An Exploratory Study of Nivolumab With or Without Ipilimumab According to the Percentage of Tumoral CD8 Cells in Participants With Advanced Metastatic Cancer
Phase: PHASE2
Conditions: Advanced Metastatic Cancer, Advanced Prostate Cancer
Sponsor: Parker Institute for Cancer Immunotherapy

P r ot oc ol Title:
A n E x pl or at or y St u d y of Ni v ol u ma b wit h or wit h o ut I pili m u ma b Acc or di n g t o
t he Per ce nt a ge of T u m or al C D 8 Cells i n Partici pa nts wit h A d va nce d Metastatic
Ca ncer
P r ot oc ol N u m ber:   PI CI 0 0 2 5
A m e n d m e nt N u m ber : 5
C o m p o u n d N u m ber:
Ni v ol u ma b, I pili m u ma b
S h ort Title:   Tr eat me nt wit h Ni v ol u ma b a n d I pili m u ma b or Ni v ol u ma b Al o ne Acc or di n g t o t he
Per ce nt a ge of T u m or al C D 8 Cells i n A d va nce d Metastatic
Ca ncer
S p o ns or N a m e a n d Le g al Re gist ere d A d dress:   
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y
1 Letter ma n Dri ve
S uite D 3 5 0 0
Sa n Fr a ncisc o, C A 9 4 1 2 9
T el:
4 1 5 -6 1 0 -5 4 6 6
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s): 
I N D N U M B E R: 1 3 8 5 2 0
E u dr a C T N U M B E R: N ot a p plica ble
A p pr o v al D at e:
Fi nal Pr ot oc ol : 0 6 A pril 2 0 1 8
A me n d me nt 1: 2 7 J ul y 2 0 1 8
A me n d me nt 2 :  1 2 J u ne 2 0 1 9
A me n d me nt 3: 0 8 J ul y 2 0 2 0
A me n d me nt 4 :  12 Marc h 2 0 2 1
A me n d me nt 5:  0 2 Fe br uar y 2 0 2 2
C O N FI D E N TI A L
T his d oc u me nt a n d its c o nte nts ar e t he pr o pert y of a n d c o nfi de ntial t o Par ker I nstit ute f or Ca ncer 
I m mu n ot her a p y. A n y u na ut h orize d c o p yi n g or use of t his d oc u me nt is pr o hi bite d.

Ni v ol u ma b, I pili m u ma b – P ar ker I nstit ute f or C a ncer I m m u n ot hera p y
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S P O N S O R A P P R O V A L P A G E
J usti n Fair c hil d
Vice Pr esi de nt, Cli nical De vel o p me nt

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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I N V E S TI G A T O R P R O T O C O L A G R E E M E N T P A G E 
 
I a gr ee: 
•  
T o ass u me r es p o nsi bilit y f or t he pr o per c o n d uct of t he st u d y at t his site.  
•  
T o c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d me nts, a n d wit h 
a n y ot her st u d y c o n d uct pr oce d ures pr o vi de d b y Par ker I nstit ute f or Ca ncer 
I m m u n ot her a p y. 
•  
N ot t o i m ple me nt a n y c ha n ges t o t he p r ot oc ol wit h o ut writte n a gree me nt fr o m Par ker 
I nstit ute f or Ca ncer I m m u n ot hera p y a n d pri or re vie w a n d writte n a p pr o val fr o m t he 
I nstit uti o nal Re vie w B oar d (I R B) or I n depe n de nt Et hics C o m mittee (I E C) e xce pt w here 
necess ar y t o eli mi nate a n i m me diate hazar d t o patie nts.  
•  
T hat I a m t h or o u g hl y f a miliar wit h t he a p pr o priate use of t he st u d y dr u g (s), as descri be d 
i n t his pr ot oc ol a n d a n y ot her i nf or mati o n pr o vi de d b y Par ker I nstit ute f or Ca ncer 
I m m u n ot her a p y i ncl u di n g, b ut n ot li mite d t o, t he c urre nt I n vesti gat or’s Br oc h ure (I B).  
•  
T hat I a m a war e of, a n d will c o m pl y wit h, G o o d Cli nical Practices ( G C P) a n d all 
a p plica ble r e g ulat or y r e q uir e me nts.  
•  
T o e ns ur e t hat all pers o ns assisti n g me wit h t he st u d y are a de q uatel y i nf or me d a b o ut t he 
st u d y dr u gs, t he Par ker I nstit ute f or Ca ncer I m m u n ot hera p y st u d y pr ot oc ol,  a n d of t heir 
st u d y-r elate d d uties a n d f u ncti o ns as descri be d i n t he pr ot oc ol. 
 
 
Si g nat ur e:  
 
 
Date:  
 
 
Na me 
( pri nt): 
 
 
 
 
Site 
N u m ber:  
Pri nci pal I n vesti gat or  
 
_ _ _ _ _ _ _ _ _ _ _  
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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A m e n d m e nt 1: 2 7  J ul y  2 0 1 8  
T e xt r e visi o ns r es ulti n g fr o m t his a me n d me nt are i nc or p orate d i n t he s y n o psis a n d b o d y of 
Pr ot oc ol A me n d me nt 1. Maj or c ha n ges t o t he pr ot oc ol are s u m marize d bel o w.  
Ke y Re visi o ns i n A m e n d m e nt 1  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Eli gi bilit y Crit eri a  
5. 1 I ncl usi o n Criteria  
Re vise d i ncl usi o n crit eri o n # 4 t o cl arif y t hat partici pa nts m ust ha ve a t u m or t hat “is 
res p o nsi ve t o i m m u n o m o d ulati o n (ie, wit h U S Prescri bi n g I nf or mati o n [ U S PI])” 
a n d t hat “ parti ci pa nts w h o ha ve fail e d or ref use d a vail a bl e a p pr o ve d tre at me nt 
o pti o ns are eli gi ble t o partici pate.”  
5. 1 I ncl usi o n Criteria  
Re vise d i ncl usi o n crit eri o n # 5 b t o i n dic at e t hat t he C T C A E versi o n 5. 0 is t o be 
use d t o gra de pri or i m m u ne -rel at e d a d verse e ve nts affe cti n g eli gi bilit y a n d t hat 
parti ci pa nts m ust be off ster oi d t hera p y a n d/ or ot her i m m u n os u p pressi ve t hera p y 
f or ≥ 1 4 da ys p ri or t o st arti n g st u d y i nt er ve nti o n. 
5. 1 I ncl usi o n Criteria  
A d de d i ncl usi o n crit eri o n # 7a t o clarif y t hat “ bi o psies s h o ul d be o bt ai ne d fr o m 
sit es t hat d o n ot p ose si g nifi ca nt ris k t o t he partici pa nt base d o n t he t u m or site a n d 
pr oc e d ure use d. Bi o ps y sites / pr oc e d ures i ncl u di n g, b ut n ot li mite d t o, t he brai n, 
o pe n l u n g/ m e di asti n u m, pa ncre as, or e n d osc o pic pr oce d ures e xte n di n g be y o n d t he 
es o p ha g us, st o m ac h, or b o wel w o ul d be c o nsi dere d t o p ose a si g nific a nt ris k t o t he 
parti ci pa nt. Pr oc e d ures t o are as t hat ar e dee me d b y t he I n vesti gat or t o be of 
n o n‑si g nific a nt ris k base d o n i n di vi d ual cli ni cal sce nari os will be per mitte d. ”  
5. 1 I ncl usi o n Criteria  
Re vise d i ncl usi o n crit eri o n # 1 3 t o i n dic at e t hat “creati ni ne cle ara nce s h o ul d be 
≥ 3 0  m L/ mi n as esti m at e d b y t he C oc kcr oft -Ga ult e q uati o n.”  
5. 1 E xcl usi o n Crit eri a  
Re vise d e xcl usi o n crit eri o n # 3 t o re m o ve refere nce t o “s uc h t hat a bs or pti o n of oral 
m e di cati o n is i m paire d. ”  
5. 1 E xcl usi o n Crit eri a  
Re vise d e xcl usi o n crit eri o n # 5c t o clarif y t he parti ci pa nt m ust be off st er oi ds 
a n d/ or ot her i m m u n os u p pressi ve t hera p y, as tre at me nt f or ir A Es, f or ≥ 3 0 da ys 
fr o m C ycl e 1, Da y 1.  
Safet y Assess me nts  
6. 6  D ose M o difi cati o ns  
( Esc al ati o n/ Titrati o n/ Ot her) 
A d de d t e xt  refere nci n g t he A p pe n di x 8:  Ma na ge me nt Al g orit h ms  f or treat m e nt of 
A Es  rel at e d t o ni v ol u ma b a n d/ or i pili m u ma b 
8. 2 Safet y Assess m e nts  
Re m o ve d refere nc e t o a d verse e ve nts of s pe ci al i nterest ( A E SIs).  
8. 3. 1 Ti m e Peri o d a n d 
Fre q ue nc y f or C olle cti n g 
A E, S A E, a n d Ot her 
Re p ort a bl e Safet y E ve nt 
I nf or mati o n 
Re m o ve d refere nc e t o a d verse e ve nts of s pe ci al i nterest ( A E SIs).  
Cl arifie d w hic h A Es a n d S A Es s h o ul d be re p ort e d pri or t o t he i niti ati o n of st u d y 
i nter ve nti o n a n d h o w ot her me dic al oc c urre nces s h o ul d be ha n dl e d d uri n g pri or t o 
t he i niti ati o n of st u d y i nter ve nti o n. 
A d de d ( b y rel ocati n g te xt fr o m Se cti o n 8. 3. 2) a n d re vise d a para gra p h descri bi n g 
h o w t o ha n dle S A Es oc c urri n g after t he e n d of t he A E re p orti n g peri o d t hat are 
c o nsi dere d t o be reas o na bl y rel at e d t o t he st u d y i nter ve nti o n or st u d y parti ci pati o n.  
I ntro d uc e d t he PI CI S A E Re p orti n g F or m ( S A E R F) as t he a p pr o priate safet y -
relate d pa per f or m f or re p orti n g S A Es t o t he S p o ns or a n d re m o ve d refere nc e t o t he 
pa per c ase re p ort f or m.  
8. 3. 2 F oll o w -u p E ve nt 
Re p orti n g  
Re m o ve d refere nc e t o a d verse e ve nts of s pe ci al i nterest ( A E SIs).  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Cl arifie d t hat all A Es a n d S A Es will be f oll o we d t hr o u g h t he f oll o w u p p hase of 
t he st u d y a n d t hat e ve nts will be f oll o we d u ntil e ve nt res ol uti o n or deat h. 
Re m o ve d refere nc e t o “ pre g na ncies” i n t he 2 n d para gra p h as pre g na nc y is 
c o nsi dere d a n S A E s o it was u n nec essar y t o i ncl u de it.  
M o ve d para gra p h descri bi n g h o w t o ha n dle c ert ai n S A Es t o Se cti o n 8. 3. 1.  
1 0. 5. 3 Rec or di n g A Es a n d 
S A Es  
Re m o ve d refere nc e t o a d verse e ve nts of s pe ci al i nterest ( A E SIs) i n t he se cti o n f or 
“ F oll o w-u p of A Es a n d S A Es.”  
1 0. 5. 4 Re p orti n g of A Es, 
S A Es, a n d Ot her 
Re p ort a bl e Safet y E ve nts 
t o t he S p o ns or 
Re m o ve d refere nc es t o t he pa per C R F a n d S A E pa per f or m a n d a d de d i n 
refere nc es t o t he PI CI S A E R F. 
1 0. 5. 5 A d diti o nal 
Re p orti n g C o nsi derati o ns  
Re m o ve d refere nc e t o a d ve rse e ve nts of s pe ci al i nterest ( A E SIs) i n t he se cti o n f or 
“ A b n or m al Li ver F u ncti o n T ests. ”  
1 0. 8  Ma na ge me nt 
Al g orit h ms  
A d de d A p pe n di x 8  (Ma na ge me nt Al g or it h ms) 
St u d y Desi g n  
4. 1 O verall Desi g n  
A d de d t e xt t o cl arif y t hat w he n t he baseli ne bi o ps y is n ot a de q uate t o o btai n 
i nf or m ati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at m e nt assi g n m e nt, a 
se c o n d baseli ne bi o ps y ma y be o btai ne d if me di call y fe asi ble a n d t he partici pa nt is 
willi n g t o u n der g o a n ot her t u m or bi o ps y.  
8. 7. 2 E nr oll m e nt 
Bi o mar kers  
A d de d t e xt t o cl arif y t hat w he n t he baseli ne bi o ps y is n ot a de q uate t o o btai n 
i nf or m ati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at m e nt assi g n m e nt, a 
se c o n d baseli ne bi o ps y ma y be o btai ne d if me di call y fe asi ble a n d t he partici pa nt is 
willi n g t o u n der g o a n ot her t u m or bi o ps y. 
9. 1 Sa m ple Siz e 
Det er mi nati o n  
A d de d t e xt t o cl arif y tra nsf or m ati o n i n t u m or gr o u p fr o m C D 8 l o w  t o C D 8 hi g h. 
St u d y I nter ve nti o n  
1. 2 Sc he ma  
Re vise d St u d y Sc he ma t o i ncl u de d oses f or ni v ol u m a b + i pili m u ma b f oll o wi n g 
pr o gressi ve disease aft er ni v ol u ma b m o n ot hera p y.  
6. 1 St u d y I nt er ve nti o n(s) 
A d mi nist ere d  
Re vise d t e xt of t he b ullets t o i ncl u de t he d ose a n d sc he d ul e of ni v ol u m a b 
m o n ot hera p y a n d ni v ol u ma b i n c o m bi nati o n wit h i pili m u m a b.  
M o ve d t e xt rel at e d t o re c or di n g A Es  a n d S A Es f or u p t o 1 0 0 da ys p ost -last d ose t o 
Se cti o n 8. 3. 1.  
6. 2 Pre parati o n/ Ha n dli n g/ 
St ora ge/ Ac c o u nta bilit y  
Cl arifie d t hat d ose pre parati o ns are base d o n t he partici pa nt’s wei g ht a n d s h o ul d be 
a dj uste d if t he partici pa nt has a 1 0 % c ha n ge i n c o m paris o n t o t heir i niti al wei g ht. 
Cl arifie d t hat f urt her g ui da nce a n d i nf or mati o n f or fi nal dis p ositi o n of u n use d 
st u d y i nter ve nti o n is pr o vi de d i n t he P har m ac y Ma n uals. 
6. 4 St u d y I nt er ve nti o n 
C o m plia nce  
Re vise d t e xt t o cl arif y t hat st u d y i nt er ve nti o n will be a d mi nist ere d b y “ a ut h ori ze d” 
sit e pers o n nel. 
6. 6. 1 D ose M o difi cati o ns 
wit h Ni v ol u ma b a n d 
I pili m u m a b 
A d de d t e xt t o cl arif y t hat “after a d mi nistrati o n first d ose of i pili m u m a b, t he 
I n vesti gat or ma y det er mi ne ( base d o n cli nic al s y m pt o ms) t he n u m ber of f ut ure 
d oses of i pili m u ma b t he parti ci pa nt will re cei ve, f or a m a xi m u m of 4 d oses. 
Partici pa nts w h o st o p i pili m u ma b d osi n g earl y d ue t o t o xi cities, ma y st art 
ni v ol u ma b m ai nt e na nce (ie, 4 d oses [ 1 2 we e ks] of ni v ol u ma b f oll o wi n g t he first 
d ose).”  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Re m o ve d te x t i n dic ati n g t hat “ h ol di n g of 1 a ge nt a n d n ot t he ot her a ge nt is n ot 
all o we d, ” a n d t hat b ot h dr u gs s h o ul d be hel d “a cc or di n g t o t he re c o m m e n de d d ose 
m o difi cati o ns.”  
7. 1 Disc o nti n uati o n of 
St u d y I nter ve nti o n  
Re vise d t e xt t o cl arif y t hat partici pa nts i n t he  ni v ol u m a b m o n ot hera p y ar m ca n 
de ci de t o e nr oll i nt o t he ni v ol u ma b a n d i pili m u ma b c o m bi nati o n treat m e nt ar m at 
t he ti me of pr o gressi o n. 
St u d y Pr oc e d ures  
1. 3 Sc he d ule of Acti vities  
Re vise d T a ble 1 a n d T a bl e 2 as f oll o ws:  
•  a d de d a c ol u m n f or first f oll o w u p visit t hat i ncl u des assess me nts t o be 
perf or m e d;  
•  re vise d t a bl e he a der t o i ncl u de o nl y st u d y da ys; 
•  cl arifi e d dise ase assess m e nt sc he d ule a cc or di n g t o c ycl e;  
•  re vise d m ulti pl e pr oc e d ure la bels ( Vital si g ns, Cli nic al c he mistry, St o ol 
c oll ecti o n); 
•  re vise d a n d/ or a d de d f o ot n otes (a, b, f, g, h, i, a n d k) t o clarif y a n d/ or el a b orat e 
o n t he st u d y pr oc e d ures a n d ti mi n g.  
5. 4 Scree n Fail ures  
Re vise d se cti o n t o re m o ve se nt e nc e i n dic ati n g t hat “rescree ne d parti ci pa nts s h o ul d 
be assi g n e d t he sa m e parti ci pa nt n u m ber as f or t he i nitial rescree ni n g.”  
Cl arific ati o n of D oc u me nt  
Ge neral Re visi o ns  
D oc u me nt u p date d t o a d dress mi n or t y p o gra p hic al err ors a n d e dit ori al c ha n ges f or 
cl arit y. 
S y n o psis  
A d de d cr oss -refere nc e t o Secti o n 9. 3. 2 (ie, Dat a Re vie w T ea m).  
4. 4 Tre at me nt Be y o n d 
Pr o gressi o n  
Re vise d t e xt i n t he 3 r d para gra p h t o re m o ve refere nce t o i nitial pr o gressi o n “ p ost -
s ur ger y. ”  
7. 1. 1 T e m p orar y 
Disc o nti n uati o n  
Re m o ve d secti o n as it was n ot a p pli ca ble t o t his pr ot oc ol.  
8. 2. 3 Vital Si g n s 
Re arra n ge d t he t e xt i n t his secti o n t o i m pr o ve fl o w.  
8. 2. 5 Cli ni cal Safet y 
L a b orat or y Assess m e nts  
A d de d t e xt t hat cl arif y t hat cli ni cal la b orat or y t ests will be perf or me d “ at t he l ocal 
i nstit uti o n” as descri be d i n t he Sc he d ul e of Acti vities. 
Re vise d t e x t t o i n di cate t hat a n y cli ni call y rel e va nt c ha n ges oc c urri n g d uri n g t he 
st u d y s h o ul d be re c or de d o n t he “a p pr o pri at e e C R F.” 
8. 2. 5. 1 L ocal La b orat or y 
Assess m e nts  
Re vise d T a ble 7 as f oll o ws:  
•  re vise d pr ofil e la bel f or Cli nic al c he mistr y; 
•  a d de d “(eit her i n direct or dire ct)” f oll o wi n g t ot al bilir u bi n  
•  a d de d r o w f or Uri nal ysis 
8. 3. 6 Dise ase -rel at e d 
E ve nts a n d/ or Disease -
relate d O ut c o mes N ot 
Q ualif yi n g as A Es or S A Es  
Re w or de d se cti o n t o clarif y h o w  a n d w he n a n i n vesti gat or s h o ul d re p ort a n e ve nt 
t hat is n ot c o nsi dere d u n derl yi n g pr o gressi o n of disease. 
8. 3. 7 Trial -li miti n g 
T o xicit y  
Re m o ve d it e m # 8 st ati n g t hat “ al o pecia will n ot be c o nsi dere d T O X. ”  
8. 3. 8 A d verse E ve nts of 
S pe cial I nt erest  
Re m o ve d secti o n as it was n ot a p pli ca ble t o t his pr ot oc ol. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
8. 3. 8. 1 S p o ns or C o nta ct 
I nf or mati o n 
Re m o ve d refere nc e t o alter nat e Me dic al M o nit or c o nta ct i nf or m ati o n i n t he st u d y 
m a n ual.  
8. 3. 8. 2 Safet y Re p orti n g 
C o nt acts  
Cl arifie d t he pr ocess f or usi n g a n d s u b mitti n g t he safet y -relate d pa per f or ms. 
8. 4 Tre at me nt of O ver d ose  
M o ve d t he defi niti o n of o ver d ose t o t he start of t he se cti o n f or cl arit y.  
Re m o ve d refere nc e t o cl assifi cati o n of de vi ati o ns i n t he M o nit ori n g Pl a n a n d 
cl arifi e d t hat t he PI is res p o nsi bl e f or re p orti n g pr ot oc ol de viati o ns of o ver d ose t o 
t he I R B/I E C.  
1 0. 1. 6 A d mi nistrati ve 
Str uct ure  
Re m o ve d refere nc e t o P K a nal yses a n d t he a p pli c a ble P K secti o n as t hese are n ot 
a p pli ca ble t o t his pr ot oc ol. 
1 0. 1. 8 S o urce 
D oc u me ntati o n  
A d de d a refere nce t o “ cli ni cal o ut c o me assess m e nt ( C O A)/ patie nt -re p orte d 
o ut c o mes ( P R O)” as t y pes of s o urce d oc u me nts.  
1 0. 5. 2 A d diti o nal E ve nts 
Re p ort e d i n t he Sa m e 
Ma n ner as a n S A E  
A d de d a cr oss -refere nc e t o Secti o n 8. 4 (i e, Tre at me nt of O ver d ose). 
1 0. 6. 4. 2 Fe male 
Partici pa nts w h o Bec o m e 
Pre g na nt  
Re m o ve d refere nc e t o “ or be wit h dra w n fr o m t he st u d y” fr o m t he b ullet descri bi n g 
o ut c o me if a fe m al e partici pa nt be c o me s pre g na nt w hil e partici pati n g. 
1 1 Refere nc es  
A d de d m o nt h t o t he versi o n dat es f or t he O p di v o a n d Yer v o y U S PIs.  
 
A m e n d m e nt 2: 1 2  J u ne 2 0 1 9  
T e xt r e visi o ns r es ulti n g fr o m t his a me n d me nt are i nc or p orate d i n t he s y n o psis a n d b o d y of 
Pr ot oc ol A me n d me nt 2. Maj or c ha n ges t o t he pr ot oc ol are s u m marize d bel o w.  
Ke y Re visi o ns i n A m e n d m e nt 2  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Eli gi bilit y Crit eri a  
5. 1 I ncl usi o n crit eri a  
Cl arific ati o n of la n g ua ge i n crit eri a # 4 t o ali g n t he te xt wit h t he st u d y p o p ul ati o n 
di versit y.  
A d de d a list of t u m or t y pes t hat are i ncl u de d i n t he st u d y.  
5. 1 I ncl usi o n crit eri a  
Re m o ve d state me nt f or criteria # 1 2 b re q uiri n g n o li ver lesi o ns t o ali g n wit h U S PI.  
5. 1 I ncl usi o n crit eri a  
Ali g ne d crit eri a # 1 0 re gar di n g A S T a n d A L T el e vati o ns t o U S PI f or O p di v o ( 3 x 
U L N) a n d re m o ve d l a n g ua ge differe nti ati n g i n di vi d uals wit h li ver lesi o ns ( 1 2a).  
5. 1 I ncl usi o n crit eri a  
Ali g ne d crit eri a # 1 2 re gar di n g t otal bilir u bi n el e vati o ns t o U S PI f or O p di v o ( 1. 5 x 
U L N) a n d re m o ve d l a n g ua ge differe nti ati n g i n di vi d uals wit h li ver lesi o ns. 
Re m o ve d criteria # 1 2 b re q uiri n g n o li ver lesi o ns f or partici pa nts wit h Gil bert 
s y n dr o me. 
5. 1 I ncl usi o n crit eri a  
A d de d l a n g ua ge t o criteria # 1 3 t o all o w f or ot her met h o ds f or  calc ulati n g cre ati ni ne 
cl eara nce be y o n d C oc kcr oft -Ga ult t o ali g n wit h sit e calc ulati o n m et h o ds  
5. 2 E xcl usi o n crit eria  
A d de d l a n g ua ge t o criteria # 8 t o cl arif y c o n diti o ns f or i n vesti gat ors decisi o n 
m a ki n g re gar di n g u nc o ntr olle d ill ness . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
8  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
5. 2 E xcl usi o n crit eria  
Re m o ve d criteria # 9 re gar di n g c ar dia c healt h t o ali g n wit h dr u g m a n ufact urer 
g ui da nce.  
5. 2 E xcl usi o n crit eria  
Cl arific ati o n of la n g ua ge i n crit eri a # 1 2 re gar di n g a ut oi m m u ne diseases t o ali g n 
wit h dr u g ma n ufa ct urer l a n g ua ge.  
5. 2 E xcl usi o n crit eria  
A d de d criteria # 1 3 descri bi n g s yste mic treat m e nt wit h c orti c ost er oi ds or ot her 
i m m u n os u p pressi ve m e dic ati o n li mits as well as use of i n hale d or t o pic al st er oi ds 
i n a bse nc e of acti ve a ut oi m m u ne disease. 
5. 2 E xcl usi o n crit eria  
A d de d l a n g ua ge t o criteria # 1 4a all o wi n g f or re ce nt or c o nc urre nt u nrelate d st u d y 
i nter ve nti o ns t o be a d mi nistere d s o l o n g as t he y are n ot a ntici pate d t o i nt erfere wit h 
t he st u d y wit h per missi o n fr o m t he Me di cal M o nit or. As a n e xc e pti o n t o t his 
re q uire m e nt, a d mi nistrati o n of 8 9Zr -Df -I A B 2 2 M 2 C i n t he c o nt e xt of a PI CI-
s p o ns ore d cli ni cal tri al d oes n ot re q uire writt e n a gree me nt fr o m t he Me dic al 
M o nit or.  
Safet y Assess me nts  
8. 3. 4 Re g ul at or y Re p orti n g 
Re q uire m e nts f or S A Es  
A d de d part ner c o m pa ni es t o list of parti es w h o ma y rec ei ve safet y re p orts 
de pe n di n g o n c o u ntr y -s pecifi c re g ulat or y re q uire m e nts. 
9. 2 P o p ulati o ns f or 
A nal ysis  
Cl arific ati o n safet y p o p ulati o n descri pti o n t o state it will i ncl u de partici pa nts w h o 
ha ve re cei ve d at le ast o ne d ose of st u d y dr u g a n d pr o vi de cl ar ific ati o n o n a nal ysis 
p o p ulati o n defi niti o ns.  
9. 3. 1. 1 Safet y M o nit ori n g  
U p date d t he safet y m o nit ori n g ass u m pti o n s o t hat t he “st a n dar d t hera p y” is 4 0 % 
i nst ea d of 3 0 % base d o n pre vi o us dat a f or t he dr u g c o m bi nati o n. Ta bl e 1 0 was 
u p date d t o refle ct t his c ha n ge i n t he “st a n dar d t hera p y” T O X rat e ass u m pti o n.  
9. 3. 1. 3 J oi nt O perati n g 
C hara cteristics f or Safet y 
a n d F utilit y M o nit ori n g 
U p date d Ta ble 1 1 t o reflect t he c ha n ge i n safet y m o nit ori n g ass u m pti o n i n Secti o n 
9. 3. 1. 1.  
9. 3. 2 Data Re vi e w Te a m  
Re m o val of sec ti o n. Gi ve n t he well-est a blis he d safet y pr ofile of ni v ol u m a b as a 
si n gl e a ge nt, a n d i n c o m bi nati o n wit h i pili m u m a b, a f or m alize d Data Re vi e w Te a m 
was dee m e d u n ne cessar y. T he S p o ns or will c o nti n ue t o m o nit or pati e nt safet y 
cl osel y via re al -ti me re vi e w of S AEs as t he y are rec ei ve d, a n d peri o di c re vie w of 
a g gre gat e safet y dat a. A d h oc me eti n gs will be hel d i n t he e ve nt t hat a p ot e ntial 
safet y c o ncer n is i de ntifie d. 
A n ote of t his has bee n a d de d t o t he S y n o psis u n der Safet y a n d F utilit y M o nit ori n g.  
9. 4. 1 Effica c y A nal yses  
U p date d l a n g ua ge t o cl arif y defi niti o n of t he st u d y p o p ulati o n a n d clarif y w hi c h 
a nal ysis p o p ulati o ns will be use d f or ea c h effic ac y a nal ysis.  
9. 4. 2 Safet y A nal yses  
Cl arific ati o n of t he st u d y p o p ulati o n defi niti o n t o ali g n wit h Se cti o n 9 . 2 a n d 
re m o val of la n g ua ge t hat was d u plic at e d fr o m Secti o n 9. 3. 1. 1. 
St u d y Desi g n  
1. 1 S y n o psis  
Cl arific ati o n of st u d y p o p ulati o n di versit y d uri n g e nr oll m e nt t o e nric h f or C D 8 
hi g h t u m ors.  
4. 1 St u d y Desi g n  
Cl arific ati o n of ti mi n g f or a sec o n d bi o ps y w he n partici pa nt is o n treat m e nt  
8. 7. 1 Ge netics  
Re m o ve d la n g ua ge i n dic ati n g use of F ut ure Bi o me dic al Researc h c o nse nt. T his has 
be e n i nc or p orat e d i nt o t he c urre nt i nf or m e d c o nse nt.  
8. 7. 3 C D 8 a n d E x pl orat or y 
Bi o mar kers  
A d de d l a n g ua ge t o all o w f or b i o psies t hat oc c ur wit hi n a 3 0 da y wi n d o w of c o nse nt 
t o be use d f or t he e nr oll m e nt bi o ps y. A d diti o nall y, if t he bi o ps y is o utsi de of t he 
3 0  da y wi n d o w, Me dic al M o nit or a p pr o val will be ne e de d. T his is t o all o w 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
9  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
parti ci pa nts t o n ot ha ve t o u n der g o m ulti pl e b i o psi es i n cl ose s ucc essi o n if n ot 
ne cessar y.  
1 0. 1. 4 I nf or m e d C o nse nt  
A d de d l a n g ua ge re gar di n g re -c o nse nt p oli c y w he n rescree ni n g is be y o n d 3 0 da ys 
fr o m C 1 D 1 a n d if t he I nstit uti o n p olic y differs fr o m t hat of Par ker t hat Par ker 
a cc e pts t his p oli c y. 
St u d y I nter ve nti o n  
1. 3 Sc he d ule of Acti vities  
Re vise d l a n g ua ge f or f o oter l t o matc h Secti o n 8. 3. 1 wit h c oll e cti o n of A Es a n d 
S A Es t o 1 0 0 da ys after t he l ast d ose of st u d y i nter ve nti o n.  
6. 1 St u d y I nt er ve nti o n(s) 
A d mi nist ere d  
A d de d wi n d o ws f or a d mi nistrati o n i n te xt t o m at c h wit h t he Sc he d ul e of Acti vities 
a d mi nistrati o n wi n d o ws a n d clarif y t hat partici pa nts w h o se e cli ni cal be nefit will 
m o ve t o ni v ol u ma b mai nt e na nc e d oses.  
6. 5. 1 Per mitt e d T hera p y  
A d de d Se cti o n 6. 5. 2 t o t he se cti o ns c o nt ai ni n g e xcl u de d me di c ati o ns. 
6. 5. 2 Pr o hi bite d T hera p y  
Cl arific ati o n of la n g ua ge f or c o nc urre nt t hera pi es t o all o w f or use of h or m o nal 
t hera p y wit h Me dic al M o nit or a p pr o val at e ntr y. 
6. 5. 2 Pr o hi bite d T hera p y  
Re vise d wi n d o w f or rec ei vi n g li ve vac ci nes t o 1 0 0 da ys  p ost l ast d ose of st u d y 
i nter ve nti o n. 
6. 5. 2 Pr o hi bite d T hera p y  
Pr o vi de d clarifi cati o n re gar di n g her bal a n d nat ural re m e di es all o wi n g f or use of 
m arij ua na a n d deri vati ves f or treat m e nts of c a nc er or c a nc er treat m e nt -rel at e d 
s y m pt o ms. 
7. 1 Disc o nti n uati o n of 
St u d y I nter ve nti o n  
Cl arific ati o n of la n g ua ge relate d t o d ose -li miti n g t o xiciti es a n d d ose re d ucti o ns. 
St u d y Pr oc e d ures  
1. 3 Sc he d ule of Acti vities  
Re vise d T a ble 1 a n d T a bl e 2 as f oll o ws:  
•  Re m o ve d assess m e nt at C 1 D 1 5 as it is n ot re q uire d f or s uffici e nt safet y 
assess m e nt 
•  S plit f o ot n ot e f or f oll o w -u p peri o d bet we e n first visit i nf or mati o n a n d s u bse q ue nt 
c oll ecti o ns 
•  A d de d i n c olle cti o n of I nf or me d C o nse nt d uri n g t he scre e ni n g peri o d  
•  Re vise d l a n g ua ge f or f o oter l t o matc h Secti o n 8. 3. 1 wit h c oll e cti o n of A Es a n d 
S A Es t o 1 0 0 da ys after t he l ast d ose of st u d y i nter ve nti o n  
•  A d de d f o ot n ote t o me dic al hist or y i n dic ati n g c oll ecti o n of pri or c a ncer t hera pi es 
a n d pr oce d ures 
•  A d de d f o ot n ote f or vital si g ns t hat p ulse o xi m etr y will o nl y be c oll ect e d at 
baseli ne  
•  A d de d f o ot n ote t o t u m or mar kers i n dic ati n g t he t y pes of m ar kers t hat m a y be 
c oll ect e d 
•  Cl arific ati o n of f o ot n ot e f or t he A E, S A E, a n d all c o nc o mit a nt m e di cati o n 
c oll ecti o n peri o d aft er c o nse nt a n d w here trial li miti n g t o xi citi es ca n be f o u n d i n 
t he pr ot oc ol b o d y 
•  A d de d assess me nt of s u bse q ue nt c a ncer t hera p y t o p ost -tre at m e nt c oll ecti o ns 
•  A d de d l a n g ua ge t o cl arif y t hat a 2 n d , o n tre at me nt bi o ps y m a y be o bt ai ne d f or 
eit her ar m if t he res ults fr o m t he pre vi o us are n ot a de q uate t o o btai n t he 
perce n ta ge of t u m oral C D 8 cells 
•  A d de d hea der t o clarif y w hat c ycles are O n -St u d y E val uati o n a n d w hi c h are t he 
ni v ol u ma b m ai nt e na nce peri o d  
8 St u d y Assess me nts a n d 
Pr oc e d ures  
Cl arific ati o n of la n g ua ge relate d t o mi ni m u m ti mi n g bet wee n d oses f or Q 3 W a n d 
Q 4 W sc he d ule. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
8. 1 Effi ca c y Assess me nts  
Cl arific ati o n of la n g ua ge relati n g t o  g ui da nce o n w het her n o n -c o ntrast C T vs M RI 
s h o ul d be use d f or vari o us a nat o mi cal l oc ati o ns i n t he case of a d ye all er g y. 
8. 1. 1 L a b orat or y 
Assess m e nts of T u m or 
Mar kers  
A d de d s u b -secti o n i n di cati n g t he t y pes of t u m or mar kers t hat ma y be c olle ct e d a n d 
se nt t o l oc al l a b orat ories f or a nal ysis as part of sta n dar d of care. 
8. 2. 3 Vital Si g ns  
Re m o ve d re q uire m e nt f or parti ci pa nts t o rest 1 0 mi n ut es pri or t o re c or di n g vit al 
si g ns. 
8. 2. 3 Vita l Si g ns 
Re vise d wi n d o w f or me as ure m e nt of vitals t o be 0 -2 0 mi n ut es pri or t o i nf usi o n.  
8. 2. 3 Vital Si g ns  
Re m o ve d p ulse o xi m etr y fr o m e ver y c oll ecti o n a n d o nl y t o be c oll ecte d at baseli ne.  
8. 2. 5. 1 L ocal La b orat or y 
Assess m e nts  
A d de d i n testi n g f or t h yr oi d sti m ulati n g h or m o ne ( T S H), trii o d ot h yr o ni ne ( T 3), 
fre e trii o d ot h yr o ni ne ( F T 3), free t h yr o xi ne ( F T 4), a n d li pase i n T a bl e 7. Cl arifi e d 
t otal bilir u bi n i ncl u de d eit her i n direct or dire ct 
8. 3. 1 Ti m e Peri o d a n d 
Fre q ue nc y f or C olle cti n g 
A E, S A E, a n d Ot her 
Re p ort a bl e Safet y E ve nt 
I nf or mati o n 
Re m o ve d la n g ua ge i n dic ati o n c oll ecti o n peri o d c o ul d g o u ntil i niti ati o n of ne 
s yst e mi c a ntic a ncer t hera p y. C oll ecti o n will g o fr o m si g ni n g of c o nse nt u ntil 1 0 0 
da ys after t he l ast d ose re gar dless of a ne w s yste mi c a n tic a ncer t hera p y. T his als o 
ali g ns t o t he f o ot n ot e i n t he Sc he d ule of Acti vities.  
8. 3. 1. 1 E ve nts Re q uiri n g 
E x pe dite d Re p orti n g t o t he 
S p o ns or  
A d de d l a n g ua ge t hat e ve nts m ust re p orte d o n a S A E Re p ort F or m wit hi n 2 4 of 
be c o mi n g a ware of t he e ve nt.  
8. 3. 6 Di se ase-rel at e d 
E ve nts a n d/ or Disease -
Relate d O ut c o mes N ot 
Q ualif yi n g as A Es or S A Es  
A d de d l a n g ua ge cl arif yi n g t hat S A Es m ust be re p ort e d wit h 2 4 h o urs of bec o mi n g 
a ware of t he e ve nt. 
8. 3. 8. 1 E mer ge nc y 
Me dic al C o nta cts  
U p date d Pri mar y Me di cal M o nit or t o Mar k o S pasic per A d mi nistrati ve C ha n ge 
N otificati o n  
1 0. 6. 3 Pre g na nc y T esti n g  
Re vise d fre q ue nc y of a d diti o nal pre g na nc y t esti n g t o state t he y will oc c ur e ver y 
c ycl e a n d wit hi n 2 4 h o urs pri or t o d osi n g, ali g ni n g t o w hat is st at e d i n t he Sc he d ul e 
of Acti viti es.  
Cl arific ati o n of D oc u me nt  
Ge neral Re visi o ns  
D oc u me nt u p date d t o a d dress mi n or t y p o gra p hic al err ors a n d e dit ori al c ha n ges f or 
cl arit y. 
C ha n ge usa ge of S A E R F a b bre vi ati o n t o S A E Re p ort F or m t hr o u g h o ut t o refl ect 
i nter nal na mi n g f or t he f or m. 
1 . 2 Sc he ma 
U p date d sc he ma f or st u d y, se parati n g o ut t he t w o ar ms of t he st u d y.  
8. 3. 7 Trial -li miti n g 
T o xicit y  
U p date l a n g ua ge t o be m ore i ncl usi ve as t o e ve nts t hat l ea d t o tri al -li miti n g t o xi cit y 
1 0. 1. 2 I nstit uti o nal Re vie w 
B oar d or I n de pe n de nt 
Et hi cs C o m mitte e  
Cl arifie d w h o t he I R B of Re c or d ( M D A n ders o n) is f or t he st u d y a n d w h o are t he 
Rel yi n g I R Bs ( U C L A, U C S F, St a nf or d, D F CI, a n d M S K C C) as well as t hat Par ker 
m ai ntai ns i nf or mati o n rel ati n g t o t hese i nstit uti o ns i n se parate d oc u m e nt ati o n.  
1 0. 6. 2. 1 Male Partici pa nts  
U p date d l a n g ua ge f or c o ntra ce pti o n g ui da nc e f or male partici pa nts t o i n dic at e 
m et h o ds ot her t ha n a bsti ne nc e t hat are ac ce pt a bl e t o use.  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 1  
A m e n d m e nt 3: 0 8  J u l y 2 0 2 0  
T e xt r e visi o ns r es ulti n g fr o m t his a me n d me nt are i nc or p orate d i n t he  s y n o psis a n d b o d y of 
Pr ot oc ol A me n d me nt 3 . Maj or c ha n ges t o t he pr ot oc ol are s u m marize d bel o w. 
Ke y Re visi o ns i n A m e n d m e nt 3  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Eli gi bilit y Crit eri a  
5. 1 I ncl usi o n crit eri a  
A d de d criteria  s pe cific t o partici pa nts wit h a d va nce d pr ostate ca ncer (criteria 
# 1 7 -2 1 ). 
5. 1 I ncl usi o n crit eri a  
U p date d  crit eri o n # 8 t o differe ntiat e t h ose partici pa nts e nr olle d bef ore 
A m e n d m e nt 3 a n d t h ose e nr olle d u n der  A m e n d me nt 3.  
5. 2 E xcl usi o n crit eria  
U p date d crit eria # 1 t o clarif y t hat t he use of a nest hesia  f or reas o ns ot her t ha n 
ge neral a nest hesia d uri n g bi o psies, p atie nt c o m f ort a n d or safet y, are t o be 
e xcl u de d. 
Safet y Assess me nts  
6. 6  D ose M o difi cati o ns 
( Esc al ati o n/ Titrati o n/ Ot her) 
U p date Ma na ge m e nt al g orit h ms f or t he st u d y i nt er ve nti o ns t o be i n li n e wit h t he 
c urre nt I n vesti gat or’s Br oc h ures. 
8. 1. 1 L a b orat or y 
Assess m e nts  of T u m or 
Mar kers  
A d de d  l a n g ua ge re q uiri n g c olle cti o n of P S A f or parti ci pa nts e nr oll e d u n der 
A m e n d m e nt 3.  
9. 1  Sa m ple Siz e 
Det er mi nati o n  
A d de d i nf or mati o n o n ar ms c o ntai ni n g a d va nc e d pr ost at e ca nc er parti ci pa nts a n d 
T a bl e 1 2 : Credi ble i nter vals f or C D 8 C o n versi o n.  
9. 2 P o p ulati o ns f or A nal ysis  U p date d p o p ul ati o ns  i n Ta ble 13 : 
•  
Re na me d Pri mar y A nal ysis P o p ulati o n t o M o difi e d I nt e nt -t o-Treat 
(mI T T) P o p ulati o n . 
•  
Safet y P o p ul ati o n  will be a nal yz e d ac c or di n g t o st u d y i nt er ve nti o n 
a ct uall y rec ei ve d . 
•  
mI T T P o p ulati o n will be a nal yz e d a cc or di n g t o t he st u d y i nter ve nti o n 
re cei ve d. 
•  
O n -treat m e nt Bi o ps y P o p ul ati o n will be parti ci pa nts wit h at le ast 1 o n-
treat m e nt  bi o ps y wit h s uffi ci e nt C D 8 res ults.  
9. 4 St atisti cal A nal yses  
U p date d l a n g ua ge t o i n dic ate t he statistic al a nal ysis pla n  c o m ple me nts t he 
pr ot oc ol a n d s u perse des it i n case of differe nces.  
9. 4. 1 Effica c y A nal yses  
Cl arific ati o n of la n g ua ge a n d i n di cati o n t hat partici pa nts will be a nal yze d 
a cc or di n g t o t he st u d y i nt er ve nti o n t o w hic h t he  partici pa nts  were assi g ne d . 
A d de d e x pl orat or y e n d p oi nt f or P S A c ha n ges fr o m baseli ne.  
9. 4. 2 Safet y A nal yses  
Cl arifie d t hat partici pa nts will be a nal yze d a cc or di n g t o t he st u d y i nt er ve nti o n 
a ct uall y rec ei ve d. A Es  will be  descri be d b y gra de a n d attri b uti o n f or ea c h st u d y 
i nter ve nti o n. 
1 0. 8 Ma na ge me nt 
Al g orit h ms  
U p date d t he Ma na ge m e nt Al g orit h ms t o ali g n wit h t he c urre nt I n vesti gat or’s 
Br oc h ures.  
St u d y Desi g n  
1. 1 S y n o psis  
•  
U p date d l a n g ua ge t o descri be a d va nc e d pr ost at e  ca ncer partici pa nt ar ms 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 2  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
•  
U p date d O bj ecti ve a n d e n d p oi nts t a bl e t o ali g n wit h Secti o n 3  
3  O bje cti ves a n d E n d p oi nts  
•  
U p date d  O bj ecti ves a n d E n d p oi nts t o i ncl u de s pe cific l a n g ua ge f or a d va nce d 
pr ost at e ca ncer p o p ul ati o n  
•  
Cl arific ati o n of e n d p oi nt t o be use d f or all p o p ulati o ns  
4. 1. 1 St u d y Desi g n  
A d de d a d diti o nal re q uire me nts f or bi o psi es f or partici pa nts i n t he a d va nce d 
pr ost at e ca ncer ar m s 
6. 3. 1 I nt er ve nti o n 
Assi g n m e nt  
A d de d l a n g ua ge s pecif yi n g t he a d va nc e d metastatic ca ncer partici pa nts are  n ot 
f or mall y ra n d o miz e d t o a treat m e nt re gi me n b ut t hat parti ci pa nts e nt eri n g wit h  
a d va nce d pr ost at e c a nc er, i n t he ne w c o h orts, will be ra n d o ml y all ocate d t o 1 of 
2  tre at me nt c o h orts. 
St u d y I nter ve nti o n  
4. 3. 2  Rati o nale f or 
Ni v ol u m a b a n d I pili m u m a b 
C o m bi nati o n T hera p y D ose 
a n d Sc he d ule  ( A d va nc e d 
Met ast ati c Ca ncer)  
U p date d hea der t o differe ntiate fr o m ne w c o h orts  
4. 3. 2. 1  Rati o nal e f or 
Ni v ol u m a b a n d I pili m u m a b 
C o m bi nati o n T hera p y D ose 
a n d Sc he d ule ( A d va nc e d 
Pr ost ate Ca nc er C o h orts A 
a n d B) 
A d de d se cti o n of c o m bi nati o n t hera p y t o be use d f or a d va nce d pr ost at e 
parti ci pa nts i n t he C D 8 l o w  a n d C D 8 hi g h ar m s. 
6. 1 St u d y I nt er ve nti o n(s) 
A d mi nist ere d  
T a bl e 1: Cl arifie d d osa ge l e vels f o r a d va nc e d m et astati c ca ncer  parti ci pa nts a n d 
a d de d i nf or m ati o n o n i nt er ve nti o ns s pecifi c t o parti ci pa nts wit h a d va nc e d pr ost at e 
c a nc er 
A d de d t he i nter ve nti o n s pe cifics f or t he parti ci pa nts wit h a d va nce d pr ostate c a nc er 
i n b ot h t he C D 8 hi g h a n d C D 8 l o w ar ms. S pe cifie d t he 2 c o h orts wit hi n t he C D 8 
l o w ar m a n d t he differe nt i nter ve nti o ns t hat will be gi ve n i n e ac h. 
6. 5. 2 Pr o hi bite d T hera p y  
A d de d clarific ati o n parti ci pa nts re cei vi n g a n dr o ge n de pri vati o n t hera p y a n d b o ne 
stre n gt he ni n g t hera pies will be all o we d t o parti ci pat e  
6. 6. 1. 1 D ose M o dific ati o ns 
a n d T o xi cit y Ma na ge me nt 
f or A d verse E ve nts 
Ass oci at e d wit h Ni v ol u ma b 
wit h or wit h o ut I pili m u m a b  
U p date d Ta ble 7 t o be t o xi cit y ma na ge m e nt re q uire me nts i nst e a d of g ui deli nes f or 
parti ci pa nt e nr olle d u n der A m e n d me nt 3 o nl y a n d a d de d f o ot n ot e a b bre vi ati o ns  
6. 6. 1. 2  D ose M o dific ati o ns 
a n d T o xi cit y Ma na ge me nt 
f or I nf usi o n-relate d 
Re acti o n Ass ociate d wit h 
Ni v ol u m a b wit h or wit h o ut 
I pili m u m a b 
U p date d Ta ble 8  t o c o ntai n c urre nt d ose m o difi cati o n a n d t o xi cit y ma na ge m e nt 
g ui deli nes f or i nf usi o n rea cti o ns . 
6. 6. 1. 4 A d diti o n al Safet y 
Pre c a uti o ns ( A d va nc e d 
Pr ost ate Ca nc er C o h ort  
O nl y)  
A d de d se cti o n re gar di n g a safet y pa use a n d disc o nti n uati o n crit eria f or t he ne w 
a d va nce d pr ost at e c o h orts.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
7. 2 Parti ci pa nt 
Disc o nti n uati o n/ Wi t h dra wal 
fr o m St u d y 
•  
U p dates  t he ti mi n g f or f oll o w-u p  assess m e nts t o s pe cif y ra di o gra p hi c 
pr o gressi o n or start of s u bse q ue nt t hera p y . 
•  
A d de d all o wa nce f or c oll ecti o n of a d h oc sca ns f or partici pa nts w h o 
disc o nti n ue f or reas o ns ot her t ha n ra di o gra p hi c dise ase  pr o gressi o n o r pri or t o 
alter nati ve t hera pies. 
St u d y Pr oc e d ures  
1. 3 Sc he d ule of Acti vities  
•  
A d de d sc he d ules f or a d va nce d pr ostate c a nc er p o p ulati o n C D 8 hi g h a n d l o w  
ar ms 
•  
Cl arifie d t hat cf D N A is t o be c olle ct e d prei nf usi o n  
•  
U p date d disease  assess m e nt l a n g ua ge t o i ncl u de all p ossi ble re as o ns f or 
st o p pi n g c oll ecti o n as well as all o wa nc e of c olle cti o n of a d h oc sc a ns 
•  
De c o u pl e d disease assess me nt fr o m c ycles  d ue t o t he c ha n ge i n c olle cti o n 
l a n g ua ge 
8. 2. 5. 1 L ocal La b orat or y 
Assess m e nts  
U p date d Ta ble 9 T S H la b orat or y c oll ecti o ns t o s pe cif y a d diti o nal c olle cti o ns ( F T 3 
a n d F T 4) will o nl y oc c ur w he n T S H is a b n or m al  a n d re m o ve d c olle cti o n of T 3 
c oll ecti o n. 
8. 7 Bi o m ar kers  
A d de d l a n g ua ge s pecif yi n g baseli ne  bi o psies will be a de q uate f or C D 8 I C H 
t esti n g w he n t he y c o nt ai n > 2 0 % t u m or n uclei  a n d m a y n ot a p pl y t he sa me t o o n -
treat m e nt bi o psies. 
Cl arific ati o n of D oc u me nt  
Ge neral Re visi o ns  
D oc u me nt u p date d t o a d dress mi n or t y p o gra p hic al err ors a n d e dit ori al c ha n ges f or 
cl arit y. 
1. 2 Sc he ma  
U p date d sc he ma f or st u d y : 
•  
A d d e d t w o ar ms f or a d va nce d pr ostate c a nc er 
•  
U p date d  f o ot n otes f or all sc he m a 
2. 2. 3  I m m u ne C he c k p oi nt 
I n hi bit or T hera pies i n t he 
Treat m e nt of Metast atic 
Castrati o n -resist a nt Pr ost at e 
Ca ncer  
A d de d se cti o n s pe cific t o a d va nce d pr ostate c a ncer.  
1 1  Refere nc es  
A d de d ne w refere nces ass ociate d wit h a d de d ba c k gr o u n d t e xt.  
 
A m e n d m e nt 4: 1 2  M arc h  2 0 2 1  
T e xt r e visi o ns r es ulti n g fr o m t his a me n d me nt are i nc or p orate d i n t he s y n o psis a n d b o d y of 
Pr ot oc ol A me n d me nt 4 . Maj or c ha n ges t o t he pr ot oc ol are s u m marize d bel o w. 
Ke y Re visi o ns i n A m e n d m e nt 4  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Safet y Assess me nts  
9. 4 St atisti cal A nal yses  
A d de d ne w e x pl orat or y e n d p oi nts f or A pri cit y Car e ™ pati e nt r e p ort e d o ut c o mes 
(P R O ) Researc h . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
St u d y I nter ve nti o n  
6. 6. 1. 1 D ose M o dific ati o ns 
a n d T o xi cit y Ma na ge me nt 
f or A d verse E ve nts 
Ass oci at e d wit h Ni v ol u ma b 
wit h or wit h o ut I pili m u m a b 
U p date d Ta ble 7 fr o m C T C A E versi o n 4 t o  C T C A E v ersi o n 5  
St u d y Desi g n  
3 O bje cti ves a n d E n d p oi nts  
U p date d O bj ecti ves a n d E n d p oi nts t o i ncl u de s pe cific l a n g ua ge f or A pri cit y Care ™ 
P R O Rese arc h  
St u d y Pr oc e d ures  
1. 3 Sc he d ule of Acti vities  
A d de d sc he d ule d assess me nts f or a d va nc e d pr ost at e ca ncer patie nts w h o o pt -i n t o 
A pricit y Car e ™ P R O  
8. 8  Pati e nt -Re p ort e d 
O ut c o m es Rese arc h  
Ne w Secti o n a d de d  
Cl arific ati o n of D oc u me nt  
Ge neral Re visi o ns  
D oc u me nt u p date d t o a d dress mi n or t y p o gra p hic al err ors a n d e dit ori al c ha n ges f or 
cl arit y. 
1 0. 8 Ma na ge me nt 
Al g orit h ms  
A p pe n di x 8  has be e n u p date d fr o m C T C A E versi o n 4. 0 t o C T C A E versi o n 5. 0  
 
A m e n d m e nt 5 : 0 2 F e br u ar y  2 0 2 2  
T e xt r e visi o ns r es ulti n g fr o m t his a me n d me nt are i nc or p orate d i n t he s y n o psis a n d b o d y of 
Pr ot oc ol A me n d me nt 5 . Maj or c ha n ges t o t he pr ot oc ol are s u m marize d bel o w. 
Ke y Re visi o ns i n A m e n d m e nt 5  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
Safet y  
6. 6. 1. 4 A d diti o nal Safet y 
Pre c a uti o ns ( A d va nc e d 
Pr ost ate Ca nc er O nl y)  
U p date d t he t e xt t o s pe cif y t he safet y criteria t hat w o ul d all o w a d diti o nal 
parti ci pa nts t o be e nr oll e d i n Pr ostate C o h ort B or Pr ostate C o h ort A , as well as 
t he criteria t hat w o ul d res ult i n s us pe nsi o n of e nr oll me nt. 
A p pe n di x 5  
1 0. 5. 1. 1  Defi niti o n of A E  
Cl arifie d t hat la borat or y  a b n or m aliti es are t o be re p ort e d as A Es o nl y if felt t o be 
cli ni call y si g nific a nt/rele va nt b y t he In vesti gat or.   
St u d y I nter ve nti o n  
S y n o psis  
U p date d st u d y pla n f or ni v ol u m a b a n d i pili m u m a b c o m bi nati o n t hera p y f or 
parti ci pa nts wit h a d va nc e d pr ost at e ca ncer wit h C D 8 l o w t u m ors i n dic ati n g t hat 
a p pr o xi matel y 1 0 parti ci pa nts will be ra n d o ml y all ocate d t o 1 of 2 c o h orts.  
Cl arifie d t hat if Pr ostate C o h ort B is det er mi ne d t o ha ve a t olera bl e safet y pr ofile, 
a n a d diti o nal 1 0 parti ci pa nts will be e nr olle d t o rec ei ve ni v ol u m a b 1 m g/ k g Q 3 W 
a n d i pili m u m a b 5 m g/ k g Q 6 W f or 2 c ycl es, t he n ni v ol u m a b m ai nte na nce 4 8 0 m g 
Q 4 W u ntil P D or i nt olera ble t o xicit y . If t he safet y pr ofile of Pr ost ate C o h ort B is 
de e m e d u na cc e pta ble, a n a d diti o nal 1 0 parti ci pa nts will be e nr olle d i n Pr ostate 
C o h ort A.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 5  
Se cti o n # a n d N a me  
Desc ri pti o n of C h a n ge  
6. 3. 1 I nt er ve nti o n 
Assi g n m e nt  
U p date d st u d y pla n f or  ni v ol u m a b a n d i pili m u m a b c o m bi nati o n t hera p y f or 
parti ci pa nts wit h a d va nc e d pr ost at e ca ncer wit h C D 8 l o w t u m ors t hat 
a p pr o xi matel y 1 0 parti ci pa nts will be ra n d o ml y all ocate d t o 1 of 2 c o h orts.  
Cl arifie d t hat if Pr ostate C o h ort B is det er mi ne d t o ha ve a t olera bl e safet y pr ofile, 
a n a d diti o nal 1 0 parti ci pa nts will be e nr olle d t o rec ei ve ni v ol u m a b 1 m g/ k g Q 3 W 
a n d i pili m u m a b 5 m g/ k g Q 6 W f or 2 c ycl es, t he n ni v ol u m a b m ai nte na nce 4 8 0 m g 
Q 4 W u ntil P D or i nt olera ble t o xicit y . If t he safet y pr ofile of Pr ost ate C o h ort B is 
de e m e d u na cc e pta ble, a n a d diti o nal 1 0 parti ci pa nts will be e nr o lle d i n Pr ostate 
C o h ort A.  
St atistic al C o nsi derati o ns  
9. 1 Sa m ple Siz e 
Det er mi nati o n  
U p date d t he statistic al c o nsi derati o ns, i ncl u di n g re visi o ns t o T a bl e 1 2,  f or t he 
c ha n ge i n sa m ple si ze f or t he parti ci pa nts wit h a d va nc e d pr ost ate c a nc er wit h C D 8 
l o w t u m ors. 
St u d y Pr oc e d ures  
1. 3 Sc he d ule of Acti vities  
M o difie d f o ot n ote c t o i n di cate d t hat partici pa nts will be c o nt a ct e d f or s ur vi val 
st at us f or a ma xi m u m of 2 ye ars fr o m t he last d ose. 
Cl arific ati o n of D oc u me nt  
Ge neral Re visi o ns  
D oc u me nt u p date d t o a d dress mi n or t y p o gra p hic al err ors a n d e dit ori al c ha n ges f or 
cl arit y. 
8. 3. 8. 1 S p o ns or C o nta ct 
I nf or mati o n 
U p date d Me di cal M o nit or  na m e  a n d c o nt act i nf or mati o n a n d re m o ve d refere nce t o 
alter nate Me dic al M o nit or c o nt act i nf or mati o n . 
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 6  
T A B L E O F C O N T E N T S  
 
T a ble of C o nte nts  ...................................................................................................................... 1 6  
List of T a bles  ............................................................................................................................ 2 1  
List of Fi g ur es  ........................................................................................................................... 2 2  
1  
Pr ot oc ol S u m mar y  ............................................................................................................ 2 3  
1. 1  
S y n o psis  .................................................................................................................. 2 3  
1. 2  
Sc he ma  .................................................................................................................... 2 5  
1. 3  
Sc he d ule of Acti vi ties .............................................................................................. 3 0  
2  
I ntr o d ucti o n ...................................................................................................................... 4 3  
2. 1  
St u d y Rati o nale  ....................................................................................................... 4 3  
2. 2  
Bac k gr o u n d  ............................................................................................................. 4 3  
2. 2. 1  
I m m u ne C hec kp oi nt I n hi bit ors  ..................................................................... 4 3  
2. 2. 2  
Bi o mar kers t o Pr e dict Be nefit fr o m Treat me nt wit h I m m u ne C hec k p oi nt 
I n hi bit ors ...................................................................................................... 4 4  
2. 2. 3  
I m m u ne C hec k p oi nt I n hi bit or T hera pies i n t he Treat me nt of A d va nce d 
Pr ostate Ca ncer  ............................................................................................ 4 7  
2. 3  
Be nefit/ Ris k Assess me nt  .......................................................................................... 4 9  
3  
O bjecti ves a n d E n d p oi nts  ................................................................................................. 5 1  
4  
St u d y Desi g n  .................................................................................................................... 5 2  
4. 1  
O ver all Desi g n  ......................................................................................................... 5 2  
4. 1. 1  
A d va nce d Pr ostate Ca ncer  ............................................................................ 5 3  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ...................................................................... 5 4  
4. 3  
J ustificati o n f or D ose ............................................................................................... 5 4  
4. 3. 1  
Rati o nale f or Ni v ol u ma b M o n ot hera p y D ose a n d Sc he d ule  .......................... 5 4  
4. 3. 2  
Rati o nale f or Ni v ol u ma b a n d I pili m u ma b C o m bi nati o n T hera p y D ose a n d 
Sc he d ule ( A d va nce d Metastatic Ca ncer)  ....................................................... 5 6  
4. 3. 2. 1  Rati o nale f or Ni v ol u ma b a n d I pili m u ma b C o m bi nati o n T hera p y 
D ose a n d Sc he d ule ( A d va nce d Pr ostate Ca ncer C o h orts A a n d B)  . 5 6  
4. 4  
Tr eat me nt Be y o n d Disease Pr o gressi o n  ................................................................... 5 7  
4. 5  
E n d of S t u d y Defi niti o n ........................................................................................... 5 8  
5  
St u d y P o p ulati o n  .............................................................................................................. 5 8  
5. 1  
I ncl usi o n Criteria  ..................................................................................................... 5 8  
5. 2  
E xcl usi o n Criteria  .................................................................................................... 6 1  
5. 3  
Lif est yle C o nsi der ati o ns  .......................................................................................... 6 2  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 7  
5. 4  
Scr ee n Fail ur es  ........................................................................................................ 6 2  
6  
St u d y I nter v e nti o n ............................................................................................................ 6 3  
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d  ......................................................................... 6 3  
6. 2  
Pr e par ati o n/ Ha n dli n g/ St or a ge/ Acc o u nta bilit y  .......................................................... 6 4  
6. 3  
Meas ur es t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  ....................................... 6 5  
6. 3. 1  
I nter ve nti o n Assi g n me nt .............................................................................. 6 5  
6. 3. 2  
Bli n di n g  ....................................................................................................... 6 6  
6. 4  
St u d y I nter ve nti o n C o m plia nce  ................................................................................ 6 6  
6. 5  
C o nc o mita nt T her a p y ............................................................................................... 6 6  
6. 5. 1  
Per m itte d T her a p y ........................................................................................ 6 6  
6. 5. 2  
Pr o hi bite d T her a p y  ....................................................................................... 6 6  
6. 6  
D ose M o dificati o ns ( Escalati o n/ Titrati o n/ Ot her)  ..................................................... 6 7  
6. 6. 1  
D ose M o dificati o ns wit h Ni v ol u ma b a n d I pili m u ma b  ................................... 6 8  
6. 6. 1. 1  D ose M o dificati o ns a n d T o xicit y Ma na ge me nt f or A d verse E ve nts 
Ass ociate d wit h Ni v ol u ma b wit h or wit h o ut I pili m u ma b  ................ 6 8  
6. 6. 1. 2  D ose M o dificati o ns a n d T o xicit y Ma na ge me nt f or I nf usi o n -relate d 
Reacti o n Ass ociat e d wit h Ni v ol u ma b wit h or wit h o ut I pili m u ma b  . 7 5  
6. 6. 1. 3  D ose Dela ys a n d I nterr u pti o ns f or Ni v ol u ma b wit h or wit h o ut 
I pili m u ma b .................................................................................... 7 7  
6. 6. 1. 4  A d diti o nal Safet y Preca uti o ns ( A d va nce d Pr ostate Ca ncer C o h ort 
O nl y)  ............................................................................................. 7 7  
6. 7  
I nter ve nti o n After t he E n d of t he St u d y .................................................................... 7 9  
7  
Disc o nti n uati o ns of St u d y I nter ve nti o n a n d Partici pa nt Disc o nti n uati o n/ Wit h dra wal  ........ 7 9  
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n  ...................................................................... 7 9  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m St u d y  ................................................ 8 0  
7. 3  
L ost t o F oll o w -u p  .................................................................................................... 8 1  
8  
St u d y Assess me nts a n d Pr oce d ures  ................................................................................... 8 1  
8. 1  
Efficac y Assess me nts ............................................................................................... 8 2  
8. 1. 1  
La b or at or y Assess me nts of T u m or Mar kers .................................................. 8 3  
8. 2  
Saf et y Assess me nts  .................................................................................................. 8 3  
8. 2. 1  
Me dical Hist or y a n d De m o gra p hic Data  ....................................................... 8 3  
8. 2. 2  
P h ysical E xa mi nati o ns  ................................................................................. 8 3  
8. 2. 3  
Vital Si g ns  ................................................................................................... 8 3  
8. 2. 4  
Electr ocar di o gr a ms ....................................................................................... 8 4  
8. 2. 5  
Cli nical Saf et y La b orat or y Assess me nts  ....................................................... 8 4  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 8  
8. 2. 5. 1  L ocal La b orat or y Assess me nts  ....................................................... 8 5  
8. 3  
A d verse E ve nts a n d Seri o us A d verse E ve nts  ............................................................ 8 5  
8. 3. 1  
Ti me Peri o d a n d Fr e q ue nc y f or C ollecti n g A E, S A E, a n d Ot her Re p orta ble 
Saf et y E ve nt I nf or mati o n .............................................................................. 8 6  
8. 3. 1. 1  E ve nts R e q uiri n g E x pe dite d Re p orti n g t o t he S p o ns or  ................... 8 6  
8. 3. 2  
F oll o w -u p E ve nt Re p orti n g  .......................................................................... 8 6  
8. 3. 3  
Met h o d of Eliciti n g A d verse E ve nt I nf or mati o n  ........................................... 8 7  
8. 3. 4  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es  .............................................. 8 7  
8. 3. 5  
Pr e g na nc y  .................................................................................................... 8 8  
8. 3. 6  
Disease -r elate d E ve nts a n d/ or Disease-relate d O ut c o mes N ot Q ualif yi n g as 
A Es or S A Es  ................................................................................................ 8 8  
8. 3. 7  
Trial -li miti n g T o xicit y .................................................................................. 8 9  
8. 3. 8  
S p o ns or C o ntact I nf or mati o n  ........................................................................ 8 9  
8. 3. 8. 1  E mer ge nc y Me dical C o ntacts  ......................................................... 8 9  
8. 3. 8. 2  Saf et y Re p orti n g C o ntacts .............................................................. 8 9  
8. 4  
Tr eat me nt of O ver d ose  ............................................................................................ 8 9  
8. 5  
P har mac o ki netics  ..................................................................................................... 9 0  
8. 6  
A nti -dr u g A nti b o dies  ............................................................................................... 9 0  
8. 7  
Bi o mar kers  .............................................................................................................. 9 0  
8. 7. 1  
Ge netics  ....................................................................................................... 9 2  
8. 7. 2  
E nr oll me nt B i o mar kers ................................................................................ 9 2  
8. 7. 3  
C D 8 a n d E x pl or at or y Bi o mar kers  ................................................................. 9 3  
8. 7. 4  
Sa m ple C ollecti o n f or L o n g -ter m F ut ure Bi o me dical Researc h .................... 9 3  
8. 7. 4. 1  O ver vie w of L o n g -ter m F ut ure Bi o me dical Researc h ..................... 9 3  
8. 7. 4. 2  Sa m ple C ollecti o n  .......................................................................... 9 4  
8. 7. 4. 3  Wit h dr a wal fr o m L o n g -ter m Sa m ple St ora ge ................................. 9 4  
8. 7. 4. 4  Pr otecti o n of Data Pri vac y a n d Data Ge nerati o n  ............................ 9 5  
8. 8  
Patie nt -Re p orte d O utc o mes Res earc h  ...................................................................... 9 5  
8. 8. 1  
Me dical Disclai mer  ...................................................................................... 9 6  
8. 8. 2  
Healt h Data Pr otecti o n  ................................................................................. 9 6  
8. 9  
Me dical Res o ur ce Utilizati o n a n d Healt h E c o n o mics  ............................................... 9 7  
9  
Statistical C o nsi der ati o ns .................................................................................................. 9 7  
9. 1  
Sa m ple Size Deter mi nati o n  ...................................................................................... 9 7  
9. 2  
P o p ulati o ns f or A nal ysis  .......................................................................................... 9 9  
9. 3  
I nteri m A nal yses ...................................................................................................... 9 9  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 9  
9. 3. 1  
Saf et y a n d F utilit y M o nit ori n g ...................................................................... 9 9  
9. 3. 1. 1  Saf et y M o nit ori n g  ........................................................................ 1 0 0  
9. 3. 1. 2  F utilit y M o nit ori n g  ...................................................................... 1 0 0  
9. 3. 1. 3  J oi nt O perati n g C haracteristics f or Safet y a n d F utilit y M o nit ori n g
 .................................................................................................... 1 0 1  
9. 4  
Statistical A nal yses  ................................................................................................ 1 0 2  
9. 4. 1  
Efficac y A nal yses ....................................................................................... 1 0 2  
9. 4. 2  
Sa f et y A nal yses .......................................................................................... 1 0 3  
9. 4. 3  
Ot her A nal yses  ........................................................................................... 1 0 3  
9. 4. 3. 1  Bi o mar ker A nal ysis  ..................................................................... 1 0 3  
9. 4. 3. 2  Patie nt -Re p orte d O utc o mes A nal ysis  ........................................... 1 0 4  
1 0  
S u p p orti n g D oc u me ntati o n a n d O perati o nal C o nsi derati o ns  ........................................... 1 0 5  
1 0. 1  
A p pe n di x  1: Re g ulat or y, Et hical a n d St u d y O versi g ht C o nsi derati o ns  .................... 1 0 5  
1 0. 1. 1  
C o m plia nce wit h La ws a n d Re g ulati o ns  ..................................................... 1 0 5  
1 0. 1. 2  
I nstit uti o nal Re vie w B oar d or I n de pe n de nt Et hics C o m mittee .................... 1 0 5  
1 0. 1. 3  
Fi na ncial Discl os ur e  ................................................................................... 1 0 6  
1 0. 1. 4  
I nf or me d C o nse nt ....................................................................................... 1 0 6  
1 0. 1. 5  
Data Pr otecti o n  ........................................................................................... 1 0 7  
1 0. 1. 6  
A d m i nistr ati ve Str uct ure ............................................................................ 1 0 7  
1 0. 1. 7  
Data Q ualit y Ass ur a nce  .............................................................................. 1 0 8  
1 0. 1. 8  
S o ur ce D oc u me ntati o n  ............................................................................... 1 0 8  
1 0. 1. 9  
St u d y a n d Site Cl os ure  ............................................................................... 1 0 9  
1 0 . 1. 1 0 Site I ns pecti o ns  .......................................................................................... 1 1 0  
1 0. 1. 1 1  Rete nti o n of Rec or ds  .................................................................................. 1 1 0  
1 0. 1. 1 2  P u blicati o n P olic y a n d Pr otecti o n of Tra de Secrets  ..................................... 1 1 0  
1 0. 2  
A p pe n di x 2: E aster n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us  ... 1 1 1  
1 0. 3  
A p pe n di x 3: R E CI S T Criteria ( Versi o n 1. 1)  ........................................................... 1 1 2  
1 0. 3. 1  
Meas ur a bilit y of T u m or at Bas eli ne  ............................................................ 1 1 2  
1 0. 3. 2  
T u m or Res p o nse E val uati o n  ....................................................................... 1 1 2  
1 0. 3. 2. 1  Baseli ne D oc u me ntati o n of T ar get a n d N o ntar get Lesi o ns  ........... 1 1 2  
1 0. 3. 2. 2  E val uati o n of T ar get Lesi o ns  ....................................................... 1 1 3  
1 0. 3. 2. 3  E val uati o n of N o ntar get Lesi o ns  .................................................. 1 1 3  
1 0. 3. 2. 4  Ne w Lesi o ns  ................................................................................ 1 1 4  
1 0. 3. 3  
E val uati o n of O ver all Res p o nse  .................................................................. 1 1 4  
1 0. 4  
A p pe n di x 4: Cli nical La b or at or y T ests  ................................................................... 1 1 6  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 0  
1 0. 5  
A p pe n di x 5: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, 
F oll o w -u p, a n d Re p orti n g  ...................................................................................... 1 1 7  
1 0. 5. 1  
Defi niti o ns  ................................................................................................. 1 1 7  
1 0. 5. 1. 1  Defi niti o n of A E  .......................................................................... 1 1 7  
1 0. 5. 1 . 2 Defi niti o n of S A E  ........................................................................ 1 1 8  
1 0. 5. 1. 3  Defi niti o n of U ne x pecte d A E  ....................................................... 1 1 9  
1 0. 5. 1. 4  Defi niti o n of Treat me nt -e mer ge nt A E .......................................... 1 2 0  
1 0. 5. 2  
A d diti o nal E ve nts Re p orte d i n t he Sa me Ma n ner as a n S A E  ....................... 1 2 0  
1 0. 5. 3  
Rec or di n g A Es a n d S A Es  ........................................................................... 1 2 0  
1 0. 5. 4  
Re p orti n g of A Es, S A Es, a n d Ot her Re p orta ble Safet y E ve nts t o  t he S p o ns or
 ................................................................................................................... 1 2 3  
1 0. 5. 5  
A d diti o nal Re p orti n g C o nsi derati o ns  .......................................................... 1 2 4  
1 0. 6  
A p pe n di x 6: C o ntr ace pti ve G ui da nce a n d C ollecti o n of Pre g na nc y I nf or mati o n  ..... 1 2 8  
1 0. 6. 1  
Defi niti o ns  ................................................................................................. 1 2 8  
1 0. 6. 1. 1  W o ma n of C hil d beari n g P ote ntial ( W O C B P)  ............................... 1 2 8  
1 0. 6. 2  
C o ntr ace pti o n G ui da nce  ............................................................................. 1 2 8  
1 0. 6. 2. 1  Male Partici pa nts  ......................................................................... 1 2 8  
1 0. 6. 2 . 2 Fe male Partici pa nts  ...................................................................... 1 2 9  
1 0. 6. 3  
Pr e g na nc y T esti n g  ...................................................................................... 1 3 0  
1 0. 6. 4  
C ollecti o n of Pr e g na nc y I nf or mati o n  .......................................................... 1 3 0  
1 0. 6. 4. 1  Male Partici pa nts wit h Part ners w h o Bec o me Pre g na nt  ................ 1 3 0  
1 0. 6. 4. 2  Fe male Partici pa nts w h o Bec o me Pre g na nt  .................................. 1 3 0  
1 0. 7  
A p pe n di x 7: Ge netics  ............................................................................................. 1 3 2  
1 0. 8  
A p pe n di x 8: Ma na ge me nt Al g orit h ms .................................................................... 1 3 3  
1 0. 9  
A p pe n di x 9: List of A b br e viati o ns  ......................................................................... 1 4 1  
1 0. 1 0  A p pe n di x 1 0: Pr ot oc ol A me n d me nt Hist or y  ........................................................... 1 4 4  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 1  
L I S T O F T A B L E S  
 
T a ble  1:  
Sc he d ule of Assess me nts A d va nc e d Metastatic Ca ncer ( Ni v ol u ma b O nl y Ar m: 
Ni v ol u ma b 3 6 0 m g Q 3 W a n d Mai nte na nce 4 8 0 m g Q 4 W)  ................................. 3 1  
T a ble  2:  
Sc he d ule of Assess me nts A d va nc e d Metastatic Ca ncer ( Ni v ol u ma b a n d 
I pili m u ma b Ar m: Ni v ol u ma b Q 3 W a n d I pili m u ma b Q 3 W [ D oses 1 & 2], t he n 
Q 6 W [ D oses 3 & 4], F oll o we d b y Si n gle -a ge nt Ni v ol u ma b Q 4 W) ..................... 3 4  
T a ble  3:  
Sc he d ule of Assess me nts A d va nc e d Pr ostate Ca ncer ( Ni v ol u ma b O nl y Ar m: 
Ni v ol u ma b 3 6 0 m g Q 3 W a n d Mai nte na nce 4 8 0 m g Q 4 W)  ................................. 3 7  
T a ble  4:  
Sc he d ule of Assess me nts A d va nc e d Pr ostate Ca ncer ( Ni v ol u ma b a n d I pili m u ma b 
Ar m: Ni v ol u ma b Q 3 W a n d I pili m u ma b Q 6 W [ C ycles 1  a n d 2], F oll o we d b y 
Si n gle -a ge nt Ni v ol u ma b Q 4 W)  .......................................................................... 4 0  
T a ble 5:  
O bjecti ves a n d C orr es p o n di n g E n d p oi nts  ........................................................... 5 1  
T a ble 6:  
St u d y I nter ve nti o n  .............................................................................................. 6 3  
T a ble 7:  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or A d verse E ve nts 
Ass ociate d wit h Ni v ol u ma b wit h or wit h o ut I pili m u ma b  .................................... 7 0  
T a ble 8:  
D ose M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or I nf usi o n -relate d 
Reacti o n Ass ociat e d wit h Ni v ol u ma b wit h or wit h o ut I pili m u ma b  ..................... 7 6  
T a ble  9:  
T o xicit y Criteria Re q uiri n g Per ma ne nt Treat me nt Disc o nti n uati o n of B ot h 
Ni v ol u ma b a n d I pili m u ma b ( A me n d me nt 3 + A d va nce d Pr ostate C o h ort O nl y)  .. 7 8  
T a ble 1 0:  
La b or at or y T ests Se nt t o t he St u d y Site’s L ocal La b orat or y f or A nal ysis  ........... 8 5  
T a ble  1 1:  
P ossi ble S u b gr o u p Sizes ..................................................................................... 9 8  
T a ble  1 2:  
Cr e di ble I nter vals f or C D 8 C o n versi o n  .............................................................. 9 9  
T a ble 1 3:  
P o p ulati o ns f or A nal ysis  .................................................................................... 9 9  
T a ble  1 4:  
R ules f or Saf et y a n d F utilit y M o nit ori n g per Ar m  ............................................ 1 0 0  
T a ble  1 5:  
O per ati n g C har acteristics U n der Var yi n g T o xicit y a n d Res p o nse Rates  ........... 1 0 1  
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 2  
L I S T O F F I G U R E S 
 
Fi g ur e 1:  
St u d y Sc he ma: A d va nce d Metastatic Ca ncer M o n ot hera p y Ar m ( C D 8 + ≥ 1 5 %)  2 6  
Fi g ur e 2:  
St u d y Sc he ma: A d va nce d Metastatic Ca ncer C o m bi nati o n Ar m ( C D 8 + < 1 5 %)  . 2 7  
Fi g ur e 3:  
St u d y Sc he ma: A d va nce d Pr ostate Ca ncer M o n ot hera p y Ar m ( C D 8 + ≥ 1 5 % [ C D 8 
Hi g h Ar m])  ........................................................................................................ 2 8  
Fi g ur e 4:  
St u d y Sc he ma: A d va nce d Pr ostate Ca ncer C o m bi nati o n Ar m ( C D 8 + < 1 5 % [ C D 8 
L o w Ar m])  ......................................................................................................... 2 9  
Fi g ur e 5:  
T u m or -i nfiltr ati n g C D 8 T-cell E x pressi o n i n Res p o n ders a n d N o n -res p o n ders t o 
P D -1 Bl oc ka de  ................................................................................................... 4 5  
Fi g ur e 6:  
T u m or -i nfiltr ati n g C D 8 T-cell E x pressi o n b y Best O verall Res p o nse  ................. 4 6  
Fi g ur e 7:  
Per ce nta ge of T u m or al C D 8 T Cells b y I m m u n o hist oc he mistr y i n Differe nt 
T u m or T y pes ...................................................................................................... 4 7  
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 3  
1  
P R O T O C O L S U M M A R Y  
1. 1  
S Y N O P SI S  
P r ot oc ol Title:  
A n E x pl or at or y St u d y of Ni v ol u ma b wit h or wit h o ut I pili m u ma b Acc or di n g t o t he Perce nt a ge of  
T u m or al C D 8 Cells i n Partici pa nts wit h A d va nce d Metastatic  Ca nc er  
S h ort Title:  
Tr eat me nt wit h Ni v ol u ma b a n d I pili m u ma b or Ni v ol u ma b Al o ne Acc or di n g t o t he Perce nt a ge of 
T u m or al C D 8  Cells  i n A d va nce d Metastatic  Ca ncer  
R ati o n ale:  
T he ai m of t his st u d y is t o pr o vi de a pr os pecti ve classificati o n of C D 8 hi g h (i m m u n ol o gicall y 
“ h ot”) vers us C D 8 l o w  (i m m u n ol o gicall y “c ol d”) t u m ors at t he ti me of treat me nt, base d o n t he 
per ce nta ge of C D 8 cells i n a t u m or bi o ps y, a n d t o a d dress t he pre dicti ve val ue of t he C D 8 
bi o mar ker f or selecti n g patie nts f or tr eat me nt wit h ni v ol u ma b wit h or wit h o ut i pili m u ma b.  
Ke y O bj ecti ves a n d E n d p oi nts:  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
•  T o deter mi ne t he cli ni cal be nefit rat e ( C B R) of 
ni v ol u ma b wit h or wit h o ut i pili m u ma b i n 
parti ci pa nts wit h a d va nc e d m et astati c ca ncer , 
i ncl u di n g a d va nce d pr ostate c a nc er. 
•  T o assess t he pr o p orti o n of partici pa nts i n t he 
ni v ol u ma b pl us i pili m u m a b ar m w h ose t u m ors will 
c ha n ge fr o m C D 8 l o w t o C D 8 hi g h as me as ure d b y 
a c ha n ge i n t he perc e nta ge of t u m oral C D 8 cells.  
•  C B R  is t he pr o p orti o n of parti ci pa nts w h o s h o w 
cli ni cal be nefit, defi ne d as C R, P R, or S D f or 
≥ 6  m o nt hs as best res p o nse b y R E CI S T v 1. 1.  
•  C ha n ge i n t he perc e nt a ge  of C D 8 c ells i n o n -
treat m e nt bi o psies fr o m baseli ne . 
Se c o n dar y  
 
•  T o deter mi ne t he safet y a n d t ol era bilit y of 
ni v ol u ma b wit h or wit h o ut i pili m u ma b i n 
parti ci pa nts wit h a d va nc e d m et astati c ca ncer , 
i ncl u di n g a d va nce d pr ostate c a nc er. 
•  T o deter mi ne t he O R R of ni v ol u m a b wit h or wit h o ut 
i pili m u ma b i n partici pa nts wit h a d va nce d metast atic 
c a nc er, i ncl u di n g a d va nc e d pr ost at e ca ncer. 
•  T o assess t he ass oci ati o n of  perce nt a ge  of C D 8 
i nfiltrati o n i n t u m or sa m ples wit h cli ni cal o utc o m es 
( O R R, P F S, a n d O S). 
•  I nci de nc e a n d se verit y of A Es base d o n C T C A E 
v 5 . 0. 
•  O R R: Defi ne d as C R or P R as best res p o nse b y 
R E CI S T v 1. 1 assess m e nt.  
•  P F S: Defi ne d as t he ti m e fr o m i nitiati o n of st u d y 
t hera p y t o dat e of first d oc u me nte d pr o gressi o n of 
dise ase  or  date of de at h d ue t o a n y ca use . 
•  O S: Defi ne d as t he ti me fr o m i niti ati o n of st u d y 
t hera p y u ntil de at h d ue t o a n y c a use . 
A E = a d verse e ve nt; C B R = cli ni cal be nefit rat e; C R = c o m pl ete res p o nse; C T C A E = C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts; O R R = o bj ecti ve res p o nse rat e; O S = o verall s ur vi val; P F S  =  pr o gressi o n -fre e s ur vi val; 
P R = partial res p o nse; R E CI S T  = Res p o nse E val uati o n Crit eri a i n S oli d T u m ors; S D = sta bl e dise ase.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 4  
O ver all D esi g n:  
T his is a n o pe n -la bel, e x pl or at or y st u d y t o e val uate ni v ol u ma b wit h or wit h o ut i pili m u ma b base d 
o n  per ce nta ge of t u m or al C D 8 cells at t he ti me of treat me nt i n partici pa nts wit h var yi n g 
a d va nce d s oli d t u m ors. Partici pa nts  w h o ha ve a t u m or wit h ≥ 1 5 % C D 8 cells (classifie d as C D 8 
hi g h) will r ecei ve ni v ol u ma b m o n ot hera p y, a n d partici pa nts  w h o ha ve a t u m or wit h <  1 5 % C D 8 
cells ( classifie d as C D 8 l o w) will r ecei ve i pili m u ma b i n c o m bi nati o n wit h ni v ol u ma b. 
N u m ber of P artici p a nt s: 
A t otal of u p t o a p pr o xi matel y 2 0 0 partici pa nts will be treate d. Be gi n ni n g wit h A me n d me nt 2, 
e nr oll me nt will be li mite d t o t u m or t y pes k n o w n t o be res p o nsi ve t o i m m u n ot hera p y, ha ve hi g h 
pr e vale nce ( >  2 0 %) C D 8 ≥ 1 5 % t u m ors, a n d/ or ha ve bee n o bser ve d i n t h e st u d y t o ha ve t u m ors 
tr a nsiti o n fr o m C D 8 l o w  t o C D 8 hi g h  f oll o wi n g i nitiati o n of i m m u n ot hera p y. Be gi n ni n g wit h 
A me n d me nt 3, a t otal of a p pr o xi matel y 2 0 partici pa nts wit h a d va nce d pr ostate ca ncer a n d 
t u m or al C D 8 <  1 5 % will be all ocate d t o 1 of 2  c o h orts usi n g c o m bi nati o ns of i pili m u ma b a n d 
ni v ol u ma b. A d va nce d pr ostate ca ncer partici pa nts  wit h t u m oral C D 8 ≥ 1 5 % will be  e nr olle d i n 
t he ni v ol u ma b m o n ot her a p y ar m. O n g oi n g m o nit ori n g f or safet y a n d f utilit y will be i m ple me nte d 
base d o n t he met h o d of T h all a n d c ollea g ues (T hall et al, 1 9 9 5 ) se paratel y i n t he C D 8 hi g h a n d 
C D 8 l o w t u m or gr o u ps. Ref er t o Secti o n  9. 1 . 
I nt er ve nti o n Gr o u ps a n d D ur ati o n:  
A d va nce d Metastatic Ca n cer : Si n gle -a ge nt ni v ol u ma b will be a d mi nistere d at 3 6 0 m g 
i ntr a ve n o usl y (I V) e ver y 3 wee ks ( Q 3 W). Partici pa nts w h o c o nti n ue t o s h o w cli nical be nefit 
after t he first disease assess me nt will recei ve ni v ol u ma b 4 8 0 m g I V e ver y 4 wee ks ( Q 4 W) u ntil 
pr o gr essi ve disease ( P D) or i nt oler a ble t o xicit y. At P D, partici pa nts will be all o we d t o cr oss o ver  
t o t he C D 8 lo w ar m of i pili m u ma b ( 1 m g/ k g) a n d ni v ol u ma b  (3 6 0 m g ). 
F or ni v ol u ma b a n d i pili m u ma b c o m bi nati o n t hera p y, ni v ol u ma b will be a d mi nistere d at 3 6 0  m g 
I V Q 3 W, a n d i pili m u ma b will be a d mi nistere d at 1 m g/ k g I V Q 3 W f or t he first 2 d oses a n d t he n 
e ver y 6 wee ks f or t he 3 r d a n d 4 t h d oses, f oll o we d b y ni v ol u ma b 4 8 0 m g I V Q 4 W  u ntil P D  or 
i nt oler a ble t o xicit y. After r ecei pt of t he first d ose of i pili m u ma b, t he I n vesti gat or ma y deter mi ne 
( base d o n cli nical s y m pt o ms) t he n u m ber of f ut ure d oses of i pili m u ma b t he partici pa nt will 
r ecei ve, f or a ma xi m u m of 4  d oses. Partici pa nts w h o st o p i pili m u ma b d osi n g earl y d ue t o 
t o xicities, ma y start ni v ol u ma b mai nte na nce (ie, 4 d oses [ 1 2 wee ks] of ni v ol u ma b f oll o wi n g t he 
first d ose). 
A d va nce d Pr ostate Ca ncer  ( A me n d me nt 3+ ): Si n gle-a ge nt ni v ol u ma b a d mi nistere d at 3 6 0 m g 
i ntr a ve n o usl y (I V) e ver y 3 wee ks ( Q 3 W). Partici pa nts w h o c o nti n ue t o s h o w cli nical be nefit 
after t he first disease assess me nt will recei ve ni v ol u ma b 4 8 0 m g I V e ver y 4 wee ks ( Q 4 W) u ntil 
pr o gr essi ve disease ( P D) or i nt oler a ble t o xicit y. At P D, partici pa nts will be all o we d t o cr oss o ver  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 5  
t o t he a d va nce d pr ostate ca ncer C D 8 l o w ar m  of i pili m u ma b ( 5  m g/ k g)  a n d ni v ol u ma b 
( 1 m g/ k g) . 
F or ni v ol u ma b a n d i pili m u ma b c o m bi nati o n t hera p y, C D 8 l o w ar m , a p pr o xi matel y 
1 0  partici pa nts  will be r a n d o ml y all ocate d i nt o 1 of 2 c o h orts, usi n g differe nt d oses of 
i pili m u ma b a d mi nister e d i n 6-wee k c ycles . Partici pa nts assi g ne d t o Pr ostate C o h ort A will 
r ecei ve ni v ol u ma b 1 m g/ k g Q 3 W a n d i pili m u ma b 3 m g/ k g e ver y 6 wee ks ( Q 6 W) f or 2 c ycles, 
t he n ni v ol u ma b mai nte na nce 4 8 0 m g Q 4 W u ntil P D or i nt olera ble t o xicit y. Partici pa nts assi g ne d 
t o Pr ostate C o h ort B will r ecei ve ni v ol u ma b 1 m g/ k g Q 3 W a n d i pili m u ma b 5 m g/ k g Q 6 W f or 
2  c ycles, t he n ni v ol u ma b mai nte na nce 4 8 0 m g Q 4 W u ntil P D or i nt olera ble t o xicit y.  If Pr ostate 
C o h ort B is deter mi ne d t o ha ve a t oler a ble safet y pr ofile ( per Secti o n 6. 6. 1. 4 ), a n a d diti o nal 
1 0  partici pa nts will be e nr olle d t o r ecei ve ni v ol u ma b 1 m g/ k g Q 3 W a n d i pili m u ma b 5 m g/ k g 
Q 6 W f or 2 c ycles, t he n ni v ol u ma b mai nte na nce 4 8 0 m g Q 4 W u ntil P D or i nt olera ble t o xicit y. If 
t he saf et y pr ofile of Pr ostate C o h ort B is dee me d u nacce pta ble, a n ad diti o nal 1 0 partici pa nts will 
be e nr olle d i n Pr ostate C o h ort A.  
S af et y a n d F utilit y M o nit ori n g:  
M o nit ori n g will be o n g oi n g d uri n g e nr oll me nt i n eac h gr o u p t o assess t he st o p pi n g r ules as 
defi ne d i n t he pr ot oc ol (see Secti o n  9. 3. 1 ). T here is n o i n de pe n de nt Data Safet y M o nit ori n g 
C o m mittee.  
1. 2  
S C H E M A  
T he st u d y sc he ma is de picte d i n Fi g u r e 1 a n d Fi g ure 2  f or a d va nce d metastatic ca ncer a n d i n 
Fi g ur e 3  a n d Fi g ur e 4  f or a d va nce d pr ostate ca ncer. 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 6  
Fi g ure 1 : 
St u d y Sc he m a : A d v a nce d Met ast atic C a ncer  M o n ot her a p y  Ar m ( C D 8 + ≥ 1 5 %) 
 
Bl = baseli ne; B x  = t u m or bi o ps y; D A = disease assess me nt; I V = i ntra ve n o us(l y); N = ni v ol u m a b; P D = pr o gressi ve disease; Q 3 W = e ver y 3 we e ks; Q 4 W = 
e ver y 4 wee ks; Q 6 W = e ver y 6 wee ks ; Q 8 W = e ver y 8 we e ks. 
a Si n gle -a ge nt ni v ol u ma b will be a d mi nist ere d at 3 6 0 m g I V Q 3 W.  Partici pa nts w h o c o nti n ue t o s h o w cli ni cal be nefit aft er t he first dise ase assess m e nt will 
re cei ve ni v ol u ma b 4 8 0 m g I V Q 4 W u ntil P D or i nt olera bl e t o xi cit y. At P D  (a n y ti m e f oll o wi n g i nitiati o n of st u d y t hera p y), partici pa nts will be all o we d t o 
cr oss-o ver t o t he A d va nce d Met astati c Ca ncer C o m bi nati o n Ar m. All de cisi o ns t o cr oss -o ver m us t be disc usse d wit h t he S p o ns or . 
b Bl o o d c olle cti o n pri or t o a d mi nistrati o n of ea c h d ose a n d at ti me of pr o gressi o n.  
c F or  partici pa nts w h o cr oss -o ver t o t he C D 8 l o w ar m , ni v ol u m a b will be a d mi nistere d at 3 6 0 m g I V Q 3 W, a n d i pili m u ma b will be a d mi nistere d at 1 m g/ k g I V 
Q 3 W f or t he first 2  d oses a n d t he n Q 6 W f or t he 3r d a n d 4t h d oses, f oll o we d b y si n gle -a ge nt ni v ol u ma b 4 8 0 m g I V Q 4 W u ntil P D or i nt olera bl e t o xicit y . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 7  
Fi g ure 2 : 
St u d y Sc he m a: A d v a nce d Met ast atic C a ncer C o m b i n ati o n Ar m ( C D 8 + < 1 5 %) 
 
Bl = baseli ne; B x = t u m or bi o ps y; D A = disease assess me nt; I = i pili m u ma b; I V = i ntra ve n o us(l y); N = ni v ol u m a b;  P D = pr o gressi ve disease; Q 3 W = e ver y 3 
we e ks; Q 4 W = e ver y 4  we e ks; Q 6 W = e ver y 6 we e ks ; Q 8 W = e ver y 8 wee ks. 
a F or ni v ol u m a b a n d i pili m u m a b c o m bi nati o n t hera p y, ni v ol u m a b will be a d mi nistere d at 3 6 0 m g I V Q 3 W, a n d i pili m u ma b will be a d mi nistere d at 1 m g/ k g I V 
Q 3 W f or t he first 2  d oses a n d t he n Q 6 W f or t he 3r d a n d 4t h d oses, f oll o we d b y si n gle -a ge nt ni v ol u ma b 4 8 0 m g I V Q 4 W u ntil P D or i nt olera bl e t o xicit y. 
b Bl o o d c olle cti o n pri or t o a d mi nistrati o n of ea c h d ose a n d at ti me of pr o gressi o n.  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 8  
Fi g ure 3 : 
St u d y Sc he m a: A d v a nce d P r ost ate C a ncer M o n ot her a p y Ar m ( C D 8 + ≥ 1 5 % [ C D 8 Hi g h Ar m]) 
 
Bl = baseli ne; B x = t u m or bi o ps y; D A = dise ase assess m e nt; I V = i ntra ve n o us(l y); N = ni v ol u m a b; P D = pr o gressi ve disease; Q 3 W = e ver y 3 we e ks; Q 4 W = 
e ver y 4 wee ks; Q 6 W = e ver y 6 wee ks; Q 8 W = e ver y 8 we e ks.  
a Si n gle -a ge nt ni v ol u ma b will be a d mi nist ere d at 3 6 0 m g I V Q 3 W. Partici pa nts w h o c o nti n ue t o s h o w cli ni cal be nefit aft er t he first dise ase a ssess m e nt will 
re cei ve ni v ol u ma b 4 8 0 m g I V Q 4 W u ntil P D or i nt olera bl e t o xi cit y. At P D  (a n yti me f oll o wi n g i niti ati o n of st u d y t hera p y),  parti ci pa nts will be all o we d t o 
cr oss-o ver t o t he A d va nce d Pr ost at e Ca ncer C o m bi nati o n T hera p y Ar m. All de cisi o ns t o cr oss -o ver m ust be disc usse d wit h t he S p o ns or.  
b Bl o o d c olle cti o n pri or t o a d mi nistrati o n of ea c h d ose a n d at ti me of pr o gressi o n.  
c F or partici pa nts w h o cr oss -o ver t o  t he C D 8 l o w ar m, ni v ol u m a b will be a d mi nistere d at 1  m g / k g I V Q 3 W, a n d i pili m u ma b will be a d mi nist ere d at 3 m g/ k g I V 
Q 6 W f or 2  c ycl es (Pr ostate C o h ort A ), f oll o we d b y ni v ol u m a b mai nt e na nc e  4 8 0 m g I V Q 4 W u ntil P D or i nt ole ra ble t o xicit y. 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
2 9  
Fi g ure 4 : 
St u d y Sc he m a: A d v a nce d P r ost ate C a ncer C o m bi n ati o n Ar m ( C D 8 + < 1 5 % [ C D 8 L o w  Ar m])  
 
Bl = baseli ne; B x =  t u m or bi o ps y; D A = disease assess me nt;  I = i pili m u ma b; I V = i ntra ve n o us(l y); N = ni v ol u m a b; P D = pr o gressi ve disease; Q 3 W = e ver y 
3  wee ks; Q 4 W = e ver y 4  wee ks; Q 6 W = e ver y 6 we e ks; Q 8 W = e ver y 8 we e ks.  
a N i v ol u m a b a n d i pili m u m a b c o m bi nati o n t hera p y will be a d mi nistere d i n 2 c o h orts. F or Pr ost a t e C o h ort A , ni v ol u m a b will be a d mi nistere d at 1 m g/ k g I V 
Q 3 W, a n d i pili m u m a b will be a d mi nistere d at 3 m g/ k g I V Q 6 W f or 2 c ycl es, f oll o we d b y ni v ol u m a b m ai nte na nce 4 8 0 m g I V Q 4 W u ntil P D or i nt ol era ble 
t o xicit y. F or Pr ost at e C o h ort B , ni v ol u ma b will be a d mi nistere d at 1 m g/ k g I V Q 3 W, a n d i pili m u ma b will be a d mi nist ere d at 5 m g/ k g I V Q 6 W f or 2 c ycles, 
f oll o we d b y ni v ol u m a b mai nt e na nc e 4 8 0 m g I V Q 4 W u ntil P D or i nt olera bl e t o xicit y . 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 0  
1. 3  
S C H E D U L E O F A C TI VI TI E S  
T he Sc he d ule of A cti vities ( S O As)  f or t he ni v ol u ma b o nl y ar m a n d ni v ol u ma b pl us i pili m u ma b 
c o m bi nati o n ar m ar e s h o w n i n T a ble  1  a n d T a ble  2  f or a d va nce d metastatic ca ncer a n d i n 
T a ble  3  a n d T a ble  4  f or a d va nce d pr ostate ca ncer. 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 1  
T a ble  1 :  
Sc he d ule of Assess me nts A d v a nce d Met ast atic C a ncer ( Ni v ol u m a b O nl y Ar m: N i v ol u m a b 3 6 0 m g Q 3 W  a n d 
M ai nt e n a nce 4 8 0 m g Q 4 W ) 
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w u p b  
C 1  
C 2  
C 3  
C 4  
C 5  
C 6  
C 7  
C 8  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
1 5 -3 0 
da ys after 
l ast d ose 
First visit 
( 9 0 da ys 
after l ast 
d ose) b  
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
I nf or m e d c o nse nta 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Me di cal, ca ncer hist or y d  
X  
 
 
 
 
 
 
 
 
 
 
 
 
P h ysi cal e xa mi nati o n  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Pr e g na nc y t est (ser u m or uri ne) e 
X e 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
E C O G perf or m a nce st at us  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Vit al si g ns (see Secti o n 8. 2. 3 )f 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
B o d y wei g ht  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
 
 
He m at ol o g y (see Ta bl e 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Cli ni cal c he mistr y (see Ta ble 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Uri nal ysis  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
1 2 -l ea d E C G 
X  
 
 
 
 
 
 
 
 
 
 
 
 
T u m or mar kers g  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
 
cf D N A ( bl o o d) h 
X  
 
 
X  
 
 
 
 
 
 
X  
 
 
Cir c ulati n g s ol u ble a nal yt es i 
X  
X  
X  
X  
X  
X  
 
 
 
 
X  
 
 
Bl o o d i m m u ne bi o m ar kers i 
X  
X  
X  
X  
X  
X  
 
 
 
 
X  
 
 
St o ol c ollecti o n j 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
T u m or bi o ps y k 
X l 
As earl y as p ossi bl e after t he 2 n d d ose of ni v ol u ma b m o n ot her a p y k a n d at P D 
 
 
 
C o nc o mit a nt m e di cati o ns m  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
A d verse e ve nts m  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Ni v ol u m a b a d mi nistrati o n n 
 
X  
 
X  
X  
X  
X o  
X  
X  
X  
 
 
 
F oll o w -u p f or o ver all s ur vi valc 
 
 
 
 
 
 
 
 
 
 
 
X  
X  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 2  
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w u p b  
C 1  
C 2  
C 3  
C 4  
C 5  
C 6  
C 7  
C 8  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
1 5 -3 0 
da ys after 
l ast d ose 
First visit 
( 9 0 da ys 
after l ast 
d ose) b  
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
Assess s u bse q ue nt ca ncer t her a p y  
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
Disease assess me nt p 
X  
C ycle 4 Da y 1 , t he n be gi n ni n g a t C ycle 6  Da y 1, re peat e ver y 8  wee ks ( ± 7  da ys) u ntil r a di o gr a p hic pr o gr essi o n or  
t he st art of s u bse q ue nt t her a p y, w hi c he ver c o m es first 
cf D N A = c ell -fre e de o x yri b o n ucleic a ci d; C x = C ycle x; E C G = el ectr oc ar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T = e n d of tre at me nt;  
P D  =  pr o gressi ve dise ase; Q 3 M  = e ver y 3 m o nt hs; Q 3 W  =  e ver y 3 we e ks; Q 4 W = e ver y 4 we e ks; Q 6 W = e ver y 6 wee ks; Q 1 2 W = e ver y 1 2 we e ks.  
a Scre e ni n g e val ua ti o ns are t o be c o n d ucte d wit hi n 2 8 da ys of t he first d ose of pr ot oc ol t hera p y. S o m e scre e ni n g pr oc e d ures m a y oc c ur o n C ycl e 1 Da y 1 as 
a p pr o pri at e. I nf or m e d c o nse nt m ust be o bt ai ne d pri or t o a n y st u d y -s pecifi c pr oc e d ures a n d m a y be o btai ne d pri or t o t he 28 -da y scre e ni n g wi n d o w.  
b Ni net y ( 9 0) da ys aft er t he last d ose t here is a visit wit h assess m e nts if n o alt er n ati ve t her a py h as st art e d. If t he parti ci pa nt has st art e d alt er nati ve t hera p y 
wit hi n t hat 9 0 da ys after t he l ast d ose , t he first f oll o w u p visit w ill be c o nta ct b y t el e p h o ne o nl y. 
c F or a ma xi m u m of 2 ye ars fr o m t he last d ose, partici pa nts will be c o nt acte d b y tel e p h o ne e ver y 3 m o nt hs t o deter mi ne t heir s ur vi val st at us.  
d Ca ncer hist or y will i ncl u de sta ge, dat e of dia g n oses, a n d pri or ca ncer t hera pi es a n d pr oce d ures. 
e Pre g na nc y tests (ser u m or uri ne) will be perf or me d at Scre e ni n g ( wit hi n 2 4 h o urs of first d ose), o n Da y 1 of e ver y c ycle t her eafter ( wit hi n 2 4 h o urs of d ose), 
a n d E O T. 
f P ulse o xi m etr y will be c olle cte d wit h vital si g ns o nl y at baseli n e. 
g T u m or m ar kers , (e g, C A 1 9-9, P S A, et c) will be c oll ecte d if perf or m e d as part of st a n dar d of care.  
h cf D N A ( bl o o d) will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 2 Da y 1, a n d E O T.  
i Circ ul ati n g s ol u ble a nal yt es a n d bl o o d i m m u ne bi o mar kers will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 1 Da ys 1 a n d 8, C yc les 2-4 Da y 1, a n d E O T.  
j St o ol c olle cti o n will be assesse d at Scre e ni n g a n d at C ycle 2 Da y 1, if p ossi bl e. If t his ti mi n g is n ot p ossi ble, a n y st o ol sa m ple c oll ecte d w hile o n tre at me nt 
w o ul d be ac ce pta ble.  
k Partici pa nts will u n der g o 3 t u m or bi o psi es: m a n dat or y baseli ne bi o ps y (f or tre at me nt assi g n m e nt base d o n perce nt of t u m oral C D 8 cells), as earl y as p ossi bl e 
after t he 2 n d d ose of  ni v ol u m a b ( Da y  2  –  Da y 1 0 of C ycle 2; h o we ver, a n y o n treat m e nt bi o ps y aft er Da y 1 of C ycle 2 will be ac ce pte d, if me dic all y feasi bl e), 
a n d at P D (if me dic all y fe asi bl e) pri or t o t he o pti o nal a d diti o n of i pili m u m a b. Re gar dl ess of d osi n g, partici pa nts s h o u l d c o nti n ue t o f oll o w assess me nts as 
ti me d.  
l If t he res ults of t he baseli ne scre e ni n g bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at me nt assi g n m e nt, a 2n d 
baseli ne bi o ps y ma y be o btai ne d, if it is me dicall y  fe asi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. A d diti o nall y, if t he res ults of t he o n 
treat m e nt bi o ps y are n ot a de q uate t o o btai n i nf or m ati o n o n t he perce nt a ge of t u m oral C D 8 c ells, a 2n d o n tre at me nt bi o ps y m a y be o bt ai ne d, if i t is m e di call y 
fe asi bl e a n d t he parti ci pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. 
m  All A Es,  S A Es, a n d all c o nc o mita nt m e di cati o ns will be c olle cte d fr o m  t he ti me t he parti ci pa nt si g ns i nf or me d c o nse nt u ntil 1 0 0 da ys after t he l ast d ose of 
st u d y i nter ve nti o n. Pri or t o i nitiati o n of st u d y i nt er ve nti o n, o nl y A Es a n d S A Es t hat are relate d t o a pr ot oc ol ma n dat e d i nter ve nti o n, i ncl u di n g t h ose t hat oc c ur 
pri or t o assi g n me nt of st u d y pr oce d ures (e g, scre e ni n g i n vasi ve pr oce d ures, s uc h as bi o psi es) s h o ul d be re p orte d. Trial-li miti n g t o xi citi es ca n be f o u n d i n 
Se cti o n 8. 3. 7 . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 3  
n Ni v ol u m a b m o n ot hera p y will be a d mi nistere d at 3 6 0 m g I V Q 3 W f or 4 c ycl es. Part i ci pa nts w h o c o nti n ue t o s h o w cli ni cal be nefit aft er t he first dise ase 
assess m e nt will re cei ve ni v ol u m a b at 4 8 0 m g I V Q 4 W u ntil P D or i nt ol era bl e t o xi cit y (starti n g at C ycl e 5).  
o Be gi n ni n g at C ycl e 5, ni v ol u ma b mai nt e na nc e ( ni v ol u ma b at 4 8 0 m g I V Q 4 W ) will be a d mi nist ere d u ntil P D or i nt ol era ble t o xicit y . 
p Sc a ns will be perf or me d wit hi n 7 da ys pri or t o Da y 1 of C ycle 4 , C ycl e 6, a n d e ver y ev e n c ycle  t hereafter u ntil deat h, disease pr o gressi o n, i nitiati o n of a n ot her 
s yst e mi c a ntic a ncer t hera p y, l oss t o f oll o w-u p, wit h dra wal of c o nse nt, or st u d y ter mi nati o n, w hic he ver oc c urs first ( Se e Se cti o n 8. 1 ). I n a d diti o n, a d h oc sc a ns, 
as part of st a n dar d of care, will be c olle ct e d f or parti ci pa nts w h o ha ve disc o nti n ue d tre at me nt f or reas o ns ot her t ha n ra di o g ra p hi c pr o gressi o n a n d pri or t o a n y 
alter nate t hera pi es . 
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 4  
T a ble  2 :  
Sc he d ule of Assess me nts A d v a nce d Met ast atic C a ncer  ( Ni v ol u m a b a n d  I pili m u m a b Ar m: N i v ol u m a b Q 3 W 
a n d Ipili m u m a b Q 3 W [ D oses 1 & 2] , t he n Q 6 W [ D oses 3 & 4], F oll o we d b y S i n gle-a ge nt N i v ol u m a b Q 4 W ) 
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w -u p  
C 1  
C 2  
C 3  
C 4  
C 5  
C 6  
C 7  
C 8  
C 9  
C 1 0  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
1 5 -3 0 da ys 
after l ast 
d ose  
First visit 
( 9 0 da ys 
after l ast 
d ose) b 
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
I nf or m e d c o nse nta 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me di cal, ca ncer hist or y d 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysi cal e xa mi nati o n  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Pr e g na nc y t est (ser u m or uri ne) e 
X e 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
E C O G perf or m a nce st at us  
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Vit al si g ns (see Secti o n 8. 2. 3 )f 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
B o d y wei g ht  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
He m at ol o g y (see Ta bl e 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Cli ni cal c he mistr y (see Ta ble 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Uri nal ysis  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
1 2 -l ea d E C G 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or mar kers g 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
cf D N A ( bl o o d) h 
X  
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
Cir c ulati n g s ol u ble a nal yt es i 
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
X  
 
 
Bl o o d i m m u ne bi o m ar kers i 
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
X  
 
 
St o ol c ollecti o n j 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
T u m or bi o ps y k 
X l 
As earl y as p ossi bl e after t he 2 n d d ose k  of i pili m u ma b  a n d after t he 4t h d ose of 
i pili m u m a b 
 
 
 
C o nc o mit a nt m e di cati o ns m  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
A d verse e ve nts m  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Ni v ol u m a b a d mi nistrati o n n 
 
X  
 
X  
X  
X  
X  
X  
X o  
X  
X  
X  
 
 
 
I pili m u ma b a d mi nistr ati o nn 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 5  
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w -u p  
C 1  
C 2  
C 3  
C 4  
C 5  
C 6  
C 7  
C 8  
C 9  
C 1 0  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
D 1  
1 5 -3 0 da ys 
after l ast 
d ose  
First visit 
( 9 0 da ys 
after l ast 
d ose) b 
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
F oll o w -u p f or o ver all s ur vi val c 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
Assess s u bse q ue nt ca ncer t her a p y  
 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
Disease assess me nt p 
X  
C ycle 4 Da y 1 , t he n be gi n ni n g a t C ycle 6  Da y 1, re peat e ver y 8  wee ks ( ± 7  da ys) u ntil r a di o gr a p hic pr o gr essi o n or  
t he st art of s u bse q ue nt t her a p y, w hi c he ver c o m es first 
cf D N A = c ell -fre e de o x yri b o n ucleic a ci d; C x = C ycle x; E C G = el ectr oc ar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; Q 3 M = e ver y 3 mo nt hs; 
Q 3 W  = e ver y 3 we e ks; Q 4 W = e ver y 4 we e ks; Q 6 W  =  e ver y 6 we e ks; Q 1 2 W = e ver y 1 2 wee ks.  
a Scre e ni n g e val uati o ns  are t o be c o n d ucte d wit hi n 2 8 da ys of t he first d ose of pr ot oc ol t hera p y. S o m e scre e ni n g pr oc e d ures m a y oc c ur o n C ycl e 1 Da y 1 as 
a p pr o pri at e. I nf or m e d c o nse nt m ust be o bt ai ne d pri or t o a n y st u d y -s pecifi c pr oc e d ures a n d m a y be o btai ne d pri or t o t he 2 8-da y scre e n i n g wi n d o w. 
b Ni net y ( 9 0) da ys aft er t he last d ose t here is a visit wit h assess m e nts if n o alt er n ati ve t her a py h as st art e d. If t he parti ci pa nt has st art e d alt er nati ve t hera p y 
wit hi n t hat 9 0 da ys after t he l ast d ose, t he first f oll o w u p visit will be c o nta c t b y t el e p h o ne o nl y. 
c F or a ma xi m u m of 2 ye ars fr o m t he last d ose , partici pa nts will be c o nt acte d b y tel e p h o ne e ver y 3 m o nt hs t o deter mi ne t heir s ur vi val st at us. 
d Ca ncer hist or y will i ncl u de  sta ge, dat e of dia g n oses, a n d pri or ca ncer t hera pi es a n d pr oce dures.  
e Pre g na nc y tests (ser u m or uri ne) will be perf or me d at Scre e ni n g ( wit hi n 2 4 h o urs of first d ose), o n Da y 1 of e ver y c ycle t her eafter ( wit hi n 2 4 h o urs of d ose), 
a n d E O T. 
f P ulse o xi m etr y will be c olle cte d wit h vital si g ns o nl y at baseli ne.  
g T u m or m ar kers (e g, C A 1 9 -9, P S A, etc) will be c oll ecte d if perf or m e d as part of st a n dar d of care.  
h cf D N A ( bl o o d) will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 2 Da y 1, a n d E O T.  
i Circ ul ati n g s ol u ble a nal yt es a n d bl o o d i m m u ne bi o mar kers will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 1 Da ys 1 a n d 8, C ycles 2 -4 Da y 1, a n d E O T.  
j St o ol c olle cti o n will be assesse d at Scre e ni n g a n d at C ycle 2 Da y 1, if p ossi bl e. If t his ti mi n g is n ot p ossi ble, a n y st o ol s a m ple c oll ecte d w hile o n tre at me nt 
w o ul d be ac ce pta ble . 
k Partici pa nts will u n der g o 3 t u m or bi o psi es: m a n dat or y baseli ne bi o ps y (f or tre at me nt assi g n m e nt base d o n perce nt of t u m oral C D 8 cells), as earl y as p ossi bl e 
after t he 2 n d d ose of i pili m u m a b a n d aft er t he 4 t h d ose of i pili m u ma b  ( Da y 2  –  Da y 1 0 of C ycl e 2  a n d C ycle 6, res pe cti vel y ; h o we ver, a n y o n treat m e nt bi o ps y 
after Da y 1 of C ycle 2 a n d C ycle 6 will be ac ce pt e d, if me dicall y fe asi ble). Re gar dless of d osi n g, partici pa nts s h o ul d c o nti n ue t o f oll o w assess me nts as ti me d.  
l If t he res ults of t he baseli ne scre e ni n g bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at me nt assi g n m e nt, a 2 n d 
baseli ne bi o ps y ma y be o btai ne d, if it is me dicall y fe asi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. A d di ti o nall y, if t he res ults of t he o n 
treat m e nt bi o ps y are n ot a de q uate t o o btai n i nf or m ati o n o n t he perce nt a ge of t u m oral C D 8 c ells, a 2n d o n tre at me nt bi o ps y m a y be o bt ai ne d, if it is m e di call y 
fe asi bl e a n d t he parti ci pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. 
m  All A Es,  S A Es, a n d all c o nc o mita nt m e di cati o ns will be c olle cte d fr o m  t he ti me t he parti ci pa nt si g ns i nf or me d c o nse nt u ntil 1 0 0 da ys after t he l ast d ose of 
st u d y i nter ve nti o n. Pri or t o i nitiati o n of st u d y i nt er ve nti o n, o nl y A Es a n d S A Es t hat are relate d t o a pr ot oc ol ma n dat e d i nter ve nti o n, i ncl u di n g t h ose t hat oc c ur 
pri or t o assi g n me nt of st u d y pr oce d ures (e g, scre e ni n g i n vasi ve pr oce d ures, s uc h as bi o psi es) s h o ul d be re p orte d. Trial -li miti n g t o xi citi es ca n be f o u n d i n 
Se cti o n 8. 3. 7 . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 6  
n Ni v ol u m a b m o n ot hera p y will be a d mi nistere d at 3 6 0 m g I V Q 3 W f or 4 c ycl es. Parti ci pa nts w h o c o nti n ue t o s h o w cli ni cal be nefit aft er t he first dise ase 
assess m e nt will re cei ve ni v ol u m a b at 4 8 0 m g I V Q 4 W u ntil P D or i nt ol era bl e t o xi cit y (starti n g at C ycl e 5).  
o Be gi n ni n g at C ycl e 7, ni v ol u ma b mai nt e na nc e ( ni v ol u ma b at 4 8 0 m g I V Q 4 W ) will be a d mi nist ere d u ntil P D or i nt ol era ble t o xicit y . 
p Sc a ns will be perf or me d wit hi n 7 da ys pri or t o Da y 1 of C ycle 4 , C ycl e 6, a n d e ver y ev e n c ycle  t hereafter u ntil deat h, disease pr o gressi o n, i nitiati o n of a n ot her 
s yst e mi c a ntic a ncer t hera p y, l oss t o f oll o w-u p, wit h dra wal of c o nse nt, or st u d y ter mi nati o n, w hic he ver oc c urs first ( Se e Se cti o n 8. 1 ). I n a d diti o n, a d h oc sc a ns, 
as part of st a n dar d of care, will be c olle ct e d f or parti ci pa nts w h o ha ve disc o nti n ue d tre at me nt f or reas o ns ot her t ha n ra di o gra p hi c pr o gressi o n a n d pri or t o a n y 
alter nate t hera pi es . 
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 7  
T a ble  3 :  
Sc he d ule of Assess me nts A d v a nce d P r ost ate C a ncer ( Ni v ol u m a b O nl y Ar m: Ni v ol u m a b 3 6 0 m g Q 3 W a n d 
M ai nt e n a nce 4 8 0 m g Q 4 W)  
Tests & Pr oce d ures  
Scre e ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w u p b  
C 1  
C 2 -4  
C 5 O n w ar ds  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
1 5 -3 0 da ys 
after l ast 
d ose  
First 
visit ( 9 0 
da ys 
after l ast 
d ose) b  
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
I nf or m e d c o nse nt a 
X  
 
 
 
 
 
 
 
Me di cal, ca ncer hist or y d  
X  
 
 
 
 
 
 
 
P h ysi cal e xa mi nati o n  
X  
 
 
X  
X  
X  
X  
 
E C O G perf or m a nce st at us  
X  
 
 
X  
X  
X  
X  
 
Vit al si g ns (see Secti o n 8. 2. 3 )e 
X  
X  
 
X  
X  
X  
X  
 
B o d y wei g ht  
X  
X  
 
X  
X  
 
 
 
He m at ol o g y (see Ta bl e 1 0 ) 
X  
 
X  
X  
X  
X  
X  
 
Cli ni cal c he mistr y (see Ta ble 1 0 ) 
X  
 
X  
X  
X  
X  
X  
 
Uri nal ysis  
X  
 
X  
X  
X  
X  
X  
 
1 2 -l ea d E C G 
X  
 
 
 
 
 
 
 
P S A f 
X  
X  
P S A will be c ollecte d e ver y c ycl e t hr o u g h o ut tr eat m e nt  
X  
 
 
cf D N A ( bl o o d) g 
X  
 
 
X g  
 
X  
 
 
Cir c ulati n g s ol u ble a nal yt es h 
X  
X  
X  
X  
 
X  
 
 
Bl o o d i m m u ne bi o m ar kers h 
X  
X  
X  
X  
 
X  
 
 
St o ol c ollecti o n i 
X  
 
 
X i 
 
 
 
 
T u m or bi o ps y j 
X k  
 
 
X j 
 
X j 
 
 
C o nc o mit a nt m e di cati o ns l 
X  
X  
X  
X  
X  
X  
X  
 
A d verse e ve nts l 
X  
X  
X  
X  
X  
X  
X  
 
Ni v ol u m a b a d mi nistrati o n m  
 
X  
 
X  
X n  
 
 
 
F oll o w -u p f or o ver all s ur vi val c 
 
 
 
 
 
 
X  
X  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 8  
Tests & Pr oce d ures  
Scre e ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w u p b  
C 1  
C 2 -4  
C 5 O n w ar ds  
Da y  
0  
D 1  
D 8  
D 1  
D 1  
1 5 -3 0 da ys 
after l ast 
d ose  
First 
visit ( 9 0 
da ys 
after l ast 
d ose) b  
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
Assess s u bse q ue nt ca ncer t her a p y  
 
 
 
 
 
X  
X  
X  
Disease assess me nt o 
X  
C ycle 4 Da y 1 , t he n be gi n ni n g at C ycle 6 Da y 1, re peat e ver y 8  wee ks ( ± 7  da ys) u ntil r a di o gr a p hic pr o gr essi o n or  
t he st art of s u bse q ue nt t her a p y, w hi c he ver c o m es first 
A pricit y Car e ™ P R O p 
X  
Partici pa nt’s dail y assess m e nt vi a A pri cit y Car e ™ di git al s m art p h o ne a p pli cati o n p   
St u d y St aff t o r e vi e w partici pa nt’s data via A pricit y O nc ol o g y ™ as per A pri cit y Healt h Tr ai ni n g Materi als p 
 
cf D N A = c ell -fre e de o x yri b o n ucleic a ci d; C x = C ycle x; E C G = el ectr oc ar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T = e n d of tre at me nt; 
P D  =  pr o gressi ve dise ase; P R O = pati e nt -re p ort e d o ut c o m es; Q 3 M  = e ver y 3 m o nt hs; Q 3 W  =  e ver y 3 wee ks; Q 4 W = e ver y 4 we e ks.  
a Scre e ni n g e val uati o ns  are t o be c o n d ucte d wit hi n 2 8 da ys of t he first d ose of pr ot oc ol t hera p y. S o m e scre e ni n g pr oc e d ures m a y oc c ur o n C ycl e 1 Da y 1 as 
a p pr o pri at e. I nf or m e d c o nse nt m ust be o bt ai ne d pri or t o a n y st u d y -s pecifi c pr oc e d ures a n d m a y be o btai ne d pri or t o t he 2 8-da y scre e ni n g wi n d o w.  
b Ni net y ( 9 0) da ys aft er t he last d ose t here is a visit wit h assess m e nts if n o alt er n ati ve ther a py h as st art e d . If t he parti ci pa nt has st art e d alt er nati ve t hera p y 
wit hi n t hat 9 0 da ys after t he l ast d ose, t he first f oll o w u p visit will be c o nta ct b y t el e p h o ne o nl y.  
c F or a ma xi m u m of 2 ye ars fr o m t he last d ose, partici pa nts will be c o nt acte d b y tel e p h o ne e ver y 3 m o nt hs t o deter mi ne t heir s ur vi val st at us.  
d Ca ncer hist or y will i ncl u de sta ge, dat e of dia g n oses, a n d pri or ca ncer t hera pi es a n d pr oce d ures.  
e P ulse o xi m etr y will be c olle cte d wit h vital si g ns o nl y at baseli ne.  
f P S A will be  c oll ecte d d uri n g e ac h c ycle d uri n g treat m e nt. A n y P S A assess m e nts c oll ecte d o utsi de of t he sc he d ule, as part of sta n dar d of c are, will be a cc e pt e d. 
g cf D N A ( bl o o d) will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 2 Da y 1, a n d E O T.  
h Circ ul ati n g s ol u ble a n al yt es a n d bl o o d i m m u ne bi o mar kers will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 1 Da ys 1 a n d 8, C ycles 2 -4 Da y 1, a n d E O T.  
i St o ol c olle cti o n will be assesse d at Scre e ni n g a n d at C ycle 2 Da y 1, if p ossi bl e. If t his ti mi n g is n ot p ossi ble, a n y st o ol s a m ple c oll ecte d w hile o n tre at me nt 
w o ul d be ac ce pta ble.  
j Partici pa nts will u n der g o u p t o 3 t u m or bi o psi es: m a n dat or y baseli ne bi o ps y (f or tre at me nt assi g n me nt base d o n perce nt of t u m oral C D 8 cells), as e arl y as 
p ossi bl e a r o u n d t he 2n d d ose of ni v ol u m a b ( ±  3  da ys of C ycl e 2  Da y 1 ; h o we ver, a n y o n tre at me nt bi o ps y ar o u n d Da y 1 of C ycle 2 will be a cc e pt e d, if 
m e di call y fe asi ble), a n d at P D (if me dic all y fe asi bl e) pri or t o t he o pti o nal a d diti o n of i pili m u ma b. Re gar dless of d osi n g  (e g, treat m e nt h ol d), parti ci pa nts 
s h o ul d c o nti n ue t o f oll o w assess me nts as ti me d.  
k If t he res ults of t he baseli ne scre e ni n g bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at me nt assi g n m e nt, a 2n d 
baseli ne bi o ps y ma y be o btai ne d, if it is me dicall y fe asi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. A d diti o nall y, if  t he res ults of t he o n 
treat m e nt bi o ps y are n ot a de q uate t o o btai n i nf or m ati o n o n t he perce nt a ge of t u m oral C D 8 c ells, a 2n d o n tre at me nt bi o ps y m a y be o bt ai ne d, if it is m e di call y 
fe asi bl e a n d t he parti ci pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. 
l All A Es, S A Es, a n d all c o nc o mita nt m e di cati o ns will be c olle cte d fr o m  t he ti me t he parti ci pa nt si g ns i nf or me d c o nse nt u ntil 1 0 0 da ys after t he l ast d ose of 
st u d y i nter ve nti o n. Pri or t o i nitiati o n of st u d y i nt er ve nti o n, o nl y A Es a n d S A Es t hat are relate d t o a pr ot oc ol ma n dat e d i nte r ve nti o n, i ncl u di n g t h ose t hat oc c ur 
pri or t o assi g n me nt of st u d y pr oce d ures (e g, scre e ni n g i n vasi ve pr oce d ures, s uc h as bi o psi es) s h o ul d be re p orte d.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
3 9  
m  Ni v ol u m a b m o n ot hera p y will be a d mi nistere d at 3 6 0 m g I V Q 3 W f or 4 c ycl es. Parti ci pa nts w h o c o nti n ue t o s h o w cli ni cal be nefit aft er t he first dise ase 
assess m e nt will re cei ve ni v ol u m a b at 4 8 0 m g I V Q 4 W u ntil P D or i nt ol era bl e t o xi cit y (starti n g at C ycl e 5).  
n Be gi n ni n g at C ycl e 5, ni v ol u ma b mai nt e na nc e ( ni v ol u ma b at 4 8 0 m g I V Q 4 W ) will be a d mi nist ere d u ntil P D or i nt ol era ble t o xicit y . 
o Sc a ns will be perf or me d wit hi n 7 da ys pri or t o Da y 1 of C ycle 4 , C ycl e 6  a n d e ver y 8  wee ks  t hereafter u ntil deat h, disease pr o gressi o n, i nitiati o n of a n ot her 
s yst e mi c a ntic a ncer t hera p y, l oss t o f oll o w-u p, wit h dra wal of c o nse nt, or st u d y ter mi nati o n, w hic he ver oc c urs first ( Se e Se cti o n 8. 1 ). I n a d diti o n, a d h oc sc a ns, 
as part of st a n dar d of care, will be c olle ct e d f or parti ci pa nts w h o ha ve disc o nti n ue d tre at me nt f or reas o ns ot her t ha n ra di o gra p hi c pr o gressi o n a n d pri or t o a n y 
alter nate t hera pi es. 
p  O pti o nal pr oc e d ure f or parti ci pa nts w h o c o nse nt t o partici pate i n t he di git al P R O usi n g a s mart p h o ne a p pli cati o n, fr o m c o nse n t u p t o 1 0 0 da ys after t he last 
d ose of st u d y i nter ve nti o n . St u dy St aff t o re vi e w partici pa nt’s data via A pri cit y O nc ol o g y ™, a cli ni cal das h b oar d we bsite at re g ul ar i nter vals per trai ni n g 
m at eri als.  
 
 
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 0  
T a ble  4 :  
Sc he d ule of Assess me nts A d v a nce d P r ost ate C a ncer ( Ni v ol u m a b a n d  I pili m u m a b Ar m: Ni v ol u m a b Q 3 W 
a n d I pili m u m a b Q 6 W [ C ycles 1  a n d 2 ], F oll o we d b y Si n gle-a ge nt Ni v ol u m a b Q 4 W)  
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w -u p ( Aft er D at e 
Off Tre at m e nt)  
C 1  
C 2  
C 3 O n w ar d  
Da y  
0  
D 1  
D 8  
D 2 2  
D 1  
D 2 2  
D 1  
1 5 -3 0 da ys 
after l ast d ose 
First visit 
( 9 0 da ys 
after l ast 
d ose) b 
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
I nf or m e d c o nse nta 
X  
 
 
 
 
 
 
 
 
 
Me di cal, ca ncer hist or y d 
X  
 
 
 
 
 
 
 
 
 
P h ysi cal e xa mi nati o n  
X  
 
 
X  
X  
X  
X  
X  
X  
 
E C O G perf or m a nce st at us  
X  
 
 
X  
X  
X  
X  
X  
X  
 
Vit al si g ns (see Secti o n 8. 2. 3 )e 
X  
X  
 
X  
X  
X  
X  
X  
X  
 
B o d y wei g ht  
X  
X  
 
X  
X  
X  
X  
 
 
 
He m at ol o g y (see Ta bl e 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
Cli ni cal c he mistr y (see Ta ble 1 0 ) 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
Uri nal ysis  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
1 2 -l ea d E C G 
X  
 
 
 
 
 
 
 
 
 
P S A f 
X  
X  
P S A will be c ollecte d e ver y c ycl e t hr o u g h o ut tr eat m e nt 
X  
 
 
cf D N A ( bl o o d) g 
X  
 
 
X  
 
 
 
X  
 
 
Cir c ulati n g s ol u ble a nal yt es h 
X  
X  
X  
X  
X  
X  
 
X  
 
 
Bl o o d i m m u ne bi o m ar kers h 
X  
X  
X  
X  
X  
X  
 
X  
 
 
St o ol c ollecti o n i 
X  
 
 
X i 
 
 
 
 
 
 
T u m or bi o ps y j 
X k  
 
 
X j 
 
X j 
 
X  
( o pti o nal) 
 
 
C o nc o mit a nt m e di cati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
A d verse e ve nts l 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Ni v ol u m a b a d mi nistrati o n m  
 
X  
 
X  
X  
X  
X n  
 
 
 
I pili m u ma b a d mi nistr ati o nm  
 
X  
 
 
X  
 
 
 
 
 
F oll o w -u p f or o ver all s ur vi val c 
 
 
 
 
 
 
 
 
X  
X  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 1  
Tests & Pr oce d ures  
Scree ni n g a 
O n -Tre at m e nt E v al u ati o ns  
E n d of 
Tre at me nt  
F oll o w -u p ( Aft er D at e 
Off Tre at m e nt)  
C 1  
C 2  
C 3 O n w ar d  
Da y  
0  
D 1  
D 8  
D 2 2  
D 1  
D 2 2  
D 1  
1 5 -3 0 da ys 
after l ast d ose 
First visit 
( 9 0 da ys 
after l ast 
d ose) b 
Q 3 M f or 
2  years c 
Wi n d o w ( da ys)  
-2 8 t o 0  
-- 
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
Assess s u bse q ue nt ca ncer t her a p y  
 
 
 
 
 
 
 
X  
X  
X  
Disease assess me nt o 
X  
B e gi n ni n g a t C ycle 2  Da y 2 2 , re peat e ver y 8  wee ks ( ± 7  da ys) u ntil r a di o gr a p hic pr o gr essi o n or  
t he st art of s u bse q ue nt t her a p y, w hi c he ver c o m es first 
A pricit y Car e ™ P R O p 
X  
Partici pa nt’s dail y assess m e nt vi a A pri cit y Car e ™ di git al s m art p h o ne a p pli cati o n p   
St u d y St aff t o r e vi e w partici pa nt’s data via A pricit y O nc ol o g y ™ as per A pri cit y Healt h Tr ai ni n g Materi als p 
 
cf D N A = c ell -fre e de o x yri b o n ucleic a ci d; C x = C ycle x; E C G = el ectr oc ar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; P R O = pati e nt -re p ort e d 
o u t c o mes; Q 3 M = e ver y 3 m o nt hs; Q 3 W  = e ver y 3  we e ks; Q 4 W = e ver y 4 we e ks; Q 6 W  =  e ver y 6 we e ks. 
a Scre e ni n g e val uati o ns  are t o be c o n d ucte d wit hi n 2 8 da ys of t he first d ose of pr ot oc ol t hera p y. S o m e scre e ni n g pr oc e d ures m a y oc c ur o n C ycl e 1 Da y 1 as 
a p pr o pri at e. I nf or m e d c o nse nt m ust be o bt ai ne d pri or t o a n y st u d y -s pecifi c pr oc e d ures a n d m a y be o btai ne d pri or t o t he 2 8-da y  scre e ni n g wi n d o w. 
b  Ni net y ( 9 0) da ys aft er t he last d ose t here is a visit wit h assess m e nts if n o alt er n ati ve t her a py h as st art e d. If t he parti ci pa nt has st art e d alt er nati ve t hera p y 
wit hi n t hat 9 0 da ys  after t he l ast d ose, t he first f oll o w u p visit will be c o nta ct b y t el e p h o ne o nl y.  
c F or a ma xi m u m of 2 ye ars fr o m t he last d ose, partici pa nts will be c o nt acte d b y tel e p h o ne e ver y 3 m o nt hs t o deter mi ne t heir s ur vi val st at us. 
d  Ca ncer hist or y will i ncl u de s ta ge, dat e of dia g n oses, a n d pri or ca ncer t hera pi es a n d pr oce d ures. 
e P ulse o xi m etr y will be c olle cte d wit h vital si g ns o nl y at baseli ne.  
f P S A will be c oll ecte d d uri n g e ac h c ycle d uri n g treat m e nt . A n y P S A assess m e nts c oll ecte d o utsi de of t he sc he d ule, as part of sta n dar d of c are, will be a cc e pt e d.  
g cf D N A ( bl o o d) will be assesse d at Scre e ni n g, prei nf usi o n  C ycl e 1 Da y 2 2  a n d E O T. 
h  Circ ul ati n g s ol u ble a nal yt es a n d bl o o d i m m u ne bi o mar kers will be assesse d at Scre e ni n g, prei nf usi o n C ycl e 1 Da ys 1 , 8, a n d 2 2 a n d C ycle 2 Da y s 1  a n d 2 2, 
a n d E O T. 
i St o ol c olle cti o n will be assesse d at Scre e ni n g a n d at C ycle 1  Da y 2 2 , if p ossi bl e. If t his ti mi n g is n ot p ossi bl e, a n y st o ol sa m ple c oll ecte d w hile o n tre at me nt 
w o ul d be ac ce pta ble.  
j Partici pa nts will u n der g o u p t o 4  t u m or bi o psi es: m a n dat or y baseli ne bi o ps y (f or tre at me nt assi g n me nt base d o n perce nt of t u m oral C D 8 cells), ±  3 da ys of t he  
2 n d d ose of ni v ol u m a b a n d wit hi n 3 da ys of t he 4 t h d ose of ni v ol u m a b ( Da y  2 2 of C ycles 1 a n d 2, re s pe cti vel y; h o we ver, a n y o n tre at me nt bi o ps y aft er Da y 2 2 
of C ycles 1 a n d 2 will be a cc e pt e d, if me dic all y fe asi bl e), bi o ps y ma y occ ur pri or t o d osi n g. Re gar dl ess of d osi n g, parti ci pa nts s h o ul d c o nti n ue t o f oll o w 
assess m e nts as ti m e d. A d diti o nall y , a n o ptio nal t u m or bi o ps y at t he ti me of pr o gressi o n ma y be o btai ne d . 
k If t he res ults of t he baseli ne scre e ni n g bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he perc e nt a ge of t u m oral C D 8 c ells f or tre at me nt assi g n m e nt, a 2n d 
baseli ne bi o ps y ma y be o btai ne d, i f it is me dicall y fe asi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. A d diti o nall y, if t he res ults of t he o n 
treat m e nt bi o ps y are n ot a de q uate t o o btai n i nf or m ati o n o n t he perce nt a ge of t u m oral C D 8 c ells, a 2n d o n tre at me nt bi o ps y m a y be o bt ai ne d, if it is m e di call y 
fe asi bl e a n d t he parti ci pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. 
l All A Es, S A Es, a n d all c o nc o mita nt m e di cati o ns will be c olle cte d fr o m  t he ti me t he parti ci pa nt si g ns i nf or me d c o nse nt u ntil 1 0 0 da ys after t he l ast dose of 
st u d y i nter ve nti o n. Pri or t o i nitiati o n of st u d y i nt er ve nti o n, o nl y A Es a n d S A Es t hat are relate d t o a pr ot oc ol ma n dat e d i nte r ve nti o n, i ncl u di n g t h ose t hat oc c ur 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 2  
pri or t o assi g n me nt of st u d y pr oce d ures (e g, scre e ni n g i n vasi ve pr oce d ures, s uc h as bi o psi es) s h o ul d be re p orte d. Trial -li miti n g t o xi citi es ca n be f o u n d i n 
Se cti o n 8. 3. 7 . 
m  Ni v ol u m a b will be a d mi nist ere d i n c o m bi nati o n wit h i pili m u m a b . T w o c o h orts will rec ei ve c o m bi nati o n t hera p y. Pr ost at e C o h ort A  will rec ei ve ni v ol u ma b 
1  m g/ k g Q 3 W  ( 4 d oses o ver 2 c ycl es)  a nd i pili m u ma b 3 m g/ k g Q 6 W  ( 2 d oses o ver 2 c ycl es) . Partici pa nts will t he n rec ei ve ni v ol u m a b at 4 8 0 m g I V Q 4 W  
u ntil P D or i nt olera bl e t o xicit y (st arti n g at C ycl e  3 ). Pr ost at e C o h ort B  will rec ei ve ni v ol u m a b 1  m g/ k g Q 3 W  ( 4 d oses o ve r 2 c ycl es)  a n d i pili m u m a b 5  m g/ k g 
Q 6 W  ( 2 d oses o ver 2 c ycl es ). Partici pa nts will t he n rec ei ve ni v ol u ma b at 4 8 0 m g I V Q 4 W  u ntil P D or i nt olera bl e t o xicit y (starti n g at C ycle 3).  
n Be gi n ni n g at C ycl e 3, ni v ol u ma b mai nt e na nc e ( ni v ol u ma b at 4 8 0 m g I V Q 4 W ) will be a d mi nist ere d u ntil P D or i nt ol era ble t o xicit y . 
o Sc a ns will be perf or me d wit hi n 7 da ys pri or t o Da y 2 2  of C ycl e 2 , t he n e ver y 8  wee ks  t hereafter u ntil deat h, dise ase pr o gressi o n, i niti ati o n of a n ot her s yst e mic 
a nti ca ncer t hera p y, l oss t o f oll o w -u p, wit h dra wal of c o nse nt, or st u d y t er mi nati o n, w hi c he ver occ urs first ( See Se cti o n 8. 1 ). I n a d diti o n, a d h oc sc a ns, as part of 
st a n dar d of c are, will be c oll ecte d f or partici pa nts w h o ha ve disc o nti n ue d tre at me nt f or re as o ns ot her t ha n ra di o gra p hic pr o g ressi o n a n d pri or t o a n y alt er nat e 
t hera pies. 
p  O pti o nal pr oc e d ure f or parti ci pa nts w h o c o nse nt t o partici pate i n t he di git al P R O usi n g a s mart p h o ne a p pli cati o n, fr o m c o nse nt u p t o 1 0 0 da ys after t he last 
d ose of st u d y i nter ve nti o n . St u d y St aff t o re vi e w partici pa nt’s data via A pri cit y O nc ol o g y ™, a cli ni cal das h boar d we bsite at re g ul ar i nter vals per trai ni n g 
m at eri als.  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 3  
2  
I N T R O D U C TI O N 
2. 1  
S T U D Y R A TI O N A L E  
T he ai m of t his st u d y is t o pr o vi de a pr os pecti ve classificati o n of C D 8 hi g h  (i m m u n ol o gicall y 
“h ot ”) vers us C D 8 l o w  (i m m u n ol o gicall y “c ol d”) t u m ors at t he ti me of treat me nt, base d o n t he 
per ce nt a ge of C D 8 cells i n a t u m or bi o ps y, a n d t o a d dress t he pre dicti ve val ue of t he C D 8 
bi o mar ker f or selecti n g patie nts f or tr eat me nt wit h ni v ol u ma b wit h or wit h o ut i pili m u ma b . 
2. 2  
B A C K G R O U N D  
I m m u n o-o nc ol o g y is a pr o misi n g ne w area f or ca ncer t hera pe utics. T he i m m u ne s yste m is 
ca pa ble of e x q uisite a da ptati o n a n d selecti ve tar geti n g, a pr ocess t hat is n o w bei n g har nesse d a n d 
dir ecte d t o war ds a d va nce d ca ncer. I m m u n o -o nc ol o g y t hera pies ma ni p ulate t he i m m u ne res p o nse  
a gai nst ca ncer i n se ver al wa ys. Vacci nes ha ve bee n de vel o pe d wit h t he g oal of pri mi n g t he 
cell ular a n d h u m or al i m m u ne r es p o nse t o war ds s pecific ca ncer a nti ge ns. Ot her t hera pies tar get 
t he s pecific mec ha nis ms t hat ca ncer cells use t o a v oi d detecti o n b y t he h ost i m m u ne s yste m. 
T hese e vasi o n mec ha nis ms ta ke a d va nta ge of i m m u ne “c hec k p oi nts” t hat re g ulate t he cell ular 
i m m u ne r es p o nse. Ma n y ca ncer t y pes hijac k  t hese mec ha nis ms t here b y re n deri n g t he i m m u ne 
s yste m u na ble t o m o u nt a n eff ecti ve a ntit u m or i m m u ne resp o nse.  
2. 2. 1  
I m m u ne C hec k p oi nt I n hi bit ors 
I m m u ne c hec k p oi nt i n hi bit ors, s uc h as i pili m u ma b a n d ni v ol u ma b, ha ve res ulte d i n re mar ka ble 
cli nical be nefits, i ncl u di n g d ur a ble cli nical res p o nses a n d i m pr o ve d s ur vi val, i n se veral t u m or 
t y pes. H o we ver, des pite t his i m porta nt a d va nce me nt, t he be nefit of i m m u n o -o nc ol o g y is li mite d 
t o a mi n orit y of patie nts a n d o nl y i n a fe w i n dicati o ns. F or e xa m ple, f oll o wi n g treat me nt wit h a 
pr o gr a m me d cell deat h -1 ( P D -1) a nti b o d y, 3 1 % t o 3 4 % of a d va nce d mela n o ma patie nts  
(We ber  et al, 2 0 1 5; R o bert et al, 2 0 1 5 ), 1 9 % t o 2 0 % of n o n-s mall cell l u n g ca ncer ( N S C L C) 
patie nts  (B or g haei et al, 2 0 1 5 ; Br a h mer et al, 2 0 1 5 ; Her bst et al, 2 0 1 6 ), a n d 2 5 % of re nal cell 
car ci n o ma ( R C C) patie nts (M otzer et al, 2 0 1 5 ) ha ve d ura ble o bjecti ve ( partial or c o m plete) 
r es p o nses a n d i m pr o ve d o ver all s ur vi val ( O S) c o m pare d wit h c o n ve nti o nal t hera pies. 
I pili m u ma b, a h u ma n m o n ocl o nal a nti b o d y ( m A b) t hat bl oc ks c yt ot o xic T-l y m p h oc yte-
ass ociate d a nti ge n -4 ( C T L A -4) o n T cells (a p pr o ve d i n 2 0 1 1), ac hie ves d ura ble cli nical 
r es p o nses i n ~ 1 0 % of patie nts wit h a d va nce d mela n o ma  a n d 5 -year O S rates of ~ 1 8 % 
(H o di  et al, 2 0 1 0; Sc ha de n d orf et al, 2 0 1 5 ; Mai o et al, 2 0 1 5 ). B ot h ni v ol u ma b a n d 
pe m br oliz u ma b , w hic h ar e a nti-P D -1 m A bs (a p pr o ve d i n 2 0 1 4), ac hie ve cli nical res p o nses i n 
3 1 % t o 3 4 % of a d va nce d mela n o ma patie nts, a n d m ost res p o nses are d ura ble ( We ber  et al, 2 0 1 5; 
R o ber t et al, 2 0 1 5). W hile t he acti vit y o bser ve d wit h si n gle-a ge nt a nti -P D -1 m A bs is si g nifica nt, 
c o m bi ne d treat me nt wit h i pili m u ma b a n d ni v ol u ma b (a p pr o ve d i n 2 0 1 5) res ults i n cli nical 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 4  
r es p o nses of 5 5 % t o 6 0 % i n metastatic mela n o ma patie nts (Ri bas et al, 2 0 1 7 ; Lar ki n et al, 2 0 1 5 ). 
Si milarl y, ni v ol u ma b pl us i pili m u ma b als o s h o we d si g nifica ntl y hi g her O R R c o m pare d wit h 
s u niti ni b ( 4 2 % vs 2 7 %) i n pr e vi o usl y u ntreate d a d va nce d R C C patie nts ( M otzer et al, 2 0 1 8 ). 
H o we ver, t he i m pr o ve me nt i n cli nical acti vit y ac hie ve d wit h ni v ol u ma b i n  c o m bi nati o n wit h 
i pili m u ma b is acc o m pa nie d b y i ncr ease d si de effects; G ra de 3 or 4 e ve nts occ urre d i n 5 9 % of 
patie nt s i n t he ni v ol u ma b pl us i pili m u ma b gr o u p, i n 2 1 % of t h ose i n t he ni v ol u ma b gr o u p, a n d i n 
2 8 % i n t he i pili m u ma b gr o u p ( W olc h o k et al, 2 0 1 7 ). T h us, t here is a critical nee d f or bi o mar kers 
t hat ca n pr e dict w hic h ca ncer patie nts will be nefit fr o m i pili m u ma b a n d ni v ol u ma b c o m bi nati o n 
t her a p y.  
2. 2. 2  
Bi o m ar kers t o Pre dict Be nefit fr o m Tre at m e nt wit h I m m u ne 
C hec k p oi nt I n hi bit ors  
Certai n t u m ors ar e pri me d a n d r ea d y t o res p o n d t o treat me nt wit h a n a nti -P D -1 a nti b o d y, a n d 
ot hers ar e n ot. Ca ncer patie nts w h o be nefit fr o m a nti -P D -1 treat me nt are c haracterize d as ha vi n g 
“ h ot” t u m ors, w her eas t h ose w h o d o n ot res p o n d t o a nti -P D -1 treat me nt are c haracterize d as 
ha vi n g “c ol d”  t u m ors. Se ver al bi o mar kers ha ve bee n pr o p ose d t o classif y a t u m or as “ h ot” 
vers us “c ol d ,” i ncl u di n g pr o gr a m me d cell deat h li ga n d -1 ( P D -L 1 ) e x pressi o n, t u m or m utati o n 
b ur de n  (Ri zv i et al, 2 0 1 5), i nterf er o n-ga m ma e x pressi o n  (A yers et al, 2 0 1 7 ), t u m or i m m u ne 
si g nat ur e (C he n et al, 2 0 1 6 ), f ecal micr o bi o me pr ofile (G o pala kris h na n et al , 2 0 1 8 ), a n d t he 
e xte nt of t he C D 8 T -cell i nfiltr ate (He g de et al, 2 0 1 6 ). T hese bi o mar kers ha ve a n ass ociati o n 
wit h t he C D 8 T -cell i nfiltr ate (Ma b y et al, 2 0 1 5 ; T h o m ps o n et al, 2 0 1 7 ; R o y a n d Tri nc hieri, 
2 0 1 7 ). Se ver al cli nical st u dies ha ve s h o w n t hat cli nical res p o nse t o a nti-P D -1 treat me nt is 
c orr elate d wit h t he pr e -tr eat me nt n u m ber or t he perce nt a ge of  t u m oral C D 8 cells (T u me h et al, 
2 0 1 4 ; C he n et al, 2 0 1 6 ; J o h ns o n et al, 2 0 1 6). T heref ore, lar ger n u m bers of t u m oral C D 8 cells 
ma y be a usef ul bi o mar ker t o i de ntif y “ h ot”  ( C D 8 hi g h)  t u m ors. 
F urt her m or e, a n i ncr ease i n t u m oral C D 8 cells has bee n o bser ve d after a nti -P D -1 treat me nt, a n d 
t his i ncr ease is ass ociate d wit h i m pr o ve d cli nical o utc o mes i n mela n o ma a n d s q ua m o us cell 
car ci n o ma of t he hea d a n d nec k ( S C C H N; C he n et al, 2 0 1 6 ; C o nc ha -Be n a ve nte et al, 2 0 1 7 ). 
F oll o wi n g a nti -P D -1 tr eat me nt, a si g nifica nt i ncrease i n i ntrat u m oral C D 8  cells was see n i n 
r es p o n ders b ut n ot i n n o n-r es p o n ders (Fi g ure 5 ). 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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Fi g ure 5 :  
T u m or -i nfilt r ati n g C D 8 T-cell E x pressi o n i n Res p o n ders a n d N o n -
res p o n ders t o P D -1 Bl oc k a de  
 
T u m or sa m pl es were stai ne d b y i m m u n o hist oc he mistr y wit h p o ol e d data i n pa nel A a n d re prese ntati ve i m a ges i n 
pa nel B. A da pt e d fr o m C he n et al. 2 0 1 6 . 
Tr eat me nt wit h i pili m u ma b m o n ot her a p y als o res ults i n a n i ncrease i n C D 4 a n d C D 8 T cells i n 
t he t u m or (Ga o et al, 2 0 1 7 ; K vist b or g et al, 2 0 1 4 ). I n a precli nical t u m or m o del, a nti-C T L A -4 
tr eat me nt of t u m or-beari n g a ni mals r es ulte d i n a si g nifica nt i ncrease i n  i ntra vasc ular C X C L 9 a n d 
E -selecti n e x pr essi o n, w hic h ar e i n v ol ve d i n me diati n g C D 8 T-cell e xtra vasati o n a n d e ntr y i nt o 
t he t u m or (Wils o n et al, 2 0 1 6 ). T her ef ore, a d di n g i pili m u ma b t o a nti-P D -1 treat me nt c o ul d 
f urt her pro m ote t he tr affic ki n g of C D 8 T cells i nt o t he t u m or micr oe n vir o n me nt. T his h y p ot hesis 
is s u p p orte d b y r ece nt fi n di n g i n a s mall s u bset of partici pa nts fr o m t he C hec k Mate 0 3 8 st u d y i n 
w hic h t he c o m bi nati o n of i pili m u ma b a n d ni v ol u ma b si g nifica ntl y i n d uce d h i g her perce nta ge of 
t u m or al C D 8 cells c o m par e d wit h ni v ol u ma b al o ne (Fi g ure  6 ; Ri bas et al, 2 0 1 7). I n a d diti o n, t he 
c o m bi nati o n of i pili m u ma b a n d ni v ol u ma b yiel de d a hi g her res p o nse rate c o m pare d wit h 
ni v ol u ma b al o ne ( Lar ki n et al, 2 0 1 5 ). 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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Fi g ure 6 :  
T u m or -i nfilt r ati n g C D 8 T-cell E x pressi o n b y Best O ver all Res p o nse 
 
C R = cli nic al res p o nse; I pi = i pili m u m a b; N E = n ot e val ua ble; Ni v o = ni v ol u ma b; P D = pr o gressi ve dise ase; 
P R  =  partial res p o nse; S D = st a bl e dise ase.  
Bi o mar ker st u d y o n P hase 1 b C he c k Mate 0 3 8 st u d y a n d t u m or bi o psies were assesse d b y i m m u n o hist oc he mistr y.  
A da pte d fr o m Ri bas oral prese ntati o n at 2 0 1 7 A A C R.  
 
I n s u m mar y, b ot h pr e-tr eat me nt t u m oral C D 8 cells a n d recr uit me nt of C D 8 T cells i n res p o nse t o 
i m m u ne c hec k p oi nt i n hi bit ors ar e ass ociate d wit h i m pr o ve d cli nical o utc o mes i n patie nts  treate d 
wit h a nti -P D -1 t her a p y. T hese data s u g gest t hat a rati o nal a p pr oac h t o c o n vert “ C D 8 l o w t u m ors 
i nt o “C D 8 hi g h t u m ors is t hr o u g h c o m bi nati o n treat me nt a p pr oac hes wit h a nti-P D -1 a n d a nti -
C T L A -4 m A bs t hat ca n r ecr uit m or e C D 8 T cells t o t he t u m or (Haa ne n, 2 0 1 7 ). 
A pr os pecti ve st u d y wit h lar ger sa m ple size is warra nte d t o c o nfir m t hat t he perce nt a ge of 
t u m or al C D 8 cells at t he ti me of tr eat me nt ca n deter mi ne res p o nsi ve ness t o a nti -P D -1 t hera p y 
a n d w het her c o m bi na ti o n t her a p y ca n c o n vert t u m ors fr o m C D 8 l o w  t o C D 8 hi g h . We pr o p ose a 
pr os pecti ve cli nical st u d y i n w hic h patie nts wit h var yi n g a d va nce d  s oli d t u m ors will be assi g ne d 
t o 1 of 2 tr eat me nt ar ms base d o n t he perce nt a ge of t u m oral C D 8 cells at t he ti me of treat me nt. 
Partici pa nts  w h o ha ve a t u m or wit h ≥ 1 5 % C D 8 cells (classifie d as C D 8 hi g h ) will recei ve 
ni v ol u ma b m o n ot her a p y, a n d partici pa nts  w h o ha ve a t u m or wit h <  1 5 % C D 8 cells (classifie d as 
C D 8 l o w ) will r ecei ve i pili m u ma b i n c o m bi nati o n wit h ni v ol u ma b. 
It is well r ec o g nize d t hat i m m u ne i nfiltrati o n varies acr oss t u m or t y pes, a n d differe nt t u m or t y pes 
ma y dis pla y a r a n ge of t her a pe utic se nsiti vities. Se veral o n g oi n g st u dies are e val uati n g 
ni v ol u ma b  tr eat me nt i n vari o us t u m or t y pes (B M S Ni v ol u ma b St u dies ). T o better assess t he 
f easi bilit y of usi n g per ce nt of  t u m or al C D 8 cells as a bi o mar ker f or selecti n g c hec k p oi nt 
i n hi bit or t her a p y a n d t o gai n m or e i nsi g ht re gar di n g t he desi g n of t he trial, we e xa mi ne d C D 8 
cells i n a set of 1 9 5 t u m or sa m ples fr o m 1 0 differe nt t u m or t y pes (Fi g ure 7 ). F or t u m or t y pes i n 
w hic h a nti -P D -1 tr eat me nt has bee n a p pr o ve d, t he classificati o n of C D 8  hi g h  t u m or is c o nsiste nt 
wit h t he cli nical be nefit r e p orte d. T he 1 5 % c ut off was selecte d bas e d o n data fr o m retr os pecti ve 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
4 7  
st u dies a n d e val uati o n of r es p o nses t o c hec k p oi nt i n hi bit ors. T his st u d y will a d va nce t he fiel d b y 
pr o vi di n g a pr os pecti ve classificati o n of C D 8 hi g h vers us C D 8 l o w t u m ors at t he ti me of 
tr eat me nt, base d o n r es p o nse t o ni v ol u ma b, a n d a d dress t he pre dicti ve val ue of t he C D 8 
bi o mar ker f or selecti n g  patie nts w h o ca n be nefit fr o m ni v ol u ma b wit h or wit h o ut i pili m u ma b . 
Fi g ure 7 :  
P erce nt a ge of T u m or al C D 8 T  C ells b y I m m u n o hist oc he mistr y i n Differe nt 
T u m or T y pes  
 
A D C = a de n oc arci n o ma; C R C = c ol orect al c a ncer; G B M = gli o bl ast o ma m ultif or me; H C C = he pat ocell ular 
c arci n o ma; I H C = i m m u n o hist oc he mistr y; M SI  =  mi cr osatellit e i nst a bl e; M S S = mi cr osatellite st a bl e; 
R C C  =  re nal cell c arci n o ma; S C C = s q ua m o us cell carci n o ma. 
I H C is perf or me d o n f or m ali n-fi xe d paraffi n-e m be d de d ( F F P E) t u m or sa m pl es o btai ne d fr o m a c o h ort 
of  u ntreate d ca ncer pati e nts. T u m or  tiss ues were fi xe d i n 1 0 % f or m ali n, e m be d de d i n paraffi n, a n d tra ns versel y 
se cti o ne d; 4 -μ m secti o ns were use d f or t he I H C st u d y. Se cti o ns were stai ne d wit h m o use a nti-h u m a n m o n ocl o nal 
a nti b o dies a gai nst C D 8  ( T her m o Scie ntific, M S-4 5 7 -S).  Q ua ntitati ve a nal ysis of I H C stai ni n g was c o n d uct e d 
usi n g t he i ma ge a nal ysis s oft ware I ma ge Sc o pe -A peri o/ L ei ca. Fi ve ra n d o m are as ( 1 m m 2 ea c h) were sele ct e d, a n d 
a c ust o miz e d s oft ware al g orit h m f or ea c h i m m u n ol o gic mar ker was use d t o det er mi ne t he perce nt a ge of p ositi ve 
c ells per hi g h -p o wer fi el d. T he dat a are e x presse d as a perce nt a ge sc ore (t otal n u m ber of p ositi ve cells di vi de d b y 
t he t ot al n u m ber of c ells  a n d m ulti plie d b y 1 0 0).  I H C stai ni n g was i nt er prete d i n c o nj u ncti o n wit h he m at o x yli n 
a n d e osi n stai ne d se cti o ns, w hic h facilitate d t he i de ntifi cati o n of mali g na nt cells a n d t h us dire ct e d I H C 
q ua ntific ati o n.  
 
2. 2. 3  
I m m u ne C hec k p oi nt I n hi bit or T her a pies i n t he Tre at m e nt of 
A d v a nce d  Pr ost ate C a ncer  
I m m u ne c hec k p oi nt t her a pies tar geti n g t he C T L A-4 a n d/ or P D -( L) 1 pat h wa y ha ve de m o nstrate d 
a s ur vi val be nefit i n m ulti ple mali g na ncies. Si n gle a ge nt i pili m u ma b a n d ni v ol u ma b ha ve bee n 
st u die d i n m ulti ple cli nical a n d pr ecli nical st u dies acr oss ma n y t u m or t y pes; h o we ver, b ot h ha ve 
ha d li mite d cli nical efficac y as m o n ot hera pies i n patie nts wit h a d va nce d pr ostate ca ncer ( A P C).  
Cli nical acti vit y has bee n o bser ve d i n s u bsets of A P C  patie nts i n a n u m ber of cli nical trials, 
i ncl u di n g a p hase 1/ 2 st u d y i n partici pa nts wit h metastatic castrati o n -resista nt pr ostate ca ncer 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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(m C R P C ) t hat e x pl or e d i pili m u ma b as m o n ot hera p y a n d i n c o m bi nati o n wit h ra di ot hera p y, 
base d o n t he pr ecli nical e vi de nce of s y ner gistic a ntit u m or acti vit y bet wee n a nti -C T L A -4 
a nti b o d y a n d r a di ot her a p y. W hile e val uati n g a d verse e ve nts, pr ostate -s pe ci ﬁc a nti ge n ( P S A) 
decli ne, a n d t u m or r es p o nse, it was f o u n d t hat i pili m u ma b e ver y 3 wee ks f or 4 d oses at 3, 5, or 
1 0 m g/ k g ± r a di ot her a p y s u g geste d cli nical a ntit u m or acti vit y wit h disease c o ntr ol a n d 
ma na gea ble A Es  (Sl o vi n et al., 2 0 1 3 ). 
Data ha ve s h o w n t hat i pili m u ma b d osi n g u p t o 1 0 m g/ k g i n m C R P C ( wit h/ wit h o ut stere otactic 
b o d y r a diati o n t her a p y) has a ma na gea ble safet y pr ofile. Metastatic castrati o n -resista nt pr ostate 
ca ncer partici pa nts w h o ha d r ecei ve d d oceta xel were e val uate d i n a ra n d o mize d cli nical trial wit h 
i pili m u ma b vers us place b o ( N C T 0 0 8 6 1 6 1 4 ). Alt h o u g h t he st u d y faile d t o meet t he pri mar y 
e n d p oi nt of i m pr o vi n g o ver all s ur vi val, it de m o nstrate d i m pr o ve d P F S a n d P S A res p o nse i n 
t h ose partici pa nts a d mi nister e d i pili m u ma b e ver y 3 wee ks f or u p t o 4 d oses c o m pare d t o place b o 
(K w o n et al., 2 0 1 4 ). P ost-st u d y a nal yses s u g geste d t hat i pili m u ma b i m pr o ve d s ur vi val i n patie nts 
wit h o ut viscer al metastasis, w h o ha d l o wer le v els of al kali ne p h os p hatase a n d ha d ele vate d 
he m o gl o bi n le vels at baseli ne ( Dr a ke et al., 2 0 1 4 ).  
I n a d o u ble-bli n d cli nical trial e val uati n g 5 9 8 A P C  patie nts, c he m ot hera p y -nai ve partici pa nts 
wer e r a n d o mize d 2: 1 t o r ecei v e i pili m u ma b at 1 0 m g/ k g ( n = 3 9 9) or place b o ( n = 1 9 9) e ver y 
3  wee ks f or u p t o 4 d oses, wit h i pili m u ma b at 1 0 m g/ k g or place b o mai nte na nce gi ve n t o 
n o n -pr o gr essi n g patie nts e ver y 3 m o nt hs (N C T 0 1 0 5 7 8 1 0 ). Alt h o u g h i pili m u ma b al o ne di d n ot 
i m pr o ve o ver all s ur vi val i n t h ose a d va nce d pr ostate ca ncer patie nts, i ncreases i n pr o gressi o n-free 
s ur vi val a n d pr ostate-s pecific a nti ge n res p o nse rates were o bser ve d, s u g gesti n g a ntit u m or 
acti vit y i n a s u bset of patie nts wit h c he m ot hera p y -nai ve metastatic castrati o n -resista nt pr ostate 
ca ncer wit h o ut viscer al metastases. (Beer et al., 2 0 1 7 ).  
I n t hese 2 lar ge p hase 3 trials (K w o n et al., 2 0 1 4 ; Beer et al., 2 0 1 7 ), i pili m u ma b (a nti-C T L A -4; 
1 0  m g/ k g Q 4 W ) f aile d t o i m pr o ve s ur vi val i n me n wit h m C R P C, w hic h ma y be attri b ute d t o t he 
i m m u n ol o gicall y “c ol d” pr ostate t u m or micr oe n vir o n me nt, c haracterize d b y l o w t u m or 
m utati o nal b ur de n, pa ucit y of T cells, a n d hi g h fre q ue nc y of i m m u n os u p pressi ve cells. 
I nter esti n gl y, i n t u m ors fr o m patie nts i n a pres ur gical cli nical trial i pili m u ma b i n d uce d 
i ntr at u m or al T cell i nfiltr ati o n; h o we ver, t his was c o u ntere d b y i ncrease d e x pressi o n of t he 
i m m u ne c hec k p oi nt, P D-L 1, wit hi n t he pr ostate t u m or micr oe n vir o n me nt ( Ga o et al. , 2 0 1 7). 
T his le d t o t he desi g n a n d accr ual of t he C hec k Mate 6 5 0 cli nical trial ( N C T 0 2 9 8 5 9 5 7 ), w hic h 
r ece ntl y de m o nstr ate d pr o misi n g d ur a ble a ntit u m or res p o nses i n a s u bset of  patie nts wit h 
m C R P C tr eate d wit h t he c o m bi nati o n  of ni v ol u ma b pl us i pili m u ma b usi n g t he a p pr o ve d 
mela n o ma d osi n g a n d sc he d ule ( ni v ol u ma b 1 m g/ k g a n d i pili m u ma b 3 m g/ k g Q 3 W u p t o 
4  c ycles, t he n ni v ol u ma b 4 8 0 m g Q 4 W) ( S har ma et al., 2 0 1 9 ). 

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T he saf et y pr ofile of i pili m u m a b i n C R P C has bee n well c haracterize d as a m o n ot hera p y at d oses 
u p t o 1 0 m g/ k g ( K w o n et al., 2 0 1 4 ; Beer et al., 2 0 1 7 ) or i n c o m bi nati o n wit h ra diati o n, at d oses  
u p t o 5  m g/ k g wit h vacci nes ( Ma da n et al., 2 0 1 2 ) a n d i n c o m bi nati o n wit h ni v ol u ma b at 
i pili m u ma b d oses of 1 a n d 3 m g/ k g ( C hec k Mate-6 5 0, S har ma et al., 2 0 1 9 ). W hile si de effects are 
ma na gea ble, data fr o m ot her t u m or t y pes, s uc h as N S C L C ( C hec k M ate -2 2 7, Hell ma n n et al., 
2 0 1 9 ; C hec k Mate-5 6 8, Rea d y et al., 2 0 1 9 ), s u g gest t hat less fre q ue nt d osi n g of i pili m u ma b ma y 
i m pr o ve t oler a bilit y w he n a d mi nister e d i n c o m bi nati o n wit h ni v ol u ma b.   
C hec k p oi nt i n hi bi t or tr eat me nt be nefit ca n be ass ociate d wit h t he prese nce of C D 8 T cells i n t he 
t u m or, a n d C T L A-4 tr eat me nt has bee n s h o w n t o pr o m ote T cell i nfiltrati o n, t h us h y p ot hesizi n g 
t hat t he c o m bi nati o n of i pili m u ma b a n d ni v ol u ma b ma y pr o m ote t u m oral T cell i nfiltrati o n a n d 
a ntit u m or i m m u nit y.  
Pr ecli nical a n d cli nical data s u p p ort t hat i pili m u ma b pr o m otes T cell i nfiltrati o n i n t he t u m or , yet 
t he necessar y d osi n g a n d sc he d uli n g of treat me nts re mai n u nclear. D ose-fi n di n g st u dies f or 
si n gle-a ge nt i pili m u ma b ha ve bee n st u die d i n m ulti ple cli nical a n d precli nical st u dies. Cli nical 
r es p o nses ar e c o nsiste ntl y o bser ve d at i pili m u ma b le vels of ≥ 3 m g/ k g, a n d a nal ysis fr o m 
mela n o ma cli nical st u dies s u g gest t hat t u m or res p o nses i m pr o ve fr o m 3 t o 1 0 m g/ k g. T he 
h y p ot hesis t hat  i pili m u ma b tri g gers l o n g-lasti n g a ntit u m or i m m u nit y s u g gests t hat pr o vi di n g it 
earlier d uri n g t he c o urse of pr ostate ca ncer ma y pr o vi de a m ore mea ni n gf ul be nefit ( K we k et al., 
2 0 1 2 ; Ma da n et al., 2 0 0 9 ). 
Pr eli mi nar y e vi de nce fr o m a d va nce d pr ostate ca ncer partici pa nts e nr olle d i n t he 
i pili m u ma b a n d ni v ol u ma b ar m of PI CI 0 0 2 5 has de m o nstrate d  cli nical acti vit y i n t u m ors wit h a 
l o w C D 8 le vels i n t he t u m or at baseli ne, i ncl u di n g a n i ncrease in t he T cell i nfiltrati o n. We  
p ost ulate t hat a l o w d ose of i pili m u ma b i n s uc h t u m ors ma y pr o vi de a m o derate C D 8 i nfiltrati o n 
(N C T 0 3 6 5 1 2 7 1 ) a n d t hat hi g her d oses of i pili m u ma b ma y res ult i n a hi g her n u m ber of 
partici pa nts ha vi n g  i ncr ease d C D 8 T cell i nfiltrati o n, a n d t hat t he c o m bi nati o n of ni v ol u ma b a n d 
i pili m u ma b ma y  r es ult i n i m pr o ve d a ntit u m or i m m u nit y (N C T 0 3 6 5 1 2 7 1 ).  
2. 3  
B E N E FI T/ RI S K A S S E S S M E N T  
Ni v ol u ma b has de m o nstr ate d d ur a ble r es p o nses e x cee di n g 6 m o nt hs as m o n ot hera p y a n d i n 
c o m bi nati o n wit h i pili m u ma b i n se ver al t u m or t y pes, i ncl u di n g N S C L C, mela n o ma, R C C, a n d 
S C C H N . I n c o nfir mat or y trials, ni v ol u ma b as m o n ot hera p y de m o nstrate d a statisticall y 
si g nifica nt i m pr o ve me nt i n O S c o m pare d wit h t he c urre nt sta n dar d of care i n partici pa nts wit h 
pr e vi o usl y tr eate d a d va nce d or metastatic N S C L C, u nresecta ble or metastatic mela n o ma, 
pr e vi o usl y tr eate d a d va nce d R C C, or pre vi o usl y treate d rec urre nt or metas tatic S C C H N. 
Ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b i m pr o ve d pr o gressi o n -free s ur vi val (P F S ) a n d 
o bjecti ve r es p o nse r ate ( O R R ) o ver i pili m u ma b al o ne i n partici pa nts wit h u nresecta ble or 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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5 0  
metastatic mela n o ma  (Ri bas et al, 2 0 1 7 ; Lar ki n et al, 2 0 1 5 ). Si milarl y, ni v ol u ma b pl us 
i pili m u ma b de m o nstr ate d si g nifica ntl y hi g her O S  a n d O R R c o m pare d wit h s u niti ni b i n 
i nter me diate- a n d p o or -ris k patie nts wit h pre vi o usl y u ntreate d a d va nce d R C C (M otzer et al, 
2 0 1 8 ). 
T he o ver all saf et y e x perie nce wit h ni v ol u ma b, as m o n ot hera p y or i n c o m bi nati o n wit h ot her 
t her a pe utics, is base d o n e x perie nce i n a p pr o xi matel y 2 0, 0 0 0  patie nts treate d t o date (Ni v ol u ma b 
I n vesti gat or’s Br oc h ur e, 2 02 0 ). F or m o n ot hera p y, t he safet y pr ofile is si milar acr oss t u m or t y pes. 
T her e is n o patter n i n t he i nci de nce, se verit y, or ca usalit y of a d verse e ve nts ( A Es ) t o ni v ol u ma b 
d ose le vel. I n p hase 3 c o ntr olle d st u dies, t he safet y pr ofile of ni v ol u ma b m o n ot hera p y is 
acce pta ble i n t he c o nte xt of t he o bser ve d cli nical efficac y a n d ma na gea ble usi n g esta blis he d 
saf et y g ui deli nes. Cli nicall y r ele va nt A Es t y pical of sti m ulati o n of t he i m m u ne s yste m were 
i nfr e q ue nt a n d ma na gea ble b y dela yi n g or st o p pi n g ni v ol u ma b treat me nt a n d usi n g ti mel y 
i m m u n os u p pr essi ve t her a p y or ot her s u p p orti ve care.  
I n se ver al o n g oi n g cli nical trials, t he safet y of ni v ol u ma b i n c o m bi nati o n wit h ot her t hera pe utics 
s uc h as i pili m u ma b, c yt ot o xic c he m ot hera p y, a nti -a n gi o ge nics, a n d tar gete d t hera pies is bei n g 
e x pl or e d. M ost st u dies ar e o n g oi n g, a n d, as s uc h, t he safet y pr ofile of ni v ol u ma b c o m bi nati o ns 
c o nti n ues t o e v ol ve. T he m ost a d va nce d c o m bi nati o n u n der de vel o p me nt is ni v ol u ma b i n 
c o m bi nati o n wi t h i pili m u ma b, w hic h is a p pr o ve d i n patie nts wit h u nresecta ble or metastatic 
mela n o ma a n d bei n g st u die d i n m ulti ple t u m or t y pes. Res ults t o date s u g gest t hat t he safet y 
pr ofile of ni v ol u ma b  a n d i pili m u ma b c o m bi nati o n t hera p y is c o nsiste nt wit h t he mec ha nis ms of 
acti o n of ni v ol u ma b a n d i pili m u ma b. T he nat ure of t he A Es is si milar t o t hat o bser ve d wit h 
eit her a ge nt use d as m o n ot her a p y; h o we ver, b ot h fre q ue nc y a n d se verit y of m ost A Es are 
i ncr ease d wit h t he c o m bi nati o n.  
O ver all, t hese fi n di n gs s u p p ort a f a v or a ble be nefit -ris k pr ofile f or ni v ol u ma b wit h or wit h o ut 
i pili m u ma b acr oss vari o us t u m or t y pes. M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d 
e x pecte d be nefits a n d ris ks a n d r eas o na bl y e x pecte d A E s of ni v ol u ma b a n d i pili m u ma b  ma y be 
f o u n d i n t he r es pecti ve I n vesti gat or’s Br oc h ures (I B; I pili m u ma b I B, 2 0 2 0; Ni v ol u ma b I B, 
2 0 2 0 ). 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
5 1  
3  
O B J E C TI V E S A N D E N D P OI N T S  
T he st u d y o bjecti ves a n d e n d p oi nts ar e liste d i n T a ble 5 . 
T a ble 5 : 
O bj ecti ves a n d C orres p o n di n g E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
•  T o deter mi ne t he  cli ni cal be nefit rat e ( C B R) of 
ni v ol u ma b wit h or wit h o ut i pili m u ma b i n 
parti ci pa nts wit h a d va nc e d m et astati c ca ncer , 
i ncl u di n g a d va nce d pr ostate c a nc er. 
•  T o assess t he pr o p orti o n of partici pa nts i n t he 
ni v ol u ma b pl us i pili m u m a b ar m w h ose t u m ors will 
c ha n ge fr o m C D 8 l o w  t o C D 8 hi g h as me as ure d b y 
a c ha n ge i n t he perc e nta ge of t u m or al C D 8 cells.  
•  C B R  is t he pr o p orti o n  of parti ci pa nts  w h o s h o w 
cli ni cal be nefit, defi ne d as C R, P R, or S D f or 
≥ 6  m o nt hs as best res p o nse b y R E CI S T v 1. 1.  
•  C ha n ge  i n t he perc e nt a ge of C D 8 c ells i n o n -
treat m e nt bi o psies fr o m baseli ne. 
Se c o n dar y  
 
•  T o deter mi ne t he safet y a n d t ol era bilit y  of 
ni v ol u ma b wit h or wit h o ut i pili m u ma b i n 
parti ci pa nts wit h a d va nc e d m et astati c ca ncer , 
i ncl u di n g a d va nce d pr ostate c a nc er. 
•  T o deter mi ne t he O R R of ni v ol u m a b wit h or wit h o ut 
i pili m u ma b i n partici pa nts wit h a d va nce d metast atic 
c a nc er, i ncl u di n g a d va nc e d pr ost at e ca ncer. 
•  T o assess t he ass oci ati o n of perce nt a ge of C D 8 
i nfiltrati o n i n t u m or sa m ples wit h cli ni cal o utc o m es 
( O R R, P F S, a n d O S). 
•  I nci de nc e a n d se verit y of A Es base d o n C T C A E 
v 5 . 0. 
•  O R R: Defi ne d as C R or P R as best res p o nse b y 
R E CI S T v 1. 1 assess m e nt.  
•  P F S: Defi ne d as t he ti m e fr o m i nitiati o n of st u d y 
t hera p y t o dat e of first d oc u me nte d pr o gressi o n of 
dise ase  or  date of de at h d ue t o a n y ca use.  
•  O S: Defi ne d as t he ti me fr o m i niti ati o n of  st u d y 
t hera p y u ntil de at h d ue t o a n y c a use . 
E x pl orat or y  
 
•  T o e val uate t u m or i m m u ne bi o m ar kers a n d t heir 
ass ociati o n wit h treat m e nt o utc o me s. 
•  T o e val uate c ha n ges i n p r ostate-specifi c a nti ge n 
( P S A) (a d va nc e d pr ost ate ca ncer).  
•  T o assess fe asi bilit y of i m pl e m e nti n g t he 
A pri cit y Care ™ di git al a p plic ati o n (a p p) f or 
par ti ci pa nts bei n g treate d wit h im m u ne c hec k p oi nt 
i n hi bit or(s) a n d t he use b y st u d y st aff of 
A pri cit y O nc ol o g y ™ we bsit e.  
•  Cli ni cal res p o nses base d o n a c o m p osite bi o m ar ker 
deri ve d fr o m n ucl eic aci ds, e pi ge netics, pr ot ei n, 
i m m u ne c ell c haracteristi cs, or ot her fa ct ors 
( C D 8 a n d ot her bi o m ar kers).  
•  A d diti o nal bi o m ar kers of pri m ar y resista nce t o 
ni v ol u ma b or i pili m u m a b c o m bi ne d wit h ni v ol u m a b 
be y o n d t he perc e nt a ge of t u m oral C D 8 cells base d 
o n a d diti o nal i m m u ne e val uati o n of baseli ne a n d o n -
treat m e nt bi o psies or bl o o d sa m ples. 
•  P ot e nti al rel ati o ns hi p of T -cell p he n ot y pi c 
c hara ct eristics a n d i m m u ne c hara ct eristics i n t he 
t u m or micr oe n vir o n me nt i n part i ci pa nts o n 
ni v ol u ma b m o n ot hera p y a n d ni v ol u m a b i n 
c o m bi nati o n wit h i pili m u ma b wit h cli ni cal o ut c o m es 
(cli nic al be nefit e n d p oi nts a n d A Es wit h a n i nt erest 
i n i m m u ne-rel at e d A Es). 
•  Wit hi n ea c h st u d y i nter ve nti o n ar m, e x pl ore t he 
p ot e ntial rel ati o ns hi p of cli ni cal 
res p o nse/resist a nc e/ A E wit h: 
o  
m R N A q ua ntit y a n d e x pressi o n i n t u m or 
a n d/ or P B M Cs  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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O bjecti ves  
E n d p oi nts  
o  
G er mli ne D N A a n d/ or t u m or ge n o mi cs  
o  
M ulti para meter c yt o metr y of t u m or a n d/ or 
P B M Cs  
o  
Im m u ne mar kers i n P B M Cs  
o  
B l o o d circ ul ati n g a nal ytes 
o  
T C R re pert oire i n t u m or a n d peri p heral bl o o d  
o  
B aseli ne a n d o n -treat m e nt micr o bi o m e 
•  I de ntif y m ol ec ul ar ( ge n o mi c, meta b oli c, a n d/ or 
pr ot e o mi c) bi o mar kers t hat m a y be i n dic ati ve of 
cli ni cal res p o nse/resist a nc e, safet y, 
p har m ac o d y na mi c acti vit y, a n d/ or m ec ha nis m of 
a cti o n of ni v ol u m a b a n d/ or i pili m u ma b i n 
c o m bi nati o n wit h ni v ol u m a b . 
•  C ha n ge i n P S A fr o m baseli ne (a d va nc e d pr ostate 
c a nc er). 
•  Fre q ue nc y of A pricit y Care ™ a p p usa ge b y 
parti ci pa nts a n d fre q ue nc y of A pricit y O nc ol o g y 
we bsite a cc ess b y st u d y st aff.  
A E = a d verse e ve nt; C B R = cli ni cal be nefit rat e; C R = c o m pl ete res p o nse; C T C A E = C o m m o n T er mi n ol o g y 
Criteria f or A d verse E ve nts; D N A = de o x yri b o n ucl eic aci d; m R N A  =  m esse n ger ri b o n ucleic a ci d; O R R = o bj ecti ve 
res p o nse rat e; O S = o verall s ur vi val; P B M C = peri p heral bl o o d m o n o n ucle ar c ell; P D = pr o gressi ve dise ase; 
P F S  =  pr o gressi o n -fre e s ur vi val; P R = parti al res p o nse; P S A = pr ost at e -s pe cific a nti ge n; R E CI S T  = Res p o nse 
E val uati o n Criteria i n S oli d T u m ors; S D = sta ble disease; T C R = T -cell re ce pt or. 
 
4  
S T U D Y  D E SI G N  
4. 1  
O V E R A L L D E SI G N  
After c o nse nti n g t o partici pate i n t his cli nical trial, partici pa nts will u n der g o t u m or bi o psies. 
C or e nee dle or i ncisi o nal bi o psies will be re q uire d. Fi ne nee dle as pirati o n is n ot acce pta ble. T he 
t u m or tiss ue will be se nt t o U ni versit y  of T e xas M D A n ders o n Ca ncer Ce nter ( M D A C C) Cli nical 
La b or at or y I m pr o ve me nt A me n d me nt ( C LI A) - a n d C olle ge of A merica n Pat h ol o gists ( C A P )-
certifie d I m m u n o hist oc he mistr y a n d I ma ge A nal ysis La b orat or ies t o deter mi ne t he perce nt a ge of 
t u m or al C D 8 cells. T he test f or C D 8 e x pressi o n is a la b orat or y de vel o pe d test use d t o deter mi ne 
partici pa nt eli gi bilit y. T his test is n ot a  F o o d a n d Dr u g A d mi nistrati o n ( F D A )-a p pr o ve d de vice 
a n d its use is i n vesti gati o nal. Partici pa nts will be assi g ne d i m m u n ot hera p y acc or di n g t o t he 
per ce nta ge of C D 8 cells i n t heir t u m or bi o psies:  
•  Partici pa nts wit h ≥ 1 5 % C D 8 cells i n t heir t u m or bi o psies (ie, C D 8 hi g h  t u m ors) will 
be tr eate d wit h si n gle -a ge nt ni v ol u ma b 
•  Partici pa nts wit h < 1 5 % C D 8 cells i n t heir t u m or bi o psies (ie, C D 8 l o w  t u m ors) will 
be tr eate d wit h ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
5 3  
Partici pa nts r ecei vi n g si n gle -a ge nt ni v ol u ma b will be m o nit ore d f or res p o nse a n d safet y. 
Partici pa nts will u n der g o 3  t u m or bi o ps y pr oce d ures t o assess i m m u ne mar kers: 
1.  Pri or t o be gi n ni n g pr ot oc ol t hera p y (ie, baseli ne bi o ps y, ma n dat or y)  
a.  If t he r es ults of t he baseli ne bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he 
per ce nta ge of t u m or al C D 8 cells f or treat me nt assi g n me nt , a sec o n d baseli ne  bi o ps y  
ma y be o btai ne d , if it is me dicall y feasi ble a n d t he partici pa nt is willi n g t o u n der g o 
a n ot her t u m or bi o ps y  
2.  D uri n g tr eat me nt (ie, o n -tr eat me nt bi o ps y; ma n dat or y if me dicall y feasi ble) at u p t o 
2  ti me p oi nts: 
a.  After r ecei vi n g t he sec o n d d ose of ni v ol u ma b  
b.  If t he r es ults of the o n -tr eat me nt bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he 
per ce nta ge of t u m or al C D 8 cells, a sec o n d o n treat me nt bi o ps y ma y be o btai ne d, if it 
is me dicall y f easi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y 
3.  At t he ti me of pr o gr essi ve disease ( P D) pri or t o t he a d diti o n of i pili m u ma b t o ni v ol u ma b 
(if me dicall y f easi ble, i n partici pa nts w h o elect t o recei ve c o m bi nati o n t hera p y) 
 
Partici pa nts r ecei vi n g ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b will als o be m o nit ore d f or 
r es p o nse a n d saf et y. Partici pa nts will u n der g o 3 t u m or bi o ps y pr oce d ures t o assess i m m u ne 
mar kers:  
1.  Pri or t o be gi n ni n g pr ot oc ol t hera p y (ie, baseli ne bi o ps y, ma n dat or y)  
a.  If t he r es ults of t he baseli ne bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he 
per ce nta ge o f t u m or al C D 8 cells f or treat me nt assi g n me nt, a sec o n d baseli ne  bi o ps y 
ma y be o btai ne d, if it is me dicall y feasi ble a n d t he partici pa nt is willi n g t o u n der g o 
a n ot her t u m or bi o ps y  
2.  D uri n g tr eat me nt (ie, o n -tr eat me nt bi o ps y, ma n dat or y if me dicall y feasi ble) at 2 ti me 
p oi nts:  
a.  After r ecei vi n g t he sec o n d d ose of i pili m u ma b  
b.  After r ecei vi n g t he 4t h d ose of i pili m u ma b. Partici pa nts w h o res p o n d t o treat me nt 
will c o nti n ue t o r ecei ve si n gle -a ge nt ni v ol u ma b. 
c.  If t he r es ults of eit her  o n -treat me nt bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n 
t he per ce nta ge of t u m or al C D 8 cells, an a d diti o nal o n -treat me nt bi o ps y ma y be 
o btai ne d, if it is me dicall y feasi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her 
t u m or bi o ps y. A n o pti o nal t u m or bi o ps y sa m ple ma y be c ollecte d u po n disease 
pr o gr essi o n.  
 
4. 1. 1  
A d v a nce d Pr ost ate C a ncer  
1.  Partici pa nts wit h a d va nce d  pr ostate ca ncer w h o are recei vi n g ni v ol u ma b i n c o m bi nati o n 
wit h i pili m u ma b will be m o nit ore d f or res p o nse a n d safet y. Partici pa nts will u n der g o 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
5 4  
o n -tr eat me nt t u m or bi o ps y pr oce d ures t o assess i m m u ne mar kers acc or di n g t o t he 
sc he d ule: 
a.  Wit hi n ± 3 da y s of t he sec o n d  d ose of ni v ol u ma b ( ma n dat or y if me dicall y feasi ble)  
b.  A sec o n d bi o ps y, if me dicall y feasi ble, s h o ul d be o btai ne d at C ycle 2 Da y  
2 2  ( ± 3  da ys of d ose a d mi nistrati o n) . A n o pti o nal t u m or bi o ps y sa m ple ma y be 
c ollecte d u p o n disease pr o gressi o n.  
 
T he st u d y desi g n sc he ma f or a d va nce d metastatic ca ncer are s h o w n i n Fi g ure 1  a n d Fi g ure 2  a n d 
f or a d va nce d pr ostate ca ncer ar e s h o w n i n Fi g ure 3  a n d Fi g ure 4 . 
4. 2  
S CI E N TI FI C R A TI O N A L E F O R S T U D Y D E SI G N  
T he st u d y p o p ulati o n r ati o nale is pr o vi de d i n Secti o n 2 , a n d t he a nal ysis gr o u ps are describe d i n 
Secti o n  9 .  
4. 3  
J U S TI FI C A TI O N F O R D O S E  
4. 3. 1  
R ati o n ale f or Ni v ol u m a b M o n ot her a p y D os e a n d Sc he d ule  
Si n gle -a ge nt ni v ol u ma b will be a d mi nistere d at 3 6 0 m g i ntra ve n o usl y (I V) e ver y 3 wee ks 
(Q 3 W ). P artici pa nts w h o co nti n ue t o s h o w cli nical be nefit after t he first disease ass ess me nt will 
r ecei ve ni v ol u ma b 4 8 0 m g I V e ver y 4 wee ks ( Q 4 W) u ntil P D or i nt olera ble t o xicit y. At P D, 
partici pa nts will be all o we d t o a d d i pili m u ma b.   
Ni v ol u m a b 3 6 0 m g Q 3 W D osi n g Re gi me n  
T h e ni v olu ma b 3 6 0 m g Q 3 W  d osi n g r e gi me n was selecte d base d o n res ults fr o m p o p ulati o n 
p har mac o ki netic ( P P K ) a n d e x p os ur e-res p o nse a nal ysis m o deli n g a n d si m ulati o n a p pr oac hes 
s uc h t hat t he y ar e pr e dicte d t o pr o vi de a p pr o xi matel y e q ui vale nt e x p os ures (ti me-a vera ge d 
stea d y-state c o nce ntr ati o n [C a v gss]) as ni v ol u ma b 3  m g/ k g e ver y 2 wee ks ( Q 2 W). T he m o del 
pr e dicte d t hat , f oll o wi n g a d mi nistr ati o n of ni v ol u ma b 3 6 0 m g Q 3 W, Ca v gss is e x pecte d t o be 
si milar t o t h ose f oll o wi n g ni v ol u ma b 3 m g/ k g or 2 4 0 m g Q 2 W, w hile mi ni m u m stea d y -state 
c o nce ntr ati o n ( C mi nss ) is pr e dicte d t o be 6 % l o wer a n d is n ot c o nsi dere d t o be cli nicall y rele va nt. 
F oll o wi n g  ni v ol u ma b 3 6 0 m g Q 3 W, ma xi m u m stea d y -state c o nce ntrati o n (C m a xss ) is pre dicte d t o 
be a p pr o xi matel y ~ 2 3 % g r eater r elati ve t o t hat f oll o wi n g ni v ol u ma b 3 m g/ k g Q 2 W d osi n g; 
h o we ver,  t he r a n ge of ni v ol u ma b e x p os ures ( me dia n a n d 9 0 % pre dicti o n i nter vals) f oll o wi n g 
a d mi nistr ati o n  of 3 6 0 m g Q 3 W acr oss t he 3 5 t o 1 6 0 k g wei g ht ra n ge is pre dicte d t o  be 
mai ntai ne d well bel o w t he c orr es p o n di n g e x p os ures o bser ve d wit h t he well -t olerate d 1 0 m g/ k g 
ni v ol u ma b Q 2 W d osi n g r e gi me n a n d is n ot c o nsi dere d t o p ut partici pa nts at i ncrease d ris k . 
A d diti o nall y, t he ni v ol u ma b Q 3 W d osi n g re gi me n was selecte d f or b ot h treat me nt ar ms t o all o w 
c o nsiste nc y i n  ti mi n g f or o btai ni n g o n-treat me nt bi o psies. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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Ni v ol u m a b 4 8 0 Q 4 W D osi n g Re gi m e n  
T he ni v ol u ma b d ose of 4 8 0  m g Q 4 W was selecte d base d o n cli nical data a n d m o deli n g a n d 
si m ulati o n a p pr oac hes usi n g P P K a n d e x p os ure-res p o nse a nal yses e xa mi ni n g relati o ns hi ps 
bet wee n ni v ol u ma b e x p os ur es a n d efficac y (e g, O S, o bjecti ve res p o nse ) a n d safet y res p o nses, 
usi n g data fr o m s t u dies i n m ulti ple t u m or t y pes ( mela n o ma, N S C L C, a n d R C C) w here b o d y 
wei g ht -n or malize d d osi n g ( m g/ k g) has bee n use d. T he P P K a nal yses ha ve s h o w n t hat e x p os ure 
t o ni v ol u ma b i ncr ease d d ose pr o p orti o nall y o ver t he d ose ra n ge of 0. 1 t o 1 0 m g/ k g a d mi nistere d 
Q 2 W, a n d n o cli nicall y mea ni n gf ul diff ere nces i n p har mac o ki netics ( P K ) acr oss et h nicities a n d 
t u m or t y pes wer e o bser ve d. Ni v ol u ma b cleara nce a n d v ol u me of distri b uti o n were f o u n d t o 
i ncr ease as b o d y wei g ht i ncr eases b ut less t ha n pr o p orti o nall y wit h i ncreasin g wei g ht, i n dicati n g 
t hat m g/ k g d osi n g r e pr ese nts a n o ver-a dj ust me nt f or t he effect of b o d y wei g ht o n ni v ol u ma b P K.  
Usi n g t he P P K a n d e x p os ur e-r es p o nse m o dels, ni v ol u ma b e x p os ures a n d pr o ba bilities of efficac y 
r es p o nses a n d ris ks of A Es wer e pr e dicte d f oll o wi n g ni v ol u ma b 4 8 0 m g Q 4 W a n d c o m pare d 
wit h t h ose f oll o wi n g ni v ol u ma b 3 m g/ k g Q 2 W. T he o verall distri b uti o ns of ni v ol u ma b Ca v gss are 
c o m par a ble f oll o wi n g a d mi nistr ati o n wit h eit her ni v ol u ma b 3  m g/ k g Q 2 W or ni v ol u ma b 4 8 0  m g 
Q 4 W. Ni v ol u ma b 4 8 0  m g Q 4 W is p r e dicte d t o res ult i n a p pr o xi matel y 4 3 % greater Cm a xss  
c o m par e d wit h ni v ol u ma b 3  m g/ k g Q 2 W; h o we ver, t hese e x p os ures are pre dicte d t o be l o wer 
t ha n t he e x p os ur e r a n ges o bser ve d at d oses u p t o ni v ol u ma b 1 0 m g/ k g Q 2 W use d i n t he 
ni v ol u ma b cli nical pr o gr a m. A lt h o u g h t he Cm a xss  of ni v ol u ma b is e x pecte d t o be greater 
f oll o wi n g ni v ol u ma b 4 8 0 m g Q 4 W c o m pare d wit h ni v ol u ma b 3 m g/ k g Q 2 W, t he pre dicte d 
C m a xss  f oll o wi n g ni v ol u ma b 4 8 0 m g Q 4 W is pre dicte d t o be well bel o w t he me dia n Cm a xss  
ac hie ve d f oll o wi n g a d mi nistr at i o n of ni v ol u ma b 1 0 m g/ k g Q 2 W, a safe a n d t olera ble d ose le vel.  
E x p os ur e -saf et y a nal ysis de m o nstr ate d t hat t he e x p os ure mar gi ns f or safet y are mai ntai ne d 
f oll o wi n g ni v ol u ma b 4 8 0 m g Q 4 W, a n d t he pre dicte d ris ks of A E res ulti n g i n disc o nti n uati o n of 
st u d y dr u g, A E ≥ Gr a de 3, a n d i m m u ne-me diate d A E ≥ Gra de 2, are pre dicte d t o be si milar 
f oll o wi n g ni v ol u ma b 4 8 0 m g Q 4 W r elati ve t o ni v ol u ma b 3 m g/ k g Q 2 W acr oss t u m or t y pes. 
Saf et y a nal yses usi n g a vaila ble data f oll o wi n g ni v ol u ma b 3 m g/ k g Q 2 W a n d 1 0 m g/ k g Q 2 W 
a d ministr ati o n i n dicate d t her e wer e n o differe nces i n A E pr ofiles acr oss b o d y wei g ht gr o u ps. 
Fi nall y, i nitial e vi de nce de m o nstr ate d  t hat, f oll o wi n g a d mi nistrati o n of ni v ol u ma b 4 8 0 m g Q 4 W, 
ni v ol u ma b has bee n s h o w n t o be well t olerate d.  
At n i v ol u ma b 4 8 0 m g Q 4 W , C mi nss  is pre dicte d t o be a p pr o xi matel y 1 6 % l o wer c o m pare d wit h 
ni v ol u ma b 3  m g/ k g Q 2 W. W hile t hese e x p os ures are pre dicte d t o be l o wer, t he y are pre dicte d t o 
be o n t he flat part of t he e x p os ur e -r es p o nse c ur ves a n d are n ot pre dicte d t o affect efficac y. 
E x p os ur e -efficac y a nal yses of m ulti ple P K meas ures a n d efficac y e n d p oi nts (e g, O S, o bjecti ve 
r es p o nse) ha ve i n dicate d t hat, f oll o wi n g a d mi nistrati o n of ni v ol u ma b 4 8 0 m g Q 4 W, efficac y is 
pr e dicte d t o be si milar t o t hat f oll o wi n g a d mi nistrati o n of ni v ol u ma b  3 m g/ k g Q 2 W acr oss 

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m ulti ple t u m or t y pes. Base d o n t hese data, ni v ol u ma b 4 8 0  m g Q 4 W is e x pecte d t o ha ve si milar 
efficac y a n d saf et y pr ofiles t o ni v ol u ma b 2 4 0  m g Q 2 W or ni v ol u ma b 3  m g/ k g Q 2 W.  
T he less fr e q ue nt d osi n g r e gi me n s ( Q 3 W a n d Q 4 W vs Q 2 W ) are desi g n e d t o aff or d greater 
c o n ve nie nce t o t he tar get patie nt p o p ulati o n a n d t o all o w c o m bi nati o n of ni v ol u ma b wit h ot her 
a ge nts.  Ref er t o t he ni v ol u ma b I B f or details (Ni v ol u ma b I B, 2 0 2 0 ). 
4. 3. 2  
R ati o n ale f or Ni v ol u m a b a n d I pili m u m a b C o m bi n ati o n T her a p y 
D os e a n d Sc he d ule  ( A d v a nce d Met ast ati c C a ncer) 
F or ni v ol u ma b a n d i pili m u ma b c o m bi nati o n t hera p y i n a d va nce d metastatic ca ncer, ni v ol u ma b 
will be a d mi nister e d at 3 6 0 m g I V Q 3 W, a n d i pili m u ma b will be a d mi nistere d at 1 m g/ k g I V 
Q 3 W f or t he first 2 d oses a n d t he n e ver y 6 wee ks f or t he 3r d a n d 4t h d oses, f oll o we d b y 
ni v ol u ma b 4 8 0 m g I V Q 4 W u ntil P D or i nt olera ble t o xicit y. T he rati o nale f or t he ni v ol u ma b 
3 6 0  m g Q 3 W a n d 4 8 0 m g Q 4 W d osi n g re gi me ns is pr o vi de d a b o ve ( Secti o n 4. 3. 1 ). 
4. 3. 2. 1  
R ati o n ale f or Ni v ol u m a b a n d I pili m u m a b C o m bi n ati o n T her a p y 
D os e a n d Sc he d ule ( A d v a nce d Pr ost ate C a ncer C o h orts A a n d B)  
F or ni v ol u ma b a n d i pili m u ma b c o m b i nati o n t hera p y i n a d va nce d pr ostate ca ncer, t here will be 
2  tr eat me nt c o h orts, b ot h of w hic h will f oll o w 6-wee k c ycles as o p p ose d t o 3 -wee k c ycles.  
Pr ostate C o h ort A:  
o  ni v ol u ma b will be a d mi nister e d at 1 m g/ k g I V Q 3 W  ( 4 d oses o ver 2 c ycles) 
o  i pili m u ma b will be a d mi nister e d at 3 m g/ k g I V Q 6 W  ( 2 d oses o ver 2 c ycles) 
o  f oll o wi n g t he first 2 c ycles, ni v ol u ma b will be a d mi nistere d at 4 8 0 m g I V Q 4 W  u ntil P D 
or i nt oler a ble t o xicit y  
Pr ostate C o h ort B:  
o  ni v ol u ma b will be a d mi nister e d at 1 m g/ k g I V Q 3 W  ( 4 d oses o ver 2 c ycles)  
o  i pili m u ma b will be a d mi nister e d at 5 m g/ k g I V Q 6 W  ( 2 d oses o ver 2 c ycles) 
o  f oll o wi n g t he first 2 c ycles, ni v ol u ma b will be a d mi nistere d at 4 8 0 m g I V Q 4 W  u ntil P D 
or i nt oler a ble t o xicit y  
 
Gi ve n data s u g gesti n g a d ose r es p o nse i n earlier st u dies of i pili m u ma b 0. 3, 3 a n d 1 0 m g/ k g 
(W olc h o k et al ., 2 0 1 0), a n d b uil di n g o n data o bser ve d i n t he c urre nt st u d y wit h l o wer d oses of 
i pili m u ma b, it is pr o p ose d t hat i ncr ease d C T L A-4 i n hi biti o n i n c o m bi nati o n wit h a n ti-P D -1 ma y 
r es ult i n gr eater i nfl u x of C D 8 T cells i nt o a n ot her wise i m m u ne-e xcl u de d A P C 
micr oe n vir o n me nt.  

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T he saf et y pr ofile of i pili m u ma b has bee n well esta blis he d i n t h o usa n ds of patie nts, b ot h as a 
m o n ot her a p y at d oses u p t o 1 0 m g/ k g e ver y 3 wee ks, a n d i n c o m bi nati o n wit h ni v ol u ma b at 
vari o us d oses a n d sc he d ules. I n t he p hase 1 st u d y C A 2 0 9 0 0 4 ( N C T 0 1 0 2 4 2 3 1 ), asce n di n g d oses 
of ni v ol u ma b ( 0. 3, 1, or 3 m g/ k g) ha ve bee n st u die d c o nc o mita ntl y wit h asce n di n g d oses of 
i pili m u ma b ( 1 or 3 m g/ k g) i n s u bjects wit h u nresecta ble or metastatic mela n o ma (Calla ha n et al ., 
2 0 1 8 ; W olc h o k et al ., 2 0 1 3). T he c o m bi nati o n of ni v ol u ma b 1 m g/ k g + i pili m u ma b 3 m g/ k g was 
assesse d as t he ma xi m u m t oler ate d d ose ( M T D) a n d ta ke n f or war d f or f urt her e val uati o n, a n d 
was s u bse q u e ntl y a p pr o ve d f or tr eat me nt of metastatic mela n o ma ( O p di v o U S PI, 2 0 2 0 ). 
Ni v ol u ma b 3 m g/ k g + i pili m u ma b 3 m g/ k g was f o u n d t o e xcee d t he M T D, b ut c o m bi nati o ns of 
ni v ol u ma b 1 m g/ k g wit h hi g her d oses of i pili m u ma b ha ve n ot bee n teste d t o date.  
T he disi n hi biti o n of T cell f u ncti o n i n d uce d b y c o m bi ne d c hec k p oi nt bl oc k a de ca n lea d t o a 
disti nct c o nstellati o n of i nfla m mat or y si de effects, c ollecti vel y ter me d i m m u ne -relate d a d verse 
e ve nts (ir A Es). I pili m u ma b, w he n gi ve n i n c o m bi nati o n wit h P D( L) -1 t hera p y , ca n i n d uce a 
s u bset of a d verse e ve nts, pr e d o mi na ntl y gastr oi ntestinal, c uta ne o us, a n d he patic, w hic h i n s o me 
cases ca n be se ver e. As s uc h, ir A E tr eat me nt g ui deli nes ha ve bee n esta blis he d a n d wi del y 
i m ple me nte d, a n d i n m ost cases ar e effecti ve i n c o ntr olli n g t hese e ve nts (see A p pe n di x  8 ; 
Ni v ol u ma b I B, 2 0 2 0 ; Ni v ol u ma b I B  A d de n d u m , 2 02 0 ). 
I n or der t o f urt her miti gate t he fr e q ue nc y a n d se verit y of t hese ir A Es, o nl y t w o d oses of 
i pili m u ma b will be a d mi nister e d, a n d t he d oses will be gi ve n less fre q ue ntl y, o n a 6 wee k 
sc he d ule. 
4. 4  
T R E A T M E N T B E Y O N D DI S E A S E P R O G R E S SI O N  
Acc u m ulati n g e vi de nce i n dicates t hat a mi n orit y of patie nts treate d wit h i m m u n ot hera p y ma y 
deri ve cli nical be nefit fr o m c o nti n ue d treat me nt des pite i nitial e vi de nce of disease pr o gressi o n 
(W olc h o k et al, 2 0 0 9 ). T her ef or e, partici pa nts recei vi n g ni v ol u ma b wit h or wit h o ut i pili m u ma b 
i n t his st u d y will be per mitte d t o c o nti n ue st u d y i nter ve nti o n be y o n d i nitial In vesti gat or -assesse d 
disease pr o gr essi o n ( acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 
1. 1  [R E CI S T v 1. 1 ]) if t he y meet t he 2 criteria liste d bel o w: 
•  I n vesti gat or-assesse d cli nical be nefit, a n d 
•  Partici pa nt is t oler ati n g st u d y i nter ve nti o n  
 
T he assess me nt of cli nical be nefit s h o ul d ta ke i nt o acc o u nt w het her t he partici pa nt is cli nicall y 
deteri or ati n g a n d u nli kel y t o  r ecei ve f urt her be nefit fr o m c o nti n ue d treat me nt.  
All decisi o ns t o c o nti n ue tr eat me nt be y o n d i nitial pr o gressi o n m ust be disc usse d wit h t he 
S p o ns or a n d d oc u me nte d i n t he st u d y r ec or ds.  

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Partici pa nts  s h o ul d disc o nti n ue st u d y i nter ve nti o n u p o n e vi de nce of f urt her pr o gressi o n, defi ne d 
as a n a d diti o nal ≥ 1 0 % i ncr ease i n t u m or b ur de n fr o m t he ti me of i nitial pr o gressi o n (i ncl u di n g 
all tar get lesi o ns a n d ne w meas ur a ble lesi o ns).  
Ne w lesi o ns ar e c o nsi der e d meas ur a ble at t he ti me of i nitial pr o gressi o n if t he dia m eters are 
≥ 1 0  m m ( e xce pt f or pat h ol o gical l y m p h n o des, w hic h m ust ha ve a s h ort a xis of ≥ 1 5 m m). A n y 
ne w lesi o n c o nsi der e d n o n -meas ur a ble at t he ti me of i nitial pr o gressi o n ma y bec o me meas ura ble 
a n d t her ef or e i ncl u de d i n t he t u m or b ur de n meas ure me nt if t h e dia meter i ncreases t o ≥ 1 0 m m 
( e xce pt f or pat h ol o gical l y m p h n o des, w hic h m ust ha ve a n i ncrease i n s h ort a xis t o ≥ 1 5 m m).  
F or statistical a nal yses t hat i ncl u de t he In vesti gat or -ass ess e d pr o gressi o n date, partici pa nts  w h o 
c o nti n ue tr eat me nt be y o n d i nitia l In vesti gat or -assesse d  disease pr o gressi o n (acc or di n g t o 
R E CI S T v 1. 1)  will be c o nsi der e d t o ha ve In vesti gat or -assess e d P D  at t he ti me of t he i nitial 
pr o gr essi o n e ve nt . 
4. 5  
E N D O F S T U D Y D E FI NI TI O N  
A partici pa nt  is c o nsi der e d t o ha ve c o m plete d t he st u d y if he/s he has c o m plete d all p hases of t he 
st u d y, i ncl u di n g t he last visit or t he last sc he d ule d pr oce d ure re q uire d f or statistical a nal ysis or 
saf et y f oll o w-u p . 
T he e n d of t his st u d y is defi ne d as t he date w he n t h e last visit of t he last partici pa nt  occ urs or t he 
date at w hic h t he last data p oi nt r e q uir e d f or statistical a nal ysis or safet y f oll o w -u p is recei ve d 
fr o m t he last partici pa nt , w hic he ver occ urs later.  
T he t otal le n gt h of t he st u d y, fr o m scr ee ni n g of t he first partici pa nt  t o t he e n d of t he st u d y, is 
e x pecte d t o be a p pr o xi matel y 4 years . 
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve r e q uests f or a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, 
als o k n o w n as wai vers or e xe m pti o ns, are n ot all o we d.  
5. 1  
I N C L U SI O N C RI T E RI A 
Partici pa nt s ar e eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y: 
Ge ner al I ncl usi o n Crit eri a  
1.  Partici pa nt  m ust be ≥ 1 8  years of a ge i ncl usi ve, at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.  
2.  Male or f e male partici pa nts of c hil d -pr o d uci n g p ote ntial m ust a gree t o use c o ntrace pti o n 
( as detaile d i n A p pe n di x 6 ) or a v oi da nce of pre g na nc y meas ures d uri n g t he st u d y a n d f or 
7 a n d 5 m o nt hs, r es pecti vel y, after t he last d ose. 
3.  Fe males of c hil d beari n g p ote ntial m ust ha ve a n e gati ve ser u m or uri ne pre g na nc y test. 

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C a ncer -specific I ncl usi o n Crit eri a  
4.  Hist ol o gicall y or c yt ol o gicall y c o nfir me d ca ncer t hat is metastatic, u nresecta ble, or 
r ec urr e nt. U n der  A me n d me nt 2  o nl y , e nr oll me nt will be li mite d t o t u m or t y pes k n o w n t o 
be r es p o nsi ve t o i m m u n ot her a p y, ha ve hi g h pre vale nce ( > 2 0 %) of C D 8 > 1 5 % t u m ors, 
a n d/ or ha ve bee n o bser ve d i n t he st u d y t o ha ve t u m ors tra nsiti o n fr o m C D 8 l o w  t o C D 8 
hi g h  f oll o wi n g i nitiati o n of i m m u n ot hera p y. 
a.  Partici pa nts wit h t hese t u m or t y pes will be eli g i ble t o partici pate re gar dless of 
scr ee ni n g C D 8 r es ults (eit her ≥ 1 5 % or <  1 5 %).  
b.  T u m or t y pes f or i n vesti gati o n u n der A me n d me nt 2 : 
i. Mela n o ma , Gastric , S mall cell l u n g ca n cer , N S C L C , H C C , C uta ne o us 
s q ua m o us cell carci n o ma, R C C , Cer vical , Gastr oes o p ha geal j u ncti o n 
ca ncer , Ur ot helial bla d der ca ncer , Sarc o ma (s oft tiss ue o nl y) , 
Ne ur oe n d ocri ne , S C C H N , O varia n , G y n ec ol o gic mali g na ncies , Mer kel 
Cell , Pr ostate , Micr osatellite i nsta bilit y hi g h C ol orectal , A nal  (s q ua m o us 
cell o nl y) 
5.  Partici pa nts w h o  ha ve r ecei ve d pri or i m m u n ot hera p y, i ncl u di n g pri or a nti -P D -1 or 
a nti-P D -L 1 t her a pies, will be all o we d t o partici pate i n t his st u d y.   
a.  Partici pa nts w h o r ecei ve d pri or a nti -P D -1 or a nti -P D -L 1 ma y partici pate o nl y if t heir 
pri or a nti -P D -1 or a nti -P D -L 1 m o n ot h era p y or c o m bi nati o n  t hera p y were N O T t he 
last tr eat me nt pri or t o partici pati o n o n t his st u d y. 
b.  P artici pa nts w h o ha d pri or i m m u n ot hera pies a n d e x perie nce d Gra de 1 -2 i m m u ne-
r elate d a d verse e ve nt (ir A E) m ust ha ve d oc u me ntati o n t hat t heir ir A Es are ≤ Gra de  1 
or baseli ne usi n g c urr e nt C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts v 5. 0 
(C T C A E  v 5. 0 ) a n d  partici pa nts m ust be off ster oi d t hera p y a n d/ or ot her 
i m m u n os u p pr essi ve t her a p y, as treat me nt f or ir A Es, f or ≥ 1 4  da ys  fr o m C ycle 1, 
Da y  1.  
c.  Partici pa nts w h o e x perie nce d Gra de 3 ir A Es c o nsisti n g of la b orat or y a b n or malities 
t hat wer e as y m pt o matic a n d ha ve n o w res ol ve d t o ≤ Gra de 1 or baseli ne a n d  
partici pa nts w h o ha ve bee n off ster oi d a n d/ or ot her i m m u n os u p pres si ve t hera p y, as 
tr eat me nt f or ir A Es, f or ≥ 3 0 da ys fr o m C ycle 1, Da y 1. 
6.  C o nc urr e nt mali g na ncies ar e per mitte d if a n y o ne of t he f oll o wi n g a p plies:  
a.  P r e vi o usl y tr eate d mali g na nc y f or w hic h all treat me nt of t hat mali g na nc y was 
c o m plete d at least 2 years bef ore e nr oll me nt a n d n o e vi de nce of disease  e xists, or 
b.  Wit h a gr ee me nt fr o m t he S p o ns or a n d P ri nci pal In vesti gat or  ( PI), partici pa nts  w h o 
ha ve a c o nc urr e nt mali g na nc y t hat is cli nicall y sta ble a n d d oes n ot re q uire t u m or -
dir ecte d tr eat me nt ar e eli gi ble t o partici pate if t he ris k of t he pri or mali g na nc y 
i nterf eri n g wit h eit her saf et y or efficac y e n d p oi nts is ver y l o w, or 
c.  Wit h a gr ee me nt fr o m t he S p o ns or a n d PI , ot her mali g na ncies ma y be per mitte d if t he 
ris k of t he pri or mali g na nc y i nterferi n g wit h eit her safet y or efficac y e n d p oi nts is 
ver y l o w . 

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7.  Pr o vi de ne wl y o btai ne d c or e nee dle or i ncisi o nal bi o ps y of a n o n -b o ne t u m or lesi o n n ot 
pr e vi o u sl y irr a diate d. Fi ne nee dle as pirati o n is n ot acce pta ble. 
a.  Bi o psies s h o ul d be o btai ne d fr o m sites t hat d o n ot p ose si g nifica nt ris k t o t he 
partici pa nt base d o n t he t u m or site a n d t he pr oce d ure use d. Bi o ps y sites/ pr oce d ures 
i ncl u di n g, b ut n ot li mite d t o, t he brai n, o pe n l u n g/ me diasti n u m, pa ncreas, or 
e n d osc o pic pr oce d ur es e xte n di n g be y o n d t he es o p ha g us, st o mac h, or b o wel w o ul d be 
c o nsi der e d t o p ose a si g nifica nt ris k t o t he partici pa nt. Pr oce d ures t o areas t hat are 
dee me d b y t he I n vesti gat or t o be of n o n‑si g n ifica nt ris k base d o n i n di vi d ual cli nical 
sce nari os will be per mitte d. 
8.  Meas ur a ble disease as defi ne d b y R E CI S T v 1. 1.  
a.  Wit h t he e xce pti o n of pr ostate ca ncer partici pa nts e nr olle d u n der A me n d me nt 3 +  w h o 
m ust ha ve meas ur a ble disease, p artici pa nts w h o d o n ot ha ve meas ura ble  disease b y 
R E CI S T criteria b ut w h ose disease ca n be o bjecti vel y meas ure d t hr o u g h t u m or 
mar kers or a n ot her disease -s pecific sta n dar d are c o nsi dere d eli gi ble.  
9.  E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1.  
1 0.  As p artate a mi n otr a nsf er ase ( A S T ) a n d ala ni ne a mi n otra nsferase ( A L T ) ≤ 3  x u p per li mit 
of n or mal ( U L N ). 
a.  Partici pa nts wit h he pat ocell ular carci n o ma ( H C C) ma y be eli gi ble pr o vi de d t he y ha ve 
A S T a n d A L T t hat ar e ≤ 5. 0 x  U L N.  
1 1.  He m o gl o bi n ≥ 9  g/ d L . 
1 2.  T otal bilir u bi n ≤ 1. 5 × U L N . 
a.  Partici pa nts wit h H C C ar e eli gi ble pr o vi de d t he y ha ve t otal bilir u bi n < 3. 0 x U L N a n d 
ar e c o nsi der e d C hil d -P u g h Class A or C hil d -P u g h Class B 7 ( C hil d -P u g h Class B wit h 
a t otal C hil d-P u g h sc or e n ot t o e xcee d  7).  
b.  Partici pa nts wit h Gil bert s y n dr o m e m ust ha ve ≤ 3 x U L N . 
1 3.  Cr eati ni ne  clear a nce s h o ul d be ≥ 3 0 m L/ mi n as esti mate d b y t he C oc kcr oft -Ga ult 
e q uati o n or ot her a p pr o priate calc ulati o n . 
1 4.  A bs ol ute ne utr o p hil c o u nt ≥ 1. 0 x  1 0 9/ L. 
1 5.  Platelets c o u nt ≥ 7 5 x 1 0 9/ L. 
I nf or m e d C o nse nt 
1 6.  Pa rtici pa nts m ust be c a pa ble of gi vi n g si g ne d i nf or me d c o nse nt as descri be d i n  
A p pe n di x  1 , w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n 
t he i nf or me d c o nse nt f or m (I C F) a n d i n t his pr ot oc ol. 
A d v a nce d P r ost at e C a ncer S pecific I ncl usi o n Criteri a  ( A me n d me nt 3+ ) 
1 7.  E vi de nce of sta ge I V pr ostate ca ncer  (as defi ne d b y A merica n J oi nt C o m mittee of Ca ncer 
criteria) o n pr e vi o us b o ne, C T a n d/ or M RI sca n.  

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1 8.  O n g oi n g a n dr o ge n de pri vati o n t hera p y ( A D T) wit h a g o na d otr o pi n -releasi n g h or m o ne 
( G n R H) a nal o g ue or a s ur gical/ me dical castrati o n wit h test oster o ne le vel of 
≤ 1. 7 3  n m ol/ L ( < 5 0 n g/ d L).  
1 9.  Partici pa nts wit h s keletal s yste m s y m pt o ms w h o are alrea d y o n me dicati o ns  (e g, 
bis p h os p h o nates a n d/ or R A N K li ga n d i n hi bit ors)  t o stre n gt he n b o nes are all o we d if t he y 
wer e starte d ˃ 2 8 da ys bef or e t he first d ose of st u d y treat me nt. 
2 0.  Partici pa nts m ust ha ve meas ur a ble disease per R E CI S T v 1. 1.  
2 1.  Ha ve r ecei ve d a n d pr o gr esse d o n pri or sec o n dar y a n dr o ge n rece pt or si g nali n g i n hi bit or 
t hera p y ( e g, a bir ater o ne, e nzal uta mi de, a pal uta mi de). Pr o gressi o n is defi ne d b y o ne or 
m or e of t he f oll o wi n g 3 criteria:  
a.  Pr ostate -s pe cific a nti ge n ( P S A) ≥ 1. 0 n g/ m L a n d risi n g P S A b y at least 
2  c o nsec uti ve meas ur e me nts a mi ni m u m of 1 -wee k a part.  
b.  S oft tiss ue pr o gr essi o n as defi ne d R E CI S T v  1. 1 ( Eise n h a uer et al., 2 0 0 9). 
c.  B o ne disease pr o gr essi o n as defi ne d b y 2 ne w b o ne lesi o ns (as per Pr ostate 
Ca ncer Cli nical Trials W or ki n g Gr o u p 3 [ P C W G 3; Sc her et al., 2 0 1 6 ]). 
 
5. 2  
E X C L U SI O N C RI T E RI A  
Partici pa nt s ar e e xcl u de d fr o m t he stu d y if a n y of t he f oll o wi n g criteria a p pl y:  
Ge ner al E xcl usi o n C rit eri a 
1.  Partici pa nts w h o ha d a me dical c o n diti o n t hat re q uire d  a s ur gical pr oce d ure a n d wer e 
s u bject t o ge ner al a nest hesia wit hi n 4 wee ks pri or t o be gi n ni n g pr ot oc ol  t hera p y are 
e xcl u de d e xce pt the use of ge neral a nest hesia d uri n g bi o ps y pr oce d ures, i n dicate d f or 
patie nt c o mf ort a n d or saf et y will be per mitte d . 
2.  Pr e g na nt or  br eastf ee di n g.  
3.  Si g nifica nt gastr oi ntesti nal dis or der(s) (e g, acti ve Cr o h n ’s disease or ulcerati ve c oliti s or 
a hist or y of e xte nsi ve gastric r esecti o n a n d/ or s mall i ntesti nal resecti o n).  
4.  Has i nterstitial l u n g disease or acti ve, n o ni nfecti o us  p ne u m o nitis.  
5.  Has a tr a ns pla nte d or ga n or has u n der g o ne all o ge neic b o ne marr o w  tra ns pla nt. 
6.  Has r ecei ve d a li ve vacci ne w it hi n 3 0 da ys pri or t o first d ose.  
7.  K n o w n h y perse nsiti vit y t o a c o m p o ne nt of pr ot oc ol  t hera p y. 
a.  Partici pa nts wit h k n o w n h y perse nsiti vit y t o i pili m u ma b a n d/ or  ni v ol u ma b are 
e xcl u de d.  
8.  U nc o ntr olle d c o nc urr e nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve i nfecti o n, 
cli nicall y si g nifica nt n o n -heali n g or heali n g w o u n ds, s y m pt o matic c o n gesti ve heart 
f ail ur e, u nsta ble a n gi na pect oris, car diac arr h yt h mia, si g nifica nt p ul m o nar y disease 
(s h ort ness of br eat h at r est or o n mil d e xerti o n), u nc o ntr olle d i nfecti o n, or ps yc hiatric 

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ill ness/s ocial sit uati o ns t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d p ose a safet y 
c o ncer n or li mit c o m plia nce wit h st u d y re q uire me nts. 
C a ncer -specific E xcl usi o n Crit eri a  
9.  Partici pa nts w h o e x perie nce d a n y ≥ Gra de 3 s y m pt o matic ir A E o n a pri or 
i m m u n ot her a p y st u d y will be e xcl u de d fr o m t his st u d y re gar dless of res ol uti o n of t he 
ir A E. 
1 0.  A n y k n o w n, u ntr eate d, br ai n metastases. Treate d partici pa nts m ust be sta ble 4 wee ks 
after c o m p leti o n of tr eat me nt f or brai n metastases, a n d i ma ge-d oc u me nte d sta bilit y is 
r e q uir e d. Partici pa nts m ust ha ve n o cli nical s y m pt o ms fr o m brai n metastases a n d ha ve 
n ot r e q uir e d s yste mic c ortic oster oi ds >  1 0 m g/ da y pre d nis o ne or e q ui vale nt f or ≥ 2 wee ks 
pri or t o first d ose of st u d y i nter ve nti o n. 
1 1.  Partici pa nts wit h a n acti ve, k n o w n or s us pecte d a ut oi m m u ne disease. Partici pa nts wit h 
t y pe I dia betes mellit us, h y p ot h yr oi dis m o nl y re q uiri n g h or m o ne re place me nt, s ki n 
dis or ders (s uc h as vitili g o, ps oriasis, or al o pecia ) n ot re q uiri n g s yste mic treat me nt, or 
c o n diti o ns n ot e x pecte d t o r ec ur i n t he a bse nce of a n e xter nal tri g ger are per mitte d t o 
e nr oll. 
1 2.  Partici pa nts wit h a c o n diti o n r e q uiri n g s yste mic treat me nt wit h eit her c ortic oster oi ds 
( > 1 0 m g dail y pr e d nis o ne e q ui vale nt) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 
1 4  da ys of start of st u d y tr eat me nt. I n hale d or t o pical ster oi ds, a n d a dre nal re place me nt 
ster oi d d oses > 1 0 m g dail y pr e d nis o ne e q ui vale nt, are per mitte d i n t he a bse nce of acti ve 
a ut oi m m u ne disease.  
Tre at m e nt -s pecific E xcl usi o n C rit eri a 
1 3.  A ntica ncer c he m ot her a p y, r a di ot hera p y, i m m u n ot hera p y, or i n vesti gati o nal a ge nts wit hi n 
1 4 da ys of first d ose of st u d y i nter ve nti o n, pr o vi de d t hat all treat me nt-relate d A Es  ha ve 
r es ol ve d. 
a.  Rece nt or c o nc urr e nt n o n -t hera pe utic i n vesti gati o nal a ge nts t hat are n ot a ntici pate d t o 
i nterf er e wit h st u d y i nter ve nti o n, ma y be per mitte d wit h writte n a gree me nt fr o m t he 
Me dical M o nit or. As a n e xce pti o n t o t his re q uire me nt, a d mi nistrati o n of 8 9Zr -Df -
I A B 2 2 M 2 C i n t he c o nte xt of a PI CI-s p o ns ore d cli nical trial d oes n ot re q uire writte n 
a gr ee me nt fr o m t he Me dical M o nit or . 
 
5. 3  
LI F E S T Y L E C O N SI D E R A TI O N S  
N o r estricti o ns ar e r e q uir e d.  
5. 4  
S C R E E N F AI L U R E S  
Scr ee n f ail ur es ar e defi ne d as partici pa nt s w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y  e nter e d i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o 
e ns ur e tr a ns par e nt r e p orti n g of scr ee n fail ure partici pa nt s t o meet t he C o ns oli date d Sta n dar ds of 
Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o re s p o n d t o q ueries fr o m re g ulat or y 

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a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, eli gi bilit y criteria, 
a n d a n y seri o us a d verse e ve nt ( S A E).  
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y be 
r escr ee ne d. 
6  
S T U D Y I N T E R V E N TI O N 
St u d y i nter ve nti o n  is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), or  
place b o i nte n de d t o be a d mi nister e d t o a st u d y partici pa nt  acc or di n g t o t he st u d y pr ot oc ol.  
6. 1  
S T U D Y I N T E R V E N TI O N( S) A D MI NI S T E R E D 
T he st u d y i nter ve nti o ns t o be a d mi nistere d i n t his st u d y are s u m marize d i n T a ble 6 . 
T a ble 6 : 
St u d y I nt er ve nti o n 
St u d y  
I nte r ve nti o n 
N a me  
 
D os a ge 
F or m ul ati o n  
 
U nit D ose 
Str e n gt h(s)  
 
D os a ge Le vel(s)  
 
R o ute of 
A d mi nistr ati o n  
 
 
S o ur ci n g  
A d v a nc e d Met ast atic C a nc er  
Ni v ol u m a b  
A q ue o us s ol uti o n  
1 0 m g/ m L  
3 6 0  m g (a d mi nistere d 
wit h i pili m u m a b)  
4 8 0 m g  ( mai nt e na nc e) 
I ntra ve n o us 
Brist ol -M yers S q ui b b  
I pili m u m a b 
A q ue o us s ol uti o n  
5 m g/ m L  
1 m g/ k g  (a d mi nist ere d 
wit h ni v ol u m a b)  
I ntra ve n o us 
Brist ol -M yers S q ui b b  
A d v a nc e d P r ost ate C a nce r  
Ni v ol u m a b  
A q ue o us s ol uti o n  
1 0 m g/ m L  
1 m g/ k g (a d mi nist ere d 
wit h i pili m u m a b)  
4 8 0 m g ( mai nt e na nc e)  
I ntra ve n o us 
Brist ol -M yers S q ui b b  
I pili m u m a b 
A q ue o us s ol uti o n  
5 m g/ m L  
3 or 5 m g/ k g 
(a d mi nist ere d wit h 
ni v ol u ma b)  
I ntra ve n o us 
Brist ol -M yers S q ui b b  
 
Partici pa nts wit h ≥ 1 5 % C D 8 cells i n t heir t u m or bi o ps y e nr olle d o n t he C D 8 hi g h ar m will be 
tr eate d wit h si n gle-a ge nt ni v ol u ma b u ntil disease pr o gressi o n. A d diti o nall y, partici pa nts e nr olle d 
o n t he C D 8 hi g h ar m i n t his st u d y c o ul d, at disease pr o gressi o n, cr oss -o ver t o t he C D 8 l o w ar m ; 
p artici pa nts wit h a d va nce d pr ostate ca ncer e nr olle d u n der A me n d me nt 3 +  w h o cr oss -o ver t o t he 
C D 8 l o w ar m will be place d i n Pr ostate C o h ort A.  
Ni v ol u ma b m o n ot her a p y a n d ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b wil l be a d mi nistere d as 
descri be d bel o w .  
•  Niv ol u m a b m o n ot her a py  ( A dv a nce d Met ast atic C a ncer a n d A dv a nce d Pr ost ate 
C a ncer) : Ni v ol u ma b will be a d mi nistere d at 3 6 0 m g as a n I V i nf usi o n o ver 
a p pr o xi matel y 3 0 mi n utes Q 3 W  ±  3 da ys (see Secti o n 4. 3. 1 ). Partici pa nts w h o 

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c o nti n ue t o s h o w cli nical be nefit after t he first disease ass ess me nt will recei ve 
ni v ol u ma b mai nte na nce 4 8 0 m g I V Q 4 W  ±  3 da ys u ntil P D or i nt ol era ble t o xicit y 
(starti n g at C ycle 5).  
•  Niv ol u m a b i n c o m bi n ati o n wit h i pili m u m a b  ( A dv a nce d Met ast atic C a ncer): 
Ni v ol u ma b will be a d mi nistere d at 3 6 0  m g as a n I V i nf usi o n o ver a p pr o xi matel y 
3 0  mi n utes Q 3 W  ±  3 da ys (see Secti o n 4. 3. 2 ), f oll o we d a p pr o xi matel y 3 0 mi n utes 
later b y i pili m u ma b, w hic h will be a d mi nistere d at 1 m g/ k g as a n I V i nf usi o n  o ver  
a p pr o xi matel y 3 0 mi n utes  (M o mtaz et al, 2 0 1 5 ). I pili m u ma b will be a d mi nistere d 
Q 3 W  ±  3 da ys f or t he first 2  d oses a n d t he n e ver y 6 wee ks f or t he 3r d a n d 4t h d oses, 
f oll o we d b y ni v ol u ma b mai nte na nce 4 8 0 m g I V Q 4 W ±  3 da ys u ntil P D or i nt o lera ble 
t o xicit y (starti n g at C ycle 7). E ac h of t he s u bse q ue nt d oses will be a d mi nistere d as 
ni v ol u ma b mai nte na nce 4 8 0 m g I V Q 4 W  ±  3 da ys o ver a p pr o xi matel y 3 0 mi n utes.  
•  Niv ol u m a b i n c o m bi n ati o n wit h i pili m u m a b ( A dv a nce d Pr ost ate C a ncer ): 
Partici pa nts i n t h e < 1 5 % C D 8 cells ( C D 8 l o w) ar m will recei ve eit her o ne of t he 
f oll o wi n g c o m bi nati o ns of ni v ol u ma b a n d i pili m u ma b: 
o  P r ost at e C o h ort A : Ni v ol u ma b will be a d mi nistere d at 1 m g/ k g  as a n I V 
i nf usi o n o ver a p pr o xi matel y 3 0 mi n utes Q 3 W  (see Secti o n 4. 3. 2 ), f oll o we d 
a p pr o xi matel y 3 0 mi n utes later b y i pili m u ma b, w hic h will be a d mi nistere d at 
3  m g/ k g  as a n I V i nf usi o n o ver a p pr o xi matel y 3 0 mi n ute s (M o mtaz et al, 2 0 1 5 ) 
Q 6 W f or t w o 6 wee k c ycles . After c o m pleti o n of 2 c ycles, ni v ol u ma b 
mai nte na nce 4 8 0 m g I V Q 4 W  ± 3 da ys will be a d mi nistere d u ntil P D or 
i nt oler a ble t o xicit y. 
o  P r ost at e C o h ort B : Ni v ol u ma b will be a d mi nistere d at 1 m g/ k g  as a n I V i nf usi o n 
o ver a p pr o xi matel y 3 0 mi n utes Q 3 W  (see Secti o n 4. 3. 2 ), f oll o we d a p pr o xi matel y 
3 0 mi n utes  later b y i pili m u ma b, w hic h will be a d mi nistere d at 5  m g/ k g  as a n I V 
i nf usi o n o ver a p pr o xi matel y 3 0 mi n utes (M o mtaz et al, 2 0 1 5 ) Q 6 W f or t w o 
6  wee k c ycles . After c o m pleti o n of 2 c ycles, ni v ol u ma b mai nte na nce 4 8 0 m g I V 
Q 4 W  ± 3 da ys  will be a d mi nistere d u ntil P D or i nt olera ble t o xicit y.  
 
F or all st u d y i nter ve nti o ns, eit her a peri p heral I V or ce ntral p ort or li ne is acce pta ble f or i nf usi o n. 
A d mi nistr ati o n of st u d y i nter ve nti o n will be perf or me d i n a m o nit ore d setti n g i n w h ic h t her e is 
i m me diate access t o tr ai ne d pers o n nel a n d a de q uate e q ui p me nt a n d me dici ne t o ma na ge 
p ote ntiall y seri o us r eacti o ns.  
6. 2  
P R E P A R A TI O N/ H A N D LI N G/ S T O R A G E/ A C C O U N T A BI LI T Y  
Partici pa nt wei g ht will be assesse d at Scree ni n g a n d Da y 1 of eac h c ycle. D ose pre pa rati o ns are 
base d o n t he partici pa nt’s wei g ht a n d s h o ul d be a dj uste d if t he partici pa nt has a 1 0 % c ha n ge i n 
c o m paris o n t o t heir i nitial wei g ht o n C ycle 1, Da y 1.  

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T he In vesti gat or or desi g nee m ust c o nfir m t hat a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
ma i ntai ne d d uri n g tr a nsit f or all st u d y i nter ve nti o n recei ve d a n d a n y discre pa ncies are re p orte d 
a n d r es ol ve d bef or e use of t he st u d y i nter ve nti o n. 
O nl y partici pa nt s e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n, a n d o nl y a ut h orize d site 
staff ma y s u ppl y or a d mi nister st u d y i nter ve nti o n. All st u d y i nter ve nti o n m ust be st ore d i n a 
sec ur e, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wit h t he la bele d st or a ge c o n diti o ns wit h access li mite d t o t he In vesti gat or a n d a ut h orize d site 
staff. 
T he In vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
r es p o nsi ble f or st u d y i nter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
r ecei pt, r ec o nciliati o n, a n d fi nal dis p ositi o n recor ds).  
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o ns are 
pr o vi de d i n t he P har mac y  Ma n ual s. 
6. 3  
M E A S U R E S T O MI NI MI Z E BI A S: R A N D O MI Z A TI O N A N D 
B LI N DI N G  
6. 3. 1  
I nter ve nti o n Assi g n m e nt  
T h e a d va nce d metastatic ca ncer p orti o n of t his st u d y  is n ot ra n d o mize d. Treat me nt assi g n me nt 
will be base d o n t he per ce nta ge of t u m oral C D 8 cells at t he i nitial bi o ps y. Partici pa nts w h o ha ve 
a t u m or wit h ≥ 1 5 % C D 8 cells will r ecei ve ni v ol u ma b m o n ot hera p y, a n d partici pa nts w h o ha ve a 
t u m or wit h < 1 5 % C D 8 cells will r ecei ve i pili m u ma b i n c o m bi nati o n wit h ni v ol u ma b . 
T he first 1 0  a d va nce d pr ostate ca ncer partici pa nts w h o e nr oll wit h a t u m or wit h < 1 5 % C D 8 cells 
will be r a n d o ml y all ocate d t o r ecei ve ni v ol u ma b 1 m g / k g i n c o m bi nati o n wit h i pili m u ma b 
3  m g/ k g (Pr ostate C o h ort A ) or ni v ol u ma b 1 m g/ k g i n c o m bi nati o n wit h i pili m u ma b 5 m g/ k g 
(Pr ostate C o h ort B ) i n a 1: 1 r ati o. 
T he r e mai ni n g 1 0 a d va nce d pr ostate ca ncer partici pa nts will n ot be ra n d o ml y all ocate d b ut 
i nstea d assi g ne d t o a n i nter ve nti o n c o h ort base d o n t he safet y o bser ve d i n b ot h c o h orts. If 
Pr ostate C o h ort B is deter mi ne d t o ha ve a t olera ble safet y pr ofile ( per Se cti o n 6. 6. 1. 4), t he 
r e mai ni n g 1 0 a d va nce d pr ostate ca ncer partici pa nts will be assi g ne d t o Pr ostate C o h ort B. If t he 
saf et y pr ofile of Pr ostate C o h ort B is dee me d u nacce pta ble, t he re mai ni n g 1 0 a d va nce d pr ostate 
ca ncer partici pa nts will be assi g ne d t o Pr os tate C o h ort A. 
All a d va nce d pr ostate ca ncer partici pa nts w h o ha ve a t u m or wit h ≥ 1 5 % C D 8 cells will recei ve 
ni v ol u ma b m o n ot her a p y. Partici pa nts w h o are ra n d o m l y all ocate d b ut d o n ot recei ve st u d y 
i nter ve nti o n f or a n y r eas o n ma y be r e place d. Ra n d o mizati o n w ill be perf or me d b y t he S p o ns or. 

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St u d y i nter ve nti o n will be a d mi nister e d b y site pers o n nel a n d trac ke d usi n g dr u g acc o u nta bilit y 
r ec or ds.  
6. 3. 2  
Bli n di n g  
T his is a n o pe n -la bel trial; t her ef or e, t he S p o ns or, In vesti gat or, a n d partici pa nt will k n o w t he 
st u d y i nter ve nti o n a d mi nister e d. 
6. 4  
S T U D Y I N T E R V E N TI O N C O M P LI A N C E  
St u d y i nter ve nti o n will be a d mi nister e d b y a ut h orize d site pers o n nel a n d trac ke d usi n g dr u g 
acc o u nta bilit y r ec or ds. N o a d diti o nal meas ures of c o m plia nce will be i nstit ute d.  
6. 5  
C O N C O MI T A N T T H E R A P Y  
A n y me dicati o n or vacci ne (i ncl u di n g o ver -t he-c o u nter or prescri pti o n me dici nes, vita mi ns, 
a n d/ or her bal s u p ple me nts) t hat t he partici pa nt  is recei vi n g at t he ti me of e nr oll me nt or recei ves 
d uri n g t he st u d y m ust be r ec or de d al o n g wit h:  
•  Reas o n f or use  
•  Dates of a d mi nistr ati o n i ncl u di n g start a n d e n d dates  
•  D osa ge i nf or mati o n i ncl u di n g d ose , a d mi nistrati o n r o ute, a n d fre q ue nc y  
 
T he Me dical M o nit or s h o ul d be c o ntacte d if t here are a n y q uesti o ns re gar di n g c o nc o mita nt or 
pri or t her a p y.  
6. 5. 1  
Per mitte d T her a p y  
C o nc o mita nt me dicati o ns or tr eat me nts (e g, aceta mi n o p he n/ paraceta m ol, di p he n h y dra mi ne) ma y 
be pr escri be d if c o nsi der e d necessar y f or a de q uate pr o p h ylactic or s u p p orti ve care e xce pt f or 
t h ose me dicati o ns i de ntifie d as “e xcl u de d” i n Secti o n 5. 2  a n d Secti o n 6. 5. 2 . 
6. 5. 2  
Pr o hi bite d T her a p y  
T he me dicati o ns liste d bel o w a r e pr o hi bite d d uri n g t he st u d y. T he S p o ns or m ust be n otifie d if a 
partici pa nt  r ecei ves a n y of t hese d uri n g t he st u d y. 
•  A n y c o nc urr e nt i n vesti gati o nal a ntica ncer t hera p y . 
•  I m m u n os u p pr essi ve me dicati o ns, i ncl u di n g c hr o nic s yste mic ster oi ds at p h ysi ol o gic 
d oses ( e q ui vale nt t o a d ose of 1 0 m g oral pre d nis o ne) 1 4 da ys bef ore t he first d ose 
( e xce pt f or partici pa nts w h o re q uire h or m o ne re place me nt t hera p y [H R T ]). A 
te m p or ar y c o urse of ster oi ds ( e g, c o ntrast aller g y, c hr o nic o bstr ucti ve p ul m o nar y 
disease) ma y be per mitte d, de pe n di n g o n t he d urati o n a n d d ose, after disc ussi o n a n d 
a gr ee me nt wit h t he Me dical M o nit or . 

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•  A n y c o nc urr e nt c he m ot her a p y, ra di ot hera p y (e xce pt palliati ve ra di ot he ra p y), 
i m m u n ot her a p y, or bi ol o gic treat me nt. C o nc urre nt use of h or m o nes f or n o nca ncer -
r elate d c o n diti o ns is per mitte d . Partici pa nts  recei vi n g ca ncer relate d  h or m o nal t hera p y 
at st u d y e ntr y ma y c o nti n ue  wit h Me dical M o nit or a p pr o val.  O n g oi n g a n dr o ge n 
de pri v ati o n t her a p y a n d b o ne stre n gt he ni n g t hera pies (s uc h as  bis p h os p h o nates a n d 
R A N K L i n hi bit ors ) ar e per missi ble u n der t he c o n diti o ns i n t he a d va nce d pr ostate 
ca ncer s pecific i ncl usi o n criteria . 
•  A n y l i ve atte n uate d vacci ne t hera pies use d f or t he pre ve nti o n of i nfecti o us diseases 
(f or u p t o 3 0 da ys pri or t o t he first d ose a n d 1 0 0  da ys after t he last  d ose of st u d y 
i nter ve nti o n). 
•  A n y b ota nical pr e par ati o n ( e g  her bal s u p ple me nts or tra diti o nal C hi nese me dici nes) 
i nte n de d t o tr eat t he disease u n der st u d y. Use of marij ua na a n d its deri vati ves f or 
tr eat me nt of s y m pt o ms r elate d t o ca ncer or t o ca ncer treat me nt are per mitte d.  
 
6. 6  
D O S E M O DI FI C A TI O N S  ( E S C A L A TI O N/ TI T R A TI O N/ 
O T H E R)  
I m m u n o-o nc ol o g y a ge nts ar e ass ociate d wit h A Es t hat ca n differ i n se verit y a n d d urati o n fr o m 
A Es ca use d b y ot her t her a pe utic classes. E arl y rec o g niti o n a n d ma na ge me nt of A Es ass ociate d 
wit h i m m u n o -o nc ol o g y a ge nts ma y miti gate  se vere t o xicit y. Ma na ge me nt al g orit h ms (see 
A p pe n di x 8 ) ha ve bee n de vel o pe d t o assist I n vesti gat ors i n assessi n g a n d ma na gi n g t he 
f oll o wi n g gr o u ps of dr u g -r elate d A Es: 
Ma na ge me nt  al g orit h ms f or A Es r elate d t o ni v ol u ma b a n d/ or i pilim u ma b : 
•  I m m u ne-me diate d c olitis  
•  I m m u ne-me diate d he patitis  
•  I m m u ne-me diate d e n d ocri n o pat hies ( h y p o p h ysitis, a dre nal i ns ufficie nc y, 
h y p ot h yr oi dis m a n d h y pert h yr oi dis m, T y pe 1 dia betes mellit us)  
•  I m m u ne-me diate d s ki n a d verse reacti o ns  
•  I m m u ne-me diate d e nce p halitis  
•  I m m u ne-me diate d p ne u m o nitis  
•  I m m u ne-me diate d ne p hritis a n d re nal d ysf u ncti o n  
•  Im m u ne -me diate d m y ocar ditis  
 
Base d o n t he a vaila ble c har acterizati o n of t he mec ha nis m of acti o n, a n d preli mi nar y data fr o m 
o n g oi n g st u dies, ni v ol u ma b wit h or wit h o ut i pili m u ma b  ma y ca use A E s si milar t o, b ut 
i n de pe n de nt of, c o nc urr e nt t her a p y, ma y e xacer bate t he fre q ue nc y or se verit y, or ma y ha ve n o n -

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o verla p pi n g t o xicities. T he a ntici pate d i m p orta nt safet y ris ks are o utli ne d bel o w. Refer t o t he 
I n vesti gat or’s Br oc h ur e of ni v ol u ma b  a n d t he I n vesti gat or ’s Br oc h ure of i pili m u ma b f or 
c o m plete s u m maries of saf et y i nf or mati o n.  
6. 6. 1  
D os e M o dific ati o ns wit h Ni v ol u m a b  a n d I pili m u m a b 
T he In vesti gat or ma y attri b ute eac h A E  t o t he c o m bi nati o n of ni v ol u ma b a n d i pili m u ma b  or t o 
ni v ol u ma b al o ne. St u d y partici pa nt s ma y  n ot ha ve a n y d ose m o dificati o ns of ni v ol u ma b  or 
i pili m u ma b d oses i n t his st u d y. After a d mi nistrati o n of t he first d ose i pili m u ma b, t he I n vesti gat or 
ma y deter mi ne ( base d o n cli nical s y m pt o ms) t he n u m ber of f ut ure d oses of i pili m u ma b t he 
partici pa nt will r ecei ve, f or a ma xi m u m of 4 d oses  (a d va nce d metastatic ca ncer) or f or a 
ma xi m u m of  2 d oses ( a d va nce d pr ostate ca ncer) . If t he i pili m u ma b is st o p pe d a n d/ or c o urse has 
bee n c o m plete d, a r e peat d ose of i pili m u ma b at a later date is n ot per mitte d.  Partici pa nts w h o 
st o p i pili m u ma b d osi n g earl y d ue t o t o xicities ma y start ni v ol u ma b mai nte na nce.  If t o xicit y d oes 
n ot r es ol ve or t he criteria f or r es u mi n g st u d y i nter ve nti o n are n ot met, t he partici pa nt  m ust be 
disc o nti n ue d fr o m ni v ol u ma b m o n ot hera p y or ni v ol u ma b a n d i pili m u ma b c o m bi nati o n t hera p y . 
A p pr o priate d oc u me ntati o n is r e q uir e d re gar di n g t h e dr u g t o w hic h t he In vesti gat or is attri b uti n g 
t he A E. If, i n t he o pi ni o n of t he In vesti gat or, t he t o xicit y is relate d t o t he c o m bi nati o n of 
2  a ge nts, t he n b ot h dr u gs s h o ul d be hel d.  
S pecific a ntici pate d or p ote ntial t o xicities ass ociat e d wit h t he a d mi nis trati o n of ni v ol u ma b wit h 
or wit h o ut i pili m u ma b , as well as t he meas ures ta ke n i nte n de d t o a v oi d or mi ni mize s uc h t o xicit y 
i n t his trial, ar e descri be d i n t he f oll o wi n g secti o ns. 
6. 6. 1. 1  
D os e M o dific ati o ns a n d T o xicit y M a n a ge m e nt f or A d vers e E ve nts 
Ass oci ate d wit h  Ni v ol u m a b w it h or w it h o ut I pili m u m a b 
A E s ass ociate d wit h ni v ol u ma b wit h or wit h o ut i pili m u ma b  e x p os ure ma y re prese nt a n 
i m m u n ol o gic eti ol o g y. T hese ir A Es ma y occ ur s h ortl y after t he first d ose or se veral m o nt hs after 
t he last d ose of tr eat me nt a n d ma y affect m ore t ha n o ne b o d y s yste m si m ulta ne o usl y. T heref ore, 
earl y r ec o g niti o n a n d i nitiati o n of tr eat me nt is critical t o re d uce c o m plicati o ns. Base d o n e xisti n g 
cli nical st u d y data, dr u g -r elate d A Es ha ve i ncl u de d p ul m o nar y t o xicit y, re nal t o xicit y (i ncl u di n g 
ac ute r e nal f ail ur e), e n d ocri ne a b n or malities, gastr oi ntesti nal  t o xicit y, der mat ol o gic t o xicit y 
(i ncl u di n g r as h), a n d he pat ot o xicit y. F or ni v ol u ma b m o n ot hera p y a n d c o m bi nati o n t hera p y, t he 
maj orit y of t hese A Es ha ve bee n ma na ge d s uccessf ull y wit h s u p p orti ve care a n d, i n m ore se vere 
cases, a c o m bi nati o n of d ose dela y, per ma ne nt disc o nti n uati o n, a n d/ or use of c ortic oster oi ds or 
H R T  ( e n d ocri n o pat hies). F or s us pecte d ir A Es, e ns ure a de q uate e val uati o n t o c o nfir m eti ol o g y or 
e xcl u de ot her ca uses. A d diti o nal pr oce d ures or tests s uc h as br o nc h osc o p y, e n d osc o p y, a n d s ki n 
bi o ps y  ma y be i ncl u de d as part of t he e val uati o n.  

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F or A me n d me nts 1 a n d 2, d ose m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes f or ir A Es 
ass ociate d wit h ni v ol u ma b wit h or wit h o ut i pili m u ma b are pr o vi de d i n T a ble 7 . F or 
A me n d me nt  3 +  ( a d va nce d pr ostate c o h orts), re q uire me nts f or t he disc o nti n uati o n of st u d y 
treat me nt f or ir A Es ass ociate d wit h ni v ol u ma b wit h or wit h o ut i pili m u ma b are pr o vi de d i n T a ble 
9 . 

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T a ble 7 : 
D ose M o dific ati o n a n d T o xicit y 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 Ni v ol u m a b 
wit h or wit h o ut I pili m u m a b  
Dr u g -Rel ate d  A d verse  
E ve nt  ( A E) per  C T C A E  V 5  
Se verit y  
Acti o n  T a ke n  
Cl arific ati o ns,  E xce pti o ns,  a n d  Res u me  Criteri a  
G astr oi ntesti n al  
C olitis  or  Diarr he a  
Gra de  2  
Dela y  d ose  
D osi n g  m a y  res u m e w he n  A E  res ol ves t o baseli ne  
Gra de  3  
Ni v ol u m a b  
m o n ot hera p y: 
Dela y  d ose  
D osi n g  m a y  res u m e w he n  A E  res ol ves t o baseli ne  
W he n  a d mi nistere d  
wit h  i pili m u ma b: 
Per ma ne ntl y 
Disc o nti n ue  
I pili m u m a b 
Ni v ol u m a b  m o n ot hera p y  ma y  be  res u me d w he n  A E res ol ves t o 
baseli ne.  If Gra de  3  di arr hea  or  c olitis rec urs w hile  o n  ni v ol u ma b  
m o n ot hera p y,  per ma ne ntl y disc o nti n ue  
Gra de  4  
Per ma ne ntl y  
disc o nti n ue  
 
Re n al  
Ser u m  Creati ni ne  I ncrease d 
Gra de  2  or  3  
Dela y  d ose  
D osi n g ma y res u m e w he n A E res ol ves t o Gra de ≤ 1 or baseli ne 
val ue  
Gra de  4  
Per ma ne ntl y  
disc o nti n ue  
 
P ul m o n ar y  
P ne u m o nitis  
Gra de  2  
Dela y  d ose  
D osi n g ma y res u m e after p ne u m o nitis has res ol ve d t o ≤ Gra de  1.  
Gra de  3  or  4  
Per ma ne ntl y  
disc o nti n ue  
 

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Dr u g -Rel ate d  A d verse  
E ve nt  ( A E) per  C T C A E  V 5  
Se verit y  
Acti o n  T a ke n  
Cl arific ati o ns,  E xce pti o ns,  a n d  Res u me  Criteri a  
He p atic  
As part at e  a mi n otra nsferase 
( A S T), ala ni ne 
a mi n otra nsferase  ( A L T), or  
t otal bilir u bi n  ( T. bili) 
i ncrease d 
A S T  or  A L T  > 3 x  a n d ≤ 5 x  
u p per  li mit of  n or mal 
( U L N) or  T. Bili > 1. 5 x  a n d 
≤ 3 x  U L N,  re gar dl ess of  
baseli ne  val ue  
Dela y  d ose  
D osi n g  m a y  res u m e w he n  la b orat or y val ues  ret ur n t o baseli ne.  
A S T  or  A L T  > 5  x  U L N  or  T.  
bili  >  3  x  U L N,  re gar dless of  
baseli ne  val ue  
Dela y d ose or 
Per ma ne ntl y 
disc o nti n ue  
In  m ost  cases of  A S T  or  A L T  > 5  x  U L N,  st u d y treat me nt will  be  
per ma ne ntl y  disc o nti n ue d.  If t he i n vesti gat or det er mi nes  a  p ossi bl e  
fa v ora ble be nefit/ris k rati o t hat warra nts  c o nti n uati o n of  st u d y 
tre at me nt, a disc ussi o n  bet wee n  t he i n vesti gat or a n d t he Me dic al 
M o nit or/  desi g nee  m ust oc c ur  a n d a writte n a gree me nt fr o m Me dic al 
M o nit or  pri or t o res u mi n g t hera p y. 
C o nc urre nt  A S T  or  A L T  > 3  x  
U L N a n d T. bili > 2  x  U L N,  
re gar dless of baseli ne  val ue  
Per ma ne ntl y  
disc o nti n ue  
 
E n d oc ri n o p at h y  
A dre nal  I ns uffici e nc y 
Gra de  2  a dre nal i ns ufficie nc y 
Dela y  d ose  
D osi n g ma y res u m e wit h la b c o nfir mati o n of h or m o ne re pla ce m e nt 
tre at me nt. 
Gra de  3  or  4  a dre nal 
i ns uffi cie nc y or  a dre nal crisis 
Dela y  d ose  or  
per ma ne ntl y  
disc o nti n ue  
Ma n dat or y  disc ussi o n  wit h  a n d a p pr o val fr o m t he Me dic al  M o nit or  
ne e de d  pri or t o res u mi n g t hera p y. If a dre nal i ns uffici e nc y  res ol ves or  
is a de q uatel y  c o ntr olle d  wit h  p h ysi ol o gic  h or m o ne  re pla ce me nt, 
parti ci pa nt m a y  n ot  re q uire disc o nti n uati o n  of  st u d y dr u g.  
H y per gl yce mia  
H y per gl yce mia  re q uiri n g 
i nitiati o n or  c ha n ge i n dail y  
ma na ge m e nt ( Gra de 2  or  3)  
Dela y  d ose  
D osi n g  m a y  res u m e if h y per gl yce mia  res ol ves t o Gra de  ≤ 1 or  baseli ne  
val ue, or  is a de q uat el y c o ntr oll e d wit h  gl uc ose -c o ntr olli n g a ge nts. 
Gra de  4  
Dela y  d ose  or  
per ma ne ntl y  
disc o nti n ue  
Ma n dat or y disc ussi o n wit h a n d a p pr o val fr o m t he Me di cal M o nit or 
ne e de d pri or t o res u mi n g t hera p y. If h y per gl yce mi a res ol ves, or is 
a de q uatel y c o ntr oll e d wit h gl uc ose -c o ntr olli n g a ge nts, partici pa nt 
m a y n ot re q uire disc o nti n uati o n of st u d y dr u g.  

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Dr u g -Rel ate d  A d verse  
E ve nt  ( A E) per  C T C A E  V 5  
Se verit y  
Acti o n  T a ke n  
Cl arific ati o ns,  E xce pti o ns,  a n d  Res u me  Criteri a  
H y p o p h ysitis/ H y p o pit uitaris m  
S y m pt o matic  Gra de  1 -3  t hat is 
als o ass ociate d wit h  
c orres p o n di n g a b n or m al  la b 
a n d/ or pit uitar y  sca n 
Dela y  d ose  
D osi n g  m a y  res u m e if e n d ocri n o pat h y  res ol ves t o be  as y m pt o matic,  or  
is a de q uatel y  c o ntr olle d  wit h  o nl y  p h ysi ol o gic  h or m o ne  re pl ac e me nt. 
Gra de  4  
Dela y  d ose  or  
per ma ne ntl y  
disc o nti n ue  
Ma n dat or y  disc ussi o n  wit h  a n d a p pr o val fr o m t he Me di cal  M o nit or  
ne e de d  pri or t o res u mi n g t hera p y. If e n d ocri n o pat h y res ol ves or  is 
a de q uatel y  c o ntr olle d  wit h  p h ysi ol o gi c  h or m o ne  re plac e me nt, 
parti ci pa nt m a y  n ot  re q uire disc o nti n uati o n  of  st u d y dr u g.  
H y pert h yr oi dis m or  
H y p ot h yr oi dis m  
Gra de  2  or  3  
Dela y  d ose  
D osi n g  m a y  res u m e if e n d ocri n o pat h y  res ol ves t o be  as y m pt o matic, or  
is a de q uatel y  c o ntr olle d  wit h  o nl y p h ysi ol o gic  h or m o ne  re plac e me nt or  
ot her me di cal  m a na ge m e n t. 
Gra de  4  
Dela y  d ose  or  
per ma ne ntl y  
disc o nti n ue  
Ma n dat or y disc ussi o n wit h a n d a p pr o val fr o m t he Me di cal M o nit or 
ne e de d pri or t o res u mi n g t hera p y. If e n d ocri n o pat h y res ol ves or is 
a de q uatel y c o ntr oll e d wit h p h ysi ol o gic h or m o ne re pla ce me nt or ot her 
m e di cal ma na ge m e nt, parti ci pa nt ma y n ot re q uire disc o nti n uati o n of 
st u d y dr u g. 
S ki n  
Ras h  
Gra de  2  ras h c o veri n g > 3 0 %  
b o d y s urfa ce  area  or  Gra de  3  
ras h 
Dela y  d ose  
D osi n g  m a y  res u m e w he n  ras h re d uces t o ≤ 1 0 %  b o d y s urfa ce  
are a 
S us pe cte d  Ste ve ns -J o h ns o n 
s y n dr o me ( SJ S), t o xic e pi der mal 
necr ol ysis  ( T E N) or  dr u g  
rea cti o n wit h  e osi n o p hilia  a n d 
s yste mic s y m pt o ms ( D R E S S) 
Dela y  d ose  
D osi n g  m a y  res u m e if SJ S,  T E N,  or  D R E S S  is r ule d o ut  a n d ras h 
re d uc es t o is ≤ 1 0 %  b o d y  s urface area 
Ne ur ol o gic al  
G uillai n -Barre  S y n dr o me ( G B S)  A n y  Gra de  
Per ma ne ntl y  
disc o nti n ue  
 
M yast he nia  Gra vis  ( M G) 
A n y  Gra de  
Per ma ne ntl y  
disc o nti n ue  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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Dr u g -Rel ate d  A d verse  
E ve nt  ( A E) per  C T C A E  V 5  
Se verit y  
Acti o n  T a ke n  
Cl arific ati o ns,  E xce pti o ns,  a n d  Res u me  Criteri a  
E nce p halitis  
A n y  Gra de  e nce p halitis 
Dela y  d ose  
Differe ntial Di a g n osis w or k u p is ma n dat or y t o r ule o ut sec o n dar y 
c a uses (i nfe cti o n, t u m or, et c). D osi n g m a y res u m e wit h Me dic al 
M o nit or disc ussi o n a n d writt e n a gre e me nt.  
A n y  Gra de  dr u g -relate d 
e nce p halitis 
Per ma ne ntl y  
disc o nti n ue  
 
M yelitis  
A n y  Gra de  m yelitis  
Dela y  d ose  
After w or k u p f or differe nti al dia g n osis, (i. e.  i nfecti o n, t u m or-rel ate d), 
if m yelitis is n ot dr u g rel ate d, t he n d osi n g ma y res u me w he n A E 
res ol ves 
A n y  Gra de  dr u g -relate d m yelitis  Per ma ne ntl y  
disc o nti n ue  
 
Ne ur ol o gic al  ( ot her t ha n G B S,  
M G,  e nc e p halitis, or  m yelitis)  
Gra de  2  
Dela y  d ose  
D osi n g  m a y  res u m e w he n  A E  res ol ves t o baseli ne  
Gra de  3  or  4  
Per ma ne ntl y  
disc o nti n ue  
 
M y oc ar ditis  
M y oc ar ditis  
S y m pt o ms  i n d uce d fr o m mil d t o 
m o derate  a cti vit y or  e xerti o n 
Dela y  d ose  
D osi n g  m a y  res u m e after m y oc ar ditis has  res ol ve d 
Se vere  or  life t hre ate ni n g, wit h 
s y m pt o ms at rest or  wit h  mi ni mal 
a cti vit y or  e xerti o n, a n d/ or w here  
i nter ve nti o n i n dic ate d. 
Per ma ne ntl y  
disc o nti n ue  
 
Ot her  Cli nic al  A E  
Pa ncreatitis: A m yl ase  or  Li pase  
i ncrease d 
Gra de  3  wit h  s y m pt o ms 
Dela y  d ose  
N ote: Gra de 3 i ncrease d a m ylase or li pase wit h o ut si g ns or 
s y m pt o ms of pa ncreatitis d oes n ot re q uire d ose del a y. D osi n g 
ma y res u me w he n patie nt bec o m es as y m pt o matic.  
Gra de  4  
Per ma ne ntl y  
disc o nti n ue  
 
U veitis  
Gra de  2  u veitis  
Dela y  d ose  
D osi n g ma y res u m e if u veitis res p o n ds t o t o pical t hera p y (e ye 
dr o ps) a n d aft er u veitis res ol ves t o Gra de ≤ 1 or baseli ne. If 
patie nt re q uires oral st er oi ds f or u veitis, t he n per ma ne ntl y 
disc o nti n ue st u d y dr u g.  
Gra de  3  or  4  u veitis  
Per ma ne ntl y  
disc o nti n ue  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
7 4  
Dr u g -Rel ate d  A d verse  
E ve nt  ( A E) per  C T C A E  V 5  
Se verit y  
Acti o n  T a ke n  
Cl arific ati o ns,  E xce pti o ns,  a n d  Res u me  Criteri a  
Ot her  Dr u g -Relate d  A E  ( n ot 
liste d a b o ve)  
Gra de  2  n o n -s ki n A E,  e xc e pt 
fati g ue 
Dela y  d ose  
D osi n g ma y res u m e w he n A E res ol ves t o Gra de ≤ 1 or baseli ne 
val ue.  
Gra de  3  A E  - First occ urre nce 
l asti n g ≤ 7  da ys  
Dela y  d ose  
D osi n g ma y res u m e w he n A E res ol ves t o Gra de ≤ 1 or baseli ne 
val ue.  
Gra de  3  A E - First  occ urre nce 
l asti n g > 7  da ys  
Per ma ne ntl y  
disc o nti n ue  
 
Re c urre nc e  of  Gra de  3  A E  of  
a n y d urati o n 
Per ma ne ntl y  
disc o nti n ue  
 
Gra de  4  or  Life -t hreate ni n g 
a d verse reacti o n 
Per ma ne ntl y  
disc o nti n ue  
 
Ot her  L a b  a b n or m aliti es  
Ot her  Dr u g -Relate d  la b 
a b n or m alit y  ( n ot liste d a b o ve)  
Gra de  3  
Dela y  d ose  
E xce pti o ns:   
N o  dela y  re q uire d f or: Gra de  3  l y m p h o pe ni a 
 
Per ma ne nt Disc o nti n uati o n f or: Gra de 3 t hr o m b oc yt o pe nia > 7 
da ys or ass ociate d wit h bl ee di n g.  
 
Gra de  4  
Per ma ne ntl y  
disc o nti n ue  
E xce pti o ns:  T he  f oll o wi n g e ve nts d o  n ot  re q uire disc o nti n uati o n  
of  st u d y dr u g:  
•  
Gra de  4  ne utr o pe ni a  ≤ 7  da ys  
•  
Gra de  4  l y m p h o pe nia or  l e u k o pe ni a 
•  
Gra de  4  is olate d electr ol yte  i m bala nces/a b n or malities t hat 
are  n ot  ass ociat e d  wit h  cli nic al se q uel ae  a n d are res p o n di n g 
t o s u p ple m e ntati o n/a p pr o priat e ma na ge me nt  wit hi n  7 2  
h o urs  of  t heir o nset  
I nf usi o n Re acti o ns  ( m a nifeste d b y  fe ve r, c hills, ri g ors, he a d ac he,  r as h, pr urit us,  art hr al gi a, h y p ote nsi o n,  h y pe rte nsi o n,  br o nc h os p as m, or  ot her  
alle r gi c -li ke re acti o ns.) 
H y perse nsiti vit y  reacti o n or  
i nf usi o n re acti o n 
Gra de  3  or  4  
Per ma ne ntl y  
disc o nti n ue  
Refer t o Secti o n 6. 6. 1. 2  o n  Tre at me nt  of  Relat e d  I nf usi o n 
Re acti o ns  
A L T = al a ni ne a mi n otra nsferase; A S T = as part at e a mi n otra nsferase;  D R E S S  = dr u g  reacti o n wit h  e osi n o p hilia  a n d s yste mic s y m pt o ms; G B S = G uillai n -B arre  
S y n dr o me; H C C = he pat oc ell ul ar c arci n o ma ; M G = M yast he nia  Gra vis; SJ S  =  St e ve ns -J o h ns o n s y n dr o me; T. bili  = t otal  bilir u bi n; T E N = t o xi c e pi der mal ne cr osis; 
U L N = u p per li mit of n or m al  
a  T o xicit y was gra de d per Nati o nal Ca ncer I nstit ut e C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts , versi o n 5 . 0 ( N CI C T C A E v5 . 0). 
b Res u me treat m e nt w he n a d verse rea cti o n i m pr o ves t o Gra de 0 or 1.  
c Res u me treat m e nt w he n A S T/ A L T ret ur ns t o baseli ne.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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6. 6. 1. 2  
D os e M o dific ati o ns a n d T o xicit y M a n a ge m e nt f or I nf usi o n -
rel ate d Re acti o n Ass oci ate d wit h Ni v ol u m a b  wit h or wit h o ut  
I pili m u m a b 
I nterr u pt or sl o w t he r ate of i nf usi o n i n partici pa nts wit h mil d or m o derate i nf usi o n reacti o ns. 
Disc o nti n ue ni v ol u ma b  m o n ot her a p y or ni v ol u ma b a n d i pili m u ma b c o m bi nati o n t hera p y  i n 
partici pa nts wit h se ver e or lif e -t hr eate ni n g i nf usi o n reacti o ns. 
D ose m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes f or i nf usi o n -relate d reacti o n ass ociate d 
wit h or wit h o ut i pili m u ma b ar e pr o vi de d i n T a ble 8 . 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
7 6  
T a ble 8 :  
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes f or I nf usi o n -rel ate d Re acti o n Ass oci ate d wit h 
Ni v ol u m a b  wit h or wit h o ut  I pili m u m a b 
G r a de  
( N CI C T C A E v  5 . 0) 
Tr e at me nt  
P re me di c ati o n at S u bse q ue nt D osi n g  
G r a de 1  
Mil d reacti o n; i nf usi o n i nterr u pti o n n ot i n di cate d; 
i nter ve nti o n n ot i n di cat e d 
Re mai n at be dsi de a n d m o nit or partici pa nt u ntil r ec o ver y fr o m 
s y m pt o ms. 
T he f oll o wi n g pr o p h yl actic pre me di cati o ns  ar e 
r ec o m me n de d f or f ut ure i nf usi o ns: 
di p he n h y dra mi ne 5 0 m g ( or e q ui val e nt) a n d/ or 
acet a mi n o p he n/ par aceta m ol 3 2 5 t o 1 0 0 0 m g at 
l east 3 0 mi n ut es bef or e a d diti o nal ni v ol u m a b 
a n d/ or i pili m u ma b a d mi nistr ati o ns 
G r a de 2  
Re q uir es t her a p y or i nf usi o n i nt err u pti o n b ut 
r es p o n ds pr o m ptl y t o s y m pt o mati c tr eat m e nt (e g, 
a nti hist a mi nes, N S AI Ds, nar c oti cs, I V fl ui ds); 
pr o p h ylactic m e dicati o ns i n dicat e d f or ≤2 4 h o urs  
St o p I nf usi o n  
Be gi n a n I V i nf usi o n of n or mal sali ne, a n d treat t he partici pa nt  wit h 
di p he n h y dra mi ne 5 0 m g I V ( or e q ui val e nt) a n d/ or 
acet a mi n o p he n/ par aceta m ol 3 2 5 t o 1 0 0 0 m g; re m ai n at be dsi de a n d 
m o nit or partici pa nt u ntil r es ol uti o n of s y m pt o ms. C ortic ost er oi d 
a n d/ or br o nc h o dilat or t hera p y m a y als o be a d mi nistere d as 
a p pr o pri at e. If t he i nf usi o n is i nt err u pte d, t he n r est art t he i nf usi o n at 
5 0 % of t he ori gi nal i nf usi o n rate w he n  s y m pt o ms r es ol ve; if n o 
f urt her c o m plicati o ns e ns ue aft er 3 0 mi n ut es, t he r at e m a y be 
i ncr ease d t o 1 0 0 % of t he ori gi nal i nf usi o n rat e. M o nit or parti ci pa nt 
cl osel y. If s y m pt o ms r ec ur, t he n n o  f urt her st u d y m e di cati o n will 
be a d mi nist er e d at t hat visit.  
F or f ut ur e i nf usi o ns, t he f oll o wi n g pr o p h ylactic 
pr e m e dicati o ns are r ec o m m e n de d:  
di p he n h y dra mi ne 5 0 m g ( or e q ui val e nt) a n d/ or 
acet a mi n o p he n/ par aceta m ol 3 2 5 t o 1 0 0 0 m g s h o ul d 
be a d mi nist er e d at least 3 0 mi n utes bef or e 
ni v ol u m a b a n d/ or i pili m u m a b i nf usi o ns. If 
necessar y, c orti c oster oi ds ( u p t o 2 5 m g of 
h y dr oc ortis o ne or e q ui val e nt) m a y be use d.  
G r a des 3 or 4  
Gr a de 3 : 
Pr ol o n ge d (i e, n ot ra pi dl y r es p o nsi ve t o 
s y m pt o mati c m e di cati o n a n d/ or brief i nt err u pti o n 
of i nf usi o n); r ec urr e nce of s y m pt o ms f oll o wi n g 
i niti al i m pr o ve m e nt; h os pit alizati o n i n di cate d f or 
ot her cli ni cal se q uel ae ( e g, re nal i m pair me nt, 
p ul m o nar y i nfiltr at es)  
Gr a de 4 : 
Life -t hreat e ni n g c o nse q ue nces; ur ge nt 
i nter ve nti o n i n di cate d 
St o p I nf usi o n  
Be gi n a n I V i nf usi o n of n or mal sali ne a n d tr eat t he parti ci pa nt as 
f oll o ws: Rec o m me n d br o nc h o dilat ors, e pi ne p hri ne 0. 2 t o 1 m g of a 
1: 1 0 0 0 s ol uti o n f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 m g 
of a 1: 1 0, 0 0 0 s ol uti o n i n j ecte d sl o wl y f or I V a d mi nistrati o n, a n d/ or 
di p he n h y dra mi ne 5 0 m g I V wit h m et h yl pr e d nis ol o ne 1 0 0 m g I V 
( or e q ui val e nt), as nee de d. Partici pa nt s h o ul d be m o nit ore d u ntil t he 
I n vesti gat or is c o mf orta bl e t hat t he s y m pt o ms will n ot r ec ur. 
Re mai n at be dsi de a n d  m o nit or partici pa nt u ntil r ec o ver y of t he 
s y m pt o ms. St u d y dr u g will be per m a ne ntl y disc o nti n ue d. 
I n vesti gat ors s h o ul d f oll o w t heir i nstit uti o nal g ui deli nes f or t he 
tr eat me nt of a na p h yl a xis. 
N o s u bse q ue nt d osi n g  
I n case of late-occ urri n g h y perse nsiti vit y s y m pt o ms (e g, a p peara nce of a l ocali ze d or ge nerali ze d pr urit us wit hi n 1 wee k after tr eat m e nt), s y m pt o m atic treat me nt m a y be gi ve n 
( e g, oral a nti hista mi ne or c orti c ost er oi ds). 
A p pr o pri ate r es uscit ati o n e q ui p m e nt s h o ul d be a vail a ble at t he  be dsi de a n d a p h ysi ci a n r ea dil y a vail a bl e d uri n g t he peri o d of dr u g a d mi nistrati o n.  
F or f urt her i nf or m ati o n, please r ef er t o t he C o m m o n Ter mi n ol o g y Crit eri a f or A d verse E ve nts v 5 . 0 ( C T C A E) at htt p:// ct e p.ca ncer. g o v 
C T C A E = C o m m o n Ter mi n ol o g y Crit eria f or  A d verse E ve nts ; N CI = Nati o nal Ca nc er I nstit ut e; N S AI Ds = n o nster oi dal a nti -i nfl a m mat or y dr u gs; I V = i ntra ve n o us 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
7 7  
6. 6. 1. 3  
D os e Del a ys a n d I nterr u pti o ns f or Ni v ol u m a b wit h or wit h o ut 
I pili m u m a b 
D ose dela ys a n d i nterr u pti o ns ar e per mitte d f or t o xicit y reas o ns (see Secti o n 6. 6. 1. 1 ). D ose 
dela ys a n d i nterr u pti o ns f or r eas o ns ot her t ha n t o xicit y, s uc h as s ur gical pr oce d ures, ma y be 
all o we d wit h Me dical M o nit or a p pr o val. T he acce pta ble le n gt h of i nterr u pti o n will de pe n d o n 
a gr ee me nt bet wee n In vesti gat or a n d Me dical M o nit or.  
6. 6. 1. 4  
A d diti o n al S afet y Prec a uti o ns ( A d v a nce d Pr ost ate C a ncer C o h ort 
O nl y)  
T he  saf et y pr ofile f or ni v ol u ma b ( 1 m g/ k g) i n c o m bi nati o n wit h i pili m u ma b ( 3  m g/ k g) is well 
esta blis he d i n mela n o ma a n d H C C at m ore fre q ue nt i pili m u ma b a d mi nistrati o n ( Q 3 W  vs Q 6 W ) 
t ha n pr o p ose d f or t his c o h ort (O p di v o U S PI, 2 0 2 0 ). He nce, c o nc urre nt e nr oll me nt will be 
p urs ue d wit h partici pa nts all ocate d t o re gi me ns c o ntai ni n g eit her i pili m u ma b 3  m g/ k g or 5  m g/ k g 
Q 6 W  f or u p t o 2 d oses i n c o m bi nati o n wit h ni v ol u ma b 1 m g/ k g. As t he c o m bi nati o n re gi me n 
wit h i pili m u ma b 5  m g/ k g has n ot bee n e xte nsi vel y st u die d, i n a d diti o n t o a d verse e ve nts bei n g 
r e vie we d b y t he S p o ns or o n a n o n g oi n g basis a n d i n vesti gat or meeti n gs c o n ve ni n g 
a p pr o xi matel y e ver y 2 wee ks t o disc uss a n d re vie w safet y e ve nts, a safet y pa use is i ncl u de d.  
E nr oll me nt will pa us e u ntil all partici pa nts ha ve bee n f oll o we d f or at least 6 wee ks. D uri n g t he 
pa use, ne w partici pa nts ma y be c o nse nte d a n d scree ne d, b ut n ot i nitiate d o n st u d y i nter ve nti o n. 
T he saf et y pa use will a p pl y t o b ot h c o h orts t o preser ve ra n d o m all ocati o n; h o we ver,  t he saf et y 
assess me nt as f oll o ws will a p pl y t o t he i pili m u ma b 5  m g/ k g c o h ort s pecificall y. T he i nitial 
5  partici pa nts e nr olle d i n t he i pili m u ma b 5  m g/ k g c o h ort will be o bser ve d f or t he occ urre nce of 
tr eat me nt-r elate d a d verse e ve nts ( T R A Es) necessitati n g disc o nti n uati o n of b ot h a ge nts ( A Es 
r e q uiri n g disc o nti n uati o n ar e i ncl u de d i n T a ble 9 ) fr o m t he be gi n ni n g of treat me nt t hr o u g h 
c o m pleti o n of t he first c yc le (ie, 6 wee ks).  
If 3 or fe wer of t he first 5 partici pa nts i n t he i pili m u ma b 5 m g/ k g c o h ort  ( Pr ostate C o h ort B) 
e x perie nce a T R A E le a di n g t o disc o nti n uati o n of b ot h a ge nts, a n a d diti o nal 1 0 partici p a nts will be 
e nr olle d t o re cei ve ni v ol u ma b 1 m g/ k g Q 3 W an d i pili m u ma b 5 m g/ k g Q 6 W f or 2 c ycles, t he n 
ni v ol u ma b mai nte na n ce 4 8 0 m g Q 4 W u ntil P D or i nt olera ble t o xicit y ( Pr ostate C o h ort B) . If 4 or 
m ore of t he first 5 partici pa nts of t he i pili m u m a b 5  m g/ k g c o h ort ( Pr ostate C o h ort B) e x peri e nce a 
T R A E lea di n g t o d isc o nti n uati o n of b ot h a ge nts, a n a d diti o nal 1 0 partici pa nts will be e nr olle d t o 
recei ve ni v ol u ma b 1 m g/ k g Q 3 W a n d i pili m u ma b 3 m g/ k g Q 6 W f or 2 c ycles, t he n ni v ol u ma b 
mai nte n a nce 4 8 0 m g Q 4 W u ntil P D or i nt olera bl e t o xicit y ( Pr ostate C o h ort A).  O nl y T R A E s 
lea di n g t o tr eat me nt disc o nti n uati o n of b ot h a ge nts occ urri n g u p u ntil t he 5t h partici pa nt i n eac h 
c o h ort c o m pletes C ycle 1 will be i ncl u de d — d ose dela ys f or a d verse e ve nts n ot ot her wise 
meeti n g criteria at t hat ti me will n ot be c o u nte d. T he st o p pi n g r ule was c h ose n as t his 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
7 8  
c orr es p o n ds t o a >  8 0 % c ha nce t hat t he t o xicit y rate i n t he c o h ort is > 4 0 %, ass u mi n g a beta ( 0. 8, 
1. 2) pri or.  
If eit her pr ostate c o h ort de m o nstr ate s 8  or greater T R A Es  re q uiri n g disc o nti n uati o n of t hera p y at 
a n y ti me, e nr oll me nt will be  s us pe n de d u ntil a n a d h oc safet y re vie w c o n ve nes a n d pr o vi des a 
r ec o m me n dati o n, as descri be d a b o ve. 
T a ble  9 : 
T o xicit y Crit eri a Re q uiri n g P er m a ne nt Tre at me nt Disc o nti n u ati o n of 
B ot h Ni v ol u m a b a n d I pili m u m a b ( A me n d me nt 3 +  A d v a nce d P r ost at e 
C o h ort O nl y)  
Partici pa nts s h o ul d be m o nit ore d f or t he occ urre nce of a n y of t he f oll o wi n g A Es t hat are c o nsi dere d b y t he 
I n vesti gat or t o be p ossi bl y, pr o ba bl y, or defi nit el y relate d t o i pili m u ma b, ni v ol u ma b, or t he i m m u n ot hera p y 
c o m bi nati o n. 
Treat m e n t wit h all st u d y i nter ve nti o n s h o ul d be m o nit ore d f or t he occ urre nce of a n y of t he f oll o wi n g T R A Es, a n d 
if a n y of t hese e ve nts occ ur, a cti o n s h o ul d be ta ke n as f oll o ws: 
•  
A n y Gra de 2 dr u g -relate d u veitis, e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o t o pic al t hera p y a n d d oes 
n ot i m pr o ve t o Gra de 1 se verit y wit hi n t he re -treat m e nt peri o d O R re q uires s yste mi c tre at me nt. 
•  
A n y Gra de 3 n o n -s ki n, dr u g-rel at e d A E lasti n g > 7 da ys, or re c urs wit h t he f oll o wi n g e xc e pti o ns f or 
l a b orat or y a b n or malities, diarr he a, c olitis, ne ur ol o gic t o xicit y, dr u g -relate d u veitis, p ne u m o nitis, 
br o nc h os pas m, h y perse nsiti vit y re acti o ns, i nf usi o n rea cti o ns, a n d e n d ocri n o pat hies:  
o  
Gra de 3 dr u g -relate d diarr he a, c olitis, ne ur ol o gi c t o xicit y, u veitis, p ne u m o nitis, br o nc h os pas m, 
m y ocar diti s, h y perse nsiti vit y re acti o n, or i nf usi o n reacti o n of a n y d urati o n re q uires disc o nti n uati o n. 
o  
Gra de 3 dr u g -relate d e n d ocri n o pat hi es, a de q uat el y c o ntr oll e d wit h o nl y p h ysi ol o gi c h or m o ne 
re pla ce me nt d o n ot re q uire disc o nti n uati o n. A dre nal i ns uffi cie nc y re q uires disc o nti n uati o n re gar dless of 
c o ntr ol wit h h or m o ne re pl ac e m e nt.  
o  
Gra de 3 dr u g -relate d la b orat or y a b n or m aliti es d o n ot re q uire treat m e nt disc o nti n uati o n e xce pt: 
 
Gra de 3 dr u g -relate d t hr o m b oc yt o pe ni a > 7 da ys or ass ociate d wit h bl ee di n g re q uires 
disc o nti n uati o n . 
 
A n y dr u g -rel at e d li ver f u ncti o n test a b n or malit y t hat m eets t he f oll o wi n g criteria req uire 
disc o nti n uati o n:  
•  
Gra de ≥ 3 dr u g -relate d A S T, A L T or total b ilir u bi n re q uires disc o nti n uati o n. 
o  
I n m ost c ases of Gra de 3 A S T, A L T e val uati o n st u d y dr u g(s) will be per ma ne ntl y 
disc o nti n ue d. If t he i n vesti gat or det er mi nes a p ossi bl e fa v ora bl e be nefit/ris k rati o t hat 
warra nts c o nti n uati o n of st u d y dr u g(s), a disc ussi o n bet wee n t he i n vesti gat or a n d t he 
Me dic al M o nit or ( or desi g ne e) m ust occ ur.  
•  
C o nc urre nt A S T or A L T > 3 x U L N a n d t ot al bilir u bi n > 2 x U L N . 
•  
A n y Gra de 4 dr u g -relate d a d verse e ve nt or la b orat or y a b n or m alit y (i ncl u di n g b ut n ot li mite d t o creati ni ne, 
A S T, A L T, or tot al b ilir u bi n), e xce pt f or t he f oll o wi n g e ve nts w hi c h d o n ot re q uire disc o nti n uati o n: 
o  
Gra de 4 ne utr o pe nia ≤ 7 da ys . 
o  
Gra de 4 l y m p h o pe ni a or l e u k o pe nia or as y m pt o m atic a m yl ase or li pase. 
o  
Is ol ate d Gra de 4 ele ctr ol yt e i m bala nces/a b n or m alities t hat are n ot ass oci at e d wit h cli nic al se q uel ae a n d 
are c orrecte d wit h s u p pl e m e nt ati o n/ a p pr o pri at e ma na ge m e nt wit hi n 7 2 h o urs of t heir o nset . 
o  
Gra de 4 dr u g -relate d e n d ocri n o pat h y a d verse e ve nts, suc h as, h y per - or h y p ot h yr oi dis m, or gl uc ose 
i nt ol era nce, w hi c h res ol ve or are a de q uatel y c o ntr olle d wit h p h ysi ol o gic h or m o ne re pl ac e me nt 
(c orti c ost er oi ds, t h yr oi d h or m o nes) or gl uc ose-c o ntr olli n g a ge nts, res pecti vel y, m a y n ot re q uire 
disc o nti n uati o n aft er  disc ussi o n wit h a n d a p pr o val fr o m t he Me dic al M o nit or  ( or desi g ne e). 
•  
A n y e ve nt t hat l ea ds t o del a y i n d osi n g l asti n g > 1 2 wee ks fr o m t he pre vi o us d ose re q uires disc o nti n uati o n, 
wit h t he f oll o wi n g e xc e pti o ns:  
o  
D osi n g dela ys t o all o w f or pr ol o n ge d ster oi d t a pers t o ma na ge dr u g -rel at e d a d verse e ve nts are all o we d.  

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Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
7 9  
o  
D osi n g dela ys l asti n g > 6 wee ks fr o m t he pre vi o us d ose t hat oc c ur f or n o n -dr u g -rel ate d reas o ns m a y be 
all o we d if a p pr o ve d b y t he Me dic al M o nit or ( or desi g ne e).  
•  
Pri or t o re -i nitiati n g treat m e nt i n a parti ci pa nt wit h a d osi n g dela y l asti n g > 6 wee ks, t he Me di cal M o nit or ( or 
desi g ne e) m ust be c o ns ulte d. T u m or assess me nts s h o ul d c o nti n ue as per pr ot oc ol e ve n if d osi n g is dela ye d. 
Peri o di c st u d y visits t o assess safet y a n d l a b orat or y st u di es s h o ul d als o c o nti n ue per S O A or m ore fre q ue ntl y 
if cli nic all y i n di cate d d uri n g s uc h d osi n g dela ys. 
•  
A n y a d verse e ve nt, l a b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he j u d g m e nt of t he I n vesti gat or, 
prese nts a s u bst a ntial cli ni cal ris k t o t he partici pa nt wit h c o nti n ue d ni v ol u ma b d osi n g.  
A E = a d verse e ve nt; A L T = al a ni ne a mi n otra nsferase; A S T = as part at e a mi n otra nsferase; S O A = Sc he d ule of 
Assess m e nts; T R A Es = tre at me nt -rel at e d a d verse e ve nt; U L N = u p per li mit of n or mal  
 
6. 7  
I N T E R V E N TI O N A F T E R T H E E N D O F T H E S T U D Y  
T her e will be n o i nter ve nti o n f oll o wi n g t he e n d of t he st u d y.  
7  
DI S C O N TI N U A TI O N S O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T  DI S C O N TI N U A TI O N/ WI T H D R A W A L  
7. 1  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N 
Partici pa nt s m ust disc o nti n ue st u d y i nter ve nti o n if t he y e x perie nce a n y of t he f oll o wi n g: 
•  I nt oler a ble t o xicit y r elate d t o st u d y i nter ve nti o n, i ncl u di n g t he de vel o p me nt of a n A E  
deter mi ne d b y t he In vesti gat or t o be u nacce pta ble e ve n wit h t he partici pa nt ’s 
p ote ntial r es p o nse t o i nter ve nti o n d u e t o t he se verit y of t he e ve nt 
•  A n y me dical c o n diti o n t hat ma y je o par dize partici pa nt  safet y if he or s he c o nti n ues 
t he st u d y i nter ve nti o n 
•  Use of a n ot her a ntica ncer t hera p y  
•  S y m pt o matic deteri or ati o n attri b ute d t o disease pr o gressi o n  t hat per assess me nt b y 
the I n vesti gat or necessitates disc o nti n uati o n of st u d y i nter ve nti o n.  
•  Ra di o gr a p hic disease pr o gr essi o n per R E CI S T v 1. 1, u nless t he partici pa nt i n t he 
ni v ol u ma b m o n ot her a p y ar m deci des t o e nr oll i nt o t he ni v ol u ma b a n d i pili m u ma b 
c o m bi nati o n tr eat me nt ar m (see A p pe n di x 3 ). Refer t o Secti o n 4. 4  f or descri pti o n of 
tr eat me nt be y o n d pr o gr essi o n. 
•  Pr e g na nc y (see A p pe n di x 6 ) 
 
Partici pa nt s ha ve t he ri g ht t o v ol u ntaril y wit h dra w fr o m st u d y i nter ve nti o n at a n y ti me f or a n y 
r eas o n. I n a d diti o n, t he In vesti gat or has t he ri g ht t o wit h dra w a partici pa nt  fr o m st u d y 
i nter ve nti o n at a n y ti me. Reas o ns f or wit h dra wal fr o m st u d y i nter ve nti on  ma y i ncl u de, b ut are 
n ot li mite d t o, t he f oll o wi n g:  
•  I n vesti gat or or S p o ns or deter mi nes it is i n t he best i nterest of t he partici pa nt  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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•  Partici pa nt  n o nc o m plia nce  
T he pri mar y r eas o n f or st u d y i nter ve nti o n disc o nti n uati o n s h o ul d be d oc u me nte d o n t he 
a p pr o priate electr o nic case r e p ort f or m ( e C R F ) pa ge. 
T he visit at w hic h disease assess me nt s h o ws P D  ma y be use d as t he e n d of treat me nt visit. 
Partici pa nt s w h o disc o nti n ue st u d y i nter ve nti o n f or a n y reas o n ot her t ha n P D  or l oss of cli nical 
be nefit ar e t o c o nti n ue assess me nts as o utli ne d i n t he Sc he d ule of Acti vities  (S O A s; see 
Secti o n  1. 3 ). 
7. 2  
P A R TI CI P A N T  DI S C O N TI N U A TI O N/ WI T H D R A W A L F R O M 
S T U D Y  
W he n  st u d y i nter ve nti o n is disc o nti n ue d, partici pa nt s s h o ul d ha ve a n e n d of 
tr eat me nt/ disc o nti n uati o n assess me nt a n d c o nti n ue f oll o w-u p assess me nts u ntil ra di o gra p hic 
pr o gr essi o n or t he start of s u bse q ue nt t hera p y, w hic he ver c o mes first, as o utli ne d i n t he S O A s 
(see Secti o n  1. 3 ). I n a d diti o n, a d h oc sca ns, as part of sta n dar d of care, will be c ollecte d f or 
partici pa nts w h o ha ve disc o nti n ue d tr eat me nt f or reas o ns ot her t ha n ra di o gra p hic pr o gressi o n 
a n d pri or t o a n y alter nate t her a pies.  I nf or mati o n o n s ur vi val f oll o w-u p a n d ne w a ntica ncer 
t her a p y will be c ollecte d f or all partici pa nt s via tele p h o ne calls, partici pa nt  me dical rec or ds, 
a n d/ or cli nic visits, u ntil a n y of t he f oll o wi n g occ urs:  
•  Deat h  
•  L ost  t o f oll o w-u p  
•  St u d y ter mi nati o n b y t he S p o ns or  
•  Partici pa nt  r e q uests t o be wit h dra w n fr o m f oll o w-u p  
•  I nvesti gat or r e q uests t hat t he partici pa nt  is wit h dra w n fr o m f oll o w-u p  
 
If a partici pa nt  r e q uests t o be wit h dr a w n fr o m t he st u d y, t he re q uest m ust be d oc u me nte d i n t he 
s o ur ce d oc u me nts a n d si g ne d b y t he In vesti gat or. T he pri mar y reas o n f or wit h dra wal fr o m st u d y 
s h o ul d be d oc u me nte d o n t he a p pr o priate e C R F pa ge . If t he partici pa nt  wit h dra ws fr o m st u d y, 
t he S p o ns or ma y r etai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h wit h dra wal of c o nse nt. 
I n a d diti o n, t he st u d y staff ma y use a p u blic i nf or mati o n s o urce (e g, c o u nt y rec or ds) t o o btai n 
i nf or mati o n a b o ut s ur vi val stat us o nl y. H o we ver, partici pa nt s w h o wit h dra w c o nse nt will n ot be 
f oll o we d f or a n y r eas o n after c o nse nt has bee n wit h dra w n. Partici pa nt s w h o recei ve st u d y 
i nter ve nti o n a n d s u bse q ue ntl y wit h dr a w fr o m t he st u d y will n ot be re place d.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
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7. 3  
L O S T T O F O L L O W -U P  
A partici pa nt  will be c o nsi der e d l ost t o f oll o w -u p if he or s he re peate dl y f ails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.  
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt  fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit: 
•  T he site m ust atte m pt t o c o ntact t he partici pa nt  a n d resc hed ule t he misse d visit as 
s o o n as p ossi ble a n d c o u nsel t he partici pa nt  o n t he i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascertai n w het her or n ot t he partici pa nt  wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st u d y. 
•  Bef or e a partici pa nt is dee me d l o st t o f oll o w-u p, t he I n vesti gat or or desi g nee will 
ma ke e ver y eff ort t o r e gai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he partici pa nt’s last k n o w n maili n g 
a d dr ess or l ocal e q ui vale nt met h o ds ). T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d or st u d y file. 
•  S h o ul d t he partici pa nt  c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dr a w n fr o m t he st u d y.  
 
8  
S T U D Y A S S E S S M E N T S  A N D P R O C E D U R E S  
Please see Se cti o n 1. 3  f or t he S O A s t o be perf or me d d uri n g t he st u d y. All acti vities m ust be 
perf or me d a n d d oc u me nte d f or eac h partici pa nt  i n t he or der of S O As . Partici pa nt s will be cl osel y 
m o nit or e d f or saf et y a n d  t oler a bilit y t hr o u g h o ut t he st u d y. Partici pa nt s s h o ul d be assesse d f or 
t o xicit y pri or t o eac h d ose; d osi n g will occ ur o nl y if t he cli nical assess me nt a n d l ocal la b orat or y 
test val ues ar e acce pta ble as dee me d b y t he PI . 
If t he ti mi n g of a pr ot oc ol -ma n date d st u d y visit c oi nci des wit h a h oli da y, wee ke n d, or ot her 
a d mi nistr ati ve disr u pti o n t hat pr ecl u des t he visit, t he visit s h o ul d be sc he d ule d o n t he nearest 
f oll o wi n g f easi ble date. T he ti me bet wee n d oses m ust n ot be less t ha n  mi n us 3 da ys  fro m t he  
n or mal sc he d ule of t he last d ose r ecei ve d ( d oses m ust n ot be a d mi nistere d <  2 5 da ys f or a Q 4 W  
sc he d ule or < 1 8 da ys a part f or a Q 3 W ).  
C ollecti o n of a n y n o n -saf et y-r elate d data or partici pa nt  sa m ples ma y be ter mi nate d b y t he 
S p o ns or at a n y  ti me if f urt her c ollecti o n of s uc h data or sa m ples is als o n ot relate d t o t he st u d y’s 
pri mar y or sec o n dar y o bjecti ve . T he decisi o n t o disc o nti n ue a n y data c ollecti o n w ill be 
c o m m u nicate d t o t he sites a n d I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee 
(I E C) b y mea ns of a me m or a n d u m a n d will n ot re q uire a pr ot oc ol a me n d me nt.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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8. 1  
E F FI C A C Y A S S E S S M E N T S  
Partici pa nt s will u n der g o t u m or assess me nts as desi g nate d i n t he S O As  (see Secti o n  1. 3 ) 
r e gar dless of d ose dela ys, u ntil l oss of cli nical be nefit as deter mi ne d b y t he In vesti gat or ( u nless 
t he partici pa nt  wit h dr a ws c o nse nt or t he S p o ns or ter mi nates t he st u d y). All partici pa nt s wh o 
disc o nti n ue st u d y i nter ve nti o n f or r eas o ns ot her t ha n ra di o gra p hic pr o gressi o n (e g, A Es ) will 
c o nti n ue t u m or assess me nts u ntil deat h, disease pr o gressi o n, i nit iati o n of a n ot her s yste mic 
a ntica ncer t her a p y, l oss t o f oll o w -u p, wit h dra wal of c o nse nt, or st u d y ter mi nati o n, w hic he ver 
occ urs first. At t he In vesti gat or’s discr eti o n, t u m or assess me nts ma y be re peate d at a n y ti me if 
P D  is s us pecte d. 
Meas ur a ble a n d e val ua ble lesi o ns s h o ul d be ass ess e d a n d d oc u me nte d at scree ni n g. T u m or 
assess me nts perf or me d as sta n dar d of care pri or t o o btai ni n g i nf or me d c o nse nt a n d wit hi n 
2 8  da ys  pri or t o tr eat me nt d o n ot ha ve t o be re peate d at scree ni n g.  
Scr ee ni n g assess me nts m ust i ncl u de c o m p ute d t o m o gra p h y ( C T ) sca ns ( wit h I V c o ntrast u nless 
c o ntr ai n dicate d a n d or al c o ntr ast as  a p pr o priate per i nstit uti o nal sta n dar ds). A s piral C T sca n of 
t he c hest ma y be o btai ne d b ut  is n ot a re q uire me nt. If a C T sca n wit h c o ntrast is c o ntrai n dicate d 
(ie, i n partici pa nt s wit h c o ntr ast aller g y or i m paire d re nal cleara nce), a n o n -c o ntrast C T sca n of 
t he c hest ma y be perf or me d a n d ma g netic res o na nce i ma gi n g ( M RI ) sca ns of t he a b d o me n, 
pel vis,  a n d hea d  ( as a p plica ble) s h o ul d be perf or me d as a p plica ble. 
If a C T sca n f or a t u m or assess me nt is perf or me d i n a p ositr o n e missi o n t o m o gra p h y ( P E T)/ C T 
sca n ner, t he C T ac q uisiti o n m ust be c o nsiste nt wit h t he sta n dar ds f or a f ull c o ntrast dia g n ostic 
C T sca n.  
B o ne sca ns (tec h neti u m -9 9 m [ T C -9 9 m]) or s o di u m fl u ori de ( Na F) P E T s h o ul d be perf or me d at 
scr ee ni n g if cli nicall y i n dicate d. If b o ne metastases are prese nt at scree ni n g a n d ca n n ot be see n 
o n C T or M RI sca ns, or if cli nicall y i n dicate d, T C -9 9 m a n d Na F -P E T b o ne sca n s s h o ul d be 
r e peate d w he n c o m plete r es p o nse ( C R) is i de ntifie d i n tar get disease or w he n pr o gressi o n i n 
b o ne is s us pecte d.  
C T sca ns of t he hea d, nec k , or e xtr e mities s h o ul d als o be perf or me d if cli nicall y i n dicate d a n d 
r e peate d t hr o u g h o ut t he st u d y if t her e is e vi de nce of disease at scree ni n g.  
All meas ur a ble a n d e val ua ble lesi o ns s h o ul d be re -assesse d at eac h s u bs e q ue nt t u m or e val u ati o n. 
T he sa me r a di o gr a p hic pr oce d ur es use d t o assess disease sites at scree ni n g s h o ul d be use d f or 
s u bse q ue nt t u m or assess me nts ( e g, sa me c o ntrast pr ot oc ol f or C T sca ns).  
Res p o ns e will be assesse d b y t he In vesti gat or usi n g R E CI S T v 1. 1  (see A p pe n di x 3 ). 
Assess me nts s h o ul d be perf or me d b y t he sa me e val uat or, if p ossi ble, t o e ns ure i nter nal 
c o nsiste nc y acr oss visits. Res ults m ust be re vie we d b y t he In vesti gat or bef ore d osi n g at t he ne xt 
c ycle.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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8. 1. 1  
L a b or at or y Assess m e nts  of T u m or M ar kers  
Res ults  f or tu m or mar kers ( e g, C A 1 9 -9, P S A , etc) will be c ollecte d if perf or me d as part of 
sta n dar d of car e. 
P S A is r e q uir e d f or partici pa nts i n t he pr ostate c o h orts u n der A me n d me nt 3 +  (see T a ble  3  a n d 
T a ble  4 ). 
8. 2  
S A F E T Y A S S E S S M E N T S  
Saf et y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g A Es , i ncl u di n g S A Es , perf or mi n g 
pr ot oc ol -s pecifie d saf et y la b or at or y assess me nts, meas uri n g pr ot oc ol s pecif y vital si g ns, a n d 
c o n d ucti n g ot her pr ot oc ol -s pecifie d tests t hat are dee me d critical t o t he safet y e val uati o n of t he 
st u d y. Pla n ne d ti mi n g f or all saf et y assess me nts is pr o vi de d i n t he S O As  (Secti o n  1. 3 ).  
Certai n t y pes of e ve nts r e q uir e i m me diate re p orti n g t o t he S p o ns or, as descri be d i n 
Secti o n  8. 3. 1. 1 . 
8. 2. 1  
Me dic al Hist or y a n d De m o gr a p hic D at a  
Me d ical hist or y, i ncl u di n g cli nicall y si g nifica nt diseases, s ur geries, ca ncer hist or y (i ncl u di n g 
sta ge, date of dia g n oses, a n d pri or ca ncer t hera pies a n d pr oce d ures), re pr o d ucti ve stat us, 
s m o ki n g hist or y, use of alc o h ol, a n d dr u gs of a b use , w ill be rec or de d at baseli ne. I n a d diti o n, all 
me dicati o ns ( e g, pr escri pti o n dr u gs, o ver-t he-c o u nter dr u gs, vacci nes, her bal or h o me o pat hic 
r e me dies, n utriti o nal s u p pleme nts) use d b y t he partici pa nt  wit hi n 2 8 da ys  pri or t o st u d y 
i nter ve nti o n will be r ec or de d . De m o gr a p hic data ma y  i ncl u de a ge, se x, a n d race/et h nicit y. 
8. 2. 2  
P h ysic al E x a mi n ati o ns  
A c o m plete p h ysical e xa mi nati o n s h o ul d be perf or me d at scree ni n g a n d s h o ul d i ncl u de  a n 
e val uati o n of t he hea d, e yes, ears, n ose, a n d t hr oat, a n d t he car di o vasc ular, der mat ol o gical, 
m usc ul os keletal, r es pir at or y, gastr oi ntesti nal, ge nit o uri nar y, a n d ne ur ol o gical s yste ms . A n y 
a b n or malit y i de ntifie d at baseli ne s h o ul d be rec or de d o n t he Me di cal Hist or y e C R F  pa ge.  
E C O G Perf or ma nce Stat us (see A p pe n di x 2 ) s h o ul d be assess e d per t he S O A s i n Secti o n  1. 3 . 
At s u bse q ue nt visits ( or as cli nic all y i n dicate d), li mite d, s y m pt o m -directe d p h ysical 
e xa mi nati o ns s h o ul d be perf or me d. C ha n ges fr o m baseli ne a b n or malities s h o ul d be rec or de d i n 
partici pa nt  n otes. Ne w or w orse ne d cli nicall y si g nifica nt a b n or malities s h o ul d be rec or de d as 
A Es  o n  t he A d verse E ve nt e C R F  pa ge . 
8. 2. 3  
Vit al Si g ns  
Vital si g ns s h o ul d i ncl u de meas ur e me nts of res pirat or y rate, p ulse rate, s yst olic a n d diast olic 
bl o o d pr ess ur e , p ulse o xi metr y ( o nl y at baseli ne), a n d te m perat ure as o utli ne d i n t he S O A 
(Secti o n 1. 3 ). Vital si g ns c ollecte d at t he scree ni n g visit s h o ul d be rec or de d o n t he e C R F. F or 

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eac h visit t her eafter, o nl y vital si g ns o btai ne d pri or t o t h e first dr u g i nf usi o n o n Da y 1 or d uri n g 
a n A E ( e g, te m per at ur e or e ve nt of f e ver) s h o ul d be rec or de d o n t he e C R F. All vital si g ns 
c ollecte d per pr ot oc ol s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.  
Vital si g ns s h o ul d be meas ur e d o n Da y 1 of e ver y c ycle pri or t o a d mi nistrati o n of st u d y 
i nter ve nti o n. Vital si g ns ma y be meas ure d, if me dicall y i n dicate d, at ot her ti me p oi nts. 
Vital si g ns s h o ul d be meas ur e d wit hi n 0 -2 0  mi n utes pri or t o t he first i nf usi o n a n d, if cli nicall y 
i n dicate d, d uri n g or after t he i nf usi o ns (see Secti o n  6 ). 
8. 2. 4  
Electr oc ar di o gr a ms  
A s i n gle E C G r ec or di n g will be o btai ne d at Baseli ne , as o utli ne d i n t he S O As  (Secti o n  1. 3 ), a n d 
ma y be o btai ne d at u nsc he d ule d ti me  p oi nts as i n dicate d.  
All E C G r ec or di n gs m ust be perf or me d usi n g a n i nstit uti o nall y  a p pr o ve d E C G. Lea d place me nt 
s h o ul d be as c o nsiste nt as p ossi ble. E C G rec or di n gs m ust be perf or me d after t he partici pa nt  has 
bee n r esti n g i n a s u pi ne p ositi o n f or at least 1 0 mi n utes. All E C Gs are t o be o btai ne d pri or t o 
ot her pr oce d ur es sc he d ule d at t hat sa me ti me (e g,  vital si g n meas ure me nts, bl o o d dra ws) a n d 
s h o ul d n ot be o btai ne d wit hi n 3 h o urs after a n y meal. Circ u msta nces t hat ma y i n d uce c ha n ges i n 
heart r ate, i ncl u di n g e n vir o n me ntal distracti o ns (e g, tele visi o n, ra di o, c o n versati o n), s h o ul d be 
a v oi de d d uri n g t he pr e -E C G r esti n g peri o d a n d d uri n g E C G rec or di n g.  
F or saf et y m o nit ori n g p ur p oses, t he In vesti gat or m ust re vie w, si g n, a n d date all E C G traci n gs. 
Pa per c o pies of E C G tr aci n gs will be ke pt as part of t he partici pa nt 's per ma ne nt st u d y file at t he 
site. T he f oll o wi n g s h o ul d be r ec or de d o n  t he a p pr o priate e C R F pa ge : heart rate, R R i nter val, 
Q R S i nter val, P R d ur ati o n, u nc orr ecte d Q T i nter val, a n d Q T c F base d o n t he mac hi ne rea di n gs of 
t he i n di vi d ual E C G tr aci n gs. A n y m or p h ol o gic wa vef or m c ha n ges or ot her E C G a b n or malities 
m ust be d oc u me nte d o n t he e C R F  pa ge .  
8. 2. 5  
Cli nic al S afet y L a b or at or y Ass ess m e n ts 
Cli nical la b or at or y tests will be perf or me d at t he l ocal i nstit uti o n as descri be d i n t he S O A s 
(Secti o n  1. 3 ). 
T he In vesti gat or m ust r e vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y r ele va nt c ha n ges occ urri n g d uri n g t he st u d y o n t he a p pr o priate  eC R F. T he la b orat or y 
r e p orts m ust be file d wit h t he s o ur ce d oc u me nts. Cli nicall y si g nifica nt a b n ormal la b orat or y 
fi n di n gs ar e t h ose t hat ar e n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
In vesti gat or t o be m or e se ver e t ha n e x pecte d f or t he partici pa nt's c o n diti o n.  
I n t he e ve nt of a Gr a de 3 or Gr a de 4 la b orat or y t o xicit y, t he test f or t he a b n or mal la b orat or y 
val ue s h o ul d be r e peate d u ntil t he e ve nt is res ol ve d t o ≥ Gra de 1 or baseli ne.  

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8. 2. 5. 1  
L oc al L a b or at or y Ass ess m e nts  
Sa m ples f or t he la b or at or y test i n T a ble 1 0  will be se nt t o t he st u d y site l ocal la b orat or y f or 
a nal ysis:  
T a ble 1 0 : 
L a b or at or y Tests Se nt t o t he St u d y Site ’s L oc al L a b or at or y f or A n al ysis  
Pr ofile  
L a b or at or y T est  
He mat ol o g y  
w hit e bl o o d cell c o u nt 
h e m o gl o bi n 
he mat ocrit  
pl at elet c o u nt  
differe ntial c o u nt ( ne utr o p hils, l y m p h oc ytes) 
Cli ni cal C he mistr y  
( Ser u m or Plas m a) 
s o di u m 
p ot assi u m  
m a g nesi u m  
gl uc ose  
B U N or urea  
c reati ni ne 
t otal bilir u bi n (i ncl u di n g eit her i n dire ct or direct) 
al kali ne p h os p hatase  
A L T  
A S T  
L D H  
T S H , F T 3 , a n d F T 4  - scree ni n g  
T S H, wit h refle xi ve  F T 3 a n d F T 4 if T S H is a b n or m al - o n tre at me nt  
Li pase  
Uri nal ysis  
 
A L T = al a ni ne a mi n otra nsferase; A S T = as part at e a mi n otra nsferase; B U N = bl o o d ure a nitr o ge n; F T 3 = fre e 
trii o d ot h yr o ni ne; F T 4 =  free t h yr o xi ne; L D H  =  la ct at e de h y dr o ge nase; T S H = th yr oi d sti m ulati n g h or m o ne 
 
8. 3  
A D V E R S E E V E N T S  A N D S E RI O U S A D V E R S E E V E N T S  
T he de fi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 5 . 
I n vesti gat ors will see k i nf or mati o n o n A E  at eac h partici pa nt  c o ntact. A E s re p orte d b y t he 
partici pa nt  ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he partici pa nt 's le gall y a ut h orize d 
r e pr ese ntati ve) or n ote d b y st u d y pers o n nel will be rec or de d i n t he partici pa nt ’s me dical rec or d 
a n d o n t he Ad verse E ve nt  e C R F  pa ge . 
T he In vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
r ec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p A Es t hat ar e seri o us, c o nsi der e d r elate d t o t he st u d y i nter ve nti o n or st u d y pr oce d ures, or t hat 
ca use d t he partici pa nt  t o disc o nti n ue t he st u d y i nter ve nti o n (see A p pe n di x 5 ). 

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8. 3. 1  
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A E , S A E , a n d Ot her 
Re p ort a ble S afet y E ve nt  I nf or m ati o n 
All A Es a n d S A Es  will be c ollecte d fr o m t he ti me t he partici pa nt  si g ns i nf or me d c o nse nt u ntil 
1 0 0 da ys after t he last d ose of st u d y i nter ve nti o n. 
Pri or t o i nitiati o n of st u d y i nter ve nti o n, o nl y A Es a n d S A Es t hat are relate d t o a pr ot oc ol-
ma n date d i nter ve nti o n, i ncl u di n g t hose t hat occ ur pri or t o assi g n me nt of st u d y pr oce d ures (e g, 
scr ee ni n g i n vasi ve pr oce d ur es, s uc h as bi o psies) s h o ul d be re p orte d. After o btai ni n g i nf or me d 
c o nse nt, b ut pri or t o i nitiati o n of st u d y i nter ve nti o n, ot her me dical occ urre nces will be rec or de d 
as me dical hist or y.  
If t he I n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me after t he e n d of t he A E 
r e p orti n g peri o d, a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n 
or st u d y partici pati o n, t he I n vesti gat or m ust pr o m ptl y n otif y t he S p o ns or or its desi g nee. T he 
I n vesti gat or s h o ul d r e p ort t hese e ve nts directl y t o t he S p o ns or or its desi g nee, eit her b y fa xi n g or 
e maili n g t he Seri o us A d verse E ve nt  Re p ort F or m  ( S A E R e p ort F or m ). 
T he met h o d of r ec or di n g  a n d r e p orti n g of A E a n d S A E are pr o vi de d i n A p pe n di x 5 . T he 
pr oce d ur e f or s u b mitti n g S A E r e p orts is pr o vi de d i n Secti o n 8. 3 . 8. 2. 
T he met h o d of r e p orti n g all deat hs ar e pr o vi de d i n A p pe n di x 5 . 
8. 3. 1. 1  
E ve nts Re q uiri n g E x pe di te d Re p orti n g t o t he S p o ns or  
Certai n e ve nts r e q uir e i m me diate r e p orti n g t o all o w t he S p o ns or t o ta ke a p pr o priate meas ures t o 
a d dr ess p ote ntial ne w ris ks i n a cli nical trial. T he In vesti gat or m ust re p ort s uc h e ve nts t o t he 
S p o ns or i m me diatel y; u n der n o cir c u msta nces s h o ul d re p orti n g ta ke place m ore t ha n 2 4 h o urs 
after t he In vesti gat or bec o mes a war e  of t he e ve nt. T he f oll o wi n g is a list of e ve nts t hat t he 
In vesti gat or m us t r e p ort t o t he S p o ns or o n a S A E Re p ort F or m  wit hi n 2 4 h o urs of  bec o mi n g 
a war e of t he e ve nt, r e gar dless of r elati o ns hi p t o st u d y i nter ve nti o n: 
•  All S A Es  ( defi ne d i n A p pe n di x 5 ) 
•  Pr e g na nc y  (see Secti o n 8. 3. 5  f or details o n re p orti n g re q uire me nts) 
•  Occ urr e nce of o ver d ose (see Secti o n 8. 4  f or details o n re p orti n g re q uire me nts)  
 
8. 3. 2  
F oll o w -u p E ve nt Re p orti n g  
T he In vesti gat or m ust r e p ort ne w si g nifica nt f oll o w -u p i nf or mati o n f or t hese e ve nts t o t he 
S p o ns or i m me diatel y (ie, n o m or e t ha n 2 4 h o urs after bec o mi n g a ware of t he i nf or mati o n). Ne w 
si g nificant i nf or mati o n i ncl u des t he f oll o wi n g:  
•  Ne w si g ns or s y m pt o ms or a c ha n ge i n t he dia g n osis  

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•  Si g nifica nt ne w dia g n ostic test res ults  
•  C ha n ge i n ca usalit y base d o n ne w i nf or mati o n  
•  C ha n ge i n t he e ve nt’s o utc o me, i ncl u di n g rec o ver y  
•  A d diti o nal narr ati ve i nf or mati o n o n t he cli nical c o urse of t he e ve nt  
 
After t he i nitial A E/ S A E r e p ort, t he In vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt  at s u bse q ue nt visits/c o ntacts. All A Es  a n d S A Es will be f oll o we d t hr o u g h t he f oll o w 
u p p hase of t he st u d y. E ve nts will be f oll o we d u ntil e ve nt res ol uti o n or deat h , t he partici pa nt  is 
l ost t o f oll o w-u p ( as defi ne d i n Secti o n  7. 3 ), or t he partici pa nt  wit h dra ws c o nse nt. F urt her 
i nf or mati o n o n f oll o w-u p pr oce d ur es is pr o vi de d i n  A p pe n di x 5 . 
F or S A Es , t he S p o ns or or a desi g nee ma y f oll o w u p b y tele p h o ne, fa x, electr o nic mail, a n d/ or a 
m o nit ori n g visit t o o btai n a d diti o nal case details a n d o utc o me i nf or mati o n (e g, fr o m h os pital 
disc har ge s u m maries, c o ns ulta nt r e p orts, a ut o ps y re p orts) i n or der t o perf or m a n i n de pe n de nt 
me dical assess me nt of t he r e p orte d case.  
8. 3. 3  
Met h o d of Eliciti n g A d vers e E ve nt I nf or m ati o n  
A c o nsiste nt met h o d ol o g y of n o n -dir ecti ve q uesti o ni n g s h o ul d be a d o pte d f or eliciti n g A E  
i nf or mati o n at all partici pa nt  e val uati o n ti me p oi nts. O pe n -e n de d a n d n o n -lea di n g ver bal 
q uesti o ni n g of t he partici pa nt  is t he preferre d met h o d t o i n q uire a b o ut A E occ urre nces. E xa m ples 
of n o n -dir ecti ve q uesti o ns i ncl u de: “ H o w ha ve y o u felt si nce y o ur last cli nic visit?”, “ Ha ve y o u 
ha d a n y ne w or c ha n ge d healt h pr o ble ms si nce y o u were last here?”  
8. 3. 4  
Re g ul at or y Re p orti n g Re q uire m e nts f or S A Es  
Pr o m pt n otificati o n b y t he In vesti gat or t o t he S p o ns or of a n  S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical r es p o nsi bilities t o war ds t he safet y of partici pa nt s a n d t he safet y of a st u d y 
i nter ve nti o n u n der cli nical i n vesti gati o n are met  (see Secti o n 8. 3. 1. 1 ). I n vesti gat ors m ust als o 
c o m pl y wit h l ocal r e q uir e me nts f or r e p orti n g S A Es t o t he I R B /I E C or ot her l ocal healt h 
a ut h orities.  
T he S p o ns or has a le gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
r e g ulat or y a ge ncies a b o ut t he saf et y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
S p o ns or will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o 
t he r e g ulat or y a ut h orit y, I R B/I E C, part ner c o m pa nies, a n d In vesti gat ors.   
E x pecte d ness will be assesse d usi n g t he I n vesti gat or ’s Br oc h ure(s) as refere nce d oc u me nts. 
Re p orti n g r e q uir e me nts will als o be base d o n t he In vesti gat or's assess me nt of ca usalit y a n d 
seri o us ness, wit h all o wa nce f or u p gr a di n g b y t he S p o ns or as nee de d. 

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I n vesti gat or saf et y r e p orts m ust be pr e pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal r e g ulat or y re q uire me nts a n d S p o ns or p olic y a n d f or war de d t o 
In vesti gat ors as necess ar y.   
A n In vesti gat or w h o r ecei ves a n In vesti gat or safet y re p ort descri bi n g a n  S A E or ot her s pecific 
saf et y i nf or mati o n ( e g, s u m mar y or listi n g of S A Es) fr o m t he S p o ns or will re vie w a n d t he n file it 
al o n g wit h t he I n vesti gat or’s Br oc h ur e a n d will n otif y t he I R B/I E C, if a p pr o priate , acc or di n g t o 
l ocal r e q uir e me nts. 
8. 3. 5  
Pre g n a nc y  
Details of all pr e g na ncies i n f e male partici pa nt s a n d fe male part ners of male partici pa nt s will be 
c ollecte d after t he start of st u d y i nter ve nti o n a n d u ntil 1 0 0 da ys  after t he last d ose. Fe male 
partici pa nt s, as well as f e male part ners of male partici pa nt s, of c hil d beari n g p ote ntial will be 
i nstr ucte d t o i m me diatel y i nf or m t he In vesti gat or if t he y bec o me pre g na nt d uri n g t he st u d y or 
wit hi n 1 0 0  da ys after t he last d ose of st u d y i nter ve nti o n. If a pre g na nc y is re p orte d, t he 
In vesti gat or s h o ul d i nf or m t he S p o ns or wit hi n 2 4 h o urs of bec o mi n g a ware of t he pre g na nc y a n d 
s h o ul d f oll o w t he pr oce d ur es o utli ne d i n A p pe n di x 6 . A b n or mal pre g na nc y o utc o mes  t hat meet 
seri o us criteria ( e g, s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital a n o malies, ect o pic 
pr e g na nc y) ar e c o nsi der e d S A Es.  
A cli nical trial specific Pr e g na nc y Re p orti n g f or m s h o ul d be c o m plete d a n d s u b mitte d 
i m me diatel y t o t he S p o ns or or its desi g nee, eit her b y fa xi n g or b y sca n ni n g a n d e maili n g t he 
f or m usi n g t he f a x n u m ber or e mail a d dress pr o vi de d t o In vesti gat ors (see Secti o n  8. 3. 8. 2 ). 
Pr e g na nc y s h o ul d n ot be r ec or de d o n t he A d verse E ve nt e C R F  pa ge . T he I n vesti gat or s h o ul d 
disc o nti n ue st u d y i nter ve nti o n a n d c o u nsel t he partici pa nt , disc ussi n g t he ris ks of t he pre g na nc y 
a n d t he p ossi ble eff ects o n t he f et us. M o nit ori n g of t he partici pa nt  s h o ul d c o nti n ue u ntil 
c o ncl usi o n of t he pr e g na nc y. A n y S A Es ass ociate d wit h t he pre g na nc y (e g, a n e ve nt i n t he fet us, 
a n e ve nt i n t he m ot her d uri n g or after t he pre g na nc y, or a c o n ge nital a n o mal y/ birt h defect i n t he 
c hil d) s h o ul d be r e p orte d o n t he S A E  R e p ort F or m . I n a d diti o n, t he In vesti gat or will s u b mit a 
cli nical trial specific Pr e g na nc y Re p orti n g f or m w he n u p date d i nf or mati o n o n t he c o urse a n d 
o utc o me of t he pr e g na nc y bec o mes a vaila ble.  
8. 3. 6  
Dis e as e -rel ate d E ve nts a n d/ or Dis e as e -rel ate d O utc o m es N ot 
Q u alif yi n g as A Es or S A Es  
Pr o gr essi o n of t he ca ncer u n der st u d y, as j u d ge d b y t he I n vesti gat or, is n ot c o nsi dere d a 
r e p orta ble e ve nt. U p o n f urt her r e vie w b y  t he I n vesti gat or, if t he e ve nt is n ot c o nsi dere d 
u n derl yi n g pr o gr essi o n of disease, it  m ust be re p orte d as a n S A E  w it hi n 2 4 h o urs or bec o mi n g 
a war e of t he e ve nt t o t he Par ker Instit ute f or Ca ncer I m m u n ot hera p y  P har mac o vi gila nce Gr o u p 
as descri be d i n Secti o n  8. 3. 8. 2 . 

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8. 3. 7  
Tri al -li miti n g T o xicit y 
Trial -li miti n g t o xicit y (T O X ) is defi ne d as t he occ urre nce of a n y a d verse e ve nt lea di n g t o 
tr eat me nt disc o nti n uati o n t hat is p ossi bl y, pr o ba bl y, or defi nitel y relate d t o ni v ol u ma b, 
i pili m u ma b, or i pili m u ma b i n c o m bi nati o n wit h ni v ol u ma b d uri n g t he i nitial 1 2 wee ks of 
tr eat me nt, u nless t her e is a clear alter nati ve e x pla nati o n . A d diti o nal disc o nti n uati o n criteria  
r e gar di n g t he a d va nce d pr ostate c o h orts ca n be f o u n d i n Secti o n 6. 6. 1. 4 . 
8. 3. 8  
S p o ns or C o nt act I nf or m ati o n  
8. 3. 8. 1  
E m er ge nc y Me dic al C o nt act s 
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y Me dical M o nit or C o ntact I nf or mati o n:  
Pri ma r y Me dical M o nit or:  
Ste p he n Ma d d oc k , M D, P h D 
 
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y  
 
1 Letter ma n Dri ve, Ste. D 3 5 0 0  
 
Sa n Fr a ncisc o, C A 9 4 0 8 0  
 
s ma d d oc k@ par kerici. or g  
T ele p h o ne N o.:  
+ 1 ( 4 1 7) 2 4 7 -7 3 9 2  ( Cell) 
8. 3. 8. 2  
S afet y Re p orti n g C o nt act s 
T he f oll o wi n g c o ntact i nf or mati o n s h o ul d be use d w he n s u b mitti n g safet y-relate d pa per f or m s 
( S A E R e p ort F or m  a n d Pr e g na nc y Re p ort F or m)  as descri be d i n A p pe n di x 5  f or S A Es a n d ot her 
r e p orta ble saf et y e ve nts. T hese  for m s s h o ul d be c o m plete d a n d s u b mitte d t o t he S p o ns or 
i m me diatel y (ie, n o m or e t ha n 2 4 h o urs after bec o mi n g a ware of  t he e ve nt), b y fa xi n g t o t he 
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y P har mac o vi gila nc e G r o u p at:  4 1 5-6 1 0 -5 4 7 1 wit hi n 
2 4 h o urs of e ve nt a war e ness. If tec h nical iss ues arise, t he f or m ma y be sca n ne d a n d e maile d t o 
saf et y @ par kerici. or g a n d please c o ntact t he Par ker I nstit ute f or Ca ncer I m m u n ot hera p y 
P har mac o vi gila nce gr o u p i m me diatel y at 4 1 5 -9 3 0 -4 4 1 4 . 
Par ker I nstit ute f or Ca ncer I m m u n ot hera p y P har mac o vi gila nce Gr o u p:  
•  P har mac o vi gila nce Fa x N u m ber:  4 1 5 -6 1 0 -5 4 7 1  
•  P har mac o vi gila nce e mail:  safet y @ par kerici. or g  
•  P har mac o vi gila nce T ele p h o ne N u m ber:  4 1 5 -9 3 0 -4 4 1 4  
 
8. 4  
T R E A T M E N T O F O V E R D O S E  
O ver d ose is defi ne d as a n y d ose hi g her t ha n t he d ose s pecifie d t o be a d mi nistere d i n acc or da nce 
wit h t he pr ot oc ol.  

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T he I n vesti gat or m ust i m me diatel y n otif y t he Par ker I nstit ute f or Ca ncer I m m u n ot hera p y 
P har mac o vi gila nce G r o u p of a n y occ urre nce of o ver d ose wit h st u d y i nter ve nti o n . 
All o ver d oses s h o ul d be r e p orte d as a n S A E  wit h t he safet y criteria of “o t her i m p ort a nt 
m e dic al e ve nt .” Details of si g ns a n d s y m pt o ms, cli nical ma na ge me nt, a n d o utc o me s h o ul d be 
r e p orte d, if a p plica ble. O ver d oses s h o ul d als o be ca pt ure d as pr ot oc ol de viati o ns. 
T he PI has t he o bli gati o n t o r e p ort t he de viati o ns t o t he I R B/I E C.  
8. 5  
P H A R M A C O KI N E TI C S  
P har mac o ki neti c par a meters ar e n ot e val uate d i n t his st u d y.  
8. 6  
A N TI -D R U G A N TI B O DI E S  
A nti b o dies t o ni v ol u ma b a n d / or i pili m u ma b are n ot e val uate d i n t his st u d y. 
8. 7  
BI O M A R K E R S  
T he p er ce nt a ge of t u m or al C D 8 cells will be deter mi ne d fr o m t u m or tiss ue usi n g 
i m m u n o hist oc he mistr y (I HC ) b y t he I m m u n o hist oc he mistr y a n d I ma ge A nal ysis La b orat ories i n 
t he De part me nt of Pat h ol o g y at M D A C C’s C LI A - a n d C A P -certifie d la b orat or y. T he test f or 
C D 8 e x pr essi o n is a la b or at or y de vel o pe d test use d t o deter mi ne partici pa nt eli gi bilit y. T his test 
is n ot a n F D A -a p pr o ve d de vice a n d its use is i n vesti gati o nal. T u m or bi o psies wit h ≥ 1 5 % C D 8 
cells i n t heir t u m or bi o psies will be classifie d as C D 8 hi g h t u m ors , a n d t h ose wit h < 1 5 % C D 8 
cells i n t heir t u m or bi o psies will be classifie d as C D 8 l o w t u m ors. T he p erce nta ge of t u m oral 
C D 8  cells at baseli ne will deter mi ne i m m u n ot hera p y treat me nt ( ni v ol u ma b wit h or wit h o ut 
i pili m u ma b) t o e val uate if t he per ce nta ge of C D 8  cells ca n pre dict cli nical be nefit t o ni v ol u ma b. 
O n tr eat me nt , t he per ce nta ge of t u m or al C D 8 cells i n t u m or bi o psies will be e val uate d t o 
deter mi ne if ni v ol u ma b i n c o m bi nati o n wit h i pili m u ma b c o n verts C D 8 l o w  t u m ors t o C D 8 hi g h  
t u m ors. 
F or baseli ne bi o ps y sa m pl es, t he tiss ue is dee me d “a de q uate” f or C D 8 I H C testi n g w he n t he 
pat h ol o gist deter mi nes t hat t he secti o n c o ntai ns > 2 0 % t u m or n uclei (ie, 2 0 % of t he t otal n uclei 
vis ualize d i n t he secti o n ar e fr o m t u m or cells). H o we ver, t he sa m ple a de q uac y metric w he n 
a p plie d t o o n-tr eat me nt bi o ps y sa m ples ma y i na d verte ntl y e xcl u de fr o m a nal ysis cases i n w hic h 
a n acti ve i m m u ne r es p o nse r es ults i n t he destr ucti o n of t u m or cells a n d, c o nse q ue ntl y, a decrease 
i n t he per ce nta ge of t u m or n uclei i n t he sa m ple (a “t u m or-free” sa m ple). T heref ore, t he defi niti o n 
of sa m ple a de q uac y f or o n -tr eat me nt bi o ps y sa m ples is bei n g clarifie d s uc h t hat C D 8 I H C testi n g 
will be perf or me d a n d r e p orte d f or sa m ples wit h feat ures i n dicati ve of a treate d t u m or be d 
c o nsisti n g of via ble c o m p o ne nts of a n effecti ve, a nti -t u m or fi br oi nfla m mat or y res p o nse. F or 
t hese cases, t he pat h ol o gist will n ote i n t he C LI A re p ort t he prese nce or a bse nce of t u m or cells as 

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detecte d a n d will n ote hist ol o gical f eat ures i n dicati ve of a n i m m u ne res p o nse (e g, gia nt cells, 
fi br o histi oc ytic c har acteristics, etc.). 
T he e x pl or at or y bi o mar ker o bjecti ves of t his st u d y are t o i de ntif y bi o mar kers ass ociate d wit h 
a nti-P D -1 a n d/ or a nti -P D -1 c o m bi ne d wit h a nti -C T L A -4 st u d y i nter ve nti o n b y assessi n g t u m or 
tiss ue a n d cir c ulati n g s ol u ble f act ors, i ncl u di n g, b ut n ot li mite d t o, de o x yri b o n ucleic aci d ( D N A ), 
ri b o n ucleic aci d (R N A ), e nz y mes, gr o wt h fact ors, c yt o ki nes, a nti b o dies, a n d i m m u ne cells i n 
tiss ue a n d bl o o d. A n ai m of t his st u d y is t o e val uate if a c o m p osite bi o mar ker ( C D 8 wit h a 
sec o n d bio mar ker) is a ble t o pr e dict cli nical be nefit t o c hec k p oi nt i n hi bit or treat me nt. 
A d diti o nall y, micr o bi o me pr ofile s ma y be e val uate d fr o m st o ol sa m ples. E val uati o n of baseli ne 
le vels a n d/ or c ha n ges wit h st u d y i nter ve nti o n ma y be perf or me d t o deter mi ne ass ociati o n wit h 
cli nical o utc o mes, i ncl u di n g cli nical r es p o nse a n d resista nce, as well as st u d y i nter ve nti o n 
t oler a bilit y. 
•  C ollecti o n of sa m ples f or bi o mar ker researc h is part of t his st u d y. T he f oll o wi n g 
sa m ples f or bi o mar ker r esearc h are re q uire d a n d will be c ollecte d fr o m all 
partici pa nt s i n t his st u d y as s pecifie d i n t he SO A s (Secti o n 1. 3 ): 
o  Bl o o d  
o  Peri p her al bl o o d m o n o n uclear cells ( P B M C s) 
o  D N A  
o  T u m or tiss ue bi o ps y ( at i nter vals s pecifie d i n Secti o n 4. 1 ) 
o  St o ol  
•  Sa m ples ma y be teste d f or ge netic a nal ysis o n t u m or a n d bl o o d sa m ples, i ncl u di n g, 
b ut n ot li mite d t o, assa ys o n circ ulati n g free D N A, D N A fr o m t u m or , bl o o d a n d/ or 
i m m u ne cells a n d T-cell r ece pt or se q ue nci n g ma y be perf or me d. T his researc h ma y 
e val uate w het her ge netic variati o n s c orres p o n d wit h o utc o mes of treat me nt. If ge netic 
variati o n is f o u n d t o pr e dict efficac y or A Es , t he data mi g ht i nf or m o pti mal use of 
t her a pies i n ca ncer partici pa nts . Circ ulati n g s ol u ble a nal ytes ma y be assess e d t hat 
ma y i ncl u de b ut ar e n ot li mite d t o i m m u ne c yt o ki nes, gr o wt h fact ors, a nti b o dies, 
a n d/ or mar kers ass ociate d wit h i m m u ne c haracteristics a n d acti vati o n or ca ncer. 
A d diti o nall y, t u m or a n d bl o o d sa m ples will be c ollecte d bef ore a n d o n st u d y 
i nter ve nti o n f or i m m u ne cell pr ofili n g, w hic h ma y i ncl u de i m m u ne cell p he n ot y pi n g, 
e n u mer ati o ns, a n d/ or acti vati o n state. B ot h ge n o me -wi de a n d tar gete d messe n ger 
R N A e x pr essi o n pr ofili n g a n d se q ue nci n g i n t u m or a n d/ or bl o o d  ma y be perf or me d t o 
defi ne ge ne si g nat ur es t hat c orrelate wit h treat me nt o utc o mes. E pi ge netic a nal yses 
ma y als o be perf or me d as t hese are i m p orta nt bi o mar kers f or s o me ca ncers.  St o ol 
sa m ples at baseli ne a n d o n treat me nt ma y be e val uate d f or micr o bi o me pr ofili n g t o 
deter mi ne if t her e is a n y ass ociati o n wit h treat me nt o utc o me.  
•  Ot her sa m ples ma y be use d f or researc h , i ncl u di n g f ut ure researc h t o de vel o p 
met h o ds, assa ys, pr o g n ostics a n d/ or c o m pa ni o n dia g n ostics  relate d t o i m m u n o-

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o nc ol o g y tr eat me nt , disease pr ocess, pat h wa ys ass ociate d wit h disease state, a n d/ or 
mec ha nis m s of acti o n of c hec k p oi nt i n hi bit or treat me nt . 
 
8. 7. 1  
Ge netics  
Sa m ple c ollecti o n, st or a ge, a n d s hi p me nt i nstr ucti o ns f or pla n ne d ge netic a nal ysis sa m ples will 
be pr o vi de d i n t he La b or at or y Ma n ual. Sa m ples s h o ul d be c ollecte d f or pla n ne d a nal ysis of 
ass ociati o ns bet wee n ge netic varia nts i n ger mli ne/t u m or D N A a n d cli nical o utc o mes t o st u d y 
i n ve nti o ns(s). Bl o o d f or pla n ne d ge netic a nal ysis will be c ollecte d f or D N A as descri be d i n t he 
S O A s i n Secti o n 1. 3 . If a d oc u me nte d la w or re g ulati o n pr o hi bits ( or l ocal I R B/I E C d oes n ot 
a p pr o ve) sa m ple c ollecti o n f or t hese p ur p oses, t he n s uc h sa m ples s h o ul d n ot be c ollecte d at t he 
c orr es p o n di n g sites. A d diti o nal D N A e xtracte d fr o m pla n ne d ge netic a nal ysis sa m ples will be 
st or e d f or f ut ur e bi o me dical r esear c h. 
I n t he e ve nt of D N A e xtr acti o n f ail ur e, a re place me nt ge netic bl o o d sa m ple ma y be re q ueste d 
fro m t he partici pa nt . Si g ne d i nf or me d c o nse nt will be re q uire d t o o btai n a re place me nt sa m ple 
u nless it was i ncl u de d i n t he ori gi nal c o nse nt.  
See A p pe n di x 7 :  f or I nf or mati o n r e gar di n g ge netic researc h. 
8. 7. 2  
E nr oll m e nt Bi o m ar kers  
C or e nee dle or i ncisi o nal t u m or bi o ps y sa m ples ( 3 -4 c ores if me dicall y feasi ble)  are re q uire d at 
scr ee ni n g f or C D 8 I H C  testi n g a n d classificati o n of C D 8 hi g h vs C D 8 l o w t u m ors. Fi ne n ee dle 
as pir ati o n sa m ples ar e n ot acce pta ble. T his test is re q uire d f or e nr oll me nt. T he test f or C D 8 
e x pr essi o n is a la b or at or y de vel o pe d test use d t o deter mi ne partici pa nt eli gi bilit y. T his test is n ot 
a n F D A-a p pr o ve d de vice  a n d its use is i n vesti gati o nal. Sa m ple c ollecti o n, st ora ge , a n d s hi p me nt 
i nstr ucti o ns ar e pr o vi de d i n t he La b or at or y Ma n ual. 
Im m u n o hist oc he mistr y  will be perf or me d i n t he C LI A-certifie d I m m u n o hist oc he mistr y a n d 
I ma ge A nal ysis La b or at ories i n t he De part me nt of Pat h ol o g y at M D A C C usi n g a Leica B o n d 
a ut ostai ner a n d a n a nti -C D 8 a nti b o d y ( La b Visi o n, T her m o -Fis her; cl o ne: C 8/ 1 4 4 B; d il uti o n 
1: 2 0) wit h 3, 3' -dia mi n o be nzi di ne c hr o m o ge n, c o u nterstai ne d wit h he mat o x yli n.  
C D 8 I H C sli des will be sca n ne d at × 2 0 ma g nifi cati o n ( Leica Bi os yste ms). I ma ge a nal ysis 
s oft war e ( A peri o I ma ge Sc o pe) will be a p plie d t o q ua ntif y t he n u m ber a n d perce nta ge of 
I H C-p ositi ve l y m p h oc ytes wit hi n desi g nate d areas. Gi ve n t he size of C D 8 -p osti ve i m m u ne cells, 
a m o difie d versi o n of t he n uclear v 9 al g orit h m has bee n de vise d as a basis f or detecti n g i m m u ne 
mar ker p ositi vit y. T his al g orit h m has bee n use d t o q ua ntif y C D 8 -p ositi ve cells i n differe nt t u m or 
t y pes, i ncl u di n g mela n o ma a n d Mer kel cell carci n o ma (C he n et al,  2 0 1 6 ; Fel d me yer et al, 2 0 1 6 ).   

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T o q ua ntif y t he le vels of C D 8 i n a t u m or, areas will be mar ke d b y a pat h ol o gist ma n uall y (ie , 
ha n d dr a w n ar o u n d t he t u m or f oci f or nee dle c ore bi o psies a n d ot her u ni q uel y s ha pe d fra g me nts 
of tiss ue) or b y a p pl yi n g 1 -m m 2 s q uar e b o xes t o q ua ntif y lar ger fra g me nts of t u m or. T he A peri o 
i ma ge a nal ysis s oft war e will q ua ntif y ( 1) t he perce nta ge of C D 8-p ositi ve cells a n d ( 2) t he 
n u m ber of C D 8 -p ositi ve cells i n a gi ve n area (t he latter re p orte d as C D 8 + cells/ m m 2). T u m ors 
wit h ≥ 1 5 % C D 8 cells will be classifie d as C D 8 hi g h  t u m ors f or partici pa nt treat me nt wit h 
ni v ol u ma b a n d < 1 5 % C D 8 cells will be classifie d as C D 8 l o w  t u m ors f or partici pa nt treat me nt 
wit h ni v ol u ma b a n d i pili m u m a b. 
If t he r es ults of t he scr ee ni n g bi o ps y are n ot a de q uate t o o btai n i nf or mati o n o n t he perce nta ge of 
t u m or al C D 8 cells f or tr eat me nt assi g n me nt, a sec o n d pre-treat me nt bi o ps y ma y be o btai ne d, if it 
is me dicall y f easi ble a n d t he partici pa nt is willi n g t o u n der g o a n ot her t u m or bi o ps y. 
8. 7. 3  
C D 8 a n d E x pl or at or y Bi o m ar kers  
A fr es h bi o ps y  is r e q uir e d at scr ee ni n g f or e nr oll me nt C D 8 I H C a nal ysis a n d ot her e x pl orat or y 
a nal ysis. If t he partici pa nt ha d a pr e vi o us bi o ps y wit hi n 3 0 da ys of c o nse nt t his ma y be use d as 
t he e nr oll me nt bi o ps y. H o we ver, t he sa m ple m ust pr o vi de o ne or t w o F F P E bl oc ks f or I H C 
a nal ysis. Sli des ar e n ot all o we d. If t he arc hi val bi o ps y is be y o n d 3 0 da ys of c o nse nt, t his will 
r e q uir e Me dical M o nit or a p pr o val. A d diti o nal o n -treat me nt t u m or bi o psies s h o ul d occ ur if 
me dicall y f easi ble  per t he S O A (see Secti o n 1. 3 ). C ore nee dle or i ncisi o nal t u m or bi o ps y 
sa m ples ar e r e q uir e d. F urt herm or e , e ver y atte m pt s h o ul d be ma de f or t he o n-treat me nt bi o psies 
t o be ta ke n fr o m t he sa me lesi o n site. Fi ne nee dle as pirati o n is n ot all o we d. 
Bl o o d will be c ollecte d f or e x pl or at or y bi o mar kers. Bl o o d ma y be use d f or w h ole bl o o d, 
P B M C s, plas ma, a n d/ or ser u m  pr e par ati o n a n d n ucleic aci d e xtracti o n. T hese b l o o d sa m ples will 
be c ollecte d as descri be d i n t he S O A s i n Secti o n 1. 3 .  
St o ol sa m ples will be c ollecte d f or micr o bi o me a nal ysis, w hic h ma y i ncl u de meta b olites as 
o utli ne d i n t he S O A s i n Secti o n 1. 3 .  
Tiss ue, bl o o d , a n d st o ol sa m ple c ollecti o n, st ora ge, a n d s hi p me nt i nstr ucti o ns are pr o vi de d i n t he 
La b or at or y Ma n ual.  
8. 7. 4  
S a m ple  C ollecti o n  f or L o n g -ter m F ut ure Bi o m e dic al Res e arc h  
8. 7. 4. 1  
O ver vie w of L o n g -ter m F ut ure Bi o m e dic al Res e arc h  
Partici pa nt s i n t his cli nical trial will be as ke d t o c o nse nt t o pr o vi de bi ol o gical sa m ples f or l o n g-
ter m f ut ur e bi o me dical r esear c h. T he o bjecti ve of c ollecti n g/retai ni n g s peci me ns f or f ut ure 
bi o me dical r esear c h is t o e x pl or e a n d i de ntif y bi o mar kers t hat i nf or m t he s cie ntific 
u n dersta n di n g of disease a n d/ or t heir t hera pe utic treat me nts. T he o verarc hi n g g oal is t o use s uc h 
i nf or mati o n t o u n dersta n d disease, safet y, a n d p ote ntial treat me nts f or f ut ure partici pa nt s. S uc h 

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r esear c h is f or bi o mar ker testi n g a n d h y p ot hesis testi n g t o a d dress e mer ge nt q uesti o ns n ot 
descri be d else w her e i n t he pr ot oc ol ( as part of t he mai n trial).  
T his r esear c h ma y i ncl u de ge netic a n d ge n o mic a nal yses ( D N A), ge ne e x pressi o n pr ofili n g 
( R N A), pr ote o mics, micr o bi o me, meta b ol o mics (ser u m, plas ma, sto ol) , a n d/ or t he meas ure me nt 
of ot her a nal ytes, de pe n di n g o n w hic h s peci me ns are c o nse nte d f or f ut ure bi o me dical researc h.  
T he c ollecti o n a n d s u b missi o n of bi ol o gical sa m ples t o be st ore d f or l o n g -ter m f ut ure bi o me dical 
r esear c h m ust be detaile d i n t he I R B/I E C-a p pr o ve d I C F. Partici pa nt s w h o d o n ot wis h t o 
partici pate i n t he f ut ur e bi o me dical r esearc h ma y still partici pate  i n t he st u d y. 
8. 7. 4. 2  
S a m ple C ollecti o n  
T he f oll o wi n g sa m ples will be c ollecte d a n d st ore d i n acc or da nce wit h a p plica ble la w f or l o ng -
ter m r esear c h p ur p oses, i ncl u di n g, b ut n ot li mite d t o, researc h o n bi o mar kers relate d t o 
i m m u n ot her a pies, s uc h as a nti-P D -1 a n d/ or a nti -C T L A -4 t hera p y , a n d diseases s uc h as ca ncer or 
i nfla m mat or y dis or ders. 
•  Bl o o d, i ncl u di n g b ut n ot li mite d t o P B M Cs , D N A, plas ma , a n d/ or ser u m 
•  R N A  
•  T u m or tiss ue  
•  St o ol sa m ples 
 
T hese sa m ples ma y be se nt t o o ne or m ore la b orat ories.  
F or sa m pli n g pr oce d ur es, st or a ge c o n diti o ns, a n d s hi p me nt i nstr ucti o ns, see t he L a b orat or y 
M a n ual.  
8. 7. 4. 3  
Wit h dr a w al fr o m L o n g -ter m S a m ple St o r a ge  
Partici pa nt s ha ve t he ri g ht t o wit h dr a w t heir c o nse nt f or t he f ut ure bi o me dical researc h of his/ her 
s peci me ns at a n y ti me f or a n y r eas o n a n d re q uest t hat t heir s peci me ns be destr o ye d. If t he 
partici pa nt  wis hes t o wit h dr a w c o nse nt f or t his testi n g, t he In vesti gat or m ust i nf or m t he M e dical 
M o nit or i n writi n g.  A n y a nal yses i n pr o gress at t he ti me of re q uest f or wit h dra wal or alrea d y 
perf or me d pri or t o t he r e q uest bei n g r ecei ve d b y t he S p o ns or will c o nti n ue t o be use d as part of 
t he o ver all r esear c h trial data a n d r es ults. N o ne w a nal yses w o ul d be ge nerate d after t he re q uest 
is r ecei ve d. I n t he e ve nt t hat t he me dical rec or ds f or t he mai n trial are n o l o n ger a vaila ble (e g, if 
t he In vesti gat or is n o l o n ger r e q uir e d b y re g ulat or y a ut h orities t o retai n t he mai n trial rec or ds) or 
t he s peci me ns ha ve bee n c o m pletel y a n on y mize d, t here will n o l o n ger be a li n k bet wee n t he 
partici pa nt’s pers o nal i nf or mati o n a n d t heir s peci me ns. I n t his sit uati o n, t he re q uest f or s peci me n 
wit h dr a wal ca n n ot be pr ocesse d.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
9 5  
8. 7. 4. 4  
Pr otecti o n of D at a  Pri v ac y a n d D at a Ge ner ati o n  
Partici pa nt  s peci me ns a n d ass ociate d data will be la bele d wit h a u ni q ue partici pa nt  i de ntificati o n 
n u m ber. Partici pa nt  me dical i nf or mati o n ass ociate d wit h t he l o n g -ter m st ora ge of s peci me ns is 
c o nfi de ntial a n d ma y be discl ose d t o t hir d parties o nl y as per mitte d b y t he I C F si g ne d by t he 
partici pa nt  or as  per mitte d or r e q uir e d b y la w.  
Gi ve n t he c o m ple xit y a n d r esear c h nat ure of t he e x pl orat or y a nal yses, data deri ve d fr o m l o n g -
ter m st or e d s peci me ns will ge ner all y n ot be pr o vi de d t o st u d y i n vesti gat ors or partici pa nt s u nless 
r e q uir e d by la w.  
Data ge ner ate d fr o m s peci me n s t hat are st ore d l o n g ter m m ust be a vaila ble f or i ns pecti o n u p o n 
r e q uest b y r e pr ese ntati ves of nati o nal or l ocal healt h a ut h orities a n d S p o ns or m o nit ors, 
r e pr ese ntati ves, a n d c olla b or at ors as a p pr o priate a n d as descri be d  i n Secti o n  1 0. 1. 1 0 . 
8. 8  
P A TI E N T -R E P O R T E D  O U T C O M E S  R E S E A R C H  
Partici pa nts e nr olle d i n t he pr ostate ca ncer c o h ort ma y be offere d t he o pti o n t o use 
A pricit y Car e ™, a patie nt -r e p orte d o utc o me ( P R O) di gital a p plicati o n, d uri n g t heir partici pati o n 
i n t his st u d y. St u d y staff will ha ve a n o p p ort u nit y  t o re vie w partici pa nt’s  data at t he 
A pricit y O nc ol o g y ™, a cli nical das h b oar d we bsite.  
T he A pricit y Car e ™ s mart p h o ne a p p all o ws partici pa nts ( or t heir desi g nee) t o self -re p ort a d verse 
e ve nts i n bet wee n cli nic visits. T he a p p als o pr o vi des e d ucati o nal i nf or mati o n a n d vi de os a b o ut 
p o te ntial A E s partici pa nt s ma y e x perie nce. A pricit y Care ™ was i nitiall y de vel o pe d f or t he 
i de ntificati o n a n d ma na ge me nt of ir A Es i n partici pa nts recei vi n g sta n dar d-of -care 
i m m u n ot her a p y f or ca ncer. 
I ncl usi o n of t he tec h n ol o g y i n t he c urr e nt PI CI 0 0 2 5 A M A D E U S pr ostate ca ncer c o h ort will 
ge ner ate i m p orta nt data o n t he f easi bilit y of i nc or p orati n g t his a p pr oac h t o P R O c ollecti o n i n a 
cli nical r esear c h setti n g. Partici pati o n i n t his researc h is o pti o nal f or st u d y partici pa nts, a n d t he 
use of A pricit y Car e ™ will n ot i m pact t he partici pa nt’s treat me nt a n d is n ot a s u bstit ute f or 
cli nical e val uati o n. T he data c ollecte d via t his a p p f or partici pa nts as well as t he 
A pricit y O nc ol o g y a p p f or t he st u d y tea m is f or e x pl orat or y researc h p ur p oses o nl y a n d will n ot 
be i nc or p or at e d i n t he PI CI 0 0 2 5 electr o nic data ca pt ure s yste m. I n t he e ve nt of A Es or S A Es t hat 
meet r e p orti n g criteria per S ecti o n 8. 3 , pr o vi ders a n d st u d y tea m me m bers will c o nti n ue t o 
f oll o w r e p orti n g pr oce d ur es per S ecti o n 1 0. 5 . T he de -i de ntifie d data c ollecte d via 
A pricit y Car e ™ a n d A pricit y O nc ol o g y ma y be use d b y S p o ns or’s researc hers a n d its affiliates, 
A pricit y Healt h, a n d/ or s har e d wit h ot her researc hers a n d/ or i nstit uti o ns f or use i n f ut ure 
r esear c h. 

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9 6  
T he cli nicia n -f aci n g p orti o n of t his a p plicati o n will pr o d uce rec o m me n dati o ns f or ir A E 
ma na ge me nt a s a d vis or y t o cli nicia ns a n d i n vesti gat ors. T he ma na ge me nt g ui deli nes will use 
al g orit h ms a n d t he t o xicit y ma na ge me nt g ui deli nes fr o m T a ble 7 . T hese d o n ot c o nstit ute 
Me dical A d vice a n d will n ot be pr ese nte d directl y t o partici pa nts.  
8. 8. 1  
Me dic al Discl ai m er  
T he A pricit y Car e ™ a p p d oes n ot ma ke a n y me dical dia g n osis, d oes n ot pr o vi de a n y treat me nt, 
a n d d oes n ot s u bstit ute me dical ser vice or c o m m u nicati o n wit h a healt hcare pr o vi der. T he 
s oft war e use d i n t his patie nt-r e p orte d st u d y is i nte n de d f or researc h p ur p oses o nl y.  
All c o nte nt f o u n d o n t he A pricit y Car e ™ a p p, i ncl u di n g te xt, i ma ges, a u di o, or ot her f or mats, are 
o nl y f or r esear c h. If Me dical Assista nc e is nee de d, partici pa nts are i nstr ucte d via t he 
A pricit y Car e ™ a p p t o call 9 1 1 a n d alert t heir healt h care pr o vi der.  
8. 8. 2  
He alt h D at a Pr otecti o n  
Partici pa nt's me dical i nf or mati o n o btai ne d b y t he A M A D E U S st u d y a n d t his o pti o nal pr oce d ure 
is c o nfi de ntial. It ma y be discl ose d t o t hir d parties o nl y as per mitte d b y t he I C F ( or se parate 
a ut h orizati o n f or use a n d discl os ur e of pers o nal healt h i nf or mati o n) si g ne d b y t he partici pa nt or 
as per mitte d or r e q uir e d b y la w. 
A pricit y will pr o vi de tr ai ni n g t o site staff. PI CI's m o nit ors will n ot ha ve access t o t he data 
c ollecte d b y A pricit y Car e ™ a n d will n ot m o nit or, i nterfere wit h or e val uate A pricit y's data 
c ollecti o n or pr oce d ur es.  
Partici pa nts will be r e gis ter e d a n d r ecei ve i nstr ucti o ns a n d trai ni n g t o use t he a p plicati o n via t he 
site-le vel r esear c h tea m. C o nse nti n g partici pa nts will be re q ueste d t o d o w nl oa d a s oft ware 
a p plicati o n i nt o t heir s mart p h o ne de vices. De vices will n ot be pr o vi de d. Partici pa nts are 
e x pecte d t o start usi n g t he a p p dail y fr o m t he ti me of i nf or me d c o nse nt u ntil t he safet y peri o d t o 
tr ac k dail y r o uti ne a n d self-m o nit ori n g of s y m pt o ms. D uri n g t he partici pa nt's e n d of treat me nt 
visit, t he y will be as ke d t o s ur ve y t heir e x perie nce usi n g t he  A pricit y Care ™ a p p.  
T hr o u g h o ut t he st u d y, t he r esear c h staff are e nc o ura ge d t o f oll o w t he st u d y pr oce d ures, i n 
a d diti o n t o t h ose i ncl u de d i n t he S O A of t his pr ot oc ol a n d are n ot li mite d t o:  
•  O n -b oar di n g t o r e gister a n d tr ai n partici pa nts i n t he use of t he A pricit y Care ™ a p p.  
•  Re vie wi n g partici pa nt’s data via A pricit y O nc ol o g y ™, a cli nical das h b oar d we bsite at 
r e g ular i nter vals per tr ai ni n g materials. 
 

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Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
9 7  
Defi niti o ns  
A pricit y Care ™ 
A s mart p h o ne di gital a p plicati o n desi g ne d f or c ollecti o n of patie nt -
re p orte d assess me nts. 
A pricit y O nc ol o g y ™ 
A cli nical das h b oar d we bsite a vaila ble f or st u d y staff t o re vie w 
partici pa nt’s data.  
 
8. 9  
M E DI C A L R E S O U R C E U TI LI Z A TI O N A N D H E A L T H 
E C O N O MI C S  
T his secti o n is n ot a p plica ble.  
9  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
9. 1  
S A M P L E SI Z E D E T E R MI N A TI O N  
A t otal of u p t o a p pr o xi matel y 2 0 0 partici pa nts wit h var yi n g t u m or t y pes will be e nr olle d. 
E nr oll me nt t o i nitial bi o ps y ma y be a b o ut 1 0 % hi g her (ie, a p pr o xi matel y 2 2 0 partici pa nts) t o 
acc o u nt f or u ne x pecte d c halle n ges o btai ni n g C D 8 i nfiltrati o n i nf or mati o n. T he selecti o n of 
2 0 0  partici pa nts is t o ha ve s ufficie nt n u m bers i n t he C D 8 hi g h  a n d C D 8 l o w  t u m or gr o u ps i n 
lar ger t u m or p o p ulati o ns t o r e p ort s u b gr o u p res p o nse rates, t he tra nsf or mati o n fr o m C D 8 l o w t o 
hi g h,  as well as t o pr e dict r es p o nse fr o m mar ker a n d cli nical i nf or mati o n. Wit h 2 0 0 partici pa nts, 
a p pr o xi matel y 4 0 a n d 1 6 0 partici pa nts are esti mate d f or t he C D 8 hi g h  a n d C D 8 l o w  t u m or 
gr o u ps, r es pecti vel y  (Fi g ur e 7 ). Cli nical be nefit rate ( C B R ) wit hi n t u m or gr o u ps is e x pecte d t o 
r a n ge fr o m 1 0 % t o 3 0 % (Ni v ol u ma b I B ). A n a vera ge C B R of 2 0 % is ass u me d t o pr o vi de 
a p pr o xi matel y 3 2 partici pa nts wit h cli nical be nefit i n t he C D 8 l o w  t u m or gr o u p. Wit h 
1 6 0  partici pa nts, a 9 5 % cr e di ble i nter val of C B R wit h 3 2  res p o n ders w o ul d be ( 1 4. 2 %, 2 6. 5 %) 
ass u mi n g a beta( 0. 4, 1. 6) pri or. Si milarl y, if t here are 3 0  partici pa nts i n t he lar gest disease 
s u b gr o u p, a 9 5 % cr e di ble i nter val of r es p o nse w o ul d be ( 8. 3 %, 3 5. 2 %) ass u mi n g 6 res p o n ders 
a n d a si milar pri or. T her e is n o pri or  f or t he e x pecte d pr o p orti o n of partici pa nts  w h o will c o n vert 
fro m C D 8 l o w t o C D 8 hi g h o n tr eat me nt as t his is a first l o o k f or t his e n d p oi nt. T he 9 5 % 
cr e di ble i nter val f or 1 6/ 1 6 0 ( 1 0 %) partici pa nts c o n verti n g  w o ul d be ( 5. 9 %, 1 5. 1 %) a n d f or 
8 0/ 1 6 0 ( 5 0 %) t he cr e di ble i nter val w o ul d be ( 4 2. 3 %, 5 7. 7 %). Si milarl y, 8 of 4 0 partici pa nts are 
i n t he C D 8 hi g h gr o u p e x pecte d t o e x hi bit be nefit , res ulti n g i n a 9 5 % cre di ble i nter val of ( 9. 5 %, 
3 3. 2 %). T he selecti o n of 2 0 0 partici pa nts all o ws a mi ni m u m reas o na ble n u m ber f or esti mati n g 
C B R i n t he C D 8 hi g h  t u m or gr o u p. F or sec o n dar y a nal yses, if t here are 2 0 res p o n ders i n a n y 
C D 8 stat us a n d/ or t u m or site gr o u p, it w o ul d be reas o na ble t o perf or m m ulti variate l o gistic 
r e gr essi o n wit h 2 varia bles t o pr e dict res p o nse. T heref ore, 2 0 0 partici pa nts is t he s mallest 
r eas o na ble sa m ple size f or t he i nitial e x pl orati o n of efficac y pre dicti o n i n t his p o p ulati o n. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
9 8  
A d diti o nal wi dt hs of cr e di ble i nter vals of C B R f or p ossi ble s u b gr o u ps sizes are prese nte d i n 
T a ble  1 1 . 
T a ble  1 1 : 
P ossi ble S u b gr o u p Sizes  
S u b gr o u p Si ze  
Cli nic al Be nefit 
R ate  
E x pe cte d S ucc ess  
9 5 % Cr e di bl e I nter v al  
1 6 0  
1 0  
1 6  
( 6. 0, 1 5. 2) 
1 2 5  
1 0  
1 2  
( 5. 3, 1 5. 5) 
1 0 0  
1 0  
1 0  
( 5. 1, 1 6. 7) 
7 5  
1 0  
8  
( 5. 0, 1 8. 7) 
5 0  
1 0  
5  
( 3. 7, 1 9. 9) 
4 0  
1 0  
4  
( 3. 2, 2 1. 2) 
3 0  
1 0  
3  
( 2. 6, 2 3. 2) 
1 6 0  
2 0  
3 2  
( 1 4. 2, 2 6. 5) 
1 2 5  
2 0  
2 5  
( 1 3. 5, 2 7. 4) 
1 0 0  
2 0  
2 0  
( 1 2. 9, 2 8. 3) 
7 5  
2 0  
1 5  
( 1 1. 9, 2 9. 6) 
5 0  
2 0  
1 0  
( 1 0. 4, 3 1. 8) 
4 0  
2 0  
8  
( 9. 5, 3 3. 2)  
3 0  
2 0  
6  
( 8. 3, 3 5. 2) 
1 6 0  
3 0  
4 8  
( 2 3. 1, 3 7. 1) 
1 2 5  
3 0  
3 8  
( 2 2. 6, 3 8. 5) 
1 0 0  
3 0  
3 0  
( 2 1. 4, 3 9. 0) 
7 5  
3 0  
2 2  
( 1 9. 6, 3 9. 6) 
5 0  
3 0  
1 5  
( 1 8. 1, 4 2. 6) 
4 0  
3 0  
1 2  
( 1 6. 9, 4 4. 0) 
3 0  
3 0  
9  
( 1 5. 2, 4 6. 0) 
 
A t otal of a p pr o xi matel y 2 0 a d va nce d pr ostate ca ncer partici pa nts wit h C D 8 l o w t u m ors will be 
tr eate d wit h t he c o m bi nati o n of ni v ol u ma b a n d i pili m u ma b, i n 1 of 2 d osi n g c o h orts. T he first 
1 0  partici pa nts e nr olle d will be r a n d o ml y all ocate d b y t he S p o ns or i nt o o ne of t w o c o h orts 
( 5 partici pa nts per c o h ort) t o  e val uate t he safet y of differe nt d ose le vels of i pili m u ma b i n 
c o m bi nati o n wit h ni v ol u ma b. If t he hi g her d ose le vel (i pili m u ma b 5 m g/ k g + ni v ol u ma b 
1  m g/ k g) is deter mi ne d t o be t oler a ble per Secti o n 6. 6. 1. 4 , a n a d diti o nal 1 0 partici pa nts will be 
e nr olle d at t his hi g her d ose le vel ( Pr ostate C o h ort B). If t he safet y pr ofile of Pr ostate C o h ort B is 
dee me d u nacce pta ble, a n a d diti o nal 1 0 partici pa nts will be e nr olle d at t h e l o wer d ose le vel 
( Pr ostate C o h ort A). 

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9 9  
We h y p ot hesize t hat hi g her d oses of i pili m u ma b will de m o nstrate a lar ger pr o p orti o n of 
partici pa nts w h o c o n vert fr o m C D 8 l o w t o C D 8 hi g h. T here is n o pri or f or t he e x pecte d 
pr o p orti o n of partici pa nts w h o will c o n vert  fr o m C D 8 l o w t o C D 8 hi g h at t he vari o us d ose le vels 
of i pili m u ma b. Wit h 1 5 partici pa nts e nr olle d i n Pr ostate C o h ort B, T a ble  1 2  pr o vi des 9 5 % 
cr e di ble i nter vals f or p ossi ble C D 8 c o n versi o n rates i n t he c o h ort. F or e xa m ple, a 9 5 % cre di ble 
i nter val ass u mi n g 6/ 1 5 ( 4 0 %) partici pa nts c o n verti n g i n t he c o h ort w o ul d be ( 1 7. 7 %, 6 4. 9 %). 
T a ble  1 2 : 
Cre di ble I nt er v als f or C D 8 C o n versi o n  
S u b g r o u p Si ze 
C D 8 C o n versi o n 
R ate  
E x pe cte d S ucc esses  
9 5 % Cr e di bl e I nter v al  
1 5  
2 0  
3  
(4. 7 , 4 2. 8 ) 
1 5  
4 0  
6  
( 17 . 7, 6 4. 9 ) 
1 5  
6 0  
9  
(3 5. 1 , 8 2. 3 ) 
 
9. 2  
P O P U L A TI O N S F O R A N A L Y S IS  
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulati o ns are defi ne d  (T a ble 1 3 ): 
T a ble 1 3 : 
P o p ul ati o ns f or A n al ysis  
P o p ul ati o n  
Desc ri pti o n  
Safet y  P o p ul ati o n  
All partici pa nts w h o rec ei ve d  at l east o ne d ose of st u d y dr u g. Parti ci pa nts  
will be a nal yze d ac c or di n g t o t he st u d y i nter ve nti o n a ct uall y re cei ve d.  
M o difie d I nte nt -t o-Treat ( mI T T)  
P o p ul ati o n  
All partici pa nts wit h s uffi ci e nt bi o ps y res ults t o be assi g ne d t o a tre at me nt 
ar m a n d w h o  re cei ve d at l east 1 d ose of st u d y dr u g . Parti ci pa nts  will be 
a nal yze d ac c or di n g t o t he st u d y i nter ve nti o n t o w hic h t he y were assi g ne d. 
O n -treat m e nt Bi o ps y P o p ul ati o n  
All partici pa nts wit h at le ast 1 o n -treat m e nt bi o ps y  wit h s uffici e nt C D 8 
res ults will be i ncl u de d i n t he anal yses  of c ha n ges i n C D 8 c o u nts  
 
9. 3  
I N T E RI M A N A L Y S E S 
9. 3. 1  
S afet y a n d F utilit y M o nit ori n g  
O n g oi n g m o nit ori n g f or saf et y a n d f utilit y will be i m ple me nte d base d o n t he met h o d of T hall 
a n d c ollea g ues ( T hall et al, 1 9 9 5 ) se paratel y i n t he C D 8 hi g h a n d C D 8 l o w t u m or gr o u ps f or 
a d va nced  metastatic ca ncer a n d a d va nce d pr ostate ca ncer partici pa nts . M o nit ori n g will be 
o n g oi n g d uri n g e nr oll me nt i n eac h gr o u p, o nce a partici pa nt recei ves treat me nt a n d t heir first 
tr eat me nt bi o ps y is perf or me d. Scr ee ni n g a n d accr ual t o eac h gr o u p will c o nti n ue u ntil s ufficie nt 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 0  
i nf or mati o n is a vaila ble t o assess t he st o p pi n g r ules as defi ne d bel o w. St o p pi n g r ules a n d 
o per ati n g c har acteristics wer e calc ulate d usi n g M ultc Lea n v 2. 1.  
9. 3. 1. 1  
S afet y M o nit ori n g  
F or trial m o nit ori n g a n d decisi o ns a b o ut f ut ure trials, T O X criteria are defi ne d i n Secti o n 8. 3. 7 . 
A partici pa nt w h o v ol u ntaril y lea ves t he trial f or a n y reas o n, i ncl u di n g t o xicit y t hat d oes n ot 
meet t he T O X criteria, will n ot c o u nt as ha vi n g a T O X. De n ote t he pr o ba bilit y of T O X b y θ
T . 
T he st o p pi n g  r ule f or a d va nce d metastatic ca ncer ar ms is gi ve n b y t he f oll o wi n g pr o ba bilit y 
state me nt: Pr ( θ T  > 0. 4 0 | data) >  0. 9 7 5. T hat is, t he trial will be st o p pe d if, at a n y ti me d uri n g t he 
st u d y, it is deter mi ne d t hat t her e is > 9 7. 5 % c ha nce t hat t he T O X rate i s > 4 0 %. T he st o p pi n g 
r ules ass u me a c o nsta nt T O X r ate f or “sta n dar d t hera p y” of 0.4 0 (Lar ki n et al, 2 0 1 5 ; W olc h o k et 
al, 2 0 1 7) a n d a pri or θ T  ~ beta ( 0. 8 , 1.2 ) f or t he c urre nt st u d y. T he st o p pi n g b o u n daries f or t his 
t o xicit y r ule ar e t o ter mi nate t he trial if t he n u m ber of partici pa nts wit h T O X c o m pare d t o t he 
n u m ber of partici pa nts ha vi n g r ecei ve d treat me nt e xcee ds t he li mits i n  T a ble  1 4 .  
T a ble  1 4 : 
R ules f or S af et y a n d F utilit y M o nit ori n g per Ar m  
If t he re are t his m a n y  
( or m ore)  
p artici p a nts e v al u a bl e f or 
r es p o nse 
St o p t he ar m if t he re are t his 
m a n y ( or m ore) p arti ci p a nts wit h 
a T O X e ve nt:  
St o p t he ar m if t he re are t his 
m a n y ( or fe we r) p arti ci p a nts w h o 
me et t he defi niti o n of s ucc ess 
defi ne d a b o ve:  
2 0  
1 3  
1  
4 0  
2 3  
3  
6 0  
3 2  
6  
8 0  
4 1  
9  
1 0 0  
5 0  
1 2  
1 2 0  
5 9  
1 5  
1 4 0  
6 8  
1 9  
 
9. 3. 1. 2  
F utilit y M o nit ori n g  
F or trial m o nit ori n g, “s uccess” will be defi ne d se paratel y b y t u m or gr o u p. F or partici pa nts wit h 
C D 8 l o w t u m ors, partici pa nts will be c o u nte d as ha vi n g s uccess if t he y meet t he defi niti o n of 
C B R or  if t he t u m or c o n verts fr o m C D 8 l o w t o C D 8 hi g h e x pressi o n. F or partici pa nts i n t he C D 8 
hi g h t u m or gr o u p, partici pa nts will be c o u nte d as s uccess if t he y meet t he defi niti o n of C B R. 
De n ote t he pr o ba bilit y of s uccess b y θ S . We ass u m e θ S  ~ beta ( 0. 4, 1. 6). T he st o p pi n g r ule is 
gi ve n b y t he f oll o wi n g pr o ba bilit y state me nt: Pr( θ S  < 0. 2 0 | data) >  0. 9 7 5. T hat is, partici pa nt 
e nr oll me nt f or a d va nce d metastatic ca ncer ar ms will be st o p pe d if, at a n y a nal ysis ti me, it is 
deter mi ne d t hat t her e i s > 9 7. 5 % c ha nce t hat t he C B R is < 2 0 %, a c o nsta nt rate t hat is at t he 
a ver a ge e x pecte d r es p o nse r ate f or t hese partici pa nts. T he st o p pi n g b o u n daries f or t his f utilit y 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 1  
r ule, s h o w n i n T a ble  1 4 , ar e desi g ne d t o ter mi nate e nr oll me nt o n t he ar m if t he n u m ber of o verall 
r es p o nses c o m par e d wit h t he n u m ber of partici pa nts e nr olle d w h o are e val ua ble d oes n ot meet 
t he r e q uir e me nts of t his ta ble. A partici pa nt is e val ua ble f or be nefit eit her o n t he date of disease 
assess me nt  or  t he date t he partici pa nt g oes off st u d y wit h o ut be nefit or if t he partici pa nt d oes n ot 
r ecei ve t he sc he d ule d disease assess me nt wit hi n 3 wee ks wit h o ut ass ociate d sc he d uli n g dela y. 
M o nit ori n g  will be carrie d o ut d uri n g e nr oll me nt  i n eac h a d va nce d metastatic ca ncer ar m . 
Partici pa nts w h o wit h dr a w fr o m t he st u d y after recei vi n g treat me nt b ut bef ore u n der g oi n g o n -
tr eat me nt bi o psies or w h o miss t he e val uati o n wi n d o w wit h o ut ass ociate d treat me nt dela y will be 
c o u nte d as n ot be nefitti n g a n d t her ef or e e val ua ble f or a nal ysis. C B R is defi ne d as best res p o nse 
of C R or partial r es p o nse ( P R ) a n y ti me or sta ble disease (S D ) lasti n g 6 m o nt hs. F or f utilit y 
m o nit ori n g p ur p oses, c o nfir mati o n of res p o nse ( C R or P R) is n ot re q uire d . A d diti o nall y, a 
partici pa nt w h o has bee n o n st u d y bet wee n 1 2  wee ks a n d 6 m o nt hs a n d has S D at t he ti me of 
data c ollecti o n will be c o u nte d as a s uccess f or t hat f utilit y a nal ysis. If t hat partici pa nt later 
pr o gr esses a n d n o l o n ger meets t he S D defi niti o n, t heir u p date d i nf or mati o n will be i ncl u de d i n 
t he m o nit ori n g a nal ysis (T a ble  1 4 ). 
9. 3. 1. 3  
J oi nt O per ati n g C h ar acteristics f or S afet y a n d F utilit y 
M o nit ori n g  
T he r ules a b o ve will a p pl y i n de pe n de ntl y t o eac h C D 8 hi g h or C D 8 a d va nce d metastatic ca ncer 
ar m. It is esti mate d t hat t here will be 4 0 partici pa nts wit h C D 8 hi g h t u m ors a n d 1 6 0 partici pa nts 
wit h C D 8  l o w t u m ors i n pr ese nti n g t he o perati n g c haracteristics bel o w. T he pr o ba bilit y of 
st o p pi n g at 2 0 partici pa nts pr o vi des t he pr o ba bilit y of st o p pi n g earl y i n t he C D 8 hi g h t u m or 
gr o u p , ass u mi n g o nl y 4 0 partici pa nts are e ntere d. T a ble  1 5  s h o ws t he o perati n g c haracteristics 
u n der var yi n g t o xicit y a n d r es p o nse r ates.  
T a ble  1 5 : 
O per ati n g C h ar act eristics U n der V ar yi n g T o xicit y a n d Res p o nse R ates  
Tr ue O ve r all 
T o xi cit y R ate  
Tr ue O ve r all 
Res p o nse R ate  
P r o b a bilit y of 
St o p pi n g at 2 0 
P arti ci p a nts  
P r o b a bilit y of 
St o p pi n g Bef ore 
1 6 0 P arti ci p a nts  
M e di a n  
( 2 5t h %ile, 7 5
t h %il e) f or 
“ C ol d ” C o h ort  
0. 1 0  
0. 0 5  
0. 7 4  
> 0. 9 9  
2 0 ( 2 0, 4 0)  
0. 1 0  
0. 3 9  
0. 9 6  
4 0 ( 2 0, 8 0)  
0. 2 0  
0. 0 7  
0. 1 2  
1 6 0 ( 1 6 0, 1 6 0)  
0. 3 0  
0. 0 1  
0. 0 1  
1 6 0 ( 1 6 0, 1 6 0)  
0. 4 0  
0. 0 0 1  
0. 0 0 1  
1 6 0 ( 1 6 0, 1 6 0)  
0. 2 0  
0. 0 5  
0. 7 4  
> 0. 9 9  
2 0 ( 2 0, 4 0)  
0. 1 0  
0. 3 9  
0. 9 6  
4 0 ( 2 0, 8 0)  
0. 2 0  
0. 0 7  
0. 1 2  
1 6 0 ( 1 6 0, 1 6 0)  
0. 3 0  
0. 0 1  
0. 0 1  
1 6 0 ( 1 6 0, 1 6 0)  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 2  
Tr ue O ve r all 
T o xi cit y R ate  
Tr ue O ve r all 
Res p o nse R ate  
P r o b a bilit y of 
St o p pi n g at 2 0 
P arti ci p a nts  
P r o b a bilit y of 
St o p pi n g Bef ore 
1 6 0 P arti ci p a nts  
M e di a n  
( 2 5t h %ile, 7 5
t h %il e) f or 
“ C ol d ” C o h ort  
0. 4 0  
0. 0 0 1  
0. 0 0 1  
1 6 0 ( 1 6 0, 1 6 0)  
0. 3 0  
0. 0 5  
0. 7 4  
> 0. 9 9  
2 0 ( 2 0, 4 0)  
0. 1 0  
0. 3 9  
0. 9 6  
4 0 ( 2 0, 8 0)  
0. 2 0  
0. 0 7  
0. 1 2  
1 6 0 ( 1 6 0, 1 6 0)  
0. 3 0  
0. 0 1  
0. 0 1  
1 6 0 ( 1 6 0, 1 6 0)  
0. 4 0  
0. 0 0 2  
0. 0 0 2  
1 6 0 ( 1 6 0, 1 6 0)  
0. 4 0  
0. 0 5  
0. 7 4  
> 0. 9 9  
2 0 ( 2 0, 4 0)  
0. 1 0  
0. 4 0  
0. 9 6  
4 0 ( 2 0, 8 0)  
0. 2 0  
0. 0 9  
0. 1 9  
1 6 0 ( 1 6 0, 1 6 0)  
0. 3 0  
0. 0 3  
0. 0 9  
1 6 0 ( 1 6 0, 1 6 0)  
0. 4 0  
0. 0 2  
0. 0 8  
1 6 0 ( 1 6 0, 1 6 0)  
0. 5 0  
0. 0 5  
0. 7 7  
> 0. 9 9  
2 0 ( 2 0, 2 0)  
0. 1 0  
0. 4 7  
0. 9 9  
4 0 ( 2 0, 6 0)  
0. 2 0  
0. 1 9  
0. 7 8  
8 0 ( 4 0, 1 4 0)  
0. 3 0  
0. 1 4  
0. 7 5  
8 0 ( 4 0, 1 4 0)  
0. 4 0  
0. 1 3  
0. 7 5  
8 0 ( 4 0, 1 6 0)  
 
9. 4  
S T A TI S TI C A L A N A L Y S E S  
T he st u d y will use a n a da pti ve a p pr oac h, wit h o n -treat me nt data g ui di n g trial a da ptati o n a n d 
s uccess or f utilit y of eac h c o m bi nati o n i n eac h st u d y s u b p o p ulati o n. 
T he statistical a nal ysis pla n will be de vel o pe d a n d fi nalize d bef ore data base l oc k a n d will 
descri be t he st u d y p o p ulati o ns t o be i ncl u de d i n t he a nal yses a n d pr oce d ures f or acc o u nti n g f or 
missi n g, u n use d, a n d s p uri o us data. T he statist ical a nal ysis pla n will ser ve as a c o m ple me nt t o 
t he pr ot oc ol a n d s u perse des it i n case of differe nces. T his secti o n is a s u m mar y of t he pla n ne d 
statistical a nal yses of t he pri mar y a n d sec o n dar y e n d p oi nts. 
9. 4. 1  
Effic ac y A n al yses  
T he efficac y a nal ysis will be base d o n t he m o difie d  Inte nt -t o-T reat (mI T T ) P o p ulati o n, w hic h 
c o m prises all e nr olle d partici pa nts wit h s ufficie nt bi o ps y res ults t o be assi g ne d t o a treat me nt 
ar m a n d w h o r ecei ve d at least o ne d ose of st u d y dr u g, u nless ot her wise s pecifie d. Partici pa nts 
will be a nal yze d acc or di n g t o t he st u d y i nter ve nti o n t o w hic h t he y were assi g ne d . 
T he pri mar y e n d p oi nt of C B R will be re p orte d a m o n g all partici pa nts wit hi n eac h st u d y 
i nter ve nti o n gr o u p wit h a 9 5 % cr e di ble i nter val ass u mi n g a beta ( 0. 4, 1. 6) pri or.  Per R E CI S T, t o 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 3  
be assi g ne d a best o ver all r es p o nse of C R or P R, c ha n ges i n t u m or meas ure me nts m ust be 
c o nfir me d b y a r e peat assess me nt t hat s h o ul d be perf or me d n o less t ha n 4 wee ks after t he criteria 
f or r es p o nse ar e first met. Partici pa nts w h o d o n ot ha ve a disease assess me nt will be c o u nte d as 
n ot ha vi n g  cli nical be nefit. I n a d diti o n, C B R a n d si milar cre di ble i nter vals will be re p orte d f or 
eac h t u m or site a n d st u d y i nter ve nti o n s u b gr o u p t hat has at least 1 0 partici pa nts. 
T he pr o p orti o n of partici pa nts w h ose t u m ors c ha n ge fr o m C D 8 l o w t o C D 8 hi g h e x pressi o n will 
be r e p orte d wit h a 9 5 % cr e di ble i nter val wit h n o pri or as t his is t he first l o o k.  
F or sec o n dar y e n d p oi nts, baseli ne C D 8 c o u nts will be e x pl ore d f or ass ociati o n wit h C B R usi n g  
l o gistic r e gr essi o n m o dels a n d wit h O S usi n g C o x re gressi o n m o dels. M ultivariate m o dels will 
be e x pl or e d wit h u p t o 1 varia ble f or e ver y 1 0  e ve nts. F or C B R pre dicti o n, a n e ve nt is a n 
o bjecti ve r es p o nse ( C R or P R or S D as defi ne d a b o ve). F or ass ociati o n wit h s ur vi val, a n e ve nt is 
a partici pa nt deat h.  
A m o n g t he O n-tr eat me nt Bi o psy P o p ulati o n, b ot h t he baseli ne a n d o n -treat me nt bi o psies will be 
ass ociate d  wit h r es p o nse a n d s ur vi val usi n g  si milar l o gistic a n d C o x re gressi o n m o dels descri be d 
a b o ve, ass u mi n g t her e ar e s ufficie nt e ve nts t o carr y o ut t he re gressi o n a nal yses. T he ass ociati o n  
of  C D 8 c ha n ges fr o m baseli ne t o o n tr eat me nt  wit h  cli nical o utc o mes will als o be e x pl ore d . 
T he e x pl or at or y e n d p oi nt of c ha n ges i n P S A ( abs ol ute a n d perce nt ) fr o m baseli ne will be 
a nal yze d b y c o h ort f or a d va nce d pr ostate ca ncer partici pa nts. 
9. 4. 2  
S afet y A n al yses  
T he saf et y a nal ysis will be base d o n t he Safet y P o p ulati o n, w hic h c o m prises all partici pa nts w h o 
r ecei ve at least o ne d ose of st u d y dr u g . Partici pa nts will be a na l yze d acc or di n g t o t he st u d y 
i nter ve nti o n act uall y r ecei ve d. 
Saf et y a n d t oler a bilit y will be assesse d t hr o u g h A Es, cli nical la b orat or y para meters, vital si g ns, 
a n d E C Gs . 
A Es will be descri be d b y gr a de a n d attri b uti o n f or eac h st u d y i nter ve nti o n. 
9. 4. 3  
Ot her A n al ys es  
B i o mar ker e x pl or at or y a nal yses will be perf or me d w he n p ossi ble a n d i ncl u de d i n t he cli nical 
st u d y r e p ort or a se par ate r esear c h r e p ort .  
9. 4. 3. 1  
Bi o m ar ker A n al ysis  
Descri pti ve statistics will be use d t o e val uate t he e x pl orat or y bi o mar kers.  Bi o mar ker a nal ysis 
will be f urt her descri be d i n a bi o mar ker a nal ysis pla n .  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 4  
9. 4. 3. 2  
P atie nt -Re p orte d O utc o m es A n al ysis  
A n e x pl or at or y a nal ysis ma y be perf or me d wit h t he patie nt -re p orte d dataset c ollecte d via 
A pricit y Car e ™, i ncl u di n g b ut n ot li mite d t o t he fre q ue nc y wit h w hic h partici pa nts c o m plete t he 
dail y s y m pt o m s ur ve y i n A pricit y Car e ™, a n d t he fre q ue nc y of A pricit y we bsite access b y 
i n vesti gati ve sites. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 5  
1 0  
S U P P O R TI N G  D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 0. 1  
A P P E N DI X  1 : R E G U L A T O R Y, E THI C A L A N D S T U D Y 
O V E R SI G H T C O N SI D E R A TI O N S  
1 0. 1. 1  
C o m pli a nce wit h L a ws a n d Re g ul ati o ns  
T his st u d y will be c o n d ucte d i n f ull c o nf or ma nce wit h t he I nter nati o nal C o u ncil f or 
Har m o nisati o n ( I C H) E 6 g ui deli ne f or G o o d Cli nical Practice ( G C P) a n d t he c o nse ns us et hical 
pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he Declarati o n of Helsi n ki a n d 
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces I nter nati o nal Et hical G ui deli ne s, 
a n d a p plica ble la ws a n d r e g ulati o ns. T he st u d y will c o m pl y wit h t he re q uire me nts of t he I C H 
E 2 A g ui deli ne ( Cli nical Saf et y Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d 
Re p orti n g). St u dies c o n d ucte d i n t he U nite d States or u n der a U. S. I n vest i gati o nal Ne w Dr u g 
(I N D) a p plicati o n will c o m pl y wit h U. S. F D A re g ulati o ns a n d a p plica ble l ocal, state, a n d fe deral 
la ws. St u dies c o n d ucte d i n t he E ur o pea n U ni o n or E ur o pea n E c o n o mic Area will c o m pl y wit h 
t he E. U. Cli nical Trial Dir ecti ve ( 2 0 0 1/ 2 0/ E C). 
1 0. 1. 2  
I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee 
T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F(s), I n vesti gat or ’s Br oc h ure, a n y i nf or mati o n t o be gi ve n 
t o t he partici pa nt , a n d r ele va nt s u p p orti n g i nf or mati o n m ust be s u b mitte d t o t he I R B/I E C a n d 
r e vie we d a nd  a p pr o ve d b y t he I R B/I E C bef ore t he st u d y is i nitiate d. I n a d diti o n, a n y partici pa nt  
r ecr uit me nt materials ( e g, a d vertise me nts) m ust be a p pr o ve d b y t he I R B/I E C. 
A n y a me n d me nts t o t he pr ot oc ol will r e q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate 
hazar d t o st u d y partici pa nt s or c ha n ges t hat i n v ol ve l o gistical or a d mi nistrati ve as pects o nl y (e g, 
c ha n ge i n Me dical M o nit or or c o ntact i nf or mati o n).  
T he In vesti gat or will be r es p o nsi ble f or t he f oll o wi n g:  
•  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m ore 
fr e q ue ntl y i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C 
•  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ur es 
•  Pr o m ptl y  d oc u me nti n g a n d  r e p orti n g a n y de viati o ns t hat mi g ht ha ve a n i m pact o n 
partici pa nt  saf et y a n d data i nte grit y t o t he S p o ns or a n d t o t he I R B/I E C i n acc or da nce wit h 
esta blis he d r e q uir e me nts, p olicies a n d pr oce d ures  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 0 6  
•  Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o re q uire me nts 
of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns. 
T he I R B of Rec or d is M D A n ders o n a n d t he Rel yi n g I R Bs are U C L A, U C S F, Sta nf or d, D F CI, 
a n d M S K C C.  Par ker mai ntai ns se par ate d oc u me ntati o n of t he i nst it uti o n’s a d dress, F W A 
n u m ber a n d e x pir ati o n date, a n d t he na me d I nstit uti o nal Official a n d I R B C o ntact, as well as 
t heir e mail a n d p h o ne n u m bers a n d will pr o vi de t hat t o t he sites. 
1 0. 1. 3  
Fi n a nci al Dis cl os ure  
I n vesti gat ors a n d S u bi n vesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n as r e q ueste d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ur e state me nts t o t he a p pr o priate healt h a ut h orities. I n vesti gat ors are 
r es p o nsi ble f or pr o vi di n g i nfor mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y (see defi niti o n of e n d of st u d y i n Secti o n  4. 5 ). 
1 0. 1. 4  
I nf or m e d C o ns e nt 
T he In vesti gat or or his/ her r e pr ese ntati ve will e x plai n t he nat ure of t he st u d y t o t he partici pa nt  or 
his/ her le gall y a ut h orize d r e pr ese ntati ve a n d a ns wer all q uesti o ns re gar di n g t he st u d y.  
Partici pa nt s m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y. Partici pa nt s or t heir le gall y 
a ut h orize d r e pr ese ntati ve will be r e q uire d t o si g n a state me nt of  i nf or me d c o nse nt t hat meets t he 
r e q uir e me nts of 2 1 C F R 5 0, l ocal r e g ulati o ns, I C H g ui deli nes, Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) r e q uir e me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y ce nter.  
T he me dical r ec or d m ust i ncl u de a st ate me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt  was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
If a p plica ble, t he I C F will c o ntai n se parate secti o ns f or a n y o pti o nal pr oce d ures. T he In vesti gat or 
or a ut h orize d desi g nee will e x plai n t o eac h partici pa nt  t he o bjecti ves, met h o ds, a n d p ote ntial 
ris ks ass ociate d wit h eac h o pti o nal pr oce d ure. Partici pa nt s will be t ol d t hat t he y are free to ref use 
t o partici pate a n d ma y wit h dr a w t heir c o nse nt at a n y ti me f or a n y reas o n. A se parate, s pecific 
si g nat ur e will be r e q uir e d t o d oc u me nt a partici pa nt ’s a gree me nt t o partici pate i n o pti o nal 
pr oce d ur es. Partici pa nt s w h o decli ne t o partici pate will n ot pr o vi de a se parate si g nat ure.  
Partici pa nt s m ust be r e-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) ( or t o a si g nifica nt 
ne w i nf or mati o n/fi n di n gs a d de n d u m i n acc or da nce wit h a p plica ble la ws a n d I R B/I E C p olic y) 
d uri n g t heir partici pati o n i n t he st u d y . T he me dical rec or d s h o ul d d oc u me nt t he re-c o nse nt 
pr ocess a n d t hat writte n i nf or me d c o nse nt was o btai ne d usi n g t he u p date d/re vise d I C F f or 
c o nti n ue d partici pati o n i n t he st u d y.  A partici pa nt w h o is rescree ne d is n ot re q uire d t o si g n 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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1 0 7  
a n ot her I C F if t he r e scr ee ni n g is be y o n d 3 0 da ys fr o m C 1 D 1 u nless t he i nstit uti o n’s p olic y is t o 
perf or m r e -c o nse nt. I n t hat case, PI CI acce pts t he i nstit uti o n’s p olic y o n re -c o nse nt.  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt  or  t o t he partici pa nt ’s le gall y a ut horize d 
r e pr ese ntati ve. All si g ne d a n d date d I C Fs m ust re mai n i n t he partici pa nt ’s st u d y file or i n t he site 
st u d y file a n d m ust be a vaila ble f or verificati o n b y st u d y m o nit ors at a n y ti me. 
T he fi nal r e vise d I R B/I E C -a p pr o ve d I C Fs m ust be pr o vi de d t o t he S p o ns or f or t he p ur p ose of 
healt h a ut h orit y s u b missi o n.  
A partici pa nt  w h o is r escr ee ne d is n ot r e q uire d t o si g n a n ot her I C F if t he rescree ni n g occ urs 
wit hi n 3 0  da ys fr o m t he pr e vi o us I C F si g nat ure date.  
T he I C F will c o ntai n a se par ate secti o n t hat a d dresses t he use of re mai ni n g ma n dat or y sa m ples 
f or o pti o nal e x pl or at or y r esear c h. T he In vesti gat or or a ut h orize d desi g nee will e x plai n t o eac h 
partici pa nt  t he o bjecti ves of t he e x pl orat or y researc h. Partici pa nt s will be t ol d t hat t he y are free 
t o r ef use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n d uri n g t he 
st or a ge peri o d. A se par ate si g nat ur e will be re q uire d t o d oc u me nt a partici pa nt 's a gree me nt t o 
all o w a n y r e mai ni n g s peci me ns  t o be use d f or e x pl orat or y researc h. Partici pa nt s w h o decli ne t o 
partici pate i n t his o pti o nal r esear c h will n ot pr o vi de t his se parate si g nat ure.  
1 0. 1. 5  
D at a Pr otecti o n  
T he S p o ns or mai ntai ns c o nfi de ntialit y sta n dar ds b y assi g ni n g a u ni q ue partici pa nt  i de ntificatio n 
n u m ber t o eac h partici pa nt  e nr olle d i n t he st u d y. T his mea ns t hat partici pa nt  na mes are n ot 
i ncl u de d i n data sets t hat ar e tr a ns mitte d t o a n y S p o ns or l ocati o n. 
Partici pa nt  me dical i nf or mati o n o btai ne d b y t his st u d y is c o nfi de ntial a n d ma y be discl ose d t o 
t hir d parties o nl y as per mitte d b y t he I C F ( or se parate a ut h orizati o n f or use a n d discl os ure of 
pers o nal healt h i nf or mati o n) si g ne d b y t he partici pa nt  or as  per mitte d or re q uire d b y la w.  
Me dical i nf or mati o n ma y be gi ve n t o a partici pa nt ’s pers o nal p h ysicia n or ot her a p pr o priate 
me dical pers o n nel r es p o nsi ble f or t he partici pa nt ’s welfare, f or treat me nt p ur p oses. 
Data ge ner ate d b y t his st u d y m ust be a vaila ble f or i ns pecti o n u p o n re q uest b y re prese ntati ves of 
nati o nal a n d l ocal healt h a ut h orities, S p o ns or m o nit ors, re prese ntati ves  a n d c olla b orat ors, a n d t he 
I R B/I E C f or eac h st u d y site, as a p pr o priate. 
1 0. 1. 6  
A d mi nistr ati ve Str uct ure  
T his trial will be s p o ns or e d a n d ma na ge d b y the Par ker I nstit ute f or Ca ncer I m m u n ot hera p y. T he 
S p o ns or will pr o vi de cli nical o per ati o ns ma na ge me nt, data ma na ge me nt, a n d me dical 
m o nit ori n g.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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1 0 8  
Ce ntr al f acilities will be use d f or certai n st u d y assess me nts t hr o u g h o ut t he st u d y (e g,  s pecifie d 
la b or at or y test a n d bi o mar ker a nal yse s), as s pecifie d i n Secti o n 8. 2. 5  a n d Secti o n 8. 7 , 
r es pecti vel y. Accr e dite d l ocal la b or at ories will be use d f or r o uti ne m o nit ori n g; l ocal la b orat or y 
r a n ges will be c ollecte d. 
1 0. 1. 7  
D at a Q u alit y Ass ur a nce  
All partici pa nt  data r elati n g t o t he st u d y will be c ollecte d via t he electr o nic data c ollecti o n (E D C ) 
s yste m o n a n e C R F u nless tr a ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e g, ce ntral 
la b or at or y data, bi o mar ker, a n d ot her bi ol o gical sa m ple data). Sites will be res p o nsi ble f or data 
e ntr y int o t he E D C s yste m a n d will r ecei ve trai ni n g f or a p pr o priate e C R F c o m pleti o n. T he 
In vesti gat or is r es p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
electr o nicall y si g ni n g a n d dati n g t he e C R F.  
T he In vesti gat or m ust mai ntai n acc ur ate d o c u me ntati o n (s o urce data, see Secti o n  1 0. 1. 8 ) t hat 
s u p p orts t he i nf or mati o n e nter e d i n t he e C R F. T he In vesti gat or m ust per mit st u d y-relate d 
m o nit ori n g, a u dits, I R B/I E C r e vie w, a n d re g ulat or y a ge nc y i ns pecti o ns a n d pr o vi de direct access 
t o s o ur ce data d oc u me nts. 
T he S p o ns or or desi g nee is r es p o nsi ble f or t he data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y 
c hec ki n g of t he data. St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m 
t hat data e nter e d o n  t he e C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble 
fr o m s o ur ce d oc u me nts; t hat t he saf et y a n d ri g hts of partici pa nt s are bei n g pr otecte d; an d t hat t he 
st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y 
a gr ee me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire me nts.  
At t he e n d of t he st u d y, t he In vesti gat or will recei ve partici pa nt  data f or his/ her  site i n a rea da ble 
f or mat o n a c o m pact disc ( or ot her r ea da ble di gital f or mat) t hat m ust be ke pt wit h t he st u d y 
r ec or ds. Ac k n o wle d ge me nt of r ecei pt of t he c o m pact disc is re q uire d. 
1 0. 1. 8  
S o urce D oc u m e nt ati o n  
S o ur ce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce o f t he partici pa nt  a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o ur ce d oc u me nts are file d at t he In vesti gat or’s site. Data e ntere d 
o n  t he e C R F t hat ar e tr a nscri be d fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discr e pa n cies m ust be e x plai ne d. T he In vesti gat or ma y nee d t o re q uest 
pr e vi o us me dical r ec or ds or tr a nsf er r ec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical 
r ec or ds m ust be a vaila ble. 
S o ur ce d oc u me nts ( pa per or electr o nic) are t h ose i n w hic h partici pa nt  data a re rec or de d a n d 
d oc u me nte d f or t he first ti me. T he y i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical a n d 
office c harts, la b or at or y n otes, me m or a n da,  cli nical o utc o me assess me nt ( C O A)/ P R O , e val uati o n 
c hec klists, p har mac y dis pe nsi n g r ec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, c o pies  of 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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1 0 9  
tr a nscri pti o ns t hat ar e certifie d after verificati o n as bei n g acc urate a n d c o m plete, micr ofic he, 
p h ot o gr a p hic ne gati ves, micr ofil m or ma g netic me dia, X -ra ys, partici pa nt  files, a n d rec or ds ke pt 
at p har macies, la b or at ories, a n d me dic o-tec h nical de part me nts i n v ol ve d i n a cli nical trial. 
W he n cli nical o bser vati o ns ar e e nter e d directl y i nt o a st u d y site’s c o m p uterize d me dical rec or d 
s yste m (ie, i n lie u of ori gi nal har dc o p y rec or ds), t he electr o nic rec or d ca n ser ve as t he s o urce 
d oc u me nt if t he s yste m has bee n vali date d i n acc or da nce wit h healt h a ut h orit y re q uire me nts 
pertai ni n g t o c o m p uterize d s yste ms use d i n cli nical researc h. A n acce pta ble c o m p uterize d data 
c ollecti o n s yste m all o ws pr eser vati o n of t he ori gi nal e nt r y of data. If ori gi nal data are m o difie d, 
t he s yste m s h o ul d mai ntai n a vie wa ble a u dit trail t hat s h o ws t he ori gi nal data as well as t he 
r eas o n f or t he c ha n ge, na me of t he pers o n ma ki n g t he c ha n ge, a n d date of t he c ha n ge. 
S o ur ce d oc u me nts t hat ar e r e q uir e d  t o verif y t he vali dit y a n d c o m plete ness of data e ntere d o n  t he 
e C R Fs m ust n ot be o bliter ate d or destr o ye d a n d m ust be retai ne d as descri be d i n Secti o n  1 0. 1. 1 1 . 
1 0. 1. 9  
St u d y a n d S ite Cl os ure  
T he S p o ns or or desi g nee r eser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y r eas o n at t he s ole discr eti o n of t he S p o ns or. Reas o ns f or ter mi nati n g t he st u d y ma y 
i ncl u de, b ut ar e n ot li mite d t o, t he f oll o wi n g: 
•  Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt  
•  T he i nci de nce or se verit y of A Es  i n t his or ot her st u dies i n dicates t he p ote ntial hazar d 
t o partici pa nt s 
•  Partici pa nt  e nr oll me nt is u nsatisfact or y 
 
T he S p o ns or will n otif y t he I n vesti gat or if t he S p o ns or deci des t o disc o nti n ue t he st u d y.  
Reas o ns f or t he earl y cl os ur e of a st u d y site b y t he S p o ns or or In vesti gat or ma y i ncl u de , b ut are 
n ot li mite d t o , t he f oll o wi n g: 
•  P o or pr ot oc ol a d her e nce  
•  I nacc ur ate or i nc o m plete data rec or din g  
•  Fail ur e of t he In vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I R B/I E C or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes  
•  N o st u d y acti vit y (ie, all partici pa nt s ha ve c o m plete d t he st u d y a n d all o bli gati o ns 
ha ve bee n f ulfille d)  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 1 0  
1 0. 1. 1 0  
Site I ns pecti o ns  
Site visits will be c o n d ucte d b y t he S p o ns or or a n a ut h orize d re prese ntati ve f or i ns pecti o n of 
st u d y data, partici pa nt s’ me dical r ec or ds, a n d e C R Fs. T he In vesti gat or will per mit nati o nal a n d 
l ocal healt h aut h orities; S p o ns or m o nit ors, re prese ntati ves , a n d c olla b orat ors; a n d t he I R Bs/ IE Cs 
t o i ns pect f acilities a n d r ec or ds r ele va nt t o t his st u d y. 
1 0. 1. 1 1  
Rete nti o n of Rec or ds  
Rec or ds a n d d oc u me nts pertai ni n g t o t he c o n d uct of t his st u d y a n d distri b uti o n of t he 
i n vestigati o nal me dici nal pr o d uct, i ncl u di n g si g ne d e C R Fs, electr o nic or pa per 
partici pa nt -r e p orte d o utc o mes data (if a p plica ble), si g ne d I C Fs, la b orat or y test res ults, a n d 
me dicati o n i n ve nt or y r ec or ds, m ust be retai ne d b y t he In vesti gat or f or t he ma xi m u m peri o d 
r e q uir e d b y a p plica ble r e g ulati o ns of rele va nt nati o nal or l ocal healt h a ut h orities. N o rec or ds ma y 
be dis p ose d of wit h o ut t he writte n a p pr o val of t he S p o ns or. T he S p o ns or will n otif y t he 
In vesti gat or w he n t he r ec or ds ar e n o l o n ger nee de d. F oll o wi n g n otificati o n fr o m t he S p o ns or, t he 
d oc u me nts ma y be destr o ye d, s u bject t o l ocal re g ulati o ns.  
Writte n n otificati o n s h o ul d be pr o vi de d t o t he S p o ns or pri or t o tra nsferri n g a n y rec or ds t o 
a n ot her p art y or m o vi n g t he m t o a n ot her l ocati o n.  
1 0. 1. 1 2  
P u blic ati o n P olic y a n d Pr otecti o n of Tr a de Secrets  
Re gar dless of t he o utc o me of a trial, t he S p o ns or is de dicate d t o o pe nl y pr o vi di n g i nf or mati o n o n 
t he trial t o healt hcar e pr of essi o nals a n d t o t he p u blic, b ot h at scie ntific c o n gresses a n d i n peer -
r e vie we d j o ur nals. T he S p o ns or will c o m pl y wit h all re q uire me nts f or p u blicati o n of st u d y 
r es ults. 
T he In vesti gat or m ust a gr ee t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or pri or t o 
s u b missi o n f or p u blicati o n or pr ese ntati o n. T his all o ws t he S p o ns or t o pr otect pr o prietar y 
i nf or mati o n a n d t o pr o vi de c o m me nts base d o n i nf or mati o n fr o m ot her st u dies t hat ma y n ot yet 
be a vaila ble t o t he In vesti gat or.  
T he S p o ns or will c o m pl y wit h t he r e q uire me nts f or p u blicati o n of st u d y res ults. I n acc or da nce 
wit h sta n dar d e dit orial a n d et hical pr actice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of 
m ultice nter trials o nl y i n t heir e ntir et y a n d n ot as i n di vi d ual ce nter data. I n t his case, a 
c o or di nati n g In v esti gat or will be desi g nate d  i n acc or da nce wit h t he Par ker I nstit ute f or Ca ncer 
I m m u n ot her a p y p u blicati o n p olic y. A ut h ors hi p will be base d o n o verall scie ntific c o ntri b uti o n 
a n d partici pa nt e nr oll me nt. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
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1 1 1  
1 0. 2  
A P P E N DI X 2 : E A S T E R N C O O P E R A TI V E O N C O L O G Y 
G R O U P ( E C O G) P E R F O R M A N C E S T A T U S  
Gr a de  
E C O G P erf or m a nce St at us  
0  
F ull y acti ve, a ble t o carr y o n all pre -diseas e perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y 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  
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 or e t ha n 5 0 % of wa ki n g h o urs  
3  
Ca pa ble of o nl y li mite d self -care; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs  
4  
C o m pletel y disa ble d; ca n n ot 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  
O ke n  M M , Cree c h R H , T or m e y D C , H ort o n J, Da vis  T E , Mc Fa d de n E T , Car b o ne P P:  T o xicit y a n d res p o nse c riteria 
o f the East er n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2.  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 1 2  
1 0. 3  
A P P E N DI X 3 : R E CI S T C RI T E RI A ( V E R SI O N 1. 1 ) 
T u m or r es p o nse will be assesse d acc or di n g t o R E CI S T v 1. 1 (Eise n ha uer et al, 2 0 0 9 ), as 
descri be d bel o w.  
1 0. 3. 1  
Me as ur a bilit y of T u m or at B as eli ne  
At baseli ne, t u m or lesi o ns/l y m p h n o des will be cate g orize d as meas ura ble or n o n meas ura ble as 
f oll o ws: 
•  Me as ur a ble  
T u m or lesi o ns:  M ust be acc ur atel y meas ure d i n ≥ 1 di me nsi o n (l o n gest dia meter i n t he 
pla ne of meas ur e me nt t o be r ec or de d wit h a mi ni m u m size of:  
o  1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m)  
o  1 0 m m cali pe r meas ur e me nt b y cli nical e xa mi nati o n (lesi o ns t hat ca n n ot be 
acc ur atel y meas ur e d wit h cali pers s h o ul d be rec or de d as n o n meas ura ble)  
o  2 0 m m b y c hest X -r a y 
Mali g na nt l y m p h n o des:  T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a 
l y m p h n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice 
t hic k ness r ec o m me n de d t o be n o greater t ha n 5 m m). 
•  N o n m e as ur a ble  
o  All ot her lesi o ns ( or disease sites), i ncl u di n g s mall lesi o ns (l o n gest dia meter 
<  1 0  m m or pat h ol o gical l y m p h n o des wit h ≥ 1 0 t o <  1 5 m m s h ort a xis)  
o  Lesi o ns c o nsi der e d tr ul y n o n meas ura ble i ncl u de t he f oll o wi n g: le pt o me ni n geal 
disease, ascites, ple ur al/ pericar dial eff usi o n, i nfla m mat or y breast disease, 
l y m p ha n gitic i n v ol ve me nt of s ki n or l u n g, a n d a b d o mi nal masses/a b d o mi nal 
or ga n o me g al y i de ntifie d b y p h ysical e xa mi nati o n t hat is n ot meas ura ble b y 
r e pr o d uci ble i ma gi n g tec h ni q ues 
 
1 0. 3. 2  
T u m or Res p o nse E v al u ati o n  
1 0. 3. 2. 1  
B as eli ne D oc u m e nt ati o n of T ar get a n d N o nt ar get Lesi o ns  
•  T ar get lesi o ns  
o  W he n > 1 meas ur a ble lesi o n is prese nt at baseli ne, all lesi o ns u p t o a ma xi m u m of 
5 lesi o ns t otal ( a n d a ma xi m u m of 2 lesi o ns per or ga n) re prese ntati ve of all 
i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get lesi o ns 

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o  It ma y be t he case t hat, o n occasi o n, t he lar gest lesi o n t hat ca n be meas ure d 
r e pr o d uci bl y s h o ul d be selecte d  
•  N o nt ar get lesi o ns  
o  All ot her lesi o ns ( or disease sites), i ncl u di n g pat h ol o gical l y m p h n o des, s h o ul d be 
i de ntifie d as n o ntar get lesi o ns 
o  It is p ossi ble t o r ec or d m ulti ple n o ntar get lesi o ns i n v ol vi n g t he sa me or ga n as a 
si n gle ite m ( e g, “m ulti ple e nlar ge d pel vic l y m p h n o des ” or “m ulti ple li ver 
metastases” ) 
 
1 0. 3. 2. 2  
E v al u ati o n of T ar get Lesi o ns  
T ar get lesi o ns will be e val uate d a n d r es p o nse rec or de d as defi ne d i n A p pe n di x Ta ble 1 . 
A p pe n di x T a ble 1 :  Res p o nse B ase d o n E v al u ati o n of T ar get Lesi o ns at E ac h Assess me nt  
C o m plete res p o nse  
Disa p peara nc e of all tar get lesi o ns; if a pat h ol o gic al l y m p h n o de, 
re d ucti o n i n t he s h ortest a xis t o < 1 0  m m  a 
P artial res p o nse  b 
≥ 3 0 % decrease i n t he s u m of t he dia meters of tar get lesi o ns relati ve 
t o t he baseli ne s u m dia meters c 
Sta ble disease  b, d 
Neit her a s ufficie nt re d ucti o n t o q ualif y as a partial res p o nse n or a 
s ufficie nt i ncrease t o q ualif y as pr o gressi o n  c 
Pr o gressi ve disease  b 
≥ 2 0 % i ncrease i n t he s u m dia meters relati ve t o t he s mallest s u m 
dia meters rec or de d (i ncl u di n g t he baseli ne s u m dia meters) i n 
c o nj u ncti o n wit h a n i ncrease of at l east 5 m m i n t hat s mallest s u m 
dia meters, or t he a p peara nce of 1 or m ore ne w lesi o ns  c,e 
a F or ea c h pat h ol o gi c al l y m p h n o de c o nsi dere d a tar get l esi o n, t he n o de m ust ha ve a s h ort a xis m eas uri n g < 1 0  m m  
t o be  c o nsi dere d as a c o m pl ete res p o nse. I n s uc h c ase s, t he s u m di a m et ers  m a y  n ot  be  z er o (a n or m al l y m p h n o de 
c a n ha ve a s h ort a xis of < 1 0  m m).  
b F or  e ac h pat h ol o gic al  l y m p h n o de  c o nsi dere d a  t ar get lesi o n, t he m eas ure me nt  of  t he s h ort a xis of  t he n o de is t o be  
i ncl u de d i n t he s u m dia meters  w he n  det er mi ni n g  partial  res p o nse, sta bl e dise ase,  a n d pr o gressi o n. 
c I n t his st u d y, t he “ baseli ne  s u m di a m et er ” is c al c ul at e d  base d  o n  t he lesi o n m eas ure me nts  o btai ne d  at scree ni n g. 
d D urati o n of st a bl e dise ase is  m eas ure d  fr o m t he dat e  of  t he first d ose  of  st u d y tre at me nt u ntil  criteria  f or 
pr o gressi ve  disease  are met  base d  o n  t he s m allest s u m di a m eters  rec or de d (i ncl u di n g t he baseli ne  s u m dia meters).  
e T he  fi n di n g of  a ne w  l esi o n s h o ul d be  u ne q ui v oc al  a n d n ot  p ossi bl y  attri b ut a bl e t o a differe nce  i n i m a gi n g 
m o dalit y  or  sca n ni n g t ec h ni q ue. P ost -baseli ne , fl u or o de o x y gl uc ose p ositr o n e missi o n t o m o gra p h y (F D G -P E T)  m a y  
be  usef ul  i n assessi n g  ne w  l esi o ns a p pare nt o n c o m p ut eri ze d t o m o gra p h y ( C T) sca n.  
 
1 0. 3. 2. 3  
E v al u ati o n of N o nt ar get Lesi o ns  
N o ntar get lesi o ns will b e e val uate d a n d res p o nse rec or de d as defi ne d i n A p pe n di x T a ble 2 . 

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A p pe n di x T a ble 2 :  Res p o nse B ase d o n E v al u ati o n of N o nt ar get Lesi o ns at E ac h 
Assess m e nt  
C o m plete res p o nse  
Disa p peara nc e of all n o n -tar get lesi o ns; all l y m p h n o des m ust be 
n o n pat h ol o gic al i n size (ie, <  1 0  m m o n t he s h ort a xis)  
N ot c o m plete res p o nse or  
n ot pr o gressi ve disease  
P ersiste nce of 1 or m ore n o n -tar get lesi o ns 
Pr o gressi ve disease  
U ne q ui v ocal pr o gressi o n  a of a n y e xisti n g n o n -tar get lesi o n or t he 
a p peara n ce of 1 or m ore ne w lesi o ns  b 
a T he partici pa nt s h o ul d st o p st u d y i nter ve nti o n, e ve n i n t he prese nce of a partial res p o nse or st a bl e dise ase, base d 
o n assess m e nt of t ar get lesi o ns.  
b T he  fi n di n g of a ne w l esi o n s h o ul d be u ne q ui v ocal a n d n ot p ossi bl y attri b uta ble t o a differe nce i n i m a gi n g 
m o dalit y or sc a n ni n g te c h ni q ue. P ost -baseli ne, fl u or o de o x y gl uc ose p ositr o n e missi o n t o m o gra p h y ( F D G -P E T)  
m a y be usef ul i n assessi n g ne w lesi o ns a p pare nt  o n c o m p ut eri z e d t o m o gra p h y ( C T) sca n.  
 
1 0. 3. 2. 4  
Ne w Lesi o ns  
T he a p pear a nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he 
i de ntificati o n of ne w r a di o gr a p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be 
u ne q ui v ocal, ie, n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y , or fi n di n gs t h o u g ht t o r e pr ese nt s o met hi n g ot her t ha n t u m or (e g, s o me “ne w ” b o ne 
lesi o ns ma y be si m pl y heali n g or flar e -u p  of pre -e xisti n g lesi o ns). T his is partic ularl y i m p orta nt 
w he n t he partici pa nt’s baseli ne lesi o ns s h o w P R or C R. F or e xa m ple, necr osis of a li ver lesi o n 
ma y be r e p orte d o n a C T sca n as a “ne w ” c ystic lesi o n, w hic h it is n ot. 
1 0. 3. 3  
E v al u ati o n of O ver all Res p o ns e  
O ver all r es p o nse base d o n t he e val uati o n of tar get a n d n o ntar get lesi o ns will be deter mi ne d as 
s h o w n i n A p pe n di x T a ble 3 . 
A p pe n di x T a ble 3 :  E v al u ati o n of O ver all Res p o nse at E ac h Assess me nt  
T ar get L esi o ns  
N o nt ar get L esi o ns  
Ne w L esi o ns  
O ver all Res p o nse  
C o m plete res p o nse  
C o m plete res p o nse  
N o  
C o m plete res p o nse  
N o tar get lesi o n a 
C o m plete res p o nse  
N o  
C o m plete res p o nse  
C o m plete res p o nse  
N ot e val ua ble b 
N o  
P artial res p o nse  
C o m plete res p o nse  
N ot c o m plete res p o nse/  
n o n -pr o gressi ve disease  
N o  
P artial res p o nse  
P artial res p o nse  
N o n -pr o gressi ve disease a n d  
n ot e val ua ble b 
N o  
P artial res p o nse  
Sta ble disease  
N o n -pr o gressi ve disease a n d  
n ot e val ua ble b 
N o  
Sta ble disease  

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T ar get L esi o ns  
N o nt ar get L esi o ns  
Ne w L esi o ns  
O ver all Res p o nse  
N ot all e val uate d  
N o n -pr o gressi ve disease  
N o  
N ot e val ua ble  
N o tar get lesi o n a 
N ot all e val uate d  
N o  
N ot e val ua ble  
N o tar get lesi o n a 
N o n -c o m plete res p o nse/ 
n o n -pr o gressi ve disease  
N o  
N o n -c o m plete res p o nse/  
n o n -pr o gressi ve disease  
Pr o gressi ve disease  
A n y  
Yes or n o  
Pr o gressi ve disease  
A n y  
Pr o gressi ve disease  
Yes or n o  
Pr o gressi ve disease  
A n y  
A n y  
Yes  
Pr o gressi ve disease  
N o tar get lesi o n a 
U ne q ui v ocal pr o gressi ve disease  
Yes or N o  
Pr o gressi ve disease  
N o tar get lesi o n a 
A n y  
Yes  
Pr o gressi ve disease  
a Defi ne d as n o t ar get lesi o ns at baseli ne.  
b N ot e val ua bl e is defi ne d as eit her w he n n o or o nl y a s u bset of lesi o n me as ure m e nts are ma de at a n assess m e nt. 
 

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1 0. 4  
A P P E N DI X 4 : C LI NI C A L L A B O R A T O R Y T E S T S  
•  Pr ot oc ol -s pecific r e q uir e me nts f or i ncl usi o n or e xcl usi o n of partici pa nt s are detaile d i n 
Secti o n 5  of t he pr ot oc ol.  
•  A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d necessar y 
b y t he In vesti gat or or r e q uir e d b y l ocal re g ulati o ns.  
•  I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort. 

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1 0. 5  
A P P E N DI X 5 : A D V E R S E E V E N T S: D E FI NI TI O N S A N D 
P R O C E D U R E S F O R R E C O R DI N G, E V A L U A TI N G, 
F O L L O W -U P, A N D R E P O R TI N G  
1 0. 5. 1  
Defi niti o ns  
1 0. 5. 1. 1  
Defi niti o n of A E  
A E Defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt , te m p orall y ass ociate d wit h t he 
use of st u d y i nter ve nti o n, w het her or n ot c o nsi dere d relate d t o t he st u d y i nter ve nti o n. 
•  N O T E: A n A E ca n t her ef or e be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n  
a b n or mal la b or at or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y 
ass ociate d wit h t he use of a st u d y i nter ve nti o n. 
 
E ve nts Meeti n g  t he A E Defi niti o n  
•  A n y a b n or malit y or deteri or ati o n i n la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, 
or uri nal ysis) or ot her saf et y assess me nts (e g, E C G, ra di ol o gical sca ns, vital si g ns 
meas ur e me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, w hic h is  c o nsi dere d cli nicall y 
si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he In ve sti gat or. 
•  E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncr ease i n fr e q ue nc y a nd/ or i nte nsit y of t he c o n diti o n . 
•  A n e w c o n diti o n detecte d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h 
it ma y ha ve bee n pr ese nt bef or e t he start of t he st u d y. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve ntio n  or a c o nc o mita nt me dicati o n.  
•  Seri o us e ve nts t hat ar e r elate d t o a pr ot oc ol -ma n date d i nter ve nti o n, i ncl u di n g t h ose t hat 
occ ur pri or t o assi g n me nt of st u d y pr oce d ures (e g, scree ni n g i n vasi ve pr oce d ures, s uc h as 
bi o psies , disc o nti n uati o n of st u d y i nter ve nti o n). 
•  A n y ne w ca ncer (t hat is n ot a c o n diti o n of t he st u d y).  
•  N ote: Pr o gr essi o n of t he ca ncer u n der st u d y is n ot a re p orta ble e ve nt. Refer t o 
Secti o n  8. 3. 6  f or a d diti o nal details. 
 

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E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  Me dical or s ur gical pr oce d ur e ( e g, e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds t o 
t he pr oce d ur e is t he A E. 
•  Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
•  A ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t he st u d y t hat d o n ot w orse n.  
•  S ur ger y pla n ne d pri or t o i nf or me d c o nse nt t o treat a  pre -e xisti n g c o n diti o n t hat has n ot 
w orse ne d.  
 
1 0. 5. 1. 2  
Defi niti o n of S A E  
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us c o n diti o ns 
ar e met. 
A n  S A E is defi ne d as a n y A E  t h at s u g gests a si g nific a nt h az ar d, c o ntr ai n dic ati o n, si de 
eff ect, or u nt o w ar d m e dic al occ urre nce t h at, at a n y d ose:  
a.  
Res ults i n de at h  
b.  
Is lif e-t hre at e ni n g 
T he ter m “lif e-t hr eate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
pa rtici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heticall y mi g ht ha ve ca use d deat h, if it were m ore se vere.  
c.  
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
I n ge ner al, h os pitalizati o n si g nifies t hat t he partici pa nt  has bee n detai ne d at t he h os pital or 
e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s office or o ut patie nt setti n g. H os pitalizati o n is defi ne d  as a n i n patie nt a d missi o n, 
r e 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 s f or t he f oll o wi n g reas o ns are n ot c o nsi dere d S A Es i n t his st u d y: 
•  a visit t o t he e mer ge nc y r o o m or ot her h os pital de part me nt f or < 2 4 h o urs t hat d oes n ot 
r es ult i n a d missi o n ( u nless c o nsi dere d a n i m p orta nt me dical or life-t hreate ni n g e ve nt) 
•  electi ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt  
•  a d missi o ns as per pr ot oc ol f or a pla n ne d me dical/s ur gical pr oce d ure  
•  r o uti ne healt h assess me nt r e q uiri n g a d missi o n f or baseli ne/tre n di n g of healt h stat us 
( e g, r o uti ne c ol o n osc o p y) 

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•  me dical/s ur gical a d missi o n ot her t ha n t o re me d y ill healt h a n d pla n ne d pri or t o e ntr y 
i nt o t he st u d y. A p pr o priate d oc u me ntati o n is re q uire d i n t hese cases 
•  a d missi o n e nc o u nter e d f or a n ot her life circ u msta nce t hat carries n o beari n g o n healt h 
stat us a n d r e q uir es n o me dical/s ur gical i nter ve nti o n (e g, lac k of h o usi n g, ec o n o mic 
i na de q uac y, car e gi ver r es pite, fa mil y circ u msta nces, a d mi nistrati ve reas o n). 
d.  
Res ults i n persist e nt or si g nific a nt dis a bilit y/i nc a p acit y  
•  T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal 
lif e f u ncti o ns. 
•  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na us ea, v o miti n g, diarr hea, i nfl ue nza, a n d 
acci de ntal tr a u ma ( e g, s pr ai ne d a n kle) , w hic h ma y i nterfere wit h or pre ve nt e ver y da y life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
e.  
Is a c o n ge nit al a n o m al y/ birt h defect  
In offs pri n g of a partici pa nt e x p ose d t o  t he st u d y i nter ve nti o n re gar dless of ti mi n g as 
deter mi ne d f or st u d y i nter ve nti o n base d o n pr o d uct half -life. A n y  s p o nta ne o us a b orti o n s h o ul d 
be r e p orte d i n t he sa me f as hi o n ( as t he S p o ns or c o nsi ders s p o nta ne o us a b orti o ns t o be 
me dicall y si g nifica nt).   
f. 
Ot her i m p ort a nt m e dic al e ve nts:  
•  Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y lif e-t hr eate ni n g or r es ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
partici pa nt  or ma y r e q uir e me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d us uall y be c o nsi dere d seri o us.  
E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot r es ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use . 
 
1 0. 5. 1. 3  
Defi niti o n of U ne x pecte d A E  
U ne x pect e d A E Defi niti o n  
•  A n y A E, t he s pecificit y or se verit y of w hic h is n ot c o nsiste nt wit h t he c urre nt I n vesti gat or 
Br oc h ur e. E x pecte d mea ns t hat t he e ve nt has pre vi o usl y bee n o bser ve d wit h t he st u d y 
i nter ve nti o n a n d is i de ntifie d a n d/ or descri be d i n t he c urre nt I B. It d oes n ot mea n t hat t he 
e ve nt is e x pecte d wit h t he u n derl yi n g disease(s), c o -m or bi dities , or c o nc o mita nt 
me dicati o ns.  
 

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Defi niti o n of Tre at m e nt -e m er ge nt A E  
Tre at m e nt -e m er ge nt A E Defi niti o n 
•  A n y u nf a v or a ble a n d u ni nte n de d dia g n osis, s y m pt o m, si g n (i ncl u di n g a n a b n or mal 
la b or at or y fi n di n g t hat is c o nsi dere d t o be cli nicall y si g nifica nt), s y n dr o me, or disease t hat 
eit her occ urs d uri n g t he st u d y, ha vi n g bee n a bse nt at baseli ne, or , if prese nt at baseli ne, 
a p pears t o ha ve w orse ne d i n se verit y or fre q ue nc y, w het her or n ot t he e ve nt is c o nsi der e d 
r elate d t o t he st u d y i nter ve nti o n. 
 
1 0. 5. 2  
A d diti o n al E ve nts R e p orte d i n t he S a m e M a n ner as a n  S A E  
A d diti o n al E ve nts Re p ort e d i n t he S a me M a n ner as a n  S A E  
•  I n a d diti o n t o t he S A E criteria i n Secti o n  1 0. 5. 1. 2 , A Es  meeti n g a n y of t he bel o w criteria, 
alt h o u g h n ot seri o us per I C H defi niti o n, are re p orta ble t o t he S p o ns or i n t he sa me 
ti mefr a me as S A Es t o meet certai n l ocal re q uire me nts. T heref ore, t hese e ve nts are 
c o nsi der e d seri o us b y t he S p o ns or f or c ollecti o n p ur p oses.  
o  A  ne w ca ncer ( n ot t he i n dicate d c o n diti o n of t he st u d y)  
o  A n o ver d ose or is a n ass ociate d  e ve nt t hat meets safet y criteri o n wit h a n 
o ver d ose  ( as s pecifie d i n Secti o n 8. 4 ). 
o  Pr e g na nc y ( as s pecifie d i n Secti o n  8. 3. 5 ) 
 
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Rec or di n g A E s a n d S A E s 
A E a n d S A E Rec or di n g  
•  W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he In vesti gat or t o re vie w all 
d oc u me ntati o n ( e g, h os pital pr o gr ess n otes, la b orat or y, a n d dia g n ostics re p orts) relate d t o 
t he e ve nt. O nl y a si n gle A E  ter m s h o ul d be rec or de d f or t he e ve nt. 
•  T he In vesti gat or will r ec or d all r ele va nt A E/ S A E i nf or mati o n i n t he e C R F.  
•  It is n ot  acce pta ble f or t he In vesti gat or t o se n d p h ot oc o pies of t h e partici pa nt ’s me dical 
r ec or ds t o t he S p o ns or i n lie u of c o m pleti o n of t he Ad verse E ve nt / Seri o us A d verse E ve nt  
eC R F pa ge.  
•  T her e ma y be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y 
t he S p o ns or. I n t his case, all partici pa nt  i de ntifiers, wit h t he e xce pti o n of t he partici pa nt  
n u m ber, will be r e dacte d o n t he c o pies of t he me dical rec or ds bef ore s u b m issi o n t o t he 
S p o ns or.  

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•  T he In vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. I n s uc h cases, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E.  
Ass ess m e nt of Se verit y 
•  T he ter ms “se ver e” a n d “seri o us” are n ot s y n o n y m o us. A n e ve nt is defi ne d as “seri o us” 
w he n it meets at least 1 of t he pr e defi ne d o utc o mes as descri be d i n t he defi niti o n of a n 
S A E, N O T  w he n it is r ate d as se vere.  Se verit y (i nte nsit y) a n d seri o us ness nee d t o be 
i n de pe n de ntl y assesse d f or eac h A E  rec or de d o n t he e C R F. 
•  T he In vesti gat or will assess t he i nte nsit y f or eac h A E a n d S A E (a n d ot her re p orta ble safet y 
e ve nts) acc or di n g t o t he N CI C T C A E, versi o n 5 . 0, w hic h ca n be f o u n d at: 
htt p://cte p. ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m. T he 
f oll o wi n g gr a di n g will be use d f or assessi n g i nte nsit y f or A Es  n ot s pecificall y liste d i n t he 
N CI C T C A E:  
o  Gr a de 1: Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic 
o bser vati o ns o nl y; i nter ve nti o n n ot i n dicate d.  
o  Gr a de 2: M o der ate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; 
li miti n g a ge-a p pr o priate i nstr u me ntal acti vities of dail y li vi n g.  
o  Gr a de 3: Se ver e or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-car e acti vities of dail y li vi n g. 
o  Gr a de 4: Lif e t hr eate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d.  
o  Gr a de 5: Deat h r elate d t o A E.  
•  A n y A E  t hat c ha n ges C T C A E gr a de o ver t he c o urse of a gi ve n e pis o de (ie, persiste nt A E ) 
will ha ve eac h c ha n ge of gr a de r ec or de d o n t he A d verse E ve nt  e C R F . 
Assess m e nt of C a us alit y  
•  T he In vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h 
occ urr e nc e of eac h A E/ S A E. 
•  A “r eas o na ble p ossi bilit y” of a r elati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal r elati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut.  
•  T he In vesti gat or will use t heir cli nical j u d g me nt, k n o wle d ge of t he partici pa nt , t he 
cir c u msta nces s urr o u n di n g t he e ve nt, a n d a n e val uati o n of a n y p ote ntial alter nati ve ca uses 
t o deter mi ne t he r elati o ns hi p. 
•  T he f oll o wi n g g ui da nce will be c o nsi dere d a n d i n vesti gate d:  
o  T e m p or al r elati o ns hi p of t he e ve nt o nset t o st u d y i nter ve nti o n a d mi nistrati o n 

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o  C o urse of t he e ve nt, wit h s pecial c o nsi derati o n of t he effects of d ose re d ucti o n, 
disc o nti n uati o n of st u d y i nter ve nti o n, or rei ntr o d ucti o n of st u d y i nter ve nti o n (as 
a p plica ble)  
o  K n o w n ass ociati o n of t he e ve nt wit h t he st u d y i nter ve nti o n or wit h si milar 
tr eat me nts 
o  K n o w n ass ociati o n of t he e ve nt wit h t he disease u n der st u d y  
o  Pr ese nce of ris k f act ors i n t he partici pa nt  or use of c o nc o mita nt me dicati o ns 
k n o w n t o i ncr ease t he occ urre nce of t he e ve nt  
o  Pr ese nce of n o n -tr eat me nt-relate d fact ors t hat are k n o w n t o be ass ociate d wit h 
t he occ urr e nce of t he e ve nt 
•  T he In vesti gat or will als o c o ns ult t he I n vesti gat or ’s Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n his/ her assess me nt. 
•  F or eac h A E/ S A E, t he In vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he has 
r e vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
•  T her e ma y be sit uati o ns i n w hic h  a n S A E has occ urre d a n d t he In vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or. H o we ver, it is ver y i m p orta nt 
t hat t he In vesti gat or al wa ys ma ke a n assess me nt of ca usalit y f or e ver y e ve nt bef ore t he 
i nitial tr a ns missi o n of t he S A E data t o t he S p o ns or. 
•  T he In vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n 
a n d se n d an  S A E f oll o w -u p r e p ort wit h t he u p date d ca usalit y assess me nt.  
•  T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
r e q uir e me nts. 
•  F or st u dies i n w hic h m ulti ple a ge nts are a d mi nistere d as part of a c o m bi nati o n re gi me n, 
t he In vesti gat or ma y attri b ute eac h A E  ca usalit y t o t he c o m bi nati o n re gi me n or t o a si n gle 
a ge nt of t he c o m bi nati o n. I n ge nera l, ca usalit y attri b uti o n s h o ul d be assi g ne d t o t he 
c o m bi nati o n r e gi me n (ie, t o all a ge nts i n t he re gi me n). H o we ver, ca usalit y attri b uti o n ma y 
be assi g ne d t o a si n gle a ge nt if , i n t he In vesti gat or’s o pi ni o n, t here are s ufficie nt data t o 
s u p p ort f ull attri b uti o n of t he A E  t o t he si n gle a ge nt. 
Is t he A E  s us pecte d t o be ca use d b y t he st u d y i nter ve nti o n o n t he basis of facts, e vi de nce, 
scie nce-bas e d r ati o nales, a n d cli nical j u d g me nt?  
•  Yes: T her e is a pla usi ble te m p or al relati o ns hi p bet wee n t he o nset of t he A E  a nd 
a d mi nistr ati o n of t he st u d y i nter ve nti o n, a n d t he A E  ca n n ot be rea dil y e x plai ne d b y t he 
partici pa nt ’s cli nical state, i nter c urre nt ill ness, or c o nc o mita nt t hera pies; a n d/ or t he A E  
f oll o ws a k n o w n patter n of r es p o nse t o t he st u d y i nter ve nti o n; a n d/ or t he A E  a bates or 
r es ol ves u p o n disc o nti n uati o n of t he st u d y i nter ve nti o n or d ose re d ucti o n a n d, if 
a p plica ble, r ea p pears u p o n r e -c halle n ge. 
•  N o: A n A E  will be c o nsi der e d r elate d, u nless it f ulfills t he f oll o wi n g criteria: E vi de nce 
e xists t hat t he A E  has a n eti o l o g y ot her t ha n t he st u d y i nter ve nti o n (e g, pre-e xisti n g 
me dical c o n diti o n, u n derl yi n g disease, i nterc urre nt ill ness, or c o nc o mita nt me dicati o n); 

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a n d/ or t he A E  has n o pla usi ble te m p oral relati o ns hi p t o a d mi nistrati o n of t he st u d y 
i nter ve nti o n ( e g, ca ncer dia g n ose d 2 da ys after first d ose of st u d y i nter ve nti o n). 
F oll o w -u p of A E s a n d S A E s 
•  T he In vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ur e me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y t he S p o ns or t o 
el uci date t he nat ur e a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble. T his ma y 
i ncl u de a d diti o nal la b or at or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or 
c o ns ultati o n wit h ot her healt h care pr ofessi o nals.  
•  Ne w or u p date d i nf or mati o n will be rec or de d o n  t he eC R F.  
•  T he In vesti gat or will s u b mit a n y u p date d data relate d t o S A E s t o t he S p o ns or wit hi n 2 4 
h o urs of r ecei pt of t he i nf or mati o n.  
 
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Re p orti n g of A Es, S A Es, a n d Ot her Re p ort a ble S afet y E ve nts t o 
t he S p o ns or 
Re p orti n g of A E s, S A Es, a n d Ot her Re p ort a ble S afet y E ve nts t o t he S p o ns or vi a a n 
Elect r o nic D at a C ollecti o n T o ol   
•  T he pri mar y mec ha nis m f or r e p orti n g A Es t o t he S p o ns or will be via electr o nic data 
c ollecti o n ( E D C) t o ol. 
•  Electr o nic r e p orti n g pr oce d ur es ca n be f o u n d i n t he E D C data e ntr y g ui deli nes ( or 
e q ui vale nt). 
•  If t he electr o nic s yste m is u na vaila ble f or m ore t ha n 2 4 h o urs, t he n t he site will use t he 
pa per A E r e p orti n g t o ol (see ne xt secti o n).  
•  Ref er e nce S ecti o n 8. 3. 1 –  Ti me Peri o d a n d Fre q ue nc y f or C ollec ti n g A E, S A E , a n d Ot her 
Re p orta ble Saf et y E ve nt I nf or mati o n f or re p orti n g ti me re q uire me nts  
•  After t he st u d y is c o m plete d at a gi ve n site, t he E D C  t o ol will be ta ke n off-li ne t o pre ve nt 
t he e ntr y of ne w data or c ha n ges t o e xisti n g data. 
•  T he site will r e p ort all S A E data t o t he Par ker I nstit ute f or Ca ncer I m m u n ot hera p y 
P har mac o vi gila nce Gr o u p  wit hi n 2 4 h o urs of site a ware ness . 
•  C o ntacts f or S A E a n d ot her r e p orta ble seri o us safet y e ve nt re p orti n g ca n be f o u n d i n 
Secti o n  8. 3. 8. 2 . 
 

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S A E a n d Ot her Re p ort a ble S af et y E ve nt Re p orti n g t o t he S p o ns or  
•  I n t he i nsta nce w her e a n S A E occ urs, a facsi mile tra ns missi o n of t he S A E  R e p ort F or m  
a n d/ or Pr e g na nc y f or m is t he pr eferre d met h o d t o tra ns mit t his i nf or mati o n t o t he Par ker 
I nstit ute f or Ca ncer I m m u n ot her a p y P har mac o vi gila nce Gr o u p. 
•  I n r ar e cir c u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y tele p h o ne 
is acce pta ble wit h a c o p y of t he S A E  R e p ort F or m  se nt via e mail . 
•  I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he In vesti gat or t o c o m plete 
a n d si g n t he S A E  R e p ort F or m  wit hi n t he desi g nate d re p orti n g ti me fra mes.  
•  C o ntacts f or S A E a n d ot her r e p orta ble safet y e ve nt re p orti n g  ca n be f o u n d i n 
Secti o n  8. 3. 8. 2 . 
 
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A d diti o n al Re p orti n g C o nsi der ati o ns  
A E a n d S A E Rec or di n g f or S peci al Circ u mst a nces  
Di a g n osis vers us Si g ns a n d S y m pt o ms  
•  A dia g n osis (if k n o w n)  or ca use of deat h  s h o ul d be rec or de d o n t he A d verse E ve nt e C R F 
r at her t ha n i n di vi d ual si g ns a n d s y m pt o ms (e g, rec or d o nl y li ver fail ure or he patitis rat her 
t ha n ja u n dice, asteri xis, a n d ele vate d tra nsa mi nases). 
•  If a c o nstellati o n of si g ns a n d/ or s y m pt o ms ca n n ot be me dically c haracterize d as a si n gle 
dia g n osis or s y n dr o me at t he ti me of re p orti n g, eac h i n di vi d ual e ve nt s h o ul d be rec or de d 
se par atel y o n t he A d verse E ve nt e C R F  pa ge.  
•  If a dia g n osis is s u bse q ue ntl y esta blis he d, all pre vi o usl y re p orte d A E s base d o n si g ns a n d 
s y m pto ms s h o ul d be n ullifie d a n d re place d b y o ne A E  re p ort base d o n t he si n gle dia g n osis, 
wit h a starti n g date t hat c orr es p o n ds t o t he starti n g date of t he first s y m pt o m of t he 
e ve nt ual dia g n osis.  
A d verse E ve nts T h at Are Sec o n d ar y t o Ot her E ve nts  
•  I n ge ner al, A E s t hat ar e sec o n dar y t o ot her e ve nts (e g, casca de e ve nts or cli nical se q uelae) 
s h o ul d be i de ntifie d b y t heir pri mar y ca use, wit h t he e xce pti o n of se vere or seri o us 
sec o n dar y e ve nts. A me dicall y si g nifica nt sec o n dar y A E  t hat is se parate d i n time fr o m t he 
i nitiati n g e ve nt s h o ul d be r ec or de d as a n i n de pe n de nt e ve nt o n t he A d verse E ve nt e C R F 
pa ge . F or e xa m ple: 
o  If v o miti n g r es ults i n mil d de h y drati o n wit h n o a d diti o nal treat me nt i n a healt h y 
a d ult, o nl y v o miti n g s h o ul d be re p orte d o n t he e C R F.  
o  If vo miti n g r es ults i n se vere de h y drati o n, b ot h e ve nts s h o ul d be re p orte d 
se par atel y o n t he e C R F. 

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o  If a se ver e gastr oi ntesti nal he m orr ha ge lea ds t o re nal fail ure, b ot h e ve nts s h o ul d 
be r e p orte d se par atel y o n t he e C R F.  
o  If dizzi ness lea ds t o a fall a n d c o nse q ue nt fract ure, all 3 e ve nts s h o ul d be 
r e p orte d se par atel y o n t he e C R F. 
o  If ne utr o pe nia is acc o m pa nie d b y a n i nfecti o n, b ot h e ve nts s h o ul d be re p orte d 
se par atel y o n t he e C R F. 
•  All A E s s h o ul d be r ec or de d se paratel y o n t he A d verse E ve nt e C R F pa ge if it is u nclear 
as t o w het her t he e ve nts ar e ass ociate d.  
P ersist e nt or Rec urre nt A d verse E ve nts  
•  A persiste nt A E  is o ne t hat e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n partici pa nt  
e val uati o n ti me p oi nts. S uc h e ve nts s h o ul d o nl y be rec or de d o nce o n t he A d verse E ve nt 
e C R F  pa ge . T he i nitial se verit y (i nte nsit y or gra de) of t he e ve nt will be rec or de d at t he 
ti me t he e ve nt is first r e p orte d. 
•  If a persiste nt A E  bec o mes m or e se vere, t he m ost e xtre me se verit y s h o ul d als o be rec or de d 
o n t he A d verse E ve nt e C R F  pa ge , a n d details re gar di n g a n y i ncreases or decreases i n 
se verit y will be ca pt ur e d o n t he A d verse E ve nt Gra de C ha n ges e C R F.  
•  If t he e ve nt bec o mes seri o us, it s h o ul d be re p orte d t o t he S p o ns or as an  S A E, a n d t he 
A d verse E ve nt e C R F  pa ge  s h o ul d be u p date d b y c ha n gi n g t he e ve nt fr o m “n o n -seri o us” t o 
“seri o us,” pr o vi di n g t he date t hat t he e ve nt beca me seri o us a n d c o m pleti n g all data fiel ds 
r elate d t o S A E s. 
•  A r ec urr e nt A E  is o ne t hat r es ol ves bet wee n partici pa nt  e val uati o n ti me p oi nts a n d 
s u bse q ue ntl y r ec urs. E ac h r ec urr e nce of a n A E  s h o ul d be rec or de d as a se parate e ve nt o n 
t he A d verse E ve nt e C R F pa ge . 
A b n or m al L a b or at or y V al ues  
•  A cli nical la b or at or y test val ue m ust be re p orte d as a n A E  if it meets a n y of t he f oll o wi n g 
criteria: 
o  is acc o m pa nie d b y cli nical s y m pt o ms 
o  r es ults i n a c ha n ge i n st u d y i nter ve nti o n (e g, d ose m o dificati o n, treat me nt 
i nterr u pti o n, or tr eat me nt disc o nti n uati o n) 
o  r es ults i n a me dical i nter ve nti o n or c ha n ge i n c o nc o mita nt me dicati o n 
o  is cli nicall y si g nifica nt i n t he In vesti gat or’s j u d g me nt  

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A b n or m al Vit al Si g n V al ues  
•  Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her a n is olate d vital 
si g n a b n or malit y s h o ul d be classifie d as a n A E . 
•  If a cli nicall y si g nifica nt vital si g n a b n or malit y is a si g n of a disease or s y n dr o me (e g, hi g h 
bl o o d pr ess ur e), o nl y t he dia g n osis (ie, h y perte nsi o n) s h o ul d be rec or de d o n t he A d verse 
E ve nt e C R F  pa ge . 
•  O bser vati o ns of t he sa me cli nicall y si g nifica nt vital si g n a b n or malit y fr o m visit t o visit 
s h o ul d o nl y be r ec or de d o nce o n t he A d verse E ve nt e C R F pa ge  (see a b o ve f or details o n 
r ec or di n g persiste nt A Es ). 
A b n or m al Li ver F u ncti o n Tests  
•  T he fi n di n g of a n ele vate d A L T or A S T ( > 3  x baseli ne val ue) i n c o m bi nati o n wit h eit her 
a n ele vate d t otal bilir u bi n ( >  2 x U L N) or cli nical ja u n dice i n t he a bse nce of c h olestasis or 
ot her ca uses of h y per bilir u bi ne mia is c o nsi dere d t o be a n i n dicat or of se vere li ver i nj ur y 
( as defi ne d b y H y's La w). T her ef ore, In vesti gat ors m ust re p ort as a n A E  t he occ urre nce of 
eit her of t he f oll o wi n g: 
o  Tr eat me nt -e mer ge nt A L T or A S T > 3 x baseli ne val ue i n c o m bi nati o n wit h 
t otal bilir u bi n > 2 x U L N ( of w hic h ≥ 3 5 % is direct bilir u bi n) 
o  Tr eat me nt -e mer ge nt A L T or A S T > 3 x baseli ne val ue i n c o m bi nati o n wit h 
cli nical ja u n dice 
•  T he m ost a p pr o priate dia g n osis or , if a dia g n osis ca n n ot be esta blis he d, t he a b n or mal 
la b or at or y val ues s h o ul d be r ec or de d o n t he A d verse E ve nt e C R F pa ge  a n d re p orte d t o t he 
S p o ns or i m me diatel y as a n  S A E . 
L ac k of Effic ac y or W orse ni n g of  U n derl yi n g Dise ase  
•  E ve nts t hat ar e clearl y c o nsiste nt wit h t he e x pecte d patter n of pr o gressi o n of t he 
u n derl yi n g disease s h o ul d n ot be rec or de d as A E s. T hese data will be ca pt ure d as efficac y 
assess me nt data o nl y. I n m ost cases, t he e x pecte d patter n of pr o gressi o n will be base d o n 
R E CI S T. I n r ar e cases, t he deter mi nati o n of cli nical pr o gressi o n will be base d o n 
s y m pt o matic deteri or ati o n. H o we ver, e ver y eff ort s h o ul d be ma de t o d oc u me nt pr o gressi o n 
t hr o u g h use of o bjecti ve criteria. If t here is a n y u ncertai nt y as t o w het her a n e ve nt is d ue t o 
disease pr o gr essi o n, it s h o ul d be re p orte d as a n A E.  
De at hs  
•  All deat hs t hat occ ur d uri n g t he pr ot oc ol -s pecifie d A E  re p orti n g peri o d, re gar dless of 
r elati o ns hi p t o st u d y i nter ve nti o n, m ust be rec or de d o n t he Deat h  e C R F pa ge a n d 
i m me diatel y r e p orte d t o t he S p o ns or (see Secti o n 8. 3. 1 ), u nless t he deat h is  attri b ute d t o 
pr o gr essi o n of disease.  
•  Deat h s h o ul d be c o nsi der e d a n o utc o me a n d n ot a disti nct e ve nt. T he e ve nt or c o n diti o n 
t hat ca use d or c o ntri b ute d t o t he fatal o utc o me s h o ul d be rec or de d as t he si n gle me dical 

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c o nce pt o n t he A d verse E ve nt e C R F  pa ge . Ge nerall y, o nl y o ne s uc h e ve nt s h o ul d be 
r e p orte d. 
•  If t he ca use of deat h is u n k n o w n a n d ca n n ot be ascertai ne d at t he ti me of re p orti n g, 
“u ne x plai ne d deat h ” s h o ul d be r ec or de d o n t he A d verse E ve nt e C R F pa ge . 
•  If t he ca use of deat h later bec o mes a vaila ble (e g, after a ut o ps y), “u ne x plai ne d deat h ” 
s h o ul d be r e place d b y t he esta blis he d ca use of deat h. 
•  T he ter m “s u d de n deat h” s h o ul d n ot be use d u nless c o m bi ne d wit h t he pres u me d ca use of 
deat h ( e g, “s u d de n car diac deat h”). 
•  If t he deat h is attri b ute d t o pr o gr essi o n of u n derl yi n g disease, “ u n derl yi n g disease" s h o ul d 
be r ec or de d o n t he Deat h  e C R F  pa ge ; n o S A E f or m is necessar y. 
•  Deat hs t hat occ ur after t he A E r e p orti n g peri o d s h o ul d be re p orte d as descri be d i n 
Secti o n  8. 3. 2 . 
P re -e xisti n g Me dic al C o n diti o ns  
•  A pr e -e xisti n g me dical c o n diti o n is o ne t hat is prese nt at t he baseli ne visit f or t his st u d y. 
S uc h c o n diti o ns s h o ul d be r ec or de d o n t he Ge neral Me dical Hist or y a n d Baseli ne 
C o n diti o ns e C R F  pa ge . 
•  A pr e -e xisti n g me dical c o n diti o n s h o ul d be rec or de d as a n A E o nl y if t he fre q ue nc y, 
se verit y, or c har acter of t he c o n diti o n w orse ns d uri n g t he st u d y. W he n rec or di n g s uc h 
e ve nts o n t he A d verse E ve nt e C R F  pa ge , it is i m p orta nt t o c o n ve y t he c o nce pt t hat t he pre-
e xisti n g c o n diti o n has c ha n ge d b y i ncl u di n g a p plica ble descri pt ors ( e g, “m ore fre q ue nt 
hea dac hes ”). 
A d verse E ve nts Ass o ci at e d wit h O ver d ose or Err or i n Dr u g A d mi nistr ati o n  
•  A n o ver d ose is t he acci de ntal or i nte nti o nal use  of a dr u g i n a n a m o u nt hi g her t ha n t he 
d ose bei n g st u die d. A n o ver d ose or i nc orrect a d mi nistrati o n of st u d y i nter ve nti o n is n ot 
itself a n A E , b ut it ma y r es ult i n a n A E . All A Es  ass ociate d wit h a n o ver d ose or i nc orrect 
a d mi nistr ati o n of st u d y i nter ve nti o n s h o ul d be rec or de d o n t he A d verse E ve nt e C R F pa ge . 
•  If t he ass ociate d A E  f ulfills seri o us ness criteria, t he e ve nt s h o ul d be re p orte d t o t he 
S p o ns or as a se par ate S A E . 
 

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A P P E N DI X 6 : C O N T R A C E P TI V E G UI D A N C E A N D 
C O L L E C TI O N O F P R E G N A N C Y I N F O R M A TI O N  
1 0. 6. 1  
Defi niti o ns  
1 0. 6. 1. 1  
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  
A w o ma n is c o nsi der e d f ertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost -me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P  
1.  Pr e me nar c hal  
2.  Pr e me n o pa usal f e male wit h 1 of t he f oll o wi n g:  
o  D oc u me nte d h yster ect o m y  
o  D oc u me nte d bilater al sal pi n gect o m y  
o  D oc u me nte d bilater al o o p h orect o m y  
N ote:  D oc u me ntati o n ca n c o me fr o m t he site p ers o n nel’s re vie w of t he partici pa nt ’s 
me dical r ec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w.  
3.  P ost me n o pa usal f e male  
o  A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use. A hi g h f ollicle -sti m ulati n g h or m o ne le vel i n t he 
p ost me n o pa usal r a n ge ma y be use d t o c o nfir m a p ost me n o pa usal state i n w o me n 
n ot usi n g h or m o nal c o ntrace pti o n or H R T. H o we ver, i n t he a bse nce of 1 2 m o nt hs 
of a me n orr hea, a si n gle f ollicle-sti m ulati n g h or m o ne meas ure me nt is i ns ufficie nt.  
o  Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 
o ne of t he n o n -estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y 
wis h t o c o nti n ue t heir H R T d uri n g t he st u d y. Ot her wise, t he y m ust disc o nti n ue 
H R T t o all o w c o nfi r mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt. 
 
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C o ntr ace pti o n G ui d a nce  
1 0. 6. 2. 1  
M ale P artici p a nt s 
Male partici pa nts wit h f e male part ners of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y  
a gr ee t o O N E of t he f oll o wi n g: 
•  Ar e a bsti ne nt fr o m pe nil e-va gi nal i nterc o urse as t heir us ual a n d preferre d lifest yle 
( a bsti ne nt o n a l o n g-ter m a n d persiste nt basis) a n d a gree t o re mai n a bsti ne nt 
•  A gr ee t o use a male c o n d o m pl us part ner use of a c o ntrace pti ve met h o d wit h a fail ure rate 
of <  1 % per year as descri b e d i n A p pe n di x T a ble 4  w he n ha vi n g pe nile -va gi nal 
i nter c o urse wit h a W O C B P w h o is n ot c urre ntl y pre g na nt. 
 

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I n a d diti o n, male partici pa nt s m ust r efrai n fr o m d o nati n g s per m f or t he d urati o n of t he st u d y a n d 
f or 7  m o nt hs after t he last d ose of st u d y i nter ve nti o n. 
Male partici pa nt s wit h a pr e g na nt or breastfee di n g part ner m ust a gree t o re mai n a bsti ne nt fr o m 
pe nile va gi nal i nter c o urse or use a male c o n d o m d uri n g eac h e pis o de of pe nile pe netrati o n d uri n g 
t he pr ot oc ol-defi ne d ti me fr a me  a n d f or 7  m o nt hs after t he last d ose of st u d y i nter ve nti o n . 
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Fe m ale P artici p a nt s 
Fe male partici pa nt s of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o use a 
hi g hl y eff ecti ve met h o d of c o ntr ace pti o n c o nsiste ntl y a n d c orrectl y as descri be d i n A p pe n di x 
T a ble 4 . 
A p pe n di x T a ble  4 : Hi g hl y Eff ecti ve C o ntr ace pti ve Met h o ds  
Hi g hl y Eff ecti ve C o nt r ace pti ve Met h o ds T h at Are User De pe n de nt  a 
F ail ure r ate of <  1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly.  
C o m bi ne d ( estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o nb  
•  Or al  
•  I ntr a va gi nal  
•  Tr a ns der mal  
Pr o gest o ge n o nl y h or m o nal c o ntr ace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  Or al  
•  I njecta ble 
Hi g hl y Eff ecti ve Met h o ds T h at Are User I n de pe n de nt a 
I m pla nta ble pr o gest o ge n-o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b 
•  I ntr a uteri ne de vice (I U D) 
•  I ntr a uteri ne h or m o ne-r eleasi n g s yste m (I U S) 
•  Bilater al t u bal occl usi o n  
V asect o mize d p art ner   
A vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is 
t he s ole male se x ual part ner of t he W O C B P a n d t he a bse nce of s per m has bee n c o nfir me d. If 
n ot, a n a d diti o nal hi g hl y eff ecti ve met h o d of c o ntrace pti o n s h o ul d be use d.  
Se x u al a bsti ne nce   

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Se x ual a bsti ne nce is c o nsi der e d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m 
heter ose x ual i nter c o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y i nter ve nti o n. 
T he r elia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he 
st u d y a n d t he pr ef err e d a n d us ual lif est yle of t he partici pa nt . 
N O T E S:  
a)  T y pical use f ail ur e r ates ma y diff er fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use 
s h o ul d be c o nsiste nt wit h l ocal r e g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or 
partici pa nt s partici pati n g i n cli nical st u dies.  
b)  H or m o nal c o ntr ace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he st u d y i nter ve nti o n, 
w hic h ma y r e d uce t he efficac y of t he c o ntrace pti ve met h o d. I n t his case, 2 hi g hl y effecti ve 
met h o ds of c o ntr ace pti o n s h o ul d be utilize d d uri n g t he treat me nt peri o d a n d f or at least 
5  m o nt hs after t he last d ose of st u d y i nter ve nti o n. 
 
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Pre g n a nc y Testi n g  
•  W O C B P s h o ul d o nl y be i ncl u de d after a c o nfir me d me nstr ual peri o d a n d a ne gati ve 
hi g hl y se nsiti ve uri ne or ser u m pre g na nc y test  wit hi n 2 4 h o urs of first d ose . 
•  A d diti o nal pr e g na nc y testi n g s h o ul d be perf or me d e ver y c ycle d uri n g t he treat me nt 
peri o d  a n d wit hi n 2 4 h o urs pri or t o d osi n g . 
•  Pr e g na nc y testi n g will be perf or me d w he ne ver a me nstr ual c ycle is misse d or w he n 
pr e g na nc y is ot her wise s us pecte d . 
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C oll ecti o n of Pre g n a nc y I nf or m ati o n  
1 0. 6. 4. 1  
M ale P artici p a nt s wit h P art ners w h o B ec o m e P re g n a nt  
•  T he In vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male 
partici pa nt ’s f e male part ner w h o bec o mes pre g na nt w hile t he male partici pa nt  is i n 
t his st u d y. T his a p plies o nl y t o male partici pa nt s w h o recei ve st u d y i nter ve nti o n. 
•  After o btai ni n g t he necessar y si g ne d i nf or me d c o nse nt fr o m t he pre g na nt fe male 
part ner dir ectl y, t he In vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o priate 
f or m a n d s u b mit it t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of t he part ner’s 
pr e g na nc y. T he f e male part ner will als o be f oll o we d t o deter mi ne t he o utc o me of t he 
pr e g na nc y. I nf or mati o n o n t he stat us of t he m ot her a n d c hil d will be f or war de d t o t he 
S p o ns or. Ge ner all y, t he f oll o w -u p will  be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t he 
esti mate d deli ver y date. A n y ter mi nati o n of t he pre g na nc y will be re p orte d re gar dless 
of f etal stat us ( pr ese nce or a bse nce of a n o malies) or i n dicati o n f or t he pr oce d ure.  
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Fe m ale P artici p a nt s w h o B ec o m e P re g n a nt  
•  T he In vesti gat or will c ollect pre g na nc y i nf or mati o n o n a n y fe male partici pa nt  w h o 
bec o mes pr e g na nt w hile partici pati n g i n t his st u d y. I nf or mati o n will be rec or de d o n 
t he a p pr o priate f or m a n d s u b mitte d t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of a 
partici pa nt 's pr e g na nc y. T he partici pa nt  will be f oll o we d t o deter mi ne t he o utc o me of 

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t he pr e g na nc y. T he In vesti gat or will c ollect f oll o w -u p i nf or mati o n o n t he partici pa nt  
a n d t he ne o nate a n d t he i nf or mati o n will be f or war de d t o t he S p o ns or. Ge nerall y, 
f oll o w-u p will n ot be r e q uir e d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t he esti mate d 
deli ver y date. A n y ter mi nati o n of pre g na nc y will be re p orte d, re gar dless of fetal 
stat us ( pr ese nce or a bse nce of a n o malies) or i n dicati o n f or t he pr oce d ure. 
•  W hile pr e g na nc y itself is n o t c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o m plicati o n or electi ve ter mi nati o n of a pre g na nc y will be re p orte d as a n A E or 
S A E. A s p o nta ne o us a b orti o n is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d 
as s uc h. A n y p ost -st u d y pr e g na nc y-relate d S A E c o nsi dere d reas o na bl y relate d t o t he 
st u d y i nter ve nti o n b y t he In vesti gat or will be re p orte d t o t he S p o ns or as descri be d i n 
Secti o n  8. 3. 5 . W hile t he In vesti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n 
i n f or mer st u d y partici pa nt s, he or s he ma y lear n of a n S A E t hr o u g h s p o nta ne o us 
r e p orti n g.  
•  A n y f e male partici pa nt  w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y i nter ve nti o n. 

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A P P E N DI X 7 : G E N E TI C S 
Use/ A n al ysis of D N A  
•  Ge netic variati o n ma y i m pact a partici pa nt ’s res p o nse t o st u d y i nter ve nti o n, 
s usce pti bilit y t o, a n d se verit y a n d pr o gressi o n of disease. Varia ble res p o nse t o st u d y 
i nter ve nti o n ma y be d ue t o ge netic deter mi na nts t hat i m pact i m m u ne res p o nse, dr u g 
a bs or pti o n, distri b uti o n, meta b olis m, a n d e xcreti o n; mec ha nis m of acti o n of t he dr u g;  
disease eti ol o g y; a n d/ or m olec ular s u bt y pe of t he disease bei n g treate d. T heref ore, 
w her e l ocal r e g ulati o ns a n d I R B/I E C all o w, a bl o o d  a n d t u m or sa m ple will be 
c ollecte d f or D N A a nal ysis fr o m c o nse nti n g partici pa nt s. 
•  D N A sa m ples will be use d f or researc h relate d t o c hec k p oi nt i n hi bit or t hera p y  or  
ca ncer a n d/ or i m m u ne dis or ders  a n d relate d diseas es or e val uati o n of ne w assa y 
tec h n ol o gies. T he y ma y als o be use d t o de vel o p tests/assa ys i ncl u di n g dia g n ostic tests 
r elate d t o c hec k p oi nt i n hi bit or t hera pies  a n d ca ncer.  Ge netic researc h ma y c o nsist of 
t he a nal ysis of o ne or m or e ca n di date ge nes or t he a nal ysis of ge netic mar kers 
t hr o u g h o ut t he ge n o me or a nal ysis of t he e ntire ge n o me (as a p pr o priate). 
•  D N A sa m ples ma y  be a nal yze d f or w h ole ge n o me se q ue nci n g a n d relat i o ns hi p t o 
cli nical o utc o mes i n r es p o nse t o st u d y i nter ve nti o n . A d diti o nal a nal yses ma y be 
c o n d ucte d if it is h y p ot hesize d t hat t his ma y hel p f urt her u n dersta n d t he cli nical data.  
•  T he sa m ples ma y be a nal yze d as part of a m ulti -st u d y assess me nt of ge netic fact ors 
i n v ol ve d i n t he r es p o nse t o c hec k p oi nt i n hi bit or t hera p y  or st u d y i nter ve nti o ns of t his 
class t o u n dersta n d st u d y disease or relate d c o n diti o ns.  
•  T he r es ults of ge netic a nal yses ma y be re p orte d i n t he cli nical st u d y re p ort or i n a 
se par ate st u d y s u m mar y.  
•  T he S p o ns or will st or e t he D N A sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ur es t o pr otect c o nfi de ntialit y.  
•  T he sa m ples will be r etai ne d w hile researc h o n c hec k p oi nt i n hi bit or t hera p y c o nti n ues 
i n acc or da nce wit h a p plica ble la w. 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 3  
1 0. 8  
A P P E N DI X 8 : M A N A G E M E N T A L G O RI T H M S  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 4  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 5  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 6  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 7  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 8  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 3 9  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 0  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 1  
1 0. 9  
A P P E N DI X 9 : LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otr a nsferase  
A P C  
a d va nce d pr ostate ca ncer  
A S T  
as partate a mi n otr a nsferase  
C A P  
C olle ge of A merica n Pat h ol o gists  
C a v gss 
ti me-a ver a ge d stea d y -state c o nce ntrati o n 
C B R  
cli nical be nefit r ate 
C LI A  
Cli nical La b or at or y I m pr o ve me nt A me n d me nt  
C m a xss  
ma xi m u m stea d y -state c o nce ntrati o n 
C mi nss  
mi ni m u m stea d y-state c o nce ntrati o n 
C O A  
cli nical o utc o me assess m e nt  
C R  
c o m plete r es p o nse  
C R F  
case r e p ort f or m 
C T  
c o m p ute d t o m o gr a p h y 
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
C T L A -4  
c yt ot o xic T -l y m p h oc yte-ass o ciate d a nti ge n -4  
D N A  
de o x yri b o n ucleic aci d  
D R E S S  
dr u g r eacti o n wit h e osi n o p hilia a n d s yste mic s y m pt o ms  
E C G  
electr ocar di o gr a m  
E C O G  
E aster n C o o per ati ve O nc ol o g y Gr o u p  
e C R F  
electr o nic case r e p ort f or m 
E D C  
electr o nic data c ollecti o n 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F F P E  
f or mali n-fi xe d par affi n-e m be d de d  
F T 3  
fr ee trii o d ot h yr o ni ne 
F T 4  
fr ee t h yr o xi ne 
G B S  
G uillai n -Barr e S y n dr o me  
G C P  
G o o d Cli nical Pr actice  
H C C  
he pat ocell ular car ci n o ma  
HI P A A  
Healt h I ns ur a nce P orta bilit y a n d Acc o u nta bilit y Act  
H R T  
h or m o ne r e place me nt t hera p y  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 2  
A b bre vi ati o n  
Defi niti o n  
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 mittee 
I H C 
i m m u n o hist oc he mistr y 
ir A E 
i m m u ne-r elate d a d verse e ve nt 
I R B 
I nstit uti o nal Re vie w B oar d  
I V 
i ntr a ve n o us(l y) 
m A b  
m o n ocl o nal a nti b o d y  
m C R P C  
metastatic castr ati o n -resista nt pr ostate ca ncer 
M D A C C  
M D A n ders o n Ca ncer Ce nter  
M G  
M yast he nia Gr a vis  
mI T T  
m o difie d I nte nt -t o-Treat  
M RI  
ma g netic r es o na nce i ma gi n g  
M SI  
micr osatellite i nsta ble  
M S S  
micr osatellite sta ble  
M T D  
ma xi m u m t oler ate d d ose  
N A F  
s o di u m fl u ori de 
N S C L C  
n o n -s mall cell l u n g ca ncer 
O R R  
o bjecti ve r es p o nse rate  
O S  
o ver all s ur vi val  
P B M C  
peri p her al bl o o d m o n o n uclear cell  
P C W G 3  
Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p 3  
P D  
pr o gr essi ve disease  
P D -1  
pr o gr a m me d cell deat h -1  
P D -L 1  
pr o gr a m me d cell deat h li ga n d -1  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P F S  
pr o gr essi o n -fr ee s ur vi val 
PI  
Pri nci pal I n vesti gat or  
P K  
p har mac o ki netic(s)  
P P K  
p o p ulati o n p har mac o ki netic  
P R  
partial r es p o nse  
P R O  
patie nt -r e p orte d o utc o mes 
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 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 3  
A b bre vi ati o n  
Defi niti o n  
R C C  
r e nal cell car ci n o ma 
R E CI S T v 1. 1  
Res p o ns e E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S C C H N  
s q ua m o us cell car ci n o ma of t he hea d a n d nec k 
S D  
sta ble disease 
S O A  
Sc he d ule of Acti vities  
T. bili  
t otal bilir u bi n 
T C -9 9 m  
tec h neti u m-9 9 m  
T O X  
trial-li miti n g t o xicit y 
T R A E(s)  
tr eat me nt-r elate d a d verse e ve nt(s) 
T S H  
t h yr oi d sti m ulati n g h or m o ne 
U L N  
u p per li mit of n or mal  
U S PI  
U S Pr escri bi n g I nf or mati o n  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  
 

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 4  
1 0. 1 0  
A P P E N DI X 1 0 : P R O T O C O L A M E N D M E N T HI S T O R Y 
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
dir ectl y bef or e t he T a ble of C o nte nts ( T O C).  
D O C U M E N T HI S T O R Y  
D oc u m e nts  
D ate of Iss u e  
A me n d me nt 5  
0 2 Fe br uar y  2 0 2 2  
A me n d me nt 4  
1 2  Mar  2 0 2 1  
A me n d me nt 3  
0 8  J ul 2 0 2 0  
A me n d me nt 2  
1 2 J u n 2 0 1 9  
A me n d me nt 1  
2 7 J ul y 2 0 1 8  
Ori gi nal Pr ot oc ol  
0 6 A pr 2 0 1 8  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 5  
1 1  
R E F E R E N C E S  
A yers M, L u ncef or d J, Ne b oz h y n M, M ur p h y E, L o b o da A, Ka uf ma n D R, et al. I F N -γ-relate d 
m R N A pr ofile pr e dicts cli nical r es p o nse t o P D -1 bl oc ka de. J Cli n I n vest. 2 0 1 7; 1 2 7: 2 9 3 0 -4 0.  
Beer T M, K w o n E D, Dr a ke C G, et al. Ra n d o mize d, D o u ble -Bli n d, P hase III Trial of I pili m u ma b 
Vers us Place b o i n As y m pt o matic or Mi ni mall y S y m pt o matic Patie nts Wit h Metastatic 
C he m ot her a p y -Nai ve Castr ati o n -Resista nt Pr ostate Ca ncer. J Cli n O nc ol . 2 0 1 7; 3 5( 1): 4 0-4 7.  
Brist ol -M yers S q ui b b ( B M S). Ni v ol u ma b St u dies. A vaila ble at: 
htt ps:// w w w. b msst u d yc o n nect. c o m/ us/e n/ healt h -st u dies/ 
B or g haei H, Paz -Ar es L, H or n L, S pi gel  D R, Stei ns M, Rea d y N E, et al. Ni v ol u ma b vers us 
D oceta xel i n A d va nce d N o ns q ua m o us N o n -S mall -Cell L u n g Ca ncer.  N E n gl J 
Me d.  2 0 1 5; 3 7 3 : 1 6 2 7– 3 9.  
Br a h mer J, Rec ka m p K L, Baas P, Cri n o L, E ber har dt W E, P o d d u bs ka ya E, et al. Ni v ol u ma b 
vers us D oceta xel i n A d va nce d S q ua m o us -Cell N o n -S mall -Cell L u n g Ca n cer.  N E n gl J 
Me d.  2 0 1 5; 3 7 3 : 1 2 3– 3 5.  
Calla ha n M K, Kl u ger H, P ost o w M A, Se gal N H, Les o k hi n A, At ki ns M B, et al. Ni v ol u ma b Pl us 
I pili m u ma b i n Patie nts Wit h A d va nce d Mela n o ma: U p date d S ur vi val, Res p o nse, a n d Safet y Data 
i n a P hase I D ose-Escalati o n St u d y. J Cli n O nc ol 2 0 1 8; 3 6( 4): 3 9 1 – 8.  
C he n P L, R o h W, Re u be n A, C o o per Z A, S pe ncer C N, Priet o P A, et al. A nal ysis of i m m u ne 
si g nat ur es i n l o n git u di nal t u m or sa m ples yiel ds i nsi g ht i nt o bi o mar kers of res p o nse a n d 
mec ha nis ms of r esista nce t o i m m u ne c hec k p oi nt bl oc ka de. Ca ncer Disc o v. 2 0 1 6; 6: 8 2 7 -3 7.  
C o nc ha -Be na ve nte F, Gillis o n M L, Bl u me nsc hei n G R, Harri n gt o n K, Fa yette J, et al. 
C har acterizati o n of p ote ntial pr e dicti v e bi o mar kers of res p o nse t o ni v ol u ma b i n C hec k Mate 1 4 1 
i n patie nts wit h s q ua m o us cell car ci n o ma of t he hea d a n d nec k ( S C C H N). J Cli n O nc ol. 
2 0 1 7; 3 5( 1 5 _s u p pl): 6 0 5 0 ( a bstr act 6 0 5 0).  
Dr a ke C G, K w o n E D, Fizazi K, et al. Res ults of s u bset a nal yses o n o verall s u r vi val ( O S) fr o m 
st u d y C A 1 8 4-0 4 3: I pili m u ma b (I pi) vers us place b o ( P b o) i n p ost -d oceta xel metastatic castrati o n -
r esista nt pr ostate ca ncer ( m C R P C). J C O. 2 0 1 4; 3 2( 4 _s u p pl): 2-2.  
Eise n ha uer E A, T her asse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
r e vise d R E CI S T g ui deli nes ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5: 2 2 8-4 7.  
Fel d me yer L, H u d ge ns C W, Ra y -L y o ns G, Na garaja n P, A u n g P P, C urr y J L, et al. De nsit y, 
distri b uti o n, a n d c o m p ositi o n of i m m u ne i nfiltrates c orrelate wit h s ur vi val i n Mer ke l cell 
car ci n o ma. Cli n Ca ncer Res. 2 0 1 6; 2 2: 5 5 5 3 -6 3.  
Ga o J, War d J F, Petta wa y C A, S hi L Z, S u b u d hi S K, Ve nce L M, et al. VI S T A is a n i n hi bit or y 
i m m u ne c hec k p oi nt t hat is i ncr ease d after i pili m u ma b t hera p y i n patie nts wit h pr ostate ca ncer. 
Nat Me d. 2 0 1 7; 2 3: 5 5 1 -7.  
G o pala kris h na n V, S pe ncer C N, Nezi L, Re u be n A, A n dre ws M C, Kar pi nets T V, et al. G ut 
micr o bi o me m o d ulates r es p o nse t o a nti -P D -1 i m m u n ot hera p y i n mela n o ma patie nts. Scie nce. 
2 0 1 8; 3 5 9: 9 7 -1 0 3.  
Haa ne n J B A G. C o n verti n g c ol d i nt o h ot t u m ors b y c o m bi ni n g i m m u n ot hera pies. Cell. 
2 0 1 7; 1 7 0: 1 0 5 5 -6.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 6  
He g de P S, Kar a ni kas V, E vers S. T he w here, t he w he n, a n d t he h o w of i m m u ne m o nit ori n g f or 
ca ncer i m m u n ot her a pies i n t he er a of c hec k p oi nt i n hi biti o n. Cli n Ca ncer Res. 2 0 1 6; 2 2: 1 8 6 5 -7 4.  
Hell ma n n M D, Paz -Ar es L, Ber na be Car o R, Z ura ws ki B, Ki m S -W, Carcere n y C osta E, et al. 
Ni v ol u ma b pl us I pili m u ma b i n A d va nce d N o n – S mall -Cell L u n g Ca ncer. Ne w E n gla n d J o ur nal 
of Me dici ne 2 0 1 9; 3 8 1( 2 1): 2 0 2 0 – 3 1.  
Her bst R S, Baas P, Ki m D W, Feli p E, Perez -Graci a J L, Ha n J Y, et al. Pe m br oliz u ma b ve rs us 
d oceta xel f or pr e vi o usl y tr eate d, P D -L 1 -p ositi ve, a d va nce d n o n -s mall-cell l u n g ca ncer 
( K E Y N O T E-0 1 0): a r a n d o mise d c o ntr olle d trial.  La ncet.  2 0 1 6; 3 8 7: 1 5 4 0 -5 0 . 
H o di F S, O’ Da y SJ, Mc Der m ott D F, We ber R W, S os ma n J A, Haa ne n J B, et al. I m pr o ve d 
s ur vi val wit h i pili m u ma b i n patie nts wit h metastatic mela n o ma. N E n gl J Me d. 2 0 1 0; 3 6 3: 7 1 1 -2 3.  
I pili m u ma b I n vesti gat or Br oc h ur e versi o n 2 3, date d 1 1-Mar -2 0 2 0. Brist ol -M yers S q ui b b 
Resear c h a n d De vel o p me nt, 2 0 2 0. D oc u me nt C o ntr ol N o. 9 3 0 0 1 7 5 3 1.  
J o h ns o n D B, Estr a da M V, Sal ga d o R, Sa nc hez V, D o xie D B, O pale ni k S R, et al. Mela n o ma-
s pecific M H C-II e x pr essi o n r e pr ese nts a t u m o ur-a ut o n o m o us p he n ot y pe a n d pre dicts res p o nse t o 
a nti-P D -1/ P D -L 1 t her a p y. Nat C o m m. 2 0 1 6; 7: 1 0 5 8 2.  
K vist b or g P, P hili ps D, Ke l der ma n S, Ha ge ma n L, Otte ns meier C, J ose p h-Pietras D, et al. A nti -
C T L A -4 t her a p y br oa de ns t he mela n o ma -reacti ve C D 8 + T cell res p o nse. Sci Tra nsl Me d. 
2 0 1 4; 6: 2 5 4r a 1 2 8.  
K we k S S, C ha E, F o n g L. U n mas ki n g t he i m m u ne rec o g niti o n of pr ostate ca ncer wit h C T L A 4 
b l oc ka de. Nat Re v Ca ncer. 2 0 1 2; 1 2( 4): 2 8 9-2 9 7.  
K w o n E D, Dr a ke C G, Sc her HI, Fizazi K, B ossi A, va n de n E ert we g h AJ M, et al. I pili m u ma b 
vers us place b o after r a di ot her a p y i n patie nts wit h metastatic castrati o n -resista nt pr ostate ca ncer 
t hat ha d pr o gr esse d after d oceta xel c he m ot hera p y ( C A 1 8 4 -0 4 3): a m ultice ntre, ra n d o mise d, 
d o u ble -bli n d, p hase 3 trial. La ncet O nc ol 2 0 1 4; 1 5( 7): 7 0 0 – 1 2.  
Lar ki n J, C hiari o n -Sile ni V, G o nzalez R, Gr o b JJ, C o we y C L, La o C D, et al. C o m bi ne d 
ni v ol u ma b a n d i pili m u ma b or m o n ot hera p y i n u n treate d mela n o ma. N E n gl J Me d. 2 0 1 5; 3 7 3: 2 3-
3 4.  
Ma b y P, Gal o n J, Lat o uc he J B. Fr a mes hift m utati o ns, ne oa nti ge ns a n d t u m or -s pecific C D 8( +) T 
cells i n micr osatellite u nsta ble c ol or ectal ca ncers. O nc oi m m u n ol o g y. 2 0 1 5; 5( 5):e 1 1 1 5 9 4 3.  
Ma da n R A, Arle n P M, M o he bta s h M, H o d ge J W, G ulle y J L. Pr ost vac-V F: a vect or -base d 
vacci ne tar geti n g P S A i n pr ostate ca ncer. E x pert O pi n I n vesti g Dr u gs. 2 0 0 9; 1 8( 7): 1 0 0 1 -1 0 1 1.  
Ma da n R A, M o he btas h M, Arle n P M, et al. I pili m u ma b a n d a p o x viral vacci ne tar geti n g 
pr ostate -s p ecific a nti ge n i n metastatic castrati o n-resista nt pr ostate ca ncer: a p hase 1 d ose-
escalati o n trial. La ncet O nc ol. 2 0 1 2; 1 3( 5): 5 0 1 -5 0 8.  
Mai o M, Gr o b JJ, Aa m dal S, B o n dar e n k o I, R o bert C, T h o mas L, et al. Fi ve -year s ur vi val rates 
f or tr eat me nt-naï ve patie nts wit h a d va nce d  mela n o ma w h o recei ve d i pili m u ma b pl us dacar bazi ne 
i n a p hase III trial. J Cli n O nc ol. 2 0 1 5; 3 3: 1 1 9 1-6.  
M o mtaz P, Par k V, Pa na geas K S, P ost o w M A, Calla ha n M, W olc h o k J D, et al. Safet y of 
i nf usi n g i pili m u ma b o ver 3 0 mi n utes. J Cli n O nc ol. 2 0 1 5; 3 3: 3 4 5 4-8.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 7  
M ot zer RJ, Esc u dier B, Mc Der m ott D F, Ge or ge S, Ha m mers HJ, Sri ni vas S, et al. Ni v ol u ma b 
vers us ever oli m us i n ad va nce d re nal-cell carci n o ma.  N E n gl J Me d.  2 0 1 5; 3 7 3 : 1 8 0 3-1 3.  
M otzer RJ, T a n nir N M, Mc Der m ott D F, Are n Fr o ntera O, Melic har  B, C h o ueiri T K, et al. 
Ni v ol u ma b pl us i pili m u ma b vers us s u niti ni b i n a d va nce d re nal -cell carci n o ma. N E n gl J Me d. 
2 0 1 8.  [ E p u b a hea d of pri nt] 
N C T 0 0 8 6 1 6 1 4 : A Ra n d o mize d, D o u ble -Bli n d, P hase 3 Trial C o m pari n g I pili m u ma b vs. Place b o 
F oll o wi n g Ra di ot her a p y i n  S u bjects Wit h Castrati o n Resista nt Pr ostate Ca ncer T hat Ha ve 
Recei ve d Pri or Tr eat me nt Wit h D oceta xel [I nter net]. cli nicaltrials. g o v; 2 0 1 6 [cite d 2 0 2 0 Ma y 
3 1]. A vaila ble fr o m: htt ps://cli nicaltrials. g o v/ct 2/s h o w/ N C T 0 0 8 6 1 6 1 4.  
N C T 0 1 0 2 4 2 3 1: D ose -es calati o n St u d y of C o m bi nati o n B M S -9 3 6 5 5 8 ( M D X -1 1 0 6) a n d 
I pili m u ma b i n S u bjects Wit h U nr esecta ble Sta ge III or Sta ge I V Mali g na nt Mela n o ma - F ull 
T e xt Vie w - Cli nical Trials. g o v [I nter net]. [cite d 2 0 2 0 J u n 5]; A vaila ble fr o m: 
htt ps://cli nicaltrials. g o v/ct 2/s h o w/ N C T 0 1 0 2 4 2 3 1.  
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I pili m u ma b vs Place b o i n As y m pt o matic or Mi ni mall y S y m pt o matic Patie nts Wit h Metastatic 
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N C T 0 2 9 8 5 9 5 7: A P hase 2 Trial of Ni v ol u ma b Pl us I pili m u ma b, I pili m u ma b Al o ne, or 
Ca bazita xel i n Me n Wit h  Metastatic Castrati o n -Resista nt Pr ostate Ca ncer   - F ull T e xt Vie w - 
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m o n ot her a p y i n a d va nce d mela n o ma patie nts: C hec k Mate 0 3 8. A A C R 2 0 1 7.  

Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 8  
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2 0 1 5; 3 4 8: 1 2 4 -8.  
R o bert C, Sc hac hter J, L o n g G V, Ar a nce A, Gr o b JJ, M ortier L, et al. Pe m br oliz u ma b vers us 
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Ni v ol u ma b, I pili m u ma b –  P ar ker I nstit ute f or C a ncer I m m u n ot hera p y  
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0  
1 4 9  
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C o m pa n y, Pri ncet o n, NJ.  

Ni v ol u ma b, I pili m u ma b – P ar ker I nstit ute f or C a ncer I m m u n ot hera p y
Pr ot oc ol PI CI 0 0 2 5 -A me n d me nt 5 , Versi o n 1. 0
4 6
Fi g ure 6 :
T u m or -i nfilt r ati n g C D 8 T-cell E x pressi o n b y Best O ver all Res p o nse
C R = cli nic al res p o nse; I pi = i pili m u m a b; N E = n ot e val ua ble; Ni v o = ni v ol u ma b; P D = pr o gressi ve dise ase; 
P R = partial res p o nse; S D = st a bl e dise ase.
Bi o mar ker st u d y o n P hase 1 b C he c k Mate 0 3 8 st u d y a n d t u m or bi o psies were assesse d b y i m m u n o hist oc he mistr y. 
A da pte d fr o m Ri bas oral prese ntati o n at 2 0 1 7 A A C R.
I n s u m mar y, b ot h pr e-tr eat me nt t u m oral C D 8 cells a n d recr uit me nt of C D 8 T cells i n res p o nse t o 
i m m u ne c hec k p oi nt i n hi bit ors ar e ass ociate d wit h i m pr o ve d cli nical o utc o mes i n patie nts treate d 
wit h a nti -P D -1 t her a p y. T hese data s u g gest t hat a rati o nal a p pr oac h t o c o n vert “ C D 8 l o w t u m ors
i nt o “C D 8 hi g h t u m ors is t hr o u g h c o m bi nati o n treat me nt a p pr oac hes wit h a nti-P D -1 a n d a nti -
C T L A -4 m A bs t hat ca n r ecr uit m or e C D 8 T cells t o t he t u m or (Haa ne n, 2 0 1 7 ).
A pr os pecti ve st u d y wit h lar ger sa m ple size is warra nte d t o c o nfir m t hat t he perce nt a ge of 
t u m or al C D 8 cells at t he ti me of tr eat me nt ca n deter mi ne res p o nsi ve ness t o a nti -P D -1 t hera p y 
a n d w het her c o m bi na ti o n t her a p y ca n c o n vert t u m ors fr o m C D 8 l o w t o C D 8 hi g h . We pr o p ose a 
pr os pecti ve cli nical st u d y i n w hic h patie nts wit h var yi n g a d va nce d s oli d t u m ors will be assi g ne d 
t o 1 of 2 tr eat me nt ar ms base d o n t he perce nt a ge of t u m oral C D 8 cells at t he ti me of treat me nt. 
Partici pa nts w h o ha ve a t u m or wit h ≥ 1 5 % C D 8 cells (classifie d as C D 8 hi g h ) will recei ve 
ni v ol u ma b m o n ot her a p y, a n d partici pa nts w h o ha ve a t u m or wit h < 1 5 % C D 8 cells (classifie d as 
C D 8 l o w ) will r ecei ve i pili m u ma b i n c o m bi nati o n wit h ni v ol u ma b.
It is well r ec o g nize d t hat i m m u ne i nfiltrati o n varies acr oss t u m or t y pes, a n d differe nt t u m or t y pes 
ma y dis pla y a r a n ge of t her a pe utic se nsiti vities. Se veral o n g oi n g st u dies are e val uati n g 
ni v ol u ma b tr eat me nt i n vari o us t u m or t y pes (B M S Ni v ol u ma b St u dies ). T o better assess t he 
f easi bilit y of usi n g per ce nt of t u m or al C D 8 cells as a bi o mar ker f or selecti n g c hec k p oi nt 
i n hi bit or t her a p y a n d t o gai n m or e i nsi g ht re gar di n g t he desi g n of t he trial, we e xa mi ne d C D 8 
cells i n a set of 1 9 5 t u m or sa m ples fr o m 1 0 differe nt t u m or t y pes (Fi g ure 7 ). F or t u m or t y pes i n 
w hic h a nti -P D -1 tr eat me nt has bee n a p pr o ve d, t he classificati o n of C D 8 hi g h t u m or is c o nsiste nt 
wit h t he cli nical be nefit r e p orte d. T he 1 5 % c ut off was selecte d bas e d o n data fr o m retr os pecti ve