A Phase 2 Randomized Study of Relatlimab Plus Nivolumab in Combination With Chemotherapy vs. Nivolumab in Combination With Chemotherapy as First Line Treatment for Participants With Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer, Recurrent Non-small Cell Lung Cancer, Metastatic Non-small Cell Lung Cancer
Sponsor: Bristol-Myers Squibb

Offi ci al  Titl e  of  St u d y:  
A  P h a s e  2  R a n d o mi z e d  St u d y  of  R el atli m a b  pl u s  Ni v ol u m a b i n  C o m bi n ati o n  wit h  
C h e m ot h er a p y  v s.  Ni v ol u m a b i n  C o m bi n ati o n  wit h  C h e m ot h er a p y  a s  Fir st  Li n e  
Tr e at m e nt f or  P arti ci p a nt s  wit h  St a g e I V  or  R e c urr e nt  N o n -s m all  C ell  L u n g  C a n c er  
( N S C L C) 
 
N C T  N u m b er:  N C T 0 4 6 2 3 7 7 5  
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):  1 1  S e p  2 0 2 4 
 
 
 

Pa ge:
1
Pr ot oc ol  N u m ber:
C A 2 2 4 1 0 4
Date :
1 8-A u g -2 0 2 0
Re vise d Date:
1 1- Se p - 2 0 2 4
R E G U L A T O R Y A G E N C Y I D E N TI FI E R N U M B E R( S)
I N D: 1 5 0 3 1 6
E U C T N u m ber : 2 0 2 3- 5 0 8 3 7 2- 1 0
W H O:
U 1 1 1 1 - 1 2 5 6- 8 1 1 5
C LI NI C A L P R O T O C O L C A 2 2 4 1 0 4
A P hase 2 Ra n d o mize d St u d y of Relat li ma b pl us Ni v ol u ma b i n C o m bi nat i on wi t h 
C he m ot h era p y vs. Ni v ol uma b i n C o m bi nat i on wi t h C he mot h era p y as First Li ne 
Treat me nt f or Partici pa nts wit h Sta ge I V or Rec urre nt N o n -s mall Cell L u n g Ca ncer 
( N S C L C)
S h ort Title:
A St u d y  of Re latli ma b pl us Ni v o l uma b i n C o m b i nati on wi t h Che m ot h era p y vs. Ni v o l uma b i n 
C o m bi nat i on wi t h C he mot h era p y i n Part ici pa nts with Sta ge I V or Rec urre nt N S C L C
Pr ot oc ol A me n d me nt N u m ber: 0 7
I nc or p or ates A d mi nistr ati ve Letters 0 3, 0 4 a n d 0 5
Me dic al M o nit ori n g C o nt act I nf or m ati o n
 Cli nical Trial P h ysicia n
Me dical M o nit or
Bri st ol M yers S q ui b b C om pa n y
3 4 0 1 Pri ncet o n Pi ke
La wre nce ville, NJ 0 8 6 4 8
e mail: 
 Cli nical Scie nt ist
Bri st ol-M yers S q ui b b C o m pa n y
3 4 0 1 Pri ncet o n Pi ke
La wre nce ville, NJ 0 8 6 4 8
e mail: 
2 4- hr E mer ge nc y Tele p h o ne N u m ber
U S A: 
I nter nati o nal: 
Brist ol -M yers S q ui b b C o m p a n y
R o ute 2 0 6 & Pr o vi nce Li ne R oa d
Pri ncet o n , NJ 0 85 4 3
A ve n ue de Fi nla n de 4
B -1 4 2 0 Brai ne -l’ Alle u d, Bel gi u m
Ote m ac hi O ne T o wer ,
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot oc ol A me n d m e n t N o: 07
Date: 1 1 -Se p - 2 0 2 4
2
1 - 2-1 Ote mac hi, C hi y o da - k u,
T o k y o 1 0 0 -0 0 0 4, Ja pa n
T his d oc u me nt is t he c o nfi de nti al a n d pr o priet ar y i nf or m ati o n of Brist ol -M yers 
S q ui b b 
C o m p a n y a n d its gl o b al affili ates ( B M S). B y re vie wi n g t his d oc u me nt, y o u a gree t o kee p it 
c o nfi de nti al a n d t o use a n d discl ose it s olel y f or t he p ur p ose of assessi n g w het her y o ur 
or g a niz ati o n will p artici p ate i n a n d/ or t he perf or m a nce of t he pr o p ose d B M S s p o ns ore d 
st u d y. A n y per mitte d discl os ures will be m a de o nl y o n a c o nfi de nti al " nee d t o k n o w " b asis 
wit hi n y o ur or g a niz ati o n or t o y o ur i n de pe n de nt et hics c o m mittee(s). A n y ot her use, c o p yi n g, 
discl os ure or disse mi n ati o n of t his i nf or m ati o n is strictl y pr o hi bite d u nless e x pressl y 
a ut h orize d i n writi n g b y B M S. A n y s u p ple me nt al i nf or m ati o n (e g, a me n d me nts) t h at m a y 
be a d de d t o t his d oc u me nt is als o c o nfi de nti al a n d pr o priet ar y t o B M S a n d m ust be ke pt i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt. A n y pers o n w h o recei ves 
t his d oc u me nt wit h o ut d ue a ut h oriz ati o n fr o m B M S is re queste 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).
© 2 0 2 4 Brist ol -M yers S q ui b b C o m p a n y
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot oc ol A me n d m e n t N o: 07
Date: 1 1- Se p - 2 0 2 4
3
D O C U M E N T HI S T O R Y
D oc u me nt 
D ate of Iss ue
S u m m ar y of C h a n ge
Pr ot oc ol 
A me n d me nt 0 7
1 1- Se p - 2 0 2 4
Maj or c ha n ges i ncl u de:
 
E n d of St u d y defi niti o n e xte n de d t o i ncl u de fi nal date o n w hic h data is t o
be c ollecte d f or s ur vi val f oll o w -u p. T he last visit defi niti o n is a d de d f or
clarit y.
 
O pti o n s ha ve bee n a d de d f or treat me nt c o nti n uati o n f or acti vel y treate d
patie nts s ho wi n g cli nical be nefit, after e n d of st u d y .
 
T he n u m ber of bl o o d c ollecti o n s f or bi o mar kers , P K, a n d q uesti o n naires
ha ve bee n re d uce d t o re d uce patie nt a n d site staff b ur de n.
 
Inf or mati o n i n A d mi nistrati ve Letters 0 3 , 0 4 a n d 0 5 ha ve bee n
i nc or p orate d. A d mi nistrati ve letter 0 2 i nf or mati o n has bee n s u perse de d i n
t his a me n d me nt; h e nce, c o nte nt is n ot i nc or p orate d i n t his A me n d me nt.
 
A d diti o nal u p dates a d de d t o ali g n t he a d mi nistrati ve refere nces wit h E U
C T R.
Pr ot oc ol 
A me n d me nt 0 6
1 9- Ma y - 2 0 2 2
 
A d de d i n rec o m me n dati o n f or a nti bi otics t o treat s u b -cli nical i nfecti o n
pri or t o ra n d o mizati o n i n t he prese nce of ele vate d ne utr o p hil a n d w hite
bl o o d c o u nts at baseli ne, a n d t he res ol uti o n of acti ve i nfecti o ns pri or t o
first d ose of st u d y treat me nt. Part 2 u p date d t o a n o pe n -la bel desi g n.
 
U p date d c he m ot hera p y o pti o ns i n Part 2.
 
Pri mar y a n d sec o n dar y e n d p oi nt s i n Part 2 u p date d t o O R R a n d P F S,
res pecti vel y.
 
Ot her mi n or re visi o ns i ncl u de clarificati o ns t o sc he d uli n g of safet y
la b orat or y, bi o mar ker a n d p har mac o ki netic c ollecti o n s, eli gi bilit y
criteria, a n d d urati o n of c o ntrace pti o n f or male a n d fe male partici pa nts
after last d ose of c he m ot hera p y.
Pr ot oc ol 
A me n d me nt 0 5 
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot oc ol A me n d m e n t N o: 07
Date: 1 1- Se p - 2 0 2 4
4
D oc u me nt 
D ate of Iss ue
S u m m ar y of C h a n ge
Pr ot oc ol 
A me n d me nt 0 4
0 1 -Dec - 2 0 2 1
 
Stratificati o n fact ors f or ra n d o mizati o n i n Part 2 u p date d t o i ncl u de
E C O G perf or ma nce stat us i n a d diti o n t o hist ol o g y a n d P D -L 1 le vel.
Ge n der a n d L A G-3 e x pressi o n le vel re m o ve d as stratificati o n fact ors .
 
T he ti me re q uire me nt s f or t he use of c o ntrace pt i o n a n d f or pre g na nc y
m o nit ori n g ha ve bee n u p date d t o ali g n wit h pr o gra m wi de s pecificati o n
f or relatli ma b.
 
N o n -li ve C O VI D vacci nati o ns ha ve bee n e val uate d as a c o nc o mita nt
me dicati o n wit h n o e x pecte d i nteracti o n wit h st u d y treat me nts as state d
i n t he Be nefit/ Ris k secti o n.
Pr ot oc ol 
A me n d me nt 0 3
3 0- J ul-2 0 2 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot oc ol A me n d m e n t N o: 07
Date: 1 1- Se p - 2 0 2 4
5
D oc u me nt 
D ate of Iss ue
S u m m ar y of C h a n ge
Pr ot oc ol 
A me n d me nt 0 2
1 6- A pr - 2 0 2 1
Ali g ns t he i m m u n ot hera p y d ose m o dificati o n criteria a n d i m m u ne -relate d 
a d verse e ve nt ma na ge me nt al g orit h ms wit h C T C A E v 5, clarifies ser ol o gic 
testi n g a n d i ncl u des vacci ne i nf or mati o n f or S A R S-C o V -2, clarifies i nf usi o n 
d urati o n 
, a n d a d ds i nstr ucti o ns f or 
l ocati o n of s pecific ma na ge me nt g ui deli nes f or se vere a d verse reacti o ns.
Pr ot oc ol 
A me n d me nt 0 1
1 1- N o v - 2 0 2 0
Clarifies i ncl usi o n/e xcl usi o n criteria a n d ali g ns t he c o nc o mita nt me dicati o n 
sectio n wit h t he U S pr o d uct la bel of c he m ot hera p y a ge nts.
Ori gi nal 
Pr ot oc ol
1 8 -A u g -2 0 2 0 
N ot a p plica ble
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
O V E R A L L R A TI O N A L E F O R P R O T O C O L A M E N D M E N T 0 7:
A me n d me nt 0 7 i nc or p orates t he f oll owi n g c ha n ges i n t he pr ot oc ol t o pr o vi de o pti o ns t o
parti ci pa nts s h o wi n g cli nical be nefit t o co nti n ue t o recei ve st u d y dr u g after clos ure of  t he st u d y.
T o acc o m m o date t hese o pti o n s, t he e n d of st u d y defi nitio n was re vise d .

E n d of  St u d y defi nit i on e xte n de d t o i ncl u de fi nal date o n w hic h data is t o be c ollecte d f or 
s ur vi val f oll ow- u p. T he l ast visit defi nit i on is a d de d f or clarity.

All o w o pti o ns f or pati e nts t o c o nti n ue t o recei ve st u d y treat me nt re gi me n after e n d of st u d y.

Decrease d n u m ber of  bl oo d c ollecti o ns f or P K , bi o mar kers , a n d q uest i on naires ( P R Os) t o 
re d uce patie nt a n d site staff b ur de n. 

I nc or p orati o n of i nf or mati on of A d mi nistrati ve Letters 0 3, 0 4 a n d 0 5.

A d dit i onal u p date s ma de t o ali g n t he a d mi nistrati ve refere nces wit h E U C T R.
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 7
Secti o n N u m ber & Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Title pa ge
 
U p date d Me dical 
M o nit ori n g 
c o ntact i nf or mati o n .
 
S p o ns or a d dress i nf or mati o n
u p date d .
 
E u dra C T N u m ber c h a n ge d t o 
E U C T N u m ber.
 
I nc or p orati o n 
of 
A d mi nistrati ve Letter s 0 5.
 
A d mi nistrati ve c ha n ge .
 
A d mi nistrati ve c ha n ge .
Ta ble 2 - 2: O n Treat me nt 
Pr oce d ural O utli ne 
( C A 2 2 4 1 0 4),
Ta ble 2- 3 : F oll o w -u p a n d 
S ur vi val Pr oce d ural O utli ne 
( C A 2 2 4 1 0 4), 
Ta ble 4 - 1: O bjecti ves a n d 
E n d p oi nts,
 
U p date d  
P R O  
c ollecti o n 
(
 
P GI S, 
  
 
 a n d P GI C ) t o ca p 
at C ycl e 36 f or part 1 a n d e ver y 
T h e c ollecti o n a n d testi n g of 
t he 
sa m ples are n o l o n ger re q uire d f or this 
st u d y. Re d uci n g t he n u m ber of sa m ple 
c ollecti o ns f or P K 
 
 will re d uce patie nt a n d site 
staff b ur de n. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 7
Secti o n N u m ber & Title
Descri pti o n of C h a n ge
Brief R ati o n ale
6 c ycles fr o m c ycle 3 6 u ntil 
e n d of st u d y f or part 2 .
Secti o n 5. 3 : E n d of St u d y 
Defi niti o n
E n d of St u d y defi niti o n e xte n de d t o 
i ncl u de fi nal date o n w hic h data is t o be 
c ollecte d f or s ur vi val foll o w -u p. T he 
last visit defi niti o n is a d de d f or clarit y
Pr o vi de o pti o ns t o partici pa nts s h o wi n g 
cli nical be nefit t o c o nti n ue t o recei ve 
st u d y dr u g after cl os ure of t he st u d y
Ta ble 7 - 1: St u d y Treat me nts 
f or C A 2 2 4 1 0 4
R o w  
2:  
Ni v ol u ma b  
pac ka gi n g 
i nf or mati o n is u p date d t o " 4 or 5 vials 
per cart o n”.
T his i nf or mati o n is u p date d as part of 
a d mi nistrati ve letter 0 4.
Secti o n 8. 2. 1 : Treat me nt 
after disc o nti n uati o n of t he 
st u d y
A d de d d etails f or st u d y dr u g treat me nt 
o pti o ns f or st u d y partici pa nts, after e n d 
of st u d y.
All o w  
partici pa nts  
w h o  
are 
de m o nstrati n g  
cli nical  
be nefit  
t o 
c o nti n ue t he st u d y dr u g re gi me n after 
t he st u d y cl os ure
Secti o n 9. 1. 2 : Patie nt-
re p orte d o utc o mes
U p date d  
P R O 
c ollecti o n 
 P GI S,  
 
 a n d P GI C) t o ca p 
at C ycle 3 6 f or part 1 a n d e ver y 6 c ycles 
fr o m c ycle 3 6 u ntil e n d of st u d y f or part 
2 
Re d uci n g  
t he 
n u m ber  
of  
P R O 
assess me nts will re d uce patie nt b ur de n.
Ta ble 9. 5. 1 - 1: 
P har mac o ki netic a n d 
I m m u n o ge nicit y Sa m pli n g 
Sc he d ule f or Relatli ma b a n d 
Ni v ol u ma b a n d 
P har mac o ki netic Sa m pli n g 
Sc he d ule f or C he m ot hera p y 
Dr u gs
Sa m ple  
c ollecti o n 
ti me p oi nts 
are
u p date d 
f or  Phar mac o ki netics 
a n d 
I m m u n o ge nicit y sa m pli n g.
S ufficie nt n u m ber of P K sa m ples ha ve 
bee n c ollecte d t o c o n d uct P o p ulati o n 
P K ( P o p P K) a n d
E x p os ure -res p o nse 
a nal yses 
wit h  
efficac y 
a n d 
safet y 
e n d p oi nts, as well as assess me nt of 
p ote ntial i m pact of i m m u n o ge nicit y o n
efficac y  
a n d  
safet y  
e n d p oi nts.
T heref ore, 
P K 
a n d 
A D A  
sa m ple 
c ollecti o n be y o n d 2 years of treat me nt 
is n o l o n ger re q uire d a n d
will 
be 
re m o ve d fr o m t his pr ot oc ol t o re d uce 
patie nt b ur de n.
Ta ble 9. 5 . 1- 1: 
P har mac o ki netic a n d 
I m m u n o ge nicit y Sa m pli n g 
Sc he d ule f or Relatli ma b a n d 
Ni v ol u ma b a n d 
P har mac o ki netic Sa m pli n g 
Sc he d ule f or C he m ot hera p y 
Dr u gs
R o w 1 1 is u p date d t o a d d “ or ma xi m u m 
of t w o years of treat me nt”
T his i nf or mati o n is u p date d as part of 
a d mi nistrati ve letter 0 3
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 7
Secti o n N u m ber & Title
Descri pti o n of C h a n ge
Brief R ati o n ale
All
Mi n or  
e dits,  
f ormatti n g ,  
a n d 
t yp o gra p hical c orrecti o ns.
Mi n or;  
t heref ore, ha ve 
n ot  bee n 
s u m marize d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

T A B L E O F C O N T E N T S  
 
 
TI T L E P A G E  ................................................................................................................ 
 
D O C U M E N T HI S T O R Y .............................................................................................. 
 
O V E R A L L R A TI O N A L E F O R P R O T O C O L A M E N D M E N T 0 7:  ............................ 
 
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 7  ................ 
 
T A B L E O F C O N T E N T S  .............................................................................................. 
 
1 S Y N O P SI S  ................................................................................................................. 
 
2 S C H E D U L E O F A C TI VI TI E S .................................................................................. 
 
3 I N T R O D U C TI O N  ..................................................................................................... 
 
3. 1 St u d y Rati o nale  ................................................................................................. 
 
3. 1. 1 Rese arc h Hy p ot hesis  ................................................................................ 
 
3. 2 Bac k gr o u n d  ....................................................................................................... 
 
3. 2. 1 Niv ol u m a b Mec h a nis m of Acti o n  ............................................................. 
 
3. 2. 2 Rel atli m a b Mec h a nis m of Acti o n  ............................................................. 
 
3. 2. 3 Niv ol u m a b pl us P D C T Cli nic al Activity  .................................................. 
 
3. 2. 4 Rel atli m a b Precli nic al a n d Cli nic al Activity  ........................................... 
 
3. 2. 5 Rel atli m a b M o n ot her a py S afety  ............................................................... 
 
 
 
3. 2. 7 Niv ol u m a b Pl us P D C T S afety  .................................................................. 
 
3. 3 Be nefit/ Ris k Assess me nt  .................................................................................. 
 
4 O BJ E C TI V E S A N D E N D P OI N T S  ........................................................................... 
 
5 S T U D Y D E SI G N ....................................................................................................... 
 
5. 1 O verall Desi g n  .................................................................................................. 
 
5. 1. 1 Scree ni n g P h ase  ....................................................................................... 
 
5. 1. 2 O n -tre at me nt P h as e ................................................................................. 
 
5. 1. 3 F oll o w -u p Peri o d  ..................................................................................... 
 
5. 1. 4 D at a M o nit ori n g C o m mittee a n d Ot her Ext er n al C o m mittees  ................ 
 
5. 1. 5 Bli n de d I n de pe n d e nt R a di ol o gy Ce ntr al Revie w  ..................................... 
 
5. 2 N u m ber of Partici pa nts  ..................................................................................... 
 
5. 3 E n d of St u d y Defi niti o n  .................................................................................... 
 
5. 4 Scie ntific Rati o nale f or St u d y Desi g n ............................................................... 
 
5. 4. 1 R ati o n ale f or Excl usi o n of P artici p a nts wit h K n o w n E pi der m al Gr o wt h 
F act or, A n a pl a stic Ly m p h o m a Ki n ase, R O S-1, a n d B -r a pi dly Acceler ate d 
Fi br os arc o m a Pr ot o -o nc o ge ne V 6 0 0 E Alter ati o ns  .................................... 
 
5. 4. 2 R ati o n ale f or D ose S afety C o nfir m ati o n  .................................................. 
 
5. 4. 3 R ati o n ale f or S h orte ne d I nf usi o n Ti me f or Niv ol u m a b pl us Rel atli m a b .. 
 
5. 4. 4 R ati o n ale f or C h oice of C he m ot her a py  ................................................... 
 
5. 4. 5 R ati o n ale f or C h oice of C o ntr ol Ar m ....................................................... 
 
 
 
 
 
5. 4. 8 R ati o n ale f or O R R as a Pri m ary E n d p oi nt i n P art 2  ............................... 
 
5. 4. 9 R ati o n ale f or Str atific ati o n  ...................................................................... 
 
5. 4. 1 0 R ati o n ale f or Bi o m arker Assess me nt  ..................................................... 
 
5. 4. 1 1 R ati o n ale f or Per mitti n g C o nti n ue d Tre at me nt i n Sel ect C ases of 
Pr o gressive Dise ase  .................................................................................... 
 
1
3
6
6
9
1 4
2 3
3 5
3 6
3 7
3 7
3 8
3 9
3 9
4 1
4 2
4 3
4 6
4 9
5 3
5 6
5 6
5 9
5 9
6 0
6 1
6 2
6 2
6 2
6 3
6 3
6 4
6 5
6 5
6 6
6 6
6 7
6 8
6 8
6 9
6 9
Cli ni c al  Pr ot o c ol
B M S- 9 8 6 0 1 6
C A 2 2 4 1 0 4
r el atli m a b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

5. 4. 1 2 R ati o n ale f or P atie nt Re p orte d O utc o mes Assess me nts  ........................ 
 
5. 5 J ustificati o n f or I m m u n ot hera p y D ose  .............................................................. 
 
5. 5. 1 J ustific ati o n f or Niv ol u m a b D ose  ............................................................ 
 
5. 5. 2 J ustif ic ati o n f or Rel atli m a b D oses ........................................................... 
 
5. 6 Cli nical P har mac ol o g y  ...................................................................................... 
 
5. 6. 1 Niv ol u m a b Cli nic al P h ar m ac ol o gy S u m m ary  ......................................... 
 
 
 
6 S T U D Y P O P U L A TI O N  ............................................................................................ 
 
6. 1 I n cl usi o n Criteria  .............................................................................................. 
 
6. 2 E xcl usi o n Criteria  ............................................................................................. 
 
6. 3 Lifest yle Restricti o ns  ........................................................................................ 
 
6. 4 Scree n Fail ures  .................................................................................................. 
 
6. 4. 1 Retesti n g D uri n g Scree ni n g or D ose S af ety C o nfir m ati o n Peri o d  .......... 
 
7 T R E A T M E N T  ........................................................................................................... 
 
7. 1 Treat me nts A d mi nistere d  .................................................................................. 
 
7. 1. 1 I m m u n ot her a py D osi n g  ............................................................................ 
 
7. 1. 2 C he m ot her a py D osi n g  ............................................................................. 
 
7. 1. 2. 1 P aclit axel a n d C ar b o pl ati n  ............................................................. 
 
7. 1. 2. 2 N a b -P aclit axel a n d C ar b o pl ati n ( P a rt 1 O nly) .............................. 
 
7. 1. 2. 3 Pe metre xe d a n d Cis pl ati n  ............................................................... 
 
7. 1. 2. 4 Pe metre xe d a n d C ar b o pl ati n  .......................................................... 
 
7. 1. 2. 5 O pti o n al C o nti n u ati o n M ai nte n a nce  .............................................. 
 
7. 2 Met h o d of Treat me nt Assi g n me nt  .................................................................... 
 
7. 3 Bli n di n g ............................................................................................................. 
 
7. 4 D osa ge M o dificati o n  ......................................................................................... 
 
7. 4. 1 D ose M o dific ati o n Criteri a f or I m m u n ot her a py  ...................................... 
 
7. 4. 2 D ose Del ay Criteri a f or C he m ot her a py  ................................................... 
 
7. 4. 3 D ose Re d ucti o ns ....................................................................................... 
 
7. 4. 3. 1 D ose Re d ucti o n f or I m m u n ot her a py ............................................... 
 
7. 4. 3. 2 D ose Re d ucti o n f or C he m ot her a py  ................................................. 
 
7. 4. 3. 3 C he m ot her a py: D ose Re d ucti o ns f or He m at ol o gic T oxicity  .......... 
 
7. 4. 3. 4 C he m ot her a py: D ose Re d ucti o ns f or N o n -he m at ol o gic T oxicities  . 
 
7. 4. 4 Criteri a t o Res u me D osi n g ....................................................................... 
 
7. 4. 4. 1 Criteri a t o Res u me Tre at me nt wit h I m m u n ot her a py  ...................... 
 
7. 4. 4. 2 Criteri a t o Res u me Tre at me nt wit h C he m ot her a py  ........................ 
 
7. 4. 5 M a n a ge me nt Al g orit h ms f or I m m u n o -O nc ol o gy A ge nt s ......................... 
 
7. 4. 6 Tre at me nt of I m m u n ot her a py I nf usi o n Re acti o ns  .................................... 
 
7. 5 Pre parati o n/ Ha n dli n g/ St ora ge/ Acc o u nta bilit y  .................................................. 
 
7. 5. 1 Ret ai ne d S a m ples f or Bi o av ail a bility/ Bi oe q uiv ale nce/ Bi oc o m p ar a bility  
 
7. 6 Tre at me nt C o m plia nce  ...................................................................................... 
 
7. 7 C o nc o mita nt T hera p y ........................................................................................ 
 
7. 7. 1 Pr o hi bite d a n d/ or Restricte d Tre at me nts ................................................. 
 
7. 7. 2 Ot her Restricti o ns a n d Prec a uti o ns  ......................................................... 
 
7. 7. 2. 1 I m a gi n g Restricti o n a n d Prec a uti o ns  ............................................. 
 
7. 7. 3 Per mitte d T her a py  ................................................................................... 
 
7. 7. 3. 1 P alli ative L oc al T her a py ................................................................. 
 
7 0
7 0
7 0
7 1
7 3
7 3
7 4
7 4
7 4
7 7
8 1
8 1
8 2
8 2
8 6
8 6
8 7
8 8
8 9
8 9
9 0
9 1
9 1
9 2
9 3
9 3
1 0 1
1 0 2
1 0 2
1 0 2
1 0 2
1 0 4
1 0 6
1 0 6
1 0 6
1 0 7
1 0 7
1 0 8
1 0 9
1 0 9
1 0 9
1 0 9
1 1 0
1 1 0
1 1 1
1 1 1
Cli ni c al  Pr ot o c ol
B M S- 9 8 6 0 1 6
C A 2 2 4 1 0 4
r el atli m a b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

7. 8 Treat me nt Aft er t he E n d of t he St u d y  ............................................................... 
 
8 DI S C O N TI N U A TI O N C RI T E RI A  ........................................................................... 
 
8. 1 Disc o nti n uati o n Fr o m St u d y Treat me nt ............................................................ 
 
8. 1. 1 I m m u n ot her a py D ose Disc o nti n u ati o n  .................................................... 
 
8. 1. 2 C he m ot her a py D os e Disc o nti n u ati o n  ...................................................... 
 
8. 1. 3 I m m u n ot her a py Tre at me nt Bey o n d Dise as e Pr o gressi o n ........................ 
 
8. 1. 4 P ost -st u dy Tre at me nt St u dy F oll o w-u p  .................................................... 
 
8. 2 Disc o nti n uati o n Fr o m t he St u d y  ....................................................................... 
 
8. 2. 1 Tre at me nt after Disc o nti n u ati o n of t he St u dy  .......................................... 
 
8. 3 L ost t o F oll o w -u p  .............................................................................................. 
 
9 S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 
 
9. 1 Efficac y Assess me nts ........................................................................................ 
 
9. 1. 1 I m a gi n g Assess me nt f or t he St u dy ............................................................ 
 
9. 1. 1. 1 Met h o ds of Me as ure me nt  ................................................................ 
 
9. 1. 1. 2 I m a gi n g a n d Cli nic al Assess me nt  ................................................... 
 
9. 1. 1. 3 BI C R C o nfir m ati o n of Pr o gressi o n  ................................................ 
 
9. 1. 2 P atie nt -re p orte d Outc o mes  ...................................................................... 
 
 
 
 
 
 
 
9. 1. 2. 4 P GI S a n d P GI C ............................................................................... 
 
9. 2 A d verse E v e nts  ................................................................................................. 
 
9. 2. 1 Ti me Peri o d a n d Fre q ue ncy f or C ollecti n g A E a n d S A E I nf or m ati o n  .... 
 
9. 2. 2 Met h o d of Detecti n g A Es a n d S A Es  ......................................................... 
 
9. 2. 3 F oll o w -u p of A Es a n d S A Es  ..................................................................... 
 
9. 2. 4 Re g ul at ory Re p orti n g Re q uire me nts f or S A Es  ......................................... 
 
9. 2. 5 Pre g n a ncy  ................................................................................................ 
 
9. 2. 6 A dverse Eve nts of S peci al I nterest  ........................................................... 
 
9. 2. 6. 1 Defi niti o n of I m m u ne -me di ate d A dverse Eve nts  ............................. 
 
9. 2. 7 L a b or at ory Test Res ult A b n or m alities  ..................................................... 
 
9. 2. 8 P ote nti al Dr u g -i n d uce d Liver I nj ury ....................................................... 
 
9. 2. 9 Ot her S afety C o nsi der ati o ns  .................................................................... 
 
9. 3 O ver d ose  ........................................................................................................... 
 
9. 4 Safet y  ................................................................................................................ 
 
9. 4. 1 P hysic al Ex a mi n ati o ns  ............................................................................. 
 
9. 4. 2 Vit al Si g ns  ................................................................................................ 
 
9. 4. 3 Electr oc ar di o gr a ms  ................................................................................. 
 
 
 
9. 4. 5 Cli nic al S afety L a b or at ory Assess me nts  .................................................. 
 
9. 4. 6 I m a gi n g S afety Ass ess me nt  ...................................................................... 
 
9. 5 P har mac o ki netics  .............................................................................................. 
 
9. 5. 1 P h ar m ac oki netics a n d A nti -dr u g A n ti b o dy (I m m u n o ge nicity) S a m ple 
C ollecti o n a n d Pr ocessi n g  .......................................................................... 
 
9. 5. 2 P h ar m ac oki netics a n d I m m u n o ge nicity S a m ple A n alyses  ....................... 
 
9. 5. 3 P h ar m ac oki netics A n alyses  ..................................................................... 
 
9. 6 I m m u n o ge nicit y Ass ess me nts  ........................................................................... 
 
1 1 2
1 1 2
1 1 2
1 1 3
1 1 4
1 1 5
1 1 6
1 1 6
1 1 7
1 1 7
1 1 7
1 1 8
1 1 8
1 1 9
1 2 0
1 2 0
1 2 0
1 2 1
1 2 1
1 2 1
1 2 2
1 2 2
1 2 2
1 2 3
1 2 3
1 2 4
1 2 4
1 2 5
1 2 5
1 2 6
1 2 6
1 2 7
1 2 7
1 2 7
1 2 7
1 2 7
1 2 7
1 2 7
1 2 7
1 2 9
1 2 9
1 2 9
1 3 2
1 3 2
1 3 2
Cli ni c al  Pr ot o c ol
B M S- 9 8 6 0 1 6
C A 2 2 4 1 0 4
r el atli m a b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

9. 6. 1 I m m u n o ge nicity A n alyses  ......................................................................... 
 
 
 
9. 9 Bi o mar kers  ........................................................................................................ 
 
 
 
 
 
 
9. 9. 2 T u m or S a m ples ......................................................................................... 
 
9. 9. 2. 1 T u m or  S a m ple C ollecti o n  ............................................................... 
 
 
 
 
9. 9. 3 A d diti o n al Rese arc h C ollecti o n  ............................................................... 
 
 
 
9. 1 0 Me dical Res o urce Utilizati o n a n d Healt h Ec o n o mics  .................................... 
 
9. 1 1 Cli nical P har mac ol o g y S u m mar y  ................................................................... 
 
1 0 S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................... 
 
1 0. 1 Sa m ple Size Deter mi nati o n ............................................................................. 
 
1 0. 1. 1 S a m ple Size Deter mi n ati o n: P art 1 ........................................................ 
 
1 0. 1. 2 S a m ple Size Deter mi n ati o n: P art 2 ........................................................ 
 
1 0. 2 P o p ulati o ns f or A nal yses  ................................................................................ 
 
1 0. 3 Statistical A nal yses  ......................................................................................... 
 
1 0. 3. 1 Effic acy A n alyses  ................................................................................... 
 
1 0. 3. 2 S afety A n alyses ....................................................................................... 
 
 
 
 
 
1 1 R E F E R E N C E S  ........................................................................................................ 
 
1 2 A P P E N DI C E S  ......................................................................................................... 
 
A P P E N DI X 1 A B B R E VI A TI O N S A N D T R A D E M A R K S  ........................................ 
 
A P P E N DI X 2 S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S  ................................. 
 
A P P E N DI X 3 A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S: 
D E FI NI TI O N S A N D P R O C E D U R E S F O R R E C O R DI N G, E V A L U A TI N G, 
F O L L O W U P A N D R E P O R TI N G  ......................................................................... 
 
A P P E N DI X 4 W O M E N O F C HI L D B E A RI N G P O T E N TI A L D E FI NI TI O N S A N D 
M E T H O D S O F C O N T R A C E P TI O N  ..................................................................... 
 
A P P E N DI X 5 R E S P O N S E E V A L U A TI O N C RI T E RI A I N S O LI D T U M O R S 
G UI D E LI N E S ( V E R SI O N 1. 1) WI T H B M S M O DI FI C A TI O N S  ........................ 
 
 
 
A P P E N DI X 7 E C O G P E R F O R M A N C E S T A T U S  ..................................................... 
 
A P P E N DI X 8 C O U N T R Y S P E CI FI C R E Q UI R E M E N T S  ......................................... 
 
1 3 2
1 3 3
1 3 3
1 3 3
1 3 3
1 3 3
1 3 4
1 3 4
1 3 4
1 3 5
1 3 5
1 3 5
1 3 5
1 3 5
1 3 6
1 4 0
1 4 0
1 4 0
1 4 1
1 4 1
1 4 1
1 4 1
1 4 1
1 4 2
1 4 4
1 4 5
1 4 6
1 4 6
1 4 6
1 4 8
1 4 9
1 5 4
1 5 5
1 6 1
1 7 1
1 7 5
1 7 9
1 8 7
1 9 6
1 9 7
Cli ni c al  Pr ot o c ol
B M S- 9 8 6 0 1 6
C A 2 2 4 1 0 4
r el atli m a b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

A P P E N DI X 9 P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E HI S T O R Y
................................................................................................................................. 
 
 
1 9 8
Cli ni c al  Pr ot o c ol
B M S- 9 8 6 0 1 6
C A 2 2 4 1 0 4
r el atli m a b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
1 
S Y N O P SI S
Pr ot oc ol Title: A P h ase 2 R a n d o mize d St u d y of Rel atli m a b pl us Ni v ol u m a b i n C o m bi n ati o n 
wit h C he m ot her a p y vs. Ni v ol u m a b i n C o m bi n ati o n wit h C he m ot her a p y as First Li ne 
Tre at me nt f or P artici p a nts wit h St a ge I V or Rec urre nt N o n -s m all Cell L u n g C a ncer 
( N S C L C)
S h ort Title:
A St u d y  of Relat li ma b pl us Ni v o l uma b i n C o m bi nat i on wi t h Che m ot h era p y vs. Ni v o l uma b i n 
C o m bi nat i on wi t h C he mot h era p y i n Part ici pa nts with Sta ge I V or Rec urre nt N S C L C
St u d y P h ase: P hase 2
R ati o n ale:
Ni v o l uma b, relatli ma b, a n d pl at i n u m d o u blet c he m ot hera p y ( P D C T) eac h ha ve n o n- o verl a p pi n g 
a nt i-ca ncer mec ha nis ms a n d ma y ha ve s y ner gist ic a n d/ or a d diti ve acti vity a s c om bi nati o n t hera p y, 
wi t h fe w o verla p pi n g t o xicities. L y m p h oc y t e-acti vat i on ge ne 3 ( L A G-3) is of te n e x presse d o n 
c hr o nicall y ex ha uste d T- cells a n d is fre q ue ntl y c o -e x presse d wi t h pr o gra m me d deat h -li ga n d 1 
( P D-L 1) o n t ol erize d t u mor -i nfiltrati n g l y m p h oc ytes ( TI Ls) acr oss t u mor t y pes. T he rati o nale f or 
c o m bi ni n g a L A G - 3 i n hi bit or a n d a n a nt i-pr o gra m me d cell deat h pr otei n 1 ( P D-1)/ P D -L 1 a ge nt 
ori gi nates fr om e vi de nce s u g gesti n g t hat L A G - 3 has a p ote nti al rol e i n T- re g ulat or y cells 
s u p pressi on a n d a nt i –P D -1 resista nce. T he c urre nt sta n dar d of care, a nt i-P D -( L) 1 ( ± a nti-c yt ot o xic 
T-l y m p h oc y t e-ass ociate d pr otei n 4 [ C T L A- 4] a nt i b o d y) i n c o m bi nat i on wi t h PD C T 
has 
d e m o nstrate d sig nifica nt i m pr o ve me nt i n overall s ur vi val ( O S) as well as pr o gressi o n -free s ur vi val 
( P F S) i n partici pa nts wit h pre vi o usl y u ntreate d met ast atic n o n-s mall cell lu n g ca ncer ( N S C L C). 
T here are se veral ca n di date bi o mar kers w hic h ma y select partici pa nt s w h o will be nefit fr o m t he 
a d ditio n of  relat li ma b t o ni v o l uma b pl us c h e mot h era p y. M ul tiple cli nical trials ha ve esta blis he d 
t he c orrelat i on bet wee n P D -L 1 e x pressio n  an d i ncrease d res p o nse t o P D - 1 a n d P D -L 1 i m m u ne 
c hec k p oi nt i n hi biti on. D at a f r o m C A2 2 4 0 2 0 de m o n strate d preli mi nar y e vi de nce t hat partici pa nts 
wi t h LA G - 3 e x pressi o n are m o re li kel y t o res p o n d t o treat me nt wit h relatli ma b i n c o m bi nati o n 
wi t h ni v ol u ma b. Rece nt ly, fi bri n o ge n-li ke pr otei n 1 ( F G L-1) was i de ntifie d as a ne w li ga n d f or 
L A G - 3 t hat is res p o nsi ble f or its T- cell i n hi bit or y fu nct i on a n d p ote nti all y a ne w mec ha nis m f or 
i m m u n o-e vasi o n. T heref ore, F G L - 1 ma y be a n o vel  bi omar ker t o pre dict o utc o m es of  ant i- P D-1 
a n d a nt i-L A G -3 t u m or t hera pi es.
T he be nefit of t he relat li ma b pl us ni v ol u ma b c o m bi nati on c o nti n ues t o be e x pl ore d i n se veral t y pes 
of  metastatic mali g na ncies.
 
 
 T he c o m bi nat i on of  
ni v o l u ma b 3 6 0 m g e ver y 3 wee ks ( Q 3 W) pl us relatli ma b 7 2 0 m g or 3 6 0 m g Q 3 W a n d 4 c ycles of 
P D C T is e x pecte d t o ha ve a s y ner gistic effect i n t he first li ne ( 1 L) N S C L C p o p ulat i on base d o n 
t he cli nical acti vit y sh o w n b y t he 2 i n di vi d ual c o m bi nat i ons ( ni v ol u ma b pl us r elat li ma b a n d 
ni v o l u ma b pl us P D C T) a n d t heir disti nct b ut c o m ple me ntar y mec ha nis ms of acti o n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he h y p ot heses o f st u d y C A 2 2 4 1 0 4 are as f oll o ws:

Part 1 ( D ose safety c o nfir mat i on) : Ni v ol u ma b, 3 6 0 m g, pl us r elat li ma b, 7 2 0 m g or 3 6 0 m g  
Q 3 W c o m bi ne d wi t h 4 cyc les of  PD C T is safe i n parti ci pa nts wi t h 1L S ta ge I V or rec urre nt 
N S C L C.

Part 2 : Ni v o l uma b pl us r elat li ma b c o m bi ne d wi t h 4 cycles of  PD C T i m pr o ves O R R w he n 
c o mpare d t o ni v ol u ma b pl us P D C T i n partici pa nts wit h 1 L S ta ge I V or rec urre nt N S C L C. 
St u d y P o p ul ati o n:
A d ult parti ci pa nts wit h hist ol o gi call y co nfir me d Sta ge I V or rec urre nt N S C L C wit h n o pri or
s yste mic t hera p y for met astatic disease, n o e pider mal gr o wt h fact or rece pt or ( E G F R), a na plast ic 
l y m p h oma 
ki nase ( A L K), R O S -1, or B- ra pi dl y accelerate d fi br osarc o ma pr ot o -o nc o ge ne 
( B R A F) V 6 0 0 E m ut atio ns, a n d a n Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or m a nce Stat us 
( E C O G P S) of ≤ 1.
Ke y I ncl usi o n Criteri a:

Males a n d fe males; ≥ 1 8 y ears of a ge or l o c al  a ge of majori t y.

Hi st olo gi call y c o nfir me d metastati c N S C L C
of  sq ua m o us ( S Q) or n o n- s q ua m o us ( N S Q)
hist ol o g y  with Sta ge I V or rec urre nt disease f ollo wi n g m ult i- mo dal t hera p y f or l ocall y 
a d va nce d disease.

Meas ura ble disease b y c o m p ute d t o mo gra p h y  or ma g net ic res o na nce i ma gi n g per Res p o nse 
E val uat i on Cri teria i n S oli d T u m ors (R E CI S T ) v1. 1 criteria; ra dio gra p hic t u mor assess me nt  
perf or m e d 
 bef ore ra n d o mizatio n .

N o pri or s yste mic a nt i-ca ncer tr e at me nt gi ve n as pri mar y  t hera p y f or a d va nce d or m etastatic 
di sease.

E C O G P S of  1 at scree ni n g a n d c o nfir me d pri or t o ra n d o mizat i on.

Parti cipa nts m ust ha ve a life e x pecta nc y  of at least 3 mo nt hs at t he ti me of first d ose. 
Ke y E xcl usi o n Criteri a:

W o me n w h o are pre g na nt or breastfee di n g.

Parti cipa nts wi t h EG F R, A L K, or R O S - 1 m ut atio ns w hic h are se nsiti ve t o a vaila ble tar gete d 
i n hi bit or t hera p y. All partici pa nts wit h N S Q hist ol o g y m ust ha ve bee n teste d f or E G F R, A L K, 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
or R O S - 1 m ut atio n stat us. Parti ci pa nts wi t h NS Q hist ol o g y  an d u n k n o w n E G F R, A L K, or 
R O S -1 stat us are e xcl u de d.

Parti cipa nts wit h k n o w n B R A F V 6 0 0 E m ut atio ns t hat are se nsiti ve t o a vaila ble tar gete d 
i n hi bit or t her a p y. Parti ci pa nts wi t h un k n o w n or i n deter mi nate B R A F m utati o n stat us are 
eli gi ble.

Parti cip a nts wi t h u ntreate d ce ntral ner v o us s yste m metastases.

Parti cip a nts wi t h le pt o me ni n geal metastases (carci n o mat o us m e ni n gitis).

C o nc urre nt mali g na nc y  re q uirin g treat m e nt .

Parti cip a nts wi t h a n acti ve, k n o w n, or s us pecte d a ut oi m m u ne disease. 

Pri or treat me nt wi t h an a nti-P D -1, a nt i-P D -L 1, a nt i-P D -L 2 , a nt i-L A G - 3, or a nti-C T L A -4 
a nt i b o d y, or a n y ot h er a nt i 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 poi nt pat h wa ys .
O bjecti ves a n d E n d p oi nts:
T a ble 1:
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
P art 1: D ose S afet y C o nfir m ati o n
Pri m ar y
T o e val uate t he pr o p orti o n of partici pa nts wit h T R A Es lea di n g t o 
disc o nti n uati o n wit hi n 1 2 wee ks after t he first d ose of ni v ol u ma b pl us 
2 differe nt d ose le vels of relatli ma b ( 3 6 0 m g a n d 7 2 0 m g) i n 
c o m bi nati o n w it h P D C T i n d ose safet y e val ua ble partici pa nts wit h 
hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C

T R A Es lea di n g t o disc o nti n uati o n 
wit hi n 1 2 wee ks after t he first d ose
Sec o n d ar y
T o e val uate t he safet y a n d t olera bilit y of ni v ol u ma b pl us 2 differe nt 
d oses of relatli ma b ( 3 6 0 m g a n d 7 2 0 m g) i n c o m bi nati o n wit h P D C T 
i n all partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C t hat were treate d d uri n g t he d ose safet y 
c o nfir mati on peri o d
 
I nci de nce of T R A Es 
lea di n g t o 
disc o nti n uati o n, A Es, 
S A Es, a n d 
select A Es
P art 2 
Pri m ar y
T o e val uate O R R of ni v ol u ma b pl us relatli ma b i n c o m bi nati o n wit h 
P D C T relati ve t o ni v ol u ma b i n c o m bi nati o n wit h P D C T i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt 
N S C L C
 
O R R per R E CI S T v 1. 1 b y BI C R
Sec o n d ar y
T o e val uate t he P F S of ni v ol u ma b pl us relatli ma b i n c o m bi nati o n 
wit h P D C T relati ve t o ni v ol u ma b i n c o m bi nati o n wit h P D C T i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt 
N S C L C
 
P F S per R E CI S T v 1. 1 b y BI C R
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 1:
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
T o e val uate t he d urati o n of res p o nse ( D o R) of ni v ol u ma b pl us 
relatli ma b i n c o m bi nati o n wit h P D C T relati ve t o ni v ol u ma b i n 
c o m bi nati o n w it h P D C T i n partici pa nts wit h hist ol o gicall y c o nfir me d 
1 L Sta ge I V or rec urre nt N S C L C
 
D o R per R E CI S T v 1. 1 b y BI C R, 
i ncl u di n g D o R 
at 6, 1 2
a n d 1 8 
m o nt hs
T o e val uate O R R a n d P F S of ni v ol u ma b pl us relatli ma b i n 
c o m bi nati o n w it h P D C T relati ve t o ni v ol u ma b i n c o m bi nati o n wit h 
P D C T i n partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C, i n s u b gr o u ps defi ne d b y P D-L 1 e x pressi o n, L A G -3 
e x pressi o n, F G-L 1 e x pressi o n
 
O R R a n d P F S per R E CI S T v 1. 1 b y 
BI C R
T o e val uate t he safet y a n d t olera bilit y of ni v ol u ma b pl us relatli ma b i n 
c o m bi nati o n w it h P D C T i n hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C.
 
I nci de nce of A Es, S A Es,
T R A Es, 
I M A Es a n d select A Es
A b bre viati o ns: 1 L = first li ne; A E = ad verse e ve nts; BI C R = bli n de d i n de pe n de nt ce ntral re vie w; F G-L 1 = fi bri n o ge n -
li ke pr otei n 1; L A G-3 = l y m p h oc yte -acti vati o n ge ne 3; N S C L C = n o n -s mall cell l u n g ca ncer; O R R = o verall res p o nse 
rate; P D C T = plati n u m d o u blet c he m ot hera p y; P D-L 1 = pr o gra m me d dea t h-li ga n d 1; P F S = pr o gressi o n free s ur vi val; 
R E CI S T = res p o nse e val uati o n criteria i n s oli d t u m ors; S A E = seri o us a d verse e ve nt; T R A E = treat me nt relate d 
a d verse e ve nts.
O ver all Desi g n:
T his m ult i-ce nter, ra n d o mize d trial will e val uate t he efficac y a n d safet y of  the c o m bi nat i on of 
ni v o l u ma b pl us r elat li ma b a n d P D C T vs ni v o l uma b a n d P D C T i n a d ults wit h u ntreate d Sta ge I V 
or rec urre nt N S C L C. T he st u d y  will be carrie d o ut i n 2 parts: Part 1, a site -a n d-s u bject bli n d d ose 
safety c o nfir mat i on a n d Part 2, a o pe n- label, ra n d o mize d, c o ntr olle d trial.
Part 1 - D o se safety c o nfi r mat i on ( n ≈ u p t o 1 2 0): Site -a n d-s u bject bli n de d, ra n d omize d d ose safety 
c o nfir mat i on. El i gi ble partici pa nts will be ra n d omize d 1: 1 t o Ar ms A or B t o e val uate t he safety 
a n d t olera bilit y of t he c o m bi natio n of  ni v ol u ma b pl us relatli ma b 7 2 0 m g a n d P D C T a n d c o nfir m 
t he safety pr ofile. T he relatli ma b 3 6 0 m g Q 3 W d ose i n Ar m B will be e val uate d t o ge nerate 
a d ditio nal safet y d at a at t hi s d ose le vel. T he ra n d o mizati on will  be stratifie d b y hist ol o g y  ( S Q vs 
N S Q). After all treate d partici pa nts ha ve bee n f oll o we d- u p f or a mi ni m u m of  12 wee ks, t he 
pri mar y  a nal ysis will ta ke place t o deter mi ne w het her t he fi nal esta blis he d t hres h ol d f or t he d ose-
safety e val ua ble p o p ulati o n has bee n met  an d t o e val uate t he t otality of  t he Part 1 safety data. I n 
a d ditio n, t he pr o p orti o n of  treat me nt-relate d a d verse e ve nts ( T R A Es) lea di n g t o disc o nt i n uati on 
wi t hi n 1 2 wee ks of  the first d ose will be m o nit ore d f or eac h ar m 
 
P art 2 ( n = 3 0 0) : Ra n d o mize d, o pe n -label, c o ntr olle d trial t hat will f urt her e val uate t he efficac y 
a n d safety of  the ni v o l u ma b, relatli ma b pl us c he mot h era p y co m bi nat i on vs ni v o l uma b pl us 
c he m ot hera p y. 
 
 
 At t his time, partici pa nts t hat are i n 
scree ni n g a n d f ou n d t o be eli gi ble will  be ra n d o mize d 1: 1 i nto e x peri me ntal Ar m C or c o ntr ol 
Ar m D of  P art 2 of t he trial. 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 
  T he stratificatio n fact ors f or ra n d o mizat i on i n P art 2 ar e hist olo g y  ( S Q vs N S Q), 
E C O G perf or ma nce stat us ( 0 vs 1) a n d P D-L 1 le vel ( ≥1 % [i ncl u di n g N Q] vs < 1 %).
N u m ber of P artici p a nts: 
I n t he d ose safet y c o nfir mat i on ( Part 1) , u p t o a p pr o xi matel y 1 2 0 partici pa nts will be ra n d o mize d 
1: 1 t o treat me nt Ar ms A or B (ie, 6 0 partici pa nts per ar m).
I n Part 2, a p pr o xi matel y 3 0 0 parti ci pa nts will be ra n d omize d 1: 1 t o t he e x peri me ntal ar m, C, or 
t he c o ntr ol ar m, D (ie, 1 5 0 partici pa nts per ar m ).
S a m ple Size Deter mi n ati o n:  P art 1 
U p t o a p pr o xi matel y 1 2 0 partici pa nts will be ra n d o mize d 1: 1 t o treat me nt Ar ms A a n d B (ie, u p 
t o 6 0 partici pa nts per ar m). 
 
 
 
 
S a m ple Size Deter mi n ati o n:  P art 2 
A p pr o xi matel y 3 0 0 parti ci pa nts will be ra n d o mize d 1: 1 (ie, 1 5 0 partici pa nts per ar m) stratifie d b y 
hist ol o g y  (S Q vs N S Q) . E C O G P S ( 0 vs 1 ) a n d P D -L 1 level ( ≥1 % [i ncl u di n g N Q] vs < 1 %). 
 
Tre at me nt Ar ms a n d D ur ati o n:
St u d y tre at me nt:
St u d y Tre at me nt f or C A 2 2 4 1 0 4
Me dic ati o n 
P ote nc y 
I P/ N o n-I P 
Relatli ma b
 
I P
Ni v ol u ma b
1 0 m g/ m L
I P
Car b o plati n
1 0 m g/ m L
I P
Cis plati n
1 0 0 m g/ vial ( 1 m g/ m L)
I P
Paclita xel
6 m g/ m L
I P
Na b -Paclita xel
1 0 0 m g/ vial
I P
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
St u d y Tre at me nt f or C A 2 2 4 1 0 4
Me dic ati o n 
P ote nc y 
I P/ N o n-I P 
Pe metre xe d
5 0 0 m g/ vial
I P
A b bre viati o n: I P = i n vesti gati o nal pr o d uct .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Fi g ure 1:
St u d y Sc he m atic
A b bre viati o ns: A E = a d verse e ve nt; A L K = a na plastic l ym p h o ma ki nase ; A U C = area u n der t he c o nce ntrati o n -ti me c ur ve; BI C R = bli n de d i n de pe n de nt ce ntral 
re vie w; E C O G P S = Easter n C o o perati ve O n c ol o g y Gr o u p Perf or ma nce Sc ore; E G F R = e pi der mal gr o wt h fact or; 
 N S C L C = N o n -s mall cell l u n g ca ncer; N Q = n o n -q ua ntifia ble; 
; O R R =
o verall res p o nse rate; O S = o verall s ur vi val; P D = pr o gressi ve disease; P D C T = plati n u m d o u blet c he m ot hera p y; 
 P F S =
pr o gressi o n -free s ur vi val; P K = p har mac o ki netic; P S = perf or ma nce stat us; P R O = patie nt -re p orte d o utc o me; Q 3 W = e ver y 3 wee ks; S A E = seri o us a d verse e ve nt; 
S Q = s q ua m o us.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he Part 1 d ose safety c o nfir mat i on p eri o d is 1 2 wee ks after t he first d ose. U p t o a p pr o xi matel y 
1 2 0 eli gi ble partici pa nts t o e nr oll i n t he st u d y will be ra n d o mize d 1: 1 t o e x peri me ntal Ar ms A 
or B. Ni v o l uma b 
pl us r elat li ma b, t he i m m u ne c hec k p oi nt i n hi bit ors here o n r eferre d t o as 
i m m u n ot hera p y, will be a d mi nistere d i n a site-a n d-s u bject bli n de d ma n ner, w hereas c he m ot hera p y 
will be a d mi nistere d as o pe n la bel. 
Ar m A: Ni v ol u ma b 3 6 0 m g Q 3 W + relat li ma b 7 2 0 m g Q 3 W + 4 c ycles of hist ol o g y-base d P D C T 
Ar m B: Ni v o l uma b 3 6 0 m g Q 3 W + r elat li ma b 3 6 0 m g Q 3 W + 4 c ycles of hist ol o g y-base d P D C T 
D uri n g t he treat me nt p hase of  Part 2 of  the st u d y, parti ci pa nts will recei ve t he f o ll owi n g tr e at me nts. 
I mm u n ot hera p y  a n d c he mot h era p y will be a d mi nistere d as o pe n-label  int er ve nt i ons.
Ar m C:   Ni v o l uma b 3 6 0 m g Q 3 W + r elat li ma b 3 6 0 m g a Q 3 W + 4 c ycles of  hist olo g y -base d 
P D C T b or
Ar m D:   Ni v o l uma b 3 6 0 m g Q 3 W + 4 c y cles o f hist ol o g y -base d P D C T b
a
T he relatli ma b d ose t o be i ncl u de d i n Ar m C will be deter mi ne d b y t he o utc o me of t he d ose safet y c o nfir mati o n 
t hat will ta ke place i n Part 1 of t he st u d y a n d ot her be nefit -ris k c o nsi derati o ns at asset le vel. T his was deter mi ne d 
t o be relatli ma b 3 6 0 m g.
b
Hist ol o g y -base d P D C T will be as f oll o ws:
N S Q: Car b o plati n area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) 5 or 6 * or cis plati n 7 5 m g/ m 2 + pe metre xe d 5 0 0 
m g/ m 2 ( mai nte na nce per mitte d) 
S Q:  Car b o plati n A U C 6 + paclita xel 2 0 0 m g/ m 2 or na b -paclita xel 1 0 0 m g/ m 2
N ote: Car b o plat i n A U C 6 f or N S Q a n d na b -pacli t axel f or S Q hist ol o g y is per mitte d o nl y  in Part
1.
D ose re d ucti o ns are n ot per mitte d f or i m m u n ot hera p y .
All p arti ci pa nts will be treate d u ntil pr o gressio n, prese nce of i ntol era ble t o xicities, wit hdra wal  of 
c o nse nt, or stu d y e n d, w hic he ver 
c o me s first. C o nti n u o us safet y eval uat i ons a n d t u mor 
assess me nts will g ui de t he decisi o n t o treat a partici pa nt wit h a d dit i onal c ycles of st u d y  t hera p y if 
t he partici pa nt has c o nfir me d cli nical be nefit. 
Parti cipa nts will be allo we d t o c o nt i n ue st u d y treat me nt u nt il t he first occ urre nce of  an y of  the 
f oll owi n g sit uat i ons:
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b

Pr o gressi ve disease defi ne d b y R E CI S T v 1. 1 u nless parti ci pa nts meet criteria f or treat me nt 
be y o n d pr o gressi o n .

Cli nical deteri orati o n s u g gest i n g t hat n o f urt her be nefit fr o m treat me nt is li kel y.

I nt olera bilit y t o t her a p y.

Parti cip a nt m eets crit eria for di sc o nti n uati on of st u d y  treat me nt .
D at a M o nit ori n g C o m mittee: 
A n i n de pe n de nt Data M o nit ori n g C om mittee ( D M C) will be ut ilize 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 St u d y  CA 2 2 4 1 0 4 d uri n g t he o pe n -label Part 2 p hase. T he 
i n de pe n de nt 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 act i ons t he c o m mitt e e dee ms 
necessar y  for t he c o nti n ui n g pr otecti o n of  part ici pa nts e nr olle d i n t his st u d y. T he i n de pe n de nt 
D M C will be c har ge d wit h assessi n g s uc h acti o ns i n li g ht of a n acce pta ble be nefit -ris k pr ofile f or 
ni v o l u ma b/relatli ma b. T he i n de pe n de nt 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 parti cipa nt safet y  data f or Part 2 of t he st u d y.
B M S will ha ve res p o nsi bility f or t he o verall c o n d uct of  the stu d y, i ncl u di n g ma na gi n g t he 
c o m m u nicat i on of  st u d y data. B M S will be res p o nsi ble f or pr o m ptl y revie wi n g t he D M C 
rec o m me n dati ons, f or pr o vidi 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 co n d uct are 
re q uire d. Details of t he i n de pe n de nt 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.
I n a d ditio n t o t he D M C, a s afet y c o m mittee ( S C) c o nsist i n g of  BM S researc h a n d de vel o p me nt 
re prese ntati ves (incl u di n g cli nical de vel o p me nt, dr u g safety,  an d statistics) a n d e xter nal 
re prese ntati ves (incl u di n g a selecti o n o f the st u d y i n vesti gat ors) will re g ularl y meet t o e val uate t he 
acc u m ulat i n g safety data of  partici pa nts o n t he d ose safety c o nfir mat i on p orti o n of  the st u d y 
( Part 1) a n d pr o vi de i n p ut t o i nter pret safet y si g nals. I nf or mati o n re vie we d at eac h ti me p o i nt may 
i ncl u de dis p osi tio n, d e m o gra p hics, A Es, T R A Es, T R A Es lea di n g t o disc o nti n uati o n, e x p os ure, 
deat h data, a n d a n y ot h er data dee me d rele va nt (la b orat or y, p at h olo g y , a ut o ps y re p orts, p h ysica l 
descri pt i ons). T he mi n utes of t hese meeti n g s will be d oc u me nte d i n t he Trial Master File. T he S C 
will n ot s hare res p o nsi bilities wi t h t he D M C (ie, t he S C is res p o nsi ble f or m o nit ori n g Part 1 a n d 
t he D M C f or Part 2). Decisi o ns o n safet y,  t o xicit y, a n d be nefit-ris k re gar di n g eac h d ose le vel will 
be s ol el y t he res p o nsi bilit y of B M S a n d will ta ke acc o u nt of t he t otalit y of t he data a vaila ble.
Alt h o u g h t he S C will meet o nl y  duri n g Part 1 of  the st u d y, t he safety of  the selecte d d ose will 
c o nti n ue t o be m o nit ore d i n Part 2. T he D M C will re g ularl y re vie w a n y p ote nti al e mer ge nt safet y 
sig n al  that was n ot o bser ve d i n Part 1 ( n ote t hat t he D M C will recei ve t he m ost rece nt Part 1 safet y 
data as well .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
2 
S C H E D U L E O F A C TI VI TI E S
T a ble 2- 1: 
Scree ni n g Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
Eli gi bilit y Assess me nts
I nf or me d C o nse nt
X
M ust be o btai ne d pri or t o perf or mi n g a n y scree ni n g pr oce d ures. 
St u d y all o ws f or re -e nr oll me nt of a partici pa nt t hat has disc o nti n ue d t he st u d y as a pre-treat me nt 
fail ure. If re-e nr olle d, t he partici pa nt m ust be r e-c o nse nte d a n d assi g ne d a ne w partici pa nt n u m ber 
fr o m I R T.
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 pri or t o ra n d o mizati o n.
Me dical Hist or y
X
I ncl u di n g disease state relate d t o t he st u d y, sta ge, hist ol o g y, m utati o n stat us, pri or t hera pies f or 
a d va nce d disease, a n d ot her rele va nt hist or y.
S afet y Assess me nts
P h y sical Meas ure me nts/ P E
X
F ull P E. I ncl u de hei g ht a n d wei g ht. Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
E C O G Perf or ma nce Stat us
X
See A p pe n di x 7 . Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
Vital Si g ns
X
O x y ge n sat urati o n, B P, heart rate, a n d te m perat ure.
O btai n at t he scree ni n g visit, wit hi n 1 4 da ys pri or t o ra n d o mizati o n .
Assess me nt of Baseli ne Si g ns 
a n d S ym pt o ms
X
Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
A E/ S A E Assess me nts
X
C ollecte d fr o m ti me of c o nse nt. All A Es/ S A Es m ust be gra de d per C T C A E v 5. All A Es ( S A Es or 
n o n- seri o us A Es) ass ociate d wit h S A R S-C o V -2 i nfecti o n c ollecte d fr o m ti me of c o nse nt.
C o nc o mita nt Me dicati o n 
C ollecti o n
X
Wit hi n 1 4 da ys pri or t o ra n d o mizati o n t hr o u g h t he st u d y treat me nt peri o d. D oc u me nt vacci ne use 
wit hi n 3 0 da ys pri or t o ra n d o mizati o n. See Secti o n 7. 7 .
Pre g na nc y Test ( W O C B P o nl y)
F S H
X
Ser u m or uri ne ( mi ni m u m se nsiti vit y e q ui vale nt u nits 2 5 I U/ L or e q ui vale nt u nits of H C G) t o be 
d o ne at Scree ni n g i n W O C B P. Ne gati ve pre g na nc y test re q uire d at Scree ni n g (a n e xte nsi o n u p t o 7 2 
h o urs pri or t o start of st u d y dr u g ma y be per missi ble i n sit uati o ns w here res ults ca n n ot be o btai ne d 
wit hi n t he sta n dar d 2 4 -h o ur wi n d o w).
F S H scree ni n g - o nl y re q uire d t o c o nfir m me n o pa use i n w o me n < 5 5 years of a ge.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 3
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 1: 
Scree ni n g Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
L a b or at or y Assess me nts
La b orat o r y Tests
X
M ust be perf or me d wit hi n 1 4 da ys pri or t o ra n d o mizati o n. See Ta ble 9. 4. 5 - 1 f or list.
X
Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
E C G ( 1 2 -lea d)
X
At rest. Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
E C Gs s h o ul d be rec or de d after t he partici pa nt has bee n s u pi ne f or at least 5 mi n utes.
Ec h ocar di o gra m
X
L V E F assess me nt wit h d oc u me nte d L V E F ≥ 5 0 % b y eit her T T E or M U G A ( T T E is preferre d test) 
wit hi n 6 m o nt hs bef ore date of first d ose. Partici pa nts wit h ot her si g nifica nt a b n or malities o n 
E C H O/ M U G A s h o ul d be disc usse d wit h t he B M S M M pri or t o e nr oll me nt.
Effic ac y Assess me nts
B o d y I ma gi n g 
X
C o ntrast -e n ha nce d C T of t he c hest, C T/ M RI of t he a b d o me n, pel vis, a n d all ot her k n o w n a n d/ or 
s us pecte d sites of disease, 
 pri or t o ra n d o mizati o n. See Secti o n 9. 1. 1. 1 f or f urt her 
details .
Br ai n I ma gi n g
X
M RI of t he brai n ( wit h o ut a n d wit h c o ntrast) is re q uire d f or A L L partici pa nts d uri n g scree ni n g t o r ule 
o ut brai n metastases,  
 pri or t o ra n d o mizati o n. C T of t he brai n ( wit h o ut a n d wit h 
c o ntrast) ca n be perf or me d if M RI is c o ntrai n dicate d. See Secti o n 9. 1. 1. 1 f or f urt her details.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 4
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 1: 
Scree ni n g Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
Bi o m ar ker Assess me nts
T u m o r Tiss ue ( Bi o mar kers)
X
E G F R, A L K, a n d R O S -1, 
B R A F V 6 0 0 E M utati o n Stat us
X
E G F R, A L K, a n d R O S -1 res ults re q uire d f or all n o ns q ua m o us partici pa nts pri or t o ra n d o mizati o n. 
Hist orical res ults o btai ne d as sta n dar d of care pri or t o scree ni n g peri o d are acce pta ble. E G F R 
m utati o n, A L K, a n d R O S -1 tests s h o ul d be perf or me d b y site ( preferre d) or b y ce ntral la b orat or y. 
T he use of F D A -a p pr o ve d or l ocal Healt h A ut h orit y-a p pr o ve d tests f or E G F R an d A L K are str o n gl y 
e nc o ura ge d. Ce ntral la b orat or y will re q uire a d diti o nal tiss ue f or ce ntral testi n g if n ot perf or me d 
l ocall y (see La b orat or y Ma n ual).
 
E G F R m utati o n test (t u m or tiss ue or bl o o d) will be perf or me d usi n g P C R -base d assa y or ne xt 
ge nerati o n se q ue nci n g. Tests ot her t ha n P C R or ne xt ge nerati o n se q ue nci n g will be re q ueste d t o 
re peat usi n g P C R or ne xt ge nerati o n se q ue nci n g-base d met h o ds.
 
A L K a n d R O S -1 rearra n ge me nt tests are ma n dat or y f or partici pa nts wit h n o ns q ua m o us 
hist ol o g y. Partici pa nts wit h k n o w n A L K/ R O S -1 tra nsl ocati o ns w hic h are se nsiti ve t o a vaila ble 
tar gete d i n hi bit or t hera p y are e xcl u de d.
 
If k n o w n stat us of B R A F V 6 0 0 E m utati o ns ( w hic h are se nsiti ve t o a vaila ble tar gete d i n hi bit or, 
t hera p y), partici pa nt is e xcl u de d. If B R A F m utati o n stat us is u n k n o w n or i n deter mi nate, 
partici pa nt ma y e nr oll.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 5
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 1: 
Scree ni n g Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
I R T/ Cli nic al Dr u g S u p plies
I R T
X
F or partici pa nt n u m ber assi g n me nt at t he ti me i nf or me d c o nse nt is o btai ne d.
O utc o mes Assess me nts
X
Part 2 o nl y .  Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
P GI S
X
Part 2 o nl y .  Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
X
Part 2 o nl y .  Wit hi n 1 4 da ys pri or t o ra n d o mizati o n.
A b bre viati o ns: A E = a d verse e ve nt; A L K
= a na plastic l y m p h o ma ki nase; B P = bl o o d pr ess ure; B R A F = B- pr ot o -o nc o ge ne; C T = c o m p ute d t o m o gra p h y; 
C T C A E = C o m m o n Ter mi n ol o g y Crit e ria f or Ad verse E ve nts; E C G = electr ocar di o gra m; E C H O = ec h ocar di o gra m ; E C O G = Easter n C o o perati ve O nc ol o g y 
Gr o u p; E G F R = e pi der mal gr o wt h fact or rece pt or ; F D A = F o o d a n d Dr u g A d mi nistrati o n ; 
 F S H = f ollicle-sti m ulati n g 
h or m o ne; H C G = h u ma n c h ori o nic g o na d otr o pi n; I R T = I nteracti ve Res p o nse Tec h n ol o g y; 
L V E F = left ve ntric ular ejecti o n 
fracti o n; M M = Me dical M o nit or ; M RI
= ma g netic res o na nce i ma gi n g; M U G A = m ulti ple gate d ac q uisiti o n s ca n;
 
 N S Q = n o n- s q ua m o us; P C R = p ol y merase c hai n reacti o n;
 
P E = p h ysical e xa mi nati o n; P GI S = Patie nt Gl o bal I m pressi o n of Se verit y; 
S A E = seri o us 
a d verse e ve nt ; S A R S -C o V - 2 = se vere ac ute res pirat or y syn dr o me c or o na vir us 2 ; S Q = s q ua m o us; T T E = tra nst h oracic ec h ocar di o gra m; W O C B P
= w o me n of 
c hil d beari n g p ote ntial.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 6
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 2: 
O n Tre at me nt Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
S afet y Assess me nts
Tar gete d P h ysical E xa mi nati o n
a n d 
E C O G Perf or ma nce Stat us
X
X
 
 
 
C o nfir m E C O G stat us o n C 1 D 1 a n d eac h s u bse q ue n t c ycle.
See A p pe n di x 7 .
P h y sical Meas ure me nts
X
X
Vital Si g ns
X
X
I ncl u di n g o x y ge n sat urati o n, B P, heart rate, a n d te m perat ure.
A E a n d S A E Assess me nts  
C o nti n u o usl y d uri n g t he st u d y 
All A Es ( S A Es or n o nseri o us A Es), i ncl u di n g t h ose ass ociate d wit h 
S A R S -C o V -2 i nfecti o n , m ust be c ollecte d c o nti n u o usl y d uri n g t he 
treat me nt peri o d. S A Es t o be a p pr o ve d i n R A V E wit hi n 5 da ys fr o m 
e ntr y. 
All A Es/ S A Es m ust be gra de d usi n g C T C A E v 5. 
Re vie w of C o nc o mita nt Me dicati o ns 
X
X
E C G ( 1 2 -lea d)
X
See n ote
E C G re q uire d o nl y o n 
S y m pt o m -base d E C G or wit h 
 ma y be perf or me d as 
re q uire d.
Ec h ocar di o gra m
See n otes
As cli nicall y i n dicate d or at 
Pre g na nc y Test ( W O C B P o nl y)
X
X
Ser u m or uri ne ( mi ni m u m se nsiti vit y e q ui vale nt u nits 2 5 I U/ L or 
e q ui vale nt u nits of H C G). T o be c o n d ucte d wit hi n 2 4 h o urs pri or t o 
treat me nt.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 7
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 2: 
O n Tre at me nt Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
L a b or at or y Assess me nts
La b orat o r y Tests
X
X
Wit hi n 7 2 h o urs pri or t o d osi n g, i ncl u di n g he mat ol o g y, ser u m c he mistr y, 
uri nal y sis, t h yr oi d f u ncti on tests,  
 
All la b orat or y res ults s h o ul d be c hec ke d pri or t o d osi n g.  
 
 Please refer t o Ta ble 
9. 4. 5- 1 Ta ble 9. 4. 5 - 1.
N ote: C 1 D 1 la bs d o n ot nee d t o be re peate d if perf or me d wit hi n 1 4 da ys 
of d osi n g. T S H is d o ne e ver y 2 c ycles.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 8
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 2: 
O n Tre at me nt Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
X *
( See 
N otes)
X *
( See n otes)
 
 
 
 
 
 
* F or C 1 D 1, val ue ta ke n at scree ni n g ( pre -ra n d o mizati on) ma y be use d 
a n d nee d n ot be re peate d
All res ults s h o ul d be c hec ke d as s o o n as p ossi bl e.
S y m pt o m -base d 
ma y be perf or me d as cli nicall y 
i n dicate d, t hereafter. 
F or 
 please refer t o t he I M A E 
 
Cli nical O bser vati o ns
See N otes
All partici pa nts s h o ul d be cli nicall y e val uate d f or a n y i m m u ne-me diate d 
e ve nts. E val uati o ns s h o ul d occ ur e ver y wee k u p t o a n d 
 
 
 Partici pa nts wit h a n y cli nical
s ym pt o ms s h o ul d i m me diatel y be e val uate d. F or n o n- d osi n g visits,
assess me nts ma y be perf or me d r em otel y b y t h e I n vesti gat or/ dele gate.
Effic ac y Assess me nts
B o d y I ma gi n g 
C o ntrast e n ha nce d C T of t he c hest, C T/ M RI of t he a b d o me n, pel vis, a n d all ot her k n o w n a n d/ or s us pecte d sites of 
disease s h o ul d occ ur e ver y 6 wee ks starti n g fr o m date of ra n d o mizati o n ( 7 da ys) u ntil 
 
(7 da ys) be gi n ni n g o n Wee k 4 9. I ma gi n g s h o ul d c o nti n ue u ntil BI C R disease pr o gressi o n or treat me nt 
disc o nti n uati o n ( w hic he ver occ urs later), partici pa nt wit h dra wal of c o nse nt, or deat h.  See Secti o n 9. 1. 1. 1 f or 
f urt her details.
Br ai n I ma gi n g 
Partici pa nts wit h a hist or y of brai n metastasis or s y m pt o ms s h o ul d ha ve a s ur veilla nce M RI ( wit h o ut a n d wit h 
c o ntrast) st u d y per sta n dar d of care 
 or s o o ner if cli nicall y i n dicate d. C T of t he 
br ai n wit h o ut a n d wit h c o ntrast ca n be perf or me d if M RI is c o ntrai n dicate d. See Secti o n 9. 1. 1. 1 f or f urt her details.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 9
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 2: 
O n Tre at me nt Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
P K a n d I m m u n o ge nicit y Assess me nts
P K Sa m ples
T hr o u g h o ut t he st u d y 
See  Secti o n 9. 5 .
I mm u n o ge nicit y Sa m ples
T hr o u g h o ut t he st u d y 
See Secti o n 9. 5 .
O utc o mes Assess me nts
X
See n ote
C o m plete d pri or t o d osi n g o n Da y 1 of eac h c ycle fr o m C ycle 1 t hr o u g h 
C y cle 1 0 a n d t he n e ver y ot her c y cle u ntil c y cle 36.
Part 2 o nl y : Co m plete d e ver y 6 c y cles fr o m C ycle 3 6 u ntil t he e n d of t he 
treat me nt peri o d.
X
See n ote
P GI S
X
See n ote
X
See n ote
P GI C
See n ote
C o m plete d pri or t o d osi n g o n Da y 1 of eac h c ycle fr o m C ycle 2 t hr o u g h 
C y cle 1 0 a n d t he n e ver y ot her c y cle u ntil C ycle 3 6 . 
Part 2 o nl y : C o m plete d e very 6 c y cles fr o m C ycle 36 u ntil t he e n d of t he 
treat me nt peri o d.
T he P GI C is n ot a d mi nistere d o n C 1 D 1
C li nic al Dr u g S u p pl y
I RT Vial Assi g n me nt
X
X
Wit hi n 1 da y pri or t o d osi n g.
St u d y Tre at me nt b, c
Pa rt 1: D ose Safet y C o nfir mati o n: 
Ni v ol u ma b + Relatli ma b + P D C T Q 3 W 
× 4 
X
X
Ar m A e: Ni v ol u ma b 3 6 0 m g Q 3 W + Relatli ma b 7 2 0 m g Q 3 W + 4 c ycles 
of P D C T Q 3 W 
Ar m B e: Ni v ol u ma b 3 6 0 m g Q 3 W + Relatli ma b 3 6 0 m g Q 3 W + 4 c ycles 
of P D C T Q 3 W 
Pa rt 2:
Ni v ol u ma b + Relatli ma b + P D C T Q 3 W 
× 4 
Ni v ol u ma b + P D C T Q 3 W × 4
X
X
Ar m C d ,e: Ni v ol u ma b 3 6 0 m g Q 3 W + Relatli ma b 3 6 0 m g Q 3 W + 4 
c ycles of P D C T Q 3 W
Ar m D: Ni v ol u ma b 3 6 0 m g Q 3 W +  4 c ycles of P D C T Q 3 W
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 0
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A b bre viati o ns: A E = a d verse e ve nt; 
 BI C R = b li n de d in de pe n de nt ce ntral re vie w; B P = bl o o d press ure; C = C ycle;  
 
C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or Ad verse E ve nts; D = Da y ; 
E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; e C R F = electr o nic case re p ort f or m; 
 
 H CG = h u ma n c h ori o nic g o na d otr o pi n; I g = i m m u n o gl o b uli n ; I R T = I nteracti ve Res p o nse Tec h n ol o g y;
M RI = ma g netic 
res o na nce i ma gi n g; 
 N S Q = n o n- s q ua m o us; P D C T = plati n u m d o u blet 
c he m ot hera p y; P GI C = Partici pa nt Gl o bal I m pressi o n of C ha n ge; P GI S = Partici pa nt Gl o bal I m pressi o n of Se verit y; P K = p har mac o ki netic s; 
 Q 3 W = e ver y 3 wee ks; R A V E E D C = Electr o nic Data Ca pt ure; S A E = seri o us a d verse e ve nt; S A R S-C o V -
2 = se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 ; T S H = t h yr oi d-sti m ulati n g h or m o ne; v = versi o n; W O C B P = w o me n of c hil d beari n g p ote ntial.
b
Pe metre xe d mai nte na nce per mitte d f or N S Q partici pa nts.
c
Treat u ntil pr o gre ssi o n, u nacce pta ble t o xicit y, wit h dra wal of c o nse nt, or st u d y e n d w h ic he ver occ urs first.
d
R elatli ma b d ose of 3 6 0 m g Q 3 W was selecte d f or Part 2. See Secti o n 5. 5. 2 . 
e
 
 
N O T E S:
1. 
If a d ose is delaye d, t he pr oce d ures sc he d ule d f or t hat sa me ti me p oi nt s h o ul d be dela y e d t o c oi nci de wit h w he n t he ti me p oi nt’s d osi n g act uall y occ ur (e xce pt 
ra di o gra p hic t u m or assess me nts) a n d c o nti n ue u ntil disease pr o gressi o n, disc o nti n uati o n d ue t o u nacce pta ble t o xicit y, wit h drawal of c o nse nt, or st u d y cl os ure.
2. 
S u p p orti n g d oc u me nts rela te d t o A E/ S A E ma y be re q uire d via a d diti o nal q ueries, a n d s o me of t he assess me nts i n t his secti o n ma y n ot be ca pt ure d as data i n 
e C R F. A d diti o nal testi n g or assess me nts ma y be perf or me d as cli nicall y necessar y or w here re q uire d b y i nstit uti o nal or l ocal r eg ulati o ns.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 1
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 3: 
F oll o w -u p a n d S ur vi v al Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
S afet y Assess me nts
Tar gete d P h ysi cal E xa mi nati o n 
a n d E C O G Perf or ma nce Stat us
X
T o assess f or p ote ntial late e mer ge nt st u d y dr u g- relate d 
iss ues.
I ncl u de wei g ht a n d E C O G perf or ma nce stat us.
Vital Si g ns
X
I ncl u di n g o x y ge n sat urati o n, B P, heart rate, a n d te m perat ure.
A E Assess me nt
X
X
S A Es s h o ul d be a p pr o ve d i n R A V E wit hi n 5 da ys fr o m 
e ntr y. All S A Es a n d n o n-seri o us A Es s h o ul d 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 mi ni m u m 
of   
 f oll o wi n g disc o nti n uati o n of st u d y treat me nt. 
Partici pa nts will be f oll o we d f o r all S A Es, n o n-seri o us A Es 
of s pecial i nterest (as defi ne d i n Secti o n 9. 2 ), a n d all A Es 
( S A Es a n d n o n-seri o us A Es) ass ociate d wit h c onfir me d or 
s us pecte d S A R S-C o V -2 i nfecti o n u ntil res ol uti o n, t he 
c o n diti on sta bilizes, t he e ve nt is ot her wise e x plai ne d, t he 
e ve nt is dee me d irre versi ble, t he partici pa nt is l ost t o f oll o w -
u p (as defi ne d i n Secti o n 8. 3 ), or f or s us pecte d cases, u ntil 
S A R S -C o V -2 i nfecti o n is r ule d o ut. All A Es/ S A Es are t o be 
gra de d usi n g C T C A E v 5. 
Re vie w of C o nc o mita nt 
Me dicati o ns
X
La b orat o r y Tests
X
Re q uire d at F oll o w -u p Visit 1. Re peat at F oll o w -u p Visit 2 
o nl y  if st u d y dr u g-relate d t o xicit y persists. Please refer t o
Ta ble 9. 4. 5- 1 Ta ble 9. 4. 5 - 1. 
Pre g na nc y Test ( W O C B P o nl y) 
X
See n otes
Ser u m or uri ne ( mi ni m u m se nsiti vit y e q ui vale nt u nits 2 5 
I U/ L or e q ui vale nt u nits of H C G) pr e g na nc y testi n g is o nl y 
re q uire d at F oll o w-u p Visits 1 a n d 2, u nless i ncrease d 
fre q ue nc y a n d d urati on is re q uire d per l ocal re g ulati o ns.
Effic ac y Assess me nts
B o d y I ma gi n g
X
F or partici pa nts w h o ha ve n ot e x perie nce d BI C R -c o nfir me d 
P D ra di o gra p hic assess me nts, or w h o disc o nti n ue st u d y 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 2
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 3: 
F oll o w -u p a n d S ur vi v al Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
treat me nts f or reas o ns ot her t ha n P D, c o ntrast-e n ha nce d C T 
of t he c hest a n d C T/ M RI of t he a b d o me n, pel vis, a n d all 
ot her k n o w n a n d/ or s us pecte d sites of disease s h o ul d 
c o nti n ue Q 6 W ( ± 7 da ys) starti n g fr o m date of 
ra n d o mizati o n ( ± 7 da ys) u ntil 
 
( ± 7 da ys) be gi n ni n g o n Wee k 4 9 u ntil BI C R disease 
pr o gressi o n or treat me nt disc o nti n uati o n ( w hic he ver occ urs 
later), partici pa nt wit h dra wal of c o nse nt, or deat h. See 
Secti o n 9. 1. 1. 1 f or f urt her details.
Br ai n I ma gi n g 
X
Partici pa nts wit h a hist or y of brai n metastasis or s y m pt o ms 
s h o ul d ha ve s ur veilla nce M RIs ( wit h o ut a n d wit h c o ntrast) 
per sta n dar d of care  
 or s o o ner if 
cli nicall y i n dicate d. C T of t he brai n wit h o ut a n d wit h 
c o ntrast ca n be perf or me d if M RI is c o ntrai n dicate d. See 
Secti o n 9. 1. 1. 1 f or f urt her details.
C ollecti o n of S ur vi val Stat us 
a n d S u bse q ue nt T hera p y 
I nf or mati o n
X
X
C ollect  
 i n S ur vi val Visits u ntil deat h, l ost t o 
f oll o w-u p, or wit h dra wal of st u d y c o nse nt.
Ma y be 
perf or me d b y p h o ne c o ntact or office visit. A d diti o nal 
s u bse q ue nt ca ncer t hera p y details s uc h as re gi me n, setti n g of 
t he re gi me n, li ne of t hera p y, start date a n d e n d date of eac h 
re gi me n, best res p o nse t o t he re gi me n, a n d date of 
pr o gressi o n after sec o n d-li ne t hera p y will be c ollecte d.
S u bse q ue nt Pr o gressi o n 
( P F S- 2)
X
X
F or partici pa nts w h o start s u bse q ue nt a nti -ca ncer t hera p y, 
s u bse q ue nt P D date a n d dia g n osis met h o d d uri n g s u bse q ue nt 
treat me nt will be rec or de d o n t he e C R F d uri n g t he F oll o w-
u p Per i o d.
P K Assess me nts
C ollecti o n of P K a n d 
I m m u n o ge nicit y Sa m ples
X
See Secti o n 9. 5 .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 3
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2 - 3: 
F oll o w -u p a n d S ur vi v al Pr oce d ur al O utli ne ( C A 2 2 4 1 0 4)
Pr oce d ure
N otes
O utc o mes Assess me nts
X
X
X
P GI S
X
P GI C
X
A b bre viati o ns: A E
= a d verse e ve nt; BI C R = b li n de d in d e pe n de nt ce ntral re vie w; B P = bl o o d press ure; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n 
Ter mi n ol o g y Cr iteria f or Ad verse E ve nts; E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; e C R F = electr o nic case re p ort f orm; 
 H C G = h u ma n c h ori o nic g o na d otr o pi n ; I g = i m m u n o gl o b uli n; M RI
= ma g netic res o na nce i ma gi n g; 
 P D = pr o gressi ve disease; P F S = pr o gressi o n -free s ur vi val; P GI C = Patie nt 
Gl o bal I m pressi o n of C h a n ge; P GI S = Patie nt Gl o bal I m pressi o n of Se verit y ; P K = p har mac o ki netic s; 
 
 R A V E E D C = Electr o nic Data Ca pt ure ; Q 6 W = e ver y 6 wee ks; 
 S A E = seri o us a d verse e ve nt; v = versi o n; W O C B P
= w o me n of c hil d beari n g p ote ntial.
N ote: I n t he e ve nt m ulti ple pr oce d ures are re q uire d at a si n gle ti me p oi nt cli nical la b orat or y sa m ple ma y be o btai ne d u p t o 5 mi n utes earlier t ha n t he n o mi nal ti me 
p oi nt, e ns uri n g t he P K sa m ples ca n be c ollecte d o n ti me.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 4
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
3 
I N T R O D U C TI O N
St u d y  C A2 2 4 1 0 4 is a P hase 2, ra n d o mize d st u d y that will e val uate ni v o l uma b pl us r elat li ma b i n 
c o m bi nat i on wi t h plati n u m-base d c he mot h era p y, vers us ni v o l u ma b pl us pl at i n u m-base d 
c he m ot hera p y i n part ici pa nts wit h pre vio usl y  u ntreate d, Sta ge I V or rec urre nt n o n -s mall cell l u n g 
ca ncer ( N S C L C). T he stu d y will ta ke place i n 2 parts: a sit e- a n d s u bject-bli n de d d ose safety 
c o nfir mat i on ( Part 1) a n d a n o pe n -label ra n d o mize d st u d y ( Part 2).
I mm u n ot hera pe utic a p pr oac hes ha ve rece ntl y de m o n strate d cli nical efficac y in se veral ca ncer 
t ypes, i ncl u di n g N S C L C. 1 T u m ors m a y m o d ulate a n d e va de t he h ost i m m u ne res p o nse t hr o u g h a 
n u m ber of  mec ha nis ms, i ncl u di n g d o w nre g ulati o n of  tu m or -s pecific a nt i ge n e x pressi o n a n d 
prese ntati o n, secret i on of a nt i-i nflam mat or y  c yt o ki nes, a n d u pre g ulat i on of i n hi bit or y  li ga n ds.
Ni v o l uma b ( B M S -9 3 6 5 5 8) is a f ull y h u ma n, i m m u n o gl o b uli n (I g) G 4 ( ka p pa) is ot y pe m o n ocl o na l 
a nt i b o d y that bi n ds t he pr o gra m me d cell deat h pr otei n 1 ( P D-1) rece pt or o n acti vate d i m m u ne cells
a n d disr u pts e n ga ge me nt of  the rece pt or wit h its li ga n ds pr o gra m me d deat h -li ga n d 1 ( P D-L 1) 
( B 7-H 1/ C D 2 7 4) 
a n d P D -L 2 
( B 7-D C/ C D 2 7 3), 
t here b y a br o gati n g i n hi bit or y si g nals a n d 
a u g me nt i n g t he h ost a ntit u m or res p o nse. I n cli nical trials, ni v ol u ma b has de m o nstrate d acti vity i n 
se veral t u mor t ypes, i ncl u di n g mela n o ma, 
re nal cell ca ncer ( R C C), a n d N S C L C. 2
( See 
Secti o n 3. 2. 1 f or more details o n t he mec ha nis m o f actio n of  ni v ol u ma b.)
Relatli ma b ( B M S-9 8 6 0 1 6) is a f ull y h u ma n l y m p h oc yt e-acti vat i on ge ne 3 ( L A G-3) s pecific 
a nt i b o d y t hat was is olate d f o ll owi n g i m m u nizati o n of tra ns ge nic mice e x pressi n g h u ma n I g ge nes. 
Relatli ma b bi n ds t o L A G -3 rece pt ors e x presse d o n T -cells wit h hi g h affi nit y a n d pre ve nts bi n di n g 
of  t his rece pt or t o cells beari n g its li ga n ds, maj or hist oc o m pati bility c o m p le x ( M H C) Class II a n d 
fi bri n o ge n-li ke pr otei n 1 ( F G L-1). 3 ,4 Rel at li ma b bi n di n g i n hi bits t he ne gati ve re g ulat or y fu n cti o n
of  LA G - 3 me diate d t hr o u g h its i nteractio n wi t h li ga n ds i n vit r o. B y bl oc ki n g t he n or m al 
d o w n -re g ulat or y pat h wa y, relatli ma b e n ha nces t he a nti-t u mor i m m u ne res p o nse a n d, t h us, has t he 
p ote nti al to i n hi bit t he gr o wt h of  mul tiple mali g na ncies w he n a d mi nister e d i n c o m bi nati o n wi t h 
ot her t hera pe utic i m m u n o-o nc ol o g y  (I O) a ge nts. D ual  chec k p o i nt in hi bit i on wi t h relatli ma b a n d 
ni v o l u ma b res ults i n e n ha nce d T- cell effect or f uncti o n t hat is greater t ha n t he effects of  either 
a nt i b o d y al one i n m uri ne s y n ge neic t u mor m o del s.5 ( See Secti o n 3. 2. 2 f or m o re bac k gr o u n d o n 
t he mec ha nis m of act i on of relatli ma b.)
T he o bject i ve of  the C A 2 2 4 1 0 4 st u d y will be t o c o nfir m t he safet y pr ofile of  ni v ol u ma b pl us 
r elat li ma b i n c o m bi nat i on wi t h plati n u m d o u blet c he m ot hera p y ( P D C T) a n d t o deter mi ne if t his 
n o vel c o m bi nat i on i m pr o ves o verall res p o nse rate ( O R R) i n part ici pa nts wit h pre vi o usl y u ntreate d 
Sta ge I V or rec urr e nt N S C L C w he n c o mpare d wi t h ni v ol u ma b plus hist ol o g y -base d P D C T. T his 
st u d y is e x pecte d t o pr o vi de i nitial, pr o of of  co nce pt e vi de nce of  the selecte d tar get d ose f or 
de vel o p me nt of  relat li ma b i n c o m bi nat i on wi t h ni v ol uma b a n d P D C T i n first li ne ( 1 L) N S C L C . 
T he use of  ni v ol u ma b i n c o m bi nat i on wi t h PD C T as a c o ntr ol ar m will ai d i n esta blis hi n g t he 
c o ntri b uti o n of t he i n di vi d ual i m m u n ot hera p y c o m p o ne nts t o t he s y ner gistic/a d dit i ve effect of t he 
r elat li ma b a n d ni v ol u ma b c o m bi nati on.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
3. 1 
St u d y R ati o n al e
Ni v o l uma b,
r elatli ma b, a n d P D C T eac h ha ve n o n- o verl a p pi n g a nt i-ca ncer mec ha nis ms a n d ma y 
ha ve s y ner gist ic a n d/ or a d ditive act i vity as c o m bi natio n t hera p y , wit h fe w o verla p pi n g t o xicities. 
L A G - 3 is of te n e x presse d o n c hr o nicall y ex ha uste d T- cells a n d is fre q ue ntl y c o -e x presse d wi t h 
P D -L 1 o n t olerize d t u mor -i nfiltrati n g l y m p h oc ytes ( TI Ls) acr oss t u mor t ypes. 6 ,7 ,8 T he rati o nale 
f or c o m bi ni n g a L A G - 3 i n hi bit or a n d a n a nt i –P D -1/ P D -L 1 a ge nt ori gi nates fr o m e vi de nce 
s u g gesti n g t hat L A G-3 has a p ote nti al r ole i n T- re g ulat or y cell ( Tre g) s u p pressio n a n d a nt i –P D -1 
resista nce.9
T he c urre nt sta n dar d of  care, a nti-P D -( L) 1 ( ± a nt i- c yt ot o xi c T-l y m p h oc y t e-ass ociate d pr otei n 4 
[ C T L A-4]) i n c o m bi nat i on wi t h PD C T has de m o nstrate d sig nifica nt i m pr o ve me nt i n o verall 
s ur vi val ( O S) as wel l as P F S 
i n part ici pa nts wi t h 
pre vi o usl y u ntreate d 
met astatic 
N S C L C. 1 0 ,1 1 ,1 2 ,1 3 ,1 4 I n t he C A 2 2 4 0 2 0 P hase 1/ 2a st u d y, t he c o m bi nati o n of  ni v ol uma b a n d 
r elat li ma b de m onstrate d t ol era bilit y, peri p heral  T-cell act i vati on, a n d preli mi nar y cli nical act i vity 
of  t he c om bi nat i on of ni v o l u ma b a n d relatli ma b i n a d va nce d mela n oma parti ci pa nt s w h o ha d bee n 
pre vi o usl y treate d wit h a nt i-P D -1/ P D -L 1 t hera p y. 1 5 ,1 6 A d dit i onall y , data fr om 
a Mar -2 0 2 0 
data base l oc k of  CA 2 2 4 0 2 0 Part C s h o we d acti vit y i n metastati c or rec urre nt N S C L C i n a n 
i m m u n ot hera p y-nai ve p o p ul at i on as well as i n r ela pse d a n d r efract or y su b gr o u ps t hat were 
pre vi o usl y treate d wi t h im m u n ot hera p y  (see Secti o n 3. 2. 4 ).1 7 T hese data i n dicate t he p ote nti al of 
ni v o l u ma b pl us relatli ma b a n d c he m ot hera p y t o i m pr o ve o n t he acti vity s h o w n b y a nti-P D -( L) 1 i n 
c o m bi nat i on wi t h c he mot h era p y.
T here are se veral ca n di date bi o mar kers w hic h ma y hel p select partici pa nt s w ho will be nefit fr o m 
t he a d ditio n of  relat li ma b t o ni v ol uma b pl us c he mot hera p y. M ul tiple cli nical trials ha ve esta blis he d 
t he c orrelat i on bet wee n P D -L 1 e x pressio n  an d i ncrease d res p o nse t o P D - 1 a n d P D -L 1 i m m u ne 
c hec k p oi nt i n hi biti on. D at a f r o m C A2 2 4 0 2 0 de m o nstrate d preli mi nar y e vi de nce t hat parti ci pa nts 
wi t h LA G - 3 e x pressi o n are m o re li kel y t o res p o n d t o treat me nt wit h relatli ma b i n c o m bi nati o n 
wi t h ni v ol u ma b.1 7 Rece nt l y, F G L -1 was i de ntifie d as a ne w li ga n d f or L A G-3 t h at i s res p o nsi ble 
f or its T- cell i n hi bit or y fu nct i on a n d p ote nti all y a ne w mec ha nis m 
f or i m m u n o-e vasi o n. 4
T heref ore, F G L - 1 ma y be a n o vel bi o mar ker t o pre dict o utc o mes of  ant i-P D - 1 a n d a nti-L A G -3 
t u mor t hera pies. T u m or m o d el  st u dies usi n g F G L 1 -K O mice de m o nstrate t hat F G L 1 has a p ote nt 
i m m u ne s u p pressi ve effect o n a nti-t u mor i m m u nit y t hat is de pe n de nt o n L A G -3. M ore o ver, F G L 1 
ma y be a p ote ntial bi o mar ker t o pre di ct t he o utc o me of a nt i-P D t hera p y , si nce hi g h plas ma F G L 1 
le vels are ass ociate d wi t h a worse res p o nse t o a nt i-P D t hera p y in N S C L C a n d mela n o ma  
parti ci pa nt s.
T he be nefit of t he relat li ma b pl us ni v ol u ma b c o m bi nati on c o nti n ues t o be e x pl ore d i n se veral t y pes 
of  metastatic ma li g na ncies. T he c o mbi nat i on of  ni v ol u ma b 3 6 0 m g e ver y 3 wee ks ( Q 3 W) pl us 
r elat li ma b 7 2 0 m g or 3 6 0 m g Q 3 W a n d 4 c ycles of PD C T is e x pecte d t o ha ve a s y ner gistic effect  
i n the 1 L N S C L C p o p ulat i on base d o n t he cli nical acti vit y s h o w n b y t he 2 i n di vi d ual c o m bi nati o ns 
( ni v ol uma b pl us r elat li ma b a n d ni v o l uma b pl us P D C T) a n d t heir di sti nct b ut c o mple me ntar y 
mec ha nis ms of  act i on. F or m o re i nf or mati o n o n t he rati onale f or t he c o m bi nat i on of  ni v ol uma b 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
a n d r elat li ma b pl us P D C T a n d t he d osi n g c h o ices f or t his st u d y, see Secti o ns 3. 2. 3 ,   
 5. 5. 1 , 
a n d 5. 5. 2 .
3. 1. 1 
R e s e ar c h H y p ot h e si s
T he h y p ot heses o f St u d y  C A 2 2 4 1 0 4 are as f oll ows:

Part 1 ( D ose safety c o nfir mat i on) : Ni v o l uma b, 3 6 0 m g, pl us relatli ma b, 7 2 0 m g or 3 6 0 m g ,
Q 3 W c o m bi ne d wi t h 4 cyc les of  PD C T is safe i n parti ci pa nts wi t h 1L S ta ge I V or rec urre nt 
N S C L C.

Part 2 : Ni v o l uma b pl us r elat li ma b c o m bi ne d wi t h 4 cycles of  PD C T i m pr o ves O R R w he n 
c o mpare d t o ni v ol u ma b pl us P D C T i n partici pa nts wit h 1 L S ta ge I V or rec urre nt N S C L C. 
3. 2 
B a c k gr o u n d
N S C L C re mai ns t he lea di n g ca use of  ca ncer -relate d m o rtality w orl d wi de, acc o u nt i n g f or 
a p pr o xi matel y 18 % of  all ca ncer deat hs. 1 8 U ntil rece ntl y, t he treat me nt of  parti ci pa nt s wi t h 
a d va nce d N S C L C w h ose t u mors di d n ot ha ve a t ar geta ble ge net ic alt er atio n was c yt ot o xic 
c he m o t hera p y al o ne. I n s pite of treat me nt, partici pa nt s wit h metastatic N S C L C treate d wit h P D C T 
ha d a me dia n s ur vi val o f a p pr o xi matel y 1 0 m ont hs a n d a 5 -year s ur vi val rate of less t ha n 5 %. T he 
i ntr o d uctio n of  im m u ne c hec k p o i nt in hi bit ors tar geti n g t he P D - 1 sig nali n g pat h wa y i n t h e 
treat me nt of  partici pa nt s wi t h NS C L C has ha d a sig nifica nt effect o n partici pa nt s ur vi val. 
Pe m br oliz u ma b c o m bi ne d wi t h ch e m ot h era p y in t he fr o nt-li ne setti n g has de m o nstrate d a n 
i m pr o ve me nt i n O S i n N S C L C parti ci pa nt s as c o mpare d t o c he m ot hera p y alo n e. 1 0 ,1 1 M o re 
rece ntl y, ni v o l u ma b pl us i pili m u ma b, a n d ni v o l u ma b pl us i pili m u ma b i n c o m bi nat i on wi t h 
c he m ot hera p y, als o s h o we d be nefit o ver c he m ot hera p y i n t his sett i n g.1 3 ,1 4 H o we ver, des pite t hese 
a d va nces, t he me d ia n s ur vi val of  1L parti ci pa nt s wi t h metastat ic N S C L C is a p pr o xi matel y 2 2 
m o nt hs i n t he n o n-s q ua m o us ( N S Q), a n d 1 5. 9 m o nt hs i n t he s q uam o us ( S Q) p o p ul at i on. 1 1 ,1 9
Ni v o l uma b has d e m o n strate d cli nical acti vit y i n s u bjects wi th  a variet y of  mali g na ncies as 
descri be d i n t he I n vestigat or’s Br oc h ure (I B). T he efficac y of  the ni v o l u ma b pl us P D C T 
c o m bi nat i on is well c haracterize d as it has bee n st u die d e xte nsi vel y i n N S C L C ( C A 2 0 9 0 1 2, 
C A 2 0 9 2 2 7, O N O - 4 5 3 8-0 4, a n d C A 2 0 9 5 6 8/ C A 2 0 9 9 L A [ ni v ol u ma b + i pili m u ma b + P D C T]). 
Res ults fr o m t hese st u dies s u g gest t hat t he a d diti o n of plati n u m-base d c he m ot hera p y t o a nti – P D -1 
treat me nt ca n i m pr o ve o ut c o m es i n a n u nselecte d parti ci pa nt p o p ulat i on a n d t hat t he re gi me n is 
well t olerate d. 2 0 T he c o m bi nat i on of  ni v ol u ma b plus c he m ot h era p y was first st u die d i n t he P hase 
1 C A 2 0 9 0 1 2 st u d y. Res ults s u p p orte d a d dit i onal de vel o p m e nt of  the c o m bi nat i on, wi t h the 
ni v o l u ma b pl us 
pe metre xe d/cis plat i n ar m re p ortin g 
a n 
1 8 -m o nt h 
O S 
rate of  
60 % 
(see Secti o n 3. 2. 3 ). I n Part 2 of t he P hase 3 C A 2 0 9 2 2 7 1 L N S C L C st u d y e val uati n g ni v ol u ma b i n 
c o m bi nat i on w ith P D C T vs P D C T, e ve n t h o u g h t he pri mar y e n d p o i nt of O S i n the N S Q p o p ulati o n 
di d n ot reac h stati stical si gnifica nce, t he c o m bi nat i o n of ni v ol u ma b pl us c he mot h era p y e x hi bit e d 
e nc o ura gi n g act i vity acr oss hist ol o gies, re gar dless of P D -L 1 e x pressi o n. T he me dia n P F S a n d O S 
were n u mericall y hi g her i n partici pa nt s w h o recei ve d ni v ol uma b pl us c he m ot hera p y wit h a me dia n 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
O S of  18. 2 7 m o nt hs vs 1 4. 7 2 m o nt hs i n t he c he m ot hera p y gr o u p, a n d a me dia n P F S of  8. 3 8 m o nt hs 
wi t h t he ni v ol u ma b c o m bi nati on vs 5. 5 2 m o nt hs i n t he c o ntr ol ar m.
I n a d diti on, d ual  i m m u n ot hera p y in c o m bi nat i on wi t h P D C T has bee n s h o w n t o i m pr o ve efficac y 
o u t co m es re p orte d b y t he c o m bi nat i on of  a nti-P D -1 pl us c he m ot h era p y wit h a ma na gea ble safet y 
pr ofile. Wit h a mi ni m u m 
f oll ow- u p of  12. 7 m o nt hs, St u d y  CA 2 0 9 9 L A, w hic h e val uate d 
ni v o l u ma b pl us i pili m u ma b i n c o m bi nati o n wi t h P D C T vs P D C T i n a si milar p o p ulati o n of  
1 L N S C L C parti ci pa nt s, re p orte d a me dia n P F S of 6. 7 mo nt hs ( 5. 6 t o 7. 8). 1 4 T he c o m bi nati o n of 
ni v o l u ma b a n d i pili m u ma b pl us 2 c yc les of  PD C T 
de m o nstrate d a s ur vi val be nefit vs 
c he m ot hera p y alo ne wi t h a hazar d rati o ( H R) f or deat h of  0. 6 6 ( 0. 5 5 t o 0. 8 0). T hi s be nefit was 
e vi de nt acr oss hist ol o gies ( S Q O S H R = 0. 6 2 a n d N S Q O S H R = 0. 6 9) a n d re gar dless of  PD- L 1 
e x pressi o n. N o ne w safet y si g nals or t o xicit ies were i de ntifie d with ni v o l uma b pl us i pili m u ma b i n 
c o m bi nat i on wi t h P D C T relat i ve t o eac h a ge nt as a m o n ot hera p y or i n c o m bi nati on.
Be y o n d t hese n o w well -st u die d c o m bi nat i ons, precli nical a n d cli nical data ha ve ge nerate d 
pr o misi n g re s ults for t he a nti -L A G -3 a ge nt relat li ma b. I n P hase 1/ 2a St u d y C A 2 2 4 0 2 0 e val uati n g 
t he c o m bi nati o n of  relatli ma b wi t h ni v ol u ma b, e vi de nce of  cli nical acti vit y was preli mi naril y 
o bser ve d acr oss 6 i m m u n ot hera p y -nai ve e x pa nsi o n c o h orts i ncl u di n g N S C L C (see  Sect i on 3. 2. 4 ). 
I n a d ditio n, precli nical  data s u g gest t hat d ual a nti-L A G -3/ P D -1 i m m u n ot hera p y  pr o mot es t u m or -
s pecific res p o nses a n d c o ul d t heref ore be less t o xic t ha n C T L A-4 bl oc ka de. 9 F or t hese reas o ns, it  
is h y p ot hesize d t hat t he c o m bi nati o n of  ni v ol u ma b pl us relatli mab a n d P D C T ma y ai d i n 
c o ntr olli n g disease pr o gressi o n t hr o u g h a s y ner gistic effect w hile mai ntai ni n g a n acce pta ble safet y 
pr ofile. I nf or mat i on re gar di n g t he c h o ice of c o ntr ol ar m ca n be f o u n d i n Sect i on 5. 4. 5 .
T he ai m of  this ra n d o mize d P h ase 2 st u d y is t o c o nfir m t he safety pr ofile of  ni v ol u ma b pl us 
r elat li ma b i n c o m bi nat i on wi t h PD C T a n d t o deter mi ne if ni v o l u ma b pl us r elat li ma b i n 
c o m binat i on wi t h P D C T i m pr o ves O R R w he n c o m pare d t o ni v ol u ma b pl us P D C T i n partici pa nts 
wi t h pre vio usl y u ntreate d Sta ge I V or rec urre nt N S C L C.
3. 2. 1 
Ni v ol u m a b M e c h a ni s m of A cti o n
Ca ncer i m m u n ot hera p y rests o n t he pre mise t hat t u mors ca n be rec o g nize d as f orei g n rat her t ha n 
as self a n d ca n be effect i vel y attac ke d b y a n acti vate d i m m u ne s yste m. A n effecti ve i m m u ne 
res p o nse i n t his setti n g is t ho u g ht t o rel y  o n im m u ne s ur veilla nce of t u m or a nti ge ns e x presse d o n 
ca ncer cells t hat ult i matel y res ults in a n a da pt i ve i m m u ne res p o nse a n d ca ncer cell deat h. 
Mea n w hile, t u mor pr o gressi o n ma y de pe n d u p o n ac q uisit i on of  traits t hat all o w ca ncer cells t o 
e va de i m m u n os ur veilla nce a n d esca pe effecti ve i n nate a n d a da pti ve i m m u ne res p o nses. 2 1 ,2 2 ,2 3
C urre nt i m m u n ot hera p y eff orts atte mpt t o brea k t he a p pare nt t olera nce of  t he i m m u ne s yste m t o 
t u mor cells a n d a nt i ge ns b y eit her i ntr o d uci n g ca ncer a ntige ns b y t hera pe ut ic vacci nat i on or b y 
m o d ulat i n g re g ulat or y c hec k p oi nts of t he i m m u ne s yste m. T-cell st i m ulati on is a c o m p le x pr ocess 
i n v ol vi n g the i nte gratio n of  nu mer o us p osi tive as well as ne gati ve c o -sti m ulat or y si g nals i n 
a d ditio n t o a nti ge n rec o g ni tio n b y t he T -cell rece pt or ( T C R).2 4 C ollect i vel y, t hese si g nals g o ver n 
t he bala nce bet wee n T -cell act i vati on a n d t ol era nce. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
P D -1 i s a me m ber of t he C D 2 8 fa mil y of T -cell c o -sti m ulat or y rece pt ors t hat als o i ncl u des C D 2 8, 
C T L A -4, i n d uci ble T- cell c o -sti m ulat or (I C O S), a n d T-l y m p h oc y t e atte n uat or ( B T L A).2 5 P D -1 
sig nali n g has bee n s h o w n t o i n hi bit C D 2 8 -me d iate d u pre g ulat i on of  int erle u ki n (I L)-2, I L-1 0, 
I L-1 3, i nterfer o n-γ (I F N-γ), a n d Bcl -x L. P D -1 e x pressi o n als o bee n n ote d t o i n hi bit T- cell 
acti vat i on a n d e x pa nsio n  of pr e vio usl y acti vate d cells. E vi de nce f or a ne gati ve re g ulat or y r ole of 
P D - 1 c o me s fr om st u dies of  PD- 1 deficie nt mice, w hic h de vel o p a va riet y of a ut oi m m u ne 
p he n ot y pes. 2 6 T hese res ults s u g gest t hat P D -1 bl oc ka de has t he p ote ntial t o acti vate a nt i-self T-cell 
res p o nses, b ut t hese res p o nses are varia ble a n d de pe n de nt u p o n vari o us h ost ge netic fact ors. T h us, 
P D -1 deficie nc y or i n hi bit i on is n ot acc o m pa nie d b y a u ni versal l oss of t olera nce t o self -a nt i ge ns.
I n vit r o, ni v ol u ma b ( B M S-9 3 6 5 5 8) bi n ds t o P D -1 wi t h hi g h affi nit y (E C 5 0 0. 3 9 -2. 6 2 n M), a n d 
i n hi bits t he bi n di n g of  PD- 1 t o its li ga n ds P D -L 1 a n d P D -L 2 (I C 5 0 1 n M). Ni v o l uma b bi n ds 
s pecificall y t o P D -1 a n d n o t t o relate d me m bers of  the C D 2 8 fa mil y s uc h as C D 2 8, I C O S, C T L A -4, 
a n d B T L A. Bl oc ka de of  the P D -1 pat h wa y b y ni v ol u ma b res ults i n a re pr o d uci ble e n ha nce me nt  
of  b ot h pr oliferati o n a n d I F N-γ release i n t he mi xe d l y m p h oc yte reactio n. Usi n g a c yt o me galo vir us 
( C M V) re-sti m ulati on assa y wi t h hu ma n peri p heral  bl oo d m o n o n uclear cells ( P B M C), t he effect  
of  ni v ol u ma b o n a nti ge n-s pecific recall res p o nse i n dicates t hat ni v o l uma b -a u g me nte d I F N-γ 
secreti o n fr om C M V -s pecific me m or y T cells i n a d ose-de pe n de nt ma n ner vers us is ot y pe -matc he d 
c o ntr ol. I n vi v o bl oc ka de of  PD- 1 b y a m uri ne a nal o g of  ni v ol u ma b e n ha nces t he a nt i-t u mor 
i m m u ne res p o nse a n d res ults i n t u m or rejecti o n i n se veral i m m u n oc o m pete nt m o use t u m or m o dels 
( M C 3 8, S A 1/ N, a n d P A N 0 2).2 7
3. 2. 2 
R el atli m a b M e c h a ni s m of A cti o n
Relatli ma b is a f ull y h u ma n a nt i b o d y s pecific f or h u ma n L A G-3 t hat was is o late d fr o m i m m u nize d 
tra ns ge nic mice e x pressi n g h u ma n I g ge nes. It is e x presse d as a n I g G 4 is ot ype a nt i b o d y that 
i ncl u des a sta bilizi n g hi n ge m utati o n ( S 2 2 8 P) f or atte n uate d Fc rece pt or bi n di n g i n or der t o re d uce 
or eli mi nate t he p ossi bilit y of  ant i b o d y- or c o m p l e me nt -me d iate d tar get cell killi n g. Relat li ma b 
bi n ds t o a defi ne d e pit o p e o n L A G - 3 wi t h hi gh affi nit y ( Kd, 0. 2 5 -0. 5 n M) a n d s pecificity a n d 
p ote ntl y bl oc k s t he i nteract i on of  LA G - 3 wi t h its li ga n d, M H C Class II (I C 5 0, 0. 7 n M). T he 
a nt i b o d y e x hi bits p ote nt i n vitr o f u ncti o nal acti vity i n re versi n g L A G - 3me diate d i n hi bit i on of a n 
a nt i ge n-s pecific m uri ne T- cell h y br i d oma o vere x pressi n g h u ma n L A G - 3 (I C 5 0, 1 n M) . I n 
a d ditio n, relat li ma b e n ha nces acti vati on o f h uma n T -cells i n s u pera nti ge n st i m ulati o n assa ys w he n 
a d de d alo ne or i n c o m bi nat i on wi t h ni v ol u ma b (a ntiP D -1 a nt i b o d y).
See als o t he I B f or relatli ma b Sect i on 4. 1 ( N o ncli nical P h ar mac o l og y  St u dies wi t h Relat li ma b) 
a n d Sect i on 4. 2 ( N o ncli nical P har mac o ki net ics wit h Relatli ma b).
3. 2. 3 
Ni v ol u m a b pl u s P D C T Cli ni c al A cti vit y
I n C A 2 0 9 0 1 2, a m ult i-ar m Phase 1 safety st u d y of ni v o l u ma b i n c he mot h era p y-nai ve N S C L C, 
5 6 s u bjects 
were 
a d mi nistere d 
ni v o l u ma b i n c o m bi nati o n 
wi t h 
ge mcita bi ne/cis plati n, 
p e m etre xe d/cis plati n, or car b o plati n/ paclita xel. O verall  res p o nse rate ( O R R) wit h t he differe nt 
c o m bi nat i ons ra n ge d fr o m 4 2 % t o 5 0 %. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
3 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ni v o l uma b i n c o m bi nat i on wit h c he m ot hera p y was m ore rece ntl y st u die d i n Part 2 of P hase 3 tri al 
C A 2 0 9 2 2 7. 2 0 A s u m mar y of  the efficac y res ults prese nte d at E ur o pea n S oci et y f or Me di c al 
O nc o l og y  ( E S M O) I-O 2 0 1 9 is s h o w n i n Ta ble 3. 2. 3 - 1.
T a ble 3. 2. 3 - 1: 
C A 2 0 9 2 2 7 P art 2 - Effic ac y O utc o mes wit h Ni v ol u m a b + 
C he m ot her a p y vs C he m ot her a p y
N S Q
S Q
All R a n d o mize d
Ni v o + 
C he m o
n = 2 7 0
C he m o
n = 2 7 3
Ni v o + 
C he m o
n = 1 0 7
C he m o
n = 1 0 5
Ni v o + 
c he m o
n = 3 7 7
C he m o
n = 3 7 8
O S
E ve nts, n % 
1 5 6 ( 5 7. 8)  
1 6 4 ( 6 0. 1)  
6 8 ( 6 3. 6)  
7 5 ( 7 1. 4)  
2 2 4 ( 5 9. 4)  
2 3 9 ( 6 3. 2)
Me dia n, m o
1 8. 8  
1 5. 6  
1 8. 3  
1 2. 0  
1 8. 3  
1 4. 7
H R ( 9 5 % CI)
0. 8 6 ( 0. 6 9 -1. 0 8) a
0. 6 9 ( 0. 5 0 -0. 9 7)
0. 8 1 ( 0. 6 7-0. 9 7)
P = 0. 1 8 5 9
1 2 -m o O S rate, 
%
6 7. 3  
5 9. 2  
6 6. 1  
4 8. 5  
6 6. 9  
5 6. 2
P F S
E ve nts, n( %) 
1 8 7 ( 6 9. 3)  
2 0 0 ( 7 3. 3)  
7 9 ( 7 3. 8)  
8 2 ( 7 8. 1)  
2 6 6 ( 7 0. 6)  
2 8 2 ( 7 4. 6)
Me dia n, m o
8. 7
5. 8
7. 1
4. 4
8. 4
5. 5
H R ( 9 5 % CI)
0. 6 7 ( 0. 5 5 -0. 8 2)
0. 5 1 ( 0. 3 7 -0. 7 0)
0. 6 2 ( 0. 5 2-0. 7 3)
1 2 -m o P F S rate, 
%
3 9. 5  
2 5. 7  
3 1. 7
9. 3
3 7. 3  
2 1. 3
O R R, n ( %)
1 3 0 ( 4 8. 1)  
8 0 ( 2 9. 3)  
6 4 ( 5 9. 8)  
3 4 ( 3 2. 4)  
1 9 4 ( 5 1. 5)  
1 1 4 ( 3 0. 2)
A b bre viati o ns: CI = c o nfi de nce i nter val; H R = hazar d rati o; n = n u m ber of s u bjects; N S Q = n o n -s q ua m o us; O R R = 
o verall res p o nse rate; O S = o verall s ur vi val; P F S = pr o gressi o n -free s ur vi val; S Q = s q ua m o us.
a
9 5. 6 2 % CI.
D ue t o t he hierarc hical nat ure of  the statistical desi g n of  CA 2 0 9 2 2 7, t he fact t hat t he pri mar y 
e n d p o i nt of O S i n t he N S Q p o p ulati o n was n ot stat isticall y si g nifica nt re n dere d a d ditio n al 
e n d p o i nts p urel y descri pt i ve. H o we ver, it is i m p orta nt t o n ote t hat O R R, P F S, a n d O S all 
d e m o nstrate d a tre n d t o war ds i m pr o ve d efficac y 
with t he ni v o l uma b 
pl us c he mot h era p y 
c o m bi nat i on vers us c he mot h era p y alo n e after a mi ni m u m f oll o w- u p of  19. 5 m o nt hs f or O S a n d 
1 8. 4 m o nt hs f o r all o t her data. T he O S H R i n all ra n d o mize d s u bjects was 0. 8 1 ( 9 5. 6 2 % c o nfi de nce 
i nter val [CI]: 0. 6 7, 0. 9 7). T he me d ia n P F S a n d O S were n u mericall y hi g her i n partici p a nt s w h o 
recei ve d ni v o l u ma b pl us c he mot h era p y, wi t h a me dia n O S of  18. 2 7 m o nt hs vs 1 4. 7 2 m o nt hs i n 
t he c he m ot hera p y gr o u p, a n d a me d ia n P F S of  8. 3 8 m o nt hs wi t h the ni v o l u ma b c o m bi nati o n vs 
5. 5 2 m o nt hs i n t he c o ntr ol ar m. I n a d ditio n, O R R was hi g her wi t h niv o l u ma b plus c he m ot h era p y 
w he n c o m pare d t o c he m ot hera p y alo ne i n t he all ra n d o mize d p o p ul at i on, as well as i n t he 
N S Q partici pa nt s ( 4 8. 1 % vs 2 5. 7 %) a n d t he S Q parti ci pa nt s u b-gr o u p ( 5 9. 8 % vs 3 2. 4 %).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
3. 2. 4 
R el atli m a b Pr e cli ni c al a n d Cli ni c al A cti vit y
L A G -3 has be e n s h o w n t o be e x presse d i n TI Ls of se veral t u m or t y pes, i ncl u di n g breast, o varia n, 
a n d l u n g ca ncers, of te n i n c o n nect i on wi t h increase d P D -1 + T- cells. 2 8 Precli nical data prese nte d 
i n rece nt years ill ustrate a clear s y ner g y bet wee n t he i n hi bit or y rece pt ors L A G - 3 a n d P D - 1 i n 
c o ntr olli n g i m m u ne h o me o stasis, pre ve nt i n g a ut oi m m u nit y, a n d e nforci n g t u mor -i n d uce d 
t olera nce. 2 9 I mp orta ntl y , d u al a ntib o d y -treate d mice s h o we d m o re r o b ust i m m u ne res p o nses t ha n 
eit her si n gle-treate d gr o u p i n t hese st u dies, a n d a nal yses o f m ut a nt mice re veale d a c o o perati ve 
re q uire me nt f or L A G- 3 a n d P D-1 i n mai ntai ni n g i m m u ne h o me ostasis.
T he si n gle-a ge nt a nt i-t u mor acti vit y of  ant i-L A G - 3 a nti b o d y (1 9 C 7) was e val uate d i n t he ver y 
i m m u n o ge nic Sa 1 N fi br osarc oma t u mor m o del .3 0 As c o mpare d t o the is ot ype c o ntr ol gr o u p, all 
d oses bet wee n 1 a n d 3 0 m g/ k g of  ant i-L A G - 3 cl o ne 1 9 C 7 de m o n strate d a nti-t u mor efficac y, 
lea di n g t o bet wee n 3 0 % a n d 6 0 % of t he mice bei n g re n dere d t u m or free at t he e n d of st u d y.
C o m bi ne d a nti -P D -1 a n d a nti -L A G -3 acti vit y was a ls o assesse d i n t he Sa 1 N m o del. I n 2 differe nt 
st u dies, a nt i-L A G - 3 a nti b o d y, C 9 B 7 W, i n hi bite d t he gr o wt h of  Sa 1 N t u mors i n mice w he n 
a d mi nistere d as m o n ot hera p y  an d w he n c o m bi ne d wi t h ant i-P D - 1 a nt i b o d y, 4 H 2. 3 1 ,3 2 T he 
c o m bi nat i on of  these 2 a nt i b o dies res ulte d i n 8 0 % t o 9 0 % t u mor -free mice a n d re d uctio ns i n 
me dia n t u m or v ol u mes s u peri or t o t hat of a nt i-P D -1 or a nti -L A G -3 a nt i b o d y mo n ot hera p y  alo n e.
Relatli ma b is bei n g i n vest i gate d, al o ne a n d i n c om bi nat i on wi t h ot her treat me nts, i n se veral t y p es 
of  ca ncer. As a si n gle t hera p y, relatli ma b de m o n strate d acti vit y i n he mat ol o gi c mali g na ncies. I n 
t he P hase 1/ 2a St u d y C A 2 2 4 0 2 2 e val uat i n g r elatli ma b m o n ot hera p y  in rela pse d or refract or y 
he mat ol o gi c B- cell mali g na ncies, o bj ecti ve res p o nses were o bser ve d i n s u bjects wi th mar gi na l 
z o ne l y m p h o ma, H o d g ki n l y m p h o ma, a n d ma nt le cell l y m p h oma. 5
P hase 1/ 2a St u d y  CA 2 2 4 0 2 0 is i n vest i gati n g the safet y, t olera bilit y, a n d effect i ve ness of  relat li mab 
wi t h a nd wi t ho ut ni v o l uma b t o tr e at vari o us s oli d t u mors. I nitial res ults p u blis he d i n 2 0 1 7 at t h e 
A merica n S o ci et y f or Cli nical O nc o l og y  ( AS C O) a n d E S M O a n n ual meet i n gs, s h o w s y ner gistic 
acti vit y w he n r elat li ma b is c o m bi ne d wi t h ni v ol u ma b i n s oli d t u mors .1 5 ,1 6 Part C of  the st u d y 
d e m o nstrate d preli mi nar y pr o of -of -c o nce pt efficac y in t he c o m bi na ti on treat me nt e x pa ns i on 
c o h ort of  ad va nce d me la n oma wi t h prior a nti-P D -( L) 1 treat me nt. 
 
 
 
 
 
 
 
 
 
 
 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
3. 2. 5 
R el atli m a b M o n ot h er a p y S af et y
T he safet y pr ofile of  relat li ma b a p pears ma na gea ble i n the 3 o n g oi n g st u dies wi t h relat li ma b 
m o n ot hera p y  
 
 wi t h no ma xi m u m t olerate d d ose 
( M T D) reac he d at a n y d ose teste d u p t o a n 8 0 0-m g f lat d ose e ver y 2 wee ks. 
 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
3. 2. 7 
Ni v ol u m a b P l u s P D C T S af et y
Ni v o l uma b i n c o m bi nat i on wi t h ch e m ot h era p y has bee n pr o ve n t o be safe. I n Part 2 of  St u d y 
C A 2 0 9 2 2 7, t he o verall safety pr ofile of  ni v ol uma b pl us P D C T i n all treate d s u bjects wi t h 
c he m ot hera p y-naï ve Sta ge I V or rec urre nt N S C L C was c o nsiste nt wit h t he esta blis he d safety 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
pr ofile of  eac h c o m p o ne nt of  the re gi me n. N o ne w safety sig nals or t o xicities were i de ntifie d 
r elat i ve t o pre vi o us e x perie nce wit h ni v ol uma b m o n ot hera p y or wit h c he m ot hera p y. Safet y res ults 
f or all treate d participa nts i n C A 2 0 9 2 2 7 Part 2 are s u m marize d i n Ta ble 3. 2. 7 - 1.
T a ble 3. 2. 7 - 1: 
S afet y Res ults: All tre ate d S u bjects i n C A 2 0 9 2 2 7 P art 2
Ni v ol u m a b + C he m ot her a p y
N = 3 7 5
C he m ot her a p y
N = 3 7 1
S afet y P ar a meters
A n y Gr a de 
Gr a de 3 - 4 
A n y Gr a de 
Gr a de 3 - 4
All- c a us alit y S A Es
1 9 5 ( 5 2. 0)  
1 4 2 ( 3 7. 9)  
1 3 1 ( 3 5. 3)  
1 0 0 ( 2 7. 0)
Dr u g -rel ate d S A Es
9 4 ( 2 5. 1)  
7 5 ( 2 0. 0)  
4 9 ( 1 3. 2)  
4 3 ( 1 1. 6)
All- c a us alit y A Es le a di n g t o D C
1 0 2 ( 2 7. 2)  
5 5 ( 1 4. 7)  
5 9 ( 1 5. 9)  
3 1 ( 8. 4)
Dr u g -rel ate d A Es le a di n g t o D C
7 3 ( 1 9. 5)  
3 6 ( 9. 6)  
3 1 ( 8. 4)  
1 2 ( 3. 2)
All- ca usalit y A Es
3 7 1 ( 9 8. 9)  
2 2 3 ( 5 9. 5)  
3 5 8 ( 9 6. 5)  
1 9 3 ( 5 2. 0)
Dr u g -relate d A Es
3 1 8 ( 8 4. 8)  
1 6 8 ( 4 4. 8)  
2 9 1 ( 7 8. 4)  
1 3 1 ( 3 5. 3)
≥ 1 5 % dr u g -relate d A Es i n a n y treat me nt 
gr o u p
A ne mia
1 2 2 ( 3 2. 5)  
3 9 ( 1 0. 4)  
1 1 7 ( 3 1. 5)  
4 3 ( 1 1. 6)
Na usea
8 4 ( 2 2. 4)  
4 ( 1. 1)  
1 0 8 ( 2 9. 1)  
5 ( 1. 3)
Decrease d a p petite
6 0 ( 1 6. 0)  
8 ( 2. 1)  
5 3 ( 1 4. 3)  
4 ( 1. 1)
Fati g ue
5 8 ( 1 5. 5)  
1 0 ( 2. 7)  
5 7 ( 1 5. 4)  
7 ( 1. 9)
All- c a us alit y Select A Es
E n d ocri ne
4 5 ( 1 2. 0)  
3 ( 0. 8)  
7 ( 1. 9)
0
Gastr oi ntesti nal
7 4 ( 1 9. 7)  
8 ( 2. 1) 
4 2 ( 1 1. 3)  
2 ( 0. 5)
He patic
8 4 ( 2 2. 4)  
1 5 ( 4. 0)  
4 0 ( 1 0. 8)  
3 ( 0. 8)
P ul m o nar y
2 5 ( 6. 7)  
7 ( 1. 9)  
1 ( 0. 3)  
1 ( 0. 3)
Re nal
5 6 ( 1 4. 9)  
6 ( 1. 6)  
3 9 ( 1 0. 5)  
3 ( 0. 8)
S ki n
1 0 0 ( 2 6. 7)  
8 ( 2. 1)  
4 3 ( 1 1. 6)  
3 ( 0. 8)
H y perse nsiti vit y/i nf usi o n reacti o ns
2 2 ( 5. 9)  
2 ( 0. 5)  
8 ( 2. 2) 
1 ( 0. 3)
Dr u g -rel ate d Select A Es
E n d ocri ne
3 8 ( 1 0. 1)  
2 ( 0. 5)  
1 ( 0. 3)
0
Gastr oi ntesti nal
4 4 ( 1 1. 7)  
4 ( 1. 1)  
2 4 ( 6. 5)  
2 ( 0. 5)
He patic
6 3 ( 1 6. 8)  
9 ( 2. 4)  
2 7 ( 7. 3)  
1 ( 0. 3)
P ul m o nar y
2 3 ( 6. 1)  
5 ( 1. 3)  
1 ( 0. 3)  
1 ( 0. 3)
Re nal
4 1 ( 1 0. 9)  
3 ( 0. 8)  
2 7 ( 7. 3)  
3 ( 0. 8)
S ki n
8 3 ( 2 2. 1)  
7 ( 1. 9)  
2 4 ( 6. 5)  
3 ( 0. 8)
H y perse nsiti vit y/i nf usi o n reacti o ns
1 5 ( 4. 0)  
2 ( 0. 5)  
7 ( 1. 9)  
1 ( 0. 3)
All- c a us alit y I M A Es Wit hi n 1 0 0 D a ys of L ast D ose Tre ate d wit h 
I m m u ne-m o d ul ati n g Me dic ati o n
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 3. 2. 7 - 1: 
S afet y Res ults: All tre ate d S u bjects i n C A 2 0 9 2 2 7 P art 2
Ni v ol u m a b + C he m ot her a p y
N = 3 7 5
C he m ot her a p y
N = 3 7 1
S afet y P ar a meters
A n y Gr a de 
Gr a de 3 - 4 
A n y Gr a de 
Gr a de 3 - 4
Diarr hea/c olitis
1 4 ( 3. 7)  
5 ( 1. 3)  
1 ( 0. 3)  
1 ( 0. 3)
He patitis
1 1 ( 2. 9)  
8 ( 2. 1)  
1 ( 0. 3)
0
P ne u m o nitis
2 0 ( 5. 3)  
7 ( 1. 9)
0
0
Ne p hritis/re nal d ysf u ncti o n
7 ( 1. 9)  
2 ( 0. 5)  
1 ( 0. 3)
0
Ras h
2 5 ( 6. 7)  
3 ( 0. 8)  
4 ( 1. 1)
0
All- c a us alit y E n d ocri ne I M A Es Wit hi n 1 0 0 D a ys of L ast D ose wit h or wit h o ut I m m u ne-m o d ul ati n g 
Me dic ati o n
A dre nal i ns ufficie nc y
2 ( 0. 5)  
1 ( 0. 3)
0
0
H y p o p h ysitis
1 ( 0. 3)  
1 ( 0. 3)
0
0
All- c a us alit y O E SIs Wit hi n 1 0 0 D a ys of L ast D ose wit h or wit h o ut I m m u ne -m o d ul ati n g Me dic ati o n
M y ast he nic s yn dr o me
1 ( 0. 3)
0
0
0
Pa ncreatitis
3 ( 0. 8) 
2 ( 0. 5)  
2 ( 0. 5)  
1 ( 0. 3)
U veitis
1 ( 0. 3)
0
0
0
M y ocar ditis
3 ( 0. 8)  
3 ( 0. 8)  
2 ( 0. 5)
0
M y ositis
1 ( 0. 3)
0
0
0
A b bre viati o ns: A E = a d verse e ve nt; C T C = c o m m o n t o xicit y criteria D C = disc o nti n uati o n; I M A Es = i m m u ne-
me diate d a d verse e ve nts; Me d D R A 
= Me dical 
Dicti o nar y f or Re g ulat or y Acti vities; N = n u m ber of s u bjects; 
O E SIs = ot her e ve nts of s pecial i nterest; S A E = seri o us a d verse e ve nt.
Me d D R A versi o n 2 2. 0; C T C versi o n 4. 0.
N ote: All e ve nts are wit hi n 3 0 da ys of t he last d ose of st u d y dr u g, u nless ot h e r wise i n dicate d.
I n a d ditio n, t he c o m bi nat i on of  2 im m u n ot hera p y  age nts, ni v o l u ma b a n d i pili m u ma b, pl us 
c he m ot hera p y i n 1 L N S C L C has als o pr o ve n t o be safe. I n St u d y  CA 2 0 9 9 L A wi t h a mi ni m um 
f oll ow- u p of  12. 7 m o nt hs, safet y res ults were c o nsiste nt wit h the k n o w n safety pr ofiles of  the 
i m m u n ot hera p y a n d c he mot h era p y c o mp o ne nts i n t hi s setti n g. T he fre q ue nc y of deat hs attri b ute d 
t o stu d y dr u g t o xicit y was si milar i n t he ni v o l uma b pl us i pili m u ma b pl us c he m ot hera p y ( 2. 0 %) 
a n d c he mot h era p y ( 1. 7 %) ar ms. N o ne w safet y si g nals or t o xicities were i de nt ifie d wi t h ni v ol u ma b 
pl us i pili m u ma b pl us c he m ot hera p y, relat i ve t o eac h a ge nt as m o n ot hera p y or i n c o m bi nati on (see 
Ta ble 3. 2. 7 -2 a nd Ta ble 3. 2. 7 - 3.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 3. 2. 7 - 2: 
C A 2 0 9 9 L A S afet y S u m m ar y
Mi ni m al 1 2. 7 -m o nt h F oll o w -u p
Ni v ol u m a b +
I pili m u m a b + C he m ot her a p y
( N = 3 5 8)
C he m ot her a p y
( N = 3 4 9)
A n y Gr a de 
Gr a de 3 - 4 
A n y Gr a de 
Gr a de 3 - 4
All A Es (re gar dless of ca usalit y), %
3 5 6 ( 9 9. 4)  
2 4 5 ( 6 8. 4)  
3 4 2 ( 9 8. 0)  
1 8 8 ( 5 3. 9)
Dr u g -relate d A Es, %
3 2 8 ( 9 1. 6)  
1 6 8 ( 4 6. 9)  
3 0 6 ( 8 7. 7)  
1 3 2 ( 3 7. 8)
All A Es lea di n g t o D C, %
1 0 1 ( 2 8. 2)  
8 1 ( 2 2. 6)  
6 1 ( 1 7. 5)  
4 3 ( 1 2. 3)
Dr u g -relate d A Es lea di n g t o D C, %
6 9 ( 1 9. 3)  
5 8 ( 1 6. 2)  
2 6 ( 7. 4)  
1 6 ( 4. 6)
All S A Es, %
2 1 5 ( 6 0. 1)  
1 6 9 ( 4 7. 2)  
1 4 9 ( 4 2. 7)  
1 1 2 ( 3 2. 1)
Dr u g -relate d S A Es, %
1 0 6 ( 2 9. 6)  
9 1 ( 2 5. 4)  
6 2 ( 1 7. 8)  
5 1 ( 1 4. 6)
A b bre viati o ns: A E = a d verse e ve nt; D C = disc o nti n uati o n; N = n u m ber of s u bjects S A E = seri o us a d verse e ve nt.
T a ble 3. 2. 7 - 3: 
C A 2 0 9 9 L A Dr u g -rel ate d Select A Es ( All Tre ate d P artici p a nts)
Mi ni m al 1 2. 7 -m o nt h F oll o w -u p
Ni v ol u m a b +
I pili m u m a b + C he m ot her a p y
( N = 3 5 8)
C he m ot her a p y
( N = 3 4 9)
A n y gr a de 
Gr a de 3 - 4 
A n y gr a de 
Gr a de 3 - 4
E n d ocri ne A E
9 2 ( 2 5. 7)  
1 0 ( 2. 8)  
1 ( 0. 3)
0
Gastr oi ntesti nal A E
8 3 ( 2 3. 2)  
2 0 ( 5. 6)  
4 1 ( 1 1. 7)  
2 ( 0. 6)
He patic A E
5 1 ( 1 4. 2)  
1 6 ( 4. 5)  
2 7 ( 7. 7)  
3 ( 0. 9)
H y perse nsiti vit y/i nf usi o n reacti o n
1 8 ( 5. 0)  
2 ( 0. 6)  
4 ( 1. 1)  
2 ( 0. 6)
P ul m o nar y A E
1 9 ( 5. 3)  
6 ( 1. 7)  
4 ( 1. 1)  
1 ( 0. 3)
Re nal A E
2 5 ( 7. 0)  
7 ( 2. 0)  
2 2 ( 6. 3)  
4 ( 1. 1)
S ki n A E
1 4 5 ( 4 0. 5)  
1 6 ( 4. 5)  
2 8 ( 8. 0)  
1 ( 0. 3)
A b bre viati o n:  A E = a d verse e ve nt; N = n u m ber of s u bjects.
3. 3 
B e n efit/ Ri s k A s s e s s m e nt
As descri be d i n Secti o n 3. 2. 3 , precli nical st u dies de m onstrate d t hat c o m bi nat i on bl o c ka de of P D -1 
a n d L A G - 3 ca n i n d uce i m m u ne act i vati on a n d ass ociate d t u mor r eject i on i n fi br osarc o ma a n d 
c olorectal  ca ncer m o d el s i n mice. I n vi v o st u dies i n m uri ne ca ncer mo dels ha ve s h o w n t hat w he n 
e x presse d at hi g h levels, c o nc o mita nt L A G -3/ P D - 1 e x pressi o n is m o stl y restricte d t o TI Ls. T his 
ma y si g nif y t hat a c o m bi nat i on i m m u n ot hera p y tar getin g t hese 2 m ole c ules ma y e nc o ura ge 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
4 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
t u mor -s pecific res p o nses, a v o i di n g n o n- s pecific or self-a nt i ge n-s pecific i m m u ne res p o nses, 
p ote nti all y re n deri n g s uc h treat me nt less t o xic t ha n C T L A-4 bl oc ka de. 9
Preli mi nar y pr o of -of -c o nce pt efficac y has bee n de m o nstrate d i n St u d y  CA 2 2 4 0 2 0, 
w here 
c o m bi nat i on d osi n g of  re latli ma b  
 pl us ni v ol u ma b 
 s h o we d t he ca pacit y t o 
i n d uce res p o nses i n pre vi o usl y hea vil y treate d a d va nce d s oli d t u mors, wit h t he a d de d a bilit y t o 
trig ger res p o nses i n t u mors t hat ha ve de m o nstrate d resista nce t o a nti-P D -( L) 1 t hera p y. I n t his 
st u d y, efficac y data i n pretreate d i m m u n ot hera p y-nai ve N S C L C s u bjects are c o m pelli n g, wi t h 
si milar O R R, D o R, a n d preli mi nar y O S t hat is c o m para ble t o o utc o mes of c he m ot hera p y alo n e i n 
s uc h p o p ul at i ons. T his i n dicates t he p ote nti al of ni v ol uma b pl us r elat li ma b a n d c he mot h era p y t o 
i m pr o ve o n t he activit y s h o w n b y a nti -P D -1 i n c o m bi nat i on w ith c he m ot hera p y (see Secti o n 3. 2. 4 ). 
T he a d dit i on o f ni v o l u ma b t o c he m ot hera p y has s h o w n acti vity i n St u d y C A 2 0 9 2 2 7 de m o nstrati n g 
i m pr o ve d O S a n d O R R vers us c he mot h era p y al one. I n a d ditio n, i m pr o ve d O S has bee n 
d e m o nstrate d b y  c om bi ni n g 2 i m m u n ot hera pies, ni v o l uma b a n d i pili m u ma b, wit h plat i n u m-base d 
c he m ot hera p y i n St u d y C A 2 0 9 9 L A.
O verall, t he safety pr ofile of  ni v ol u ma b i n c o m bi nat i on wi t h relat li ma b is ma na gea ble a n d 
ge nerall y c o nsiste nt acr oss t he pr o gra m’s o n g o i n g cli nical trials, wit h n o M T D reac he d at a n y d ose 
teste d u p t o  
 of  ni v ol u ma b a n d  
 of  relat li ma b a d mi nistere d  
 
 M ost 
A Es re p orte d are l ow- gra de ( Gra de 1 t o 2) wit h relati vel y fe w r elat e d 
hi g h -gra de ( Gra de 3 t o 4) A Es. T he safety pr ofile of ni v o l u ma b i n c o m bi nati on w ith c he m ot hera p y 
i n C A 2 0 9 2 2 7 was als o acce pta ble a n d c o nsiste nt wi t h the safety pr ofile of  eac h i n di vi d ual 
c o mp o ne nt, a n d it was ma na gea ble usi n g t he A E 
 pre vi o u sl y esta blis he d 
f or ni v o l uma b. T he c o m bi nati o n of  2 im m u n ot hera pi es, ni v o l uma b a n d i pili m u ma b, wit h P D C T 
i n C A 2 0 9 9 L A als o d e m o nstrate d acce pta ble safet y i n 1 L N S C L C, wi t h no n e w safety si g nals or 
t o xicities i de ntifie d. I n b ot h C A 2 0 9 2 2 7 a n d C A 2 0 9 9 L A, acr oss all A E cate g ories ( S A Es, A Es 
lea di n g t o disc o nti n uati on of  st u d y dr u g, A Es), all-ca usalit y a n d dr u g -relate d e ve nts were hi g her 
wi t h the i m m u n ot hera p y pl us c he mot h era p y treat me nt c o m bi nat i on w he n 
c o mpare d t o 
c he m ot hera p y treat me nt al o ne. See Secti o n 3. 2. 7 .
T he a ge nts t o be use d i n t he st u d y ha ve s h o w n well -defi ne d t o xicit y pr ofiles base d o n a safety 
data base c o m pr ise d of  partici pa nts treate d wit h 
eit her i m m u ne c hec k p oi nt i n hi bit or as 
m o n ot hera p y  or i n c o m bi nat i on wi t h eac h ot her or wit h c he mot h era p y, acr oss m ult i ple t u mor 
t ypes. W hile t he c o m bi nat i on of relat li ma b, ni v ol u ma b, a n d plati n u m-base d c he m ot hera p y has n ot 
bee n pre vi o usl y e val uate d i n N S C L C, relatli ma b a n d ni v ol u ma b c o m bi ne d wit h o xali plati n-base d 
c he m ot hera p y is c urre nt l y bei n g assesse d i n gastric or gastr oes o p ha geal j u nct i on a de n ocarci n o ma 
i n St u d y  CA 2 2 4 0 6 0. 3 3 After a data base l oc k i n A pr - 2 0 2 0 t o i nf or m t he Data M o ni t ori n g 
C o m mitte e ( D M C), t he rec o m me n dati on was t o c o nti n ue t he st u d y with o ut a n y m o dificat i on 
d uri n g a me eti n g hel d o n 0 8- J u n-2 0 2 0. Preli mi nar y res ults f or St u d y  CA 2 2 4 0 6 0, as of  data base 
l oc k date 1 9- N o v -2 0 2 0, are n o w a vaila ble. E ve n t h o u g h t here were differe nces i n t he treat me nt  
di sc o nti n uati ons a n d S A Es re gar dless of  ca usalit y i n t he R N C ar m, I M A Es were n ot i ncrease d. 
T hese safet y data are n ot c o nsi dere d t o re prese nt a c ha n ge t o t he o verall ris k -be nefit pr ofile f or t he 
r elat li ma b de vel o p me nt pr o gra m.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A patter n of i m m u ne -relate d A Es has bee n defi ne d, f or w hic h 
 ha ve bee n 
de vel o pe d; t hese are pr o vi de d i n  
 M ost hi g h -gra de e ve nts were ma na gea ble wi t h t he 
use of  corti c oster oids or h or m o ne r e place me nt t hera p y (e n d ocri n o pat hies) as i nstr ucte d i n t hese 
alg ori t h ms. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A d dit i onal details o n t he safet y  pr ofil e of ni v ol u ma b a n d relatli ma b, i ncl u di n g res ults fr om ot h er 
cli nical st u dies, are als o a vaila ble i n t he ni v o l u ma b a n d relatli ma b I Bs.
C O VI D -1 9 V acci nes
B M S has gi ve n c o nsi deratio n re gar di n g t he be nefit/ris k of  CO VI D - 1 9 vacci nati o n d uri n g 
parti ci pat i on i n B M S-9 8 6 0 1 6 (relat li ma b) a n d B M S-9 3 6 5 5 8 ( ni v o l uma b) cli nical trials. Base d o n 
t he re vie w of c urre nt a vaila ble data a n d e vi de nce t o date, k n o wle d ge of t he mec ha nis ms o f act i on 
of  t he C O VI D-1 9 vacci nes a n d Relat li ma b a n d Ni v olu ma b I M P, a bi ol o gi cal or p har mac o l ogi cal 
i nteract i on occ urri n g bet wee n t he vacci ne a n d t he I M P t hat w o ul d ne gati vel y i m pact t he 
be nefit/ris k f or partici pa nts i n B M S relatli ma b a n d ni v o l u ma b cli nical trials is n ot e x pecte d; 
h o we ver, data will c o nt i n ue t o be re vie we d. T heref ore, at  t his time, a C O VI D -1 9 vacci ne gi ve n 
t o partici pa nts i n t his trial is c o nsi dere d a c o nc o mita nt me dicat i on wi t h no i nteracti o n.
4 
O B J E C TI V E S A N D E N D P OI N T S
T a ble 4- 1: 
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
P art 1: D ose S afet y C o nfir m ati o n
Pri m ar y
T o e val uate t he pr o p orti o n of partici pa nts wit h T R A Es 
lea di n g t o disc o nti n uati o n wit hi n 1 2 wee ks after t he first 
d ose of ni v ol u ma b pl us 2 differe nt d ose le vels of 
relatli ma b ( 3 6 0 m g a n d 7 2 0 m g) i n c o m bi nati o n wit h 
P D C T i n d ose -safet y e val ua ble partici pa nts wit h 
hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
T R A Es lea di n g t o disc o nti n uati o n wit hi n 1 2 
wee ks after t he first d ose
Sec o n d ar y
T o e val uate t he safet y a n d t olera bilit y of ni v ol u ma b pl us 2 
differe nt d oses of relatli ma b ( 3 6 0 m g a n d 7 2 0 m g) i n 
c o m bi nati o n w it h P D C T i n all partici pa nts wit h 
hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C 
t hat were treate d d uri n g t he d ose safet y c o nfir mati o n 
peri o d
 
I nci de nce of T R A Es lea di n g t o disc o nti n uati o n, 
A Es, S A Es, a n d select A Es
E x pl or at or y
T o e val uate t he efficac y of ni v ol u ma b pl us 2 differe nt 
d oses of relatli ma b ( 3 6 0 m g a n d 7 2 0 m g) i n c o m bi nati o n 
wit h P D C T i n all ra n d o mize d partici pa nts wit h 
 
O R R per R E CI S T v 1. 1 b y BI C R
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 4 - 1: 
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C 
ra n d o mize d i n t he d ose safet y c o nfir mati o n peri o d
T o c haracterize t he i m m u n o ge nic p ote ntial of relatli ma b 
a n d ni v ol u ma b i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
A nti- relatli ma b a n d a nti-ni v ol u ma b a nti b o dies 
a n d t heir r elati o ns hi p wit h 
ot her o utc o me 
meas ures
T o c haracterize P K of relatli ma b a n d ni v ol u ma b i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C
 
P K meas ure me nts of relatli ma b a n d ni v ol u ma b
T o c h aracterize partici pa nt perce pti o ns of t he 
b ot hers o me ness of t he si de effects of treat me nt i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C
 
Pr o p orti o n of partici pa nts e x perie nci n g b ot her 
P art 2 
Pri m ar y
T o e val uate O R R of ni v ol u ma b pl us relatli ma b i n 
c o m bi nati o n w it h P D C T relati ve t o ni v ol u ma b i n 
c o m bi nati o n w it h P D C T i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
O R R per R E CI S T v 1. 1 b y BI C R
Sec o n d ar y
T o e val uate t he P F S of ni v ol u ma b pl us relatli ma b i n 
c o m bi nati o n w it h P D C T relati ve t o ni v ol u ma b i n 
c o m bi nati o n w it h P D C T i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
P F S per R E CI S T v 1. 1 b y BI C R
T o e val uate O R R a n d P F S of ni v ol u ma b pl us relatl i ma b i n 
c o m bi nati o n w it h P D C T relati ve t o ni v ol u ma b i n 
c o m bi nati o n w it h P D C T i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C, i n s u b gr o u ps 
defi ne d b y P D -L 1 e x pressi o n, L A G -3 e x pressi o n, F G -L 1 
e x pressi o n
 
O R R a n d P F S per R E CI S T v 1. 1 b y BI C R
T o e val uate t he d urati o n of res p o nse ( D o R) of ni v ol u ma b 
pl us relatli ma b i n c o m bi nati o n wit h P D C T relati ve t o 
 
D o R per R E CI S T v 1. 1 b y BI C R, i ncl u di n g D o R 
at 6, 1 2 a n d 1 8 m o nt hs
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 4 - 1: 
O bjecti ves a n d E n d p oi nts
O bjecti ves
E n d p oi nts
ni v ol u ma b i n c o m bi nati o n wit h P D C T i n partici pa nts wit h 
hist ol o gicall y c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
T o e val uate t he safet y a n d t olera bilit y of ni v ol u ma b pl us 
relatli ma b i n c o m bi nati o n wit h P D C T i n hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
I nci de nce of A Es, S A Es, T R A Es, I M A Es a n d 
select A Es
E x pl or at or y
T o e val uate O S of ni v ol u ma b pl us relatli ma b i n 
c o m bi nati o n w it h P D C T vs ni v ol u ma b i n c o m bi nati o n 
wit h P D C T i n partici pa nts wit h hist ol o gicall y c o nfir me d 
1 L Sta ge I V or rec urre nt N S C L C
 
O S
T o c haracterize t he i m m u n o ge nic p ote ntial of relatli ma b 
a n d ni v ol u ma b i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
A nti- relatli ma b a n d a nti-ni v ol u ma b a nti b o dies 
a n d t heir r elati o ns hi p wit h 
ot her o utc o me 
meas ures
T o c haracterize P K of relatli ma b a n d ni v ol u ma b i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C
 
P K meas ure me nts of relatli ma b a n d ni v ol u ma b
T o c haracterize c ha n ges i n disease -relate d s y m pt o ms, a n d 
p h y sical f u ncti o n i n partici pa nts wit h hist ol o gicall y 
c o nfir me d 1 L Sta ge I V or rec urre nt N S C L C
 
Mea n 
c ha n ge fro m baseli ne 
 
T o c haracterize partici pa nt perce pti o ns of t he 
b ot hers o me ness of t he si de effects of treat me nt i n 
partici pa nts wit h hist ol o gicall y c o nfir me d 1 L Sta ge I V or 
rec urre nt N S C L C
 
Pr o p orti o n of partici pa nts e x perie nci n g b ot her 
A b bre viati o ns: 1 L = first li ne; A E = a d verse e ve nt; BI C R = bli n de d i n de pe n de nt ce ntral re vie w; 
 
L A G -3 = 
l ym p h oc y t e-acti vati o n ge ne 3; N S C L C = n o n- s mall cell l u n g ca ncer; 
 
O R R = o verall res p o nse rate; O S = o verall s ur vi val; 
 
P D C T = plati n u m d o u blet c he m ot hera p y; P D -L 1 = pr o gra m me d deat h -li ga n d 1; P F S = 
pr o gressi o n -free s ur vi val; P GI C = Partici pa nt Gl o bal I m pressi o n of C ha n ge; P GI S = Partici pa nt Gl o bal I m pressi o n of 
Se verit y ; P K = p har mac o ki netic; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; S A E = seri o us a d verse 
e ve nt ; T R A E = treat me nt relate d a d verse e ve nt .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
5 
S T U D Y D E SI G N
5. 1 
O v er all D e si g n
T his m ult i-ce nter, ra n d o mize d trial will e val uate t he efficac y a n d safety of  the c o m bi nat i on of 
ni v o l u ma b pl us r elat li ma b a n d P D C T vs ni v o l uma b a n d P D C T i n a d ults wit h u ntreate d Sta ge IV 
or rec urre nt N S C L C. T he st u d y  will be carrie d o ut i n 2 parts: Part 1, a site -a n d-s u bject bli n d d ose 
safety c o nfir mat i on a n d Part 2, a n o pe n -label, ra n d o mize d, c o ntr olle d trial.
T he st u d y  desi g n sc he matic is prese nte d i n Fi g ure 5. 1 -1 .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Fi g ure 5. 1 - 1: 
St u d y Desi g n Sc he m atic
A b bre viati o ns: A E = a d verse e ve nt; A L K = a na plastic l ym p h o ma ki nase ; A U C = area u n der t he c o nce ntrati o n -ti me c ur ve; BI C R = bli n de d i n de pe n de nt ce ntral 
re vie w; E C O G P S = Easter n C o o perati ve O n c ol o g y Gr o u p Perf or ma nce Sc ore; E G F R = e pi der mal gr o wt h fact or; 
 N S C L C = n o n -s mall cell l u n g ca ncer; N Q = n o n- q ua ntifia ble; N S Q = n o n -s q ua m o us; O R R =
o verall res p o nse rate; O S = o verall s ur vi val; P D = pr o gressi ve disease; P D C T = plati n u m d o u blet c he m ot hera p y; 
 P F S =
pr o gressi o n -free s ur vi val; P K = p har mac o ki netic; P S = perf or ma nce stat us; P R O = patie nt -re p orte d o utc o me; Q 3 W = e ver y 3 wee ks; S A E = seri o us a d verse e ve nt; 
S Q = s q ua m o us.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 7
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Part 1 - D o se safety c o nfi r mat i on ( n ≈ u p t o 1 2 0): Site -a n d-s u bject bli n de d, ra n d omize d d ose safety 
c o nfir mat i on. El i gi ble partici pa nts will be ra n d omize d 1: 1 t o Ar ms A or B t o e val uate t he safety 
a n d t olera bilit y of t he c o m bi natio n of  ni v ol u ma b pl us relatli ma b 7 2 0 m g a n d P D C T a n d c o nfir m 
t he safety pr ofile. T he relatli ma b 3 6 0 m g Q 3 W d ose i n Ar m B will be e val uate d t o ge nerate 
a d ditio nal safet y d at a at t hi s d ose le vel. T he ra n d o mizati on will  be stratifie d b y hist ol o g y  ( S Q vs 
N S Q). After all t reate d partici p a nts ha ve bee n f oll owe d u p f or a mi ni m u m of  12 wee ks, t he pri mar y 
a nal ysis will ta ke place t o deter mi ne w het her t he fi nal esta blis he d t hres h ol d f or t he d ose -safet y 
e val ua ble p o p ulat i on has bee n met a n d t o e val uate t he t otalit y of t he Part 1 safet y data. 
In a d ditio n, t he pr o p orti o n of  T R A Es lea di n g t o disc o nti n uati o n wit hi n 1 2 wee ks of t he first d ose 
will be m o nit ore d f or eac h ar m 
 
 
If, base d o n t he d ose safety c o nfir mat i on, t he re gi me n i ncl u di n g relatli ma b 7 2 0 m g ( Ar m A) is 
c o nfir me d t o be safe, t he n t his d ose le vel will be e val uate d i n Part 2 of t he trial a gai nst t he c o ntr ol 
ar m. If, base d o n t he d ose safety c o nfir mat i on, t he re gi me n i ncl u di n g relatli ma b 7 2 0 m g is n ot 
c o nfir me d t o be safe, b ut t he re gi me n i ncl u di n g r elat li ma b 3 6 0 m g ( Ar m B) is c o nfir me d t o be 
safe, t he n t he latter will be t he d ose e val uate d i n Part 2. If b ot h Ar m A a n d Ar m B are c o nfi r me d 
t o be safe, or Ar m A is c o nfir me d t o be safe w hile Ar m B is n ot, t he n t he selecte d d ose f or 
de vel o p me nt c o ntai ne d i n Arm A (relat li ma b 7 2 0 m g Q 3 W) will  be the o ne use d i n Part 2. If neither 
re gi me n is c o nfir me d t o be safe at a n y p oi nt d uri n g t he d ose safety c o nfir mat i on, t he n Part 2 of t he 
st u d y wo ul d n ot ta ke place. Relatli ma b d ose of  36 0 m g Q 3 W was selecte d fr om t he c o n d uct of 
Part 1 , tar get rece pt or e n ga ge me nt, a n d be nefit -ris k assess me nt c o nsi derati o ns at asset le vel.
I n a d diti on, f or Part 1, a n e xter nal c o ntr ol ar m will be c o nstr ucte d. T hi s a p pr oac h will be descri be d 
i n detail i n a statistical a nal ysis pla n ( S A P).
Part 2 ( n = 3 0 0) : Ra n d o mize d, o pe n -label, c o ntr olle d trial t hat will f urt her e val uate t he efficac y 
a n d safety of  the ni v o l u ma b, relatli ma b pl us c he mot h era p y co m bi nat i on vs ni v o l uma b pl us 
c he m ot hera p y. 
 
 
 At t his ti me, partici pa nts t hat 
are i n scree ni n g a n d f o u n d t o be e li gi ble will be ra n d o mize d 1: 1 i nt o e x peri me ntal Ar m C or c o nt r ol 
Ar m D of  P art 2 of t he trial. 
 
 
 
 T he stratificati on fact ors f or ra n d o mizati on i n Part 2 are hist ol o g y ( S Q vs N S Q) , 
E C O G perf or ma nce stat us ( 0 vs 1) a n d P D-L 1 le vel ( ≥1 % [i ncl u di n g N Q] vs < 1 %).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
5. 1. 1 
S cr e e ni n g P h a s e
Parti cipa nts will pr o vi de wri tte n i nf or me d c o nse nt t o partici pate i n t he st u d y before c o mpleti n g 
a n y pr ot oc ol -s pecifie d pr oce d ures or e val uat i ons n ot c o nsi dere d t o be part of  the partici pa nt’s 
sta n dar d care. Afte r sig ni n g t he i nf or me d c o nse nt f or m (I C F), parti ci pa nts will be e val uate d f or 
e ntr y crit eria d uri n g t he Scree ni n g P eri o d 
 bef ore ra n d omizat i on. Re -e nr o ll me nt 
after scree n fail ure will be all o we d. I ma gi n g of t he brai n with ma g net ic res o na nce ima gi n g ( M RI) 
( wit h a n d with o ut c o ntrast) is re q uire d of all partici pa nts d uri n g Scree ni n g. C o m p ute d t o m o gra p h y 
( C T) of  the brai n ( wit h o ut a n d wit h c o nt rast) ca n be perf or me d if M RI is c o ntrai n dicate d.
A 1 2 -lea d 
electr ocar dio gr a m  ( E C G) a n d ec h ocar di o gra m are re q uire d d uri n g scree ni n g.
 
 
 
 
 
 
 
 
 
 
 
 
5. 1. 2 
O n -tr e at m e nt P h a s e
T he Part 1 d ose safety c o nfir mat i on p eri o d is 1 2 wee ks after t he first d ose. U p t o a p pr o xi matel y 
1 2 0 eli gi ble part ici pa nts t o e nr oll i n t he st u d y will be ra n d omize d 1: 1 t o e x peri me ntal Ar ms A 
or B. Ni v o l uma b 
pl us r elat li ma b, t he i m m u ne c hec k p oi nt i n hi bit ors here o n r eferre d t o as 
i m m u n ot hera p y, will be a d mi nistere d i n a site-a n d-s u bject bli n de d ma n ner, w hereas c he m ot hera p y 
will be a d mi nistere d as o pe n la bel. 
Ar m A:   Ni v o l uma b 3 6 0 m g Q 3 W + relat li ma b 7 2 0 m g Q 3 W + 4 c ycles of hist ol o g y-base d P D C T 
Ar m B:   Ni v o l uma b 3 6 0 m g Q 3 W + relat li ma b 3 6 0 m g Q 3 W + 4 c ycles of hist ol o g y-base d P D C T 
D uri n g t he treat me nt p hase of  Part 2 of  the st u d y, parti ci pa nts will recei ve t he f o ll owi n g tr e at me nts. 
I mm u n ot hera p y  a n d c he mot h era p y will be a d mi nistere d as o pe n-label  int er ve nt i ons.
Ar m C:
Ni v o l uma b 3 6 0 m g Q 3 W + r elat li ma b 3 6 0 m g a Q 3 W + 4 c ycles of  hist olo g y -base d 
P D C T b or
Ar m D: Ni v o l uma b 3 6 0 m g Q 3 W + 4 c y cles of hist ol o g y-base d P D C T b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
5 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
a
T he relatli ma b d ose t o be i ncl u de d i n Ar m C will be deter mi ne d b y t he o utc o me of t he d ose safet y c o nfir mati o n 
t hat will ta ke place i n Part 1 of t he st u d y a n d ot her be nefit -ris k c o nsi derati o ns at asset le vel. T his was deter mi ne d 
t o be relatli ma b 3 6 0 m g Q 3 W.
b
Hist ol o g y -base d P D C T will be as f oll o ws:
N S Q: Car b o plati n area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) 5 or 6 * or cis plati n 7 5 m g/ m 2 + pe metre xe d 5 0 0 
m g/ m 2 ( mai nte na nce per mitte d) 
S Q:  Car b o plati n A U C 6 + paclita xel 2 0 0 m g/ m 2 or na b -paclita xel 1 0 0 m g/ m 2 
* N O T E: Car b o plati n A U C 6 f or N S Q a n d na b -paclita xel f or S Q hist ol o g y is per mitte d o nl y i n Part 1.
 
 
 
 
 
D ose re d ucti o ns are n ot per mitte d f or i m m u n ot hera p y .
P h ysical e xa mi nat i ons, vit al si g n meas ure me nts, 1 2 -lea d electr ocar dio gra ms ( E C G), a n d cli nical 
la b orat or y e val uati ons will be perf or me d at selecte d ti mes t hr o u g h o ut t he d osi n g i nter val (refer t o 
Ta ble 2- 2 ). P artici pa nts will be clos el y mo ni t or e d for A Es t hr o u g h o ut t he st u d y . S a mples will be 
c ollecte d bef ore a n d aft er stu d y dr u g ad mi nistrati o n f or P K a nal ysis a n d p har mac o d y na mic 
para m eter meas ure me nts. See Secti o n 2 f or furt her details.
All p arti ci pa nts will be treate d u ntil pr o gressi o n, prese nce of i ntol era ble t o xicities, wit hdra wal  of 
c o nse nt, or stu d y e n d, w hic he ver 
c o me s first. C o nti n u o us safety e val uat i ons a n d t u mor 
assess me nts will g ui de t he decisi o n t o treat a partici pa nt wit h a d dit i onal c ycles of st u d y  t hera p y if 
t he part ici pa nt has c o nfir me d cli nical be nefit. 
Parti cipa nts will be allo we d t o c o nt i n ue st u d y treat me nt u nt il t he first occ urre nce of  an y of  the 
f oll owi n g sit uat i ons:

Pr o gressi ve disease ( P D ) defi ne d b y Res p o nse E val uat i on Cri teria i n S oli d T u m ors (R E CI S T )
v 1. 1 (A p pe n di x 5 ) u nless partici pa nts meet 
criteria f or treat me nt be y o n d pr o gressi o n 
(Secti o n 8. 1. 3 ).

Cli nical deteri orati o n s u g gest i n g t hat n o f urt her be nefit fr o m treat me nt is li kel y.

I nt olera bilit y t o stu d y t hera p y.

Parti cip a nt m eets crit eria for di sc o nti n uati on of st u d y  treat me nt as s h o w n i n Secti o n 8. 1 .
5. 1. 3 
F oll o w -u p P eri o d
L o n g -t er m fol l ow -u p s h o ul d c o nti n ue u nt il wi t hdra wal  of c o nse nt, deat h, or st u d y ter mi nati on b y 
t he S p o ns or. T he d urati o n of t he st u d y fr o m st art of ra n d o mizati o n i n t he d ose safet y c o nfir mat i on 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
p eri o d t o t he fi nal a nal ysis o f P F S is a p pr o xi matel y 4 8 m o nt hs 
 
Ti mi n g f or l on g -t er m fol l ow- u p will be as f oll ows: A ssess me nts s h o uld c o nt i n ue as descri be d i n 
Ta ble 2- 3 .

S af et y F o ll ow- u p:  
 
 
 
 
 If t he partici pa nt disc o nt i n ues st u d y dr u g d ue t o a 
cli nicall y si g nifica nt A E, t he parti ci pa nt will be f o ll o we d u ntil res ol uti on o f the A E or t he e ve nt 
is c o nsi dere d t o be sta ble a n d/ or c hr o nic.

T u m or Assess me nt a n d Res p o nse F o ll ow- u p: P artici pa nts w h o disc o nt i n ue st u d y treat me nts 
f or reas o ns ot her t ha n P D as per BI C R or deat h s h oul d c o nt i n ue t o ha ve t u mor assess me nt as 
per Secti o n 9. 1. 1. 1 u ntil P D as per , deat h, l ost t o f oll ow- u p, or wit h dra wal of  co nse nt,
w hic he ver ha p pe ns earlier. Parti ci pa nts wit h a hist or y of brai n metastasis or s y m pt o ms s h o ul d 
c o nti n ue t o ha ve s ur veilla nce M RIs 
( wit ho ut a n d wi t h co ntrast) per sta n dar d of  care 
 or s o o ner if cli nicall y i n dicate d.

S ur vi val F o ll ow- u p:  
 
 
 
 
 
 F or 
parti ci pa nts w h o are disc o nt i n ue d wi t ho ut BI C R -c o nfir me d P D, t u mor assess me nts s h o uld 
c o nti nu e t o b e p erf or m e d base d o n Ta ble 2 - 3. I nfor m at i on o n t he s u bse q ue nt P D, s u bse q ue nt 
a nt i-ca ncer t hera p y, a n d o utc o me m ust be c ollecte d. 
5. 1. 4 
D at a M o nit ori n g C o m mitt e e a n d Ot h er E xt er n al C o m mitt e e s
A n i n de pe n de nt D M C will be ut ilize d t o pr o vide ge neral o versi g ht a n d safety c o nsi deratio ns f or 
St u d y  C A2 2 4 1 0 4 d uri n g Part 2 p hase. T he i n de pe n de nt D M C will pr o vide a d vice t o t he S p o n s or 
re gar di n g actio ns t he c o m mittee dee ms necessar y f or t he c o nt i n ui n g pr otecti o n of  partici pa nts 
e nr o lle d i n t his st u d y. T he i n de pe n de nt D M C will be c har ge d wit h assessi n g s uc h acti ons i n li g ht 
of  an acce pta ble be nefit -ris k pr ofile f or ni v o l u ma b/relat li mab. T he i n de pe n de nt 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 mo ni t or partici pa nt safety data f or Part 2 of t he st u d y .
B M S will ha ve res p o nsi bility f or t he o verall c o n d uct of  the stu d y, i ncl u di n g ma na gi n g t he 
c o m m u nicat i on of  st u d y data. B M S 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 ons, f or pr o vidi 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 co n d uct are 
re q uire d. Details of the i n de pe n de nt 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.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
I n a d ditio n t o t he D M C, a s afet y c o m mittee ( S C) c o nsist i n g of  BM S researc h a n d de vel o p me nt 
re prese ntati ves (incl u di n g cli nical de vel o p me nt, dr u g safety,  an d statistics) a n d e xter nal 
re prese ntati ves (i ncl u di n g a selecti o n of the st u d y i n vesti gat ors) will re g ularl y meet t o e val uate t he 
acc u m ulat i n g safety data of  partici pa nts o n t he d ose safety c o nfir mat i on p orti o n of  the st u d y 
( Part 1) a n d pr o vi de i n p ut t o i nter pret safe t y si g nals. I nf or mati o n re vie we d at eac h ti me p oi nt may 
i ncl u de dis p osi tio n , d e m o gra p hics, A Es, S A Es, T R A Es, T R A Es lea di n g t o disc o nti n uati o n, 
e x p os ure, deat h data, a n d a n y ot her data dee me d rele va nt (la b orat or y, pat h olo g y , a ut o ps y re p orts, 
p h ysical descri pt i ons). T he mi n utes of t hese meet i n gs will be d oc u me nte d i n t he Trial Masterfile. 
T he S C will n ot s hare res p o nsi bilities wi t h the D M C (ie, t he S C is res p o nsi ble f or m o nit ori n g 
Part 1 a n d t he D M C f or Part 2). Decisi o ns o n safet y, t o xicit y,  a n d be nefit-ris k re gar di n g eac h d ose 
le vel will  be s olel y the res p o nsi bility of  BM S a n d will ta ke acc o u nt of  the t otality of  the data 
a vaila ble. 
Alt h o u g h t he S C will meet o nl y  duri n g Part 1 of  the st u d y, t he safety of  the selecte d d ose will 
c o nti n ue t o be m o nit ore d i n Part 2. T he D M C will re g ularl y re vie w a n y p ote ntial e mer ge nt safet y 
sig n al  that was n ot o bser ve d i n Part 1 ( n ote t hat t he D M C will recei ve t he m ost rece nt Part 1 safet y 
data as well).
5. 1. 5 
Bli n d e d I n d e p e n d e nt R a di ol o g y C e ntr al R e vi e w
A BI C R is rec o m me n de d b y re g ulat or y age ncies i n sit u atio ns w here cli nical sit e i ma ge 
i nter pretatio n is varia ble a n d res ults of  ima ge 
meas ure me nts 
are i m p orta nt f or eli gi bilit y 
deter mi nat i on, safety,  an d/ or efficac y e n d p o i nts. S pecificall y , BI C R of  sca ns ma y mit i gate bias 
re gar di n g e n d p oi nt assess me nt d ue t o t he s u bjecti vity i n v ol ve d i n lesi on meas ure me nt a n d 
i nter pretatio n of  O R R a n d P F S. Si tes s h o uld s u b mit all i ma ges t o BI C R o n a c o nt i n ui n g basis. 
H o we ver, s h o ul d t he BI C R i nter pretatio n be i n c o nflict wit h t he l ocal eval uat i on, treat me nt 
decisi o ns will be base d o n i n vesti gat or assess me nt a n d n ot t he BI C R res ul ts pr o vi de d to t he sit e. 
See Secti o n 9. 1. 1. 3 f or more i nf or m at i on o n BI C R c o nfir mat i on of pr o gressi o n.
5. 2 
N u m b er of P arti ci p a nt s
I n t he d ose safet y c o nf irmat i on ( Part 1) , u p t o a p pr o xi matel y 1 2 0 partici pa nts will be ra n d o mize d 
1: 1 t o treat m e nt Ar ms A or B (ie, 6 0 partici pa nts per ar m).
I n Part 2, a p pr o xi matel y 3 0 0 parti ci pa nts will be ra n d omize d 1: 1 t o t he e x peri me ntal ar m, C, or 
t he c o ntr ol ar m, D (ie, 1 5 0 partici pa nts per ar m).
5. 3 
E n d of St u d y D efi niti o n
T he start of t he trial is defi ne d as first visit f or first partici pa nt scree ne d. E n d of trial is defi ne d as 
t he last visit or sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of  Acti vit ies f or t he last partici pa n t. 
 
or t he fi nal date o n 
w hic h data is t o be c ollecte d f or s ur vi val f oll o w- u p, w hic he ver occ ur s later .
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
5. 4 
S ci e ntifi c R ati o n al e f or St u d y D e si g n
T u m ors a n d t he t u m or micr oe n vir o n me nt are k n o w n t o e x press a vari et y of  fact ors t hat i m pe de a 
r o b ust im m u ne res p o nse fr om eli mi nat i n g t he t u m or. S ol u ble a n d me m bra ne -b o u n d fact ors ha ve 
bee n s h o w n t o i n hi bit t he c yt ol ytic act i vity of  tu m o r-i nfiltrati n g T- cells (e g, P D -L 1 e x pressi o n; 
T G F -beta). I n a d dit i on, s o me t u mor -deri ve d fact ors are a ble t o e n ha nce im m u ne 
s yste m 
c o u nter -re g ulat or y s yste ms (e g, i ncrease d Tre gs). Fi nall y, s u b o pti mal t u mor a nti ge n deli ver y  a nd 
prese ntati o n has bee n p ost ul ate d as a n ot her mec ha nis m b y w hic h t u mors ca n s uccessf ull y e va de 
i m m u ne s yste m rec o g niti on.
Ca ncer t hera pe utics s uc h as c he mot h era p y ma y mo d ulate t u mor/i m m u ne s yste m int eract i ons i n 
fa v or of t he i m m u ne s yste m. C he m ot hera p y ca n res ult i n t u m or cell deat h wit h a res ulta nt i ncrease 
i n t u mor a nti ge n deli ver y t o a nti ge n-prese nt i n g cells. T u m or cell deat h ma y als o lea d t o a re ducti o n 
i n s ol uble a n d me m bra ne -b o u n d fact ors i n hi biti n g t u mor -i nfiltrati n g T- cells. C he m ot h era p y ma y 
als o disr u pt i m m u ne s yste m re g ulat or y net w or ks b y decreasi n g n u m bers of Tre gs.
Des pite rece nt i n n o vati o ns i n ca ncer tr e at me nt, alter nati ve t hera pies are ne e de d f or partici pa nts 
wi t h ad va nce d N S C L C (see Sect i on 3. 2 ). T he rece nt F o o d a n d Dr u g A d mi nistrati o n ( F D A) 
a p pr o vals of  ni v ol u ma b i n c o m b i nati on wi t h ipili m u ma b a n d ni v o l u ma b i n c o m bi nat i on wi t h 
i pili m u ma b pl us P D C T i n 1 L N S C L C 
i ncrease t he ar ma me ntari u m of  im m u n ot hera p y 
c o m bi nat i ons t hat ha ve i m pr o ve d t he pr o g n osis of t his p o p ulat i on. H o we ver, still less t ha n 5 0 % of 
parti ci pa nt s are e x pecte d t o be nefit fr o m a nti– P D -1/ P D -L 1 c o m bi nat i on t hera p y , hi g hli g hti n g t he 
nee d f or f urt her i n vesti gati on i nto ot her strate gies s uc h as si m ulta ne o us i n hi biti on. C o m bi nat i on 
i m m u ne-m o d ul at i n g t hera pies ha ve a n e m er gi n g r ole i n pr o d uci n g dee p a n d d ura ble res p o nses i n 
a variet y of  tu m or t y pes. Earl y cli nical data fr o m trials st u d yi n g relatli ma b i n c o m bi nat i on wi t h 
ni v o l u ma b, a n d t he c o m bi nat i on of  ni v ol uma b wit h c he m ot hera p y, s u g gest t hat t here ma y be a 
p ote nti al for i ncreasi n g be nefit b y c o m bi ni n g t hese dr u gs d ue t o t he vast a m o u nt of rece pt ors t hat 
are tar gete d b y t heir n o n-o verla p pi n g mec ha nis ms of act i on (see Sect i on 3. 2. 3 ). O verall, t he safet y 
pr ofile of  relat li ma b i n c o m bi nat i on wi t h ni v ol u ma b has bee n ma na gea ble, a n d t here were n o 
k n o w n a d dit i onal t o xicit ies wit h t he relat li ma b c o m bi nati on wi t h ni v ol u ma b. Si milarl y, t he safety 
pr ofile of  ni v ol u ma b has bee n ma na gea ble 
b ot h i n c o m bi nat i on wi t h ipili m u ma b a n d i n 
c o m bi nat i on wi t h che m ot hera p y. T heref ore, it is e x pecte d t hat t he a d dit i on of  relat li ma b t o 
ni v o l u ma b a n d c he m ot hera p y will pr o vi de a n acce pta ble be nefit-ris k ratio.
5. 4. 1 
R ati o n al e f or E x cl u si o n of P arti ci p a nt s wit h K n o w n E pi d er m al Gr o wt h 
F a ct or, A n a pl a sti c L y m p h o m a Ki n a s e, R O S- 1, a n d B -r a pi dl y 
A c c el er at e d Fi br o s ar c o m a Pr ot o- o n c o g e n e V 6 0 0 E Alt er ati o n s
E pi d er m al gr o wt h fact or rece pt or ( E G F R)-m ut a nt t u mors c o m m o nl y dis pla y l ower TI Ls, P D -L 1 
e x pressi o n, a n d t u mor m ut atio nal  bur de n t ha n E G F R -wil d -t ype t u mors. C o nsiste nt wit h t his, 
parti ci pa nt s wit h E G F R-m utate d carci n o mas deri ve less cli nical be nefit fr o m P D -1 a xis bl oc ka de. 
I n a d diti on, cli nical trials ha ve de m o nstrate d t hat partici pa nt s wit h acti o na ble m olec ular alterati o ns 
s uc h as E G F R m utati o ns or A L K tra nsl ocati ons ha ve l o wer res p o nse rates t o c hec k p oi nt i n hi bit i on 
wi t h PD- 1 or P D -L 1 i n hi bit ors. Treat me nts f or E G F R m ut atio ns, a na plast ic l y m p h oma ki nase 
( A L K) tra nslo c ati o ns, R O S - 1 rearra nge me nts, a n d B- ra pidl y accelerate d fi br osarc o ma pr ot o -
o nc o ge ne ( B R A F) V 6 0 0 E m utati o ns ha ve s h o w n i m pressi ve res ults a n d are n o w F D A a p pr o ve d i n 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
N S C L C. F or t hat reas o n, 1 L sta n dar d of  care f or partici pa nts wit h a n y of t hese cli nicall y acti ona ble 
alt er atio ns is tar gete d t hera p y rat her t ha n i m m u n ot hera p y an d/ or c he m ot hera p y. Parti ci pa nts 
k n o w n t o ha ve t hese a b n or m alities will be e xcl u de d fr o m t his st u d y. E xcl u di n g t hese partici pa nts 
will hel p t o re d uce t he p ote ntiall y c o nf o u n di n g effects of  these a b n or malities o n t he st u d y 
e n d p o i nts.
Si nce B R A F V 6 0 0 E is n ot yet  wi del y teste d, it will n ot be a re q uire me nt t o test f or B R A F m utati o ns 
at scree ni n g i n t his st u d y. H o we ver, partici pa nts wi t h a kn o w n B R A F V 6 0 0 E m ut atio n will be 
e xcl u de d. 
5. 4. 2 
R ati o n al e f or D o s e S af et y C o nfir m ati o n
I n or d er t o c o nfir m t he safety pr ofile of  relat li ma b i n c o m bi nat i on wi t h ni v ol u ma b at t he c h ose n 
de vel o p me nt d ose, a d ose safet y c o nfir mat i on p hase will be c o n d ucte d pri or t o Part 2 of t he st u d y. 
T he rel at li ma b 3 6 0 m g Q 3 W d ose will be e val uate d t o ge nerate a d dit i onal safet y data at t hi s d ose 
le vel.   
 partici pa nts will be treate d wit h eac h re gi me n a n d will be f oll owe d f or at least 1 2 
wee ks aft er t he first d ose t o i de ntif y the rate of  partici pa nts t hat e x perie nce treat me nt -relate d 
t o xicities t hat lea d t o disc o nt i n uati on d uri n g t he 1 2 -wee k 
e val uat i on peri o d. C o nti n u o us 
m o nit ori n g of partici pa nt safet y  will be perf or me d t o re vie w c u m ulat i ve t o xicity data.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 
5. 4. 3 
R ati o n al e f or S h ort e n e d I nf u si o n Ti m e f or Ni v ol u m a b pl u s R el atli m a b
L o n g i nf us i on ti mes, es peciall y w he n m ulti p le a ge nts are a d mi nistere d t o a n i n di vi d ual, place a 
b ur de n o n partici pa nt s a n d treat me nt ce nters. Esta blis hi n g t hat ni v o l uma b a n d relatli ma b ca n be 
safel y a d mi nistere d usi n g a s h orter i nf usi o n ti me of 3 0 mi n utes d urati o n w ill di mi nis h t his b ur de n, 
pr o vi de d t he safet y pr ofile re m ai ns ma na gea ble.
Pre vi o us cli nical st u dies of  ni v ol u ma b i n c o m bi nat i on wi t h relatli ma b ha ve use d a 6 0 -mi n ute 
i nf usi on d urati o n. H o we ver, rel at li ma b d oses 
 ha ve bee n safel y a d mi nistered as 
a si n gle a ge nt vial ( S A V) o ver 6 0 mi n utes i n st u d y C A 2 2 4 0 2 0. I n t his st u d y, t he hi g her d ose of 
7 2 0 m g of  relatli ma b t o be c o-a d mi nistere d wit h ni v o l u ma b o ver 3 0 mi n utes will n ot e xcee d t his 
I V a d mi nistrati o n 
rate. A d dit i onall y , ni v o l uma b 
a n d r elat li mab 
ha ve 
bee n 
pre vi o usl y 
c o -a d mi nistere d as a F D C wit h n o a p pare nt i ncrease i n i nf usi on- r elate d reactio ns, c o m pare d wi t h 
se q ue ntial a d mi nistratio n.
O verall, i nf usi on reacti ons i ncl u di n g hi g h -gra de h y perse nsit i vity reacti ons ha ve bee n u nc o m m o n 
acr oss ni v o l uma b or relatli ma b cli nical st u dies or t h e c o m bi nati o n of  ni v ol u ma b a n d relatli ma b. 
F urt her m or e, a 3 0 -mi n ute brea k aft er t he i m m u n ot hera p y inf usi o n  will e ns ure t he a p pr o priate 
safety m o nit ori n g bef ore t he start of  the c he m ot hera p y i nf usi o n. O verall, a c ha n ge i n safety pr ofile 
is n ot a ntici pate d wit h 3 0 -mi n ute i nf usi o n of ni v o l u ma b i n c o m bi nat i on wi t h relatli ma b.
5. 4. 4 
R ati o n al e f or C h oi c e of C h e m ot h er a p y
1 L treat me nt of a d va nce d N S C L C is hist ol o g y s pecific. I n S Q N S C L C, car b o plat i n pl us paclita xel 
is a sta n dar d of  care re gi me n f or parti ci pa nt s wi t h ne wl y dia g n ose d a d va nce d or met astatic N S C L C 
w h o d o n ot ha ve E G F R m ut atio ns or A L K tra nslo c ati o ns. Parti ci pa nts wi t h NS Q hist ol o g y  ma y 
recei ve cis plat i n or car b o plat i n with pe metre xe d wi t h opt i onal pe metre xe d as mai nte na nce t hera p y. 
Alt h o u g h s o me b ut n ot all meta -a nal yses a n d ra n d o mize d st u dies ha ve de m o n strate d t hat 
cis plati n-base d re gi me ns ma y pr o d uce i m pr o ve d s ur vi val c o m pare d 
t o car b o plat i n-base d 
re gi me ns, ma n y parti ci pa nts are n ot i deal ca n di dates f or cis plati n d ue t o its hi g her t o xicity.  
Car b o pl at i n-base d c he m ot hera p y is r o uti nel y use d i n cli nical pract ice a n d cli nical trials.
Pri or data fr o m C A 2 0 9 0 1 2 s u g gest si milar efficac y a n d safety w he n c o m bi ni n g ni v o l u ma b wi t h 
c he m ot hera p y, re gar dless of t he c he m ot hera p y bac k b o ne. Partici pa nts wit h S Q a n d N S Q hist ol o g y 
ma y recei ve t he f oll o wi n g plat i n u m-d o u blet bac k b o ne i n t heir re gi me ns:

S Q hist ol o g y: 4 c ycles of  car b o plati n A U C 6 + pac lita xel 20 0 m g/ m 2 or car b o plat i n 
A U C 6 + na b -pacli ta xel ( 1 0 0 mg/ m 2 )a

N S Q hist ol o g y : 4 c ycles of  car b o plat i n A U C 5 or 6 a + pe metre xe d 5 0 0 m g/ m 2 or cis plat i n 
7 5 m g/ m 2 + pe m etre xe d 5 0 0 mg/ m 2
a  Na b -paclit a xel for S Q a n d car b o pl at i n A U C 6 f or N S Q hist olo g y  is a p plica ble t o Part 1 o nl y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 a n d car b o plati n d ose has bee n restricte d t o A U C 5 f or n o n-s q ua m o us hist ol o g y t o 
ali g n wi t h gl obal sta n dar d of  care a n d t o re d uce variat i on i n ma na ge me nt of  this parti ci pa nt  
p o p ul at i on. 1
5. 4. 5 
R ati o n al e f or C h oi c e of C o ntr ol Ar m
A k e y  r e q uire me nt ste m mi n g fr o m c urre nt health a ut h orit y g uideli nes f or e valuat i on of  tr e at me nt 
c o m bi nat i ons is t o de m o nstrate t he c o ntri b ut i on of  eac h c o m p o ne nt t o t he o verall effect of  the 
re gi me n bei n g teste d. A t ypical wa y  to ac hie ve t his is b y c o m par i n g t he c o m bi nat i on t hera p y to 
t he o ne or m o re of  the m o n ot hera pi es t o pr o ve n o n- i nferi ority or s u peri ority.  Ni v ol u ma b pl us 
c he m ot hera p y was teste d i n st u d y CA 2 0 9 2 2 7. E ve n t ho u g h t he c o m bi nat i on di d n ot ac hie ve 
sig nifica nce o n its pri mar y e n d p o i nt of pr ol o n gi n g O S vs P D C T al o ne i n N S Q partici pa nt s, t he 
ni v o l u ma b pl us c he mot h era p y re gi me n was de m o nstrate d t o be acti ve a n d t olera ble i n t he all 
c o mer p o p ul at i on acr oss hist ol o gi es a n d re gar dless of  PD- L 1 e x pressio n . S pecificall y, t he 
1 2 -m o nt h O S rates were 6 7 % a n d 5 9 % wit h ni v o l u ma b pl us P D C T a n d P D C T al o ne, res pecti vel y. 
I n all ra n d o mize d parti ci pa nt s a n d i n S Q N S C L C, ni v o l uma b pl us P D C T s h o we d i m pr o ve d 
efficac y vs P D C T acr oss e n d p o i nts. I n descri pt i ve a nal yses, P F S, O R R, a n d D o R were n u mericall y 
i m pr o ve d wit h ni v ol uma b pl us c he m ot hera p y vs c he m ot hera p y b y itself. O R R f or t he c o m bi nat i on 
i n t he N S Q parti ci pa nt s was 4 8. 1 % vs 2 5. 7 % f or P D C T. I n t he S Q partici pa nt s, O R R was 5 9. 8 % 
vs 3 2. 4 % i n t he c he mot h era p y ar m. F or c o mparis o n wi t h hist orical data, O R R f or t he P hase 3 
st u dies t h at le d t o t he re g ulat or y a p pr o val of t he pe m br oliz u ma b plus c he m ot h era p y c o m bi nat i on 
was 4 7. 6 % i n N S Q parti ci pa nt s a n d 5 7. 9 % i n t he S Q p o p ulat i on. Li ke wise, i n N S Q s u bjects, 
me dia n P F S ( m P F S) was 8. 7 m o nt hs f or ni v ol u ma b pl us P D C T vs 5. 8 m o nt hs i n t he P D C T o nl y 
gr o u p ( H R = 0. 6 7); w herea s i n t he S Q partici pa nt s m P F S was 7. 1 m o nt hs f or ni v o l uma b pl us 
P D C T vs 4. 4 m o nt hs i n t he P D C T ar m ( H R = 0. 5 1). T he m P F S of  pe m br oliz u ma b plus P D C T i n 
t he afor e m e nt i one d tri als w as 8. 8 mo nt hs i n N S Q parti ci pa nt s ( H R = 0. 5 2) a n d 6. 4 mo nt hs i n t he 
S Q p o p ulat i on ( H R = 0. 5 6).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
5. 4. 8 
R ati o n al e f or O R R a s a Pri m ar y E n d p oi nt i n P art 2
O R R is a n acce pta ble P hase 2 e n d p o i nt in o nc o l og y  st u dies i n N S C L C t hat all o ws res ults t o be 
assesse d earlier w he n c o mpare d wi t h sur vi val -base d e n d p o i nts. Earl y access t o O R R data is 
nec essar y due t o t he ra pi dl y c ha n gi n g la n dsca pe i n N S C L C a n d is c o nsi dere d s ufficie nt t o esta blis h 
pr o of -of -c o nce pt t o help g ui d e f urt her de vel o p me nt of t he i n vesti gati onal a ge nt(s). A n a d va nta ge 
of  OR R o ver s ur vi val-base d e n d p o i nts is t he direct attri b uti o n of  tu m or res p o nse t o t hera p y 
beca use i n t he a bse nce of  treat me nt, s p o nta ne o us t um o r re gressi on is hi g hl y u nli kel y. F urt her m ore, 
O R R has bee n de m o nstrate d t o be a p ote ntial s urr o gate e n d p oi nt f or c hec k p o i nt i n hi bit or t hera pies 
i n N S C L C. A meta -a nal ysis o f 14 trials i ncl u di n g o ver 1 0, 0 0 0 partici pa nt s wit h a d va nce d N S C L C 
s u b mitte d t o t he F D A bet wee n 2 0 0 3 a n d 2 0 1 3 de m o nstrate d a str o n g trial-le vel ass ociat i on 
bet wee n O R R a n d P F S. 4 2 ,4 3 ,4 4 . I n t he C A 2 2 4 - 0 4 7 trial of  ni v ol u ma b + r elat li ma b F D C vs 
ni v o l u ma b m o n ot hera py i n first li ne a d va nce d mela n oma, t he cli nicall y mea ni n gf ul i m pr o ve me nt 
of  O R R ( 4 3. 1 % vs 3 2. 6 %) le d t o a statisticall y si g nifica nt i m pr o ve me nt i n P F S [ 1 0. 1 m o nt hs ( 9 5 % 
CI, 6. 4 – 1 5. 7) vs 4. 6 m o nt hs ( 9 5 % CI, 3. 4 – 5. 6)]. 4 5 ,4 6
I n a met a-a nal ysis c o n d ucte d usi n g p o ol e d data fr o m 6 3 trials a n d 7 8 i m m u ne c hec k p oi nt t hera p y 
treat me nt ar ms ( n > 3 0, 0 0 0), re prese nti n g 1 5 differe nt t u mor t ypes acr oss differe nt li nes of 
t hera pies, i ncl u di n g N S C L C, O R R , a n d 6- m o nt h D o R was s h o w n t o be pr o g n ostic f or 1 2 -m o nt h 
O S. 4 7 T he pri mar y O R R assess me nt will be perf or me d b y BI C R i n Part 2 a n d will be f urt her 
c haracterize d b y t he d ura bilit y a n d de pt h of res p o nses t o esta blis h t he c o ntri b uti o n of c o m p o ne nts 
of  r elat li ma b a n d ni v ol u ma b.
5. 4. 9 
R ati o n al e f or Str atifi c ati o n
I n or der t o mi ni mize 
t he p ote nti al for i m bala nces acr oss treat me nt ar ms, t here will 
be 
3 stratificati on fact ors ut ilize d i n Part 2 of  this trial: hist o l og y  (S Q vs N S Q) , P D -L 1 e x pressi o n 
( ≥1 % t u mor cell s urface e x pressi o n [incl u des N Q] vers us < 1 % t u mor cell s urface e x pressi o n)
a nd E C O G perf or m a nce stat us ( 0 vs 1). 
T he pr o g n osti c i m plicati ons of  hist olo g y  are well esta blis he d, e ve n bef ore t he a d ve nt of 
i m m u n ot hera p y,4 8 he nce differe nt c he m ot hera p y re gi me ns are i n dicate d acc or di n g t o hist ol o g y, 
wi t h pe metre xe d mai nte na nce c urre nt l y fa v ore d o nl y f or a de n ocarci n oma.
Wit h re gar d t o P D -L 1 e x pressi o n, pre vi o us cli nical st u dies wi t h ni v ol u ma b m o n ot hera p y  ha v e 
s h o w n partici pa nt s wi t h PD- L 1 p osit i ve t u mors ma y ha ve better o utc o m es wi t h PD- 1- base d 
t hera pies t ha n t hose wi t h n on -e x pressi o n. Par tici pa nts i n t he c urre nt trial will t heref ore be stratifie d 
b y P D -L 1 stat us as t he effect of  PD -L 1 e x pressi o n o n res p o nse t o a nti-P D - 1 a n d a nt i-L A G -3 
c o m bi nat i on t hera pies is n ot y et k n o w n. T he pr o p ortio n of  N Q for P D -L 1 e x pressi o n is c urre nt l y 
esti mate d at 5 % -1 0 % i n 1 L N S C L C trials.  Gi ve n t he s mall pr o p orti o n of  partici pa nt s wi t h NQ 
sa m ple, N Q will be cate g oriz e d wit h t he P D-L 1 ≥1 % gr o u p. T he P D -L 1 ≥ 1 % gr o u p was c h ose n 
beca use t he pre vale nce of t his gr o u p wit hi n t he q ua nt ifia ble parti ci pa nt s is e x pecte d t o be sli g htl y 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
hi g her ( 5 7 % -6 0 %) t ha n of t he P D -L 1 < 1 % gr o u p, a n d t h us t he prese nce of N Q parti ci pa nt s i n t he 
P D -L 1 ≥ 1 % gr o u p is less li kel y t o dil ute treat me nt effect i n t his gr o u p; i n a d ditio n, it will be 
sli g htl y m o re r o b ust a gai nst a p ote ntial i m bala nce of N Q parti ci pa nt s acr oss ar ms. 4 9 ,5 0
E C O G P S i s als o a well-esta blis he d pr o g n ostic cli nical fact or i n N S C L C. 4 9 ,5 0 ,5 1
Alt h o u g h E C O G perf or ma nce stat us ( P S) a n d ge n der are b ot h well-esta blis he d pr o g n ostic cli nical 
fact ors i n N S C L C,5 2 E C O G ( 0 vs 1) was selecte d as a stratificat i on fact or i n t his st u d y o n t he basis 
of  t he hi g her pr o g nosti c v alu e c o m pare d wi t h ge n der. I n t he ni v o l uma b pl us P D C T ar m  in Part 2 
of  t he C A 2 0 9 2 2 7 1 L N S C L C st u d y , me dia n O S was 2 4. 3 mo nt hs i n s u bjects wi t h E C O G P S of 0 
vs 1 7. 9 m o nt hs i n partici pa nts wit h E C O G P S of 1. F or ge n der, t he me d ia n O S was 1 7. 9 m o nt hs 
i n males vs 2 0. 7 m o nt hs i n fe male s.4 3 , 5 2
D ue t o its s maller sa m ple size a n d beca use its pri mar y p ur p ose is safety,  Part 1 will be stratifie d 
b y hist o l og y  ( S Q vs N S Q) o nl y.
5. 4. 1 0 
R ati o n al e f or Bi o m ar k er A s s e s s m e nt
I mm u ne c hec k p o i nt sig nali n g 
 si gnifica ntl y da m pe ns 
a nt i-t u mor i m m u ne res p o nses i n differe nt t u m or t y pes, i ncl u di n g N S C L C. U nf ort u natel y, n ot all 
parti ci pa nt s res p o n d t o im m u ne c hec k p o i nt bl oc ka de; t heref ore, t here is a c o m pelli n g nee d f or a 
better u n dersta n di n g of fact ors (e g, bi o mar kers) t hat w o ul d pre dict res p o nse a n d pr o gressi o n. 
 
 
 
 
 
 
 
5. 4. 1 1 
R ati o n al e f or P er mitti n g C o nti n u e d Tr e at m e nt i n S el e ct C a s e s of 
Pr o gr e s si v e Di s e a s e
Acc u m ulat i n g 
cli nical 
e vi de nce 
i n dicates 
s o me 
parti ci pa nts 
treate d 
wit h  
i m m u ne 
s yste m-sti m ulati n g a ge nts ma y de vel o p pr o gressi o n of disease ( b y c o n ve nti onal res p o nse criteria) 
bef ore d e m o nstr ati n g cli nical O R a n d/ or sta ble disease ( S D). T hi s p he n o me n o n was o bser ve d i n 
a p pr o xi matel y 10 % of  su bjects i n t he P hase 1 st u d y of ni v o l u ma b a n d has bee n o bser ve d wi t h 
i pili m u ma b m o n ot hera p y  as well , s u g gesti n g t hat it is n ot a dr u g -s pecific occ urre nce. 
T w o h y p ot heses ha ve bee n p ut f ort h t o e x plai n t his p he n o me n o n. First, e n ha nce d i nfla m mati on 
wi t hi n t u mors c o ul d lea d t o a n i ncrease i n t u mor size, w hic h w o ul d a p pear as e nlar ge d i n dex 
lesio ns a n d as ne wl y visi ble, s mall no n -i n de x lesio ns. O ver ti me, b ot h t he ma li g na nt a n d 
i nfla m mat or y porti o ns of  the mass 
ma y 
t he n de crease, lea di n g t o o vert sig ns of  cli nical 
i m pr o ve me nt. Alt er nat i vel y, i n s ome i n di vi d uals, t he ki net ics of  tu m or gr o wt h ma y i nitiall y 
o ut pace a nti-t u mor i m m u ne act i vity.  With s ufficie nt ti me, t he a nt i-t u mor acti vit y will  do m i nate 
a n d bec o me 
cli nicall y ap p are nt. T heref ore, 
parti ci pa nts will 
be all o we d 
t o c o nt i n ue 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
6 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i m m u n ot hera p y after i nitial i n vesti gat or-assesse d R E CI S T v 1. 1 -defi ne d pr o gressi o n if t he y ar e 
assesse d t o be deri vi n g cli nical be nefit a n d t olerati n g st u d y dr u g. S uc h partici pa nts m ust 
di sc o nti n ue st u d y t hera p y u p o n e vi de nce of f urt her pr o gressi o n as defi ne d i n Sect i on 8. 1. 3 .
5. 4. 1 2 
R ati o n al e f or P ati e nt R e p ort e d O ut c o m e s A s s e s s m e nt s
T he e val uat i on of t he partici pa nt’s e x perie nce i n t he e val uat i on of bi o p har mace ut ical treat me nts is 
i m p orta nt t o f ull y u n dersta n d t he i m pact of  suc h pr o d ucts o n h o w partici pa nts feel a n d f unct i on.  
Pati e nt -re p orte d o utc o m es ( P R Os) ha ve bee n i nc or p orate d i n o nc olo g y  trials i n or der t o m o re f ull y 
u n dersta n d t he parti ci pa nt’s e x perie nce. I n a d ditio n, t here is a n i ncrease d f oc us fr om t he cli nical 
c o m m u nit y o n t he s pecific c o nce pts t hat are i nfl ue nce d b y t hera pe utic pr o d ucts, i ncl u di n g 
di sease-relate d s y m pt o ms, s y m pt omat ic A Es, a n d p h ysical f u ncti oni n g. W he n use d i n ta n de m with 
tra ditio n al  cli nical meas ures, 
t he 
 
 ca n pr o vi de a d diti onal  c o nte xt f or safety a n d efficac y res ults. I n t he 
c urre nt trial, the partici pa nt’s e x perie nce will be directl y  meas ure d t hr o u g h t he 
 t he 
 fr o m the  
 
 
t he Pati e nt Gl o bal I mpressi o n of  Se verit y (P GI S), a n d t he Pati e nt Gl o bal I mpressi o n  of C ha n ge 
( P GI C). T he Ce nter f or Dr u g E val uat i on a n d Researc h has deter mi ne d t hat t he 
 
d e m o nstrate d a de q uate e vi de nce of  co nte nt vali dit y a n d cr oss-secti o nal meas ure me nt pr o perties 
(ie, i nter nal c o nsiste nc y relia bility,  test -retest relia bility,  co n ver ge nt vali dit y,  an d k n o w n -gr o u ps 
vali dit y)  to me as ure s y m pt o ms of  NS C L C i n t he c o nte xt of  the partici pa nt p o p ul atio n bei n g st u die d 
i n t his trial.
5. 5 
J u stifi c ati o n f or I m m u n ot h er a p y D o s e
T w o r elat li ma b d oses, 3 6 0 m g Q 3 W a n d 7 2 0 m g Q 3 W, were selecte d t o be e val uate d i n 
c o -a d mi nistrati o n wi t h 36 0 m g ni v o l u ma b Q 3 W pl us plat i n u m-base d c he mot h era p y in t he d ose 
safety c o nfir mat i on p orti o n of  this st u d y (Part 1). 
 
 
 
 I n a d diti on, b ot h i m m u n ot hera p y 
dr u gs will be c o -a d mi nistere d i n a si n gle I V ba g. T he P K a n d safety pr ofile of  relat li ma b i n c o -
a d mi nistrati o n wit h ni v o l u ma b is n ot e x pecte d t o be differe nt t ha n t hat of  se q ue ntial a dmi nistrati o n 
i m ple me nte d pre vi o usl y i n ot h er cli nical trials. Pl ease als o refer t o t he details o n cli nical act i vity 
a n d be nefit -ris k assess me nt of  relat li ma b a n d ni v o l u ma b c o -a d mi nistrati o n i n Secti o ns 3. 2. 4 a n d 
 res pectivel y.
5. 5. 1 
J u stifi c ati o n f or Ni v ol u m a b D o s e
Ni v o l uma b P K has bee n e xte nsi vel y st u die d i n m ult i ple t u mor t ypes, i ncl u di n g me la no m a, 
N S C L C, R C C, classical H o d g ki n’s 
l y m p h oma,  SC C H N, c o l orectal ca ncer, a n d ur ot helial 
carci n o ma 
a n d has bee n safel y a d mi nistere d at d oses u p t o 1 0 m g/ k g 
Q 2 W. Ni v o l uma b 
m o n ot hera p y  was ori gi nall y  ap pr o ve d as a b o d y wei g ht -base d d ose of  3 mg/ k g Q 2 W a n d was
u p date d t o 2 4 0 m g Q 2 W or 4 8 0 m g Q 4 W i n m ult i ple i n dicat i ons. 5 3 ,5 4
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ni v o l uma b 3 6 0 m g Q 3 W is als o u n der e val uat i on i n m o n ot hera p y  an d i n c o m bi nati o n t hera p y 
st u dies. Less fre q ue nt 3 6 0 m g Q 3 W 
 d osi n g re gi me ns ca n re d uce t he b ur de n t o 
parti ci pa nts of  fre q ue nt, len gt h y  IV treat me nts a n d all o w c o m bi nat i on of  ni v ol u ma b wi t h ot her 
a ge nts usi n g alter nat i ve d osi n g re gi me ns. 
5. 5. 2 
J u stifi c ati o n f or R el atli m a b D o s e s
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 T he P K a n d 
safety pr ofile of  relat li ma b w he n c o -a d mi nistere d wit h ni v o l u ma b is n ot e x pecte d t o be differe nt  
t ha n t hat of se q ue nt ial a d mi nistrati o n i m ple me nte d pre vi o usl y i n ot h er cli nical trials. Pl ease als o 
refer t o t h e details o n t he be nefit -ris k assess me nt of  relat li ma b a n d ni v o l u ma b c o -a d mi nistrati o n 
i n 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
5. 6 
Cli ni c al P h ar m a c ol o g y
Cli nical p har mac ol o g y  of relatli ma b i n c o m bi nati on wi t h ni v o l u ma b is c urre nt l y bei n g e val uate d 
i n a n u m ber of  tu m or t ypes, i ncl u di n g mela n o ma, N S C L C, gastric ca ncer, a n d H C C. T he 
i n di vi d ual relatli ma b a n d ni v ol u ma b P K is n ot altere d w he n t he 2 dr u gs are gi ve n i n c om bi nati o n. 
T he effect of ot her dr u gs o n t he P K of  r elat li ma b has n ot bee n f or mall y in vest i gate d. H o we ver, it 
is u nli kel y  that ot her c he m ot hera pies will ha ve a n i m pact o n t he P K of  relat li ma b gi ve n t hat 
r elat li ma b is a n I g G 4 m o n ocl o nal  a ntib o d y , w hic h is li kel y eli mi nate d b y me c ha nis ms si milar t o 
t hat o f ot her a nt i b o dies, na mel y n o ns pecific cata b olis m.
5. 6. 1 
Ni v ol u m a b Cli ni c al P h ar m a c ol o g y S u m m ar y
Ni v o l uma b p har mac o ki net ics ( P K) was assesse d usi n g a p o p P K a p pr oac h f or si n gle-a ge nt 
ni v o l u ma b.
T he P K of si n gle -a ge nt ni v o l u ma b was st u die d i n p arti ci pa nt s o ver a dose ra n ge of 0. 1 t o 2 0 m g/ k g 
a d mi nistere d as a si n gle d ose or as m ult i ple d oses of  ni v ol u ma b as a 6 0 -mi n ute i ntra ve n o us 
i nf usi on e ver y  2 or 3 wee ks. Ni v ol u ma b cleara nce ( C L) decreases o ver ti me, wit h a mea n ma xi mal 
re d uctio n ( % c oefficie nt of variati o n [ C V %]) f r o m baseli ne val ues of 2 4. 5 % ( 4 7. 6 %), res ulti n g i n 
a g e o metric mea n stea d y -st at e cleara nce ( C Lss) ( C V %) of 8. 2 m L/ h ( 5 3. 9 %) i n parti ci pa nt s wit h 
metastati c t u m ors; t he decrease i n C Lss is n ot c o nsi dere d cli nicall y rele va nt. Ni v o l uma b cleara nce 
d oes n o t decrease o ver ti me i n parti ci pa nt s wit h c o m pletel y resecte d mela n o ma, as t he ge o metric 
mea n p o p ulat i on cleara nce is 2 4 % l o wer i n t his parti ci pa nt p o p ul at i on c o m pare d wit h part ici pa nts 
wi t h metastatic me la n oma at stea d y state. T he ge o m etric mea n v o l ume of distri b ut i on at stea d y 
state ( Vss) ( C V %) is 6. 8 L ( 2 7. 3 %), a n d ge o m etric mea n eli mi nat i on half -life (t 1/ 2) is 2 5 da ys 
( 7 7. 5 %). Stea d y-state c o nce ntrati o ns of ni v ol u ma b were reac he d b y 1 2 wee ks w he n a d mi nistere d 
at 3 m g/ k g e ver y 2 wee ks, a n d s yste mic acc u mul ati o n was 3. 7 -f ol d. T he e x p os ure t o ni v o l uma b 
i ncreases d ose pr o p orti o nall y o ver t he d ose ra n ge of 0. 1 t o 1 0 m g/ k g a d mi nistere d e ver y 2 wee ks. 
T he pre di cte d e x p os ure ( Ca v g a n d C ma x) of ni v ol u ma b aft er a 3 0-mi n ute i nf usi o n is c o mpara ble 
t o t hat o bser ve d with a 6 0 -mi n ute i nf usi o n.
S pecific P o p ul at i ons: T he p o p P K a nal ysis s u g geste d t hat t he f oll owi n g fact ors ha d n o cli nicall y 
i m p orta nt effect o n t he cleara nce of  ni v ol u ma b: a ge ( 2 9 t o 8 7 ye ars), wei g ht ( 3 5 t o 1 6 0 k g), ge n der, 
race, baseli ne lactate de h y dr o ge nase ( L D H), P D -L 1 e x pressi o n, s oli d t u m or t ype, t u m or size, re na l 
i m pair me nt, a n d mil d he patic i m pair me nt. 
Re nal I mp ai r me nt: T he effect of  re nal i m pair me nt o n t he cleara nce of  ni v ol uma b was e val uate d 
b y a p o p P K a nal ysis i n parti ci pa nt s wi t h mil d (esti mate d gl o m er ular filtrati on rate [e G F R] 6 0 t o 
8 9 m L/ mi n/ 1. 7 3 m 2 ), m o derate (e G F R 3 0 t o 5 9 m L/ mi n/ 1. 7 3 m 2 ), or se vere (e G F R 1 5 t o 
2 9 m L/ mi n/ 1. 7 3 m 2 ) re nal i m pair me nt. N o cli nicall y i m p orta nt differe nces i n t he cleara nce of  
ni v o l u ma b were f ou n d bet wee n parti ci pa nts wit h re nal i m pair me nt a n d partici pa nt s wi t h nor m al 
re nal f u ncti on.
He pati c I mp ai r me nt: T he effect of  he patic i m pair me nt o n t he cleara nce of  ni v ol uma b was 
e val uate d b y p o p P K a nal yses i n parti ci pa nt s wit h H C C a n d i n partici pa nt s wit h ot her t u m ors wit h 
mil d he patic i m pair me nt (t otal bilir u bi n [ T B] less t ha n or e q ual t o t he u p per li mit of n or mal [ U L N] 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
a n d A S T greater t ha n U L N or T B greater t ha n 1 t o 1. 5 ti mes U L N a n d a n y as partate 
a mi n otra nsferase [ A S T]) a n d i n H C C part ici pa nts wit h mo derate he pati c i m pair me nt ( T B greater 
t ha n 1. 5 t o 3 ti mes U L N a n d a n y AS T). N o  cli nicall y i m p orta nt differe nces i n t he cleara nce of 
ni v o l u ma b were f o u n d bet wee n parti ci pa nt s wit h mil d/ mo derate he pati c i m pair me nt.
F ull details o n t he cli nical  p har mac o lo g y  as pects of ni v o l u ma b ca n be f ou n d i n t he I n vest i gat or’s 
Br oc h ure a n d pr o d uct la bel.
6 
S T U D Y P O P U L A TI O N
F or e ntr y  int o t he st u d y , t h e foll o wi n g criteria M U S T be met.
6. 1 
I n cl u si o n Crit eri a
1)
Si g ne d Writte n I nf or me d C o nse nt
a)
Parti cipa nts m ust ha ve si g ne d a n d date d a n I nst ituti o nal Re vie w B oar d (I R B)/I n de pe n de nt 
Et hics C o m mittee 
(I E C)-a p pr o ve d wri tte n I C F i n acc or da nce wi t h re g ulat or y an d 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i nstituti o nal  gui deli nes. T hi s m u st be o btai ne d b efore t he perf or m a nce of  an y 
pr ot oc ol -r elate d pr oce d ures t hat are n ot part of n or mal partici pa nt care.
b)
Parti cipa nts m ust be willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, treat me nt sc he d ule, 
a n d la b orat or y testi n g.
2)
T y pe of P artici p a nt a n d T ar get Dise ase C h ar acteristics
a)
Easter n C o o perati ve O nc o l og y  Gr o u p ( E C O G) P S of 1 at scree ni n g a n d c o nfir me d pri or 
t o ra n d o mizati on.
b)
Parti cipa nts m ust ha ve a life e x pecta nc y  of at least 3 mo nt hs at t he ti me of first d ose.
c)
Hi st olo gi call y c o nfir me d met astatic N S C L C of  SQ or N S Q hist ol o g y wi t h Sta ge I V A/ B 
(as defi ne d b y t he 8t h I nter nati o nal Ass oci atio n  for t he St u d y  of L u n g Ca ncer 
Cl assificat i on) or rec urre nt disease f oll owi n g m u lti-m o dal  thera p y f or l ocall y a d va nce d 
di sease.
 
e)
N o pri or s yste mic a nt i-ca ncer tr e at me nt (i ncl u di n g E G F R a n d A L K i n hi bit ors) gi ve n as 
pri mar y  t hera p y for a d va nce d or m etastatic disease.
f)
Pri or defi nit i ve c he m ora diati o n f or l ocall y a d va nce d disease is per mitte d as l o n g as t he last 
a d mi nistrati o n of  che m ot hera p y or ra di ot hera p y (w hic he ver was gi ve n last) occ urre d at 
least 6 m o nt hs pri or t o e nr oll me nt. 
g)
Pri or a dj u va nt or ne oa dj u va nt c he m ot h era p y for earl y -sta ge lu n g ca ncer i s per mitte d if 
c o mplete d at l east 6 mo nt hs pri or t o i ni tiat i n g st u d y treat me nt.
h)
Pri or palliat i ve ra di ot hera p y t o n o n-ce ntral ner v o us s yste m ( C N S) lesio n s m ust ha ve bee n 
c o mplete d at least 2 wee ks pri or t o treat me nt. Partici pa nts wit h s y m pt o mat ic t u m or lesi ons 
at baseli ne t hat ma y re q uire palliat i ve ra diot h era p y wi t hi n 4 wee ks of  first treat me nt are 
str o n gl y e nc o ura ge d t o recei ve palliat i ve ra di ot hera p y pri or t o treat me nt.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i)
Meas ura ble disease b y C T or M RI per R E CI S T v 1. 1 criteria (A p pe n di x 5 ); ra dio gra p hic 
t u mor assess me nt perf or me d  
 pri or t o ra n d o mizat i on.
j)
Tar get lesi ons ma y be l ocate d i n a pre vi o usl y irra diate d fiel d if t here is d oc u me nte d 
r a dio gra p hic di sease pr o gressio n i n t hat si te after t he c om p leti on of ra diat i on t hera p y .
3)
A ge a n d Re pr o d ucti ve St at us
I n vesti gat ors s hall c o u nsel w ome n o f c hil d beari n g p ote nti al ( W O C B P), a n d male part ici pa nts w h o 
are se x uall y act i ve wit h W O C B P, o n t he i m p orta nce of pre g na nc y pre ve nti o n, t he i m plicati o ns of 
a n u ne x pecte d pre g na nc y, a n d t he p ote ntial o f fetal t o xicit y o cc urri n g d ue t o tra ns missi o n of st u d y 
dr u g, prese nt i n se mi nal fl ui d, t o a de vel o pi n g fet us, e ve n if t he part ici pa nt has u n der g o ne a 
s uccessf ul vasect o m y  or if t he part ner is pre g na nt.

T he i n vest i gat or s hall e val uate t he effecti ve ness of t he c o ntrace pti ve met h o d i n relati o ns hi p t o 
t he first d ose of st u d y int er ve nt i on.

L ocal  la ws a n d re g ulat i ons ma y re q ui r e t h e us e of alter nati ve a n d/ or a d ditio n al c o ntrace ptio n 
met h o ds.
a)
Fe male Partici pa nts 
i)
Fe males, a ges 1 8 or l o c al  a ge of majori t y. 
ii) W o me n w h o 
are n ot of  chil d beari n g p ote nti al are e xe m pt fr om 
c o ntrace pti ve 
re q uire me nts.
iii) W o me n parti ci pa nts m ust ha ve d oc u m e nte d pr o of t hat t he y are n ot of  chil d beari n g
p ote nti al.
i v) W O C B P m u st ha ve a ne gat i ve hi g hl y se nsitive uri ne or ser u m pre g na nc y test 
( mi ni m u m se nsitivit y 2 5 I U/ L or e q ui vale nt u nits of  hu ma n c h orio nic g o na d otr o pi n) 
wi t hi n 2 4 h o urs prior t o t he start of st u d y  treat me nt.
( 1) If a uri ne test ca n n ot be c o nfir m e d as ne gati ve (e g, a n a m bi g u o us res ult), a ser u m 
pre g na nc y t est is re q uire d. I n s uc h cases, t he partici pa nt m ust be e xcl u de d fr om 
parti ci pat i on if t he ser u m pre g na nc y res ult is p ositi ve.
v)
A d dit i onal re q uire me nts f or pre g na nc y testi n g d uri n g a n d after stu d y i nter ve nt i on are 
l ocate d i n Secti o n 2 , Sc he d ule of Assess me nts.
vi) T he i n vesti gat or is res p o nsi ble f or re vie w of  me dical hist or y , me nstr ual  hist or y, a n d 
rece nt se x ual acti vit y to decrease t he ris k f or i ncl usi o n of  a wo m a n wi t h an earl y 
u n detecte d pre g na nc y.
vii) W O C B P m ust a gree t o f oll ow i nstr uctio ns f or me t ho d(s) of  co ntrace pti o n defi ne d in 
A p pe n di x 4 a n d as descri be d bel o w a n d i ncl u de d i n t he I C F.
viii) 
W O C B P are per mitte d t o use h or m o nal  co ntrace pti o n met h o ds (as descri be d i n 
A p pe n di x 4)
i x) A female partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt or breastfee di n g, 
a n d at least o ne of t he f o ll owi n g c o n di tio ns a p plies:
( 1) Is n ot a W O C B P. 
O R
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
b)
Male Parti ci pa nts 
i)
Males, a ges 1 8 or l o c al  a ge of majori t y. 
ii) Males w h o are se x uall y act i ve wi t h 
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 defi ne d i n  A p pe n di x 4 a n d as descri be d bel o w.
iii) Az o os per mic males are n ot e xe m pt fr om c o ntrace pti ve re q uire me nts a n d will be 
re q uire d t o al wa ys use a late x or ot her s ynt hetic c o n d o m duri n g a n y se x ual act i vity 
(e g, va gi nal, a nal, or al ) wi t h W O C B P e ve n if t he partici pa nt has u n der g o ne a s uccessf ul 
vasect o m y  or if t he part ner is pre g na nt.
i v) Male parti ci pa nts are re q uir e d t o us e a c o n d o m d uri n g t he i nter ve nt i on peri o d a n d f or
at least 6 m o nt hs after t he last c he m ot hera p y (a p plica ble t o paclit a x el, na b -pacli ta xel, 
p e m etre xe d, a n d car b o plat i n) d ose of  st u d y int er ve nt i on ( or a t otal of 1 1 m o nt hs f or 
male partici pa nts recei vi n g cis plat i n), w hic he ver is l on ger.
v)
Fe male part ners of  males parti ci pat i n g i n t he st u d y sh o ul d be a d vise d t o use hi g hl y 
effect i ve met h o ds of c o ntrace pti o n d uri n g t he st u d y i nter ve nti on peri o d a n d f or at least 
6 m o nt hs aft er t he last c he m ot hera p y (a p plica ble t o paclita xel, na b -pacli t a x el, 
p e m etre xe d, a n d car b o plat i n) d ose of  the ma le p arti ci pa nt’s st u d y int er ve nt i on ( or a 
t otal of 1 1 mo nt hs f or male partici pa nts recei vi n g cis plati n), w hic he ver is l on ger.
vi) 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 o m pe nile va gi nal i nterc o urse or use a male c o n d o m d uri n g eac h e pis o de of 
pe nile pe netrati o n d uri n g t he i nter ve nt i on peri o d a n d f or at least 6 m o nt hs after t he last 
c he m ot hera p y (a p plica ble t o paclita xel, na b -pacli t axel, pe metre xe d , a n d car b o plati n) 
d ose of  st u d y int er ve nt i o n ( or a t otal of 1 1 m o nt hs f or male parti ci pa nts recei vi n g 
cis plati n), w hic he ver is l on ger.
vii) Male partici pa nts m ust refrai n fr o m d o nat i n g s per m d uri n g t he i nter ve nti on peri o d a n d 
f or at least 6 m o nt hs after t he last c he m ot hera p y (a p plica ble t o paclita xel, na b -
paclita xel, p e m etre xe d, a n d car b o plati n) d ose ( or a t otal of 1 1 m o nt hs f or ma le 
parti ci pa nts recei vi n g cis plat i n), w hic he ver is l on ger.
viii) 
Breastfee di n g part ners s h o uld be a d vise d t o c o ns ult t heir healt h care pr o vi ders 
a b o ut usi n g a p pr o priate hi g hl y effective c o ntrace ptio n d uri n g t he ti me t he part ici pa nt 
is re q uire d t o use c o n d o ms.
6. 2 
E x cl u si o n Crit eri a
1)
Me dic al C o n diti o ns
a)
W o me n w h o are breastfee di n g
b)
M utati o n stat us:
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i)
E G F R m ut ati o ns w hic h are se nsit i ve t o a vaila ble tar gete d i n hi bit or t hera p y (i ncl u di n g, 
b ut n ot li mite d t o, delet i ons i n e x o n 1 9 a n d e x o n 2 1 [ L 8 5 8 R] s u bstit uti o n m ut atio ns) 
are e xcl u de d. All p arti ci pa nts wi t h NS Q hist ol o g y  must ha ve bee n teste d f or E G F R 
m utati o n stat us; use of  an F D A- a p pr o ve d or l ocal Healt h A ut h ority t est (tiss ue or bl o o d) 
is str o n gl y e nc o ura ge d. Partici pa nts wit h N S Q hist ol o g y a n d u n k n o w n E G F R stat us are 
e xcl u de d.
ii) A L K tra nslo c ati o ns w hic h are se nsiti ve t o a vaila ble tar gete d i n hi bit or t hera p y ar e 
e xcl u de d. All parti ci pa nts wi t h NS Q hist ol o g y  m ust ha ve bee n teste d f or A L K m utati o n
stat us; use of a n F D A-a p pr o ve d or lo c al  H e alt h Aut h ori t y t est is str o n gl y e nc o ura ge d. 
Parti cip a nts wi t h N S Q hist olo g y  a n d u n k n o w n A L K stat us are e xcl u de d.
iii) R O S - 1 tra nslo c ati o ns w hic h are se nsitive t o a vaila ble tar gete d i n hi bit or t hera p y ar e 
e xcl u de d. All p art ici pa nts wi t h NS Q hist ol o g y  must ha ve bee n teste d f or R O S -1 
tra nslo c ati o n stat us. Parti cipa nts wi t h NS Q hist ol o g y  an d u n k n o w n R O S - 1 stat us are 
e xcl u de d.
i v) K n o w n B R A F V 6 0 0 E m ut atio ns w hic h are se nsiti ve t o a vaila ble tar gete d i n hi bit or 
t hera p y are e xcl u de d. If B R A F m utati o n stat us is un k n o w n or i n deter mi nate, partici pa nt 
ma y e nr oll.
c)
Parti cipa nts wi t h u ntreate d C N S metastases. Partici pa nts are eli gi ble if C N S metastases are 
as y m pt o mat ic a n d d o n ot re q uire i m me diate treat me nt or ha ve bee n treate d a n d partici pa n ts 
ha ve ne ur ol o gicall y ret ur ne d t o baseli ne (e xce pt f or resi d ual si g ns or s y m pt o ms r elate d t o 
t he C N S treat me nt). I n a d ditio n, parti ci pa nts m u st ha ve bee n eit her of f c ortic oster oids 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 on. Brai n i ma gi n g perf or me d 
 pri or t o 
ra n d omizat i on m ust d oc u m e nt ra dio gra p hi c sta bilit y of C N S lesio n s a n d s h o uld be 
perf or m e d after c o mplet i on of a n y C N S -di recte d t hera p y.
d)
Parti cip a nts wi t h le pt o me ni n geal metastases (carci n o mat o us m e ni n gitis).
e)
C o nc urre nt ma li g na nc y re q uirin g tr e at me nt or hist or y  of pri or ma li g na nc y act i ve wi t hi n 
2 years pri or t o ra n d o mizati o n (ie, parti ci pa nts wi t h a hist or y of pri or ma li g na nc y ar e 
eli gi ble if tr e at me nt was c o mple te d at least 2 years bef ore ra n d o mizati on a n d t he partici pa nt  
has n o e vi de nce of disease). Partici pa nts wit h hist or y o f pri or earl y-sta ge basal/ S Q cell s ki n 
ca ncer or n o ni n vasi ve or i n sit u ca ncers t hat ha ve u n der g o ne defi nit i ve treat me nt at  an y 
ti me are als o eli gi ble.
f)
Parti cipa nts wi t h an act i ve, k n o w n, or s us pecte d a ut oi m m u ne disease. Parti ci pa nts wi t h 
t ype I dia betes me llit us, h y p ot h y r oidis m  onl y  re q uirin g h or m o ne re place me nt, s ki n 
di s or ders (s uc h as vit ili g o, ps oriasis, or al o peci a) n ot re q uiri n g s yste mic treat me nt, or 
c o n ditio ns n ot e x pecte d t o rec ur i n the a bse nce of  an e xt er nal trig ger are per mitte d t o e nr oll.
g)
Parti cipa nts wit h a c o n ditio n re q uirin g s yste mic treat me nt wi t h either c ortic oster oids 
( > 1 0 m g 
dail y pre d nis o ne e q ui vale nt) wi t hi n 1 4 da y s or ot her i m m u n os u p pressi ve 
me dicat i ons wi t hi n 3 0 da ys of  ra n d o mizati o n. I n hale d or t o pical st er oids, a n d a dre na l 
r e place me nt ster oid d oses > 1 0 m g dail y pre d nis o ne e q ui vale nt, are per mitte d i n t h e 
a bse nce of act i ve a ut oi m m u ne disease.
h)
K n o w n  
h u ma n 
i m m u n o deficie nc y 
virus 
( HI V) 
p osit i ve 
wi t h 
an 
ac q uir e d 
i m m u n o deficie nc y sy n dr o me -defi ni n g o p p ort u nisti c i nfecti on wi t hi n t he last ye ar, or a 
c urre nt C D 4 c o u nt < 3 5 0 cells/ μ L. Partici pa nts wit h HI V are eli gi ble if:
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i)
t he y ha ve recei ve d a ntir etr o vir al thera p y ( AR T) f or at least 4 wee ks pri or t o 
ra n d omizat i on as cli nicall y i n dicate d w hile e nr o lle d o n st u d y.
i)
t he y c o nti n ue o n A R T as cli nicall y i n dicate d w hile e nr olle d o n st u d y.
ii) C D 4 c o u nts a n d viral l oa d are m o nit ore d per sta n dar d of care b y a l ocal healt h care 
pr o vi der.
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 ( p artici pa nts 
e nr o lle d wit h k n o w n HI V nee d m o nit ori n g of  C D 4 c o u nts a n d vir al loa d d uri n g t he st u d y 
a n d A R T a d mi nistere d as cli nicall y i n dicate d). HI V -p osi tive partici pa nts m ust be e xcl u de d
w here ma n date d l ocall y (see A p pe n di x 8 ).
i)
Parti cip a nts wi t h serio us or u nc o ntr olle d me dical dis or ders.
j)
Parti cipa nts m ust ha ve rec o vere d fr o m t he effects of maj or s ur ger y or si g nifica nt tra u mat ic 
i nj ur y at least 1 4 da ys bef ore first treat me nt.
k)
Parti cipa nts wi t h int erstitial l u 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.
m)
K n o w n me dical c o n ditio 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.
n)
N ot 
A p plic a ble 
as per A me n d me nt 
0 2: Se vere ac ute res pirat or y cor o na vi r us 2 
( S A R S-C o V -2) i nfec tio n (ei t her s us pecte d or c o nfir me d) wit hi n 1 2 wee ks of scree ni n g.
o)
Se vere i nfect i on wi t hi n 4 wee ks pri or t o scree ni n g
i)
A d dit i onall y , i n t he case of  prior S A R S -C o V - 2 i nfecti on, s y m pt o ms m u st ha ve 
c o mpletel y res ol ve d a n d base d o n i n vesti gat or assess me nt i n c o ns ult atio n wi t h the 
cli nical trial p h ysic ia n, t here are n o se q uelae t hat w o ul d place t he partici pa nt at a hi g her 
ris k of recei vi n g i n vesti gati o nal treat me nt.
N ote: C or o na vir us di sease 2 0 1 9 ( C O VI D-1 9) P C R viral testi n g ma y be re q uire d pri or t o 
ra n d omizat i o n base d o n s pecific c o u ntr y /re gio n al gui deli nes, a n d t he res ul t of t his testi n g 
ma y i m pact st u d y partici pat i on. Testi n g res ults s h o uld be disc usse d wi t h the Me dical 
M o ni t or t o c o nfir m eli gi bility.  
2)
Pri or/ C o nc o mit a nt T her a p y
a)
Pri or tr e a t me nt wit h a n a nt i-P D -1, a nti-P D -L 1, a nti-P D -L 2, or a nti-C T L A - 4 a nti b o d y, or 
a n y ot h er a nt i 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 o i nt 
pat h wa ys.
b)
Pri or treat m e nt wit h L A G- 3-tar gete d a ge nts.
c)
C o nc urre nt use of i m m u n os u p pressi ve a ge nts.
d)
C o nc urre nt use o f i m m u n os u p pressi ve d oses of s yste mic c ortic oster oids (e xce pt as state d 
i n Secti o n 7. 7. 3 ).
e)
A n y 
c o nc urre nt 
a nti-ne o pl astic 
t hera p y 
(ie, 
c he m ot hera p y, 
h or m o nal  thera p y, 
i m m u n ot hera p y, e xte nsi ve n o n- palliat i ve ra diat i on t hera p y, or sta n dar d or i n vesti gati ona l 
a ge nts f or treat me nt of N S C L C).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
7 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
f)
Parti cipa nts w h o ha ve recei ve d a li ve/atte n uate d vacci ne wi t hi n 3 0 da ys bef ore first 
treat me nt.
g)
Treat me nt wit h b ota ni c al pre parati ons (e g, her bal  su p ple me nts or tra diti onal C hi nese 
me dici nes) i nte n de d f or ge neral  he alt h su p p ort or t o tr e at t h e dise ase u n der st u d y withi n 
2 wee ks pri or t o ra n d o mizat i on/treat me nt. Refer t o Secti o n 7. 7. 1 f or pr o hi bite d t hera pies.
h)
Parti cipa nts c urre ntl y i n ot her i nter ve nt i onal t rials, i ncl u di n g t h ose f or C O VI D-1 9, ma y n ot 
parti ci pate i n B M S cli nical trials u nt il t he pr ot oc ol-s pecific was h o ut peri o d is ac hie ve d. If 
a st u d y particip a nt has recei ve d a n i n vesti gatio nal  
CO VI D - 1 9 vacci ne or ot her 
i n vesti gati on al pr o d uct desi g ne d t o treat or pre ve nt C O VI D -1 9 pri or t o scree ni n g, 
e nr o ll me nt m u st be dela ye d u nt il t he bi o l ogic i m pact of  the vacci ne or i n vesti gati onal 
pr o d uct is sta bilize d, as deter mi ne d b y disc ussi o n bet wee n t he i n vest i gat or a n d t he Me dica l 
M o ni t or.
3)
P h ysic al a n d L a b or at or y Test Fi n di n gs
a)
Parti cip a nts wi t h Gra de 2 peri p heral ne ur o pat h y
b)
 
i)
> 2 i nstituti o nal  u p per li mit of nor mal  ( U L N). 
ii) Parti cipa nts wi t h 
 bet wee n > 1 t o 2 × U L N will be per mitte d if re peat  
le vels wit hi n 2 4 h o urs are ≤ 1 × U L N. If 
 are bet wee n > 1 t o 2 × U L N 
wi t hi n 2 4 h o urs, t he parti ci pa nt ma y u n der g o a car diac e val uat i on a n d be c o nsi dere d 
f or tr e at me nt, base d o n a fa v ora ble be nefit -ris k assess me nt b y t he I n vesti gat or. W he n 
re peat levels wi t hi n 2 4 h o urs are n ot a vaila ble, a re peat test s h o ul d be c o n d ucte d as 
s o o n as p ossi ble. If 
 be y o n d 2 4 h o urs are < 2 × U L N, t he 
parti ci pa nt ma y u n der g o a car diac e val uat i on a n d be c o nsi dere d f or treat me nt base d o n 
a fa v ora ble be nefit -ris k assess me nt b y t he I n vestigat or. N otificati o n of  t he decisio n  t o 
e nr o ll t he partici pa nt has t o be ma de t o t he B M S Me dical M o nit or or desi g nee.
c)
Left ve ntric ular eje ctio n fracti on ( L V E F) assess me nt wit h d oc u me nte d L V E F < 5 0 % b y 
eit her tra nst h oracic ec h ocar dio gr a m  (T T E) or m ult i ple gate d ac q uisit i on ( M U G A) sca n 
( T T E preferre d test) wit hi n 6 m ont hs pri or t o start of st u d y treat me nt. 
d)
W hite bl o o d cells < 2 0 0 0/ μ L ( SI u ni ts: < 2 × 1 09 / L). 
 
 
 
e)
A bs ol ute Ne utr o p hil C o u nt ( A N C) < 1 5 0 0/ μ L ( SI u nits: < 1. 5 × 1 0 9 / L)
 
 
 
f)
Pl at elets < 1 0 0, 0 0 0/μ L ( SI u nits: < 1 0 0 × 1 09 / L)
g)
He m o gl o bi n < 9. 0 g/ d L ( SI u nits: < 9 0 g/ L)
h)
Ser u m  creati ni ne > 1. 5 × U L N, u nless creati ni ne cleara nce ( Cr Cl) ≥ 5 0 m L/ mi n ( meas ure d 
or calc ulate d usi n g t he C oc kcr oft -Ga ult f or m ula)
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
i)
As partate a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase ( A L T):  > 3. 0U L N (5 × 
U L N if li ver metastases are prese nt)
j)
T otal  bilir u bi n ( T B) > 1. 5 × U L N (e xce pt partici pa nts wi t h Gil bert s y n dr ome w h o m u st 
ha ve a T B le vel of < 3. 0 × U L N)
k)
A n y p osit i ve test res ult f or he patitis B vir us or he patitis C vir us ( H C V) i n dicati n g prese nce 
of  vir us (e g, he patitis B s urface a nti ge n [ A ustralia a nti ge n] p ositi ve, or he patitis C a nti b o d y 
[a nti-H C V] p osit i ve [e xce pt if H C V-rib o n ucleic aci d ( R N A) ne gat i ve]).
4)
Aller gies a n d A d verse Dr u g Re acti o n
a)
Hi st or y of aller g y or h yperse nsi tivi t y t o st u d y dr u g c o mp o ne nts.
b)
A n y c o ntrai n dicat i on t o a n y of t he st u d y dr u gs. I n vesti gat ors s h o ul d refer t o l ocal pac ka ge 
i nsert or S u m mar y of Pr o d uct C haracteristics.
5)
Ot her E xcl usi o n Criteri a
a)
Pris o ners or parti ci pa nts w h o are i n v olu ntaril y  incarcerate d. ( N ote : U n der certai n s pecific 
circ u msta nces a n d o nl y i n c o u ntries w here l ocal re g ulati ons per mit, a pers o n w h o has bee n 
i m pris o ne d ma y be i ncl u de d or per mitte d t o c o nti n ue as a partici pa nt. Strict c o n ditio ns 
a p pl y a n d B M S a p pr o val is re q uire d.)
b)
Parti cipa nts w h o are c o m p uls oril y detai ne d f or treat me nt of eit her a ps yc hiatric or p h ysica l 
(e g, i nfecti ous disease) ill ness.
c)
A n y ot h er seri o us or u nc o ntr olle d me dical dis or der, acti ve i nfecti on, p h ysical e xa m 
fi n di n g, lab orat or y  fi n di n g, altere d me nt al stat us, or ps yc hi atric c o n ditio n t hat, i n t he 
o pi ni o n of  the i n vesti gat or, w o ul d li mit a partici pa nt's a bilit y t o c o m p l y with t he st u d y 
re q uire me nts, s u bsta ntiall y i ncrease ris k t o t he partici pa nt, or i m pact t he i nter preta bility o f 
st u d y res ults.
d)
Parti cipa nts wi t h a hist ory of  scree n fail ure t o a n y a nt i-P D - 1 or a nti-P D -L 1 a nt i b o d y 
cli nical trial d ue t o P D -L 1 -ne gat i ve stat us.
Eli gi bilit y crit eria f or t his st u d y ha ve bee n caref ull y c o nsi dere d t o e ns ure t he safet y of t he st u d y 
parti ci pa nts a n d t hat t he res ults of  the st u d y ca n be use d. It is i m perati ve t hat partici pa nts f ull y 
meet all eli gi bilit y criteria.
Parti cip a nt Re -e nr oll me nt:  This st u d y per mit s t he re-e nr oll me nt of  a partici pa nt w h o has 
di sc o nti n ue d t he st u d y as a scree n fail ure (ie, partici pa nt has n ot bee n ra n d omize d ). If re-e nr olle d, 
t he partici pa nt m ust be re- c o nse nte d.
6. 3 
Lif e st yl e R e stri cti o n s
N ot a p plica ble. N o restrict i ons are re q uire d.
6. 4 
S cr e e n F ail ur e s
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut w h o 
are n ot s u bseq ue nt l y ra n d o mize d i n t he st u d y/i ncl u de d i n t he a nal ysis p o p ul at i on. A mi ni mal set 
of  scree n fail ure i nf or mati on is re q uire d t o e ns ure tra ns pare nt re p orti n g of  scree n fail ure 
parti ci pa nts, t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Tri als p u blis hi n g re q uire me nts, as 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
a p plica ble, a n d t o res p o n d t o q ueries fr om re g ulat or y aut h ori ties. Mi ni mal i nf or mati on i ncl u des 
date of c o nse nt, de m o gra p h y , scree n fail ure details, eli gi bility crit eria, a n d a n y S A Es.
6. 4. 1 
R et e sti n g D uri n g S cr e e ni n g or D o s e S af et y C o nfir m ati o n P eri o d
Parti cip a nt Re -e nr oll me nt: T hi s st u d y per mit s t he re-e nr oll me nt of  a partici pa nt t hat has 
di sc o nti n ue d t he st u d y as a pre -tr e at me nt fail ure (ie, parti ci pa nt has n ot bee n ra n d o mize d). If 
re-e nr olle d, t he partici pa nt m ust be re-c o nse nte d.
T he m o st c urre nt res ult pri or t o ra n d o mizati on 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 partici pa nt’s m ost c urre nt, cli nical state.
La b orat or y  para meters a n d/ or assess me nts t hat are i ncl u de d i n Ta ble 2 -2 (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 ossi ble well - q ualifie d partici pa nts. C o ns ultati on 
wi t h the Me di cal Mo ni t or ma y be nee de d t o i de ntif y w het her re peat testi n g of  an y part ic ular 
para m eter is cli nicall y rele va nt.
Te stin g f or as y m pt o matic S A R S-C o V -2 i nfect i on, f or e xa m ple b y RT- P C R or vi r al a ntige n is n ot 
re q uire d. H o we ver, 
s o me parti ci pa nts ma y de vel o p s us pecte d or c o nfir me d 
s y m pt o matic 
S A R S -C o V - 2 i nfecti o n or be disc o vere d t o ha ve as y m pt o mat ic S A R S-C o V -2 i nfect i on d uri n g t he 
scree ni n g peri o d.  I n s uc h cases, partici pa nts ma y be c o nsi dere d eli gi ble f or t he st u d y after meet i n g 
all i ncl usi on/e xcl usi o n cri t eria relate d t o acti ve i nfecti o n, a n d after meeti n g t he f oll owi n g cri t eria:

At  least 1 0 da ys ( 2 0 da ys f or se vere/critical ill ness) ha ve passe d si nce s y m pt o ms first a p peare d 
or p osit i ve R T-P C R or viral a nt i ge n test res ult, a n d

At  least 2 4 h o urs ha ve passe d si nce last fe ver wi t h o ut t he use of  fe ver -re d uci n g me dicat i ons,  
a n d

Ac ute s y m pt o ms (e g, c o u g h, s h ort ness of breat h) ha ve res o l ve d a n d

I n t he o pi ni on o f t he i n vest i gat or, t here are n o C O VI D- 1 9-relate d se q uelae t hat ma y place t he 
parti ci pa nt at a hi g her ris k of receivi n g i n vest i gati onal treat me nt, a n d

Ne gati ve f oll o w -u p S A R S -C o V -2 R T -P C R or viral a nt i ge n test base d o n i nstituti o nal , local or 
r e gio nal  g ui deli nes.
7 
T R E A T M E N T
St u d y  treat me nt is defi ne d as a n y i n vesti gati onal treat me nt(s), mar kete d pr o d uct(s), or me d ical 
de vice i nte n de d t o be a d mi nistere d t o a st u d y participa nt acc or di n g t o t he st u d y  ra n d o mizati on or 
treat me nt all ocati o n.
St u d y  
treat me nt 
i ncl u des 
b ot h 
I n vesti gati onal 
( Me dici nal) 
Pr o d uct 
(I P/I M P) 
a n d 
N o n -i n vesti gati onal ( Me dici 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 o ll owi n g:
A n I P, als o k n o w n as I M P i n s ome re gio ns, is defi ne d as a p har mace ut ical f or m of a n act i ve 
s u bsta nce bei n g teste d or use d as a refere nce i n a cli nical st u d y, i ncl u di n g pr o d ucts alrea d y wit h a 
mar ket i n g a ut h orizat i on b ut us e 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 orize d i n dicati o n, or w he n use d t o gai n f urt her i nf or mati on 
a b o ut t he a ut h orize d f or m.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ot her me d icatio ns use d as s u p p ort or esca pe me d icatio n f or pre ve ntati ve, dia g n osti c, or t hera pe utic 
reas o ns, as c o mp 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 nsi dere d as n o n-I Ps.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7 - 1: 
St u d y Tre at me nts f or C A 2 2 4 1 0 4
Pr o d uct Descri pti o n / 
Cl ass a n d D os a ge 
F or m
P ote nc y 
I P/ N o n-I M P
Bli n de d or 
O pe n L a bel a
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)
Relatli ma b b
I P
O pe n
 
St ore 2 t o 8° C; d o n ot freeze; 
pr otecte d fr o m li g ht
Ni v ol u ma b c
1 0 m g/ m L
I P
O pe n
1 0 0 m g/ vial ( 1 0 m g/ m L) 
1 0 m L vial
4 or 5 vials per cart o n
St ore 2 t o 8° C; d o n ot freeze; 
pr otecte d fr o m li g ht
Car b o plati n
1 0 m g/ m L
I P
O pe n
4 5 0 m g vial ( 1 0 m g/ m L)
4 5 m L
4 vials /cart o n
Pr o d uct s h o ul d be st ore d as per 
mar ket pr o d uct c o n diti o ns
Cis plati n ,
1 0 0 m g/ vial 
( 1 m g/ m L)
I P
O pe n
1 0 0 m g/ vial ( 1 m g/ m L)
4 vials/cart o n
Pr o d uct s h o ul d be st ore d as per 
mar ket pr o d uct c o n diti o ns
Paclita xel ,
6 m g/ m L
I P
O pe n
1 0 0 m g/ vial ( 6 m g/ m L)
1 6. 7 m L
4 vials/cart o n
Pr o d uct s h o ul d be st ore d as per 
mar ket pr o d uct c o n diti o ns
Na b -Paclita xel d ,
1 0 0 m g/ vial
I P
O pe n
1 0 0 m g per vial a n d 
1 vial per cart o n
Pr o d uct s h o ul d be st ore d as per 
mar ket pr o d uct c o n diti o ns
Pe metre xe d ,
5 0 0 m g/ vial
I P
O pe n
5 0 0 m g per vial a n d 
1 vial per cart o n
Pr o d uct s h o ul d be st ore d as per 
mar ket pr o d uct c o n diti o ns
A b bre viati o ns: I P = I n vesti gati o nal Pr o d uct; N o n-I M P = N o n -I n vesti gati o nal Me dical Pr o d uct; S m Pc = s u m mar y of pr o d uct c haracteristics.
a
T he i m m u n ot hera p y dr u g vials will be deli vere d t o t he p har mac y as o pe n la bel, w hereas t he site pers o n nel will recei ve t he fi n al i nf usi o n ba g i n a bli n de d ma n ner
i n  Part 1. Part 2 is o pe n -la bel.
b
Ma y  be la bele d as eit her “ B M S - 9 8 6 0 1 6-0 1” or “ Relatli ma b”.
c
Ma y  be la bele d as eit her “ B M S - 9 3 6 5 5 8-0 1” or “ Ni v ol u ma b”.
d
F or B M S pr o visi o ne d na b -paclita xel t he pr o d uct ma y be la bele d as “ paclita xel na b” or “ A bra xa ne”.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 4
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
N o n -B M S pr o d ucts ma y be o btai ne d b y t he i n vesti gati o nal sites as l ocal c o m mercial pr o d ucts i n certai n c o u ntries if all o we d b y  l ocal re g ulati o ns. In t hese cases, 
pr o d ucts ma y be i n a differe nt pac k size/ p ote nc y/ p har mace utical f or m t ha n liste d i n t he ta ble. T hese pr o d ucts s h o ul d be pre pare d/st ore d/a d mi nistere d i n acc or da nce 
wit h t he pac ka ge i nserts or S m P C.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 5
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 1 
Tr e at m e nt s A d mi ni st er e d
D uri n g t he treat me nt p hase, partici pa nts will recei ve o ne of  the treat me nt re gi me ns b y ar m 
descri be d i n Ta ble 7. 1 -1 . I m m u n ot hera p y will be a d mi nistere d i n a bli n de d ma n ner, w hile 
c he m ot hera p y will  be u n bli n de d i n Part 1. Part 2 will be o pe n -la bel. D ose re d uctio ns are n ot 
per mitte d f or i m m u n ot hera p y  st u d y tr e at me nts.
T a ble 7. 1 - 1:  
Selecti o n a n d Ti mi n g of D ose f or E ac h P artici p a nt
St u d y 
Tre at me nt
U nit D ose S tre n gt h(s)/ D os a ge 
L e vel(s)
D os a ge F or m ul ati o n
Fre q ue nc y of A d mi nistr ati o n
R o ute of 
A d mi nistr ati o n
Ar m A
Ni v ol u ma b 3 6 0 m g Relatli ma b 7 2 0 m g 
Hist ol o g y -base d P D C T
Q 3 W
I V i nf usi o n
Ar m B
Ni v ol u ma b 3 6 0 m g Relatli ma b 3 6 0 m g 
Hist ol o g y -base d P D C T
Q 3 W
I V i nf usi o n
Ar m C
Ni v ol u ma b 3 6 0 m g Relatli ma b 3 6 0 
m g a Hist ol o g y -base d P D C T
Q 3 W
I V i nf usi o n
Ar m D
Ni v ol u ma b 3 6 0 m g  Hist ol o g y -base d 
P D C T
Q 3 W
I V i nf usi o n
A b bre viati o ns: I V = i ntra ve n o us; P D C T = plati n u m d o u blet c he m ot hera p y; Q 3 W = e ver y 3 wee ks.
a
Or relatli ma b 3 6 0 m g Q 3 W de pe n di n g o n t he d ose safet y c o nfir mati o n a nal ysis.
7. 1. 1 
I m m u n ot h er a p y D o si n g
Parti cipa nts will recei ve mas ke d ni v o l uma b a n d relatli ma b, f oll owe d b y c he mot h era p y o n Da y 1 
of  ever y  3-wee k c ycle. I n Ar ms A, B, a n d C, ni v ol u ma b will be c o -a d mi nistere d wi t h relat li ma b 
i n a si n gle ba g I V o ver a p pr o xi matel y 3 0 mi n utes. Ar m D p artici pa nts will recei ve ni v ol u ma b I V 
o ver a p pr o xi matel y 3 0 mi n utes. 
 
 Parti ci pa nts s h o uld be c ar efull y m o nit ore d f or i nf usi on r eact i ons d ur i n g 
c o -a d mi nistrati o n. If a n ac ute i nf usi on reacti o n is n ote d, partici pa nt s h o ul d be ma na ge d acc or di n g 
t o Secti o n 7. 4. 1 . T he 4 c ycles of c he m ot hera p y will be a d mi nistere d in all ar ms per Secti o n 7. 1. 2 . 
At  the ti me of c o m p leti on of t he 4 c ycles of c he m o t hera p y, partici pa nts w h o ha ve n ot e x perie nce d 
di sease pr o gressi o n will c o nti n ue t o recei ve i m m u n ot hera p y Q3 W starti n g o n Da y  1 of t he 
f oll owi n g c ycle:

T here will be n o d ose escalat i ons or re d ucti o ns of i m m u n ot hera p y all o we d.

Pr e m e dicat i ons are n ot rec o m me n de d f or t he first d ose of i m m u n ot hera p y.

Parti cipa nts s ho ul d be caref ull y m o nit ore d f or i nf usi on reactio ns d uri n g i m m u n ot hera p y
a d mi nistrati o n. 

If a n ac ute i nf usi on reactio n is n ote d, partici pa nts s h o uld be ma na ge d acc or di n g t o 
Secti o n 7. 4. 6 .

Parti cipa nts s h o ul d recei ve i m m u n ot hera p y 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 e n ds, w hic he ver occ urs first.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b

D oses of i m m u n ot hera p y 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 partici pa nt t olerates t he treat me nt acc or di n g t o Secti o n 7. 4. 1 .

D osi n g visit s must n ot be s ki p pe d, o nl y dela ye d. See Secti o n 7. 4 a n d Secti o n 8. 1 .

T he assess me nt f or disc o nt i n uati on of  i m m u n ot hera p y s h o uld be ma de se paratel y fr om
t he 
assess me nt t o disc o nti n ue c he m ot hera p y. 

If crit eria f or disc o nti n uati o n of i m m u n ot hera p y are met , P D C T ma y c o nti n ue u nt il 4 c ycles 
ha ve bee n c o m p lete d. 

If criteria f o r di sc o nti n uatio n of  PD C T are met , i m m u n ot hera p y may c o nt i n ue u ntil pr o gressi on 
or u nacce pta ble t o xicit y, w hic he ver occ urs first.

If a parti ci pa nt meets crit eria f or disc o nt i n uati on a n d i n vestigat or is u na ble t o deter mi ne 
w het her t he e ve nt is r elate d t o all or a n y 1 st u d y dr u g, t he partici pa nt s h o ul d disc o nt i n ue all 
st u d y dr u gs a n d be ta ke n off t he treat me nt p hase of t he st u d y.
T he i m m u n ot hera p y i nject i ons ca n be i nf use d u n dil ute d or dil ute d. All i nf usi o ns m ust be pr o m pt l y 
f oll owe d b y a dil ue nt fl us h t o clear t he li ne of I P bef ore starti n g t he c he m ot hera p y  inf usi o n (s). 
T he sec o n d i nf usi o n w ill al wa ys be t he c he m ot hera p y st u d y dr u g(s) a n d will start after t he i nf usi o n 
li ne has bee n fl us he d, filters c ha n ge d, a n d t he partici pa nt has bee n o bser ve d t o e ns ure n o i nf usi o n 
reactio n has occ urre d. T he ti me bet wee n i m m u n ot hera p y a n d c he m ot hera p y i nf usi o ns i s 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 o re or less de pe n di n g o n t he situati o n. I nstructi o ns 
f or dil utio n a n d i nf usi on of  im m u n ot hera p y  injecti o ns will be pr o vi de d i n t he P har mac y Ma n ual. 
Care m ust be ta ke n t o ass ure sterilit y o f t he pre pare d s olut 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. F or details o n
pre pare d dr u g st ora ge, 
pre parati o n, a n d a d mi nistratio n, pl ease r efer t o t he I Bs a n d/ or P har mac y Ma n ual. T he selectio n 
a n d ti mi n g of d ose f or eac h partici pa nt is pr o vi de d i n Ta ble 7. 1 - 1.
St u d y  treat me nt will be dis pe nse d b y I R T at t he st u d y visits as liste d i n Secti o n 2 ( Sc he d ule of
Acti vit ies). F urt her details re gar di n g pre parati o n a n d a d mi nistrati o n will be pr o vi de d se paratel y i n 
site/ p har mac y trai ni n g materials.
7. 1. 2 
C h e m ot h er a p y D o si n g
I n all 4 st u d y ar ms, 4 c ycles of t he hist olo g y -base d P D C T o pti o n selecte d b y t he i n vesti gat or will 
be a d mi nistere d o n Da y  1 Q3 W. Parti ci pa nts wit h N S Q hist ol o g y ma y als o recei ve o pti o nal 
mai nte na nce t hera p y with 5 0 0 m g/ m 2 pe metre xe d al o ne o n Da y  1 of eac h 3 -wee k c ycle u nt il 
di sease pr o gressi o n or u nacce pta ble t o xicity or ot her reas o ns s pecifie d i n t he pr ot oc ol 
(Secti o n 8. 1. 2 ).
Hist ol o g y -b ase d c he m ot her a p y:

S Q hist ol o g y :  

C ar b o plat i n A U C 6 + paclita xel 2 0 0 m g / m2

C ar b o plat i n A U C 6 + na b -pacli t a x el 1 0 0 m g / m2 a
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b

N S Q hist ol o g y:

C ar b o plat i n A U C 5 or 6 a + pe metre xe d 5 0 0 m g / m2

C is plati n 7 5 m g/ m2 + pe metre xe d 5 0 0 m g / m2
a Na b -paclita xel f or S Q a n d car b o plati n A U C 6 f or N S Q hist ol o g y  are a p plica ble t o Part 1 o nl y.
All 
c he mot h era p y
a ge nts’
pre parati o n,
pre me dicati o n,
a d mi nistrati o n,
m o nit ori n g,
a n d
ma na ge me nt of c o mplicati o ns are t o f oll ow l ocal prescript i on g ui deli nes a n d re g ulatio ns. T he d ose
of c he mot h era p y ma y be ca p pe d per l ocal sta n dar ds.
 
 
 
 
 
7. 1. 2. 1 
P a clit a x el a n d C ar b o pl ati n
Parti cip a nts will recei ve pacli t a x el 2 0 0 m g / m2 as a 1 8 0- mi n ute I V i nf usi o n wi t h car b o plat i n at a
d ose of A U C of  5 or 6 as a 3 0- mi n ute I V i nf usi o n o n Da y 1 of a 3 -wee k c ycle, or at d oses per t he
l ocal prescri bi n g i nf or mat i on. T he i nf usi o n time ca n f oll o w l ocal i nstituti o nal  sta n dar ds.
Paclita xel d osi n g calc ulat i ons s h o uld be base d o n t he b o d y s urface area calc ulat i on. T he d ose ma y
re mai n t he sa me if t he parti ci pa nt’s wei g ht is wi t hi n 1 0 % of t he baseli ne wei g ht
or pri or d ose
wei g ht.
Car b o pl at i n s h o ul d be gi ve n f oll owi n g paclita xel o n Da y 1 of eac h c ycle, a n d t he car b o plati n d ose
will be calc ulate d usi n g t he Cal vert f or m ula as f o ll o ws:
Car b o pl at i n d ose ( m g) = tar get A U C × ( Cr Cl [ m L/ mi n] + 2 5)
Cr Cl calc ulatio n is base d o n t he C oc kcr oft -Ga ult
f or mul a a n d s h o ul d i ncl u de t he m o st rece nt
ser u m creati ni ne a n d m o st rece nt wei g ht. N O T E:  If calc ulatio n of t he Cr Cl b y t he C oc kcr oft -
Ga ul t f or mul a yie l ds a res ult of > 1 2 5 m L/ mi n, t he n a Cr Cl s h o uld be calc ulate d b y a n alter native
f or mul a per i nstituti o nal sta n dar ds or ca p pe d at 1 2 5 m L/ mi n.
T he d ose of car b o plat i n ma y be ca p pe d per l ocal sta n dar ds.
Pr e m e dicat i ons f or use wit h paclita xel i ncl u de t he f oll owi n g:

Oral or I V c o rtic oster oid s h o uld be gi ve n acc or di n g t o l ocal sta n dar d at a d ose e q ui vale nt
t o de xa met has o ne 2 0 m g 1 2 h o urs a n d 6 h o urs pri or t o paclita xel a d mi nistratio n. Oral or I V.

I V di p he n h y dra mi ne ( or its e q ui vale nt) 5 0 m g a n d H 2 -bl oc ker ( per l ocal sta n dar d of care)
s h o uld be a d mi nistere d 3 0 t o 6 0 mi n utes pri or t o paclita xel i nf usi o n.

D oses 
of
paclita xel
a n d/ or
car b o plat i n
ma y
be
i nterr u pte d,
dela ye d,
re d uce d,
or
di sc o nti n ue d de pe n di n g o n h o w well t he partici pa nt t olerates t he treat me nt.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 1. 2. 2 
N a b -P a clit a x el a n d C ar b o pl ati n ( P art 1 O nl y)
Parti cipa nts i n Part 1 will recei ve n a b -paclit a xel 1 0 0 mg/ m 2 as a 3 0- mi n ute I V i nf usi on o n Da ys 
1, 
 c ycle. Car b o plati n at a d ose of A U C 5 or 6 as a 3 0-mi n ute I V i nf usi o n 
s h o uld be a d mi nistere d i m me diatel y after na b -paclita xel o n Da y 1 of  eac h 3-wee k c ycle or at d oses 
per t he l o c al  prescri bi ng i nf or mat i on. T he i nf usi o n ti me ca n f o ll ow l o c al  inst ituti o nal sta n dar ds.
Na b -pacli ta xel d osi n g calc ulati ons s h o ul d be base d o n t he b o d y s urface area calc ulat i on. T he d ose 
ma y re mai n t he sa me if t he part ici pa nt’s wei g ht is wit hi n 1 0 % of t he baseli ne wei g ht or prior d ose 
wei g ht.
Car b o pl at i n s h o ul d be gi ve n f oll owi n g na b -pacli ta xel o n Da y 1 of eac h c ycle, a n d t he car b o plati n 
d ose will be calc ulate d usi n g t he Cal vert f or m ula as f oll o ws:
Car b o pl at i n d ose ( m g) = tar get A U C × ( Cr Cl [ m L/ mi n] + 2 5)
Cr Cl  calc ulat i on is base d o n t he C oc kcr oft -Ga ul t f or mula a n d s h o uld i ncl u de t he m o st rece nt ser u m 
creati ni ne a n d m o st rece nt wei g ht. N O T E: If calc ulat i on of  the Cr Cl b y t he C oc kcr oft -Ga ult  
f or mula yiel ds a res ult of  > 12 5 m L/ mi n, t he n a Cr Cl s h o uld be calc ulate d b y a n al ter nati ve f or m ula 
per i nstit uti o nal sta n dar ds or ca p pe d at 1 2 5 m L/ mi n.
T he d ose of  car b o plat i n ma y be ca p pe d per l ocal sta n dar ds. N o pre me dicati o n is re q uire d f or 
na b -pacli ta xel prior t o a d mi nistrati o n.
7. 1. 2. 3 
P e m etr e x e d a n d Ci s pl ati n
Pe metre xe d d osi n g calc ulat i ons s h o uld be base d o n t he b o d y s urface area calc ulat i on. T he d ose
ma y re mai n t he sa me if t he parti ci pa nt’s wei g ht is wi t hi n 1 0 % of the wei g ht use d t o calc ulate t he
pre vi o us d ose.
Pr e m e dicat i ons f or use wit h p e metre xe d i ncl u de t he f o ll owi n g:

Oral or I V c ortic oster oi d s h o ul d be gi ve n acc or di n g t o local sta n dar ds at a d ose e q ui vale nt t o 
de xa met has o ne 4 m g t wice dail y ( BI D) o n  the da y pri or t o, t he da y of , a n d t he da y aft er t he 
a d mi nistratio n of pe metre xe d.

Oral f olic acid 3 5 0 t o 1 0 0 0 mc 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
pe metre xe d, wit h at least 5 d oses of f olic acid a d mi nistere d i n t he 7 da ys pri or t o t he first d ose.
Oral
f olic acid s h o ul d 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 pe metre xe d a n d
f or 2 1 da ys aft er t he last d ose of pe m etre xe d. I ntra m usc ular (I M) i njecti on of vit a mi n B 1 2
1 0 0 0 mc g
s h o ul d be gi ve n a p pr o xi matel y 1 wee k
pri or t o t he first d ose of pe m etre xe d a n d
re peate d e ver y 3 c ycles t hereafter d uri n g pe metre xe d treat me nt. S u bse q ue nt i njecti o ns of
vit a mi n B 1 2 ma y be gi ve n o n t he sa me da y as pe metre xe d ( partici pa nt wit h N S Q
hist ol o g y
ma y be gi n f olic aci d a n d vit a mi n B 1 2 pri or t o ra n d o mizati o n i n a nticipat i on of pe metre xe d) .

A nt iemet ic pre me dicat i on will be a d mi nistere d acc or di n g t o l ocal sta n dar ds. Rec o m me n de d
a nt iemet ic tr e at 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 a n ot her c ortic oster oi d ma y be s u bstitute 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
discret i on
a n d
l oc al
sta n dar ds of
care).
A d diti o nal 
use
of
a ntie metic
pr e m e dicat i ons ma y be e mpl o y e d at t he di scretio n of t he i n vest i gat or.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
8 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Parti cipa nts will recei ve p e m etre 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 o n o n D a y 1
wi t h cis plat i n at a d ose of 7 5 m g/ m 2 i nf usi o n as per l ocal sta n dar d practice o n Da y  1 of  a 3-wee k
treat me nt c ycle f or u p t o 4 c ycles.
D osi n g cal c ulatio ns s h o ul d be base d o n t he b o d y s urface area calc ulat i on a n d ma y be ca p pe d per
l ocal sta n dar ds. T he d ose ma y r e mai n t he sa me if t he partici pa nt’s wei g ht
is wi t hi n 1 0 % of t he
baseli ne wei g ht or pri or d ose wei g ht.
Cis plat i n will be
a d mi nistere d t o partici pa nts
at least 3 0 mi n utes
f oll owi n g t he e n d
of
t h e
pe metre xe d i nf usi on. Pretreat me nt h y drat i on f or cis plati n ca n f oll ow l ocal sta n dar d of care, or use
1 t o 2 liters of  fl ui d ( per lo c al  sta n dar ds) i nf use d I V f or 8 t o 1 2 h o urs prior t o ci s plati n i nf usi on is
rec o m me n de d. A de q uate h y drati o n a n d uri nar y o ut p ut m ust
be ma i ntai ne d f or at least 2 4 h o urs
f oll owi n g cis plat i n a d mi nistrati o n. A d mi nistrati o n a n d m o nit ori n g s h o uld be perf or m e d acc or di n g
t o l ocal sta n dar ds. Use
of ma n nit o l f oll owi n g
t he cis plati n i nf usi on s h o uld als o foll o w l oc al
sta n dar ds of care.
D oses
of pe metre xe d a n d/ or cis plat i n
may be i nterr u pte d, dela ye d, re d uce d, or disc o nti n ue d
de pe n di n g o n h o w well t he parti cipa nt t olerates t he treat me nt. See Secti o ns 7. 4. 2 , 7. 4. 3 , a n d 8. 1
f or m ore details.
All parti ci pa nts w h o
will recei ve cis plat i n s h o uld ha ve a u dio m etric testi n g perf or me d pri or t o
i nitiati on of t hera p y a n d pri or t o s u bse q ue nt d oses of cis plati n, or as per l ocal sta n dar ds of care.
Parti cip a nts w h o disc o nt i n ue cis plat i n alo n e ma y, at t he i n vesti gat or’s di screti on, be s witc he d t o
p e m etre xe d/car b o plat i n f or t he r e mai n der of t he P D C T ( u p t o 4 c ycles i n t ot al). D o si n g f or
p e m etre xe d/car b o plat i n f or s uc h partici p a nts s h o ul d f oll ow t he i nstr uctio ns i n  Secti on 7. 1. 2. 4 .
7. 1. 2. 4 
P e m etr e x e d a n d C ar b o pl ati n
Pe metre xe d d osi n g calc ulat i ons s h o uld be base d o n t he b o d y s urface area calc ulat i on. T he d ose
ma y re mai n t he sa me if t he parti ci pa nt’s wei g ht is wi t hi n 1 0 % of the wei g ht use d t o calc ulate t he
pre vi o us d ose.
Pre me dic ati o ns f or use wit h pe metre xe d:

Oral or I V c o rtic oster oid pr e m e d for pe metre xe d s h o uld be gi ve n acc or di n g t o l ocal sta n dar ds
at a d ose e q ui vale nt t o de xa met has o ne 4 m g BI D o n t he da y pri or t o, t he da y of , a n d t he
d a y aft er t he a d mi nistrati o n of p e m etre xe d.

Oral f olic aci d 3 5 0 t o 1 0 0 0 mc g
dail y s h o uld be gi ve n starti n g 1 wee k pri or t o t he fir st d ose 
of  pe metre xe d, wit h at le ast 5 d os es of fol ic aci d a d mi nistere d i n t he 7 da y s pri or t o t he first
d ose. Oral
f olic acid s h o uld be c o nti n ue d dail y t hr o u g h o ut t he treat me nt
wit h pe metre xe d
a n d f or 2 1 da ys aft er t he last d ose of pe m etre xe d. I M i njecti o n of vit a mi n B 1 2
1 0 0 0 mc g
s h o uld be gi ve n a p pr o xi matel y 1 wee k
pri or t o t he first d ose of pe metre xe d a n d re peate d
e ver y
3
c ycles
t hereafter
d uri n g
pe m etre xe d
treat me nt.
S u bse q ue nt
i njecti o ns of
vit a mi n B 1 2 ma y
be gi ve n o n t he sa me da y as pe metre xe d ( partici pa nt wit h N S Q hist ol o g y
ma y be gi n f olic aci d a n d vit a mi n B 1 2 pri or t o ra n d o mizati on i n a nt ici pati on of pe metre xe d).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Parti cip a nts will recei ve 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,
f oll owe d b y car b o plati n at a d ose of A U C 5 or 6 ( Part 1) or A U C 5 ( Part 2) as a 3 0- mi n ut e I V
i nf usi on o n Da y 1 of a 3-wee k
treat me nt c ycle, f or u p t o 4 c ycles.
Pe metre xe d d osi n g calc ulat i ons s h o uld be base d o n t he b o d y s urface area calc ulat i on. T he d ose
ma y re mai n t he sa me if t he partici pa nt’s wei g ht is wi t hi n 1 0 % wei g ht use d t o calc ulate t he pre vi o us
d ose.
T he car b o plat i n d ose will be calc ulate d usi n g t he Cal vert f or mula as f oll ows:
Car b o pl at i n d ose ( m g) = Tar get A U C × ( Cr Cl [ m L/ mi n] + 2 5)
Cr Cl calc ulat i on is base d o n t he C o c kcr oft-Ga ult f or m ula (see i ncl usi o n criteri o n i n Secti o n 6. 1 )
a n d s h o uld i ncl u de t he m o st rece nt ser u m creati ni ne a n d m o st rece nt wei g ht. N O T E:  If calc ulatio n
of t he Cr Cl b y t he C oc kcr oft -Ga ult f or mul a yie l ds a res ult of  > 1 2 5 m L/ mi n,
t he n a Cr Cl s h o ul d
be calc ulate d b y a n alter nati ve f or mula per i nstituti o nal sta n dar ds or ca p pe d at 1 2 5 m L/ mi n.
D oses of pe metre xe d a n d/ or car b o plati n ma y be i nterr u pte d, dela ye d, re d uce d, or disc o nt i n ue d
de pe n di n g
o n
h o w well
t he parti ci pa nt t olerates t he treat me nt. All
c he mot h era p y a ge nts’
pre parati o n, pre me dicat i on, a d mi nistrati o n, m o nit ori n g, a n d ma na ge me nt of c o m p licati ons are t o
f oll ow
l ocal prescri pti o n g ui deli nes a n d re g ulat i ons. T he d ose of c he m ot hera p y ma y
be ca p pe d
per l ocal sta n dar ds.
7. 1. 2. 5 
O pti o n al C o nti n u ati o n M ai nt e n a n c e
After C ycle 4 of  che m ot hera p y, part ici pa nts wit h N S Q hist ol o g y w h o ha ve S D or
res p o nse are
per mitte d
t o recei ve p e m etre xe d
5 0 0
m g / m2
alo ne
as
mai nte na nce t hera p y u ntil disease 
pr o gressi o n or u nacce pta ble t o xicit y.
7. 2 
M et h o d of Tr e at m e nt A s si g n m e nt
After t he partici pa nt’s i nitial eli gi bilit y is esta blis he d a n d i nf or me d c o nse nt has bee n o b tai ne d, t he
parti ci pa nt m ust be e nr olle d i nto t he st u d y via t he I R T. S pecific i nstr uctio ns f or usi n g I R T will be
pr o vi de d t o t he i n vesti gati o nal sit e i n a se parate d oc u m e nt. T he i n vesti gat or or desi g nee will
r e gister t he partici pa nt f or e nr oll me nt b y f oll owi n g
t he e nr o ll 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 uire d f or e nr oll me nt:

Date t hat i nf or me d c o nse nt was o b t aine d

Date of birt h
O nce e nr olle d i n I R T, e nr olle d partici pa nts t hat ha ve met all eli gi bilit y criteria will be ra n d o mize d 
t hr o u g h I R T. T he f oll owi n g i nf or mati on is re q uir e d for parti ci pa nt ra n d o mizati o n:

Parti cipa nt n u m ber
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Parti cipa nts meet i n g all eli gi bilit y criteria will
be stratifie d as f oll ows:

Part 1 : B y
t u mor hist ol o g y (S Q vs
N S Q ). Parti ci pa nts will be ra n d omize d i n a 1: 1 ratio t o 
A r ms A a n d B. E nr oll me nt will e n d after u p t o a p pr o xi matel y 1 2 0 part ici pa nts are ra n d o mize d.

P art 2 : B y t u mor hist ol o g y ( S Q vs N S Q),
E C O G p e r f o r m a n c e st at u s ( 0 v s 1 ), 
P D -L 1 level (1 [i ncl u des N Q ] vs < 1 % ). Parti ci pa nts will be ra n d omize d i n a 1: 1 ratio t o 
treat me nt a n d c o ntr ol ar ms. E nr o ll me nt will e n d aft er a p pr o xi matel y 3 0 0 part ici pa nts are 
ra n d omize d.
T he e xact pr oce d ures f or usi n g t he I R T will be detaile d i n t he I R T ma n ual.
7. 3 
Bli n di n g
P art 1 is site-a n d -s u bject bli n de d t o i m m u n ot her a p y tre at me nt o nl y. Access t o treat me nt c o des 
will be restricte d fr om all part ici pa nts a n d site pers o n nel pri or t o pri mar y data base l oc k, wit h 
e xce pti o ns as s pecifie d bel o w. C he m ot hera p y treat me nt will be a d mi nistere d as o pe n la bel.
P art 2 is o pe n- l a bel. 
 
 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 4 
D o s a g e M o difi c ati o n
N o d ose re d ucti o ns or escalati o ns f or i m m u n ot hera p y  are permit te d.
7. 4. 1 
D o s e M o difi c ati o n
Crit eri a f or I m m u n ot h er a p y
All A Es/ S A Es m ust be gra de d usi n g C o m m o n Ter mi n o l og y  Criteria f or A d verse E ve nts ( C T C A E) 
v 5. 
T he criteria f or d ose dela y, res u m ptio n, a n d disc o nti n uati o n f or i m m u n ot hera p y ha ve bee n 
i nte grate d t o a p pl y t o i m m u n ot hera p y tr e at me nt wit h eit her ni v o l uma b or ni v o l uma b pl us 
r elat li ma b, he ncef ort h referre d t o as i m m u n ot hera p y. Dela y i m m u n ot hera p y dosi n g f or a n y A E, 
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 ge me nt of  the i n vest i gat or, warr a nts 
d el a yi n g t he d ose of st u d y me dicat i on. S pecific ma na ge me nt g ui deli nes ( d ose del a y, res u mpt i on,  
a n d disc o nt i n uati on) f or e x pecte d A Es a n d S A Es f or t he ni v o l uma b + relatli ma b c o m bi nat i on 
t hera p y ca n be f ou n d i n Ta ble 7. 4. 1 - 1. A d ditio nal i nf or mat i on o n ma na ge me nt of A Es a n d S A Es 
wi t h ni v ol u ma b a n d relatli ma b is f o u n d i n 
 
F or partici pa nts w h o re q uire d el a y of im m u n ot hera p y , re-e val uate wee kl y, or m o re fre q ue ntl y, if 
cli nicall y i n dicate d, a n d res u me d osi n g w he n crit eria t o res u me treat me nt are met  (see Secti o n  
7. 4. 2 ). C o nti n ue t u m or assess me nts per pr ot oc ol e ve n if d osi n g is dela ye d. 
T he assess me nt f or d ose dela ys o f i m m u n ot hera p y s h o ul d be ma de se paratel y fr om t he assess me nt  
t o dela y c h e mot h era p y.
St u d y  treat me nt must als o be del a ye d f or S A R S- C o V -2 i nfect i on , eit her c o nfir me d or s us pecte d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
G astr oi ntesti n al
C olitis o r Diarr hea
Gra de 2 
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o 
baseli ne 
Gra de 3 
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o 
baseli ne
Gra de 4 
Per ma ne ntl y disc o nti n ue
Re n al
Ser u m Creati ni ne I ncrease d 
Gra de 2 or 3 
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o Gra de 
≤ 1 o r baseli ne val ue
Gra de 4 
Per ma ne ntl y disc o nti n ue
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 4
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
P ul m o n ar y
P ne u m o nitis
Gra de 2 
Dela y d ose
D osi n g ma y res u me after p ne u m o nitis has 
res ol ve d t o ≤ Gra de 1.
Gra de 3 or 4
Per ma ne ntl y disc o nti n ue
He p atic
As partate a mi n otra nsferase 
( A S T), ala ni ne 
a mi n otra nsferase ( A L T), or 
t otal bilir u bi n ( T. bili) 
i ncrease d
A S T or A L T > 3 x a n d ≤ 5 x 
u p per li mit of n or mal ( U L N) 
or  T. Bili  > 1. 5 x a n d ≤ 3 x 
U L N, re gar dless of baseli ne 
val ue
Dela y d ose
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 S T or A L T > 5 x U L N or 
T. bili > 3 x U L N, re gar dless 
of baseli ne val ue
Dela y d ose or per ma ne ntl y disc o nti n ue  
I n m ost cases of A S T or A L T > 5 x U L N, st u d y 
treat me nt will be per ma ne ntl y disc o nti n ue d. If 
t he i n vesti gat or deter mi nes a p ossi ble fa v ora ble 
be nefit/ris k rati o t hat warra nts c o nti n uati o n of 
st u d y treat me nt, a disc ussi o n bet wee n t he 
i n vesti gat or a n d t he Medical M o nit or/ desi g nee 
m ust occ ur a n d a p pr o val fr o m Me dical M o nit or 
pri or t o res u mi n g t hera p y
C o nc urre nt A S T or A L T > 3 
x U L N a n d T. bili > 2 x U L N, 
re gar dless of baseli ne val ue
Per ma ne ntl y disc o nti n ue 
E n d ocri n o p at h y
A dre nal I ns ufficie nc y 
Gra de 2 a dre nal 
i ns ufficie nc y
Dela y d ose
D osi n g ma y res u me after a de q uatel y c o ntr olle d 
wit h h or m o ne re place me nt.
Gra de 3 or 4 a dre nal 
i ns ufficie nc y or a dre nal 
crisis
Dela y d ose or per ma ne ntl y disc o nti n ue 
Ma n dat or y disc ussi o n wit h a n d a p pr o val fr o m t he 
Me dical M o nit o r nee de d pri or t o res u mi n g 
t hera p y. If a dre nal i ns ufficie nc y res ol ves or is 
a de q uatel y c o ntr olle d wit h p h ysi ol o gic h or m o ne 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 5
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
re place me nt, partici pa nt ma y n ot re q uire 
disc o nti n uati o n of st u d y dr u g.
H y per gl yce mia
H y per gl yce mia re q uiri n g 
i nitiati on or c h a n ge i n dail y 
ma na ge me nt ( Gra de 2 or 3)
Dela y d ose
D osi n g ma y res u me if h y per gl yce mia res ol ves t o 
Gra de ≤1 or baseli ne val ue, or is a de q uatel y 
c o ntr olle d wit h gl uc ose-c o ntr olli n g a ge nts.
Gra de 4
Dela y d ose or per ma ne ntl y disc o nti n ue 
Ma n dat or y disc ussi o n w it h a n d a p pr o val fr o m t he 
Me dical M o nit or nee de d pri or t o res u mi n g 
t hera p y. If h yper gl y ce mia res ol ves, or is 
a de q uatel y c o ntr olle d wit h gl uc ose-c o ntr olli n g 
a ge nts, partici pa nt ma y n ot re q uire 
disc o nti n uati o n of st u d y dr u g.
H y p o p h ysitis/ H y p o pit uitaris m  
S y m pt o matic Gra de 1 -3 t hat 
is als o ass ociate d wit h 
c orres p o n di n g a b n or mal la b 
a n d/ or pit uitar y sca n
Dela y d ose 
D osi n g ma y res u me if e n d ocri n o pat h y res ol ves t o 
be as y m pt o matic, or is a de q uatel y c o ntr olle d wit h 
o nl y  p h ysi ol o gic h or m o ne re place me nt.
Gra de 4
Dela y d ose or per ma ne ntl y disc o nti n ue 
Ma n dat or y disc ussi o n wit h a n d a p pr o val fr o m t he 
Me dical M o nit or nee de d pri or t o res u mi n g 
t hera p y. If e n d ocri n o pat h y res ol ves or is 
a de q uatel y c o ntr olle d wit h p h ysi ol o gic h or m o ne 
re place me nt, partici pa nt ma y n ot re q uire 
disc o nti n uati o n of st u d y dr u g.
H y pert h y r oi dis m or  
H y p ot h yr oi dis m
Gra de 2 or 3
Dela y d ose
D osi n g ma y res u me if e n d ocri n o pat h y res ol ves t o 
be as y m pt o matic, or is a de q uatel y c o ntr olle d wit h 
o nl y  p h ysi ol o gic h or m o ne re place me nt or ot her 
me dical ma na ge me nt.
Gra de 4
Dela y d ose or per ma ne ntl y disc o nti n ue 
Ma n dat or y disc ussi o n wit h a n d a p pr o val fr o m t he 
Me dical M o nit or nee de d pri or t o res u mi n g 
t hera p y. If e n d ocri n o pat h y res ol ves or is 
a de q uatel y c o ntr olle d wit h p h ysi ol o gic h or m o ne 
re place me nt or ot her me dical ma na ge me nt, 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 6
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
partici pa nt ma y n ot re q uire disc o nti n uati o n of 
st u d y dr u g.
S ki n
Ras h
Gra de 2 ras h c o veri n g > 3 0 % 
b o d y s urface area or Gra de 3 
ras h 
Dela y d ose 
D osi n g ma y res u me w he n ras h re d uces t o ≤ 1 0 % 
b o d y s urface area 
S us pecte d Ste ve ns -J o h ns on 
s yn dr o me ( SJ S), t o xic 
e pi der mal necr ol ysis ( T E N) 
or  dr u g reacti o n wit h 
e osi n o p hilia a n d s yste mic 
s ym pt o ms ( D R E S S)
Dela y d ose
D osi n g ma y res u me if SJ S, T E N, or D R E S S is 
r ule d o ut a n d ras h re d uces t o is ≤ 1 0 % b o d y 
s urface area
Gra de 4 ras h or c o nfir me d 
SJ S, T E N, or D R E S S
Per ma ne ntl y disc o nti n ue
Ne ur ol o gic al
G uillai n -Barre S y n dr o me 
( G B S)
A n y  Gra de
Per ma ne ntl y disc o nti n ue
M y ast he nia Gra vis ( M G) 
A n y  Gra de
Per ma ne ntl y disc o nti n ue
E nce p halitis
A n y  Gra de e nce p halitis 
Dela y d ose 
After w or k u p f or differe ntial dia g n osis, (ie, 
i nfecti o n, t u m or-relate d), if e nce p halitis is n ot 
dr u g relate d, t he n d osi n g ma y res u me w he n A E 
res ol ves 
A n y  Gra de dr u g-relate d 
e nce p halitis 
Per ma ne ntl y disc o nti n ue
M y elitis
A n y  Gra de m yelitis
Dela y d ose
After w or k u p f or differe ntial dia g n osis, (ie, 
i nfecti o n, t u m or-relate d), if m yelitis is n ot dr u g 
relate d, t he n d osi n g ma y res u me w he n A E 
res ol ves 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 7
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
A n y  Gra de dr u g-relate d 
m yelitis
Per ma ne ntl y disc o nti n ue
Ne ur ol o gical ( ot her t ha n 
G B S, M G, e nce p halitis, or  
m yelitis)
Gra de 2
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o 
baseli ne 
Gra de 3 or 4
Per ma ne ntl y disc o nti n ue
Ot her Cli nic al A E
Pa ncreatitis: 
A m ylase or Li pase i ncrease d
Gra de 3 wit h s y m pt o ms 
Dela y d ose
N ote: Gra de 3 i ncrease d a m ylase or li pase 
wit h o ut si g ns or s y m pt o ms of pa ncreatitis d oes 
n ot re q uire d ose dela y. 
D osi n g ma y res u me w he n partici pa nt bec o mes 
as ym pt o matic.
Gra de 4
Per ma ne ntl y disc o nti n ue
U veitis 
Gra de 2 u veitis
Dela y d ose
D osi n g ma y res u me if u veitis res p o n ds t o t o pical 
t hera p y (e ye dr o ps) a n d after u veitis res ol ves t o 
Gra de ≤ 1 or baseli ne. If partici pa nt re q uires oral 
ster oi ds f or u veitis, t he n per ma ne ntl y disc o nti n ue 
st u d y dr u g. 
Gra de 3 or 4 u veitis
Per ma ne ntl y disc o nti n ue
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 8
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
Ot her Dr u g -Relate d A E ( n ot 
liste d a b o ve)
Gra de 2 n o n -s ki n A E, e xce pt 
fati g ue
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o Gra de 
≤ 1 o r baseli ne val ue.
Gra de 3 A E - Fir st 
occ urre nce lasti n g ≤ 7 da ys
Dela y d ose
D osi n g ma y res u me w he n A E res ol ves t o Gra de 
≤ 1 o r baseli ne val ue.
Gra de 3 A E - First occ urre nce 
lasti n g > 7 da ys
Per ma ne ntl y disc o nti n ue
Rec urre nce of Gra de 3 A E of 
a n y d urati on
Per ma ne ntl y disc o nti n ue
Gra de 4 or Life -t hreate ni n g 
a d verse reacti o n
Per ma ne ntl y disc o nti n ue
Ot her L a b a b n or m alities 
Ot her Dr u g -Relate d la b 
a b n or malit y ( n ot liste d a b o ve)
Gra de 3
Dela y d ose
E xce pti o ns:
N o dela y  re q uire d f or: Gra de 3 l y m p h o pe nia .
Per ma ne nt Disc o nti n uati o n f or: Gra de 3 
t hr o m b oc yt o pe nia > 7 da ys or ass ociate d wit h 
blee di n g. 
Gra de 4
Per ma ne ntl y disc o nti n ue
E xce pti o ns: T he f oll o wi n g e ve nts d o n ot re q uire 
disc o nti n uati o n of st u d y dr u g: 
Gra de 4 ne utr o pe nia ≤ 7 da y s
Gra de 4 l y m p h o pe nia or le u k o pe nia
Gra de 4 is olate d electr ol yte 
i m bala nces/a b n or malities t hat are n ot ass ociate d 
wit h cli nical se q uelae a n d are res p o n di n g t o 
s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n 
7 2 h o urs of t heir o nset
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
9 9
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 1 - 1: 
A d verse E ve nt Criteri a f or Del a y, Res u m pti o n, a n d Disc o nti n u ati o n of I m m u n ot her a p y
Dr u g -Rel ate d A d verse 
E ve nt ( A E) per C T C A E V 5
Se verit y 
Acti o n T a ke n
Cl arific ati o ns, E xce pti o ns, a n d Res u me 
Criteri a
I nf usi o n Re acti o ns ( m a nifeste d b y fe ver, c hills, ri g ors, he a d ac he, r as h, pr urit us, art hr al gi a, h y p ote nsi o n, h y perte nsi o n, br onc h os p as m, or ot her 
aller gic -li ke re acti o ns)
H y perse nsiti vit y reacti o n or 
i nf usi o n reacti o n
Gra de 3 or 4
Per ma ne ntl y disc o nti n ue
Refer t o Secti o n 7. 4. 6  o n Treat me nt of Relate d 
I nf usi o n Reacti o ns 
A b bre viati o ns: A E = a d verse e ve nt; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C T C A E = C o m m o n Ter mi n ol o g y  Criteria f or Ad verse 
E ve nts; D R E S S = dr u g reacti o n wit h e osi n o p hilia a n d s yste mic s y m pt o ms; G B S = G uillai n -Barre s y ndr o me; M G = m yast he nia gr a vis; SJ S = Ste ve ns -J o h ns o n 
s yn dr o me; T. bili = t otal bilir u bi n; T E N = t o xic e pi der mal necr ol ysis; U L N = u p per li mit of n or mal.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 0
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 4. 2 
D o s e D el a y Crit eri a f or C h e m ot h er a p y
C he m ot h era p y dr u gs s h o uld be dela ye d f or a n y of t he e ve nts liste d bel o w. T he dela y s h o ul d occ ur 
o n treat me nt Da y 1 

A bs ol ute ne utr o p hil c o u nt ( A N C) < 1 5 0 0/ L ( SI u nits: < 1. 5 × 1 09 / L)

Pl at e lets < 1 0 0 / μ L ( SI u nits: < 10 0 × 1 0 9 / L)

A n y
Gra de
2 n o n- s ki n, n o n- he mat ol o gi c, dr u g -relate d A E
(e xcl u di n g Gra de
2 alo pecia, 
Gra de 2 fat i g ue, a n d Gra de 2 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 lab orat or y a b n or malit y,
wi t h t he f oll owi n g
e xce ptio ns
f or
l y m p h o pe nia, A S T, A L T, or T B :

Gra de 3 l y m p h o pe nia d oes n ot re q uire d ose dela y.

If a parti ci pa nt has a baseli ne A S T, A L T, or T B t hat is wi t hi n n or m al li mits, dela y d osi n g 
f or dr u g-relate d Gra de 2 t o xicit y.

If a parti cip a nt has baseli ne A S T, A L T, or T B wit hi n t he Gra de 1 t o xicity ra n ge, del a y 
d osi n g f or dr u g -relate d Gra de ≥3 t o xicit y.

A n y A E, lab orat or y  ab n or m alit y, or i nterc 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  stu d y me dicat i on. I n vest i gat ors s h o ul d c o ns ult l ocal 
la beli n g f or t he c he m ot hera p y dr u gs bei n g a d mi nistere d t o a n y gi ve n partici pa nt f or a d diti o nal 
g ui da nce o n d ose del a ys.
D ose m o dific at i ons liste d are s pecific t o U S Prescri bi n g I nf or mati on ( U S PI). Variat i ons ma y a p pl y 
per l ocal la bel. Partici pa nts recei vi n g cis plat i n wi t h pe metre xe d m ust
di sc o nti n ue cis plat i n if t he
calc ulate d Cr Cl decreases t o < 5 0 m L/ mi n
( base d o n t he C oc kcr oft -Ga ult
for mula). T he ot her
dr u g ( pe metre xe d) ma y be c o nt i n ue d, a n d t he plati n u m a ge nt ma y, at t he i n vesti gat or’s di screti on,  
be
s witc he d t o car b o plati n f or t he rest of t he c ycles w he n
t he parti ci pa nt meets
retreat me nt
criteria. N ote t hat pe metre xe d ca n o nl y be a d mi nistere d if Cr Cl is 4 5 m L/ mi n
(calc ulate d per 
C oc kcr oft -Ga ul t f or mula).
If a partici pa nt recei vi n g car b o plat i n wi t h pacli t a x el m u st disc o nti n ue car b o plat i n, paclita xel may 
be c o nt i n ue d at t he i n vesti gat or’s discreti o n.
If a n y n o n- he mat ol o gi c A E
meet i n g t he d ose dela y crit eria a b o ve is felt t o be relate d t o o nl y
1 parti c ular a ge nt i n t he P D C T re gi me n, t he n t hat a ge nt alo ne ma y be o m itt e 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 mai nt ai n
s y nc hr o nize d d osi n g of t he re gi me n, t he
o mitte d a ge nt s h oul d be res u me d wi t h t he 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 crit eria are met.
Pl ease refer t o Secti o n 7. 4. 3. 2 t o det er mi ne if d ose re d ucti o n of 
t he res u me d a ge nt is re q uire d.
If b ot h dr u gs i n t he P D C T re gi me n are del a ye d, t he n t he partici pa nt s h o ul d be re-e val uate d
wee kl y
or
m o re fre q ue ntl y if cli nicall y
i n dicate d u ntil re-treat me nt crit eria are met
(as per
Sect i on 7. 4. 4. 2 ).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
St u d y  treat me nt must als o be del a ye d f or S A R S- C o V -2 i nfect i on, ei t her c o nfir me d or s us pecte d.
D osi n g of  im m u n ot hera p y  a n d b ot h c he m ot hera p y a ge nts s h o uld be dela ye d if a n y criteria f or
i m m u not hera p y or b ot h P D C T a ge nts are met.
7. 4. 3 
D o s e R e d u cti o n s
7. 4. 3. 1 
D o s e R e d u cti o n f or I m m u n ot h er a p y
N o d ose re d ucti o ns f or i m m u n ot hera p y  are per mitte d.
7. 4. 3. 2 
D o s e R e d u cti o n f or C h e m ot h er a p y
D ose re d uctio ns f or c he m ot hera p y ma y
be re q uire d a n d will be perf or me d acc or di n g t o T a bl e 
7. 4. 3. 2 - 1 or per i nst ituti o nal g ui deli nes. C he m ot h era p y d ose re d ucti ons are per ma ne nt; o nce t h e
d ose of a n y c he mot h era p y a ge nt is re d uce d, it ma y n ot be
re-escalate d i n s u bse q ue nt c ycles,
e xce pt as n ote d w he n
starti n g p e m etre xe d ma i nte na nce t hera p y. T he d ose re d ucti o ns f or eac h
a ge nt i n t he P D C T re gi me n are n ot li n ke d a n d ma y
be a djuste d i n de pe n de ntl y as s u m marize d
bel o w.
T a ble 7. 4. 3. 2 - 1: 
D ose M o dific ati o ns of C he m ot her a pe utic A ge nts
D ose Le vel
C ar b o pl ati n
Pe metre xe d
N a b -
P aclit a xel a
P aclit a xel 
Cis pl ati n
Starti n g 
d ose
A U C 6 or A U C 5
5 0 0 m g/ m 2
1 0 0 m g/ m 2
2 0 0 m g/ m 2
7 5 m g/ m 2
First d ose 
re d ucti on
A U C 5 (if starti n g d ose is A U C 6) or 
A U C 4 (if starti n g d ose is A U C of 5)
3 7 5 m g/ m 2
7 5 m g/ m 2
1 5 0 m g/ m 2
5 6 m g/ m 2
Sec o n d d ose 
re d ucti on
A U C 4 (if starti n g d ose is A U C 6) or 
A U C 3 (if starti n g d ose is A U C 5)
2 5 0 m g/ m 2
5 0 m g/ m 2
1 0 0 m g/ m 2
3 8 m g/ m 2
T hir d d ose 
re d ucti on
Disc o nti n ue
Disc o nti n ue   
Disc o nti n ue   
Disc o nti n ue  
Disc o nti n ue
A b bre viati o n A U C = area u n der t he c o nce ntrati o n -ti me c ur ve.
a Na b -pacli ta x el for S Q hi st olo g y  is a p plica ble t o Part 1 o nl y.
D ose m o dificat i ons liste d are s pecific t o U S prescri bi n g i nf or mati on ( U S PI). Variat i ons ma y a p pl y 
per l o c al  la bel.
A n y p arti ci pa nts wi t h 2 prior d ose re d ucti o ns f or 1 a ge nt w h o e x perie nces a t o xicit y that w o ul d 
ca use a t hir d d ose re d ucti o n m ust be disc o nt i n ue d fr om t hat a ge nt.
7. 4. 3. 3 
C h e m ot h er a p y: D o s e R e d u cti o n s f or H e m at ol o gi c T o xi cit y
D ose m o dificat i ons f or he mat ol o gic t o xicities (acc or di n g t o C T C A E v 5) are s u m marize d i n Ta ble 
7. 4. 3. 3 - 1. D o se a dj ust me nt s are base d o n na dir bl o o d c o u nts (assesse d as per l ocal sta n dar ds) si nce
t he prece di n g dr u g a d mi nistrati o n. D ose
le vel a djust me nt s f or P D C T are relati ve t o t hat of t he
prece di n g a d mi nistratio n. Ge nerall y, b ot h c he m ot hera p y a ge nts i n t he P D C T re gi me n s h o uld be
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
d ose re d uce d t o get her f or he mat ol o gic
t o xicit y.
 
 
 
 
 
 
 
 
 
 
 
 
F or i nci de nces of c he m ot hera p y i n d uce d a ne mia or ca ncer -ass ociate d 
a ne mia, re d bl o o d cell tra nsf usi o ns are rec o m me n de d. I n partici pa nts w h o ref use R B C tra nsf usi o ns, 
er yt hr o p oiesis-sti m ulati n g a ge nts ma y be a d mi nistere d as per l ocal sta n dar ds.
Use l ocal sta n dar ds of care f or ot her pre vi o usl y descri be d s u p p orti ve meas ures. A d dit i onall y ,
pr o p h ylact ic a nt i bi otics ma y be use d acc or di n g t o l ocal sta n dar ds of care. I n vestigat ors are 
str o n gl y rec o m me n de d t o ha ve a hi g h i n de x of s us pici on f or i nfecti on a n d c o nsi der starti n g br oa d 
s pectr u m a nt i bi otics earl y f or a n y fe ver or si gns of  infect i on in partici pa nts wit h ne utr o pe nia. 
Pl ease re p ort a n y a nt i bi otic or gr o wt h fact or use o n t he electr o nic case re p ort f or m (e C R F).
D ose m o dificat i ons liste d are s pecific t o U S PI. Variati ons ma y a p pl y per l ocal la bel.
T a ble 7. 4. 3. 3 - 1: 
D ose M o dific ati o ns f or He m at ol o gic T o xicit y ( B ase d o n N a dir C o u nts)
T o xicit y
C ar b o pl ati n 
P aclit a xel
N a b -P aclit a xel a
Pe metre xe d 
Cis 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 × 1 0 9/ L)
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
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 × 1 0 9/ L)
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Gra de 4
( < 2 5, 0 0 0/ m m 3; < 2 5. 0 × 1 0 9/ L)
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
Re d uce
1 d ose le vel
a Na b -pacli ta x el for S Q hi st olo g y  is a p plica ble t o Part 1 o nl y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 4. 3. 4 
C h e m ot h er a p y: D o s e R e d u cti o n s f or N o n - he m at ol o gi c T o xi citi e s
D ose a dj ust me nts f or c he m ot hera p y f or n o n -he mat ol o gi c t o xicit ies d uri n g treat me nt are descri be d 
i n Sect i on 7. 4. 3. 2 . All d ose re d uctio ns s h o uld be ma de base d o n t he w o rst-gra de t o xicit y. 
Parti cipa nts e x perie nci n g a n y of  the t o xicities d uri n g t he pre vi o us c ycle s h o uld ha ve t heir 
c he m ot hera p y dela ye d u ntil retreat me nt criteria are met a n d t he n re d uce d f or all s u bse q ue nt c ycles 
b y 1 d ose level or disc o nti n ue d as a p pr o priate. D ose levels f or t he 2 dr u gs i n t he P D C T re gi me n 
are n ot li n ke d a n d ma y be re d uce d i n de pe n de nt l y, as s u m marize d i n Ta ble 7. 4. 3. 4 - 1.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 7. 4. 3. 4 - 1: 
D ose M o dific ati o ns f or N o n -he m at ol o gic T o xicit y
T o xicit y
C ar b o pl ati n
P aclit a xel
N a b -P aclit a xel b
Pe metre xe d
Cis pl ati n
Fe brile ne utr o pe nia
Gra de ≥ 3
Re d uce 1 d ose le vel  
Re d uce 1 d ose le vel  
Re d uce 1 d ose le vel  
Re d uce 1 d ose le vel  
Re d uce 1 d ose le vel
Diarr hea
Gra de ≥ 3
N o c ha n ge 
Re d uce 1 d ose le vel 
N o c ha n ge 
Re d uce 1 d ose le vel 
N o c ha n ge
Aller gic reacti o n a
Gra de ≥ 3
Disc o nti n ue
Disc o nti n ue
Disc o nti n ue   
Disc o nti n ue   
Disc o nti n ue
Ne ur o pat h y
Gra de 2
Re d uce 1 d ose le vel 
N o c ha n ge
N o c ha n ge
N o c ha n ge 
Re d uce 1 d ose le vel
Ne ur o pat h y
Gra de 3 - 4
Disc o nti n ue
Disc o nti n ue 
Re d uce 1 d ose le vel 
Disc o nti n ue   
Disc o nti n ue
Cr Cl < 5 0 m L/ mi n
N o c ha n ge
Disc o nti n ue if Cr Cl 
< 2 0 m L/ mi n
N o c ha n ge
N o c ha n ge
Disc o nti n ue
Ot her Gra de ≥ 3 t o xicit y
(e xce pt f or fati g ue a n d tra nsie nt 
art hral gia a n d m yal gia)
A dj ust as me dicall y 
i n dicate d
A dj ust as me dicall y 
i n dicate d
A dj ust as me dicall y 
i n dicate d
A dj ust as me dicall y 
i n dicate d
A dj ust as me dicall y 
i n dicate d
A b bre viati o n: Cr Cl = Creati ni ne Cleara nce ; U S PI = U S Prescri bi n g I nf or mati o n.
a
O nl y t he dr u g(s) ca usi n g t he h y perse nsiti vit y reacti o n or ac ute i nf usi o n reacti o n (Gra de 3) re q uire(s) disc o nti n uati o n. All ot her dr u gs ma y be c o nti n ue d.
N ote: D ose m o dificati o ns liste d are s pecific t o U S PI. Variati o ns ma y a p pl y per l ocal la bel.
b Na b -paclita xel f or S Q hist ol o g y is a p plica ble t o Part 1 o nl y .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 5
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 4. 4 
Crit eri a t o R e s u m e D o si n g
7. 4. 4. 1 
Crit eri a t o R e s u m e Tr e at m e nt wit h I m m u n ot h er a p y
Parti cipa nts ma y res u me treat me nt wit h st u d y dr u g if t he y ha ve c o mplete d A E ma na ge me nt 
(ie, c ortic oster oid ta per) or are o n ≤ 1 0 m g pre d nis o ne or e q ui vale nt, a n d meet t he re q uire me nts 
per Ta ble 7. 4. 1 - 1.
Parti cipa nts wi t h SA R S -C o V - 2 i nfecti on ( eit her c o nfir me d or s us pecte d) ma y res u me treat me nt 
aft er all of t he f oll o wi n g : 1) at least 1 0 da ys ( 2 0 da ys f or se vere/critical ill ness) ha ve passe d si nce 
s y m pt o ms first a p peare d or p osit i ve test res ult (e g, R T -P C R or viral a nt i ge n), 2) res ol uti o n of ac ute 
s y mpt o ms (incl u di n g at least 2 4 h o urs has passe d si nce last fever wi t ho ut fever re d uci n g 
me dicat i ons), 3) e val uat i on b y t he i n vesti gat or wit h c o nfir mat i on t hat t here are n o se q uelae t hat 
w o ul d place t he parti ci pa nt at a hi g her ris k of  recei vi n g i n vesti gati ona l tr e at me nt, a n d
4) c o ns ultat i on b y t he Me dical 
M o ni t or. F or s us pecte d cases, treat me nt ma y als o res u me if 
S A R S -C o V -2 i nfecti o n is r ule d o ut a n d ot her criteria t o res u me treat me nt are met.
Pri or t o r e -i nitiati n g treat me nt i n a partici pa nt wit h a dosi n g del a y lasti n g > 8 wee ks, t he Me dical 
M o ni t or ( or desi g nee) m ust be c o ns ulte d. C o nti n ue t u m or assess me nts per pr ot oc ol e ve n if d osi n g 
is dela ye d. C o nti n ue peri o dic st u d y visits t o assess safety a n d la b orat or y st u dies e ver y 8 wee ks or 
m o r e 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.
7. 4. 4. 2 
Crit eri a t o R e s u m e Tr e at m e nt wit h C h e m ot h er a p y

Parti cipa nts ma y res u me treat me nt wit h c he m ot hera p y whe n t he A N C ret ur ns t o ≥ 1 5 0 0/ μ L 
( SI u nit s: ≥1. 5 × 1 0 9 / L), t he plat elet c o u nt ret ur ns t o ≥1 0 0 , 0 0 0/ μ L ( SI u nits: ≥1 0 0 × 1 0 9 / L), 
a n d all ot her 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 
alo pecia a n d fati g ue).

If a partici pa nt fails t o meet criteria f or re-treat me nt, t he n re-treat me nt s h o uld be dela ye d, a n d 
t he partici pa nt s h o ul d be re-e val uate d wee kl y or m ore fre q ue ntl y as cli nicall y i n dicate d. A n y 
parti ci pa nt w h o fails t o rec o ver fr o m t o xicit y at tri b uta ble t o c he m ot hera 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 uld 
di s c o nti 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 c he mot h era p y tr e at me nt, please f oll o w t he d ose -re d ucti o n rec o m me n dati o ns 
i n Secti o n 7. 4. 3. 2 .

Parti cipa nts wi t h SA R S -C o V - 2 i nfecti on ( eit h er c o nfir me d or s us pecte d) ma y res u me 
treat me nt after all of t he f oll o wi n g : 1) at least 1 0 da ys ( 2 0 da ys f or se vere/critical ill ness) ha ve 
passe d si nce s y m pt o ms first a p peare d or p ositi ve test res ult (e g, R T -P C R or vi r al a ntige n), 2) 
res olut i on of  ac ute s y m pt o ms (i ncl u di n g at least 2 4 h o urs has passe d si nce last fever wi t ho ut 
fe ver re d uci n g me dicati ons), 3) e val uat i on b y t he in vesti gat or wit h c o nfir mat i on t hat t here are 
n o se q uelae t hat w o ul d pl ace t he partici pa nt at  a hi gher ris k of  recei vi n g i n vesti gati onal 
treat me nt, a n d 4) c o ns ultat i on b y t he M e dical M o ni t or. F or s us pecte d cases, treat me nt ma y 
als o res u me if S A R S -C o V -2 i nfecti on is r ule d o ut a n d ot her criteria t o res u me treat me nt are 
met.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 4. 5 
M a n a g e m e n t Al g orit h m s f or I m m u n o-O n c ol o g y A g e nt s
I O a ge nts are ass ociate d wit h A Es t hat ca n differ i n se verity a n d d urati o n t ha n A Es ca use d b y ot her 
t hera pe utic classes. Ni v olu ma b a n d rel at li ma b are c o nsi dere d I O a ge nts i n t his pr ot oc ol. Beca use 
of  the p ote ntial f or cli nicall y mea ni n gf ul 
T R A Es re q uirin g earl y rec o g nitio n  an d pr o m pt 
i nter ve nt i on, ma na ge me nt al g orit h ms ha ve bee n de vel o pe d t o assist i n vest i gat ors i n assessi n g a n d 
ma na gi n g t he f o ll owi n g gr o u ps of A Es:
T he a b o ve al g ori t h ms are f ou n d i n t he ni v o l uma b a n d relatli ma b I Bs as well as i n  
 of 
t his pr ot oc ol.
7. 4. 6 
Tr e at m e nt of I m m u n ot h er a p y I nf u si o n R e a cti o n s
Si nce ni v o l u ma b a n d r elat li ma b c o ntai n o nl y hu ma n I g 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 tivit y react i ons. H o we ver, if s uc h a reacti o n were 
t o occ ur, it mi g ht ma nifest wit h fe ver, c hills, ri g ors, hea dac he, ras h, pr urit us, art hr algias, 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 on reacti ons s h o uld 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 criteria are met. 
I nf usi on reactio ns s h o uld be gra de d acc or di n g t o Nati o nal  Ca ncer I nstit ut e ( N CI) C T C A E v 5 
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 tr e at 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 dicate 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 partici pa nt u nt il rec o ver y fr om
s y m pt o ms. 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 o ns:  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 at least 3 0 mi n utes bef or e
a d ditio nal i m m u n ot hera p y a d mi nistratio ns.
F or Gr a de
2 s y m pt o ms ( m o der ate re acti o n re q uires t her a p y o r i nf usi o n i nterr u pti o n b ut
res p o n ds
p r o m ptl y
t o s y m pt o m atic
t re at me nt [e g, a nti hist a mi nes,
n o nster oi d al
a nti -
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
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, I V 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 i nf usi o n, be gi n a n I V i nf usi o n of n or mal sali ne, a n d treat
t he parti ci pa nt wit h
di p he 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
partici pa nt
u nt il
res ol uti on of
s y 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 o n is i nterr u pte d, t he n restart t he i nf usi o n at 5 0 % of
t he 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
i ncrease d t o 1 0 0 % of t he ori gi nal i nf usi on rate. M o nit or partici pa nt cl o sel y. If s y m pt o ms rec ur,
t he n
n o
f urt her
i m m u n ot hera p y 
will
be
a d mi nistere d
at
t hat 
visit .
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 nit or
t he
parti ci pa nt u nt il
res olut i 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 e C R F.

F or
f uture
i nf usi o ns, t he
f oll owi n g 
pr o p h ylacti c
pre me dicat i ons
are
rec om 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 mg
s h o ul d be a d mi nistere d at least 3 0 mi n utes
bef o re i m m u n ot hera p y i nf usi ons. If necessar y ,
c ortic oster oids ( u p t o 2 5 m g of S ol u C ortef 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 nfiltr ates]. Gr a de
4:  Life
t hre ate ni n g; press or or ve ntil at or y
s u p p ort i n dic ate d):

I mme diatel y disc o nt i n ue i nf usi on of i m m u n ot hera p y. Be gi n a n I V i nf usi o n of n or m al
sali ne
a n d treat t he partici pa nt as f oll 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 uti 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 oluti o n
i njecte d
sl owl 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. Partici pa nt s h o ul d be m o nit ore d
u ntil t h e 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. I m m u n ot hera p y will
be per ma ne ntl y disc o nt i n ue d. I n vesti gat ors s h o ul d f oll ow t heir i nstit uti o nal g ui deli nes f or t he
treat me nt of a na p h yla xis. Re m ai n at be dsi de a n d m o nit or partici pa nt u ntil
rec o ver y of 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 l ocalize 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).
7. 5 
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y
T he I P s h o ul d be st ore d i n a sec ure area acc or di n g t o l ocal re g ulat i ons. It is t he res p o nsi bility of  
t he i n vesti gat or t o e ns ure t hat t he I P is o nl y  dispe nse d t o st u d y partici pa nts. T he I P m u st be 
di s pe nse d o nl y fr o m official st u d y sit es b y a ut h orize d pers o n nel acc or di n g t o l ocal re g ulati ons.
T he pr o d uct st ora ge ma n a ger s h o uld e ns ure t hat t he st u d y treat me nt is st ore d i n acc or da nce wi t h 
t he e n vir o n me ntal c o n ditio n s (t e mperat ure, li ght , a n d h u mi dit y)  as deter mi ne d b y B M S. If 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
c o ncer ns re gar di n g t he q ualit y or a p peara nce of  the st u d y treat me nt arise, t he stu d y treat me nt
s h o uld n ot be di s pe nse d a n d c o ntact B M S i m me diatel y.
St u d y  treat me nt n ot s u p plie d b y B M S will be st ore d i n acc or da nce wit h t he pac ka ge i nsert.
I P d oc u me ntati o n ( w het her s u p plie d b y B M S or n ot) m u st be mai ntai ne d t hat i ncl u des all pr ocesses 
re q uire d t o e nsure dr u g is acc uratel y a d mi nistere d. T hi s i ncl u des d oc u m e ntatio 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 uir e d 
pr ocesses (e g, re q uire d dil ue nts, a d mi nistrati o n sets).
F urt her g ui da nce a n d i nf or m atio n f or fi nal dis p osi tio n  of u n use d st u d y tr e at me nts are pr o vide d i n 
A p pe n di x 2 .
7. 5. 1 
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/ Bi o c o m p ar a bilit y
At  t he ti me of r e c eipt of  t he I P b y t he i n vesti gat or or desig nee, B M S will s pecif y t he a p pr o priat e 
n u m ber of  co ntai ners or u nits t o select f or rete nti o n, t he c o n ditio ns of  sa m ple st ora ge, re q uire d 
d urati o n of  sa mple rete ntio n, a n d pr o visi o n s f or ret ur ni n g or dis p osi n g of  the I P. W he n sa m ples 
are selecte d, c o ntai ners or u nits s h o ul d be place d i n pac ka gi n g wi t h a ta m per -e vide nt seal pr o vi de d 
b y B M S or s o urce d b y  t he site. Pac ka ge labeli n g s h o ul d clearl y  ide nt if y t he c o nte nts as rete ntio n 
sa m ples a n d state t hat t he I P s h o ul d be st ore d i n t he restricte d area wit h li mite d access.
A d dit i onal details re gar di n g t h e rete nti o n pr ocess will be pr o vi de d i n t he P har mac y Ma n ual ( or i n 
ot her wri tte n i nf or mati o n) pr o vi de d t o t he site.
7. 6 
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 partici pa nt’s 
me dical rec or d a n d e C R F. T hi s will be s o urce data verifie d b y t he B M S U n bli n de d Si t e M o nit or 
t hr o u g h re g ularl y sc he d ule d m o nit ori n g visits.
7. 7 
C o n c o mit a nt T h er a p y
7. 7. 1 
Pr o hi bit e d a n d/ or R e stri ct e d Tr e at m e nt s
T he f oll owi n g me d icati ons are pr o hi bite d d uri n g t he st u d y (u nless utilize d t o treat a dr u g -relate d 
A E):

I mm u n os u p pressi ve a ge nts

I mm u n os u p pressi ve d oses of s yste mic c ortic oster oi ds (e xce pt as state d i n Secti o n 7. 7. 3 )

A n y c o nc urre nt a nti -ne o pl astic t hera p y (ie, c he m ot hera p y, h or m o nal t hera p y, i m m u n ot hera p y, 
e xte nsi ve, n o n-palliat i ve ra diatio n t hera p y , or sta n dar d or i n vesti gati onal a ge nts f or treat me nt 
of  N S C L C)

A n y li ve/atte n uate d vacci ne (e g, varicella ; z oster; ye ll o w fe ver; r ota vir us; oral  pol i o; a n d 
measles, m u m ps, r u bella) wi t hi n 3 0 da ys pri or t o r a n d o mi z ati o n, d uri n g tr e at me nt, a n d u ntil 
 p ost-last d ose.

A d mi nistrati o n of  a li ve or re plicati o n c o m pete nt C O VI D - 1 9 vacci ne is pr o hi bite d wi t hi n 3 0 
da ys pri or t o ra n d o mizat i on. Li ve or re plicat i on c o m pete nt C O VI D -1 9 vacci nes s h o ul d n ot be 
use d d uri n g t he st u d y , incl u di n g t he treat me nt peri o d , safety f oll ow u p -peri o d a n d wi t hi n   
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 0 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 f oll owi n g last d ose of  IP. 
C O VI D -1 9 vacci nes t hat are N O T li ve n or re plicati on 
c o mpete nt are per mitte d d uri n g t he st u d y  a n d after t he last d ose of I P.

N o n -li ve C O VI D - 1 9 vacci nat i on is c o nsi dere d a si m ple c o nc o mit a nt me d icati on wi t hi n t he 
st u d y. H o we ver, t he efficac y a n d safety of  no n -li ve vacci nes (incl u di n g n o n- li ve C O VI D - 1 9 
vacci nes) i n partici pa nts recei vi n g relatli ma b a n d/ or ni v ol uma b pl us P D C T is u n k n o w n.
N o data are a vaila ble o n t he res p o nse t o C O VI D - 1 9 vacci nes. T he f oll owi n g are N O T li ve 
vacci nes: i nact i vate d vacci nes (e g, heat-kille d a n d f or mali n -kille d vacci nes), s u b u nit vacci nes (e g, 
i nfl ue nza a n d p ne u m oc occal vacci nes), t o x oi d vacci nes, n ucleic aci d vacci nes t hat d o n ot e nc o de 
p ote nti all y i nfecti o us vir us (e g, Pfizer/ Bi o N Tec h a n d M o der na 
C O VI D - 1 9 vacci nes), a n d 
re plicati on- i nc om p ete nt rec o m bi na nt vect or vacci nes (e g, Astra Ze neca/ U ni versit y of  Oxf or d 
C O VI D - 1 9 vacci ne). Pl ease c o ntact t he cli nical trial ph ys icia n or Me dical 
M o ni t or wit h a n y 
q uesti o ns relate d t o C O VI D -1 9 vacci nes. 

A n y b ota ni cal pre paratio n (e g , her bal s u p ple me nts or tra diti o nal C hi nese me dici nes) i nte n de d 
t o treat t he disease u n der st u d y or pr o vi de s u p p orti ve care. Use of marij ua na a n d its deri vat i ves 
f or treat me nt of  s y m pt o ms relate d t o ca ncer o r ca ncer tr e at me nt are per mitte d if o btai ne d b y 
me dical prescri pti o n or if its use (e ve n wi t ho ut a me d ical prescri pti on) has bee n le galize d 
l ocall y.
T he i n vesti gat or m u st als o a d here t o t he c o ntrai n dicat i ons, preca ut i ons, a n d dr u g i nteractio ns 
f ou n d i n t h e U S PI or lo c al  la bel for eac h of t he c he m ot hera p y  a ge nts.
7. 7. 2 
Ot h er R e stri cti o n s a n d Pr e c a uti o n s
Parti cipa nts wi t h a co n di tio n re q uirin g s yste mic tr e at me nt wit h eit her c ortic oster oids ( > 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 on s wi t hi n 1 4 da ys of 
ra n d omizat i on are e xcl u de d. I n hale d or t o pical ster oids a n d a dre nal re place me nt ster oi d d oses 
> 1 0 m g dail y pre d nis o ne e q ui vale nt are per mitte d i n t he a bse nce of act i ve a ut oi m m u ne disease.
7. 7. 2. 1 
I m a gi n g R e stri cti o n a n d Pr e c a uti o n s
It is t he local i ma gi n g facilit y’s res p o nsi bility t o deter mi ne, base d o n partici p a nt attri b utes 
(e g, aller g y hist or y , dia betic hist or y , a n d re nal st at us), t he a p pr o priate i ma gi n g m o dalit y a n d 
c o ntrast re gi me n per i ma gi n g st u d y. I ma gi n g c o ntrai n dicat i ons a n d c o ntrast ris ks are t o be 
c o nsi dere d i n t his assess me nt. Partici pa nts wit h re nal i ns ufficie nc y are t o be assesse d as t o w het her 
or n ot t he y sh o ul d recei ve c o ntrast a n d if s o, w hic h c o ntrast a ge nt a n d d ose is a p pr o priate. S pecific 
t o M RI, 
partici pa nts wi t h se vere re nal ins ufficie nc y (ie, est i mate d gl o mer ular filtrati on rate 
< 3 0 m L/ mi n/ 1. 7 3 m 2 ) are at i ncrease d ris k of  ne p hr o ge nic s yste mic fi br osis; t heref ore, M RI 
c o ntrast is c o ntrai n dicate d. I n a d ditio n, parti ci pa nts ma y be e xcl u de d fr om M RI if t he y ha ve 
t att o os, metallic i m pla nts, pace ma kers, etc. T his will be o utli ne d i n t he i ma ge ma n ual.
Ge nt le h y drat i on bef ore a n d aft er I V c o ntrast s h o ul d f oll ow l ocal sta n dar d of  care. T he ult i mate 
decisi o n t o perf or m M RI i n a n i n di vi d ual partici pa nt i n t his st u d y rests wi t h the site ra di ol o gist, 
t he i n vest i gat or, a n d sta n dar ds set b y t he lo c al  Et hics C o m mittee.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 7. 3 
P er mitt e d T h er a p y

Parti cipa nts are per mitte d t he use of t o pical, oc ular, i ntra -artic ular, i ntra nasal, a n d i n halati o nal 
c ortic oster oids ( wi t h mi ni mal s yste mic a bs or pti o n). 

A dre nal r e place me nt ster oid d oses > 1 0 m g dail y  pre d nis o ne are per mitte d. 

A br ief (less t ha n 3 wee ks) c o urse of c ortic oster oi ds f or pr o p h yla xis (e g, c o ntrast d y e aller g y) 
or f or treat me nt of  no n -a ut oi m m u ne c o n ditio n s (e g, del a ye d-t ype h y perse nsit i vity react i on 
ca use d b y a c o ntact aller ge n) is per mitte d.

Re g ular c o nc o mita nt use of  bi p h os p h o nates a n d R A N K -L i n hi bit ors f or pre ve nt i on or 
re d uctio n of  s keletal-r elate d e ve nts i n part ici pa nts wit h bo ne metastases is all o we d if i nit iate d 
pri or t o fi rst d ose of st ud y  treat me nt. 

Pri or palliat i ve r a diot h era p y must ha ve bee n c o m plete d at l east 2 wee ks prior t o treat m e nt.
7. 7. 3. 1 
P alli ati v e L o c al T h er a p y
Palliat i ve l ocal t hera p y, i ncl u di n g palliati ve ra diati o n t hera p y a n d palliati ve s ur gical resectio n, t o 
s y m pt o mat ic n o n- t ar get b o ne lesi ons, s ki n lesi o ns, or C N S lesi ons is per mitte d pri or t o 
di sc o nti n uati on of st u d y  treat me nt f or partici pa nts w h o d o n ot ha ve e vi de nce of o verall cli nical or 
r a dio gra p hic pr o gressi o n per R E CI S T v 1. 1. Palliati ve l ocal t hera p y t o lesi o ns ca usi n g he m o pt ysis 
ma y als o be per mitte d pri or t o disc o nt i n uati on of st u d y  tr e at me nt i n partici pa nts w h o d o n ot ha ve 
e vi de nce of  overall cli nical or ra di o gra p hic pr o gressi o n per R E CI S T v 1. 1, pr o vi de d t hat t he lesi o ns 
u n der g o i n g palliat i ve l ocal thera p y are n ot t he o nl y sites of  meas ura ble di sease a n d t he case is 
di sc usse d wit h a n d a p pr o ve d b y t he B M S Me dical M o nit or.
Parti cipa nts re q uiri n g palliat i ve l ocal t hera p y s h o ul d be e val uate d f or o bj ect i ve e vi de nce of disease 
pr o gressi o n pri or t o t he i nit iati on of s uc h t hera p y,  partic ularl y if t he m ost rece nt t u m or assess me nt 
was m o re t ha n 4 wee ks pri or t o t he start of  local  thera p y. If pr o gressi o n per R E CI S T v 1. 1 is 
i de ntifie d o n a n y t u mor assess me nts pri or t o t he i nitiati on of  palliat i ve l ocal t hera p y, t he n 
parti ci pa nts m u st eit her di sc o nti n ue st u d y dr u g treat me nt or t he y must me et criteria t o c o nt i n ue 
treat me nt be y o n d pr o gressi o n (Sect i on 8. 1. 2 ) i n or der t o res u me i m m u n ot hera p y after palliat i ve 
l ocal t hera p y. If ra dio gra p hic pr o gressi o n per R E CI S T v 1. 1 is i de ntifie d pri or t o t h e i ni tiat i on of 
palliat i ve l ocal t hera p y, sit es m u st re q uest a BI C R fr om t he t hir d-part y  ra diol o g y  ve n d or 
(Secti o n 5. 1. 5 ). H o we ver, t he i nitiati on of palliat i ve l ocal t hera p y nee d n ot be dela ye d t o a wait t he 
assess me nt b y t he BI C R.
T he p ote nti al f or o verl a p pi n g t o xicities wi t h ra di ot hera p y an d i m m u n ot hera p y curre nt l y is n ot 
k n o w n; h o we ver, a nec d otal data s u g gest t hat it is t olera ble. As c o nc urre nt ra diot hera p y  an d t he 
i m m u n ot hera p y re gi me ns e val uate d i n t his st u d y ha ve n ot bee n f or mall y e val uate d, w he ne ver 
palliat i ve radi ot h era p y is re q uir e d for a t u m or l esio n , t he n i m m u n ot hera p y s h o uld be wi t h hel d f or 
at least 1 wee k bef ore, d uri n g, a n d 1 wee k after ra diati o n. Partici pa nts s h o ul d be cl osel y m o nit ore d 
f or a n y p ote nti al t o xicit y duri n g a n d after recei vi n g ra diot h era p y, a nd A Es s h o uld res ol ve t o 
Gra de ≤1 pri or t o res u mi n g i m m u n ot hera p y .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
7. 8 
Tr e at m e nt Aft er t h e E n d of t h e St u d y
At  the e n d of  the st u d y, B M S will n ot c o nt i n ue t o pr o vi de B M S -s u p plie d st u d y treat me nt t o 
parti ci pa nts/i n vesti gat ors u nless B M S c h o oses t o e xte n d t he st u d y. T he i n vesti gat or s h o ul d e ns ure 
t hat t he partici pa nt recei ves a p pr o priate sta n dar d of care t o treat t he c o n dit i on u n der st u d y .
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 treat me nt if an y o f the f o ll owi n g 
occ ur: a) t he st u d y is ter mi nate d d ue t o safety c o ncer ns; b) t he de vel o p me nt of  ni v ol u ma b or 
r elat li ma b is ter mi nate d f or ot her reas o ns, i ncl u di n g, b ut n ot li mite d t o, lac k of efficac y a n d/ or n ot 
meet i n g t he 
st u d y 
objecti ves; 
c) 
t he 
parti ci pa nt 
ca n 
o btai n 
me d icati on 
fr om  
a 
g o ver n me nt -s p o ns ore d or pri vate healt h pr o gra m. I n all cases, B M S will f o ll ow l o c al  re g ulati ons.
8 
DI S C O N TI N U A TI O N C RI T E RI A
8. 1 
Di s c o nti n u ati o n F r o m St u d y Tr e at m e nt
All part ici pa nts w h o disc o nti n ue st u d y dr u g s h o uld c o mpl y  with pr ot oc ol -s pecifie d f oll ow- u p 
pr oce d ures as o utli ne d i n Ta ble 2 - 3. T he o nl y e xce ptio n t o t his re q ui re me nt is w he n a partici pa nt  
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 oses t he 
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 y c hiatric or p h ysical ill ness; see Sect i on 8. 2 ). If st u d y dr u g is di sc o nti n ue d pri or t o t he 
parti ci pa nt's c o m p leti o n of  the st u d y, t he reas o n f or disc o nt i n uati on m u st be d oc u m e nte d i n t he 
parti ci pa nt's me dical rec or ds a n d e ntere d o n t he a p pr o priate e C R F pa ge.
F or all parti ci pa nts, gl o bal  deterior ati o n of  healt h st at us re q uiri n g disc o nt i n uati on of  treat me nt 
wi t ho ut o bject 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 matic 
deteri or ati o n’ i n t he s o urce data a n d i n t he e C R F. T u m or assess me nts f or partici pa nts w h o 
di sc o nti n ue st u d y treat me nt wit h o ut ra di o gra p hic pr o gressi o n, c o nfir me d b y BI C R (Secti o n 5. 1. 5 ), 
s h o uld c o nti n ue as per pr ot oc ol  (r efer t o S e cti o n 2 ) u ntil ra dio gra p hic pr o gressi o n is deter mi ne d 
b y BI C R.
C he m ot h era p y d ose re d ucti o n is all o we d o n st u d y. A n y partici pa nt wit h 2 pri or d ose re d ucti o ns t o 
1 a ge nt w h o e x perie nces a t o xicit y t hat w o ul d ca use a t hir d d ose re d ucti o n m u st be disc o nt i n ue d 
fr om t hat a ge nt.
Parti cipa nts M U S T di sc o nti n ue I P f or a n y of the f oll o wi n g reas o ns:

Parti cipa nt’s re q uest t o st o p stu d y treat me nt. Partici pa nts w h o re q uest t o disc o nti n ue st u d y 
treat me nt will r e mai n i n t he st u d y an d m ust c o nti n ue t o be f oll owe d f or pr ot oc ol -s pecifie 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 partici pa nt s pecificall y with dra ws 
c o nse nt f or a n y f urt her c o ntact wit h hi m/ her or pers o ns pre vi o usl y a ut h orize d b y partici pa nt t o 
pr o vi de t hi s i nf or mati on . See Sectio n 8. 2 .)

A n y cli nical A E, lab orat or y  ab n or malit y, or i nterc urre nt ill ness w hic h, i n t he o pi ni o n of  the 
i n vesti 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 
parti ci pa nt .

Ter mi nat i on of t he st u d y  b y B M S.

L oss of a bilit y t o freel y pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v o l unt ar y i ncarcerati o n f or 
treat me nt of  either a ps yc hiatric or p h ysical (e g, i nfecti ous disease) ill ness. ( N ote: U n der 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
s pecific circ u msta nces a n d o nl y i n c o u ntries w here lo c al  re g ulat i ons per mit, a partici pa nt w h o 
has bee n i m pris o ne d ma y be per mitte d t o c o nti n ue as a partici pa nt. Strict c o n dit i ons a p pl y a n d 
B M S a p pr o val is re q uire d.)

Di sease pr o gressio n i n t he a bse nce of cli nical be nefit as deter mi ne d b y t he i n vesti gat or.

N o nc o m plia nce of  t he parti ci pa nt wit h pr ot oc ol -ma n date d pr oce d ures base d o n t he j u d g me nt 
a n d a gree me nt of b ot h t he i n vest i gat or a n d S p o ns or.

I n t he case of pre g na nc y, t he i n vesti gat or must i m me diatel y, wit hi n 2 4 h o urs of a ware ness of 
t he p re g na nc y, n otif y t he B M S Me dical M o ni t or/ desi g nee of  this e ve nt. T he st u d y treat me nt 
m ust 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, d ose ta peri n g if necessar y f or 
parti ci pa nt safet y) .
8. 1. 1 
I m m u n ot h er a p y D o s e Di s c o nti n u ati o n
I mm u n ot hera p y  treat me nt s h o uld be per m a ne ntl y di sc o nti n ue d per crit eria i n Ta ble 7. 4. 1 - 1 o n 
Secti o n 7. 4. 1 .

Di sc o nti n ue i m m u n ot hera p y for a n y  AE, l a b orat or y a b n or malit y, or int erc urre nt ill ness w hic h 
i n t he j u d g me nt of  t he i n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he partici pa nt wit h 
co nti n ue d  
ni v o l u ma b 
a n d  
relatli ma b 
d osi n g.  
F or  
disc o nt i n uati ons  
d ue  
t o 
ne utr o pe ni a/ ne utr o p hil c o u nt decrease d assesse d t o be relate d t o st u d y dr u gs b y t h e 
I n vesti gat or, a disc ussi o n s h o ul d ta ke place with t he B M S Me dical M o nit or ( or desi g nee) pri or 
t o disc ont i n uati on.

A n y e ve nt t hat lea ds t o dela y i n d osi n g lasti n g > 8 wee ks fr o m t he pre vi o us d ose re q uires 
di sc o nti n uati on of st u d y  dr u g, wit h t he fol l owi n g e xce pt i ons:

D osi n g dela ys t o all o w f or pr ol o n ge d ster oi d ta pers t o ma na ge dr u g -relate d A E are all o we d.

D osi n g dela ys lasti n g > 8 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 Me dical M o nit or ( or desi g nee).
T he assess me nt f or disc o nt i n uati on of  im m u n ot hera p y  sh o ul d be ma de se paratel y fr o m the 
assess me nt t o disc o nti n ue c he m ot hera p y.
Pri or t o re-i nitiati n g tr e at me nt i n a parti ci pa nt wi t h a dosi n g dela y lasti n g > 8 wee ks, t he B M S 
Me dical M o ni t or ( or desi g nee) 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 de laye d. Peri o di c 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 nti n ue e ver y 6 wee ks or m ore fre q ue ntl y if cli nicall y in dicate d d uri n g s uc h d osi n g 
d el a ys.
Refer t o t he Sc he d ule o f Acti vities f or data t o be c ollecte d at t he ti me of treat me nt disc o nti n uati on 
a n d f o ll ow- u p a n d f or a n y  furt her e val uat i ons t hat ca n be c o m p lete d.
I n t he case of pre g na nc y, t he i n vesti gat or must i m me diatel y, wit hi n 2 4 h o urs of a ware ness of t he 
pre g na nc y, n otif y  the B M S Me dical M o ni t or/ desi g nee of  this e ve nt. I n m ost cases, t he st u d y 
treat me nt will be p er m a ne nt l y disc o nti n ue d i n a n a p pr o priate ma n ner (e g, d ose ta perin g if 
necessar y  for parti ci pa nt safet y) . Refer t o  Sectio n 9. 2. 5 Pre g na nc y. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
All partici pa nts w h o disc o nt i n ue st u d y treat me nt s h o ul d c om p l y with pr ot oc ol -s pecifie d f oll ow- u p 
pr oce d ures as o utli ne d i n Secti on 2 . T h e o nl y e xc e ptio n t o t his re q ui re me nt is w h e n a p arti ci pa nt 
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 oses t he 
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 hiatric or p h ysical ill ness).
If st u d y treat me nt is disc o nti n ue d pri or t o t he partici pa nt’s c om p leti on of t he st u d y , t he reas o n f or 
t he di sc o nti n uati on m ust be d o c u m e nte d i n t he pa rtici pa nt’s me dical rec or ds a n d e ntere d o n t he 
a p pr o priate e C R F pa ge.
8. 1. 2 
C h e m ot h er a p y D o s e Di s c o nti n u ati o n
E xce pt w here s pecifie d bel o w, c he mot h era p y dr u gs i n t he P D C T re gi me n or p e m etre xe d s h o uld 
be disc o nt i n ue d f or a n y of t he f o ll owi n g reas o ns:

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 t est a b n or malit y t hat meets t he f oll owi n g criteria re q uires 
di sc o nti n uati on:

A S T or A L T > 5 -1 0 × U L N f or > 2 wee k s

A S T or A L T > 1 0 × U L N

T B > 5 × U L N

C o nc urre nt A S T or A L T > 3 × U L N a n d T B > 2 × U L N

A n y dr u g -relate d A E w hic h rec urs after 2 prior d ose re d ucti o ns f or t he sa me dr u g-r elate d A E 
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 reactio n. T he dr u g n ot fel t t o be relate d t o 
t he h y perse nsit i vity reactio n or i nf usi o n  reactio n m a y  be c o nti n ue d.

A n y Gra d e 4 dr u g-r elate d A E w hic h t he i n vesti gat or dee ms is i na p pr o priate t o be ma na ge d b y 
d ose re d ucti o n(s) re q uires disc o nt i n uati on of t he dr u g(s) felt t o 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 ve nt t hat l ea ds to dela 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 pre vio us 
d ose re q uires disc o nt i n uati on of s uc h 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 > 8 wee ks fr o m t he pre vi o us d ose t hat occ ur f or n o n- dr u g -relate d reas o ns 
ma y be all o we d if a p pr o ve d b y t he B M S Me dical M o nit or. Pri or t o re-i nitiati n g treat me nt i n a 
parti ci pa nt wit h a d o si n g dela y lasti n g > 6 wee ks, t he B M S Me di c al Mo ni t or m u st be c o ns ulte d. 
P eri o dic st u d y  visits to assess safet y a n d la b orat or y st u dies s h o ul d als o c o nti n ue e ver y 6 wee ks 
or m 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 E, lab orat or y  ab n or m alit y, or i nterc urre nt ill ness w hic h, i n t he j u d g me nt of  the 
i n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he partici pa nt wit h c o nti n ue d PD C T d osi n g. 
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 m ot hera p y dr u gs bei n g a d mi nistere d t o 
a n y gi ve n partici pa nt f or a d dit i onal g ui da nce o n d ose disc o nti n uati o n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
I n parti ci pa nts f or w h o m it was i n dicate d t hat ma i nte na nce pe metre xe d t hera p y wo ul d be 
a d mi nistere d, 4 c ycles of  che m ot hera p y s h o uld be gi ve n pri or t o starti n g t he ma i nte na nce 
treat me nt. H o we ver, partici pa nts w h o e x perie nce Gra de 4 treat me nt -relate d he mat ol o gi c t o xicit y 
or Gra de 3 treat me nt -relate d n o n-he mat ol o gic t o xicit y ma y start ma i nte na nce t hera p y after 
 of  che m ot hera p y. T he nat ure a n d gra de of  the t o xicit y must be clearl y not e d a n d t he 
Me dical M o nit or m ust be n otifie d.
N ote: If t he i n vesti gat or is u na ble t o deter mi ne w het her a n A E is d ue t o i m m u n ot hera p y or P D C T, 
t he n all dr u gs m ust be disc o nt i n ue d. T he assess me nt f or disc o nti n uati o n of i m m u n ot hera p y s h o ul d 
be ma de se paratel y fr o m the assess me nt ma de f or di sc o nti n uati on of  PD C T. If crit eria f or 
di sc o nti n uati on of  im m u n ot hera p y  is met  before t he 4 P D C T c ycles ha ve bee n co m plete d, t he n 
P D C T m a y c o nt i n ue u ntil 4 c ycles ha ve bee n c o m plete d.
A partici pa nt i n an y ar m w h o is disc o nti n ue d fr om c he m ot hera p y tr e at me nt d ue t o t o xicities relate d 
t o c he m ot hera p y o nl y will re mai n o n t he st u d y a n d c o ntin ue t o recei ve i m m u n ot hera p y .
8. 1. 3 
I m mu n ot h er a p y 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
Acc u m ulat i n g e vi de nce i n dicates a mi n orit y of  partici pa nts 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.2 7
Parti cipa nts treate d wit h i m m u n ot hera p y  ( ni v ol u ma b [ ± relatli ma b]) will be per mitte d t o c o nti n ue 
treat me nt be y o n d i nitial R E CI S T v 1. 1 -defi ne d P D, assesse d b y t he i n vesti gat or as l on g as t he y 
meet t he f o ll owi n g cri teria:

I n vesti gat or-assesse d cli nical be nefit

T ol era nce of st u d y treat me nt

Sta bl e perf or ma nce stat us

Treat me nt be y o n d pr o gressi o n will n ot dela y a n i m mi ne nt i nter ve 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 met astases)

Parti cip a nt pr o vi des wri tte n i nf or me d c o nse nt pri or t o recei vi n g a d ditio n al i m m u n ot hera py 
treat me nt. All ot her ele me nts of  the ma i n c o nse nt i ncl u di n g descri pt i on of  reas o na bl y 
f oreseea ble ris ks or disc omf o rts or ot her alter nati ve treat me nt o ptio ns will st ill a p pl y.
Ra di o gra p hic assess me nt/sca n(s) s h o uld c o nti n ue i n acc or da nce wi t h the Secti o n
2 Sc he d ule of 
Act i vities f or t he d urati o n of  the treat me nt be y o n d pr o gressi o n a n d s h o uld be s u b mitt e d t o t he 
ce ntral ima gi n g ve n d or . T he assess me nt of  cli nical be nefit s h o uld be bala nce d b y cli nical 
j u d g me nt as t o w het her t he parti ci pa nt is cli nicall y deteri orati n g a n d u nli kel y t o recei ve a n y be nefit  
fr om c o nt i n ue d treat me nt wit h i m m u n ot hera p y.
If t he i n vesti gat or feels t hat t he i m m u n ot hera p y treate d partici pa nt c o nt i n ues t o ac hie ve cli nical 
be nefit b y  c o nti n ui n g treat me nt, t he partici pa nt s h o uld re mai n o n t he tri al a nd c o nti n ue t o recei v e 
m o nit ori n g acc or di n g t o t he Sc he d ule o f Act i vities, Ta ble 2- 2 .
F or t he partici pa nts w h o c o nt i n ue i m m u n ot hera 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 nal 1 0 % 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 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
fr om t i me of i nitial P D. T his i ncl u des a n i ncrease i n t he s u m of diameters of all tar get lesi o ns a n d/ 
or t he di a meters of  ne w meas ura ble lesi ons c o m p are d t o t he ti me of  init ial P D. I mm u n ot hera p y 
treat me nt s h o uld be disc o nt i n ue d per ma ne ntl y u p o n d oc u me ntati o n of f urt her pr o gressi o n.
Ne w lesi ons are c o nsi dere d meas urea 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 ol o gical  ly 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- meas urea ble at t he ti me of  init ial pr o gressi o n ma y 
bec o me meas urea ble a n d t heref ore i ncl u de d i n t he t u m or b ur de n if t he l o n gest di a meter i ncreases 
t o at  least 1 0 m m (e xce pt f or pat h ol o gical l y m p h n o des, w hic h m u st 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 i n t ot al tu m or b ur de n b y 1 0 % is s olel y due t o 
incl usi o n of  ne w lesio ns w hic h bec o me me as ura ble, t hese ne w lesi ons m ust de m o nstrate a n 
a bs o l ute i ncrease of at least 5 m m.
8. 1. 4 
P o st - st u d y Tr e at m e nt St u d y F oll o w-u p
I n t his st u d y, O R R a n d P F S are ke y efficac y e n d p o i nts. P os t-stu d y f oll ow- u p is of  critical 
i m p orta nce a n d is esse ntial t o preser vi n g p arti ci pa nt safety a n d t he i nte grit y of t he st u d y. 
Parti cipa nts w h o disc o nt i n ue st u d y treat me nt m u st c o nti n ue t o be f oll owe d (i n t his st u d y or a 
r ollo ver st u d y ) for c ollecti o n of  res p o nse o utc o me a n d/ or s ur vi val foll o w -u p data as re q ui re d a n d 
i n li ne with  Secti o n 5 u nt il deat h or t he c o ncl usi o n of t he st u d y.
If pr o gressi o n as per BI C R has n ot occ urre d bef ore treat m e nt disc o nti n uatio n, t u m or assess me nts 
s h o uld c o nt i n ue acc or di n g t o t he Sc he d ule of Acti vities, Ta ble 2- 3 .
Parti cipa nts s h o uld u n der g o  
 of safety f oll o w-u p p ost last d ose of st u d y dr u g.
 
 
 
8. 2 
Di s c o nti n u ati o n F r o m t h e St u d y
Parti cipa nts w h o re q uest t o disc o nti n ue st u d y treat me nt will re mai n i n t he st u d y a n d m ust c o nti n ue 
t o be f oll owe d f or pr ot oc ol -s pecifie d f oll ow - u p pr oce d ures. T he o nl y  exce pt i on t o t his is w he n a 
parti ci pa nt s pecifically 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 partici pa nt t o pr o vi de t his i nf or mat i on.
If a partici pa nt 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 all ot h er 
pers o ns pre vi o usl y a ut h o rize d b y t he parti ci pa nt t o pr o vi de t his i nf or mati on, t he f oll owi n g nee ds 
t o be met.

Parti cipa nts s h o uld n otif y  the i n 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, w he ne ver 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 d ical rec or ds b y t he 
i n vesti gat or, as t o w het her t he wit h dra wal is fr o m f urt her treat me nt wit h st u d y tr e at me nt o nl y 
or als o fr o m st u d y pr oce d ures a n d/ or p ost -treat me nt st u d y foll o w -u p, 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.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b

I n t he e ve nt t hat vit al stat us ( w het her t he partici pa nt is ali ve or dea d) is bei n g meas ure d, 
p u blicl y  availa ble i nf or mati on s h o uld be use 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 wit h l ocal la w.

If t he parti ci pa nt wit h dra ws c o nse nt f or discl os ure of  fut ure i nf or mati on, t he s p o ns or ma y 
retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of c o nse nt.
8. 2. 1 
Tr e at m e nt aft er Di s c o nti n u ati o n of t h e St u d y
At  the c o nclusi o n  of t he st u d y, parti ci pa nt s re mai ni n g o n st u d y treat me nt w h o c o ntin ue t o 
d e m o nstrate cli nical be nefit ma y be eli gi ble t o recei ve B M S s u p plie d st u d y dr u g treat ment . St u d y
dr u g treat me nt w o ul d be pr o vi de d via a r oll over st u d y re q uiri n g a p pr o val by res p o nsi ble healt h 
a ut h orit y a n d I R B/ E C or t hr o u g h a n ot her mec ha nis m at t he discreti o n of B rist ol M yers S q ui b b. 
8. 3 
L o st t o F oll o w - u p

All reas o na ble efforts m u st be ma de t o l ocate partici pa nts t o deter mi ne a n d re p ort t heir o n g oi n g 
stat us. T his i ncl u des f oll ow- u p wi t h pers o ns a ut h orize d b y t he partici pa nt.

L ost t o f oll o w -u p is defi ne d b y  t he i na bilit y t o reac h t he partici pa nt after a mi ni m u m of t hree
d oc u m e nte d p h o ne calls, faxes, or e mails as well as lac k of  res p o nse b y parti ci pa nt t o o ne 
r e gistere d mail letter. All atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or ds.

If it is deter mi ne d t hat t h e partici pa nt has die d, t he sit e will use per missi ble l ocal met h o ds t o 
o btai n date a n d ca use of deat h.

If i n vesti gat or’s use of thir 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 partici pa nt’s i nf or me d c o nse nt, t he n t he i n vesti gat or ma y use a 
S p o ns or -retai ne d t hir d-part y  re prese ntati ve t o assist sit e staff wi t h obt ai ni n g part ici pa nt’s 
c o ntact i nf or mati o n or ot her p u blic vit al stat us data neces sar y to c o m p lete t he f oll ow- u p 
p orti o n of  t he st u d y. 

T he si t e st aff a nd re prese ntati ve will c o ns ul t p u blicl y a vaila ble s o urces, s uc h as p u blic healt h 
r e gistries a n d data bases, i n or der t o o btai n u p date d c o ntact i nf or mati o n.

If after all atte m pts, t he partici pa nt re mai ns l ost t o f oll 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 vest i gat or s h o ul d be re p orte d a n d d oc u me nte d i n t he partici pa nt’s me dical 
rec or ds.
9 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S

St u d y  pr oce d ures a n d ti mi n g are s u m marize d i n t he Sc he d ule of Acti vities. 

Pr ot oc ol  wai vers or e xe m pti ons are n ot all o we d.

All i m me diate safety c o ncer ns m ust be disc usse d wi t h the S p o ns or i m me diatel y u p o n 
occ urre nce or a ware ness t o deter mi ne if t he parti cipa nt s h o ul d c o nti n ue or disc o nti n ue 
treat me nt.

A d here nce t o t he st u d y desig n re q uire me nts, i ncl u di n g t hose s pecifie d i n t he Sc he d ule of  
Act i vities, is esse ntial a n d re q uire d f or st u d y c o n d uct.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b

All 
scree ni n g e val uat i ons m ust 
be c o m p lete d a n d re vie we d t o c o n firm 
t hat p ote ntial 
parti ci pa nts meet all eli gi bilit y cri teria bef ore ra n d o mizati on. T he i n vest i gat or will mai ntai n a 
scree ni n g l og t o rec or d details of all partici pa nts scree ne d a n d t o c o nfi r m eli gi bilit y or rec or d 
reas o ns f or scree ni n g fail ure, as a p plica ble.

Pr oce d ures c o n d ucte d as part of  the partici pa nt’s r o uti ne cli nical ma na ge me nt (e g, bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of  inf or m e d c o nse nt ma y be utilize d f or scree ni n g or baseli ne 
p ur p oses pr o vi de d t he pr oce d ure meets t he pr ot oc ol -defi ne d crit eria a n d has bee n perf or m e d 
wi t hi n t he ti mefra me defi ne d i n t he Sc he d ule of Acti vities.

I ma ges will be s u b mitt e d t o a c e ntr al ima gi n g v e n d or f or BI C R at a n y time d uri n g t he st u d y. 
Pri or t o sca n ni n g first partici pa nt, sites s h o uld be q ualifie d a n d u n dersta n d t he i ma ge 
ac q uisit i on g ui deli nes a n d s u b missi on pr ocess as o utli ne d i n t he C A 2 2 4 1 0 4 I ma gi n g Ma n ual 
pr o vi de d b y t he ce ntral i ma gi n g ve n d or.
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 perf or m e d as 
cli nicall y i n dicate d or t o c o m p l y with l ocal re g ulat i ons. La b orat or y  to xi cities (e g, s us pecte d 
dr u g -i n d uce d li ver e nz y me e val uat i ons) will be m o nit ore d d uri n g t he f oll ow- u p p hase via o n -
sit e/lo c al  la bs u nt il all st u d y dr u g-r elate d t o xicities res ol ve, ret ur n t o baseli ne, or are de e me d 
irre versi ble.
If a partici pa nt s h o ws p ul m o nar y-relate d sig ns ( h y p o xi a, fe ver) or s y m pt o ms (e g, d ys p nea, c o u g h, 
fe ver) c o nsiste nt wit h p ossi ble p ul m o nar y  AEs, t he partici pa nt s h o ul d be i m me diatel y e val uate d 
t o r ule o ut p ul m o nar y t o xicity,  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 
alg ori t h m in t he B M S -9 8 6 0 1 6 (relat li ma b) a n d B M S-9 3 6 5 5 8 ( ni v o l uma b) I Bs.
S o m e o f the 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 F. T he y 
are i nte n de d t o be use d as safety m o nit or i 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.
9. 1 
Effi c a c y A s s e s s m e nt s
9. 1. 1 
I m a gi n g A s s e s s m e nt f or t h e St u d y
I ma ges will be s u b mitte d t o a ce ntral i ma gi n g ve n d or f or BI C R at a n y ti me d uri n g t he st u d y. Pri or 
t o sca n ni n g first partici pa nt, sites s h o uld be q ualifie d a n d u n dersta n d t he i ma ge ac q uisitio n 
g ui deli nes a n d s u b missi on pr ocess as o utli ne d i n t he I ma gi n g Ma n ual pr o vi de d b y t he ce ntral 
i ma gi n g ve n d or. Scree ni n g a n d o n -st u d y ima ges s h o ul d be ac q uire d as o utli ne d i n Secti o n 2
Sc he d ule of Act i vities.
T u m or assess me nts at  ot her ti me p o i nts ma y be perf or m e d if cli nicall y i n dicate d a n d s h o uld be 
s u b mitte d t o t he ce ntral ima gi n g ve n d or as s o o n as p ossi ble. U nsc he d ule d C T/ M RI s h o uld be 
s u b mitte d t o ce ntral i ma gi n g ve n d or. X- ra ys a n d b o ne sca ns t hat clearl y de m o n strate i nter va l 
pr o gressi o n o f disease, f or e xa m ple m ost c o m m o nl y  as u ne q ui v ocal lesio n s t hat are u n mista ka bl y 
ne w si nce t he pri or C T/ M RI, s h o ul d be s u b mitte d t o ce ntral i ma gi n g ve n d or. Ot her wise, t he y do 
n ot nee d t o be s u b mitte d ce ntrall y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
9. 1. 1. 1 
M et h o d s of M e a s ur e m e nt
C o ntrast -e n ha nce d C T of  t he c hest, a b d o me n, pel vis, a n d all ot h er k n o w n a n d/ or s us pecte d sit es 
of  disease s h o uld be p erf or m e d f or t u mor assess me nts. I ma ges s h o uld be ac q uire d wi t h slice 
t hic k ness of 5 m m or less wit h n o i nter ve ni n g ga p (c o nti g u o us). E ver y att e mpt s h o ul d be ma d e t o 
i ma ge eac h partici pa nt usi n g a n i de ntical ac q uisiti on pr ot oc ol o n t he sa me sca n ner f or all i ma gi n g 
ti me p oi nts. 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 nt s a n d t u mor res p o nse t o g ui de 
o n g oi n g st u d y treat me nt deci sio ns will be assesse d b y t he i n vesti gat or usi n g t he R E CI S T v 1. 1 
criteria.
If a partici pa nt has a c o ntrai n dicat i on f or C T I V c o ntrast, t he n a n o n -c o ntrast C T of t he c hest a n d 
a c o ntrast-e n ha nce d M RI of  the a b d o me n, pel vis, a n d ot her k n o w n/s us pecte d sites of  disease 
s h o uld be o btai ne d.
If a partici pa nt has a c o ntrai n dicati o n f or b ot h M R a n d C T I V c o ntrasts, t he n a n o n-c o ntrast C T of 
t he c hest a n d a n o n- c o ntrast M RI of  the a b d o me n, pel vis, a n d ot her k n o w n/s us pecte d sites of 
di sease s h o uld be o btai ne d. 
If a parti ci pa nt has a c o nt rai n dicati on f or M RI 
(e g, i nc om pati ble pace ma ker) i n a d ditio n t o 
c o ntrai n dicat i on t o C T i ntra ve n o us c o ntrast, t he n a n o n -c o ntrast C T of t he c hest, a b d o me n, pel vis, 
a n d ot her k n o w n/s us pecte d sites of disease is acce pta ble.
Use of C T c o m p o ne nt of a p ositr o n e missi o n t o m o gr a p h y ( P E T)-C T sc a n ner: C o m bi ne d 
m o dali t y sca n ni n g s uc h as wi t h PE T -C T is i ncreasi n gl y use d i n cli nical care a n d is a 
m o dali t y/tec h n ol og y  t hat is i n ra pi d e v ol uti on; t heref ore, t he rec o m me n dat i ons o utli ne d here ma y 
c ha n ge rat her q uic kl y wi t h time. At  prese nt, l ow d ose or atte n uati o n c orrectio n C T p orti o ns of  a 
c o m bi ne d P E T -C T are of  li mite d use i n a nat o micall y base d efficac y assess me nts a n d it is t heref ore 
s u g geste d t hat t he y s h o ul d n ot be s u bst itute d f or de dicate d dia g n ostic c o ntrast -e n ha nce d C T sca ns 
f or a nat o micall y base d R E CI S T v 1. 1 meas ure me nts. H o we ver, if a sit e ca n d oc u m e nt t hat t he 
C T perf or me d as part of  a PE T -C T is of  id e nti cal dia g n osti c q uali t y to a di a g n ostic C T 
( wit h I V a n d or al  co ntrast), t he n t he C T p orti o n of  the P E T -C T ca n be use d f or R E CI S T v 1. 1 
meas ure me nts. N ote, h o we ver, t hat t he P E T p orti o n of  the C T i ntr o d uces a d ditio n al  data w hic h 
ma y bias a n i n vest i gat or if it is n ot r o uti nel y or seriall y p erf or me d.
B o ne sca n or P E T sca n is n ot a de q uate f or assess me nt of R E CI S T v 1. 1 res p o nse i n tar get lesi o ns. 
I n selecte d circ u msta nces w here s uc h m o dalities are t he s ole mo d ali t y use d t o assess certai n n o n-
tar get or ga ns, t h ose n o n-tar get or ga ns ma y be e val uate d less fre q ue ntl y. F or e xa m ple, b o ne sca ns 
ma y nee d t o be re peate d o nl y w he n c o m p lete res p o nse ( C R) is i de ntifie d i n tar get disease or w he n 
pr o gressi o n i n b o ne is s us pecte d.
B o ne sca ns ma y  be c ollecte d per lo c al  sta n dar ds, as cli nicall y in dicate d.
M RI of
brai n ( wit h o ut a n d wit h c o ntrast) s h o ul d be ac q uire d as o utli ne d i n Secti o n 2 ( Sc he d ule of 
Act i vities). C T of  the brai n ( wit h o ut a n d wi th c o nt rast) ca n be per f or me d if M RI is c o ntrai n dicate d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 1 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
9. 1. 1. 2 
I m a gi n g a n d Cli ni c al A s s e s s m e nt
T u m or assess me nts s h o uld c o nt i n ue as per t he pr ot oc ol -defi ne d i ma gi n g sc he d ule re gar dless if 
d osi n g is dela ye d or disc o nti n ue d. C ha n ges i n t u m or me as ure me nts a n d t u mor res p o nses will  be 
assesse d b y t he sa me i n vesti gat or or desi g nee usi n g R E CI S T v 1. 1 criteria. I n vest i gat ors will re p ort 
t he n u m ber a n d size of  ne w lesi o ns t hat a p pear w hile o n stu d y. T he ti me p oi nt of  tu m or assess me nts 
will be re p orte d o n t he e C R F base d o n t he i n vesti gat or’s assess me nt usi n g R E CI S T v 1. 1 criteria 
(see A p pe n di x 5  f or s pecifics of  RE CI S T v 1. 1 criteria t o be use d i n t his st u d y). Assess me nts of 
P R a n d C R m u st be c o nfir me d at least 4 wee ks ( 2 8 da y s) after i nitial res p o nse. A best o verall 
res p o nse of S D re q uires a mi ni m u m of 3 5 da ys o n st u d y fr om r a n d o mizat i on t o t he date of  the first 
i ma gi n g assess me nt.
9. 1. 1. 3 
BI C R C o nfir m ati o n of Pr o gr e s si o n 
Si tes s h o uld s u b mit all sca ns t o t he ce ntral i ma gi n g ve n d or o n a r olli n g basis t hr o u g h o ut t he 
d urati o n of t he st u dy.  BI C R of  sca ns will occ ur o n a r olli n g basis, bli n de d t o treat me nt ar m, cli nica l 
data, a n d i n vest i gat or assess me nt of s u b mitte d sca ns. W he n pr o gressi o n per R E CI S T v 1. 1 criteria 
is assesse d b y t he i n vesti gat or, t he sit e will i nf or m t he ce ntral i ma gi n g ve n d or i n or der f or BI C R 
assess me nt of pr o gressi o n t o be perf or me d. T he BI C R will be c o m p lete d, a n d t he res ults pr o vi de d 
t o t he sit e as s pecifie d i n t he i ma gi n g ve n d or d oc u me nts, pr o vi de d t here are n o pe n di n g i ma gi n g 
q ueri es t o t he site. All details o n t he timeli nes a n d ass ociate d pr ocess re q uire me nts will be o utli ne d 
i n t he I ma gi n g Ma n ual.
Parti cipa nts w h ose pr o gressi o n is n ot c o nfir me d b y t he BI C R will be re q uire d t o c o nt i n ue t u mor 
assess me nts (if cli nicall y feasi ble) acc or di n g t o t he pr ot oc ol -s pecifie d sc hed ule or s o o ner if 
cli nicall y i n dicate d. Als o, if parti ci pa nts di sc o nti n ue treat me nt wit h o ut ra di o gra p hic pr o gressi o n, 
t u mor assess me nts will c o nti n ue acc or di n g t o t he pr ot oc ol -s pecifie d sc he d ule, as n ote d i n 
Secti o n 2 ( Sc he d ule of Acti vities) u ntil pr o gressi o n has bee n assesse d b y BI C R.
All st u d y tr e at me nt d e cisio n s will be base d o n t he i n vesti gat or’s assess me nt of t u mor i ma ges a n d 
n ot o n t he BI C R assess me nt.
9. 1. 2 
P ati e nt -r e p ort e d O ut c o m e s
T he e val uati o n of P R Os is a n i ncreasi n gl y i m p orta nt as pect of cli nical efficac y i n o nc o l og y  trials. 
S uc h data pr o vi de a n u n dersta n di n g of t he i m pact of treat me nt fr o m t he partici pa nt’s pers pect i ve 
a n d of fer i nsi g hts i nt o partici pa nt e x perie nce t hat ma y n ot be ca pt ure d t hr o u g h p h ysicia n re p orti n g.
Parti cipa nts will be as ke d t o c o m plete t he 
 
 t he P GI S, a n d t he P GI C at desi g nate d stu d y visit s. Effect i ve wi t h Pr ot oc ol 
A me n d me nt 7, P R O assess me nts will be c o m p lete d pri or t o d osi n g o n Da y  1 of eac h c ycle fr om 
C ycle 1 ( wi t h t he e xce pt i on of  t he P GI C, w hic h is first co m plete d d uri n g C ycle 2) t hr o u g h C y cl e 
1 0 a n d t he n e ver y ot her c ycle u nt il C ycle 3 6 . F or par tici pa nts i n Part 2 o nl y , assess me nts will 
c o nti n ue o nce e ver y 6 cycles fr om C ycle 3 6 u nt il t he e n d of  the treat me nt. Parti cipa nts i n b ot h 
Part s 1 a n d 2 will be as ke d t o c o m plete P R Os d uri n g fol l ow -u p Visits 1 a n d 2 d uri n g t he l o n g -ter m 
f oll ow- u p peri o d. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he P R Os s h o ul d be c o m p lete d i n t he f oll owi n g or der:
2)
P GI S
3)
P GI C (e xce pt f or C 1 D 1 w he n it is n ot c o m plete d)
 
W he n p ossi ble, partici pa nts s h o ul d c o m plete t he P R O meas ures pri or t o a n y  ot her assess me nts or 
st u d y pr oce d ures w hen t he y are bei n g a d mi nistere d d uri n g st u d y visit s. T he q uesti o n naires will be 
pr o vi de d i n t he parti ci pa nt’s preferre d lan g ua ge. If e xce pt i onal circ u msta nces precl u de t he 
c o nti n ue d a d mi nistrati o n of  meas ures usi n g pl a n ne d m o dalit ies, t he n alter nate a d mi nist ratio n 
met h o ds m a y be re q uire d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
9. 1. 2. 4 
P GI S a n d P GI C
T he P GI S a n d P GI C will be i ncl u de d as a d d iti onal  ex pl orat or y  en d p o i nts. T he P GI S is a si n gle 
ite m that assesses parti ci pa nts’ perce pti o ns of  overall se verit y of ca ncer s y m pt o ms f or t he last 
7 d a y s wi t h res p o nse o pti o ns ra n gi n g fr o m “ n o ne” t o “ ver y se vere.” T he P GI C assesses 
parti ci pa nts’ perce pt io ns of  overall c ha n ge i n s y m pt o m se verit y si nce bef ore treat me nt a n d 
assesses w het her or n ot partici pa nts feel suc h a c ha n ge is mea ni n gf ul. Res p o nse o pti o ns f or t his 
ite m ra n ge fr o m “ m uc h w orse” t o “ m uc h i m pr o ve d.” Data c o llecte d via t he P GI S a n d P GI C will
be use d as a nc h or m eas ures t o f urt her c o nfir m t hres h ol ds f or me a ni n gf ul c ha n ge f or t he N S C L C -
S A Q.
9. 2 
A d v er s e E v e nt s
T he defi nit i ons of a n A E or S A E ca n be f ou n d i n A p pe n di x 3 .
A Es will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he 
parti ci pa nt's le gall y a ut h orize d re prese ntati ve). 
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u m e nt i n g, a n d re p orti n g 
e ve nts t hat meet t he defi nit i on o f a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g u p A Es t hat 
are seri o us, c o nsi dere d relate d t o t he st u d y treat me nt or t he st u d y, or t hat ca use d t he partici pa nt t o 
di sc o nti n ue bef ore c o m pleti n g t he st u d y. 
I M A Es are A Es c o nsiste nt wit h a n i m m u ne-me diate d mec ha nis m or i m m u ne -me diate d c o m p o ne nt 
f or w hic h n o n- i nfla m mator y  etiol o gi es (e g, i nfecti o n or t u m or pr o gressi o n) ha ve bee n r ule d o ut. 
I M A Es ca n i ncl u de e ve nts wit h a n alter nate etiol o g y  w hic h were e xacer bate d b y t he i n d ucti on of 
a ut oi m m u nit y.  I nf or mati on s u p p orti n g t he assess me nt will be c ollecte d o n t he partici pa nt ’s e C R F.
Use C T C A E v 5 defi nit i ons a n d gra di n g f or safet y re p orti n g of  all A Es a n d S A Es o n t he case 
re p orti n g f or m.
C o nt acts f or S A E re p orti n g s pecifie d i n A p pe n di x 3.
9. 2. 1 
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E I nf or m ati o n
A p pe n di x 1  i n t he I B re prese nts t he Refere nce Safet y I nf or mat i on t o deter mi ne e x pecte d ness of 
S A Es f or e x pe dite d re p orti n g.
All A Es a n d S A Es m ust be c ollecte d fr o m t he t i me of si g ni n g t he c o nse nt, i ncl u di n g t h ose t h o u g ht 
t o be ass ociate d wi t h pr ot oc ol-s pecifie d pr oce d ures a n d w ithi n  
 of  disc o nti n uati on of 
d osi n g. All S A Es a n d all A Es ( S A Es a n d n o n -serio us A Es) ass ociate d wit h c o nfir me d or s us pecte d 
S A R S -C o V - 2 i nfecti on m ust be c o llecte d fr o m t he d at e of t he parti ci pa nt ’s wri tte n c o nse nt u ntil 
 f oll owi n g disc o nt in uat i on of d osi n g. F or parti ci pa nts ra n d o mize d a n d ne ver treate d wit h 
st u d y dr u g, S A Es s h o uld be c ollecte d f or 3 0 da y s fr o m t he date of ra n d omizat i on.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he i n vesti gat or m u st re p ort a n y S A E t h at o c c urs after t hese ti me peri o ds a n d t hat is belie ve d t o 
be rela te d t o st u d y dr u g or pr ot oc ol-s pecifie d pr oce d ure (e g, a f oll o w-u p s ki n bi o ps y).

Me dical occ urre nces t hat be gi n bef ore t he start of st u d y treat me nt b ut after o btai ni n g i nf or me d 
c o nse nt will be rec or de d o n t he a p pr o priate secti o n of t he eC R F m o d ul e.

All S A E s will be rec or de d a n d re p orte d t o S p o ns or or desi g nee wi t hi n 2 4 h o urs , as in dicate d 
i n A p pe n di x 3 . 

T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or or desi g nee wi t hi n 2 4 h o urs
of u p date d i nf or mat i on bei n g a vaila ble.
I n vesti gat ors are n ot o bli gate d t o acti vel y see k A Es or S A Es i n f or mer st u d y partici pa nts. 
H o we ver, if t he i n vesti gat or learns of  a n y S AE, i ncl u di n g a deat h, at a n y time after a partici pa nt 
has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt reas o na bl y relate d t o t he st u d y 
treat me nt or st u d y partici pat i on, t he i n vest i gat or m ust pr o m ptl y n otif y t he S p o ns or.
T he met h o d of  eval uati n g a n d assessi n g ca usalit y of  AEs a n d S A Es a n d t he pr oce d ures f or 
c o mplet i n g a n d re p orti n g/tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe ndi x 3.
9. 2. 2 
M et h o d of D et e cti n g A E s a n d S A E s
A Es 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 p artici pa nt. Care s h o uld be ta ke n n ot t o i ntr o d uce bias w he n c ollect i n g A E a n d/ or 
S A Es. I n q uir y a b o ut s peci fic A Es s h o ul d be g ui de d b y cli nical j u d ge me nt i n t he c o nte xt of k n o w n 
A Es, w he n a p pr o priate f or t he pr o gra m or pr ot oc ol.
E ver y  AE m ust be assesse d b y t he i n vesti gat or wit h re gar d t o w het her it is c o nsi dere d i m m u ne 
me diate d. F or e ve nts w hic h are p ote nti ally i m m u ne me diate d, a d dit i onal i nf or mat i on will  be 
c ollecte d o n t he partici pa nt’s e C R F.
All n o nseri o us A Es ( n ot o nl y  th ose dee m e d t o be treat me nt relate d) s h o ul d be c ollecte d 
c o nti n u o usl y d uri n g t he scree ni n g p eri o d, treat me nt peri o d a n d f or a mi ni m u m of   
 
f oll owi n g disc o nt i n uati on of st u d y  treat me nt.
9. 2. 3 
F oll o w -u p of A E s a n d S A E s

N o nseri o us A Es s h o uld be f oll owe d t o r es olut i on or sta bilizat i on or re p orte d as S A Es if t he y 
bec o me s erio us (see A p pe n di x 3).

F o ll ow -u p is als o re q uire d f or n o nseri o us A Es t h at ca use i nterr u pti o n or disc o nt i n uati o n of  
st u d y tr e at me nt a n d f or t h ose prese nt at t he e n d of st u d y tr e at 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 nseri o us A E pa ge of 
t he C R F ( pa per or electr o nic). C o m plet i on of  su p pl e me ntal CR Fs ma y be re q ueste d f or A Es 
a n d/ or la b orat or y a b n or malities t hat are re p orte d/i de nt ifie d d uri n g t he c o urse of t he st u d y.
After t he i nit ial A E/ S A E re p ort, t he i n vest i gat or is re q uire d t o pr oacti vel y f oll ow eac h parti ci pa nt 
at s u bse q ue nt visit s/c o ntacts. All S A Es, n o n- s erio us A Es of  special i nterest (as defi ne d i n 
Secti o n 9. 2 ), a n d A Es ( S A Es a n d n o n- serio us A Es) ass ociate d wi t h co nf irme d or s us pecte d 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S A R S -C o V - 2 i nfecti on will be f oll owe d u nt il res olut i on, u ntil t he c o n ditio n sta bilizes, u ntil t h e 
e ve nt is ot her wise e x plai ne d, t he e ve nt is dee m e d irre versi ble, or u ntil t he parti ci pa nt is l ost t o 
f oll ow- u p (as defi ne d i n Sect i on 8. 3 ) or f or s us pecte d cases, u ntil S A R S-C o V -2 i nfect i on is r ule d 
o ut.
F urt her i nf or mat i on o n f o ll ow- u p pr oce d ures i s gi ve n i n A p pe n di x 3 .
9. 2. 4 
R e g ul at or y R e p o rti n g R e q uir e m e nt s f or S A E s

Pr o m pt n otificat i on b y t he i n vesti gat or t o t he S p o ns or of  SA Es is esse nt ial s o t hat le gal 
o bli gat i ons a n d et hic al res p o nsi bilit ies t o war ds t he safety of  partici pa nts a n d t he safety of  a 
pr o d uct u n der cli nical i n vesti gati o n are m et.

A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g S A Es or ot h er s pecific 
safety i nf or mati o n (e g, s u m mar y or listi n g of  SA Es) fr om t he S p o ns or will file it alo n g wi t h 
t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate, acc or di n g t o l ocal re q uire me nts.
S p o ns or or desi g nee will be re p orti n g A Es t o re g ulat or y aut h ori ties a n d et hics c o m mittees 
acc or di n g t o l ocal a p plica ble la ws i ncl u di n g E ur o pea n U ni o n  Cli nical Trials Re g ulati on 5 3 6/ 2 0 1 4
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. A S U S A R (s us pecte d, 
u ne x pecte d serio us a d verse reactio n) is a s u bset of S A Es a n d will be re p orte d t o t he a p pr o priate 
re g ulat or y a ut h orities a n d i n vesti gat ors f oll owi n g l ocal  a n d glo b al  g ui deli nes a n d re q uire me nts.
9. 2. 5 
Pr e g n a n c y
If, fol l owi n g i nitiati on of  the st u d y treat me nt, it is s u bse q ue ntl y disc o vere d t hat a partici pa nt is 
pre g na nt or ma y ha ve bee n pre g na nt at  the ti me of  st u d y ex p os ure, i ncl u di n g d uri n g at least 
7 m o nt hs after t he last d ose of c he m ot hera p y (a p plica ble t o paclita x el, na b-pacli ta xel, pe metre xe d,
a n d car b o plat i n) or 1 4 m o nt hs aft er t he last d ose of  cis plati n a n d 5 m o nt hs after t he last d ose of 
i m m u n ot hera p y, t he i n vesti gat or must i m me diatel y  notif y  t he B M S Me dical M o nit or/ desig nee of 
t his e ve nt a n d c o mplete a n d f or wa r d a Pre g na nc y Sur 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 wit h S A E re p orti n g pr oce d ures descri be d i n 
A p pe n di x 3.
If t he i n vesti gat or deter mi nes a p ossi ble fa v ora ble be nefit-ris k r atio t hat warra nts c o nti n u at i on of  
st u d y treat me nt or re-i nitiati on of  st u d y treat me nt, a disc ussi o n bet wee n t he i n vesti gat or a n d t he 
B M S Me dical M o nit or/ desi g nee m ust occ ur. 
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 veilla nce F or m.
A n y pre g na nc y t hat occ urs i n a fe male part ner of  a male st u d y partici pa nt s h o ul d be re p orte d t o 
S p o ns or or desi g nee. I n or der f or S p o ns or or desi g nee t o c o llect an y pre g na nc y s ur veilla nce 
i nf or mat i on fr om t he female part ner, t he female part ner m ust sig n a n I C F f or 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.
If a n y se x ual acti vit y (e g, va gi nal, a nal, oral ) has occ urre d bet wee n a ma le partici pa nt a n d a 
pre g na nt part ner(s) wit h o ut t he use of a c o n d o m d uri n g a n d at least f or 6 m o nt hs after t he last d ose 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
of  c he m ot hera p y (a p plica ble t o paclita xel, pe metre xe d, a n d car b o plat i n) or 1 1 m o nt hs after t he la st 
d ose of  cis plati n a d mi nistrati o n, t he i nf or mati o n s h o uld be re p orte d t o t he S p o ns or or desi g nee, 
e ve n if t he male partici pa nt has u n der g o ne a s uccessf ul vasect o m y .
I n or der f or S p o ns or or desi g nee t o c o llect a n y pre g na nc y s ur veilla nce i nf or mat i on fr o m t he fe male 
part ner, t he fe male part ner(s) m ust si g n a n I C F f or disclos ur e of  t his i nf or mati on. I nf or m at i on o n 
t he pre g na nc y will be c ollecte d o n t he Pre g na nc y S ur veilla nce F or m.
9. 2. 6 
A d v er s e E v e nt s of S p e ci al I nt er e st
9. 2. 6. 1 
D efi niti o n of I m m u n e -m e di at e d A d v er s e E v e nt s
I M A Es are s pecific e ve nts t hat i ncl u de p ne u m o ni tis, di arr hea/c olitis, he pat itis, ne p hri tis/re nal 
d y sf u ncti on, 
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 
me llit us, a n d h y p o p h y sitis) f or w hic h 
part ici pant s recei ve d 
i m m u n os u p pressi ve me dicati on f or treat me nt of t he e ve nt, wit h t he e xce pt i on of 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, 
dia 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 
wi t ho 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   
 of t he last d ose. T his list 
is s u bject t o c ha n ge base d o n 
 c ha n ge of Me d D R A versi on. T he fi n al 
list use d will be descri be d i n t he cli nical st u d y re p ort ( C S R).
Ta ble 9. 2. 6. 1 -1 bel o w pr o vi des a s u m mar y  of t he I M A E cate g ories a n d t he ir res pecti ve preferre d 
t er ms. T his list is s u bject t o c ha n ge base d o n 
 or c ha n ge of  Me d D R A 
versi o n. T he fi nal list use d will be descri be d i n t he C S R.
T a ble 9. 2. 6. 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 Incl 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 patitis
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
H y p ot h yr oi dis m/t h yr oi ditis
T h y r 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 oiditis (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
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 9. 2. 6. 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 Incl u de d U n der I M A E C ate g or y
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
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase; A L P = al kali ne p h os p hate; A S T = as partate a mi n otra nsferase; 
I M A E = i m m u ne me diate d a d verse e ve nt; P T = prefer re d ter m.
9. 2. 7 
L a b or at or y T e st R e s ult A b n or m aliti e s
T he f o ll owi n g la b orat or y  test res ult a b n or malities s h o ul d be ca pt ure d o n t he n o nseri o us A E e C R F 
pa ge or S A E Re p ort F or m  electr o nic, as a p pr o priate. Pa per for ms are o nl y i nte n de d as a bac k -u p 
o pti o n w he n t he electr o nic s yste m is n ot f u ncti o ni n g.

A n y la b orat or y  test res ult t hat is cli nicall y si g nifica nt or meets t he defi niti on of a n S A E 

A n y la b orat or y test res ult a b n or malit y t hat re q uire d t he parti ci pa nt t o ha ve st u d y treat me nt 
di sc o nti n ue d or i nterr u pte d

A n y la b orat or y test res ult a b n or malit y t hat re q uire d t he parti ci pa nt t o recei ve s pecific 
c orrecti ve t hera p y
It is e x pecte d t hat w here ver p ossi ble, t he cli nical rat her t ha n la b orat or y ter m w o ul d be use d b y t he 
re p orti n g i n vesti gat or (e g, a ne mia vers us l o w he m ogl o bi n val ue).
9. 2. 8 
P ot e nti al Dr u g -in d u c e d Li v er I nj ur y
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 ab 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 n e d crit eria, m ust be re p orte d as S A Es (see Secti o n 9. 2 a n d A p pe n di x 3  f or re p orti n g 
details).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
9. 2. 9 
Ot h er S af et y C o n si d er ati o n s
A n y si g nifica nt w orse ni n g n ote d d uri n g i nteri m or fi nal p h ysical e xa mi nat i ons, E C G, x- r a y 
fil mi n g, a ny ot h er p ote ntial s af et y assess me nt re q uire d or n ot re q uire d b y pr ot o c ol s h o uld al s o be 
rec or de d as a n o nseri o us or seri o us A E, as a p pr o priate, a n d re p orte d acc or di n gl y.
9. 3 
O v er d o s e
F or t his st u d y, a n y d ose of  im m u n ot hera p y  greater t ha n t he pl a n ne d d ose wit hi n a 2 4 -h o ur ti me 
p eri o d will be c o nsi dere d a n o ver d ose.
A n o ver d ose is defi ne d as t he acci de ntal or i nte nt i onal a d mi nistrati o n of a n y d ose of a pr o d uct t hat 
is c o nsi dere d b ot h e xcessi ve a n d me dicall y i m p orta nt. All occ urre nces of  over d ose m ust be 
re p orte d as a n S A E (see Secti o n 9. 2 ).
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificat i ons will be ma de b y t he i n vesti gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val uat i on of t he partici pa nt.
9. 4 
S af et y
Pl a n ne d ti me p o i nts f or all safety assess me nts are liste d i n t he Sc he d ule of Act i vities.
9. 4. 1 
P h y si c al E x a mi n ati o n s
See Secti o n 2 Sc he d ule of Act i vities.
9. 4. 2 
Vit al S i g n s
See Secti o n 2 Sc he d ule of Act i vities.
9. 4. 3 
El e ctr o c ar di o gr a m s
See Secti o n 2 Sc he d ule of Act i vities.
9. 4. 5 
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s

I n vesti gat ors m ust d oc u me nt t heir re vie w of eac h la b orat or y safet y re p ort.

L ocal  la b orat or y tests ma y be use d t o g ui de cli nical decisio n s a n d deter mi ne eli gi bilit y f or 
d osi n g o nce eli gi bilit y t o partici p ate i n t his st u d y has bee n c o nfir me d b y ce ntral la b orat or y 
res ults.

A ce ntral/l ocal la b orat or y will perf or m t he a nal yses a n d will pr o vi de refere nce ra n ges f or t hese 
tests.

D uri n g scree ni n g a n d treat me nt, u nless ot her wise i n dicate d i n Ta ble 2 - 1 a n d Ta ble 2 - 2, res ults 
of  cli nical la b orat or y tests must be re vie we d pri or t o d osi n g .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Cli nical safet y la b orat or y assess me nts are pr o vi de d i n Ta ble 9. 4. 5 - 1.
T a ble 9. 4. 5 - 1:   
Cli nic al S afet y L a b or at or y Assess me nts
He m at ol o g y C o m plete Bl o o d C o u nt –
 
 
 
 
 
      
He m o gl o bi n
He m at o crit
T otal  le u k oc yte c o u nt, i ncl u di n g differe ntial
L y m p h oc y te c o u nt
Pl at elet c o u nt
C he mistr y
A S T
A L T
T otal  Bilir u bi n
A L P
L D H
Creati ni ne
Bl o o d urea ni tr o ge n or ser u m urea
Fast i n g gl uc ose
Ma g nesi u m (scree ni n g, pre -d ose, a n d 
c o mplet i on of P D C T)
Al b u mi n - scree ni n g o nl y
S o di u m
P otassi u m
C hl ori de
Calci u m
P h os p h or us
A m ylase - scree ni n g o nl y
Li pase - scree ni n g o nl y
T S H, free T 3 a n d free T 4 - scree ni n g 
T S H Q 6 W, wit h refle xi ve f T 3 a n d f T 4 if T S H 
is a b n or mal - o n treat m e nt
Uri n al ysi s
Pr otei n
Gl uc ose
Bl o o d
Le u k oc y te esterase
S pecific gra vit y
p H
Micr osc o pi c e xa mi nati o n o f t he se di me nt if bl o o d, pr otei n, or le u k oc ytes esterase are p ositi ve 
o n t he di pst ic k
Ser ol o g y
He pati tis B/ C ( H B V s A G, H C V a nti b o d y, or H C V R N A) - scree ni n g o nl y
Ot her A n al yses
Pre g na nc y test ( W O C B P o nl y: 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). 
F S H scree ni n g - o nl y re q uire d t o c o nfir m me n o pa use i n w o me n < a ge 5 5
HI V testi n g m ust be perf or me d as per l ocal re g ulati o ns - scree ni n g o nl y. See A p pe n di x 8 .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A b bre viati o ns: A L P = al kali ne p h os p hate; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; 
 
 F S H = f ollicle-sti m ulati n g h or m o ne; L D H = lactate de h y dr o ge nase; H B V s A G = he patitis 
B s urface a nti ge n; H C V = he patitis C; HI V = h u ma n i m m u n o deficie nc y vir us; H C G = h u ma n c h ori o nic g o na d otr o pi n; 
R N A = ri b o n ucleic aci d; P D C T = plati n u m d o u blet c he m ot hera p y; T S H = t h y r oi d sti m ulati n g h or m o ne; W O C B P = 
w o me n of c hil d beari n g p ote ntial.
9. 4. 6 
I m a gi n g S af et y A s s e s s m e nt
A n y i nci de ntal fi n di n gs of  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  sh o ul d 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. Please see Secti o n 7. 7. 2. 1 f or a d ditio nal  details.
9. 5 
P h ar m a c o ki n eti c s
9. 5. 1 
P h ar m a c o ki n eti c s a n d A nti -dr u g A nti b o d y (I m m u n o g e ni cit y) S a m pl e 
C oll e ct i o n a n d Pr o c e s si n g
Ser u m  sa mple c ollecti o n f or ni v o l uma b a n d relatli ma b P K a n d a nt i-dr u g a nti b o d y (A D A) 
assess me nts, as well as plas ma sa m ple c o llecti o n f or cis plat i n, car b o plat i n, paclita xel, a n d 
p e m etre xe d i n Part 2 will be perf or me d as per detaile d sc h e d ule pr o vi de d i n Ta ble 9. 5. 1 - 1. All o n -
treat me nt P K ti me p oi nts are i nte n de d t o ali g n wit h da ys o n w hic h st u d y treat me nt is a d mi nistere d. 
Pre d ose sa m pl es s h o ul d be c ollecte d wit hi n 3 0 mi n utes bef ore t he start of d ose a d mi nistrati o n. If 
it is k n o w n t hat a d ose is g oi n g t o be del a ye d, t he n t he pre d ose sa m ple s h o uld be c o llecte d j ust 
pri or t o t he del a ye d d ose. H o we ver, if a pre -d ose sa m ple is c ollecte d b ut t he d ose i s s u bse q ue ntl y 
d el a ye d, a n a d ditio nal pre d ose sa m ple s h o ul d n ot be c ollecte d.
F or I V a d mi nistrati o n, t he e n d of  inf usi o n ( E OI) occ urs w he n t he e ntire ni v o l u ma b + relatli ma b 
d ose i n t he i nf usi o n ba g is a d mi nistere d t o t he partici pa nt. If t he site i nf uses dr u g wit h o ut a fl us h, 
t he n c o llect t he E OI -P K sa m ple wi t hi n a p pr o xi matel y 5 mi n utes after E OI. If a fl us h is 
a d mi nistere d t o clear t he I V li nes of t he dr u g a n d t o e ns ure deli ver y of t he e ntire dr u g d ose, t he n 
dra w t he E OI -P K sa mple wi t hi n a p pr o xi matel y 5 mi n utes after e n d of  th e fl us h. If t he E OI is 
d el a ye d t o be y o n d t he n o mi nal i nf usi on d urati o n ( 3 0 mi n), t he c ollect i on of  this sa m ple s h o uld 
als o be d el a ye d acc or di n gl y. E OI sa mples ma y n ot be c ollecte d fr om t he sa me I V access as t he 
dr u g was a d mi nistere d. Dra w bl o o d sa mples fr om a sit e ot her t ha n t he i nf usi o n sit e (ie, 
c o ntralateral arm)  on da ys of i nf usi o n f o r all pre-d ose a n d E OI -P K sa m ples. Please e ns ure acc urate 
d oc u m e ntatio n of  t he ti me a n d date of sa m ple c ollecti o n.
S a m ples will be e val uate d f or de vel o p me nt of A D A. S a m ples ma y 
als o be a nal yze d f or 
ne utralizi n g a nt i b o dies a n d P K sa m ples ma y be use d f or A D A a nal ysis i n t he e ve nt of i ns ufficie nt 
v o l ume, t o c o m p lete i m m u n o ge nicity assess me nt, or t o f oll ow- u p o n s us pecte d i m m u n o ge nicity 
r elate d A Es.
F urt her details of  s a mple c ollectio n, pr ocessi n g, a n d s hi p me nt will be pr o vi de d i n t he la b orat or y 
pr oce d ures ma n ual.
I mm u n o ge nicit y of  ni v ol u ma b a n d r elat li ma b will be assesse d per t he sta n dar d ni v o l u ma b a n d 
r elat li ma b i m m u n o ge nicity a nal ysis pla n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 2 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 9. 5. 1 - 1: 
P h ar m ac o ki netic a n d I m m u n o ge nicit y S a m pli n g Sc he d ule f or Rel atli m a b a n d Ni v ol u m a b 
a n d P h ar m ac o ki netic S a m pli n g Sc he d ule f or C he m ot her a p y Dr u gs
St u d y D a y of S a m ple 
C ollecti o n
( 1 C ycle = 3 W ee ks)
E ve nt
Ti me 
Rel ati ve t o 
St art of 
I nf usi o n 
( hr: mi n)
Ni v ol u m a b 
P K Ser u m 
S a m ples
Ni v ol u m a b 
I M G ( A D A) 
Ser u m 
S a m ples
Rel atli m a b 
P K Ser u m 
S a m ples
Rel atli m a b 
I M G ( A D A) 
S a m ples
C he m ot her a p y 
P K Pl as m a 
S a m ples
C y cle 1 Da y 1
Pre d ose a
0: 0 0 
X
X
X
X
-
E OI b
0: 3 0 
X
X
-
E n d of 
c he m ot hera p y 
i nf usi o nc
-
-
-
X
C y cle 1 Da y 1 0d
2 1 6: 0 0 
X
X
C y cle 2 Da y  1
Pre d ose a
0: 0 0 
X
X
X
X
-
E n d of 
c he m ot hera p y 
i nf usi o nc
-
-
-
-
-
X
C y cle 3 Da y  1
Pre d ose a
0: 0 0 
X
X
X
X
C y cle 5 Da y 1
Pre d ose a
0: 0 0 
X
X
X
X
C y cle 5 Da y  1
E OI b
0: 0 0 
X
X
C y cle 9 Da y  1
Pre d ose a
0: 0 0 
X
X
X
X
-
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 0
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 9. 5. 1 - 1: 
P h ar m ac o ki netic a n d I m m u n o ge nicit y S a m pli n g Sc he d ule f or Rel atli m a b a n d Ni v ol u m a b 
a n d P h ar m ac o ki netic S a m pli n g Sc he d ule f or C he m ot her a p y Dr u gs
St u d y D a y of S a m ple 
C ollecti o n
( 1 C ycle = 3 W ee ks)
E ve nt
Ti me 
Rel ati ve t o 
St art of 
I nf usi o n 
( hr: mi n)
Ni v ol u m a b 
P K Ser u m 
S a m ples
Ni v ol u m a b 
I M G ( A D A) 
Ser u m 
S a m ples
Rel atli m a b 
P K Ser u m 
S a m ples
Rel atli m a b 
I M G ( A D A) 
S a m ples
C he m ot her a p y 
P K Pl as m a 
S a m ples
E ver y 6 c ycles after C ycle 
9 Da y  1 (e g, C 1 5 D 1, 
C 2 1 D 1, a n d s o o n) u ntil 
e n d of treat me nt or  
ma xi m u m of t w o years of
treat me nte
Pre d ose a
0: 0 0 
X
X
X
X
A b bre viati o ns: A D A = a nti dr u g a nti b o d y; I M G = i m m u n o ge nicit y ; I V = i ntra ve n o us; P K = p har mac o ki netic.
a
Pre d ose sa m ples s h o ul d be c ollecte d j ust bef ore starti n g t he i nf usi o n ( prefera bl y  wit hi n 3 0 mi n utes). H o we ver, if a pre d ose sa m ple is c ollecte d b ut t he d ose is 
s u bse q ue ntl y dela ye d, a n a dditi o nal pre d ose sa m ple s h o ul d n ot be c ollecte d t hat a d ose is g oi n g t o be dela ye d, t he n t he pre d ose sa m ple s h o ul d be c ollecte d j ust 
pri or t o t he dela ye d d ose .
b
T he e n d of i nf usi o n ( E OI) o cc urs w he n t he e ntire d ose i n t he i nf usi o n ba g is a d mi nistere d t o t he partici pa nt. If dil ue nt is use d t o fl us h t he d ose re mai ni n g i n t he 
i nf usi o n li ne, t he n t he E OI will occ ur whe n t here is n o d ose re mai ni n g i n t he i nf usi o n li ne after a fl us h. A P K sa m ple s ho ul d be ta ke n i m me diatel y pri or t o t he 
E OI, prefera bl y wit hi n 2 mi n utes pri or t o t he E OI. If t he E OI is dela ye d be y o n d t he n o mi nal i nf usi o n d urati o n ( 3 0 mi n), t he c ollecti o n of t his sa m ple s h o ul d als o 
be dela ye d acc or di n gl y. E OI sa m ples ma y n ot be c ollec te d fr o m t he sa me I V access as t he dr u g was a d mi nistere d.
c
T his sa m ple s h o ul d be c ollecte d at t he e n d of eac h c he m ot hera p y i nf usi o n a d mi nistrati o n. F or e xa m ple, if a partici pa nt is rec ei vi n g car b o plati n + paclita xel, t he n 
c ollect car b o plati n sa m ple at t he e n d of car b o plati n i nf usi o n, a n d paclita xel sa m ple at t he e n d of paclita xel i nf usi o n.
d
T his sa m ple s h o ul d be c ollecte d i n c o nj u ncti o n w it h t he bi o mar ker sa m ple.
e
All P K a n d I M G sa m ples c ollecte d be y o n d t w o years of treat me nt , b ut pri or t o P A 7 will be a nal yze d .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 1
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
9. 5. 2 
P h ar m a c o ki n eti c s a n d I m m u n o g e ni cit y S a m pl e A n al y s e s
Treat me nt assi g n me nts will  be release d t o t he bi oa nal yt ical la b orat or y in or der t o mi ni mize 
u n necessa r y a nal ysis a n d/ or rea nal ysis of P K/a nti-dr u g a nti b o d y  ( A D A) sa m ples.
T he ser u m  s a mples will  be a nal yze d f or dr u gs ( ni v olu ma b a n d rel at li ma b), a nti-ni v o l uma b A D A, 
a n d a nt i- r elat li ma b A D A, b y vali date d i m m u n oassa ys. O nl y sa m ples t hat are p osit i ve f or t he 
p rese nce of  ant i-ni v o l uma b/a nt i-relatli ma b a nt i b o dies will be a nal yze d as a p pr o priate f or a nti-
ni v o l u ma b/a nti-r elat li ma b ne utralizi n g acti vity.
C o nce ntrati o n a nal yses f or ni v ol u ma b a n d relatli ma b i n ser u m a n d c he m ot hera p y dr u gs (cis plati n, 
car b o plat i n, paclita xel, a n d pe metre xe d) will be perf or me d b y vali date d bioa nal y tical met h o d(s).
Bi oa nal y tic al sa m ples desi g nate d f or assess me nts (e g, i m m u n o ge nicity,  PK, or bi o mar ker) fr o m 
t he sa me c ollecti o n ti me p oi nt ma y be use d i nterc ha n gea bl y f or a nal yses, if re q uir ed (i ncl u di n g, 
b ut n ot li mite d t o, i ns ufficie nt v o l ume f or c o mple me nt assess me nt, t o f oll ow- u p o n s us pecte d 
i m m u n o ge nicity- relate d A E, etc).
A d dit i onall y , resi d ual bi oa nal ytical sa m ples will be arc hi ve d f or u p t o 2 0 years after t he e n d of t he 
st u d y or t he ma xi m u m peri o d all o we d b y a p plica ble la w a n d ma y be use d f or p ote ntial e x pl orat or y 
bi oa nal ysis (incl u di n g, b ut n ot li mite d t o, a nal ysis of  dr u g-A D A i m m u ne c o mple xes, met a b o lite 
a nal yses, etc) a n d/ or f or a d dit i onal met h o d p ur p oses (i ncl u di n g, b ut n ot li mite d t o, cr oss-
vali dat i on, A D A/ P K select i vity,  c ut p oint , etc).
9. 5. 3 
P h ar m a c o ki n eti c s A n al y s e s 
T he ni v o l u ma b a n d r elat li ma b c o nce ntrati o ns data o btai ne d i n t his st u d y ma y be c o m bi ne d wi t h 
d at a f r o m ot her st u dies i n t he cli nical de velo p me nt pr o gra m  t o de velo p or refi ne a p o p P K m o del . 
T his m o d el  ma y be use d t o e val uate t he effects of i ntri nsic a n d e xtri nsic c o variates o n t he P K a n d 
t o deter mi ne meas ures of  in di vi d ual e x p os ure (s uc h as stea d y-state pea k, tr o u g h, a n d ti me-
a vera ge d c o nce ntrati o n). I n a d dit i on, m o d el -deter mi ne d e x p os ures m a y be use d f or E- R a nal yses. 
Res ults of p o p P K a n d E- R a nal yses will be re p orte d se paratel y.
T he c o nce ntratio n data o btai ne d f or t he c he m ot hera pies ( cis plati n, car b o plat i n, pacli t a x el, a n d 
p e m etre xe d) will be s u m marize d.
9. 6 
I m m u n o g e ni cit y A s s e s s m e nt s
9. 6. 1 
I m mu n o g e ni cit y A n al y s e s
Details re gar di n g i m m u n o ge nicit y sa m ple c ollecti o n a n d pr ocessi n g ca n be f ou n d i n Sect i on 9. 5 .
All i m m u n o ge nicit y a nal yses will be perf or me d usi n g t he I m m u n o ge nicit y E val ua ble Part ici pa nts 
p o p ul at i on. A listi n g will be pr o vi de d f or all a vaila ble i m m u n o ge nicity data. A baseli ne A D A -
p osi tive part ici pa nt is defi ne d as a partici p a nt wit h p osi tive ser oc o n versi o n detecte d i n t he last 
sa m ple bef ore i nitiati on of  tr e at me nt. A n A D A-p osi tive partici p a nt i s a p artici pa nt wit h at le ast 1 
A D A p osit ive sa m ple relat i ve t o baseli ne after i nitiatio n of t he treat me nt. F or eac h dr u g, fre q ue nc y 
di stri b uti on of  baseli ne A D A -p osi tive parti ci pa nts a n d A D A -p osi tive parti ci pa nts aft er i nitiati on 
of  the treat me nt will 
be s u m marize d. T o 
e xa mi ne t he p ote nti al relati ons hi p bet wee n 
i m m u n o ge nicity a n d safet y,  a ta ble s u m marizi n g t he fre q ue nc y a n d t y pe of A Es of s pecial i nterest 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
ma y 
be e x pl ore d b y i m m u n o ge nicity stat us. I n a d ditio n, p ote nti al relat i ons hi ps bet wee n 
i m m u n o ge nicity a n d efficac y a n d/ or P K ma y als o be e x plor e d.
9. 9 
Bi o m ar k er s
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 
9. 9. 2 
T u m or S a m pl e s
 s peci me ns will be o btai ne d fr o m c o nse nt i n g partici pa nts pri or t o treat me nt t o 
c haracterize i m m u ne cell p o p ulati o ns, 
 
 T u m or tiss ue ac q uire d as a fres h bi o ps y  duri n g 
scree ni n g 
 or a rece nt 
arc hi ve d t u mor sa mple 
 
 
 m u st be a vaila ble f or s u b missi on pri or t o 
ra n d omizat i on. Fi ne nee dle as pirat i ons or ot her c yt ol o g y  sa m ples are n ot acce pta ble. S u b missio n 
of  o n-treat me nt a n d u p o n pr o gressi o n bi o ps y sa m ples s h o ul d be c o llecte d if me dicall y feasi ble. 
9. 9. 2. 1 
T u m or S a m pl e C oll e cti o n
T he i n vesti gat or, i n c o ns ultati o n wi t h the ra diol o g y  staff, m ust deter mi ne t he de gree of  ris k 
ass ociat e d wit h t he pr oce d ure a n d fi n d it acce pta ble. Bi o psi es ma y be d o ne wit h l ocal a nest hesia 
or c o nsci o us se datio n. I nstit utio nal g ui deli nes f or t he safe perf or m a nce of  bi opsies s h o uld be 
f oll owe d. E xcisi o nal bi o psies ma y be perf or m e d t o o btai n 
 sam ples. I n vasi ve 
pr oce d ures t hat re q uire ge neral a nest hesia s h o uld n ot be perf or m e d t o o btai n a bi o ps y s peci me n; 
h o we ver, if a s ur gical pr oce d ure is perf or me d f or a cli nical i n dicat i on, e xcess t u m or tiss ue ma y be 
use d f or researc h p ur p oses wit h t he c o nse nt of t he parti ci pa nt . Detaile d i nstr uctio ns of  the 
o btai ni n g, pr ocessi n g, la beli n g, ha n dli n g, st ori n g, a n d s hi p pi n g of s peci me ns will be pr o vi de d i n a 
se parate La b orat or y Ma n ual.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
 
 
 
9. 9. 3 
A d diti o n al R e s e ar c h C oll e cti o n
T his pr ot oc ol will i ncl u de resi d ual sa m ple st ora ge f or a d dit i onal researc h.
F or N o n -U S Sites
A d dit i onal researc h is o pti o nal f or all st u d y  partici pa nts, e xce pt w here rete nti o n a n d/ or c ollect i on 
is pr o hi bite d b y lo c al  la ws or re g ulat i ons, et hics c o m mittees, or i nstitut i onal re q uire me nts. 
T his c o llecti on f or a d ditio nal researc h is i nte n de d t o e x pa n d t he tra nslati onal Researc h a n d 
De vel o p me nt ca pa bilit y at  B M S, a n d will s u p p ort as yet u n defi ne d researc h ai ms t hat will a d va nce 
o ur u n dersta n di n g of  di sease a n d o pti o ns f or treat me nt. 
 
 
 
 
S a m ple C ollecti o n a n d St or a ge
All re q uests f or access t o sa mpl es or data f or a d di tio n al researc h will be vette d t hr o u g h a di verse 
c o m mittee of  the st u d y sp o ns or’s se nior lea ders i n Researc h a n d De vel o p me nt ( or desi g nee) t o 
e ns ure t he researc h s u p p orts a p pr o priate a n d well-defi ne d scie nt ific researc h acti vities.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 8
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 3 9
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
9. 1 0 
M e di c al R e s o ur c e Utili z ati o n a n d H e alt h E c o n o mi c s
Heal t hcare res o urce utilizati o n will n ot be c ollecte d.
9. 1 1 
Cli ni c al P h ar m a c ol o g y S u m m ar y
T he P K of  ni v ol uma b were st u die d i n par tici pa nts o ver a d ose ra n ge of  0. 1 t o 1 0 m g/ k g 
a d mi nistere d as a si n gle d ose or as m ulti p le d oses of  ni v ol uma b Q 2 W or Q 3 W. T he ge o met ric 
mea n ( % c oefficie nt of variat i on) cl eara nce ( C L) was 9. 5 mL/ h ( 4 9. 7 %), ge o m etric mea n v olu m e 
of  distrib ut i on at stea d y state was 8. 0 L ( 3 0. 4 %), a n d ge o met ric mea n eli mi nat i on half -life was 
2 6. 7 da ys ( 1 0 1 %). Stea d y -state c o nce ntrati o ns of  ni v ol u ma b were reac he d b y 1 2 wee ks w he n 
a d mi nistere d at 3 m g/ k g Q 2 W, a n d s yste mic acc u m ulat i on was a p pr o xi matel y 3 f o l d. T he e x p os ure 
t o ni v o l uma b i ncrease d d ose pr o p orti o nall y o ver t he d ose ra n ge of 0. 1 t o 1 0 m g/ k g a d mi nistere d 
Q 2 W. T he C L of  ni v ol uma b i ncrease d wi t h i ncreasi n g b o d y wei g ht. T he p o p P K a nal ysis s u g geste d 
t hat t he f oll owi n g fact ors ha d n o cli nicall y i m p orta nt effect o n t he C L
of  ni v ol u ma b: a ge 
( 2 9 t o 8 7 years), ge n der, race, baseli ne L D H, P D -L 1. A p o p P K a nal ysis s u g geste d n o differe nce 
i n C L of  ni v ol u ma b base d o n a ge, ge n der, race, t u mor t yp e, baseli ne t u mor size, a n d he pat ic 
i m pair me nt.
Alt h o u g h E C O G stat us, baseli ne gl o mer ular filtrati o n rate, al b u mi n, a n d b o d y wei g ht ha d a n effect  
o n ni v o l uma b C L, t he effect was n ot cli nicall y mea ni n gf ul. W he n ni v o l u ma b is a d mi nistere d i n 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
c o m bi nat i on wi t h ipili m u ma b, t he C L of ni v o l uma b was i ncrease d b y 2 4 %, w hereas t here was n o  
effect o n t he C L of  ipili m u ma b. A d dit i onall y , p o p P K a n d E- R a nal yses ha ve bee n perf or m e d t o 
s u p p ort use of  24 0 m g Q 2 W d osi n g i n a d ditio n  t o t he 3 m g/ k g Q 2 W re gi me n. Usi n g t he p o p P K
m o d el , e x p os ure of  ni v ol u ma b at 2 4 0 m g flat d ose was i de ntical t o a d ose of  3 mg/ k g f or 
parti ci pa nts wei g hi n g 8 0 k g, w hic h was t he a p pr o xi mate me dia n b o d y  wei g ht i n ni v ol u ma b cli nical 
trials.
F ull details o n t he cli nical p har mac o l og y  as pects of ni v ol u ma b ca n be f o u n d i n t he I B.
1 0 
S T A TI S TI C A L C O N SI D E R A TI O N S
1 0. 1 
S a m pl e Si z e D et er mi n ati o n 
1 0. 1. 1 
S a m pl e Si z e D et er mi n ati o n: P art 1
U p t o a p pr o xi matel y 1 2 0 partici pa nts will be ra n d o mize d 1: 1 t o treat me nt Ar ms A a n d B (ie, u p 
t o 6 0 partici pa nts per ar m). 
 
 
 
 
1 0. 1. 2 
S a m pl e Si z e D et er mi n ati o n: P art 2
A p pr o xi matel y 3 0 0 parti ci pa nts will be ra n d o mize d 1: 1 (ie, 1 5 0 partici pa nts per ar m) stratifie d b y
hist ol o g y  (S Q vs N S Q) a n d P D -L 1 level  ( ≥1 % [incl u di n g N Q] vs < 1 %). 
 
 
 
 
 
 
 
 
1 0. 2 
P o p ul ati o n s f or A n al y s e s
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulat i ons are defi ne d:
P o p ul ati o n
Descri pti o n of P art 2 P o p ul ati o ns 
Descri pti o n of P art 1 P o p ul ati o ns
All E nr olle d Partici pa nts 
All partici pa nts w h o si g ne d a n I C F 
a n d were re gistere d i n t he I R T f or Part 
2 of t he st u d y.
All partici pa nts w h o si g ne d a n I C F a n d 
were re gistere d i n t he I R T f or t he d ose 
safet y c o nfir mati o n part of t he st u d y.
All Ra n d o mize d Partici pa nts 
All e nr olle d partici pa nts w h o were 
ra n d o mize d t o a n y treat me nt ar m i n 
t he st u d y. T his p o p ulati o n will be use d 
f or t he efficac y a nal ysis. 
Sa me defi niti o n as f or Part 2. T his 
p o p ulati o n will be use d f or t he 
(e x pl orat or y) efficac y a nal ysis.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
P o p ul ati o n
Descri pti o n of P art 2 P o p ul ati o ns 
Descri pti o n of P art 1 P o p ul ati o ns
All Treate d Partici pa nts
All ra n d o mize d partici pa nts w h o 
recei ve d at least 1 d ose of a n y st u d y 
treat me nt. U nless state d ot her wise, 
t his p o p ulati o n will be use d f or t he 
safet y a nal ysis.
Sa me defi niti o n as f or Part 2. T he 
pri mar y  d ose safet y c o nfir mati o n 
a nal ysis will be base d o n t he D ose-
Safet y E val ua ble Partici pa nts 
( defi niti o n bel o w); u nless s pecifie d 
ot her wise. All Treate d Partici pa nts will 
be use d f or t he rest of safet y a nal yses.
D ose -Safet y  E val ua ble 
Partici pa nts
N ot a p plica ble
All treate d partici pa nts i n t he d ose 
safet y c o nfir mati o n w h o ha ve 
c o m plete d t he safet y c o nfir mati o n 
peri o d of 1 2 wee ks a n d ha ve recei ve d 
at least 3 c ycles of st u d y dr u g 
(i ncl u di n g all 4 c o m p o ne nts: P D C T, 
ni v ol u ma b, a n d relatl i ma b), or t h ose 
w h o disc o nti n ue d a n y st u d y dr u g d ue t o 
t o xicit y pri or t o c o m pleti n g t he safet y 
e val uati o n peri o d.
A b bre viati o ns: C = c ycle; D = da y; I C F = i nf or me d c o nse nt f or m; I R T = I nteracti ve Res p o nse Tec h n ol o g y; P D C T = 
plati n u m d o u blet c he m ot hera p y .
1 0. 3 
St ati sti c al A n al y s e s
T he S A P will  be de vel o p e d a n d fi nalize d bef ore data base l oc k a n d will descri be t he selectio n of  
parti ci pa nts t o be i ncl u de d i n t he a nal yses a n d pr oce d ures f or acc o u nti n g f or missi n g, u n use d, a n d 
s p urio us data. Bel o w is a s u m mar y of pl a n ne d statistical a nal yses of  the pri mar y a n d sec o n dar y 
e n d p o i nts.
A descri pt i on o f the partici pa nt p o p ulat i on will be i ncl u de d i n a statistical o ut p ut re p ort, i ncl u di n g 
s u b gr o u ps of a ge, ge n der, a n d race.
F or Part 1, t he d ose safet y  c o nfir mat i on, t he a n al yses of all pri mar y a n d sec o n dar y e nd p oi nts are 
descri be d i n Secti o n 1 0. 3. 2 .
F or Part 2, t he a nal yses f or t he pri mar y a n d sec o n dar y  e nd p oi nts are descri be d i n Sect i on 1 0. 3. 1 .

O R R fi nal a nal ysis ( Pri mar y anal ysis) : 
 
 N o f or mal hy p ot hesis testi n g is 
pl a n ne d. O R R differe nce bet wee n t he t w o ar ms a n d t he c orres p o n di n g 2 -side d 9 0 % e xact CIs 
will be i ncl u de d. T he differe nce i n O R R will  be c o nsidere d mea ni n gf ul if t he l ower b o u n d of 
t he 9 0 % CI is a b o ve 0 i n fa v or of t he treat me nt ar m. At t his a nal ysis, a descri pti ve a nal ysis of 
sec o n dar y efficac y e n d p oi nts will be pr o vi de d. 

Fi nal a nal ysis f or P F S: 
 
 P F S will be esti mate d usi n g t he K M tec h ni q ues. P F S rates 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 o ll ow- u p) a n d me dia n P F S will be prese nte d al o n g wit h 
t heir ass ociate d 9 0 % CIs. A stratifie d H R will be calc ulate d usi n g C o x m o del wit h t he 2- si de d 
9 0 % CIs will  be re p orte d. T he P F S be nefit ma y be c o nsidere d mea ni n gf ul if t he u p per b o u n d 
of  t he 9 0 % CI f or H R is bel o w 1.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
1 0. 3. 1 
Effi c a c y A n al y s e s
Efficac y e n d p o i nts a n d a nal yses are descri be d i n Ta ble 1 0. 3. 1 - 1 a n d will be perf or me d o n t he 
ra n d omize d p o p ulati o n.
T a ble 1 0. 3. 1 - 1: 
A n al ysis of P art 2 Pri m ar y a n d Sec o n d ar y Effic ac y E n d p oi nts
E n d p oi nt
St atistic al A n al ysis Met h o ds
Pri mar y : O R R per R E CI S T v 1. 1 b y BI C R
O R R  is defi ne d 
as t he n u m ber 
of 
ra n d o mize d 
partici pa nts wit h a B O R of C R or  PR base d o n BI C R 
assess me nts ( usi n g R E CI S T v 1. 1 criteria) di vi de d b y t he 
n u m ber of ra n d o mize d partici pa nts f or eac h treat me nt 
gr o u p. T he B O R per BI C R is defi ne d as t he best o verall 
c o nfir me d res p o nse desi g nati o n, as deter mi ne d b y t he 
BI C R, rec or de d bet wee n t he date of ra n d o mizati o n a n d 
t he date of o bjecti vel y d oc u me nte d pr o gr essi o n per 
R E CI S T v 1. 1 or t he date of s u bse q ue nt a nti-ca ncer 
t hera p y, w hic he ver occ urs first. F or partici pa nts wit h o ut 
d oc u me nte d pr o gr essi o n as per BI C R or  su bse q ue nt 
t hera p y, all a vaila ble res p o nse desi g nati 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 after t he i nitial 
res p o nse.
P oi nt esti mate a n d c o nfi de nce i nter val will be use d t o 
descri be O R R. A 2- si de d 9 0 % e xact CIs f or differe nce 
of res p o nse rates bet wee n t he treat me nt gr o u ps will be 
re p orte d. 
T he n u m ber a n d perce nta ge of partici pa nts i n eac h 
cate g or y of B O R will be pr ese 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 2- si de d 
9 0 % CI 
  
will be prese nte d b y 
treat me nt gr o u p.
Sec o n dar y: P F S per R E CI S T v 1. 1 b y BI C R
P F S 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 first date of d oc u me nte d 
pr o gressi o n , base d o n BI C R assess me nts ( per R E CI S T 
v 1. 1) , or deat h d ue t o a n y ca use, w hic he ver occ urs first.
Ce ns ori n g r ules f or PF S are pr ese nte d i n Ta ble 1 0. 3. 1 -
2 .
P F S will be c o m pare d bet wee n t he 2 treat me nt gr o u ps 
usi n g a stratifie d H R usi n g C o x m o del. A 9 0 % CI f or 
H R will als o be pr o vi de d. 
P F S will be esti mate d usi n g t he K M tec h ni q ues. P F S 
rates 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) a n d me dia n 
P F S will 
be 
prese nte d al on g wit h t heir ass ociate d 9 0 % CIs. T he 
esti mates will be deri ve d fr o m t he K M esti mates a n d 
cor res p o n di n g CIs will be deri ve d usi n g t he Gr ee n w o o d
f or m ula or Br o o k me yer-Cr o wle y met h o d as a p plica ble.
Sec o n dar y: 
P F S 
per R E CI S T 
v 1. 1 b y BI C R 
i n 
s u b gr o u ps defi ne d b y P D -L 1 
e x pressi o n, L A G -3 
e x pressi o n, F G L-1 e x pressi o n
P F S is defi ne d t he sa me wa y as f or t he pri mar y a nal ysis.
P F S will be esti mate d usi n g t he K M tec h ni q ues i n eac h 
s u b gr o u p. P F S rates 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) a n d me dia n P F S 
will be prese nte d al o n g wit h t heir ass ociate d 9 0 % CIs. 
T he esti mates will be deri ve d fr o m t he K M esti mates 
a n d c orres p o n di n g CIs 
will 
be deri ve d usi n g
t he 
Gree n w o o d f or m ula or Br o o k me yer-Cr o wle y met h o d as 
a p plica ble.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A b bre viati o ns: BI C R = bli n de d i n de pe n de nt c e ntral re vie w; B O R = best o verall res p o nse; CI = c o nfi de nce i nter val; 
C M H = C oc hra n -Ma ntel Hae nszel; C R = c o m plete res p o nse; F G L -1 = fi bri n o ge n -li ke pr otei n 1; H R = hazar d rati o; 
K M = Ka pla n Meier; L A G -3 = l y m p h oc y te-acti vati o n ge ne 3; O R R = o verall res p o nse rate; P D -L 1 = pr o gra m me d 
deat h -li ga n d 1; P F S = pr o gr essi o n -free s ur vi val; P R = partial res p o nse; R E CI S T = Res p o nse E val uati o n Cr iteria i n 
S oli d T u m ors;
.
T a ble 1 0. 3. 1 - 2: 
Ce ns ori n g Sc he me Use d i n 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
D oc u me nte d pr o gressi o n per R E CI S T v 1. 1 
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
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 
Date of deat h 
Pr o gresse d
P D or deat h after starti n g s u bse q ue nt a nti -
ca ncer t hera p y
Date of P D or deat h
Pr o gresse d
A b bre viati o ns: P D = pr o gressi ve disease; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors; v = versi o n.
1 0. 3. 2 
S af et y A n al y s e s
T he assess me nt of safety will  be base d o n fre q ue nc y of  deat hs, A Es, S A Es, A Es
lea di n g t o
di sc o nti n uati on o f st u d y dr u g, select A Es, I M A Es, a n d a b n or malities i n s pecific cli nical la b orat or y
assess me nts. See Secti o n 9. 2 f or details. A Es will be c o de d usi n g t he mo st c urre nt versi o n of t he
Me d D R A. All A Es a n d la b orat or y val ues will be gra de d f or se verit y acc or di n g t o t he N CI C T C A E
v 5. 
S af et y e n d p o i nts a n d a nal yses are descri be d i n Ta ble 1 0. 3. 2 - 1 a n d will be perf or me d o n t he treate d 
p o p ul at i on, u nless ot her wise s pecifie d.
T a ble 1 0. 3. 2 - 1:   
D ose S afet y C o nfir m ati o n Pri m ar y a n d Sec o n d ar y E n d p oi nts
E n d p oi nt 
St atistic al A n al ysis Met h o ds
Pri mar y
Wit hi n eac h ar m of Part 1, t he pr o p orti o n of partici pa nts i n t he d ose -safet y e val ua ble p o p ulati o n 
w h o ha d a T R A E lea di n g t o disc o nti n uati o n of a n y  c o m p o ne nt i n t he re gi me n (I O, c he m o, or 
b ot h) wit hi n 1 2 wee ks of t he first d ose will be prese nte d, al o n g wit h e xact 2-si de d 9 0 % CI 
 
 f or eac h treat me nt ar m. A 2- si de d 9 5 % CI f or differe nce of t hese rates 
bet wee n t he treat me nt gr o u ps will als o be c o m p ute d.
Sec o n dar y 
Safet y a n d t olera bilit y (i nci de nce of T R A Es lea di n g t o disc o nti n uati o n, A Es, S A Es, a n d select 
A Es) will be assesse d o n all treate d partici pa nts wit hi n Part 1.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A b bre viati o ns: A E = a d verse e ve nt; CI = c o nfi de nce i nter val; I O = i m m u n ot hera p y; S A E = seri o us a d verse e ve nt; 
; T R A E = treat me nt relate d a d verse e ve nt.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nica l Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
r elatli ma b
1 1 
R E F E R E N C E S
1
Mell ma n I, C o u k os G, Dra n off G. Ca ncer i m m u n ot hera p y c o mes of a ge. Nat ure 2 0 1 1; 4 8 0-9.
2
 
3
A n dre ws L P, Marcisca n o 
A F, Dra ke C G , Vi g nali D A A . L A G 3 ( C D 2 2 3) as a ca ncer 
im m u n ot hera p y  tar get. I m m u n o l Re v 2 0 1 7; 2 7 6 -9 6.
4
Wa n g J, Sa n ma me d M F, Datar I, et al. Fi bri n o ge n -li ke pr otei n 1 is a maj or i m m u ne i n hi bit or y 
li gan d of L A G -3. Cell 2 0 1 9; 1 7 6: 3 3 4 -4 7.e 1 2.
5
I n vesti gat or Br oc h ure Rel at li ma b B M S -9 8 6 0 1 6. Bri st ol-M yers 
S q ui b b C o m p a n y; 2 0 1 9. 
D oc u m e nt C o ntr ol N o. 9 3 0 0 7 1 6 2 0.
6
C ha u vi n J M, Pa glia n o O, F o urca de J, et  al. TI GI T a n d P D -1 i m pair t u mor a nti ge n-s pecific 
C D 8 ⁺ T cells i n mela n oma partici pa nts. J Cli n I n vest 2 0 1 5; 1 2 5: 2 0 4 6- 5 8. 
7
S pei ser D E, Utzsc h nei der D T, O berle S G, et al. T cell differe nt iati on i n c hr o nic i nfecti o n a nd 
ca ncer: f u ncti o nal a da ptati o n or e x ha usti o n? Nat Re v I m m u n o l 2 0 1 4; 1 4: 7 6 8 -7 4. 
8
S har ma P, H u -Li es k o va n S, War g o J A, Ri bas A . Pri mar y, ada pt i ve, a n d a c q uire d resista nce t o 
ca ncer im m u n ot hera p y . cell 2 0 1 7; 1 6 8: 7 0 7-2 3. 
9
W o o S R, T ur nis M E, G ol d ber g M V, et al. I mm u ne i n hi bit or y mol ec ules L A G - 3 a n d P D -1 
s y ner gisticall y re g ulate T- cell f unct i on t o pr o m ote t u moral  im m u ne esca pe. Ca ncer Res 
2 0 1 2; 7 2: 9 1 7 - 2 7.
1 0
Ga n d hi L, R o dri g uez -A bre u D, Ga d geel S, et al. Pe m br o liz u ma b pl us c he m ot hera p y i n 
m etastatic n o n –s mall -cell l u n g ca ncer. N E n gl J Me d 2 0 1 8; 3 7 8: 2 0 7 8- 9 2.
1 1
Paz -Ares L, L uft A, Vice nte D, et al. Pe m br oliz u ma b pl us che m ot hera p y f or sq ua m o us n o n –
small -cell l u n g ca ncer. N E n gl J Me d 2 0 1 8; 3 7 9: 2 0 4 0- 5 1.
1 2
S oci ns ki M A, J otte R M, Ca p p uzz o F , et al. Atez oliz u ma b f or first-li ne treat me nt of m etastatic 
n o ns q ua m o us N S C L C. N E n gl  J Me d 2 0 1 8; 3 7 8: 2 2 8 8- 2 3 0 1.
1 3
Peters S, Ra mali n ga m S S, Paz- Ares L, et al. Ni v o l u ma b + lo w - dose ipili m u ma b v ers us
p lati n u m-d o u blet che m ot hera p y as first-li ne treat me nt f or ad va nce d n o n -small cell lu n g 
ca ncer: C hec k Mate 2 2 7 Part 1 fi nal a nal ysis . A n nals of  Onc o l og y 2 0 1 9; 3 0 (s u p pl_ 5): v 8 5 1 -
v 9 3 4.
1 4
Rec k M, Ci ulea n u T -E, C o b o D ols M , et al. Ni v o l uma b ( NI V O) + i pili m u ma b (I PI) + 2 c ycles 
of  plati n u m-d o u blet c he m ot hera p y (c he mo) vs 4 c y cles of  c he mo as first-li ne ( 1 L) treat me nt 
(t x) f or sta ge I V/rec urre nt n o n-s mall cell l u n g ca ncer ( N S C L C): C hec k Mate 9 L A. J Cli n O nc ol 
2 0 2 0 ; (s u p pl):a bstr 9 5 0 1.
1 5
Asciert o P A, Mel er o I, B hatia S, et  al. Init ial efficac y of a nt i-l y m p h oc yt e acti vat i on ge ne -3 
(a nti –L A G -3; B M S -9 8 6 0 1 6) i n c o m bi nati o n wi t h ni v ol uma b ( ni v o) i n pts wit h me la n oma  
                                                       
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 4 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nica l Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
r elatli ma b
                                                                                                                                                                                  
( M E L) pre vio usl y  tr e at e d wit h a nti– P D -1/ P D -L 1 t hera p y. J Cli n O nc o l 2 0 1 7; 3 5 (s u p pl):a bstr 
9 5 2 0 .
1 6
Asciert o P A, B o n o P, B hatia S, et al. Efficac y of  BM S -9 8 6 0 1 6, a m o n ocl o n al  ant i b o d y tha t 
tar gets l y m p h oc yt e acti vat i on ge ne - 3 ( L A G-3), i n c o m bi nat i on wi t h ni v ol uma b i n pts wi t h 
mela n o ma. Pr ocee di n gs fr om t he 2 0 1 7 E S M O C o n gress;
2 0 1 7 Se p 8 -1 2; Ma dri d, 
S pai n. 
A bstract L B A 1 8.
1 7
Data o n File.
1 8
Je mal A, Bra y F, Ce nter M M, et al. Gl o bal ca ncer stat istics. C A Ca ncer J Cli n 2 0 1 1; 6 1: 6 9 -
9 0.
1 9
Ga d geel S, R o dri g uez -A bre u D, S pera nza G, et al.  Up date d anal ysis fr o m KE Y N O T E -1 8 9: 
p e m br o liz u ma b or p lace b o p l us p e metre xe d a n d p lati n u m f or p re vi o usl y u nt reate d m etastatic 
n o ns q ua m o us n o n –s mall - cell l u n g cancer. J Cli n O nc o l 2 0 2 0; 3 8( 1 4): 1 5 0 5 - 1 7.
2 0
Paz -Ares L, Ci ulea n u T E, Y u X, et al . Ni v olu ma b ( NI V O) + pl at i n u m-d o u blet c he m ot h era p y 
(c he m o) vs c he mo as first-li ne ( 1 L) treat me nt (t x) f or a d va nce d n o n- s mall cell l u n g ca ncer 
(a N S C L C): C hec k Mate 2 2 7 - part 2 fi nal a nal ysis. A n n O nc o l 2 0 1 9; 3 0(s u p pl 1 1): X 1 6 7-X 1 6 8 .
2 1
Par d oll D. D oes t he i m m u ne s yste m see t u mors as f or eig n or self? A n n u Re v I mm u n o l
2 0 0 3; 2 1: 8 0 7 - 3 9.
2 2
Zi t vo g el  L, Tes niere A, Kr oe m er G. Ca ncer des pite i m m u n os ur veilla nce: i m m u n oselecti on 
a n d i m m u n os u b versi on. Nat Re v I m m u n o l 2 0 0 6; 6: 7 1 5 - 2 7.
2 3
D u n n G P, Br uce A T, I ke da H, Ol d LJ, Sc hrei ber R D . Ca ncer i m m u n oe diti n g: fr om 
i m m u n os ur veilla nce t o t u m or esca pe. Nat I m m u n ol 2 0 0 2; 3: 9 9 1- 8.
2 4
Gree n wal d RJ, Free ma n GJ , S h ar pe A H. T he B 7 famil y  re visit ed. A n n u Re v I mm u n o l 
2 0 0 4; 2 3: 5 1 5 - 4 8.
2 5 Free ma n G J, L o n g AJ, I wai Y, et al. E nga ge me nt of  t he P D - 1 i m m u n o hi bit or y rece pt or b y a 
n o vel B 7 fa mil y me m ber lea ds t o ne gati ve re g ulatio n of  ly m p h oc y t e acti vat i on. J E x p M e d 
2 0 0 0; 1 9 2 1 0 2 7 - 3 4.
2 6
S har pe A H, W herr y EJ, A h me d R, Free ma n GJ . T he f u ncti on of pr o gra m me d cell deat h 1 a n d 
its li ga n ds i n re g ulati n g a ut oi m m u nity a n d i nfect i on. Nat I m m u n o l 2 0 0 7; 8: 2 3 9 - 4 5.
2 7
W o lch o k J D, H o os A, O’ Da y S, et al. G ui deli nes f or t he e val uat i on o f i m m u ne t hera p y acti vity 
i n s oli d t u m ors:  i m m u ne-r elate d res p o nse crit eria. Cli n Ca ncer Res 2 0 0 9; 1 5: 7 4 1 2 - 2 0.
2 8
He Y, Y u H, R oze b o o m  L, et al. L A G- 3 pr otei n ex pressi o n i n n o n -small c ell l u n g ca ncer a n d 
its relatio ns hi p wi t h PD- 1/ P D -L 1 a n d tu m or -infiltrat i n g ly m p h oc y tes. J T h orac O nc ol 
2 0 1 7; 1 2: 8 1 4 - 2 3.
2 9
O kaza ki T, O kaza ki I M, Wa n g 
J, et al. P D - 1 a n d L A G - 3 i n hi bit or y c o -rece pt ors act 
s y ner gisticall y t o pre ve nt a ut oi m m u nity i n mice. J E x p Me d 2 0 1 1; 2 0 8: 3 9 5 - 4 0 7.
3 0
Efficac y of a nt i-L A G -3 a nti b o d y  1 9 C 7 i n Sa 1 N t u m or -beari n g mice ( St u d y  B D X- 1 4 0 8-2 5 1). 
Bri st ol-M yers S q ui b b C o m pa n y; 2 0 1 3. D oc u me nt C o ntr ol N o. 9 3 0 0 7 1 2 6 5.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nica l Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
r elatli ma b
                                                                                                                                                                                  
3 1
A nt i-t u mor acti vit y of  ant i-P D - 1 a n d a nti-L A G - 3 a nti b o dies alo ne a n d i n c o m bi nat i on i n a 
S A 1 N fi br osarc o ma t u mor m o d el  (St u d y  MD X -1 1 0 6 -0 5 9). Brist ol -M yers S q ui b b C o m pa n y; 
2 0 1 3. D oc u me nt C o ntr ol  N o. 9 3 0 0 5 4 2 5 3.
3 2
C o nfir mati o n of  ant itu m or acti vit y o f ant i-L A G - 3 a nt i b o d y al one a n d i n c o m bi nat i on w ith a nt i-
P D - 1 a nti b o d y in a Sa 1 N fi br osarc o ma t u mor m o del  (St u d y  BD X - 1 4 0 8-2 2 4). Brist ol M yers 
S q ui b b C o m pa n y; 2 0 1 3. D oc u me nt C o ntr ol N o. 9 3 0 0 7 1 2 7 2.
3 3
Fee n e y K, Kell y R, Li pt o n L R, et  al. C A2 2 4- 0 6 0: a ra n d o mize d, o pe n label , p hase II trial of  
r elat li ma b (a nti-L A G -3) a n d ni v o l u ma b wi t h c he m ot hera p y vers us ni v o l u ma b wi t h 
c he m ot hera p y as first-li ne treat me nt i n parti ci pa nts wi t h gastric or gastr oes o p h a geal j u ncti on 
a de n ocarci n o ma. J Cli n O nc o l 2 0 1 9; 3 7( 1 5 s u p pl):a bstr T P S 4 1 4 3 .
4 2
Li ps o n, EJ, Ta w bi, H A, Sc ha de n d orf, D, et  al. Relat li ma b ( R E L A) pl us ni v o l u ma b ( NI V O) 
vers us NI V O i n first -li ne a d va nce d mela n oma: pri mar y p hase III res ults fr o m R E L A TI VI T Y -
0 4 7 ( C A 2 2 4 -0 4 7). J Cli n O nc o l 2 0 2 1; 3 9(s u p pl; a bstr 9 5 0 3).
4 3
H ussei n A. Ta w bi, M. D., P h. D., Dir k Sc ha de n d orf, M. D. Rel at li ma b a n d Ni v o l uma b vers us 
Ni v o l uma b i n U ntreate d A d va nce d Mela n o ma . N E n gl  J Me d 2 0 2 2; 3 8 6: 2 4- 3 4
4 4
Bl u me nt hal  G M, K ar uri S W, Z ha n g H, et al. O verall res p o nse rate, pr o gressio n -free s ur vi val, 
a n d o verall s ur vi val wi t h tar gete d a n d sta n dar d t hera pies i n a d va nce d n o n- s mall-cell l u n g 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nica l Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
r elatli ma b
                                                                                                                                                                                  
ca ncer: U S F o o d a n d Dr u g A d mi nistrati o n trial-le vel a n d parti ci pa nt -level a nal yses. J Cli n 
O nc o l. 2 0 1 5; 3 3( 9): 1 0 0 8-1 0 1 4. d oi : 1 0. 1 2 0 0/J C O. 2 0 1 4. 5 9. 0 4 8 9
4 5
Li ps o n EJ, Ta w bi H A, Sc ha de n d orf D, et al. Relat li ma b ( R E L A) pl us ni v o l u ma b ( NI V O) 
vers us NI V O i n first -li ne a d va nce d mela n oma: pri mar y p hase II I res ults fr om R E L A TI VI T Y -
0 4 7 ( C A 2 2 4 -0 4 7). J Cli n O nc o l 2 0 2 1; 3 9(s u p pl; a bstr 9 5 0 3).
4 6
H ussei n A. Ta w bi, M. D., P h. D., Dir k Sc ha de n d orf, M. D.
Relat li ma b a n d Ni v o l uma b vers us 
Ni v o l uma b i n U ntreate d A d va nce d Mela n o ma . N E n gl  J Me d 2 0 2 2; 3 8 6: 2 4- 3 4.
4 7
Pee y -S ei  K o k, W o n- Hee Y o o n, et  al. Tu m or Res p o nse E n d P oi nt s as S urr o gates f or O verall 
S ur vi val i n I mm u ne C hec k p oi nt I n hi bit or Tri als: A S y st e mat ic Re vie w a n d M et a -A nal ysis. 
J C O Precisi o n O nc ol og y  2 0 2 1; 5; 1 1 5 1- 1 1 5 9
4 8
Sta n dfiel d L, West o n A R, Barracl o u g h H, Va n K o ot e n M, Pa vla kis N. Hist ol o g y as a treat me nt 
effect m o difier i n a d va nce d n o n- s mall cell l u n g ca ncer: a s yste matic re vie w of  t he e vide nce. 
Res pir ol o g y  2 0 1 1; 1 6: 1 2 1 0- 2 0.
4 9
A p hase 3, ra n d o mize d st u d y of ni v ol u ma b pl us i pili m u ma b i n c o m bi nati o n wi t h che m ot hera p y
alo ne as first li ne t hera p y in sta ge I V n o n- s mall cell l un g ca ncer ( N S C L C) C A 2 0 9 9 L A:
Cli nical 
St u d y  
Re p ort. Brist ol -M yers  
S q ui b b 
C o m pa n y; 
2 0 2 0. 
D oc u m e nt C o ntr ol 
N o. 9 3 0 1 4 8 1 8 3.
5 0
A n o pe n -la bel, ra n d o mize d, p hase 3 trial of  ni v ol uma b, or ni v ol u ma b pl us i pili m u ma b, 
or ni v ol u ma b pl us plati n u m d o u blet c he m ot hera p y vers us pl at i n u m d o u blet c he m ot hera p y 
i ns u bjects wi t h che m ot hera p y nai ve sta ge I V or rec urre nt n o n- s mall cell l un g ca ncer 
( N S C L C) C A 2 0 9 2 2 7: Cli nical St u d y  Re p ort Part 2. Brist ol -M yers S q ui b b C o m pa n y; 2 0 1 9. 
D oc u m e nt C o ntr ol  N o. 9 3 0 1 4 5 2 6 6.
5 1
Jir o ute k M R. Pr o g n ostic fact ors i n a d va nce d n o n- s mall cell l u n g ca ncer: a nal ysis of  Easter n 
C o o perati ve O nc o l og y  gr o u p trials fr om 1 9 8 1 -1 9 9 2. A n n ual Meeti n g of t he A merica n S ociet y 
of  Cli nical O n c olo g y . L os A n geles, CA: Pr oc A m S oc Cli n O nc o l 1 7; 1 9 9 8 .
5 2
Br uec kl W M, Fic ker J H, Zei tler G. Cli nicall y rele va nt pr o g n osti c a n d pre dict i ve mar kers f or 
i m m u ne-c hec k p o i nt-i n hi bit or (I CI) t hera p y in n o n- s mall cell l u n g ca ncer ( N S C L C). B M C 
Ca ncer 2 0 2 0; 2 0, 1 1 8 5 - 1 2 0 1.
5 3
O P DI V O ( ni v ol uma b) U S Prescri bi n g I nf or mati o n. Pri ncet o n, NJ: Brist ol -M yers 
S q ui b b; 
2 0 2 0.
5 4
O p di v o ® A n ne x I S u m mar y of  Pr o d uct C haracterist ics. Bri st ol-M yers 
S q ui b b C o m pa n y; 
2 0 2 0 .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nica l Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
r elatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
1 2 
A P P E N DI C E S
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 1 
A B B R E VI A TI O N S A N D T R A D E M A R K S
Ter m
Defi niti o n
1 L
first li ne
A D A
a nt i-dr u g a nt i b o d y
A E
a d verse e ve nt
A L K
a na plast ic l y m p h oma ki nase
A L P
alkali ne p h os p hate
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 R T
a nt iretr o vir al t hera p y
A S C O
A merica n S ociet y f or Cli nical O nc ol og y
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n-ti me c ur ve
BI C R
bli n de d i n de pe n de nt ce ntral re vie w
BI D, bi d
bis i n die, t wice dail y
B M S
Bri st ol- M yers S q ui b b C o m p a n y
B O R
best o verall res p o nse
B P
bl o o d press ure
B R A F
B- r a pidl y  accelerate d fi br osarc o ma pr ot o-o nc o ge ne
B T L A
T-l y m p h oc y te atte n uat or
C
c ycle
C B C
c o mplete bl o o d c o u nt
CI
c o nfi de nce i nter val
C L
cleara nce
C Lss
stea d y-state cleara nce
C M H
C oc hra n -M a nt el -Hae nszel
C M V
c yt o me galo vir us
C N S
ce ntral ner v o us s yste m
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ter m
Defi niti o n
C O VI D - 1 9 
c or o na vir us disease 2 0 1 9
C R
c o mplete res p o nse
C r Cl
creati ni ne cleara nce
C R F
Case Re p ort F or m, pa per or electr o nic
C S R
cli nical st u d y re p ort
C T
c o mp ute d t o m o gra p h y
C T C
C o m m o n T o xi cit y Crit eria
C T C A E
C o m m o n Ter mi n o l og y  Crit eri a for A d verse E ve nts
C T L A - 4
c yt ot o xic T -l y m p h oc yte-ass ociate d pr otei n 4
D C
di sc o nti n uati on
DI LI
dr u g -i n d uce d li ver i nj ur y
D M C
Data M o nit ori n g C o m mittee
D o R
d urati o n of  res p o nse
E C G
electr ocar dio gr a m
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
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 g
e xe m pli gratia (f or e xa m ple)
e G F R
esti mate d gl o m er ular filtrat i on
E G F R
e pider mal  gr o wt h fact or rece pt or
E OI
e n d of i nf usi o n
E- R
e x p os ure-res p o nse
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ter m
Defi niti o n
E S M O
E ur o pea n S ociet y f or Me dical O nc o l og y
F D A
F o o d a n d Dr u g A d mi nistrati o n
F D C
fi xe d d ose c o m bi nati on
F G L - 1
fi bri n o ge n-li ke pr otei n 1
F S H
f ollicle sti m ulati n g h or m o ne
G B S
G uillai n -Barre s y n dr o me
H B V
he pat itis B vir us
H C G
h u ma n c h ori o nic g o na d otr o pi n
H C V
he pat itis C vir us
HI V
h u ma n im m u n o deficie nc y v irus
H R
hazar d rati o
I B
I n vesti gat or’s Br oc h ure
I C 5 0
half ma xi mal i n hi bit or y  c o nce ntratio n
I C F
i nf or me d c o nse nt f or m
I C O S
i n d uci ble T-cell c osti m ulat or
ie
i d est (t hat is)
I E C
I n de pe n de nt Et hics C o m mittee
I F N-γ
i nterfer o n-γ
I g
i m m u n o glo b uli n
I L
i nterle u ki n
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ter m
Defi niti o n
I M
i ntr a musc ular
I M A E
i m m u ne-me diate d a d verse e ve nt
I M G
i m m u n o ge nicity
I O
i m m u n o-o nc ol o g y
I P/I M P
In vest i gati onal ( Me dici nal) Pr o d ucts
I R B
I nstituti o nal  Re vie w B oar d
I R T
I nteracti ve Res p o nse Tec h n ol og y
I U
I nter nati o nal U nit
I V
i ntra ve n o us
K d
di ss o ciat i on c o nsta nt
L A G - 3
l y m p h oc yt e-acti vat i on ge ne 3
L D H
lactate de h ydr o ge nase
L V E F
left ve ntric ular eje ctio n f r a ctio n
Me d D R A
Me dical Dict i onar y f or Re g ulat or y  Acti vities
M H C
maj or hist oc o m pati bilit y c o mple x
m P F S
me dia n pr o gressi o n- free s ur vi val
M RI
ma g net ic res o na nce i ma gi n g
M T D
ma xi m u m t olerate d d ose
M U G A
m ult i ple gate d ac q uisiti on sca n
N
n u m ber of s u bjects or o bser vati o ns
N/ A
n ot a p plica ble
N CI
Nati o nal Ca ncer I nst itut e
N o n -I P/ N o n-I M P 
n o n- i n vesti gati onal (me dici nal ) pr o d ucts 
N S C L C
n o n- s mall c ell lu n g ca ncer
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ter m
Defi niti o n
N Q
n o n- q ua nt ifia ble
N S Q
n o n- s q ua m o us
O E SI
ot her e ve nts of s pecial i nterest
O F
O’ Brie n -Fle mi n g
O R R
o verall res p o nse rate
O S
o verall s ur vi val
P B M C
p eri p heral  blo o d m o n o n uclear cells
P D
pr o gressi ve disease
P D C T
pl at i n u m d o u blet c he m ot hera p y
P D - 1
pr o gra m me d cell deat h pr otei n 1
P D -L 1
pr o gra m me d deat h -li ga n d 1
P E T
p osi tr o n e missi on t o m o gra p h y
P F S
pr o gressi o n free s ur vi val
P GI C
Pati e nt Glo b al  I mpressi o n  of C ha n ge
P GI S
Pati e nt Glo b al  I mpressi o n  of Se verit y
P K
p har mac o ki net ics
P P K
p o p ul at i on p har mac o ki net ics
P R
parti al res p o nse
P R O
pati e nt re p orte d o utc o me
P S
perf or m a nce stat us
P T
preferre d ter ms
Q 2 W
e ver y 2 wee ks
Q 3 W
e ver y 3 wee ks
Q 4 W
e ver y 4 wee ks
Q 6 W
e ver y 6 wee ks
R C C
re nal cell ca ncer
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 5 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Ter m
Defi niti o n
R E CI S T
Res p o nse E val uat i on Cri t eria i n S oli d T u m ors
R N A
rib o n ucleic aci d
R T -P C R
re verse tra nscri pti o n p ol y merase c hai n reacti on
S A E
serio us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A R S -C o V - 2 
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2
S A V
si n gle a ge nt vial
S C
safety c o m mittee
S C C H N
s q ua m o us cell carci n o ma of t he hea d a n d nec k
S D
sta ble disease
S Q
s q ua m o us
t 1/ 2
eli mi nat i on half -life
T B, T. bili 
t otal bilir u bi n
T C R
T- cell rece pt or
TI Ls
t u mor i nfiltrat i n g l y m p h oc yt es
T R A E
treat me nt -relate d a d verse e ve nt
Tre g
T- re g ulat or y cells
T S H
t h yr oid- sti m ulati n g h or m o ne
T T E
tra nst h oracic ec h ocar di o gra m
U L N
u p per li mit of n or mal
U S PI
U S Prescri bi n g I nf or mati o n
Vss
v o l ume of distri b ut i on at stea d y  state
W O C B P
w o m e n of c hil d beari n g p ote ntial
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 2 
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S
T he ter m  ‘ Partici pa nt’ is use d i n t he pr ot oc ol t o refer t o a pers o n w h o has c o nse nte d t o partici pate 
in t he cli nical researc h st u d y. T h e t er m ‘S u bject’ use d i n t he C R F is i nte n de d t o refer t o a pers o n 
( Partici pa nt) w h o has c o nse nte d t o partici pate i n t he cli nical researc h st u d y.
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S
G O O D C LI NI C A L P R A C TI C E
T his st u d y  will be c o n d ucte d i n acc or da nce with:

C o nse ns us et hical pri nci ples deri ve d fr om i nter nati o nal g ui deli nes i ncl u di n g t he Declarat i on 
of  Helsi n ki a n d C o u ncil f or I nter nati onal Or ga nizat i ons of  
Me dical Scie nces ( CI O M S) 
I nter nati o nal Et hical G ui deli nes G o o d Cli nical Practice ( G C P), 

as a p plica ble b y t he I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) a n d G o o d Cli nical Pract ice 
( G C P) g uideli nes

i n acc or da nce wi t h the et hical pri nci ples u n derl yi n g E ur o pea n U ni o n Cli nical Tri al s Re g ulat i on 
5 3 6/ 2 0 1 4

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 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 oc ol. T he pr ot oc ol a nd a n y a me n d me nts 
a n d t he parti cipa nt i nf or me d c o nse nt will recei ve a p pr o val/fa v ora ble o pi ni o n b y I nstit utio nal 
Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (I R B/I E C) , a n d re g ulat or y a ut h orities acc or di n g t o 
a p plica ble l ocal re g ulat i ons pri or t o i nit iati on of t he st u d y .
All p ote nti al serio us breac hes m ust be re p orte d t o t he S p o ns or or desi g nee i m me diatel y. A 
p ote nti al serio us breac h is defi ne d as a Q uali t y Iss u e ( e g, pr ot oc ol de viat i on, etc) t hat i s li kel y t o 
affect, t o a sig nifica nt de gree o ne or m o re of  the f oll owi n g:  (1) t he p h ysical, safety or me nt al 
i nte grit y of one or m or e s u bjects/ partici pa nts; ( 2) t he scie ntific val ue of the t rial ( e g, relia bility a n d 
r o b ust ness of ge nerate d data). Ite ms ( 1) or ( 2) ca n be ass ociate d wit h either G C P Re g ulat i on(s) or 
Tri al pr ot oc ol(s).
Pers o n nel i n v ol ve d i n c o n d ucti n g t his st u d y will be q ualifie d b y e d 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). 
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E
Bef ore st u d y 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, partici pa nt 
recr uit me nt mat erials 
(eg, a d vertise me nts), a n d a n y ot h er wri tte n i nf or mati o n t o be pr o vi de d t o s u bjects/ partici pa nts. T he 
i n vesti gat or or B M S s h o ul d als o pr o vi de t he I R B/I E C wit h a c o p y of t he I n vesti gat or Br oc h ure or 
pr o d uct la beli n g i nf or mat i on t o be pr o vi de d t o s u bjects/ parti ci pa nts a n d a n y u p dates. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he i n vest i gat or, S p o ns or or desi g nee s h o ul d pr o vi de t he I R B/I E C wit h re p orts, up dates a n d ot her 
i nf or mat i on (eg, e x pe dite d safety re p orts, a me n d me nts, a n d a d mi nistrati ve letters) acc or di n g t o 
re g ulat or y re q uire me nts or inst itut i on pr oce d ures.
C O M P LI A N C E WI T H T H E P R O T O C O L A N D P R O T O C O L R E VI SI O N S
T he i n vesti gat or s h o ul d n ot i m ple me nt a n y de viati o n or c ha n ge t o t he pr ot oc ol  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 st u d y  s u bjects/ partici pa nts. 
If a de viati on 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 o r 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 ntatio 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 health a ut h orit 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 ntial ris k t o t he 
parti ci pa nt: ( 1) t he c o nse nt f or m must be re vise d a n d s u b mitt e d t o t he I R B(s)/I E C(s) f or re vie w 
a n d a p pr o val/fa v ora ble o pi ni o n; ( 2) t he re vise d f or m must be use d t o o btai n c o nse nt fr om 
s u bjects/ partici pa nts 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/ partici pa nts pri or t o e nr oll me nt.
If t he re visi on is d o ne via a n a d mi nistrati ve letter, i n vesti gat ors m ust i nf or m t heir I R B(s)/I E C(s).
FI N A N CI A L DI S C L O S U R E
I n vesti gat ors a n d s u b-I n vesti gat ors will pr o vi de t he S p o ns or wi t h sufficie nt, acc urate fi na ncial 
i nf or mat i on i n acc or da nce wi t h lo c al  re g ulatio ns t o all o w t he S p o ns or t o s u b mit c o mplete a n d 
acc urate fi na ncial cert ificati o n or di sclos ure state me nts t o t he a p pr o priate healt h a ut h orities. 
I n vesti gat ors are res p o nsi ble f or pro vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of 
t he st u d y a n d for 1 year after c o mplet i on of t he st u d y .
I N F O R M E D C O N S E N T P R OC E S S
I n vesti gat ors m ust e ns ure t hat s u bjects/ partici pa nts 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 ntia l ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he y v ol unt eer 
t o partici pate. 
I n sit u atio ns w here c o nse nt ca n n ot be gi ve n b y s u bjects/ partici pa nts, t heir le gall y acce pta ble 
re prese ntati ves (as per c o u ntr y gui deli nes) are clearl y a nd f ull y i nf or me d a b o ut t he p ur p ose, 
p ote nti al ris ks, a n d ot her critical iss ues re gar di n g cli nical st u dies i n w hic h t he partici p a nt 
v o l unt eers t o partici pate. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S p o ns or or desi g nee 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 here t o t he et hical pri nci ples 
t hat ha ve t heir ori gi n i n t he Declarati o n o f Helsi n ki.
I n vesti gat ors m ust:

Pr o vi de a c o p y  of t he c o nse nt f or m a n d writte n i nf or mati o n a b o ut t he st u d y i n t he la n g ua ge i n 
w hic h t he part ici pa nt is m ost pr oficie nt pri or t o cli nical st u d y partici pati 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 f or parti ci pa nt or partici pa nt's le gall y acce pta ble re prese ntati ve t o 
i n q uire a b o ut t he details of t he st u d y.

O btai n a n i nf or me d c o nse nt si g ne d a n d pers o nall y date d b y  t he participa nt or t he parti ci pa nt's 
le gall y acce pta ble re prese ntati ve a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt 
di sc ussi on. 

O btai n t he I R B/I E C’s writte n a p pr o val/fa v ora ble o pi ni o n o f the writte n i nf or me d c o nse nt f or m 
a n d a n y ot her i nf or mat i on t o be pr o vi de d t o t he s u bjects/ partici pa nts, pri or t o t he be gi n ni n g of 
t he st ud y, a n d after a n y re visi o ns are c o m plete d f or ne w i nf or mat i on.
If i nf or me d c o nse nt is i nitiall y gi ve n b y a partici pa nt’s le gall y acce pta ble re prese ntati ve or l e g al 
g uar di a n, a n d t he partici pa nt s u bse q ue nt l y bec o me s ca pa ble of ma ki n g a n d c o m m u nicati n g his or 
her i nf or me d c o nse nt d uri n g t he st u d y, c o nse nt m ust a d diti o nall y be o btai ne d fr o m t he partici pa nt.
Re vise t he i nf or me d c o nse nt w he ne ver i m p orta nt ne w i nf or mati on bec o me s a vaila ble t hat is 
r ele va nt t o t he partici pa nt's c o nse nt. T he i n vesti gat or, or a per s o n desi g nate d b y t he i n vesti gat or, 
s h o uld f ull y i nf or m the parti ci pa nt or t he parti ci pa nt's le gall y acce pta ble re prese ntati ve or le gal 
g uar di a n, of  all pert i ne nt as pects of  the st u d y an d of  an y ne w i nf or mati o n rele va nt t o t he 
parti ci pa nt's willi n g ness t o c o ntin ue parti ci pat i on i n t he st u d y. T his c o m m u nicati o n s h o uld be 
d oc u m e nte d. 
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y su bjects/ parti ci pa nts m u st 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’/ partici pa nts’ si g ne d I C F a n d, i n t he U S, t he s u bjects’/ partici pa nts’ si g ne d HI P A A 
A ut h ori zat i on.
T he c o nse nt f or m must als o i ncl 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 partici pa nt rec or ds. 
S u bjects/ partic i pa nts u na ble t o gi ve t heir writte n c o nse nt (e g, str o ke or s u bjects/ partici pa nts 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 with t he c o nse nt of  a le gall y acce pta ble 
re prese ntati ve. T he parti ci pa nt 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 xte nt 
c o mpat i ble wi t h his or her u n dersta n di n g, a n d s h o uld t his parti ci pa nt bec o me ca pa ble, he or s he 
s h o uld pers o nall y si g n a n d date t he c o nse nt f or m as s o o n as p ossi ble. T he e x plicit wis h of  a 
parti ci pa nt w h o is u na ble t o gi ve his or her wri tte n c o nse nt, b ut w h o is ca pa ble of  for mi n g a n 
o pi ni o n a n d assessi n g i nf or mat i on t o ref use partici pati o n i n, or t o be wit h dra w n fr o m, t he cli nical 
st u d y at a n y time s h o ul d be c o nsi dere d b y  t he i n vestigat or.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he rig hts, safety,  an d well -bei n g of  the st ud y s u bjects/ partici pa nts are t he m o st i m p orta nt 
c o nsi derati o ns a n d s h o ul d pre vail o ver i nterests of scie nce a n d s ociet y.
B M S C O M MI T M E N T T O DI V E R SI T Y I N
C LI NI C A L T RI A L S
T he missi o n of  BM S is t o tr a nsfor m  patie nts’ li ves t hr o u g h scie nce b y disc o veri n g, de vel o pi n g, 
a n d deli veri n g i n n o vat i ve me d ici nes t hat hel p t he m pre vail o ver seri o us di seases. 
B M S is c o m mitte d t o d oi n g its part t o e ns ure t hat patie nts ha ve a fair a n d j ust o p p ort u ni t y to 
ac hie ve o pti mal healt h o utc o mes.
B M S is w or ki n g t o i m pr o ve t he recr ui t me nt of a di verse partici pa nt p o p ul at i on wi t h t he g oal t hat 
t he cli nical trial bec o mes m ore reflect i ve of t he real-w orl d p o p ul at i on a n d t he pe o ple i m pacte d b y 
t he diseases st u die d.
D A T A P R O T E C TI O N, D A T A P RI V A C Y, A N D D A T A S E C U RI T Y
B M S c ollects a n d pr ocesses pers o nal data of  st u d y part ici pa nts, patie nts, healt h care pr o vi ders ,
a n d researc hers f or bi o p har mace ut ical researc h a n d de vel o p me nt t o a d va nce i n n o vati ve, hi g h -
q ualit y me dici nes t hat a d dress t he me dical nee ds of patie nts. B M S e ns ures t he pri vac y, pr otecti o n ,
a n d c o nfi de nt iality of  s uc h pers o nal d at a t o c o mpl y  wit h a p plica ble la ws. T o ac hie ve t hese g oals, 
B M S has i nter nal p o licies t hat i n dicate meas ures a n d c o ntr ols f or pr ocessi n g pers o nal data. B M S 
a d heres t o t hese sta n dar ds t o e ns ure t hat c ollect i on a n d p r ocessi n g of pers o nal data are li mite d a n d 
pr o p orti o nate t o t he p ur p ose f or w hic h B M S c ollects s uc h pers o nal data. T hi s p ur p ose is clearl y 
a n d u na m bi g u o usl y n otifie d t o t he i n di vi d ual at t he ti me of c o llecti on of pers o nal data. I n t he tr ue 
s pirit of scie nce, B M S is de dicate d t o s hari n g cli nical trial i nf or mat i on a n d data wit h parti ci pa nt s, 
me dical/researc h c o m m u nit ies, t he me dia, p olic y ma kers, a n d t he ge neral p u blic. T his is d o ne i n a 
ma n ner t hat safe g uar ds parti ci pa nt pri vac y  a n d i nf or me d c o nse nt w hile res pect i n g t he i nte grity of  
nat i onal re g ulat or y syste ms. Cli nical trial data, healt h -relate d researc h, a n d p har mac o vi gila nce 
acti vit ies o n k e y -c o de d healt h data tra nsferre d b y B M S acr oss nati o nal b or ders is d o ne i n 
c o mpl ia nce with t he rel e va nt data pr otecti o n la ws i n t he c o u ntr y a n d G C P re q uire me nts.
B M S pr otects Pers o nal I nf or mati on wi t h ade q uate a n d a p pr o priate sec urity c o ntr ols as i n dicate d 
u n der t he data pr otecti o n la ws. T o ali g n wi t h the rec o m me n de d sec urity sta n dar ds, B M S has 
a d o pte d i nter nal sec urity sta n dar ds a n d p olicies t o pr otect pers o nal data at e ver y sta ge of 
its pr ocessi n g.
T o s u p ple me nt t hese sta n dar ds, B M S e nters i nt o C li nical T rial Agree me nt s ( C T A gs) wi t h 
c o nfi de nt iality o bli gat i ons t o e ns ure pr o per ha n dli n g a n d pr otecti o n of  pers o nal data b y t hir d 
parti es accessi n g a n d ha n dli n g pers o nal data.
B M S ta kes u na ut h orize d access a n d discl os ure of  Pers o nal I nf or mat i on ver y  serio usl y. B M S has 
a d o pte d t he sec urity sta n dar ds t hat i ncl u de Nati o nal I nstitute of  Sta n dar ds a n d Tec h n o l og y 
C y bersec urit y Fra me w or k f or st u dies i n t he U S . B M S ali g ns with t hese sta n dar ds t o c o nti n u o usl y 
assess a n d i m pr o ve its a bilit y t o pr otect, detect, a n d res p o n d t o c y ber attac ks a n d ot her 
u na ut h ori ze d atte mpts t o access pers o nal data. T hese sta n dar ds als o aid i n mit i gati n g p ossi ble 
a d verse effects. F urt her m ore, B M S I nf or mati on Tec h n o l og y  has defi ne d 6 pri nci ples t o pr otect o ur 
di gi t al res o urces a n d i nf or mat i on: 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
1)
Res p o nsi bilit ies of I T Pers o n nel
2)
Sec uri n g t he B M S Di gital I nfrastr uct ure
3)
I de ntit y a n d Access Ma na ge me nt
4)
E xter nal Part ner C o n nect i ons
5)
C y ber T hreat Detecti o n a n d Res p o nse
6)
I nter nal C y ber I nci de nt I n vesti gati on
S O U R C E D O C U M E N T S
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 mp ora ne o us, ori gi 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 
electr o nicall y. If s o urce data are create d (first e ntere d), m o difie d, mai ntai ne d, arc hi ve d, retrie ve d, 
or tra ns mitte d electr o nicall y via c o m p uterize d s yste ms (a n d/ or a n y ot h er ki n d of  electr o nic 
de vices) as part 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 
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 r ec 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 ul d 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. 
S T U D Y T R E A T M E N T R E C O R D S
Rec or ds f or stu d y treat me nts relatli ma b, ni v o l u ma b, a n d P D C T ( 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 st u d y treat me nt i nte grit y an d tracea bility fr om recei pt, 
pre parati o n, a d mi nistrati o n, a n d t hr o u g h destr ucti o n or ret ur n. Rec or ds m ust be ma de a vaila ble f or 
re vie w at t he re q uest of B M S/ desi g nee or a Healt h A ut h orit y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
If
T he n
S u p plie d b y B M S 
( or its 
ve n d ors):
Rec or ds or l ogs m ust c o mpl y wi t h ap plica ble r e g ulat i 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 dis pe nse d t o a n d ret ur ne d b y  eac h partici pa nt , 
i ncl u di n g u ni q ue part ici pa nt i de ntifiers

a mo u nt tra nsferre d t o a n ot her area/site f or di s pe nsi n g or 
st ora ge

n o nst 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 site, 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/ bi oc o m para bilit y,  if 
a p plica ble 

dates a n d i nit ials 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 g atio n of  
A ut h ori t y For m .
S o urce d 
b y sit e, a n d n ot 
s u p plie d b y 
B M S 
or 
its 
ve n d ors (e xa m ples i ncl u de I P 
s o urce d fr o m t he sites st oc k 
or c o m mercial s u p pl y, or a 
s pecialty p har mac y)
T he 
i n vesti gat or or 
desi g nee 
acce pts res p o nsi bility 
f or 
d oc u m e nt i n g tracea bility a n d st u d y treat me nt i nte grit y in 
acc or da nce wi t h re q uire me nts a p plica ble u n der la w a n d t he 
S O Ps/sta n dar ds of t he s o urci n g p har mac y.
B M S or desi g nee will  pr o vi de f or ms t o facilitate i n ve nt or y c o ntr ol if t he i n vesti gati o nal site d oes
n ot ha ve a n esta blis he d s yste m t hat meets t hese re q uire me nts.
C A S E R E P O R T F O R M S
A n i n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d 
t o rec or d all o bser vat i ons a n d ot h er data perti ne nt t o t he i n vesti 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 di scre pa ncies m ust be 
e x plai ne d. A d dit i onal cli nical 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 or desi g nee electr o nic data ca pt ure t o ol, electr o nic C R Fs will be 
pre pare d f or all data c 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 electr o nic S A E f or m an d Pre g na nc y S ur veilla nce f or m, res pecti vel y. If 
electr o nic S A E f or m is n ot a vaila ble, a pa per S A E f or m ca n be use d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T he c o nfi de ntialit y of rec or ds t hat c o ul d i de ntif y su bjects/ parti ci pa nts m u st be pr otecte d, 
res pecti n g t he pri vac y a n d c o nfi de ntialit y r ules in acc or da nce wi t h the 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, must be pr o m 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 vestigat or a n d w h o is dele gate d t hi s tas k o n t he 
Del 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. T he i nvest i gat or m ust retai n a c o p y of t he C R Fs i ncl u di n g rec or ds of  the c ha n ges a n d 
c orrectio ns.
Eac h i n di vi d ual electr o nicall y si g ni n g electr o nic C R Fs m ust meet S p o ns or or desi g nee trai ni n g 
re q uire me nts a n d m ust o nl y  access t he B M S electr o nic data ca pt ure t o ol usi n g t he u ni q ue user 
acc o u nt pr o vi de d b y S p o ns or or desi g nee. User acc o u nts are n ot t o be s hare d or reassi g ne d t o ot her 
i n di vi d uals
M O NI T O RI N G
M o ni t ori n g details descri bi n g strate g y, i ncl u di n g defi nit i on of  st u d y critical data ite ms a n d 
pr ocesses (e g, ris k-base d i nitiati ves i n o perati o ns a n d q uali t y suc h as ris k ma na ge me nt a n d 
mit i gati on strate gies a n d a nal ytical ris k-base d m o nit ori n g), met h o ds, res p o nsi bilities, a n d 
re q uire me nts, i ncl u di n g ha n dli n g of  no nc o m p lia nce iss ues a n d m o nit ori n g tec h ni q ues (ce ntral, 
r e mot e , or o n-sit e mo ni t orin g) are pr o vi de d i n t he m o nit ori n g pla n.  
Re prese ntati ves of B M S m ust be all o we d t o visit all st u d y  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 re mai n acce pta ble.
I n a d ditio n, t he st u d y  ma y be e val uate d b y S p o ns or or desi g nee i nter nal a u dit ors a n d g o ver n me nt 
i ns pect ors w h o m ust be all o we d access t o C R Fs, s o urce d oc u me nts, ot her st u d y files, a n d st u d y 
facilities. B M S a u dit re p orts will be ke pt c o nfi de ntial.
T he i n vesti gat or m ust n otif y B M S pr o m ptl y of  an y i ns pect i ons sc he d ule d b y re g ulat or y a ut h orities, 
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 S p o ns or or desi g nee.
R E C O R D S R E T E N TI O N
T he i n vesti gat or ( 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 f or t he peri o d s pecifie d b y B M S or desi g nee, w hic he ver is l 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 ust c o ntact B M S pri or t o destr o yi n g a n y rec or ds 
ass ociate d wit h t he st u d y.
B M S or d esi g nee will  notif y t he i n vest i gat or ( or hea d of  t he st u d y sit e 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.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
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, retire me nt), t he rec or ds s hall be 
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 site, I R B). N otice 
of  s uc h tra nsfer will be gi ve n i n writi n g t o B M S or desi g nee. 
R E T U R N O F S T U D Y T R E A T M E N T
F or t hi s st u d y, st u d y treat me nts (t h ose s u p plie d b y B M S, a ve n d or or s o urce d b y t he i n vesti gat or) 
s uc h as partiall y use d st u d y treat me nt c o ntai ners, vials a n d s yri n ges ma y be destr o ye d o n sit e. 
If..
T he n
St u d y  treat me nts s u p plie d b y 
B M S (i ncl u di n g its ve n d ors
A n y u n use d st u d y  tr e at me nts s u p plie d b y B M S ca n o nl y  be 
destr o y e d after bei n g i ns pecte d a n d rec o ncile d b y t he 
res p o nsi ble St u d y  M o ni t or u nless 
st u d y treat me nts 
c o ntai ners m ust be i m me diatel y destr o y e d as re q uire d f or 
safety,  or t o meet 
l ocal re g ulat i ons (e g, c yt ot o xi cs or 
bi o l ogics).
If st u d y treat me nts will be ret ur ne d, t he ret ur n will be 
arra n ge d b y t he res p o nsi ble St u d y M o nit or.
St u d y  tr e at me nts s o urce d b y sit e, 
n ot s u p plie d b y B M S 
( or its 
ve n d ors) (e xa m ples i ncl u de st u d y 
treat me nts s o urce d fr o m t he sit es 
st o c k or c o m mercial s u p pl y, or a 
s pecialty p har mac y)
It is t he i n vesti gat or’s or desi g nee’s res p o nsi bilit y t o dis p ose 
of  all c o ntai ners acc or di n g t o t he i nst ituti o nal  g ui deli nes a n d 
pr oce d ures.
It is t he i n vesti gat or’s or desi g nee’s res p o nsi bilit y t o arra n ge f or dis p osal, pr o vi de d t hat pr oce d ures 
f or pr o per dis p osal ha ve bee n esta blis he d acc or di n g t o a p plica ble fe deral, state, l ocal, a n d 
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 p osal 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.

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 tracea bility 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, i e, 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 vestigat or’s or desi g nee’s res p o nsi bilit y t o arra n ge f or dis p osal of all e m pty c o ntai ners.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
If c o n diti ons f or destr ucti o n ca n n ot be met t he res p o nsi ble St u d y M o nit or will ma ke arra n ge me nts 
f or ret ur n of  st u d y treat me nts pr o vi de d b y B M S ( or its ve n d ors). Destr uct i on of  no n - st u d y 
treat me nts s o urce d b y t he site, n ot s u p plie d b y B M S, is s olel y t he res p o nsi bilit y o f the i n vest i gat or 
or desi g nee.
I n or der t o be nefit p ote ntial st u d y p artici pa nts, patie nts, healt hcare pr o vi ders a n d researc hers, a n d 
t o  help B M S h o n or its c o m mit me nts t o st u d y  partici pa nts, B M S will ma ke i nf or mati o n a b o ut  
cli nical researc h st u dies a n d a s u m mar y of  their res ults a vaila ble t o t he p u blic as per re g ulat or y 
a n d B M S re q uire me nts. B M S will p ost st u d y inf or mat i on o n l o c al , n atio nal  or r e gio nal  data bases 
i n c om p lia nce wit h nati onal a n d i nter nat i onal sta n dar ds f or discl o s ure. B M S ma y als o v olu ntaril y 
di s close i nf or mat i on t o a p plica ble data bases.
C LI NI C A L S T U D Y R E P O R T
A Si g nat 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 eac h C S R relate d t o t his pr ot oc ol , t he f oll owi n g crit eria will be use d t o select t he si g nat or y 
i n vesti gat or:

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

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 desig nee

Parti cipa nt recr ui t me nt (e g, a mo n g t he t o p q uartile of e nr ollers)

I n v ol ve me nt i n trial desi g n

Re gi o 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 re gio n  or c o u ntr y)
I n or der t o be nefit p ote ntial st u d y p artici pa nts, patie nts, healt hcare pr o vi ders a n d researc hers, a n d 
t o hel p B M S h o n or its c o m mit me nts t o stu d y p arti ci pa nts, B M S will ma ke i nf or mati on a b o ut 
cli nical researc h st u dies a n d a s u m mar y of  their res ults a vaila ble t o t he p u blic as per re g ulat or y 
a n d B M S re q uire me nts. B M S will p ost st u d y  inf or mat i on o n l o c al , n atio nal  or r e gio nal  data bases 
i n c om p lia nce wit h nati onal a n d i nter nat i onal sta n dar ds f or discl o s ure. B M S ma y als o v olu ntaril y 
di s close i nf or mat i on t o a p plica ble data bases.
S CI E N TI FI C P U B LI C A TI O N S
T he data c ollecte d d uri n g t hi s st u d y are c o nfi de ntial a n d pr o priet ar y t o S p o ns or or desig nee. 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) g o ver ni n g [ St u d y site or I n vesti gat or] partici pat i on 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 
S p o ns or or desi g nee at t he earliest practica ble ti me pri or t o s u b missi on or prese ntati o n a n d 
ot her wi se wit hi n t he ti me peri o d set f ort h i n t he C T A g.
S ci e nt ific P u blicat i ons (s uc h as a bstracts, c o n gress p o di u m  prese ntatio ns a n d p osters, a n d 
ma n uscri pts) of t he st u d y  r es ults will be a c olla b orati ve eff ort bet wee n t he st u d y S p o ns or a n d t he 
e xter nal a ut h ors.  N o p u blic prese ntati o n or p u blica tio n of a n y i nteri m res ults ma y be ma de b y a n y 
pri nci pal i n vesti gat or, s u b-i n vesti gat or or a n y ot her me m ber of  the stu d y staff wi t ho ut t he pri or 
wri tte n c o nse nt of t he S p o ns or.  
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 6 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A ut h ors hi p of  pu blicat i ons at B M S is ali g ne d wi t h t he criteria of  t he I nter natio nal C o m mittee of 
Me dical J o ur nal E dit ors (I C MJ E, w w w.ic mje. or g). A ut h ors hi p select i on is base d u p o n si g nifica nt 
c o ntri b uti o ns t o t he st u d y (ie, I C MJ E criteri o n # 1). A ut h ors m ust me et all 4 I C MJ E crit eria f or 
a ut h ors hi p:
1)
S u bsta nt ial i ntellect ual c o ntri b utio n t o t he c o nce pti o n or desi g n of t he w or k; or t he ac q uisit i on 
of  data (ie, e val ua ble s u bjects wit h q uality dat a), a nal ysis, or i nter pretati o n of data f or t he w or k 
(e g, pr o ble m s ol vi n g, a d vice, e val uati on, i nsi g hts a n d c o ncl usi o n) ; A N D
2)
Drafti n g t he w or k or re visi n g it crit icall y f or i m p orta nt i ntellect ual c o nte nt; A N D
3)
Fi nal a p pr o val of t he versi o n t o be p u blis he d; A N D
4)
A gree me nt t o be acc o u nta ble f or all as pects of  t he w or k i n e ns uri n g t hat q uesti o ns relate d t o 
t he acc urac y or i nte grit y of a n y p art of t he w or k are a p pr o priatel y i n vest i gate d a n d res ol ve d.
T h ose w h o ma ke t he m o st sig nifica nt c o ntri b ut i ons, as defi ne d a b o ve, will be c o nsi dere d b y B M S 
f or a ut h ors hi p of  t he pri mar y p u blicat i on. S u b -i n vesti gat ors will ge nerall y  not be c o nsi dere d f or 
a ut h ors hi p in t he pri mar y  p u blicati on. Ge o gra p hic re prese ntati o n will als o be c o nsi dere d.  
A ut h ors will be liste d b y  or d er of si g nifica nt c o ntri b uti ons ( hi g hest t o l o west), wi t h t he e xce pti on 
of  the last a ut h or. A ut h ors i n first a n d last p osi tio n ha ve pr o vi de d t he m o st sig nifica nt c o ntri b uti o ns 
t o t he w or k. 
F or sec o n dar y a nal yses a n d r elate d p u blicat i ons, a ut h or list a n d a ut h or or der ma y var y  fr o m 
pri mar y t o reflect a d di tio nal c o ntri b ut i ons.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 3 
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S: 
D E FI NI TI O N S A N D P R O C E D U R E S F O R R E C O R DI N G , 
E V A L U A TI N G, F O L L O W U P A N D R E P O R TI N G
A D V E R S E E V E N T S
A d verse E ve nt Defi niti o n:
A n A d verse E ve nt ( A E) i s defi ne d as a n y ne w u nt o war d me dical occ urre nce or w orse ni n g of a 
pree xist i n g me dical c o n diti on i n a c li nical i n vesti gati o n partici pa nt a d mi nistere d st u d y treat me nt
a n d t hat d oes n ot ne cessaril y ha ve a ca usal r el atio ns hi p wi t h t his treat me nt. 
A n A E ca n t heref ore be a n y u nf a v ora ble a n d u ni nte n de d sig n (s uc h as a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of st u d y 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 io ns 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.

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 ver 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 pecif 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).
D E FI NI TI O N O F S A E
If a n e ve nt is n ot a n A E per defi nit i on a b o ve, t he n it ca n n ot be a n S A E e ve n if serio us c o n ditio ns 
are met.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S E RI O U S A D V E R S E E V E N T S
Seri o us A d verse E ve nt ( S A E) is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y 
d ose:
Res ults i n deat h
Is life-t hreate ni n g ( defi ne d as a n e ve nt i n w hic h t he parti ci pa nt w as at ri s k of deat h at t he ti me 
of  the 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 ui res i n patient  h os pitalizati o n or ca uses pr ol o n gati o n of e xisti n g h os pi talizati on (see N O T E 
bel o w)
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 pi t al de part me nt < 2 4 h o urs, t hat d oes n ot res ul t 
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)

e lecti 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 heal t h assess me nt re q uiri n g a d missio n f or baseli ne/tre n di n g of  healt h stat us (e. g., 
r o utine c ol o n osc o p y )

me dical/s ur gical a d missi o n ot her t ha n t o re me d y ill healt h a n d pl a n ne d pri or t o e ntr y i nto 
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 circ u msta nce t hat carries n o beari n g o n healt h stat us 
a n d re q uires n o me d ical/s ur gical i nter ve ntio n (e. g., lac 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 circ u msta nces, a d mi nistrati ve reas o n)

a d missi o n f o r a d mi nistrati o n of a ntica ncer t hera p y i n t he a bse nce of a n y ot her S A Es (a p plies 
t o o nc ol o g y pr ot oc ols)
Res ults i n persis te nt or sig nifica nt di sa bilit y/i nca pacit y
Is a c o n ge nital a n oma l y/ birt h defect
Is a n i m p orta nt me dical e ve nt ( defi ne d as a me d ical e ve nt(s) t hat ma y n ot be i m me diatel y life-
t hreate ni n g or res ult i n deat h or h os pi talizati on b ut, base d u p o n a p pr o priate me d ical a n d 
scie ntific j u d g me nt, ma y je o par dize t he partici pa nt or ma y re q uire i nter ve nt i on [e. g., me d ical, 
s ur gical] t o pre ve nt o ne of t he ot her serio us o utc o mes liste d i n t he defi nit i on a b o ve.) E xa m ples 
of  suc h e ve nts i ncl u de, b ut are n ot li mite d t o, i nte ns i ve tr e at me nt i n a n e mer ge nc y ro 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 9. 2. 7 f or t he defi niti on of p ote nti al DI LI.) 
Pre g na nc y a n d p ote nti al dr u g i n d uce d li ver i nj ur y ( DI LI) m ust f oll ow t he sa me tra ns missi on t i mi n g 
a n d pr ocesses t o B M S as use d f or S A Es (see  secti o n 9. 2. 5 f or re p orti n g pre g na ncies).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A n y c o m p o ne nt of a st u d y  e n d p oi nt t hat is c o nsi dere d relate d t o st u d y t hera p y s ho ul d be re p orte d 
as S A E (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 u st be 
re p orte d).
E V A L U A TI N G A E S A N D S A E S
Assess me nt of C a us alit y

T he i n vesti gat or is o bli gate d t o assess t he relat i ons hi p bet wee n st u d y  int er ve nt i on a n d eac h 
occ urre nce of eac h A E/ S A E.

A “reas o na ble p ossi bilit y” of  a relat i ons hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relat i ons hi p ca n n ot be r ul e d o ut.

T he i n vest i gat or will use cli nical j u d g me nt t o deter mi ne t he relati ons hi p.

Alt er nat i ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati ons hi p of t he e ve nt t o st u d y i nter ve nt i on a d mi n istratio n 
will be c o nsi dere d a n d i n vest i gate d.

T he i n vesti gat or will 
als o c o ns ult t he I n vesti gat or’s Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mat i on, f or mar kete d pr o d ucts, i n his/ her assess me nt.

F or eac h A E/ S A E, t he i n vesti gat or m u st d oc u me nt i n t he me d ical n ote s t hat he/s he has 
re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usality.

T here ma y be sit u atio ns i n w hic h a n S A E has o c c urre d a n d t he i n vesti gat or has mi ni ma l 
i nf or mat i on t o i ncl u de i n t he i nit ial re p ort t o S p o ns or. H o we ver, it is ver y i m p orta nt t hat t he 
i n vesti gat or al wa ys ma ke a n assess me nt of  ca usalit y f or e ver y e ve nt bef ore t he i nitial 
tra ns missi on of t he S A E data t o S p o ns or.

T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of  ca usalit y i n li g ht of  fol l ow- u p i nf or mati on 
a n d se n d a S A E f o ll ow- u p re p ort wi t h t he u p date d ca usality assess me nt.

T he ca usalit y assess me nt is o ne of  t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts.
F oll o w -u p of A Es a n d S A Es
If o nl y  li mite d i nf or mati on is i nitiall y a vaila ble, f oll o w-u p re p orts are re q ui re d. ( N ote: F ollo w -
u p S A E re p orts m ust i ncl u de t he sa me i n vest i 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 ons hi p t o st u d y treat me nt or if ne w 
i nf or mat i on bec o me s a vaila ble, t he S A E re p ort m ust be u p date d a n d s u b mitte d wit hi n 2 4 h o urs 
t o B M S ( or desi g nee) usi n g t he sa me pr oce d ure use d f or tra ns mitti n g t he i nitial S A E re p ort.
All S A Es m ust be f o ll owe d t o res ol ut i on or sta bilizati o n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
R E P O R TI N G O F S A E S T O S P O N S O R O R D E SI G N E E

S A Es, w het her r elate d or n ot relate d t o st u d y treat me nt, a n d pre g na ncies m ust be re p orte d 
t o B M S ( or desi g nee) i m me diatel y withi 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.

T he re q uir e d met h o d f or S A E data re p orti n g is t hr o u g h t he e C R F.

T he pa per S A E Re p ort F or m  is o nl y i nte n de d as a bac k - u p o pti o n w he n t he electr o nic 
data ca pt ure ( E D C) s y st e m is u na vaila ble/ n ot f u nctio ni n g f or tra ns missi on of  t he e C R F 
t o B M S ( or desi g nee).

I n this case, t he pa per f or m is tra ns mitte d via e mail or c o nfir me d facsi mile (fa x) 
tra ns missi on

W he n pa per f or ms are use d, t he ori gi nal pa per f or ms are t o re mai n o n site

Pre g na ncies m ust be rec or de d o n a pa per Pre g na nc y  S ur veilla nce F or m a n d tra ns mitt e d vi a 
e mail or c o nfir me d facsi mile (fa x) tra ns missi o n
S A E E m ail A d dress: Refer t o C o nt act I nf or m ati o n list.
S A E F acsi mile N u m ber: Refer t o C o nt act I nf or m ati o n list.
S A E Tele p h o ne C o nt act
(re q uire d f or S A E a n d pre g na nc y  re p ortin g): Refer t o C o ntact 
I nf or mat i on list
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 4 
W O M E N O F C HI L D B E A RI N G P O T E N TI A L D E FI NI TI O N S A N D 
M E T H O D S O F C O N T R A C E P TI O N
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. 
P er m a 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 he f o ll 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 ntatio 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 state is defi ne d as 1 2 mo n t hs of a me n orr hea i n a w o ma n o ver a ge 4 5 years 
i n t he a bse nce of  ot her bi o l ogi cal or p h ysiol o gical ca uses. I n a d ditio n, females u n der t he a ge 
of  55 years m ust h a ve a ser u m follicle sti m ulati n g h or m o ne, ( F S H) level > 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 re 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 le vels 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 urati o n of  t he was h o ut peri o d is a f uncti o n of  t he t ype of  HR T use d. T he d urati o n of 
t he was h o ut peri o d bel 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 ul d 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  for va gi nal h or m o n al  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 t he ser u m FS 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.
E n d of Rele v a nt S yste mic E x p os ure

E n d of  rele va nt s yste mic e x p os ure is t he time p oi nt w here t he I M P or a n y act i ve maj or 
meta b o lites has decrease d t o a c o nce ntrati o n t hat is n o l on ger c o nsi dere d t o be rele va nt f or 
h u ma n terat o ge nicity or fetot o xi cit y. T his s h o uld be e val uate d i n c o nte xt of  safet y mar gi ns 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
fr om t he n o -o bser ve d a d verse effect le vel ( N O A E L) or t he ti me re q uire d f or 5 half -li ves of t he 
I M P t o pass.
M E T H O D S O F C O N T R A C E P TI O N
L ocal  la ws a n d re g ulati ons ma y re q uire use of alter nat i ve a n d/ or a d diti onal c o ntrace pti o 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 m o nal  co ntrace pti o n ass ociate d wi t h 
i n hi biti on of  o vul at i on a n d/ or i m pla ntatio n ( T hi s met h o d of c o ntrace ptio n ca n o nl y  be use d 
b y W O C B P parti ci pa nts i n st u dies w here h or mo nal  c o ntrace ptio n is per mitte d b y  t he st u d y 
pr ot oc ol )b 

o ral ( birt h c o ntr ol pills)

i ntra va gi nal ( va gi nal birt h c o ntr ol s u p p osit ories, ri n gs, crea ms, gels)

tra ns der mal 

C o m bi ne d (estr o ge n-a n d pr o gest o ge n -c o ntai ni n g) h or m o nal  co ntrace pti o n m u st be gi n at 
least 3 0 da ys prior t o i ni tiatio n of  st u d y t hera p y

Pr o gest o ge n -o nl y  hor m o nal  co ntrace pti o n ass ociate d wit h i n hi biti on of  ov ulat i on ( T his 
met h o d of  co ntrace pti o n ca n o nl y 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 ptio n is per mitte d b y  t he st u d y pr ot oc ol)b 

or al  

i njecta ble 

Pr o gest o ge n -o nl y  hor m o nal c o ntrace ptio n m u st be gi n at least 3 0 da y s pri or t o i ni tiat i on of 
st u d y t hera p y
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  hor m o n al  co ntrace pti o n ass ociate d wit h 
i n hi biti on of 
o v ul at i on a n d/ or i m pla ntati o n ( T his met h o d of c o ntrace pti o n ca n o nl y  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 per mitte d b y  t he st u d y pr ot oc ol)b

I ntra uteri ne de vice (I U D)

I ntra uteri ne h or m o ne- releasi n g s yste m (I U S) ( T his met h o d of  co ntrace pt i on ca n o nl y  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 n al c o ntrace ptio n is per mitte d b y t h e 
st u d y pr ot oc ol) b , c

Bilateral t u bal occl usi o n

Vasect o mize d part ner
Male partici pa nts will b e  re q uir e d t o al wa ys use a late x or ot her s y nt hetic c o n d o m d uri n g a n y s ex ual 
acti vit y (e g, va gi nal, a nal, oral) wit h W O C B P; 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 or if t heir part ner is alrea d y pre g na nt or breastfee di n g.
 
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 effective met h o d o nly if defi ne d as refr ai ni n g fr o m 
heter osex u al i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wi t h t he st u dy tre at me nt. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
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  the 
st u dy a n d t he preferre d an d us u al lifestyle of t he p artici p a nt.

C o nti n u o us a bsti ne nce m ust be gi n at least 3 0 da ys pri or t o i nit iati on of st u d y  t hera p y

It is n ot necessar y t o use a n y ot her 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 co m plete 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 ghl y  effecti ve c o nt race pti o n m u st 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.

P eri o dic a bst i ne nce (i ncl u di n g b ut n ot li mite d t o cale n dar, s y m pt ot her mal, p ost -o v ulati o n 
met h o ds), wit h dra wal ( c oit us i nterr u pt us), s per mici des o nl y, a n d lactatio nal  ame n orr h oea 
met h o d ( L A M) are n ot acce pta ble met h o ds of c o ntrace pti o n f or t his st u d y .
N O T E S: 
a
T y pical use fail ure rates ma y  differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be c o nsiste nt 
wit h l ocal re g ulati o ns re gar di n g t he use of c o ntrace pti ve met h o ds f or partici pa nts partici pati n g i n cli nical st u dies. 
b
H or m o nal c o ntrace pti o n m a y be s usce pti ble t o i nteracti o n wit h t he st u d y treat me nt, w hic h ma y  re d uce t he 
efficac y of t he c o ntrace pti ve met h o d. H or m o nal c o ntrace pti o n is per missi ble o nl y  wh 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 onal e x p os ures s uc h t hat c o ntrace pti o n 
w o ul d be i neffecti ve or res ult i n i ncrease d e x p os ures t hat c o ul d be p ote ntiall y hazar d o us.  I n t his case, alter nati ve 
met h o ds of c o ntrace pti o n s h o ul d be utilize d. 
c
I ntra uteri ne h o r m one releasi n g s yste ms are acce pta ble met h o ds of c o ntrace pti o n i n t he a bse nce of defi niti ve dr u g 
i nteracti o n st u dies w he n h or m o ne e x p os ures fr o m i ntra uteri ne de vices d o n ot alter c o ntrace pti o n effecti ve ness
Less T h a n Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds T h at Are User De pe n de nt
F ail ure r ate of > 1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly.

Male or female c o n d o m wi t h or with o ut s per mici de.  Mal e a n d female c o n d o ms ca n n ot be 
use d si m ulta ne 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 actio 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)
U n acce pt a ble Met h o ds of C o ntr ace pti o n

P eri o dic a bst i ne nce (cale n dar, s y m pt ot her mal, p ost-o v ul atio n met h o ds)

Wit h dra wal(c o itus 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)
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
C O L L E C TI O N O F P R E G N A N C Y I N F O R M A TI O N
G ui da nce f or c ollecti o n of  Pre g na nc y Inf or m at i on a n d o utc 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. 5  a n d t he A p pe n di x f or A d verse E ve nts a n d Seri o us 
A d verse E ve nts Defi nit i ons a n d pr oce d ures f or E val uat i n g, F oll ow- u p a n d Re p orti n g .
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 5 
R E S P O N S E E V A L U A TI O N C RI T E RI A I N S O LI D T U M O R S 
G UI D E LI N E S ( V E R SI O N 1. 1) WI T H B M S M O DI FI C A TI O N S
1 
E V A L U A TI O N O F L E SI O N S
S oli d t u mors will be e v aluate d usi n g R es p o nse E val uat i on C riteria In S ol i d T u m ors versi o n 1. 1 
( R E CI S T 1. 1) g ui deli ne wit h B M S m o dificati o ns.1
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 ura ble as 
f oll ows:
1. 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 pat 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 ust 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 be 
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 ns m u st meet t he criteri o n of  a sh ort a xis of 
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 ra 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 mo r. 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 (f or C T sca n t his is al most al wa 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 gitt al or cor o nal ). T he s maller of t hese meas ures is t he sh ort a xi s. 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 o f 2 0 m m 
a n d q ualifies as a ma li g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s ho ul d be rec or de d as t he 
n o de me as ure me nt. All ot h er pat h ol o gical n o des (t h ose wit h s h ort a xis 1 0 m m b ut < 1 5 m m)  
s h o uld be c o nsi dere d n o n- tar get lesi ons. 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 ogical a n d s h o ul d n ot be rec or de d or f o ll owe 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 
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 dia 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 ns c o nsi dere d tr ul y n o n- meas ura ble 
i ncl u de: le pt o me ni n geal 
di sease, i nflam mat or y  breast disease, 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  ide nt ifie d b y p h ysical e xa m that is n ot meas ura ble 
b y 
re pr o d uci ble i ma gi n g tec h ni q ues.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 7 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
N ote: Lesi o n s 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 pl ai n fil ms are n ot c o nsi dere 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 ons. 

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 Of ‘ T ar g et’ A n d ‘ N o n T ar g et’ L e si o n s
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 otal (a n d a ma xi m u m of  tw o lesi ons per or ga n) re prese ntati ve of  all i n v ol ve d or ga ns s h o ul d 
be i de ntifie d as tar get lesio ns a n d will be rec or de d a n d meas ure d at baseli ne (t his mea ns i n 
i nsta nces w here pati e nts ha ve o nl y  one or t wo or ga n sites i n v ol ve d a ma xi m u m of  tw o a n d f our 
lesio ns res pect i vel y will be rec or de d).
N ote: A ma xi m u m o f t w o lesio n s ca n be s electe 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 lesi o ns ca n be selecte d (selecte d fr o m o ne l u n g or o ne lesi o n fr o m eac h). A ma xi m u m o f 
t wo 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 (l esio ns wi t h t he l on gest 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 len 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 h e lar gest lesi on d oes 
n ot len d itself t o re pr o d uci ble me as ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesio n  whic 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 l y 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 us e d as r ef er e n c e t o furt her c haracterize a n y o bject i 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 h er lesio n s ( or sites of  disease) i ncl u di n g pat h o l ogi cal ly 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 nt s are n ot re q uire d a n d 
t hese lesi ons s h o ul d be f oll owe 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, it is p ossi ble t o rec or d mul tiple n o n- tar get 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 ul tiple li ver m etastases’).
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
2 
R E S P O N S E C RI T E RI A
2. 1 
E v al u ati o n of T ar g et L e si o n s

C o m plete Res p o nse ( C R): Di sa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l y m p h n o des 
( w het her tar get or n o n -tar get) must ha ve re d uct i on 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 di a meters of  tar get lesio ns, 
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 dia meters of tar get lesio n s, 
ta ki n g as r efere 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 rel at i ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate 
a n a bs o l ute i ncrease of at least 5 m m. ( N ote: t he a p peara nce of o ne or m ore ne w lesi ons is als o 
c o nsi dere d pr o gressi o n).

St a ble Dise ase ( S D): Nei 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 ore tar get lesi o ns 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 m all t o meas ure ( d ue t o missi n g or p o or q u ali t y ima ges), a n d 
t he s u m of dia meters of  the r e mai ni n g meas ure d t ar get lesio n s (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 o ve. 
2. 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
2. 1. 1. 1 
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 act ual s h ort a xis me as 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 lesi ons, 
t he ‘s u m’ of  lesio ns ma y n ot be zer o e ve n if c o m plete 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 ollecti o n 
met h o ds ma y t heref ore be desi g ne d t o ha ve tar get n o dal lesi ons rec or de d i n a se parate secti on 
w here, i n or der t o q ualif y  for 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 h ort a xis meas 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 lesi o ns.
2. 1. 1. 2 
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  small (e g, 2 m m). 
H o we ver, s omet i mes lesio ns or l y m p h n o des w hic h are rec or de d as t ar get lesi ons at baseli ne 
bec o me s o fai nt on C T sca n t hat the ra 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 urs 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 o f the ra di o l ogi st t hat t he lesio n  
has li kel y disa p peare d, t he meas ure me nt s h o ul d be rec or de d as 0 m m . If t h e l esio n  is belie ve d t o 
be prese nt a n d is fai nt l y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be 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 ntl 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 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
s m all t o meas ur e, a d efa ult val u e of 5 mm s h o uld be assi g ne d i n t his circ u msta nce as well). T his 
d efa ul t val ue is deri ve d fr om t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit 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 no n -re pr o d uci ble, t heref ore 
pr o vi di n g t his defa ult 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 reiterate, h o we ver, if t he ra diol o gist i s a ble t o pr o vide a n act ual  meas ure, t hat s h o uld b e 
rec or de d, e ve n if it is bel o w 5 m m.
2. 1. 1. 3 
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 de d t o get her t o calc ulate t he tar get lesio n  su m . Similarl y, as lesio ns c o alesce, a pla ne bet wee n 
t he m ma y be ma i ntaine 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 co al esce d s uc h t hat t he y are n o l on ger se para ble, t he 
vect or of  the l on gest dia meter i n t his i nsta nce s h o uld be t he ma xi mal l on gest dia meter f or t he 
‘c oalesce d lesi o n’.
2. 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 ns 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 n o n -tar get lesi ons. W hile s o me 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  quali tati vel y at t he ti me p oi nts s pecifie d i n 
t he pr ot oc ol.

C o m plete Res p o nse ( C R): Di sa 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 ogical i n size ( < 1 0 m m  s h ort a xis). 

N o n -C R / N o n-P D: Persiste nce of o 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 n s.
2. 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 ditio n al e x pla natio n as f o ll ows:
2. 2. 1. 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 ac hie ve ‘ u ne q ui v ocal pr o gressi o n’ o n t he basis of  the n o n- t ar get disease, t here 
m ust be a n o verall le vel o f 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 get disease, t he o verall t u m or b ur de n has i ncrease d s ufficie ntl y t o mer it 
di sc o nti 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 lesi ons is 
us uall y n ot s ufficie nt t o q ualif y for u ne q ui v ocal  pr o gressio n stat us. Pl e ural eff usio n s, peri car dial 
eff usi o ns a n d ascites will n ot be f o ll owe d as tar get or n o n -t ar get lesio ns a n d will n ot c o ntri b ute t o 
res p o nse or pr o gressi o n. T he desi g n ati o n of  overall pr o gressi o n s olel y on t he basis of  cha n ge i n 
n o n- tar get disease i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y rare.
2. 2. 1. 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 o me trials w he n it is n ot a criteri o n of st u d y e ntr y t o ha ve meas ura ble 
di sease. T he sa me ge neral  co 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 pretatio n of a n i ncrease i n n o n -meas ura ble 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
di sease 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 nit i on:  
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 w he n assessi n g patie nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall  disease b ur de n base d o n t he c ha n ge 
i n n o n- meas ur a ble disease is c o mpara 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 
decl are P D f or meas ura ble disease: ie, a n i ncrease i n t u m or b ur de n re prese nt i n g a n a d diti onal 7 3 % 
i ncrease i n ‘ v ol ume’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease di a meter i n a me as ura ble lesio 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 o calize d t o wi des prea d, or ma y be 
descri be d as ‘s ufficie nt t o r e q uire a c ha n ge i n t hera p y’. If ‘u ne q ui v ocal  pr o gressio n ’ is see n, t he 
pati e nt s h o uld be c o nsi dere d t o ha ve ha d o ve rall P D at t hat p oi nt. W hile it w o uld be i d e al  t o ha ve 
o bj ect i ve crit eria t o a p pl y t o n o n- meas ura ble di sease, t he ver y  nat ure of  that disease ma kes it 
i m p ossi ble t o d o s o; t heref ore t he i ncrease m ust be s u bsta ntial.
2. 2. 2 
N e w L e si o n s
T he a p peara nce of ne w mali g n a nt lesio ns de n otes di sease pr o gressio n; t heref ore, s o me 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 criteria f or t he i de ntificat i on of 
ne w r a dio gra p hic lesio ns; h o we ver, t he fi n di n g of a ne w lesio n  sh o ul d be u ne q ui v ocal: ie, n ot 
attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g m o dalit y or fi n di n gs t h o u g ht 
t o re prese nt s o met hi n g ot her t ha n t u mor (f or e xa m ple, s o me ‘ ne w’ b o ne lesi ons ma y be si m pl y 
heali n g or flare of pre -e xist i n g lesi ons). T his is parti c ularly i m p orta nt w he n t he patient ’s baseli ne 
lesio ns s h o w partial or c o m plete 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 ollect i ons ( ple ural eff usi ons, peri car dia l eff usio ns, a n d ascites) will n ot be 
c o nsi dere d ne w lesi o ns 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 t he e ve nt a ne w fl ui d 
c ollect i on 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 de, b ut t he a p peara nce 
of  a ne w fl ui d c ollecti on alo ne s h o ul d n ot res ul t in a n assess me nt of Pr o gressi ve Di sease ( P D). A 
lesio n 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 hat was n ot sca n ne d at baseli ne 
is c o nsi dere d a ne w lesi on a n d will i n dicate disease pr o gressi o n. A n e xa m ple of t his is t he patient  
w h o has visceral disease at baseli ne a n d w hile o n stu d y has a C T or M RI brai n or dere d w hic h 
re veals metastases. T he pati e 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 t hat was n ot 
prese nt i n pri or C T ca n be c o nsi dere d a ne w lesi o n a n d will res ult i n Pr o gressi ve Disease ( P D).
If a ne w lesi on is e q ui v ocal, f or e xa m ple beca use of it s s mall size, c o nti n 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 gressi o n s h o uld be declare d usi n g t he date of  the i nitial sca n. W hile F D G -P E T 
res p o nse assess me nts nee d a d ditio n al  st u d y, it is s o met i mes reas o na ble t o inc or p o rate t he use of  
F D 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 gressi o n ( partic ularl y 
p ossi ble ‘ ne w’ disease). Ne w lesi o ns o n t he basis of F D G -P E T i ma gi n g ca n be i de nt ifie d acc or di n g 
t o t he f oll o wi n g al g orit h m:
1)
Ne gati ve F D G -P E T at baseli ne, wit h a p osi tive F D G -P E T at f oll ow- u p is a sig n of  PD base d 
o n a ne w lesi o n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli 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 urri n g at t hat site (if s o, t he 
date of  PD will be t he date of  t he i nitial a b n or mal FD G -P E T sca n). If t he p osi tive 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 sit e 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.
2. 3 
R e s p o n s e A s s e s s m e nt
2. 3. 1 
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 re q uire me nt f or 
c o nfir mat i on a n d ce ns ori n g r ules re gar di n g s u bse q ue nt t hera p y. T he patie 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 b ot h tar get a n d n o n-tar get disease a n d will als o ta ke i nt o 
c o nsi derati o n t he a p peara nce of  ne w lesio n s. F urt her m ore, de pe n di n g o n t he nat ure of  the st u d y 
a n d t he pr ot oc ol re q uire me nts, it ma y als o re q uire c o nfir mat or y meas ure me nt.
2. 3. 2 
Ti m e P oi nt R e s p o n s e
At  eac h pr ot oc ol  specifie d time p oi nt, a res p o nse assess me nt occ urs. Ta ble 2. 3. 2 - 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 ti me p oi nt f or patie nts w h o ha ve 
meas ura ble disease at baseli ne. W he n patie nts ha ve n o n -meas ura ble (t heref ore n o n -tar get) disease 
o nl y , Ta ble 2. 3. 2 - 2 is t o be use d. 
T a ble 2. 3. 2 - 1: 
Ti me P oi nt Res p o nse
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 plete 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
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2. 3. 2 - 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 n o 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 h e n n o lesi ons ca n be meas ure d is n ot a d vise d.
2. 3. 3 
B e st O v er all R e s p o n s e 
Best res p o nse deter mi nati o n of  co m plete or partial res p o nse re q uires c o nfir mati o n: C o m p lete or 
parti al 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 da ys) 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 2. 3. 3 -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 o m t he date of first treat me nt or ra n d omizat i on date.
F or e xa m ple, if t he first sc he d ule d f oll ow- u p i ma gi n g visit is Wee k 6 ( ± 7 da ys) f or a partic ular 
p r 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 start date (refere nce date is c o nsi dere d Da y  1 o n st u d y).  If t he s u bject 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 d e d i n t he s u m o f tar get lesi o 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 ul d be rec or de d e ve n t h o 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 wit h C R ma y n ot ha ve a t otal s u m of ‘zer o’ o n t he case re p ort f or m ( C R F).
T a ble 2. 3. 3 - 1:  
Best O ver all Res p o nse ( C o nfir m ati o n of C R a n d P R Re q uire d)
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
Best 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
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
T a ble 2. 3. 3 - 1:  
Best O ver all Res p o nse ( C o nfir m ati o n of C R a n d P R Re q uire d)
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
Best O ver all Res p o nse
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 ble disease, P D = pr o gressi ve disease, a n d 
N E = i ne val ua ble
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 disease 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 whet 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’ ma y be clai me d 
w h e 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 ori 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.
2. 3. 4 
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 mor m eas 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 ul d be p erf or me 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 mat i on of  a pre vi o usl y i de ntifie d C R e ve n wi t 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 P R 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 oi nt will be all o we d bet wee n P R/ C Rs f or c o nfir mat i on.
Verific ati o n of Pr o gressi o n : Pr o gressi o n of  disease s h o ul d 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 on s h o ul d be declare d usi n g t he date of t he 
i nitial sca n. If re peat sca ns d o n ot c o nfir m P D, t he n t he s u bject is c o nsi dere d t o n ot ha ve 
pr o gre ssi ve disease.
2. 4 
R E F E R E N C E S
1
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s o li d t u m ors: 
re vise d R E CI S T g ui deli ne ( versi on 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 -4 7.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 8
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 8 9
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 0
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 1
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 2
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 3
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S -9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 4
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 5
8 . 0
A p p r o v e d
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 7 
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
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
Refere nce: O ke n M M, Creec h R H, et al. T o xicit y a n d Res p o nse Criteria of t he Easter n C o o perati ve O nc ol o g y Gr o u p. 
A m J Cli n O nc ol 1 9 8 2; 5: 6 4 9 - 6 5 5.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 8   
C O U N T R Y S P E CI FI C R E Q UI R E M E N T S
C o u ntr y -s pecific l a n g u a ge
Secti o n 2 Fl o w C hart/ Ti me a n d E ve nts Sc he d ule,
Ta ble 2- 1 : Scree ni n g Assess me nts - La b orat or y
Tests
A d d “ HI V” t o t he list of la b orat or y tests
Secti o n 6. 2 E xcl usi o n
Criteria, E xcl usi o n cr iteri o n 1h j
“ K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) p ositi ve wit h a n
ac q uire d i m m u n o deficie nc y s yn dr o me” t o be re place d wit h
“ P ositi ve test f or HI V”.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
A P P E N DI X 9 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E HI S T O R Y
O ver all R ati o n ale f or Pr ot oc ol A me n d me nt 0 6:
A me n d me nt 0 6 i nc or p orates t he f oll owi n g desi g n c ha n ges, 
 
 
 
 
 
 
 
 
 
 a n d t he car b o plat i n d ose has 
bee n restricte d t o A U C 5 f or n o n -s q ua m o us hist ol o g y t o ali g n with gl o bal sta n dar d of care 
a n d t o re d uce variati o n i n ma na ge me nt of t his part ici pa nt p o p ulati o n.1
A d dit i onall y , t he pri mar y a n d sec o n dar y e n d p oi nts i n Part 2 ha ve bee n u p date d t o o verall res p o nse 
rate ( O R R) a n d pr o gressi o n -free s ur vi val ( P F S), res pecti vel y. O R R is a n acce pta ble P hase 2 
e n d p o i nt in o nc o l og y  st u dies i n n o n- s mall cell l u n g ca ncer ( N S C L C) t hat all o ws res ults t o be 
assesse d earlier w he n c o mpare d wi t h s ur vi val-base d e n d p o i nts. F urt her m ore, a str o n g trial-le vel 
ass ociat i on has bee n esta blis he d bet wee n O R R a n d P F S i n a meta -a nal ysis of  ad va nce d N S C L C 
st u dies. 2
 
 
 
 
 
 
Ot her 
re visi o ns i ncl u de clarificat i ons t o sc he d uli n g of  safet y lab orat o r y, bi o mar ker 
a n d 
p har mac o ki net ic c o llecti ons, eli gi bilit y crit eria, i ncl u di n g a re visio n  of t he d urati o n of  
c o ntrace pti o n f or fe male partici pa nts a n d male partici pa nts a n d t heir fe male part ners after last d ose 
of  che m ot hera p y a n d rec o m me n dati o n t o c o nsi de r treati n g s u b-cli nical i nfecti on i n t he prese nce 
of  ele vate d ne utr o p hil a n d w hite bl o o d cell c o u nts at baseli ne.
Refere nces:
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
1 Ga n d hi L, R o dri g uez -A bre u D, Ga d geel S, et al. Pe m br o liz u ma b pl us c he mot h era p y i n metastatic 
n o n- s mall c ell lu n g ca ncer . N E n gl J Me d 2 0 1 8; 3 7 8: 2 0 7 8- 2 0 9 2.
2 Bl u me nt hal  GM, Kar uri S W , Z ha n g H, et  al. O verall res p o nse rate, pr o gressi o n -free s ur vi val, 
a n d o verall s ur vi val wit h tar gete d a n d sta n dar d t hera pies i n a d va nce d n o n-s mall-cell lu n g ca ncer: 
U S F o o d a n d Dr u g A d mi nistrati o n 
trial-le vel a n d part ici pa nt-le vel a nal yses. J Cli n O n c ol
2 0 1 5; 3 3: 1 0 0 8 - 1 4.
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 6
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
Title Pa ge 
U p date d Me dical M o nit or c o ntact 
i nf or mati o n
U p date d st u d y title
T o i ncl u de t he m ost rece nt st u d y 
c o ntact. 
Title u p date d t o reflect t he d o u ble -
bli n d desi g n
Ta ble 2 -1: Scree ni n g Pr oce d ural 
O utli ne
 
A d de d ti me peri o d f or 
c ollecti o n of P h ysical 
Meas ure me nts/ P E, 
E C O G, a n d Vital si g ns .
 
Re m o val of refere nce t o 
rec o nse nt per A me n d me nt 
0 3. 
 
P R O c ollecti o n f or Part 2 
has bee n a d de d. 
 
Clarificati o n of ti mefra me of 
c ollecti o ns 
 
Rec o nse nt per A me n d me nt 
0 3 was a p plica ble t o 
partici pa nts i n Part 1. 
 
A d d assess me nts f or Part 2.
Ta ble 2 -2: O n Trea t me nt 
Pr oce d ural O utli ne
Secti o n 5. 1 O verall Desi g n
Secti o n 5. 1. 2 O n -treat me nt P hase
Secti o n 5. 4. 4 Rati o nal f or C h oice 
of C he m ot hera p y
Secti o n 7. 1. 2 C he m ot hera p y 
D osi n g
Ta ble 9. 4. 5 -1 Cli nical Safet y
La b orat o r y Assess me nts
 
 
 
 
A d de d clarificati o n 
re gar di n g na b-paclita xel 
a d mi nistrati o n. 
 
 
Ta ble 2 - 1: Scree ni n g Pr oce d ural 
O utli ne
A d de d 
 P GI S, 
 
at 
Scree ni n g f or Part 2
 
 
Ta ble 2 -3: F oll o w -u p a n d 
S ur vi val Pr oce d ural O utli ne
A d diti o nal descri pti o n of 
pr o gressi ve di sease assess me nt 
re m o ve d.
E dite d f or c o ncise ness as assess me nt 
of disease pr o gressi o n is a sta n dar d 
pr oce d ure.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
1 9 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 6
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 3. 1. 1, Researc h 
H y p ot hesis 
Ta ble 4 -1, O bjecti ves a n d 
E n d p oi nts
Secti o n 5. 4. 8 Rati o nale f or O R R 
as a Pri mar y E n d p oi nt i n Part 2
Secti o n 8. 1. 4 P ost -st u d y 
Treat me nt St u d y F oll o w - u p
 
U p date d t o reflect O R R as 
pri mar y  e n d p oi nt f or Part 
2. 
 
 
 
 
I ncl u de d rati onale f or 
O R R as pri mar y e n d p oi nt
f or Part 2
T o u p date a n d j ustif y pri mar y a n d 
sec o n dar y e n d p oi nt c ha n ges i n Part 2.
Ta ble 4. 1, O bjecti ves a n d 
E n d p oi nts
Re m o ve d o bjecti ves pertai ni n g t o 
a nal yzi n g mea ni n gf ul c ha n ge 
t hres h ol ds fr o m b ot h Parts 1 a n d 2.
 
 
 
 
 
 
Secti o n 2 Sc he d ule of Acti vities, 
Ta ble 2 -2 O n- treat me nt 
Pr oce d ural O utli ne
 
Fi g ure 5. 1 -1, St u d y Desi g n 
Sc he matic
Secti o n 5. 1. 2 , O n -Treat me nt
P hase
Secti o n 7. 1, Treat me nts 
A d mi nistere d
U p date d relatli ma b d ose t o 3 6 0 m g 
f or Part 2.
T o clarif y t he selecte d relatli ma b d ose 
of 3 6 0 m g Q 3 W i n c o m bi nati o n wit h 
ni v ol u ma b a n d P D C T 
 
 
 
 
Secti o n 5. 1. 3 F oll o w -u p Peri o d 
U p date d t o s pecif y t u m or a n d 
res p o nse assess me nt. 
A d de d f or clarit y a n d t o e ns ure 
a de q uate f oll o w-u p t o pre ve nt missi n g 
data f or sec o n dar y o bjecti ve of P F S.
Secti o n 5. 3 E n d of St u d y 
Defi niti o n 
U p date d t he e n d of st u d y 
defi niti o n. 
 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 6
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
 
Secti o n 5. 4. 4, Rati o nale f or 
C h oice of C he m ot hera p y
Secti o n 7. 1. 2 C he m ot hera p y 
D osi n g
Secti o n 7. 1. 2. 2 Na b -Paclita xel 
a n d Car b o plati n
Secti o n 7. 1. 2. 4 Pe metre xe d a n d 
Car b o plati n
Secti o n 7. 4. 2 D ose Dela y Criteria 
f or C he m ot hera p y
Secti o n 7. 4. 3. 2 D ose Re d ucti o n 
f or C he m ot hera p y
Secti o n 7. 4. 3. 3 C he m ot hera p y 
D ose Re d ucti o ns f or He mat ol o gic 
T o xicit y
Ta ble 7. 4. 3. 3 -1: D ose 
M o dificati o n s f or He mat ol o gic 
T o xicit y ( Base d o n Na dir C o u nts)  
Ta ble 7. 4. 3. 4 -1 D ose 
M o dificati o ns f or N o n -
he mat ol o gic T o xicit y 
U p date d t o reflect t hat na b -
paclita xel f or S Q a n d ca r bo plati n 
A U C 6 f or N S Q is a p plica ble t o 
Part 1 o nl y .
 
 
 
 
 
 
 
Secti o n 5. 5 J ustificati o n f or 
I m m u n ot hera p y D ose 
Secti o n 5. 5. 2 J ustificati o n f or 
Relatli ma b D ose
U p date d t o pr o vi de rati o nale f or 
selecti o n of 3 6 0 m g relatli ma b 
d ose.
T o disc uss t he j ustificati o n f or t he 
selecti o n of relatli ma b 3 6 0 m g Q 3 W 
i n c o m bi nati o n wit h ni v ol u ma b   
 
 
 
Secti o n 6. 1, I ncl usi o n Criteria, 3) 
A ge a n d Re pr o d ucti ve Stat us, i x),
( 2); b), i v), v), vi), vii), a n d viii). 
Secti o n 9. 2. 5 Pre g na nc y
U p date d t otal d urati o n of 
c o ntrace pti o n t o 7 a n d 1 1 m o nt hs 
p ost -last d ose of c he m ot hera p y 
(a p plica ble t o paclita xel, na b -
paclita xel, pe metre xe d , a n d 
car b o plati n) a n d 1 4 a n d 1 1 m o nt hs 
p ost last d ose of cis plati n, 
w h ic he ver is l on ger, f or fe male 
partici pa nts a n d male partici pa nts 
a n d t heir part ners, res pecti vel y. 
T o pr o vi de a m o re precise d urati o n of 
c o ntrace pti o n per la bel of i n di vi d ual 
c he m ot hera p y a ge nts.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 6
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 7, Treat me nt
Ta ble 7 -1: St u d y Treat me nts f or 
C A 2 2 4 1 0 4 
Secti o n 7. 1 Treat me nts 
A d mi nistere d
Secti o n 7. 1. 1 I m m u n ot hera p y 
D osi n g
Me nti o n of place b o has bee n 
re m o ve d. 
 
 
 
Secti o n 9. 1. 1. 3 BI C R 
C o nfir mati o n of Pr o gressi o n 
Re m o val of rec urre nce fr o m t he 
secti o n title. 
Rec urre nce is n ot a p plica ble i n t he 
metastatic setti n g.
Secti o n 9. 1. 2. 4 P GI S a n d P GI C
Re m o val of assess me nt of 
ps y c h o metric meas ure me nts. 
Data c ollecte d via t he P GI S a n d P GI C 
will be use d as a nc h or meas ures t o 
f urt her c o nfir m t hres h ol ds f or 
mea ni n gf ul c ha n ge f or t he 
 rath e r t ha n t o assess 
ps y c h o metric meas ure me nt pr o perties.
Secti o n 9. 5. 1 P har mac o ki netic 
a n d A nti -dr u g A nti b o d y Sa m ple 
C ollecti o n a n d Pr ocessi n g
Secti o n 9. 5. 2 P har mac o ki netics 
a n d I m m u n o ge nicit y 
Secti o n 9. 5. 3 P har mac o ki netic 
A nal y sis 
Secti o n 9. 6 I m m u n o ge ni cit y 
Assess me nts
Secti o n 9. 6. 1 I m m u n o ge nicit y 
A nal y ses 

Sc he d ule a n d details of P K 
a n d i m m u n o ge nicit y 
assess me nts u p date d t o 
se parate e n d of i nf usi o n 
sa m pli n g f or i m m u n ot hera p y 
vs c he m ot hera p y.

A nal y ses descri pti ons a d de d t o 
S ecti o ns 9. 5. 2, 9. 5. 3, a n d 9. 6. 

U p date d f or clarit y.

E n d of i nf usi o n c he m ot hera p y 
sa m pli n gs f or P K a n d 
i m m u n o ge nicit y a nal yses. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 6
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
A p pe n di x 2: St u d y G o ver na nce 
C o nsi derati o ns
A d de d 2 ne w secti o ns: B M S 
C o m mit me nt t o Di versit y i n 
Cli nical Trials a n d Data Pr otecti o n, 
Data Pri vac y, a n d Data Sec urit y
A d de d t o ali g n wit h B M S 
c o m mit me nt t o di versit y i n cli nical 
trials a n d t o c o m pl y wit h E ur o pea n 
U n i o n Cli nical Trials Re g ulati o n ( E U -
C T R) re q uire me nts. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
O ver all R ati o n ale f or t he Pr ot oc ol A me n d me nt 0 4, 0 1 -Dec - 2 0 2 1
 
 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
Stratificat i on fact ors f or ra n d o mizat i on i n Part 2 ha ve bee n u p date d t o i ncl u de Easter n C o o perati ve 
O nc o l og y  Gr o u p ( E C O G) perf or ma nce stat us i n a d diti on t o hist ol o g y a n d P D -L 1 le vel; ge n der a n d 
L A G - 3 e x pressi o n le vel ha ve bee n r e mo v e d as stratificati on fact ors; ce ns ori n g defi ni tio n  for 
pr o gressi o n -free s ur vi val was u p date d t o ali g n wit h t he cli nical pr o gra m. 
T he re q uire me nts f or c o ntrace pti o n a n d pre g na nc y m o nit ori n g ha ve bee n u p date d t o ali g n wi t h 
pr o gra m -wi de s pecificati ons f or r elat li ma b. T he Be nefit/ Ris k secti on n o w i ncl u des a d ditio nal 
i nf or mat i on t o a d dress C O VI D -1 9 vacci nat i ons. 
T hese c ha n ges a p pl y t o all parti cipa nts.
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
Pr ot oc ol  c ha n ges liste d bel o w ha ve bee n i nc or p orate d i nt o t he pr ot oc ol s u m mar y. 

Ti tle Pa ge
U p date of Cli nical Scie nt ist  
A d mi nistrati ve c ha n ge.

Ta ble 2 -1, Scree ni n g 
Pr oce d ural  O utli ne 
( C A 2 2 4 1 0 4)
Vi t als si g ns, o btai ne d d uri n g 
scree ni n g, are n o l o n ger 
re q uire d t o be re-o b tai ne d 
wi t hi n 7 2 h o urs prior t o 
ra n d omizat i on.
Cl arifie d e x pectatio ns re gar di n g 
c ollect i ons of vital si g ns pri or t o 
ra n d omizat i on t o re d uce 
parti ci pa nt b ur de n.

Vi t al Sig ns 

 
 
 
 
 
. I n 
Part 2, L A G -3 l e vels are n o 
l on ger re q uire d pri or t o 
ra n d omizat i on.
 
 
 
Ge n der a n d L A G -3 are n o 
l on ger stratificat i on fact ors i n 
t his st u d y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale

Ta ble N ote a n d 
Secti o n 7. 1. 2 
C he m ot h era p y 
d osi n g
I n vesti gat or is n o l o n ger 
re q uire d t o decide o n 
c he m ot hera p y treat me nt 
base d o n hist ol o g y  prior t o 
ra n d omizat i on. 
Re m o v e d l a n g ua ge i nc o nsiste nt 
wi t h I R T f u ncti onalit y.  

Ta ble 2 -2, O n -treat me nt 
Pr oce d ural  O utli ne 
( C A 2 2 4 1 0 4)

La b orat or y  Tests

Secti o n 3. 3 Be nefit/ Ris k

Ta ble 9. 4. 5 -1, Cli nical 
S af et y La b orat or y  
Assess me nts 
Re m o ve d c oa g ulati o n pr ofile 
fr om la b orat or y 
re q uire me nts.
Re m o ve d c oa g ulati o n pr ofile 
fr om t he la b orat or y 
re q uire me nts as it was a 
t yp o gra p hic err or a n d n ot 
re q uire d for t he st u d y  
parti ci pa nt p o p ulat i on

Cli nical 
O bser vati o ns 
E val uat i ons ma y n o w occ ur 
via virt ual tele p h o ne 
assess me nt, at t he 
i n vesti gat or’s discreti on.
T he i n vest i gat or ma y deter mi ne 
if t he cli nical o bser vati o ns ma y 
be c o m p lete d as a re m ote 
assess me nt

Ta ble 2 -2, O n -treat me nt 
Pr oce d ural  O utli ne 
( C A 2 2 4 1 0 4): F o ot n ote a
Te xt of f o ot n ote a has bee n 
re vise d t o better s pecif y 
o n g oi n g safet y assess me nts. 
Cl arificat i on. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale

Secti o n, 3. 3, 
Be nefit/ Ris k Assess me nt

Secti o n 7. 7. 1, Pr o hi bite d 
a n d/ or Restricte d 
Treat me nts
La n g ua ge has bee n a d de d t o 
a d dress C O VI D -1 9 i nfect i on 
preca uti o ns i ncl u de d i n t he 
st u d y pr oce d ures a n d t he 
desi g nati o n o f t he n o n-li ve 
C O VI D -1 9 vacci nat i ons as a 
c o nc o mita nt me dicat i on wi t h 
n o e x pecte d i nteracti o n wit h 
st u d y tr e at me nts.
U p date d ri s k/ be nefit la n g ua ge 
t o a d d c o nsi derati o n of C O VI D -
1 9 vacci nat i on d uri n g 
par tici pat i on i n relatli ma b a n d 
ni v o l u ma b cli nical trials a n d t o 
s pecif y C O VI D-1 9 vacci nes 
gi ve n t o partici pa nts i n t his trial 
are c o nsi dere d a c o nc o mit a nt 
me dicat i on. 

Secti o n 5, St u d y  Desi g n

Fi g ure 
5 - 1 
St u d y 
Desi g n

Secti o n 5. 1, O verall 
Desi g n

Secti o n 5. 1. 1, Scree ni n g 
P hase 

Secti o n 7. 2 , Met h o d of 
Treat me nt Assi g n me nt

Secti o n 9. 8. 2. 2, L A G - 3 
a n d P D-L 1 E x pressi o n
Stratificat i on fact ors ha ve 
bee n u p date d t o hist ol o g y , 
P D -L 1, a n d E C O G 
perf or m a nce stat us. Ge n der 
a n d L A G-3 are n o l o n ger 
stratificati on fact ors i n t his 
st u d y. P D-L 1 n o n -
q ua nt ifia ble partici pa nts will 
be i ncl u de d i n t he P D-L 1 ≥ 
1 % strat u m.
I n Part 2, L A G-3 l e vels are 
n o l o n ger re q ui re d prior t o 
ra n d omizat i on.
 
 
 
L A G -3 has bee n re m o ve d. 
Ge n der has bee n re place d b y 
E C O G o n t he basis o f t he 
hi g her pr o g n ostic val ue 
c o mpare d wi t h ge n der. 
P D -L 1 n o n -q ua nt ifia ble 
parti ci pa nts will n o w be 
i ncl u de d i n t he P D-L 1 ≥ 1 % 
strat u m instea d of t he P D -L 1 < 
1 % strat u m b eca use t he 
pre vale nce o f P D -L 1 ≥ 1 % 
wi t hi n t he q ua ntifia ble 
parti ci pa nts is e x pecte d t o be 
sli g htl y hi g her ( 5 7 % -6 0 %) t ha n 
of  t he P D-L 1 < 1 % gr o u p.

Secti o n 5, St u d y  Desi g n, 
Fi g ure 5 -1 St u d y  Desi g n
F or Ar m  D, t he place b o d ose 
has bee n re m o ve d. 
T he pl ace b o d ose will be i n 
ali g n me nt wit h relatli ma b d ose 
f or Part B. As state d i n f o ot n ote 
b, t he relat li ma b d ose 7 2 0 m g 
Q 3 W will be re place d wit h 3 6 0 
m g Q 3 W if t he 7 2 0 m g d ose is 
n ot deter mi ne d t o be safe.  
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale

Secti o n 5. 4. 8, Rati o nale 
f or stratificati o n
Stratificat i on fact ors 
u p date d . 
Rati o nale was u p date d t o reflect 
c ha n ges i n t he stratificat i on 
fact ors ( Secti o n 5. 1)
Te xt u p date d t o reflect 
c ha n ge i n stratificat i on 
fact ors. 

Secti o n 6. 1, I ncl usi o n  
Cri teria 
Cri t erio n 2) T y pe of 
Parti cipa nt a n d Tar get 
Di sease C haracteristics c) 
L A G -3 re m o ve d t o reflect 
t hat L A G-3 is n o l o n ger 
stratificati on fact or or nee de d 
f or ra n d o mizati on i n Part 2 
of  t he st u d y.  
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale

Secti o n 6. 1, I ncl usi o n  
Cri teria 
Cri t erio n 3) A ge a n d 
Re pr o d ucti ve Stat us b) Male 
Parti cip a nts
U p date d t he d urati o n of 
c o ntrace pti o n f or male 
parti ci pa nts, fe male part ners 
of  males partici pat i n g i n t he 
st u d y, i ncl u di n g fe male 
part ners w h o are pre g na nt or 
breast fee di n g t o 1 1 m o nt hs 
aft er t he last c he m ot hera p y 
d ose of t he male partici pa nt’s 
st u d y int er ve nti o n.  U p date d 
t he ti me fra me d uri n g w hic h 
male partici pa nts m ust 
refrai n fr om d o nati n g s per m 
t o 1 1 mo nt hs after t he last 
c he m ot hera p y d ose.
U p date d acc or di n g t o t he 
re q uire me nts of all 
c he m o t hera p y a ge nts per la bel, 
w hic h is l o n ger t ha n f or 
i m m u n ot hera p y.

Secti o n 7. 2, Met h o d of 
Treat me nt Assi g n me nt
Re vise d te xt t o s pecif y  t hat 
f or particip a nt 
ra n d omizat i on, 
 
rat her t ha n date of birt h is 
re q uire d. 
Ali g n me nt wit h I R T 
f u ncti onal ity.

Secti o n 9. 2. 5, 
Pre g na nc y
C ha n ge d t he d urati o n t o 
re p ort pre g na nc y fr om 3 3 
wee ks t o 1 4 m o nt hs after t he 
last d ose c he m ot hera p y a n d 5 
m o nt hs after t he last d ose of 
i m m u n ot hera p y. I ncrease d 
t he re p orti n g peri o d f or male 
parti ci pa nts f or se x ual 
acti vit y wi t ho ut a c o n d o m  
fr om 3 3 wee ks t o 1 1 m o nt hs. 
U p date d acc or di n g t o t he 
re q uire me nts of all 
c he m ot hera p y a ge nts per la bel, 
w hic h is l o n ger t ha n f or 
i m m u n ot hera p y.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 0 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale

Secti o n 9. 5, 
P har mac o ki net ics a n d 
I mm u n o ge nicit y
All occ urre nces of t he w or d 
pl ace b o re mo ve d fr o m  Ta ble 
9. 5 -1, P har mac o ki net ic a n d 
I mm u n o ge nicit y Sa m pli n g 
Sc he d ule f or Ni v ol u ma b a n d 
Relatli ma b f or All 
Parti cipa nts ( Part 1 a n d
Part 2). 
T he d urati o n of  P K f oll ow 
u p has bee n ca p pe d at 2 
years t o reflect c urre nt 
cli nical e x perie nce.
Re m o v al  of t yp o gra p hical err or.
T w o y ears c ollect i on is 
a de q uate base d o n a lar ge 
data base of ni v o l uma b a n d 
r elat li ma b P K/I M G data acr oss 
vari o us st u di es a n d i n dicat i ons

Secti o n 1 1, Refere nces
Refere nces ha ve bee n 
u p date d per c ha n ges i n 
Secti o n 3. 3 Be nefit/ Ris k, 
Secti o n 5. 4. 8, Rati o nale f or 
Stratificat i on a n d Secti o n 
7. 4. 3. 3, C he m ot hera p y: D ose 
Re d ucti o ns f or He mat ol o gic 
T o xicit y.
Refere nce sect i on u p date d t o 
ali g n wit h re vise d pr ot oc ol 
secti ons.

A p pe n di x 2, St u d y  
G o ver na nce 
C o nsi derati o ns
La n g ua ge a d de d f or t he 
c o n ditio n of  r e mot e 
m o nit o ri n g a n d t o reflect 
B M S p olic y f or 
di sse mi nati on of st u d y  
i nf or mat i on. 
Ali g ne d wit h u p date d B M S 
pr oce d ures f or C O VI D -1 9 
res p o nse a n d f or re p orti n g of 
st u d y data a n d disse mi nati on of 
st u d y inf or mat i on, as 
i nc or p orate d i nt o t he sta n dar d 
te xt f or pr ot oc ols. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 4
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
Brief R ati o n ale
T hr o u g h o ut t he pr ot oc ol
Mi n or e di t orial a n d f or mat c ha n ges t hat d o n ot affect c o nte nt.
O ver all R ati o n ale f or t he Pr ot oc ol A me n d me nt 0 3, 3 0 -J ul - 2 0 2 1
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 3
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
B r ief R ati o n ale
Pr ot oc ol  c ha n ges liste d bel o w ha ve bee n i nc or p orate d i nt o t he pr ot oc ol s y n o psis. 

Secti o n 2, Sc he d ule of 
Act i vities, Ta ble 2-1, 
Scree ni n g Pr oce d ural 
O utli ne ( C A 2 2 4 1 0 4)
A d de d la n g ua ge descri bi n g 
c o nse nt f or c urre nt a n d ne w 
parti ci pa nts f or Pr ot oc ol 
A me n d me nt 3
Pr o vi de e x pectati o ns f or 
parti ci pa nt c o nse nt f or Pr ot oc ol 
A me n d me nt 0 3.

Eli gi bilit y Assess me nts

Secti o n 2, Sc he d ule of 
Act i vities, Ta ble 2-2, 
O n -st u d y Pr oce d ural 
O utli ne ( C A 2 2 4 1 0 4)

Tar gete d P h y sical 
E xa mi nat i on

La b orat or y  Assess me nts, 
La b orat or y  Tests

F o ot n ote 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 3
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
B r ief R ati o n ale
 

Cli nical O bser vat i ons
A d de d Cli nical O bser vat i ons 
r o w.
Ali g ne d la b orat or y  assess me nts 
wi t h i ncrease d safety 
m o nit ori n g i ncl u de d i n Pr ot oc ol 
A me n d me nt 0 3.

Secti o n 2, Sc he d ule of 
Act i vities, Ta ble 2-3: 
F o ll ow- u p a n d S ur vi val 
Pr oce d ural  O utli ne 
( C A 2 2 4 1 0 2)
 
A E Assess me nt 
C ha n ge d t he d urati o n o f 
c ollect i on of S A E a n d n o n -
serio us A Es f o ll owi n g 
di sc o nti n uati on of st u d y  
treat me nt fr o m   
 
C ha n ge ma de t o i ncrease t he 
d urati o n of  ~ 5 ti mes st u d y dr u g 
half -life a n d ali g n acr oss 
pr ot oc ol  secti ons.

Secti o n, 3. 3, 
Be nefit/ Ris k Assess me nt
U p date d l a n g ua ge t o 
descri be rece nt safet y 
i nf or mat io n f r o m t he st u d y 
a n d res ult i n g safet y 
meas ures.
T hese c ha n ges were ma de t o 
ali g n wit h u p date d cli nical 
e x perie nce.

Secti o n 5. 1. 3 F oll o w - u p

Secti o n 7. 7. 1 Pr o hi bite d 
a n d/ or Restricte d 
Treat me nts

Secti o n 8. 1. 4 P ost -stu d y 
Treat me nt St u d y  
F o ll ow- u p

Secti o n 9. 2. 1 Ti me 
P eri o d a n d Fre q ue nc y  
f or C ollecti n g A E a n d 
S A E I nf or m at i on

Secti o n 9. 2. 2 Met h o d of 
Detecti n g A E a n d S A Es

Secti o n 9. 2. 6. 1 
Defi nit i on o f I mm u ne -
me diate d A d verse 
E ve nts
 
 
 
 
 
T he i ncrease d safet y f oll ow- u p 
of   
 re prese nts
~ 5 ti mes st u d y  dr u g half-life.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S u m m ar y of ke y c h a n ges f or Pr ot oc ol A me n d me nt 0 3
Secti o n N u m ber & Title 
Descri pti o n of C h a n ge
B r ief R ati o n ale

Secti o n 6. 2 , E xclusi o n  
Cri teria
3) P h y sical a n d 
La b orat or y  Test 
Fi n di n gs ii) 

Secti o n 7. 4. 1 D ose 
M o dificat i on Cri t eria for 
I mm u n ot hera p y ,   
 
 
 
 
 
T he i n vest i gat or rat her t ha n a 
car diol o gi st will n o w assess 
 a n d be nefit-
ris k f or treat me nt i n t he 
st u d y. 
 
 
 
 
 
T o a v oi d u n necessar y  dela ys, 
t his c ha n ge all o ws t he 
i n vesti gat or t he fle xi bility t o 
e val uate as y m pt o matic   
 
 at scree ni n g with o ut 
t he nee d f or a car di o l ogi st 
c o ns ultati o n.
,

Secti o n 9. 4. 5 Cli nical 
S af et y La b orat or y  
Assess me nts, Ta ble 
9. 4. 5 -1 Cli nical Safet y 
La b orat or y  Assess me nts
N ote a d de d t o s pecif y t hat 
C B C wit h differe nt ial m ust 
be e val uate d o n 
c he m ot hera p y treat me nt da ys 
f or all p artici pa nts. 
 
 a d de d t o la b orat or y 
assess me nts.
Parti cipa nts place d o n na b -
paclita xel will ha ve a d dit i onal 
d osi n g da ys 
 
 Safety la bs ( C B C wit h 
differe nt ial) s h o uld be 
perf or m e d i n a d dit i on t o Da y  1.
T o ali g n wit h i ncrease d safet y  
m o nit ori n g. 
O ver all R ati o n ale f or t he Pr ot oc ol A me n d me nt 0 2, 1 6 -A pr - 2 0 2 1
T he pri mar y  reas o ns f or t hese c ha n ges are t o ali g n t he i m m u n ot hera p y d os e mo dificat i on crit eria 
a n d i m m u ne-relate d a d verse e ve nt ma na ge me nt 
al g orit h ms wi t h the c urre nt C o m m o n 
Ter mi n o l og y Cri t eria f or A d verse E ve nts ( C T C A E) versi o n 5; clarif y t he ser ol ogi c testi n g f or 
se vere ac ute res pirat or y sy n dr o me c or o na vir us 2 ( S A R S-C o V -2), a n d i ncl u de i nf or mat i on of  on 
c or o na vir us disease 2 0 1 9 ( C O VI D-1 9) vacci nat i o n a n d was h o ut peri o ds; clarif y t he i nf usi on 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 4
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
d urati o n
; a d d i nstr uctio ns f or l ocatio n of  specific 
ma na ge me nt g ui deli nes f or  se vere a d verse reactio ns; a n d i nc or p orate a d dit i onal u p dates t o 
i m pr o ve ali g n me nt acr oss pr ot oc ol secti ons a n d/ or clarif y e x pectati o ns f or eli g i bility,  assess me nts, 
a n d sa m ple c o llecti ons. 
I n a d ditio n, t his pr ot oc ol  ame n d me nt ma kes mi n o r clar ificati o ns f or c o nsiste nc y t hr o u g h o ut t he 
pr ot oc ol .
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 2: 
Sc he d ule of 
Act i vities

A d de d la n g ua ge o n ti mi n g 
of  inf or m e d c o nse nt a n d 
pr oce d ures re gar di n g re -
e nr o ll me nt of partici pa nts 
w h o were c o nsi dere d pre-
treat me nt fail ures.

Cl arifie d i nf or me d c o nse nt n ote o n 
ti mi n g a n d re-e nr o ll me nt of 
parti ci pa nts dee me d pre-treat me nt 
fail ures.

A d de d i nstr ucti o ns t o 
c o ntact B M S Me dical 
M o ni t or w he n partici pa nts 
wi t h si g nifica nt 
car dio vasc ular 
a b n or malities are 
c o nsi dere d f or e nr oll me nt.

Cl arifie d e x pectatio ns a b o ut 
parti ci pa nts wit h sig nifica nt 
car dio vasc ular a b n or malit ies a n d 
a d de d i nstr ucti o ns t o i nf or m B M S 
Me dical M o nit or w he n patie nts wit h 
sig nifica nt a b n or m alities are 
c o nsi dere d f or e nr oll me nt.

Refere nce d st u d y  
La b orat or y  Ma n ual f or 
s pecific t u m or c ollecti on 
g ui da nce.

Cl arifie d re q uire me nts a n d 
e x pectatio ns f or t u m or c ollect i ons.

A d de d la n g ua ge t o i n dicate 
t hat lo c al  la b orat or y testi n g 
is t he preferre d testi n g f or 
E G F R, A L K, R O S -1, a n d 
B R A F V 6 0 0 E m utati o ns 
stat us.

Cl arifie d e x pectatio n f or l o c al  
la b orat or y testi n g f or E G F R, A L K, 
R O S -1, a n d B R A F V 6 0 0 E m ut ati o n 
stat us.

A d de d la n g ua ge f or 
c o nti n u o us c ollect i on of 
A Es/ S A Es (i ncl u di n g t h ose 
ass ociate d wit h S A R S-
C o V -2 i nfect i on) d uri n g 
t he treat me nt peri o d.

Cl arifie d e x pectatio ns a b o ut 
c o nti n u o us c ollect i on of A Es/ S A Es, 
i ncl u di n g t h ose ass ociate d wit h 
S A R S -C o V -2 i nfect i on, d uri n g t he 
treat me nt perio d.

Re m o v e d l a n g ua ge 
i nstr ucti n g t he re gra di n g of 

U p date d l a n g ua ge t o reflect ne w 
i m m u n ot hera p y d ose mo dificat i on 
secti on a n d i m m u ne -r elate d a d verse 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 5
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
A Es t o C T C A E v 4 f or 
ma na ge me nt.
e ve nt (ir A E) ma na ge me nt alg ori t h ms 
t hat ali g n wit h C T C A E v 5.

A d de d a d dit i onal t i me 
p oi nts f or c ollect i on of 
S A R S -C o V -2 ser ol o g y .

Cl arifie d e x pectatio ns o n S A R S -
C o V -2 ser u m c ollecti o ns a n d use of 
res ults for eli gi bilit y.

A d de d or u p date d details 
t o N otes c olu m ns f or 
 a n d b o d y 
i ma gi n g.

U p date d or c orrecte d N otes as 
nee de d t o cl arif y e xpectati o ns a n d/ or 
t o better ali g n wit h pr ot oc ol te xt.
Secti o n 1: 
S y n o psis
Secti o n 5: St u d y  
Desi g n; Fi g ure 
5. 1 - 1
U p date d Fi g ure 5. 1 -1; delete d 
t er m, or 2 years i n dia gra m.
C orrecte d t y p o gra p hi c al err or, as st u d y 
treat me nt is u nt il P D or u nacce pta ble 
t o xicit y.
Secti o n 5. 1. 1: 
Scree ni n g P hase

Cl arifie d la n g ua ge o n 
all o wa ble t i me fr o m bi o ps y 
t o 3 mo nt hs pri or t o 
ra n d omizat i on.

U p date d w or di n g t o clarif y  t hat 
ti meli ne is fr o m ra n d omizat i on, n ot 
fr om e nr oll me nt.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 6
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 5. 4. 3: 
Rati o nale f or 
S h orte ne d 
I nf usi on Ti me f or 
Ni v o l uma b pl us 
Relatli ma b
A d de d la n g ua ge clarif yi n g t he 
e xte n de d i nf usi o n ti me 
 
 
 t o mai ntai n e n d ot o xi n 
s pecificati o ns. 
A d de d clarificat i on t o ali g n wit h t he 
P har mac y  Ma n ual.
Secti o n 5. 5. 1: 
J ustificati o n f or 
Ni v o l uma b D ose
U p date d l a n g ua ge o n sta n dar d 
of  care.
Del ete d pe m br oliz u ma b pl us 
c he m ot hera p y as t he sta n dar d of care, as 
ot her treat me nts ha ve bee n a p pr o ve d. 
Secti o n 5. 5. 2 : 
J ustificati o n f or 
Relatli ma b D oses
U p date d te xt a n d a d de d 
la n g ua ge with m o re rece nt 
data a n d a d de d 
P K/ p har mac o d y na mic 
i nf or mat i on o n rel at li ma b a n d 
ni v o l u ma b.
A d de d u p date d data re gar di n g t he P P K 
m o del  t hat pre dicts rece pt or occ u pa nc y.
Secti o n 5. 6: 
Cli n ical 
P har mac o l og y
A d de d te xt o n t he cli nical 
p har mac o l og y  of relatli ma b 
a n d ni v o l uma b. 
A d de d descri pt i on of t he cli nical 
p har mac o l og y  of ni v ol uma b a n d 
r elat li ma b.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 7
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 1: 
S y n o psis
Secti o n 6. 1: 
I ncl usi on Cri t eria
Cri t erio n 2) c) i ) a n d Ke y 
I ncl usi on Cri t eria: a d de d te xt 
t o refere nce t he La b orat or y 
Ma n ual f or a d dit i onal 
i nf or mat i on o n t u m or 
c ollect i on.
Refere nce d La b orat or y  Ma n ual f or 
a d ditio nal  inf or m atio n o n t u m or 
c ollect i on.
Secti o n 6. 2: 
E xcl usi o n Cri t eria
T he f oll owi n g 
c ha n ges were 
ma de: 

Cri teria 1) c, d, e, a n d g):  
a djuste d ti me fra mes t o 
reflect u p t o partici pa nt  
ra n d omizat i on.

Cri t erio n 1) h): a d de d te xt 
t o clar if y re q uire me nts f or 
parti ci pat i on of partici pa nts 
w h o are HI V p osit i ve.

Cri t erio n  
1)  
n):  
was 
r e mo ve d a n d Criteri o n 1) o) 
te xt  
was  
a dde d  
f or 
parti ci pa nts wi t h pre vio us 
e x p os ure t o S A R S -C o V - 2.

Cri t erio n 2) h): was a d de d 
f or p artici pa nts c urre ntl y i n 
ot her i n vesti gati onal trials, 
i ncl u di n g  
t hose  
f or 
C O VI D - 1 9.
Cri t erio n 3) b) ii): te xt was 
a d de d re gar di n g retesti n g 
of  
 car d iac 
c o ns ultati o n,  
a n d 
n otificati o n  
of   
BM S 
Me dical M o nit or.
C ha n ge d t o clarif y ti mi n g of s pecific 
e xcl usi o n cri teria a n d t o i ncl u de ne w 
cli nical a p pr oac hes f or pre vi o us 
e x p os ure t o viral i nfect i ons, was h o ut 
peri o d, parti cipa nts i n ot her 
i n vesti gati onal tri a ls, a n d la b orat or y 
tests.
Secti o n 6. 4. 1: 
Retesti n g D uri n g 
Scree ni n g or 
D ose Safet y 
C o nfir mati o n 
P eri o d
A d de d te xt descri bi n g testi n g 
a n d retesti n g of partici pa nts 
w h o ma y  d e v elo p s us pecte d or 
c o nfir me d s y m pt o mat ic 
C O VI D -1 9 d uri n g t he 
scree ni n g peri o d.
Cl arifie d e x pectatio ns f or eli gi bilit y a n d 
retesti n g of partici pa nts wit h s us pecte d 
or c o nfir me d s y m pt o mat ic C O VI D- 1 9.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 8
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 7. 1. 1: 
I mm u n ot hera p y  
D osi n g
A d de d te xt t o clarif y e xte n de d 
i nf usi on ti mes of 
i m m u n ot hera p y d osi n g 
 
 
Cl arifie d i nf usi o n ti mes base d o n 
parti ci pa nt weig ht a n d ali g ne d wi t h 
P har mac y  Ma n ual.
Secti o n 7. 1. 2. 3: 
P e m etre xe d a n d 
Cis plat i n
U p date d d urati o n of 
c he m ot hera p y treat me nt t o 4 
c ycles.
C orrecte d t y p o gra p hi c al err or t o clarif y 
t he c orrect d uratio n of  c he m ot hera p y 
treat me nt.
Secti o n 7. 2: 
Met h o d of 
Treat me nt 
Assi g n me nt
Re m o ve d t he f oll o wi n g criteria 
f or participa nt ra n d o mizat i on:
Will
parti ci pa nt be treate d 
wi t h cis plati n, if eli gi ble
( N S Q partici pa nts o nl y) ?
Will part ici pa nt be treate d 
wi t h 
na b -pacli t a x el,
if 
eli gi ble
( S Q parti cipa nts 
o nl y) ?
Will part ici pa nt be treate d
wi t h  
pe metre xe d 
mai nte na nce, 
if eli gi ble 
( N S Q partici pa nts o nl y) ?
Cl arifie d I R T f u nct i onalit y,  as it d oes 
n ot ca pt ure c he m ot hera p y  re gi me ns as 
part of t he re q uire d ra n d o mizat i on 
criteria.
Secti o n 7. 4. 1: 
D ose 
M o dificat i on 
Cri teria f or 
I mm u n ot hera p y;
Secti o n 7. 4. 2: 
D ose Dela y  
Cri teria f or 
C he m ot h era p y;
Secti o n 7. 4. 3. 3: 
C he m ot h era p y: 
D ose Re d ucti o ns 
f or H e mat olo gi c 
T o xicit y;
Secti o n 7. 4. 3. 4: 
C he m ot h era p y: 
D ose Re d ucti o ns 
f or N o n-
U p date d cri t eria for 
i m m u n ot hera p y d ose dela y, 
res u mpt i on, a n d 
di sc o nti n uati on. A d de d 
s us pecte d or c o nfir me d S A R S-
C o V -2 i nfect i on as a criteri o n 
t o dela y tr e at me nt as well as 
criteria f or res u m pti on of 
treat me nt. A d de d 
 mo dif yi n g te xt fr o m pri or 
para gra p h f or mat.
U p date d d ose dela y, res u m pt i on a n d 
di sc o nti n uati on cri t eria t o ali g n wit h t he 
c urre nt C T C A E v 5.
U p date d d ose dela y criteria t o i ncl u de 
e x pectatio ns i n cases of s us pecte d or 
c o nfir me d S A R S -C o V -2 i nfect i on a n d 
criteria f or res u m pti on of treat me nt.
C o m bi ne d criteria f or dela y, res u m p tio n, 
a n d disc o nt i n uati on of i m m u n ot hera p y  
i nto a ta bl e t o facilitate access a n d 
c o mpre he nsi o n.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 1 9
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
h e mat olo gi c 
T o xicit ies; 
Secti o n 7. 4. 4: 
Cri teria t o 
Res u me D osi n g;
Secti o n 7. 4. 6: 
Treat me nt of 
I mm u n ot hera p y  
I nf usi on 
React i ons;
Secti o n 8. 1. 1: 
I mm u n ot hera p y  
D ose 
Di sc o nti n uatio n;
Secti o n 9. 2: 
A d verse E ve nts
Secti o n 7. 4. 2: 
D ose Dela y  
Cri teria f or 
C he m ot h era p y;
Ta ble 7. 4. 3. 4 - 1 
D ose 
M o dificat i ons f or 
N o n -he mat ol o gi c 
T o xicit y
A d de d te xt clarif yi n g t hat d ose 
m o dificati o n g ui da nce fr o m  
l ocal c he mot h era p y la bels ma y 
var y  fr o m U S PI. 
Cl arifie d t hat ma na ge me nt of 
c he m ot hera p y a d verse e ve nts per l ocal 
la bel is all owe d. 
Ta ble 7. 4. 3. 3. -1 
D ose 
M o dificat i ons f or 
He m at olo gi c 
T o xicit y ( Base d 
o n Na di r C o u nts)
U p date d te xt t o clar if y wi n d o w 
of  Gra de 3 plat elet le vels. 
U p date d t o ai d i n rea di n g 
c o mpre he nsi o n.
Secti o n 7. 4. 4. 2: 
Cri teria t o 
Res u me 
Treat me nt wit h 
C he m ot h era p y
U p date d cri t eria t o res u me 
c he m ot hera p y f or A N C a n d 
pl at elet c o u nts.
C orrecte d t y p o gra p hi c al err ors.
Secti o n 7. 7. 1: 
Pr o hi bite d a n d/ or 
A d de d te xt o n C O VI D- 1 9 
vacci nati o n, was h o ut peri o d, 
Cl arifie d g uida nce re gar di n g C O VI D - 1 9 
vacci nes as c o nc o mit a nt t hera p y. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 2 0
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Restricte d 
Treat me nts
a n d pr o hi bit i on of use after last 
st u d y dr u g treat me nt. 
Secti o n 8. 1. 3: 
I mm u n ot hera p y 
Treat me nt 
Be y o n d Di sease 
Pr o gressi o n
U p date d l a n g ua ge fr o m 
“ ni v o l u ma b” t o 
“i m m u n ot hera p y. ”
C orrecte d t y p o gra p hi c al err ors.
Secti o n 9. 1. 2: 
Pati e nt -re p orte d 
O utc o m es
A d de d la n g ua ge o n c o m plet i on 
of  t he P R O meas ures i n t he 
parti ci pa nt’s preferre d 
la n g ua ge as well as use of 
alter nate a d mi nistrati o n 
met h o ds. 
Cl arifie d e x pectatio ns f or a d mi nistrati o n 
of  P R O e val uati ons i n e xte n uat i n g 
circ u msta nces. 
Secti o n 9. 2. 1: 
Ti me Peri o d a n d 
Fre q ue nc y f or 
C ollect i n g A E 
a n d S A E 
I nf or mat i on
U p date d I B secti o n w here 
Refere nce Safet y I nf or mat i on 
is f ou n d.
C orrecte d t y p o gra p hi c al err or for 
l ocat i on of Refere nce Safet y  
I nf or mat i on i n rele va nt relatli ma b a n d 
ni v o l u ma b I B a n d c he m ot hera p y 
treat me nts.
A d de d te xt t o descri be 
c ollect i on of all A Es a n d S A Es 
i n t he c o nte xt of S A R S-C o V - 2 
i nfecti on. 
I ncl u de d la n g ua ge f or A E/ S A E 
c ollect i on i n t he c o nte xt of S A R S-C o V -
2 i nfect i on.
Secti o n 9. 2. 3: 
F o ll ow- u p of  A Es 
a n d S A Es 
U p date d l a n g ua ge t o i ncl u de 
f oll ow- u p of  S A Es a n d 
n o nseri o us A Es ass oci ate d 
wi t h c o nfir me d or s us pecte d 
S A R S -C o V -2 i nfect i on.
I ncl u de d la n g ua ge f or c ollecti on of 
A E/ S A E e ve nts i n t he c o nte xt of S A R S -
C o V -2 i nfect i on a n d t he d urati o n of t he 
f oll ow- u p. 
Secti o n 9. 4. 5: 
Cli nical Safet y  
La b orat or y  
Assess me nts
A d de d te xt t o Ta ble 9. 4. 5- 1
• 
Che mistr y : mo difie d 
ma g nesi u m c o llecti on t o 
scree ni n g, pre-d ose, a n d 
c o mplet i on of P D C T
Cl arifie d assess me nts relate d t o 
ma g nesi u m.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 2 1
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
S U M M A R Y O F K E Y C H A N G E S F O R P R O T O C O L A M E N D M E N T 0 2
Secti o n N u m ber 
& Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 9. 5: 
P har mac o ki net ics 
a n d 
I mm u n o ge nicit y
•
A d de d te xt t o clarif y t he 
c ollect i on of P K ti me 
p oi nts a n d ali g n me nt wit h 
st u d y tr e at me nt da ys.
•
Ta ble 9. 5 -1: M o difie d 
ta ble t o reflect t he Place b o 
c ollect i on.
C ha n ge d t o clarif y ti mi n g a n d ali g n me nt 
P K sa m ple c o llecti on wi t h st u d y 
treat me nt da ys.
All
Ma de mi n or f or matti n g a n d 
t yp o gra p hical c orrecti o ns.
Beca use t hese c ha n ges are mi n or, t he y  
ha ve n ot bee n s u m marize d.
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 2 2
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v

Cli nical Pr ot oc ol
C A 2 2 4 1 0 4
B M S - 9 8 6 0 1 6
relatli ma b
O ver all R ati o n ale f or t he Pr ot oc ol A me n d me nt 0 1, 1 1 -N o v - 2 0 2 0
Pr ot oc ol  A me n d me nt 0 1 is bei n g i m ple me nte d t o i nc or p orate t w o ke y c ha n ges t hat 1) clarif y t h e 
i ncl usi on/e xcl usi o n  criteria a n d 2) ali g n t he c o nc o mita nt me dicati ons sect i on wi t h t he U S pr o d uct 
la bel of t he c he m ot hera p y a ge nts t o be a d mi nistere d as part of t he st u d y dr u g re gi me n.
S u m m ar y of ke y c h a n ges of Pr ot oc ol A me n d me n t 0 1
Secti o n 
N u m ber & 
Title
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n 6. 2: 
E xcl usi o n 
Cri teria
E xcl usi o n cri t eria 3. h) ser u m 
creati ni ne; t he creatini ne 
cleara nce ( Cr Cl) val ue was 
c ha n ge d t o > 5 0 mL / mi n 
( meas ure d or calc ulate d usi n g 
t he C oc kcr oft -Ga ult f or m ula) 
T he re nal f u nct i on eli gi bilit y cri t erio n was 
m o dif ie d t o c o mpl y wit h label restri ct i ons 
of  p e metre xe d a n d t o a v oi d t he ris k of 
e nr o lli n g partici pa nts wit h b or derli ne 
all o wa ble Cr Cl le vels w h o ma y nee d t o be 
di sc o nti n ue d fr om cis plat i n wit hi n a s h ort 
peri o d of  ti me.
Secti o n 7. 7. 1 
Pr o hi bite d 
a n d/ or 
Restricte d 
Treat me nts
A d de d t he w or ds “ dr u g 
i nteract i ons” t o t he la n g ua ge 
descri bi n g i n vest i gat or 
a d here nce t o U S PI or l ocal 
la bel f or eac h o ne of t he 
c he m ot hera p y a ge nts.
M o difie d t he c o nc o mita nt me dicat i on 
i nstr uctio ns t o refere nce t he dr u g 
i nteract i on i nf or mati o n i n t he U S PI f or t he 
r ele va nt c he m ot hera p y a ge nts. 
Pr ot o c ol  A m e n d m e nt  N o:  0 7
D at e:  1 1- S e p- 2 0 2 4
2 2 3
8 . 0
A p p r o v e d 
9 3 0 1 5 8 1 1 1
8 . 0
v
A p p r o v e d 
1 . 0
v