Conditions: Solid Tumors
Keywords: Solid tumor MSB0011359C (M7824) Metastatic or Locally Advanced Solid Tumors Bintrafusp alfa INTR@PID
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 600
Healthy volunteers: no

Brief summary:
The main purpose of this Phase I study was to test MSB0011359C (M7824) at different dose levels to see if it is safe and well tolerated when given once every 2 weeks. Phase I means the study drug has not previously been given to humans or has only been given to a limited number of people, although it has been extensively studied in animals. Based on this information, it is hoped to find out which dose could be best for the treatment of patients. There are two parts of this research study: a dose-escalation part and an expansion part. Dose escalation means that the first people taking part in the study will receive low doses of the study drug, and as more people take part, the additional participants will receive a higher dose. This is done to find the safest dose for the study drug. Expansion means that after the dose-escalation part of the study has looked at the safety and effectiveness of different doses, many more people will be invited to take part in the study and will receive the study drug at the safest dose. Additional purposes of the study are to find out whether the study drug has anti-cancer effects and how the study drug is processed by the body.

Detailed description:
This is a Phase I, open-label, dose-escalation trial with consecutive parallel-group expansion in selected solid tumor indications. The current trial wascomposed of a standard dose escalation "3 + 3" cohort design, for which 3 to 6 subjects will be enrolled at each dose level depending on the occurrence of dose limiting toxicities (DLTs), followed by a consecutive parallel-group expansion in selected solid tumor in dications. Cohorts of 3 subjects with metastatic or locally advanced solid tumors, for which no standard effective therapy exists or standard therapy has failed, will receive MSB0011359C (M7824) at escalating dose levels. After determination of the Maximum tolerated dose (MTD), enrollment in several expansion cohorts will be opened to determine the safety, pharmacokinetic (PK) / Pharmacodynamic, and clinical activity of MSB0011359C (M7824). Subjects who have experienced a confirmed complete response (CR) should continue treatment through the end of 12 months, although additional treatment is possible. In the case of progressive disease (PD), subjects should continue treatment through their next tumor assessment. Additional indications will be planned based on emerging data in the field.

Arms:
arm 1: None

Interventions: intervention 1: MSB0011359C
Intervention descriptions: intervention 1: Subjects would receive intravenous infusion of MSB0011359C once every 2 weeks in a dose escalation fashion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal from the trial or investigational medicinal product (IMP) occurs.

Protocol document:
Prot_000.pdf: 


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





SAP_001.pdf: 
M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
I nte gr ate d A n al ysis Pl a n of t he Cer vic al C a ncer a n al ysis 
f or t he C S R a d de n d u m (c ut off d ate: 1 4 M a y 2 0 2 1)   
Cli nic al St u d y  Pr ot oc ol 
I de ntific ati o n N o. 
E M R 2 0 0 6 4 7 -0 0 1  
Title  
A 
P hase I, o pe n -l a bel, 
m ulti ple-asce n di n g d ose trial t o 
i n vesti gate t h e safet y, t olera bilit y, p h ar mac o ki netics, bi ol o gical 
a n d cli nical acti vit y of M 7 8 2 4 ( 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 a n d e x pa nsi o n t o 
selecte d i n dicati o ns 
St u d y P h ase  
P hase I  
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C)  
Cli nic al St u d y  Pr ot oc ol 
Versi o n  
3 1 J a n uar y 2 0 1 9 / Versi o n 7. 0  
I nte gr ate d A n al ysis Pl a n 
A ut h or  
C o or di n ati n g A ut h or  
 
 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
0 5 A pr  2 0 2 2  / Versi o n 2 .0  
I nte gr ate d A n al ysis Pl a n 
Re vie wers  
 
F u n cti o n  
N a m e  
 
 
 
 
Dir e ct or, Bi o st ati sti c s, M er c k H e alt h c ar e 
K G a A  
 
St u d y Bi o st ati sti ci a n, E M D S er o n o  
 
Bi o st ati sti ci a n, M er c k H e alt h c ar e K G a A  
 
 E M D 
S er o n o  
 
 M er c k H e alt h c ar e K G a A  
 
 M er c k H e alt h c ar e K G a A  
 
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 1  b y M erc k K G a A, D ar mst a dt, Ge r m a n y or its aff ili ate. All ri g hts reser ve d. 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
P P D


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 /4 1  
 
  
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: E M R 2 0 0 6 4 7 -0 0 1  
A P hase I, o pe n -la bel, m ulti ple-asce n di n g d ose tri al t o i n vesti gate t he s afet y, t olera bilit y, 
p har mac o ki netics, bi ol o gical a n d cli nical acti vit y of M 7 8 2 4 ( 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 v a 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.  
A p pr o val of t h e I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n 
E L D O R A D O  via e Si g nat ure . Wit h t he a p pr o val, t he Merc k res p o nsi ble f or eac h of t he a n al ysis 
als o ta kes res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a de q uat el y.  
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d o c u me nt.  
 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
1  
T a ble of C o nte nts   
A p pr o val Pa ge  
 ..............................................................................................................2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b br e viati o ns a n d Defi niti o n of Ter ms  ....................................6  
3  
M o dificati o n Hist or y  ............................................................................8  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  ...............................................8  
5  
O bjecti ves a n d E n d p oi nts  .....................................................................8  
6  
O ver vie w of Pla n ne d A nal yses  .............................................................8  
6. 1  
Decisi o n after disc o nti n uati o n of N S C L C a n d B T C trials  ...................9  
7  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli ni cal St u d y Pr ot o c ol  ......1 0  
8  
A nal ysis P o p ulati o ns a n d S u b gr o u ps ..................................................1 0  
8. 1  
Defi niti o n of A nal ysis P o p ulati o ns  .....................................................1 0  
8. 2  
S u b gr o u p D efi niti o n a n d Para meterizati o n  ........................................1 1  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ..........................................1 2  
9. 1  
Data Ha n dli n g After C ut -off Date  ......................................................1 2  
9. 2  
Defi niti o n of Bas eli ne a n d C ha n ge fr o m Baseli ne  .............................1 3  
9. 3  
St u d y Da y / St u d y Treat me nt Da y  ......................................................1 3  
9. 4  
Defi niti o n of D urati o n a n d ‘ti me si nce’ Varia bles  .............................1 3  
9. 5  
C o n versi o n Fact ors  .............................................................................1 3  
9. 6  
Date of Last C o nta ct  ...........................................................................1 4  
9. 7  
Ti me Wi n d o w  .....................................................................................1 4  
9. 8  
Defi niti o n of O n -treat me nt Peri o d ......................................................1 4  
9. 9  
I m p utati o n of Missi n g Data ................................................................1 5  
9. 1 0  
Si g nifica nce Le v el  ..............................................................................1 6  
9. 1 1  
Prese ntati o n of C o nti n u o us a n d Q ualitati ve Varia bles  .......................1 6  
9. 1 2  
Re p orti n g C o n ve nti o ns  .......................................................................1 6  
9. 1 3  
Preferre d Ter m f or A n al ysis of W H O -D D C o de d Data  .....................1 6  
9. 1 4  
Data c ollecte d aft er Rei nitiate d Treat me nt  .........................................1 6  
1 0  
St u d y Partici pa nts  ...............................................................................1 7  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................1 7  
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis P o p ulati o ns  ..............1 8  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................1 8  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /4 1  
 
  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis P o p ul ati o n .......1 8  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................1 8  
1 1. 1  
De m o gra p hics  .....................................................................................1 9  
1 1. 2  
Me dical His t or y ..................................................................................1 9  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................1 9  
1 1. 4  
Pri or A nti -ca ncer T hera p y  ..................................................................2 0  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................2 0  
1 3  
St u d y Treat me nt: C o m plia nce a n d E x p os ure  .....................................2 0  
1 4  
Efficac y A nal yses  ...............................................................................2 1  
1 4. 1  
Best O verall Res p o nse  ........................................................................2 1  
1 4. 1. 1  
Best O verall Res p o nse Acc or di n g t o R E CI S T 1. 1 as Assesse d b y 
I n v esti gat or .........................................................................................2 1  
1 4. 1. 2  
S u b gr o u p A n al ysis f or Best O verall Res p o nse Acc or di n g t o 
R E CI S T 1. 1 as Assess e d b y I n v esti gat or  ...........................................2 2  
1 4. 2  
D urati o n of Res p o nse  .........................................................................2 2  
1 4. 3  
Pr o gressi o n Free S ur vi val  ...................................................................2 3  
1 4. 4  
O verall S ur vi val  ..................................................................................2 5  
1
 
 
1 4. 5. 1  
E val uati o n of P ote ntial Effect of A D A/ n A b o n bi ntraf us p alf a 
Efficac y  ...............................................................................................2 8  
1 5  
Safet y A nal yses  ..................................................................................2 9  
1 5. 1  
A d verse E v e nts  ...................................................................................2 9  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................3 0  
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y Treat me nt  ......3 1  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................3 1  
1 5. 2. 1  
Deat hs  .................................................................................................3 1  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................3 1  
1 5. 2 . 3 
Ot her A d verse E ve nts of I nterest  ........................................................3 2  
1 5. 2. 3. 1  
I nf usi o n Relate d Reacti o n ...................................................................3 2  
1 5. 2. 3. 2  
I m m u ne Rel ate d A d verse E ve nts ........................................................3 2  
1 5. 2. 3. 3  
P ote ntial T G F β -me diate d S ki n T E A E  ................................................3 3  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................3 4  
Gl o bal Versi o n I D: C CI
C C


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /4 1  
 
  
1 5. 3. 1  
He mat ol o g y a n d C he mistr y Para meters  .............................................3 4  
1 5. 4  
Vital Si g ns  ..........................................................................................3 7  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................3 7  
1 6  
A nal ys es of Ot her E n d p oi nts  ..............................................................3 7  
1 6. 1  
P har mac o ki netics  ................................................................................3 7  
1 6. 1. 1  
Missi n g P K Data  .................................................................................3 7  
1 6. 1. 2  
Descri pti ve P K A nal ysis  .....................................................................3 8  
1 6. 1. 3  
P har mac o ki netic Para meter A nal ysis  .................................................3 9  
 
 
1 6. 3  
Patie nt Re p orte d O utc o m e  ..................................................................4 1  
1 7  
Refere n ces  ...........................................................................................4 1  
1 8  
A p pe n dices  .........................................................................................4 1  
 
Gl o bal Versi o n I D: C CI
C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /4 1  
 
  
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms  
A D A  
a nti -dr u g a nti b o d y  
A Da M  
a nal ysis d ata m o del  
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nt of s p ecial i nterest  
B O R  
best o verall res p o ns e  
c B O R  
co nfir me d best o verall res p o nse  
C DI S C  
cli nical data i nterc ha n ge sta n dar ds c o ns orti u m  
C E OI  
C o nce ntrati o n o bser ve d at t he e n d of i nf usi o n  
CI  
c o nfi de nce i nter val 
C R  
c o m plete res p o nse  
C S R  
cli nical st u d y re p ort  
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 tr o u g h 
C o nce ntrati o n o bser ve d at t he e n d of t he d osi n g i nter val  
C V %  
c oeffi cie nt of variati o n  
D R  
d urati o n of res p o ns e  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E O T  
e n d of treat me nt  
Ge o Mea n  
ge o m etric mea n  
Ge o C V %  
ge o m etric c o effici e nt of variati o n  
H A H A  
h u ma n a nti h u ma n 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 
I A P 
I nte grate d A nal ysis Pla n 
ir A E 
i m m u ne-relate d a d verse e ve nt 
I R R 
I nf usi o n-Relate d Reacti o ns  
L L N  
l o wer li mit of n or mal 
l o g St D 
sta n dar d de viati o n of l o g -tra nsf or me d data 
Ma x  
mi nii m u m  
Me d D R A  
me dical dicti o nar y f or re g ulat or y acti vities  
Mi n  
ma xi m u m  
N A  
n ot a p plica ble  
n A b  
ne utralizi n g anti b o d y  
N C  
n ot calc ulate d  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
N CI  
nati o nal ca ncer i nstit ute  
N E  
n ot e val ua ble  
N R  
n o res ult  
O S  
o verall s ur vi val  
P D  
pr o gressi ve dise ase  
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 K  
p har ma c oki netic(s)  
P K A D A  
P har mac o ki netic A D A A nal ysis Set  
P K A D A C C  
P har mac o ki netic A D A A nal ysis Set f or Cer vical Ca ncer  
P K A S  
P har mac o ki netic A n al ysis Set  
P K A S C C  
P har mac o ki netic A n al ysis Set f or Cer vical Ca n cer  
P K N A B  
P har mac o ki netic n A b A nal ysis Set  
P K N A B C C  
P har mac o ki netic n A b A nal ysis Set f or Cer vical Ca ncer  
P R  
partial res p o nse  
P T  
Preferre d ter m  
R E CI S T  
res p o nse ev al uati o n criteria i n s oli d t u m ors  
S A F  
safet y a n al ysis set 
S A P  
statistical a nal ysis pla n 
S D  
sta ble disease 
S D T M  
st u d y data ta b ul ati o n m o del 
SI  
s yste m i nter nati o nal 
S M C  
safet y m o nit ori n g c o m mittee 
S O C  
s yste m or ga n class 
St D  
sta n dar d de viati o n 
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 f act or-beta  
T N R  
titer n o res ult 
T T P  
ti me t o pr o gressi o n 
U L N  
u p per li mit of n or mal  
W B C  
w hite  bl o o d cell  
W H O -D D  
W H O Dr u g Dicti o nar y  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
3  
M o dific ati o n Hist or y   
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1. 0  
2 8 M A Y 2 0 2 1  
 
N ot a p pli c a bl e   
2. 0  
0 5 A P R 2 0 2 2  
 
- C a n c ell ati o n of t h e C S R a d d e n d u m a n d t h e 
c orr e s p o n di n g st ati sti c al a n al y s e s  
- C a n c ell ati o n of t h e fi n al a n al y si s aft er t h e d at a b a s e 
l o c k 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n  
T he p ur p ose of t his i nte grate d a nal ysis pla n (I A P) is t o d oc u me nt t ec h nical a n d det aile d 
s pecificati o ns f or t he a n al yses of d ata c ollecte d f or bi ntraf us p alfa i n t h e d ose escala ti o n a n d 
e x pa nsi o n p hases u n der pr ot oc ol E M R 2 0 0 6 4 7 -0 0 1 t o get u p date d res ults f or a Cli nical St u d y 
Re p ort ( C S R) a d de n d u m a n d t o get res ults m ore partic ularl y i n t h e partici pa nts  wit h cer vical 
ca ncer.  
T he la b orat or y c o de 
M S B 0 0 1 1 3 5 9 C was us e d i n E M R 2 0 0 6 4 7 -0 0 1 pr ot oc ol, 
M 7 8 2 4 is t he 
c o m pa n y c o d e of t he i n vesti gati o nal a nti -P D -L 1/ T G F β Tra p (a nti -P D -L 1/ T G F β RII) dr u g a n d 
bi ntraf us p alfa is t he I nt er nati o nal N o n pr o prietar y Na me f or M 7 8 2 4. Res ults of a nal yses des cri be d 
i n t his I A P will be i ncl u de d i n a n a d de n d u m t o t he C S R. T he data c ut off date f or a nal yses will be 
1 4 Ma y 2 0 2 1. A d diti o nall y, t he pl a n ne d a nal ys es i de ntifie d i n t his I A P will be i ncl u de d i n 
re g ulat or y s u b missi o ns or f ut ure ma n uscri pts.  A n y p ost-h oc, or u n pla n ne d a nal ys es perf or me d t o 
pr o vi de res ults  f or i ncl usi o n i n a C S R or a n a d den d u m, b ut n ot i de ntifie d i n t his pr os pecti ve I A P, 
will be clearl y i de ntifie d i n t he C S R a d de n d u m.  
5  
O bjecti ves a n d E n d p oi nts   
T his I A P will o nl y a d dress a nal yses f or t he p ur p ose of t he C S R a d de n d u m. T he o bjecti ves a n d 
c orres p o n di n g e n d p oi nts acc or di n g t o t he pr ot oc ol ha ve alr ea d y bee n descri be d  i n t he I A P v ersi o n 
1. 0 ( 1 5 Se pte m ber 2 0 2 0) f or t he C S R  ( 0 2 Marc h 2 0 2 1). 
6  
O ver vie w of Pl a n ne d A n al yses   
T his I A P will o nl y a d dress a nal ys es f or t h e p ur p ose of t he C S R  a d de n d u m . A d diti o nal statistical 
a nal ysis pla ns f or Safet y M o nit ori n g C o m mittee ( S M C) a nal ys es , f or t he i nteri m a n d pri mar y 
a nal ys es  b y c o h ort, a n d f or t he C S R ha ve bee n de vel o pe d se paratel y.   
Gl o bal Versi o n I D: C CI
P P D
P P D


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
T he a nal yses will be perf or me d se paratel y i n 3 sets of o ut p uts f or: 
1.  Partici pa nts wit h cer vical ca ncer will be defi ne d acc or di n g t o t he f oll o wi n g criteria  ( CC set 
of o ut p uts) :  
o  Partici pa nts i n D ose Escalati o n ha vi n g “ C E R VI X U T E RI” as a t u m or t y p e 
acc or di n g t o t he dise ase hist or y  
o  Partici pa nts i n D ose E x pa nsi o n bei n g p art of t he Cer vical c o h ort.  
2.  All d ose le vels i n d ose escalati o n w here partici pa nts recei v e d ot h er t ha n 1 2 0 0 m g or 
5 0 0  m g fl at d ose, i.e. D ose Escal ati o n c o h orts ( 0. 3 m g/ k g -> 1 0 m g/ k g, 1 m g/ k g, 1 m g/ k g -
> 1 2 0 0 m 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) a n d H C C 3 m g/ k g c o h ort 
( D E set of o ut p uts). 
3.  All c o h orts of D ose E x pa nsi o n recei vi n g 1 2 0 0 m g  or 5 0 0 m g flat d ose: H C C D ose 
Asce n di n g C o h ort -1 2 0 0 m g, H C C 2 L, 
M ela n o ma P D -L 1 Fail, N S C L C Bi o mar ker, 
N S C L C 
P D -L 1 
Fail, 
Pa ncreatic 
A de n ocarci n o ma , Es o p ha geal  A de n ocarci n o ma , 
C ol orectal  Carci n o ma , Tri ple Ne gati ve  Breast Ca ncer , Gli o blast o ma, S q ua m o us  Cell  
Carci n o ma  of  Hea d a n d Nec k , Cer vical, N S C L C-2 L 5 0 0 m g, N S C L C -2 L 1 2 0 0 m g , 
N S C L C -2 L c o h orts c o m bi ne d  ( X P set of o ut p uts). 
All t he a nal yses will be perf or me d i n partici pa nts wit h cer vical ca ncer  ( C C set of o ut p uts). This 
first set of ta bles a n d fi g ures will i ncl u de 3 cate g ori es : Cer vical Ca ncer - D os e Escalati o n, Cer vi cal 
Ca ncer - D os e E x pa nsi o n, Cer vical C a ncer - P o ol e d. I n t h e listi n gs, a n a d diti o nal c ol u m n will be 
a d de d t o s pecif y t he i nf or mati o n: Cer vical Ca n cer - D ose Es calati o n, C er vical Ca n cer - D ose 
E x pa nsi o n.  
I n a d diti o n, su bject dis p ositi o n, e x p os ure, A D A/ n A b cat e g ories a n d S afet y a nal yses will be 
prese nte d b y c o h ort a n d all c o h orts c o m bi ne d  i n t h e D E set of o ut p uts a n d i n t he X P set of o ut p uts. 
A data re vie w me eti n g will be hel d pri or t o a n y d ata base l oc k. I n a d diti o n, n o data base ca n b e 
l oc ke d u ntil t his I A P has bee n a p pr o ve d (e x ce pt f or e mer ge nc y). 
T he a n al yses descri be d a b o ve will be perf or me d b ase d o n 1 4t h M a y 2 0 2 1 c ut off d ate.   
6. 1  
Decisi o n after disc o nti n u ati o n of N S C L C a n d B T C tri als   
T he data re vie w o utc o me fr o m t he 3 ra n d o mize d c o ntr olle d st u dies i n N S C L C a n d B T C 
( M S 2 0 0 6 4 7-0 0 0 5, M S 2 0 0 6 4 7 -0 0 3 7, M S 2 0 0 6 4 7 _ 0 0 5 5) a p pears t o i n dicate, c o nsiste ntl y acr oss 2 
i n dicati o ns, eit her p o orer o bser ve d h azar d rati os f or P F S a n d O S i n t he e x peri me ntal ar ms wit h 
bi ntraf us p alf a or l o w li k eli h o o d f or bi ntraf us p alf a t o a d d be nefits c o m pare d t o sta n dar d of care. 
Base d o n t his, t he decisi o n was ma de t o ca ncel t he C S R a d de n d u m a n d t he c o rres p o n di n g statistical 
a nal ys es descri be d i n t his i A P.  T he st u d y res ults ha ve bee n descri be d i n C S R a p pr o ve d o n 
0 2 Mar 2 0 2 1 base d o n d at a c ut off d ate of 1 5 Ma y 2 0 2 0.    
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
7  
C h a n ges t o t he Pl a n ne d 
A n al yses i n t he 
Cli nic al 
St u d y  
Pr ot oc ol   
T here will be n o fi n al a n al ysis aft er t he d ata base l oc k.  
8  
A n al ysis P o p ul ati o ns  a n d S u b gr o u ps   
8. 1  
Defi nit i o n of A n al ysis P o p ul ati o ns   
T he f oll o wi n g a nal ysis sets are d efi ne d:  
Scree ni n g A n al ysis Set ( S C R):  All partici p a nts w h o si g ne d t h e i nf or me d c o nse nt f or m.  
S afet y A n al ysis Set ( S A F): All partici pa nts w h o recei v e at least 1 d ose of trial treat me nt.  
F ull A n al ysis Set ( F A S):  All partici pa nts w h o recei ve at least 1 d ose of trial treat me nt.  
P h ar m a c o ki netic ( P K ) A n al ysis Set ( P K A S):  All partici pa nts w h o c o m plete at least 1 i nf usi o n 
of i n vesti gati o nal me dici nal pr o d uct (I M P), a n d w h o pr o vi de at least o n e p ost -d ose sa m ple wit h 
meas ura ble c o n ce ntrati o n of bi ntraf us p alfa. T he  P har mac o ki netic A D A A nal ysis Set ( P K A D A) 
is defi ne d as a s u b p op ulati o n of t he P K A nal ysis  Set a n d restrict e d t o partici pa nts w h o ha ve i n 
a d diti o n at least o ne vali d res ult of A D A at a n y  ti me p oi nt, a n d t he P har mac o ki netic n A b A nal ysis 
Set ( P K N A B) is defi ne d as a s u b p o p ulati o n of  t he P K A S a n d restricte d t o partici pa nts w h o h a ve 
i n a d diti o n at least o ne vali d res ult of n A b at a n y ti me p oi nt.  
P K A n al ysis Set f or C er vic al C a ncer ( P K A S C C):  All partici pa nts  dia g n os e d wit h cer vical 
ca ncer w h o c o m plete at least 1 i nf usi o n of I M P, a n d w h o pr o vi de at least o ne p ost -d ose sa m ple 
wit h meas ura ble c o n ce ntrati o n of bi ntraf us p alfa. T he P har m ac o ki netic A D A A nal ysis Set f or 
Cer vical Ca n cer ( P K A D A C C) is defi ne d as a s u b p o p ulati o n of t he P K A S C C a n d restricte d t o 
partici pa nts w h o ha ve i n a d diti o n at least o ne vali d res ult of A D A at a n y ti m e p oi nt, a n d t he 
P har mac o ki netic n A b A n al ysis Set f or Cer vical Ca ncer ( P K N A B C C) is defi ne d as a s u b p o p ulati o n 
of t he P K A S C C a n d restricte d t o partici pa nts w h o ha ve i n a d diti o n at least o ne vali d res ult of n A b 
at a n y ti me p oi nt.  
I m m u n o ge nicit y A n al ysis Set (I M M):  All partici pa nts w h o recei ve d at least 1 d ose of trial dr u g 
a n d w h o ha ve at least o n e vali d res ult of A D A (i. e. A D A is ne gati ve, or p ositi ve wit h or wit h o ut 
t he titer res ult a vaila ble) at a n y ti me p oi nt. 
T he defi niti o n of t h e S A F a n d t he F A S are i d e nti cal i n t he n o n -ra n d o mize d part of t his st u d y; t he 
S A F ter mi n ol o g y will be use d f or t he safet y a nal ysis a n d t he F A S ter mi n ol o g y will be use d f or 
effic ac y a nal ysis.  I n t he N S C L C sec o n d -li ne c o h ort w here p artici pa nts are ra n d o mize d i n 5 0 0 m g 
or 1 2 0 0 m g a r ms, partici pa nts will be a nal yze d as ra n d o mize d f or efficac y a nal ysis ( F A S) a n d as 
act uall y tr eate d f or safet y a n al ysis ( S A F). If a p artici pa nt recei v es m ore t ha n o ne d ose le vel, t he 
partici pa nt will be classifie d acc or di n g t o t he first d ose le vel recei ve d.  
T he f oll o wi n g t a ble s u m marizes t he use of t he a n al ysis sets i n t he differe nt a nal ys es.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
 
A n al y si s P o p ul ati o n  
A n al y s e s  
F ull A n al y si s S et  
S af et y  A n al y si s 
S et  
I m m u n o g e ni cit y 
S et  
B a s eli n e C h ar a ct eri sti c s  
✓ 
 
 
C o m pli a n c e a n d E x p o s ur e  
 
✓ 
 
Effi c a c y  
✓ 
 
 
   
 
 
 
S af et y a n d T ol er a bilit y  
 
✓ 
 
8. 2  
S u b gr o u p D efi niti o n a n d P ar a meteriz ati o n   
Efficac y will be a n al yze d b y s u b gr o u p cat e g ories  (the cate g or y “ missi n g” will n ot be i ncl u de d i n 
a n y s u b gr o u p a nal ysi s):  
•  A ge  
o  A ge ≥ 1 8 - < 5 0 years  
o  A ge ≥ 5 0 - < 6 5 years  
o  A ge ≥ 6 5 years  
•  Hist ol o g y  
o  S q ua m o us cell carci n o ma  
o  A de n ocarci n o ma  
o  A de n os q ua m o us cell carci n o ma  
o  Ot her  
•  N u m ber of pri or treat me nt li nes ( metastatic/l ocall y a d v a nce d pri or a nti -ca ncer dr u g t h era pies  
( wit h o ut ta ki n g i nt o acc o u nt R T li nes al o ne)) 
o  0  
o  1  
o  2  
o  3  
o   ≥4  
•  Pri or Be v aciz u ma b use  
o  Yes  
o  N o  
Gl o bal Versi o n I D: C CI
C


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
•  Pri or a nti -ca ncer ra di ot hera p y (a n y ra di ot hera p y will be ta ke n i nt o acc o u nt)  
o  Yes  
o  N o  
•  E C O G P S at baseli ne  
o  E C O G P S 0  
o  E C O G P S 1  
•  R ace  
o  W hite  
o  Blac k or Afri ca n A merica n  
o  Asia n  
o  A merica n I n dia n or Alas ka Nati ve  
o  Nati ve Ha w aiia n or Ot her Pacific Isla n d er  
o  N ot c ollecte d at t his site  
o  Ot her  
•  P o ole d Re gi o n  
o  N ort h A meric a  
o  E ur o pe  
o  Asia  & Pacific  
•  A D A  stat us 
o  E ver p ositi ve  
o  Ne ver p ositi ve  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss sites.  T he 
“site” fact or will n ot be c o nsi dere d i n st atistical m o dels or f or  s u b gr o u p a nal yses d ue t o t he hi g h 
n u m ber of partici pati n g sites i n c o ntrast t o t he a nti ci pate d s mall n u m ber of partici pa nts treate d  at 
eac h site.  
All a nal ys es will be perf or me d usi n g S A S ® S oft ware v ersi o n 9. 2 or hi g her.  
9. 1  
D at a  H a n dli n g A fter C ut -off D ate   
B y its nat ur e, d ata after c ut -off m a y be i nc o m plete a n d s u bject t o f urt her c ha n ge  a n d will n ot be 
use d f or s u m mar y statistics, statistical a nal yses , listi n gs or i m p utati o ns .  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
St o p dates are n ot affecte d b y t his r ule, e. g. a st o p date of A Es, w hic h starts pri or t o t he c ut -off, 
b ut st o ps after date of c ut -off, will n ot be c ha n ge d . 
9. 2  
Defi niti o n of B aseli ne  a n d C h a n ge fr o m B aseli ne   
T he last a vaila ble assess me nt pri or t o t h e start of st u d y tr eat me nt is d efi ne d as “ baseli ne” val u e or 
“ baseli ne” assess me nt f or safet y a n d efficac y a nal yses. If a n assess me nt is  pla n ne d t o be perf or me d 
pri or t o t he first d os e of st u d y tr eat me nt i n t he pr ot oc ol a n d t he ass ess me nt is perf or me d o n t he 
sa me da y as t he first d os e of st u d y tr eat me nt, it will be ass u me d t hat it was perf or me d pri or t o 
st u d y treat me nt a d mi nistrati o n, if assess me nt ti me p oi nt is n ot c ollecte d or is missi n g. If ass ess me nt 
ti me p oi nts are c ollecte d, t he o bser ve d ti me p oi nt will be use d t o det er mi ne pre-d os e o n st u d y da y 
1 f or baseli ne calc ul ati o n. U nsc he d ule d assess me nts will be use d i n t he deter mi nati o n of b aseli ne. 
H o we ver, if ti me is missi n g, a n u ns c he d ule d assess me nt o n st u d y da y 1 will be c o nsi dere d t o ha ve 
bee n o btai ne d after st u d y treat me nt a d mi nistrati o n.  
Patie nts w h o start treat me nt a n d disc o nti n ue fr o m t he st u d y o n t he sa me da y ma y ha v e t w o 
differe nt  s ets of data c oll ecte d o n st u d y da y 1 ( o ne d uri n g st u d y a n d o n e i n t he E n d of Treat me nt 
( E O T) visit. Data re p orte d at t he E O T visit are n ot eli gi ble f or baseli ne s electi o n.  
If a s c he d ule d pre-d os e meas ur e me nt act uall y occ urre d p ost -d ose, t he n t he c orres p o n di n g 
meas ure me nt will be tr eate d a n d a nal yze d si milar t o a n u nsc he d ule d p ost -d ose meas ure m e nt.  
9. 3  
St u d y D a y / S t u d y T re at me nt  D a y   
Treat me nt da y is defi ne d relati ve t o t he start of trial treat me nt.  Treat me nt D a y 1 is defi ne d as t he 
date of first a d mi nistrati o n of trial tr eat me nt.  T he da y b ef ore t he first a d mi nistrati o n of trial 
treat me nt is defi ne d as Treat me nt da y -1 (t here is n o T reat me nt da y 0).  
9. 4  
Defi niti o n of D ur ati o n  a n d ‘ti me si nce’ V ari a bles   
D urati o n ( da ys) will be calc ulate d b y t he differe nce of start a n d st o p date + 1 da y, if n ot ot her wise 
s pecified.  F or e x a m ple, s ur vi val ti me ( da ys) = d ate of deat h –  d ate of first d ose of trial treat me nt 
+ 1.  
T he ti me si nce a n e ve nt ( e. g. ti me si nce first dia g n osis) will be calc ulate d as refere nce date mi n us 
date of e v e nt. I n ge n eral, t he refere n ce dat e will be t he date of first d ose of trial treat me nt.  
9. 5  
C o n versi o n F act ors   
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years:  
1 wee k = 7 d a ys, 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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. 6  
D ate of L ast C o nt act   
T he date of last c o nta ct will be deri ve d f or partici pa nts n ot k n o w n t o h a ve die d at t he a nal ysis 
c ut off usi n g t he latest c o m plete date pri or t o or at t he data c ut -off date fr o m t he f oll o wi n g:  
•  All partici pa nt assess me nt dates (e. g., bl o o d dra ws [la b orat or y, P K], vital si g ns, E C O G 
perf or ma n ce stat us, el ectr ocar di o gra m [ E C G], t u m or assess me nts , q ualit y of life assess me nts) 
•  Star t a n d e n d dates of a ntica ncer t hera pies a d mi nistere d after disc o nti n uati o n of st u d y 
i nter ve nti o n 
•  A E start a n d e n d d ates  
•  Last k n o w n t o be ali ve date fr o m “S u bject Stat us / S ur vi val F oll o w -U p ” e C R F pa ge St u d y 
i nter ve nti o n start a n d e n d dates 
•  St u d y dr u g start  a n d e n d dates (i ncl u di n g rei nitiati o n of treat me nt) 
•  Date of disc o nti n uati o n ta ke n fr o m t he “St u d y T er mi nati o n ” e C R F pa ge ( d o n ot use if reas o n 
disc o nti n uati o n is l ost t o f oll o w -u p)  
Data c ollect e d after rei nitiate d treat me nt will be c o nsi dere d i n t he deri v ati o n of t he last k n o w n t o 
be ali ve date.  
T he last k n o w n t o be ali v e date will be c o m plete d b y t he date of deat h f or d ea d partici p a nts.  
O nl y dates ass oci ate d wit h act ual e x a mi nati o ns of t he partici pa nt re p orte d i n t he e C R F will be 
use d i n t he deri vati o n. D ates ass o ciate d wit h a t ec h nical o perati o n u nrelate d t o partici p a nt stat us 
s uc h as t he date a bl o o d sa m ple was pr ocesse d will n ot be use d. 
9. 7  
Ti me  W i n d o w  
N ot A p plica ble.  
9. 8  
Defi niti o n of O n -tre at me nt P eri o d  
T he o n -treat me nt peri o d will i ncl u de t he i nitial treat me nt peri o d as well as t he rei nitiati o n of 
treat me nt peri o d, as a p pli ca ble. W het her a partici pa nt rei nitiates treat me nt (f oll o wi n g t he r ules as 
o utli ne d i n t he pr ot oc ol) or n ot, t he o n -treat me nt peri o d is defi ne d as t he ti me fr o m t he first trial 
dr u g  a d mi nistrati o n t o t he last trial dr u g a d mi nistrati o n date + 3 0 d a ys or t he earl iest d ate of 
s u bse q ue nt a ntica n cer dr u g (a ntica n cer t h era p y, a ntica ncer s ur ger y a n d a ntica ncer ra di ot hera p y) 
t hera p y mi n us 1 da y, w hi c he ver occ urs first, u nless ot her wise state d.  
F or i m m u ne -relat e d A Es as liste d i n Secti o n 1 5. 2. 3. 2 , a n e x pa n de d o n-tr eat me nt peri o d will be 
use d as a defa ult f or a n y a nal ysis: Ti me fr o m t he first trial dr u g a d mi nistrati o n t o t he last trial dr u g 
a d mi nistrati o n date + 9 0 da ys, d eat h O R t o  t he earliest date of s u bse q ue nt a ntica ncer t h era p y mi n us 
1 da y, w hic he v er occ urs first, u nless ot her wise state d.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
9. 9  
I m p ut ati o n of M issi n g D at a   
U nless ot her wise s pecifi e d all data w ill be e val uate d as o bser ve d, a n d n o i m p utati o n met h o d f or 
missi n g val ues will be us e d.  
I n all p artici pa nt d ata listi n gs, i m p ute d v al ues will be prese nt e d a n d i m p ute d i nf or mati o n will b e 
fla g ge d. 
Missi n g statistics, e. g. w he n t he y ca n n ot b e calc ul ate d, s h o ul d be pres e nte d as “ n d ”. F or e x a m ple, 
if n = 1, t he meas ur e of varia bilit y ( S D) ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as “ n d”. 
A ge  
I n c o m plete dates (date of i nf or me d c o nse nt, date of birt h ) f or t he 
calc ulati o n of a ge will be i m p ute d as f oll o ws : 
•  I n cas e of missi n g da y f or at least o ne date, b ut m o nt h a n d year a v aila ble 
f or b ot h dates:  t he da y of i nf or me d c o ns e nt a n d t h e da y of birt h will be 
set t o 1. 
•  I n case of missi n g m o nt h f or at least o ne date, b ut year a vaila bl e f or 
b ot h dates, t he da y a n d t h e m o nt h of i nf or me d c o nse nt a n d t he da y a n d 
m o nt h of birt h will be set t o 1 . 
Deat h  
Missi n g or partial dat es of deat h will be i m p ute d as f oll o ws : 
•  If t he d ate is missi n g, it will be i m p ute d as t he last k n o w n date t o be 
ali ve 
•  If t he da y or m o nt h is missi n g, deat h will be i m p ute d as t he ma xi m u m 
bet wee n t he last k n o w n date t o be ali ve a n d t he i m p ute d date of deat h 
w here:  
•  
Missi n g da y: 1st da y of t he m o nt h a n d year of deat h  
•  
Missi n g da y a n d m o nt h: J a n uar y 1st of t he year of deat h  
 
A d verse e ve nts  
I n c o m plete A E-relate d d ates will be i m p ute d as f oll o ws:  
•  I n case t h e o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he 
o nset m o nt h a n d year, or t he o nset year are e q u al t o t he start of trial 
treat me nt t he n t he o nset date will be re place d b y t he mi ni m u m of start 
of tr ial treat me nt a n d A E res ol uti o n date (if n ot missi n g).  
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be 
re place d b y 1. 
•  I n c o m plete st o p dates will be re place d b y t h e last da y of t he m o nt h (if 
da y is missi n g o nl y), if n ot res ulti n g i n  a date later t ha n t he d ate of 
partici pa nt's deat h. I n t he later case t he date of deat h will be use d t o 
i m p ute t he i nc o m plete st o p date.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
•  I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.   
9. 1 0  
Si g nific a nce L e vel   
N o statistical tests will b e perf or me d f or a n y of t he st u d y e n d p oi nts.  F or descri pti ve p ur p oses, 
9 5 % c o nfi de n ce i nter vals ( CIs) will be calc ul ate d w here i n dicate d.  
9. 1 1  
Prese nt ati o n of C o nti n u o us a n d Q u alit ati ve V ari a bles   
C o nti n u o us varia bles will be s u m marize d usi n g d escri pti ve statistics i.e. n u m ber of n o n -missi n g 
val ues a n d n u m ber of missi n g val ues [i.e. n ( missi n g)], mea n, me dia n, sta n dar d de viati o n  ( St D), 
Q 1, Q 3, mi ni m u m  ( Mi n), a n d ma xi m u m ( Ma x).  
Q ualitati ve varia bles will be s u m marize d b y c o u nts a n d perce nta ges.  U nless ot her wise state d, t he 
calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of p artici pa nts of t he a nal ysis s et of i nterest. 
T heref ore, 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 n at or a n d prese nte d as a 
se parat e cat e g or y.  
I n case t he a nal ysis refers o nl y t o certai n visits, perce nta ges will be base d o n t he n u m ber of 
partici pa nts still prese nt i n t he trial at t hat visit, u nless ot her wise s pecifie d.  
U nless ot her wise s pecifi e d, ti me t o e ve nt e n d p oi nts will be prese nte d i n m o nt hs. S u m mar y 
statistics will be re p orte d wit h 1 di git.  
9. 1 2  
Re p orti n g C o n ve nti o ns   
Mea n, me dia n, Q 1, Q 3, Mi n , a n d Ma x  will ha ve t he sa me precisi o n as S D T M data ( n u m ber of 
di gits) f or n o n -d eri ve d data, a n d St D  s h o ul d be dis pla ye d t o o ne di git m ore t h a n t he mea n. Statistics 
o n deri ve d data will be r o u n de d t o reas o na ble di gits, w hereas ma xi mal di gits s h o ul d be a vaila ble 
i n C DI S C A Da M data sets. Perce nta ges will be re p orte d t o o ne deci mal place. T he r o u n di n g will 
be perf or m e d t o t he cl osest i nte ger / first deci mal usi n g t he c o m m o n mi d -p oi nt bet wee n t he t w o 
c o nsec uti ve val ues. F or e x a m ple, 5. 1 t o 5. 4 will be r o u n de d t o a n i nte ger of 5, a n d 5. 5 t o 5. 9 will 
be r o u n de d t o a n i nte ger of 6.  
9. 1 3  
Preferre d T er m f or A n al ysis of W H O -D D C o de d D at a   
F or d ata c o de d acc or di n g t o W H O -D D (e. g., c o n c o mita nt me dicati o ns), s u m maries will be d o n e 
o n t he preferre d ter m le v el w here t h e preferre d ter m is c orres p o n di n g t o c o des e n di n g i n 0 1 0 0 1. 
Wit h t his a p pr oac h, variati o ns  of salt f or ms of acti ve i n gre die nts will be a n al yze d u n der t he sa me 
ter m, e. g. di p h e n h y dra mi ne a n d di p he n h y dra mi n e h y dr oc hl ori de will be a nal yze d as t he sa me 
preferre d t er m di p he n h y dra mi ne.  
9. 1 4  
D at a c ollecte d after R ei niti ate d T re at me nt   
Data c ollecte d after rei nitiati o n of treat me nt will be i ncl u de d i n t he s u m mar y statistics a n d will be 
s h o w n i n listi n gs. 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
1 0  
St u d y P artici p a nt s  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt  dis p ositi o n a n d 
st u d y treat me nt/st u d y dis c o nti n uati o ns.  
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns  
A n alysis sets: Scree ni n g a n alysis set  - 3 differe nt sets of o ut p uts:  
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Esc al ati o n/ H C C 3 m g/k g c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Ex p a nsi o n c o h orts  
T he f oll o wi n g p ara m eters will be s u m marize d f or all partici pa nt s.  
•  T otal n u m ber of partici pa nts scree n e d o verall  
•  N u m ber of partici pa nt s w h o disc o nti n ue d fr o m t he trial pri or t o first d ose of treat me nt 
•  Reas o n f or disc o nti n uati o n of trial pri or t o first d ose of treat me nt (di d n ot meet eli gi bilit y  
criteria, wit h dr a w of c o nse nt , ot her) 
•  N u m ber of partici pa nts w h o recei ve d n o treat me nt  
•  N u m ber of partici pa nts w h o recei ve d at least 1 d ose of trial treat me nt ( Safet y A nal ysis Set)  
•  N u m ber of p artici pa nts wit h treat me nt o n -g oi n g  
•  N u m ber of partici pa nts w h o disc o nti n ue d t he treat me nt  
•  N u m ber of rei nitiate d partici pa nt s 
•  Reas o ns f or treat me nt disc o nti n uati o n –  f or rei nitiate d partici pa nts, t he reas o n of tr eat me nt 
disc o nti n uati o n d uri n g t h e first peri o d will be des cri be d  
o  A d verse e ve nt  
o  L ost t o f oll o w -u p  
o  Pr ot oc ol n o n -c o m plia nce  
o  Deat h  
o  Pr o gressi ve disease  
o  Wit h dre w c o nse nt  
o  Ot her  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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  
 
  
•  N u m ber of p artici pa nts w h o disc o nti n ue d t he treat me nt b ut are still i n st u d y f or f oll o w -u p  –  
t his will e x cl u de partici pa nts wit h re-i nitiate d treat me nt o n g oi n g 
•  N u m ber of partici pa nt s w h o disc o nti n ue d fr o m t he st u d y 
•  Reas o ns f or st u d y disc o nti n uati o n 
o  L ost t o f oll o w -u p  
o  Deat h  
o  Wit h dre w c o nse nt  
o  Ot her  
A n alysis sets: F ull a n alysis set   
T he f oll o w -u p ti me till c ut-off date  will be defi ne d as t he ti me fr o m t he date of first d ose t o t he 
c ut-off dat e . Des cri pti ve statistics will be pr o vi de d.  
1 0. 2  
Pr ot oc ol De vi ati o ns  / E xcl usi o n fr o m A n al ysis P o p ul ati o ns  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
Will n ot be re p orte d . 
1 0. 2. 2  
Re as o ns 
Le a di n g t o t he 
E xcl usi o n fr o m 
a n 
A n al ysis 
P o p ul ati o n   
Will n ot be re p orte d . 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics   
T he a nal ysis of de m o gra p hic a n d baseli ne c haracteristics of t he st u d y p o p ulati o n is critical  f or 
descri bi n g t he h o m o ge n eit y or heter o ge neit y of t he st u d y p o p ulati o n bet wee n st u d y treat me nt 
gr o u ps. I n ge neral, s u m maries of t he k e y d e m o gra p hics b y st u d y treat me nt gr o u p f or t he a n al yze d 
p o p ulati o n are t o be pr o vi de d. If ra n d o mizati o n strata or s u b gr o u ps e xist t he n a s u m mar y of t he 
de m o gra p hics f or t he s u b gr o u p or ra n d o mize d strat a ma y be rele va nt t o f ull y c haracterize t he st u d y 
p o p ulati o n.  
A n alysis sets: F ull  a n alysis set –  1 set of o ut p u ts: 
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
1 1. 1  
De m o gr a p hics   
De m o gra p hic a n d baseli n e c haracteristics will be s u m marize d usi n g t he f oll o wi n g i nf or m ati o n:   
•  Se x: Male, F e male  
•  R ace: W hite, B lac k or Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n or ot h er Pacifi c Isla n der, O t her, U n k n o w n  
•  Et h nicit y: His pa nic or Lati n o, N ot His pa nic or Lati n o  
•  A ge ( years): s u m mar y st atistics  
•  A ge cat e g ories:  
•  < 6 5 years,  
•  ≥ 6 5 years  
•  6 5 -7 4,  
•  7 5 -8 4,  
•  ≥8 5  years   
•  P o ole d Re gi o n:  
•  N ort h A meric a  
•  E ur o pe  
•  Asia  
•  Rest of t he W orl d  
De m o gra p hics will be e xtracte d fr o m t he “ De m o gra p hics” e C R F pa ge.   
S pecificati o ns f or c o m p utati o n:  
•  A ge ( years) = ( dat e of i nf or me d c o nse nt - d ate  of birt h + 1) / 3 6 5. 2 5  
•  I n v esti gat or site c o des will be use d f or t he deter mi nati o n of t he partici pa nt ’s ge o gra p hic 
re gi o n. 
1 1. 2  
Me dic al Hist or y   
Will n ot be re p orte d . 
1 1. 3  
Ot her B aseli ne C h ar acteristics   
T he f oll o wi n g c haracteristics will be ta b ulate d base d o n data c ollecte d at s cree ni n g:  
•  P D -L 1 e x pressi o n i n t u m or cells: > = 1 %, > = 5 %, > = 1 0 %, > = 2 5 %, > = 5 0 %, > = 8 0 % , 
•  P D -L 1  e x pressi o n i n t u m or micr oe n vir o n me nt: > = 1 %, > = 5 %, > = 1 0 %, > = 2 5 %, > = 5 0 %, 
> = 8 0 % , 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
•  P D -L 1 e x pressi o n i n w h ole t u m or: > = 1 %, > = 5 %, > = 1 0 %, > = 2 5 %, > = 5 0 %, > = 8 0 % . 
A listi n g of t he P D -L 1 e x pressi o n at s cree ni n g will als o be pr o vi de d wit h t he f oll o wi n g 
i nf or mati o n: c o hort, partici pa nt i de ntifier, a ge, ge n der, race, c o nfir m e d Best O verall Res p o nse per 
R E CI S T 1. 1 as assesse d b y I n v esti gat or,  u ni q ue sa m ple ide ntifier , visit, collecti o n date, P D -L 1 i n 
t u m or cells, P D -L 1 i n t u m or micr oe n vir o n me nt, P D -L 1 i n w h ole t u m or.  
1 1. 4  
Pri or  A nti -c a ncer T her a p y   
Will n ot be re p orte d . 
1 2  
P re vi o us  or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
Will n ot b e re p orte d . 
1 3  
St u d y Tre at me nt: C o m pli a nce a n d E x p os ure   
A n alysis Sets: S afety a n alysis set  - 3 differe nt sets of o ut p uts:  
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
- 
P artici p a n ts i ncl u de d i n D ose Esc al ati o n/ H C C 3 m g/k g c o h orts 
- 
P artici p a nts i ncl u de d i n D ose Ex p a nsi o n c o h orts  
Partici pa nts will recei ve a n I V i nf usi o n of bi ntraf us p alfa o v er o nce e ver y 2 wee ks u ntil P D has 
bee n c o nfir me d b y a sca n, u nacce pta ble t o xicit y, or occ urre n ce 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 he pr ot oc ol.  
Eac h c ycl e of bi ntraf us p alfa  is defi ne d b y a 2-wee k peri o d.  
W het her t he partici pa nt  rei nitiates t he treat me nt or n ot, t he d urati o n of treat me nt of bi ntraf us p alf a 
(i n wee ks) d uri n g t h e st u d y is defi n e d as:  
d urati o n = ( date of last d ose -date of first d ose + 1 4
7
)  
F or partici pa nts w h o rei nitiate t he treat me nt, t he d urati o n of t hera p y will be t he  o verall treat me nt 
d urati o n:  
d urati o n = ( date of last d ose  i n s ec o n d p eri o d-date of first d ose  i n first p eri o d+ 1 4
7
)  
A s u m mar y ta ble of t he d urati o n of t hera p y ( wee ks) will be pr o vi de d , t o get her wit h t he ass ociate d 
listi n g 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
1 4  
Effic ac y A n al yses   
A n alysis Sets: F ull a n alysis set  –  1 set of o ut p uts:  
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
1 4. 1  
Best O ver all Res p o nse   
Best o ver all res p o nse ( B O R)  will be assesse d bas e d o n t he t u m or res p o nse at differe nt e val uati o n 
ti me p oi nts fr o m baseli ne u ntil t he first d oc u me nte d disease pr o gressi o n f or R E CI S T.  O nl y t u m or 
assess me nts perf or me d b ef ore t h e start of a n y f urt her a nti ca n cer tr eat me nt will be c o nsi dere d i n 
t he assess me nt of B O R. Cli nical deteri or ati o n will n ot be c o nsi d ere d as d oc u me nte d diseas e 
pr o gressi o n.  
O bjecti ve Res p o nse ( O R)  is defi ne d as c o m plete res p o nse ( C R) or partial resp o nse ( P R) 
acc or di n g t o e val uati o n criteria fr o m start date u ntil d oc u me nte d disease pr o gressi o n. Partici pa nts  
w h o d o n ot ha v e a n o n -treat me nt ra di o gra p hic t u m or assess me nt d ue t o earl y pr o gressi o n, w h o 
recei v e a nti-t u m or treat me nts ot her t ha n t he st u d y treat me nts pri or t o reac hi n g a C R or P R, or w h o 
die, pr o gress, or dr o p o ut f or a n y reas o n pri or t o reac hi n g a C R or P R will be c o u nte d as n o n -
res p o n ders i n t he assess me nt of O R. Eac h partici pa nt  will ha ve a n o bjecti ve res p o nse stat us ( 0: n o 
O R; 1: O R). O R rate ( O R R) is t he pr o p orti o n of patie nts wit h O R i n t he a nal ysis set.  
Dise ase C o ntr ol R ate  (D C R)  is defi ne d as t he pr o p orti o n of partici p a nt s wit h B O R acc or di n g t o 
e val uati o n criteri a  of C R, P R, S D . 
1 4. 1. 1  
Best O ver all Res p o nse Acc or di n g t o R E CI S T 1. 1 as Assesse d 
b y I n vesti g at or   
T he c o nfir me d B O R acc or di n g t o d ata c ollecte d i n t he e C R F f or R E CI S T 1. 1 res p o nse criteri a as 
assesse d b y t he i n vesti gat or will be defi ne d acc or di n g t o t he f oll o wi n g r ules:  
•  C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a p art a n d b ef ore pr o gressi o n  
•  P R = at le ast t w o d eter mi nati o ns of P R or b etter at least 4 wee ks a p art a n d bef ore pr o gressi o n 
(a n d n ot q ualif yi n g f or a C R) 
•  S D = at least o ne S D assess me nt ( or better) ≥ 6 wee ks aft er start date a n d bef ore pr o gressi o n 
(a n d n ot q ualif yi n g f or C R or P R) 
•  P D = pr o gressi o n ≤ 1 2 w ee ks aft er start dat e (a n d n ot q ualif yi n g f or C R, P R or S D)  
T he f oll o wi n g r ule will a d diti o nall y b e a p plie d re gar di n g d eri vati o n of B O R:  
•  Partici pa nts w h o miss t he first t w o p o st-bas eli ne t u m or e val uati o ns a n d s u bse q ue ntl y are 
o bser ve d t o ha v e P D will be assi g n e d a n ot -e val ua ble B O R ( N E) ( i.e. t u m or assess me nt of P D 
is > 1 2 wee ks after start date a n d t here is n o t u m or assess me nt i n bet wee n).  
W he n e val uati n g O R, b ot h  C R a n d P R m u st be c o nfir me d b y re peate d  assess me nts perf or me d n o 
less t ha n 4 wee ks after t h e criteri a f or res p o nse are first met.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /4 1  
 
  
T he c o nfir me d O R R will be calc ulate d f or eac h c o h ort  ( C C d ose escal ati o n a n d C C e x pa nsi o n) 
a n d o verall (all C C p o ole d t o get h er)  wit h a t w o -si de d 9 5 % CI usi n g t he Cl o p per-Pears o n met h o d 
(e x act CI f or a bi n o mial pr o p orti o n as c o m p ute d b y defa ult b y t h e F R E Q pr oce d ure usi n g t h e 
E X A C T o pti o n).  
I n a d diti o n, t he n u m ber a n d perce nta ge of partici p a nts wit h c o nfir me d B O R of C R, P R, S D, P D, 
a n d N E will be ta b ulate d.  
T he n u m ber a n d perce nta ge of partici pa nts wit h c o nfir me d D C R will be ta b ulate d t o get her wit h a 
t w o-si de d 9 5 % CI.  
A listi n g will prese nt  t h e t u m or assess me nt a n d o verall res p o nse per R E CI S T 1. 1 as assesse d b y 
t he i n vesti gat or i ncl u di n g:  c o h ort, partici pa nt i de ntifier, a ge, se x, race, u nc o nfir me d a n d 
c o nfir me d B O R, visit, date(s) of i ma gi n g, des cri pti o n of tar get lesi o ns (size, site, stat u s, t y pe, 
met h o d, res p o nse), n o n tar get lesi o ns (stat us, site, met h o d, res p o nse), a n d n e w lesi o ns (site, stat us, 
met h o d), s u m of lesi o n dia meters, perce nt c ha n ge i n tar get lesi o ns at baseli ne, a n d o verall 
res p o nse, s orte d b y c o h ort, partici pa nt i de ntifier, a n d visit. 
T he i n di vi d ual perce nta ge of c ha n ge i n t he s u m of dia meters si nce baseli ne will be dis pla ye d o ver 
ti me per c o h ort o n a s pi d er pl ot, t o get her wit h t he first occ urre n ce of ne w lesi o n a n d partici pa nt 
off treat me nt. T he c ha n ge i n t he su m of d ia meters bet wee n b as eli ne a n d t he best post -baseli ne 
assess me nt (i.e. mi ni m u m c ha n ge si nc e baseli ne) will be dis pla ye d f or eac h partici pa nt per c o h ort 
o n a waterfall gra p h. T h e s u m of dia meters i ncl u des all tar get lesi o ns (l o n gest dia meter f or n o n -
n o dal lesi o ns a n d s h ort a xis f or n o dal tar get lesi o ns). F or s pi der pl ots a n d waterfall pl ots, t h e 
perce nt c ha n ge fr o m baseli ne i n t he s u m of dia meters will be dis pla ye d f or vali d ti me p oi nt 
assess me nts, o nl y. F or t h e p ur p ose of t his a nal ysis, a vali d ti me p oi nt assess me nt is defi ne d as a 
c o m plete assess me nt of all tar get lesi o ns re p orte d at baseli ne.  
A n a d diti o nal waterfall pl ot will be create d i n w hic h t he P D -L 1 e x pressi o n at Scree ni n g ( % i n 
T u m or Cells, % i n T u m or Micr oe n vir o n me nt, % i n W h ole T u m or) will be prese nte d ; a differe nt 
c ol or will be use d t o dis pla y eac h of t he val ues f or t he c o nfir me d B O R as assesse d  b y t he 
i n vesti gat or.  
1 4. 1. 2  
S u b gr o u p A n al ysis f or Best O ver all Res p o nse Acc or di n g t o 
R E CI S T 1. 1 as Assesse d b y I n vesti g at or   
Best O verall Res p o nse b ase d o n c o nfir me d res p o nses, O R R a n d D C R acc or di n g t o R E CI S T 1. 1 
as a dj u dicate d b y I n vesti gat or will als o be e val uat e d i n o n all s u b gr o u ps defi ne d i n 8. 2 . T he y will 
be calc ulat e d f or eac h c o h ort ( C C d ose escalati o n a n d C C e x pa nsi o n) a n d o verall (all C C p o ole d 
t o get her) wit h a t w o-si d e d 9 5 % CI. 
1 4. 2  
D ur ati o n of Res p o nse   
T he D urati o n of Res p o ns e ( D R) is me as ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ P R u ntil t he first date of P D or deat h d ue t o a n y ca us e wit hi n 8 4  d a ys ( 1 2 wee k s) of last t u m or 
assess me nt if d eat h o cc urre d d uri n g t he first year of f oll o w -u p, or wit hi n 1 6 8 da ys ( 2 4 wee ks) of 
last t u m or assess me nt if deat h occ urre d d uri n g t h e f oll o wi n g years of f oll o w-u p.  T he a n al ysis of 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /4 1  
 
  
D R will be p erf or m e d a m o n g p artici pa nts of t he F ull A nal ysis Set w h o met c o nfir me d C R/ P R 
acc or di n g t o R E CI S T 1. 1 as assesse d b y t he I n vesti gat or  
D R will be ce ns ore d i n t he f oll o wi n g s ce nari os:  
•  Partici pa nts w h o d o n ot e x perie nce a n e ve nt ( P D or deat h) will be ri g ht -ce ns ore d o n t he date of 
t heir last e val ua ble ( n o n-missi n g a n d n o n “ N ot E v al ua ble”) t u m or assess me nt.  
•  If deat h wit h o ut pre vi o usl y d oc u m e nte d P D is o bser ve d after m ore t ha n 8 4 da ys ( 1 2 wee ks) 
d uri n g t he first year of f oll o w -u p, or after m or e t ha n 1 6 8 da ys ( 2 4 wee ks) d uri n g t he f oll o wi n g 
years of f oll o w -u p of last t u m or assess me nt, t he patie nt will be ri g ht -ce ns ore d at t h e date of 
t he last e val ua ble t u m or assess me nt.  
•  Partici pa nts w h o start ne w a nti -ca ncer treat me nt pri or t o a n e ve nt will be ce ns ore d o n t he date 
of t he last e val ua bl e t u m or assess me nt bef ore a nti -ca ncer t hera p y is gi ve n.  
•  Partici pa nts wit h a n e ve nt after t w o or m ore missi n g t u m or assess me nts will be ce ns ore d o n t he 
date of t he last e v al ua ble t u m or assess me nt.  
•  Partici pa nts w h o d o n ot ha ve a baseli ne t u m or assess me nt or w h o d o n ot ha ve a n y p ost -bas eli ne 
t u m or assess me nts will b e ce ns ore d o n t he d ate of first d ose u nless d eat h o cc urre d o n or bef ore 
t he ti me of t he sec o n d pl a n ne d t u m or assess me nt i n w hic h case t he deat h will be c o nsi dere d 
a n e ve nt.  
D R = ( date of P D or deat h/ce ns ori n g –  date of o bj ecti ve res p o ns e + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
T he a nal ysis of  D R will be perf or me d wit h a Ka pla n -Meier m et h o d ( pr o d u ct -li mit esti mates) a n d 
a s u m mar y of ass ociate d statistics will be prese nte d i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % CIs. 
T he CIs f or t he me dia n will be calc ulat e d acc or di n g t o Br o o k me yer a n d Cr o wle y ( 1 9 8 2) a n d CIs 
f or t he s ur vi val f u ncti o n esti mates at M o nt h 3, 6, 1 2, 2 4 a n d 3 6 m o nt hs ( de pe n di n g o n act ual d ata) 
will be deri ve d usi n g t he l o g -l o g tra nsf or m ati o n acc or di n g t o Kal bfleisc h a n d Pre ntice ( 1 9 8 0) 
( C O N F T Y P E =l o gl o g defa ult o pti o n i n S A S P R O C LI F E T E ST).  T he esti mate of sta n dar d err or 
will be c o m p ute d usi n g Gree n w o o d’s f or m ula.  
T he ti me a n d d urati o n of res p o nse per partici p a nt  will als o be dis pla ye d i n a s wi m mer gra p h i n 
partici pa nt s wit h u nc o nfir me d/c o nfir me d C R/ P R. A partici pa nt listi n g will pr o vi d e t he f oll o wi n g 
i nf or mati o n: c o h ort, partici pa nt i de ntifier, a ge, se x, race, date of first res p o nse, d urati o n of 
res p o nse, date of last t u m or assess me nt, ce ns ori n g reas o n. 
1 4. 3  
Pr o gressi o n Free S ur vi v al   
Pr o gressi o n Free S ur vi val ( P F S) ti me is defi ne d as t he ti me (i n m o nt hs ) fr o m first a d mi nistrati o n 
of trial tr eat me nt u ntil t h e first d ate of P D or deat h d ue t o a n y ca use wit hi n 8 4  da ys ( 1 2 wee ks) of 
last t u m or assess me nt if deat h occ urre d d uri n g t he first year of f oll o w -u p, or wit hi n 1 6 8 da ys ( 2 4 
wee ks) of last t u m or assess me nt if deat h occ urre d d uri n g t he f oll o wi n g years of f oll o w -u p.  
T he a nal ysis of P F S will be perf or me d acc or di n g t o R E CI S T 1. 1 assesse d b y t he I n v esti gat or.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /4 1  
 
  
P F S will be ce ns ore d i n t he f oll o wi n g s ce nari os:  
•  Partici pa nts w h o d o n ot e x perie nce a n e ve nt ( P D or deat h) will be ri g ht -ce ns ore d o n t he date of 
t he last e val ua ble ( n o n missi n g a n d n o n “ N ot E v al ua ble”) t u m or assess me nt. 
•  If deat h wit h o ut pre vi o usl y d oc u m e nte d P D is o bser ve d after m ore t ha n 8 4 da ys ( 1 2 wee ks) 
d uri n g t he first year of f oll o w -u p, or after m or e t ha n 1 6 8 da ys ( 2 4 wee ks) d uri n g t he f oll o wi n g 
years of f oll o w -u p of last t u m or assess me nt, t he patie nt will be ri g ht -ce ns ore d at t h e date of 
t he last e val ua ble t u m or assess me nt.  
•  Partici pa nts w h o start ne w a nti -ca ncer treat me nt pri or t o a n e ve nt will be ce ns ore d o n t he date 
of t he last e val ua bl e t u m or assess me nt bef ore a nti -ca ncer t hera p y is gi ve n.  
•  Partici pa nts wit h a n e v e nt after t w o or m or e s u bse q ue nt missi n g res p o ns e assess me nts (i. e. 2 
ti mes t he sc he d ule d ti me i nter val bet wee n t w o s u bse q ue nt res p o nse ass ess me nts) will be 
ce ns ore d o n t h e date of t he last e val ua ble t u m or assess me nt.  
•  Partici pa nts w h o d o n ot ha ve a baseli ne t u m or assess me nt or w h o d o n ot ha ve a n y p ost -bas eli ne 
t u m or assess me nts will b e ce ns ore d o n t he d ate of first d ose u nless d eat h o cc urre d o n or bef ore 
t he ti me of t he sec o n d pl a n ne d t u m or assess me nt i n w hic h case t he deat h will be c o nsi dere d 
a n e ve nt.  
P F S = ( date of P D or deat h/ce ns ori n g –  d ate of t he first d ose + 1)/  3 0. 4 3 7 5 ( m o nt hs).  
T he date of P F S e ve nt / ce ns ori n g will be defi ne d i n Ta ble 1 .  
T a ble 1  
Pr o g ressi o n -free S ur vi v al E ve nt / Ce ns ori n g  
P F S E v e nt St at u s  
C e n s ori n g  
D at e of e v e nt / c e n s ori n g  
Pr o gr e s s e d or 
di e d  
 
Wit hi n t w o s u b s e q u e nt s c h e d ul e d 
t u m or a s s e s s m e nt s aft er l a st 
r e s p o n s e a s s e s s m e nt of C R, P R or 
S D  
E v e nt  
Mi ni m u m( D at e of P D, D at e of 
d e at h)  
Ot h er wi s e  
C e n s or e d  
D at e of l a st t u m or a s s e s s m e nt wit h 
o ut c o m e C R, P R or S D or d at e of 
fir st d o s e, w h at e v er i s l at er 
N eit h er pr o gr e s s e d n or di e d  
C e n s or e d  
D at e of l a st t u m or a s s e s s m e nt wit h 
o ut c o m e C R, P R or S D or d at e of 
fir st d o s e, w h at e v er i s l at er 
P F S : p r o gr e s si on -fr e e sur vi v al  
T he a nal ysis of P F S ti me will be perf or me d wit h a Ka pla n -Mei er met h o d wit h t he sa me a p pr oac h 
as f or D R descri be d i n Secti o n  1 4. 2 .  Ka pla n-Meier esti mates ( pr o d u ct -li mit esti mates) will be 
prese nte d t o get her wit h a s u m mar y of ass ociate d st atistics i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % 
CIs. P F S rates wit h t heir CI  at 3, 6, 1 2, 1 8, 2 4 a n d 3 6 m o nt hs ( de pe n di n g o n act ual data) will be 
prese nte d, as well as t he n u m ber of partici p a nts at ris k a n d faile d.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
A partici p a nt listi n g will pr o vi de t he f oll o wi n g i n f or mati o n: c o h ort, p artici p a nt i de ntifier, a ge, se x, 
race, dat e of first a d mi nistrati o n, date of last t u m or assess me nt, date of e ve nt/ce ns ori n g, 
e ve nt/ce ns ori n g reas o n, ti me t o e ve nt.  
1 4. 4  
O ver all S ur vi v al   
T he o verall s ur vi val ( O S) ti me is defi ne d as t he d ate fr o m first d ose  t o d eat h d ue t o a n y ca use:  
O S = ( date of e ve nt/ce ns ori n g –  d ate of t he first d ose + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
F or patie nts ali ve at t he ti me of data c ut -off date or w h o are l ost t o f oll o w u p, O S will be ce ns ore d 
at t he last date k n o w n t o be ali ve.  
T he date of e ve nt / ce ns ori n g is defi ne d i n Ta ble 2 . 
T a ble 2  
S ur vi v al  E ve nt / C e ns ori n g   
 
D ate of e ve nt / ce ns ori n g  
Ce ns ori n g  
P artici pa nt s ali ve or l ost t o f oll o w -
u p  bef ore or at c ut -off date  
Last date k n o w n t o be ali ve  (as defi ne d i n Secti o n 9. 6 ) 
Yes   
P artici pa nt s w h o die d bef ore or at 
c ut -off date  
Date  of deat h  
N o  
T he a nal ysis of O S ti me will be perf or me d wit h a Ka pla n -Meier met h o d wit h t he sa me a p pr oac h 
as f or D R descri be d i n Secti o n  1 4. 2 .  Ka pla n-Meier esti ma tes ( pr o d u ct-li mit esti mates) will be 
prese nte d t o get her wit h a s u m mar y of ass ociate d st atistics i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % 
CIs.  O S rat es wit h t heir CI  at 3, 6, a n d 1 2, 1 8, 2 4 a n d 3 6 m o nt hs ( de pe n di n g o n act ual data) will 
be prese nt e d, as w ell as t he n u m ber of p artici pa nts at ris k a n d faile d.  
A partici p a nt listi n g will pr o vi de t he f oll o wi n g i nf or mati o n: c o h ort, p artici p a nt i de ntifier, a ge, se x, 
race, dat e of first a d mi nistrati o n, date of last t u m or assess me nt, date of e ve nt/ce ns ori n g, 
e ve nt/ce ns ori n g reas o n, ti me t o e ve nt.  
1 4. 5  
I m m u n o ge nicit y  
A n alysis Sets: I m m u n o ge nicity a n alysis s et - 3 differe nt sets of o ut p uts:  
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Esc al ati o n/ H C C 3 m g/k g c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Ex p a nsi o n c o h orts  
A nti -dr u g  a nti b o d y (A D A ) will be  assess e d bef ore t he trial tr eat me nt start, a n d o n Da ys 1 5, 2 9, 
4 3, 8 5 after  t he start of i nf usi o n, 6-wee kl y u p t o/i ncl u di n g Wee k 2 5, e ver y 1 2 wee ks after Wee k 
2 5 , a n d d uri n g safet y f oll o w -u p (t he ter m H A H A is use d i n t he e C R F) . Sa m ples c ollecte d after t he  
o n -treat me nt peri o d (e. g. safet y f oll o w-u p) will be i ncl u de d i n t he a nal ysis as well.  If t h e sa m pl e 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
is p ositi ve f or A D A , it will be re-a nal yz e d t o deter mi ne t he titer. T he A D A  res ults will be deri ve d 
base d o n t he al g orit h m i n Ta ble 3 . 
T a ble 3   
Al g orit h m f or t he Deri v ati o n of A D A  Res ults   
S a m pl e S cr e e n R e s ult  
C o nfir m at or y  
Tit er  
A D A  R e s ult  
N e g ati v e  
N A  
N A  
N e g ati v e  
N R  
N A  
N A  
N R  
P o siti v e  
N e g ati v e  
N A  
N e g ati v e  
P o siti v e  
N R  
N A  
N R  
P o siti v e  
P o siti v e  
N u m b er  
N u m b er  
P o siti v e  
P o siti v e  
N R  
P o siti v e -T N R  
N R = n o r e s ult, N A = n ot a p pli c a bl e, T N R = tit er n o r e s ult.  
Ne gati ve, n u m ber, or p ositi ve -T N R are vali d res ults w hile n u m ber a n d p ositi ve -T N R are 
c o nsi dere d as p ositi ve. Partici pa nt s will be c h aracterize d i nt o differe nt cate g ori es base d o n t he 
criteria i n  Ta bl e 4 . 
T a ble 4   
P artici p a nt s C h ar acteri ze d b ase d o n A D A  Res ults   
C at e g or y  
D efi niti o n  
P arti ci p a nt  at Ri s k ( D e n o mi n at or f or 
I n ci d e n c e) 
N e v er 
p o siti v e  
N o p o siti v e r e s ult s at a n y ti m e p oi nt  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
r e s ult at a n y ti m e p oi nt 
E v er p o siti v e  
At l e a st o n e p o siti v e r e s ult at a n y ti m e p oi nt, 
i n cl u di n g b a s eli n e 
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
r e s ult at a n y ti m e p oi nt 
Pr e -e xi sti n g  
A p o siti v e A D A r e s ult pri or t o tr e at m e nt wit h 
bi ntr af u s p alf a  
N u m b er of p arti ci p a nt s wit h v ali d b a s eli n e 
r e s ult 
Tr e at m e nt 
b o o st e d  
A p o siti v e A D A r e s ult pri or t o tr e at m e nt wit h 
bi ntr af u s p alf a  a n d t h e tit er ≥ 8* b a s eli n e tit er at 
l e a st o n e p o st-b a s eli n e v al u e  
N u m b er of p arti ci p a nt s wit h v ali d b a s eli n e 
r e s ult a n d at l e a st o n e v ali d p o st-b a s eli n e 
r e s ult 
Tr e at m e nt 
e m er g e nt   
N ot p o siti v e pri or t o tr e at m e nt wit h bi ntr af u s p alf a  
a n d wit h at l e a st o n e p o siti v e p o st -b a s eli n e r e s ult  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -b a s eli n e r e s ult a n d wit h o ut p o siti v e 
b a s eli n e r e s ult (i n cl u di n g mi s si n g, N R)  
Tr a n si e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s h a v e (a si n gl e 
p o si ti v e e v al u ati o n, or d ur ati o n b et w e e n fir st a n d 
l a st p o siti v e r e s ult < 1 6 w e e k s) a n d l a st 
a s s e s s m e nt n ot p o siti v e.  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -b a s eli n e r e s ult a n d wit h o ut p o siti v e 
b a s eli n e r e s ult (i n cl u di n g mi s si n g, N R)  
P er si st e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s h a v e d ur ati o n 
b et w e e n fir st a n d l a st p o siti v e r e s ult ≥1 6 w e e k s or 
a p o siti v e e v al u ati o n at t h e l a st a s s e s s m e nt  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -b a s eli n e r e s ult a n d wit h o ut p o siti v e 
b a s eli n e r e s ul t (i n cl u di n g mi s si n g, N R)  
Sa m ples wit h a re p orta ble A D A titer will als o be teste d i n t he t w o n A b assa ys, P D -L 1 a n d T G F 
beta. T he n A b  res ults will be deri ve d base d o n t he al g orit h m in Ta bl e  5 . Partici pa nts  will be 
c haracteriz e d i nt o differe nt n A b cate g ories b ase d o n t he criteria i n  T a ble 6 . 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
T a ble  5  
Al g orit h m f or t he Deri v ati o n of n A b Res ults   
A D A C o nfir m at or y R e s ult  
n A b R e s ult  
D eri v e d n A b R e s ult  
N e g ati v e  
N A  
N e g ati v e  
N R  
N A  
N R  
N A ( s cr e e n N R)  
N A  
N A  
N A ( s cr e e n n e g ati v e)  
N A  
N e g ati v e  
P o siti v e  
N R  
N R  
P o siti v e  
P o siti v e  
P o siti v e  
P o siti v e  
N e g ati v e  
N e g ati v e  
A D A = a nti dr u g a nti b o d y, N A = n ot a p pli c a bl e, n A b = n e utr ali zi n g a nti b o d y, N R = n o r e s ult.  
T a ble 6  
P artici p a nts C h ar acteri ze d b ase d o n n A b Res ults   
C at e g or y  
D efi niti o n  
P arti ci p a nt s  
at  
Ri s k  ( D e n o mi n at or  f or 
I n ci d e n c e) 
N e v er p o siti v e  
N o n A b p o siti v e r e s ult s at a n y ti m e p oi nt  
N u m b er of p arti ci p a nt s  wit h at l e a st o n e v ali d 
A D A r e s ult at a n y ti m e p oi nt  
E v er p o siti v e  
At l e a st o n e n A b p o siti v e r e s ult at a n y ti m e p oi nt  
N u m b er of p arti ci p a nt s  wit h at l e a st o n e v ali d 
A D A r e s ult at a n y ti m e p oi nt  
Pr e -e xi sti n g  
A p o siti v e n A b r e s ult pri or t o tr e at m e nt 
wit h 
bi ntr af u s p alf a  
N u m b er 
of 
p arti ci p a nt s  wit h 
v ali d 
A D A 
b a s eli n e r e s ult  
Tr e at m e nt 
e m er g e nt  
N ot n A b p o siti v e pri or t o tr e at m e nt wit h bi ntr af u s p 
alf a a n d wit h at l e a st o n e n A b p o siti v e p o st -
b a s eli n e r e s ult  
N u m b er of p arti ci p a nt s  wit h at l e a st o n e A D A 
v ali d p o st -b a s eli n e r e s ult a n d wit h o ut n A b 
p o siti v e b a s eli n e r e s ult s (i n cl u di n g mi s si n g, 
N R)  
Tr a n si e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s  h a v e ( a si n gl e 
n A b p o siti v e e v al u ati o n, or d ur ati o n b et w e e n fir st 
a n d l a st n A b p o siti v e r e s ult < 1 6 w e e k s) a n d l a st 
A D A a s s e s s m e nt n ot n A b p o siti v e.  
N u m b er of p arti ci p a nt s  wit h at l e a st o n e A D A 
v ali d p o st -b a s eli n e r e s ult a n d wit h o ut n A b 
p o siti v e b a s eli n e r e s ult s (i n cl u di n g mi s si n g, 
N R)  
P er si st e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s  h a v e d ur ati o n 
b et w e e n fir st a n d l a st n A b p o siti v e r e s ult ≥1 6 
w e e k s or a n A b p o siti v e e v al u ati o n at t h e l a st A D A 
a s s e s s m e nt  
N u m b er of p arti ci p a nt s  wit h at l e a st o n e A D A 
v ali d p o st -b a s eli n e r e s ult a n d wit h o ut n A b 
p o siti v e b a s eli n e r e s ult s (i n cl u di n g mi s si n g, 
N R)  
A D A = a nti dr u g a nti b o d y, n A b = n e utr ali zi n g a nti b o d y, N R = n o r e s ult.  
St art of I m m u n o ge nicit y Res p o nse ( Ser oc o n versi o n)  
F or p artici pa nts wit h a n y p ositi ve A D A/ n A b res p o nse, t he d ate of t he first assess me nt wit h p ositi ve 
A D A res ult will be c o nsi dere d as start date of A D A res p o nse.  
Ti me t o o nset ( wee ks) of A D A res p o ns e will be calc ulate d as:  
( Date of first p ositi ve A D A assess me nt –  start date of bi ntraf us p alf a treatme nt + 1) / 7  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
N ote: If t he first p ositi ve is pri or t o t he start of treat me nt, t he f or m ula is re vise d t o:  
( Date of first p ositi ve A D A assess me nt –  start date of bi ntraf us p alf a treat me nt) / 7 
D ur ati o n of I m m u n o ge nicit y Res p o nse  
D urati o n of A D A i m m u n o ge ni cit y res p o nse ( wee ks) is defi ne d as:  
( Date of l ast p ositi ve A D A assess me nt –  date of first p ositi ve A D A assess me nt + 1) / 7  
F or partici pa nts wit h pre -e xisti n g p ositi ve, d urati o n will be calc ul ate d fr o m start date of bi ntraf us p 
alfa treat me nt rat her t h a n fr o m date of first p ositi ve assess me nt. Partici pa nts still o n treat me nt at 
t he data c ut-off a n d p ositi ve assess me nt at t heir last assess me nt bef ore c ut -off will be ce ns ore d at 
t he date of last ass ess me nt. 
F or A D A/ n A b res ults, t he f oll o wi n g a nal ysis will be descri be d i n eac h c o h ort a n d i n all c o h orts 
c o m bi ne d  (t he titer s u m maries will be pr o vi de d if t he titer data is a v aila ble): 
•  T he fre q u e nc y a n d perce nta ge of eac h A D A/ n A b cate g or y will be ta b ul ate d  
•  T he A D A titer val ue b y ti me p oi nt w ill be s u m marize d 
•  T he ma xi m u m o bser ve d A D A titer per partici pa nt will be ta b ulate d. F or eac h discrete titer 
val ue, perce nta ges will be calc ulate d usi n g t he t otal n u m ber of partici pa nts i n eac h A D A stat us 
gr o u p as t he de n o mi nat or.  
•  T he ti me t o first A D A p osi ti ve res p o nse will be s u m marize d 
•  T he d urati o n of A D A i m m u n o ge nicit y res p o nse will be s u m marize d  
A listi n g of all i n di vi d ual A D A res ults fr o m e ver p ositi ve partici pa nts will be pre pare d b y ti me 
p oi nt. T he listi n g will i ncl u de c o h ort, partici pa nt  i de ntifier, a ge, ge n der, race, A D A cate g ories, 
date of assess m e nt a n d res ults of scree ni n g, c o nfir mat or y a n d titer val ues .  
A listi n g of n A b res ults fr o m e ver p ositi ve p artici pa nts (i n eit her assa y) will be pr o vi de d wit h t he 
f oll o wi n g: c o h ort, partici pa nt i de ntifier , a ge, se x, race, ass a y ( P D-L 1 or T G F β ), n A b cate g ories 
stat us, visit, date of assess me nt a n d res ults of scree ni n g, titer v al ues.  
1 4. 5. 1  
E v al u ati o n of P ote nti al Effect of A D A/ n A b o n bi ntr af us p alf a 
Effic ac y   
P ote ntial effect of A D A o n c o nfir me d B O R, P F S a n d O S will be e val uate d o n:  
•   A D A p ositi ve stat us : e ver p ositi ve vs  ne ver p ositi ve  
A listi n g of effic ac y ass ess me nts f or I n vesti gat or assess me nt, a n d i m m u n ol o g y para meters f or 
A D A p ositi ve p artici pa nt s will be pre pare d i ncl u di n g:  c o h ort, p artici pa nt i de ntifier, a ge, se x, A D A 
a n d n A b cate g ori es , date of first st u d y tr eat me nt, tr eat me nt d urati o n, c B O R, P F S, ti me t o res p o nse, 
D R a n d O S. Partici pa nts wit h treat me nt o n g oi n g or res p o nse o n g oi n g  will b e fla g ge d.  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
1 5  
S afet y A n al yses   
T he safet y e val uati o n will be perf or m e d b y c o h ort a n d all c o h orts c o m bi ne d ( w here a p plica bl e).  
A n alysis Sets: S afety a n alysis set  - 3 differe nt sets of o ut p uts:  
- 
P artici p a nts i ncl u de d i n Cervic al C a ncer c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Esc al ati o n/ H C C 3 m g/k g c o h orts  
- 
P artici p a nts i ncl u de d i n D ose Ex p a nsi o n c o h orts  
1 5. 1  
A d verse E ve nts   
T he safet y e val uati o n will be perf or m e d b y c o h ort a n d all c o h orts c o m bi ne d ( w here a p plica bl e).  
A n alysis Sets: S afety a n alysis set  
Treat me nt e mer ge nt a d v erse e v e nts ( T E A Es) are t h ose e ve nts wit h o nset dates occ urri n g d uri n g 
t he o n-treat me nt peri o d or if t he w orse ni n g of a n e ve nt is d uri n g t he o n-tr eat me nt peri o d as defi n e d 
i n Secti o n Err or! R efere nce s o urce n ot f o u n d. .  Ad verse e ve nts will be c o de d usi n g t he m ost 
rece nt versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) at t he ti me of d ata 
c ut-off.  
C ha n ges i n t o xicit y gra d e, seri o us ness or o utc o m e of A Es are rec or de d as se parate e ntri es i n t he 
e C R F wit h ass ociate d e n d a n d start dates (start date e q uals e n d date of pre vi o us e ntr y). S uc h e ntri es 
re p orti n g t he sa me e ve nt i n s uc h i m me diatel y c o ns ec uti ve peri o ds will be c o nsi dere d as o ne e ve nt 
i n t he a nal ysis i n case of a c ha n ges i n t o xicit y gra d e. T hese e ve nts will be ke pt as se parat e rec or ds 
i n t he data b ase i n or der t o mai ntai n t he f ull det aile d hist or y of t he e ve nts. T he start date of t he 
i nitial rec or d i n t he se q ue nce is ta ke n as start date of t he e ntire e ve nt. D urati o n of t he A E a n d t he 
T E A E fla g will be a dj ust e d acc or di n gl y i n t he a nal ysis.  
All a nal yses descri be d i n Secti o n Err or! Refere nce s o urce n ot f o u n d.  will be base d o n T E A Es 
(starte d d uri n g t he o n-treat me nt peri o d) u nless ot h er wise s pecifie d.  T h e A E listi n gs will i ncl u de 
all A Es ( w het her treat me nt -e mer ge nt or n ot).  A Es o utsi de t he o n -treat me nt peri o d will be fla g ge d 
i n t he listi n gs. A E occ urri n g d uri ng t h e rei nitiati o n p hase will be c o nsi dere d i n t he s u m mar y t a bles 
a n d will be fla g ge d i n t he listi n gs.  
•  Rel ate d A d verse E ve nts:  a d vers e e ve nts wit h rel ati o ns hi p t o st u d y treat me nt (as rec or de d o n 
t he A E e C R F pa ge, Relati o ns hi p wit h st u d y tr eat m e nt = Relate d) re p ort e d b y t h e i n vesti gat or 
a n d t h ose of u n k n o w n relati o ns hi p (i.e. n o a ns w er t o t he q uesti o n “ R elati o ns hi p wit h st u d y 
treat me nt”).  
•  Seri o us A d verse E ve nts ( S A E):  seri o us a d verse e ve nts (as rec or de d o n t he A E e C R F pa ge, 
Seri o us A d verse E v e nt = Yes).  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /4 1  
 
  
•  A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n:  a d verse e ve nts l ea di n g t o per ma ne nt 
disc o nti n uati o n of st u d y treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n ta ke n wit h st u d y 
treat me nt = Dr u g wit h dra w n).  
•  A d verse E ve nt Le a di n g t o De at h:  a d verse e ve nt l ea di n g t o deat h (as rec or de d o n t he A E e C R F 
pa ge, O utc o me = Fatal, as well as A Es of Gra de 5).  
•  A d verse E ve nts of S peci al I nterest ( A E SI):  A d verse e v e nts of s pecial i nterest will be 
i de ntifie d acc or di n g t o a pre-s pecifie d searc h list of Me d D R A Preferre d Ter ms.  Cate g ories 
of A E SI i ncl u de:  
o  I nf usi o n-Relate d 
Reacti o ns i ncl u di n g h y perse nsiti vit y: a n y i nf usi o n -relate d 
reacti o n or h y p erse nsiti vit y (re gar dl ess of gra de) (see descri pti o n i n 1 5. 2. 3. 1 ) 
o  I m m u ne Relat e d A d verse E ve nts (ir A E) i ncl u di n g a ut oi m m u ne dis or ders (see 
descri pti o n i n  1 5. 2. 3. 2 ) 
o  S ki n A E p ossi bl y relate d t o T G F β i n hi biti o n (see d escri pti o n i n  1 5. 2. 3. 3 ) 
o  A ne mia  
•  Blee di n g e ve nts  are t h os e A Es bel o n gi n g t o t he M e d D R A S M Q Hae m orr ha ge ter ms (e x cl u di n g 
la b orat or y ter ms). 
•  A ne mi a e ve nts  are t h ose A Es bel o n gi n g t o t he Me d D R A H L T A nae mias N E C, H L T A nae mias 
hae m ol ytic i m m u ne, H L T A nae mias hae m ol ytic N E C or P T = Hae m o gl o bi n decrease d.  
1 5. 1. 1  
All A d verse E ve nts   
A  ta ble prese nti n g t he o verall s u m mar y of A Es will be prese nt e d b y c o h ort  a n d all c o h orts 
c o m bi ne d  ( w here a p plica ble) wit h t he f oll o wi n g i nf or mati o n:   
•  T E A Es  
•  Relate d T E A Es  
•  Seri o us T E A Es  
•  Relate d seri o us T E A Es  
•  T E A Es, gra de ≥ 3  
•  T E A Es, gra de ≥ 4  
•  Relate d T E A Es, gra de ≥ 3  
•  Relate d T E A Es, gra de ≥ 4  
•  T E A Es lea di n g t o deat h  
•  Relate d T E A Es lea di n g t o deat h  
•  T E A Es of s peci al i nterest (all cate g ories liste d)  
•  Relate d T E A Es of s pecial i nterest (all cate g ories liste d)  
•  T E A Es lea di n g t o st u d y t er mi nati o n  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
•  Relate d T E A Es lea di n g t o  st u d y ter mi nati o n 
•  Blee di n g T E A E  
•  Relate d blee di n g T E A E  
A listi n g  i ncl u di n g all a d verse e ve nts, a n d a listi n g i ncl u di n g a d v erse e v e nts wit h o nset date after 
t he C S R c ut off (i.e. bet wee n 1 5 M A Y 2 0 2 0 a n d 1 4 M A Y 2 0 2 1) will be pr o vi de d a n d will c o ntai n 
t he f oll o wi n g i nf or m ati o n: c o h ort, partici pa nt i de ntifier, a ge, ge n d er, race, preferre d ter m, re p orte d 
ter m f or t he a d verse e v e nt, start date, e n d d ate, d urati o n of A E (i n da ys), da y relati ve t o t he first 
i nf usi o n, da y rel ati ve t o t he m ost rece nt i nf usi o n pri or t o AE o nset, relati o ns hi p t o st u d y treat me nt, 
t o xicit y gra de, acti o n(s) ta ke n, o utc o me, seri o us n ess ( Y/ N), A E SI i nf usi o n-relate d ( Y/ N), A E SI 
i m m u ne-relate d ( Y/ N), me dicati o n a d mi nistere d. T he listi n g will be s orte d b y c o h ort, p artici pa nt 
i de ntifier, a n d start d ate.  
1 5. 1. 2  
A d verse 
E ve nts 
Le a di n g t o 
Disc o nti n u ati o n 
of 
St u d y 
Tre at me nt   
Will n ot be re p orte d . 
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 5. 2. 1  
De at hs   
Will n ot be re p orte d . 
1 5. 2. 2  
Seri o us A d verse E ve nts   
Will n ot be re p orte d . 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
1 5. 2. 3  
Ot her A d verse E ve nts of I nterest   
1 5. 2. 3. 1  
I nf usi o n Rel ate d Re acti o n  
I nf usi o n Relate d Reacti o ns (I R R) are defi ne d as a d verse e v e nts wit h P Ts acc or di n g t o a pre-
s pecifie d M e d D R A s earc h list, w hic h starte d o n t he st u d y dr u g d osi n g date ( n ot pri or t o t h e 
i nf usi o n of st u d y dr u g) or t he f oll o wi n g d a y of st u d y dr u g i nf usi o n.  I R R ca n be s plit i nt o 
Reacti o ns, a n d Si g ns a n d s y m pt o ms s u b gr o u ps as f oll o ws:    
T a ble 7 : Criteri a f or I nf usi o n-Rel ate d Re acti o ns   
I nf u si o n r el at e d r e a cti o n s 
R e a cti o n s –  c o n si d er e d w h e n o n s et i s o n t h e d a y of bi ntr af u s p alf a  i nf u si o n ( d uri n g 
or aft er t h e i nf u si o n) or t h e d a y aft er t h e n bi ntr af u s p alf a  i nf u si on (irr e s p e cti v e of 
r e s ol uti o n d at e): 
•  
I nf u si o n r el at e d r e a cti o n  
•  
Dr u g h y p er s e n siti vit y   
•  
A n a p h yl a cti c r e a cti o n   
•  
H y p er s e n siti vit y   
•  
T y p e I h y p er s e n siti vit y   
 
Si g n s a n d S y m pt o m s –  o c c urri n g o n t h e d a y of bi ntr af u s p alf a  i nf u si o n ( d uri n g or 
aft er t h e i nf u si o n) a n d r e s ol v e d wit h e n d d at e t h e d a y of bi ntr af u s p alf a  or t h e d a y 
aft er : 
•  
P yr e xi a  
•  
C hill s   
•  
Fl u s hi n g  
•  
H y p ot e n si o n  
•  
D y s p n e a  
•  
W h e e zi n g  
•  
B a c k p ai n  
•  
A b d o mi n al p ai n  
•  
Urti c ari a  
1 5. 2. 3. 2  
I m m u ne Rel ate d A d verse E ve nts  
I m m u ne-relat e d a d v erse e ve nts (ir A Es) will be i de ntifie d pr o gra m maticall y. A Es w hic h satisf y all 
of t he f oll o wi n g criteri a will be fla g ge d as i m m u n e -rel ate d: 
1) T he A E preferre d  t er m matc hes a preferre d t er m o n t he list of pre-selecte d Me d D R A ter ms. 
2) T he A E o nset or w orse ni n g occ urs aft er t he first st u d y dr u g a d mi nistrati o n a n d n o m ore t ha n 9 0 
da ys after l ast d ose  , or t he earliest date of s u bse q ue nt a ntica n cer t hera p y mi n us 1 da y, 
w hic he ver occ urs first  
3) O n t he A E e C R F pa ge, t he q uesti o n “ Were C ortic oster oi ds, I m m u n os u p pressa nts, or h or m o nal 
t hera p y (e. g. T h yr oi d) a p plie d? ” has t he a ns wer “ Yes” selecte d. 
4) O n t he i m A E e C R F pa ge, eit her:  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
a.  T he q uesti o n “ D o es a n y of t h e f oll o wi n g pr o vi de a clear eti ol o g y f or t he e ve nt? ” has t he 
a ns wer “ N o” sele cte d, i n dicati n g t h at t he A E is n ot attri b uta ble t o u n derl yi n g ca ncer 
disease/ P D, pri or or c o nc o mita nt me dicati o ns/ pr oce d ures, n or a n ot her me di cal c o n diti o n 
s uc h as a n i nf ecti o n or pre-e xisti n g disease.  
O R  
b.    T he i m A E e C R F i n dicates t hat a bi o ps y was perf or me d a n d t h e q uesti o n “Is t he 
hist o pat h ol o g y/ bi o ps y c o nsiste nt wit h a n i m m u ne -me diate d e ve nt? ” has t he a ns wer “ Yes” 
selecte d. 
I n t h e cas e t hat criteria ( 1) t hr o u g h ( 3) are met, a n d e ntries f or c o n diti o n ( 4) are missi n g, t he 
f oll o wi n g r ules will be a p plie d:  
•   If t he a ns wer t o “ D o es a n y of t he f oll o wi n g pr o vi de a clear eti ol o g y f or t he e ve nt? ” ( 4a) 
is missi n g, t he e ve nt will be c o nsi dere d as ir A E (irres pecti ve of bi o ps y res ults).  
•   If t he a ns w er t o “Is t he hist o pat h ol o g y/ bi o ps y c o nsiste nt wit h a n i m m u ne-me diate d 
e ve nt? ” ( 4 b) is missi n g, or if n o bi o ps y was p erf or me d, a n d c o n diti o n ( 4a) is n ot satisfie d 
(i.e. “ Yes ” is selecte d as t he a ns wer t o t he q uesti o n “ D oes a n y of t he f oll o wi n g pr o vi d e 
a clear eti ol o g y f or t he e ve nt? ”), t he e ve nt will be c o nsi dere d as a n o n -ir A E. 
1 5. 2. 3. 3  
P ote nti al T G F β -me di ate d S ki n  T E A E   
S ki n A E p ossi bl y relate d t o T G F β i n hi biti o n will b e selecte d b ase d o n Me d D R A P Ts acc or di n g t o 
a pre-s p ecifie d M e d D R A searc h list:  
N arr o w defi niti o n:  
•  Kerat oa ca nt h o ma  
•  S q ua m o us cell carci n o ma of s ki n  
Br o a d defi niti o n  has a d diti o nal P Ts:  
•  H y p er kerat h osis  
•  Acti nic kerat osis  
•  Basal cell carci n o ma  
•  Li p s q ua m o us cell carci n o ma  
•  B o we n´s disease   
Gl o bal Versi o n I D: C CI








M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /4 1  
 
  
1 5. 4  
Vit al Si g ns   
Will n ot be re p orte d . 
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns   
Will n ot be re p orte d . 
1 6  
A n al yses of Ot her E n d p oi nts   
1 6. 1  
P h ar m ac o ki netics   
T he a nal ys es descri be d i n t his secti o n will be perf or me d b y t he Cli nical P K/ P har mac o d y na mics  
gr o u p ( C P K) of Tra nslati o nal Me dici ne, Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y, or b y a 
C o ntract Researc h Or ga niz at i o n selecte d b y t he S p o ns or. P har mac o ki netic listi n gs a n d i n di vi d ual 
data will be pres e nte d base d o n t he S A F. S u m maries a n d statistical a nal yses will be base d o n t he 
P K A S a n d/ or P K A S C C. O nl y s u b gr o u p s a m ple siz e wit h a mi ni mal 3 s u bjects will be dis pla ye d.  
P har mac o ki netic c o nce ntrati o ns/ P K para meter refer t o bi ntraf us p alfa c o nce ntr ati o n/ P K 
para meters.  
1 6. 1. 1  
Missi n g P K D at a   
C o nce ntr ati o ns bel o w t he l o w er li mit of ass a y q u a ntificati o n  
P har mac o ki netic c o n ce ntrati o ns bel o w t he l o wer li mit of q ua ntificati o n ( < L L O Q) will be ta ke n as 
zer o f or descri pti ve statistics.  
De vi ati o ns, missi n g c o nce ntr ati o ns , a n d a n o m al o us v al ues  
C o nce ntrati o ns will be set t o missi n g i n s u m mar y t a bles if t he val ue i s re p orte d as n o res ult. 
P har mac o ki netic c o nce ntrati o ns w hic h are err o ne o us d ue t o a pr ot oc ol vi olati o n (as defi ne d i n t h e 
cli nical trial pr ot oc ol ), d oc u me nte d ha n dli n g err or, or a nal ytical err or (as d oc u me nte d i n t he 
bi oa nal ytical re p ort) ma y be e x cl u de d fr o m t he P K a nal ysis if a gree d u p o n pri or t o perf or mi n g a 
statistical a nal ysis. I n t his case t he rati o nale f or e x cl usi o n m ust be pr o vi de d i n t he rele va nt 
listi n g/ta ble a n d/ or Cli nical Trial Re p ort ( C T R).  
E xcl usi o ns f or c o nce ntr ati o n d at a ( a n d CE OI / Ctr o u g h) descri pti ve st atistics  
- P ositi ve pre -d ose val ues o n Da y 1  
- C o nce ntrati o n o bser ve d at t he e n d of i nf usi o n ( C E OI ) < L L O Q 
- I n cas e of misse d d ose, e x cl u de all c o nce ntr ati o ns u ntil i nte n de d d osi n g is res u me d 
- C o nce ntrati o n o bser ve d at t he e n d of t he d osi n g i nter val ( C tr o u g h) val ues i n case sa m ples are 
ta ke n at least 7 da ys l ate or earl y 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
A n y 
ot her 
P K 
c o nce ntrati o ns t hat 
a p pear i m pla usi ble t o t he 
P har mac o ki neticist/  
P K/ P har mac o d y na mics  Data A nal yst m ust n ot be e x cl u de d fr o m t he a nal ysis. A n y i m pla usi ble  
data will be d oc u me nte d i n t he rele va nt listi n g/ta ble a n d/ or C T R.  
If a P K para meter ca n n ot be deri ve d fr o m a s u bj ect’s c o n ce ntr ati o n data, t he para meter will be 
c o de d as N C ( n ot calc ul ate d). ( N ote t hat N C val ues will n ot be ge nerate d be y o n d t he da y t hat a  
s u bject disc o nti n ues t he treat me nt). F or statistical a nal ys es, P K para m eters c o de d as N C will be 
set t o missi n g. 
If a n i n di vi d ual s u bject has a k n o w n bi ase d esti mate of a P K para meter ( d ue, f or e x a m ple, t o a 
de viati o n fr o m t he assi g ne d d ose le v el), t his s u bj ect/ val ue will be e x cl u de d fr o m t he d escri pti ve 
statistics a n d i nstea d t he res ult will be liste d o nl y. 
1 6. 1. 2  
Descri pti ve P K A n al ysis   
Prese nt ati o n of P K C o n ce ntr ati o n D at a  
A b y -parti ci pa nt listi n g will prese nt P K sa m ple ti mes, ti me de viati o ns, a n d c o nce ntrati o ns base d 
o n t he S A F. C o nce ntr ati o ns will be re p orte d wit h t he sa me precisi o n as t he s o urce dat a.  
Ta bles:  
P har mac o ki netic c o nce ntrati o ns will be pres e nte d i n ta bles a n d d escri pti v el y s u m marize d b y 
treat me nt a n d c o h ort (as a p pr o priate) se p aratel y, d a y, a n d n o mi nal ti me usi n g: n, arit h metic mea n 
( Mea n), St D, c oefficie nt of vari ati o n ( C V %), Mi n, me dia n ( Me dia n), M a x, n of l o g-tr a nsf or m e d 
data ( n, Ge o), ge o metri c mea n ( Ge o M ea n), St D of l o g-tr a nsf or m e d data (l o g St D), a n d ge o metric 
c oeffi cie nt of vari ati o n ( Ge o C V %). S u m maries will be base d o n t he P K A S a n d se paratel y 
P K A S C C  b y d ose . 
A d diti o nal ta ble(s) will s u m marize P K c o nce ntrati o ns wit h f urt her stratificati o n b y A D A s u bsets 
e ver p ositi ve a n d ne ver p ositi ve, base d o n P K A D A C C  b y d ose . A d diti o nal ta ble(s) will s u m marize 
P K c o nce ntr ati o ns wit h f urt her s u b -str atificati o n b y n A b s u bsets e ver p ositi ve a n d ne ver p ositi ve, 
base d o n P K N A B C C  b y d ose . F or n A b s u bsets, s u m maries will be d o ne f or e ver p ositi ve i n eit her 
of 2 n A b assa ys ( P D -L 1 a n d T G F ß rece pt or ne utralizati o n; P D -L 1 +/ T G F ß +, P D -L 1 +/ T G F ß −, 
P D -L 1 −/ T G F ß +) vers us ne ver p ositi ve ( P D -L 1 −/ T G F ß −). A d diti o nal ta bl e(s) will s u m marize P K 
c o nce ntr ati o ns wit h stratificati o n b y Asia n vers us n o n -Asia n, base d o n P K A S C C  b y d ose . O nl y 
s u b gr o u p s a m ple siz e wit h a mi ni mal 3 s u bjects will be dis pla ye d. 
Descri pti ve statistics of P K c o nce ntrati o ns will be calc ulate d usi n g v al ues wit h t he sa me precisi o n 
as t he s o urce data a n d r o u n de d f or re p orti n g p ur p oses o nl y. T h e f oll o wi n g c o n v e nti o ns will be 
a p plie d w he n re p orti n g d escri pti ve statistics of P K c o nce ntr ati o n data:  
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n:  
 
3 si g nifica nt di gits  
St D, l o g St D:    
 
 
 
 
4 si g nifica nt di gits  
C V %, Ge o C V %:  
 
 
 
 
1 deci mal place  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
S u bjects f or w h o m t h e Wee k 1 d ose a m o u nt differs fr o m t he s u bse q ue nt d ose will ha ve t he rele va nt 
Wee k 1 data e x cl u de d fr o m statistics.  
Fi g ures:  
N o c o nce ntr ati o n fi g ures are pla n n e d t o be pr o d u ce d.  
1 6. 1. 3  
P h ar m ac o ki netic P ar a meter A n al ysis   
T he P K para meters liste d bel o w will be ta ke n directl y fr o m t he o bser ve d bi ntraf us p alfa 
c o nce ntr ati o n -ti me data.  
C tr o u g h 
T he c o nce ntr ati o n o bser ve d at t he e n d of t he d osi n g i nter val, bef ore ne xt d osi n g 
(ser u m tr o u g h c o n ce ntrati o n) 
C E OI  
T he c o nce ntrati o n o bser ve d at t he e n d of i nf usi o n  
F or s u bjects i n t he P K A S C C, a cc u m ulati o n Acc u m ulati o n rati os f or C tr o u g h ( Ctr o u g h Da y X / C tr o u g h 
Da y 1 5) a n d C E OI  ( CE OI  Da y X / C E OI  Da y 1) wi ll be deri ve d t o ass ess ti me-de pe n de nt P K effects.  
Prese nt ati o n of P K P ar a meter D at a  
I n di vi d ual P K para meters will be liste d b y n o mi nal st u d y da y b ase d o n t h e S A F. I n di vi d ual P K 
para meters will be re p orte d wit h t he sa me precisi o n as t he s o urce data.  
Ta bles : 
P har mac o ki netic para meter data will be prese nte d i n ta bles a n d descri pti vel y s u m marize d b y 
treat me nt ( d os e, e. g. 1 2 0 0 m g) a n d c o h ort (as a p pr o priate) se paratel y, a n d da y usi n g: n, Mea n, 
St D, C V %, Mi n, Me dia n, Ma x, n, Ge o, Ge o Mea n, l o g St D, Ge o C V % , a n d t he 9 5 % CI  f or t he 
Ge o Mea n ( L CI 9 5 % G M, U CI 9 5 % G M). S u m maries will be base d o n t he P K A S a n d se paratel y 
P K A S C C  b y d ose . 
A d diti o nal ta ble(s) will s u m marize C tr o u g h a n d C E OI  wit h f urt her stratificati o n b y A D A s u bsets e v er 
p ositi ve a n d ne ver p ositi ve, base d o n P K A D A C C  f or 1 2 0 0 m g d ose . A d diti o nal ta ble(s) will 
s u m marize C tr o u g h a n d C E OI  wit h f urt h er s u b -stratificati o n b y n A b s u bs ets e ver p ositi ve a n d ne v er 
p ositi ve, base d o n P K N A B C C  f or 1 2 0 0 m g d ose.. F or n A b s u bsets, s u m maries will be d o ne f or 
e ver p ositi ve i n eit her of 2 n A b assa ys ( P D -L 1 a n d T G F ß rece pt or ne utr alizati o n; P D -L 1 +/ T G F ß +, 
P D -L 1 +/ T G F ß −, P D -L 1 −/ T G F ß +) vers us ne ver p ositi ve ( P D -L 1 −/ T G F ß −). A d diti o nal ta ble(s) 
will s u m marize C tr o u g h a n d C E OI  wit h stratificati o n b y Asia n vers us n o n -Asia n, base d o n P K A S C C  
f or 1 2 0 0 m g d ose. A d diti o nal ta ble(s) will s u m marize Ctr o u g h a n d C E OI  wit h f urt her s u b -
stratificati o n b y A D A s u bsets e ver p ositi ve a n d ne ver p ositi ve a n d, neste d wit hi n, Asia n vers us 
n o n -Asia n, base d o n P K A D A C C  f or 1 2 0 0 m g d ose.. F or n A b e ver-p ositi ve s u bjects, ser u m 
bi ntraf us p alf a C tr o u g h will be descri pti vel y s u m marize d i n a d diti o nal ta ble(s) f or n A b st at us 
s u b gr o u ps ( p ositi ve i n a n y of 2 n A b assa ys), base d o n P K N A B C C 1 2 0 0 m g d ose gr o u p . A d diti o nal 
ta ble(s) will s u m marize Ctr o u g h of A D A Treat me nt -e merge nt s u bjects a n d n A b Treat me nt -e mer ge nt 
s u bjects b y P K da y relati ve t o da y of ser oc o n versi o n, base d o n P K A D A C C a n d P K N A B C C, 
res pecti vel y (all s u bjects wit h C C). O nl y s u b gr o u p sa m ple siz e wit h a mi ni mal 3 s u bjects will be 
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /4 1  
 
  
dis pla ye d. All a b o v e will be s u m ma rize d b y tr eat me nt ( d ose, e. g. 1 2 0 0 m g acr oss c o h orts) a n d 
c o h ort (as a p pr o priate /s p ecifie d) s e paratel y (). 
P har mac o ki netic para met ers will be re p ort e d t o 3 si g nifica nt fi g ures. I n e x p ort datasets, as well as 
i n t he S D T M P P d o mai n, P K para meters will b e pro vi de d wit h f ull precisi o n a n d will n ot be 
r o u n de d. Descri pti ve statistics of P K para meter data will be calc ulate d usi n g f ull precisi o n val ues 
a n d r o u n de d f or re p orti n g p ur p os es o nl y.  
T he f oll o wi n g c o n v e nti o ns will be a p plie d w he n re p orti n g des cri pti ve sta tistics of P K para meter 
data:  
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI:  
3 si g nifica nt di gits  
S tD, l o gSt D:   
 
 
 
 
4 si g nifica nt di gits  
C V %, Ge o C V %:  
 
 
 
 
1 deci mal place  
S u bjects f or w h o m t he first d ose a m o u nt differs fr o m t he s u bse q ue nt d ose will ha ve t he rele v a nt 
first d ose data e x cl u de d fr o m statistics. 
Fi g ures : 
I n di vi d ual Ctr o u g h a n d C E OI  val ues will be pl otte d a gai nst act ual ti me p oi nts o n a li near scale, f or all 
s u bjects b y tr eat me nt a n d c o h ort. Pl ots of i n di vi d ual data will be base d o n t he S A F.  
Arit h metic  mea n C tr o u g h ± St D will be pl otte d vers us n o mi nal da y o n a li n ear s cale , b ase d o n t he 
P K A S  a n d se p aratel y P K A S C C  b y d os e . Arit h metic mea n C E OI  ± St D will be pl otte d vers us 
n o mi nal da y o n a li near scale , bas e d o n t he P K A S C C  b y d ose .. A d diti o nal fi g ures will prese nt 
Mea n C
tr o u g h a n d C E OI  wit h f urt her str atificati o n b y A D A s u bsets e ver p ositi ve a n d n e ver p ositi ve, 
base d o n P K A D A C C  1 2 0 0 m g . A d diti o nal fi g ures will prese nt Mea n Ctr o u g h a n d C E OI  wit h f urt her 
s u b-stratificati o n b y n A b s u bsets e ver p ositi ve (eit her assa y)  a n d n e v er p ositi ve, bas e d o n 
P K N A B C C  1 2 0 0 m g . A d diti o nal fi g ures will prese nt Mea n Ctr o u g h a n d C E OI  wit h stratificati o n b y 
Asia n vers us n o n -Asia n, base d o n P K A S C C  f or 1 2 0 0 m g. O nl y s u b gr o u p sa m ple siz e wit h a 
mi ni mal 3 s u bjects will be dis pla ye d.  
F o r A D A tr eat me nt-e m er ge nt s u bj ects wit h at l east o ne C tr o u g h meas ure me nt bef ore a n d after A D A 
ser oc o n versi o n, i n di vi d ual C tr o u g h will be pl otte d vers us relati ve P K da y f or t he P K A D A C C b y 
d ose  (f or rea d a bilit y, s plit f urt her i nt o gr o u ps of 1 0 s u bjects or fe wer as n ee de d). B o x pl ots will be 
pre pare d f or C tr o u g h vers us relati ve P K da y  f or t he P K A D A C C b y d ose. 
F or n A b tr eat me nt -e mer ge nt s u bjects wit h at least o ne C tr o u g h meas ure me nt bef ore a n d after n A b 
ser oc o n versi o n (earliest of 2 assa ys if p ositi ve i n b ot h), i n di vi d ual Ctr o u g h will be pl otte d vers us 
relati ve P K da y f or t he P K N A B C C b y d ose (f or rea da bilit y, s plit f urt her i nt o gr o u ps of 1 0 s u bjects 
or fe wer as nee d e d). B o x pl ots will be pre pare d f or C tr o u g h vers us relati ve P K da y  f or t he 
P K N A B C C b y d os e . .  
Gl o bal Versi o n I D: C CI


M 7 8 2 4  
 
 
M 7 8 2 4 i n Met ast atic or L oc all y A d v a nce d S oli d T u m o rs 
E M R 2 0 0 6 4 7 -0 0 1 (I A P f or a d de n d u m of C S R) –  Versi o n 1. 0  
 
 
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 /4 1  
 
  
All a b o ve will be s u m marize d b y tr eat me nt ( d ose, e. g. 1 2 0 0 m g acr oss c o h orts) a n d c o h ort (as 
a p pr o priate/s pe cifie d) s e paratel y. 
 
  
 
1 6. 3  
P atie nt Re p orte d O utc o me   
Will n ot be re p orte d . 
1 7  
Refere nces   
Br o o k me yer, R. a n d Cr o wle y, J. ( 1 9 8 2), A C o nfi de nce I nter val f or t he M e dia n S ur vi val Ti me, 
Bi o metrics, 3 8, 2 9 – 4 1.  
Cl o p per CJ, Pears o n E S ( 1 9 3 4). T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n t he case of 
t he bi n o mial. Bi o metri ka; 2 6, 4 0 4-4 1 3.  
Eise n ha uer E A, T herasse P, B o gaerts J, et al.  ( 2 0 0 9),  Ne w res p o nse  e v al uati o n criteri a 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; 4 5: 2 2 8 -4 7.  
Kal bfleisc h, J. D. a n d Pre ntice, R. L. ( 1 9 8 0), T he Statistical A nal ysis of Fail ure Ti me Data, Ne w 
Y or k: J o h n Wile y & S o ns.  
Ka pla n E L, Mei er P  ( 1 9 5 8). N o n para metric esti mati o n fr o m i nc o m plete o bser vati ons. J A m Stat 
Ass oc. 5 3: 4 5 7 -8 1 . 
Nati o nal 
Ca ncer I nstit ute. 
N CI 
dicti o nar y 
of 
ca n cer t er ms 
–  sec o n d-li ne t hera p y. 
htt ps:// w w w.ca ncer. g o v/ p u blicati o ns/ dicti o naries/ca ncer -ter ms? C drI D = 3 4 6 5 1 3 
(access e d 
2 9 
Marc h 2 0 1 7).  
1 8  
A p pe n dices   
N ot a p plica ble.  
 
Gl o bal Versi o n I D: C CI
C CI