A Phase III, Randomized, Open Label Trial of Nivolumab in Combination With Ipilimumab Versus Pemetrexed With Cisplatin or Carboplatin as First Line Therapy in Unresectable Pleural Mesothelioma
Phase: PHASE3
Conditions: Mesothelioma
Sponsor: Bristol-Myers Squibb



Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
R e vise d Pr ot oc ol N o.: 0 2
Date: 2 5 -A pr -2 0 1 9
2
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 u este 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).
Re place all pre vi o us versi o n(s) of t he pr ot oc ol wit h t his re vise d pr ot oc ol a n d please pr o vi de a c o p y 
of  this re vise d pr ot oc ol  t o all st u d y pers o n nel u n der y o ur s u per visi on, a n d arc hi ve t he pre vi o us 
versi o ns.

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
R e vise d Pr ot oc ol N o.: 0 2
Date: 2 5 -A pr -2 0 1 9
4
D oc u me nt
D ate of Iss ue
S u m m ar y of C h a n ge
Ori gi nal 
Pr ot oc ol
2 5- Ma y - 2 0 1 6
N ot a p plica ble

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
St u d y Desi g n : T his is a n o pe n la bel, ra n d o mize d, P hase 3 st u d y i n a d ult ( 1 8 years) male a n d fe male s u bjects, as a 
first li ne t hera p y f or dia g n ose d u nresecta ble mali g na nt ple ural mes ot heli o ma . 
S u bjects i n eac h ar m will be stratifie d b y:

hist ol o g y: E pit heli oi d vs n o n- e pit heli oi d

ge n der: male or  fe male
S u bjects will be ra n d o mize d i n 1: 1 a n d treate d wit h o ne of t he f oll o wi n g o pe n -la bel treat me nts:

Ar m A: ni v ol u ma b a d mi nistere d I V o ver 3 0 mi n utes at 3 m g/ k g e ver y 2 wee ks c o m bi ne d wit h i pili m u ma b 
a d mi nistere d I V o ver 3 0 mi n utes at 1 m g/ k g e ver y 6 wee ks u ntil pr o gr essi o n, u nacce pta ble t o xicit y, or  ot her 
reas o ns s pecifie d i n t he pr ot oc ol a n d f or a  ma xi m u m treat me nt d ur ati o n of 2 years,. Treat me nt be y o n d i nitial 
i n vesti gat or-assesse d a n d BI C R c o nfir me d pr o gr essi o n acc or di n g t o a da pte d m o difie d R E CI S T ( m-R E CI S T) 
a n d/ or R E CI S T 1. 1 defi ne d pr o gr essi o n is per mitte d if t he s u bject has i n vesti gat or assesse d cli nical be nefit a n d 
is t olerati n g ni v ol u ma b, as s pecifie d i n Secti o n 4. 6

Ar m B : p e metre xe d pl us cis plati n or car b o plati n c h e m ot hera p y a d mi nistere d o n d a y 1 of e ver y 2 1 da y s f or u p 
6 c ycles. C he m ot hera p y treat me nt will c o nti n ue u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, or  co m pleti o n 
of 6 c y cles, w hic he ver c o mes first. 
O n -st u d y t u m or assess me nts will be gi n at Wee k 6 p ost ra n d o mizati o n (7 da ys) a n d be perf or me d e ver y 6 wee ks 
(7 da y s) f or t he first 1 2 m o nt hs a n d e ver y 1 2 wee ks ( ± 7 da ys) t hereafter, or u ntil disease pr o gressi o n is c o nfir me d , 
w h ic he ver occ urs first.
E nr oll me nt will e n d after a p pr o xi matel y 6 0 0 s u bjects ha ve bee n ra n d o mize d.
St u d y P o p ul ati o n: S u bjects m ust meet all eli gi bilit y criteria s pecifie d i n Secti o n 3. 3  of t he pr ot oc ol, i ncl u di n g t he 
f oll o wi n g:
Ke y I ncl usi o n Cri teri a

Male a n d fe male s u bjects ( 1 8 years of a ge).

Hist ol o gicall y pr o ve n dia g n osis of M P M, t h orac osc o p y is hi g hl y rec o m me n de d.

A d va nce d u nresecta ble disease t hat is n ot a me na ble t o th e ra p y wit h c urati ve i nte nt (s ur ger y wit h or  wit h o ut 
c he m ot hera p y). S u bjects t hat ref use p ote ntiall y c urati ve s ur ger y are i neli gi ble
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

A vaila ble (arc hi val a n d/ or fres h) pat h ol o gical sa m ples f or ce ntralize d P D -L 1 I H C testi n g d uri n g t he scree ni n g 
peri o d. S u bjects ca n n ot be ra n d o mize d u ntil t he t u m or tiss ue f or P D -L 1 testi n g has bee n recei ve d at t he Ce ntral 
La b, h o we ver, t he res ult of t he testi n g is n ot re q uire d pri or t o ra n d o mizati o n. S u bjects ca n i nitiate t hera p y bef ore 
t he res ult of P D-L 1 testi n g is a vaila ble. 

Pri o r palliati ve ra di ot hera p y is acce pta ble, b ut at least 1 4 da ys m ust ha ve passe d si nce t he a d mi nistrati o n of t he 
ra di ot hera p y a n d all si g ns of t o xicit y m ust ha ve re mitte d.

E C O G Perf or ma nce Stat us of 0 -1 ( A p pe n di x 1 ).

Meas ura ble disease, defi ne d as at least 1 lesi o n meas ure d i n u p t o t w o p ositi o ns at t hree se parate le vels o n 
tra ns verse c uts of C T sca n t hat is s uita ble f or re peate d assess me nt usi n g a da pte d m o difie d Res p o nse E val uati o n 
Criteria i n S oli d T u m ors [ m -R E CI S T] f or ple ural mes ot heli o ma

A de q uate he mat ol o gical, re nal a n d he patic f u ncti o ns
Ke y E xcl usi o n Criteri a

Pri miti ve p erit oneal, pericar dial a n d t u nica va gi nalis testis  mes ot heli o m as

Br ai n metastasis, e xce pt if s ur gicall y resecte d or  treate d wit h stere ota xic ra di ot hera p y wit h n o e v ol uti o n wit hi n 
t he 3 m o nt hs bef ore i ncl usi o n, a n d as y m pt o matic. I n a d diti o n, s u bjects m ust be eit her off c ortic oster oi ds, or o n a 
sta ble or decreasi n g d ose of 1 0 m g dail y pre d nis o ne ( or e q ui vale nt) f or at least 2 wee ks pri or t o ra n d o mizati o n ,

Pri o r treat me nt wit h a dj u va nt or ne oa dj u va nt c h e m ot hera p y; ra dical ple ur o p ne u m o nect o m y wit h or  wit h o ut 
i nte nsit y m o d ulate d ra di ot hera p y, or n o n-palliati ve R T 

Pri o r i ntra o perati ve or  i ntraca vitar y c he m ot hera p y f or p le ural m es ot heli o ma

Pri o r treat me nt wit h a n a nti-P D -1, a nti -P D -L 1, a nti -P D -L 2, 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.

Hist o r y of c hr onic i nf la m mat or y or a ut oi m m u ne disease

C o nc urre nt or pri or mali g na nc y re q uiri n g or a ntici pate d t o re q uire c o nc urre nt i nter ve nti o n

S u bjects wit h i nterstitial l u n g disease t hat is s y m pt o matic o r m a y i nterfere wit h t he detecti o n or ma na ge me nt of 
s uspecte d dr u g -relate d p ul m o nar y t o xicit y.
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 ucts (I P/I M P) a n d N o n -i n vesti gati o nal [ Me dici nal] 
Pr o d ucts ( N o n -I P/ N o n-I M P) as liste d:
St u d y Dr u g f or C A 2 0 9 7 4 3
Me dic ati o n 
P ote nc y 
I P/ N o n-I P 
Ni v ol u ma b
1 0 m g/ ml
I M P
I pili m u ma b
5 m g/ ml
I M P
Pe metre xe d
2 5 m g/ ml
I M P
Pe metre xe d ( C hi na)
Varies per mar ket pr o d uct
I M P
Cis plati n
1 m g/ ml
I M P
Cis plati n ( C hi na)
Varies per mar ket pr o d uct
I M P
Car b o plati n
1 0 m g/ ml
I M P
Car b o plati n ( C hi na)
Varies per mar ket pr o d uct
I M P
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 1

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
St u d y Assess me nts : T his st u d y will c o nsist of t hree p hases: scree ni n g, treat me nt, a n d f oll o w - u p.
Scree ni n g P h ase

Be gi ns b y esta blis hi n g t he s u bject’s i nitial eli gi bilit y a n d si g ni n g of t he i nf o r me d c o nse nt (I C F).

S u bject is e nr olle d usi n g t he I nteracti ve We b Res p o nse S yste m (I W R S).

T u m o r tiss ue (arc hi val or rece nt t u m or bi o ps y) m ust be s u b mitte d b y t he site t o a t hir d-part y ve n d or f or 
deter mi nati o n of P D -L 1 stat us. A n e mail c o m m u nicati o n will be se nt b y t he t hir d part y ve n d or t o site f or 
c o nfir mati on u p o n recei vi n g t u m or tiss ue. S u bjects ca n i nitiate t hera p y bef ore t he res ult of P D -L 1 I H C testi n g.

S u bject is assesse d f or st u d y eli gi bilit y 
All scree ni n g assess me nts a n d pr oce d ures m ust be perf or me d wit hi n 2 8 da ys pri o r t o treat me nt, u nless ot her wise 
s pecifie d.
Tre at me nt P h ase

T he treat me nt be gi ns wit h t he call t o t he I W R S t o ra n d o mize t he patie nt.

Treat me nt s h o ul d be gi n wit hi n 3 cale n dar da ys of ra n d o mizati o n.
Ar m A :

ni v ol u ma b 3 m g/ k g I V will be a d mi nistere d e ver y 2 wee ks.

i pili m u ma b 1 m g/ k g I V will be a d mi nistere d e ver y 6 wee ks  on t he sa me da y  as t he a d mi nistrati o n of 
ni v ol u ma b.

O n t he da y of i nf usi o n of ni v ol u ma b a n d i pili m u ma b, ni v ol u ma b is t o be a d mi nistere d first. T he sec o n d 
i nf usi o n will al wa ys be i pili m u ma b, a n d will start at least 3 0 mi n utes after c o m pleti o n of t he ni v ol u ma b 
i nf usi o n.
Ni v ol u ma b 3 m g/ k g e ver y 2 wee ks a n d i pili m u ma b 1 m g/ k g e ver y 6 wee ks will be c o nti n ue d u ntil pr o gr essi o n of 
disease, disc o nti n uati o n d ue t o t o xicit y, wit h dra wal of c o nse nt, a ma xi m u m treat me nt d urati o n of 2 years, or  st u d y 
cl os ure. S u bjects m a y  disc o nti n ue o nl y i pili m u ma b a n d c o nti n ue treat me nt wit h ni v ol u ma b if certai n circ u msta nces 
are met ( o utli ne d i n f ull pr ot oc ol).
Ar m B :

Pe metre xe d ( 5 0 0 m g/ m 2) pl us cis plati n ( 7 5 m g per meter of B S A) or car b o plati n ( A U C of 5 m g per milliliter 
per mi n ute) all o n da y 1, e ver y 2 1 da ys f or 6 c ycles or u ntil disease pr o gressi o n or u nacce pta ble t o xicit y. T he 
use of cis plati n is preferre d, h o we ver or car b o plati n ma y be us e d at t he discreti o n o n t he i n vesti gat or, a n d t he 
reas o n f or usi n g car b o plati n i nstea d of cis plati n m ust be re p orte d i n t he C R F.
O verall s ur vi val is t he pr i mar y e n d p oi nt of t he st u d y. O verall s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati on t o 
t he date o f deat h. S u bjects will be assesse d f or res p o nse b y C T sca ns be gi n ni n g at 6 wee ks (7 da y s) after 
ra n d o mizati o n a n d c o nti n ui n g e ver y 6 wee ks (7 da ys) f or 1 2 m o nt hs a n d e ver y 1 2 wee ks ( 7 da ys) t hereafter, u ntil 
pr o gressi o n is BI C R c o nfir me d. I n t he a bsence of pr o gressi o n after 1 2 m o nt hs, t u m or assess me nt s h o ul d occ ur e ver y 
1 2 wee ks ( 1 wee k) u ntil disease pr o gressi o n is BI C R c o nfir me d. A s u bject w h o has n ot die d will be ce ns ore d at last 
k n o w n ali ve date. O S will be f oll o we d c o nti n u o usl y w h ile s u bjects are o n t he st u d y dr u gs a n d e ver y 3 m o nt hs via 
i n-pers o n or p h o ne c o ntact after s u bjects disc o nti n ue t he st u d y dr u gs. All ra n d o mize d s u bjects will be e val uate d.
St atistic al C o nsi der ati o ns :
S a m ple Size: 
A p pr o xi matel y 6 0 0 s u bjects were t o be ra n d o mize d t o t w o treat me nt gr o u ps i n a 1: 1 rati o, wit h 6 0 6 s u bjects act uall y 
ra n d o mize d. T he sa m ple size is base d o n t he c o m paris o n of t he pri mar y e n d p oi nt of O S bet wee n treat me nt gr o u ps, 
wit h t w o -si de d o verall al p ha of 0. 0 5 f or O S .
F or O S, a p pr o xi matel y 4 7 3 e ve nts (ie, deat hs), o bser ve d a m o n g t he 6 0 6 ra n d o mize d s u bjects, pr o vi des 9 0 % p o wer t o 
detect a n a vera ge hazar d rati o ( H R) of 0. 7 2 wit h a t ype 1 err or of 0. 0 5 (t w o-si de d). T here is o n e pla n ne d i nteri m 
a nal ysis of O S f or s u peri orit y at a p pr o xi matel y 8 5 % of t otal e ve nt s, i e, 4 0 3 deat hs. It is esti mate d t hat it will ta ke 
a p pr o xi matel y 3 8/ 5 6 m o nt hs t o o bser ve t he re q uire d n u m ber of e ve nts f or t he i nteri m/fi nal O S a nal ysis.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
2 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
u n derl yi n g E ur o pea n U ni o n Di recti ve 2 0 0 1/ 2 0/ E C a n d t he U nite d States C o de of  Fe deral 
Re g ulati o ns, Tit le 2 1, Part 5 0 ( 2 1 C F R 5 0) a n d 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 mplia nce wi t h t he pr ot o c ol. T he pr ot oc ol a nd a n y a me n d me nts 
a n d t he s u bject i nf or me d c o nse nt will recei ve I nstituti 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 val/fa v ora ble o pi ni o n pri or t o i nit iati on of t he st u d y .
All p ot e nti al serio us breac hes m ust be re p orte d t o S p o ns or or desi g ne e i m me diatel y. A serio us 
breac h is a breac h of  the c o n dit i ons a n d pri nci ples of  GC P i n c o n nect i on wi t h the 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 safety o r p h ysical or me ntal i ntegri t y 
of  t he s u bjects of t he st u d y or t he scie nt ific val ue of t he st u d y.
P ers 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 ucat i on, 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  stu d y  pers o n nel w here sa nctio ns ha ve bee n i n v o ke d or w here 
t here has bee n scie nt ific misc o n d uct or fra u d ( e g, l oss of me dical lice ns ure, de bar me nt). 
2. 2
I n stit uti o n al R e vi e w B o ar d/I n d e p e n d e nt Et hi c s C o m mitt e e 
Bef ore st u d y init iati on, t he i n vesti gat or m u st ha ve wri tte n a n d date d a p pr o val/fa v ora ble o pi ni o n 
fr om 
t he 
I R B/I E C 
f or t he 
pr ot oc ol , c o nse nt 
f or m, s u bject
recr uit me nt mat erials 
(e g, a d vertise me nts), a n d a n y ot her wri tte 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 uld als o pr o vi de t he I R B/I E C wi t h a co p y  of t he I n vesti gator Br oc h ure or pr o d uct 
la beli n g i nf or mati on 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 vest i gat or, S p o ns or or desi g nee s h o uld 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 mat i on (e g, e x pe dite d safety re p orts, a me n d me nts, a n d a d mi nistrati ve lett ers) acc or di n g t o 
re g ulat or y r e q uire me nts or inst itut i on pr oce d ures.
2. 3
I nf or m e d C o n s e nt
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 vol u nteer t o partici pate. 
I n sit uati ons 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 nt ial 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 s u bject v o l unt eers t o partici pate. 
S p o ns or or desi g n ee will pr o vi de t he i n vest i gat or wit h a n a p pr o priate (ie, Glo b al  or L ocal) sa m ple 
i nf or me d c o nse nt f or m whic h will  incl u de all el e 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 mple i nf or me d c o nse nt f or m will a d h er e t o t h e et hical pri nci ples 
t hat ha ve t heir ori gi n i n t he Declarati o n o f Helsi n ki.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
3 6

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
I n vesti gat ors m ust:

Pr o vi d e a c o p y  of t he c o nse nt f or m an d wri tte n i nf or mati o n a b o ut t he st u d y in t he la n g ua ge
i n w hic h t he s u bject is m o st pr oficie nt pri or t o cli nical st u d y partici pat i on. 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  for s u bject or s u bject's le gall y acce pta ble re prese ntati ve t o i n q uire 
a b o ut t he details o f t he st u d y.

O bt a i n an i nf o r me d c o nse nt sig ne d a n d pers o nall y date d b y t he s u bject or t he s u bject'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 wri tte n a p pr o val/fa v ora ble o pi ni o n of  the wri tte n i nf or me d c o nse nt 
f or m a nd a n y ot her i nf or m at i on t o be pr o vide d t o t he s u bjects, prior 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 visio n s are c o mplete d f or ne w i nf or mat i on.
If i nf or me d c o nse nt is i nitiall y gi ve n b y a s u bject’s le gall y acce pta ble re prese ntati ve or le gal 
g uar di a n, a n d t he s u bject s u bse q ue ntl y bec o me s ca pa ble of ma ki n g a n d c om m u nicati n g his or her
i nf or me d c o nse nt d urin g t he st u d y , c o nse nt m ust a d dit i onall y  be o btai ne d fr o m t he s u bject.
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 on bec o me s a vaila ble t hat is 
r ele va nt t o t he s u bject'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 uld f ull y  inf or m  t he s u bject or t he s u bject's le ga ll y acce pta ble re prese ntati ve or le gal g uar dia n, 
of  all perti ne nt as pects of  the st u d y a n d of a n y ne w i nf or mat i on rele va nt t o t he s u bject's willi n g ness 
t o c o nti n ue partici pat i on i n t he st u d y. T his c om m u nicat i on s h o ul d be d oc u m e nte d. 
T he c o nfi de ntialit y o f rec or ds t hat c o ul d i de nt if 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 nt iality 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 orizat i on.
T he c o nse nt f or m must als o incl u de a state me nt t hat B M S a n d re g ulat or y aut h ori ties ha ve direct 
access t o s u bject rec or ds. 
S u bject s u na ble t o gi ve t heir written 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 s u bject
m ust als o be i nf or me d a b o ut t he nat ure of  the st u d y to t he e xt e nt c o m p ati ble wi t h his or her
u n dersta n di n g, a n d s h o ul d t his s u bject 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 so o n as p ossi ble. T he e x plicit  wis h of  a s u bject w h o is u na ble t o give his or 
her wri tte 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 on t o ref use 
parti ci pat i on i n, or t o b e wi t hdra w n fr o m, t he cli nical st u d y at a n y time s h o uld be c o nsi dere d b y 
t he i n vest i 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 uld pre vail  o ver i nterests of scie nce a n d s ociety.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
3 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
3
I N V E S TI G A TI O N A L P L A N
3. 1
S t u d y D e si g n a n d D ur ati o n
Pr ot oc ol  C A 2 0 9 7 4 3 is a ra n d omize d ( 1: 1), o pe n -label, P hase 3 trial i n s u bjects 1 8 years ol d wit h 
u ntreate d u nresecta ble M P M, e val uat i n g n i v ol u ma b c o m bi ne d wi t h ipili m u ma b vers us p e metre xe d 
pl us c is plati n or c ar b o plat i n as a first li ne treat me nt.
S u bject s will u n der g o scree ni n g e valu ati o ns t o deter mi ne eli gi bilit y wi t hi n 2 8 da ys pri or t o first 
treat me nt . It is e x pecte d t hat 8 0 0 s u bjects will be e nr olle d, a n d a p pr o xi matel y 6 0 0 s u bjects will be 
ra n d omize d. 
Ra n d o mizati o n w ill be stratifie d acc or di n g t o t u m or hist ol o g y : e pit helioi d vs sarc omat oi d or mi xe d 
hist ol o g y  su bt y p es a n d t o ge n der: ma le vs fe male. T u m or sa mple f or P D -L 1 stat us assess me nt is 
re q uir e d prior t o ra n d o mizat i on, b ut res ults are n ot nee de d f or ra n d omizat i on.
S u bject s will be treate d wit h o ne of t he f o ll owi n g: 

Ar m A ( n i v ol u ma b/ipili m u ma b C o m b o) : n i v ol uma b 3 m g/ k g I V e ver y  2 wee ks + ipili m u ma b
1 m g/ k g I V e ver y 6 wee ks u nt il disease pr o gressi o n , u nacce pta ble t o xicit y, , or a ma xi m u m 
treat me nt d uratio n of  2 years.

Ar m B ( C o ntr ol Ar m): p e metre xe d 5 0 0 m g/ m 2 pl us c is plati n 7 5 m g/ m 2 or car b o plat i n 
( A U C of  5 mg per milliliter per mi n ute), o n d a y  1 of a 2 1- da ys c ycle f or 6 c ycles or u ntil 
di sease pr o gressio n or u nacce pta ble t o xicit y . T he c h oice of c is plati n is preferre d, h o we ver t he 
us e of  car b o plat i n is at t h e discreti on of  t he i n vesti gat or, a n d t he reas o n f or usi n g car b o plati n 
m ust be d oc u m e nte d i n t he C R F. Ar m B d os e c al c ulat i on s will be a d mi nistere d acc or di n g t o 
la bel a n d/ or l ocal polic y i n t er ms of  inf usi o n sche ma (incl u di n g b ut n ot li mite d t o h y drati o n 
pr ot oc ol s). Vi ta mi ns B 1 2 a n d B 9 s u p ple me ntati o n a n d de xa met has o ne pr e m e dicatio n ar e
re q uire d f or all s u bjects recei vi n g p e metre xe d. De xa m et has o ne ca n be gi ve n as I V i nf usi o n o n 
t he da y of treat me nt as re q uire d by pe metre xe d l a b el a n d/ or lo c al  S O C.
C o m parat or sel ect i on
I n C A 2 0 9 7 4 3 st u d y, n i v ol u ma b c o m bi ne d wi t h ipili m u ma b will  be c o mpare d t o t he wi del y 
a p pr o ve d sta n dar d of  care: p e metre xe d pl us c is plati n. C ar b o plat i n will be all o we d i nstea d of  
c is plati n, as per t he i n vesti gat or assess me nt, base d o n p u blis he d data fr o m a n e x pa n de d access 
pr o gra m o n 1, 7 0 4 c he m o -nai ve s u bjects wi t h MP M c o nfir me d si milar res p o nse rates, ti me-t o-
pr o gressi o n a n d o n e -ye ar s ur vi val usi n g p e metre xe d pl us car b o plat i n a n d p e metre xe d pl us 
c is plati n.1 4
Alt h o u g h, b e vaciz u ma b c o m bi ne d t o p e metre xe d a n d cis plati n has i m pr o ve d O S a n d P F S i n 
che m o -nai ve M P M s u bjects, c o m pare d t o p e metre xe d pl us c is plati n, i n o ne ra n d o mize d si n gle 
c o u ntr y st u d y1 5 , b e vaciz u ma b was n ot c o nsi dere d as part of t he c o ntr ol  ar m for t he c urre nt st u d y, 
gi ve n t he fol l owi n g:

T his strate g y  is n ot a p pr o ve d b y a n y re g ulat or y a ge nc y, 

P ati e nts o ver 7 5 y ears of a ge were e xcl u d e d f r o m t his st u d y,
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
3 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Tre at me nt P h ase

T he treat me nt be gi ns wit h t he call t o t he I W R S t o ra n d omize t he s u bject.

Treat me nt s h o ul d be gi n wit hi n 3 cale n dar d a y s of ra n d omizat i on.
Ar m A (Ni v ol u m a b /I pili m u m a b C o m bi n ati o n ):
N ote: 1 c ycle = 6 wee ks

N i v ol uma b 3 m g/ k g I V will be a d mi nistere d e ver y 2 wee ks.

Ipili m u ma b 1 m g/ k g I V will be a d mi nistere d e ver y 6 wee ks o n t he sa me da y as t he 
a d mi nistrati o n of n i v ol u ma b.

O n t he da y of  inf usi o n of  bot h  ni v ol u ma b a n d i pili m u ma b, n i v ol u ma b is t o be a d mi nistere d 
first. T he i nf usi on ti me f or ni v ol uma b will be 3 0 mi n utes. I pili m u ma b will al wa ys be i nf use d 
aft er ni v o l uma b a n d will
st art at least 3 0 mi n utes aft er t he c o mplet i on of  the n i v ol u ma b
i nf usi on. T he i nf usi o n ti me f or i pili m u ma b will be 3 0 mi n utes.

N i v ol uma b 3 m g/ k g Q 2 wee ks a n d ipili m u ma b 1 m g/ k g Q 6 wee ks will be c o nt i n ue d u ntil t he 
pr o gressi o n of  disease, disc o nt i n uati on d ue t o t o xicit y, wi t hdra wal of  co nse nt, or stu d y cl os ure . 
A s per S ectio n 4. 5. 5. 2 S u bject s ma y disc o nti n ue o nl y ipili m u ma b a n d c o nt i n ue treat me nt wit h 
n i v ol u ma b if re q uire me nts of secti on S ectio n 4. 5. 4 are met .

Treat me nt be y o n d i nit ial i n vesti gat or-assesse d a n d BI C R c o nfir me d pr o gressi o n as defi ne d b y 
a da pte d m- R E CI S T f or ple ural mes ot heli o ma a n d R E CI S T 1. 1, is per mitte d if t he s u bject has 
i n vesti gat or-assesse d cli nical be nefit a n d is t olerat i n g treat me nt, as per S ecti o n 4. 6 .
Ar m B (C o ntr ol Ar m ):

P e m etre xe d ( 5 0 0 m g/ m 2)
pl us c is plati n ( 7 5 m g per met er of  BS A) or car b o plat i n ( A U C of 
5 m g per milliliter per mi n ute) all o n d a y  1 of 2 1 d a y s c ycle, f or 6 c ycles or u ntil disease 
pr o gressi o n a n d u nacce pta ble t o xicit y. T he use of  cis plati n is preferre d, h o we ver car b o plat i n 
ma y b e us e d at t he discretio n of  t he i n vesti gat or, an d t he reas o n f or usi n g car b o plat i n i nstea d 
of  cis plati n m ust be re p orte d i n t he C R F . 
Pre me dic ati o n Re gi me n:
1.
Vi ta mi n S u p ple me ntati o n:
Pri or t o tr e at m e nt, a n d i n or der t o re d uce t he ri s k of he mat ol o gi c a n d gastr oi ntesti nal t o xicit y 
d ue t o p e metre xe d, .s u p ple me ntati o n wi t h oral f olic acid a n d i ntra m usc ular vit a mi n B 1 2 is 
re q uire d a n d has t o be starte d 1 wee k pri or t o t he fir st da y of t hera p y. After ra n d o mizat i on, t his 
pr e m e dicat i on will be di sc o nti n ue d i n pati e nts ra n do mize d t o Ar m 
A ( ni v ol uma b 
a n d 
ipili m u ma b)

Or al  fol ic aci d 3 5 0 t o 1 0 0 0 μ g dail y s h o uld be gi ve n starti n g 1 wee k pri or t o C ycle 1 d a y 
1 , wit h at least 5 d oses of f olic aci d a d mi nistere d i n t he 7 da ys pri or t o t h e first d ose. F or 
pati e nts ra n d omize d to Ar m B, o ral f olic aci d s h o uld be c o nt i n ue d dail y t hr o u g h o ut 
treat me nt wit h pe metre xe d, a n d f or 2 1 da ys after t he last d ose of p e metre xe d ( Da y 1 0 5). 

I ntra musc ular (I M) i njecti o n of  vita mi n B 1 2 1 0 0 0 μ g s h o uld be gi ve n a p pr o xi matel y o ne 
wee k pri or t o C ycle 1 d a y  1. F or patie nts ra n d o mize d t o Ar m B, re peat i ntra m usc ular 
vit a mi n B 1 2 1 0 0 0 μ g d uri n g treat me nt as per l ocal p olic y.
2.
C orti c oster oids:
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
O n Ar m B o nl y , t he rec o m me n dat i on is t o ad mi nister de xa met has o ne 4 m g orall y t wice dail y 
t he da y bef ore, t he day o f, a n d t he da y after p e metre xe d a d mi nistratio n . Si tes ma y f o ll ow l ocal 
p olic y  for c orti c oster oid a d mi nistrati o n.

V ita mi n B 1 2 a n d De xa met has o ne/c orti c oster oids s h o uld be a d mi nistere d as per l ocal p olic y. 
De xa met has o ne ca n be gi ve n as I V i nf usi o n o n t he d a y of treat me nt. 

St u d y  assess me nts are t o be c ollecte d as o utli ne d i n 5. 1 .

U p o n c o m plet i on of d osi n g, s u bjects will e nter t he F oll ow- u p P hase .
F oll o w -u p P h ase :
T he p ost -treat me nt f oll ow- u p be gi ns w he n t he decisi o n is ma de t o disc o nti n ue a s u bject fr o m all 
treat me nt i n Ar m A , or w he n u p t o 6 c ycles of c he m ot hera p y  are c o m p lete d o n Ar m  B.
S u bject s w h o di sc o nti n ue tr e at me nt f or reas o ns ot her t ha n disease pr o gressi o n will  co nti n ue t o 
ha ve t u mor assess me nts (if cli nicall y feasi ble) acc or di n g t o t he sc he d ule i n Ta ble 5. 1 - 3 u ntil 
pr o gressi o n is c o nfir me d b y BI C R.
At  the ti me of  in vest i gat or-assesse d r a dio gra p hic pr o gressi o n per a da pte d m- R E CI S T a n d/ or 
R E CI S T 1. 1 criteria f or assess me nt of  res p o nse, sites m ust s u b mit C T sca n f or bli n de d i n de pe n de nt  
c o m mittee re vie w. Di sease pr o gressi o n m u st be c o nfir me d b y BI C R pri o r t o disc o nt i n uati on of  
treat me nt. S u bjects will be f o ll owe d f or dr u g -relate d t o xicities u ntil these t o xicit ies res ol ve, ret ur n 
t o baseli ne or ar e d e e m e d irre versi ble. All a d verse e ve nts will be d o c u m e nte d f or a mi ni m u m of 
1 0 0 da y s after t he last d ose of st u d y me dicatio n. 
After c o mpleti o n of  the first t wo f oll ow- u p visit s, s u bjects will be f oll owe d e ver y 3 m o nt hs f or 
s ur vi val. S ur vi val F oll o w-u p visi ts ma y be perf or me d b y p h o ne c o ntact or office visit. B M S ma y 
re q uest t hat s ur vi val data be c ollecte d o n all treate d s u bjects o utsi de of  the pr ot oc ol  defi ne d 
wi n d o w. At  that ti me of  this re q uest, eac h s u bject will be c o ntacte d t o deter mi ne t heir s ur vi val 
stat us u nless t he s u bject ha d wit h dra w n c o nse nt f or all c o ntact .
3. 2
P o st St u d y A c c e s s t o T h er a p y
At  the c o nclusi o n of  the st u d y, s u bjects w h o c o nt i n ue t o de m o nstrate cli nical be nefit will b e 
eli gi ble t o recei ve B M S s u p plie d st u d y dr u g. St u d y dr u g will be pr o vi de d via a n e xte nsi o n of  t he 
st u d y, a r oll over st u d y  r e q uirin g a p pr o val b y  res p o nsi ble health a ut h orit y a n d et hics c om mit tee or 
t hr o u g h a n ot her mec ha nis m at t he discreti on of  B M S. B M S reser ves t he rig ht t o ter mi nate access 
t o B M S s u p plie d st u d y dr u g if a n y of t h e foll o wi n g occ ur: a) t he mar keti n g a p plicat i on is rejecte d 
b y res p o nsi ble healt h a ut h orit y; b) t he st ud y is ter mi nate d d ue t o safety c o ncer ns; c) t he s u bject
ca n o btai n me dicati o n fr o m a g o ver n me nt s p o ns ore d or pri vate healt h pr o gra m; or d) t hera pe utic 
alter nati ves bec o me a vaila ble i n t he l ocal mar ket.
3. 3
St u d y P o p ul ati o n
F or e ntr y int o t he stu d y, t he f oll owi n g crit eria M U S T be met
( 2 8 da y s scree ni n g p eri o d fr o m 
e nr o ll me nt t o first treat me nt): 
3. 3. 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
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 1

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
a)
S u bject s m ust ha ve si g ne d a n d date d a n 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 wi t h re g ulat or y an d i nstituti o nal  gui deli nes. T his m u st be o b tai 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 s u bject care.
b)
S u bject s 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, a n d 
la b orat or y t esti n g.
2.
T ar get P o p ul ati o n
a)
Hi st olo gi call y pr o ve n di a g n osis of mali g na nt ple ural mes ot heli o ma ( M P M) wi t h 
deter mi nat i on of e pit heli o id vs n o n -e pit helioi d hist ol o g y , t horac osc o p y  is hi g hl y 
rec o m me n de d.
b)
M ust ha ve a d va nce d u nresecta ble di sease t hat is n ot a me na ble t o t hera p y with c urativ e 
i nte nt (s ur ger y with or wit h o ut c he m ot hera p y). S u bject s t hat ref use p ote nti all y curati ve 
s ur ger y are i neli gi ble.
c)
A vaila ble (arc hi val a n d/ or fres h) pat h ol o gical sa m ples f o r ce ntralize d P D-L 1 I H C testi n g .
S u bjects ca n n ot be ra n d o mize d u nt il t he t u m or sa m ple has bee n recei ve d at t he ce ntral 
la b orat or y, b ut testi n g res ult is n ot re q uire d pri or t o ra n d o mizati on.
d)
Pri or palliat i ve ra di ot hera p y is acce pta ble, h o we ver at  least 1 4 da ys must ha ve passe d 
pri or t o fi rst treat me nt, a n d all si g ns of t o xicit y m ust ha ve re mitte d. Pri or p r o p h ylactic 
r a diot h era p y t o a ple ur o desis drai na ge tract or bi o ps y site is allo we d
e)
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us of 0 -1 (A p pe n di x 1 ).
f)
Meas ura ble disease
is defi ne d as
i)
Mes ot heli o ma t u m or t hic k ness per pe n dic ular t o t he c hest wall or me diast i n u m, t hat 
ca n be meas ure d i n u p t o t w o p ositi o ns at t hree se parate le vels o n tra ns verse c uts of 
C T sca n (c uts m ust be at least 1 0 m m a part), f or a t otal of u p t o 6 meas ure me nts.  
Eac h si n gle t u m or meas ure me nt m ust be at least 1 0 m m t o q ualif y as meas ura ble 
di sease a n d c o ntri b ute t o t he s u m t hat defi nes t he ple ural meas ure me nt. See A p pe n di x  
4 .
ii) N o n -pl e ural metastatic tar get lesio n s meas ure d u ni-di me nsi o nall y  as per R E CI S T 1. 1 
criteria. See A p pe n di x 4.
iii) P ati e nts w h o prese nt wit h o ut ple ural lesi o ns t hat ca n be c o nsi dere d meas ura ble, b ut 
wi t h metastatic lesio n s meeti n g crit eria for tar get l esio n  b y R E CI S T 1. 1 criteria ma y 
be c o nsi d ere d f or i nclusi o n  after c o ns ult atio n wi t h t he Me dical M o nit or.
g)
S u bject
Re -e nr oll me nt: T his st u d y per mits t he re-e nr oll me nt of  a s u bject t hat has 
di sc o nti n ue d t he st u d y as a pre-treat me nt fail ure (ie, s u bject has n ot bee n ra n d o mize d / has 
n ot bee n treate d) . If r e-e nr olle d, t he s u bject m ust be re -c o nse nte d.
h)
S u bjects wit h a hist or y  of ple ur o desi s are all o we d o n st u d y.
3.
A ge a n d Re pr o d ucti ve St at us
a)
Males a n d Fe males , a ges 1 8 years, i ncl usi ve
b)
W o me n of  chil d beari n g p ote ntial  (W O C B P) 
m ust 
ha ve a ne gat i ve ser u m or uri ne 
pre g na nc y test ( mi ni m u m se nsit i vity 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 treat me nt start.
c)
W o me n m ust n ot be breast fee di n g.
d)
W o me n of  chil d beari n g p ot e nti al ( WO C B P) m ust 
a gree t o f oll ow i nstr uctio ns f or 
met h o d(s) of c o ntrace pti o n fr o m t he ti me of e nr oll me nt f or t he d urati o n of treat me nt wit h: 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
i)
A R M A: f or a peri o d of  30 d a y s ( d uratio n of  ov ulat or y  cyc le) pl us t he ti me re q uir e d 
f or t he i n vesti gati o nal dr u g t o u n der g o fi ve half -li ves. T he t er mi nal half -life of  
n i v ol u ma b is u p t o 2 5 da ys. W O C B P ra n d o mize d t o recei ve n i v ol u ma b pl us 
ipili m u ma b s h o uld use a n a de q uate m et h o d t o a v oi d pre g na nc y for 2 3 wee ks ( 3 0 d a y s 
pl us t he ti me re q uire d f or n i v ol u ma b t o u n der g o fi ve half -li ves) after t he last d ose of 
i n vesti gati onal dr u g . 
ii) A R M B: c he m ot hera p y pl us 5- half -li ves of  che m ot hera p y  pl us 3 0 d a y s ( d uratio n of 
o v ul at or y cycle) f or a t otal of 3 0 da ys p ost treat me nt c o m p leti on o r a d urati o n s pecifie d 
b y t he l o c al  la bels of t he c he m ot hera p y dr u gs recei ve d, w hic he ver is l o n ger.
e)
M e n w h o are se x uall y acti ve wit h W O C B P m ust a gree t o f o ll ow i nstr ucti o ns f or met h o d(s) 
of  c o ntrace ptio n f or t he d urati o n of  treat me nt wi t h:
i)
A R M A: n i v ol u ma b pl us 5 half -li ves of  ni v ol u ma b pl us 9 0 da ys ( d uratio n of  sper m 
t ur n o ver) f or a t otal of 3 1 wee ks p ost treat me nt c o m plet i on.
ii) Ar m B: c he mot h era p y pl us 5 half -li ves of  che m ot hera p y  pl us 9 0 da ys ( d urati o n of 
s per m t ur n o ver) f or a t otal of 9 0 da ys p ost treat me nt c o m plet i on or a d urati o n s p ecifie d 
b y t he l ocal la bels of  the c he m ot hera p y dr u gs recei ve d, w hic he ver is l on ger (f or 
s u bjects treate d i n t he c o ntr ol ar m).
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 act i ve are als o e xe mp t fr o m c o ntrace pti ve re q uire me nts, 
a n d st ill m ust u n der g o pre g na nc y testi n g as descri be d i n t his s e ctio n.
I n vesti gat ors s hall c o u nsel W O C B P, a n d male s u bjects w h o are se x uall y acti ve with W O C B P, o n 
t he i m p orta nce of  pre g na nc y pre ve nt i on a n d t he i m plicati on s of  an u ne x pecte d pre g na nc y. At  
mi ni m u m, s u bjects m ust a gree t o use o ne hi g hl y effect i ve met h o d of c o ntrace pti o n as descri be d i n 
A p pe n di x 3 .
3. 3. 2
E x cl u si o n Crit eri a
1.
T ar get Dise ase E xce pti o ns
a)
Pri mit i ve perit o neal, pericar dial, testis or t u nica va gi nalis mes ot heli o ma.
b)
Brai n metastasis, e xce pt if s ur gicall y resecte d or treate d wit h stere ota xic ra di ot hera p y wit h 
n o e v ol ut i on wi t hi n t he 3 m o nt hs b ef or e i ncl usi o n. I n a d ditio n, s u bjects m u st be 
as y m pt o mat ic a n d eit her off c ortic oster oids, or o n a sta ble or decr easi n g d os e of  1 0 m g  
dail y  pre d nis o ne ( or e q ui vale nt) f or at least 2 wee ks pri or t o first treat me nt. 
c)
U n deter mi ne d hist o l og y  of e pit helioi d vs n o n -e pit helioi d stat us
2.
Me dic al Hist or y a n d C o nc urre nt Dise ases
a)
Pri or treat m e nt wit h a n a nti-P D -1, a nti -P D -L 1, a nti-P D -L 2, a nt i-C T L A -4 a nt i 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 on or c hec k p oi nt 
pat h wa ys.
b)
Pri or t hera p y for M P M
(i ncl u di ng c he m o t hera p y [ a dju va nt, ne o adj u va nt], ra dical 
pl e ur o p ne u mo n ect o m y wit h or wit ho ut i nte nsi ty m o d ul ate d ra diot h era p y, a n d n o n-
palliat i ve R T) 
c)
Pri or i ntra o perati ve or i ntraca vitar y c he mot h era p y for pl e ural mes ot heli o ma.
d)
S u bject s wi t h pr e vio us mali g na ncies (e xce pt n o n- mela n o ma s ki n ca ncers, a n d i n sit u 
ca ncers s uc h as t he f oll owi n g: bla d der, gastri c, c olo n, cer vical/ d ys plasia, mela n o ma, or 
breast) are e xcl u de d u nless a c o m plete re missi o n was ac hie ve d at least 3 years pri or t o first  
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
treat me nt a n d n o a d ditio nal t hera p y is re q uir e d or a nt ici pate d t o be re q uire d d uri n g t he 
st u d y p erio d.
e)
Ot her 
acti ve mal i g na nc y re q uiri n g c o nc urre nt i nter ve nt i on
or w here 
c o nc urre nt 
i nter ve nt i on is a ntici pate d w hile o n st u d y.
f)
S u bject s wi t h an acti ve, k n o w n or s us pecte d a ut oi m m u ne disease. S u bject s wi t h ty pe I 
di a betes me llit us, h y p ot h y r oidis 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)
S u bject s wit h a c o n diti on 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 dicat i ons wi t hi n 1 4 da ys of  
first tr e at me nt. I n h al e d or t o pical ster oids, a n d a dre nal re place me nt ster oi d > 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.
h)
S u bject s wi t h int erstitial lu n g disease t hat is s y m pt o mat ic or ma y i nterfere wi t h the 
detecti o n or ma na ge me nt of s us pecte d dr u g -relate d p ul m onar y t o xicit y.
i)
K n o w n me dic al co n di tio n  that, i n t he i n vesti gat or’s o pi ni o n, w o ul d i ncrease t he ris k 
ass ociate d wit h st u d y partici pati o n or stu d y dr u g a d mi nistrati o n or i nterfere wi t h the 
i nter pretatio n of  s afet y res ults.
j)
S u bjects wit h seri o us or u nc o ntr olle d me dical dis o r ders
k)
Treat me nt wit h b ota ni cal pre parati o ns (e g her bal s u p ple me nts or tra diti onal C hi nese 
me dici nes) i nte n de d f or ge neral healt h s u p p ort or t o treat t he di sease u n der st u d y wit hi n 2 
wee ks pri or t o ra n d o mizat i on/treat m e nt.
3.
P h ysic al a n d L a b or at or y Test Fi n di n gs
a)
K n o w n h ist or y of testi n g p ositi ve 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). P osit i ve test f or h u ma n 
i m m u n o deficie nc y vir us ( HI V). 
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 (e g, 
G er m a ny , S o ut h Africa ).
b)
A n y p osi tive test res ult f or he patitis B vir us or he patit is C vir us i n dicati n g prese nce of 
vir us, e. g. He pati tis B s urface a ntige n ( H Bs A g, A ustralia a nt i ge n) p ositi ve, or He patitis C 
a nt i b o d y (a nti-H C V) p osi tive (e xce pt if H C V -R N A ne gat i ve)
c)
I na de q uate he mat ol o gic, re nal or he patic f uncti o n defi ne d b y a n y of t he f oll owi n g 
scree ni n g la b orat or y val ues:
i) W B C < 2 0 0 0/L
ii) Ne utr o p hils < 1 5 0 0/L
iii) Platelets < 1 0 0 x 1 0 3/L
i v) He m o gl o bi n < 9. 0 g/ d L
v) S er u m  creati ni ne > 1. 5 x U L N u nless creati ni ne cleara nce ≥ 4 0 m L/ mi n ( meas ure d or 
calc ulate d usi n g t he C oc kr oft -Ga ult f or m ula)
vi) A S T/ A L T > 3. 0 x U L N ( > 5 x U L N if li ver metastases)
vii) T otal  Bilir u bi n > 1. 5 x U L N (e xce pt s u bjects wit h Gil bert S y n dr o me w h o m ust ha ve a 
t otal bilir u bi n le vel < 3. 0 m g/ d L)
4.
Alle r gies a n d A d verse Dr u g Re acti o n
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 4

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
3. 5
Di s c o nti n u ati o n of S u bj e c ts f oll o wi n g a n y Tr e at m e nt wit h St u d y Dr u g 
S u bject s M U S T 
disc o nt i n ue i n vesti gati onal pr o d uct (a n d n o n- i n vesti gati onal pr o d uct at  the 
di scretio n of  t he i n vesti gat or) f or a n y of t he f o ll owi n g reas o ns:

S u bject ’s re q uest t o st o p st u d y treat me nt

A n y cli nical ad verse e ve nt ( A E), lab orat or y a b n or malit y or c o nc urre nt ill ness w hic h, i n t he 
o pi ni o n of t he i n vest i gat or, i n dicates t hat c o nti n ue d partici pati on i n t he st u d y is n ot i n t he best 
i nterest of t he s u bject

Di sease pr o gressio n ( must be c o nfir me d b y BI C R pri or t o disc o nti n uatio n of  tr e at me nt)

Ter mi nat i on of t he st u d y b y Brist ol -M yers S q ui b b ( B M S )

L oss of  abilit 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 unt ar il y i ncarcerati o n 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e g, i nfect i ous di sease) ill ness

Pre g na nc y *

A d dit i onal pr ot oc ol -s pecifie d reas o ns f or disc o nt i n uati o n as per S ectio n 4. 5. 5 .

Gl o bal d et eri orati o n of  healt h stat us re q uiri n g disc o nti n uat i on of  tr e at me nt wit h o ut o bj ect i ve 
e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as ‘s y m pt o mat ic deteri orati o n’
i n t he s o urce data a n d i n t he case re p ort f or m. T u m or assess me nts f or s u bjects w h o disc o nti n ue 
st u d y treat me nt wi t ho ut ra di o gra p hic pr o gressi o n, s h o uld c o nti n ue as per pr ot oc ol  unt il 
r a dio gra p hic pr o gressi o n is deter mi ne d.
* I n t he case of  pre g na nc y, t he in vest i gat or m ust i m me diatel y n otif y  the S p o ns or or desi g n ee of 
t his e ve nt. I n m ost cases, t he st u d y dr u g will be per ma ne nt l y disc o nti n ue d i n a n a p pr o priate ma n ner 
(e g, dose ta peri n g if necessar y  for s u bject safety) . Please c o ntact t he S p o ns or or desi g n ee wi t hi n 
2 4 h o urs of  aware ness of  the pre g na nc y . If the i n vesti gat or deter mi nes a p ossi ble fav ora ble 
be nefit/ris k r atio t h at warra nts c o nt i n uati on of  st u d y dr u g, a disc ussi o n bet wee n t he i n vesti gat or 
a n d t he S p o ns or or desi g n e e m u st occ ur, if l ocal re g ulat io ns all o w.
All s u bjects w h o di sc o nti n ue st u d y dr u g s h o ul d c o mpl y wi t h pr ot oc ol specifie d f oll ow- u p 
pr oce d ures as o utli ne d i n S ectio n 5. 1 . T he o nl y  exce pt i on t o t his re q uire me nt is w he n a s u bject
wi t hdra 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 fol l ow- u p or l os es t h e 
a bilit y t o co 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 hi atric or p h ysical ill ness).
If st u d y dr u g is di sc o nti n ue d pri or t o t he s u bject’s c o m p leti o n of  the st u d y, t he reas o n f or t he 
di sc o nti n uati on m u st be d oc u m e nte d i n t he s u bject’s me dical 
rec or ds a n d e ntere d o n t he 
a p pr o priate case re p ort f or m ( C R F) pa ge.
3. 6
P o st St u d y Dr u g St u d y F oll o w u p
I n t his st u d y, o verall s ur vi val is a k e y  pri mar y  e n d p o i nt. P ost st u d y fol l ow- u p is of  critic al 
i m p orta nce a n d is esse ntial t o preser vi n g s u bject safety a n d t he i nte grit y o f the st u d y. S u bject s w h o 
di sc o nti n ue st u d y dr u g m ust c o nti n ue t o be f oll owe d f or c ollect i on of  out c o me a n d/ or s ur vi val 
f oll ow- u p data as re q uire d a n d i n li ne wit h S ectio n 5. 1 u ntil deat h or t he c o ncl usi o n of t he st u d y .
B M S m a y re q uest t hat s ur vi val data be c ollecte d o n all treate d/ra n d o mize d s u bjects o utsi de of t he 
pr ot oc ol  defi ne d wi n d o w. At t he ti me of t his re q uest, eac h s u bject will be c o ntacte d t o deter mi ne 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
t heir s ur vi val stat us u nless t he s u bject has wi t hdra w n c o nse nt f or all co ntacts or i s l ost t o fol l ow-
u p. 
3. 6. 1
Wit h dr a w al of C o n s e nt
S u bject s w h o re q uest t o disc o nt i n ue st u d y dr u g will re mai n i n t he st u d y an d m u st c o nt i n ue t o be 
f oll owe d f or pr ot oc ol s peci fie d f oll ow- 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 s u bject
s pecificall y wi t hdra 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 s u bject t o pr o vi de t his i nf or matio n. S u bject s s h o uld n otif y t he in vesti gat or of  the 
decisi o n t o wit h dra w c o nse nt fr o m f ut ure f oll ow- u p i n writi n g , if p ossi ble. T he wi t hdra 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 in vest i gat or, as t o w het her t he 
wi t hdra wal  is fr o m furt her treat me nt wi t h st u d y dr u g o nl y or als o fr om st u d y pr oce d ures a n d/ or 
p ost treat me nt st u d y fol l ow- 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 vit al 
stat us ( w het her t he s u bject is ali ve or dea d) is bei n g meas ure d, p u blicl y a vaila ble i nf or mati on 
s h o uld be u se d t o deter mi ne vit al stat us o nl y  as a p pr o priatel y di recte d i n acc or da nce wi t h lo c al 
la w.
3. 6. 2
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 s u bjects 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 ow- u p wi t h pers o ns a ut h orized b y  t he s u bject as n ote d a b o ve. L ost t o f o ll ow- u p 
is defi ne d b y t he i na bility t o reac h t he s u bject 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 s u bject t o o n e r e gistere d ma il letter. All att e mpts 
s h o uld be d oc u me nte d i n t he s u bject’s me dical rec or ds. If it is deter mi ne d t hat t he s u bject has die d,  
t he site will use per missi ble l ocal met h o ds t o o btai n t he date a n d ca use of deat h.
If in vesti gat or’s use of t hir d -part y  re prese ntati ve t o assist i n t he f oll ow- 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 s u bject’s i nf or me d c o nse nt, t he n t he in vest i 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 wi t h o btai ni n g s u bject’s c o ntact i nf or mati o n or ot her 
p u blic vital stat us data neces s ar y t o c o mplete 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 mat i on. If after all atte m pts, t he s u bject re mai ns 
l ost t o f oll ow- 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 uld be 
re p orte d a n d d oc u me nte d i n t he s u bject’s me dical rec or ds.
4
S T U D Y D R U G
St u d y  dr u g i ncl u des b ot h In vesti gati o nal [ Me dici nal] Pr o d uct (I P/I M P) a n d N o n -in vest i gati ona l 
[Me di ci nal] Pr o d uct (N o n- I P/ N o n-I M P) a n d ca n c o nsist of t he f oll o wi n g:
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 4- 1:
St u d y Dr u gs f or C A 2 0 9 7 4 3 :
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
Bl i n de d or 
O p e 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 i njecti o na
1 0 0 m g/ vial
( 1 0 m g/ m L)
I P
O p e n La bel
1 0 m L vial c o ntai ni n g a clear t o o pale sce nt, 
c ol or less t o pale yell o w li q ui d; ma y c o ntai n 
partic ulates; 5
vials/cart o n
St ore 2 t o 8° C. St ore i n 
or i gi nal pac ka ge. D o n ot 
freeze. Pr otect fr o m li g ht.
I pili m u ma b i njecti o n
2 0 0 m g/ vial ( 5 
m g/ m L)
I P
O p e n La bel
4 0 m L via l c o ntai ni n g a clear, c ol orless liq ui d; ma y 
c o ntai n partic ulates; 4 vials/cart o n
St ore 2 t o 8° C. St ore i n 
or i gi nal pac ka ge. D o n ot 
freeze. Pr otect fr o m li g ht.
Cis plati n C o n ce ntrate f or 
s ol uti o n f or i nf usi o nb
1 0 0 m g/ vial ( 1 
m g/ ml)
I P
O p e n La bel
1 0 0 m L vial c o ntai ni n g a clear, c ol orless s ol uti o n; 
4 vials/cart o n
D o n ot st ore a b o ve 2 5° C. 
D o n ot refri gerate or 
freeze. Kee p t he vial i n 
t he o uter cart o n.
Cis plati n I nf usi o n 
( C hi na)
Varies as per 
mar ket pr o d uct
I P
O p e n -la bel
As per mar ket pr o d uct
St ore as i n dicate d o n 
mar ket pr o d uct.
Car b o plati n S ol uti o n f or 
I V I njecti o nb
4 5 0 m g/ vial 
( 1 0 m g/ m L)
I P
O p e n La bel
4 5 m L vial c o ntai ni n g a sterile, c ol orless t o sli g htl y 
yell o w a q ue o us s ol uti o n; 4 vials/cart o n
St ore at or bel o w 2 5° C. 
Pr otect fr o m li g ht.
Car b o plati n I njecti o n
( C hi na)
Varies per 
mar ket pr o d uct
I P
O p e n -la bel
As per mar ket pr o d uct
St ore as i n dicate d o n 
mar ket pr o d uct
Pe metre xe d
5 0 0 m g/ vial
I P
O p e n La bel
W hite t o eit her li g ht
yell o w or gr ee n -yell o w
l y o p hilise d p o w der, 1 vial/cart o n
St ore at 2 5° C.
E xc ursi o ns per mitte d
( 1 5-3 0° C)
Pe metre xe d Dis o di u m 
f or I njecti o n ( C hi na)
5 0 0 m g/ vial
I P
O pe n la bel
As per mar ket pr o d uct
St ore as i n dicate d o n 
mar ket pr o d uct
a
Ma y  be la bele d as eit her “ B M S - 9 3 6 5 5 8-0 1” or “ n i v ol u ma b”.
b
T hese pr o d uct s 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 ons. 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 ho ul d be pr e pare d/st ored/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).
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
4 9

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
4. 1
I n v e sti g ati o n al Pr o d u ct
A n i n vesti gati onal pr o d uct, als o k n o w n as i n vesti gati o nal me dici nal pr o d uct i n s ome r e gio n s, is 
defi ne d a p har mace ut ical f or m of a n acti ve s u bsta nce or place b o bei n g teste d or use d as a refere nce 
i n a cli nical st u d y. T hese i ncl u de pr o d ucts alrea d y wi t h a mar ket i n g a ut h orizat i on b ut use d or 
asse m ble d (for m ulate d or pac ka ge d) differe nt l y t ha n t he a ut h orize d f or m, or use d f or a n 
u na ut h ori ze d i n d icatio n, or w he n use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
T he i n vesti gati onal pr o d uct s h o uld be st ore d i n a sec ure area acc or di n g t o lo c al  re g ulat i ons. It is 
t he res p o nsi bility of  the i n vesti gat or t o e ns ure t hat i n vesti gati onal pr o d uct is o nl y  dis pe nse d t o 
st u d y s u bjects. T he i n vesti gati onal 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 ulat i ons.
4. 2
N o n -i n v e sti g ati o n al Pr o d u ct
Ot her me d icati ons use d as s u p p orti ve care or me dicat i ons f or pre ve ntati ve, di a g n ostic, or 
t hera pe utic reas o ns, as c o m p o ne nts of  the st a n dar d of  care f or a gi ve n dia g n osis, ma y be c o nsid er e d 
as n o n- i n vesti gati onal pr o d ucts. 
Pr e m e dicat i on use d wi t h Pe metre xe d ( Vita mi n s u p ple me ntatio n a n d de xa met has o ne) will n ot be 
s u p plie d b y Brist ol-M yers S q ui b b.
4. 3
St or a g e of St u d y Dr u g
T he pr o d uct st ora ge ma na ger s h o uld e ns ure t hat t he st u d y dr u g is st ore d i n acc or da nce wi t h the 
e n vir o n me ntal c o n ditio ns (t e mperat ure, li g ht, a n d h u mi di t y) as deter mi ne d b y B M S . If c o ncer ns 
re gar di ng t he q ualit y o r a p peara nce of t he st u d y dr u g arise, t he st u d y dr u g s h o ul d n ot be dis pe nse d
a n d c o ntact B M S i m me diatel y.
St u d y  dr u g 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 onal 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 hi s i ncl u des 
d oc u m e nt atio 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 t e mperat ures, 
rec o nstit uti o n, a n d use of re q uired pr ocesses ( e g, re q uire d dil ue nts, a d mi nistrati o n sets).
I nf usi on- r elate d s u p plies ( e g, I V ba gs, i n-li ne filters, 0. 9 % Na Cl s ol uti on) will n ot be s u p plie 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 ulat i ons.
F or n i v ol uma b a n d ipili m u ma b , pl ease refer t o t he c urre nt versi o n of  the I n vesti gat or Br oc h ures 
a n d/ or p har mac y r efere nce s heets f or c o mplete st ora ge, ha n dli n g, di s pe nsi n g, a n d i nf usi on 
i nf or mat i on.
Pl ease refer t o Secti o n 9. 2. 2 f or g uida nce o n I P rec or ds a n d d oc u me ntati o n.
4. 4
M et h o d of A s si g ni n g S u bj e ct I d e ntifi c ati o n
After t he s u bject’s i nitial eli gi bilit y is esta blis he d a n d i nf or me d c o nse nt h as bee n o btai ne d, t he 
s u bject m ust be e nr olle d i nto t he stu d y b y a n i nteracti ve we b res p o nse s yste m (I W R S) t o o btai n 
t he s u bject n u m ber. E ver y s u bject t hat si g ns t he i nf or me d c o nse nt f or m m ust be assi g ne d a s u bject
n u m ber i n I WR S . S pecific i nstr ucti o ns f or usi n g I W R S will be pr o vi de d t o t he i n vest i gati onal site 
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
i n a se parate d oc u me nt. T he i n vesti gat or or desi g nee will  re gister t he s u bject f or e nr oll me nt b y 
f oll owi n g t he e nr oll me nt pr oce d ures esta blis he d b y B M S. T he f oll owi n g i nf or mati o n is re q uir e d 
f or e nr oll me nt:

Date t hat i nf or me d c o nse nt was o b tai ne d

Date of birt h

Ge n der at birt h 

Arc hi ve d t u m or tiss ue s u b missi o n date
O nce e nr olle d i n I WR S , s u bjects t hat ha ve met all eli gi bilit y cr iteria will be rea d y to be ra n d o mize d 
t hr o u g h I W R S. T he f oll owi n g i nf or m at i on is re q uire d f or s u bject ra n d o mizati on:

S u bject n u m ber

Date of birt h

Ge n der at birt h 

T u m or hist ol o g y : e pit helioi d vs sarc o m at oid or mi xe d hist ol o g y  
S u bject s will be ra n d omize d i n a 1: 1 rati o t o o ne of t w o treat me nt ar ms.
E nr oll me nt will st o p o nce a p pr o xi matel y 6 0 0 s u bjects ha ve bee n ra n d omize d.
T he e xact pr oce d ures f or usi n g t he I W R S will be detaile d i n t he I WR S ma n ual.
4. 5
S el e cti o n a n d Ti mi n g of D o s e f or E a c h S u bj e ct
T he d osi n g sc he d ule is detaile d bel o w i n Ta ble 4. 5 - 1.
All s u bjects will be m o nit ore d c o nt i n u o usl y f or A Es w hile o n st u d y treat me nt. Treat me nt 
m o dificati o ns ( e g, d ose dela y, re d ucti o n, retreat me nt, or disc o nti n uati on) will be base d o n s pecific 
la b orat or y a n d a d verse e ve nt criteria, as descri be d i n Secti o ns 4. 5. 2 , 4. 5. 3 , 4. 5. 4 , 4. 5. 5 .
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Cli n ical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 4. 5 - 1:  
D osi n g Sc he d ule (Ar m A: 1 C ycle = 6 wee ks ; A r m B: 1 C ycle = 3 wee ks )
Wee k 1
± 3 da ys
Wee k 2
Wee k 3
± 3 da ys
Wee k 4
Wee k 5
± 3 da ys
Wee k 6
Ar m A a, b, c
Ni v ol u ma b 3 m g/ k g q 2 w ks
+ I pili m u ma b 1 m g/ k g q 6 w ks 
C ycle 1 D a y 1
Ni v ol u ma b
+I pili m u ma b
C ycle 1 D a y 1 5
Ni v ol u m a b
C ycle 1 D a y 2 9
Ni v ol u ma b
Ar m B c, d,e
Pe metre xe d 5 0 0 m g/ m 2
± Cis plati n 7 5 m g/ m 2
( or Car b o plati n A U C 5)
C ycle 1 D a y 1
Pe metre xe d + Cis plati n 
(or  Car b o plati n)
C ycle 2 D a y 1
Pe metre xe d + Cis plati n 
(or  Car b o plati n)
a
B ot h ni v ol u ma b a n d i pili m u ma b s h o ul d be a d mi nistere d as 3 0 mi n ute i nf usi o ns. Ni v ol u ma b is t o be a d mi nistere d first. T he sec o n d i nf usi o n will be i pili m u ma b 
a n d will start at least 3 0 mi n utes a fter c o m pleti o n of t he ni v ol u ma b i nf usi o n.
b
Treat me nt c o nti n ue d u ntil disc o nti n uati o n d ue t o t o xicit y, wit h dra wal of c o nse nt, ma xi m u m treat me nt d urati o n of 2 years, or  st u d y cl os ure. I n t he e ve nt of 
i n vesti gat or assesse d ra di o gra p hic disease pr o gressi o n, treat me nt ma y be dela ye d until c o nfir mati o n of pr o gressi o n b y BI C R .
c
Pr e -treat me nt oral f olic aci d 3 5 0 t o 1 0 0 0 μ g dail y s h o ul d be gi ve n starti n g 1 wee k  pri or t o t he first d ose. I ntra m usc ular vita mi n B 1 2 1 0 0 0 μ g pre me dicati o n is 
re q uire d a p pr o xi matel y 1 wee k pri or t o c ycle 1 da y 1. O n Ar m B o nl y, re peat i ntram usc ular vita mi n B 1 2 1 0 0 0 μ g d uri n g treat me n t as per l ocal p olic y.
d
Rec o m me n dati o n is t o a d mi nister de xa met has o ne 4 m g orall y t wice dail y t he da y b ef ore, t he da y of, a n d t he da y after pe metre xed a d mi nistrati o n. Sites t o f oll o w 
l ocal p olic y f or c ortic oster oi ds a d mi nistrati on.
e
Treat me nt t o c o nti n ue f or 6 cycles u ntil disease pr o gr essi o n or  unacce pta ble t o xicit y. I n t he e ve nt of i n vesti gat or assesse d ra di o gra p hic disease pr o gressi o n, 
treat me nt ma y be dela ye d u ntil c o nfir mati o n of pr o gressi o n b y BI C R.
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Date: 2 5- A pr- 2 0 1 9
5 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
4. 5. 1
D o si n g
4. 5. 1. 1
Ni v ol u m a b pl u s I pili m u m a b
S u bjects will recei ve tr e at me nt wit h ni v o l u ma b as a 3 0 mi n ute i nf usi on 3 m g/ k g e ver y 2 wee ks
a n d i pili m u ma b as a 3 0 mi n ute i nf usi on 1 m g/ k g e ver y 6 wee ks, starti n g o n Da y  1, u nt il
pr o gressi o n, u nacce pta ble t o xicit y, wi t hdra wal of c o nse nt, or t he st u d y en ds, w hic he ver occ urs
first. S u bjects 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 ra n d o mizati o n.
D osi n g calc ulat i ons 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 
r e-calc ulate s u bse q ue nt d oses if t he s u bject’s 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 uld be r o u n de d u p t o t he nearest milli gra m per i nstit uti o nal 
sta n dar d. S u bjects ma y be d ose d n o les s tha n 1 2 da ys fr o m t he pre vi o us d ose d uri n g e ver y 2 wee ks 
ni v o l u ma b d ose. T here will be n o d ose m o dificati o ns all o we d. S u bjects s h o uld be caref ull y 
m o nit ore d f or i nf usi on r eact i ons. If an ac ute i nf usi o n r eact i on is n ote d, s u bjects s h o uld be ma na ge d 
acc or di n g t o Secti o n 4. 8. 2
W he n st u d y dr u gs ( ni v o l uma b a n d i pili m u ma b) are t o be a d mi nistere d o n t he sa me da y, ni v o l u mab 
is t o be a d mi nistere d first. Ni v o l uma b i nf usi on m ust be pr o m pt l y f oll o we d b y a sali ne fl us h t o 
clear t he li ne of  ni v ol u ma b bef ore starti n g t he i pili m u ma b i nf usi on. T he sec o n d i nf usi on will 
alwa ys be t he i pili m u ma b st u d y  dr u g a n d will start after t he i nf usi o n li ne has bee n fl us he d, filt ers 
c ha n ge d a n d s u bject has bee n o bser ve d t o e ns ure n o i nf usi on reacti on has occ urre d. T he ti me i n 
bet wee n i nf usi o ns is e x pecte d t o be a p pr o xi matel y 3 0 mi n utes b ut ma y be m ore or less de pe n di n g 
o n t he sit uati o n.
Ni v o l uma b i njecti on ( 1 0 mg/ m L) is t o be a d mi nistere d as a n I V i nf usi on t hr o u g h a 0. 2 -micr o n t o 
1. 2 -micr o n p ore size, l o w -pr otei n bi n di n g i n-li ne filter at t he pr ot oc ol-s pecifie d d oses. It is n ot t o 
be a d mi nistere d as a n I V p us h or b ol us i njecti on. Ni v o l uma b i njecti o n ca n be i nf use d u n dil ute d 
( 1 0 mg/ m L) or dil ute d wit h 0 . 9 % S o diu m  C hl ori de I njecti on, U S P t o 5 % De xtr ose I njecti o n, U S P, 
mi ni m u m pr otei n c o nce ntrati o ns ca n be f o u n d i n t he I n vest i gat or Br oc h ure.
I nstr uctio ns f or dil ut i on a n d i nf usi on of  ni v ol uma b i njecti on ma y be pr o vi de d i n t he p har mac y 
bi n der, or p har mac y re fere nce s heet. Care m ust be ta ke n t o ass ure sterility o f the pre pare d s ol ut i on 
as t he pr o d uct d oes n ot c o ntai n a n y a nt i micr o bial preser vati ve or bacteri ostatic a ge nt. 
N o i nc o m pati bilities ha ve bee n o bser ve d bet wee n ni v o l u ma b i njecti on a n d p ol y vi n yl c hlori d e 
( P V C), n o n- P V C/ n o n -D E H P ( di( 2-et h yl he x yl) p ht halate) I V c o m p o ne nts, or glass b ottl es ha ve 
bee n o bser ve d.
I pili m u ma b i njecti on ( 5 m g/ m L) ca n be use d f or I V a d mi nistrati o n wi t ho ut dil ut i on aft er 
tra nsferri n g t o a P V C ( p ol y vi n yl c hlori de), n o n- P V C/ n o n -D E H P ( di-[ 2-et h yl he x yl] p ht halate) or 
gl ass c o ntai ner, a n d is sta ble f or 2 4 h o urs at 2 º C t o 8º C or r o o m te m perat ure/r o o m li g ht ( R T/ R L). 
T he pr o d uct ma y be i nf use d usi n g a v o l umetric p u m p at pr ot oc ol s pecifie d d ose t hr o u g h a P V C 
I V s ol uti on i nf usi o n set wit h a n i n -li ne, sterile, n o n p yr o ge nic, l o w-pr otei n -bi n di n g filter ( p ore size 
of  0. 2 micr o meter t o 1. 2 micr o met er). T he dr u g ca n be dil ute d wi t h 0. 9 % n or m al sali ne or 5 % 
De xtr ose I njecti o n t o c o nce ntrati o ns bet wee n 1 m g/ m L a n d 4 m g/ m L. I pili m u ma b i njecti on m u st 
n ot be a d mi nistere d as a n I V p us h or b ol us i njecti o n. Care must be ta ke n t o ass ure sterili t y of  t he 
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
pre pare d s olut i ons si nce t he dr u g pr o d uct d oes n ot c o nt ai n a n y a nt i micr o bial preser vat i ves or 
bacteri ostati c age nts. At  t he e n d of t he i nf usi on, fl us h t he li ne wit h a s ufficie nt q ua ntit y of  nor m al 
sali ne or 5 % de xtr ose s ol ut i on. F or i pili m u ma b st ora ge i nstr ucti o ns, refer t o i pili m u ma b I B a n d/ or 
p har mac y refere nce s heets.
Se parate i nf usi o n ba gs a n d filters s h o uld b e use d w he n a d mi nisteri n g n i v ol u ma b a n d ipili m u ma b
o n t he sa me da y .
D oses of  ni v ol uma b
a n d/ or ipili m u ma b ma y be i nterr u pte d, dela ye d, or disc o nt i n ue d de pe n di n g 
o n h o w well t he s u bject t olerates t he tr e at me nt. D o si n g visit s are n ot s ki p pe d, o nl y dela ye d. F o r 
m o re details, see Secti o n 4. 5. 2. 1 f or d ose dela ys , Secti o n 4. 5. 4 f or res u mi n g treat me nt, a n d 4. 5. 5. 1
f or treat me nt disc o nti n uati o n.
Re fer t o t he ni v o l u ma b a n d i pili m u ma b I Bs a n d p har mac y ma n uals 
f or s pecific i nf usi on 
pre parati o n rec o m me n dat i ons.
4. 5. 1. 2
P e m etr e x e d pl u s Ci s pl ati n or C ar b o pl ati n
S u bjects ra n d o mize d t o Ar m B will recei ve treat me nt wit h pe metre xe d at a d ose of 5 0 0 m g/ m² as 
a 1 0- mi n ute I V i nf usi on o n Da y 1 of  a q 21 d a y s c ycle wi t h cis plati n at a d ose of  75 m g/ m² or 
car b o plat i n Area U n der t he C ur ve ( A U C) 5 as a I V i nf usi on as per la bel, o n Da y 1 of e ver y 2 1 da ys 
per c y cle f or 6 c ycles.
Cis plat i n or car b o plati n i n c o m bi nati o n wi t h pe metre xe d will be a d mi nistere d acc or di n g t o la bel 
a n d/ or l ocal p o lic y i n ter ms of inf usi o n sc he ma (i ncl u di n g b ut n ot li mite d t o h y drat i on pr ot oc ols).
T he use of  cis plati n is pr ef erre d, h o we ver, car b o plat i n ma y be use d at t he discret i on of  the 
i n vesti gat or. Swit c hi n g fr o m c is plati n to car b o plati n a n d vice versa are all o we d, a n d t he reas o n f or 
t hat s witc h m ust be re p orte d i n t he C R F. If swi tc hi n g is d ue t o t o xicit y an d eit her cis plat i n or 
car b o plat i n is disc o nti n ue d, t he ot her st u d y dr u g ma y be c o nti n ue d for t h e re mai n der of t he c ycles.
4. 5. 1. 3
Pr e -m e di c ati o n s f or u s e wit h P e m etr e x e d a n d Ci s pl ati n : 

Or al  corti c oster oid s h o uld be gi ve n acc or di n g t o l ocal sta n dar ds or at  a dose e q ui vale nt t o 
de xa met has o ne 4 m g BI D o n t he da y  prior t o, t he da y  of, a n d t he da y after t he a d mi nistratio n 
of  pe metre xe d. Oral fol ic acid 3 5 0 t o 1 0 0 0 μ g dail y s h o uld be gi ve n starti n g 1 wee k pri or t o 
t he first d ose of p e metre xe d, wit h at least 5 d oses of f o lic aci d a d mi nistere d i n t he 7 da ys pri or 
t o t he first d ose. Oral f olic aci d s h o uld be c o nt i n ue d dail y t hr o u g h o ut t he treat me nt wit h 
p e metre xe d a n d f or 2 1 da ys after t he last d ose of p e metre xe d. I ntra musc ular (I M) i nject i on o f 
vit a mi n B 1 2 1 0 0 0 μ g s h o uld be gi ve n a p pr o xi matel y o ne wee k pri or t o t he first d ose of 
p e metre xe d wi t h re peat a d mi nistrati o n d uri n g treat me nt as per l ocal p olic y.

Pri or t o pe metre xe d a n d c is plati n/car b o plat i n i nf usi on, ant iemet ic pr e m e dicat i on will be
a d mi nistere d acc or din g t o l ocal sta n dar ds. Rec o m me n de d 
a nt iemet ic treat me nts are
de xa met has o ne ( d osi n g acc or di n g t o l ocal sta n dar ds; a n e q ui vale nt d ose of  an ot her
c ortic oster oid ma y be s u bstitut e d) a n d a 5- H T 3 rece pt or a nta g o nist (t ype per i n vesti gat or
di scretio n a n d l ocal sta n dar ds-of -care). A d dit i onal use of  ant iemet ic pre -me dicat i ons ma y b e 
e mpl o y e d at t he discreti on of t he I n vest i gat or.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 4

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
4. 5. 2
D o s e D el a y Crit eri a
4. 5. 2. 1
D o s e D el a y Crit eri a f or Ni v ol u m a b pl u s I pili m u m a b
I n t he case of  in vest i gat or assesse d r a dio gra p hic pr o gressi o n of  disease, d osi n g ma y be dela ye d 
u nt il c o nfir mati on of pr o gressi o n b y i n de pe n de nt ce ntral re vie w. If t he i n de pe n de nt ce ntral re vie w 
re p ort d oes n ot c o nfir m disease pr o gressi o n, treat me nt m ust be c o nti n ue d.
D ose dela y crit eria a p pl y to all dr u g -relate d A Es. Treat m e nt dela y u p t o 6 wee ks f or ni v o l uma b 
a n d u p t o 1 2 wee ks f or ipili m u ma b fr o m  t he last d ose are all o wa ble (a n y d ose dela ys greater t ha n 
t hese will re q uire a p pr o val fr o m t he me dical mo ni t or).
T u m or assess me nts f or all s u bjects s h o uld c o nt i n ue as per pr ot oc ol e ve n if d osi n g is dela ye d. 
Ni v o l uma b a n d i pili m u ma b a d mi nistrati o n s h o ul d be dela ye d f or t he f o ll owi n g:

Gra de 2 n o n -s ki n, dr u g-relate d a d verse e ve nt, e xce pt f or 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 -r elate d A E

Gra de 3 dr u g -relate d la b orat or y a b n or mality wi t h t he f oll owi n g e xce pt i ons:

Gra de 3 l y m p h o pe nia or as y m pt o mat ic a m ylase or li pase d oes n ot re q uire a d ose dela y n or 
re q uires c o ns ultati on wi t h t h e me dical mo ni t or

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

A n y A E, lab orat or y  ab n or m alit y or i nter -c urre nt ill ness w hic h, i n t he j u d g me nt of  the 
i n vesti gat or, warra nts dela yi n g t he d ose of st u d y m e dicat i on.
S u bject s recei vi n g i pili m u ma b i n c o m bi nat i on wit h ni v o l uma b t hat ha ve dr u g -relate d t o xicities 
t hat meet t he crit eria for d ose del a y, s h o uld ha ve b ot h dr u gs (i pili m u ma b a n d ni v o l u ma b) dela ye d 
u nt il r etr e at me nt crit eria are met. 
Resc he d uli n g:

Ni v o l uma b ma y be dela ye d u nt il the ne xt pla n ne d ipili m u ma b d ose if t he ne xt ipili m u ma b d ose 
is sc he d ule d wi t hi n t he ne xt 1 2 d a y s. T his will per mit p eri o di c ipili m u ma b d osi n g t o be 
s y nc hr o nize d wit h n i v ol u ma b d osi n g.

I pili m u ma b s h o uld be d ose d at t he s pecifie d i nter val re gar dless of  an y dela ys i n i nter ve ni n g 
n i v ol uma b d oses. H o we ver, i n or der t o m ai ntai n perio di c s y nc hr o nize d d osin g of  ipili m u ma b
a n d n i v ol u ma b, t he d osi n g da ys of  ni v ol u ma b a n d ipili m u ma b ma y be a dj uste d wi t hi n t h e
per mitte d ± 3 da y wi n d o w, as l on g as c o nsec ut i ve n i v ol u ma b d oses are gi ve n at least 1 2 da ys 
a part. I pili m u ma b ma y be dela ye d be y o n d t he 3 da y wi n d o w if nee de d t o s y nc hr o nize wit h t he 
ne xt n i v ol uma b d ose.

If a n ipili m u ma b d ose is d el a ye d be y o n d 6 wee ks fr om t he pri or ipili m u ma b d ose, t he n
s u bse q ue nt I pili m u ma b d oses s h o ul d be resc he d ule d t o mai ntai n t he 6 wee k i nter val bet wee n
c o nsec ut i ve I pili m u ma b d oses.

A d ose del a y of ipili m u ma b w hic h res ults i n n o ipili m u ma b d osi n g f or > 1 2 wee ks re q uires
I pili m u ma b disc o nt i n uati on wi t h f oll owi n g e xce pt i o n: D osi n g dela ys t o ma na ge dr u g-relate d 
a d verse e ve nts, s uc h as pr ol o n ge d ster oi d ta pers, are all o we d. Pri or t o re -i nitiati n g treat me nt 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 5

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
i n a s u bject wit h a d osi n g dela y last i n g > 1 2 wee ks, t he B M S me dical m onit 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 del a ye d.
4. 5. 2. 2
D o s e D el a y Crit eri a f or P e m etr e x e d a n d Ci s pl ati n or C ar b o pl ati n
I n t he case of  in vest i gat or assesse d r a dio gra p hic pr o gressi o n of  disease, d osi n g ma y be dela ye d 
u nt il c o nfir mati on of pr o gressi o n b y i n de pe n de nt ce ntral re vie w. If t he i n de p e n de nt ce ntral re vie w 
re p ort d oes n ot c o nfir m disease pr o gressi o n, treat me nt m ust be c o nti n ue d.
P e m etre xe d a n d c is plati n or car b o plat i n s h o ul d be b ot h dela ye d f or t he f o ll owi n g:

A bs ol ute ne utr o p hil c o u nt ( A N C) < 1 5 0 0/ µ L or Prese nce of fe brile ne utr o pe nia 

Pl at elets < 1 0 0, 0 0 0/ m m 3

A n y Gra de 2 n o n- s ki n, n o n- he mat ol o gi c, dr u g -r elate d a d verse e ve nt, e xce pt f or alo p e ci a, 
fati g ue or la b orat or y a b n or malities

A n y Gra de 3 s ki n dr u g- relate d A E

A n y Gra de 3 dr u g -relate d la b orat or y a b n or mality,  wit h t h e foll o wi n g e xce pt i ons:
o
Gra de 3 l y m p h o pe nia d oes n ot re q uire a d ose dela y
o
If a s u bject has a baseli ne A S T, A L T or t otal bilir u bi n t hat is wi t hi n n or mal li mits, 
d el a y d osi n g f or dr u g -relate d Gra de 2 t o xicit y.
o
If a s u bject has baseli ne A S T, A L T, or t otal bilir u bi n wit hi n t he Gra de 1 t o xicit y ra n ge, 
d el a y d osi n g f or dr u g -relate d Gra de 3 t o xicit y.

A n y a d verse e ve nt, la b orat or y ab 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 vest i gat or, warra nts dela yi n g t he d ose of st u d y me dicat i on. I n vesti gat ors s h o ul d c o ns ult  
l ocal la beli n g f or t he c he mot h era p y dr u gs bei n g a d mi nistere d t o a n y gi ve n s u bject f or 
a d ditio nal  g ui da nce o n d ose dela ys.
I n a d ditio n, s u bjects m ust di sc o nti n ue c is plati n if t he calc u late d creati ni ne cleara nce decreases t o 
< 5 0 m L/ mi n ( base d o n t he C o c kr oft Ga ult f or mul a). Pe metre xe d ma y be c o nt i n ue d, a n d t he 
pl at i n u m a g e nt ma y, at t he i n vestigat or’s di screti on, be s wi tc he d t o car b o plat i n f or t h e r e mai n der 
of  t he plati n u m d o u blet c ycles w he n t he s u bject meets t he crit eria t o res u me d osi n g as s pecifie d i n 
Secti o n 4. 5. 4. 3 .
If a n y n o n-he mat ol o gi c a d verse e ve nt meet i n g t he d ose dela y criteria a b o ve is felt t o be relate d t o 
o nl y  one parti c ular a ge nt i n t he plati n u m d o u blet c he m ot hera p y re gi me n, t he n t hat a ge nt al o n e 
ma y be o mitte d f or t hat c ycle w hile t he ot her a ge nt is gi ve n. I n or der t o ma i ntai n s y nc hr o nize d 
d osi n g of  the re gi me n, t he o mitte d a ge nt s h o ul d be res u me d wi t h the ne xt sc he d ule d c ycle o nce 
t he A E has i m pr o ve d a n d retreat me nt criteria are met.
S u bse q ue nt d ose re d ucti o ns ma y be re q uire d as p er Secti o n 4. 5. 3. 2 . S u bject s wi t h he mat olo gi c 
t o xicit y ma y recei ve gr o wt h fact ors (i ncl u di n g G-C S F a n d er y t hr o p oiet i n) at t he discret i on of  t he 
i n vesti gat or.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 6

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
If b ot h dr u gs i n t he pl at i n u m d o u blet c he mot h erap y re gi me n are dela ye d, t he n t he s u bject 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 u ntil re -tr e at me nt criteria are met 
(as per S ecti o n 4. 5. 4. 3 ).
4. 5. 3
D o s e R e d u cti o n s
4. 5. 3. 1
Ni v ol u m a b or I pili m u m a b
T here will be n o d ose re d ucti o ns f or n i v ol uma b or ipili m u ma b .
4. 5. 3. 2
P e m etr e x e d a n d Ci s pl ati n or C ar b o pl ati n
T his sect i on i ncl u des i nf or mat i on o n d ose m o dificati o ns f or p e metre xe d, c is plati n a n d car b o plat i n.
A ma xi m u m of  2 dose re d ucti o ns per st u d y dr u g are per mitte d; if a d ditio n al re d uct i ons are 
re q uire d, t hat partic ular st u d y dr u g m u st be d isc o nti n ue d. O nce a d ose has bee n decrease d, it s h o uld 
r e mai n re d uce d f or all s u bse q ue nt d osi ng u nless d ose i s f urt her re d uce d. N o d ose escalati ons will 
be allo we d. If o ne of  t he st u d y dr u gs is dela ye d d ue t o dr u g relate d t o xicities d uri n g a treat me nt 
c ycle, t he ot her stu d y dr u gs i n t he re gi me n ma y be a d mi nistere d at t he di screti on of  the 
i n vesti gat or; w he n d osi n g is res u me d, d ose re d ucti o n s h o ul d o nl y be a p plie d t o t he st u d y dr u g t hat 
was wi t h hel d.
It is rec om me n de d t hat all part ici pa nts w h o recei ve cis plat i n s h o uld ha ve a u dio m etric testi n g 
perf or m e d pri or t o i nitiati on of  t hera p y a nd pri or t o s u bs e q ue nt d oses of cis plati n, as per l ocal or 
i nstituti o nal sta n dar ds of care. Rec o m me n dati o ns f or d ose m o dificat i ons f or p e metre xe d c is plati n
a n d car b o plat i n s h o uld be c o nsi dere d wi t h lo c al i nstituti o nal  sta n dar ds. T he d ose levels f or 
P e m etre xe d, Cis plat i n an d car b o pl at i n are liste d i n Ta ble 4. 5. 3. 2 - 1:
T a ble 4. 5. 3. 2 - 1:
D ose Le vels f or Pe metre xe d , Cis pl ati n , a n d C ar b o pl ati n
Pe metre xe d
Cis pl ati n
C ar b o pl ati n
Starti n g D ose
5 0 0 m g/ m ²
7 5 m g/ m ²
A U C 5. 0
D ose Le vel - 1
3 7 5 m g/ m²
5 6 m g/ m ²
A U C 4. 0
D ose Le vel - 2
2 5 0 m g/ m ²
3 8 m g/ m ²
A U C 3. 0
D ose Le vel - 3
St o p dr u g
St o p dr u g
St o p dr u g

H e m at ol o gi c T o xi cit y
D ose m o dificat i on g ui deli nes f or he mat ol o gic t o xicities (acc or di n g t o C T C A E versi o n 4) are 
s u m marize d i n Ta ble 4. 5. 3. 2 - 2. D o se a dj ust me nts f or he mat ol o gic t o xicit y at t he start of  a 
s u bse q ue nt c ycle s h o ul d be base d o n na dir he mat ol o gic c o u nts fr o m t he pre vi o us c ycle of t hera p y; 
treat me nt ma y be d el a ye d t o all o w t he he mat ol o gi c t o xi cities t o ret ur n t o Gra de 1. Aft er t he first 
c ycle, gr o wt h fact ors are per missi ble t o all o w f or he mat ol o gi cal rec o ver y. Pl ease use l ocal 
sta n dar ds of care i n t he use of t hese s u p p orti ve meas ures.
A d dit i onall y , t he use of pr o p h ylactic d ose a nti bi otics is t o be use d acc or di n g t o l ocal sta n dar ds of 
care. Please n ote a n y a nti bi otic or gr o wt h fact or use o n t he e C R F.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 4. 5. 3. 2 - 2:
D ose M o dific ati o ns f or He m at ol o gic T o xicities
T o xicit y
Pe metre xe d
Cis pl ati n
C ar b o pl ati n
Ne utr o p hil c o u nt Decre ase d 
Gra de 4 ( < 5 0 0/ m m 3 or < 0. 5 x 
1 0 ^ 9/ L)
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel
A ne mi a 
Gra de 2 ( < 1 0. 0 - 8. 0 g/ d L; < 6. 2 -
4. 9 m m ol/ L; < 1 0 0 - 8 0 g/ L)
Re d uce o ne d ose le vel
N o c ha n ge
N o c ha n ge
A ne mi a 
Gra de 3 ( < 8. 0 g/ d L; 
< 4. 9 m m ol/ L; < 8 0 g/ L)
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel
A ne mi a Gr a de 4 
( Life t hreate ni n g c o nse q ue nces)
H ol d dr u g 
H ol d dr u g
H ol d dr u g
Pl atelet c o u nt decre ase d
Gra de 3 ( < 5 0, 0 0 0 - 2 5, 0 0 0/ m m 3; 
< 5 0. 0 - 2 5. 0 x 1 0 ^ 9/ L)
N o c ha n ge
N o c ha n ge
N o c ha n ge
Pl atelet c o u nt decre ase d
Gra de 4 ( < 2 5, 0 0 0/ m m 3; < 2 5. 0 x 
1 0 ^ 9/ L)
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel

N o n -h e m at ol o gi c T o xi cit y
D ose m o dificat i on g ui deli nes f or n o n -he mat ol o gi c t o xicities (acc or di n g t o C T C A E versi o n 4) are 
s u m marize d i n Ta ble 4. 5. 3. 2 - 3. Treat me nt ma y be dela ye d t o all o w t he n o n-he mat ol o gi c t o xicit ies 
t o ret ur n t o Gra de 2 or bac k t o baseli ne (e xcl u di n g al o pecia a n d s ki n a n d nail c ha n ges).
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 4. 5. 3. 2 - 3:
D ose M o dific ati o ns f or N o n -he m at ol o gic T o xicit y a
T o xicit y
Pe metre xe d
Cis pl ati n
C ar b o pl ati n
Fe brile
Ne utr o pe nia 
Gra de 3
Re d uce o ne d ose le vel
Re d uce o ne d ose le vel 
Re d uce o ne d ose le v el
Diarr hea 
Gra de 3
Re d uce o ne d ose le vel
N o c ha n ge
N o c ha n ge
Aller gic
Reacti o n
Gra de 3
Re d uce o ne d ose le vel 
Re d uce o ne d ose le vel 
Re d uce o ne d ose le v el
Parest hesia 
Gra de 2
N o c ha n ge
Re d uce o ne d ose le vel 
Re d uce o ne d ose le v el
Parest hesia
Gra de 3
Re d uce o ne d ose le vel
Re d uce t w o d ose le vels 
Re d uce t w o d ose le ve ls
a
If c o nsi dere d i n t he best i nterest of t he s u bject, a n d c o nsiste nt wit h l ocal practice, i n vesti gat ors ma y deci de to use
s u p p orti ve meas ures/treat me nt, a n d/ or sec o n dar y pr o p h yla xis i nstea d of d ose re d ucti o ns f or t he ne xt c ycle. Al s o, if 
t o xicit y ca n clearl y be attri b ute d t o o ne of t he dr u gs, t he i n vesti gat or m a y ch o ose t o o nl y  dose re d uce o ne o f t h e
c yt ot o xics.
Cis plat i n i n d uces ne p hr ot o xicit y, w hic h is c u mulati ve, it is t heref ore c o ntra -i n dicate d i n s u bjects
wi t h re nal im pair me nt. D ose a dj ust me nt  for c is plati n after rec o ver y fr o m r enal t o xicit y is all o we d 
as per S ecti o n 4. 5. 4. 3 , a n d car b o plat i n s h o uld als o be c o nsi dere d as per l ocal insti t utio n al 
sta n dar ds.
4. 5. 4
Crit eri a t o R e s u m e D o si n g
4. 5. 4. 1
Crit eri a t o R e s u m e Ni v ol u m a b D o si n g
S u bject s 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, wi t h t he f oll owi n g e xce pt i ons:

S u bject s ma y res u me treat me nt i n t he prese nce of Gra de 2 fat i g ue

S u bject s 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 tr e at me nt i n 
t he prese nce of Gra de 2 s ki n t o xicit y

F or s u bjects wit h Gra de 2 A S T/ A L T, or t otal bilir u bi n ele vat i ons, 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 m e nt wit h c ortic oster oids, if nee de d, is 
c o mplete.

S u bject s wi t h co m bi ne d Gra de
2 A S T/ A L T 
A N D 
t ot al bilir u bi n val ues meeti n g 
di sc o nti n uati on para meters ( Secti o n 4. 5. 5. 1 ) 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 xicity,  diarr hea or c o litis m ust ha ve res ol ve d t o baseli ne bef ore 
treat me nt is res u me d. S u bject s wit h persiste nt Gra de
1 p ne u m o nit is aft er c o mplet i on of  a 
ster oid ta per o ver at least 1 m o nt h ma y be eli gi ble f or retreat me nt if disc u sse d wi t h an d 
a p pr o ve d b y B M S Me dical M o nit or.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 9

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

S u bject s w h o recei ve d s yste mic c ortic oster oids f or ma na ge me nt of  an y dr u g -relate d t o xicit y 
m ust be of f c ortic oster oids or ha ve ta pere d d o w n t o a n e q ui vale nt d ose of  pre d nis o ne 
1 0 m g/ da y.

S u bject s wit h dr u g -relate d e n d ocri n o pat hies a de q uatel y co ntr olle d wi t h onl y p h ysi ol o gi c 
h or m o ne r e place me nt ma y res u me tr e at me nt after c o ns ultati o n wi t h the B M S Me dical 
M o ni t or.

D ose d el a y of  ni v ol u ma b w hic h res ults i n treat me nt d el a y of  > 6 wee ks re q uires tr e at me nt 
di sc o nti nuat i on, wi t h e xce pti ons as n ote d i n Sect i on 4. 5. 5. 1 .
4. 5. 4. 2
Crit eri a t o R e s u m e I pili m u m a b D o si n g
S u bject s ma y res u me treat me nt wit h n i v ol u ma b a n d ipili m u ma b w he n dr u g -relate d A E(s) 
res ol ve(s) t o Gra de 1 or baseli ne val ue, wit h t he f oll o wi n g e xce pt i ons:

S u bject s ma y res u me treat me nt i n t he prese nce of Gra de 2 fat i g ue.

S u bject s 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 o f Gra de 2 s ki n t o xicit y.

S u bject s wit h baseli ne Gra de 1 A S T/ A L T or t otal bilir u bi n w h o re q uire d ose dela ys f or reas o ns 
ot her t ha n a 2 -Gra de s hift i n A S T/ A L T or t otal bilir u bi n ma y res u me treat me nt i n t he prese nce 
of  Gra de 2 A S T/ A L T or t otal  bilir u bi n.

S u bject s wit h c o m bi ne d Gra de 2 A S T/ A L T a n d t otal bilir u bi n val ues meet i n g disc o nt i n uati on 
para m eters ( Secti o n 4. 5. 5. 2 ) s h o ul d ha ve treat me nt per ma ne ntl y disc o nt i n ue d.

Dr u g -relate d p ul m o nar y  to xi cit y, di arr hea, or c o litis m ust ha ve res ol ve d t o baseli ne bef ore 
treat me nt is res u me d.

S u bject s w h o recei ve d s yste mic c ortic oster oids f or ma na ge me nt of  an y dr u g -relate d t o xicit y 
m ust be of f c ortic oster oids or ha ve ta pere d d o w n t o a n e q ui vale nt d ose of  pre d nis o ne 
1 0 m g/ da y.

Dr u g -relate d e n d ocri n o pat hies a de q uatel y co ntr olle d wi t h onl y p h ysi ol o gic h or m o n e 
r e 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 ni t or.

D ose d el a y of  ipili m u ma b w hic h res ults i n n o i pili m u ma b d osi n g f or > 1 2 wee ks re q uir es 
ipili m u ma b disc o nti n uat i on, wi t h e xce pti ons as n ote d i n Secti o n 4. 5. 5. 2 .

I pili m u ma b ma y n ot be res u me d s o o ner t ha n 6 wee ks (3 d a y s) aft er t he pri or ipili m u ma b
d ose.

I n ge neral , s u bjects w h o me et criteria t o res u me ipili m u ma b will als o ha ve met criteria t o 
res u me n i v ol u ma b, s o it s h o ul d be feasi ble t o s y nc hr o nize d osi n g of b ot h dr u gs w he n res u mi n g 
ipili m u ma b . I n or d er t o facilitate t his, t he d osi n g da ys of  ni v ol u ma b a n d ipili m u ma b ma y b e 
a djuste d wit hi n t he per mitte d 3 d a y  wi n d o w, as l on g as c o nsec ut i ve n i v ol u ma b d oses are 
gi ve n at least 1 2 da y s a part.
4. 5. 4. 3
Crit eri a t o R e s u m e D o si n g f or P e m etr e x e d a n d Ci s pl ati n or C ar b o pl ati n

S u bject s ma y res u me treat me nt wit h plati n u m d o u blet c he m ot hera p y w he n t he A N C ret ur ns t o 
1 5 0 0/ µl , t he pl at elet c o u nt ret ur ns t o 1 0 0, 0 0 0/ m m 3, a n d all ot h er dr u g -relate d t o xicities 
ha ve ret ur ne d t o baseli ne or Gra de 1 ( or Gra de 2 f or al o pecia a n d fat i g ue).
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

If a s u bject fails t o me et crit eria for r e -treat me nt, t he n re-treat me nt s h o uld be dela ye d, a n d t he 
s u bject s h o ul d be re-e val u ate d wee kl y or m ore fre q ue nt l y as cli nicall y in dicate d. 

A n y s u bject w h o fails t o rec o ver fr o m  t o xicit y attri b uta ble t o plat i n u m d o u blet c he m ot h era p y 
t o baseli ne or Gra de 1 (e xce pt Gra de 2 al o peci a a n d fati g ue) wi t hi n 6 wee ks fr om t he last 
d ose gi ve n s h o ul d disc o nt i n ue t he dr u g(s) t hat ca use d t he dela y.
W he n 
res u mi n g plati n u m d o u blet c he m ot hera p y treat me nt, please f oll ow t he d ose re d ucti on 
rec o m me n dati ons i n Sect i on 4. 5. 3. 2 .
4. 5. 5
Tr e at m e nt Di s c o nti n u ati o n Crit eri a
F or all s u bjects, gl o bal deteri orati o n of health st at us re q uiri n g disc o nt i n uati on o f treat me nt wit h o ut 
o bj ect i ve e vi de nce of  disease pr o gressi o n at t hat ti me s h o uld be re p orte d as ‘s y m pt o matic 
deteri or ati o n’ i n t he s o urce data a n d i n t he case re p ort f or m. E v er y  eff ort s h o ul d be ma de t o 
d oc u m e nt o bj ect i ve pr o gressi o n (ie, ra di o gra p hic c o nfir mati o n) e ve n aft er disc o nt i n uati o n of 
treat me nt.
4. 5. 5. 1
Ni v ol u m a b D o s e Di s c o nti n u ati o n
Ni v o l uma b treat me nt s h o ul d be per ma ne nt l y disc o nti n ue d f or t he f oll owi n g:

A n y Gra de 2 dr u g -r elate d u veit is, e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o t o pic al 
t hera p y a nd d o es n ot i m pr o v e t o Gra de 1 se veri t y wit hi n t he re-treat me nt p erio d O R r e q ui res 
s ystemic treat me nt 

A n y Gra de
3 dr u g -r elate d br o nc h os pas m, h y perse nsit i vity reactio n, or i nf usi on reacti on,  
re gar dless of d uratio n;

A n y Gra de
3 n o n- s ki n, dr u g -relate d a d verse e ve nt lasti n g > 7 da ys, wit h t he f oll owi n g 
e xce pti o ns f or dr u g relate d u vei tis, p ne u m o nit is, br o nc h os pas m, diarr hea, c o litis, ne ur o l ogi c 
t o xicit y, h y perse nsit i vity reacti ons, i nf usi on reactio ns, e n d ocri n o pat hies, a n d la b orat or y 
a b n or malities:

Gra de 3 dr u g -relate d u veit is, p ne u m o nit is, br o nc h os pas m, diarr hea, c olit is, ne ur o l ogi c t o xicity,  
h y perse nsi tivit y react i on, or i nf usi o n reacti o n of a n y d urat i on re q uires disc o nti n uati o n.

A n y Gra de
3 dr u g -relate d e n d ocri n o pat hies a de q uatel y co ntr olle d wi t h onl y p h ysi ol o gi c 
h or m o ne r e place me nt d o n ot re q uire disc o nt i n uati on.
A dre nal 
i ns ufficie nc y re q uir es
di sc o nti n uati on re gar dless o f c o ntr ol wit h hor m o ne re pl ace me nt.

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 on e xce pt:

Gra de
3 dr u g -relate d t hr o m b oc yt o p e nia > 7 da ys or ass ociate d wi t h blee di n g re q uires 
di sc o nti n uati on

Gra de ≥ 3 dr u g relate d A S T, A L T, or T otal Bilir u bi n re q uires disc o nt i n uati on *

C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N
* I n m o st cases of  Gra de
3 A S T or A L T ele v atio n, st u d y dr u g(s) will be p er m a ne nt l y 
di sc 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 uat i on 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 di c al 
M o ni t or/ desi g nee m ust occ ur.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 1

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

A n y Gra de 4 dr u g -relate d a d verse e ve nt or lab orat or y  ab n or m alit y (incl u di n g b ut n ot li mite d 
t o creati ni ne, A S T, A L T, or T otal Bilir u bi n), e xce pt f or t he f oll owi n g e ve nts w hic h d o n ot 
re q uir e disc o nti n uatio 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 or as y m pt o m atic a m ylase or li pase

Is olate d Gra de 4 electr ol yt e 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 h eir o nset

Gra de 4 dr u g -relate d e n d ocri n o pat h y ad verse e ve nts, s uc h as, h y per - or h y p ot h y r oidis m, 
or gl uc ose i ntol era nce, w hic h res ol ve or are a de q uatel y c o ntr olle d wi t h ph ysi o l ogi c 
h or m o ne re place me nt (c ortic oster oids, t h yr oid 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 ui re disc o nti n uati on aft er disc ussi on wi t h a nd a p pr o val  fr o m t h e 
B M S Me di c al Mo ni t or. Gra de 4 a dre nal i ns ufficie nc y re q uires disc o nt i n uati on re gar dless 
of  c o ntr ol wit h hor m o ne re place me nt.

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 
di sc o nti n uati on, wi t h t h e fol l owi 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 -r elate d a d verse e ve nts 
are all o we d. Pri or t o r e-i nitiati n g treat me nt i n a s u bject wi t h a dosi 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 d ical mo ni t or m ust be c o ns ulte d. T u m or 
assess me nts s h o ul d c o nt i 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 s afet y a n d la b orat or y st u dies s h o uld als o c o nt i n ue e ver y 6 wee ks
or m o re 
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 d ical m o nit or. Pri or t o re-i nitiat i n g 
treat me nt i n a s u bject wi t h a dosi n g dela y lasti n g > 6 wee ks, t he B M S me d ical m o nit or 
m ust be c o ns ulte d. T u m or assess me nts s h o uld c o nt i n ue as per pr ot oc ol  eve n if d osi n g is 
d el a ye d. Peri o dic st u d y visits t o assess safety a n d la b orat or y st u dies s h o ul d als o c o nt i n ue 
e ver y 6 wee ks or m or e f re 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 d verse e ve nt, la b orat or y ab 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 in vest i gat or, prese nts a s u bsta ntial cli nical ris k t o t he s u bject wi t h co nti n ue d n i v ol u mab
d osi n g.
N ote: If ni v o l u ma b is disc o nti n ue d f or a n y reas o n, i pili m u ma b ma y n ot be c o nti n ue d alo ne.
4. 5. 5. 2
I pili m u m a b D o s e Di s c o nti n u ati o n
I pili m u ma b s h o uld be per m a ne nt l y disc o nti n ue d if a n y of t he foll o wi n g criteria are met:

A n y Gra de 2 dr u g -r elate d u veit is or e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o t o pic al 
t hera p y an d d oes n ot i m pr o ve t o Gra de
1 se verit y withi n 2 wee ks O R re q uires s yste mic 
treat me nt;

A n y Gra de 3 br o nc h os pas m or ot her h y perse nsi ti vit y reacti on;

A n y ot h er Gra de 3 n o n -s ki n, dr u g-relate d a d verse wit h t he f oll owi n g e xce pt i ons f or la b orat or y 
a b n or malities, Gra de 3 na usea a n d v o mit i n g, Gra de 3 ne utr o pe nia a n d t hr o m b oc y t o p e nia, a n d 
s y m pt o mat ic e n d ocri n o pat hies w hic h res ol ve d ( wit h or wit h o ut h or m o ne s u bstit utio n);
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

A n y dr u g -relate d li ver f u ncti o n test ( L F T) a b n or mality t hat meets t he f o ll owi n g criteria re q uire 
di sc o nti n uati on:

A S T or A L T > 8 x U L N

T ot al  bilir u bi n > 5 x U L N

C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N

A n y Gra de 4 dr u g -r elate d a d verse e ve nt or la b orat or y ab n or malit y, e xce pt f or t he f oll owi n g 
e ve nts, w hic h d o n ot re q uire disc o nt i n uati on:

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

Gra de
3 a m ylase or li pase a b n or malities n ot ass ociate d wi t h sy m pt o ms or cli nical 
ma nifestati o ns of pa ncreatit is 

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 wi t h cli nical 
se q uelae a n d are c orrecte d wit h s u p ple me ntatio n/a p pr o pri ate ma na ge me nt wi t hi n 7 2 h o urs of 
t heir o nset

A n y treat me nt d el a y res ultin g i n n o i pili m u ma b d osi n g f or > 1 2 wee ks wit h t he f oll owi n g 
e xce pti o ns: D osi n g dela ys t o ma na ge dr u g -r elate d a d verse e ve nts, s uc h as pr ol o n ge d ster oid 
ta pers, are all o we d. Pri or t o r e-i nitiati n g treat me nt i n a s u bject wit h a d osi n g dela y  lasti n g 
> 1 2 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 nt i n ue 
as per pr ot oc ol e ve n if d osi n g is dela ye d.

D osi n g dela ys res ultin g i n n o ipili m u ma b d osi n g f or > 1 2 wee ks 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 d ical m o nit or. Pri or t o re-i nitiati n g 
treat me nt i n a s u bject wi t h a d osi n g dela y lasti n g > 1 2 wee ks, t he B M S me dical m onit or m ust 
be c o ns ulte d. T u m or assess me nts s h o u l d c o nti n ue as per pr ot oc ol e ve n if d osi n g is dela ye d.

A n y a d verse e ve nt, la b orat or y ab 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 s u bject wit h c o nti n ue d ipili m u ma b
d osi n g
T he a ssess me nt f or disc o nti n uati on o f ipili m u ma b s h o uld be ma de se paratel y fr o m t he assess me nt 
ma de f or disc o nt i n uati on of  ni v ol u ma b. Alt h o u g h t here is o verla p a mo n g t he disc o nt i n uati on 
criteria, if disc o nt i n uati on criteria are met f or ipili m u ma b b ut n ot f or ni v ol u ma b , treat me nt wi t h 
n i v ol u ma b ma y c o nt i n ue if ipili m u ma b is disc o nti n ue d.
If a s u bject me ets crit eria f or disc o nti n uati on a n d i n vesti gat or is u na ble t o deter mi ne w het her t he 
e ve nt is r elate d t o b ot h or o ne st u d y dr u g, t he s u bject s h o uld disc o nt i n ue b o t h ni v ol uma b
a n d 
ipili m u ma b a n d be ta ke n off t he treat me nt p hase of t he st u d y .
4. 5. 5. 3
P e m etr e x e d a n d Ci s pl ati n or C ar b o pl ati n D o s e Di s c o nti n u ati o n
E xce pt w here s pecifie d b el o w, b ot h c he m ot hera p y dr u gs i n t he pl at i n u m d o u blet c he m ot hera p y 
re gi me n s h o ul d be disc o nti n ue d f or a n y of t he foll o wi n g:

A n y Gra de 3 peri p h er al  ne ur o pat h y

Gra de 3 dr u g -relate d t hr o m b oc yt o pe nia ass ociate d wit h cli nicall y si g nifica nt blee di n g

A n y dr u g -r elate d li ver f unct i on test ( L F T) a b n or malit y that me ets t he f oll owi n g criteria 
re q uires disc o nt i n uati on:
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

A S T or A L T > 5 -1 0 x U L N f or > 2 wee ks

A S T or A L T > 1 0 x U L N

T ot al  bilir u bi n > 5 x U L N

C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N

A n y cis plati n-relate d decrease i n creati ni ne cleara nce t o < 5 0 m L/ mi n ( usi n g t he C o c kr oft 
Ga u lt for m ula) re q ui res disc o nti n uati on of cis plat i n 

A n y dr u g -relate d a d verse e ve nt w hic h rec urs after t w o pri or d ose re d ucti o ns f or t he sa me dr u g-
r elate d a d verse e ve nt (as s pecifie d i n Sect i ons 4. 5. 3. 2 ) re q uires disc o nti n uati on of  t he dr u g(s) 
w hic h was/ were pre vi o usl y d ose re d uce d.

A n y 
Gra de

3 dr u g -relate d h y perse nsit i vity reacti o n or i nf usi on reactio n re q uir es
di sc o nti n uati on o f t he dr u g(s) felt t o be ca usi n g t he reacti o n. T he dr u g n ot felt t o be relate d t o
t he h y perse nsit i vity r e a ctio n or i nf usi o n  reactio n m a y  be c o nti n ue d.

A n y Gra de 4 dr u g -relate d a d verse e ve nt w hic h t he i n vesti gat or dee m s is i na p pr o priate t o be
ma na ge d b y d ose re d ucti on(s) re q uires disc o nt i n uati o n of  the dr u g(s) felt to be ca usi n g t he
e ve nt. T he dr u g n ot felt t o be relate d t o t he e ve nt ma y be c o nti n ue d.

A n y e v e nt t h at l e a ds t o d el a y in d osi n g of  a n y st u d y dr u g(s) f or > 6 wee ks fr o m t he pr e vio us
d ose re q uires disc o nt i nuat i on of t hat dr u g(s) wit h t he f o ll owi n g e xce pt i on:

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 d ical m o nit or. Pri or t o re-i nitiati n g
treat me nt i n a s u bject wi t h a d osi n g dela y lasti n g > 6 wee ks, t he B M S me d ical m o nit or
m ust be c o ns ulte d. Peri o dic st u d y  visits t o assess safety a n d la b orat or y st u dies s h o uld als o 
c o nti n ue e ver y 6 wee ks or m o re fre q ue ntl y if cli nicall y i n dicate d d uri n g s uc h d osi n g
d el a ys.

A n y a d verse e ve nt, la b orat or y ab 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 s u bject wit h c o nt i n ue d plati n u m 
d o u bl et c he m ot hera p y d osi n g. I n vesti gat ors s h o uld c o ns ult l ocal la bel i n g f or t he c he mot h era p y 
dr u gs bei n g a d mi nistere d t o a n y gi ve n s u bject f or a d diti onal g ui da nce o n d ose disc o nti n uat i on.

S u bject s recei vi n g pe metre xe d/cis plati n w h o 
disc o nti n ue cis plat i n alo ne ma y, 
at t he 
i n vesti gat or’s discret i on, be s witc he d t o pe metre xe d /car b o plat i n f or t he re mai n der of  the 
pl at i n u m d o u blet c ycles, w he n t he s u bject meets retreat me nt criteria, as s pecifie d i n Sect i on 
4. 5. 4. 3 .
4. 6
Tr e at m e nt B e y o n d Di s e a s e Pr o gr e s si o n ( Ar m A o nl y )
Acc u m ulat i n g 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 nit ial e vi de nce of P D. 
S u bject s will be per mitte d t o c o nti n ue o n ni v ol u ma b pl us i pili m u ma b f or treat me nt be yo n d i ni tial 
a da pte d m- R E CI S T f or mes ot heli o ma a n d/ or R E CI S T 1. 1 defi ne d P D as l on g as t he y meet t he 
f oll owi n g criteria:

I n vesti gat or-assesse d cli nical be nefit.

T ol era nce of st u d y dr u g

Sta bl e p erf or ma n ce stat us
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 4

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

Treat me nt be y o n d pr o gressi o n will n ot d el a y a n i m mi ne nt i nter ve nt i on t o pre ve nt serio us 
c o mplicat i ons o f di sease pr o gressio n (e g, C N S m etastases)

S u bject pr o vi des writte n i nf or me d c o nse nt pri or t o recei vi n g a d diti o n al n i v ol u m a b
a n d i pili m u m a b tre at me nt. All ot her ele me nts of t he m ai n 
c o nse nt i ncl u di n g 
descri pti o n of re as o n a bl y f oresee a ble ris ks o r  disc o mf orts, or ot her alter n ati ve 
tre at me nt o pti o ns will still a p pl y.
T he decisi o n t o c o nti n ue treat me nt be y o n d i nitial i n vesti gat or-assesse d a n d i n de pe n de nt ce ntral 
re vie w c o nfir me d pr o gressi o n m ust be a p pr o ve d b y 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. A f o ll ow- u p sca n s h o ul d be perf or me d wit hi n si x ( 6 ) wee ks 7 da ys o f origi nal 
P D t o deter mi ne w het her t here has bee n a decrease i n t he t u m or size, or c o nti n ue d pr o gressi o n of 
di sease. 
If t he i n vesti gat or feels t hat t he s u bject c o nt i n ues t o ac hie ve cli nical be nefit b y c o nt i n ui n g 
treat me nt, t he s u bject s ho ul d r e mai n o n t he trial a nd c o nti n ue t o recei ve m o nit ori n g acc or di n g t o 
t he Ti me a n d E ve nts Sc he d ule i n S ect i on 5. 1 .
F or t he s u bjects w h o c o nt i n ue n i v ol u ma b a n d i pili m u ma b st u d y thera p y be y o n d pr o gressi o n, 
f urt her pr o gressi o n is defi ne d as a n a d ditio n al  10 % i ncrease i n t u mor b ur de n wi t h a mi ni m u m 5 
m m a bs o l ute i ncrease fr o m time of  ini tial PD. T his i ncl u des a n i ncrease i n t he s u m of dia meters 
of  all tar get lesi ons a n d/ or t he dia meters of ne w meas ura ble lesi o ns c o m pare d t o t he ti me o f i nitial 
P D. N i v ol uma b / i pili m u ma b tr e at me nt s h o uld be di sc o nti n ue d per ma ne nt l y u p o n d oc u me ntati o n 
of  furt her pr o gressi o n.
Ne w lesi ons are c o nsi dere d meas ur ea ble at t he ti me of  init ial pr o gressi o n  if t he l on gest dia meter 
is at least 1 0 m m (e xce pt f or pat h olo gi cal l y m p h n o des w hic h m ust ha ve a s h ort a xis of at least 1 5 
m m). 
A n y ne w lesio n  co nsi dere d n o n- me as urea ble at t he ti me of  init ial pr o gressi o n ma y 
s u bse q ue ntl y bec o me meas urea ble a n d t heref ore i ncl u de d i n t he t u mor b ur de n if t he l on gest 
di a meter i ncreases t o at least 1 0 m m (e xce pt f or pat h o l ogi cal l y m p h n o des w hic h m ust ha ve a s h ort 
a xis of at least 1 5 m m). I n sit u atio ns w here t he relati ve i ncrease in t ot al  t u mor b ur de n b y 1 0 % is 
s olel y d ue t o i ncl usi o n of  ne w lesio ns w hic h bec o me meas ura ble, t hese ne w lesi ons m u st 
d e m o nstrate a n a bs o l ute i ncrease of at least 5 m m.
4. 7
Bli n di n g/ U n bli n di n g
A n o pe n -label (rat her t ha n bli n de d) st u d y desi g n was selecte d beca u se t he ma na ge me nt of si milar 
A Es will differ bet wee n treat me nt ar ms, gi ve n t he differe nt me c ha nis ms of  actio n of  differe nt 
treat me nt ar ms. If t his trial is bli n de d, t he ma na ge me nt of  AEs w o ul d p ote nti all y be d el a yed or 
detri me ntal  t o t he s u bject.
4. 8
Tr e at m e nt C o m pli a n c e
Treat me nt c o m p lia nce will be m o nit ore d b y dr u g acc o u nta bilit y as well as t he s u bject’s me dica l 
rec or d a n d e C R F.
 
 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 5

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
 
 
 
4. 8. 2
Tr e at m e nt of Ni v ol u m a b or I pili m u m a b R el at e d I nf u si o n R e a cti o n s
Si nce n i v ol u ma b a n d ipili m u ma b c o ntai n o nl y h u ma n i m m u n o gl o b uli n pr otei n se q ue nces, t he y are 
u nli kel y  t o be i m m u n o ge nic a n d i n d uce i nf usi on or h y perse nsi tivi t y reacti ons. H o we ver, if s uc h a 
reactio n were t o occ ur, it mi g ht ma nifest wi t h fe ver, c hills, rig ors, hea dac he, ras h, pr uri t us, 
art hral gias, h y p o - or h y perte nsi o n, br o nc h os pas m, or ot her s y m pt o ms. All Gra de 3 or 4 i nf usi o n 
reactio ns s h o ul d be re p orte d wit hi n 2 4 h o urs t o t he B M S Me dical M o nit or a n d re p orte d as a n S A E 
if crit eria are met. I nf usi on reacti ons s h o uld be gra de d acc or di n g t o N CI C T C A E ( Versio n 4) 
g ui deli nes.
Treat me nt rec o m me n dati o ns are pr o vi de d bel o w a n d ma y be m o difie d base d o n l ocal treat me nt 
sta n dar ds a n d g ui deli nes, as a p pr o priate:
F or Gr a de 1 s y m pt o ms: ( mil d re acti o n; i nf usi o n i nterr u pti o n n ot i n dic ate d; i nter ve nti o n n ot 
i n dic ate d):

Re mai n at be dsi de a n d m o nit or s u bject u ntil rec o ver y fr o m sy m pt o m s. T he f oll owi n g 
pr o p h ylact ic pr e m e dicatio ns are rec o m me n de d f or f ut ure i nf usi ons: di p he n h y dra mi ne 5 0 m g  
( or e q ui vale nt) a n d/ or aceta mi n o p he n/ paraceta m ol 3 2 5 t o 1 0 0 0 mg at l east 3 0 mi n utes bef ore 
a d ditio nal  ni v ol u ma b or ipili m u m a b a d mi nistratio ns.
F or G r a de 2 s y m pt o ms: ( m o der ate re acti o n re q uire d t her a p y o r  inf usi o n i nterr u pti o n b ut 
res p o n ds 
pr o m ptl y 
t o s y m pt o m atic 
tre at me nt (e g, a nti hist a mi nes, 
n o n -ster oi d al 
a nti -i nfl a m m at or y 
dr u gs, 
n arc otics, 
c ortic oster oi ds, 
br o nc h o dil at ors, 
IV 
fl ui ds); 
pr o p h yl actic me dic ati o ns i n dic ate d f or 2 4 h o urs):

St o p t he n i v ol uma b or ipili m u ma b i nf usi on, be gi n a n I V i nf usi on of  nor mal  sali ne, a n d treat 
t he s u bject wi t h di phe n h y dra mi ne 5 0 m g I V ( or e q ui vale nt) a n d/ or aceta mi n o p he n/ paraceta m o l 
3 2 5 t o 1 0 0 0 m g ; re mai n at be dsi de a n d m o nit or s u bject u ntil res ol uti on of  sy m pt o ms. 
C orti c oster oid a n d/ or br o nc h o dilat or t hera p y ma y als o be a d mi nistere d as a p pr o priate. If t he 
i nf usi on is i nterr u pte d, t he n restart t he i nf usi on at 5 0 % of  the ori gi nal i nf usi on rate w he n 
s y m pt o ms res ol ve; if n o f urt her c o mplicat i ons e ns ue aft er 3 0 mi n utes, t he rate ma y be 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 6

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
i ncrease d t o 1 0 0 % of  the ori gi nal i nf usi on rate. M o ni t or s u bject cl o sel y. If s y m pt o ms rec ur, 
t he n n o f urt her n i v ol u ma b or ipili m u ma b will be a d mi nistere d at t hat visi t. A d mi nister 
di p he n h y dra mi ne 5 0 m g I V, a n d re mai n at be dsi de a n d m o ni t or t he s u bject u ntil res o l uti on of 
s y m pt o ms. T he a mo u nt of  st u d y dr u g i nf use d m ust be rec or de d o n t he electr o nic case re p ort 
f or m (e C R F).

F or 
f ut ure i nf usi ons, t he f oll owi n g 
pr o p h ylacti c pr e m e dicat i ons are rec o m me n de d: 
di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n/ paraceta m o l 3 2 5 t o 1 0 0 0 m g  
s h o uld be a d mi nistere d at least 3 0 mi n utes bef o re n i v ol uma b
or ipili m u ma b i nf usi o ns. If 
necessar y , c ortic oster oids ( u p t o 2 5 m g of  h y dr oc ortis o ne or e q ui vale nt) ma y be use d.
F or Gr a de 3 or 4 s y m pt o ms: (se vere re acti o n, Gr a de 3: pr ol o n ge d [ie, n ot r a pi dl y res p o nsi ve 
t o s y m pt o m atic me dic ati o n a n d/ or brief i nterr u pti o n of i nf usi o n]; rec urre nce of s y m pt o ms 
f oll o wi n g i niti al i m pr o ve me nt; h os pit aliz ati o n i n dic ate d f or ot her cli nic al se q uel ae (e g, re n al 
i m p air me nt, p ul m o n ar y i nfiltrates). Gr a de
4: Life -t hre ate ni n g; press or o r  ve ntil at or y 
s u p p ort i n dic ate d):
I mme diatel y disc o nti n ue i nf usi on of  ni v ol u ma b or ipili m u ma b . Be gi n a n I V i nf usi on of  nor mal 
sali ne a n d treat t he s u bject as f o ll ows: Rec o m me n d br o nc h o dilat ors, e pi ne p hri ne 0. 2 t o 1 m g of  a 
1: 1 0 0 0 s ol ut i on f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 m g of a 1: 1 0, 0 0 0 s ol uti on i njecte d 
slo wl y f or I V a d mi nistrati o n, a n d/ or di p he n h y dra mi ne 5 0 m g I V wit h met h yl pre d nis o l one 1 0 0 m g 
I V ( or e q ui vale nt), as nee de d. S u bject s h o uld be m o nit o re d u ntil t he i n vesti gat or is c o mf o rta ble 
t hat t he s y m pt o ms will n ot rec ur. N i v ol uma b
or ipili m u ma b will be p er m a ne ntl y disc o nt i n ue d. 
I n vesti gat ors s h o ul d f oll ow t hei r i nstituti o nal  g ui deli nes f or t he treat me nt of a na p h yla xis. Re mai n 
at be dsi de a n d m o nit or s u bject u ntil rec o ver y o f t he s y m pt o ms.
I n case of late- occ urri n g h y perse nsit i vity s y m pt o ms (e g, a p peara nce of a localize d or ge neralize d 
pr uri t us wi t hi n 1 wee k 
aft er treat me nt), s y m pt o matic treat me nt ma y be gi ve n (e g, oral 
a nt i hista mi ne or c ortic oster oi ds).
4. 9
D e str u cti o n or R et ur n of I n v e sti g ati o n al Pr o d u ct
F or t his st u d y, I P (t hose 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 parti all y 
use d st u d y  dr u g c o ntai ners, vials a n d s yrin ges ma y be destr o ye d o n site. 
A n y u n use d I P s u p plie d b y B M S ca n o nl y be destr o y e d aft er 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 I P c o ntai ners m ust be i m me diatel y destr o ye d as re q uire d f or 
safety,  or t o meet lo c al  re g ulati ons (e g, c y t ot o xic or biol o gi cs).
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 
i nstituti 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 pos al  are ke pt. 
T he f o ll owi 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 om t he dr u g.

O n -sit e dis p osal pract ices a n d pr oce d ures are i n a gree me nt wi t h ap plica ble la ws a n d 
re g ulat i ons, 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.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

Wr itte n pr oce d ures f or o n -sit e di s p osal are a vaila ble a n d f oll owe d. T he pr oce d ures m u st be 
file d wit h t he site’s S O Ps a n d a c o p y pr o vide d t o B M S u p o n re q uest.

Rec or ds are ma i ntai ne d t hat all o w f or traceabilit y of  eac h c o ntai ner, i ncl u di n g t he date 
di s p ose d of , q u a 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 bility t o arra n ge f or dis p osal of all e m pt y c o ntai ners.
If c o n ditio 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 r et ur n of I P pr o vide d b y B M S ( or i ts ve n d ors). Destr uctio n of  no n -I P s o urce d b y t he sit e, n ot 
s u p plie d b y B M S, is s olel y t he res p o nsi bility of  t he i n vesti gat or or desig nee.
Pl ease refer t o Secti o n 9. 2. 2 f or a d ditio nal g ui da nce o n I P rec or ds a n d d oc u me ntati o n.
4. 1 0
R et ai n e d S a m pl e s f or Bi o a v ail a bilit y / Bi o e q ui v al e n c e
N ot A p plica ble. 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
5
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
5. 1
Fl o w C h art/ Ti m e a n d E v e nt s S c h e d ul e 
T a ble 5. 1 - 1:
Scree ni n g Pr oce d ur al O utli ne ( C A 2 0 9 7 4 3 )
Pr oce d ure
Scree ni n g
Visit
N otes
Eli gi bilit y Assess me nts a
I nf or me d C o nse nt
X
Ori gi nal I C i n scree ni n g f or pr ot oc ol partici pati o n; St u d y all o ws f or re -e nr oll me nt of a 
s u bject t hat has disc o nti n ue d t he st u d y as a pre-treat me nt fail ure. If re-e nr olle d, t he s u bject
m ust be re -c o nse nte d a n d assi g ne d a ne w s u bject n u m ber fro m I W R S.
I ncl usi o n/ E xcl usi o n Criteria
X
All i ncl usi o n/e xcl usi o n criteria s h o ul d be assesse d at scree ni n g a n d c o nfir me d pri or t o first 
d ose .
Me dical Hist or y
X
T u m o r Tiss ue Sa m ple C ollecti o n
X
T u m o r sa m ple f or P D-L 1 testi n g is ma n dat or y, t o be s hi p pe d t o Ce ntral La b orat or y u p t o 
4 2 da ys pri or t o ra n d o mizati o n. A fres h or arc hi ve d pre -treat me nt t u m or bi o ps y s peci me n
wit hi n 6 m o nt hs of ra n d o mizati o n is re q uire d f or f ull eli gi bilit y of a s u bject. A mi ni m u m of 
1 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 bl oc k ( preferre d) O R a mi ni m u m 
of 1 0 F F P E u nstai ne d secti o ns are re q uire d. S u bject s ca n i nitiate t her a p y bef ore t he res ult 
of P D -L 1 I H C testi n g.
Scree ni n g/ Baseli ne T u m or Assess me nt
X
C T sca n of c hest a n d u p per a b d o me n ( u p per a b d o me n i ncl u des i ma gi n g d o w n t o t he iliac 
crests), a n d all ot her k n o w n sites of disease wit hi n 2 8 da ys pri or t o first d ose.
T u m o r a ssess me nts f oll o w m o difie d m -R E CI S T f or mali g na nt ple ural mes ot heli o ma a n d 
R E CI S T 1. 1 criteria f or metastatic lesi o ns.
U p t o 6 ple ural meas ure me nts are re q uire d f or t he st u d y a n d eac h ple ural meas ure me nt 
m ust be ≥ 1 0 m m i n le n gt h.
Pri o r Me dicati ons
X
A n y  pri or me dicati o ns s u bjects recei ve d t o treat ca ncer.
S afet y Assess me nts 
P h y sical E xa mi nati o n/ P h ysical 
Meas ure me nts / E C O G Perf or ma nce 
Stat us
X
Hei g ht, wei g ht, B S A (scree ni n g o nl y), si g ns a n d s y m pt o ms wit hi n 1 4 da ys pri or t o first 
d ose
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
6 9

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 5. 1 - 1:
Scree ni n g Pr oce d ur al O utli ne ( C A 2 0 9 7 4 3 )
Pr oce d ure
Scree ni n g
Visit
N otes
Vital Si g ns
X
O btai n vital si g ns ( B P, H R, R R a n d te m perat ure) at t he scree ni n g  visit a n d wit hi n 7 2 h o urs 
pri or t o first d ose . Vital si g n meas ure me nts are t o be perf or me d i n sa me p ositi o n as t he first 
meas ure me nt a n d f or all s u bse q ue nt visits.
Seri o us A d verse E ve nts Assess me nt
X
Fr o m ti me of i nf or me d c o nse nt
E C G
X
Wit hi n 1 4 da ys pri or t o first d ose . E C G Q Tc calc ulati o n as per SO C .
La b orat o r y Tests
X
C B C w/ differe ntial, C he mistr y pa nel i ncl u di n g: Al b u mi n , L D H,  A S T, A L T, A L P, T. Bili, 
B U N or ser u m urea le vel, creati ni ne, Ca, M g, Na, K, Cl, p h os p ha te, gl uc ose, a m ylase, 
li pase, T S H, Free T 4, Free T 3, He patitis B s urface a nti ge n ( H B V s A g), he patitis C 
a nti b o d y ( H C V A b) or He patitis C R N A ( H C V R N A), a n d HI V (w h ere l ocall y ma n date d, 
[e g, re q uire d f or sites i n Ger ma n y a n d S o ut h Africa]). Wit hi n 1 4 da ys pri or t o first 
treat me nt.
S u bjects w h o test p ositi ve f or he patitis C b ut ha ve u n detecta ble H C V R N A are all o we d t o 
e nr oll
Pre g na nc y Test ( W O C B P o nl y)
X
Ser u m or uri ne wit hi n 2 4 h o urs of first d ose
T u m o r Tiss ue sa m ple:
X
A fres h or arc hi ve d t u m or tiss ue sa m ple is ma n dat or y, t o be s hi p pe d t o Ce ntral La b orat or y 
pri or t o ra n d o mizati o n 
St u d y Dr u g
E nr oll me nt i n I W R S
X
S u bjects will be ra n d o mize d u p o n all scree ni n g assess me nt c o m p leti o n. Ra n d o mizati o n 
assi g n me nt m ust occ ur at least 2 4 h o urs pri or t o first d osi n g da y t o all o w f or pre-
me dicati o n de xa met has o ne re gi me n f or Ar m B .
a
All scree ni n g assess me nts m ust be c o m plete d a n d s u bject s ho ul d be treate d wit hi n 2 8 da y s, e xce pt E C O G, p h ysical assess me nts, si g ns a n d s y m pt o ms, 
c o nc o mita nt me dicati o n, E C G a n d la b orat or y  tests s h o ul d be d o ne wit hi n 1 4 da y s pri or t o first treat me nt, vital si g ns wit hi n 7 2 h o urs, pr e g na nc y test m ust be 
wit hi n 2 4 h o urs pri or t o first d ose, a n d I C F m ust be si g ne d, scree ni n g C T, a n d t u m or sa m ple m ust be s hi p pe d wit hi n 4 2 da ys be f ore ra n d o mizati o n.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
7 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
a C ycle le n gt h: Ar m A 1 C ycl e = 6 wee ks; Ar m B 1 C ycle = 3 wee ks.
b
Ar m A: Visits occ ur e ver y 2 wee ks
c
Ar m B: Visits occ ur e ver y 3 wee ks
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
7 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 5. 1 - 3:
F oll o w u p peri o d (C A 2 0 9 7 4 3 ): B ot h tre at me nt ar ms
Pr oce d ure
F oll o w u p Visit 
1 a n d 2 a
S ur vi v al 
f oll o w u pb
N otes
S u bject St at us
S ur vi val Stat us
X
X
E ver y 3 m o nt hs after F U 2; ma y be acc o m plis he d b y visit, p h o ne c o ntact or 
e mail, t o i ncl u de assess me nt of s u bse q u e nt a nti -ca ncer t hera p y
a
F oll o w -u p visit 1 ( F U 1) = 3 0 da y s fr o m t he last d ose ± 7 da ys or c oi nci des wit h t he date of disc o nti n uati o n ( ± 7 da y s) if date of disc o nti n uati on is greater t h a n 
3 5 da ys after last d ose, F oll o w -u p visit 2 ( F U 2) = 9 0 da ys ( ± 7 da y s) fr o m f oll o w-u p visit 1
b
E ver y 3 M o nt hs ( ± 7 da ys) fr o m F U 2
N O T E: A r m B: After c o m pleti o n of F oll o w u p Visit 1 a n d 2, s u bjects e nter s ur vi val f oll o w u p a n d s h o ul d o nl y c o m pl ete assess me nts f or E Q-5 D.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
7 5

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
5. 1. 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
Retesti n g of la b orat or y para meters a n d/ or ot her assess me nts wit hi n a n y si n gle Scree ni n g or Lea d -
i n perio d will be per mitte d (i n a d dit i on t o a n y  para meters t hat re q uire a c o nfir mat or y v alu e).
A n y ne w res ult will o verri de t he pre vi o us res ult (ie, t he m o st c urre nt res ult pri or t o Ra n d o mizat i on)  
a n d is t he val ue b y w hic h st u d y incl usi o n will be assesse d, as it re prese nts t he s u bject’s m o st 
c urre nt, cli nical state.
La b orat or y  p ar a meters a n d/ or assess me nt s t hat are i ncl u de d i n Ta ble 5. 1 - 1, Scree ni n g Pr oce d ural 
O utli ne ma y be re peate d i n a n eff ort t o fi n d all p os si ble well-q ualifie d s u bjects. C o ns ultati o n wit h 
t he Me dical M o nit or ma y be nee de d t o i de ntif y w het her re peat testi n g of  a n y part ic ular para meter
is cli nicall y rele va nt.
5. 2
St u d y M at eri al s

N CI C T C A E versi o n 4

n i v ol u ma b I n vestigat or Br oc h ure

ipili m u ma b I n vesti gat or Br oc h ure

P har mac y  Bi n der

La b orat or y  ma n uals f or c o llecti o n a n d ha n dli n g of  bl oo d (i ncl u di n g P K , bi o mar ker a n d 
i m m u n o ge nicity)  a n d tiss ue s peci me ns

Si te ma n ual f or o perati o n of I nteracti ve V oice Res p o nse S yste m (I W R S), i ncl u di n g e nr oll me nt 
w or ks heets

Ma n ual f or e ntr y  of lo c al  la b orat or y data

Pre g na nc y S ur veilla nce F or ms

m- R E CI S T f or ma li g na nt ple ural mes ot heli o ma p oc ket g ui de

St u d y  I ma gi n g Ma n ual
5. 3
S af et y A s s e s s m e nt s
At  scree ni n g, a me d ical 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 ditio ns. T he 
scree ni n g e xa mi nati ons s h o ul d i ncl u de wei g ht, hei g ht, E C O G Perf or ma n c e Stat us, bl o o d press ure 
( B P), heart rate ( H R), a n d t e mperat ure. Scree ni n g assess me nts s h o uld be per f or me d wi t hi n 2 8 da ys
pri or t o first d ose. Baseli ne si g ns a n d s y m pt o ms are t h ose t hat are assesse d wit hi n 1 4 da ys pri or t o 
first dose. C o nc o mita nt  me dicat i ons will be c o llecte d fr o m wi t hi n 1 4 da ys pri or t o t h e first d ose 
t hr o u g h the st u d y treat me nt peri o d (see S ectio n 5. 1 )
Scre e ni n g l ocal la b orat or y assess me nts s h o uld be d o ne wi t hi n 1 4 da ys pri or t o first d ose a n d are 
t o i ncl u de: C B C wi t h differe ntial, C he mistr y  pa n el incl u di n g L F Ts ( A L T, A S T, t otal bilir u bi n, 
alkali ne p h os p hatase), B U N or ser u m urea level,  creatini ne, Ca, Na, K , Cl, p h os p hate, L D H, 
gl uc ose, a n d t h y r oid pa nel  incl u di n g T S H, free T 3, a n d free T 4.
T he f oll owi n g baseli ne l ocal la b orat or y assess me nts s h o ul d be d o ne wi t hi n 1 4 da ys pri or t o fi rst 
treat me nt: He patit is 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)
a n d HI V testi n g 
( w here l ocall y ma n date d, [e g, re q uire d f or sites i n Ger ma n y a n d S o ut h Africa]).
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Scree ni n g pre g na nc y  tests f or W O C B P m u st be perf or m e d wi t 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. 
W hile o n -st u d y the f oll owi n g l ocal la b or at or y assess me nts are t o be d o ne wi t hi n 3 da ys pri or t o 
eac h d ose: C B C wi t h differe ntial, LF Ts ( A L T, A S T, t otal  bilir u bi n, al kali ne p h os p hatase), B U N 
or ser u m urea le vel, creati ni ne, al b u mi n (if cli nicall y in dicate d), Ca, M g, Na, K, Cl, p h os p hate, 
L D H, gl u c ose, a m ylase, a n d li pase. T h yr oi d f u nct i on t esti n g is t o be d o ne e ver y 6 wee ks re gar dless 
of  treat me nt ar m.
S u bject s will be e val uate d f or safety 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 wo safet y f o ll ow- u p visit s. 
O nce s u bjects reac h t he s ur vi val f oll ow- u p p hase , eit her i n-pers o n visit s or d oc u me nte d tele p h o ne 
calls t o assess t he s u bject’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.
T he start a n d st o p ti me of  the st u d y thera p y i nf usi o ns a n d a n y i nterr u ptio ns or i nf usi on rate 
re d uctio ns s h o ul d be d oc u me nte d. 
P h ysical e xa mi nat i ons are t o be perf or m e 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- serio us or seri o us a d verse e ve nt pa ge.
A d dit i onal meas ures, i ncl u di n g n o n- st u d y re q uire d lab orat or y  tests, s h o uld be p erf or m e d as 
cli nicall y i n dicate d or to c o m pl y  wit h lo c al  re g ulatio n s. 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 ons) will be m o nit ore d d uri n g t he f oll ow- u p p hase via o n si t e/lo c al 
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 deeme d irre versi ble.
If a s u bject s h o ws p ul m o n ar y -relate d sig ns ( h y p o xia, fever) or s y m pt o ms (e g, d y s p nea, c o u g h, 
fe ver) c o nsiste nt wit h p ossi ble p ul m o nar y  ad verse e ve nts, t he s u bject 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  to xi cit y, acc or di n g t o t he s us pecte d p ul m o nar y  to xi cit y 
ma na ge me nt al g orit h m i n t he B M S -9 3 6 5 5 8 ( n i v ol u ma b) I n vesti gat or Br oc h ure.
S o m e of t he assess me nts referre d t o i n t his sect i on ma y n ot be ca pt ure d as data i n t he e C R Fs. T he y 
are i nte n de d t o be use d as safety m o nit ori n g b y t he treatin g p h ysicia n. A d dit i onal testi n g or 
assess me nts ma y be perf or m e d as cli nicall y necessar y or w here re q uire d b y i nstituti o nal or l ocal 
re g ulat i ons.
5. 4
I m a gi n g A s s e s s m e nt f or th e St u d y
I ma ges will be s u b mitte d t o a n i ma gi n g t hir d -part y ra di o l og y  ve n d or f or ce ntral re vie w. Sites will 
be trai ne d pri or t o scree ni n g t he first stu d y s u bject. I ma ge ac q uisit i on g ui deli nes a n d s u b missio n 
pr ocess will be o utli ne d i n t he st u d y Ima gi n g Ma n u al  pr o vi de d b y t he r a diol o g y  ve n d or. T u m or 
assess me nts s h o uld b e s u b mi tt e d t o t h e t hir d-part y ra di ol o g y  ve n d or as t he y ar e p erfor me d o n a n 
o n g oi n g basis.
Scree ni n g assess me nts are t o be p erf or m e d wi t hi n 2 8 da ys pri or t o fi rst dose. All k n o w n sit es of 
di s ease s h o uld be assesse d at baseli ne. Rec o g nizi n g t hat n ot all cases of  ad va nce d u nresecta ble 
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mali g na nt ple ural mes ot heli o ma ca n be assesse d wi t h 6 ple ural meas ure me nts, t he m- R E CI S T 
s u g geste d g ui da nce has bee n a da pte d i n t his st u d y to all o w f or t he assess me nt  of u p t o 6 
meas ure me nts rat her t ha n a fi xe d n u m ber. Meas ure me nts will be i n u p t o 2 p ositi o ns at 3 se parate 
le vels o n tra ns verse c uts of  CT sca n (c uts m ust be at least 1 0 m m a part). Eac h si n gle t u mor 
meas ure me nt m ust be at least 1 0 m m i n le n gt h t o q uali f y as meas urea ble disease a n d c o ntri b ute t o 
t he s u m t hat defi nes t he ple ural u ni -di me nsi o n al meas ure me nt. T he ma xi m u m n u m ber of pl e ural 
lesio ns, u p t o 6, t hat q ualif y as me as urea ble disease m u st be use d. K n o w n met astatic M P M n o n-
pl e ural lesio ns (i ncl u di n g n o dal  or s u bc uta ne o us lesi ons) meet i n g R E CI S T 1. 1 criteria, will als o 
be c o nsi dere d meas ura ble disease.
Ra di o gra p hic t u m or res p o nse will be assesse d at 6 wee ks( 7 da ys) fr o m fir st d ose date, t he n e ver y 
6 wee ks ( 7 da ys) f or t he first 1 2 m o nt hs ( u nt il week 4 8) a n d e ver y 1 2 wee ks ( 7 da ys) t hereafter, 
u nt il disease pr o gressi o n is d oc u me nte d. 
Ra di ol o g y  assess me nts m ust be ke pt t o sc he d ule irres pecti ve of a n y dela ys i n a treat me nt c ycle. If 
t he sc he d ule ca n n ot be ke pt all att e mpts m ust be ma de t o u n derta ke t he re q uire d i ma gi n g as s o o n 
as p ossi ble t he n s u bject m ust be p ut bac k o n ori gi nal i ma gi n g sc he d ule.
T u m or meas ure me nts s h o ul d be ma de b y  t he sa me i n vesti gat or or ra di ol ogist f or eac h assess me nt 
w he ne ver p ossi ble. C ha n ge i n t u mor meas ure me nts a n d t u mor resp o nse will be assesse d b y t he 
I n vesti gat or usi n g t he a da pte d m-R E CI S T a n d/ or R E CI S T 1. 1 criteria ( See A p pe n di x 4 ).
I n a d ditio n, s u bjects recei vi n g ni v o l uma b a n d i pili m u ma b treat me nt be y o n d pr o gressi o n m u st 
c o nti n ue t u m or assess me nts u ntil s uc h treat me nt ha s bee n disc o nti n ue d. See Secti o n 4. 6 .
A n y i nci de ntal fi n di n gs of  pote nti al cli nical rele va nce t hat are n ot direct l y ass ociate d wit h t he 
o bj ect i ves of  the pr ot oc ol  s h o uld be e val uate d a n d ha n dle d b y t he St u d y  In vesti gat or as per 
sta n dar d me dical/cli nical j u d g me nt.
5. 5
Effi c a c y A s s e s s m e nt s
T he pri mar y e n d p o i nt is o verall s ur vi val ( O S) i n all ra n d o mize d s u bjects. See S ecti o n 8. 3. 1 f or t he 
defi nit i ons of  OS . E ver y  eff ort will be ma de t o c ollect s ur vi val data o n all s u bjects i ncl u di n g 
s u bjects wit hdra w n fr o m treat me nt f or a n y reas o n, w h o are eli gi ble t o partici pate i n t he st u d y a n d 
w h o ha ve n ot wit h dra w n c o nse nt f or s ur vi val data c o llecti o n. If t he deat h of  a s u bject is n ot 
re p orte d, all dates i n t his st u d y re prese nti n g a date of s u bject c o ntact will be use d i n deter mi nati on 
of  t he s u bject’s last k n o w n date ali ve.
T he sec o n dar y efficac y e n d p o i nts of  the st u d y are o verall res p o nse rate ( O R R), disease c o ntr ol 
rate ( D C R), a n d pr o gressi o n free s ur vi val ( P F S), base d o n BI C R assess me nt i n all ra n d omize d 
s u bjects. See S ecti o n 8. 3. 2 f or t he defi nit i ons of  OR R , D C R , a n d P F S . All ra n d o mize d s u bjects 
will be m o nit ore d b y ra di o gra p hic assess me nt o n a n e ver y - 6-wee k sc he d ule ( 7 da y s) f or t he first 
1 2 m o nt hs ( u nt il wee k 4 8) a n d e ver y  1 2 wee ks (7 da ys ) t hereafter [ be gi n ni n g fr o m t he first o n-
st u d y assess me nt o n wee k 6 (7 da ys )], t o deter mi ne c ha n ges i n t u m or size. A da pte d m -R E CI S T 
a n d R E CI S T 1. 1 criteria will be use d f or t he assess me nt.
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6
A D V E R S E E V E N T S
A n A dverse Eve nt ( A E) is defi ne d as a n y ne w u nt o war d me d ical occ urre nce or w o rse ni n g of  a 
pree xist i n g me d ical c o n ditio n  in a cli nical i n vesti gatio n s u bject a d mi nistere d st u d y treat me nt a n d 
t hat d oes n ot necessaril y ha ve a ca usal relat i ons hi p wi t 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 t e mp orall y  ass ociate d wit h t he use of  st u d y treat me nt , w het her or 
n ot c o nsi dere d rel ate d t o t he st u d y treat me nt.
E ve nts Meeti n g
t he A E Defi niti o n

A n y a b n or mal la b orat or y test res ults ( he mat olo g y , cli nical c he mistr y, or uri nal ysis) or 
res ults fr om 
ot her safety assess me nts (e g, E C G, 
ra di ol ogi cal sca ns, vit al si g ns 
meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nicall y si g nifica nt 
i n t he me d ical a n d scie nt ific j u d g me nt of  t he i n vesti gat or. N ote t hat a b n or mal la b tests or 
ot her safety assess me nts s h o uld o nl y be re p orte d as A Es if t he fi nal dia g n osis is n ot 
a vaila ble. O nce t he fi nal dia g n osis is k n o w n, t he re p orte d ter m  s ho ul d be u p date d t o be t he 
di a g n osis.

E xacer bat i on of a c hr o nic or i nter mitte nt pre -e xisti n g c o n dit i on i ncl u di n g either a n i ncrease 
i n fre q ue nc y a n d/ or i nte nsity of t he c o n dit i on.

Ne w c o n dit i ons detecte d or dia g n ose d after st u d y i nter ve nt i on a d mi nistrati o n e ve n t h o u g h it 
ma y ha ve bee n prese nt bef ore t he start of t he st u d y.
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Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of  a sus pecte d o ver d ose of  either st u d y i nter ve nt i on 
or a c o nc o mit a nt me dicat i on. O v er d ose, as a ver bati m ter m (as re p orte d b y t he i n vest i gat or), 
s h o uld n ot be re p orte d as a n A E/ S A E u nless it is a n i nte nt i onal o ver d ose ta ke n wit h p ossi ble 
s uicid al /s elf-har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of  se q uelae a n d 
s h o uld s pe cif y "i nte nt i onal o ver d ose" as t he ver bati m ter m
E ve nts N O T Meeti n g t he A E Defi niti o n

Me dical or s ur gical pr oce d ure (e g, e n d osc o p y, a p pe n dect o m y): t he c o n ditio n  that lea ds t o 
t he pr oce d ure is t he A E.

Si t u atio ns i n w hic h 
a n u nt o war d me d ical occ urre nce di d
n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).
T he ca usal relat i ons 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 relat i ons hi p ca n be o ne of t he f o ll owi n g:

Relate d: T here is a reas o na ble ca usal relatio 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 relatio n s 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 relat i ons hi p" mea ns t here is e vi de nce t o s u g gest a ca usal relat i ons hi p. 
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 uest i oni n g, 
e xa mi nat i on, or e val uat i on of a s u bject. (I n or der t o pre ve nt re p orti n g bias, s u bjects s h o ul d n ot be 
q uesti o ne d re gar di n g t he s pecific oc c urre nce of o ne or m ore A Es.)
S p o ns or or desi g nee will be re p orti n g a d verse e ve nts t o re g ulat or y aut h ori ties a n d et hics 
c o m mittees acc or di n g t o l ocal ap plica ble la ws i ncl u di n g E ur o pea n Di recti ve 2 0 0 1/ 2 0/ E C a n d F D A 
C o de of Fe deral Re g ulat i ons 2 1 C F R Parts 3 1 2 a n d 3 2 0.
6. 1
S eri o u s A d v er s e E v e nt s
A S eri o us A dverse Eve nt ( S A E) is a n y u nt o war d me dical occ urre nce t hat 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 s u bject 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 o re se vere)

re q uires i npat ient h os pitalizati o n or ca uses pr ol o n gati o n of e xist i n g h os pitalizati o n (see N O T E
bel o w)

res ults i n persiste nt or si g nifica nt disa bility/ i nca pacit y

is a co n ge ni t al 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 ul t i n deat h or h os pi talizati on b ut, base d u p o n a p pr o priate me d ical an d 
scie ntific j u d g me nt, ma y je o par dize t he s u bject or ma y re q uire i nter ve nt i on [e g, me d ical, 
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 nit i on a b o ve.) E xa m ples 
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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 pi talizatio n.) P ote nti al 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 6. 4 f or t he defi niti on of p ote nti al DI LI.)
S us pecte d tra ns missi o n of  an i n fecti ous 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 dr u g 
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 ot e nt ial dr u g i n d uce d li ver i nj ur y ( DI LI) are n ot 
alwa ys seri o us b y re g ulat or y  defi niti on, t hese e ve nts m ust be ha n dle d as S A Es. ( See Secti o n 6. 1. 1
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 en d p o i nt that is c o nsi der e d r elate d t o stu d y t hera p y (e g, deat h is a n 
e n d p o i 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) s h o ul d be re p orte d 
as S A E (see Secti o n 6. 1. 1 f or re p orti n g details).
N O T E : 
T he f o ll owi n g h os pi talizatio ns are n ot c o nsi dere d S A Es i n B M S cli nical st u dies: 

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)

elect i ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt

a d missi o ns as per pr ot oc ol f or a pla n ne d me dical/s ur gical pr oce d ure

r o utine 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 on osc o p y )

me dical/s ur gical a d missi o n ot her t ha n t o r e me d y ill healt h a n d pl a n n e d prior t o e ntr y  int o 
t he st u d y. A p pr o priate d oc u me ntatio n is re q ui re d i n t hese cases

a d missi o n e nc o u ntere d f or a n ot her life c ircu 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 ntio n ( e g, l a c k of  ho usi n g, ec o n o mic i na de q uac y, 
care gi ver res pite, fa mil y circu msta nces, a d mi nistrati ve reas o n)

A d missi o n f or a d mi nistrati o n of  a nt ica ncer t hera p y in t he a bse nce of  an y ot h er S A Es 
(a p plies t o o nc ol o g y pr ot oc ols)
6. 1. 1
S eri o u s A d v er s e E v e nt C oll e cti o n a n d R e p orti n g
Secti o ns 5. 6. 1 a n d 5. 6. 2 i n t he I n vesti gat or Br oc h ure
(I B) re prese nt t he Refere nce Safet y 
I nf or mat i on t o deter mi ne e x pecte d ness of  seri o us a d verse e ve nts f or e x pe dite d re p orti n g. 
F o ll owi n g t he s u bject’s writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her relate d or n ot 
r elate d t o st u d y dr u g, m ust be c o llecte d, i ncl u di n g t hose t ho u g ht t o be ass ociate d wi t h pr ot oc ol-
s pecifie d pr oce d ures . All S A Es m ust be c o llecte d t hat occ ur d uri n g t he scree ni n g p eri o d a n d wi t hi n
1 0 0 d a y s of t he last d ose of  st u d y dr u g. If a p plica ble, S A Es m u st be c ollecte d t hat relate t o a n y 
later pr ot oc ol-s pecifie d pr oce d ure (e g, a f o ll ow- u p s ki n bi o ps y). F or s u bjects 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  ra n d omizat i on/treat m e nt assig n me nt. 
T he i n vesti gat or m u st re p ort a n y S A E t hat occ urs after t hese ti me p eri o ds a n d t hat is belie ve d t o 
be relate d t o st u d y dr u g or pr ot oc ol -s pecifie d pr oce d ure. 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
8 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
A n S A E re p ort m u st be c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its seri o us ness. 
If t he i n vesti gat or belie ves t hat a n S A E is n ot relate d t o st u d y dr u g, b ut is p ote ntiall y relate d t o t he 
c o n ditio ns of  the st u d y (s uc h as wi t hdra wal of  pre vi o us t hera p y or a c o mplicat i on of  a st u d y 
pr oce d ure), t he relat i ons hi p m u st be s pecifie d i n t he narrati ve secti o n o f t he S A E Re p ort F or m.
S A Es, w het her rel at e d or n ot r elat e 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 S p o ns or 
or desi g n ee wi t 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 o llecti on 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.
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 on t o:
S A E E m ail A d dress: Refer t o C o ntact I nf or mati on list.
S A E F acsi mile N u m ber: Refer t o C o ntact I nf or matio n list.
F or stu 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 missio 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 on,  
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 m s are t o re mai n o n sit e.
S A E Tele p h o ne C o nt act
(re q uired f or S A E a n d pre g na nc y re p orti n g): Refer t o C o nt act
I nf or mat i on list.
If o nl y  li mite d i nf or mati on 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 u st i ncl u de t he sa me i n vesti gat or ter m(s) i nitiall y re p orte d.) 
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 stu d y dr u g or if ne w i nf or mati on 
bec o me s a vaila ble, t he S A E re p ort must be u p date d a n d s u b mi tt e d wit hi n 2 4 h o urs t o S p o ns or or 
desi g n ee usi n g t he sa me pr oce d ure use d f or tra ns mitt i n g t he i nitial S A E re p ort.
All S A Es m ust be f oll owe d t o res ol ut i on or sta bilizati o n.
B M S will be re p orti n g a d verse e ve nts t o re g ulat or y a ut h orit ies a n d et hics c o m mittees acc or di n g t o 
l ocal ap plica ble la ws i ncl u di n g E ur o pea n Di recti ve 2 0 0 1/ 2 0/ E C a n d F D A C o de of  Fe deral 
R e g ulatio 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 
React i on) is a s u bset of  SA Es a n d will be re p orte d t o t he a p pr o priate re g ulat or y aut h ori ties a n d 
i n vesti gat ors f oll owi n g l ocal a n d gl o bal g ui deli nes a n d re q uire me nts.
6. 2
N o n s e ri o u s A d v er s e E v e nt s
A n o nseri o us a dverse eve nt is a n A E n ot classifie d as seri o us.
6. 2. 1
N o n s eri o u s A d v er s e E v e nt C oll e cti o n a n d R e p orti n g
T he c ollect i on of  no ns eri o us A E i nf or mati o n s h o ul d be gi n at i ni tiat i on of  st u d y dr u g. N o nserio us 
A E i nf or mat i on s h o uld also be c o llecte d fr om t he start of  a place b o lea d-i n p eri o d or ot her 
o bser vat i onal peri o d i nte n de d t o esta blis h a baseli ne stat us f or t he s u bjects.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
8 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
N o nseri o us A Es s h o uld be f oll owe d t o res oluti o n or sta bilizat i on, or re p orte d as S A Es if t he y 
bec o me serio us (see Sect i on 6. 1. 1 ). F o ll ow- 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 ptio n or d isc o nti n uati on of st u d y dr u g 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 u st be rec or de d a n d descri be d o n t he n o nserio us A E 
pa ge of t he C R F ( pa per or electr o nic) s h o uld be c ollecte d c o nti n u o usl y d uri n g t he treat me nt peri o d 
a n d f or a mini m u m  of 1 0 0 da ys fol l owi n g disc o nt i n uati on of st u d y  treat me nt.
E ver y  ad verse e ve nt m u st 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 nti all y i m m u ne-me d iate d, a d ditio nal i nf or mat i on w ill 
be c o llecte d o n t he s u bject’s case re p ort f or m.
C o m plet i on o f 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 malit ies t hat 
are re p orte d/i de nt ifie d d uri n g t he c o urse of t he st u d y.
6. 3
Pr e g n a n c y
If, f oll owi n g i nitiati on of  the st u d y dr u g, it is s u bse q ue ntl y disc o vere d t hat a stu d y s u bject is 
pre g na nt or ma y ha ve bee n pre g na nt at t he ti me o f st u d y e x p osure, i ncl u di n g d uri n g at least 5 half -
li ves aft er pr o d uct a d mi nistratio n, t he i n vesti gat or m ust i m me diatel y n otif y t he S p o ns or or 
desi g n ee of  this 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 
wi t hi n 2 4 h o urs of  aware ness of  the e ve nt a n d i n acc or da nce wi t h SA E re p orti n g pr oce d ures 
descri be d i n Secti o n 6. 1. 1 .
I n m ost cases, t he st u d y dr u g 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  for s u bject safet y). Pl ease call t he S p o ns or or desi g n e e wi t hi n 2 4 h o urs of 
a ware ness o f t he pre g na nc y.
Pr ot oc ol -re q uire d pr oce d ures f or stu d y disc o nt i n uati o n a n d f oll ow- u p m us t be perf or m e d o n t he 
s u bject.
T he i n vest i gat or m ust i m me diatel y n otif y t he S p o ns or or desi g n ee of  t his e ve nt a n d c o mplete a n d 
f or war d a Pre g na nc y S ur veilla nce F or m  to S p o ns or or desi g n ee wi t hi n 2 4 h o urs of  aware 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 Sect i on 6. 1. 1 . 
F o ll ow- u p i nf or mati on re gar di n g t he c o urse of  the pre g na nc y, i ncl u di n g peri natal  an d ne o natal 
o utc o m e a n d, w here a p plica ble, offs pri n g i nf or mati on m u st be re p orte d o n t he Pre g na nc y 
S ur veill a 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 n ee. I n or der f or B M S t o c ollect a n y pre g na nc y s ur veilla nce i nf or mati o n fr om t he 
fe male part ner , t he female part ner m u st si gn a n i nf or me d c o nse nt f or m for discl o s ure of  this 
i nf or mat i on. 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.
6. 4
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, timel y c o nfir mat i on of  init ial li ver-r elate d la b orat or y a b n or malit ies s h o uld 
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, meet i n g 
t he defi ne d criteria, m ust be re p orte d as S A Es (see Secti o n 6. 1. 1 f or re p orti n g details).
P ote nti al dr u g i n d uce d li ver i nj ur y is defi ned as:
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
8 9

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
1. A T ( A L T or A S T) ele vati o n > 3 ti mes u p per li mit of n or mal ( U L N) 
A N D
2. T otal bilir u bi n > 2 ti mes U L N, wi t ho ut i nit ial fi n di n gs of  c hol estasis ( ele vate d ser u m alkali ne 
p h os p hatase),
A N D
3. N o  ot her i m me diatel y a p pare nt p ossi ble ca uses of  AT ele vat i on 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 pati tis, pre -e xist i 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.
6. 5
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 nte rim o r fi nal p h ysical e xa mi nat i ons, electr ocar di o gra m, 
x- r a y fil mi n g, a n y ot her p ote nti al safety assess me nt re q uire d or n ot re q uire d b y pr ot oc ol  sh 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 pr iate, a n d re p orte d acc or di n gl y.
6. 5. 1
A d v er s e E v e nt s of I nt er e st
Defi nit i on o f i m m u ne-me diate d a d verse e ve nts (I M A Es)
I mm u ne- me d iate d A Es are s pecific e ve nts (t hat i ncl u de p ne u m o ni tis, diarr hea/c o litis, he pat itis, 
ne p hrit is/re nal 
d ysf u ncti o n, 
ras h, 
a n d 
e n d ocri ne 
(a dre nal 
i ns ufficie nc y, 
h y p ot h y r oidis m/t h y r oidi tis, h y pert h y r oidis m, dia betes mellit us, a n d h y p o p h ysit is) f or w hic h 
s u bjects recei ve d i m m u n os u p pressi ve me dicat i on f or treat me nt of t he e ve nt, wit h t he e xce pti o n o f 
e n d ocri ne e ve nts ( h y p ot h yr oidis m/t h yr oi di tis, h y pert h y r oidis m, h y p o p h ysit is, di a betes me llit us, 
a dre nal i ns ufficie nc y), w hic h are i ncl u de d re gar dless of  treat me nt si nce t hese e ve nts are of te n 
ma na ge d wit h o ut i m m u n os u p pressi o n.
I M A Es i ncl u de e ve nts, re gar dless of ca usality,  occ urri n g wit hi n 1 0 0 da ys of t he last d ose. T his list 
is s u bject t o c ha n ge base d o n Healt h A ut h orit y fee d bac k or c ha n ge of Me d D R A versi on. T he fi na l 
list use d will be descri be d i n t he C S R.
Ta ble 6. 5. 1 - 1 bel o w pr o vi des a s u m mar y o f the I M A Es cate g or y a n d t heir res pect i ve P Ts. T his list 
is s u bject t o c ha n ge base d o n Healt h A ut h ority fee d bac k or c ha n ge of Me d D R A versi on. T he fi na l 
list use d will be descri be d i n t he C S R.
T a ble 6. 5. 1 - 1:
Preferre d Ter ms I ncl u de d i n A n al ysis of I M A Es t o S u p p ort
W ar ni n gs a n d Prec a uti o ns
I M A E C ate g or y 
P Ts i ncl u de d u n der I M A E C ate g or y
P ne u m o nitis 
P ne u m o nitis, I nterstitial l u n g disease
Diarr hea/ C olitis 
Diarr hea, C olitis, E nter oc olitis
He pat ot o xicit y 
He pat ot o xicit y, He patitis, He patitis ac ute, A ut oi m m u ne
he patitis, A S T i ncrease d, A L T i ncrease d, Bilir u bi n 
i ncrease d, A L P i ncrease d
A dre nal i ns ufficie nc y
A dre nal i ns ufficie nc y
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
9 0

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
T a ble 6. 5. 1 - 1:
Preferre d Ter ms I ncl u de d i n A n al ysis of I M A Es t o S u p p ort
W ar ni n gs a n d Prec a uti o ns
I M A E C ate g or y 
P Ts i ncl u de d u n der I M A E C ate g or y
H y p ot h yr oi dis m/ T h yr oi ditis
H y p ot h yr oi dis m, T h yr oi ditis, T h yr oi ditis ac ute 
(c olla pse d wit h t h yr oi ditis f or fre q ue nc y), A ut oi m m u ne 
t h yr oi ditis (c olla pse d wit h t h yr oi ditis f or fre q ue nc y)
H y pert h y r oi dis m
H y pert h y r oi dis m
H y p o p h ysitis
H y p o p h ysitis
Dia betes mellit us
Dia betes mellit us, Dia betic ket oaci d osis
Ne p hritis a n d re nal d ysf u ncti o n
Ne p hritis, Ne p hritis aller gic, T u b ul oi nterstitial 
ne p hritis, Ac ute re nal fail ure, Re nal fail ure, I ncrease d 
creati ni ne
Ras h
Ras h, Ras h mac ul o pa p ular
7
D A T A M O NI T O RI N G C O M M I T T E E A N D O T H E R E X T ER N A L 
C O M MI T T E E S
A Data M o ni t ori n g C o m mittee ( D M C) will be utilize d t o pr o vi de ge neral o versi g ht a n d safety 
c o nsi derati o ns f or t his st u d y, C A 2 0 9 7 4 3. T he D M C will pr o vi de a d vice t o t he S p o ns or re gar di n g 
actio ns t he c o mmit tee dee ms necessar y  for t h e c o nt i n ui n g pr otecti o n of  s u bjects e nr olle d i n t his 
st u d y. T he D M C will be c har ge d with assessi n g s uc h act i ons i n li g ht of a n acce pta ble ris k/ be nefit 
pr ofile f or n i v ol uma b . T he D M C will act i n a n a d vis or y ca pacity t o B M S a n d w ill m onit or s u bject
safety data f or t he st u d y .
T he D M C will be a d vis or y t o t he cli nical st u d y lea ders hi p tea m. T he cli nical st u d y lea ders hi p will 
ha ve res p o nsi bility f or o verall c o n d uct of  the st u d y incl u di n g ma na gi n g t he c o m m u nicati o n of 
st u d y data. T he gr o u p will be res p o nsi ble f or pr o m ptl y re vie wi n g t he D M C rec om me n dat i ons, f or 
pr o vi di n g g ui da nce re gar di n g t he c o nti n uat i on or ter mi nati o n of  the st u d y, a n d f or deter mi ni n g 
w het her a me n d me nts t o t he pr ot oc ol or c ha n ges t o t he st u d y  c o n d uct are re q uire d.
Det ails o f t he D M C res p o nsi bilit ies a n d pr oce d ures will be s pecifie d i n t he D M C c harter.
Bli n de d I n de pe n de nt C e ntral Re vie w ( BI C R)
A BI C R will be e m plo y e d f or i nter pretatio n of  ra dio gra p hic pr o gressi o n e ve nts. At  the ti me of  
i n vesti gat or-assesse d i nitial r a dio gra p hic pr o gressi o n per a da pte d M o difie d R E CI S T a n d/ or 
R E CI S T 1. 1 criteria i n a n y gi ve n s u bject, t he sit e m ust re q uest t he in de pe n de nt ce ntral re vie w fr o m 
t he t hir d part y r a diol o g y  ve n d or f or c o nfir mat i on of pr o gressi o n. 
T u m or assess me nts f or eac h s u bject s h o uld be s u b mitt e d t o t he ra di ol og y  ve n d or as t he y ar e 
perf or m e d o n a n o n g oi n g basis. T he bli n de d, i n de pe n de nt ra di ol ogists will re vie w all a vaila ble 
t u mor assess me nts f or t hat gi ve n s u bject a n d deter mi ne if a da pte d m- R E CI S T a n d/ or R E CI S T 1. 1 
criteria f or pr o gressi o n ha ve bee n met . T he i n de pe n de nt assess me nt of  whet her or n ot t he gi ve n 
s u bject met  criteria f or pr o gressi o n will be pr o vi de d t o t he sit e. S u bject s w h ose disease pr o gressi o n 
is n ot c o nfir me d ce ntrall y will be re q uire d t o c o nti n ue tr e at me nt  a n d t u mor assess me nts acc or di n g 
t o t he pr ot oc ol -s pecifie d sc he d ule. S u bse q ue nt t u m or assess me nts m ust be s u b mitte d t o t he t hir d 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
9 1

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
part y  r a diol o g y  ve n d or f or s u bse q ue nt re vie w a n d ma y be disc o nti n ue d w he n t he i n vesti gat or a n d 
i n de pe n de nt ra di ol o gists b ot h assess t he s u bject t o ha ve met criteria f or pr o gressi o n.
T he BI C R will als o re vie w t u mor i ma ges i n all ra n d omize d s u bjects t o deter mi ne a da pte d m-
R E CI S T a n d/ or R E CI S T 1. 1 best o verall res p o nse f or t he a nal yses of O R R. 
At  ti me of  anal ysis of  OR R, t u mor assess me nts will use BI C R
i n all ra n d o mize d s u bjects t o 
deter mi ne pr o gressi o n a n d res p o nse f or t he a nal yses of  PF S a n d O R R. Details of  the BI C R 
res p o nsi bilities a n d pr oce d ures will be s pecifie d i n t he BI C R c harter.
8
S T A TI S TI C A L C O N SI D E R A T I O N S
8. 1
S a m pl e S i z e D et er mi n ati o n
T he st u d y  acc o u nts f or t he pri mar y e n d p o i nt of O S . O verall t w o-sid e d al p h a (t y pe o ne err or rate) 
is set at 0. 0 5 . A p pr o xi matel y 6 0 0 pati e nts were t o be ra n d omize d wi t h 1: 1 rati o t o t w o treat me nt 
ar ms, wit h 6 0 6 p atie nts act uall y ra n d o mize d. 4 7 3 O S e ve nts will be nee de d f or t he fi nal a nal ysis. 
T he sa m ple size is calc ulate d t o c o m pare O S bet wee n ni v o l uma b c o m bi n e d wit h i p ili m u ma b ( Arm 
A) a n d pe m etre xe d plus ci s plati n or c ar b o plat i n re gi me n ( Ar m B). O ne f or mal i nteri m a nal ysis is 
pl a n ne d f or O S at  4 0 3 O S e ve nts. Ta ble 8. 1 - 1 s u m marizes t he ke y para meters of trial desi g n.
O verall s ur vi val: T he k e y  desi g n para m eters are s h o w n i n Ta ble 8. 1 - 1, w here O S e n d p oi nt will 
utilize a gr o u p se q ue ntial desi g n ( G S D) wit h o ne i nteri m a nal ysis at 4 0 3 O S e ve nts a n d fi nal 
a nal ysis at 4 7 3 O S e ve nts. St o p pi n g b o u n daries of G S D at t he i nteri m a n d fi nal O S a nal yses will 
be deri ve d base d o n t he e xact n u m ber of deat hs usi n g La n -De Mets al p ha s pe n di n g f u ncti on wi t h 
O’ Brie n -Fle mi n g b o u n daries. Gi ve n accr ual rate of  3 4 patie nts per m o nt h, it is est i mate d t hat it 
will ta ke a p pr o xi matel y 3 8/ 5 6 m o nt hs t o o bser ve t he re q uire d n u m ber of  eve nts f or t he 
i nteri m/fi nal O S a nal ysis.
A n e x p o ne nt ial distri b ut i on is ass u me d f or t he O S ti me of c o ntr ol Ar m B wi t h a me dia n O S ti me 
of  1 6 m o nt hs a n d hazar d rate of 0. 0 4 3 . T o ca pt ure s o me o bser ve d feat ures o n t he s ur vi val c ur ves 
of  im m u n o -t hera pies, a piece wise e x p o ne nt ial m o dels is ass u me d f or t he s ur vi val ti me o n 
ni v o l u ma b pl us i pili m u ma b ar m. I n partic ular, a piece wise e x p o ne nt ial wit h hazar d rates of 0. 0 43 , 
0. 0 3 3, a n d 0. 0 0 0 1 i n t he f oll owi n g p ost first d ose ti me wi n d o ws: first 6 m o nt hs , 6 m o nt hs t o 3 4 
m o nt hs , a n d aft er 3 4 m o nt hs , will pr o vi de a dela y of  treat me nt effect i n t he first 6 m o nt hs, a n 
e x p o ne nt ial distri b uti on of O S fr o m 6 m o nt hs t o 3 4 mo nt h s, a n d a lo n g ter m  s ur vi val rate platea u 
starti n g a p pr o xi matel y at 3 4 m o nt hs . Si m ulat i on e val uat i on of  trial desi g n s h o ws t hat t he a b o ve 
pi ece wise e x p o ne nt ial distri b uti on w ill pr o d uce a 90 % p o wer i n l o g -ra n k test. T he n u merical val ue 
of  t ype o ne err or rate i n si m ulat i on is 5 %.
If t he sa me si m ple ass u m pti on of e x p o ne nt ial distri b uti ons is ass u me d f or O S ti mes o n Ar m A, t he 
st u d y desi g n has a p pr o xi matel y 9 0 % p o wer t o detect a hazar d r atio o f 0. 7 2 ( Ar m A vs Ar m B).
T he a b o ve s a mple size calc ulatio n was base d o n a si m ulati on m o del i nc or p orati n g as pects of 
i m m u n o-o nc ol o g y  t hera pies, s uc h as dela ye d se parati o n a n d l o n g ter m be nefit usi n g E A S T 6.
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
w h o c o ntin ue st u d y treat ment  be yo n d pr o gressi o n, t he B O R s h o uld be deter mi ne d base d o n 
res p o nse desi g nati ons rec or de d u p t o t he ti me of t he i nit ial BI C R c o nfir me d pr o gressi o n. 
As part of  the e val uat i on of  OR R, d urati o n of  res p o nse a n d ti me t o res p o nse will be e val uate d. 
D O O R is defi ne d as t he t i me bet wee n t he date of first res p o nse t o t he date of t he first d oc u me nte d 
t u mor pr o gressi o n ( per a da pte d m -R E CI S T a n d/ or R E CI S T 1. 1 criteria) or deat h d ue t o a n y ca use. 
S u bjects w h o neit her pr o gress n or die will be ce ns ore d o n t he date of t h eir last assess me nt. T T O R 
is defi ne d as t he ti me fr o m ra n d omizat i on t o t he date of t he first C R or P R. D O O R a n d T T O R will 
be e val uate d f or res p o n ders ( C R or P R) o nl y.
P F S as deter mi ne d b y BI C R is defi ne d as t he ti me fr om ra n d o mizati on t o t he date of  the first 
d oc u m e nte d t u mor pr o gressi o n ( per a da pte d m- R E CI S T a n d/ or R E CI S T 1. 1 crit eria) as assesse d 
b y BI C R or deat h d ue t o a n y  ca use. S u bjects w h o die wit h o ut a re p orte d pri or pr o gressi o n will be 
c o nsi dere d t o ha ve pr o gresse d o n t he date of t heir deat h. S u bjec ts w h o di d n ot pr o gress or die will 
be ce ns ore d o n t he d at e of  t heir last e val ua ble t u m or assess me nt. S u bjects w h o di d n ot ha ve a n y 
o n stu d y t u mor assess me nts a n d di d n ot die will be ce ns ore d o n t he date t he y were ra n d o mize d. 
S u bjects w h o starte d a n y s u bse q ue nt a nti -ca ncer t hera p y wit ho ut a pri or re p orte d pr o gressi o n will 
be ce ns ore d at t he last e val ua ble t u m or assess me nt pri or t o i nit iati on of t he s u bse q ue nt a nt i-ca ncer 
t hera p y. T u m or assess me nts are sc he d ule d t o be perf or m e d at wee k 6 (7 da ys) fr om first d ose 
date, e ver y 6 wee ks u nt il wee k 4 8 ( 7 da ys) a n d t he n e ver y 12 wee ks (7 d a y s) u nt il disease 
pr o gressi o n or treat me nt disc o nti n uati o n, w hic he ver occ urs later.
A d dit i onal sec o n dar y e n d p o i nts i ncl u de P D -L 1 Pr otei n E x pressi o n le vel. P D -L 1 e x pressi o n is 
defi ne d as t he perce nt of  tu m or cells d e m o nstrati n g pl as ma me m bra ne P D -L 1 stai ni n g of  an y 
i nte nsit y usi n g t he vali date d D A K O P D-L 1 I H C assa y .
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. 4
A n al y s e s
8. 4. 1
D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s
D e m o gra p hics a n d baseli ne la b orat or y res ults will be s u m marize d b y treat me nt ar m as ra n d o mize d 
usi n g descri pt i ve statistics for all ra n d o mize d s u bjects.
8. 4. 2
Effi c a c y A n al y s e s
8. 4. 2. 1
Pr i m ar y e n d p oi nt a n al y s e s
T he distri b ut i on of O S will be c o m pare d i n t w o ra n d o mize d ar ms at t he i nteri m a n d fi nal a nal ysis 
via a t w o -si de d, l og- ra n k test stratifie d b y hist olo g y a n d ge n der wit h a n o verall si g nifica nce leve l 
of  0. 05 . A gr o u p se q ue ntial testi n g pr oce d ure will be a p plie d t o O S t o c o nt r ol the o verall t ype I 
err or f or i nteri m a n d fi nal a nal yses. T he s pe n di n g f u ncti o n is descri be d i n Sect i on 8. 1 . T he hazar d 
r atio ( H R) a n d t he c orres p o n di n g t w o -side d 1 0 0 x ( 1 -a djuste d ) % c o nfide nce i nter vals ( CI) will 
be est i mate d i n a stratifie d C o x pr o p orti o nal  hazar ds m o d el  usi n g ra n d omize d ar m as a si n gle 
c o variate. T he O S c ur ves f or eac h ra n d o mize d ar m will be esti mate d usi n g t he Ka pla n-Meier ( K M) 
pr o d uct -li mit met h o d. T w o si de d, 9 5 % c o nfi de nce i nter vals f or me d ia n O S will be c o mp ute d b y 
Br o o k m e yer a n d Cr o wl e y met h o d ( usi n g l og- l og tra nsf or mati o n). S ur vi val rates at 6, 1 2, 1 8, 2 4, 
3 6, 4 8 m o nt hs a n d 5 year will be est i mate d usi n g K M est i mates o n t he O S c ur ve f or eac h 
ra n d omize d ar m pr o vi de d mi ni m u m f oll ow- u p is lo n ger t ha n ti me-p oi nt t o ge nerate t he rate. 
Ass oci ate d t wo- si de d 9 5 % CIs will be calc ulate d usi n g t he Gree n w o o d f or mula ( usi n g l og- l og 
tra nsf or mati o n). 
8. 4. 2. 2
S e c o n d ar y e n d p oi nt s a n al y s e s
O R Rs or D C Rs a n d t heir c orres p o n di n g 9 5 % e xact CIs will be calc ulate d usi n g t he Cl o p per -
Pears o n m et h o d f or eac h treat me nt gr o u p.
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B M S - 9 3 6 5 5 8
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9
S T U D Y M A N A G E M E N T
9. 1
C o m pli a n c e
9. 1. 1
C o m pli a n c e wit h t h e Pr ot o c ol a n d Pr ot o c ol 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  with o ut pri or 
re vie w a n d d o c u m e 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 aut h ori t y) e xce pt w here necessar y t o eli mi nate a n i m me diate 
hazar d(s) t o stu 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 r ele va nt a p pr o val/fa v ora ble o pi ni o n( s), t he de viat i on 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 

Re g ulat or y  Aut h ori t y(ies), if a p plica ble b y lo c al  r e g ulat i ons per nat i onal re q uire me nts)
D oc u m e nt atio n of  ap 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  the
I R B(s)/I E C(s) a n d if a p plica ble, als o b y l ocal heal t h aut h ori t y, m u st 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 nti al ris k t o t h e s u bject: ( 1) 
t he c o nse nt f or m 
must be re vise d a n d s u b mitte d t o t he I R B(s)/I EC(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 must be use d t o o btai n c o nse nt fr om 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 must  
be use d t o o btai n c o nse nt fr o m ne w s u bjects prior t o e nr oll me nt.
If t he re visi on is d o ne via a n a d mi nistrativ e l etter, i n vestigat ors m ust i nf or m  t heir I R B(s)/I E C(s).
9. 1. 2
M o nit ori n g
B M S or desi g n ee re prese ntati ves will re vie w data ce ntrall y t o i de ntif y p ote ntial iss ues t o deter mi ne 
a sc he d ule of o n-sit e visits f or tar gete d re vie w of st u d y rec or ds. 
Re prese ntati ves of B M S m ust be all o we d t o visit all st u d y  sit e lo c ati o ns peri o di call y t o assess t he 
data q ualit y a n d st u d y int e 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 om pare t he m 
wi t 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 vest i gat or, a n d verif y t hat t he 
facilities r e 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 m e nts:
I n a d ditio n, t he st u d y ma y be e val uate d b y B M S or desi g n ee 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  an y i ns pect i ons sc he d ule d b y r e g ulat or y aut h ori ties, 
a n d pr o m pt l y f or war d c o pies of ins pect i on re p orts t o B M S or desi g n e e. 
9. 1. 2. 1
S o ur c e D o c u m e nt ati o n
T he I n vestig at 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, origi nal  a n d attri b uta ble, w het her t he data are ha n d -wri tte n o n pa per or e ntere d 
ele ctr 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 ele ctr o nicall y via c o m p uterize d s yste ms (a n d/ or a n y ot h er ki n d of  electr o nic 
de vices) as par t of  re g ulate d cli nical trial act i vities, s uc h s yste ms m ust be c o mplia nt wit h all 
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a p plica ble la ws a n d re g ulatio 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 vit ies, s uc h pa per rec or ds s h o uld be certifie d c o pies. A certifie d c o p y co nsists of  a co p y  of 
ori gi nal  inf or mat i on t hat has bee n verifie d, as i n dicate d b y a date d sig nat ure, as a n e xact c o p y 
ha vi n g all o f t he sa me attrib utes a n d i nf or mat i on as t he ori gi nal. 
9. 2
R e c or d s
9. 2. 1
R e c or d s R et e nti o n
T he i n vesti gat or ( or hea d of  the st u d y site i n Ja pa n) m u st retai n all st u d y rec or ds a n d s o urce 
d oc u m e nts f or t he ma xi m u m p eri o d re q uire d b y a p plica ble re g ulati ons a n d g ui deli nes, or 
i nstituti o n pr oce d ures, or for t h e peri o d s pecifie d b y B M S or desi g n ee, w hic he ver is l on ger. T he 
i n vesti gat or ( or hea d of t he st u d y site i n Ja pa n) m u st c o ntact B M S or desi g n ee 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 n ee will  notif y t he i n vesti gat or ( or hea d of  t he st u d y site i n Ja pa n) 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 om t he st u d y (e g, rel ocati o n, r etire me nt), t he rec or ds s hall b e 
tra nsferre d t o a mut uall y  agree d u p o n desi g nee (e g, a n ot her i n vesti gat or, st u d y sit e, I R B). N otice 
of  s uc h tra nsfer will be gi ve n i n writ i n g t o B M S or desi g n ee.
9. 2. 2
St u d y Dr u g R e c or d s 
Rec or ds f or I P a n d n o n- i n vesti gati o nal pr o d ucts ( w het her s u p plie d b y B M S, its ve n d ors, or t he 
sit e) m ust s u bsta ntiate I P i nte grit y a nd tracea bility fr om receipt, 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.
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 a c urre nt dis p ositio n r e c or d of  st u d y dr u g 
(in ve nt orie d a n d di s pe nse d) is ma i ntai ne d at t h e st u d y sit e t o i ncl u de i n vesti gati onal pr o d uct a n d 
n o n- i n vesti gati onal pr o d uct(s) Rec or ds or l ogs m ust c o mpl y  with a p plica ble re g ulati ons a n d 
g ui deli nes a n d s h o ul d i ncl u de:

a mo u nt recei ve d a n d place d i n st ora ge area

a mo u nt c urre ntl y  in st ora ge area

la bel i de ntificati on n u m ber or batc h n u m ber 

a mo 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 n st u d y  dis p ositio n (e g, l ost, waste d) 

a mo u nt destr o y e d at st u d y sit e, if a p plica ble

a mo 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 
Re vise d Pr ot oc ol N o.: 0 2
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C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

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 o f A ut h ori t y For m .
B M S will  pr o vide f or ms t o facilitate i n ve nt or y c o ntr ol if t he i n vesti gatio 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.
9. 2. 3
C a s e R e p ort F or 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 vat i ons a n d ot h er data perti ne nt t o t h e i nvest i gati on o n eac h i n di vi d ual treate d 
or e ntere d as a c o ntr ol in t he i n vesti gati on. Data t hat are deri ve d fr om 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 d iscre pa ncies m ust be 
e x plai ne d. A d dit i onal cli nica l i nf or mati on 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 o f 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 nt ifie 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 o r desi g n e e electr o nic data ca pt ure t o ol, electr o nic C R Fs will b e 
pre pare d f or all data c ollect i on 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 ele ctr o nic S A E f or m an d Pre g na nc y S ur veilla nce for m , res pecti vel y. If 
e lectr 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  in t hose c ircu msta nces per mitte d b y st u d y-s pecific C R F c o mplet i on g u i deli nes pr o vi de d b y 
S p o ns or of desi g n ee. 
T he c o nfi de ntialit y o f rec or ds t hat c o ul d i de nt if 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 ul es 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 nit ials 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 p lete d C R F, S A E/ pre g na nc y C R Fs, m ust be pr om pt l 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 vestig at or a n d w h o is dele g at e d t his t as k o n t h e 
D el e g atio n of  Aut h ori t y For m . S u bi n vest i 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 p lete 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 u st 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 n e e 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 n ee. 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.
9. 3
Cli ni c al St u d y R e p ort a n d P u bli c ati o n s
A Si g n at or y  I n vesti gat or m ust be selecte d t o si g n t he cli nical st u d y re p ort. 
F or t his pr ot oc ol, t he Si g nat or y I n vest i gat or will be selecte d as a p pr o priate base d o n t he f o ll owi n g 
criteria:

E xter nal Pri nci pal I n vest i gat or desi g nate d at pr ot oc ol de vel o p me nt
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C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b

Nati o nal C o or di nati n g I n vest i gat or 

St u d y  Steeri n g C o m mittee c hair or t heir desi g nee

S u bject recr uitme nt  (e g, a m o n g t he t o p q uartile of e nr o llers)

I n v ol ve me nt i n trial desi g n

Re gi o n al  re prese ntatio n ( e g, a m o n g t o p q uartile of  e nr ollers fr om a  specifie d r e gio n  or c o u ntr y)

Ot her criteria (as deter mi ne d b y  t he st u d y t e a m)
T he data c o llecte d d uri n g t his st u d y are c o nfi de ntial an d pr o pri et ar y to B M S or desi g n e e. A n y 
p u blicat i ons or a bstracts arisi n g fr om t his st u d y must a d here t o t he p u blicat i on 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 sit e or I n v esti g at 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 ons t o 
B M S or desi g n e e at t he earliest practica ble t i me pri or t o s u b missi on or prese ntati o n a n d ot her wise 
wi t hi n t he ti me peri o d set f ort h i n t he C T A.
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1 0 1

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
1 0
G L O S S A R Y O F T E R M S
Ter m
Defi niti o n
T N M Sta gi n g
T N M is a ca ncer sta gi n g s yste m f or s oli d t u m or wit h n u meric c o des: 
T : i n dicates if t he t u m or is ori gi nal site or has i n va de d near b y tiss ue
N: i n dicates l y m p h n o des t hat are i n v ol ve d
M: i n dicates
metastasis
B R A F
B R A F is a h u ma n ge ne t hat ma kes a pr otei n calle d B -Raf.
m- R E CI S T
M o difie d -R E CI S T criteria f or ple ural mes ot heli o ma.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
1 1
LI S T O F A B B R E VI A TI O N S
Ter m
Defi niti o n
A E
a d verse e ve nt
AI
acc u m ulat i on i n de x
AI _ A U C
A U C Acc u m ulat i on I n de x; rat i o of A U C( T A U) at stea d y state t o 
A U C( T A U) after t he first d ose
AI _ C ma x
C m a x Acc u m ulat i on I n de x; rati o of C ma x at stea d y state t o C ma x after 
t he first d ose
AI _ Cta u
Cta u Acc u m ulat i on I n de x; rati o of Cta u at stea d y  st ate t o Cta u after t he 
first d ose
A L T
ala ni ne a mi n otra nsferase
A N C
a bs o l ute ne utr o p hil c o u nt
A S T
as partate a mi n otra nsferase
A P C
A nt i ge n-Prese nt i n g Cells
A T
a mi n otra nsa mi nases
A U C
area u n der t he c o nce ntrati o n-ti me c ur ve
A U C(I N F)
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o e xtra p olate d t o 
i nfi nite ti me
A U C( 0 -T)
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n
A U C( T A U)
area u n der t he c o nce ntrati o n-ti me c ur ve i n o ne d osi n g i nter val
B C G
Bacill us Cal mette G ueri n vacci ne
BI C R
Bli n de d I n de pe n de nt C o m mittee Re vie w
B MI
b o d y  mass i n de x
B M S
Bri st ol- M yers S q ui b b
B P
bl o o d press ure
B Rt
T ot al  a mo u nt rec o vere d i n bile
% B Rt
T ot al  perce nt of a d mi nistere d d ose rec o vere d i n bile
B U N
bl o o d urea nitr o ge n
C
Celsi us
C 1 2
c o nce ntrati o n at 1 2 h o urs
C 2 4
c o nce ntrati o n at 2 4 h o urs
Ca + +
calci u m
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Ter m
Defi niti o n
Ca v g
a vera ge c o nce ntrati o n
C B C
c o mplete bl o o d c o u nt
Ce x pecte d- t a u
e x pecte d c o nce ntrati o n i n a d osi n g i nter val
C F R
C o de of Fe deral Re g ulat i ons 
CI
c o nfi de nce i nter val
C 1 -
c hl ori de
C Lcr
creati ni ne cleara nce
c m
ce nt i meter
C m a x, C M A X
ma xi m u m o bser ve d c o nce ntrati o n
C mi n, C MI N
tr o u g h o bser ve d c o nce ntrati o n
C N S
Ce ntral  ner v o us s yste m
C R C
Cli nical Researc h Ce nter
C R F
Case Re p ort F or m, pa per or electr o nic
Ct
E x pecte d c o nce ntrati o n at a certai n t i me, us uall y at t he e n d of a n 
e x pecte d f ut ure d osi n g i nter val (e g, c o nce ntrati o n at 2 4 h o urs, 
c o nce ntrati o n at 1 2 h o urs, etc.)
Cta u
C o nce ntrati o n i n a d osi n g i nter val (e g, c o nce ntrati o n at 2 4 h o urs, 
c o nce ntrati o n at 1 2 h o urs, etc.)
Ctr o u g h
Tr o u g h o bser ve d plas ma c o nce ntrati o n
C V
c oefficie nt of variat i on
C Y P
c yt o c hr o me p- 4 5 0
D/ C
di sc o nti n ue
d L
deciliter
D Rt
T ot al  a mo u nt rec o vere d i n dial ysate
% D Rt
T ot al  perce nt of a d mi nistere d d ose rec o vere d i n dial ysate
D S M I V
Di a g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders ( 4t h E dit i on)
E A
e xte nt of a bs or pti o n
E C G
electr ocar dio gr a m
e C R F
Electr o nic Case Re p ort F or m
E D C
Electr o nic Data Ca pt ure
E E G
electr oe nce p hal o gra m
e g
e xe m pli gratia (f or e xa m ple)
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 4

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Ter m
Defi niti o n
E S R
E x pe dite d Safet y Re p ort
F
bi oa vaila bilit y
F b
fracti o n of b o u n d dr u g
F D A
F o o d a n d Dr u g A d mi nistrati o n
FI
fl uct uatio n I n de x ([ C m a x-Cta u)/ Ca v g])
f u
fracti o n of u n b o u n d dr u g
g
gr a m
G C
gas c hr o mat o gra p h y
G C P
G o o d Cli nical Pract ice
G cri t eria
a djuste d R 2 val ue of ter mi nal eli mi nat i on p hase
G G T
ga m ma -gl uta m yl  tra nsferase
G F R
gl o m er ular filtrat i on rate
h
h o ur
H Bs A g
he pat itis B s urface a nti ge n
H B V
he pat itis B vir us
H C V
he pat itis C vir us
H C O 3 -
bicar b o nate
HI V
H u m a n I m m u n o deficie nc y Vir us
H R
heart rate
H R T
h or m o ne re pl ace me nt t hera p y
I C D
I nter nati o nal Classificati on of Diseases
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n 
ie
i d est (t hat is)
I E C
I n de pe n de nt Et hics C o m mittee
I M P
i n vesti gati onal me dici nal pr o d ucts
I N D
I n vesti gati onal Ne w Dr u g E xe m pt i on
I R B
I nstituti o nal  Re vie w B oar d
I U
I nter nati o nal U nit
I V
i ntra ve n o us
K
slo p e of  t he ter mi nal p hase of  t h e lo g c o nce ntrati o n -ti me c ur ve
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 5

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Ter m
Defi niti o n
K 3 E D T A
p otassi u m  et h yle ne dia mi netetraacetic aci d
K +
p otassi u m
k g
kil o gra m
z
ter mi nal dis p osi tio n  rate c o nsta nt
L
liter
L C
li q ui d c hr omat o gra p h y
L C S S
L u n g Ca ncer S y m pt o m Scale
L C S S -Mes o
L u n g Ca n cer S y m pt o m Scale - Mes ot heli o ma
L D H
lactate de h ydr o ge nase
l n
nat ural  lo g ari t h m
Lz _ Start
T he ti me p oi nt starti n g t he l og- li near eli mi nati o n P hase defi ni n g t he
ter mi nal half life
Lz _ E n d
T he ti me p oi nt e n di n g t he l og- li near eli mi nat i o n P hase
defi ni n g t he 
ter mi nal half life
Lz _ N
N u m ber of  ti me p oi nts i n t he l og- li near eli mi nati o n P hase defi ni n g t h e 
ter mi nal half life
m g
milli gra m
M g + +
ma g nesi u m
MI C
mi ni m u m i n hi bit or y  c o nce ntratio n
mi n
mi n ute
m L
milliliter
m m H g
milli meters of merc ur y
M P M
Mali g na nt ple ural mes ot heli o ma
M R _ A U C( 0 -T)
Rati o of  meta b o lite A U C( 0 -T) t o pare nt A U C( 0 - T), c orrecte d f or 
m o lec ular wei g ht
M R _ A U C(I N F)
Rati o of  met a b o lite A U C(I N F) t o pare nt A U C(I N F), c orrecte d f or 
m o lec ular wei g ht
M R _ A U C( T A U)
Rati o of  meta b o lite A U C( T A U) t o pare nt A U C( T A U), c orrecte d f or 
m o lec ular wei g ht
M R _ C ma x
Rati o of  meta b o lite C ma x t o pare nt C ma x, c orrecte d f or m o lec ular 
w ei g ht
M R _ Cta u
Rati o of  meta b o lite Cta u t o pare nt Cta u, c orrecte d f or m olec ular wei g ht
M R T
mea n resi de nce t i me
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 6

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Ter m
Defi niti o n
M S
mass s pectr o metr y
M T D
ma xi m u m t olerate d d ose
g
micr o gra m
N
n u m ber of s u bjects or o bser vati o ns
Na +
s o diu m
N/ A
n ot a p plica ble
n g
na n o gra m
N S C L C
N o n s mall c ell lu n g ca ncer
p A U Ce
E xtra p olate d partial A U C fr o m last q ua nt ifia ble c o nce ntrati o n t o i nfi nity
P b
perce nt of b o u n d dr u g
P D
p har mac o d y na mics
P K
p har mac o ki net ics
P u
perce nt of u n b o u n d dr u g
Q C
q ualit y c o ntr ol
R 2
c oefficie nt of deter mi nat i on
R B C
re d blo o d cell
R C C
Re nal cell carci n o ma
S A E
serio us a d verse e ve nt
S D
sta n dar d de viati on
S O P
Sta n dar d O perati n g Pr oce d ures
s p.
s pecies
S u bj
s u bject
t
t e mperat ure
T
ti me
T A O
Tri al Access O nli ne, t he B M S i m ple me ntati o n of a n E D C ca pa bilit y
T- H A L F
Half life
T- H A L Feff _ A U C
Effect i ve eli mi nati on half life t hat e x plai ns t he de gree of A U C 
acc u m ulat i on o bser ve d
T- H A L Feff _ C ma x
Effect i ve eli mi nati on half life t hat e x plai ns t he de gree of C ma x 
acc u m ulat i on o bser ve d)
T ma x, T M A X
ti me of ma xi m u m o bser ve d c o nce ntrati o n
T R _ A U C( 0 -T)
A U C( 0 -T) treat me nt rati o
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 7

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
Ter m
Defi niti o n
T R _ A U C(I N F)
A U C(I N F) treat me nt rati o
T R _ C m a x
C m a x treat me nt ratio
U V
ul tra viol et
V A S
Vi s u al A nalo g Scale
Vss/ F ( or Vss)
a p pare nt v ol u me o f distri b ut i on at stea d y  state
Vz
V ol u me of  distri b uti on of  ter mi nal p hase (if I V a n d if m ult i-e x p o ne nt ial 
decli ne)
W
was h o ut
W B C
w hite bl o o d cell
W H O
W o rld Heal t h Or ga nizati on
W O C B P
w o m e n of c hil d beari n g p ote ntial
x g
ti mes gra vity
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 0 8

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
A P P E N DI X 1
E C O G P E R F O R M A N C E S T A T U S 
E C O G P E R F O R M A N C E S T A T U S
a
0
F ull y  acti ve, a ble t o carr y o n all pre-disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, eg, li g ht h o use w or k, office w or k
2
A m b ulat or y  a n d ca pa ble of all selfcare b ut u na ble t o carr y o ut a n y w or k acti vities. U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3
Ca pa ble of o nl y li mite d selfcare, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs
4
C o m pletel y disa ble d. Ca n n ot carr y o n a n y selfcare. T otall y c o nfi ne d t o be d or c hair
5
Dea d
 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 1 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
A P P E N DI X 3
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
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 owi n g me narc he a n d u nt il bec o mi n g p ost -me n o pa usal u nless 
p er m a ne nt l y sterile. 
Per ma ne nt 
sterilizati on 
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

Pr e m e narc hal

Pr e m e n o pa usal fe male wit h 1 of t h e fol l owi n g:

D oc u m e nte d h ysterect o m y

D oc u m e nte d bilateral sal pi n gect o m y

D oc u m e nte d bilateral o o p h orect o m y
N ote:
D oc u m e nt atio n ca n c o me fr om t he sit e pers o n nel’s re vie w of  the partici pa nt’s me dica l 
rec or ds, me dical e xa mi nati on, or m e dical hist or y int er vie w.

P os t me n o pa usal fe male

A p ost m e n o pa usal st at e is defi ne d as 1 2 m o nt hs of  ame n orr hea i n a w o m a n o ver a ge 4 5 
years i n t he a bse nce of  ot her bi o l ogical or p h ysi o l ogical ca uses. I n ad di tio n , females 
u n der t he a ge of  55 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.
N ote:
Fe males treate d wit h h or m o ne r e place me nt t hera p y, ( H R T) are li kel y t o ha ve art ificiall y 
s u p presse d F S H levels a n d ma y re q uire a was h o ut peri o d i n or der t o o btai n a p h ysi ol o gic F S H 
le vel. T he d uratio n of t h e w as h o ut p eri o d i s a fu n cti o n of  t he t yp e of  H R T us e d. T h e d ur atio n of 
t he was h o ut peri o d b el o w are s u g geste d g ui deli nes a n d t he i n vesti gat ors s h o uld use t heir 
j u d ge me nt i n c hec ki n g ser u m F S H le vels. 

1 wee k mi ni m u m f or va gi nal h or m o nal pr o d ucts (ri n gs, crea ms, gels)

4 wee k mi ni m u m f or tra ns der mal pr o d ucts

8 wee k mi ni m u m f or oral pr o d ucts
Ot her pare nteral  pr o d ucts ma y re q uire was h o ut peri o ds as l on g as 6 m o nt hs. If the ser u m F S H 
le vel is > 4 0 mI U/ ml at a n y ti me d uri n g t he was h o ut peri o d, t he w o m a n ca n be c o nsi dere d 
p ost m e n o pa usal.
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 C I 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
O ne of  the hi g hl y effecti ve met h o ds of  co ntrace pti o n 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 nt il t he e n d of  rele va nt s yste mic e x p os ure, defi ne d as 2 3 wee ks aft er t he e n d of 
st u d y tr e at me nt.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 2 2

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
L ocal  la ws a n d re g ulat i ons ma y re q uire use of  alter nat i ve a n d/ or a d dit i onal c o ntrace ptio n 
met h o ds.
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 mo n al c o ntrace ptio n ass o ci at e d wit h 
i n hi biti on of o v ulat i on a n d/ or i m pla ntati o n ( T hese met h o ds of c o ntrace ptio n c a n n ot be 
use d b y W O C B P partici pa nts i n st u dies w here h or m o nal c o ntrace ptio n i s pr o hi bite d)b 

or al  ( birt h c o ntr ol pills)

i ntra va gi nal ( va gi nal birth c o ntr ol s u p p osit ories, ri n gs, crea ms, gels)

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 

or al  

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 mpla nta ble pr o gest o ge n -o nl y h or m o nal c o nt race ptio n ass ociate d wi t h in hi bi tio n of  
o v ul at i on a n d/ or i m pla ntati o n ( T his met h o d of  co ntrace pti o n ca n n ot be use d b y W O C B P 
parti ci pa nts i n st u dies w here h or m o nal c o ntrace pti o n is pr o hi bite d) b

I ntra uteri ne de vice (I U D)c

I ntra uteri ne h or m o ne-r eleasi n g s yst e m (I U S) ( T his met h o d of c o ntrace pti o n ca n n ot be use d 
b y W O C B P partici pa nts i n st u dies w here h or m o nal c o ntrace pti o n is pr o hi bite d)
b, 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 d e 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 bst i ne nce
Sex u al a bsti ne nce is c o nsi dere d a hi g hly effec tive 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 tre at me nt. 
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 h er met h o d of  co ntrace pti o n w he n c o m p lete a bsti ne nce is 
electe d. 

W O C B P parti ci pa nts w h o c h o ose c o m p lete a bsti ne nce m u st 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 effect i 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 bst i ne nce 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
1 2 3

Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
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 ons 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 m a y  be s usce pti ble t o i nteracti on wit h t he st u d y treat me nt, w hic h m a y  re d uce t he 
efficac y of t he c o ntrace pti ve met h o d.  Hor m o nal c o ntrace pti o n is per missi ble o nl y w h e 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 o r 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.  In 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 v e dr u g i nteracti o n st u dies w h e 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
U n acce pt a ble Met h o ds of C o ntr ace pti o n

Male or female c o n d o m wi t h or wit ho 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 n e o usl y

Di a 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  or al hor m o n al  co ntrace pti o n, w here i n hi biti on of  ov ulati o n is n ot t he 
pri mar y  mec ha nis m of act i on ( T his met h o d of  co ntrace pti o n ca n n ot be use d b y W O C B P 
parti ci pa nts i n st u dies w here h or m o nal c o ntrace pti o n is pr o hi bite d)

P eri o dic a bst i ne nce (cale n dar, s y m pt ot her mal, p ost-o v ul at i on 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 m et 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 T I A L.
Male partici pa nts wi t 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 o ll owi 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 y ste mic e x p os ure.

Inf or m  an y a n d all part ner(s) of  their part ici pati on i n a cli nical dr u g st u d y an d t he nee d t o 
c o mpl y  wit h c o ntrace ptio n i nstr ucti o ns as di recte d b y t he i n vestig at or.

Male partici pa nts will be re q uire d t o al wa ys use a late x or ot her s y nt het ic c o n d om d uri n g a n y 
se x ual acti vity (e g, va gi nal, a nal, oral) wit h WO C B P; e ve n if t he part ici pa nts ha ve u n der g o ne 
a s uccessf ul vasect o m y or if t heir part ner is alrea d y pre g na nt or breastfee di n g. Males s h o ul d 
c o nti n ue t o use a c o n d o m w hile o n st u d y a n d f or a t otal of  31 wee ks aft er e n d of  treat me nt 
( d urati o n of s per m t ur n o ver). Wit h dra wal ( c oit us i nterr u pt us) a n d/ or t he use of  a sper mici de 
wi t ho ut a c o n d o m  are n ot acce pta ble met h o ds of c o ntrace pti o n or fetal pr otecti o n.

Fe male part ners of  males p arti ci pat i n g i n t he st u d y to c o nsi der use of effect i 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 3 1 wee ks aft er t he e nd 
of  treat me nt i n t he male partici pa nt.

Male parti ci pa nts wi t 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 om se x ual a cti vit y or us e a mal e c o n d o m d uri n g a n y se x ual a cti vit y (e g, va gi nal, a n al, or al) 
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B M S - 9 3 6 5 5 8
ni v ol u ma b
e ve n if t he partici pa nts ha ve u n der g o ne a s uccessf ul vasect o m y, w hile o n st u d y a n d f or a 
t otal of 3 1 wee ks aft er e n d of  treat me nt. Wit h dra wal  (c o itus i nterr u pt us) a n d/ or t he use of  a 
s per mici de with o ut a c o n d o m are n ot acce pta ble met h o ds of c o ntrace pti o n or fetal pr otecti o n.

Refrai n fr om d o nat i n g s per m f or t h e d ur atio n of  t h e st u d y tr e at me nt w hile o n st u d y  a nd f or a 
t otal of 3 1 wee ks after e n d of treat me nt.
C O L L E C T I 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 ollect i on of Pre g na nc y I nfor m at i on a n d o ut c o m e 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 Sect i on 9. 2. 3 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 nit i ons a n d pr oce d u res f or E val uati n g, F oll ow- u p a n d Re p orti n g
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
A P P E N DI X 4
M O DI FI E D R E CI S T C RI T E RI A I N M A LI G N A N T P L E U R A L 
M E S O T H E LI O M A
M ali g na nt ple ural mes ot helio m a a n d n o n-ple ural  l esio n s will be assesse d as f o ll ows:
1
M E A S U R E M E N T C RI T E RI A
1. 1
M e a s ur e m e nt of M ali g n a nt P l e ur al L e si o n s
M ali g n a nt ple ur al mes ot heli o m a lesi o ns: Rec o g nizi n g t hat n ot all cases of  mali g na nt ple ural 
mes ot heli o ma ca n be assesse d wi t h si x ple ural meas ure me nts, t he m o difie d R E CI S T s u g geste d 
g ui da nce p u blis he d i n refere nce t o M P M
1 has bee n a da pte d i n t his st u d y to all o w f or t he 
assess me nt of u p t o 6 meas ure me nts, rat her t ha n a fi xe d n u m ber. Res p o nse t o treat me nt is 
e val uate d b y meas uri n g u ni -di me nsi o n al t u mor t hic k ness per pe n dic ular t o t he c hest wall i n u p t o 
2 p osi tio ns at 3 differe nt l e vels o n C T. T he s u m of u p t o 6 meas ure me nts is defi ne d as t he ple ural 
u ni- di me nsi o nal meas ure.  Eac h si n gle t u mor meas ure me nt m ust be at least 1 0 m m i n le n gt h t o 
q ualif y as meas urea ble disease a n d c o ntri b ute t o t he s u m t hat defi nes t he ple ural u ni - variate 
meas ure. T he ma xi m u m n u m ber of  ple ural lesio ns, u p t o 6, t hat q ualif y as meas ura ble disease 
m ust be use d. Tra ns verse c uts at  least 1 c m a part a n d r elate d t o a nat o mical la n d mar ks i n t he 
t hora x are c h ose n t o all o w re pr o d uci ble assess me nt at lat er ti m e p oi nts. If a meas ura ble t u mor i s 
prese n t, tra ns verse c uts i n t he u p per t hora x, a b o ve t he le vel of  the mai n br o nc hi di visi o n  is 
preferre d. At  reassess me nt, ple ural t hic k ness is meas ure d at t he sa me p osi tio n a n d at t he sa me 
le vel b y t he sa me o bser ver. T hi s meas ure me nt d oes n ot necessaril y re present  t he greatest t u m or 
t hic k ness at t he le vel. 
T he s u m of u p t o 6 ple ur al t hic k ness me as ure me nts = o ne u ni v ari ate di a meter .
T he s u m of t he ple ur al me as ure me nts is c o nsi dere d o ne t ar get lesi o n.
1. 2
M e a s ur e m e nt of N o n - Pl e ur al L e si o n s
N o n -ple ur al lesi o ns: N o n -ple ural lesio n s, s uc h as n o dal , s u bc uta ne o us, a n d ot h er met astatic 
M P M lesi ons, s h o uld be meas ure d u ni- di me nsi o nall y as per t he R E CI S T 1. 1 g ui deli nes wi t h 
B M S m o dificat i ons. At  baseli ne, t u mor lesi ons/l y m p h n o des will be cate g orize d as meas ura ble 
or n o n -meas u ra ble as f oll ows:
1. 2. 1
M e a s ur a bl e
T u m or lesi o ns: M ust be acc uratel y meas ure d i n at least o ne di me nsi o n (lo n gest dia meter i n t he 
pl a ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:
1 0 m m b y C T / M RI sca n (sca n slice t hic k ness n o greater t ha n 5 m m) , or 2 x slice t hic k ness if 
greater t ha n 5 m m.
M ali g n a nt l y m p h n o des: T o be c o nsi dere d p at h ol o gi call y e nlar ge d a n d meas ura ble, a l y m p h 
n o de m u st be 1 5 m m i n s h ort a xis w he n assesse d b y C T / M RI sca n (sca n slice t hic k ness 
rec o m me n de d t o be n o greater t ha n 5 m m).
L y m p h n o des merit s pecial me nt i on si nce t he y are n or m al a nat o mical str uct ures w hic h ma y b e 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or. Pat h ol o gical  no des w hic h are defi ne d as 
meas ura ble a n d ma y be i de ntifie d as tar get lesio n s m ust meet t he crit erio n of  a sh ort a xis of 
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B M S - 9 3 6 5 5 8
ni v ol u ma b
1 5 m m b y C T / M RI sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m. 
T he s h ort a xis of  the n o de is t he di a meter n or m all y use d b y r a diol o gists t o j u d ge if a n o de is 
i n v ol ve d b y s oli d t u mor. N o dal  size is n or mall y re p orte d as t w o di me nsi o ns i n t he pla ne i n w hic h 
t he i ma ge is o btai ne d (for C T sca n t his is al most alwa ys t he a xial pla ne; f or M RI t he pla ne of  
ac q uisit i on ma y be a xial, sa gi tt al or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or 
e xa m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of  
2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o uld b e 
rec or de d as t he n o de meas ure me nt. All ot h er pat h ol o gi cal n o des (t h ose wi t h s hort a xis 1 0 m m 
b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n -t ar g et lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are 
c o nsi dere d n o n-pat h o l ogi cal a nd s h o ul d n ot be rec or de d or f oll o we d.
N ote: Lesi o ns o n X -Ra y  are n ot t o be selecte d as Tar get or N o n-Tar get Lesi o ns.
1. 2. 2
N o n -M e a s ur a bl e
All ot h er lesio n s are c o nsi dere d n o n- meas ura ble, i ncl u di n g s mall lesi ons (lo n gest di a meter 
< 1 0 m m or pat h ol o gical l y m p h n o des wi t h 1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y 
n o n- meas ura ble 
lesio n s. Lesi o n s c o nsi dere d tr ul y n o n- meas ura ble 
i ncl u de: lept o m e ni n geal 
di sease, i nflam mat or y  breast di sease, l y m p ha n gitic i n v ol ve me nt of  ski n or l un g, a b d o mi na l 
masses/a b d o mi nal 
or ga n o me gal y i de ntifie d b y p h ysical e xa m t hat is n ot meas ura ble 
b y 
re pr o d uci ble i ma gi n g tec h ni q ues.
N ote: Lesi o ns o n X -Ra y  are n ot t o be selecte d as Tar get or N o n-Tar get Lesi o ns.
1. 3
S p e ci al c o n si d er ati o n s r e g ar di n g l e si o n m e a s ur a bilit y
1. 3. 1
B o n e l e si o n s

B o ne sca n, P E T sca n a n d plai n fil ms are n ot c o nsidere d a de q uate i ma gi n g tec h ni q ues t o 
meas ure b o ne lesio n s. H o we ver, t hese tec h niq ues ca n be use d t o c o nfir m t he prese nce or 
di sa p peara nce of b o ne lesi o ns. 

L y tic b o ne lesi o ns or mi xe d l y tic- blast ic lesio n s, with i de ntifi a ble s oft tiss ue c o m p o ne nts, t hat 
ca n be e val uate d b y cr oss sectio nal  i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be c o nsi dere d 
as me as ura ble lesi ons if t he s oft tiss ue c o m p o ne nt meets t he defi nit i on of  meas ura bilit y 
descri be d a b o ve.

Bl astic b o ne lesio ns are n o n -meas ura ble.
1. 4
B a s eli n e D o c u m e nt ati o n o f ‘ T ar g et’ a n d ‘ N o n -T ar g et’ L e si o n s
As n ote d i n Sect i on 1. 1  a b o ve, t he s u m of t he ple ural mea s ure me nts ta ke n is c o nsi dere d o ne 
tar get lesi on.
F or n o n- ple ural lesi ons, w he n m o re t ha n o ne meas ura ble lesi on is prese nt at baseli ne all lesio n s 
u p t o a ma xi m u m of  fi ve lesio ns t ot al (a n d a ma xi m u m of  t w o lesio n s p er or ga n) re prese ntativ e 
of  all i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get l esio n s a n d will be rec or de d a n d meas ure d at  
baseli ne (t his me a ns i n i nsta nces w here pat ient s ha ve o nl y o ne or t wo or ga n sites i n v ol ve d a 
ma xi m u m o f t wo a n d f o ur lesi o ns res pect i vel y will be rec or de d).
Re vise d Pr ot oc ol N o.: 0 2
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
N ote: A ma xi m u m of  t wo l esio n s ca n be selecte d per or ga n s yste m. F or e xa m ple, a ma xi m u m o f 
t wo l u n g lesio n s ca n be selecte d (selecte d fr om o ne l u n g or o n e lesi on fr om eac h). A ma xi m u m 
of  t w o l y m p h n o des ca n be selecte d at baseli ne, as t he l y m p hatic s yste m is c o nsi dere d o ne or ga n.
Tar get l esio ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wi t h t h e lo n g est di a meter), be 
re prese ntati ve of  all i n v ol ve d or ga ns, b ut i n a d ditio n s h o uld be t hose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts. It ma y be t he case t hat, o n occasio n, t he lar gest lesi o n  d oes 
n ot len d itself t o re pr o d uci ble meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesio n  w hic h 
ca n be meas ure d re pr o d uci bl y s h o ul d be selecte d.
A s u m of t he di a meters (lo n gest f or n o n- n o dal  lesio n s, s h ort a xis f or n o dal  lesio n s) f or all tar get 
lesio ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters. If ly m p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xi s is a d de d i nto t h e s u m. T he baseli ne 
s u m dia meters will be use d as r efer e n c e t o furt her c haracteri ze a n y o bjecti ve t u mor re gressi o n i n 
t he meas ura ble di me nsi o n of t he disease.
All ot her lesio n s ( or sit es of disease) i ncl u di n g pat h olo gi cal l y m p h n o des s h o uld be i de ntifie d as 
n o n- tar get lesio n s a n d s h o uld als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uire d a n d 
t hese lesi o ns s h o ul d b e f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( more details t o f oll o w). I n a d di tio n, i t is p ossi ble t o rec or d mul tipl e n o n -t ar g et lesio ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m on t he case rec or d f or m (e g, ‘ mul tiple e nlar ge d pel vic l y m p h 
n o des’ or ‘ m ult i ple li ver metastases’).
2
E V A L U A TI O N O F L E SI O N S
T ot al T u m or Me as ure me nt:   T he T otal T u m or Meas ure is e q ual t o t he s u m of t he U ni variate Dia meter (s u m of u p 
t o 6 ple ural t hic k ness meas ure me nts as n ote d a b o ve) pl us t he s u m of t he u ni-di me nsi o nal meas ure me nts of a n y n o n -
ple ural tar get lesi o ns.
T otal T u m or Meas ure me nt = Ple ural lesi o n U ni variate Dia meter + S u m of n o n -ple ural tar get lesi o ns
N o n -pl e ural a n d ple u ral s oli d t u mors will be e val uate d usi n g R es p o nse E val uat i on C rit eria I n
S oli d T u m ors versi o n 1. 1 ( R E CI S T 1. 1 ) g ui deli ne wi t h B M S m o dificat i ons .2
3
R E S P O N S E C RI T E RI A
3. 1
E v al u ati o n of T ar g et L e si o n s
3. 1. 1
S p e ci al N ot e s o n t h e A s s e s s m e nt of T ar g et L e si o n s

C o m plete Res p o nse ( C R): Disa p peara nce of  all tar get lesi ons. A n y pat h o l ogi cal l y m p h 
n o des ( w het her tar get or n o n -tar get) must ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m.

P arti al Res p o nse 
( P R): At  least a 3 0 % decrease i n t he s u m of t he T otal  Tu m or 
Meas ure me nt , ta ki n g as refere nce t he baseli ne s u m dia meters.

Pr o gressi ve Dise ase ( P D): At  least a 2 0 % i ncrease i n t he s u m of  t he T otal  Tu m or 
Meas ure me nt , ta ki n g as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if 
t hat is t he s mallest o n st u d y). I n a d ditio n t o t he relati ve i ncrease of  20 %, t he s u m must als o 
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
d e m o nstrate a n a bs ol ute i ncrease of at least 5 m m . ( N ote: t he a p peara nce of o ne or more ne w 
lesio ns is als o c o nsi dere d pr o gressi o n).

St a ble Dise ase ( S D): N ei t her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o 
q ualif y  for P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y .

N ot E v al u a ble ( N E): If o ne or m or e t ar g et lesi ons i ncl u di n g n o n- ple ural  a nd ple ural lesi ons 
acce d de d i n t he T ot al  Tu m or Meas ure me nt ca n n ot be meas ure d or a de q uatel y assesse d as 
eit her f ull y res ol ve d or t o o s mall t o meas ure ( d ue t o missi n g or p o or q ualit y ima ges), a n d t he 
s u m of dia meters of  the re mai ni n g meas ure d tar get lesi ons (if a n y) has n ot i ncrease d 
s ufficie ntl y t o meet Pr o gressi ve Disease as defi ne d a b ove. 
3. 1. 2
L y m p h n o d e s
L y m p h n o des i de ntifie d as tar get lesio n s s h o uld al wa ys ha ve t he a ct u al sh ort a xis meas ure me nt 
rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi natio n), e ve n if t he n o des 
re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l y m p h n o des are i ncl u de d as tar get 
lesio ns, t he ‘s u m’ of lesi ons ma y n ot be zer o e ve n if c o m p lete res p o nse crit eria are met, si nce a 
n or m al l y m p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. Case re p ort f or ms or ot her data 
c ollect i on met h o ds ma y t h er efor e b e d esi g ne d t o ha ve tar get n o dal  lesio ns rec or de d i n a se parate 
secti on w here, i n or der t o q ualif y f or C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. F or P R, 
S D a n d P D, t he act ual  s hort a xis me as ure me nt of t he n o des is t o be i ncl u de d i n t he s u m of  tar get 
lesio ns.
3. 1. 2. 1
T ar g et l e si o n s t h at b e c o m e ‘t o o s m all t o m e a s ur e’
W hile o n st u d y, all lesio n s ( n o dal an d n o n- n o dal ) rec or de d at baseli ne s h o uld ha ve t heir act ual 
meas ure me nts rec or de d at  eac h s u bse q ue nt e val uat i on, e ve n w he n ver y s mall (e g, 2 m m). 
H o w e ver, s o met i mes lesio ns or l y m p h n o des w hic h are rec or de d as tar get lesi ons at baseli ne 
bec o me s o fai nt on C T sca n t hat t he r a diol o gi st ma y n ot feel c o mf orta ble assi g ni n g a n e xact 
meas ure a n d ma y re p ort t he m as bei n g ‘t o o s mall t o me as ure’. W he n t his occ ur s it is i m p orta nt 
t hat a val ue be rec or de d o n t he case re p ort f or m. If it is t he o pi ni o n of  the r a diol o gi st t hat t he 
lesio n has li kel y disa p peare d, t he meas ure me nt s h o uld be rec or de d as 0 m m. If the lesio n  is 
belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ul t v al u e of  5 mm 
s h o uld b e assi g ne d as t h e r efere nce dia meter. ( N ote: It is less li kel y t hat t his r ule will be use d f or 
l y m p h n o des si nce t he y us uall y ha ve a defi na ble size w he n n or mal a n d are fre q ue nt l y s urr o u n de d 
b y fat s uc h as i n t he retr o perit o ne u m; h o we ver, if a l y m p h n o de is belie ve d t o be prese nt a n d is 
fai ntl y see n b ut t o o s mall t o meas ure, a defa ul t val ue of  5 mm s h o uld be assi g ne d i n t his 
circ u msta nce as well). T his defa ul t val ue is deri ve d fr om t he 5 m m C T slice t hic kness ( but 
s h o uld n ot be c ha n ge d wi t h var yi n g C T slice t hic k ness). T he meas ure me nt of  these lesi ons is 
p ote nti all y n o n- re pr o d uci ble, t heref ore pr o vi di n g t his defa ul t val ue will  pre ve nt false res p o nses 
or pr o gressi o ns base d u p o n meas ure me nt err or. T o rei t er ate, h o we ver, if t he ra diol o gist i s a ble t o 
pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if it is bel o w 5 m m.
3. 1. 2. 2
L e si o n s t h at s plit or c o al e s c e o n tr e at m e nt
W he n n o n- n o dal  lesio n s ‘fra g me nt’, t he l on gest dia meters of  the fra g me nte d p orti o ns s h o uld be 
a d d e d t o g et h er t o c alc ul at e t h e t ar g et lesio n  s u m. Si milarl y, as lesio n s c o alesce, a pla ne bet wee n 
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
t he m ma y be mai ntai ne d t hat w o ul d ai d i n o btai ni n g ma xi mal dia meter me as ure me nts of  eac h 
i n di vi d ual lesio n . If the lesio n s ha ve tr ul y c o alesce d s uc h t h at t he y ar e n o l on ger se para ble, t he 
vect or of  the l on gest di a meter i n t his i nsta nce s h o uld be t he ma xi mal l on gest di a meter f or t he 
‘c oalesce d lesi o n’.
3. 2
E v al u ati o n of N o n -T ar g et L e si o n s
T his sectio n pr o vi des t he defi ni tio n s of  t he crit eri a use d t o d eter mi ne t he t u mor res p o nse f or t he 
gr o u p of  no n -t ar g et lesi ons. W hile 
s ome n o n- tar get lesi ons ma y act uall y be meas ura ble, t he y 
nee d n ot be meas ure d a n d i nstea d s h o uld be assesse d o nl y q uali tati vel y at t he time p oi nts 
s pecifie d i n t he pr ot oc ol.

C o m plete Res p o nse ( C R) : Disa p peara nce of all n o n -t ar get lesio n s. All l y m p h n o des m ust be 
n o n- pat h o l ogi cal in size ( < 1 0 m m s h ort a xis). 

N o n -C R/ N o n -P D: Persiste nce of o ne or m ore n o n -t ar get lesio n(s)

Pr o gressi ve Dise ase ( P D): U ne q ui v ocal pr o gressi o n of e xist i n g n o n-tar get lesio ns.
3. 2. 1
S p e ci al N ot e s o n A s s e s s m e nt of Pr o gr e s si o n of N o n -T ar g et Di s e a s e
T he c o nce pt of pr o gressi o n of n o n -tar get disease re q uires a d diti onal e x pla nat i on as f o ll ows:
3. 2. 2
E v al u ati o n of B e st O v er all R e s p o n s e
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y tr e at me nt u ntil 
di sease pr o gressi o n or t he last res p o nse rec or de d, ta ki n g i nto acc o u nt a n y ce ns ori n g r ules 
re gar di n g s u bse q ue nt t hera p y. T h e p atie nt’s best o verall res p o nse assi g n me nt will de pe n d o n t he 
fi n di n gs of  bot h  tar get a nd n o n- tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he 
a p peara nce of ne w lesi o ns.
3. 2. 2. 1
W h e n t h e p ati e nt al s o h a s m e a s ur a bl e di s e a s e
I n t his s ettin g, t o a c hie ve ‘ u ne q ui v ocal pr o gressi o n’ o n t he basis of  t he n o n- tar get disease, t here 
m ust be a n o verall lev el  of s u bsta ntial w orse ni n g i n n o n- tar get disease s uc h t hat, e ve n i n 
prese nce of  SD or P R i n t ar g et disease, t he o verall t u mor b ur de n has i ncrease d s ufficie ntl y t o 
merit disc o nt i n uati on of  thera p y A m o dest ‘i ncrease’ i n t he size of  one or m o re n o n- tar get 
lesio ns is us uall y n ot s ufficie nt t o q ualif y f or u ne q ui v ocal pr o gressi o n stat us. Pl e ural eff usi ons,  
p eri car dial eff usio n s a n d as cit es will n ot be f oll owe d as t ar g et or n o n- tar get lesio ns a n d will n ot 
c o ntri b ute t o res p o nse or p r o gressi o n. T he d esi g n ati o n o f o verall pr o gressi o n s olel y o n t he basis 
of  cha n ge i n n o n- t ar g et disease i n t he face of  SD or P R of  tar get disease will t heref ore be 
e xtre mel y rare.
3. 2. 2. 2
W h e n t h e p ati e nt h a s o nl y n o n -m e a s ur a bl e di s e a s e
T his circ u msta nce arises i n s ome trials w he n it is n ot a criteri o n of  st u d y ent r y to ha ve 
meas ura ble disease. T he sa me ge neral c o nce pts a p pl y here as n ote d a b o ve, h o we ver, i n t his 
i nsta nce t here is n o meas ura ble disease assess me nt t o fact or i nt o t he i nter pretati o n o f a n i ncrease 
i n n o n- meas ura ble disease b ur de n. Beca use w orse ni n g i n n o n- tar get disease ca n n ot be easil y 
q ua nt ifie d ( b y defi nitio n : if all lesi ons are tr ul y n o n- meas ura ble) a usef ul test t hat ca n be a p plie d 
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B M S - 9 3 6 5 5 8
ni v ol u ma b
w he n assessi n g pat ient s f or u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall 
di sease b ur de n base d o n t he c ha n ge i n n o n-meas ura ble disease is c o m para ble i n ma g nit u de t o t he 
i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble disease: ie, a n i ncrease i n t u mor 
b ur de n re prese nti n g a n a d ditio n al 73 % i ncrease i n ‘ v olu me’ ( w hic h is e q ui vale nt t o a 2 0 % 
i ncrease dia meter i n a meas ura ble lesi o n). E xa m ples i ncl u de, a n i ncrease i n l y m p ha n gitic disease 
fr om l oc ali z e d t o wides prea d, or ma y be descri be d as ‘s ufficie nt t o re q ui r e a c h a n g e i n t hera p y’. 
If ‘ u ne q ui v ocal pr o gressi o n ’ is see n, t he p atie nt s h o uld be c o nsi dere d t o ha ve ha d o verall P D at 
t hat p oi nt. W hile it w o uld b e i deal t o ha ve o bjecti ve crit eria t o a p pl y t o n o n-meas ura ble disease, 
t he ver y  nat ure of  that disease ma kes it im p ossi ble t o d o s o; t heref ore t he i ncrease m u st be 
s u bsta ntial.
3. 2. 3
N e w L e si o n s
T he a p peara nce of  ne w mali g na nt 
lesi ons de n otes disease pr o gressi o n; t heref ore, s ome  
c o m me nts o n detecti o n of  ne w lesio n s are i m p orta nt. T here are n o s pecific crit eria f or t he 
i de ntificati on of  ne w r a dio gra p hic lesio n s; h o we ver, t he fi n din g of  a ne w lesi on s h o uld b e 
u ne q ui v ocal: ie, n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dali t y or fi n di n gs t ho u g ht t o re prese nt s o met hi n g ot h er t ha n t u mor (f or e xa m ple, s ome ‘ ne w’ 
b o ne lesio n s ma y 
be si m pl y heali n g or flare of  pre-e xist i n g lesio n s). T his is part ic ularl y 
i m p orta nt w he n t he patie nt’s baseli ne lesio ns s h o w parti al or c o m p lete res p o nse. F or e xa m ple, 
necr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a ‘ ne w’ c yst ic lesi on, w hic h it is 
n ot.
N O T E: Fl ui d c o llecti ons ( ple ural eff usio n s, p eri car dial eff usio ns, a n d as cites) will n ot be 
c o nsi dere d ne w lesi ons a n d will n ot c o ntri b ute t o res p o nse or pr o gressi o n. I n the e ve nt a ne w 
fl uid c o llecti o n is see n o n a p ost -baseli ne i ma gi n g e xa m, a c o m me nt ma y be ma d e, b ut t he 
a p peara nce of  a ne w fl ui d c o llecti on alo n e s h o ul d n ot res ult i n a n assess me nt of  Pr o gressi ve 
Di sease ( P D). A lesi on i de ntifie d o n a f oll ow- u p st u d y in a n a nat o mical l ocat i on t h at was n ot 
sca n ne d at baseli ne is c o nsi dere d a ne w lesi o n a n d will i ndicate disease pr o gressi o n . A n e xa m ple 
of  this is t he pat ient  wh o has visceral disease at baseli ne a n d w hile o n st u d y has a C T or M RI 
brai n or dere d w hic h re veals metastases. T he patie nt’s brai n metastases are c o nsi dere d t o be 
e vi de nce of  PD e ve n if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne . A lesio n i de ntifie d o n 
C hest X- Ra y  that was n ot prese nt i n pri or C T ca n be c o nsi dere d a ne w lesio n a n d will res ult i n 
Pr o gressi ve Disease ( P D).
If a ne w lesio n is e q ui v ocal, f or e xa m ple beca use of  its small size, c o ntin ue d f oll ow- u p 
e val uat i on will  clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is defi nitel y 
a ne w lesio n , t he n pr o gressio n s h o ul d b e declare d usi n g t h e d at e of  t he init ial sca n. W hile F D G -
P E T res p o nse assess me nts nee d a d ditio n a l st u d y, it is s omet i mes reas o na ble t o i nc or p orate t he 
use of  FD G -P E T sca n ni n g t o c o m p le me nt C T 
sca n ni n g i n assess me nt of  pr o gressio n 
( partic ularl y p ossi ble ‘ ne w’ disease). Ne w lesi ons o n t he basis of F D G -P E T i ma gi n g ca n b e 
i de ntifie d acc or di n g t o t he f ollo wi n g al g ori t h m:
1.
Ne gati ve F D G -P E T at b as eli n e, wi t h a p ositive F D G -P E T at f oll o w - u p is a si g n of P D b as e d 
o n a ne w lesi o n.
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
2.
N o F D G -P E T at  baseli ne a n d a p osi tive F D G -P E T at f oll ow- u p: If t he p osi tive F D G -P E T at  
f oll ow- u p c orres p o n ds t o a ne w sit e of  disease c o nfir me d b y C T, t his is P D. If the p osi tive 
F D G -P E T at f ol l ow- u p is n ot c o nfi r me d as a ne w sit e of disease o n C T, a d ditio nal f oll ow- u p 
C T sca ns are nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urrin g at t h at si te (if s o, t he 
d at e of  P D will b e t h e d at e of t he i nitial a b n or mal F D G -P E T sca n). If  t he p ositive F D G -P E T 
at fol l ow- u p c orres p o n ds t o a pre -e xist i n g site of disease o n C T t hat is n ot pr o gressi n g o n t he 
basis of t he a nat o mic i ma ges, t his is n ot P D.
3. 3
R e s p o n s e A s s e s s m e nt
3. 3. 1
Ti m e P oi nt R e s p o n s e
A t eac h pr ot oc ol  specifie d time p oi nt, a res p o nse assess me nt occ urs. Ta ble 3. 3. 1 - 1 pr o vi des a 
s u m mar y of  the o verall res p o nse stat us calc ulati o n at eac h time p oi nt f or pati e nts w h o ha ve 
meas ura ble 
disease at baseli ne. W he n 
p at ient s ha ve n o n- me as ura ble (t heref ore n o n- tar get) 
di sease o nl y, Ta ble 3. 3. 1 - 2is t o be use d. 
T a ble 3. 3. 1 - 1:
Ti me P oi nt Res p o nse: P atie nts Wit h T ar get ( ± N o n -T ar get) Dise ase
T ar get Lesi o ns
N o n -T ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C R
C R
N o
C R
C R
N o n -C R/ n o n- P D
N o
P R
C R
N ot e val uate d
N o
P R
P R
N o n -P D or n ot all e val uate d
N o
P R
S D
N o n -P D or n ot all e val uate d
N o
S D
N ot all e val uate d
N o n -P D
N o
N E
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D
C R = c o m pl ete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve disease a n d N E = i ne val ua ble
T a ble 3. 3. 1 - 2:
Ti me P oi nt Res p o nse: P atie nts wit h N o n -t ar get Dise ase O nl y
N o n -T ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C R
N o
C R
N o n -C R/ n o n- P D
N o
N o n -C R/ n o n- P D a
N ot all e val uate d
N o
N E
U n e q ui v ocal P D
Yes or N o
P D
A n y
Yes
P D
C R = c o m plete res p o nse, P D = pr o gressi ve disease a n d N E = i ne val ua ble
a
N o n -C R/ n o n- P D is pr eferre d o ver S D f or no n -tar get disease si nce S D is i ncreasi n gl y use d as e n d p oi nt f or 
assess me nt of efficac y i n s o me trials s o t o assi g n t his cate g or y w he n n o lesi o ns ca n be meas ure d is n ot a d vise d.
Re vise d Pr ot oc ol N o.: 0 2
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
3. 3. 2
B e st O v er all R e s p o n s e 
C o m pl ete or partial res p o nses ma y be clai me d o nl y if t he criteria f or eac h are met at a 
s u bse q ue nt ti me p oi nt of  4 wee ks ( 2 8 d a y s) later. I n t his circ u msta nce, t he best o verall 
res p o nse ca n be i nter prete d as i n Ta ble 3. 3. 2 - 1. W he n S D is belie ve d t o be best res p o nse, it must 
meet t he pr ot oc ol s pecifie d mi ni m u m t i me fr om t he date of first treat me nt or ra n d o mizat i on date.
F or e xa m ple, if t he first sc he d ule d f oll o w- u p i ma gi n g visit is Wee k 6 ( ± 7 da ys) f or a parti c ul ar 
pr ot oc ol , a Best Res p o nse of S D ca n o nl y be ma de after t he s u bject is o n-st u d y for a mi ni m u m  of 
6 wee ks ( 4 2 d a y s) mi n us 7 da ys, f or a n a bs o l ute mi ni m u m time o n -st u d y of 3 5 da ys fr om t he 
refere nce st art date (refere nce date is c o nsi dere d Da y  1 o n st u d y).  If t he s ubject is n ot o n -st u d y 
f or at least t his a mo u nt of  ti me, a n y t u mor assess me nt i n dicati n g sta ble disease bef ore t his time 
p eri o d will ha ve a Best Res p o nse of N E u nless P D is i de nt ifie d.
S peci al n ote o n res p o nse assess me nt: W he n 
n o dal  disease is i ncl u de d i n the s u m of  tar get 
lesio ns a n d t he n o des decrease t o ‘ n or mal’ size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt 
re p orte d o n sca ns. T his meas ure me nt s h o uld be rec or de d e ve n t ho u g h t he n o des are n or mal i n 
or der n ot t o o verstate pr o gressi o n s h o uld it be base d o n i ncrease i n size of  the n o des. As n ote d 
earlier, t his mea ns t hat patie nts wi t h CR ma y n ot ha ve a t ot al su m of  ‘zer o’ o n t he case re p ort 
f or m ( C R F).
T a ble 3. 3. 2 - 1:
Best O ver all Res p o nse 
O ver all Res p o nse 
First Ti me P oi nt
O ver all Res p o nse 
S u bse q ue nt Ti me P oi nt
B est O ver all Res p o nse
C R
C R
C R
C R
P R
S D, P D O R P R a
C R
S D
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, 
P D
C R
P D
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, 
P D
C R
N E
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met , ot her wise, 
N E
P R
C R
P R
P R
P R
P R
P R
S D
S D
P R
P D
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, 
P D
P R
N E
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, 
N E
N E
N E
N E
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta bl e disease, P D = pr o gressi ve disease, a n d 
N E = i ne val ua ble
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Cli nical Pr ot oc ol
C A 2 0 9 7 4 3
B M S - 9 3 6 5 5 8
ni v ol u ma b
a
If a C R is tr ul y met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease meeti n g P R 
criteria relati ve t o baseli ne, ma kes t he disease P D at t hat p oi nt (si nce diseas e m ust ha ve rea p peare d after C R). 
Best res p o nse w o ul d de pe n d o n w h et her mi ni m u m d urati o n f or S D was met. H o we ver, s o meti mes ‘ C R’ m a y  be 
clai me d w he n s u bse q ue nt sca ns s u g gest s mall lesi o ns were li kel y still prese nt a n d i n fact t he patie nt ha d P R, n ot 
C R at t he first ti me p oi nt. U n der t hese circ u msta nces, t he or i gi nal C R s h o ul d be c ha n ge d t o P R a n d t he best 
res p o nse is P R.
3. 3. 3
C o nfir m ati o n S c a n s
Verific ati o n of Res p o nse: T o be assi g ne d a stat us of C R or P R, c ha n ges i n t u m or meas ure me nts 
m ust be c o nfi r me d b y c o nsec ut i ve or s u bse q ue nt re peat assess me nts t hat s h o uld be perf or m e d n o 
less t ha n 2 8 da ys after t he cri t eria f or res p o nse are first met . S u bse q ue nt d oc u me ntati o n of a C R 
ma y pr o vi de c o nfir mati o n of  a pre vi o usl y i de ntifie d C R e ve n wit h a n int er ve ni n g N E or P R (e g, 
C R N E C R or C R P R C R ). S u bse q ue nt d oc u me ntati o n of  a PR ma y pr o vi de c o nfir matio n of  a
pre vi o usl y i de ntifie d P R e ve n wi t h an i nter ve ni n g N E or S D (e g, P R N E P R or P R S D P R). 
H o we ver, o nl y o ne ( 1) i nter ve ni n g ti me p o i nt will be all o we d bet wee n P R / C Rs f or c o nfir mati on.
Verific ati o n 
of Pr o gressi o n : Pr o gressi o n of  disease s h o uld be verifie d i n cases w here 
pr o gressi o n is e q ui v ocal. If re peat sca ns c o nfir m P D, t he n pr o gressi o n  s ho ul d be declare d usi n g 
t he date of  the i nitial sca n. If re peat sca ns d o n ot c o nfir m PD, t he n t he s u bject is c o nsi dere d t o 
n ot ha ve pr o gressi ve disease.
 
 
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