Open-label, Phase I/II Study to Evaluate Pharmacokinetics, Pharmacodynamics, Safety, and Anticancer Activity of Avelumab in Pediatric Subjects From Birth to Less Than 18 Years of Age With Refractory or Relapsed Solid Tumors and Lymphoma
Phase: PHASE1
Conditions: Refractory or Relapsed Solid Tumors, Lymphoma
Sponsor: EMD Serono Research & Development Institute, Inc.

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
M S 1 0 0 0 7 0 - 0 3 0 6
Title
O pe n -la bel,
P hase 
I/II 
st u d y 
to 
e val uate 
p har mac o ki netics, p h ar mac o d y na mics, safety,  an d 
a ntica ncer acti vit y of a vel u ma b i n pe diatric s u bjects 
fr o m birt h t o less t ha n 1 8 ye ars of a ge wit h refract or y 
or rela pse d s oli d t u m or s a n d l ym p h o ma
S h ort Tri al N a me
P hase I/II st u d y of a vel u ma b i n pe diatric ca ncer 
s u bjects
Tri al P h ase
I/II
I N D N u m ber
E u dr a C T N u m ber
2 0 1 7 -0 0 2 9 8 5 -2 8
C o or di n ati n g I n vesti g at or
S p o ns or
F or all c o u ntries e xce pt t he U S A:
Merc k K Ga A, Fra n kf urter Str. 2 5 0 
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
4 5 A Mi d dlese x T ur n pi ke 
Billerica, M A 0 1 8 2 1, U S A
Me dical Res p o nsi ble: 
Office p h o ne : 
M o bile p h o ne : 
Cli nic al Tri al Pr ot oc ol Versi o n
1 5 Se pte m ber 2 0 1 7/ Versi o n 2. 0
Re pl aces Cli nic al Tri al Pr ot oc ol 
Versi o n
1 4 A u g ust 2 0 1 7/ Versi o n 1 . 0
C urre nt Cli nic al Tri al Pr ot oc ol 
A m e n d me nt
N ot a p plica ble
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
P P D
P P D
P P D
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
- C o nfi de ntial -
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 m a y  not – 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 out e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y,  
or its affi liate. C o p y ri g ht © 20 1 7 b y  Merc k K Ga A, Dar msta dt, Ger ma n y,  or its affiliate. All ri g hts 
reser ve d.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 7
T a ble of C o nte nts
Ta ble of C o nte nts .............................................................................................................. 3
Ta ble of Ta bles
..............................................................................................................7
Ta ble of Fi g ures
..............................................................................................................7
List of A b bre viati o ns ...........................................................................................................8
1
S y n o psis ..............................................................................................1 1
2
S p o ns or, I n vesti gat ors, a n d Trial A d mi nistrati ve Str uct ure ...............2 5
2. 1
I n vesti gati o nal Sites............................................................................2 5
2. 2
St u d y  C o or di nati o n / M o nit ori n g........................................................2 5
2. 3
Safet y  M o nit ori n g C o m mittee............................................................2 6
3
Bac k gr o u n d I nf or mati o n .....................................................................2 6
3. 1
Pr o gra m me d Cell Deat h a n d L i ga n ds.................................................2 6
3. 2
A vel u ma b ............................................................................................2 7
3. 3
Rati o nale f or t he C urre nt Cli nical Trial a n d O verall Be nefit a n d 
Ris k C o nsi derati o ns ............................................................................2 8
4
Trial O bjecti ves ..................................................................................2 9
4. 1
Pri mar y  O bjecti ves .............................................................................2 9
4. 2
Sec o n dar y  O bjecti ves .........................................................................2 9
5
I n vesti gati o nal Pla n ............................................................................3 0
5. 1
O verall Trial Desi g n a n d Pla n ............................................................3 0
O verall Desi g n ....................................................................................3 1
Trial Treat me nt A d mi nistrati o n a n d Sc he d ule ...................................3 8
D ose M o dificati o n a n d A d verse Dr u g Reacti o ns Re q uiri n g 
Treat me nt Disc o nti n uati o n .................................................................3 9
5. 2
Disc ussi o n of Trial Desi g n ................................................................ .4 0
I ncl usi o n of S pecial P o p ulati o ns ........................................................4 2
5. 3
Selecti o n of Trial P o p ulati o n ..............................................................4 2
I ncl usi o n Criteria ................................................................................4 2
E xcl usi o n Criteria ...............................................................................4 4
5. 4
Criteria f or I nitiati o n of Trial Treat me nt ............................................4 6
5. 5
Criteria f or S u bject Wit h dra wal ..........................................................4 6
Wit h dra wal fr o m Trial T hera p y ..........................................................4 7
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 7
Wit h dra wal fr o m t he Trial ..................................................................4 7
5. 6
Pre mat ure Ter mi nati o n of t he Trial ....................................................4 8
5. 7
Defi niti o n of E n d of Trial ...................................................................4 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 .....................................................................................................4 9
6. 1
Descri pti o n of I n vesti gati o nal Me dici nal Pr o d uct ..............................4 9
6. 2
D osa ge a n d A d mi nistrati o n ................................................................4 9
A vel u ma b ............................................................................................4 9
Sta n dar d of Care .................................................................................5 1
6. 3
As si g n me nt t o Treat me nt Gr o u ps .......................................................5 1
6. 4
N o ni n vesti gati o nal Me dici nal Pr o d ucts t o Be Use d ...........................5 2
6. 5
C o nc o mita nt Me dicati o ns a n d T hera pies ...........................................5 2
Per mitte d Me dici nes ...........................................................................5 2
Pr o hi bite d Me dici nes ..........................................................................5 2
Ot her I nter ve nti o ns .............................................................................5 3
S pecial Preca uti o ns .............................................................................5 3
Ma na ge me nt of S pecific A d verse E ve nts or A d verse Dr u g 
Reacti o ns .............................................................................................5 4
6. 6
Pac ka gi n g a n d La beli n g of t he I n vesti gati o nal Me dici nal Pr o d uct ....6 3
6. 7
Pre parati o n, Ha n dli n g, a n d St ora ge of t he I n vesti gati o nal 
Me dici nal Pr o d uct ...............................................................................6 3
6. 8
I nvesti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y .............................6 4
6. 9
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce .........6 5
6. 1 0
Bli n di n g ..............................................................................................6 5
6. 1 1
E mer ge nc y  U n bli n di n g.......................................................................6 5
6. 1 2
Treat me nt of O ver d ose .......................................................................6 5
6. 1 3
Me dical Care of S u bjects after E n d of Trial .......................................6 6
7
Trial Pr oce d ures a n d Assess me nts ......................................................6 6
7. 1
Sc he d ule of Assess me nts ....................................................................6 6
Scree ni n g a n d Baseli ne Pr oce d ures a n d Assess me nts ........................6 6
Treat me nt Peri o d ................................................................................6 8
E n d of Treat me nt ................................................................................6 9
Safet y  F oll o w-u p ................................................................................7 0
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 7
L o n g -ter m F oll o w-u p ..........................................................................7 0
7. 2
De m o gra p hic a n d Ot her Baseli ne C haracteristics ..............................7 1
De m o gra p hic Data.............................................................................. 7 1
Dia g n osis of S oli d T u m ors or L y m p h o mas ........................................7 1
Me dical Hist or y ..................................................................................7 1
Vital Si g ns a n d P h y sical E xa mi nati o n................................................7 1
C o m p ute d T o m o gra p h y or Ma g netic Res o na nce I ma gi n g Sca ns 
f or T u m or Assess me nt ........................................................................7 2
Car dia c Assess me nts ..........................................................................7 2
Cli nical L a b orat or y Tests ...................................................................7 2
7. 3
Efficac y  Assess me nts .........................................................................7 3
7. 4
Assess me nt of Safet y ..........................................................................7 3
A d verse E ve nts ...................................................................................7 4
Pr e g na nc y a n d I n Uter o Dr u g E x p os ure.............................................7 8
La b orat or y  Assess me nts.....................................................................7 9
Vital Si g ns, P h y sical E xa mi nati o ns, a n d Ot her Assess me nts.............8 0
7. 5
P har mac o ki netics ................................................................................8 1
B o d y Fl ui d(s) ......................................................................................8 1
P h ar mac o ki netic Calc ulati o ns ............................................................8 1
7. 6
Bi o mar kers ..........................................................................................8 1
A nti dr u g A nti b o d y ..............................................................................8 3
7. 7
Ot her Assess me nts ..............................................................................8 4
S u bject -re p orte d O utc o mes/ Q ualit y of Life .......................................8 4
8
Statistics ..............................................................................................8 4
8. 2
Ra n d o mizati o n ....................................................................................8 4
8. 3
E n d p oi nts ............................................................................................8 4
Pri mar y  E n d p oi nts..............................................................................8 4
Sec o n dar y  E n d p oi nts..........................................................................8 5
8. 4
A nal y sis Sets.......................................................................................8 6
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
Ge neral C o nsi derati o ns .......................................................................8 7
A nal y ses of Pri mar y E n d p oi nts..........................................................8 8
A nal y ses of Sec o n dar y E n d p oi nts......................................................9 0
A nal y sis of Safety a n d Ot her E n d p oi nts .............................................9 3
8. 6
I nteri m a n d A d diti o nal Pla n ne d A nalys es ..........................................9 4
9
Et hical a n d Re g ulat or y As pects ..........................................................9 5
9. 1
Res p o nsi bilities of t he I n vesti gat or ....................................................9 5
9. 2
S u bject I nf or mati o n a n d I nf or me d C o nse nt .......................................9 5
9. 3
S u bject I de ntificati o n a n d Pri vac y ......................................................9 6
9. 4
E mer ge nc y  Me dical S u p p ort a n d S u bject Car d..................................9 7
9. 5
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects .....................9 7
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 ..........9 7
9. 7
Healt h A ut h orities............................................................................... 9 8
1 0
Trial Ma na ge me nt ...............................................................................9 8
1 0. 1
Case Re p ort F or m Ha n dli n g ...............................................................9 8
1 0. 2
S o urce Data a n d S u bject Files ............................................................9 8
1 0. 3
I n vesti gat or Site File a n d Arc hi vi n g...................................................9 9
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 ..........................................................................................9 9
1 0. 5
C ha n ges t o t he Cli nical Trial Pr ot oc ol ................................................9 9
1 0. 6
Cli nical St u d y  Re p ort a n d P u blicati o n P olic y..................................1 0 0
Cli nical St u d y  Re p ort .......................................................................1 0 0
P u blicati o n ........................................................................................1 0 0
1 1
Refere nces Cite d i n t he Te xt .............................................................1 0 1
1 2
A p pe n dices .......................................................................................1 0 3
A p pe n di x I :
C o ntrace pti ve G ui da nce ....................................................................1 0 4
A p pe n di x II:
Si g nat ure Pa ges a n d Res p o nsi b le Pers o ns f or t he Trial....................1 0 6
Si g n at ure P a ge – Pr ot oc ol Le a d ....................................................................................1 0 7
Si g n at ure P a ge – C o or di n ati n g I n vesti g at or ...............................................................1 0 8
Si g n at ure P a ge – Pri nci p al I n vesti g at or ......................................................................1 0 9
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge ....................................1 1 0
A p pe n di x III:
La ns k y a n d Kar n ofs k y P erf or ma nce Scales ....................................1 1 1
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
A p pe n di x I V:
Pr ot oc ol A me n d me nts a n d L ist of C ha n ges .................................... 1 1 4
T a ble of T a bles
Ta ble 1
Sc he d ule of Assess me nts – A vel u ma b ............................................... 1 8
Ta ble 2
Sc he d ule of Assess me nts – P har mac o ki netic a n d A nti dr u g 
A nti b o d y  Sa m pli n g............................................................................. 2 4
Ta ble 3
Detaile d D ose Re -Escalati o n/ De -Escalati o n Sc he me ......................... 3 4
Ta ble 4 
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 Ass ociate d wit h A vel u ma b ................................................ 5 5
Ta ble 5  
Ma na ge me nt of I mm u ne -relate d A d verse Eve nts .............................. 5 7
Ta ble 6
Cli nical L a b orat or y Assess me nts ....................................................... 8 0
Ta ble 7
S u bject C haracterizati o n Base d o n A nti dr u g A nti b o d y  Res ults......... 9 2
T a ble of Fi g ures
Fi g ure 1
Sc he matic of t he Trial Desi g n ............................................................ 3 1
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
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 n tidr u g a nti b o d y
A D R
A d verse dr u g reacti o n
A E(s)
A d verse e ve nt(s)
A L T
Ala ni ne a mi n otra nsferase
A S T
As partate a mi n otra nsferase
B O R
Best o verall res p o nse
B U N
Bl o o d urea nitr o ge n
C L
Cleara nce
C E OI
P las ma c o nce ntrati o n o bser ve d at t he e n d of i nf usi o n
C ma x
Ma xi m u m plas ma c o nce ntrati o n o bser ve d p ost d ose
C tr o u g h
Mi ni m u m p ost d ose tr o u g h
c o nce ntrati o n
C R
C o m plete res p o nse
C R O
C o ntract Researc h Or ga nizati o n
C T 
C o m p ute d t o m o gra p h y 
C T L A- 4
C y t ot o xic T-l ym p h oc y te-ass ociate d a nti ge n - 4
D L 1
Starti n g d ose le vel of 1 0 m g/ k g a vel u ma b e ver y  2 wee ks
D L - 1
L o wer d ose le vel of 3 m g / k g a vel u ma b e ver y 2 wee ks 
D L 2
I ncrease d d ose le vel of u p t o 2 0 m g/ da y  a vel u ma b e ver y 2 wee ks
D L T
D ose -li miti n g t o xicit y
D O R
D urati o n of res p o nse
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
F A S
F ull a nal ys is set
1 8F D G -P E T/ C T
F l u or o de o xy gl uc ose F 1 8- p ositr o n e missi o n t o m o gra p h y/
c o m p ute d t o m o gra p h y
F F P E
F or mali n -fi xe d paraffi n-e m be d de d
G C P
G o o d Cli nical Practice
Ge o C V
Ge o metric c oefficie nt of variati o n
Ge o Mea n
Ge o metric mea n
G G T
Ga m ma -gl uta m yl tra nsferase
H B V
He patitis B vir us
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
H C V
He patitis C vir us
I B
I n vesti gat or’s Br oc h ure
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 G 1
I m m u n o gl o b uli n G 1
I M P
I n vesti gati o nal Me dici nal Pr o d uct
I N R
I nter nati o nal n or malize d rati o
ir A E
I m m u ne-relate d a d verse e ve nt
I RB
I nstit uti o nal Re vie w B oar d
I R R
I nf usi o n-relate d reacti o n
ir R E CIS T
I m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors
I R T
I nteracti ve res p o nse tec h n ol o g y
I V
Intra ve n o us
M C C
Mer kel cell carci n o ma
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M RI
Ma g netic res o na nce i ma gi n g
M T D
Ma xi m u m t olerate d d ose
m T PI
M o difie d t o xicit y  pr o ba bilit y i nter val
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 nts
N S AI D
N o nster oi dal a nti -i nfla m mat or y dr u g
N S C L C
N o n -s mall cell l u n g ca ncer
O R
O bjecti ve res p o nse
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
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 D -L 2
Pr o gra m me d deat h li ga n d 2
P E T
P ositr o n e missi o n t o m o gra p h y
P F S
Pr o gressi o n -free s ur vi val
P K
P har mac o ki netic(s)
P o p P K
P o p ulati o n p har mac o ki netic(s)
P R
Partial res p o nse
p T
Tar get pr o ba bilit y  rate
R B C
Re d bl o o d cell
R E CI S T 1. 1
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 P 2 D
Rec o m me n de d P hase II d ose
S A E(s)
Seri o us a d verse e ve nt(s)
S A P
Statistical A nal y sis Pla n
S D
Sta ble disease
S M C
Safet y  M o nit ori n g C o m mittee
t1/ 2
Half -life
T 4
Free t h y r o xi ne
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
T S H
T h y r oi d-sti m ulati n g h or m o ne
T T R
Ti me t o res p o nse
U L N
U p per li mit of n or mal
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
M S 1 0 0 0 7 0 - 0 3 0 6
Title
O pe n -la bel, 
P hase 
I/II 
st u d y 
to 
e val uate 
p har mac o ki netics, 
p har mac o d y na mics, 
safety,  an d 
a ntica ncer acti vit y of a vel u ma b i n pe diatric s u bjects 
fr o m birt h t o less t ha n 1 8 ye ars of a ge wit h refract or y 
or rela pse d s oli d t u m or s a n d l ym p h o ma
Tri al P h ase
I/II
I N D N u m ber
F D A c o vere d tri al
Y es
E u dr a C T N u m ber
2 0 1 7 -0 0 2 9 8 5 -2 8
C o or di n ati n g I n vesti g at or
S p o ns or
F or all c o u ntries e xce pt t he U S A :
Merc k K Ga A, Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
F or sites i n t he U S A :
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, Inc.
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A 0 1 8 2 1, U S A
Tri al ce nters/c o u ntries
A p pr o xi matel y  5 0 sites i n N ort h A merica, E ur o pe, 
Mi d dle East, S o ut h A merica , a n d Asia Pacific , 
i ncl u di n g a p pr o xi matel y 1 0 sites i n t he U S A
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
First s u bject i n: Ja n uar y 2 0 1 8
Last s u bject o ut: Ja n uar y 2 0 2 2
Tri al Re gistr ies
E U Cli nical Trials Re gister: 
htt ps:// w w w.cli nicaltrialsre gister.e u/ (re gistrati o n 
# 2 0 1 7 -0 0 2 9 8 5 -2 8)
C li nical Trials. g o v ( U S A): htt ps://cli nicaltrials. g o v/ 
(re gistrati o n # t o c o me)
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
O bjecti ves:
Pri m ar y o bjecti ves
P h ase I 

T o e val uate t he safet y a n d t olera bilit y of a vel u ma b

T o deter mi ne t he rec o m me n de d P hase II d ose ( R P 2 D) of a vel u ma b i n pe diatric s u bjects 0 t o 
< 1 8 y ears of a ge wit h s oli d t u m ors a n d l ym p h o ma
P h ase II 

T o assess a ntit u m or acti vit y of a vel u ma b b y  deter mi ni n g t he o bjecti ve res p o nse rate ( O R 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 CIS T 1. 1) a n d as
a dj u dicate d b y  the I n vesti gat or i n 2 e x pa nsi o n c o h orts i n s pecifie d t u m or t ypes i n pe diatric 
s u bjects treate d wit h a vel u ma b
Sec o n d ar y o bjecti ves 
P h ase I 

T o assess a ntit u m or acti vit y of a vel u ma b b y  deter mi ni n g t he O R R acc or di n g t o R E CI S T 1. 1 
a n d as adj u dicate d b y  th e I nvesti gat or i n pe diatric s u bjects wit h s oli d t u m ors a n d l ym p h o ma 
treate d wit h a vel u ma b 

T o assess pr o gressi o n -free s ur vi val ( P F S) base d o n I n vesti gat or assess me nts, d urati o n of 
res p o nse ( D O R), ti me t o res p o nse (T T R ), a n d o verall s ur vi val ( O S)

T o c haract erize t he p har mac o ki netics ( P K) of a vel u ma b

T o assess t he i m m u n o ge nicit y  of a vel u ma b

T o e val uate pr o gra m me d deat h li ga n d 1 ( P D -L 1) e x pressi o n; t u m or-i nfiltrati n g T-cell acti vit y;  
T- cell p o p ulati o n; a n d T- cell, B- cell, a n d N K -cell n u m bers i n t u m or tiss ue at Baseli ne a n d at 
c o nfir me d pr o gressi o n (if t u m or tiss ue is o btai ne d)

T o meas ure c ha n ges i n vacci nati o n -relate d a nti b o d y co nce ntrati o ns ( di p ht heria, teta n us, a n d 
p ne u m oc occal c o nj u gate)
P h ase II

T o e val uate t he safet y a n d t olera bilit y of a vel u ma b

T o assess P F S base d o n I n vesti gat or assess me nts , T T R, D O R , a n d O S

T o c haracterize t he P K of a vel u ma b

T o assess t he i m m u n o ge nicit y  of a vel u ma b

T o e val uate P D -L 1 e x pressi o n; t u m or-i nfiltrati n g T- cell acti vit y; T- cell p o p ulati o n; a n d T- cell, 
B- cell, a n d N K -cell n u m bers i n t u m or tiss ue at Baseli ne a n d at c o nfir me d pr o gressi o n (if t u m or 
tiss ue is o btai ne d)

T o meas ure c ha n ges i n vacci nati o n -relate d a nti b o d y co nce ntrati o ns ( di p ht heria, teta n us, a n d 
p ne u m oc occal c o nj u gate)
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
Met h o d ol o g y: 
T his is a m ultice nter, o pe n -la bel, i nter nati o nal, P hase I/II st u d y to e val uate t he d ose, safety a n d 
t olera bilit y, a ntit u m or acti vit y, P K, a n d p har mac o d y na mics of a vel u ma b i n pe diatric s u bjects 0 t o 
< 1 8 ye ars of a ge wit h refract or y or rela pse d mali g na nt s oli d t u m ors (i ncl u di n g ce ntral ner v o us 
s yste m t u m ors) a n d l ym p h o ma f or w hic h n o sta n dar d t hera py i s a vaila ble or f or w hic h t he s u bject 
is n ot eli gi ble f or t he e xisti n g t hera py.
T he st u d y will c o nsist of 2 parts: t he d ose -fi n di n g part ( P hase I) a n d t he t u m or-s pecifie d 
e x pa nsi o ns part ( P hase II). I n the P hase I d ose -fi n di n g part of t he st u d y, t he R P 2 D of a vel u ma b 
i n c hil dre n will be deter mi ne d. S u bjects will be e nr olle d i n se q ue ntial c o h orts of 3 t o 6 s u bjects 
eac h. At least 1 2 s u bjects m ust be e val ua ble f or t he pri mar y  anal ys is. T he starti n g dose will be t he 
sa me as t he c urre ntl y rec o m me n de d d ose i n a d ults, 1 0 m g/ k g e ver y 2 wee ks. T he safety of t his 
d ose le vel a n d t he nee d f or d ose d e -escalati o n will be base d o n t he fre q ue nc y of d ose -li miti n g 
t o xicities (D L Ts) t o e ns ure t hat a n y gi ve n d ose le vel d oes n ot e xcee d t he ma xi m u m t olerate d d ose 
( M T D). T he M T D esti mate is t he hi g hest d ose teste d of a vel u ma b ass ociate d wit h t he occ urre nce 
of D L Ts wit hi n t he first 2 c ycles of treat me nt i n < 3 3 % of s u bjects, pr o vi de d t hat a hi g her d ose 
le vel of a vel u ma b wa s teste d a n d ha d a n ass ociate d D L T rate ≥3 3 %. If t he D L T rate wit hi n t he 
first 2 c ycles of treat me nt is < 3 3 % f or all teste d d ose le vels, t he n t he M T D will n ot ha ve bee n 
reac he d. If t he starti n g d ose le vel is c o nfir me d as safe, t his d ose will be selecte d as R P 2 D if it 
pr o vi des si milar e x p os ure i n c hil dre n t o t h ose i n a d ults. If e x p os ure is n ot a de q uate, a decisi o n 
ca n be ma de t o escalate t o a d ose le vel u p t o 2 0 m g / k g.
O nce t he R P 2 D is deter m i ne d, P hase II will be gi n wit h 2 e x pa nsi o n c o h orts i n 2 s pecifie d t u m or 
t ypes. T he s pecifie d t u m or t ypes will be selecte d base d o n e mer gi n g data fr o m t his st u d y an d ot her 
o n g oi n g st u dies. T hese data m a y  incl u de cli nical data wit h a vel u ma b or wit h ot her i m m u ne 
c hec k p oi nt i n hi bit ors, or precli nical data pr o vi di n g a d diti o n al rati o nale f or a s pecific t u m or t y pe. 
Eac h e x pa nsi o n c o h ort will f oll o w Si m o n’s O pti mal T w o -sta ge Desi g n. If t here are 2 or m ore 
s u bjects wit h c o nfir me d o bjecti ve res p o nses wit hi n t he first 2 3 s u bjects treate d at t he R P 2 D, t he n 
a n a d diti o nal 3 3 s u bjects will be e nr olle d a n d treate d at t hat d ose le vel. If t here are 1 or n o s u bjects 
wit h c o nfir me d o bjecti ve res p o nses i n t he first 2 3 s u bjects treate d at t he R P 2 D wit hi n a mi ni m u m 
f oll o w-u p of 1 6 wee ks, t he n t he c o h ort will be cl ose d f or f urt her e nr oll me nt. 
T he st u d y  is ai me d at defi ni n g a si n gle R P 2 D i n t he a ge gr o u p 0 t o < 1 8 years. H o we ver, if at a n y 
ti me d uri n g t he st u d y, data s u g gest a differe nce i n t olera bilit y b y a ge, t his will be disc usse d wit h 
t he Safety M o nit ori n g C o m mittee ( S M C). T he f oll o wi n g r ules will be use d:

T he first 3 s u bjects i n t he i nitial c o h ort will be 1 t o < 1 8 y ears of a ge .

S u bse q ue nt c o h orts ma y  be o pe n t o s u bjects 0 t o < 1 8 ye ars of a ge, or a narr o wer a ge ra n ge, 
base d o n e mer gi n g data, as a gree d b y t he S M C.
A vel u ma b will be a d mi nistere d e ver y 2 wee ks u ntil c o nfir me d pr o gressi o n , deat h , u nacce pta ble 
t o xicit y, or a n y c riteri o n f or wit h dra wal occ urs . A c ycle is defi ne d as 2 wee ks. I n P hase I, t he D L T 
o bser vati o n peri o d is defi ne d as a 2 8- d a y  peri o d ( 2 c ycles) be gi n ni n g wit h t he first a vel u ma b 
a d mi nistrati o n. Eac h s u bject will be f oll o we d f or 1 2 m o nt hs after his/ her e n d of treat me nt .
Baseli ne i ma gi n g will be perf or me d wit hi n 2 8 da ys pri or t o re gistrati o n a n d C y cle 1 Da y 1 
treat me nt i n or der t o esta blis h Baseli ne disease stat us of tar get a n d n o ntar get lesi o ns acc or di n g 
t o R E CIS T 1. 1. Acce pta ble m o dalities i ncl u de C T sca ns ( nec k, c hest, a b d o me n, a n d pel vis as 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
nee de d), a n d C T c hest wit h c o ntrast t o get her wit h M RI of t he a b d o me n a n d pel vis. T he sa me 
i ma gi n g m o dalit y ( C T or M RI) s h o ul d be use d t hr o u g h o ut t he st u d y f or a partic ular s u bject. A 
b o ne sca n ( b o ne sci nti gra p h y ) or fl u or o de o x y gl uc ose F 1 8-p ositr o n e missi o n t o m o gra p h y / C T 
(1 8F D G -P E T/ C T) is re q uire d at Baseli ne i n s u bjects wit h t u m ors k n o w n t o metastasize t o b o ne, 
wit h s u bse q ue nt ra di o gra p hic disease re-e val uati o n o nl y  if b o ne metastases are prese nt at 
Baseli ne. Baseli ne C N S i ma gi n g wil l n ot be re q uire d wit h t he e xce pti o n of s ym pt o matic 
s u bjects t o e val uate f or C N S metastases. 
A C T or M RI will be perf or me d e ver y 8 wee ks f or t he first 2 4 wee ks, t he n e ver y 12 wee ks 
t hereafter (a wi n d o w of 5 da y s pri or t o d osi n g is all o we d). If partial resp o nse ( P R), c o m plete 
res p o nse ( C R), or pr o gressi ve disease ( P D) is o bser ve d acc or di n g t o R E CI S T 1. 1, a c o nfir mati o n 
C T or M RI  s h o ul d be perf or me d acc or di n g t o R E CIS T 1. 1, prefera bl y at t he re g ularl y sc he d ule d 
8- wee k assess me nt i nter val, b ut n o s o o ner t ha n 4 wee ks after t he i nitial d oc u me ntati o n of res p o nse 
or c o nfir me d disease pr o gressi o n. T u m or assess me nt s h o ul d be re peate d at t he E n d of Treat me nt
Visit if m ore t ha n 4 wee ks ha ve passe d si nce t he last e val uati o n.
Pl a n ne d n u m ber of s u bjects: 
P h ase I: 1 2 t o 3 6 s u bjects
P h ase II: 4 6 t o 1 1 2 s u bjects ( 2 3 t o 5 6 s u bjects per t u m or t y pe) f or 2 c o h orts
Pri m ar y e n d p oi nts: 
P h ase I

Occ urre nce a n d se verit y of treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) ≥Gra de 3 acc or di n g 
t o 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 nts (N CI -C T C A E )
v ersi o n 4. 0 3

D L Ts t o deter mi ne t he R P 2 D .
Sec o n d ar y e n d p oi nts: 
P h ase I

C o nfir me d B O R acc or di n g t o R E CIS T 1. 1 a n d as a dj u dicate d b y  t he I n vesti gat or

D O R, T T R, P F S per R E CI S T 1. 1 a n d as a dj u dicate d b y  t he I n vesti gat or, a n d O S

Occ urre nce a n d se verit y of T E A Es , A Es of s pecial i nterest, a n d treat me nt-relate d A Es, a n d 
i nci de nce of la b orat or y a b n or malities , as gra de d b y N CI-C T C A E v 4. 0 3

Vital si g ns (i ncl u di n g bl o o d press ure a n d heart rate)

Si n gle - a n d m ulti ple -d ose P K pr ofiles of a vel u ma b (ie, Cma x , A U C, t1/ 2, a n d C tr o u g h, as data 
per mit) 

I m m u n o ge nicit y as meas ure d by a vel u ma b A D A, i ncl u di n g n e utralizi n g a nti b o dies (N A bs )

Assess me nt of t u m or P D -L 1  ex pressi o n; t u m or-i nfiltrati n g T- cell acti vit y; T- cell p o p ulati o n; 
a n d T- cell, B- cell, a n d N K -cell n u m bers at Baseli ne a n d at c o nfir me d pr o gressi o n (if t u m or 
tiss ue is o btai ne d)

Vacci nati o n -relate d a nti b o d y c o nce ntrati o ns.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7
P h ar m ac o ki netics: 
Sa m ples f or P K assess me nts will be c ollecte d fr o m all s u bjects i n t he st u d y, as per t he Sc he d ule 
of Assess me nts - P K a n d A D A Sa m pli n g , a n d i nitiall y stratifie d by w ei g ht ( < 1 0 k g a n d ≥1 0 k g). 
F or t he first 3 6 s u bjects, P K sa m ples will be c ollecte d d uri n g treat me nt C ycles 1, 2, 3, 5, 7, 8, 1 3, 
1 9, 2 5, a n d e ver y 6 c ycles t hereafter; at t he E n d of Treat me nt Visit; a n d at t he 3 0- Da y  Safet y 
F oll o w -u p Visit . F or t he rest of t he s u bjects, m ore s parse P K sa m ples will be c ollecte d. 
Ot her assess me nts: 
Bl o o d sa m ples f or a nal ys is of A D A (i ncl u di n g N A bs) will be dra w n pre d ose at C ycles 1, 2, 3, 5, 
7, 1 3, 1 9, 2 5, a n d e ver y 6 cyc les t hereafter, as well as at t he E n d of Treat me nt Visit a n d t he 3 0- Da y  
Safet y  F oll o w-u p Visit. Acc o m pa n yi n g P K sa m ples will be c ollecte d as t he sa me ti me. 
 
 
 
Ke y i ncl usi o n criteri a: 
Male or fe male s u bjects 0 t o < 1 8 years of a ge at t he ti me of first treat me nt d ose wit h hist ol o gicall y 
or c yt ol o gically c o nfir me d s oli d mali g na nt t u m ors or l ym p h o ma ; c o nfir me d pr o gressi o n o n or 
refract or y t o sta n dar d t hera p y or n o sta n dar d t hera p y  availa ble; a vaila bilit y of arc hi val f or mali n-
fi xe d, paraffi n -e m be d de d bl oc k c o ntai ni n g t u m or tiss ue , or sli des, or a fres h/rece nt t u m or bi o ps y  
pri or t o a vel u ma b treat me nt; a de q uate b o ne marr o w, ki d ne y , a n d li ver f u ncti o n.
Ke y e xcl usi o n criteri a: 
Pri or t hera py wit h a n y a nti b o d y or dr u g tar getin g T- cell c ore g ulat or y pr otei ns; c o nc urre nt 
a ntica ncer treat me nt or i m m u n os u p pressi ve a ge nts; pri or or ga n tra ns pla ntati o n; si g nifica nt ac ute 
or c hr o nic i nfecti o ns; ot her si g nifica nt diseases or c o n diti o ns t hat mi g ht i m pair t he s u bject’s 
t olera nce of trial treat me nt.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7
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:
S u bjects 
will 
recei ve 
a n 
i ntra ve n o us 
(i v) 
i nf usi o n 
of 
a vel u ma b 
o ver 
1 
h o ur 
(- 1 0 mi n ut es/+ 2 0 mi n utes, or 5 0 t o 8 0 mi n utes) o nce e ver y 2 wee ks. T o miti gate i nf usi o n -relate d 
reacti o ns, a pre me dicati o n re gi me n of a n a nti hista mi ne ( H 1 rece pt or bl oc ker s uc h as 
di p he n h y dra mi ne) a n d aceta mi n o p he n ( paraceta m ol; i v or oral e q ui vale nt) is ma n dat or y  3 0 t o 
6 0 mi n utes pri or t o eac h d ose of st u d y  dr u g f or t he first 4 a vel u ma b a d mi nistrati o n s. T his ca n 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 d pre me dicati o n 
s pecifically f or a vel u ma b is n ot per mitte d.
T he d ose of a vel u ma b will b e calc ulate d base d o n t he wei g ht of the s u bject deter mi ne d wit hi n 
7 2 h o urs pri or t o t he d a y  of dr u g a d mi nistrati o n. T he d ose of a vel u ma b use d f or t he pre vi o us 
a d mi nistrati o n ca n be re peate d if t he c h a n ge i n t he s u bject’s wei g ht is wit hi n 1 0 % of t he wei g ht 
use d f or t he pre vi o us d ose calc ulati o n. S u bjects will recei ve a vel u ma b o nce e ver y 2 wee ks u ntil 
c o nfir me d pr o gressi o n , deat h , u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal occ urs.
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: 
Treat me nt wit h a vel u ma b will c o nti n ue as per pr ot oc ol s pecificati o ns u ntil c o nfir me d pr o gressi o n , 
deat h , u nacce pta ble t o xicit y, or a ny criteri o n f or wit h dra wal occ urs . 
S u bjects w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a mi ni m u m of 1 2 m o nt hs base d o n 
cli nical j u d g me nt of be nefit a n d/ or u ntil c o nfir me d pr o gressi o n , deat h , u nacce pta ble t o xicit y, or 
a n y criteri o n f or wit h dra wal occ urs, after c o nfir mati o n of res p o nse as s pecifie d i n t he pr ot oc ol.
Eac h s u bject will be f oll o we d f or a n a d diti o nal 1 2 m o nt hs after t he s u bject’s e n d of treat me nt .
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
St atistic al met h o ds: 
Descri pti ve statistics will be use d t o s u m marize t he trial res ults. 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. Statistics f or c o nti n u o us varia bles ma y i ncl u de m ea ns, me dia ns, ra n ges, a n d 
a p pr o priate meas ures of varia bilit y . I n P hase I, descri pti ve statistics will be e xa mi ne d f or 
i n dicati o ns of D L T. I n P hase II, B O R will be e val uate d acc or di n g t o R E CI S T 1. 1 base d o n 
I n vesti gat or assess me nts of disease at differe nt ti me p oi nts.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
T a ble 1
Sc he d ule of Assess me nts – A vel u m a b
Tre at m e nt Peri o d a
(-3/ + 1 d a ys)
1 C ycle = 1 4 D a ys
                     E n d Of Tre at me nt/ F oll o w -U p b
Assess me nts
Scree ni n g
(2 8 D a ys 
Pri or t o 
E nr oll me nt)
C ycle 1  
C ycle 2
C ycle 3
C ycle 4  
C ycle 5  
C ycle 6  
C ycle 7
U ntil E O T
E O T/
Wit h dr a w al 
Visi tb
S afet y 
F oll o w -u p c
S ur vi v al 
F oll o w -u p d
Wee k 1
( D a y 1)
Wee k 3
( D a y 1 5)
Wee k 5 
( D a y 2 9)
Wee k 7 
( D a y 4 3)
Wee k 9
( D a y 5 7)
Wee k 1 1
( D a y 7 1)
Wee k 1 3 
( D a y 8 5) 
> Wee k 1 3 
( D a y 8 5)
Wit hi n
7 D a ys of 
Decisi o n t o 
Disc o nti n ue
Visit 
3 0 D a ys
(5 d a ys) 
After 
L ast T x 
P h o ne C all 
9 0 D a ys 
(5 d a ys) 
After 
L ast T x
E ver y 
1 2 Wee ks 
( ± 1 Wee k) 
After L ast 
T x
Writte n i nf or me d 
c o nse nt/asse nt
X
Writte n 
 
i nf or me d c o nse nt/
asse nt f or o pti o nal 
s u bst u dies if 
a p plica ble
X
I ncl usi o n/e xcl usi o n 
criteria
X
Me dical hist or y 
X
Disease hist or y 
(i ncl u di n g pri or 
treat me nt re gi me ns)
X
De m o gra p hic data
X
P h y sical e xa mi nati o n, 
wei g ht, a n d hei g h te
X  
X  
X  
X  
X  
X  
X
X
Q 2 we e ks
X
X
Vital si g n sf
X  
X  
X  
X  
X  
X  
X
X
Q 2 we e ks
X
X
Perf or ma nce stat u s g
X  
X  
X  
X  
X  
X  
X
X
Q 2 we e ks
X
X
1 2 -lea d E C Gh Err or! 
Refere nce s o urce n ot f o u n d.
X  
X  
X  
X
X
X
B o ne gr o w t h 
assess me nt si
X
Perf or me d 
a n n uall y
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
Tre at m e nt Peri o d a
(-3/ + 1 d a ys)
1 C ycle = 1 4 D a ys
                     E n d Of Tre at me nt/ F oll o w -U p b
Assess me nts
Scree ni n g
(2 8 D a ys 
Pri or t o 
E nr oll me nt)
C ycle 1  
C ycle 2
C ycle 3
C ycle 4  
C ycle 5  
C ycle 6  
C ycle 7
U ntil E O T
E O T/
Wit h dr a w al 
Visi tb
S afet y 
F oll o w -u p c
S ur vi v al 
F oll o w -u p d
Wee k 1
( D a y 1)
Wee k 3
( D a y 1 5)
Wee k 5 
( D a y 2 9)
Wee k 7 
( D a y 4 3)
Wee k 9
( D a y 5 7)
Wee k 1 1
( D a y 7 1)
Wee k 1 3 
( D a y 8 5) 
> Wee k 1 3 
( D a y 8 5)
Wit hi n
7 D a ys of 
Decisi o n t o 
Disc o nti n ue
Visit 
3 0 D a ys
(5 d a ys) 
After 
L ast T x 
P h o ne C all 
9 0 D a ys 
(5 d a ys) 
After 
L ast T x
E ver y 
1 2 Wee ks 
( ± 1 Wee k) 
After L ast 
T x
C o nc o mita nt 
me dicati o ns a n d 
pr oce d ure sj
X
C o nc o mita nt me dicati o ns a n d pr oce d ures are c ollecte d t hr o u g h t he Safet y F oll o w -u p Visit
       X
    
A E c ollecti o n k
A E s are c ollecte d t hr o u g h t he Safet y F oll o w-u p Visit
Treat me nt- relate d n o n-seri o us A Es are c ollecte d u ntil t he 9 0-d a y  Safet y F oll o w-u p P h o ne Call. b
X
S A E c ollecti o n k
All S A Es are d oc u me nte d t hr o u g h t he 9 0 -d a y  Safet y F oll o w-u p P h o ne Call
O n g oi n g S A Es at t he 9 0 -d a y  Safet y F oll o w-u p P h o ne Call will be f oll o we d u p b
X
S a m ples a n d L a b or at or y Assess me nt sl
He m at ol o g y m
X  
X  
X  
X  
X  
X  
X  
X
Q 2 we e ks
X
X
L y m p h oc yt e s u bset 
q ua ntificati o n n
X
X
X
C oa g ulati o n 
( he m ostae ol o g y)o
X  
X  
X  
X
X
X
Q 4 w ee ks
( o d d-
n u m bere d 
c ycles o nl y)
X
X
F ull ser u m c he mistr y p
X  
X
X
X
C ore ser u m 
c he mistr y p
X  
X  
X  
X  
X  
X
Q 2 we e ks
Uri nal ysi sq
X  
X
X
X
X
Q 4 w ee ks
X
X
Pre g na nc y tes tr
X  
X
X
X
X
Q 4 w ee ks
X
X
T 4 a n d T S H s
X  
X
X
X
Q 8 w ee ks
X
Bl o o d f or c yt o ki ne st
X  
X  
X
X
X
Bl o o d f or 
vacci nati o n -relate d 
a nti b o die su
X
X
X
H B V a n d H C V 
scree ni n g testsv
X
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
Tre at m e nt Peri o d a
(-3/ + 1 d a ys)
1 C ycle = 1 4 D a ys
                     E n d Of Tre at me nt/ F oll o w -U p b
Assess me nts
Scree ni n g
(2 8 D a ys 
Pri or t o 
E nr oll me nt)
C ycle 1  
C ycle 2
C ycle 3
C ycle 4  
C ycle 5  
C ycle 6  
C ycle 7
U ntil E O T
E O T/
Wit h dr a w al 
Visi tb
S afet y 
F oll o w -u p c
S ur vi v al 
F oll o w -u p d
Wee k 1
( D a y 1)
Wee k 3
( D a y 1 5)
Wee k 5 
( D a y 2 9)
Wee k 7 
( D a y 4 3)
Wee k 9
( D a y 5 7)
Wee k 1 1
( D a y 7 1)
Wee k 1 3 
( D a y 8 5) 
> Wee k 1 3 
( D a y 8 5)
Wit hi n
7 D a ys of 
Decisi o n t o 
Disc o nti n ue
Visit 
3 0 D a ys
(5 d a ys) 
After 
L ast T x 
P h o ne C all 
9 0 D a ys 
(5 d a ys) 
After 
L ast T x
E ver y 
1 2 Wee ks 
( ± 1 Wee k) 
After L ast 
T x
Baseli ne t u m or 
e val uati o n/sta gi n g 
( C T/ M RI/ ot her 
esta blis he d met h o ds )x
X
T u m or 
e val uati o n/sta gi n g 
d uri n g treat me nt 
( C T/ M RI/ ot her 
esta blis he d met h o ds )y
X 
(e ver y 
8 we e ks)
E ver y 
8 we e ks f or 
t he first 
2 4 we e ks, 
t he n e ver y 
1 2 we e ks 
t hereafter
X
D osi n g
Re gistrati o n z
X
Pretreat me n ta a
X  
X  
X  
X
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
Tre at m e nt Peri o d a
(-3/ + 1 d a ys)
1 C ycle = 1 4 D a ys
                     E n d Of Tre at me nt/ F oll o w -U p b
Assess me nts
Scree ni n g
(2 8 D a ys 
Pri or t o 
E nr oll me nt)
C ycle 1  
C ycle 2
C ycle 3
C ycle 4  
C ycle 5  
C ycle 6  
C ycle 7
U ntil E O T
E O T/
Wit h dr a w al 
Visi tb
S afet y 
F oll o w -u p c
S ur vi v al 
F oll o w -u p d
Wee k 1
( D a y 1)
Wee k 3
( D a y 1 5)
Wee k 5 
( D a y 2 9)
Wee k 7 
( D a y 4 3)
Wee k 9
( D a y 5 7)
Wee k 1 1
( D a y 7 1)
Wee k 1 3 
( D a y 8 5) 
> Wee k 1 3 
( D a y 8 5)
Wit hi n
7 D a ys of 
Decisi o n t o 
Disc o nti n ue
Visit 
3 0 D a ys
(5 d a ys) 
After 
L ast T x 
P h o ne C all 
9 0 D a ys 
(5 d a ys) 
After 
L ast T x
E ver y 
1 2 Wee ks 
( ± 1 Wee k) 
After L ast 
T x
A vel u ma b 
a d mi nistrati o n b b
X  
X  
X  
X  
X  
X
X
Q 2 we e ks
A E s: a d verse e ve nts; β h C G: beta -h u ma n c h ori o nic g o na d otr o pi n; C 1 D 1: C ycle 1 Da y 1; C N S: ce ntral ner v o us s yste m; C R: c o m plete res p o nse; C T: c o m p ute d t o m o gra p h y; 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; 
; 
 
H B V: he patitis B vir us; H C V: he patitis C vir us; I G F: i ns uli n -li ke gr o wt h fact or; 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 nts; P D: pr o gressi ve disease; P R: partial res p o nse; Q: e ver y; Q Tc: c orrecte d Q T; R E CI S T 1. 1: Res p o nse E val uati o n Criteria i n S oli d T u m ors versi o n 1. 1; S A E: seri o us a d verse e ve nt; 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; T x: treat me nt.
a.
Treat me nt peri o d: A ti me wi n d o w  of u p t o 3 da ys bef ore a n d 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 treat me nt pr oce d ures. T he bi w ee kl y, 1 4 -d a y  treat me nt 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.
b.
E n d of treat me nt/f oll o w-u p: All s u bjects will ha ve a n E O T Visit wit hi n 7 da ys after t he decisi o n t o disc o nti n ue st u d y treat me nt. All A E s wi ll be d oc u me nte d d uri n g t he 3 0 -d a y  Safet y F oll o w -U p Visit a n d t he 
9 0 -da y Safet y F o ll o w-u p P h o ne Call. A ll S A Es a n d all treat me nt-relate d n o nseri o us A Es nee d t o be d oc u me nte d t hr o u g h t he st u d y’s Safet y F oll o w -u p P h o ne Call, defi ne d at 9 0 da ys ( ± 5 da ys ) after t he last I M P 
a d mi nistrati o n. S u bjects wit h a n o n g oi n g S A E at t he 9 0- da y Safet y F oll o w -u p P h o ne Call m ust be m o nit ore d a n d f oll o we d b y t he 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.” A n y S A E assesse d as relate d t o a ve l u ma b 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 a vel u ma b. S u bjects wit h o ut P D 
at t he E O T 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 8 wee ks f or t he first 2 4 wee ks of tr e at me nt, t he n e ver y 1 2 we e ks) or t he start of s u bse q ue nt a ntica ncer t hera p y ( w hic he ver c o mes 
first). I n a d diti o n, s u bjects will be f oll o we d e ver y 1 2 wee ks ( ± 1 w ee k) 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); see f o ot n ote d . 
c.
Safet y F oll o w -u p: D uri n g t he p ost-treat me nt Safet y F oll o w - u p Visit, seri o us a n d n o n -seri o us A Es t hat t he I n vesti gat or belie ves t o ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o st u d y dr u g will be rec or de d 
i n t he e C R F. 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 3 0-da y peri o d, t he 3 0 -da y Safet y F oll o w -u p visit s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of t his ne w t hera p y.
d.
S u r vi val f oll o w-u p: After disc o nti n uati o n of st u d y treat me nt, p ost -st u d y s ur vi val stat us will be c ollecte d e ver y 1 2 wee ks ± 1 we e k u ntil t he s u bject’s deat h, u ntil 1 2 m o nt hs after ter mi nati o n of treat me nt of t he last 
s u bject, or u ntil e n d of st u d y, w hic he ver occ urs first. F oll o w -u p will i ncl u de c ollecti o n of i nf or mati o n o n s u bse q ue nt a ntica ncer t hera pies. Tele p h o ne c o ntact is acce pta ble.
e.
P h y sical e xa mi nati o n: A f ull p h ysical e xa mi nati o n s h o ul d be perf or me d at Scree ni n g a n d at t he E O T Visit . P h y sical e xa mi nati o ns at all ot her visits s h o ul d be directe d t o si g ns a n d s y m pt o ms. If t he p h ysical 
e xa mi nati o n at Scree ni n g is perf or me d wit hi n 3 da ys of C 1 D 1, it d oes n ot ha ve t o be re peate d at C 1 D 1. Wei g ht is meas ure d at e ver y visit, a n d hei g ht is meas ure d at Scree ni n g a n d e ver y 4 wee ks t hereafter.
f.
Vital si g ns: Bl o o d press ure a n d heart rate will be rec or de d i n a seate d p ositi o n after a 5 -mi n ute rest , if a p plica ble. At eac h cli nic visit, 2 bl o o d press ure rea di n gs will be ta ke n at least 1 h o ur a part.
g.
Perf or ma nce stat us: La ns k y perf or ma nce stat us ≥5 0 % f or s u bjects ≤1 6 years of a ge, or Kar n ofs k y scale ≥5 0 % f or s u bjects > 1 6 years of a ge. 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7
h.
1 2 -Lea d E C G : All s u bjects re q uire a si n gle E C G meas ure me nt after 5 mi n utes rest i n a s u pi ne p ositi o n at Scree ni n g a n d as i n dicate d . If pr ol o n ge d Q Tc i nter val is s us pecte d, t he E C G s h o ul d be re-e val uated b y  a 
q ualifie d pers o n (ie, a car di ol o gist) at t he i nstit uti o n f or c o nfir mati o n. A d diti o nal E C Gs will be perf or me d as cli nicall y i n dicate d. Cli nicall y si g nifica nt fi n di n gs see n o n f oll o w- up E C Gs s h o ul d be rec or de d as 
A E s.  
i.
B o ne gr o w t h assess me nts: T o m o nit or t he effects of treat me nt o n gr o wi n g b o nes, t he f oll o wi n g assess me nts will be perf or me d at Baseli ne a n d a n n uall y t hereafter: d ual -e ner g y X -ra y a bs or pti o metr y, b o ne a ge 
deter mi nati o n, a n d bl o o d le vels of i ns uli n -li ke gr o wt h fact or (I G F)-1, I G F bi n di n g pr otei n -3, vita mi n D, l utei nizi n g h or m o ne, f ollicle -sti m ulati n g h or m o ne, estra di ol, a n d test oster o ne.
j.
C o nc o mita nt me dicati o ns a n d pr oce d ures : C o nc o mita nt me dicati o ns a n d treat me nts will be rec or de d fr o m 2 8 da ys pri or t o t he start of st u d y treat me nt a n d t hr o u g h t he Safet y F oll o w-u p Visit ( 5 da ys). All 
c o nc o mita nt me dicati o ns s h o ul d be rec or de d i n t he e C R F, i ncl u di n g s u p p orti ve care dr u gs ( e g, a ntie metic treat me nt a n d pr o p h yla xis), t he dr u gs use d t o treat a d verse e ve nts or c hr o nic diseases, a n d n o n dr u g 
s u p p orti ve i nter ve nti o ns (e g, tra nsf usi o ns).
k.
A d verse e ve nt assess me nts: A Es s h o ul d be d oc u me nte d a n d rec or de d at eac h visit usi n g t he N CI -C T C A E versi o n 4. 0 3. F or S A Es, t he acti ve re p orti n g peri o d w ill be gi n fr o m t he ti me t hat i nf or me d c o nse nt/asse nt 
is pr o vi de d, w hic h is o btai ne d pri or t o t he s u bject’s partici pati o n i n t he st u d y (ie, pri or t o u n der g oi n g a n y st u d y-relate d pr oce d ure a n d/ or recei vi n g st u d y treat me nt) t hr o u g h a n d i ncl u di n g 9 0 cale n dar da ys ( ± 5 da ys) 
after t he last d ose of st u d y treat me nt. S A Es occ urri n g t o a s u bject after t he acti ve re p orti n g peri o d has e n de d s h o ul d be re p orte d t o t he S p o ns or if t he I n vesti gat or bec o mes a w are of t he m; at a mi ni m u m, all S A Es 
t hat t he I n vesti gat or beli e ves ha ve at least a reas o na ble p ossi bilit y of  bei n g relate d t o a vel u ma b are t o be re p orte d t o t he S p o ns or. Seri o us a n d n o nse ri o us A Es s h o ul d be rec or de d o n t he e C R F fr o m t he ti me t he 
s u bject has ta ke n at least 1 d ose of st u d y treat me nt t hr o u g h t he s u bject’s last visit. If a s u bject be gi ns a ne w a ntica ncer t hera p y, t he A E re p orti n g peri o d f or n o nseri o us A Es e n ds at t he ti me t he ne w treat me nt is 
starte d. Deat h m ust be re p orte d if it occ urs d uri n g t he S A E re p orti n g peri o d after t he last d ose of st u d y treat me nt, irres pecti ve of a n y i nter ve ni n g treat me nt. D uri n g t he p ost -treat me nt Safet y F oll o w - u p ( b e yo n d 
3 0 da ys t hr o u g h 9 0 cale n dar da ys after last d ose of st u d y treat me nt), seri o us or n o nseri o us A Es s us pecte d t o be relate d t o a vel u ma b base d o n t he I n vesti gat or’s assess me nt s h o ul d be rec or de d o n t he e C R F.
l.
La b orat or y assess me nts: O n t h ose wee ks w he n n o ot her assess me nts are re q uire d as per t he Sc he d ule of Assess me nts, a visit t o t he cli nical site is n ot re q uire d u nless t he I n vesti gat or c o nsi ders it necessar y.
m.
H e m at ol o g y: C o m plete bl o o d c o u nt res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n. N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nts were perf or me d w it hi n 7 da ys pri or t o t hat date.
n.
L y m p h oc yte s u bset q ua ntificati o n: T- cell p o p ulati o n; T- cell, B-cell, a n d N K -cell n u m bers.
o.
C oa g ulati o n ( he m ostase ol o g y): N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nts were perf or me d wit hi n 7 d a y s pri or t o t hat date. 
p.
Ser u m c he mistr y: F ull ser u m c he mistr y will be perf or me d d uri n g Scree ni n g, C 1 D 1 ( pre d ose), E O T Visit, a n d t he 3 0 -da y Safet y F oll o w -u p Visit . N o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nts were 
perf or me d wit hi n 7 d a y s pri or t o t hat date. C ore ser u m c he mistries will be perf or me d d uri n g ot her treat me nt visits. C ore ser u m c he mistr y res ults m ust be a vaila ble a n d re vie we d pri or t o d ose a d mi nistrati o n.
q.
Uri nal ysis: A f ull uri nal ysis ( di pstic k pl us micr osc o pic e val uati o n) is re q uire d at Scree ni n g a n d at t he E O T Visit, a n d a basic uri nal ysi s ( di pstic k o nl y) at eac h visit i n dicate d pri or t o a d mi nistratio n of trial dr u g. If 
t he basic uri nal ysis is a b n or mal, t he n a f ull uri nal ysis s h o ul d be perf or me d.
r.
Ser u m/ uri ne pre g na nc y test: F or fe male s u bjects of c hil d beari n g p ote ntial, meas ure ser u m β h C G at Scree ni n g a n d uri ne or ser u m β h C G t hereafter. 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 a d mi nistrati o n of a vel u ma b.
s.
T 4 a n d T S H: Perf or m tests at Scree ni n g; C 1 D 1 ( pre d ose, if > 1 4 da ys after i nitial Scree ni n g); e ver y 6 wee ks f or 2 s u bse q ue nt meas ure me nts (e g, Wee k 6/ 7, Wee k 1 2/ 1 3); e ver y 8 wee ks t hereafter ( b e yo n d 
Wee k
1 2/ 1 3); E O T Visit; a n d if cli nicall y i n dicate d. T here is n o nee d t o re peat o n C 1 D 1 if Scree ni n g assess me nts were perf or me d wit hi n 1 4 d a y s pri or t o C 1 D 1.
t.
C y t o ki nes: Refer t o t he La b orat or y Ma n ual f or t he s pecific c yt o ki nes t o be meas ure d.
u.
Vacci nati o n -relate d a nti b o dies: A nti b o d y titers f or di p ht heria, teta n us, a n d p ne u m oc occal c o nj u gate ( P C V-7) will be meas ure d.
v.
H B V a n d H C V scree ni n g: T he H B V scree ni n g pa nel i ncl u des 3 tests: he patitis B s urface a nti ge n ( H Bs A g), he patitis B s urface a nti b o d y ( H Bs A b), a n d he patitis B c ore a nti ge n ( H Bc A b). T he H C V scree ni n g test 
assesses t he prese nce or a bse nce of a nti b o dies t o H C V.
x.
Baseli ne t u m or e val uati o n/sta gi n g: T u m or assess me nts will i ncl u de all k n o w n or s us pecte d disease sites. I ma gi n g ma y i ncl u de n ec k, a b d o me n, pel vis, a n d c hest C T or M RI sca ns (if M RI is use d, C T of c hest is 
ma n dat or y ; f or trial sites i n Ger ma n y, o nl y M RI is t o be use d). Baseli ne C N S i ma gi n g will n ot be re q uire d wit h t he e xce pti o n of s y m pt o matic s u bjects t o e val uate f or C N S metastases. A b o ne sca n ( b o ne 
sci nti gra p h y) or 1 8F D G -P E T/ C T is re q uire d at Baseli ne i n s u bjects wit h t u m ors k n o w n t o metastasize t o b one .
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7
y.
T u m or assess me nts p ost -Baseli ne: T u m or e val uati o n has a ti me wi n d o w  of 5 da ys pri or t o d osi n g (- 5 da ys) a n d 5 da ys after t he E O T Visit. C T or M RI sca ns will be perf or me d e ver y 4 treat me nt c ycles (e ver y 
8 we e ks) f or t he first 2 4 we e ks, t he n e ver y 1 2 wee ks t hereafter. If b o ne metastases were prese nt at Baseli ne, or if ne w b o n e m etastases are s us pecte d, b o ne sci nti gra p h y or 1 8F D G -P E T/ C T w ill be re peate d e ver y 
8 we e ks f or t he first 2 4 wee ks, t he n e ver y 1 2 w e e ks t hereafter. B o ne i ma gi n g is als o re q uire d at t he ti me of C R c o nfir mati o n f or s u bjects w h o ha d b o ne metastases at Baseli ne. If P R, C R, or P D is o bser ve d 
acc or di n g t o R E CI S T 1. 1, a c o nfir m ati o n C T or M RI s h o ul d be perf or me d , prefera bl y at t he re g ularl y sc he d ule d 8-wee k assess me nt b ut n o s o o ner t ha n 4 we e ks after t he first d oc u me ntati o n of res p o nse or 
c o nfir me d disease pr o gressi o n. T u m or assess me nt s h o ul d be re peate d at t he E O T Visit if m ore t ha n 4 we e ks ha ve passe d si nce t he last e val uati o n. 
z.
Re gistrati o n pri or t o d osi n g: Re gistrati o n of s u bjects will pr ocee d t hr o u g h t he use of a n i nteracti ve res p o nse tec h n ol o g y s ys te m.
aa.
Pretreat me nt: Pre me dicati o n wit h a n a nti hista mi ne ( H 1 rece pt or bl oc ker suc h as di p he n h y dra mi ne) a n d wit h paraceta m ol (aceta mi n o p he n) a p pr o xi matel y 3 0 t o 6 0 mi n utes pri or t o t he first 4 d oses of a vel u ma b is 
ma n dat or y. Pre me dicati o n ca n be a d mi nistere d f or s u bse q ue nt a vel u ma b d oses base d u p o n cli nical j u d g me nt a n d prese nce/se ver it y of pri or i nf usi o n reacti o n. T his re gi me n ma y be m o difie d base d o n l ocal 
treat me nt sta n dar ds a n d g ui deli nes as a p pr o priate pr o vi de d it d oes n ot i ncl u de s yste mic c ortic oster oi ds.
b b. A vel u ma b a d mi nistrati o n: A vel u ma b w ill be gi ve n as a 1-h o ur i nf usi o n e ver y 2 wee ks ( 1 4 da ys). T he bi w ee kl y, 1 4 -d a y  treat me nt 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.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
T a ble 2
Sc he d ule of Assess me nts – P h ar m ac o ki netic a n d A nti dr u g A nti b o d y S a m pli n g
Tre at m e nt Peri o d (-3/ + 1 d a ys)
1 C ycle = 1 4 D a ys
F oll o w -u p
Visits
C ycle 1 
( Wee k 1)
C ycle 2 
( Wee k 3)
C ycle 3 
( Wee k 5)
C ycle 5 
( Wee k 9)
C ycle 7 
( Wee k 1 3)
C ycle 8 
( Wee k 1 5)
C ycle 1 3
( Wee k 2 5)
C ycle 1 9
( Wee k 3 7)
C ycle 2 5
( Wee k 4 9) 
a n d E ver y 
6 C ycles 
T here after
E O T/
Wit h dr a w al
Visit
( Wit hi n 7 D a ys of 
Decisi o n t o 
Disc o nti n ue)
3 0 -D a y
S afet y F oll o w -
u p
( ± 5 D a ys)
First 3 6 s u bjects: P K bl o o d 
sa m ples i n s u bjects < 1 0 k g at 
Baseli ne a, b
Pre d ose, E OI, 
a n d 
4 8 -9 6 h
Pre d ose
Pre d ose a n d 
E OI
Pre d ose
Pre d ose 
a n d E OI
Pre d ose 
Pre d ose 
Pre d ose
a n d E OI
Pre d ose
X
X
First 3 6 s u bjects: P K bl o o d 
sa m ples i n s u bjects ≥1 0 k g at 
Baseli ne a, b
Pre d ose,
E OI,
3 h, a n d
4 8 -9 6 h
Pre d ose
Pre d ose a n d 
E OI
Pre d ose
Pre d ose a n d 
E OI 
Pre d ose 
Pre d ose
a n d E OI
Pre d ose a n d 
E OI
Pre d ose
X
X
P K bl o o d sa m ples i n s u bjects 
be y o n d t he first 3 6 a, b
Pre d ose
a n d E OI
Pre d ose
Pre d ose a n d 
E OI
Pre d ose
Pre d ose 
a n d E OI
Pre d ose 
Pre d ose 
Pre d ose
a n d E OI
Pre d ose
X
X
Bl o o d sa m ples f or A D A 
(i m m u n o ge nicit y) testi n gc
Pre d ose 
Pre d ose 
Pre d ose 
Pre d ose 
Pre d ose
—
Pre d ose 
Pre d ose 
Pre d ose
X
X
A D A: a nti dr u g a nti b o dies; E OI: e n d of i nf usi o n; E O T: E n d of Treat me nt; P K: p har mac o ki netic(s).
a.
Pre d ose bl o o d sa m ples f or P K deter mi nati o ns will be c ollecte d fr o m all s u bjects wit hi n 2 h o urs pri or t o trial treat me nt i nf us i on. P K , A D A , a n d bi o mar ker s a mples c ollecte d at t he sa me pre d ose ti me p oi nt ca n be use d i nterc ha n gea bl y if 
t he de dicate d sa m ple has i ns ufficie nt q ua ntit y, as t he s u bject’s pare nt(s)/ g uar dia n(s) will ha ve c o nse nte d t o all c ollecti o ns a n d tests. P K sa m pli n g ca n be a dj uste d base d o n t he P K data o btai ne d fr o m t he first 3 s u bjects.
b.
P ost d ose sa m ples f or P K a n al ysis will be c ollecte d at E OI a n d at t he s u bse q ue nt ti mes i n dicate d. T he ti me p oi nt wi n d o w f or t he E OI a n d 3 -h o ur sa m ples is ± 3 0 mi n utes. A d diti o nal P K sa m ples will be c ollecte d d ur i n g t he 
E O T/ Wit h dra wal Visit a n d at t he 3 0- da y Safet y F oll o w -u p Visit. P K sa m ples f or a vel u ma b will be c ollecte d fr o m all s u bjects i n P hase I a n d P hase II of t he st u d y . E ver y eff ort s h o ul d be ma de t o c ollect P K s a m ples as cl ose t o t he 
pr ot oc ol -prescri be d t i me p oi nt as p ossi ble, a n d t o rec or d t he e xact ti me i n s o urce d oc u me nt. Pr ot oc ol de viati o ns will be ca pt ure d if sa m ples are n ot c ollecte d, or if sa m ple c ollecti o n ti mes are n ot rec or de d. 
c.
Bl o o d sa m ples f or A D A a nal ysis will be c ollecte d wit hi n 2 h o urs pri or t o t he first, sec o n d, t hir d, fift h, a n d se ve nt h d oses of a vel u ma b ( C ycles 1, 2, 3, 5, a n d 7) a n d t he n e ver y 1 2 wee ks ( 6 c ycles) t hereafter w hile o n treat me nt. 
A d diti o nal sa m ples f or A D A a nal ysis will be c ollecte d d uri n g t he E O T/ Wit h dra wal Visit a n d t he 3 0 -da y Safet y F oll o w -u p Visit. P K , A D A , a n d bi o mar ker s a mples c ollecte d at t he sa me ti me p oi nt ca n be use d i nterc ha n gea bl y if t he 
de dicate d sa m ple has i ns ufficie nt q ua ntit y, as t he s u bject’s pare nt(s)/ g uar dia n(s) will ha ve c o nse nte d t o all c ollecti o ns a n d tests. 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
2
S p o ns or, I n vesti g at ors , a n d Tri al A d mi nistr ati ve Str uct ure
T he S p o ns or of t his cli nical trial wit h a vel u ma b is E M D Ser o n o Researc h & De vel o p me nt 
I nstit ute, I nc. ( E M D Ser o n o R & D), Billerica, M A, i n t he U nite d States of A merica ( U S A), a n d 
Merc k K Ga A, Dar msta dt, Ger ma n y, o utsi de t he U S A.
A c o ntract researc h or ga nizati o n ( C R O), 
 will u n derta ke t he 
o per ati o nal as pects of t his st u d y. Details of s uc h str uct ures a n d ass ociate d pr oce d ures will be 
defi ne d i n a se parate I ntegrate d Pr oject Ma na ge me nt Pla n mai ntai ne d b y Q ui ntiles I M S. T he 
I nte grate d Pr oject Ma na ge me nt 
Pla n will be pre pare d b y  the Q ui ntiles I M S Cli nical Pr oject 
Ma na ger i n c o o perati o n wit h ot her Q ui ntiles I MS O perati o nal Tea m Lea ds. 
T he C o or di nati n g I n vesti gat or, 
 
, re prese nts all I nvesti gat ors f or decisi o ns a n d disc ussi o ns re gar di n g t his trial, 
c o nsiste nt wit h t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 G o o d Cli n ical 
Practice ( 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 nvesti gat or will pr o vi de 
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 dice s.
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries: E U Cli nical Trials Re gister, 
htt ps:// w w w.cli nicaltrialsre gister.e u/
(re gistrati o n 
n u m ber 
2 0 1 7 -0 0 2 9 8 5 -2 8 ) 
a n d 
Cli nical Trials. g o v ( U S A), htt ps://cli nicaltrials. g o v/ (re gistrati o n n u m ber t o c o me).
2. 1
I n vesti g ati o n al Sites
T he st u d y will be c o n d ucte d i n a p pr o xi matel y 5 0 sites i n N ort h A merica, E ur o pe, Mi d dle East, 
S o ut h A merica , a n d Asia Pacific, i ncl u di n g a p pr o xi matel y 1 0 sites i n t he U SA .
2. 2
St u d y C o or di n ati o n / M o nit ori n g
T he S p o ns or will c o or di nate t he st u d y an d will utilize t he s u p p ort of 1 or m ore C R Os f or s o me 
acti vities of t he st u d y. T he S p o ns or will perf or m o versi g ht of t he acti vities perf or me d b y  the C R Os.
T he Cli nical St u d y  Su p plies de part me nt of t he S p o ns or will s u p pl y th e st u d y me dicati o n of 
a vel u ma b. Cli nical s u p pl y is perf or me d b y t he Cli nical Trial S u p pl y f u ncti o n of t he S p o ns or.
S u bject e nr oll me nt will be ma na ge d b y  a n i nteracti ve res p o nse tec h n ol o g y (I R T) s yste m. Safet y 
la b orat or y assess me nts will be perf or me d l ocall y. Res ults fr o m t hese l ocal la b orat ories will be 
rec or de d acc or di n g t o t he electr o nic case re p ort f or m ( e C R F) c o m pleti o n g ui deli nes .
P har mac o ki netic ( P K), 
, i m m u n o ge nicity, a n d 
 will 
be perf or me d ce ntrall y u n der t he res p o nsi bilit y  a n d/or s u per visi o n of t he S p o ns or. 
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI
C CI
C CI
P P D
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
T he Gl o bal Dr u g Safet y De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y, or t heir desi g nate d 
re prese ntati ves will s u per vise dr u g safety a n d t he ti mel y re p o rti n g of a d verse e ve nts ( A Es) a n d 
seri o us a d verse e ve nts ( S A Es).
Q ualit y  ass ura nce of t he st u d y c o n d uct will be perf or me d b y t he De vel o p me nt Q ualit y Ass ura nce 
De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y.
T he D e part me nt of Gl o bal Bi ostatistics will s u per vise t he statistical a nal yses, w hic h will be 
o uts o urce d t o Q ui ntilesI M S.
2. 3
S afet y M o nit ori n g C o m mittee
A Safet y M o nit ori n g C o m mittee ( S M C) will re vie w t he safet y a n d a vaila ble P K data o n a re g ular 
basis. T he S M C will c o nsist of per ma ne nt me m bers fr o m t he S p o ns o r ( Gl o bal Dr u g Safet y  Pr o d uct 
Lea der, Me dical Res p o nsi ble, Cli nical P har mac ol o gist , a n d Bi ostatisticia n) a n d/ or C R O (Earl y 
Cli nical 
De vel o p me nt 
Lea d, 
Me dical 
Lea d, 
Bi ostatisticia n, 
a n d Gl o bal 
Dr u g 
Safet y 
Re prese ntati ve ), t he partici pati n g I n vesti gat or(s) (f or P hase I-rec o m me n de d P hase II d ose [R P 2 D ]
p orti o n o nl y ), a n d ot her o pti o nal me m bers wit h e x pertise i n t he ma na ge me nt of pe diatric ca ncer 
s u bjects. A d h oc me m bers ma y  be i n vite d as nee de d . M ore details will be descri be d i n t he S M C 
C harter .
T he S M C will deci de o n rele va nt d ose -li miti n g t o xicities ( D LTs ) f or pr ot oc ol criteria a n d will 
deci de b y  co nse ns us o n d ose escalati o n, d ose d e -escalati o n, s us pe nsi o n of e nr oll me nt, a n d/ or 
declarati o n of t he ma xi m u m t olerate d d ose ( M T D) a n d/ or R P 2 D , 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. I n a d diti o n, t he S M C ma y deci de t o st u d y a s pecific c o h ort.
T he S M C m a y  mo 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. T he s pecific w or ki n g pr oce d ur es 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.
3
B ac k gr o u n d I nf or m ati o n
3. 1
Pr o gr a m me d Cell De at h a n d Li g a n ds
T he pr o gra m me d deat h 1 ( P D -1) rece pt or a n d P D -1 li ga n ds 1 a n d 2 ( P D -L 1 , P D-L 2 ) pla y i nte gral
r oles i n i m m u ne re g ulati on. E x presse d o n acti vate d T cells, P D - 1 is acti vate d b y  PD- L 1 a n d P D -L 2  
e x presse d b y  str o mal cells, t u m or cells, or b ot h, i nitiati n g T- cell deat h a n d l ocalize d i m m u ne 
s u p pressi o n (D o n g 1 9 9 9 ; Free ma n 2 0 0 0; D o n g 2 0 0 2 ; T o palia n 2 0 1 2a) a n d p ote ntiall y  pr o vi di n g 
a n i m m u ne-t olera nt e n vir o n me nt f or t u m or de vel o p me nt a n d gr o wt h. C o n versel y, i n hi biti o n of 
t his i nteracti o n ca n e n ha nce l ocal T- cell res p o nses a n d me diate a ntit u m or acti vit y in n o ncli nical 
a ni mal m o dels 
(D o n g 
2 0 0 2;
I wai 2 0 0 2 ). T he 
P D -L 1 
m ol ec ule is e x presse d as a n 
i m m u ne-i n hi bit or y c hec k p oi nt o n e pit helial a n d vasc ular e n d ot helial cells, as well as by a n u m ber 
of i m m u ne cells, a n d is e m pl o y e d b y t u m or cells as i m m u ne esca pe mec ha nis m.
A ge nts tar geti n g P D -L 1, P D - 1, a n d relate d m olec ules are collecti vel y  referre d t o as i m m u ne 
c hec k p oi nt i n hi bit ors (ICI s). Cli nical acti vit y of I CIs, i ncl u di n g a vel u ma b, has bee n o bser ve d i n 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
mela n o ma, n o n -s mall cell l u n g ca ncer (N S C L C) , ur ot helial cell carci n o ma, re nal cell carci n o ma, 
o varia n ca ncer, Mer kel cell c arci n o ma ( M C C), a n d H o d g ki n’s ly m p h o ma, a m o n g ot hers. 
I n t he cli nical setti n g, treat me nt wit h a nti b o dies t hat bl oc k t he P D - 1 – P D -L 1 i nteracti o n ha ve bee n 
re p orte d t o pr o d uce o bjecti ve res p o nse rates ( O R Rs) of 7 % t o 3 8 % i n s u bjects wit h a d va nce d or 
metast atic s oli d t u m ors, wit h t olera ble safety pr ofiles (Bra h mer 2 0 1 2; T o palia n 2 0 1 2 b; Ha mi d 
2 0 1 3 ). N ota bl y, res p o nses a p peare d pr ol o n g e d, wit h d urati o ns of 1 ye ar or m ore f or t he maj orit y 
of s u bjects.
Se veral st u dies wit h c hec k p oi nt i n hi bit ors i n pe diatric patie nts wit h ca ncer are c urre ntl y o n g oi n g. 
I n a pe diatric st u d y of i pili m u ma b, n o u ne x pecte d safety fi n di n gs were n ote d, a n d earl y si g ns of 
cli nical acti vity were see n i n pe diatric patie nts wit h ca ncer (Merc ha nt 2 0 1 6 ). A P hase II st u d y of 
ni v ol u ma b s h o we d n o o bjecti ve res p o nses i n patie nts wit h rela pse d/refract or y oste osarc o ma, 
E wi n g s arc o ma, a n d r ha b d o m yo sarc o ma; P hase I data i n rela pse d/refract or y s oli d t u m ors was n ot 
re p orte d (Da vis 2 0 1 7 ). A P hase I/II st u d y of pe m br oliz u ma b i n pe diatric patie nts wit h a d va nce d 
mela n o ma or P D -L 1 + a d va nce d, rela pse d, or refract or y soli d t um ors or l ym p h o mas s h o we d l o w 
t o xicit y a n d d ura ble a ntit u m or acti vit y i n vari o us t u m or t ypes, s pecificall y H o d g ki n ’s l ym p h o ma, 
mes ot heli o ma, 
mali g na nt 
ga n gli o gli o ma, l ym p h oe pit helial 
carci n o ma, a n d a dre n oc ortical 
carci n o ma (Ge oer ger
2 0 1 7a ). T he i M A T RI X-Atez oliz u ma b st u d y exa mi ne d atez oliz u ma b i n 
pe diatric a n d y o u n g a d ult patie nts wit h refract or y/rela pse d s oli d t u m ors (Ge oer ger
2 0 1 7 b) .
Preli mi nar y  anti -t u m or acti vit y was see n i n H o d g ki n ’s l ym p h o ma
a n d i n si n gle patie nts wit h 
E wi n g sarc o ma a n d at y p ical mali g na nt r ha b d oi d t u m or. T he p h ar mac o ki netic a n d safet y pr ofiles 
f or all dr u gs were si milar i n c hil dre n as i n a d ults. P D-L 1  e x pressi o n was varia ble acr oss pe diatric 
s oli d t u m ors s u bt ypes .
3. 2
A vel u m a b
T he I n vesti gati o nal Me dici nal 
Pr o d uct (IM P) 
f or t his trial is a vel u ma b , t he I nter nati o nal 
N o n pr o prietar y  Na me f or t he S p o ns or’s a nti-P D -L 1 m o n ocl o nal 
a nti b o d y 
MS B 0 0 1 0 7 1 8 C . 
A vel u ma b is bei n g de velo pe d i n o nc ol o gical setti n gs b y M erc k K Ga A, Dar msta dt, Ger ma n y, a n d 
b y  its s u bsi diar y, E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc., Billerica, M A, U S A.
A vel u ma b is a f ully h u ma n i m m u n o gl o b uli n G 1 (I gG 1) m o n ocl o nal a nti b o d y t hat selecti vely bi n ds 
t o P D -L 1  an d c o m petiti vel y bl oc ks its i nteracti o n wit h P D - 1. C o m pare d wit h a nti-P D - 1 a nti b o dies 
t hat tar get T- cells, a vel u ma b tar gets t u m or cells. T heref ore , it is h y p ot hesize d t o ha ve fe wer si de 
effects, i ncl u di n g a l o wer ris k of a ut oi m m u ne -relate d safety iss ues, as bl oc k a de of P D -L 1  lea ves 
t he P D -L 2 /P D - 1 pat h wa y  intact t o pr o m ote peri p heral self -t olera nce (Latc h ma n 2 0 0 1 ). F or 
c o m plete details of t he i n vitr o a n d n o ncli nical st u dies, refer t o t he c urre nt I n vesti gat or’s
Br oc h ure (IB) .
A vel u ma b is c urre ntl y u n der e val uati o n i n se veral P hase I, II, a n d III st u dies i n vari o us t u m or 
i n dicati o ns i n t he a d ult s u bject p o p ulati o n, i ncl u di n g N S C L C, gastric ca ncer, M C C , re nal cell 
carci n o ma, ur ot helial ca ncer, a n d o varia n ca ncer. I n Marc h 
2 0 1 7, t he U S F o o d a n d Dr u g 
A d mi nistrati o n gra nte d accelerate d a p pr o val t o a vel u ma b f or t he treat me nt of patie nts 1 2 ye ars of 
a ge a n d ol der wit h metastatic M C C.
I n Ma y 20 1 7, t he i n dicati o n was e xte n de d via accelerate d 
a p pr o val t o i ncl u de patie nts w it h l ocally a d va nce d or metastatic ur ot helial carci n o ma, w h o ha ve 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
disease pr o gressi o n d uri n g or f oll o wi n g plati n u m -c o ntai ni n g c he m ot hera p y or wit hi n 1 2 m o nt hs 
of ne oa dj u va nt or a dj u va nt treat me nt wit h plati n u m- c o ntai ni n g c he m ot hera p y ( Ba ve ncio 2 0 1 7) .
M ore t ha n 3, 7 2 0 s u bjects ha ve bee n treate d wit h a vel u ma b t o date. I n t he d ose-escalati o n p orti o n 
of t he P hase I st u d y, t here was n o e vi de nce of differe nces i n t he safet y pr ofile acr oss all 
a d mi nistere d d ose le vels fr o m 1 m g/ k g t o 2 0 m g/ k g. T he M T D was n ot reac he d. 
T he rec o m me n de d P hase II/III d ose i n a d ults was deter mi ne d t o be 1 0 m g/ k g 
a vel u ma b 
a d mi nistere d i ntra ve ne o usl y e ver y 2 wee ks. A vel u ma b treat me nt is c o nti n ue d u ntil c o nfir me d 
pr o gressi o n, deat h , u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal occ urs . Pr o misi n g 
cli nical acti vit y was o bser ve d i n se veral t u m or t ypes i n a d ults. Refer t o t he m ost rece nt versi o n of 
t he I B f or u p date d i nf or mati o n re gar di n g c urre nt cli nical st u dies wit h a vel u ma b. 
3. 3
R ati o n ale f or t he C urre nt Cli nic al Tri al a n d O ver all Be nefit 
a n d Ris k C o nsi der ati 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, I CH G C P, a n d 
an y  a d diti o nal a p plica ble re g ulat or y re q uire me nts.
Base d o n t he a vaila ble n o ncli nical a n d cli nical data t o date (i ncl u di n g m o deli n g a n d si m ulati o n 
res ults usi n g a d ult P K data fr o m o n g oi n g a vel u ma b st u dies), t he c o n d uct of t he trial s pecifie d i n 
t his pr ot oc ol is c o nsi dere d j ustifia ble.
Refer t o t he I B f or f urt her i nf or mati o n a b o ut t he n o ncli nical a n d cli nical pr o gra ms a n d g ui da nce 
f or t he I n vesti gat or.
R ati o n ale f or t he C urre nt Cli nic al Tri al
Base d o n t he s uccess of c hec k p oi nt i n hi bit or t hera pies i n a d ult t um ors, t here is a rati o nale t o 
e x pl ore t heir acti vit y in pe diatric mali g n a ncies. Pe diatric t u m ors a p pear t o bear t he sa me hall mar ks 
of se nsiti vit y to I CIs, na mel y  the prese nce of i m m u ne cell i nfiltrates, e x pressi o n of P D -L 1  in t u m or 
a n d/ or i nfiltrati n g i m m u ne cells (Ge oer ger , 2 0 1 7a; Ge oer ger , 2 0 1 7 b) a n d hi g h m utati o n b ur de n i n 
s o me cases (Mara belle 2 0 1 5 ). T he pe diatric patie nt p o p ulati o n i n t he P hase I part of t his st u d y will 
i ncl u de s u bjects wit h c o m m o n pe diatric t u m ors, s uc h as ne ur o blast o ma a n d sarc o mas, as well as 
rarer t u m ors occ urri n g i n s u bjects d uri n g c hil d h o o d. M ost 
pe diatric t u m ors s hare se veral 
c haracteristics: t he y are pre d o mi na ntl y  of e m br yo nal ori gi n, ha ve pea k i nci de nce i n c hil d h o o d a n d 
a d olesce nce, a n d ha ve well -esta blis he d g ui deli nes f or t heir dia g n osis a n d ma na ge me nt i n t he first -
a n d sec o n d-li ne setti n gs. I n c o ntrast, t u m ors occ urri n g i n a d ults are ge nerall y  carci n o mas, w hic h 
are e xtre mel y rare i n c hil dre n. T hese t u m ors are m ostl y  of e pit helial ori gi n, a n d t heir i nci de nce 
rises wit h a ge, us uall y starti n g i n t he t hir d deca de of life. Dia g n osis a n d ma na ge me nt of t hese 
t u m ors are us uall y e xtra p olate d fr o m a d ult data. Treat me nt of t hese t u m ors wit h I CIs ha ve bee n 
st u die d e xte nsi vel y i n a d ults, b ut ver y little data are a vaila ble i n c hil dre n (Da vis 2 0 1 7 ; Ge oer ger , 
2 0 1 7a; Ge oer ge r, 2 0 1 7 b).
Base d o n t he acce pta ble safety a n d e nc o ura gi n g efficac y data of a vel u ma b i n a d ults, a n d t he 
precli nical rati o nale s u p p orti n g t he r ole of t he i m m u ne s yste m i n t he pat h o ge nesis of pe diatric 
mali g na ncies (Mara belle 2 0 1 5 ), a vel u ma b will be e val uate d i n a br oa d p o p ulati o n of pe diatric 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
patie nts wit h t u m ors. At t he prese nt ti me, there is n o vali date d patie nt selecti o n strate g y in pe diatric 
ca ncers. I n t he P hase I part of t he st u d y, t he ai ms are t o defi ne t he R P2 D a n d assess t he safet y a n d 
t olera bilit y of a vel u ma b. T he P hase II part of t he st u d y is desi g ne d t o e na ble a f or mal statistical 
assess me nt a n d c haracterizati o n of t he a ntit u m or acti vit y of a vel u ma b as deter mi ne d b y t he O R R, 
a n d a r o b ust statistical desi g n t o all o w f or clear c o ncl usi o ns t o be dra w n re gar di n g t he be nefit of 
treat me nt wit h a vel u ma b i n pe diatric patie nts wit h s pecifie d t u m or ty pes.
O ver all B e nefit a n d Ris k C o nsi der ati o ns
T he ris k-be nefit relati o ns hi p has bee n caref ull y co nsi dere d i n t he pla n ni n g of t he trial. Base d o n 
t he a vaila ble n o ncli nical a n d cli nical i nf or mati o n t o date, a vel u ma b pr o vi des a p ositi ve be nefit -ris k 
stat us wit h s oli d t u m ors, a n d t he c o n d uct of t he trial is c o nsi dere d j ustifia ble usi n g t he d ose a n d 
d ose re gi me n of a vel u ma b as s pecifie d i n t his cli nical trial pr ot oc ol. 
S pecific ris ks ass ociate d wit h t he use of a vel u ma b as a m o n ocl o n al a nti b o d y ha ve bee n o bser ve d. 
T he pri mar y  ris ks of e x p os ure t o a vel u ma b i ncl u de i nf usi o n-relate d reacti o ns (IR Rs) a n d i m m u ne-
relate d A Es 
(ir A Es). Pre me dicati o n wit h 
a n a ntihista mi ne ( H 1 rece pt or bl oc ker
s uc h as 
di p he n h y dra mi ne ) a n d wit h aceta mi n o p he n ( paraceta m ol) a p pr o xi matel y 30 t o 6 0 mi n utes pri or t o
eac h d ose, o nce e ver y 2 wee ks f or t he first 4 i nf usi o ns is ma n dat or y . T his re gi me n ma y  be m o difie d 
base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes, as a p pr o priate.
4
Tri al O bjecti ves
4. 1
Pri m ar y O bjecti ve s
P h ase I

T o e val uate t he safet y a n d t olera bilit y of a vel u ma b

T o deter mi ne t he R P 2 D of a vel u ma b i n pe diatric s u bjects 0 t o < 1 8 ye ars of a ge wit h s oli d 
t u m ors a n d l ym p h o ma
P h ase II

T o assess a ntit u m or acti vit y of a vel u ma b b y  deter mi n i n g t he O R R acc or di n g t o R E CI S T 1. 1 
a n d as a dj u dicate d b y  the I n vesti gat or i n 2 e x pa nsi o n c o h orts i n s pecifie d t u m or t ypes i n 
pe diatric s u bjects treate d wit h a vel u ma b
4. 2
Se c o n d ar y O bjecti ves
P h ase I

T o assess a ntit u m or acti vit y of a vel u ma b b y  deter mi ni n g t he O R R acc or di n g t o R E CI S T 1. 1 
a n d as a dj u dicate d b y  the In vesti gat or i n pe diatric s u bjects wit h s oli d t u m ors a n d l ym p h o ma 
treate d wit h a vel u ma b 

T o assess pr o gressi o n -free s ur vi val ( P F S) base d o n I n vesti gat or assess me nts, d urati o n of 
res p o nse ( D O R), ti me t o res p o n d ( T T R), a n d o verall s ur vi val ( O S)

T o c haracterize t he P K of a vel u ma b

T o assess t he i m m u n o ge nicit y  of a vel u ma b
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7

T o e val uate P D -L 1 e x pressi o n; t u m or -i nfiltrati n g T-cell acti vit y; T-cell p o p ulati o n; a n d T -cell, 
B- cell, a n d N K -cell n u m bers i n t u m or tiss ue at Baseli ne a n d at c o nfir me d pr o gressi o n (if t u m or 
tiss ue is o btai ne d)

T o meas ure c ha n ges i n vacci nati o n -relate d a nti b o d y co nce ntrati o ns ( di p ht heria, teta n us, a n d 
p ne u m oc occal c o nj u gate)
5
I n vesti g ati o n al Pl a n
5. 1
O ver all Tri al Desi g n a n d Pl a n
T his is a m ultice nter, o pe n -la bel, i nter nati o nal, P hase I/II st u d y to e val uate t he d ose, safet y an d 
t olera bilit y, a ntit u m or acti vit y, P K, a n d p har mac o d yna mics of a vel u ma b i n pe diatric s u bjects 0 t o 
< 1 8 ye ars of a ge wit h refract or y or rela pse d mali g na nt s oli d t u m ors (i ncl u di n g ce ntral ner v o us 
s yste m t u m ors) a n d ly m p h o ma f or w hic h n o sta n dar d t hera p y is a vaila ble or f or w hic h t he s u bject 
is n ot eli gi ble f or t he e xisti n g t hera py.
T he st u d y will c o nsist of 2 p arts: t he d ose -fi n di n g p art ( P hase I) a n d t he t u m or-s pecifie d e x pa nsi o n 
p art ( Phase II). D uri n g P hase I, t he R P 2 D of a vel u ma b i n c hil dre n will be deter mi ne d. D uri n g 
P hase II, 2 e x pa nsi o n c o h orts will be e nr olle d, wit h s pecific t u m ors c h ose n base d o n a vaila ble data 
fr o m t he P hase I part of t he st u d y, o n g oi n g st u dies wit h a vel u ma b a n d ot her I CIs, cli nical a n d 
n o ncli nical c he m ot hera p y  c o m bi nati o n data, a n d a n y p u blis he d literat ure.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
O ver all Desi g n
Pla n ne d n u m ber of s u bjects:

P hase I : 1 2 t o 3 6 s u bjects

P hase II: 4 6 t o 1 1 2 s u bjects ( 2 3 t o 5 6 s u bjects per t u m or t y pe) f or 2 c o h orts
T he trial desi g n sc he matic is prese nte d i n Fi g ure 1.
Fi g ure 1
Sc he m atic of t he Tri al Desi g n
      R P 2 D: r e c o m m e n d e d P h a s e II d o s e; T B D: t o b e d et er mi n e d.
P h ase I St u d y Desi g n
I n t he d ose -fi n di n g part of t he st u d y, su bjects will be e nr olle d i n se q ue ntial c o h orts of 3 t o 
6 s u bjects eac h; t he first 3 s u bjects will be ≥1 ye ar ol d. At least 1 2 s u bjects m ust be e val ua ble f or 
t he pri mar y  anal y sis. P hase I will be c o m plete d w he n at least 1 2 D L T- e val ua ble s u bjects ha ve 
bee n treate d at a d os e le vel c o nfir me d t o be safe. P hase II will t he n be gi n.
T he starti n g d ose will be t he sa me as rec o m me n de d d ose i n a d ults, 1 0 m g/ k g a vel u ma b 
a d mi nistere d i ntra ve n o usl y (i v) o nce e ver y 2 wee ks, w hic h is base d o n m o deli n g a n d si m ulati o n 
res ults usi n g a d ult P K data fr o m o n g oi n g a vel u ma b st u dies as descri be d i n Secti o n 5. 2 . A vel u ma b 
will be a d mi nistere d u ntil c o nfir me d pr o gressi o n , deat h , u nacce pta ble t o xicit y, or a ny criteri o n f or 
wit h dra wal occ urs . I n Phase I , t he D L T o bser vati o n peri o d is defi ne d as a 2 8 -d a y  peri o d ( 2 c ycles) 
be gi n ni n g wit h t he first a vel u ma b a d mi nistrati o n.
P h a s e I
P h a s e II
A v el u m a b si n gl e -
a g e nt d o s e 
e s c al ati o n
n = 1 2 -3 6
     R P 2 D
T u m or t yp e A
( T B D)
n = 2 3 -5 6
T u m or t yp e B
( T B D)
n = 2 3 -5 6
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
T he first c o h ort of 3 t o 6 s u bjects will be e nr olle d at t he starti n g d ose le vel of 1 0 m g/ k g ( D L 1). 
Base d o n t he n u m ber of s u bjects e x perie nci n g D L Ts at t he c o m pleti o n of t he first c o h ort, t he d ose 
f or t he ne xt c o h ort of s u bjects ca n be ke pt t he sa me or m o difie d. 

If D L 1 is c o nfir me d as safe, t his d ose will be selecte d as R P 2 D if it pr o vi des a de q uate e x p os ure 
i n c hil dre n c o m pare d wit h a d ults.

If e x p os ure is n ot a de q uate ( w he n c o m pare d wit h a d ult p o p ulati o n P K [ Po p P K ]-si m ulate d 
val ues f or me dia n a n d dis tri b uti o n of e x p os ure [ Cma x , A U C, a n d C tr o u g h]), a decisi o n ca n b e 
ma de t o escalate t o a d ose le vel u p t o 2 0 m g/ k g ( D L2) . 

If at a n y p oi nt t he m o difie d t o xicit y pr o ba bilit y inter val (m T PI ) res ults i n dicate a d ose 
de- escalati o n is warra nte d , t he ne xt s u bjects will be e nr olle d at l o wer d ose le vel of 3 m g / k g 
e ver y 2 wee ks ( D L -1). D ose re -escalati o n ca n be per mitte d base d o n t he m T PI  res ults as l o n g 
as t he c urre nt d ose le vel has n ot bee n deter mi ne d t o ha ve e xcee de d t he M T D.
T he M T D 
esti mate is t he hi g hest d ose teste d of a vel u ma b ass ociate d wit h t he occ urre nce of D L Ts wit hi n 
t he first 2 c ycles of treat me nt i n < 3 3 % of s u bjects, pr o vi de d t hat a hi g her d ose le vel of 
a vel u ma b was teste d a n d ha d a n ass ociate d D L T rate ≥3 3 %.
S u bjects will ret ur n t o t he cli nic at re g ular i nter v als f or assess me nts (see Secti o n  7. 1 a n d Ta ble 1 ). 
A vel u ma b treat me nt will c o nti n ue u ntil:

P D (see Secti o n 5. 5. 1) or deat h

U nacce pta ble t o xicit y

A n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d (see Secti o n 5. 5).
Treat me nt ca n c o nti n ue past t he i nitial deter mi nati o n of c o nfir me d disease pr o gressi o n (see 
Secti o n  6. 2).
S u bjects w h o ha ve e x perie nce d a c o m plete res p o nse ( C R) s h o ul d be treate d f or a mi ni m u m of 
1 2 m o nt hs base d o n cli nical j u d g me nt of b e nefit a n d/ or u ntil c o nfir me d pr o gressi o n per ir R E CI S T
(B o h nsac k 2 0 1 4) , u nacce pta ble t o xicit y, or a n y c riteri o n f or wit h dra wal occ urs , after c o nfir mati o n 
of res p o nse as s pecifie d i n t his pr ot oc ol. I n case a s u bject wit h a c o nfir me d C R rela pses after 
st o p pi n g treat me nt, d uri n g l o n g-ter m f oll o w- u p b ut pri or t o t he E n d of Trial, 1 re-i nitiati o n of 
treat me nt will be 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 Me dical 
M o nit or. 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 treat me nt disc o nti n uati o n of t he i nitial a vel u ma b 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 will 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 nt safety 
la b orat or y res ults m ust be a vaila ble a n d verifie d pri or t o re -i nitiati n g treat me nt. S u bjects w h o re-
i nitiate treat me nt will sta y o n st u d y an d will be treate d a n d m o nit ore d acc or di n g t o t he pr ot oc ol 
a n d t he Sc he d ule of Assess me nts (Ta ble 1 ).
T he pri mar y P hase I e n d p oi nts are:

Occ urre nce a n d se verity of treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) ≥Gra de 3 acc or di n g 
t o N CI -C T C A E v 4. 0 3

D L Ts t o deter mi ne t he R P 2 D
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 11 7
Safet y  en d p oi nts i ncl u de i nci de nce of A Es a n d la b orat or y ab n or malities assesse d t hr o u g h o ut t he 
trial a n d e val uate d usi n g t he 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 nts ( N CI -C T C A E) v 4. 0 3 , a n d vital si g ns.
5. 1. 1. 1. 1
M o difie d T o xicit y Pr o b a bilit y I nter v al
D ose escalati o n/ de -escalati o n r ules will f oll o w t he m T PI met h o d. Briefly, t he m T PI met h o d relies 
o n a statistical pr o ba bilit y al g or it h m t o c o m p ute t he p osteri or pr o ba bilit y  of 3 d osi n g i nter vals t hat 
reflect t he relati ve differe nce bet wee n t he t o xicit y rate of eac h d ose le vel t o t he tar get pr o ba bilit y 
rate ( p T = 0. 3) , usi n g all s u bjects treate d i n pri or a n d c urre nt c o h orts at t he sa me d ose le vel t o 
deter mi ne w het her f ut ure c o h orts s h o ul d i n v ol ve d ose re-escalati o n, n o c ha n ge i n d ose, or d ose 
de- escalati o n. If t he t o xicit y rate of t he c urre nt d ose is far s maller t ha n p T, t he m T PI  will 
reco m me n d escalati n g t he d ose; if t he t o xicit y rate is cl ose t o p T, t he m T PI  will rec o m me n d
c o nti n ui n g at t he c urre nt d ose; a n d if it is far greater t ha n p T, t he m T PI will rec o m me n d de-
escalati o n. Decisi o n r ules are base d o n calc ulati n g u nit pr o ba bilit y  mass of 3 d osi n g i nter vals 
c orres p o n di n g t o u n der, pr o per, a n d o ver d osi n g i n ter ms of t o xicit y . S pecificall y, t he u n der d osi n g 
i nter val is defi ne d as ( 0, p T - e 1), t he o ver d osi n g i nter val as ( p T + e 2, 1) a n d t he pr o per d osi n g 
i nter val as ( p T - e 1, p T + e 2), w her e e 1 a n d e 2 are s mall fracti o ns. Base d o n t he safety pr ofile of 
a vel u ma b, e 1 is preselecte d as 0. 0 5, a n d e 2 is selecte d as 0. 0 3. T heref ore, t he tar get i nter val f or 
t he D L T rate is ( 0. 2 5, 0. 3 3). T he detaile d d ose -fi n di n g r ules base d o n t he m T PI  are ill ustrate d i n 
Ta ble 3 . 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 7
T a ble 3
Det aile d D ose Re -Esc al ati o n/ De -Esc al ati o n Sc he me
N u m ber of S u bjects Tre ate d at C urre nt D ose
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0 
1 1 
1 2
N u m ber of D L Ts
0
N A  
N A
E
E 
E 
E 
E 
E 
E 
E 
E 
E
1
D
S 
S 
S 
S
E 
E 
E 
E 
E 
E 
E
2
D U
D
S 
S 
S 
S 
S 
S 
S 
S
E
3
D U  
D U
D  
D
S 
S 
S 
S 
S 
S
4
D U  
D U  
D U
D  
D
S 
S 
S 
S
5
D U  
D U  
D U  
D U  
D U
D
S 
S
6
D U  
D U  
D U  
D U  
D U  
D U
D
7
D U  
D U  
D U  
D U  
D U  
D U
8
D U  
D U  
D U  
D U  
D U
9
D U  
D U  
D U  
D U
1 0
D U  
D U  
D U
1 1
D U  
D U
1 2
D U
E = Escalate t o t he ne xt hi g her d ose, or if c urre nt d ose le vel is D L 1, sta y o n D L 1. Escalati o n t o D L 2 is all o we d if 
e x p os ure at D L 1 is n ot a de q uate.
S = Sta y at t he c urre nt d ose.
D = De -escalate t o t he ne xt l o wer d ose le vel.
D U = De -escalate t o t he ne xt l o wer d ose le vel; t he c urre nt d ose is u nacce pta bl y t o xic.
Tar gete d D L T rate at M T D = 3 3 %.
As a n e xa m ple, if t he t otal n u m ber of s u bjects treate d at D L 1 is 3, t he n t he f oll o wi n g d osi n g r ules 
will be a p plie d:

0 or 1 D L T 
re mai n at t he sa me d ose le vel (ie, D L 1)

2 D L Ts 
de -escalate t o D L -1 a n d all o w f or p os si ble re-escalati o n t o D L 1

≥3 D L Ts 
de- escalate t o D L - 1, as D L 1 is i nt olera ble.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 1 7
R ules f or d ose fi n di n g usi n g t he m T PI met h o d will be t he f oll o wi n g:

T he tar get e nr oll me nt c o h ort size will be 3 t o 6 s u bjects.

T he first c o h ort will i nitiall y c o m prise 3 s u bjects 1 t o < 1 8 years of a ge at t he ti me of first 
treat me nt d ose at 1 0 m g / k g ( D L 1). U p t o 3 a d diti o nal s u bjects ( 0 t o < 1 8 ye ars of a ge) ca n be 
a d de d if t he first 3 s u bjects e x perie nce 0 or 1 D L T at D L1.

After t he first 3 s u bjects i n t he i nitial c o h ort are treate d wit h D L 1, P K data will be e val uate d 
a n d dr u g e x p os ure i n t hese s u bjects vers us a d ults will be a nal yz e d t o deter mi ne if e x p os ure is 
a de q uate. E x p os ure data are re q uire d bef ore a n y  a d diti o nal s u bjects are d ose d.

I ntra patie nt d ose escalati o n is n ot per mitte d.

After eac h c o h ort, t he n u m ber of D L Ts will be assesse d t o deter mi ne t he d ose le vel f or t he ne x t 
c o h ort usi n g t he m T PI desi g n.

D L Ts will be re vie we d b y  SM C me m bers , a n d t he decisi o n t o o pe n eac h ne w c o hort will be 
ma de b y  t he S M C.

T he sec o n d a n d later c o h orts will be e nr olle d w he n all s u bjects e val ua ble f or D L T at t he c urre nt 
d ose c o h ort ha ve bee n e val uate d f or at least 2 c ycles ( 2 8 da ys), or w he n m ore t ha n 1 s u bject i n 
a c o h ort e x perie nces a D L T, w hic he ver c o mes first. T he ne xt c o h ort will recei ve t he d ose le vel
as assi g ne d if a d ose m o dificati o n is re q uire d .

If D L 1 is c o nfir m e d as safe, t his d ose will be selecte d as R P 2 D if it pr o vi des a de q uate e x p os ure 
i n c hil dre n c o m pare d wit h a d ults. 

A decisi o n ca n be ma de i n a c o h ort defi ne d b y  the S M C t o test a d ose le vel a b o ve 1 0 m g / k g (u p 
t o 2 0 m g/ k g ) if b ot h of t he f oll o wi n g c o n diti o ns are met:

E x p os ure ac hie ve d at 1 0 m g/ k g d oes n ot reac h t hera pe uti c le vels esta blis he d i n a d ults

1 0 m g/ k g was de m o nstrate d t o be safe.

If a s u bject d oes n ot recei ve at least 2 i nf usi o ns of a vel u ma b wit hi n t he D L T o bser vati o n peri o d 
( 2 c ycles = 2 8 d a y s) f or reas o ns ot her t ha n st u d y dr u g-relate d t o xicit y, a n ot her s u bject will be 
e nr olle d t o re place t hat s u bject at t he c urre nt d ose le vel.

A vel u ma b treat me nt will c o nti n ue u ntil:

C o nfir me d P D (see Secti o n  5. 5. 1) or deat h

U nacce pta ble t o xicit y

A n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d (see Secti o n 5. 5).

Treat me nt ca n c o nti n ue past t he i nitial deter mi nati o n of c o nfir me d disease pr o gressi o n per 
ir R E CIS T (see Secti o n  6. 2 ).

P hase I will be c o m plete d w he n at least 1 2 D L T- e val ua ble s u bjects ha ve bee n treate d at a d ose 
le vel c o nfir me d t o be safe a n d si milar e x p os ure t o t hat i n a d ults is ac hie ve d .

A d diti o nal s u bjects ( u p t o 6 per c o h ort) ca n be e nr olle d at a n y do se le vel deter mi ne d t o be bel o w 
t he M T D t o f urt her assess varia bilit y of P K or safet y  b y a ge.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
5. 1. 1. 1. 2
Defi niti o n of D ose -li miti n g T o xicit y
Se verit y  of A Es will be gra de d accor di n g t o N CI -C T C A E versi o n 4. 0 3. F or t he p ur p ose of d ose 
fi n di n g, a n y of t he f oll o wi n g A Es occ urri n g d uri n g t he pri ma r y DL T o bser vati o n peri o d ( 2 8-d a y
peri o d [ 2 treat me nt c ycles] ) t hat are attri b uta ble t o a vel u ma b will be classifie d as D L Ts:
He m at ol o gic:
1.
Gra de 4 ne utr o pe nia of > 7 da y s i n d urati o n
2.
Gra de 3 ne utr o pe nic i nfecti o n
3.
Gra de 3 t hr o m b oc yt o pe nia wit h blee di n g
4.
Gra de 4 t hr o m b oc y t o pe nia > 7 d a y s
5.
Gra de 4 a ne mia.
N o n he m at ol o gic:
1.
A n y  Gra de 3 t o xicit y , e xce pt f or a n y of t he f oll o wi n g:
a.
Tra nsie nt (7 2 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
b.
Tra nsie nt (7 2 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he , na usea, or e mesis t hat 
res ol ves t o Gra de 1 or t o baseli ne
c.
Gra de 3 diarr hea or Gra de 3 s ki n t o xicit y that res ol ves t o Gra de 1 i n less t ha n 7 d a y s after 
me dical ma na ge me nt ( e g, i m m u no s u p pressa nt treat me nt) has bee n i nitiate d
d.
Gra de 3 a m yl ase or li pase a b n or malit y t hat is n ot ass ociate d wit h  cli nical ma nifestati o ns 
of pa ncreatitis
e.
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
f.
Si n gle la b orat or y val ues o ut of n or mal ra n ge t hat are u nli kel y  relate d t o trial treat me nt 
acc or di n g t o t he I n vesti gat or, 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 B aseli ne wit hi n 7 d a y s wit h a de q uate me dical ma na ge me nt.
2.
I na bilit y t o c o m plete at least 2 i nf usi o ns of a vel u ma b d uri n g t he D L T o bser vati o n peri o d d ue 
t o treat me nt-relate d t o xicit y.
W hile t he r ules f or a dj u dicati n g D L Ts i n t he c o nte xt of d ose fi n di n g/ d ose e x pa nsi o n p hases are 
s pecifie d a b o ve, a n A E n ot liste d a b o ve, or a n A E meeti n g t he D L T criteria a b o ve b ut occ urri n g 
o utsi de of t he D L T o bser vati o n peri o d , m a y  be defi ne d as a D L T after c o ns ultati o n bet wee n 
S p o ns or a n d I n vesti gat or, base d o n t he e mer gi n g safet y pr ofile.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 /1 1 7
5. 1. 1. 1. 3
Defi niti o n of M a xi m u m T oler ate d D ose
T he M T D esti mate is t he hi g hest d ose teste d of a vel u ma b ass ociate d wit h t he occ urr e nce of D L Ts 
wit hi n t he first 2 c ycles of treat me nt i n < 3 3 % of s u bjects, pr o vi de d t hat a hi g her d ose le vel of 
a vel u ma b was teste d a n d ha d a n ass ociate d D L T rate ≥3 3 %. If t he D L T rate wit hi n t he first 
2 c ycles of treat me nt is < 3 3 % f or all teste d d ose le vels, t he n t he M T D will n ot ha ve bee n reac he d.
5. 1. 1. 1. 4
Defi niti o n of Rec o m me n de d P h ase II D ose
T he R P 2 D is defi ne d as t he d ose of a vel u ma b c h ose n f or f urt her cli nical de vel o p me nt i n p e diatrics.
P har mac o ki netics, p har mac o d y na mics, safety,  an d a ntit u m or acti vit y data ca n res ult i n selecti o n 
of a n R P 2 D le vel t hat is l o wer or hi g her t ha n t he c urre nt a d ult d osa ge of 1 0 m g/ k g, as l o n g as it 
d oes n ot e xcee d t he M T D.
5. 1. 1. 1. 5
A ge R a n ge f or E ac h C o h ort i n P h ase I
T he st u d y is ai me d at defi ni n g a si n gle R P 2 D i n t he a ge gr o u p of 0 t o < 1 8 years at t he ti me of first 
treat me nt d ose . H o we ver, if at a n y ti me d uri n g t he st u d y, data s u g gest a differe nce i n t olera bilit y 
b y  a ge, t his will be disc usse d wit h t he S M C. T he f oll o wi n g r ules will be use d:

T he i nitial c o h ort will be o pe n t o s u bjects 0 t o < 1 8 ye ars of a ge; t he first 3 s u bjects will be 
≥1 ye ar of a ge .

S u bse q ue nt c o h orts of 3 t o 6 s u bje cts eac h ma y  be o pe n t o s u bjects 0 t o < 1 8 ye ars of a ge or a 
narr o wer a ge ra n ge, base d o n e mer gi n g data, as a gree d o n b y  t he S M C.
5. 1. 1. 1. 6 
E n d of P h ase I
W he n at least 1 2 D L T- e val uable s u bjects ha ve bee n treate d at a d ose le vel c o nfir me d t o be safe, 
e nr oll me nt i n P hase I will be c o m plete a n d P hase II will be gi n.
P h ase II St u d y Desi g n
T he deter mi nati o n of t he R P 2 D i n c hil dre n will tri g ger t he e nr oll me nt of 2 e x pa nsi o n c o h orts. 
S pecific t u m ors will be c h ose n f or t he e x pa nsi o n c o h orts base d o n a vaila ble data fr o m t he P hase I 
part of t he st u d y, o n g oi n g st u dies wit h a vel u ma b a n d ot her I CIs, cli nical a n d n o ncli nical 
c o m bi nati o n c he m ot hera p y data, a n d a n y p u blis he d literat ure. T hese data m a y  incl u de cli nical data 
wit h a vel u ma b or wit h ot her i m m u ne c hec k p oi nt i n hi bit ors, or precli nical data pr o vi di n g a d diti o nal 
rati o nale f or a s pecific t u m or t ype.
Eac h e x pa nsi o n c o h ort will f oll o w Si m o n’s O pti mal T w o -sta ge Desi g n (Si m o n 1 9 8 9 ). If t here are 
2 or m ore
s u bjects wit h c o nfir me d o bjecti ve res p o nse a m o n g t he first 2 3 s u bjects treate d at t he 
R P 2 D, t he n a n a d diti o nal 3 3 s u bjects will be e nr olle d a n d treate d at t hat d ose le vel. If t here is 1 or 
n o s u bjects wit h a c o nfir me d o bjecti ve res p o nse a m o n g t he first 2 3 s u bjects treate d at t he R P 2 D 
wit h a mi ni m u m f oll o w -u p of 1 6 wee ks, t he n t he c o h ort will be cl ose d f or f urt her e nr ol lme nt. 
S u bjects will ret ur n t o t he cli nic at re g ular i nter vals f or assess me nts (see Secti o n  7. 1 a n d Ta ble 1 ). 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
A vel u ma b treat me nt will c o nti n ue u ntil:

C o nfir me d P D (see Secti o n  5. 5. 1 ) or deat h

U nacce pta ble t o xicit y

A n y  criteri o n f or wit h dra wal fr o m t he trial or trial treat me nt is f ulfille d (see Secti o n 5. 5 ).
Tr eat me nt ca n c o nti n ue past t he i nitial deter mi nati o n of c o nfir me d disease pr o gressi o n (see 
Secti o n 6. 2 ).
S u bjects w h o ha ve e x perie nce d a c o m plete res p o nse ( C R) s h o ul d be treate d f or a m i ni m u m of 
1 2 m o nt hs base d o n cli nical j u d gme nt of be nefit a n d/or u ntil c o nfir me d pr o gressi o n per ir R E CIS T , 
u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal occ urs , after c o nfir mati o n of res p o nse as 
s pecifie d i n t his pr ot oc ol. I n case a s u bject wit h a c o nfir me d C R rela pses after st o p pi n g treat me nt, 
d uri n g l o n g-ter m f oll o w-u p b ut pri or t o t he E n d of Trial, 1 re-i nitiati o n of treat me nt will be 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 Me dical M o nit or. 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 that le d t o treat me nt 
disc o nti n uati o n of t he i nitial a vel u ma b t hera p y. Pri or t o r e-i nitiati o n of t he st u d y treat me nt, 
mali g na nt disease will be ra di ol o gically r e-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 nt safet y la b orat or y res ults 
m ust be a vaila ble a n d ver ifie d pri or t o re-i nitiati n g 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 pr ot oc ol a n d t he Sc he d ule of 
Assess me nts (Ta ble 1) .
Eac h su bject will be f oll o we d f or a d diti o nal 1 2 m o nt hs after e n d of treat me nt .
T he pri mar y  Phase II e n d p oi nt is co nfir me d best o verall res p o nse ( B O R) acc or di n g t o R E CI S T 1. 1 .
Safet y  en d p oi nts i ncl u de i nci de nce of A Es a n d la b orat or y ab n or malities assesse d t hr o u g h o ut t he 
trial a n d e val uate d usi n g N CI-C T C A E v 4. 0 3 , a n d vital si g ns.
Tri al Tre at me nt A d mi nistr ati o n a n d Sc he d ule
T he trial Sc he d ule of Assess me nts is prese nte d i n Ta ble 1 , a n d t he Sc he d ule of Assess me nts - P K
a n d A nti dr u g A nti b o d y ( A D A) Sa m pli n g i n Ta ble 2.
S u bjects will recei ve i v i nf usi o ns of a vel u ma b o nce e ver y  2 wee ks. 
T o miti gate i nf usi o n-relate d reacti o ns, pre me dicati o n wit h a nti hista mi ne ( H 1 rece pt or bl oc ker
s uc h as di p he n h y d ra mi ne) a n d aceta mi n o p he n ( paraceta m ol), base d o n l ocal treat me nt sta n dar ds 
a n d g ui deli nes, a p pr o xi matel y 30 t o 6 0 mi n utes pri or t o eac h d ose, o nce e ver y 2 wee ks f or t he first 
4 d ose s of a vel u ma b is ma n dat or y . Pre me dicati o n ca n be a d mi nistere d b e y o n d t he f o urt h d ose of
a vel u ma b base d u p o n cli nical j u d g me nt a n d prese nce/se verit y of pri or i nf usi o n reacti o ns. 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 ,
pr o vi de d it d oes n ot i ncl u de s yste mic c ortic oster oi ds (ster oi d pre me d icati o n s pecifically f or 
a vel u ma b is n ot per mitte d).
T he f or m ulati o n a n d pac ka gi n g i nf or mati o n of a vel u ma b is pr o vi de d i n Secti o n  6.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
St a n d ar d of C a re
N ot a p plica ble.
D ose M o dific ati o n 
a n d 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
D ose M o dific ati o n f or A vel u m a b
T he d ose of a vel u ma b will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d wit hi n 
7 2 h o urs pri or t o t he da y of dr u g a d mi nistrati o n. T he d ose of a vel u ma b use d f or t he pre vi o us 
a d mi nistrati o n ca n be re peate d if t he c ha n ge i n t he s u bject’s wei g ht is wit hi n 1 0 % of t he wei g ht 
use d f or t he last d ose calc ulati o n.
I n P hase I, d ose escalati o n/ de -escalati o n r ules will f oll o w t he m T PI  met h o d (see Secti o n  5. 1. 1. 1. 1 ).
I n P hase II, e ac h s u bject will sta y on t he a vel u ma b R P 2 D d ose u nless treat me nt nee ds t o be 
st o p pe d. T here will be n o d ose re d ucti o ns i n P hase II. D osi n g m o dificati o ns (c ha n ges i n i nf usi o n 
rate) are descri be d i n Secti o n 5. 1. 3. 2 a n d Secti o n  6. 5. 5 .
A d verse Dr u g Re acti o ns Re q uiri n g A vel u m a b Tre at me nt 
Disc o nti n u ati o n or M o dific ati o ns
T he f oll o wi n g a d verse dr u g reacti o ns (A D Rs ; f or defi niti o n, see Secti o n
7. 4. 1. 1 ) re q uire 
per ma ne nt treat me nt disc o nti n uati o n of a vel u ma b:

A n y  Gra de 4 A D R, e xce pt f or t he f oll o wi n g:

Gra de 4 li pase or a m yl ase a b n or malit y t hat is n ot ass ociate d wit h cli nical ma nifestati o ns of 
pa ncreatitis. T he Me dical 
M o nit or 
m ust 
be c o ns ulte d f or s uc h li pase a n d a m yl ase 
a b n or malities.

Gra de 4 ne utr o pe nia of ≤7 da y s i n d urati o n

Gra de 4 t hr o m b oc y t o pe nia wit h o ut blee di n g

Ot her 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 baseli ne wit hi n 7 da y s wit h a de q uate me dical ma na ge me nt.

A n y  Gra de 3 A D R e xce pt f or a n y of t he f oll o wi n g: 

Tra nsie nt ( ≤7 2 h o urs) Gra de 3 fl u-li ke s ym pt o ms or fe ver, w hic h are c o ntr olle d wit h 
me dical ma na ge me nt

Tra nsie nt ( ≤7 2 h o urs) Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, or e mesis t hat 
res ol ve t o Gra de ≤1 or baseli ne wit h a p pr o priate me dical ma na ge me nt

Gra de 3 diarr hea or Gra de 3 s ki n t o xicit y  t hat res ol ves t o Gra de 1 i n less t ha n 7 d a y s after 
me dical ma na ge me nt ( e g, i m m u no s u p pressa nt treat me nt) has bee n i nitiate d

Gra de 3 li pase or a m y lase a b n or malit y t hat is n ot ass ociate d wit h cli nical ma nifestati o ns of 
pa ncreatitis. T he Me dical 
M o nit or 
m ust 
be c o ns ulte d f or s uc h li pase a n d a m yl ase 
a b n or malities.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7

Ot he r si n gle la b orat or y val ues o ut of n or mal ran ge t hat d o n ot ha ve a ny cli nical c orrelate

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 2 A D R s h o ul d be ma na ge d as f oll o ws:

I nf usi o n s h o ul d n ot be gi ve n i n case of o n g oi n g Gra de 2 A D R o n t he da y  of trial treat me nt 
a d mi nistrati o n.

Treat me nt ca n be res u me d acc or di n g t o ori gi nal sc he d u le o nce A D R res ol ves t o Gra de ≤1. 
U p t o 2 s u bse q ue nt st u d y dr u g d oses m a y  be o mitte d. If m ore t ha n 2 d ose s are s ki p pe d, 
treat me nt ma y be res u me d after c o ns ultati o n wit h t he st u d y Me dical M o nit or.
See t he g ui deli nes f or ha n dli n g i nf usi o n-relate d reacti o ns ( Secti o n 6. 5. 5. 1 ),se vere h y perse nsiti vit y  
reacti o ns a n d fl u-li ke sy m pt o ms ( Secti o n 6. 5. 5. 2) , a n d ir A Es ( Secti o n 6. 5. 5. 3 ).
5. 2
Disc ussi o n of Tri al Desi g n
I n t he P hase I d ose -fi n di n g part of t he st u d y, t he R P 2 D i n c hil dre n 0 t o < 1 8 ye ars of a ge will be 
deter mi ne d. I n Phase II, 2 e x pa nsi o n c o h orts will be o pe ne d i n 2 s pecifie d t u m or t ypes selecte d 
base d o n e mer gi n g data fr o m t his a n d ot her o n g oi n g st u dies. T hese data ma y  i ncl u de cli nical data 
wit h a vel u ma b or wit h ot her I CIs, or precli nical data pr o vi di n g a d diti o nal rati onale i n a s pecific 
t u m or t ype.
S u bjects will n ot be selecte d f or e nr oll me nt i n eit her P hase I or P hase II part of t he st u d y  base d o n 
a n y molec ular c haracteristics, s uc h as P D -L 1  ex pressi o n, beca use t he o pti mal strate g y for selecti o n 
of pe diatric s u bjects w h o deri ve ma xi m u m be nefit fr o m a vel u ma b is c urre ntl y u n k n o w n.
Beca use t he be nefit of a vel u ma b i n pe diatric s u bjects wit h ca ncer has n ot yet  bee n esta blis he d, 
eli gibilit y  criteria are ai me d t o e ns ure t hat t he s u bjects ha ve e x ha uste d a vaila ble sta n dar d t hera p y.  
I n ad diti o n, a sta n dar d set of criteria f or a vel u ma b st u dies has bee n i nc or p orate d, s uc h as e xcl usi o n 
of s u bjects pre vi o usl y treate d wit h a n I CI, a bse nce of acti ve a ut oi m m u ne disease t hat ca n be 
e xacer bate d b y a vel u ma b, a n d a de q uate or ga n f u ncti o n.   
J ustific ati o n f or D ose
T he P hase I, d ose -fi n di n g part of t he st u d y will esta blis h t he R P 2 D of a vel u ma b i n pe diatric 
s u bjects. T he starti n g d ose will be t he sa me as t he rec o m me n de d a d ult d osi n g re gi me n , 1 0 m g / k g 
e ver y 2 wee ks. Treat me nt will c o nti n ue u ntil c o nfir me d pr o gressi o n , deat h , u nacce pta ble t o xicit y, 
or a n y criteri o n f or wit h dra wal occ urs . T he a d ult d ose was selecte d as t he starti n g d ose i n t his 
st u d y f or se veral reas o ns, as descri be d bel o w. 
I n a cli nical trial of a d ult ca ncer s u bjects treate d wit h avel u ma b at d oses ra n gi n g fr o m 1 m g/ k g t o 
2 0 m g/ k g ( St u d y E M R 1 0 0 0 7 0 -0 0 1), the M T D was n ot reac he d. A d ose of 1 0 m g/ k g e ver y 2 wee ks 
was c h ose n as t he d ose re gi me n e x pecte d t o ac hie ve > 9 5 % tar get occ u pa nc y i n all s u bjects (refer 
t o Secti o n 5. 2 of t he I B ). 
Si m ulati o n was c o n d ucte d base d o n t he a d ult P o p P K m o del t o fi n d a d ose t hat w o ul d ha ve 
e x p os ure si milar t o t hat o bser ve d i n a d ult p o p ulati o n. First- c ycle P K data s h o we d t hat t he 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
e x p os ure s we re si milar or te n de d t o be l o wer i n s u bjects wit h l o wer b o d y  wei g hts f oll o wi n g 
a d mi nistrati o n of a vel u ma b 1 0 m g/ k g i v e ver y 2 wee ks. I n t he first si m ulati o n, t he cleara nce ( C L) 
wa s ass u me d t o be relate d t o b o d y wei g ht as a p o wer f u ncti o n , wit h e x p o ne nts of 0. 8 5 o n C L a n d 
of 1 o n v ol u me of distri b uti o n ( V) as re p orte d i n t he literat ure (De n g 2 0 1 1 ). A n a lter nati ve m o del 
usi n g esti mate d e x p o ne nt ( 0. 5 6 5 f or C L  an d 0. 4 7 2 f or ce ntral v ol u me) fr o m t he a d ult P o p P K 
m o del ha d bee n als o e x pl ore d. It ha d bee n n ote d t hat all o metric e x p o ne nts esti mate d fr o m data 
wit hi n s pecies (s uc h as a d ult s u bjects) w e re t ypicall y  smaller t ha n t h ose o bser ve d f or bet wee n -
s pecies scali n g, w hic h w a s li kel y due t o a narr o wer b o d y  wei g ht ra n ge i n a d ults f or a gi ve n s pecies 
(a p pr o xi matel y 2- t o 3- f ol d) (Bai 2 0 1 2 ). F or t his reas o ns, t he first si m ulati o n wit h fi xe d e x p o ne nts 
f or C L  (0. 8 5) a n d V ( 1) was c o nsi dere d t o be m ore rele va nt f or a p o p ulati o n li ke c hil dre n wit h a 
wi de ra n ge of b o d y wei g hts. T his m o del pre dicte d t hat 1 0 m g/ k g wa s nee de d t o ac hie ve si milar or 
relati vely l o wer e x p os ure i n c hil dre n t o t hat in a d ult s, a n d 1 5 t o 2 0 m g/ k g d ose w o ul d p ote ntiall y 
lea d t o a hi g her e x p os ure i n c hil dre n t ha n t hat i n t he a d ults. T heref ore , 1 0 m g / k g w a s rec o m me n de d 
f or t he starti n g d ose t o a v oi d p ote ntial overe x p os ure i n s o me of t he b o d y wei g ht gr o u ps.
O n g oi n g 
p e diatric st u dies wit h 
ot her 
P D -L 1 
a nti b o dies
( ni v ol u ma b, pe m br oliz u ma b , 
atez oliz u ma b) were i nitiate d at t he a d ult a p pr o ve d d ose (Brist ol M y ers S q ui b b 2 0 1 3 ; Merc k, S h ar p 
& D o h me 2 0 1 5;
Ge oer ger 2 0 1 7 b ). T his is als o c o nsiste nt wit h rece nt e x perie nce wit h ot her 
tar gete d a ge nts i n pe diatric o nc ol o g y . A 
rece nt st u d y exa mi ne d d ose -fi n di n g st u dies of 
1 5 pre d o mi natel y s mall m olec ular tar gete d a ge nts (Pa oletti 2 0 1 3) . F or 7 5 % of t he c o m p o u n ds, t he 
pe diatric R P 2 D was bet wee n 9 0 % a n d 1 3 0 % of t he a d ult d ose , a n d t he fi n di n gs were si milar t o 
t h ose re p orte d i n a d ults i n ter ms of eit her M T D/ M A D 
or R P 2 D, a n d P K c o ncl usi o ns. T he 
tra diti o nal a p pr oac h of starti n g bel o w t he a d ult d ose res ulte d i n m ore t ha n 6 0 % of c hil dre n bei n g 
u n der d ose d. Of n ote, 3 m o n ocl o nal a nti b o dies were a m o n g t he 1 5 m olec ular tar gete d a ge nts. F or 
all 3, t he pe diatric R P 2 D was t he sa me as i n a d ults (Pa oletti 2 0 1 3 ). Ta ke n t o get her, t hese data 
s u g gest t hat f or bi ol o gics i n ge neral, a n d f or I CIs i n partic ular, selecti o n of t he a d ult d ose as t he 
starti n g d ose i n c hil dre n is a p pr o priate.
Si milarl y , t here is n o e vi de nce t o i n dicate t hat t he a vel u ma b safety pr ofile s h o ul d be differe nt i n 
c hil dre n c o m pare d wit h
a d ults. I n the pe diatric st u dies of i pili m u ma b, pe m br oliz u ma b, 
atez oli u ma b, a n d ni v ol u ma b, t he nat ure a n d ti mi n g of irA Es was si milar t o t hat see n i n a d ults 
(Merc ha nt 2 0 1 6) . T heref ore, t here are li mite d data t o s u g gest t hat c hil dre n are at i ncrease d ris k of 
ir A Es (Da vis 2 0 1 7 ; Ge oer ger , 2 0 1 7a ; Ge oer ger , 2 0 1 7 b) . T he safety of a vel u ma b i n p e diatric 
s u bjects will be c haracterize d usi n g sta n dar d met h o ds (e g, c haracteriz ati o n of A Es, la b orat ory 
a b n or malities, vital si g ns). 
A vel u ma b is c haracterize d b y  2 mai n rec og nize d t ypes of a d verse e ve nts: ir A Es a n d I R Rs (refer
t o I B, Secti o n 5. 3. 1. 3. 1 . 6 a n d Secti o n 5. 3. 1. 3. 1. 7 ). Beca use i n hi biti o n of P D -L 1  sti m ulates t he 
i m m u ne s yste m, i nfla m mat or y reacti o ns c ollecti vel y referre d t o as ir A Es mi g ht occ ur (We ber 
2 0 1 5 ; P ost o w 2 0 1 5 ; Nai d o o 2 0 1 5 ). I mm u ne -relate d A Es are a k n o w n class effect of I CI s a n d ma y 
i ncl u de p ne u m o nitis, c olitis, he patitis, e n d ocri n o pat hies , der matitis, ne p hritis a n d renal 
d y sf u ncti o n, e nce p halitis, e ye  dis or ders (i ncl u di n g u veitis a n d iritis), a n d other i m m u ne- me diate d 
reacti o ns (i ncl u di n g m y ositis a n d m y ocar ditis ). T he maj orit y  of ir A Es ha ve bee n mil d a n d res p o n d 
t o i m m u n os u p pressi ve treat me nt (ie, gl uc oc ortic oi ds) . G ui da nce is pr o vi de d t o I nvesti gat or s t hat 
a n y A E
s us pecte d t o ha ve a n u n derl y i n g i m m u ne-me diate d mec ha nis m , a n d wit h o ut ot her 
c o nfir me d eti ol o g y, s h o ul d be c o nsi dere d i m m u ne relate d a n d ma na ge d acc or di n g t o g ui deli nes 
descri be d i n t he pr ot oc ol. 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 /1 1 7
I n a d diti o n t o ir A Es, t he ot her rec o g nize d t o xicit y of a vel u ma b is I RRs
(refer t o t he I B f or 
a d diti o nal i nf or mati o n). I nf usi o n-relate d reacti o ns fre q ue ntl y occ ur wit h ot her m o n ocl o nal 
a nti b o dies c o m m o nl y use d i n c hil dre n, i ncl u di n g rit u xi ma b a n d i nfli xi ma b. St u dies s u g gest t hat 
t he rate of i nf usi o n reacti o ns is si milar i n a d ults a n d i n c hil dre n, i ncl u di n g c hil dre n ≤5 ye ars ol d
( Dale 2 0 1 4; Aesc hli ma n n 2 0 1 4 ). 
Little is k n o w n a b o ut t he l o n g-ter m effects of c hec k p oi nt i n hi biti o n o n t he de vel o pi n g i m m u ne 
s yste m, alt h o u g h precli nical data s u g gest a r ole f or P D -L 1 i n t he de vel o p me nt a n d f u ncti o n of 
T cells (Fra ncisc o 2 0 0 9 ). Reass uri n gl y, t here were n o c ha n ges i n a bs ol ute l ym p h oc y te c o u nt a n d 
i n fre q ue nc y of i m m u ne-cell s u bsets i n peri p heral bl o o d m o n o n uclear cells o btai ne d fr o m a d ult
ca ncer s u bjects pre - a n d p ost -treat me nt wit h a vel u ma b (Le p o ne 2 0 1 5 ). Gi ve n t he e x pecte d p o or 
s ur vi val of t he s u bject p o p ulati o n t o be e nr olle d o n t his trial, t he p ote ntial be nefit of t hera pe utic 
effect o ut wei g hs t he t he oretical ris k of l o n g-ter m i m m u ne d ysf u ncti o n.
I n su m mar y , base d o n t he wi de t hera pe utic i n de x a n d t he lac k of s pecific safety c o ncer ns i n t he 
pe diatric a ge gr o u p, t he starti n g d ose i n t he d ose -fi n di n g part of t he st u d y was selecte d t o be t he 
a d ult R P 2 D , 1 0 m g/ k g 
e ver y 2 wee ks. Detaile d g ui deli nes o n t he earl y rec o g niti o n a n d 
ma na ge me nt of ir A Es a n d I RRs will be pr o vi de d t o t he I nvesti gat or s, s u bjects, a n d care gi vers. 
R ati o n ale f or P h ase I E n d p oi nt
O ne of t he o bjecti ves of t he P hase I d ose -fi n di n g part of t he st u d y will be t o de ter mi ne R P 2 D of 
a vel u ma b i n pe diatric ca ncer s u bjects 0 t o < 1 8 years of a ge. T he R P 2 D will be c h ose n base d o n 
t he o verall safety pr ofile, P K, a n d p har mac o d y na mics. Deter mi nati o n of t he R P 2 D is c o m m o nl y 
t he pri mar y  objecti ve of d ose -fi n di n g st u dies i n o nc o l o g y, i ncl u di n g pe diatric st u dies 
(D o ussa u 2 0 1 2 ). T he e n d p oi nt c orres p o n di n g t o t his o bjecti ve will be D L Ts t o deter mi ne t he 
R P 2 D.
I ncl usi o n of S peci al P o p ul ati o ns
All s u bjects i n t his st u d y  bel o n g t o a s pecial p o p ulati o n, na mel y chil dre n. See Secti o n  5. 2 f or t he 
rati o nale t o i ncl u de t his p o p ulati o n.
5. 3
Selecti o n of Tri al P o p ul ati o n
O nl y  i n di vi d uals w h o f ulfill all i ncl usi o n criteria wit h o ut matc hi n g a n y e xcl usi o n criteria ma y  b e 
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 bje ct’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’s pare nt(s)/ le gal g uar dia n(s) ha ve 
pr o vi de d writte n i nf or me d c o nse nt a n d t he s u bject has pr o vi de d writte n asse nt ( w he n a ge 
a p pr o priate a n d per l ocal re g ulati o ns) , f oll o wi n g t he pr oce d ure descri be d i n Secti o n 9. 2 .
I ncl usi o n Criteri a
S u bje ct eli gi bilit y sh o ul d be re vie we d a n d d oc u me nte d b y  the I n vesti gat or or dele gate of t he 
I n vesti gat or’s st u dy tea m bef ore s u bjects are i ncl u de d i n t he st u d y.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
F or i ncl usi o n i n t he tr ial, all of t he f oll o wi n g i ncl usi o n criteria m ust be f ulfille d:
1.
Si g ne d writte n i nf or me d c o nse nt f or m (I C F) bef ore a n y trial-relate d pr oce d ure is u n derta ke n 
t hat is n ot part of t he sta n dar d patie nt ma na ge me nt. T he si g ne d I CF i n dicates t hat t he mi n or 
s u bject’s pare nt(s)/le gal g uar dia n(s) ha ve bee n i nf or me d of all perti ne nt as pects of t he st u d y, 
base d o n l ocal re g ulati o ns. S u bjects als o m ust pr o vi de asse nt w he n a ge a p pr o priate a n d per 
l ocal re g ulati o ns.
2.
Male a n d fe male s u bjects 0 t o < 1 8 y ears of a ge at t he ti me of first treat me nt d ose.
3.
A vaila bilit y  of f or mali n-fi xe d paraffi n -e m be d de d ( F F P E) bl oc k c o ntai ni n g t u m or tiss ue or a 
mi ni m u m of 1 0 ( prefera bl y  2 5) u nstai ne d t u m or sli des (c ut wit hi n 1 wee k) s uita ble f or P D-L 1  
e x pressi o n assess me nt, fr o m a rece ntl y o btai ne d ( wit hi n 6 m o nt hs) 
bi o ps y  fr o m a 
n o n- irra diate d area. If tiss ue is u na vaila ble i n bl oc k or sli des, a ma n dat or y t u m or bi o ps y m ust 
be perf or me d pri or t o a vel u ma b treat me nt f or s u bjects i n P hase II.
4.
S u bjects wit h hist ol o gicall y  or c yt ol o gicall y pr o ve n dia g n osis of mali g na nt s oli d t u m or 
(i ncl u di n g C N S t u m ors) or l ym p h o ma i n P hase I, or s pecifie d t u m or t ypes i n P hase II wit h 
meas ura ble disease at Baseli ne (at least 1 u ni di me nsi o nal, ra di o gra p hicall y  meas ura ble lesi o n 
base d o n R E CI S T v 1. 1).
5.
C o n fir me d pr o gressi o n o n or refract or y t o sta n dar d t hera p y, or n o sta n dar d t hera p y a vaila ble.
6.
La ns k y p erf or ma nce stat us ≥5 0 % f or s u bjects ≤1 6 ye ars of a ge, or Kar n ofs k y  scale ≥5 0 % f or 
s u bjects > 1 6 years of a ge.
7.
A de q uate b o ne marr o w f u ncti o n, i ncl u di n g:
a.
A bs ol ute ne utr o p hil c o u nt 1, 0 0 0/ m m 3 or 1 x 1 0 9/ L at least 5 d a y s foll o wi n g t he 
last d ose of gra n ul oc yte c ol o n y sti m ulati n g fact or 
b.
Platelets 5 0, 0 0 0/ m m 3 or 5 0 x 1 0 9/ L
c.
He m o gl o bi n 8 g/ d L ( ma y  ha ve bee n tra nsf use d).
8.
A de q uate he patic f u ncti o n, defi ne d b y : 
a.
a t otal ser u m bilir u bi n le vel ≤1. 5 × t he u p per li mit of n or mal ra n ge ( U L N)
b.
a n as partate a mi n otra nsferase ( A S T) le vel ≤3. 0 × U L N
c.
a n ala ni ne a mi n otra nsferase ( A L T) le vel ≤3. 0 × U L N 
or, f or s u bjects wit h 
d oc u me nte d metastatic disease t o t h e li ver, A S T a n d A L T le vels ≤5 × U L N.  
Patie nts wit h d oc u me nte d Gil bert disease are all o we d if t otal bilir u bi n is < 3 × U L N.
9.
A de q uate re nal f u ncti o n, defi ne d b y an esti mate d creati ni ne cleara nce ≥5 0 m L / mi n ( P hase I) 
or ≥3 0 m L / mi n ( P hase II) acc or di n g t o t he C oc k cr oft-Ga ult f or m ula or b y  24- h o ur uri ne 
c ollecti o n f or creati ni ne cleara nce or acc or di n g t o l ocal i nstit uti o nal sta n dar d met h o d.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 7
1 0. Ne gati ve ser u m pre g na nc y  test at Scree ni n g f or all p ost me narc hal girls, girls ≥1 0 years of a ge, 
or per l ocal or i nstit uti o nal g ui deli nes.
1 1. Hi g hl y effecti ve c o ntrace pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % per year) 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. I n this trial, a s u bject is 
c o nsi dere d t o be of c hil d beari n g p ote ntial if, i n t he o pi ni o n of t he I n vesti gat or, he/s he is 
bi ol o gicall y ca pa ble of ha vi n g c hil dre n a n d is se x uall y acti ve. ( 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 I 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 f or t he 
d urati o n of trial treat me nt, a n d at least f or 6 0 da ys after sto 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 hysicia n s h o ul d be i nf or me d i m me diatel y).
1 2. Esti mate d life e x pecta nc y of at least 3 m o nt hs. 
E xcl usi o n C riteri a
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.
Pri or t hera py wit h a n y a nti b o d y or 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 P D -1, P D -L 1, or c y t ot o xic T-l ym p h oc y te a nti ge n- 4.
2.
C o nc urre nt a ntica ncer treat me nt (e g, c yt ore d ucti ve t hera p y, ra di ot hera py, i m m u ne t hera py,  
c yt o ki ne t hera p y, m o n ocl o nal 
a nti b o d y, tar gete d s mall m olec ule 
t hera py) or a n y 
i n vesti gati o nal dr u g wit hi n 2 wee ks pri or t o start of st u d y treat me nt, or n o t rec o vere d fr o m 
A Es relate d t o s uc h t hera pies, wit h t he f oll o wi n g e xce pti o ns: 
a.
S h ort -c o urse, b o ne -directe d , 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 is per mitte d (c o nc urre ntl y or wit hi n t he pretreat me nt peri o d).
b.
Er y t hr o p oieti n a n d dar be p oeti n -α are per mitte d.
c.
H or m o nal t hera pies acti n g o n t he h y p ot hala mic- pit uitar y- g o na dal a xis are per mitte d 
(ie, l utei nizi n g h or m o ne-releasi n g h or m o ne a g o nists/a nta g o nists). N o ot her h or m o nal 
a ntica ncer t hera p y is per mitte d.
3.
Maj or s ur ger y  f or a n y reas o n, e xce pt dia g n ostic bi o ps y, wit hi n 4 wee ks pri or t o start of st u d y 
treat me nt a n d/ or if t he s u bject has n ot f ull y rec o vere d fr o m s ur ger y wit hi n 4 wee ks of t he trial
treat me nt.
4.
S u bjects recei vi n g i m m u n os u p pressi ve a ge nts (s uc h as ster oi ds) f or a n y rea s o n s h o ul d b e 
ta pere d off t hese dr u gs bef ore i nitiati o n of t he trial treat me nt, wit h t he f oll o wi n g e xce pti o ns: 
a.
S u bjects wit h a dre nal i ns ufficie nc y 
ma y co nti n ue c ortic oster oi ds at p h y si ol o gic 
re place me nt d ose. 
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 1 7
b.
A d mi nistrati o n of ster oi ds 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 ntra- oc ular, or i n halati o n) is per mitte d.
c.
Pre vi o us or o n g oi n g a d mi nistrati o n of s yste mic ster oi ds f or t he ma na ge me nt of a n ac ute 
aller gic p he n o me n o n is acce pta ble as l o n g as it is a ntici pate d t hat t he a d mi nistrati o n of 
ster oi ds will be c o m plete d i n 1 4 da ys, or t hat t he d ose after 1 4 da ys will be e q ui vale nt 
t o t he p h ysi ol o gic re place me nt d ose.
5.
Pre vi o us mali g na nt disease ( ot her t ha n t he t u m or disease f or t his trial) wit hi n t he last 5 years 
(e xce pt a de q uately treate d n o n- mela n o ma s ki n ca ncers, carci n o ma i n sit u of s ki n, bla d der, 
cer vi x, c ol o n/rect u m, breast, or pr ostate) u nless a c o m plete re missi o n wit h o ut f urt her 
rec urre nce was ac hie ve d at least 2 years pri or t o st u d y entr y  an d t he s u bject w as dee me d t o 
ha ve bee n c ure d wit h n o a d diti o nal t hera p y re q uire d or a ntici pate d t o be re q uire d
6.
Pri or 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. 
7.
Si g nifica 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:
a.
K n o w n 
h ist or y of 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.
b.
He patitis B vir us or he patitis C vir us ( H C V) i nfecti o n ( defi ne d as 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).
c.
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 uli n 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). S u bjects wit h late nt 
t u berc ul osis i nfecti o n w h o are dee me d t o re q uire treat me nt b y t h e In vesti gat or are n ot 
eli gi ble.
8.
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: 
a.
S u bjects wit h dia betes t y pe 1, vi tili g o, ps oriasis, or h yp ot h y r oi d/ h ypert 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.
b.
A d mi nistrati o n of ster oi ds 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 y ste mic 
e x p os ure (t o pical, i ntra nasal, i ntra- oc ular, or i n halati o n) is a cce pta ble.
9.
K n o w n pri or se vere h y perse nsiti vit y  to i n vesti gati o nal pr o d uct or a n y c o m p o ne nt i n its 
f or m ulati o ns.
1 0. Persisti n g t o xicit y relate d t o pri or t hera p y of Gra de > 2 N CI -C T C A E v 4. 0 3 (e xce pt ne ur o pat h y 
[see e xcl usi o n criteri o n # 1 1] a n d al o pecia).
1 1. Ne ur o pat h y ≥Gra de 3
1 2. Pre g na nc y  or lactati o n
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 1 7
1 3. K n o w n alc o h ol or dr u g a b use as deter mi ne d b y t he I n vesti gat or
1 4. Hist or y  of u nc o ntr olle d i nterc urre nt ill ness, i ncl u di n g b ut n ot li mite d t o:
a.
H y perte nsi o n u nc o ntr olle d b y  sta n dar d t hera pies ( n ot sta bilize d t o 1 5 0/9 0 m m H g or 
l o wer)
b.
U nc o ntr olle d acti ve i nfecti o n.
c.
U nc o ntr olle d dia betes (e g , he m o gl o bi n A 1c ≥8 %).
1 5. Cli nicall y  si gnifica nt (ie, acti ve) car di o vasc ular disease: cere bral vasc ular acci de nt/str o ke or 
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 pect oris , c o n gesti ve 
heart fail ure ( Ne w Y or k Heart Ass ociati o n Classificati o n Class ≥II), cli nicall y si gnifica nt 
ve ntric ular arr h yt h mia (ie, ve ntric ular tac h ycar dia, ve ntric ular fi brillati o n, or T orsa des de 
p oi ntes), dia g n ose d or s us pecte d c o n ge nital or ac q uire d pr ol o n ge d Q Tc s yn dr o me, or seri o us
u nc o ntr olle d car diac arr h yt h mia re q uiri n g me dicati o n/acti ve i nter ve nti o n.
1 6. All ot her si g nifica nt diseases (e g, se vere gastr oi ntesti nal c o n diti o ns s uc h as diarr hea, c olitis, 
i nfla m mat or y bo wel disease, ulce r, or p ne u m o nitis; e n d-sta ge ki d ne y  disease or c hr o nic ki d ne y 
disease re q uiri n g he m o dial y sis; or u nc o ntr olle d ast h ma), w hic h, i n t he o pi ni o n of t he 
I n vesti gat or, mi g ht i m pair t he s u bject’s t olera nce of trial treat me nt.
1 7. A n y  ps yc hiatric c o n diti o n, i ncl u di n g rece nt ( wit hi n 1 0 d a y s) or acti ve s uici dal i deati o n or 
be ha vi or 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 or t hat w o ul d 
li mit c o m plia nce wit h trial re q uire me nts.
1 8. A d mi nistrati o n of a li ve vacci ne wit hi n 2 8 da y s pri or t o st u d y e ntr y a n d w hile o n trial.
1 9. Ra pi dl y  pr o gressi ve disease.
2 0. K n o w n c o n ge nital i m m u n o deficie nc y .
5. 4
Criteri a f or I niti ati o n of Tri 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 Scree ni n g V isit. I n di vi d uals w h o d o n ot 
meet t he criteria f or i nitiati n g treat me nt (scree n fail ures) m a y  be rescree ne d. T he pare nt(s)/le gal 
g uar dia ns of rescree ne d partici pa nts will si g n a ne w I CF, a ne w s u bject n u m ber will be assi g ne d, 
a n d t he Scree ni n g pr oce d ures will be c o n d ucte d . 
5. 5
Criteri a f or S u bject Wit h dr a w al
S u bjects w h o ha ve e x perie nce d a c o m plete res p o nse ( C R) s h o ul d be treate d f or a mi ni m u m of 
1 2 m o nt hs base d o n cli nical j u d g me nt of be nefit a n d/or u ntil c o nfir me d pr o gressi o n per ir R E CIS T, 
u nacce pta ble t o xicit y, or a n y criteri o n f or wit h dra wal occ urs , after c o nfir mati o n of res p o nse as 
s pecifie d i n t his pr ot oc ol. Eac h s u bject will be f oll o we d f or a d diti o nal 1 2 m o nt hs after e n d of 
treat me nt.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 /1 1 7
Wit h dr a w al
fr o m Tri al T her a p y
A s u bject m ust be wit h dra w n fr o m a vel u ma b if a n y of t he f oll o wi n g occ ur s: 

S u bject or his/ her pare nt(s)/l e gal re prese ntati ve(s) wit h dra w c o nse nt.

S u bject l ost t o f oll o w u p .

Partici p ati o n i n a n ot her cli nical trial.

A n y  e ve nts t hat u nacce pta bl y e n da n ger t he safety of t he s u bject.

S u bjects meeti n g t he defi niti o n of c o nfir me d P D w hile o n treat me nt base d o n ir R E CI S T.
S u bjects w h o e x perie nce c o nfir me d disease pr o gressi o n ma y be per mitte d t o c o nti n ue treat me nt 
wit h a vel u ma b per Secti o n  6. 2. 1 . 

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w s y m pt o ms t hat are 
dee me d b y  the In vesti gat or t o be cli nicall y si gnifica nt or si g nifica nt w orse ni n g of e xisti n g 
s ym pt o ms.

U nacce pta ble t o xicit y .

Occ urre nce of a n e xcl usi o n criteri o n t hat is cli nicall y rele va nt a n d affects t he s u bject’s safety, 
if trial treat me nt disc o nti n uati o n is c o nsi dere d necessar y by t he I n 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 dr u g (if a p plica ble).

Occ urre nc e of a n y Gra de ≥ 3 A D Rs or as defi ne d i n Secti o n  5. 1. 3. 2.

Occ urre nce of A Es res ulti n g i n t he disc o nti n uati o n of t he trial treat me nt bei n g desire d or
c o nsi dere d necessar y  by t he In vesti gat or a n d/ or t he s u bject. 

Occ urre nce of pre g na nc y.

Use of a 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 trial treat me nt if c o nsi dere d necessar y b y t he i n vesti gat or 
or t he S p o ns or.

N o nc o m plia nce (see Secti o n  6. 9 ).
Wit h dr a w al fr o m t he Tri al
S u bjects ma y wit h dra w fr o m t he trial at a n y ti me wit h o ut gi vi n g a reas o n a n d at t heir o w n re q uest
or t he re q uest of t heir le gall y acce pta ble re pres e ntati ve. Th e y  ma y be wit h dra w n at a ny t i me at t he 
discreti o n of t he In vesti gat or or S p o ns or f or safet y or be ha vi oral reas o ns or t he i na bilit y of t he 
s u bject t o c o m pl y wit h t he pr ot oc ol -re q uire d sc he d ule of st u d y visits or pr oce d ures at a gi ve n st u d y 
site.
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 trial u nless t he s u bject a n d/ or 
his/ her pare nt(s)/le gal re prese ntati ve(s) a gree t o be f oll o we d f or s ur vi val, w hic h m a y  incl u de 
verificati o n of me dical rec or ds. S u bjects s h o ul d be e x plicitl y as ked at t he ti me of wit h dra wal of 
c o nse nt if t he y wo ul d all o w s ur vi val i nf or mati o n t o be c ollecte d , i ncl u di n g verificati o n of 
me dical/ p u blic rec or ds as per mitte d b y  local re g ulati o ns. T hese res p o nse s h o ul d acc or di n gl y be 
ca pt ure d i n t he e C R F.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 1 7
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 ( E n d of Treat me nt
Visit) s h o ul d be perf or me d, 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 E n d of Safet y F oll o w - u p e C R F pa ge 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 safet y  an 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.
If a s u bject d oes n ot ret ur n f or a sc he d ule d visit, e ver y eff ort s h o ul d be ma de t o c o ntact t he s u bject 
or his/ her le gal re prese ntati ve. All atte m pts t o c o ntact t he s u bject a n d i nf or mati o n recei ve d d uri n g 
c o ntact atte m pts m ust be d oc u me nte d i n t he s u bject’s me dical recor d. I n a n y circ u msta nce, e ver y 
eff ort s h o ul d be ma de t o d oc u me nt s u bject o utc o me, if p ossi ble. T he In vesti gat or s h o ul d i n q uire 
a b o ut t he reas o n f or wit h dra wal, re q uest t hat t he s u bject ret ur n f or a fi nal visit, if a p plica ble, a n d 
f oll o w u p wit h t he s u bject re gar di n g a ny u nres ol ve d A Es.
If t he s u bject or le gal re prese ntati ve ref uses f urt her visits, t he s u bject s h o ul d c o nti n ue t o be 
f oll o we d f or s ur vi val u nless t he s u bject or le gal re prese ntati ve wit h dra ws c o nse nt f or discl os ure 
of f ut ure i nf ormati o n or f or f urt her c o ntact. I n t his case, n o f urt her st u d y-s pecific e val uati o ns 
s h o ul d be perf or me d, a n d n o a d ditio nal data s h o ul d be c ollecte d. T he S p o ns or ma y  retai n a n d 
c o nti n ue t o use a n y data c ollecte d bef ore s uc h wit h dra wal of c o nse nt.
5. 6
Pre m at ure Ter mi n ati o n of t he Tri al
T he cli nical trial ma y  be ter mi nate d pre mat urel y or s us pe n de d at t he re q uest of Healt h A ut h orities 
or if ne w safety or efficac y inf or mati o n lea ds t o a n u nfa v ora ble be nefit ris k assess me nt f or 
a vel u ma b. T he S p o ns or ma y disc o nti n ue t he trial if it bec o mes u nj ustifia ble f or me dical or et hical 
reas o ns, f or p o or e nr oll me nt, or beca use of disc o nti n uati o n of cli nical de vel o p me nt of a vel u ma b 
or wit h dra wal of a vel u ma b fr o m t he mar ket f or safet y reas o ns.
Healt h A ut h orities a n d I nde pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R 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 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 o f t he f oll o wi n g:

Ne w i nf or mati o n lea di n g t o a n u nfa v ora ble be nefit -ris k assess me nt of t he trial treat me nt, e g, 
d ue t o: 

E vi de nce of i nefficac y  of t he trial treat me nt.

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.

Ot her u nfa v ora ble safet y fi n di n gs.
( N ote: E vi de nce of i nefficac y  m a y arise fr o m t his trial or fr o m ot her trials; u nfa v ora ble safety 
fi n di n gs ma y arise fr o m cli nical or n o ncli nical e xa mi nati o ns, e g, t o xic ol o g y.)

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 trial treat me nt.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 /1 1 7
I n t he sit uati o n of a pre mat ure ter mi nati o n of t he trial, s u bjects o n treat me nt w h o are ha vi n g a 
cli nical be nefit ma y  co nti n ue t o recei ve a vel u ma b base d o n In vesti gat or’s re q uest a n d i n 
c o ns ultati o n a n d a gree me nt wit h t he S p o ns or.
5. 7
Defi niti o n of E n d of Tri al
T he e n d of t he trial will be defi ne d as 1 ye ar after t he last s u bject c o m pletes his/ her E n d of 
T reat me nt Visit.
A cli nical trial pr ot oc ol ma y  n ot be c o nsi dere d cl ose d as l o n g as:

A n y  s u bject is still recei vi n g a vel u ma b .

Visits s pecifie d b y  t he pr ot oc ol are still ta ki n g place .

Pr oce d ures or i nter ve nti o ns acc or di n g t o t he pr ot oc ol are still bei n g u n derta ke n i n a n y s u bject .

T he p ost -treat me nt F oll o w -u p Peri o d , defi ne d i n t he cli nical trial pr ot oc ol as bei n g part of t he 
trial, has n ot yet bee n c o m plete d f or a n y s u bject.
T he S p o ns or ma y  ter mi nate t he st u d y at a n y ti me o nce access a vel u ma b f or s u bjects still 
be nefitti n g is pr o visi o ne d via a r ollo ver st u d y, e x pa n de d access , mar kete d pr o d uct , or a not her 
mec ha nis m of access as a p pr o priate.
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
I nvesti 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 p y in 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 o rizati 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 f or m. I n this trial, 
t he IM P
is a vel u mab.
6. 1
Descri pti o n of I n vesti g ati o n al Me dici n al Pr o d uct
A vel u ma b is a sterile, clear, a n d c ol orless s ol uti o n i nte n de d f or i v a d mi nistrati o n. It is prese nte d 
at a c o nce ntrati o n of 2 0 m g/ m L  in si n gle-use gl ass vials 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 / yell o w p ol y pr o p yl e ne fli p -off seal.
6. 2
D os a ge a n d A d mi nistr ati o n
A vel u m a b
S u bjects will recei ve a n i v i nf usio n of a vel u ma b o ver 1 h o ur (-1 0 mi n utes/ + 2 0 mi n utes, ie, 
5 0 t o 8 0 mi n utes) o nce e ver y  2 wee ks. 
T he d ose of a vel u ma b will be calc ulate d base d o n t he wei g ht of t he s u bject deter mi ne d wit hi n 
7 2 h o urs pri or t o a d mi nis trati o n. T he d ose of a vel u ma b use d f or t he pre vi o us a d mi nistrati o n ca n 
be re peate d if t he c ha n ge i n t he s u bject’s wei g ht is wit hi n 1 0 % of t he wei g ht use d f or t he last d ose 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 1 7
calc ulati o n . S u bjects will recei ve a vel u ma b o nce e ver y 2 wee ks u ntil t he criteria i n Secti o ns  5. 4 , 
5. 5. 1 , a n d 5. 5. 2 are met.
R ules f or d ose m o dificati o ns d uri n g t he P hase I part of t he st u d y  are descri be d i n Secti o n 5. 1. 1. 1.  
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. 5. 1 . 
I n or der t o miti gate i nf usi o n-relate d reacti o ns, pre me dicati o n wit h a n a nti hista mi ne ( H 1 rece pt or 
bl oc ker s uc h as di p he n h y dra mi ne ) a n d wit h aceta mi n o p he n ( paraceta m ol) a p pr o xi matel y 30 t o 
6 0 mi n utes pri or t o eac h d ose of st u d y dr u g f or t he first 4 i nf usi o ns is ma n dat or y . T his re gi me n 
ma y  be m o difie d base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes, as a p pr o priate. Ster oi d 
pre me dicati o n s pecificall y  f or a vel u ma b is n ot per mitte d. 
A vel u ma b treat me nt ma y  co nti n ue past t he i nitial deter mi nati o n of c o nfir me d p r o gressi o n per 
irR E CI S T as l o n g as t he f oll o wi n g criteria are met:

N o ne w s y m pt o ms or w orse ni n g of pre vi o us s y m pt o ms

T olera nce of a vel u ma b

Sta ble perf or ma nce stat us ( La ns k y p erf or ma nce stat us ≥5 0 % f or s u bjects ≤1 6 years of a ge, or 
Kar n ofs k y scale ≥5 0 % f or s u bjects > 1 6 ye ars of a ge)

Treat me nt will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt seri o us c o m plicati o ns of disease 
pr o gressi o n ( e g, C N S metastases)
T he decisi o n t o c o nti n ue treat me nt s h o ul d be disc us se d wit h t he Me dical M o nit or a n d d oc u me nte d 
i n t he trial rec or ds.
A ra di o gra p hic assess me nt s h o ul d be perf or me d wit hi n 8 wee ks of ori gi nal P D t o deter mi ne 
w het her t here has bee n a decrease i n t he t u m or size, or c o nfir me d P D per ir R E CIS T . T he 
assess me nt of cli nical be nefit s h o ul d be bala nce d b y cli nical j u d g me nt as t o w het her t he s u bject is 
cli nicall y deteri orati n g a n d u nli kel y  to recei ve a n y be nefit fr o m c o nti n ue d treat me nt wit h 
a vel u ma b.
If t he I n vesti gat or feels t hat t he s u bject will c o nti n ue t o ac hie ve cli nical be nefit b y  co nti n ui n g 
treat me nt, a n d after disc ussi o n wit h t he Me dical M o nit or, t he s u bject ca n re mai n o n t he trial, 
c o nti n ue t o recei ve a vel u ma b treat me nt, a n d c o nti n ue t o u n der g o m o nit ori n g acc or di n g t o t he 
Sc he d ule of Assess me nts (Ta ble 1 ). T he decisi o n t o c o nti n ue treat me nt b e y o n d c o nfir me d 
pr o gressi o n s h o ul d be a p pr o ve d b y t he S p o ns or a n d d oc u me nte d i n t he trial rec or ds.
F or s u bjects w h o c o nti n ue a vel u ma b b e y o n d c o nfir me d P D per ir R E CI S T, f urt her pr o gressi o n is 
defi ne d as a n a d diti o nal 1 0 % i ncrease i n t u m or b ur de n v ol u me fr o m ti me of c o nfir me d P D. T his 
i ncl u des a n i ncrease i n t he s u m of all tar get lesi o ns a n d/ or t he de vel o p me nt of ne w meas ura ble 
lesi o ns. F urt her pr o gressi o n be y o n d c o nfir me d P D will re q uire disc o nti n uati o n of a vel u ma b 
t hera py.
A d diti o nall y , s u bjects recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a 
mi ni m u m of 1 2 m o nt hs
base d o n cli nical j ud g me nt of be nefit a n d/ or u ntil c o nfir me d disease 
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 occ urs , after c o nfir mati o n of 
res p o nse a n d at t he discreti o n of t he I n vesti gat or. I n case s uc h s u bject’s disease rela pses after 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
st o p pi n g treat me nt, b ut p ri or t o t he e n d of t he trial, 1 re-i nitiati o n of treat me nt will be 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 wit h
t he Me dical M o nit or . 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 that le d t o treat me nt 
disc o nti n uati o n of t he i nitial a vel u ma b t hera p y. Pri or t o r e-i nitiati o n of t he st u d y treat me nt, 
mali g na nt disease will be ra di ol o gically r e-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 nt safet y la b orat or y res ults 
m ust be a vaila ble a n d verifie d pri or t o re-i nitiati n g treat me nt. S u bjects w h o re-i nitiate treat me nt 
will sta y on st u d y an d will be treate d a n d m o nit ore d acc or di n g t o t he pr ot oc ol a n d t he “ U ntil E O T” 
sc he d ule i n t he Sc he d ule of Assess me nts (Ta ble 1 ).
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 ap pr o priate me dical 
t hera py (i ncl u di n g e pi ne p hri ne, c ortic oster oi ds, i v a nti hista mi nes, br o nc h o dilat ors, a n d o x y ge n) 
m ust be a vaila ble f or use i n t he treat me nt of I R Rs. I nf usi o n of a vel u ma b wil l 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 act oi d reacti o n. F oll o wi n g t he first 4 a vel u ma b
i nf usi o ns, s u bjects m ust be o bser ve d f or 2 h o urs p ost i nf usi o n f or p ote ntial I R Rs. 
As wit 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. A vel u ma b 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 a n d a d mi nistrati o n o f t hera p y for se vere 
aller gic/h y perse nsiti vit y  reacti o ns, 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. S ter oi ds, e pi ne p hri ne , aller g y me dicati o ns (a nti hista mi nes), or e q ui vale nts s h o ul d be 
a vaila ble f or i m me diate access.
If 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. 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  an d fl u-li ke s ym pt o ms
acc or di n g to t he Nati o nal Ca ncer I nstit ute are f o u n d i n 
Secti o ns 6. 5. 5. 1 a n d 6. 5. 5. 2 , res pecti vely. A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of 
a na ph y lactic 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) ca n be f o u n d at htt ps:// w w w.res us. or g. u k/ pa ges/reacti o n. p df. S u bjects a n d t heir le gal 
re prese ntati ve s h o ul d be i nstr ucte d to re p ort a n y d ela ye d reacti o ns t o t he In vesti gat or i m me diately.
St a n d ar d of C are
N ot a p plica ble.
6. 3
Assi g n me nt t o Tre at me nt Gr o u ps
O nce t he s u bject or le gal re prese ntati ve has pr o vi de d a si g ne d I C F a n d meets all i ncl usi o n criteria 
a n d d oes n ot mee t a n y e xcl usi o n criteri o n, t he In vesti gat or or dele gate will re q uest trial re gistrati o n 
usi n g t he I RT i m me diatel y pri or t o t he first treat me nt. T he trial is f ull y co ntr olle d b y  the IR T , 
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. T he vial n u m ber is 
li n ke d via t he G M P -q ualifie d s y ste 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.
S u bject i de ntifiers will c o m prise 1 7 di gits, t he first 1 0 di gits re prese nti n g t he trial n u m ber, t he 
f oll o wi n g 3 di gits re prese nti n g t he site n u mber, a n d t he last 4 di gits re prese nti n g t he s u bject 
n u m ber, w hic h is all ocate d se q ue ntiall y starti n g wit h 0 0 0 1.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 /1 1 7
I n t he P hase I d ose -fi n di n g p art of t he st u d y , s u bjects will be assi g ne d t o se q ue ntial c o h orts of 3 t o 
6 s u bjects eac h. P hase II will ha ve 2 e x pa nsi o n c o h orts, wit h s pecific t u m ors c h ose n base d o n 
a vaila ble data fr o m t he c urre nt st u d y, ot her o n g oi n g st u dies wit h a vel u ma b or ot her I CIs, cli nical 
a n d n o ncli nical c o m bi nati o n c he m ot hera p y d ata, a n d a n y p u blis he d literat ure. 
6. 4
N o ni n vesti g ati o n al Me dici n al Pr o d ucts t o B e Use d
Ma n dat or y  pre me dicati o n wit h a n a ntihista mi ne ( H 1 rece pt or bl oc ker s uc h as di p he n h y dra mi ne ) 
a n d aceta mi n o p he n (paraceta m ol) f or t he first 4 d oses is re q uire d i n all s u bjects t o be treate d wit h 
a vel u ma b (see Secti o n  5. 1. 2 f or details).
6. 5
C o nc o mit a nt Me dic ati o ns a n d T her a pies
Per mitte d Me dici nes
A n y  me dicati o ns, t hera pies, or pr oce d ures ( 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  for t he s u bject’s welfare a n d will n ot i nterfere wit h t he trial 
me dicati o n ma y  be gi ve n at t he In 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 h y perse nsiti vit y r eacti o ns, a n d treat me nt of 
fe ver or fl u-li ke sy m pt o ms are descri be d i n Secti o n  6. 5. 5. 2 .
Resc ue me dicati o ns ma y be a d mi nistere d d ue t o a ntici pate d a d verse reacti o ns or a ntici pate d 
e mer ge nc y sit uati o ns.
A d mi nistrati o n of ster oi ds 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 o s ure (t o pical, 
i ntra nasal, i ntra-oc ular, or i n halati o n) are acce pta ble.
A n y  ad diti o nal c o nc o mita nt t hera p y t hat bec o mes necessar y  duri n g t he trial, a n d a n y c ha 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.
Pr o hi bite d Me dici nes
Pr o hi bite d pri or a n d c o nc o mita nt dr u gs a n d treat me nts i ncl u de t he f oll o wi n g (see E xcl usi o n 
Criteria i n Secti o n 5. 3. 2 ): 

S y ste mic a ntica ncer t hera p y 2 wee ks pri or t o start of st u dy treat me nt

I m m u n os u p pressi ve me dicati o n wit hi n 7 d a y s pri or t o re gistrati o n a n d C y cle 1 of treat me nt, 
e xce pt t he f oll o wi n g (see Secti o n 6. 5. 5 ): 

I ntra nasal, i n hale d, a n d t o pical ster oi ds, a n d l ocal ster oi d i njecti o ns (e g, i ntra-artic ular 
i njecti o n)

S ys te mic c ortic oster oi ds at p h ysi ol o gic d oses

S ter oi ds as pre me dicati o n f or h y perse nsiti vit y reacti o ns (e g, C T sca n pre me dicati o n , 
tra nsf usi o n of bl o o d pr o d ucts ; ster oi d pre me dicati o n s pecifically f or a vel u ma b is n ot 
per mitte d ).
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 /1 1 7

Vacci nati o n 4 wee ks pri or t o t he first d ose of a vel u ma b a n d w hile o n trial, e xce pt f or 
a d mi nistrati o n of i nacti vate d vacci nes ( e g, i nacti vate d i nfl ue nza vacci nes)

Pri or t hera py wit h a n a nti -P D -1, a nti -P D -L 1, a nti -P D -L 2, a nti -C D 1 3 7, or a nti-C T L A - 4
a nti b o d y (or a n y ot her a nti b o d y  or dr u g s pecificall y tar geti n g T cell c o-sti m ulati o n or i m m u ne 
c hec k p oi nt pat h wa ys).

A b use of alc o h ol or ot her dr u gs d uri n g t he trial.
I n a d diti o n, the f o ll o wi n g treat me nts m ust n ot be a d mi nistere d d uri n g t he trial:

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs (ie, 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 or f or t he treat me nt of ir A Es), or ot her 
e x peri me ntal p har mace utical pr o d ucts. 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.

Gr o wt h fact ors ( gra n ul oc yte c ol o n y sti m ulati n g fact or or gra n ul oc y te-macr o p ha ge c ol o n y 
sti m ulati n g fact or). E xce pti o n: er yt hr o p oieti n a n d dar be p oieti n -α m a y  be prescri be d at t he 
I n vesti gat or’s discreti o n.

Her bal re me dies wit h i m m u n osti m ulati n g pr o perties (e g, 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 (e g, h yperici n).
C o nc o mita nt me dicati o ns a n d treat me nts will be rec or d e d fr o m 2 8 d a y s pri or t o t he start of st u d y 
treat me nt a n d u p t o 9 0 da y s after t he last d ose of st u d y tr eat me nt (at D a y s 3 0 a n d 9 0 p ost -treat me nt 
5 da y s). All c o nc o mita nt me dicati o ns, i ncl u di n g s u p p orti ve care dr u gs ( e g, a ntie metic treat me nt 
a n d pr o p h yl a x is), t he dr u gs use d t o treat A Es
or c hr o nic diseases, a n d n o n dr u g s u p p orti ve 
i nter ve nti o ns (e g, tra nsf usi o ns), s h o ul d be rec or de d i n t he a p pr o priate 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. N o n dr u g i nter ve nti o 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 o n s h o ul d als o be rec or de d i n t he eC R F.
Ot her I nter ve nti o ns
T h e 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 da 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).
Pri or palliati ve ra di ot hera p y t o metastatic lesi o ns is per mitte d, pr o vi de d it has bee n c o m plete d 
4 8 h o urs pri or t o s u bject re gistrati o n .
Palli ati ve s h ort-c o urse, li mite d-fiel d, b o ne -directe d ra di ot hera py 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 be ma de acc or di n g t o R E CI S T 1. 1 (Eise n ha uer 2 0 0 9 ) a n d as 
a dj u dicate d b y  the I n vesti gat or a n d n ot base d o n t he necessit y f or palliati ve b o ne -directe d 
ra di ot hera py.
S peci al Prec a uti o ns
As a r o uti ne preca uti o n, s u bjects e nr olle d i n t his trial m ust be o bser ve d f or 2 h o urs p ost i nf usi o n
f or t he first 4 i nf usi o ns (e xce pt f or c o n diti o ns defi ne d i n Secti o n 6. 4 ), 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 a ge nts. At all ti mes d uri n g a vel u ma b 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 v it y reacti o n acc or di n g t o 
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 7
i nstit uti o nal sta n dar ds m ust be ass ure d. I n or der t o treat p ossi ble h y perse nsiti vit y reacti o ns,
met h y l pre d nis ol o ne 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 a vel u ma b wil l 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 I R R. T he treat me nt rec o m me n dati o ns f or I RRs a n d se vere h yperse nsiti vit y  reacti o ns 
acc or di n g t o t he N CI are as o utli ne d i n Secti o ns 6. 5. 5. 1 a n d 6. 5. 5. 2 , res pecti vel y.
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 
earliest after wee ks of treat me nt. S uc h e ve nts m a y  co nsist of , b ut are n ot li mite d t o, persiste nt ras h, 
diarr hea a n d c olitis, p ne u m o nitis, e n d ocri n o pat hies, m y ositis, 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, or u veitis a n d ot her i nfla m mat or y e ye c o n diti o ns. T he 
s pectr u m of h y p ot hetical ir A Es als o i ncl u des f or mati o n of a ut o -a nti b o dies li ke a nti n uclear 
anti b o dies or a nti -ne utr o p hi l c yt o plas mic a nti b o dies . See Secti o n 6. 5. 5. 3 f or details o n t he 
ma na ge me nt of ir A Es.
M a n a ge me nt 
of S pecific A d verse E ve n ts or A d verse Dr u g 
Re acti o ns
I nf usi o n-Rel ate d Re acti o ns
I n or der t o miti gate 
i nf usi o n-relate d reacti o ns, s u bjects m ust
be pre me dicate d wit h 
a n 
a nti hista mi ne ( H 1 rece pt or bl oc ker
s uc h as di p he n h y dra mi ne ) a n d wit h 
aceta mi n o p he n 
( paraceta m ol) a p pr o xi matel y 30 t o 6 0 mi n utes bef ore t he first 4 i nf usi o ns of a vel u ma b , or 
acc or di n g t o l ocal sta n dar ds (e xcl u di n g ster oi ds). Pre me dicati o n s h o ul d be a d mi nistere d f or 
s u bse q ue nt a vel u ma b d oses base d u p o n cli nical j u d g me nt a n d prese nce/se verit y  of pri or i nf usi o n 
reacti o ns.
Ma na ge me nt of i nf usi o n -relate d reacti o ns s h o ul d f oll o w g ui deli nes set f ort h i n Ta ble 4.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
T a ble 4
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 
Ass oci ate d wit h A vel u m a b
N CI -C T C A E Gr a d e 
Tr e at m e nt M o difi c ati o n f or A v el u m a b
Gr a d e 1 – mil d

Mil d tr a n si e nt r e a cti o n; i nf u si o n i nt err u pti o n n ot 
i n di c at e d; i nt er v e nti o n n ot i n di c at e d.

D e cr e a s e t h e a v el u m a b i nf u si o n r a t e b y 5 0 % 
a n d m o nit or cl o s el y f or a n y w or s e ni n g.
Gr a d e 2 – m o d er at e

T h er a p y or i nf u si o n i nt err u pti o n i n di c at e d b ut 
r e s p o n d s pr o m ptl y t o s y m pt o m ati c tr e at m e nt 
(e g , a nti hi st a mi n e s, N S AI D s, n ar c oti c s, i v
fl ui d s); pr o p h yl a cti c m e di c ati o n s i n di c at e d f or 
2 4 h o ur s.

T e m p or aril y di s c o nti n u e a v el u m a b i nf u si o n.

R e s u m e i nf u si o n at 5 0 % of pr e vi o u s r at e o n c e 
i nf u si o n-r el at e d r e a cti o n h a s r e s ol v e d or 
d e cr e a s e d t o at l e a st Gr a d e 1 i n s e v erit y, a n d 
m o nit or cl o s el y f or a n y w or s e ni n g.
I nf u si o n 
ti m e s h o ul d b e e xt e n d e d t o 2 h o ur s, a n d 
s u bj e ct s h o ul d r e c ei v e t h e f ull d o s e.
Gr a d e 3 or Gr a d e 4 – s e v er e or lif e -t hr e at e ni n g

Gr a d e 3: Pr ol o n g e d ( e g , n ot r a pi dl y r e s p o n si v e 
t o s y m pt o m ati c m e di c ati o n a n d/ or bri ef 
i nt err u pti o n of i nf u si o n); r e c urr e n c e of 
s y m pt o m s f oll o wi n g i niti al i m pr o v e m e nt; 
h o s pit ali z ati o n i n di c at e d f or cli ni c al s e q u el a e.

Gr a d e 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; 
ur g e nt i nt er v e nti o n i n di c at e d.

St o p t h e a v el u m a b i nf u si o n i m m e di at el y a n d 
di s c o n n e ct i nf u si o n t u bi n g fr o m t h e s u bj e ct.

S u bj e ct s h a v e t o b e wit h dr a w n i m m e di at el y 
fr o m a v el u m a b tr e at m e nt a n d m u st n ot r e c ei v e 
a n y f urt h er a v el u m a b tr e at m e nt.
i v: i ntr a v e n o u s; N CI -C T C A E : N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt ; N S AI D s : 
n o n st er oi d al a nti -i nfl a m m at or y dr u g s.
O nce t he a vel u ma b i nf usi o n rate has bee n decrease d b y  50 % or
i nterr u pte d d ue t o a n 
i nf usi o n-relate d reacti o n, it m ust re mai n decrease d f or all s u bse q ue nt i nf usi o ns. If a s u bject 
e x perie nces a Gra de 3 or Gra de 4 i nf usi o n-relate d reacti o n at a n y ti me, t he s u bject m ust 
disc o nt i n ue a vel u ma b. If a n i nf usi o n reacti o n occ urs, all details a b o ut dr u g pre parati o n a n d 
i nf usi o n m ust be rec or de d.
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) ca n be f o u n d at 
htt ps:// w w w.res us. or g. u k/ pa ges/reacti o n. p df (U K Res uscitati o n C o u ncil ). S u bjects or t heir le gal 
re prese ntati ve s h o ul d be i nstr ucte d t o re p ort a n y d ela ye d reacti o ns t o the I nvesti gat or i m me diately.
A.
S y m pt o ms

I m paire d air wa y

Decrease d o x y ge n sat urati o n ( < 9 2 %)

C o nf usi o n

Let har g y

H y p ote nsi o n

Pale/cla m m y  s ki n
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 /1 1 7

C y a n osis.
B.
Ma na ge me nt

E pi ne p hri ne i njecti o n a n d / or met h y l pre d nis ol o ne i nf usi o n

S u bject s h o ul d be place d o n m o nit or i m me diatel y

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, 
i n d o met haci n or c o m para ble n o nster oi dal a nti -
i nfla m mat or y dr u g d ose (e g, i b u pr ofe n or na pr o xe n s o di u m) ma 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 a vel u ma b i v i nf usi o n. Alter nati ve treat me nts f or fe ver 
(e g, aceta mi n o p he n [ paraceta m ol]) ma y  be gi ve n t o s u bjects at t he discreti o n of t he In vesti gat or.
I m m u ne-rel ate d A d verse E ve nts
Beca use 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 verity ( N CI -C T C A E gra de):

Gra de 1 t o 2: treat sy 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 ( persiste nt): ma na ge si milar t o hi g h - gra de A E ( Gra de 3 t o 4)

Gra 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 5.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 / 1 1 7
T a ble 5
M a n a ge me nt of I m m u ne-r el ate d A d verse E ve nts
G a str oi nt e sti n al ir A E s
S e v erit y of Di arr h e a/ C oliti s
( N CI-C T C A E v 4. 0 3)
M a n a g e m e nt
F oll o w -u p
Gr a d e 1
Di arr h e a: < 4 st o ol s/ d a y o v er 
B a s eli n e
C oliti s: a s y m pt o m ati c 
C o nti n u e a v el u m a b t h er a p y
S y m pt o m ati c tr e at m e nt , e g , 
l o p er a mi d e)
Cl o s e m o nit ori n g f or w or s e ni n g s y m pt o m s
E d u c at e s u bj e ct t o r e p ort w or s e ni n g 
i m m e di at el y
If w or s e n s:
Tr e at a s Gr a d e 2, 3 , or 4 
Gr a d e 2
Di arr h e a: 4 t o 6 st o ol s p er d a y o v er 
B a s eli n e; i v fl ui d s i n di c at e d 
< 2 4 h o ur s; n ot i nt erf eri n g wit h A D L
C oliti s: a b d o mi n al p ai n; bl o o d i n 
st o ol 
D el a y a v el u m a b t h er a p y
S y m pt o m ati c tr e at m e nt
If i m pr o v e s t o Gr a d e 1: 
R e s u m e a v el u m a b t h er a p y
If p er si st s > 5 t o 7 d a y s or r e c urs:
Tr e at a s Gr a d e 3 t o 4
Gr a d e 3 t o 4
Di arr h e a ( Gr a d e 3): ≥7 st o ol s p er 
d a y o v er B a s eli n e; i n c o nti n e n c e; 
i v fl ui d s ≥2 4 h o ur s ; i nt erf eri n g wit h 
A D L
C oliti s ( Gr a d e 3): s e v er e a b d o mi n al 
p ai n, m e di c al i nt er v e nti o n 
i n di c at e d, p erit o n e al si gn s
Gr a d e 4: lif e -t hr e at e ni n g, 
p erf or ati o n
Wi t h h ol d a v el u m a b f or 
Gr a d e 3
P er m a n e ntl y di s c o nti n u e 
a v el u m a b f or Gr a d e 4 or 
r e c urr e nt Gr a d e 3.
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
C o n si d er l o w er e n d o s c o p y
If i m pr o v e s: 
C o nti n u e st er oi d s u ntil Gr a d e 1, t h e n t a p er 
o v er at l e a st 1 m o nt h , r e s u m e a v el u m a b 
t h er a p y f oll o wi n g st er oi d s t a p er (f or i niti al 
Gr a d e 3).
If w or s e n s, p er si st s > 3 t o 5 d a y s, or r e c ur s 
aft er i m pr o v e m e nt:
A d d i nfli xi m a b 5 m g/ k g (if n o 
c o ntr ai n di c ati o n), N ot e: I nfli xi m a b s h o ul d n ot 
b e u s e d i n c a s e s of p erf or ati o n or s e p si s 
D er m at ol o gi c al ir A E s
Gr a d e of R a s h
( N CI-C T C A E v 4 . 0 3)
M a n a g e m e nt
F oll o w -u p
Gr a d e 1 t o 2 
C o v eri n g ≤ 3 0 % b o d y s urf a c e ar e a 
C o nti n u e a v el u m a b t h er a p y 
S y m pt o m ati c t h er a p y ( e g , 
a nti hi st a mi n e s, t o pi c al 
st er oi d s) 
If p er si st s > 1 t o 2 w e e k s or r e c ur s: 
Wi t h h ol d a v el u m a b t h er a p y
C o n si d er s ki n bi o p s y 
D el a y a v el u m a b t h er a p y
C o n si d er 0. 5 t o 1. 0 m g/ k g/ d a y pr e d ni s o n e or
e q ui v al e nt. O n c e i m pr o vi n g, t a p er st er oi d s 
o v er at l e a st 1 m o nt h, c o n si d er pr o p h yl a cti c 
a nti bi oti c s f or o p p ort u ni sti c i nf e cti o n s, a n d 
r e s u m e a v el u m a b t h er a p y f oll o wi n g st er oi d s 
t a p er
If w or s e n s: 
Tr e at a s Gr a d e 3 t o 4 
Gr a d e 3 t o 4
C o v eri n g > 3 0 % b o d y s u rf a c e ar e a; 
lif e t hr e at e ni n g c o n s e q u e n c e s 
Wi t h h ol d a v el u m a b f or 
Gr a d e 3.
P er m a n e ntl y di s c o nti n u e f or 
Gr a d e 4 or r e c urr e nt Gr a d e 3
C o n si d er s ki n bi o p s y 
D er m at ol o g y c o n s ult 
If i m pr o v e s t o Gr a d e 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h a n d 
a d d pr o p h yl a cti c a nti bi oti c s f or o p p ort u ni sti c 
i nf e cti o n s 
R e s u m e a v el u m a b t h er a p y f oll o wi n g 
st er oi d s t a p er (f or i niti al Gr a d e 3).
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 / 1 1 7
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt 
P ul m o n ar y  ir A E s
Gr a d e of P n e u m o niti s
( N CI-C T C A E v 4 . 0 3)
M a n a g e m e nt
F oll o w -u p
Gr a d e 1
R a di o gr a p hi c c h a n g e s o nl y 
C o n si d er wit h h ol di n g
a v el u m a b t h er a p y 
M o nit or f or s y m pt o m s e v er y 
2 t o 3 d a y s 
C o n si d er p ul m o n ar y a n d 
i nf e cti o u s di s e a s e c o n s ult s 
R e -a s s e s s at l e a st e v er y 3 w e e k s
If w or s e n s: 
Tr e at a s Gr a d e 2 or Gr a d e 3 t o 4 
Gr a d e 2
Mil d t o m o d er at e n e w s y m pt o m s 
Wi t h h ol d a v el u m a b t h er a p y
P ul m o n ar y a n d I nf e cti o u s 
Di s e a s e c o n s ult s
M o nit or s y m pt o m s d ail y, 
c o n si d er h o s pit ali z ati o n 
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt 
C o n si d er br o n c h o s c o p y, l u n g 
bi o p s y 
R e -a s s e s s e v er y 1 t o 3 d a y s 
If i m pr o v e s: 
W h e n s y m pt o m s r et ur n t o n e ar B a s eli n e, 
t a p er st er oi d s o v er at l e a st 1 m o nt h, 
c o n si d er pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s, a n d t h e n r e s u m e 
a v el u m a b t h er a p y f oll o wi n g st er oi d s t a p er
If n ot i m pr o vi n g aft er 2 w e e k s or w or s e ni ng: 
Tr e at a s Gr a d e 3 t o 4 
Gr a d e 3 t o 4
Gr a d e 3: S e v er e n e w s y m pt o m s; 
N e w/ w or s e ni n g h y p o xi a; 
Gr a d e 4: lif e t hr e at e ni n g 
P er m a n e ntl y d i s c o nti n u e 
a v el u m a b t h er a p y
H o s pit ali z e 
P ul m o n ar y a n d I nf e cti o u s 
Di s e a s e c o n s ult s
1. 0 t o 2 . 0 m g/ k g/ d a y 
pr e d ni s o n e e q ui v a l e nt 
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
C o n si d er br o n c h o s c o p y, l u n g 
bi o p s y 
If i m pr o v e s t o B a s eli n e: 
T a p er st er oi d s o v er at l e a st 6 w e e k s 
If n ot i m pr o vi n g aft er 4 8 h o ur s or w or s e ni n g: 
A d d a d diti o n al i m m u n o s u p pr e s si o n ( e g , 
i nfli xi m a b, c y cl o p h o s p h a mi d e, i v
i m m u n o gl o b uli n, or m y c o p h e n ol at e m of etil) 
H e p ati c ir A E s
Gr a d e of Li v er T e st El e v ati o n
( N CI-C T C A E v 4 . 0 3)
M a n a g e m e nt
F oll o w -u p
Gr a d e 1
Gr a d e 1 A S T or A L T > U L N t o 3. 0 x 
U L N a n d / or t ot al bilir u bi n > U L N t o 
1. 5 x U L N 
C o nti n u e a v el u m a b t h er a p y
C o nti n u e li v er f u n cti o n m o nit ori n g 
If w or s e n s: 
Tr e at a s Gr a d e 2 or 3 t o 4 
Gr a d e 2
A S T or A L T > 3. 0 t o ≤5 x U L N 
a n d/ or t ot al bilir u bi n > 1. 5 t o 
≤3 x U L N 
Wi t h h ol d a v el u m a b t h er a p y
I n cr e a s e fr e q u e n c y of 
m o nit ori n g t o e v er y 1 t o 
2 d a y s 
If r et ur n s t o B a s eli n e: 
T a p er st er oi d s o v er at l e a st 1 m o nt h, 
c o n si d er pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s, a n d r e s u m e 
a v el u m a b t h er a p y f oll o wi n g st er oi d s t a p er.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 1 7
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt.
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
C o n s ult g a str o e nt er ol o gi st/ 
h e p at ol o gi st
C o n si d er o bt ai ni n g M RI/ C T 
s c a n of li v er a n d li v er bi o p s y 
if cli ni c all y w arr a nt e d
If w or s e n s: Tr e at a s Gr a d e 3-4.
Gr a d e 3 t o 4
A S T or A L T > 5 x U L N a n d/ or t ot al 
bilir u bi n > 3 x U L N 
Di s c o nti n u e a v el u m a b 
t h er a p y 
I n cr e a s e fr e q u e n c y of 
m o nit ori n g t o e v er y 1 t o 
2 d a y s 
1. 0 t o 2. 0 m g/ k g/ d a y 
m et h yl pr e d ni s ol o n e i v or i v 
e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
C o n s ult g a str o e nt er ol o gi st
C o n si d er o bt ai ni n g M RI/ C T 
s c a n of li v er a n d li v er bi o p s y 
if cli ni c all y w arr a nt e d (f or tri al 
sit e s i n G er m a n y, o nl y M RI i s 
t o b e u s e d)
If r et ur n s t o Gr a d e 2: 
T a p er st er oi d s o v er at l e a st 1 m o nt h 
If d o e s n ot i m pr o v e i n > 3 t o 5 d a y s, 
w or s e n s or r e b o u n d s: 
A d d m y c o p h e n ol at e m of etil 6 0 0 m g/ m 2 (f or 
s u bj e ct s 2 t o 1 8 y e ar s of a g e) t wi c e d ail y 
If n o r e s p o n s e wit hi n a n a d diti o n al 3 t o 
5 d a y s, c o n si d er ot h er i m m u n o s u p pr e s s a nt s 
p er l o c al g ui d eli n e s
R e n al ir A E s
Gr a d e of Cr e ati ni n e I n cr e a s e d
( N CI-C T C A E v 4. 0 3)
I niti al M a n a g e m e nt
F oll o w - u p M a n a g e m e nt
Gr a d e 1
C r e ati ni n e i n cr e a s e d
> U L N – 1. 5 x U L N
C o nti n u e a v el u m a b t h er a p y
C o nti n u e r e n al f u n cti o n m o nit ori n g
If w or s e n s:
Tr e at a s Gr a d e 2 t o 3 or 4
Gr a d e 2 t o 3
Cr e ati ni n e i n cr e a s e d 
> 1. 5 – 6 x U L N
Wi t h h ol d a v el u m a b t h er a p y
I n cr e a s e fr e q u e n c y of 
m o nit ori n g t o e v er y 3 d a y s
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt.
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s
C o n si d er r e n al bi o p s y
If r et ur n s t o B a s eli n e:
T a p er st er oi d s o v er at l e a st 1 m o nt h, a n d 
r e s u m e a v el u m a b t h er a p y f oll o wi n g st er oi d s 
t a p er.
If w or s e n s: 
Tr e at a s Gr a d e 4.
Gr a d e 4
Cr e ati ni n e i n cr e a s e d > 6 x U L N
P er m a n e ntl y di s c o nti n u e 
a v el u m a b t h er a p y
M o nit or cr e ati ni n e d ail y
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt.
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s
C o n si d er r e n al bi o p s y
N e p hr ol o g y c o n s ult
If r et ur n s t o Ba s eli n e:
T a p er st er oi d s o v er at l e a st 1 m o nt h.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 1 7
C ar di a c ir A E S
M y o c ar diti s
I niti al M a n a g e m e nt
F oll o w - u p M a n a g e m e nt
N e w o n s et of c ar di a c si g n s or 
s y m pt o m s a n d / or n e w l a b or at or y 
c ar di a c bi o m ar k er el e v ati o n s ( e g ,
tr o p o ni n, C K-M B, B N P) or c ar di a c 
i m a gi n g a b n or m aliti e s s u g g e sti v e 
of m y o c ar diti s.
Wi t h h ol d a v el u m a b t h er a p y
H o s pit ali z e 
I n t h e pr e s e n c e of lif e 
t hr e at e ni n g car di a c 
d e c o m p e n s ati o n, c o n si d er 
tr a n sf er t o a f a cilit y 
e x p eri e n c e d i n a d v a n c e d 
h e art f ail ur e a n d arr h yt h mi a 
m a n a g e m e nt
C ar di ol o g y c o n s ult t o 
e st a bli s h eti ol o g y a n d r ul e 
o ut i m m u n e -m e di at e d 
m y o c ar diti s. 
G ui d eli n e b a s e d s u p p orti v e 
tr e at m e nt a s p er c ar di ol o gy 
c o n s ult. a
C o n si d er m y o c ar di al bi o p s y 
if r e c o m m e n d e d p er 
c ar di ol o g y c o n s ult.
If s y m pt o m s i m pr o v e a n d i m m u n e-m e di at e d 
eti ol o g y i s r ul e d o ut, r e - st art a v el u m a b 
t h er a p y.
If s y m pt o m s d o n ot i m pr o v e/ w or s e n, vir al 
m y o c ar diti s i s e x cl u d e d, a n d i m m u n e -
m e di at e d eti ol o g y i s s u s p e ct e d or c o nfir m e d 
f oll o wi n g c ar di ol o g y c o n s ult, m a n a g e a s 
i m m u n e-m e di at e d m y o c ar diti s.
I m m u n e-m e di at e d m y o c ar diti s
P er m a n e ntl y di s c o nti n u e 
a v el u m a b.
G ui d eli n e b a s e d s u p p orti v e 
tr e at m e nt a s a p pr o pri at e a s 
p er c ar di ol o g y c o n s ult. a
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt.
O n c e i m pr o vi n g, t a p er st er oi d s o v er at l e a st 
1 m o nt h a n d a d d pr o p h yl a cti c a nti bi oti c s f or 
o p p ort u ni sti c i nf e cti o n s.
If n o i m pr o v e m e nt or w or s e ni n g, c o n si d er 
a d diti o n al i m m u n o s u p pr e s s a nt s ( e g ,
a z at hi o pri n e, c y cl o s p ori n e A)
a L o c al g ui d eli n e s, or (f or e x a m pl e) E S C ( E ur o p e a n S o ci et y of C ar di ol o g y) or A m eri c a n H e art A s s o ci ati o n (A H A )
g ui d eli n e s 
E S C g ui d eli n e s w e b sit e:  htt p s:// w w w. e s c ar di o. or g/ G ui d eli n e s/ Cli ni c al -Pr a cti c e -G ui d eli n e s
A H A g ui d eli n e s w e b sit e:
htt p:// pr of e s si o n al. h e art. or g/ pr of e s si o n al/ G ui d eli n e s St at e m e nt s/ s e ar c hr e s ult s.j s p ? q = & y = &t = 1 0 0 1
E n d o cri n e ir A E s
E n d o cri n e Di s or d er
M a n a g e m e nt
F oll o w -u p
Gr a d e 1 or Gr a d e 2
e n d o cri n o p at hi e s ( h y p ot h yr oi di s m, 
h y p ert h yr oi di s m, a dr e n al 
i n s uffi ci e n c y, t y p e I di a b et e s 
m ellit u s)
—
C o nti n u e h or m o n e r e pl a c e m e nt/ s u p pr e s si o n 
a n d m o nit ori n g of e n d o cri n e f u n cti o n a s 
a p pr o pri at e
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 / 1 1 7
Gr a d e 3 or Gr a d e 4
e n d o cri n o p at hi e s ( h y p ot h yr oi di s m, 
h y p ert h yr oi di s m, a dr e n al 
i n s uffi ci e n c y, t y p e I di a b et e s 
m ellit u s)
Wi t h h ol d a v el u m a b t h er a p y
C o n si d er h o s pit ali z ati o n
E n d o cri n ol o g y c o n s ult
St art t h yr oi d h or m o n e 
r e pl a c e m e nt t h er a p y (f or 
h y p ot h yr oi di s m), a nti -t h yr oi d 
tr e at m e nt (f or 
h y p ert h yr oi di s m), 
c orti c o st er oi d s (f or a dr e n al 
i n s uffi ci e n c y), or i n s uli n (f or 
t y p e I di a b et e s m ellit u s) a s 
a p pr o pri at e.  
R ul e -o u t s e c o n d ar y 
e n d o cri n o p at hi e s ( i e, 
h y p o pit uit ari s m / 
h y p o p h y siti s)
R e s u m e a v el u m a b o n c e s y m pt o m s a n d/ or 
l a b or at or y t e st s i m pr o v e ( wit h or wit h o ut 
h or m o n e r e pl a c e m e nt/ s u p pr e s si o n).
C o nti n u e h or m o n e r e pl a c e m e nt/ 
s u p pr e s si o n a n d m o nit ori n g of e n d o cri n e 
f u n cti o n a s a p pr o pri at e 
H y p o pit uit ari s m/ H y p o p h y siti s 
( s e c o n d ar y e n d o cri n o p at hi e s)
If s e c o n d ar y t h yr oi d a n d/ or 
a dr e n a l i n s uffi ci e n c y i s 
c o nfir m e d ( i e, s u b n or m al 
s er u m T 4 wit h 
i n a p pr o pri at el y l o w T S H 
a n d/ or l o w s er u m c orti s ol 
wit h i n a p pr o pri at el y l o w 
A C T H) :

R ef er t o e n d o cri n ol o gi st 
f or d y n a mi c t e sti n g a s 
i n di c at e d a n d 
m e a s ur e m e nt of ot h er 
h or m o n e s ( F S H, L H, 
G H/I G F -1, pr ol a cti n , 
t e st o st er o n e i n m e n, 
e str o g e n s i n w o m e n) 

St art h or m o n e 
r e pl a c e m e nt/ 
s u p pr e s si v e t h er a p y a s 
a p pr o pri at e 

P erf or m pit uit ar y M RI 
a n d vi s u al fi el d 
e x a mi n ati o n a s 
i n di c at e d
If h yp o p h y siti s c o nfir m e d:

C o nti n u e a v el u m a b if 
mil d or m o d er at e 
s y m pt o m s w it h n or m al 
M RI. R e p e at t h e M RI i n 
1 m o nt h
R e s u m e a v el u m a b o n c e s y m pt o m s a n d 
h or m o n e t e st s i m pr o v e ( wit h or wit h o ut 
h or m o n e r e pl a c e m e nt).
I n a d diti o n, f or h y p o p h y siti s wit h a b n or m al 
M RI, r e s u m e a v el u m a b o nl y o n c e s hri n k a g e 
of t h e pit uit ar y gl a n d o n M RI s c a n i s 
d o c u m e nt e d. 
C o nti n u e h or m o n e r e pl a c e m e nt/ 
s u p pr e s si o n t h er a p y a s a p pr o pri at e.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 1 7

Wi t h h ol d a v el u m a b if 
s e v er e s y m pt o m s or 
lif e-t hr e at e ni n g 
s y m pt o m s of 
h y p o p h y siti s a n d/ or 
a b n or m al M RI. 
C o n si d er 
h o s pit ali z ati o n. I niti at e 
hi g h -d o s e 
c orti c o st er oi d s ( 1 t o 
2
m g/ k g/ d a y 
m et h yl pr e d ni s ol o n e i v
or e q ui v al e nt) f oll o w e d 
b y c orti c o st er oi d s t a p er 
d uri n g at l e a st 1 m o nt h.
Ot h er ir A E s ( n ot d e s cri b e d a b o v e)
Gr a d e of ot h er ir A E s
( N CI-C T C A E v 4. 0 3)
Gr a d e of ot h er ir A E s
( N CI-C T C A E v 4. 0 3)
Gr a d e of ot h er ir A E s
( N CI-C T C A E v 4. 0 3)
Gr a d e 2 or Gr a d e 3 cli ni c al si g n s 
or s y m pt o m s s u g g e sti v e of a 
p ot e nti al ir A E
Wi t h h ol d a v el u m a b t h er a p y 
p e n di n g cli ni c al i n v e sti g ati o n
If ir A E i s r ul e d o ut, m a n a g e a s a p pr o pri at e 
a c c or di n g t o t h e di a g n o si s a n d c o n si d er r e -
st arti n g a v el u m a b t h er a p y
If ir A E i s c o nfir m e d, tr e at a s Gr a d e 2 or 3 
ir A E
Gr a d e 2 ir A E or fir st o c c urr e n c e 
of Gr a d e 3 ir A E 
Wi t h h ol d a v el u m a b t h er a p y
1. 0 t o 2. 0 m g/ k g/ d a y 
pr e d ni s o n e or e q ui v al e nt  
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult a s 
a p pr o pri at e
If i m pr o v e s t o Gr a d e 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h a n d 
r e s u m e a v el u m a b t h er a p y f oll o wi n g st er oi d s 
t a p er 
R e c urr e n c e of s a m e Gr a d e 3 
ir AE s 
P er m a n e ntl y di s c o nti n u e 
a v el u m a b t h er a p y
1. 0
t o 2. 0 m g/ k g/ d a y
pr e d ni s o n e or e q ui v al e nt
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult a s 
a p pr o pri at e
If i m pr o v e s t o Gr a d e 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h 
Gr a d e 4 
P er m a n e ntl y di s c o nti n u e 
a v el u m a b t h er a p y
1. 0
t o 2. 0 m g/ k g/ d a y
pr e d ni s o n e or e q ui v al e nt 
a n d/ or ot h er 
i m m u n o s u p pr e s s a nt a s 
n e e d e d
A d d pr o p h yl a cti c a nti bi oti c s 
f or o p p ort u ni sti c i nf e cti o n s 
S p e ci alt y c o n s ult.
If i m pr o v e s t o Gr a d e 1: 
T a p er st er oi d s o v er at l e a st 1 m o nt h 
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 1 7
R e q uir e m e nt f or 1 0 m g p er d a y  or 
gr e at er pr e d ni s o n e or e q ui v al e nt 
f or m or e t h a n 1 2 w e e k s f or 
r e a s o n s ot h er t h a n h or m o n al 
r e pl a c e m e nt f or a dr e n al 
i n s uffi ci e n c y
P er si st e nt Gr a d e 2 or 3 ir A E 
l a sti n g 1 2 w e e k s or l o n g er
P er m a n e ntl y di s c o nti n u e 
a v el u m a b t h er a p y
S p e ci alt y c o n s ult
A C T H : a dr e n o c orti c otr o pi c h or m o n e ; A D L : a cti viti e s of d ail y li vi n g ; A L T : al a ni n e a mi n otr a n sf er a s e ; A S T : a s p art at e 
a mi n otr a n sf er a s e ; B N P : B-t y p e n atri ur eti c p e pti d e; C K -M B : cr e ati n e ki n a s e -m y o c ar di al fr a cti o n b ; C T : c o m p ut e d 
t o m o gr a p h y; F S H : f olli cl e sti m ul ati n g h or m o n e; G H : gr o wt h h or m o n e ; I G F- 1: i n s uli n-lik e gr o wt h f a ct or ; ir AE : 
i m m u n e-r el at e d a d v er s e e v e nt; L H : l ut ei ni zi n g h or m o n e; M RI : m a g n eti c r e s o n a n c e i m a gi n g ; N CI -C T C A E : 
N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt; T 4 : fr e e t h yr o xi n e; T S H : t h yr oi d-
sti m ul ati n g h or m o n e ; U L N : u p p er li mit of n or m al.
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
A vel u ma b is f or m ulate d as a 2 0. 0 m g /m L  sol uti o n a n d is s u p plie d b y  the S p o ns or i n si n gle-use 
glass vials, st o p pere d wit h a r u b ber se pt u m a n d seale d wit h a n al u mi n u m / yell o w p ol y pr o p y le ne 
fli p-off seal.
A vel u ma b will be pac ka ge d a n d la bele d i n acc or da nce wit h all a p plica ble re g ulat or y r e q uire me nts 
a n d G o o d Ma n ufact uri n g Practice g ui deli nes. Eac h b o x of avel u ma b will c o ntai n 1 vial. T he 
i nf or mati o n o n t he la bel 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. 
A vel u ma b will be s hi p pe d i n s uita ble tra ns p ort c o ntai ners acc or di n g t o its st ora ge a n d s hi p pi n g 
c o n diti o ns. S hi p me nts are m o nit ore d wit h te m perat ure c o ntr ol de vices.
 
T he c o nte nts of t he a vel u ma b vials are sterile a n d n o n p yr o ge nic, a n d d o n ot c o ntai n bacteri ostatic 
preser vati ves. A n y s pills 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 vel u ma b m ust be st ore d at 
 u ntil use, wit h a te m perat ure l o g mai ntai ne d dail y . All 
me dicati o n b o xes s u p plie d t o eac h trial site m ust be st ore d caref ull y, safel y, a n d se parately fr o m 
ot her dr u gs.
A vel u ma b st ore d at r o o m te m perat ure 
 or at ele vate d te m perat ures 
 
f or e xte n de d peri o ds is s u bject t o de gra dati o n. A vel u ma b m ust n ot b e fr oze n. R o u g h s ha ki n g of 
a vel u ma b m ust be a v oi de d.
F or a p plicati o n i n t his trial, a vel u ma b m ust be 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) or as i n dicate d i n t he P har mac y  Ma n ual . Detaile d i nf or mati o n o n i nf usi o n ba gs a n d 
me dical de v ices t o be use d f or t he pre parati o n of t he dil uti o ns a n d s u bse q ue nt a d mi nistrati o n will 
be pr o vi de d i n t he P har mac y  Ma n ual.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
A vel u ma b m ust n ot be use d f or a n y p ur p ose ot her t ha n t he trial. T he a d mi nistrati o n of a vel u ma b 
t o s u bjects w h o ha ve n ot bee n e nr olled i nt o t he trial is n ot c o vere d b y  t he trial i ns ura nce.
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.
St ora ge, ha n dli n g, pre parati o n, a n d dis p osal of a vel u ma b s h o ul d be acc or di n g t o l ocal i nstit uti o nal 
g ui deli nes.
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 nvesti gat or is res p o nsi ble f or e ns uri n g acc o u nta bilit y for trial dr u g , i ncl u di n g rec o nciliati o n 
of dr u gs a n d mai nte na nce of dr u g rec or ds.

U p o n recei pt of trial dr u g , t he I n vesti gat or ( or desi g nee) will c hec k f or acc urate deli ver y  an d 
ac k n o wle d ge recei pt b y  si g ni n g ( or i nitiali n g) a n d dati n g t he d oc u me ntati o n pr o vi de d b y  the 
S p o ns or a n d ret ur ni n g it t o t he S p o ns or. A c o p y will be re tai ne d f or t he I n vesti gat or Site File.

T he dis pe nsi n g of t he trial dr u g will be caref ull y rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y 
f or ms pr o vi de d b y t he S p o ns or, a n d a n acc urate acc o u nti n g will be a vaila ble f or verificati o n b y 
t he S p o ns or’s M o nit or at eac h m o nit ori n g visit.

T rial dr u g acc o u nta bilit y rec or ds will i ncl u de:

co nfir mati o n of trial dr u g deli ver y  t o t he trial site.

the i n ve nt or y  at t he site of trial dr u g pr o vi de d b y t he S p o ns or a n d pre pa re d at t he site.

the u se of eac h d ose by eac h s u bject .

d ates, q ua ntities, batc h n u m bers, e x pir y dates a n d (f or trial dr u g pre pare d at t he site) 
f or m ulati o n, as well as t he s u bjects’ trial n u m bers.

T he I n vesti gat or s h o ul d mai ntai n rec or ds t hat a de q uatel y d oc u me nt t hat:

t he s u bjects were pr o vi de d t he d oses s pecifie d by t he cli nical trial pr ot oc ol .

all trial dr u g pr o vi de d b y t he S p o ns or was f ull y  rec o ncile d.
U n use d trial dr u g m ust n ot be use d f or a n y p ur p ose ot her t ha n t he c urre nt trial. A n y  trial dr u g t hat 
has bee n dis pe n se d t o a s u bject m ust n ot be redis 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 c ollect t he trial dr u g acc o u nta bilit y f or ms a n d 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 t o t he S p o ns or or 
a ut h orizi n g t heir destr ucti o n b y  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 T rial 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  For 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 linical 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 F or 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 :
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 1 7

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 trial.

d ate of destr ucti o n(s).

na me a n d si g nat ure of t he I n vesti gat or/ p har macist.
It m ust be e ns ure d at eac h trial site t hat t he trial dr u g is n ot use d:

after t he e x pir y date.

after t he retest date u nless t he trial dr u g is rea nal yze 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 Cli nical Trial M o nit or.
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 trial treat me nt 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 trial dr u g a d mi nistrati o n. T he i nf or mati o n of eac h trial dr u g 
a d mi nist rati o n, i ncl u di n g t he date, ti me, a n d d ose of trial dr u g, 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 dr u g 
a d mi nistrati o n is acc urate f or eac h s u bject. A n y r eas o n f or n o nc o m plia nce s h o ul d be d oc u me nte d.
N o n c o m plia nce is defi ne d as a s u bject missi n g > 1 c ycle of trial treat me nt f or n o nme dical reas o ns
a n d barri n g a n y e xte n uati n g circ u msta nces i n t he o pi ni o n of t he I nvesti gat or . If 1 c ycle 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 c ycle a n d t he last a d mi nistere d t reat ment c y cle 
wa s 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.
6. 1 0
Bli n di n g
T his is a n o pe n -la bel trial. T heref ore, trial treat me nt is n ot bli n de d.
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 v er d ose is defi ne d as a n y dose 5 % or m ore
t ha n t he calc ulate d d ose f or t hat partic ular 
a d mi nistrati o n . A n y  o ver d ose m ust be rec or de d i n t he trial dr u g 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  c ase of o ver d ose, w het her or n ot ass oci ate d wit h a n A E (seri o us or 
n o n seri o us), m ust be re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner usi n g t he S A E Re p ort F or m 
(see Secti o n 7. 4. 1. 4 ).
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 /1 1 7
T here are n o k n o w n s ym pt o ms of a vel u ma b o ver d ose t o date. T he In vesti gat or s h o ul d use his or 
her cli nical j u d g me nt w he n treati n g a n o ver d ose of t he trial dr u g.
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. T he S p o ns or will n ot 
pr o vi de a n y a d diti o nal care t o s u bjects after t he y lea ve t he trial beca use s uc h care s h o ul d n ot differ 
fr o m w hat is n or mall y  e xpecte d f or s u bjects wit h s oli d t u m ors u nless it differs fr o m l ocal la ws a n d 
re g ulati o ns.
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 h e 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. 5 .
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 s ur vi val f oll o w-u p will c o nti n ue 
u ntil u p t o 1 year after t he last su bject recei ves t he last d ose of a vel u ma b or t he last s u bject dies, 
w hic he ver c o mes first. T he S p o ns or ma y  ter mi nate t he st u d y at a n y ti me, a n d t here m a y  be 
all o wa nce f or s u bjects t o e nter a r ollo ver st u d y, e x pa n de d access ,or ot her mec ha nis m f or a vel u ma b 
access as a p pr o priate.
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 S c he d ule of A ssess me nts is pr o vi de d i n Ta ble 1. T he Sc he d ule of Assess me nts -
P har mac o ki netic a n d A nti dr u g A nti b o d y  Sa m pli n g is pr o vi de d i n Ta ble 2 , a n d t he P K/ A D A 
pr oce d ures are disc usse d i n Secti o n  7. 5 .
Pri or t o perf or mi n g a n y  trial assess me nts t hat are n ot part of r o uti ne me dical care f or t he s u bject, 
t he In vesti gat or will o btai n writ te n i nf or me d c o nse nt as descri be d i n Secti o n  9. 2 .
Scree ni n g a n d B aseli ne Pr oce d ures a n d Assess me nts
T he Scree ni n g pr oce d ures a n d B aseli ne assess me nts will be c o m plete d wit hi n 2 8 da y s bef ore trial 
treat me nt starts.
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 as sess me nts are starte d, 
t he s u bject’s pare nts /le gal g uar dia ns will be as ke d t o si g n t he I C F. A disc ussi o n a b o ut c o n d ucti n g 
t u m or sa m pli n g at t he ti me of pr o gressi o n s h o ul d be part of t he i nitial i nf or me d c o nse nt pr ocess.
T he Scree ni n g pr oce d ures a n d B aseli ne assess me nts will be c o m plete d wit hi n 2 8 da ys of si g ni n g 
t he I CF a n d pri or t o re gistrati o n a n d a vel u ma b i nf usi o n o n C y cle 1 D a y  1. Fail ure t o esta blis h 
eli gi bilit y wit hi n 2 8 d a y s w o ul d res ult i n Scree ni n g fail ure, a n d t he s u bject will be e xcl u de d fr o m 
t he trial. H o we ver, s u bjects ca n be rescree ne d base d o n t he I n vesti gat or’s j u d g me nt a n d f oll o wi n g 
S p o ns or a p pr o val. I n t his case, t he pare nt(s)/le gal g uardia n (s) of rescree ne d partici pa nts will si g n 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 1 7
a ne w I CF, a ne w s u bject n u m ber will be assi g ne d, a n d t he Scree ni n g pr oce d ures will be 
c o n d ucte d. 
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 de m o gra p hic 
i nf or mati o n ( birt h date, se x, a n d race as per mitte d b y l ocal re g ulati o ns ), 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 s oli d t u m or or l ym p h o ma , pre vi o us a n d o n g oi n g a ntica ncer 
t hera pies, a n d b aseli ne me dical c o n diti o n (c o nc o mita nt me dicati o ns a n d pr oce d ures 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 B aseli ne Assessme nts V isit.
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, i ncl u di n g rec or di n g 
b o d y  hei g ht a n d wei g ht, vital si g ns, 1 2- lea d E C G, a n d a deter mi nati o n of perf or ma nce stat us (usi n g 
La ns k y perf or ma nce stat us f or s u bjects ≤1 6 years of a ge or Kar n ofs k y  scale f or s u bjects 
> 1 6 ye ars of a ge). Baseli ne data i nf or mati o n s h o ul d be c o m plete d bef ore t he c ollecti o n of bl o o d 
sa m ples, t u m or bi o psies , or a n y in vasi ve pr oce d ure ot her t ha n t he af ore me nti o ne d vital si g ns, 
de m o gra p hics , a n d cli nical hist or y i nf or mati o n.
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, a n d f ull uri nal y sis ( di pstic k pl us micr osc o pic e val uati o n). F ree t h yr o xi ne ( T 4) a n d 
t h yr oi d-sti m ulati n g h or m o ne ( T S H) will als o be assesse d at Scree ni n g f or all s u bjects. 
D uri n g Scree ni n g , a ser u m beta -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 scree ni n g tests will be 
perf or me d f or all scree n e d s u bjects, as t hese c o n diti o ns are trial e ntr y e xcl usi o n criteria (see 
Secti o n 5. 3. 2 ). 
As per mitte d b y  local or i nstit uti o nal re g ulati o ns, s u bjects w h o are of c hil d beari n g p ote ntial 
( defi ne d as, i n t he o pi ni o n of t he I n vesti gat or, t he s u bject is bi ol o gicall y c a pa ble of ha vi n g c hil dre n 
a n d is se x uall y acti ve) will be as ke d t o affir m t hat t he y meet t he criteria f or c orrect use of 2 of t he 
selecte d met h o ds of c o ntrace pti o n (see A p pe n di x I). As per mitte d b y  local or i nstit uti o nal 
re g ulati o ns, the I nvesti gat or or his or her desi g nee will disc uss wit h t he s u bject t he nee d t o use 
2 hi g hl y effecti ve c o ntrace pti o n met h o ds 
c o nsiste ntl y an d c orrectl y a n d d oc u me n t s uc h 
c o n versati o n i n t he s u bject ’s c hart. I n a d diti o n, t he I n vesti gat or or his or her desi g nee will i nstr uct 
t he s u bject t o call i m me diatel y if 1 or b ot h selecte d c o ntrace pti o n met h o ds are disc o nti n ue d, or if 
pre g na nc y  is k n o w n or s us pecte d i n t he s u bject or t he s u bject’s part ner.
Baseli ne tu m or e val uati o n (t ype a n d sta gi n g, etc.) will be perf or me d usi n g C T or M RI (see 
Secti o n 7. 2. 5 f or details). T he t u m or e val uati o n will i ncl u de all k n o w n or s us pecte d disease sites. 
I ma gi n g m a y  incl u de nec k, c hest, a b d o me n, a n d pel vis C T or M RI  sca ns (if M RI is use d, C T of 
c hest is ma n d at or y; f or trial sites i n Ger ma n y, o nl y M RI  is t o be use d) . Baseli ne C N S i ma gi n g will 
n ot be re q uire d wit h t he e xce pti o n of s ym pt o matic s u bjects t o e val uate f or C N S metastases. A 
b o ne sca n ( b o ne sci nti gra p h y) or fl u or o de o x ygl uc ose F 1 8 -p ositr o n e missi o n t om o gra p h y/ C T 
(1 8F D G -P E T/ C T ) is re q uire d at Baseli ne i n s u bjects wit h t u m ors k n o w n t o metastasize t o b o ne.
S u bjects are re q uire d t o pr o vi de t u m or tiss ue sa m ples, see Secti o n 7. 6. 1 f or details. T u m or tiss ue 
ca n be arc hi val tiss ue ( bl oc ks prefera ble) or fr o m a bi o ps y perf or me d d uri n g scree ni n g ( bl oc ks or 
sli des, bl oc ks prefera ble).
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 /1 1 7
Bl o o d sa m ples will be c ollecte d pri or to t he first d ose of a vel u ma b t o deter mi ne b aseli ne 
l ym p h oc y te s u bset q ua ntificati o n (ie, T-c ell, B- cell, a n d N K -cell n u m bers a n d T- cell p o p ulati o n) 
a n d f or assessi n g baseli ne vacci nati o n -relate d a nti b o d y titers a n d c yt o ki nes.
 
 
 
 
 
 
Tre at me nt Peri o d
I n t his trial, trial treat me nt will be gi ve n u ntil c o nfir me d disease pr o gressi o n, si g nifica nt cli nical 
deteri orati o n ( c o nfir me d cli nical pr o gressi o n), deat h, 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 trial treat me nt is f ulfille d (see Secti o n 5. 5. 1 ). T reat me nt ma y c o nti n ue 
past t he i nitial deter mi nati o n of c o nfir me d disease pr o gressi o n acc or di n g t o irR E CI S T if t he 
s u bject’s perf or ma nce stat us has re mai ne d sta ble a n d if, i n t he o pi ni o n of t he In vesti gat or, t he 
s u bject will be nefit fr o m c o nti n ue d treat me nt (see Secti o n 6. 2 ). A d diti o nall y , s u bjects w h o ha ve 
e x perie nce d a C R s h o ul d be treated f or a mi ni m u m of 1 2 m o nt hs base d o n cli nical j u d gme nt of 
be nefit a n d/ or u ntil c o nfir me d disease pr o gressi o n or u nacce pta ble t o xicit y, after c o nfir mati o n of 
res p o nse, at t he discreti o n of t he I n vesti gat or. 
I n case s uc h s u bject’s disease rela pses after st o p pi n g treat me nt, b ut pri or t o t he e n d of t he trial, 
1 re-i nitiati o n of treat me nt will be all o we d at t he discreti o n of t he In vesti gat or a n d wit h t he 
a gree me nt wit h t he Me dical M o nit or . I n or der t o be eli gi ble f or re-treat me nt, t he s u bject m ust n ot 
ha ve ex perie nce d a n y t o xicit y  that le d t o treat me nt disc o nti n uati o n of t he i nitial a vel u ma b t hera py. 
Pri or t o re-i nitiati o n of t he st u d y treat me nt, mali g na nt disease will be ra di ol o gically 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 nt safety la b orat or y res ults m ust be a vaila ble a n d verifie d pri or t o re-
i nitiati n g treat me nt. S u bjects w h o re-i nitiate treat me nt will sta y on st u d y an d will be treate d a n d 
m o nit ore d acc or di n g t o t he pr ot oc ol a n d t he “ U ntil E O T” sc he d ule i n t he Sc he d ule of Assess me nts. 
S u bjects w h o re -i nitiate treat me nt will sta y o n 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 pr ot oc ol (see Ta ble 1 ).
St u d y  treat me nt m ust be gi n wit hi n 2 8 da y s of Scree ni n g . W hile o n trial treat me nt, s u bjects will be 
as ke d t o visit t he trial site o nce e ver y  2 wee ks d uri n g t he treat me nt peri o d. A ti me wi n d o w of u p 
t o 3 da y s bef ore or 1 da y  after t he sc he d ule d visit da y  will be per mitte d f or all trial pr oce d ures; 
h o we ver, t he bi wee kl y , 1 4 -d a y  treat me nt sc he d ule s h o ul d be strictl y ad here d t o, a n d s u bjects 
s h o ul d ret ur n t o t he tar get date e ve n if t he pre vi o us visit was off sc he d ule. 
T u m or e val uati o n (see Secti o n 7. 3 ) will be perf or me d e ver y 8 wee ks starti n g at C y cle 5 f or t he 
first 2 4 wee ks , t he n e ver y 1 2 wee ks u ntil t he e n d of treat me nt or wit h dra wal fr o m t he st u d y, a n d 
at t he E n d of Treat me nt/ Wit h dra wa l Visit if m ore t ha n 4 wee ks has passe d si nce t he last e val uati o n.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 /1 1 7
S u bjects will recei ve a vel u ma b b y  iv i nf usi o n f oll o wi n g pretreat me nt wit h a n a nti hista mi ne ( H 1 
rece pt or bl oc ker
s uc h as di p he n h y dra mi ne ) a n d aceta mi n o p he n (paraceta m ol; oral or i v), 
a p pr o xi matel y  30 t o 6 0 mi n utes p ri or t o eac h d ose, o nce e ver y 2 wee ks f or t he first 4 i nf usi o ns 
(see Secti o n 5. 1. 2 ).
Assess me nts t o be perf or me d d uri n g t he treat me nt peri o d are prese nte d i n  Ta ble 1 a n d Ta ble 2 . 
E n d of Tre at me nt
S u bjects w h o disc o nti n ue treat me nt will ha ve E n d of Treat me nt a n d Safet y  Foll o w -u p V isits as 
i n dicate d i n Ta ble 1 . All A E i nf or mati o n f or s u bjects w h o disc o nti n ue a vel u ma b s h o ul d be 
c ollecte d as descri be d i n Secti o n 7. 4. 1. 2 . 
T he p ossi bilit y  of t he s u bject u n der g oi n g o pti o nal t u m or sa m pli n g at c o nfir me d pr o gressi o n will 
be disc usse d wit h t he s u bject’s pare nt(s)/le gal g uar dia n(s) a n d t he s u bject ( w he n a ge a p pr o priate 
a n d per l ocal re g ulati o ns) d uri n g t he i nitial i nfor me d c o nse nt disc ussi o n. T he a p pr o priate ti mi n g 
of t he o pti o nal t u m or sa m pli n g s h o ul d be disc usse d wit h t he S p o ns or a n d Me dical M o nit or.
E n d of Tre at me nt Visit 
S u bjects m ust u n der g o a n E n d of Treat me nt Visit after disc o nti n uati o n of treat me nt 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 y s of t he decisi o n t o disc o nti n ue 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. Please refer t o  Ta ble 1 f or 
t he s pecific assess me nts t o be perf or me d.
A n y  su bject w h o e x perie nces a n A E t hat ma n dates disc o nti n uati o n of st u d y treat me nt s h o ul d ha ve 
a n E n d of Treat me nt V isit as s o o n as p ossi ble after t he decisi o n t o di sc onti n ue st u d y treat me nt 
( wit hi n 7 d a ys). At t he E n d of Treat me nt V isit, 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 2) :

D oc u me ntati o n of A Es , seri o us A Es, a n d c o nc o mita nt me dicati o n a n d pr oce d ures

P h y sical e xa mi nati o n, i ncl u di n g vital si g ns, b o d y  wei g ht, a n d hei g ht

Perf or ma nce stat us (La ns k y  perf or ma nce stat us f or s u bjects ≤1 6 years of a ge, or Kar n ofs k y 
scale f or s u bjects > 1 6 y ears of a ge)

1 2 -lea d E C G

La b orat or y  he mat ol o g y, he m ostase ol o g y ( coa g ulati o n) , f ull ser u m c h e mistr y, f ull uri nal ys is 
( di pstic k pl us micr osc o pic e val uati o n), a n d T 4 a n d T S H le vels

Pre g na nc y  test f or fe male s u bjects of c hil d beari n g p ote ntial

Bl o o d sa m ple f or l y m p h oc y te s u bset q ua ntificati o n

Bl o o d sa m ple f or P K deter mi nati o ns 

Bl o o d sa m ple f or meas uri n g c yt o ki nes a n d vacci nati o n -relate d a nti b o dies
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 /1 1 7
S afet y F oll o w -u p
F oll o w -u p wit h eac h s u bject will be c o n d ucte d 3 0 da y s ( ± 5 da y s) a n d 9 0 da y s ( ± 5 da y s) after t he 
last d ose of a vel u ma b. T he 3 0 -D a y  Safet y F oll o w -u p Visit s h o ul d be perf or me d at t he trial site; 
t he 9 0 -D a y  Safet y F oll o w -U p ca n be perf or me d via tele p h o ne co ntact . Eac h f oll o w-u p will i ncl u de 
a n assess me nt of safety para meters as descri be d i n Ta ble 1 . A ll S A Es a n d all treat me nt-relate d 
n o nseri o us A Es nee d t o be d oc u me nte d t hr o u g h t he st u d y ’s 9 0 -d a y  Safet y F oll o w -u p P h o ne Call .
D uri n g t he p ost -treat me nt safet y foll o w -u p peri o d, A Es a n d S A Es t hat t he I nvesti gat or belie ves 
ha ve at least a reas o na ble p ossi bilit y  of bei n g relate d t o st u d y dr u g are t o be rec or de d o n t he e C R F.
A n y  S AE assesse d as relate d t o st u d y  treat me nt 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 st u d y treat me nt. S u bjects or t heir le gal 
re prese ntati ve will als o be as ke d a b o ut a n y a ntit u m or t hera p y.
L o n g -term F oll o w -u p
After disc o nti n uati o n of st u d y treat me nt, p ostst u d y  sur vi val stat us will be c ollecte d e ver y 12 wee ks
( ± 1 wee k) u ntil deat h, u ntil 1 2 m o nt hs after ter mi nati o n of treat me nt of t he last s u bject, or u ntil 
e n d of st u d y, w hic he ver occ urs first. T his f oll o w-u p will i ncl u de c ollecti o n of i nf or mati o n o n 
s u bse q ue nt a ntica ncer t hera pies. Tele p h o ne c o ntact is acce pta ble.
S u bjects wit h o n g oi n g S A E s re p orte d at t he 9 0 -D a y S afet y F oll o w -u p tele p h o ne call or re p orte d 
d uri n g s ur vi val f oll o w-u p tele p h o ne calls m ust be m o nit ore d a n d f oll o we d u p b y  t he In 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 .”
A n y  su bse q ue nt a ntica ncer t hera pies a n d t he date of a n y res p o nse a n d s u bse q ue nt pr o gressi o n 
s h o ul d be ca pt ure d i n t he e C R F.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
7. 2
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics
De m o gr a p hic D at a
At Scree ni n g, t he f oll o wi n g de m o gra p hic data will be c ollecte d: 

D ate of birt h ( base d o n l ocal re g ulati o ns); se x ( ge n der); race a n d et h nicit y (w he n per mitte d b y  
l ocal re g ulati o ns); c hil d beari n g p ote ntial i n girls a n d t he a bilit y to fat her c hil d re n i n b o y s; 
hei g ht; a n d wei g ht

Me dical
hist or y a n d disease hist or y : pre vi o us ill ness, c o nc o mita nt ill ness at e ntr y i nt o t he trial, 
aller gies, pri or t hera pies a n d re gi me ns f or t he tar get i n dicati o n (rele va nt pre vi o us me dicati o ns), 
c o nc o mita nt t hera pies t o be c o nti n ue d d uri n g t he trial, a n d treat me nts st o p pe d or c ha n ge d at 
e ntr y i nt o t he trial

Perf or ma nce stat us (La ns k y  perf or ma nce stat us f or s u bjects ≤1 6 years of a ge, or Kar n ofs k y 
scale f or s u bjects > 1 6 ye ars of a ge).
Di a g n osis of S oli d T u m ors or L y m p h o m as
T he ca ncer 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 mali g na nc y , 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 a p pr o priate sta gi n g s ys te m f or eac h t u m or t yp e

All t hera py use d f or pri or treat me nt of t he mali g na nc y  (incl u di n g s ur ger y, ra diati o n t hera p y, 
c he m ot hera p y, a n d i m m u n ot hera py)

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 un ot hera p y

C urre nt si g ns a n d s ym pt o ms of t he mali g na nc y  a n d A Es fr o m c urre nt a n d pre vi o us a ntica ncer 
treat me nts

C urre nt disease stat us.
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 wi t hi n 2 8 da y s pri or t o Scree ni n g .
Vit al Si g ns a n d P h ysic al E x a mi n ati o n
T he assess me nts liste d bel o w will be perf or me d d uri n g Scree ni n g a n d as i n dicate d i n t he Sc he d ule 
o f Assess me nts (Ta ble 1 ).
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 a 5- mi n ute rest), a n d 
arterial bl o o d press ure (after a 5-mi n ute rest) , will be rec or de d. 
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g, ge neral a p peara nce, der mat ol o gical, p ul m o nar y , 
car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, 
ne ur ol o gic a n d m usc ul os keletal 
s yste ms, hea d/ nec k, e xtre mities, e yes, ears, n ose, t hr oat, a n d c o g niti ve stat us) will be perf or me d 
a n d t he res ults d oc u me nte d.
B o d y wei g ht a n d hei g ht will be rec or d e d.
C o m p ute d 
T o m o gr a p h y or M a g netic 
Res o n a nce 
I m a gi n g 
Sc a ns f or T u m or Assess me nt
Baseli ne i ma gi n g will be perf or me d wit hi n 2 8 da y s pri or t o re gistrati o n a n d C y cle 1 D a y 1 
treat me nt i n or der t o esta blis h B aseli ne disease stat us of tar get a n d n o ntar get lesi o ns acc or di n g t o 
R E CI S T 1. 1 . Acce pta ble m o dalities i ncl u de C T sca ns (nec k, c hest, a b d o me n, a n d pel vis as 
nee de d ), a n d C T c hest wit h
c o ntrast t o get her wit h M RI  of t he a b d o me n a n d pel vis . T he sa me 
i ma gi n g m o dalit y  (C T or M RI ) s h o ul d be use d t hr o u g h o ut t he st u d y for a partic ular s u bject. 
C o m p ute d t o m o gra p hy i ma ges fr o m a w h ole -b o d y  PE T /C T m a y  be use d as l o n g as i ma gi n g q ualit y 
a n d t he slice t hic k ness of t he C T i ma ges are of t he q ualit y  fr o m a de dicate d C T sca n . T he use of 
i v c o ntrast is preferre d u nless t here is a hist or y of aller g y or ot her ris k i n t he o pi ni o n of t he 
In vesti gat or (c hest X- ra y is n ot acce pta ble ). O t her i ma gi n g m o dalities ma y be perf or me d at t he 
discreti o n of t he I n vesti ga t or a n d as cli nicall y i n dicate d.
Baseli ne t u m or b ur de n s h o ul d be deter mi ne d as o utli ne d i n Secti o n 7. 3 . In ge neral, lesi o ns detecte d 
at Scree ni n g/ B aseli 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  an 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 b o ne scan ( b o ne sci nti gra p h y) or 1 8F D G -P E T/ C T will be re q uire d at Baseli ne i n s u bjects wit h 
t u m ors k n o w n t o metastasize t o b o ne , wit h ra di o gra p hic disease re-e val uati o n o nl y  if b o ne 
metastases are prese nt at Base li ne. Ot her wise, b o ne i ma gi n g will be re q uire d o nl y if ne w b o ne 
metastases are s us pecte d. A d diti o nal i ma gi n g m a y  nee d t o be perf or me d i n case b o ne metastasis 
are detecte d , a n d t hese s h o ul d be f oll o we d i n acc or da nce wit h R E CI S T 1. 1. B aseli ne C N S i magi n g 
will n ot be re q uire d wit h t he e xce pti o n of s y m pt o matic s u bjects t o e val uate f or C N S metastases.
C ar di ac Assess me nts
A ll s u bjects re q uire a si n gle 1 2 -lea d E C G at B aseli ne a n d at ot her visits as i n dicate d i n t he 
Sc he d ule of Assess me nts (Ta ble 1) after t he s u bject has bee n i n a s u pi ne p ositi o n br eat hi n g q uietl y 
f or 5 mi n utes. T he E C G res ults will be use d t o e val uate t he heart rate, atrial ve ntric ular c o n d ucti o n, 
Q R a n d Q T i nter vals, a n d p ossi ble arr h yt h mias. If pr ol o n ge d Q Tc is s us pecte d, t he n t he E C G 
s h o ul d be re-e val uate d b y a q ualifie d pers o n ( ie, a car di ol o gist) at t he i nstit uti o n f or c o nfir mati o n.
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 
cli nical la b orat or y test res ults will ser ve n ot o nl y  as t he B aseli ne val ues f or s u bse q ue nt safety 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 / 1 1 7
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 entr y  criteria 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.  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
T o deter mi ne t he O R R, t he a ntica ncer acti vit y of a vel u ma b will be e val uate d b y  perf or mi n g 
C T/ M RI  sca ns u ntil c o nfir me d disease pr o gressi o n or t he start of ne w a ntica ncer t herap y . 
A C T or M RI  will be perf or me d e ver y 8 wee ks f or t he first 2 4 wee ks, t he n e ver y 12 wee ks 
t hereafter (a wi n d o w of 5 da y s pri or t o d osi n g is all o we d, a n d ± 5 da y s at t he E n d of Treat me nt 
Visit ). I n case partial res p o nse ( P R), c o m plete res p o nse ( C R), or pr o gressi ve disease ( P D) is 
o bser ve d acc or di n g t o R E CI S T 1. 1, a c o nfir mati o n C T or M RI  s h o ul d be perf or me d acc or di n g t o 
R E CI S T 1. 1, prefera bl y a t t he re g ularly s c he d ule d 8-wee k assess me nt i nter val, b ut n o s o o ner t ha n 
4 wee ks after t he i nitial d oc u me ntati o n of res p o nse or c o nfir me d disease pr o gressi o n. T u m or 
assess me nt s h o ul d be re peate d at t he E n d of Treat me nt Visit if m ore t ha n 4 wee ks ha ve passe d 
si nce t he last e val uati o n.
Treat me nt decisi o ns will be ma de b y  the I n vesti gat or base d o n t he I nvesti gat or ’s assess me nt of 
disease stat us. I n vesti gat or’s assess me nt of o bjecti ve t u m or res p o nse t o treat me nt will be 
perf or me d acc or di n g t o R E CI S T 1. 1 (all me as ure me nts s h o ul d be rec or de d i n metric n otati o n, as 
descri be d i n R E CI S T 1. 1 ).
7. 4
Assess me nt of S afet y
T he safety pr ofile of t he trial treat me nts 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 yz i n g of b aseli ne me dical c o n diti o ns, A Es,
p h y sical e x a mi nati o n fi n di n gs (i ncl u di n g vital 
si g ns), a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y  a p pare nt t o xicit y e x perie nce d b y t he s u bject will be perf or me d 
t hr o u g h o ut t he c o urse of t he trial, fr o m t he ti me of t he s u bject’s asse nt ( w he n a ge a p pr o priate a n d 
per l ocal re g ulati o ns) a n d t he s u bject’s le gal re prese ntati ve si g nat ure of i nf or me d c o nse nt. Trial 
site pers o n nel will re p ort an y  A E, w het her o bser ve d b y t he In vesti gat or or re p orte d b y t he s u bject 
a n d/ or his/ her pare nt(s)/le gal re prese ntati ve(s) (see Secti o n 7. 4. 1. 2 ). Gi ve n 
t he i nte n de d 
mec ha nis m of acti o n of a vel u ma b, partic ular atte nti o n will be gi ve n t o A Es t hat ma y  foll o w t he 
e n ha nce d T- cell acti vati o n, s uc h as der matitis, c olitis, he patitis, u veitis, or ot her I RR. 
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 in dicate d, f or si g ns or 
s ym pt o ms of u veitis.
T he re p orti n g peri o d f or A Es is descri be d i n Secti o n  7. 4. 1. 3.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
T he safety a ssess me nts will be perf or me d acc or di n g t o t he Sc he d ule of Assess me nts (see Ta ble 1 ).
A d verse E ve nts
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 utica l 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.
T he I n vesti gat or is re q uire d t o gra de t he se verity o r t oxicit y  of eac h A E.
I n vesti gat ors will refere nce N CI -C T C A E v 4. 0 3 ( p u blicati o n date: 1 4 J une 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 verit y) 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 gra 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 Gr a de 5 f oll o wi n g his or her best 
me dical j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g 

Gra de 5 or Deat h 
Acc or di n g t o S p o ns or 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 a n S A E. H o we ver, a la b orat or y ab 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 1 of t he seri o us criteria descri be d bel o w.
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 his 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 (e g, 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.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 / 1 1 7
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 trial treat me nt usi n g 
t he f oll o wi n g defi niti 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 trial treat me nt i ncl u de, b ut m a y  not 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 trial treat me nt, k n o w n si de effects of trial treat me nt, me dical hist or y, c o nc o mita nt 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 I M P. T he A E c o ul d n ot me dicall y ( p har mac ol o gicall y/
cli nicall y) be attri b ute d t o t he trial treat me nt u n der st u d y in 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 trial treat me nt u n der st u d y in t his cli nical trial pr ot oc ol. 
Tre at me nt -e mer ge nt A d verse E ve nt ( T E A E)
Treat me nt -e mer ge nt a d verse e ve nts are defi ne d as e ve nts wit h o nset dates occ urri n g o n treat me nt 
or e ve nts t hat w orse n o n treat me nt.
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 or 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 (e g, o n a n E C G traci n g) 
s h o ul d n ot be r e 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 y m 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 dica ll y i m p orta nt b y t he I n vesti gat or. If 
a la b orat or y ab n or malit y  fulfills t hese criteria, t he i de ntifie d me dical c o n diti o n (e g, 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.
A d verse Dr u g Re acti o n ( A D R)
A d verse dr u g reacti o ns are defi ne d i n t his st u d y as a n y AEs s us pecte d t o be relate d t o st u d y 
treat me nt b y t he I n vesti gat or a n d/or S p o ns or.
S eri o us A d verse E ve nt
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 use d 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 gs 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 d efect.

Is ot her wise c o nsi dere d t o be me dically i m p orta nt. 
N ote: i m p orta nt me dical e ve nts t hat m a 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 
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 /1 1 7
ma y  je o pardize 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. E xa m ples 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 de part me nt or at h o me, bl o o d d y scrasias 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.
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 n S A E, as descri be d i n 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 ( e g, a n 
o ver ni g ht sta y to facilitate t hera py 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 (e g, 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.
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 well 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 uld n ot be re p orte d as a n ( 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 f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he A E re p orti ng peri o d (as defi ne d i n Secti o n 7. 4. 1. 3 ).
Pre defi ne d A Es of S peci al I nterest f or S afet y M o nit ori n g
A n y  AE t hat is s us pecte d t o be a p ote ntial ir A E, as well as I RRs, will be c o nsi dere d a n a d verse 
e ve nt of s pecial i nterest . 
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 or le gall y res p o nsi ble re prese ntati ve will be q uerie d o n c ha n ges i n 
t he s u bject’s c o n diti o n. D uri n g t he re p orti n g peri o d, a n y unfa 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/re prese ntati ve 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. 
All S A Es m u st be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o priate S A E e C R F pa ge 
( S A E SID T) 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 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 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 trial treat me nt, 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. 
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.
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 s ur veilla nce will be gi n w he n t he s u bject is i nitiall y i ncl u de d i n 
t he trial ( date of first si g nat ure of i nf or me d c o nse nt) a n d c o nti n ue t hr o u g h t he 9 0 - Da y S afet y 
F oll o w -u p P h o ne Call, w hic h is defi ne d as occ urri n g 9 0 d a y s ( ± 5 da ys) after last st u d y dr u g 
a d mi nistrati o n . 
A n y  S A E assesse d as relate d t o I M P 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 IM P.
Pr oce d ure f or Re p orti n g 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 u ri n g t he re p orti n g peri o d, t he In vesti gat or m ust 
i m mediatel y  (wit hi n a ma xi m u m of 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 n S A E ( or f oll o w-u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a n S A E Re p ort For m m ust be c o m plete d i m me diatel y t hereafter i n t he e C R F.
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n paralle l (e g, me dical hist o r y or c o nc o mita nt 
dr u gs). A d diti o nal d o c u me nts ma y  be pr o vi de d b y  the In vesti gat or, if a vaila ble (e g, la b orat or y 
res ults, h os pital re p ort, or a ut o ps y re p ort). 
T he In 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 (e g, a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, or 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/ desi g nee m a y  h ave 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 necessar y  to e ns ure 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 ual l y be ma de via t he res p o nsi ble Mo nit or, alt h o u g h i n e xce pti o nal 
circ u m sta nces t he Gl o bal Dr u g Safet y D e part me nt of t he S p o ns or m a y  co ntact t he In vesti gat or 
directl y  t o o btai n clarificati o n or t o o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
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 nce wit h 
a p plica ble la ws a n d re g ulati o ns.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 ularly deat hs) i n v ol vi n g trial s u bjects t o t he I EC/I R B 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, t he S p o ns 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 safety of s u bjects, i m pact t he c o n d uct of t he trial, or alter t he 
I E C’s/I R B’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 nvesti 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 relate d t o t he a d mi nistere d pr o d uct (“s us pecte d 
u ne x pecte d seri o us a d verse reacti o ns,” or 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 nvesti gat or s will be ta ke n i nt o acc o u nt.
W he n s pecificall y  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/ 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 E C/IR B a n d will mai ntai n rec or ds of 
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, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y  n otif yi n g t he c o ncer ne d I E C/I R B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns 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 d oc u me nts.
M o nit ori n g of S u bjects wit h A d verse E ve nts
A n y  AE t hat occ urs d uri n g t he c o urse of a cli nical trial m ust be m o nit ore d a n d f oll o we d u p a n d 
are assesse d f or fi nal o utc o me at t he Safet y F oll o w -u p P h o ne Call at 9 0 d a y s ( ± 5 d a y s) after t he 
last I MP a d mi nistrati o n . A ll S A Es a n d all treat me nt-relate d n o nseri o us A Es nee d t o be 
d oc u me nte d t hr o u g h t he st u d y ’s Safet y F oll o w-u p P h o ne Call.
All S A Es o n g oi n g at t he Safet y  Foll o w -u p P h o ne Call m ust be m o nit ore d a n d f oll o we d u p b y  t h e 
In 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 .”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 In vesti gat or t o e ns ure t hat a n y necessar y  ad 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. 
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 t he I n vesti gat or t o be relate d t o trial treat me nt (e g, 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 Es. 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 e C 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 vesti gat or m ust n otif y  the S p o ns 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 ne as 
descri be d f or S A E re p orti n g i n Secti o n  7. 4. 1. 4 . 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 gat or m ust n otif y  t he S p o ns 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.
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/ desi g nee m ust be n otifie d 
wit h o ut dela y , a n d t he s u bject m ust be f oll o we d as me nti o ne d a b o ve.
L a b or at or y Assess me nts
C li nical la b orat or y sa m ples, as detaile d i n t he Sc he d ule of Assess me nts (see Ta ble 1) a n d liste d i n 
Ta ble 6 , will
be c ollecte d a n d a nal yze d l ocall y. L o cal la b orat or y sa m ples a n d res ults will be 
rec or de d i n t he e C R Fs acc or di n g t o t he e C R F c o m pleti o n g ui deli nes. 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 
f ull safet y tests liste d i n Ta ble 6 will be ta ke n fr o m n o nfas te d s u bjects as detaile d i n t he Sc he d ule 
of Assess me nts (Ta ble 1 ). Uri nal ys is, a n d T 4 a n d T S H tests will be perf or me d o nl y at t he ti me 
p oi nts defi ne d i n Ta ble 1.
Sa m ple c ollecti o n, details of bl o o d v ol u me b y  visit a n d assess me nt, la beli n g, a n d st ora ge
re q uire me nts will be s u m marize d i n a se parate La b orat or y  Ma n ual or Ma n ual of O perati o ns.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 /1 1 7
T a ble 6
Cli nic al L a b or at or y Assess me nts
F ull C h e mi str y
C or e C h e mi str y a
H e m at ol o g y
Al b u mi n
Al k ali n e p h o s p h at a s e
A b s ol ut e l y m p h o c yt e c o u nt
Al k ali n e p h o s p h at a s e
A L T
A b s ol ut e n e utr o p hil c o u nt
A L T
A S T
H e m at o crit
A m yl a s e
B U N/t ot al ur e a
H e m o gl o bi n
A S T
C al ci u m
Pl at el et c o u nt
G G T
C hl ori d e
R B C c o u nt
B U N/t ot al ur e a
Cr e ati ni n e
W h it e bl o o d c ell c o u nt a n d diff er e nti al c o u nt
C al ci u m
Gl u c o s e
C hl ori d e
P h o s p h or u s/ P h o s p h at e s
C h ol e st er ol
M a g n e si u m
Cr e ati n e ki n a s e
P ot a s si u m
Cr e ati ni n e
S o di u m
C R P
T ot al bilir u bi n
Gl u c o s e
Li p a s e
H e m o st a s e ol o g y
L D H
A m yl a s e
a P T T
Li p a s e
Cr e ati n e ki n a s e
Pr ot hr o m bi n ti m e/I N R
P h o s p h or u s/ P h o s p h at e s
M a g n e si u m
B a si c Uri n al y si s ( di p sti c k, i n cl u di n g m a cr o s c o pi c 
a p p e ar a n c e, bilir u bi n, bl o o d, c ol or, gl u c o s e, 
k et o n e s, l e u k o c yt e e st er a s e, nitrit e, p H, pr ot ei n, 
s p e cifi c gr a vit y, ur o bili n o g e n)
F ull uri n al y si s ( di p sti c k pl u s mi cr o s c o pi c 
e v al u ati o n) t o b e p erf or m e d o nl y at t h e S cr e e ni n g 
a n d E n d of Tr e at m e nt V i sit
P ot a s si u m
S o di u m
T ot al bilir u bi n
T ot al pr ot ei n
Uri c a ci d
T ot alit y of bi n di n g A D A
Tri gl y c eri d e s
T S H a n d T 4
H or m o n e
A D A : a nti dr u g a nti b o d y; A L T : al a ni n e a mi n otr a n sf er a s e ; a P T T : a cti v at e d p arti al t hr o m b o pl a sti n ti m e ; A S T : 
a s p art at e a mi n otr a n sf er a s e ; B U N : bl o o d ur e a nitr o g e n ; C R P : C- r e a cti v e pr ot ei n; G G T : 
g a m m a -gl ut a m yltr a n sf er a s e ; I N R: i nt er n ati o n al n or m ali z e d r ati o; L D H : l a ct at e d e h y dr o g e n a s e ; R B C: r e d bl o o d 
c ell ; T S H : t h yr oi d-sti m ul ati n g h or m o n e ; T 4 : fr e e t h yr o xi n e.
a.
C or e s er u m c h e mi stri e s.
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 Baseli 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 In vesti gat or has deter mi ne d t hat t he a b n or malit y is c hr o nic or sta ble.
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
Vital si g ns, perf or ma nce stat us, a n d 1 2 -lea d E C G will be assesse d acc or di n g t o t he Sc he d ule of 
Assess me nts ( see Ta ble 1) .
D o c u me nt N o. 
 
O bject N o. 
 
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 ule of Assess me nts (see Ta ble 1 ) a n d d oc u me nte d i n t he e C R F. A b n or mal fi n di n gs are t o b e 
reassesse d at s u bse q ue nt visits.
B o d y wei g ht will be rec or de d at Scree ni n g a n d at s u bse q ue nt visi ts as i n dicate d i n t he Sc he d ule of 
Assess me nts (see Ta ble 1 ) a n d d oc u me nte d i n t he e C R F. Hei g ht will be meas ure d at Scree ni n g
a n d e ver y 4 wee ks t hereafter.
All ne wl y  dia g n ose d or w orse ni n g c o n diti o ns, si g ns, a n d s ym pt o ms o bser ve d fr o m Scree 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 fe male s u bjects of c hil d beari n g p ote ntial, a ser u m β h C G pre g na nc y  test will be carrie d o ut 
d uri n g Scree ni n g, a n d uri ne or ser u m β h C G pre g na nc y  tests will be carrie d o ut at t he visits 
i n dicate d i n t he Sc he d ule of Assess me nts (see Ta ble 1) . 
7. 5
P h ar m ac o k i netics
Bl o o d sa m ples f or p o p ulati o n P K deter mi nati o ns after a si n gle d ose as well as m ulti ple d oses of 
a vel u ma b will be c ollecte d fr o m all s u bjects i n t he st u d y ( P hase I a n d P hase II).
Sa m ples f or P K assess me nts will be c ollecte d as per t he Sc he d ule of Assess me nts - P K a n d A D A 
Sa m pli n g (see Ta ble 2 ) a n d stratifie d b y  wei g ht ( < 1 0 k g a n d ≥1 0 k g) f or t he first 3 6 s u bjects. 
P har mac o ki netic sa m ples will be c ollecte d d uri n g treat me nt C ycl es 1, 2, 3, 5, 7, 8, 1 3, 1 9, 2 5, a n d 
e ver y 6 c ycles t hereafter. A d diti o nal P K sa m ples will be c ollecte d at t he E n d of Treat me nt Visit 
a n d t he 3 0 -D a y  Safet y F oll o w-u p Visit . Ser u m c o nce ntrati o ns of a vel u ma b will be deter mi ne d b y 
a vali date d met h o d. After t he first 3 6 s u bjects, a m ore s parse P K sa m pli n g sc he d ule will
be 
f oll o we d.
B o d y Fl ui d(s)
Sa m ple c ollecti o n, details of bl o o d v ol u me b y  visit a n d assess me nt, la beli n g, st ora ge, a n d s hi p me nt 
re q uire me nts will be s u m marize d i n a se parate La b orat or y  Ma n ual or Ma n ual of O perati o ns .
P h ar m ac o k i netic C alc ul ati o ns
T he met h o d ol o g y  a n d s oft ware f or P K calc ulati o ns a n d P K para meter esti mati o n will be s pecifie d
i n t he Statistical A nal ysis Pla n ( S A P).
7. 6
Bi o m ar k ers
St ora ge a n d a nal ys es of bi o mar ker sa m ples will be ha n dle d acc or di n g t o t he s pecificati o ns as 
descri be d i n t he I CF.
D o c u me nt N o. 
 
O bject N o. 
 
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
A nti d r u g A nti b o d y
A n o ver vie w of h u ma n A D A
i m m u n o ge nicity asses s me nts (i ncl u di n g ne utralizi n g a nti b o dies 
[ NA b s]) pla n ne d i n t he trial is pr o vi de d i n t he Sc he d ule of Assess me nts - P K a n d A D A Sa m pli n g 
(see Ta ble 2 ).
A bl o o d sa m ple f or b aseli ne A D A a nal ysis will be c ollecte d wit hi n 2 h o urs pri or t o trial treat me n t 
a d mi nistrati o n o n C y cle 1 D a y 1 . F urt her bl o o d sa m ples f or A D A a nal ysis will be c ollecte d 
pre d ose ( wit hi n 2 h o urs pri or t o trial treat me nt) d uri n g C y cles 2, 3, 5, 7, 1 3, 1 9, 2 5, a n d e ver y 
6 c ycles t hereafter f or as l o n g as t he s u bject is recei vi n g trial treat me nt; at t he E n d of Treat me nt
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
V isit; a n d at t he 3 0 -da y Safet y F oll o w -u p V isit. Sa m ples p ositi ve f or A D A will be re -a nal yz e d t o 
deter mi ne t h e titer a n d teste d f or ne utralizi n g ca pacit y.
7. 7
Ot her Assess me nts
S u bject -re p orte d O utc o mes/ Q u alit y of Life
See  A p pe n di x III f or t he La ns k y a n d Kar n ofs k y perf or ma nce scales. Detaile d met h o d ol o g y  will 
be i ncl u de d i n t he Ma n ual of O perati o ns.
8. 2
R a n d o miz ati o n
N ot a p plica ble.
8. 3
E n d p oi nts
Pri m ar y E n d p oi nt s
P hase I a n d P hase II pri mar y e n d p oi nts are as f oll o ws.
P h ase I

O cc urre nce a n d se verit y of T E A Es ≥Gra de 3 acc or di n g t o N CI -C T C A E v 4. 0 3

D L Ts t o deter mi ne t he R P 2 D
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
P h ase II

C o nfir me d B O R acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y t he In vesti gat or .
D ose -li miti ng t o xicities are descri be d i n Secti o n 5. 1. 1. 1. 2 , a n d t he R P 2 D is defi ne d i n Secti o n 
5. 1. 1. 1. 4 .
Best o ver all res p o nse is defi ne d as t he best res p o nse o btai ne d a m o n g all t u m or assess me nt visits 
after t he date of t he first d ose of a vel u ma b u ntil c o nfir me d disease pr o gressi o n. It will be 
deter mi ne d acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y  t he In vesti gat or . O nl y t u m or 
assess me nts perf or me d bef ore t he start of a n y f urt her a ntica ncer treat me nt will be c o nsi dere d i n 
t he assess me nt of B O R. Cli nical deteri orati o n will n ot be c o nsi dere d as d oc u me nte d disease 
pr o gressi o n.
If dee me d a p pr o priate base d o n e mer gi n g data fr o m t his trial, a n I nde pe n de nt Re vie w C o m mittee
ma y  be a d de d at a later date f oll o wi n g a pr ot oc ol a me n d me nt.
Sec o n d ar y E n d p oi nt s
P hase I a n d P hase II sec o n dar y e n d p oi nts are as f oll o ws.
P h a se I

C o nfir me d B O R acc or di n g t o R E CI S T 1. 1 a n d as a dj u dicate d b y t he In vesti gat or

D O R, T T R , P F S per R E CIS T 1. 1 a n d as a dj u dicate d b y  t he I n vesti gat or, a n d O S

Occ urre nce a n d se verit y of T E A Es, A Es of s pecial i nterest, a n d treat me nt-relate d A Es, a n d 
i nci de nce of la b orat or y a b n or malities, as gra de d b y N CI-C T C A E v 4. 0 3

V ital si g ns (i ncl u di n g bl o o d press ure a n d heart rate)

Si n gle - a n d m ulti ple -d ose P K pr ofiles of a vel u ma b (ie, C ma x , A U C, t1/ 2, a n d C tr o u g h, as data 
per mit ) 

I m m u n o ge nicity as meas ure d b y a v el u ma b A D A , i ncl u di n g N A bs

Assess me nt o f t u m or P D -L 1  ex pressi o n; t u m or-i nfiltrati n g T- cell acti vit y; T- cell p o p ulati o n; 
a n d T -cell, B- cell, a n d N K -cell n u m bers at Baseli ne a n d at c o nfir me d pr o gressi o n (if t u m or 
tiss ue is o btai ne d)

V acci nati o n-relate d a nti bo d y  c o nce ntrati o ns.
P h ase II 

D O R, T T R, P F S per R E CI S T 1. 1 a n d as a dj u dicate d b y  t he I n vesti gat or, a n d O S

Occ urre nce a n d se verit y of T E A Es, A Es of s pecial i nterest, a n d treat me nt-relate d A Es, a n d 
i nci de nce of la b orat or y a b n or malities, as gra de d b y N CI-C T C A E v 4. 0 3

Vital si g ns (i ncl u di n g bl o o d press ure a n d heart rate)

Si n gle - a n d m ulti ple -d ose P K pr ofiles of a vel u ma b (ie, C ma x , A U C, t1/ 2, a n d C tr o u g h, as data 
per mit)

I m m u n o ge nicity as meas ure d b y a vel u ma b A D A , i ncl u di n g N A bs
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7

Assess me nt o f t u m or P D -L 1  e x pressi o n; t u m or-i nfiltrati n g T- cell acti vit y; T- cell p o p ulati o n; 
a n d T-cell, B- cell, a n d N K -cell n u m bers at Baseli ne a n d at c o nfir me d pr o gressi o n (if t u m or 
tiss ue is o btai ne d)

V acci nati o n-relate d a nti b o d y c o nce ntrati o ns.
D ur ati o n of res p o nse is defi ne d, f or s u bjects wit h a n O R, as t he ti me fr o m first d oc u me ntati o n of 
O R ( C R or P R) t o t he date of first d oc u me ntati o n of o bjecti ve P D or deat h d ue t o a n y ca use ,
w hic he ver occ urs first. If a s u bject has n ot ha d a n e ve nt ( P D or deat h), D O R is ce ns ore d at t he dat e 
of last a de q uate t u m or assess me nt. Ce ns ori n g r ules are t he sa me as f or P F S.
Ti me t o res p o nse is defi ne d, f or s u bjects wit h a n O R , as t he ti me fr o m t he date of first d ose of 
a vel u ma b t o t he first d oc u me ntati o n of O R ( C R or P R), w hic h is s u bse q ue ntl y c o nfir me d.
Pr o gressi o n- free sur vi v al is defi ne d as t he ti me fr o m t he date of first d ose of a vel u ma b t o t he 
date of t he first d oc u me ntati o n of o bjecti ve P D per R E CI S T 1. 1 or deat h d ue t o a n y ca use, 
w hic he ver occ urs first. P r o gressi o n-free s ur vi val data will be ce ns ore d o n t he date of t he last 
a de q uate t u m or assess me nt f or s u bjects w h o d o n ot ha ve a n e ve nt ( P D or deat h), f or s u bjects w h o 
start a ne w a ntica ncer t hera p y pri or t o a n e ve nt, or f or s u bjects wit h a n e ve nt after 2 or m ore 
missi n g t u m or ass ess me nts. S u bjects 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 -Baseli ne t u m or assess me nts will be ce ns ore d o n t he start date u nless deat h occ urre d 
o n or bef ore t he ti me of t he sec o n d pla n ne d t u m or assess me nt, i n w hic h case t he d eat h will be 
c o nsi dere d a n e ve nt.
O ver all sur vi v al is defi ne d as t he ti me fr o m t he date of first d ose of a vel u ma b t o t he date of deat h 
d ue t o a n y ca use. S u bjects last k n o w n t o be ali ve will be ce ns ore d at date of last c o ntact.
8. 4
A n al ysis Sets
F ull A n al ysis Set (F A S ): All s u bjects e nr olle d i n t he st u d y a n d recei ve at least 1 d ose of a vel u ma b.
S afet y A n al ysis Set ( S A F): All s u bjects w h o recei ve at least 1 d ose of a vel u ma b. I n t his trial, t he 
S A F = F A S.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
Per -Pr ot oc ol ( P P) A n al ysis Set: A s u bset of t he F A S; will i ncl u de all F A S s u bjects w h o di d n ot 
ha ve a n y cli nicall y i m p orta nt pr ot oc ol de viati o ns. 
D L T A n al ysis Set ( P h ase I o nl y) : All s u bjects wit h data use d f or i m ple me nti n g t he d ose 
escalati o n sc he d ule. T hese s u bjects will ha ve recei ve d all trial treat me nt a d mi nistrati o ns i n t he 
D L T e val uati o n peri o d (first 2 c ycles of treat me nt) or st o p pe d treat me nt beca use of D L Ts i n t he 
D L T e val uati o n peri o d.
P K A n al ysis Set: All s u bjects w h o c o m plete at least 1 a d mi nistrati o n of a vel u ma b a n d w h o 
pr o vi de at least 1 sa m ple wit h meas ura ble c o nce ntrati o ns of a vel u ma b (at least 1 pre d ose a n d 
2 p ost d ose fr o m 2 or m ore treat me nt c ycles) .
I m m u n o ge nicit y A n al ysis Set: All s u bjects w h o c o m plete at least 1 a d mi nistrati o n of a vel u ma b, 
a n d w h o 
ha ve pr o vi de d a bl o o d sa m ple pri or t o a n y a vel u ma b treat me nt a n d at least 
1 p ost -treat me nt sa m ple. 
Bi o m ar ker A n al ysis S ets: All s u bjects w h o c o m plete at least 1 a d mi nistrati o n of a vel u ma b, a n d 
w h o ha ve pr o vi de d t he a p pr o priate bl o o d /ser u m/ plas ma sa m ples f or bi o mar ker assess me nts .
8. 5
Descri pti o n of St atistic al A n al ysis
Ge ner al C o nsi der ati o ns
F ull details of all pla n ne d a nal ys e s will be descri be d i n t he trial S A P.
A nal y ses f or P hase I will be p rese nte d b y  d ose le vel a n d o verall, a n d a nalys es f or P hase II will be 
prese nte d b y e x pa nsi o n c o h ort a n d o verall, if n ot state d ot her wise .
All data rec or de d d uri n g t he trial will be prese n te d i n i n di vi d ual data listi n gs perf or me d o n t he 
S A F. All data will 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 
use d u nless ot her wise s pecifie d i n t he S A P. All data will be prese nte d i n a descri pti ve ma n ner. 
Eac h c o h ort wi ll be a nal yze d se parately, a n d n o m ulti plicit y  adj ust me nt acr oss c o h orts will be 
perf or me d. 
Descri pti ve statistics will be use d t o s u m marize t he trial res ults, ie, statistics f or c o nti n u o us 
varia bles ma y  i ncl u de n u m ber of s u bjects ( n); mea n, sta n dar d de viati o n; me dia n, 2 5t h Perce ntile -
7 5t h Perce ntile ( Q 1 -Q 3), mi ni m u m, a n d ma xi m u m . 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 nt y  of esti mates will be assesse d b y c o nfi de nce i nter vals
( CIs). 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 n u m ber of 
s u bjects i n 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 AP. 
B aseli ne
I n ge neral t he last n o nmissi n g meas ure me nt pri or t o ra n d o mizati o n will ser ve as t he B aseli ne 
meas ure me nt f or efficac y. If n o s uc h a val ue is a vaila ble, t he last meas ure me nt pri or t o t he first 
trial dr u g a d mi nistrati o n will be use d as t he B aseli ne meas ure me nt wit h t he e xce pti o n of pre -
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
ra n d o mizati o n assess me nts use d f or t he derivati o n of efficac y  e n d p oi nts (e g, t u m or assess me nt at 
baseli ne, w hic h will be set t o missi n g, if n ot d o ne pri or t o ra n d o mizati o n).
T he last a vaila ble assess me nt pri or t o t he start of st u d y treat me nt is defi ne d as “ Baseli ne” val ue or 
“ Baseli ne” assess me nt f or safet y . 
O n -Tre at me nt
O n -treat me nt P eri o d is defi ne d as t he ti me fr o m t he first d ose of st u d y treat me nt t hr o u g h mi ni m u m 
( 3 0 da y s + last d ose of st u d y treat me nt, start da y  of ne w a nti -ca ncer t hera p y – 1 d a y ), u nless 
ot her wise state d.
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 S A F. Baseli ne s u m maries a n d efficac y a nal ys es will be perf or me d o n t he 
F A S. A nal ys es of P K varia bles will be perf or me d o n t he P K A nal ysis Set. A nal ysis of pe ri p heral 
bl o o d m o n o n uclear cell p har mac o d y n a mic data will be perf or me d o n t he I m m u n o ge nicity 
A nal y sis Set. A nal ys es of bi o mar kers will
be perf or me d o n t he res pecti ve Bi o mar ker A nal y sis 
Sets. 
T he esti mati o n of P K para meters will be perf or me d usi n g t he vali date d s oft ware t o ol P h oe ni x ®
Wi n N o nli n 6. 3 ® ( or later). All ot her statistical a nal yses will be perf or me d usi n g S A S ® Versi o n 
9. 2 or hi g her.
A n al yse s of P ri m ar y E n d p oi nts
P h ase I: Occ urre nce a n d Se verit y
of Tre at me nt -e mer ge nt 
A d verse E ve nts ≥ Gr a de 3
A d verse e ve nts will be c o de d acc or di n g t o Me dical 
Dicti o nar y  for Re g ulat or y  Acti vities
( Me d D R A). Se verit y of A Es will be gra de d usi n g t he N CI-C T C A E v 4. 0 3 t o xicit y  gra di n g scale. 
A d verse e ve nts (seri o us a n d n o nseri o us) will be c o nsi dere d T E A Es w he n e mer gi n g or w orse ni n g 
i n t he o n -treat me nt peri o d, 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 
dr u g a d mi nistrati o n date + 3 0 d a y s or t he earliest date of s u bse q ue nt a ntica ncer dr u g t hera p y mi n us 
1 da y , w hic he ver occ urs first, u nless ot her wise state d. 
T he fre q ue nc y of s u bjects e x perie nci n g T E A Es
≥Gra de 3 , re gar dless of relate d ness t o trial 
treat me nt, will be s u m marize d b y  s yste m or ga n class a n d preferre d ter m at eac h d ose le vel a n d 
descri be d i n ter ms of se verit y. Si milar s u m maries will als o be pr o vi de d f or T E A Es ≥Gra de 3
relate d t o trial treat me nt.
P h ase I: Deter mi n ati o n of Rec o m me n de d P h ase II D ose
F or deter mi nati o n of R P 2 D, i n di vi d ual s u bject data fr o m t he d ose escalati o n part of t he st u d y will 
be re p orte d b y d ose le vel. 
I n a d diti o n, t he f oll o wi n g will be a nalyz e d:
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7

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 d a D L T d u ri 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  s u bjects i n t he D L T 
A nal y sis Set d uri n g t he D LT e val uati o n peri o d

At eac h d ose le vel a n d o verall, t he n u m ber a n d pr o p orti o n of T E A Es ≥Gra de 3 b y  s u bjects i n 
t he D L T A nalys is Set d uri n g 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 teste d of a vel u ma b ass ociate d wit h t he occ urre nce of 
D L Ts wit hi n t he first 2 c ycles of treat me nt i n < 3 3 % of s u bjects, pr o vi de d t hat a hi g her d ose of 
a vel u ma b was teste d a n d ha d a n ass ociate d D L T rate ≥3 3 %. If t he D L T rate wit hi n t he first 
2 c ycles of treat me nt is < 3 3 % f or all teste d d ose le vels, t he n t he M T D will n ot ha ve bee n reac he d. 
P h ase II: C o nfir me d Best O ver all Res p o nse Acc or di n g t o 
R E CI S T 1. 1 a n d I n vesti g at or
Best o verall r es p o nse will be e val uate d acc or di n g t o R E CI S T 1. 1 a n d b ase d o n t he I nvesti gat or’s 
assess me nt s of disease at differe nt e val uati o n ti me p oi nts fr o m t he first trial a d mi nistrati o n date 
u ntil c o nfir me d disease pr o gressi o n .
O nl y  tu m or assess me nts perf or me d bef or e t he start of a n y f urt her a nti ca ncer treat me nt will be 
c o nsi dere d i n t he assess me nt of B O R. Cli nical deteri orati o n will n ot be c o nsi dere d pr o gressi o n. 
S u bjects w h o d o n ot ha ve a n o n -treat me nt ra di o gra p hic t u m or assess me nt d ue to earl y pr o gre ssi o n, 
w h o recei ve a ntit u m or treat me nts ot her t ha n t he trial 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.
O bj ecti ve res p o nse is defi ne d as C R or P R acc or di n g t o R E CI S T 1. 1 fr o m t he date of first d ose of 
a vel u ma b u ntil d oc u me nte d disease pr o gressi o n. B ot h C R a n d P R m ust be c o nfir me d b y  re peat 
assess me nts acc or di n g t o R E CI S T 1. 1, prefera bl y at t he re g ularly sc he d ule d 8- wee k assess me nt 
i nter val, b ut n o s o o ner t ha n 4 wee ks after t he i nitial d oc u me ntati o n of res p o nse or c o nfir me d 
disease pr o gressi o n . S u bjects w h o d o n ot ha ve 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 ve a ntit 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 nres p o n ders i n t he assess me nt of O R
T he a nal ys is of t he B O R will be c o n d ucte d usi n g t he F A S . 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 c o h ort . A 2-si de d 9 5 % Cl o p per- Pears o n CI 
will be c o nstr ucte 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.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
A n al yse s of Sec o n d ar y E n d p oi nts
P h ase I: C o nfir me d Best O ver all Res p o nse 
Acc or di n g t o 
R E CI S T 1. 1 a n d I n vesti g at or
Best o verall res p o nse will be e val uate d acc or di n g t o R E CIS T 1. 1 a n d base d o n t he I nvesti gat or’s 
assess me nts of disease at differe nt e val uati o n ti me p oi nts fr o m t he first trial a d mi nistrati o n date 
u ntil c o nfir me d disease pr o gressi o n .
O nl y  tu m or assess me nts perf or me d bef ore t he start of a n y f urt her a ntica ncer treat me nt will be 
c o nsi dere d i n t he assess me nt of B O R. Cli nical deteri orati o n will n ot be c o nsi dere d pr o gressi o n. 
S u bjects w h o d o n ot ha ve 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 ve a ntit u m or treat me nts ot her t ha n t he trial treatme 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 nres p o n ders i n t he assess me nt of O R.
O bjecti ve res p o nse is defi ne d as C R or P R acc or di n g t o R E CI S T 1. 1 fr o m t he date of first d ose of 
a vel u ma b u ntil d oc u me nte d disease pr o gressi o n. B ot h C R a n d P R m ust be c o nfir me d b y  re peat 
assess me nts acc or di n g t o R E CI S T 1. 1, prefera bl y at t he re g ularly sc he d ule d 8- wee k assess me nt 
i nter val, b ut n o s o o ner t ha n 4 wee ks after t he i nitial d oc u me ntati o n of res p o nse or c o nfir me d 
disease pr o gressi o n . S u bjects w h o d o n ot ha ve 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 ve a ntit 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 nres p o n ders i n t he assess me nt of O R .
T he a nal ys is of t he B O R will be c o n d ucte d usi n g t he F A S. 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, w ill be ta b ulate d b y  dose le vel a n d o verall. A 2- si de d 9 5 % 
Cl o p per -Pears o n CI will be c o nstr ucte 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.
P h ase I a n d P h ase II : Ot her Effic ac y E n d p oi nts
T he f oll o wi n g pa ra meters will be calc ulate d usi n g t he F A S:

D O R i n s u bjects wit h c o nfir me d B O R of C R or P R: ti me (i n m o nt hs) fr o m t he first occ urre nce 
of C R or P R t o eit her P D or occ urre nce of deat h d ue t o a n y ca use

T T R , w hic h is t he ti me (i n m o nt hs) fr o m t he date of first d ose of a vel u ma b t o t he first 
d oc u me ntati o n of O R ( C R or P R), w hic h is s u bse q ue ntl y  c o nfir me d

P F S , w hic h is t he ti me (i n m o nt hs) fr o m first st u d y dr u g a d mi nistrati o n t o eit her first 
o bser vati o n of P D or occ urre nce of deat h d ue t o a n y ca use wit hi n 1 2 wee ks of t he last t u m or 
assess me nt, w hic he ver occ urs first

O S ti me (i n m o nt hs), calc ulate d f or all s u bjects. 
D urati o n of res p o nse, P F S , a n d O S will be prese nte d i n s u bject listi n gs a n d a nal yze d usi n g t he 
Ka pla n -Meier met h o d i n F A S b y  dose/c o h ort . Ti me t o res p o nse will be prese nte d i n s u bject listi n gs 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
a n d s u m marize d i ncl u di n g n u m ber of s u bjects ( n); mea n,
sta n dar d de viati o n; me dia n, Q 1, Q 3 , 
mi ni m u m, a n d ma xi m u m b y  d ose/c o h ort.
P h ase I a n d P h ase II: S afet y A n al yses
Safet y  anal y ses i n P hase I a n d P hase II will be perf or me d o n t he S A F. T he safety e n d p oi nts will 
be ta b ulate d b y d ose le vel or c o h ort , usi n g descri pti ve statistics.
Safet y  assess me nts will be base d o n re vie w of t he i nci de nce of T E A Es, A Es of s pecial i nterest, 
treat me nt-relate d A Es, a n d c ha n ges i n vital si g ns, a n d la b orat or y val ues ( he mat ol o g y, c oa g ulati o n, 
a n d ser u m c he mistr y).
A d verse E ve nts
All A Es will be c o de d acc or di n g t o Me d D R A. Se verit y of A Es will be gra de d usi n g t he N CI -
C T C A E v 4. 0 3 t o xicit y  gra di n g scale. 
Treat me nt -e mer ge nt a d verse e ve nt s are defi ne d as e ve nts wit h o nset dates occ urri n g o n-treat me nt 
or e ve nts t hat w orse n o n -treat me nt.
T he fre q ue nc y of s u bjects e x perie nci n g T E A Es, re gar dless of relate d ness t o trial treat me nt, will 
be s u m marize d b y  sys te m or ga n class a n d preferre d ter m f or eac h treat me nt ar m. Si milar 
s u m maries will als o be pr o vi de d f or seri o us T E A Es, T E A Es lea di n g t o per ma ne nt disc o nti n uati o n 
of trial treat me nt, T E A Es b y  ma xi m u m se verit y, T E A Es relate d t o trial treat me nt, T E A Es wit h 
fatal o utc o me, a n d treat me nt-e mer ge nt a d ve rse e ve nts of s pecial i nterest, s uc h as ir A Es.
L a b or at or y V al ues 
La b orat or y  res ults will be classifie d b y  gra de acc or di n g t o N CI -C T C A E v 4. 0 3. T he w orst 
o n -treat me nt gra des f or c he mistr y an d he mat ol o g y  la b orat or y res ults will be s u m marize d. S hifts 
i n t o xicit y gra di n g fr o m Baseli ne t o hi g hest gra de d uri n g t he o n -treat me nt peri o d will be dis pla y e d. 
F or la b orat or y tests wit h o ut 
a n N CI -C T C A E gra de defi niti o n, res ults will 
be prese nte d 
cate g oricall y (e g, bel o w, wit hi n, or a b o ve n or mal li mits).
Vit al Si g ns
Vital si g ns ( b o dy t e m perat ure, res pirat or y rate, heart rate, a n d bl o o d press ure), rec or de d acc or di n g 
t o t he Sc he d ule of Assess me nts (Ta ble 1 ), will be presente 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 
versi o n of Me d D R A.
P h ase I a n d P h ase II: P h ar m ac o ki netic Pr ofiles of A vel u m a b
Si n gle - a n d m ulti ple-d ose P K pr ofiles of a vel u ma b, i ncl u di n g C ma x , A U C, t1/ 2, a n d Ctr o u g h, as data 
per mit, will be calc ulate d.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
P K A n al ysis Set
Descri pti ve statistics of P K data will be calc ulate d f or all s u bjects i n t he P K A nal ysis Set.
A vel u ma b ser u m c o nce ntrati o ns will be pr o vi de d i n listi n gs a n d descri pti vel y s u m marize d b y d a y  
a n d n o mi nal ti me, al o n g wit h b y b o d y wei g ht, a ge or act ual d ose as a p pr o priate, usi n g t he n u m ber 
of n o n missi n g o bser vati o ns, arit h metic mea n, 
sta n dar d de viati o n, c oefficie nt of variati o n, 
mi ni m u m, me dia n, a n d ma xi m u m. 
P har mac o ki netic c o nce ntrati o ns a t t he e n d of i nf usi o n ( CE OI ) a n d tr o u g h c o nce ntrati o ns ( Ctr o u g h)
will be a d diti o nall y su m marize d b y  no mi nal ti me da y  on sc he d ule d visits. Descri pti ve statistics 
will a d diti o nall y sh o w t he ge o metric mea n ( Ge o Mea n), t he ge o metric c oefficie nt of variati o n 
( Geo C V) a n d t he 9 5 % CI f or t he Ge o Mea n. 
P har mac o ki netic c o nce ntrati o n data will be re p orte d usi n g t he sa me precisi o n as t he s o urce data. 
Descri pti ve P K a nal ysis will be perf or me d usi n g t he c o m p uter pr o gra m P h oe ni x Wi n N o nli n 
versi o n 6. 4, or hi g her ( Certara, L. P., 1 6 9 9 S Ha nle y R oa d, St L o uis, M O 6 3 1 4 4, U S A). 
P o p ul ati o n P h ar m ac o ki netic A n al ysis
Sa m ple d P K pr o files fr o m t his st u d y ma y be a n al yze d j ointl y wit h da ta fr o m ot her st u dies b y
n o n li near m i xe d effect a pp r oach, i n or d er t o descri be t h e P K c o nce nt rati o n tim e pr o file foll o we d
b y m ulti ple d ose i nfusi o n of a vel um a b; t o i de nti f y c o variates e x plai nin g ( part of ) t he bet wee n
s u bject P K varia bil it y; a n d t o estim ate t he resi d ual P K i nter-i nd i vi d ual va riabil it y.T he P K A nal ys is 
Set will
be use d. M ore deta ils will be gi ve n i n a se parate Data
A nal ys is Pla n for P o p ulati o n
P har m ac o ki netic A n al ysis. T he resul ts will b e rep orte d se par atel y.
P h ase I a n d P h ase II: A vel u m a b A nti dr u g A nti b o dies
S u bjects will be c haracterize d i nt o differe nt cate g ories a n d s u m marize d b y d ose le vel or c o h ort 
base d o n t he criteria i n Ta ble 7.
T a ble 7
S u bject C h ar acteriz ati o n B ase d o n A nti dr u g A nt i b o d y Res ults
C at e g or y
D efi niti o n
S u bj e ct 
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 s u bj e ct s wit h at l e a st 1 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 1 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 s u bj e ct s wit h at l e a st 1 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 
a v el u m a b
N u m b er of s u bj e ct 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 
a v el u m a b a n d t h e tit er ≥8 x B a s eli n e tit er w hil e 
o n a v el u m a b tr e at m e nt
N u m b er of s u bj e ct s wit h v ali d B a s e li n e a n d 
at l e a st 1 v ali d p o st - Ba s eli n e r e s ult
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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 a v el u m a b 
a n d wit h at l e a st 1 p o siti v e p o st - Ba s eli n e r e s ult
N u m b er of s u bj e ct s wit h at l e a st 1 v ali d 
p o st - Ba 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 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 s u bj e ct s h a v e a si n gl e 
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 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 s u bj e ct s wit h at l e a st 1 v ali d 
p o st - Ba 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 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 s u bj e ct 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 s u bj e ct s wit h at l e a st 1 v ali d 
p o st - Ba 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 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 di e s ; N R : n ot r e c or d e d.
Dr u g c o nce ntrati o n i n ser u m f or A D A e ver -p ositi ve s u bjects vers us A D A ne ver -p ositi ve s u bjects 
will be descri pti vel y s u m marize d t o e val uate t he p ote ntial effect of A D A o n P K.
P h ase I a n d P h ase II: Bi o m ar kers
S u m mar y  statistics f or P D -L 1 e x pressi o n a n d i nfiltrati o n b y l ym p h oc y te s u b p o p ulati o ns i n t u m or 
tiss ue will be pr o vi de d f or all pre pla n ne d ti me p oi nts, se paratel y  for eac h d ose le vel, a n d o verall . 
C ha n ges t o baseli ne le vels will als o be prese nte d as a p plica ble. Pr ofiles o ver ti me will be dis pla y e d 
o n a per -s u bject basis.  
Details of t he statistical a nal y sis of bi o mar kers will be prese nte d i n t he S A P.
P h ase 
I a n d 
P h ase 
II: 
V acci n ati o n -rel ate d 
A nti b o d y 
C o nce ntr ati o ns 
C ha n ges i n a nti b o d y c o nce ntrati o ns of 3 vacci nes ( di p ht heria, teta n us, a n d p ne u m oc occal 
c o nj u gate) will be s u m marize d.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
P h ase I a n d P h ase II: S afet y
Safet y  assess me nts will als o be base d o n re vie w of E C G a n d perf or ma nce stat us .
1 2 lea d E C G a n d perf or ma nce stat us, rec or de d acc or di n g t o t he Sc he d ule of Assess me nts (Ta ble 
1 ), will be liste d f or eac h s u bject.
8. 6
I nteri m a n d A d diti o n al Pl a n ne d A n al yses
N o i nteri m a nal ysis f or efficac y is pla n ne d f or t his trial. T here will be peri o dic safety re vie w b y  
t he S M C. Details will be pr o vi de d i n t he S M C C harter.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
9
Et hic al a n d Re g ul at or y As pects
9. 1
Res p o nsi bilities of t he 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, a n d a n y ot her a p plica ble re g ulati o ns. T he In vest i gat or m ust e ns ure t hat o nl y 
s u bjects or t heir le gal re prese ntati ves 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.
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 o o d a n d Dr u g 
A d mi nistrati o n 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  t o t he de m o nstrati o n of 
efficac y an d safet y of a n I MP ( w hic h are c o nsi dere d “c o vere d cli nical trials” b y  the F D A), t he 
In vesti ga t or a n d all s u b-In vesti gat or s are o bli ge d t o discl ose a n y fi na ncial i nterest t hat 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 de q uate i nf or mati o n will be pr o vi de d t o s u bjects a n d t heir pare nt(s)/ le gal g uar dia n(s), a n d 
i nf or me d c o nse nt(s) will be si g ne d b y  pare nt(s)/le gal g uar dia n (s). A n u nc o n diti o nal pr ere q uisite 
f or a s u bject’s partici pati o n i n t he trial is t he writte n 
i nf or me d c o nse nt of her/ his 
pare nt (s)/le gal g uar dia n (s), w hic h m ust be gi ve n bef ore a n y trial-relate d acti vities are carrie d o ut. 
W he n a p plica b le a n d as per l ocal re g ulati o ns, asse nt will be pr o vi de d b y  s u bjects.
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 a n d his / her pare nt(s)/ g uar dia n(s) b y 
t he I n vesti gat or bef ore i nf or me d c o nse nt is o btai ne d (a pers o n desi g nate d b y t he I n vesti gat or may 
gi ve t he i nf or mati o n, if per mitte d b y  l ocal re g ulati o ns). A disc ussi o n a b o ut t u m or sa m pli n g at t he 
ti me of pr o gressi o n s h o ul d be part of t he i nitial i nf or me d c o nse nt c o n versati o n .
A s u bject/ pare nt/ g uar dia n 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 I CH G C P a n d a p plica ble l ocal re q uire me nts, a n d it will be pr o vi de d b y  the 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 ad 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 a n d his/ her pare nt(s)/le ga l g uar dia n(s), t he I n vesti gat or or a desi g nate will i nf or m
ver ball y t he s u bject a n d his/ her pare nt(s)/le gal g uar dia n(s) 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 a n d his/ her pare nt(s)/le gal g uar dia n(s) 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 t o 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.
If per mitte d b y  l ocal re g ulati o ns, a pers o n ot her t ha n t he I n vesti gat or ma y i nf or m t he s u bject a n d 
his/ her pare nt(s)/le gal g uar dia n(s) 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  t he 
s u bject’s pare nt(s)/le gal g uar dia n(s) , t he s u bject ( w he n a p plica ble as per l ocal re g ulati o ns), a n d 
t he In vesti gat or . 
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
T he 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 it 
m ust be safel y arc hi ve d s o t hat t he f or ms ca n be retrie ve d at a n y t i 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 a n d his/ her pare nt(s)/le gal g uar dia n(s) 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 m a y be rele va nt t o i nf or me d c o nse nt, 
t he In vesti 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 s u bjects a n d t heir pare nt(s)/le gal g uar dia n(s) a n d s u b mit t he m t o t he I RB /IE C f or 
re vie w a n d o pi ni o n. Usi n g the 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 In 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 his/ her pare nt(s)/le gal g uar dia n(s) a n d o btai n ne w writte n c o nse nt f or c o nti n ue d partic i pati o n 
i n t he trial. T he s u bject ( w he n a ge a p pr o priate a n d per l ocal re g ulati o ns) a n d his/ her pare nt(s)/le gal 
g uar dia n(s) 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 a b o ut t he c ha n ges.
9. 3
S u bject I de ntific ati o n a n d Pri v ac y
A u ni q ue n u m ber will be assi g ne d t o eac h s u bject, i m me diatel y 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. All s u bject data c ollecte d i n t he trial will be st ore d u n der t he a p pr o priate s u bject n u m ber. 
O nl y  the I n vesti gat or will be a ble t o li n k trial da ta t o a n i n di vi d ual s u bject via a n i de ntificati o n list 
ke pt at t he site. F or eac h s u bject, ori gi nal me dical data will be accessi ble f or t he p ur p oses of s o urce 
data verificati o n b y  the M o nit or, a u dits, a n d re g ulat or y ins pecti o ns, b ut s u bject c o nfi de ntialit y w ill 
be strictl y  mai ntai ne d.
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. S u 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 dat a 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.
If t he s u bject meets all i ncl usi o n criteria a n d d oes n ot meet a n y of t he e xcl usi o n criteria, t he s u bject 
re gistrati o n ce nter will recei ve c o nfir mati o n, re gister t he s u bject a n d i nf or m t he I nves ti gat or a n d 
t he S p o ns or of t he re gistrati o n n u m ber b y  fa x. If t he s u bject is i neli gi ble f or t he trial, a s u bject 
n u m ber will be all ocate d a n d d oc u me nte d.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
9. 4
E mer ge nc y Me d ic 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  the C R O 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 n vesti 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 n vesti gat or is a vaila ble w he n a n e ve nt occ urs, he/s he 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 y sicia n. T his i ncl u des t he pr o visi o n of a 2 4- h o ur 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 will 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.
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 will be pr o vi de d f or eac h c o u ntr y partici pati n g t o t he trial. I ns 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.
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 his 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 t o t he res p o nsi ble I E C or I R B f or its fa v ora ble o pi ni o n or 
a p pr o val, w hic h will be file d i n t he I n vesti gat or Site File. A c o p y will be file d i n t he S p o ns or Trial 
Master File at
Q ui ntilesI M S.
T he I E C or I R B will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora ble o pi ni o n 
or a p pr o val was gi ve n a n d t he me m bers a n d v oti n g me m bers prese nt. Writte n 
e vi de nce of 
fa v ora ble o pi ni o n or a p pr o val t hat clearly i de ntifies t he trial, t he cli nical trial pr ot oc ol versi o n a n d 
the S u bject I nf or mati o n a n d I CF 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 his cli nical trial pr ot oc ol will als o be s u b mitte d t o t he c o ncer ne d I E C or I R B, 
bef ore i m ple me ntati o n 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 EC or 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.
Pla ns f or a n y su bsta ntial 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 RB bef ore t he y are i m ple me nte d (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 R B 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.
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
9. 7
He alt h A ut h orities
T he cli nical trial pr ot o c ol a n d a n y a p plica ble d oc u me ntati o n (e g, 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
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 c o m pleti o n g ui deli nes.
T he mai n p ur p ose of t he e C R F is t o o btai n data re q uire d b y  the cli nical trial pr ot oc ol i n a c o m plete, 
acc urate, le gi ble a n d ti mel y ma n ner . T he data i n t he e C R F s h oul d be c o nsiste nt wit h t he rele va nt 
s o urce d oc u me nts.
T he I nvesti gat or or desi g nee is res p o nsi ble f or e ns uri n g t hat t he data c ollecte d i n t he c o urse of t his 
trial is acc urate a n d d oc u me nte d a p pr o priatel y o n all a p plica ble f or ms. T he y  will t he n be 
pr ocesse d , e val uate d, a n d st ore d i n a n o n ym o us f or m i n acc or da nce wit h a p plica ble data pr otecti o n 
re g ulati o ns. T he I n vesti gat or m ust e ns ure t hat t he e C R Fs a n d a n y ot her ass ociate d d oc u me nts 
f or war de d t o S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a ny s u bject na mes.
T he data will be e ntere d i nt o a vali date d data base. T he S p o ns or or its desi g nee will be res p o nsi ble 
f or data 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 a n d q ualit y ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files 
of t he fi nal, c o m plete e C R Fs will be pr o vi de d t o t he I n vesti gat ors at t he c o m pleti o n of t he trial.
1 0. 2
S o urce D at a a n d S u bject Files
T he I n vesti gat or m ust kee p a file ( me dical file, ori gi nal me dical rec or ds) o n pa per or electr o nicall y 
f or e ver y s u bject i n t he trial. 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. 
T his file will c o ntai n t he de m o gra p hic a n d me dical i nf or mati o n f or t he s u bject liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 

S u bject’s f ull na me, date of birt h, se x, hei g ht, wei g ht

Me dical hist 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)

Trial i de ntificati o n, ie, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d su bject n u m ber

Dates f or e ntr y  i nt o t he trial (i nf or me d c o nse nt) a n d 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 his cli nical trial pr ot oc ol

All A Es

Date t hat t he s u bject left t he trial i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he trial or 
I M P (if a p plica ble).
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
All d oc u me nts c o ntai ni n g s o urce data m ust be file d, i ncl u di n g, b ut n ot li mite d t o C T or M RI  sca n 
i ma ges, E C G rec or di n gs, a n d la b orat or y res ults. S uc h d oc u me nts m ust bear t he s u bject n u m ber 
a n d t he date of t he pr oce d ure. If p ossi ble, t his 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. As necessar y , me dical e val uati o n of s uc h rec or ds 
s h o ul d be perf or me d ; all e val uati o ns s h o ul d be d oc u me nte d, si g ne d, a n d date d b y the I n vesti gat or.
Electr o nic s u bject files will be pri nte d w he ne ver t he M o nit or perf or ms s o urce data verificati o n. 
Pri nt o uts m ust be si g ne d a n d date d b y t he I n vesti gat or, c o u ntersi g ne d by t he M o n it or, a n d ke pt i n 
a safe place at t he site.
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, per l ocal re q uire me nts 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 nts 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 F(s). 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, the 
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 rec 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 CH 
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.
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 CH 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 ular 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 ual it 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 n vesti gat or Site File, t he c o m plete d C R Fs, all I M P a n d 
I M P acc ou 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 EC/I R B 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 o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0 -0 3 0 6
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 1 7
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/IR B or t o Healt h A ut h orities 
o nl y  where re q ueste d b y  perti 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 St u d y Re p ort a n d P u blic at i o n P olic y
Cli nic al St u d y Re p ort
After c o m pleti o n of t he P hase I a n d P hase II of t he trial, a Cli nical St u d y Re p ort will be writte n 
b y  t he S p o ns or i n c o ns ultati o n wit h t he C o or di nati n g I n vesti gat or f oll o wi n g t he g ui da nce i n I C H 
T o pic E 3. 
P u blic ati o n
P osti n g of data o n t he E U Cli nical Trials Re gister a n d Cli nical Trials. g o v sites is pla n ne d a n d will 
occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal trial s u bject or a n ot her a p pr o priate date t o 
meet a p plica ble re q uire me nts.
T he first p u blicati o n wi ll i ncl u de t he res ults of t he a nal ysis of t he pri mar y  en d p oi nts a n d will 
i ncl u de data fr o m all trial sites t hat pr o vi de d e val ua ble data. T he I n 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 bl icati 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  I n vesti gat ors or t heir re prese ntati ves will re q uire re vie w b y  the S p o ns or bef ore 
s u b missi o n. T he S p o ns or will n ot s u p press p u blicati o n, b ut mai ntai ns t he ri g ht t o dela y  pu blicati o n 
i n or der t o pr otect i ntellect ual pr o perty ri g hts.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
1 1
Refere nces Cite d i n t he Te xt
Aesc hli ma n n F A, H ofer K D, Sc h nei der C, et al. I nfli xi ma b i n pe diatric r he u mat ol o g y p atie nts: a 
retr os pecti ve a nalys is of i nf usi o n reacti o ns a n d se vere a d verse e ve nts d uri n g 2 2 4 6 i nf usi o ns o ver 
1 2 y ears. J R he u m 2 0 1 4; 4 1; 1 4 0 9- 1 5.
Bai S, J or ga K, Xi n Y, et al. A g ui de t o rati o nal d osi n g of m o n ocl o nal a nti b o dies. Cli n. 
P har mac o ki net 2 0 1 2; 5 1 ( 2):1 1 9 – 3 5.
Ba ve nci o [ pac ka ge i nsert]. R oc kla n d, M A: E M D Ser o n o, I nc; 2 0 1 7.
B o h nsac k O, H o os A, L u dajic K. A da ptati o n a n d m o dificati o n of t he i m m u ne relate d res p o nse 
criteria (IR R C): i r R E CIS T. J Cli n O nc ol 2 0 1 4; 1 5(s u p pl);e 2 2 1 2 1 -e 2 2 1 2 1.
Brist ol M y ers S q ui b b C o m pa n y . Briefi n g d oc u me nt f or t he Pe diatric S u bc o m mittee of the 
O nc ol o gic Dr u gs A d vis or y  C o m mittee Meeti n g. 0 5 N o v 2 0 1 3.
Bra h mer J R, T y k o di S S, C h o w L Q, et al. Safet y  an d acti vit y of a nti-P D -L 1 a nti b o d y in 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.
Dale R C, Bri l ot F, D uff y  LV. Utilit y  an d safet y of rit u xi ma b i n pe diatric a ut oi m m u ne a n d 
i nfla m mat or y C N S disease. Ne ur ol o g y  2 0 1 4; 8 3: 1 4 2- 5 0. 
Da vis K L, F o x E, Rei d J M, et al. I nitial res ults of a p hase I/II st u d y of ni v ol u ma b a n d i pili m u ma b 
i n pe diatric patie nts wit h rela pse d/refract or y soli d t u m ors— A C O G st u d y. J Cli n O nc ol 
2 0 1 7; 3 5(s u p pl; a bstr 1 0 5 2 6).
De n g R, I yer S, T heil F P, et al. Pr ojecti n g h u ma n p har mac o ki netics of t hera pe utic a nti b o dies fr o m 
n o ncli nic al data. W hat ha ve we lear ne d? M A bs 2 0 1 1 ; 3( 1):6 1 – 6.
D o n g H, Z h u G, Ta ma da K, et al. B 7 -H 1, a t hir d me m ber of t he B 7 fa mil y, c o-sti m ulates T- cell 
pr oliferati o n a n d i nterle u ki n -1 0 secreti o n. Nat Me d 1 9 9 9; 5: 1 3 6 5- 9.
D o n g H, Str o me S E, Sal o ma o D R, et al. T u m or -ass ociate d B 7 -H 1 pr o m otes T -cell a p o pt osis: a 
p ote ntial mec ha nis m 
o f i m m u ne e vasi o n. Nat 
Me d 
2 0 0 2; 8: 7 9 3- 8 0 0. [ Errat u m, Nat 
Me d 
2 0 0 2; 8: 1 0 3 9.]
D o uss a u A, Asselai n B, Le Dele y  MC. D ose -fi n di n g desi g ns i n pe diatric p hase I cli nical trials: 
C o m paris o n 
b y  si m ulati o ns i n a
realistic ti meli ne fra me w or k. C o nte m p 
Cli n 
Tr ials 
2 0 1 2; 3 3: 6 5 7 -6 5. 
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 ( V ersi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 - 4 7.
Free ma n GJ, L o n g AJ, I wai Y, et al. E n ga ge me nt of t he P D - 1 i m m u n oi n hi bit or y rece pt or b y  a 
n o vel B 7 fa mil y me m ber lea ds t o ne gati ve re g ulati o n of l ym p h oc yt e acti vati o n. J E x p Me d 
2 0 0 0; 1 9 2: 1 0 2 7 - 3 4.
Fra ncisc o L M, Sali nas V H, Br o w n K E, et al. P D-L 1 re g ulates t he de vel o p me nt, mai nte na nce, a n d 
f u ncti o n of i n d uce d re g ulat or y T cells. J E x p Me d 2 0 0 9; 2 0 6( 1 3): 3 0 1 5- 2 9.
Ge oer ger B, Ka n g HJ, Yale n -Ore n M, et al. P hase I/II K E Y N O T E- 0 5 1 st u d y of pe m br oliz u ma b 
( pe m br o) i n pe diatric patie nts ( pts) wit h a d va nce d mela n o ma or a P D-L 1 + a d va nce d, rela pse d, or 
refract or y s oli d t u m or or l ym p h o ma. J Cli n O nc ol 2 0 1 7a; 3 5(s u p pl; a bstr 1 0 5 2 5).
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
Ge oer ger B, Kars ki E E, Z waa n M, et al. A p hase I/II st u d y of atez oliz u ma b i n pe diatric a n d y o u n g 
a d ult patie nts wit h refract or y/rela pse d s oli d t u m ors (i M A T RIX- Atez oliz u ma b). J Cli n O nc ol 
2 0 1 7 b; 3 5(s u p pl; a bstr 1 0 5 2 4).
Ha mi d O, R o bert C, Da u d A, et al. Safet y a n d t u m or res p o nses wit h la m br oliz u ma b (anti -P D -1) 
i n mela n o ma. N E n gl J Me d 2 0 1 3; 3 6 9: 1 3 4 - 4 4.
I wai Y, Ishi da M, Ta na ka Y, et al. I nv ol ve me nt of P D -L 1  on t u m or cells i n t he esca pe fr o m h ost 
i m m u ne s yste m a n d t u m or i m m u n ot hera p y by P D -L 1  bl oc ka de. Pr oc N atl Aca d Sci U S A 
2 0 0 2; 9 9: 1 2 2 9 3 - 7.
Latc h ma n Y, W o o d C R, C her n o va T, et al. P D -L 2  is a sec o n d li ga n d f or P D-1 a n d i n hi bits T cel l 
acti vati o n. Nat I m m u n ol 2 0 0 1; 2( 3): 2 6 1 - 8.
Le p o ne L M, D o na h ue R N, Farsaci B, et al. E val uati o n of i m m u ne cell s u bsets of ca ncer patie nts 
treate d wit h a vel u ma b, a f ull y hu ma n I g G 1 a nti -P D -L 1 M A b ca pa ble of me diati n g A D C C of 
h u ma n t u m or cells. Ca ncer R es 2 0 1 5; A u g ust 1 ;a bstr 1 3 1 6.
Mara belle A, Gr a y  J. T u m or -tar gete d a n d i m m u ne-tar gete d m o n ocl o nal a nti b o dies: G oi n g fr o m 
passi ve t o acti ve i m m u n ot hera p y. Pe diatr Bl o o d & Ca ncer 2 0 1 5 ; 6 2( 8): 1 3 1 7– 2 5.
Merc ha nt M, Wri g ht M, Bair d K, et al. P hase 1 cli nical trial of i pili m u ma b i n pe diatric patie nts 
wit h a d va nce d s oli d t u m ors. Cli n Ca ncer Res 2 0 1 6: 2 2( 6): 1 3 6 4- 7 0.
Merc k S har p & D o h me C or p. A st u d y of pe m br oliz u ma b ( M K-3 4 7 5) i n pe diatric partici pa nts wit h 
a d va nce d mela n o ma or a d va nce d, rela pse d, or refract or y pd- l 1-p ositi ve s oli d t u m ors or l ym p h o ma 
( M K- 3 4 7 5-0 5 1/ K E Y N O T E -0 5 1) . A vaila ble at: htt ps://cli nicaltri als. g o v/ct 2/s h o w/ N C T 0 2 3 3 2 6 6 8.
N ai d o o J, Pa ge D B, Li T, et al. T o xicities of t he a nti-P D - 1 a n d a nti-P D -L 1 i m m u ne c hec k p oi nt 
a nti b o dies. A n n O nc ol 2 0 1 5; 2 6: 2 3 7 5 - 9 1. 
Pa olett i X, Ge oer ger B, D oz F, et al. A c o m parati ve a nal ys is of pae diatric d ose -fi n di n g trials of 
m olec ularl y tar gete d a ge nts wit h a d ults’ tria ls. E ur J Ca ncer 2 0 1 3; 4 9: 2 3 9 2- 4 0 2. 
P ost o w 
M A. 
2 0 1 5 
A S C O 
E d ucati o nal 
B o o k. 
A vaila ble 
at: 
htt p:// meeti n gli brar y .asc o. or g/ E d B o o k Trac ks/ 2 0 1 5 % 2 0 A S C O % 2 0 A n n ual % 2 0 Meeti n g. 
Si m o n R. 
O pti mal 
t w o-sta ge desi g ns
f or P hase II cli nical trials. C o ntr ol 
Cli n 
Trials 
1 9 8 9; 1 0( 1): 1 -1 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 m m u nit y. C urr O pi n I m m u n ol 2 0 1 2a;2 4: 2 0 7 - 1 2.
T o palia n S L , H o di F S, Bra h mer J R, et al. Sa fet 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 - 5 4.
We ber J S, Ya n g J C, At ki ns M B, et al. T o xicities of i m m u n ot hera py f or t he practiti o ner. J Cli n 
O nc ol 2 0 1 5; 3 3( 1 8): 2 0 9 2 - 9.
W or ki n g 
Gr o u p of t he Res usc itati o n C o u ncil ( U K). E mer ge nc y  treat me nt of a na p h yl actic 
reacti o ns: g ui deli nes f or healt hcare pr o vi ders.
Res uscitati o n C o u ncil ( U K);Ja n uar y 20 0 8. 
A vaila ble 
at: 
htt ps:// w w w.res us. or g. u k/a na p h y la xis/e mer ge nc y-treat me nt- of-a na p h ylactic-
reacti o ns/.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
1 2
A p pe n dice s
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
A p pe n di x I:
C o ntr ace pti ve G ui d a nce 
I n t his cli nical trial of c hil dre n < 1 8 ye ars of a ge, a fe male or male s u bject is c o nsi dere d t o be of 
c hil d beari n g p ote ntial (a n d t heref ore re q uire d t o use 2 hi g hl y  effecti ve met h o ds of birt h c o ntr ol) 
if, i n t he o pi ni o n of t he I n vesti gat or, t he s u bject is bi ol o gicall y ca pa ble of ha vi n g c hil dre n a n d is 
se x uall y acti ve.
Birt h C o ntr ol Met h o ds C o nsi dere d as Hi g hl y Effecti ve
Acc or di n g t o t he Cli nic al Trials Facilitati o n Gr o u p ( C T F G), “ 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)

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, 3

se x ual a bsti ne nce4
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 MP, w h ic h ma y re d uce t he efficac y of  the 
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 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 the 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
4 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 met 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. T he relia bilit y of 
se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he pr eferre d a n d us ual 
lifest yle of t he s u bject.
D o c u me nt N o. 
 
O bject N o. 
 
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
C o ntr ace pti ve G ui d a nce
Hi g hl y  Eff e cti v e C o ntr a c e pti v e M et h o d s T h at Ar e U s er D e p e n d e nt 
F ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n -c o nt ai ni n g ) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n b
or al 
i ntr a v a gi n al 
tr a n s d er m al 
Pr o g e st o g e n -o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b
or al 
i nj e ct a bl e
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er I n d e p e n d e nt 
I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n b
I ntr a ut eri n e d e vi c e (I U D)
I ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S)
bil at er al t u b al o c cl u si o n
V a s e ct o mi z e d p art n er 
( A v a s e ct o mi z e d p art n er i s a hi g hl y eff e cti v e c o ntr a c e pti o n m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e m al e 
s e x u al p art n er of t h e W O C B P a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. If n ot, a n a d diti o n al hi g hl y eff e cti v e 
m et h o d of c o ntr a c e pti o n s h o ul d b e u s e d. )
S e x u al a b sti n e n c e 
( S e x u al a b sti n e n c e i s c o n si d er e d a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m h et er o s e x u al 
i nt er c o ur s e d uri n g t h e e ntir e p eri o d of ri s k a s s o ci at e d wit h t h e st u d y dr u g. T h e r eli a bilit y of s e x u al a b sti n e n c e 
n e e d s t o b e e v al u at e d i n r el ati o n t o t h e d u r ati o n of t h e st u d y a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e 
p arti ci p a nt.) 
N O T E S: 
a) T y pi c al u s e f ail ur e r at e s m a y diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. U s e s h o ul d b e c o n si st e nt 
wit h l o c al r e g ul ati o n s r e g ar di n g t h e u s e of c o ntr a c e pti v e m et h o d s f or p arti ci p a nt s p arti ci p ati n g i n cli ni c al st u di e s. 
b) H or m o n al c o ntr a c e pti o n m a y b e s u s c e pti bl e t o i nt er a cti o n wit h t h e st u d y dr u g, w hi c h m a y r e d u c e t h e effi c a c y 
of t h e c o ntr a c e pti v e m et h o d. I n t hi s c a s e 2 hi g hl y eff e cti v e m et h o d s of c o ntr a c e pti o n s h o ul d b e utili z e d d uri n g t h e 
tr e at m e nt p eri o d a n d f or at l e a st 6 0 d a y s aft er t h e l a st d o s e of st u d y tr e at m e nt .
D o c u me nt N o. 
 
O bject N o. 
 
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
A p pe n di x II: 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 o c u me nt N o. 
 
O bject N o. 
 
C CI

A v el u m a b 
P h as e 1111 st u d y of a v el u m a b i n p e di at ri c c a n c e r s u bj e cts 
M S 1 0 0 0 7 0- 0 3 0 6 
Si g n at ure P a g e- Pr ot oc ol Le a d 
T ri al Titl e: 
O p e n-l a b el, 
P h as e 
IIII 
st u d y 
t o 
e v al u at e 
p h ar m a c o ki n eti cs, 
p h ar m a c o d y n a mi cs, 
s af et y, a n d 
a nti c a n c er a cti vit y of a v el u m a b i n p e di atri c s u bj e cts 
fr o m birt h t o l ess t h a n 1 8 y e ars of a g e wit h r efr a ct or y 
or r el a ps e d s oli d t u m ors a n d l y m p h o m a 
I N D N u m b e r: 
E u d r a C T N u m b e r: 
Cli ni c al T ri al P r ot o c ol D at e/ 
V e rsi o n: 
P r ot o c ol L e a d: 
I a p pr o v e t h e d esi g n of t h e cli ni c al tri al: 
 
2 0 1 7·· 0 0 2 9 8 5- 2 8 
1 5 S e pt e m b er 2 0 1 7 N crsi o n 2. 0 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e, a c a d e mi c d e gr e e: 
 
F u n cti o n I Titl e: 
I nstit uti o n: 
E M D S er o n o R es e ar c h & D e v el o p m e nt I nstit ut e, I nc. 
A d dr ess: 
T el e p h o n e n u m b er: 
M o bil e n u m b er: 
E- m ail a d dr ess: 
4 5 A Mi d dl es e x T u m pi k e 
Bill eri c a, M A 0 1 8 2 0, U S A 
 
 
 
D o c u m e nt N o. 
 
O bj e ct N o. 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1 0 7 1 1 1 7 
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D

A vel u ma b 
M S 1 0 0 0 7 0- 0 3 0 6 
P hase 1/II st u d y of a vel u ma b i u p e di atri c c a n c er s u bjects 
Si g n at ur e P a g e- C o or di n ati n g I n v esti g at or 
Tri al Titl e 
O p e n-l a b el, 
P h as e 
!III 
st u d y 
t o 
e val uate 
p h ar m a c o ki n eti cs, 
p h ar m a c o d y n a mi cs, 
safet y, 
a n d 
a nti c a n c er a cti vit y of a v el u m a b i n p e di atri c s u bjects 
fr o m birt h t o less t ha n 1 8 years of a ge wit h r efr a ct or y 
or rela pse d s oli d t u m ors a n d l y m p h o m a 
I N D N u m b er 
 
E u dr a C T N u m b er 
2 0 1 7- 0 0 2 9 8 5- 2 8 
Cli ni c al Tri al Pr ot o c ol D at e/ V ersi o n 
1 5 S e pt e m b er 2 0 1 7/ V ersi o n 2. 0 
I a p pr o ve t he desi g n of t h e cli ni c al trial a n d I u n dersta n d a n d will c o n d u ct t he trial a c c or di n g t o 
t he cli ni c al trial pr ot o c ol, a n y a p pr o v e d pr ot o c ol a m e n d m e nts, I nter nati o nal C o u ncil 
f or 
H ar m o nis ati o n 
G o o d 
Cli ni c al 
Practice 
( T o pic E 6) 
a n d all a p plica ble H e alt h 
A ut h orit y 
r e q uir e m e nts a n d n ati o n al la ws. 
Si g n at ur e 
Date of Si g n at ur e 
N a m e, a c a d e mi c d e gr e e: 
F u n cti o n I Title: 
I nstit uti o n: 
A d dr ess: 
T el e p h o n e n u m b er: 
Fa x n u m b er: 
E- mail a d dress: 
D o c u m e nt N o. 
 
O bj e ct N o. 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1 0 8 1 1 1 7 
C CI
C CI
C CI
P P D
P P D
P P D
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
Si g n at ure P a ge – Pri nci p al I n vesti g at or
Tri al Title
O pe n -la bel, 
P hase 
I/II 
st u d y 
to 
e val uate 
p har mac o ki netics, p har mac o d y na mics, safety,  an d 
a ntica ncer acti vit y of a vel u ma b i n pe diatric s u bjects 
fr o m birt h t o less t ha n 1 8 years of a ge wit h refract or y 
or rela pse d s oli d t u m or s a n d l ym p h o ma
I N D N u m ber
E u dr a C T N u m ber
2 0 1 7 -0 0 2 9 8 5 -2 8
Cli nic al Tri al Pr ot oc ol D ate/
Versi o n
1 5 Se pte m ber 2 0 1 7/ Versi o n 2. 0
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.
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 btai 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 nts. 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 n e cessar 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:
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me:
F u ncti o n / Title:
I nstit uti o n:
E M D Ser o n o, I nc.
A d dress:
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A 0 1 8 2 1, U S A
Tele p h o ne n u m ber:
E- mail a d dress:
Na me:
F u ncti o n / Title:
Se ni or Cli nical Trial Lea d
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt
Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
P ollert
A p pe n di x III :
L a ns k y a n d K ar n ofs k y Perf or m a nce Sc ales
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
L a ns k y Perf or m a nce Sc ale
D o c u me nt N o. 
 
O bject N o. 
 
L a ns k y pl a y- p elf orlllil n c e s c al e f or p e di atJi. c p ati e nts 
T his s c al e m a y b e us e d wit h c hil dr e n a g e 1- 1 6 w h o h a v e a n y t y p e of m ali g n a n c y . 
It m a y b e us e d f or b ot h i n p ati e nts & o ut p ati e nts , a n d f or p ati e nts u n d er g oi n g a cti v e 
tr e at m e nt as w ell as lo n g-t er m f oll o w- u p. It i s r at e d b y p ar e nts b as e d o n t h eir 
c hil d' s a cti vit y o v er t h e p ast w e e k. P ar e nts fill o ut t h e ass ess m e nt b as e d o n t h e 
dir e cti o ns o n t h e f or m, a n d t h e f or m i s r e a d m mist er e d o v er ti m e t o ass ess f or 
c h a n g es i n p erf or m a n c e st at us. 
A n e x c er pt of t h e r el e v a nt dir e cti o ns f or p ar e nts i s as f oll o ws: 
" T hi n k a b o ut y o ur c hil d's pl a y a n d a cti vit y o v er t h e past w e e k. T hi n k: a b o ut b ot h 
g o o d d a ys a n d b a d d a ys. A v er a g e o ut t his p eri o d. N o w r e a d t h e d es cri pti o ns a n d 
pi c k t h e o n e t h at b est d es cri b es y o ur c hil d's pl a y d uri n g t h e p ast w e e k." 
De.s CJi. pti o n 
n or m al 
r estri cti o ns wit h str e n u o us p h ysi c al a cti vit y 
b ut g ets tir e d m or e q ui c kl y 
J 
r o- b ot h gr e at er r estri cti o n of, a n d less ti m e s p e nt i n, a cti v e pl a y 
1 6 0"' u p a n d ar o u n d , b ut mi ni m a l a cti v e pl a y; k e e ps b us y wit h q ui et er a cti viti es 
F' 
yi n g ar o u n d m u c h of t h e d a y , b ut g ets dr ess e d; n o a cti v e pl a y; p arti ci p at es 
i n all q ui et p l a y a n d a cti viti es 
m ostl y i n b e d; p arti ci p at es i n q ui et a cti viti es 
p o-
t u c k: i n b e d ; n e e ds h el p e v e n f or q ui .et pl a y 
1 ? 0' oft e n sl e e pi n g; p l a y i s e ntir el y li mit e d t o v er y p assi v e a cti viti es 
lr d o es n ot pl a y n or g et o ut of b e d 
p--] j u nr es p o nsi v e 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
K ar n ofs k y Perf or m a nce Sc ale
D o c u me nt N o. 
 
O bject N o. 
 
Til e K a m of s k y P erf o mt a n c e S c a fe I n d e x a llo w s p a tie nt s t o b e cl a s si fi e d a s t o th e ir f u n cti o n al 
im p a ir m e nt T hi s c a n b e u s e d t o c o m p ar e eff e cti v e n e s s of diff er e nt t her a p ie s a n d t o a s s e s s th e 
pr o g n o s i s i n in d ivi d u a l p a ,tie nt s . T h e lo w er t h e K a m of s k y s c or e , t he w or s e t h e s u r vi v al f or m o st 
s e rio u s illn e s s e s. 
K A R N O F S K Y P E R F O R M A N C E S T A T U S S C A L E D E A NI TI O N S R A TI N G( %) 
C RI T E RI A 
l l O O j Nor mal n o co m plai nts ; n o e vi de n <Je of disease . 
t o carr y o n n or mal acti vit y a n d t o w or k ; n o F 
t o carr y o n n or mal acti vity; mi n or si g n s 
s p e ci al c ar e n e e d e d 
or s y m pt o ms of disease . 
8.0 
! N or mal ac.ti vit y wi t h eff ort; s o me si g n s or 
s y m pt o ms of disease . 
7 0 
Cares f or s elf; u na b le t o carr y o n n or mal 
! U na ble t o w or k ; a b le t o li v e at h o me a n d care f or 
acti vit y or t o d o acti ve w or k . 
! m ost 
var yi n g a m o m d of assista nce 
6 0 
occas io nal a.ssista n <Je, b ut i s a ble t o 
care f or m ost of his p ers o n al nee ds . 
5 0 
c o nsi dera bl e assista nce a n d fre q uent 
care . 
4 0 ! Disabled; re q uires s pecial care a n d a.ssisil mce. 
Se verel y disa b le d; h os p ita.l a d missi o n i s 
ltJna ble t o car e f or self; re q uires e q ui vale nt of 
lir u ncate d a.lt h o n g h deat h n ot i m mi n e nt 
or h os pital 
disease ma y b e 
l w 
sic k; b os p ita.l a d missi o n necessar y; acti,.'e 
pr o gressi n g . ra pidl y . 
s u p p or b ve treat me nt necessar y . 
fl O j Mo nl n m d; fata.l pr ocesses pr o gressi n g ra pidl y. 
0 
lf >ead 
R e fer e n c e s : 
Cr o o k s , V, W all er S , et al . T h e u s e of t he K a m of s k y P erf or m a n c e S c a l e i n d e ter m i nin g o u t c o m e s 
a n d ri sk i n g e ri atric o ut p ati e nt s . J G er o nt o L 1 9 9 1 ; 4 6 : M 1 3! ». 4 1 4 4. 
d e H a a n R, A ar o n s o n A, et al. M e a s u ri ng q u a lit y of lif e i n st r o k e . Str o k e . 19 9 3 ; 2 4 :3 2 0- 3 2 7. 
H oll e n P J, G m ll a RJ , et al. M e a s ur e m e nt of q u a lit y of life i n p at i ent s wit h lu n g c a n c er i n 
m u ltic e nt er tri al s of n e w t h era pi e s . C a n c e r. 1 9 9 4 ; 7 3: 2 0 8 7- 2 0 9 8. 
O ' T o ol e O M , G o ld e n A M. E v a l uat in g c a n c er p ati e nt s f or r eh a b ilit ati o n p ot e nti al. W e st J M e d. 
1 9 9 1; 1 5 5 : 3 8 4- 3 8 7. 
O xf or d T e xt b o o k of P a lli at iv e M e d ici n e , O xf or d U n i ver s it y P r e s s. 1 9 9 3; 1 0 9 . 
S c h a g 1 C C, H ei n ric h R L, G a n z P A. K a m of s k y p erf o mt a n c e st at u s r evi sit e d: R e lia bir it y, v al idit y , 
a n d g u id e li ne s. J O li n O n c o lo g y . 1 9 8 4 ; 2: 18 7- 1 9 3. 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
A p pe n di x I V:
Pr ot oc ol A me n d me nts a n d List of C h a n ges
D o c u me nt N o. 
 
O bject N o.
 
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
A me n d me nt # 1
Effecti ve 1 5 Se pte m ber 2 0 1 7 f or all sites.
R ati o n ale
T he rati o nale f or t his a me n d me nt is t o ma ke a d mi nistrati ve c ha n ges a n d re m o ve a state me nt 
i ncl u de d i n t he pr ot oc ol.
M aj or Scie ntific C h a n ges
N o ne.
A d mi nistr ati ve a n d E dit ori al C h a n ges
A d mi nistrati ve c ha n ges :

C ha n ge I N D n u m ber fr o m 
 per re quest b y t he F D A f or res u b missi o n .

C ha n ge of a d dress f or t he c o or di nati n g i n vesti gat or, effecti ve 0 1 Se pte m ber 2 0 1 7.

C orrect t he na me of t he S p o ns or f or Ca na da fr o m E M D Ser o n o t o Merc k K Ga A

U p date t he na me a n d a d dress of t he cli nical trial lea d o n t he 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 .

U p date t he versi o n a n d date of t he a me n d me nt t hr o u g h o ut t he d oc u me nt.
E dit orial c ha n ges:
T he f oll o wi n g state me nt was i na d verte ntl y  i ncl u de d i n t he pr ot oc ol beca use of a c o p y-a n d-paste 
err or; t he state me nt has bee n re m o ve d i n 3 places i n t he pr ot oc ol: A n i n de pe n de nt i ma gi n g 
ve n d or will be e n ga ge d t o rea d a n d i nter pret all c o m p ute d t o m o gra p h y ( C T)/ ma g netic res o na nce 
i ma gi n g ( M RI) data. Res p o nses will be e val uate d usi n g R E CIS T 1. 1.
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
C o m p aris o n wit h Cli nic a l Tri al Pr ot oc ol Versi o n 1. 0, 1 4 A u g ust 2 0 1 7
C h a n g e
S e cti o n 
P a g e( s)
Pr e vi o u s W or di n g
N e w  W or di n g
R ati o n al e
I N D N u m b er
Titl e p a g e, 
S y n o p si s titl e 
p a g e , 
si g n at ur e 
p a g e s of 
pr ot o c ol l e a d, 
pri n ci p al 
i n v e sti g at or, 
a n d 
c o or di n ati n g 
i n v e sti g at or
P a g e s 1, 1 1, 
1 0 7, 1 0 8, a n d 
1 0 9
 
C h a n g e of titl e 
a n d a d dr e s s of 
c o or di n ati n g 
i n v e sti g at or
Titl e p a g e, 
S y n o p si s titl e 
p a g e, 
S e cti o n 2, 
C o or di n ati n g 
i n v e sti g at or
si g n at ur e 
p a g e
P a g e s 1, 1 1, 
2 5, 1 0 8
C o or di n ati n g i n v e sti g at or’ s n e w 
l o c ati o n a s of 0 1 S e pt e m b er 
2 0 1 7
C h a n g e of 
s p o n s or a d dr e s s 
f or C a n a d a
Titl e p a g e, 
S y n o p si s titl e 
p a g e, S e cti o n 
2
P a g e s 1, 1 1, 
2 5
F or all c o u ntri e s e x c e pt t h e 
U S A a n d C a n a d a
F or sit e s i n t h e U S A a n d 
C a n a d a
F or all c o u ntri e s e x c e pt t h e U S A
F or sit e s i n t h e U S A
I n c orr e ct s p o n s or a d dr e s s f or 
C a n a d a
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D

A vel u m a b
P h ase I/II st u d y of a vel u m a b i n pe di atric c a ncer s u bjects
M S 1 0 0 0 7 0- 0 3 0 6
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 1 7
C h a n g e
S e cti o n 
P a g e( s)
Pr e vi o u s W or di n g
N e w  W or di n g
R ati o n al e
U p d at e C T P 
v er si o n a n d d at e
Titl e p a g e, 
si g n at ur e 
p a g e s of 
pr ot o c ol l e a d, 
pri n ci p al 
i n v e sti g at or, 
a n d 
c o or di n ati n g 
i n v e sti g at or
P a g e s 1, 1 0 7, 
1 0 8, a n d 1 0 9
1 4 A u g u st 2 0 1 7/ V er si o n 1. 0
1 5 S e pt e m b er 2 0 1 7/ V er si o n 2. 0
1 5 S e pt e m b er 2 0 1 7/ V er si o n 2. 0
A d mi ni str ati v e c h a n g e
R e m o v e d
s e nt e n c e s a b o ut 
i n d e p e n d e nt 
i m a gi n g v e n d or
5. 1. 1. 1, 
5. 1. 1. 2, a n d 
7. 2. 5
P a g e s 3 2, 3 8, 
a n d 7 2
A n i n d e p e n d e nt i m a gi n g v e n d or 
will b e e n g a g e d t o r e a d a n d 
i nt er pr et all c o m p ut e d 
t o m o gr a p h y ( C T)/ m a g n eti c 
r e s o n a n c e i m a gi n g ( M RI) d at a. 
R e s p o n s e s will b e e v al u at e d 
u si n g R E CI S T 1. 1.
N o n e
C o p y -a n d -p a st e err or — n o 
i n d e p e n d e nt r e a d f or s e c o n d ar y 
o bj e cti o n s ar e pl a n n e d.
N a m e a n d c o nt a ct 
i nf or m ati o n of 
cli ni c al tri al l e a d
S p o n s or 
R e s p o n si bl e 
P er s o n s n ot 
N a m e d o n t h e 
C o v er p a g e
P a g e 1 1 1
 L e a d
E M D S er o n o, I n c.
4 5 A Mi d dl e s e x T ur n pi k e
Bill eri c a, M A 0 1 8 2 1, U S A
S e ni or Cli ni c al Tri al L e a d
M er c k K G a A
Fr a n kf urt er Str. 2 5 0
6 4 2 9 3 D ar m st a dt
S e ni or Cli ni c al Tri al L e a d
M er c k K G a A
Fr a n kf urt er Str. 2 5 0
6 4 2 9 3 D ar m st a dt
G er m a n y
N e w tri al l e a d
D o c u me nt N o. 
 
O bject N o. 
 
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D