati o ns, si milarl y flat e x p os ure-res p o ns e relati o ns hi ps f or 
efficac y a n d s afet y as o bser ve d i n s u bjects wit h m ela n o ma ca n be e x pecte d, as t he a nti -t u m or 
effect of pe m br oliz u ma b is dri ve n t hr o u g h i m m u n e s yste m acti vati o n rat her t ha n t hr o u g h a direct 
i nteracti o n wit h t u m or cells, re n deri n g it i n de pe n d e nt of t he s pecifi c t u m or t y pe.  I n a d diti o n, 
a vaila ble P K res ults i n s u bjects wit h mela n o ma, N S C L C, a n d ot her t u m or t y p es s u p p ort a lac k of 
mea ni n gf ul differe nce i n p har mac o ki netic e x p os ures o btai ne d at teste d d oses a m o n g t u m or t y pes. 
T h us, t he 2 0 0 m g Q 3 W fi x e d- d ose re gi me n is c o nsi dere d a n a p pr o priat e fi x e d d ose f or ot her 
t u m or i n dicati o ns as well.   
 
A fi x e d d ose re gi me n will si m plif y t he d osi n g re gi me n t o be m ore c o n v e nie nt f or p h ysi cia ns a n d 
t o re d uce p ote ntial f or d osi n g err ors. A fi x e d d osi n g sc h e me will als o re d u ce c o m ple xit y i n t he 
l o gistical c hai n at treat m e nt facilities a n d re d uce wasta ge. T h e e xisti n g data s u g gest 2 0 0 m g 
Q 3 W as t he a p pr o priate d ose f or pe m br oliz u ma b. 
4. 2. 3  
R ati o n al e f or E n d p oi nt s  
4. 2. 3. 1  
Effi c a c y E n d p oi nt s  
T he effi cac y e n d p oi nts t o be use d i n t his st u d y 
 f or pr ostate 
ca ncer, sca ns, a n d meas ura ble  a n d e val ua ble dis ease assess me nts) are t h ose t y picall y use d t o 
assess a nti -t u m or acti vit y of m C R P C. 
4. 2. 3. 2  
S af et y E n d p oi nt s  
T he pri mar y safet y o bjecti ve of t his trial is t o c haracterize t he safet y a n d t ol era bilit y of 
A D X S 3 1 - 1 4 2 al o ne a n d i n c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) i n s u bjects wit h 
m C R P C.  T he pri mar y safet y a nal ysis will be base d o n s u bjects w h o e x perie nce d t o xicities as 
defi ne d b y C T C A E criteria.  Safet y will be assesse d b y q ua ntif yi n g t he t o xicities a n d gra d es 
e x perie nce d b y s u bjects w h o ha ve r ecei v e d A D X S 3 1 - 1 4 2 al o ne a n d i n c o m bi nati o n wit h 
pe m br oliz u ma b ( M K- 3 4 7 5), i ncl u di n g seri o us a d verse e v e nts ( S A Es) a n d e ve nts of cli nical 
i nterest ( E CIs). 
Safet y will be assesse d b y r e p orte d a d vers e e x perie nces usi n g C T C A E v 4. 0 3. T he attri b uti o n t o 
dr u g, t i me-of - o nset, d ur ati 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.  A Es will be a n al yz e d i ncl u di n g b ut n ot li mite d t o all A Es, S A Es, 
la b orat or y c h a n ges  a n d L m S ur veilla nce M o nit ori n g. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 2  of 9 4  
 
 
 
 
 
 
 
 
5  M E T H O D O L O G Y 
5. 1  
E ntr y Crit eri a  
5. 1. 1  
Di a g n o si s/ C o n diti o n f or E ntr y i nt o t h e Tri al  
T he st u d y will be c o n d ucte d i n male s u bjects wit h hist ol o gicall y c o nfir me d m C R P C w h o ha ve 
pr o gresse d or bec o m e resista nt t o n o m ore t ha n 2 pri or s yste mic treat me nt re gi me ns wit h 
c he m ot hera p y, t ar gete d t hera pies , r a di o p har m ace uticals, or i m m u n ot hera p y i n t he metastatic 
setti n g.  H or m o nal tr eat me nt will n ot be c o nsi dere d w he n det er mi ni n g t he n u m ber of pri or 
re gi me ns i n t he metastati c setti n g.  S u bjects ca n n ot ha ve ha d m ore t h a n 1 pri or c he m ot hera pe utic 
re gi me n i n t he metastatic setti n g.  S u bjects wit h e vi de nce of pr o gressi ve b o ne or ot her 
metastases ar e acce pta bl e.  S u bjects ma y re mai n o n castrati o n t hera p y (l utei nizi n g - h or m o ne-
releasi n g h or m o ne [ L H R H] a g o nist or a nta g o nist) d uri n g t he tri al. 
5. 1. 2  
S u bj e ct I n cl u si o n Crit eri 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.  Be willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt f or t he trial. 
2.  Be ≥1 8 years of a ge o n d a y of si g ni n g i nf or me d c o nse nt. 
3.  Ha ve pr o gressi ve metast atic castr ati o n resista nt pr ostate ca n cer, o n a n dr o ge n de pri vati o n 
t hera p y, bas e d o n as least o ne of t he f ollo wi n g crit eria:  
a. P S A pr o gr essi o n defi n e d as 2 5 % i ncreas e o ver baseli ne val ue wit h a n i n creas e i n t he 
a bs ol ute val ue of at least 2 n g/ m L t hat is c o nfir me d b y a n ot h er P S A le vel wit h a mi ni m u m 
of a 1- w ee k i nter v al wit h a mi ni m u m P S A of 2 n g/ ml.  
b. Pr o gr essi o n of bi- di me nsi o nall y meas ura ble s oft tiss ue ( n o dal metastasis) assesse d wit hi n 
1 m o nt h pri or t o re gistr ati o n b y a C T sca n or M RI of t he a b d o me n a n d p el vis ( please refer 
t o Secti o n  7. 1. 2. 5. 1  f or defi niti o ns of meas ura ble disease). 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 3  of 9 4  
 
 
 
 
 
 
 
 
c. Pr o gressi o n of b o ne disease ( e val ua ble dis ease) ( ne w b o ne lesi o n(s)) b y b o ne sca n. ( Please 
refer t o Secti o n  7. 1. 2. 5. 1  f or defi niti o ns of e val u a ble disease). 
4.  Has disc o nti n ue d a ntia n dr o ge ns ( bical uta mi de, nil uta mi de) > 6 wee ks a n d e nzal uta mi de or 
a birater o n e > 4 w ee ks pri or t o Da y 1 of trial treat me nt 
5.  Ha ve a p erf or ma nce stat us of 0 or 1 o n t he E C O G Perf or ma n ce Scale.  
6.  De m o nstrate a d e q uate or ga n f u ncti o n as defi ne d i n  Ta ble 3 .  All scree ni n g la bs s h o ul d be 
perf or me d wit hi n 2 8 da ys of treat me nt i nitiati o n.  
T a bl e 3   A d e q u at e Or g a n F u n cti o n L a b or at or y V al u e s  
S yste m  
L a b or at or y V al ue  
He m at ol o gic  
 
A bs ol ute ne utr o p hil c o u nt ( A N C) a 
≥1 0 0 0 / mc L  
Platelets a 
≥7 5, 0 0 0 / mc L  
He m o gl o bi n a 
≥9 g/ d L or ≥5. 6 m m ol/ L  
L y m p h oc ytes  
≥5 0 0 / mc L  
Re n al  
 
Ser u m creati ni ne  O R  
Meas ure d or calc ulate d b creati ni ne 
cleara nce ( Cr Cl)  
( G F R ca n als o be use d i n plac e of 
creati ni ne or Cr Cl)  
≤1. 5 X u p per li mit of n or mal ( U L N) O R  
≥5 0 m L/ mi n f or s u bj ect 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 bj ects wit h t otal bilir u bi n le vels > 
1. 5 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 if li ver metastases are prese nt  
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 P artial T hr o m b o plasti n Ti me 
(a P T T) 
≤1. 5 X U L N u nless s u bj ect is recei vi n g a ntic oa g ula nt t hera p y  
as l o n g as P T or I N R is wit hi n t hera pe utic ra n ge of i nte n de d 
use of a ntic oa g ula nts  
≤1. 5 X U L N u nless s u bj ect is recei vi n g a nti c oa g ula nt t hera p y  
as l o n g as 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 A N C, Platelets a n d He m o gl o bi n re q uire me nts ca n n ot be met b y use of rece nt tra nsf usi o n or gr o wt h 
fact or s u p p ort ( G-C S F, er yt hr o p oieti n, etc) wit hi n 2 wee ks pri or t o treat me nt i nitiati o n   
b   Creati ni ne cleara nce s h o ul d be calc ulate d per i nstit uti o nal sta n dar d.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 4  of 9 4  
 
 
 
 
 
 
 
 
7.  Male s u bjects s h o ul d a gr ee t o use a n a de q uat e met h o d of c o ntrace pti o n starti n g wit h t he first 
d ose of st u d y t h era p y t hr o u g h 1 2 0 da ys (a p pr o xi matel y 4 m o nt hs) after t h e last d ose of st u d y 
t hera p y. 
5. 1. 3  
S u bj e ct E x cl u si o n Crit eri a  
T he s u bject m ust be e x cl u de d fr o m partici p ati n g i n t he trial if t he s u bject:  
1.  Recei ve d m or e t ha n 2 pri or s yste mic treat me nt re gi me ns wit h c he m ot hera p y, tar gete d 
t hera p y, r a di o p har mace uticals, or i m m u n ot hera p y i n t he metastatic setti n g or recei ve d m ore 
t ha n 1 pri or c he m ot hera p e utic re gi me n i n t he metastatic setti n g. 
2.  Is c urr e ntl y p artici pati n g a n d recei vi n g st u d y t hera p y or h as partici pat e d i n a st u d y of a n 
i n vesti gati o nal a ge nt a n d recei v e d st u d y t h era p y or use d a n i n vesti gati o nal de vice wit hi n 4 
wee ks of t he f irst d ose of treat me nt. 
3.  Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g a n y s yste mic ster oi d t hera p y, 
a birater o n e acetate, ot her a n dr o ge n s y nt hesis i n hi bit ors or a n y f or m of i m m u n os u p pressi ve 
t hera p y wit hi n 7 da ys pri or t o Da y 1 of trial treat me nt.  T he use of p h ysi ol o gic d oses of 
c ortic oster oi ds ma y be a p pr o ve d aft er c o ns ultati o n wit h t he S p o ns or. 
4.  Has ha d a pri or m o n ocl o nal a nti b o d y or a ut ol o g o us cell ular i m m u n ot hera p y  wit hi n 4  wee ks 
pri or t o st u d y D a y 1 or w h o has n ot rec o v ere d (i.e., ≤Gra de 1 or at baseli ne) fr o m A Es  d ue t o 
a ge nts a d mi niste re d m or e t ha n 4 wee ks earlier. 
-  N ote:  S u bjects c urr e ntl y recei vi n g de n os u ma b are a n e x ce pti o n a n d ma y q ualif y, h o we ver 
i ntr o d ucti o n of de n os u ma b is n ot all o we d w hile o n st u d y. 
5.  Has ha d pri or c he m ot her a p y, t ar gete d s m all m olec ule t hera p y, or ra di ati o n t hera p y wit hi n 2 
wee ks pri or t o st u d y Da y 1 or w h o has n ot rec o vere d (i.e., ≤Gra de 1 or at b aseli ne) fr o m A Es  
d ue t o a pre vi o usl y a d mi nistere d a ge nt. 
-  N ote:  S u bjects wit h ≤Gra de 2 n e ur o pat h y are a n e x ce pti o n t o t his criteri o n a n d ma y 
q ualif y f or t he st u d y wit h S p o ns or a p pr o val. 
6.  Has a k n o w n a d diti o nal mali g na n c y t hat is pr o gressi n g or re q uires acti ve treat me nt.  
E x ce pti o ns i ncl u de basal cell car ci n o ma of t he s ki n; s q ua m o us cell carci n o ma of t he s ki n or 
s u perficial ur ot h elial ca n cer 2 years p ost t hera p y. 
7.  Has k n o w n acti ve ce ntr al ne r v o us s yst e m ( C N S) metastases a n d/ or carci n o mat o us 
me ni n gitis.  S u 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 sta ble ( wit h o ut e vi de nce of pr o gressi o n b y i ma gi n g f or at least 4  wee ks pri or t o t he first 
d ose of trial tre at me nt a n d a n y n e ur ol o gic s y m pt o ms ha ve ret ur n e d t o baseli ne), ha ve n o 
e vi de nce of ne w or e nlar gi n g brai n met astases, a n d are n ot usi n g ster oi ds f or at least 7 da ys 
pri or t o trial treat me nt.  T his e x ce pti o n d oes n ot i ncl u de carci n o mat o us me ni n gitis w hic h i s 
e x cl u de d re gar dl ess of cli nical sta bilit y.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 5  of 9 4  
 
 
 
 
 
 
 
 
8.  Has a n acti ve a ut oi m m u ne disease re q uiri n g s yste mic treat me nt wit hi n t he past 3 m o nt hs 
(i.e., wit h use of diseas e m o dif yi n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve dr u gs).  
Re place me nt t her a p y ( e. g., t h yr o x i ne, i ns uli n or p h ysi ol o gic c ortic oster oi d re place me nt 
t hera p y f or a dr e nal or pit uitar y i ns ufficie nc y, etc.) is n ot c o nsi dere d a f or m of s yste mic 
treat me nt. 
-  N ote:  S u bjects wit h vitili g o or res ol ve d c hil d h o o d ast h ma/at o p y ma y b e all o we d wit h 
S p o ns or a p pr o val. 
-  N ote:  S u bjects w h o  re q uire i nter mitte nt use of i n hale d ster oi ds, br o nc h o dilat ors or l ocal 
ster oi d i njecti o ns ma y b e all o we d wit h S p o ns or a p pr o val. 
-  N ote:  S u bjects wit h h y p ot h yr oi dis m sta ble o n h or m o ne re place me nt or Sj o gre ns s y n dr o me 
ma y b e all o we d wit h S p o ns or a p pr o val. 
9.  Has e vi de nce of i nterstiti al l u n g diseas e or c urre nt  p ne u m o nitis or a hist or y of ( n o n-
i nfecti o us) p ne u m o nitis t hat re q uire d ster oi ds. 
1 0.  Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y . Pri or t o d osi n g with A D X S 3 1 - 1 4 2, t he 
s u bject m ust be at least 5 half-li ves fr o m t heir l ast d ose of a nti bi otic. 
1 1.  Has a hist or y of listeri osis or c urr e nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y 
a b n or malit y t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere wit h t he s u bject’s 
partici pati o n f or t he f ull d urati o n of t he trial, or is n ot i n 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.  
1 2.  Has k n o w n ps yc hiatri c or s u bsta nce a b use dis or ders t hat w o ul d i nterfere wit h c o o perati o n 
wit h t he re q uire me nts of t he trial.   
1 3.  Has recei ve d pri or t hera p y wit h a n a nti -P D - 1, a nti-P D - L 1, or a nti-P D - L 2 a ge nt or if t he 
s u bject has pre vi o usl y partici pate d i n a Merc k M K-3 4 7 5 cli nical trial.   ( N ot a p plica ble i n 
e nr oll me nt t o Part A)  
1 4.  Has a hist or y o f h u ma n i m m u n o deficie nc y vir us ( HI V) ( HI V 1/ 2 a nti b o dies). 
1 5.  Has a hist or y of he p atitis B or he p atitis C.  
1 6.  Has recei ve d a li ve vacci ne wit hi n 3 0 da ys pri or t o Da y 1 of trial treat me nt. 
1 7.  Has i m pla nte d me dical d e vice(s) t h at p ose a hi g h ris k f or c ol o nizati o n a n d/ or ca n n ot be 
easil y re m o ve d ( e. g., pr ost hetic j oi nts, artificial heart val ves, pace ma k ers, ort h o pe dic 
scre w(s), metal plate(s), b o ne graft(s), or ot her e x o ge n o us i m pla nt(s)).  N O T E: M ore 
c o m m o n de vices a n d pr ost hetics w hic h i ncl u de art erial a n d ve n o us ste nts, d e ntal a n d breast 
i m pla nts a n d ve n o us access de vices (e. g., P ort -a- Cat h or Me di p ort) are per mitte d.  S p o ns or 
m ust be c o ntacte d pri or t o c o nse nti n g a n y s u bject w h o has a n y ot her d e vice a n d/ or i m pla nt.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 6  of 9 4  
 
 
 
 
 
 
 
 
1 8.  Patie nts  w h o are c urre ntl y r ecei vi n g or w h o ha ve recei v ed a n y PI 3 K wit hi n 3 0 da ys pri or t o 
re gistrati o n. 
1 9.  A n y c urr e ntl y re q uiri n g or a ntici pate d t o re q uire T N F bl oc k i n g a ge nt (e. g., i nfli xi ma b) 
t hera p y f or di a g n osis of r he u mat ol o gic disease or i nfla m mat or y b o wel disease 
(e. g., a n k yl osi n g s p o n d ylitis, Cr o h n disease, pla q ue ps oriasis, ps oriatic art hritis , r he u mat oi d 
art hritis, or ulcer ati ve c olitis)  d uri n g st u d y t h era p y a d mi nistrati o n a n d wit hi n 3 0 da ys of t he 
last d ose of st u d y t hera p y. 
2 0.  Has a c o ntr ai n dicati o n t o a d mi nistrati o n of tri met h o pri m/s ulfa met h o x az ole a n d a m picilli n. 
2 1.  Has c o ntrai n dicati o n t o a d mi nistrati o n of N S AI D S. 
2 2.  Has u n der g o n e maj or s ur ger y wit hi n 6 wee ks pri or t o t he i nitiati o n of A D X S 3 1- 1 4 2 
treat me nt.  N O T E: All t o xicities a n d/ or c o m plicati o ns m ust ha ve rec o v ere d t o baseli ne or 
Gra de 1 pri or t o t he i nitiati o n of A D X S 3 1- 1 4 2 st u d y t hera p y.  S p o ns or m ust be c o ntacte d 
pri or t o e nr olli n g s u bjects o n t he st u d y w h o rece ntl y ha d maj or s ur ger y or h a v e ne w artificial 
i m pla nt, a n d/ or de vices. 
2 3.  Is or has a n i m me diate fa mil y m e m ber (s p o us e or c hil dre n) w h o is directl y i n v ol ve d wit h t his 
trial, t hat is e m pl o ye d b y t he i n vesti gati o nal site or S p o ns or, u nless pr os pecti ve I nstit uti o nal 
Re vie w B o ar d (I R B) a p pr o val ( b y c h air or desi g n ee) is gi ve n all o wi n g e x ce pti o n t o t his 
criteri o n f or a s pecific s u bject.  
2 4.  Has se vere h y perse nsiti vit y ( ≥Gra de 3) t o pe m br oliz u ma b a n d/ or a n y of its e x ci pie nts. 
5. 2  
Tri al Tr e at m e nt s  
T he treat me nts t o be us e d i n t his trial are o utli ne d bel o w i n  Ta ble 4 .  Trial treat me nt s h o ul d be gi n 
wit hi n 5 da ys of eli gi bilit y c o nfir mati o n.  
T a bl e 4   Tri al Tr e at m e nt s  
Dr u g  
D ose  
R o ute of 
A d mi nistr ati o n  
Re gi me n  
A D X S 3 1 -1 4 2  
0. 5  x 1 0 9, 1 x 1 0 9, 5 x 1 0 9, or 
1 x 1 0 1 0 cf u  
I V i nf usi o n 
Da y 1 of W ks 1, 4 a n d 7, Q 1 2 W 
c ycle  
P e m br oliz u ma b 
( M K-3 4 7 5)  
2 0 0 m g  
I V i nf usi o n 
Q 3 W  
5. 2. 1  
D o s e S el e cti o n/ M o difi c ati o n  
T he d oses t o be use d i n eac h part of t he trial are d escri be d b el o w. 
5. 2. 1. 1  
D o s e S el e cti o n  
T he rati o nale f or t he A D X S 3 1- 1 4 2 starti n g d ose a n d t he pe m br oliz u ma b ( M K- 3 4 7 5) fi x e d d ose 
are disc usse d i n Secti o n 4. 2. 2 .  I n Part A of t he tri al, t he st u d y w as ori gi nall y desi g ne d t o i ncl u de 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 7  of 9 4  
 
 
 
 
 
 
 
 
d ose- escalati o n/ de-es calati o n wit h t he decisi o ns base d o n i nteri m safet y dat a re vie w or pre -
defi ne d D L T criteria ( Secti o n 5. 2. 1. 1. 1  – D ose Li miti n g T o xicit y Criteria) a n d be base d o n 3 
d osi n g i nter vals ( b el o w R P 2 D, at R P 2 D, or a b o ve R P 2 D) acc or di n g t o a m T PI wit h 
pre cal c ulate d decisi o ns t hat ca n easil y b e referre d t o (Ta ble 5 ) [3 0 , 3 1 ].  T he  T PI m et h o d w o ul d 
pr o vi de f or e x p os ure  t o f e wer s u bjects t o t o xic d oses a b o ve t he M T D a n d yi el d si milar 
pr o ba bilities i n i de ntif yi n g t he c orr ect M T D, e v e n w he n t he sa m ple size is matc he d [3 1 ].  A 
mi ni m u m of 3 s u bjects will be e val uate d i n  eac h c o h ort bef ore d ose-escalati o n decisi o ns are 
ma de.  Ta ble 5 c o nsists of all t he d ose- es calati o n r ules f or t he trial.  If t he t o xicit y rat e of t he 
c urre ntl y use d d os e le vel is wit hi n t he “ u n der d osi n g” i nter val, t he m T PI desi g n rec o m me n d e d 
escalati n g t he d ose l e vel; i n t he case of pr o per d osi n g, t h is desi g n w o ul d rec o m me n d c o nti n ui n g 
at t he c urr e nt d ose; f or cases w her e t o xicities i n dicate “ o ver d osi n g”, t he m T PI desi g n w o ul d 
rec o m me n d de-escalati n g t he d os e le vel.  As  d osi n g w as n ot deter mi ne d b ase d o n t his st u d y 
al o ne, it was deci d e d t hat escalati o n t o 5 x 1 0 9 cf u or 1 x 1 01 0 cf u w o ul d n o l o n ger b e i ncl u de d i n 
t his st u d y d esi g n. T his is base d o n o verall re vie w of t he safet y d ata acr oss t he L m -base d pr o gra m 
of cli nical  trials w hic h deter mi ne d t hat t he starti n g d ose w o ul d be 1 x 1 09 cf u. At t he R P 2 D le vel 
i n Part A u p t o 1 0 s u bjects ma y be e nr olle d.  T h e S p o ns or reser ves t he ri g ht t o a d d a d diti o nal 
s u bjects i n or der t o f urt h er e val u ate safet y a n d t ol era bilit y.  All decisi o ns o n d ose-escalati o n a n d 
d ose de- es calati o n will be ma de b y t he S p o ns or o nl y aft er disc ussi o ns bet wee n S p o ns or a n d 
I n v esti gat ors ha ve o cc urr e d.  
T a bl e 5   D o s e D e ci si o n s f or A D X S 3 1 -1 4 2 M o n ot h er a p y  ( T ar g et e d D L T R at e = 2 5 %) 
T he ta ble is base d o n a sa m ple size of 2 1 s u bjects.  T w o para m eters e psil o n 1 a n d e psil o n2 are s et 
at defa ult val ues [3 0 ] of 0. 0 5.  X-a xis is n u m ber of s u bjects treat e d at c urre nt d ose; y-a xis is 
n u m ber of t o xicities . 




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 2 9  of 9 4  
 
 
 
 
 
 
 
 
He mat ol o gi c:  
1.  Gra de 4 h e mat ol o gi c t o xicit y.  
2.  Fe brile n e utr o pe nia, d efi ne d as a bs ol ute ne utr o p hil c o u nt ( A N C) < 1 0 0 0/ m m3  wit h a si n gle 
te m perat ur e of > 3 8. 3 d e grees C (1 0 1  de grees F) or a s ustai ne d te m perat ure of > 3 8 de grees C 
(1 0 0. 4 de grees F) f or m ore t ha n 1 h o ur. 
3.  Gra de 3 t hr o m b o c yt o p e nia lasti n g > 7 2 h o urs. 
4.  Gra de 4 t hr o m b o c yt o p e nia. 
N o n -He mat ol o gic:  
1.  ≥ Gra de 3 n o n- he mat ol o gic t o xicit y, (e x cl u di n g n a usea, v o miti n g a n d/ or di arr hea lasti n g < 3 
da ys a n d re v ersi ble wit h me dical i nter ve nti o n). 
2.  Gra de 3 n o n- he mat ol o gic la b orat or y val u e  t hat d oes n ot d o w n gra de t o Gra d e 2 wit hi n 3 da ys 
after o nset of t he e v e nt des pite o pti mal me dical ma na ge me nt  (e x cl u di n g tra nsie nt Gra de 3 
la b orat or y val u e a b n or m alities re versi ble wit hi n 5 da ys a n d wit h o ut me dical i nter ve nti o n). 
3.  Lister e mia: p ositi ve bl o o d c ult ure(s) al o n g wit h persiste nt (f or  7 2 h o urs p ost d ose) s y m pt o ms 
c o nsiste nt wit h listere mia (e. g., fe v er a n d m us cle ac hes, ofte n prece de d b y diarr hea or ot her 
gastr oi ntesti nal s y m pt o ms).  
4.  > Gra d e 3 fl u-li ke or c yt oki ne releas e s y m pt o ms t hat persist f or > 2 4  h o urs after A D X S 3 1 -
1 4 2 a d mi nistrati o n des pite s y m pt o matic treat me nt ( Refer t o  Secti o n  7. 2. 3. 2 ). 
S u bjects w h o e x perie nce a D L T  at D os e Le vel -1 of 0. 5 x 1 0 9 will be  disc o nti n ue d fr o m st u d y 
treat me nt.  H o we v er, s u bjects w h o e x perie nce a D L T at D L  1 of 1 x 1 09 ma y be eli gi ble t o 
recei v e A D X S 3 1- 1 4 2 at a l o wer d ose l e vel f or s u bse q ue nt d oses a n d c ycles f oll o wi n g disc ussi o n 
a n d a gree me nt bet w ee n t he I n vesti gat or a n d S p o ns or. 
5. 2. 1. 1. 2  
P art A – A D X S 3 1 -1 4 2 M o n ot h er a p y  
Part A of t he trial c o m plete d. T he A D X S 3 1- 1 4 2 m o n ot hera p y d oses t hat w ere t o be use d i n t his 
trial are o utli ne d bel o w i n Ta b le 6.  T he starti n g d ose le vel of A D X S 3 1- 1 4 2 m o n ot hera p y i n 
Part  A is 1  x 1 09 cf u ( D L 1).  T he d ose w as t o be escalate d, re mai n t he sa m e or be de -escalate d 
base d o n i nteri m saf et y d ata re vie w fr o m ot her A d va xis trial s at a partic ular d ose le vel or 
acc or di n g t o pr e- defi ne d D L T criteri a (see Secti o n  5. 2. 1. 1. 1 ) i n acc or da nce wit h t he m T PI desi g n 
(see Ta bl e 5 ), a n d after c o ns ultati o n wit h t he S p o ns or a n d I n vesti gat or, u ntil t he R P 2 D is 
selecte d. H o w e ver, base d o n safet y data fr o m ot her A d va xis trials t hat use si milar c o nstr ucts, it 
was deci de d t h at escalati o n t o 5 x 1 0 9 cf u or 1 x 1 01 0 cf u w o ul d n o l o n ger be i ncl u de d i n t his 
st u d y desi g n. T his is bas e d o n overall re vie w of t he safet y d ata acr oss t he L m - b ase d pr o gra m of 
cli nical trials, w hic h esta blis he d t hat t he starti n g d ose of 1 x 1 0 9 cf u is m ore t olera ble t ha n hi g h er 
d oses. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 0  of 9 4  
 
 
 
 
 
 
 
 
T a bl e 6   A D X S 3 1 -1 4 2 M o n ot h er a p y D o s e s t o b e u s e d i n P art A  
D ose Le vel  
D ose  
R o ute of A d mi nistr ati o n  
Re gi me n  
1 
1 x 1 0 9 cf u 
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 1 2 -wee k c ycle  
2 
5 x 1 0 9 cf u  
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 1 2 -wee k c ycle  
3 
1 x 1 0 1 0 cf u  
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 1 2 -wee k c ycle 
- 1 
. 5 x 1 0 9 cf u  
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 1 2 -wee k c ycle  
5. 2. 1. 1. 3  
P art B – A D X S 3 1 -1 4 2 + P e m br oli z u m a b ( M K -3 4 7 5) C o m bi n ati o n 
T h er a p y  
Part B c o nsists of a m o difie d 3 + 3 desi g n t o i de ntif y a rec o m me n d e d R P 2 D of t he c o m bi nati o n 
w hic h will be use d i n t he Part B e x pa nsi o n p hase. T he starti n g A D X S 3 1 - 1 4 2 d ose f or Part B will 
be t he R P 2 D deter mi ne d i n Part A.  F or e x a m ple , if 1 x 1 09 cf u is deter mi ne d t o be t he R P 2 D i n 
Part A t he n t hat will be t he starti n g d os e.  T he A D X S 3 1- 1 4 2 d ose will n ot be escalat e d  i n Part B.  
H o we ver, i f t he A D X S 3 1- 1 4 2 d ose of 1 x 1 09 cf u ( D ose Le vel 1) is n’t t olera ble i n c o m bi nati o n, 
t he n t he d ose of A D X S 3 1- 1 4 2 will be de- es calate d t o  a d ose of 0. 5 x 1 09 cf u ( D ose Le vel - 1) i n 
c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) 2 0 0 m g.  
I nteri m safet y d ata re vi e w a n d/ or D L Ts o bser ve d at t he first d ose le vel  will be use d t o deter mi ne 
t he nee d f or de-escal ati o n t o t he ne xt l o wer d ose le vel. D eter mi nati o n  t o d ose de-es calate will be 
ma de acc or di n g t o  a m o difie d  3 + 3 desi g n as f oll o ws:  
 
A n i nitial c o h ort of 3 s u bjects will be  e nr olle d at d oses of A D X S 3 1 - 1 4 2 1 x 1 09 cf u i n 
c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) 2 0 0 m g.  
 
•  If 0/ 3 s u bjects de vel o p a D L T,  
o  A n ot her 3 s u bjects will be e nr olle d at t his d ose le v el.  
 If 0, 1 or 2 of t he 3 n e w s u bjects de vel o ps a D L T (f or a t otal of 0/ 6, 1/ 6 or 
2/ 6 s u bjects wit h a D L T at t his d ose le vel), t he c urre nt d ose will be 
c o nsi dere d t he R P 2 D a n d t he trial will pr ocee d t o t he d ose e x pa nsi o n 
sta ge. 
 If 3 of t he 3 n e w s u bjects de vel o p a D L T (f or a t otal of 3/ 6 s u bjects wit h a 
D L T at t his d ose le vel), t he d ose will be de -escal ate d t o D L - 1 a n d a d os e 
of A D X S 3 1 - 1 4 2 0. 5 x 1 09 will be a d mi nistere d i n c o m bi nati o n wit h 
pe m br oliz u ma b ( M K- 3 4 7 5) 2 0 0 m g. 
•  If 1/ 3 s u bjects de vel o p a D L T,  
o  A n ot her 3 s u bjects will be e nr olle d at t his d ose le v el.  
 If 0 or 1 of t he 3 n e w s u bjects de vel o ps a D L T (f or a t otal of 1/ 6 or 2/ 6 
s u bjects wit h a D L T at t his d ose le vel), t he c urre nt d ose will be c o nsi dere d 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 1  of 9 4  
 
 
 
 
 
 
 
 
t he rec o m me n d e d M T D, a n d t he trial will pr ocee d t o t he d ose e x pa nsi o n 
sta ge. 
 If > 1 of t h e 3 ne w s u bjects de vel o p a D L T (f or a t otal of > 2/ 6 s u bjects 
wit h a D L T at t his d ose le vel), t he d ose will be de -escal ate d t o D L - 1 of 
A D X S 3 1 - 1 4 2 0. 5 x 1 09 i n c o m bi nati o n wit h pe m br oliz u ma b ( M K- 3 4 7 5) 
2 0 0 m g. 
•  If 2/ 3 or 3/ 3 s u bjects de v el o ps a D L T t he d ose will be de-es calate d.  
 
If, f oll o wi n g t he r ules a b o ve t he d ose is de-escal ate d, t he 3 + 3 r ules a b o ve will be re peat e d. 
S h o ul d a d diti o nal de-escalati o n be re q uire d, a d os e l o wer t ha n 0. 5 x 1 0 9 ma y b e c o nsi dere d  or 
t he S p o ns or ma y deci de t o ta ke ot her acti o n (e. g. , st o p t he trial) base d o n a c o m pre he nsi ve 
re vie w of t h e data fr o m t his trial as well as ot her trials. 
T his pr ot oc ol will als o all o w  de-escalati o n t o a n i nter me diate, n ot pre- defi ne d a n d n ot 
pre vi o usl y-st u die d d os e, if e val uati o n of t o xicit y at s uc h a d ose is desire d i n lie u of pr ocee di n g 
directl y t o t he d os e e x pa nsi o n sta ge of t he trial.   
T a bl e 7 A D X S 3 1 -1 4 2 a n d P e m br oli z u m a b ( M K-3 4 7 5) C o m bi n ati o n T h er a p y D o s e s 
t o b e u s e d i n Tri al P art B 
Dr u g  
D ose 
Le vel  
D ose  
R o ute of 
A d mi nistr ati o n  
Re gi me n  
A D X S 3 1 -1 4 2  
1 1 
1 x 1 0 9 
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 
1 2 -wee k c ycle  
- 1 
0. 5  x 1 0 9 
I V i nf usi o n 
Da y 1 of W ee ks 1, 4 a n d 7 of 
1 2 -wee k c ycle  
P e m br oliz u ma b 
( M K-3 4 7 5)  
 
2 0 0 m g  
I V i nf usi o n 
Da y 1 Q 3 W of 1 2 -wee k  c ycle  
C o h ort E x pa nsi o n:  O nce t he R P 2 D is deci de d, a n a d diti o nal c o h ort of s u bjects will be e nr olle d 
at t he selecte d R P 2 D f or c o m bi nati o n t hera p y.  T h e n u m ber of s u bjects will de pe n d o n t he 
n u m ber of s u bjects pr e vi o usl y treate d i n t he d ose-fi n di n g p orti o n.  It is pla n ne d  t o treat a t otal of 
a p pr o xi matel y 3 0 s u bjects at t he R P 2 D.  S u bjects will be e nr olle d o n a r olli n g basis. 
5. 2. 1. 2  
Tr e at m e nt D el a y s a n d M o difi c ati o n s  
5. 2. 1. 2. 1  
P e m br oli z u m a b ( M K -3 4 7 5)  
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 ( M K- 3 4 7 5) 
e x p os ure ma y re pr ese nt a n i m m u n ol o gic eti ol o g y.  T hese A Es  ma y o cc 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 m e nt.  Pe m br oliz u ma b ( M K- 3 4 7 5) 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 hreateni n g A Es as p er  Ta ble 8  bel o w. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 2  of 9 4  
 
 
 
 
 
 
 
 
T a bl e 8   D o s e M o difi c ati o n G ui d eli n e s f or Dr u g -R el at e d A d v er s e E v e nt s wit h 
P e m br oli z u m a b ( M K -3 4 7 5)  
T o xicit y  
H ol d 
Tre at me nt 
F or Gr a de  
Ti mi n g f or Rest arti n g 
Tre at me nt  
Disc o nti n ue S u bject  
Diarr hea/ C olitis  
2- 3 
T o xicit y res ol ves t o Gra de 
0- 1.  
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose  or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 wee ks.  
4  
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  
H y p o p h ysitis  
2 -4  
T o xicit y res ol ves t o Gra de 
0- 1.  T hera p y wit h 
pe m br oliz u ma b ( M K-3 4 7 5) 
ca n be c o nti n ue d w hile 
e n d ocri ne re place me nt 
t hera p y is i nstit ute d. 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose  or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 wee ks.  
A S T, A L T, or 
I ncrease d 
Bilir u bi n  
2  
T o xicit y res ol ves t o Gra de 
0- 1 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose.  
3 -4  
P er ma ne ntl y disc o nti n ue  
(see e xce pti o n bel o w)1 
P er ma ne ntl y disc o nti n ue  
T y pe 1 dia betes 
mellit us  ( T 1 D M) 
(if ne w o nset) or 
H y per gl yce mia  
T 1 D M or 3 -
4 
H ol d pe m br oliz u ma b 
( M K 3 4 7 5) f or ne w o nset 
T y pe 1 dia betes mellit us or 
Gra de 3 -4 h y per gl yce mia 
ass ociate d wit h e vi de nce of 
beta cell fail ure  
Res u me pe m br oliz u ma b ( M K-3 4 7 5) w he n 
s u bj ects are cli nicall y a n d met a b olicall y 
sta ble. 
H y pert h yr oi dis m  
3  
T o xicit y res ol ves t o Gra de 
0- 1 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose  or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 wee ks.  
4  
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  
H y p ot h yr oi dis m  
1- 4 
T hera p y wit h 
pe m br oliz u ma b ( M K-3 4 7 5) 
ca n be c o nti n ue d w hile 
t h yr oi d re place me nt t hera p y 
is i nstit ute d 
T hera p y wit h pe m br oliz u ma b ( M K-3 4 7 5) 
ca n be c o nti n ue d w hile t h yr oi d re place me nt 
t hera p y is i nstit ute d. 
I nf usi o n Reacti o n 
3- 4 
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  
P ne u m o nitis  
2  
T o xicit y res ol ves t o Gra de 
0- 1 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 wee ks.  
3 -4  or 
Rec urre nt  2 
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 3  of 9 4  
 
 
 
 
 
 
 
 
T o xicit y  
H ol d 
Tre at me nt 
F or Gr a de  
Ti mi n g f or Rest arti n g 
Tre at me nt  
Disc o nti n ue S u bject  
Re nal Fail ure or 
Ne p hritis  
2  
T o xicit y res ol ves t o Gra de 
0- 1 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2 wee ks.  
3- 4 
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  
All Ot her Dr u g -
Relate d T o xicit y 2 
3  or Se vere  
T o xicit y res ol ves t o Gra de 
0- 1 
T o xicit y d oes n ot res ol ve wit hi n 1 2 wee ks 
of last d ose or i na bilit y t o re d uce 
c ortic oster oi d t o 1 0 m g or less of pre d nis o ne 
or e q ui vale nt per da y wit hi n 1 2  wee ks.  
4 
P er ma ne ntl y disc o nti n ue  
P er ma ne ntl y disc o nti n ue  
N ote:  P er ma ne ntl y disc o nti n ue f or a n y se vere or Gra de 3 ( Gra de 2 f or p ne u m o nitis) dr u g -r elate d A E t hat rec urs 
or a n y life -t hreate ni n g e ve nt. 
1 F or s u bj ects wit h li ver metastasis w h o be gi n treat me nt wit h Gra de 2 A S T or A L T, if A S T or A L T i ncreases b y 
greater t ha n or e q ual t o 5 0 % relati ve t o baseli ne a n d lasts f or at least 1 wee k t he n s u bj ects s h o ul d be 
disc o nti n ue d.  
2 S u bj ects  wit h i nt olera ble or persiste nt Gra de 2 dr u g -relate d A E ma y h ol d st u d y me dicati o n at p h ysicia n 
discreti o n.  P er ma ne ntl y disc o nti n ue st u d y dr u g f or persiste nt Gra de 2 a d verse reacti o ns f or w hic h treat me nt wit h 
st u d y dr u g has bee n hel d, t hat d o n ot rec o ver to Gra de 0 -1 wit hi n 1 2 wee ks of t he last d ose.  
If t o xicit y d o es n ot res ol ve t o Gra de 0-1 wit hi n 1 2 wee ks after last i nf usi o n, trial treat me nt 
s h o ul d be disc o nti n ue d after c o ns ultati o n wit h t he S p o ns or.  Wit h I n v esti gat or a n d S p o ns or 
a gree m e nt, s u bjects  wit h a la b orat or y A E  still at Gra de 2 after 1 2 w ee ks ma y c o nti n ue treat me nt 
i n t he trial o nl y if as y m pt o matic a n d c o ntr olle d.  F or i nf or mati o n o n t he ma na ge me nt of A Es, s ee 
Secti o n 5. 6. 1 . 
S u bjects w h o e x perie nce a rec urre n ce of t he sa me se vere or life -t hreate ni n g ( per C T C A E) e ve nt 
at t he sa me gr a de or greater wit h re -c halle n ge of p e m br oliz u ma b ( M K - 3 4 7 5) s h o ul d be 
disc o nti n ue d fr o m trial tr eat me nt.  
5. 2. 1. 2. 2  
A D X S 3 1 -1 4 2  
T he m ost li kel y a ntici pat e d A Es ass ociat e d wit h A D X S 3 1 - 1 4 2 are c o m prise d pri maril y of 
i n di vi d ual fl u-li ke s y m pt o ms (e. g., fati g ue, let har g y a n d l o w gra d e fe v er) or c yt o ki n e rel ease 
s y m pt o ms (e. g., c o nstit uti o nal s y m pt o ms s uc h as fe ver, c hills, ri g ors, hea dac he, na usea, 
v o miti n g, tac h ycar dia, s h ort ness of breat h, h y p ote nsi o n, a n d ras h).  T h ese s y m pt o ms us uall y 
prese nt wit hi n 2- 4 h o urs after t he c o m pleti o n of i nf usi o n a n d are ofte n mil d t o m o derate a n d 
tra nsie nt i n nat ure or res p o n d q uic kl y t o s y m pt o matic treat me nt.  I n rare i nst a nces, t he y ma y l ast 
u p t o 2 4 h o urs. N o c u m ulati ve or dela ye d t o xicit y has bee n o bser ve d. 
Less li kel y A E’s i ncl u de i ncreas e heart rate, l o w bl o o d press ure, m uscle ac hes, hea dac hes, 
aller gic r eacti o n, c h a n ges i n bl o o d c he mistr y, c h a n ges i n bl o o d c o u nts, a n d s h ort ter m c ha n ges i n 
li ver f u ncti o n. 
Rare b ut seri o us A Es i ncl u de hi g h fe ver, diffic ult y breat hi n g a n d h y p ote nsi o n. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 4  of 9 4  
 
 
 
 
 
 
 
 
A D X S 3 1 - 1 4 2 has a tr o pis m f or t he li ver.  Tra nsi e nt as y m pt o matic ele vati o ns of 
A L T a n d al kali ne p h os p h atase were o bser ve d after d osi n g wit h A D X S 1 1 - 0 0 1 i n t he P hase 1 trial 
wit h o ut pr o p h ylactic m e dicati o n a d mi nistrati o n.  F or t hat reas o n, s u bjects wit h si g nifica nt li ver 
disease ar e e x cl u de d, a n d partic ular atte nti o n is t o be pai d t o he patic a b n or malities.  
T he d ose of A D X S 3 1- 1 4 2 will n ot be m o difie d (e. g., re d uce d or i ncrease d) u nless if it is 
deter mi ne d t hat t he t o xicities are clearl y attri b ute d t o A D X S 3 1- 1 4 2 or t he c o m bi nati o n, t he 
treat me nt m o dificati o n g ui deli nes f or dr u g-relate d A Es i n Ta ble 9  s h o w n b el o w are t o b e 
f oll o we d. 
T a bl e 9 Tr e at m e nt D el a y/ Di s c o nti n u ati o n G ui d eli n e s f or Dr u g -R el at e d A d v er s e 
E v e nt s -A D X S 3 1 -1 4 2  
T o xicit y  
Gra de  
H ol d treat me nt  
Ti mi n g f or restarti n g 
treat me nt 
Disc o nti n ue treat me nt 
He mat ol o gic  
1 -3  
N o  
N/ A  
N/ A  
4 
Yes  
T o xicit y res ol ves t o 
≤Gra de 1 or baseli ne  
T o xicit y d oes n ot 
res ol ve t o ≤Gra de 1 or 
baseli ne wit hi n 1 2 
wee ks  
N o n -
he mat ol o gic, 
e xcl u di n g 
c yt o ki ne 
release 
s y m pt o ms 
a n d D L Ts  
1  
N o  
N/ A  
N/ A  
2- 3 
Yes  
T o xicit y res ol ves t o 
≤Gra de 1  
T o xicit y n ot res ol ve d 
t o ≤Gra de 1 wit hi n 1 2 
wee ks of last i nf usi o n a 
4 
N/ A  
P er ma ne nt l y 
disc o nti n u e treat me nt  
P er ma ne nt l y 
d isc o nti nue treat me nt  
a Wit h I n vesti gat or a n d S p o ns or a gree me nt, s u bjects wit h a n o n -he me A E (e. g., al o p ecia, n e ur o p at h y) still at gra d e 2 aft er 1 2 
we e ks, ma y c o nti n u e treat me nt if o nl y as y m pta metic a n d c o ntr olle d.  
5. 2. 2  
Ti mi n g of D o s e A d mi ni str ati o n  
Trial treat me nt s h o ul d be a d mi nis tere d o n Da y 1 of Wee k 1, 4 a n d 7 (f or A D X S 3 1- 1 4 2) or Q 3 W 
(f or pe m br oliz u ma b [ M K- 3 4 7 5]) i n eac h 1 2-w ee k c ycle after all pr oce d ures/assess me nts ha ve 
bee n c o m plete d as detail e d o n t he Trial Fl o w C hart ( Secti o n 6 ).  Trial treat me nt ma y b e 
a d mi nistere d u p t o 7 da ys bef ore or after t he sc h e d ule d Da y 1 of eac h c ycl e d ue t o a d mi nistrati ve 
reas o ns. 
T rial treat me nts will be a d mi nistere d as a 3 0 mi n ute I V i nf usi o n f or p e m br oliz u ma b ( M K - 3 4 7 5) 
a n d 
 (treat me nt c ycle i nter v als ma y be i ncrease d d ue t o 
t o xicit y as des cri be d i n Secti o n 5. 2. 1. 2 ).  Sites s h o ul d ma ke e ver y eff ort t o tar get re q uire d 
i nf usi o n ti mi n g. H o we ver, gi ve n t h e vari a 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 
 is per mitte d.  
Patie nts  will recei ve eit h er  oral 8 0 m g tri met h o pri m/4 0 0 m g s ulfa met h o x az ole o nce dail y f or 
7 da ys  or 1 6 0 m g tri met h o pri m / 8 0 0 m g s ulfa met h o x az ole ( D S) t hree ti mes o ver t he c o urse of 
t he 7 da ys.  S u bjects wit h k n o w n aller g y t o s ulfa dr u gs ma y recei ve a m picilli n 5 0 0 m g f o ur ti mes 
dail y f or 7 da ys be gi n ni n g o n D a y 4 (a p pr o xi matel y 7 2 h o u rs) after eac h st u d y treat me nt 
i nf usi o n. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 5  of 9 4  
 
 
 
 
 
 
 
 
D uri n g c o m bi nati o n d osi n g i n Part B, t here s h o ul d be a p pr o xi matel y 
 bet wee n t he e n d 
of t he first i nf usi o n a n d t he start of t he sec o n d i nf usi o n.  T he pe m br oliz u ma b ( M K- 3 4 7 5) 
i nf usi o n will be a d mi nistere d first, f oll o w e d b y t he A D X S 3 1- 1 4 2 re q uire d pr o p h ylactic re gi me n 
at least
 pri or t o t he A D X S 3 1- 1 4 2 i nf usi o n. 
T he P har mac y M a n ual c o ntai ns s pecific i nstr ucti o ns f or A D X S 3 1- 1 4 2 d ose pre parati o n a n d 
a d mi nistrati o n, a n d pe m br oliz u ma b ( M K- 3 4 7 5) 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. 3  
A d mi ni str ati o n of A D X S 3 1 -1 4 2  
5. 2. 4  
Pr etr e at m e nt Pr o p h yl a xi s R e gi m e n  
Mil d t o m o derate fl u-li ke s y m pt o ms a n d c yt o ki ne releas e s y m pt o ms (e. g., c o nstit uti o nal 
s y m pt o ms s uc h as f e ver, c hills, ri g ors, fati g u e, hea dac he, n a usea, v o miti n g, tac h ycar dia, 
s h ort ness of breat h, h y p ote nsi o n, a n d ras h) are c o m m o nl y s ee n a n d t y picall y occ ur 2- 4 h o urs 
after i m m u n ot hera p y a n d ofte n res ol ve wit hi n 1 2- 2 4 h o urs.  Pr o p h ylactic me dicati o ns are 
i nte n de d t o re d uce t he i nfla m mat or y res p o nse.  Pri or t o a d mi nisteri n g a n y pr o p h ylactic 
me dicati o ns ( o n Da y 1 of Wee ks 1, 4, a n d 7 of eac h 1 2- wee k c ycle), place a 
S u bjects  s h o ul d recei ve t he f oll o wi n g pretreat me nt pr o p h yla xis re gi me n t hr o ug h a t e m p orar y I V : 
•  I V Fl ui d H y dr ati o n: 
•  N or mal sali ne (e. g., 5 0 0 m L o ver 3 0 mi n utes) 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 6  of 9 4  
 
 
 
 
 
 
 
 
Pre me dicati o n Re gi me n:  
•  A nti hista mi ne  - P O or I V  (e. g., di p he n h y dra mi ne 2 5 m g or e q ui vale nt ), o n ce   
•  N S AI Ds  - P O (e. g., n a pr o x e n 2 2 0 m g or i b u pr ofe n 4 0 0 m g), o n ce 
•  A ntie metic  - P O or I V (e. g., p r o met h azi ne or o n da nsetr o n), o nce 
•  Hista mi ne H 2 -rece pt or a nta g o nist - P O or I V (e. g., fa m oti di ne 2 0 m g or e q ui vale nt ), o nce 
Vital si g ns will be ta ke n i m me diatel y bef ore eac h st u d y treat me nt i nf usi o n.  
Pretreat me nt me dicati o n s h o ul d be gi v e n o n t he d a y of d osi n g a n d c o m plet e d at least 3 0 mi n utes 
pri or t o t he start of t he assi g ne d st u d y treat me nt.  A d diti o nal N S AI D d os es a n d a ntie metic 
a d mi nistrati o n s h o ul d be gi ve n p er la bel or pac k a ge i nsert p ost i nitial a d mi nistrati o n o n Da y 1 
a n d Da y 2, as n ee d e d.  T he prescri be d d osa ge of t he selecte d N S AI D a n d a ntie metic will be at 
t he discreti o n of t he I n v esti gat or. 
D o n ot s u bstit ute aceta mi n o p he n f or t he s electe d N S AI D f or pr o p h yl actic treat me nt si nce 
aceta mi n o p he n d o es n ot ha ve si milar a nti- i nfla m mat or y pr o perties t hat c o ul d a meli orate c yt o ki ne 
releas e s y m pt o ms. 
5. 2. 5  
P o st -Tr e at m e nt M o nit ori n g  
Vital si g ns will be ta ke n e ver y 
f oll o wi n g eac h st u d y 
treat me nt i nf usi o n.  F o ur h o urs after t h e st u d y treat me nt , t he I n v esti gat or m ust e ns ure t he s u bject 
is i n sta ble me dical c o n diti o n a n d i n t he I n v esti gat or’s o pi ni o n ca n be s afel y disc har ge d b ef ore 
bei n g r eleas e d .  I n t he e v e nt t hat t he s u bject is n ot sta ble, t he I n vesti gat or m ust ta ke acti o n t o 
pr o vi de a p pr o priate me di cal care ( Refer t o T a ble 1 0 ). 
5. 2. 6  
Tri al Bli n di n g/ M a s ki n g  
T his is a n o pe n-la bel trial; t heref or e, t he S p o ns or, I n vesti gat or a n d s u bject will k n o w t he 
treat me nt a d mi nistere d. 
5. 3  
Tr e at m e nt All o c ati o n  
S u bjects partici pati n g i n t his trial will be all ocate d b y n o n -ra n d o m assi g n m e nt. 
5. 4  
Str atifi c ati o n  
Treat me nt gr o u ps will n ot be stratifie d.  
5. 5  
C o n c o mit a nt M e di c ati o n s/ V a c ci n ati o n s ( All o w e d & Pr o hi bit e d)  
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e x cl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g trial.  If t here is a cli nical i n dicati o n f or o ne of t hes e or ot her me dicati o ns or 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 7  of 9 4  
 
 
 
 
 
 
 
 
vacci nati o ns s pecificall y pr o hi bite d d uri n g t he tri al, disc o nti n uati o n fr o m trial t hera p y or 
vacci nati o n ma y b e re q uire d.  T he I n v esti gat or s h o ul d d isc uss a n y q u esti o ns re gar di n g t his wit h 
t he S p o ns or.  T he fi nal d ecisi o n o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h t he 
I n v esti gat or a n d/ or t he s u bject's pri mar y p h ysicia n.  H o 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 m e nt of t he 
I n v esti gat or, t he S p o ns or, a n d t he s u bject. 
5. 5. 1  
A c c e pt a bl e C o n c o mit a nt M e di c ati o n  
All treat me nts t hat t he In vesti gat or c o nsi ders necessar y f or a s u bject’s w elfare ma y b e 
a d mi nistere d at t he discr eti 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 n c o mita nt me dicati o n a n d t hera pies will be rec or de d i n t he electr o nic case 
re p ort f or m (e C R F) i ncl u di n g all pres cri pti o n, o ver-t he-c o u nt er ( 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 p eri o d, d oc u m e ntati o n of dr u g 
d osa ge, fr e q ue nc y, r o ute, a n d date s h o ul d als o be i ncl u de d o n t he C R F. 
All c o nc o mita nt me dicati o ns recei v e d wit hi n 2 8 da ys b ef ore i nf or me d c o ns e nt is si g ne d a n d 
t hr o u g h t he 3 0-Da y F oll o w -U p peri o d s h o ul d be rec or de d i n t he e C R F.  C o n c o mita nt 
me dicati o ns a d mi nistere d t o treat S A Es a n d E CIs s h o ul d be rec or de d as d efi ne d i n Secti o n 7. 2  
5. 5. 2  
Pr o hi bit e d C o n c o mit a nt M e di c ati o n s  
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 S cree ni n g a n d 
Treat me nt P hase (i ncl u di n g r etreat me nt f or p ost- c o m plete res p o nse rela pse) of t his trial:  
•  A nti -ca ncer t her a p y i ncl u di n g b ut n ot li mite d t o h or m o nal, c he m ot hera p y, ra diati o n 
t hera p y, a n d tr eat me nt wit h tar geti n g a ge nts (e. g., t yr osi ne ki n ase i n hi bit ors).  H o we ver, 
occasi o nal t hera p y f or palliati o n of pai n is all o we d. N ote:  Ra diati o n t hera p y t o a 
s y m pt o matic s oft tiss ue lesi o n, b o ne lesi o ns or t o t he brai n ma y be all o we d after 
c o ns ultati o n wit h S p o ns or.  Ra di o p har mace uticals (ra di u m, str o nti u m, etc.) are n ot 
acce pta ble.  
•  I m m u n ot her a p y n ot s pecifie d i n t his pr ot oc ol; u nless a p pr o ve d b y I n v esti gat or a n d 
S p o ns or  
•  Bis p h os p h o nates a n d d e n os u ma b  
o  N ote:  S u bjects alrea d y b ei n g treate d wit h bis p h os p h o nates or de n os u ma b ma y 
c o nti n ue treat me nt, h o w e ver, i ntr o d ucti o n of eit her is n ot all o we d w hile o n st u d y. 
•  I n v esti gati o nal a ge nts ot her t ha n A D X S 3 1 - 1 4 2 a n d pe m br oliz u ma b ( M K- 3 4 7 5) 
•  PI 3 K a n d T N F α  i n hi bit ors 
•  Li ve v acci n es wit hi n 3 0 da ys pri or t o t he first d os e of trial treat me nt a n d w hile 
partici pati n g i n t he tri al.  E x a m ples of li ve vacci nes i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: measles, m u m ps, r u bella, c hic k e n p o x, yell o w fe ver, ra bies, B a cille C al mette -


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 8  of 9 4  
 
 
 
 
 
 
 
 
G ueri n  ( B C G), a n d t y p h oi d ( oral) vacci ne.  Seas o nal i nfl ue nza vacci n es f or i njecti o n are 
ge n erall y kille d vir us vacci nes a n d are all o w e d; h o we ver i ntra nasal i nfl ue nz a vacci nes 
(e. g., Fl u-Mist ®) are li ve atte n uate d vacci nes, a n d are n ot all o we d.  
•  S yste mic g l uc oc ortic oi ds f or a n y p ur p os e ot her t h a n t o m o d ulate s y m pt o ms fr o m a n e ve nt 
of cli nical i nterest of s us pecte d i m m u n ol o gic eti ol o g y  or t o ma n a ge c yt o ki n e release 
s y m pt o ms.  T he use of p h ysi ol o gic d oses of c ortic oster oi ds ma y be a p pr o ve d after 
c o ns ultati o n wit h t he S p o ns or.  I nter mitte nt use of i n hale d ster oi ds is all o we d f or 
ma na ge me nt of ast h ma.  
•  A nti -i nfecti ves s h o ul d be a v oi de d.  N ote: S u bjects wit h a d oc u me nte d i nfecti o us 
c o m plicati o n s h o ul d recei ve oral or I V a nti bi otics or ot her a nti- i nfecti ve a ge nts as 
c o nsi dere d a p pr o priat e b y t he tr eati n g I n vesti gat or f or a gi ve n i nfecti o us c o n diti o n, 
acc or di n g t o sta n d ar d i nstit uti o nal practice.  
•  Aceta mi n o p he n is n ot t o be use d f or pre- m e dicati o n beca use it d oes n ot h a ve a nti-
i nfla m mat or y pr o perties re q uire d f or A E a m eli orati o n b ut ma y be use d f or s u p p orti ve care 
meas ures; f or s u bj ects  w here na pr o x e n a n d i b u pr ofe n are c o ntrai n dicate d, a n alter native 
a nti-i nfla m mat or y s h o ul d be use d.  S p o ns or c o ns ultati o n is rec o m me n de d. 
S u bjects w h o, i n t he assess me nt of t he I n vesti gat or, re q uire t h e 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.  S u bjects ma y recei ve 
ot her me dicati o ns t hat t he In vesti gat or dee ms t o be me dicall y necessar y.  
T he E x cl usi o n Criteria descri be ot her me dicati o ns t hat are pr o hi bite d i n t his trial. 
T here are n o pr o hi bite d t hera pies d uri n g t he P ost- Treat me nt F oll o w - u p P hase. 
5. 6  
R e s c u e M e di c a ti o n s & S u p p orti v e C ar e 
5. 6. 1  
S u p p orti v e C ar e G ui d eli n e s  
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 b y t he 
treati n g I n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of A Es  wit h 
p ote ntial i m m u n ol o gic eti ol o g y ar e o utli ne d bel o w.  W here a p pr o priate, t h ese meas ures i ncl u de 
t he use of oral or i ntra ve n o us treat me nt wit h c orti c oster oi ds as well as a d diti o nal a nti-
i nfla m mat or y a ge nts if s y m pt o ms d o n ot i m pr o ve wit h a d mi nistrati o n of c ortic oster oi ds.  N ote 
t hat several c o urses of st er oi d ta peri n g ma y b e necessar y as s y m pt o ms ma y w orse n w he n t h e 
ster oi d d ose is decr ease d.  F or eac h dis or d er, atte m pts s h o ul d be ma de t o r ule o ut ot her ca us es 
s uc h as metastatic disease or bact erial 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 car e.  T he tr eat me nt g ui deli nes are i nte n de d t o be a p plie d w h e n t he i n vesti gat or 
deter mi nes t he e v e nts t o be relate d t o p e m br oliz u ma b  ( M K- 3 4 7 5) or A D X S 3 1 - 1 4 2. 
N ote:  If aft er e v al uati o n, t he e ve nt is deter mi ne d n ot t o be relate d, the 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 Secti o n  5. 2. 1  f or d ose 
m o dificati o n.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 3 9  of 9 4  
 
 
 
 
 
 
 
 
It ma y b e necessar y t o p erf or m c o n diti o nal pr oce d ures s uc h as br o nc h osc o p y, e n d os c o p y, or s ki n 
p h ot o gra p h y as part of e v al uati o n of t he e ve nt. 
5. 6. 1. 1  
P n e u m o niti s:  
o  F or Gr a de 2 e ve nts , treat wit h s yst e mic c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o 
Gra de 1 or less, ster oi d ta per s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 
4 wee ks.  
o  F or Gr a de 3- 4 e ve nts , i m me diatel y treat wit h I V st er oi ds.  A d mi nister a d diti o nal a nti-
i nfla m mator y m eas ur es, as nee de d.  
o  A d d pr o p h yl actic a nti bi otics f or o p p ort u nistic i nfecti o ns i n t he case of pr ol o n ge d 
ster oi d a d mi nistrati o n. 
5. 6. 1. 2  
Di arr h e a:  
S u bjects s h o ul d be caref ull y m o nit ore d f or si g ns a n d s y m pt o ms of e nter oc olitis (s uc h as 
diarr hea, a b d o mi nal pai n, bl o o d or m uc us i n st o ol, wit h or wit h o ut fe ver) a n d of b o wel 
perf or ati o n (s uc h as p erit o neal si g ns a n d ile us). 
o  All s u bjects w h o e x perie nce diarr hea 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 uffici e 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.  F or Gra de 2 or hi g her diarr h ea, c o nsi der GI 
c o ns ultati o n a n d e n d osc o p y t o c o nfir m or r ule o ut c olitis. 
o  F or Gr a de 2 di arr he a/c olitis  t hat persists > t ha n 3 da ys, ad mi nister oral 
c ortic osteroi ds. 
o  F or Gr a de 3 o r 4 di arr he a/c olitis  t hat persists > 1 wee k, treat wit h I V ster oi ds 
f oll o we d b y hi g h d os e or al ster oi ds. 
o  W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, ster oi d ta per s h o ul d be starte d a n d 
c o nti n ue d o ver n o less t h a n 4 wee ks. 
5. 6. 1. 3  
Di a b et e s:  
T y pe 1  di a betes mellit us ( T 1 D M) (if n e w o nset, i n cl u di n g dia b etic ket oaci d osis [ D K A]) 
or ≥ Gra d e 3 h y per gl yce mia, if ass ociate d wit h ket osis ( ket o n uria) or meta b olic aci d osis 
( D K A) 
o  F or T 1 D M  or Gr a de 3 - 4 H y p er gl yce mia  
 I ns uli n re place m e nt t hera p y is rec o m me n de d f or T 1 D M  a n d f or Gra de 3- 4 
h y per gl yce mia ass ociate d wit h m eta b olic aci d osis or ket o n uria. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 0  of 9 4  
 
 
 
 
 
 
 
 
 E val uate s u bjects  wit h ser u m gl uc os e a n d a m eta b olic pa nel, uri ne ket o n es, 
gl yc os ylate d h e m o gl o bi n, a n d C- pe pti de. 
5. 6. 1. 4  
H y p o p h y siti s:  
o  F or Gr a de 2  e ve nts, treat wit h c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o Gra de 1 
or less, ster oi d ta per s h o ul d be starte d a n d c o nti n ue d o ver n o less t ha n 4 wee ks.  
Re place me nt of a p pr o pri ate h or m o nes ma y b e re q uire d as t he ster oi d d ose is ta pere d. 
o  F or Gr a de 3 - 4 e ve nts, tr eat wit h a n i nitial d ose of I V c ortic oster oi ds f oll o we d b y oral 
c ortic oster oi ds.  W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, ster oi d ta per s h o ul d be 
starte d a n d c o nti n ue d o v er n o less t ha n 4 w ee ks.  Re place me nt of a p pr o pri ate 
h or m o nes ma y be r e q uire d as t he ster oi d d ose is ta pere d. 
5. 6. 1. 5  
H y p ert h yr oi di s m or H y p ot h yr oi di s m:  
T h yr oi d dis or d ers ca n occ ur at a n y ti me d uri n g treat me nt.  M o nit or s u bjects f or c ha n ges 
i n t h yr oi d f u ncti o n ( at t he start of treat me nt, peri o dicall y d uri n g treat me nt, a n d as 
i n dicate d based o n cli nical e val uati o n) a n d f or cli nical si g ns a n d s y m pt o ms of t h yr oi d 
dis or ders. 
o  Gr a de 2  h y p ert h yr oi dis m e ve nts (a n d Gr a de 3 - 4 h y p ot h yr oi dis m): 
 I n h y p ert h yr oi dis m, n o n-selecti ve beta- bl oc kers (e. g., pr o pra n ol ol) are s u g geste d 
as i nitial t hera p y.  
 I n h y p ot h yr oi dis m, t h yr oi d h or m o ne re place me nt t hera p y, wit h le v ot h yr o xi ne or 
li ot h yr o ni ne, is i n dicate d per sta n dar d of care. 
o  Gr a de 3 - 4 h y pert h yr oi dis m 
 Treat wit h a n i nitial d ose of I V c ortic oster oi d f oll o we d b y oral c ortic oster oi ds.  
W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, ster oi d ta per s h o ul d be starte d a n d 
c o nti n ue d o ver n o less t h a n 4 wee ks.  Re pl ace m e nt of a p pr o priate h or m o nes ma y 
be re q uir e d as t he ster oi d d ose is ta pere d.  
5. 6. 1. 6  
H e p ati c:  
o  F or Gr a de 2  e ve nts, m o nit or li ver f u ncti o n tests m ore fre q ue ntl y u ntil val ues ret ur n t o 
baseli ne (c o nsi der wee kl y). 
 Treat wit h I V or oral c ortic oster oi ds  
o  F or Gr a de 3 - 4 e ve nts, tr eat wit h I V c ortic oster oi ds f or 2 4 t o 4 8 h o urs. 
o  W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, a ster oi d ta per s h o ul d be start e d a n d 
c o nti n ue d o ver n o les s t h a n 4 wee ks. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 1  of 9 4  
 
 
 
 
 
 
 
 
5. 6. 1. 7  
R e n al F ail ur e or N e p hriti s:  
o  F or Gr a de 2  e ve nts, treat wit h c ortic oster oi ds. 
o  F or Gr a de 3 - 4 e ve nts, tr eat wit h s yste mic c ortic oster oi ds.  
o  W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, ster oi d ta per s h o ul d be starte d a n d 
c o nti n ue d o ver n o less t h a n 4 wee ks.  
5. 6. 1. 8  
C yt o ki n e R el e a s e S y m pt o m s:  
C yt o ki ne r el ease sy m pt o ms are a c o nstellati o n of i nfla m mat or y s y m pt o ms res ulti n g fr o m 
c yt o ki ne ele vati o ns ass ociate d wit h T cell e n ga ge me nt a n d pr oliferati o n.  S y m pt o ms 
relate d t o c yt o ki ne releas e ma y i ncl u de c o nstit utio nal s y m pt o ms s uc h as fe ver, c hills, 
ri g ors, h ea dac he, n a usea, v o miti n g, ras h, tac h ycar dia, h y p ote nsi o n a n d s h ort ness of 
breat h , w hic h us u all y pr ese nts se veral h o urs after t he i nf usi o n a n d ma y last f or u p t o 
2 4 h o urs.  T hese s y m pt o ms are ca use d b y a n i ncrease i n c yt o ki nes s uc h as T N F α, I F Nγ 
a n d I L- 6, all of w hic h ha ve bee n s h o w n t o o cc ur after i m m u n ot hera p y a d mi nistrati o n, 
res ulti n g fr o m t he b o d y’s i m m u ne res p o nse t o t he t hera p y.  S y m pt o ms are ofte n 
G ra de 1- 2 a n d tra nsient, res ol vi n g wit h s y m pt o matic ma na ge me nt wit hi n 3 0 mi n utes  t o 
1 h o ur.  I n rare i nsta nces ( ~ 1 %) G ra de 3- 4 h y p ote nsi o n has bee n see n.  T heref ore, cl ose 
m o nit ori n g of bl o o d press ure is re q uire d at baseli n e, a n d d uri n g t he 4- h o ur p ost-i nf usi o n 
peri o d.  I ncr eas e d le vels of I L- 6 ha v e  bee n str o n gl y ass o ciate d wit h ca pillar y lea k w hic h 
ma nifests as h y p ote nsi o n d ue t o t he c yt o ki nes i n v ol ve d.  We ha ve o bser v e d ele vate d I L - 6 
le vels after i nf usi o n of i m m u n ot hera p y, wit h pea k le vels occ urri n g 2-4 h o urs after 
i nf usi o n.  E mer gi n g e vi de nce i n dicates t hat I L - 6 a nta g o nists, s uc h as t ociliz u ma b, ha ve 
de m o nstrate d g o o d res ults i n treati n g c yt o ki n e-i n d uce d h y p ote nsi o n [ 3 3- 3 5 ] a n d is 
t heref or e r ec o m me n de d f or cases of se vere h y p ote nsi o n refract or y t o s u p p orti ve care 
(e. g., fl ui ds a n d/ or pr ess ors). 
T he ma na ge m e nt of c yt o ki ne releas e s y m pt o ms a n d g ui deli nes f or s u bse q ue nt treat me nt 
f or s u bjects w h o ha v e e x perie nce d t hese A Es  are s h o w n i n Ta ble 1 0 . 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 2  of 9 4  
 
 
 
 
 
 
 
 
T a bl e 1 0   R e c o m m e n d e d M a n a g e m e nt G ui d eli n e s f or A d v er s e E v e nt s A s s o ci at e d wit h C yt o ki n e R el e a s e  
T o xicit y  
N CI C T C A E 
Gr a de or Se verit y  
Tre at me nt  
M o dific ati o n f or S u bse q ue nt i nf usi o ns  
H y p ote nsi o n  
1  
Mil d  
•  S u p p orti ve care  
•  I ncrease pretreat me nt I V fl ui ds (e. g., 
5 0 0   ml -1 L n or mal sali ne)  
Fe ver,  
C o nstit uti o nal s y m pt o ms  
1  
•  S u p p orti ve care  
•  N o m o dificati o n  
H y p ote nsi o n  
2  
M o derate  
•  Fl ui ds  
•  I ncrease m o nit ori n g of vital si g ns 
•  If h y p ote nsi o n persists , c o nsi d er l o w d ose 
c ortic oster oi ds (e. g. , h y dr oc ortis o ne 1 0 0 m g I V 
o ver 3 0 sec o n ds ) 
•  If h y p ote nsi o n persists des pite fl ui ds a n d l o w d ose 
ster oi ds a d mi nister 1 l o w d ose of press ors 
(e. g., 0. 3  m g e pi ne p hri ne I M)  
•  E xte n d i nf usi o n ti me t o 2 h o urs.  
•  I ncrease pretreat me nt I V fl ui ds (e. g. 
5 0 0  ml -1 L n or mal sali ne)  
•  I nc or p orate Gl uc oc ortic oi d- 
H y dr oc ortis o ne or e q ui vale nt - 5 0 m g, 
I V, as pre me dicati o n 
All ot her c yt o ki ne release 
s y m pt o ms (e. g. c hills, 
ri g ors, fe ver, na usea, 
v o miti n g)  
2  
•  A p pr o priate s u p p orti ve care meas ure  
•  E xte n d i nf usi o n ti me t o 2 h o urs.  
•  C o nsi der i ncreasi n g d oses of 
pr o p h ylactic me dicati o ns  
H y p ote nsi o n  
3  
S e vere 
•  Fl ui ds  a n d a d mi nister c ortic osteri o ds   
•  I ncrease m o nit ori n g of vital si g ns 
•  If h y p ote nsi o n w orse ns or is u nres p o nsi ve t o t he 
a b o ve meas ures, a d mi nister hi g h d ose press ors 
(e. g., do pa mi ne 1 0 µ g/ k g/ mi n) + /- 1 d ose 
t ociliz u ma b *( 4 m g/ k g o ver 1 h o ur)  
•  If t he s u bj ect’s c o n diti o n d oes n ot i m pr o ve or 
sta bilize des pite t he a b o ve me as ures, c o nsi der 
a d mi nistrati o n of a 2n d d ose  of  t ociliz u ma b per 
i n vesti gat or’s discreti o n w he n cli nicall y i n dicate d, 
•  Disc uss wit h S p o ns or  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 3  of 9 4  
 
 
 
 
 
 
 
 
T o xicit y  
N CI C T C A E 
Gr a de or Se verit y  
Tre at me nt  
M o dific ati o n f or S u bse q ue nt i nf usi o ns  
please see A C T E M R A prescri b i n g i nf or mati o n (as 
a b o ve)  +/ - a d diti o nal c ortic oster oi ds  
All ot her c yt o ki ne release 
s y m pt o ms (e. g. c hills, 
ri g ors, fe ver, na usea, 
v o miti n g)  
3  
•  A p pr o priate s u p p orti ve care meas ures  
•  E xte n d i nf usi o n ti me t o 2 h o urs.  
•  C o nsi der i ncreasi n g  d oses of 
pr o p h ylactic d ose of N S AI D, or 
a ntie metic as a p pr o priate 
H y p ote nsi o n/ Or ga n 
t o xicit y, mec ha nical 
ve ntilati o n  
4  
Life t hreate ni n g  
•  Vi gila nt s u p p orti ve care  
•  Fl ui ds, hi g h d ose  press ors  
•  T ociliz u ma b  per i n vesti gat or’s discreti o n w he n 
cli nicall y i n dicate d, please see A C T E M R A 
prescri bi n g i nf or mati o n  ( 4 m g/ k g o ver 1 h o ur) +/- 
c ortic oster oi ds ( h y dr oc ortis o ne  1 0 0 m g I V i nf use d 
o ver 3 0 sec o n ds a d mi nistere d e ver y 2 h o urs u ntil 
s y m pt o ms res ol ve t o < Gra de 1) 
•  P er ma ne ntl y disc o nti n ue  treat me nt 
* T ociliz u ma b  is a h u ma nize d, i m m u n o gl o b uli n G 1 k (I g G 1 k) a nti-h u ma n I L -6 R m A b a p pr o ve d f or treat me nt of a d ult p atie nts wit h m o deratel y t o se verel y a cti ve 
r he u mat oi d art hritis ( R A) w h o h a ve h a d a n i n a d e q u ate res p o nse t o Disease-M o dif yi n g A nti -R h e u matic Dr u gs ( D M A R Ds), f or t he treat me nt of acti ve p ol yartic ular j u ve nile 
i di o pat hic art hritis ( PJI A), a n d acti ve s yste mic j u ve nile i di o p at hic art hritis ( SJI A) i n p atie nts 2 years of a ge a n d ol d er. Tociliz u ma b w or ks b y pre ve nti n g I L -6 bi n di n g t o 
b ot h cell -ass ociate d a n d s ol u ble IL- 6 Rs. Alt h o u g h, it is n ot i n dicate d f or t h e treat me nt of c yt o ki n e release s y m pt o ms e mer gi n g cli nical e x perie nce at se veral i ns tit uti o ns has 
c o ncl u de d t hat t o ciliz u ma b is a n effe cti ve treat me nt f or se vere or life -t hreate ni n g c yt o ki n e releas e s y m pt o ms.[3 2 -3 5 ] 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 4  of 9 4  
 
 
5. 6. 1. 9  
Li st eri o si s a n d Li st eri a I nf e cti o n – I d e ntifi c ati o n a n d 
M a n a g e m e nt  
A pers o n wit h wil d -t y pe (wt )listeri osis us uall y prese nts wit h fe ver a n d m uscle ac h es, 
s o meti mes prece d e d b y diarr hea or ot her gastr oi ntesti nal s y m pt o ms.  Al m ost e ver y o ne 
w h o is dia g n ose d wit h listeri osis has a n "i n v asi ve" i nfecti o n, i n w hic h t he b acteria s prea d 
be y o n d t h e gastr oi ntes ti nal tract.  T he s y m pt o ms v ar y wit h t he i nfecte d pers o n.  Pre g n a nt 
w o me n t y picall y e x perie nce fe v er a n d ot her n o n-s pecific s y m pt o ms, s uc h as fati g u e a n d 
ac hes.  H o we ver, i nfecti o ns d uri n g pre g na n c y ca n lea d t o miscarria ge, still birt h, 
pre mat ure d eli ver y, or lif e -t hreate ni n g i nfecti o n of t he ne w b or n.  I n p e o ple ot her t ha n 
pre g na nt w o me n, s y m pt o ms ca n i ncl u de hea dac h e, stiff nec k, c o nf usi o n, l oss of bala nce, 
a n d c o n v ulsi o ns i n a d diti o n t o fe ver a n d m uscle ac hes.  Listeri osis ca n prese nt i n 
differe nt w a ys.  I n ol der a d ults a n d pe o ple wit h i m m u n oc o m pr o misi n g c o n diti o ns, 
se ptice mia a n d me ni n gitis are t he m ost c o m m o n cli nical prese ntati o ns [3 6 ].  S u bjects 
ma y n ee d i m me diate e v al uati o n wit h a brai n C T sca n or M RI a n d a l u m bar p u nct ure wit h 
t he a nal ysis of s pi nal fl ui d t o r ule o ut me ni n gitis. 
F or s y m pt o matic patie nts, dia g n osis is c o nfir me d o nl y aft er is olati o n of L m  fr o m a 
n or mall y sterile site, s u c h as bl o o d or s pi nal fl ui d (i n t he setti n g of n er v o us s yste m 
i n v ol ve me nt), or a m ni otic fl ui d/ place nta (i n t he s etti n g of pre g n a nc y).  St o ol sa m ples are 
of li mite d use a n d are n ot rec o m me n de d. Listeria m o n oc yt o ge n es ca n b e is olate d rea dil y 
o n r o uti ne me dia, b ut car e m ust be ta ke n t o disti n g uis h t his or ga nis m fr o m ot her Gra m-
p ositi ve r o ds, partic ularl y di p ht her oi ds.  Selecti ve e nric h me nt me dia i m pr o ve rates of 
is olati o n fr o m c o nta mi nate d s peci me ns.  Y o u ca n e x pect t hat t he c ult ures will ta ke 
a p pr o xi matel y 1 - 2 da ys f or gr o wt h.  I m p orta ntl y, a ne gati ve c ult ure d oes n ot r ule o ut 
i nfecti o n i n t he prese n ce of str o n g cli nical s us pici o n. Ser ol o gical tests are u nrelia ble, a n d 
n ot rec o m me n de d at t he prese nt ti me [3 6 ]. 
Listeri osis is treate d wit h a wi de ra n ge of a nti bi otics.  I n precli nical st u dies, wt -L m  a n d 
A D X S 3 1- 1 4 2 ar e s usce pti ble t o t he l o west teste d c o nce ntrati o n of t he f oll o wi n g 
a nti micr o bial a ge nts:
5. 6. 1. 1 0  
M a n a g e m e nt a n d S ur v eill a n c e of Li st eri a d uri n g  St u d y 
P arti ci p ati o n  
A s u bject w h o e x perie nces a fe v er ( C T C A E Gra d e 1 or greater) 2 4 h o urs f oll o wi n g t he 
c o m pleti o n of A D X S 3 1- 1 4 2 i nf usi o n s h o ul d be starte d o n N S AI D S, h y drati o n a n d ot her 
a p pr o priate m eas ur es t o treat t he fe ver.   I n t he e v e nt t hat t he fe ver p ersists or w orse ns 
4 8 h o urs f oll o wi n g t he c o m pleti o n of A D X S 3 1- 1 4 2 i nf usi o n, t he n oral or br oa d s pectr u m 
I V a nti bi otics s h o ul d be c o nsi dere d b ase d o n t he s u bject’s me dical c o n diti o n.  If t he fe v er 
re mai ns u nres p o nsi ve t o oral/I V a nti bi otics 7 2 h o urs f oll o wi n g t he c o m pleti o n of t he 
i nf usi o n, t he n a bl o o d c ult ure s h o ul d be o btai ne d t o e val uate f or listere mia a n d deter mi ne 
t he a p pr o priat e treat me nt c o urse f or t he s u bject.  A n i n fecti o us disease c o ns ult s h o ul d be 
o btai ne d f or f urt her ma n a ge me nt of t hes e s u bjects. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 5  of 9 4  
 
 
All s u bjects will recei ve a 6 - m o nt h c o urse of a n oral a nti bi otic re gi me n as a pr o p h yl actic 
meas ure f oll o wi n g t he c o m pleti o n of t he last d ose of A D X S 3 1- 1 4 2 treat me nt or at t he 
ti me of st u d y disc o nti n uati o n.  T his a d diti o nal safet y meas ure is i nte n de d t o era dicate L m  
fr o m t he b o d y.  It is e x pecte d t hat a s u bject will partici pate i n t he st u d y u ntil t he 
c o m pleti o n of t he f ull 3- year L m  Sur veilla nce M o nit ori n g peri o d.  H o we ver, f oll o wi n g 
t he c o m pleti o n of t he 6-m o nt h oral a nti bi otic treat me nt, a s u bject will be eli gi ble t o 
partici pate i n ot her i n vesti gati o nal cli nical st u dies.  
 
L m  Sur veilla nce M o nit ori n g will als o be i nitiate d f oll o wi n g t he c o m pleti o n of t he last  
d ose of A D X S 3 1- 1 4 2 tr eat me nt or at t he ti me of st u d y disc o nti n uati o n.  T his m o nit ori n g 
will i ncl u de o btai ni n g a bl o o d sa m ple f or C B C, c o m pre he nsi ve meta b olic p a nel ( C M P ), 
i ncl u di n g C-reacti ve pr otei n (C R P ) a n d Er yt hr oc yte Se di me ntati o n Rate ( E S R ), a n d 
bl o o d c ult ures f or t he d etecti o n of listeria.  Testi n g will be perf or me d o n all s u bjects w h o 
ha ve recei ve d at least o n e d ose of A D X S 3 1- 1 4 2 a n d occ urs e v er y 3 m o nt hs ( ± 2 wee ks) 
f or 3 years  be gi n ni n g 3 m o nt hs after t he last d ose of st u d y treat me nt. 
S h o ul d a dia g n osis of listeri osis be ma de at a n y p oi nt after treat me nt wit h A D X S 3 1- 1 4 2 
a n d t he 6- m o nt h c o urse of oral a nti bi otics is c o m plete d, i m me diate a n d i nte nsi ve I V 
a nti bi otic treat me nt ( am picilli n +/ - ge nta m yci n or ot her I V a nti bi otic re gi m e n as 
i n dicate d) is re q uir e d.  A n i nfecti o us disease c o ns ult s h o ul d be o btai ne d. Base d o n eac h 
i n di vi d ual s u bject’s case a n d at t he discreti o n of t he treati n g p h ysicia n, t he re m o val of 
a n y f orei g n me di cal o bject t hat has bee n prese nt si nce treat me nt wit h A D X S 3 1- 1 4 2 was 
i nitiate d ma y be warra nte d.  It is e xtre mel y i m p orta nt t hat t he In vesti gat or, his/ her 
researc h staff, ot her h ealt hcare pr o vi ders i n v ol ve d i n t he care of t he s u bject as well as 
eac h s u bject partici pati n g i n t his st u d y are e d u cate d a n d ma de a ware of t he si g ns a n d 
s y m pt o ms of listeri osis a n d t he p ote ntial f or dela ye d listere mia/listeri osis.  E d ucati o nal 
materials f or t he In vesti gat or, researc h staff, h ealt h care pr o vi ders a n d s u bjects  will be 
pre par e d , a n d e d ucati o nal trai ni n g perf or me d. 
5. 6. 1. 1 1  
N a u s e a/ v o miti n g  
Na usea a n d  v o miti n g s h o ul d be treate d a g gressi vel y. I n a d diti o n t o t he pr o p h ylactic 
a ntie metic t hera p y s u bjects recei ve pri or t o eac h i nf usi o n, c o nsi derati o n s h o ul d be gi ve n 
t o s u bse q ue nt a d mi nistrati o n of a ntie metic t hera p y e ver y 8 h o urs, as nee d e d acc or di n g t o 
stan dar d i nstit uti o nal practice.  S u bjects s h o ul d als o be str o n gl y e nc o ura ge d t o mai ntai n 
li beral oral fl ui d i nta ke. 
5. 6. 1. 1 2  
M a n a g e m e nt of I nf u si o n R e a cti o n s  
 
W hile t here is s o me o verla p bet wee n i nf usi o n reacti o n s y m pt o ms a n d c yt o ki ne releas e 
s y m pt o ms, i nf usi o n reacti o n s y m pt o ms t y picall y o cc ur d uri n g t he i nf usi o n, w hile 
c yt o ki ne release s y m pt o ms t y picall y occ ur aft er t he i nf usi o n a n d are me di ate d b y a 
differe nt mec ha nis m of acti o n.  Si g ns/s y m pt o ms of i nf usi o n reacti o ns ma y i ncl u de: 
aller gic r eacti o n/ h y pers e nsiti vit y (i ncl u di n g dr u g fe ver); art hral gi a (j oi nt pai n); 
br o nc h os pas m; c o u g h; dizzi ness; d ys p nea (s h ort ness of breat h); fati g u e (ast he nia, 
let har g y, malaise); h ea dac he; h y perte nsi o n; h y p ot e nsi o n; m yal gia ( m uscl e pai n); na usea; 
pr uritic/itc hi n g; ras h/ des q ua mati o n;  ri g ors/c hills; s weati n g ( dia p h oresis); tac h ycar dia; 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 6  of 9 4  
 
 
t u m or pai n ( o nset or e x acer bati o n of t u m or pai n d u e t o treat me nt); urticaria ( hi ves, welts, 
w heals); a n d v o miti n g . 
Ta ble 1 1  pr o vi des tr eat m e nt g ui deli nes f or s u bjects w h o e x perie nce a n i nf usi o n reacti o n 
ass ociate d wit h a d mi nistr ati o n of A D X S 3 1- 1 4 2 or pe m br oliz u ma b ( M K- 3 4 7 5). 
T a bl e 1 1   A D X S 3 1 -1 4 2 or P e m br oli z u m a b ( M K -3 4 7 5) I nf u si o n R e a cti o n 
Tr e at m e nt G ui d eli n e s  
N CI C T C A E Gr a de  
M a n a ge me nt  
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 bj ect is dee me d me dicall y st a ble i n t he o pi ni o n of t he I n vesti gat or.  
Gr a de 2  
Re q uires 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 D S, narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns i n di cate d 
f or ≤2 4 hrs.  
St o p I nf usi o n a n d m o nit or s y m pt o ms.  
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 D S   
  
Aceta mi n o p he n  
Narc o tics 
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 bj ect is dee me d me dicall y st a 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 o ne 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 rat e.  
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 bj ect 
s h o ul d be pre me dicate d f or t he ne xt sc hed ule d d ose.  
 
Pe m br oliz u m a b ( M K -3 4 7 5) Rel ate d:  
S u bj ects 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 trial treat me nt 
a d mi nistrati o n.  
Gr a de 3 : 
Pr ol o n ge d (e. g., n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or ot her 
cli nical se q uelae (e. g., re nal 
i m pair me nt, p ul m o nar y i nfiltr ates) 
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  
 
N S AI D S  
A nti hista mi nes    
Aceta mi n o p he n  
Narc otics   
 
O x y ge n  
Press ors    
 
C ortic oster oi ds  
E pi ne p hri ne  
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 bj ect is dee me d me dicall y st a ble i n t he o pi ni o n of t he I n vesti gat or.  
H os pitalizati o n ma y be i n dicat e d.  
Gr a de 4 : 
Life -t hreate ni n g; press or or 
ve ntilat or y s u p p ort i n dicate d  
S u bj ects w h o e x perie nce a Gr a de 4 reacti o n s h o ul d be per ma ne ntl y  
disc o nti n ue d fr o m treat me nt. S u bj ects w h o e x perie nce a gra de 3 
reacti o n ma y be disc o nti n ue d. Disc ussi o n wit h t he S p o ns or is 
rec o m me n de d. 
 
Pe m br oliz u m a b ( M K -3 4 7 5) Rel ate d:  
If Gra de 3 or Gra de 4 i nf usi o n reacti o n t o pe m br oliz u ma b ( M K-3 4 7 5), 
s u bj ect is per ma ne ntl y disc o nti n ue d fr o m f urt her pe m br oliz u ma b 
( M K-3 4 7 5) trial treat me nt a d mi nistrati o n  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 7  of 9 4  
 
 
5. 6. 2  
Di et  
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. 
5. 6. 3  
U s e i n Pr e g n a n c y  
If a male s u bject i m pre g n ates his fe male p art ner, t he st u d y p ers o n nel at t he site m ust be 
i nf or me d i m me diatel y a n d t he pre g na n c y re p orte d t o t he S p o ns or, a n d f oll o we d as 
descri be d i n Secti o n 7. 2. 2 . 
5. 7  
S u bj e ct St u d y P arti ci p ati o n  
Eac h s u bject ma y p artici pate i n t he st u d y f or u p t o 5 years fr o m t he ti me i nf or me d 
c o nse nt is si g ne d t hr o u g h t he fi nal st u d y c o ntact.  T his i ncl u des a st u d y treat me nt p hase 
(a p pr o xi matel y 2 4 m o n t hs), a n d a 3- year p ost-A D X S 3 1 - 1 4 2 treat me nt L m  Sur veilla nce  
M o nit ori n g peri o d.  It is e x pecte d t hat a s u bject will partici pate i n t he st u d y u ntil t he 
c o m pleti o n of t he f ull 3- year L m  Sur veilla nce M o nit ori n g peri o d.  H o we ver, f oll o wi n g 
t he c o m pleti o n of t he 6-m o nt h oral a nti bi otic treat me nt, s u bject s will be eli gi ble t o 
partici pate i n ot her i n vesti gati o nal cli nical st u dies.  
5. 8  
M aj or a n d Mi n or S ur g eri e s a n d A D X S 3 1 -1 4 2 Tr e at m e nt  
N o f or mal st u dies of t he effect of A D X S 3 1- 1 4 2 o n w o u n d heali n g ha ve b ee n c o n d ucte d.  
H o we ver, base d o n its m ec ha nis m of acti o n it is n ot e x pecte d t hat a d mi nistrati o n of 
A D X S 3 1 - 1 4 2 w o ul d c o m plicate w o u n d heali n g.  T heref ore, a s u bject ma y i nitiate or 
res u me st u d y treat me nt 2 wee ks after mi n or s ur ger y (i.e., s ur ger y i n v ol vi n g little ris k t o 
t he life of t he s u bject; s p ecificall y, a n o p erati o n o n t he s u perficial str u ct ures of t he b o d y 
or a ma ni p ulati ve pr o ce d ure t hat d oes n ot i n v ol ve a seri o us ris k) if t he w o u n d has 
c o m pletel y h eale d a n d t here are n o w o u n d h eali n g c o m plicati o ns.  A s u bject w h o has 
w o u n d heali n g c o m plicati o ns f oll o wi n g mi n or s ur ger y, recei ve d m aj or s ur ger y or 
re q uires ne w i m pla nts a n d/ or de vices ( p er mitte d b y t he pr ot o c ol) d uri n g t he c o urse of t he 
st u d y, m ust wait a mi ni m u m of 6 wee ks a n d m ust ha ve rec o vere d fr o m a n y t o xicit y 
(e. g., ret ur n t o b aseli ne or Gra d e 1) a n d/ or c o m plicati o n bef ore t he ne xt i nf usi o n of st u d y 
treat me nt. S p o ns or c o ns ultati o n is re q uire d pri or t o res u mi n g st u d y treat me nt f or t hese 
s u bjects.  If t he treat me nt is dela ye d d ue t o c o n c o mita nt s ur ger y b e y o n d 1 2 wee ks,  t he 
s u bject ma y b e disc o nti n ue d fr o m t he st u d y. 
5. 9  
S u bj e ct Wit h dr a w al/ Di s c o nti n u ati o n Crit eri a  
S u bjects ma y wit h dr a w c o nse nt at a n y ti me f or a n y reas o n or b e disc o nti n ue 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 o cc ur.  I n a d diti o n, a 
s u bject ma y b e wit h dra w n b y t he 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 tri al pla n is vi olate d, or f or a d mi nistrati ve a n d/ or ot her safet y reas o ns.  
S pecifi c details re gar di n g disc o nti n uati o n or wit h dra wal are pr o vi d e d i n Secti o n  7. 1. 4  . 
S u bjects ma y be dis c o nti n ue d fr o m t he trial f or a n y of t he f oll o wi n g reas o ns: 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 8  of 9 4  
 
 
•  T he  s u bject wit h dra ws c o nse nt 
•  D oc u me nte d d iseas e pr o gressi o n (ra di o gra p hic a n d/ or cli nical) 
•  U nacce pta ble a d vers e e x perie nces as des cri be d i n Secti o n 5. 2. 1. 2  
•  Deat h  
•  I n v esti gat or’s decisi o n t o wit h dra w t he s u bject  
•  N o nc o m plia nce wit h trial treat me nt or pr o ce d ure re q uire me nts  
•  T he s u bject is l ost t o f oll o w - u p 
•  C o m plete d 2 4 m o nt hs of st u d y treat me nt wit h A D X S 3 1- 1 4 2/ pe m br oliz u ma b 
( M K-3 4 7 5).  N ote:  2 4 mo nt hs of st u d y me dicat i o n is calc ulate d fr o m t he d ate of 
first d ose. 
•  Ac hie ve d ir C R (c o m plet e res p o nse)  
•  Ra n d o mize d/ Re gistere d b ut ne ver recei v e d st u d y dr u g 
•  St u d y t er mi nate d b y S p o ns or 
•  Ot her (s pecif y)  
T he E n d of Tr eat 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  a n d 
Secti o n  7. 1. 5 .  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 E/ S A E  
m o nit ori n g as descri be d i n  Secti o n  7. 2. 3. 1 .  I n a d diti o n t o t he L m  S ur veilla nce 
M o nit ori n g, s u bjects  w h o disc o nti n ue f or reas o ns ot her t ha n pr o gressi ve disease will ha ve 
p ost- treat me nt f oll o w-u p (
 e ver y 4 w ee ks a n d i ma gi n g e v er y 1 2 wee ks) 
u ntil disease pr o gressi o n, i nitiati n g a n a nti-ca ncer t hera p y,  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 t he S p o ns or e n ds t he st u d y. 
5. 1 0  S u bj e ct R e pl a c e m e nt Str at e g y  
S u bjects will n ot be re place d. 
5. 1 1  Cli ni c al Crit eri a f or E arl y Tri al T er mi n ati o n  
Earl y trial ter mi nati o n will be t he res ult of t he criteria s pecifie d bel o w: 
1.  Q ualit y or q u a ntit y of d at a rec or di n g is i nacc urate or i nc o m plete  
2.  P o or a d here n ce t o pr ot oc ol a n d re g ulat or y re q uire me nts 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 9  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 4 9  of 9 4  
 
 
3.  I n ci de nce or se v erit y of a d verse dr u g reacti o n i n t his or ot her st u dies i n dicates a 
p ote ntial healt h hazar d t o s u bjects 
4.  Pla ns t o  m o dif y or disc o nti n ue t he de vel o p me nt of t he st u d y treat me nt 
I n t he e ve nt of t h e S p o ns or’s decisi o n t o n o l o n ger s u p pl y st u d y treat me nt, a m ple 
n otificati o n will be pr o vi de d s o t hat a p pr o priat e a dj ust me nts t o s u bject treat me nt ca n be 
ma de.  










 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 4  of 9 4  
 
 
 
 
 
 
 
 
7 
T RI A L P R O C E D U R E S  
7. 1  
Tri al Pr o c e d ur e s  
T he  Trial Fl o w C h art  - S ecti o n 6  s u m marizes t he trial pr oce d ures t o be p erf or me d at eac h 
visit.  I n di vi d ual trial pr o ce d ures are d escri b e d i n detail bel o w.  It ma y be n ecessar y t o 
perf or m t hes e pr oce d ures at u nsc he d ule d ti me p oi nts if dee me d cli nicall y n ecessar y b y 
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 S p o ns or f or 
reas o ns r elate 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 m a y b e 
p ote ntiall y se nsiti ve i n nat ure ( e. g., HI V, h e patitis C, etc.), a n d t h us l ocal re g ul ati 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 bt ai ne d fr o m t he s u bject.  I n t hese cases, 
s uc h e val uati o ns/testi n g will be perf or me d i n acc or da nce wit h t h ose re g ul ati o ns. 
7. 1. 1  
A d mi ni str ati v e Pr o c e d ur e s  
7. 1. 1. 1  
I nf or m e d C o n s e nt 
T he I n vesti gat or m ust o btai n d oc u me nte d i nf or me d c o nse nt fr o m eac h p ote ntial s u bject 
pri or t o part ici pati n g i n a cli nical trial. 
7. 1. 1. 1. 1  
G e n er al I nf or m e d C o n s e nt  
C o nse nt m ust be d oc u me nte d b y t he s u bject’s date d si g nat ure o n a c o ns e nt f or m al o n g 
wit h t he date d si g n at 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 bje ct bef ore 
partici pati o n i n t he trial.  
T he i nitial i nf or me d c o ns e nt f or m, a n y s u bse q u e nt re vise d writte n i nf or m e d c o nse nt f or m 
a n d a n y writte n i nf or m ati o n pr o vi de d t o t he s u bject m ust recei ve t he I R B/ 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.  T h e s u bject s h o ul d be i nf or me d i n a 
ti mel y ma n ner if ne w i nf or mati o n bec o mes a v aila ble t hat ma y b e rel e va nt t o t he s u bject’s 
willi n g ness t o c o nti n ue p artici pati o n i n t he trial.  T he c o m m u nicati o n of t his i nf or mati o n 
will be pr o vi de d a n d d oc u me nte d via a re vise d c o nse nt f or m or a d d e 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 n at ure. 
S pecifics a b o ut a trial a n d t he trial p o p ulati o n will be a d de d t o t he c o nse nt f or m te m plate 
at t he pr ot oc ol le vel. 
T he i nf or me d c o ns e nt will a d here t o I R B 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 m e nts. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 5  of 9 4  
 
 
 
 
 
 
 
 
7. 1. 1. 2  
I n cl u si o n/ E x cl u si o n Crit eri a 
All i ncl usi o n a n d e x cl usi o n criteria will be re vie w e d b y t h e I n vesti gat or or q ualifie d 
desi g nee t o e ns ur e t hat t he s u bject q ualifies f or t he trial.  
7. 1. 1. 3  
S u bj e ct  I d e ntifi c ati o n C ar d 
All s u bjects will be gi ve n a S u bject I de ntificati o n Car d i de ntif yi n g t he m as partici pa nts i n 
a researc h trial.  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 b e utilize d i n t he e ve nt of a n e mer ge n c y.  T he I n v esti gat or or 
q ualifie d desi g nee will pr o vi de t he s u bject wit h a S u bject I d e ntificati o n Car d after t h e 
s u bject pr o vi des writte n i nf or me d c o ns e nt. 
7. 1. 1. 4  
M e di c al  Hi st or y  
A me dical hist or y will be o btai ne d b y t h e I n vesti gat or or q ualifie d d esi g n ee.  Me dical 
hist or y w ill i ncl u de all acti ve c o n diti o ns, a n d a n y c o n diti o n dia g n ose d wit hi n t he pri or 
1 0 years t hat are c o nsi d er e d t o be cli nicall y si g nifi ca nt b y t he I n vesti gat or.  Details 
re gar di n g t he disease f or w hic h t he s u bject has e nr olle d i n t his st u d y will be rec or d e d 
se parat el y a n d n ot liste d as me dical hist or y. 
7. 1. 1. 5  
S ur gi c al Hi st or y  
A s ur gi cal hist or y will be o btai ne d b y t h e i n vesti gat or or q ualifie d d esi g n ee.  S ur gical 
hist or y will i ncl u de all cli nicall y rele va nt s ur geries i ncl u di n g, b ut n ot li mite d t o artificial 
( pr ost hetic) j oi nts, i m pla nts a n d/ or de vices, s uc h as p orts or ste nts.  S ur gi cal pr oce d ures 
t hat occ ur after st u d y e nr oll me nt will be d oc u me nte d se paratel y. 
7. 1. 1. 6  
Pri or a n d C o n c o mit a nt M e di c ati o n s R e vi e w  
7. 1. 1. 6. 1  
Pri or M e di c ati o n s  
T he i n vesti gat or or q ualifie d desi g n ee will re vi e w a n d rec or d pri or me di cati o n use, 
i ncl u di n g a n y pr ot o c ol-s pecifie d w as h o ut re q uire me nt, a n d rec or d pri or m e dicati o n ta ke n 
b y t he s u bject wit hi n 2 8 da ys b ef ore i nf or me d c o nse nt is si g ne d.  Treat me nt f or t he 
disease f or w hic h t he s u bject has e nr olle d i n t h is st u d y will be rec or d e d se p aratel y a n d 
n ot liste d as a pri or me di cati o n.  I n a d diti o n, all prescri pti o n a n d n o n pres cri pti o n 
me dicati o n (e x cl u di n g vita mi ns a n d n utriti o nal s u p ple me nts) ta ke n b y t he s u bject fr o m 
2 8 da ys pri or t o si g ni n g i nf or me d c o ns e nt a nd u p t o a n d i ncl u di n g 3 0 d a ys after t he l ast 
a d mi nistrati o n of A D X S 3 1- 1 4 2, if a n y, s h o ul d be rec or d e d i n t he e C R F.  All me dicati o ns 
relate d t o r e p orta ble S A Es will be rec or d e d i n t he me dical rec or d a n d o n t h e C R F.  A n y 
a d diti o n, deleti o n, or c ha n ge i n t he d os e of t hese me dicati o ns will als o be rec or d e d.  
Ge neric n a mes s h o ul d be use d t o eli mi nate c o nf usi o n t hat ma y res ult fr o m tra de na m es.  
Pr ot oc ol- ma n date d pr o p h yl actic me dicati o ns a n d a nti bi otics s h o ul d als o be ca pt ure d i n 
t he C R F al o n g wit h a n y a d diti o n. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 6  of 9 4  
 
 
 
 
 
 
 
 
7. 1. 1. 6. 2  
C o n c o mit a nt M e di c ati o n s  
T he I n vesti gat or or q u alifie d desi g nee will rec or d me dicati o n, if a n y, ta ke n b y t he s u bject 
d uri n g t he tri al.  All me dicati o ns relate d t o re p orta ble S A Es a n d E CIs s h o ul d be rec or de d 
as defi ne d i n Secti o n 7. 2 . 
7. 1. 1. 6. 3  
N o n -Dr u g Tr e at m e nt/ Pr o c e d ur e s  
T he I n vesti gat or or q u alifie d desi g nee will d oc u me nt a n y n o n-dr u g treat me nt or s ur gi cal 
pr oce d ur es.  All treat me nts/ pr oce d ures relate d t o re p orta ble A E/ S A Es  a n d E CIs s h o ul d be 
rec or d e d as defi ne d i n Secti o n 7. 2  
7. 1. 1. 7  
Di s e a s e D et ail s a n d Tr e at m e nt s  
7. 1. 1. 7. 1  
Pri or C a n c er Hi st or y  
T he I n vesti gat or or q u alifie d desi g nee will o btai n pri or a n d c urre nt det ails re gar di n g 
disease stat us.  
7. 1. 1. 7. 2  
Pri or C a n c er Tr e at m e nt  
T he In vesti gat or or q u alifie d desi g nee will re vie w all pri or ca n cer treat me nts i ncl u di n g 
s yste mic treat me nts, ra di ati o n a n d s ur geries. 
7. 1. 1. 7. 3  
S u b s e q u e nt A nti -C a n c er T h er a p y St at u s  
T he In vesti gat or or q u alifie d desi g nee will re vie w all ne w a nti -ne o plastic t hera p y 
i nitiate d after t he last d os e of trial treat me nt.  If a s u bject i nitiates a ne w a nti-ca ncer 
t hera p y wit hi n 3 0 da ys after t he last d ose of trial treat me nt, t he 3 0- da y Safet y F oll o w - u p 
visit m ust occ ur bef ore t h e first d ose of t he n e w t h era p y.  O n ce ne w a nti -ca ncer t hera p y 
has bee n i nitiate d t he s u bject will m o ve i nt o f oll o w - u p. 
7. 1. 1. 8  
A s si g n m e nt of S u bj e ct I d e ntifi c ati o n N u m b er  
After gi vi n g si g n e d i nf or me d c o nse nt, s u bjects will be assi g ne d a u ni q ue n u m ber t o be 
use d as i de ntificati o n t hr o u g h o ut t he trial. 
7. 1. 2  
Cli ni c al Pr o c e d ur e s/ A s s e s s m e nt s  
7. 1. 2. 1  
A d v er s e E v e nt ( A E) M o nit ori n g  
T he I n vesti gat or or q u alifie d desi g nee will assess eac h s u bject t o e val uate f or p ote ntial 
ne w or w ors e ni n g A Es / SA E s fr o m t he ti me writte n i nf or me d c o nse nt is o bt ai ne d t hr o u g h 
t he c o m pleti o n of t he 3 0- Da y f oll o w- u p.  A d v erse e ve nts a n d S A Es  e x perie nce d d uri n g 
t his peri o d will be re p ort e d a n d rec or d e d i n t he e C R F.  A d verse e x perie nces will be  
gr a de d a n d rec or de d t hr o u g h o ut t he st u d y a n d d uri n g t he f oll o w- u p peri o d acc or di n g t o 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 7  of 9 4  
 
 
 
 
 
 
 
 
C T C A E v 4. 0 3 ( Refer t o Secti o n  1 2. 2 ).  T o xicities will be c haracterize d i n ter ms of 
seri o us ness, ca us alit 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 st u d y treat me nt. 
Please ref er t o Secti o n 7. 2  f or detaile d i nf or mati o n re gar di n g t he assess me nt a n d 
rec or di n g of A Es. 
7. 1. 2. 2  
P h y si c al E x a mi n ati o n  
T he I n vesti gat or or q u alifie d desi g nee will perf or m a c o m plete p h ysical e x a mi nati o n 
d uri n g t he s cree ni n g p eri o d.  Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d 
as me dical hist or y.  Cli nicall y si g nifica nt a b n or mal fi n di n gs n ote d d uri n g t h e treat me nt 
peri o d s h o ul d be rec or de d as a n A E.  A p h ysical e x a mi nati o n s h o ul d als o be perf or me d 
be f ore eac h treat me nt a d mi nistrati o n a n d at t he e n d of t hera p y as s pecifie d i n t he Trial 
Fl o w C hart ( Secti o n 6 ). 
7. 1. 2. 3  
Vit al Si g n s  
T he I n vesti gat or or q u alifie d desi g nee will ta ke vital si g ns at scree ni n g, pri or t o t he 
a d mi nistrati o n of eac h d ose of trial treat me nt, e ver y 
 f or 
f oll o wi n g eac h A D X S 3 1 - 1 4 2 d ose, a n d at treat me nt disc o nti n uati o n as s pecifie d i n t he 
Trial Fl o w C hart ( Secti o n 6 ).  Vital si g ns s h o ul d i ncl u de te m perat ure, p uls e, res pirat or y 
rate, wei g ht a n d bl o o d pr ess ure.  H ei g ht will be m eas ure d at scree ni n g o nl y.  D uri n g Part 
B, wei g ht will be c ollecte d o nce at e ver y visit.  
7. 1. 2. 4  
E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) P erf or m a n c e 
S c al e  
T he In vesti gat or or q u alifie d desi g nee will assess E C O G stat us (see Secti o n 1 2. 1 ) 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 dis c o nti n uati o n 
of trial treat me nt as s p ecifie d i n t he Trial Fl o w C h art ( Secti o n 6 ). 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 8  of 9 4  
 
 
 
 
 
 
 
7. 1. 2. 6  
T u m or  I m a gi n g a n d A s s e s s m e nt of Di s e a s e 
C o m p ute d t o m o gra p h y ( C T), ma g n etic res o n a nce i ma gi n g ( M RI) or b o ne sca n will be 
c o nsi dere d t he b est  c urr e ntl y a vaila ble a n d re pr o d uci ble met h o ds t o meas ure tar get 
lesi o ns (as defi ne d i n Secti o n 7. 1. 2. 5. 2 ) selecte d f or res p o nse assess me nt.  C o n ve nti o nal 
C T a n d M RI of t h e a b d o me n/ pel vis s h o ul d be perf or me d wit h c o nti g u o us c uts of 1 0 m m 
or less.  S piral C T sca n s h o ul d be perf or me d usi n g a 5 m m c o nti g u o us rec o nstr ucti o n 
al g orit h m ( as a ge n eral r ule, lesi o n dia meter s h o ul d be n o less t ha n d o u ble t he slice 
t hic k ness).  Lesi o ns o n c hest x-ra ys will be acce pta ble as meas ura ble lesi o ns w he n t he y 
are cl earl y d efi ne d a n d s urr o u n de d b y aerat e d l u n g; h o we v er, C T is prefera ble.  
Ultras o u n d will n ot be a n acce pta ble met h o d t o meas ure diseas e. B o ne sca n res p o nse 
assess me nt will be  pri maril y bas e d o n t he P C W G 2 criteria. [3 8 ] 
7. 1. 2. 6. 1  
M e a s ur a bl e a n d N o n -m e a s ur a bl e L e si o n s a n d Di s e a s e  
Meas ura ble l esi o ns will be t h ose t hat ca n b e acc uratel y meas ure d i n at least o ne 
di me nsi o n wit h t he l o n gest dia meter ≥1 0 m m (f or s piral C T sca n or M RI sca n, ≥5 m m).  
Meas ura ble dis ease will be prese nt if t he s u bj ect has 1 or m ore meas ura bl e lesi o ns.  
N o n -meas ur a ble lesi o ns/ disease will be all ot her l esi o ns ( or sites of diseas e), i ncl u di n g 
s mall lesi o ns (t h ose wit h all meas ure me nts < 1 0 m m wit h s piral C T or < 5 m m wit h M RI), 
or a n y of t he f oll o wi n g:  b o ne lesi o ns, le pt o me ni n geal disease, ascites, ple ural or 
pericar dial eff usi o n, l y m p ha n gitis, c utis/ p ul m o nis, a b d o mi nal masses t hat are n ot 
c o nfir me d a n d f oll o we d b y i ma gi n g tec h ni q u es, c ystic lesi o ns, a n d lesi o ns occ ur ri n g 
wit hi n a pre vi o usl y irra di ate d area u nless t he y are d oc u me nte d as ne w lesi o ns si nce t he 
c o m pleti o n of ra diati o n t hera p y. 
7. 1. 2. 6. 2  
T ar g et/ N o n -T ar g et L e si o n s  
All meas ura ble lesi o ns, u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, 
s h o ul d be i de ntifie d as tar get lesi o ns t o be meas ure d a n d rec or d e d at baseli ne.  T he tar get 
lesi o ns s h o ul d be re pres e ntati ve of all i n v ol ve d or ga ns.  T ar get lesi o ns will be selecte d 
base d o n t heir size (t he lesi o n wit h t he l o n gest dia meter) a n d s uita bilit y f or acc urate 
re peat e d meas ur e me nts.  At baseli ne, a s u m of t he l o n gest dia meters f or all tar get lesi o ns 
will be calc ulate d a n d rec or de d as t he b aseli ne t u m or b ur de n.  T h e baseli ne s u m will be 
use d as t he refer e nce p oi nt t o deter mi ne t he o bjecti ve t u m or res p o nse of t he tar get 
lesi o ns. 
Meas ura ble l esi o ns ot her t ha n t he tar get lesi o ns a n d all sites of n o n- meas ura ble disease 
will be i de ntifie d as n o n -tar get lesi o ns a n d will be rec or d e d at bas eli ne.  N o n-tar get 
lesi o ns will be e val uate d at t he sa me ti me p oi nts as tar get lesi o ns. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 5 9  of 9 4  
 
 
 
 
 
 
 
 
7. 1. 2. 6. 3  
R e s p o n s e i n M e a s ur a bl e L e si o n s ( R E CI S T 1. 1)  
At baseli ne, t he s u m of t he l o n gest dia meters ( S u m D) of all tar get lesi o ns ( u p t o 2 lesi o ns 
per or ga n, u p t o t otal 5 lesi o ns) is meas ure d.  At eac h s u bse q ue nt t u m or ass ess me nt ( T A), 
t he S u m D of t he tar get lesi ons a n d of ne w, meas ura ble lesi o ns are a d de d t o get h er t o 
pr o vi de t he t otal meas ur a ble t u m or b ur de n ( T M T B):  
T M T B = S u m D tar get lesi o ns + S u m D ne w, meas ura ble lesi o ns 
Perce nta ge c ha n ges i n T M T B per assess me nt ti me p oi nt descri be t he size a n d gr o wt h 
ki netics o f b ot h ol d a n d ne w meas ura ble lesi o ns as t he y a p pear.  At eac h T A, t he 
res p o nse i n tar get a n d ne w meas ura bl e lesi o ns is defi ne d bas e d o n t he c h a n ge i n T M T B 
(after r uli n g o ut ir P D) as f oll o ws: 
•  C o m plete Res p o nse ( C R) :  disa p peara n ce of all tar get lesi o ns.  An y p at h ol o gical 
l y m p h n o des ( w h et her tar get or n o n-tar get) m ust ha ve re d u cti o n i n s h ort a xis t o 
≤1 0 m m. 
•  Partial Res p o nse ( P R) :  At least a 3 0 % decrease i n s u m of dia meter of tar get 
lesi o ns, ta ki n g as r efere n ce t he bas eli ne s u m dia meter. 
•  Sta ble Disease ( S D) :  N eit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or P D, ta ki n g as refere nce t h e s mallest s u m dia meters w hile o n 
st u d y. 
•  Pr o gr essi ve Diseas e ( P D) :  At least a 2 0 % i ncrease i n t he s u m  of dia meters of 
tar get lesi o ns, ta ki n g as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he 
baseli ne  s u m if t hat is t he s mallest o n st u d y). I n a d diti o n t o t he relati ve i ncrease of 
2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m. ( N ote:  
t he a p peara nce of o n e or m ore ne w lesi o ns is als o  c o nsi dere d pr o gressi o n). 
7. 1. 2. 6. 4  
I m m u n e-R el at e d R e s p o n s e i n M e a s ur a bl e L e si o n s 
(ir R E CI S T) 
I n a d diti o n t o e val uati o n usi n g R E CI S T 1. 1 criteri a, a n i m m u ne res p o nse a da ptati o n of 
R E CI S T will be a p plie d t o t his trial.  T he esse ntial differe n ces b et wee n ir R E CI S T a n d 
R E CI S T criteri a ar e as f oll o ws:  
•  Ne w meas urea bl e lesi o ns d o n ot necessaril y  c o nstit ute pr o gressi ve diseas e a n d 
t he y s h o ul d be a d de d i nt o t he t otal t u m or b ur de n. Ne w n o n- meas ura bl e lesi o ns d o 
n ot c o nstit ute disease pr o gressi o n b ut will pre ve nt t he deter mi nati o n of a n ir C R. 
•  S u bjects  wit h a n i nitial fi n di n g of pr o gressi ve disease (ir P D) b ef ore or at t h e 
1 2- wee k i ma gi n g ass ess me nt, b ut wit h o ut ra pi d cli nical deteri orati o n, re q uire 
c o nfir mati o n of ir P D wit h a sec o n d, c o nsec uti ve s ca n o btai ne d ≥4 w ee ks fr o m t he 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 0  of 9 4  
 
 
 
 
 
 
 
 
i nitiati o n d oc u me ntati o n.  S u bjects  will c o nti n ue t o recei v e st u d y treat me nt u ntil 
ir P D is c o nfir me d at t his later ti me p oi nt.   
At baseli ne, t he s u m of t he l o n gest dia meters ( S u m D) of all tar get lesi o ns ( u p t o 2 per 
or ga n a n d 5 i n t otal) is meas ure d.  At eac h s u bse q ue nt t u m or assess me nt, t he S u m D of 
t he tar get lesi o ns a n d of ne w, meas ura ble lesi o ns ( ≥1 0 m m [l y m p h n o des ≥1 5 m m i n 
s h ortest dia meter]; u p t o 2 ne w lesi o ns per or ga n, t otal 5 ne w lesi o ns) are a d de d t o get her 
t o pr o vi de t he t otal meas ura ble t u m or b ur de n ( T M T B): 
T M T B = S u m D tar get lesi o ns + S u m D ne w, meas ura ble lesi o ns 
Perce nta ge c ha n ges i n T M T B per assess me nt ti me p oi nt descri be t he size a n d gr o wt h 
ki netics of b ot h ol d a n d ne w meas ura ble lesi o ns as t he y a p pear.  At eac h t u m or 
assess me nt, t he res p o ns e i n tar get a n d ne w m eas ura ble lesi o ns is defi ne d base d o n t he 
c ha n ge i n T M T B (after r uli n g o ut ir P D) as f oll o ws: 
•  C o m plete Res p o nse (ir C R) :  c o m plete disa p peara nce of all tar get a n d ne w, 
meas ura ble l esi o ns, wit h t he e x ce pti o ns of l y m p h n o des w hic h m ust decrease t o 
< 1 0  m m i n s h ort a xis  
•  Partial Res p o nse (ir P R) :  decrease i n T M T B ≥3 0 % relati ve t o baseli ne (see bel o w) 
•  Sta ble Disease (ir S D) :  n ot meeti n g criteria f or ir C R or ir P R, i n a bse nce of ir P D 
•  Pr o gr essi ve Diseas e (ir P D):   i ncrease i n T M T B ≥2 0 % relati ve t o na dir 
7. 1. 2. 6. 5  
R e s p o n s e i n N o n -m e a s ur a bl e l e si o n s ( R E CI S T 1. 1)  
W hile s o me n o n- tar get lesi o ns ma y act uall y b e meas ura ble, t he y n ee d n ot b e meas ure d 
a n d i nstea d s h o ul d be ass esse d o nl y q u alitati vel y. 
•  C o m plete Res p o nse ( C R):  Disa p peara nce of all n o n -tar get lesi o ns a n d 
n or malizati o n of t u m or mar ker le v el.  All l y m p h n o des m ust be n o n-pat h ol o gical 
i n size ( < 1 0 m m s h ort a xis).  
•  N o n -C R/ N o n -P D :  Persiste nce of o n e or m ore n o n-tar get lesi o n(s) a n d/ or 
mai nte na nce of t u m or mar ker l e vel  a b o v e t he n or mal li mits. 
•  Pr o gr essi ve Diseas e ( P D):   U ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get lesi o ns. 
(N ote: t he a p pear a nce of o ne or m ore n e w lesi o ns is als o c o nsi dere d pr o gressi o n). 
W he n t he s u bject als o has meas ura ble disease, t o ac hie ve ‘ u ne q ui v ocal pr o gressi o n’ o n 
t he basis of n o n-tar get disease, t here m ust be a n o verall le vel of s u bsta ntial w orse ni n g i n 
n o n- tar get diseas e s uc h t hat, e ve n i n pres e nce of S D or P R i n tar get diseas e, t he o verall 
t u m or b ur de n has i ncr eas e d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 1  of 9 4  
 
 
 
 
 
 
 
 
I n t he e ve nt t hat t he s u bj ect has o nl y n o n- meas ura ble disease, t he sa m e ge n eral c o n ce pts 
a p pl y as n ote d a b o ve, h o we ver, i n t his i nsta nce t h ere is n o meas ura ble disease assess me nt 
t o fact or i nt o t he i nter pr etati o n of a n i ncrease i n n o n-meas ura bl e disease b ur de n.  Beca use 
w orse ni n g i n n o n- tar get disease ca n n ot be easil y q ua ntifie d, a usef ul test t hat ca n be 
a p plie d w he n ass essi n g s u bjects f or u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease 
i n o verall disease b ur de n base d o n t he c h a n ge i n n o n -meas ura bl e disease is c o m para ble i n 
ma g nit u de t o t he i ncreas e t hat w o ul d be re q uire d t o declare P D f or meas ura ble disease: 
(i.e., a n i ncr ease i n t u m or b ur de n re prese nti n g a n a d diti o nal 7 3 % i ncrease i n ‘ v ol u me’ 
w hic h is e q ui vale nt t o a 2 0 % i nc rease dia meter i n a meas ura ble lesi o n). 
7. 1. 2. 6. 6  
I m m u n e-R el at e d R e s p o n s e i n N o n -m e a s ur a bl e L e si o n s  
At eac h t u m or ass ess me nt, t he prese nce of a n y n e w, n o n -meas ura ble lesi o ns is assesse d.  
T he prese n ce of s uc h lesi o ns will r ule o ut a n o verall res p o nse of ir C R.  A n i n creas e i n t he 
size or n u m ber of ne w, n o n- meas ura bl e lesi o ns d oes n ot necessaril y i m pl y a n o verall 
res p o nse of ir P D; if t hes e lesi o ns bec o me meas ura ble ( ≥1 0 m m) at a s u bse q ue nt t u m or 
assess me nt, t heir meas ur e me nt will at t hat p oi nt start t o c o ntri b ute t o t h e T M T B.  
I n a d diti o n, t he res p o nse i n n o n-tar get lesi o ns is defi ne d as f oll o ws: 
•  C o m plete Res p o nse (ir C R):  c o m plete disa p peara nce of all n o n- t ar get lesi o ns 
•  Sta ble Disease (ir S D) :  n o n-tar get lesi o ns are sta ble 
•  Pr o gr essi ve Diseas e (ir P D) :  u ne q ui v ocal i ncreas es i n n u m ber or size of n o n-tar get 
lesi o ns.  T o ac hie ve u n e q ui v ocal pr o gressi o n of n o n-tar get lesi o ns, t here m ust be 
a n o verall le v el of s u bsta ntial w orse ni n g of n o n- tar get disease t hat is of a 
ma g nit u de t hat t he tr eati n g p h ysicia n w o ul d feel it is i m p ort a nt t o c ha n ge t hera p y 
N O T E:   E q ui v ocal fi n di n gs of pr o gressi o n of n o n-tar get lesi o ns (e. g., s m all a n d 
u ncertai n ne w lesi o ns; c ystic c ha n ges or n ecr osis i n e xisti n g lesi o ns) s h o ul d be 
c o nsi dere d ir S D, a n d treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d asse ss me nt. 
7. 1. 2. 6. 7  
O v er all R e s p o n s e  
O verall r es p o nse will be deter mi ne d bas e d o n R E CI S T 1. 1 criteria a n d b y ir R E CI S T 
criteria.  T h e differe nces are n ote d b el o w i n  Ta ble 1 2 .  O verall res p o nse acc or di n g t o 
ir R E CI S T is deri ve d fr o m t he res p o nses i n meas ura ble lesi o ns ( bas e d o n T M T B) a n d t h e 
prese nce of a n y n o n -meas ura ble lesi o ns.  
T a bl e 1 2  T u m or R e s p o n s e E v al u ati o n: C o m p ari s o n of R E CI S T 1. 1 a n d 
ir R E CI S T 
Criteri a  
R E CI S T 1. 1  
ir R E CI S T 
Ne w meas ura ble 
lesi o ns ( ≥ 1 0 m m) 
Al wa ys re prese nts P D  
I nc or p orate d i nt o t u m or b ur de n 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 2  of 9 4  
 
 
 
 
 
 
 
 
Ne w n o n -
meas ura ble lesi o ns 
( < 1 0 m m) 
Al wa ys re prese nts P D  
D oes n ot defi ne pr o gressi o n b ut 
precl u des ir C R  
N o n -T ar get lesi o ns  
C ha n ges c o ntri b ute t o defi ni n g B O R of C R, 
P R, S D, a n d P D  
C o ntri b ute t o defi ni n g ir C R 
(c o m plete disa p peara nce 
re q uire d) 
C R  
Disa p peara nce of all lesi o ns  
Disa p peara nce of all lesi o ns  
P R  
≥ 3 0 % decrease i n t h e s u m of t he l o n gest 
dia meter of all tar get lesi o ns c o m pare d wit h 
baseli ne, i n a bse nce of ne w lesi o ns or 
u ne q ui v ocal pr o gressi o n of n o n -tar get 
lesi o ns 
≥ 3 0 % decrease i n t u m or b ur de n 
c o m pare d wit h baseli ne  
S D  
Neit her s ufficie nt s hri n ka ge t o q ualif y f or 
P R n or s ufficie nt i ncrease t o q ualif y f or P D, 
ta ki n g as refere nce t he s mallest s u m 
dia meters w hile o n st u d y  
Neit her a 3 0 % decrease i n t u m or 
b ur de n c o m pare d wit h baseli ne 
n or a 2 0 % i ncrease c o m pare d 
wit h na dir ca n be esta blis he d  
P D  
At least 2 0 % i ncrease i n s u m of dia meters 
of tar get lesi o ns, ta ki n g as refere nce t he 
s mallest s u m o n st u d y. I n a d diti o n t o t he 
relati ve i ncrease of 2 0 %, t he s u m m ust als o 
de m o nstrate a n a bs ol ute i ncre ase of at least 
5 m m.  T he a p peara nce of o ne or m ore ne w 
lesi o ns is als o c o nsi dere d pr o gressi o n.  
At least 2 0 % i ncrease i n t u m or 
b ur de n c o m pare d wit h na dir (at 
a n y si n gle ti me p oi nt) a 
ir R E CI S T = i m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors; B O R = best o verall 
res p o nse; C R = c o m plete res p o nse; ir C R = i m m u ne-relate d c o m plete res p o nse; P D = pr o gressi ve 
disease;  P R = partial res p o nse; S D = sta ble disease;  
a S u bj ects  wit h a n i nitial fi n di n g of pr o gressi ve disease (ir P D) bef ore or at t he 1 2 -wee k i ma gi n g 
assess me nt, b ut wit h o ut ra pi d cli nical deteri orati o n, re q uire c o nfir mati o n of ir P D wit h a se c o n d, 
c o nsec uti ve sca n o btai ne d ≥ 4 wee ks fr o m t he i nitiati o n d oc u me ntati o n.   S u bj ects  will c o nti n ue t o 
recei ve st u d y treat me nt u ntil ir P D is c o nfir me d at t his later ti me p oi nt.  B O R will t heref ore i ncl u de 
res p o nses occ urri n g at a n y ti me bef ore disease pr o gressi o n a n d after earl y pr o gressi o n (i.e., wit hi n t he 
first 1 2 wee ks of t he st u d y). 
7. 1. 2. 6. 8  
B e st O v er all R e s p o n s e ( R E CI S T 1. 1)  
T he best o ver all res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y 
treat me nt u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire m e nt f or c o nfir mati o n.  
T he s u bject’s best o verall res p o nse assi g n me nt will de pe n d o n t he fi n di n gs of b o t h tar get 
a n d n o n-tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara n ce of ne w lesi o ns 
Ta ble 1 3 . 
T a bl e 1 3   B e st O v er all R e s p o n s e ( R E CI S T 1. 1)  
T ar get Lesi o ns  
N o n -T ar get Lesi o ns  
O ver all Res p o nse  
B aseli ne (I n de x) a n d  
Ne w M e as ur a ble Lesi o ns  
B aseli ne Lesi o ns  
U ne q ui v oc al Ne w 
Lesi o ns  
C R  
C R  
N o  
C R  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 3  of 9 4  
 
 
 
 
 
 
 
 
T ar get Lesi o ns  
N o n -T ar get Lesi o ns  
O ver all Res p o nse  
B aseli ne (I n de x) a n d  
Ne w M e as ur a ble Lesi o ns  
B aseli ne Lesi o ns  
U ne q ui v oc al Ne w 
Lesi o ns  
C R  
N o n -C R/ N o n -P D  
N o  
P R  
C R  
N E  
N o  
P R  
P R  
N o n -P D or N E  
N o  
P R  
S D  
N o n -P D or N E  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
T he i m m u ne- relat e d best o verall res p o ns e (ir B O R) is t he best irC R  o verall res p o nse o ver 
t he st u d y as a w h ole, r ec or de d bet wee n t he dat e of first d ose u ntil t he last T A pri or t o 
s u bse q ue nt t hera p y (i ncl u di n g t u m or res ecti o n s ur ger y) f or t he i n di vi d ual s u bject i n t he 
st u d y (Ta ble 1 4 ).  As wit h t he pri mar y defi niti o ns of t u m or res p o nse, earl y pr o gressi o n 
(i.e., ir P D occ urri n g pri or t o Wee k 1 2) will n ot precl u de a n ir B O R of ir C R, ir P R or ir S D 
res ulti n g fr o m t he Wee k 1 2 assess me nt.  A n assess me nt of ir P D at or after Wee k 1 2 will 
precl u de a s u bse q ue nt ir B O R of ir C R, ir P R or ir S D.  H o we ver, a n y p ost- pr o gressi o n 
cli nical acti vit y i n s u bjects wit h ir B O R of ir P D ma y b e s u m marize d f or e x pl orat or y 
p ur p oses. 
T a bl e 1 4  I m m u n e-R el at e d B e st O v er all R e s p o n s e (ir B O R)  
T ar get Lesi o ns  
B aseli ne (I n de x) a n d  
Ne w M e as ur a ble Lesi o ns  
N o n -T ar get Lesi o ns a 
ir R C O ver all 
Res p o nse  
T ot al M e as ur a ble T u m or B ur de n 
( T M T B) 
B aseli ne Lesi o ns  
U ne q ui v oc al Ne w 
Lesi o ns  
ir C R 
ir C R 
N o  
ir C R 
ir C R 
ir S D 
N o  
ir P R 
ir P R 
ir C R or ir S D 
N o  
ir P R 
ir S D 
ir C R or ir S D 
N o  
ir S D 
ir P D 
A n y  
Yes or N o  
ir P D 
A n y  
U ne q ui v ocal 
Pr o gressi o n  
Yes or N o  
ir P D 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 4  of 9 4  
 
 
 
 
 
 
 
 
T ar get Lesi o ns  
B aseli ne (I n de x) a n d  
Ne w M e as ur a ble Lesi o ns  
N o n -T ar get Lesi o ns a 
ir R C O ver all 
Res p o nse  
T ot al M e as ur a ble T u m or B ur de n 
( T M T B) 
B aseli ne Lesi o ns  
U ne q ui v oc al Ne w 
Lesi o ns  
A n y  
A n y  
Yes  
ir P D 
ir C R = i m m u ne-relate d c o m plete res p o nse; ir P R = i m m u ne-relate d partial res p o nse; ir S D = i m m u ne-
relate d sta ble disease; ir P D = i m m u ne-relate d pr o gressi ve disease 
a A n y i ncrease i n t he size or n u m ber of n o n -meas ura ble lesi o ns d oes n ot necessaril y i m pl y a n o verall 
res p o nse of ir P D.  If t hese lesi o ns bec o me meas ura ble ( ≥1 0 m m) at a s u bse q ue nt assess me nt, t heir 
meas ure me nt will at t hat p oi nt start t o c o ntri b ute t o t he t otal meas ura ble t u m or b ur de n.  T o ac hie ve 
u ne q ui v ocal pr o gressi o n of n o n -tar get lesi o ns, t here m ust be s u bsta ntial w orse ni n g i n n o n-t ar get disease 
t hat is of a ma g nit u de t hat t he i n vesti gat or feels it is i m p orta nt t o c ha n ge t hera p y.  E q ui v ocal fi n di n gs of 
pr o gressi o n of n o n -tar get lesi o ns (e. g., s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges or necr osis i n 
e xisti n g lesi o ns) s h o ul d be c o nsi dere d ir S D, a n d treat me nt ma y c o nti n ue u nt il t he ne xt assess me nt. 
7. 1. 2. 6. 9  
Tr e at m e nt aft er I niti al E vi d e n c e of R a di ol o gi c Di s e a s e 
Pr o gr e s si o n  
I m m u n ot her a p y ma y pr o d uce a ntit u m or effects b y p ote ntiati n g e n d o ge n o us ca ncer-
s pecific i m m u ne res p o ns e.  T he res p o nse patter ns see n wit h s uc h a n a p pr oac h ma y e xte n d 
be y o n d t h e t y pi cal ti me c o urse of res p o nses see n wit h c yt ot o xic a ge nts a n d ca n ma nifest 
as a cli nical r es p o nse after a n i nitial i ncreas e o n t u m or b ur de n or e ve n t he a p peara n ce of 
ne w lesi o ns.  If r a di ol o gi cal i ma gi n g s h o ws pr o gressi ve disease ( P D), s u bjec ts ma y 
c o nti n ue o n st u d y wit h t h e o pti o n of c o nti n ui n g treat me nt, pr o vi de d t here is: 
•  N o deteri or ati o n i n E C O G perf or ma nce st at us 
•  A bse nce of si g ns a n d s y m pt o ms (i ncl u di n g w orse ni n g of la b orat or y val u es) 
i n dicati n g diseas e pr o gr essi o n 
•  A bse nce of ra pi d pr o gressi o n of disease 
•  A bse nce of pr o gr essi ve t u m or at critical a n at 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 v e nti o n 
T u m or assess me nt s h o ul d be re peate d ≥4 w ee ks l ater t o c o nfir m P D.  If re peat i ma gi n g 
s h o ws a re d u cti o n i n t he t u m or b ur de n de m o nstrati n g C R, partial res p o ns e ( P R) or sta ble 
disease ( S D) c o m par e d t o t he i nitial sca n, treat me nts ma y be c o nti n ue d or res u me d.  If 
re peat i ma gi n g s h o ws c o nti n ue d pr o gressi o n of disease, s u bjects will be disc o nti n ue d 
fr o m st u d y t hera py, u nless t he basis f or t he P D ass ess me nt is e nlar ge d t u m or- drai ni n g 
l y m p h n o des i n t he pr ese nce of a t ar get t u m or re d ucti o n.  I n d eter mi ni n g w het her or n ot 
t u m or b ur de n has i ncr eas e d or decrease d, I n v esti gat ors s h o ul d c o nsi der all tar get lesi o ns 
as well as n o n-tar get lesi o ns.  If t he re p eat i ma gi n g c o nfir ms i nitiall y d oc u me nte d P D b ut 
s h o ws n o e vi de nce of f urt her t u m or pr o gressi o n, s u bjects s h o ul d be disc o nti n ue d fr o m 
t he st u d y treat me nt. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 5  of 9 4  
 
 
 
 
 
 
 
 
7. 1. 2. 7  
C orr el ati v e St u di e s Bl o o d S a m pli n g  
7. 1. 3  
L a b or at or y Pr o c e d ur e s/ A s s e s s m e nt s  
Details re gar di n g s p ecifi c la b orat or y pr oce d ures/assess me nts t o be perf or m e d i n t his trial 
are pr o vi d e d bel o w.  
7. 1. 3. 1  
L a b or at or y S af et y E v al u ati o n s ( H e m at ol o g y a n d C h e mi str y)  
La b orat or y tests f or he m at ol o g y, c h e mistr y, a n d ot hers are s p ecifie d i n  T a ble 1 5 .  T he 
t otal a m o u nt of bl o o d t o be dra w n o v er t he c o urse of t he trial (fr o m pre-tri al t o p ost-trial 
visits), i ncl u di n g a p pr o xi mate bl o o d b y visit a n d b y sa m ple t y pe p er s u bject ca n be f o u n d 
i n t he Pr oce d ures M a n ual. 
T a bl e 1 5  L a b or at or y T e st s  
He m at ol o g y  
C he mistr y  
Ot her  
He mat ocrit  
Al b u mi n  
P T (I N R)  (scree ni n g o nl y) 
He m o gl o bi n  
Al kali ne p h os p hatase  
a P T T  (scree ni n g o nl y) 
Platelet c o u nt  
Ala ni ne a mi n otra nsferase ( A L T)  
T otal trii o d ot h yr o ni ne ( T 3)  
W B C (t otal a n d differe ntial)  As partate a mi n otra nsferase ( A S T)  
Free t h yr o xi ne ( T 4)  
Re d Bl o o d Cell C o u nt  
Lactate de h y dr o ge nase ( L D H) 
T h yr oi d sti m ulati n g h or m o ne ( T S H)  
A bs ol ute Ne utr o p hil C o u nt  
Car b o n Di o xi de ( C O 2 or bicar b o nate)  
 
 
Calci u m  
Ser u m creati ni ne O R creati ni ne 
cleara nce  
 
C hl ori de   
Bl o o d f or c orrelati ve st u dies  
 
Creati ni ne  
 
 
Gl uc ose  
 
 
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 
a b o ve t he u p per li mit of n or mal)  
 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 6 6  of 9 4  
 
 
 
 
 
 
 
 
He m at ol o g y  
C he mistr y  
Ot her  
 
T otal pr otei n  
 
 
Bl o o d Urea Nitr o ge n  
 
 
Er yt hr o c yte Se di me ntati o n Rate * 
 
 
C- Reacti ve Pr otei n * 
 
La b orat or y tests s h o ul d b e perf or me d wit hi n 3 da ys pri or t o d osi n g.  Res ults m ust be 
re vie we d b y t h e I n vesti gat or or q ualifie d d esi g n ee a n d f o u n d t o be acce pt a ble per 
I n cl usi o n Criteria (Ref er t o  Ta ble 3 ) pri or t o eac h d ose of trial treat me nt.  
* L m  S ur veilla nce M o nit ori n g will i ncl u de r o uti ne m o nit ori n g of C B C, C M P (i ncl u di n g 
C R P, E S R) a n d bl o o d c ult ures. F oll o wi n g c o m pleti o n of st u d y treat me nt or at t he ti me of 
st u d y disc o nti n uati o n, if earlier, t esti n g will be perf or me d o n all s u bjects w h o ha ve 
recei v e d at least o ne d ose of A D X S 3 1-1 4 2. It will occ ur  e v er y 3 m o nt hs ( + 2 wee ks) f or 
3 years  be gi n ni n g 3 m o nt hs after t he last d ose of st u d y treat me nt. C R P, E S R, a n d bl o o d 
c ult ures ar e o nl y c ollecte d d uri n g t he L m  S ur veilla nce M o nit ori n g p eri o d, a n d n ot d uri n g 
t he mai n part of t he st u d y. Lactate d e h y dr o ge n ase ( L D H) is o nl y c ollect e d d uri n g t he 
mai n part of t he st u d y, a n d is n ot c ollecte d d uri n g t he L m  S ur veilla nce M o nit ori n g peri o d 
(it is n ot part of t he sta n dar d C M P). 
7. 1. 4  
Ot h er Pr o c e d ur e s  
7. 1. 4. 1  
Wit h dr a w al/ Di s c o nti n u ati o n  
W he n a s u bject disc o nti n ues/ wit h dra ws pri or t o tri al c o m pleti o n, all a p plica ble acti vities 
sc he d ule d f or t h e fi nal tri al visit s h o ul d be perf or me d at t he ti me of disc o nti n uati o n.  A n y 
A Es  w hic h ar e pres e 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 d a nce wit h t he saf et y r e q uire me nts o utli ne d i n  Secti o n 7. 2 .  S u bjects w h o a) attai n a 
C R or b) c o m plete 2 4 m o nt hs of treat me nt ma y dis c o nti n ue treat me nt.  After 
disc o nti n ui n g treat me nt f oll o wi n g assess me nt of C R, t hese s u bjects s h o ul d ret ur n t o t he 
site f or a Saf et y F oll o w- u p Visit ( descri be d i n Secti o n 7. 1. 5. 3 ) a n d t he n pr o cee d t o t he 
F oll o w- U p Peri o d of t h e st u d y ( des cri be d i n Secti o n 7. 1. 5. 3 ). 
7. 1. 5  
Vi s it R e q uir e m e nt s 
Visit re q uire me nts ar e o utli ne d i n Secti o n 6 .  S pecific pr oce d ure-relate d d et ails are 
pr o vi de d a b o ve i n Secti o n 7. 1 . 
7. 1. 5. 1  
S cr e e ni n g P eri o d  
Scree ni n g peri o d  – t his 2 8- da y peri o d will start w he n t he first scree ni n g e v al uati o n is 
perf or me d.  T his d oes n ot i ncl u de si g ni n g of I nf or me d C o nse nt or was h- o ut peri o ds. 
I nf or me d C o nse nt - pri or t o c o n d ucti n g scree ni n g e val uati o ns eac h s u bject m ust si g n a 
c o p y of t he m ost c urr e nt I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee 








 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 0  of 9 4  
 
 
 
 
 
 
 
 
m o nit ore d cl osel y, i n cl u di n g a d diti o nal testi n g a n d bl o o d c ult ure (s), f or p ossi ble 
listeri osis.  T his testi n g ma y b e perf or me d at t he i n vesti gati ve site or at a n ot her 
acce pta ble l ocati o n f oll o wi n g c o ns ultati o n wit h t he S p o ns or.  D uri n g t he L m  S ur v eilla nce 
M o nit ori n g peri o d all r el ate d la bs wit h p ositi ve bl o o d c ult ures f or Listere mia a n d all 
c o nc o mita nt me dicati o ns  use d t o treat t he i nfecti o n will  be ca pt ure d  as A Es.  
E ver y eff ort s h o ul d be m a de t o c ollect i nf or mati o n re gar di n g disease stat us u ntil t he start 
of ne w a nti-ca ncer tr eat me nt, disease pr o gressi o n, or e n d of t he st u d y.  S u bjects w h o 
disc o nti n ue f or reas o ns ot her t ha n pr o gressi ve disease will ha ve p ost- treat me nt f oll o w- u p 
f or disease stat us u ntil disease pr o gressi o n, i nitiati n g an a nti-ca n cer t hera p y, 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.  After d o c u me nte d disease pr o gressi o n, eac h 
s u bject will be f oll o we d b y tele p h o n e f or s afet y.  F or s u bjects w h o disc o nti n ue treat me nt 
f or reas o ns ot her t ha n pr o gr essi o n, 
 testi n g s h o ul d c o nti n ue e ver y 4 wee ks 
a n d i ma gi n g s h o ul d c o nti n ue e ver y 1 2 wee ks ( ± 1 wee k) u ntil disease pr o gressi o n. 
7. 2  
A s s e s si n g a n d R e c or di n g A d v er s e E v e nt s  
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a p atie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har m ace utical pr o d uct a n d w hic h d oes n ot 
necessaril y h a ve t o ha v e a ca usal relati o ns hi p wit h t his treat me nt.  A n A E ca n t heref ore 
be a n y u nfa v ora ble a n d u ni nte n de d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g, f or 
e x a m ple), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he use of a me dici nal pr o d uct 
or pr ot oc ol-s pecifie d pr o ce d ure, w het her or n ot c o nsi dere d rel ate d t o t he m e dici nal 
pr o d uct or pr ot oc ol-s p ecifie d pr oce d ure.  A n y w orse ni n g (i. e., a n y cli nicall y si g nifica nt 
a d verse c ha n ge i n fre q u e nc y a n 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 A d va xis’ or Merc k’s pr o d uct, is als o a n A E. 
C ha n ges res ulti n g fr o m n or mal gr o wt h a n d de v el o p me nt t hat d o n ot var y si g nifica ntl y i n 
fre q ue n c y or se v erit y fr o m e x pecte d le vels are n ot t o be c o nsi dere d A Es.  E x a m ples of 
t his ma y i ncl u de, b ut are n ot li mite d t o, teet hi n g, t y pical cr yi n g i n 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 h ysi ol o gicall y a p pr o priat e ti me.  
A d va xis’ or Merc k’s pr o d uct i ncl u des a n y p har mace utical pr o d uct, bi ol o gi cal pr o d uct, 
de vice, dia g n ostic a ge nt or pr ot oc ol-s pecifie d pr o ce d ure, w het her i n vesti gati o nal 
(i ncl u di n g place bo or acti ve c o m parat or me dicati o n) or mar ket e 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 A d v a xis or Merc k f or h u ma n use. 
A d verse e ve nts ma y occ ur d uri n g t h e c o urs e of t h e use of a n A d va xis or Merc k pr o d u ct 
i n cli nical trials or wit hi n t he 3 0- Da y F oll o w - U p p eri o d, or pres cri be d i n cli nical practice, 
fr o m o ver d ose ( w het h er acci de nt al or i nte nti o nal), fr o m a b use a n d fr o m wit h dra wal. 
A d verse e ve nts ma y als o occ ur i n scree n e d s u bjects d uri n g a n y pre -all ocati o n baseli ne 
peri o d as a r es ult of a pr ot oc ol-s pecifie d i nter ve nti o n, i ncl u di n g 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.  All A Es will be 
rec or d e d fr o m t he ti me t h e c o nse nt f or m is si g ne d t hr o u g h t he c o m pleti o n of t he 3 0-Da y 
F oll o w- U p peri o d of t he st u d y or t he i nitiati o n of a ne w a ntica ncer t hera p y, w hic he ver is 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 1  of 9 4  
 
 
 
 
 
 
 
 
earlier. A d vers e E ve nts a n d S A Es  e x perie nce d d uri n g t his peri o d will be re p orte d a n d 
rec or d e d i n t he e C R F.  T he re p orti n g ti mefra me f or A Es  meeti n g a n y seri o us criteria is 
descri be d i n Secti o n 7. 2. 3. 1 . 
7. 2. 1  
D efi niti o n of a n O v er d o s e f or T hi s Pr ot o c ol a n d R e p orti n g of 
O v er d o s e t o t h e S p o n s or  
F or p ur p os es of t his trial, a n o ver d ose will be def i ne d as a n y d ose e x cee di n g t he 
prescri be d d os e f or A D X S 3 1- 1 4 2 or ≥1 0 0 0 m g of pe m br oliz u ma b ( M K- 3 4 7 5).  N o 
s pecific i nf or m ati o n is a vaila ble o n t he treat me nt of o ver d ose of A D X S 3 1- 1 4 2 or 
pe m br oliz u ma b ( M K- 3 4 7 5).  I n t he e v e nt of o ver d ose, t he s u bject s h o ul d be o bser ve d 
cl osel y f or si g ns of t o xicit y.  A p pr o priate s u p p orti ve treat me nt s h o ul d be pr o vi de d if 
cli nicall y i n dicat e d.  
If a n A E(s) is ass ociat e d wit h (“res ults fr o m”) a n o ver d ose, t he A E(s) is re p orte d as a 
S A E , e ve n if n o ot her s eri o us ness criteria are met.  
If a n o ver d ose is ta ke n wit h o ut a n y ass oci ate d cli nical s y m pt o ms or a b n or mal la b orat or y 
res ults, t he o ver d ose is r e p orte d as a n o n-seri o us E CI, usi n g t he ter mi n ol o g y “acci de ntal 
or i nte nti o nal o ver d ose wit h o ut a d verse effect.” 
All re p orts of o ver d ose wit h a n A E m ust be re p ort e d wit hi n 2 4 h o urs t o i n Ve nti v Healt h 
C li nical P har mac o vi gila n ce ( Att n: i V H S A E Re p orti n g; F A X 8 6 6- 8 8 0- 9 3 4 3 or e mail:  
i 3 dr u gsafet y P V @i n ve nti v healt h.c o m). 
7. 2. 2  
R e p orti n g of Pr e g n a n c y a n d L a ct ati o n t o t h e S p o n s or  
Alt h o u g h pr e g na nc y a n d lactati o n are n ot c o nsi dere d A Es , it is t he res p o nsi bilit y of 
I n v esti gat ors or t heir d esi g nees t o re p ort a n y pre g n a nc y or lactati o n i n a s u bject’s part ner 
(s p o nta ne o usl y re p orte d t o t he m) t hat occ urs d uri n g t he trial or wit hi n 1 2 0 days of 
c o m pleti n g t he trial, or 3 0 da ys f oll o wi n g cessati o n of treat me nt if t he s u bj ect i nitiates 
ne w a ntica n cer t h era p y, w hic he ver is earlier.  All fe male part ners of m ale s u bjects w h o 
bec o me pr e g na nt 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 p re g n a nc y.  
Pre g n a nc y o utc o mes of s p o nta ne o us a b orti o n, misse d a b orti o n, be ni g n h y d ati dif or m 
m ole, bli g hte d o v u m, fet al deat h, i ntra uteri n e deat h, miscarria ge a n d still birt h m ust be 
re p orte d as S A Es  (I m p orta nt Me dical E ve nts).  If t he pre g na n c y c o nti n ues t o ter m, t he 
o utc o me ( healt h of i nf a 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 of a ware n ess t o i n Ve nti v Healt h Cli nical 
P har mac o vi gila nce ( Att n: i H C S A E Re p orti n g; F A X 8 6 6 - 8 8 0- 9 3 4 3 or e m ail:  
i 3 dr u gsafet y P V @i n ve nti v healt h.c o m) 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 2  of 9 4  
 
 
 
 
 
 
 
 
7. 2. 3  
I m m e di at e R e p orti n g of A d v er s e E v e nt s t o t h e S p o n s or 
7. 2. 3. 1  
S eri o u s A d v er s e E v e nt s  
A S A E  is a n y A E occ urri n g at a n y d ose or d uri n g a n y us e of A d v a xis’ or Merc k’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 n ca p acit 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 ne w ca ncer (t h at is n ot a c o n diti o n of t he st u d y); 
•  Is ass ociate d wit h a n o v er d ose; 
•  Is a n i m p orta nt me dical e ve nt  
Refer t o  Ta bl e 1 6  f or a d diti o nal details re gar di n g eac h of t he a b o ve criteria. 
Pr o gr essi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n A E u nless it res ults i n 
h os pitalizati o n or deat h. 
A n y S A E, or f oll o w u p t o a S A E, i ncl u di n g deat h d ue t o a n y ca us e , t hat occ urs t o a n y 
s u bject fr o m t he ti me t he c o nse nt is si g ne d t hr o u g h t he c o m pleti o n of t he 9 0 -Da y F oll o w -
U p peri o d of t h e st u d y, w het her or n ot relate d t o A d va xis’ or Merc k’s pr o d u ct, m ust be 
re p orte d wit hi n 2 4 h o urs of a ware ness t o i n Ve nti v Healt h Cli nical P har mac o vi gila nce 
( Att n: i H C S A E Re p orti n g; F A X 8 6 6- 8 8 0- 9 3 4 3 or e mail: 
i 3 dr u gsafet y P V @i n ve nti v healt h.c o m). 
N o n -seri o us E CIs  will be f or war de d t o i n Ve nti v H ealt h Cli nical a n d will be ha n dle d i n 
t he sa me ma n ner as S A Es.  C o nc o mita nt me dicati o ns a d mi nistere d t o treat S A Es a n d 
E CIs s h o ul d be r ec or de d t hr o u g h t he c o m pleti o n of t he 3 0- Da y F oll o w -U p peri o d. 
A d diti o nall y, a n y S A E, c o nsi dere d b y a n I n vesti gat or w h o is a q ualifie d p h ysicia n, t o be 
relate d t o t he A d v a xis’ or Merc k’s pr o d uct t hat is br o u g ht t o t he atte nti o n of t he 
In v esti gat or at a n y ti me o utsi de of t he ti me per i 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 diatel y t o i n V e nti v Healt h Cli nical P har mac o vi gila nce 
( Att n: i H C S A E Re p orti n g; F A X 8 6 6- 8 8 0- 9 3 4 3 or e mail:  
i 3 dr u gsafet y P V @i n ve nti v healt h.c o m). 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 3  of 9 4  
 
 
 
 
 
 
 
 
S A E re p orts a n d a n y ot h er rel e va nt safet y i nf or m ati o n are t o be f or war de d t o:  i n Ve nti v 
Healt h Cli nical P har mac o vi gila nce ( Att n: i H C S A E Re p orti n g; F A X 8 6 6 - 8 8 0- 9 3 4 3 or 
e mail:  i 3 dr u gsafet y P V @i n ve nti v healt h.c o m). 
A d verse E v e nt re p orts meeti n g t h e re q uire me nts of a 7 Da y Re p orts, 1 5 Da y Re p orts, or 
t he re q uire m e nts f or i ncl usi o n i n t he A n n ual Peri o dic Re p orts will be s u b mitte d as 
re q uire d t o F D A, E ur o p ea n U ni o n ( E U), P har mace utical a n d Me dical De vi ces a ge n c y 
( P M D A) or ot her l o cal re g ulat ors.  I n vesti gat ors will be pr o vi de d a c o p y of t he 
s u b missi o n a n d will utilize t his f or s u b missi o n t o l ocal I R B/ E Cs as re q uire d.  T he 
s u b missi o n will cr oss refere nce t he S p o ns or’s I n v esti gati o nal C o m p o u n d N u m ber (I N D, 
C S A, etc.).  
All s u bjects wit h S A Es m ust be f oll o we d u p f or o utc o me. 
7. 2. 3. 2  
E v e nt s of Cli ni c al I nt er e st  
Selecte d n o n -seri o us a n d S A Es  are als o k n o w n as E CIs a n d m ust be re p orte d t o t he 
S p o ns or.  E CIs m ust be r ec or de d as s uc h o n t he A d verse E ve nt C R Fs / w or ks heets a n d 
re p orte d wit hi n 2 4 h o urs t o i n Ve nti v Healt h Cli nical P har mac o vi gila nce ( Att n: i H C S A E 
Re p orti n g; F A X 8 6 6- 8 8 0- 9 3 4 3 or e mail:  i 3 dr u gsafet y P V @i n v e nti v healt h.c o m). 
E CIs f or t his trial i n cl u de: 
1.  O ver d ose, 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, w hic h is n ot ass ociate d wit h cli nical 
s y m pt o ms or a b n or mal la b orat or y res ults. 
2.  A n ele vate d A S T or A L T v al ue t hat is ≥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 val ue t hat is ≥2 X t he u p per li mit of n or mal a n d, at t he sa m e ti me, a n 
al kali ne p h os p hatase v al ue t hat is ≤2 X t he u p per li mit of n or mal, as deter mi ne d b y 
wa y of pr ot oc ol- s pecifie d lab orat or y testi n g or u nsc he d ule d la b orat or y testi n g. * 
3.  C yt o ki ne rel ease s y n dr o me ( C R S): S u bjects prese nti n g wit h all  6 s y m pt o ms of C R S  
t hat i ncl u de na usea, h ea d ac he, tac h ycar dia, h y p ote nsi o n, ras h, a n d s h ort ness of 
breat h . 
4.  Lister e mia  
5.  H y p ote nsi o n – > Gra d e 2  
6.  A n y A E  > Gr a de 3  
* N ote:  T hese criteria are base d u p o n a v aila ble re g ulat or y g ui da n ce d o c u me nts. T he 
p ur p ose of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic t ests t hat ma y re q uire 
a n a d diti o nal e val uati o n f or a n u n derl yi n g eti ol o g y. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 4  of 9 4  
 
 
 
 
 
 
 
 
E CIs t hat occ ur i n a n y s u bject fr o m t he dat e of first d ose t hr o u g h 3 0 d a ys f oll o wi n g 
cessati o n of treat me nt, or t he i nitiati o n of a ne w a ntica ncer t h era p y, w hic he ver is earlier, 
m ust be re p orte d wit hi n 2 4 h o urs of a w are n ess t o i n Ve nti v Healt h Cli nical 
P har mac o vi gila nce ( Att n: i H C S A E Re p orti n g; F A X 8 6 6 - 8 8 0- 9 3 4 3 or e m ail:  
i 3 dr u gsafet y P V @i n ve nti v healt h.c o m). 
7. 2. 4  
E v al u ati n g A d v er s e E v e nt s  
A n In vesti gat or w h o is a q ualifie d p h ysi cia n will e val uate all A Es  acc or di n g t o t he 
C T C A E v 4. 0 3 .  A n y A E  t hat c ha n ges C T C A E gra de o ver t h e c o urs e of a gi ve n e pis o de 
will ha ve eac h c ha n ge of gr a de rec or d e d o n t he A E  C R Fs  acc or di n g t o  T a ble 1 6 .   All 
A Es  re gar dless of C T C A E gr a de m ust als o be e val uate d f or seri o us ness. S y m pt o ms 
ass ociate d wit h C yt o ki ne Release S y n dr o me ( C R S) w hic h i ncl u de n a use a, he a d ac he, 
t ac hyc ar di a, hy p ote nsi o n, r as h, a n d s h ort ness of bre at h M U S T be re p ort e d as i n di vi d ual 
s y m pt o ms. If a su bject ma nifest all fi ve C R S s y m pt o ms, t he n C R S ca n be re p orte d as a 
si n gle e v e nt. Ot her wise t he y m ust be re p orte d i n di vi d uall y as it is n ot a tr ue C R S. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 5  of 9 4  
 
 
 
 
 
 
 
 
T a bl e 1 6   E v al u ati n g A d v er s e E v e nt s  
V 4. 0 3  
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 nc es; 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 S A E  is a n y A E  occ urri n g at a n y d ose or d uri n g a n y use of A d va xis or Merc k 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 bj ect, 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 oes n ot i ncl u de a n A E  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 s i 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 [i ncl u di n g h os pitalizati o n f or a n 
electi ve pr oce d ure] f or a pree xisti n g c o n diti o n w hic h has n ot w orse ne d d oes n ot c o nstit ute a S A E .); or 
 
† Is a co n ge nit al a n o m al y/ birt h defect  (i n offs pri n g of s u bj ect 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) or  
 
Is a n o ver d ose ( w het her acci de ntal or i nte nti o nal).  A n y A E  ass ociate d wit h a n o ver d ose is c o nsi dere d a S A E . A n o ver d ose t hat is n ot 
ass ociate d wit h a n A E  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 
S A E  w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he e ve nt ma y j e o par dize t he s u bj ect 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 E . 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 E  ca use t he A d va xis or Merc k pr o d uct t o be disc o nti n ue d?  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 6  of 9 4  
 
 
 
 
 
 
 
 
Rel ati o ns hi p 
t o test dr u g  
Di d t he A d va xis or Merc k pr o d uct ca use t he A E ? T he deter mi nati o n of t he li keli h o o d t hat t he A d va xis or Merc k pr o d uct ca use d t he A E  will 
be pr o vi de d b y a n i n vesti gat or w h o is a q ualifie d p h ysicia n. T he i n vesti gat or’s si g ne d/ date d i nitials o n t he s o urce d oc u me nt or w or ks heet 
t hat s u p p orts t he ca usalit y n ot e d o n t he A E f or m, e ns ures t hat a me dicall y q ualifie d assess me nt of ca usalit y was d o ne. T his i nitiale d 
d oc u me nt m ust be retai ne d f or t he re q uire d re g ulat or y ti me fra me. T he criteria bel o w are i nte n de d as refere nce g ui deli nes t o assist t he 
i n vesti gat or i n assessi n g t he li keli h o o d of a relati o ns hi p bet wee n t he test dr u g a n d t he A E  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 a re t o be use d t o assess t he rel ati o ns hi p bet w ee n t he A d v a xis or M erc k pr o d uct a n d t h e 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 A d va xis or Merc k pr o d uct 
ca use d t he A E:  
 
E x p os ure  
Is t here e vi de nce t hat t he s u bj ect was act uall y e x p ose d t o t he Merc k 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 ur e 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 A d va xis or Merc k 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 uced 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 pl ai 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  
Rel ati o ns hi p  
T he f oll o wi n g c o m p o ne nts a re t o be use d t o assess t he rel ati o ns hi p bet w ee n t he test dr u g a n d t he A E: (c o nti n ue d) 
t o A d v a xis or 
M erc k 
pr o d uct  
(c o nti n ue d)  
Dec h alle n ge  
W as t he A d va xis or Merc k 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 d ec 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 ve d des pite c o nti n uati o n of t he A d va xis or Merc k pr o d uct; or ( 3) t he trial is a si n gle-d ose dr u g trial); or ( 4) 
Merc k pr o d uct(s) is/are o nl y use d o ne ti me.)  
 
Rec h alle n ge  
W as t he s u bj ect re -e x p ose d t o t he A d va xis or Merc k 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 r ec 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 tr ial); or ( 3) A d va xis or Merc k pr o d uct(s) is/are use d o nl y o ne ti me). 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 7  of 9 4  
 
 
 
 
 
 
 
 
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 A D V A XI S O R  M E R C K 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 
A D V A XI S O R  M E R C K P R O D U C T  PO 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 U. S. C LI NI C A L M O NI 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 A d va xis or Merc k 
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 v esti gat or w h o is a q ualifi e 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 n A d v a xis or 
M erc k pr o d uct rel ati o ns hi p).  
Defi nite:  
T he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m a d mi nistrati o n of t he st u d y dr u g, t he e ve nt f oll o ws a k n o w n 
res p o nse patter n t o t he st u d y dr u g a n d base d o n t he k n o w n p har mac ol o g y of t he st u d y dr u g, t he e ve nt is clearl y relate d t o 
t he effect of t he st u d y dr u g 
Pr o b a ble:  
T he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m a d mi nistrati o n of t he st u d y dr u g a n d t he e ve nt f oll o ws a k n o w n 
res p o nse patter n t o t he st u d y dr u g A N D t he e ve nt can n ot ha ve bee n reas o na bl y e x plai ne d b y a n i nterc urre nt me dical 
c o n diti o n or t he e ve nt ca n n ot be t he effect of a c o nc o mita nt me dicati o n  
P ossi ble  
T he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m a d mi nistrati o n of t he st u d y dr u g or t he e ve nt f oll o ws a k n o w n 
res p o nse patter n t o t he st u d y dr u g B U T t he e ve nt c o ul d ha ve bee n pr o d uce d b y a n i nterc urre nt me dical c o n diti o n w hic h, 
base d o n t he pat h o p h ysi ol o g y of t he c o n diti o n, a n d t he p har mac ol o g y of t he st u d y dr u g, w o ul d be u nli kel y relate d t o t he 
use of t he st u d y dr u g or t he e ve nt c o ul d be t he effect of a c o nc o mita nt me dicati o n  
U nli kel y  
T he e ve nt is clearl y d ue t o ca uses disti nct fr o m t he use of t he st u d y dr u g, s uc h as a d oc u me nte d pre -e xisti n g c o n diti o n, t he 
effect of a c o nc o mita nt me dic ati o n, a ne w c o n diti o n  w hic h, base d o n t he pat h o p h ysi ol o g y of t he c o n diti o n, a n d t he 
p har mac ol o g y of t he st u d y dr u g, w o ul d be u nli kel y relate d t o t he use of t he st u d y dr u g  
U nrel ate d  
T he e ve nt d oes n ot f oll o w a te m p oral relati o ns hi p t o t he st u d y treat me nt a d mi nistrati o n (t o o earl y, late, or st u d y 
treat me nt(s) n ot ta ke n) or t her e is a reas o na ble ca usal relati o ns hi p bet wee n a n ot her dr u g, c o nc urre nt disease, or 
circ u msta nce a n d t he A E  




 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 7 9  of 9 4  
 
 
 
 
 
 
 
 
•  V ital si g ns 
•  B aseli ne s afet y la bs i ncl u di n g he mat ol o g y a n d s er u m c he mistr y  
•  B aseli ne i m m u n ol o g y dat a 
•  
 
•  
 
8. 2. 2  
St u d y C o n d u ct  
I nf or mati o n a b o ut st u d y c o n d uct will be pres e nte d b y treat me nt d ose.  S u bject dis p ositi o n 
at t he e n d of t he st u d y will be ta b ulate d i ncl u di n g t he n u m ber of s u bjects w h o c o m plete d 
t he st u d y as w ell as t he r eas o n f or disc o nti n uati o n f or n o n-c o m pleters.  T he n u m ber of 
s u bjects i n eac h of t h e a n al ysis p o p ulati o ns, t he d urati o n of ti me o n st u d y, a n d t he 
n u m ber of i njecti o ns will als o be dis pla ye d.  T he n u m ber a n d t y pe of pr ot oc ol vi olati o ns 
will be s u m marize d.  
8. 2. 3  
S af et y E n d p oi nt s  
A Es will be c o de d usi n g Me d D R A a n d will be prese nte d b y S yste m/ Or ga n/ Class a n d 
preferre d t er m.  S o me A Es will be cate g orize d a n d s u m marize d b y Gra de as defi ne d i n 
C T C A E v 3. 0.  C o nc o mita nt me dicati o ns will be c o de d usi n g t he C T C A E v 4. 0 a n d 
s u m marize d b y dr u g cl ass a n d ge neri c na me. 
Ta bles a n d gr a p hs will s h o w c ha n ges fr o m baseli n e t hr o u g h o ne year i n: 
•  P h ysical e x a mi nati o n  
•  V ital si g ns 
•  Safet y l a bs, i ncl u di n g h e mat ol o g y a n d ser u m c he mistr y 
Ot her saf et y d ata t hat will be prese nte d i n cl u de:  
•  D L T  
•  A d verse e ve nts al o n g wit h t heir se verit y a n d p ote ntial relati o ns hi p t o st u d y 
treat me nt 
•  Injecti o n site reacti o ns  
•  C o nc o mita nt me dicati o ns  
•  P r o p h yla xis treat me nt 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 0  of 9 4  
 
 
 
 
 
 
 
 
8. 2. 4  
Effi c a c y E n d p oi nt s  
•  T u m or res p o nse, ti me t o t u m or pr o gressi o n usi n g R E CI S T, ir R E CI S T or P C W G 2 
as a p pr o priat e 
•  S ur vi val of s u bjects at ti me p oi nts u p t o 2 4 m o nt hs  
•  P F S of s u bjects at ti me p oi nts u p t o 2 4 m o nt hs 
•  
D urati o n of res p o ns e will be meas ure d fr o m t he ti me t he meas ure me nt crit eria are met f or 
ir C R/ir P R ( w hic he ver is first rec or d e d) u ntil t he first date t hat pr o gressi ve disease or 
deat h is o bjecti vel y d oc u me nte d.  S u bjects w h o d o n ot rela pse will be ce ns ore d at t he da y 
of t heir last t u m or assess me nt.  
Ti me t o pr o gr essi o n will be defi ne d as t he ti me fr o m t he first da y of treat me nt u ntil t he 
date pr o gr essi ve disease or deat h is first re p orte d.  S u bjects w h o die wit h o ut a re p orte d 
pri or pr o gressi o n will be c o nsi dere d t o ha v e pr o gresse d o n t he da y of t heir deat h.  
S u bjects w h o di d n ot pr o gr ess will be ce ns ore d at t he da y of t heir last t u m or assess me nt. 
T u m or res p o nse r ate is t he t otal n u m ber of C Rs pl us P Rs di vi de d b y t he n u m ber of 
treate d s u bjects.  Disease c o ntr ol rate is t he n u m ber of s u bjects w h o ha v e C R + P R + S D f or 
a mi ni m u m of 1 2 wee ks f oll o wi n g t he first d a y of treat me nt, di vi de d b y t he n u m ber of 
res p o nse-e val ua ble s u bjects.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 1  of 9 4  
 
 
 
 
 
 
 
 
9 
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  
9. 1  
I n v e sti g ati o nal Pr o d u ct  
T he i n vesti gat or s hall ta k e res p o nsi bilit y f or a n d s hall ta ke all ste ps t o mai ntai n 
a p pr o priate rec or ds a n d e ns ure a p pr o priate s u p pl y, st ora ge, ha n dli n g, distri b uti o n a n d 
usa ge of i n vesti gati o nal pr o d uct i n acc or da n ce wit h t he pr ot oc ol a n d a n y a p plica ble la ws 
a n d re g ulati o ns. 
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 7 . 
9. 2  
P a c k a gi n g a n d L a b eli n g I nf or m ati o n  
Cli nical s u p plies will be affi x e d wit h a cli nical la b el i n acc or d a nce wit h re g ulat or y 
re q uire me nts. 
9. 3  
Cli ni c al S u p pli e s Di s cl o s ur e  
T his trial is o pe n -la bel; t heref ore, t he s u bject, t he trial site pers o n nel, t he S po ns or a n d/ or 
desi g nee are n ot bli n de d t o treat me nt.  Dr u g i de ntit y ( na m e, stre n gt h) 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. 
9. 4  
St or a g e a n d h a n dli n g R e q uir e m e nt s  
9. 4. 1  
St or a g e G ui d eli n e s  
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. 
M K - 3 4 7 5 is s hi p pe d at 2 – 8° C.  It is i m perati ve t hat all M K - 3 4 7 5 dr u g s hi p me nts be 
st ore d refri ger ate d at 2 – 8° C i m me diatel y after recei ve d.  
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 a n a ut h orize d pers o n at 
t he trial site. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 2  of 9 4  
 
 
 
 
 
 
 
 
Detaile d st ora ge a n d ha n dli n g i nf or mati o n ca n be f o u n d i n t he P har mac y M a n ual.  
Cli nical s u p plies ma y n ot be use d f or a n y p ur p ose ot her t ha n t hat state d i n t he pr ot oc ol. 
9. 4. 2  
H a n dli n g R e q uir e m e nt s  
A D X S 3 1 - 1 4 2 is a li ve L m  t hat has bee n atte n uate d at least l o gs m ore t ha n wil d-t y pe L m  
a n d is clear e d b y ga m ma i nterfer o n k n o c k -o ut mice lac ki n g a d a pti ve i m m u nit y.  It has 
als o bee n altere d b y a n irre versi ble d eleti o n of t he vir ule nce ge n e w hic h is esse ntial f or 
cell-t o-cell s prea d of L m  i nfecti o n.  A D X S 3 1- 1 4 2 has n ot bee n a d mi nistere d t o a n y 
h u ma n s u bject pri or t o t his cli nical trial.  H o we ver, se veral cli nical trials ha ve bee n 
c o n d ucte d wit h a si milar L m - L L O i m m u n ot hera p y 
 i ncl u di n g 2 st u dies i n 
a d va nce d cer vical ca ncer, o ne st u d y i n CI N, o n e st u d y i n hea d a n d nec k ca n cer, a n d o n e 
st u d y i n a nal ca ncer.  T h e e xter nal bacterial vect or a n d ele me nts re g ulati n g e x pressi o n of 
t he f usi o n pr otei ns are i d e ntical i n t hese i m m u n ot hera pies.  It h as bee n a d mi nistere d 
i ntra ve n o usl y o v er 5 0 0 ti mes t o o ver 2 0 0 s u bjects (at t he ti me of t his writi n g) wit h o nl y 
mil d -m o derate si de effects ass ociate d wit h i nf usi o n.   
Wil d -t y pe L m  is gr a m- p ositi ve, n o n-s p ore-f or mi n g, fac ultati ve bacilli are he m ol yti c a n d 
catalase - p ositi ve.  Alt h o u g h healt h y a d ults a n d c hil dre n ca n c o ntract a wil d-t y pe Listeri a  
i nfecti o n, t he y d o n ot us uall y bec o me seri o usl y ill.  Pe o ple at ris k of se vere ill ness fr o m 
w il d-t y pe Listeria ar e pr e g na nt w o m e n, ne w b or ns, a n d pers o ns wit h i m paire d i m m u ne 
f u ncti o n. 
E ve n t h o u g h A D X S 3 1- 1 4 2 is n o n- pat h o ge nic, all L m  s pecies are classifie d as 
acc or di n g t o t he Bi osaf et y i n Micr o bi ol o gical a n d Bi o me dical La b orat ories ( B M B L) 5t h 
E diti o n [3 7 ].  I n t h e U S t here c urre ntl y is n o met h o d t o reclassif y A d v a xis atte n uate d L m  
strai ns i n a ma n ner t hat differe ntiat es t hem fr o m t he m ore vir ule nt wil d t y p e pare nt strai n 
1 0 4 0 3 S.  U ni versal preca uti o ns a n d i nstit uti o nal g ui deli nes s h o ul d be use d w he n ha n dli n g 
i n vesti gati o nal dr u gs a n d h u ma n s peci me ns.  Preca uti o ns as state d i n t he B M B L 5t h 
E diti o n f or wil d -t y pe L m  i ncl u de: 
Wil d- ty p e L m  p oses a p ot e nti al h az ar d t o l a b or at ory pers o n nel.  T he Gr a m-
p ositive, n o n-s p ore-f or mi n g, aer o bic b acilli are he m olytic a n d c at al ase- p ositive. 
B acteri a h ave b ee n is ol ate d fr o m s oil, d ust, h u m a n f o o d, a ni m als, a n d 
asy m pt o m atic h u m a ns. M ost c ases of listeri osis h ave arise n fr o m e ati n g 
c o nt a mi n ate d f o o d pr o d ucts, m ost n ot a bly s oft c heeses, r a w me at, a n d u n w as he d 
r a w ve get a bles.  Alt h o u g h he alt hy a d ults a n d c hil dre n c a n c o ntr act a Listeri a 
i nfecti o n, t hey d o n ot us u ally bec o me s eri o usly ill. At risk of severe ill ness are 
pre g n a nt w o me n, ne w b or ns, a n d pers o ns wit h i m p aire d i m m u ne f u ncti o n. 
L a b or at ory H az ar ds:   Wil d -ty pe L m  m ay be i n t he e nvir o n me nt a n d m a y be f o u n d 
i n feces, cer e br os pi n al fl ui d ( C S F), a n d bl o o d, as well as f o o d a n d e nvir o n me nt al 
m ateri al s.  I n gesti o n is t he m ost c o m m o n m o d e of ex p os ure, b ut wil d-ty pe L m  c a n 
als o c a use eye a n d ski n i nfecti o ns f oll o wi n g a direct ex p os ur e.  Wil d -ty pe L m 
i nfecti o ns i n pre g n a nt w o me n occ ur m ost ofte n i n t he t hir d tri mester a n d m ay 
preci pit ate l a b or.  Tr a ns pl ace nt al tr a ns missi o n of L m p oses a gr ave risk t o t he 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 3  of 9 4  
 
 
 
 
 
 
 
 
fet us a n d m ay res ult i n disse mi n ate d a bscesses c o ntri b uti n g t o a m ort ality r ate of 
ne arly 1 0 0 %. 
Rec o m m e n de d Prec a uti o ns:   Bi os afety 
pr actices, c o nt ai n me nt 
e q ui p me nt, a n d f acilities are rec o m m e n de d f or activities wit h cli nic al s peci me ns 
a n d c ult ures k n o w n or s us pecte d t o c o nt ai n t he a g e nt.  Gl oves a n d eye pr ot ecti o n 
s h o ul d be w or n w hile h a n dli n g t he a ge nt.  Pre g n a nt w o me n w h o w ork wit h 
Listeri a m o n ocyt o ge nes i n t he cli nic al or rese arc h l a b or at ory setti n g s h o ul d be 
f ully i nf or me d of t he p ote nti al h az ar ds ass oci ate d wit h t he or g a nis m, i ncl u di n g 
p ote nti al risks t o t he fet us.  
A d diti o nal details re g ar di n g ha n dli n g of b ot h pr o d ucts ca n be f o u n d i n t he P har mac y 
Ma n ual.  
9. 5  
R et ur n s a n d R e c o n cili ati o n  
T he I n vesti gat or is r es p o nsi ble f or kee pi n g acc urate rec or ds of t he cli nical s u p plies 
recei v e 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 t he 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. 
U p o n c o m pleti o n or ter mi nati o n of t he st u d y, all u n use d a n d/ or partiall y us e d 
i n vesti gati o nal pr o d u ct will be destr o ye d at t he site per i nstit uti o nal p olic y.  It is t he 
I n v esti gat or’s r es p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y c o nt ai ners, pr o vi de d t hat 
pr oce d ur es f or pr o per dis p osal ha ve bee n esta blis h e d acc or di n g t o a p plica bl e fe deral, 
state, l ocal a n d i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d pr o vi d e d t hat a p pr o priate 
rec or ds of dis p osal ar e ke pt. 
1 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. 1  C o nfi d e nti alit y  
T he c o nfi de ntialit y of r ec or ds a n d i nf or mati o n t hat c o ul d i de ntif y s u bjects m ust be 
pr otecte d, r es pecti n g pri v ac y a n d c o nfi de ntialit y r ules i n acc or d a nce wit h a p plica ble 
re g ulat or y r e q uireme nts.  
T he i n vesti gat or will a gr ee t o mai ntai n i n c o nfi de nce all i nf or mati o n f ur nis he d b y t h e 
S p o ns or a n d all data ge n erate d i n t he st u d y, e x ce pt as pr o vi de d or re q uire d b y la w, a n d 
will di v ul ge s uc h i nf or m ati o n t o t he I R B wit h t he u n dersta n di n g t hat c o nfi d e ntialit y will 
be mai ntai ne d b y t he c o m mittee.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 4  of 9 4  
 
 
 
 
 
 
 
 
T he i de ntit y of all s u bjects i n t his st u d y m ust re m ai n c o nfi de ntial, a n d o nl y t he i nitials of 
sai d s u bjects will a p pear o n t he C R F.  Q ualifie d re prese ntati ves fr o m t he rel e va nt 
re g ulat or y a ge ncies, t he S p o ns or, or its a ge nts ma y i ns pect t he s u bj ect/st u d y rec or ds.  
S u bject data o btai ne d d uri n g t he st u d y ma y be prese nte d i n scie ntific p u blicati o ns, b ut at 
n o ti me will s u bject na mes be use d.  
1 0. 2  C o m pli a n c e wit h Fi n a n ci al Di s cl o s ur e R e q uir e m e nt s  
Fi na ncial Discl o s ur e r e q uire me nts are o utli ne d i n t he U S F o o d a n d Dr u g A d mi nistrati o n 
Re g ulati o ns, Fi n a ncial Discl os ure b y Cli nical I n v esti 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, bas e d o n t hese re g ul ati o ns, w het her a re q uest f or 
Fi na ncia l Discl os ur e i nf or mati o n is re q uire d.  It is t he I n v esti 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 u c h re q u est.  T he I n vesti gat or/s u bi n vesti gat or(s) 
a gree, if re q u este d b y t he S p o ns or i n acc or d a 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 arr a 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 ur ate certificati o n a n d discl os ure state me nts.  
T he I n vesti gat or/s u bi n vesti gat or(s) f urt her a gree t o pr o vi de t his i nf or mati o n o n a 
Certificati o n/ Discl os ure F or m, c o m m o nl y k n o w n as a fi na n cial discl os ure f or m, pr o vi de d 
b y t he S p o ns or or t hr o u g h a sec ure pass w or d- pr ot ecte d el ectr o nic p ort al 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.  T his m a y i n v ol ve t h e 
tra ns missi o n of i nf or mati o n t o c o u ntries t hat d o n ot ha ve la ws pr otecti n g p ers o nal data. 
1 0. 3  C o m pli a n c e wit h l a w, A u dit a n d D e b ar m e nt  
I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) G ui da nce o n G o o d Cli nical Practice 
([ G C P] C P M P/I C H/ 1 3 5/ 9 5) a n d t he S p o ns or re q uire t he In vesti gat or t o b e a ware of 
his/ her o bli gati o ns i n t he c o n d uct of t his st u d y. 
Re prese ntati ves of t h e S p o ns or m ust be all o we d t o visit all st u d y site l ocati o ns 
peri o dicall y t o assess dat a q ualit y a n d st u d y i nte grit y.  O n site, t he y will re vie w st u d y 
rec or ds a n d directl y c o m pare t he m wit h t he ori gi n al s o urce d o c u me nts, disc uss t he 
c o n d uct of t he st u d y wit h t he In v esti gat or, a n d v erif y t hat t he facilities re m ai n acce pta ble.  
I n a d diti o n, t he st u d y ma y be e val uat e d b y a u dit ors desi g nat e d b y t he S p o ns or a n d b y 
g o ver n me nt i ns pect ors w h o m ust be all o we d access t o C R Fs, s o urce d oc u m e nts, a n d all 
ot her st u d y files.  S p o ns or a u dit re p orts will be ke pt c o nfi de ntial. 
T H E I N V E S TI G A T O R M U S T N O TI F Y T H E S P O N S O R P R O M P T L Y O F A N Y 
I N S P E C TI O N S S C H E D U L E D B Y R E G U L A T O R Y A U T H O RI TI E S A N D 
P R O M P T L Y F O R W A R D C O PI E S O F I N S P E C TI O N R E P O R T S T O T H E S P O N S O R.  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 5  of 9 4  
 
 
 
 
 
 
 
 
1 0. 4  C o m pli a n c e wit h Tri al R e gi str ati o n a n d R e s ult s P o sti n g 
R e q uir e m e nt s  
U n der t he ter ms of t he F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act ( F D A M A) a n d 
t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act ( F D A A A), t he S p o ns or of t he trial 
is s olel y res p o nsi ble f or deter mi ni n g w h et her t h e 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.  I nf or mati o n p oste d will all o w s u bjects t o i de ntif y 
p ote ntiall y a p pr o priate tri als f or t heir diseas e c o n diti o ns a n d p urs ue partici p ati o n b y 
calli n g a ce ntr al 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 tri al l ocati o ns a n d 
trial site c o ntact i nf or mati o n. 
1 0. 5  Q u alit y M a n a g e m e nt S y st e m  
B y si g ni 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 u alit 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 ar ea 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 u cte d 
a n d data are ge n er ate 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 C P , 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. 
1 0. 6  D at a M a n a g e m e nt  
T he In vesti gat or or q u alifie d desi g nee is res p o nsi ble f or rec or di n g a n d v erif yi n g t he 
acc ur ac y of s u bject data.  B y si g ni n g t his pr ot oc ol, t he I n v esti gat or ac k n o wl e d ges t hat 
his/ her electr o nic si g n at ure is t he le gall y bi n di n g e q ui vale nt of a writte n si g nat ure.  B y 
e nteri n g his/ her electr o ni c si g nat ure, t he I n v esti gat or c o nfir ms t hat all rec or de d data ha v e 
bee n verifie d as acc urate.  
Detaile d i nf or mati o n r e gar di n g Data M a na ge m e nt pr oce d ures f or t his pr ot o c ol will be 
pr o vi de d se paratel y. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 6  of 9 4  
 
 
 
 
 
 
 
 
1 1  LI S T O F R E F E R E N C E  
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2 0 0 9. 6 6 : p. 1- 2 7. 
2.  
H ussai n, S. F. a n d Y. Paters o n, C D 4 + C D 2 5 + re g ul at ory T cells t h at secrete 
T G F bet a a n d I L -1 0 are prefere nti ally i n d uce d by a v acci ne vect or.  J I m m u n ot her, 
2 0 0 4. 2 7 ( 5): p. 3 3 9- 4 6. 
3.  
S ha ha bi, V., et al., Devel o p me nt of a Listeri a m o n ocyt o ge nes b as e d v acci n e 
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I m m u n ol, 1 9 9 6. 8 ( 5): p. 6 4 3- 5 0. 
5.  
Gree n wal d, R.J., G.J. Free ma n, a n d A. H. S har pe, T he B 7 f a mily revisite d.  A n n u 
Re v I m m u n ol, 2 0 0 5. 2 3 : p. 5 1 5- 4 8. 
6.  
O kaza ki, T., et al., P D -1 i m m u n orec e pt or i n hi bits B cell rece pt or - me di ate d 
si g n ali n g by recr uiti n g src h o m ol o gy 2- d o m ai n-c o nt ai ni n g tyr osi ne p h os p h at ase 2 
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C he m nitz, J. M., et al., S H P - 1 a n d S H P- 2 ass oci ate wit h i m m u n orece pt or 
tyr osi ne- b ase d s witc h m otif of pr o gr a m me d de at h 1 u p o n pri m ary h u m a n T cell 
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1 0.  
Rile y, J. L., P D - 1 si g n ali n g i n pri m ary T cells. I m m u n ol Re v, 2 0 0 9. 2 2 9 ( 1): p. 
1 1 4- 2 5. 
1 1.  
Fra n cisc o, L. M., P. T. Sa ge, a n d A. H. S har pe, T he P D - 1 p at h w ay i n t oler a nce a n d 
a ut oi m m u nity.  I m m u n ol Re v, 2 0 1 0. 2 3 6 : p. 2 1 9- 4 2. 
1 2.  
A gata, Y., et al., Ex pressi o n of t he P D- 1 a nti ge n o n t he s urf ace of sti m ul ate d 
m o use T a n d B ly m p h ocytes.  I nt I m m u n ol, 1 9 9 6. 8 ( 5): p. 7 6 5- 7 2. 
1 3.  
Vi b ha kar, R., et al., A ctiv ati o n -i n d uce d ex pr essi o n of h u m a n pr o gr a m me d d e at h- 1 
ge ne i n T- ly m p h ocytes. E x p Cell Res, 1 9 9 7. 2 3 2 ( 1): p. 2 5- 8. 
1 4.  
Nis hi m ura, H., T. H o nj o, a n d N. Mi nat o, F acilit ati o n of bet a selecti o n a n d 
m o dific ati o n of p ositive selecti o n i n t he t hy m us of P D - 1-deficie nt mi ce.  J E x p 
Me d, 2 0 0 0. 1 9 1 ( 5): p. 8 9 1- 8. 
1 5.  
Parr y, R. V., et al., C T L A - 4 a n d P D- 1 rece pt ors i n hi bit T-cell activ ati o n by disti nct 
mec h a nis ms.  M ol Cell Bi ol, 2 0 0 5. 2 5 ( 2 1): p. 9 5 4 3- 5 3. 
1 6.  
Br o w n, J. A., et al., Bl ock a de of pr o gr a m me d de at h- 1 li g a n ds o n de n dritic cells 
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1 7.  
D o n g, H., et al., T u m or- ass oci ate d B 7- H 1 pr o m otes T-cell a p o pt osis: a p ote nti al 
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1 8.  
S har pe, A. H. a n d G.J. Free ma n, T he B 7 - C D 2 8 s u perf a mily. Nat Re v I m m u n ol, 
2 0 0 2. 2 ( 2): p. 1 1 6- 2 6. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 7  of 9 4  
 
 
 
 
 
 
 
 
1 9.  
F o urca de, J., et al., P D - 1 is a re g ul at or of N Y-E S O - 1-s pecific C D 8 + T cell 
ex p a nsi o n i n mel a n o m a p atie nts.  J I m m u n ol, 2 0 0 9. 1 8 2 ( 9): p. 5 2 4 0- 9. 
2 0.  
Macia g, P. C., S. Ra d ul o vic, a n d J. R ot h ma n, T he first cli nic al use of a live -
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2 1.  
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2 4.  
Wi nsl o w, D. L. a n d M. L. Steele, Listeri a b actere mi a a n d perit o nitis ass oci ate d 
wit h a perit o ne ove n o us s h u nt: s uccessf ul tre at me nt wit h s ulf a met h ox az ole a n d 
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C harlier, C., et al., Listeri a m o n ocyt o ge nes- ass oci ate d j oi nt a n d b o ne i nfecti o ns: a 
st u dy of 4 3 c o nsec utive c ases. Cli n I nfect Dis, 2 0 1 2. 5 4 ( 2): p. 2 4 0- 8. 
2 6.  
Weir, R. E., et al., Myc o b acteri al p urifie d pr ot ei n deriv atives sti m ul ate i n n ate 
i m m u nity: M al a wi a ns s h o w e n h a nce d t u m or necr osis f act or al p h a, i nterle uki n-
1 bet a (I L- 1 bet a), a n d I L- 1 0 res p o nses c o m p are d t o t h ose of a d olesce nts i n t he 
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2 7. 
Ca m pisi, L. , et al., S ple ni c C D 8 al p h a( +) d e n dritic cells u n der g o r a pi d 
pr o gr a m mi n g by cyt os oli c b acteri a a n d i nfl a m m ati o n t o i n d uce pr otective 
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Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 8  of 9 4  
 
 
 
 
 
 
 
 
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mel a n o m a pr o g n osis.  Met h o ds M ol Bi ol, 2 0 1 4. 1 1 0 2 : p. 2 8 7- 3 2 4. 
4 3.  
G o o de n, M.J., et al., T he pr o g n ostic i nfl ue nce of t u m o ur- i nfiltr ati n g ly m p h ocytes 
i n c a ncer: a s yste m atic r evie w wit h met a- a n alysis. Br J Ca ncer, 2 0 1 1. 1 0 5 ( 1): p. 
9 3- 1 0 3. 
4 4.  
Sc hrei ber, R. D., L.J. Ol d, a n d M.J. S m yt h, C a ncer i m m u n oe diti n g: i nte gr ati n g 
i m m u nity's r oles i n c a ncer s u p pressi o n a n d pr o m oti o n. Scie nce, 2 0 1 1. 3 3 1 ( 6 0 2 4): 
p. 1 5 6 5- 7 0. 
4 5. 
Bre m n es,  R. M.,  et  al., T he  r ole  of  t u m or -i nfiltr ati n g  i m m u ne  cells  a n d  c hr o nic 
i nfl a m m ati o n at t he t u m or site o n c a ncer devel o p me nt, pr o gressi o n, a n d pr o g n osis: 
e m p h asis o n n o n-s m all cell l u n g c a ncer.  J T h orac O nc ol, 2 0 1 1. 6 ( 4): p. 8 2 4- 3 3. 
4 6.  
Tal ma d ge, J. E., I m m u ne cell i nfiltr ati o n of pri m ary a n d met ast atic lesi o ns: 
mec h a nis ms a n d cli nic al i m p act.  Se mi n Ca ncer Bi ol, 2 0 1 1. 2 1 ( 2): p. 1 3 1- 8. 
4 7.  
S hira be, K., et al., T u m or-i nfiltr ati n g ly m p h ocytes a n d he p at ocell ul ar c arci n o m a: 
p at h ol o gy a n d cli nic al m a n a ge me nt.  I nt J Cli n O nc ol, 2 0 1 0. 1 5 ( 6): p. 5 5 2- 8. 
4 8.  
N os h o, K., et al., T u m o ur- i nfiltr ati n g T-cell s u bsets, m olec ul ar c h a n ges i n 
c ol orect al c a ncer, a n d pr o g n osis: c o h ort st u dy a n d liter at ure revie w.  J Pat h ol, 
2 0 1 0. 2 2 2 ( 4): p. 3 5 0- 6 6. 
4 9. 
Bellati, F., et al., I m m u n ol o gy of gy nec ol o gic n e o pl as ms: a n alysis of t he 
pr o g n ostic si g nific a nce of t he i m m u ne st at us.  C urr Ca ncer Dr u g Tar gets, 2 0 0 9. 
9 ( 4): p. 5 4 1- 6 5. 
5 0.  
O ble, D. A., et al., F o c us o n TI Ls: pr o g n ostic si g nific a nce of t u m or i nfiltr ati n g 
ly m p h ocytes i n h u m a n m el a n o m a. Ca ncer I m m u n, 2 0 0 9. 9 : p. 3. 
5 1.  
U p pal uri, R., G. P. D u n n, a n d J. S. Le wis, Jr., F oc us o n TI Ls: pr o g n ostic 
si g nific a nce of t u m or i nfiltr ati n g ly m p h ocytes i n he a d a n d neck c a ncers. Ca ncer 
I m m u n, 2 0 0 8. 8 : p. 1 6. 
5 2.  
D u n n, G. P., I. F. D u n n, a n d W. T. C urr y, F oc us o n TI Ls: Pr o g n ostic si g nific a nce 
of t u m or i nfiltr ati n g ly m p h ocytes i n h u m a n gli o m a.  Ca ncer I m m u n, 2 0 0 7. 7 : p. 1 2. 
5 3.  
C ha n g, W.J., et al., I nfl a m m ati o n-rel ate d f act ors pre dicti n g pr o g n osis of g astric 
c a ncer. W orl d J Gastr oe nter ol, 2 0 1 4. 2 0 ( 1 6): p. 4 5 8 6- 9 6. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 8 9  of 9 4  
 
 
 
 
 
 
 
 
5 4.  
Prest o n, C. C., et al., T he r ati os of C D 8 + T cells t o C D 4 + C D 2 5 + F O X P 3 + a n d 
F O X P 3 - T cells c orrel ate wit h p o or cli nic al o utc o me i n h u m a n ser o us ov ari a n 
c a ncer. P L o S O ne, 2 0 1 3. 8 ( 1 1): p. e 8 0 0 6 3. 
5 5.  
Y o o n, H. H., et al., Pr o g n ostic i m p act of F ox P 3 + r e g ul at ory T cells i n rel ati o n t o 
C D 8 + T ly m p h ocyte d e nsity i n h u m a n c ol o n c arci n o m as.  P L o S O ne, 2 0 1 2. 7 ( 8): 
p. e 4 2 2 7 4. 
5 6. 
Ki m,  S. T.,  et  al., T u m or- i nfiltr ati n g  ly m p h ocytes,  t u m or  c h ar a cteristics,  a n d 
rec urre nce i n p atie nts wit h e arly bre ast c a n cer. A m J Cli n O nc ol, 2 0 1 3. 3 6 ( 3): p. 
2 2 4- 3 1. 
5 7.  
Mat hai, A. M., et al., R ole of F ox p 3- p ositive t u m or- i nfiltr ati n g ly m p h ocytes i n t he 
hist ol o gic fe at ures a n d cli nic al o utc o mes of he p at ocell ul ar c arci n o m a.  A m J S ur g 
Pat h ol, 2 0 1 2. 3 6 ( 7): p. 9 8 0- 6. 
5 8.  
Li u, F., et al., C D 8( +) cyt ot oxic T cell a n d F O X P 3( +) re g ul at ory T cell 
i nfiltr ati o n i n rel ati o n t o bre ast c a ncer s urvi v al a n d m olec ul ar s u bty pes. Breast 
Ca ncer Res Treat, 2 0 1 1. 1 3 0 ( 2): p. 6 4 5- 5 5. 
5 9.  
Kir k, R., Risk f act ors. C D 8 +: F O X P 3 + cell r ati o is a n ovel s urviv al m arker f or 
c ol orect al c a ncer.  Nat R e v Cli n O nc ol, 2 0 1 0. 7 ( 6): p. 2 9 9. 
6 0.  
Pe d oee m, A., et al., Pr o gr a m me d de at h- 1 p at h w ay i n c a ncer a n d a ut oi m m u nity.  
Cli n I m m u n ol, 2 0 1 4. 1 5 3 ( 1): p. 1 4 5- 5 2. 
6 1.  
Z ha n g, X., et al., Str uct ur al a n d f u ncti o n al a n alysis of t he c osti m ul at ory rece pt or 
pr o gr a m me d de at h- 1.  I m m u nit y, 2 0 0 4. 2 0 ( 3): p. 3 3 7- 4 7. 
6 2.  
C he n g, X., et al., Str uct ure a n d i nter acti o ns of t he h u m a n pr o gr a m me d cell de at h 
1 rece pt or.  J Bi ol C he m, 2 0 1 3. 2 8 8 ( 1 7): p. 1 1 7 7 1- 8 5. 
6 3.  
S he p par d, K. A., et al., P D - 1 i n hi bits T-cell rece pt or i n d uce d p h os p h oryl ati o n of 
t he Z A P 7 0/ C D 3zet a si g n al os o me a n d d o w nstre a m si g n ali n g t o P K Ct het a. F E B S 
Lett, 2 0 0 4. 5 7 4 ( 1- 3): p. 3 7- 4 1. 
6 4.  
Ott, P. A., F. S. H o di, a n d C. R o bert, C T L A - 4 a n d P D-1/ P D - L 1 bl ock a d e: ne w 
i m m u n ot her a pe utic m o d alities wit h d ur a ble cli nic al be nefit i n mel a n o m a p atie nts. 
Cli n Ca ncer Res, 2 0 1 3. 1 9 ( 1 9): p. 5 3 0 0- 9. 
6 5.  
Ya o, S. a n d L. C he n, P D - 1 as a n i m m u ne m o d ul at ory rece pt or. Ca n cer J, 2 0 1 4. 
2 0 ( 4): p. 2 6 2- 4. 
6 6.  
Nis hi m ura, H., et al., Devel o p me nt ally re g ul ate d ex pressi o n of t he P D- 1 pr otei n 
o n t he s urf ace of d o u ble- ne g ative ( C D 4 -C D 8 -) t hy m ocytes. I nt I m m u n ol, 1 9 9 6. 
8 ( 5): p. 7 7 3- 8 0. 
6 7.  
H ua n g, X., et al., P D - 1 ex pressi o n by m acr o p h a g es pl ays a p at h ol o gic r ole i n 
alteri n g micr o bi al cle ar a nce a n d t he i n n ate i nfl a m m at ory res p o nse t o se psis.  Pr oc 
Natl Aca d Sci U S A, 2 0 0 9. 1 0 6 ( 1 5): p. 6 3 0 3- 8. 
6 8. 
Pe na - Cr uz, V., et al., P D - 1 o n i m m at ure a n d P D- 1 li g a n ds o n mi gr at ory h u m a n 
L a n ger h a ns cells re g ul ate a nti ge n- prese nti n g cell activity. J I n vest Der mat ol, 
2 0 1 0. 1 3 0 ( 9): p. 2 2 2 2- 3 0. 
6 9.  
Keir, M. E., et al., P D - 1 a n d its li g a n ds i n t oler a nce a n d i m m u nity. A n n u R e v 
I m m u n ol, 2 0 0 8. 2 6 : p. 6 7 7- 7 0 4. 
7 0.  
Kari m, R., et al., T u m or- ex presse d B 7 - H 1 a n d B 7- D C i n rel ati o n t o P D-1 + T -cell 
i nfiltr ati o n a n d s urviv al of p atie nts wit h cervic al c arci n o m a. Cli n Ca ncer Res, 
2 0 0 9. 1 5 ( 2 0): p. 6 3 4 1- 7. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9 0  of 9 4  
 
 
 
 
 
 
 
 
7 1.  
Ta u be, J. M., et al., C ol oc aliz ati o n of i nfl a m m at ory res p o nse wit h B 7- h 1 
ex pressi o n i n h u m a n mel a n ocytic lesi o ns s u p p orts a n a d a ptive resist a nce 
mec h a nis m of i m m u ne es c a pe.  Sci Tra nsl Me d, 2 0 1 2. 4 ( 1 2 7): p. 1 2 7ra 3 7. 
7 2.  
Sa n ma me d, M. F. a n d L. C he n, I n d uci ble ex pressi o n of B 7-H 1 ( P D - L 1) a n d its 
selective r ole i n t u m or sit e i m m u ne m o d ul ati o n. Ca ncer J, 2 0 1 4. 2 0 ( 4): p. 2 5 6- 6 1. 
7 3.  
T o palia n, S. L., C. G. Dra ke, a n d D. M. Par d oll, T ar geti n g t he P D- 1/ B 7 -H 1( P D -L 1) 
p at h w ay t o activ ate a nti-t u m or i m m u nity.  C urr O pi n I m m u n ol, 2 0 1 2. 2 4 ( 2): p. 
2 0 7- 1 2. 
 
 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9 1  of 9 4  
 
 
 
 
 
 
 
 
A p pe n dices 
1 1. 1  E C O G P erf or m a n c e St at u s  
Gr a 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. R estricte d i n p h ysicall y stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht or se 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 a n d ca pa ble of all self -care, b ut u na ble t o 
carr y o ut a n y w or k acti vities. U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.  
3 
I n be d > 5 0 % of t he ti me. Ca p a 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 k i 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 he E aster n C o o per ative O nc ol o gy Gr o u p, R o bert 
C o mis M. D., Gr o u p C h air.  
1 1. 2  C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s V 4. 0 3 ( C T C A E) 
T he desc ri pti o ns a n d gr a di n g scal es f o u n d i n t he re vise d C T C A E v 4. 0 3 will be utilize d 
f or A E  r e p orti n g ( htt p://cte p.ca ncer. g o v/re p orti n g/ ctc. ht ml). 
1 1. 3  I m m u n e R e s p o n s e M o difi c ati o n t o R e s p o n s e E v al u ati o n Crit eri a i n 
S oli d T u m or s (ir R E CI S T) f or E v al u ati n g R e s p o n s e i n S oli d T u m or s  
ir R E CI S T will be use d i n t his st u d y f or assess me nt of t u m or res p o nse.  W hile eit her C T 
or M RI ma y b e utilize d, as per ir R E CI S T, C T is t he preferre d i ma gi n g tec h ni q ue i n t his 
st u d y. 


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9 2  of 9 4  
 
 
 
 
 
 
 
 
1 2  LI S T O F A B B R E VI A TI O N S 
A E  
A d verse e ve nt  
AJ C C T N M  
A merica n J oi nt C o m mittee o n Ca ncer t u m or n o de metastasis sta gi n g 
A L T  
ala ni ne tra nsa mi nase  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A P C  
a nti ge n -prese nti n g cells  
A S T  
as partate tra nsa mi nase  
B C G  
B acille Cal mette -G ueri n  
B O R  
best o verall res p o nse  
 
 
C B C  
c o m plete bl o o d c o u nt  
cf u  
c ol o n y f or mi n g u nit(s)  
C ma x  
Ma xi m u m c o nce ntrati o n  
C mi n  
Mi ni m u m c o nce ntrati o n  
C M P  
C o m pre he nsi ve meta b olic pa nel  
C N S  
ce ntral ner v o us s yste m  
C R  
c o m plete res p o nse  
Cr Cl  
Creati ni ne cleara nce  
C R F  
case re p ort f or m 
C R P  
C -reacti ve Pr otei n 
C T  
c o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
C T L  
c yt ot o xic T l y m p h oc ytes  
D K A  
dia betic ket oaci d osis  or  
D L  
d ose le vel  
D L T  
d ose li miti n g t o xicit y  
E CI  
e ve nt(s) of cli nical i nterest  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
 
 
E R C  
Et hical Re vie w C o m mittee  
E S R  
Er yt hr oc yte se di me ntati o n rate  
E U  
E ur o pea n U ni o n  
 
 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D A A A  
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act  
F D A M A  
F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act  
G F R  
gl o mer ular filtrati o n rate  
H Bs A g  
He patitis B s urface a nti ge n  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H P V  
h u ma n pa pill o ma vir us  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9 3  of 9 4  
 
 
 
 
 
 
 
 
I B 
I n vesti gat or Br oc h ure  
I C H 
I nter nati o nal C o u ncil f or  Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mitte e 
I g 
i m m u n o gl o b uli n 
I N D 
I n vesti gati o nal ne w dr u g 
I N R 
I nter nati o nal n or malize d rati o 
ir A E 
i m m u ne-relate d a d verse e ve nt 
I R B 
I nstit uti o nal Re vie w B oar d  
ir B O R 
i m m u ne-relate d best o verall res p o nse 
ir C R 
i m m u ne-relate d c o m plete res p o nse 
ir E CI 
i m m u ne-relate d e ve nt of cli ni cal i nterest 
ir P D 
i m m u ne-relate d pr o gressi ve disease 
ir P R 
i m m u ne-relate d partial res p o nse 
ir R C 
i m m u ne-relate d res p o nse criteria 
ir R E CI S T 
i m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors 
ir S D 
i m m u ne-relate d sta ble disease 
I TI M 
i m m u n orece pt or t yr osi ne-base d i n hi biti o n m otif  
I T S M 
i m m u n orece pt or t yr osi ne-base d s witc h m otif  
I V 
i ntra ve n o us 
L D H  
lactate de h y dr o ge nase 
L H R H  
l utei nizi n g h or m o ne releasi n g h or m o ne 
L L O  
listeri ol ysi n O 
L m  
Listeri a m o n ocyt o ge nes  
m A b  
m o n ocl o nal a nti b o d y  
m C R P C  
metastatic castrate -resista nt pr ostate ca ncer 
M D S Cs  
m yel oi d -deri ve d s u p press or cells  
M H C  
maj or hist oc o m pati bilit y c o m ple x  
M RI  
ma g netic res o na nce i ma gi n g 
M T D/ M A D  
ma xi m u m t olerate d d ose/ ma xi m u m all o wa ble d ose  
m T PI  
m o difie d t o xicit y pr o ba bilit y i nter val  
N CI  
Nati o nal Ca ncer I nstit ute  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g(s) 
O T C  
o ver t he c o u nter  
P A P  
pr ostatic aci d p h os p hatase  
P B M Cs  
peri p heral bl o o d m o n o n uclear cells  
P C W G 2  
Pr ostate Ca ncer W or ki n g Gr o u p 2  
P D  
pr o gressi ve disease; pr o gra m me d deat h  
P D -L  
pr o gra m me d deat h li ga n d  
P F S  
pr o gressi o n -free s ur vi val  
PI 3 K  
P h os p h oi n ositi de 3 -ki nase  


 
 
Pr ot oc ol A D X S 1 4 2 -0 3, A me n d me nt 8  
C o nfi de ntial  
A D X S 3 1 -1 4 2, P e m br oliz u ma b ( M K -3 4 7 5)  
P a ge 9 4  of 9 4  
 
 
 
 
 
 
 
 
P K  
p har mac o ki netic  
P M D A  
P har mace utical a n d Me dical De vices A ge nc y  
P R  
partial res p o nse  
P S A  
pr ostate s pecific a nti ge n  
P S C A  
pr ostate ste m cell a nti ge n  
P S M A  
pr ostate -s pecific me m bra ne a nti ge n 
P T  
pr ot hr o m bi n ti me  
P T T  
partial t hr o m b o plasti n ti me  
 
 
Q 2 W  
e ver y 2 wee ks  
Q 3 W  
e ver y 3 wee ks  
Q 4 W  
e ver y 4 wee ks  
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 P 2 D  
rec o m me n de d P hase 2 d ose 
S A E  
seri o us a d verse e ve nt 
S D  
sta ble disease 
S O P  
Sta n dar d O perati n g Pr oce d ure  
S u m D  
s u m of t he l o n gest dia meters  
T A  
t u m or assess me nt 
T A As  
t u m or-ass ociate d a nti ge ns  
T F T  
t h yr oi d f u ncti o n test 
T G F β 
tra nsf or mi n g gr o wt h fact or beta 
t L L O 
tr u ncate d listeri ol ysi n O 
T 1 D M  
T y pe 1 Dia betes Mellit us  
T M T B  
t otal meas ura ble t u m or b ur de n 
T N F α 
t u m or necr osis fact or al p ha 
Tre g  
T re g ulat or y cells  
U L N  
u p per li mit of n or mal  
U S( A)  
U nite d States ( of A merica)  
V -t y pe 
varia ble -t y pe 
W B C  
w hite bl o o d cell  
wt  
w il d-t y pe