Conditions: Mesothelioma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 605
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the effectiveness and tolerability of the combination of Nivolumab and Ipilimumab compared to Pemetrexed and Cisplatin or Carboplatin in patients with unresectable pleural mesothelioma.

Detailed description:

Arms:
arm 1: Specified dose on specified days arm 2: Specified dose on specified days

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab intervention 3: Pemetrexed intervention 4: Cisplatin intervention 5: Carboplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_000.pdf: 


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 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 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
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 .
Re vise d Pr ot oc ol N o.: 0 2
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5 1


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.
Re vise d Pr ot oc ol N o.: 0 2
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 
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
5 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
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
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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 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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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 
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B M S - 9 3 6 5 5 8
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
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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
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.
Re vise d Pr ot oc ol N o.: 0 2
Date: 2 5- A pr- 2 0 1 9
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
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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).
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B M S - 9 3 6 5 5 8
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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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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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B M S - 9 3 6 5 5 8
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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
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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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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.
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B M S - 9 3 6 5 5 8
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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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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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SAP_001.pdf: 
Offi ci al Titl e of St u d y:  
A P hase III, Ra n d o mize d, O pe n La bel Trial of Ni v ol u ma b i n c o m bi nati o n wit h I pili m u ma b 
Vers us Pe metre xe d wit h Cis plati n or Car b o plati n as First Li ne T hera p y i n  
u nresecta ble Ple ural Mes ot heli o ma ( C hec k Mate 7 4 3: C H E C K p oi nt pat h wa y a n d 
ni v ol u M A b cli nical Trial E val uati o n 7 4 3)  
 
N C T N u m b er:  N C T 0 2 8 9 9 2 9 9  
D o c u m e nt D at e ( D at e i n w hi c h d o c u m e nt w a s l a st r e vi s e d) : N o v e m b er 0 7, 2 0 19 


S T A TI S TI C A L A N A L Y SI S P L A N
F O R C LI NI C A L S T U D Y R E P O R T
A P h a s e III, R a n d o mi z e d, O p e n L a b el Tri al of Ni v ol u m a b i n c o m bi n ati o n wit h I pili-
m u m a b V er s u s P e m etr e x e d wit h Ci s pl ati n or C ar b o pl ati n a s Fir st Li n e T h er a p y i n 
u nr e s e ct a bl e Pl e ur al M e s ot h eli o m a ( C h e c k M at e 7 4 3: C H E C K p oi nt p at h w a y a n d 
ni v ol u M A b cli ni c al Tri al E v al u ati o n 7 4 3)
P R O T O C O L C A 2 0 9 7 4 3
V E R SI O N # 1. 1
D A T E : 0 7- N O V- 2 0 1 9




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3
7. 1. 1 
A dverse Eve nts, Seri o us A dverse Eve nts, M ulti ple Eve nts, Select A dverse 
Eve nts, Ot her Eve nts of S peci al I nterest a n d I m m u ne- Me di ate d A dverse 
Eve nts ..................................................................................................................... 2 6
7. 1. 1. 1 
Select A dverse Eve nts ( E U S u b missi o n) .................................................................. 2 7
7. 1. 1. 2  
Ot her Eve nts of S peci al I nterest .............................................................................. 2 7
7. 1. 1. 3 
I m m u ne- Me di ate d A dverse Eve nts ( U S S u b missi o n) ................................................ 2 7
7. 1. 2 
L a b or at or y Tests ..................................................................................................... 2 8
7. 2 
St u d y C o n d uct ........................................................................................................ 2 8
7. 3 
St u d y P o p ulati o n .................................................................................................... 2 9
7. 3. 1 
S u bject Di s p ositi o n ................................................................................................. 2 9
7. 3. 2  
De m o gr a p hics a n d Ot her B aseli ne Dise ase C h ar acteristics .................................... 2 9
7. 3. 3  
Me dic al Hist ory...................................................................................................... 3 0
7. 3. 4 
Pri or T her a py  A ge nts ............................................................................................. 3 0
7. 3. 5 
P hysic al Ex a mi n ati o ns............................................................................................ 3 0
7. 3. 6 
B aseli ne P hysic a l Me as ure me nts ............................................................................ 3 0
7. 3. 7  
Discre p a ncies bet wee n I V R S a n d C R F Str atific ati o n F act ors ................................. 3 0
7. 4 
E xte nt of E x p os ure ................................................................................................. 3 0
7. 4. 1 
A d mi nistr ati o n of St u dy T her a py............................................................................. 3 1
7. 4. 2  
M o dific ati o ns of St u dy T her a py .............................................................................. 3 3
7. 4. 2. 1  
D ose Del a ys ........................................................................................................... 3 3
7. 4. 2. 2 
I nf usi o n I nterr u pti o ns a n d R ate C h a n ges ................................................................ 3 3
7. 4. 2. 3  
D ose Esc al a ti o ns .................................................................................................... 3 3
7. 4. 2. 4  
D ose Re d u cti o ns ..................................................................................................... 3 3
7. 4. 2. 5  
D ose O missi o ns ...................................................................................................... 3 4
7. 4. 2. 6 
P arti al Disc o nti n u ati o n of I pili m u m a b i n t he Ar m A ............................................... 3 4
7. 4. 3. 1 
I m m u ne M o d ul ati n g Me dic ati o n ............................................................................. 3 5
7. 4. 3. 2 
S u bse q ue nt C a ncer T her a py ................................................................................... 3 6
7. 5 
Efficac y .................................................................................................................. 3 6
7. 5. 1 
A n alysis of O b jective Res p o nse R at e....................................................................... 3 7
7. 5. 2 
Ti me t o T u m o r Res p o nse a n d D ur ati o n of Res p o nse ............................................... 3 7
7. 5. 3 
A n alysis of  D C R ..................................................................................................... 3 8
7. 5. 4 
A n alysis of Pr o gressi o n- Free S urviv al .................................................................... 3 8
7. 5. 6 
A n alysis of O ver all S urviv a l.................................................................................... 3 9
7. 5. 8 
S u bset A n alyses of Over all S ur viv al ........................................................................ 4 1
7. 5. 9 
C urre nt St at us of P F S  a n d O S F oll ow- u p................................................................ 4 1
7. 5. 1 0 
I nteri m A n alysis of  Over all S urviv al ....................................................................... 4 2
7. 6 
S afet y ..................................................................................................................... 4 3
7. 6. 1  
De a t hs....................................................................................................................4 3
7. 6. 2 
Seri o us A d verse Eve nts ........................................................................................... 4 3
7. 6. 3 
A dverse Eve nts Le a di n g t o Disc o n ti n u ati o n of St u dy T her a py................................. 4 3
7. 6. 4 
A dverse Eve nts Le a di n g t o D ose M o dific ati o n........................................................ 4 3
7. 6. 5 
A dverse Eve nts ....................................................................................................... 4 4




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
5
LI S T O F T A B L E S
Ta ble 2. 5- 1: 
Pr ot oc ol A me n d me nts ............................................................................ 1 0
Ta ble 4. 2. 5. 1- 1: 
Ce ns ori n g Sc he me use d i n Pri mar y Defi niti o n of P F S ............................ 1 6
Ta ble 4. 2. 5. 2- 1: 
Ce ns ori n g Sc he me f or Sec o n dar y Defi niti o n of P F S............................... 1 8
Ta ble 5- 1: 
S u m mar y of Ke y Desi g n Pa ra meters ...................................................... 2 3
Ta ble 7. 4. 1- 1: 
St u d y T hera p y Para meter De fi niti o ns-  Ni v ol u ma b a n d I pili m u ma b ........ 3 1
Ta ble 7. 4. 1- 2: 
St u d y T hera p y Para meter De fi niti o ns- Pe metre xe d/ Cis plati n................... 3 1
Ta ble 7. 4. 1- 3: 
St u d y T hera p y Para meter Defi niti o ns- Pe metre xe d/ Car b o plati n .............. 3 2
Ta ble 7. 4. 2. 4- 1:  
D ose Le vels f or Pe metre xe d, Cis plati n, a n d Car b o plati n ......................... 3 4
Ta ble 7. 4. 2. 4- 2: 
Calc ulate d D ose Ra n ges a n d Relate d D ose Le vels .................................. 3 4
Ta ble 1 0- 1:  
D oc u me nt Hist or y .................................................................................. 5 4
A p pe n di x Ta ble 1:  
Deri vati o n of Cl ustere d A E .................................................................... 5 6


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
6
LI S T O F FI G U R E S
Fi g ure 2. 1- 1: 
St u d y Desi g n Sc he matic ........................................................................... 9
Fi g ure 4. 2. 5. 1- 1: 
P F S Pri mar y Defi niti o n .......................................................................... 1 6
Fi g ure 4. 2. 5. 2- 1: 
P F S Sec o n da r y Defi niti o n ...................................................................... 1 7




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
8
Sc he d ule of A n al yses:
A f or mal i nteri m a nal ysis f or t he O S is pla n ne d af ter 4 0 3 deat hs ha ve bee n o bser ve d. T his f or mal 
c o m paris o n of O S will all o w f or earl y st o p pi n g f or s u pe ri orit y. A n i n de pe n de nt statisticia n e xter nal 
t o B M S will perf or m t he a nal ysis. 
T he fi nal O S a nal ysis is t ar gete d t o occ ur w he n at le ast 4 7 3 deat hs e ve nts ha ve bee n o bser ve d 
a m o n g ra n d o mize d s u bjects. 
2 
S T U D Y D E S C RI P TI O N
2. 1 
St u d y D e si g n
Pr ot oc ol C A 2 0 9 7 4 3 is a ra n d o mize d ( 1: 1), o pe n-la bel, 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 uati n g ni v ol u ma b c o m bi ne d wit h i pili m u ma b vers us pe metre xe d 
pl us cis plati n or car b o plati n as a first li ne treat me nt.
S u bjects  will u n der g o scree ni n g e val u ati o ns t o deter mi ne eli gi bilit y wit 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 o lle d, a n d a p pr o xi matel y 6 0 0 s u bjects will be 
ra n d o mize d. 
Ra n d o mizati o n will be stratifie d acc or di n g t o t u m or hist ol o g y: E pit heli oi d vs n o n-e pit heli oi d a n d 
se x: male vs fe male. T u m or sa m ple f or P D- L 1 st at us assess me nt is re q uire d pri or t o ra n d o mizati o n, 
b ut res ults are n ot nee de d f or ra n d o mizati o n. 
S u bjects will be treate d wit h o ne of t he f oll o wi n g: 
•
Ar m A ( ni v ol u ma b/i pili m u ma b C o m b o): ni v ol u ma b  3 m g/ k g I V e ver y 2 wee ks + i pili m u ma b 
1 m g/ k g I V e ver y 6 wee ks u ntil disease pr o gressi o n, u nacce pta ble t o xi cit y, or a ma xi m u m 
treat me nt d urati o n of 2 years.
•
Ar m  B  ( C o ntr ol  Ar m):  pe metre xe d  5 0 0  m g/ m 2  pl us  cis plati n 7 5  m g/ m 2  or  car b o plati n  
( A U C of 5 m g 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 
disease pr o gressi o n or u nacce pta ble t o xicit y. T he c h o ice of cis plati n is preferre d, h o we ver t he 
us e of car b o plati n is at t h e discreti o n 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 o c u me nte d i n t he C R F. Ar m B d ose calc ulati o ns will be a d mi nistere d acc or di n g t o 
la bel a n d/ or l o cal p olic y i n t er ms of i nf usi o n sc he ma (i ncl u di n g b ut n ot li mite d t o h y drati o n 
pr ot oc ols).  Vita 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  pre me dicati o n  ar e
re q uire d f or all su bjects recei vi n g pe metre xe d. De xa met 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 b y pe metre xe d la b el a n d/ or l o c al S O C.
T he st u d y desi g n sc he matic is prese nte d i n Fi g ure 2. 1- 1 .


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
9
Fi g ure 2. 1- 1: 
St u d y Desi g n Sc he m atic
2. 2 
Tr e at m e nt A s si g n m e nt
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  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
•
se x: 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 o pe n-la bel treat me nts  Ar m A or Ar m B.
2. 3  
Bli n di n g a n d U n bli n di n g
T his is a n o pe n la bel st u d y.  After partici pa nts are ra n d o mize d, desi g nate d pers o n nel of t he S p o ns or 
will ha ve access t o ra n d o mizati o n assi g n me nt pri or t o data base loc k t o facilitate data a nal ysis. 
 
 
 
 
 


Statistical A nal ysis Pla n
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 5 
Pr ot o c ol A m e n d m e nt s
T a ble 2. 5- 1:
Pr ot oc ol A me n d me nts
D oc u me nt  
D ate of Iss ue
S u m m ar y of C h a n ges
Re vise d Pr ot oc ol 
0 2
    2 5 -A pr- 2 0 1 9
•
C ha n ge of pr o gressi o n fr ee s ur vi val fr o m  c o- pri mar y t o sec o n dar y 
e n d p oi nt a n d re m o val of hierarc hical testi n g of sec o n dar y e n d p oi nts
•
U p date of t he statistical ass u m pti o ns f or t he pri mar y a nal ysis i n li g ht 
of e mer gi n g data fr o m e xter nal st u dies
•
Clarificati o n of BI C R assesse d pr o gressi o n 
•
La n g ua ge u p date d f or vacci nes f or pr o hi bite d treat me nt
•
U p date d 
•
U p date d a d verse e ve nt defi niti o ns
•
U p date d A p pe n di x 2 
 
•
U p date d A p pe n di x 3 W o me n of C hil d Beari n g P ote ntial Defi niti o n 
a n d Met h o ds of C o ntrace pti o n




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
1 2
pr ofile f or ni v ol u ma b. T he D M C will act i n a n a d vis or y ca pacit y t o B M S a n d will m o nit or s u bject
safet y 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 bilit y f or o verall c o n d uct of t he st u d y i ncl 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 o m me n dati o ns, f or 
pr o vi di n g g ui da nce re gar di n g t he c o nti n uati o n or ter mi nati o n of t he 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.
Details of t he D M C res p o nsi bilities a n d pr oce d ures will be s pecifie d i n t he D M C c harter.
2. 7  
Bli n d e d I n d e p e n d e nt C e ntr al R e vi e w ( BI C R)
A BI C R will be e m pl o ye d f or i nt er pretati o n of ra di o gra p hic pr o gressi o n e ve nts. At t he ti me of 
i n vesti gat or- assesse d i nitial ra di o 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 i n a n y gi ve n s u bject, t he sit e m ust re q uest t he i n de pe n de nt ce ntral re vie w fr o m t he t hir d 
part y r a di ol o g y ve n d or f or c o nfir mati o n of pr o gressi o n. 
T u m or assess me nts f or eac h s u bject s h o ul d be s u b mi tte d t o t he ra di ol o g y ve n d or as t he y are per-
f or me 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 o gists will re vie w all a vaila ble t u m or 
assess me nts f or t hat gi ve n s u bject a n d deter mi n e 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 w het her or n ot t he gi ve n s u bject
met crit eria f or pr o gressi o n will be pr o vi de d t o t he s ite. S u bjects 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  treat me nt a n d t u m or 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 part y 
r a di ol o g y ve n d or f or s u bse q ue nt re vie w a n d ma y b e 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 m or i ma ges i n all ran d o mize 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 a nal ysis of O R R, t u m or 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 P F S a n d O R R. Details of t he BI C R res p o nsi bil-
ities a n d pr oce d ures will be s pecifie d i n t he BI C R c harter.
3  
O B J E C TI V E S
3. 1 
Pri m ar y O bj e cti v e s
•
T o c o m pare o verall s ur vi val ( O S) of ni v ol u ma b c o m bi ne d wit h i pili m u ma b t o pe metre xe d pl us 
cis plati n or car b o plati n re gi me n as first li ne treat me nt i n s u bjects  wit h u nresecta ble mali g na nt 
ple ural mes ot heli o ma.
3. 2 
S e c o n d ar y O bj e cti v e s
•
T o  assess t he  o bjecti ve  res p o nse  rat e  ( O R R)  as  deter mi ne d  b y  Bli n de d  I n de pe n de nt  
C o m mittee Re vie w ( BI C R), of ni v ol u ma b c o m bi ne d wit h i pili m u ma b a n d pe metre xe d pl us 




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
1 4
( usi n g a da pte d m- R E CI S T a n d/ or R E CI S T v 1. 1 criteria) di vi de d b y t he n u m ber of all ra n d o mize d
s u bjects. Best O verall Res p o nse ( B O R) is defi ne d as t he best res p o nse, as deter mi ne d  b y t he BI C R, 
rec or de d bet wee n t he dat e of r a n d o mizati o n a n d t he date of o bjecti vel y d o c u me nte d 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 v 1. 1 criteria or t he date of s u bse q ue nt t hera p y (i ncl u di n g 
t u m or- directe d ra di ot hera p y a n d t u m or- directe d s ur ger y), w hic he ver occ urs first. F or s u bjects 
wit h o ut d oc u me nte d pr o gressi o n or s u bse q ue nt t hera p y, all a vaila ble res p o nse desi g n ati o ns will 
c o ntri b ute t o t he B O R deter mi nati o n. C o nfir mati o n of res p o nse is re q uire d at least 4 wee ks aft er 
t he i nitial res p o nse.
4. 2. 2 
Ti m e t o R e s p o n s e
Ti me t o Res p o nse ( T T R) is defi ne d as t he ti me fr o m ran d o mizati o n t o t he date of t he first c o n-
fir me d d o c u me nte d res p o nse ( C R or P R), as assesse d b y t he BI C R. T T R will be e val uate d f or 
res p o n ders ( c o nfir me d C R or P R) o nl y.
4. 2. 3  
D ur ati o n of R e s p o n s e
D urati o n of Res p o nse ( D O R) is defi ne d as t he ti me bet wee n t he date of first d oc u me nte d res p o nse 
( C R or P R) t o t he date of t he first d oc u me nte d t u m or pr o gressi o n as deter mi ne d b y t he BI C R ( per 
a da pte d  m- R E CI S T a n d/ or R E CI S T v 1. 1 crit eria), or deat h d ue t o a n y ca use, w hic he ver occ urs 
first. S u bjects w h o start s u bse q ue nt t hera p y wit h o 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 nts pri or t o i nitiati o n of t he s u bse q ue nt a ntica ncer t hera p y. 
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 bjects w h o neit her pr o gress n or die, D O R will be ce ns ored o n t he date 
of t h eir last e val ua ble t u m or assess me nt. D O R  will be e val uate d f or res p o n ders (c o nfir me d C R or 
P R) o nl y.
4. 2. 4  
Di s e a s e C o ntr ol R at e ( D C R)
D C R is defi ne d as t he pr o p orti o n of all ra n d o mize d s u bjects w h ose B O R is eit her C R or P R or S D 
per a da pte d m- R E CI S T a n d/ or R E CI S T 1. 1 criteria as assesse d b y BI C R. 
4. 2. 5 
Pr o gr e s si o n- Fr e e S ur vi v al
T w o defi niti o ns are use d f or a nal ysis of Pr o gressi o n- Free S ur vi val ( P F S). T he pri mar y defi niti o n 
acc o u nts f or s u bse q ue nt t hera p y b y ce ns ori n g at t he last e val ua ble t u m or assess me nt o n or pri or t o 
t he date of s u bse q ue nt t hera p y. T he sec o n dar y defi niti o n is irres pecti ve of s u bse q ue nt t hera p y a n d 
d oes n ot acc o u nt f or s u bse q ue nt t hera p y. 
Cli nical deteri or ati o n i n t he a bse nce of u ne q ui v o cal e vi de nce of 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 v 1. 1 criteria) is n ot c o nsi dere d pr o gressi o n f or p ur p oses of deter mi ni n g P F S.
P F S rates at fi xe d ti me p oi nts T (e. g. 6 m o nt hs, de pe n di n g o n t he mi ni m u m f oll o w- u p) are defi ne d 
as t he pr o ba bilit y t hat a s u bject has n ot pr o gresse d a n d is ali ve at ti me T f oll o wi n g ra n d o mizati o n.
T he first o n-st u d y t u m or assess me nt is sc he d ule d t o be c o n d ucte d at 6 wee ks ( ± 1 wee k) f oll o wi n g 
ra n d o mizati o n. S u bse q ue nt t u m or assess me nts are sc he d ule d e ver y 6 wee ks (± 1 wee k) u p t o 
1 2  m o nt hs, t he n e ver y 1 2 wee ks u ntil disease pr o gressi o n.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
1 5
4. 2. 5. 1 
Pri m ar y D efi niti o n of Pr o gr e s si o n- Fr e e S ur vi v al ( A c c o u nti n g f or 
S u b s e q u e nt T h er a p y)
T he pri mar y defi niti o n of P F S ( P F S tr u ncate d at s u bse q ue nt t hera p y) is defi ne d as t he ti me bet wee n 
t he date of r a n d o mizati o n a n d t he date of first d oc u me nte d t u m or pr o gressi o n, base d o n BI C R 
assess me nts ( per a da pte d m- R E CI S T a n d/ or R E CI S T v 1. 1 criteria), or deat h d ue t o a n y ca use, 
w hic he ver occ urs first. Fi g ure 4. 2. 5. 1- 1: s h o w t he gra p hic dis pla y of pri mar y defi niti o n of P F S. 
S u bjects w h o die wit h o ut a re p orte d 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 h eir deat h. T he f oll o wi n g ce ns ori n g r ules will be a p plie d f or t he pri mar y defi niti o n of P F S:
•
S u bjects w h o di d n ot pr o gress or die will be ce ns ore d o n t he date 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 st u d y t u m or assess me nts a n d di d n ot die will be ce ns ore d o n 
t heir date of ra n d omizati o n.
•
S u bjects w h o recei ve s u bse q ue nt a nti-ca ncer t her a p y pri or t o d oc u me nte d pr o gressi o n will be 
ce ns ore d at t he date of t he last e val ua ble t u m or assess me nt c o n d ucte d o n or pri or t o t he date 
of i nitiati o n of t he s u bse q ue nt a nti-ca ncer t hera p y.
•
S u bjects w h o di d n ot ha ve a d oc u me nte d pr o gressi o n a n d recei ve d s u bse q ue nt a nti-ca ncer 
t hera p y will be ce ns ore d at t he date of t he last e val ua ble t u m or assess me nt c o n d ucte d o n or 
pri or t o t he i nitiati o n of t he s u bse q ue nt a nti-ca ncer t hera p y.
Ce ns ori n g r ules f or t he pri mar y defi niti o n of P F S ( P F S tr u ncate d at s u bse q ue nt t hera p y) are pre-
se nte d as f oll o ws a n d i n Ta ble 4. 2. 5. 1- 1 . 


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Fi g ure 4. 2. 5. 1- 1: 
P F S Pri m ar y Defi niti o n
T a ble 4. 2. 5. 1- 1:  
Ce ns ori n g Sc he me Use d i n Pri m ar y Defi niti o n of P F S
Sit u ati o n 
D ate of Pr o gressi o n or Ce ns ori n g  
O utc o me 
N o baseli ne t u m or assess me nts *
Date of ra n d o mizati o n
Ce ns ore d 
N o o n st u d y t u m or assess me nts a n d n o deat h *  
Date of ra n d o mizati o n
Ce ns ore d
S u bse q ue nt a nti-ca ncer t hera p y starte d wit h-
o ut deat h or pr o gressi o n per R E CI S T v 1. 1 re-
p orte d pri or or o n t he sa me da y
Date of last e val ua ble t u m or assess me nt 
pri or t o or o n t he date of i nitiati o n of t he 
s u bse q ue nt a nti-ca ncer t hera p y
Ce ns ore d 
D oc u me nte d pr o gressi o n per R E CI S T v 1. 1
a n d n o ne w a nti-ca ncer starte d bef ore
Date of t he first d oc u me nte d pr o gressi o n
per R E CI S T v 1. 1
(e xcl u des cli nical pr o gressi o n)
Pr o gresse d 
N o pr o gressi o n a n d n o deat h, a n d n o ne w a nti-
ca ncer t hera p y starte d
Date of last e val ua ble t u m or assess me nt  
Ce ns ore d 
Deat h  wit h o ut pr o gressi o n per R E CI S T v 1. 1
a n d n o ne w a nti-ca ncer starte d bef ore
Date of deat h
Pr o gresse d 
* T u m or assess me nts a n d deat h if a n y, occ urri n g after start of s u bse q ue nt a nti-ca ncer t hera p y are n ot c o nsi dere d.


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4. 2. 5. 2 
S e c o n d ar y D efi niti o n of Pr o gr e s si o n Fr e e S ur vi v al (Irr e s p e cti v e of 
S u b s e q u e nt T h er a p y)
T he sec o n dar y defi niti o n of P F S (I T T defi niti o n) is defi ne d as t he ti me bet wee n t he date of ra n-
d o mizati o n a n d t he date of first d oc u me nte d t u m or pr o gressi o n, base d o n BI C R assess me nts ( per 
a da pte d m- R E CI S T a n d/ or R E CI S T v 1. 1 crit eria), or deat h d ue t o a n y ca use, w hic he ver occ urs 
first. Fi g ure 4. 2. 5. 2- 1: s h o w t he gra p hic dis pla y of sec o n dar y defi niti o n of P F S. 
S u bjects w h o die wit h o ut a re p orte d 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 h eir deat h. T he f oll o wi n g ce ns ori n g r ules will be a p plie d f or t he sec o n dar y defi niti o n of P F S:
•
S u bjects w h o di d n ot pr o gress or die will be ce ns ore d o n t he date 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 st u d y t u m or assess me nts a n d di d n ot die will be ce ns ore d o n 
t heir date of ra n d omizati o n.
Ce ns ori n g r ules f or t he sec o n dar y defi niti o n of  P F S (I T T defi niti o n) are prese nte d as f oll o ws a n d 
i n Ta ble 4. 2. 5. 2- 1 . 
Fi g ure 4. 2. 5. 2- 1: 
P F S Sec o n d ar y Defi niti o n










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5 
S A M P L E SI Z E A N D P O W E R
T h e st u d y acc o u nts f or a pri mar y e n d p oi nt: O S. O verall t w o-si d e d al p ha (t y pe I err or rate) is set at 
0. 0 5 f or e val uati n g O S. A p pr o xi matel y 6 0 0 patie nts were t o be ra n d o mize d wit h 1: 1 r ati o t o t w o 
treat me nt ar ms wit h 6 0 6 s u bjects 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 par e O S bet wee n ni v ol u ma b c o m bi ne d wit h i pili-
m u ma b ( Ar m A) a n d pe metre xe d pl us cis plati n or car b o plati n re gi me n ( A r m B). O ne f or mal i n-
teri m a nal ysis is pla n ne d f or O S at 4 0 3  O S e ve nts. T a ble 5- 1 s u m marizes t he ke y para meters of 
trial desi g n.
O verall s ur vi val: T he ke y desi g n para meters are s h o w n i n Ta ble 5- 1,  w here O S e n d p oi nt will uti-
lize 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 o n wit h O’ Brie n-
Fle mi n g b o u n daries. Gi ve n accr ual r ate of 3 4 patie nts per m o nt h,  it is esti mate d t hat it will t a k e 
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 nt eri m/fi nal O S 
a nal ysis.
A n e x p o ne ntial distri b uti o n is ass u me d f or t h e O S ti me of c o ntr ol Ar m B wit h a me dia n O S ti me 
of 1 6  m o nt hs a n d hazar d r at e 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  i m m u n o-t hera pies,  a  piece wise  e x p o ne ntial  m o dels  is  ass u me d  f or  t he  s ur vi val  t i me  o n  
ni v ol 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 ntial wit h hazar d rates of 0. 0 4 3, 
0. 0 3 3, a n d 0. 0 0 0 1 i n t he f oll o wi n g p ost first d ose ti me wi n d o ws: first 6- m o nt h, 6  m o nt h t o 3 4 
m o nt h, a n d after 3 4 m o nt h, 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 ntial distri b uti o n of O S fr o m 6  m o nt h t o 3 4 m o nt h, a n d a l o n g t er m s ur vi val rate platea u starti n g 
a p pr o xi matel y at 3 4 m o nt h. Si m ulati o n e val uati o n of trial d esi g n s h o w t hat t he a b o ve piece wise 


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e x p o ne ntial distri b uti o n will pr o d uce a 9 0 % p o wer i n l o g-ra n k test. T he n u merical val ue of t y p e 
o ne err or rate i n s i m ulati o n is 0. 0 5. 
T he a b o ve sa m ple size calc ulati o n was base d o n a si m ulati o n 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 li ke dela ye d se para ti o n a n d l o n g ter m be nefit usi n g E A S T 6.
T a ble 5- 1: 
S u m m ar y of Ke y Desi g n P ar a meters
Pri m ar y E n d p oi nts
O S
Tar gete d P o wer
9 0 %
Al p ha 
0. 0 5 2-si de d ( 0. 0 3 at I A; 0. 0 4 1 at F A)
Sa m ple Size 
6 0 6
E x pecte d n u m ber of e ve nts f or I A ( perce nta ge of tar get e ve nt) 
4 0 3 ( 8 5 %)
Tar get n u m ber of e ve nts
4 7 3
D urati o n ( m o nt hl y accr ual rate = 3 4 patie nts)
5 6  m o nt hs 
6 
S T U D Y P E RI O D S, T R E A T M E N T R E GI M E N S A N D P O P U L A TI O N S F O R 
A N A L Y S E S
6. 1 
St u d y P eri o d s
•
Baseli ne peri o d:
−
Baseli ne e val uati o ns or e ve nts will be defi ne d as e val uati o ns or e ve nts t hat occ ur bef ore 
t he date a n d ti me of t he first d ose of st u d y treat me nt. E val uati o ns (la b orat or y t ests, ) o n t he 
sa me date a n d ti me of t he first d ose of st u d y treat me nt will be c o nsi dere d as baseli ne 
e val uati o ns. E ve nts ( A Es) o n t he sa me date a n d ti me of t he first d ose of st u d y treat me nt 
will n ot be c o nsi dere d as pre-tr eat me nt e ve nts.
−
I n cases w here t he ti me ( o nset ti me of e ve nt or e val uati o n ti me a n d d osi n g ti me) is missi n g 
or n ot c ollecte d, t he f oll o wi n g defi niti o ns will a p pl y:
♦
Pre-treat me nt A Es will be defi ne d as A Es  wit h a n o nset date pri or t o b ut n ot i ncl u di n g 
t he da y of t he first d ose of st u d y treat me nt;
♦
Baseli ne e val uati o ns (la b orat or y tests)  w ill be defi ne d as e val uati o ns wit h a date o n or 
pri or t o t he da y of first d ose of st u d y treat me nt.
−
If t here are m ulti ple vali d assess me nts o n or pri or t o t he first d ose of st u d y treat me nt:
♦
F or la b orat or y t ests, t he latest n o n missi n g la bs val ue o n or bef ore first d ose date (a n d 
ti me  if c ollecte d)  will be  use d as t he baseli ne  i n t he  a nal yses. F or  ' LI P A S E'  a n d  
' G L U C O S E', f or treate d s u bjects o nl y, t he last pre d ose assess me nt wit h n o n- missi n g 
t o xicit y gra de will be c o nsi dere d as baseli ne. If m ulti ple assess me nts e xist wit h t h e 
sa me c ollecti o n date (an d ti me if c ollecte d) a n d e ntr y d ate a n d ti me, t he n  t he first 
o bser vati o n is use d as baseli ne.
♦
F or 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 ( P S), t he lat est 
E C O G P S val ue pri or t o or o n t he first d ose date (a n d ti me if c ollecte d) will be use d as 


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t he baseli ne i n t he a nal yses. If m ulti ple rec or ds fall o n t he last date t he n t he rec or d wit h 
t he hi g hest val ue of E C O G P S will be c o nsi dere d as baseli ne.
♦
F or P D- L 1, a m o n g t he rec or ds pri or t o or o n first d ose date (a n d ti me if c ollecte d), 
i de ntif y first t h ose wit h q ua ntifia ble test res ult. If t here are n o rec or ds wit h q ua ntifia ble 
test res ult, t he n select t h ose wit h i n deter mi na nt res ult (“I N D E T E R MI N A T E”). If t here 
are n o rec or ds wit h i n deter mi na nt test res ult , t he n select t h ose wit h u na vaila ble res ult 
(“ N O T E V A L U A B L E). If t here are n o rec or ds wit h u na vaila ble test res ult, t he n select 
t h ose wit h n ot re p orte d or n ot a vaila ble res ult (all ot her rec or ds). T he lat est rec or d will 
be use d as t he baseli ne i n t he a nal yses. If t here is m ore t ha n o ne rec or d f or t he lat est 
date, t he n c h o ose t he o ne wit h t he greatest s peci me n I D.
♦
F or A nti- Dr u g A nti b o d y ( A D A), t he rec or d relate d t o t he m ost rece nt assess me nt 
a m o n g  t h ose  rec or ds  w here  date  (a n d  ti me  if  c ollecte d) of ni v ol u ma b/i pili m u ma b
i m m u n o gl o b uli n  (I M G)  assess me nt  is  less  t ha n  or  e q ual  t o  t he  date  (a n d  ti me  if  
c ollecte d) of t he first ni v ol u ma b/i pili m u ma b d ose date.
•
P ost baseli ne peri o d:
−
O n-treat me nt A Es will be defi ne d as A Es  wit h a n o nset date a n d ti me o n or after t he date 
a n d ti me of t he first d ose of st u d y tr e at me nt ( or wit h a n o nset date o n or after t he da y of 
first d ose of st u d y treat me nt if ti me is n ot c ollecte d or is missi n g). F or s u bjects w h o are off 
st u d y treat me nt, A Es  will be i ncl u de d if e ve nt occ urre d wit hi n a safet y wi n d o w of 1 0 0 da ys 
aft er t he last d ose of st u d y treat me nt.  N o “s u btracti n g r ule” will be a p plie d w he n a n A E 
occ urs b ot h pre-treat me nt a n d p ost-treat me nt wit h t he sa me preferre d ter m a n d gra de.
−
O n-tr e at me nt e val u ati o ns (la b orat or y t ests) will be defi ne d as e val uati o ns ta ke n aft er t he 
d a y ( a n d ti me, if c ollecte d a n d n ot missi n g) of first d ose of st u d y tr e at me nt. F or s u b jects 
w h o are off st u d y tr eat me nt, e val uati o ns s h o ul d be wit hi n a safet y wi n d o w of 1 0 0 da ys
after t he last d ose of st u d y treat me nt.
−
Late- e mer ge nt dr u g-relate d A Es w ill be defi ne d as dr u g-relate d A Es wit h a n o nset date 
greater t ha n 1 0 0 da ys aft er t he last d ose of st u d y treat me nt i n s u bjects w h o are off st u d y 
treat me nt.
6. 2 
Tr e at m e nt R e gi m e n s
Treat me nt gr o u p “as ra n d o mize d” c orres p o n ds t o t he treat me nt gr o u p assi g ne d b y t he I nteracti ve 
Res p o nse Tec h n ol o g y (I R T) s yste m.
•
Ar m A:  ni v ol u ma b 3 m g/ k g I V e ver y 2 wee ks + i pili m u ma b 1 m g/ k g I V e ver y 6 wee ks
•
Ar m B:  pe metre xe d 5 0 0 m g/ m 2 pl us cis plati n 7 5 m g/ m 2 or car b o plati n ( A U C of 5 m g per 
milliliter per mi n ute), o n da y 1 of a 2 1- d a ys c ycle f or 6 c ycles
T he treat me nt gr o u p “as tr eate d” will be sa me as t he treat me nt gr o u p “as ra n d o mize d” b y I R T 
u nless a s u bject recei ve d t he i nc orrect st u d y tr e at me nt f or t he e ntire peri o d of treat me nt, i n w hic h 
case t he s u bject’s treat me nt gr o u p “as treate d” will be defi ne d as t he i nc orrect st u d y treat me nt.
U nless ot her wise s pecifie d, t he safet y a nal ysis will be base d o n t he treat me nt gr o u p “as treate d”.




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7. 1. 1  
A d v er s e E v e nt s, S eri o u s A d v er s e E v e nt s, M ulti pl e E v e nt s, S el e ct 
A d v er s e E v e nt s, Ot h er E v e nt s of S p e ci al I nt er e st a n d I m m u n e- M e di at e d 
A d v er s e E v e nt s
Dr u g-relate d A Es are t h ose e ve nts wit h relati o n s hi p t o st u d y dr u g “ Relate d”, as rec or de d o n t he 
C R F. If t he relati o ns hi p t o st u d y dr u g is missi n g, t he A E will be c o nsi dere d as dr u g-r elate d. 
S eri o us a d verse e ve nts c o nsist of A Es dee me d seri o us b y t he I n vesti gat or a n d fla g ge d acc or di n gl y 
i n t he C R F a n d cli nical data base.
A d verse e ve nts le a di n g t o st u d y dr u g disc o nti n uati o n are A Es wit h acti o n ta ke n re gar di n g st u d y 
dr u g(s) = “ Dr u g was disc o nti n ue d”. 
A d verse e ve nts lea di n g t o d ose dela y are A Es wit h a cti o n ta ke n re gar di n g st u d y dr u g(s) = “ Dr u g
was dela ye d”.
A d verse e ve nts lea di n g t o d ose re d ucti o n are A E s wit h acti o n ta ke n re gar di n g st u d y dr u g(s) = 
“ D ose was re d uce d”.
A d verse e ve nts  will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), 
a n d t he m ost rece nt versi o n of t he dicti o nar y at t he ti me of t he data base l oc k will be use d. A d verse 
e ve nts res ults will be gra de d f or se verit y us i n g N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E) a n d t he m ost rece nt versi o n of t he crit eria at t h e ti me of t he data base l o c k will 
be use d.
I n t he A E s u m mar y ta bles, u nless ot her wise s pecifie d, su bjects will be c o u nte d o nl y o nce at t he 
Preferre d Ter m ( P T), o nl y o nce at t he S yst e m Or ga n Class ( S O C), a n d o nl y o nce at s u bject le vel 
f or t he c o u nti n g of t otal n u m ber of s u bjects wit h a n A E. T he A E ta bles will be s orte d b y t he S O Cs 
a n d t he n P Ts. S O C will be or dere d b y desce n di n g fre q ue nc y o verall a n d t he n al p ha beticall y. P Ts 
will be or dere d wit hi n S O C b y desce n di n g fre q ue nc y o verall a n d t he n al p ha beticall y. T he s orti n g 
will be d o ne base d o n t he ‘ A n y Gra de’ c ol u m n of t h e e x peri me ntal ar m w he n ar ms are prese nte d 
si d e- b y-si de.
U nless ot her wise s pecifie d, t he A E s u m mar y ta bles w ill be restricte d t o o n-treat me nt e ve nts re-
gar dless of t he ca usalit y.
A nal yses t hat ta ke i nt o acc o u nt t he m ulti ple o cc urre nces of a gi ve n a d verse e ve nt will be c o n d ucte d 
(see Secti o n 7. 6. 9 ). T o pre pare t hese a nal yses, t he C R F data will be pr ocesse d acc or di n g t o sta n d-
ar d B M S al g orit h ms 9 i n or der t o c olla pse a d verse e ve nt rec or ds i nt o u ni q ue rec or ds base d o n t he 
preferre d t er m. T hes e data will be prese nte d as t he r ate per 1 0 0 pers o n- years of e x p os ure. T hese 
a nal yses will t a ke i nt o acc o u nt all o n-tr eat me nt e ve nts (all o wi n g m ore t ha n 1 e ve nt per s u bject) 
a n d t he t otal e x p os ure ti me. T he pers o n- year e x p os ure will be c o m p ute d as t he s u m o ver t he s u b-
jects’ e x p os ure e x presse d i n years w here t he e x p os ure ti me is defi ne d as 
•
( Date of last d ose of st u d y treat me nt - date of first d ose of st u d y tr eat me nt + 1 0 1 da ys )/ 3 6 5. 2 5, 
f or s u bject w h o are off st u d y treat me nt a n d were f oll o we d f or at least 3 0 da ys ( or 1 0 0 da ys, 
de pe n di n g o n t he a nal ysis) after last d ose of st u d y treat me nt.


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•
( Last k n o w n ali ve date - date of first d ose of st u d y treat me nt + 1)/ 3 6 5. 2 5, f or s u bjects w h o are 
still o n-treat me nt or w h o are off st u d y tr eat me nt a n d were f oll o we d less t ha n 1 0 0 da ys aft er 
last d ose of st u d y treat me nt.
7. 1. 1. 1 
S el e ct A d v er s e E v e nt s ( E U S u b mi s si o n)
T he select A d verse E ve nts (select A Es) c o nsist of a list of preferre d ter ms gr o u pe d b y s pecific 
cate g or y (e. g. p ul m o nar y e ve nts, gastr oi ntesti nal e ve nts cate g ories, etc.). A Es t hat ma y differ fr o m 
or be m ore se vere t ha n A Es ca use d b y n o n-i m m u n ot hera pies a n d A Es w h ose earl y rec o g niti o n a n d 
ma na ge me nt ma y miti gate se vere t o xicit y are i ncl u de d as select A Es. Cate g ories of sele ct A Es 
ma y i ncl u de s u bcate g ories (e. g. a dre nal dis or ders, dia betes, pit uitar y dis or ders, a n d t h yr oi d dis or-
ders are s u bcate g ories of t he e n d ocri ne e ve nt cate g or y).
T he list of Me d D R A pr eferre d t er ms use d t o i de n tif y select a d verse e ve nts is re visite d q uarterl y 
a n d u p date d acc or di n gl y. T he preferre d t er ms use d  f or t he selecti o n at t he ti me of t he data base 
l o c k will be pr o vi de d b y cate g ories/s u bcate g ories.
I n a d diti o n t o t he fre q ue nc y a n d w orst se verit y of select A Es, ti me-t o o nset, ti me-t o res ol uti o n,
a n d ti me-t o res ol uti o n w here i m m u ne m o d ulati n g me d icati o n was i nitiate d will be a nal yze d f or 
eac h s pecific cate g or y/s u bcate g or y of dr u g-rel ate d select A Es w he n a p plica ble.
F urt her details o n t he defi niti o ns of select a d verse e ve nt, ti me-t o o nset a n d ti me-t o r es ol uti o n ar e 
descri be d i n A P P E N DI X 1 .
7. 1. 1. 2  
Ot h er E v e nt s of S p e ci al I nt er e st
Ot her e ve nts of s pecial i nt erest ( O E O SI) c o nsist of a list of pr eferre d t er ms gr o u pe d b y s pecific 
cate g or y. T he list of Me d D R A pr eferre d t er ms us e d  t o i de ntif y  O E O SI is re visite d q uarterl y a n d 
u p date d acc or di n gl y. T he preferre d ter ms use d f or t he selecti o n at t he ti me of t he data base l oc k b y 
cate g ories will be pr o vi de d.
7. 1. 1. 3 
I m m u n e- M e di at e d A d v er s e E v e nt s ( U S S u b mi s si o n)
I n or der t o f urt her c haracterize A Es of s pecial cli nical i nterest, a nal ysis of i m m u ne- me diate d A Es 
(I M A E) will be c o n d ucte d. I M A Es are s pecific e ve nts ( or gr o u ps of P Ts descri bi n g s pecific e ve nts)
t hat i ncl u de p ne u m o nitis, diarr hea/c olitis, he patitis, ne p hritis/re nal d ysf u ncti o n, ras h, e n d ocri ne 
(a dre nal i ns ufficie nc y, h y p ot h yr oi dis m/t h yr oi ditis, h y pert h yr oi dis m, dia betes mellit us, a n d h y-
p o p h ysitis), a n d ot her s pecific e ve nts, c o nsi dere d as p ote ntial i m m u ne- me diate d e ve nts b y i n ves-
ti gat or t hat  meet t he defi niti o n s u m marize d bel o w: 
•
t h ose occ urri n g wit hi n 1 0 0 da ys of t he last d ose, 
•
re gar dless of ca usalit y,
•
treate d  wit h  i m m u ne- m o d ulatin g  me dicati o n  ( of  n ote,  e n d ocri ne  A Es s uc h  as  a dre nal  
i ns ufficie nc y,
 h y p ot h yr oi dis m/t h yr oi ditis,
 h y pert h yr oi dis m,
 dia betes
 mellit us,
 a n d
 
h y p o p h ysitis are c o nsi dere d I M A Es re gar dless of  i m m u ne- m o d ulati n g me dicati o n use, si nce 
e n d ocri ne dr u g reacti o ns are ofte n ma na ge d wit h o ut i m m u ne- m o d ulati n g me dicati o n).


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
2 8
•
wit h n o clear alt er n ate eti ol o g y base d o n i n vesti gat or assess me nt, or wit h a n i m m u ne- me d iate d 
c o m p o ne nt 
T he list of Me d D R A preferre d t er ms use d t o i de ntif y I M A Es is re visite d q uarterl y a n d u p date d 
acc or di n gl y. T he preferre d ter ms use d f or t he selecti o n at t he ti me of t he data base l oc k b y cate g o-
ries will be pr o vi de d.
7. 1. 2 
L a b or at or y T e st s
Cli nical la b orat or y para meters ( he mat ol o g y, ser u m c h e mistr y a n d electr ol ytes) will be e val uate d.
La b orat or y tests will be gra de d usi n g t he N CI C o m m o n Ter mi n ol o g y Crit eria, a n d t he m ost rece nt 
versi o n of t he crit eria at t he ti me of t he data base l oc k will be use d.
Cli nical la b orat or y data w ill be first a nal yze d usi n g I nter nati o nal S yst e m of U nits ( SI). A nal yses 
will be re peate d usi n g U S c o n ve nti o nal u nits.
I n t he la b orat or y s u m mar y ta bles, u nless ot her wise s pecifie d, s u bjects will be co u nte d o nl y o nce 
f or eac h la b para meter acc or di n g t o t heir w orst o n treat me nt C T C gra de ( w orst bei n g t he hi g hest 
C T C gra de). T he la b orat or y ta bles a n d listi n gs will be s orte d b y la b orat or y c ate g or y, la b orat or y 
s u bcate g or y a n d la b orat or y test c o de se q ue nce n u m ber.
7. 2 
St u d y C o n d u ct
T he f oll o wi n g pr o gra m ma ble de viati o ns will be c o nsi dere d as r ele va nt pr ot oc ol de viati o ns. 
Eli gi bilit y:
•
S u bjects wit h o ut meas ura ble disease at baseli ne as per i n vesti gat or
•
S u bjects wit h baseli ne E C O G P S > 1
•
S u bjects w h o recei ve d pri or tr eat 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
•
S u bjects w h o recei ve d pri or c he m o t hera p y f or ple ural  mes ot heli o ma
O n-st u d y:
•
S u bjects recei vi n g a nti- ca ncer t hera p y (c he m ot h er a p y, h or m o nal t hera p y,  i m m u n ot hera p y,  
sta n dar d  or  i n vesti gati o nal a ge nts  f or  treat me nt  of ple ural mes ot heli o ma)  w hile  o n  st u d y  
t hera p y


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
2 9
•
S u bjects treate d differe ntl y t ha n as ra n d o mize d (s u bjects w h o recei ve d t he wr o n g tr eat me nt f or 
t he e ntire treat me nt peri o d, e xcl u di n g t he ne ver treate d)
T he Rele va nt Pr ot oc ol De viati o ns will be s u m marize d a n d liste d base d o n all ra n d o mize d s u bjects, 
b y treat me nt gr o u p a n d o verall. 
E nr oll me nt b y c o u ntr y a n d sit e, a n d e nr oll me nt b y m o nt h w ill be s u m marize d a n d liste d f or all 
e nr olle d s u bjects.
A b y-s u bject listi n g of batc h n u m bers f or all treate d s u bjects will be pr o vi de d.
7. 3 
St u d y P o p ul ati o n
A nal yses i n t his secti o n will be ta b ulate d f or all ran d o mize d s u bjects b y tr eat me nt gr o u p as ra n-
d o mize d, u nless ot her wise s pecifie d.
7. 3. 1 
S u bj e ct Di s p o siti o n
T he t otal n u m ber of s u bjects e nr olle d (ra n d o mize d or n ot ra n d o mize d) w ill be prese nte d al o n g 
wit h t he reas o n f or n ot bei n g ra n d o mize d. T his a nal ysis will be perf or me d o n t he all e nr olle d s u b-
jects p o p ulati o n o nl y.
N u m ber of s u bjects ra n d o mize d b ut n ot treat e d al o n g wit h t he reas o n f or n ot bei n g treate d w ill be 
ta b ulate d b y treat me nt gr o u p as ra n d o mize d.
N u m ber of s u bjects w h o disc o nti n ue d st u d y treat me nt al o n g wit h c orres p o n di n g reas o n will be 
ta b ulate d b y treat me nt gr o u p as treate d. Reas o n f or disc o nti n uati o n will be deri ve d fr o m s u bject 
stat us C R F pa ge. T his a nal ysis will be perf or me d o nl y o n t he all treate d s u bjects p o p ulati o n.
A b y-s u bject listi n g f or all tr eate d s u bjects will be pr o vi de d s h o wi n g t he s u bject’s off tre at me nt 
date a n d w het her t he s u bject c o nti n ue i n t he treat me nt peri o d/st u d y al o n g wit h t he reas o n f or g oi n g 
off tr e at me nt peri o d/st u d y. A b y-s u bject listi n g f or all enr olle d s u bjects will als o be pr o vi de d, 
s h o wi n g w het her t he s u bject was ra n d o mize d/treate d al o n g wit h t he reas o n f or n ot bei n g ra n d o m-
ize d/treate d.
7. 3. 2  
D e m o gr a p hi c s a n d Ot h er B a s eli n e Di s e a s e C h ar a ct eri sti c s
T he f oll o wi n g d e m o gra p hic a n d baseli ne disease c h aracteristics will be s u m marize d a n d liste d b y 
treat me nt gr o u p as ra n d o mize d:
•
A ge (c o nti n u o us)
•
A ge cate g orizati o n ( < 6 5, ≥6 5 a n d < 7 5, ≥7 5 a n d < 8 5, ≥8 5, ≥7 5, ≥6 5)
•
Se x ( Male vs. Fe male)
•
Race ( W hite, Blac k or Africa n A merica n, Asia n, Ot her)
•
Et h nicit y ( His pa nic/ Lati n o a n d N ot His pa nic/ Lati n o)
•
C o u ntr y b y ge o gra p hic re gi o n
•
Baseli ne E C O G perf or ma nce stat us


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 0
•
T o bacc o use ( Ne ver, F or mer, C urre nt, U n k n o w n)
•
Disease sta ge at st u d y e ntr y ( Sta ge I, Sta ge II, Sta ge III, Sta ge I V)
•
Ti me fr o m i nitial disease dia g n osis t o ra n d o mizati o n ( < 1 year, ≥1 year)
•
Baseli ne hist ol o g y cell t y pe ( E p it heli oi d, Mi xe d, Sarc o mat oi d, Ot her)
•
Sit es of diseases (all lesi o ns)
•
N u m ber of disease sites per s u bject (all lesi o ns)
•
N u m ber of tar get lesi o ns, n o n-tar get lesi o n s a n d disease sites at baseli ne as per BI C R
•
T u m or b ur de n: s u m of t he dia meters of tar get lesi o ns at baseli ne
•
Re gi o n ( N ort h A merica, E U, Asia, Rest of W orl d)
S u m mar y t a ble (cr oss-ta b ulati o n) b y treat me nt gr o u p f or stratificati o n fact or  w ill be pr o vi de d t o 
s h o w a n y discre pa ncies bet wee n w hat was rep orte d t hr o u g h I R T vs. C R F at baseli ne. T his s u m-
mar y will b e p erf or me d base d o n all ra n d o mize d s u bjects.
7. 3. 3  
M e di c al Hi st or y
A b y-s u bject listi n g of ge neral me dical hist or y f or all ra n d o mize d s u bjects will be pr o vi de d.
7. 3. 4 
Pri or T h er a p y A g e nt s
Pri or ca ncer t hera p y will be s u m marize d b y treat me nt gr o u p a n d o verall. Pri or s yste mic ca ncer 
t hera p y will be s u m marize d b y tre at me nt gr o u p a n d o verall a n d liste d b y s u b ject. Pri or ra di ot her-
a p y a n d pri or s ur ger y r elate d t o ca ncer will be liste d b y s u bject.
7. 3. 5 
P h y si c al E x a mi n ati o n s
S u bjects wit h a b n or mal baseli ne p h ysical e xa mi nati o n will be liste d b y s u bject.
7. 3. 6  
B a s eli n e P h y si c al M e a s ur e m e nt s
Baseli ne p h ysical meas ure me nts will be liste d b y s u bject.
7. 3. 7  
Di s cr e p a n ci e s b et w e e n I V R S a n d C R F Str atifi c ati o n F a ct or s
S u m mar y t a bles (cr oss-ta b ulati o ns) b y treat me nt gr o u p f or eac h stratificati o n fact or w ill be pr o-
vi de d t o s h o w a n y discre pa ncies bet wee n w hat was re p orte d t hr o u g h I V R S vs. C R F data ( base-
li ne).
7. 4 
E xt e nt of E x p o s ur e
Listi n gs will i ncl u de all a vaila ble e x p os ure data. A nal yses will be pe rf or me d b y treat me nt gr o u p 
“as treate d” i n all treate d s u bjects, u nless ot her wise s pecifie d.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 1
7. 4. 1  
A d mi ni str ati o n of St u d y T h er a p y 
T he f oll o wi n g para meters will be s u m marize d ( descri pti ve statistics) b y treat me nt gr o u p:
•
N u m ber of d oses recei ve d
•
C u m ulati ve d ose
•
Relati ve d ose i nt e nsit y ( %) usi n g t he f oll o wi n g cate g ories: < 5 0 %; 5 0 - < 7 0 %; 7 0 - < 9 0 %; 
9 0 - < 1 1 0 %; ≥1 1 0 %
D urati o n of st u d y t hera p y will be s u m marize d ( descri pti ve statistics) b y treat me nt gr o u p. 
A b y-s u bject listi n g of d osi n g of st u d y me dicati o n (rec or d of st u d y me dicati o n, i nf usi o n details,
a n d d ose c ha n ges) will be als o pr o vi de d. 
T a ble 7. 4. 1- 1: 
St u d y T her a p y P ar a meter Defi niti o ns-  Ni v ol u m a b a n d I pili m u m a b 
Ni v ol u m a b
 I pili m u m a b
D osi n g sc he d ule per pr ot oc ol 
3 m g/ k g e ver y 2 wee ks
1 m g/ k g e ver y 6  wee ks
D ose
D ose ( m g/k g) is defi ne d as T otal 
D ose a d mi nistere d ( m g)/ M ost re-
ce nt wei g ht ( k g). D ose a d mi nis-
tere d i n m g at eac h d osi n g date a n d 
wei g ht are c ollecte d o n t he C R F.
D ose ( m g/k g) is defi ne d as T otal 
D ose a d mi nistere d ( m g)/ M ost re-
ce nt wei g ht ( k g). D ose a d mi nis-
tere d i n m g at eac h d osi n g date a n d 
wei g ht are c ollecte d o n t he C R F.
C u m ulati ve D ose
C u m d ose ( m g/k g) is s u m of t he 
d oses ( m g/ k g) a d mi nistere d t o a 
s u bject.
C u m d ose ( m g/k g) is s u m of t he 
d oses ( m g/ k g) a d mi nistere d t o a 
s u bject.
Relati ve d ose i nte nsit y ( %)
C u m d ose ( m g/ k g)/[( Last 
Ni v ol u ma b d ose date -  Ni v ol u ma b 
start d ose date + 1 4) x 3/ 1 4] x 1 0 0
C u m d ose ( m g/ k g)/[( Last 
Ni v ol u ma b d ose date -  Ni v ol u ma b 
start d ose date + 4 2) x 1/ 4 2] x 1 0 0
D urati o n of treat me nt ( o verall)
Last Ni v ol u ma b d ose date -
Ni v ol u ma b start d ose date + 1
Last I pili m u ma b d ose date - I pili-
m u ma b start d ose date + 1
T a ble 7. 4. 1- 2: 
St u d y T her a p y P ar a meter Defi niti o ns- Pe metre xe d/ Cis pl ati n
Pe metre xe d
Cis pl ati n
D osi n g sc he d ule per pr ot oc ol
5 0 0 m g/ m² e ver y 3 wee ks 
7 5 m g/ m² e ver y 3 wee ks 
D ose
D ose ( m g/ m²) is defi ne d as T otal 
D ose a d mi nistere d ( m g)/ M ost rece nt 
B S A. D ose a d mi nistere d i n m g at 
eac h d osi n g date is c ollecte d o n t he 
C R F a n d B S A is deri ve d fr o m m ost 
rece nt wei g ht a n d baseli ne hei g ht 
als o c ollecte d o n t he C R F.
D ose ( m g/ m²) is defi ne d as T ot al 
D ose a d mi nistere d ( m g)/ M ost re-
ce nt B S A. D ose a d mi nistere d i n m g 
at eac h d osi n g date is c ollecte d o n 
t he C R F a n d B S A is deri ve d fr o m 
m ost rece nt wei g ht a n d baseli ne 
hei g ht als o c ollecte d o n t he C R F.
C u m ulati ve D ose
C u m d ose ( m g/ m²) is s u m of t he 
d oses ( m g/ m²) a d mi nistere d t o a 
s u bject.
C u m d ose ( m g/ m²) is s u m of t he 
d oses ( m g/ m²) a d mi nistere d t o a 
s u bject.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 2
T a ble 7. 4. 1- 2: 
St u d y T her a p y P ar a meter Defi niti o ns- Pe metre xe d/ Cis pl ati n
Pe metre xe d
Cis pl ati n
Relati ve d ose i nte nsit y ( %)
C u m d ose ( m g/ m²)/[( Last 
Pe metre xe d d ose date - Pe metre xe d
Start d ose date + 2 1) x 5 0 0/ 2 1] x 
1 0 0
C u m d ose ( m g/ m²)/[( Last Cis plati n
d ose date - Cis plati n Start d ose date 
+ 2 1) x 7 5/ 2 1] x 1 0 0
D urati o n of treat me nt ( o verall)
Last d ose date - Start d ose date + 1
(start d ose date of t he c o m bi nati o n 
is t he first date bet wee n t he first 
d ose dates of t he t w o dr u gs of t he 
c o m bi nati o n a n d last d ose date of 
t he c o m bi nati o n is t he last date be-
t wee n t he last d ose dates of t he t w o 
dr u gs of t he c o m bi nati o n)
Last d ose date - Start d ose date + 1
T a ble 7. 4. 1- 3: 
St u d y T her a p y P ar a meter Defi niti o ns- Pe metre xe d/ C ar b o pl ati n  
Pe metre xe d
C ar b o pl ati n
D osi n g sc he d ule per pr ot oc ol 
5 0 0 m g/ m² e ver y 3 wee ks
A U C 5 o n da y 1 of e ver y 3 wee k 
c ycle
D ose
D ose ( m g/ m²) is defi ne d as T otal 
D ose a d mi nistere d i n m g at eac h 
d osi n g date is c ollecte d o n t he C R F 
a n d B S A is deri ve d fr o m m ost re-
ce nt wei g ht a n d baseli ne hei g ht als o 
c ollecte d o n t he C R F.
D ose ( A U C) is defi ne d as T otal 
D ose a d mi nistere d ( m g)/(creati ni ne 
cleara nce + 2 5). D ose a d mi nistere d 
i n m g at eac h d osi n g date is c ol-
lecte d o n t he C R F a n d creati ni ne 
cleara nce deri ve d fr o m t he C R F 
data.
C u m ulati ve D ose
C u m d ose ( m g/ m²) is s u m of t he 
d oses ( m g/ m²) a d mi nistere d t o a 
s u bject.
C u m d ose ( A U C) is s u m of t he 
d oses ( A U C) a d mi nistere d t o a s u b-
ject.
Relati ve d ose i nte nsit y ( %)
C u m d ose ( m g/ m²)/[( Last
Pe metre xe d d ose date - Pe metre xe d 
Start d ose date + 2 1) x 5 0 0/ 2 1] x 
1 0 0
C u m d ose ( A U C)/[( Last d ose date 
of Car b o - Start d ose date of Car b o
+ 2 1) x 5/ 2 1] x 1 0 0
D urati o n of treat me nt ( o verall) 
Last d ose date - Start d ose date + 1
(start d ose date of t he c o m bi nati o n 
is t he first date bet wee n t he first 
d ose dates of t he t w o dr u gs of t he 
c o m bi nati o n a n d last d ose date of 
t he c o m bi nati o n is t he last date be-
t wee n t he last d ose dates of t he t w o 
dr u gs of t he c o m bi nati o n)
Last d ose date - Start d ose date + 1
D urati o n of treat me nt ( mai nte-
na nce)
Last Pe metre xe d  mai nte na nce d ose 
date- first Pe metre xe d  mai nte na nce 
d ose date + 1


Statistical A nal ysis Pla n
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
T a ble 7. 4. 1- 3: 
St u d y T her a p y P ar a meter Defi niti o ns- Pe metre xe d/ C ar b o pl ati n  
Pe metre xe d
C ar b o pl ati n
C u m ulati ve d ose ( mai nte na nce) 
C u m d ose ( m g/ m²) is s u m of t h e 
d oses ( m g/ m²) a d mi nistere d t o a 
s u bject i n t he mai nte na nce p hase.
7. 4. 2  
M o difi c ati o n s of St u d y T h er a p y
7. 4. 2. 1  
D o s e D el a y s
Eac h ni v ol u ma b a n d i pili m u ma b i nf usi o n ma y be d ela ye d. A d ose w ill be c o nsi dere d as act uall y 
d ela ye d if t he dela y is e xcee di n g 3 da ys (i.e. greater t ha n or e q ual t o 4 da ys fr o m sc he d ule d d osi n g 
date) f or ni v ol u ma b a n d i pili m u ma b. All st u d y dr u gs m ust be dela ye d u ntil treat me nt ca n res u me. 
Reas o n f or d ose dela y will be r etrie ve d fr o m C R F d osi n g pa ges.
T he f oll o wi n g para meters will be s u m marize d b y treat me nt gr o u p:
•
N u m ber of s u bjects wit h at least o ne d ose dela ye d, t he n u m ber of d ose dela ys per s u bject, t he 
reas o n f or d ose dela y a n d t he le n gt h of d ose d ela y.
7. 4. 2. 2 
I nf u si o n I nt err u pti o n s a n d R at e C h a n g e s
Eac h ni v ol u ma b or i pili m u ma b i nf usi o n ca n be i nt e rr u pte d a n d/ or t he I V i nf usi o n rate ca n be re-
d uce d. T his i nf or mati o n will be retrie ve d fr o m C R F d osi n g pa ges.
T he f oll o wi n g para meters will be s u m marize d b y treat me nt gr o u p:
•
N u m ber of s u bjects wit h at least o ne d ose i nf usi o n i nt e rr u pti o n, t he reas o n f or i nt err u pti o n, 
a n d t he n u m ber of i nf usi o n i nterr u pti o ns per s u bject.
•
N u m ber of s u bjects wit h at le ast o ne I V i nf usi o n r ate re d ucti o n, t he reas o n f or re d ucti o n a n d 
t he n u m ber of i nf usi o n wit h I V rate re d ucti o n per s u bject.
7. 4. 2. 3  
D o s e E s c al ati o n s
D ose escalati o ns ( wit hi n s u bject) are n ot per mitte d f or eit her ni v ol u ma b or i pili m u ma b.
7. 4. 2. 4  
D o s e R e d u cti o n s
D ose re d ucti o ns ( wit hi n s u bject) are n ot per mitte d f or eit her ni v ol u ma b or i pili m u ma b.  D ose of 
plati n u m d o u blet c he m ot hera p y ma y be m o difie d f or t o xicit y . D ose le vels of plati n u m d o u blet 
c he m ot hera p y are defi ne d i n t he pr ot oc ol as f oll o ws:


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 4
T a ble 7. 4. 2. 4- 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/ m²
7 5 m g/ m²
A U C 5. 0
D ose Le vel - 1
3 7 5 m g/ m²
5 6 m g/ m²
A U C 4. 0
D ose Le vel - 2
2 5 0 m g/ m²
3 8 m g/ m²
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
F or a n y c ycle, it will be defi ne d as a d ose re d ucti o n if t he o bser ve d d ose le vel ( base d o n calc ulate d 
a d mi nistere d d ose) is bel o w t he d ose le vel of t h e pre vi o usl y a d mi nistere d d ose. D ose ra n ges f or 
d ose le vels of plati n u m d o u blet c he m ot h era p y are defi ne d i n Ta ble 7. 4. 2. 4- 2.
T a ble 7. 4. 2. 4- 2:  
C alc ul ate d D ose R a n ges a n d Rel ate d D ose Le vels
D ose Le vel
D ose Ra n ge
Pe metre xe d ( m g/ m² )
Cis plati n ( m g/ m² )
Car b o plati n ( A U C)
Le vel 0
≥4 3 7. 5
≥6 5. 5
≥4. 5
Le vel - 1
< 4 3 7. 5 a n d ≥3 1 2. 5
< 6 5. 5 a n d ≥4 7
< 4. 5 a n d ≥3. 5
Le vel - 2
< 3 1 2. 5
< 4 7
< 3. 5
T he reas o n f or d ose re d ucti o n as re p orte d b y t he i n vesti gat or will be ta b ulate d f or all i nsta nces of 
d ose re d ucti o n base d o n t he D ose C ha n ge C R F pa ge. A cate g or y ‘ U n k n o w n’ w ill be defi ne d f or 
all re d ucti o ns wit h n o reas o n re p orte d b y t he i n vesti gat or.
T he f oll o wi n g will be s u m marize d f or c he m ot hera pe utic a ge nt ar m o nl y:
•
N u m ber a n d perce nta ge of s u bjects wit h at le ast o ne d ose re d ucti o n a n d reas o n of t he d ose 
re d ucti o n, n u m ber a n d perce nta ge of s u bjects wit h a d ose re d ucti o n t o d ose le v el - 1, n u m ber 
a n d perce nta ge of s u bjects wit h a d ose re d ucti o n t o d ose le vel - 2.
7. 4. 2. 5  
D o s e O mi s si o n s
D ose o missi o ns are n ot per mitte d  f or eit her ni v ol u ma b or i pili m u ma b.
7. 4. 2. 6 
P arti al Di s c o nti n u ati o n of I pili m u m a b i n t h e Ar m A
S u bjects treate d wit h ni v ol u ma b a n d i pili m u ma b ma y disc o nti n ue i pili m u ma b a n d c o nti n ue t o re-
cei ve ni v ol u ma b (ie, pa rtial disc o nti n uati o n). 
T he f oll o wi n g will be s u m marize d f or s u bjects recei vi n g t he i m m u n ot hera p y i n t he ar m A 
•
N u m ber a n d perce nta ge of s u bjects w h o ha d partial disc o nti n uati o n of i pili m u ma b.
•
Reas o n f or partial disc o nti n uati o n.




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 6
F or eac h cate g or y/s u bcate g or y of dr u g-r elate d sel ect A Es (a n y gra de, gra de 3- 5) a n d I M A Es (a n y 
gra de, gra de 3- 5), t he f oll o wi n g will be re p orte d f or eac h treat me nt gr o u p:
•
T he t otal i m m u ne m o d ulati n g me dicati o n treat me nt d urati o n (e xcl u di n g o verla ps), d urati o n of 
hi g h d ose of c ortic oster oi d, i nitial d ose of c ortic oster oi d, a n d ta peri n g d urati o n (s u m mar y 
statistics)
D urati o n re prese nts t he t otal d urati o n t he s u bject recei ve d t he c o nc o mita nt me dicati o n of i nterest. 
If t he s u bject t o o k t he me dicati o n p eri o dicall y, t he n D U R A TI O N is t he s u m mati o n of all us e. 
I nitial d ose re prese nts t he d ose of t he c o nc omita nt me dicati o n of i nt erest recei ve d at t he st art of 
t he e ve nt. I n t he case m ulti ple me dicati o ns starte d o n t he sa me date, t he hi g hest e q ui vale nt d ose is 
c h ose n a n d c o n verte d t o m g/ k g b y di vi di n g b y t he s u bject’s rece nt wei g ht.
T hese a nal yses, e xce pt t he o nes relate d t o I M A Es  will be c o n d ucte d usi n g t he 3 0- da y safet y wi n-
d o w. T he a nal yses relate d t o I M A Es will be c o n d ucte d usi n g t he 1 0 0- d a y safet y wi n d o w.
7. 4. 3. 2 
S u b s e q u e nt C a n c er T h er a p y
N u m ber a n d perce nta ge of s u bjects recei vi n g s u bse q ue nt ca ncer t hera pies will be s u m marize d f or 
all ra n d o mize d s u bjects. Cate g ories i ncl u de: 
•
S u bse q ue nt s yste mic t hera p y 
•
S u bse q ue nt s ur ger y f or treat me nt of t u m ors 
•
S u bse q ue nt ra di ot hera p y f or treat me nt of t u m ors
A b y-s u bject listi n g of s u bse q ue nt ca ncer t hera p y w ill als o be pr o d uce d f or all ra n d o mize d s u b-
jects.
7. 5 
Effi c a c y
Pri nci pal a nal yses of pr o gressi o n free s ur vi va l ( P F S) a n d o bjecti ve res p o nse rate ( O R R) will be 
base d o n t he Bli n de d I n de pe n de nt Ce ntral Re vie w ( BI C R) e val uati o n, u nless n ote d ot her wise. 
A nal yses i n t his secti o n will be ta b ulate d f or all ran d o mize d s u bjects b y tr eat me nt gr o u p as ra n-
d o mize d, u nless ot her wise s pecifie d.
U nless s tate d ot her wise, w he ne ver a stratifie d a nal ysis is s pecifie d, t he f oll o wi n g stratificati o ns 
fact ors (rec or de d at ra n d o mizati o n as per I R T) will be use d:
•
Hist ol o g y
•
Se x
F or assessi n g t he sec o n dar y o bjecti ves of t his st u d y, n o testi n g pr oce d ure  w ill be use d.
C o nfi de nce i nt er vals  ( CI) f or pri mar y e n d p oi nt a nal yses  will be base d o n n o mi n al si g nifica nce 
le vel a dj uste d f or pri mar y e n d p oi nts a n d i nteri m a nal yses t o preser ve o verall t y pe o ne err or rate.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 7
Al p ha (
f or t he CI will be t he sa me as n o mi nal si g nifica nce le vel f or h y p ot hesis testi n g. CIs f or 
ot her e n d p oi nts will be at t he t w o-si d e d 9 5 % le v el. All p- val ues re p orte d w ill be t w o-si de d. P-
val ues will be r o u n de d t o t he f o urt h deci mal p lace. P oi nt esti mates a n d c o nfi de nce b o u n ds f or 
efficac y v aria bles will be r o u n de d t o t he sec o n d deci mal place.
A b y-s u bject listi n g of efficac y res ults will be prese nte d i ncl u di n g treat me nt gr o u p, treat me nt 
d urati o n, BI C R pr o gressi o n date, o verall s ur vi val, deat h date, etc. 
7. 5. 1  
A n al y si s of O bj e cti v e R e s p o n s e R at e
O ne of t he o bjecti ves of t he st u d y is t o esti mate t he O R R per BI C R i n t he treat me nt gr o u ps a m o n g 
all ra n d o mize d s u bjects.
T he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y of B O R per BI C R (c o m plete res p o nse 
[ C R], partial res p o nse [ P R], sta ble disease [ S D], pr o gressi ve disease [ P D], or u na ble t o deter mi ne 
[ U T D]) will be prese nte d, b y treat me nt gr o u p. Esti mates of res p o nse rate, al o n g wit h its e xact t w o-
si de d 9 5 % CI b y Cl o p per a n d Pears o n 1 0 will be prese nte d, b y treat me nt gr o u p. 
Si milar a nal yses will be re peate d base d o n t he i n vesti gat or’s assess me nt of O R R. A cr oss ta b ula-
ti o n of BI C R best res p o nse vers us t he i n vesti gat or best res p o nse will be prese nte d, b y treat me nt 
gr o u p a n d b y res p o nse cate g ories. C o nc or da nce Rate of Res p o n ders will be c o m p ute d as t he fre-
q ue nc y wit h w hic h i n vesti gat or a n d BI C R a gree o n classificati o n of a s u bject as res p o n der vs. n o n 
res p o n der/ U T D as a pr o p orti o n of t he t ot al n u m ber of ra n d omize d s u b jects assesse d b y b ot h t he 
i n vesti gat or a n d BI C R.
T he f oll o wi n g s u bject-le v el gra p hics will als o be pr o vi de d:
•
F or t he res p o n ders o nl y, ti me c o urses of t he f oll o wi n g e ve nts of i nt erest w ill be gra p hicall y 
dis pla ye d: t u m or res p o nse.
•
F or res p o nse e val ua ble s u bjects (ra n d o mize d s u b jects wit h baseli ne a n d at least o ne o n-st u d y 
t u m or assess me nt), 
−
A bar pl ot s h o wi n g t he best % re d ucti o n fr o m baseli ne i n s u m of dia meter of tar get lesi o ns 
base d o n BI C R assess me nt f or eac h s u bject will be pr o d uce d (e xcl u di n g assess me nts after 
P D a n d assess me nts after start of s u bse q ue nt a nti-ca ncer t hera p y).
−
A pl ot of i n di vi d ual ti me c o urse of t u m or b ur de n c ha n ge per BI C R assess me nt w ill b e 
pr o d uce d. 
A b y-s u bject listi n g of best o verall res p o nse w ill be prese nte d i ncl u di n g treat me nt gr o u p, best 
o verall res p o nse per BI C R a n d dates of C R/ P R/ pr o gressi o n. 
A b y-s u bject listi n g of per ti me p oi nt t u m or res p o nse per BI C R will be prese nte d. 
7. 5. 2 
Ti m e t o T u m or R e s p o n s e a n d D ur ati o n of R e s p o n s e
D urati o n of r es p o nse ( D O R) a n d ti me t o res p o nse ( T T R) w ill als o be e val uate d f or s u bjects w h o 
ac hie ve d c o nfir me d P R or C R. T he D O R f or eac h tr eat me nt gr o u p will be esti mate d usi n g t he 


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
3 8
Ka pla n- Meier ( K M) pr o d uct li mit met h o d a n d will be dis pla ye d gra p hicall y. A ta ble will be pr o-
d uce d prese nti n g n u m ber of e ve nts, n u m ber of s u bjects i n v ol ve d, me dia ns, a n d 9 5 % CIs f or t he 
me dia ns. Me dia n val ues of D O R, al o n g wit h t w o-si de d 9 5 % CI i n eac h treat me nt gr o u p w ill be 
c o m p ute d base d o n a l o g-l o g tra nsf or mati o n met h o d. 
T he stat us of s u bjects w h o are ce ns ore d i n t he D O R K M a nal ysis will be ta b ulate d f or eac h treat-
me nt gr o u p i ncl u di n g t he f oll o wi n g cate g ories:
•
O n g oi n g f oll o w- u p (c urre nt [last sca n wit hi n a de q uate wi n d o w vs c ut off date], n ot c urre nt)
•
Off-st u d y (l ost t o f oll o w- u p, wit h dra w c o nse nt, ne ver treate d)
•
Recei ve d s u bse q ue nt a ntica ncer t hera p y.
T T R, w hic h d oes n ot i n v ol ve ce ns ori n g, will be s u m marize d b y treat me nt gr o u p i n all res p o n ders 
usi n g descri pti ve statistics. 
A b y-s u bject listi n g will be prese nte d i ncl u di n g tr eat me nt gr o u p, best res p o nse, ti me t o res p o nse, 
d urati o n of r es p o nse, w het her t he s u bject was ce ns ore d f or d urati o n of res p o nse, a n d, if s o, t he 
reas o n. 
7. 5. 3  
A n al y si s of D C R
Si milar t o O R R a nal ysis, BI C R- deter mi ne d D C R i n ar m A a n d B will be esti mate d a n d its c orre-
s p o n di n g 9 5 % e xact t w o-si de d CIs will be calc ulate d usi n g t he Cl o p per Pears o n met h o d. T his 
a nal ysis will als o be perf or me d f or D C R as assesse d b y t he i n vesti gat ors.
7. 5. 4  
A n al y si s of Pr o gr e s si o n- Fr e e S ur vi v al
T he P F S f u ncti o n (as deter mi ne d b y BI C R) f or eac h tr eat me nt gr o u p will be esti mate d usi n g t he 
K M pr o d uct li mit met h o d a n d will be dis pla ye d gra p hicall y. A t w o-si de d 9 5 % CI f or me dia n P F S 
i n eac h treat me nt gr o u p will be c o m p ute d via t he l o g-l o g tra nsf or mati o n met h o d. P F S rat es at fi xe d 
ti me p oi nts ( e. g. 6 m o nt hs, de pe n di n g o n t he mi ni m u m f oll o w- u p) will be prese nte d al o n g wit h 
t heir ass ociate d 9 5 % CIs. T hese esti mates will be deri ve d fr o m t he Ka pla n Meier esti mate a n d 
c orres p o n di n g CIs will be deri ve d base d o n Gree n w o o d 1 1 f or m ula f or varia nce deri vati o n a n d o n 
l o g-l o g tra nsf or mati o n a p plie d o n t he s ur vi v or f u ncti o n1 2 .
A nal yses of P F S (as deter mi ne d b y BI C R) will be c o n d ucte d base d o n t he pri mar y defi niti o n a n d 
sec o n dar y defi niti o n of P F S. 
T he s o urce of P F S e ve nt ( pr o gressi o n or deat h) will be s u m marize d b y treat me nt gr o u p. T he stat us 
of s u bjects w h o are ce ns ore d (as per pri mar y defi niti o n of P F S) i n t he P F S K M a nal ysis will be 
ta b ulate d f or eac h treat me nt gr o u p i ncl u di n g t he f oll o wi n g cate g ories:
•
O n-st u d y ( o n-treat me nt, i n f oll o w- u p)
•
Off-st u d y (l ost t o f oll o w- u p, wit h dra w c o nse nt, ne ver treate d)
•
N o baseli ne t u m or assess me nt
•
N o o n-st u d y t u m or assess me nt a n d n o deat h








Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 2
I n a d diti o n, ti me t o treat me nt disc o nti n uati o n w ill be s u m marize d a n d prese nte d b y treat me nt 
gr o u p usi n g a Ka pla n- Meier c ur ve w here b y t he last d ose date will be t he e ve nt d ate f or t h ose 
s u bjects w h o are off st u d y t hera p y. M e dia n d urati o n of st u d y t hera p y a n d ass ociate d 9 5 % CI will 
be pr o vi de d. S u bjects w h o are still o n st u d y t hera p y will be ce ns ore d o n t heir last d ose date.
A b y-s u bject listi n g will als o be pr o d uce d t o acc o m p a n y t he s u bject ti me fr o m last e val ua ble t u m or 
assess me nt.
7. 5. 1 0 
I nt eri m A n al y si s of O v er all S ur vi v al
A n i n de pe n de nt st atisticia n e xter nal t o B M S w ill perf or m t he a nal ysis. I n a d diti o n t o t he f or mal 
pla n ne d i nteri m a nal ysis f or O S, t he Data M o nit ori n g C o m mittee ( D M C) will ha ve access t o peri-
o dic u n- bli n de d i nt eri m r e p orts of efficac y a n d safet y t o all o w a ris k/ be nefit assess me nt. Details 
are i ncl u de d i n t he D M C c harter.
A f or mal i nt eri m a nal ysis f or s u peri orit y of O S i n s u bjects w h o were ra n d o mize d t o Ar m A vs. 
s u bjects w h o were ra n d o mize d t o Ar m B  will be perf or me d o n all ra n d o mize d s u bjects w he n a p-
pr o xi ma tel y 4 0 3 deat hs ha ve bee n o bser ve d (a p pr o xi matel y 8 5 % ( 4 0 3/ 4 7 3) of t he t otal n u m ber of 
deat hs re q uire d f or t he fi nal a nal ysis).
T his O S c o m paris o n will be teste d usi n g t he i nt eri m m o nit ori n g feat ure of E A S T s oft ware base d 
o n a ge neralizati o n of t he La n- D e Mets Al p ha s pe n di n g f u ncti o n a p pr oac h usi n g a n O’ Brie n- Fle m-
i n g st o p pi n g b o u n dar y t o r eject H0 , c o ntr olli n g f or a t w o-si de d o verall α of 5 %. F or e xa m ple, if 
e xactl y 4 0 3 deat hs are i n t he l oc ke d data base at t he i nteri m a nal ysis, H 0 w o ul d be rejecte d if t he p-
val ue fr o m t he l o g-ra n k test is p < 0. 0 3. If t he n u m ber of deat hs is n ot e xactl y 4 0 3 at t he ti me of 
t he i nteri m a nal ysis, t he n o mi nal critical p oi nt a n d val ue of b ot h t he i nteri m a n d fi nal a nal yses will 
be calc ulate d base d u p o n t he o bser ve d i nf or mati o n fracti o n. 
If t he st u d y c o nti n ues be y o n d t he i nt eri m a nal ysis a n d e xactl y 4 0 3 deat hs at t h e i nt eri m a nal ysis 
a n d e xactl y 4 7 3 deat hs are i n t he l oc ke d data base at t he fi nal a nal ysis, H 0 w o ul d b e r ejecte d if t he 
p- val ue fr o m t he l o g-r a n k t est is p < 0. 0 4 1. All e v e nts i n t he data base at t he ti me of t he l o c k will 
be use d. T he fi nal a nal ysis will be c o n d ucte d after at least 4 7 3 deat hs occ urs. 
T he D M C will re vie w t he s afet y a n d efficac y data fr o m t he inf or mal i nt eri m a nal yses a n d will 
deter mi ne if t he st u d y s h o ul d c o nti n ue wit h or wit h o ut c ha n ges or if accr ual s h o ul d be st o p pe d. 
S u bject e nr oll me nt will c o nti n ue w hile waiti n g f or t he D M C’s decisi o ns.
T he c hair of t he D M C a n d t he s p o ns or ca n call a n u nsc he d ule d re vie w of t he safet y data.
At t he ti me of t he f or mal i nt eri m a nal ysis f or s u peri orit y of O S, t he D M C ma y rec o m me n d c o n-
ti n ui n g or st o p pi n g t he trial. If t he trial c o nti n ues be y o n d t he f or mal i nt eri m a nal ysis, t he n o mi nal 
critical p oi nt f or t he fi nal O S a nal ysis will be deter mi ne d usi n g t he recalc ulate d i nf or mati o n frac-
ti o n at t h e ti me of t he i nt eri m a nal ysis, as descri be d a b o ve. T he fi nal O S hazar d r ati o a n d corre-
s p o n di n g c o nfi de nce i nt er val will be re p orte d w here b y t he c o nfi de nce i nt er val will be a dj uste d 
acc or di n gl y (i.e. usi n g t he recalc ulate d n o mi nal α  le vel at t he fi nal a nal ysis). 
If t he trial is st o p pe d f or s u peri orit y of O S at t he i nt eri m, t he p- val ue fr o m t he i nt eri m stratifie d
l o g-ra n k test will be c o nsi dere d t he fi nal pri mar y a nal ysis res ult.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 3
7. 6 
S af et y
A nal yses i n t his secti o n will be ta b ulate d f or all treate d s u b jects b y treat me nt gr o u p as treate d, 
u nless ot her wise s pecifie d.
7. 6. 1  
D e at h s
Deat hs will be s u m marize d b y treat me nt gr o u p:
•
All deat hs, reas o ns f or deat h.
•
Deat hs wit hi n 3 0 da ys of last d ose recei ve d, reas o ns f or deat h.
•
Deat hs wit hi n 1 0 0 da ys of last d ose recei ve d, reas o ns f or deat h.
A b y-s u bject listi n g of deat hs will be pr o vi de d f or t he all e nr olle d s u bjects p o p ulati o n.
7. 6. 2 
S eri o u s A d v er s e E v e nt s
Seri o us a d verse e ve nts  will be s u m marize d b y  treat me nt gr o u p:
•
O verall s u m mar y of S A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5) prese nte d b y 
S O C/ P T.
•
O verall s u m mar y of dr u g-r elate d S A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5) 
prese nte d b y S O C/ P T.
All a nal yses  will be c o n d ucte d usi n g t he 3 0- d a y safet y wi n d o w. 
A b y-s u bject S A E listi n g w ill be pr o vi de d f or t he “e nr olle d  s u bjects” p o p ulati o n.
7. 6. 3  
A d v er s e E v e nt s L e a di n g t o Di s c o nti n u ati o n of St u d y T h er a p y
A Es lea di n g t o disc o nti n uati o n will be s u m marize d b y treat me nt gr o u p:
•
O verall s u m mar y of A Es lea di n g t o disc o nti n uati o n  b y w orst C T C gra de (a n y gra de, gra de 3- 4, 
gra de 5) prese nte d b y S O C/ P T.
•
O verall s u m mar y of dr u g-r elate d A Es lea di n g t o disc o nti n uati o n b y w orst C T C gra de (a n y 
gra de, gra de 3- 4, gra de 5) prese nte d b y S O C/ P T.
T he a nal ys es  will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
A b y-s u bject A Es lea di n g t o disc o nti n uati o n listi n g will be pr o vi de d.
7. 6. 4  
A d v er s e E v e nt s L e a di n g t o D o s e M o difi c ati o n
A Es lea di n g t o d ose dela y/re d ucti o n  will be s u m marize d b y tr eat me nt gr o u p:
•
O verall s u m mar y of A Es lea di n g t o d ose dela y/re d ucti o n b y w orst C T C gra de (a n y gra de, 
gra de 3- 4, gra de 5) prese nte d b y S O C/ P T.
•
O verall s u m mar y of r elate d A Es lea di n g t o d os e d ela y/re d ucti o n b y w orst C T C gra de (a n y 
gra de, gra de 3- 4, gra de 5) prese nte d b y S O C/ P T.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 4
T he a nal ysis will be c o n d ucte d usi n g t he 3 0- d a y safet y wi n d o w.
A b y-s u bject A Es lea di n g t o d ose dela y/re d ucti o n listi n g will be pr o vi de d.
7. 6. 5  
A d v er s e E v e nt s
A d verse e ve nts  will be s u m marize d b y treat me nt gr o u p.
T he f oll o wi n g a nal yses will be c o n d ucte d usi n g t he 3 0 da ys safet y wi n d o w o nl y:
•
O verall s u m mar y of a n y A Es b y w orst C T C gra de  ( 1, 2, 3, 4, 5, n ot re p orte d, t otal) prese nte d 
b y S O C/ P T.
•
O verall s u m mar y of a n y A Es prese nte d b y w ors t C T C gra de (a n y gra de, gra de 3- 4, gra de 5) 
b y S O C/ P T. T his ta ble will be restricte d t o e ve nts wit h a n i nci de nce greater or e q ual t o 5 % i n 
a n y treat me nt gr o u p.
•
O verall s u m mar y of a n y n o n-seri o us A Es prese nte d b y S O C/ P T. T his ta ble will be restr icte d 
t o e ve nts wit h a n i nci de nce greater or e q ual t o 5 % i n a n y treat me nt gr o u p.
•
O verall s u m mar y of a n y A Es t hat re q uire d i m m u ne m o d ulati n g me dicati o n b y w orst C T C 
gra de (a n y gra de, gra de 3- 4, gra de 5) prese nte d b y S O C/ P T.
•
O verall s u m mar y of dr u g-r elate d A Es b y w orst C T C gra de ( 1, 2, 3, 4, 5, n ot re p orte d, t ot al) 
prese nte d b y S O C/ P T. 
T he f oll o wi n g a nal yses will be c o n d ucte d usi n g t he 3 0 da ys safet y wi n d o w a n d re peate d usi n g t he 
1 0 0 da ys safet y wi n d o w:
•
O verall s u m mar y of dr u g-r elate d A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5) 
prese nte d b y S O C/ P T.
A b y-s u bject A E listi n g will be pr o vi de d. A b y-s u bject listi n g of a n y A E re q uiri n g i m m u ne m o d-
ulati n g  me dicati o ns will als o be pr o vi de d.
7. 6. 6 
S el e ct A d v er s e E v e nt s ( E U S u b mi s si o n)
U nless ot her wise s pecifie d, a nal yses will be perf or me d b y select A E cate g or y. A nal yses will als o 
be re peate d b y s u bcate g or y of e n d ocri ne e ve nts.
7. 6. 6. 1 
I n ci d e n c e of S el e ct A E
S elect A Es  will be s u m marize d b y treat me nt gr o u p f or eac h cate g or y/s u bcate g or y. 
T he f oll o wi n g a nal yses will be c o n d ucte d usi n g t he 3 0- d a y safet y wi n d o w o nl y:
•
O verall s u m maries of a n y select A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5)
prese nte d b y Cate g or y or S u bcate g or y/ P T.
•
O verall s u m maries of a n y dr u g-r elate d select A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, 
gra de 5) prese nte d b y Cate g or y or S u bcate g or y/ P T.


Statistical A nal ysis Pla n
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
•
O verall s u m maries of a n y seri o us select A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 
5) prese nte d b y Cate g or y or S u bcate g or y / P T.
•
O verall s u m maries of dr u g-r elate d seri o us select A Es b y w orst C T C gra de (a n y gra de, gra de 
3- 4, gra de 5) prese nte d b y Cat e g or y or S u bcate g or y / P T.
•
O verall s u m maries of  a n y select A Es lea di n g t o disc o nti n uati o n b y w orst C T C gra de (a n y 
gra de, gra de 3- 4, gra de 5) prese nte d b y Cate g or y or S u bcate g or y / P T.
•
O verall s u m maries of dr u g-r elate d select A Es lea di n g t o disc o nti n u ati o n b y w orst C T C gra de
(a n y gra de, gra de 3- 4, gra de 5) prese nte d b y Cate g or y or S u bcate g or y / P T.
•
S u m mar y of fre q ue nc y of u ni q ue select A Es b y Cate g or y.
A b y-s u bject select A E listi n g will be pr o vi de d.
7. 6. 6. 2 
Ti m e-t o O n s et of S el e ct A E
Ti me-t o o nset of dr u g-r elate d select A Es (a n y gra de, gra de 3- 5)  w ill be s um marize d f or eac h cat-
e g or y/s u bcate g or y b y treat me nt gr o u p.
Ti me-t o o nset a n al yses are restricte d t o treate d s u bjects w h o e x perie nce d at least o ne dr u g-relate d 
select A E i n t he cate g or y/s u bcate g or y. T he a nal yses will be c o n d ucte d usi n g t he 3 0- da y safet y 
wi n d o w.
A d diti o nal details re gar di n g t he ti me-t o o nset defi niti o n are descri be d i n ti me-t o o nset defi niti o n 
s u bsecti o n of A P P E N DI X 1 .
7. 6. 6. 3 
Ti m e-t o R e s ol uti o n of S el e ct A E
Ti me-t o r es ol uti o n of t he f oll o wi n g s pecific e ve nts will be s u m marize d se paratel y f or eac h cate-
g or y/s u bcate g or y.
•
Ti me-t o r es ol uti o n of dr u g-relate d select A E (a n y  gra de, gra de 3- 5) b y treat me nt gr o u p
•
Ti me-t o res ol uti o n of dr u g-relate d select A E (a n y  gra de, gra de 3- 5) w here i m m u ne m o d ulati n g 
me dicati o n was i nitiate d, b y treat me nt gr o u p
Ti me-t o r es ol uti o n a n al yses are restricte d t o treate d s u bjects w h o e x perie nce d t he s pecific e ve nts. 
Ti me-t o r es ol uti o n w here i m m u ne m o d ulati n g me dicat i o n was i nitiate d a nal yses are restricte d t o 
treate d s u bjects w h o e x perie nce d t he s pecific e ve nts a n d w h o recei ve d i m m u ne m o d ulati n g me d-
icati o n d uri n g t he l o n gest select A E.
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
T he f oll o wi n g s u m mar y st atistics will be re p orte d: perce nta ge of s u bjects wit h res ol uti o n of t he 
l o n gest select A E, me dia n ti me-t o res ol uti o n al o n g wit h 9 5 % CI ( deri ve d fr o m Ka pla n- Meier es-
ti mati o n) a n d ra n ges.
See ti me-t o res ol uti o n defi niti o n s u bs ecti o n of A P P E N DI X 1 f or a d diti o nal details.


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 6
7. 6. 7 
I m m u n e- M e di at e d A d v er s e E v e nt s ( U S S u b mi s si o n)
I M A Es  will be s u m marize d b y treat me nt gr o u p f or eac h i m m u ne- me diate d cate g or y / P T usi n g t he 
1 0 0- d a y safet y wi n d o w:
•
O verall s u m mar y of n o n- e n d ocri ne I M A Es b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 
5)  w here i m m u ne m o d ulati n g me dicati o n was i nitiate d prese nte d b y Cate g or y / P T.
•
O verall s u m mar y of e n d ocri ne I M A Es b y w orst C T C  gra de (a n y gra de, gra de 3- 4, gra de 5)
prese nte d b y Cate g or y / P T.
•
O verall s u m mar y of n o n- e n d ocri ne I M A Es lea di n g t o disc o nti n uati o n b y w orst C T C gra de 
(a n y gra de, gra de 3- 4, gra de 5)  w here i m m u ne m o d ulati n g me dicati o n was i nitiate d prese nte d 
b y Cate g or y / P T.
•
O verall s u m mar y of e n d ocri ne I M A Es le a di n g t o disc o nti n uati o n b y w orst C T C gra de (a n y 
gra de, gra de 3- 4, gra de 5) prese nte d b y Cate g or y / P T.
•
O verall s u m mar y of n o n- e n d ocri ne I M A Es le a di n g t o d ose d ela y or r e d u cti o n b y w orst C T C 
gra de (a n y gra de, gra de 3- 4, gra de 5)  w here i m m u ne m o d ulati n g me dicati o n was i nitiate d 
prese nte d b y Cate g or y / P T
•
O verall s u m mar y of e n d ocri ne I M A Es lea di n g t o d ose dela y or re d ucti o n b y w orst C T C gra de 
(a n y gra de, gra de 3- 4, gra de 5) prese nte d b y Cate g or y / P T.
•
S u m maries of ti me-t o o nset a n d ti me-t o res ol uti o n of n o n-e n d ocri ne I M A Es w here i m m u ne 
m o d ulati n g me dicati o n was i nitiate d prese nte d b y Cate g or y.
•
S u m maries of ti me-t o o nset a n d ti me-t o res ol uti o n of e n d ocri ne I M A Es prese nte d b y Cate g or y.
A b y-s u bject listi n g of I M A Es  will be pr o vi de d. B y-s u bject listi n gs of ti me-t o res ol uti o n f or l o n g-
est I M A Es cl uster (a n y gra de a n d gra de 3- 5 i n se parate s u m maries) will als o be pr o vi de d. F or ne w 
st u dies w hic h c ollect i n vesti gat or assess me nt of p ote ntial I M A E data, a b y-s u bject listi n g of A Es 
c o nsi dere d as i m m u ne- me diate d e ve nts per i n ves ti gat or b ut n ot q ualifie d f or I M A Es defi niti o n 
will als o be pr o vi de d.
I n a d diti o n, f or all ni v ol u ma b treate d s u bjects w h o e x perie nce d at least o ne I M A E, t he f oll o wi n g 
data prese ntati o n will be pr o vi de d:
•
S u m mar y  of  s u bjects  w h o  were  re-c halle n ge d  wit h  ni v ol u ma b  b y  I M A E cate g or y,  wit h  
e xte n de d f oll o w- u p 
•
S u m mar y  of  s u bjects  w h o  were  re-c halle n ge d  wit h  ni v ol u ma b  or  i pili m u ma b  b y  I M A E  
cate g or y,  wit h e xte n de d f oll o w- u p
F or t hese, r e- c halle n ge is c o nsi dere d t o ha ve occ urre d w he n last ni v ol u ma b a n d/ or i pili m u ma b 
i nf usi o n was a d mi nistere d after t he o nset of a n I M A E.
7. 6. 8  
Ot h er E v e nt s of S p e ci al I nt er e st
O E O SI  will be s u m marize d b y treat me nt gr o u p f or eac h cate g or y.
T he f oll o wi n g a nal yses will be c o n d ucte d  usi n g t he 1 0 0- d a y safet y wi n d o w:


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 7
•
O verall s u m mar y of O E O SI b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5) prese nte d b y 
Cate g or y / P T
•
O verall s u m mar y of dr u g-relate d O E O SI b y w orst C T C gra de (a n y gra de, gra de 3- 4, gra de 5)
prese nte d b y Cate g or y / P T
A b y-s u bject listi n g of O E O SI  will be pr o vi de d.
7. 6. 9  
M ulti pl e E v e nt s
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d:
•
A ta ble s h o wi n g t he t otal n u m ber a n d rate (e x p os ure a dj uste d) of occ urre nces f or all A Es. 
•
A  ta ble  s h o wi n g  t he  t otal  n u m ber  a n d  rate  (e x p os ure  a dj uste d) of  o cc urre nces  f or  A Es
occ urri n g i n at least 5 % of s u bjects i n a n y treat me nt gr o u p.
I n a d diti o n, t he rate (e x p os ure a dj uste d) a n d its 9 5 % CI e val uate d f or differe nt ti me i nter vals will 
be dis pla ye d gra p hicall y f o r eac h tre at me nt gr o u p. T his a nal ysis will be li mite d t o t h e rat e of all 
A Es a n d all dr u g-r elate d A Es. T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y safet y wi n d o w.
A listi n g dis pla yi n g t he u ni q ue i nsta nces of all A Es, i.e., after d u plicates ha ve bee n eli mi nate d a n d 
o verla p pi n g a n d c o nti g u o us occ urre nces of t he sa me e ve nt (i.e. sa me P T) ha ve bee n c olla pse d will 
be pr o vi de d. N o f or mal c o m paris o ns will be ma de bet wee n treat me nt gr o u ps.
7. 6. 1 0 
L a b or at or y P ar a m et er s
T he a nal ysis p o p ulati o n f or eac h la b orat or y test is restricte d t o treate d s u bjects w h o u n der we nt t hat 
la b orat or y t est. La b orat or y tests (i n a d diti o n t o t he tests s pecifie d b el o w) wit h C T C criteria c ol-
lecte d i n t he s pecific st u dies ma y als o be i ncl u de d i n t he s u m maries.
7. 6. 1 0. 1  
H e m at ol o g y
T he f oll o wi n g will be s u m marize d  b y tr e at me nt gr o u p as w orst C TC gra de o n-treat me nt per s u b-
ject a n d as s hift ta ble of w orst o n-treat me nt C TC gra de c o m pare d t o baseli ne C T C gra de per s u b-
ject: he m o gl o bi n ( H B), platelets, w hite bl o o d c o u nts ( W B C), a bs ol ut e ne utr o p hils c o u nt ( A N C) 
a n d l y m p h oc yte c o u nt ( L Y M P H).
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
A b y-s u bject listi n g of t hese la b orat or y para meters will be pr o vi de d.
7. 6. 1 0. 2 
S er u m C h e mi str y
T he f oll o wi n g will be s u m marize d  b y tr e at me nt gr o u p as w orst C T C gra de o n-treat me nt per s u b-
ject a n d as s hift ta ble of w orst o n-treat me nt C T C gra de c o m pare d t o baseli ne C T C gra de per s u b-
ject: A L T, A S T, al kali ne p h os p hatase ( A L P), t otal bilir u bi n a n d creati ni ne. 
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.


Statistical A nal ysis Pla n
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
A b y-s u bject listi n g of t hese la b orat or y para meters will be pr o vi de d.
7. 6. 1 0. 3 
El e ctr ol yt e s
T he f oll o wi n g will be s u m marize d  b y tr e at me nt gr o u p as w orst C T C gra de o n-treat me nt per s u b-
ject a n d as s hift ta ble of w orst o n-treat me nt C T C gra de c o m pare d t o baseli ne C T C gra de per s u b-
ject: s o di u m ( hi g h a n d l o w), p otassi u m ( hi g h a n d l o w), calci u m ( hi g h a n d l o w), ma g nesi u m ( hi g h 
a n d l o w), a n d Gl uc ose Ser u m (fasti n g h y per gl yce mia a n d h y p o gl yce mia re gar dless of fasti n g sta-
t us)
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
A b y-s u bject listi n g of t hese la b orat or y para meters will be pr o vi de d.
7. 6. 1 0. 4  
A d diti o n al A n al y s e s
I n a d diti o n, f urt her a nal yses o n s pecific la b orat or y para meters will be p erf or me d b y treat me nt 
gr o u p:
A b n or mal He patic F u ncti o n Test
T he n u m ber of s u bjects wit h t he f oll o wi n g la b orat or y a b n or malities fr o m o n-tr eat me nt e val uati o ns 
will be s u m marize d b y treat me nt gr o u p:
•
A L T or A S T > 3 x U L N, > 5 x U L N, > 1 0 x U L N a n d > 2 0 x U L N
•
T ot al bilir u bi n > 2 x U L N
•
C o nc urre nt ( wit hi n 1 da y) A L T or A S T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N
•
C o nc urre nt ( wit hi n 3 0 da ys) A L T or A S T > 3 x U L N a n d t ot al bilir u bi n > 2 x U L N
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
A b y-s u bject listi n g of t hese s pecific a b n or malities will be pr o vi de d.
A b n or mal T h yr oi d F u ncti o n Test
T he n u m ber of s u bjects wit h t he f oll o wi n g la b orat or y a b n or malities fr o m o n-tr eat me nt e val uati o ns 
will be s u m marize d b y treat me nt gr o u p:
•
T S H val ue > U L N a n d
−
wit h baseli ne T S H val ue ≤U L N
−
wit h at least o ne F T 3/ F T 4 test val ue < L L N  wi t hi n 2- wee k wi n d o w after t he a b n or mal T S H 
test
−
wit h all F T 3/ F T 4 test val ues ≥ L L N  wit hi n 2- wee k wi n d o w after t he a b n or mal T S H test
−
wit h F T 3/ F T 4 missi n g wit hi n 2- wee k wi n d o w after t he a b n or mal T S H test.
•
T S H < L L N a n d
−
wit h baseli ne T S H val ue ≥L L N


Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
4 9
−
wit h at least o ne F T 3/ F T 4 test val ue > U L N  wit hi n 2- wee k wi n d o w aft er t he a b n or mal 
T S H test
−
wit h all F T 3/ F T 4 test val ues ≤ U L N  wit hi n 2- wee k wi n d o w after t he a b n or mal T S H test
−
wit h F T 3/ F T 4 missi n g wit hi n 2- wee k wi n d o w after t he a b n or mal T S H test
T he a nal yses will be c o n d ucte d usi n g t he 3 0- d a y s afet y wi n d o w.
A b y-s u bject listi n g of t hese s pecific a b n or malities will be pr o vi de d.
7. 6. 1 1 
P h y si c al M e a s ur e m e nt s
P h ysical meas ure me nts will be liste d b y s u bject.
7. 6. 1 2  
N o n- Pr ot o c ol M e di c al Pr o c e d ur e s
N o n- pr ot oc ol me dical pr oce d ures will be liste d b y s u bject.
 
 
 
 
 
 
 
 
 








Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
5 3
 
 
 
8  
C O N V E N TI O N S
T he f oll o wi n g c o n ve nti o ns ma y be use d f or i m p uti n g partial dates f or a nal yses re q uiri n g dates: 
•
F or missi n g a n d partial a d verse e ve nt o nset d ates, i m p utati o n will be p erf or me d usi n g t he 
A d verse E ve nt D o mai n Re q uire me nts S pecificati o n 1 3
•
F or  missi n g  a n d  partial a d verse  e ve nt  res ol u ti o n  dates,  i m p utati o n  will  be  p erf or me d as  
f oll o ws:
−
If o nl y t he d a y of t he m o nt h is missi n g, t he last d a y of t he m o nt h will be use d t o r e place 
t he missi n g da y. If t he i m p ute d date is after t he deat h date or t he last k n o w n ali ve date, t he n 
t he latest k n o w n ali ve date or deat h date is c o nsi dere d as t he res ol uti o n date. 
−
If t he da y a n d m o nt h are missi n g or a date is c om pletel y missi n g, it will be c o nsi dere d as 
missi n g.
•
Missi n g a n d partial n o n-st u d y me dicati o n d o mai n dates w ill be i m p ute d usi n g t he deri vati o n 
al g orit h m  descri be d  i n  4. 1. 3  of  B M S  N o n- St u d y  Me dicati o n  D o mai n  Re q uire me nts  
S pecificati o n 1 4 .
•
Missi n g a n d partial ra di ot hera p y a n d s ur ger y dates  will be i m p ute d usi n g al g orit h m descri be d 
i n A P P E N DI X 2 .
•
F or deat h dates, t he f oll o wi n g c o n ve nti o ns will be use d f or i m p uti n g partial dates:
−
If o nl y t he d a y of t he m o nt h is missi n g, t he 1st of t he m o nt h will be use d t o re place t he 
missi n g d a y. T he i m p ute d date will be c o m p are d t o t he last k n o w n ali ve date a n d t he 
ma xi m u m will be c o nsi dere d as t he deat h date. 
−
If t he m o nt h or t he year is missi n g, t he death date will be i m p ute d as  t he last k n o w n ali ve 
date. 
−
If t he date is c o m pletel y missi n g b ut t he reas o n f or deat h is prese nt, t he deat h date will be 
i m p ute d as t he last k n o w n date ali ve. 
•
F or date of pr o gressi o n after start of st u d y t hera p y, t he f oll o wi n g c o n ve nti o ns will be use d f or 
i m p uti n g partial dates: 
−
If o nl y t he d a y of t he m o nt h is missi n g, t he 1st of t he m o nt h will be use d t o re place t he 
missi n g da y. I n case of t he date of deat h is prese nt a n d c o m plete, t he i m p ute d pr o gressi o n 
date will be c o m pare d t o t he date of deat h. T he mi ni m u m of t he i m p ute d pr o gressi o n date 
a n d date of deat h will be c o nsi dere d as t he date of pr o gressi o n. 
−
If t he da y a n d m o nt h are missi n g or a date is c om pletel y missi n g, it will be c o nsi dere d as 
missi n g. 
•
F or date of pr o gressi o n t o pri or t hera pies, t he f oll o wi n g c o n ve nti o ns will be use d f or i m p uti n g 
partial dates: 
−
If o nl y t he d a y of t he m o nt h is missi n g, t he 1st of t he m o nt h will be use d t o re place t he 
missi n g da y. 




Statistical A nal ysis Pla n
C A 2 0 9 7 4 3
B M S- 9 3 6 5 5 8
ni v ol u ma b
5 5
A P P E N DI X 1 
TI M E- T O O N S E T A N D TI M E- T O R E S O L U TI O N D E FI NI TI O N A N D 
C O N V E N TI O N S F O R S E L E C T A D V E R S E E V E N T S, I M M U N E- M E DI A T E D A D-
V E R S E E V E N T S A N D E V E N T S O F S P E CI A L I N T E R E S T
Ti me-t o o nset defi niti o n
Ti me-t o o nset of A E ( a n y gra de) f or a s pecific cate g or y is defi ne d as t he ti me bet wee n t he da y of 
t he first d ose of st u d y treat me nt a n d t he o nset date of t he earliest A E ( of a n y gra de) i n t his cate g or y.
T he ti me-t o o nset of A E ( gra de 3- 5) f or a s pecific cate g or y is defi ne d si milarl y wit h a n o nset date 
c orres p o n di n g t o a gra de 3- 5 A E.
Ti me-t o o nset of dr u g-relate d A E (a n y gra de or gra de 3- 5) f or a s pecific cate g or y is defi ne d si mi-
larl y b ut restricte d t o dr u g-relate d A E.
Ti me-t o o nset f or a s p ecific s u bcate g or y is defi ne d si milarl y b ut restricte d t o e ve nt of t his s u bcat-
e g or y.
Ti me-t o res ol uti o n defi niti o n
I n or der t o deri ve t he ti me-t o res ol uti o n, o verla p pi n g or c o nti g u o us A Es wit hi n a s pecific cate g or y
or s u bcate g or y will be c olla pse d i nt o w hat will be ter me d “cl ustere d” A Es. F or e xa m ple, if a s u b-
ject ( wit h o ut pre-treat me nt A E) e x perie nce d a n A E fr o m 1st t o 5t h Ja n uar y, a n ot her A E ( wit h dif-
fere nt  P T  b ut  wit hi n  sa me  cate g or y)  fr o m  6t h t o  1 1t h Ja n uar y  a n d sa me  A E  fr o m  1 0t h t o 
1 2 t h Ja n uar y, t hese will be c olla pse d i nt o o ne cl ustere d A E fr o m 1st t o 1 2t h Ja n uar y. A p pe n di x 
Ta ble 1 is s u m marizi n g ke y deri vati o n ste ps f or eac h t y pe of cl ustere d A Es.
Ti me-t o r es ol uti o n of A E  (a n y gra de) f or a s pecific cate g or y is defi ne d as t he l o n gest ti me fr o m 
o nset t o c o m plete res ol uti o n or i m pr o ve me nt t o t he gra de at baseli ne a m o n g all cl ustere d  A Es
e x perie nce d b y t he s u bject i n t his cate g or y per a d verse e ve nt criteria cate g or y. E ve nts w hic h w ors-
e ne d i nt o gra de 5 e ve nts ( deat h) or ha ve a res ol uti o n date e q ual t o t he date of deat h are c o nsi dere d 
u nres ol ve d. If a cl ustere d A E is c o nsi dere d as u nres ol ve d, t he res ol uti o n date will be ce ns ore d t o 
t he last k n o w n ali ve date. I m pr o ve me nt t o t he gra de at baseli ne i m plies t hat all differe nt e ve nts i n 
t he cl ustere d a d verse e ve nt s h o ul d at least ha ve i m pr o ve d t o t he c orres p o n di n g (i.e. wit h sa me 
preferre d ter m) baseli ne gra de. T his meas ure is defi ne d o nl y f or s u bjects w h o e x perie nce d at least 
o ne A E i n t he s pecific cate g or y.
T he ti me-t o res ol uti o n of A E ( gra de 3- 5) f or a s pecific cate g or y is defi ne d si milarl y wit h a n o nset 
date c orres p o n di n g t o a gra de 3- 5 A E.
Ti me-t o r es ol uti o n of dr u g-relate d A E (a n y gra de or gra de 3- 5) f or a s pecific cate g or y is defi ne d 
si milarl y b ut restricte d t o dr u g-r elate d A E.
T he ti me-t o r es ol uti o n of A E (a n y gra de or gra de 3- 5, dr u g-relate d or all) w here i m m u ne m o d u-
lati n g me dicati o n was i nitiate d is defi ne d si milarl y. F or data prese ntati o n n ot restricte d t o I M A E, 
t he a d diti o nal c o n diti o n t hat t he s u bject starte d a n i m m u ne m o d ulati n g me dicati o n d uri n g t he l o n g-
est A E res ol uti o n peri o d  will be a p plie d.