A Phase I, Open-label, Multiple-ascending Dose Trial to Investigate the Safety, Tolerability, PK, Biological and Clinical Activity of MSB0011359C in Subjects With Metastatic or Locally Advanced Solid Tumors and Expansion to Selected Indications
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: EMD Serono Research & Development Institute, Inc.



M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 9 3
Pr ot oc ol T a ble of C o nte nts
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 2
Ta ble of I n -Te xt Ta bles ....................................................................................................... 7
Ta ble of I n -Te xt Fi g ures ...................................................................................................... 7
List of A b bre viati o ns ........................................................................................................... 8
1
S y n o psis ..............................................................................................1 5
Sc he d ule of Assess me nt s ................................................................................................... 3 3
2
S p o ns or, I n vesti gat ors, a n d Trial A d mi nistrati ve Str uct ure ............... 5 0
2. 1
I n vesti gati o nal Sites............................................................................ 5 0
2. 2
Trial C o or di nati o n / M o nit ori n g ......................................................... 5 0
2. 2. 1
Safet y  M o nit ori n g C o m mittee............................................................ 5 1
2. 2. 2
Ce ntral Rea der a n d I n de pe n de nt E n d p oi nt Re vie w C o m mittee ......... 5 1
3
Bac k gr o u n d I nf or mati o n ..................................................................... 5 2
3. 1
I n vesti gati o nal Me dici nal Pr o d uct...................................................... 5 2
3. 2
3. 2. 1
3. 2. 2
P har mac o ki netics / I m m u n o ge nicit y  Fi n di n gs ................................... 5 8
3. 2. 3
T o xic ol o g y .......................................................................................... 5 9
3. 3
Brief S u m mar y  of t he Cli nical Fi n di n gs f or M S B 0 0 1 1 3 5 9 C............. 6 1
3. 4
3. 4. 1
3. 4. 2
3. 5
S u m mar y  of t he O verall Be nefit a n d Ris k.......................................... 6 9
3. 5. 1
I nf usi o n-relate d Reacti o ns / H yperse nsiti vit y .................................... 7 0
3. 5. 2
I m m u ne-relate d A d verse E ve nts / A ut oi m m u ne Dis or ders................7 1
3. 5. 3
T G F β I n hi biti o n Me diate d S ki n Reacti o ns................................ .........7 2
3. 5. 4
A ne mia ................................................................................................7 3
3. 5. 5
Blee di n g A d verse E ve nts ....................................................................7 3
3. 5. 6
Alterati o ns i n W o u n d Heali n g or Re pair of Tiss ue Da ma ge .............. 7 3
3. 5. 7
E m br y ofetal T o xicit y ..........................................................................7 3
3. 5. 8
P ote ntial Be nefit .................................................................................7 4
4
Trial O bjecti ves ..................................................................................7 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 9 3
4. 1
Pri mar y  O bjecti ves .............................................................................7 4
4. 2
Sec o n d ar y O bjecti ves ......................................................................... 7 4
4. 3
5
I n vesti gati o nal Pla n ............................................................................ 7 5
5. 1
O verall Trial Desi g n a n d Pla n ............................................................ 7 5
5. 1. 1
O verall Trial Desi g n ........................................................................... 7 6
5. 1. 2
Trial Me dicati o n A d mi nistrati o n a n d Sc he d ule .................................. 8 0
5. 1. 3
M S B 0 0 1 1 3 5 9 C D ose Escalati o n
........................................................ 8 1
5. 1. 4
E x pa nsi o n C o h orts .............................................................................. 8 3
5. 1. 5
Pla n ne d N u m ber of S u bjects ..............................................................8 3
5. 1. 6
Pla n ne d Treat me nt D urati o n ...............................................................8 3
5. 1. 7
D ose M o dificati o n a n d A D Rs Re q uiri n g Treat me nt 
Disc o nti n uati o n ...................................................................................8 4
5. 1. 8
A nal y sis C ut off Dates ......................................................................... 8 6
5. 2
Disc ussi o n of Trial Desi g n ................................................................. 8 7
5. 2. 1
I ncl usi o n of S pecial P o p ulati o ns ........................................................8 8
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................8 8
5. 3. 1
I ncl usi o n Criteria ................................................................................ 8 8
5. 3. 2
E xcl usi o n Criteria ( A p plica ble t o All S u bjects, I ncl u di n g All 
E x pa nsi o n C o h orts) ............................................................................9 4
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................ 9 6
5. 5
Criteria f or S u bject Wit h dra wal .......................................................... 9 7
5. 5. 1
Wit h dra wal Fr o m Trial Treat me nt ...................................................... 9 7
5. 5. 2
Wit h dra wal Fr o m t he Trial
................................................................. 9 7
5. 6
Pre mat ure Ter mi nati o n of t he Trial .................................................... 9 8
5. 7
Defi niti o n of E n d of Trial ................................................................... 9 9
6
I n vesti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Trial .....................................................................................................9 9
6. 1
Descri pti o n of t he I n vesti gati o nal Me dici nal Pr o d uct........................ 9 9
6. 2
D osa ge a n d A d mi nistrati o n ..............................................................1 0 0
6. 3
Assi g n me nt t o Treat me nt Gr o u ps................................ .....................1 0 1
6. 4
N o ni n vesti gati o nal Me dici nal Pr o d ucts t o be Use d .......................... 1 0 1
6. 5
C o nc o mita nt Me dicati o ns a n d T hera pies ......................................... 1 0 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 9 3
7. 4
Assess me nt of Safet y................................ ........................................1 3 9
7. 4. 1
A d verse E ve nts ................................................................................. 1 4 0
7. 4. 2
Pre g na n c y  a n d I n Uter o Dr u g E x p os ure........................................... 1 4 5
7. 4. 3
Cli nical L a b orat or y Assess me nts ..................................................... 1 4 6
7. 4. 4
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts........... 1 4 8
7. 5
P har mac o ki netics .............................................................................. 1 4 9
7. 5. 1
D ose Escalati o n P hase ...................................................................... 1 4 9
7. 5. 2
E x pa nsi o n P hase ............................................................................... 1 4 9
7. 5. 3
B o d y Fl ui d ........................................................................................ 1 4 9
7. 6
7. 6. 1
7. 6. 2
7. 6. 3
7. 7
Ot her Assess me nts ............................................................................1 5 4
7. 7. 1
A D A A nal ys is................................................................................... 1 5 4
7. 7. 2
7. 7. 3
Healt h -relate d Q ualit y of Life .......................................................... 1 5 4
8
Statistics ............................................................................................ 1 5 6
8. 1
8. 1. 1
D ose Escalati o n ................................................................................ 1 5 7
8. 1. 2
E x pa nsi o n C o h orts ............................................................................ 1 5 7
8. 2
Ra n d o mizati o n .................................................................................. 1 6 0
8. 3
E n d p oi nts .......................................................................................... 1 6 0
8. 3. 1
Pri mar y  E n d p oi nts............................................................................ 1 6 0
8. 3. 2
Se c o n dar y E n d p oi nts........................................................................1 6 0
8. 3. 3
8. 3. 4
Safet y  E n d p oi nts............................................................................... 1 6 2
8. 4
A nal y sis Sets.....................................................................................1 6 3
8. 5
Descri pti o n of Statistical A nal y ses ................................................... 1 6 3
8. 5. 1
Ge neral C o nsi derati o ns .....................................................................1 6 3
8. 5. 2
A nal y sis of Pri mar y E n d p oi nts.........................................................1 6 4
8. 5. 3
A nal y sis of Ot her E n d p oi nts.............................................................1 6 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 9 3
8. 5. 4
A nal y sis of Safety................................ .............................................1 6 7
8. 6
I nteri m a n d A d diti o nal Pla n ne d A nalys es ........................................ 1 6 8
9
Et hical a n d Re g ulat or y  As pects........................................................ 1 7 0
9. 1
Res p o nsi bilities of t he I n vesti gat or .................................................. 1 7 0
9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt ..................................... 1 7 1
9. 3
S u bject I de ntificati o n a n d Pri vac y .................................................... 1 7 2
9. 4
E mer ge nc y  Me dical S u p p ort a n d S u bject Car d................................ 1 7 2
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects ................... 1 7 2
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d ........ 1 7 3
9. 7
Healt h A ut h orities ............................................................................. 1 7 3
1 0
Trial Ma na ge me nt ............................................................................. 1 7 3
1 0. 1
Electr o nic Case Re p ort F or m Ha n dli n g ............................................ 1 7 3
1 0. 2
S o urce Data a n d S u bject Files .......................................................... 1 7 4
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g................................................. 1 7 5
1 0. 4
M o nit ori n g, Q ualit y Ass ura nce, a n d I ns pecti o n b y Healt h 
A ut h orities ........................................................................................ 1 7 5
1 0. 5
C ha n ges t o t he Cli nical Trial Pr ot oc ol .............................................. 1 7 5
1 0. 6
Cli nical Trial Re p ort a n d P u blicati o n P olic y .................................... 1 7 6
1 0. 6. 1
Cli nical Trial Re p ort ......................................................................... 1 7 6
1 0. 6. 2
P u blicati o n ........................................................................................ 1 7 6
1 0. 7
Rec or d Re te nti o n i n Ja pa n................................................................ 1 7 6
1 1
Refere nces Cite d i n t he Te xt .............................................................1 7 7
1 2
A p pe n dices ....................................................................................... 1 8 3
A p pe n di x 1
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us.............. 1 8 4
A p pe n di x 2 
G ui da nce o n C o ntrace pti o n ..............................................................1 8 5
A p pe n di x 3 
Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial................... 1 8 6
Si g nat ure Pa ge – Pr ot oc ol L ea d ....................................................................................... 1 8 7
Si g nat ure Pa ge – C o or di nati n g I n vesti gat or................................ ....................................1 8 8
Si g nat ure Pa ge – Pri nci pal I n vesti gat or ........................................................................... 1 8 9
S p o ns or Res p o nsi ble Pers o ns N ot Na me d o n t he C o ver Pa ge ........................................1 9 0
A p pe n di x 4
Pr ot oc ol A me n d me nts a n d L ist of C ha n ges ..................................... 1 9 1
C ha n ges fr o m Versi o n 7. 1 t o Versi o n 7. 2 i ncl u de d i n t he A me n d me nt: .........................1 9 2
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 9 3
T a ble of I n-Te xt T a bles
Ta ble 1
Sc he d ule of Assess me nts – D ose Escalati o n P hase............................ 3 3
Ta ble 2
Sc he d ule of Assess me nts – E x pa nsi o n P hase ..................................... 3 8
Ta ble 3
Sc he d ule of Assess me nts – P har mac o ki netic Sa m pli n g, 
 
, a n d Ge ne E x pressi o n Sa m pli n g......................................... 4 4
Ta ble 4
M o dificati o n of D ose Escalati o n Base d o n D L T O bser vati o ns .......... 8 2
Ta ble 5
Wait Peri o ds Bet wee n D osi n g of S u bjects Wit hi n a D ose / 
E x pa nsi o n C o h ort ............................................................................. 1 0 4
Ta ble 6
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n -relate d 
Reacti o ns Ca use d b y M S B 0 0 1 1 3 5 9 C ............................................... 1 0 5
Ta ble 7
Ma na ge me nt of I mm u ne -Relate d A d verse E ve nts ........................... 1 0 8
Ta ble 8
Assess me nt of Tar get Lesi o n Res p o nse: C o n ve nti o nal R E CI S T 
a n d m R E CIS T Assess me nt f or He pat ocell ular Carci n o ma 
F oll o wi n g t he A merica n Ass ociati o n f or t he St u d y of L i ver 
Disease – J o ur nal of t he Nati o nal Ca ncer I nstit ute G ui deli ne.......... 1 3 5
Ta ble 9
Criteria f or Res p o nse Assess me nts I nc or p orati n g M RI  a n d 
Cli nical Fact ors ................................................................................. 1 3 8
Ta ble 1 0
S u m mar y  of Pr o p ose d R A N O Res p o nse Criteria............................. 1 3 9
Ta ble 1 1
Re q uire d La b orat or y  Pa nel Tests...................................................... 1 4 7
Ta ble 1 2
T he 9 5 % E xact ( Cl o p per -Pears o n) C o nfi de nce I nter vals f or O R R 
Base d o n 3 0 E nr olle d S u bjects ......................................................... 1 5 8
T a ble of I n-Te xt Fi g ures
Fi g ure 1
Sc he matic of Trial Desi g n .................................................................. 8 0
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 9 3
List of A b bre vi ati o ns
A C T H
a dre n oc ortic otr o pic h or m o ne
A D A
a nti dr u g a nti b o d y
A D C C
a nti b o d y-de pe n de nt cell -me diate d c y t ot o xicit y
A D R
a d verse dr u g reacti o n
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A F P
al p ha-fet o pr otei n
A L K
a na plastic l y m p h o ma ki nase
A L T
ala ni ne a mi n otra nsferase
A N A
a nti n uclear a nti b o d y
A N C
a bs ol ute ne utr o p hil c o u nt
a P T T
acti vate d partial t hr o m b o plasti n ti me
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
A U C 0- ∞
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m t he ti me of 
d osi n g e xtra p olate d t o i nfi nit y
A U C 0-t
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m t he ti me of 
d osi n g t o t he ti me of t he last o bser vati o n
β- H C G
β- h u ma n c h ori o nic g o na d otr o pi n
B O R
best o verall res p o nse
C A - 1 2 5
ca ncer a nti ge n 1 2 5
C ma x
ma xi m u m ser u m c o nce ntrati o n o bser ve d p ost d ose
C mi n
mi ni m u m ser u m c o nce ntrati o n o bser ve d p ost d ose
C R
c o m plete res p o nse
C R O
C o ntract Researc h Or ga nizati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 9 3
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 A d verse E ve nts
C T L A- 4
c yt ot o xic T l ym p h oc y te a nti ge n- 4
C tr o u g h
tr o u g h c o nce ntrati o n 
D C R
disease c o ntr ol rate
D L T
d ose -li miti n g t o xicit y
E C 5 0
effecti ve c o nce ntrati o n e xerti n g 5 0 % effect
E C G
electr ocar di o gra m
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us
e C R F
electr o nic case re p ort f or m
E G F R
e pi der mal gr o wt h fact or rece pt or
E M A
E ur o pea n Me dici nes A ge nc y
E O R T C Q L Q- B N 2 0
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire Brai n M o d ule
E O R T C Q L Q- C 3 0
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire C ore i nstr u me nt
E O R T C Q L Q- C X 2 4
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire Cer vical Ca ncer M o d ule
E O R T C Q L Q-
H C C 1 8 - M
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire He pat ocell ular Carci n o ma 
M o d ule – M o difie d
E O R T C Q L Q- O E S 1 8
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire Oes o p ha geal M o d ule
E O R T C Q L Q- O V 2 8
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y  of Life Q uesti o n naire O varia n M o d ule
F A C S
fl u oresce nce-acti vate d cell s orter
F A C T
F u ncti o nal Assess me nt of Ca ncer T hera p y
F D A
F o o d a n d Dr u g A d mi nistrati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 9 3
F F P E
f or mali n fi xe d, paraffi n e m be d de d
F H SI - 8
F A C T He pat o biliar y  Sy m pt o m I n de x – 8 q uesti o ns 
FI S H
fl u oresce nce i n sit u hy bri dizati o n
F O L F O X
o xali plati n, 5 -fl u or o uracil, a n d f oli nic aci d 
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G G T
ga m ma -gl uta m y ltra nsferase
G L P
G o o d La b orat or y  Practice
H A H A
h u ma n a nti h u ma n a nti b o d y
H B V
he patitis B vir us
H C C
he pat ocell ular carci n o ma
H C V
he patitis C vir us
H D V
he patitis D vir us
H g b
he m o gl o bi n
HI V
h u ma n i m m u n o deficie nc y vir us
H P V
h u ma n pa pill o ma vir us
I B
I n vesti gat or’s Br oc h ure
I C5 0
5 0 % i n hi bit or y  c o nce ntrati o n 
I CF
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g
i m m u n o gl o b uli n 
I H C
i m m u n o hist oc he mistr y
I M P
I n vesti gati o nal Me dici nal Pr o d uct
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 / 1 9 3
I N R
i nter nati o nal n or malize d rati o
I P M P
I nte grate d Pr oject Ma na ge me nt Pla n
ir A E
i m m u ne-relate d a d verse e ve nt
i R A N O
i m m u ne-relate d R A N O
I RB
I nstit uti o nal Re vie w B oar d
I R C
I n de pe n de nt E n d p oi nt Re vie w C o m mittee
I WR S
i nteracti ve we b res p o nse s yste m
K P S
Kar n ofs k y Perf or ma nce Stat us
L D H
lactate de hy d r o ge nase
M A H A
m o use a nti b o d y a gai nst h u ma n a nti b o d y
M C H
mea n c or p usc ular he m o gl o bi n
M C H C
mea n c or p usc ular he m o gl o bi n c o nce ntrati o n
M D S Cs
m y el oi d- deri ve d s u p press or cells
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M o A
mec ha nis m of acti o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 9 3
M RI
ma g netic res o na nce i ma gi n g
M T D
m a xi m u m-t olerate d d ose
N B F
ne utral - b uffere d f or mali n
N CI
Nati o nal Ca ncer I nstit ute 
N K
nat ural killer
N O A E L
n o- o bser ve d -a d verse- effect le vel
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u gs
N S C L C
n o n- s mall cell l u n g ca ncer 
N S C L C -S A Q
N o n - Small Cell L u n g Ca ncer S y m pt o m Assess me nt 
Q uesti o n naire
O S
o verall s ur vi val 
P B M C
peri p heral bl o o d m o n o n uclear cell
P D
pr o gressi ve disease
P D - 1
pr o gra m me d deat h 1
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 S
Patie nt Gl o bal I m pressi o n of Se verit y
P h E ur
E ur o pea n P har mac o peia 
P K
p har mac o ki netic(s)
P R
partial res p o nse
p S M A D
p h os p h or y late d S M A D
P T
pr ot hr o m bi n ti me
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 9 3
 
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R F
r he u mat oi d fact or
S A E
seri o us a d verse e ve nt
S A P
Statistical A nal y sis Pla n
S C C H N
sq ua m o us cell carci n o ma h ea d a n d n ec k
S D
sta ble disease
S M C
Safet y  M o nit ori n g C o m mittee
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2
ter mi nal half-life
T 4
free t hyr o xi ne
T E A E
treat me nt-e mer ge nt a d verse e ve nt
T G F β
tra nsf or mi n g gr o wt h fact or-beta 
T G F β RII
tra nsf or mi n g gr o wt h fact or-beta rece pt or II
tma x
ti me t o reac h ma xi m u m c o nce ntrati o n
T M T B
t otal meas ure d t u m or bur de n
T N B C
tri ple-ne gati ve breast ca ncer
T N M
T u m or N o de Metastasis Classificati o n of Mali g na nt T u m ors 
( UI C C)
Tre g
re g ulat or y T-cells
T S H
t h yr oi d-sti m ulati n g h or m o ne
T T P
ti me t o pr o gressi o n
UI C C
U ni o n I nter nati o nale C o ntre le Ca ncer
U L N
u p per li mit of n or mal
U S P
U nite d States P har mac o peia
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 / 1 9 3
W B C
w hite bl o o d cell
λ z
ter mi nal eli mi nati o n rate c o nsta nt
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 9 3
Met h o d ol o g y: 
T his is a P hase I, ope n -la bel, d ose- escalati o n trial wit h c o nsec uti ve parallel -gr o u p e x pa nsi o n 
i n selecte d s oli d t u m or i n dicati o ns.
D ose esc al ati o n 
T he c urre nt trial is c o m p ose d of a sta n dar d d ose escalati o n “ 3 + 3” c o h ort desi g n, f or w hic h 
3 t o 6 s u bjects will be e nr olle d at eac h d ose level de pe n di n g o n t he occ urre nce of d ose -li miti n g 
t o xicities ( D LTs), f oll o we d b y a co nsec uti ve parallel -gr o u p e x pa nsi o n i n selecte d s oli d t u m or 
i n dicati o ns.  
C o h orts of 3 s u bjects wit h metastatic or l ocall y  ad va nce d s oli d t u m ors, f or w hic h n o sta n dar d 
effe cti ve t hera p y exists or sta n dar d t hera py has faile d, will recei ve M S B 0 0 1 1 3 5 9 C at escalati n g 
d ose le vels.  The starti n g M S B 0 0 1 1 3 5 9 C
d ose is 1 m g/ k g; t he hi g hest e n visa ge d d ose i n t he 
d ose escalati o n part is 2 0 m g/ k g , b ut t his m a y  be e x pa n de d base d o n t he st u d y safet y d ata.  T he 
d ose ra n ge a n d sc he d ule f or t his trial were de vel o pe d base d o n safet y c o nsi derati o ns as well as 
o n precli nical P K /
 a n d e x perie nce wit h t he pare nt 
a vel u ma b a nti b o d y c urre ntl y u n der cli nical de vel op me nt .
D ose esc al ati o n ( 3 + 3 desi g n) will be perf or me d at t he f oll o wi n g d ose le vels

1 m g/ k g

3 m g/ k g

1 0 m g/ k g

2 0 m g/ k g

3 0 m g/ k g

2 4 0 0 m g flat d ose
T he first s u bject of eac h c o h ort will be o bser ve d f or at least 5 da y s bef ore t he sec o n d s u bject 
ca n be treate d.  S u bse q ue nt s u bjects ma y recei ve first d osi n g at n o less t ha n 4 8-h o ur i nter vals 
bet wee n s u bjects. A D L T is defi ne d as a n y Gra de ≥ 3 a d verse e ve nt (A E ) assesse d t o be relate d 
t o in vesti gati o nal me dici nal pr o d uct (I M P) b y  th e I n vesti gat or a n d / or S p o ns or occ urri n g i n 
t he D L T e val uati o n peri o d ( 2 1 da ys after first a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C ) c o nfir me d by 
t he Safet y M o nit ori n g C o m mittee ( S M C) t o be rele va nt f or t he I MP treat me nt.  T he M T D is 
defi ne d as t he hi g hest d ose le vel at w hic h n o m ore t ha n 1 s u bject o ut of 6 s u bjects treate d i n a 
c o h ort a n d e val ua ble f or D L T deter mi nati o n e x perie nces a D L T.
At eac h d ose le vel, s u bjects will recei ve M S B 0 0 1 1 3 5 9 C
as a 1-h o ur i ntra ve n o us (I V) i nf usi o n 
( 1 2 0 mi n utes
f or t he 3 0 m g/ k g a n d 2 4 0 0 m g  flat-d ose c o h orts) o nce e ver y 2 wee ks u ntil 
pr o gressi ve disease ( P D) has bee n c o nfir me d b y  a su bse q ue nt sca n, u nacce pta ble t o xicit y, or 
occ urre nce of a n y c riteri o n f or wit h dra wal fr o m t he trial or t he I M P as o utli ne d i n t his pr ot oc ol.  
I n or der t o miti gate p ote ntial i nf usi o n-relate d reacti o ns, p re me dicati o n wit h a n a nti hista mi ne 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 / 1 9 3
a n d wit h paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 2 5 - 5 0 m g 
di p he n h y dra mi ne a n d 
5 0 0- 6 5 0 m g 
paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt) a p pr o xi matel y 30 t o 
6 0 mi n utes pri or t o eac h d ose of M S B 0 0 1 1 3 5 9 C is ma n dat or y f or t he first 2 i nf usi o ns, after 
w hic h pre me dicati o n is o pti o nal a n d at t he discreti o n of t he I n vesti gat or.  Ster oi ds as 
pre me dicati o n are n ot per mitte d .   
As t he 2 0 m g / k g c o h ort i n t he d ose escalati o n p orti o n has cleare d S M C e val uati o n, a n 
a d diti o nal c o h ort at t he 3 0 m g/ k g d ose le vel will be i nitiate d, i n parallel t o t he o n g oi n g 
e x pa nsi o n c o h orts.  The 3 0 m g/ k g c o h ort will be e nr olle d i n a 3 + 3 desi g n wit h S M C e val uati o n 
after t he first 3 s u bjects a n d n o m ore t ha n 6 e val ua ble s u bjects t o be e nr olle d .  T his c o h ort 
s h o ul d pr o vi de a d diti o nal i nsi g ht i nt o d ose pr o p orti o nalit y  of P K a n d 
 para meters 
a n d s u p p ort safety c o nsi derati o ns at hi g her e x p os ures t ha n t he e x pa nsi o n -p hase d ose 
of 1 2 0 0 m g o nce e ver y  2-wee ks . 
Wit h t he sa fet y of t he 3 0 m g/ k g c o h ort esta blis he d, a fi xe d d ose c o h ort of 2 4 0 0 m g o nce e ver y 
2 wee ks will be e nr olle d i n a 3 + 3 desi g n wit h S M C e val uati o n after t he first 3 s u bjects a n d 
n o m ore 
t ha n 6 e val ua ble s u bjects t o be e nr olle d .
T his c o h ort s h o ul d s u p p ort safet y 
c o nsi derati o ns at hi g her e x p os ures t ha n t he c urre nt e x pa nsi o n p hase d ose of 1 2 0 0 m g o nce 
e ver y 2 wee ks, i ncl u di n g t h ose f or alter nati ve d osi n g re gi me ns i n P hase II a n d P hase III st u dies.
F or P K / 
p ur p oses, after at least t he first 2 c o h orts ha ve bee n e val uate d wit h 
acce pta ble safet y a n d f or e x pl orat or y P K /  
 relati o ns hi ps, a decisi o n will be ma de t o 
i nitiate u p t o 2 c o h orts of 3 s u bjects eac h, o ne at 0. 1 m g/ k g a n d o ne at 0. 3 m g/ k g, w hic h w ill 
i ncrease o n t he sec o n d d ose a n d all s u bse q ue nt d oses t o a 1 2 0 0 m g /i nf usi o n flat d ose de pe n de nt 
u p o n S M C cleara nce a n d o nl y  if t he S p o ns or a n d C o or di nati n g I n vesti gat or ha ve deter mi ne d a 
mea ni n gf ul d ose f or t he i ntras u bject escalati o n.  After t he M T D ha s bee n reac he d or t he 
2 0 m g/ k g c o h ort has bee n declare d b y  the S M C as t he hi g hest n o n- M T D d ose assesse d, t he n 
f urt her P K a nal ys es m a y  be perf or me d.  If dee me d necessar y , t he 1, 3, 1 0, a n d 2 0 m g/ k g c o h orts 
ma y  eac h e nr oll u p t o a n a d diti o nal 1 0 s u bjects ( u p t o 4 0 t otal) f or t he p ur p ose of esta blis hi n g 
t he P K / 
 relati o ns hi p.  O n t he sec o n d d ose a n d all s u bse q ue nt d oses , t he 1 m g / k g 
c o h ort m a y  increase t o a 1 2 0 0 m g/i nf usi o n flat d ose. N o D L T e val uati o ns will be perf or me d 
i n t hese s u p ple me ntal c o h orts. 
E x p a nsi o n 
After deter mi nati o n of t he M T D, a M S B 0 0 1 1 3 5 9 C
d ose f or f urt her i n vesti gati o n will b e 
selecte d a n d e nr oll me nt i n e x pa nsi o n c o h orts i n selecte d t u m or i n dicati o ns will be o pe ne d t o 
deter mi ne t he safety a n d cli nical acti vit y of M S B 0 0 1 1 3 5 9 C .  T he i n dicati o ns were c h ose n si nce 
t he y offer t he p ote ntial f or tra nsf or mati ve treat me nt wit h a bilit y t o esta blis h a n i nitial pr o of of 
pri nci ple of a ntit u m or acti vit y  of M S B 0 0 1 1 3 5 9 C wit h g o o d feasi bilit y.
T he selecte d d ose of M S B 0 0 1 1 3 5 9 C
f or t he e x pa nsi o n c o h orts will be i nf usi o ns of 1 2 0 0 m g
f or all e x pa nsi o n c o h orts e xce pt f or t he sec o n d-li ne N S C LC c o h ort.  T he sec o n d-li ne N S C L C
c o h ort will be ra n d o mize d t o 1 of 2 d ose le vels 5 0 0 m g ( 4 0 s u bjects) a n d 1 2 0 0 m g ( 4 0 s u bjects). 
T hese d oses will be a d mi nistere d as “flat” d oses i n de pe n de nt of t he b o d y  wei g ht as 1- h o ur I V 
i nf usi o ns o nce e ver y 2 w ee ks u ntil P D has bee n c o nfir me d b y a s u bse q ue nt sca n, u nacce pta ble 
t o xicit y, or occ urre nce of a n y criteri o n f or wit h dra wal fr o m t he trial or t he I M P as o utli ne d i n 
t his pr ot oc ol.  
I n t he d ose -escalati o n part of t he st u d y, pre me dicati o n wit h a n a nti hista mi ne a n d wit h 
paraceta m ol 
(aceta mi n o p he n) has 
bee n 
ma n dat or y  in 
or der
t o miti gate 
p ote ntial 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 9 3
i nf usi o n-relate d reacti o ns.  Base d o n a n i nitial safet y assess me nt i n t he d ose-escalati o n c o h orts 
at d ose le vels of 1, 3, 1 0 , a n d 2 0 m g/ k g
wit h a c ut off date of 0 4 M a y
2 0 1 6 , n o s u bject was 
re p orte d wit h a treat me nt-e mer ge nt a d verse e ve nt ( T E A E) wi t h a Preferre d Ter m of 
i nf usi o n-relate d reacti o n; h o we ver usi n g a p ost -re p orti n g a nal ys is acc or di n g t o criteria o utli ne d 
i n t he Statistical A nal ys is Pla n, 3 s u bjects were re p orte d wit h T E A Es t hat were classifie d as 
“i nf usi o n-relate d reacti o ns,” wit h t he Preferre d Ter ms of a b d o mi nal pa i n, p y re xia, a n d bac k 
pai n ( N ote: t hese e ve nts are u n der g oi n g f urt her re vie w) . Base d o n t he a b o ve o bser vati o ns a n d 
i n or der t o f urt her i n vestigate t he p ote ntial f or i nf usi o n-relate d reacti o ns, f or s u bjects i n t he 
N S C L C bi o mar ker c o h ort bei n g treate d at t he U nite d States (U S ) Nati o nal Ca ncer I nstit ute
( N CI), pre me dicati o n will be o pti o nal. 
T his a p pr oac h i n t he li mite d n u m ber of s u bjects 
e nr olle d i n t he N S C L C bi o mar ker c o h ort a n d u n der cl ose s ur veilla nce of e x perie nce d 
In vesti gat ors at t he N CI i n vesti gati o nal site a p pears t o be j ustifie d. F or all ot her escalati o n a n d 
e x pa nsi o n c o h orts, pre me dicati o n is ma n dat or y f or at least t he first 2 i nf usi o ns, a n d t hereafter, 
o pt i o nal at t he discreti o n of t he In vesti gat or.  If Gra de ≥ 2 i nf usi o n reacti o ns are see n d ur i n g 
t he first t w o i nf usi o ns preme dicati o n s h o ul d n ot be st o p pe d.  Base d o n safet y  data f or s u bjects 
treate d wit h pre me dicati o n f or o nl y  the first 2 i nf usi o ns, t he pr ot oc ol mi g ht be a me n de d at a 
later ti me p oi nt t o all o w d osi n g wit h o ut pre me dicati o n f or all s u bject i nf usi o ns.  
Res p o nse t o tre at me nt
S u bjects fr o m eit her t he d ose -escalati o n or t he e x pa nsi o n p orti o ns of t he trial w h o ha ve 
e x perie nce d sta ble disease ( S D), a partial res p o nse ( P R), or a c o m plete res p o nse ( C R) s h o ul d 
be treate d t hr o u g h t he e n d of 1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble .  If t he 
I n vesti gat or belie ves t hat a s u bject m a y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be 
per missi ble after disc ussi o n wit h t he Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble .  
I n t he case of P D, s u bjects s h o ul d c o nti n ue treat me nt t hr o u g h t heir ne xt t u m or assess me nt, if 
t he y meet t he criteria descri be d i n t his pr ot oc ol.  If t here is f urt her e vi de nce of P D t hereafter, 
trial treat me nt s h o ul d be disc o nti n ue d; h o we ver c o nti n ue d treat me nt is p ossi ble i n c o ns ultati o n 
wit h t he Me dical M o nit or.  For s u bjects w h o ac hie ve S D, a C R or P R o n M S B 0 0 1 1 3 5 9 C 
t hera py a n d t he n s u bse q ue ntl y de vel o p disease pr o gressi o n after st o p pi n g t hera p y, b ut pri or t o 
t he e n d of t he trial, 1 r e-i nitiati o n c o urse of treat me nt at t he sa me d ose a n d sc he d ule a n d 
treat me nt d urati o n u p t o 1 2 m o nt hs is all o we d at t he discreti o n of t he I nvesti gat or a n d 
a gree me nt of t he trial M e dical R es p o nsi ble. T he I n vesti gat or will nee d t o c o nfir m t hat t he 
be nefit of re-i nitiati n g treat me nt o ut wei g hs a n y ris k i n v ol ve d, s uc h as t hat w hic h le d t o i nitial 
treat me nt disc o nti n uati o n. M ore o ver, f or s u bjects i n w hic h B O R was S D, t he In vesti gat or 
s h o ul d c o nfir m n o ot her reas o na ble treat me nt o pti o ns are a vaila ble.
S u bjects will be m o nit ore d a n d assesse d f or safet y a n d efficac y para meters at re g ular i nter vals 
t hr o u g h o ut t he trial.
Pl a n ne d n u m ber of s u bjects: 
D ose escalati o n: fr o m 3 t o 8 2 s u bjects.
E x pa nsi o n:  U p t o a p pr o xi matel y  5 6 6 s u bjects.
Pri m ar y e n d p oi nts:
T he pri mar y  e n d p oi nts f or t he d ose -escalati o n part of t he trial are t he:

N u m ber, se verity, a n d d urati o n of T E A Es acc or di n g t o t he N CI
C o m m o n Ter mi n ol o g y  
Criteria f or A d verse E ve nts ( C T C A E) v 4. 0 3
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 9 3

N u m ber, se verity a n d d urati o n of treat me nt-relate d a d verse e ve nts (A Es ) f or all d ose gr o u ps 
/ i n dicati o ns acc or di n g t o C T C A E v 4. 0 3

Occ urre nce of D L Ts d uri n g t he first 3 wee ks ( 2 1 da y s) of treat me nt i n t he d ose -escalati o n 
part of t he trial
E xce pt f or t he gli o blast o ma c o h ort, t he pri mar y efficac y en d p oi nt f or t he d ose -e x pa nsi o n part 
of t he trial is t he c o nfir me d B O R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d b y  t he I n de pe n de nt 
E n d p oi nt Re vie w C o m mittee (I R C) a n d will be e val uate d b y  co nfir me d o bjecti ve res p o nse rate 
( O R R).  F or gli o blast o ma, t he pri mar y e n d p oi nt will be disease c o nt r ol acc or di n g t o R A N O as 
a dj u dicate d b y t he I R C .
Sec o n d ar y e n d p oi nts:  
T he s ec o n d ar y e n d p oi nts f or t he d ose- esc al ati o n p art of t he tri al are t he:

M S B 0 0 1 1 3 5 9 C P K pr ofile (f or d ose escalati o n), i ncl u di n g area u n der t he c o nce ntrati o n -
ti me c ur ve (A U C ), ma xi m u m ser u m c o nce ntrati o n o bser ve d p ost d ose ( Cma x ), mi ni m u m 
ser u m c o nce ntrati o n o bser ve d p ost d ose (C mi n ), a n d ter mi nal half-life (t1/ 2)

Ser u m titers of a nti M S B 0 0 1 1 3 5 9 C a nti b o dies

B O R acc or di n g t o R E CI S T 1. 1 per I n vesti gat or assess me nt .
T he sec o n d ar y e n d p oi nts f or t he e x p a nsi o n p art of t he tri al are t he: 

M S B 0 0 1 1 3 5 9 C P K
pr ofile (f or d ose escalati o n), i ncl u di n g A U C, Cma x , Cmi n , a n d t1/ 2

Ser u m titers of a nti M S B 0 0 1 1 3 5 9 C a nti b o dies

N u m ber, se verity, a n d d urati o n of T E A Es a n d treat me nt-relate d T E A Es acc or di n g t o t he 
N CI -C T C A E v 4. 0 3

B O R acc or di n g t o R E CI S T 1. 1 per I n vesti gat or assess me nt .
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 9 3
 
 
 
 
 
 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 9 3
F or asce n di n g d ose -p orti o n a n d d ose -e x p a nsi o n p orti o n:
U ni nfecte d, H C V, a n d H B V -i nfecte d s u bjects are eli gi ble.
If me dicall y  in dicate d, 
su bjects i nfecte d wit h H B V m ust be treate d a n d o n a sta ble d ose of a nti virals (e g, 
e nteca vir, te n of o vir, or la mi v u di ne; a def o vir or i nterfer o n are n ot all o we d) at st u d y entr y 
a n d wit h pla n ne d m o nit ori n g 
a n d ma na ge me nt 
acc or di n g t o a p pr o priate la beli n g 
g ui da nce.  S u bjects o n active H C V t hera py at st u d y entr y  must be o n a sta ble d ose 
wit h o ut 
d oc u me nte d 
cli nicall y si g nifica nt li ver f u ncti o n test
or 
he mat ol o gic 
a b n or malities ( m ust meet criteria bel o w) a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt 
acc or di n g t o a p pr o priate la beli n g g ui da n ce.  
A d diti o nal criteria f or all H C C s u bjects i ncl u de:
o
C hil d -P u g h A or B 7
o
E C O G P S 0 or 1
o
A l b u mi n ≥2. 8 g/ d L
o
Inter nati o nal n or malize d rati o (I N R) < 1. 7
o
A de q uate he mat ol o gical f u ncti o n defi ne d b y W B C c o u nt ≥ 2. 5 × 1 0 9/ L wit h a bs ol ute 
ne utr o p hil c o u nt ( A N C) ≥ 1. 5 × 1 0 9/ L, ly m p h oc y te c o u nt ≥ 0. 5 × 1 0 9/ L, platelet c o u nt 
≥ 5 0 × 1 0 9/ L, a n d he m o gl o bi n ≥ 9 g/ d L  
o
S u bjects wit h n o aller gies t o c o ntrast a n d able t o t olerate c o m p ute d t o m o gra p h y ( C T)
or ma g netic res o na nce i ma gi n g ( M RI) c o ntrast i n t he o pi ni o n of t he I n vesti gat or

N S C L C, sec o n d li ne:  Hist ol o gicall y c o nfir me d Sta ge III b/I V or rec urre nt N S C L C.  
M ust n ot ha ve recei ve d c hec k p oi nt i n hi bit or pre vi o usl y  (c o ns ult wit h Me dical M o nit or 
if necessar y ).  Must ha ve e x perie nce d disease pr o gressi o n after a n acce pta ble t hera p y 
defi ne d as f oll o ws:
o
S u bjects m ust ha ve pr o gresse d d uri n g or after a mi ni m u m of 2 c ycles of 1 c o urse of a 
plati n u m -base d c o m bi nati o n t hera p y ad mi nistere d f or t he treat me nt of metastatic 
disease.  A hist or y of c o nti n uati o n ( use of a n o n- plati n u m a gent fr o m i nitial 
c o m bi nati o n) or s witc h ( use of a differe nt a ge nt) mai nte na nce t hera p y is per mitte d 
pr o vi de d t here was n o pr o gressi o n after t he i nitial c o m bi nati o n.  A switc h of a ge nts 
d uri n g treat me nt f or t he ma na ge me nt of t o xicities is als o per mitte d pr o v i de d t here was 
n o pr o gressi o n after t he i nitial c o m bi nati o n
O R
o
S u bjects m ust ha ve pr o gresse d wit hi n 6 m o nt hs of c o m pleti o n of a plati n u m -base d 
a dj u va nt, ne oa dj u va nt, or defi niti ve c he m ot hera p y, or c o nc o mita nt c he m ora diati o n 
re gi me n f or l ocall y a d va nce d disease
S u bjects wit h n o n-s q ua m o us cell N S C L C of u n k n o w n m utati o nal
stat us will re q uire 
testi n g (l ocal la b orat or y, or ce ntral la b orat or y if l ocal testi n g is n ot a vaila ble). S u bjects
wit h k n o w n E G F R m utati o n a n d / or A L K tra nsl ocati o n are eli gi ble if t he y ha ve recei ve d 
at least 1 li ne of t yr osi ne ki nase i n hi bit or t hera py .  S u bjects wit h R O S 1 rearra n ge me nt 
m ust ha ve recei ve d t yr osi ne ki nase i n hi bit or t hera p y if l ocall y a p pr o ve d.  T hese s u bjects 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 9 3
d o n ot re q uire pri or treat me nt wit h s yste mic c he m ot hera p y.  S u bjects wit h lar ge cell 
ne ur oe n d ocri ne ca ncer of t he l u n g are n ot eli gi ble   

N S C L C, a nti -P D - 1 / a nti -P D -L 1 f ail ure:  S u bjects wit h h ist ol o gically c o nfir me d Sta ge 
I V ( metastatic) or rec urre nt N S C L C ( per 7t h I nter nati o nal Ass ociati o n f or t he St u d y  of 
L u n g Ca ncer classificati o n) w h o ha ve e x ha uste d sta n dar d treat me nt o pti o ns i n t he 
o pi ni o n of t he I n vesti gat or are t o be e nr olle d.  At a mi ni m u m, s u bjects nee d t o ha ve 
recei ve d a n d faile d plati n u m -base d c he m ot hera p y a n d m ust ha ve recei ve d a nti-P D - 1 or 
a nti-P D -L 1 as m o n ot hera p y  an d faile d wit h disease pr o gressi o n.  In a d diti o n, s u bjects 
s h o ul d ha ve e x ha uste d ot her i n dicate d dri ver m utati o n t hera p y, as a p pr o priate  

Mel a n o m a, a nti -P D - 1 / a nti -P D -L 1 f ail ure:  S u bjects wit h u nresecta ble Sta ge III or 
metastatic ( Sta ge I V) mela n o ma w h o ha ve e x ha uste d sta n dar d treat me nt o pti o ns i n t he 
o pi ni o n of t he i n vesti gat or are t o be e nr olle d. At a mi ni m u m, s u bjects nee d t o ha ve 
recei ve d a nti-P D -1 or a nti-P D -L 1  as m o n o - or c o m bi nati o n t herap y  an d faile d wit h 
disease pr o gressi o n .  Als o m ust ha ve faile d a p pr o priate s yste mic t hera pies i ncl u di n g 
B R A F i n hi bit or if B R A F V 6 0 0 m utati o n p ositi ve

P a ncre atic a de n oc arci n o m a, sec o n d li ne or gre ater:  Hist ol o gicall y  co nfir me d 
pa ncreatic a de n ocarci n o ma (s ubjects wit h e n d ocri ne or aci nar pa ncreatic carci n o ma are 
n ot eli gi ble).  M ust ha ve u nresecta ble or l ocall y  a d va nce d or metastatic disease
o
Pri or t hera p y wit h ≥ 1 s y ste mic c he m ot hera py re gi me n f or u nresecta ble or metastatic 
pa ncreatic ca ncer or u n willi n g / una ble t o recei ve s yste mic c he m ot hera p y .  S u bjects 
m ust n ot ha ve recei ve d pre vi o us ra di ot hera p y f or meas ura ble lesi o ns
o
Disease pr o gressi o n w hile recei vi n g or after disc o nti n ui n g palliati ve c he m ot hera p y

C ol orect al 
c a ncer ( C R C), t hir d li ne or gre ater :  Hist ol o gicall y  co nfir me d 
a de n ocarci n o ma of t he c ol o n or rect u m
o
S u bjects m ust ha ve pr o gresse d d uri n g or after a sec o n d- li ne of sys te mic treat me nt 
o
Pri or faile d t hera py m ust ha ve i ncl u de d at least a fl u or o p yri mi di ne, o xali plati n, 
iri n oteca n (si n gle or i n c o m bi nati o n) a n d be vaciz u ma b ( w here a p pr o ve d).  For 
s u bjects w h o ha d wil d-t ype R A S t u m ors, cet u xi ma b or pa nit u m u ma b treat me nt m ust 
ha ve occ urre d   

T N B C , sec o n d-li ne or gre ater :  T u m or m ust be c o nfir me d ne gati ve f or estr o ge n 
rece pt ors, pr o gester o ne rece pt or s, a n d H E R 2
o
E R ne gati ve defi ne d b y:   E R I HC < 1 % reacti ve cells
o
P R ne gati ve defi ne d b y:  P R IH C < 1 % reacti ve cells
o
H E R -2 ne gati ve defi ne d b y  o ne of f o ur sit uati o ns bel o w:
1.
H E R 2 Breast I H C = 0
2.
H E R 2 Breast I H C = 1 +
3.
H E R 2 Breast I H C = 2 + A N D FI S H -ne gati ve ( n o n-a m plifie d)
4.
FI S H n o n -a m plifie d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 9 3
o
S u bjects m ust ha ve pr o gresse d d uri n g or after first -li ne of c he m ot hera py 

O v ari a n c a ncer, pl ati n u m resist a nt or refr act or y , pre vi o usl y tre ate d s yste mic all y:  
Hist ol o gicall y c o nfir me d e pit helial o varia n, fall opia n t u be, or perit o neal ca ncer (s u bjects 
wit h n o n- e pit helial t u m or, i ncl u di n g mali g na nt mi xe d M ülleria n t u m ors wit h o ut hi g h 
gra de ser o us c o m p o ne nt, or o varia n t u m or s wit h l o w mali g na nt p ote ntial [ie, b or derli ne 
t u m ors] are n ot eli gi ble)
o
M ust n ot be a ca n di date f or s ur gical resecti o n wit h c urati ve i nte nt
o
M ust ha ve p lati n u m resista nt / refractor y disease, defi ne d as disease pr o gressi o n
wit hi n 1 8 0 da y s f oll o wi n g t he last a d mi nistere d d ose of plati n u m t hera p y  (resista nt), 
or lac k of res p o nse or disease pr o gressi o n w hile 
recei vi n g t he m ost rece nt 
plati n u m -base d t hera p y (refract or y), or pr o gressi o n o n / after last n o n- plati n u m -base d 
c he m ot h era p y
o
Treat me nt hist or y  of at least 2 pri or s yste mic re gi me ns, i ncl u di n g pri or e x p os ure t o 
plati n u m a n d ta xa ne a ge nts.  
o
B R C A stat us m ust be re p orte d if k n o w n

Es o p h a ge al a de n oc arci n o m a, p ost - pl ati n u m, sec o n d li ne or gre ater:  Hist ol o gicall y 
c o nfir me d rec urre nt or metastatic es o p ha geal a de n ocarci n o ma.  M ust ha ve u nresecta ble
( Sta ge III or I V) disease
o
M ust ha ve recei ve d at least o n e pre vi o us plati n u m -c o ntai ni n g c he m ot hera p y re gi me n.  
S u bjects wit h H E R 2- p os iti ve t u m ors m ust ha ve recei ve d pri or trast uz u ma b

Gli o bl ast o m a, p ost -te m oz ol o mi de / r a di ati o n, sec o n d li ne:  Hist ol o gicall y  co nfir me d 
Gra de I V mali g na nt gli o ma (s u bjects wit h e xtracra nial metastatic or le pt o meni n geal are 
n ot eli gi ble)  
o
Pre vi o us treat me nt wit h ra di ot hera p y a n d te m oz ol o mi de
o
T olera nce t o ga d oli ni u m
o
A n i nter val of at least 1 2 wee ks after t he e n d of pri or ra di ot hera p y  is re q uire d u nless 
t here is eit her hist ol o pat h ol o gic c o nfir mati o n of rec urre nt t u m or or ne w e n ha nce me nt 
o n M RI  o utsi de of t he ra di ot hera p y treat me nt fiel d
o
First rec urre nce of gli o blast o ma
o
Kar n ofs k y Perf or ma nce Stat us ≥ 7 0
o
S u bjects m ust n ot ha ve recei ve d pri or be vaciz u ma b or ot her a nti -vasc ular e n d ot helial 
gr o wt h fact or or a ntia n gi o ge nic treat me nts

S C C H N , sec o n d li ne or gre ater :  Hist ol o gicall y  co nfir me d rec urre nt or metastatic 
S C C H N ( oral ca vit y, p har y n x, lar yn x), S ta ge III/I V a n d n ot a me na ble t o l ocal t hera p y 
wit h c urati ve i nte nt (s ur ger y  or ra diati o n t hera py wit h or wit h o ut c he m ot hera p y)   
o
T u m or pr o gressi o n or rec urre nce wit hi n 6 m o nt hs of last d ose of plati n u m t hera p y  i n 
t he a dj u va nt (ie wit h ra diati o n after s ur ger y), pri mar y  (ie, wit h ra diati o n), rec urre nt, 
or metastatic setti n g
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 9 3
o
S u bjects ma y  ha ve recei ve d pri or cet u xi ma b 
o
H u ma n pa pill o ma vir us t u m or testi n g m ust be re p orte d if k n o w n

Cer vic al c a ncer, sec o n d li ne or gre ater :  Hist ol o gicall y c o nfir me d rec urre nt or 
persiste nt s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma, or a de n ocarci n o ma of 
t he cer vi x f oll o wi n g sta n dar d of care treat me nt wit h s yste mic t hera py f or a d va nce d 
disease (ty picall y d o u blet c yt ot o xic c he m ot hera p y a n d be vaciz u ma b , w here a p pr o ve d )  
o
H u ma n pa pill o ma vir us t u m or testi n g m ust be re p orte d if k n o w n
6. E C O G P S of 0 t o 1 at trial e ntr y
7. Disease m ust 
be meas ura ble 
wit h at least 1 u ni di me nsi o nal l y meas ura ble 
lesi o n b y  
R E CI S T 1. 1
Ke y e xcl usi o n criteri a ( a p plic a ble t o all s u bjects, i ncl u di n g all e x p a nsi o n c o h orts)
1. C o nc urre nt treat me nt wit h n o n -per mitte d dr u gs a n d ot her i nter ve nti o ns
2. E xce pt f or t he a nti-P D - 1 / a nti-P D -L 1 -e x perie nce d N S C L C a n d mela n o ma e x pa nsi o n 
c o h orts, pri or t hera py wit h a n y anti b o d y  / dr u g tar geti n g T- cell c ore g ulat or y pr otei ns 
(i m m u ne c hec k p oi nts) s uc h as a nti-P D - 1, a nti-P D -L 1 , or a nti-c yt ot o xic T- l ym p h oc y te 
a nti ge n - 4 ( C T L A- 4 a nti b o d y) is n ot all o we d (c o ns ult wit h M e dical M o nit or as nee de d) , 
i ncl usi ve of i ntra he patic, l ocalize d a d mi nistrati o n of s uc h age nts
3. A ntica ncer treat me nt wit hi n 2 8 da y s bef ore t he start of trial treat me nt, f or e xa m ple
c yt ore d ucti ve t hera p y, ra di ot hera p y ( wit h t he e xce pti o n of palliati ve ra di ot hera p y deli vere d 
i n a n or mal or ga n -s pari n g tec h ni q ue), i m m u ne t hera py, or c yt o ki ne t hera p y ( wit h t he 
e xce pti o n of s orafe ni b f or s u bjects wit h H C C, w hic h m ust ha ve bee n st o p pe d wit hi n 
1 4 da y s)
4.
M aj or s ur ger y wit hi n 2 8 da y s bef ore t he start of trial treat me nt (pri or dia g n ostic bi o ps y  is 
per mitte d )
5. S y ste mic t hera p y wit h i m m u n os u p pressi ve a ge nts wit hi n 7 d a y s bef ore t he start of trial 
treat me nt; or use of a n y i n vesti gati o nal dr u g wit hi n 2 8 da y s bef ore t he start of trial treat me nt
(N ote:   f or s u bjects wit h gli o blast o ma, ster oi d use is all o we d acc or di n g t o sta n dar d of care 
a n d l ocal g ui deli nes)
6. Pre vi o us mali g na nt disease ( ot her t ha n t he tar get mali g na nc y  t o be i n vesti gate d i n t his trial) 
wit hi n t he last 3 years.  S u bjects wit h a hist or y of cer vical carci n o ma i n sit u, s u perficial or 
n o n- i n vasi ve bla d der ca ncer, or basal cell or s q ua m o us cell carci n o ma i n sit u pre vi o usl y  
treate d wit h c urati ve i nte nt are N O T e xcl u de d.  S u bjects wit h ot her l ocalize d mali g na ncies 
treate d wit h c urati ve i nte nt nee d t o be disc usse d wit h t he Me dical M o nit or
7. Ra pi dl y  pr o gressi ve disease w hic h, i n t he o pi ni o n of t he I nvesti gat or, ma y  pre dis p ose t o 
i na bilit y t o t olerate treat me nt or trial pr oce d ures
8. S u bjects wit h acti ve ce ntral ner v o us s yste m ( C N S) metastases ca usi n g cli nical s ym pt o ms or 
metastases t hat re q uire t hera pe utic i nter ve nti o n are excl u de d .  S u bjects wit h a hist or y  of 
treate d C N S metastases ( b y sur ger y  or ra diati o n t hera p y) are n ot eli gi ble u nless t he y ha ve 
f ull y rec o vere d fr o m treat me nt, de m o nstrate d n o pr o gressi o n f or at least 2 m o nt hs, a n d d o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 9 3
n ot re q uire c o nti n ue d ster oi d t hera p y . S u bjects wit h C N S metastases i nci de ntall y detecte d 
d uri n g S cree ni n g w hic h d o n ot ca use cli nical s ym pt o ms a n d f or w hic h sta n dar d of care 
s u g gests n o t hera pe utic i nter ve nti o n is i n dicate d s h o ul d be disc usse d wit h t he S p o ns or
Me dical Res p o nsi ble
9. Recei pt of a n y or ga n tra ns pla ntati o n, i ncl u di n g all o ge neic ste m-cell tra ns pla ntati o n, b ut 
wit h t he e x ce pti o n of tra ns pla nts t hat d o n ot re q uire i m m u n os u p pressi o n (e g, c or neal 
tra ns pla nt, hair tra ns pla nt) 
A d diti o nal e xcl usi o n criteria f or s u bjects i n t he H C C c o h ort i ncl u de:
Cli nical ascites (t hat is, n ot per ra di ol o gical assess me nt o nl y ) wit hi n past 6 m o nt hs
n ot 
a de q uatel y c o ntr olle d wit h me dical t hera p y; hist or y  of variceal blee di n g wit hi n past 
3 m o nt hs ; hist or y of u nc o ntr olle d he patic e nce p hal o pat h y i n t he past 3 m o nt hs; or hist or y 
o f o bstr ucti ve ja u n dice n ot a me na ble t o ste nti n g i n t he past 3 m o nt hs
He patitis D vir us ( H D V) c o-i nfecti o n wit h he patitis B vir us ( H B V; if H B V s urface a nti ge n
or H B V D N A p ositi vit y  at Scree ni n g t he n m ust c hec k f or H D V stat us)
C he m oe m b olizati o n or ra di oe m b olizati o n wit hi n 2 8 da ys pri or t o I M P a d mi nistrati o n
I n vesti g ati o n al Me dici n al Pr o d uct: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule:
F or t he d ose -escalati o n c o h orts (e xce pt f or t he 2 4 0 0 m g flat-d ose c o h ort), the d ose of 
M S B 0 0 1 1 3 5 9 C will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d o n t he da y 
pri or t o or t he da y  of eac h dr u g a d mi nistrati o n.  
F oll o wi n g safety a n d P K a nal ys is of t he Escalati o n c o h orts, a flat d ose of 1 2 0 0 m g/i nf usi o n 
was c h ose n f or all e x pa nsi o n c o h orts, e xce pt f or t he N S C L C sec o n d-li ne c o h ort, i n w hic h 
4 0 s u bjects will recei ve 5 0 0 m g/i nf usi o n a n d 4 0 s u bjects will recei ve 1 2 0 0 m g/i nf usi o n .
M S B 0 0 1 1 3 5 9 C
will be a d mi nistere d o nce e ver y 2 wee ks as a 1- h o ur (- 1 0 / +2 0 mi n utes, t hat 
is, o ver 5 0 t o 8 0 mi n utes) I V i nf usi o n.  S u bjects e nr olle d i n t he 3 0 m g/ k g a n d 2 4 0 0 m g flat-d ose 
c o h orts m a y  ha ve a t otal i nf usi o n ti me of u p t o 1 2 0 mi n utes.
I n or der t o miti gate p ote ntial i nf usi o n-relate d reacti o ns, p re me dicati o n wit h a n a nti hista mi ne 
a n d wit h
paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 2 5- 5 0
m g 
di p he n h y dra mi ne a n d 
5 0 0- 6 5 0 m g 
paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt) a p pr o xi matel y 30 t o 
6 0 mi n utes pri or t o eac h d ose of M S B 0 0 1 1 3 5 9 C 
is ma n dat or y
f or t he first 2 i nf usi o ns.  
Pre me dicati o n is o pti o nal a n d at t he discreti o n of t he I nvesti gat or after t he sec o n d i nf usi o n
( pre me dicati o n is o pti o nal f or all i nf usi o ns f or s u bjects i n t he N S C L C bi o mar ker c o h ort bei n g 
treate d at t he U S N CI ).  If Gra de ≥2 i nf usi o n reacti o ns are see n d ur i n g t he first tw o i nf usi o ns,
pre me dicati o n s h o ul d n ot be st o p pe d.   Ster oi ds as pre me dicati o n are n ot per mitte d.
Refere nce t her a p y:  d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: 
N ot a p plica ble .
Pl a n ne d tri al a n d tre at me nt d ur ati o n per s u bject: 
S u bjects will recei ve M S B 0 0 1 1 3 5 9 C
u ntil pr o gressi o n has bee n c o nfir me d b y  a su bse q ue nt 
sca n, u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m t he trial or I MP occ urs as 
o utli ne d i n t his pr ot oc ol.  
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 9 3
N S C L C , a nti-P D -1 / a nti -P D -L 1 f ail ure c o h ort: 8 0 s u bjects will be e nr olle d t o c haracterize 
t he t olera bilit y, safety pr ofile, a n d f or preli mi nar y  eval uati o n of a ntit u m or acti vit y for 
pre vi o usl y  a nti-P D -1 / a nti-P D -L 1  treate d s u bjects. Wit h 8 0 e nr olle d s u bjects, t he st u d y has 
9 2 % p o wer t o r ule o ut a 5 % O R R w he n t he tr ue O R R is 1 5 % wit h 1 -si de d 0. 05 al p ha.
T here will be o ne pla n ne d i nteri m a nal yses f or i nter nal pla n ni n g p ur p oses.  There is n o 
m ulti plicit y  adj ust me nt is a p plie d t o t he i nteri m a nal ysis.  The i nteri m a nal ysis wil l occ ur w he n 
t he first 4 0 s u bjects are e val ua ble f or res po nse assess me nt at 1 2 wee ks (t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore 
W ee k 1 2).
Mel a n o m a, 
a nti -P D -1 / a nti -P D -L 1 f ail ure c o h ort: 
3 0 s u bjects will be e nr olle d t o 
c haracterize t he t olera bilit y, safety p r ofile, a n d f or preli mi nary e val uati o n of a ntit u m or acti vit y 
f or pre vi o usl y  a nti-P D - 1 / a nti-P D -L 1 treate d s u bjects.  Wit h 3 0 s u bjects w h o were treate d wit h 
pri or a nti-P D - 1 / a nti-P D -L 1  thera p y,  th e st u d y has 8 7 % p o wer t o r ule o ut a 5 % O R R w he n t he 
tr ue O R R is 2 0 % wit h 1 -si de d 0. 1 al p ha.
T here will be o ne pla n ne d i nteri m a nal ysis f or i nter nal pla n ni n g p ur p oses.  There is n o 
m ulti plicit y  adj ust me nt a p plie d t o t he i nteri m a nal ysis.  The i nteri m a nal ys is will occ ur w he n 
t he 3 0 s u bjects are e val ua ble f or res p o nse assess me nt at 1 2 wee ks (t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at Wee k 
1 2 or disc o nti n ue d t he st u d y bef ore 
Wee k
1 2).
N S C L C , sec o n d-li ne c o h ort:  U p t o 8 0 s u bjects will be enr olle d (ra n d o mize d i n a 1: 1 rati o t o 
recei ve eit her 5 0 0 or 1 2 0 0 m g /i nf usi o n) t o c haracterize t he t olera bilit y, safety pr ofile, f or 
preli mi nar y  e val uati o n of a ntit u m or acti vit y , a n d t o s u p p ort t he o verall P K data t o c haracterize 
t he e x p os ure -res p o nse relati o ns hi p.  Wit h 3 0 s u bjects w h o recei ve d 1 2 0 0 m g/i nf usi o n were 
treate d wit h pri or plati n u m -base d t hera p y , t he st u d y has 8 2 % p o wer t o r ule o ut a ≤2 0 % O R R 
w he n t he tr ue O R R is 4 0 % wit h 1 -si de d 0. 1 al p ha. 
T here will be o ne pla n ne d i nteri m a nal ysis f or inter nal pla n ni n g p ur p oses.  There is n o 
m ulti plicit y  adj ust me nt is a p plie d t o t he i nteri m a nal ysis.  The i nteri m a nal ysis will occ ur w he n 
t he 3 0 s u bjects are e val ua ble f or res p o nse assess me nt at 1 2 wee ks (t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore 
W ee k 1 2).
If ≤4 res p o n ders are o bser ve d at t he i nteri m a nal ys is, n o f urt her s u bjects will be 
e nr olle d i nt o t he N S C LC sec o n d -li ne c o h ort.  
P a ncre atic a de n oc arci n o m a , C R C , a n d cer vic al c a ncer c o h orts: U p t o 3 0 s u bjects will be 
e nr olle d i n eac h c o h ort.  O ne i nteri m a nal ysis is pla n ne d f or eac h c o h ort w he n t he 3 0 t h s u bject 
fr o m eac h c o h ort is e val ua ble f or res p o nse assess me nt at 1 2 wee ks (t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore W ee k 
1 2). 
Wit h 3 0 s u bjects treate d, t he st u d y has a p pr o xi matel y 79 % p o wer t o r ule o ut a ≤ 1 0 % O R R 
( n ull h yp ot hesis) w he n t he tr ue O R R is 2 5 % wit h 1 -si de d 0. 1 al p ha. 
O v ari a n c a ncer, T N B C, a n d es o p h a ge al a de n oc arci n o m a c o h orts:  U p t o 3 0 s u bjects will 
be e nr olle d i n eac h c o h ort.  O ne i nteri m a nal ys is is pla n ne d f or eac h c o h ort w he n t he 3 0 t h
s u bject fr o m eac h c o h ort is e val ua ble f or res p o nse assess me nt at 1 2 wee ks ( t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore 
W ee k 1 2). 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 9 3
Wit h 3 0 s u bjects treate d, t he st u d y has a p pr o xi matel y 87 % p o wer t o r ule o ut a ≤ 1 5 % O R R 
( n ull h yp ot hesis) w he n t he tr ue O R R is 3 5 % wit h 1 -si de d 0. 1 al p ha.
Gli o bl ast o m a c o h ort:  U p t o 3 0 s u bjects will be e nr olle d t o c haracterize t he t olera bilit y, safety 
pr ofile, a n d f or preli mi nar y  eval uati o n of a ntit u m or acti vit y.  O ne i nteri m a nal ys is is pla n ne d 
w he n t he 3 0 s u bjects are e val ua ble f or res p o nse assess me nt at 1 2 wee ks (t hat is, ha v e eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore 
W ee k 1 2).
Wit h 3 0 s u bjects treate d, t he st u d y has a p pr o xi matel y 9 7% p o wer t o r ule o ut a ≤ 5 0 % D C R
(n ull h y p ot hesis) w he n t he tr ue D C R is 8 0 % at t he 5 % t y pe I err or rate ( 1-si de d).
S C C H N c o h ort:  U p t o 3 0 s u bjects will be e nr olle d t o c haracterize t he t olera bilit y, safety 
pr ofile, a n d f or preli mi nar y  eval uati o n of a ntit u m or acti vit y.  O ne i nteri m a nal ys is is pla n ne d 
w he n t he 3 0 s u bjects are e val ua ble f or res p o nse assess me nt at 1 2 wee ks (t hat is, ha ve eit her 
c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or disc o nti n ue d t he st u d y bef ore 
W ee k 1 2).
Wit h 3 0 s u bjects treate d, t he st u d y has a p pr o xi matel y 8 7% p o wer t o r ule o ut a ≤ 1 5 % O R R 
( n ull h yp ot hesis) w he n t he tr ue O R R is 3 5 % at t he 1 0 % t y pe I err or rate ( 1- si de d).
T he t otal sa m ple size f or t he st u d y (d ose escalati o n a n d d ose e x pa nsi o n) is e x pecte d t o be u p 
t o a p pr o xi matel y 6 4 2 s u bjects. 
Statistics f or c o nti n u o us varia bles m a y  incl u de mea ns, me dia ns, ra n ges, a n d a p pr o priate 
meas ures of varia bilit y .  Q ualitati ve varia bles will be s u m marize d b y  co u nts a n d perce nta ges.  
T he u ncertai nt y of esti mates will be assesse d b y c o nfi de nce i nter vals.  T he res ults of t he safet y 
e val uati o ns will be ta b ulate d a n d dis pla y e d b y  dose le vel / e x pa nsi o n c o h ort.  O nl y  e xpl orat or y 
statistical a nal ysis will be perf or me d.  Descri pti ve statistics will be e xa mi ne d f or i n dicati o ns of 
d ose -relate d t o xicit y.
Listi n gs will be pr o d uce d u p o n c o m pleti o n of eac h d ose -escalati o n c o h ort of s u bjects a n d t he 
decisi o n as t o w het her t o pr ocee d wit h d ose -escalati o n, d ose -re d ucti o n or t o e nr oll a n ot her 
c o h ort at t he sa me d ose le vel will be deter mi ne d b y  re vie wi n g t hese data.  Full details of t he 
pla n ne d a nal ys es will be descri be d i n t he trial Statistical A nal ys is Pla n, se paratel y for t he 
d ose -escalati o n part a n d t he e x pa nsi o n part.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 9 3
Sc he d ule of Assess me nts
T a ble 1
Sc he d ule of Assess me nts – D ose Esc al ati o n P h ase
Me as ure
Scree ni n g 
Assess me nts
Tre at me nt P h ase
(-3 / + 1 d a ys) a
E o T Visit 
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -
u p b, c
D a y -2 8 t o
First 
Tre at me nt
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7  
V 7  
V 8  
V 9
V 1 0
U ntil 
Pr o gressi o n
O n t he D a y of 
or Wit hi n 
7 D a ys of 
Decisi o n t o 
Disc o nti n ue d
2 8 D a ys 
( ± 5 d a ys) 
after L ast 
Tre at me nt e
1 0 Wee ks 
( ± 2 w e e ks) 
after L ast 
Tre at me nt
E ver y   
1 2 Wee ks 
( ± 2 w e e ks)
W 1  
W 1
W 2  
W 3  
W 4  
W 5  
W 7  
W 7  
W 9
W 1 1
W 1 3
D 1  
D 2  
D 8
D 1 5
D 2 2
D 2 9
D 4 3
D 4 4-
5 0 a
D 5 7
D 7 1
D 8 5
Writte n i nf or me d c o nse nt
X
I ncl usi o n / e xcl usi o n criteria
X  
X
Me dical hist or y
X
Ca ncer d isease hist or y 
X
Pri or a ntica ncer dr u g / 
ra di ot hera p y / pr oce d ures
X
Ot her pri or me dicati o ns
X
De m o gra p hic data
X
H B V a n d H C V testi n g 
X
O p ht hal m ol o g y e xa mi nati o n 
i ncl u di n g slit la m p e val uati o n 
i ncl usi ve of t he a nteri or 
se g me nt a n d wit h vis ual 
ac uit y f
X
P h ysical e xa mi n ati o n f
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
6- wee kl y
X
X  
X
Der mat ol o gical assess me nt g
X
X  
X  
X  
X  
X  
X 
6- wee kl y
X
X  
X
1 2 lea d E C G h
X  
X / Xh
X  
X  
X / Xh
X / Xh
X
X 
6- wee kl y
n or mal 
E C Gs
X  
X
Vital si g ns i ncl u di n g wei g ht 
a n d hei g ht ( hei g ht at 
Scree ni n g o nl y) i
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
2- wee kl y
X
X  
X
E C O G P S j
X  
X j
X  
X  
X  
X  
X  
X  
X  
X 
2- wee kl y
X
X  
X
E nr oll me nt (if eli gi ble) k
X  
X k
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 9 3
T a ble 1
Sc he d ule of Assess me nts – D ose Esc al ati o n P h ase
Me as ure
Scree ni n g 
Assess me nts
Tre at me nt P h ase
(-3 / + 1 d a ys) a
E o T Visit 
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -
u p b, c
D a y -2 8 t o
First 
Tre at me nt
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7  
V 7  
V 8  
V 9
V 1 0
U ntil 
Pr o gressi o n
O n t he D a y of 
or Wit hi n 
7 D a ys of 
Decisi o n t o 
Disc o nti n ue d
2 8 D a ys 
( ± 5 d a ys) 
after L ast 
Tre at me nt e
1 0 Wee ks 
( ± 2 w e e ks) 
after L ast 
Tre at me nt
E ver y   
1 2 Wee ks 
( ± 2 w e e ks)
W 1  
W 1
W 2  
W 3  
W 4  
W 5  
W 7  
W 7  
W 9
W 1 1
W 1 3
D 1  
D 2  
D 8
D 1 5
D 2 2
D 2 9
D 4 3
D 4 4-
5 0 a
D 5 7
D 7 1
D 8 5
He mat ol o g y /
he m ostase ol o g y l
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
2- wee kl y
X
X  
X
C ore ser u m c he mistr y m
X  
X  
X  
X  
X
X  
X 
2- wee kl y
F ull ser u m c he mistr y m
X
X
X
X 
6- wee kl y
X
X  
X
Ser u m electr o p h oresis
X
X
X
Uri nal ysis n
X
X
X
X 
6- wee kl y
X
X  
X
β- H C G pre g na nc y test (if 
a p plica ble) o
X  
X
X  
X  
X
X 
4- wee kl y
X  
X
T u m or e val uati o n / sta gi n g 
( C T Sca n / M RI / ot her) c, p, q
X
X
X
6 wee kl y u p 
t o 1 2 
m o nt hs / 
t he n 
1 2 wee kl y
X
X c
D o c u me ntati o n of A Es,
c o nc o mita nt me dicati o n s, a n d 
pr oce d ures
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
2- wee kl y
X
X b
X b
X b
Fr ee T 4 a n d T S H 
X
X
X
X 
6- wee kl y
X  
X
A C T H (e xce pt bac kfill 
c o h orts)
X
A N A a n d R F
X
X
6- wee kl y
X
P K sa m pli n g 
See  Ta ble 3
A D A s a mpli n g
See  Ta ble 3
P D -L 1 tar get occ u pa nc y 
See  Ta ble 3
I m m u n o m o nit ori n g 
See  Ta ble 3
S ol u ble fact ors
See  Ta ble 3
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 9 3
s ur vi val f oll o w-u p will c o nti n ue u ntil 1 ye ar after t he last s u bject recei ves t he last d ose of tr ial dr u g (see Secti o n 7. 1. 4. 3 f or details). After c o m pleti o n of t he F oll o w -u p peri o d t he a p pr o priate 
electr o nic Case Re p ort F or m secti o n f or Trial Ter mi nati o n m ust be c o m plete d.
d
All s u bjects m ust u n der g o a n E n d -of -Treat m e nt visit after disc o nti n uati o n of I M P f or a n y reas o n.  T his visit s h o ul d be perf or me d wit hi n 7 da ys after t he decisi o n t o di sc o nti n ue trial treat me nt 
b ut bef ore a n y ne w a nti ne o plastic t hera p y is starte d (if p ossi ble), w hic he ver occ urs earlier . If it is k n o w n t o t he I n vesti gat or at t he ti me of t he E n d-of -Treat me nt visit t hat t he s u bject will start 
ne w treat me nt wit hi n 2 8 da ys of last treat me nt or t he y will be u na ble t o ret ur n wit hi n 2 8 da ys o f last treat me nt, assess me nts ass ociate d wit h t he 2 8 -Da y Safet y F oll o w -u p visit ma y be c o n d ucte d 
at t he E n d -of -Treat me nt visit.  
e
T u m or e val uati o n at t he 2 8 -Da y Safet y F oll o w -u p visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .  If a n ot her a nti ne o plastic t hera p y is a d mi nistere d 
b ef ore t he e n d of t he 2 8 -da y peri o d, t he 2 8 -Da y Safet y F oll o w -u p visit s h o ul d be c o n d ucte d bef ore t he start of ne w t hera p y if possi ble . If it is k n o w n t o t he I n vesti gat or at t he ti me of  the 
E n d -of -Treat me nt visit t hat t he s u bject will start ne w treat me nt wit hi n 2 8 da ys of last treat me nt or t he y will be u na ble t o ret ur n wit hi n 2 8 da ys of last treat me nt, assess me nts ass ociate d wit h t he 
2 8 -Da y S afet y F oll o w -u p visit ma y be c o n d ucte d at t he E n d -of -Treat me nt visit .
f
Scree ni n g, D a y 1, 2 8 -Da y Safet y F oll o w -u p , a n d 1 0 -Wee k Safet y F oll o w -u p visits s h o ul d i ncl u de a f ull p h ysical e xa m.  All ot her visits s h o ul d ha ve a f oc use d p h ysical e xa m i nati o n.  E ye si g ns 
a n d s y m pt o ms s h o ul d be c hec ke d at eac h visit .  If cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate o p ht hal m ol o g y e xa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y s h o ul d be o btai ne d wit hi n 2 da ys .
g  
A ssess me nts f or s ki n lesi o ns or ras h wit h bi o ps y of s us pici o us lesi o ns.  Der mat ol o gical c o ns ults s h o ul d be re q ueste d as nee de d. See Secti o n  6. 5. 4. 5 .
h
E C G t o be ta ke n wit hi n 4 h o urs bef ore d osi n g a n d as s o o n as p ossi ble after c o m pleti o n of t he i nf usi o n.  If o nl y a si n gle “ X”, t he n o nl y E C G bef ore d osi n g is re q uire d.  All E C Gs u p t o a n d 
i ncl u di n g Wee k 1 3 ( Visit 1 0 ) are t o be ta ke n i n tri plicate wit h di gital u pl oa di n g f or ce ntralize d a nal ysis.  All E C Gs after Wee k 1 3 are si n gle E C Gs o btai ne d acc or di n g t o l ocal pr oce d ure a n d 
will N O T be di gitall y u pl oa de d.   
i
Vit al si g ns s h o ul d be assesse d pred ose ( wit hi n 1 5 mi n utes of start of i nf usi o n), t he n e ver y 1 5 ( ± 2) mi n utes after t he start of i nf usi o n ( 1 5, 3 0, 4 5, 6 0 [e n d i nf usi o n] mi n utes after start of i nf usi o n ),
a n d 1 5 ( ± 5), 3 0 ( ± 5), 6 0 ( ± 5), 1 2 0 ( ± 1 0), a n d 3 6 0 ( ± 1 5) mi n utes after t he e n d of i nf usi o n f or t he first 2 i nf usi o ns.   S u bjects s h o ul d re mai n i n t he cli nic f or o bser vati o n d uri n g t his ti me peri o d.   
If t here were n o cli nicall y si g nifica nt c ha n ges i n vi tal si g ns d uri n g t he first 2 i nf usi o ns, t he n t he vital si g ns sc he d ule f or s u bse q ue nt i nf usi o ns will be pre d ose ( wit hi n 1 5 mi n utes o f start of 
i nf usi o n), 1 5 ( ± 2) a n d 3 0 ( ± 2) mi n utes after t he start of i nf usi o n, a nd 3 0 ( ± 5) a n d 6 0 ( ± 5) mi n utes after t he e n d of i nf usi o n .
j 
If t he Scree ni n g E C O G P S was perf or me d wit hi n 3 da ys pri or t o C ycle 1 Da y 1, it d oes n ot ha ve t o be re peate d at C ycle 1 Da y 1.
k
E nr oll me nt will be d o ne after t he c o nfir mati o n of f ulfilli n g all Scree ni n g i ncl usi o n criteria wit h o ut matc hi n g a n y e xcl usi o n criteri o n.   In t he case of ne w cli nical la b orat or y a b n or malities detecte d 
pri or t o t he first d ose, t he eli gi bilit y of t he s u bject s h o ul d be rec o nsi dere d.
l
He mat ol o g y (i ncl u di n g c o m plete bl o o d c o u nt) a n d he m o stase ol o g y assess me nts are detaile d i n Ta ble 1 1 .  F ollicle-sti m ulati n g h or m o ne at Scree ni n g, if a p plica ble (Secti o n 7. 1. 1 ).  Co m ple te 
bl o o d c o u nt res ults m ust als o be dra w n a n d re vie we d wit hi n 4 8 h o urs pri or t o d ose a d mi nistrati o n.
F or s u bjec ts e x perie nci n g si g ns of a ne mia i ncl u di n g, b ut n ot li mite d t o , a si g nifica nt dr o p i n 
H g b val ue, es peciall y H g b < 8 g/ d L, r o uti ne m o nit ori n g of H g b, re d bl o o d cells, a n d he mat ocrit s h o ul d be perf or me d wee kl y.
m
F ull c he mistr y ( whic h i ncl u des c ore c he mistr y) a n d c ore ser u m c he mistr y sa m ples are detaile d i n Ta ble 1 1 .  Sa m ples f or c ore c he mistr y res ults m ust be dra w n a n d re vie we d wit hi n 4 8 h o urs 
pri or t o d ose a d mi nistrati o n.
n
A f ull uri nal ysis is re q uire d at Scree ni n g a n d t he 2 8 -Da y Safet y F oll o w -u p visit a n d basic uri nal ysis ( pr otei n c o nte nt o nl y) at eac h visit i n dicate d pri or t o a d mi nistrati o n of st u d y dr u g.  If 
uri nal ysis (f ull or basic) is p ositi ve f or pr otei n, se di me nt will be e val uate d (see Ta ble 1 1 f or details).
o
β- H C G m ust be deter mi ne d fr o m ser u m at Scree ni n g a n d fr o m eit her uri ne or ser u m sa m ple t hereafter at eac h i n dicate d visit .  Res ults of t he m ost rece nt pre g na nc y test s h o ul d be availa ble pri or 
t o ne xt d osi n g.
p
T u m or E val uati o ns d uri n g Scree ni n g m ust be perf or me d wit hi n 2 8 da ys pri or t o C ycle 1 Da y 1 i n or der t o d oc u me nt t he baseli ne stat us of t he t u m or disease usi n g R E CI S T 1. 1 tar get a n d 
n o n -tar get lesi o ns (see Secti o n 7. 3 ).  S u bse q ue nt t u m or e val uati o ns ha ve a ti me wi n d o w of 5 da ys pri or t o d osi n g ( -5 da ys).  I n case a t u m or res p o nse acc or di n g t o R E CI S T 1. 1 is d oc u me nte d 
d uri n g t he c o urse of t he trial, c o nfir mati o n of t he res p o nse s h o ul d be perf or me d acc or di n g t o R E CI S T 1. 1 n o s o o ner t ha n 4 wee ks ( prefera bl y at t he sc he d ule d 6 -wee k i nter val) after t he i nitial 
d oc u me ntati o n (see Secti o n 7. 3 ). F or s u bjects c o nti n ui n g treat me nt be y o n d 1 2 m o nt hs (i n c o ns ultati o n wit h t he Me dical M o nit or) t u m or e val uati o ns s h o ul d ta ke place e ver y 1 2 wee ks.
q
Brai n C T/ M RI sca n (eit her, wit h c o ntrast preferre d) is re q uire d at Scree ni n g if n ot perf or me d wit hi n t he pre vi o us 6 wee ks.  T hereafter, brai n C T/ M RI sca n s h o ul d be d o ne if cli nicall y i n dicate d 
b y de vel o p me nt of ne w s pecific s y m pt o ms.  A b o ne sca n s h o ul d be d o ne at Scree ni n g a n d be y o n d as cli nicall y i n dicate d. B o ne metastases detecte d at Scree ni n g nee d t o be f oll o we d at t he 
s u bse q ue nt t u m or e val uati o n visits.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 9 3
T a ble 2
Sc he d ule of Assess me nts – E x p a nsi o n P h ase
Me as ure
Scree ni n g 
Assess me nts
Tre at me nt P h ase
(-3 / + 1 d a ys) a
E o T Visit 
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -
u p b, c
D a y -2 8 t o
First 
Tre at me nt
V 1  
V 2
V 3  
V 4  
V 5  
V 6  
V 7  
V 7  
V 8  
V 9  
V 1 0
U ntil 
Pr o gressi o n
O n t he D a y of 
or Wit hi n 
7 D a ys of 
Decisi o n t o 
Disc o nti n ue d
2 8 D a ys 
( ± 5 d a ys) 
after L ast 
Tre at me nt e
1 0 Wee ks 
( ± 2 w e e ks)  
after L ast 
Tre at me nt e
E ver y   
1 2 Wee ks 
( ± 2 w e e ks)
W 1
W 1  
W 2  
W 3
W 4  
W 5
W 7  
W 7
W 9
W 1 1
W 1 3
D 1  
D 2  
D 8
D 1 5
D 2 2
D 2 9
D 4 3
D 4 4 -
5 0 a
D 5 7
D 7 1
D 8 5
Writte n i nf or me d c o nse nt
X
I ncl usi o n / e xcl usi o n criteria
X  
X
Me dical hist or y
X
Ca ncer d isease hist or y 
X
Pri or a ntica ncer dr u g / 
ra di ot hera p y / pr oce d ures
X
Ot her pri or me dicati o ns
X
De m o gra p hic data
X
Ra n d o mizati o n ( N S C L C 
sec o n d-li ne o nl y: ≤4 da ys 
pri or t o first d ose)
X
Patie nt -re p orte d o utc o mes 
(s u bjects i n H C C, es o p ha geal 
a de n ocarci n o ma, 
gli o blast o ma, mela n o ma, 
o varia n ca ncer, S C C H N, 
T N B C , cer vical ca ncer, a n d 
N S C L C [sec o n d -li ne a n d 
a nti-P D -1/ P D -L 1 fail ure ]
c o h orts)f
X  
X
X  
X  
X  
X  
X  
X
2- wee kl y u p 
t o Wee k 2 5
X
X
H B V a n d H C V testi n g 
X
O p ht hal m ol o g y e xa mi nati o n 
i ncl u di n g slit la m p e val uati o n 
i ncl usi ve of t he a nteri or 
se g me nt a n d wit h vis ual 
ac uit y g
X
F ull p h ysical e xa mi n ati o n g
X  
X
X  
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 9 3
T a ble 2
Sc he d ule of Assess me nts – E x p a nsi o n P h ase
Me as ure
Scree ni n g 
Assess me nts
Tre at me nt P h ase
(-3 / + 1 d a ys) a
E o T Visit 
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -
u p b, c
D a y -2 8 t o
First 
Tre at me nt
V 1  
V 2
V 3  
V 4  
V 5  
V 6  
V 7  
V 7  
V 8  
V 9  
V 1 0
U ntil 
Pr o gressi o n
O n t he D a y of 
or Wit hi n 
7 D a ys of 
Decisi o n t o 
Disc o nti n ue d
2 8 D a ys 
( ± 5 d a ys) 
after L ast 
Tre at me nt e
1 0 Wee ks 
( ± 2 w e e ks)  
after L ast 
Tre at me nt e
E ver y   
1 2 Wee ks 
( ± 2 w e e ks)
W 1
W 1  
W 2  
W 3
W 4  
W 5
W 7  
W 7
W 9
W 1 1
W 1 3
D 1  
D 2  
D 8
D 1 5
D 2 2
D 2 9
D 4 3
D 4 4 -
5 0 a
D 5 7
D 7 1
D 8 5
F oc use d p h ysical 
e xa mi n ati o n g
X  
X
X  
X 
6- wee kl y
X
Der mat ol o gical assess me nt h
X
X
X  
X 
6- wee kl y
X
X  
X
N S C L C bi o mar ker c o h ort
1 2 -lea d E C Gi
X
X / Xi
X  
X  
X / Xi
X / Xi
X
X 
6- wee kl y
n or mal 
E C Gs
X  
X
Ot her e x pa nsi o n c o h orts:
1 2 lea d E C G i 
X  
X
X
X 
6- wee kl y
n or mal 
E C Gs
X  
X
Vital si g ns i ncl u di n g wei g ht 
a n d hei g ht ( hei g ht at 
Scree ni n g o nl y) j
X  
X
X  
X  
X  
X  
X  
X  
X 
2- wee kl y
X
X  
X
E C O G P S k
X  
X
X  
X  
X  
X  
X  
X 
4- wee kl y
X
X  
X
E nr oll me nt (if eli gi ble) l
X  
X l
He mat ol o g y /
he m ostase ol o g y m
X  
X
X  
X  
X  
X  
X  
X 
4- wee kl y
X
X  
X
C ore ser u m c he mistr y n
X
X
X  
X 
4- wee kl y
F ull ser u m c he mistr y n
X
X
X
X 
8- wee kl y
X
X  
X
Uri nal ysis o
X
X
X
X 
8- wee kl y
X
X  
X
β- H C G pre g na nc y test (if 
a p plica ble) p
X  
X
X
X
X 
4- wee kl y
X  
X
T u m or e val uati o n / sta gi n g 
( C T Sca n / M RI / p h ot o gra p hs 
of s ki n lesi o ns / ot her) c, q,r,s
X
X
X 
6- wee kl y u p 
t o 
1 2 m o nt hs / 
t he n 
1 2 -wee kl y
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 9 3
T a ble 2
Sc he d ule of Assess me nts – E x p a nsi o n P h ase
Me as ure
Scree ni n g 
Assess me nts
Tre at me nt P h ase
(-3 / + 1 d a ys) a
E o T Visit 
S afet y F oll o w -u p
L o n g -ter m 
F oll o w -
u p b, c
D a y -2 8 t o
First 
Tre at me nt
V 1  
V 2
V 3  
V 4  
V 5  
V 6  
V 7  
V 7  
V 8  
V 9  
V 1 0
U ntil 
Pr o gressi o n
O n t he D a y of 
or Wit hi n 
7 D a ys of 
Decisi o n t o 
Disc o nti n ue d
2 8 D a ys 
( ± 5 d a ys) 
after L ast 
Tre at me nt e
1 0 Wee ks 
( ± 2 w e e ks)  
after L ast 
Tre at me nt e
E ver y   
1 2 Wee ks 
( ± 2 w e e ks)
W 1
W 1  
W 2  
W 3
W 4  
W 5
W 7  
W 7
W 9
W 1 1
W 1 3
D 1  
D 2  
D 8
D 1 5
D 2 2
D 2 9
D 4 3
D 4 4 -
5 0 a
D 5 7
D 7 1
D 8 5
A D A = a nti dr u g a nti b o d y; A E = a d verse e ve nts; A N A = a nti n uclear a nti b o d y; β- H C G = β -h u ma n c h ori o nic g o na d otr o pi n; C T = c o m p ute d t o m o gra p h y; D L T = d ose-li miti n g 
t o xicit y; E C G = electr ocar di o gra m; E C O G P S = Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us; E O R T C Q L Q -B N 2 0 = E ur o pea n Or ga nisati o n f or Researc h a n d 
Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire Brai n M o d ule ; E O RT C Q L Q -C 3 0 = E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire C ore i nstr u me nt; E O R T C Q L Q -C X 2 4 = E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire Cer vical Ca ncer M o d ule;
E O R T C Q L Q -O E S 1 8 = Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire Oes o p ha geal M o d ule ; E O R T C Q L Q -H C C 1 8 - M = E ur o pea n 
Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire He pat ocell ular Carci n o ma M o d ule – M o difie d ; E O R T C Q L Q -O V 2 8 = E ur o pea n Or ga nisati o n 
f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life Q uesti o n naire O varia n M o d ule; E o T = E n d -of - Treat me nt; F H SI -8 = F A C T [ F u ncti o nal Assess me nt of Ca ncer T hera p y] 
He pat o biliar y S y m pt o m I n de x – 8 q uesti o ns ; F S H = f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = he patitis C vir us; H g b = he m o gl o bi n; HI V = h u ma n 
i m m u n o deficie nc y vir us; I M P = i n vesti gati o nal me dici nal pr o d uct; I V = i ntra ve n o us; M RI
= ma g netic res o na nce i ma gi n g; N S C L C -S A Q = N o n -s mall Cell L u n g Ca ncer S y m pt o m 
Assess me nt Q uesti o n naire; P D = p r o gressi ve disease; P G I S = Patie nt Gl o bal I m pressi o n of Se verit y ; P K = p har mac o ki netics; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ; R F = r he u mat oi d fact or; S M C = Safet y M o nit ori n g C o m mittee; T G F β = tra nsf or mi n g gr o wt h fact or beta; T S H = t hyr oi d -sti m ulati n g h or m o ne; T 4 = free t h yr o xi ne.
A fter at le ast 5 0 s u bjects acr oss t he d ose esc al ati o n a n d all e x p a nsi o n c o h orts h a ve bee n e v al u ate d f or s afet y b y t he S M C , wit h a p pr o pri ate S M C s afet y rec o m me n d ati o n a n d if t he 
S p o ns or c o nsi ders P K c h ar acteriz ati o n a de q u at e, t he n D a y 2, 8, a n d 2 2 visits m a y be s ki p pe d.  Als o, t he S afet y F oll o w -u p visit ( 1 0 w e e ks after t he l ast d ose) m a y be c o n d ucte d b y p h o ne
wit h o ut t he sc he d ule d assess me nts .
U nless st ate d ot her wise i n a f o ot n ote, all pr oce d ures a n d s a m ples s h o ul d occ ur pri or t o tri al dr u g a d mi nistr ati o n.
a
A ti me wi n d o w of u p t o 3 da ys bef ore or 1 da y after t he sc he d ule d visit da y (-3 / + 1 da ys) will be per mitte d f or all pr oce d ures (e xce pt Da y 2 a n d t he Da y 4 4 -5 0 visit).  T he bi -wee kl y 1 4 -da y  
sc he d ule s h o ul d be strictl y a d here d t o, ret ur ni n g t o t he tar get date e ve n if t he pre vi o us visit was off sc he d ule. If a n y Scree ni n g pr oce d ures are c o n d ucte d wit hi n 3 da ys pri or t o Da y 1 of trial 
treat me nt ( Wee k 1, Da y 1), t he assess me nts sc he d ule d o n Wee k 1, Da y 1 d o n ot nee d t o be re peate d e xce pt f or t he e val uati o n of A Es a n d c o nc o mita nt me dicati o ns . T he Da y 4 4 -5 0 visit is t o 
acc o m m o date c ollecti o n of t u m or bi o ps y material a n d ass ociate d P K  a n d 
 sa m pli n g (see Ta ble 3 ); t he Da y 4 4 -5 0 visit is o nl y t o occ ur if t he t u m or bi o ps y a n d ass ociate d P K  sa m pli n g 
ca n n ot be perf or me d at t he Da y 4 3 visit.
b
See Secti o n 7. 4. 1. 3 f or defi niti o n of t he A E Re p orti n g peri o d a n d Secti o n 7. 4. 1. 6 f or mo nit ori n g of s u bjects wit h A Es.
c
S u bjects wit h o ut pr o gressi ve disease at 2 8 -Da y Safet y F oll o w -u p visit will be f oll o we d u p f or disease pr o gressi o n ( C T / M RI sca ns e ver y 1 2 wee ks
wit h t he first assess me nt 1 2 w ee ks after 
t he pre vi o us t u m or assess me nt [sc he d ule d ti me p oi nt]) u ntil P D.  I n a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks f or s ur vi val (i ncl u di n g assess me nt of a n y f urt her t u m or t hera p y).  T he 
s ur vi val f oll o w-u p will c o nti n ue u ntil 1 year after t he last s u bject recei ves t he last d ose of trial dr u g (see Secti o n 7. 1. 4. 3 f or details).
After c o m pleti o n of t he F oll o w-u p peri o d t he a p pr o priate 
electr o nic Case Re p ort F or m secti o n f or Trial Ter mi nati o n m ust be c o m plete d.
d
All s u bjects m ust u n der g o a n E n d -of -Treat m e nt visit after disc o nti n uati o n of I M P f or a n y reas o n.  T his visit s h o ul d be perf or me d wit hi n 7 da ys after t he decisi o n t o di sc o nti n ue trial treat me nt 
b ut bef ore a n y ne w a nti ne o plastic t hera p y is starte d (if p ossi ble), w hic he ver occ urs earlier . If it is kn o w n t o t he I n ve sti gat or at t he ti me of t he E n d-of -Treat me nt visit t hat t he s u bject will start 
ne w treat me nt wit hi n 2 8 da ys of last treat me nt or t he y will be u na ble t o ret ur n wit hi n 2 8 da ys of  last treat me nt, assess me nts ass ociate d wi t h t he 2 8 -Da y Safet y F oll o w -u p visit ma y b e c o n d ucte d 
at t he E n d -of -Tr eat me nt visit.  
e
T u m or e val uati o n at t he 2 8 -Da y Safet y F oll o w -u p visit s h o ul d o nl y be perf or me d if n o disease pr o gressi o n has bee n d oc u me nte d pre vi o usl y .  If a n ot her a nti ne o plastic t hera p y is a d mi nistere d 
bef ore t he e n d of t he 2 8 -da y peri o d, t he 2 8 -Da y Saf et y F oll o w-u p visit s h o ul d be c o n d ucte d bef ore t he start of ne w t hera p y if p ossi ble. If a n ot her a nti ne o plastic t hera p y is a d mi nistere d bef ore 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 9 3
u 
P re me dicati o n wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 2 5 -5 0 m g di p he n h y dra mi ne a n d 5 0 0 - 6 5 0 m g paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt)
a p pr o xi matel y 3 0 t o 6 0 mi n utes pri or t o eac h d ose of M S B 0 0 1 1 3 5 9 C is o pti o nal a n d at t he discreti o n of t he I n vesti gat or after t he sec o n d i nf usi o n ( pre me dicati o n is o pti o nal f or all i nf usi o ns 
f or s u bjects i n t h e N S C L C bi o mar ker c o h ort bei n g treate d at t he U S Nati o nal Ca ncer I nstit ute).  If Gra de ≥ 2 i nf usi o n reacti o ns are see n d uri n g t he first t w o i nf usi o ns pre me dicati o n s h o ul d 
n ot be st o p pe d.  Ster oi ds as pre me dicati o n are n ot per mitte d. M S B 0 0 1 1 3 5 9 C s h o ul d be a d mi nistere d b y I V i nf usi o n o ver 1 h o ur (-1 0 mi n utes / + 2 0 mi n utes, t hat is, o ver 5 0 t o 8 0 mi n utes ).  
S u bjects m ust be o bser ve d f or at least 2 h o urs after t he e n d of i nf usi o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 9 3
Har m o nisati o n (I C H) T o pic E 6 G o o d C li nical P ractice ( G C P; hereafter referre d t o as I C H G C P) .  
T he C o or di nati n g I n vesti gat or will pr o vi d e e x pert me dical i n p ut a n d a d vice relati n g t o trial desi g n 
a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off of t he cli nical trial re p ort. 
Si g nat ure pa ges f or t he Pr ot oc ol Lea d a n d t he C o or di nati n g I n vesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n A p pe n di x 3 .
T he trial will a p pear i n Cli nical Trials . g o v, E u dra C T, a n d all ot her re q uire d re gistries .
2. 2. 1
S afet y M o nit ori n g C o m mittee
T o e ns ure s u bjects’ safet y d uri n g t he d ose -escalati o n part of t he trial as well as t he e x pa nsi o n part, 
a Sa fety M o nit ori n g C o m mittee ( S M C) will re vie w t he safety data o n a re g ular basis. T he S M C 
c o nsists of per ma ne nt c ore me m ber s fr o m t he S p o ns or a n d C R O (at least t he Me dical Res p o nsi ble, 
t he Gl o bal Dr u g Safet y Pr o d uct Lea d er, a n d t he Bi os tatisticia n f or t he e x pa nsi o n part ), th e 
C o or di nati n g In vesti gat or, a n d a n e xter nal e x pert wit h e x pertise i n t he ma na ge me nt of ca ncer 
patie nts . D uri n g t he d ose -escalati o n p orti o n of t he trial , t he S M C will e val uate t he safet y a n d P K 
data a n d will deci de o n d ose -li miti n g t o xicities (D L Ts) releva nt f or t he treat me nt a n d will a d vise 
o n d ose escalati o n or s us pe nsi o n of e nr oll me nt, wit h t he fi nal a dj u dicati o n bei n g a S p o ns or 
prer o gati ve.  D uri n g t he d ose -asce nsi o n p hase of t he he pat ocell ular carci n o ma ( H C C) c o h ort, t he 
S M C will e val uate t he safet y data of eac h c o h ort pri or t o o pe ni n g e nr oll me nt t o eac h s u bse q ue nt 
c o h ort.  D uri n g t he e nr oll me nt p hase of t he e x pa nsi o n part of t he trial (see Secti o n 3. 4. 1) , t he S M C 
will m o nit or o n a n o n g oi n g basis (f or e xa m ple, w he n 4 0, 1 2 0, 2 0 0, 2 9 0, 3 8 0, a n d 4 8 0 s u bjects 
ha ve bee n e nr olle d a n d treate d f or at least 4 wee ks ), all safety i nf or mati o n of t he part ici pati n g 
s u bjects a n d will deci de b y  co nse ns us o n c o nti n uati o n, m o dificati o n, or s us pe nsi o n of t he trial or 
of a partic ular e x pa nsi o n c o h ort. T he S M C ma y m o dif y  the fre q ue nc y of meeti n gs as dee me d 
a p pr o priate b y  the S M C d uri n g t he c o urse of t he trial.  The s pecific w or ki n g pr oce d ures will be 
descri be d i n a n S M C c harter, w hic h will be esta blis he d pri or t o t he start of recr uit me nt .
2. 2. 2
Ce ntr al 
Re a der 
a n d 
I n de pe n de nt 
E n d p oi nt 
Re vie w 
C o m mittee
A ce ntral facilit y m a y
rea d a n d i nter pret all ra di o gra p hic sca ns f or s u bjects e nr olle d i n t he 
e x pa nsi o n c o h ort s (f or d ose escalati o n, ra di o gra p hic sca ns will be rea d l ocall y; h o we ver, a ce ntral 
re vie w ma y o cc ur at S p o ns or re q uest ). T he data f or all i ma ges will be tra nsferre d fr o m trial sites 
t o t he ce ntral rea di n g ce nter f or e val uati o n. Sca ns will be e val uate d at t he ce ntral facilit y in 
acc or da nce wit h Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1 ( R E CIS T 1. 1 , 
Eise n ha uer 2 0 0 9) or R es p o nse A ssess me nt i n Ne ur o - Onc ol o g y  (R A N O) f or s u bjects i n t he 
gli o blast o ma c o h ort (We n 2 0 1 0) a n d a d diti o nall y usi n g i m m u ne-relate d R E CI S T (ir R E CIS T) , 
m o difie d i m m u ne-relate d R A N O (i R A N O; O ka da 2 0 1 5) f or s u bjects i n t he gli o blast o ma , a n d
m o difie d R E CI S T ( m R E CIS T) f or s u bjects i n t he H C C c o h ort (see Le nci o ni 2 0 1 0 ). T he i ma gi n g 
data will be tra nsferre d t o t he S p o ns or or desi g nee at re g ular i nter vals. A ma n ual fr o m t he ve n d or 
will be pr o vi de d t o eac h trial site. T he res ults of t he ce ntral rea d will n ot be a vaila ble i n real ti me 
a n d will n ot be use d f or trial s u bject ma na ge me nt.  L ocal i nter pretati o n of ra di o gra p hic sca ns will 
be us e d b y t he I n vesti gat or f or real -ti me trial s u bject ma na ge me nt decisi o ns.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 9 3
were o bser ve d a n d 1 5 m g / k g, t he hi g hest d ose teste d, was deter mi ne d t o be safe (M orris 2 0 1 4 ). 
T he maj or A E was e mer ge nt s ki n t u m ors a n d h y per kerat osis. 
I n a small trial of i di o pat hic 
p ul m o nar y  fi br osis, t he m ost c o m m o n A E was fati g ue (L o n ni n g 2 0 1 1 ). I n a st u d y of 1 6 s u bjects 
wit h 
f ocal se g me ntal gl o mer ul oscler osis, t he o nl y  A E
was 
p ust ular ras h i n 2 s u bjects 
(Trac ht ma n 2 0 1 1 ). T β M 1 , a n a nti b o d y i n hi biti n g t he T G F II rece pt or, was well t olerate d w he n 
st u die d at d oses as hi g h as 2 4 0 m g wit h diarr hea as t he o nl y  D L T e ve nt (C o h n 2 0 1 4 ). N ota bl y , 
o ne e ve nt of l o w he m o gl o bi n ( H g b) was o bser ve d i n t he h i g h-d ose gr o u p.
Im p orta ntl y , t he 
precli nical pr ofile of M S B 0 0 1 1 3 5 9 C is pre d o mi na ntl y  be ni g n a n d hi g hl y c o m para ble t o t hat of 
a vel u ma b. 
O verall, e vi de nce s u g gests n o n- o verla p pi n g t o xicit y pr ofiles f or a nti-P D -L 1 a n d 
a nti-T G F β a ge nt classes. T here is a t he oretical p ote ntia l of i m m u ne-relate d a d verse e ve nts (ir A Es) 
t hat w o ul d be t he c o nse q ue nce of a d o u ble bl oc ka de of ne gati ve re g ulat or y l o o ps of t he i m m u ne 
s yste m; h o we ver, ta ke n t o get her, t he precli nical pr ofile of M S B 0 0 1 1 3 5 9 C a n d cli nical e vi de nce 
of eac h pat h wa y  su g gests a l o w ris k of s yner gistic t o xicit y ste m mi n g fr o m t he d ual -f u ncti o nality 
of M S B 0 0 1 1 3 5 9 C.
T he safet y pr ofile is descri be d i n t he I B f or a vel u ma b a n d is briefl y s u m marize d here (refer t o t he 
c urre nt a vel u ma b I B).  As of a c ut off date of 0 5 N o ve m ber 2 0 1 4, o ver all 5 5 8 s u bjects ha ve recei ve d 
at least 1 d ose of a vel u ma b.  In ge neral, t he safet y anal ys is s u g gests a n acce pta ble safety pr ofile 
wit h m ost e ve nts eit her i n li ne wit h t h ose e x pecte d i n s u bjects wit h a d va nce d s oli d t u m ors or wit h 
si milar class effects of m o n ocl o nal a nti b o dies bl oc ki n g t he P D - 1 / P D -L 1 a xis.  Inf usi o n-relate d 
reacti o ns i ncl u di n g h y perse nsiti vit y  an d ir A Es / a ut oi m m u ne dis or ders ha ve bee n i de ntifie d as 
i m p orta nt ris ks f or a vel u ma b a n d t h us c o nsi dere d p ote ntial ris ks f or M S B 0 0 1 1 3 5 9 C.  Ma na ge me nt 
alg orit h ms i ncl u de ster oi ds, ot her i m m u ne -s u p pressa nts, st u d y dr u g i nterr u pti o n / disc o nti n uati o n , 
a n d s u p p orti ve ma na ge me nt .
Anti -P D -L 1  has s h o w n a n o verall rate of i nf usi o n reacti o ns of 
a p pr o xi matel y 10 % ( Gra de 3 / 4 a p pr o xi matel y 0. 4 % [fell t o 0. 2 % wit h ma n dat or y  preme dicati o n]; 
n o Gra de 5 ).  
A brief s u m mar y of safet y ex perie nce wit h t he P D - 1 i n hi bit ors ni v ol u ma b ( O p di v o ®) a n d 
pe m br oliz u ma b ( Ke ytr u da ®) is gi ve n here, base d o n prescri bi n g i nf or mati o n (refer t o c urre nt la bel 
i nf or mati o n f or u p date d i nf or mati o n).  For pe m br oliz u ma b t he secti o n o n War ni n gs 
a n d 
Preca uti o ns 
i ncl u des 
a d verse 
reacti o ns 
of 
i m m u ne-me diate d 
p ne u m o nitis 
( 2. 9 %), 
i m m u ne-me diate d 
c olitis 
( 1 %), 
i m m u ne-me diate d 
he patitis 
( 0. 5 %), 
i m m u ne-me diate d 
h y p o p h y sitis 
( 0. 5 %), 
re nal 
failure 
( 0. 5 %) 
a n d 
i m m u ne-me diate d 
ne p hritis 
( 0. 7 %), 
i m m u ne-me diate d h y pert h y r oi dis m ( 1. 2 %) a n d h y p ot h y r oi dis m ( 8. 3 %), a n d a variet y  of ot her 
i m m u ne-me diate d a d verse reacti o ns occ urri n g i n less t ha n 1 % of patie nts.  I n a d diti o n, a war ni n g 
f or e m br yofetal t o xicit y is pr o vi de d.  For ni v ol u ma b the secti o n o n War ni n g 
a n d Preca uti o ns 
i ncl u des a d verse reacti o ns of i m m u ne-me diate d p ne u m o nitis ( 2. 2 %) wit h fatal i m m u ne -me diate d 
p ne u m o nitis i n 0. 9 % ( 5/ 5 7 4), i m m u ne- me dicate d c olitis ( 2. 2 %), i m m u ne-me diate d he patitis 
( 1. 1 %), i m m u ne-me diate d 
ne p hritis 
a n d 
re nal d y sf u ncti o n 
( 0. 7 %), i m m u ne-me diate d 
h y pert h y r oi dis m ( 3 %) a n d h yp ot h y r oi dis m ( 8 %) a n d a variet y of ot her i m m u ne-me diate d a d verse 
reacti o ns occ urri n g i n less t ha n 1 % of patie nts. In a d diti o n , a war ni n g f or e m br yofetal t o xicit y is 
pr o vi de d .   
Safet y  ex perie nce wit h vari o us T G F tar geti n g a ge nts descri be d i n t he literat ure s u g gests n o 
o verla p pi n g i m m u ne-relate d pr ofile wit h c o m p o u n ds of t he a nti-P D - 1 / a nti-P D -L 1  class. I n 
P hase I trials, t he e x perie nce wit h 
a m olec ule 
wit h 
a hi g hl y si milar mec ha nis m 
t o t he 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 9 3
o pt i o nal at t he discreti o n of t he In vesti gat or.  If Gra de ≥ 2 i nf usi o n reacti o ns are see n d uri n g 
t he first t w o i nf usi o ns, pre me dicati o n s h o ul d n ot be st o p pe d.  Base d o n safet y  data f or s u bjects 
treate d wit h pre me dicati o n f or o nl y t he first 2 i nf usi o ns, t he pr ot oc ol mi g ht be a me n de d at a 
later ti me p oi nt t o all o w d osi n g wit h o ut pre me dicati o n f or all s u bject i nf usi o ns

S pecial preca uti o ns f or m o nit ori n g 
of s u bjects
a n d ma na ge me nt 
of i nf usi o n-relate d 
reacti o ns / h y perse nsiti vit y  as descri be d i n Secti o ns   6. 5. 4. 1 a n d 6. 5. 4. 2   

I nf usi o n-relate d reacti o ns / h y perse nsiti vit y  (a n y gra de) are c o nsi dere d as A E SI
re q uiri n g 
e x pe dite d re p orti n g fr o m t he I nvesti gat or t o t he S p o ns or.  For n o nseri o us A E SI s, a n A E SI 
Re p ort F or m has t o be c o m plete d; f or seri o us e ve nts, a n S A E Re p ort F or m has t o be use d (see 
Secti o n  7. 4. 1. 4).
3. 5. 2
I m m u ne-rel ate d A d verse E ve nts / A ut oi m m u ne Dis or ders
I m m u ne-relate d A Es are A E SIs.
T he f oll o wi n g ir A Es are i m p orta nt i de ntifie d ris ks f or M S B 0 0 1 1 3 5 9 C. 

I m m u ne-relate d p ne u m o nitis

I m m u ne-relate d he patitis

I m m u ne-relate d c olitis

I m m u ne-relate d ne p hritis a n d re nal dys f u ncti o n

I m m u ne-relate d e n d ocri n o pat hies (t h yr oi d dis or ders, a dre nal i ns ufficie nc y, t ype 1 dia betes 
mellit us, pit uitar y  dis or ders)

I m m u ne-relate d ras h

Ot her i m m u ne- relate d e ve nts ( m yositis, m y oca r ditis, e nce p halitis)
T he f oll o wi n g ir A Es are i m p orta nt p ote ntial ris ks f or M S B 0 0 1 1 3 5 9 C:

G uillai n -Barré s y n dr o me

U veitis

Pa ncreatitis

M y ast he nia gra vis/ m yast he nic s y n dr o me
I m m u ne-relate d A Es / a ut oi m m u ne dis or ders are e ve nts t hat are relate d t o t he p har mac ol o g y  of 
c hec k p oi nt i n hi bit ors a n d ca n be e x plai ne d b y a n i m m u ne -p he n o me n o n after ot her eti ol o gies ha ve 
bee n r ule d o ut. Rele va nt cli nical safet y e x perie nce has bee n ge nerate d wit h t he pare nt a nti-P D -L 1 
a vel u ma b a nti b o d y.

As of 0 5 N o ve m ber 2 0 1 4, a c u m ulati ve re vie w re veale d 5 6 cases of p ote ntial irA Es o ut of 
4 8 0 s u bjects ( 1 1. 7 %) treate d i n t he d ose -e x pa nsi o n part of T rial E M R 1 0 0 0 7 0-0 0 1 a n d 4 cases 
o ut of 5 0 s u bjects ( 8. 0 %) treate d i n t he d ose -escalati o n part of T rial E M R 1 0 0 0 7 0- 0 0 1. 
A 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 9 3
c ust o mize d Me dical Dicti o nar y  for Re g ulat or y  Acti vities ( Me d D R A) q uer y was use d f or data 
retrie val fr o m t he cli nical data base wit h pre defi ne d Preferre d Ter ms of p ote ntial ir A Es.

Of 6 9 p ote ntial ir A Es re p orte d, 1 3 were S A Es ( 1 8. 8 %) a n d 5 6 were n o nseri o us A Es ( 8 1. 1 %).  
I n t he maj orit y of t he cases, t here was a pla usi ble te m p oral ass ociati o n bet wee n t he e ve nt o nset 
a n d t he dr u g a d mi nistrati o n.  Of t hese 6 9 e ve nts, 4 6 e ve nts ( 6 6. 7 %) were assesse d as 
treat me nt-relate d b y  the In vesti gat or a n d 2 3 e ve nts ( 3 3. 3 %) were 
assesse d as n ot 
treat me nt-relate d by t he In vesti gat or.

T we nt y -si x e ve nts were assesse d as Gra de 1, 2 9 e ve nts as Gra de 2, 1 1 e ve nts as Gra de 3, 
2 e ve nts as Gra de 4, a n d 1 e ve nt ( p ne u m o nitis) as Gra de 5 ( n ote:  2 m ore e ve nts of a ut oi m m u ne 
he patitis ha d a fatal o utc o me; h o we ver, t he y  were assesse d as Gra de 3 wit h a s u bse q ue nt fatal 
li ver fail ure).

Base d o n t he ir A E cases t hat ha ve bee n o bser ve d wit h a vel u ma b , all trial In vesti gat ors will be
trai ne d t o be ma de a ware of t he fre q ue nc y an d se verit y of t he o bser ve d e ve nts a n d t o pr oacti vel y 
a d mi nister ster oi d treat me nt f or a n y s us pici o n of ir A Es.  
Base d o n cli nical e x perie nce wit h a vel u ma b a n d wit h ot her a ge nts bl oc ki n g t he P D -1 / P D -L 1  
pat h wa y , ir A Es / a ut oi m m u ne dis or ders are a n i m p orta nt p ote ntial ris k f or M S B 0 0 1 1 3 5 9 C. 
Ris k
ma na ge me nt meas ures si milar t o t he lea d pr o gra m i ncl u de:

I nstr ucti o ns f or trial treat me nt disc o nti n uati o n or i nterr u pti o n i n case of ir A Es / a ut oi m m u ne 
dis or ders (see Secti o n 6. 5. 4. 3 ). 

G ui da nce f or t he me dical ma na ge me nt of ir A Es / a ut oi m m u ne dis or ders i ncl u di n g s pecific 
g ui da nce wit h re gar d t o t he affecte d or ga n / b o d y  s yste m (see Secti o n 6. 5. 4. 3 ).  

ir A Es / a ut oi m m u ne dis or ders (a ny gra de) are c o nsi dere d as A E SI s re q uiri n g e x pe dite d 
re p orti n g fr o m t he I n vesti gat or t o t he S p o ns or. F or n o nseri o us A E SIs , a n A E SI  Re p ort F or m 
has t o be c o m plete d; f or seri o us e ve nts, a n S A E Re p ort F or m has t o be use d. 

Re g ular la b orat or y tests o n para meters i n dicati ve f or a ut oi m m u ne dis or ders will be perf or me d 
as detaile d i n t he Sc he d ules of Assess me nts (see Ta ble 1 a n d Ta ble 2 ).

T o hel p m o nit or f or a ut oi m m u ne effects, baseli ne o p ht hal m ol o g y e xa mi nati o n i ncl u di n g slit 
la m p i ncl usi ve of t he a nteri or se g me nt a n d i ncl u di n g vis ual ac uit y.  If cli nicall y rele va nt e ye 
si g ns or s ym pt o ms d uri n g t he st u d y, a p pr o priate o p ht hal m ol o g y  exa mi nati o n wit hi n 2 da y s 
i ncl u di n g slit la m p i ncl usi ve of t he a nteri or se g me nt a n d i ncl u di n g vis ual ac uit y.
3. 5. 3
T G F β I n hi biti o n M e di ate d S ki n Re acti o ns
S ki n A Es, p ossi bl y  due t o T G F β i n hi biti o n, i ncl u di n g h y per kerat osis, K A, a n d/ or c S C C, are A E SI s 
a n d i m p orta nt i de ntifie d ris ks f or M S B 0 0 1 1 3 5 9 C . T he distri b uti o n of lesi o ns te n ds t o be i n s u n 
e x p ose d areas.
F or n o nseri o us A E SIs , a n A E SI  Re p ort F or m has t o be c o m plete d; f or seri o us e ve nts, a n S A E 
Re p ort F or m has t o be use d (see Secti o n  7. 4. 1. 4) .
See Secti o n  6. 5. 4 f or ris k ma na ge me nt meas ures f or T G F β i n hi biti o n me diate d ski n reacti o ns .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 / 1 9 3
3. 5. 8
P ote nti al Be nefit
A direct be nefit is c o nsi dere d u nl i kel y for partici pa nts i n t his P hase I trial, es peciall y in t he l o w 
d ose s of t he d ose -escalati o n part; theref ore , o nl y  s u bjects wit h mali g na ncies f or w hic h n o sta n dar d 
effecti ve t hera py e xists or s u bjects ha vi n g e x perie nce d a fail ure of sta n dar d t hera py are eli gible 
f or t his part of t he trial.  Ho we ver, preli mi nar y  res ults fr o m t he E M R 1 0 0 0 7 0 - 0 0 1 trial wit h t he 
pare nt a vel u ma b a nti b o d y de m o nstrate pr o misi n g cli nical a ntit u m or acti vit y.  Gi ve n t he pr ecli nical 
m o dels de m o nstrati n g t hat M S B 0 0 1 1 3 5 9 C
p ossesses s u peri or a ntit u m or acti vities relati ve t o 
m o n ot hera p y wit h eit her P D -L 1  bl oc ka de or T G F β se q uestrati o n, cli nical be nefit mi g ht be 
e x pecte d at si milar or l o wer d oses t ha n t h ose see n wit h a vel u ma b .
A s of 0 4 M a y  20 1 6, 1 s u bject wit h pa ncreatic ca ncer ( 3 m g / k g c o h ort) has bee n re p orte d wit h a 
c o nfir me d P R acc or di n g t o R E CI S T ( o n g oi n g at 6 m o nt hs).  In a d diti o n, S D has bee n re p orte d 
5 s u bjects ( 4 1. 7 %), i ncl u di n g 1 s u bject i n t he 1 m g/ k g c o h ort, a n d 2 s u b jects i n eac h of t he 3 a n d 
1 0 m g/ k g c o h orts.
Fi ve s u bjects ( 4 1. 7 %) were re p orte d wit h a B O R of P D.  At t he ti me of t he data 
c ut off, 8 s u bjects ( 6 6. 7 %) re mai ne d o n treat me nt.
I n c o ncl usi o n, t he ris k-be nefit rati o of treat me nt wit h M S B 0 0 1 1 3 5 9 C
i n t he tar gete d trial 
p o p ulati o n a p pears p ositi ve gi ve n t he p o or pr o g n osis of s u bjects wit h a d va nce d mali g na ncies wit h 
n o sta n dar d treat me nt o pti o ns.
T his cli nical trial will be c o n d ucte d i n c o m plia nce wit h t he cli nical trial pr ot oc ol, t he sta n dar ds  
sti pulate d  in Article 1 4, Para gra p h 3, a n d Article 8 0- 2 of t he P har mace utical Affairs La w i n Ja pa n; 
a n d t he “ Mi nisterial Or di na nce o n t he Sta n dar ds f or t he I mple me ntati o n of Cli nical St u dies o n 
P har mace utical Pr o d uct” ( G o o d Cli nical Practice [ G C P]) i n Ja pa n , G C P (I C H T o pic E 6), a n d t he 
a p plica ble nati o nal re g ulat or y  re q uire me nts.
4
Tri al O bjecti ves
4. 1
Pri m ar y O bjecti ves
T he pri mar y  objecti ve of t he d ose escalati o n part of t he st u d y is t o deter mi ne t he safety, t olera bility, 
a n d t he ma xi m u m -t olerate d d ose ( M T D) of M S B 0 0 1 1 3 5 9 C i n s u bjects wit h metastatic or l ocall y 
a d va nce d s oli d t u m ors.
E xce pt f or t he gli o blast o ma c o h ort, t he pri mar y  objecti ve of t he efficac y ex pa nsi o n c o h orts is t o 
assess t he best o verall res p o nse ( B O R) acc or di n g t o Res p o nse E val uati o n Criteria i n S oli d T u m ors 
versi o n 1. 1 ( R E CI S T 1. 1).  F or gli o blast o ma, t he pri mar y o bjecti ve is t o assess t he disease c o ntr ol 
rate ( D C R) acc or di n g t o R A N O.
4. 2
Sec o n d ar y O bjecti ves
T he s ec o n dar y o bjecti ves are:

T o c haracterize t he P K pr ofile of M S B 0 0 1 1 3 5 9 C 

T o e val uate t he i m m u n o ge nicit y  of M S B 0 0 1 1 3 5 9 C a n d its relati o ns hi p t o dr u g e x p os ure
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 9 3
E val uati o n of safety will als o i ncl u de t he i nci de nce a n d se verity of p ote ntial ir A Es, w hic h m a y  
ma nifest after wee ks of treat me nt ( Attia 2 0 0 5, Cala br o 2 0 1 0,  Di Giac o m o 2 0 1 1,  Kae hler 2 0 1 0 , 
P ha n 2 0 0 3,  W olc h o k 2 0 1 0 ). S uc h i m m u ne-me diate d a d verse e ve nts ma y i ncl u de p ne u m o nitis , 
c olitis, he patitis, h y p o p h y sitis, ne p hritis, a n d th y r oi ditis ( h yp o or h y pert h yr oi dis m).  
T he i de ntifie d a n d p ote ntial ris ks are f urt her descri be d (see Secti o ns 3. 5 a n d 6. 5. 4) .
All D L Ts will be m o nit ore d ce ntrall y, a n d t he decisi o n t o escalate t o t he ne xt d ose le vel will be 
deter mi ne d b y  t he S M C as o utli ne d i n Secti o n 2. 2. 1.  
After t he 1 a n d 3 m g/ k g c o h orts ha ve c o m plete d t he D L T e val uati o n peri o d, a preli mi nar y P K 
a nal ys is will be perf or me d.  De pe n di n g o n t he res ults of t his a nal ysis, i ncl u di n g P K li nearity, a 
decisi o n will be ma de t o i nitiate u p t o 2 c o h orts of 3 s u bjects eac h, o ne at 0. 1 m g/ k g a n d o ne at 
0. 3 m g/ k g, w hic h will i ncrease o n t he sec o n d d ose a n d all s u bse q ue nt d oses t o a 1 2 0 0 m g/i nf usi o n 
flat d ose , de pe n de nt u p o n S M C cleara nce a n d o nl y  if t he S p o ns or a n d C o or di nati n g I n vesti gat or 
ha ve deter mi ne d a mea ni n gf ul d ose f or t he i ntras u bject escalati o n.  No D L T e val uati o ns will be 
perf or me d i n t hese fle xi ble c o h orts.   
After t he M T D has bee n reac he d or t he 2 0 m g / k g c o h ort has bee n declare d b y  the S M C as t he 
hi g hest n o n- M T D d ose assesse d, t he n f urt her P K a nal yses m a y be perf or me d. If dee me d necessar y , 
t he 1, 3, 1 0, a n d 2 0 m g / k g c o h orts ma y eac h e nr oll u p t o a n a d diti o nal 1 0 s u bjects ( u p t o 4 0 t otal) 
f or t he p ur p ose of P K pr ofile a n d p ossi ble P K / 
 m o deli n g if t here has bee n S M C 
cleara nce at t he hi g her or sa me ( 2 0 m g / k g) d ose le vel.  O n t he sec o n d d ose a n d all s u bse q ue nt 
d oses , t he 1 m g/ k g c o h ort ma y  increase t o a 1 2 0 0 m g/i nf usi o n flat d ose. N o D L T e val uati o ns will 
be perf or me d i n t hese s u p ple me ntal c o h orts.  These l o wer d ose c o h ort e x pa nsi o ns f or P K pr ofile 
a n d P K / 
 p ur p oses m a y  pr ocee d i n parallel wit h t he e x pa nsi o n c o h orts if dee me d 
a p pr o priate b y t he S p o ns or a n d C o or di nati n g I n vesti gat or base d o n t he M T D al o ne .
I n t he c o h orts recei vi n g 0. 1 m g/ k g a n d 0. 3 m g/ k g a n d i n t he a d diti o nal s u bjects e nr olle d f or t he 
p ur p ose of P K pr ofile a n d p ossi ble P K / 
 m o deli n g, it is i nte n de d t o i nte nsif y the P K
a nal ys is b y  ta ki n g 3 a d diti o nal P K sa m ples d uri n g t he first treat me nt c ycle. T hese sa m ples are 
sc he d ule d t o be ta ke n at 8 t o 1 2 h o urs, 3 t o 5 da ys, a n d 1 0 t o 1 2 da y s after t he i nitiati o n of t he first 
i nf usi o n of t he st u d y dr u g. T he sa m ples are t o be ta ke n at a n y  ti me d uri n g t hese i nter vals. E xact 
sa m pli n g ti me m ust
be rec or de d. T hese sa m ples are la belle d as o pti o nal i n t he Sc he d ule of 
Assess me nts (Ta ble 3 ) b ut t he y are hi g hl y i m p orta nt t o all o w a s ufficie ntl y detaile d a nal ys is a n d 
descri pti o n of t he M S B 0 0 1 1 3 5 9 C
P K pr ofile.
As t he 2 0 m g/ k g c o h ort i n t he d ose escalati o n p orti o n has cleare d S M C e val uati o n, a d diti o nal 
c o h orts at 3 0 m g/ k g a n d 2 4 0 0 m g flat d ose will be i nitiate d, i n parallel t o t he o n g oi n g e x pa nsi o n 
c o h orts.  The 3 0 m g/ k g a n d t he 2 4 0 0 m g flat -d ose c o h orts will be e nr olle d i n a 3 + 3 desi g n wit h 
S M C e val uati o n after t he first 3 s u bjects a n d n o m ore t ha n 6 e val ua ble s u bjects t o be e nr olle d .  
T hese c o h orts s h o ul d pr o vi de a d diti o nal i nsi g ht i nt o d ose pr o p orti o nalit y  of P K a n d 
 
para meters a n d s u p p ort safety c o nsi derati o ns at hi g her e x p os ures t ha n t he c urre nt e x pa nsi o n p hase 
d ose of 1 2 0 0 m g o nce e ver y  2 wee ks.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 9 3
5. 1. 1. 2
E x p a nsi o n C o h orts
T he d ose f or t he e x pa nsi o n c o h orts was deter mi ne d b y  the S p o ns or base d o n t he safety 
o bser vati o ns a n d P K /
 data fr o m t he d ose escalati o n part of t he trial. T he flat d oses f or 
e xte nsi o n part will be i m ple me nte d after cleara nce of 2 0 m g / k g escalati o n c o h ort b y  the S M C.  
E xce pt f or t he sec o n d-li ne N S C L C c o h ort, all s u bjects i n e x pa nsi o n c o h orts will be recei vi n g 
1 2 0 0 m g (flat d ose) e ver y 2 wee ks.  Su bjects i n t he sec o n d-li ne N S C L C c o h ort will be ra n d o mize d 
t o recei ve eit her 5 0 0 or 12 0 0 m g e ver y  2 wee ks (see Secti o n 3. 4. 1. 1 f or rati o nales).  
S u bjects i n t he e x pa nsi o n c o h orts will recei ve M S B 0 0 1 1 3 5 9 C
as a 1 -h o ur I V i nf usi o n o nce e ver y 
2 wee ks u ntil P D has bee n c o nfir me d b y  a su bse q ue nt sca n, u nacce pta ble t o xicity,  or occ urre nce 
of a n y criteri o n f or wit h dra wal fr o m t he trial or t he I M P (see Secti o n 5. 5) .  
S u bjects w h o ha ve e x perie nce d S D, P R , or C R s h o ul d c o nti n ue treat me nt t hr o u g h t he e n d of 
1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble . If t he In vesti gat or belie ves t hat a s u bject
ma y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be per miss i ble after disc ussi o n wit h t he 
Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble .
I n t he case of P D, s u bjects s h o ul d 
c o nti n ue treat me nt t hr o u g h t heir ne xt t u m or assess me nt, if t he y meet t he criteria descri be d i n 
Secti o n  5. 5. 1.  If t here is f urt her e vi de nce of P D t hereafter, trial treat me nt s h o ul d be disc o nti n ue d; 
h o we ver , c o nti n ue d treat me nt is p ossi ble i n c o ns ultati o n wit h t he Me dical M o nit or .  F or s u bjects 
w h o ac hie ve S D, a C R or P R o n M S B 0 0 1 1 3 5 9 C
t hera py a n d t he n s u bse q ue ntl y de vel o p disease 
pr o gressi o n after st o p pi n g t hera p y, b ut pri or t o t he e n d of t he trial, 1 re-i nitiati o n c o urse of
treat me nt at t he sa me d ose a n d sc he d ule a n d treat me nt d urati o n u p t o 1 2 m o nt hs is all o we d at t he 
discreti o n of t he I nvesti gat or a n d a gree me nt of t he trial Me dical Res p o nsi ble (see Secti o n  5. 1. 6).
T he I n vesti gat or will nee d t o c o nfir m t hat t he be nefit of re -i nitiati n g treat me nt o ut wei g hs a ny ris k 
i n v ol ve d, s uc h as t hat w hic h le d t o i nitial treat me nt disc o nti n uati o n. M ore o ver, f or s u bjects i n 
w hic h B O R was S D, t he In vesti gat or s h o ul d c o nfir m n o ot her reas o na ble treat me nt o pti o ns are 
a vaila ble.
F or s u bjects i n t he mela n o ma, S C C H N, a n d T N B C c o h orts o nl y , s ym pt o m se verit y will be 
assesse d usi n g 2 patie nt -re p orte d o utc o mes q uesti o n naires:

Patie nt Gl o bal I m pressi o n of Se verit y ( P GI S )

Select ite ms fr o m t he E O R T C Q L Q- C 3 0
F or s u bjects i n t he es o p ha geal a de n ocarci n o ma c o h ort o nl y , s ym pt o m se verit y will be assesse d 
usi n g 3 patie nt -re p orte d o utc o mes q uesti o n naires:

P GI S

Select ite ms fr o m t he E O R T C Q L Q- C 3 0

Select ite ms fr o m t he E O R T C Q L Q- O E S 1 8
F or s u bjects i n t he gli o blast o ma c o h ort o nl y , s ym pt o m se verit y will be assesse d usi n g 2 patie nt -
re p orte d o utc o mes q uesti o n naires:

P GI S
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 9 3

Select ite ms fr o m t he E O R T C Q L Q- B N 2 0
F or s u bjects i n t he o varia n ca ncer c o h ort o nl y, sy m pt o m se verit y  will be assesse d usi n g 3 patie nt-
re p orte d o utc o mes q uesti o n naires:

P GI S

Select ite ms fr o m t he E O R T C Q L Q- C 3 0

Select ite ms fr o m t he E O R T C Q L Q- O V 2 8
F or s u bjects i n t he N S C L C sec o n d-line a n d a nti-P D -1/ P D -L 1  fail ure c o h orts o nl y, s ym pt o m 
se verity will be assesse d usi n g 2 patie nt -re p orte d o utc o mes q uesti o n naires:

P GI S

N S C L C S y m pt o m Assess me nt Q uesti o n naire ( N S C L C- S A Q)
F or s u bjects i n t he H C C e x pa nsi o n c o h ort o nl y , s ym pt o m se verity will be assesse d usi n g 
2 patie nt -re p orte d o utc o mes q uesti o n naires:

P GI S

E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y  of Li fe Q uesti o n naire 
He pat ocell ular Carci n o ma M o d ule – M o difie d ( E O R T C Q LQ- H C C 1 8 -M)
F or s u bjects i n t he cer vical ca ncer c o hort o nl y , s ym pt o m se verit y will be assesse d usi n g 
3 patie nt -re p orte d o utc o mes q uesti o n naires:

P GI S

Select ite ms fr o m t he E O R T C Q L Q- C 3 0

Select ite ms fr o m t he E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of 
Life Q uesti o n naire Cer vical C a ncer M o d ule ( E O R T C Q L Q- C X 2 4) .
Asce n di n g D ose H C C
After t he 3 m g / k g c o h ort i n t he d ose escalati o n p orti o n has cleare d S M C e val uati o n, t he 3 m g/ k g 
H C C c o h ort ma y initiate.  O nce t he 2 0 m g/ k g d ose -escalati o n c o h ort has bee n cleare d a n d dee me d 
safe by t he S M C, a n H C C asce n di n g 1 2 0 0 m g flat-d ose c o h ort will be i nitiate d.
F or s u bject s i n t he H C C 1 2 0 0 m g asce n di n g -d ose c o h ort o nl y, s ym pt o m se verit y will be assesse d 
usi n g 2 patie nt -re p orte d o utc o mes q uesti o n naires:

P GI S

F u ncti o nal Assess me nt of Ca ncer T hera p y ( F A C T) He pat o biliar y  Sy m pt o m I n de x – 8 q uesti o ns 
( F H SI- 8).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 9 3
5. 1. 3
M S B 0 0 1 1 3 5 9 C D ose Esc al ati o n
T he d ose -escalati o n part of t he trial is e x pecte d t o e nr oll bet wee n 3 a n d 8 2 s u bjects.  Eli gi ble 
s u bjects will be patie nts wit h metastatic or l ocall y ad va nce d s oli d t u m ors w h o ha ve faile d sta n dar d 
t hera pies or w h o ha ve n o sta n dar d effecti ve t hera p y a vaila ble.
5. 1. 3. 1
St arti n g D ose
T he starti n g d ose of M S B 0 0 1 1 3 5 9 C will be 1 m g/ k g.
5. 1. 3. 2
D ose Esc al ati o n
T he d ose escalati o n will use a sta n dar d 3 + 3 sc he me wit h t he f oll o wi n g pla n ne d d oses ( o nce e ver y 
2 wee ks) :

1 m g/ k g

3 m g/ k g

1 0 m g/ k g

2 0 m g/ k g

3 0 m g/ k g

2 4 0 0 m g flat d ose
T he D L T peri o d is defi ne d as 2 1 d a y s after t he start of t hera p y.  T he first s u bject of each c o h ort 
will be o bser ve d f or at least 5 da y s bef ore t he sec o n d s u bject ca n be treate d. T hereafter, wit hi n 
eac h c o h ort 4 8 h o urs m ust pass bef ore a ne w s u bject ca n i nitiate d osi n g.  O n ce t he 3 or 6 s u bjects 
ha ve passe d t he 2 1- d a y  DL T  eval uati o n peri o d t he S M C will re vie w t he safety a n d a vaila ble P K 
data t o deci de u p o n f urt her d ose escalati o n . P har mac o ki netic data fr o m t he pre vi o us c o h ort will 
be re q uire d f or S M C re vie w (f or e xa m ple, w he n t he S M C is re vie wi n g safety data fr o m t he 
1 0 m g/ k g c o h ort, a vaila ble P K data fr o m t he 3 m g/ k g c o h ort); h o we ver, P K data fr o m t he c o h ort 
u n der re vie w will n ot be re q uire d .
T he criteria f or m o vi n g fr o m 1 d ose le vel t o a n ot her d o n ot all o w escalati o n t o t he ne xt c o h ort i n 
cases w here ≥2 of 3 or 6 s u bjects i n a c o h ort e x perie nce a D L T .  If 1 D L T i n 3 s u bjects is o bser ve d , 
t his c o h ort will be a ut o maticall y e x pa n de d t o 6 s u bjects wit h S M C meeti n g after t he 6 t h s u bject 
c o m pletes t he D L T e val uati o n peri o d .  L i ke wise, if at t he hi g hest d ose le vel (3 0 m g/ k g) n o D L Ts 
occ urre d i n t he first 3 s u bjects, t he c o h ort ma y be e x pa n de d t o 6 s u bjects wit h S M C meeti n g after 
t he 6 t h s u bject c o m pletes t he D L T e val uati o n peri o d.
T he M T D is defi ne d as t he hi g hest d ose w here fe wer t ha n 2 of 6 s u bjects e x perie nce a D L T.  Th us, 
t he M T D c o h ort s h o ul d accr ue a t otal of 6 s u bjects.  If 1 of 6 s u bjects has e x perie nce d a D L T at a 
d ose bel o w 1 0 m g / k g, d ose escalati o n will be m o difie d (Ta ble 4) .
T he D L T criteria will n ot a p pl y  t o a ny of t he e x pa nsi o n c o h orts.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 9 3
T a ble 4
M o dific ati o n of D ose Esc al ati o n B ase d o n D L T O bser v ati o ns 
D ose Esc al ati o n Sc he d ule Sce n ari os
D ose of M S B 0 0 1 1 3 5 9 C
( mg/ k g)
D ose Le vels
N o D L T at 
D ose Le vel
D L T at Le vel 1 ( 1 m g / kg) or 
D L T at Le vel 2 ( 3 m g / kg)
Le vel 1
1 m g/ k g
1
Le vel 2
3 m g/ k g
3
Le vel 3
1 0 m g/ k g
7 a
Le vel 4
2 0 m g/ k g
1 0
Le vel 5
3 0 m g/ k g
2 0
Le vel 6
2 4 0 0 m g
N o m o dificati o n
D L T = d ose -li miti n g t o xicit y.
a  If 1 of 6 s u bjects has a D L T at d ose le vel 1 or 2.
5. 1. 3. 3
D ose -Li miti n g T o xicit y
A D L T is defi ne d as a n y  Gra de ≥ 3 A E assesse d as relate d t o t he I M P b y  t he I n vesti gat or a n d / or 
S p o ns or (t hat is, Gra de ≥ 3 A D R ; gra di n g acc or di n g t o t he N CI -C o m m o n Ter mi n ol o g y  Criteria 
f or A d verse E ve nts versi o n v 4. 0 3 [ C T C A E v 4. 0 3] ) occ urri n g i n t he D L T e val uati o n peri o d 
( 2 1 d a y s after first a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C) c o nfir me d b y t he S M C t o be rele va nt f or t he 
I M P treat me nt.  T he S M C rec o g nizes t hat i n t he a bse nce of pri or h u ma n e x perie nce wit h 
M S B 0 0 1 1 3 5 9 C, 
a c o nser vati ve a p pr oac h will be a d o pte d i n ascri bi n g t he rele va nce of t he 
treat me nt-relate d t o xicit y to I M P. Treat me nt -relate d S A Es will be ascri be d as relate d t o dr u g 
e xce pt w here a clear relati o ns hi p t o t he u n derl yi n g disease or rec o g nize d c o m or bi ditie s is e vi de nt.
A D L T is s pecific all y defi ne d as t he f oll o wi n g:
A n y  Gra de ≥ 3 a d verse e ve nt t hat is relate d t o M S B 0 0 1 1 3 5 9 C, 
occ urri n g d uri n g t he D L T 
e val uati o n peri o d ( 2 1 da y s after first a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C), e xce pt f or t h ose liste d 
bel o w.   Als o, ele vate d ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase ( A S T) 
3 ti mes t he u p per li mit of n or mal ( U L N) ra n ge a n d a c o nc o mita nt ele vati o n of bilir u bi n 2 ti mes 
t he U L N attri b uta ble t o st u d y dr u g c o nstit utes a D L T.

Gra de 3 i nf usi o n-relate d reacti o ns res ol vi n g wit hi n 6 h o urs fr o m t he e n d of i nf usi o n a n d 
c o ntr olle d wit h me dical ma na ge me nt.

Tra nsie nt (≤ 6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver, w hic h is c o ntr olle d wit h me dical 
ma na ge me nt.

Tra nsie nt ( ≤ 2 4 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, e mesis t hat res ol ves 
t o Gra de ≤ 1.

Gra de 3 H g b decrease ( < 8. 0 g/ d L) t hat res ol ves t o at least 9 g/ d L wit hi n 1 4 da ys or c ha n ges i n 
ass ociate d re d bl o o d cell para meters d uri n g s uc h a H g b decrease t hat res ol ve wit hi n 1 4 d a y s 
wit h o ut bl o o d tra nsf usi o n or er y t hr oi d gr o wt h fact or use. 

Mali g na nt s ki n lesi o n t hat is l ocal a n d ca n be resecte d wit h ne gati ve resecti o n mar gi n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 9 3
D ose -li miti n g t o xicities t hat re q uire treat me nt disc o nti n uati o n are descri be d i n Secti o n 5. 1. 7. 2.
S u bjects w h o d o n ot c o m plete t he D L T o bser vati o n peri o d f or reas o ns ot her t ha n a D L T will be 
re place d.
5. 1. 4
E x p a nsi o n C o h ort s
After a n M S B 0 0 1 1 3 5 9 C
d ose f or f urt her i n vesti gati o n is esta blis he d, e nr oll me nt of se veral 
e x pa nsi o n c o h orts will be o pe ne d t o deter mi ne t he safety a n d cli nical acti vit y of M S B 0 0 1 1 3 5 9 C
i n s pecific i n dicati o ns (see Secti o n 3. 4. 2 f or details). 
F oll o wi n g safety a n d P K a nal ysis of t he escalati o n c o h orts, a flat d ose of 1 2 0 0 m g/i nf usi o n was 
c h ose n f or all e x pa nsi o n c o h orts, e xce pt f or t he N S C L C sec o n d -li ne c o h ort, i n w hic h 4 0 s u bjects 
will recei ve 5 0 0 m g/i nf usi o n a n d 4 0 s u bjects will recei ve 1 2 0 0 m g/i nf usi o n .
5. 1. 5
Pl a n ne d N u m ber of S u bjects
T he pla n ne d n u m ber of t he e val ua ble s u bjects f or t his trial is deri ve d fr o m t he d ose -escalati o n 
“ 3 + 3” desi g n a n d t he e x pa nsi o n c o h ort sizes:

D ose -escalati o n p hase: 3 t o 8 2 s u bjects.

E x pa nsi o n c o h ort s: U p t o a p pr o xi matel y  5 6 6 s u bjects.
T he fi nal sa m ple size, h o we ver, m a y  var y de pe n di n g o n t he t otal n u m ber of d ose le vels t o be 
escalate d a n d teste d, a n d t he s u bject re place me nt f or D L T e val uati o ns if a p plica ble. 
I n t he e ve nt t hat ra pi d recr uit me nt i n t he e x pa nsi o n p hase i m pacts s u p pl y of I M P, t he scree ni n g of 
ne w s u bjects f or a n y c o h ort ma y be te m p oraril y pa use d wit h 2 4 h o urs’ n otice t o I n vesti gat ors.
5. 1. 6
Pl a n ne d Tre at me nt D ur ati o n
T he trial d urati o n f or a s u bject is esti mate d t o be u p t o 2 y ears. T his i ncl u des a 2 8- d a y S cree ni n g 
peri o d ( decisi o n will be ma de i n t his peri o d f or s u bjects’ trial i ncl usi o n if all eli gi bilit y  criteria are 
met), a treat me nt d urati o n u ntil c o nfir me d P D , u nacce pta ble t o xicit y, or a n y criteri o n f or 
wit h dra wal fr o m t he trial or I M P occ urs (see Secti o n 5. 5 ) a n d a 2 8- D a y  Safet y Foll o w -u p visit 
4 wee ks af ter t he last d ose of M S B 0 0 1 1 3 5 9 C
a d mi nistrati o n.
S u bjects w h o ha ve e x perie nce d S D, P R , or C R s h o ul d c o nti n ue treat me nt t hr o u g h t he e n d of 
1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble . If t he In vesti gat or belie ves t hat a s u bject 
ma y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be per miss i ble after disc ussi o n wit h t he 
Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble .
I n t he case of P D, s u bjects s h o ul d 
c o nti n ue treat me nt t hr o u g h t heir ne xt t u m or assess me nt, if t he y meet t he criteria descri be d i n 
Secti o n  5. 5. 1.  
F or s u bjects w h o ac hie ve S D, a P R or C R o n M S B 0 0 1 1 3 5 9 C t hera py a n d t he n s u bse q ue ntly 
de vel o p disease pr o gressi o n after st o p pi n g t hera p y , b ut pri or t o t he e n d of t he trial, 1 re-i nitiati o n 
c o urse of treat me nt at t he sa me d ose a n d sc he d ule a n d treat me nt d urati o n u p t o 1 2 m o nt hs is 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 9 3
all o we d at t he discreti o n of t he I n vesti gat or a n d a gree me nt of t he trial Me dical Res p o nsi ble . A 
disc ussi o n bet wee n t he I n vesti gat or a n d S p o ns or s h o ul d ta ke place . T he I n vesti gat or will nee d t o 
c o nfir m t hat t he be nefit of re -i nitiati n g treat me nt o ut wei g hs a n y ris k i n v ol ve d, s uc h as t hat w hic h 
le d t o i nitial treat me nt disc o nti n uati o n. 
M ore o ver, f or s u bjects i n w hic h B O R was S D, t he 
In vesti gat or s h o ul d c o nfir m n o ot her reas o na ble treat me nt o pti o ns are a vaila ble.   I n or der t o be 
eli gi ble f or retreat me nt, t he s u bject m ust n ot ha ve e x perie nce d a n y t o xicit y t hat le d t o per ma ne nt 
treat me nt disc o nti n uati o n of t he i nitial M S B 0 0 1 1 3 5 9 C
t hera py, u nless t he t o xicit y is dee me d t o be 
ma na gea ble a n d t he p ote ntial be nefit o ut wei g hs t he ris k of re-e x p os ure.  Pri or t o re-i nitiati o n of 
t he trial treat me nt, mali g na nt disease nee ds t o be ra di ol o gicall y re-sta ge d t o assess all k n o w n sites 
of t he disease a n d t o esta blis h a ne w baseli ne for s u bse q ue nt t u m or meas ure me nts. Rele va nt safety 
la b orat or y res ults m ust be a va ila ble a n d verifie d pri or t o re-i nitiati n g of treat me nt . S u bjects w h o 
re-i nitiate treat me nt will sta y on trial a n d will be treate d a n d m o nit ore d acc or di n g t o t he Sc he d ules 
of Assess me nt f or t he E x pa nsi o n p orti o n of t he trial starti n g at Wee k 1, Da y 1 (see Ta ble 2) .
M ore o ver, a n y A D Rs s h o ul d be f oll o we d u ntil t he y  res ol ve, ret ur n t o Baseli ne, or are irre versi ble 
(see Secti o n 7. 1. 4 f or details). 
Pla n ne d first s u bject i n: Q 3, 2 0 1 5.
Pla n ne d date las t s u bject o ut ( d ose escalati o n, i ncl u di n g f oll o w- u p): Q 3, 2 0 1 9.
Pla n ne d date last s u bject o ut (after e x pa nsi o n a n d f oll o w- u p): Q 4, 2 0 2 1.
5. 1. 7
D ose 
M o dific ati o n 
a n d 
A D Rs 
Re q uiri n g 
Tre at me nt 
Disc o nti n u ati o n
5. 1. 7. 1
D ose M o dific ati o n
F or t he d ose -escalati o n c o h orts (e xce pt f or t he 2 4 0 0 m g 
flat-d ose c o h ort) , the d ose of 
M S B 0 0 1 1 3 5 9 C will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d o n t he da y  pri or 
t o or t he da y  of eac h dr u g a d mi nistrati o n. 
E ac h s u bject will sta y on t he M S B 0 0 1 1 3 5 9 C
d ose le vel assi g ne d i n t he trial u nless treat me nt nee ds 
t o be st o p pe d.  D osi n g m o dificati o ns (c ha n ges i n i nf usi o n rate) a n d d ose dela y s are descri be d i n 
Secti o ns  5. 1. 7. 2 a n d 6. 5. 4 a n d s u bsecti o ns.  T here are n o d ose re d ucti o ns.
5. 1. 7. 2
A d verse 
Dr u g 
Re acti o ns
Re q uiri n g 
Tre at me nt 
Disc o nti n u ati o n 
Certai n A D Rs , defi ne d as a n A E assesse d as relate d t o M S B 0 0 1 1 3 5 9 C
b y  the I n vesti gat or a n d / or 
S p o ns or , ma y  re q uire per ma ne nt treat me nt disc o nti n uati o n of M S B 0 0 1 1 3 5 9 C (liste d bel o w).  F or 
certai n A D R s assesse d t o be i m m u ne-relate d, Ta ble 7 criteria m a y s u perse de t his secti o n. T hese 
criteria m a y  all o w t he s u bject t o c o nti n ue o n st u d y if me dicall y i n dicate d after c o ns ultati o n wit h 
M e dical M o nit or.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 9 3
A n y Gr a de 4 A D Rs re q uire per m a ne nt tre at me nt disc o nti n u ati o n e x ce pt f or si n gle la b orat or y 
val ues o ut of n or mal ra n ge t hat d o n ot ha ve a n y cli nical c orrelate a n d res ol ve t o Gra de ≤ 1 or 
Baseli ne gra de wit hi n 7 da y s wit h a de q uate me dical ma na ge me nt.
A n y Gr a de 3 A D Rs re q uire tre at me nt disc o nti n u ati o n e xce pt f or a n y of t he f oll o wi n g:  

Tra nsie nt (≤ 6 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver, w hic h is c o ntr olle d wit h me dical 
ma na ge me nt.

Tra nsie nt ( ≤ 2 4 h o urs) Gra de 3 fati g ue, l ocal reacti o ns , hea dac he, na usea, e mesis t hat res ol ves 
t o ≤ Gra de 1 or Baseli ne gra de . 

T u m or flare p he n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites of k n o w n or 
s us pecte d t u m or.

A n y  Gra de ≥ 3 dr u g -relate d a m ylase or li pase a b n or malit y that is n ot ass ociate d wit h s ym pt o ms 
or cli nical ma nifestati o ns of pa ncreatitis. T he St u d y  Me dical M o nit or s h o ul d be c o ns ulte d f or 
s uc h Gra de ≥ 3 a m ylase or li pase a b n or malities.
If t he a m ylase or li pase a b n or malit y not 
ass ociate d wit h s ym pt o ms or cli nical ma nifest ati o ns of pa ncreatitis has n ot res ol ve d t o 
Gra de ≤1 wit hi n t he s u bse q ue nt 2 c ycles ( 2 8 d a y s), t he s u bject s h o ul d per ma ne ntl y  disc o nti n ue 
treat me nt wit h M S B 0 0 1 1 3 5 9 C
u nless a p pr o ve d t o c o nti n ue b y  Me dical M o nit or after s pecific 
re q uest fr o m site In vesti gat o r.

Gra de 3 H g b decrease ( < 8. 0 g/ d L) t hat is cli nicall y ma na gea ble wit h bl o o d tra nsf usi o ns or 
er yt hr oi d gr o wt h fact or use d oes n ot re q uire treat me nt disc o nti n uati o n. 
D uri n g 
t he 
2 1- D a y -D L T peri o d, a G ra de 3 H g b decrease ( < 8. 0 g/ d L) re q uires treat me nt disc o nti n uati o n, 
u nless it res ol ves t o at least 9 g/ d L wit hi n 1 4 d a y s or c ha n ges i n ass ociate d re d bl o o d cell 
para meters d uri n g s uc h a H g b decrease t hat res ol ve wit hi n 1 4 da y s wit h o ut bl o o d tra nsf usi o n
or er y t hr oi d gr o wt h fact or use.

I ncreases i n Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us ( E C O G P S) ≥ 3 t hat
res ol ves t o 2 b y Da y 1 of t he ne xt c ycle (i nf usi o ns s h o ul d n ot be gi ve n if t he E C O G P S is ≥3 
o n t he da y  of I M P a d mi nistrati o n a n d s h o ul d be dela ye d u ntil E C O G P S ≤ 2 ).

Kerat oaca nt h o ma a n d s q ua m o us cell carci n o ma of t he s ki n. A n y s us pici o us s ki n lesi o n s h o ul d 
be bi o psie d a n d be s ur gicall y  re m o ve d. T he St u d y Me dical M o nit or s h o ul d be c o ns ulte d.

Gra de 3 or 4 d e r mat ol o gical irA Es, treat me nt s h o ul d be dela y e d a n d treat me nt starte d acc or di n g 
t o Ta ble 7 , if c o n diti o n i m pr o ves t o Gra de 1, treat me nt ma y  be res u me d.  If ≥2 c o nsec uti ve 
d oses are misse d , t he Me dical M o nit or s h o ul d be c o ns ulte d.  

Gra de 3 or 4 s ym pt o matic e n d ocri n o pat hies (e g, t h yr oi ditis or h y p o p h y sitis), treat me nt s h o ul d 
be dela y e d a n d treat me nt starte d acc or di n g t o Ta ble 7,  if c o n diti o n i m pr o ves t o Gra de 1, 
treat me nt m a y  be res u me d.  If ≥2 c o nsec uti ve d oses are misse d , t he Me dical M o nit or s h o ul d 
be c o ns ulte d  

Ot her i m m u ne- relate d A D Rs, see Ta ble 7.
A n y Gr a de 2 A D R s h o ul d be m a n a ge d as f oll o ws:

If a Gra de 2 A D R res ol ves t o Gra de ≤ 1 b y  the last d a y  of t he c urre nt c ycle, treat me nt ma y 
c o nti n ue.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 9 3

If a Gra de 2 A D R d oes n ot res ol ve t o Gra de ≤ 1 b y  the last d a y  of t he c urre nt c ycle b ut it is 
ma na gea ble a n d / or n ot cli nicall y rele va nt , t he A D R s h o ul d be disc usse d wit h t he M e dical 
M o nit or a n d base d u p o n disc ussi o n it is p ossi ble t he i nf usi o n will be gi ve n o n t he f oll o wi n g 
c ycle.  If at t he e n d of t he f oll o wi n g c ycle, t he e ve nt has n ot res ol ve d t o Gra de 1, disc ussi o n 
s h o ul d be ha d wit h t he M e dical M o nit or a b o ut per ma ne ntl y  disc o nti n ui n g treat me nt wit h 
M S B 0 0 1 1 3 5 9 C .

U p o n t he sec o n d occ urre nce of t he same Gra de 2 A D R i n t he sa me s u bject (e xce pt f or fati g ue 
a n d h or m o ne i ns ufficie ncies t hat ca n be ma na ge d b y  re place me nt t hera p y), c o nti n uati o n of 
treat me nt wit h M S B 0 0 1 1 3 5 9 C
has t o be disc usse d wit h t he Me dical M o nit or a n d mi g ht be 
per ma ne ntl y disc o nti n ue d .

I nf usi o n-relate d reacti o ns a n d h y perse nsiti vit y  reacti o ns ( Gra des 1 t o 4) s h o ul d be ha n dle d 
acc or di n g t o t he g ui deli nes pr o vi de d i n Secti o ns 6. 5. 4. 1 a n d 6. 5. 4. 2 , res pecti vel y.

A ne mia s h o ul d be ha n dle d acc or di n g t o t he g ui deli nes pr o vi de d i n Secti o n  6. 5. 4. 4 .

If i m m u ne-relate d A D R, see Ta ble 7.
5. 1. 8
A n al ysis C ut o ff D ates
After t he e n d of t he d ose -escalati o n part of t he trial, a f ull a nal y sis f or safet y an d P K / 
data will be perf or me d . T he data c ut off date will be 6 wee ks after t he last s u bject of t he escalati o n 
part has recei ve d his / her first a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C .  At t he ti me o f t his a me n d me nt 
w he n a d di n g t he 2 4 0 0 m g flat -d ose c o h ort, t he f ull a nal ys is f or t he d ose -escalati o n part of t he trial 
ha d bee n c o m plete d.  For t he 2 4 0 0 m g flat-d ose c o h ort, a n a nal ysis will be perf or me d at least 
6 wee ks after last s u bject first d ose.
F or t he H C C asce n di n g-d ose c o h ort, a n i nteri m a nal ys is will be c o n d ucte d 1 2 wee ks after t he 
3 0 t h s u bject i n t he 1 2 0 0 m g asce n di n g-d ose p orti o n recei ve d t he first d ose.
F or t he N S C L C a nti-P D -1 / a nti-P D -L 1  fail ure c o h ort, a n i nteri m a nal ysis will be c o n d ucte d 
1 2 wee ks after t he 4 0 t h s u bject i n t he c o h ort starte d treat me nt.
F or t he mela n o ma 
a nti-P D - 1 / a nti-P D -L 1  fail ure c o h ort, N S C L C sec o n d-li ne, pa ncreatic 
a de n ocarci n o ma, 
C R C, 
T N B C , o varia n 
ca ncer, 
es o p ha geal 
a de n ocarci n o ma, 
S C C H N, 
gli o blast o ma , a n d cer vical ca ncer c o h orts, a n i nteri m a nal ys is f or t hat c o h ort will be c o n d ucte d 
1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d treat me nt.
T he pri mar y  data c ut off f or t he a nal ysis of eac h e x pa nsi o n c o h ort se paratel y will be 2 4 wee ks after 
t he last s u bject i n t hat c o h ort starte d treat me nt ( 6 0t h s u bject f or t he H C C c o h ort). 
Fi nal data c ut off will be after s u bjects are eit her e nr olle d i nt o a r oll-o ver trial or wit h dra w n after 
c o m plet i n g at least t he Safet y Foll o w -u p visit at 1 0 Wee ks (± 2 wee ks) after Last Tr eat me nt (see 
Ta ble 1) . 
.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 9 3
5. 2
Disc ussi o n of Tri al Desi g n
T his is a P hase I, o pe n -la bel, d ose -escalati o n trial wit h pla n ne d e x pa nsi o n c o h orts . A n o pe n -la bel, 
u n bli n de d desi g n is a p pr o priate f or a d ose -escalati o n trial wit h c o nsec uti ve e x pa nsi o n c o h orts i n 
a d va nce d ca ncer s u bjects si nce s u bjects ha ve e x ha uste d treat me nt o pti o ns.
I n t his trial, t he assess me nt of t he safet y an d t olera bilit y  of t he IM P wit h t he deter mi nati o n of t he
M T D (i n t he d ose -escalati o n part o nl y ) is set t o be t he pri mar y  objecti ve. T he deter mi nati o n of 
t he M T D is o ne of t he first maj or ste ps i n t he de vel o p me nt of a c o m p o u n d e nteri n g earl y cli nical 
de vel o p me nt beca use it mi g ht be deter mi ne d t hat t he hi g hest t olera ble d ose is i m p orta nt i n f ut ure 
cli nical de vel o p me nt i n or der t o ac hie ve t he best efficac y t o ris k rati o f or s u bjects. T he M T D will 
be deter mi ne d usi n g a sta n dar d “ 3 + 3 s u bjects” d ose -escalati o n desi g n base d o n D L T assess me nts, 
w hic h is c o m m o nl y use d i n first-i n-ma n o nc ol o g y trials (Cr o wle y  20 0 6 ). T he ai m of t his desi g n 
is t o ma xi mize t he pr otecti o n t o s u bjects a n d re d uce t he c ha nces of m ore s u bjects t o be e x p osed t o 
p ossi ble dr u g t o xicities . All t hese assess me nts will be c orrelate d t o P K / 
para meters t o 
p ote ntiall y  ai d selecti o n of t he m ost mea ni n gf ul d ose f or t he e x pa nsi o n c o h ort s or f ut ure st u dies .
T he e nric h me nt of d ose -escalati o n c o h orts bel o w t he M T D are reas o na ble f or i m m u n ot hera pe utic 
a ntica ncer c o m p o u n ds ( w hic h is i n c o ntrast t o m ost c he m ot hera pies, t hat are t y picall y gi ve n at t he 
M T D), as t he o pti mal bi ol o gical effects mi g ht n ot be e xcl usi vel y obser ve d at t he M T D le vel 
(T o pali a n 2 0 1 2 b) a n d si nce it ma y  facilitate c haracterizati o n of t he P K a n d P K /
pr ofiles.  T he i ncl usi o n of l o w -d ose i ntras u bject escalati o n c o h orts is reas o na ble si nce it facilitates 
c haracterizati o n of t he P K pr ofile a n d acc o u nts f or escalat i o n t o a mea ni n gf ul d ose le vel .
A reaso na bl y safe starti n g d ose of 1 m g / k g has bee n c h ose n ta ki n g als o i nt o acc o u nt t he 
i nf or mati o n fr o m t he cli nical e x perie nce wit h t he pare nt m o n ocl o nal a nti b o d y, a vel u ma b, a n d t he 
pre dicte d lac k of o verla p pi n g i m m u ne-relate d safet y pr ofile wit h T G F β i n hi biti o n, as pre vi o usl y  
disc usse d . 
I nitial d ose setti n g f oll o ws t he pri nci ple t hat t he starti n g d ose s h o ul d be 
p har mac ol o gicall y  acti ve b ut als o reas o na bl y safe t o use. T his i nitial d ose esti mati o n al g orit h m is 
pr o p ose d i n G ui del i ne I CH S 9 (E M E A/ C H M P/I C H/ 6 4 6 1 0 7/ 2 0 0 8 ) a n d a p plica ble f or a n en d- sta ge 
ca ncer p o p ulati o n.
I n the c urre nt st u d y, t he 1 m g/ k g 
starti n g d ose is pr ojecte d t o ha ve 
a p pr o xi matel y 2 0 % of f ull a ntit u m or acti vit y an d t heref ore ac hie ves a n a p pr o priate bala nce of 
p ote ntial f or t hera pe utic acti vit y as well as reas o na ble fracti o n of bi ol o gic acti vit y, w hic h mi g ht 
ha ve safety i m plicati o ns.  In a d diti o n, precli nical e vi de nce di d n ot s u g gest i m m u ne-relate d 
t o xicities.
I n a d diti o n t o deter mi ni n g t he M T D, t he trial will ser ve t o e x pl ore bi ol o gic a n d cli nical para meters 
after e x p os ure t o M S B 0 0 1 1 3 5 9 C . D ue t o a li mite d u n dersta n di n g of t he i nteracti o n of t he i m m u ne 
s yste m a n d t u m ors i n ca ncer s u bjects, t here ca n be n o certai nt y t hat t he d oses t o be e xa mi ne d will 
b e ass ociate d wit h rele va nt a ntit u m or acti vit y, alt h o u g h preli mi nar y  res ults wit h t he pare nt 
a vel u ma b a nti b o d y s u g gest pr o misi n g cli nical a ntit u m or acti vit y.  T he selecti o n of t he d ose t o be 
use d f or f urt her cli nical e val uati o n will be base d o n t he best c urre nt scie ntific k n o wle d ge.
T he tar get p o p ulati o n f or t he d ose -escalati o n part c o m prises s u bjects wit h metastatic or l ocall y 
a d va nce d s oli d t u m ors w h o ha ve e x ha uste d sta n dar d treat me nt o pti o ns . Base d o n t he cli nical 
literat ure, N S C L C has s o me res p o nsi ve ness t o t he a nti-P D - 1 / P D -L 1  class (Getti n ger 2 0 1 4 ) a n d 
t o a vel u ma b (refer t o c urre nt a vel u ma b I B) a n d is t heref ore j ustifie d here f or b ot h t he a nti-P D -1 / 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 9 3
a nti-P D -L 1 naï ve a n d e x perie nce d s u b gr o u ps i n t he setti n g of p ost -plati n u m d o u blet pr o gressi o n
a n d, as a p pr o priate, dri ver m utati o n t hera py.  I n or der t o o btai n a tre n d of bi ol o gical / cli nical 
acti vit y, t o assess tar get e n ga ge me nt base d o n t u m or bi o ps y  s am ples a n d t o c ollect f urt her safet y 
data, a treat me nt e x pa nsi o n at a mea ni n gf ul d ose le vel t o be i de ntifie d d uri n g t he d ose-escalati o n 
part t o e ns ure f urt her de vel o p me nt i n selecte d setti n gs is j ustified. F urt her m ore, t he re q uire me nt 
of baseli ne a n d o n- treat me nt t u m or bi o psies i n t he e x pa nsi o n p hase is j ustifie d si nce t he bi ol o gic 
g oal is t o assess tar get e n ga ge me nt t o ai d f ut ure de vel o p me nt.  D ata fr o m t he e x pa nsi o n c o h orts
will all o w e x pl orati o n of w h et her t he e x pressi o n of t u m or or peri p heral P D -L 1 pat h wa y 
bi o mar kers or T G F β pat h wa y  bi o mar kers are ass ociate d wit h cli nical res p o nse t o M S B 0 0 1 1 3 5 9 C
a n d w het her P D -L 1 e x pressi o n or mar kers relate d t o T G F mi g ht ser ve as mar kers
f or patie nt 
selecti o n i n t he f ut ure de vel o p me nt pr o gra m of M S B 0 0 1 1 3 5 9 C .
T he tests a n d a nal yses t o e xa mi ne t he bi ol o gic effects of M S B 0 0 1 1 3 5 9 C
d osi n g will i ncl u de t he 
assess me nt of mar kers of i m m u ne acti vati o n k n o w n t o s h o w t y pical c ha n ges after treat me nt wit h 
t hera pies bl oc ki n g i m m u ne c hec k p oi nts. T hese details a n d ot her mar kers of i nterest are s pecifie d 
i n Secti o n 7. 6 .
5. 2. 1
I ncl usi o n of S peci al P o p ul ati o ns
N ot a p plica ble.
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y pers o ns meeti n g all i ncl usi o n criteria a n d n o e xcl usi o n criteria ma y be e nr olle d i nt o t he trial 
as s u bjects.  Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical 
care, t he I n vesti gat or will e ns ure t hat t he s u bject has pr o vi de d writte n i nf or me d c o nse nt f oll o wi n g
t he pr oce d ure descri be d i n Secti o n 9. 2.
5. 3. 1
I ncl usi o n Criteri a
F or i ncl usi o n i n t he trial, all of t he f oll o wi n g i ncl u si o n criteria m ust be f ulfille d.
5. 3. 1. 1
I ncl usi o n Criteri a f or D ose Esc al ati o n
1.
A bilit y  to u n dersta n d t he p ur p ose of t he st u d y, pr o vi de si g ne d a n d date d i nf or me d c o nse nt, 
a n d a ble t o c o m pl y wit h all pr oce d ures
2.
Male or fe male s u bjects a ge d ≥ 1 8 y ears
3.
Hist ol o gicall y or c yt ol o gicall y  pr o ve n metastatic or l ocally a d va nce d s oli d t u m ors, f or w hic h 
n o effecti ve sta n dar d t hera p y e xists or sta n dar d t hera p y has faile d
4.
Life e x pecta nc y  ≥ 1 2 wee ks as j u d ge d b y t he I n vesti gat or
5.
E C O G perf or ma nce stat us of 0 t o 1 at trial e ntr y 
6.
M ust ha ve e val ua ble or meas ura ble disease at baseli ne
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 9 3
7.
A de q uate he mat ol o gical f u ncti o n defi ne d b y  w hite bl o o d cell ( W B C) c o u nt ≥ 3 × 1 0 9/ L wit h 
a bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥ 0. 5 × 1 0 9/ L, platelet c o u nt 
≥1 2 0 × 1 0 9/ L, a n d H g b ≥9 g/ d L
8.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤ 1. 5 × U L N, a n A S T
le vel ≤2. 5 × U L N, a n d a n A L T le vel ≤2. 5 × U L N . F or s u bjects wit h li ver i n v ol ve me nt i n 
t heir t u m or, A S T ≤5. 0 × U L N, A L T ≤5. 0 × U L N , a n d bilir u bin ≤ 3. 0 × U L N is acce pta ble
9.
A de q uate re nal f u ncti o n defi ne d b y a n esti mate d creati ni ne cleara nce > 5 0 m L / mi n acc or di n g 
t o t he C oc kcr oft -Ga ult f or m ula or b y  meas ure of creati ni ne cleara nc e fr o m 2 4- h o ur uri ne 
c ollecti o n
1 0.
Hi g hl y effecti ve c o ntrace pti o n (t hat i s, met h o ds wit h a fail ure rate of less t ha n 1 % per ye ar) 
f or b ot h male a n d fe male s u bjects if t he ris k of c o nce pti o n e xists ( N ote: T he effects of t he 
trial treat me nt o n t he de vel o pi n g h u ma n fet us are u n k n o w n; t h us, w o me n of c hil d beari n g 
p ote ntial a n d me n m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n, defi ne d i n  A p pe n di x 2 or 
as sti p ulate d i n nati o nal or l ocal g ui deli nes ). Hi g hl y
effecti ve c o ntrace pti o n m ust be use d 
3 0 da y s pri or t o first trial treat me nt a d mi nistrati o n, f or t he d urati o n of trial treat me nt, a n d at 
least f or 4 m o nt hs after st o p pi n g trial treat me nt. S h o ul d a w o ma n bec o me pre g na nt or s us pect 
s he is pre g na nt w hile s he or her part ner is partici pati n g i n t his trial, t he treati n g p h y sicia n 
s h o ul d be i nf or me d i m me diately.
5. 3. 1. 2
I ncl usi o n Criteri a f or E x p a nsi o n C o h ort s
1.
A bilit y  to u n dersta n d t he p ur p ose of t he st u d y, pr o vi de si g ne d a n d date d i nf or me d c o nse nt, 
a n d a ble t o c o m pl y wit h all pr oce d ures . I n Ja pa n, if a s u bject is < 2 0 ye ars, t he writte n 
i nf or me d c o nse nt fr o m his/ her pare nt or g uar dia n will be re q uire d i n a d diti o n t o t he s u bject’s 
writte n c o nse nt
2.
Male or fe male s u bjects a ge d ≥ 1 8 y ears
3.
A vaila bilit y  of fres h t u m or bi o psies (e xcl u di n g b o ne bi o psies) is ma n dat or y  for eli gi bilit y  i n 
t he N S C L C 
bi o mar ker e x pa nsi o n, N S C L C 
a nti-P D -1/ P D -L 1  fail ure a n d mela n o ma 
a nti-P D -1/ P D -L 1 fail ure c o h orts (it is prefera ble t o n ot bi o ps y  a tar get lesi o n; h o we ver, if o nl y 
o ne lesi o n is a mena ble f or bi o ps y  a n d it is t he o nl y tar get lesi o n, t he M e dical M o nit or s h o ul d 
be c o ns ulte d f or s u bject eli gi bilit y).  The bi o ps y  or s ur gical s peci me n m ust ha ve bee n 
c ollecte d wit hi n 2 8 d a y s pri or t o t he first I M P a d mi nistrati o n.  For ot her e x pa nsi o n c o h orts,
availa bilit y  of eit her t u m or arc hi val material or fres h bi o psies wit hi n 2 8 d a y s is acce pta ble 
(e xcl u di n g b o ne bi o psies) wit h o ne of t hese bei n g ma n dat or y  (w here p ossi ble fres h bi o psies 
are preferre d ). If n o arc hi val material is a vaila ble a n d o nl y o ne lesi o n is a me na ble f or bi o ps y 
a n d it is t he o nl y t ar get lesi o n, t he Me dical M o nit or s h o ul d be c o ns ulte d f or s u bject eli gi bilit y.
T u m or bi o psies a n d t u m or arc hi val material m ust be s uita ble f or bi o mar ker assess me nt as 
descri be d i n t he La b orat or y  fl o wc hart
4.
Life e x pecta nc y  ≥ 1 2 wee ks as j u d ge d b y t he I n vesti gat or
5.
S u bjects m ust ha ve o ne of t he f oll o wi n g:  

N S C L C bi o m ar ker c o h ort:  S u bjects m ust ha ve h ist ol o gicall y or c yt ol o gicall y co nfir me d 
Sta ge III b or I V N S C L C wit h rela pse d, refract or y or pr o gressi ve disease o n or after a si n gle 
li ne of plati n u m -base d c he m ot hera p y.  I n a d diti o n, s u bjects s h o ul d ha ve e x ha uste d ot her 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 9 3
i n dicate d treat me nt o pti o ns s uc h as dri ver m utati o n t hera p y.  Pre vi o us treat me nt wit h 
c o m bi nati o n i m m u n ot hera p y is pr o hi bite d.   S u bjects wi t h n o n-s q ua m o us cell N S C L C of 
u n k n o w n m utati o nal
stat us will re q uire testi n g (l ocal la b orat or y, or ce ntral la b orat or y if 
l ocal testi n g is n ot a vaila ble). T h ose s u bjects wit h e pi der mal gr o wt h fact or rece pt or 
( E G F R) m utati o n a n d / or ana plastic l ym p h o ma ki n ase ( A L K) tra nsl ocati o n m ust
ha ve 
receive d pri or t y r osi ne ki nase i n hi bit or t hera p y  an d t h ose wit h R O S 1 rearra n ge me nt m ust 
ha ve receive d pri or t yr osi ne ki nase i n hi bit or t hera p y if l ocally a p pr o ve d.  Pri or plati n u m -
base d c he m ot hera p y is n ot re q uire d i n t hese s u bjects.  S u bjects wit h 
lar ge cell 
ne ur oe n d ocri ne ca ncer of t he l u n g are n ot eli g i ble f or t his c o h ort.  
E nr oll me nt will a d diti o nall y  be as f oll o ws: 
a.
S u bjects w h o are naï ve t o t he a nti-P D - 1 / a nti-P D -L 1  class – 1 5 s u bjects wit h paire d 
bi o psies
b.
S u bjects w h o ha ve rela pse d, refract or y, or pr o gressi ve disease f oll o wi n g a n a nti -P D - 1 
or a nti -P D -L 1 a ge nt – 1 5 s u bjects wit h paire d bi o psies   

H C C, sec o n d li ne or s or afe ni b i nt oler a nt:  Hist ol o gicall y  co nfir me d H C C.  Must be 
u nresecta ble or a d va nce d disease n ot a mena ble t o c urati ve resecti o n.  Must ha ve ha d
pr o gressi o n f oll o wi n g 1 li ne of pri or s orafe ni b t hera p y (m ust ha ve recei ve d at least 1 4 d a y s 
of s orafe ni b at least 4 0 0 m g per da y ) or pre vi o usl y c o nsi dere d t o be s orafe ni b i nt olera nt  
T he H C C c o h ort will be c o m pos e d of 2 p orti o ns, a n asce n di n g-d ose p orti o n a n d a n 
e x pa nsi o n p orti o n: 
F or t he asce n di n g - d ose p orti o n:
1)
3 m g/ k g d ose c o h ort , u p t o N = 6
2)
1 2 0 0 m g flat - d ose c o h ort, u p t o N = 3 0
F or asce n di n g - d ose p orti o n a n d d ose -e x p a nsi o n p orti o n:
U ni nfecte d, H C V, a n d H B V -i nfecte d s u bjects are eli gi ble. If me dicall y i n dicate d, su bjects 
i nfecte d wit h H B V m ust be treate d a n d o n a sta ble d ose of a nti virals (e g, e nteca vir , 
te n of o vir, or la mi v u di ne; a def o vir or i nterfer o n are n ot all o we d) at st u d y entr y  an d wit h 
pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o a p pr o priate la beli n g g ui da nce.  S u bjects 
o n acti ve H C V t hera py at st u d y entr y  must be o n a sta ble d ose wit h o ut d oc u me nte d 
cli nicall y si gnifica nt li ver f u ncti o n test or he mat ol o gic a b n ormalities
( m ust meet criteria 
bel o w) a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o a p pr o priate la beli n g 
g ui da nce .  
A d diti o nal criteria f or all H C C, sec o n d -li ne c o h ort s u bjects i ncl u de:
o
C hil d -P u g h A or B 7
o
E C O G 0 or 1
o
A l b u mi n ≥2. 8 g/ d L
o
Inter nati o nal n or malize d rati o (I N R) < 1. 7
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 9 3
o
A de q uate 
he mat ol o gical f u ncti o n defi ne d b y  
WB C c o u nt ≥ 2. 5 × 1 0 9/ L wit h 
A N C ≥1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥ 0. 5 × 1 0 9/ L, platelet c o u nt ≥5 0 × 1 0 9/ L, a n d 
he m o gl o bi n ≥ 9 g/ d L 
o
S u bjects wit h n o aller gies t o c o ntrast a n d able t o t olerate c o m p ute d t o m o gra p h y ( C T) or 
ma g netic res o na nce i ma gi n g ( M RI) c o ntrast i n t he o pi ni o n of t he I n vesti gat or

N S C L C, sec o n d li ne:  Hist ol o gicall y  c o nfir me d Sta ge III b/I V or rec urre nt N S C L C.  M ust 
n ot ha ve recei ve d c hec k p oi nt i n hi bit or pre vi o usl y  (c o ns ult wit h M e dical M o nit or 
if 
necessar y ).  M ust ha ve e x perie nce d disease pr o gressi o n after a n acce pta ble t hera p y defi ne d 
as f oll o ws:
o
S u bjects m ust ha ve pr o gresse d d uri n g or after a mi ni m u m of 2 c ycles of 1 c o urse of a 
plati n u m -base d c o m bi nati o n t hera py a d mi nistere d f or t he treat me nt of metastatic disease.  
A hist or y  of c o nti n uati o n ( use of a n o n- plati n u m a ge nt fr o m i nitial c o m bi nati o n) or s witc h 
( use of a differe nt a ge nt) mai nte na nce t hera py is per mitte d pr o vi de d t here was n o 
pr o gressi o n after t he i nitial c o m bi nati o n.  A switc h of a ge nts d uri n g treat me nt f or t he 
ma na ge me nt of t o xicities is als o per mitte d pr o vi de d t here was n o pr o gressi o n after t he 
i nitial c o m bi nati o n
O R
o
S u bjects m ust ha ve pr o gresse d wit hi n 6 m o nt hs of c o m pleti o n of a plati n u m - base d 
a dj u va nt, ne oa dj u va nt, or defi niti ve c he m ot hera p y, or c o nc o mita nt c he m ora diati o n 
re gi me n f or l ocall y a d va nce d disease
S u bjects wit h n o n -s q ua m o us cell N S C LC of u n k n o w n m utati o nal stat us will re q uire testi n g 
(l ocal la b orat or y, or ce ntral la b orat or y if l ocal testi n g is n ot a vaila ble). S u bjects wit h k n o w n 
E G F R m utati o n a n d / or A L K tra nsl ocati o n are eli gi ble if t he y ha ve recei ve d at least 1 li ne 
of t yr osi ne ki nase i n hi bit or t hera p y.   S u bjects wit h R O S 1 rearra n ge me nt m ust ha ve recei ve d 
t yr osi ne ki nase i n hi bit or t hera py if l ocally a p pr o ve d.  These s u bjects d o n ot re q uire pri or 
treat me nt wit h s yste mic c he m ot hera p y.  S u bjects wit h lar ge cell ne ur oe n d ocri ne ca ncer of 
t he l u n g are n ot eli gi ble

N S C L C, a nti -P D -1 / a nti -P D -L 1 f ail ure: S u bjects wit h h ist ol o gicall y co nfir me d Sta ge 
I V ( metastatic) or rec urre nt N S C L C ( per 7t h I nter nati o nal Ass ociati o n f or t he St u d y  of 
L u n g Ca ncer classificati o n) w h o ha ve e x ha uste d sta n dar d treat me nt o pti o ns i n t h e o pi ni o n 
of t he In vesti gat or are t o be e nr olle d. At a mi ni m u m, s u bjects nee d t o ha ve recei ve d a n d 
faile d plati n u m -base d c he m ot hera p y a n d m ust ha ve recei ve d a nti-P D - 1 or a nti-P D -L 1  as 
m o n ot hera p y a n d faile d wit h disease pr o gressi o n.  In a d diti o n, s u bjects s h o ul d ha ve 
e x ha uste d ot her i n dicate d dri ver m utati o n t hera p y, as a p pr o priate   

Mel a n o m a, 
a nti -P D - 1 / a nti -P D -L 1 f ail ure:  S u bjects wit h u nresecta ble Sta ge III or 
metastatic ( Sta ge I V) mela n o ma w h o ha ve e x ha uste d sta n dar d treat me nt o pti o ns i n t he 
o pi ni o n of t he i n vesti gat or are t o be e nr olle d. At a mi ni m u m, s u bjects nee d t o ha ve 
recei ve d a nti-P D - 1 or a nti -P D -L 1  as m o n o - or c o m bi nati o n t hera py a n d faile d wit h disease 
pr o gressi o n .  Als o m ust ha ve faile d a p pr o priate s yste mic t hera pies i ncl u di n g B R A F 
i n hi bit or if B R A F V 6 0 0 m utati o n p ositi ve
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 9 3

P a ncre atic a de n oc arci n o m a, sec o n d li ne or gre ater:  Hist ol o gicall y  co nfir me d 
pa ncreatic a de n ocarci n o ma (s u bjects wit h e n d ocri ne or aci nar pa ncreatic carci n o ma are n ot 
eli gi ble).  M ust ha ve u nresecta ble or l ocall y a d va nce d or metastatic disease
o
Pri or t hera py wit h ≥ 1 s yste mic c he m ot hera p y re gi me n f or u nresecta ble or metastatic 
pa ncreatic ca ncer or u n willi n g / u na ble t o recei ve s yste mic c he m ot hera p y.  Su bjects 
m ust n ot ha ve recei ve d pre vi o us ra di ot hera p y f or meas ura ble lesi o n s
o
Disease pr o gressi o n w hile recei vi n g or after disc o nti n ui n g palliati ve c he m ot hera p y

C ol orect al c a ncer 
( C R C), t hir d li ne
or 
gre ater :  Hist ol o gicall y  co nfir me d 
a de n ocarci n o ma of t he c ol o n or rect u m
o
S u bjects m ust ha ve pr o gresse d d uri n g or after a sec o n d- li ne of sys te mic treat me nt 
o
Pri or faile d t hera p y must ha ve i ncl u de d at least a fl u or o pyr i mi di ne, o xali plati n, 
iri n oteca n (si n gle or i n c o m bi nati o n) a n d be vaciz u ma b ( w here a p pr o ve d).  F or s u bjects 
w h o h a d wil d -t ype R A S t u m ors, cet u xi ma b or pa nit u m u ma b treat me nt m ust ha ve 
occ urre d

Tri ple -ne g ati ve bre ast c a ncer ( T N B C), sec o n d li ne or gre ater :  T u m or
m ust be 
c o nfir me d ne gati ve f or estr o ge n rece pt ors, pr o gester o ne rece pt ors, a n d H E R 2 defi ne d as 
f oll o ws:
o
E R n e gati ve defi ne d b y:   E R I HC < 1 % reacti ve cells
o
P R ne gati ve defi ne d b y:  P R IH C < 1 % reacti ve cells
o
H E R -2 ne gati ve defi ne d b y  o ne of f o ur sit uati o ns bel o w:
1.
H E R 2 Breast I H C = 0
2.
H E R 2 Breast I H C = 1 +
3.
H E R 2 Breast I H C = 2 + A N D fl u oresce nce i n sit u h y bri dizati o n (FI S H )-ne gati ve 
( n o n-a m plifie d)
4.
FI S H n o n -a m plifie d
o
S u bjects m ust ha ve pr o gresse d d uri n g or after first li ne of c he m ot hera py 

O v ari a n c a ncer, pl ati n u m resist a nt or refr act or y, pre vi o usl y s yste mic all y tre ate d:  
Hist ol o gicall y c o nfir me d e pit helial o varia n, fall opia n t u be, or perit o neal ca ncer (s u bjects 
wit h n o n- e pit helial t u m or, i ncl u di n g mali g na nt mi xe d M ülleria n t u m ors wit h o ut hi g h gra de 
ser o us c o m p o ne nt, or o varia n t u m ors wit h l o w mali g na nt p ote ntial [ie, b or derli ne t u m ors] 
are n ot eli gi ble)  
o
M ust n ot be a
ca n di date f or s ur gical resecti o n wit h c urati ve i nte nt
o
M ust ha ve p lati n u m resista nt / refractor y disease, defi ne d as disease pr o gressi o n wit hi n 
1 8 0 da y s f oll o wi n g t he last a d mi nistere d d ose of plati n u m t hera p y (resista nt), or lac k of 
res p o nse or disease pr o gressi o n w hile rec ei vi n g t he m ost rece nt plati n u m-base d t hera p y 
(refract or y), or pr o gressi o n o n / after last n o n -plati n u m - base d c he m ot hera p y
o
Treat me nt hist or y  of at least 2 pri or s yste mic re gi me ns, i ncl u di n g pri or e x p os ure t o 
plati n u m a n d ta xa ne a ge nts
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 9 3
o
B R C A stat us m ust be re p orte d if k n o w n

Es o p h a ge al a de n oc arci n o m a, p ost -pl ati n u m, sec o n d li ne or gre ater:  Hist ol o gicall y 
c o nfir me d rec urre nt or metastatic es o p ha geal a de n ocarci n o ma .  M ust ha ve u nresecta ble
( Sta ge III or I V) disease
o
M ust ha ve recei ve d at least o n e pre vi o us plati n u m -c o ntai ni n g c he m ot hera p y re gi me n.  
S u bjects wit h H E R 2- p os iti ve t u m ors m ust ha ve recei ve d pri or trast uz u ma b

Gli o bl ast o m a, p ost -te m oz ol o mi de / r a di ati o n, sec o n d li ne:  Hist ol o gicall y  co nfir me d 
Gra de I V mali g na nt gli o ma (s u bjects wit h e x tracra nial metastatic or le pt o meni n geal are 
n ot eli gi ble)  
o
Pre vi o us treat me nt wit h ra di ot hera p y a n d te m oz ol o mi de
o
T olera nce t o ga d oli ni u m
o
A n i nter val of at least 1 2 wee ks after t he e n d of pri or ra di ot hera py is re q uire d u nless 
t here is either hist ol o pat h ol o gic c o nfir mati o n of rec urre nt t u m or or ne w e n ha nce me nt 
o n M RI  o utsi de of t he ra di ot hera p y treat me nt fiel d
o
First rec urre nce of gli o blast o ma
o
Kar n ofs k y Perf or ma nce Stat us ( K P S) ≥ 7 0
o
S u bjects m ust n ot ha ve recei ve d pri or be vaciz u ma b or ot her a nti-vasc ular e n d ot helial 
gr o wt h fact or or a ntia n gi o ge nic treat me nts

S q u a m o us cell carci n o m a he a d a n d n ec k
( S C C H N), sec o n d li ne or gre ater:   
Hist ol o gicall y c o nfir me d rec urre nt or metastatic S C C H N ( oral ca vit y, p har y n x, lar yn x), 
S ta ge III/I V a n d n ot a me na ble t o l ocal t hera p y wit h c urati ve i nte nt (s ur ger y or ra diati o n 
t hera py wit h or wit h o ut c he m ot hera p y)
o
T u m or pr o gressi o n or rec urre nce wit hi n 6 m o nt hs of last d ose of plati n u m t hera py i n t he 
a dj u va nt (ie wit h ra diati o n after s ur ger y), pri mar y  (ie, wit h
ra diati o n), rec urre nt, or 
metastatic setti n g.
o
S u bjects ma y  ha ve recei ve d pri or cet u xi ma b
o
H P V t u m or testi n g m ust be re p orte d if k n o w n

Cer vic al c a ncer, sec o n d li ne or gre ater :  Hist ol o gicall y  c o nfir me d rec urre nt or persiste nt 
s q ua m o us cell carci n o ma, a de n os q ua m o us carci n o ma, or a de n ocarci n o ma of t he cer vi x 
f oll o wi n g sta n dar d of care treat me nt wit h s yste mic t hera py f or a d va nce d disease (ty picall y 
d o u blet c y t ot o xic c he m ot hera py a n d be vaciz u ma b , w here a p pr o ve d )  
o
H P V t u m or testi n g m ust be re p orte d if k n o w n
6.
E C O G perf or ma nce stat us of 0 t o 1 at trial e ntr y  
7.
Disease 
m ust 
be meas ura ble 
wit h 
at least 1 u ni di me nsi o nal l y meas ura ble 
lesi o n b y  
R E CI S T 1. 1.
8.
A de q uate he mat ol o gical f u ncti o n defi ne d b y  w hite bl o o d cell ( W B C) c o u nt ≥ 3 × 1 0 9/ L wit h 
A N C
≥ 1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥ 0. 5 × 1 0 9/ L, platelet c o u nt ≥1 2 0 × 1 0 9/ L, a n d 
H g b ≥9 g/ d L 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 9 3
9.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤ 1. 5 × t he U L N , a n A S T
le vel ≤2. 5 × U L N, a n d a n A L T le vel ≤2. 5 × U L N .  For s u bjects wit h li ver i n v ol ve me nt i n 
t heir tu m or , A S T ≤ 5. 0 × U L N, A L T ≤5. 0 × U L N , a n d bilir u bi n ≤ 3. 0 is acce pta ble
1 0.
A de q uate re nal f u ncti o n defi ne d b y a n esti mate d creati ni ne cleara nce > 5 0 m L / mi n acc or di n g 
t o t he C oc kcr oft -Ga ult f or m ula or b y  meas ure of creati ni ne cleara nc e fr o m 2 4- h o ur uri ne 
c ollecti o n
1 1.
Hi g hl y effecti ve c o ntrace pti o n (t hat is, met h o ds wit h a fail ure rate of less t ha n 1 % per ye ar) 
f or b ot h male a n d fe male s u bjects if t he ris k of c o nce pti o n e xists ( N ote: T he effects of t he 
trial treat me nt o n t he de vel o pi n g h u ma n fet us are u n k n o w n; t h us, w o me n of c hil d beari n g 
p ote ntial a n d me n m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n, defi ne d i n  A p pe n di x 2 or 
as sti p ulate d i n nati o nal or l ocal g ui deli nes ). Hi g hl y
effecti ve c o ntrace pti o n m ust be use d 
3 0 da y s pri or t o first trial treat me nt a d mi nistrati o n, f or t he d urati o n of trial treat me nt, a n d at 
least f or 4 m o nt hs after st o p pi n g trial treat me nt. S h o ul d a w o ma n bec o me pre g na nt or s us pect 
s he is pre g na nt w hile s he or h er part ner is partici pati n g i n t his trial, t he treati n g p h y sicia n 
s h o ul d be i nf or me d i m me diately.
5. 3. 2
E xcl usi o n Criteri a ( A p plic a ble t o A ll S u bjects, Incl u di n g A ll 
E x p a nsi o n C o h orts)
S u bjects are n ot eli gi ble f or t his trial if t he y  f ulfill a n y of t he f oll o wi n g e xcl usi o n criteria:
1.
C o nc urre nt treat me nt wit h n o n -per mitte d dr u gs a n d ot her i nter ve nti o ns (see Secti o n 6. 5. 2 a n d 
Secti o n  6. 5. 3, res pecti vel y). 
2.
E xce pt f or t he a nti-P D - 1 / a nti-P D -L 1 -e x perie nce d N S C L C 
e x pa nsi on a n d mela n o ma 
e x pa nsi o n c o h orts , pri or t hera py wit h a n y a nti b o d y / dr u g tar geti n g T -cell c o re g ulat or y pr otei ns 
(im m u ne c hec k p oi nts) s uc h as a nti-P D - 1, a nti-P D -L 1 , or a nti-C T L A -4 a nti b o d y (c o ns ult 
Me dical M o nit or if necessar y ) is n ot all o we d (c o ns ult wit h Me dical M o nit or as nee de d) , 
i ncl usi ve of i ntra he patic, l ocalize d a d mi nistrati o n of s uc h a ge nts
3.
A ntica ncer treat me nt wit hi n 2 8 da y s bef ore t he start of trial treat me nt, f or e xa m ple,
cyt ore d ucti ve t hera p y , ra di ot hera py ( wit h t he e xce pti o n of palliati ve ra di ot hera py deli vere d i n
a n or mal or ga n -s pari n g tec h ni q ue), i m m u ne t hera p y, or c yt o ki ne t hera py ( wit h t he e xce pti o n 
of s orafe ni b f or s u bjects wit h H C C, w hic h m ust ha ve bee n st o p pe d wit hi n 1 4 da ys)
4.
M aj or s ur ger y wit hi n 2 8 d a y s bef ore t he start of trial treat me nt (pri or dia g n ostic bi o ps y  is 
per mitte d )
5.
S y ste mic t hera p y wit h i m m u n os u p pressi ve a ge nts wit hi n 7 d a y s bef ore t he start of trial 
treat me nt; or use of a n y i n vesti gati o nal dr u g wit hi n 2 8 da y s bef ore t he start of trial treat me nt
(N ote:   f or s u bjects wit h gli o blast o ma, ster oi d use is all o we d acc or di n g t o sta n dar d of care a n d 
l ocal g ui deli nes)
6.
Pre vi o us mali g na nt disease ( ot her t ha n t he tar get mali g na nc y  to be i n vesti gate d i n t his trial) 
wit hi n t he last 3 ye ars.  Su bjects wit h a hist or y  of cer vical carci n o ma i n sit u, s u perficial or
n o- i n vasi ve bla d der ca ncer, or basal cell or s q ua m o us cell carci n o ma i n sit u pre vi o usl y t reate d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 9 3
wit h c urati ve i nte nt are N O T e xcl u de d.  S u bjects wit h ot her l ocalize d mali g na ncies treate d 
wit h c urati ve i nte nt nee d t o be disc usse d wit h t he Me dical M o nit or
7.
Ra pi dl y  pr o gressi ve disease w hic h,
i n t he o pi ni o n of t he In vesti gat or, ma y  pre dis p ose t o 
i na bilit y t o t olerate treat me nt or trial pr oce d ures
8.
S u bjects wit h acti ve ce ntral ner v o us s yste m ( C N S) metastases ca usi n g cli nical s ym pt o ms or
metastases t hat re q uire t hera pe utic i nter ve nti o n are e xcl u de d.  Su bjects wit h a hist or y  of treate d 
C N S metastases ( by s ur ger y or ra diati o n t hera p y) are n ot eli gi ble u nless t he y ha ve f ull y 
rec o vere d fr o m treat me nt, de m o nstrate d n o pr o gressi o n f or at least 2 m o nt hs, a n d d o n ot 
re q uire c o nti n ue d ster oi d t hera py .  S u bjects wit h C N S metastases i nci de ntall y detecte d d uri n g 
S cree ni n g w hic h d o n ot ca use cli nical s ym pt o ms a n d f or w hic h sta n dar d of care s u g gests n o 
t hera pe utic i nter ve nti o n is i n dicate d s h o ul d be dis c usse d wit h 
t he S p o ns or
Me dical 
Res p o nsi ble
9.
Recei pt of a n y or ga n tra ns pla ntati o n, i ncl u di n g all o ge neic ste m-cell tra ns pla ntati o n, b ut wit h 
t he e xce pti o n of tra ns pla nts t hat d o n ot re q uire i m m u n os u p pressi o n (e g, c or neal tra ns pla nt, 
hair tra ns pla nt)
1 0. Si g nifi ca nt ac ute or c hr o nic i nfecti o ns i ncl u di n g, a m o n g ot hers:

K n o w n hist or y  of testi n g p ositi ve test f or h u ma n i m m u n o deficie nc y  vir us ( HI V) or k n o w n 
ac q uire d i m m u n o deficie nc y  sy n dr o me 

E xce pt f or t he H C C c o h ort, H B V or H C V i nfecti o n (H B V s urface a nti ge n p ositi ve a n d H B V 
c ore a nti b o d y positi ve wit h refle x t o p ositi ve H B V D N A or H B V c ore a nti b o d y positi ve 
al o ne wit h refle x t o p ositi ve H B V D N A or p ositi ve H C V a nti b o d y wit h refle x t o p ositi ve 
H C V R N A )

S u bjects wit h acti ve t u berc ul osis ( hist or y of e x p os ure or hist or y  of p ositi ve t u berc ul osis test; 
pl us , prese nce of cli nical s y m pt o ms, p h y sical or ra di o gra p hic fi n di n gs)
1 1. Acti ve a ut oi m m u ne disease t hat mi g ht deteri orate w he n recei vi n g a n i m m u n osti m ulat or y 
a ge nt:

S u bjects wit h dia betes t ype I, vitili g o, al o pecia, ps oriasis, h y p o- or h y pert h y r oi d disease 
n ot re q uiri n g i m m u n os u p pressi ve treat me nt are eli gi ble

S u bjects re q uiri n g h or m o ne re place me nt wit h c ortic oster oi ds are eli gi ble if t he ster oi ds are 
a d mi nistere d o nl y f or t he p ur p ose of h or m o nal re place me nt a n d at d ose s ≤ 1 0 m g of 
pre d nis o ne or e q ui vale nt per da y

A d mi nistrati o n of ster oi ds f or ot her c o n diti o ns t hr o u g h a r o ute k n o w n t o res ult i n a mi ni mal 
s yste mic e x p os ure (t o pical, i ntra nasal, i ntr o-oc ular, or i n halati o n) is acce pta ble
1 2. K n o w n se vere h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies ( Gra de ≥ 3 N CI -C T C A E 
v 4. 0 3) or rece nt, wit hi n 5 m o nt hs,
hist or y  of u nc o ntr olle d ast h ma (ie, 3 or m ore feat ures of 
partiall y  c o ntr olle d ast h ma)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 9 3
1 3. Persisti n g t o xicit y (e xce pt al o pecia a n d vitili g o) relate d t o pri or t hera py
Gra de
>
1 
N CI -C T C A E v 4. 0 3 ; h o we ver , se ns or y ne ur o pat h y Gra de ≤ 2 is acce pta ble
1 4. Pre g na nc y  or c urre ntl y i n lactati o n 
1 5. K n o w n alc o h ol or dr u g a b use
1 6. Cli nicall y  si g nifica nt car di o vasc ular / cereb r o vasc ular disease as f oll o ws: cere bral vasc u lar 
acci de nt / str o ke ( < 6 m o nt hs pri or t o e nr oll me nt), m y ocar dial i nfarcti o n ( < 6 m o nt hs pri or t o 
e nr oll me nt), u nsta ble a n gi na, c o n gesti ve heart fail ure ( Ne w Y or k 
Heart 
Ass ociati o n 
Classificati o n Class ≥II), or seri o us car diac arr hyt h mia
1 7. Cli nicall y  releva nt diseases (f or e xa m ple, i nfla m mat or y bo wel disease) a n d / or u nc o ntr olle d 
me dical c o n diti o ns , w hic h, i n t he o pi ni o n of t he In vesti gat or, mi g ht i m pair t he s u bject’s 
t olera nce or a bilit y t o partici pate i n t he trial
1 8. A n y  ps yc hiatric c o n diti o n t hat w o ul d pr o hi bit t he u n dersta n di n g or re n deri n g of i nf or me d 
c o nse nt
1 9. Le gal i nca pacit y or li mite d le gal ca pacit y
2 0. Vacci ne a d mi nistrati o n wit hi n 4 wee ks of I MP a d mi nistrati o n. Vacci nati o n wit h li ve vacci nes 
w hile o n trial is pr o hi bite d.
A d mi nistrati o n of i nacti vate d vacci nes is all o we d (f or e xa m ple,
i nacti vate d i nfl ue nza vacci nes)
A d diti o n al e xcl usi o n criteri a f or s u bjects i n t he H C C c o h ort i ncl u de:
2 1. Cli nical ascites (t hat is, n ot per ra di ol o gical assess me nt o nl y ) wit hi n past 6 m o nt hs n ot 
ade q uatel y c o ntr olle d wit h me dical t hera p y; hist or y  of variceal blee di n g wit hi n past 3 m o nt hs ; 
hist or y  of u nc o ntr olle d he patic e nce p hal o pat h y i n t he past 3 m o nt hs; or hist or y of o bstr ucti ve 
ja u n dice n ot a me na ble t o ste nti n g i n t he past 3 m o nt hs
2 2. He patitis D vir us ( H D V) c o -i nfecti o n wit h he patitis B vir us ( H B V; if H B V s urface a nti ge n or 
H B V D N A p ositi vit y  at Scree ni n g t he n m ust c hec k f or H D V stat us)
2 3. C he m oe m b olizati o n or ra di oe m b olizati o n wit hi n 2 8 da ys pri or t o I M P a d mi nistrati o n
5. 4
Criteri a f or I niti ati o n of Tr i al Tre at me nt
T he i ncl usi o n a n d e xcl usi o n criteria will be c hec ke d at t he S cree ni n g visit. Eli gi ble s u bjects will 
be e nr olle d bef ore treat me nt start after verificati o n of f ulfilli n g all i ncl usi o n criteria wit h o ut 
matc hi n g a n y e xcl usi o n criteri o n. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 9 3
5. 5
Criteri a f or S u bject Wit h dr a w al
5. 5. 1
Wit h dr a w al F r o m Tri al Tre at me nt   
S u bjects will be wit h dra w n fr o m trial treat me nt f or a n y of t he f oll o wi n g reas o ns:

C o nfir me d P D per R E CI S T 1. 1 or R A N O f or s u bjects wit h gli o blast o ma : S u bjects s h o ul d 
c o nti n ue treat me nt b e y o n d t he i nitial deter mi nati o n of P D, t hr o u g h t heir ne xt t u m or assess me nt,
pr o vi de d: 
a. T here are n o ne w Gra de 2 or greater s ym pt o ms or si g nifica nt w orse ni n g of e xisti n g 
s ym pt o ms.
b. T here is n o decrease i n E C O G P S .
c. I n t he o pi ni o n of t he I n vesti gat or, t he s u bject d oes n ot re q uire ne w a ntica ncer t hera p y.
S u bjec ts s h o ul d be disc o nti n ue d fr o m treat me nt t hereafter if f urt her e vi de nce of P D ; h o we ver,
c o nti n ue d treat me nt is p ossi ble i n c o ns ultati o n wit h t he Me dical M o nit or

Occ urre nce of a n e xcl usi o n criteri o n, w hic h is cli nicall y rele va nt a n d affects t he s u bject’s 
safety, if disc o nti n uati o n is c o nsi dere d necessar y b y t he In vesti gat or a n d / or S p o ns or

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal ca ncer t hera p y  

Occ urre nce of Gra de ≥ 3 A D Rs or re petiti ve Gra de 2 A D Rs e xce pt as all o we d as defi ne d i n 
Secti o n  5. 1. 7. 2

Occ urre nce of A Es, at t he I n vesti gat or’s discreti o n

Pre g na nc y

Use of pr o hi bite d c o nc o mita nt dr u g , as defi ne d i n Secti o n 6. 5. 2,  w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he I M P

N o n -a d here nce / n o n-c o m plia nce t o t he trial pr ot oc ol or trial re q uire me nts (see Secti o n 6. 9)

Wit h dra wal of c o nse nt

Partici pati o n i n a n y  ot her trial.
F or s u bjects w h o miss ≥2 c o nsec uti ve d oses f or me dical reas o ns, t he Me dical M o nit or s h o ul d be 
c o ns ulte d.
I n the d ose -escalati o n p hase, t he o nl y s u bjects t hat ma y  be re place d are t h ose t hat d o n ot c o m plete 
t he 2 1-d a y  D L T o bser vati o n peri o d f or reas o ns ot her t ha n a D L T.
5. 5. 2
Wit h dr a w al F r o m t he Tri al
S u bjects ma y wit h dra w fr o m t he trial at a ny ti me wit h o ut gi vi n g a reas o n. Wit h dra wal of c o nse nt 
will be c o nsi dere d wit h dra wal fr o m t he tri al.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 9 3
A s u bject m ust be wit h dra w n i f a n y of t he f oll o wi n g occ ur d uri n g t he trial :

Wit h dra wal of t he s u bjec t’s c o nse nt

Partici pati o n i n a n y ot her t hera pe utic trial d uri n g t he treat me nt d urati o n of t his trial; h o we ver, 
s u bjects will c o nti n ue t o be f oll o we d f or s ur vi val
If a s u bject fails t o atte n d sche d ule d trial assess me nts, t he In vesti gat or m ust deter mi ne t he reas o ns 
a n d t he circ u msta nces as c o m pletel y a n d acc uratel y as p ossi ble.
I n case of wit h dra wal fr o m t he trial, t he assess me nts sc he d ule d f or t he last visit ( 2 8-Da y  Safet y 
F oll o w -u p visit) s h o ul d be perf or me d (see Secti o n 7. 1. 3 ), if p ossi ble, wit h f oc us o n t he m ost 
rele va nt assess me nts.  I n a n y case, t he a p pr o priate 2 8- Da y  Safet y F oll o w -u p electr o nic case re p ort 
f or m (e C R F) visit m ust be c o m plete d. I n case of wit h dra wal, s u bjects will be as ke d t o c o nti n ue 
safety a n d s ur vi val f oll o w- u p, w hic h i ncl u des t he c ollecti o n of data o n s ur vi val a n d s u bse q ue nt 
a ntica ncer t hera p y. After c o m pleti o n of t he F oll o w -u p peri o d or after t he E n d - of-Treat me nt visit, 
w hate ver is a p plica ble, t he a p pr o priate e C R F secti o n f or Trial Ter mi nati o n m ust be c o m plete d.
If a s u bject is wit h dra w n pri or t o disease pr o gressi o n f or a n y reas o n i n t he e x pa nsi o n part of t he 
trial, t he s u bject will n ot be re place d. I n t he d ose -escalati o n part , t he o nl y  su bjects t hat m a y  be 
re place d are t h ose t hat d o n ot c o m plete t he 2 1 -d a y  D LT o bser vati o n peri o d f or reas o ns ot her t ha n 
a D L T.
After pri m ar y a n al yses are c o mplete d, s u bjects ma y e nr oll i nt o a r oll-o ver trial bef ore pla n ne d e n d 
of t he trial or wit hra w n
after t he y ha ve at least c o m plete d t he Safet y F oll o w - u p at 1 0 Wee ks 
( ± 2 wee ks) after Last Treat me nt.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he w h ole trial ma y  be disc o nti n ue d pre mat urely i n t he e ve nt of a n y of t he f oll o wi n g:

Ne w i nf or mati o n lea di n g t o u nfa v ora ble ris k - be nefit j u d g me nt of t he I M P, f or e xa m ple, d ue t o
o
e vi de nce of i nefficac y of t he I MP,
o
occ urre nce of si g nifica nt pre vi o usl y  un k n o w n a d verse reacti o ns or u ne x pecte dl y  hi gh 
i nte nsit y or i nci de nce of k n o w n a d verse reacti o ns, or
o
ot her u nfa v ora ble safet y fi n di n gs.
( N ote: Evi de nce of i neffic acy m ay arise fr o m t his tri al or fr o m ot her tri als; u nf av or a ble 
s afety fi n di n gs m ay 
arise fr o m cli nic al or n o n -cli nic al ex a mi n ati o ns, f or ex a m ple, 
t oxic ol o gy.)

S p o ns or’s decisi o n t hat c o nti n uati o n of t he trial is u nj ustifia ble f or me dical or et hical reas o ns

P o or e nr oll me nt of s u bjects ma ki n g c o m pleti o n of t he trial wit hi n a n acce pta ble ti me fra me 
u nli kel y

Disc o nti n uati o n of de vel o p me nt of t he S p o ns or’s I M P
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 9 3
Healt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees (IE Cs) / I nstit uti o nal Re vie w B oar ds 
(IR Bs) will be i nf or me d a b o ut t he disc o nti n uati o n of t he trial i n acc or da nce wit h a p plica ble 
re g ulati o ns.
T he w h o le trial ma y be ter mi nate d or s us pe n de d u p o n re q uest of Healt h A ut h orities.
5. 7
Defi niti o n of E n d of Tri al
If t he trial is n ot ter mi nate d f or a reas o n gi ve n i n Secti o n  5. 6, t he e n d of t he trial is defi ne d as w he n 
s u bjects are eit her e nr olle d i nt o a r oll-o ver trial or wit h dra w n after c o m pleti n g at least t he Safet y 
F oll o w - u p visit at 1 0 Wee ks ( ± 2 wee ks) after Last Treat me nt.
6
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n 
t he Tri al
T he ter m “In vesti gati o nal Me dici nal Pr o d uct” refers t o a n acti ve s u bsta nce or a place b o bei n g 
teste d or use d as a refere nce t hera py i n a cli nical trial, i ncl u di n g pr o d ucts t hat ha ve a mar keti n g 
a ut h orizati o n b ut are f or m ulate d , pac ka ge d , or a d mi nistere d differe ntl y  fr o m t he a ut h orize d f or m, 
use d f or a n u na ut h orize d i n dicati o n, or use d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d for m .  
T he o nl y  IM P use d i n t his trial is M S B 0 0 1 1 3 5 9 C .
6. 1
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct
M S B 0 0 1 1 3 5 9 C 
dr u g pr o d uct is pr o vi de d as eit her a sterile freeze-drie d or a sterile li q ui d 
f or m ulati o n.
Eac h vial of P o w der f or C o nce ntrate f or S ol u ti o n f or I nf usi o n (freeze-dr ie d f or m ulati o n) is 
pac ka ge d i n U nite d States P har mac o peia ( U S P) a n d E ur o pea n P har mac o peia ( P h E ur) t y pe I gl ass 
vial s.  Eac h vial is fille d wit h 4 5 m g of M S B 0 0 1 1 3 5 9 C
( 4 5 m g/ vial) as preser vati ve -free p o w der 
c o ntai ni n g histi di ne, tre hal ose di h y drate, s o di u m c hl ori de, L -met hi o ni ne a n d p ol ys or bate 2 0 
( T wee n 2 0). T he vials are cl ose d wit h a r u b ber st o p per i n l yo p hilizati o n f or mat c o m pl yi n g wit h 
U S P a n d P h E ur a n d seale d wit h a n al u mi n u m plastic cri m pi n g ca p. O nl y e x ci pie nts t hat c o nf or m 
t o t he c urre nt U S P a n d / or P h E ur are use d f or M S B 0 0 1 1 3 5 9 C
dr u g pr o d uct.
T he C o nce ntrate f or S ol uti o n f or I nf usi o n (li q ui d f or m ulati o n) is pac ka ge d at a 1 0 m g / m L 
c o nce ntrati o n i n U S P / Ph E ur t y pe I 5 0 R vials t hat are fille d wit h dr u g pr o d uct s ol uti o n t o all o w 
a n e xtracta ble v ol u me of 6 0 m L ( 6 0 0 m g/ 6 0 m L).  T he vials are cl ose d wit h r u b ber st o p pers wit h 
t he sa me c o m p ositi o n as use d f or freeze-drie d f or m ulati o n, b ut i n ser u m f or mat c o m pl yi n g wit h 
U S P a n d P h E ur wit h a n al u mi n u m cri m p seal cl os ure.  
T he li q ui d f or m ulati o n, c o m pare d wit h t he freeze -drie d f or m ulati o n, has t he sa me c o m p ositi o n i n 
ter ms of e xci pie nts, q ualitati vel y  an d q ua ntitati vel y , e xce pt f or t he a d diti o n of water.  Of n ote,
t here is n o c ha n ge t o t he dr u g s u bsta nce pr ocess.
F or a p plicati o ns i n cli nical st u dies, t he freeze-drie d f or m ulati o n m ust be rec o nstit ute d wit h 4. 5 m L  
water f or i njecti o n a n d f urt her dil ute d wit h 0. 9 % sali ne s ol uti o n (s o di u m c hl ori de i njecti o n) 
s u p plie d i n a n i nf usi o n ba g.  The li q ui d f or m ulati o n is dil ute d dire ctl y wit h 0. 9 % sali ne s ol uti o n.  
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 9 3
T he esti mate d v ol u mes of deli ver y  are a ntici pate d t o be n o m ore t ha n 2 5 0 m L, w hic h are cli nicall y 
acce pta ble.  F or s u bjects re q uiri n g d oses t hat w o ul d e xcee d t he ma x i m u m all o wa ble c o nce ntrati o n 
i n 2 5 0 m L (e g, s u bjects i n t he 3 0 m g/ k g c o h ort), M S B 0 0 1 1 3 5 9 C ma y  be dil ute d i n 0. 9 % s o di u m 
c hl ori de t o a t otal v ol u me of 5 0 0 m L  pr o vi de d t he fi nal c o nce ntrati o n ra n ge is 0. 1 6 m g / m L t o 
9. 6 m g/ m L .  Detaile d i nf or mati o n o n i nf usi on pre parati o n a n d a d mi nistrati o n are pr o vi de d i n t he 
pr ot oc ol a n d ma n ual of pre parati o n. 
S u bjects w h o recei ve d t he freeze-drie d f or m ulati o n bef ore t he i ntr o d ucti o n of t he li q ui d 
f or m ulati o n will re mai n o n t he freeze-drie d f or m ulati o n .
6. 2
D os a ge a n d A d mi nistr ati o n
S u bjects will recei ve I V i nf usi o n of M S B 0 0 1 1 3 5 9 C o ver 1 h o ur ( -1 0 mi n utes / + 2 0 mi n utes, t hat 
is, o ver 5 0 t o 8 0 mi n utes) o nce e ver y 2 wee ks as detaile d i n t he Sc he d ules of Assess me nts (see 
Ta ble 1 a n d Ta ble 2 ).  S u bjects e nr olle d i n t he 3 0 m g/ k g a n d t he 2 4 0 0 m g  flat-d ose c o h orts w h o 
re q uire a dr u g v ol u me of 5 0 0 m L  m a y  ha ve a t otal i nf usi o n ti me of u p t o 1 2 0 mi n utes i n t he a bse nce 
of a n y hist or y  of i nf usi o n reacti o n.  M o dificati o ns of t he i nf usi o n rate d ue t o i nf usi o n-relate d 
reacti o ns are descri be d i n Secti o n  6. 5. 4. I n or der t o miti gate p ote ntial i nf usi o n-relate d reacti o ns, 
p re me dicati o n wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 
2 5- 5 0 m g di p he n h y dra mi ne a n d 5 0 0 -6 5 0 m g paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt)
a p pr o xi matel y 30 t o 6 0 mi n utes pri or t o eac h d ose of M S B 0 0 1 1 3 5 9 C is ma n dat or y  f or t he first 
2 i nf usi o ns a n d is o pti o nal a n d at t he discreti o n of t he I n vesti gat or after t he sec o n d i nf usi o n
( pre me dicati o n is o pti o nal f or all i nf usi o ns f or s u bjects i n t he N S C L C bi o mar ker c o h ort bei n g 
treate d at t he U S N CI ).  If Gra de ≥ 2 i nf usi o n reacti o ns are see n d uri n g t he first t w o i nf usi o ns 
pre me dicati o n s h o ul d n ot be st o p pe d.  Ster oi ds as pre me dicati o n are n ot per mitte d.
S pecial 
preca uti o ns f or m o nit ori n g 
of s u bjects
a n d ma na ge me nt 
of i nf usi o n-relate d reacti o ns /
h y perse nsiti vit y  incl u di n g m o dificati o ns of t he i nf usi o n rate a n d st o p pi n g of trial dr u g are 
descri be d i n Secti o n  6. 5. 4 a n d s u bsecti o ns.
T he starti n g d ose of M S B 0 0 1 1 3 5 9 C i n t he d ose -escalati o n p orti o n is 1 m g/ k g ( d ose-escalati o n 
acc or di n g t o 3 + 3 desi g n u p t o 3 0 m g/ k g is i nte n de d) a n d t he treat me nt c ycle will be 2 wee ks 
( 1 4 d a y s).  T he first s u bject of each c o h ort will be o bser ve d f or at least 5 da y s bef ore t he sec o n d 
s u bject ca n be treate d.  S u bse q ue nt s u bjects ma y  recei ve first d osi n g at n o less t ha n 4 8- h o ur 
i nter vals bet wee n s u bjects.  T he d ose of M S B 0 0 1 1 3 5 9 C i n t he e x pa nsi o n will be deter mi ne d fr o m 
t he d ose -escalati o n p orti o n of t he trial. 
F or t he d ose -escalati o n c o h orts (e xce pt f or t he 2 4 0 0 m g 
flat-d ose c o h ort) , the d ose of 
M S B 0 0 1 1 3 5 9 C will be calc ula te d base d o n t he wei g ht of t he s u bject deter mi ne d o n t he da y pri or 
t o or t he da y  of eac h dr u g a d mi nistrati o n. S u bjects will recei ve M S B 0 0 1 1 3 5 9 C o nce e ver y 
2 wee ks u ntil c o nfir me d pr o gressi o n, u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m 
t he trial or I MP occ urs (see Secti o n  5. 5).  S u bjects w h o ha ve e x perie nce d S D, P R , or C R s h o ul d 
c o nti n ue treat me nt t hr o u g h t he e n d of 1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble . If t he 
In vesti gat or belie ves t hat a s u bject m a y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be 
per miss i ble after disc ussi o n wit h t he Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 9 3
F oll o wi n g safety a n d P K a nal ysis of t he Escalati o n c o h orts, a flat d ose of 1 2 0 0 m g/i nf usi o n was 
c h ose n f or all e x pa nsi o n c o h orts, e xce pt f or t he N S C L C sec o n d -li ne c o h ort, i n w hic h 4 0 s u bjects 
will recei ve 5 0 0 m g/i nf usi o n a n d 4 0 s u bjects will recei ve 1 2 0 0 m g/i nf usi o n.
F or s u bjects w h o ac hie ve S D, a P R or C R o n M S B 0 0 1 1 3 5 9 C t hera py a n d t he n s u bse q ue ntly 
de vel o p disease pr o gressi o n after st o p pi n g t hera p y , b ut pri or t o t he e n d of t he trial, 1 re-i nitiati o n 
c o urse of treat me nt at t he sa me d ose a n d sc he d ule a n d treat me nt d urati o n u p t o 1 2 m o nt hs is 
all o we d at t he discreti o n of t he I n vesti gat or a n d a gree me nt of t he trial Me dical Res p o nsi ble
(see 
Secti o n 5. 1. 6 ). T he I n vesti gat or will nee d t o c o nfir m t hat t he be nefit of re-i nitiati n g treat me nt 
o ut wei g hs a n y r is k i n v ol ve d, s uc h as t hat w hic h le d t o i nitial treat me nt disc o nti n uati o n. M ore o ver, 
f or su b jects i n w hic h B O R was S D, t he In vesti gat or s h o ul d c o nfir m n o ot her reas o na ble treat me nt 
o pti o ns are a vaila ble.  S u bjects re-i nitiati n g treat me nt s h o ul d be assesse d acc or di n g t o t he 
Sc he d ules of Assess me nt f or t he E x pa nsi o n p orti o n of t he trial starti n g at Wee k 1, Da y  1 (see Ta ble 
2) .
6. 3
Assi g n me nt t o Tre at me nt Gr o u ps
T he In vesti gat or or dele gate will assi g n a u ni q ue s u bject i de ntifier n u m ber t o eli gi ble s u bjects i n 
c hr o n ol o gical or der at t he ti me of i nf or me d c o nse nt si g nat ure. 
S u bject i de ntifiers will b e 
c o m prised of di gits re prese nti n g t he trial n u m ber, t he site n u m ber, an d t he s u bject n u m ber, w hic h 
is all ocate d se q ue ntially.
S u bject e nr oll me nt will be ma na ge d ma n uall y d uri n g t he escalati o n 
p hase a n d f or t he N S C L C bi o mar ker c o h ort.  Enr ol lme nt f or ot her e x pa nsi o n c o h orts will utilize 
a n i nteracti ve we b res p o nse s yste m (I WR S ).
N S C L C sec o n d -li ne c o h ort
O nce t he s u bject has pr o vi de d a si g ne d I nf or me d C o nse nt F or m (I C F) a n d meets all i ncl usi o n a n d 
n o e xcl usi o n criteria, t he I n vesti gat or or dele gate will re q uest t he d ose gr o u p assi g n me nt usi n g t he 
I W R S.  
Qualifie d s u bjects will
be ra n d o mize d i n a 1: 1 rati o t o recei ve eit her 5 0 0 or 
1 2 0 0 m g/i nf usi o n of M S B 0 0 1 1 3 5 9 C .  T he c o h ort is f ull y co ntr olle d b y  t he I WR S, w hic h assi g ns 
treat me nt i n di vi d ual ( u ni q ue) vial n u m bers f or eac h s u bject.  The vial n u m ber is li n ke d via t he 
G o o d Ma n ufact uri n g Practice q ualifie d s yste m t o t he c orres p o n di n g treat me nt as well as t o t he 
s u bject.  All ocati o n of s u bjects will n ot be stratifie d.
6. 4
N o ni n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
I n or der t o miti gate p ote ntial i nf usi o n-relate d reacti o ns, pre me dicati o n wit h a n a nti hista mi ne a n d 
wit h paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 2 5- 5 0 m g
di p he n h y dra mi ne a n d 5 0 0- 6 5 0 m g 
paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt) a p pr o xi matel y 3 0 t o 6 0 mi n utes pri or t o eac h 
d ose of M S B 0 0 1 1 3 5 9 C is ma n dat or y
f or t he first 2 i nf usi o ns a n d is o pti o nal a n d at t he discreti o n 
of t he I n vesti gat or after t he sec o n d i nf usi o n ( pre me dicati o n is o pti o nal f or all i nf usi o ns f or s u bjects 
i n t he N S C L C bi o mar ker c o h ort bei n g treate d at t he U S N CI ). If Gra de ≥ 2 i nf usi o n reacti o ns are 
see n d uri n g t he first t w o i nf usi o ns pre me dicati o n s h o ul d n ot be st o p pe d.  T his re gi me n m a y  be 
m o difie d 
base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate.
Ster oi ds as 
pre me dicati o n are n ot per mitte d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 9 3
As wi t h all m o n ocl o nal 
a nti b o d y thera pies, t here is a ris k of aller gic reacti o n i ncl u di n g 
a na p h yl actic s h oc k. M S B 0 0 1 1 3 5 9 C
s h o ul d be a d mi nistere d i n a setti n g t hat all o ws f or i m me diate 
access t o a n i nte nsi ve care u nit or e q ui vale nt e n vir o n me nt a n d a d mi nistrati o n of t hera p y for 
a na p h yl a xis, s uc h as t he a bilit y to i m ple me nt i m me diate res uscitati o n meas ures.
Ster oi ds 
( de xa met has o ne 1 0 m g ), e pi ne p hri ne ( 1: 1, 0 0 0 dil uti o n), aller g y me dicati o ns (I V a nti hista mi nes), 
br o nc h o dilat ors, or e q ui vale nts , a n d o x y ge n s h o ul d be a vaila ble f or i m me diate access. I nf usi o n of 
M S B 0 0 1 1 3 5 9 C
will be st o p pe d i n case of Gra de ≥2 i nf usi o n-relate d, aller gic, or a na p h yl actic 
reacti o ns.  F oll o wi n g M S B 0 0 1 1 3 5 9 C i nf usi o ns, s u bjects m ust be o bser ve d f or a mi ni m u m of 
2 h o urs p ost e n d of i nf usi o n f or p ote ntial i nf usi o n-relate d reacti o ns, e xce pt n ote t hat d uri n g t he 
first 2 d oses i n t he escalati o n p hase t here will be a mi ni m u m 2 4- h o ur i npatie nt o bser vati o n .  Please 
see t he g ui deli nes f or ha n dli n g of i nf usi o n-relate d reacti o n i n Secti o n 6. 5. 4. 1 .
If a n aller gic reacti o n occ urs, t he s u bject m ust be treate d acc or di n g t o t he b est a vaila ble me dical 
practice.  G ui deli nes f or ma na ge me nt of i nf usi o n-relate d reacti o ns a n d se vere h y perse nsiti vit y 
reacti o n acc or di n g t o t he N CI are f o u n d i n Secti o n  6. 5. 4.
F urt her preca uti o ns are pr o vi de d i n Secti o n 6. 5. 4.  F or pr o p h yl a xis of fl u-li ke s ym pt o ms , a 
n o n- ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D) f or e xa m ple, i b u pr ofe n 4 0 0 m g
or c o m para ble 
N S AI D d ose, m a y  be a d mi nistere d 2 h o urs bef ore a n d 8 h o urs after t he start of eac h d ose of 
M S B 0 0 1 1 3 5 9 C
I V i nf usi o n.
6. 5
C o nc o mit a nt Me dic ati o ns a n d T her a pies
All c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si gnat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he eC R F, n oti n g t he na me, d ose, 
d urati o n a n d i n dicati o n of eac h dr u g.   N o n dr u g i nter ve nti o ns ( ot her t ha n vita mi ns) a n d a n y c ha n ges 
t o a c o nc o mita nt me dicati o n or ot her i nter ve nti on s h o ul d als o be rec or de d i n t he e C R F.
6. 5. 1
Per mitte d Me dici nes
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y  the cli nical trial pr ot oc ol) t hat are c o nsi dere d 
necessar y  to pr otect s u bject welfare a n d will n ot i nterfere wit h t he trial me dicati o n ma y  b e gi ve n 
at t he I n vesti gat or’s discreti o n.
Ot her dr u gs t o be use d f or pr o p h yl a xis, treat me nt of a na p h ylactic reacti o ns, i nf usi o n-relate d 
reacti o ns, a n d se vere h y perse nsiti vit y  reacti o ns / fl u-li ke s ym pt o ms a n d ir A Es are descri be d i n
Secti o ns  5. 1. 7. 2, 6. 4, a n d 6. 5. 4.
Palliati ve ra di ot hera py deli vere d i n a n or mal or ga n -s pari n g tec h ni q ue m a y  be a d mi nistere d d uri n g 
t he trial. T he assess me nt of P D will n ot be base d o n t he necessit y f or palliati ve ra di ot hera p y. 
6. 5. 2
Pr o hi bite d Me dici nes
As state d f or t he e xcl usi o n criteria i n Secti o n 5. 3. 2 , s u bjects m ust n ot ha ve ha d c he m ot hera p y, 
ra di ot hera py ( ot her t ha n palliati ve ra di ot hera py deli vere d i n a n or mal or ga n -s pari n g tec h ni q ue as 
descri be d i n Secti o n  6. 5. 1), maj or s ur ger y, or recei ve d a n ot her i n vesti gati o nal a ge nt wit hi n 2 8 da y s 
bef ore t he start of trial treat me nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 9 3
T he f oll o wi n g tre at me nts m ust n ot be a d mi nistere d d uri n g t he tri al:

I m m u n ot hera p y i ncl u di n g i nterfer o n, i m m u n os u p pressi ve dr u gs (f or e xa m ple, c he m ot hera p y or 
s yste mic c ortic oster oi ds e xce pt f or s h ort ter m treat me nt of aller gic reacti o ns, e n d ocri ne 
re place me nt t hera py at l o w -d ose pre d n is o ne [≤ 1 0 m g dail y] or e q ui vale nt , or f or t he treat me nt 
of ir A Es or ot her a p pr o priate s h ort-ter m ster oi d use ), or ot her e x peri me ntal p har mace utical 
pr o d ucts. S h ort ter m a d mi nistrati o n of s yste mic ster oi d or ot her i m m u n os u p pressa nt s uc h as 
i nfli xi ma b or m y c o p he n olate (t hat is, f or aller gic reacti o ns or t he ma na ge me nt of ir A Es) is 
all o we d. 
Ster oi ds wit h n o or mi ni mal s yste mic effect (t o pical, i n halati o n) are all o we d.   
N ote: f or s u bjects wit h gli o blast o ma, ster oi d use is all o we d.

A def o vir .

Pr o p h y lactic use of cortic oster oi ds f or i nf usi o n -relate d reacti o ns is pr o hi bite d.

A n y  li ve vacci ne t hera pies f or t he pre ve nti o n of i nfecti o us disease .  Ad mi nistrati o n of 
i nacti vate d vacci nes is all o we d (f or e xa m ple, i nacti vate d i nfl ue nza vacci nes).

Bl o o d tra nsf usi o ns a n d er yt hr oi d gr o wt h fact ors are n ot all o we d d uri n g t he 2 1- d a y  DL T wi n d o w 
d uri n g t he escalati o n p hase.
If t he a d mi nistrati o n of a n o n-per mitte d c o nc o mita nt dr u g bec o mes necessar y  d uri n g t he trial, t he 
s u bject will be wit h dra w n fr o m trial treat me nt ( the Me dical M o nit or
m a y be c o ntacte d t o disc uss 
w het her t he I M P m ust be disc o nti n ue d ).
Me dicati o ns ot her
t ha n t h ose s pecificall y e xcl u de d i n t his trial (as o utli ne d i n t his secti o n ) ma y be 
a d mi nistere d f or t he ma na ge me nt 
of s ym pt o ms 
ass ociate d wit h 
t he a d mi nistrati o n of 
M S B 0 0 1 1 3 5 9 C as re q uire d. 
T hese
mi g ht 
i ncl u de a nal gesics, a nti-e metics, a nti hista mi nes, 
di uretics, a nti-a n xiet y me dicati o ns, a n d me dicati o n f or pai n ma na ge me nt, i ncl u di n g narc otic 
a ge nts.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he trial a n d a n y cha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n , a n d i n dicati o n of eac h dr u g.
6. 5. 3
Ot her I nter ve nti o ns
T he f oll o wi n g n o n- dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he trial (a n d wit hi n 2 8 d a y s 
bef ore t he start of trial treat me nt):

Maj or s ur ger y  (e xcl u di n g pri or dia g n ostic bi o ps y)

Her bal re me dies wit h i m m u n osti m ulati n g pr o perties ( f or e xa m ple, mistlet oe e xtract) or k n o w n 
t o p ote ntiall y i nterfere wit h maj or or ga n f u ncti o n (f or e xa m ple, h yperici n)

S u bjects s h o ul d n ot a b use alc o h ol or ot her dr u gs d uri n g t he trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 9 3
6. 5. 4
S peci al Prec a uti o ns
F or s u bjects e nr olle d i n t his st u d y pri or t o t he declarati o n of t he M T D or t he d ose t o be use d i n t he 
e x pa nsi o n p hase of t he st u d y (i n t he case M T D 
is n ot reac he d), i n-h o use o bser vati o n i n a 
h os pitalize d setti n g f or at least 2 4 h o urs will occ ur f or t he first 2 d oses a d mi nistere d t o eac h s u bject
(Ta ble 5 ).  To facilitate P K a n d bi o mar ker sa m pli n g, s u bjects m a y  re mai n i n-h o use t hro u g h a n 
a d diti o nal 2 4 h o urs if necessar y .  A n urse, n urse practiti o ner / p h y sicia n’s assista nt, or p h y sicia n 
will c o m m u nicate wit h t he first s u bject of eac h c o h ort after t he first treat me nt t o assess f or a n y 
si de effects o n or after Da y 5 b ut bef ore e nr olli n g a s u bse q ue nt s u bject.  C o h orts at a d ose t hat ha s
bee n cleare d b y  t he S M C will re q uire a mi ni m u m of 4 8 h o urs bet wee n t he first d ose a d mi nistrati o n 
i n t he first s u bject a n d first d ose i n s u bse q ue nt s u bjects.
O nce t he M T D / d ose t o be use d i n t he e x pa nsi o n p hase of t he st u d y has bee n declare d t here is n o 
waiti n g peri o d bet wee n d osi n g of s u bjects.
T a ble 5
W ait 
Peri o ds B et wee n D osi n g of S u bjects W it hi n a D ose / E x p a nsi o n 
C o h ort
Bef ore M T D/ P h ase II
D ose Decl ar ati o n / 
Bef ore D ose Cle ar a nce
Bef ore M T D/ P h ase II
D ose Decl ar ati o n / 
After D ose Cle ar a nce a
After M T D/ P h ase II 
D ose Decl ar ati o n
I n-h o use ( h os pitalizati o n) o bser vati o n
2 4 h o urs
N o ne
N o ne
Wait peri o d bet w ee n first s u bject first 
d ose a n d s u bse q ue nt s u bjects i n a 
c o h ort
5 da ys
4 8 h o urs
N o ne
H C C = he pat ocell ular carci n o ma; M T D = ma xi m u m -t olerate d d ose; S M C = Safet y M o nit ori n g C o m mittee.
a  Su bjects i n t he H C C asce n di n g-d ose c o h ort ma y be gi n e nr olli n g pri or t o declarati o n of t he M T D / d ose t o be use d i n t he e x pa nsi o n 
p hase of t he st u d y b y t he S M C; h o we ver, t he S M C m ust ha ve cleare d t he starti n g d ose f or t he H C C c o h ort as safe i n t he d ose -
escalati o n p hase of t he st u d y.
As a r o uti ne preca uti o n, s u bjects all e nr olle d i n t his trial (t hat is, b ot h t he d ose -escalati o n a n d t he 
e x pa nsi o n c o h orts) m ust be o bser ve d f or 2 h o urs p ost e n d of i nf usi o n, i n a n area wit h res uscitati o n 
e q ui p me nt a n d e mer ge nc y age nts. 
At all ti mes d uri n g M S B 0 0 1 1 3 5 9 C treat me nt, i m me diate 
e mer ge nc y treat me nt of a n i nf usi o n-relate d reacti o n or a se vere h y perse nsiti vit y reacti o n acc or di n g 
t o i nstit utio nal sta n dar ds m ust be ass ure d.  I n or der t o treat p ossi ble a na p h ylactic reacti o ns, f or 
i nsta nce, de xa met has o ne 1 0 m g a n d e pi ne p hri ne i n a 1: 1 0 0 0 dil uti o n or e q ui vale nts s h o ul d al wa ys 
be a vaila ble al o n g wit h e q ui p me nt f or assiste d ve ntilati o n. 
I nf usi o n of M S B 0 0 1 1 3 5 9 C will be st o p pe d i n case of Gra de ≥ 2 h y perse nsiti vit y , i nfla m mat or y 
res p o nse, or a na p hyl actic reacti o n.   T he treat me nt rec o m me n dati o ns f or i nf usi o n-relate d reacti o ns 
a n d severe h y perse nsiti vit y  reacti o ns acc or di n g t o t he N CI are o utli ne d i n Secti o ns 6. 5. 4. 1 a n d
6. 5. 4. 2 , res pecti vely.
I n vesti gat ors s h o ul d als o m o nit or s u bjects cl osel y for p ote ntial ir A Es, w hic h ma y  bec o me ma nifest 
after se veral wee ks of treat me nt. S uc h e ve nts ma y  c o nsist of persiste nt ras h, diarr hea a n d c olitis, 
a ut oi m m u ne he patitis, art hritis, gl o mer ul o ne p hr itis, car di o m yo pat h y, or u veitis a n d ot her 
i nfla m mat or y e ye c o n diti o ns.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 9 3
6. 5. 4. 1
I nf usi o n-rel ate d Re acti o n s
I nf usi o n-relate d reacti o ns, i ncl u di n g h yperse nsiti vit y , are defi ne d i n t his secti o n. 
A.
S y m pt o ms:

Fe ver

C hills

Ri g ors

Dia p h oresis

Hea dac he
B.
Ma na ge me nt
(see Ta ble 6)
T a ble 6
Tre at me nt M o dific ati o n f or S y m pt o ms of I nf usi o n-rel ate d Re acti o ns 
C a use d b y M S B 0 0 1 1 3 5 9 C
N CI -C T C A E Gr a de 
Tre at me nt M o dific ati o n f or M S B 0 0 1 1 3 5 9 C
Gr a de 1 – mi l d
Mil d tra nsie nt reacti 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 dicate d.
Decrease t he M S B 0 0 1 1 3 5 9 C
i nf usi o n rate b y 5 0 % a n d 
m o nit or cl osel y f or a n y w orse ni n g.
T he t otal i nf usi o n ti me f or M S B 0 0 1 1 3 5 9 C
s h o ul d n ot 
e xcee d 1 2 0 mi n utes
Gr a de 2 – m o der ate
T hera p y or i nf usi o n i nterr u pti o n i n dicate d b ut res p o n ds 
pr o m ptl y t o s y m pt o matic treat me nt (f or e xa m ple, 
a nti hista mi nes, N S AI Ds, narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns i n dicate d f or 2 4 h o urs .
St o p M S B 0 0 1 1 3 5 9 C
i nf usi o n.
Res u me i nf usi o n at 5 0 % of pre vi o us rate o nce i nf usi o n-
relate d reacti o n has res ol ve d or decrease d t o at least 
Gra de 1 i n se verit y, a n d m o nit or cl osel y f or a n y 
w orse ni n g
Gr a de 3 or Gr a de 4 – se vere or life-t hre ate ni n g
Gra de 3: Pr ol o n ge d (f or e xa m ple, n ot ra pi dl y res p o nsi ve 
t o s y m pt o matic me dicati 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 nitial 
i m pr o ve me nt; h os pitalizati o n i n dicate d f or cli nical 
se q uelae.
Gr a de 4: Life-t hreate ni n g c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d.
St o p t he M S B 0 0 1 1 3 5 9 C
i nf usi o n i m me diatel y a n d 
disc o n nect i nf usi o n t u bi n g fr o m t he s u bject.
S u bjects ha ve t o be wit h dra w n i m me diatel y fr o m 
M S B 0 0 1 1 3 5 9 C
treat me nt a n d m ust n ot recei ve a n y 
furt her M S B 0 0 1 1 3 5 9 C
treat me nt
I V = i ntra ve n o us; N CI -C T C A E = Nati o nal Ca ncer I nstit ute -C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nt; 
N S AI Ds = n o nster oi dal a nti -i nfla m mat or y dr u gs.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 9 3
A d diti o n al M o dific ati o ns f or S u bjects W it h Gr a de 2 I nf usi o n-rel ate d Re acti o ns
If, i n t he e ve nt of a Gra de 2 i nf usi o n-relate d reacti o n t hat d oes n ot i m pr o ve or w orse ns after 
i m ple me ntati o n of t he m o dificati o ns i n dicate d i n Ta ble 6 (i nclu di n g re d uci n g t he i nf usi o n rate b y 
5 0 %), t he I n vesti gat or ma y  co nsi der treat me nt wit h c ortic oster oi ds a n d t he i nf usi o n of I M P s h o ul d 
be st o p pe d f or t hat d a y . At t he ne xt i nf usi o n, t he I nvesti gat or m a y
c o nsi der t he a d diti o n of 
H 2 -bl oc ker a nti hista mi nes (f or e xa m ple, fa m oti di ne or ra niti di ne), i n a d diti o n t o pre me dicati o n,
f or select s u bjects. H o we ver, p r o p h ylactic ster oi ds are N O T per mitte d. If t he s u bject has a sec o n d 
i nf usi o n-relate d reacti o n Gra de ≥ 2 o n t he sl o wer i nf usi o n rate, wit h or wit h o ut t he a d diti o n of 
f urt her me dicati o n t o pre me dicati o n , t he i nf usi o n s h o ul d be st o p pe d a n d t he s u bject re m o ve d fr o m 
M S B 0 0 1 1 3 5 9 C
treat me nt.
6. 5. 4. 2 
Se vere H y perse nsiti vit y R e acti o ns a n d Fl u-li ke S y m pt o ms
If a h y perse nsiti vit y  reacti o n occ urs, t he s u bject m ust be treate d acc or di n g t o t he best a vaila ble
me dical practice. A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h ylactic reacti o ns 
acc or di n g t o t he W or ki n g Gr o u p of t he Res uscitati o n C o u ncil ( U nite d Ki n g d o m) a n d ca n be f o u n d
at htt ps:// w w w.res us. or g. u k/ pa ges/rea cti o n. p df. 
S u bjects s h o ul d be i nstr ucte d t o re p ort a n y 
dela y e d reacti o ns t o t he I n vesti gat or i m me diatel y.
A.
S y m pt o ms

I m paire d air wa y

D ecrease d o x y ge n sat urati o n ( < 9 2 %)

C o nf usi o n

L et har g y

H y p ote nsi o n

P ale / cla m m y s ki n

C ya n osis .
B.
Ma na ge me nt
1.
E pi ne p hri ne i njecti o n a n d I V de xa met has o ne
2.
Patie nt s h o ul d be place d o n car diac, bl o o d press ure, heart rate, a n d o x y ge n sat urati o n 
m o nit or i m me diatel y
3.
Alert i nte nsi ve care u nit f or p ossi ble tra nsfer if re q uire d.
F or pr o p h yl a xis of fl u-li ke s ym pt o ms , a N S AI D , f or e xa m ple, i b u pr ofe n 4 0 0 m g or c o m para ble 
N S AI D d ose, m a y  be a d mi nistere d 2 h o urs bef ore a n d 8 h o urs after t he start of eac h d ose of 
M S B 0 0 1 1 3 5 9 C
I V i nf usi o n.
6. 5. 4. 3
I m m u ne-Rel ate d A d verse E ve nts
Si nce i n hi biti o n of P D -L 1 sti m ulates t he i m m u ne s yste m, ir A Es m a y  occ ur.  
Treat me nt of ir A Es is mai nl y  de pe n de nt u p o n se verit y (N CI -C T C A E gra de) :
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 9 3

Gra de 1 t o 2:  treat s y m pt o maticall y  or wit h m o derate d ose ster oi ds, m ore fre q ue nt m o nit ori n g

Gra de 1 t o 2 ( p ersiste nt):  ma na ge si milar t o hi g h gra de A E ( Gr a de 3 t o 4)

G ra de 3 t o 4:  treat wit h hi g h- d ose c ortic oster oi ds.
Treat me nt of ir A Es s h o ul d f oll o w g ui deli nes set f ort h i n  Ta ble 7.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 9 3
T a ble 7
M a n a ge me nt of I m m u ne-Rel ate d A d verse E ve nts
G astr oi ntesti n al ir A Es
Se verit y of D i arr he a / C olitis
( N CI-C T C A E v 4. 0 3)
M a n a ge me nt
F oll o w -u p
Gr a de 1
Diarr hea: < 4 st o ols/ da y o ver Baseli ne
C olitis: as y m pt o matic 
C o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y
S y m pt o matic treat me nt ( f or 
e xa m ple, l o pera mi de)
Cl ose m o nit ori n g f or w orse ni n g s y m pt o ms
E d ucate s u bject t o re p ort w orse ni n g i m me diatel y
If w orse ns:
Treat as Gra de 2 or 3/ 4 
Gr a de 2
Diarr hea : 4 t o 6 st o ols per da y o ver 
Baseli ne ; I V fl ui ds i n dicate d < 2 4 h o urs ; 
n ot i nterferi n g wit h A D L
C olitis: a b d o mi nal pai n; bl o o d i n st o ol 
Dela y M S B 0 0 1 1 3 5 9 C
t hera p y
S y m pt o matic treat me nt
If i m pr o ves t o Gra de 1: 
Res u me M S B 0 0 1 1 3 5 9 C
t hera p y
If persists > 5 t o 7 da ys or rec ur:
0. 5 t o 1 m g/ k g/ da y met h yl pre d nis ol o ne or 
e q ui vale nt 
W he n s y m pt o ms i m p r o ve t o Gra de 1, ta per 
ster oi ds o ver at least 1 m o nt h, c o nsi der 
pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns, a n d res u me M S B 0 0 1 1 3 5 9 C
t hera p y per 
pr ot oc ol.
If w orse ns or persists > 3 t o 5 da ys wit h oral 
ster oi ds:
Treat as Gra d e 3 t o 4
Gr a de 3 t o 4
Diarr hea ( G ra de 3): ≥7 st o ols per da y 
o ver Baseli ne ; i nc o nti ne nce; I V fl ui ds 
≥2 4 h o urs ; i nterferi n g wit h A D L
C olitis ( G ra de 3):  se vere a b d o mi nal 
pai n, me dical i nter ve nti o n i n dicate d, 
perit o neal si g ns
G ra de 4: life -t hreate ni n g, perf orati o n
Disc o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y per pr ot oc ol
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or 
e q ui vale nt
A d d pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns 
C o nsi der l o wer e n d osc o p y
If i m pr o ves: 
C o nti n ue ster oi ds u ntil Gra de 1, t he n ta per o ver at 
least 1 m o nt h
If persists > 3 t o 5 da ys, or rec ur s after 
i m pr o ve me nt:
A d d i nfli xi ma b 5 m g/ k g ( if n o c o ntrai n dicati o n), 
N ote: I nfli xi ma b s h o ul d n ot be use d i n cases of 
perf orati o n or se psis 
Per ma ne ntl y disc o nti n ue I M P
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 9 3
Der m at ol o gic al ir A Es
Gr a de of R as h
( N CI-C T C A E v 4. 0 3)
M a n a ge me nt
F oll o w -u p
Gr a de 1 t o 2 
C o veri n g ≤ 3 0 % b o d y s urface area 
S y m pt o matic t hera p y ( f or 
e xa m ple, a nti hista mi nes, t o pical 
ster oi ds) 
C o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y
If persists > 1 t o 2 wee ks or rec urs: 
C o nsi der s ki n bi o ps y 
C o nsi der dela yi n g M S B 0 0 1 1 3 5 9 C t hera p y
C o nsi der 0. 5 t o 1 m g/ k g/ da y met h yl pre d nis ol o ne 
I V or oral e q ui vale nt. O nce i m pr o vi n g, ta per 
ster oi ds o ver at least 1 m o nt h, c o nsi der 
pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns, a n d res u me M S B 0 0 1 1 3 5 9 C
t hera p y
If w orse ns: 
Tre at as Gra de 3 t o 4 
Gr a de 3 t o 4
C o veri n g > 3 0 % b o d y s urface area ; 
life-t hreate ni n g c o nse q ue nces 
Dela y or disc o nti n ue 
M S B 0 0 1 1 3 5 9 C t hera p y
C o nsi der s ki n bi o ps y 
Der mat ol o g y c o ns ult 
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or I V 
e q ui vale nt 
If i m pr o ves t o Gra de 1: 
Ta per ster oi ds o ver at least 1 m o nt h a n d a d d 
pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns 
Res u me M S B 0 0 1 1 3 5 9 C
t hera p y (e xce pt i n cases 
of T o xic E pi der mal Necr ol ysis or 
Ste ve ns -J o h ns o n S y n dr o me)
P ul m o n ar y ir A Es
Gr a de of P ne u m o nitis
( N CI-C T C A E v 4. 0 3)
M a n a ge me nt
F oll o w -u p
Gr a de 1
Ra di o gra p hic c ha n ges o nl y 
C o nsi der dela y of 
M S B 0 0 1 1 3 5 9 C
t hera p y 
M o nit or f or s y m pt o ms e ver y 
2 t o 3 da ys 
C o nsi der P ul m o nar y a n d 
I nfecti o us Disease c o ns ults 
Re -i ma ge at least e ver y 3 wee ks
If w orse ns: 
Treat as Gra de 2 or Gra de 3 t o 4 
Gr a de 2
Mil d t o m o derate ne w s y m pt o ms 
Dela y M S B 0 0 1 1 3 5 9 C
t hera p y
P ul m o nar y a n d I nfecti o us 
Disease c o ns ults
M o nit or s y m pt o ms dail y, 
c o nsi der h os pitalizati o n 
1 m g/ k g/ da y met h yl -
pre d nis ol o ne I V or oral 
e q ui vale nt 
C o nsi der br o nc h osc o p y , l u n g 
bi o ps y 
Re -i ma ge e ver y 1 t o 3 da ys 
If i m pr o ves: 
W he n s y m pt o ms ret ur n t o near Baseli ne , ta per 
ster oi ds o ver at least 1 m o nt h a n d t he n res u me 
M S B 0 0 1 1 3 5 9 C
t hera p y a n d c o nsi der pr o p h ylactic 
a nti bi otics
If n ot i m pr o vi n g after 2 wee ks or w orse ni n g: 
Treat as Gra de 3 t o 4 
Per ma ne ntl y disc o nti n ue I M P
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 9 3
Gr a de of P ne u m o nitis
( N CI-C T C A E v 4. 0 3)
M a n a ge me nt
F oll o w -u p
Gr a de 3 t o 4
Se vere ne w s y m pt o ms; Ne w / w orse ni n g 
h y p o xia; l ife-t hreate ni n g 
Disc o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y
H os pitalize 
P ul m o nar y a n d I nfecti o us 
Disease c o ns ults
2 t o 4 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or I V 
e q ui vale nt 
A d d pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns 
C o nsi der br o nc h osc o p y, l u n g 
bi o ps y 
If i m pr o ves t o Baseli ne: 
Ta per ster oi ds o ver at least 6 wee ks 
If n ot i m pr o vi n g after 4 8 h o urs or w orse ni n g: 
A d d a d diti o nal i m m u n os u p pressi o n ( f or e xa m ple,
i nfli xi ma b, c ycl o p h os p ha mi de, I V
i m m u n o gl o b uli n, or m yc o p he n olate m ofetil) 
Per ma ne ntl y disc o nti n ue I M P
He p atic ir A Es
Gr a de of Li ver Test Ele v ati o n
( N CI-C T C A E v 4. 0 3)
M a n a ge me nt
F oll o w -u p
Gr a de 1
Gra de 1 A S T or A L T > U L N t o 3. 0 x U L N 
a n d / or t otal bilir u bi n > U L N t o 1. 5 x U L N 
C o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y
C o nti n ue li ver f u ncti o n m o nit ori n g 
If w orse ns: 
Treat as Gra de 2 or 3 t o 4 
Gr a de 2
A S T or A L T > 3. 0 t o ≤ 5 x U L N a n d / or 
t otal bilir u bi n > 1. 5 t o ≤ 3 x U L N 
F or s u bjects wit h li ver i n v ol ve me nt at 
B aseli ne ( Baseli ne A S T ≤5. 0 × U L N, 
A L T ≤5. 0 × U L N, a n d bilir u bi n ≤3. 0)
Dela y M S B 0 0 1 1 3 5 9 C 
t hera p y
I ncrease fre q ue nc y of 
m o nit ori n g t o e ver y 3 da ys 
C o nti n ue M S B 0 0 1 1 3 5 9 C 
t hera p y
If ret ur ns t o Baseli ne: 
Res u me r o uti ne m o nit ori n g, res u me 
M S B 0 0 1 1 3 5 9 C t hera p y
If ele vati o ns persist > 5 t o 7 da ys or w orse n: 
0. 5 t o 1 m g/ k g/ da y met h yl pre d nis ol o ne or oral 
e q ui vale nt a n d w he n L F T ret ur ns t o Gra de 1 or 
Baseli ne, ta per ster oi ds o ver at least 1 m o nt h, 
c o nsi der pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns, a n d res u me M S B 0 0 1 1 3 5 9 C t hera p y
C o nti n ue li ver f u ncti o n m o nit ori n g 
If w orse ns: 
Treat as Gra de s 3 t o 4
Gr a de s 3 t o 4
A S T or A L T > 5 x U L N a n d / or t otal 
bilir u bi n > 3 x U L N 
Disc o nti n ue M S B 0 0 1 1 3 5 9 C 
t hera p y 
I ncrease fre q ue nc y of 
m o nit ori n g t o e ver y 1 t o 
2 da ys 
If ret ur ns t o Gra de 2: 
Ta per ster oi ds o ver at least 1 m o nt h 
If d oes n ot i m pr o ve i n > 3 t o 5 da ys, w orse ns or 
re b o u n ds: 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 9 3
F or s u bjects wit h li ver i n v ol ve me nt at 
B aseli ne ( Baseli ne A S T ≤ 5. 0 × U L N, 
A L T ≤ 5. 0 × U L N, a n d bilir u bi n ≤ 3. 0) 
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or I V 
e q ui vale nt
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns 
C o ns ult gastr oe nter ol o gist
C o nsi der o btai ni n g M RI/ C T 
sca n of li ver a n d li ver bi o ps y 
if cli nicall y warra nte d
Dela y M S B 0 0 1 1 3 5 9 C 
t hera p y
I ncrease fre q ue nc y of 
m o nit ori n g t o e ver y 3 da ys
A d d m yc o p he n olate m ofetil 1 gra m ( g) t wice dail y 
If n o res p o nse wit hi n a n a d diti o nal 3 t o 5 da ys, 
c o nsi der ot her i m m u n os u p pressa nts per l ocal 
g ui deli nes 
Per ma ne ntl y disc o nti n ue I M P
If ret ur ns t o Baseli ne: 
Res u me r o uti ne m o nit ori n g, c o nsi der res u mi n g 
M S B 0 0 1 1 3 5 9 C t hera p y
If ele vati o ns persist > 5 t o 7 da ys or w orse n: 
0. 5 t o 1 m g/ k g/ da y met h yl pre d nis ol o ne or oral 
e q ui vale nt a n d w he n L F T ret ur ns t o Gra de 1 or 
Baseli ne, ta per ster oi ds o ver at least 1 m o nt h, 
c o nsi der pr o p h ylactic a nti bi otics f or o p p ort u n istic 
i nfecti o ns, a n d res u me M S B 0 0 1 1 3 5 9 C t hera p y.
If d oes n ot i m pr o ve i n > 3 t o 5 da ys, w orse ns or 
re b o u n ds: 
Disc o nti n ue M S B 0 0 1 1 3 5 9 C t hera p y 
I ncrease fre q ue nc y of m o nit ori n g t o e ver y 1 t o 
2 da ys 
1 t o 2 m g/ k g/ da y met h yl pre d nis ol o ne I V or I V 
e q ui vale nt
A d d pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns 
C o ns ult gastr oe nter ol o gist
C o nsi der o btai ni n g M RI/ C T sca n of li ver a n d li ver 
bi o ps y if cli nicall y warra nte d
If d oes n ot i m pr o ve i n > 3 t o 5 da ys, w orse ns or 
re b o u n ds: 
A d d m yc o p he n olate m ofetil 1 gra m ( g) t wice dail y 
If n o res p o nse wit hi n a n a d diti o nal 3 t o 5 da ys, 
c o nsi der ot her i m m u n os u p pressa nts per l ocal 
g ui deli nes 
Per ma ne ntl y disc o nti n ue I M P
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 9 3
C ar di ac ir A Es
M y oc ar ditis
M a n a ge me nt
F oll o w -u p
Ne w o nset of car diac si g ns or s y m pt o ms 
a n d / or ne w la b orat or y car diac bi o mar ker 
ele vati o ns (e g, tr o p o ni n, creati ne 
ki nase -M B, brai n natri uretic pe pti de) or 
car diac i ma gi n g a b n or malities s u g gesti ve 
of m y ocar ditis
Wit h h ol d M S B 0 0 1 1 3 5 9 C
t hera p y.
H os pitalize. 
I n t he prese nce of 
life-t hreate ni n g car diac 
dec o m pe nsati o n, c o nsi der 
tra nsfer t o a facilit y 
e x perie nce d i n a d va nce d heart 
fail ure a n d arr h yt h mia 
ma na ge me nt.
Car di ol o g y c o ns ult t o 
esta blis h eti ol o g y a n d r ule o ut 
i m m u ne-me diate d 
m y o car ditis.
G ui deli ne base d s u p p orti ve 
treat me nt as per car di ol o g y 
c o ns ult. a
C o nsi der m y ocar dial bi o ps y if 
rec o m me n de d per car di ol o g y 
c o ns ult.
If s y m pt o ms i m pr o ve a n d i m m u ne-me diate d 
eti ol o g y is r ule d o ut, re-start M S B 0 0 1 1 3 5 9 C
t hera p y.
If s y m pt o ms d o n ot i m pr o ve/ w orse n, viral 
m y o car ditis is e xcl u de d, an d i m m u ne -me diate d 
eti ol o g y is s us pecte d or c o nfir me d f oll o wi n g 
car di ol o g y c o ns ult, ma na ge as i m m u ne -me diate d 
m y o car ditis.
I m m u ne-me diate d m y ocar ditis 
Per ma ne ntl y disc o nti n ue 
M S B 0 0 1 1 3 5 9 C .
G ui deli ne base d s u p p orti ve 
treat me nt as a p pr o priate as 
per car di ol o g y c o ns ult. a
Met h yl pre d nis ol o ne 1 t o 
2 m g/ k g/ da y.
O nce i m pr o vi n g, ta per ster oi ds o ver at least 
1 m o nt h a n d a d d pr o p h ylactic a nti bi otics f or 
o p p ort u nistic i nfecti o ns.
If n o i m pr o ve me nt or w orse ni n g, c o nsi der 
a d d iti o nal i m m u n os u p pressa nts (e g, azat hi o pri ne, 
c ycl os p ori ne A).
a L ocal g ui deli nes, or e g, E ur o pea n S ociet y of Car di ol o g y or A merica n Heart Ass ociati o n g ui deli nes
E ur o pea n S ociet y of Car di ol o g y g ui deli nes we bsite: htt ps:// w w w.escar di o. or g/ G ui deli nes/ Cli nical -Practice -G ui deli nes
A merica n Heart Ass ociati o n g ui deli nes we bsite:
htt p:// pr ofessi o nal heart. or g/ pr ofessi o nal/ G ui deli nes State me nts/searc hres ults.js p? q = & y = &t = 1 0 0 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 9 3
E n d ocri ne ir A Es
E n d ocri ne Dis or der
M a n a ge me nt
F oll o w -u p
As y m pt o matic T S H a b n or malit y
C o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y  
If T S H < 0. 5 x L L N , or T S H > 2 x U L N, or c o nsiste ntl y o ut of ra n ge i n 
2 s u bse q ue nt meas ure me nts: i ncl u de T 4 at s u bse q ue nt c ycles as cli nicall y 
i n dicate d; c o nsi der e n d ocri n ol o g y c o ns ult 
S y m pt o matic e n d ocri n o pat h y 
E val uate e n d ocri ne f u ncti o n 
C o nsi der pit uitar y sca n 
S y m pt o matic wit h a b n or mal 
la borat or y / pit uitar y sca n: 
Dela y M S B 0 0 1 1 3 5 9 C
t hera p y
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or b y 
m o ut h e q ui vale nt 
I nitiate a p pr o priate h or m o ne 
t hera p y 
N o a b n or mal la b orat or y /
pit uitar y M RI sca n b ut 
s y m pt o ms persist: 
Re peat la b orat ories i n 1 t o 
3 wee ks / M RI i n 1 m o nt h 
If i m pr o ves ( wit h or wit h o ut h or m o ne 
replace me nt): 
Ta per ster oi ds o ver at least 1 m o nt h a n d c o nsi der 
pr o p h ylactic a nti bi otics f or o p p ort u nistic 
i nfecti o ns 
Res u me M S B 0 0 1 1 3 5 9 C
t hera p y 
S u bjects wit h a dre nal i ns ufficie nc y ma y nee d t o 
c o nti n ue ster oi ds wit h mi neral oc ortic oi d 
c o m p o ne nt 
S us pici o n of a dre nal crisis ( f or e xa m ple,
se vere de h y drati o n, h y p ote nsi o n, s h oc k o ut 
of pr o p orti o n t o c urre nt ill ness )
Dela y or disc o nti n ue M S B 0 0 1 1 3 5 9 C
t hera p y 
R ule o ut se psis 
Stress d ose of I V ster oi ds wit h mi neral oc ortic oi d acti vit y 
I V fl ui ds 
C o ns ult e n d ocri n ol o gist 
If a dre nal crisis r ule d o ut, t he n treat as a b o ve f or s y m pt o matic e n d ocri n o pat h y 
Re n al ir A Es
Re n al Dis or der
M a n a ge me nt
F oll o w -u p
Gra de 1 or Gra de 2
Re peat re nal f u ncti o n 
la b orat or y tests / uri ne 
se di me nt e ver y 2 t o 3 da ys
St o p treat me nt u ntil ret ur n t o 
baseli ne
Re nal d ysf u ncti o n / i m m u ne -relate d 
ne p h ritis
E val uate re nal f u ncti o n 
C o nsi der b i o ps y t o c o nfir m 
n e p hritis a n d i m m u ne-relate d 
i nfla m mat or y pr ocess
If ret ur ns t o Gra de 2: 
Ta per ster oi ds o ver at least 1 m o nt h 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 9 3
Disc o nti n ue s u bject fr o m 
M S B 0 0 1 1 3 5 9 C
t hera p y
1 t o 2 m g/ k g/ da y 
met h yl pre d nis ol o ne I V or I V 
e q ui vale nt
A d d pr o p h ylactic a nti bi otics 
f or o p p ort u nistic i nfecti o ns 
If d oes n ot i m pr o ve i n > 3 t o 5 da ys, w orse ns or 
re b o u n ds: 
A d d m yc o p he n olate m ofetil 1 gra m ( g) t wice dail y
If n o res p o nse wit hi n a n a d diti o nal 3 t o 5 da ys, 
c o nsi der ot her i m m u n os u p pressa nts per l ocal 
g ui deli nes
A D L = acti vities of dail y li vi n g; A L T = ala ni ne a mi n otra nsferase ; A S T = as partate a mi n otra nsferase ; C T = c o m p ute d 
t o m o gra p h y; ir A E = i m m u ne-relate d a d verse e ve nt; I V = i ntra ve n o us; L F T = li ver f u ncti o n test; L L N = l o wer li mit of n or mal;
M RI
= ma g netic res o na nce i ma gi n g ; N CI -C T C A E = Nati o nal Ca ncer I nstit ute -C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nt s; T 4 = free t h yr o xi ne; T S H = t h yr oi d-sti m ulati n g h or m o ne; U L N = u p per li mit of n or mal .
6. 5. 4. 4
T G F β I n hi biti o n M e di ate d S ki n Re acti o ns
S ki n assess me nts are perf or me d at Scree ni n g peri o d a n d e ver y 6 wee ks f or all s u bjects per 
Sc he d ule of Acti vities (see Ta ble 1 Err or! Refere nce s o urce n ot f o u n d. ). 
S ki n A Es, p ossi bl y  due t o T G F β i n hi biti o n, i ncl u di n g h y per kerat osis, K A, a n d/ or c S C C, are A E SI s 
a n d i m p orta nt i de ntifie d ris ks f or M S B 0 0 1 1 3 5 9 C . T he distri b uti o n of lesi o ns te n ds t o be i n 
s u n-e x p ose d areas.
Ma na ge me nt g ui deli nes f or p ote ntial T G F β i n hi biti o n me diate d s ki n reacti o ns are:
1.
Disc o nti n uati o n or i nterr u pti o n is n ot re q uire d i n m ost cases. C o nti n uati o n of treat me nt s h o ul d 
be e val uate d b y t he I n vesti gat or. 
2.
E m ollie nts ma y  c o nti n ue to be use d.
3.
Dia g n ostic a n d treat me nt pla n s h o ul d be de vel o pe d i n c olla b orati o n bet wee n I n vesti gat or a n d 
der mat ol o gist.
I n ge neral, treat me nt of T G F β me diate d s ki n lesi o ns s uc h as h y per kerat osis, 
K A a n d c S C C s h o ul d be base d o n l ocal g ui deli nes/ S o C.
Lesi o n e val uati o n s h o ul d i ncl u de 
e xcisi o n bi o ps y of o ne re prese ntati ve lesi o n t o c o nfir m dia g n osis.
4.
Treat me nt a n d F oll o w -u p f or K A a n d c S C C will de pe n d o n n u m ber a n d l ocalizati o n of lesi o ns.
F or si n gle lesi o ns: F ull e xcisi o n ma y  be rec o m me n de d.

I n case of m ulti ple lesi o ns or l ocati o n n ot s uita ble f or f ull e xcisi o n, ot her treat me nt o pti o ns 
ma y  be offere d by t he der mat ol o gist, s uc h as:

M o hs 
s ur ger y, cr y ot hera p y, or ot her sta n dar d treat me nt o pti o ns de pe n di n g o n t he 
pat h ol o g y

Use of reti n oi ds, if rec o m me n de d b y  der matol o gist, ma y  be c o nsi dere d after disc ussi o n 
wit h Me dical M o nit or. 
5.
Cl ose cli nical F oll o w-u p f or r e-e val uati o n, res ol uti o n, or p ote ntial rec urre nce s h o ul d b e 
i m ple me nte d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 9 3
6.
S p o nta ne o us res ol uti o n of K A lesi o ns wit h o ut s ur gical i nter ve nti o n has bee n o bser ve d, 
t ypicall y occ urri n g wit hi n wee ks after disc o nti n ui n g M S B 0 0 1 1 3 5 9 C .
C o ns ult wit h st u d y  Me dical M o nit or, as nee de d, f or ma na ge me nt of T G F β me diate d s ki n lesi o ns.
6. 5. 4. 5
A ne mi a
Ris k ma na ge me nt meas ures i n a d diti o n t o r o uti ne la b orat or y  tests will i ncl u de:

S u bjects m ust e nter t he st u d y  wit h H g b val ues at least 9 g/ d L

R o uti ne m o nit ori n g of H g b, re d bl o o d cells, a n d he mat ocrit will be perf or me d e ver y wee k u p 
t o Wee k 5 a n d t he n e ver y 2 wee ks t hereafter ( pri or t o treat me nt)

I nstr ucti o ns f or st u d y treat me nt disc o nti n uati o n or m o dificati o n i n case of a ne mia will be 
pr o vi de d, briefl y descri be d here:
o
D uri n g t he 2 1- D a y -D L T peri o d, a gra de 3 H g b decrease ( < 8. 0 g/ d L) re q uires treat me nt 
disc o nti n uati o n, u nless it res ol ves t o at least 9 g/ d L wit hi n 1 4 da y s or c ha n ge s i n ass ociate d 
re d bl o o d cell para meters d uri n g s uc h a H g b decrease t hat res ol ve wit hi n 1 4 d a y s wit h o ut 
bl o o d tra nsf usi o n or er y t hr oi d gr o wt h fact or use. H o we ver, if after t he 2 1- Da y -D L T peri o d
t he s u bject e x perie nces a Gra de 3 H g b decrease ( < 8. 0 g/ d L ) t hat is cli nicall y ma na gea ble 
wit h bl o o d tra nsf usi o ns or er yt hr oi d gr o wt h fact or use , t his d oes n ot re q uire treat me nt 
disc o nti n uati o n
o
Es peciall y if H g b < 7 g/ d L, t he I n vesti gat or s h o ul d c o nsi der bl o o d tra nsf usi o n 
o
I n case of a n y H g b < 8 g/ d L , t he I nvesti ga t or s h o ul d use discreti o n t o i nitiate a ne mia w or k 
u p, i ncl u di n g C o o m bs, ha pt o gl o bi n, i n direct bilir u bi n a n d peri p heral s mear, a n d pr ot hr o m bi n 
ti me (P T ), acti vate d partial t hr o m b o plasti n ti me (a P T T), i nter nati o nal n or malize d rati o 
(I N R); H g b, re d bl o o d cells, a n d he mat ocrit are t o be cl osel y m o nit ore d

If a s u bject e x perie nces si g nifica nt a ne mia, t he n t he a m o u nt of bl o o d t o be dra w n m a y  be 
re d uce d b y  not ta ki n g bl o o d at selecte d ti me p oi nts f or P D -L 1  tar get occ u pa nc y, 
i m m u n o m o nit ori n g, s ol u ble fact ors, a n d T G F β.  The decisi o n t o re d uce t he ti me p oi nts f or t hese 
bi o mar kers will be ta ke n b y  the I n vesti gat or i n c o ns ultati o n wit h t he Me dical M o nit or.  This 
will be d oc u me nte d.  Bl o o d will c o nti n ue t o be ta ke n as sc he d ule d f or safet y a nal ys es, P K, a n d 
A D As .
6. 5. 4. 6
Blee di n g A d verse E ve nts
M uc os al/ N o n -t u m or Blee di n g
If a Gra de 2 treat me nt-relate d T E A E i m pr o ves t o Gra de ≤ 1 or c o m pletel y res ol ves b y  the d a y  
bef ore t he ne xt i nf usi o n, st u d y  i nter ve nti o n ma y be c o nti n ue d.
If a Gra de 2 treat me nt-relate d n o n-t u m or blee di n g d oes n ot i m pr o ve t o Gra de ≤ 1 or c o m pletel y 
res ol ve by t he da y bef ore t he ne xt i nf usi o n, b ut it is ma na gea ble a n d/ or n ot cli nicall y rele va nt, t he 
Me dical M o nit or s h o ul d be c o ns ulte d t o assess if it is cli nicall y reas o na ble t o a d mi nister t he 
f oll o wi n g i nf usi o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 9 3
F or Gra de 3 n o n- t u m or blee di n g, st u d y treat me nt m ust be per ma ne ntl y disc o nti n ue d u nless a n 
alter nati ve e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mita nt use of a ntit hr o m b otic a ge nts, 
tra u matic e ve nt, etc.). I n case of alter nati ve e x pla nati o ns f or t he Gra de 3 blee di n g e ve nt, st u d y 
treat me nt s h o ul d be hel d u ntil t he e ve nt rec o vers t o Gra de ≤ 1.
F or Gra de 4 n o n- t u m or blee di n g, treat me nt m ust be per ma ne ntl y disc o nti n ue d if n o alter nati ve 
e x pla nati o n is i de ntifie d.
T u m or Blee di n g
F or Gra de ≥ 2 t u m or blee di n g, st u d y  treat me nt m ust be hel d u ntil t he e ve nt rec o vers t o Gra de ≤ 1. 
Treat me nt s h o ul d be per ma ne ntl y  disc o nti n ue d if t he I nvesti gat or c o nsi ders t he partici pa nt t o be 
at ris k f or a d diti o nal se vere blee di n g.
6. 5. 4. 7
Alter ati o ns i n W o u n d He ali n g or Tiss ue D a m a ge R e p air
Ma na ge me nt 
s h o ul d be disc usse d wit h 
t he Me dical 
M o nit or 
o n a case-b y -case basis.  
Der mat ol o gical c o ns ults s h o ul d be re q ueste d as nee de d.
6. 5. 4. 8
D ose I nterr u pti o ns f or A d verse E ve nts N ot Rel ate d t o St u d y 
Dr u g 
I n case of Gra de 3 a n d Gra de 4 A Es n ot st u d y dr u g relate d, t he st u d y treat me nt ma y be i nterr u pte d 
base d o n t he I n vesti gat or assess me nt a n d t he s u bject will be me dicall y  treate d f or t he e ve nt.
If t he A E re d uces t o a l o wer t olera ble gra de t he st u d y treat me nt mi g ht be res u me d i n t he s u bse q ue nt 
c ycle. If t he A E re mai ns t he sa me i n s pite of me dical treat me nt u ntil t he ne xt treat me nt (sec o n d 
c ycle after t he A E occ urre d) a disc ussi o n wit h t he Me dical M o nit or s h o ul d occ ur a n d c o nsi derati o n 
of a p ossi ble e x te nsi o n of t he d ose i nterr u pti o n f or u p t o 1 a d diti o nal c ycle or a per ma ne nt 
wit h dra wal fr o m t he st u d y treat me nt s h o ul d be c o nsi dere d.
If u p o n t he res u me d st u d y treat me nt t he s u bject e x perie nces t he sa me A E t his s h o ul d be 
redisc usse d wit h t he M e dical M o nit or t o assess per ma ne nt wit h dra wal fr o m t he st u d y treat me nt.
G ra de 3 a n d 4 l a borat or y a b n or malities t hat d o n ot ha ve cli nical si g nifica nce d o n ot re q uire d ose 
i nterr u pti o n.
6. 6
P ac k a gi n g a n d L a beli n g
of t he I n vesti g ati o n al Me dici n al 
Pr o d uct
M S B 0 0 1 1 3 5 9 C freeze-drie d f or m ulati o n is prese nte d at a c o nce ntrati o n of 4 5 m g/ vial i n U S P a n d 
P h E ur t y pe I glass vial cl ose d wit h a r u b ber st o p per a n d seale d wit h a n al u mi n u m cri m pi n g ca p.  
M S B 0 0 1 1 3 5 9 C
li q ui d f or m ulati o n is prese nte d at a 1 0 m g/ m L c o nce ntrati o n i n a U S P / P h E ur 
t ype I 5 0 R vial cl ose d wit h a r u b ber st o p per a n d seale d wit h a n al u mi n u m cri m p seal cl os ure.  T he 
st o p per is ma de of elast o mer c o m pl yi n g wit h U S P a n d P h E ur .  Vials are fille d wit h 6 1. 2 m L  of 
dr u g pr o d uct s ol uti o n i n or der t o all o w a n e xtracta ble v ol u me of 6 0 m L .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 9 3
Pac ka gi n g a n d la beli n g will be i n acc or da nce wit h a p plica ble l ocal re g ulat or y re q uire me nts a n d 
a p plica ble G o o d Ma n ufact uri n g Practice g ui deli nes. 
M S B 0 0 1 1 3 5 9 C will be pac ke d i n b o xes 
c o ntai ni n g a s uita ble n u m ber of vials.
T he i nf or mati o n o n t he me dicati o n will be i n acc or da nce 
wit h a p pr o ve d s u b missi o n d oc u me nts. 
M S B 0 0 1 1 3 5 9 C will be s hi p pe d i n tra ns p ort c o ol c o ntai ners
 are m o nit ore d wit h 
te m perat ure c o ntr ol de vices.
6. 7
Pre p ar ati o n, H a n dli n g , a n d 
of t he I n vesti g ati o n al 
Me dici n al Pr o d uct
M S B 0 0 1 1 3 5 9 C 
dr u g pr o d uct s h o ul d be st ore d 
u ntil use. 
M S B 0 0 1 1 3 5 9 C m ust n ot be fr oze n a n d s h o ul d be st ore d i n t he ori gi nal pac ka gi n g.  
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g , st ora ge, a n d dis p osal of M S B 0 0 1 1 3 5 9 C
will 
be pr o vi de d i n t he P har mac y  Ma n ual.
M S B 0 0 1 1 3 5 9 C
m ust n ot be use d f or a n y p ur p ose ot her t ha n t he st u d y.  The a d mi nistrati o n of I MPs 
t o s u bjects w h o ha ve n ot bee n e nr olle d i nt o t he st u d y is n ot c o vere d b y t he st u d y i ns ura nce.
T he c o nte nts of t he M S B 0 0 1 1 3 5 9 C
vials are sterile a n d n o n p y r o ge nic, a n d d o n ot c o ntai n 
bacteri ostatic preser vati ves.  An y  spills t hat occ ur s h o ul d be clea ne d u p usi n g t he facilit y’s 
sta n dar d clea n u p pr oce d ures f or bi ol o gic pr o d ucts.
A n y  un use d p orti o n of t he s ol uti o n s h o ul d be discar de d i n bi o hazar d waste dis p osal wit h fi nal 
dis p osal b y  acce pte d l ocal a n d nati o nal sta n dar ds of i nci nerati o n.
6. 8
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y
T he I n vesti gat or (i n Ja pa n, hea d of t he st u d y  site) is res p o nsi ble f or e ns uri n g I M P acc o u nta bilit y, 
i ncl u di n g rec o nciliati o n of dr u gs a n d mai nte na nce of rec or ds. I n Ja pa n, the hea d of t he st u d y  site 
ca n dele gate t he c o ntr ol of a n d acc o u nta bilit y f or t he I MP t o a n i n vesti gati o nal pr o d uct st ora ge 
ma na ger .

U p o n recei pt of I MP, t he res p o nsi ble pers o n (i n Ja pa n, t he hea d of t he st u d y site or t he 
i n vesti gati o nal pr o d uct st ora ge ma na ger ) will c hec k f or acc urate deli ver y  an d ac k n o wle d ge 
recei pt by si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me ntati o n a n d r et ur ni n g it t o t he 
l ocati o n s pecifie d. A c o p y  will be arc hi ve d f or t he I n vesti gat or Site File.

I M P dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y  for ms s o t hat acc urate 
rec or ds will be a vaila ble f or verificati o n at eac h m o nit ori n g visi t.

Trial site I M P acc o u nta bilit y  rec or ds will i ncl u de t he f oll o wi n g:

C o nfir mati o n of I M P recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  of I M P pr o vi de d f or t he cli nical trial a n d pre pare d at t he site.

T he use of eac h d ose b y eac h s u bject.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 9 3

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y u n use d I M P.

Dates, q ua ntities, batc h n u m bers, vial n u m bers, e x pir y dates, f or m ulati o n (f or I M P pre pare d 
at t he site), a n d t he i n di vi d ual s u bject trial n u m bers.
T he I n vesti gat or site s ho ul d mai ntai n rec or ds, w hic h
a de q uatel y d oc u me nt t hat s u bjects were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all I MPs pr o vi de d were f ull y rec o ncile d.  I n 
Ja pa n, the hea d of t he st u d y site s h o ul d mai ntai n rec or ds t hat all I M Ps pr o vi de d were f ully 
rec o ncile d.
U n use d I MP m ust n ot be use d f or a n y pur p ose ot her t ha n t he prese nt trial. N o I MP t hat is 
dis pe nse d t o a s u bject ma y be re dis pe nse d t o a differe nt s u bject.
T he S p o ns or’s M o nit or will peri o dicall y  collect a n d re vie w t he I M P acc o u nta bilit y for ms a n d 
w here a p plica ble, will c hec k all ret ur ns ( b ot h u n use d a n d use d c o ntai ners) bef ore arra n gi n g f or 
t heir ret ur n or a ut h orizi n g t heir destr ucti o n by t he trial site .
At t he c o ncl usi o n or ter mi nati o n of t his trial, trial site pers o n nel a n d t he C li nical Trial M o nit or will 
c o n d uct a fi nal pr o d uct s u p pl y in ve nt or y  on t he I n vesti gati o nal Dr u g Acc o u nta bilit y  F or ms a n d all 
u n use d c o ntai ners will be destr o ye d. I nstr ucti o ns f or destr ucti o n of pr o d uct will be pr o vi de d t o 
t he site. T he C li nical Trial M o nit or will be s u p plie d wit h a c o p y f or fili n g of t he I n vesti gati o nal 
Dr u g Acc o u nta bilit y  For ms. T his d oc u me ntati o n m ust c o ntai n a rec or d of cli nical s u p plies use d, 
u n use d , a n d destr o ye d a n d s hall i ncl u de i nf or mati o n o n

all a d mi nistere d u nits,

all u n use d u nits,

all destr o ye d u nits ( d uri n g t he trial),

all destr o ye d u nits at t he e n d of t he trial,

date of destr ucti o n(s),

na me a n d si g nat ure of t he In vesti g at or / p har macist / hea d of t he st u d y site or t he i n vesti gati o nal 
pr o d uct st ora ge ma na ger .
It m ust be e ns ure d at eac h trial site t hat t he I MP is n ot use d

after t he e x pir y date, a n d

after t he retest date u nless t he I MP is rea nalyz e d a n d its retest date e xte n de d.
T his is t o be cl osel y  m o nit ore d b y t he C li nical Trial M o nit or .
Destr ucti o n of use d a n d u n use d st u d y inter ve nti o n(s ) s h o ul d be perf or me d at site if all o we d b y
l ocal la w o nl y after S p o ns or a ut h orizati o n. If t hat is n ot p ossi ble, t he S p o ns or/ desi g nee will b e
res p o nsi ble.
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y inter ve nti o n(s) are
pr o vi d e d i n t he P har mac y Ma n ual.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 9 3
6. 9
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce
I n t his trial, s u bjects will recei ve I M P ( M S B 0 0 11 3 5 9 C I V i nf usi o ns) at t he i n vesti gati o nal site. 
Well -trai ne d me dical staff will m o nit or a n d perf or m t he I MP a d mi nistrati o n. T he i nf or mati o n of 
eac h I M P a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d ose of I M P will be rec or de d o n t he e C R F. 
T he In vesti gat or will ma ke s ure t hat t he i nf or mati o n e ntere d i nt o t he e C R F re gar di n g I M P 
a d mi nistrati o n is acc urate f or eac h s u bject. A n y  reas o n f or n o n c o m plia nce s h o ul d be d oc u me nte d.
N o nc o m plia nce is defi ne d as a s u bject missi n g > 1 a d mi nistrati o n of trial treat me nt f or n o n me dical 
reas o ns. If 1 treat me nt a d mi nistrati o n was misse d a n d t he i nter val bet wee n t he s u bse q ue nt 
treat me nt a n d t he last a d mi nistere d treat me nt is l o n ger t ha n 4 wee ks f or n o n me dical reas o ns, t he 
criteria of i ns ufficie nt c o m plia nce are met as well.   C o nti n uati o n of treat me nt s h o ul d be disc usse d 
wit h t he Me dical M o nit or.
6. 1 0
Bli n di n g
N ot a p plica ble .
6. 1 1
E mer ge nc y U n bli n di n g
N ot a p plica ble.
6. 1 2
Tre at me nt of O ver d ose
A n o ver d ose is defi ne d as a n y  d ose 5 % greater t ha n t he hi g hest d ose i ncl u de d i n t he cli nical trial 
pr ot oc ol. A n y o ver d ose m ust be rec or de d i n t he trial me dicati o n secti o n of t he e C R F.
F or m o nit ori n g p ur p oses, a n y  case of o ver d ose, w het her or n ot ass ociate d wit h a n A E (seri o us or 
n o nseri o us ), m ust be re p orte d t o t he S p o ns or’s Gl o bal Dr u g Safet y de part me nt i n a n e x pe dite d 
ma n ner usi n g t he Seri o us A d verse E ve nt Pa per Re p ort F or m f oll o wi n g t he sa me ti meli nes as S A E 
re p orti n g i n a d diti o n t o e nteri n g t he O ver d ose i n t he A E secti o n of t he e C R F (see Secti o n 7. 4. 1. 4 ).
T here are n o k n o w n s ym pt o ms of M S B 0 0 1 1 3 5 9 C o ver d ose t o date. T he In vesti gat or s h o ul d 
m o nit or cl osel y for A Es s h o ul d a n o ver d ose occ ur a n d use his or her cli nical j u d g me nt i n pr o vi di n g 
s ym pt o matic
/ s u p p orti ve care as me dicall y  in dicate d.  There is n o k n o w n a nti d ote f or 
M S B 0 0 1 1 3 5 9 C.
6. 1 3
Me dic al C are of S u bjects A fter E n d of Tri al
After a s u bject has c o m plete d t he trial or has wit h dra w n earl y, us ual treat me nt will be 
a d mi nistere d, if re q uire d, i n acc or da nce wit h t he trial site’s sta n dar d of care a n d ge nerall y  acce pte d 
me dical practice a n d de pe n di n g o n t he s u bject’s i n di vi d ual me dical nee ds.
U p o n wit h dra wal fr o m t he trial, s u bjects m a y  recei ve w hate ver care t he y an d t heir p h y sicia ns a gree 
u p o n. S u bjects will be f oll o we d f or s ur vi val a n d A Es as s pecifie d i n Secti o n  7. 1. 4.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 9 3
7
Tri al Pr oce d ures a n d Assess me nts
7. 1
Sc he d ule of Assess me nts
A c o m plete sc he d ule of assess me nts f or t he d ose -escalati o n p hase of t he trial is pr o vi de d i n  Ta ble
1 a n d f or t he e x pa nsi o n p hase i n Ta ble 2.   Sa m ple c ollecti o n f or P K, 
 
 pr o vi de d i n Ta ble 3.
Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical care, t he 
I n vesti gat or will e ns ure t hat t he s u bject or t he s u bject’s le gal re prese ntati ve has pr o vi de d writte n 
i nf or me d c o nse nt acc or di n g t o t he pr oce d ure descri be d i n Secti o n 9. 2.
7. 1. 1
Scree ni n g a n d B aseli ne Pr oce d ures a n d Assess me nts
T here is a 2 8- d a y  was h o ut / rec o ver y peri o d f or pri or a ntica ncer treat me nt (f or e xa m ple, 
c yt ore d ucti ve t hera p y, ra di ot hera py [ wit h t he e xce pti o n of palliati ve ra di ot hera py deli vere d i n a 
n or mal or ga n- s pari n g tec h ni q ue], i m m u ne t hera p y, or c yt o ki ne t her a p y e xce pt f or er yt hr o p oieti n) 
a n d maj or s ur ger y bef ore t he start of trial treat me nt ( Secti o n 5. 3. 2) .  He mat ol o g y, he m ostase ol o g y 
a n d c he mistr y la b orat or y sa m ples m ust be dra w n a n d re vie we d wit hi n 4 8 h o urs pri or t o d ose 
a d mi nistrati o n .
D uri n g t he Scree ni n g peri o d a n d bef ore a n y trial-relate d i n vesti gati o ns a n d assess me nts are starte d, 
t he s u bjects will be as ke d t o si g n t he rele va nt I CFs. 
T he s u bjects’ i nf or mati o n t hat will be 
d oc u me nte d d uri n g Scree ni n g i ncl u des t he de m o gra p hic i nf or mati o n ( birt h date, se x, et h nicit y, 
a n d race) a n d t he c o m plete me dical hist or y , i ncl u di n g t he hist or y  of t he t u m or disease a n d pri or 
a ntica ncer t hera pies, pre vi o us me dicati o ns ( pri or 3 0 da y s t o si g ni n g of I CF ), c o nc o mita nt 
me dicati o ns, a n d baseli ne me dical c o n diti o n (t he i nf or mati o n of c o nc o mita nt me dicati o ns a n d A Es 
will be m o nit ore d t hr o u g h o ut t he trial treat me nt peri o d). 
M ore o ver, a n E mer ge nc y  Me dical 
S u p p ort car d will be ha n de d o ut at t he baseli ne assess me nts visit.
D uri n g Scree ni n g , s u bjects will u n der g o a c o m plete p h y sical e xa mi nati o n, der mat ol o gical 
assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us lesi o ns), rec or di n g 
vital si g ns,i ncl u di n g b o d y  wei g ht a n d hei g ht ( hei g ht o nl y  at Scree ni n g) , 1 2- lea d electr ocar di o gra m 
(E C G ), o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p i ncl usi ve of t he a nteri or se g me nt a n d 
i ncl u di n g vis ual ac uity, a n d a deter mi nati o n of t he E C O G P S (A p pe n di x 1 ).
T he Scree ni n g
la b orat or y exa mi nati o n i ncl u des he mat ol o g y , he m ostase ol o g y , f ull ser u m 
c he mistr y, ser u m electr o p h oresis ( d ose escalati o n o nl y), a n d f ull uri nalys is. A dre n oc ortic otr o pic 
h or m o ne (d ose -escalati o n c o h orts o nl y wit h t he e xce pti o n of t he bac kfill c o h orts ), a nti n uclear 
a nti b o d y (A N A s), r he u mat oi d fact or ( R F), free t h yr o xi ne ( T 4), a n d T S H will als o be assesse d at 
Scree ni n g . 
D uri n g Scree ni n g , a ser u m β- h u ma n c h ori o nic g o na d otr o pi n ( β-H C G) pre g na nc y  test will be 
perf or me d f or fe males of c hil d beari n g p ote ntial a n d bl o o d H B V
a n d H C V testin g will be 
perf or me d f or all Scree ni n g s u bjects as t hese c o n diti o ns are trial e ntr y excl usi o n criteria (e xce pt 
f or s u bjects i n t he H C C e x pa nsi o n c o h ort, see Secti o n 5. 3. 1. 2 ). A fe male is c o nsidere d of 
c hil d beari n g p ote ntial (t hat is fertile) f oll o wi n g m e narc he a n d u ntil bec o mi n g p ost me n o pa usal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 9 3
u nless per ma ne ntl y sterile. Per ma ne nt sterilizati o n met h o ds i ncl u de h y sterect o m y, bilateral t u bal 
occl usi o n or sal pi n gect o m y, a n d bilateral o o p h orect o m y.   A p ost me n o pa usal state is defi ne d as n o 
me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use. 
A hi g h f ollicle -sti m ulati n g h or m o ne 
( F S H) le vel ( > 4 0 mI U/ m L ) i n t he p ost me n o pa usal ra n ge m a y
b e use d t o c o nfir m a 
p ost me n o pa usal state i n fe males n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt 
t hera p y.
T he t u m or e val uati o n (t y pe / sta gi n g, etc.) will be perf or me d usi n g C T sca n or M RI  (if M RI is 
use d, C T of c hest is ma n dat or y
[f or trial sites i n c o u ntries wit h ra diati o n e x p os ure c o ntr ol f or 
s u bjects, o nl y  MRI  m a y be use d] ; f or s u bjects i n t he H C C c o h ort, c o ntrast is ma n dat or y ) as well 
as t u m or mar kers or a n y ot her esta blis he d met h o ds (see Secti o n 7. 2. 5 f or details). B o ne sca ns 
s h o ul d be perf or me d as cli nicall y i n dicate d.  A brai n C T / M RI sca n (eit her, c o ntrast preferre d) is 
re q uire d at Scree ni n g if n ot perf or me d wit hi n t he pre vi o us 6 wee ks.
C ollecti o n of t u m or bi o psies or arc hi ve d s ur gical s peci me n will als o be d o ne d uri n g t his peri o d, if 
a pplica ble ( o pti o nal f or t he d ose -escalati o n p hase). S u bjects i n t he e x pa nsi o n c o h orts are re q uire d 
t o pr o vi de t u m or tiss ue sa m ples, see Secti o n 5. 3. 1 a n d Secti o n 7. 6. 2. 3 f or details.  
B aseli ne sa m ples f or A D As
(the ter m f or A D A o n t he C R F is h u ma n -a nti h u ma n a nti b o dies 
[H A H A ]) a n d P Gt (i ncl u di n g c ha n ges i n ge ne e x pressi o n t hr o u g h ge ne e x pressi o n e val uati o n 
s h o ul d be c ollecte d [see Ta ble 3] ). 
F or s u bjects i n t he H C C 1 2 0 0 m g asce n di n g-d ose c o h ort, H C C e x pa nsi o n c o h ort, es o p ha geal 
a de n ocarci n o ma, gli o blast o ma, mela n o ma, o varia n ca ncer, S C C H N, T N B C, cer vical ca ncer, a n d 
N S C L C sec o n d-li ne a n d a nti-P D -1/ P D -L 1  fail ure c o h orts, s u bject-re p orte d o utc o mes / s ym pt o m 
se verity
assess me nts
(P GI S, F H SI - 8, E O R T C Q L Q -C 3 0, 
E O R T C Q L Q -C X 2 4,
E O R T C 
Q L Q -B N 2 0, E O R T C Q L Q -H C C 1 8 -M, 
E O R T C Q L Q -O E S 1 8, E O R T C Q L Q -O V 2 8 , a n d/ or 
N S C L C- S A Q ) will be a d mi nistere d a n d c o m plete d b y t he s u bjects at Scree ni n g t o c ollect baseli ne 
data a b o ut t heir s ym pt o m se verit y.
F or s u bjects i n t he N S C L C sec o n d-li ne c o h ort, o nce a s u bject has bee n deter mi ne d t o meet all 
i ncl usi o n a n d n o e xcl usi o n criteria, t he s u bject will be ra n d o mize d as descri be d i n Secti o n 6. 3.
St u d y  treat me nt s h o ul d start ≤ 4 da y s after ra n d o mizati o n.
7. 1. 2
Tre at me nt Peri o d
F or t his pr ot oc ol , a c ycle is defi ne d as 1 4 da y s.  I n this trial, t he treat me nt will be gi ve n u ntil 
c o nfir me d pr o gressi o n, u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m t he trial or I M P 
occ urs (see Secti o n 5. 5) .
S u bjects w h o ha ve e x perie nce d a S D, P R , or C R
s h o ul d c o nti n ue 
treat me nt t hr o u g h t he e n d of 1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble . If t he 
In vesti gat or belie ves t hat a s u bject m a y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be 
per miss i ble after disc ussi o n wit h t he Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble . I n 
t he case of P D, s u bjects s h o ul d c o nti n ue treat me nt t hr o u g h t heir ne xt t u m or assess me nt, if t he y 
meet t he criteria descri be d i n Secti o n  5. 5. 1 .  
F or s u bjects
w h o ac hie ve S D, a P R or C R o n M S B 0 0 1 1 3 5 9 C t hera py a n d t he n s u bse q ue ntly 
de vel o p disease pr o gressi o n after st o p pi n g t hera p y , b ut pri or t o t he e n d of t he trial, 1 re-i nitiati o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 9 3
c o urse of treat me nt at t he sa me d ose a n d sc he d ule a n d treat me nt d urati o n u p t o 1 2 m o nt hs is 
all o we d at t he discreti o n of the I nvesti gat or a n d a gree me nt of t he trial Me dical M o nit or . T he 
I n vesti gat or will nee d t o c o nfir m t hat t he be nefit of re-i nitiati n g treat me nt o ut wei g hs a n y ris k 
i n v ol ve d, s uc h as t hat w hic h le d t o i nitial treat me nt disc o nti n uati o n. M ore o ver, f or s u bjects i n 
w hic h B O R was S D, t he In vesti gat or s h o ul d c o nfir m n o ot her reas o na ble treat me nt o pti o ns are 
a vaila ble.  I n or der t o be eli gi ble f or retreat me nt, the s u bject m ust n ot ha ve e x perie nce d a n y t o xicit y 
t hat le d t o per ma ne nt treat me nt disc o nti n uati o n of t he i nitial M S B 0 0 1 1 3 5 9 C t hera p y.  Pri or t o 
re-i nitiati o n of t he st u d y treat me nt, mali g na nt disease nee ds t o be ra di ol o gicall y re-sta ge d t o assess 
all k n o w n sites of t he disease a n d t o esta blis h a ne w baseli ne f or s u bse q ue nt t u m or meas ure me nts. 
Rele va n t safety la b orat or y sa m ples m ust be dra w n a n d res ults a vaila ble a n d verifie d pri or t o 
re-i nitiati n g of treat me nt. S u bjects w h o re -i nitiate treat me nt will sta y o n st u d y a n d will be treate d 
a n d m o nit ore d acc or di n g t o t he S c he d ule of A ssess me nt f or t he E x pa n si o n p orti o n of t he trial
starti n g at Wee k 1, Da y 1 (see Ta ble 2 ).
S u bjects will be as ke d t o visit t he i n vesti gati o nal site acc or di n g t o t he Sc he d ules of Assess me nts 
(see Ta ble 1 a n d Ta ble 2) . A ti me wi n d o w of u p t o 3 da y s bef ore or 1 da y af ter t he sc he d ule d visit 
da y  (-3 / + 1 da y s) will be per mitte d f or all st u d y  pr oce d ures (e xce pt o n Da y  2 an d t he Da y  4 4- 5 0
visit ). I n a d diti o n, t he t u m or e val uati o n (see Secti o n 7. 3 ) has a t u m or assess me nt visiti n g ti me 
wi n d o w of 5 d a y s pri or t o d osi n g (-5 d a y s).  F urt her m ore, if a n y Scree ni n g pr oce d ures are 
c o n d ucte d wit hi n 3 d a y s pri or t o D a y  1 of trial treat me nt ( Wee k 1, Da y 1), t he assess me nts 
sc he d ule d o n Wee k 1, D a y  1 d o n ot nee d t o be re peate d e xce pt f or t he e val uati o n of A Es a n d 
c o nc o mita nt me dicati o ns .
7. 1. 2. 1
D ose -Esc al ati o n P h ase Tre at me nt Peri o d
F or t he d ose -escalati o n p hase, i n-h o use o bser vati o n i n a h os pitalize d setti n g f or at least 2 4 h o urs 
will occ ur f or t he first 2 M S B 0 0 1 1 3 5 9 C d oses a d mi nistere d t o eac h s u bject.  T he first s u bject of 
each c o h ort will be o bser ve d f or at least 5 da ys bef ore t he sec o n d s u bject ca n be treate d. 
S u bse q ue nt s u bjects ma y recei ve first d osi n g at n o less t ha n 4 8 -h o ur i nter vals bet wee n s u bjects.
D uri n g t he treat me nt peri o d, t he f oll o wi n g assess me nts will be perf or me d (see  Ta ble 1 a n d Ta ble 
3 f or t he detaile d sc he d ule):

D L Ts will be assesse d d uri n g t he first 2 1 d a y s of trial treat me nt f or eac h d ose le vel of t he 
d ose -escalati o n part (see Secti o n  5. 1. 3. 2 )

A Es a n d c o nc o mita nt me dicati o ns will be d oc u me nte d at eac h st u d y visit

E C O G P S will be assesse d pri or t o trial treat me nt o n Da y  1 ( u nless t he Scree ni n g E C O G P S 
was perf or me d wit hi n 3 da y s pri or t o Da y 1) a n d acc or di n g t o  Ta ble 1 t hereafter

P h y sical e xa mi nati o n will be perf or me d pri or t o trial treat me nt o n Da y  1 (Wee k 1), D a y  2, 
D a y 8 , a n d t he n pri or t o trial treat me nt acc or di n g t o  Ta ble 1

E y e si g ns a n d s y m pt o ms s h o ul d be c hec ke d.  If cli nicall y re le va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y  sh o ul d be o btai ne d wit hi n 2 da y s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 9 3

Der mat ol o gical assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us 
lesi o ns acc or di n g t o  Ta ble 1 )

Vital si g ns i ncl u di n g b o d y wei g ht, will be as sesse d pri or t o trial treat me nt acc or di n g t o  Ta ble 1

T he 1 2- lea d E C G will be assesse d pri or t o a n d as s o o n as p ossi ble after i nf usi o n acc or di n g t o 
Ta ble 1

T he la b orat or y he mat ol o g y an d he m ostase ol o g y tests will be assesse d pri or t o trial treat me nt 
acc or di n g t o Ta ble 1.
C o m plete bl o o d c o u nt res ults m ust be dra w n a n d re vie we d wit hi n 
4 8 h o u rs pri or t o d ose a d mi nistrati o n

F ull ser u m c he mistr y (i ncl u des c ore c he mistr y) a n d c ore ser u m c he mistr y will be assesse d pri or 
t o trial treat me nt acc or di n g t o Ta ble 1 .  Sa m ples f or c ore c he mistr y res ults m ust be dra w n a n d 
re vie we d wit hi n 4 8 h o urs pri or t o d ose a d mi nistrati o n

Sa m ples f or A N As a n d R F acc or di n g t o  Ta ble 1

Ser u m electr o p h oresis at Wee k 1 3 ( Visit 1 0)

A basic uri nal ys is will be perf or me d pri or t o trial treat me nt acc or di n g t o  Ta ble 1

A ser u m H C G pre g na nc y  test will be re q uire d at Scree ni n g, uri ne or ser u m β- H C G pre g na nc y  
test will be perf or me d acc or di n g t o Ta ble 1.   Res ults of t he m ost rece nt pre g na nc y  test s h o ul d 
be a vaila ble pri or t o ne xt d osi n g (if a p plica ble)

T he t u m or e val uati o n (see Secti o n 7. 3 ) will be perf or me d at Wee k 7, a n d t he n o nce e ver y 
6 wee ks, wit h a t u m or assess me nt visiti n g ti me w i n d o w of 5 da ys pri or t o d osi n g.  F or s u bjects 
c o nti n ui n g treat me nt be y o n d 1 2 m o nt hs (i n c o ns ultati o n wit h t he Me dical M o nit or) , t u m or 
e val uati o ns s h o ul d ta ke place e ver y  1 2 wee ks

P K sa m ples will be dra w n as detaile d i n Ta ble 3

Free T 4 a n d T S H will be meas ure d pri or t o trial treat me nt acc or di n g t o  Ta ble 1

A D A
sa m ples will be dra w n as detaile d i n Ta ble 3.   The ter m f or A D A o n t he C R F is 
h u ma n -a nti h u ma n a nti b o dies ( H A H A )

P D -L 1  tar get occ u pa nc y  sa m ples will be dra w n as detaile d i n Ta ble 3 (see Secti o n 7. 6. 1)

T he i m m u n o m o nit ori n g a n d s ol u ble fact ors will be perf or me d as detaile d i n Ta ble 3 a n d as 
descri be d i n Secti o n 7. 6. 1. 2

Sa m ples f or T G F β 1, 2 a n d 3 deter mi nati o n a n d q ua ntificati o n of p h os p h or y late d S M A D 2/ 3 
( p S M A D 2/ 3) will be dra w n as detaile d i n Ta ble 3 ( n ote: Sa m ples f or p S M A D 2/ 3 will n ot be 
c ollecte d i n t he bac kfill , 3 0 m g/ k g , or 2 4 0 0 m g flat-d ose d ose -escalati o n c o h orts)

Bl o o d sa m ples f or ge ne e x pressi o n e val uati o n will be c ollecte d acc or di n g t o Ta ble 3 (pri or t o 
st u d y dr u g a d mi nistrati o n w here a p plica ble)

F or s u bjects u n der g oi n g t he o pti o nal Wee k 7 bi o ps y , t he bi o p s y s h o ul d be perf or me d wit hi n 
7 da y s after t he Wee k 7 I M P a d mi nistrati o n (Ta ble 3) .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 9 3
7. 1. 2. 2
E x p a nsi o n P h ase Tre at me nt Peri o d
D uri n g t he treat me nt peri o d, t he f oll o wi n g assess me nts will be perf or me d (see  Ta ble 2 a n d Ta ble 
3 f or t he detaile d sc he d ule):

F or s u bjects i n t he H C C 1 2 0 0 m g asce n di n g-d ose c o h ort, H C C e x pa nsi o n c o h ort, es o p ha geal 
a de n ocarci n o ma, gli o blast o ma, mela n o ma, o varia n ca ncer, S C C H N, T N B C, cer vical ca ncer, 
a n d N S C L C sec o n d-li ne a n d a nti-P D -1/ P D -L 1  fail ure c o h orts, s u bject-re p orte d o utc o mes / 
s ym pt o m se verity assess me nts (P GI S, F H SI -8, E O R T C Q L Q- C 3 0, E O R T C Q L Q- C X 2 4, 
E O R T C Q L Q- B N 2 0, E O R T C Q L Q- H C C 1 8 -M, E O R T C Q L Q- O E S 1 8, E O R T C Q L Q- O V 2 8 , 
a n d/ or N S C L C- S A Q ) will be c o m plete d pri or t o a n y st ud y -relate d pr oce d ures as i n dicate d i n 
Ta ble 2

A Es a n d c o nc o mita nt me dicati o ns will be d oc u me nte d i n eac h st u d y visit
F or a n y bi o psies or ot her pr oce d ures res ulti n g i n tiss ue ac q uisiti o n, official pat h ol o g y  re p orts 
m ust be file d a n d a vaila ble f or re vie w if re q ueste d

E C O G P S will be assesse d pri or t o trial treat me nt o n Da y  1 ( u nless t he Scree ni n g E C O G P S 
was perf or me d wit hi n 3 da y s pri or t o Da y 1) a n d acc or di n g t o  Ta ble 2 t hereafter

P h y sical e xa mi nati o n will be perf or me d pri or t o trial treat me nt o n Da y  1 (Wee k 1) a n d t he n 
pri or t o trial treat me nt acc or di n g t o  Ta ble 2

E y e si g ns a n d s y m pt o ms s h o ul d be c hec ke d.  If cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y sh o ul d be o btai ne d wit hi n 2 da y s

Der mat ol o gical assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us 
lesi o ns acc or di n g t o  Ta ble 2)

Vital si g ns , i ncl u di n g b o d y wei g ht, will be assesse d pri or t o trial treat me nt acc or di n g t o Ta ble 
2

T he 1 2 -lea d E C G will be assesse d acc or di n g t o  Ta ble 2

T he la b orat or y he mat ol o g y an d he m ostase ol o g y tests will be assesse d pri or t o trial treat me nt 
acc or di n g t o Ta ble 2.  C o m plete bl o o d c o u nt res ults m ust be dra w n a n d re vie we d wit hi n 
4 8 h o u rs pri or t o d ose a d mi nistrati o n .  F or s u bjects e x perie nci n g si g ns of a ne mia i ncl u di n g, b ut 
n ot li mite d t o , a si g nifica nt dr o p i n H g b val ue, es peciall y H g b < 8 g/ d L, r o uti ne m o nit ori n g of 
H g b, re d bl o o d cells, a n d he mat o crit s h o ul d be perf or me d wee kl y

F ull ser u m c he mistr y (i ncl u des c ore c he mistr y) a n d c ore ser u m c he mistr y will be assesse d pri or 
t o trial treat me nt acc or di n g t o Ta ble 2 .  Sa m ples f or c ore c he mistr y res ults m ust be dra w n a n d 
re vie we d wit hi n 4 8 h o urs pri or t o d ose a d mi nistrati o n  

A basic uri nal ys is will be perf or me d pri or to trial treat me nt e ver y  acc or di n g t o Ta ble 2

Sa m ples f or A N As a n d R F acc or di n g t o  Ta ble 2

A ser u m H C G pre g na nc y  test will be re q uire d at Scree ni n g, uri ne or ser u m β- H C G pre g na nc y  
test will be perf or me d acc or di n g t o Ta ble 2 .  Res ults of t he m ost rece nt pre g na nc y  test s h o ul d 
be a vaila ble pri or t o ne xt d osi n g (if a p plica ble)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 9 3
E O R T C Q L Q- B N 2 0, E O R T C Q L Q- H C C 1 8 -M, E O R T C Q L Q- O E S 1 8, E O R T C Q L Q- O V 2 8 , 
a n d/ or N S C L C- S A Q ) will be c o m plete d pri or t o a n y st u d y-relate d pr oce d ures as i n dicate d i n 
Ta ble 2

D oc u me nta ti o n of A Es a n d c o nc o mita nt me dicati o n

P h y sical e xa mi nati o n i ncl u di n g vital si g ns a n d b o d y wei g ht

E y e si g ns a n d s y m pt o ms s h o ul d be c hec ke d.  If cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y s h o ul d be o btai ne d wit hi n 2 da ys

Der mat ol o gical assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us 
lesi o ns)

L a b orat or y he mat ol o g y, he m ostase ol o g y , f ull ser u m c he mistr y, a n d b asic uri nal y sis

Sa m ples f or A N As a n d R F ( Escalati o n p hase)

E C O G perf or ma nce stat us will be assesse d

Bl o o d sa m ples f or ge ne e x pressi o n e val uati o n (e x pa nsi o n c o h orts o nl y )

O pti o nal “ pr o gressi o n bi o ps y ” f or s u bjects w h o ha d ac hie ve d at least S D f or ≥1 2 wee k s b ut 
w h o s u bse q ue ntl y disc o nti n ue d st u d y treat me nt d ue t o a n assess me nt of P D.  The o pti o nal 
“ pr o gressi o n bi o ps y” will be use d t o e val uate t he p ote ntial mec ha nis ms of t u m or esca pe.
7. 1. 4
P ost -Tre at me nt F oll o w -u p
7. 1. 4. 1
2 8 -D a y S afet y F oll o w -u p Visit
A Safet y F oll o w - u p visit is sc he d ule d 4 wee ks ( 2 8 ± 5 d a y s) after t he last a d mi nistrati o n of 
M S B 0 0 1 1 3 5 9 C b ut bef ore a n y ne w t hera p y is starte d, if p ossi ble, w hic he ver occ urs earlier. If it 
is k n o w n t o t he I n vesti gat or at t he ti me of t he E n d - of-Treat me nt visit t hat t he s u bject will start ne w 
treat me nt wit hi n 2 8 da y s of last treat me nt or t he y will be u na ble t o ret ur n wit hi n 2 8 da y s of last 
treat me nt, assess me nts ass ociate d wit h t he 2 8- Da y  Safet y F oll o w-u p visit ma y  be c o n d ucte d at t he 
E n d - of-Treat me nt visit.   T he 2 8- D a y  Safet y F oll o w -u p visit will c o m prise a f ull assess me nt f or 
safety, i m m u n o ge nicity, a n d t u m or res p o nse as a p pr o priate, w hic h will i ncl u de t he f oll o wi n g (refer 
t o Ta ble 1, Ta ble 2, a n d Ta ble 3 ):

F or s u bjects i n t he H C C 1 2 0 0 m g asce n di n g-d ose c o h ort, H C C e x pa nsi o n c o h ort, es o p ha geal
a de n ocarci n o ma, gli o blast o ma, mela n o ma, o varia n ca ncer, S C C H N, T N B C, cer vical ca ncer, 
a n d N S C L C sec o n d-li ne a n d a nti-P D -1/ P D -L 1  fail ure c o h orts, s u bject-re p orte d o utc o mes / 
s ym pt o m se verity assess me nts (P GI S, F H SI -8, E O R T C Q L Q -C 3 0, E O R T C Q L Q- C X 2 4, 
E O R T C Q L Q- B N 2 0, E O R T C Q L Q- H C C 1 8 -M, E O R T C Q L Q- O E S 1 8, E O R T C Q L Q- O V 2 8 , 
a n d/ or N S C L C- S A Q ) will be c o m plete d pri or t o a n y st u d y-relate d pr oce d ures as i n dicate d i n 
Ta ble 2

A Es, c o nc o m ita nt me dicati o ns

Vital si g ns a n d b o d y wei g ht
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 9 3

P h y sical e xa mi nati o ns

E y e si g ns a n d s y m pt o ms s h o ul d be c hec ke d.  If cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y s h o ul d be o btai ne d wit hi n 2 da ys

Der mat ol o gical assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us 
lesi o ns)

T he 1 2 -lea d E C G

T he la b orat or y  he mat ol o g y, he m ostase ol o g y , f ull ser u m c he mistr y, ser u m electr o p h oresis tests
( d ose escalati o n o nl y), a n d f ull uri nal ysis

E C O G perf o r ma nce stat us will be assesse d

T he uri ne β -H C G pre g na nc y  test (i n fe males of c hil d beari n g p ote ntial)

T he t u m or e val uati o n ( o nl y to be perf or me d, if n o disease pr o gres si o n was d oc u m e nte d 
pre vi o usl y )

F ree T 4 a n d T S H

Sa m ples f or A N As a n d R F ( E x pa nsi o n c o h orts )

P K sa m ple

A D A
sa m ple (see Secti o n 7. 7. 1 ).  The ter m f or A D A o n t he C R F is h u ma n -a nti h u ma n 
a nti b o dies (H A H A )

T he i m m u n o m o nit ori n g a n d s ol u ble fact ors will be perf or me d as descri be d i n Secti o n 7. 6. 1. 2
a n d Secti o n 7. 6. 2. 2 a n d Ta ble 1, Ta ble 2 , a n d Ta ble 3

Sa m ples f or T G F β deter mi nati o n a n d p S M A D 2/ 3 ( d ose-escalati o n p hase o nl y ; n ote: Sa m ples 
f or p S M A D 2/ 3
will n ot be c ollecte d i n t he bac kfill or 3 0 m g/ k g d ose -escalati o n c o h orts) 
q ua ntificati o n as descri be d i n  Ta ble 3

Sa m ples f or viral l oa d testi n g ( H B V, H C V) a n d al p ha-fet o pr otei n ( H C C sec o n d-li ne c o h ort, 
b ot h asce n di n g d ose a n d e x pa nsi o n)

Bl o o d sa m ples f or ge ne e x pressi o n e val uati o n f or s u bjects wit h P D ( d ose-escalati o n c o h orts 
o nl y ).
7. 1. 4. 2
S afet y F oll o w -u p Visit
All s u bjects will ha ve a s u bse q ue nt visit sc he d ule d 1 0 wee ks ( ± 2 wee ks)
after t he last 
a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C .  If a n ot her a nti ne o plastic t hera py i s a d mi nistere d bef ore t he e n d 
of t he 1 0- wee ks peri o d, t he 1 0- W ee k Safet y F oll o w -u p visit mi g ht be c o n d ucte d as a p h o ne call 
wit h o ut p h y sical or la b orat or y assess me nts.
Ot her wise, the visit will i ncl u de t he f oll o wi n g f ull 
assess me nt of safet y para meters (refer t o  Ta ble 1, Ta ble 2 , a n d Ta ble 3 ):

A Es t hat are dee me d attri b uta ble t o trial dr u g b y  t he I n vesti gat or a n d c o nc o mita nt me dicati o ns 
(i ncl u di n g f urt her a nti-ca ncer t hera p y ) will be d oc u me nte d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 9 3

Vital si g ns a n d b o d y  wei g ht will be meas ure d

P h y sical e xa mi nati o n will be perf or me d

E y e si g ns a n d s y m pt o ms s h o ul d be c hec ke d.  If cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m o l o g y exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y sh o ul d be o btai ne d wit hi n 2 da y s

Der mat ol o gical assess me nts (assess me nts f or s ki n lesi o ns or ras h wit h bi o ps y  of s us pici o us 
lesi o ns)

E C O G perf or ma nce stat us will be assesse d

1 2- lea d E C G will be assesse d

La b orat or y  testi n g c o nsisti n g of t he f oll o wi n g will be assesse d:
o
H e mat ol o g y, he m ostase ol o g y, f ull ser u m c he mistr y, a n d uri nalys is
o
T 4, a n d T S H le vels

Sa m ples f or A N As a n d R F ( E x pa nsi o n c o h orts )

P K sa m ple will be c ollecte d

A D A sa m ple .  T he ter m f or A D A o n t he C R F is h u ma n-a nti h u ma n a nti b o dies ( H A H A)

Sa m ples f or viral l oa d testi n g ( H B V, H C V; H C C sec o n d -li ne c o h ort, b ot h asce n di n g d ose a n d 
e x pa nsi o n)

A uri ne β -H C G pre g na nc y  test (i n w o me n of c hil d bearin g p ote ntial) will be c o n d ucte d.
N ote:   After at least 5 0 s u bjects acr oss t he d ose escalati o n a n d all e x pa nsi o n c o h orts ha ve bee n 
e val uate d f or safety b y  the S M C, wit h a p pr o priate S M C safety rec o m me n dati o n t he 1 0- Wee k 
Safet y  F oll o w-u p visit ma y  be c o n d ucte d b y p h o ne wit h o ut t he sc he d ule d asses s me nts.
7. 1. 4. 3
L o n g -ter m F oll o w -u p / T ri al T er mi n ati o n
All S A Es o n g oi n g at t he 2 8 -D a y  Safet y F oll o w - u p visit m ust be m o nit ore d a n d f oll o we d u p b y  the 
I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is doc u me nte d as 
“l ost t o f oll o w- u p”.  I n ad diti o n, all trial dr u g -relate d S A Es occ urri n g after 2 8- D a y  Safet y 
F oll o w -u p visit a n d o n g oi n g at t he Safet y F oll o w - u p visit ha ve t o be f oll o we d u p i n t he sa me 
ma n ner. 
S u bjects wit h o ut P D at t he 2 8- Da y  Safet y F oll o w -u p visit will be f oll o we d u p f or disease 
pr o gressi o n ( C T / M RI  sca ns e ver y 1 2 wee ks wit h t he first assess me nt 1 2 wee ks after t he pre vi o us 
t u m or assess me nt [sc he d ule d ti me p oi nt]) u ntil P D.  
After t he 2 8- D a y  Safet y F oll o w -u p visit, s u bjects will be f oll o we d q uarterl y  (± 1 4 d a y s) f or 
s ur vi val (i ncl u di n g assess me nt of a n y furt her a ntica ncer t hera py).  The s ur vi val f oll o w- u p will 
c o nti n ue u ntil 1 ye ar after t he last s u bject recei ves t he last d ose of M S B 0 0 1 1 3 5 9 C .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 9 3
After c o m pleti o n of t he F oll o w - u p peri o d or at disc o nti n uati o n of t he trial, w hate ver is 
a p plica ble / c o mes first, t he a p pr o priate e C R F secti o n f or Trial Ter mi nati o n m ust be c o m plete d.
7. 1. 5
Bl o o d C o ns u m pti o n f or Cli nic al Assess me nts
T he o verall a m o u nt of bl o o d t o be dra w n fr o m a si n gle s u bject m ust n ot e xcee d 1 2 0 m L / da y an d 
5 5 0 m L  in a n 8- wee k peri o d f or safety la b orat or y testi n g, pre g na nc y  testi n g, P K a nal yses, 
, a n d a nti b o d y e val uati o n.
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
T he assess me nts a n d pr oce d ures descri be d i n t his secti o n m ust be perf or me d d uri n g t he Scree ni n g
peri o d.
7. 2. 1
De m o gr a p hic D at a
T he f oll o wi n g de m o gra p hic data will be rec o rde d :

S u bject i de ntifier

Date of birt h

Se x

Et h nicit y

Race .
7. 2. 2
Di a g n osis of T u m or
T he t u m or disease i nf or mati o n t hat will be d oc u me nte d a n d verifie d at t he Scree ni n g visit f or eac h 
s u bject i ncl u des:

Detaile d hist or y  of t he t u m or, i ncl u di n g hist o pat h ol o gical dia g n osis, gra di n g a n d sta gi n g i n 
acc or da nce wit h 
t he U ni o n 
I nter nati o nale C o ntre 
le Ca ncer
T u m or N o de 
Metastasis 
Classificati o n at di a g n osis ( UIC C T N M)
o
T he M cate g or y (M 0 or M 1) of t he t u m or at t he ti me of st u d y entr y , base d o n scree ni n g 
assess me nts

All t hera py use d f or pri or treat me nt of t he t u m or (i ncl u di n g s ur ger y, ra di ot hera py a n d 
c he m ot hera p y, i m m u n ot hera p y , etc)

A n y  ot her c o n diti o ns t hat were treate d wit h c he m ot hera p y, ra diati o n t hera py,  or i m m u n ot hera p y

C urre nt ca ncer si gns a n d s ym pt o ms a n d si de effects fr o m c urre nt a n d / or pre vi o us a ntica ncer 
treat me nts

C urre nt ca ncer disease stat us

B R C A , t u m or H P V a n d t u m or mis matc h-re pair stat us d oc u me ntati o n, if k n o w n

S m o ki n g hist or y (f or N S C LC a n d cer vical ca ncer e x pa nsi o n c o h ort s o nl y ).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 9 3
7. 2. 3
Me dic al Hist or y
I n or der t o deter mi ne t he s u bject’s eli gi bilit y to t he trial, a c o m plete me dical hist or y  of eac h s u bject 
will be c ollecte d a n d d oc u me nte d d uri n g Scree ni n g , w hic h will i ncl u de, b ut ma y n ot be li mite d t o, 
t he f oll o wi n g:

Past a n d c o nc o mita nt n o n -ma li g na nt diseases a n d treat me nts

All me dicati o ns ta ke n a n d pr oce d ures carrie d o ut wit hi n 3 0 da y s pri or t o Scree ni n g
F or t he trial e ntr y , all t he s u bjects m ust f ulfill all i ncl usi o n criteria descri be d i n Secti o n 5. 3. 1 , a n d 
n o ne of t he s u bjects s h o ul d ha ve a n y e xcl usi o n criteri o n fr o m t he list descri be d i n Secti o n 5. 3. 2.
7. 2. 4
Vit al Si g ns a n d P h ysic al E x a mi n ati o n
Vital si g ns i ncl u di n g b o d y  te m perat ure, res pirat or y rate, heart rate (after 5- mi n ute rest), a n d arterial 
bl o o d press ure (after 5 -mi n ute rest) , b o d y  wei g ht a n d hei g ht will be rec or de d at st u d y e ntr y. 
P h y sical e xa mi nati o ns will be perf or me d acc or di n g t o Ta ble 1 a n d Ta ble 2.
A n o p ht hal m ol o g y 
e xa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt a n d wit h vis ual ac uit y
s h o ul d be c o n d ucte d.
T he E C O G P S will be d oc u me nte d d uri n g t he Scree ni n g p hase.
7. 2. 5
C T or M RI Sc a ns f or T u m or Assess me nt at B aseli ne
A C T sca n or M RI (if M RI  is use d, C T of c hest is ma n dat or y
[f or trial sites i n c o u ntries wit h 
ra diati o n e x p os ure c o ntr ol f or s u bjects, o nl y  MRI  m a y be use d ]; f or s u bjects i n t he H C C c o h ort, 
m ulti p has e C T wit h c o ntrast is ma n dat or y ) of t he c hest, a b d o me n, a n d pel vis (at a mi ni m u m a n d 
ot her esta blis he d assess me nts of t u m or b ur de n if C T / M RI  ima gi n g is n ot s ufficie nt f or t he 
i n di vi d ual s u bject; ot her re gi o ns as s pecificall y re q uire d f or s pecific t u m or in dicati o ns) will be 
perf or me d wit hi n 2 8 da ys pri or t o trial treat me nt start i n or der t o d oc u me nt t he baseli ne stat us of 
t he t u m or disease usi n g R E CI S T 1. 1 tar get a n d n o n- tar get lesi o ns a n d sec o n daril y usi n g m R E CI S T 
f or s u bjects i n t he H C C c o h ort (see ve n d or ma n ual) .  F or s u bjects i n t he gli o blast o ma c o h ort, t he 
assess me nt will be ma de acc or di n g t o R A N O . H o we ver, if t he res ults of a C T sca n or M RI 
perf or me d wit hi n 4 wee ks pri or t o first treat me nt are a vaila ble, t he Scree ni n g C T / M RI  d oes n ot 
nee d t o be perf or me d. 
A brai n C T / M RI sca n (eit her, c o ntrast preferre d) is re q uire d at Scree ni n g if n ot perf or me d wit hi n 
t he pre vi o us 6 wee ks. T hereafter, brai n C T / M RI sca n s h o ul d be d o ne if cli nicall y in dicate d b y  
de vel o p me nt of ne w s pecific s y m pt o ms.
A b o ne sca n s h o ul d be d o ne at Scree ni n g as cli nicall y i n dicate d.
7. 2. 6
C ar di ac Assess me nts
A 1 2- lea d E C G will be rec or de d at Scree ni n g . T he E C G will be rec or de d after t he s u bject has 
bee n i n a s u pi ne p ositi o n breat hi n g q uietl y f or 5 mi n utes. T he E C G res ults wil l be use d t o e val uate 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 9 3
t he heart rate, atrial-ve ntric ular c o n d ucti o n, Q R , Q T , a n d c orrecte d Q T
i nter vals, a n d p ossi ble 
arr h yt h mias .
T he d ose escalati o n a n d N S C L C bi o mar ker c o h orts m ust utilize di gital E C Gs.  T he E C Gs will be 
d oc u me nte d b y  rec or di n g date a n d ti me of c ollecti o n.  All E C G res ults m ust be re vie we d at t he 
site b y  the I n vesti gat or or a me dicall y  qualifie d desi g nee f or cli nical ma na ge me nt of t he s u bject.  
T he di gital E C Gs will als o be electr o nicall y tra nsferre d t o t he ce ntral E C G la b orat or y to be rea d 
b y  a car di ol o gist.  T he res ult of t he ce ntral rea d will be use d f or statistical e val uati o n of E C G data.  
F or t he N S C L C bi o mar ker c o h ort, all E C Gs after Wee k 1 3 are si n gle E C Gs o btai ne d acc or di n g t o 
l ocal pr oce d ure a n d will N O T be di gitally u pl oa de d.  F or all ot her e x pa nsi o n c o h orts, E C Gs are t o 
be perf or me d acc or di n g t o l ocal pr oce d ures a n d will N O T be di gitall y u pl oa de d.
Di gital E C G u pl oa di n g a n d ce ntral rea di n g will n ot be use d f or t he re mai ni n g e x pa nsi o n c o h orts.
T he I n vesti gat or will j u d ge t he o verall i nter pretati o n as n or mal or a b n or mal. If a b n or mal, it will 
be deci de d if t he a b n or malit y is cli nicall y si g nifica nt or n ot cli nicall y si g nifica nt a n d t he reas o n 
f or t he a b n or malit y will be rec or de d o n t he e C R F. A b n o r mal val ues will n ot be rec or de d as A Es 
u nless t he y  are t he reas o n f or disc o nti n uati o n of t he trial I M P d ue t o A Es or are S A Es.
7. 2. 7
Cli nic al L a b or at or y Tests
Bl o o d sa m ples will be c ollecte d at Scree ni n g f or cli nical la b orat or y para meter e val uati o ns. T hese 
clinical la b orat or y test res ults will ser ve n ot o nl y  as t he baseli ne val ues f or s u bse q ue nt safety 
cli nical la b orat or y eval uati o ns d uri n g t he trial, b ut als o hel p t o ma ke s ure t hat eac h e nr olle d s u bject 
f ulfills all t he trial e ntr y criteria as liste d i n Secti o n 5. 3. 1 a n d d oes n ot meet a n y of t he trial 
e xcl usi o n criteria f or la b orat or y para meters as liste d i n Secti o n 5. 3. 2 . Detaile d descri pti o n of 
la b orat or y assess me nts is pr o vi de d i n Secti o n 7. 4. 3.
7. 3
Effic ac y Assess me nts
F or all s u bjects i n all c o h orts, t u m or res p o nse assess me nt will be perf or me d b y  CT sca n or M RI 
(if M RI  is use d, C T of c hest is ma n dat or y [f or trial sites i n c o u ntries wit h ra diati o n e x p os ure c o ntr ol 
f or s u bjects, o nl y M RI ma y be use d], f or s u bjects i n t he H C C c o h ort, m ulti p hase C T wit h c o ntrast 
is ma n dat or y) i ma gi n g of t he c hest / a b d o me n / pel vis ( pl us ot her re gi o ns as s pecificall y re q uire d 
f or s pecific t u m or ty p es) a n d ot her esta blis he d assess me nts of t u m or b ur de n if C T / M R I i ma gi n g 
is i ns ufficie nt f or t he i n di vi d ual s u bject.  All t he sca ns perf or me d at Baseli ne a n d ot her i ma gi n g 
perf or me d as cli nicall y re q uire d ( ot her s u p p orti ve i ma gi n g) nee d t o be re peate d at s u bse q ue nt 
visits.  In ge neral, lesi o ns detecte d at Baseli ne nee d t o be f oll o we d usi n g t he sa me i ma gi n g 
met h o d ol o g y a n d prefera bl y  t he sa me i ma gi n g e q ui p me nt at s u bse q ue nt t u m or e val uati o n visits.
A brai n C T / M RI  sca n (eit her, wit h c o ntrast preferre d) is re q uire d at Scree ni n g if n ot perf or me d 
wit hi n t he pre vi o us 6 wee ks.  Thereafter brai n C T / M RI  sca n s h o ul d be perf or me d, if cli nicall y 
i n dicate d b y  de vel o p me nt of ne w s pecific s ym pt o ms. 
A b o ne sca n s h o ul d be perf or me d at 
S cree ni n g a n d b e y o n d as cli nicall y in dicate d. 
S ki n metastasis ca n be use d as tar get lesi o ns 
acc ordi n g t o R E CI S T 1. 1 usi n g meas ure me nts b y  cali per, if t he y fulfill R E CI S T 1. 1 f or tar get 
lesi o ns as descri be d bel o w. T he prese nce of ne w c uta ne o us lesi o ns will be c o nsi dere d dia g n ostic 
of pr o gressi o n f or R E CI S T 1. 1, e ve n if n ot i ma ge d. F or eac h s u bject, the In vesti gat or will 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 9 3
desi g nate 1 or m ore of t he f oll o wi n g meas ures of t u m or stat us t o f oll o w f or deter mi ni n g res p o nse:
C T or M RI  ima ges of pri mar y  an d / or metastatic t u m or masses, p h y sical e xa mi nati o n fi n di n gs, 
a n d t he res ults of ot her assess me nts. All a vaila ble i ma ges c ollecte d d uri n g t he trial peri o d will be 
c o nsi dere d. T he m ost a p pr o priate meas ures t o e val uate t he t u m or stat us of a s u bject s h o ul d be 
use d. T he meas ure(s) t o be c h ose n f or se q ue ntial e val uati o n d uri n g t he trial ha ve t o c orres p o n d t o 
t he meas ures use d t o d oc u me nt t he pr o gressi ve t u m or stat us t hat q ualifies t he s u bject f or 
e nr oll me nt. T he t u m or res p o nse assess me nt will be assess e d a n d liste d acc or di n g t o t he Sc he d ule 
of A ssess me nts (refer t o Ta ble 1 a n d Ta ble 2 ).
T he f oresee n treat me nt d urati o n is u ntil disease pr o gressi o n verifie d b y  a sca n s u bse q ue nt t o t he 
i nitial d oc u me ntati o n of P D , u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal fr o m t he trial 
or I M P occ urs (see Secti o n  5. 5 ). Bef ore st o p pi n g t he tre at me nt, pr o gressi ve dise ase s h o ul d be 
c o nfir me d b y i m a gi n g 4 t o 6 wee k s (prefer a bl y 6 wee ks , b ut n ot l ater) after pr o gressi o n h as 
bee n di a g n ose d acc or di n g t o R E CI S T 1. 1. If pr o gressi o n is base d o n t he occ urre nce of a n e w 
lesi o n i n a n area n ot sca n ne d at B aseli ne, a f urt her o n- st u d y sca n 6 wee ks later s h o ul d be 
c o nsi dere d bef ore perf or mi n g t he 2 8 -Da y  Safet y F oll o w - u p visit. Treat me nt m a y  be c o nti n ue d 
des pite pr o gressi o n acc or di n g t o R E CI S T 1. 1 at a n y ti me if:

T here are n o ne w s y m pt o ms or w orse ni n g of e xisti n g s y m pt o ms.

T here is n o decrease i n E C O G P S .

T he I n vesti gat or d oes n ot c o nsi der it necessa r y t o a d mi nister a sal va ge t hera p y. 
T he treat me nt s h o ul d be st o p pe d i m me diatel y, if t he s u bject d oes n ot t olerate M S B 0 0 1 1 3 5 9 C
a n ym ore or if t hera pe utic fail ure occ urs, w hic h re q uires ur ge nt treat me nt wit h a n a d diti o nal dr u g 
or res ults i n cli nicall y  si g nifica nt pr o gressi o n / deteri orati o n. 
T u m or res p o nses t o treat me nt will be assi g ne d base d o n t he e val uati o n of t he res p o nse of tar get, 
n o n- tar get, a n d ne w lesi o ns acc or di n g t o R E CI S T 1. 1 (all meas ure me nts s h o ul d be rec or de d i n 
metric 
n otati o n)
a n d sec o n darily usi n g m R E CI S T f or s u bjects i n t he H C C 
c o h ort (see
Secti o n 7. 3. 2) . F or s u bjects i n t he gli o blast o ma c o h ort, t he assess me nt will be ma de acc or di n g t o 
R A N O.

T o assess o bjecti ve res p o nse, t he t u m or b ur de n at baseli ne will be esti mate d a n d use d f or 
c o m paris o n wit h s u bse q ue nt meas ure me nts. At baseli ne, t u m or lesi o ns will be cate g orize d i n 
tar get a n d n o n- tar get lesi o ns acc or di n g t o R E CI S T 1. 1 a n d sec o n darily usi n g m R E CI S T f or 
s u bjects i n t he H C C c o h ort. F or s u bjects i n t he gli o blast o ma c o h ort, t he assess me nt w ill be 
ma de acc or di n g t o R A N O.
Res ults f or t hese e val uati o ns will be rec or de d wit h as m uc h s pecificity as p ossi ble s o t hat pre - a n d 
p ost -treat me nt res ults will pr o vi de t he best o p p ort u nit y f or e val uati n g t u m or res p o nse. 
A n y  CR or P R s h o ul d be c o nfir me d acc or di n g t o R E CI S T 1. 1 or R A N O f or s u bjects wit h 
gli o blast o ma . I n t he c ase of a P R or C R, a c o nfir m at or y C T or M RI sc a n m ust be d o ne n o 
s o o ner t h a n 4 wee ks ( prefer a bl y at t he sc he d ule d 6-wee k i nter v al) . 
T he In vesti gat or ma y  perf or m sca ns i n a d diti o n t o a sc he d ule d trial sca n f or me dical reas o ns or if 
t he In vesti gat or s us pects P D . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 9 3
As o utli ne d i n Secti o n  5. 1 , treat me nt s h o ul d c o nti n ue wit h t he i n vesti gati o nal dr u g a n d t he s u bject 
ma y  remai n o n st u d y acc or di n g t o t he I n vesti gat or’s decisi o n a n d i n a gree me nt wit h t he s u bject i n 
case of P D acc or di n g t o R E CIS T 1. 1 , m R E CIS T ( H C C) , or R A N O ( gli o blast o ma) . 
S u bjects w h o ha ve e x perie nce d S D, P R , or C R s h o ul d c o nti n ue treatme nt t hr o u g h t he e n d of 
1 2 m o nt hs , alt h o u g h a d diti o nal treat me nt is p ossi ble . If t he In vesti gat or belie ves t hat a s u bject 
ma y  be nefit fr o m treat me nt b e y o n d 1 2 m o nt hs, it ma y  be per miss i ble after disc ussi o n wit h t he 
Me dical M o nit or
a n d t he S p o ns or Me dical Res p o nsi ble . S u bjects re-i nitiati n g treat me nt s h o ul d be 
assesse d acc or di n g t o t he Sc he d ule of Assess me nts ( see Secti o n 5. 1. 6 ).
7. 3. 1
I m m u ne-relate d Res p o nse C riteri a
T he ir R E CIS T is o nl y  assesse d b y  the i n de pe n de nt ra di ol o g y re vie w, n ot as a n I nvesti gat or 
assess me nt.
Bel o w is a s u m mar y of ir R E CIS T (f or m ore c o m pre he nsi ve i nf or mati o n, refer t o B o h nsac k 2 0 1 4 ).
1.
T otal meas ure d t u m or bur de n ( T M T B): Baseli ne -selecte d tar get lesi o ns a n d ne w meas ura ble 
lesi o ns s h o ul d N O T be assesse d se parately.   Meas ure me nts 
of t h ose lesi o ns s h o ul d be 
c o m bi ne d i nt o t he T M T B , a n d o ne c o m bi ne d assess me nt pr o vi de d.
2.
Ne w Meas ura ble Lesi o ns: I n ir R E CIS T, criteria f or u ni di me nsi o nal lesi o n meas ur eme nt a p pl y 
t o b ot h tar get a n d ne w meas ura ble lesi o ns: a mi ni m u m
1 0 m m i n t he l o n gest dia meter f or 
n o n- n o dal lesi o ns, a n d a mi ni m u m 1 5 m m i n s h ort a xis f or l ym p h n o des.   S maller lesi o ns 
c o ntri b ute t o t he n o n-tar get or ne w n o n- meas ura ble t u m or b ur de n, b ut d o n ot get meas ure d.
3.
ir P R if n o Tar get Lesi o ns: If ne w meas ura ble lesi o ns a p pear i n s u bjects wit h n o tar get lesi o ns 
at B aseli ne, ir P D will be assesse d. T hat ir P D ti me p oi nt will be c o nsi dere d a n e w B aseli ne, 
a n d all s u bse q ue nt ti me p oi nt s will be c o m pare d wit h it f or res p o nse assess me nt. 
A n 
assess me nt of ir P R is p ossi ble if t he T M T B of ne w meas ura ble lesi o ns decreases b y  ≥3 0 % 
c o m pare d wit h t he first ir P D d oc u me ntati o n.
4.
N o n -Tar g et Lesi o ns: I n ali g n me nt wit h R E CI S T 1. 1, B aseli ne selecte d n o n-tar get lesi o ns ca n 
ne ver c o n vert t o meas ura ble lesi o ns, n ot e ve n if t he y i ncrease i n size at s u bse q ue nt ti me p oi nt s 
a n d bec o me meas ura ble.   O nl y  tr ue ne w lesi o ns ca n be meas ure d a n d c o ntri b ute t o t he T M T B.
E xa m ple: A s u bject has m ulti ple l u n g metastases, all s maller t ha n 1 0 m m a n d selecte d as n o- tar get 
lesi o ns at B aseli ne. If, at a s u bse q ue nt ti me p oi nt s o me of t hese n o n- tar get lesi o ns i ncrease a n d 
bec o me > 1 0 m m, a n d 1 ne w lesi o n > 1 0 m m a p pears, o nl y the ne w meas ura ble lesi o n will 
c o ntri b ute t o t he T M T B, a n d n ot t he B aseli ne selecte d n o n-tar get lesi o n t hat i ncrease d i n size. 
Ot her wise s uc h a n i ncrease w o ul d ma ke persisti n g n o n- tar get lesi o ns s witc h i nt o t he ne w 
meas ura ble lesi o n cate g or y , w hic h w o ul d be i nacc urate, as t he lesi o n e xiste d at B aseli ne.
5.
ir P D Base d o n N o n -Tar g et Lesi o ns: In ir R E CI S T, a s u bsta ntial a n d u ne q ui v ocal i ncrease of 
n o n-tar get lesi o ns is i n dicati ve of pr o gressi o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 7 / 1 9 3
≥1 0 m m i n dia meter. 
T he c ystic or s ur gical ca vit y sh o ul d n ot be meas ure d i n deter mi ni n g 
res p o nse.
N o n meas ura ble disease is defi ne d as eit her u ni di me nsi o nall y  meas ura ble lesi o ns, masses wit h 
mar gi ns n ot clearl y defi ne d, or lesi o ns wit h ma xi mal per pe n dic ular dia meters less t ha n 1 0 m m.
N U M B E R O F L E SI O N S
If t here are m ulti ple c o ntrast -e n ha nci n g lesi o ns, a mi ni m u m of t he 2 lar gest lesi o ns s h o ul d be 
meas ure d, a n d t he s u m of t he pr o d ucts of t he per pe n dic ular dia meters of t hese lesi o ns s h o ul d be 
deter mi ne d. A ma xi m u m of 5 of t he lar gest lesi o ns ma y  be meas ure d. 
I n ge neral, t he lar gest 
e nlar gi n g lesi o n(s) s h o ul d be selecte d; h o we ver, e m p hasis s h o ul d als o be place d o n lesi o ns t hat 
all o w re pr o d uci ble re peate d meas ure me nts. 
Occas i o nally, t he lar gest lesi o ns ma y  not le n d 
t he msel ves t o re pr o d uci ble meas ure me nts, a n d t he ne xt lar gest lesi o ns t hat ca n be meas ure d 
re pr o d uci bly s h o ul d be selecte d. 
F or s u bjects w h o ha ve m ulti ple lesi o ns of w hic h o nl y  1 or 2 are i ncreasi n g i n size, t he enlar gi n g 
lesi o ns s h o ul d be c o nsi dere d t he tar get lesi o ns f or e val uati o n of res p o nse. T he ot her lesi o ns will 
be c o nsi dere d n o ntar get lesi o ns a n d s h o ul d als o be rec or de d. 
D E FI NI TI O N O F R A DI O G R A P HI C R E S P O N S E
Ra di o gra p hic res p o nse s h o ul d be deter mi ne d i n c o mparis o n wit h t he t u m or meas ure me nt o btai ne d 
at pretreat me nt Baseli ne f or deter mi nati o n of res p o nse, a n d t he s mallest t u m or meas ure me nt at 
eit her pretreat me nt Baseli ne or after i nitiati o n of t hera py s h o ul d be use d f or deter mi nati o n of 
pr o gressi o n. Ta ble 9 lists t he criteria f or ra di o gra p hic c ha n ges after t hera p y. I n t he e ve nt t hat t he 
ra di o gra p hic c ha n ges are e q ui v ocal a n d it is u nclear w het her t he s u bject is sta ble or has de vel o pe d 
pr o gressi ve disease, it is per missi ble t o c o nti n ue treat me nt a n d o bser ve t he s u bject cl osel y, f or 
e xa m ple at 4- wee k i nter vals. If s u bse q ue nt i ma gi n g st u dies de m o nstrate t hat pr o gressi o n has 
occ urre d, t he date of pr o gressi o n s h o ul d b e t he date of t he sca n at w hi c h t his iss ue was first raise d.  
All meas ura ble a n d n o n meas ura ble lesi o ns s h o ul d be assesse d usi n g t he sa me tec h ni q ues as at 
Baseli ne . I deall y, s u bjects s h o ul d be i ma ge d o n t he sa me M RI sca n ner, or at least wit h t he sa me 
ma g ne t stre n gt h, f or t he d urati o n of t he st u d y t o re d uce diffic ulties i n i nter preti n g c ha n ges.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 9 3
T a ble 9
Criteri a f or Res p o nse Assess me nts I nc or p or ati n g M RI 
a n d Cli nic al 
F act ors
Assess me nt 
Criteri a
C o m plete res p o nse
Re q uires all of t he f oll o wi n g: c o m plete disa p peara nce of all e n ha nci n g meas ura ble 
a n d n o n meas ura ble disease s ustai ne d f or at least 4 w ee ks; n o ne w lesi o ns; sta ble or 
i mpr o ve d n o ne n ha nci n g ( T 2/ F L AI R) lesi o ns; s u bjects must be off c ortic oster oi ds ( or 
o n p h ysi ol o gic re place me nt d oses o nl y); a n d sta ble or i m pr o ve d cli nicall y.
N ote: S u bjects wit h n o n meas ura ble disease o nl y ca n n ot ha ve a c o m plete res p o nse; 
t he best res p o nse p ossi ble is sta ble disease.
Partial res p o nse
Re q uires all of t he f oll o wi n g: ≥ 5 0 % decrease c o m pare d wit h base li ne i n t he s u m of 
pr o d ucts of per pe n dic ular dia meters of all meas ura ble e n ha nci n g lesi o ns s ustai ne d f or 
at least 4 wee ks; n o pr o gressi o n of n o n meas ura ble disease; n o ne w lesi o ns; sta ble or 
i mpr o ve d n o ne n ha nci n g ( T 2/ F L AI R) lesi o ns o n sa me or l o wer d ose of c ortic oster oi ds 
c o m pare d wit h baseli ne sca n; t he c ortic oster oi d d ose at t he ti me of t he sca n
e val uati o n s h o ul d be n o greater t ha n t he d ose at ti me of baseli ne sca n; a n d sta ble or 
i mpr o ve d cli nicall y. 
N ote: S u bjects wit h n o n meas ura ble disease o nl y ca n n ot h a ve a partial res p o nse; t he 
best res p o nse p ossi ble is sta ble disease.
Sta ble disease
Re q uires all of t he f oll o wi n g: d oes n ot q ualif y f or c o m plete res p o nse, partial 
res p o nse, or pr o gressi o n; sta ble n o ne n ha nci ng ( T 2/ F L AI R) lesi o ns o n sa me or l o wer 
d ose of c ortic oster oi ds c o m pare d wit h baseli ne sca n. I n t he e ve nt t hat t he 
c ortic oster oi d d ose w as i ncrease d f or ne w s y m pt o ms a n d si g ns wit h o ut c o nfir mati o n 
of disease pr o gressi o n o n ne ur oi m a gi n g, a n d s u bse q ue nt f oll o w-u p i ma gi n g s h o ws 
t hat t his i ncrease i n c orticoster oi ds w as re q uire d beca use of disease pr o gressi o n, t he 
last sca n c o nsi dere d t o s h o w sta ble disease will be t he sca n o btai ne d w he n t he 
c ortic oster oi d d ose was e q ui vale nt t o t he baseli ne d ose.
Pr o gressi ve disease
Defi ne d b y a n y of t he f oll o wi n g: ≥ 2 5 % i ncrease i n s u m of t he pr o d ucts of 
per pe n dic ular dia meters of e n ha nci n g lesi o ns c o m pare d wit h t he s mallest t u mor 
meas ure me nt o btai ne d eit her at baseli ne (if n o decrease) or best res p o nse, o n sta ble or
i ncreasi n g d oses of c ortic oster oi ds* ; si g nifica nt i ncrease i n T 2/ F L AI R n o ne n ha nci n g 
lesi o n o n sta ble or i ncreasi n g d oses of c ortic oster oi ds c o m pare d wit h baseli ne sca n or 
best res p o nse after i nitiati o n of t hera p y* n ot ca use d b y c o m or bi d e ve nts (e g, ra diati o n 
t hera p y, de m yeli nati o n, isc he mic i nj ur y, i nfecti o n, seiz ures, p ost o perati ve c ha n ges, or 
ot her treat me nt effects); a n y ne w lesi o n; clear cli nical deteri orati o n n ot attri b uta ble t o
ot her ca uses a part fr o m t he t u m or (e g, seiz ures, me dicati o n a d verse effects, 
c o m plicati o ns of t hera p y, cere bro vasc ular e ve nts, i nfecti o n, a n d s o o n) or c ha n ges i n 
c ortic oster oi d d ose; fail ure t o ret ur n f or e val uati o n as a res ult of deat h or deteri orati n g 
c o n diti o n; or clear pr o gressi o n of n o n meas ura ble disease.
A b bre viati o ns: M RI, ma g netic res o na nce i ma gi n g; F L A I R, fl ui d-atte n uate d i n versi o n rec o ver y.
N O T E. All meas ura ble a n d n o n meas ura ble lesi o ns m ust be assesse d usi n g t he sa me tec h ni q ues as at baseli ne.
* Sta ble d oses of c ortic oster oi ds i ncl u de s u bjects n ot o n c ortic oster oi ds.
T he defi niti o n of cli nical deteri orati o n is left t o t he discreti o n of t he I n vesti gat or, b ut it is 
rec o m me n de d t hat a decli ne i n t he K P S fr o m 1 0 0 or 9 0 t o 7 0 or less, a decli ne i n K P S of at least 
2 0 fr o m 8 0 or less, or a decli ne i n K P S fr o m a n y B aseli ne t o 5 0 or less, f or at least 7 d a y s, be 
c o nsi dere d ne ur ol o gic deteri orati o n u nless attri b uta ble t o c o m or bi d e ve nts or c ha n ges i n 
c ortic oster oi d d ose. Si milarl y , a decli ne i n t he E C O G P S a n d W H O perf or ma nce sc ores fr o m 0 or 
1 t o 2 or 2 t o 3 w o ul d be c o nsi dere d ne ur ol o gic deteri orati o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 9 3
M U L TI F O C A L T U M O R S
F or m ultif ocal lesi o ns, pr o gressi ve disease is defi ne d as ≥2 5 % i ncrease i n t he s u m of pr o d ucts of 
per pe n dic ular dia meters of all meas ura ble lesi o ns c o m pare d wit h t he s mallest t u m or meas ure me nts 
after i nitiati o n of t hera p y (Ta ble 9 ). T he a p peara nce of a ne w lesi o n or u ne q ui v ocal pr o gressi o n 
of n o ntar get lesi o ns will als o be c o nsi dere d pr o gressi o n. Partial res p o nse is defi ne d as ≥ 5 0 % 
decrease, c o m pare d wit h Baseli ne, i n t he s u m of pr o d ucts of per pe n dic ular dia meters of all 
meas ura ble lesi o ns s ustai ne d f or at least 4 wee ks wit h sta ble or decreasi n g c ortic oster oi d d oses.
Ta ble 1 0 s u m marizes t he ra di ol o gical a n d cli nical criteria f or t u m or res p o nse assess me nts 
acc or di n g t o R A N O.
T a ble 1 0
S u m m ar y of Pr o p ose d R A N O Res p o nse Criteri a
Criteri a
C o m plete Res p o nse
P arti al Res p o nse
St a ble Dise ase
Pr o gressi ve Dise ase
T 1 ga d oli ni u m 
e n ha nci n g disease
N o ne
≥ 5 0 % decrease
< 5 0 % decrease b ut 
< 2 5 % i ncrease
≥ 2 5 % i ncrease
T 2/ F L AI R
Sta ble or decrease 
Sta ble or decrease
Sta ble or decrease
I ncrease *
N e w  Lesi o n
N o ne
N o ne
N o ne
Prese nt *
C ortic oster oi ds
N o ne
Sta ble or decrease 
Sta ble or decrease
N ot a p plica ble * *
Cli nical stat us
Sta ble or i ncrease 
Sta ble or i ncrease 
Sta ble or i ncrease
Decrease *
Re q uire me nt f or 
res p o nse
All
All
All
A n y *
F L AI R = fl uid- atte n uate d i n versi o n rec o ver y; R A N O = Res p o nse A ssess me nt i n Ne ur o-O nc ol o g y .
* Pr o gressi o n occ urs w he n t his criteri o n is prese nt.
* * I ncrease i n c ortic oster oi ds al o ne will n ot be ta ke n i nt o acc o u nt i n deter mi ni n g pr o gressi o n i n t he a bse nce of 
persiste nt cli nical deteri orati o n.
7. 4
Assess me nt of S afet y
T he safety pr ofile of t he I MP will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d a nal ys is of 
baseli ne me dical c o n diti o ns, A Es , p h y sical e xa mi nati o n fi n di n gs i ncl u di n g vital si g ns a n d e yes 
si g ns a n d sy m pt o ms, a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y ap pare nt t o xicit y ex perie nce d b y  eac h s u bject will be perf or me d 
fr o m t he ti me of gi vi n g i nf or me d c o nse nt a n d t hr o u g h o ut t he trial. T he I n vesti gat or will re p ort 
a n y AEs , w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  the s u bject (see Secti o n 7. 4. 1. 2) . 
Gi ve n t he i nte n de d M o A , partic ular atte nti o n will be gi ve n t o A Es t hat ma y f oll o w t he e n ha nce d 
T -cell acti vati o n s uc h as persiste nt ras h, diarr hea a n d c olitis, a ut oi m m u ne he patitis, art hritis, 
gl o mer ul o ne p hritis, car di o m yo pat h y, u veitis a n d ot her i nfla m mat or y eye c o n diti o ns , or ot her 
i m m u ne-relate d reacti o ns. 
O p ht hal m ol o gic e xa mi nati o ns s h o ul d be c o nsi dere d, w he n cli nicall y 
i n dicate d, f or si g ns or sy m pt o ms of u veitis. F urt her m ore, d ue t o t he a nti -T G F β acti vit y, partic ular 
atte nti o n will als o be gi ve n t o e ve nts ass ociate d wit h,
a ne mia, a n d ras h wit h h y per kerat osis /
k erat oaca nt h o ma a n d sq ua m o us cell carci n o ma of t he s ki n .
T he re p orti n g peri o d f or A E s is descri be d i n Secti o n 7. 4. 1. 3.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 9 3
T he safet y assess me nts will be perf or me d acc or di n g t o t he S c he d ules of A ssess me nts (see Ta ble 1
a n d Ta ble 2 ).
7. 4. 1
A d verse E ve nts
7. 4. 1. 1
A d verse E ve nt Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. A n 
A E ca n t heref ore be a n y unfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct. 
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n / ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
I n case of a fatalit y, t h e ca use of deat h is c o nsi dere d as a n A E, a n d t he deat h is c o nsi dere d as its 
O U T C O M E.
T he I n vesti gat or is re q uire d t o gra de t he se verit y or t o xicit y of eac h A E .
I n vesti gat ors will refere nce t he N CI -C T C A E v 4. 0 3 ( p u blicati o n date: 1 4 J u ne 2 0 1 0 ), a descri pti ve 
ter mi n ol o g y t hat ca n be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y / i nte nsit y; hereafter referre d t o as se verity ) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt G ra des are als o pr o vi de d.
If a partic ular A E’s se verit y is n ot s pecifically gra de d b y t he g ui da nce d oc u me nt, t he I n vesti gat or 
is t o use t he ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5 f oll o wi n g his o r her best 
me dical j u d g me nt.
Gr a de 1:
Mil d
Gr a de 2:
M o derate
Gr a de 3:
Se vere
Gr a de 4:
Life -t hreate ni n g or disa bli n g
Gr a de 5:
Deat h 
Acc or di n g t o t he S p o ns or ’s c o n ve nti o n, a n y cli nical A E wit h se verity of Gra de 4 or 5 m ust als o 
be re p orte d as an S A E as per Secti o n 7. 4. 1. 4 ; ho we ver, a la b orat or y  a b n or malit y of Gra de 4, s uc h 
as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us o nl y  if t he c o n diti o n meets o ne of t he seri o us 
criteria descri be d bel o w.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 9 3
If deat h occ urs , t he pri mar y  ca use of deat h or e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” will be rec or de d as t he o utc o me of t h is s pecific e ve nt a n d deat h will 
n ot be rec or de d as se parate e ve nt. O nl y , if n o ca use of deat h ca n be re p orte d ( f or e xa m ple, s u d de n 
deat h, u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o t he I M P usi n g t he 
f oll o wi n g defi ni ti o ns.  Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o t he 
M S B 0 0 1 1 3 5 9 C i ncl u de, b ut ma y  n ot be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d t he 
M S B 0 0 1 1 3 5 9 C, 
t he k n o w n safet y pr ofile of M S B 0 0 1 1 3 5 9 C, 
me dical hist or y , c o nc o mitant 
me dicati o n, c o urse of t he u n derl yi n g disease, trial pr oce d ures.
U nrel ate d:
N ot reas o na bl y relate d t o t he IM P. 
T he A E c o ul d n ot me dicall y  ( p har mac ol o gically
/ cli nicall y) be attri b ute d t o t he I MP u n der st u d y i n t his cli nical trial pr ot oc ol. A 
reas o na ble alter nati ve e x pla nati o n m ust be a vaila ble.
Rel ate d:
Reas o na bl y relate d t o t he I M P.  T he A E c o ul d me dicall y ( p har mac ol o gicall y /
cli nicall y) be attri b ute d t o t he IM P
u n der st u d y  i n t his cli nical trial pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n o r m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (f or e xa m ple, o n a n 
E C G trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o treat me nt disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  
t he I n vesti gat or. If a la b orat or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical c o n diti o n 
(f or e xa m ple, a ne mia, i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he a b n or mal val ue 
itself.
7. 4. 1. 1. 1  
A d verse Dr u g Re acti o n ( A D R)
A n A D R is defi ne d i n t his trial as a n y A E assesse d as relate d t o M S B 0 0 1 1 3 5 9 C
b y  the In vesti gat or 
a n d / or S p o ns or .
7. 4. 1. 1. 2
Seri o us A d verse E ve nt s
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h,

Is life-t hreate ni n g (N ote: T he ter m “life-t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is 
at ris k of deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca used deat h 
if it was m ore se vere ),

Re q uires i n patie nt h os pitalizati o n or pr ol o n g s a n e xisti n g h os pitalizati o n,

Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacity,

Is a c o n ge nital a n o maly or birt h defect, or

Is ot her wise c o nsi dere d t o be me dicall y i m p orta nt. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 9 3
N ote: I mp orta nt me dical e ve nts t hat ma y  not res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y  be c o nsi dere d as S A Es w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y 
ma y  je o par dize t he s u bject or m a y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d a b o ve.  Exa m pl es of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot 
res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use. A n y t yp e 
o f ne w (sec o n dar y) ca ncer i ncl u di n g s q ua m o us cell ca ncer of t he s ki n s h o ul d be c o nsi dere d as 
me dicall y  i m p orta nt c o n diti o n. 
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n I M P  is als o 
c o nsi dere d a S A E , as descri be d in Secti o n 7. 4. 1. 4 .
E ve nts T h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y trial treat me nt or trial pr oce d ures (f or 
e xa m ple, a n o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) 
are n ot c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (f or e xa m ple, u n desira ble effects of a n y ad mi nistere d 
treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es.
7. 4. 1. 1. 3
E ve nts N ot t o Be C o nsi dere d as A Es / S A Es 
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or fre q ue nc y duri n g 
t he trial are defi ne d as Baseli ne Me dical C o n diti o ns, a n d are n ot t o be c o nsi dere d A Es.
A E / S A Es O bser ve d i n Ass oci ati o n Wit h Dise ase Pr o gressi o n 
Pr o gressi o n of t he disease / dis or der bei n g st u die d assesse d b y  meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as we ll as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n A E / S A E , u nless t he s u bject’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d a n d / or u nless t he o utc o me is fatal wit hi n t he A E re p orti n g 
peri o d (as defi ne d i n Secti o n 7. 4. 1. 3 ).
7. 4. 1. 1. 4
Pre defi ne d 
A Es 
of S peci al 
I nterest ( A E SI) f or S afet y 
M o nit ori n g
T he A E SIs f or M S B 0 0 1 1 3 5 9 C
are s u m marize d i n Secti o n 3. 5.  T he re p orti n g of A E SI is defi ne d 
i n Secti o n 7. 4. 1. 4.
7. 4. 1. 2
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts
At eac h trial visit, t he s u bject will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d , a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, 
w het her re p orte d b y t he s u bject or o bser ve d b y  t he In vesti gat or. 
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he e C R F.  
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 9 3
All S A Es a n d all n o nseri o us A Es of s pecial i nterest m ust be a d diti o nall y doc u me nte d a n d re porte d 
usi n g t he a p pr o priate S A E Re p ort F or m or t he A E SI  Re p ort F or m , res pecti vel y as descri be d i n 
Secti o n 7. 4. 1. 4 .
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n (o nset a n d 
res ol uti o n dates a n d ti mes t o be c o m plete d w he n it is i m p orta nt t o assess t he ti me of A E o nset 
relati ve t o t he rec or de d treat me nt a d mi nistrati o n ti me), its se verit y, its ca usal relati o ns hi p wit h t he 
trial treat me nt, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or ot her acti o n ta ke n, 
i ncl u di n g d ose m o dificati o n or disc o nti n uati o n of t he I MP, a n d its o utc o me. I n ad diti o n, seri o us 
cases s h o ul d be i de ntifie d a n d t he a p pr o priate seri o us ness criteria d oc u me nte d. 
If a n A E 
c o nstit utes a D L T t his has t o be d oc u me nte d acc or di n gl y.
S pecific g ui da nce ca n be f o u n d i n t he e C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns.
7. 4. 1. 3
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d
T he A E re p orti n g peri o d f or safet y sur veilla nce be gi ns w he n t he s u bject is i ncl u de d i nt o t he trial 
( date a n d ti me of first si g nat ure of i nf or me d c o nse nt) a n d c o nti n ues t hr o u g h t he trial’s 2 8- Da y 
Safet y  F oll o w-u p visit, defi ne d as 2 8 da ys ( ± 5 da ys) after l ast trial dr u g a d mi nistrati o n.  After t he 
2 8- D a y  Safet y F oll o w -u p visit o nl y  AEs t hat are dee me d attri b uta ble t o trial dr u g b y  the 
I n vesti gat or s h o ul d be d oc u me nte d u ntil t he 1 0-Wee k Safet y F oll o w -u p visit , defi ne d as 1 0 wee ks 
( ± 2 wee ks) after t he last trial dr u g a d mi nistrati o n.
A n y  S A E assesse d as relate d t o M S B 0 0 1 1 3 5 9 C
m ust be re p orte d w he ne ver it occ urs, irres pecti ve 
of t he ti me ela pse d si nce t he last a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C . 
7. 4. 1. 4
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts, A d verse 
E ve nts of S peci al I nterest 
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y ( wit hi n a ma xi m u m 2 4 h o urs after bec o mi n g a ware of t he e ve nt) i nf or m t he S p o ns or 
or its desi g nee usi n g t he S A E Re p ort F or m f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
I n e xce pti o nal circ u msta nces, a S A E ( or f oll o w-u p i nf or mati o n) ma y  be re p orte d b y tele p h o ne; i n 
t hese cases, S A E R e p ort F or m m ust be pr o vi de d i m me diatel y  t hereafter.
Re p orti n g pr oce d ures a n d ti meli nes are t he sa me f or a n y ne w i nf or mati o n o n a pre vi o usl y  re p orte d 
S A E ( = f oll o w -u p).
Rele va nt pa ges fr o m t he e C R F m a y  be pr o vi de d i n parallel (f or e xa m ple, me dical hist or y , 
c o nc o mita nt dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  t he I n vesti gat or, if a vaila ble (f or 
e xa m ple, la b orat or y res ults, h os pital re p ort, a n d a ut o ps y re p ort). I n all cases, t he i nf or mati o n 
pr o vi de d o n t he S A E R e p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he 
e C R F.  
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 9 3
T he I n vesti gat or m ust res p o n d t o a n y re q uest f or f oll o w- u p i nf or mati o n (f or e xa m ple, a d diti o nal 
i nf or mati o n, o utc o me fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y q uesti o n t he S p o ns or 
or desi g nee ma y ha ve o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial re p orts.  
T his is n ecessar y t o e ns ure a pr o m pt assess me nt of t he e ve nt b y  the S p o ns or or desi g nee a n d (as 
a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us uall y  be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he Gl o bal Dr u g Safet y de part me nt ma y  co ntact t he I n vesti gat or directl y t o o btai n 
f urt her i nf or mati o n or t o disc uss t he e ve nt.
A d verse E ve nts of S peci al I nterest
I n t he e ve nt of a n o nseri o u s Gra de ≥ 3 A E SI , t he I nvesti gat or m ust c o m plete t he A E SI  Re p ort 
F or m a n d pr o vi de it t o t he S p o ns or / desi g nee i m me diatel y (wit hi n 2 4 h o urs) f oll o wi n g t he s pecific 
c o m pleti o n i nstr ucti o ns.  Seri o us A E SI s ha ve t o be re p orte d i n a n e x pe dite d ma n ner as S A Es as 
o utli ne d a b o ve. F or Gra de 1 a n d Gra de 2 n o nseri o us A E SI s, t he A E SI  Re p ort F or m s h o ul d be 
pr o vi de d t o t he S p o ns or / desi g nee wit hi n 5 w or ki n g d a y s f oll o wi n g t he s pecific c o m pleti o n 
i nstr ucti o ns.
D ose - Li miti n g T o xicities
Eac h e ve nt meet i n g t he criteria of a D L T (see Secti o n 5. 1. 3. 3 ) has t o be rec or de d i n t he e C R F 
wit hi n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.  Seri o us D L Ts ha ve t o be re p orte d i n a n 
e x pe dite d ma n ner as S A Es as o utli ne d a b o ve.
7. 4. 1. 5
S afet y Re p orti n g t o He alt h A ut h orities, I n de pe n de nt Et hics 
C o m mittees / I nstit uti o n al Re vie w B o ar ds a n d I n vesti g at ors
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da n ce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g trial s u bjects t o t he I E C / I RB t hat a p pr o ve d t he 
trial.
I n acc or da nce wit h I C H G C P g ui deli nes , t he S p o ns or or desi g nee will i nf or m t he I n vesti gat or of 
“fi n di n gs t hat c o ul d a d versel y affect t he safet y of s u bjects, i m pact t he c o n d uct of t he trial , or alter 
t he IE C’s / I RB’s a p pr o val / fa v ora ble o pi ni o n t o c o nti n ue t he trial ”. I n partic ular a n d i n li ne wit h 
res pecti ve re g ulati o ns, t he S p o ns or / desi g nee will i nf or m t he I n vesti gat or of A Es t hat are b ot h 
seri o us a n d u ne x pecte d a n d are c o nsi dere d t o be related t o t he a d mi nistere d pr o d uct (s us pecte d 
u ne x p ecte d seri o us a d verse reacti o n s [S U S A Rs ]). T he I n vesti gat or s h o ul d place c o pies of Safet y 
Re p orts i n t he I nvesti gat or Site File. 
Nati o nal re g ulati o ns wit h re gar d t o Safet y Re p ort 
n otificati o ns t o I n vesti gat ors will be ta ke n i nt o acc o u nt.
W he n s pecifically re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or or desi g nee will pr o vi de 
a p pr o priate Safet y  Re p orts directl y  to t he c o ncer ne d lea d I EC / I RB a n d will mai ntai n rec or ds of 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 9 3
t hese n otificati o ns. 
W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, the I n vesti gat or will be res p o nsi ble f or pr o m ptl y  notif y i n g t he c o ncer ne d I E C / I RB 
of a n y Safet y Re p orts pr o vi de d b y  the S p o ns or or desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
F or trials c o vere d b y t he E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities re gar di n g 
t he re p orti n g of S A Es / S U S A Rs / Safet y  Iss ues will be carrie d o ut i n acc or da nce wit h t hat 
Directi ve a n d wit h t he relate d Detaile d G ui da nce.
7. 4. 1. 6
M o nit ori n g of S u bjects W it h A d verse E ve nts
A d verse e ve nts are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he trial (see Secti o n 7. 4. 1. 3 ) 
a n d are assesse d f or fi nal o utc o me at t he 2 8 -Da y  Safety F oll o w -u p visit .  After t he 2 8 -Da y  Safety 
F oll o w -u p visit , o nl y  AEs t hat are dee me d attri b uta ble t o t he trial dr u g b y t h e In vesti gat or s h o ul d 
be d oc u me nte d u ntil t he 1 0- Wee k Safet y F oll o w -u p visit, defi ne d as 1 0 wee ks ( ± 2 wee ks) after 
t he last trial dr u g a d mi nistrati o n .
All S A Es o n g oi n g at t he 2 8- D a y  Safet y F oll o w -u p visit m ust be m o nit ore d a n d f oll o we d u p b y  the 
I n vesti gat or u ntil sta bilizati o n or u ntil t he o utc o me is k n o w n, u nless t he s u bject is d oc u me nte d as 
“l ost t o f oll o w- u p”.  In a d diti o n, all trial dr u g -relate d S A Es occ urri n g after t he 2 8- Da y  Safet y 
F oll o w -u p visit a n d o n g oi n g at t he Safet y F oll o w -u p visit m ust be f oll o we d u p i n t he sa me ma n ner.  
Reas o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d.  It is als o t he 
res p o nsi bilit y of t he I n vestigat or t o e ns ure t hat a n y necessar y a d diti o nal t hera pe utic meas ures a n d 
f oll o w-u p pr oce d ures are perf or me d. 
7. 4. 2
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure 
O nl y  pre g na ncies c o nsi dere d b y  the I n vesti gat or t o be relate d t o trial treat me nt (f or e xa m ple,
res ulti n g fr o m a dr u g i nteracti o n wit h a c o ntrace pti ve me dicati o n) are c o nsi dere d t o be A E s; 
h o we ver, all pre g na ncies wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n 
Secti o n 7. 4. 1. 3 m ust be rec or de d b y  co n ve nti o n i n t he A E pa ge / secti o n of t he eC R F. T he sa me 
r ule a p plies t o pre g na ncies i n fe male s u bjects a n d t o pre g na ncies i n fe male part ners of male 
s u bjects. T he I n ve sti gat or m ust als o n otif y  the S p o ns or or desi g nee i n a n e x pe dite d ma n ner of a n y 
pre g na nc y  usi n g t he Pa per Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d acc or di n g t o t he 
sa me ti meli nes as descri be d f or S A E re p orti n g i n Secti o n 7. 4. 1. 4 . 
I n vesti gat ors m ust 
acti vel y foll o w u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he s u bjects are wit h dra w n fr o m t he trial.
T he I n vesti gator m ust n otif y  the S p o ns or or desi g nee of t hese o utc o mes usi n g t he Pre g na nc y 
Re p ort F or m . If a n a b n or mal o utc o me occ urs , t he S A E Re p ort F or m will be use d if t he s u bject 
s ustai ns a n e ve nt a n d t he Pare nt -C hil d / Fet us A d verse E ve nt Re p ort F or m if t he c hil d / fet us 
s ustai ns a n e ve nt.
A n y  ab n or mal o utc o me m ust be re p orte d i n a n e x pe dite d ma n ner as descri be d i n Secti o n 7. 4. 1. 4,  
w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da y s after deli ver y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 9 3
I n the e ve nt of a pre g na nc y  in a s u bject occ urri n g d uri n g t he c o urse of t he trial, t he s u bject m ust 
be disc o nti n ue d fr o m trial me dicati o n i m me diatel y. T he S p o ns or or desi g nee m ust be n otifie d 
wit h o ut dela y  a n d the s u bject m ust be f oll o we d as me nti o ne d a b o ve.
7. 4. 3
Cli nic al L a b or at or y Assess me nts
It is esse ntial t hat t he S p o ns or be pr o vi de d wit h a list of la b orat or y n or mal ra n ges bef ore s hi p me nt 
of I MP. A n y c h a n ge i n la b orat or y n or m al ra n ges d uri n g t he trial will a d dit i o nall y be f or war de d t o 
t he C R O a n d t he S p o ns or.
Bl o o d sa m ples will be ta ke n fr o m n o n- faste d s u bjects. All r o uti ne la b orat or y anal y ses will be 
perf or me d at a la b orat or y facilit y local t o t he i n vesti gati o nal site a n d rele va nt res ults m ust be dra w n
a n d c hec ke d bef ore a d mi nistrati o n of M S B 0 0 1 1 3 5 9 C.
T he re p ort of t he res ults m ust be retai ne d 
as a part of t he s u bject’s me dical rec or d or s o urce d oc u me nts. Bl o o d sa m ples f or t he tests liste d 
i n Ta ble 1 1 will be ta ke n fr o m n o n -faste d s u bjects d uri n g t he Scree ni n g p hase , at t he 2 8- Da y  Safet y 
F oll o w -u p visit, a n d d uri n g t he treat me nt p hase as s pecifie d i n t he Sc he d ules of Assess me nts 
(Ta ble 1 a n d Ta ble 2) . C o m plete bl o o d c o u nt a n d c ore ser u m c he mistr y m ust be c hec ke d wit hi n 
4 8 h o urs pri or t o eac h d ose a d mi nistrati o n .
Ser u m electr o p h oresis, A C T H ( d ose-escalati o n c o h orts o nl y), A N A, R F, T 4, T SH, a n d uri nal ysis 
will be assesse d at t he ti me p oi nts defi ne d i n t he Sc he d ules of Assess me nts (Ta ble 1 a n d Ta ble 2) . 
If c o nfir mati o n of a s u bject’s p ost me n o pa usal stat us is necessar y , a F S H le vel will als o be 
perf or me d at Scree ni n g , see Secti o n 7. 1. 1.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 9 3
T a ble 1 1
Re q uire d L a b or at or y P a nel Tests
F ull C he m istr y
He m at ol o g y
Al b u mi n
A bs ol ute l y m p h oc yte c o u nt
Al kali ne p h os p hatase *
A bs ol ute ne utr o p hil c o u nt
A la ni ne a mi n otra nsferase *
He mat ocrit
A m ylase
He m o gl o bi n
As partate a mi n otra nsferase *
Platelet c o u nt
G a m ma- gl uta m yltra nsferase
R B C c o u nt
Bl o o d urea nitr o ge n / t otal urea *
W hite bl o o d cell
c o u nt a n d differe ntial c o u nt
Calci u m *
Re d bl o o d cell m or p h ol o g y * *
C hl ori de *
Retic ul oc ytes
C h olester ol
M ea n c or p usc ular he m o gl o bi n
Creati ne ki nase
Mea n c or p usc ular v ol u me
Creati ni ne *
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n
C-reacti ve pr otei n
Gl uc ose *
He m ost ase ol o g y
Lactate de h y dr o ge nase
A cti vate d partial t hr o m b o plasti n ti me
Li pase
Pr ot hr o m bi n ti me / i nter nati o nal n or malize d rati o
P h os p h or us / ph os p hates *
Ma g nesi u m *
B asic Uri n al ysis ( di pstic k, i ncl u di n g macr osc o pic a p peara nce, bilir u bi n, 
bl o o d, c ol or, gl uc ose, ket o nes, le u k oc yte esterase, nitrite, p H, pr otei n, s pecific 
gra vit y, ur o bili n o ge n)
F ull uri nal ysis ( di pstic k pl us micr osc o pic e val uati o n) t o be perf or me d o nl y at 
t he Scree ni n g a n d 2 8 -Da y Safet y F oll o w -u p visits a n d a basic uri nal ysis pri or 
t o eac h a d mi nistrati o n of t he I M P.
P otassi u m *
S o di u m *
T otal bilir u bi n / i n direct bilir u bi n*
T otal pr otei n
Uric aci d
T otalit y of bi n di n g A D A s
Tri gl yceri des
A F P ( H C C c o h ort o nl y)
A C T H ( d ose-esc al ati o n c o h orts o nl y) , A N A, R F, T S H, a n d T 4
H or m o ne
F ollicle -sti m ulati n g h or m o ne (if a p plica ble)
He p atitis Scree ni n g a
He patitis B s urface a nti ge n, he patitis B c ore a nti b o d y
He patitis B D N A ( q ua ntitati ve P C R) a
He patitis C A nti b o d y, He patitis C R N A ( q ua ntitati ve P C R)
a
He patitis D a nti b o d y b
A C T H =a dre n oc ortic otr o pic h or m o ne; A D A = a nti dr u g a nti b o d y; A N A = a nti n uclear a nti b o d y; H C C = he pat ocell ular carci n o ma; 
I M P =I n vesti gati o nal Me dici nal Pr o d uct; P C R = p ol y merase c hai n reacti o n; R F =r he u mat oi d fact or; T S H =t h yr oi d -sti m ulati n g 
h or m o ne ; T 4 =f ree t h yr o xi ne.
* C ore ser u m c he mistries
* * O nl y  i n case of a ne mia o nset assesse d as relate d t o st u d y treat me nt  
a
If he patitis B s urface a nti ge n p ositi ve a n d he patitis B c ore a nti b o d y p ositi ve, t he n refle x t o q ua ntitati ve H B V D N A ( P C R) ; if 
he patitis B c ore a nti b o d y p ositi ve al o ne, t he n refle x t o q ua ntitati ve he patitis B D N A ( P C R); i f he patitis C a nti b o d y p ositi ve, 
t he n refle x t o q ua ntitati ve he patitis C R N A ( P C R) .  If s u bject is p ositi ve f or he patitis B or C, t he n viral l oa d will be f oll o we d 
b y q ua ntitati ve P C R acc or di n g t o  Ta ble 3.
b If he patitis B s urface a nti ge n or he patitis B D N A p ositi vit y at Scree ni n g t he n m ust c hec k f or he patitis D stat us (he patitis D 
anti b o d y) .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 9 3
If a s u bject has a cli nicall y si g nifica nt a b n or mal la b orat or y test val ue t hat is n ot prese nt at B aseli ne, 
t he test will be re peate d wee kl y a n d t he s u bject will be f oll o we d u ntil t he test val ue has ret ur ne d 
t o t he n or mal ra n ge or t he I n vesti gat or has deter mi ne d t hat t he a b n or malit y is c hr o nic or st a ble.
7. 4. 4
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts
T he E C O G P S will be assesse d at Scree ni n g a n d at s u bse q u e nt visits as i n dicate d i n t he Sc he d ules
of A ssess me nts (Ta ble 1 a n d Ta ble 2) a n d d oc u me nte d i n t he e C R F.
B o d y  wei g ht will be meas ure d at Scree ni n g a n d at s u bse q ue nt visits as i n dicate d i n t he Sc he d ules 
of Assess me nts (Ta ble 1 a n d Ta ble 2) a n d d oc u me nte d i n t he eC R F. B o d y  hei g ht will be meas ure d 
at Scree ni n g o nl y.
A p h ysical e xa mi nati o n will be c o n d ucte d at Scree ni n g a n d at s u bse q ue nt visits as i n dicate d i n t he 
Sc he d ules of Assess me nts (Ta ble 1 a n d Ta ble 2 ) a n d d oc u me nte d i n t he eC R F ( detaile d descri pti o n 
i n Secti o n 7. 1) . A n y  ab n or malities arisi n g or w orse ni n g after t he si g ni n g of t he I C F s h o ul d be 
d oc u me nte d i n t he eC R F A d verse E ve nt secti o n (see Secti o n 7. 4. 1) . A b n or mal fi n di n gs are t o be 
reassesse d at s u bse q ue nt visits.
A n o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt 
a n d wit h vis ual ac uit y s h o ul d be c o n d ucte d at Scre e ni n g.  At s u bse q ue nt visits, e ye si g ns a n d 
s ym pt o ms s h o ul d be c hec ke d.  If t here are a n y cli nicall y rele va nt fi n di n gs t he n a n a p pr o priate 
o p ht hal m ol o g y  exa mi nati o n i ncl u di n g slit la m p e val uati o n i ncl usi ve of t he a nteri or se g me nt a n d 
wit h vis ual ac uit y  s h oul d be o btai ne d wit hi n 2 da ys.
Di gital 1 2- lea d E C Gs will be rec or de d i n tri plicate at Scree ni n g a n d at trial visits as i n dicate d i n 
t he Sc he d ules of Assess me nts (Ta ble 1 a n d Ta ble 2 ) u ntil Wee k 1 3 ( Visit 1 0). S u bse q ue nt E C Gs 
will be o btai ne d as si n gle rec or di n gs. F or im me diate safety assess me nts , 1 E C G will be l ocally 
a nal yz e d at eac h ti me p oi nt (see Secti o n 7. 2. 6) . All E C Gs o btai ne d i n tri plicate will be f or mall y 
a nal y z e d t o e val uate w het her M S B 0 0 1 1 3 5 9 C has a n y effects o n car diac electr o p h ysi ol o g y , a n d i n 
partic ular re p olarizati o n .  Alt h o u g h precli nical data s h o ws n o car di o vasc ular si g nal, wee kl y E C G 
assess me nts wit h tri plicates a n d di gital rec or di n g are j ustifie d d ue t o t he n ee d t o c haracterize 
e x p os ure / Q Tc relati o ns hi ps t o facilitate f ut ure cli nical rati o nale.
All ne wl y  dia g n ose d or w orse ni n g c o n diti o ns, si gns a n d s ym pt o ms o bser ve d si nce S cree ni n g, 
w het her relate d t o trial treat me nt or n ot, are t o be re p orte d as A Es.
F or female s u bjects of c hil d beari n g p ote ntial, ser u m β- H C G pre g na nc y  test will be carrie d o ut 
d uri n g t he Scree ni n g p hase. A uri ne or ser u m β- H C G test will be perf or me d acc or di n g t o  Ta ble 1
a n d Ta ble 2 d uri n g t he treat me nt p hase , at t he 2 8 -Da y  Safet y F oll o w - u p visit , a n d at t he Safet y  
F oll o w - u p visit . Res ults of t he m ost rece nt pre g na nc y  test s h o ul d be a vaila ble pri or t o t he ne xt 
d osi n g of I M P. S u bjects w h o
are p ost me n o pa usal (a ge-relate d a me n orr hea ≥ 1 2 c o nsec uti ve 
m o nt hs 
a n d if nee de d
F S H > 4 0 mI U/ m L
[i n t he p ost me n o pa usal ra n ge] as o utli ne d i n 
Secti o n 7. 1. 1 ), or w h o h a ve u n der g o ne h y sterect o m y or bilateral o o p h orect o m y  are e xe m pt fr o m 
pre g na nc y  testi n g.
If necessar y  to c o nfir m p ost me n o pa usal stat us, a n F S H will be dra w n at 
Scree ni n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 5 / 1 9 3
F H SI - 8:  T he F H SI -8 is a patie nt -rep orte d o utc o me q uesti o n naire desi g ne d t o assess s y m pt o ms i n 
patie nts wit h pa ncreatic a n d he pat o biliar y  ca ncers ( Y o u nt 2 0 0 2).  It is a n 8- ite m i n de x pai n 
( 3 ite ms), fati g ue ( 2 ite ms), wei g ht l oss, na usea, a n d ja u n dice, wit h eac h ite m sc ore d o n a 5- p oi nt 
scale ( 0 = n ot at all; 4 = ver y m uc h).
F or s u bjects i n t he H C C e x pa nsi o n c o h ort, s ym pt o m se verit y will be assesse d usi n g t he P GI S a n d 
a m o difie d versi o n of a ca ncer -s pecific i nstr u me nt f or t he assess me nt of he pat o biliar y  s ym pt o ms
(E O R T C Q L Q -H C C 1 8 - M) as i n dicate d i n t he Sc he d ules of Assess me nts (Ta ble 2) .
E O R T C Q L Q -H C C 1 8 - M:  T he E O R T C Q L Q -H C C 1 8 -M is a m o difie d versi o n of t he E O R T C’s 
H C C -s pecific m o d ule (Blaze b y  20 0 4 ).  It c o nsists of 1 7 patie nt -re p orte d ite ms i nte n de d pr o vi de 
c o m pre he nsi ve H C C -relate d s ym pt o m c o vera ge w hile mi ni mizi n g patie nt assess me nt b ur de n.  The 
E O R T C Q L Q -H C C 1 8 -M 
i ncl u des 7 ite ms fr o m t he E O R T C Q L Q -C 3 0 meas uri n g d y s p nea 
( 1 ite m), fati g ue ( 3 ite ms), l oss of a p petite ( 1 ite m), a n d na usea a n d v o miti n g ( 2 ite ms).  Th e 
E O R T C Q L Q- H C C 1 8 -M 
i ncl u des a n a d diti o nal 1 0 ite ms fr o m t he E O R T C’s H C C -s pecific 
m o d ule meas uri n g se nse of taste ( 1 ite m), wasti n g ( 1 ite m), a b d o mi nal bl oati n g ( 1 ite m), ja u n dice 
( 1 ite m), pr urit us ( 1 ite m), s h o ul der pai n ( 1 ite m), a b d o mi nal pai n ( 1 ite m), fe ver ( 2 ite ms), an d 
earl y satiety ( 1 ite m).  Eac h of t hese ite ms is rate d o n a 4- p oi nt res p o nse scale ( 1 = n ot at all; 
4 = ver y  m uc h).
F or s u bjects i n t he es o p ha geal a de n ocarci n o ma c o h ort o nl y , s ym pt o m se verit y will be assesse d 
usi n g t he P GI S, select ite ms fr o m t he E O R T C Q L Q -C 3 0, a n d select ite ms fr o m t he E O R T C 
Q L Q -O E S 1 8 as i n dicate d i n t he Sc he d ul e of Assess me nts (Ta ble 2) .  For t he es o p ha geal 
a de n ocarci n o ma c o h ort, t he selecte d E O R T C Q L Q -C 3 0 ite ms meas ure fati g ue ( 3 ite ms) a n d pai n 
( 2 ite ms).
E O R T C Q L Q -O E S 1 8 :  T he E O R T C Q L Q -O E S 1 8 is a n 1 8- ite m patie nt -re p orte d o utc o me 
q uesti o n naire create d t o meas ure f u ncti o ni n g, s ym pt o ms, a n d healt h -relate d q ualit y of life iss ues 
s pecific t o es o p ha geal ca ncer (Blaze b y 2 0 0 3 ).  A su bset of t he E O R T C Q L Q -O E S 1 8 ite ms ha ve 
bee n selecte d f or a d mi nistrati o n i n t he es o p ha geal a de n ocarci n o ma c o h ort t o re d uce patie nt b ur de n 
w hile 
all o wi n g f or ke y  tu m or -relate d s ym p t o ms t o be assesse d.  T he selecte d E O R T C 
Q L Q -O E S 1 8 ite ms meas ure d y s p ha gia ( 3 ite ms) a n d refl u x pai n ( 2 ite ms). Eac h of t hese ite ms is 
rate d o n a 4-p oi nt res p o nse scale ( 1 = n ot at all; 4 = ver y  m uc h).
F or s u bjects i n t he gli o blast o ma c o h ort o nl y , s ym pt o m se verit y will be assesse d usi n g t he P GI S 
a n d select ite ms fr o m t he E O R T C Q L Q -B N 2 0 as i n dicate d i n t he Sc he d ule of Assess me nts (Ta ble 
2) . 
E O R T C Q L Q -B N 2 0 :
T he E O R T C Q L Q -B N 2 0 is a 2 0- ite m patie nt -re p orte d o utc o me 
q uesti o n naire create d t o meas ure f u ncti o ni n g, s ym pt o ms, a n d healt h -relate d q ualit y of life iss ues 
s pecific t o brai n ca ncer (Ta p h o or n 2 0 1 0 ). A s u bset of t he E O R T C Q L Q -B N 2 0 ite ms ha ve bee n 
selecte d f or a d mi nistrati o n i n t he gli o blast o ma c o h ort t o re d uce patie nt b ur de n w hile all o wi n g f or 
ke y  fu ncti o nal i m pacts of t he pri mar y  tu m or t o be assesse d. T he selecte d E O R T C Q L Q- B N 2 0 
ite ms meas ure m ot or d y sf u ncti o n ( 3 ite ms), c o m m u nicati o n deficit ( 3 ite ms), a n d dr o wsi ness 
( 1 ite m). Eac h of t hese ite ms is rate d o n a 4-p oi nt res p o nse scale ( 1 = n ot at all; 4 = ver y  m uc h).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 8 / 1 9 3
T a ble 1 2
T he 9 5 % E x act ( Cl o p per -Pe ars o n) C o nfi de nce I nter v als f or O R R B ase d 
o n 3 0 E nr olle d S u bjects
O R R
9 5 % E x act C o nfi de nce I nter v al
0. 2 0
( 0. 0 7 7, 0. 3 8 6)
0. 3 0
( 0. 1 4 7, 0. 4 9 4)
0. 4 0
( 0. 2 2 7, 0. 5 9 4)
0. 5 0
( 0. 3 1 3, 0. 6 8 7)
0. 6 0
( 0. 4 0 6, 0. 7 7 3)
0. 7 0
( 0. 5 0 6, 0. 8 5 3)
H C C asce n di n g -d ose c o h ort
I n or der t o f urt her assess t he t olera bilit y a n d safety of M S B 0 0 1 1 3 5 9 C i n s u bjects wit h H C C, u p t o 
3 6 s u bjects m a y  be e nr olle d i n t he asce n di n g d ose part of t he H C C c o h ort.  Si x s u bjects will be 
e nr olle d at 3 m g/ k g o nce t he 3 m g / k g d ose le vel i n t he d ose escalati o n part of t he trial has bee n 
cleare d b y  the S M C.  T hirt y  s u bjects will be e nr olle d at a 1 2 0 0 m g  flat d ose o nce t he 2 0 m g/ k g 
d ose le vel i n t he d ose escalati o n part of t he trial has bee n cleare d b y t he S M C.  
H C C sec o n d-li ne or s or afe ni b-i nt oler a nt c o h ort
U p t o 7 0 s u bjects will be e nr olle d i n t he H C C sec o n d-li ne or s orafe ni b-i nt olera nt c o h ort at t he d ose 
selecte d b y  the S M C d uri n g t he d ose -escalati o n part of t he trial, f or t he p ur p ose of assessi n g 
efficac y base d o n t he B O R .  A n i nitial e nr oll me nt of 3 0 s u bjects will accr ue if > 6 of 3 0 s u bjects 
i n t he H C C 1 2 0 0 m g flat-d ose asce n di n g -d ose c o h ort ha ve a res p o nse (t hat is a n O R R of at least 
2 0 % ).  The pri mar y  anal ysis will be 2 4 wee ks after t he 6 0t h s u bject starte d treat me nt.  The a nal ys is 
will i ncl u de t he 3 0 s u bjects fr o m t he H C C 1 2 0 0 m g flat-d ose asce n di n g-d ose c o h ort a n d 
3 0 s u bjects fr o m t he H C C sec o n d-li ne or s orafe ni b-i nt olera nt c o h ort (assu mes a si milar tar get 
p o p ulati o n as per t he i ncl usi o n criteria) .  A n a d diti o nal 4 0 s u bjects ma y  s u bse q ue ntl y be e nr olle d 
i n or der t o gat her a d diti o nal safety data .
Wit h 6 0 s u bjects treat e d ( 3 0 s u bjects fr o m t he H C C 1 2 0 0 m g flat -d ose asce n di n g-d ose c o h ort an d 
3 0 s u bjects fr o m t he H C C sec o n d-li ne or s orafe ni b-i nt olera nt c o h ort), t he st u d y has a p pr o xi matel y
8 8 % p o wer t o r ule o ut a ≤ 2 0 % O R R ( n ull h y p ot hesis) w he n t he tr ue O R R is 3 5 % at t he 1 0 % t y p e 
I err or rate (1- si de d).
N S C L C a nti -P D -1 / a nti -P D -L 1 fail ure c o h ort
Wit h 8 0 s u bjects treate d, t he st u d y has a p pr o xi matel y 92 % a n d 9 9 % p o wer t o r ule o ut a ≤ 5 % O R R 
( n ull h y p ot hesis) w he n t he tr ue O R R is 1 5 % a n d 2 0 %, res pecti vely, at t he 5 % t ype I err or rate 
( 1-si de d).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 9 / 1 9 3
Mel a n o m a
a nti -P D -1 / a nti -P D -L 1 fail ure c o h ort
T he g oal of t his c o h ort is a n e x pl orati o n of a nti-P D -L 1  retreat me nt a n d i nitial cli nical res p o nses 
as a wa y t o s h o w c o nfi de nce i n t he pr o of- of-mec ha nis m of t he a d diti o n of T G F β i n hi biti o n t o t he 
a nti-P D -L 1 mec ha nis m.  Wit h 3 0 s u bjects w h o were treate d wit h pr i or a nti-P D - 1 / a nti-P D -L 1  
t hera py, t he st u d y has 8 7 % p o wer t o r ule o ut a 5% O R R w he n t he tr ue O R R is 2 0 % wit h 1 -si de d 
0. 1 al p ha.
N S C L C sec o n d-li ne co h ort
Wit h 3 0 sec o n d-li ne s u bjects treate d at 1 2 0 0 m g/i nf usi o n , t he st u d y has a p pr o xi matel y 82 % p o wer 
t o r ule o ut a ≤ 2 0 % O R R ( n ull h y p ot hesis) w he n t he tr ue O R R is 4 0 % at t he 1 0 % t y pe I err or rate 
( 1-si de d). 
A n i nteri m a nal ysis will occ ur w he n t he 3 0 s u bjects are e val ua bl e f or res p o nse assess me nt at 
1 2 wee ks (t hat is, ha ve eit her c o m plete d t he sec o n d t u m or reassess me nt at W ee k 1 2 or 
disc o nti n ue d t he st u d y bef ore W ee k 1 2).   If ≤4 res p o n ders are o bser ve d at t he i nteri m a nal ys is, n o 
f urt her s u bjects will be e nr olle d i nt o t he N S C LC sec o n d -li ne c o h ort.
P a ncre atic a de n oc arci n o m a , C R C , a n d cer vic al c a ncer c o h orts
Wit h 3 0 s u bjects treate d, t he st u d y  has a p pr o xi matel y 7 9 % p o wer t o r ule o ut a ≤ 1 0 % O R R ( n ull 
h y p ot hesis) w he n t he tr ue O R R is 2 5 % at t he 1 0 % t y pe I err or rate (1- si de d).
O v ari a n c a ncer, T N B C, a n d es o p h a ge al a de n oc arci n o m a c o h orts
Wit h 3 0 s u bjects treate d, t he st u d y  has a p pr o xi matel y 8 7 % p o wer t o r ule o ut a ≤ 1 5 % O R R ( n ull 
h y p ot hesis) w he n t he tr ue O R R is 3 5 % at t he 1 0 % t y pe I err or rate (1- si de d).
Gli o bl ast o m a c o h ort
Wit h 3 0 s u bjects treate d, t he st u d y  h as ap pr o xi matel y  97 % p o wer t o r ule o ut a ≤ 5 0 % D C R (n ull 
h y p ot hesis) w he n t he tr ue D C R is 8 0 % at t he 5 % t y pe I err or rate ( 1- si de d).
S C C H N c o h ort
Wit h 3 0 s u bjects treate d, t he st u d y  has a p pr o xi matel y 8 7% p o wer t o r ule o ut a ≤ 1 5 % O R R ( n ull 
h y p ot hesis) w he n t he tr ue O R R is 3 5 % at t he 1 0 % t y pe I err or rate ( 1-si de d).
All e x p a nsi o n c o h orts
E xce pt f or t he gli o blast o ma c o h ort, t he pri mar y  efficac y e n d p oi nt f or t he d ose e x pa nsi o n-part of 
t he trial is t he c o nfir me d B O R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d b y  the I n de pe n de nt 
E n d p oi nt Re vie w C o m mittee (IR C) a n d will be e val uate d b y  co nfir me d O R R .  F or gli o blast o ma, 
t he pri mar y e n d p oi nt will be disease c o ntr ol .  
F or eac h c o h ort se paratel y (e xce pt f or t he H C C c o h ort), u p o n c o nti n uati o n of t he c o h ort u p t o t he 
tar geted sa m ple size, t he pri mar y  anal ys is will occ ur 2 4 wee ks after t he start of treat me nt i n t he 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 0 / 1 9 3
last s u bject e nr olle d.  F or t he H C C c o h ort, t he pri mar y  a nalys is will be after 6 0 s u bjects (i ncl u di n g 
3 0 s u bjects fr o m t he asce n di n g d ose a n d 3 0 s u bjects fr o m t he sec o n d li ne e x pa nsi o n c o h ort).
T he t otal sa m ple size f or t he e x pa nsi o n c o h orts is e x pecte d t o be u p t o a p pr o xi matel y 5 6 6 s u bjects.
8. 2
R a n d o miz ati o n
N S C L C sec o n d -li ne c o h ort
Q ualifie d s u bjects will be ra n d o mize d at a 1: 1 rati o t o recei ve eit her 5 0 0 or 1 2 0 0 m g /i nf usi o n
M S B 0 0 1 1 3 5 9 C
usi n g per m ute d bl oc k ra n d o mizati o n. Ra n d o mizati o n will n ot be stratifie d. 
Ra n d o mizati o n will occ ur u p o n c o m pleti o n of t he Scree ni n g pr oce d ures a n d deter mi nati o n of 
s u bject eli gi bilit y as descri be d i n Secti o n 6. 3 .
N ot a p plica ble f or s u bjects n ot i ncl u de d i n t he N S C L C sec o n d -li ne c o h ort.
8. 3
E n d p oi nts
8. 3. 1
Pri m ar y E n d p oi nts
T he pri mar y  e n d p oi nts f or t he d ose-escalati o n part of t h e trial are t he:

N u m ber, se verit y , a n d d urati o n of T E A Es acc or di n g t o t he N CI-C T C A E v 4. 0 3

N u m ber, se verity a n d d urati o n of treat me nt-relate d A Es f or all d ose gr o u ps / i n dicati o ns 
acc or di n g t o C T C A E v 4. 0 3

Occ urre nce of D L Ts d uri n g t he first 3 wee ks ( 2 1 da y s) of treat me nt i n t he d ose -escalati o n part 
of t he trial
E xce pt f or t he gli o blast o ma c o h ort, the pri mar y efficac y en d p oi nt f or t he d ose -e x pa nsi o n part of 
t he trial is t he c o nfir me d B O R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d b y t he I R C ( Secti o n 2. 2. 2)
a n d will be e val uate d b y c o nfir me d O R R . F or gli o blast o ma, t he pri mar y  e n d p oi nt will be disease 
c o ntr ol acc or di n g t o R A N O as a dj u dicate d b y t he I R C .
8. 3. 2
Sec o n d ar y E n d p oi nts
T he s ec o n dar y e n d p oi nts f or t he d ose-escalati o n part of t he trial are t he:

M S B 0 0 1 1 3 5 9 C P K
pr ofile (f or d ose escalati o n), i ncl u di n g A U C , Cma x , Cmi n , a n d t1/ 2

Ser u m titers of a nti M S B 0 0 1 1 3 5 9 C a nti b o dies

B O R acc or di n g t o R E CI S T 1. 1 per I n vesti gat or assess me nt
T he sec o n dar y  e n d p oi nts f or t he e x pa nsi o n part of t he trial are t he: 

M S B 0 0 1 1 3 5 9 C P K
pr ofile (f or d ose escalati o n), i ncl u di n g A U C, Cma x , Cmi n , a n d t1/ 2

Ser u m titers of a nti M S B 0 0 1 1 3 5 9 C a nti b o dies
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 4 / 1 9 3
Descri pti ve statistics will be use d t o s u m marize t he trial res ults, t hat is, statistics f or c o nti n u o us 
varia bles m a y  incl u de mea ns, 
me dia ns, 
ra n ges, a n d a p pr o priate meas ures 
of varia bilit y . 
Q ualitati ve varia bles will be s u m marize d b y  c o u nts a n d perce nta ges. T he u ncertai n t y of esti mates 
will be assesse d b y  co nfi de nce i nter vals.
U nless ot her wise s pecifie d, t he calc ulati o n of pr o p orti o ns 
will be base d o n t he sa m ple size of t he a nal ysis set of i nterest. C o u nts of missi n g o bser vati o ns 
will be i ncl u de d i n t he de n o mi nat or a n d prese nte d as a se parate cate g or y if n ot ot her wise s pecifie d 
i n t he S A P .
T he D L T A nal ys is Set is t he u n derlyi n g data set f or t he M T D deter mi nati o n. Safet y a nal ys es will 
be perf or me d o n t he Safet y  Anal ys is Set.  Baseli ne s u m maries a n d efficac y a nal yses will
be 
perf or me d o n t he F ull A nal y sis Set.
A nal ys es of P K varia bles will be perf or me d o n t he P K 
A nal y sis Set .  A nal ys is of ser u m titers of A nti -M S B 0 0 1 1 3 5 9 C 
A nti b o dies (A D A ) will be 
perf or me d o n t he I m m u n o ge nicit y A nalys is Set. 
 
 
T he esti mati o n of P K para meters will be perf or me d usi n g Wi n N o nli n ® Versi o n 5. 0 or hi g her. All 
ot her statistical a nal ys es will be perf or me d usi n g S A S ®
Versi o n
9. 1. 3 or hi g her, or R, 
Versi o n 2. 1 0. 1 or h i gher.
U nless ot her wise s pecifie d, t he e n d p oi nt a nal yses descri be d i n t he f oll o wi n g will be perf or me d 
se paratel y f or b ot h t he d ose -escalati o n part a n d t he e x pa nsi o n part of t he trial.
8. 5. 2
A n al ysis of Pri m ar y E n d p oi nts
8. 5. 2. 1
M a xi m u m -T oler ate d D ose Deter mi n ati o n
F or d eter mi nati o n of t he M T D, i n di vi d ual s u bject data fr o m t he d ose -escalati o n part will be 
re p orte d. 
I n a d diti o n, f or t he fi nal statistical a nal ysis, t he f oll o wi n g will be a nalyz e d:

At eac h d ose le vel, t he n u m ber a n d pr o p orti o n of s u bjects i n t he D L T A nal y sis Set w h o 
e x perie nce a D L T d uri n g t he D L T e val uati o n peri o d.

At eac h d ose le vel, t he n u m ber a n d pr o p orti o n of T E A Es e x perie nce d b y  su bjects i n t he D L T 
A nal y sis Set d uri n g t he D L T e val uati o n peri o d.
T he M T D will be deter mi ne d acc or di n g t o t he d ose -escalati on pla n descri be d i n Secti o n 5. 1. 3. 2 . 
T he M T D is defi ne d as t he hi g hest d ose le vel at w hic h n o m ore t ha n 1 s u bject o ut of 6 s u bjects 
treate d i n a c o h ort a n d e val ua ble f or D L T deter mi nati o n e x perie nces a D L T.
8. 5. 2. 2
Best O ver all Res p o ns e
E xce pt f or t he gli o blast o ma c o h ort, t he pri mar y efficac y en d p oi nt f or t he d ose -e x pa nsi o n part of 
t he st u d y is t he c o nfir me d B O R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d b y  the I R C a n d will be 
e val uate d b y t he c o nfir me d O R R .  F or gli o blast o ma, t he pri mar y en d p oi nt will be disease c o ntr ol 
acc or di n g t o R A N O as a dj u dicate d b y t he I R C .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 5 / 1 9 3
E xce pt f or t he gli o blast o ma c o h ort, t he he pri mar y  efficac y para meter i n t he e x pa nsi o n part is t he 
B O R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d b y  t he IR C ( Secti o n 2. 2. 2 ) a n d will be e val uate d b y 
c o nfir me d O R R .  For gli o blast o ma, t he pri mar y  efficac y para meter will be disease c o ntr ol 
acc or di n g t o R A N O as a dj u dicate d b y t he I R C.
T he pri mar y  anal ys is of t he B O R w ill be c o n d ucte d i n t he F ull A nal ys is Set. T he n u m ber a n d 
pr o p orti o n of B O R ( defi ne d as C R + P R) will be ta b ulate d. F or t he gli o blast o ma c o h ort, t he 
pr o p orti o n of B O R of C R, P R, or S D ≥1 2 wee ks acc or di n g t o R A N O will be ta b ulate d. T he 
2- si de d 9 5 % Cl o p per-Pears o n CI will be c o nstr ucte d . 
F or a B O R of P R or C R, c o nfir mati o n of t he res p o nse acc or di n g t o R E CI S T 1. 1 ( Eise n ha uer 2 0 0 9) 
or R A N O f or s u bjects wit h gli o blast o ma (We n
2 0 1 0 ) will be re q uire d f or t he fi nal a nal ys is.  T he 
i nteri m a nal ys is will be base d o n u nc o nfir me d res p o nse. T he res p o nse at eac h sc he d ule d t u m or 
assess me nt a n d t he B O R will be liste d f or eac h s u bject.  The O R R, defi ne d as t he pr o p orti o n of 
s u bjects wit h B O R of P R or C R, will be ta b ulate d f or eac h c o h ort. 
8. 5. 3
A n al ysis of Ot her E n d p oi nts
8. 5. 3. 1
Effic ac y P ar a meters
Cli nical efficac y  para meters will be a nalyz e d descri pti vel y i n t he F ull A nal y sis Set.  
F or t he d ose escalati o n part of t he trial, t he sec o n dar y efficac y en d p oi nt is B O R acc or di n g t o 
R E CI S T 1. 1 per In vesti gat or assess me nt. F or a B O R of P R or C R, c o nfir mati o n of t he res p o nse 
acc ordi n g t o R E CI S T 1. 1 (Eise n ha uer 2 0 0 9 ) will be re q uire d. T he res p o nse at eac h sc he d ule d 
t u m or assess me nt a n d t he B O R will be liste d f or eac h s u bject. T he O R R , defi ne d as t he pr o p orti o n 
of s u bjects wit h B O R of P R or C R, will be ta b ulate d b y  d ose le vel.
F or t he d ose -e x pa nsi o n part of t he trial, t he f oll o wi n g sec o n dar y efficac y en d p oi nts will be 
assesse d:

D urati o n of res p o nse, acc or di n g t o R E CI S T 1. 1 a n d a dj u dicate d b y  t he I R C, will be calc ulate d 
f or eac h s u bject wit h a c o nfir me d res p o nse a n d will be a nal yz e d usi n g t he Ka pla n -Meier met h o d

D C R , defi ne d as t he pr o p orti o n of s u bjects wit h B O R of C R, P R, or S D f or ≥1 2 wee ks will be 
ta b ulate d wit hi n eac h e x pa nsi o n c o h ort

P F S a n d T T P ti me (acc or di n g t o R E CI S T 1. 1 a n d a dj u dicate d by t he I R C) a n d O S ti me will be 
prese nte d i n listi n gs a n d a nal yz e d usi n g t he Ka pla n -Meier met h o d i n eac h e x pa nsi o n c o h ort 
se paratel y if t he c o h ort e nr olls t he f ull pla n ne d n u m ber of s u bjects
8. 5. 3. 2 
P h ar m ac o k i netic Pr ofile
Plas ma c o nce ntrati o ns of M S B 0 0 1 1 3 5 9 C
will be deter mi ne d b y  a vali date d met h o d at t he ti mes 
liste d i n Sc he d ules of Assess me nts (refer t o Ta ble 1 a n d Ta ble 2 ).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 6 / 1 9 3
T he f oll o wi n g P K para meters will be esti mate d a n d re p orte d i n t he P K A nal ysis Set:

A U C 0-t ( d ose escalati o n p orti o n , H C C, a n d N S C L C bi o mar ker c o h orts o nl y ): Area u n der t he 
c o nce ntrati o n-ti me c ur ve fr o m t he ti me of d osi n g t o t he ti me of t he last o bser vati o n (calc ulate d 
b y  li near tra pez oi dal s u m mati o n).

A U C 0- ∞( d ose escalati o n p orti o n , H C C, a n d N S C L C bi o mar ker c o h orts o nl y ): Area u n der t he 
c o nce ntrati o n-ti me c ur ve fr o m t he ti me of d osi n g e xtra p olate d t o i nfi nit y (calc ulate d b y  the 
li near tra pez oi dal s u m mati o n a n d e xtra p olate d t o i nfi nit y usi n g Clast/ λz).

λ z ( d ose escalati o n p orti o n , H C C, a n d N S C LC bi o mar ker c o h orts o nl y ): Ter mi nal eli mi nati o n 
rate c o nsta nt. T he val ue of λ z is deter mi ne d fr o m t he sl o pe of t he re gressi o n li ne of l o g 
(c o nce ntrati o n) vs. ti me wit h t he f oll o wi n g c o nstrai nts: (i) t here m ust be at least 3 c o nsec uti ve 
meas ura ble c o nce ntrati o ns, (ii) all c o nce ntrati o ns m ust be decli ni n g wit h ti me, a n d (iii) t he 
c orrelati o n c oefficie nt (r) of re gressi o n m ust be ≥ 0. 9 5.

C ma x : Ma xi m u m ser u m c o nce ntrati o n o bser ve d p ost d ose .

C mi n : Mi ni m u m
ser u m c o nce ntrati o n o bser ve d p ost d ose .

tma x ( d ose escalati o n p orti o n , H C C, a n d N S C L C bi o mar ker c o h orts o nl y ): Ti me at w hic h t he 
C ma x occ urs.

t½ ( d ose escalati o n, H C C, a n d N S C L C bi o mar ker c o h orts o nl y) : 
Eli mi nati o n half -life, 
deter mi ne d as 0. 6 9 3/ λ z.
T he P K para meters will be s u m marize d usi n g descri pti ve statistics. I ndi vi d ual as well as mea n 
c o nce ntrati o n-ti me pl ots will be de picte d.
U nres ol ve d missi n g data ma y  be i m p ute d w he n t he a nal ys is i nte grity i s affecte d. T he c o nser vati ve 
pri nci ple will be use d f or data i m p utati o n.
8. 5. 3. 3
Ser u m Titers of A nti -M S B 0 0 1 1 3 5 9 C
A nti b o dies ( A D A )
I m m u n o ge nicity testi n g strate g y  will be i m ple me nte d a n d c o n d ucte d i n li ne wit h:

I m m u n o ge nicity 
Assess me nt 
of 
Bi otec h n ol o g y -Deri ve d 
T hera pe utic 
Pr otei ns 
( E M E A/ C H M P/ B M W P/ 1 4 3 2 7/ 2 0 0 6).

I m m u n o ge nicity assess me nt of m o n ocl o nal 
a nti b o dies i nte n de d f or i n vi v o cli nical use 
(E ur o pea n Me dici nes A ge nc y [ E M A]/ C H M P/ B M W P/ 8 6 2 8 9/ 2 0 1 0).

F o o d a n d Dr u g A d mi nistrati o n ( 2 0 0 9, draft) G ui da nce f or I n d ustr y: Assa y  De vel o p me nt f or 
I m m u n o ge nicity Testi n g of T hera pe utic Pr otei ns.
A q ualifie d met h o d t hat uses a n aci d diss ociati o n ste p t o detect A D As i n t he prese nce of e xcess 
dr u g i n h u ma n ser u m will be a p plie d. Re m o val of dr u g after aci d treat me nt is n ot re q uire d. T he 
A D A titers of p ositi ve sa m ples will be deter mi ne d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 8 / 1 9 3
8. 5. 4. 3
P h ysic al E x a mi n ati o n, I ncl u di n g Vit al Si g ns a n d 1 2 -le a d 
Electr oc ar di o gr a m
V ital si g ns ( b o dy te m perat ure, res pirat or y rate, heart rate, a n d bl o o d press ure) , e ye si g ns a n d 
s ym pt o ms base d o n S yste m Or ga n Class of “e ye dis or ders” , a n d 1 2-lea d E C G rec or de d acc or di n g 
t o t he Sc he d ule s of Assess me nts (refer t o Ta ble 1 a n d Ta ble 2) will be prese nte d. 
F urt her details will be pr o vi de d i n t he S A P base d o n c urre nt safet y e x perie nce a p pl yi n g t he latest 
Me d D R A versi o n.
8. 6
I nteri m a n d A d diti o n al Pl a n ne d A n al yses
E nr oll me nt of ex pa nsi o n c o h orts will n ot be st o p pe d f or t he p ur p ose of c o n d ucti n g t heir res pecti ve
i nteri m a nal ys es b ut will st o p if f utilit y  is met as s pecifie d.
D ose Esc al ati o n P art
I n t he d ose -escalati o n part, t he trial data will be e val uate d bef ore decisi o n is ma de t o g o t o t he ne xt 
d ose le vel or t o start wit h treat me nt i n t he e x pa nsi o n part .
E x p a nsi o n P art
F or all e x pa nsi o n c o h orts e xce pt gli o blast o ma c o h ort, t he e n d p oi nts i n t hese i nteri m a nal yses are 
O R R (c o nfir mati o n is n ot re q uire d).  F or gli o blast o ma, t he e n d p oi nt i n t he i nteri m a nal ys is will be 
D C R. T here is n o m ulti plicit y a dj ust me nt is a p plie d t o t he i nteri m a nal ys es.  T he decisi o n r ules at 
t he i nteri m a nal yses ser ve as g ui da nce a n d are n o n- bi n di n g.  In t he a bse nce of a c o ntr ol ar m , 
o utc o mes i n t his si n gle ar m st u d y ha ve t o be i nter prete d wit h ca uti o n, b ot h at i nteri m a n d fi nal 
a nal ys es.
H C C asce n di n g -d ose c o h ort
A n i nteri m a nal ysis will be c o n d ucte d 1 2 wee ks after t he fi nal s u bject i n t he asce n di n g-d ose 
p orti o n recei ve d t heir first d ose.
If ≤ 6 res p o nses are o bser ve d i n t he 3 0 s u bjects at t he i nteri m a nal ysis, t he e nr oll me nt i nt o H C C 
sec o n d-li ne or s orafe ni b-i nt olera nt c o h ort will be st o p pe d.  This decisi o n criteri o n has 3 9 % 
pr o ba bilit y  of rejecti n g t he n ull h yp ot hesis if t he tr ue res p o nse rate is 2 0 % a n d 6 % pr o ba bilit y  of 
rejecti n g t he alter nati ve h y p ot hesis if t he tr ue res p o nse rate is 3 5 %.
E nr oll me nt of H C C sec o n d -li ne or s orafe ni b-i nt olera nt c o h ort will n ot be st o p pe d f or t he p ur p ose 
of c o n d ucti n g t his i nteri m a nal ysis b ut will st o p if f utilit y  is met as s pecifie d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 9 / 1 9 3
H C C sec o n d-li ne or s or afe ni b-i nt oler a nt c o h ort
N o i nteri m a nal ys is is pla n ne d.
N S C L C a nti -P D - 1 / a nti-P D -L 1 f ail ure c o h ort
O ne i nteri m a nal ys is is pla n ne d f or t his c o h ort 1 2 wee ks after t he 4 0 t h s u bject i n t his c o h ort starte d 
treat me nt. 

If ≤ 2 r es p o nses are o bser ve d i n t he 4 0 s u bjects at t he i nteri m a nal ys is, t he e nr oll me nt will be 
st o p pe d.  T his decisi o n criteri o n has 3 2 % pr o ba bilit y  of rejecti n g n ull h y p ot hesi s if t he tr ue 
res p o nse rate is 5 % a n d 5 % pr o ba bilit y  of rejecti n g alter nati ve h y p ot hesi s if t he tr ue res p o nse 
rate is 15 %. 

If 3 t o 4 res p o nses are o bser ve d at t he i nteri m a nal ys is, t he e nr oll me nt will be te m p oraril y 
st o p pe d u ntil the first 4 0 s u bjects ha ve c o m plete d t u m or assess me nt at Wee k 2 4. After a re vie w 
of t he t otalit y  of data, i ncl u di n g d urati o n of res p o nse, D C R , a n d safety, t he S p o ns or will ma ke 
a decisi o n as t o w het her t o res u me t he accr ual. 

If ≥ 5 res p o nses are o bser ve d at t he i nteri m a nal ys is, a n a d diti o nal 4 0 s u bjects will be e nr olle d.  
Wit h 5 res p o nses a n d usi n g B a y esia n pri nci pal, t he p osteri or pr o ba bilit y  of tr ue O R R bei n g 
a b o ve 1 5 % (alter nati ve h y p ot hesis) is a p pr o xi matel y  4 1 % a n d t he p osteri or pr o ba bilit y  of tr ue 
O R R bei n g bel o w 5 % ( n ull h y p ot hesis) is a p pr o xi matel y  2 %.
Mel a n o m a a nti -P D - 1 / a nti-P D -L 1 f ail ure c o h ort
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
N S C L C sec o n d -li ne c o h ort
T here is o ne pla n ne d i nteri m a nal ys is.  The pri mar y  objecti ve of t he i nteri m a nal ysis is t o assess 
t he t olera bilit y, safet y, a n d preli mi nar y a ntit u m or acti vit y. 
T he pla n ne d i nteri m a nal ysis will occ ur 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.  If ≤ 4 res p o n ders are o bser ve d at t he i nteri m a nal ysis, n o f urt her s u bjects will be 
e nr olle d i nt o t he N S C LC sec o n d -li ne c o h ort.
P a ncre atic a de n oc arci n o m a sec o n d-li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt. 
C R C t hir d -li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 0 / 1 9 3
S C C H N sec o n d-li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
T N B C sec o n d -li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
O v ari a n p ost -pl ati n u m sec o n d-li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt. 
Es o p h a ge al p ost -pl ati n u m sec o n d-li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
Gli o bl ast o m a sec o n d -li ne c o h ort 
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
Cer vic al c o h ort
O ne i nteri m a nal ysis is pla n ne d f or t his c o h ort 1 2 wee ks after t he 3 0 t h s u bject i n t he c o h ort starte d 
treat me nt.
A d diti o n al I nteri m A n al yses
I n ge neral, i nteri m a nalys es at ti me p oi nts t hat are n ot s pecifie d i n t he pr ot oc ol ma y  be perf or me d 
f or i nter nal pla n ni n g p ur p oses.
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t h e I n vesti g at or
T he I nvesti gat or is res p o nsi ble f or t he c o n d uct of t he trial at t he site a n d will e ns ure t hat t he trial 
is perf or me d i n acc or da nce wit h t his pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of 
Helsi n ki, I CH G C P , t he sta n dar ds stip ulate d i n Article 1 4, Para gra p h 3, a n d Article 8 0- 2 of t he 
P har mace utical Affairs La w i n Ja pa n; a n d t he “ Mi nisterial Or di na nce o n t he Sta n dar ds f or t he 
I m ple me ntati o n of Cli nical St u dies o n P har mace utical Pr o d uct” ( G C P) i n Ja pa n, a n d a n y ot her 
a p plica ble re g ulati o ns. T he I nvesti gat or m ust e ns ure t hat o nl y  su bjects w h o ha ve gi ve n i nf or me d 
c o nse nt are i ncl u de d i n t he trial. T hr o u g h o ut t his cli nical trial pr ot oc ol, In vesti gat or refers t o b ot h 
t he pri nci pal i n vesti gat or a n d a ny s u bi n vesti gat ors .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 1 / 1 9 3
Acc or di n g t o U nite d States C o de of Fe deral Re g ulati o ns Part 5 4. 2 (e), f or trials c o n d ucte d i n a n y 
c o u ntr y that c o ul d res ult i n a pr o d uct s u b missi o n t o t he U nite d States F D A f or mar keti n g a p pr o val 
a n d c o ul d c o ntri b ute si g nifica ntl y to t he de m o nstrati o n of efficac y an d s afet y of a n I M P ( w hic h 
are c o nsi dere d “c o vere d cli nical trials” b y  t he F D A), t he I n vesti gat or a n d all s u bin vesti gat ors are 
o bli ge d t o discl ose a n y f i na ncial i nterest w hic h t he y, t heir s p o uses or t heir de pe n de nt c hil dre n m a y  
ha ve i n t he S p o ns or or t he S p o ns or’s pr o d uct u n der st u d y. T his i nf or mati o n is re q uire d d uri n g t he 
trial a n d f or 1 2 m o nt hs f oll o wi n g c o m pleti o n of t he trial.
9. 2
S u bject I nf or m ati o n a n d I nf or me d C o nse nt
A n u nc o n diti o nal prere q uisite f or eac h s u bject pri or t o partici pati o n i n t he trial is wri tte n i nf or me d 
c o nse nt, w hic h m ust be gi ve n bef ore a n y trial-relate d acti vities are carrie d o ut.   I n Ja pa n, w he n a 
s u bject is < 2 0 ye ars of a ge, t he writte n i nf or me d c o nse nt m ust be o btai ne d fr o m t he s u bject’s 
pare nt or g uar dia n i n a d diti o n t o t he s u bject’s v ol u ntar y  writte n c o nse nt.  A de q uate i nf or mati o n 
m ust t heref ore be gi ve n t o t he s u bject b y  the I nvesti gat or or a n a p pr o priate desi g nee (if l ocal 
re g ulati o ns per mit) bef ore i nf or me d c o nse nt is o btai ne d. 
A s u bject i nf or mati o n s heet m ust be pre pare d i n t he l ocal la n g ua ge i n acc or da nce wit h Ja pa n G C P 
a n d I CH G C P a n d will be pr o vi de d b y  t he S p o ns or f or t he p ur p ose of o btai ni n g i nf or me d c o nse nt. 
I n a d diti o n t o pr o vi di n g t his writte n i nf or mati o n t o a p ote ntial s u bject, t he I nvesti gat or or a 
desi g nate will i nf or m t he s u bject ver ball y  of all perti ne nt as pects of t he trial, usi n g la n g ua ge c h ose n 
s o t hat t he i nf or mati o n ca n be f ull y an d rea dil y un derst o o d b y  la ypers o ns. T he s u bject will be gi ve n 
s ufficie nt ti me t o rea d t he i nf or mati o n a n d t he o p p ort u nit y  to as k q uest i o ns a n d t o re q uest 
a d diti o nal i nf or mati o n a n d clarificati o n.
If per mitte d b y  nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y  inf or m t he s u bject 
a b o ut t he trial a n d si g n t he I CF , as a b o ve.
If per mitte d b y  nati o nal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y  inf or m t he s u bject 
a b o ut t he trial a n d si g n t he I CF, as a b o ve.
After t he i nf or mati o n is pr o vi de d b y  the I n vesti gat or, t he I CF m ust be si g ne d a n d date d b y  the 
s u bject or t he s u bject’s le gal re prese ntati ve a n d t he I n vesti gat or. 
F o r all trial sites, the si g ne d a n d date d declarati o n of i nf or me d c o nse nt will re mai n at t he 
I n vesti gat or’s site, a n d m ust be safely arc hi ve d s o t hat t he f or ms ca n be retrie ve d at a n y ti me f or 
m o nit ori n g, a u diti n g a n d i ns pecti o n p ur p oses. A c o p y of t he si g ne d a n d date d i nf or mati o n a n d 
I CF s h o ul d be pr o vi de d t o t he s u bject pri or t o partici pati o n.
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y  be rele va nt t o i nf or me d c o nse nt, 
t he I nvesti gat or will re vise t he s u bject i nf or mati o n s heet a n d a n y ot her writte n i nf or mati o n t o be
pr o vi de d t o t he s u bjects a n d s u b mit t he m t o t he I R B f or re vie w a n d o pi ni o n. Usi n g t he a p pr o ve d 
re vise d s u bject i nf or mati o n s heet a n d ot her writte n i nf or mati o n, the I n vesti gat or will e x plai n t he 
c ha n ges t o t he pre vi o us versi o n t o eac h trial s u bject a n d o btai n ne w writte n c o nse nt f or c o nti n ue d 
partici pati o n i n t he trial. T he s u bject will be gi ve n s ufficie nt ti me t o rea d t he i nf or mati o n a n d t he 
o p p ort u nit y  to as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d clarificati o n ab o ut t he 
c ha n ges.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 2 / 1 9 3
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue s u bject n u m ber will be assi g ne d t o eac h s u bject at i ncl usi o n ma n uall y  for t he d ose 
escalati o n a n d N S C L C bi o mar ker c o h orts a n d b y  the I WR S s yste m f or ot her e x pa nsi o n c o h orts.  
T he s u bject n u m ber will be assi g ne d i m me diately after i nf or me d c o nse nt has bee n o btai ne d.  T his 
n u m ber will ser ve as t he s u bject’s i de ntifier i n t he trial as well as i n t he cli nical trial data base.
T he s u bject’s data c ollecte d i n t he trial will be st ore d u n der t his n u m ber.  O nl y  the I n vesti gat or 
will be a ble t o li n k t he s u bject’s trial data t o t he s u bject via a n i de ntificati o n list ke pt at t he site. 
T he s u bject’s ori gi nal me dical data t hat are re vie we d at t he site d uri n g s o urce data verificati o n b y 
t he M o nit or, a u dits, a n d Healt h A ut h orit y i ns pecti o ns will be ke pt strictl y c o nfi de ntial.
Data pr otecti o n a n d pri vac y  re g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr ocessi n g, a n d 
st ori n g s u bject data.  Su bjects will be i nf or me d acc or di n gl y a n d will be re q ueste d t o gi ve t heir 
c o nse nt o n data ha n dli n g pr oce d ures i n acc or da nce wit h nati o nal re g ulati o ns .
Bl o o d a n d t u m or tiss ue sa m ples f or P Gt a n d bi o mar kers will be st ore d f or u p t o 1 0 years after trial 
c o m pleti o n. D uri n g t his ti me, t he sa m ples ma y be rea nal yz e d f or ne wly i de nt ifie d mar kers or wit h
n e w or i m pr o ve d tec h n ol o gy . After 1 0 years, t he sa m ples will be destr o y e d or f ull y an o n y mize d 
or a ne w I E C / I RB a p pr o val a n d i nf or me d c o nse nt will be re q ueste d t o kee p t he sa m ples f or a n 
a d diti o nal peri o d. If t u m or tiss ue re mai ns, t he site will be n otifie d a n d t he t u m or tiss ue will be 
ret ur ne d t o t he site u p o n re q uest. If t he site d oes n ot re q uest t he ret ur n of t he t u m or tiss ue, it will 
be destr o ye d.
9. 4
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d
S u bjects will be pr o vi de d wit h E mer ge nc y Me dical S u p p ort car ds s u p plie d b y  t he S p o ns or f or use
d uri n g trial partici pati o n i n or der t o pr o vi de cli nical trial s u bjects wit h a wa y  of i de ntif yi n g 
t he msel ves as partici pati n g i n a cli nical trial a n d t o gi ve healt h care pr o vi ders access t o a n y
i nf or mati o n a b o ut t his partici pati o n t hat ma y  be nee de d t o deter mi ne t he c o urse of me dical 
treat me nt f or t he s u bject.
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n vesti gat or cari n g f or t he 
affecte d s u bject. T he I nvesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact i nf or mati o n o n 
t he car d f or t his p ur p ose. If t he I nvesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. 
A n y  su bse q ue nt acti o n will 
f oll o w t he sta n dar d pr ocess esta blis he d f or 
I n vesti gat ors.
I n cases w here t he I n vesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o 
c o ntact a S p o ns or p h ysicia n. T his i ncl u des t he pr o visi o n of a 2 4 -h o ur t oll-free c o ntact n u m ber at 
a call ce nter, w here b y t he healt h care pr o vi ders w ill be gi ve n access t o t he a p pr o priate S p o ns or 
p h y sicia n t o assist wit h t he me dical e mer ge nc y a n d t o pr o vi de s u p p ort.
9. 5
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects
I ns ura nce c o vera ge s hall be pr o vi de d f or eac h c o u ntr y partici pati n g t o t he trial. Ins ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 3 / 1 9 3
I n Ja pa n, t he S p o ns or is e ntirel y res p o nsi ble f or A Es t hat are ass ociate d wit h t his st u d y a n d i m pair 
t he healt h of t he s u bjects, e xce pt f or A Es ca use d b y a n i nte nti o nal a n d / or si g nifica n t de viati o n o n 
t he part of t he In vesti gat or, t he st u dy site, a n d / or t he s u bject. T he S p o ns or will pr o vi de i ns ura nce 
t o f ulfill t his res p o nsi bilit y.
9. 6
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t he cli nical trial pr ot oc ol will be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts (s uc h as t he I CF) t o t he res p o nsi ble I E C / I RB f or its 
fa v ora ble o pi ni o n / a p pr o val.  The writte n fa v ora ble o pi ni o n / a p pr o val of t he I EC / I RB will be 
file d i n t he I n vesti gat or Site File, a n d a c o py will be file d wit h t he C R O.
T he trial m ust n ot start at a site bef ore t he S p o ns or has o btai ne d writte n c o nfir mati o n of fa v ora ble 
o pi ni o n / a p pr o val fr o m t he c o ncer ne d I E C / I R B.  The I E C / I R B will be as ke d t o pr o vi de 
d oc u me ntati o n of t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n / a p pr o val was gi ve n, a n d 
of t he me m bers a n d v oti n g me m bers prese nt at t he meeti n g.  
Writte n e vi de nce of fa v ora ble 
o pi ni o n / a p pr o val t hat clearl y i de ntifies t he trial, t he cli nical trial pr ot oc ol versi o n a n d t he S u bject 
I nf or mati o n a n d I C F versi o n re vie we d s h o ul d be pr o vi de d.  W here p ossi ble, c o pies of t he meeti n g 
mi n utes s h o ul d be o btai ne d.
A me n d me nts t o t he cli nical trial will als o be s u b mitte d t o t he c o ncer ne d I E C / I RB, bef ore 
i m ple mentati o n i n case of s u bsta ntial c ha n ges (see Secti o n 1 0. 5 ).  Rele va nt safety i nf or mati o n will 
be s u b mitte d t o t he I E C / I RB d uri n g t he c o urse of t he trial i n acc or da nce wit h nati o nal re g ulati o ns 
a n d re q uire me nts.
9. 7
He alt h A ut h orities
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n (f or e xa m ple, I n vesti gati o nal 
Me dici nal Pr o d uct D ossier, S u bject I nf or mati o n a n d I CF ) will be s u b mitte d or n otifie d t o t he 
Healt h A ut h orities i n acc or da nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site.
1 0
Tri al M a n a ge me nt
1 0. 1
Electr o nic C ase Re p ort F or m H a n dli n g
Refer t o t he Ma n ual of O perati o ns
f or e C R F ha n dli n g g ui deli nes.  
T he I n vesti gat or or desi g nee will be res p o nsi ble f or e nteri n g trial data i n t he e C R F pr o vi de d b y  
t he C R O a n d f oll o w t he data sta n dar ds of t he S p o ns or. It is t he In vesti gat or’s res p o nsi bilit y to 
e ns ure t he acc urac y of t he data e ntere d i n t he e C R Fs.
T he data will be e ntere d i nt o a vali date d data base. T he C R O will be res p o nsi ble f or data re vie w 
a n d pr ocessi n g, i n acc or da nce wit h t he S p o ns or’s data ma na ge me nt pr oce d ures.
Data base l oc k 
will occ ur o nce q ualit y  co ntr ol pr oce d ure, a n d q ualit y  ass ura nce pr oce d ures (if a p plica ble) ha ve 
bee n c o m plete d. All P D F files of t he e C R Fs will be pr o vi de d t o t he In vesti gat ors at t he c o m pleti o n 
of t he trial.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 4 / 1 9 3
1 0. 2
S o urce D at a a n d S u bject Files
T he I nvesti gat or m ust kee p a s u bject file ( me dical file, ori gi nal me dical rec or ds) o n pa per or 
electr o nicall y for e ver y s u bject i ncl u de d i n t he trial. 
T his file will c o ntai n t he a vaila ble 
de m o gra p hic a n d me dical i nf or mati o n f or t he s u bject, a n d s h o ul d be as c o m plete as p ossi ble. I n 
partic ular, t he f oll o wi n g data s h o ul d be a vaila ble i n t his file: 

S u bject’s f ull na me

Date of birt h

Se x

Race

Hei g ht

Wei g ht

Me dical h ist or y a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he trial)

T u m or disease i nf or mati o n

Trial i de ntificati o n ( E M R 2 0 0 6 4 7- 0 0 1)

Date of s u bje ct’s i ncl usi o n i nt o t he trial ( t hat is, date of gi vi n g i nf or me d c o nse nt)

S u bject n u m ber i n t he trial

Dates of t he s u bject’s visits t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he cli nical trial pr ot oc ol

All A Es o bser ve d i n t he s u bject

Dat e of s u bject’s e n d of trial

Date of a n d reas o n f or earl y wit h dra wal of t he s u bject fr o m t he t rial or fr o m I M P, if a p plica ble.
It m ust be p ossi ble t o i de ntif y eac h s u bject b y usi n g t his s u bject file.
A d diti o nall y , a n y ot her d oc u me nts c o ntai ni n g s o urce data m ust be file d. T his i ncl u des ori gi nal 
pri nt o uts of data rec or de d or ge nerate d b y  aut o mate d i nstr u me nts, p h ot o gra p hic ne gati ves, X -ra ys, 
C T or M RI  sca n i ma ges, E C G rec or di n gs, la b orat or y val ue listi ngs, etc. S uc h d oc u me nts m ust 
bear at least t he s u bject n u m ber a n d t he date w he n t he pr oce d ure was perf or me d. I nf or mati o n 
s h o ul d be pri nte d b y  the i nstr u me nt use d t o perf or m t he assess me nt or meas ure me nt, if p ossi ble. 
I nf or mati o n t hat ca n n ot be pri nte d by a n a ut o mate d i nstr u me nt will be e ntere d ma n uall y. Me dical 
e val uati o n of s uc h rec or ds s h o ul d be d oc u me nte d as necessar y  a n d t he d oc u me ntati o n si g ne d a n d 
date d b y t he In vesti gat or.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 5 / 1 9 3
1 0. 3
I n vesti g at or Site File a n d Arc hi vi n g
U p o n i nitiati o n of t he trial, t he I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File 
c o ntai ni n g all necessar y  trial d oc u me nts , w hic h will be c o m plete d t hr o u g h o ut t he trial a n d u p date d 
as necessar y. T he file m ust be a vaila ble f or re vie w b y t he M o nit or, d uri n g S p o ns or a u dits a n d f or 
i ns pecti o n b y Healt h A ut h orities d uri n g a n d after t he trial a n d m ust be safel y arc hi ve d f or at least 
1 5 ye ars ( or l o n ger, i n acc or da nce wit h t he l ocal re q uire me nts of Ja pa n G C P or as ot her wise 
n otifie d b y  the S p o ns or) after t he e n d of t he trial. T he d oc u me n ts t o be arc hi ve d i ncl u de t he S u bject 
I de ntificati o n Li st a n d t he si g ne d s u bject I C Fs. If arc hi vi n g of t he I n vesti gat or Site File is n o l o n ger 
p ossi ble at t he site, t he I n vesti gat or m ust n otif y  t he S p o ns or / desi g nee.
All ori gi nal s u bject files ( me dical r ec or ds ) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, 
or practice) f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica ble re g ulati o ns, a n d / or as per 
I C H G C P g ui deli nes, w hic he ver is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o 
destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or.
I n Ja pa n, the hea d of t he st u d y site m ust retai n all rec or ds, i ncl u di n g d oc u me nts a n d data, w hic h 
relate t o t he cli nical st u d y in acc or da nce wit h Ja pa n G C P.   T he hea d of t he st u d y  site m ust retai n 
t he rec or ds at t he site ( h os pital, researc h i nstit ute, or practice) f or t he l o n gest p ossi ble ti me 
per mitte d b y  Ja pa n G C P , a n d / or as per I CH G C P g ui deli nes, w hic he ver is l o n ger. I n an y  case, 
t he hea d of t he st u d y site sh o ul d e ns ure t hat n o destr ucti o n of me dical rec or ds is perf or me d wit h o ut 
t he writte n a p pr o val of t he S p o ns or.   T he In vesti gat or m ust retai n rec or ds, i ncl u di n g d oc u me nts 
a n d data, w hic h relate t o t he cli nical st u d y  in acc or da nce wit h t he i nstr ucti o ns fr o m t he hea d of t he 
st u d y site.
1 0. 4
M o nit ori n g, 
Q u alit y Ass ur a nce , a n d I ns pecti o n b y He alt h 
A ut h orities
T his trial will be m o nit ore d i n acc or da nce wit h t he I C H G C P a n d a n y o t her a p plica ble re g ulati o ns.  
T he site M o nit or will perf or m visits t o t he trial site at re g u lar i nter vals.
T he cli nical trial pr ot oc ol, eac h ste p of t he data ca pt ure pr oce d ure, a n d t he ha n dli n g of t he data, 
i ncl u di n g t he fi nal cli nical trial re p ort, will be s u bject t o i n de pe n de nt Q ualit y  Ass ura nce acti vities.  
A u dits ma y  be c o n d ucte d at a n y t i me d uri n g or after t he trial t o e ns ure t he vali dit y a n d i nte grit y of 
t he trial data.
Re prese ntati ves of t he Q ualit y  Ass ura nce u nit fr o m t he S p o ns or or a desi g nate d 
or ga nizati o n, as well as Healt h A ut h orities, m ust be per mitte d t o access all trial d oc u me nts a n d 
ot her materials at t he site, i ncl u di n g t he I nvesti gat or Site File, t he c o m plete d eC R Fs, all I MP a n d
I M P acc o u nta bilit y rec or ds, a n d t he ori gi nal me dical rec or ds or files f or eac h s u bject.
1 0. 5
C h a n ges t o t he Cli nic al Tri al Pr ot oc ol
C ha n ges t o t he cli nical trial pr ot oc ol will be d oc u me nte d i n writi n g . S u bsta nti ve a me n d me nts will 
us uall y  re q uire s u b missi o n t o t he Healt h A ut h orities a n d t o t he rele va nt I E C / I RB f or a p pr o val or 
fa v ora ble o pi ni o n. I n s uc h cases, t he a me n d me nt will be i m ple me nte d o nl y  after a p pr o val or 
fa v ora ble o pi ni o n has bee n o btai ne d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 6 / 1 9 3
Mi n or ( n o ns u bsta ntial) pr ot oc ol a me n d me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y  
t he S p o ns or a n d at t he site. T he y  will be s u b mitte d t o t he rele va nt I E C / I RB or t o Healt h 
A ut h orities o nl y  wh e re re q ueste d b y p e rti ne nt re g ulati o ns. A n y  ame n d me nt t hat c o ul d affect t he 
s u bject’s a gree me nt t o partici pate i n t he trial re q uires a d diti o nal i nf or me d c o nse nt pri or t o 
i m ple me ntati o n f oll o wi n g t he pr ocess as descri be d i n Secti o n 9. 2 .
1 0. 6
Cli nic al Tri al Re p ort a n d P u blic ati o n P olic y
1 0. 6. 1
Cli nic al Tri al Re p ort
After c o m pleti o n of t he trial, or c o m pleti o n of a partic ular c o h ort or c o h orts if a p plica ble, a cli nical 
trial re p ort acc or di n g t o I C H T o pic E 3 will be writte n b y  the S p o ns or or t he desi g nate d C R O i n 
co ns ultati o n wit h t he I n vesti gat or. 
1 0. 6. 2 
P u blic ati o n
T he first p u blicati o n will be a p u blicati o n of t he res ults of t he a nal y sis of t he pri mar y en d p oi nt(s) 
t hat will i ncl u de data fr o m all trial sites t hat partici pate d i n t he d ose -escalati o n part of t he trial.
T he In vesti gat or will i nf or m t he S p o ns or i n a d va nce a b o ut a n y pla ns t o p u blis h or prese nt data 
fr o m t he trial. A n y p u blicati o ns a n d prese ntati o ns of t he res ults (a bstracts i n j o ur nals or 
ne ws pa pers, oral prese ntati o ns, etc.), eit her i n w h ole or i n part, b y  In vesti gat ors or t heir 
re prese ntati ves will re q u ire pres u b missi o n re vie w b y t he S p o ns or.
T he S p o ns or will n ot s u p press or vet o p u blicati o ns b ut mai ntai ns t he ri g ht t o dela y  p u blicati o n i n 
or der t o pr otect i ntellect ual pr o pert y ri g hts.
1 0. 7
Rec or d Rete nti o n i n J a p a n
T he hea d of t he st u d y  site a n d t he In vesti g at or will retai n all rec or ds as descri be d i n Secti o n  1 0. 3.
T he S p o ns or a n d a n y pers o n w h o esta blis hes a n I E C / I RB m ust retai n all rec or ds, i ncl u di n g 
d oc u me nts a n d data, w hic h relate t o t he cli nical trial f or t he re q uire d peri o d i n acc or da nce wit h 
Ja pa n G C P.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 7 / 1 9 3
1 1
Refere nces Cite d i n t he Te xt
Aar o ns o n N. K., A h me dzai S., B ulli n ger M. et al. T he E O R T C c ore q ualit y of life q uesti o n naire: 
I nteri m res ults of a n i nter nati o nal fiel d st u d y. I n: Os o ba D. e d. Effect of Ca ncer o n Q ualit y  of Life. 
B oca Rat o n, F L: C R C Press 1 9 9 1: 1 8 5- 2 0 3.
A da ms S, et al. Safet y  an d cli nical acti vit y of atez oliz u ma b (a nti-P D -L 1 ) i n c o m bi nati o n wit h na b -
paclita xel i n patie nts wit h tri ple-ne gati ve breast ca ncer, A bstract n u m ber: 8 5 0 4 7 7. 1 0t h Dece m ber, 
0 7. 3 0  Sa n A nt o ni o, T X, U nite d States.
Attia P, P ha n G Q, Ma ker A V, et al. A ut oi m m u nit y  correlates wit h t u m or re gressi o n i n pa tie nts 
wit h metastatic mela n o ma treate d wit h a nti-c yt ot o xic T- l ym p h oc y te a nti ge n- 4. J Cli n O nc ol
2 0 0 5 ; 2 3( 2 5):6 0 4 3 - 5 3. 
Baratelli F, Lee J M, Hazra S, et al. P G E( 2) c o ntri b utes t o T G F -beta i n d uce d T re g ulat or y cell 
f u ncti o n i n h u ma n n o n-s mall cell l u n g ca ncer. A m J Tra nsl Res 2 0 1 0; 2( 4): 3 5 6 - 6 7.
Blaze b y J M, C o nr o y  T, Ha m merli d E, et al. Cli nical a n d ps y c h o metric vali dati o n of a n E O R T C 
q uesti o n naire m o d ule, t he E O R T C Q L Q -O E S 1 8, t o assess q ualit y  of life i n patie nts w it h 
oes o p ha geal ca ncer. E ur J Ca ncer. 2 0 0 3 J ul 3 1; 3 9( 1 0): 1 3 8 4 - 9 4.
Blaze b y J M, C urrie E, Zee B C Y, et al. De vel o p me nt of a q uesti o n naire m o d ule t o s u p ple me nt t he 
E O R T C Q L Q- C 3 0 t o assess q ualit y  of life i n patie nts wit h he pat ocell ular carci n o ma, t he E O R T C 
Q L Q -H C C 1 8. E ur J Ca ncer 2 0 0 4; 4 0( 1 6): 2 4 3 9 -4 4.
B o h n sac k O, H o os A, L u dajic K. A da ptati o n of t he i m m u ne relate d res p o nse criteria: ir R E CI S T 
A n n O nc ol 2 0 1 4; 2 5(s u p pl 4): 1 1 P oster 1 0 7 0.
Bra h mer J R, T y k o di S S, C h o w L Q M, et al. Safet y a n d acti vit y of a nti -P D -L 1 a nti b o d y i n patie nts 
wit h a d va nce d ca ncer. N E n gl J Me d 2 0 1 2; 3 6 6( 2 6): 2 4 5 5 -6 5.
Br u na A, Dar ke n R S, R oj o F, et al. Hi g h T G F β -s ma d acti vit y co nfers p o or pr o g n osis i n gli o ma 
patie nts a n d pr o m otes cell pr oliferati o n de pe n di n g o n t he met h y lati o n of t he P D G F -B g e ne. Ca ncer 
Cell 2 0 0 7; 1 1: 1 4 7 -6 0.
Cala br ò L, Da nielli R, Si gal otti L,  et al. Cli nical st u dies wit h a nti-C T L A- 4 a nti b o dies i n n o n-
me la n o ma i n dicati o ns. Se mi n O nc ol 2 0 1 0; 3 7( 5): 4 6 0 -6 7.
C o h n A, La h n M M, Willia ms K E, et al. A p hase I d ose -escalati o n st u d y t o a pre defi ne d d ose of a 
tra nsf or mi n g gr o wt h fact or-β 1 m o n ocl o nal a nti b o d y (T β M 1) i n patie nts wit h metastatic ca ncer. 
I nt J O nc ol 2 0 1 4; 4 5( 6): 2 2 2 1- 3 1.  
Cr o wle y  J, A n kerest D P. Ha n d b o o k of Statistics i n Cli nical O nc ol o g y, 2 n d E diti o n. C R C Press 
2 0 0 6.
Cli nical Trial Facilitati o n Gr o u p, Rec o m me n dati o ns relate d t o co ntrace pti o n a n d pre g na nc y  testi n g 
i n cli nical trials, A d vis or y  no n- bi n di n g g ui da nce s u p p orte d b y  nati o nal c o m pete nt a ut h orities, 
R o me 
2 0 1 4- 0 9- 1 5 2 0 1 4, 
htt p:// w w w. h ma.e u/filea d mi n/ dateie n/ H u ma n 
Me dici nes/ 0 1 -A b o ut 
H M A/ W or ki n g Gr o u ps/ C T F G/ 2 0 1 4 0 9 H M A C T F G C o n trace pti o n. p df.
Dalal BI, Ke o w n P A, Gree n ber g A H. I m m u n oc y t oc he mical l ocalizati o n of secrete d tra nsf or mi n g 
gr o wt h fact or-beta 1 t o t he a d va nci n g e d ges of pri mar y  tu m ors a n d t o l ym p h n o de metastases of 
h u ma n ma m mar y  carci n o ma. A m J Pat h ol 1 9 9 3; 1 4 3: 3 8 1- 3 8 9.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 8 / 1 9 3
Desr uissea u S, Pal mari J, Gi usti C, et al. Deter mi nati o n of T G F[ beta] 1 pr otei n le vel i n h u ma n 
pri mar y  breast ca ncers a n d its relati o ns hi p wit h s ur vi val. Br J Ca ncer 2 0 0 6; 9 4: 2 3 9- 2 4 6.
Di Giac o m o A M, Bia gi oli M, Mai o M . T he e mer gi n g t o xicit y pr ofiles of a nti-C T L A- 4 a nti b o dies 
acr oss cli nical i n dicati o ns. Se mi n O nc ol 2 0 1 1; 3 7( 5): 4 9 9- 5 0 7.
D oi T, Pi ha -Pa ul S A, Jalal SI , et al. Pe m br oliz u ma b ( M K-3 4 7 5) f or patie nts ( pts) wit h a d va nce d 
es o p ha geal carci n o ma: Preli mi nar y  res ults fr o m K E Y N O T E - 0 2 8. J Cli n O nc ol 2 0 1 5; 3 3 (s u p pl; 
a bstr 4 0 1 0).  
D ola n D E, G u pta S. P D -1 pat h wa y  i n hi bit ors: c ha n gi n g t he la n dsca pe of ca ncer i m m u n ot hera p y. 
Ca ncer C o ntr ol 2 0 1 4; 2 1( 3): 2 3 1- 3 7.
D o n k or M K, Sar kar A, Li M O. T G F -β 1 pr o d uce d b y  acti vate d C D( +) T -cells a nta g o nize d T- cell
s ur veilla nce of tu m or de vel o p me nt. O nc oi m m u n ol o g y  2 0 1 2; 1( 2): 1 6 2- 7 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 oli d t u m o urs: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 - 4 7.
El -K h o ueir y
A B, Meler o
I, Cr oce nzi
T S,
et al. P hase I/II safety a n d a ntit u m or acti vit y of 
ni v ol u ma b i n patie nts wit h a d va nce d he pat ocell ular carci n o ma ( H C C). Cli n O nc ol 2 0 1 5; 3 3 (s u p pl; 
a bstr L B A 1 0 1 ).
E M A/ C H M P/ B M W P/ 8 6 2 8 9/ 2 0 1 0 . G ui deli ne o n I mm u n o ge nicit y  assess me nt of m o n ocl o nal 
a nti b o dies i nt e nde d f or i n vi v o cli nical use.
E M E A/ C H M P/ B M W P/ 1 4 3 2 7/ 2 0 0 6 . 
G ui deli ne 
o n 
I m m u n o ge nicit y 
Assess me nt 
of 
Bi otec h n ol o g y- Deri ve d T hera pe utic Pr otei ns .
E M E A/ C H M P/I C H/ 6 4 6 1 0 7/ 2 0 0 8 . 
I CH 
S 9 
N o ncli nical 
E val uati o n 
f or 
A ntica ncer 
P har mace uticals .
Fai vre SJ, Sa nt or o A, Kelle y  RK, et al. A P hase 2 st u d y of a n o vel tra nsf or mi n g gr o wt h fact or-beta
( T G F-β) 1 rece pt or ki nase i n hi bit or, L Y 2 1 5 7 2 9 9 m o n o h y drate ( L Y), i n patie nts wit h a d va nce d 
he pat ocell ular carci n o ma ( H C C). J Cli n O nc ol 2 0 1 4; (s u p pl 3; a bstr L B A 1 7 3).
F D A, 2 0 0 5. Esti mati n g t he Ma xi m u m Safe Starti n g D ose i n I nitial Cli nical Trials f or T hera pe utics 
i n A d ult Healt h y V ol u nteers. 
Frie d ma n E, G ol d LI, Kli mstra D, et al. Hi g h le vels of tra nsf or mi n g gr o wt h fact or beta 1 c orrelate 
wit h disease pr o gressi o n i n h u ma n c ol o n ca ncer. Ca ncer E pi de mi ol o g y , Bi o mar kers & Pre ve nti o n: 
A P u blicati o n of t he A merica n Ass ociati o n f or Ca ncer Researc h, C os p o ns ore d b y  the A merica n 
S ocie t y of Pre ve nti ve O nc ol o g y 1 9 9 5; 4: 5 4 9- 5 5 4.
F uji wara K, I ke da H, Y os hi m ot o T. A b n or malities i n e x pressi o n of ge nes, m R N A, a n d pr otei ns of 
tra nsf or mi n g gr o wt h fact or-beta rece pt or t ype I a n d t ype II i n h u ma n pit uitar y  ade n o mas. Cli n 
Ne ur o pat h ol 1 9 9 8; 1 7: 1 9 -2 6.
Getti n ger S N, S he p her d F, A nt o nia J, et al. First -li ne ni v ol u ma b ( A nti-P D -1; B M S -9 3 6 5 5 8, 
O N O -4 5 3 8) m o n ot he ra p y i n a d va nce d N S C L C: safety, efficac y, a n d c orrelati o n of o utc o mes wit h 
P D -L 1  stat us. J Cli n O nc ol 2 0 1 4; 3 2: 5s, (s u p pl; a bstr 8 0 2 4).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 9 / 1 9 3
G o b bi H, Artea ga C L , Je nse n R A, et al. L oss of e x pressi o n of tra nsf or mi n g gr o wt h fact or beta 
t ype II rece pt or c orrelates wit h hi g h t u m o ur gra de i n h u ma n breast i n-sit u a n d i n vasi ve carci n o mas. 
Hist o pat h ol o g y  2 0 0 0; 3 6: 1 6 8- 1 7 7.
G orsc h S M, Me m oli V A, St u kel T A, et al. I m m u n o hist oc he mical stai ni n g f or tra nsf or mi n g g r o wt h 
fact or β 1 ass ociates wit h d isease p r o gressi o n i n h u ma n b reast ca ncer. C a ncer Res 1 9 9 2; 5 2: 6 9 4 9 -
6 9 5 2.
G o u die D R, D’ Alessa n dr o M, Merri ma n B, et al. M ulti ple self-heali n g s q ua m o us e pit heli o ma is 
ca use d b y a disease -s pecific s pectr u m of m utati o ns i n T G F B R 1. Nat Ge net 2 0 1 1; 4 3( 4) 3 6 5- 6 9.
Grei mel E, B ott o mle y  A, C ull A, et al. A n i nter nati o nal fiel d st u d y of t he relia bilit y an d vali dit y 
of a disease -s pecific q uesti o n naire m o d ule (t he Q L Q -O V 2 8) i n assessi n g t he q ualit y of life of 
patie n ts wit h o varia n ca ncer. E ur J Ca ncer. 2 0 0 3 J ul 3 1; 3 9( 1 0): 1 4 0 2 - 8.
Grei mel E R, K ulja nic Vlasic K, Wal de nstr o m A C, et al. T he E ur o pea n Or ga ni sati o n f or Researc h 
a n d Treat me nt of Ca ncer ( E O R T C) Q ualit y -of -Life q uesti o n naire cer vical ca ncer m o d ule. Ca ncer
2 0 0 6; 1 0 7( 8): 1 8 1 2 - 2 2.
Ha ma nis hi J, Ma n dai M, I ke da T, et al. Safet y a n d a ntit u m or acti vit y of a nti-P D -1 a nti b o d y, 
n i v ol u ma b, i n patie nts wit h plati n u m-resista nt o varia n ca ncer. J Cli n O nc ol 2 0 1 5; 3 3 4 0 1 5- 2 2.
Ha o N B, L ü M H, Fa n Y H, et al. Macr o p ha ges i n t u m or micr oe n vir o n me nts a n d t he pr o gressi o n 
of t u m ors. Cli n De v I m m u n ol 2 0 1 2;i d 9 4 8 0 9 8.
Hazel ba g S , G orter A, Ke nter G G, et al. Tra nsf or mi n g gr o wt h fact or -beta 1 i n d uces t u m or str o ma 
a n d re d uces t u m or i nfiltrate i n cer vical ca ncer. H u m Pat h ol 2 0 0 2; 3 3( 1 2): 1 1 9 3 - 9.
Hazel ba g S, Ke nter G G, G orter A, et al. Pr o g n ostic rele va nce of T G F -beta 1 a n d P AI -1 i n cer vi cal 
ca ncer. I nt J Ca ncer 2 0 0 4; 1 1 2( 6): 1 0 2 0- 8.
Heere n A M, P u nt S, Blee ker M C, et al. Pr o g n ostic effect of differe nt P D -L 1 e x pressi o n patter ns 
i n s q ua m o us cell carci n o ma a n d a de n ocarci n o ma of t he cer vi x. M o d Pat h ol 2 0 1 6; 2 9( 7) 7 5 3 - 6 3.
H otc h kiss R S, M ol da wer L L. Parallels bet wee n ca ncer a n d i nfecti o us disease. N E n gl J Me d 2 0 1 4; 
3 7 1( 4): 3 8 0 - 8 3.
Iz u m ot o S, Arita N, O h nis hi T, et al. Micr osatellite i nsta bilit y an d m utate d t ype II tra nsf or mi n g 
gr o wt h fact or -[ beta] rece pt or ge ne i n gli o mas. Ca ncer Lett 1 9 9 7; 1 1 2: 25 1- 2 5 6.
Jac hi mcza k P, Hess d örfer B, Fa bel -Sc h ulte K, et al. Tra nsf or mi n g gr o wt h fact or-beta -me diate d 
a ut ocri ne gr o wt h 
re g ulati o n of 
gli o mas 
as detecte d 
wit h 
p h os p h or ot hi oate 
a ntise nse 
oli g o n ucle oti des. I nt J Ca ncer 1 9 9 6; 6 5: 3 3 2 - 3 3 7.
Je o n H S, Je n J. T G F -beta si g nali n g a n d t he r ole of i n hi bit or y Sma ds i n n o n- s mall cell l u n g ca ncer. 
J T h orac O nc ol 2 0 1 0 A pr; 5( 4): 4 1 7 - 1 9.
Kae hler K C, Piel S, Li vi n gst o ne E, et al. U p date
o n i m m u n ol o gic t hera p y wit h a nti-C T L A - 4
a nti b o dies i n mela n o ma: i de ntificati o n of cli nical a n d bi ol o gical res p o nse patter ns, i m m u ne-relate d 
a d verse e ve nts, a n d t heir ma na ge me nt. Se mi n O nc ol 2 0 1 0; 3 7( 5):4 8 5- 9 8.
K ha n S A, J o yce J, Ts u da T. Q ua ntificati o n of acti ve a n d t otal tra nsf or mi n g gr o wt h fact or -β le vels 
i n ser u m a n d s oli d or ga n tiss ues b y bi oassa y. B M C Res N otes 2 0 1 2; 5: 6 3 6
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 0 / 1 9 3
Kjell ma n C, Ol ofss o n S P, Ha nss o n O, et al. E x pressi o n of T G F -β is of or ms, T G F -β rece pt ors, a n d 
S ma d m olec ules at differe nt sta ges of h u ma n gli o ma. I nt J Ca ncer 2 0 0 0; 8 9: 2 5 1- 2 5 8.
K o mi y a ma S, K ura has hi T, Is hi ka wa M, et al. E x pressi o n of T G F ß 1 a n d its rece pt ors is ass ociate d 
wit h bi ol o gical feat ures of o varia n ca ncer a n d se nsiti vit y to paclita xel/ car b o plati n. O nc ol Re p 
2 0 1 1; 2 5: 1 1 3 1 - 1 1 3 8.
K u bicz k o va l, Se dlari k o va L, Haje k R et al. T G F β -a n e xcelle nt ser va nt b ut a ba d master. J Tra nsl
Me d 2 0 1 2; 1 0: 1 8 3 .
Le D T, Ura m J N, Wa n g H, et al. P D - 1 bl oc ka de i n t u m ors wit h mis matc h -re pair deficie nc y . N 
E n gl J Me d 2 0 1 5; 3 7 2: 2 5 0 9 - 2 0.
Leas k A, A bra ha m, D. T G F -β si g nali n g a n d t he fi br otic res p o nse. Fase b J 2 0 0 4; 1 8: 8 1 6 - 2 7.
Le br u n, J. T he d ual role of T G F b i n h u ma n ca ncer:  fr o m tu m or s u p pressi o n t o ca ncer metastasis 
2 0 1 2, I nter n Sc h olarl y R es Net w or k.
Le nci o ni, R, Ll o vet, J M. M o difie d R E CI S T ( m R E CIS T) assess me nt f or h e pat ocell ular carci n o ma. 
Se mi n L i ver Dis 2 0 1 0; 3 0: 5 2 -6 0.
L o n ni n g S, Ma n nic k J, Mc P hers o n JM. A nti b o d y tar geti ng of T G F -β i n ca ncer patie nts. C urr 
P har m Bi otec h n ol 2 0 1 1; 1 2( 1 2): 2 1 7 6- 1 8 9.
Mc Carrier K P, At ki ns o n T M, De B us k K P, et al. Q ualitati ve d e vel o p me nt a n d co nte nt v ali dit y of 
t he N o n -s mall Cell L u n g Ca ncer S y m pt o m 
Assess me nt 
Q uesti o n naire 
( N S C LC- S A Q), a
patie nt -re p orte d outc o me instr u me nt . Cli n T her 2 0 1 6; 3 8( 4): 7 9 4 - 8 1 0.
Melisi D, Is hi ya ma S, Scla bas G M, et al. L Y 2 1 0 9 7 6 1, a n o vel tra nsf or mi n g gr o wt h fact or beta 
rece pt or t ype I a n d t ype II d ual i n hi bit or, as a t hera pe utic a p pr oac h t o s u p pressi n g pa ncreatic ca ncer 
metastasis. M ol Ca ncer T her 2 0 0 8; 7: 8 2 9- 8 4 0.
M orris 
J C, Ta n A R, Ole n ki T E, et al. P hase I st u d y of G C 1 0 0 8 (fres oli m u ma b): a h u ma n 
tra nsf or mi n g gr o wt h fact or-beta ( T G F β) m o n ocl o nal a nti b o d y in patie nts wit h a d va nce d mali g na nt 
mela n o ma or re nal carci n o ma. P L o S O ne 2 0 1 4; 9( 3):e 9 0 3 5 3.
M u C Y, H ua n g J A, C he n Y et al. Hi g h e x pressi o n of P D -L 1 i n l u n g ca ncer ma y  c o ntri b ute t o p o or 
pr o g n osis a n d t u m or cells i m m u ne esca pe t hr o u g h s u p pressi n g t u m or i nfiltrati n g de n dritic cells 
mat urati o n. Me d O nc ol 2 0 1 1 Se p; 2 8( 3): 6 8 2- 8 8.
Oettle H, Hil bi g A, Se ufferlei n T, et al. P hase I/II st u d y of tra be derse n ( A P 1 2 0 0 9) m o n ot hera p y 
f or t he treat me nt of patie nts wit h a d va nce d pa ncreatic ca ncer, mali g na nt mela n o ma a n d c ol orectal 
carci n o ma. J Cli n O nc ol 2 0 1 1; 2 9:s u p pl;a bstr 2 5 1 3.
O ka da H, Weller M, H ua n g R, et al. I m m u n ot hera p y  res p o nse a n d assess me nt i n ne ur o -o nc ol o g y  
(i R A N O): A re p ort of t he R A N O w or ki n g gr o u p. La ncet O nc ol 2 0 1 5; 1 6( 1 5):e 5 3 4 - 4 2.
Os hi m ori N, Oristial D, F uc hs E. T G F -β pr o m otes heter o ge neit y a n d dr u g resista nce i n s q ua m o us 
cell carci n o ma. Cell 2 0 1 5; 1 6 0: 9 6 3- 7 6.
P ha n G Q, Ya n g J C, S herr y  R M, et al. Ca ncer re gressi o n a n d a ut oi m m u nit y i n d uce d b y c ytot o xic 
T l ym p h oc y te-ass ociate d a nti ge n 4 bl oc ka de i n patie nts wit h metastatic mela n o ma. Pr oc Natl Aca d 
Sci U S A 2 0 0 3 ; 1 0 0( 1 4):8 3 7 2 - 7 7. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 1 / 1 9 3
R o bert C, L o n g G V, Bra d y  B, et al. Ni v ol u ma b i n pre vi o usl y u ntreate d mela n o ma wit h o ut B R A F 
m utati o n. N E n gl J Me d 2 0 1 5; 3 7 2 : 3 2 0- 3 3 0.
Sa m ps o n J H, Vla h o vic G, Sa he bja m S, et al. Preli mi nar y  safety a n d acti vit y of ni v ol u ma b a n d its 
c o m bi nati o n wit h i pili m u ma b i n rec urre nt gli o blast o ma ( G B M): C H E C K M A T E - 1 4 3. J Cli n O nc ol 
2 0 1 5 ; 3 3 (s u p pl; a bstr 3 0 1 0).
Se gal N H, A nt o nia SJ, Bra h mer J R, et al. Preli mi nar y  data fr o m a m ulti -ar m e x pa nsi o n st u d y of 
M E DI 4 7 3 6, a n a nti -P D -L 1 a nti b o d y. J Cli n O nc ol 2 0 1 4; 3 2: 5s (s u p pl; a bstr 3 0 0 2).
Sei wert T Y, Ha d da d RI , G u pta S , et al. A ntit u m or acti vit y an d safet y of pee m br oliz u ma b i n 
patie nts ( pts) wit h a dva nce d s q ua m o us cell carci n o ma of t he hea d a n d nec k ( S C H H N: Preli mi nar y 
res ults fr o m t he K E Y N O T E- 0 1 2 e x pa nsi o n c o h ort. J Cli n O nc ol 2 0 1 5 ; 33: (s u p pl; a bstr L B A 6 0 0 8 ).
S mir ne C, Ca ma n d o na M, Ala bis o O, Bell o ne G, E ma n uelli G: Hi g h ser u m le vels of tra nsf or mi n g 
gr o wt h fact or-beta 1, interle u ki n - 1 0 a n d v asc ular e n d ot helial gr o wt h fact or i n pa ncreatic 
a de n ocarci n o ma patie nts. Mi ner va Gastr oe nter ol Diet ol 1 9 9 9; 4 5: 2 1 -2 7.
S o n g S, Y ua n P, W u H, et al. De n dritic cells wit h a n i ncrease d P D -L 1 b y  TG F β i n d uce T- cell
a ner g y f or t he c yt ot o xicit y of he pat ocell ular carci n o ma cells. I nter nati o nal I m m u n o p har mac ol o g y 
2 0 1 4; 2 0: 1 1 7 - 1 2 3.
S o uza -F o nseca -G ui maraes F, S m y t h MJ. M y el oi d T G F - β res p o nsi ve ness pr o m otes metastases. 
Ca ncer Disc o v 2 0 1 3; 3( 8); 8 4 6 - 4 8.
Sterlacci W, W olf D, Sa vic S. et al. Hi g h tra nsf or mi n g gr o wt h fact or β e x pressi o n re prese nts a n 
i m p orta nt pr o g n ostic para me ter f or s ur gicall y resecte d n o n- s mall cell l u n g ca ncer. H u ma n 
Pat h ol o g y  2 0 1 2; 4 3: 3 3 9-4 9.
S uz u ki E, Ka p o or V, C he u n g H K, et al. S ol u ble t y pe II tra nsf or mi n g gr o wt h fact or-beta rece pt or 
i n hi bits esta blis he d m uri ne mali g na nt mes ot heli o ma t u m or gr o wt h b y au g me nti n g h ost a ntit u m or 
i m m u nit y. Cli n Ca ncer Res 2 0 0 4 ; 1 0( 1 7): 5 9 0 7-9 1 8. 
Sz n ol M, L o n g o D L. Release t he h o u n ds! Acti vati n g t he T-cell res p o nse t o ca ncer. N E n gl J Me d 
2 0 1 5; 3 7 2( 4): 3 7 4 -7 5.
Ta p h o or n MJ, Claasse ns L, Aar o ns o n N K, et al. A n i nter nati o nal vali dati o n st u d y of t he E O R T C 
brai n ca ncer m o d ule ( E O R T C Q L Q- B N 2 0) f or assessi n g healt h -relate d q ualit y  of life a n d 
s ym pt o ms i n brai n ca ncer patie nts. E u r J Ca ncer. 20 1 0 A pr 3 0; 4 6( 6): 1 0 3 3 - 4 0.
T o palia n S L , Dra ke C G, Par d oll D M. Tar geti n g t he P D -1/ B 7 -H 1 ( P D-L 1 ) pat h wa y  to acti vate 
a nti-t u m or i mm u nit y . C urr O pi n i n I m m u n ol 2 0 1 2a ; 2 4: 2 0 7-2 1 2.
T o palia n S L , H o di F S, Bra h mer J R, et al. Safet y, acti vit y a n d i m m u ne c orrelates of a nti-P D - 1 
a nti b o d y i n ca ncer. N E n gl J Me d 2 0 1 2b ; 3 6 6( 2 6): 2 4 4 3- 4 5 4.
Trac ht ma n H, Fer ve nza F C, Gi ps o n D S, et al. A p hase 1, si n gle-d ose st u d y of fres oli m u ma b, a n 
a nti-T G F -β a nti b o d y, i n treat me nt-resista nt pri mar y  focal se g me ntal gl o mer ul oscler osis.  Ki d ne y
I nt 2 0 1 1; 7 9( 1 1): 1 2 3 6-2 4 3.
Va n Aarse n L A, Le o ne D R, H o S, et al. A nti b o d y -me diate d bl oc ka de of i nte gri n al p ha v beta 6 
i n hi bits t u m or pr o gressi o n i n vi v o b y  a tra nsf or mi n g gr o wt h fact or-beta -re g ulate d mec ha nis m.
Ca ncer Res 2 0 0 8; 6 8( 2): 5 6 1 - 7 0. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 2 / 1 9 3
We ber 
J S, K u d c ha d kar R R, Gi b ne y  GT, et al U p date d s ur vi val, t o xicit y an d bi o mar kers of 
ni v ol u ma b wit h/ wit h o ut pe pti de vacci ne i n patie nts naï ve t o, or pr o gresse d o n , i pili m u ma b. J Cli n 
O nc ol 2 0 1 4; 3 2:s u p pl;a bstr 3 0 0 9.
We n P Y, Mac d o nal d D R, Rear d o n D A, et al. U p date d resp o nse assess me nt criteria f or hi g h -gra de 
gli o mas: res p o nse assess me nt i n ne ur o -o nc ol o g y  wor ki n g gr o u p. J Cli n O nc ol 2 0 1 0; 2 8( 1 1): 
1 9 6- 7 2.
W olc h o k 
J D, Ne y ns B, Li nette G, et al. I pili m u ma b m o n ot hera p y  in patie nts wit h pretreate d 
a d va nce d mela n o ma: a ra n d o mise d, d o u ble -bli n d, m ultice ntre, p hase 2, d ose -ran gi n g st u d y. La ncet 
O nc ol 2 0 1 0; 1 1: 1 5 5- 6 4.
Wrzesi ns ki S H, Wa n Y Y, Fla vell R A. Tra nsf or mi n g gr o wt h fact or-beta a n d t he i m m u ne res p o nse: 
i m plicati o ns f or a ntica ncer t hera py. Cli n Ca ncer Res 2 0 0 7; 1 3( 1 8 Pt 1): 5 2 6 2 - 7 0.
Ya ma da N, Kat o M, Ya mas hita H, et al. E n ha nce d e x pressi o n of tra nsf or mi n g gr o wt h fact or-β a n d 
its t yp e -I a n d t yp e -II rece pt ors i n h u ma n gli o blast o ma. Int J Ca ncer 1 9 9 5; 6 2: 3 8 6 - 3 9 2.
Y o u nt S, Cella D, We bster K, et al. Assess me nt of patie nt -re p orte d cli nical o utc o me i n pa ncreatic 
a n d ot her he pat o biliar y  ca ncers: T he F A C T He pat o biliar y  Sy m pt o m I nde x. J Pai n S y m pt o m 
Ma na g 2 0 0 2; 2 4: 3 2 - 4 4.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 3 / 1 9 3
1 2
A p pe n dices
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 4 / 1 9 3
A p pe n di x 1
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us
E C O G P S a
Gra de
E C O G
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, f or e xa m ple, li g ht h o use w or k, office w or k
2
A m b ulat or y a n d ca pa ble of all self -care, b ut u na ble t o carr y o ut a n y w o r k acti vities; u p a n d a b o ut 
> 5 0 % of w a ki n g h o urs
3
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair > 5 0 % of wa ki n g h o urs
4
C o m pletel y disa ble d; ca n n ot carr y o n a n y self -care; t otall y c o nfi ne d t o be d or c hair
5
Dea d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 5 / 1 9 3
A p pe n di x 2
G ui d a nce o n C o ntr ace pti o n
Birt h c o ntr ol met h o ds c o nsi dere d as hi g hl y effecti ve
Ali g ne d wit h t he Cli nical Trials Facilitati o n Gr o u p (C T F G 2 0 1 4 ) “ Rec o m me n dati o ns relate d t o 
c o ntrace pti o n a n d pre g na nc y  testi n g i n cli nical trials” met h o ds t hat ca n ac hie ve a fail ure rate of 
less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y are c o nsi dere d as hi g hl y effecti ve birt h 
c o ntr ol met h o ds, s uc h as :

c o m bi ne d (estr o ge n a n d pr o gester o ne c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n1 ( oral, i ntra va gi nal, tra ns der mal)

pr o gester o ne - o nly h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1 ( oral, 
i njecta ble, i m pla nta ble2 , 3)

i ntra uteri ne de vice (I U D)2

i ntra uteri ne h or m o ne-releasi n g sys te m (I U S)2

bilateral t u bal occl usi o n 2

vasect o mize d part ner 2, 4

se x ual a bsti ne nce 5
1 H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he efficac y of t he 
c o ntrace pti o n met h o d
2 C o ntrace pti o n met h o ds i n t he c o nte xt of t his g ui da nce are c o nsi dere d t o ha ve l o w user de pe n de nc y
3 N ot a p pr o ve d i n Ja pa n
4 Vasect o mise d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat t he part ner is t he s ole se x ual part ner 
of t he w o ma n of  chil d beari n g p ote ntial trial partici pa nt a n d t hat t he vasect o mize d part ner has recei ve d me dical 
assess me nt of t he s ur gical s uccess
5 I n t he c o nte xt of t his g ui da nce se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve me t h o d o nl y if defi ne d as refrai ni n g 
fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts. A bsti ne nce 
nee ds t o be i n li ne wit h t he preferre d a n d us ual lifest yle of t he s u bject. Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, 
s y m pt ot her mal, p ost-o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 6 / 1 9 3
A p pe n di x 3
Si g n at ure P a ges a n d Res p o nsi ble Pers o ns f or t he Tri al
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 7 / 1 9 3
Si g n at ure P a ge – Pr ot oc ol Le a d
Tri al Title:
A P hase I, o pe n -la bel, m ulti ple -asce n di n g d ose trial 
t o 
i n vesti gate 
t he 
safety, 
t olera bilit y, 
p har mac o ki netics, bi ol o gical a n d cli nical acti vit y of 
M S B 0 0 1 1 3 5 9 C 
i n s u bjects wit h 
metastatic 
or 
l ocall y ad va nce d s oli d t u m ors a n d e x pa nsi o n t o 
selecte d i n dicati o ns
I N D N u m ber:
E u dr a C T N u m ber:
2 0 1 5- 0 0 4 3 6 6- 2 8
Cli nic al Tri al Pr ot oc ol D ate / Versi o n:
2 2 J u ne 2 0 2 1 / Versi o n 7. 2- B E -E S -I T-F R
Pr ot oc ol Le a d:
I a p pr o ve t he desi g n of t he cli nical trial:
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
Merc k Bi o p har ma C o. Lt d.
( Affiliate of Merc k K Ga A, Dar msta dt, Ger ma ny)
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 9 / 1 9 3
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
A P hase I, o pe n -la bel, m ulti ple -asce n di n g d ose 
trial t o i n vesti gate t he safety, 
t olera bility,  
p har mac o ki netics, bi ol o gical a n d cli nical acti vit y 
of M S B 0 0 1 1 3 5 9 C i n s u bjects wit h metastatic or 
l ocall y ad va nce d s oli d t u m ors a n d e x pa nsi o n t o 
selecte d i n dicati o ns
I N D N u m ber
E u dr a C T N u m ber
2 0 1 5- 0 0 4 3 6 6- 2 8
Cli nic al Tri al Pr ot oc ol D ate / Versi o n
2 2 J u ne 2 0 2 1 / Versi o n 7. 2- B E -E S -I T-F R
Ce nter N u m ber
Pri nci p al I n vesti g at or
I, t he u n dersi g ne d, a m res p o nsi ble f or t he c o n d uct of t he trial at t his site a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil f or Har m o nisati o n G o o d Cl i nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt h A ut h orit y  re q uire me nts a n d nati o nal la ws, a n d i n Ja pa n, t he Declarati o n of 
Helsi n ki, 
t he sta n dar ds sti p ulate d i n Article 
1 4, Para gra p h 3, a n d Article 
8 0- 2 of t he 
P har mace utical Affairs La w i n Ja pa n; a n d t he “ Mi nisterial Or di na nce o n t he Sta n dar ds f or t he 
I m ple me ntati o n of Cli nical St u dies o n P har mace utical Pr o d uct” ( G o o d Cli nical Practice) i n Ja pa n.
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o bta i n a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I nvesti gati o nal Me dici nal 
Pr o d uct a n d a n y  ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n 
s olel y for t he p ur p ose of c o m pl yi n g wit h t he re g ulat or y re q uire me nt s. I t heref ore a gree t o s u p pl y 
t he S p o ns or wit h a n y necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties 
i ncl u di n g t h ose of my s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet 
Healt h A ut h orit y  re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C )
M S B 0 0 1 1 3 5 9 C i n Met ast atic or L oc all y A d v a nce d S oli d T u m ors
E M R 2 0 0 6 4 7 - 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 1 / 1 9 3
A p pe n di x 4
Pr ot oc ol A me n d me nts a n d List of C h a n ges
Pre vi o us Pr ot oc ol A me n d me nts
A m e n d m e nt 
N u m b er
S u b st a nti al
( Y e s/ N o)
D at e
R e gi o n or C o u ntr y
I n cl u d e d i n t h e 
c urr e nt d o c u m e nt     
( Y/ N)
A me n d me nt 1 . 0
Yes
1 6 J u ne 2 0 1 5
Gl o bal
Yes
A me n d me nt 2. 0
Yes
1 7 J ul y 2 0 1 5
Gl o bal
Yes
A me n d me nt 3. 0
Yes
2 9 Oct o ber 2 0 1 5
Gl o bal
Yes
A me n d me nt 3. 1
N o
1 2 Ja n uar y 2 0 1 6
Bel gi u m, Ger ma n y, 
Ital y, S pai n, a n d U nite d 
Ki n g d o m
Yes
A me n d me nt 3. 2
N o
0 9 Fe br uar y 2 0 1 6
Bel gi u m, Ger ma n y, 
Ital y, S pai n, a n d U nite d 
Ki n g d o m
N o
A me n d me nt 3. 3
Yes
1 8 A pril 2 0 1 6
All c o u ntries e xce pt 
V H P - partici pati n g 
c o u ntries ( Bel gi u m, 
Ger ma n y, Ital y, S pai n, 
a n d U nite d Ki n g d o m)
Yes
A me n d me nt 3. 4
N o
2 5 A u g ust 2 0 1 6
All c o u ntries e xce pt 
V H P - partici pati n g 
c o u ntries ( Bel gi u m, 
Ger ma n y, Ital y, S pai n, 
a n d U nite d Ki n g d o m)
Yes
A me n d me nt 3. 5
Yes
2 5 A u g ust 2 0 1 6
V H P - partici pati n g 
c o u ntries ( Bel gi u m, 
Ger ma n y, Ital y, S pai n, 
a n d U nite d Ki n g d o m)
Yes
A me n d me nt 3. 6
Yes
1 2 A u g ust 2 0 1 6
Ja pa n
N o
A me n d me nt 4. 0
Yes
1 4 Dece m ber 2 0 1 6
Gl o bal
Yes
A me n d me nt 4. 1
Yes
1 4 Dece m ber 2 0 1 6
Ja pa n
N o
A me n d me nt 5. 0
Yes
2 2 Fe br uar y 2 0 1 7
Gl o bal
Yes
A me n d me nt 5. 1
Yes
2 2 Fe br uar y 2 0 1 7
Ja pa n
N o
A me n d me nt 5. 2
N o
1 5 J u ne 2 0 1 7
Fra nce
Yes
A me n d me nt 5. 3
N o t a p plica ble 
3 1 A u g ust 2 0 1 7
U nite d States
Yes
A me n d me nt 5. 4
N o t a p plica ble
0 9 J ul y 2 0 1 8
U nite d States
Yes
A me n d me nt 6. 0
Yes
3 1 Ja n uar y 2 0 1 9
Gl o bal
Yes
A me n d me nt 6. 1
Yes
0 4 J u ne 2 0 1 9
V H P - partici pati n g 
c o u ntries (Bel gi u m, 
Fra nce, Ger ma n y, Ital y, 
S pai n, a n d U nite d 
Ki n g d o m) )
Yes
T he mai n p ur p ose of t his pr ot oc ol a me n d me nt ( Versi o n 7. 2- B E -E S -I T-F R , 2 2 J u ne 2 0 2 1) is t o 
u p date t he ris k classificati o n a n d ris k mi ni mizati o n meas ures.  T he e n d of trial is als o re vise d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: C CI
C CI
C CI