Risk-based, Response-adapted, Phase II Open-label Trial of Nivolumab + Brentuximab Vedotin (N + Bv) for Children, Adolescents, and Young Adults With Relapsed/Refractory (R/R) CD30 + Classic Hodgkin Lymphoma (cHL) After Failure of First-line Therapy, Followed by Brentuximab + Bendamustine (Bv + B) for Participants With a Suboptimal Response (CheckMate 744: CHECKpoint Pathway and Nivolumab Clinical Trial Evaluation)
Phase: PHASE2
Conditions: Hodgkin Disease
Sponsor: Bristol-Myers Squibb

Offi ci al  Titl e  of  St u d y:  
Ri s k -b a s e d,  R e s p o n s e -a d a pt e d,  P h a s e  II O p e n -l a b el Tri al  of  Ni v ol u m a b  + Br e nt u xi m a b  V e d oti n  ( N + 
B v) f or C hil dr e n, A d ol e s c e nt s, a n d Y o u n g A d ult s Wit h R el a p s e d/ R efr a ct or y ( R/ R) C D 3 0 + Cl a s si c 
H o d g ki n L y m p h o m a ( c H L) Aft er F ail ur e of Fir st -li n e T h er a p y, F oll o w e d b y Br e nt u xi m a b + 
B e n d a m u sti n e  ( B v + B) f or P arti ci p a nt s  Wit h  a S u b o pti m al  R e s p o n s e  ( C h e c k M at e 7 4 4:  C H E C K p oi nt 
P at h w a y a n d Ni v ol u m a b Cli ni c al Tri al E v al u ati o n)  
 
N C T  N u m b er:  N C T 0 2 9 2 7 7 6 9  
D o c u m e nt  D at e  ( D at e i n w hi c h  d o c u m e nt  w a s  l a st r e vi s e d): 2 6  M ar c h  2 0 2 1  

A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
P h o ne: 
il: 
Pa ge:  1  
Pr ot oc ol  N u m ber:  C A 2 0 9 7 4 4  
I N D N u m ber:  1 1 9, 3 8 0  
E U D R A C T  N u m ber  2 0 1 6 -0 0 2 3 4 7 -4 1  
Date  2 3 -Se p -2 0 1 6  
Re vise d Date:  2 6 -Mar -2 0 2 1  
 
C LI NI C A L  P R O T O C O L  C A 2 0 9 7 4 4  
Ris k -base d, res p o nse -a da pte d, P hase II o pe n-la bel trial of ni v ol u ma b + bre nt u xi ma b ve d oti n 
( N + B v) f or c hil dre n, a d olesce nts, a n d y o u n g a d ults wit h rela pse d/refract or y ( R/ R) C D 3 0 + 
classic H o d g ki n l y m p h o ma (c H L) after fail ure of first-li ne t hera p y, f oll o we d b y bre nt u xi ma b + 
be n da m usti ne ( B v + B) f or partici pa nts wit h a s u b o pti mal res p o nse.  
C hec k Mate  7 4 4: C H E C K p oi nt  pat h wa y  a n d ni v ol u ma b cli nical Trial  E val uati o n  
Pr ot oc ol A me n d me nt  N u m ber:  0 4  
 
Cli nic al  Tri al  P h ysici a n  - Me dic al  M o nit or  
 
8 6 M orris  A ve n ue  
S u m mit,  NJ  0 7 9 0 1  
Cli nic al Scie ntist  
 
Cel ge ne,  a B M S  C o m pa n y  
R o ute de Perre u x 1, B o u dr y - S witzerla n d  
 
e ma 
e ma 
 
2 4- hr E mer ge nc y Tele p h o ne  N u m ber  
U S A:  
I nter nati o nal: 
Ja pa n: 
 
Brist ol -M yers  S q ui b b  Rese arc h  a n d  De vel o p me nt  
3 4 0 1 Pri ncet o n Pi ke 
La wre nce,  NJ  0 8 6 4 8 U S A  
 
A ve n ue de Fi nla n de 4 
B- 1 4 2 0 Brai ne -l’ Alle u d, Bel gi u m  
 
6- 5- 1 Nis hi - S hi nj u k u, S hi nj u k u-k u,  
T o k y o, 1 6 3- 1 3 2 8, Ja pa n 
 
T his d oc u me nt is t he c o nfi de nti al a n d pr o priet ar y i nf or m ati o n of Brist ol -M yers S q ui b b 
C o m p a n y a n d its gl o b al affili ates ( B M S). B y re vie wi n g t his d oc u me nt, y o u a gree t o kee p it 
c o nfi de nti al a n d t o use a n d discl ose it s olel y f or t he p ur p ose of assessi n g w het her y o ur 
or g a niz ati o n will  p artici p ate  i n a n d/ or  t he perf or m a nce   of t he pr o p ose d  B M S  s p o ns ore d 
P h o ne 
il: 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
st u d y. A n y per mitte d discl os ures will be m a de o nl y o n a c o nfi de nti al " nee d  t o k n o w " b asis 
wit hi n  y o ur or g a niz ati o n or t o y o ur  i n de pe n de nt et hics c o m mittee(s).  A n y  ot her  use,  c o p yi n g, 
discl os ure  or  disse mi n ati o n  of  t his  i nf or m ati o n  is  strictl y  pr o hi bite d  u nless  e x pressl y  
a ut h orize d i n writi n g b y B M S. A n y s u p ple me nt al i nf or m ati o n (e. g., a me n d me nts) t h at m a y 
be a d de d t o t his d oc u me nt is als o c o nfi de nti al a n d pr o priet ar y t o B M S a n d m ust be ke pt i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt. A n y pers o n w h o recei ves 
t his d oc u me nt wit h o ut d ue a ut h oriz ati o n fr o m B M S is re q ueste d t o ret ur n it t o B M S or 
pr o m ptl y  destr o y  it. All  ot her  ri g hts reser ve d.  Refere nces  t o B M S  i n t his pr ot oc ol m a y a p pl y 
t o  p art ners  t o  w hic h  B M S  h as  tr a nsferre d  o bli g ati o ns,  e. g.,  a  C o ntr act  Rese arc h  
Or g a niz ati o n ( C R O).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr ot oc ol  A me n d me nt  N o.:  0 4  
Date:  2 6 -Mar -2 0 2 1  
2 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
3 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
D O C U M E N T HI S T O R Y  
 
D oc u me nt  
D ate  of  Iss ue 
S u m m ar y  of  C h a n ge  
 
 
 
Pr ot oc ol 
A me n d me nt  0 4  
 
 
 
2 6 -Mar -2 0 2 1  
Cl ose d  recr uit me nt of  R 1  c o h ort 
. T otal  c o h ort size f or R 1  was  re d uce d. A d de d  clarif yi n g state me nts 
t o pla n ni n g of sa m ple size f or eac h c o h ort. 
C orrecte d  a t y p o i n t he Descri pti o n  f or Res p o nse -e val ua ble Partici pa nts  i n 
Secti o n 1 0. 2, P o p ulati o ns f or A nal yses.  
A d de d  B M S  sta n dar d f or C O VI D -1 9  pr ot oc ol  la n g ua ge. 
Ot her  mi n or  e dits were  ma de,  as descri be d  i n t he S u m mar y  of  Ke y  C ha n ges  
 
 
 
 
Re vise d 
Pr ot oc ol  0 3  
 
 
 
 
2 6 -Mar -2 0 1 8  
T he res p o nse assess me nt b y i n vesti gat ors usi n g L u ga n o 2 0 1 4 res p o nse 
criteria was a d de d as a sec o n dar y e n d p oi nt t o all o w f or a c o m pre he nsi ve 
i nter pretati o n of  t he st u d y data.  G ui da nce  f or c ollecti o n a n d s u b missi o n of 
t u m or assess me nts was a d de d t o s u p p ort t he e val uati o n of t his ne w 
sec o n dar y e n d p oi nt. 
C o ntrace pti o n  re q uire me nts f or fe male partici pa nts  of  c hil d beari n g  p ote ntial 
were m o difie d t o pr o perl y ali g n wit h Ni v ol u ma b cli nical researc h sta n dar d 
g ui deli nes a n d bre nt u xi ma b la bel.  
Ot her  mi n or  e dits were  ma de,  as descri be d  i n t he S u m mar y  of  Ke y  C ha n ges.  
 
 
 
 
 
 
Re vise d 
Pr ot oc ol  0 2  
 
 
 
 
 
 
 
0 1 -J u n-2 0 1 7  
 
t he c o-pri mar y  e n d p oi nt C M R  rate has  bee n  a d de d. 
 
 
 
Clarificati o n a b o ut c o ntrace pti o n g ui deli nes was nee de d i n or der t o a v oi d 
c o nf usi o n a n d t o har m o nize differe nces bet wee n t he pr ot oc ol a n d gl o bal 
pr o d uct la bels ( Bre nt u xi ma b a n d Be n da m usti ne). A c o m m o n a p pr oac h f or  
all I M Ps re q uires 6 m o nt hs  of c o ntrace pti o n after last I M P  d ose f or W O C B P 
a n d 7 m o nt hs f or males wit h part ners of W O C B P. A d diti o nall y, clarificati o n 
was  pr o vi de d  a b o ut t he re q uire me nt f or 2 c o ntrace pti o n  met h o ds  or c o m plete 
a bsti ne nce. 
Ot her  mi n or  e dits were  ma de,  as descri be d  i n t he S u m mar y  of  Ke y  C ha n ges. 
I nc or p orates c ha n ges fr o m A d mi nistrati ve Letter 0 3 
A d mi nistrati ve 
Letter 0 3  
1 4 -A pr -2 0 1 7  
Create d  t o clarif y  a n i nc o nsiste nc y i n t he pr ot oc ol  ta ble bet wee n  t he X i n t he 
Ta ble 2. -2 c ol u m ns f or pre g na nc y testi n g at D 1 5 visits a n d t he n otes.  
Re vise d 
Pr ot oc ol  0 1  
0 1 -Mar -2 0 1 7  
I nc or p orates c ha n ges fr o m A me n d me nt  0 2,  A d mi nistrati ve  Letter  0 1  a n d 
A d mi nistrati ve Letter 0 2  
 
 
 
 
 
A me n d me nt  0 2  
 
 
 
 
 
0 1 -Mar -2 0 1 7  
 
 
A d diti o nall y,  clarif yi n g:  R 1  C o ns oli dati o n  T hera p y  ma y  be  i ncl usi ve of  all 
t y pes of Ra diati o n T hera p y ( R T) per i nstit uti o nal g ui deli nes, a d ds u p t o 2 
a d diti o nal c ycles of B v + B wit h B M S M M a p pr o val f or R 2 c o h ort  
c o ns oli dati o n  t hera p y dela ys  (t o be  c o nsiste nt wit h  t he a p pr oac h ta ke n f or 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
4 
 
D oc u me nt  
D ate  of  Iss ue 
S u m m ar y  of  C h a n ge  
I n d ucti o n P hase, N + B v), deletes w or di n g “f or bi o mar ker a nal ysis” as t he 
bi o ps y is re q uire d per Sta n dar d of Care a n d pr o vi de d t o B M S f or hist ol o gic 
c o nfir mati o n  of  disease  a n d bi o mar ker  testi n g, m o dificati o n  of  re q uire me nts 
f or F D G-P E T at scree ni n g a n d d uri n g treat me nt i n ali g n me nt wit h Sta n dar d 
of Care practices, a n d L Y RI C 2 0 1 6 criteria will be a d de d as a n e x pl orat or y 
e n d p oi nt f or f ut ure data a nal ysis acc or di n g t o refi ne me nt of L U G A N O 
classificati o n i n t he era of i m m u n o m o d ulat or y t hera p y.  
Ot her  mi n or  clarificati o ns were  ma de  
 
 
 
 
 
 
 
A d mi nistrati ve 
letter 0 2 
 
 
A d mi nistrati ve 
letter 0 1 
 
 
 
 
Ori gi nal 
Pr ot oc ol  
1 4 -Ja n-2 0 1 7  
 
 
 
1 7 -N o v -2 0 1 6  
 
 
 
 
 
2 3 -Se p -2 0 1 6  
T o clarif y  e q ui vale nt H 1/ H 2  bl oc ker  pre -me dicati o ns  are per mitte d  a n d sites 
s h o ul d f oll o w i nstit uti o nal practice f or ste m cell c ollecti o ns t o r ule o ut b o ne 
marr o w disease i n v ol ve me nt. T o c orrect a fra g me nt se nte nce, per 
be n da m usti ne pac ka ge i nsert.  
C ha n ge I n Me dical M o nit or C o ntact I nf or mati o n.  
T o clarif y: B v  P K  c ollecti o ns are plas ma  a n d ser u m. 
T o c orrect err or  i n la n g ua ge t hat c o nflicts  wit h  ot her  e xisti n g  la n g ua ge: 
N S A E/ S A E c ollecte d u ntil F U 2 ( Da y 1 0 0), a n d treat me nt Be y o n d 
Pr o gressi o n is per mitte d, per t he st u d y desi g n.  
N ot  A p plica ble  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr ot oc ol  A me n d me nt  N o.:  0 4  
Date:  2 6 -Mar -2 0 2 1  
4 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
O V E R A L L  R A TI O N A L E  F O R  P R O T O C O L  A M E N D M E N T  0 4:  
T he  pri mar y  reas o n f or t his a me n d me nt  is t he cl osi n g of recr uit me nt i nt o t he R 1  c o h ort. T he  c o h ort 
is bei n g m o difie d 
. T he  ori gi nal  R 1  c o h ort size was 
esti mate d t o a p pr o xi matel y 4 0 partici pa nts. 
 
It was  c o nsi dere d 
t o re d uce n u m ber of accr ue d R 1 partici pa nts fr o m 4 0 t o 2 8 a n d cl osi n g recr uit me nt i n c o h ort R 1. 
I m p orta ntl y, cl osi n g recr uit me nt t o da y will  still all o w t he pla n ne d a nal yses of t he R 1  c o h ort t o be 
c o n d ucte d wit h acce pta ble precisi o n base d o n n = 2 8. 
 
 
t he  t otal  n u m ber  of  st u d y  
partici pa nts  (see Secti o n  5. 2) a n d st u d y c o m pleti o n date ( Ma y- 2 0 2 4) of t he st u d y C A 2 0 9 7 4 4 were 
re vise d. Lastl y, B M S sta n dar d f or C O VI D-1 9 pr ot oc ol la n g ua ge has bee n a d de d t o  t he pr ot oc ol. 
A d diti o nal re visi o ns, i ncl u di n g t o secti o ns of  t he S y n o psis, ha ve bee n ma de t o ali g n t he pr ot oc ol 
wit h res pect t o t hese c ha n ges.  
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  P R O T O C O L  A M E N D M E N T  0 4  
Secti o n  N u m ber 
& Title  
Descri pti o n of C h a n ge  
Brief  R ati o n ale  
Title  Pa ge  
A d de d Cli nical Scie ntist 
U p date d f or Me dical  M o nit or.  
Me dical  M o nit or has c ha n ge d. 
U p date d ke y st u d y c o ntacts. 
Secti o n 5. 1. 1  
Data  M o nit ori n g 
C o m mittee a n d 
Ot her E xter nal 
C o m mittees  
A d de d clarit y t o pla n ni n g of sa m ple 
size f or eac h c o h ort. 
U p date d t o gi ve act ual n u m ber of 
partici pa nts i n eac h c o h ort.  
Secti o n   5. 2 
N u m ber  of  
Partici pa nts  
A d de d act ual n u m bers of partici pa nts 
t o eac h c o h ort. 
Re vise d  sa m ple size of R 1  c o h ort. 
U p date d  t o gi ve  act ual n u m ber  of  
 partici pa nts  i n eac h c o h ort.  
 
 
 
 
 
 
 
 
Secti o n 6. 1  
I ncl usi o n Criteria  
Re vise d secti o n f or A ge a n d 
Re pr o d ucti ve stat us f or males  w h o 
are se x uall y acti ve wit h W O C B P.  
T he  d urati o n  of  c o ntrace pti o n  
re q uire me nt 
p ost -treat me nt 
c o m pleti o n  f or  male  partici pa nts  
w h o  are  se x uall y  acti ve  wit h  
W O C B P   was   re vise d  fr o m  7 
m o nt hs t o  6 m o nt hs base d  o n t he 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  P R O T O C O L  A M E N D M E N T  0 4  
Secti o n  N u m ber 
& Title  
Descri pti o n of C h a n ge  
Brief  R ati o n ale  
 
 
i nf or mati o n i n t he pr o d uct la bels 
of
 bre nt u xi ma b
 ve d oti n
 a n d
 
be n da m usti ne.  S uc h  re q uire me nt  
f or ni v ol u ma b was re m o ve d. 
Secti o n  7. 6. 1  
Pr o hi bite d a n d/ or 
Restricte d 
Treat me nts  
U p date d te xt t o i ncl u de details  o n 
h o w t o ha n dle li ve C O VI D- 1 9 
vacci nes.  
A d de d B M S sta n dar d f or 
C O VI D - 1 9 pr ot oc ol la n g ua ge. 
Secti o n  7. 6. 3 
Per mitte d 
T hera p y  
U p date d te xt t o i ncl u de details  h o w t o 
ha n dle n ot li ve C O VI D- 1 9 vacci nes. 
A d de d B M S sta n dar d f or 
C O VI D - 1 9 pr ot oc ol la n g ua ge. 
Secti o n  9. 2. 8  
Ot her Safet y 
C o nsi derati o ns  
U p date d te xt t o i ncl u de details f or 
C R F  t o ca pt ure C O VI D - 1 9 relate d 
A Es/ S A Es  as per n or mal re p orti n g 
pr oce d ure.  
A d de d B M S sta n dar d f or 
C O VI D - 1 9 pr ot oc ol la n g ua ge. 
Secti o n  1 0. 1  
Sa m ple  Size  
Deter mi nati o n  
A d de d clarit y t o pla n ni n g of sa m ple 
size f or eac h c o h ort. 
U p date d t o gi ve act ual n u m ber of 
partici pa nts i n eac h c o h ort.  
Secti o n 1 0. 2  
P o p ulati o ns f or 
A nal yses  
I n t he Descri pti o n c ol u m n f or 
Res p o nse- e val ua ble Partici pa nts, 
c orrecte d se nte nces fr o m P M D 
( Pr o gressi ve Meta b olic Disease) t o 
P M R  ( Partial Meta b olic  Res p o nse).  
C orrecte d d ue t o t y p o. 
A p pe n di x 2  
St u d y 
G o ver na nce 
C o nsi derati o ns  
U p date d m o nit ori n g details.  
U p date d la n g ua ge t o all o w f or 
re m ote m o nit ori n g. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T A B L E  O F  C O N T E N T S  
TI T L E  P A G E  ................................................................................................................ 
1  
D O C U M E N T  HI S T O R Y..............................................................................................  
3  
O V E R A L L  R A TI O N A L E  F O R  P R O T O C O L  A M E N D M E N T  0 4: ............................ 
5  
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  P R O T O C O L  A M E N D M E N T  0 4................  
5  
T A B L E  O F  C O N T E N T S..............................................................................................  
7  
1 S Y N O P SI S.................................................................................................................  
1 0  
2.  S C H E D U L E  O F  A C TI VI TI E S.................................................................................  
1 9  
3.  I N T R O D U C TI O N .................................................................................................... 
3 8  
3. 1  St u d y Rati o nale  ................................................................................................. 
3 8  
3. 2  Bac k gr o u n d ....................................................................................................... 
4 1  
3. 2. 1  Niv ol u m a b Mec h a nis m of Acti o n  ............................................................. 
4 2  
3. 2. 2  Cli nic al  P h ar m ac ol o gy S u m m ary ............................................................ 
4 3  
3. 2. 3  S afety S u m m ary........................................................................................  
4 4  
3. 3  Be nefit/ Ris k  Assess me nt  .................................................................................. 
4 4  
4.  O BJ E C TI V E S  A N D  E N D P OI N T S  .......................................................................... 
4 6  
5.  S T U D Y  D E SI G N......................................................................................................  
4 9  
5. 1  O verall  Desi g n  .................................................................................................. 
4 9  
5. 1. 1  D at a  M o nit ori n g C o m mittee  a n d Ot her  Exter n al  C o m mittees  ................ 
5 1  
5. 2  N u m ber of Partici pa nts  ..................................................................................... 
5 3  
5. 3  E n d  of St u d y Defi niti o n .................................................................................... 
5 4  
5. 4  Scie ntific  Rati o nale f or St u d y Desi g n...............................................................  
5 4  
5. 5  J ustificati o n f or D ose ........................................................................................ 
5 4  
6.  S T U D Y  P O P U L A TI O N  ........................................................................................... 
5 5  
6. 1  I ncl usi o n Criteria  .............................................................................................. 
5 5  
6. 2  E xcl usi o n Criteria  ............................................................................................. 
5 8  
6. 3  Lifest yle  Restricti o ns  ........................................................................................ 
5 9  
6. 4  Scree n Fail ures..................................................................................................  
5 9  
6. 4. 1  Retesti n g  D uri n g Scree ni n g or Le a d -I n Peri o d  ....................................... 
5 9  
7.  T R E A T M E N T  .......................................................................................................... 
6 0  
7. 1  Treat me nts  A d mi nistere d..................................................................................  
6 2  
7. 1. 1  Tre at me nt  of  I nf usi o n Re acti o ns .............................................................. 
6 3  
7. 1. 1. 1  Met h o d of  Tre at me nt  Assi g n me nt ................................................... 
6 4  
7. 2  Bli n di n g.............................................................................................................  
6 4  
7. 3  D osa ge M o dificati o n.........................................................................................  
6 4  
7. 4  Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  .................................................. 
6 7  
7. 5  Treat me nt  C o m plia nce......................................................................................  
6 8  
7. 6  C o nc o mita nt T hera p y........................................................................................  
6 8  
7. 6. 1  Pr o hi bite d a n d/ or Restricte d  Tre at me nts.................................................  
6 8  
7. 6. 2  Ot her  Restricti o ns  a n d Prec a uti o ns.........................................................  
6 8  
7. 6. 2. 1  M o biliz ati o n a n d C ollecti o n  of Peri p her al  Bl o o d Ste m Cells  ........ 
6 9  
7. 6. 2. 2  I m a gi n g Restricti o n  a n d Prec a uti o ns ............................................. 
6 9  
7. 6. 3  Per mitte d  T her a py ................................................................................... 
6 9  
7. 7  Treat me nt  After t he  E n d of  t he St u d y...............................................................  
7 0  
8.  DI S C O N TI N U A TI O N  C RI T E RI A  .......................................................................... 
7 0  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
8. 1  Disc o nti n uati o n fr o m St u d y Treat me nt ............................................................ 
7 2  
8. 1. 1  P ost  St u dy Tre at me nt  St u dy F oll o w-u p....................................................  
7 2  
8. 1. 2  Tre at me nt  Bey o n d Pr o gressi o n................................................................  
7 3  
8. 2  Disc o nti n uati o n fr o m t he St u d y ........................................................................ 
7 3  
8. 3  L ost  t o F oll o w-U p.............................................................................................  
7 4  
9.  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....................................................  
7 4  
9. 1  Efficac y  Assess me nts........................................................................................  
7 5  
9. 1. 1  T u m or Assess me nts  .................................................................................. 
7 5  
9. 1. 2  I m a gi n g Assess me nt  f or t he St u dy............................................................  
7 5  
9. 2  A d verse E ve nts  ................................................................................................. 
7 6  
9. 2. 1  Ti me  Peri o d  a n d Fre q ue ncy f or C ollecti n g A E a n d S A E I nf or m ati o n .... 
7 6  
9. 2. 2  Met h o d of Detecti n g A Es  a n d S A Es.........................................................  
7 7  
9. 2. 3  F oll o w- u p of A Es  a n d S A Es  ..................................................................... 
7 7  
9. 2. 4  Re g ul at ory Re p orti n g Re q uire me nts  f or S A Es.........................................  
7 7  
9. 2. 5  Pre g n a ncy ................................................................................................ 
7 8  
9. 2. 6  L a b or at ory Test  Res ult  A b n or m alities ..................................................... 
7 8  
9. 2. 7  P ote nti al  Dr u g I n d uce d Liver  I nj ury ( DI LI) ............................................ 
7 9  
9. 2. 8  Ot her  S afety C o nsi der ati o ns .................................................................... 
7 9  
9. 2. 9  M a n a ge me nt Al g orit h ms f or I m m u n o- O nc ol o gy A ge nts ......................... 
7 9  
9. 3  O ver d ose ........................................................................................................... 
8 0  
9. 4  Safet y  ................................................................................................................ 
8 0  
9. 4. 1  P hysic al  Ex a mi n ati o ns.............................................................................  
8 1  
9. 4. 2  Vit al  Si g ns ................................................................................................ 
8 1  
9. 4. 3  Cli nic al  S afety L a b or at ory Assess me nts  .................................................. 
8 1  
9. 4. 4  I m a gi n g S afety Assess me nt  ...................................................................... 
8 1  
9. 5  P har mac o ki netic................................................................................................  
8 1  
9. 6  P har mac o d y na mics  ........................................................................................... 
8 2  
9. 7  P har mac o ge n o mics  ........................................................................................... 
8 2  
9. 8  Bi o mar kers  ........................................................................................................ 
8 2  
9. 8. 1  Bi o m arkers  i n t he T u m or ......................................................................... 
8 2  
9. 8. 2  Bi o m arkers  i n t he Bl o o d .......................................................................... 
8 3  
9. 8. 3  A d diti o n al Rese arc h  C ollecti o n  ............................................................... 
8 4  
9. 8. 4  Ot her  Assess me nts  ................................................................................... 
8 5  
9. 9  Healt h  Ec o n o mics O R  Me dical  Res o urce  Utilizati o n  a n d Healt h  Ec o n o mics . 
8 5  
9. 9. 1  O utc o mes  Rese arc h  Assess me nts  ............................................................. 
8 5  
9. 9. 1. 1  E Q - 5 D- 3 L ....................................................................................... 
8 5  
9. 9. 1. 2  F u ncti o n al Assess me nt  of C a ncer T her a py - Ly m p h o m a ( F A C T- 
Ly m)  ...................................................................................................... 
8 6  
1 0.  S T A TI S TI C A L  C O N SI D E R A TI O N S  ................................................................... 
8 7  
1 0. 1  Sa m ple  Size Deter mi nati o n.............................................................................  
8 7  
1 0. 2  P o p ulati o ns f or A nal yses ................................................................................ 
8 7  
1 0. 3  Statistical  A nal yses  ......................................................................................... 
8 7  
1 0. 3. 1  Effic acy  A n alyses  ................................................................................... 
8 7  
1 0. 3. 2  S afety A n alyses.......................................................................................  
8 9  
1 0. 3. 3  Ot her  A n alyses ....................................................................................... 
8 9  
1 0. 3. 3. 1  P h ar m ac oki netic A n alyses ............................................................ 
8 9  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
1 0. 3. 3. 2  I m m u n o ge nicity A n alyses ............................................................. 
1 0. 3. 3. 3  Bi o m arker  A n alyses  ...................................................................... 
1 0. 3. 3. 4  E Q - 5 D- 3 L ..................................................................................... 
1 0. 3. 3. 5  F A C T -Ly m.....................................................................................  
1 0. 3. 3. 6  Me dic al  Res o urce  Utiliz ati o n  ....................................................... 
1 0. 3. 4 I nteri m A n alyses.....................................................................................  
1 1. R E F E R E N C E S  ....................................................................................................... 
1 2 A P P E N DI C E S  ......................................................................................................... 
A P P E N DI X  1 A B B R E VI A TI O N S  A N D  T R A D E M A R K S  ........................................ 
A P P E N DI X  2 S T U D Y  G O V E R A N C E  C O N SI D E R A TI O N S  .................................... 
A P P E N DI X 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:  
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.........................................................................  
A P P E N DI X  4 W O M E N  O F  C HI L D B E A RI N G  P O T E N TI A L  D E FI NI TI O N S  A N D 
M E T H O D S O F C O N T R A C E P TI O N.....................................................................  
A P P E N DI X  5 K A R N O F S K Y  A N D  L A N S K Y  C RI T E RI A  ........................................ 
A P P E N DI X  6 I M A GI N G L E SI O N  E V A L U A TI O N  C RI T E RI A  ............................... 
A P P E N DI X 7 M A N A G E M E N T A L G O RI T HI M S F O R I M M U N O -O N C O L O G Y  
A G E N T S.................................................................................................................  
A P P E N DI X  8 R A DI O T H E R A P Y  G UI D E LI N E S  F O R  T H E  R 1  C O H O R T  .............. 
A P P E N DI X  9 R E VI S E D  P R O T O C O L  S U M M A R Y  O F  C H A N G E  HI S T O R Y  ........ 
8 9  
8 9  
9 0  
9 0  
9 0  
9 0  
9 1  
9 8  
9 9  
1 0 2  
 
 
1 1 0  
1 1 3  
1 1 6  
1 1 7  
 
1 2 1  
1 2 9  
1 3 5  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
1 
S Y N O P SI S  
Pr ot oc ol Title:  
Ris k -base d,  res p o nse-a da pte d, P hase  II o pe n-la bel trial of  ni v ol u ma b + bre nt u xi ma b ve d oti n ( N + 
B v) f or c hil dre n, a d olesce nts, a n d y o u n g a d ults wit h rela pse d/refract or y ( R/ R) C D 3 0 + classic 
H o d g ki n  l y m p h o ma  (c H L)  after  fail ure  of  first -li ne  t hera p y,  f oll o we d  b y  bre nt u xi ma b  +  
be n da m usti ne ( B v + B)  f or partici pa nts  wit h  a s u b o pti mal res p o nse. C hec k Mate  7 4 4: C H E C K p oi nt 
pat h wa y a n d ni v ol u ma b cli nical Trial E val uati o n. 
St u d y P h ase:  II 
R ati o n ale:  
Classical H o d g ki n l y m p h o ma (c H L) is c haracterize d b y rare mali g na nt Ree d Ster n ber g cells 
s urr o u n de d b y a n e xte nsi ve b ut i neffecti ve i nfla m mat or y i m m u ne cell i nfiltrate. Rece nt  w or k  has 
de m o nstrate d t hat c hr o m os o me 9 p 2 4. 1/ C D 2 7 4 ( P D -L 1) P D C D 1 L G 2 ( P D -L 2)  ge netic alterati o ns 
i ncrease t he P D-1 li ga n ds e x pressi o n, a n d are descri be d as a defi ni n g feat ure of c H L. T he 9 p 2 4 
a m plic o n als o c o ntai ns J A K 2, a n d c o p y n u m ber- de pe n de nt J A K 2-si g nal tra ns d ucers a n d acti vat ors 
of tra nscri pti o n w hic h ca n f urt her i ncrease P D - 1 li ga n d e x pressi o n. 
T hese ge netic alterati o ns c o m m o nl y f o u n d i n c H L i n dicate t hat P D -1 bl oc ka de is a reas o na ble 
tar get i n t his disease. I n a d diti o n, E pstei n-Barr vir us ( E B V) i nfecti o n ca n i ncrease e x pressi o n of 
P D -1 li ga n ds i n E B V -p ositi ve H o d g ki n l y m p h o mas ( H Ls). T his st u d y  will ali g n wit h t he c urre nt 
strate g y t o i nte grate c hec k p oi nt bl oc ka de ( ni v ol u ma b) i nt o t he treat me nt of c H L. 
St u d y P o p ul ati o n:  
Males  a n d  fe males,  5  t hr o u g h  3 0  years  of  a ge,  wit h  c o nfir me d  c H L,  e xcl u di n g  n o d ular  
l y m p h oc yte-pre d o mi na nt c H L, after fail ure of or n o n -res p o nse t o first-li ne t hera p y. Partici pa nts 
> 1 6 years  of a ge m ust ha ve  a Kar n ofs k y perf or ma nce le vel ≥ 5 0 %, a n d partici pa nts  ≤ 1 6 years  of 
a ge  m ust  ha ve  a  La ns k y  perf or ma nce  le vel  ≥ 5 0.  Partici pa nts  w h o  pre vi o usl y  recei ve d  a n  
all o ge neic  a n d/ or A S C T  f or c H L are e xcl u de d, as are partici pa nts  wit h  pri or  e x p os ure t o a nti- P D 1, 
a nti-P D L 1, a nti -P D -L 2, a nti C D 1 3 7, or a nti -C T L A -4 a nti b o dies, or a n y ot her a nti b o d y or dr u g 
s pecificall y tar geti n g T-cell c o-sti m ulati o n or c hec k p oi nt pat h wa ys. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
O bjecti ves a n d E n d p oi nts:  
 
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
R 1  ( L o w Ris k)  C o h ort:  T o  descri be  t he c o m plete 
R 1  C o h ort:  C M R  r ate at  a n y  ti me pri or  t o R T  a n d  E F S  
meta b olic  res p o nse ( C M R) rate pri or  t o R T  a n d 
r ate at  3  ye ars  
e ve nt-free  s ur vi val  ( E F S)  rate  at  3  years,  as  
assesse d  b y  bli n de d  i n de pe n de nt  ce ntral  re vie w  
( BI C R), usi n g L u ga n o 2 0 1 4 res p o nse criteria. 
•  
T he  C M R  rate  is  defi ne d  as  t he  pr o p orti o n  of  all  
res p o nse-e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  
BI C R,  ac hie ve best  res p o nse of  C M R  usi n g  L u ga n o  2 0 1 4 
criteria. 
 
•  
E F S is t he ti me fr o m t he date of first treat me nt t o t he 
earliest  occ urre nce  of  c o m p osite  e ve nts  i ncl u di n g  t he  
f oll o wi n g: 
 
− 
Hi g h -d ose  c he m ot hera p y  f oll o we d b y  a ut ol o g o us 
ste m cell tra ns pla nt ( H D C T/ A S C T) 
 
− 
Disease  pr o gressi o n  per  L u ga n o  ( 2 0 1 4) 
 
− 
Fail ure  t o ac hie ve C M R  after 4 c ycles of  N + B v  a n d 
2 c ycles of B v + B  
 
− 
Sec o n dar y  mali g na nc y  
 
− 
Deat h  d ue  t o a n y ca use 
 
•  
Partici pa nts  w h o  di d  n ot  ha ve  a n  “e ve nt”  will  be  
ce ns ore d  at  t he  last  a de q uate  t u m or  assess me nt.  
Partici pa nts  w h o  start  s u bse q ue nt  a ntica ncer  t hera p y  
(t hat is n ot  part  of  H D C T/ A S C T)  wit h o ut  a pri or  re p orte d 
“e ve nt” will be ce ns ore d at t he last t u m or assess me nt 
pri or  t o  or  o n  t he  da y  of  t he  s u bse q ue nt  a ntica ncer  
t hera p y. 
 
•  
Ot her  defi niti o ns  of  E F S,  e m pl o yi n g  s o me w hat differe nt 
ce ns ori n g r ules, ma y be a d de d as se nsiti vit y a nal yses.  
R 2  ( Sta n dar d Ris k)  C o h ort:  T o  descri be  t he 
R 2  C o h ort:  C M R  r ate at  a n y  ti me pri or  t o H D C T/ A S C T  
c o m plete meta b olic res p o nse ( C M R) rate pri or t o 
H D C T/ A S C T  b y  BI C R,  usi n g  L u ga n o  2 0 1 4  
res p o nse criteria 
•  
T he  C M R  rate  is  defi ne d  as  t he  pr o p orti o n  of  all  
res p o nse-e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  
BI C R,  ac hie ve best  res p o nse of  C M R  usi n g  L u ga n o  2 0 1 4 
criteria. 
Sec o n d ar y  i n B ot h  R 1  a n d  R 2  C o h orts:  
 
T o assess o verall res p o nse rate ( O R R) ( C M R + 
partial meta b olic res p o nse [ P M R]) usi n g L u ga n o 
2 0 1 4  criteria  of  t he  l o w  ris k  a n d  sta n dar d  ris k  
c o h orts  f oll o wi n g  4  c ycles  of  ni v ol u ma b  a n d  
bre nt u xi ma b ve d oti n b y BI C R.  
O R R  f oll o wi n g  4  c ycles  of  ni v ol u m a b  +  bre nt u xi m a b  
ve d oti n tre at me nt  
•  
O R R  is  defi ne d  as  t he  pr o p orti o n  of  all  res p o nse - 
e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  BI C R,  
ac hie ve a best res p o nse of C M R or P M R usi n g L u ga n o 
2 0 1 4 criteria.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
O bjecti ves  
E n d p oi nts  
T o  assess  P F S  rate at 3  years  b y  BI C R  usi n g 
L u ga n o 2 0 1 4 criteria  
P F S  r ate at  3  ye ars  
•  
T he a nal ysis is perf or me d w he n partici pa nts ha ve bee n 
f oll o we d f or 3 years.  P F S  is t he ti me fr o m t he date  of  first 
treat me nt  t o  t he  date  of  first  d oc u me nte d  disease  
pr o gressi o n b y BI C R or deat h. Partici pa nts w h o  neit her 
pr o gress n or die will be ce ns ore d at t he last a de q uate 
t u m or  assess me nt.  Partici pa nts  w h o  start  s u bse q ue nt  
a ntica ncer  t hera p y  (t hat  is  n ot  part  of  H D C T/ A S C T  
C o ns oli dati o n T hera p y f or R 2 C o h ort) wit h o ut a pri or 
re p orte d pr o gressi o n  or  deat h  will  be  ce ns ore d  at t he last 
t u m or assess me nt pri or t o i nitiati o n of t he s u bse q ue nt 
a ntica ncer t hera p y.  
•  
Ot her  defi niti o ns  of  P F S,  e m pl o yi n g  s o me w hat differe nt 
ce ns ori n g r ules, ma y be a d de d as se nsiti vit y a nal yses.  
D urati o n  of  Res p o nse  ( D O R) will  be  e val uate d  f or 
t h ose partici pa nts w h o ac hie ve d P M R or C M R b y 
BI C R  as  well  as  f or  t h ose  partici pa nts  w h o  
ac hie ve d  C M R  b y  BI C R  pri or  t o R T  i n t he l o w ris k 
c o h ort  a n d  f or  t h ose  partici pa nts  w h o  ac hie ve d  
C M R pri or t o H D C T/ A S C T i n t he sta n dar d ris k 
c o h ort. 
D O R  
•  
D O R  is defi ne d  as t he ti me fr o m first res p o nse ( C M R or 
P M R)  t o  t he  date  of  E F S  ( R 1)/ P F S  ( R 2)  e ve nt.  F or  
partici pa nts  w h o  di d  n ot  ha ve  a n e ve nt, t he D O R  will  be 
ce ns ore d  o n  t he  date  of  t heir  last  t u m or  assess me nt.  
Partici pa nts  w h o  start  s u bse q ue nt  a ntica ncer  t hera p y  
(t hat is n ot  part  of  H D C T/ A S C T)  wit h o ut  a pri or  re p orte d 
E F S/ P F S  e ve nt  will  be  ce ns ore d  at  t he  last  t u m or  
assess me nt  pri or  t o  i nitiati o n  of  t he  s u bse q ue nt  
a ntica ncer t hera p y.  
T o e val uate efficac y as assesse d  b y i n vesti gat ors 
usi n g L U G A N O ( 2 0 1 4) res p o nse criteria.  
All  effic ac y e n d p oi nts a b o ve,  per  i n vesti g at or assess me nts  
R 1  c o h ort: C M R  rate pri or  t o R T  a n d E F S  at 3 years 
R 2 c o h ort: C M R rate pri or t o H D C T/ A S C T  
B ot h R 1 a n d R 2 c o h orts: O R R f oll o wi n g 4 c ycles of N + B v 
treat me nt, P F S rate at 3 years, a n d D O R. 
T o  descri be  t he  t o xicit y  of  ni v ol u ma b  +  
bre nt u xi ma b  i n c o m bi nati o n  i n pe diatric  a n d y o u n g 
a d ult  partici pa nts  wit h  rela pse d  or  refract or y  
classical H o d g ki n’s  l y m p h o ma (c H L) after fail ure 
of first -li ne treat me nt. 
T o xicit y/ S afet y E n d p oi nts  are seri o us a n d  n o n -seri o us A Es, 
cli nical la b orat or y tests ( he mat ol o g y, c he mistr y, uri nal ysis), 
vital si g n meas ure me nts, etc.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
O bjecti ves  
E n d p oi nts  
E x pl or at or y  
 
•  
T o assess o verall s ur vi val ( O S) i n all treate d 
partici pa nts  i n  t he  S R  a n d  L R  c o h orts,  
res pecti vel y. 
•  
Ass ociati o n  of  bi o mar ker  le vels wit h  res p o nse 
i ncl u di n g O R R, P F S, a n d O S. 
•  
O S is defi ne d as t he ti me fr o m t he date of first d ose of 
st u d y dr u g u ntil t he date of deat h f or a n y reas o n. If t he 
partici pa nt is ali ve or t he vital stat us is u n k n o w n, t he 
partici pa nt will be ce ns ore d at t he date t he partici pa nt 
was last k n o w n t o be ali ve.  
 
•  
T o  assess  c ha n ges  i n  bi o mar kers  i n  t he  
peri p heral  bl o o d,  s uc h  as  s ol u ble  fact ors,  
i m m u ne  cells,  a n d  vacci nate d  a nti b o d y  
c o nce ntrati o ns. 
•  
T o  assess  bi o mar kers  i n t he t u m or tiss ue, s uc h as P D -L 1 
e x pressi o n, 9 p 2 4. 1 c o p y n u m ber alterati o n, a n d t u m or 
i nfiltrati n g  l y m p h oc ytes  a n d  t heir  ass ociati o n  wit h  
res p o nse. 
•  
T o  s u m marize c ha n ges i n bi o mar ker  le vels o ver  ti me (see 
pr ot oc ol Secti o n 9. 8 ). 
 
•  
T o  c haracterize  p har mac o ki netics  ( P K)  of  
ni v ol u ma b
 a n d
 bre nt u xi ma b
 f oll o wi n g
 
c o m bi nati o n t hera p y.  
•  
Ser u m sa m ples will be c ollecte d t o c haracterize P K of 
ni v ol u ma b a n d bre nt u xi ma b.  
•  
Sa m ples will be e val uate d f or t he prese nce of a nti -dr u g 
a nti b o d y. 
•  
T o  c haracterize  t he  i m m u n o ge nicit y  of  
ni v ol u ma b
 a n d
 bre nt u xi ma b
 f oll o wi n g
 
c o m bi nati o n t hera p y.  
•  
T o  e val uate  partici pa nt -re p orte d  ge neral  
healt h  stat us a n d ca ncer-s pecific q ualit y  of  life 
( Q o L). 
•  
T o  i n vesti gate  t he  effect of  4  p ote ntial  ris k  
fact ors o n E F S a n d O R R. 
•  
Ge neral healt h stat us as assesse d b y  t he E Q-5 D -3 L, a n d 
ca ncer-s pecific Q o L as assesse d b y t he F A C T-L y m  
•  
See  defi niti o n  of  E F S  a n d O R R  a b o ve (see ris k fact ors i n 
pr ot oc ol Secti o n 3. 1 ) 
•  
T he sa me efficac y  varia bles  detaile d  a b o ve a n d meas ure d 
f or L U G A N O 2 0 1 4 will be e x pl ore d f or L Y RI C 2 0 1 6. 
•  
I m ple me ntati o n of L Y RI C 2 0 1 6 f or efficac y 
assess me nts.  
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
O ver all Desi g n:  
 
Ris k  Str atific ati o n  Al g orit h m  
St a ge  at  I niti al 
Di a g n osis  
Ti me t o Rel a pse 
(fr o m e n d of  t her a p y) 
B s y m pt o ms or e xtr a n o d al 
dise ase at rel a pse, e xte nsi ve 
dise ase w here  r a di ati o n  t her a p y 
w as c o ntr ai n dic ate d at rel a pse, 
or rel a pse i n a pri or r a di ati o n 
fiel d 
Rel a pse  Ris k 
C ate g or y  
I A, II A 
≥ 1 2  m o nt hs  
N o  
R 1  C o h ort: 
L o w Ris k  
3- 1 2  m o nt hs  
(≤ 3 c ycles a n d n o  R T)  
I B, II B, III A 
> 1 2 m o nt hs  
N o  
All Ot hers  
R 2  C o h ort:  
 
St a n d ar d  Ris k  
 
C A 2 0 9 7 4 4  is  a  P hase  2,  o pe n -la bel  st u d y  of  N + B v  f or  c hil dre n  a n d  y o u n g  a d ults  wit h  
rela pse d/refract or y c H L. Partici pa nts  w h o  d o n ot ac hie ve C M R  after 4 c ycles of N + B v  will  recei ve 
B v + B  t o hel p ac hie ve  C M R.  T here  are 2 treat me nt c o h orts: o ne wit h  partici pa nts at l o w ris k rela pse 
( R 1 c o h ort), a n d o ne wit h  partici pa nts  at sta n dar d ris k rela pse ( R 2 c o h ort) (Ta ble  5. 1- 1 a n d Fi g ure 
5. 1 - 1). 
•  R 1 c o h ort will recei ve N + B v f or 2 c ycles ( 6 wee ks) f oll o we d b y T u m or Assess me nts ( T A). 
Partici pa nts wit h ra di o gra p hic pr o gressi o n, as assesse d b y I n vesti gat or ( per A p pe n di x 6 ) at 
C ycle  2 N + B v,  will  be ta ke n off  st u d y treat me nt a n d e nter f oll o w- u p ( u nless treat me nt be y o n d 
pr o gressi o n is a p pr o ve d b y t he Brist ol -M yers S q ui b b ( B M S) Me dical M o nit or, per Secti o n  
8. 1. 2 ). All ot her partici pa nts will recei ve 2 a d diti o nal c ycles of N + B v st u d y t hera p y (t otal 4 
c ycles = 1 2 wee ks).  
− Partici pa nts  w h o  ha ve a C M R,  as assesse d  b y BI C R,  after a t otal of 4 c ycles ( 1 2 wee ks)  of 
N + B v  will  recei ve a n a d diti o nal  2 c ycles of  treat me nt of  N + B v  (f or a t otal of 6 c ycles [ 1 8 
wee ks]),  f oll o we d b y Ra diati o n T hera p y ( R T), per i nstit uti o nal g ui deli nes ( See  A p pe n di x  
8 : Ra di ot hera p y G ui deli nes f or R 1 C o h ort f urt her rec o m me n dati o ns). 
− Partici pa nts   wit h o ut  a C M R  after  4 c ycles  of N + B v,  as assesse d   b y BI C R,  will  recei ve 
2 c ycles of B v + B; partici pa nts w h o ac hie ve C M R after t hese 2 c ycles will pr ocee d wit h 
R T, per  i nstit uti o nal g ui deli nes ( See A p pe n di x 8: Ra di ot hera p y  G ui deli nes f or R 1 C o h ort 
f urt her rec o m me n dati o ns). 
− Partici pa nts  w h o  ha ve ra di o gra p hic pr o gressi o n after c ycle  4 N + B v,  as assesse d  b y BI C R, 
( u nless Treat me nt  Be y o n d Pr o gressi o n is a p pr o ve d b y B M S  Me dical  M o nit or,  per  Secti o n 
8. 1. 2  of  t he  pr ot oc ol) or  t h ose w h o   d o  n ot ac hie ve C M R,  as assesse d   b y BI C R,  after 
2 c ycles of B v + B will be ta ke n off st u d y treat me nt a n d e nter f oll o w - u p. 
•  R 2 c o h ort will recei ve N + B v f or 2 c ycles ( 6 wee ks), f oll o we d b y T A. Partici pa nts wit h 
ra di o gra p hic pr o gressi o n, as assesse d b y I n vesti gat or ( per A p pe n di x 6) at C ycle  2 N + B v,  will 
be ta ke n off   st u d y treat me nt a n d e nter  f oll o w-u p   ( u nless Treat me nt   Be y o n d  Pr o gressi o n is 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
a p pr o ve d  b y B M S  Me dical  M o nit or,   per Secti o n   8. 1. 2). All   ot her partici pa nts  will  recei ve 
2 a d diti o nal c ycles of N + B v st u d y t hera p y (t otal 4 c ycles = 1 2 wee ks). 
− Partici pa nts w h o ha ve C M R, as assesse d b y BI C R, after a t otal of 4 c ycles of N + B v will 
pr ocee d wit h H D C T/ A S C T ( perf or me d per i nstit uti o nal g ui deli nes). 
♦ Partici pa nts wit h C M R will ha ve t he o pti o n t o recei ve u p t o t w o a d diti o nal c ycles of 
N + B v if t heir H D C T/ A S C T has t o be p ost p o ne d f or a n y reas o n (t his re q uires pri or 
B M S Me dical M o nit or a p pr o val). 
− Partici pa nts   wit h o ut  a C M R,  as assesse d   b y BI C R,  after  4 c ycles  of N + B v  will  recei ve 
2 c ycles of B v + B.  
♦ Partici pa nts  i n  C M R,  as  assesse d  b y  BI C R,  after  2  c ycles  of  B v + B  will  recei ve  
H D C T/ A S C T ( perf or me d per i nstit uti o nal g ui deli nes).  
♦ Partici pa nts   wit h o ut C M R  as assesse d   b y BI C R  will   ha ve a n o pti o n  t o recei ve 
2 a d diti o nal c ycles of B v + B (t his re q uires pri or B M S Me dical M o nit or a p pr o val). If 
t hese  partici pa nts  attai n  C M R,  as  assesse d  b y  BI C R,  t he y  will  pr ocee d  wit h  
H D C T/ A S C T ( perf or me d per i nstit uti o nal g ui deli nes).  
♦ Partici pa nts wit h C M R will ha ve t he o pti o n t o recei ve u p t o t w o a d diti o nal c ycles of 
B + B v if t heir H D C T/ A S C T has t o be p ost p o ne d f or a n y reas o n (t his re q uires pri or 
B M S Me dical M o nit or a p pr o val). 
− Partici pa nts  w h o  ha ve ra di o gra p hic pr o gressi o n after c ycle  4 N + B v,  as assesse d  b y BI C R, 
d uri n g  st u d y  treat me nt  ( u nless  Treat me nt  Be y o n d  Pr o gressi o n  is  a p pr o ve d  b y  B M S  
Me dical  M o nit or,  per  Secti o n  8. 1. 2 of  t he pr ot oc ol) or t h ose w h o d o n ot ac hie ve C M R, as 
assesse d b y BI C R, after fi nal c ycle of B v + B will be ta ke n off st u d y treat me nt a n d e nter 
f oll o w-u p.  
 
R 1  a n d  R 2  C o h ort  F oll o w -u p  Visits  will  occ ur  Da y  3 0,  a n d  t he n  s y nc he d  u p  wit h  t u m or  
assess me nts  Da y  1 0 0 a n d t he n 6, 1 2, 1 8, 2 4, a n d 3 6 m o nt hs P ost - C o ns oli dati o n T hera p y/ Treat me nt 
Disc o nti n uati o n. O nce partici pa nts reac h t he s ur vi val f oll o w -u p p hase, eit her i n -pers o n visits or 
d oc u me nte d tele p h o ne calls/e mail c orres p o n de nce t o assess t he partici pa nt’s  stat us are acce pta ble. 
T u m or assess me nts are re q uire d f or partici pa nts w h o ha ve n ot ra di o gra p hicall y pr o gresse d, per 
BI C R, as per Ta ble 2 - 3 a n d Secti o n 9. 1  of t he pr ot oc ol. If I n vesti gat or t u m or assess me nt = C M R 
f or a treat me nt relate d- decisi o ns ti me p oi nt ( C ycle 4 I n d ucti o n, or C ycle 2 or 4 I nte nsificati o n, as 
a p plica ble) b ut BI C R assess me nt differs, a n d as a res ult st u d y treat me nt is disc o nti n ue d a n d 
H D C T/ A S C T  (f or  R 2  C o h ort)  a n d  R T  (f or  R 1  C o h ort)  is  perf or me d  i n  f oll o w -u p,  t u m or  
assess me nts  s h o ul d  c o nti n ue  t o  be  pr o vi de d  u ntil  ra di o gra p hic  pr o gressi o n  per  I n vesti gat or  
Assess me nt, per L U G A N O 2 0 1 4.  F or t hese cases, it is rec o m me n de d t o f oll o w t he sa me sca n 
fre q ue nc y a n d m o dalit y as w he n BI C R assess me nt = C M R ( per ta ble 2.- 4: 1 0 0 da ys a n d t he n 6, 
1 2,  1 8,  2 4,  a n d  3 6  m o nt hs  p ost -C o ns oli dati o n  T hera p y/ Treat me nt  Disc o nti n uati o n),  b ut  at  a  
mi ni m u m t he M o nt h 3 6 t u m or assess me nt is re q uire d.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
N u m ber  of P artici p a nts:  
A p pr o xi matel y 1 0 0 partici pa nts  were  pla n ne d t o be e nr olle d, wit h  a p pr o xi matel y  8 0 treate d ( 4 0 i n 
eac h c o h ort), i n c o nsi derati o n of p ote ntial scree ni n g fail ures or t h ose w h o are treate d b ut n ot 
res p o nse-e val ua ble.  A mi ni m u m  of  2 5  treate d partici pa nts  ( R 1: 5, R 2:  2 0) will  be pe diatric  ( 5 t o < 
1 8 years ol d), u nless B M S St u d y Tea m i nstr ucts ot her wise.  
T he  pr ot oc ol reflecte d a pr o p osal t o i ncl u de a t otal of 1 0 0 e nr olle d partici pa nts  t o o btai n 8 0 treate d 
partici pa nts (a ge 5 t o < 3 0), wit h 4 0 partici pa nts per c o h ort, a n d a mi ni m u m of 2 5 pe diatric 
partici pa nts (a ge 5 t o < 1 8).  
Alt h o u g h t he pr o p ose d sa m ple 
size i n t he pr ot oc ol was n ot i nte n de d t o s u p p ort statistical h y p ot hesis testi n g, 9 0 % c o nfi de nce 
i nter vals ( CI), c orres p o n di n g t o a ra n ge of o bser ve d res p o nse rates, were  pr o vi de d t o ill ustrate t he 
precisi o n of esti mati o n ( See Ta ble 1 0. 3. 1- 1 ). 
St u d y C A 2 0 9 7 4 4 is bei n g c o n d ucte d i n 1 1 c o u ntries w orl d wi de (alt h o u g h o nl y 1 0 of t he m ha ve 
bee n  a ble t o recr uit partici pa nts)  wit h  7 5 acti vate d sites i n t otal; h o we ver, o nl y 2 0 %  of  t he t otalit y 
 
 
 
 
I n li g ht of a b o ve, t he pr ot oc ol is bei n g m o difie d  t o re d uce t he t otal n u m ber  of partici pa nts  fr o m 8 0 
t o  7 2 (t otal n u m ber of treate d partici pa nts e nr olle d R 1 = 2 8 a n d R 2 = 4 4) 
 
wit h  a n o verall sizea ble p o p ulati o n 
t hat  ca n  s u p p ort  a  f ut ure  assess me nt  of  be nefit/ris k.  Ass u mi n g  2 4  res p o n ders  o ut  of  2 8  R 1  
partici pa nts, t he e xact 2 -si de d 9 0 % c o nfi de nce i nter val w o ul d be 7 0. 2 3 % t o 9 4. 9 7 %. 
See  Secti o n  1 0 f or details  o n statistical c o nsi derati o ns a n d sa m ple size deter mi nati o n.  
of  t he sites recr uite d R 1  partici pa nts.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Tre at me nt Ar ms a n d D ur ati o n:  
St u d y  Tre at me nt:  
 
St u d y  Tre at me nts  f or C A 2 0 9 7 4 4  
Pr o d uct 
Descri pti o n / 
Cl ass  a n d  D os a ge 
F or m  
P ote nc y  
I P/ N o n-I M P 
Bli n de d or 
O pe n  L a bel  
P ac k a gi n g  / 
A p pe ar a nce  
St or a ge 
C o n diti o ns 
( per l a bel) 
Ni v ol u ma b 
( B M S-9 3 6 5 5 8 -0 1)  
S ol uti o n  f or 
I njecti o na 
 
1 0 0  m g  
( 1 0 m g/ m L)  
 
 
I M P 
 
 
O pe n  la bel 
1 0 m L Vial/ Clear 
t o o palesce nt 
c ol orless t o pale 
yell o w  li q ui d. Ma y 
c o ntai n particles.  
 
2 t o 8°C.  Pr otect 
fr o m li g ht a n d 
freezi n g 
Bre nt u xi ma b 
Ve d oti n  p o w der  f or 
s ol uti o n f or 
I njecti o nb  
 
 
5 0  m g  
 
 
I M P 
 
 
O pe n  La bel  
W hite t o off -w hite 
l y o p hilize d 
preser vati ve -free 
ca ke or  p o w der  i n a 
si n gle-use vial f or 
rec o nstit uti o n 
 
2 t o 8°C.  Pr otect 
fr o m li g ht a n d 
freezi n g 
Be n da m usti ne 
p o w der  f or s ol uti o n 
f or I njecti o nb  
O R  
Be n da m usti ne 
S ol uti o n f or  
I njecti o nb  
 
2 5 m g or  
1 0 0  m g  
 
O R  
1 0 0  m g/ 4  ml  
( 2 5 m g/ ml)  
 
 
 
 
I M P 
 
 
 
 
O pe n  la bel 
W hite t o off -w hite 
l y o p hilize d  p o w der  
i n a si n gle-d ose  vial 
f or rec o nstit uti o n 
O R  
Clear  a n d c ol orless 
t o yell o w  rea d y-t o- 
dil ute s ol uti o n  
1 5  t o 2 5 °C 
( p o w der) 
O R  
2 t o 8 C 
(s ol uti o n). 
Pr otect  fr o m 
li g ht 
a Ma y  be  la bele d as eit her  “ B M S-9 3 6 5 5 8 -0 1”  or  “ Ni v ol u ma b.” 
b T hese pr o d ucts ma y be o btai ne d b y t he i n vesti gati o nal sites as l ocal c o m mercial pr o d uct i n certai n c o u ntries if 
all o we d b y l ocal re g ulati o ns. I n t hese cases, pr o d ucts ma y be a differe nt pac k size/ p ote nc y t ha n liste d i n t he ta ble. 
T hese pr o d ucts s h o ul d be pre pare d/st ore d/a d mi nistere d i n acc or da nce wit h t he pac ka ge i nsert or s u m mar y of 
pr o d uct c haracteristics ( S m P C)  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
2.  
S C H E D U L E O F A C TI VI TI E S  
Scree ni n g assess me nts f or  t his st u d y are s u m marize d i n Ta ble 2 - 1, i n d ucti o n I M P treat me nt a n d 
p ost- I M P t hera p y pr oce d ures i n Ta ble 2 - 2, i nte nsificati o n I M P treat me nt a n d p ost-I M P t hera p y 
pr oce d ures i n Ta ble 2 - 3, f oll o w-u p assess me nts i n Ta ble 2 - 4, bi o mar ker sa m pli n g sc he d ule i n 
Ta ble 2 - 5, a n d p har mac o ki netic ( P K) a n d i m m u n o ge nicit y sa m pli n g sc he d ule i n Ta ble 2 - 6. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -1:  
Scree ni n g  Assess me nts  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 0  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
Visit  
Scree ni n g 
( D a y -2 8  t o -1)  
Scree ni n g 
( D a y -1 4  t o -1)  
Scree ni n g 
( D a y -1)  
Scree ni n g  N otes  
Eli gi bilit y  Assess me nts  
 
 
 
 
I nf or me d C o nse nt  
X 
 
 
 
I ncl usi o n / E xcl usi o n  Criteria  
X 
 
 
 
Me dical  Hist or y  
X 
 
 
 
Pri or  S yste mic  T hera p y  
X 
 
 
 
Kar n ofs k y  / La ns k y Perf or ma nce 
Stat us ( P S)  
 
X 
 
Kar n ofs k y  ≥ 5 0  f or partici pa nts > 1 6  years  of  a ge or  La ns k y  ≥ 5 0 
f or partici pa nts ≤ 1 6 years of a ge ( A p pe n di x 5 ) 
I R T Partici pa nt  Assi g n me nt / 
C o h ort Assi g n me nt  
 
X 
 
 
C o ntact I R T  f or partici pa nt  n u m ber  assi g n me nt (a n d c o h ort 
assi g n me nt,  per  Ta ble 5. 1 - 1- Ris k  Stratificati o n  Al g orit h m), 
w he n  i nf or me d c o nse nt is o btai ne d.  Tri g gers  dr u g  s hi p me nt. 
S afet y  Assess me nts  
 
 
 
 
 
C o m plete  P h ysical  E xa mi nati o n 
( P E) 
 
 
X 
 
S ki n & m uc us me m bra nes, L y m p h n o de areas (e g, 
s u b ma n di b ular, cer vical,  s u pracla vic ular, a xillar y,  or  i n g ui nal 
l y m p h n o de), a b d o mi nal or ga ns (e g, s plee n, li ver), a n d 
ne ur ol o gical e xa mi nati o n  
P h ysical  Meas ure me nts  
 
X 
 
Hei g ht,  wei g ht,  R R  (res pirati o n rate), a n d B S A  ( b o d y s urface 
area) 
Vital  Si g ns  
 
X 
 
Te m perat ure,  B P,  H R  
Pre g na nc y  Test  (ser u m or  uri ne)  
 
 
X 
Ser u m  or  uri ne  res ults wit hi n  2 4  h o urs  pri or  t o first d ose,  f or 
W O C B P o nl y.  
C o nc o mita nt  Me dicati o ns  
 
X 
 
 
Assess me nt of  Si g ns  a n d S y m pt o ms   
X 
 
 
M o nit or  f or Seri o us  A d verse  E ve nts  
X 
 
 
 
C B C  wit h  Differe ntial  a n d Platelets   
X 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -1:  
Scree ni n g  Assess me nts  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 1  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
Visit  
Scree ni n g 
( D a y -2 8  t o -1)  
Scree ni n g 
( D a y -1 4  t o -1)  
Scree ni n g 
( D a y -1)  
Scree ni n g  N otes  
C he mistr y  (e xcl u di n g L F Ts)  
 
X 
 
Uric  aci d, B U N  or  ser u m urea  le vel, creati ni ne, Ca,  M g,  K,  Cl, 
Na, p h os p hate, a m ylase, li pase, gl uc ose, a n d L D H  
L F T assess me nts  
 
X 
 
A S T, A L T,  t otal bilir u bi n,  al kali ne p h os p hatase  
T h yr oi d  F u ncti o n  Tests  
 
X 
 
T h yr oi d  Sti m ulati n g  H or m o ne  ( T S H) (refle x t o free T 3,  free T 4 
f or a b n or mal T S H res ult), 
Uri nal ysis  
 
X 
 
T otal  pr otei n,  gl uc ose,  bl o o d,  le u k oc yte esterase,  s pecific gra vit y, 
a n d p H 
 
Ser ol o g y  
 
X 
 
 
He patitis  B s urface a nti ge n,  a n d he patitis  C a nti b o d y  or  H C V 
ri b o n ucleic aci d. Testi n g  f or HI V  m ust  be  perf or me d  at sites, 
w here ma n date d l ocall y.  
Effic ac y  
 
 
 
 
 
 
 
 
 
 
 
T u m or Assess me nts  
F D G  P E T-C T  or  P E T -M RI,  or  
F D G -P E T  wit h  C T/ M RI  
 
 
 
 
 
 
 
 
X 
 
 
T o be  perf or me d  wit hi n  2 8  da ys  pri or  t o first d ose.  
F D G -P E T w h ole -b o d y (t o p -of -hea d t o mi d -t hi g hs) a n d all 
k n o w n/s us pecte d  sites of  disease will  be  use d  f or meta b olic 
res p o nse assess me nt. 
If t he C T perf or me d as part of a F D G P E T-C T is of c o m para ble 
q ualit y t o a dia g n ostic C T ( wit h I V c o ntrast preferre d) t he n t he 
a de q uate-d ose C T of F D G P E T -C T ca n be use d f or t u m or 
meas ure me nts. If l o w d ose C T is use d f or P E T -C T, perf or m 
c o ntrast e n ha nce d C T nec k, c hest, a b d o me n -pel vis a n d ot her 
k n o w n  or  s us pecte d sites of  disease  wit h  I V c o ntrast.  Ga d oli ni u m 
e n ha nce d M RI is acce pta ble if C T c o ntrast is c o ntrai n dicate d.  
N o n -c o ntrast M RI/ C T  is acce pta ble  if C T  a n d M R  c o ntrasts  are 
c o ntrai n dicate d. 
If C N S i n v ol ve me nt is s us pecte d, perf or m Brai n M RI wit h o ut 
a n d wit h  Ga d oli ni u m  c o ntrast at baseli ne  t o e xcl u de s u bjects wit h 
brai n i n v ol ve me nt.  
See  Secti o n  9. 1  f or f urt her details.  
Bi o m ar ker  S a m pli n g  
See  N ote  
See  I ncl usi o n Criteria  2c  a n d Ta ble  2- 5 f or details  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 2  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
S afet y  
Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
Kar n ofs k y/ 
La ns k y 
Perf or ma nce 
Stat us  
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X d 
Kar n ofs k y P S f or 
partici pa nts  > 1 6  years  a n d 
La ns k y  P S  f or partici pa nts  
≤ 1 6  years  of  a ge (A p pe n di x  
5 ) 
 
 
Tar gete d 
P h ysical 
E xa mi nati o n  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X d 
S ki n  & m uc us  me m bra nes, 
L y m p h n o de areas (e g, 
s u b ma n di b ular, cer vical, 
s u pracla vic ular, a xillar y,  or 
i n g ui nal l y m p h n o de), 
a b d o mi nal or ga ns (e g, 
s plee n, li ver), a n d 
ne ur ol o gical e xa mi nati o n  
P h ysical 
Meas ure me nts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X d 
Wei g ht  
Vital  Si g ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X d 
Te m perat ure,  B P,  H R  
C B C wit h 
Differe ntial  a n d 
Platelets  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X d 
C ollecte d  wit hi n  3 da ys 
pri or t o eac h d ose  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 3  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
 
 
C he mistr y 
(e xcl u di n g 
L F Ts)  
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X d 
Uric aci d, B U N or ser u m 
urea le vel, creati ni ne, Ca, 
M g,  K,  Cl,  Na,  p h os p hate, 
a m ylase, li pase, gl uc ose, 
a n d L D H 
C ollecte d  wit hi n  3 da ys 
pri or t o eac h d ose  
 
L F T  
assess me nts  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X d 
A S T, A L T,  a n d t otal 
bilir u bi n  
C ollecte d  wit hi n  3 da ys 
pri or t o eac h d ose  
T h yr oi d 
F u ncti o n  Tests 
( T F Ts) 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X d 
T S H (refle x t o free T 3  a n d 
free T 4  if a b n or mal res ult) 
t o be perf or me d at e ver y 
ot her c ycle  
 
Uri nal ysis  
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X d 
T otal pr otei n, gl uc ose, 
bl o o d,  le u k oc yte esterase, 
s pecific gra vit y, a n d p H 
 
Pre g na nc y  Test 
(ser u m or  uri ne)  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X d 
Ser u m or uri ne wit hi n  
2 4 h o urs pri or t o first d ose 
a n d t he n D 1 of e ver y c ycle 
(a n d D 8  f or C ycle  1 N + B v),  
f or W O C B P.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 4  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
C o nc o mita nt 
Me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X d 
 
M o nit or f or 
A d verse  E ve nts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X d 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 5  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
Effic ac y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or 
Assess me nts  
F D G  P E T-C T  
or  P E T-M RI,  or 
F D G -P E T wit h 
C T/ M RI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
F D G -P E T  w h ole -b o d y  (t o p- 
of -hea d t o mi d -t hi g hs) a n d 
all k n o w n/s us pecte d  sites of 
disease  will be use d f or 
meta b olic res p o nse 
assess me nt, u ntil t he 
partici pa nt is i n BI C R 
assesse d C M R, p ost - 4 
c ycles of N + B v. C T/ M RI 
f or N/ C/ A/ P a n d ot her 
k n o w n or s us pecte d sites of 
disease.  See  g ui deli nes  fr o m 
Ta ble 2. - 1 a n d Secti o n 9. 1  
Partici pa nts  w h o  e x perie nce 
P D/ P M D per BI C R, will 
c o me off treat me nt a n d 
e nter f oll o w-u p, u nless 
treat me nt be y o n d 
pr o gressi o n is a p pr o ve d per 
Secti o n 5. 1  a n d Secti o n  
8. 1. 2  
Bi o m ar ker  S a m pli n g  
 
See  Ta ble  2- 5 f or details  
P K a n d  I m m u n o ge nicit y S a m pli n g  
 
See  Ta ble  2- 6 f or details  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 6  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
O utc o mes  
Rese arc h  
Assess me nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
E Q- 5 D -3 L  a n d 
F A C T -L y m  
X- 
pre - 
d ose  
 
 
 
 
X 
 
 
 
 
X 
 
 
 
C o m plete  f or partici pa nts  
≥ 1 2 years ol d. 
( See Secti o n  9. 9. 1 ) 
Me dic al  
Res o urce  
Utiliz ati o n  
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X d 
 
See  Secti o n  9. 9  
 
Pre - 
me dic ati o ns  
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
See Secti o n 7. 1. 1  f or 
pr o p h ylactic  pre me dicati o n 
re q uire me nts f or 
c o m bi nati o n t hera p y  
St u d y Dr u g  
A d mi nistr ati o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
I R T Treat me nt 
Assi g n me nt  
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
C o ntact  I R T t o assi g n I M P 
treat me nt 
Ni v ol u ma b e 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
See  Secti o n  7 
Bre nt u xi ma b 
Ve d oti n e 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
See  Secti o n  7 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -2:  
I n d ucti o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 7  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I n d ucti o n P h ase  ( N + B v) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 
D 1  
C 1 
D 8  
C 1 
D 1 5  
C 2 
D 1  
C 2 
D 1 5  
C 3 
D 1  
C 3 
D 1 5  
C 4 
D 1  
C 4  D 1 5  
C 5 D 1, 
C 6 D 1 c 
C 5 D 1 5, 
C 6 D 1 5 c 
P ost -I M P 
T her a p y  
N otes  
 
 
E ve nt  
 
 
 
 
 
D a y 
1 5 a  
 
 
 
 
 
D a y 1 5 b  
 
 
 
+/ - 7 d a y wi n d o w f or 
C 2 D 1 5  I n d ucti o n P h ase, 
per f o ot n ote a  
+/ - 3 d a y  wi n d o w  f or all 
ot her visits  
 
Ra diati o n 
T hera p y  ( R T) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
F or  R 1  C o h ort,  wit h  BI C R 
assesse d C M R a n d 
C o m pleti o n of I n d ucti o n, 
C ycle 6.  
 
 
 
 
 
H D C T/ A S C T  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
F or R 2 C o h ort wit h BI C R 
assesse d C M R,  after C ycle 
4.  
If a d diti o nal treat me nt is 
re q uire d pri or  H D C T/ A S C T 
f or BI C R assesse d C M R 
p ost 4 c ycles of N + B v; it 
s h o ul d be a c ycle of N + B v. 
F oll o w  sa me pr oce d ures  as 
C 5 D 1, C 6 D 1 ( N + B v)  
I n d ucti o n P hase.  See 
Secti o n 5. 1 . 
a Partici pa nts w h o e x perie nce pr o gressi ve meta b olic disease ( P M D), per A p pe n di x 6  as assesse d b y I n vesti gat or at C ycle 2, will c o me off treat me nt a n d e nter 
f oll o w-u p, u nless M M a p pr o ves Treat me nt Be y o n d Pr o gressi o n ( T B P). C ycle 3, N + B v d oes n ot re q uire treat me nt dela y w hile a waiti n g res u lts, t heref ore C 2 
I n d ucti o n T u m or Assess me nt has +/- 7 da y wi n d o w.  
b  R 1  partici pa nts  wit h  C o m plete  Meta b olic  Res p o nse ( C M R), assesse d b y  BI C R  , will ha ve  2 a d diti o nal c ycles of  N + B v  pri or  t o R T  a n d t he n e nter F oll o w -u p.  R 2 
partici pa nts  wit h  C M R,  assesse d  b y  BI C R, will  pr ocee d  t o ha ve  H D C T/ A S C T  a n d t he n e nter F oll o w -u p.  Partici pa nts  wit h  Pr o gressi ve Meta b olic  Disease ( P M D), 
assesse d b y  BI C R,  will  c o me off  treat me nt a n d e nter F oll o w -U p,  u nless  M M  a p pr o ves  T B P.  R 1  or  R 2  partici pa nts  wit h  Partial  Meta b olic  Res p o nse/ N o  Meta b olic 
Res p o nse ( P M R/ N M R) assesse d b y BI C R,  or B M S M M a p pr o ve d T B P   (Secti o n 8. 1. 2 ), will e nter I nte nsificati o n P hase (Ta ble 2 - 3). 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 8  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
c If a p plica ble: R 1 c o h ort- N + B v I n d ucti o n P hase ( C ycles 5 a n d 6) re q uire d p ost -C M R (assesse d  b y BI C R) at C ycle 4 Ra di o gra p hic Assess me nt. R 2 C o h ort - If 
C ycle 4 I n d ucti o n T u m or Assess me nt is C M R (assesse d b y BI C R) a n d C ycles 5 a n d 6 are a p pr o ve d b y B M S Me dical M o nit or, d ue t o d ela y  i n H D C T/ A S C T. 
d  Safet y  Assess me nts a n d Me dical  Res o urce  Utilizati o n  s h o ul d be  c ollecte d,  wit hi n  3 da ys,  pri or  t o C o ns oli dati o n  T hera p y.  
e Bre nt u xi ma b  ve d oti n  will  be  a d mi nistere d  at C 1 D 1  a n d ni v ol u ma b  will  be  a d mi nistere d  o n  C 1 D 8.  At  all s u bse q ue nt c ycles,  b ot h  st u d y dr u gs  will  be  a d mi nistere d 
o n t he sa me da y. Bre nt u xi ma b ve d oti n will be a d mi nistere d first f oll o we d b y a mi ni m u m 3 0 -mi n ute rest. Ni v ol u ma b will be a d mi nistere d sec o n d. I R T s h o ul d 
be c o ntacte d wit hi n 3 da ys pri or t o st u d y dr u g a d mi nistrati o n t o recei ve vial assi g n me nt.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -3:  
I nte nsific ati o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
2 9  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I nte nsific ati o n P h ase ( B v + B) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 D 1, 
C 2 D 1  
C 2  D 1 5  
* C 3 D 1,  C 4 D 1, 
C 5 D 1, C 6 D 1  
* C 4 D 1 5  
P ost -I M P 
T her a p y  
N otes  
E ve nt  
R 1/ R 2  w/ o 
C M R a  
D a y 1 5  
* R 2,  O N L Y  w/ 
M M  a p pr o v al b  
* R 2,  O N L Y  
if a p plic a ble  
 
+/ - 3 d a y  wi n d o w  f or all  visits  
S afet y  Assess me nts  
 
 
 
 
 
 
Kar n ofs k y/  La ns k y Perf or ma nce 
Stat us  
 
X 
 
 
X 
 
 
X c 
Kar n ofs k y P S f or partici pa nts > 1 6 
years  a n d La ns k y  P S  f or partici pa nts  
≤ 1 6  years  of  a ge (A p pe n di x  5) 
 
 
Tar gete d  P h ysical  E xa mi nati o n  
 
 
X 
 
 
 
X 
 
 
 
X c 
S ki n  & m uc us  me m bra nes,  L y m p h  n o de 
areas (e g, s u b ma n di b ular, cer vical, 
s u pracla vic ular, a xillar y, or i n g ui nal 
l y m p h n o de), a b d o mi nal or ga ns (e g, 
s plee n, li ver), a n d ne ur ol o gical 
e xa mi nati o n 
P h ysical  Meas ure me nts  
X 
 
X 
 
X c 
Wei g ht  
Vital  Si g ns  
X 
 
X 
 
X c 
Te m perat ure,  B P,  H R  
C B C  wit h  Differe ntial  a n d 
Platelets  
X 
 
X 
 
X c 
C ollecte d  wit hi n  3 da ys  pri or  t o eac h 
d ose  
 
 
C he mistr y  (e xcl u di n g L F Ts)  
 
 
X 
 
 
 
X 
 
 
 
X c 
Uric aci d, B U N or ser u m urea le vel, 
creati ni ne, Ca, M g, K, Cl, Na, 
p h os p hate,  a m ylase,  li pase, gl uc ose,  a n d 
L D H  
C ollecte d  wit hi n  3 da ys  pri or  t o eac h 
d ose  
 
L F T assess me nts  
 
X 
 
 
X 
 
 
X c 
A S T, A L T,  a n d t otal bilir u bi n  
C ollecte d  wit hi n  3 da ys  pri or  t o eac h 
d ose  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -3:  
I nte nsific ati o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 0  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I nte nsific ati o n P h ase ( B v + B) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 D 1, 
C 2 D 1  
C 2  D 1 5  
* C 3 D 1,  C 4 D 1, 
C 5 D 1, C 6 D 1  
* C 4 D 1 5  
P ost -I M P 
T her a p y  
N otes  
E ve nt  
R 1/ R 2  w/ o 
C M R a  
D a y 1 5  
* R 2,  O N L Y  w/ 
M M  a p pr o v al b  
* R 2,  O N L Y  
if a p plic a ble  
 
+/ - 3 d a y  wi n d o w  f or all  visits  
 
T h yr oi d  F u ncti o n  Tests ( T F Ts) 
 
X 
 
 
X 
 
 
X c 
T S H (refle x t o free T 3 a n d free T 4 if 
a b n or mal res ult) t o be perf or me d at 
e ver y ot her c ycle  
Uri nal ysis  
X 
 
X 
 
X c 
T otal  pr otei n,  gl uc ose,  bl o o d,  le u k oc yte 
esterase, s pecific gra vit y, a n d p H  
 
Pre g na nc y  Test  (ser u m or  uri ne)  
 
X 
 
 
X 
 
 
X c 
Ser u m  or  uri ne  wit hi n  2 4  h o urs  pri or  t o 
first d ose a n d t he n D 1 of e ver y c ycle 
(a n d D 8 f or C ycle 1 N + B v), f or 
W O C B P.  
C o nc o mita nt  Me dicati o ns  
X 
 
X 
 
X c 
 
M o nit or  f or A d verse  E ve nts  
X 
 
X 
 
X c 
 
Effic ac y  
 
 
 
 
 
 
 
 
 
 
T u m or Assess me nts  
F D G  P E T-C T  or  P E T -M RI,  or  
F D G -P E T  wit h  C T/ M RI  
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
F D G -P E T w h ole -b o d y (t o p -of -hea d t o 
mi d -t hi g hs) a n d all k n o w n/s us pecte d 
sites of disease will be use d f or 
meta b olic  res p o nse assess me nt, u ntil  t he 
partici pa nt is i n BI C R assesse d C M R. 
C T/ M RI f or N/ C/ A/ P a n d ot her k n o w n 
or s us pecte d sites of disease. See 
g ui deli nes fr o m Ta ble 2 - 1 a n d Secti o n  
9. 1  
Partici pa nts  w h o  e x perie nce P D/ P M D, 
per  BI C R,  will  c o me off  treat me nt a n d 
e nter f oll o w -u p, u nless treat me nt  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -3:  
I nte nsific ati o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 1  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I nte nsific ati o n P h ase ( B v + B) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 D 1, 
C 2 D 1  
C 2  D 1 5  
* C 3 D 1,  C 4 D 1, 
C 5 D 1, C 6 D 1  
* C 4 D 1 5  
P ost -I M P 
T her a p y  
N otes  
E ve nt  
R 1/ R 2  w/ o 
C M R a  
D a y 1 5  
* R 2,  O N L Y  w/ 
M M  a p pr o v al b  
* R 2,  O N L Y  
if a p plic a ble  
 
+/ - 3 d a y  wi n d o w  f or all  visits  
 
 
 
 
 
 
be y o n d  pr o gressi o n  is a p pr o ve d  per 
Secti o n 5. 1  a n d 8. 1. 2 . 
Bi o m ar ker  S a m pli n g  
See  Ta ble  2- 5 f or details  
P K a n d  I m m u n o ge nicit y 
S a m pli n g  
See  Ta ble  2- 6 f or details  
O utc o mes  Rese arc h  Assess me nts   
 
 
 
 
 
 
E Q- 5 D -3 L  a n d F A C T -L y m  
 
 
X 
 
 
X 
 
C o m plete  f or partici pa nts  ≥ 1 2  years 
ol d.  
( See Secti o n  9. 9. 1 ) 
Me dic al  Res o urce  Utiliz ati o n  
X 
 
X 
 
X c 
See  Secti o n  9. 9  
 
Pre -me dic ati o ns  
 
X 
 
 
X 
 
 
See  Secti o n  7. 1. 1  f or pr o p h ylactic 
pre me dicati o n re q uire me nts f or 
c o m bi nati o n t hera p y  
St u d y  Dr u g  A d mi nistr ati o n  
 
 
 
 
 
 
I R T Treat me nt  Assi g n me nt  
X 
 
X 
 
 
C o ntact  I R T t o assi g n I M P treat me nt 
Bre nt u xi ma b  Ve d oti n  
X 
 
X 
 
 
See  Secti o n  7 
Be n da m usti ne  
X 
 
X 
 
 
Deli vere d  o n  Da ys  1 a n d 2 of  2 1 -da y 
c ycle ( See Secti o n 7)  
 
Ra diati o n  T hera p y  ( R T) 
 
 
 
 
 
X 
F or  R 1  C o h ort,  wit h  C M R,  assesse d  b y 
BI C R, u p o n c o m pleti o n of 
I nte nsificati o n P hase. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -3:  
I nte nsific ati o n I M P Tre at me nt  a n d  P ost -I M P T her a p y  ( R T, H D C T/ A S C T)  Pr oce d ures  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 2  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
I nte nsific ati o n P h ase ( B v + B) 
C o ns oli d ati o n 
P h ase  
 
Visit  
C 1 D 1, 
C 2 D 1  
C 2  D 1 5  
* C 3 D 1,  C 4 D 1, 
C 5 D 1, C 6 D 1  
* C 4 D 1 5  
P ost -I M P 
T her a p y  
N otes  
E ve nt  
R 1/ R 2  w/ o 
C M R a  
D a y 1 5  
* R 2,  O N L Y  w/ 
M M  a p pr o v al b  
* R 2,  O N L Y  
if a p plic a ble  
 
+/ - 3 d a y  wi n d o w  f or all  visits  
 
 
 
H D C T/ A S C T  
 
 
 
 
 
 
 
X 
F or  R 2  C o h ort  wit h  C M R,  assesse d  b y 
BI C R, u p o n c o m pleti o n of 
I nte nsificati o n P hase. 
If a d diti o nal treat me nt is re q uire d pri or 
H D C T/ A S C T  f or BI C R  assesse d  C M R 
p ost  2- 4 c ycles of  B + B v;  it s h o ul d be  a 
c ycle of B + B v. 
a B v + B I nte nsificati o n P hase ( C ycles  1 a n d 2) a p plica ble f or partici pa nts  wit h P M R/ N M R (assesse d b y  BI C R) or M M a p pr o ve d T B P per Secti o n 8. 1. 2  at C ycle 
4 I n d ucti o n Peri o d Ra di o gra p hic Assess me nt.  
b  R 2  partici pa nts w h o d o n ot ha ve C M R (assesse d b y BI C R) after 2 c ycles of B v + B ma y recei ve 2 a d diti o nal c ycles ( C ycles 3 a n d 4), u p o n a p pr o val fr o m B M S 
Me dical M o nit or. R 2 Partici pa nts w h o ac hie ve C M R after C ycle 2 or 4 T u m or Assess me nt, per BI C R b ut ha ve a dela y  i n C o ns oli dati o n T hera p y ma y recei ve 
u p t o 2 a d diti o nal c ycles of B v + B wit h a p pr o val fr o m B M S M M. ( See Secti o n 5. 1 ) 
c Safet y  Assess me nts a n d Me dical  Res o urce  Utilizati o n  s h o ul d be  c ollecte d,  wit hi n  3 da ys,  pri or  t o C o ns oli dati o n  T hera p y.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -4:  
F oll o w -U p  Assess me nts  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 3  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
Visit  
 
D a y 3 0  
 
D a y 1 0 0  
Res p o nse / 
S ur vi v al / 
F U  
 
F oll o w -u p  N otes  
E ve nt  
F U 1 
F U 2 
 
 
Visit  Wi n d o w  
+/ - 7 d a ys  
+/ - 7 d a ys  
+/ -1 4  d a ys   
S afet y  Assess me nts  
 
 
 
 
Kar n ofs k y/ La ns k y  Perf or ma nce 
Stat us  
X 
 
 
Kar n ofs k y  P S  f or partici pa nts  > 1 6  years  a n d La ns k y  P S 
f or partici pa nts ≤ 1 6 years of a ge ( A p pe n di x 5 ) 
 
Tar gete d  P h ysical  E xa mi nati o n  
 
X 
 
X 
 
S ki n & m uc us me m bra nes, L y m p h n o de areas (e g, 
s u b ma n di b ular, cer vical, s u pracla vic ular, a xillar y,  or 
i n g ui nal l y m p h n o de),  a b d o mi nal or ga ns  (e g, s plee n, 
li ver), a n d ne ur ol o gical e xa mi nati o n 
 
M o nit or  f or A d verse  E ve nts  
 
X 
 
X 
 
A d verse  e ve nt assess me nts will  c o nti n ue u ntil  all relate d 
A Es ha ve res ol ve d, ret ur ne d t o baseli ne, or are dee me d 
irre versi ble. ( See Secti o n 9. 2 ) 
C B C  wit h  Differe ntial  a n d Platelets  
X 
X 
if F U 1  res ults a b n or mal 
 
 
C he mistr y  (e xcl u di n g L F Ts)  
X 
X 
if F U 1  res ults a b n or mal 
 
Ca,  M g,  K,  Cl,  Na,  a m ylase,  li pase, gl uc ose,  a n d L D H  
L F T assess me nts  
X 
X 
if F U 1  res ults a b n or mal 
 
A S T, A L T, a n d t otal bilir u bi n  
T h yr oi d  F u ncti o n  Tests ( T F Ts) 
X 
X 
if F U 1  res ults a b n or mal 
 
T S H (refle x t o free T 3  a n d free T 4  if a b n or mal res ult) t o 
be perf or me d at e ver y ot her c ycle  
Uri nal ysis  
X 
X 
if F U 1  res ults a b n or mal 
 
T otal  pr otei n,  gl uc ose,  bl o o d,  le u k oc yte esterase, 
s pecific gra vit y, a n d p H 
Pre g na nc y  Test  (ser u m or  uri ne)  
X 
X 
 
F or  W O C B P  O nl y  
Effic ac y  Assess me nts  
 
 
 
 
S u bse q ue nt  A nti -Ca ncer  T hera p y  
X 
X 
X 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -4:  
F oll o w -U p  Assess me nts  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 4  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
Visit  
 
D a y 3 0  
 
D a y 1 0 0  
Res p o nse / 
S ur vi v al / 
F U  
 
F oll o w -u p  N otes  
E ve nt  
F U 1 
F U 2 
 
 
Visit  Wi n d o w  
+/ - 7 d a ys  
+/ - 7 d a ys  
+/ -1 4  d a ys   
Ot her  Pri mar y  Mali g na ncies  
X 
X 
X 
 
 
 
 
 
 
 
T u m or  Assess me nts  
 
 
 
 
 
 
See  N ote  
After t he s u bjects ac hie ve BI C R assesse d C M R: 
C T/ M RI of nec k, c hest, a b d o me n, pel vis, a n d ot her 
k n o w n or s us pecte d sites of disease; perf or me d at 1 0 0 
da ys a n d t he n 6, 1 2, 1 8, 2 4, a n d 3 6 m o nt hs p ost - 
C o ns oli dati o n  T hera p y/ Treat me nt  Disc o nti n uati o n  or  if 
pr o gressi o n is s us pecte d base d o n cli nical si g ns a n d 
s y m pt o ms. If t he res ults of  t he C T  or  M RI  is e q ui v ocal, 
f oll o w-u p F D G P E T ma y be o btai ne d f or clarificati o n.  
S u bjects wit h BI C R assesse d P M R/ N M R u p o n 
c o m pleti o n of st u d y treat me nt will pr o vi de t u m or 
assess me nts d uri n g  f oll o w-u p  at t he sa me ti me i nter vals 
s pecifie d ( or at a mi ni m u m, per Sta n dar d of Care). 
See  Secti o n  5. 1  a n d 9. 1  f or f urt her details.  
Bi o m ar ker  S a m pli n g  
See  N ote  
See  Ta ble  2 -5  f or details  
P K a n d  I m m u n o ge nicit y S a m pli n g  
See  N ote  
See  Ta ble  2- 6 f or details  
O utc o mes  Rese arc h  Assess me nts  
 
 
E Q -5 D -3 L  
See  N ote  
C ollecte d  at first f oll o w-u p  t u m or assess me nt,  t he n 
e ver y 6 m o nt hs f or 2 years  
Me dic al  Res o urce  Utiliz ati o n  
X 
X 
 
See  Secti o n  9. 9  
S ur vi v al  St at us  
X 
X 
X 
 
F oll o w -u p Visits will occ ur Da y 3 0, Da y 1 0 0, a n d t he n 6, 1 2, 1 8, 2 4, a n d 3 6 m o nt hs P ost -C o ns oli dati o n T hera p y/ Treat me nt Disc o nti n uati o n; t he n S ur vi val F U 
Visits c o nti n ue yearl y t hereafter, u ntil st u d y c o m pleti o n. O nce partici pa nts c o m plete F U 1 a n d 2, eit her i n -pers o n visits or d oc u me nte d tele p h o ne calls/e mail 
c orres p o n de nce t o assess t he partici pa nt’s stat us are acce pta ble.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -5:  
Bi o m ar ker  S a m pli n g  Sc he d ule  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 5  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
Visit  
 
E ve nt  
 
Visit 
Wi n d o w  
 
T u m or 
Bi o ps y a  
S ol u ble 
Bi o m ar ker, 
Ser u m  
S ol u ble 
Bi o m ar ker, 
Pl as m a  
Peri p her al 
Bl o o d 
I m m u ne 
Cell  S u bsets  
 
S N P  
 
Visit  N otes  
Scree ni n g 
( Da y -2 8  
t o -1)  
 
 
 
X 
 
 
 
 
F or mali n -fi xe d paraffi n-e m be d de d 
( F F P E) t u m or bl oc k  or  a mi ni m u m  of 
2 0 sli des.  
 
C ycle  1 
Da y  1 
 
Pre d ose ( B v) 
 
wit hi n 3 
da ys  pri or  
 
 
X 
 
X 
 
X 
 
X 
 
 
C ycle  2 
Da y  1 
 
Pre d ose 
( N + B v) 
 
wit hi n 3 
da ys  pri or  
 
 
X 
 
X 
 
X 
 
 
 
C ycle  3 
Da y  1 
 
Pre d ose 
( N + B v) 
 
wit hi n 3 
da ys  pri or  
 
 
X 
 
X b 
 
X 
 
 
 
C ycle  4 
Da y  1 
 
Pre d ose 
( N + B v) 
 
wit hi n 3 
da ys  pri or  
 
 
X 
 
X 
 
X 
 
 
 
C ycle  4 
Da y  1 5  
 
 
+/ - 3 da ys  
 
 
X 
 
X 
 
X 
 
 
F or  C ycle  4/ Da y  1 5,  I n d ucti o n P hase 
T u m or Assess me nt O nl y  
 
W he n 
Cli nicall y 
I n dicate d 
 
 
 
 
X 
o pti o nal  
 
 
 
 
All partici pa nts ma y v ol u nteer t o 
u n der g o t u m or bi o psies at a n y ti me 
d uri n g  t hera p y if cli nicall y  i n dicate d. 
W he n t u m or bi o ps y is perf or me d, 
s u b missi o n of t u m or bi o ps y is 
e nc o ura ge d. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -5:  
Bi o m ar ker  S a m pli n g  Sc he d ule  ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 6  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
Visit  
 
E ve nt  
 
Visit 
Wi n d o w  
 
T u m or 
Bi o ps y a  
S ol u ble 
Bi o m ar ker, 
Ser u m  
S ol u ble 
Bi o m ar ker, 
Pl as m a  
Peri p her al 
Bl o o d 
I m m u ne 
Cell  S u bsets  
 
S N P  
 
Visit  N otes  
 
U p o n 
Pr o gressi o n  
 
 
 
X 
o pti o nal  
 
X o pti o nal  
 
X o pti o nal  
 
X o pti o nal  
 
 
Sa m ples  fr o m partici pa nts  t hat ha ve 
c o nfir me d  pr o gressi o n  are o pti o nal.  
 
F U  1 - 
Da y  3 0  
P ost Last 
Treat me nt  
( +/- 7 da ys)  
 
wit hi n 3 
da ys  pri or  
 
 
X 
 
X 
 
X 
 
Partici pa nts  will  e nter F oll o w -u p  P ost - 
C o ns oli dati o n T hera p y/ Treat me nt 
Disc o nti n uati o n, as a p plica ble.  
a Partici pa nts  ma y u n der g o t u m or bi o ps y d uri n g scree ni n g or s u b mit  arc hi val t u m or tiss ue c ollecte d pri or t o o btai ni n g i nf or me d c o nse nt. Rela pse d partici pa nts 
m ust ha ve a rece nt bi o ps y sa m ple wit hi n 9 0 da ys fr o m c ollecti o n of i nf or me d c o nse nt or o btai ne d d uri n g scree ni n g. Rare cases ma y  all o w sa m ples > 9 0 da ys 
fr o m c ollecti o n of  t he i nf or me d c o nse nt.  Refer  t o Secti o n  9. 8. 1  f or f urt her details.  I n or der  t o be  treate d, t he sa m ple m ust meet  t he mi ni m u m  q ualit y  re q uire me nts, 
as deter mi ne d  b y  t he ce ntral la b orat or y d uri n g  t he scree ni n g peri o d.  N ote:  U n der  s pecial circ u msta nces,  if t u m or tiss ue pr o vi de d  is dee me d  i na de q uate, c o ntact 
t he Me dical M o nit or f or a p pr o val t o be gi n treat me nt. 
b  If t he partici pa nt is < 1 8 K g, C ycle 3 Da y 1 S ol u ble Bi o mar ker, Plas ma Sa m ple is n ot re q uire d. I n vesti gat ors s h o ul d f oll o w t he ir bl o o d v ol u me i nstit uti o nal 
g ui deli nes f or bl o o d v ol u me c ollecti o n.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
T a ble  2 -6:  
P K  a n d  I m m u n o ge nicit y S a m pli n g Sc he d ule ( C A 2 0 9 7 4 4) 
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 7  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
 
Visit  
Ti me 
Rel ati ve  t o 
D osi n g  
 
E ve nt  
 
Visit 
Wi n d o w  
B v P K Bl o o d 
S a m ple  C ollecti o n  
(ser u m a n d 
pl as m a/ M M A E)  
B v 
I m m u n o ge nicit y 
( A D A) Bl o o d 
S a m ple  C ollecti o n  
Ni v ol u m a b 
P K Bl o o d 
S a m ple 
C ollecti o n  
Ni v ol u m a b 
I m m u n o ge nicit y 
( A D A) Bl o o d  S a m ple 
C ollecti o n  
C ycle  1 
Da y  1 
 
0: 0 0  
Pre d ose 
( B v) ,a 
 
 
X 
 
X 
 
 
C ycle  1 
Da y  8 
 
0: 0 0  
Pre d ose  
( N) a 
 
 
 
 
X 
 
X 
 
C ycle  2 
Da y  1 
 
0: 0 0  
Pre d ose 
( N + B v) a, b 
 
 
X 
 
X 
 
X 
 
X 
C ycle  3 
Da y  1 
 
0: 0 0  
Pre d ose 
( N + B v)a, b 
 
 
X 
 
X 
 
X 
 
X 
C ycle  4 
Da y  1 
 
0: 0 0  
Pre d ose 
( N + B v)a, b 
 
 
X 
 
X 
 
X 
 
X 
 
F U  2 - 
Da y  1 0 0  
 
P ost  Last  
Treat me nt 
( +/- 7 da ys) c 
 
+/ - 7 da ys  
 
X 
 
X 
 
X 
 
X 
a Pre -d ose sa m ples s h o ul d be ta ke n j ust pri or  t o t he a d mi nistrati o n ( prefera bl y wit hi n 3 0 mi n, b ut  n ot s o o ner t ha n 2 4  h o urs da y of d osi n g). If st u d y me dicati o n 
d ose s h o ul d be dela ye d, P K/ A D A c ollecti o n s h o ul d be d o ne pre -d ose t he da y d osi n g res u mes. H o we ver, if st u d y me dicati o n d ose is dela ye d a n d a pre -d ose 
sa m ple was alrea d y c ollecte d, t here is n o nee d t o c ollect a n a d diti o nal pre-d ose sa m ple.  
b  It is acce pta ble  t o c ollect t he pre -d ose  sa m ple f or ni v ol u ma b  a n d bre nt u xi ma b  ve d oti n  at t he sa me ti me, as l o n g as it is c ollecte d  pri or  t o t he start of  t he i nf usi o n. 
c Partici pa nts  will  e nter  f oll o w-u p  P ost -C o ns oli dati o n  T hera p y/ Treat me nt  Disc o nti n uati o n,  as a p plica ble. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
3.  
I N T R O D U C TI O N 
3. 1  
St u d y  R ati o n al e  
Classical H o d g ki n l y m p h o ma (c H L) is c haracterize d b y rare mali g na nt Ree d Ster n ber g cells 
s urr o u n de d b y a n e xte nsi ve b ut i neffecti ve i nfla m mat or y i m m u ne cell i nfiltrate. 1 ,2 ,3 Rece nt w or k 
has  de m o nstrate d  t hat  c hr o m os o me  9 p 2 4. 1/ C D 2 7 4  ( P D -L 1)  P D C D 1 L G 2  ( P D -L 2)  ge netic  
alterati o ns i ncrease t he P D -1 li ga n ds e x pressi o n,  a n d are descri be d  as a defi ni n g feat ure  of c H L. 4 
T he  9 p 2 4 a m plic o n als o c o ntai ns J A K 2, a n d c o p y n u m ber- de pe n de nt J A K 2-si g nal tra ns d ucers a n d 
acti vat ors of tra nscri pti o n w hic h ca n f urt her i ncrease P D - 1 li ga n d e x pressi o n.2 
T hese ge netic alterati o ns c o m m o nl y f o u n d i n c H L i n dicate t hat P D -1 bl oc ka de is a reas o na ble 
tar get i n t his disease. I n a d diti o n, E pstei n-Barr vir us ( E B V) i nfecti o n ca n i ncrease e x pressi o n of 
P D - 1 li ga n ds i n E B V -p ositi ve  H o d g ki n l y m p h o mas ( H Ls).5 T his st u d y  will  ali g n wit h t he c urre nt 
strate g y t o i nte grate c hec k p oi nt bl oc ka de ( ni v ol u ma b) i nt o t he treat me nt of c H L. 
H o d g ki n l y m p h o ma is di vi de d i nt o 2 br oa d pat h ol o gical cate g ories: classical c H L (i ncl u di n g 
l y m p h oc yte-ric h  classical,  n o d ular  scler osi n g,  mi xe d  cell ularit y,  a n d  l y m p h oc yte  de plete d  
s u bt y pes) a n d n o d ular l y m p h oc yte pre d o mi na nt c H L. H o d g ki n l y m p h o ma has a bi m o dal a ge 
distri b uti o n i n  hi g hl y i n d ustrialize d s ocieties a n d  ar o u n d t he  w orl d, wit h  pea k   i nci de nce at 
1 5- 3 4 years  of a ge a n d a gai n at 5 0-6 0  years.  A si g nifica nt pr o p orti o n of cases occ ur i n t he pe diatric 
a ge gr o u p, t he maj orit y of w hic h prese nt i n a d olesce nts, a n d a mi n orit y of t he cases are see n i n 
patie nts y o u n ger t ha n 1 0 years of a ge. 6 
T he  treat me nt f or b ot h  c hil dre n a n d a d ults wit h  c H L is t he sa me: c he m ot hera p y ± ra diati o n t hera p y. 
T he f oc us of  pe diatric c H L treat me nt  re gi me ns is t he re d ucti o n of late t o xicit y w hile mai ntai ni n g 
e xcelle nt  o utc o mes. T heref ore,  treat me nt is ris k base d  a n d res p o nse a da pte d. Treat me nt  decisi o ns 
f or pe diatric c H L are base d o n stratificati o n i nt o t w o ris k gr o u ps (c o h orts). 
T he  sta n dar d c he m ot hera pe utic re gi me ns f or first-li ne treat me nt i n ne wl y - dia g n ose d pe diatric  c H L 
var y bet wee n  t he U S  a n d E ur o pe, ma ki n g t he direct  c o m paris o n  of o utc o mes fr o m differe nt  st u dies 
diffic ult.  T he  m ost c o m m o n m ulti -a ge nt re gi me ns i n t he U nite d  States  ( U S) are A B V E/ A B V E -P C 
(a dria m yci n, ble o m yci n, vi ncristi ne, et o p osi de ±  pre d nis o ne, c ycl o p h os p ha mi de) a n d B E A C O P P 
( ble o m yci n,  et o p osi de,  a dria m yci n,  c ycl o p h os p ha mi de,  vi ncristi ne,  pre d nis o ne,  pr ocar bazi ne).  
T he  m ost  c o m m o n  m ulti -a ge nt  re gi me ns  i n  E ur o pe  are  O P P A  ( vi ncristi ne,  pre d nis o ne,  
pr ocar bazi ne,  a dria m yci n); O E P A  ( vi ncristi ne, et o p osi de, pre d nis o ne, a dria m yci n);  a n d C O P D A C 
(c ycl o p h os p ha mi de, vi ncristi ne,  pre d nis o ne, dacar bazi ne). Se veral  a d verse  ris k fact ors ha ve bee n 
i de ntifie d t o ha ve pr o g n ostic si g nifica nce i n patie nts  wit h  rec urre nt or refract or y c H L after fail ure 
of first-li ne t hera p y.7 Ti me  t o i nitial treat me nt fail ure is a str o n g pre dict or of s ur vi val f or patie nts. 
8 , 9 Res p o nse t o t hera p y pri or t o hi g h -d ose c he m ot hera p y f oll o we d b y a ut ol o g o us ste m cell 
tra ns pla nt ( H D C T/ A S C T) has als o bee n  rec o g nize d as a n i m p orta nt pr o g n ostic fact or.1 0 T he  m ost 
pre dicti ve  pr o g n ostic fact ors i de ntifie d f or pe diatric  patie nts  wit h  rela psi n g or refract or y ( R/ R) 
c H L i ncl u de pri mar y  pr o gressi o n or earl y rela pse, c he m ot hera p y -resista nt disease  at rela pse, a n d 
t he  prese nce  of  disease  pri or  t o  A S C T.  F oll o wi n g  a  retr os pecti ve  a nal ysis  of  t he  CI B M T R  
data base, c o nsisti n g of partici pa nts me dia n a ge 2 1 ( 3 - 2 9) years, 5 0 % of w h o m were Sta ge I -II or 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
3 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Sta ge III -I V at dia g n osis, a n d recei ve d a n A S C T bet wee n 1 9 9 5-2 0 1 0, 4 ris k fact ors, all easil y 
a vaila ble at t he ti me of A S C T,  ha ve bee n  i de ntifie d a n d ca n be  use d  t o pre dict  o utc o me i n c hil dre n, 
a d olesce nt, a n d y o u n g a d ult R/ R c H L patie nts p ost A S C T. 1 1 T hese 4 ris k fact ors ( perf or ma nce 
stat us < 9 0 vs.  ≥ 9 0, ti me fr o m dia g n osis t o rela pse/refract or y disease  < 1 yr vs. ≥ 1 year,  e xtra n o dal 
disease at t he ti me of A S C T, a n d c he m ose nsiti vit y), were i de ntifie d as i m pacti n g P F S i n t his 
p o p ulati o n. 1 1 
I n pe diatric a d olesce nt a n d y o u n g a d ult st u dies, w hile pr o g n ostic fact ors are c o m m o nl y use d t o 
stratif y t hera p y, t here has bee n varia bilit y i n t he ris k stratificati o n use d b y c o o perati ve gr o u ps.1 2 
T he E ur o Net -P H L -C 1 pr ot oc ol stratifie d patie nts, de pe n di n g o n ti me of rela pse.  1 3 C hil dre n’s 
O nc ol o g y Gr o u p ( C O G) has pr o p ose d a c o m pre he nsi ve ris k -stratifie d, res p o nse-base d al g orit h m 
f or treati n g c hil dre n wit h rela pse d a n d refract or y c H L.7 A n ali g ne d ris k -stratifie d al g orit h m will 
be use d t o se parate partici pa nts i nt o t he R 1 vs R 2 ris k c o h orts i n t he prese nt pr ot oc ol  (Ta ble 5. 1 - 
1 ). Partici pa nts  wit h  late rela pse of l o w-sta ge disease  will  be stratifie d i nt o t he l o w-ris k c o h ort a n d 
are  pre dicte d   t o  ha ve   e xcelle nt  o utc o mes   wit h   c o n ve nti o nal   c he m ot hera p y   or  
c he m ora di ot hera p y. 1 4 ,1 5 ,1 6 ,1 7 ,1 8 Si milarl y,  partici pa nts wit h  earl y  sta ge disease,  w h o  ha ve earl y 
rela pse after li mite d t hera p y ( < 4 c ycles of  c he m ot hera p y  a n d n o  ra diati o n) are als o e x pecte d  t o 
ha ve g o o d o utc o mes wit h c o n ve nti o nal  c he m ot hera p y. 1 9 Partici pa nts wit h earl y rela pse, or 
e xtra n o dal disease, or B s y m pt o ms at rela pse ha ve w orse pr o g n osis a n d will be classifie d as 
sta n dar d ris k partici pa nts. 2 0 ,2 1 ,2 2 F or t he sta n dar d ris k c o h ort i n t his st u d y, o nl y partici pa nts w h o 
attai n a c o m plete meta b olic  res p o nse ( C M R) t o sal va ge t hera p y, pre vi o usl y  i de ntifie d as o ne  of 
t he str o n gest pre dict ors of l o n g-ter m o utc o me,2 3 ,2 4 will pr ocee d t o H D C T/ A S C T.  
Disease stat us f oll o wi n g sal va ge t hera p y is t he m ost i m p orta nt pr o g n ostic fact or f or l o n g -ter m 
o utc o me. 2 5 ,2 6 ,2 7 F u ncti o nal i ma gi n g ( FI) wit h 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) sca ns has bec o me i m p orta nt i n meas uri n g res p o nse t o t hera p y a n d ca n ser ve as a 
mar ker of c he m ose nsiti ve disease. Patie nts ac hie vi n g a C M R after sal va ge c he m ot hera p y ha ve a 
l o n g-ter m rela pse-free s ur vi val of ~ 7 5 %  p ost-A S C T.  I n c o ntrast, patie nts  wit h  e vi de nce  of resi d ual 
disease pri or t o H D C T/ A S C T ha ve a l o n g -ter m rela pse-free s ur vi val t hat is o nl y ~ 2 5 %.2 4 
Beca use res ults fr o m  sal va ge t hera p y i nfl ue nce l o n g-ter m e ve nt-free s ur vi val ( E F S) p ost-A S C T, 
it is i m p orta nt t o de vel o p well -t olerate d re gi me ns t hat i ncrease c o m plete res p o nse ( C R) rates pre- 
A S C T. 2 8 T here is c urre ntl y n o c o nse ns us or i de ntifie d best sal va ge c he m ot hera p y re gi me n i n 
pe diatric a n d a d olesce nt patie nts wit h R/ R H L. Se veral re gi me ns ha ve bee n use d. T hese i ncl u de 
t he use of if osfa mi de, car b o plati n, a n d et o p osi de (I C E).2 9 I n E ur o pe t he c urre nt  sta n dar d a p pr oac h 
f or retrie val re gi me n f or pe diatric patie nts is alter nati n g I E P-A B V D. I n or der t o re d uce t he l o n g - 
ter m treat me nt-relate d e ve nts re p orte d wit h  I C E, C O G  has als o e x pl ore d ot her  retrie val re gi me ns, 
s uc h  as  if osfa mi de  wit h  vi n orel bi ne  (I V)  o n  t heir  A H O D 0 0 P 1  pr ot oc ol,  or  ge mcita bi ne  +  
vi n orel bi ne ( G V). M ore rece ntl y, A H O D 0 5 2 1  e val uate d t he a d diti o n of b ortez o mi b,  a pr oteas o me 
i n hi bit or, t o if osfa mi de/ vi n orel bi ne I V.3 0 Beca use  of t his varia bilit y, t he c o m paris o n of o utc o mes 
bet wee n st u dies is diffic ult. T he U nite d Ki n g d o m  H D 3 trial  re p orte d t he o utc o me of 8 0 c hil dre n 
a n d a d olesce nts a ge d < 1 8  years  w h o  ha d eit her pri mar y  refract or y H L  or rela pse d after ac hie vi n g 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
a first re missi o n. All b ut 1 patie nt ha d c he m ot hera p y  al o ne as t heir pri mar y  treat me nt. Treat me nt 
at rela pse was pre d o mi na ntl y a c o m bi nati o n c he m ot hera p y pl us i n v ol ve d fiel d ra diati o n t hera p y 
(I F R T)  ( N  = 5 0;  6 3 %).  Sal va ge  treat me nt  a m o n gst  t he  re mai ni n g  3 0  patie nts  c o nsiste d  of  
c he m ot hera p y al o ne ( N = 1 9, 2 4 %), I F R T ( N = 6; 8 %) or e xcisi o n bi o ps y i n t he l y m p h oc yte 
pre d o mi na nt s u bt y pes ( N = 3; 4 %).  T we nt y -t hree patie nts  ( 7 0 %) ac hie ve d a C R  f oll o wi n g sal va ge. 
F ort y -t hree patie nts ( 5 5 %) u n der we nt ste m cell tra ns pla nt. A t otal of 1 7/ 2 3 patie nts ( 7 4 %) w h o 
were  i n C R at t he e n d of sal va ge t hera p y  a n d w h o  di d n ot recei ve  A S C T are ali ve wit h o ut rela pse 
( me dia n f oll o w u p ti me 1 0 5 m o nt hs; ra n ge 5 3- 1 2 8  m o nt hs).3 1 T hese res ults de m o nstrate d t hat 
c hil dre n ca n be c ure d wit h sal va ge t hera p y al o ne,  reser vi n g H D C T/ A S C T  f or patie nts  wit h  eit her 
earl y rela pse/ pri mar y resista nt disease or p o or res p o nse t o sal va ge c he m ot hera p y. 3 2 ,3 3 ,3 4 ,3 5 
Gi ve n  t hat bre nt u xi ma b  ve d oti n a n d ni v ol u ma b b ot h ha ve d oc u me nte d hi g h  si n gle-a ge nt res p o nse 
rates i n c H L a n d als o w or k  t hr o u g h disti nct  mec ha nis ms  of acti o n, it is e x pecte d t hat c o m bi nati o n 
t hera p y c o ul d p ote ntiall y be m ore  effecti ve i n  t he sal va ge treat me nt setti n g t ha n a d mi nistrati o n  of 
eit her a ge nt al o ne. M ore o ver, b ot h a ge nts are well t olerate d,  ha ve fe w o verla p pi n g t o xicities, a n d 
ca n be i nf use d i n t he o ut patie nt setti n g. T his st u d y will e val uate t he safet y  a n d a ntit u m or acti vit y 
of c o m bi nati o n t hera p y wit h  ni v ol u ma b + bre nt u xi ma b ve d oti n ( N + B v) i n a p o p ulati o n of patie nts 
after fail ure of sta n dar d fr o ntli ne c he m ot hera p y. Partici pa nts n ot ac hie vi n g a n a de q uate  res p o nse 
( C M R) f oll o wi n g N + B v  will  be f urt her treate d wit h  bre nt u xi ma b ve d oti n + be n da m usti ne ( B v + B) 
bef ore c o ns oli dati o n.  
R ati o n ale f or Ni v ol u m a b + Bre nt u xi m a b  Ve d oti n  
M ost H/ R S cells str o n gl y  e x press C D 3 0, a me m ber of  t he T N F cell rece pt or s u perfa mil y t hat has 
hi g hl y restricte d e x pressi o n i n n or mal cells. Bre nt u xi ma b ve d oti n has bee n s h o w n t o kill H/ R S 
cells t hr o u g h t he i ntracell ular release of  M M A E, disr u pti n g t he micr ot u b ule net w or k a n d lea di n g 
t o G 2/ M cell c ycle arrest a n d a p o pt osis. T he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) a n d 
E ur o pea n Me dici nes A ge nc y ( E M A) ha ve a p pr o ve d bre nt u xi ma b ve d oti n f or a d ult patie nts wit h 
c H L after fail ure of A S C T or after fail ure of at least 2 pri or m ulti -a ge nt c he m ot hera p y  re gi me ns 
i n patie nts w h o are n ot ca n di dates f or A S C T. P ost -A S C T mai nte na nce  t hera p y wit h bre nt u xi ma b 
ve d oti n has rece ntl y bee n f o u n d t o pr ol o n g P F S i n a d ults wit h  rec urre nt c H L.3 6 T he  c o m bi nati o n 
of N + B v  is c urre ntl y  bei n g  st u die d i n a P hase  1/ 2 trial of a d ults wit h  R/ R  c H L after fail ure of first- 
li ne t hera p y. T his st u d y is acti vel y e nr olli n g ( Cli nical Trials. g o v i de ntifier: N C T 0 2 5 7 2 1 6 7). I n 
a d diti o n a P hase 1/ 2 trial of t his c o m bi nati o n i n a d ults wit h C D 3 0 + R/ R N H L is als o u n der wa y 
( Cli nical Trials. g o v i de ntifier: N C T 0 2 5 8 1 6 3 1). I n t hat st u d y, t he st u d y tea m re vie we d all a vaila ble 
safet y data of  t he 6 treate d s u bjects t hat were e nr olle d i n C o h ort A d uri n g t he D L T peri o d. Base d 
o n t he safet y data a vaila ble fr o m t hese s u bjects a n d st u d y N C T 0 2 5 7 2 1 6 7 wit h  si milar c o m bi nati o n 
i n H o d g ki n l y m p h o ma, t he st u d y tea m rec o m me n de d a n d e n d orse d t he e x pa nsi o n of t he st u d y t o 
C o h ort B. 
R ati o n ale f or Bre nt u xi m a b  Ve d oti n  + Be n d a m usti ne  
Bre nt u xi ma b ve d oti n a n d be n da m usti ne are hi g hl y acti ve w he n a d mi nistere d as si n gle a ge nts t o 
patie nts  wit h  R/ R  c H L  ( 3 4 %  a n d  3 3 %  C R  rates,  res pecti vel y)  a n d  ha ve  ma na gea ble  safet y  
pr ofiles. 3 7 ,3 8 As re p orte d at t he 2 0 1 5 A S H meeti n g, i n a n o n g oi n g P hase 1/ 2, si n gle-ar m, 2-sta ge, 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
o pe n- la bel st u d y e val uati n g t he safet y a n d efficac y of bre nt u xi ma b ve d oti n i n c o m bi nati o n wit h 
be n da m usti ne f or t he treat me nt of patie nts wit h pri mar y refract or y disease or  i n first rela pse,3 9 
5 5 patie nts wit h  a me dia n  a ge of 3 6 years  (ra n ge 1 9 - 7 9) were  e nr olle d. Fift y - o ne perce nt of patie nts 
ha d rela pse d disease a n d 4 9 % of patie nts ha d pri mar y refract or y disease after fr o ntli ne t hera p y. 
N o  d ose -li miti n g  t o xicities  were  o bser ve d.  T he  rec o m me n de d  d ose  of  be n da m usti ne  i n  
c o m bi nati o n wit h bre nt u xi ma b ve d oti n ( 1. 8 m g/ k g q 3 w ks) was 9 0 m g/ m 2. T he C R rate of t he 
c o m bi nati o n was  7 4 % ( 3 9/ 5 3 patie nts  e val ua ble f or res p o nse) a n d t he o verall  res p o nse rate ( O R R) 
( C R a n d partial  re missi o n) was  9 3 % ( 4 9/ 5 3 patie nts).  T he  C R  rate was  6 4 % a n d 8 4 % f or refract or y 
a n d rela pse d patie nts, res pecti vel y. T his re gi me n is well t olerate d i n t he patie nt p o p ulati o n fr o m 
t his st u d y.3 9 
3. 2  
B a c k gr o u n d  
W hile   t he treat me nt  of c H L  has  i m pr o ve d dra maticall y  o ver   t he past   2 deca des,  wit h  re p orte d 
5- year E F S rates bet wee n 8 0 % -9 0 %, t here is still a s u bset of patie nts w h o eit her rela pse or i n 
w h o m first-li ne treat me nt fails. Te n perce nt t o 1 5 % of patie nts wit h l ocalize d disease a n d 2 5 % of 
patie nts wit h a d va nce d c H L ha ve rec urre nt disease after first -li ne treat me nt.4 0 ,4 1 ,4 2 Patie nts wit h 
c H L w h o  are refract or y t o i nitial t hera p y, or rela pse after pri mar y  i nitial c he m ot hera p y, ha ve  p o or 
o utc o me. 4 3 ,4 4 
T here is  c urre ntl y n o  c o nse ns us or i de ntifie d best  sal va ge c he m ot hera p y re gi me n i n pe diatric a n d 
a d olesce nt  partici pa nts  wit h  rela pse d/refract or y  c H L.  Gi ve n  t hat  bre nt u xi ma b  ve d oti n  a n d  
ni v ol u ma b b ot h ha ve d oc u me nte d hi g h si n gle- a ge nt res p o nse rates i n c H L a n d als o w or k  t hr o u g h 
disti nct mec ha nis ms of acti o n, it is e x pecte d t hat  c o m bi nati o n t hera p y  c o ul d p ote ntiall y be m ore 
effecti ve i n t he sal va ge treat me nt setti n g t ha n a d mi nistrati o n of eit her a ge nt al o ne.  
Bac k gr o u n d i nf or mati o n o n ni v ol u ma b ca n be f o u n d i n t he ni v ol u ma b I n vesti gat or Br oc h ure 
(I B).4 5 
Bre nt u xi ma b  ve d oti n  is a C D 3 0 -directe d  a nti b o d y- dr u g  c o nj u gate ( A D C) c o nsisti n g of 
3 c o m p o ne nts:  1)  t he  c hi meric  I g G 1  a nti b o d y  c A C 1 0,  s pecific  f or  h u ma n  C D 3 0;  2)  t he  
micr ot u b ule- disr u pti n g a ge nt m o n o met h yl a uristati n E ( M M A E); a n d 3) a pr otease -clea va ble 
li n ker t hat c o vale ntl y attac hes M M A E t o c A C 1 0. T he pri mar y mec ha nis m of a ntica ncer acti vit y 
of  bre nt u xi ma b  ve d oti n  is  bi n di n g  of  t he  A D C  t o  C D 3 0 -e x pressi n g  cells,  f oll o we d  b y  
i nter nalizati o n of t he A D C-C D 3 0 c o m ple x, a n d t he release of M M A E via pr ote ol ytic clea va ge. 
Bi n di n g of M M A E t o t u b uli n disr u pts t he micr ot u b ule net w or k wit hi n t he cell, s u bse q ue ntl y 
i n d uci n g cell c ycle arrest   a n d  a p o pt otic deat h   of  t he cell.  A d diti o nal i nf or mati o n re gar di n g 
bre nt u xi ma b  ve d oti n ca n be f o u n d i n t he pr o d uct prescri bi n g  i nf or mati o n.4 6 
Be n da m usti ne h y dr oc hl ori de is a n o vel al k ylati n g a ge nt 4 7 ,4 8 a p pr o ve d f or use i n t he treat me nt of 
c hr o nic  l y m p h oc ytic  le u ke mia,  a n d  f or  i n d ole nt  n o n -c H L.  Be n da m usti ne  c o nsists  of  a  
mec hl oret ha mi ne gr o u p, a be nzi mi daz ole ri n g, a n d a b ut yric aci d si de c hai n, cr ossli n ks bet wee n 
de o x yri b o n ucleic aci d ( D N A) bases, a n d pr o d uces direct c yt ot o xic da ma ge. 4 9 ,5 0 ,5 1 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T here are n o p u blis he d retrie val  trials t hat ris k stratif y usi n g a strate g y i de ntical t o t he o ne i n t his 
st u d y  (Ta ble  5. 1 - 1)  t o  ser ve  as  a n hist orical  c o ntr ol. We  ha ve  i de ntifie d  m ulti ple p u blis he d 
pe diatric 9  a n d  a d ult  retrie val  trials  t hat  ha ve   e nr olle d  si milar  patie nts   t o  o ur   st u d y 
p o p ulati o n. 3 7 ,5 2 ,5 3 
F or t he l o w ris k / R 1 c o h ort, t he ai m is t o de m o nstrate 3 -year E F S i n partici pa nts treate d wit h o ut 
a ut ol o g o us ste m cell resc ue. T he  S T -H D - 8 6 cli nical trial f or patie nts  wit h  pr o gressi ve a n d rela pse d 
H o d g ki n disease  after pri mar y  treat me nt i n t he pe diatric  D A L/ G P O H  st u dies is t he o nl y pe diatric 
c o o perati ve gr o u p trial re p orti n g l o n g -ter m s ur vi val i n patie nts w h o di d n ot recei ve a ut ol o g o us 
ste m cell resc ue. I n t his trial, 1 0 year disease-free s ur vi val f or 5 7 partici pa nts wit h earl y rela pse 
treate d wit h o ut ste m cell resc ue was 5 5 %. 
I n t he sta n dar d ris k / R 2 c o h ort, t he pri mar y e n d p oi nt is t he C M R rate at a n y ti me pri or t o 
A S C T. Hist orical C M R rates attai ne d b y eit her bre nt u xi ma b or be n da m usti ne m o n ot hera p y are 
a p pr o xi matel y 3 5 % ( Ta ble 3. 2- 1). 
T a ble 3. 2- 1: 
Res p o nse  R ates  f or Bre nt u xi m a b  Ve d oti n  or Be n d a m usti ne 
M o n ot her a p y  
 
 
Tri al  
 
N 
 
S al v a ge  Re gi me n  
Res p o nse ti me 
p oi nt  
( me di a n c ycles 
deli vere d)  
 
Res p o nse 
m o d alit y  
 
C R  r ate 
Y o u nes,  2 0 1 2 3 7  
1 0 2  
Bre nt u xi ma b  
Best  res p o nse ( 9) 
P E T & C T  
3 5 %  
M os k o witz,  2 0 1 3 5 3  
3 4  
Be n da m usti ne  
Best  res p o nse ( 4) 
P E T & C T  
3 5 %  
C orazzelli 5 2  
4 1  
Be n da m usti ne  
Best  res p o nse ( 2-8)  
P E T & C T  
3 1 %  
 
3. 2. 1  
Ni v ol u m a b  M e c h a ni s m  of  A cti o n  
Ca ncer i m m u n ot hera p y  rests o n t he pre mise t hat t u m ors ca n be rec o g nize d as f orei g n rat her t ha n 
as self a n d ca n be effecti vel y attac ke d b y a n acti vate d i m m u ne s yste m. A n effecti ve i m m u ne 
res p o nse i n t his setti n g is t h o u g ht t o rel y o n i m m u ne  s ur veilla nce of t u m or a nti ge ns e x presse d  o n 
ca ncer  cells  t hat  ulti matel y  res ults  i n  a n  a da pti ve  i m m u ne  res p o nse  a n d  ca ncer  cell  deat h.  
Mea n w hile,  t u m or pr o gressi o n ma y de pe n d  u p o n ac q uisiti o n of traits  t hat all o w ca ncer  cells t o 
e va de i m m u n os ur veilla nce a n d esca pe effecti ve i n nate a n d a da pti ve i m m u ne res p o nses. 5 4 ,5 5 ,5 6 
C urre nt i m m u n ot hera p y  eff orts atte m pt t o brea k t he a p pare nt t olera nce of t he i m m u ne s yste m  t o 
t u m or cells a n d a nti ge ns b y eit her i ntr o d uci n g ca ncer a nti ge ns b y t hera pe utic vacci nati o n or b y 
m o d ulati n g re g ulat or y c hec k p oi nts of t he i m m u ne s yste m. T-cell sti m ulati o n is a c o m ple x pr ocess 
i n v ol vi n g  t he  i nte grati o n  of  n u mer o us  p ositi ve  as  well  as  ne gati ve  c o-sti m ulat or y  si g nals  i n  
a d diti o n t o a nti ge n rec o g niti o n b y t he T -cell rece pt or. 5 7 C ollecti vel y, t hese si g nals g o ver n t he 
bala nce bet wee n T -cell acti vati o n a n d t olera nce.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
P D - 1 is a me m ber  of  t he C D 2 8  fa mil y of T-cell c o-sti m ulat or y rece pt ors t hat als o i ncl u des C D 2 8, 
C T L A  4,  I C O S,  a n d  B T L A.  5 8 P D -1  si g nali n g  has  bee n  s h o w n  t o  i n hi bit  C D - 2 8-me diate d 
u pre g ulati o n of I L -2, I L -1 0, I L -1 3, i nterfer o n -γ (I F N-γ) a n d Bcl-x L. P D -1 e x pressi o n als o bee n 
n ote d t o i n hi bit T cell acti vati o n, a n d e x pa nsi o n of pre vi o usl y acti vate d cells. E vi de nce f or a 
ne gati ve re g ulat or y r ole of P D -1 c o mes fr o m st u dies of P D -1 deficie nt mice, w hic h de vel o p a 
variet y of a ut oi m m u ne p he n ot y pes. 5 9 T hese res ults s u g gest t hat P D -1 bl oc ka de has t he p ote ntial 
t o acti vate a nti-self T-cell res p o nses, b ut t hese res p o nses are varia ble  a n d de pe n de nt u p o n vari o us 
h ost ge netic  fact ors. T h us,  P D - 1 deficie nc y  or i n hi biti o n is n ot  acc o m pa nie d  b y a u ni versal l oss of 
t olera nce t o self-a nti ge ns. 
I n vitr o, ni v ol u ma b ( B M S-9 3 6 5 5 8) bi n ds t o P D -1 wit h hi g h affi nit y ( E C 5 0  0. 3 9-2. 6 2 n M), a n d 
i n hi bits t he bi n di n g of P D-1 t o its li ga n ds P D -L 1 a n d P D -L 2 (I C 5 0 ±  1 n M). Ni v ol u ma b bi n ds 
s pecificall y t o P D - 1 a n d n ot t o relate d me m bers  of t he C D 2 8  fa mil y s uc h as C D 2 8,  I C O S, C T L A - 
4 a n d B T L A.  Bl oc ka de of  t he P D - 1 pat h wa y b y ni v ol u ma b res ults i n a re pr o d uci ble e n ha nce me nt 
of b ot h pr oliferati o n  a n d I F N-γ release i n t he mi xe d  l y m p h oc yte reacti o n. Usi n g  a c yt o me gal o vir us 
( C M V)  resti m ulati o n  assa y  wit h  h u ma n  peri p heral  bl o o d  m o n o n uclear  cells,  t he  effect  of  
ni v ol u ma b o n a nti ge n s pecific recall res p o nse i n dicates t hat ni v ol u ma b a u g me nte d  I F N-γ secreti o n 
fr o m C M V s pecific me m or y  T-cells i n a d ose- de pe n de nt ma n ner vers us  is ot y pe-matc he d c o ntr ol. 
I n vi v o bl oc ka de of P D-1 b y a m uri ne a nal o g of ni v ol u ma b e n ha nces t he a nti -t u m or i m m u ne 
res p o nse a n d res ult i n t u m or rejecti o n i n se veral i m m u n oc o m pete nt m o use t u m or m o dels ( M C 3 8, 
S A 1/ N,  a n d P A N 0 2). 6 0 
3. 2. 2  
Cli ni c al  P h ar m a c ol o g y  S u m m ar y  
Si n gle- d ose  P K  of  ni v ol u ma b  was  e val uate d  i n  partici pa nts  wit h  m ulti ple  t u m or  t y pes  i n  
C A 2 0 9 0 0 1, w hereas  m ulti ple - d ose P K  is bei n g e val uate d i n partici pa nts  i n C A 2 0 9 0 0 3. I n a d diti o n, 
a preli mi nar y p o p ulati o n p har mac o ki netic ( P P K) m o del has bee n de vel o pe d wit h data fr o m 3 5 0 
partici pa nts fr o m C A 2 0 9 0 0 1, C A 2 0 9 0 0 2, a n d C A 2 0 9 0 0 3. 
Si n gle- d os e P K  of ni v ol u ma b was  e val uate d i n 3 9 partici pa nts  wit h  m ulti ple  t u m or t y pes i n st u d y 
C A 2 0 9 0 0 1 i n t he d ose ra n ge of 0. 3 t o 1 0 m g/ k g. T he me dia n T ma x acr oss si n gle d oses ra n ge d 
fr o m 1. 6 t o 3 h o urs wit h  i n di vi d ual val ues ra n gi n g fr o m 0. 9 t o 7 h o urs. Ge o metric  mea n  C ma x  a n d 
A U C(I N F) of ni v ol u ma b a d mi nistere d at d osa ges of 0. 3 m g/ k g, 1 m g/ k g, 3 m g/ k g, a n d 1 0 m g/ k g 
de m o nstrate d a p pr o xi mate d ose pr o p orti o nalit y. Ge o metric mea n cleara nce ( C L), after a si n gle 
i ntra ve n o us (I V) d ose, ra n ge d fr o m 0. 1 3 t o 0. 1 9 m L/ h/ k g, w hile mea n v ol u me of distri b uti o n 
d uri n g t he ter mi nal p hase ( Vz) varie d  bet wee n  8 3 t o 1 1 3 m L/ k g  acr oss d oses. T here  was  m o derate 
varia bilit y  i n P K  para meters  a m o n g partici pa nts,  wit h  c oefficie nt  of variati o n  ( C V) of 2 0 % t o 3 2 % 
i n C ma x, 3 9 % t o 4 7 % i n A U C(I N F), 1 7 % t o 4 3 % i n cleara nce, a n d 2 3 % t o 4 0 % i n Vz. B ot h 
eli mi nati o n a n d distri b uti o n  of  ni v ol u ma b  a p pear t o  be  i n de pe n de nt  of d ose i n t he  d ose  ra n ge 
st u die d. A d diti o nal  details  are pr o vi de d  i n t he ni v ol u ma b I B.4 5 
A preli mi nar y  P P K  m o del was  de vel o pe d b y n o nli near mi xe d  effect m o deli n g usi n g data  fr o m 3 5 0 
partici pa nts  fr o m C A 2 0 9 0 0 1, C A 2 0 9 0 0 2, a n d C A 2 0 9 0 0 3. Cleara nce  of ni v ol u ma b is i n de pe n de nt 
of d ose i n t he d ose ra n ge ( 0. 1 t o 1 0 m g/ k g) a n d t u m or t y pes st u die d. T he  b o d y wei g ht-n or malize d  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
d osi n g pr o d uces a p pr o xi matel y  c o nsta nt tr o u g h c o nce ntrati o ns o ver a wi de  ra n ge of b o d y wei g hts, 
a n d he nce is a p pr o priate f or f ut ure cli nical trials of ni v ol u ma b.  
I n  a  st u d y  of  ni v ol u ma b  i ncl u di n g  pe diatric  partici pa nts  ( C A 2 0 9 0 7 0),  preli mi nar y  a nal ysis  
i n dicates partici pa nts 6 t o 1 2 years ol d ha d a si milar e x p os ure t o ni v ol u ma b as a d ults. After t he 
first d ose ( 3 m g/ k g e ver y 2 wee ks), t he ge o metric mea n of o bser ve d C mi n was 2 0. 8 µ g/ m L 
c o m pare d t o ~ 1 8 µ g/ m L i n a d ults wit h m ulti ple s oli d t u m ors.  
3. 2. 3  
S af et y  S u m m ar y  
Ni v ol u ma b has bee n st u die d i n a p pr o xi matel y 1 2, 3 0 0 partici pa nts a n d is wi del y a p pr o ve d i n 
m ulti ple  i n dicati o ns. E xte nsi ve details  o n t he safet y pr ofile  of ni v ol u ma b are a vaila ble i n t he I B,4 5 
a n d will n ot be re peate d herei n. 
O verall,  t he  safet y  pr ofile  of  ni v ol u ma b  m o n ot hera p y  as  well  as  c o m bi nati o n  t hera p y  is  
ma na gea ble  a n d  ge nerall y  c o nsiste nt  acr oss  c o m plete d  a n d  o n g oi n g  cli nical  trials  wit h  n o  
ma xi m u m t olerate d d ose reac he d at a n y d ose teste d u p t o 1 0 m g/ k g. M ost a d verse e ve nts ( A Es) 
were l o w -gra de ( Gra de 1 t o 2) wit h relati vel y fe w relate d hi g h -gra de ( Gra de 3 t o 4) A Es. T here 
was  n o patter n  i n t he i nci de nce, se verit y, or ca usalit y of  A Es  wit h  res pect t o ni v ol u ma b d ose le vel. 
A patter n  of i m m u ne-relate d A Es  has bee n  defi ne d, f or w hic h  ma na ge me nt  al g orit h ms  ha ve bee n 
de vel o pe d; t hese are pr o vi de d i n A p pe n di x 7 . M ost hi g h-gra de e ve nts were ma na gea ble wit h  t he 
use of c ortic oster oi ds or h or m o ne re place me nt t hera p y (e n d ocri n o pat hies) as i nstr ucte d i n t hese 
al g orit h ms. F or a d diti o nal material, see t he ni v ol u ma b I B. 4 5 
A d diti o nal details  o n t he safet y pr ofile  of ni v ol u ma b, i ncl u di n g res ults fr o m ot her cli nical st u dies, 
are als o a vaila ble i n t he ni v ol u ma b I B. 4 5 
3. 3  
B e n efit/ Ri s k  A s s e s s m e nt  
Ni v ol u m a b  
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 reas o na bl y a ntici pate d 
A Es of ni v ol u ma b ma y be f o u n d i n t he I B. 4 5 A rece nt re p ort fr o m a P hase 1 st u d y  of ni v ol u ma b 
i n partici pa nts wit h a d va nce d he mat ol o gical mali g na ncies de m o nstrate d a hi g h res p o nse rate i n 
partici pa nts wit h  rela pse d or refract or y c H L, wit h a n O R R of  8 7 % ( 2 0/ 2 3 partici pa nts) a n d a C R 
rate of 1 7 % ( 4/ 2 3 partici pa nts).  T he  res p o nses o btai ne d were  d ura ble wit h  a 6-m o nt h  pr o gressi o n- 
free s ur vi val ( P F S) of 8 6 % a n d n o si g nifica nt differe nce  i n t he O R R  i n t he s u bset of 1 8 partici pa nts 
i n w h o m bre nt u xi ma b ve d oti n treat me nt ha d pre vi o usl y  faile d.6 1 T his  was  de m o nstrate d f urt her i n 
a P hase 2 re gistrati o nal st u d y i n hea vil y pretreate d c H L patie nts wit h fail ure of pri or  A S C T a n d 
bre nt u xi ma b  ve d oti n  treat me nt:  ni v ol u ma b  de m o nstrate d  hi g h  I R R C -assesse d  O R R  of  6 6 %,  
i n vesti gat or-assesse d O R R of 7 3 %,  t he p ote ntial t o pr o d uce d ura ble res p o nses i ncl u di n g d ura ble 
partial res p o nses, wit h o n g oi n g res p o nses i n 6 2 % of patie nts at data c ut -off a n d a n acce pta ble 
safet y pr ofile, c o nsiste nt wit h pre vi o us re p orts. 6 2 F D A  rece ntl y a p pr o ve d si n gle-a ge nt ni v ol u ma b 
f or t he treat me nt of a d ults wit h R/ R c H L f oll o wi n g fail ure of A S C T a n d bre nt u xi ma b ve d oti n. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Bre nt u xi m a b  Ve d oti n  
Bre nt u xi ma b ve d oti n is ge nerall y well t olerate d i n pe diatric patie nts at a d ose of  u p t o 1. 8 m g/ k g 
e ver y 3 wee ks. Fi ve partici pa nts a ge d 1 2 -1 7 wit h  c H L were e nr olle d i n t he pi v otal P hase 2 trial 6 3 
t hat  le d  t o  t he  F D A  a p pr o val  a n d  t here  were  n o  c o m m o n  se vere  t o xicities  or  pre mat ure  
disc o nti n uati o n of  t hera p y relate d t o a n A E. Te n partici pa nts a ge d 2 t o 1 8 years wit h rela pse d or 
refract or y c H L recei ve d si n gle-a ge nt bre nt u xi ma b ve d oti n i n a n i nter nati o nal pe diatric P hase 1 
st u d y. A P hase 2 st u d y is i n pr o gress  ( N C T 0 1 4 9 2 0 8 8). T he  c o m bi nati o n of  bre nt u xi ma b ve d oti n 
wit h  ge mcita bi ne is bei n g  i n vesti gate d i n a C O G  P hase  1/ 2 trial f or rela pse d/refract or y c H L u p t o 
a ge 3 0 years ( N C T 0 1 7 8 0 6 6 2). Res ults  fr o m t he P hase 1 part als o c o nfir m t hat t he c o m bi nati o n is 
ge nerall y well t olerate d, a n d t he P hase  2 part is recr uiti n g partici pa nts. I n a d diti o n, bre nt u xi ma b 
ve d oti n c o m bi ne d wit h  c he m ot hera p y i n t he fr o ntli ne setti n g i n hi g h-ris k pe diatric  c H L is c urre ntl y 
bei n g i n vesti gate d i n 2 acti ve trials. A P hase 2 st u d y is i n vesti gati n g t he earl y res p o nse rate a n d 
P F S  of  bre nt u xi ma b  ve d oti n  as  a  s u bstit ute  f or  vi ncristi ne  i n  t he  E ur o pea n  O E P A/ C O P Dac  
re gi me n ( N C T 0 1 9 2 0 9 3 2). I n a  6 0 0-patie nt  ra n d o mize d P hase 3 trial, C O G  is e val uati n g t he 
efficac y  of  bre nt u xi ma b  ve d oti n  as  a  re place me nt  f or  ble o m yci n  i n  t he  A B V E -P C  re gi me n  
( N C T 0 2 1 6 6 4 6 3). T his trial is o n g oi n g wit h  data m o nit ore d  c o nti n u o usl y b y t he i n de pe n de nt Data 
Safet y a n d M o nit ori n g B oar d. N o ne of t he st o p pi n g r ules ha ve bee n tri g gere d. 
Be n d a m usti ne  
Be n da m usti ne is a bif u ncti o nal mec hl oret ha mi ne deri vati ve wit h a be nzi mi daz ole heter oc yclic 
ri n g. Data fr o m 2 ra n d o mize d trials ha ve res ulte d i n a p pr o val of be n da m usti ne as sec o n d-li ne 
t hera p y f or i n d ole nt rela pse d a n d refract or y i n d ole nt n o n- H o d g ki n l y m p h o ma.6 4 ,6 5 I n patie nts  wit h 
H o d g ki n l y m p h o ma, be n da m usti ne has  bee n  s h o w n t o be hi g hl y acti ve a n d has i n d uce d c o m plete 
re missi o n i n  2 5 %- 3 5 %  of  ver y  hea vil y pretreate d   a d ults,5 2 ,5 3 ,6 6 ,6 7 i ncl u di n g  t h ose w h o  ha ve  
recei ve d pri or a ut ol o g o us he mat o p oietic ste m cell resc ue.6 8 Be n da m usti ne has bee n st u die d as a 
si n gle a ge nt i n pe diatrics. 6 9 C o m bi ni n g be n da m usti ne wit h  ot her a ge nts ma y  i m pr o ve b ot h t he rate 
a n d d urati o n of res p o nse. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
4.  
O B J E C TI V E S  A N D  E N D P OI N T S  
 
O bjecti ves  
E n d p oi nts  
Pri m ar y  
 
R 1  ( L o w Ris k)  C o h ort:  T o  descri be  t he c o m plete 
R 1  C o h ort:  C M R  r ate at  a n y  ti me pri or  t o R T  a n d  E F S  
meta b olic  res p o nse ( C M R) rate pri or  t o R T  a n d 
r ate at  3  ye ars  
e ve nt-free  s ur vi val  ( E F S)  rate  at  3  years,  as  
assesse d  b y  bli n de d  i n de pe n de nt  ce ntral  re vie w  
( BI C R), usi n g L u ga n o 2 0 1 4 res p o nse criteria . 
•  
T he  C M R  rate  is  defi ne d  as  t he  pr o p orti o n  of  all  
res p o nse-e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  
BI C R,  ac hie ve best  res p o nse of  C M R  usi n g  L u ga n o  2 0 1 4 
criteria. 
 
•  
E F S is t he ti me fr o m t he date of first treat me nt t o t he 
earliest  occ urre nce  of  c o m p osite  e ve nts  i ncl u di n g  t he  
f oll o wi n g: 
 
− 
Hi g h -d ose  c he m ot hera p y  f oll o we d b y  a ut ol o g o us 
ste m cell tra ns pla nt ( H D C T/ A S C T) 
 
− 
Disease  pr o gressi o n  per  L u ga n o  ( 2 0 1 4) 
 
− 
Fail ure  t o ac hie ve C M R  after 4 c ycles of  N + B v  a n d 
2 c ycles of B v + B  
 
− 
Sec o n dar y  mali g na nc y  
 
− 
Deat h d ue  t o a n y ca use 
 
•  
Partici pa nts  w h o  di d  n ot  ha ve  a n  “e ve nt”  will  be  
ce ns ore d  at  t he  last  a de q uate  t u m or  assess me nt.  
Partici pa nts  w h o  start  s u bse q ue nt  a ntica ncer  t hera p y  
(t hat is n ot  part  of  H D C T/ A S C T)  wit h o ut  a pri or  re p orte d 
“e ve nt” will be ce ns ore d at t he last t u m or assess me nt 
pri or  t o  or  o n  t he  da y  of  t he  s u bse q ue nt  a ntica ncer  
t hera p y. 
 
•  
Ot her  defi niti o ns  of  E F S,  e m pl o yi n g  s o me w hat differe nt 
ce ns ori n g r ules, ma y be a d de d as se nsiti vit y a nal yses.  
 
•  
R 2  ( Sta n dar d Ris k)  C o h ort:  T o  descri be  t he 
R 2  C o h ort:  C M R  r ate at  a n y  ti me pri or  t o H D C T/ A S C T  
c o m plete meta b olic res p o nse ( C M R) rate pri or t o 
H D C T/ A S C T  b y  BI C R,  usi n g  L u ga n o  2 0 1 4  
res p o nse criteria 
•  
T he  C M R  rate  is  defi ne d  as  t he  pr o p orti o n  of  all  
res p o nse-e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  
BI C R,  ac hie ve best  res p o nse of  C M R  usi n g  L u ga n o  2 0 1 4 
criteria. 
Sec o n d ar y  i n B ot h  R 1  a n d  R 2  C o h orts:  
 
T o assess o verall res p o nse rate ( O R R) ( C M R + 
partial meta b olic res p o nse [ P M R]) usi n g L u ga n o 
2 0 1 4  criteria  of  t he  l o w  ris k  a n d  sta n dar d  ris k  
c o h orts  f oll o wi n g  4  c ycles  of  ni v ol u ma b  a n d  
bre nt u xi ma b ve d oti n b y BI C R.  
O R R  f oll o wi n g  4  c ycles  of  ni v ol u m a b  +  bre nt u xi m a b  
ve d oti n tre at me nt  
•  
O R R  is  defi ne d  as  t he  pr o p orti o n  of  all  res p o nse - 
e val ua ble  partici pa nts  w h o,  assesse d  b y  t he  BI C R,  
ac hie ve a best res p o nse of C M R or P M R usi n g L u ga n o 
2 0 1 4 criteria.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
O bjecti ves  
E n d p oi nts  
T o  assess  P F S  rate at 3  years  b y  BI C R  usi n g 
L u ga n o 2 0 1 4 criteria  
P F S  r ate at  3  ye ars  
•  
T he a nal ysis is perf or me d w he n partici pa nts ha ve bee n 
f oll o we d f or 3 years.  P F S  is t he ti me fr o m t he date  of  first 
treat me nt  t o  t he  date  of  first  d oc u me nte d  disease  
pr o gressi o n b y BI C R or deat h. Partici pa nts w h o  neit her 
pr o gress n or die will be ce ns ore d at t he last a de q uate 
t u m or  assess me nt.  Partici pa nts  w h o  start  s u bse q ue nt  
a ntica ncer  t hera p y  (t hat  is  n ot  part  of  H D C T/ A S C T  
C o ns oli dati o n T hera p y f or R 2 C o h ort) wit h o ut a pri or 
re p orte d pr o gressi o n  or  deat h  will  be  ce ns ore d  at t he last 
t u m or assess me nt pri or t o i nitiati o n of t he s u bse q ue nt 
a ntica ncer t hera p y.  
•  
Ot her  defi niti o ns  of  P F S,  e m pl o yi n g  s o me w hat differe nt 
ce ns ori n g r ules, ma y be a d de d as se nsiti vit y a nal yses.  
D urati o n  of  Res p o nse  ( D O R) will  be  e val uate d  f or 
t h ose partici pa nts w h o ac hie ve d P M R or C M R b y 
BI C R  as  well  as  f or  t h ose  partici pa nts  w h o  
ac hie ve d  C M R  b y  BI C R  pri or  t o R T  i n t he l o w ris k 
c o h ort  a n d  f or  t h ose  partici pa nts  w h o  ac hie ve d  
C M R pri or t o H D C T/ A S C T i n t he sta n dar d ris k 
c o h ort. 
D O R  
•  
D O R  is defi ne d  as t he ti me fr o m first res p o nse ( C M R or 
P M R)  t o  t he  date  of  E F S  ( R 1)/ P F S  ( R 2)  e ve nt.  F or  
partici pa nts  w h o  di d  n ot  ha ve  a n e ve nt, t he D O R  will  be 
ce ns ore d  o n  t he  date  of  t heir  last  t u m or  assess me nt.  
Partici pa nts  w h o  start  s u bse q ue nt  a ntica ncer  t hera p y  
(t hat is n ot  part  of  H D C T/ A S C T)  wit h o ut  a pri or  re p orte d 
E F S/ P F S  e ve nt  will  be  ce ns ore d  at  t he  last  t u m or  
assess me nt  pri or  t o  i nitiati o n  of  t he  s u bse q ue nt  
a ntica ncer t hera p y.  
T o e val uate efficac y as assesse d  b y i n vesti gat ors 
usi n g L U G A N O ( 2 0 1 4) res p o nse criteria.  
All  effic ac y e n d p oi nts a b o ve,  per  i n vesti g at or assess me nts  
R 1  c o h ort: C M R  rate pri or  t o R T  a n d E F S  at 3 years 
R 2 c o h ort: C M R rate pri or t o H D C T/ A S C T  
B ot h R 1 a n d R 2 c o h orts: O R R f oll o wi n g 4 c ycles of N + B v 
treat me nt, P F S rate at 3 years, a n d D O R. 
T o  descri be  t he  t o xicit y  of  ni v ol u ma b  +  
bre nt u xi ma b  i n c o m bi nati o n  i n pe diatric  a n d y o u n g 
a d ult  partici pa nts  wit h  rela pse d  or  refract or y  
classical H o d g ki n’s  l y m p h o ma (c H L) after fail ure 
of first -li ne treat me nt. 
T o xicit y/ S afet y E n d p oi nts  are seri o us a n d  n o n -seri o us A Es, 
cli nical la b orat or y tests ( he mat ol o g y, c he mistr y, uri nal ysis), 
vital si g n meas ure me nts, etc.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
O bjecti ves  
E n d p oi nts  
E x pl or at or y  
 
•  
T o assess o verall s ur vi val ( O S) i n all treate d 
partici pa nts  i n  t he  S R  a n d  L R  c o h orts,  
res pecti vel y. 
•  
Ass ociati o n  of  bi o mar ker  le vels wit h  res p o nse 
i ncl u di n g O R R, P F S, a n d O S. 
•  
O S is defi ne d as t he ti me fr o m t he date of first d ose of 
st u d y dr u g u ntil t he date of deat h f or a n y reas o n. If t he 
partici pa nt is ali ve or t he vital stat us is u n k n o w n, t he 
partici pa nt will be ce ns ore d at t he date t he partici pa nt 
was last k n o w n t o be ali ve.  
 
•  
T o  assess  c ha n ges  i n  bi o mar kers  i n  t he  
peri p heral  bl o o d,  s uc h  as  s ol u ble  fact ors,  
i m m u ne  cells,  a n d  vacci nate d  a nti b o d y  
c o nce ntrati o ns. 
•  
T o  assess  bi o mar kers  i n t he t u m or tiss ue, s uc h as P D -L 1 
e x pressi o n, 9 p 2 4. 1 c o p y n u m ber alterati o n, a n d t u m or 
i nfiltrati n g  l y m p h oc ytes  a n d  t heir  ass ociati o n  wit h  
res p o nse. 
•  
T o  s u m marize c ha n ges i n bi o mar ker  le vels o ver  ti me (see 
pr ot oc ol Secti o n 9. 8 ). 
 
•  
T o  c haracterize  p har mac o ki netics  ( P K)  of  
ni v ol u ma b
 a n d
 bre nt u xi ma b
 f oll o wi n g
 
c o m bi nati o n t hera p y.  
•  
Ser u m sa m ples will be c ollecte d t o c haracterize P K of 
ni v ol u ma b a n d bre nt u xi ma b.  
•  
Sa m ples will be e val uate d f or t he prese nce of a nti -dr u g 
a nti b o d y. 
•  
T o  c haracterize  t he  i m m u n o ge nicit y  of  
ni v ol u ma b
 a n d
 bre nt u xi ma b
 f oll o wi n g
 
c o m bi nati o n t hera p y.  
•  
T o  e val uate  partici pa nt -re p orte d  ge neral  
healt h  stat us a n d ca ncer-s pecific q ualit y  of  life 
( Q o L). 
•  
T o  i n vesti gate  t he  effect of  4  p ote ntial  ris k  
fact ors o n E F S a n d O R R. 
•  
Ge neral healt h stat us as assesse d b y  t he E Q-5 D -3 L, a n d 
ca ncer-s pecific Q o L as assesse d b y t he F A C T-L y m  
•  
See  defi niti o n  of  E F S  a n d O R R  a b o ve (see ris k fact ors i n 
pr ot oc ol Secti o n 3. 1 ) 
•  
T he sa me efficac y  varia bles  detaile d  a b o ve a n d meas ure d 
f or L U G A N O 2 0 1 4 will be e x pl ore d f or L Y RI C 2 0 1 6. 
•  
I m ple me ntati o n of L Y RI C 2 0 1 6 f or efficac y 
assess me nts.  
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
4 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
5.  
S T U D Y  D E SI G N  
5. 1  
O v er all  D e si g n  
C A 2 0 9 7 4 4  is  a  P hase  2,  o pe n -la bel  st u d y  of  N + B v  f or  c hil dre n  a n d  y o u n g  a d ults  wit h  
rela pse d/refract or y c H L. Partici pa nts  w h o  d o n ot ac hie ve C M R  after 4 c ycles of N + B v  will  recei ve 
B v + B  t o hel p ac hie ve  C M R.  T here  are 2 treat me nt c o h orts: o ne  wit h  partici pa nts at l o w ris k rela pse 
( R 1 c o h ort), a n d o ne wit h  partici pa nts  at sta n dar d ris k rela pse ( R 2 c o h ort) ( Ta ble 5. 1- 1 a n d Fi g ure 
5. 1 -1).  
T a ble  5. 1-1:  
Ris k  Str atific ati o n  Al g orit h m  
 
St a ge  at  I niti al 
Di a g n osis  
Ti me t o Rel a pse 
(fr o m e n d of  t her a p y) 
B s y m pt o ms or  e xtr a n o d al dise ase 
at  rel a pse,  e xte nsi ve dise ase w here 
r a di ati o n t her a p y w as 
c o ntr ai n dic ate d at rel a pse, or 
rel a pse i n a pri or r a di ati o n fiel d  
Rel a pse  Ris k 
C ate g or y  
I A, II A 
≥ 1 2  m o nt hs  
N o  
R 1  C o h ort: 
L o w Ris k  
3- 1 2  m o nt hs  
(≤ 3 c ycles a n d n o  R T)  
I B, II B, III A 
> 1 2 m o nt hs  
N o  
All  Ot hers  
R 2  C o h ort:  
 
St a n d ar d  Ris k  
 
Fi g ure  5. 1-1:  
St u d y  Desi g n  Sc he m atic  
 
•  R 1 c o h ort will recei ve N + B v f or 2 c ycles ( 6 wee ks) f oll o we d b y T u m or Assess me nts ( T A). 
Partici pa nts  wit h  ra di o gra p hic pr o gressi o n, as assesse d  b y I n vesti gat or ( per A p pe n di x 6 ) at 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
C ycle  2 N + B v,  will  be ta ke n off st u d y treat me nt a n d e nter f oll o w- u p ( u nless treat me nt be y o n d 
pr o gressi o n is a p pr o ve d b y t he Brist ol -M yers S q ui b b ( B M S) Me dical M o nit or, per Secti o n  
8. 1. 2 ). All ot her partici pa nts will recei ve 2 a d diti o nal c ycles of N + B v st u d y t hera p y (t otal 4 
c ycles = 1 2 wee ks).  
− Partici pa nts  w h o  ha ve a C M R, as  assesse d b y  BI C R,  after a t otal of 4 c ycles  ( 1 2 wee ks)  of 
N + B v  will recei ve a n a d diti o nal 2 c ycles of treat me nt of  N + B v (f or a t otal  of 6 c ycles [ 1 8 
wee ks]), f oll o we d b y Ra diati o n T hera p y ( R T), per i nstit uti o nal  g ui deli nes ( See  A p pe n di x  
8 : Ra di ot hera p y G ui deli nes f or R 1 C o h ort f urt her rec o m me n dati o ns). 
− Partici pa nts   wit h o ut  a C M R  after  4 c ycles of  N + B v,  as assesse d   b y BI C R,  will  recei ve 
2 c ycles of B v + B; partici pa nts w h o ac hie ve C M R after t hese 2 c ycles will pr ocee d wit h 
R T, per  i nstit uti o nal g ui deli nes ( See A p pe n di x 8: Ra di ot hera p y  G ui deli nes f or R 1 C o h ort 
f urt her rec o m me n dati o ns). 
− Partici pa nts  w h o  ha ve ra di o gra p hic pr o gressi o n after C ycle  4 N + B v,  as assesse d  b y BI C R, 
( u nless Treat me nt  Be y o n d Pr o gressi o n is a p pr o ve d b y B M S  Me dical  M o nit or,  per  Secti o n 
8. 1. 2) or t h ose w h o  d o n ot ac hie ve C M R,  as assesse d  b y BI C R,  after 2 c ycles of B v + B  will 
be ta ke n off st u d y treat me nt a n d e nter f oll o w- u p. 
•  R 2 c o h ort will recei ve N + B v f or 2 c ycles ( 6 wee ks), f oll o we d b y T A. Partici pa nts wit h 
ra di o gra p hic pr o gressi o n, as assesse d b y I n vesti gat or ( per A p pe n di x 6 ) at C ycle  2 N + B v, will 
be ta ke n off st u d y treat me nt a n d e nter f oll o w -u p ( u nless Treat me nt Be y o n d Pr o gressi o n is 
a p pr o ve d  b y B M S  Me dical   M o nit or,  per Secti o n   8. 1. 2). All   ot her partici pa nts  will  recei ve 
2 a d diti o nal c ycles of N + B v st u d y t hera p y (t otal 4 c ycles = 1 2 wee ks). 
o  Partici pa nts  w h o  ha ve C M R,  as assesse d  b y BI C R,  after a t otal of 4 c ycles of N + B v 
will  pr ocee d  wit h  H D C T/ A S C T  ( perf or me d  per  i nstit uti o nal  g ui deli nes).  
Partici pa nts wit h C M R will ha ve t he o pti o n t o recei ve u p t o t w o a d diti o nal c ycles 
of N + B v if t heir H D C T/ A S C T has t o be p ost p o ne d f or a n y reas o n (t his re q uires 
pri or B M S Me dical M o nit or a p pr o val).  
− Partici pa nts   wit h o ut  a C M R,  as assesse d   b y BI C R,  after  4 c ycles of  N + B v  will  recei ve 
2 c ycles of B v + B.  
o  Partici pa nts i n C M R, as assesse d b y BI C R, after 2 c ycles of B v + B will recei ve 
H D C T/ A S C T ( perf or me d per i nstit uti o nal g ui deli nes).  
o  Partici pa nts   wit h o ut C M R  as assesse d   b y BI C R  will   ha ve a n  o pti o n t o recei ve 
2 a d diti o nal c ycles of B v + B (t his re q uires pri or B M S Me dical M o nit or a p pr o val). 
If t hese partici pa nts attai n C M R, as assesse d b y BI C R, t he y will pr ocee d wit h 
H D C T/ A S C T ( perf or me d per i nstit uti o nal g ui deli nes).  
o  P artici pa nts wit h  C M R will ha ve t he o pti o n t o recei ve u p t o t w o a d diti o nal c ycles 
of B + B v if t heir H D C T/ A S C T has t o be p ost p o ne d f or a n y reas o n (t his re q uires 
pri or B M S Me dical M o nit or a p pr o val).  
− Partici pa nts  w h o  ha ve ra di o gra p hic pr o gressi o n after C ycle  4 N + B v,  as assesse d  b y BI C R, 
d uri n g  st u d y  treat me nt  ( u nless  Treat me nt  Be y o n d  Pr o gressi o n  is  a p pr o ve d  b y  B M S  
Me dical M o nit or, per Secti o n 8. 1. 2) or t h ose w h o d o n ot ac hie ve C M R, as assesse d b y 
BI C R, after fi nal c ycle of B v + B will be ta ke n off st u d y  treat me nt a n d e nter f oll o w- u p. 
•  R 1 a n d R 2 C o h ort F oll o w -u p Visits will occ ur Da y 3 0, a n d t he n s y nc he d u p wit h t u m or 
assess me nts  o n  Da y  1 0 0  a n d  t he n  6,  1 2,  1 8,  2 4,  a n d  3 6  m o nt hs  P ost - C o ns oli dati o n 
T hera p y/ Treat me nt   Disc o nti n uati o n. O nce   partici pa nts reac h  t he s ur vi val f oll o w- u p p hase,  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
eit her  i n-pers o n  visits  or  d oc u me nte d  tele p h o ne  calls/e mail  c orres p o n de nce  t o  assess  t he  
partici pa nt’s  stat us are acce pta ble. T u m or  assess me nts are re q uire d f or partici pa nts w h o  ha ve 
n ot ra di o gra p hicall y pr o gresse d, per BI C R, as per Ta ble 2 - 4 a n d Secti o n 9. 1 . If I n vesti gat or 
t u m or assess me nt = C M R f or a treat me nt relate d-decisi o ns ti me p oi nt ( C ycle 4 I n d ucti o n, or 
C ycle 2 or 4 I nte nsificati o n, as  a p plica ble) b ut BI C R assess me nt differs, a n d as a res ult st u d y 
treat me nt  is  disc o nti n ue d  a n d  H D C T/ A S C T  (f or  R 2  C o h ort)  a n d  R T  (f or  R 1  C o h ort)  is  
perf or me d i n f oll o w - u p, t u m or assess me nts  s h o ul d c o nti n ue t o be pr o vi de d u ntil ra di o gra p hic 
pr o gressi o n  per  I n vesti gat or  Assess me nt,  per  L U G A N O  2 0 1 4.  F or  t hese  cases,  it  is  
rec o m me n de d t o f oll o w t he sa me sca n fre q ue nc y a n d m o dalit y as w he n BI C R assess me nt = 
C M R ( per ta ble 2. -4: 1 0 0 da ys a n d t he n 6, 1 2, 1 8, 2 4, a n d 3 6 m o nt hs p ost - C o ns oli dati o n 
T hera p y/ Treat me nt  Disc o nti n uati o n), b ut  at a mi ni m u m  t he M o nt h  3 6 t u m or assess me nt  is 
re q uire d. 
 
5. 1. 1  
D at a M o nit ori n g C o m mitt e e a n d Ot h er E xt er n al C o m mitt e e s  
T w o i n de pe n de nt c o m mittees will be utilize d, a St u d y Steeri n g C o m mittee ( S S C) a n d a Data 
M o nit ori n g C o m mittee ( D M C).  
T he  S S C  will be c o m prise d of c o u ntr y -le vel s u bject matter  e x perts, wit h  c hair ma n re prese ntati o n 
fr o m eac h of t he C o o perati ve Gr o u ps (e g, C O G a n d E ur o net). T he y will pr o vi de g ui da nce f or 
st u d y desi g n a n d i n p ut as nee de d  t hr o u g h o ut t he c o urse of t he st u d y. T he  S S C  will  assist wit h  da y- 
t o- da y ma na ge me nt/ o versi g ht of t he st u d y a n d wit h  i m ple me nti n g t he m o nit ori n g r ules f or t o xicit y. 
A D M C will be esta blis he d t o pr o vi de o versi g ht a n d safet y a n d efficac y c o nsi derati o ns a n d t o 
pr o vi de a d vice t o t he s p o ns or re gar di n g acti o ns t he c o m mittee dee ms  necessar y  f or t he c o nti n ui n g 
pr otecti o n of partici pa nts e nr olle d i n t he st u d y. T he D M C will be c har ge d wit h assessi n g s uc h 
acti o ns  i n  li g ht  of  a n  acce pta ble  be nefit/ris k  pr ofile  f or  c o m bi nati o n  t hera p y  of  N + B v  i n  
c o m bi nati o n wit h t hera p y of B v + B deli vere d se q ue ntiall y i n a s u bset of partici pa nts w h o ha ve 
s u b o pti mal res p o nse t o N + B v.  T he  D M C  will  act i n a n a d vis or y ca pacit y t o B M S  a n d will  m o nit or 
partici pa nt  safet y a n d e val uate t he a vaila ble efficac y data f or t he st u d y. T he o nc ol o g y  t hera pe utic 
area of B M S has pri mar y  res p o nsi bilit y f or desi g n a n d c o n d uct of t he st u d y. 
T he  i nci de nce  of  ni v ol u ma b,  bre nt u xi ma b  ve d oti n,  or  be n da m usti ne -relate d  t o xicit y  will  be  
m o nit ore d  i n all partici pa nts  treate d wit h  at least o ne d ose of st u d y dr u g at t he c o m bi nati o n  d oses 
defi ne d i n t he pr ot oc ol. T he prescri bi n g i nf or mati o n f or bre nt u xi ma b ve d oti n, ni v ol u ma b, a n d 
be n da m usti ne i n di vi d uall y descri be  a d verse e ve nts c o m m o nl y o bser ve d relati ve t o t he a ge nts (i.e., 
ne utr o pe nia or peri p heral ne ur o pat h y wit h  bre nt u xi ma b  ve d oti n; i m m u ne-me diate d  a d verse  e ve nts 
wit h ni v ol u ma b), as well as less c o m m o n seri o us fi n di n gs. If a n a d h oc meeti n g is esta blis he d 
base d o n t he i nci de nce of  e ve nts e xcee di n g t hat e x pecte d wit h t he a ge nts as re p orte d wit h  si n gle- 
a ge nt a d mi nistrati o n,  t he D M C  will  re vie w safet y data  a n d pr o vi de rec o m me n dati o ns. I n t he e ve nt 
t hat t he D M C rec o m me n ds ter mi nati n g t he st u d y or ma ki n g si g nifica nt c ha n ges t o st u d y desi g n, 
B M S  will  i nf or m Healt h  A ut h orities  of t he D M C  rec o m me n dati o n. I n a d diti o n, B M S  ma y  c o ns ult 
wit h Healt h A ut h orities bef ore ma ki n g t he fi nal decisi o n.  
A d diti o nall y,  r ules t hat will  tri g ger a n a d- h oc D M C  meeti n g  will  be esta blis he d  t o e val uate be nefit- 
ris k a n d nee d t o a me n d or st o p t he st u d y f or t he f oll o wi n g: 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Ras h  > Gra de  3, p ul m o nar y  t o xicit y, a n d peri p heral ne ur o pat h y as rec o g nize d t o xicities ass ociate d 
wit h  t hese a ge nts w he n  deli vere d  as m o n ot hera p y, will  be cl osel y m o nit ore d f or p ote ntial st o p pi n g 
of t he st u d y if t he A E rates are dee me d u nacce pta bl y hi g h. Ras h ≥ Gra de 3 will be classifie d as 
er yt he ma  m ultif or me,  Ste ve ns-J o h ns o n S y n dr o me, or t o xic e pi der mal necr olisis  ( T E N) per C T C  
4. 0 criteria. P ul m o nar y t o xicit y will be defi ne d b y d ys p nea ≥ G ra de 3, h y p o xia ≥ Gra de 3, or 
p ne u m o nitis ≥ Gra de  2.  T here  m ust  be  n o  e vi de nce  of  ot her  eti ol o gies,  i ncl u di n g  left  atrial  
h y perte nsi o n, c o n gesti ve heart  fail ure, i nfecti o n, meta b olic  a b n or malities,  or ca ncer  relate d ca uses 
(e g,  mali g na nt  pericar ditis).  Peri p heral  ne ur o pat h y  e ve nts  i ncl u de  b ot h  se ns or y  a n d  m ot or  
ne ur o pat h y ≥ Gra de 3. 
A Ba yesia n r ule is a d o pte d f or t his m o nit ori n g. Eac h c o h ort i n t his st u d y will be m o nit ore d 
se paratel y. 
F or ras h > G ra de 3 a n d p ul m o nar y t o xicit y, t he pri or distri b uti o n f or eac h t o xicit y p is a Beta 
distri b uti o n wit h  para meters  α  = 1 a n d β  = 1 9. T his  Beta  distri b uti o n has a mea n  of 5 %; t he s u p p ort 
f or p ≤ 1 0 % is 8 6 %. If  gi ve n t he o bser ve d data at a d -h oc m o nit ori n g, t he p osteri or pr o ba bilit y of 
p ≥ 5 % is 0. 8 or hi g her, it will be c o nsi dere d c o m pelli n g e vi de nce t hat t he t o xicit y  rate of eac h is 
u nacce pta ble a n d t he st u d y will be referre d t o t he D M C f or re vie w a n d c o nsi derati o n f or earl y 
cl os ure. 
T his m o nit ori n g will be perf or me d f or e ver y D M C meeti n g. O perati o nall y t he m o nit ori n g will 
re q uire, f or e xa m ple, ≥ 2/ 6, ≥ 3/ 2 0, or ≥ 4/ 4 0 partici pa nts  wit h  t he t o xicit y i n q uesti o n f or  t he r ule 
t o be met.  T he  e xact r ule will  de pe n d o n t he n u m ber of partici pa nts  i n t he de n o mi nat or at t he ti me 
of t he i nteri m m o nit ori n g. T he st u d y will t olerate at m ost 3 partici pa nts wit h res pect t o eac h 
t o xicit y i n eac h c o h ort at t he e n d. 
Wit h a n i nitial  pla n ne d sa m ple size of  N =  4 0, if t he tr ue rate of t he t o xicit y is 5 %, 1 0 %, or 1 5 %, 
res pecti vel y, t he c ha nce  of o bser vi n g 4 or m ore  partici pa nts  wit h  t he t o xicit y i n q uesti o n are 1 4 %, 
5 8 %, a n d 8 7 %, res pecti vel y. 
F or peri p heral ne ur o pat h y  t o xicit y, t he pri or distri b uti o n f or eac h t o xicit y p is a Beta distri b uti o n 
wit h  para meters  α  = 4 a n d β  = 1 6. T his  Beta  distri b uti o n  has  a mea n  of 2 0 %; t he s u p p ort f or p 
≤ 3 0 % is 8 7 %.  If gi ve n  t he o bser ve d  data at i nteri m  m o nit ori n g, t he  p osteri or pr o ba bilit y  of p 
≥ 2 0 % is 0. 8  or hi g her, it will be c o nsi dere d c o m pelli n g e vi de nce  t hat t he t o xicit y rate of eac h is 
u nacce pta ble  a n d t he st u d y will  be referre d t o D M C  f or re vie w a n d c o nsi derati o n f or earl y cl os ure. 
O perati o nall y  t his will  re q uire, f or e xa m ple, ≥ 4/ 6, ≥ 7/ 2 0, or ≥ 1 1/ 4 0 partici pa nts  wit h  peri p heral 
ne ur o pat h y t o xicit y f or t he r ule t o be met.  T he  e xact r ule will  de pe n d o n t he n u m ber of  partici pa nts 
i n t he de n o mi nat or at t he ti me of t he i nteri m m o nit ori n g. T he st u d y will t olerate at m ost 1 0 
partici pa nts wit h peri p heral ne ur o pat h y i n eac h c o h ort at t he e n d. 
Wit h  a n i nitial pla n ne d sa m ple size of  N = 4 0, if t he tr ue rate of t he peri p heral  ne ur o pat h y is 2 0 %, 
2 5 % or 3 0 % res pecti vel y, t he c ha nce  of o bser vi n g 1 1 or m ore  partici pa nts  wit h  t o xicities are 1 6 %, 
4 2 %, a n d 6 9 % res pecti vel y. 
If t he n u m ber of patie nts  ac hie vi n g C M R  per bli n de d i n de pe n de nt ce ntral re vie w ( BI C R) at c ycle 
4 assess me nt  is 5 or fe wer a m o n g t he first 2 0 treate d R 2  patie nts,  t he n f urt her accr ual  f or a d diti o nal 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
patie nts  i n t he R 2  c o h ort will  be halte d. T he  S p o ns or will  t h or o u g hl y re vie w all efficac y a n d safet y 
data,  a n d earl y ter mi nati o n of t he R 2  c o h ort ma y  be c o nsi dere d if t he c o ncl usi o n d oes n ot warra nt 
s uccess of t he st u d y f or t his c o h ort. 
A d diti o nal st u d y g o ver na nce c o nsi derati o ns are detaile d  i n A p pe n di x 2 . 
5. 2  
N u m b er of P arti ci p a nt s  
A p pr o xi matel y 1 0 0 partici pa nts  were  pla n ne d t o be e nr olle d, wit h  a p pr o xi matel y  8 0 treate d ( 4 0 i n 
eac h c o h ort), i n c o nsi derati o n of p ote ntial scree ni n g fail ures or t h ose w h o are treate d b ut n ot 
res p o nse-e val ua ble.  A mi ni m u m  of 2 5 treate d partici pa nts  ( R 1: 5, R 2:  2 0) will  be pe diatric  ( 5 t o < 
1 8 years ol d), u nless B M S St u d y Tea m i nstr ucts ot her wise.  
T he  pr ot oc ol reflecte d a pr o p osal t o i ncl u de a t otal of 1 0 0 e nr olle d partici pa nts  t o o btai n 8 0 treate d 
partici pa nts (a ge 5 t o < 3 0), wit h 4 0 partici pa nts per c o h ort, a n d a mi ni m u m of 2 5 pe diatric 
partici pa nts (a ge 5 t o < 1 8).  
Alt h o u g h t he pr o p ose d sa m ple 
size i n t he pr ot oc ol was n ot i nte n de d t o s u p p ort statistical h y p ot hesis testi n g, 9 0 % c o nfi de nce 
i nter vals ( CI), c orres p o n di n g t o a ra n ge of o bser ve d res p o nse rates, were  pr o vi de d t o ill ustrate t he 
precisi o n of esti mati o n ( See Ta ble 1 0. 3. 1- 1 ) 
St u d y C A 2 0 9 7 4 4 is bei n g c o n d ucte d i n 1 1 c o u ntries w orl d wi de (alt h o u g h o nl y 1 0 of t he m ha ve 
bee n  a ble t o recr uit partici pa nts)  wit h  7 5 acti vate d sites i n t otal; h o we ver, o nl y 2 0 %  of  t he t otalit y 
 
 
 
 
I n li g ht of a b o ve, t he pr ot oc ol is bei n g m o difie d  t o re d uce t he t otal n u m ber  of partici pa nts  fr o m 8 0 
t o  7 2 (t otal n u m ber of treate d partici pa nts e nr olle d R 1 = 2 8 a n d R 2 = 4 4) 
 
wit h  a n o verall sizea ble p o p ulati o n 
t hat  ca n  s u p p ort  a  f ut ure  assess me nt  of  be nefit/ris k.  Ass u mi n g  2 4  res p o n ders  o ut  of  2 8  R 1  
partici pa nts, t he e xact 2 -si de d 9 0 % c o nfi de nce i nter val w o ul d be 7 0. 2 3 % t o 9 4. 9 7 %. 
See  Secti o n  1 0 f or details  o n statistical c o nsi derati o ns a n d sa m ple size deter mi nati o n.  
of  t he sites recr uite d R 1  partici pa nts.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
5. 3  
E n d of St u d y D efi niti o n  
T he start of t he trial is defi ne d as t he first visit f or t he first scree ne d partici pa nt. T he e n d of t he 
trial is defi ne d  as t he last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of Acti vities  i n Secti o n  2 f or 
t he last partici pa nt. St u d y c o m pleti o n is defi ne d as t he fi nal date o n w hic h data f or t he pri mar y 
e n d p oi nt is e x pecte d t o be c ollecte d. 
5. 4  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
See  Secti o n  3. 1 . 
5. 5  
J u stifi c ati o n f or D o s e  
Ni v ol u m a b  
Partici pa nts s h o ul d recei ve ni v ol u ma b at a d ose of 3 m g/ k g as a 3 0 -mi n ute  I V i nf usi o n, o n Da y 1 
of eac h treat me nt c ycle e ver y 3 wee ks, u ntil pr o gressi o n, u nacce pta ble t o xicit y, wit h dra wal of 
c o nse nt, or t he st u d y e n ds, w hic he ver occ urs first. Partici pa nts  s h o ul d be gi n st u d y treat me nt wit hi n 
3 cale n dar da ys of treat me nt assi g n me nt.  
D osi n g calc ulati o ns s h o ul d be base d  o n t he b o d y wei g ht assesse d  at baseli ne.  It is n ot necessar y  t o 
re-calc ulate s u bse q ue nt d oses if t he partici pa nt  wei g ht is wit hi n  1 0 % of t he wei g ht use d  t o calc ulate 
t he pre vi o us d ose. All d oses s h o ul d be r o u n de d u p or t o t he nearest milli gra m per i nstit uti o nal 
sta n dar d. 
I n a st u d y of ni v ol u ma b i ncl u di n g pe diatric partici pa nts ( C A 2 0 9 0 7 0), preli mi nar y a nal ysis has 
s h o w n t he pe diatric partici pa nts ( 6 – 1 2 yrs)  ha ve a si milar e x p os ure t o a d ults. P ost t he first d ose 
( 3 m g/ k g Q 2 W),  t he ge o metric  mea n  of o bser ve d C mi n  is 2 0. 8 u g/ m L c o m pare d  t o ~ 1 8  u g/ m L i n 
a d ults wit h m ulti ple s oli d t u m ors.  
Bre nt u xi m a b Ve d oti n  
Bre nt u xi ma b ve d oti n is ge nerall y well t olerate d i n pe diatric patie nts at a d ose of  u p t o 1. 8 m g/ k g 
e ver y 3 wee ks. Fi ve partici pa nts a ge d 1 2 -1 7 wit h  c H L were e nr olle d i n t he pi v otal P hase 2 trial 6 3 
t hat  le d  t o  t he  F D A  a p pr o val  a n d  t here  were  n o  c o m m o n  se vere  t o xicities  or  pre mat ure  
disc o nti n uati o n of t hera p y relate d t o a n A E. 
Be n d a m usti ne  
After  4  c ycles  of  N + B v,  partici pa nts  wit h  res p o nse  assess me nt  of  P M R/ N M R  will  recei ve  
i nte nsificati o n t hera p y wit h bre nt u xi ma b ve d oti n + be n da m usti ne ( 9 0 m g/ m2), t o hel p ac hie ve 
C M R pri or t o H D C T/ A S C T ( or R T).  
I n a P hase  1/ 2 st u d y of bre nt u xi ma b ve d oti n + be n da m usti ne i n R/ R  c H L ( me dia n a ge of  3 6 years 
[ra n ge 1 9-7 9]), t he re p orte d rec o m me n de d d oses of bre nt u xi ma b ve d oti n ( 1. 8 m g/ k g) o n Da y 1 
a n d be n da m usti ne ( 9 0 m g/ m 2) were  deli vere d  o n Da ys  1 a n d 2 i n 3-wee k  c ycles, res pecti vel y. T he 
safet y pr ofile was ma na gea ble. T he mai n t o xicit y o bser ve d wit h t he c o m bi nati o n was i nf usi o n - 
relate d reacti o ns ( 5 6 % o verall).  T he  m ost c o m m o n s y m pt o ms (≥ 1 0 %) were  p yre xia ( 2 6 %), c hills 
( 2 0 %), d ys p nea a n d na usea ( 1 5 % eac h), fl us hi n g ( 1 3 %), a n d h y p ote nsi o n ( 1 1 %). Pre me dicati o n 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
wit h c ortic oster oi ds a n d a nti hista mi nes was i nstit ute d wit h a pr ot oc ol a me n d me nt a n d a p peare d 
effecti ve. 
6.  
S T U D Y P O P U L A TI O N  
F or  e ntr y i nt o t he st u d y, t he f oll o wi n g criteria M U S T  be met.  
6. 1  
I n cl u si o n Crit eri a  
1)  Si g ne d  Writte n  I nf or me d C o nse nt  
a) Partici pa nts  m ust ha ve  si g ne d a n d date d  a n I nstit uti o nal Re vie w  B oar d/I n de pe n de nt Et hics 
C o m mittee  (I R B/I E C)  a p pr o ve d  writte n  i nf or me d  c o nse nt  f or m  i n  acc or da nce  wit h  
re g ulat or y a n d i nstit uti o nal g ui deli nes. T his m ust be o btai ne d bef ore t he perf or ma nce of 
a n y pr ot oc ol- relate d pr oce d ures t hat are n ot part of n or mal partici pa nt care. 
b)  Partici pa nts  m ust be willi n g  a n d a ble t o c o m pl y wit h  sc he d ule d visits,  treat me nt sc he d ule, 
la b orat or y tests, a n d ot her re q uire me nts of t he st u d y 
c) F or partici pa nts u na ble  t o gi ve t heir writte n  c o nse nt, i n acc or da nce  wit h l ocal  re g ulati o ns, 
o ne or b ot h pare nts,  a g uar dia n, or  a le gall y acce pta ble  re prese ntati ve m ust  be i nf or me d of 
t he st u d y pr oce d ures a n d m ust d oc u me nt per missi o n  b y si g ni n g t he i nf or me d c o nse nt f or m 
a p pr o ve d f or t he st u d y pri or t o cli nical st u d y partici pati o n  
d)  Eac h partici pa nt m ust be i nf or me d a b o ut t he nat ure of  t he st u d y t o t he e xte nt c o m pati ble 
wit h his or her u n dersta n di n g. S h o ul d a partici pa nt bec o me ca pa ble or reac h t he a ge of 
maj orit y, his or her c o nse nt s h o ul d be o btai ne d as s o o n as p ossi ble. T he e x plicit wis h of a 
partici pa nt w h o  is a mi n or or u na ble t o gi ve his or her writte n  c o nse nt, b ut w h o  is ca pa ble 
of  f or mi n g  a n  o pi ni o n  a n d  assessi n g  i nf or mati o n  t o  ref use  partici pati o n  i n,  or  t o  be  
wit h dra w n fr o m, t he cli nical st u d y at a n y ti me s h o ul d be c o nsi dere d b y t he i n vesti gat or. 
e) Mi n ors w h o are j u d ge d t o be of a n a ge of reas o n as deter mi ne d b y l ocal re q uire me nts 
s h o ul d  als o  gi ve  t heir  asse nt.  T he  asse nt  s h o ul d  be  d oc u me nte d  base d  o n  l ocal  
re q uire me nts. C o nti n ue d asse nt s h o ul d be d oc u me nte d w he n i m p orta nt ne w i nf or mati o n 
bec o mes a vaila ble t hat is rele va nt t o t he partici pa nt’s asse nt.  
2)  T y pe  of P artici p a nt  a n d  T ar get Dise ase  C h ar acteristics  
a) Partici pa nts m ust  ha ve meas ura ble  disease,  d oc u me nte d b y pat h ol o gical a n d ra di o gra p hic 
criteria 
i) Partici pa nts  
wit h  
pat h ol o gicall y  
c o nfir me d 
c H L, 
e xcl u di n g 
n o d ular 
l y m p h oc yte- pre d o mi na nt H L, after fail ure or n o n-res p o nse t o first-li ne t hera p y. 
( 1) Rela pse d  disease  is  defi ne d  as  ac hie vi n g  a  C R  t o  pre vi o us  t hera p y  b ut  t he n  
pr o gressi n g 3 m o nt hs or m ore after c o m pleti o n of t hat t hera p y.  
( 2) Refract or y  disease is defi ne d as ne ver ac hie vi n g a C R t o pre vi o us t hera p y or 
ac hie vi n g  a C R  b ut t he n pr o gressi n g wit hi n  3 m o nt hs of c o m pleti o n of t hat t hera p y. 
ii) At  least  1  meas urea ble  site  of  disease  acc or di n g  t o  t he  L u ga n o  2 0 1 4  criteria  
(I nter nati o nal W or ki n g Gr o u p criteria). 7 0 ,7 1 
iii) Partici pa nts m ust ha ve F D G -P E T -a vi d a n d bi di me nsi o nal meas urea ble disease of at 
least 1. 5 c m i n l o n gest a xis as d oc u me nte d b y ra di o gra p hic tec h ni q ue ( C T preferre d). 
b)  Perf or ma nce Le vel:  Kar n ofs k y ≥ 5 0 f or partici pa nts > 1 6 years of  a ge or La ns k y ≥ 5 0 f or 
partici pa nts ≤ 1 6 years of a ge (A p pe n di x 5 ). Partici pa nts w h o are u na ble t o wal k beca use 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
of paral ysis,  b ut w h o  are i n a w heelc hair,  will  be c o nsi dere d a m b ulat or y  f or t he p ur p ose of 
assessi n g t he perf or ma nce sc ore.  
c) E val ua ble t u m or tiss ue (arc hi ve d or ne w  bi o ps y) m ust be pr o vi de d t o t he ce ntral la b orat or y 
as f or mali n -fi xe d paraffi n -e m be d de d ( F F P E) t u m or bl oc k or sli des. I n or der  t o be treate d, 
t he sa m ple m ust meet t he mi ni m u m q ualit y re q uire me nts, as deter mi ne d b y t he ce ntral 
la b orat or y d uri n g t he scree ni n g peri o d. N ote:  U n der s pecial circ u msta nces,  if t u m or tiss ue 
pr o vi de d  is  dee me d  i na de q uate,  c o ntact  t he  Me dical  M o nit or  f or  a p pr o val  t o  be gi n  
treat me nt. 
3)  A ge a n d Re pr o d ucti ve St at us  
a) Males  a n d Fe males, a ges  5 t o 3 0 years, i ncl usi ve 
b)  W o me n  of  c hil d beari n g  p ote ntial  ( W O C B P)  m ust  ha ve  a  ne gati ve  ser u m  or  uri ne  
pre g na nc y test ( mi ni m u m se nsiti vit y 2 5 I U/ L or e q ui vale nt u nits of H C G)  wit hi n  2 4 h o urs 
pri or t o t he start of st u d y treat me nt  
c) W o me n  m ust  n ot be breastfee di n g  
d)  W O C B P m ust a gree t o f oll o w i nstr ucti o ns f or 2 met h o ds of c o ntrace pti o n or c o m plete 
a bsti ne nce (liste d i n A p pe n di x 4 ) f or t he d urati o n of treat me nt wit h i n vesti gati o nal dr u gs 
(all I M Ps) a n d f or a n a d diti o nal 6 m o nt hs p ost-treat me nt c o m pleti o n. 
e) Males w h o are se x uall y acti ve wit h W O C B P m ust a gree t o f oll o w i nstr ucti o ns f or 2 
met h o ds of  c o ntrace pti o n or c o m plete a bsti ne nce (liste d i n A p pe n di x 4) f or t he d urati o n  of 
treat me nt  wit h  i n vesti gati o nal  dr u gs  (all  I M Ps)  a n d  f or  a n  a d diti o nal  6  m o nt hs  p ost- 
treat me nt c o m pleti o n.  I n a d diti o n, male  partici pa nts  m ust  be willi n g  t o refrai n fr o m s per m 
d o nati o n d uri n g t his ti me. 
f) Az o os per mic  males  are  e xe m pt  fr o m  c o ntrace pti ve  re q uire me nts.  W O C B P  w h o  are  
c o nti n u o usl y n ot heter ose x uall y acti ve are als o e xe m pt fr o m c o ntrace pti ve re q uire me nts, 
a n d still m ust u n der g o pre g na nc y testi n g as descri be d i n t his secti o n. 
 
I n vesti gat ors s hall c o u nsel W O C B P,  a n d male  partici pa nts  w h o  are se x uall y acti ve wit h  W O C B P, 
o n t he i m p orta nce of pre g na nc y pre ve nti o n a n d t he i m plicati o ns of a n u ne x pecte d pre g na nc y. 
I n vesti gat ors s hall a d vise o n t he use of hi g hl y effecti ve met h o ds of c o ntrace pti o n. A d diti o nal 
details are pr o vi de d i n A p pe n di x 4. 
4)  P h ysic al  a n d  L a b or at or y Test  Fi n di n gs  
a) Scree ni n g  la b orat or y val ues m ust  meet  t he f oll o wi n g criteria: 
i) A de q uate b o ne marr o w  f u ncti o n defi ne d  as t he f oll o wi n g: 
( 1) F or  partici pa nts  wit h o ut k n o w n b o ne marr o w  i n v ol ve me nt: 
(a) Peri p heral  a bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 7 5 0/ m m 3 
( b) P latelet c o u nt ≥ 7 5, 0 0 0/ m m3 (tra nsf usi o n i n de pe n de nt, defi ne d  as n ot recei vi n g 
platelet tra nsf usi o ns f or at least 7 da ys pri or t o e nr oll me nt). Partici pa nts wit h 
k n o w n b o ne marr o w  metastatic  disease  will  be eli gi ble f or st u d y pr o vi de d t he y 
meet  t he platelet  c o u nts f oll o wi n g tra nsf usi o n, h o we ver t he y will  n ot be eli gi ble 
f or assess me nt of he mat ol o gic t o xicit y 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
( 2) F or  partici pa nts  wit h  k n o w n b o ne marr o w  i n v ol ve me nt: 
(a) Partici pa nts  wit h  c yt o pe nias sec o n dar y t o k n o w n b o ne marr o w  i n v ol ve me nt are 
eli gi ble re gar dless of A N C or platelet c o u nts  
( b) Partici pa nts ma y be e nr olle d a n d recei ve tra nsf usi o ns pr o vi de d t he y are n ot 
k n o w n t o be refract or y t o re d cell or platelet  tra nsf usi o ns. Partici pa nts  wit h  b o ne 
marr o w i n v ol ve me nt will n ot be e val uate d f or he mat ol o gic t o xicit y  re gar dless 
of A N C or platelet c o u nts at t he ti me of dia g n osis.  
ii) Creati ni ne cleara nce or ra di ois ot o pe G F R ≥ 7 0 ml/ mi n/ 1. 7 3 m 2 or a ser u m creati ni ne 
base d o n a ge/ ge n der as f oll o ws: 
 
A ge  
M a xi m u m  Ser u m  Cre ati ni ne  ( m g/ d L) 
 
M ale  
Fe m ale  
1 t o < 2 years  
0. 6  
0. 6  
2 t o < 6 years  
0. 8  
0. 8  
6 t o < 1 0  years  
1 
1 
1 0  t o < 1 3  years  
1. 2  
1. 2  
1 3  t o < 1 6  years  
1. 5  
1. 4  
≥ 1 6  years  
1. 7  
1. 4  
N ote:  t he t hres h ol d val ues  i n t his ta ble were  deri ve d  fr o m t he Sc h wartz  f or m ula f or esti mati n g  G F R, 7 2  
utilizi n g c hil d le n gt h a n d stat ure data p u blis he d b y t he U S Ce nters f or Disease C o ntr ol a n d Pre ve nti o n  
 
iii) A de q uate he patic f u ncti o n as e vi de nce d  b y t he f oll o wi n g: 
( 1) T otal  bilir u bi n  ≤ 1. 5 x u p per li mit  of n or mal ( U L N) 
( 2) S G P T  (ala ni ne a mi n otra nsferase  [ A L T]) ≤ 3 x U L N.  F or  t he p ur p ose of  t his st u d y, 
t he U L N f or S G P T is 4 5 U/ L 
5)  Pri or  A nti -t u m or T her a p y  
a) Partici pa nts  m ust ha ve  recei ve d first-li ne a nti-ca ncer  t hera p y t hat faile d 
b)  Partici pa nts m ust  ha ve f ull y  rec o vere d fr o m t he ac ute t o xic effects of all pri or a nti -ca ncer 
c he m ot hera p y pri or t o si g ni n g c o nse nt. 
c) M yel os u p pressi ve c he m ot hera p y: At  least 1 4 da ys  after t he last d ose of  m yel os u p pressi ve 
c he m ot hera p y. 
d)  He mat o p oietic gr o wt h  fact ors: At  least 1 4 da ys after t he last d ose of a l o n g-acti n g gr o wt h 
fact or (e g, Ne ulasta) or 7 da ys f or s h ort -acti n g gr o wt h fact or. F or a ge nts t hat ha ve k n o w n 
A Es occ urri n g be y o n d 7 da ys after a d mi nistrati o n, t his peri o d m ust be e xte n de d be y o n d 
t he ti me d uri n g w hic h A Es are k n o w n t o occ ur. T he d urati o n of t his i nter val m ust be 
disc usse d wit h t he B M S Me dical M o nit or.  
e) Bi ol o gic (a nti-ne o plastic  a ge nt): At  least 3 half -li ves after t he last d ose of a bi ol o gic a ge nt. 
f) M o n ocl o nal  a nti b o dies:  At  least  3  half -li ves  of  t he  a nti b o d y  after  t he  last  d ose  of  a  
m o n ocl o nal a nti b o d y.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
g)  Ble o m yci n: At least 2 8 da ys m ust ha ve ela pse d si nce t he m ost rece nt d ose  of ble o m yci n, 
t o all o w a de q uate ti me t o detect e vi de nce of ble o m yci n-relate d p ul m o nar y t o xicit y 
 
6. 2  
E x cl u si o n  Crit eri a  
1)  Me dic al C o n diti o ns  
a) Partici pa nts wit h a n i m m u n o deficie nc y t hat e xiste d pri or t o dia g n osis, s uc h as pri mar y 
i m m u n o deficie nc y  s y n dr o mes,  or ga n  tra ns pla nt  reci pie nts,  a n d  partici pa nts  o n  c urre nt  
s yste mic i m m u n os u p pressi ve a ge nts are n ot eli gi ble 
b)  Acti ve  cere bral/ me ni n geal  disease  relate d t o t he u n derl yi n g mali g na nc y  
c) Hist or y  of pr o gressi ve  m ultif ocal le u k oe nce p hal o pat h y ( P M L) 
d)  Pre -e xisti n g ne ur o pat h y of ≥ Gra de  2 
e) A n y acti ve Gra de 3 or hi g her ( per C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
[ C T C A E]  versi o n  4)  viral,  bacterial  or  f u n gal  i nfecti o n  pri or  t o  t he  first  d ose  of  
bre nt u xi ma b ve d oti n; r o uti ne a nti micr o bial pr o p h yla xis is per mitte d  
f) 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 rec 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  
g)  Ot her seri o us  u n derl yi n g me dical  c o n diti o n t hat, i n t he o pi ni o n of  t he i n vesti gat or, w o ul d 
i m pair t he a bilit y t o recei ve or t olerate t he pla n ne d treat me nt a n d f oll o w- u p 
h)  Pri or mali g na nc y  acti ve wit hi n  t he pre vi o us 3 years  e xce pt f or l ocall y c ura ble ca ncers  t hat 
ha ve bee n  a p pare ntl y c ure d, s uc h as basal  or s q ua m o us cell s ki n ca ncer, s u perficial bla d der 
ca ncer, or carci n o ma i n sit u of t he pr ostate, cer vi x, or breast  
i) K n o w n  hist or y  of  p ositi ve  test  f or  h u ma n  i m m u n o deficie nc y  vir us  ( HI V)  or  k n o w n  
ac q uire d  i m m u n o deficie nc y s y n dr o me ( AI D S). N O T E:  Testi n g  f or HI V  m ust be perf or me d 
at sites w here ma n date d l ocall y.  
2)  Pri or/ C o nc o mit a nt  T her a p y  
a) Partici pa nts  w h o  recei ve d m ore t ha n o ne li ne of a nti-ca ncer  t hera p y or are treat me nt nai ve 
are n ot eli gi ble 
b)  Pre vi o usl y recei ve d a n all o ge neic a n d/ or a ut ol o g o us S C T  f or H L  
c) Partici pa nts  w h o  ha ve recei ve d a pri or  s oli d or ga n  tra ns pla ntati o n are n ot  eli gi ble 
d)  Partici pa nts  wit h   a  c o n diti o n re 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  pre 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 first d ose of st u d y me dicati o n.  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  pre 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.  
e) P ri or e x p os ure t o a nti-P D 1,  a nti-P D L 1,  a nti-P D -L 2,  a nti-C D 1 3 7  or  a nti- C T L A - 4 a nti b o d y, 
or a n y ot her a nti b o d y or dr u g s pecificall y tar geti n g T -cell c o-sti m ulati o n or c hec k p oi nt 
pat h wa ys  
f) Pri or ra diati o n  t hera p y wit hi n  3 wee ks,  or c hest ra diati o n ≤ 1 2 wee ks pri or t o first d ose of 
st u d y dr u g(s) 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
5 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
g)  A n y  c o nc urre nt  a nti -ne o plastic  t hera p y  (ie,  c he m ot hera p y,  h or m o nal  t hera p y,  
i m m u n ot hera p y, e xte nsi ve, n o n-palliati ve ra diati o n  t hera p y, or sta n dar d or i n vesti gati o nal 
a ge nts f or treat me nt of c H L)  
h)  Pri or  e x p os ure t o be n da m usti ne  
i) Li ve  vacci ne  ( < 4 wee ks pri or t o t he start of st u d y treat me nt) 
3)  P h ysic al  a n d  L a b or at or y Test Fi n di n gs  
a) A n y p ositi ve test f or he patitis B or C vir us i n dicati n g ac ute or c hr o nic i nfecti o n, a n d/ or 
detecta ble vir us  
4)  Aller gies  a n d  A d verse  Dr u g  Re acti o n  
a) Hist or y  of  aller g y or h y perse nsiti vit y  t o st u d y dr u g  c o m p o ne nts 
b)  Partici pa nts wit h seri o us or u nc o ntr olle d me dical dis or ders t hat, i n t he o pi ni o n of t he 
i n vesti gat or,  ma y  i ncrease  t he  ris k  ass ociate d  wit h  st u d y  partici pati o n  or  st u d y  dr u g  
a d mi nistrati o n,  i m pair t he a bilit y of t he partici pa nt  t o recei ve pr ot oc ol t hera p y, or i nterfere 
wit h t he i nter pretati o n of st u d y res ults  
5)  Ot her  E xcl usi o n Criteri a  
a) Pris o ners or partici pa nts w h o are i n v ol u ntaril y i ncarcerate d. ( N ote: u n der certai n s pecific 
circ u msta nces  a pers o n w h o  has bee n  i m pris o ne d ma y  be i ncl u de d or per mitte d  t o c o nti n ue 
as a partici pa nt. Strict c o n diti o ns a p pl y a n d B M S a p pr o val is re q uire d). 
b)  Partici pa nts  w h o  are c o m p uls oril y detai ne d  f or treat me nt of  eit her a ps yc hiatric  or p h ysical 
(e g, i nfecti o us disease) ill ness 
 
Eli gi bilit y criteria f or t his st u d y ha ve bee n caref ull y c o nsi dere d t o e ns ure t he safet y of  t he st u d y 
partici pa nts a n d t hat t he res ults of t he st u d y ca n be use d. It is i m perati ve t hat partici pa nts f ull y 
meet all eli gi bilit y criteria.  
6. 3  
Lif e st yl e  R e stri cti o n s  
N ot  a p plica ble. N o  restricti o ns are re q uire d. 
6. 4  
S cr e e n  F ail ur e s  
Scree n fail ures are defi ne d as partici pa nts 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 ra n d o mize d/e ntere d i n t he st u d y/i ncl u de d i n t he a nal ysis p o p ulati o n. 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 ure tra ns pare nt re p orti n g of scree n fail ure 
partici pa nts, 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 res p o n d t o q ueries fr o m re g ulat or y a ut h orities. Mi ni mal  i nf or mati o n i ncl u des 
date of c o nse nt, 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 Es.  
6. 4. 1  
R et e sti n g  D uri n g  S cr e e ni n g  or  L e a d -I n P eri o d  
Partici pa nt  Re -e nr oll me nt:  T his  st u d y  per mits  t he  re -e nr oll me nt  of  a  partici pa nt  t hat  has  
disc o nti n ue d t he st u d y as a pre- treat me nt fail ure. 
T he  m ost c urre nt  res ult pri or t o treat me nt assi g n me nt is t he val ue  b y w hic h  st u d y i ncl usi o n will  be 
assesse d, as it re prese nts t he partici pa nt’s m ost c urre nt, cli nical state.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
7.  
T R E A T M E N T  
St u d y dr u g i ncl u des b ot h I n vesti gati o nal ( Me dici nal) Pr o d uct (I P/I M P) a n d N o n- i n vesti gati o nal 
( Me dici nal) Pr o d uct ( N o n-I P/ N o n-I M P). St u d y dr u gs f or t his st u d y are s u m marize d i n  Ta ble 7 - 1. 

 
 
Cli nical  Pr ot oc ol  
C A 2 0 9 7 4 4  
B M S -9 3 6 5 5 8  
ni v ol u ma b  
 
T a ble  7-1:  
St u d y  Tre at me nts  f or C A 2 0 9 7 4 4  
 
Pr o d uct  Descri pti o n  / 
Cl ass a n d D os a ge 
F or m  
P ote nc y  
I P/ N o n-I M P 
Bli n de d  or  O pe n 
L a bel  
P ac k a gi n g  / 
A p pe ar a nce  
St or a ge  C o n diti o ns 
( per l a bel) 
Ni v ol u ma b 
( B M S-9 3 6 5 5 8 -0 1)  
S ol uti o n  f or I njecti o na 
 
1 0 0  m g  ( 1 0 m g/ m L)  
 
I M P 
 
O pe n  la bel 
1 0 m L Vial/ Clear t o 
o palesce nt c ol orless t o 
pale  yell o w  li q ui d. Ma y 
c o ntai n particles.  
 
2 t o 8°C.  Pr otect  fr o m 
li g ht a n d freezi n g 
 
Bre nt u xi ma b Ve d oti n 
p o w der  f or s ol uti o n f or 
I njecti o nb  
 
 
5 0  m g  
 
 
I M P 
 
 
O pe n  La bel  
W hite t o off -w hite 
l y o p hilize d 
preser vati ve -free ca ke 
or  p o w der  i n a si n gle- 
use vial f or 
rec o nstit uti o n 
 
 
2 t o 8°C.  Pr otect  fr o m 
li g ht a n d freezi n g 
Be n da m usti ne  p o w der 
f or s ol uti o n f or 
I njecti o nb  
O R  
Be n da m usti ne  
S ol uti o n  f or I njecti o nb  
 
 
2 5  m g  or  1 0 0  m g 
O R  
1 0 0  m g/ 4  ml  
( 2 5 m g/ ml)  
 
 
 
I M P 
 
 
 
O pe n  la bel 
W hite t o off -w hite 
l y o p hilize d p o w der  i n a 
si n gle-d ose vial f or 
rec o nstit uti o n 
O R  
Clear a n d c ol orless t o 
yell o w  rea d y-t o-dil ute 
s ol uti o n 
 
 
1 5  t o 2 5 °C ( p o w der) 
O R  
2 t o 8 C  (s ol uti o n). 
Pr otect  fr o m li g ht. 
a Ma y  be  la bele d as eit her  “ B M S-9 3 6 5 5 8 -0 1”  or  “ Ni v ol u ma b.” 
b T hese pr o d ucts ma y be o btai ne d b y t he i n vesti gati o nal sites as l ocal c o m mercial pr o d uct i n certai n c o u ntries if all o we d b y l o cal re g ulati o ns. I n t hese cases, 
pr o d ucts  ma y be a differe nt pac k size/ p ote nc y t ha n  liste d i n t he ta ble. T hese pr o d ucts s h o ul d be pre pare d/st ore d/a d mi nistere d i n acc or da nce wit h t he pac ka ge 
i nsert or s u m mar y of pr o d uct c haracteristics ( S m P C) 
 
 
 
 
 
 
 
 
 
 
Pr ot oc ol A me n d me nt N o.: 0 4  
Date: 2 6 -Mar -2 0 2 1  
6 1  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
7. 1  
Tr e at m e nt s  A d mi ni st er e d  
T he  selecti o n a n d ti mi n g of d ose f or eac h partici pa nt  is descri be d  i n Ta ble  7. 1- 1. T he  start a n d st o p 
ti me of t he st u d y t hera p y i nf usi o ns a n d a n y i nterr u pti o ns or i nf usi o n rate re d ucti o ns s h o ul d be 
d oc u me nte d.  
T a ble  7. 1-1:  
Selecti o n  a n d  Ti mi n g  of D ose  
 
St u d y  Tre at me nt  
U nit d ose 
stre n gt h(s)/ D os a ge le vel(s) 
D os a ge f or m ul ati o n 
Fre q ue nc y  of  A d mi nistr ati o n  
R o ute of 
A d mi nistr ati o n  
Ni v ol u ma b  
3 m g/ k g  
2 1 -da y  c ycles 
I V 
Bre nt u xi ma b  Ve d oti n  
1. 8  m g/ k g a 
2 1 -da y  c ycles 
I V 
Be n da m usti ne  
9 0  m g/ m 2 / da y 
2 1 -da y  c ycles ( o n Da ys  1 a n d 2)  
I V 
a If t he partici pa nt  wei g hs  m ore  t ha n 1 0 0  k g,  t he d ose  calc ulati o n  f or B v  s h o ul d be  1 0 0  K g.  See  l ocal pac ka ge  i nsert 
or PI L f or f urt her g ui da nce.  
 
Ni v ol u m a b + Bre nt u xi m a b Ve d oti n  A d mi nistr ati o n  
Eli gi ble  partici pa nts  will  recei ve treat me nt wit h   bre nt u xi ma b  ve d oti n at  1. 8 m g/ k g I V as   a 
3 0 mi n ute i nf usi o n o n Da y 1 of e ver y 2 1- da y c ycle.  
F or  C ycle  1 o nl y, ni v ol u ma b  will  be a d mi nistere d  al o ne o n Da y  8 of  C ycle  1. Ni v ol u ma b  i njecti o n 
at 3 m g/ k g is t o be a d mi nistere d as a n I V i nf usi o n o ver 3 0 mi n utes. Detaile d i nstr ucti o ns f or 
dil uti o n a n d i nf usi o n of  ni v ol u ma b i njecti o n will  be pr o vi de d i n t he p har mac y  ma n ual or refere nce 
s heets. Care m ust be ta ke n t o ass ure sterilit y of t he pre pare d s ol uti o n as t he pr o d uct d oes n ot 
c o ntai n a n y a nti micr o bial preser vati ve or bacteri ostatic a ge nt.  
B y deli veri n g bre nt u xi ma b ve d oti n, a directl y c yt ot o xic a ge nt, 1 wee k pri or t o ni v ol u ma b i n 
C ycle  1,  it  is  a ntici pate d  t hat  t u m or -ass ociate d  a nti ge ns  will  be  release d  a n d  a vaila ble  f or  
prese ntati o n  t o resi de nt c yt ot o xic T-cells at t he sa me ti me t hat t hese cells bec o me  acti vate d t hr o u g h 
P D -1 bl oc ka de. H o we ver, beca use of t he l o n g half -life of ni v ol u ma b t here is n o rati o nale t o 
c o nti n ue sta g gere d d osi n g be y o n d C ycle 1. 
F or  C ycle  2 a n d be y o n d,  ni v ol u ma b  s h o ul d be a d mi nistere d at least 3 0 mi n utes  after t he c o m pleti o n 
of bre nt u xi ma b ve d oti n i nf usi o n. Partici pa nts  s h o ul d be gi n st u d y treat me nt wit hi n  3 cale n dar  da ys 
of treat me nt assi g n me nt.  
D osi n g calc ulati o ns s h o ul d be base d o n t he b o d y  wei g ht assesse d at baseli ne ( C ycle 1, Da y 1). It 
is n ot necessar y t o re-calc ulate s u bse q ue nt d oses if t he partici pa nt wei g ht is wit hi n 1 0 % of t he 
wei g ht use d t o calc ulate t he pre vi o us d ose. All d oses s h o ul d be r o u n de d u p or t o t he nearest 
milli gra m per i nstit uti o nal sta n dar d.  
T he  rec o m me n de d d ose f or  bre nt u xi ma b ve d oti n  per its  prescri bi n g i nf or mati o n is 1. 8 m g/ k g  via 
I V i nf usi o n a d mi nistere d e ver y 3 wee ks.4 6 T his d ose a n d sc he d ule was e val uate d i n t w o pi v otal 
P hase  2  st u dies  ( S G 0 3 5 -0 0 0 3  a n d  S G 0 3 5 -0 0 0 4)  i n  patie nts  wit h  C D 3 0 -p ositi ve he mat ol o gic 
mali g na ncies.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Bre nt u xi m a b + Be n d a m usti ne D osi n g  
After 4 c ycles of N + B v, R 1 ( or R 2) c o h ort wit h t u m or assess me nt of P M R/ N M R will recei ve 
a u g me nt t hera p y wit h B v + B, wit h o bjecti ve t o ac hie ve C M R pri or t o R T ( or H D C T/ A S C T). 
Eli gi ble  partici pa nts  will  recei ve bre nt u xi ma b ve d oti n ( 1. 8 m g/ k g) o n Da y  1 a n d be n da m usti ne ( 9 0 
m g/ m 2) o n Da ys  1 a n d 2 of a 2 1-da y  c ycle, res pecti vel y. Be n da m usti ne s h o ul d be a d mi nistere d  at 
least 3 0 mi n utes after t he c o m pleti o n of bre nt u xi ma b ve d oti n i nf usi o n o n Da y 1 of eac h c ycle. 
A d mi nistrati o n of bre nt u xi ma b ve d oti n a n d be n da m usti ne s h o ul d perf or me d i n acc or da nce wit h 
t heir  res pecti ve  prescri bi n g  i nf or mati o n.4 6 ,4 9 See  l ocal  pac ka ge  i nsert  or  PI L  f or  f urt her  
i nf or mati o n. 
7. 1. 1  
Tr e at m e nt of I nf u si o n R e a cti o n s  
I nf usi o n-relate d  reacti o ns  ha ve  bee n  re p orte d  a n d  ma y  occ ur  d uri n g  t he  i nf usi o n  of  st u d y  
treat me nt(s) N + B v a n d B v + B c ycles of t hera p y. T he i nf usi o n s h o ul d be a d mi nistere d at a site 
pr o perl y e q ui p pe d a n d staffe d t o ma na ge a na p h yla xis s h o ul d it occ ur. All s u p p orti ve meas ures 
c o nsiste nt  wit h  o pti mal patie nt  care s h o ul d be gi ve n  t hr o u g h o ut t he st u d y acc or di n g  t o i nstit uti o nal 
sta n dar ds. S u p p orti ve meas ures ma y i ncl u de e xte n di n g t he i nf usi o n ti me a n d/ or a d mi nisteri n g 
me dicati o ns f or i nf usi o n -relate d reacti o ns. 
I nf usi o n or h y perse nsiti vit y  reacti o ns ma y occ ur t o eit her bre nt u xi ma b ve d oti n, be n da m usti ne, or 
ni v ol u ma b. If s uc h a reacti o n were  t o occ ur, it mi g ht  ma nifest  wit h  fe ver, c hills, ri g ors, hea dac he, 
ras h,  pr urit us,  art hral gia,  h y p ote nsi o n,  h y perte nsi o n,  br o nc h os pas m,  or  ot her  aller gic-li ke 
reacti o ns.  I nf usi o n  reacti o ns  s h o ul d  be  gra de d  acc or di n g  t o  Nati o nal  Ca ncer  I nstit ute  ( N CI)  
C T C A E ( versi o n 4) g ui deli nes.  
Re q uire d  P re me dic ati o ns  f or Ni v ol u m a b + Bre nt u xi m a b  Ve d oti n  
All  partici pa nts  recei vi n g c o m bi nati o n  t hera p y wit h  N + B v  will  recei ve pr o p h ylactic pre me dicati o n 
at least 3 0 mi n utes pri or t o d osi n g st u d y dr u g(s) wit h fa m oti di ne 4 0 m g I V (a d ult) or 0. 5 m g/ k g 
( pe diatric) a n d di p he n h y dra mi ne 5 0 m g I V (a d ult) or 1 m g/ k g ( pe diatric) [ or e q ui vale nt H 2/ H 1 
bl oc kers] pri or t o e ver y c ycle fr o m C ycle  2. F or  partici pa nts  i n C ycle  5 a n d be y o n d w h o ha ve ha d 
n o i nf usi o n  reacti o ns, H 1/ H 2 bl oc kers (e g,: di p he n hr dra mi ne) d ose ma y be l o were d t o 2 5 m g ( or 
e q ui vale nt) or o mitte d per i n vesti gat or discreti o n. Aceta mi n o p he n 6 5 0 m g (a d ult) or 1 5 m g/ k g 
( pe diatric)  ma y  be  i ncl u de d  as  a  pre me dicati o n  per  i n vesti gat or  discreti o n.  Partici pa nts  w h o  
e x perie nce a Gra de 1 or Gra de 2 i nf usi o n -relate d reacti o n w hile recei vi n g pre me dicati o n s h o ul d 
be  pre me dicate d  a d di n g  met h yl pre d nis ol o ne  4 0  m g  I V  (a d ult)  or  0. 3  m g/ k g  ( pe diatric)  or  
e q ui vale nt. If t he o nset of  a reacti o n occ urs d uri n g a n i nf usi o n, t he i nf usi o n ma y  be i nterr u pte d f or 
treat me nt of t he i nf usi o n-relate d reacti o n, i ncl u di n g treat me nt wit h  a nti hista mi nes,  c ortic oster oi ds, 
a n d/ or br o nc h o dilat or t hera p y, as a p pr o priate. Partici pa nts w h o e x perie nce a Gra de 3 i nf usi o n - 
relate d reacti o n t o bre nt u xi ma b  ve d oti n or ni v ol u ma b  ma y  p ote ntiall y  recei ve a d diti o nal  treat me nt 
wit h t he st u d y  dr u g(s) at t he discreti o n of t he i n vesti gat or after disc ussi o n wit h t he s p o ns or.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
If a na p h yla xis or a Gra de 4 i nf usi o n-relate d reacti o n occ urs, a d mi nistrati o n of t he i m plicate d 
a ge nt(s)  ( bre nt u xi ma b  ve d oti n  a n d/ or  ni v ol u ma b)  s h o ul d  be  i m me diatel y  a n d  per ma ne ntl y  
disc o nti n ue d a n d partici pa nt w o ul d e nter f oll o w- u p. 
I n case of late-occ urri n g h y perse nsiti vit y s y m pt o ms t o ni v ol u ma b (e g, a p peara nce of a l ocalize d 
or ge neralize d  pr urit us wit hi n 1 wee k after ni v ol u ma b treat me nt), s y m pt o matic treat me nt ma y be 
gi ve n (e g, oral a nti hista mi ne or c ortic oster oi ds).  
F or  a d diti o nal treat me nt g ui da nce of  i m m u ne me diate d  a d verse  e ve nts see A p pe n di x 7 . 
Re q uire d  P re me dic ati o ns  f or Bre nt u xi m a b  Ve d oti n  + Be n d a m usti ne  
Pr o p h ylactic pre me dicati o n wit h c ortic oster oi ds a n d a nti hista mi nes will be a d mi nistere d t o all 
s u bjects a p pr o xi matel y  3 0 t o 6 0 mi n utes pri or t o i nf usi o n of bre nt u xi ma b ve d oti n ( o n da ys w he n 
bre nt u xi ma b  ve d oti n a n d be n da m usti ne are a d mi nistere d).  Rec o m me n de d d oses f or pre me dicati o n 
are t he f oll o wi n g:  
•  Met h yl pre d nis ol o ne 1 0 0  m g  I V or e q ui vale nt (e g, de xa met has o ne 2 0 m g  I V) f or a d ults a n d 
0. 8 m g/ k g f or pe diatric  partici pa nts.  
•  Di p he n h y dra mi ne 5 0 m g  I V or e q ui vale nt ( 1 m g/ k g  f or pe diatric  partici pa nts).  
 
Pre me dicati o n  wit h  aceta mi n o p he n ma y  als o be gi ve n at t he discreti o n  of t he treati n g i n vesti gat or. 
F or i n di vi d ual partici pa nts w h o disc o nti n ue be n da m usti ne a n d c o nti n ue o n bre nt u xi ma b ve d oti n, 
pre me dicati o n (c ortic oster oi ds a n d a nti hista mi nes) f or si n gle -a ge nt bre nt u xi ma b ve d oti n ma y be 
re d uce d or disc o nti n ue d at t he discreti o n of t he i n vesti gat or. 
Partici pa nts  w h o  e x perie nce a Gra de  3 or Gra de  4 i nf usi o n-relate d reacti o n ma y  p ote ntiall y  recei ve 
a d diti o nal treat me nt wit h  bre nt u xi ma b ve d oti n at t he discreti o n  of t he i n vesti gat or after disc ussi o n 
wit h t he S p o ns or. 
7. 1. 1. 1  
M et h o d of Tr e at m e nt A s si g n m e nt  
T his  is  a n  o pe n -la bel  st u d y.  A n  ali g ne d  ris k-stratifie d  al g orit h m  will be  use d  (Ta ble  5. 1 - 1). 
Partici pa nts wit h late rela pse of l o w -sta ge disease will be stratifie d i nt o t he l o w-ris k c o h ort, a n d 
partici pa nts wit h earl y rela pse, e xtra n o dal disease or B s y m pt o ms at rela pse, e xte nsi ve disease 
w here  ra diati o n t hera p y was  c o ntrai n dicate d  at rela pse, or rela pse i n a pri or ra diati o n fiel d will  be 
stratifie d i nt o t he sta n dar d-ris k c o h ort. All partici pa nts will be assi g ne d t o treat me nt usi n g a n 
I nteracti ve Res p o nse Tec h n ol o g y (I R T). Bef ore  t he st u d y is i nitiate d, eac h user  will  recei ve l o g i n 
i nf or mati o n a n d directi o ns o n h o w t o access t he I R T. 
St u d y treat me nt will  be dis pe nse d  at t he st u d y visits  as liste d i n Sc he d ule of Acti vities  (Secti o n  2). 
7. 2  
Bli n di n g  
T his  is a n o pe n -la bel st u d y, bli n di n g pr oce d ures are n ot a p plica ble. 
7. 3  
D o s a g e M o difi c ati o n  
Partici pa nts  ma y  be d ose d wit hi n a +/ - 3- da y wi n d o w at t he start of  eac h c ycle. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Ni v ol u m a b D ose  Del a ys  
T here will be n o d ose escalati o ns or re d ucti o ns of ni v ol u ma b all o we d. Pre me dicati o ns are n ot 
rec o m me n de d f or t he first d ose of ni v ol u ma b. 
Partici pa nts  s h o ul d be caref ull y  m o nit ore d f or i nf usi o n reacti o ns d uri n g ni v ol u ma b a d mi nistrati o n. 
If a n ac ute i nf usi o n reacti o n is n ote d, partici pa nts s h o ul d be ma na ge d acc or di n g t o Secti o n  7. 1. 1. 
D oses of ni v ol u ma b ma y be i nterr u pte d, dela ye d, or disc o nti n ue d de pe n di n g o n h o w well t he 
partici pa nt  t olerates  t he  treat me nt.  D osi n g  visits  are  n ot  s ki p pe d,  o nl y  dela ye d.  Ni v ol u ma b  
a d mi nistrati o n s h o ul d be dela ye d f or t he f oll o wi n g: 
•  Gra de  2 n o n-s ki n, dr u g-relate d a d verse e ve nt, wit h  t he e xce pti o n of fati g ue 
•  Gra de  2 dr u g -relate d creati ni ne,  A S T,  A L T  a n d/ or T otal  Bilir u bi n  a b n or malities 
•  Gra de  3 s ki n, dr u g-relate d a d verse e ve nt 
•  Gra de  3 dr u g -relate d la b orat or y a b n or malit y, wit h  t he f oll o wi n g e xce pti o ns: 
− Gra de  3 l y m p h o pe nia or as y m pt o matic  a m ylase or  li pase d oes  n ot re q uire d ose dela y  
− Gra de  ≥ 3 A S T,  A L T,  T otal Bilir u bi n  will  re q uire d ose disc o nti n uati o n (see secti o n 8) 
•  A n y  A E,  la 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 me nt  of  t he 
i n vesti gat or, warra nts dela yi n g t he d ose of st u d y me dicati o n. 
 
Partici pa nts w h o  re q uire dela y  of ni v ol u ma b s h o ul d be re -e val uate d wee kl y  or m ore  fre q ue ntl y if 
cli nicall y i n dicate d a n d res u me ni v ol u ma b d osi n g w he n re- treat me nt criteria are met. 
Partici pa nts  ma y  res u me  treat me nt  wit h  st u d y  dr u g  w he n  t he  dr u g -relate d  A E(s)  res ol ve  t o 
Gra de ≤ 1 or baseli ne val ue, wit h t he f oll o wi n g e xce pti o ns: 
•  Partici pa nts  ma y  res u me treat me nt i n t he prese nce  of Gra de  2 fati g ue 
•  Partici pa nts w h o ha ve n ot e x perie nce d a Gra de 3 dr u g -relate d s ki n A E  ma y  res u me treat me nt 
i n t he prese nce of Gra de 2 s ki n t o xicit y 
•  F or partici pa nts wit h Gra de 2 A S T, A L T, or T BI LI ele vati o ns, d osi n g ma y res u me w he n 
la b orat or y  val ues  ret ur n  t o  baseli ne  a n d  ma na ge me nt  wit h  c ortic oster oi ds,  if  nee de d,  is  
c o m plete. 
•  Partici pa nts wit h c o m bi ne d Gra de 2 A S T/ A L T A N D T BI LI val ues meeti n g disc o nti n uati o n 
para meters s h o ul d ha ve treat me nt per ma ne ntl y disc o nti n ue d. 
•  Dr u g -relate d p ul m o nar y t o xicit y, diarr hea, or c olitis m ust ha ve res ol ve d t o baseli ne bef ore 
treat me nt is res u me d. Partici pa nts wit h persiste nt Gra de 1 p ne u m o nitis after c o m pleti o n of a 
ster oi d ta per o ver at least 1 m o nt h ma y be eli gi ble f or retreat me nt if disc usse d wit h a n d 
a p pr o ve d b y B M S Me dical M o nit or. 
 
Partici pa nts  wit h  dr u g -relate d  e n d ocri n o pat hies  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 place me nt ma y res u me treat me nt after c o ns ultati o n wit h t he B M S Me dical M o nit or.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
If ni v ol u ma b treat me nt is dela ye d  f or a n y reas o n, bre nt u xi ma b  ve d oti n m ust  als o be dela ye d  u ntil 
t he partici pa nt has a p pr o priatel y  rec o vere d a n d is a ble t o res u me t he c o m bi nati o n treat me nt o n t he 
first da y of t he s u bse q ue nt c ycle. 
Rec o m me n de d  D o se M o dific ati o n  f or Bre nt u xi m a b -rel ate d E ve nts  
Ta ble 7. 3 -1 descri bes t he rec o m me n de d d ose m o dificati o ns f or bre nt u xi ma b ve d oti n treat me nt 
ass ociate d   t o xicit y. D oses  re d uce d  f or bre nt u xi ma b   ve d oti n-relate d t o xicit y  s h o ul d  n ot be 
re-escalate d wit h o ut  disc ussi o n wit h  t he s p o ns or. D ose  escalati o n of bre nt u xi ma b ve d oti n be y o n d  
1. 8 m g/ k g is n ot per mitte d.  
D ose re d ucti o ns bel o w 1. 2 m g/ k g are n ot all o we d, a n d t o xicities s h o ul d be ma na ge d wit h d ose 
dela ys.  
If bre nt u xi ma b ve d oti n treat me nt is dela ye d f or  a n y reas o n, ni v ol u ma b m ust  als o be dela ye d  u ntil 
t he partici pa nt  has a p pr o priatel y  rec o vere d a n d is a ble t o res u me t he c o m bi nati o n treat me nt o n t he 
first da y of t he s u bse q ue nt c ycle. Ni v ol u ma b s h o ul d o nl y be gi ve n al o ne i n case a decisi o n has 
bee n ma de t o per ma ne ntl y disc o nti n ue bre nt u xi ma b ve d oti n. 
T a ble  7. 3-1:  
D ose  M o dific ati o ns f or Bre nt u xi m a b  Ve d oti n  
 
T o xicit y  
Gr a de 1 
Gr a de 2 
Gr a de 3 
Gr a de 4 
Peri p heral 
Ne ur o pat h y  
C o nti n ue  at sa me 
d ose le vel  
Re d uce  d ose  t o 
1. 2 m g/ k g a n d 
res u me treat me nta 
Wit h h ol d  ( dela y) u ntil 
t o xicit y res ol ves t o 
≤ Gra de  2 or  baseli ne, 
t he n res u me treat me nt 
at 1. 2 m g/ k g or 
disc o nti n ue if 
re d ucti o n has alrea d y 
occ urre d.  
Disc o nti n ue  treat me nt 
N o n -he mat ol o gic 
(e xce pt peri p heral 
ne ur o pat h y)  
C o nti n ue  at sa me 
d ose le vel  
C o nti n ue  at sa me 
d ose le vel  
Wit h h ol d  ( dela y) d ose 
u ntil t o xicit y is  
≤ Gra de 2 or has 
ret ur ne d t o baseli ne, 
t he n res u me treat me nt 
at t he sa me d ose  le velb  
Wit h h ol d d ose u ntil 
t o xicit y is ≤ Gra de  2 or 
has ret ur ne d t o 
baseli ne, t he n re d uce 
d ose t o 1. 2 m g/ k g a n d 
res u me treat me nt, or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat ora, b,c 
He mat ol o gic d  
C o nti n ue  at sa me 
d ose le vel  
C o nti n ue  at sa me 
d ose le vel  
Wit h h ol d  ( dela y) u ntil  t o xicit y res ol ves t o 
≤ Gra de  2 or  baseli ne,  t he n res u me treat me nt at 
t he sa me d ose le vele. Gr o wt h fact or s u p p ort 
( G-C S F  or  G M -C S F)  s h o ul d be  c o nsi dere d  f or 
s u bse q ue nt c ycles.  If Gra de  4 ne utr o pe nia  rec urs 
des pite gr o wt h fact or s u p p ort, c o nsi der 
disc o nti n uati o n or d ose re d ucti o n t o 1. 2 m g/ k g.  
a D ose re d ucti o ns bel o w  1. 2  m g/ k g  are n ot  all o we d, a n d t o xicities s h o ul d be  ma na ge d  wit h  d ose  dela ys.  
b  Partici pa nts w h o de vel o p Gra de 3 or 4 electr ol yte la b orat or y a b n or malities ma y  c o nti n ue st u d y  treat me nt wit h o ut 
d ose dela y.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
c Treat me nt  s h o ul d be  disc o nti n ue d  f or s u bjects w h o  e x perie nce  Gra de  4 i nf usi o n-relate d reacti o ns. 
d  S u p p ort  wit h  bl o o d  pr o d uct  tra nsf usi o ns all o we d per  i nstit uti o nal sta n dar d of  care. 
e Partici pa nts  w h o  de vel o p  Gra de  3 or  4 l y m p h o pe nia ma y  c o nti n ue st u d y treat me nt wit h o ut  d ose  dela y.  
 
Rec o m me n de d  D ose  M o dific ati o n  f or Be n d a m usti ne -rel ate d E ve nts  
Be n da m usti ne a d mi nistrati o n  s h o ul d be dela ye d  i n t he e ve nt of a Gra de  4 he mat ol o gic t o xicit y or 
cli nicall y si g nifica nt ≥ Gra de 2 n o n -he mat ol o gic t o xicit y. O nce n o n -he mat ol o gic t o xicit y has 
rec o vere d t o ≤ Gra de  1 a n d/ or t he bl o o d  c o u nts ha ve  i m pr o ve d ( A bs ol ute Ne utr o p hil C o u nt [ A N C] 
≥ 1 x 1 09/ L, platelets  ≥ 7 5 x 1 09/ L) be n da m usti ne ca n be rei nitiate d at t he discreti o n  of t he treati n g 
p h ysicia n. I n a d diti o n, d ose re d ucti o n ma y be warra nte d. See l ocal pac ka ge i nsert or PI L f or 
f urt her i nf or mati o n. 
D ose m o dificati o ns f or n o n -he mat ol o gic t o xicit y: f or ≥ Gra de 3 n o n he mat ol o gic t o xicit y t hat 
rec urs, re d uce t he d ose t o 6 0 m g/ m2 o n Da ys 1 a n d 2 of eac h c ycle. See l ocal pac ka ge i nsert or 
PI L f or f urt her i nf or mati o n.  
7. 4  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  
T he i n vesti gati o nal pr o d uct s h o ul d be st ore d i n a sec ure area acc or di n g t o l ocal  re g ulati o ns. It is 
t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat i n vesti gati o nal pr o d uct is o nl y dis pe nse d t o 
st u d y partici pa nts.  T he  i n vesti gati o nal pr o d uct m ust  be dis pe nse d  o nl y fr o m official  st u d y sites b y 
a ut h orize d pers o n nel acc or di n g t o l ocal re g ulati o ns. 
T he pr o d uct st ora ge ma na ger s h o ul d e ns ure t hat t he st u d y  treat me nt is st ore d i n acc or da nce wit h 
t he  e n vir o n me ntal  c o n diti o ns  (te m perat ure,  li g ht,  a n d  h u mi dit y)  as  deter mi ne d  b y  B M S.  If  
c o ncer ns re gar di n g t he q ualit y or a p peara nce of t he st u d y treat me nt arise, t he st u d y treat me nt 
s h o ul d n ot be dis pe nse d a n d B M S s h o ul d be c o ntacte d i m me diatel y. 
St u d y treat me nt n ot s u p plie d b y B M S will be st ore d i n acc or da nce wit h t he pac ka ge i nsert. 
I n vesti gati o nal pr o d uct d oc u me ntati o n ( w het her s u p plie d b y B M S  or n ot) m ust be mai ntai ne d  t hat 
i ncl u des  all  pr ocesses  re q uire d  t o  e ns ure  dr u g  is  acc uratel y  a d mi nistere d.  T his  i ncl u des  
d oc u me ntati o n  of  dr u g  st ora ge,  a d mi nistrati o n  a n d,  as  a p plica ble,  st ora ge  te m perat ures,  
rec o nstit uti o n, a n d use of re q uire d pr ocesses (e g, re q uire d dil ue nts, a d mi nistrati o n sets). 
Ni v ol u ma b vials m ust be st ore d at a  te m perat ure of 2-8 de grees Celsi us a n d s h o ul d be pr otecte d 
fr o m li g ht a n d freezi n g. If st ore d i n a glass fr o nt refri gerat or, vials  s h o ul d be st ore d i n t he cart o n. 
Rec o m me n de d safet y meas ures f or pre parati o n a n d ha n dli n g of ni v ol u ma b i ncl u de la b orat or y 
c oats a n d gl o ves.  
F or  details  o n  pre pare d  dr u g  st ora ge a n d use ti me of ni v ol u ma b u n der r o o m te m perat ure/li g ht a n d 
refri gerati o n, please refer t o t he ni v ol u ma b I n vesti gat or Br oc h ure4 5 secti o n f or “ Rec o m me n de d 
St ora ge a n d Use C o n diti o ns” a n d/ or p har mac y ma n ual. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Detaile d   dr u g  pre parati o n  a n d  dr u g  acc o u nta bilit y  i nstr ucti o ns  f or  bre nt u xi ma b  ve d oti n  a n d 
be n da m usti ne are pr o vi de d i n t he P har mac y Bi n der . 
I nf usi o n relate d s u p plies (e g. I V ba gs, i n-li ne filters, 0. 9 % Na Cl  s ol uti o n) will  n ot  be pr o vi de d b y 
t he s p o ns or a n d s h o ul d be p urc hase d l ocall y if per mitte d b y l ocal re g ulati o ns. 
7. 5  
Tr e at m e nt C o m pli a n c e  
Treat me nt c o m plia nce will be   m o nit ore d b y dr u g acc o u nta bilit y as well as b y t he partici pa nt’s 
me dical rec or d a n d Case Re p ort F or m ( C R F).  
7. 6  
C o n c o mit a nt  T h er a p y  
7. 6. 1  
Pr o hi bit e d a n d/ or R e stri ct e d Tr e at m e nt s  
T he f oll o wi n g me dicati o ns are pr o hi bite d d uri n g t he st u d y ( u nless utilize d t o treat a dr u g-relate d 
A E):  
•  I m m u n os u p pressi ve a ge nts 
•  I m m u n os u p pressi ve d oses of s yste mic c ortic oster oi ds 
•  A n y  c o nc urre nt a nti-ne o plastic  t hera p y (ie, c he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, 
e xte nsi ve, n o n -palliati ve  ra diati o n t hera p y, or sta n dar d or i n vesti gati o nal a ge nts f or  treat me nt 
of c H L)  
•  Li ve  vacci nes  
− Li ve  c or o na vir us disease  2 0 1 9 ( C O VI D- 1 9) vacci nes  s h o ul d ge nerall y  n ot be a d mi nistere d 
t o a s u bject d uri n g t he st u d y, i ncl u di n g t he treat me nt a n d safet y f oll o w-u p peri o d. Li ve 
vacci nes are defi ne d as t h ose t hat are ca pa ble of tra ns mitti n g i nfecti o us se vere ac ute 
res pirat or y  s y n dr o me  c or o na vir us  ( S A R S-C o V -2)  or  ot her  vir uses.  If  it  ca n n ot  be  
deter mi ne d w het her or n ot t he vacci ne is li ve, it is rec o m me n de d t hat t he vacci ne n ot be 
a d mi nistere d  u ntil it is c o nfir me d  t hat t here is n o ris k of viral  i nfecti vit y wit hi n  t he s u bject. 
If a patie nt has  recei ve d a li ve C O VI D - 1 9 vacci ne  pri or t o scree ni n g, e nr oll me nt  s h o ul d be 
dela ye d u ntil t he i m pact of t he vacci ne is sta bilize d, u nless a dela y w o ul d c o m pr o mise 
patie nt healt h.  
•  N o data are a vaila ble o n t he res p o nse t o C O VI D -1 9 vacci nes. T he efficac y a n d safet y of 
vacci nati o n i n s u bjects w h o  are recei vi n g ni v ol u ma b, bre nt u xi ma b  ve d oti n, a n d be n da m usti ne 
are u n k n o w n. Please c o ntact t he Me dical M o nit or wit h a n y q uesti o ns relate d t o C O VI D -1 9 
vacci nes.  
•  Refer t o t he bre nt u xi ma b ve d oti n a n d be n da m usti ne prescri bi n g i nf or mati o n f or a d diti o nal 
pr o hi bite d me dicati o ns. 4 6 ,4 9 See l ocal pac ka ge i nsert or PI L f or f urt her i nf or mati o n.  
7. 6. 2  
Ot h er R e stri cti o n s a n d Pr e c a uti o n s  
Partici pa nts wit h a c o n diti o n re 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  pre 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 first d ose 
of st u d y me dicati o n are e xcl u de d. 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 pre 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.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
6 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A d diti o nall y,  please  f oll o w  l ocal  pr o p h yla xis  g ui deli ne  rec o m me n dati o n  f or  o p p ort u nistic  
i nfecti o ns i n t his patie nt p o p ulati o n 
7. 6. 2. 1  
M o bili z ati o n a n d C oll e cti o n of P eri p h er al Bl o o d St e m C ell s  
A ut ol o g o us peri p heral bl o o d ste m cells ( P B S Cs) ma y be c ollecte d fr o m c o nse nti n g partici pa nts 
after a n y c ycle of t hera p y. Partici pa nts w h o ha d b o ne marr o w i n v ol ve me nt at t he ti me of st u d y 
e nr oll me nt m ust u n der g o re peat b o ne marr o w bi o psies (at least t w o sites) pri or t o ste m cell 
c ollecti o n or  f oll o w i nstit uti o nal practices  t o r ule o ut  b o ne marr o w  disease  i n v ol ve me nt. Ste m  cells 
will  n ot be c ollecte d u ntil t he b o ne marr o w  bi o psies are ne gati ve f or disease  i n v ol ve me nt or b o ne 
marr o w disease is r ule d o ut, as per i nstit uti o nal practice. Ste m cells ma y be c ollecte d f oll o wi n g 
A N Y  c ycle of t hera p y, s u bse q ue nt t o t he de m o nstrati o n of ne gati ve b o ne marr o w  bi o psies or b o ne 
marr o w disease r ule d o ut, per i nstit uti o nal practice. 
I nstit uti o nal sta n dar d o perati n g pr oce d ures s h o ul d be use d  f or t he c ollecti o n pr oce d ure.  
7. 6. 2. 2  
I m a gi n g R e stri cti o n a n d Pr e c a uti o n s  
If a partici pa nt has a k n o w n aller g y t o c o ntrast material, l ocal  pr o p h yla xis sta n dar ds ma y be use d 
t o o btai n t he assess me nt wit h c o ntrast if at all p ossi ble, or use t he alter nate m o dalit y. I n cases 
w here c o ntrast is strictl y c o ntrai n dicate d, a n o n -c o ntrast sca n will s uffice. S h o ul d a partici pa nt 
ha ve a c o ntrai n dicati o n f or C T  I V c o ntrast, a n o n-c o ntrast  C T  c hest a n d a c o ntrast e n ha nce d  M RI 
of t he a b d o me n a n d pel vis ma y be o btai ne d. 
St u d y- relate d  M RI  i ma gi n g  will  be  perf or me d  per  t he  fre q ue nc y  s pecifie d  i n  t he  pr ot oc ol.  
I n vesti gat ors ma y  o btai n a d diti o nal f oll o w- u p M RI  sca ns as me dicall y  i n dicate d. F or  ot her l ocall y 
perf or me d  i ma gi n g,  it  is  t he  l ocal  i ma gi n g  facilit y’s  res p o nsi bilit y  t o  deter mi ne,  base d  o n  
partici pa nt  attri b utes  (e g,  aller g y  hist or y,  dia betic  hist or y,  a n d  re nal  stat us),  t he  a p pr o priate  
i ma gi n g  m o dalit y,  a n d  c o ntrast  re gi me n  f or  eac h  partici pa nt.  I ma gi n g  c o ntrai n dicati o ns  a n d  
c o ntrast ris ks s h o ul d be  c o nsi dere d  i n t his assess me nt.  Partici pa nts  wit h  re nal i ns ufficie nc y s h o ul d 
be assesse d as t o w het her or n ot t he y s h o ul d recei ve c o ntrast, a n d if s o, w hat t y pe a n d d ose of 
c o ntrast is a p pr o priate. S pecific  t o M RI,  partici pa nts  wit h  se vere re nal i ns ufficie nc y (ie, esti mate d 
gl o mer ular filtrati o n rate < 3 0 m L/ mi n/ 1. 7 3 m 2) are at i ncrease d ris k of ne p hr o ge nic s yste mic 
fi br osis. M RI  c o ntrast  s h o ul d n ot be gi ve n t o t his partici pa nt p o p ulati o n, w h o  s h o ul d be e xcl u de d 
fr o m t he st u d y. I n a d diti o n, partici pa nts  wit h  s ur gicall y i m pla nte d de vices  ( pace ma ker, dee p  brai n 
sti m ulat or, metallic i m pla nts, etc.) i nc o m pati ble wit h M RI s h o ul d n ot u n der g o s uc h i ma gi n g 
tec h ni q ues.  T he  l ocal  i ma gi n g  facilit y  a n d  i n vesti gat or  s h o ul d  deter mi ne  t he  a p pr o priate  
preca uti o ns or g ui deli nes  t hat s h o ul d be i nstit ute d f or partici pa nts wit h  tatt o os, b o d y pierci n gs, or 
ot her b o d y art. 
T he ulti mate decisi o n  t o perf or m M RI i n a n i n di vi d ual partici pa nt i n t his st u d y  rests wit h t he site 
ra di ol o gist, t he i n vesti gat or, a n d t he sta n dar d set b y t he l ocal Et hics C o m mittee. 
7. 6. 3  
P er mitt e d T h er a p y  
I n c ycles wit h ni v ol u ma b, partici pa nts are per mitte d t he use of t o pical, oc ular, i ntra-artic ular, 
i ntra nasal,  a n d  i n halati o nal  c ortic oster oi ds  ( wit h  mi ni mal  s yste mic  a bs or pti o n).  A dre nal  
re place me nt ster oi d d oses > 1 0 m g  dail y  pre d nis o ne are per mitte d.  A brief  (less t ha n 3 wee ks)  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
c o urse  of  c ortic oster oi ds f or  pr o p h yla xis (e g,  c o ntrast  d ye aller g y)   or f or treat me nt  of 
n o n- a ut oi m m u ne  c o n diti o ns  (e g,  dela ye d -t y pe  h y perse nsiti vit y  reacti o n  ca use d  b y  a  c o ntact  
aller ge n) is per mitte d.  
C O VI D -1 9 vacci nes t hat are N O T li ve ca n be a d mi nistere d d uri n g t he st u d y, i ncl u di n g d uri n g 
ni v ol u ma b, bre nt u xi ma b  ve d oti n, a n d be n da m usti ne treat me nt a n d after t he last a d mi nistrati o n of 
res pecti ve treat me nts. C O VI D-1 9 vacci nes t hat are N O T li ve s h o ul d be ha n dle d i n t he sa me 
ma n ner as ot her vacci nes.  
T he  f oll o wi n g are N O T  c o nsi dere d  li ve vacci nes  a n d t he decisi o n t o vacci nate  s h o ul d be ma de  b y 
t he i n vesti gat or a n d partici pa nt:  i nacti vate d vacci nes  (e g, heat -kille d  a n d f or mali n-kille d  vacci nes), 
s u b u nit vacci nes, t o x oi d vacci nes, n ucleic aci d vacci nes  t hat d o n ot e nc o de p ote ntiall y i nfecti o us 
vir us  ( Pfizer/ Bi o N Tec h  a n d  M o der na  C O VI D -1 9  vacci nes)  a n d  re plicati o n -i nc o m pete nt 
rec o m bi na nt vect or vacci nes. 
F or C O VI D -1 9 vacci nes re q uiri n g m ore t ha n 1 d ose, t he f ull series (e g, b ot h d oses of a 2 - d ose 
series) s h o ul d be c o m plete d pri or t o e nr oll me nt w he n feasi ble, a n d w he n a dela y i n e nr oll me nt 
w o ul d n ot p ut t he patie nt  at ris k. If a patie nt  has recei ve d a s pecific C O VI D - 1 9 vacci nati o n  d uri n g 
t he c o urse of t he st u d y, t he t y pe of vacci ne a n d date(s) recei ve d s h o ul d be rec or de d o n t he 
c o nc o mita nt me dicati o ns C R F pa ge. 
N o  data  are  a vaila ble  o n  t he  res p o nse  t o  C O VI D -1 9  vacci nes.  T he  efficac y  a n d  safet y  of  
vacci nati o n i n s u bjects w h o  are recei vi n g ni v ol u ma b, bre nt u xi ma b ve d oti n, a n d be n da m usti ne are 
u n k n o w n. Please c o ntact t he Cli nical Trial P h ysicia n or Me dical M o nit or wit h a n y q uesti o ns 
relate d t o C O VI D-1 9 vacci nes.  
7. 7  
Tr e at m e nt Aft er t h e E n d of t h e St u d y  
At t he e n d of t he st u d y, B M S will n ot c o nti n ue t o pr o vi de B M S -s u p plie d st u d y treat me nt t o 
partici pa nts/i n vesti gat ors  u nless B M S  c h o oses t o e xte n d t he st u d y. T he  i n vesti gat or s h o ul d e ns ure 
t hat t he partici pa nt recei ves a p pr o priate sta n dar d of care. 
8.  
DI S C O N TI N U A TI O N  C RI T E RI A  
Ni v ol u ma b treat me nt s h o ul d be per ma ne ntl y  disc o nti n ue d f or t he f oll o wi n g: 
•  Disease  pr o gressi o n  as deter mi ne d  b y I n vesti gat or Assess me nt  at C ycle  2, N + B v  or  b y  BI C R 
t hereafter d uri n g treat me nt peri o d wit h t he e xce pti o n as per Secti o n 8. 1. 2  (treat me nt be y o n d 
pr o gressi o n).  
•  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 pical 
t hera p y a n d d oes n ot i m pr o ve t o Gra de 1 se verit y O R re q uires s yste mic treat me nt 
•  A n y Gra de 3 n o n -s ki n, dr u g-relate d A E lasti n g > 7 da ys, wit h t he f oll o wi n g e xce pti o ns f or 
la b orat or y a b n or malities, 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 
reacti o ns, i nf usi o n reacti o ns, a n d e n d ocri n o pat hies: 
− Gra de 3 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 reacti 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 
− Gra de  3  dr u g -relate d  e n d ocri n o pat hies  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 place me nt d o n ot re q uire disc o nti n uati o n 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
− Gra de   3 dr u g -relate d la b orat or y a b n or malities d o   n ot re q uire treat me 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 nia > 7 da ys or ass ociate d wit h blee di n g re q uires 
disc o nti n uati o n  
♦ Gra de  ≥ 3 dr u g-relate d A S T,  A L T,  or T BI LI  re q uires disc o nti n uati o n *  
♦ C o nc urre nt A S T  or A L T  > 3 x U L N a n d T BI LI  > 2 x U L N  
* I n m ost cases  of Gra de 3 A S T  or A L T ele vati 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  deter mi nes  a p ossi ble 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 dr u g(s), a disc ussi o n bet wee n t he i n vesti gat or a n d t he 
B M S Me dical M o nit or/ desi g nee m ust occ ur.  
•  A n y  Gra de  4 dr u g-relate d A E  or la b orat or y a b n or malit y, e xce pt f or t he f oll o wi n g e ve nts w hic h 
d o n ot re q uire disc o nti n uati o n: 
− Gra de  4 ne utr o pe nia ≤ 7 da ys  
− Gra de  4 l y m p h o pe nia or le u k o pe nia 
− Is olate d Gra de  4 a m ylase  or li pase a b n or malities t hat are n ot ass ociate d  wit h  s y m pt o ms or 
cli nical ma nifestati o ns of pa ncreatitis  
− Is olate d Gra de  4 electr ol yte i m bala nces/a b n or malities  t hat are n ot ass ociate d  wit h  cli nical 
se q uelae a n d are c orrecte d  wit h  s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n  7 2 h o urs 
of t heir o nset 
− Gra de  4  dr u g -relate d  e n d ocri n o pat h y  A Es,  s uc h  as  a dre nal  i ns ufficie nc y,  A C T H  
deficie nc y,  h y per - or  h y p ot h yr oi dis m,  or  gl uc ose  i nt olera nce,  w hic 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 place me nt  (c ortic oster 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, ma y n ot re q uire disc o nti n uati o n 
after disc ussi o n wit h a n d a p pr o val fr o m t he B M S Me dical M o nit or 
•  A n y e ve nt t hat lea ds t o dela y i n d osi n g lasti n g > 6 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 xce pti o ns: 
− D osi n g  dela ys  t o  all o w  f or  pr ol o n ge d  ster oi d  ta pers  t o  ma na ge  dr u g -relate d  A Es  are  
all o we d. Pri or  t o re-i nitiati n g treat me nt i n  a partici pa nt  wit h   a  d osi n g dela y  lasti n g 
> 6 wee ks fr o m t he pre vi o us d ose, t he B M S Me dical M o nit or 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 dic  st u d y visits 
t o  assess  safet y  a n d  la b orat or y  st u dies  s h o ul d  als o  c o nti n ue  e ver y  6  wee ks  or  m ore  
fre q ue ntl y if cli nicall y i n dicate d d uri n g s uc h d osi n g dela ys. 
− D osi n g dela ys lasti n g > 6 wee ks fr o m t he pre vi o us d ose t hat occ ur f or n o n - dr u g-relate d 
reas o ns ma y be all o we d if a p pr o ve d b y t he B M S Me dical M o nit or. Pri or t o re-i nitiati n g 
treat me nt i n a partici pa nt wit h  a d osi n g dela y  lasti n g > 6 wee ks,  t he B M S  Me dical  M o nit or 
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 dic st u d y  visits  t o assess safet y a n d la b orat or y st u dies s h o ul d als o c o nti n ue 
e ver y 6 wee ks or m ore fre q ue ntl y if cli nicall y i n dicate d d uri n g s uc h d osi n g dela ys. 
•  A n y  A E,  la 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 me nt  of  t he  
i n vesti gat or, prese nts a s u bsta ntial cli nical 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  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
8. 1  
Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt  
Partici pa nts M U S T disc o nti n ue i n vesti gati o nal pr o d uct (a n d n o n -i n vesti gati o nal pr o d uct at t he 
discreti o n of t he i n vesti gat or) f or a n y of t he f oll o wi n g reas o ns:  
•  Partici pa nt’s  re q uest t o st o p st u d y treat me nt. Partici pa nts  ( or t heir pare nts,  g uar dia ns, or le gall y 
acce pta ble re prese ntati ves o n t heir be half, as a p plica ble) w h o re q uest t o disc o nti n ue st u d y 
treat me nt will re mai n i n t he st u d y a n d m ust c o nti n ue t o be f oll o we d f or pr ot oc ol-s pecifie d 
f oll o w- u p pr oce d ures.  T he  o nl y e xce pti o n t o t his is w he n a partici pa nt s pecificall y  wit h dra ws 
c o nse nt f or a n y f urt her c o ntact wit h  hi m/ her  or pers o ns pre vi o usl y a ut h orize d b y partici pa nt t o 
pr o vi de t his i nf or mati o n  
•  A n y cli nical A E, la b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he o pi ni o n of t he 
i n vesti gat or, i n dicates t hat c o nti n ue d partici pati o n  i n t he st u d y is n ot i n t he best  i nterest of t he 
partici pa nt  
•  Ter mi nati o n  of t he st u d y b y B M S  
•  L oss of a bilit y  t o freel y pr o vi de c o nse nt  t hr o u g h i m pris o n me nt or i n v ol u ntaril y i ncarcerati o n 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e g, i nfecti o us disease) ill ness 
 
Refer t o t he Sc he d ule of Acti vities i n Secti o n 2  f or data t o be c ollecte d at t he ti me of treat me nt 
disc o nti n uati o n a n d f oll o w- u p a n d f or a n y f urt her e val uati o ns t hat ca n be c o m plete d. 
I n  t he  case  of  pre g na nc y,  t he  i n vesti gat or  m ust  i m me diatel y  n otif y  t he  B M S  Me dical  
M o nit or/ desi g nee of t his e ve nt. I n t he e ve nt a n or mal healt h y fe male partici pa nt bec o mes  pre g na nt 
d uri n g a cli nical trial, t he st u d y treat me nt m ust be disc o nti n ue d i m me diatel y. I n m ost cases, t he 
st u d y treat me nt will be per ma ne ntl y disc o nti n ue d i n a n a p pr o priate ma n ner (e g, d ose ta peri n g if 
necessar y  f or  partici pa nt  safet y).  Please  call  t he  B M S  Me dical  M o nit or  wit hi n  2 4  h o urs  of  
a ware ness of  t he pre g na nc y. If t he i n vesti gat or deter mi nes a p ossi ble 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 treat me nt, a disc ussi o n bet wee n t he i n vesti gat or a n d t he B M S 
Me dical M o nit or/ desi g nee m ust occ ur.  
All  partici pa nts  w h o  disc o nti n ue st u d y treat me nt s h o ul d c o m pl y wit h  pr ot oc ol-s pecifie d f oll o w-u p 
pr oce d ures as o utli ne d i n Secti o n 2. T he o nl y  e xce pti o n t o t his re q uire me nt is w he n a partici pa nt 
wit h dra ws c o nse nt f or all st u d y  pr oce d ures i ncl u di n g p ost -treat me nt st u d y f oll o w-u p or l oses t he 
a bilit y t o c o nse nt freel y (ie, is i m pris o ne d or i n v ol u ntaril y i ncarcerate d f or t he treat me nt of eit her 
a ps yc hiatric or p h ysical ill ness).  
If st u d y treat me nt is disc o nti n ue d pri or  t o t he partici pa nt’s  c o m pleti o n of t he st u d y, t he reas o n f or 
t he disc o nti n uati o n m ust be d oc u me nte d i n t he partici pa nt’s me dical rec or ds a n d e ntere d o n t he 
a p pr o priate C R F pa ge.  
8. 1. 1  
P o st  St u d y  Tr e at m e nt  St u d y F oll o w -u p  
I n t his st u d y, E F S  is a ke y e n d p oi nt of  t he st u d y. P ost  st u d y f oll o w- u p is of critical i m p orta nce a n d 
is  esse ntial  t o  preser vi n g  partici pa nt  safet y  a n d  t he  i nte grit y  of  t he  st u d y.  Partici pa nts  w h o  
disc o nti n ue st u d y treat me nt m ust c o nti n ue t o be f oll o we d f or c ollecti o n of o utc o me a n d/ or s ur vi val 
f oll o w- u p data as re q uire d a n d i n li ne wit h Secti o n 9  u ntil deat h or t he c o ncl usi o n of t he st u d y. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
8. 1. 2  
Tr e at m e nt  B e y o n d Pr o gr e s si o n  
E vi de nce i n dicates a mi n orit y  of s u bjects treate d wit h i m m u n ot hera p y  ma y  deri ve cli nical  be nefit 
des pite  i nitial  e vi de nce  of  P D,  7 3 e g,  d ue  t o  i nfla m mat or y  reacti o n  si m ulati n g  pr o gressi o n  
(“t u m or flare” or pse u d o pr o gressi o n). Pse u d o pr o gressi o n is well  descri be d  i n ne ur o- o nc ol o g y, a n d 
refers  t o  ra di o gra p hic  e nlar ge me nt  of  t u m or  lesi o ns  t hat  w o ul d  be  i nter prete d  as  disease  
pr o gressi o n b y c o n ve nti o nal res p o nse criteria, b ut u p o n hist ol o gic e xa mi nati o n re veals necr osis 
a n d/ or i nfla m mati o n (treat me nt effect)  a n d n ot disease pr o gressi o n. 7 3 A si milar p he n o me n o n has 
bee n  o bser ve d  i n vari o us t u m ors w he n  treate d wit h  i m m u n ot hera pe utic a ge nts, i n w hic h  tra nsie nt 
e nlar ge me nt of lesi o ns or  a p peara nce of ne w lesi o ns is attri b uta ble  t o t he i nfl u x of i m m u ne  cells. 
T hese p ote ntial i m m u ne treat me nt effects c o m plicate  t he e val uati o n of res p o nse a n d ma y lea d t o 
pre mat ure  disc o nti n uati o n of t hera p y. F urt her m ore,  t he ti me peri o d t o pse u d o pr o gressi o n or t u m or 
flare wit h differe nt i m m u ne t hera pies varies i n differe nt mali g na ncies. 
Treat me nt  be y o n d  pr o gressi o n  will  be  per mitte d,  per  t he  st u d y  desi g n.  Partici pa nts  meeti n g  
pr o gressi o n defi ne d b y rela pse d disease (after C M R) or pr o gressi ve disease (after P M R, N M R) 
per L u ga n o criteria ma y c o nti n ue recei vi n g st u d y me dicati o n be y o n d i n vesti gat or -assesse d or 
BI C R assesse d, pr o gressi o n ( per Secti o n 5. 1 ) as l o n g as t he y meet t he f oll o wi n g criteria: 
•  C o nti n ue t o meet  all ot her  st u d y pr ot oc ol eli gi bilit y criteria 
•  I n vesti gat or-assesse d  cli nical be nefit,  a n d d o n ot ha ve  ra pi d disease  pr o gressi o n  
•  Sta ble  perf or ma nce  stat us 
•  Treat me nt   be y o n d  pr o gressi o n will   n ot dela y  a n i m mi ne nt i nter ve nti o n t o  pre ve nt seri o us 
c o m plicati o ns of disease pr o gressi o n 
•  Partici pa nts  will   be re-c o nse nte d  wit h  a n i nf or me d  c o nse nt  d oc u me nt descri bi n g   a n y 
reas o na bl y f oreseea ble ris ks or disc o mf ort a n d ot her alter nati ve treat me nt o pti o ns 
•  T olera nce of st u d y dr u g  
 
T he  decisi o n  t o c o nti n ue treat me nt be y o n d i n vesti gat or -assesse d  pr o gressi o n s h o ul d be disc usse d 
wit h t he B M S Me dical M o nit or a n d d oc u me nte d i n t he st u d y  rec or ds. 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 orati n g a n d u nli kel y t o 
recei ve f urt her be nefit fr o m c o nti n ue d treat me nt. 
8. 2  
Di s c o nti n u ati o n fr o m t h e St u d y  
Partici pa nts  w h o  re q uest t o disc o nti n ue st u d y treat me nt will  re mai n i n t he st u d y a n d m ust c o nti n ue 
t o be f oll o we d f or pr ot oc ol-s pecifie d f oll o w-u p pr oce d ures. T he  o nl y e xce pti o n t o t his is w he n a 
partici pa nt  s pecificall y  wit h dra ws  c o nse nt  f or  a n y  f urt her  c o ntact  wit h  hi m/ her  or  pers o ns  
pre vi o usl y a ut h orize d b y partici pa nt t o pr o vi de t his i nf or mati o n. Wit h dra wal of c o nse nt ma y be 
re q ueste d b y partici pa nts, pare nts, g uar dia ns, or le gall y acce pta ble  re prese ntati ves, i n acc or da nce 
wit h l ocal re g ulati o ns. T he wis hes of mi n or partici pa nts t o wit h dra w t heir asse nt s h o ul d als o be 
res pecte d. 
•  Partici pa nts s h o ul d n otif y t he i n vesti gat or of t he decisi o n t o wit h dra w c o nse nt fr o m f ut ure 
f oll o w- u p i n writi n g, w he ne ver p ossi ble. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
•  T he  wit h dra wal  of  c o nse nt  s h o ul d  be  e x plai ne d  i n  detail  i n  t he  me dical  rec or ds  b y  t he  
i n vesti gat or, as t o w het her t he wit h dra wal  is fr o m f urt her treat me nt wit h st u d y treat me nt o nl y 
or als o fr o m st u d y pr oce d ures a n d/ or p ost treat me nt st u d y f oll o w -u p, a n d e ntere d o n t he 
a p pr o priate C R F pa ge.  
•  I n t he e ve nt t hat vital stat us ( w het her t he partici pa nt is ali ve or dea d) is bei n g meas ure d, 
p u blicl y a vaila ble i nf or mati o n s h o ul d be use d t o  deter mi ne vital stat us o nl y as a p pr o priatel y 
directe d i n acc or da nce wit h l ocal la w.  
•  If t he partici pa nt wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he s p o ns or ma y 
retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt. 
 
8. 3  
L o st  t o F oll o w -U p  
•  All  reas o na ble eff orts  m ust  be ma de t o l ocate partici pa nts  t o deter mi ne  a n d re p ort t heir o n g oi n g 
stat us. T his i ncl u des f oll o w- u p wit h pers o ns a ut h orize d b y t he partici pa nt. 
•  L ost  t o f oll o w-u p is defi ne d b y  t he i na bilit y t o reac h t he partici pa nt after a mi ni m u m  of t hree 
d oc u me nte d p h o ne calls, fa xes, or e mails as well as lac k of res p o nse b y partici pa nt t o o ne 
re gistere d mail  letter. All  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 ds. 
•  If it is deter mi ne d t hat t he partici pa nt has die d, t he site will use per missi ble l ocal met h o ds t o 
o btai n date a n d ca use of deat h. 
•  If i n vesti gat or’s use of  t hir d-part y  re prese ntati ve t o assist i n t he f oll o w-u p  p orti o n of t he st u d y 
has bee n i ncl u de d i n t he partici pa nt’s i nf or me d c o nse nt, t he n t he i n vesti gat or ma y use a 
S p o ns or- retai ne d  t hir d-part y  re prese ntati ve  t o  assist  site  staff  wit h  o btai ni n g  partici pa nt’s  
c o ntact i nf or mati o n or ot her p u blic vital stat us data necessar y t o c o m plete t he f oll o w - u p 
p orti o n of t he st u d y. 
•  T he site staff  a n d re prese ntati ve will c o ns ult p u blicl y a vaila ble s o urces, s uc h as p u blic healt h 
re gistries a n d data bases, i n or der t o o btai n u p date d c o ntact i nf or mati o n. 
•  If after all atte m pts, t he partici pa nt  re mai ns l ost t o f oll o w- u p, t he n t he last k n o w n ali ve date as 
deter mi ne d  b y t he i n vesti gat or s h o ul d be re p orte d a n d d oc u me nte d i n t he partici pa nt’s  me dical 
rec or ds. 
 
9.  
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  
•  St u d y pr oce d ures a n d ti mi n g are s u m marize d i n t he Sc he d ule of Acti vities  (Secti o n  2). 
•  Pr ot oc ol wai vers  or e xe m pti o ns are n ot all o we d. 
•  All  i m me diate  safet y  c o ncer ns  m ust  be  disc usse d  wit h  t he  S p o ns or  i m me diatel y  u p o n  
occ urre nce  or  a ware ness  t o  deter mi ne  if  t he  partici pa nt  s h o ul d  c o nti n ue  or  disc o nti n ue  
treat me nt. 
•  A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Acti vities, is esse ntial a n d re q uire d f or st u d y c o n d uct. 
•  All  scree ni n g  e val uati o ns  m ust  be  c o m plete d  a n d  re vie we d  t o  c o nfir m  t hat  p ote ntial  
partici pa nts meet  all eli gi bilit y criteria bef ore ra n d o mizati o n. T he  i n vesti gat or will  mai ntai n  a 
scree ni n g l o g t o rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d 
reas o ns f or scree ni n g fail ure, as a p plica ble. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
•  Pr oce d ures  c o n d ucte d as part  of  t he partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of i nf or me d c o nse nt ma y be utilize d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ure meets t he pr ot oc ol -defi ne d criteria a n d has bee n perf or me d 
wit hi n t he ti mefra me defi ne d i n t he Sc he d ule of Acti vities.  
 
9. 1  
Effi c a c y  A s s e s s m e nt s  
9. 1. 1  
T u m or A s s e s s m e nt s  
I ma gi n g a n d res p o nse criteria are base d  o n t he I nter nati o nal L y m p h o ma W or ki n g Gr o u p’s re vise d 
rec o m me n dati o ns f or mali g na nt l y m p h o ma.7 0 ,7 1 Pri mar y res p o nse assess me nt will be e val uate d 
usi n g  L u ga n o  2 0 1 4  Cl assificati o n  ( A p pe n di x  6 ).  I n  a d diti o n,  L Y RI C  2 0 1 6  will  be  use d  f or  
e x pl orat or y res p o nse assess me nt i nter nall y. 7 4 
F or P E T -base d assess me nts, a res p o nse of pr o gressi ve meta b olic disease ( P M D), n o meta b olic 
res p o nse ( N M R), partial meta b olic res p o nse  ( P M R), or c o m plete  meta b olic  res p o nse ( C M R) will 
be  deter mi ne d.  T he  P E T  sca n  meta b olic  u pta ke  will  be  gra de d  usi n g  t he  Dea u ville  5 -p oi nt 
scale7 5 ,7 6 wit h a sc ore of <  4 c o nsi dere d t o re prese nt a C M R (see A p pe n di x 6). 
Assess me nt  will  be  perf or me d  b y  P E T  wit h  C T/ M RI  of  dia g n ostic  q ualit y,  wit h  disease  
i n v ol ve me nt deter mi ne d b y f ocal F D G u pta ke i n n o dal a n d e xtra n o dal (i ncl u di n g s plee n, li ver, 
b o ne marr o w,  a n d t h yr oi d) sites t hat is c o nsiste nt wit h  l y m p h o ma, acc or di n g  t o t he patter n  of  F D G 
u pta ke. I n a d diti o n t o P E T -base d  assess me nt,  u p t o si x of t he lar gest n o des, n o dal masses,  or ot her 
i n v ol ve d lesi o ns t hat are meas ura ble i n t w o dia meters s h o ul d be i de ntifie d as tar get lesi o ns usi n g 
C T/ M RI i ma ges perf or me d al o n g wit h P E T; if p ossi ble t he y  s h o ul d be fr o m dis parate re gi o ns of 
t he b o d y a n d t he y s h o ul d i ncl u de me diasti nal a n d retr o perit o neal  areas of disease w he ne ver t hese 
sites are i n v ol ve d. 
After t he s u bjects ac hie ve BI C R assesse d C M R, M RI/ C T -base d assess me nts will be perf or me d. 
T he P E T -C T or P E T -M RI t hat is C M R ( per BI C R assess me nt) will be use d as baseli ne f or 
M RI/ C T -base d assess me nt. Res p o nse will be cate g orize d as pr o gressi ve disease ( P D), sta ble 
disease ( S D), partial res p o nse ( P R), or c o m plete res p o nse ( C R).  
S u bjects wit h BI C R  assesse d P M R/ N M R u p o n  c o m pleti o n of  st u d y treat me nt will pr o vi de t u m or 
assess me nts at  t he  sa me  ti me  i nter vals  s pecifie d  i n  f oll o w -u p  ( or  at  a  mi ni m u m,  per  S O C).  
M o dalit y s h o ul d be per Sta n dar d of Care. 
P M D/ P D  i ncl u des ra di ol o gical e vi de nce of pr o gressi o n per L u ga n o Classificati o n  Re vise d  Sta gi n g 
S yste m  f or  mali g na nt  l y m p h o ma.  If  cli nical  pr o gressi o n  is  deter mi ne d  b y  t he  i n vesti gat or,  
ra di o gra p hic sta gi n g s h o ul d als o be perf or me d t o deter mi ne res p o nse assess me nt per L u ga n o 
Classificati o n Re vise d Sta gi n g S yste m f or mali g na nt l y m p h o ma.  
9. 1. 2  
I m a gi n g A s s e s s m e nt  f or t h e St u d y  
Partici pa nts will be e val uate d f or t u m or res p o nse b y F D G P E T -C T or P E T -M RI, or F D G -P E T 
wit h  C T/ M RI,  per t he Sc he d ule of  Acti vities  (Secti o n  2) at s pecifie d ti me p oi nts. BI C R  is re q uire d 
f or treat me nt relate d- decisi o ns at N + B v,  C ycle   4  a n d B v + B,  C ycle   2  a n d  4 (as a p plica ble). 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T heref ore,  treat me nt w o ul d be wit h hel d, u ntil t he res ults are o btai ne d, u nless cli nicall y i n dicate d 
t o treat s o o ner. Refer  t o Secti o n  5. 1 f or a d diti o nal st u d y desi g n details,  i ncl u di n g re q uire me nts f or 
t u m or assess me nts  w he n  a patie nt is disc o nti n ue d fr o m treat me nt, d ue t o I n vesti gat or disa gree me nt 
wit h BI C R assess me nt.  
I ma gi n g m o dalit y s h o ul d re mai n t he sa me f or eac h partici pa nts d uri n g t his p hase of t he st u d y. 
After  t he patie nt is i n C M R  b y P E T  per BI C R,  pr o gressi o n of  disease  will  be f oll o we d b y M RI/ C T 
sca ns of dia g n ostic q ualit y. T o re d uce ra diati o n e x p os ure, partici pa nts will be all o we d t o s witc h 
m o dalit y  t o M RI d uri n g f oll o w-u p. If  t he res ults of t he C T or M RI is e q ui v ocal, f oll o w-u p F D G - 
P E T ma y be o btai ne d f or clarificati o n (see Ta ble 2 - 4). 
I ma ges will  be s u b mitte d t o a n i ma gi n g c ore la b. Sites  s h o ul d be trai ne d pri or  t o sca n ni n g t he first 
st u d y partici pa nt. I ma ge ac q uisiti o n  g ui deli nes a n d s u b missi o n pr ocess  will  be o utli ne d i n t he B M S 
C A 2 0 9 7 4 4 I ma gi n g Ma n ual t o be pr o vi de d b y t he c ore la b. 
9. 2  
A d v er s e  E v e nt s  
T he  defi niti o ns of a n A E  or seri o us a d verse  e ve nt ( S A E) ca n be f o u n d i n A p pe n di x 3 . 
A Es will be 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 re prese ntati ve).  
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d re p orti 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 
are seri o us, c o nsi dere d  relate d t o t he st u d y treat me nt or  t he st u d y, or t hat ca use d t he partici pa nt  t o 
disc o nti n ue bef ore c o m pleti n g t he st u d y.  
9. 2. 1  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E I nf or m ati o n 
T he  c ollecti o n of n o nseri o us A E  i nf or mati o n s h o ul d be gi n at i nitiati o n of st u d y treat me nt u ntil F U 
2 ( Da y 1 0 0) t he ti me p oi nts s pecifie d i n t he Sc he d ule of Acti vities ( Secti o n 2 ). N o nseri o us A E 
i nf or mati o n  s h o ul d  als o  be  c ollecte d  fr o m  t he  start  of  a  place b o  lea d-i n  peri o d  or  ot her  
o bser vati o nal peri o d i nte n de d t o esta blis h a baseli ne stat us f or t he partici pa nts. 
Secti o ns 5. 6. 1 a n d 5. 6. 2 i n t he ni v ol u ma b I B 4 5 re prese nt t he Refere nce Safet y I nf or mati o n t o 
deter mi ne e x pecte d ness of  S A Es  f or  e x pe dite d re p orti n g. F oll o wi n g t he partici pa nt’s writte n  
c o nse nt ( or t he pare nt/ g uar dia n/le gall y  a p p oi nte d re prese ntati ve’s per missi o n) t o partici pate  i n t he 
st u d y, all S A Es, w het her relate d or n ot relate d t o st u d y dr u g, m ust be c ollecte d, i ncl u di n g t h ose 
t h o u g ht t o be ass ociate d wit h pr ot oc ol-s pecifie d pr oce d ures. 
All  S A Es  m ust be c ollecte d t hat occ ur  d uri n g t he scree ni n g peri o d a n d u ntil F U 2  ( Da y 1 0 0).  
•  Me dical  occ urre nces  t hat be gi n bef ore  t he start of st u d y treat me nt b ut after o btai ni n g i nf or me d 
c o nse nt will be rec or de d o n t he a p pr o priate secti o n of t he e C R F. 
•  All S A Es will be rec or de d a n d re p orte d  t o S p o ns or or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x 3. 
•  T he  i n vesti gat or will  s u b mit a n y u p date d S A E  data  t o t he s p o ns or wit hi n  2 4 h o urs of t his bei n g 
a vaila ble. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
I n vesti gat ors  are  n ot  o bli gate d  t o  acti vel y  see k  A Es  or  S A Es  i n  f or mer  st u d y  partici pa nts.  
H o we ver, 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 a partici pa nt 
has bee n  disc har ge d  fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt reas o na bl y relate d t o t he st u d y 
treat me nt 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. 
T he met h o d of e val uati n g, a n d assessi n g ca usalit y of A Es a n d S A Es a n d t he pr oce d ures f or 
c o m pleti n g a n d re p orti n g/tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 3 . 
9. 2. 2  
M et h o d  of  D et e cti n g A E s  a n d S A E s  
A d verse  e ve nts  ca n  be  s p o nta ne o usl y  re p orte d  or  elicite d  d uri n g  o pe n -e n de d  q uesti o ni n g,  
e xa mi nati o n,  or e val uati o n of a partici pa nt. (I n or der t o pre ve nt re p orti n g bias,  partici pa nts s h o ul d 
n ot be q uesti o ne d re gar di n g t he s pecific occ urre nce of o ne or m ore A Es.) 
F or  partici pa nts  ra n d o mize d/assi g ne d t o treat me nt a n d ne ver treate d wit h  st u d y dr u g, S A Es  s h o ul d 
be c ollecte d f or 3 0 da ys fr o m t he date of treat me nt assi g n me nt. 
E ver y  A E   m ust  be assesse d   b y t he  i n vesti gat or wit h  re gar d t o  w het her it is  c o nsi dere d 
i m m u ne- me diate d. F or  e ve nts w hic h  are p ote ntiall y  i m m u ne-me diate d,  a d diti o nal  i nf or mati o n will 
be c ollecte d o n t he partici pa nt’s C R F. 
9. 2. 3  
F oll o w -u p  of  A E s  a n d  S A E s  
•  N o nseri o us A Es  s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n,  or re p orte d as S A Es  if t he y 
bec o me seri o us (see A p pe n di x 3). 
•  F oll o w- u p is als o re q uire d f or n o nseri o us A Es t hat ca use i nterr u pti o n or disc o nti n uati o n of 
st u d y treat me nt a n d f or t h ose prese nt at t he e n d of st u d y treat me nt as a p pr o priate. 
•  All i de ntifie d n o nseri o us A Es m ust be rec or de d a n d descri be d o n t he n o nseri o us A E pa ge of 
t he C R F ( pa per or electr o nic). C o m pleti o n of s u p ple me ntal C R Fs ma y be re q ueste d f or A Es 
a n d/ or la b orat or y a b n or malities t hat are re p orte d/i de ntifie d d uri n g t he c o urse of t he st u d y. 
 
After  t he i nitial A E/ S A E  re p ort, t he i n 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  S A Es will  be f oll o we d u ntil  res ol uti o n, u ntil  t he c o n diti o n 
sta bilizes, u ntil t he e ve nt is ot her wise e x plai ne d, or u ntil t he partici pa nt is l ost t o f oll o w- u p. 
F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is gi ve n i n A p pe n di x 3.  
9. 2. 4  
R e g ul at or y  R e p orti n g  R e q uir e m e nt s  f or S A E s  
•  Pr o m pt n otificati o n b y t he i n vesti gat or t o t he S p o ns or of S A Es is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of a 
pr o d uct u n der cli nical i n vesti gati o n are met.  
•  A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g S A Es or ot her s pecific 
safet 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 file it al o n g wit h 
t he I B 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 re q uire me nts. 
 
S p o ns or  or  desi g nee  will  be  re p orti n g  A Es  t o  re g ulat or y  a ut h orities  a n d  et hics  c o m mittees  
acc or di n g  t o l ocal a p plica ble la ws i ncl u di n g E ur o pea n Directi ve  2 0 0 1/ 2 0/ E C a n d F D A  C o de of  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Fe deral Re g ulati o ns 2 1 C F R Parts 3 1 2 a n d 3 2 0. A S U S A R ( S us pecte d, U ne x pecte d Seri o us 
A d verse Reacti o n)  is a s u bset of S A Es  a n d will  be re p orte d t o t he a p pr o priate re g ulat or y a ut h orities 
a n d i n vesti gat ors f oll o wi n g l ocal a n d gl o bal g ui deli nes a n d re q uire me nts. 
9. 2. 5  
Pr e g n a n c y  
If, f oll o wi n g i nitiati o n of t he st u d y treat me nt, it is s u bse q ue ntl y disc o vere d t hat a partici pa nt is 
pre g na nt or  ma y  ha ve  bee n   pre g na nt at  t he ti me of   st u d y  e x p os ure,  i ncl u di n g  d uri n g at least 
5  half- li ves  after  pr o d uct  a d mi nistrati o n,  t he  i n vesti gat or  m ust  i m me diatel y  n otif y  t he  B M S  
Me dical  M o nit or/ desi g nee of t his e ve nt a n d c o m plete a n d f or war d a Pre g na nc y  S ur veilla nce F or m 
t o B M S  Desi g nee  wit hi n  2 4 h o urs of  a ware ness of  t he e ve nt a n d i n acc or da nce  wit h  S A E  re p orti n g 
pr oce d ures descri be d i n A p pe n di x 3  
I n m ost cases, t he st u d y treat me nt will  be per ma ne ntl y  disc o nti n ue d i n a n a p pr o priate ma n ner (e g, 
d ose ta peri n g if necessar y  f or partici pa nt safet y). Please  call t he B M S  Me dical  M o nit or wit hi n  2 4 
h o urs of a ware ness of t he pre g na nc y.  
Pr ot oc ol- re q uire d pr oce d ures f or st u d y disc o nti n uati o n a n d f oll o w-u p m ust be perf or me d o n t he 
partici pa nt.  
F oll o w- u p i nf or mati o n re gar di n g t he c o urse of t he pre g na nc y, i ncl u di n g peri natal a n d ne o natal 
o utc o me  a n d,  w here  a p plica ble,  offs pri n g  i nf or mati o n  m ust  be  re p orte d  o n  t he  Pre g na nc y  
S ur veilla nce F or m.  
A n y pre g na nc y t hat occ urs i n a fe male part ner of a male st u d y partici pa nt s h o ul d be re p orte d t o 
S p o ns or or desi g nee. I n or der f or S p o ns or or desi g nee t o c ollect a n y pre g na nc y s ur veilla nce 
i nf or mati o n fr o m t he fe male part ner, t he fe male part ner m ust si g n a n i nf or me d c o nse nt f or m f or 
discl os ure of  t his i nf or mati o n. I nf or mati o n o n t his pre g na nc y will be c ollecte d o n t he Pre g na nc y 
S ur veilla nce F or m.  
9. 2. 6  
L a b or at or y T e st R e s ult A b n or m aliti e s  
T he f oll o wi n g la b orat or y  test res ult a b n or malities s h o ul d be ca pt ure d o n t he n o nseri o us A E C R F 
pa ge or S A E Re p ort F or m  electr o nic, as a p pr o priate. Pa per f or ms are o nl y i nte n de d as a bac k -u p 
o pti o n w he n t he electr o nic s yste m is n ot f u ncti o ni n g. 
•  A n y  la b orat or y test res ult t hat is cli nicall y si g nifica nt or  meets  t he defi niti o n  of a n S A E  
•  A n y la b orat or y test res ult a b n or malit y t hat re q uire d t he partici pa nt t o ha ve st u d y treat me nt 
disc o nti n ue d or i nterr u pte d 
•  A n y  la b orat or y  test  res ult  a b n or malit y  t hat  re q uire d  t he  partici pa nt  t o  recei ve  s pecific  
c orrecti ve t hera p y  
 
It is e x pecte d  t hat w here ver p ossi ble,  t he cli nical rat her t ha n la b orat or y ter m w o ul d be use d  b y t he 
re p orti n g i n vesti gat or (e g, a ne mia vers us l o w he m o gl o bi n val ue). 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
7 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
9. 2. 7  
P ot e nti al  Dr u g  I n d u c e d Li v er  I nj ur y ( DI LI) 
W here ver p ossi ble, ti mel y c o nfir mati o n of i nitial li ver -relate d la b orat or y a b n or malities s h o ul d 
occ ur pri or t o t he re p orti n g of a p ote ntial DI LI  e ve nt. All  occ urre nces  of p ote ntial DI LIs,  meeti n g 
t he defi ne d criteria, m ust be re p orte d as S A Es (see A p pe n di x 3  f or re p orti n g details). 
P ote ntial dr u g  i n d uce d li ver i nj ur y is defi ne d as: 
A T  ( A L T or A S T)  ele vati o n > 3 x U L N 
A N D  
T otal  bilir u bi n  >  2 x U L N,  wit h o ut  i nitial  fi n di n gs  of  c h olestasis  (ele vate d  ser u m  al kali ne  
p h os p hatase),  
A N D  
N o  ot her i m me diatel y a p pare nt  p ossi ble ca uses of A T  ele vati o n a n d h y per bilir u bi ne mia, i ncl u di n g, 
b ut n ot li mite d t o, viral  he patitis,  pre-e xisti n g c hr o nic or ac ute li ver disease,  or t he a d mi nistrati o n 
of ot her dr u g(s) k n o w n t o be he pat ot o xic. 
9. 2. 8  
Ot h er S af et y C o n si d er ati o n s  
A n y  si g nifica nt w orse ni n g n ote d d uri n g i nteri m or fi nal p h ysical e xa mi nati o ns, electr ocar di o gra m, 
x- ra y fil mi n g, a n y ot her p ote ntial safet y assess me nt re q uire d or n ot re q uire d b y pr ot oc ol s h o ul d 
als o be rec or de d as a n o nseri o us or seri o us A E, as a p pr o priate, a n d re p orte d acc or di n gl y. 
T he  C R F  will  ca pt ure  C O VI D - 1 9-relate d  A Es/ S A Es  as  per  n or mal  re p orti n g  pr oce d ure  (e g,  
c ha n ges i n st u d y visit sc he d ules, missi n g st u d y visits, st u d y dr u g m o dificati o n/ disc o nti n uati o n, 
st u d y disc o nti n uati o n, etc.). 
 
9. 2. 9  
M a n a g e m e nt  Al g orit h m s  f or I m m u n o-O n c ol o g y  A g e nt s  
I m m u n o-o nc ol o g y (I -O) a ge nts are ass ociate d wit h A Es t hat ca n differ i n se verit y a n d d urati o n 
t ha n A Es  ca use d b y ot her t hera pe utic classes. Ni v ol u ma b  is c o nsi dere d  a n i m m u n o- o nc ol o g y a ge nt 
i n t his pr ot oc ol. Earl 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  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 A Es: 
•  Gastr oi ntesti nal  
•  Re nal  
•  P ul m o nar y  
•  He patic  
•  E n d ocri n o pat h y  
•  S ki n  
•  Ne ur ol o gical  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T he  a b o ve al g orit h ms  are f o u n d i n t he ni v ol u ma b I B4 5 a n d A p pe n di x 7  of  t his pr ot oc ol.  
9. 3  
O v er d o s e  
A n  o ver d ose is defi ne d as t he acci de ntal  or i nte nti o nal a d mi nistrati o n  of a n y d ose of a pr o d uct t hat 
is  c o nsi dere d  b ot h  e xcessi ve  a n d  me dicall y  i m p orta nt.  All  occ urre nces  of  o ver d ose  m ust  be  
re p orte d as a n S A E (see Secti o n 9. 2  a n d A p pe n di x 3 ). 
I n t he e ve nt of a n o ver d ose t he [i n vesti gat or/treati n g p h ysicia n] s h o ul d: 
•  C o ntact t he Me dical  M o nit or i m me diatel y 
•  Cl osel y  m o nit or  t he partici pa nt f or A Es/ S A Es  a n d la b orat or y a b n or malities. 
•  D oc u me nt t he q ua ntit y of t he e xcess d ose as well  as t he d urati o n of t he o ver d osi n g i n t he C R F.  
 
Decisi o ns  re gar di n g  d ose  i nterr u pti o ns  or  m o dificati o ns  will  be  ma de  b y  t he  i n vesti gat or  i n  
c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val uati o n of t he partici pa nt. 
9. 4  
S af et y  
Pla n ne d ti me p oi nts f or all safet y assess me nts  are liste d i n t he Sc he d ule of Acti vities  (Secti o n  2). 
At scree ni n g, a me dical hist or y will be o btai ne d t o ca pt ure rele va nt u n derl yi n g c o n diti o ns. T he 
scree ni n g e xa mi nati o ns s h o ul d i ncl u de wei g ht, hei g ht, Kar n ofs k y / La ns k y Perf or ma nce Stat us, 
bl o o d press ure  ( B P), heart  rate ( H R), a n d te m perat ure. Scree ni n g  assess me nts  s h o ul d be perf or me d 
wit hi n 2 8 da ys pri or t o treat me nt assi g n me nt. 
Scree ni n g  l ocal  la b orat or y  assess me nts  s h o ul d  be  d o ne  wit hi n  1 4  da ys  pri or  t o  treat me nt  
assi g n me nt; see Ta ble 2 - 1 f or a list of assess me nts. 
Scree ni n g pre g na nc y tests f or W O C B P m ust be perf or me d wit hi n 2 4 h o urs pri or t o t he i nitial 
a d mi nistrati o n of st u d y dr u g. 
T he f oll o wi n g scree ni n g l ocal la b orat or y assess me nts s h o ul d be d o ne wit hi n 2 8 da ys pri or t o 
treat me nt assi g n me nt: He patitis B a n d C testi n g ( H B V s A g a n d H C V A b or H C V R N A). 
O n -st u d y l ocal la b orat or y assess me nts s h o ul d be d o ne wit hi n 3 cale n dar da ys pri or t o eac h d ose: 
see Ta ble 2-1 f or a list of assess me nts.  
T h yr oi d f u ncti o n testi n g (refle x t o free T 3,  a n d free T 4  if a b n or mal res ult) is t o be d o ne e ver y ot her 
c ycle. 
O n  treat me nt pre g na nc y tests s h o ul d be perf or me d  as per  t he Sc he d ule of  Acti vities  ( Secti o n 2).  
Partici pa nts  will  be e val uate d  f or safet y if t he y ha ve recei ve d a n y st u d y dr u g. T o xicit y  assess me nts 
will  be c o nti n u o us d uri n g t he treat me nt p hase as well  as d uri n g t he first t w o safet y f oll o w- u p visits. 
O nce  partici pa nts  reac h  t he  s ur vi val  f oll o w -u p  p hase,  eit her  i n -pers o n  visits  or  d oc u me nte d  
tele p h o ne calls/e mail c orres p o n de nce t o assess t he partici pa nt’s stat us are acce pta ble. 
A d verse e ve nts a n d la b orat or y val ues  will  be gra de d acc or di n g t o t he N CI -C T C A E  versi o n 4.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
P h ysical  e xa mi nati o ns  are  t o  be  perf or me d  as  cli nicall y  i n dicate d.  If  t here  are  a n y  ne w  or  
w orse ni n g cli nicall y si g nifica nt c ha n ges si nce t he last e xa m, re p ort c ha n ges o n t he a p pr o priate 
n o n-seri o us or S A E pa ge. 
O n treat me nt l ocal la b orat or y assess me nts are t o be c o m plete d wit hi n 3 cale n dar da ys pri or t o 
d osi n g.  
A d diti o nal  meas ures,  i ncl u di n g  n o n -st u d y  re q uire d  la b orat or y  tests,  s h o ul d  be  perf or me d  as  
cli nicall y i n dicate d or t o c o m pl y  wit h l ocal  re g ulati o ns. La b orat or y t o xicities (e g, s us pecte d dr u g 
i n d uce d li ver e nz y me e val uati o ns) will be m o nit ore d  d uri n g t he f oll o w-u p p hase via o n site/l ocal 
la bs u ntil all st u d y dr u g relate d t o xicities res ol ve, ret ur n t o baseli ne, or are dee me d irre versi ble. 
If a partici pa nt  s h o ws p ul m o nar y-relate d si g ns ( h y p o xia, fe ver) or s y m pt o ms (e g. d ys p nea, c o u g h, 
fe ver) c o nsiste nt wit h p ossi ble p ul m o nar y a d verse e ve nts, t he partici pa nt s h o ul d be i m me diatel y 
e val uate d  t o  r ule  o ut  p ul m o nar y  t o xicit y,  acc or di n g  t o  t he  s us pecte d  p ul m o nar y  t o xicit y  
ma na ge me nt al g orit h m i n t he ni v ol u ma b I B. 4 5 
S o me  of t he assess me nts referre d t o i n t his secti o n ma y  n ot  be  ca pt ure d as data i n t he e C R F. T he y 
are i nte n de d t o be use d as safet y m o nit ori n g b y t he treati n g p h ysicia n. A d diti o nal testi n g or 
assess me nts ma y be perf or me d as cli nicall y necessar y  or w here re q uire d b y i nstit uti o nal or l ocal 
re g ulati o ns. 
9. 4. 1  
P h y si c al E x a mi n ati o n s  
Refer  t o Sc he d ule of  Acti vities  i n Secti o n  2. 
9. 4. 2  
Vit al Si g n s  
Refer  t o Sc he d ule of  Acti vities  i n Secti o n  2.  
9. 4. 3  
Cli ni c al  S af et y  L a b or at or y  A s s e s s m e nt s  
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. See Secti o n 2 f or 
a d diti o nal details o n t he assess me nts t o be c o n d ucte d.  
9. 4. 4  
I m a gi n g S af et y A s s e s s m e nt  
A n y i nci de ntal fi n di n gs of p ote ntial cli nical rele va nce t hat are n ot directl y ass ociate d wit h t he 
o bjecti ves of t he pr ot oc ol s h o ul d be e val uate d a n d ha n dle d b y t he St u d y I n vesti gat or as per 
sta n dar d me dical/cli nical j u d g me nt. 
9. 5  
P h ar m a c o ki n eti c  
Sa m ples f or P K a n d i m m u n o ge nicit y assess me nts will be c ollecte d f or all partici pa nts recei vi n g 
ni v ol u ma b a n d bre nt u xi ma b ve d oti n as descri be d i n Ta ble 2 - 5. All ti me p oi nts are relati ve t o t he 
start of t he pre vi o us st u d y dr u g a d mi nistrati o n. After c ycle 1 ( o nce b ot h st u d y dr u gs of t he 
c o m bi nati o n are a d mi nistere d  o n t he sa me da y),  pre d ose sa m ples are t o be c ollecte d relati ve t o t he 
star of bre nt u xi ma b ve d oti n. All  o n-treat me nt ti me p oi nts are i nte n de d t o ali g n wit h  da ys  o n w hic h 
st u d y dr u gs is a d mi nistere d, if d osi n g occ urs o n a differe nt da y, t he P K a n d i m m u n o ge nicit y 
sa m pli n g s h o ul d be a dj uste d acc or di n gl y. F urt her details of sa m ple c ollecti o n, pr ocessi n g, a n d 
s hi p me nt will be pr o vi de d i n t he la b orat or y pr oce d ures ma n ual. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A  detaile d  sc he d ule  of  P K  a n d  i m m u n o ge nicit y  e val uati o ns  f or  ni v ol u ma b  a n d bre nt u xi ma b  
ve d oti n is pr o vi de d i n Ta ble 2 - 5. P K sa m ples will be a nal yze d f or ni v ol u ma b a n d bre nt u xi ma b 
ve d oti n  b y vali date d  li ga n d  bi n di n g assa ys.  I m m u n o ge nicit y sa m ples will   be a nal yze d f or 
a nti-ni v ol u ma b a nti b o dies b y a vali date d i m m u n o ge nicit y assa y; sa m ples ma y als o be a nal yze d 
f or  ne utralizi n g  a nti b o dies  b y  a  vali date d  met h o d.  Ser u m  sa m ples  ma y  be  a nal yze d  b y  a n  
e x pl orat or y  met h o d  t hat  meas ures  a nti -dr u g  a nti b o dies  f or  tec h n ol o g y  e x pl orati o n  p ur p oses;  
e x pl orat or y  res ults  will  n ot  be  re p orte d.  Ser u m  sa m ples  desi g nate d  f or  P K  or  bi o mar ker  
assess me nts  ma y  als o be use d  f or i m m u n o ge nicit y a nal ysis if re q uire d (e g, i ns ufficie nt v ol u me f or 
c o m plete i m m u n o ge nicit y assess me nt or t o f oll o w u p o n s us pecte d i m m u n o ge nicit y- relate d A E). 
9. 6  
P h ar m a c o d y n a mi c s  
See  Secti o n  9. 8. 2 a n d 1 0. 3. 3. 3 . 
9. 7  
P h ar m a c o g e n o mi c s  
See  Secti o n  9. 8. 2.  
9. 8  
Bi o m ar k er s  
Peri p heral bl o o d a n d t u m or tiss ue will be c ollecte d pri or t o t hera p y  a n d at selecte d ti me p oi nts o n 
treat me nt as o utli ne d  i n Secti o n  2, u nless restricte d b y l ocal re q uire me nts. A variet y  of fact ors t hat 
c o ul d p ote ntiall y pre dict cli nical res p o nse t o ni v ol u ma b will be i n vesti gate d i n peri p heral bl o o d 
a n d  i n  t u m or  s peci me ns  ta ke n  fr o m  all  partici pa nts  pri or  t o  treat me nt.  Data  fr o m  t hese  
i n vesti gati o ns will be e val uate d f or ass ociati o ns wit h res p o nse, s ur vi val, a n d/ or safet y ( A E) data. 
All sa m ples  c ollecte d ma y  als o be use d f or f ut ure  e x pl orat or y a nal yses  ( u nless restricte d b y l ocal 
re q uire me nts) t o assess bi o mar kers ass ociate d wit h ni v ol u ma b treat me nt. C o m plete i nstr ucti o ns 
o n t he c ollecti o n, pr ocessi n g, ha n dli n g, a n d s hi p me nt of all sa m ples descri be d herei n will be 
pr o vi de d i n a se parate pr oce d ure ma n ual at t he ti me of st u d y i nitiati o n. 
9. 8. 1  
Bi o m ar k er s  i n t h e T u m or  
T u m or Bi o ps y  
T u m or bi o ps y  s peci me ns will  be o btai ne d t o c haracterize  i m m u ne cell p o p ulati o ns a n d e x pressi o n 
of selecte d t u m or mar kers. Bi o ps y sa m ples s h o ul d be e xcisi o nal, i ncisi o nal or c ore nee dle. Fi ne 
nee dle bi o psies are n ot all o we d beca use t he arc hitect ure of t he t u m or i n its micr oe n vir o n me nt 
ca n n ot  be  assesse d. T u m or  tiss ue  ( o btai ne d  d uri n g  t he  scree ni n g p hase  or  c ollecte d  pri or  t o 
o btai ni n g i nf or me d c o nse nt) m ust be pr o vi de d f or  bi o mar ker a nal ysis. Partici pa nts wit h rela pse d 
disease m ust pr o vi de a rece nt bi o ps y sa m ple wit hi n 9 0 da ys pri or  t o o btai ni n g i nf or me d c o nse nt 
or o btai n it d uri n g t he scree ni n g peri o d. I n rare cases w here a rece nt t u m or tiss ue ca n n ot be 
pr o vi de d d ue t o i ncrease d ris k of c o m plicati o ns, bi o psies ol der t ha n 9 0 da ys fr o m t he date of 
c o nse nt ma y be s u b mitte d.  T he reas o n m ust  be clearl y d oc u me nte d i n t he me dical  rec or d a n d t he 
B M S  Me dical  M o nit or m ust be c o ntacte d. I n or der f or partici pa nts t o be treate d, t he sa m ple m ust 
meet  t he  mi ni m u m  q ualit y  re q uire me nts,  as  deter mi ne d  b y  t he  ce ntral  la b orat or y  d uri n g  t he  
scree ni n g peri o d. Mi ni m u m  of 1 F F P E  t u m or tiss ue bl oc k ( preferre d) O R  a mi ni m u m  of 2 0 F F P E 
u nstai ne d secti o ns are re q uire d f or assess me nt of P D -L 1 stat us a n d ot her bi o mar ker e val uati o ns. 
N ote:  U n der s pecial circ u msta nces,  if t u m or tiss ue pr o vi de d is dee me d  i na de q uate, c o ntact t he 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Me dical  M o nit or f or a p pr o val t o be gi n treat me nt. All  partici pa nts  ma y  v ol u nteer  t o u n der g o t u m or 
bi o ps y at a n y ti me d uri n g t hera p y if cli nicall y i n dicate d (e g, u p o n pr o gressi o n). W he n t u m or 
bi o ps y is perf or me d, s u b missi o n of  t u m or bi o ps y is o pti o nal, b ut e nc o ura ge d f or t he p ur p oses of 
u n dersta n di n g mec ha nis ms of resista nce t o t hera p y. 
T he bi o mar kers descri be d bel o w will be a nal yze d t o t he e xte nt p ossi ble c o nsi deri n g t hat t u m or 
tiss ue pr o vi de d b y s o me of t he partici pa nts ma y be i ns ufficie nt t o c o m plete t he f ull pa nel of 
bi o mar kers pr o p ose d i n t his pr ot oc ol.  
C h ar acteriz ati o n of T u m or  I nfiltr ati n g L y m p h oc ytes ( TI Ls) a n d  T u m or  A nti ge ns  
I m m u n o hist oc he mistr y (I H C) ma y be use d t o assess t he n u m ber, c o m p ositi o n, a n d f u ncti o n of 
i m m u ne  i nfiltrates  i n  or der  t o  defi ne  t he i m m u ne  cell  s u bsets  prese nt  wit hi n  f or mali n-fi xe d, 
paraffi n  e m be d de d ( F F P E) t u m or tiss ue bef ore a n d after e x p os ure t o t hera p y. T hese  I H C a nal yses 
ma y i ncl u de, b ut n ot necessaril y be li mite d t o, t he f oll o wi n g mar kers: C D 3 0, C D 3, C D 4, C D 8, 
F O X p 3,  P D - 1, P D -L 1,  P D -L 2,  H L A -D R,  C D 5 6,  C D 6 8,  C D 1 6 3,  P A X 5,  p S T A T 3,  a n d M H C  class 
I/II. 
C h ar acteriz ati o n of T u m or  Ge n ot y pe  a n d  P he n ot y pe  
Ge ne m utati o ns,  c hr o m os o mal tra nsl ocati o ns, c o p y n u m ber alterati o ns, m R N A  a n d mi R N A ge ne 
e x pressi o n, a n d e pi ge netic m o dificati o ns wit hi n t u m ors  ma y be c haracterize d a n d e x pl ore d b y 
tec h n ol o gies i ncl u di n g b ut n ot li mite d t o I H C, FI S H, R N Ase q, a n d w h ole e x o me se q ue nci n g. 
Ass ociati o ns of altere d t u m or cell ge netic str uct ure, ge ne e x pressi o n, disease heter o ge neit y a n d 
s u bt y pes  wit h  ni v ol u ma b  efficac y  will  be  perf or me d.  E B V  stat us  usi n g  E B E R  test  ma y  be  
e xa mi ne d if n ot pre vi o usl y k n o w n. 
9. 8. 2  
Bi o m ar k er s i n t h e Bl o o d  
S ol u ble  Bi o m ar kers  i n Ser u m  
S ol u ble fact ors, s uc h as c yt o ki nes, c he m o ki nes, a n d s ol u ble rece pt ors ma y be c haracterize d a n d 
q ua ntifie d  b y  i m m u n oassa ys  i n  ser u m.  C ollecte d  ser u m  sa m ples  ma y  als o  be  use d  f or  t he  
assess me nt of vacci nate d a nti b o d y c o nce ntrati o ns. 
S ol u ble  Bi o m ar ker i n Pl as m a  
Plas ma  sa m ples  will  be  c ollecte d  a n d  assesse d  f or  a d diti o nal  c yt o ki nes  a n d  s ol u ble  fact ors,  
i ncl u di n g s ol u ble P D -L 1  as well as circ ulati n g free  D N A  t o deter mi ne  Mi ni mal  Resi d ual  Disease 
( M R D) b y hi g h-t hr o u g h p ut se q ue nci n g. 
Peri p her al  Bl o o d I m m u ne Cells  S u bset  A n al ysis  
Peri p heral bl o o d sa m ples will be c ollecte d pri or t o i nitiati o n of st u d y t hera p y a n d at desi g nate d 
ti me p oi nts o n-treat me nt f or i m m u ne cell s u bset a nal ysis (Ta ble 2 - 5). C ollecti o n of peri p heral 
bl o o d is ma n dat or y at all ti me p oi nts. Bl o o d sa m ples ma y be use d f or i m m u n o p he n ot y pi n g or 
c haracterizati o n  of t he i m m u ne cell s u bsets i n t he circ ulati o n, i ncl u di n g, b ut n ot li mite d t o, T-cells, 
B- cells, N K cells, m yel oi d -deri ve d s u p press or cells, or s u b p o p ulati o ns of t he af ore me nti o ne d 
i m m u ne cell t y pes. T hese  sa m ples ma y  als o be use d  t o assess i m m u ne cell f u ncti o n or a nti ge n 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
s pecific T-cell pr oliferati o n or acti vati o n pe n di n g e mer gi n g i nf or mati o n fr o m ot her ni v ol u ma b 
st u dies. 
Si n gle N ucle oti de P ol y m or p his m ( S N P) A n al ysis  
I n or der t o i de ntif y p ote ntial p ol y m or p his ms ass ociate d wit h safet y a n d efficac y of ni v ol u ma b, 
selecte d  ge nes  ma y  be  e val uate d  f or  si n gle  n ucle oti de  p ol y m or p his ms  ( S N P).  A nal ysis  ma y  
i ncl u de b ut n ot li mite d t o ge nes ass ociate d  wit h  C D 3 0  a n d T N F  rece pt ors a n d a p o pt osis, P D -1/ P D - 
L 1 pat h wa y a n d acti vate d T cell p he n ot y pe, i ncl u di n g P D -1, P D -L 1, P D -L 2, a n d C T L A -4. T he 
ge netic i nf or mati o n i n t his bl o o d sa m ple ma y als o be use d t o e xa mi ne ger mli ne ( pre dis p osi n g) 
c haracteristics as well as t o i de ntif y ge netic i nf or mati o n s pecific t o y o ur t u m or. A bl o o d sa m ple 
will be o btai ne d at Da y 1, u nless restricte d b y l ocal re q uire me nts.  
9. 8. 3  
A d diti o n al R e s e ar c h C oll e cti o n  
Rete nti o n of sa m ple c ollecti o n f or a d diti o nal researc h is ma n dat or y f or all partici pa nts, e xce pt 
w here pr o hi bite d b y l ocal la ws or re g ulati o ns. 
T his  pr ot oc ol will  i ncl u de resi d ual sa m ple st ora ge f or a d diti o nal researc h. 
T his  rete nti o n  f or  a d diti o nal  researc h  is  i nte n de d  t o  e x pa n d  t he  tra nslati o nal  researc h  a n d  
de vel o p me nt ( R & D) ca pa bilit y  at B M S, a n d will s u p p ort  as yet u n defi ne d researc h ai ms t hat will 
a d va nce o ur u n dersta n di n g of disease a n d o pti o ns f or treat me nt. It ma y als o be use d t o s u p p ort 
healt h a ut h orit y re q uests f or a nal ysis, a n d a d va nce me nt of p har mac o dia g n ostic de vel o p me nt t o 
better  tar get dr u gs t o t he ri g ht patie nts. T his ma y  als o i ncl u de ge netic/ ge n o mic e x pl orati o n ai me d 
at e x pl ori n g disease pat h wa ys, pr o gressi o n a n d res p o nse t o treat me nt etc.  
All re q uests f or access t o sa m ples or data f or a d diti o nal researc h  will be vette d t hr o u g h a di verse 
c o m mittee  of  t he  st u d y  s p o ns or’s  se ni or  lea ders  i n  R & D  t o  e ns ure  t he  researc h  s u p p orts  
a p pr o priate a n d well -defi ne d scie ntific researc h acti vities.  
•  Resi d ual t u m or a n d bl o o d sa m ples fr o m bi o mar ker c ollecti o ns (see Ta ble 9. 8. 3 - 1) will be 
retai ne d f or a d diti o nal researc h p ur p oses 
 
Sa m ples will be sec urel y st ore d b y t he B M S Bi ore p osit or y  
or at a B M S  a p pr o ve d 
t hir d part y st ora ge ma na ge me nt facilit y. 
Sa m ples  will  be st ore d i n a c o de d fas hi o n, a n d n o researc her will  ha ve access t o t he ke y. T he ke y 
is sec urel y hel d  b y t he I n vesti gat or at t he cli nical site, s o t here is n o direct  a bilit y f or a researc her 
t o c o n nect a sa m ple t o a s pecific i n di vi d ual. 
A d diti o nal researc h sa m ples will be retai ne d f or 1 5 years or t he ma xi m u m all o we d b y a p plica ble 
la w. N o a d diti o nal sa m pli n g is re q uire d f or resi d ual c ollecti o ns. 
F urt her details of sa m ple c ollecti o n a n d pr ocessi n g will be pr o vi de d t o t he site i n t he pr oce d ure 
ma n ual.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T a ble  9. 8. 3-1:  
Resi d u al  S a m ple  Rete nti o n  f or A d diti o n al  Rese arc h  Sc he d ule  
 
S a m ple  T y pe  
Ti me p oi nts  f or w hic h  resi d u al s a m ples will  be  ret ai ne d 
P K  
All  
T u m or  Bi o ps y  
All  arc hi ve d  a n d fres h pre -treat me nt t u m or sa m ples as well  as all o n -treat me nt t u m or 
bi o psies  
Ser u m  
All  
Plas ma  
All  
W h ole  bl o o d  
C 1 D 1  
 
9. 8. 4  
Ot h er A s s e s s m e nt s  
N ot  a p plica ble. 
9. 9  
H e alt h  E c o n o mi c s  O R  M e di c al  R e s o ur c e  Utili z ati o n  a n d  H e alt h 
E c o n o mi c s  
Me dical  res o urce utilizati o n  data,  ass ociate d  wit h  me dical  e nc o u nters, will  be c ollecte d i n t he C R F 
b y t he i n vesti gat or a n d st u d y site pers o n nel f or all partici pa nts t hr o u g h o ut t he st u d y. Pr ot oc ol - 
ma n date d pr oce d ures, tests, a n d e nc o u nters are e xcl u de d. 
T he data c ollecte d ma y be use d t o c o n d uct e x pl orat or y ec o n o mic a nal yses a n d will i ncl u de t he 
f oll o wi n g: 
•  N u m ber a n d  d urati o n  of me dical  care e nc o u nters,   i ncl u di n g s ur geries,  a n d  ot her selecte d 
pr oce d ures (i n patie nt a n d o ut patie nt) 
•  D urati o n  of h os pitalizati o n  (t otal da ys  le n gt h of sta y, i ncl u di n g d urati o n b y  war ds;  e g, i nte nsi ve 
care u nit) 
•  N u m ber a n d c haracter  of dia g n ostic a n d t hera pe utic tests a n d pr oce d ures  
•  O ut patie nt me dical  e nc o u nters a n d treat me nts (i ncl u di n g p h ysicia n  or e mer ge nc y  r o o m visits, 
tests a n d pr oce d ures, a n d me dicati o ns). 
 
9. 9. 1  
O ut c o m e s  R e s e ar c h A s s e s s m e nt s  
9. 9. 1. 1  
E Q -5 D -3 L  
T he E Q - 5 D- 3 L7 7 is a ge neric m ulti-attri b ute healt h -state classificati o n s yste m b y w hic h healt h is 
descri be d  i n  5  di me nsi o ns:  m o bilit y,  self -care,  us ual  acti vities,  pai n/ disc o mf ort,  a n d  
a n xiet y/ de pressi o n. Eac h  di me nsi o n is e val uate d usi n g 3 le vels: n o pr o ble ms, s o me pr o ble ms, a n d 
se vere pr o ble ms. Res p o nses t o t hese 5 di me nsi o ns are c o n verte d i nt o 1 of 2 4 3 u ni q ue E Q -5 D 
healt h  state  descri pti o ns,  w hic h  ra n ge  bet wee n  n o  pr o ble ms  o n  all  5  di me nsi o ns  ( 1 1 1 1 1)  t o  
se vere/e xtre me pr o ble ms o n all 5 di me nsi o ns ( 3 3 3 3 3). Usi n g a p pr o priate c o u ntr y -s pecific val ue 
wei g hti n g al g orit h ms, a res p o n de nt’s self -descri be d healt h state ca n be c o n verte d i nt o a utilit y 
re prese nti n g t he s ocietal desira bilit y  of his/ her o w n  healt h. I n a d diti o n, t he E Q - 5 D i ncl u des a vis ual 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
a nal o g ue scale ( V A S) all o wi n g a res p o n de nt t o rate his/ her healt h o n  a scale ra n gi n g fr o m  0 – 1 0 0 
wit h 0 bei n g t he w orst healt h state i ma gi na ble a n d 1 0 0 bei n g t he best healt h state i ma gi na ble. 
T he  E Q - 5 D- 3 L will  be a d mi nistere d  t o all treate d partici pa nts  t hat are of t he a ge 1 2 or ol der at t he 
ti me of first treat me nt ( C 1 D 1). Assess me nts will be c ollecte d o n-treat me nt d uri n g t he i n d ucti o n 
a n d i nte nsificati o n  p hase a n d d uri n g f oll o w - u p p hases  as o utli ne d i n  St u d y  Assess me nts  (Secti o n  
2 ). 
9. 9. 1. 2  
F u n cti o n al  A s s e s s m e nt  of  C a n c er  T h er a p y  - L y m p h o m a  ( F A C T-L y m)  
T he  F A C T -L y m  is a vali date d  ca ncer-s pecific Q o L  meas ure  i n pe o ple wit h  l y m p h o ma. T he  F A C T - 
L y m c o m bi nes a ge neric c ore c o nsisti n g of t he F A C T -Ge neral w hic h c o nstit utes t he c ore of all 
s u bscales, a n d ca n be use d wit h  patie nts of a n y t u m or t y pe, wit h  1 5 a d diti o nal l y m p h o ma-tar gete d 
ite ms t hat c o ver s y m pt o ms c H L patie nts ma y e x perie nce (e g, s welli n g, ni g ht s weats). C ore ite ms 
are  classifie d  as:  p h ysical  well -bei n g,  s ocial/fa mil y  well -bei n g,  e m oti o nal  well -bei n g,  a n d  
f u ncti o nal well- bei n g. 
T he  F A C T  i nstr u me nts use  a 5- p oi nt i nte nsit y t y pe of rati n g scale (fr o m ‘ n ot at all’ t o ‘ ver y m uc h’). 
Res p o n de nts are i nstr ucte d t o a ns wer q uesti o ns wit h res pect t o t heir e x perie nces a n d f u ncti o ni n g 
o ver t he pre vi o us 7 da ys. 
T he F A C T -L y m will be a d mi nistere d t o all treate d partici pa nts t hat are of  t he a ge 1 2 or ol der at 
t he ti me of first treat me nt ( C 1 D 1). Assess me nts  will  be c ollecte d o n-treat me nt d uri n g t he i n d ucti o n 
a n d i nte nsificati o n p hase as o utli ne d i n St u d y Assess me nts ( Secti o n 2).  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
1 0.  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
1 0. 1  
S a m pl e  Si z e  D et er mi n ati o n  
D ue t o hi g h i nitial c ure rates f or pe diatric  H o d g ki n l y m p h o ma, a  ra n d o mize d trial i n t he retrie val 
setti n g was dee me d n ot feasi ble d ue t o l o w patie nt n u m bers, e ve n wit h t he c o m bi ne d C O G a n d 
E ur o pea n  net w or ks.  T his  si n gle -ar m  st u d y  was  i nitiall y  tar geti n g  t o  treat  a p pr o xi matel y  4 0  
partici pa nts  i n eac h ris k c o h ort. Partici pa nts  w h o  are n ot  res p o nse-e val ua ble i n t he R 2  ( S R) gr o u p 
will be re place d. See Secti o n 1 0. 2 f or t he defi niti o n of “res p o nse-e val ua ble.” 
Act ual  n u m ber of treate d partici pa nts was  2 8 i n R 1  a n d 4 4 i n R 2.  
1 0. 2  
P o p ul ati o n s  f or A n al y s e s  
 
P o p ul ati o n  
Descri pti o n  
E nr olle d  Partici pa nts  
All  partici pa nts  w h o  si g ne d i nf or me d c o nse nt. 
Treate d  Partici pa nts  
All  partici pa nts  w h o  recei ve d at least 1 d ose  of  st u d y treat me nt. 
Res p o nse -e val ua ble Partici pa nts  
All  treate d partici pa nts  w h o  reac h o ne  of  t he f oll o wi n g e n d p oi nts: P M R  at a n y 
ti me, C M R  at a n y ti me, or  c o m pleti o n of  si x c ycles of  t hera p y ( N + B v x 4 pl us 
B v + B x ≥ 2). Partici pa nts w h o c o me off earl y f or t o xicit y wit h o ut a C M R or 
P M R are e val ua ble.  
Res p o n ders  
Partici pa nts  w h o  ac hie ve d C M R  or  P M R  
 
U nless  ot her wise n ote d, t he f oll o wi n g s pecifies t he p o p ulati o ns f or pri mar y  a nal yses. T he  pri mar y 
a nal ysis of E F S,  P F S,  a n d O S  will  be  perf or me d  o n t he Treate d  Partici pa nts.  T he  pri mar y  a nal ysis 
of t he C M R  rate a n d O R R  will  be perf or me d  o n t he Res p o nse-e val ua ble  Partici pa nts.  T he  pri mar y 
a nal ysis of D O R will be perf or me d o n t he Res p o n ders. 
1 0. 3  
St ati sti c al  A n al y s e s  
Bel o w  is a s u m mar y of pla n ne d statistical a nal yses. 
1 0. 3. 1  
Effi c a c y A n al y s e s  
 
E n d p oi nt  
St atistic al A n al ysis Met h o ds  
R 1 c o h ort: 
C M R rate 
pri or t o R T 
a n d E F S  at 3 
years.  
R 1  C o h ort:  
T he esti mate d C M R rate a n d e xact 2 -si de d 9 0 % CI will be pr o vi de d. See 
e xa m ples  i n  Ta ble  1 0. 3. 1 - 1).  I n  a d diti o n  t o  t he  Res p o nse- E val ua ble 
Partici pa nts, t he a nal ysis of C M R rate will be carrie d o ut f or All Treate d 
Partici pa nts as well.  
 
R 2 c o h ort: 
C M R rate 
pri or t o 
H D C T/ A S C T.  
T he  E F S  f u ncti o n  a n d  t he  3 -year  E F S  rate  will  be  esti mate d  usi n g  t he  
Ka pla n -Meier  pr o d uct-li mit met h o d. Its c orres p o n di n g 9 0 % CI  will  be deri ve d 
base d  o n  Gree n w o o d  f or m ula  f or  varia nce  deri vati o n  a n d  o n  l o g -l o g 
tra nsf or mati o n a p plie d o n t he s ur vi v or f u ncti o n s(t) -. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
E n d p oi nt  
St atistic al A n al ysis Met h o ds  
 
I n a d diti o n t o t he All  Treate d  Partici pa nts,  t he E F S  a nal ysis will  als o be  carrie d 
o ut f or t he f oll o wi n g s u b gr o u p: 
- Partici pa nts  w h o  ac hie ve d  C M R,  we nt  i nt o  R T,  a n d  di d  n ot  recei ve  
H D C T/ A S C T.  
R 2  C o h ort:  
T he esti mate d C M R rate a n d e xact 2 -si de d 9 0 % CI will be pr o vi de d. See 
e xa m ples  i n  Ta ble  1 0. 3. 1 - 1).  I n  a d diti o n  t o  t he  Res p o nse- E val ua ble 
Partici pa nts, t he a nal ysis of C M R rate will be carrie d o ut f or All Treate d 
Partici pa nts as well.  
 
T he  st atistic al  a n al yses  descri be d  a b o ve  will  a p pl y  t o  b ot h  t he  BI C R  
assess me nts a n d t he i n vesti g at or assess me nts, res pecti vel y.  
R 1  a n d R 2 
C o h orts:  
 
O R R  
f oll o wi n g 4 
c ycles of 
N + B v,  
P F S  at 3 
years,  
D O R  
O R R:  
T he esti mate d O R R rate a n d a n e xact 2 -si de d 9 0 % CI will be pr o vi de d.  I n 
a d diti o n t o t he Res p o nse-e val ua ble  Partici pa nts  as of t he st art of 5t h c ycle, t he 
O R R a nal ysis will als o be carrie d o ut f or All Treate d Partici pa nts.  
 
P F S:  
T he  P F S f u ncti o n a n d t he 3 -year P F S  rate will be esti mate d  usi n g t he Ka pla n - 
Meier pr o d uct -li mit met h o d. I n a d diti o n t o All Treate d Partici pa nts, t he P F S 
a nal ysis will als o be perf or me d f or t h ose w h o ac hie ve d C M R.  
 
D O R:  
T he D O R will be esti mate d usi n g t he Ka pla n -Meier pr o d uct -li mit met h o d. I n 
a d diti o n t o t he Res p o n ders ( C M R or P M R), t he D O R a nal ysis will als o be 
perf or me d f or t he s u b gr o u p of t h ose partici pa nts w h o ac hie ve d C M R. 
 
T he  st atistic al  a n al yses  descri be d  a b o ve  will  a p pl y  t o  b ot h  t he  BI C R  
assess me nts a n d t he i n vesti g at or assess me nts, res pecti vel y.  
O S  
T he  O S  will  be  esti mate d usi n g  t he Ka pla n -Meier  pr o d uct -li mit met h o d  f or t he 
L R a n d S R c o h orts, res pecti vel y.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
8 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T a ble 1 0. 3. 1- 1:  
E x a m ples of  9 0 % CIs  f or t he Res p o nse  R ate  ( O R R R ate  or C M R 
R ate)  
 
N u m ber of 
Res p o nse - 
e v al u a ble 
P artici p a nts  
 
N u m ber  of 
Res p o n ders  
 
O bser ve d 
Res p o nse R ate  ( %) 
E x act  2-si de d 9 0 %  CI  
L o wer  Li mit  ( %) 
U p per  Li mit  ( %) 
4 0  
5 
1 2. 5 0  
5. 0 6  
2 4. 5 0  
4 0  
1 0  
2 5. 0 0  
1 4. 2 4  
3 8. 7 1  
4 0  
1 5  
3 7. 5 0  
2 4. 7 3  
5 1. 7 2  
4 0  
2 0  
5 0. 0 0  
3 6. 1 1  
6 3. 8 9  
4 0  
2 5  
6 2. 5 0  
4 8. 2 8  
7 5. 2 7  
4 0  
3 0  
7 5. 0 0  
6 1. 2 9  
8 5. 7 6  
4 0  
3 5  
8 7. 5 0  
7 5. 5 0  
9 4. 9 4  
4 0  
4 0  
1 0 0. 0 0  
9 2. 7 8  
1 0 0. 0 0  
 
1 0. 3. 2  
S af et y A n al y s e s  
Safet y  a nal yses  will be  perf or me d i n  all treate d partici pa nts per  c o h ort as well f or  L R/ S R  c o h orts 
c o m bi ne d. Descri pti ve  statistics of safet y will  be prese nte d   usi n g N CI  C T C A E  versi o n 4.  All 
o n-st u d y A Es,  dr u g-relate d A Es,  S A Es  a n d dr u g-relate d S A Es  will  be  ta b ulate d usi n g  w orst  gra de 
per  N CI  C T C A E criteria b y s yste m  or ga n class a n d Me d D R A preferre d ter m. O n -st u d y la b 
para meters i ncl u di n g he mat ol o g y, c he mistr y, li ver f u ncti o n, t h yr oi d f u ncti o n, a n d re nal f u ncti o n 
will be s u m marize d usi n g w orst gra de per C T C A E criteria.  
1 0. 3. 3  
Ot h er A n al y s e s  
1 0. 3. 3. 1  
P h ar m a c o ki n eti c A n al y s e s  
Ser u m sa m ples will be c ollecte d t o c haracterize t he P K of ni v ol u ma b a n d bre nt u xi ma b. T he P K 
data fr o m t his trial ma y   be  p o ole d wit h   ot her trials t o  de vel o p  a  p o p ulati o n P K   m o del. 
M o del- deter mi ne d  e x p os ures will  be use d  f or e x p os ure-res p o nse a nal yses of selecte d efficac y a n d 
safet y e n d p oi nts. T he m o deli n g res ults will be re p orte d se paratel y. 
1 0. 3. 3. 2  
I m m u n o g e ni cit y A n al y s e s  
A listi n g will  be pr o vi de d of all a vaila ble i m m u n o ge nicit y data.  T he  fre q ue nc y of partici pa nts  wit h 
at least 1 p ositi ve a nti -dr u g a nti b o d y ( A D A) assess me nt, a n d t he fre q ue nc y of partici pa nts w h o 
de vel o p A D A after a ne gati ve baseli ne assess me nt, will be pr o vi de d. Detaile d met h o d ol o g y f or 
e x pl orat or y a nal yses i ncl u di n g bi o mar kers  a n d i m m u n o ge nicit y will  be descri be d  i n t he statistical 
a nal ysis pla n. 
1 0. 3. 3. 3  
Bi o m ar k er A n al y s e s  
S u m mar y  statistics f or t u m or a n d peri p heral bl o o d bi o mar kers  s uc h as, b ut  n ot li mite d t o, P D -L 1, 
s ol u ble fact ors, i m m u ne cells, a n d vacci nate d a nti b o d y c o nce ntrati o ns a n d t heir c orres p o n di n g 
c ha n ges ( or perce nt   c ha n ges) fr o m baseli ne  will   be ta b ulate d  b y  pla n ne d  st u d y visit  t o assess 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
p har mac o d y na mic effects. I n a d diti o n, t he ti me c o urse of  bi o mar ker  o utc o mes will  be i n vesti gate d 
gra p hicall y; if t here is i n dicati o n of mea ni n gf ul patter n acr oss ti me, f urt her a nal ysis ma y be 
perf or me d t o c haracterize t he relati o ns hi p. Res ults fr o m t u m or a n d peri p heral bl o o d bi o mar kers 
will be ta b ulate d a n d ass ociati o ns bet wee n bi o mar kers a n d efficac y or safet y meas ures will be 
assesse d. Met h o ds s uc h as, b ut n ot li mite d t o, l o gistic re gressi o n will be use d t o e x pl ore p ossi ble 
ass ociati o ns bet wee n meas ures of peri p heral bl o o d, t u m or bi o psies a n d cli nical o utc o me. M ore 
details of bi o mar ker a nal yses will be descri be d i n t he statistical a nal ysis pla n.  
1 0. 3. 3. 4  
E Q -5 D -3 L  
All  partici pa nts  w h o  ha ve a n assess me nt  at baseli ne a n d at least 1 s u bse q ue nt assess me nt  w hile  o n 
treat me nt will be a nal yze d. Q uesti o n naire c o m pleti o n rates at eac h assess me nt at eac h ti me p oi nt 
will be esti mate d f or t he E Q -5 D q uesti o n naire as a w h ole. Sc ores a n d p ost -baseli ne c ha n ges i n 
sc ores f or t he E Q - 5 D- 3 L V A S  a n d E Q - 5 D- 3 L utilit y  i n de x will  be  s u m marize d at eac h assess me nt 
ti me p oi nt usi n g a p pr o priate descri pti ve  statistics (ie, N,  mea n  wit h  sta n dar d de viati o n a n d 9 5 % CI, 
me dia n, first a n d t hir d q uartiles, mi ni m u m, ma xi m u m). Pr o p orti o ns of partici pa nts re p orti n g n o, 
m o derate,  or  se vere  pr o ble ms  i n  eac h  di me nsi o n  will  be  re p orte d.  U K  prefere nce - wei g hti n g 
al g orit h m will be use d t o deri ve E Q - 5 D-3 L V A S a n d E Q - 5 D- 3 L utilit y i n de x i n base case. 
1 0. 3. 3. 5  
F A C T -L y m  
All  partici pa nts  w h o  ha ve a n assess me nt  at baseli ne a n d at least 1 s u bse q ue nt assess me nt  w hile  o n 
treat me nt will be a nal yze d. Q uesti o n naire c o m pleti o n rates at eac h assess me nt at eac h ti me p oi nt 
will be esti mate d f or t he F A C T -L y m. Sc ores a n d p ost -baseli ne c ha n ges i n t he c ore s u bscales of 
t he  F A C T-L y m  a n d  t he  i n di vi d ual  l y m p h o ma -s pecific  ite ms  will  be  s u m marize d  at  eac h  
assess me nt  ti me p oi nt usi n g a p pr o priate descri pti ve  statistics (ie, N, mea n wit h  sta n dar d de viati o n 
a n d 9 5 % CI, me dia n, first a n d t hir d q uartiles, mi ni m u m, ma xi m u m). T he Trial O utc o me I n de x 
( T OI), w hic h is s u m mar y i n de x of t he p h ysical well-bei n g, f u ncti o nal well -bei n g a n d a d diti o nal 
c o ncer ns scales will be calc ulate d.  Ti me t o mea ni n gf ul  w orse ni n g i n scale sc ores will be deri ve d 
(f or t he l y m p h o ma c o ncer ns scale, T OI a n d t otal sc ore), if feasi ble. 
1 0. 3. 3. 6  
M e di c al R e s o ur c e Utili z ati o n  
Me dical  res o urce utilizati o n  data will  be a nal yze d se paratel y. 
1 0. 3. 4  
I nt eri m A n al y s e s  
N ot  a p plica ble. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
1 1.  
R E F E R E N C E S  
R E F E R E N C E S  F O R  T H E  U S E  O F  C O N D O M S  WI T H  S P E R MI CI D E.  
Kestel ma n  P.  et.  al., Efficac y  of  t he  Si m ulta ne o us Use   of  C o n d o ms  a n d S per mici des  Fa mil y 
Pla n ni n g Pers pecti ves. V ol 2 3 ( 5); Oct o ber 1 9 9 1. 
Ga b ba y M B,   T h o mas J,  Gi b bs A,  H ol d  P.   A  Ra n d o mize d  Cr oss o ver Trial   of  t he I m pact  of 
A d diti o nal S per mici de o n C o n d o m Fail ure Rates. Se x Tra ns m Dis 2 0 0 8; 3 5: 8 6 2- 8 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 
1 J uszcz y ns ki P, O u ya n g J, M o nti S, et al. T he A P 1 -de pe n de nt secreti o n of galecti n -1 b y Ree d 
Ster n ber g  cells f osters i m m u ne pri vile ge i n  classical  H o d g ki n l y m p h o ma. Pr oc  Natl  Aca d  Sci 
U S A 2 0 0 7; 1 0 4: 1 3 1 3 4- 9.  
2  Gree n  M R,  M o nti S,  R o di g SJ,  et al. I nte grati ve a nal ysis re veals selecti ve 9 p 2 4. 1  a m plificati o n, 
i ncrease d  P D-1  li ga n d  e x pressi o n,  a n d  f urt her  i n d ucti o n  via  J A K 2  i n  n o d ular  scler osi n g  
H o d g ki n l y m p h o ma  a n d pri mar y me diasti nal lar ge  B-cell l y m p h o ma. Bl o o d.  2 0 1 0; 1 1 6: 3 2 6 8- 
3 2 7 7.  
3  
K u p pers R.  T he  bi ol o g y of H o d g ki n's l y m p h o ma. Nat Re v Ca ncer. 2 0 0 9; 9: 1 5-2 7.  
4 R oe mer, M G M, A d va ni R H, Li g o n A H, et al. P D -L 1 a n d P D -L 2 ge netic alterati o ns defi ne 
classical  H o d g ki n l y m p h o ma a n d pre dict o utc o me. Prese nte d  at t he 5 7t h  A merica n  S ociet y  of 
He mat ol o g y  A n n ual  Meeti n g.  J o ur nal  of  Cli nical  O nc ol o g y.  A pril  1 1,  2 0 1 6  d oi:  
1 0. 1 2 0 0/J C O. 2 0 1 6. 6 6. 4 4 8 2.  
5  Gree n  M R,  R o di g S,  J uszcz y ns ki P,  et al. C o nstit uti ve  A P - 1 acti vit y a n d E B V  i nfecti o n i n d uce 
P D -L 1  i n H o d g ki n l y m p h o mas a n d p osttra ns pla nt l y m p h o pr oliferati ve dis or ders: I m plicati o ns 
f or tar gete d t hera p y. Cli n Ca ncer Res. 2 0 1 2; 1 8: 1 6 1 1- 1 6 1 8. 
6 Cair o  2 0 1 2:  Cair o  M S,  Per ki ns  S L,  e dit ors.  He mat ol o gical  mali g na ncies  i n  c hil dre n,  
a d olesce nts a n d y o u n g a d ults. W orl d Scie ntific P u blis hi n g C o; 2 0 1 2. 
7 Har ker -M urra y  P D,  Drac ht ma n  R A,  H o d gs o n D C,  et al. Stratificati o n  of treat me nt i nte nsit y i n 
rela pse d pe diatric H o d g ki n l y m p h o ma. Pe diatric Bl o o d & Ca ncer. 2 0 1 4; 6 1: 5 7 9 – 5 8 6. 
8 J osti n g A, R ueffer U, Fra n kli n J, et al. Pr o g n ostic fact ors a n d treat me nt o utc o me i n pri mar y 
pr o gressi ve H o d g ki n l y m p h o ma: a re p ort fr o m t he Ger ma n  H o d g ki n L y m p h o ma St u d y  Gr o u p. 
Bl o o d. 2 0 0 0; 9 6( 4): 1 2 8 0- 1 2 8 6. 
9 Sc hell o n g,  G,  D orffel  W,  Cla viez  A,  et  al.  Sal va ge  t hera p y  of  pr o gressi ve  a n d  rec urre nt  
H o d g ki n's disease: res ults fr o m a m ultice nter st u d y of t he pe diatric D A L/ G P O H H D st u d y 
gr o u p. J Cli n O nc ol. 2 0 0 5; 2 3( 2 5): 6 1 8 1- 6 1 8 9. 
1 0 C h o pra,  R,  Mc Milla n  A K,  Li nc h  D C,  et  al.  T he  place  of  hi g h -d ose  B E A M  t hera p y  a n d  
a ut ol o g o us b o ne marr o w  tra ns pla ntati o n i n p o or-ris k H o d g ki n's disease.  A si n gle-ce nter ei g ht- 
year st u d y of 1 5 5 patie nts. Bl o o d. 1 9 9 3: 8 1( 5): 1 1 3 7- 1 1 4 5. 
1 1 Sat wa ni  P,  A h n  K W,  Carreras  J,  et  al.  A  pr o g n ostic  m o del  pre dicti n g  a ut ol o g o us  
tra ns pla ntati o n o utc o mes i n  c hil dre n, a d olesce nts  a n d y o u n g  a d ults wit h H o d g ki n l y m p h o ma. 
B o ne Marr o w Tra ns pla nt. 2 0 1 5; 5 0: 1 4 1 6- 1 4 2 3. 
1 2 Kell y  K M.  Ma na ge me nt  of  c hil dre n  wit h  hi g h -ris k  H o d g ki n  l y m p h o ma.  Br  J  Hae mat ol.  
2 0 1 2: 1 5 7; 3 – 1 3.  
1 3 Da w  S,  W y n n  R,  Wallace  H.  Ma na ge me nt  of  rela pse d  a n d  refract or y  classical  H o d g ki n  
l y m p h o ma i n c hil dre n a n d a d olesce nts. Br J Hae mat ol. 2 0 1 1; 1 5 2: 2 4 9 – 2 6 0. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
1 4 Nac h ma n  J B.  Ra n d o mize d  c o m paris o n  of  l o w -d ose  i n v ol ve d -fiel d  ra di ot hera p y  a n d  n o  
ra di ot hera p y  f or  c hil dre n  wit h  H o d g ki n’s  disease  w h o  ac hie ve  a  c o m plete  res p o nse  t o  
c he m ot hera p y. J Cli n O nc ol. 2 0 0 2; 2 0: 3 7 6 5 – 3 7 7 1. 
1 5 Sc hell o n g  G,  D orffel  W,  Cla viez  A,  et  al.  Sal va ge  t hera p y  of  pr o gressi ve  a n d  rec urre nt  
H o d g ki n’s disease: Res ults fr o m a m ultice nter st u d y of t he pe diatric D A L/ G P O H -H D st u d y 
gr o u p. J Cli n O nc ol. 2 0 0 5; 2 3: 6 1 8 1 – 6 1 8 9. 
1 6 H o d g ki n L y m p h o ma, Nati o nal C o m pre he nsi ve Ca ncer Net w or k Cli nical Practice G ui deli nes 
i n O nc ol o g y. 2 0 1 2 [cite d 2 0 1 2 9- 8- 2 0 1 2]; Versi o n 2. 2 0 1 2. 
1 7 Metz ger M L, H u ds o n M M, Krasi n MJ, et al. I nitial res p o nse t o sal va ge t hera p y deter mi nes 
pr o g n osis i n rela pse d pe diatric H o d g ki n l y m p h o ma patie nts. Ca ncer. 2 0 1 0; 1 1 6: 4 3 7 6 – 4 3 8 4. 
1 8 Sie nia ws ki M, Fra n kli n J, N o g o va L, et al. O utc o me of patie nts e x perie nci n g pr o gressi o n or 
rela pse after pri mar y treat me nt wit h t w o c ycles of c he m ot hera p y a n d ra di ot hera p y f or earl y- 
sta ge fa v ora ble H o d g ki n’s l y m p h o ma. J Cli n O nc ol. 2 0 0 7; 2 5: 2 0 0 0 – 2 0 0 5. 
1 9 A p pel B E, C he n L, B u xt o n A B, et al. Mi ni mal treat me nt of l o w -ris k, pe diatric l y m p h oc yte- 
pre d o mi na nt H o d g ki n l y m p h o ma: a re p ort fr o m t he C hil dre n's O nc ol o g y Gr o u p. J o ur nal of 
Cli nical O nc ol o g y. P u blis he d o nli ne o n Ma y 1 6, 2 0 1 6; D OI: 1 0. 1 2 0 0/J C O. 2 0 1 5. 6 5. 3 4 6 9. 
2 0 Wi m mer  R S,  C ha u ve net A R,  L o n d o n W B,  et al. A P E  c he m ot hera p y f or c hil dre n wit h  rela pse d 
H o d g ki n disease:  A Pe diatric  O nc ol o g y Gr o u p trial. Pe diatr  Bl o o d Ca ncer.  2 0 0 6; 4 6: 3 2 0 – 3 3 4. 
2 1 Lies k o vs k y  Y E,  D o nal ds o n  S S,  T orres  M A,  et  al.  Hi g h -d ose  t hera p y  a n d  a ut ol o g o us  
he mat o p oietic  ste m cell tra ns pla ntati o n f or rec urre nt or refract or y pe diatric  H o d g ki n’s disease: 
Res ults a n d pr o g n ostic i n dices. J Cli n O nc ol. 2 0 0 4; 2 2: 4 5 3 2 – 4 5 4 0. 
2 2 A k htar S, El Wes hi A, Ra hal M, et al. Hi g h -d ose c he m ot hera p y a n d a ut ol o g o us ste m cell 
tra ns pla nt  i n  a d olesce nt  patie nts  wit h  rela pse d  or  refract or y  H o d g ki n’s  l y m p h o ma.  B o ne  
Marr o w Tra ns pla nt. 2 0 1 0; 4 5: 4 7 6 – 4 8 2. 
2 3  M os k o witz C H,  Ya hal o m J, Zele netz  A D,  et al. Hi g h - d ose c he m o-ra di ot hera p y f or rela pse d or 
refract or y H o d g ki n l y m p h o ma a n d t he si g nifica nce of  pre-tra ns pla nt f u ncti o nal i ma gi n g. Br  J 
Hae mat ol. 2 0 1 0; 1 4 8: 8 9 0 – 8 9 7. 
2 4 M os k o witz  AJ,  Ya hal o m  J,  Ke walra ma ni  T,  et  al.  Pretra ns pla ntati o n  f u ncti o nal  i ma gi n g  
pre dicts o utc o me f oll o wi n g a ut ol o g o us ste m cell tra ns pla ntati o n f or rela pse d a n d refract or y 
H o d g ki n l y m p h o ma. Bl o o d. 2 0 1 0; 1 1 6: 4 9 3 4 – 4 9 3 7. 
2 5 Bier ma n PJ, Ba gi n R G, Ja ga n nat h S, et al. Hi g h d ose c he m ot hera p y f oll o we d b y a ut ol o g o us 
he mat o p oietic resc ue i n H o d g ki n's disease: l o n g -ter m f oll o w-u p i n 1 2 8 patie nts. A n n O nc ol. 
1 9 9 3; 4( 9): 7 6 7 -7 7 3.  
2 6 A n dre M, He nr y -A mar M, Pic o J -L, et al. C o m paris o n of hi g h -d ose t hera p y a n d a ut ol o g o us 
ste m-cell tra ns pla ntati o n wit h c o n ve nti o nal t hera p y f or H o d g ki n's disease i n d ucti o n fail ure:  a 
case-c o ntr ol st u d y. S ociete Fra ncaise  de Greffe  de M oelle.  J Cli n  O nc ol. 1 9 9 9; 1 7( 1): 2 2 2- 2 2 9. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
2 7 P o pat, U, H osi n g C, Sali ba R M, et al. Pr o g n ostic fact ors f or disease pr o gressi o n after hi g h - 
d ose c he m ot hera p y a n d a ut ol o g o us he mat o p oietic ste m cell tra ns pla ntati o n f or rec urre nt or 
refract or y H o d g ki n's l y m p h o ma. B o ne Marr o w Tra ns pla nt. 2 0 0 4; 3 3( 1 0): 1 0 1 5- 1 0 2 3. 
2 8 M os k o witz C H, Matasar  MJ, Zele netz A D, et al. N or malizati o n of pre -A S C T,  F D G -P E T 
i ma gi n g wit h sec o n d-li ne, n o n-cr oss-resista nt, c he m ot hera p y pr o gra ms i m pr o ves e ve nt-free 
s ur vi val i n patie nts wit h H o d g ki n l y m p h o ma. Bl o o d. 2 0 1 2; 1 1 9: 1 6 6 5- 7 0. 
2 9 M os k o witz,  C H,  Ni mer  S D,  Zele netz  A D,  et  al.  A  2 -ste p  c o m pre he nsi ve  hi g h- d ose 
c he m ora di ot hera p y sec o n d-li ne pr o gra m f or rela pse d a n d refract or y H o d g ki n disease:  a nal ysis 
b y i nte nt t o treat a n d de vel o p me nt of a pr o g n ostic m o del. Bl o o d. 2 0 0 1; 9 7( 3): 6 1 6- 6 2 3. 
3 0  H ort o n T M,  Drac ht ma n  R A,  C he n  L,  et al. A p hase II st u d y of b ortez o mi b  i n c o m bi nati o n wit h 
if osfa mi de/ vi n orel bi ne  i n  pe diatric  patie nts  a n d  y o u n g  a d ults  wit h  refract or y/rec urre nt  
H o d g ki n l y m p h o ma: a C hil dre n's O nc ol o g y Gr o u p st u d y. Br  J Hae mat ol.  2 0 1 5: 1 7 0( 1): 1 1 8- 2 2. 
3 1 S ha n kar A, Ha y war d J, Kir k w o o d A, et al. Treat me nt o utc o me i n c hil dre n a n d a d olesce nts 
wit h  rela pse d H o d g ki n l y m p h o ma - res ults of t he U K H D 3 rela pse treat me nt strate g y. Britis h 
J o ur nal of Hae mat ol o g y. 2 0 1 4; 1 6 5: 5 3 4- 5 4 4. 
3 2 St o ne ha m S, As hle y S, Pi n kert o n C R, et al. O utc o me after a ut ol o g o us he m o p oietic ste m cell 
tra ns pla ntati o n i n rela pse d or refract or y c hil d h o o d H o d g ki n disease.  J Pe diatr  He mat ol  O nc ol. 
2 0 0 4; 2 6: 7 4 0 -7 4 5.  
3 3 Sc hell o n g  G,  D orffel  W,  Cla viez  A,  et  al.  Sal va ge  t hera p y  of  pr o gressi ve  a n d  rec urre nt  
H o d g ki n’s disease: Res ults fr o m a m ultice nter st u d y of t he pe diatric D A L/ G P O H -H D st u d y 
gr o u p. J Cli n O nc ol. 2 0 0 5; 2 3: 6 1 8 1- 6 1 8 9. 
3 4 Si b o n D, Brice P. O pti mal treat me nt f or rela psi n g patie nts wit h H o d g ki n l y m p h o ma. E x pert 
Re v He mat ol. 2 0 0 9; 2( 3): 2 8 5- 9 5. 
3 5  G or de-Gr osjea n S, O berli n O, Le bla nc T, et al. O utc o me of c hil dre n a n d a d olesce nts wit h 
rec urre nt/refract or y classical H o d g ki n l y m p h o ma,  a st u d y fr o m t he S ociete  Fra ncaise  de L utte 
c o ntre le Ca ncer des E nfa nts et des A d olesce nts ( S F C E). Br J Hae mat ol. 2 0 1 2; 1 5 8: 6 4 9 – 6 5 6. 
3 6  M os k o witz, C H,  Na de ma nee  A,  Masszi  T,  et al. Bre nt u xi ma b  ve d oti n as c o ns oli dati o n t hera p y 
after a ut ol o g o us ste m -cell tra ns pla ntati o n i n patie nts wit h H o d g ki n's l y m p h o ma at ris k of 
rela pse or pr o gressi o n ( A E T H E R A): a ra n d o mise d, d o u ble- bli n d, place b o -c o ntr olle d, p hase 3 
trial. T he La ncet. 2 0 1 5; 3 8 5: 1 8 5 3- 1 8 6 2. 
3 7 Y o u nes A, G o pal A K, S mit h S E, et al. Res ults of a pi v otal p hase II st u d y of bre nt u xi ma b 
ve d oti n  f or  patie nts  wit h  rela pse d  or  refract or y  H o d g ki n’s  l y m p h o ma.  J  Cli n  O nc ol.  
2 0 1 2; 3 0( 1 8): 2 1 8 3 -9.  
3 8 M osc o witz AJ, Ha mli n P A Jr, Perales M A, et al. P hase II st u d y of be n da m usti ne i n rela pse d 
a n d refract or y H o d g ki n l y m p h o ma. J Cli n O nc ol. 2 0 1 3; 3 1( 4): 4 5 6- 6 0. 
3 9 La Casce A S, B ocie k G, Sa was A, et al. 3 9 8 2  Bre nt u xi ma b Ve d oti n Pl us Be n da m usti ne: A 
Hi g hl y Acti ve  Sal va ge Treat me nt  Re gi me n  f or Patie nts  wit h  Rela pse d  or Refract or y  H o d g ki n 
L y m p h o ma. 2 0 1 5 A merica n S ociet y of He mat ol o g y A n n ual Meeti n g. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
4 0 L o hri A, Bar nett M, Faire y R N, et al. O utc o me of treat me nt of first rela pse of H o d g ki n's 
disease after pri mar y c he m ot hera p y: i de ntificati o n of ris k fact ors fr o m t he Britis h C ol u m bia 
e x perie nce 1 9 7 0 t o 1 9 8 8. Bl o o d. 1 9 9 1; 7 7( 1 0): 2 2 9 2- 2 2 9 8. 
4 1 L o n g o  D L,  D uffe y  P L,  Y o u n g  R C,  et  al.  C o n ve nti o nal -d ose  sal va ge  c o m bi nati o n  
c he m ot hera p y i n patie nts rela psi n g wit h H o d g ki n's disease after c o m bi nati o n c he m ot hera p y: 
t he l o w pr o ba bilit y f or c ure. J Cli n O nc ol. 1 9 9 2; 1 0( 2): 2 1 0- 2 1 8. 
4 2 Fer me  C,  M o u nier N,  Di vi ne M,  et al. I nte nsi ve sal va ge t hera p y wit h  hi g h - d ose c he m ot hera p y 
f or patie nts wit h a d va nce d H o d g ki n's disease i n rela pse or fail ure after i nitial c he m ot hera p y: 
res ults  of  t he  Gr o u pe  d' Et u des  des  L y m p h o mes  de  l' A d ulte  H 8 9  Trial.  J  Cli n  O nc ol.  
2 0 0 2; 2 0( 2): 4 6 7 -4 7 5.  
4 3 Re vie we d  i n Har ker -M urra y  P D,  et al. Stratificati o n  of  treat me nt i nte nsit y i n rela pse d pe diatric 
H o d g ki n l y m p h o ma. Pe diatr Bl o o d Ca ncer. 2 0 1 4; 6 1: 5 7 9- 5 8 6. 
4 4 Sat wa nit  et al. A pr o g n ostic m o del  pre dicti n g  a ut ol o g o us tra ns pla ntati o n o utc o mes i n c hil dre n, 
a d olesce nts  a n d  y o u n g  a d ults  wit h  H o d g ki n  l y m p h o ma.  B o ne  Marr o w  Tra ns pla ntati o n.  
2 0 1 5; 5 0: 1 4 1 6 -1 4 2 3.  
4 5 Ni v ol u ma b  I n vesti gat or  Br oc h ure,  Versi o n  1 5.  Brist ol -M yers  S q ui b b  Researc h  a n d  
De vel o p me nt; 2 0 1 6. D oc u me nt C o ntr ol N o. 9 3 0 0 3 8 2 4 3. 
4 6  A D C E T RI S  [ pac ka ge i nsert]. B ot hell, W A:  Seattle  Ge netics;  2 0 1 6.  
4 7 Str u m ber g  D,  Harstric k  A,  D oll  K,  et  al.  Be n da m usti ne  h y dr oc hl ori de  acti vit y  a gai nst  
d o x or u bici n- resista nt h u ma n breast carci n o ma cell li nes. A ntica ncer Dr u gs. 1 9 9 6; 7: 4 1 5- 2 1. 
4 8 Le o ni L M, Baile y B, Reifert J, et al. Be n da m usti ne ( Trea n da) dis pla ys a disti nct patter n of 
c yt ot o xicit y a n d u ni q ue mec ha nistic feat ures c o m pare d wit h ot her al k ylati n g a ge nts. Cli n 
Ca ncer Res. 2 0 0 8; 1 4: 3 0 9 - 1 7. 
4 9  Trea n da [ pac ka ge  i nsert]. N ort h  Wales,  P A:  Ce p hal o n; 2 0 1 5.  
5 0 Le o ni L M. Be n da m usti ne: resc ue of a n effecti ve a nti ne o plastic a ge nt fr o m t he mi d -t we ntiet h 
ce nt ur y. Se mi n He mat ol. 2 0 1 1; 4 8: S 4- 1 1. 
5 1 O we n  J S,  Mel he m  M,  Passarell  J A,  et  al.  Be n da m usti ne  p har mac o ki netic  pr ofile  a n d  
e x p os ure –res p o nse relati o ns hi ps i n patie nts  wit h i n d ole nt n o n - H o d g ki n’s l y m p h o ma.  Ca ncer 
C he m ot her P har mac ol. 2 0 1 0; 6 6: 1 0 3 9 - 4 9. 
5 2 C orazzelli G, et al. Efficac y a n d safet y of be n da m usti ne f or t he treat me nt of patie nts wit h 
rec urri n g H o d g ki n l y m p h o ma. Br J Hae mat ol 2 0 1 3; 1 6 0( 2): 2 0 7- 1 5. 
5 3 M os k o witz AJ, Ha mli n P A Jr, Perales M -A, et al. P hase II st u d y  of be n da m usti ne i n rela pse d 
a n d refract or y H o d g ki n l y m p h o ma. J Cli n O nc ol. 2 0 1 3; 3 1( 4): 4 5 6- 4 6 0. 
5 4 Par d oll D. D oes t he i m m u ne s yste m see t u m ors as f orei g n or self? A n n u Re v I m m u n ol. 
2 0 0 3; 2 1: 8 0 7 -3 9.  
5 5 Zit v o gel L, Tes niere A, Kr oe mer G. Ca ncer des pite i m m u n os ur veilla nce: i m m u n oselecti o n 
a n d i m m u n os u b versi o n. Nat Re v I m m u n ol. 2 0 0 6; 6: 7 1 5- 2 7. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
5 6 D u n n G P, Br uce A T, I ke da H, et al. Ca ncer i m m u n oe diti n g: fr o m i m m u n os ur veilla nce t o 
t u m or esca pe. Nat I m m u n ol. 2 0 0 2; 3: 9 9 1- 8. 
5 7 Gree n wal d  RJ,  Free ma n  G H,  S har pe  A H.  T he  B 7  fa mil y  re visite d.  A n n u  Re v  I m m u n ol.  
2 0 0 4; 2 3: 5 1 5 -4 8.  
5 8 Free ma n FJ, L o n g AJ, I wai Y, et al. E n ga ge me nt of t he P D -1 i m m u n o hi bit or y rece pt or b y a 
n o vel B 7 fa mil y me m ber lea ds t o ne gati ve re g ulati o n of l y m p h oc yte acti vati o n. J E x p Me d 
2 0 0 0; 1 9 2( 7): 1 0 2 7- 3 4. 
5 9 S har pe A H, W herr y EJ, A h me d R, et al. T he f u ncti o n of pr o gra m me d cell deat h 1 a n d its 
li ga n ds i n re g ulati n g a ut oi m m u nit y a n d i nfecti o n. Nat ure I m m u n ol. 2 0 0 7; 8: 2 3 7- 4 5. 
6 0  W olc h o k J D, H o os A,  O’ Da y  S,  et al. G ui deli nes f or t he e val uati o n of i m m u ne t hera p y acti vit y 
i n s oli d t u m ors: i m m u ne-relate d res p o nse criteria. Cli n Ca ncer Res. 2 0 0 9; 1 5: 7 4 1 2- 2 0. 
6 1 A nsell  S M, Les o k hi n A M, B orrell o I, et al. P D -1 bl oc ka de wit h ni v ol u ma b i n rela pse d or 
refract or y H o d g ki n’s l y m p h o ma. N E n gl J Me d. 2 0 1 5; 3 7 2: 3 1 1- 3 1 9. 
6 2 Y o u nes A, Sa nt or o A, S hi p p M, et al. Ni v ol u ma b f or classical H o d g ki n’s l y m p h o ma after 
fail ure of b ot h a ut ol o g o us ste m-cell tra ns pla ntati o n a n d bre nt u xi ma b ve d oti n: a m ultice ntre, 
m ultic o h ort,
 si n gle -ar m
 p hase
 2
 trial.
 P u blis he d
 O nli ne
 2 0 -J ul- 2 0 1 6 
htt p:// d x. d oi. or g/ 1 0. 1 0 1 6/ S 1 4 7 0 -2 0 4 5( 1 6) 3 0 1 6 7 -X.  
6 3 Y o u nes A, G o pal A K, S mit h S E, et al. Res ults of a pi v otal p hase II st u d y of bre nt u xi ma b 
ve d oti n  f or  patie nts  wit h  rela pse d  or  refract or y  H o d g ki n’s  l y m p h o ma.  J  Cli n  O nc ol.  
2 0 1 2; 3 0: 2 1 8 3 -9.  
6 4 Ka hl  B S,  et  al.  Be n da m usti ne  is  effecti ve  t hera p y  i n  patie nts  wit h  rit u xi ma b -refract or y, 
i n d ole nt B-cell n o n-H o d g ki n l y m p h o ma: res ults fr o m a M ultice nter St u d y. Ca ncer. 2 0 1 0; 
1 1 6( 1): 1 0 6 -1 4.  
6 5 Frie d ber g  J W,  et  al.  Be n da m usti ne  i n  patie nts  wit h  rit u xi ma b -refract or y  i n d ole nt  a n d  
tra nsf or me d n o n- H o d g ki n's l y m p h o ma: res ults fr o m a p hase II m ultice nter,  si n gle-a ge nt st u d y. 
J Cli n O nc ol. 2 0 0 8; 2 6( 2): 2 0 4- 1 0. 
6 6 A nastasia  A,  et  al.  Be n da m usti ne  f or  H o d g ki n  l y m p h o ma  patie nts  faili n g  a ut ol o g o us  or  
a ut ol o g o us a n d all o ge neic ste m cell tra ns pla ntati o n: a retr os pecti ve st u d y of t he F o n dazi o ne 
Italia na Li nf o mi. Br J Hae mat ol. 2 0 1 4; 1 6 6( 1): 1 4 0- 2. 
6 7 G hes q uieres H, et al. Cli nical e x perie nce of be n da m usti ne i n rela pse d or refract or y H o d g ki n 
l y m p h o ma: a retr os pecti ve a nal ysis of t he Fre nc h c o m passi o nate use pr o gra m i n 2 8 patie nts. 
Le u k L y m p h o ma. 2 0 1 3. 
6 8 Els o uei di, R, M ulat A, M o ura d H. Be n da m usti ne treat me nt i n a hea vil y pretreate d H o d g ki n 
l y m p h o ma patie nt. J O nc ol P har m Pract. 2 0 1 4. 
6 9 Fraser C, et al. O pe n -la bel be n da m usti ne m o n ot hera p y f or pe diatric patie nts wit h rela pse d or 
refract or y ac ute le u ke mia:  efficac y a n d t olera bilit y. J Pe diatr He mat ol  O nc ol 2 0 1 4; 3 6( 4): 2 1 2- 
8.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
7 0 C hes o n B D, Fis her RI, Barri n gt o n S F, et al: Rec o m me n dati o ns f or i nitial  e val uati o n, sta gi n g, 
a n d res p o nse assess me nt  of H o d g ki n a n d n o n-H o d g ki n l y m p h o ma: t he  L u ga n o classificati o n. 
J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9- 6 8. 
7 1 Barri n gt o n  S F,  Mi k haeel  N G,  K osta k o gl u L,  et al: R ole  of i ma gi n g i n t he sta gi n g a n d res p o nse 
assess me nt  of  l y m p h o ma:  c o nse ns us  of  t he  I nter nati o nal  C o nfere nce  o n  Mali g na nt  
L y m p h o mas I ma gi n g W or ki n g Gr o u p. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 4 8- 5 8. 
7 2  Sc h wartz  et al. J Pe ds.  1 9 8 5; 1 0 6: 5 2 2.  
7 3  W olc h o k J D, H o os A,  O’ Da y  S,  et al. G ui deli nes f or t he e val uati o n of i m m u ne t hera p y acti vit y 
i n s oli d t u m ors: i m m u ne-relate d res p o nse criteria. Cli n Ca ncer Res. 2 0 0 9; 1 5: 7 4 1 2- 2 0. 
7 4 C hes o n B D et al, 2 0 1 6, Refi ne me nt of t he L u ga n o Classificati o n l y m p h o ma res p o nse criteria 
i n t he era of i m m u n o m o d ulat or y t hera p y. Bl o o d, 1 2 8( 2 1): 2 4 8 9- 2 4 9 6. 
7 5 Bi g gi A, Galla mi ni A, C ha u vie S, et al. I nter nati o nal vali dati o n st u d y f or i nteri m P E T i n 
A B V D -treate d, a d va nce d-sta ge h o d g ki n l y m p h o ma: i nter pretati o n criteria a n d c o nc or da nce 
rate a m o n g re vie wers. J N ucl Me d. 2 0 1 3; 5 4: 6 8 3- 9 0. 
7 6 Barri n gt o n S F, Qia n W, S o mer EJ, et al. C o nc or da nce bet wee n f o ur E ur o pea n ce ntres of P E T 
re p orti n g criteria desi g ne d f or use i n m ultice ntre  trials i n H o d g ki n l y m p h o ma. E ur  J N ucl Me d 
M ol I ma gi n g. 2 0 1 0; 3 7: 1 8 2 4 – 1 8 3 3. 
7 7  E ur o Q ol Gr o u p. E ur o Q ol --a ne w facilit y f or t he meas ure me nt  of  healt h -relate d q ualit y  of life. 
Healt h P olic y. 1 9 9 0; 1 6: 1 9 9 – 2 0 8. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
1 2  
A P P E N DI C E S  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
9 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  1 
A B B R E VI A TI O N S A N D T R A D E M A R K S  
 
Ter m  
Defi niti o n  
A D A  
a nti- dr u g a nti b o d y 
A E  
a d verse  e ve nt 
AI D S  
ac q uire d  i m m u n o deficie nc y s y n dr o me 
A L T  
ala ni ne a mi n otra nsferase  
A N C  
a bs ol ute ne utr o p hil c o u nt 
A S T  
as partate  a mi n otra nsferase 
BI C R  
bli n de d i n de pe n de nt ce ntral re vie w 
B M S  
Brist ol -M yers  S q ui b b  
B P  
bl o o d press ure  
B S A  
b o d y s urface area 
B v + B  
bre nt u xi ma b  ve d oti n pl us be n da m usti ne  
c H L 
classical  H o d g ki n’s l y m p h o ma 
C M R  
c o m plete meta b olic  res p o nse 
C M V  
c yt o me gal o vir us 
C O G  
C hil dre n’s  O nc ol o g y Gr o u p  
C O V -1 9  
C or o na vir us Disease  2 0 1 9  
C R F  
Case  Re p ort F or m,  pa per  or electr o nic 
C T  
c o m p ute d t o m o gra p h y 
DI LI  
dr u g-i n d uce d li ver i nj ur y 
D M C  
Data  M o nit ori n g C o m mittee  
D N A  
de o x yri b o n ucleic aci d 
D O R  
d urati o n of res p o nse 
E B V  
E pstei n -Barr  vir us  
E F S  
e ve nt-free s ur vi val 
E M A  
E ur o pea n Me dici nes  A ge nc y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D G -P E T  
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 F P E  
f or mali n-fi xe d paraffi n -e m be d de d 
FI  
f u ncti o nal i ma gi n g 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
Ter m  
Defi niti o n  
G- C S F  
gra n ul oc yte c ol o n y sti m ulati n g fact or 
H B V  
he patitis  B vir us  
H C V  
he patitis  C vir us  
H D C T/ A S C T  
hi g h- d ose c he m ot hera p y f oll o we d b y  a ut ol o g o us ste m cell tra ns pla nt 
HI V  
H u ma n  I m m u n o deficie nc y Vir us  
H L  
H o d g ki n’s L y m p h o ma  
H R  
heart rate 
I B 
I n vesti gat or Br oc h ure  
I C E 
if osfa mi de, car b o plati n, et o p osi de 
I C F 
I nf or me d C o nse nt F or m  
I E C 
I n de pe n de nt Et hics  C o m mittee  
I F R T 
i n v ol ve d fiel d ra diati o n t hera p y 
I H C 
i m m u n o hist oc he mistr y 
I M P 
i n vesti gati o nal me dici nal  pr o d ucts  
I P 
i n vesti gati o nal pr o d uct  
I R B 
i nstit uti o nal Re vie w  B oar d  
I R T 
I nteracti ve res p o nse tec h n ol o g y 
I S R T 
i n v ol ve d site ra diati o n t hera p y 
I V 
if osfa mi de wit h  vi n orel bi ne  
I V 
I ntra ve n o us 
I V R S 
i nteracti ve v oice  res p o nse s yste m 
L Di  
l o n gest dia meter  
L R  
l o w ris k 
M M A E  
m o n o met h yl a uristati n E 
M RI  
ma g netic res o na nce i ma gi n g 
N + B v  
ni v ol u ma b pl us bre nt u xi ma b ve d oti n  
N CI  
Nati o nal Ca ncer  I nstit ute 
N M R  
n o meta b olic  res p o nse 
O R R  
o verall res p o nse rate 
O S  
o verall s ur vi val 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
Ter m  
Defi niti o n  
P B M C  
peri p heral bl o o d m o n o n uclear cells 
P D  
pr o gra m me d deat h  
P D  
pr o gressi ve disease  
P F  
p h ysical e xa mi nati o n 
P F S  
pr o gressi o n- free s ur vi val 
P K  
p har mac o ki netics  
PI L  
Patie nt  I nf or mati o n Leaflet  
P M D  
pr o gressi ve meta b olic  diseases  
P M L  
pr o gressi ve m ultif ocal  le u k oe nce p hal o pat h y 
P M R  
partial  meta b olic  res p o nse 
P P K  
p o p ulati o n p har mac o ki netics  
P R  
partial  res p o nse 
P S  
perf or ma nce stat us 
R/ R  
rela psi n g/refract or y 
R R  
res pirati o n rate 
R T  
ra diati o n t hera p y 
S A E  
seri o us a d verse e ve nt 
S A R S -C o v - 2 
Se vere ac ute res pirat or y  s y n dr o me c or o na vir us 
S D  
sta ble disease  
S R  
sta n dar d ris k 
S S C  
St u d y Steeri n g  C o m mittee  
T A  
t u m or assess me nts 
T BI LI  
t otal bilir u bi n  
T B P  
treat me nt be y o n d pr o gressi o n  
T F T  
t h yr oi d f u ncti o n tests 
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  
U nite d States  
W O C B P  
w o me n  of c hil d beari n g p ote ntial  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  2 
S T U D Y  G O V E R A N C E  C O N SI D E R A TI O N S  
T he  ter m ‘ Partici pa nt’ is use d  i n t he pr ot oc ol t o refer t o a pers o n w h o  has c o nse nte d  t o partici pate 
i n t he cli nical researc h st u d y. T he  ter m ‘ S u bject’ use d  i n t he e C R F is i nte n de d t o refer t o a pers o n 
( Partici pa nt) w h o has c o nse nte d t o partici pate i n t he cli nical researc h st u d y. 
R E G U L A T O R Y  A N D  E T HI C A L  C O N SI D E R A TI O N S 
G O O D C LI NI C A L P R A C TI C E  
T his  st u d y will  be c o n d ucte d i n acc or da nce wit h:  
•  G o o d Cli nical  Practice  ( G C P), 
•  as defi ne d b y  t he I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) 
•  i n acc or da nce  wit h  t he et hical pri nci ples  u n derl yi n g E ur o pea n U ni o n Directi ve  2 0 0 1/ 2 0/ E C  
•  U nite d  States  C o de of Fe deral  Re g ulati o ns, Title  2 1,  Part  5 0 ( 2 1 C F R 5 0) 
•  a p plica ble l ocal re q uire me nts. 
 
T he st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol. T he pr ot oc ol  a n d a n y a me n d me nts 
a n d t he partici pa nt i nf or me d c o nse nt will recei ve a p pr o val/fa v ora ble o pi ni o n b y I nstit uti o nal 
Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (I R B/I E C),  a n d re g ulat or y a ut h orities acc or di n g t o 
a p plica ble l ocal re g ulati o ns pri or t o i nitiati o n of t he st u d y.  
All p ote ntial seri o us breac hes m ust be re p orte d t o S p o ns or or desi g nee i m me diatel y. A seri o us 
breac h is a breac h of t he c o n diti o ns a n d pri nci ples of G C P i n c o n necti o n wit h t he st u d y or t he 
pr ot oc ol, w hic h  is li kel y t o affect, t o a si g nifica nt de gree,  t he safet y or  p h ysical or me ntal  i nte grit y 
of t he s u bjects of t he st u d y or t he scie ntific val ue of t he st u d y.  
Pers o n nel  i n v ol ve d  i n  c o n d ucti n g  t his  st u d y  will  be  q ualifie d  b y  e d ucati o n,  trai ni n g,  a n d  
e x perie nce t o perf or m t heir res pecti ve tas ks.  
T his  st u d y will  n ot  use t he ser vices of st u d y pers o n nel w here  sa ncti o ns ha ve  bee n  i n v o ke d or w here 
t here has bee n scie ntific misc o n d uct or fra u d (e g, l oss of me dical lice ns ure, de bar me nt). 
I N S TI T U TI O N A L R E VI E W  B O A R D/I N D E P E N D E N T  E T HI C S  C O M MI T T E E  
Bef ore st u d y i nitiati o n, t he i n vesti gat or m ust ha ve writte n a n d date d a p pr o val/fa v ora ble o pi ni o n 
fr o m t he I R B/I E C f or t he pr ot oc ol,  c o nse nt f or m, partici pa nt  recr uit me nt materials 
(e g, a d vertise me nts),  a n d a n y ot her writte n  i nf or mati o n t o be  pr o vi de d t o s u bjects. T he  i n vesti gat or 
or B M S s h o ul d als o pr o vi de t he I R B/I E C wit h a c o p y of t he I n vesti gat or Br oc h ure or pr o d uct 
la beli n g i nf or mati o n t o be pr o vi de d t o s u bjects a n d a n y u p dates. 
T he  i n vesti gat or, S p o ns or or desi g nee s h o ul d pr o vi de t he I R B/I E C wit h  re p orts, u p dates a n d ot her 
i nf or mati o n (e g, e x pe dite d safet y re p orts, a me n d me nts, a n d a d mi nistrati ve letters) acc or di n g t o 
re g ulat or y re q uire me nts or i nstit uti o n pr oce d ures. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
C O M P LI A N C E  WI T H  T H E  P R O T O C O L  A N D  P R O T O C O L  R E VI SI O N S  
T he i n vesti gat or s h o ul d n ot i m ple me nt a n y de viati o n or c ha n ge t o t he pr ot oc ol wit h o ut pri or 
re vie w a n d d oc u me nte d a p pr o val/fa v ora ble o pi ni o n of a n a me n d me nt fr o m t he I R B/I E C (a n d if 
a p plica ble, als o b y l ocal healt h a ut h orit y) e xce pt w here necessar y t o eli mi nate a n i m me diate 
hazar d(s) t o st u d y s u bjects.  
If a de viati o n  or c ha n ge t o a pr ot oc ol is i m ple me nte d t o eli mi nate a n i m me diate hazar d(s)  pri or t o 
o btai ni n g rele va nt  a p pr o val/fa v ora ble o pi ni o n(s) t he de viati o n or c ha n ge will be s u b mitte d, as 
s o o n as p ossi ble t o: 
•  I R B/I E C f or 
•  Re g ulat or y A ut h orit y(ies),  if a p plica ble  b y l ocal re g ulati o ns ( per nati o nal re q uire me nts) 
 
D oc u me ntati o n  of  a p pr o val/fa v ora ble  o pi ni o n  si g ne d  b y  t he  c hair pers o n  or  desi g nee  of  t he  
I R B(s)/I E C(s) a n d if a p plica ble, als o b y l ocal healt h a ut h orit y m ust be se nt t o B M S. 
If  a n  a me n d me nt  s u bsta ntiall y  alters  t he  st u d y  desi g n  or  i ncreases  t he  p ote ntial  ris k  t o  t he  
partici pa nt: ( 1) t he c o nse nt f or m m ust be re vise d a n d s u b mitte d t o t he I R B(s)/I E C(s) f or re vie w 
a n d a p pr o val/fa v ora ble o pi ni o n; ( 2) t he re vise d f or m m ust be use d  t o o btai n c o nse nt fr o m s u bjects 
c urre ntl y e nr olle d i n t he st u d y if t he y are affecte d b y t he a me n d me nt; a n d ( 3) t he ne w f or m m ust 
be use d t o o btai n c o nse nt fr o m ne w s u bjects pri or t o e nr oll me nt.  
If t he re visi o n is d o ne via a n  a d mi nistrati ve letter, i n vesti gat ors  m ust i nf or m t heir I R B(s)/I E C(s). 
FI N A N CI A L  DI S C L O S U R E  
I n vesti gat ors a n d s u b-I 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 i n acc or da nce wit h l ocal re g ulati o ns 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 ure  state me nts  t o  t he  a p pr o priate  healt h  a ut h orities.  
I n vesti gat ors are res p o nsi ble f or pr o vi di n g i nf or 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. 
I N F O R M E D C O N S E N T  P R O C E S S  
I n vesti gat ors m ust e ns ure t hat s u bjects are clearl y a n d f ull y i nf or me d a b o ut t he p ur p ose, p ote ntial 
ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he y v ol u nteer t o partici pate. 
I n sit uati o ns w here c o nse nt ca n n ot be gi ve n t o s u bjects, t heir le gall y acce pta ble re prese ntati ves 
(as per c o u ntr y g ui deli nes) are clearl y a n d f ull y i nf or me d a b o ut t he p ur p ose, p ote ntial ris ks, a n d 
ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he partici pa nt v ol u nteers t o partici pate.  
S p o ns or or desi g nee  will  pr o vi de t he i n vesti gat or wit h  a n a p pr o priate (ie, Gl o bal or L ocal)  sa m ple 
i nf or me d c o nse nt f or m w hic h will i ncl u de all ele me nts re q uire d b y I C H, G C P a n d a p plica ble 
re g ulat or y re q uire me nts. T he sa m ple i nf or me d c o nse nt f or m will a d here t o t he et hical pri nci ples 
t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
I n vesti gat ors m ust:  
•  Pr o vi de a c o p y  of t he c o nse nt f or m a n d writte n  i nf or mati o n a b o ut t he st u d y i n t he la n g ua ge i n 
w hic h  t he partici pa nt  is m ost pr oficie nt  pri or t o cli nical st u d y partici pati o n.  T he  la n g ua ge m ust 
be n o n-tec h nical a n d easil y u n derst o o d. 
•  All o w  ti me  necessar y  f or  partici pa nt  or  partici pa nt's  le gall y  acce pta ble  re prese ntati ve  t o  
i n q uire a b o ut t he details of t he st u d y. 
•  O btai n  a n i nf or me d c o nse nt si g ne d a n d pers o nall y date d  b y t he partici pa nt or t he partici pa nt's 
le gall y acce pta ble re prese ntati ve a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt 
disc ussi o n.  
•  O btai n  t he I R B/I E C’s writte n  a p pr o val/fa v ora ble o pi ni o n of t he writte n  i nf or me d c o nse nt f or m 
a n d a n y ot her i nf or mati o n t o be pr o vi de d t o t he s u bjects, pri or t o t he be gi n ni n g of  t he st u d y, 
a n d after a n y re visi o ns are c o m plete d f or ne w i nf or mati o n.  
 
If i nf or me d c o nse nt is i nitiall y gi ve n b y a partici pa nt’s le gall y acce pta ble re prese ntati ve or le gal 
g uar dia n, a n d t he partici pa nt s u bse q ue ntl y bec o mes  ca pa ble of ma ki n g  a n d c o m m u nicati n g his  or 
her i nf or me d c o nse nt d uri n g t he st u d y, c o nse nt m ust  a d diti o nall y be o btai ne d fr o m t he partici pa nt.  
Re vise  t he  i nf or me d c o nse nt  w he ne ver  i m p orta nt  ne w i nf or mati o n bec o mes a vaila ble t hat is 
rele va nt t o t he partici pa nt's c o nse nt. T he i n vesti gat or, or a pers o n desi g nate d b y t he i n vesti gat or, 
s h o ul d f ull y i nf or m t he partici pa nt or t he partici pa nt's le gall y acce pta ble re prese ntati ve or le gal 
g uar dia n,  of  all  perti ne nt  as pects  of  t he  st u d y  a n d  of  a n y  ne w  i nf or mati o n  rele va nt  t o  t he  
partici pa nt's willi n g ness t o c o nti n ue partici pati o n i n t he st u d y. T his c o m m u nicati o n s h o ul d be 
d oc u me nte d.  
T he  c o nfi de ntialit y  of  rec or ds t hat c o ul d i de ntif y s u bjects m ust  be pr otecte d, res pecti n g t he pri vac y 
a n d c o nfi de ntialit y  r ules a p plica ble t o re g ulat or y re q uire me nts, t he s u bjects' si g ne d I C F a n d, i n t he 
U S, t he s u bjects’ si g ne d HI P A A A ut h orizati o n.  
T he c o nse nt f or m m ust als o i ncl u de a state me nt t hat B M S a n d re g ulat or y  a ut h orities ha ve direct 
access t o partici pa nt rec or ds.  
F or  mi n ors,  acc or di n g  t o l ocal le gislati o n, o ne or b ot h pare nts or a le gall y acce pta ble  re prese ntati ve 
m ust be i nf or me d of t he st u d y  pr oce d ures a n d m ust si g n t he i nf or me d c o nse nt f or m  a p pr o ve d f or 
t he st u d y pri or t o cli nical st u d y partici pati o n. T he e x plicit wis h of a mi n or, w h o is ca pa ble of 
f or mi n g a n o pi ni o n a n d assessi n g t his i nf or mati o n t o ref use partici pati o n i n, or t o be wit h dra w n 
fr o m, t he cli nical st u d y at a n y ti me s h o ul d be c o nsi dere d b y t he i n vesti gat or. 
Mi n ors w h o  are j u d ge d t o be of a n a ge of reas o n m ust als o gi ve t heir writte n  asse nt. 
S u bjects u na ble t o gi ve t heir writte n  c o nse nt (e g, str o ke or  s u bjects wit h  or se vere de me ntia) ma y 
o nl y be e nr olle d i n t he st u d y wit h  t he c o nse nt of a le gall y acce pta ble  re prese ntati ve. T he  partici pa nt 
m ust als o be i nf or me d a b o ut t he nat ure of t he st u d y t o t he e xte nt c o m pati ble wit h his or her 
u n dersta n di n g, a n d s h o ul d t his partici pa nt bec o me ca pa ble, he or s he s h o ul d pers o nall y si g n a n d 
date t he  c o nse nt  f or m as s o o n as p ossi ble. T he  e x plicit wis h  of a partici pa nt  w h o  is u na ble t o gi ve 
his or her writte n  c o nse nt, b ut w h o  is ca pa ble of  f or mi n g a n o pi ni o n a n d assessi n g  i nf or mati o n t o 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
ref use partici pati o n  i n, or t o be wit h dra w n  fr o m, t he cli nical st u d y at a n y ti me s h o ul d be c o nsi dere d 
b y t he i n vesti gat or. 
T he ri g hts,  safet y, a n d well - bei n g of t he st u d y s u bjects are t he m ost  i m p orta nt c o nsi derati o ns a n d 
s h o ul d pre vail o ver i nterests of scie nce a n d s ociet y. 
S O U R C E D O C U M E N T S  
T he  I n vesti gat or  is  res p o nsi ble  f or  e ns uri n g  t hat  t he  s o urce  data  are  acc urate,  le gi ble,  
c o nte m p ora ne o us, ori gi nal a n d attri b uta ble, w het her t he data  are ha n d-writte n  o n pa per  or e ntere d 
electr o nicall y.  If s o urce data are create d (first e ntere d), m o difie d, mai ntai ne d, arc hi ve d, retrie ve d, 
or  tra ns mitte d  electr o nicall y  via  c o m p uterize d  s yste ms  (a n d/ or  a n y  ot her  ki n d  of  electr o nic  
de vices) as part of re g ulate d cli nical trial acti vities, s uc h s yste ms m ust be c o m plia nt wit h all 
a p plica ble la ws a n d re g ulati o ns g o ver ni n g use of electr o nic rec or ds a n d/ or electr o nic si g nat ures. 
S uc h  s yste ms ma y  i ncl u de, b ut are n ot li mite d t o, electr o nic  me dical/ healt h  rec or ds ( E M Rs/ E H Rs), 
a d verse  e ve nt  trac ki n g/re p orti n g,  pr ot oc ol  re q uire d  assess me nts,  a n d/ or  dr u g  acc o u nta bilit y  
rec or ds). 
W he n  pa per rec or ds fr o m s uc h s yste ms are use d  i n place  of  electr o nic  f or mat t o perf or m  re g ulate d 
acti vities, s uc h pa per rec or ds s h o ul d be certifie d c o pies. A certifie d c o p y c o nsists of a c o p y of 
ori gi nal i nf or mati o n t hat has bee n verifie d, as i n dicate d b y a date d si g nat ure, as a n e xact c o p y 
ha vi n g all of t he sa me attri b utes a n d i nf or mati o n as t he ori gi nal. 
S T U D Y  T R E A T M E N T  R E C O R D S  
Rec or ds f or st u d y treat me nts ( w het her s u p plie d b y  B M S,  its ve n d ors, or  t he site) m ust s u bsta ntiate 
st u d y treat me nt i nte grit y a n d tracea bilit y fr o m recei pt, pre parati o n, a d mi nistrati o n, a n d t hr o u g h 
destr ucti o n or ret ur n. Rec or ds m ust be ma de  a vaila ble f or re vie w at t he re q uest of B M S/ desi g nee 
or a Healt h A ut h orit y. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
If 
T he n  
S u p plie d b y B M S ( or its ve n d ors):  
Rec or ds or l o gs m ust c o m pl y wit h a p plica ble 
re g ulati o ns a n d g ui deli nes a n d s h o ul d i ncl u de: 
•  a m o u nt recei ve d a n d place d  i n st ora ge 
area 
•  a m o u nt c urre ntl y i n st ora ge area 
•  la bel i de ntificati o n n u m ber or batc h 
n u m ber  
•  a m o u nt dis pe nse d  t o a n d ret ur ne d b y eac h 
partici pa nt, i ncl u di n g u ni q ue partici pa nt 
i de ntifiers 
•  a m o u nt tra nsferre d t o a n ot her area/site f or 
dis pe nsi n g or st ora ge 
•  n o nst u d y dis p ositi o n (e g, l ost, waste d)  
•  a m o u nt destr o ye d at st u d y site, if 
a p plica ble 
•  a m o u nt ret ur ne d t o B M S  
•  retai n sa m ples f or 
bi oa vaila bilit y/ bi oe q ui vale nce, if 
a p plica ble 
•  dates  a n d i nitials of pers o n  res p o nsi ble f or 
I n vesti gati o nal Pr o d uct 
dis pe nsi n g/acc o u nta bilit y, as per t he 
Dele gati o n of A ut h orit y F or m. 
S o urce d b y site, a n d n ot s u p plie d b y B M S or 
its ve n d ors (e xa m ples i ncl u de I P s o urce d fr o m 
t he  sites  st oc k  or  c o m mercial  s u p pl y,  or  a  
s pecialt y p har mac y) 
T he
 i n vesti gat or
 or
 desi g nee
 acce pts
 
res p o nsi bilit y f or d oc u me nti n g tracea bilit y a n d 
st u d y  dr u g  i nte grit y  i n  acc or da nce  wit h  
re q uire me nts  a p plica ble  u n der  la w  a n d  t he  
S O Ps/sta n dar ds of t he s o urci n g p har mac y. 
T hese  rec or ds s h o ul d i ncl u de: 
•  la bel i de ntificati o n n u m ber or batc h 
n u m ber  
•  a m o u nt dis pe nse d  t o a n d ret ur ne d b y eac h 
partici pa nt, i ncl u di n g u ni q ue partici pa nt 
i de ntifiers 
•  dates  a n d i nitials of pers o n  res p o nsi ble f or 
I n vesti gati o nal Pr o d uct 
dis pe nsi n g/acc o u nta bilit y, as per t he 
Dele gati o n of A ut h orit y F or m. 
B M S  or  desi g nee  will  pr o vi de  f or ms t o facilitate i n ve nt or y c o ntr ol if t he i n vesti gati o nal site d oes  n ot  ha ve  a n 
esta blis he d s yste m t hat meets t hese re q uire me nts.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
C A S E  R E P O R T  F O R M S  
A n i n vesti gat or  is re q uire d t o pre pare a n d mai ntai n  a de q uate a n d acc urate  case hist ories  desi g ne d 
t o rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he i n vesti gati o n o n eac h i n di vi d ual treate d 
or e ntere d as a c o ntr ol i n t he i n vesti gati o n. Data t hat are deri ve d fr o m s o urce d oc u me nts a n d 
re p orte d o n t he C R F m ust be c o nsiste nt wit h t he s o urce d oc u me nts or  t he discre pa ncies m ust be 
e x plai ne d. A d diti o nal cli nical i nf or mati o n ma y be c ollecte d a n d a nal yze d i n a n eff ort  t o e n ha nce 
u n dersta n di n g of pr o d uct safet y. C R Fs ma y be re q ueste d f or A Es  a n d/ or la b orat or y a b n or malities 
t hat are re p orte d or i de ntifie d d uri n g t he c o urse of t he st u d y. 
F or sites usi n g t he S p o ns or or desi g nee electr o nic data ca pt ure t o ol, electr o nic C R Fs will be 
pre pare d  f or all data  c ollecti o n fiel ds e xce pt f or fiel ds s pecific t o S A Es  a n d pre g na nc y, w hic h  will 
be  re p orte d  o n  t he  electr o nic  S A E  f or m  a n d  Pre g na nc y  S ur veilla nce  f or m,  res pecti vel y.  If  
electr o nic S A E f or m is n ot a vaila ble, a pa per S A E f or m ca n be use d. S paces ma y be left bla n k 
o nl y i n t h ose circ u msta nces per mitte d b y st u d y -s pecific C R F c o m pleti o n g ui deli nes pr o vi de d b y 
S p o ns or or desi g nee. 
T he  c o nfi de ntialit y  of  rec or ds t hat c o ul d i de ntif y s u bjects m ust  be pr otecte d, res pecti n g t he pri vac y 
a n d c o nfi de ntialit y r ules i n acc or da nce wit h t he a p plica ble re g ulat or y re q uire me nt(s).  
T he i n vesti gat or  will mai ntai n  a si g nat ure s heet t o d oc u me nt si g nat ures a n d i nitials of  all pers o ns 
a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n C R Fs. 
T he  c o m plete d  C R F,  S A E/ pre g na nc y C R Fs,  m ust be pr o m ptl y  re vie we d, si g ne d, a n d date d  b y t he 
i n vesti gat or or q ualifie d p h ysicia n w h o is a s u bi n vesti gat or a n d w h o is dele gate d t his tas k o n t he 
Dele gati o n of  A ut h orit y  F or m.  S u bi n vesti gat ors i n Ja pa n ma y  n ot be dele gate d  t he C R F  a p pr o val 
tas k f or electr o nic C R Fs, re vie w a n d a p pr o val/si g nat ure is c o m plete d electr o nicall y t hr o u g h t he 
B M S electr o nic data ca pt ure t o ol. T he i n vesti gat or m ust retai n a c o p y of t he C R Fs i ncl u di n g 
rec or ds of t he c ha n ges a n d c orrecti o ns. 
Eac h i n di vi d ual electr o nicall y si g ni n g electr o nic C R Fs m ust meet S p o ns or or desi g nee trai ni n g 
re q uire me nts a n d m ust o nl y access t he B M S electr o nic data ca pt ure t o ol usi n g t he u ni q ue user 
acc o u nt pr o vi de d b y S p o ns or or desi g nee. User  acc o u nts are n ot t o be s hare d or reassi g ne d t o ot her 
i n di vi d uals 
M O NI T O RI N G  
M o nit ori n g  details  descri bi n g  strate g y,  i ncl u di n g  defi niti o n  of  st u d y  critical  data  ite ms  a n d  
pr ocesses  (e g,  ris k -base d  i nitiati ves  i n  o perati o ns  a n d  q ualit y  s uc h  as  ris k  ma na ge me nt  a n d  
miti gati o n  strate gies  a n d  a nal ytical  ris k -base d  m o nit ori n g),  met h o ds,  res p o nsi bilities,  a n d  
re q uire me nts,  i ncl u di n g  ha n dli n g  of  n o nc o m plia nce iss ues  a n d m o nit ori n g   tec h ni q ues 
(ce ntral, re m ote, or o n-site m o nit ori n g) are pr o vi de d i n t he m o nit ori n g pla n. 
Re prese ntati ves  of B M S  m ust be all o we d t o visit  all st u d y site l ocati o ns peri o dicall y t o assess t he 
data q ualit y a n d st u d y i nte grit y. O n  site t he y will  re vie w st u d y rec or ds a n d directl y  c o m pare t he m 
wit h  s o urce d oc u me nts, disc uss t he c o n d uct of t he st u d y wit h t he i n vesti gat or, a n d verif y t hat t he 
facilities re mai n acce pta ble. Certai n C R F pa ges a n d/ or electr o nic files ma y ser ve as t he s o urce 
d oc u me nts:  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
I n a d diti o n, t he st u d y ma y be e val uate d b y S p o ns or or desi g nee i nter nal  a u dit ors a n d g o ver n me nt 
i ns pect ors w h o m ust be all o we d access t o C R Fs, s o urce d oc u me nts, ot her st u d y files, a n d st u d y 
facilities. B M S a u dit re p orts will be ke pt c o nfi de ntial. 
T he i n vesti gat or  m ust  n otif y  B M S  pr o m ptl y  of  a n y i ns pecti o ns sc he d ule d b y re g ulat or y  a ut h orities, 
a n d pr o m ptl y f or war d c o pies of i ns pecti o n re p orts t o S p o ns or or desi g nee. 
R E C O R D S R E T E N TI O N  
T he i n vesti gat or m ust retai n all st u d y rec or ds a n d s o urce d oc u me nts f or t he ma xi m u m peri o d 
re q uire d b y a p plica ble re g ulati o ns a n d g ui deli nes, or i nstit uti o n pr oce d ures, or f or t he peri o d 
s pecifie d b y B M S or desi g nee, w hic he ver is l o n ger. T he i n vesti gat or m ust c o ntact B M S pri or t o 
destr o yi n g a n y rec or ds ass ociate d wit h t he st u d y. 
B M S  or desi g nee will  n otif y  t he i n vesti gat or w he n  t he st u d y rec or ds are n o  l o n ger nee de d.  
If t he i n vesti gat or wit h dra ws fr o m t he st u d y (e g, rel ocati o n, retire me nt), t he rec or ds s hall be 
tra nsferre d t o a m ut uall y a gree d u p o n desi g nee (e g, a n ot her i n vesti gat or, st u d y site, I R B). N otice 
of s uc h tra nsfer will be gi ve n i n writi n g t o B M S or desi g nee. 
R E T U R N  O F  S T U D Y  T R E A T M E N T  
F or t his st u d y, st u d y  treat me nts (t h ose s u p plie d b y  B M S,  a ve n d or  or s o urce d b y t he i n vesti gat or) 
s uc h as partiall y use d st u d y treat me nt c o ntai ners, vials a n d s yri n ges ma y be destr o ye d o n site. 
 
If.. 
T he n  
St u d y  treat me nts s u p plie d b y B M S (i ncl u di n g 
its ve n d ors 
A n y  u n use d  st u d y treat me nts s u p plie d b y  B M S 
ca n o nl y  be  destr o ye d  after bei n g i ns pecte d  a n d 
rec o ncile d b y t he res p o nsi ble St u d y M o nit or 
u nless  st u d y  treat me nts  c o ntai ners  m ust  be  
i m me diatel y destr o ye d as re q uire d f or safet y, 
or t o meet l ocal re g ulati o ns (e g, c yt ot o xics or 
bi ol o gics).  
If st u d y treat me nts will be ret ur ne d, t he ret ur n 
will  be  arra n ge d  b y  t he  res p o nsi ble  St u d y  
M o nit or.  
St u d y  treat me nts s o urce d b y site, n ot s u p plie d 
b y  B M S  ( or  its  ve n d ors)  (e xa m ples  i ncl u de  
st u d y treat me nts s o urce d fr o m t he sites st oc k 
or  c o m mercial  s u p pl y,  or  a  s pecialt y  
p har mac y)  
It
 is
 t he
 i n vesti gat or’s
 or
 desi g nee’s
 
res p o nsi bilit y  t o  dis p ose  of  all  c o ntai ners  
acc or di n g  t o  t he  i nstit uti o nal  g ui deli nes  a n d  
pr oce d ures.  
 
It is t he i n vesti gat or’s or desi g nee’s res p o nsi bilit y t o arra n ge f or dis p osal, pr o vi de d t hat pr oce d ures 
f or  pr o per  dis p osal  ha ve bee n  esta blis he d   acc or di n g t o  a p plica ble fe deral, state, l ocal,  a n d 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 0 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d pr o vi de d t hat a p pr o priate  rec or ds of dis p osal are ke pt. 
T he f oll o wi n g mi ni mal sta n dar ds m ust be met:  
•  O n -site dis p osal practices  m ust n ot e x p ose h u ma ns t o ris ks fr o m t he dr u g.  
•  O n -site  dis p osal  practices  a n d  pr oce d ures  are  i n  a gree me nt  wit h  a p plica ble  la ws  a n d  
re g ulati o ns, i ncl u di n g a n y s pecial re q uire me nts f or c o ntr olle d or hazar d o us s u bsta nces. 
•  Writte n pr oce d ures f or o n -site dis p osal are a vaila ble a n d f oll o we d. T he pr oce d ures m ust be 
file d wit h t he site’s S O Ps a n d a c o p y pr o vi de d t o B M S u p o n re q uest. 
•  Rec or ds  are  mai ntai ne d  t hat  all o w  f or  tracea bilit y  of  eac h  c o ntai ner,  i ncl u di n g  t he  date  
dis p ose d of, q ua ntit y  dis p ose d, a n d i de ntificati o n of  t he pers o n dis p osi n g t he c o ntai ners. T he 
met h o d of  dis p osal, ie, i nci nerat or, lice nse d sa nitar y la n dfill, or lice nse d waste  dis p osal  ve n d or 
m ust be d oc u me nte d. 
•  Acc o u nta bilit y a n d dis p osal rec or ds are c o m plete, u p-t o-date,  a n d a vaila ble f or t he M o nit or t o 
re vie w t hr o u g h o ut t he cli nical trial peri o d. 
 
It is t he i n vesti gat or’s or desi g nee’s res p o nsi bilit y t o arra n ge f or dis p osal of  all e m pt y c o ntai ners. 
If c o n diti o ns f or destr ucti o n ca n n ot be met  t he res p o nsi ble St u d y  M o nit or will  ma ke arra n ge me nts 
f or ret ur n of st u d y treat me nts pr o vi de d b y B M S ( or its ve n d ors). Destr ucti o n of n o n-  st u d y 
treat me nts s o urce d b y t he site, n ot s u p plie d b y B M S,  is s olel y t he res p o nsi bilit y of t he i n vesti gat or 
or desi g nee. 
C LI NI C A L  S T U D Y  R E P O R T  A N D  P U B LI C A TI O N S  
F or  t his pr ot oc ol, t he Si g nat or y  I n vesti gat or will  be  selecte d as a p pr o priate base d  o n t he f oll o wi n g 
criteria: 
•  E xter nal Pri nci pal I n vesti gat or desi g nate d  at pr ot oc ol de vel o p me nt  
•  Nati o nal C o or di nati n g I n vesti gat or 
•  St u d y Steeri n g  C o m mittee  c hair or  t heir desi g nee  
•  Partici pa nt  recr uit me nt (e g, a m o n g t he t o p q uartile  of e nr ollers) 
•  I n v ol ve me nt i n trial desi g n  
•  Re gi o nal re prese ntati o n (e g, a m o n g t o p q uartile  of e nr ollers  fr o m a s pecifie d re gi o n or c o u ntr y) 
•  O t her criteria (as deter mi ne d  b y t he st u d y tea m) 
 
T he data c ollecte d d uri n g t his st u d y  are c o nfi de ntial a n d pr o prietar y  t o S p o ns or or desi g nee. A n y 
p u blicati o ns or a bstracts arisi n g fr o m t his st u d y m ust a d here t o t he p u blicati o n re q uire me nts set 
f ort h i n t he cli nical trial a gree me nt ( C T A) g o ver ni n g [ St u d y site or I n vesti gat or] partici pati o n i n 
t he st u d y. T hese re q uire me nts i ncl u de, b ut are n ot  li mite d t o, s u b mitti n g pr o p ose d p u blicati o ns t o 
S p o ns or  or  desi g nee  at  t he  earliest  practica ble  ti me  pri or  t o  s u b missi o n  or  prese ntati o n  a n d  
ot her wise wit hi n t he ti me peri o d set f ort h i n t he C T A.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X 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: 
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  
A D V E R S E E V E N T S  
 
A d verse E ve nt Defi niti o n:  
A n A d verse E ve nt ( A E) is defi ne d as a n y ne w u nt o war d me dical  occ urre nce or w orse ni n g of a 
pree xisti n g  me dical  c o n diti o n i n a cli nical i n vesti gati o n partici pa nt a d mi nistere d  st u d y dr u g a n d 
t hat d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his treat me nt. 
A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (s uc h as a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of st u d y dr u g, w het her or n ot 
c o nsi dere d relate d t o t he st u d y dr u g. 
 
S E RI O U S  A D V E R S E  E V E N T S  
 
Seri o us A d verse E ve nt ( S A E) is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y 
d ose:  
Res ults  i n deat h  
Is life-t hreate ni n g ( defi ne d as a n e ve nt i n w hic h t he partici 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)  
Re q uires  i n patie nt h os pitalizati o n  or  ca uses pr ol o n gati o n  of  e xisti n g h os pitalizati o n  (see N O T E 
bel o w)  
N O T E:  
T he  f oll o wi n g h os pitalizati o ns are n ot  c o nsi dere d S A Es  i n B M S  cli nical st u dies: 
o  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 < 2 4 h o urs, t hat d oes 
n ot  res 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) 
o  electi ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt 
o  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  
o  r o uti ne healt h assess me nt re 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) 
o  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 
o  a d missi o n e nc o u ntere 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 re q uires 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, care gi ver res pite, fa mil y circ u msta nces, a d mi nistrati ve 
reas o n) 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
o  a d missi o n f or a d mi nistrati o n of a ntica ncer t hera p y i n t he a bse nce of a n y ot her 
S A Es (a p plies t o o nc ol o g y pr ot oc ols) 
Res ults  i n persiste nt  or  si g nifica nt disa bilit y/i nca pacit y  
Is a c o n ge nital  a n o mal y/ birt h  defect  
is a n i m p orta nt me dical e ve nt ( defi ne d as a me dical e ve nt(s) t hat ma y n ot  be i m me diatel y life - 
t hreate ni n g  or  res ult  i n  deat h  or  h os pitalizati o n  b ut,  base d  u p o n  a p pr o priate  me dical  a n d  
scie ntific j u d g me nt, ma y je o par dize t he partici pa nt or ma y re q uire i nter ve nti o n [e g, me dical, 
s ur gical] t o pre ve nt o ne of t he ot her seri o us o utc o mes liste d i n t he defi niti o n  a b o ve.) E xa m ples 
of s uc h e ve nts i ncl u de, b ut are n ot li mite d t o, 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  res ult  i n  
h os pitalizati o n.) P ote ntial dr u g i n d uce d li ver i nj ur y ( DI LI) is als o c o nsi dere d a n i m p orta nt 
me dical e ve nt. ( See Secti o n 8. 1. 1  f or t he defi niti o n of p ote ntial DI LI.) 
 
S us pecte d tra ns missi o n of a n i nfecti o us a ge nt (e g, pat h o ge nic or n o n pat h o ge nic) via t he st u d y 
treat me nt is a n S A E. 
Alt h o u g h pre g na nc y, o ver d ose, ca ncer, a n d p ote ntial dr u g i n d uce d li ver i nj ur y ( DI LI) are n ot 
al wa ys seri o us b y re g ulat or y defi niti o n, t hese e ve nts m ust  be ha n dle d as S A Es.  ( See Secti o n  9. 2. 5 
f or re p orti n g pre g na ncies). 
A n y  c o m p o ne nt of a st u d y e n d p oi nt t hat is  c o nsi dere d relate d t o st u d y t hera p y s h o ul d be re p orte d 
as S A E (e g, deat h is a n e n d p oi nt, if deat h occ urre d d ue t o a na p h yla xis, a na p h yla xis m ust be 
re p orte d). 
E V A L U A TI N G  A E S  A N D  S A E S  
 
Assess me nt  of  C a us alit y  
T he  ca usal  relati o ns hi p t o st u d y dr u g  is deter mi ne d  b y  a p h ysicia n  a n d s h o ul d be  use d  t o assess 
all a d verse e ve nts ( A E). T he ca usal relati o ns hi p ca n be o ne of t he f oll o wi n g:  
Relate d:  T here  is a reas o na ble ca usal relati o ns hi p bet wee n  st u d y dr u g a d mi nistrati o n  a n d 
t he A E. 
N ot  relate d: T here  is  n ot  a reas o na ble ca usal relati o ns hi p bet wee n   st u d y  dr u g 
a d mi nistrati o n a n d t he A E. 
T he  ter m "reas o na ble ca usal   relati o ns hi p" mea ns  t here is  e vi de nce t o  s u g gest  a ca usal 
relati o ns hi p. 
 
F oll o w -u p  of  A Es  a n d  S A Es  
If o nl y  li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w-u p  re p orts are re q uire d. 
( N ote: F oll o w-u p S A E re p orts m ust i ncl u de t he sa me i n vesti gat or ter m(s) i nitiall y re p orte d.)  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
If a n o n g oi n g S A E c ha n ges i n its i nte nsit y or relati o ns hi p t o st u d y dr u g or if ne w i nf or mati o n 
bec o mes a vaila ble, t he S A E re p ort m ust  be u p date d a n d s u b mitte d wit hi n 2 4  h o urs t o  B M S  
( or desi g nee) usi n g t he sa me pr oce d ure use d f or tra ns mitti n g t he i nitial S A E re p ort. 
All  S A Es  m ust be f oll o we d t o res ol uti o n or sta bilizati o n. 
 
R E P O R TI N G  O F  S A E S  T O  S P O N S O R  O R  D E SI G N E E  
 
•  S A Es,  w het her  relate d or  n ot  relate d t o st u d y dr u g,  a n d pre g na ncies  m ust  be  re p orte d t o B M S 
( or desi g nee) wit hi n 2 4 h o urs of a ware ness of t he e ve nt. 
•  S A Es  m ust be rec or de d o n t he S A E  Re p ort F or m;  pre g na ncies o n a Pre g na nc y  S ur veilla nce 
F or m (electr o nic or pa per f or ms).  
•  T he  preferre d  met h o d f or S A E  data re p orti n g c ollecti o n is t hr o u g h t he e C R F. 
•  T he pa per S A E/ pre g na nc y s ur veilla nce f or ms are o nl y i nte n de d as a bac k -u p o pti o n w he n 
t he e C R F s yste m is n ot f u ncti o ni n g. 
o  I n t his case, t he pa per f or ms are t o be tra ns mitte d via e mail or c o nfir me d  facsi mile (fa x) 
tra ns missi o n t o: 
 
S A E  E m ail  A d dress:  Refer  t o  C o nt act  I nf or m ati o n  list.  
S A E  F acsi mile  N u m ber:  Refer  t o C o nt act I nf or m ati o n list. 
F or  st u dies ca pt uri n g S A Es  t hr o u g h electr o nic  data  ca pt ure ( E D C), electr o nic  s u b missi o n is t he 
re q uire d met h o d f or re p orti n g. I n t he e ve nt t he electr o nic  s yste m is u na vaila ble f or tra ns missi o n, 
pa per f or ms m ust be use d  a n d s u b mitte d i m me diatel y. W he n  pa per f or ms are use d, t he ori gi nal 
pa per f or ms are t o re mai n o n site.  
S A E  Tele p h o ne  C o nt act  (re q uire d  f or  S A E  a n d  pre g na nc y  re p orti n g):  Refer  t o  C o ntact  
I nf or mati o n list 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X 4  
W O M E N  O F  C HI L D B E A RI N G  P O T E N TI A L  D E FI NI TI O N S  A N D 
M E T H O D S O F C O N T R A C E P TI O N  
N ote : t he re q uire me nts f or c o ntrace pti o n are a p plica ble t o all partici pa nts  treate d wit h a n y of t he 
I M Ps a d mi nistere d i n t he st u d y: ni v ol u ma b, bre nt u xi ma b ve d oti n, a n d be n da m usti ne. 
D E FI NI TI O N S  
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 dere d fertile 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.  Per ma ne nt  sterilizati o n  met h o ds  i ncl u de  h ysterect o m y,  bilateral  
sal pi n gect o m y, a n d bilateral o o p h orect o m y. 
W o me n i n t he f oll o wi n g c ate g ories are n ot  c o nsi dere d  W O C B P  
•  Pre me narc hal  
•  Pre me n o pa usal  fe male wit h 1 of  t he f oll o wi n g: 
− D oc u me nte d h ysterect o m y  
− D oc u me nte d bilateral  sal pi n gect o m y 
− D oc u me nte d bilateral  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 pers o n nel’s re vie w of t he partici pa nt’s me dical 
rec or ds, me dical e xa mi nati o n, or me dical hist or y i nter vie w. 
•  P ost me n o pa usal fe male 
− A p ost me n o pa usal state is defi ne d as 1 2 m o nt hs of a me n orr hea i n a w o ma n o ver a ge 4 5 
years  i n t he a bse nce  of ot her  bi ol o gical or p h ysi ol o gical ca uses. I n a d diti o n, fe males u n der 
t he a ge  of  5 5 years  m ust  ha ve   a ser u m f ollicle sti m ulati n g  h or m o ne, ( F S H) le vel 
> 4 0 mI U/ m L  t o c o nfir m me n o pa use.  
 
C O N T R A C E P TI O N  G UI D A N C E  F O R  F E M A L E  P A R TI CI P A N T S  O F  C HI L D  B E A RI N G 
P O T E N TI A L  
T w o effecti ve met h o ds  of c o ntrace pti o n, wit h  a mi ni m u m of o ne hi g hl y effecti ve liste d bel o w, is 
re q uire d  d uri n g  st u d y  d urati o n  a n d  u ntil  t he  e n d  of  rele va nt  s yste mic  e x p os ure,  defi ne d  as  
a p pr o xi matel y 6 m o nt hs after t he e n d of  st u d y treat me nt wit h i n vesti gati o nal dr u gs (I M Ps). L ocal 
la ws a n d re g ulati o ns ma y re q uire use of alter nati ve a n d/ or a d diti o nal c o ntrace pti o n met h o ds. See 
t he c urre nt prescri bi n g i nf or mati o n/c o u ntr y-s pecific la bel/ S m P C f or bre nt u xi ma b ve d oti n a n d 
be n da m usti ne pre g na nc y/c o ntrace pti o n i nf or mati o n. 
 
Hi g hl y  Effecti ve  C o ntr ace pti ve  Met h o ds  T h at  Are  User  De pe n de nt  
F ail ure r ate of < 1 % per ye ar w he n  use d  c o nsiste ntly a n d c orrectly. a 
•  
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 
− oral  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
− i ntra va gi nal 
− tra ns der mal 
•  
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  
− oral  
− i njecta ble 
Hi g hl y  Effecti ve  Met h o ds  T h at  Are  User  I n de pe n de nt 
•  
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  
•  H or m o nal  met h o ds  of  c o ntrace pti o n i ncl u di n g oral  c o ntrace pti ve pills  c o ntai ni n g a 
c o m bi nati o n  of estr o ge n   a n d pr o gester o ne,   va gi nal  ri n g, i njecta bles, i m pla nts a n d 
i ntra uteri ne h or m o ne-releasi n g s yste m (I U S)c 
•  I ntra uteri ne de vice (I U D)c 
•  Bilateral t u bal occl usi o n  
•  
Vasect o mize d  part ner  
A v asect o mize d p art ner is a hi g hly effective c o ntr ace pti o n met h o d pr ovi de d t h at t he p art ner 
is t he s ole m ale  sex u al p art ner of t he W O C B P  a n d t he a bse nce of s per m h as bee n  c o nfir me d. 
If n ot, a n a d diti o n al hi g hly effective met h o d of c o ntr ace pti o n s h o ul d be use d. 
•  
Se x ual  a bsti ne nce  
Sex u al a bsti ne nce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m 
heter osex u al  i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h  t he st u dy dr u g. T he 
reli a bility of sex u al a bsti ne nce nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy 
a n d t he preferre d a n d us u al lifestyle of t he p artici p a nt. 
•  It is n ot necessar y t o use a n y ot her met h o d of c o ntrace pti o n w he n c o m plete a bsti ne nce is 
electe d. 
•  W O C B P partici pa nts w h o c h o ose c o m plete a bsti ne nce  m ust c o nti n ue t o   ha ve pre g na nc y 
tests, as s pecifie d i n Secti o n 2 . 
•  Acce pta ble  alter nate   met h o ds  of hi g hl y effecti ve c o ntrace pti o n   m ust be  disc usse d  i n t he 
e ve nt t hat t he W O C B P partici pa nts c h o oses t o f ore g o c o m plete a bsti ne nce  
N O T E S:  
a T y pical use fail ure rates ma y  differ 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 re 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 nts  partici pati n g  i n cli nical st u dies. 
b  H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he st u d y dr u g, w hic h ma y re d uce t he efficac y 
of  t he c o ntrace pti ve  met h o d.  H or m o nal  c o ntrace pti o n  is per missi ble  o nl y  w he n  t here is s ufficie nt e vi de nce t hat 
t he I M P a n d ot her st u d y me dicati o ns will n ot alter h or m o nal e x p os ures s uc h t hat c o ntrace pti o n w o ul d be 
i neffecti ve or  res ult i n i ncrease d e x p os ures  t hat c o ul d  be  p ote ntiall y  hazar d o us.  I n t his case, alter nati ve met h o ds 
of c o ntrace pti o n s h o ul d be utilize d.  
c I ntra uteri ne de vices  a n d i ntra uteri ne h or m o ne  releasi n g s yste ms are acce pta ble  met h o ds  of  c o ntrace pti o n  i n t he 
a bse nce of defi niti ve dr u g i nteracti o n st u dies w he n h or m o ne e x p os ures fr o m i ntra uteri ne de vices d o n ot alter 
c o ntrace pti o n effecti ve ness  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
U n acce pt a ble  Met h o ds  of  C o ntr ace pti o n  
•  Male or fe male c o n d o m  wit h or wit h o ut s per mici de.  Male a n d fe male c o n d o ms ca n n ot be 
use d si m ulta ne o usl y 
•  Dia p hra g m wit h  s per mici de 
•  Cer vical  ca p wit h  s per mici de 
•  Va gi nal S p o n ge wit h  s per mici de 
•  Pr o gest o ge n- o nl y oral   h or m o nal  c o ntrace pti o n, w here   i n hi biti o n  of  o v ulati o n is n ot   t he 
pri mar y mec ha nis m of acti o n  
•  Peri o dic a bsti ne nce (cale n dar, s y m pt ot her mal, p ost - o v ulati o n met h o ds)  
•  Wit h dra wal  (c oit us i nterr u pt us). 
•  S per mici de o nl y  
•  Lactati o n  a me n orr hea  met h o d  ( L A M) 
 
C O N T R A C E P TI O N  G UI D A N C E  F O R  M A L E  P A R TI CI P A N T S  WI T H  P A R T N E R( S)  O F 
C HI L D B E A RI N G P O T E N TI A L.  
Male partici pa nts wit h fe 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 gree t o t he f oll o wi n g d uri n g t he treat me nt a n d u ntil t he e n d of rele va nt s yste mic e x p os ure.  
•  I nf or m a n y a n d all part ner(s) of t heir partici pati o n i n a cli nical dr u g st u d y a n d t he nee d t o 
c o m pl y wit h c o ntrace pti o n i nstr ucti o ns as directe d b y t he i n vesti gat or. 
•  Male partici pa nts are re q uire d t o use a c o n d o m f or st u d y d urati o n a n d u ntil e n d of rele va nt 
s yste mic e x p os ure defi ne d as 7 m o nt hs after t he e n d of treat me nt wit h i n vesti gati o nal dr u gs 
(I M Ps). 
•  Fe male part ners of males partici pati n g i n t he st u d y t o c o nsi der use of effecti ve met h o ds of 
c o ntrace pti o n u ntil t he e n d of rele va nt s yste mic e x p os ure, defi ne d as 7 m o nt hs after t he e n d of 
treat me nt wit h i n vesti gati o nal dr u gs (I M Ps). 
•  Male  partici pa nts wit h  a pre 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 nterc 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 treat me nt a n d u ntil 7 m o nt hs after t he e n d of  treat me nt wit h i n vesti gati o nal dr u gs 
(I M Ps). 
•  Refrai 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  treat me nt a n d u ntil 7 m o nt hs after 
t he e n d of treat me nt wit h i n vesti gati o nal dr u gs (I M Ps). 
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 
G ui da nce f or c ollecti o n of Pre g na nc y I nf or mati o n a n d o utc o me of pre g na nc y o n t he Pre g na nc y 
S ur veilla nce F or m  is pr o vi de d i n Secti o n  9. 2. 5 a n d t he A p pe n di x f or A d verse E ve nts a n d Seri o us 
A d verse E ve nts Defi niti o ns a n d pr oce d ures f or E val uati n g, F oll o w- u p a n d Re p orti n g 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  5 
K A R N O F S K Y  A N D  L A N S K Y  C RI T E RI A  
 
S T A T U S  
S T A T U S  
K A R N O F S K Y  
L A N S K Y  
K A R N O F S K Y  or 
L A N S K Y  
N or mal,  n o  c o m plai nts 
F ull y  acti ve, n or mal  
1 0 0  
A ble  t o carr y o n  n or mal  acti vities; mi n or  si g ns or 
s y m pt o ms of disease 
Mi n or  restricti o ns i n 
p h ysicall y  stre n u o us 
acti vit y 
9 0  
N or mal  acti vit y  wit h  eff ort; s o me si g ns or  s y m pt o ms of 
disease  
Acti ve,  b ut  tires m ore 
q uic kl y  
8 0  
Cares  f or self. U na ble  t o carr y  o n  n or mal  acti vit y  or  t o d o 
acti ve w or k  
S u bsta ntial restricti o n of, 
a n d less ti me s pe nt, i n pla y 
acti vit y 
7 0  
Re q uires  occasi o nal  assista nce,  b ut  a ble t o care f or m ost of 
his nee ds  
O ut  of  be d,  b ut  mi ni mal 
acti ve pla y; kee ps b us y 
wit h q uiet acti vities  
6 0  
Re q uires  c o nsi dera ble  assista nce  a n d fre q ue nt me dical  care 
Gets  dresse d, b ut  i nacti ve 
m uc h of da y; n o acti ve 
pla y,  a ble t o partici pate  i n 
q uiet pla y  
5 0  
Disa ble d.  Re q uires  s pecial care a n d assista nce 
M ostl y  i n be d;  partici pates 
i n s o me q uiet acti vities 
4 0  
Se verel y  disa ble d.  H os pitalizati o n  i n dicate d t h o u g h deat h 
n o n i m mi ne nt  
I n be d;  nee ds  assista nce 
e ve n f or q uiet pla y  
3 0  
Ver y  sic k. H os pitalizati o n  necessar y.  Acti ve  s u p p orti ve 
treat me nt necessar y 
Ofte n  slee pi n g; pla y 
li mite d t o passi ve 
acti vities 
2 0  
M ori b u n d  
N o  pla y;  d oes  n ot  get  o ut 
of be d  
1 0  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  6 
I M A GI N G L E SI O N  E V A L U A TI O N  C RI T E RI A  
F or P E T -base d assess me nts, a cli nical res p o nse of pr o gressi ve meta b olic disease ( P M D), n o 
meta b olic res p o nse ( N M R), partial meta b olic res p o nse ( P M R), or c o m plete meta b olic res p o nse 
( C M R) will be deter mi ne d. P M D/ P D i ncl u des ra di ol o gical e vi de nce of pr o gressi o n per L u ga n o 
Classificati o n  Re vise d  Sta gi n g S yste m  f or mali g na nt l y m p h o ma. T he  P E T  sca n meta b olic u pta ke 
will be gra de d usi n g t he Dea u ville 5 -p oi nt scale, wit h a sc ore of ≤ 3 c o nsi dere d t o re prese nt a 
C M R.  
Dea u ville  5- p oi nt scale:  1-  n o u pta ke   a b o ve  bac k gr o u n d;  2-  u pta ke ≤ me diasti n u m;   3- u pta ke  
> me diasti n u m b ut ≤ li ver; 4 = u pta ke m o deratel y > li ver; 5- u pta ke mar ke dl y hi g her t ha n li ver  
a n d/ or ne w lesi o ns; X- ne w areas of u pta ke u nli kel y t o be relate d t o l y m p h o ma. 
 
T a ble  1:  
C M R / C R  
Res p o nse/ Site  
F D G  P E T -C T -B ase d  
( C o m plete Met a b olic  Res p o nse)  
C T -B ase d ( C R) a 
All  of  t he f oll o wi n g: 
 
 
 
 
 
 
 
L y m p h  n o des  a n d e xtral y m p hatic 
sites 
Sc ore  1,  2 or  3 wit h  or  wit h o ut  a 
resi d ual mass o n 5-P oi nt -Scale  
It is rec o g nize d t hat i n Wal de yer’s 
ri n g or e xtra n o dal sites wit h hi g h 
p h ysi ol o gic u pta ke or wit h 
acti vati o n wit hi n  s plee n or  marr o w 
(e g, wit h  c he m ot hera p y  or  m yel oi d 
c ol o n y-sti m ulati n g fact ors), u pta ke 
ma y be greater t ha n n or mal 
me diasti n u m a n d/ or li ver. I n t his 
circ u msta nce, c o m plete meta b olic 
res p o nse ma y be i nferre d if u pta ke 
at sites of i nitial i n v ol ve me nt is n o 
greater t ha n s urr o u n di n g n or mal 
tiss ue e ve n if t he tiss ue has hi g h 
p h ysi ol o gic u pta ke.  
 
 
 
 
 
 
Tar get  n o des/ n o dal  masses  m ust 
re gress t o ≤ 1. 5 c m i n L Di  
 
N o  e xtral y m p hatic  sites of  disease  
N o n -meas ure d  lesi o n 
N ot  a p plica ble 
A bse nt  
Or ga n  e nlar ge me nt 
N ot  a p plica ble 
Re gress  t o n or mal  
Ne w  lesi o ns 
N o ne  
N o ne  
B o ne  marr o w  
N o  e vi de nce of  F D G -a vi d disease 
i n marr o w 
N or mal b y m or p h ol o g y; if 
i n deter mi nate, I H C ne gati ve  
a C T -Base d  c o ul d  als o  a p pl y t o M RI -Base d  
N ote: C hes o n  B D, Fis her RI, Barri n gt o n S F, et al:  Rec o m me n dati o ns f or  i nitial e val uati o n, sta gi n g, a n d res p o nse 
assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o ma: t he L u ga n o classificati o n. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9 -6 8.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
T a ble  2:  
P M R /  P R  
Res p o nse/ Site  
F D G  P E T -C T -B ase d  
( P arti al Met a b olic  Res p o nse)  
C T -B ase d ( P R) a 
All  of  t he f oll o wi n g: 
 
 
 
 
 
L y m p h  n o des  a n d e xtral y m p hatic 
sites 
 
 
Sc ore  4 or  5 wit h  re d uce d u pta ke 
c o m pare d wit h baseli ne a n d 
resi d ual mass(es) of a n y size 
At  i nteri m, t hese fi n di n gs s u g gest 
res p o n di n g disease 
At  e n d of  treat me nt, t hese fi n di n gs 
s u g gest resi d ual disease 
≥ 5 0 %  decrease  i n S P D  of  u p  t o 
6 tar get meas ura ble n o des a n d 
e xtra n o dal sites  
 
W he n a lesi o n is t o o s mall t o 
meas ure  o n  C T,  assi g n 5 m m  X 
5 m m  as t he defa ult  val ue;  w he n  n o 
l o n ger visi ble, 0 X 0 m m; f or a 
n o de > 5 m m X 5 m m, b ut s maller 
t ha n n or mal, use act ual 
meas ure me nt f or calc ulati o n  
N o n -meas ure d  lesi o n 
N ot  a p plica ble 
A bse nt/ n or mal,  re gresse d, b ut  n o 
i ncrease 
Or ga n  e nlar ge me nt 
N ot  a p plica ble 
S plee n  m ust  ha ve  re gresse d b y  
> 5 0 %  i n le n gt h be y o n d  n or mal  
Ne w  lesi o ns 
N o ne  
N o ne  
 
 
 
 
 
B o ne  marr o w  
Resi d ual  u pta ke  hi g her  t ha n u pta ke 
i n n or mal marr o w b ut re d uce d 
c o m pare d wit h baseli ne  
( diff use u pta ke c o m pati ble wit h 
reacti ve c ha n ges fr o m 
c he m ot hera p y  all o we d).  If t here are 
persiste nt f ocal c ha n ges i n t he 
marr o w i n t he c o nte xt of a n o dal 
res p o nse, c o nsi derati o n s h o ul d be 
gi ve n t o f urt her e val uati o n wit h 
M RI or bi o ps y or a n i nter val sca n.  
 
 
 
 
 
N ot  a p plica ble 
a C T -Base d  c o ul d  als o  a p pl y t o M RI -Base d  
N ote: C hes o n  B D, Fis her RI, Barri n gt o n S F, et al:  Rec o m me n dati o ns f or  i nitial e val uati o n, sta gi n g, a n d res p o nse 
assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o ma: t he L u ga n o classificati o n. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9 -6 8.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 1 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
T a ble  3:  
N M R  / S D  
Res p o nse/ Site  
F D G P E T -C T -B ase d 
( N M R) 
C T -B ase d a 
( S D) 
 
Tar get  n o des/ n o dal  masses, 
e xtra n o dal lesi o ns  
Sc ore  4 or  5 wit h  n o  si g nifica nt 
c ha n ge i n F D G u pta ke fr o m 
baseli ne at i nteri m or e n d of 
treat me nt 
< 5 0 %  decrease  i n S P D  of  u p  t o 6 
tar get meas ura ble n o des a n d 
e xtra n o dal sites; n o criteria f or 
Pr o gressi ve Disease met  
N o n -meas ure d  lesi o n 
N ot  a p plica ble 
N o  i ncrease c o nsiste nt wit h 
Pr o gressi o n  
Or ga n  e nlar ge me nt 
N ot  a p plica ble 
N o  i ncrease c o nsiste nt wit h 
Pr o gressi o n  
Ne w  lesi o ns 
N o ne  
N o ne  
B o ne  marr o w  
N o  c ha n ge fr o m baseli ne  
N ot  a p plica ble 
a C T -Base d  c o ul d  als o  a p pl y t o M RI -Base d  
N ote: C hes o n  B D, Fis her RI, Barri n gt o n S F, et al:  Rec o m me n dati o ns f or  i nitial e val uati o n, sta gi n g, a n d res p o nse 
assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o ma: t he L u ga n o classificati o n. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9 -6 8.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
T a ble  4:  
P M D /  P D  
Res p o nse/ Site  
F D G P E T -C T -B ase d 
( P M D) 
C T -B ase d  ( P D)a  
At  le ast o ne  of  t he f oll o wi n g: 
 
 
 
 
 
 
 
 
I n di vi d ual tar get n o des/ n o dal 
masses  
E xtra n o dal  lesi o ns 
 
 
 
 
 
 
Sc ore 4 or 5 wit h a n i ncrease i n 
i nte nsit y of  u pta ke  fr o m baseli ne 
a n d/ or ne w F D G -a vi d f oci 
c o nsiste nt wit h l y m p h o ma at 
i nteri m or e n d-of -treat me nt 
assess me nt 
A n  i n di vi d ual n o de/lesi o n  m ust  be 
a b n or mal wit h:  
L Di > 1. 5  c m & 
I ncrease b y  ≥ 5 0 %  fr o m P P D  na dir  & 
A n  i ncrease i n L Di or  S Di  fr o m na dir  
0. 5  c m f or lesi o ns ≤ 2 c m 
1. 0  c m f or lesi o ns > 2 c m 
 
I n t he setti n g of s ple n o me gal y, t he 
s ple nic le n gt h m ust i ncrease b y > 
5 0 %  of  t he e xte nt of  its pri or  i ncrease 
be y o n d baseli ne (e g, a 1 5 c m s plee n 
m ust i ncrease t o 1 6 c m). If n o pri or 
s ple n o me gal y, m ust i ncrease b y at 
least 2 c m fr o m baseli ne 
Ne w  or  rec urre nt s ple n o me gal y 
N o n -meas ure d  lesi o n 
N o ne  
Ne w or clear pr o gressi o n of 
pree xisti n g  n o n meas ure d  lesi o ns 
 
 
 
 
 
Ne w  lesi o ns 
 
Ne w F D G -a vi d f oci c o nsiste nt 
wit h l y m p h o ma rat her t ha n 
a n ot her eti ol o g y  (e. g., i nfecti o n, 
i nfla m mati o n). 
If u ncertai n  re gar di n g eti ol o g y of 
ne w lesi o ns, bi o ps y or i nter val 
sca n ma y be c o nsi dere d. 
Re gr o wt h  of  pre vi o usl y  res ol ve d 
lesi o ns 
A ne w n o de > 1. 5 c m i n a n y a xis 
A ne w  e xtra n o dal site > 1. 0  c m i n 
a n y a xis; if < 1. 0  c m i n a n y a xis, its 
prese nce  m ust  be  u ne q ui v ocal  a n d 
m ust be  attri b uta ble  t o l y m p h o ma. 
Assessa ble disease of a n y size 
u ne q ui v ocall y attri b uta ble t o 
l y m p h o ma. 
B o ne  marr o w  
Ne w  or  rec urre nt F D G -a vi d f oci 
Ne w  or  rec urre nt i n v ol ve me nt 
a C T -Base d  c o ul d  als o  a p pl y t o M RI -Base d  
N ote: C hes o n  B D, Fis her RI, Barri n gt o n S F, et al:  Rec o m me n dati o ns f or  i nitial e val uati o n, sta gi n g, a n d res p o nse 
assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o ma: t he L u ga n o classificati o n. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9 -6 8.  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X 7  
M A N A G E M E N T  A L G O RI T HI M S  F O R  I M M U N O-O N C O L O G Y 
A G E N T S  
T hese ge neral g ui deli nes c o nstit ute g ui da nce t o t he I n vesti gat or a n d ma y be s u p ple me nte d b y 
disc ussi o ns  wit h t he Me dical  M o nit or  re prese nti n g t he S p o ns or. T he g ui da nce a p plies t o all 
i m m u n o- o nc ol o g y a ge nts a n d re gi me ns. 
A ge neral pri nci ple is t hat differe ntial dia g n oses s h o ul d be dili ge ntl y e val uate d acc or di n g t o 
sta n dar d me dical practice. N o n-i nfla m mat or y eti ol o gies s h o ul d be c o nsi dere d a n d a p pr o priatel y 
treate d. 
C ortic oster oi ds  are a pri mar y  t hera p y f or i m m u n o- o nc ol o g y dr u g-relate d a d verse  e ve nts. T he  oral 
e q ui vale nt  of  t he rec o m me n de d I V  d oses ma y   be c o nsi dere d   f or a m b ulat or y  patie nts  wit h 
l o w-gra de t o xicit y. T he l o wer bi oa vaila bilit y  of  oral  c ortic oster oi ds s h o ul d be ta ke n i nt o acc o u nt 
w he n s witc hi n g t o t he e q ui vale nt d ose of oral c ortic oster oi ds.  
C o ns ultati o n wit h a me dical or s ur gical s pecialist, es peciall y pri or t o a n i n vasi ve dia g n ostic or 
t hera pe utic pr oce d ure, is rec o m me n de d. 
T he  fre q ue nc y a n d se verit y of t he relate d a d verse e ve nts c o vere d  b y t hese al g orit h ms will de pe n d 
o n t he i m m u n o- o nc ol o g y a ge nt or re gi me n bei n g use d. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 2  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 3  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 4  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 5  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 6  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 7  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 8  
A p p r o v e d  v 51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 2 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  8 
R A DI O T H E R A P Y  G UI D E LI N E S  F O R  T H E  R 1  C O H O R T  
 
Ra di ot hera p y is effecti ve  f or selecte d patie nts  wit h  H o d g ki n l y m p h o ma a n d s h o ul d be c o nsi dere d 
f or i nc or p orati o n i nt o sal va ge pr o gra ms. T he p ur p ose of t his d oc u me nt is t o pr o vi de ra diati o n 
g ui deli nes f or patie nts i n t he R 1 c o h ort.  Rela pse a n d refract or y H o d g ki n l y m p h o ma is m ore 
a g gressi ve t ha n de n o v o disease, c o nse q ue ntl y ra di ot hera p y rec o m me n dati o ns are differe nt t ha n 
t h ose f o u n d i n t he u pfr o nt C O G a n d E ur o net H L st u dies, i ncl u di n g sli g htl y hi g her ra diati o n d ose 
t o 3 0- 3 0. 6 G y.   Ra di ot hera p y v ol u mes f or t he R 1  c o h ort are e x pecte d t o be of m o dest size, utilizi n g 
a d va nce d ra diati o n c o nce pt i ncl u di n g m o der n fiel d desi g n base d o n P E T a n d C T i ma gi n g a n d 
m o der n  ra diati o n  tec h ni q ues  i ncl u di n g  breat h -h ol d  tec h ni q ues,  I M R T,  V M A T,  a n d/ or  pr ot o n 
t hera p y w he n a vaila ble.  Patie nts re q uiri n g  e xcessi vel y lar ge ra diati o n fiel ds  s h o ul d be  treate d o n 
t he R 2 c o h ort a n d recei ve hi g h d ose c he m ot hera p y a n d a ut ol o g o us ste m cell tra ns pla nt i nstea d of 
lar ge fiel d ra diati o n. I n i nsta nces w here patie nts e nr olle d a n d treate d o n t he R 1 c o h ort are f o u n d 
t o ha ve lar ge R T v ol u mes or hi g her ra diati o n d oses t o critical or ga ns t ha n t he i n vesti gat or or 
pr ot oc ol all o ws, a disc ussi o n wit h t he steeri n g c o m mittee is rec o m me n de d as t he best c o urse of 
acti o n f or t he i n di vi d ual patie nt.  
G e n er al  Pri n ci pl e s — I n v ol v e d Sit e  R a di ati o n  T h er a p y  (I S R T) 
 
T he I nter nati o nal L y m p h o ma Ra diati o n O nc ol o g y Gr o u p (I L R O G) rec o m me n de d g ui deli nes f or 
c o ns oli dati ve ra di ot hera p y is t o use I n v ol ve d Site Ra di ot hera p y  (I S R T)1 2. I S R T tar gets t he pre- 
treat me nt sites of i n v ol ve me nt wit h  mar gi n  base d  o n t he f usi o n of t he C T  si m ulati o n wit h  t he pre - 
treat me nt P E T/ C T  sca n, wit h  lar ger mar gi ns  utilize d  w he n  t here is less certai nt y bet wee n  t he f usi o n 
of t he sca ns.  F or t he p ur p oses of t his retrie val st u d y, t he pre-treat me nt sca n will be t he P E T/ C T 
sca n o btai ne d pri or t o starti n g Ni v ol u ma b  + bre nt u xi ma b ve d oti n. I n t he s pecial i nsta nce * *, w here 
t he patie nt rela pse d q uic kl y after i nitial c he m ot hera p y a n d is e nr olle d i n R 1, t he s u m of all P E T/ C T 
sca ns wit hi n t he pri or 1 2 m o nt hs s h o ul d be use d t o de vel o p t he I S R T fiel d. 
I n di c ati o n s f or R a di ot h er a p y  
 
P atie nts  i n t he R 1  c o h ort, w h o  h a ve:  
1)  C M R after 4 c ycles of N + B V, will ha ve 2 a d diti o nal c ycles of N + B V a n d t he n will recei ve  
I S R T. 
2)  Sta ble or partial  res p o nse t o t he first 4 c ycles of N + B V, w h o t he n ac hie ve a C M R f oll o wi n g 
2 a d diti o nal c ycles of B V + B, will als o recei ve I S R T.  
 
 
1 H o d gs o n  D C,  Die d k ma n n  K,  Tereza kis  S,  C o nsti ne  L.  I m ple me ntati o n of  c o nte m p oarar y  ra diati o n t hera p y 
pla n ni n g  c o nce pts  f or pe diatric  H o d g ki n  l y m p h o ma: G ui deli nes  fr o m t he I nter nati o nal L y m p h o ma  Ra diati o n 
o nc ol o g y Gr o u p.  Pr act R a di at O nc ol. 2 0 1 5 Mar -A pr; 5( 2): 8 5 -9 2 . 
 
2 S pec ht  L, Ya hal o m  J, Illi d ge T, Bert helse n  A K,  C o nsti ne  L S, Eic h  H T,  Giri ns k y  T, H o p pe  R T,  Ma uc h  P,  Mi k haeel 
N G, N g A; I L R O G.  M o der n ra diati o n t hera p y f or H o d g ki n l y m p h o ma: fiel d a n d d ose g ui deli nes fr o m t he 
i nter nati o nal l y m p h o ma ra diati o n o nc ol o g y gr o u p. I nt J R a di at O nc ol Bi ol P hys. 2 0 1 4 J ul 1 5; 8 9( 4): 8 5 4 -6 2  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 0  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
R a di ot her a p y  D ose  a n d Sc he d ule  
T he  I S R T d ose is 3 0 0 0 c G y ( 1 5 0 c G y  per da y) or 3 0 6 0 c G y ( 1 8 0 c G y per da y) t o t he I S R T v ol u me. 
Fracti o nati o n sc he d ule a m o n g t hese t w o o pti o ns is at p h ysicia n’s discreti o n. 
T he  treat me nt will   be  gi ve n  5  da ys  per wee k.  T he  t otal ela pse d treat me nt ti me will   be 
a p pr o xi matel y 3. 5- 4 wee ks ( 1 7- 2 0 sessi o ns). 
 
Ti mi n g  of R a di ot her a p y a n d  St arti n g  Criteri a  
Treat me nt s h o ul d be gi n n o later t ha n 6 wee ks fr o m t he start of t he last c ycle of  c he m ot hera p y or 
w he n bl o o d c o u nts ha ve rec o vere d. 
 
M o d alit y  
P h ot o ns wit h  a n o mi nal e ner g y of ≥ 4 M V  a n d ≤ 1 8 M V are preferre d.  I n t he u n us ual circ u msta nce 
of a n is olate d s u perficial lesi o n, electr o n fiel ds ma y  be use d. C o n ve nti o nal, c o nf or mal,  a n d I M R T 
tec h ni q ues are all o we d i n t his st u d y. Patie nts recei vi n g I M R T s h o ul d ha ve t his deli vere d wit h 6- 
1 0 M V p h ot o n bea ms, a n d 1 8  M V p h ot o n bea ms s h o ul d n ot be use d t o deli ver I M R T. Pr ot o n 
t hera p y is all o we d. 
 
Tre at me nt  P ositi o n  
T he  patie nt  s h o ul d al wa ys be treate d i n t he s u pi ne p ositi o n. S o me  i nstit uti o ns ma y i ncli ne fe male 
patie nts t o re d uce breast d ose, a n d t his is acce pta ble. T he use of a breast b oar d t o re d uce breast 
d ose  i n  fe male  patie nts  is  acce pta ble.  Re pr o d uci ble  set u ps  are  critical,  a n d  a p pr o priate  
i m m o bilizati o n de vices s h o ul d be use d t o e ns ure re pr o d uci ble set u p. M o derate dee p i ns pirat or y 
breat h h ol d tec h ni q ue, res pirat or y  gati n g or  trac ki n g tec h ni q ues are rec o m me n de d a n d s h o ul d be 
c o nsi dere d  a n d e val uate d f or patie nts  wit h  me diasti nal  i n v ol ve me nt at i nstit uti o ns wit h  e x perie nce 
a n d t he tec h n ol o g y t o utilize t his tec h ni q ue. 
 
Tre at me nt Pl a n ni n g  
C T ( v ol u metric) base d pla n ni n g is re q uire d t o o pti mize d ose t o t he tar get v ol u me w hile re d uci n g 
d ose t o n or mal tiss ues. Slices  ≤ 5 m m  t hic k s h o ul d be ta ke n t hr o u g h o ut t he e xte nt of t he irra diate d 
v ol u me., W here fiel ds i ncl u de t he me diasti n u m or p ul m o nar y hila t he e ntire l u n g v ol u me s h o ul d 
be sca n ne d t o e na ble acc urate  esti mates of w h ole l u n g d ose. A D ose  V ol u me  Hist o gra m  ( D V H) is 
necessar y t o deter mi ne tar get c o vera ge a n d e val uate d ose t o n or mal tiss ues.  
 
I n- R o o m Verific ati o n  of S p ati al  P ositi o ni n g  
I ma ge g ui da nce t o verif y patie nt p ositi o n is a n i m p orta nt sta n dar d feat ure of c o nte m p orar y R T 
deli ver y. I nstit uti o nal pr ot oc ols s h o ul d be i n place c o m m o n t o verif y patie nt p ositi o n. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 1  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
T ar get V ol u mes  (see fi g ure 1 bel o w)  
Rec o m me n dati o ns  of  T he  I nter nati o nal  C o m missi o n  o n  Ra diati o n  U nits  a n d  Meas ure me nts  
(I C R U) f or prescri pti o n met h o ds a n d n o me nclat ure will be utilize d f or t his st u d y. 
 
I S R T v ol u mes s h o ul d be use d  f or 3 0 0 0 c G y ( 1 5 0 c G y/fracti o n) or 3 0 6 0 c G y ( 1 8 0c G y/fracti o n) 
 
 
I S R T s h o ul d be li mite d t o 4 or fe wer sites ( per Ger ma n H o d g ki n St u d y Gr o u p defi niti o n) if 
i n v ol ve me nt is j ust a b o ve t he dia p hra g m or 3 or fe wer sites if i n v ol ve me nt is a b o ve a n d bel o w t he 
dia p hra g m.  
 
P ost -C he m ot her a p y  Cli nic al  T ar get V ol u me  ( C T V) 
F or I S R T: T he C T V s h o ul d f oll o w t he I S R T v ol u mes a n d i ncl u de all t he i n v ol ve d l y m p h n o des 
a n d l y m p hatic tiss ue at rela pse j ust pri or t o i nitiati n g N + B V, b ut m ust ta ke i nt o acc o u nt t he 
re d ucti o n i n a xial dia meter t hat has occ urre d wit h c he m ot hera p y. T y picall y l y m p h n o des will be 
c o nsi dere d  i n v ol ve d if t he y are P E T-a vi d, b ut l y m p ha de n o pat h y t hat is > 2. 5c m t hat a p pears t o be 
pat h ol o gical e ve n if it is n ot P E T a vi d (f or e xa m ple necr otic n o des) s h o ul d be i ncl u de d. T he 
c o nce pt is t hat all areas of l y m p h o ma i nfiltrati o n nee ds t o be tar gete d, h o we ver f oll o wi n g a g o o d 
res p o nse t o c he m ot hera p y, pre vi o usl y dis place d n or mal tiss ue s h o ul d n ot be irra diate d e g l u n g 
dis place d  b y  me diasti nal  l y m p h  n o des,  or  b o wel  dis place d  b y  para -a ortic  n o des.  A nteri or  
me diasti nal  disease  will s hri n k i n a xial  dia meter a wa y fr o m  t he l u n g wit h c he m ot hera p y, a n d t he 
wi dt h of  t he C T V s h o ul d reflect t his c ha n ge. T he s u peri or a n d i nferi or v ol u me of  t he I S R T C T V 
s h o ul d c orres p o n d t o t he i nitial sites of i n v ol ve me nt. W he n c o nt o uri n g t he C T V v ol u me, o ne 
s h o ul d c o nsi der i nacc uracies i n matc hi n g patie nt p ositi o ni n g a n d t he varia ble i nter nal a nat o m y 
s hifts t hat c ha n ge wit h disease v ol u me a n d patie nt p ositi o n bet wee n dia g n ostic a n d treat me nt 
p ositi o ns e ve n wit h  t he best  i ma ge f usi o n s oft ware. As  a g ui deli ne, a mar gi n  of 1. 5 c m  a b o ve a n d 
bel o w t he i n v ol ve d l y m p h n o des is rec o m me n de d. I n t he nec k, o n a gi ve n a xial c ut, t he w h ole 
n o dal f ossa/le vel t hat c o ntai ne d t he i nitiall y a b n or mal n o de(s) s h o ul d be c o nt o ure d as t he C T V. 
 
I nter n al T ar get V ol u me  (I T V) 
T he  I T V e nc o m passes  t he C T V  wit h  a n a d de d mar gi n  t o acc o u nt  f or variati o n  i n s ha pe a n d m oti o n 
wit hi n t he patie nt. Res pirat or y m oti o n, f or e xa m ple, will pr o d uce m o ve me nt of t he me diasti nal 
str uct ures a n d s plee n, a n d a n a d diti o nal mar gi n  ar o u n d t he C T V  is re q uire d t o acc o u nt f or t his a n d 
s h o ul d be base d o n i nstit uti o nal g ui deli nes. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 2  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Pl a n ni n g  T ar get V ol u me  ( P T V) 
T he  P T V  s h o ul d e nc o m pass  t he C T V  a n d I T V, a n d acc o u nts  f or ge o metric  variati o n  i n dail y  set u p. 
It s h o ul d ta ke i nt o acc o u nt t he re pr o d uci bilit y of t he i m m o bilizati o n, a n d t he acc urac y  of t he dail y 
set u p i ma gi n g a n d s h o ul d be base d  o n i nstit uti o nal g ui deli nes.  T he  P T V  mar gi n ma y  ra n ge fr o m 
3- 5 m m o n t he C T V i n t he nec k t o 5- 1 0 m m o n t he I T V i n t he me diasti n u m a n d a b d o me n. 
 
Tar gets  at n o n-c o nti g u o us sites nee d  t o be se paratel y i de ntifie d. Ge nerall y,  i n cases f or w hic h  t w o 
P T V  tar gets are > 3  c m a part, t hese s h o ul d be treate d se paratel y u nless t here is a c o m pelli n g reas o n 
t o treat u ni n v ol ve d tiss ue i n bet wee n. 
Fi g ure 1 
 
Fi g ure 1: De picts a patie nt w h o rela pses 3 years f oll o wi n g c he m ot hera p y a n d is e nr olle d i n R 1. 
O n  t he left is a P E T  i ma ge de m o nstrati n g t he t w o sites of rela pse i n t he ri g ht s u pracla vic ular f ossa 
a n d me diasti n u m dra w n i n pi n k.  O n t he ri g ht is t he I S R T tar get v ol u mes bei n g treate d t o 3 0 0 0 
c G y.  T his i ncl u des pi n k ( prec he m ot hera p y sites of rela pse), bl ue (I T V), a n d gree n ( P T V). 
 
T ar get D ose  
T he  t otal d ose  will  be 3 0 0 0- 3 0 6 0 c G y 
I n t he s pecial circ u msta nce * *,  w here  patie nt  rec urs wit hi n  1 2 m o nt hs of i nitial c he m ot hera p y, t he 
I S R T fiel d t hat c o ntai ns all P E T a vi d disease si nce t he ori gi nal dia g n osis will be i ncl u de d i n t he 
I T V (fi g ure  2), wit h  a  v ol u me re d ucti o n after  2 1 0 0 c G y ( 1 5 0 c G y/fracti o n)  or  1 9 8 0 c G y ( 1 8 0 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 3  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
c G y/fracti o n)  ( P hase 1), t o j ust t he I S R T fiel d base d  o n i n v ol ve d sites at rela pse f or t he re mai ni n g 
9 0 0c G y ( 1 5 0c G y/fracti o n) or 1 0 2 0 c G y ( 1 8 0 c G y/fracti o n) ( P hase 2). 
 
Fi g ure 2:  
A 
B 
C 
D 
 
 
Fi g ure 2:  2 3 y o prese nts wit h Sta ge II A H L treate d wit h A B V D x 3 wit h i nitial P E T/ C T ( A). 
Rela pses 6 m o nt hs later wit h P E T/ C T ( B).  R T f or patie nt e nr olle d i n R 1 st u d y i ncl u des site of 
rec urre nce ( pi n k) a n d sites i n v ol ve d wit hi n t he pri or 1 2 m o nt hs (re d) i n t he I S R T fiel d wit h I T V 
( bl ue) a n d P T V  ( gree n) ( C) bei n g treate d t o 2 1 G y.  Re d uce d  v ol u me t o j ust t he site of  rec urre nce 
t o a n a d diti o nal d ose of 9 G y f or a t otal d ose of 3 0 G y ( D). 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 4  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
Or g a ns at Ris k  a n d  T ar get c o ver a ge G o als  
T he  f oll o wi n g d ose c o nstrai nts s h o ul d  be c o nsi dere d  f or t he pr ot oc ol:  
 
 
preferre d  
u n acce pt a ble  
C T V/I T V  D 9 9 %  
≥ 9 5 %  
< 9 5 %  
P T V D 1 0 %  
≤ 1 1 0 %  
> 1 1 0 %  
P T V D 9 5 %  
≥ 9 5 %  
< 9 2 %  
P T V D 0. 0 3  cc 
≥ 7 5 %  
< 7 5 %  
L u n gs  ( mea n) 
≤ 1 4  G y  
> 1 4  G y  
L u n gs  V 2 0  
≤ 2 5 %  
> 3 0 %  
S pi nal  c or d ma x  d ose  
≤3 5 G y  
> 3 5  G y  
S pi nal  c or d ma x  d ose,  pri or  R T  
C o m bi ne d  < 4 4  G y  
C o m bi ne d  > 5 0 *  G y  
Heart  ( mea n) 
≤1 5 G y  
> 1 8. 5 G y  
Heart  ( mea n), pri or  R T  
C o m bi ne d  < 2 0  G y  
C o m bi ne d  > 2 0 G y  
Breast  ( mea n) 
≤ 4 G y  
N o ne  
Par oti ds  ( mea n) 
≤ 1 5  G y * *  
> 2 4 G y  
* 5 0 G y (c u m ulati ve t otal d ose t o t he s pi ne) is ass ociate  wit h  a ris k of 0, 2 % m yel o pat h y  
* * I n n o dal sites l ocate d cl ose t o par oti d  gla n ds, at least o ne par oti d  gla n d is s pare d t o a mea n  d ose 
of less t ha n 2 0 G  

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 5  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
A P P E N DI X  9 
R E VI S E D  P R O T O C O L  S U M M A R Y  O F  C H A N G E  HI S T O R Y  
O ver all R ati o n ale f or Re vise d  Pr ot oc ol 0 3: 2 6- M ar-2 0 1 8  
T he res p o nse assess me nt b y i n vesti gat ors usi n g L u ga n o 2 0 1 4 res p o nse criteria was a d de d as a 
sec o n dar y  e n d p oi nt  t o  all o w  f or  a  c o m pre he nsi ve  i nter pretati o n  of  t he  st u d y  data.  F or  t his  
res p o nse-a da pte d trial, BI C R  assess me nt  is utilize d  f or t u m or assess me nts  ( T A) at st u d y treat me nt- 
relate d decisi o n ti me- p oi nts t o deter mi ne  f urt her treat me nt. If t he T A  b y i n vesti gat or is C M R  b ut 
BI C R assess me nt differs a n d st u d y  treat me nt disc o nti n ue d, c ollecti o n of t u m or assess me nts u ntil 
i n vesti gat or assesse d ra di o gra p hic pr o gressi o n, per L u ga n o 2 0 1 4 will all o w f or t he i nter pretati o n 
of t hese cases. G ui da nce f or c ollecti o n a n d s u b missi o n of  t u m or assess me nts  was  a d de d t o s u p p ort 
t he e val uati o n of t his ne w sec o n dar y e n d p oi nt. 
C o ntrace pti o n re q uire me nts f or fe male partici pa nts of c hil d beari n g p ote ntial were m o difie d t o 
pr o perl y ali g n wit h  Ni v ol u ma b cli nical researc h sta n dar d g ui deli nes  ( o ne hi g hl y effecti ve  met h o d) 
a n d bre nt u xi ma b la bel (t w o effecti ve met h o ds). T heref ore t he pr ot oc ol was a me n de d t o re q uire 
t w o effecti ve  met h o ds, wit h  o ne hi g hl y  effecti ve, t o i m pr o ve c o ntrace pti o n o pti o ns a n d fle xi bilit y 
f or partici pa nts, w hile mai ntai ni n g t he re q uire me nts f or all 3 I M Ps. 
Ot her  mi n or e dits were  ma de,  as descri be d  i n t he S u m mar y  of  Ke y  C ha n ges. 
T his is a p plica ble f or all st u d y partici pa nts.  
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 3  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
Secti o n  #  1:  
A d diti o n  of  sec o n dar y e n d p oi nt 
T o  a d diti o nall y e val uate efficac y 
S y n o psis  a n d  
e n d p oi nts, per  i n vesti gat or assess me nts, 
Secti o n  4:  
 
usi n g  L u ga n o  2 0 1 4  res p o nse criteria. 
O bjecti ves  a n d  
 
E n d p oi nts  
 
 
Secti o n # 1: 
S y n o psis a n d 
Secti o n 5: 
St u d y Desi g n  
Deleti o n of e xa m ples f or 
Ra diati o n  T hera p y a n d a d diti o n of 
refere nce t o R T G ui deli nes 
A p pe n di x 8 
T o  refere nce R T  g ui deli nes, create d b y 
C O G a n d E ur o net, f or R 1 C o h ort 
C o ns oli dati o n T hera p y. 
 
A d diti o nal g ui da nce f or t u m or 
assess me nts  w he n  i n vesti gat or 
assess me nt  is C M R,  b ut BI C R 
differs.  
T o s u p p ort ne w sec o n dar y e n d p oi nt t o 
e val uate efficac y e n d p oi nts, per 
i n vesti gat or assess me nts, usi n g L u ga n o 
2 0 1 4 res p o nse criteria. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 6  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 3  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
Secti o n  #. 2:  
Ta ble  2.- 2 
A me n d  C ycle  5 a n d 6, Da y  1 a n d 
Da y 1 5 I n d ucti o n t o b ot h 
refere nce f o ot n ote c. 
 
U p date F o ot n ote c t o reflect 
p ote ntial a p plicati o n f or R 2 
c o h ort, if a d diti o nal  c ycles are 
a p pr o ve d f or c o ns oli dati o n 
t hera p y dela y 
 
A me n d  f o ot n ote e t o f o ot n ote d, i n 
C o ns oli dati o n P hase C ol u m n. 
A d mi nistrati ve clarificati o ns, f or 
c o nsiste nc y wit h e xisti n g pr ot oc ol 
la n g ua ge i n t he ta ble f o ot n otes a n d 
secti o n 5. 1. 
Secti o n  #. 2:  
Ta ble 2.- 4, 
a n d Secti o n  
9. 1: Efficac y 
Assess me nt  
A d d refere nce t o secti o n 5. 1, f or 
cases w here i n vesti gat or 
assess me nts  differ  fr o m BI C R,  at 
a real-ti me rea d. 
T o s u p p ort ne w sec o n dar y e n d p oi nt t o 
e val uate efficac y e n d p oi nts, per 
i n vesti gat or assess me nts, usi n g L u ga n o 
2 0 1 4 res p o nse criteria. 
Secti o n  #. 2:  
Ta ble 2.- 5, 
a n d Secti o n  
6. 1: I ncl usi o n 
Criteria 2c  
T he  mi ni m u m  n u m ber of  sli des 
( 2 0) was re m o ve d f or i ncl usi o n 
criteria 2c a n d a d de d t o Ta ble  2.- 5 
I n rare cases, < 2 0 sli des ma y  still meet 
mi ni m u m eli gi bilit y re q uire me nts, 
t heref ore t his la n g ua ge was rel ocate d. 
Secti o n  7. 1. 1: 
Treat me nt  f or 
I nf usi o n 
Reacti o ns  
A d d  refere nce t o a p pe n di x 7 
T o refere nce a d diti o nal treat me nt 
g ui da nce i m m u ne me diate d  a d verse 
e ve nts. 
Secti o n  1 0. 3. 1  
A d diti o n of  Statistical  A nal ysis 
Met h o d f or a ne w sec o n dar y 
e n d p oi nt. 
T o a d diti o nall y e val uate efficac y 
e n d p oi nts, per  i n vesti gat or assess me nts, 
usi n g L u ga n o 2 0 1 4 res p o nse criteria. 
A p pe n di x 4: 
C o ntrace pti o n 
G ui da nce f or 
Fe male 
Partici pa nts  of 
C hil d Beari n g 
P ote ntial  
M o dificati o n of c o ntrace pti o n 
g ui da nce t o re q uire 2 effecti ve 
met h o ds, wit h  a mi ni m u m  of o ne 
hi g hl y effecti ve. 
T o i ncrease fle xi bilit y of c o ntrace pti o n 
o pti o ns, w hile mai ntai ni n g ali g n me nt 
wit h  PI/ S M P C  re q uire me nts f or all I M Ps 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 7  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
t he c o-pri mar y  
e n d p oi nt C M R  rate has bee n  a d de d. 
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 3  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
A p pe n di x  8:  
Ra di ot hera p y 
G ui deli nes f or 
t he R 1  C o h ort  
A d diti o n of  a p pe n di x f or R T 
G ui deli nes  
Create d  b y C O G  a n d E ur o net, t o pr o vi de 
f urt her g ui da nce f or R 1 C o h ort 
C o ns oli dati o n T hera p y. 
All  
Mi n or f or matti n g a n d 
t y p o gra p hical c orrecti o ns  
Mi n or, t heref ore ha ve  n ot  bee n 
s u m marize d 
 
O ver all R ati o n ale f or Re vise d  Pr ot oc ol 0 2: 0 1-J u n -2 0 1 7  
 
Clarificati o n  a b o ut  c o ntrace pti o n  g ui deli nes  was  nee de d  i n  or der  t o  a v oi d  c o nf usi o n  a n d  t o  
har m o nize  differe nces  bet wee n  t he  pr ot oc ol  a n d  gl o bal  pr o d uct  la bels  ( Bre nt u xi ma b  a n d  
Be n da m usti ne). A c o m m o n a p pr oac h f or all I M Ps re q uires 6 m o nt hs of c o ntrace pti o n after last 
I M P  d ose  f or  W O C B P  a n d  7  m o nt hs  f or  males  wit h  part ners  of  W O C B P.  A d diti o nall y,  
clarificati o n  was  pr o vi de d  a b o ut  t he  re q uire me nt  f or  2  c o ntrace pti o n  met h o ds  or  c o m plete  
a bsti ne nce. 
Ot her  mi n or e dits were  ma de,  as descri be d  i n t he S u m mar y  of  Ke y  C ha n ges. 
T his is a p plica ble t o all st u d y patie nts.  
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 2  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
Secti o n  # 2:  
Ta bles  2.- 1 t o 
2.- 4 
A d de d refere nce t o secti o n 9. 1- 
Efficac y Assess me nt.  
Mi n or u p date, t o cr oss-refere nce 
i nf or mati o n i n Secti o n 9. 1 
Secti o n  # 2:  
Ta ble  2.- 5, 
f o ot n ote b 
M o ve f o ot n ote b t o C ycle  3 Da y  1 
S ol u ble, Bi o mar ker Sa m ple  
Mi n or c orrecti o n,  d ue t o i nc o nsiste nc y 
wit h f o ot n ote la n g ua ge. 
Secti o n  # 1:  
S y n o psis; 
Secti o n  # 4  
A d de d c o-pri mar y  e n d p oi nt of 
C M R rate f or R 1 C o h ort.  
T his  c o-pri mar y  e n d p oi nt  was  a d de d  
  
 
 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 8  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 2  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
O bjecti ves  a n d 
E n d p oi nts  
 
 
Secti o n  # 5. 1. 1 
Data 
M o nit ori n g 
C o m mittee 
a n d Ot her 
E xter nal 
C o m mittees  
U p date d D M C  la n g ua ge t o better 
disti n g uis h t he 3 o verarc hi n g 
cate g ories (ras h ≥ 3, p ul m o nar y 
t o xicit y, a n d peri p heral 
ne ur o pat h y) fr o m s u bcate g ories 
a n d c orrecti n g  i nc o nsiste nc y wit h 
n u m ber of o bser vati o ns a n d % 
re q uire d f or e ve nts w here N = 4 0 
Mi n or c orrecti o ns, d ue t o 
i nc o nsiste ncies wit h  ot her la n g ua ge 
wit hi n t his secti o n.  
Secti o n  # 6. 1: 
I ncl usi o n 
Criteria  
I ncl usi o n criteria 3 d was  m o difie d 
t o reflect 2 met h o ds of 
c o ntrace pti o n or c o m plete 
a bsti ne nce (fr o m A p pe n di x 4) are 
re q uire d d uri n g st u d y treat me nt 
u ntil 6 m o nt hs fr o m last d ose of 
all I M Ps f or W O C B P.  
C orrecte d d ue t o i nc o nsiste nc y wit h 
Secti o n 7 refere nce t o f oll o w S M P C/ PI 
f or B v  a n d be n da m usti ne a d mi nistrati o n 
g ui deli nes.  
Secti o n  # 6. 1: 
I ncl usi o n 
Criteria  
I ncl usi o n criteria 3e was  m o difie d 
t o reflect 2 met h o ds of 
c o ntrace pti o n or c o m plete 
a bsti ne nce (fr o m  A p pe n di x 4) are 
re q uire d d uri n g st u d y treat me nt 
u ntil 7 m o nt hs fr o m last d ose of 
all I M Ps f or males wit h part ners 
of W O C B P. A d diti o nall y, t o 
refrai n fr o m s per m d o nati o n 
d uri n g t his ti me.  
C orrecte d d ue t o i nc o nsiste nc y wit h 
Secti o n 7 refere nce t o f oll o w S M P C/ PI 
f or B v  a n d be n da m usti ne a d mi nistrati o n 
g ui deli nes  
Secti o n  # 6. 1: 
I ncl usi o n 
Criteria  
I ncl usi o n criteria 5e was  m o difie d 
t o re q uire 3 half-life was h-o ut f or 
bi ol o gics.  
Mi n or c orrecti o n,  d ue t o i nc o nsiste nc y 
wit h i ncl usi o n criteria 5 f f or 
m o n ocl o nal a nti b o dies.  
Secti o n  # 7. 1:  
S pecif y  a mi ni m u m  of  3 0 mi n utes 
is re q uire d bet wee n e n d of B v 
i nf usi o n a n d be n da m usti ne. 
Mi n or clarificati o n,  f or c o nsiste nc y  wit h 
g ui da nce pr o vi de d f or c o m bi nati o n 
t hera pies i n t his trial. 
Secti o n  # 7. 6. 1  
Delete d “ See secti o n 7. 6. 2. 1 
re gar di n g ste m cell c ollecti o n 
(e g: Ne ulasta)” 
Mi n or clarificati o n, as t his is n ot 
a p plica ble n or  f urt her descri be d  i n 
secti o n 7. 6. 2. 1. 

Cli nical  Pr ot oc ol 
B M S -9 3 6 5 5 8  
C A 2 0 9 7 4 4  
ni v ol u ma b  
Pr ot oc ol  A me n d me nt  N o.:  0 4 
Date: 2 6 -Mar -2 0 2 1  
1 3 9  
A p p r o v e d  v  51 . 0  
9 3 0 1 0 3 5 0 5  5 . 0  
 
 
 
S U M M A R Y  O F  K E Y  C H A N G E S  F O R  R E VI S E D  P R O T O C O L  0 2  
Secti o n 
N u m ber  & 
Title  
 
Descri pti o n of C h a n ge  
 
Brief  R ati o n ale  
Secti o n  # 9. 1. 1  Clarifie d  i ma gi n g m o dalit y  is per 
Sta n dar d of Care  i n f oll o w- u p f or 
patie nts wit h P M R/ N M R.  
Mi n or clarificati o n  of la n g ua ge i n t his 
secti o n. 
Secti o n  # 
1 0. 3. 1:  
Efficac y 
A nal ysis  
U p date d statistical a nal ysis 
met h o d f or C M R rate.  
U p date d d ue t o t he a d diti o n of  
c o-pri mar y  e n d p oi nt ( C M R rate) f or R 1 
c o h ort. 
A p pe n di x 4: 
W O C B P  
Defi niti o n  a n d 
Met h o ds of 
C o ntrace pti o n  
U p date d la n g ua ge re gar di n g 
c o ntrace pti o n re q uire me nts f or all 
I M Ps: 2 met h o ds, 6 m o nt hs after 
last d ose of all I M Ps f or W O C B P, 
a n d 7 m o nt hs after last d ose  of all 
I M Ps f or males wit h part ners of 
W O C B P.  
C orrecte d d ue t o i nc o nsiste nc y wit h 
Secti o n 7 refere nce t o f oll o w S M P C/ PI 
f or B v  a n d be n da m usti ne a d mi nistrati o n 
g ui deli nes.  
All  
Mi n or f or matti n g a n d 
t y p o gra p hical c orrecti o ns  
Mi n or, t heref ore ha ve  n ot  bee n 
s u m marize d