Conditions: Oncology Solid Tumors
Keywords: Palliative Radiotherapy Advanced solid tumors M3814 Avelumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 57
Healthy volunteers: no

Brief summary:
The main purpose of the study was to evaluate a safe, tolerable recommended Phase II dose (RP2D) and/or the maximum tolerated dose (MTD) of M3814 when given in combination with avelumab with and without radiotherapy in participants with selected advanced solid tumors.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: M3814 intervention 2: M3814 intervention 3: Avelumab intervention 4: Radiotherapy
Intervention descriptions: intervention 1: Participants received M3814 twice daily (BID) continuously starting from Day 1 until progressive disease (PD) or unacceptable toxicity. intervention 2: Participants received M3814 concomitantly with RT once (QD) daily starting Day 1 for 5 days per week for 2 weeks in total. intervention 3: Participants received avelumab once every 2 weeks (Q2W) starting from Day 1 until PD or unacceptable toxicity. intervention 4: Participants received radiotherapy at the dose of 3 grays (Gy) per day starting Day 1 for 5 days per week for 2 weeks.

Protocol document:
Prot_000.pdf: 
A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 1 6 6
Cli nic al St u d y Pr ot oc ol
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A 
M ultice nter, 
O pe n -La bel, 
D ose 
Escalati o n 
P hase I St u d y  to E val uate t he Safet y , T olera bilit y, 
P har mac o ki netics ,
a n d 
F o o d  
E ffect 
o n 
P har mac o ki netics of t he D N A -P K I n hi bit or M 3 8 1 4 
i n C o m bi nati o n wit h A vel u ma b wit h a n d wit h o ut 
Palliati ve 
Ra di ot hera p y 
i n Partici pa nts 
wit h 
Selecte d A d va nce d S oli d T u m ors
St u d y N u m ber:
M S 2 0 1 9 6 4 - 0 0 0 1
Merc k C o m p o u n d:
M S B 0 0 1 0 7 1 8 C (a vel u ma b), M S C 2 4 9 0 4 8 4 A 
( M 3 8 1 4)
Merc k Re gistere d C o m p o u n d N a me i n 
J a p a n:
N ot a p plica ble
St u d y P h ase:
P hase I
S h ort Title:
P hase I St u d y  of A vel u ma b-M 3 8 1 4 C o m bi nati o ns
C o or di n ati n g I n vesti g at or:
 
 
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
F or all c o u ntries e xce pt t he U S a n d Ca na da:
Merc k K G a A 
Fra n kf urter Str. 2 5 0
Dar msta dt, Ger ma n y
I n t he U S a n d Ca na da:
E M D Ser o n o Rese arc h & De vel o p me nt 
I nstit ute, I nc.
A n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
4 5 A Mi d dlese x T ur n pi ke,
Billerica, M A, U S A.
Gl o bal Versi o n I D: 
P P D
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 6 6
Me dical Res p o nsi ble: 
Na me: Sara h C he n n o ufi, M D, P h D.
Ge neral Merc k P h o ne N u m ber : + 4 9 6 1 5 1 7 2 
5 8 4 7 5
Ge neral Merc k Fa x N u m ber : N ot a p plica ble
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
Pr ot oc ol Versi o n:
/ Versi o n 3. 0
Re pl aces Versi o n:
2 6 J u ne 2 0 1 9/ Versi o n 2. 0
A p pr o v al D ate:
2 6 N o ve m ber 2 0 2 0
Me dic al 
M o nit or 
N a me a n d C o nt act
I nf or m ati o n:
U S:
Gl o b al: 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D
P P D
P P D


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 6 6
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
1. 0
Ori gi n al Pr ot o c ol
0 8 A u g 2 0 1 8
2. 0
Gl o b al Pr ot o c ol A m e n d m e nt
2 6 J u n 2 0 1 9
3. 0
Gl o b al Pr ot o c ol A m e n d m e nt
2 5 N o v 2 0 2 0
Pr ot oc ol Versi o n 3 . 0 ( 2 5 N o ve m ber 2 0 2 0)
O ver all R ati o n ale f or t he A me n d me nt
T he maj or p ur p ose of t his gl o bal pr ot oc ol a me n d me nt is t o re vise u p war ds t he n u m ber of 
pa rtici pa nts pla n ne d f or Part A (a vel u ma b + M 3 8 1 4 ), a n d f or Part B (a vel u ma b + M 3 8 1 4 
+ r a di ot hera p y) t o acc o m m o date t he n u m ber of d ose le vels of M 3 8 1 4 w hic h ha ve bee n or will be 
assesse d i n Part A a n d Part B.
 
 
 
H o we ver, o ver t he c o urse of t his cli nical trial, Safet y  M o nit ori n g C o m mittee ( S M C) has deci de d, 
as a preca uti o nar y  meas ure t o i ntr o d uce a n d assess i n b ot h Part A a n d Part B, t he a d diti o nal 
i nter me diate d ose le vels of M 3 8 1 4 i n or der t o ge nerate f urt her safet y an d p har mac o ki netic ( P K) 
data, he nce o pti mize t he safety o f partici pa nt w h o w o ul d be e nr olle d i n t he ne xt d ose le vel c o h orts . 
As a res ult, t he t otal n u m ber of partici pa nts t hat will be e nr olle d mi g ht e xcee d t he n u m ber of 
partici pa nts i nitiall y pla n ne d . T heref ore, as a n n o u nce d i n t he first versi o n of t he pr ot oc ol, t his 
pr ot oc ol a me n d me nt has bee n de vel o pe d t o i m ple me nt t he c ha n ge i n n u m ber of st u d y partici pa nts .
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 6 6
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e
U p d at e d t h e U S M e di c al M o nit or 
n a m e a n d c o nt a ct i nf or m ati o n .
T o b e c o n si st e nt wit h c urr e nt i nf or m ati o n.
1. 3 S c h e d ul e of A cti viti e s 
T a bl e 1 ( P art A) a n d T a bl e 4 
( P art F E)
T h e fr e q u e n c y of uri n e di p sti c k 
a n al y si s a n d p h y si c al 
e x a mi n ati o n u p d at e d. Aft er 
Vi sit 3, t h e uri n e di p sti c k a n al y si s 
a n d p h y si c al e x a mi n ati o n m u st 
b e p erf or m e d at Vi sit 6 a n d t h e n 
e v er y 8 w e e k s .
T o a v oi d t h e o n -sit e vi sit b et w e e n t w o 
a v el u m a b a d mi ni str ati o n s.
1. 3 S c h e d ul e of A cti viti e s 
T a bl e 1 ( P art A), T a bl e 3 
( P art B) , a n d T a bl e 4 
( P art F E)
Cl arifi e d t h at s af et y foll o w -u p 
p eri o d will b e 3 0 d a y s a n d 9 0 
d a y s aft er t h e l a st d o s e of 
a v el u m a b .
F or cl arit y a n d c o n si st e n c y wit h 
S e cti o n 4. 1. 1. 3.
1. 3 S c h e d ul e of A cti viti e s 
T a bl e 2 a n d T a bl e 3 ( P art B)
8. 2. 5 Cli ni c al S af et y 
L a b or at or y A s s e s s m e nt s
T h e n a m e of l a b or at o r y t e st 
u p d at e d fr o m “ T 4” (t h yr o xi n e) t o 
“fr e e T 4” (fr e e t h yr o xi n e).
F or cl arit y a n d c o n si st e n c y wit h ot h er 
s e cti o n s.
1. 3 S c h e d ul e of A cti viti e s 
T a bl e 2 ( P art B)
S p e cifi e d t h at p h y si c al 
e x a mi n ati o n a n d di p sti c k 
uri n al y si s s h o ul d b e p erf or m e d 
e v er y 6 w e e k s st arti n g fr o m 
Vi sit 1 3.
S p e cifi e d t h at h e m at ol o g y a n d 
s er u m c h e mi str y s h o ul d b e 
p erf or m e d e v er y 4 w e e k s 
st arti n g fr o m Vi sit 1 3 .
S p e cifi e d t h at fr e e T 4 a n d 
t h yr oi d-sti m ul ati n g h or m o n e
(T S H ) s h o ul d b e p erf or m e d 
e v er y 6 w e e k s st arti n g fr o m 
Vi sit 2.
T o pr o vi d e a d diti o n al g ui d a n c e r e g ar di n g t h e 
a s s e s s m e nt ti m e p oi nt s.
1. 3 S c h e d ul e of A cti viti e s 
T a bl e 7 ( P h ar m a c o ki n eti c 
a n d Bi o m ar k er Bl o o d 
S a m pli n g S c h e d ul e –
P art F E )
P K s a m pl e c oll e cti o n ti m e p oi nt 
s hift e d fr o m D a y 1 3 -h o ur 
p o st d o s e t o D a y 2 2 4 -h o ur 
p o st d o s e .
T o b ett er e v al u at e t h e eff e ct of f o o d o n t h e 
P K of M 3 8 1 4. T hi s c h a n g e di d n ot aff e ct t h e 
t ot al n u m b er of bl o o d dr a w s or t ot al v ol u m e 
of bl o o d c oll e ct e d or t h e d ur ati o n of
p arti ci p a nt’ s vi sit .
 
 
 
 
 
 
 
 
2. 3. 1 S u m m ar y of M 3 8 1 4 
D at a a n d P ot e nti al B e n efit s 
a n d Ri s k s
I n cl u d e d t h e m o st r e c e nt s af et y 
d at a of M 3 8 1 4.
T o ali g n wit h t h e M 3 8 1 4 I B V er si o n 8. 0.
2. 3 . 1 S u m m ar y of M 3 8 1 4 
D at a a n d P ot e nti al B e n efit s 
a n d Ri s k s
2. 3. 1. 1 S u m m ar y of M 3 8 1 4 
T a bl et F or m ul ati o n a n d 
P ot e nti al B e n efit s a n d Ri s k s
4. 3 J u stifi c ati o n f or D o s e 
( M 3 8 1 4)
T h e t er m u s e d t o s p e cif y t h e 
M 3 8 1 4 f or m ul ati o n u p d at e d fr o m 
“ p o w d er i n c a p s ul e ( Pi C)” t o 
“ c a p s ul e”.
T o ali g n wit h t h e M 3 8 1 4 I B V er si o n 8. 0.
2. 3. 2 S u m m ar y of P ot e nti al 
B e n efit s a n d Ri s k s of 
A v el u m a b
I n cl u d e d t h e m o st r e c e nt s af et y 
d at a of a v el u m a b .
T o ali g n wit h t h e a v el u m a b I B V er si o n 1 0. 0
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 6 6
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
4. 3. 1 J u stifi c ati o n f or D o s e 
( M 3 8 1 4)
 
T o ali g n wit h t h e M 3 8 1 4 I B V er si o n 8. 0.
4. 3. 3 J u stifi c ati o n f or D o s e 
(A v el u m a b )
T h e j u stifi c ati o n f or a v el u m a b 
d o s e s el e cti o n w a s u p d at e d .
T o ali g n wit h t h e a v el u m a b I B V er si o n 1 0 . 0.
5. 2 E x cl u si o n Crit eri a
6. 5. 3 Pr o hi bit e d M e di ci n e s
6. 8 S p e ci al Pr e c a uti o n s
A d d e d t h at c o n c o mit a nt u s e of 
m e di c ati o n s a n d/ or h er b al 
s u p pl e m e nt s k n o w n t o b e 
i n hi bit or s or i n d u c er s of C Y P 2 C 9 
i s pr o hi bit e d.
A d d e d t h at c o n c o mit a nt u s e of 
m e di c ati o n s a n d/ or h er b al 
s u p pl e m e nt s k n o w n t o b e 
s u b str at e s of C Y P 2 C 9 i s t o b e 
u s e d wit h c a uti o n a n d s af et y 
s h o ul d b e m o nit or e d cl o s el y.
T o k e e p c o n si st e n c y wit h ot h er M 3 8 1 4
cli ni c al tri al pr ot o c ol s, t hi s m o difi c ati o n w a s 
a d d e d a s r e q u e st e d b y t h e A ut h oriti e s f or 
ot h er M 3 8 1 4 cli ni c al tri al pr ot o c ol s. 
 
 
 
 
I n a d diti o n, b a s e d o n t h e a v ail a bl e d at a, it i s 
n ot pr e di ct e d t h at M 3 8 1 4 dir e ctl y i n hi bit 
C Y P 2 C 9 t o a cli ni c all y r el e v a nt d e gr e e, b ut it 
c a n n ot b e e x cl u d e d. T h er e f or e, dr u g s
m et a b oli z e d b y C Y P 2 C 9 ar e n ot pr o hi bit e d. 
H o w e v er, i n c a s e of c o n c o mit a nt tr e at m e nt 
wit h M 3 8 1 4 a n d dr u g s m et a b oli z e d b y 
C Y P 2 C 9, p a rti ci p a nt s s h o ul d b e cl o s el y 
m o nit or e d.
Al s o , dr u g s m et a b oli z e d b y 
C Y P 2 C 9 wit h a n arr o w t h er a p e uti c i n d e x 
s h o ul d b e a v oi d e d if p a rti ci p a nt s c a n n ot b e 
cl o s el y m o nit or e d .
6. 6. 2 D o s e S el e cti o n 
( P art F E), 6. 6. 4 D o s e 
E s c al ati o n R ul e s, 9. 2 
S a m pl e Si z e D et er mi n ati o n
T er m “ e v al u a bl e” d el et e d
F or c o n si st e n c y wit h s y n o p si s a n d t o pr o vi d e 
m or e cl arit y o n t h e t ot al n u m b er of 
p arti ci p a nt s t h at mi g ht b e e nr oll e d i n e a c h 
p art of t h e st u d y.
6. 8 S p e ci al Pr e c a uti o n s
T e xt a d d e d t o s p e cif y t h at 
“ Dr u g s w hi c h ar e s u b str at e s of 
P- gl y c o pr ot ei n ( P-g p ), b r e a st 
c a n c er r e si st a n c e pr ot ei n
(B C R P ), or o r g a ni c c ati o n 
tr a n s p ort er 1 (O C T 1 ) wit h a 
n arr o w t h er a p e uti c i n d e x ar e t o 
b e u s e d wit h c a uti o n” .
B a s e d o n a r e c e nt u p d at e of t h e d r u g-dr u g 
i nt er a cti o n a s s e s s m e nt, B C R P, P -g p, a n d 
O C T 1 s u b str at e s ar e n ot pr o hi bit e d. 
H o w e v er, p a rti ci p a nt s tr e at e d wit h t h e s e 
s u b str at e s t h at h a v e a n arr o w t h er a p e uti c 
i n d e x s h o ul d b e cl o s el y m o nit or e d d u e t o a 
p ot e nti al ri s k of i n cr e a s e i n e x p o s ur e of 
B C R P, P- g p, a n d O C T 1 s u b str at e s.
 
 
 
 
 
 
 
.
A p p e n di x 2 St u d y 
G o v er n a n c e
T e xt u p d at e d t o i n cl u d e d efi niti o n 
of st u d y st art d at e, t h e fir st a ct of 
r e cr uit m e nt.
M a n d at or y c h a n g e a p er t h e pr ot o c ol 
t e m pl at e V er si o n 1 4 .
A p p e n di x 4 A d v er s e E v e nt s: 
D efi niti o n s a n d Pr o c e d ur e s 
f or R e c or di n g, E v al u ati n g, 
F oll o w -u p, a n d R e p or ti n g
A d v er s e e v e nt of s p e ci al i nt er e st 
(A E SI ) li st of a v el u m a b u p d at e d 
t o i n cl u d e m y a st h e ni a 
gr a vi s/ m y a st h e ni c s y n dr o m e .
T o ali g n wit h t h e a v el u m a b I B V er si o n 1 0. 0.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 6 6
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
A p p e n di x 1 1 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
E- m ail a d dr e s s u p d at e d .
T o b e c o n si st e nt wit h c urr e nt i nf or m ati o n.
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s.
Mi n or; t h er ef or e, h a v e n ot b e e n s u m m ari z e d .
- C o nfi d e nti al –
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 0 b y M er c k K G a A, D ar m st a dt, 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 6 6
T a ble of C o nte nts
Title Pa ge
..............................................................................................................1
Ta ble of C o nte nts
..............................................................................................................7
List of Ta bles
............................................................................................................ 11
List of Fi g ures
............................................................................................................ 12
1
Pr ot oc ol S u m mar y .............................................................................. 13
1. 1
S y n o psis .............................................................................................. 13
1. 2
Sc he ma ................................................................................................ 18
1. 3
Sc he d ule of Acti vities ......................................................................... 20
2
I ntr o d ucti o n......................................................................................... 49
2. 1
St u d y  Rati o nale................................................................................... 49
2. 1. 1
C o m bi ni n g a D N A Da ma ge A ge nt wit h M 3 8 1 4, a D N A 
Re pair -Tar gete d T hera p y .................................................................... 49
2. 1. 2
C o m bi ni n g Ra diati o n, a D N A Da ma ge A ge nt wit h M 3 8 1 4, a 
D N A Re pair -Tar gete d T hera p y a n d I m m u n ot hera p y......................... 50
2. 2
Bac k gr o u n d ......................................................................................... 52
2. 2. 1
Cli nical Res p o nse a n d Resista nce t o I m m u ne C hec k p oi nt 
I n hi bit ors............................................................................................. 52
2. 2. 2
D N A Re pair Pat h wa y s Alterati o ns are Ca ncer Dri vers a n d Affect 
Res p o nse t o I m m u n ot hera p y .............................................................. 53
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 53
2. 3. 1
S u m mar y  of M 3 8 1 4 Data a n d P ote ntial Be nefits a n d Ris ks .............. 54
2. 3. 1. 1
S u m mar y  of M 3 8 1 4 Ta blet F or m ulati o n a n d P ote ntial Be nefits 
a n d Ris ks .............................................................................................5 5
2. 3. 2
S u m mar y  of P ote ntial Be nefits a n d Ris ks of A vel u ma b .................... 56
2. 3. 3
S u m mar y  of P ote ntial Be nefits a n d Ris ks of Ra di ot hera p y ...............5 6
2. 3. 4
S u m mar y  of P ote ntial Be nefits a n d Ris ks of t he Treat me nt 
C o m bi nati o ns ...................................................................................... 57
2. 3. 5
S u m mar y  Be nefit/ Ris k State me nt.......................................................5 8
3
O bjecti ves a n d E n d p oi nts ................................................................... 58
3. 1
Part A ..................................................................................................5 8
3. 2
Part B ..................................................................................................5 9
3. 3
Part F E ................................................................................................6 1
4
St u d y  Desi g n.......................................................................................6 2
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 6 6
4. 1
O verall Desi g n ....................................................................................6 2
4. 1. 1
St u d y  Peri o ds...................................................................................... 63
4. 1. 1. 1
Scree ni n g Peri o d ................................................................................. 63
4. 1. 1. 2
Treat me nt Peri o d ................................................................................ 63
4. 1. 1. 3
F oll o w -U p Peri o ds .............................................................................. 64
4. 2
Scie ntific Rati o nale f or St u d y Desi g n ................................................ 64
4. 3
J ustificati o n f or D ose .......................................................................... 66
4. 3. 1
M 3 8 1 4 ................................................................................................. 66
4. 3. 2
Ra di ot hera p y ....................................................................................... 68
4. 3. 3
A vel u ma b ............................................................................................ 69
4. 4
E n d of St u d y  Defi niti o n...................................................................... 70
5
St u d y  P o p ulati o n................................................................................. 70
5. 1
I ncl usi o n Criteria ................................................................................ 70
5. 2
E xcl us i o n Criteria............................................................................... 73
5. 3
Lifest y le C o nsi derati o ns..................................................................... 77
5. 3. 1
Meals a n d Dietar y  Restricti o ns........................................................... 77
5. 3. 2
Caffei ne, Alc o h ol, a n d T o bacc o ......................................................... 77
5. 3. 3
Acti vit y ...............................................................................................7 7
5. 4
Scree n Fail ures .................................................................................... 77
6
St u d y  Inter ve nti o n(s) .......................................................................... 78
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 79
 
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g .............................................................................................. 82
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt ..........................................................8 2
6. 3. 2
Bli n di n g................................ ..............................................................8 2
6. 4
St u d y  Inter ve nti o n C o m plia nce ..........................................................8 2
6. 5
C o nc o mita nt T hera p y................................ .........................................8 2
6. 5. 1
Resc ue Me dici ne ................................................................................. 83
6. 5. 2
Per mitte d Me dici nes ...........................................................................8 3
6. 5. 3
Pr o hi bite d Me dici nes ..........................................................................8 3
6. 5. 4
Ot her I nter ve nti o ns .............................................................................8 5
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 6 6
6. 5. 5
Pre me dicati o n f or A vel u ma b .............................................................. 85
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 85
6. 6. 1
D ose Selecti o n ( Part A a n d Part B) .................................................... 86
6. 6. 2
D ose Selecti o n ( Part F E) .................................................................... 86
6. 6. 3
Defi niti o n of D ose -Li miti n g T o xicit y ................................................8 8
6. 6. 4
D ose Escalati o n R ules ........................................................................ 89
6. 6. 5
D osi n g I nstr ucti o ns ............................................................................. 91
6. 6. 5. 1
Part A ( M 3 8 1 4 + A vel u ma b) .............................................................. 91
6. 6. 5. 2
Part B ( M 3 8 1 4 + Ra di ot hera p y + A vel u ma b) .................................... 92
6. 6. 5. 3
Part F E ................................................................................................ 93
6. 6. 5. 4
Part A, Part B a n d Part F E .................................................................. 94
6. 6. 6
Treat me nt Be y o n d Pr o gressi o n ........................................................... 94
6. 6. 6. 1
Treat me nt Be y o n d I nitial Pr o gressi o n ................................................ 94
6. 6. 6. 2
Treat me nt Be y o n d C o nfir me d Pr o gressi o n ........................................ 94
6. 6. 7
C o nti n uati o n of St u d y  Inter ve nti o n After L ocal Treat me nt of 
Disease Pr o gressi o n ............................................................................ 95
6. 7
St u d y  Inter ve nti o n After t he E n d of t he St u d y ................................... 95
6. 8
S pecial Preca uti o ns ............................................................................. 96
6. 9
Ma na ge me nt of A d verse E ve nts of I nterest ........................................ 97
6. 9. 1
A d verse Dr u g Reacti o ns Re q uiri n g M 3 8 1 4 Treat me nt 
Disc o nti n uati o n or M o dificati o ns ....................................................... 97
6. 9. 2
A d verse Dr u g Reacti o ns Re q uiri n g A vel u ma b Treat me nt 
Disc o nti n uati o n or M o dificati o ns ....................................................... 99
6. 9. 2. 1
Ma na ge me nt of I nf usi o n-Relate d Reacti o ns .................................... 1 00
6. 9. 2. 2
I m m u ne-Relate d A d verse E ve nts ..................................................... 1 00
6. 9. 3
Ra di ot hera p y .....................................................................................1 0 6
6. 9. 3. 1
Ma na ge me nt of A d verse Dr u g Reacti o ns f or Ra di ot hera p y............. 1 0 6
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ............................................................. 1 07
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n .............................................. 1 07
7. 1. 1
Rec halle n ge .......................................................................................1 0 8
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................. 1 08
7. 3
L ost t o F oll o w U p .............................................................................1 0 9
8
St u d y  Assess me nts a n d Pr oce d ures..................................................1 0 9
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 6 6
8. 1
Efficac y  Assess me nts a n d Pr oce d ures..............................................1 1 0
8. 1. 1
Cli nical Assess me nts........................................................................ 1 1 0
8. 1. 1. 1
T u m or Res p o nse Assess me nt ........................................................... 1 10
8. 1. 1. 2
S ur vi val F oll o w- u p................................ ...........................................1 1 1
8. 2
Safet y  Assess me nts a n d Pr oce d ures ................................................. 1 12
8. 2. 1
P h y sical E xa mi nati o ns ...................................................................... 1 12
8. 2. 2
Vital Si g ns ........................................................................................ 1 12
8. 2. 3
Electr ocar di o gra ms ........................................................................... 1 13
8. 2. 4
Es o p ha geal E n d osc o p y ..................................................................... 1 13
8. 2. 5
Cli nical Safet y  La b orat or y Assess me nts .......................................... 1 13
8. 2. 6
Perf or ma nce Stat us ........................................................................... 1 14
8. 2. 7
Safet y  M o nit ori n g C o m mittee.......................................................... 1 14
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ................................... 1 15
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n .................................................. 1 15
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts . 1 15
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts ............. 1 15
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ... 1 16
8. 3. 5
Pre g na nc y ......................................................................................... 1 16
8. 4
Treat me nt of O ver d ose ..................................................................... 1 17
8. 5
P har mac o ki netics .............................................................................. 1 18
8. 9
Healt h Ec o n o mi cs ............................................................................. 1 21
8. 1 0
I m m u n o ge nicity Assess me nts .......................................................... 1 22
9
Statistical C o nsi derati o ns .................................................................. 1 22
9. 3
P o p ulati o ns f or A nal y ses .................................................................. 1 23
9. 4
Statistical A nal y ses ...........................................................................1 2 4
9. 4. 1
Efficac y  A nalys es .............................................................................1 2 4
9. 4. 2
Safet y  A nalys es ................................................................................1 2 4
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 / 1 6 6
9. 4. 3
Ot her A nal ys es ..................................................................................1 2 7
9. 4. 4
Se q ue nce of A nal ys es ....................................................................... 1 28
1 0
Ref ere nces ......................................................................................... 1 28
1 1
A p pe n dices ....................................................................................... 1 33
A p pe n di x 1
A b bre viati o ns .................................................................................... 1 34
A p pe n di x 2
St u d y  G o ver na nce............................................................................. 1 36
A p pe n di x 3
C o ntrace pti o n .................................................................................... 1 42
A p pe n di x 4
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g .............................................. 1 44
A p pe n di x 5
Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w-u p Assess me nts ......... 1 49
A p pe n di x 6
Cli nical L a b orat or y Tests ................................................................. 1 50
A p pe n di x 8
Ra diati o n T hera p y ............................................................................ 1 52
A p pe n di x 9
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 60
A p pe n di x 1 0
S p o ns or Si g nat ure Pa ge .................................................................... 1 63
A p pe n di x 1 1
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 64
A p pe n di x 1 2
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 1 66
List of T a bles
Ta ble 1
Sc he d ule of Acti vities - Part A ( M 3 8 1 4 + A vel u ma b) ....................... 20
Ta ble 2
Sc he d ule of Acti vities – D ose -Li miti n g T o xicit y E val uati o n 
Peri o d – Part B ( M 3 8 1 4 + Ra di ot hera p y + A vel u ma b) ...................... 26
Ta ble 3
Sc he d ule of Acti vities – Safet y  F oll o w-u p Peri o d - Part B ( M 3 8 1 4 
+ Ra di ot hera p y + A vel u ma b)............................................................. 3 0
Ta ble 4
Sc he d ule of Acti vities – Part F E ( M 3 8 1 4 + A vel u ma b)..................... 3 5
Ta ble 5
P har mac o ki netic a n d  
 Bl o o d Sa m pli n g Sc he d ule – Part 
A ( M 3 8 1 4 + A vel u ma b) ..................................................................... 42
Ta ble 6
P har mac o ki netic a n d 
Bl o o d Sa m p li n g Sc he d ule – Part 
B ( M 3 8 1 4 + Ra di ot hera p y + A vel u ma b) ............................................ 44
Ta ble 7
P har mac o ki netic a n d 
 Bl o o d Sa m pli n g Sc he d ule – Part 
F E ( M 3 8 1 4 + A vel u ma b).................................................................... 47
Ta ble 8
St u d y  O bjecti ves a n d E n d p oi nts – Part A ...........................................5 8
Ta ble 9
St u d y  O bjecti ves a n d E n d p oi nts – Part B ...........................................5 9
Ta ble 1 0
St u d y  O bjecti ves a n d E n d p oi nts – Part F E .........................................6 1
Ta ble 1 1
A d mi nistrati o n of St u d y  Inter ve nti o n(s) ............................................. 79
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 6 6
Ta ble 1 2
E xa m ple of P ossi ble D ose Le vels of M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b i n Part F E .......................................................................... 87
Ta ble 1 3
E xa m ple of P ossi ble D ose Le vels of M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b ( Part A) .............................................................................. 90
Ta ble 1 4
E xa m ple of P ossi ble D ose Le vels of M 3 8 1 4 i n C o m bi nati o n wit h 
Ra di ot hera p y a n d A vel u ma b ( Part B) ................................................. 91
Ta ble 1 5
D ose M o dificati o ns f or M 3 8 1 4 a n d Ra di ot hera p y D uri n g Part B 
of t he St u d y ......................................................................................... 98
Ta ble 1 6
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n-relate d 
Reacti o ns Ass ociate d wit h A vel u ma b .............................................. 1 00
Ta ble 1 7
Ma na ge me nt of I mm u ne -Relate d A d verse E ve nts ........................... 1 01
Ta ble 1 8
Acce pta ble P har mac o ki netic Wi n d o ws f or A vel u ma b ..................... 1 19
Ta ble 1 9
Acce pta ble P har mac o ki netic Wi n d o ws f or M 3 8 1 4 .......................... 1 19
Ta ble 2 0
Pr ot oc ol -Re q uire d Cli nical La b ora t or y Assess me nts....................... 1 50
Ta ble 2 1
Ra diati o n Treat me nt Sc he d ule.......................................................... 1 5 3
Ta ble 2 2
E xa m ple of Ke y  C o m p o ne nts of a n I nte nsity -m o d ulate d Ra diati o n 
T hera p y S ys te m ................................................................................ 1 55
Ta ble 2 3
Tar get V ol u me a n d Critical Str uct ure C o nstrai nts wit h 
C o m plia nce Criteria ..........................................................................1 5 6
List of Fi g ures
Fi g ure 1
St u d y  Desi g n Sc he ma - Part A a n d B ................................................. 18
Fi g ure 2
St u d y  Desi g n Sc he ma - Part F E .......................................................... 19
Fi g ure 3
Efficac y  of M 3 8 1 4 i n C o m bi nati o n wit h A vel u ma b a n d I o nizi n g 
Ra diati o n i n t he M C 3 8 T u m or M o del ................................................ 51
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 6 6
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: A M ultice nter, O pe n -La bel, D ose Escalati o n P hase I St u d y  to E val uate t he Safet y,  
T olera bilit y , P har mac o ki netics , a n d F o o d Effect o n P har mac o ki netics of t he D N A -P K I n hi bit or 
M 3 8 1 4 i n C o m bi nati o n wit h A vel u ma b wit h a n d wit h o ut Palliati ve Ra di ot hera p y i n Partici pa nts 
wit h Selecte d A d va nce d S oli d T u m ors
S h ort Title: P hase I St u d y of A vel u ma b -M 3 8 1 4 C o m bi nati o ns
R ati o n ale: T his st u d y is part of a cli nical de vel o p me nt pr o gra m w hic h ai ms t o e val uate t he cli nical 
utilit y  of M 3 8 1 4, a D N A da ma ge tar get a ge nt wit h a vel u ma b, a n a nti-pr o gra m me d deat h -li ga n d 1 
(P D -L 1 ) t hera p y wit h a n d wit h o ut ra di ot hera p y ( R T) i n a br oa d ra n ge of ca ncers.
T he first part of t his st u dy ( Part A) will assess M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b i n partici pa nts 
wit h a d va nce d or metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, sta n dar d t hera p y 
has faile d, or partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera p y kn o w n t o pr o vi de 
cli nical be nefit f or t heir c o n diti o n.
T he sec o n d part of t his st u d y ( Part B) will assess M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b a n d R T i n 
partici pa nts wit h a d va nce d or metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, 
sta n dar d t hera py has faile d, or partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera py 
k n o w n t o pr o vi de cli nical be nefit f or t heir c o n diti o n a n d are a me na ble t o recei ve R T .
T he t hir d part of t his st u d y (Part F E ) will assess f o o d effect ( F E) o n p har mac o ki netic s ( P K) of 
M 3 8 1 4 w he n a d mi nistere d i n c o m bi nati o n wit h a vel u ma b u n der faste d a n d fe d c o n diti o ns , i n 
partici pa nts wit h a d va nce d or metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, 
sta n dar d t hera py has faile d, or partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera py 
k n o w n t o pr o vi de cli nical be nefit f or t heir c o n diti o n.
O bjec ti ves a n d E n d p oi nts:
P art A
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D a n d/ or t h e M T D 
of M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b 
O c c urr e n c e of D L T s fr o m fir st tr e at m e nt t o pl a n n e d fi n al 
a s s e s s m e nt at t h e e n d of D L T p eri o d at 3 w e e k s
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI-C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4/ 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
P h ar m a c o ki n eti c s
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of M 3 8 1 4 a n d 
a v el u m a b w h e n gi v e n a s c o m bi n ati o n t h er a p y

P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s, a s f e a si bl e 
( e. g. Cm a x, Cmi n , R a c c[ Cm a x], R a c c[ A U C] a n d t1/ 2 )

P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C m a x , tm a x, Cmi n , 
C a v g, fl u ct u ati o n i n d e x, A U C0-t , A U C0- ∞, R a c c[ Cm a x],
R a c c[ A U C], t 1/ 2 , V z/f, C L/f, a n d Λ z)
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n
c o m bi n ati o n wit h M 3 8 1 4
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b i n 
p arti ci p a nt s wit h l o c all y a d v a n c e d or a d v a n c e d s oli d 
t u m or s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
A D A = a nti dr u g 
a nti b o d y, 
B O R = b e st 
o v er all 
r e s p o n s e, C R = c o m pl et e 
r e s p o n s e, D L T = d o s e -li miti n g t o xi cit y, 
D O R = d ur ati o n of r e s p o n s e, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e 
St at u s, M T D = m a xi m u m t ol er at e d d o s e, 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 s, P D = pr o gr e s si v e di s e a s e, P F S = pr o gr e s si o n -fr e e s ur vi v al, P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e 
E v al u ati o n Crit eri a I n S oli d T u m or s, 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.
P art B
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D a n d/ or t h e M T D
of M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b 
a n d r a di ot h er a p y
O c c urr e n c e of D L T s fr o m fir st tr e at m e nt t o pl a n n e d fi n al 
a s s e s s m e nt at t h e e n d of D L T p eri o d at 4 w e e k s
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b a n d 
r a di ot h er a p y

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI-C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S

I n ci d e n c e, s e v erit y a n d o ut c o m e s of R T-i n d u c e d 
t o xi cit y
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
P h ar m a c o ki n eti c s
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of M 3 8 1 4 a n d 
a v el u m a b w h e n gi v e n i n c o m bi n ati o n wit h 
r a di ot h er a p y

P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s, a s f e a si bl e 
( e. g. Cm a x, Cmi n , R a c c[ Cm a x], R a c c[ A U C] a n d t1/ 2 )

P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C m a x , tm a x, Cmi n , 
C a v g, fl u ct u ati o n i n d e x, A U C 0-t , A U C0- ∞, R a c c[ C m a x],
R a c c[ A U C], t 1/ 2 , V z/f, C L/f, a n d Λ z)
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n 
c o m bi n ati o n wit h M 3 8 1 4 pl u s r a di ot h er a p y
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b a n d 
r a di ot h er a p y i n p arti ci p a nt s wit h l o c all y a d v a n c e d a n d 
a d v a n c e d s oli d t u m or s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
A D A = a nti dr u g 
a nti b o d y, 
B O R = b e st 
o v er all 
r e s p o n s e, C R = c o m pl et e 
r e s p o n s e, D L T = d o s e -li miti n g t o xi cit y, 
D O R = d ur ati o n of r e s p o n s e, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e 
St at u s, M T D = m a xi m u m t ol er at e d d o s e, 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 s, P D = pr o gr e s si v e di s e a s e, P F S = pr o gr e s si o n -fr e e s ur vi v al, P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e 
E v al u ati o n Crit eri a I n S oli d T u m or s, 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 , R T =r a di ot h er a p y.
P art F E
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a n d c o m p ar e t h e p h ar m a c o ki n eti c 
pr ofil e of M 3 8 1 4 u n d er f a st e d a n d f e d c o n diti o n s
Ar e a u n d er t h e M 3 8 1 4 pl a s m a c o n c e ntr ati o n -ti m e c ur v e 
( A U C) fr o m ti m e z er o t o t h e l a st q u a ntifi a bl e s a m pli n g 
ti m e ( A U C0-t ) a n d m a xi m u m M 3 8 1 4 pl a s m a c o n c e ntr ati o n 
o b s er v e d ( C m a x)
S e c o n d ar y
S a f et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b
u n d er f a st e d 
a n d f e d c o n diti o n s

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI- C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n 
c o m bi n ati o n wit h M 3 8 1 4 u n d er f a st e d a n d f e d 
c o n diti o n s
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b i n 
p arti ci p a nt s wit h l o c all y a d v a n c e d or a d v a n c e d s oli d 
t u m or s, u n d er f a st e d a n d f e d c o n diti o n s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti gat or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
A D A = a nti dr u g 
a nti b o d y, 
B O R = b e st 
o v er all 
r e s p o n s e, C R = c o m pl et e 
r e s p o n s e, D O R = d ur ati o n 
of 
r e s p o n s e, 
E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at 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 s, P D = pr o gr e s si v e di s e a s e, P F S = pr o gr e s si o n- fr e e 
s ur vi v al, P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a I n S oli d T u m or s.
O ver all Desi g n: 
T his is a P hase I, m ultice nter st u d y  c o nsisti n g of 3 parts ( Part A , Part B , a n d Part F E).

Part A ai ms t o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) a n d/ or t he rec o m me n de d P hase II 
d ose ( R P 2 D ) of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h a vel u ma b.

Part B ai ms t o deter mi ne t he M T D a n d/ or t he R P 2 D of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h 
a vel u ma b a n d R T .

Part B will be i nitiate d o nce a first d ose le vel of Par t A has bee n declare d as safe 
a n d t olera ble b y t he Safet y  M o nit ori n g C o m mittee (S M C ).

Part F E ai ms t o e val uate t he F E o n P K of M 3 8 1 4 f oll o wi n g a d mi nistrati o n of M 3 8 1 4 i n 
c o m bi nati o n wit h a vel u ma b u n der faste d a n d fe d c o n diti o ns . O nl y  doses of M 3 8 1 4 alrea d y 
declare d as safe a n d t olera ble i n Part A b y  the S M C will be i n vesti gate d i n t his p art of t he st u d y.

T he ta blet f or m ulati o n of M 3 8 1 4 will be use d i n t his st u d y .

A d diti o nal d osi n g re gi me ns of M 3 8 1 4 a n d a vel u ma b ( Part A a n d Part F E ) or M 3 8 1 4, a vel u ma b, 
a n d R T ( Part B) ma y be i ntr o d uce d b y pr ot oc ol a me n d me nt t o be e x pl ore d.

A n i ncrease i n t he sa m ple size f or Part A, Part B , a n d/ or Part F E of t he st u d y t o acc o m m o date 
a d diti o nal d ose le vels ma y be a d de d b y pr ot oc ol a me n d me nt.

I n a d diti o n, e x pa nsi o n c o h orts i n defi ne d a d va nce d s oli d t u m or i n dicati o ns ma y  be a d de d b y  
a me n d me nt t o e x pl ore preli mi nar y  efficac y of t he c o m bi nati o n re gi me ns st u die d i n Part A 
a n d/ or Part B.
N u m ber of P artici p a nts: 
I n t his st u d y, f or eac h part ( A a n d B) t he sa m ple size will de pe n d o n t he n u m ber of d ose -li miti n g 
t o xicities (D L Ts ) o bser ve d at t he differe nt d ose le vels a n d t he n u m ber of teste d or e x pa n de d d ose 
le vels f or M 3 8 1 4 as d ose escalati o n will be g ui de d b y  a Ba yesia n l o gistic re gressi o n m o del wit h 
o ver d ose c o ntr ol. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 6 6
A t w o-para meter l o gistic m o del will be use d t o descri be t he d ose -t o xicit y relati o n f or M 3 8 1 4. 
 cli nical data of M 3 8 1 4 are use d t o set u p t he m o del. It is a ntici pate d t hat 6 t o 
3 0 partici pa nts i n Part A (3 t o 6 partici pa nts at eac h d ose le vel ) a n d 6 t o 2 4 partici pa nts i n Part B 
( 3 t o 6 partici pa nts at eac h d ose le vel) m a y  be nee de d. I n a d diti o n, 6 t o 1 2 pa rtici pa nts will be 
e nr olle d i n Part F E t o assess t he F E o n P K of M 3 8 1 4. T h us, t he t otal n u m ber of partici pa nts ma y  
be 1 8 t o 6 6.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: 
P art A : M 3 8 1 4 
will be a d mi nistere d t wice dail y  (BI D) c o nti n u o usl y, i n c o m bi nati o n wit h 
a vel u ma b 8 0 0 m g o nce e ver y  2 wee ks ( Q 2 W) starti n g o n Da y 1 u ntil pr o gressi ve disease ( P D ) or 
u nacce pta ble t o xicit y. T he starti n g d ose of M 3 8 1 4 i n Part A will be 1 0 0 m g BI D. S u bse q ue nt d ose s
a n d sc he d ule s will be deter mi ne d b y  t he S M C.
P art B : M 3 8 1 4 will be a d mi nistere d o nce dail y  (Q D). Ra di ot hera p y  will be gi ve n at t he d ose of 
3 G y  per d a y . M 3 8 1 4 a n d R T will b ot h be gi ve n starti n g Da y  1 for 5 d a y s/ wee k f or 2 wee ks . 
A vel u ma b 8 0 0 m g will be a d mi nistere d Q 2 W starti n g o n Da y 1 u ntil P D or u nacce pta ble t o xicit y .
T he starti n g d ose of M 3 8 1 4 i n t he first c o h ort of Part B will b e 1 0 0 m g t otal dail y d ose. H o we ver, 
t his starti n g d ose mi g ht be a dj uste d b y t he S M C base d o n safety, P K, a n d p har mac o d y na mic (P d )
data ge nerate d d uri n g t he first d ose le vel i n Part A a n d/ or e mer gi n g data fr o m t he o n g oi n g cli nical 
st u dies i n v ol vi n g M 3 8 1 4.
P art F E : M 3 8 1 4 will be a d mi nistere d BI D c o nti n u o usl y, i n c o m bi nati o n wit h a vel u ma b 8 0 0 m g 
Q 2 W starti n g o n D a y  1 until P D or u nacce pta ble t o xicit y. T he starti n g d ose of M 3 8 1 4 will be
1 0 0 m g BI D . S u bse q ue nt d oses a n d sc he d ule s will be deter mi ne d b ase d o n t he P K a n d safet y data
ge nerate d i n pre vi o us c o h orts of b ot h of Part A a n d Part F E.
I n v ol ve me nt of S peci al C o m mittee(s): Yes (S M C )
T he S M C c o nsists of c ore ( v oti n g) me m bers fr o m t he S p o ns or ( Gl o bal Patie nt Safet y  Pr o d uct 
Lea der 
[C hair ], Me dical 
Res p o nsi ble, 
Cl i nical P har mac ol o gist 
a n d Bi ostatisticia n), 
t he 
C o or di nati n g I n vesti gat or, a n d (if a p plica ble) t he Me dical M o nit or of t he C o ntract Researc h 
Or ga nizati o n ( C R O ). A d h oc me m bers ma y be i n vite d as nee de d (if dee me d necessar y).
T he S M C will re g ularl y re vie w t he safet y data of partici pa nts e nr olle d i n a n y  part of t his st u d y. It 
will deci de o n rele va nt D L T base d o n criteria defi ne d i n t he pr ot oc ol a n d will pr o vi de 
rec o m me n dati o n b y  co nse ns us o n d ose escalati o n, d ose de- escalati o n, or s us pe nsi o n of e nr oll me nt 
a n d/ or declarati o n of t he M T D a n d/ or t he R P 2 D.
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 / 1 6 6
1. 2
Sc he m a
Fi g ure 1
St u d y Desi g n Sc he m a - P art A a n d B
BI D =t wi c e d ail y, d = d a y, D L T = d o s e -li miti n g t o xi cit y, E o T = E n d of Tr e at m e nt, F D/ W =fr a cti o n d a y s/ w e e k, F U =f oll o w-u p, m o = m o nt h s, P D = Pr o gr e s si v e Di s e a s e, 
Q 2 W = e v er y 2 w e e k s, Q D = o n c e d ail y, 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, R T =r a di ot h er a p y. 
a All p arti ci p a nt s will b e f oll o w e d u p f or s ur vi v al a n d u s e of s u b s e q u e nt a nti c a n c er tr e at m e nt b y p h o n e e v er y 3 m o u ntil 1 2 m o aft er l a st p arti ci p a nt h a s r e c ei v e d t h e 
l a st d o s e of st u d y i nt er v e nti o n s or di e s, w hi c h e v er c o m e s fir st.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 6 6
Fi g ure 2
St u d y Desi g n Sc he m a - P art F E
BI D =t wi c e d ail y, d = d a y, D L T = d o s e -li miti n g t o xi cit y, E o T = E n d of Tr e at m e nt, F U =f oll o w-u p, m o = m o nt h s, P D = Pr o gr e s si v e Di s e a s e, Q 2 W = e v er y 2 w e e k s. 
a All p arti ci p a nt s will b e f oll o w e d u p f or s ur v i v al a n d u s e of s u b s e q u e nt a nti c a n c er tr e at m e nt b y p h o n e e v er y 3 m o u ntil 1 2 m o aft er l a st p arti ci p a nt h a s r e c ei v e d t h e 
l a st d o s e of st u d y i nt er v e nti o n s or di e s, w hi c h e v er c o m e s fir st.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 6 6
1. 3
Sc he d ule of Acti vities
T a ble 1
Sc he d ule of Acti vities - P art A ( M 3 8 1 4 + A vel u m a b)
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
Si g n e d I nf or m e d C o n s e nt
X
I n cl u si o n/ E x cl u si o n 
Crit eri a
X 
X
D e m o gr a p h y
X
M e di c al Hi st or y
X
β- H C G Pr e g n a n c y T e st 
(if a p pli c a bl e)
X 
X
X
Q 4 W
X
S er u m β- H C G at S cr e e ni n g ( ca n b e u p t o 
2 8 d a y s pri or t o t h e fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o ns) ; uri n e β- H C G t h er e aft er f or 
W O C B P . R e s ult s of m o st r e c e nt pr e g n a n c y t e st 
s h o ul d b e a v ail a bl e pri or t o a d mi ni str ati o n of 
st u d y i nt er v e nti o n.
F S H (if a p pli c a bl e)
X
S e e S e cti o n 8. 2. 5 , A p p e n di x  3 a n d A p p e n di x 6 .
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
I nf e cti o n S cr e e n 
( H e p atiti s B a n d C), 
O pti o n al HI V T e st
X
H e p atit i s B a n d C t e st at S cr e e ni n g ( ca n b e u p 
t o 2 8 d a y s pri or t o t h e fir st st u d y i nt er v e nti o n s)
u nl e s s d o n e ≤3 m o pri or t o S cr e e ni n g. HI V t e st 
p er l o c al pr a cti c e a n d l o c al r e g ul at or y g ui d a n c e.
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X
All ti m e p oi nt s: w ei g ht, t e m p er at ur e, di a st oli c 
a n d s y st oli c B P, p ul s e , p ul s e o xi m etr y, a n d 
r e s pir at or y r at e. S cr e e ni n g o nl y: h ei g ht. 
T o b e p erf or m e d pri or t o t h e a d mi ni str ati o n of 
st u d y i nt er v e nti o n o n D a y 1. O nl y r e q uir e d at 
E o T if p arti cip a nt h a s n ot st art e d a n e w 
a nti t u m or tr e at m e nt.
S cr e e ni n g p eri o d: c a n b e u p t o 2 8 d a y s pri or t o 
t h e fir st st u d y i nt er v e nti o n s.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
P h y si c al E x a m ( P E)
X 
X
X
P erf or m at 
V i sit 6 
(W e e k 8 ) 
a n d t h e n 
Q 8 W
X 
X
C o m pl et e P E at S cr e e ni n g ( ca n b e u p t o 
2 8 d a y s p ri or t o t h e fir st st u d y i nt er v e nti o ns),
D a y 1 pri or t o t h e fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o n s, a n d D a y 2 2 . A P E o nl y r e q uir e d 
at E o T if p arti ci p a nt h a s n ot st art e d a n e w 
a nti t u m or tr e at m e nt. S y m pt o m-ori e nt e d P E at 
e a c h vi sit if d e e m e d n e c e s s ar y b y t h e 
I n v e sti g at or.
E C O G P erf or m a n c e 
St at u s
X
X 
X 
X 
X 
X 
X 
X
A E A s s e s s m e nt
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
C o nti n u o u sl y, at E o T, a n d S af et y F U, o n g oi n g 
tr e at m e nt-e m er g e nt A E s s h o ul d b e e v al u at e d.
At L o n g -t er m F U, o nl y n e e d e d if p arti ci p a nt h a s
n ot st art e d a n e w a ntit u m or tr e at m e nt.
C o n c o mit a nt M e di c ati o n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
H e m at ol o g y, S er u m 
C h e mi str y
X 
X
X 
X
Q 4 W 
X 
X
B a s eli n e c o m pl et e h e m at ol o g y a n d c or e s er u m 
c h e mi str y a n al y s e s c o ul d b e p erf or m e d wit hi n 
t h e S cr e e ni n g p eri o d (c a n b e u p t o 2 8 d a y s 
pri or t o t h e fir st a d mi ni str ati o n of st u d y
i nt er v e nti o ns ). Pri or t o t h e a d mi ni str ati o n of 
st u d y i nt er v e nti o n s, t h e m o st r e c e nt c o m pl et e 
h e m at ol o g y a n d c or e s er u m c h e mi str y r e s ult s 
m u st b e a v ail a bl e a n d r e vi e w e d. S e e 
A p p e n di x 6 .
Di p sti c k Uri n al y si s
X 
X
X
P erf or m at 
V i sit 6 
(W e e k 8 ) 
a n d t h e n 
Q 8 W
X
F ull uri n al y si s ( di p sti c k +
mi cr o s c o pi c a n al y si s) 
s h o ul d b e p erf or m e d o nl y at S cr e e ni n g a n d 
E o T. If di p sti c k uri n al y si s at ot h er a s s e s s m e nt s 
i s a b n or m al, f ull a n al y si s s h o ul d b e p erf or m e d. 
S e e A p p e n di x  6.
Fr e e T 4, T S H
X 
X
X
Q 6 W
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
1 2 - L e a d E C G (i n cl u di n g 
Q T c F)
X 
X 
X 
X
X
P K -m at c h e d di git al 1 2 -l e a d r e sti n g E C G will b e 
p erf or m e d i n tri pli c at e at pr e d o s e, 1, 2 a n d 6 h 
p o st - M 3 8 1 4 a d mi ni str ati o n b ef or e bl o o d 
c oll e cti o n f or P K, 
 s a m pli n g, 
f oll o w e d b y vit al si g n s aft er t h e m or ni n g d o s e 
o nl y. T h e a s s e s s m e nt s h o ul d b e p erf or m e d 
aft er t h e p arti ci p a nt h a s b e e n i n s u pi n e p o siti o n 
br e at hi n g q ui etl y f or ≥5
mi n at pr e d o s e a n d all 
p o st d o s e s a m pli n g ti m e s.
T u m or A s s e s s m e nt 
( R E CI S T v 1. 1)
X
D a y 5 6,
D a y 1 1 2, 
D a y 1 6 8, 
t h e n 
Q 1 2 W
X 
X
X
T u m or i m a gi n g b y C T or M RI at B a s eli n e t o 
d o c u m e nt t u m or l e si o n b ur d e n. C a n b e u p t o 2 8 
d a y s pri or t o fir st st u d y i nt er v e nti o n.
T h e n at D 5 6, D 1 1 2, D 1 6 8 a n d t h e n Q 1 2 W , u ntil 
c o nfir m e d P D , t h e start of s u b s e q u e nt s y st e mi c 
a nti c a n c er t h er a p y, or t h e e n d of t h e st u d y. At 
E o T/ L o n g -t er m F U, t u m or r e s p o n s e 
a s s e s s m e nt i s o nl y r e q uir e d if p arti ci p a nt h a s 
n ot pr o gr e s s e d or h a s n ot st art e d a n e w 
tr e at m e nt.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m 
F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, vi sit s 
will b e e v er y 2 w k s o n d a y s of a v el u m a b 
i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y i nt er v e nti o n s 
f or a n y r e a s o n m u st u n d er g o E o T Vi sit wit hi n 
7 d a y s aft er d e ci si o n t o di s c o nti n u e st u d y 
i nt er v e nti o n s, b ut (if p o s si bl e) b ef or e a n y n e w 
a nti n e o pl a sti c t h er a p y i s st art e d.
T h e s af et y f oll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s ( ± 5 d a y s) aft er t h e l a st 
d o s e of a v el u m a b, s e e S e cti o n 4. 1. 1 . 3.
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi n 
7 d a y s 
of 
d e ci si o n 
t o 
di s c o nti
n u e )
3 0 d 
(± 5)

9 0 d 
(± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a ys/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( av el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s , a s 
n e e d e d t h er e aft er . S e e S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st -C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
T u m or M at eri al 
X
S e e N ot e s
 
 
 
 
 
 
 
 
 
 
S ur vi v al
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
All p arti ci p a nt s will b e f oll o w e d u p f or s ur v i v al 
a n d u s e of s u b s e q u e nt a nti c a n c er tr e at m e nt (b y 
p h o n e aft er E o T) e v er y 1 2 w k s u ntil 1 y e ar aft er 
l a st p arti ci p a nt h a s r e c ei v e d t h e l a st d o s e of 
st u d y i nt er v e nti o n s or di e s, w hi c h e v er c o m e s 
fir st.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 6 6
: p h o n e c all vi sit.
A E = a d v er s e e v e nt, β- H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n, BI D =t wi c e d ail y, B P = bl o o d pr e s s ur e, C T = c o m p ut e d t o m o gr a p h y, ct D N A = cir c ul ati n g t u m or D N A,
d = d a y s, E C G = el e ctr o c ar di o gr a m, E C O G = E a st er n C o o p er ati v e O n c ol o g y Gr o u p, E o T = E n d of Tr e at m e nt V i sit, F S H =f olli cl e -sti m ul ati n g h or m o n e, F U =f oll o w -u p, 
HI V = h u m a n i m m u n o d efi ci e n c y vir u s, m o = m o nt h s, M RI = m a g n eti c r e s o n a n c e i m a gi n g, P E = p h y si c al e x a m i n ati o n; P K = p h ar m a c o ki n eti c, P D = pr o gr e s si v e di s e a s e, 
, Q T c F = Fri d eri ci a' s C orr e cti o n F or m ul a, Q x W = e v er y x w e e k s, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s, fr e e 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 , w k = w e e k, WO C B P = w o m e n of c hil d b e ari n g p ot e nti al .
T a ble 2
Sc he d ule of Acti vities – D ose - Li miti n g T o xicit y E v al u ati o n Peri o d – P a rt B 
( M 3 8 1 4 + R a di ot her a p y + A vel u m a b)
St u d y  P eri o d
S cr e e ni
n g
D L T E v al u ati o n P eri o d W e e k 1 t o 4
( M 3 8 1 4 + R T + a v el u m a b)
N ot e s
St u d y  Vi sit
1 
2 
3- 6 
7- 1 0 
1 1 
1 2 
1 3
St u d y  D a y
( ± Vi sit wi n d o w )
-3 5 t o - 1 
1
2- 5
(± 1)
8- 1 1
(± 1)
1 2
1 5
(± 1)
2 9
(± 1)
M 3 8 1 4
X 
X 
X 
X
M 3 8 1 4 Q D 5 d/ w k ( o nl y o n d a y s of r a di ati o n). S e e S e cti o n 
6. 6. 5. 2 .
R T 3 G y  × 1 0 ( 5 FD / W)
X 
X 
X 
X
R T 3 G y/fr a cti o n, 5 F D / w k. R T t o b e gi v e n 1. 5 h ( ± 3 0 mi n) 
aft er M 3 8 1 4 .
Pr e m e di c ati o n A v el u m a b
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s, a s n e e d e d 
t h er e aft er. S e e S e ctio n 6. 5 . 5.
A v el u m a b
X
X 
X
8 0 0 m g i v Q 2 W  u ntil P D; o n D a y 1 a v el u m a b will b e gi v e n pri or 
t o M 3 8 1 4. F or p o st -P D tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-
C R tr e at m e nt, s e e S e cti o n 4. 1. 1 . 2.
Si g n e d I nf or m e d C o n s e nt
X
I n cl u si o n/ E x cl u si o n Crit eri a
X 
X
D e m o gr a p h y
X 
X
M e di c al Hi st or y
X
β- H C G Pr e g n a n c y T e st 
(if a p pli c a bl e)
X 
X
X
S er u m β- H C G at S cr e e ni n g; uri n e β- H C G t h er e aft er f or
W O C B P. R e s ult s of m o st r e c e nt pr e g n a n c y t e st s h o ul d b e 
a v ail a bl e pri or t o a d mi ni str ati o n of st u d y i nt er v e nti o n.
F S H (if a p pli c a bl e)
X
S e e S e cti o n 8. 2 .5 , A p p e n di x  3 a n d A p p e n di x 6
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 6 6
St u d y  P eri o d
S cr e e ni
n g
D L T E v al u ati o n P eri o d W e e k 1 t o 4
( M 3 8 1 4 + R T + a v el u m a b)
N ot e s
St u d y  Vi sit
1 
2 
3- 6 
7- 1 0 
1 1 
1 2 
1 3
St u d y  D a y
( ± Vi sit wi n d o w )
-3 5 t o - 1 
1
2- 5
(± 1)
8- 1 1
(± 1)
1 2
1 5
(± 1)
2 9
(± 1)
M 3 8 1 4
X 
X 
X 
X
M 3 8 1 4 Q D 5 d/ w k ( o nl y o n d a y s of r a di ati o n). S e e S e cti o n 
6. 6. 5. 2 .
R T 3 G y  × 1 0 ( 5 FD / W)
X 
X 
X 
X
R T 3 G y/fr a cti o n, 5 F D / w k. R T t o b e gi v e n 1. 5 h ( ± 3 0 mi n) 
aft er M 3 8 1 4 .
Pr e m e di c ati o n A v el u m a b
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s, a s n e e d e d 
t h er e aft er. S e e S e ctio n 6. 5 . 5.
A v el u m a b
X
X 
X
8 0 0 m g i v Q 2 W  u ntil P D; o n D a y 1 a v el u m a b will b e gi v e n pri or 
t o M 3 8 1 4. F or p o st -P D tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-
C R tr e at m e nt, s e e S e cti o n 4. 1. 1 . 2.
I nf e cti o n S cr e e n ( H e p atiti s 
B a n d C); O pti o n al HI V T e st
X
H e p atiti s B a n d C t e st at S cr e e ni n g u nl e s s d o n e ≤3 m o pri or 
t o S cr e e ni n g. HI V t e st p er l o c al pr a cti c e a n d l o c al r e g ul at or y 
g ui d a n c e.
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X
H ei g ht at S cr e e ni n g o nl y, w ei g ht at S cr e e ni n g a n d D a y 2 9. 
T e m p er at ur e, di a st oli c a n d s y st oli c bl o o d pr e s s ur e , p ul s e ,
p ul s e o xi m etr y , a n d r e s pir at or y r at e at e a c h vi sit.
S cr e e ni n g p eri o d : c a n b e u p t o 3 5 d a y s pri or t o t h e fir st 
a d mi ni str ati o n of st u d y i n t er v e nti o n s.
P h y si c al E x a m ( P E)
X 
X
X
( D 5)
X
X
Q 6 W  
St arti n g 
V i sit 1 3
A c o m pl et e P E at S cr e e ni n g ( c a n b e u p t o 3 5 d a y s pri or t o t h e 
fir st a d mi ni str ati o n of st u d y i nt er v e nti o n s), D 1 pri or t h e st art of 
st u d y i nt er v e nti o n, D 5 ( R T fr a cti o n 5), D 1 2 ( R T fr a cti o n 1 0) a n d 
D 2 9. P E will r e p ort fi n di n g s i n t h e irr a di at e d ar e a. S y m pt o m -
ori e nt e d P E w h e n e v er d e e m e d n e c e s s ar y b y t h e I n v e sti g at or.
E s o p h a g e al e n d o s c o p y 
(if r el e v a nt)
X
O nl y r e q uir e d i n c a s e of a cti v e e s o p h a giti s or cli ni c al si g n s of 
e s o p h a giti s a n d if it i s e sti m at e d t h at t h e r a di ati o n fi el d s will 
i n v ol v e a n y p orti o n of t h e e s o p h a g u s .
Cli ni c al E x a mi n ati o n of 
Ti s s u e s i n R T Ar e a
X 
X
X 
X
R e q uir e d o n e a c h d a y of R T s c h e d ul e.
E C O G P S
X 
X 
X 
X
X 
X
A d v er s e E v e nt A s s e s s m e nt
X 
X 
X 
X 
X 
X 
X
C o n c o mit a nt M e di c ati o n
X 
X 
X 
X 
X 
X 
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 6 6
St u d y  P eri o d
S cr e e ni
n g
D L T E v al u ati o n P eri o d W e e k 1 t o 4
( M 3 8 1 4 + R T + a v el u m a b)
N ot e s
St u d y  Vi sit
1 
2 
3- 6 
7- 1 0 
1 1 
1 2 
1 3
St u d y  D a y
( ± Vi sit wi n d o w )
-3 5 t o - 1 
1
2- 5
(± 1)
8- 1 1
(± 1)
1 2
1 5
(± 1)
2 9
(± 1)
M 3 8 1 4
X 
X 
X 
X
M 3 8 1 4 Q D 5 d/ w k ( o nl y o n d a y s of r a di ati o n). S e e S e cti o n 
6. 6. 5. 2 .
R T 3 G y  × 1 0 ( 5 FD / W)
X 
X 
X 
X
R T 3 G y/fr a cti o n, 5 F D / w k. R T t o b e gi v e n 1. 5 h ( ± 3 0 mi n) 
aft er M 3 8 1 4 .
Pr e m e di c ati o n A v el u m a b
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s, a s n e e d e d 
t h er e aft er. S e e S e ctio n 6. 5 . 5.
A v el u m a b
X
X 
X
8 0 0 m g i v Q 2 W  u ntil P D; o n D a y 1 a v el u m a b will b e gi v e n pri or 
t o M 3 8 1 4. F or p o st -P D tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-
C R tr e at m e nt, s e e S e cti o n 4. 1. 1 . 2.
H e m at ol o g y a n d S er u m 
C h e mi str y
X 
X
X 
( D 5)
X
X
Q 4 W  
St arti n g 
V i sit 1 3
B a s eli n e c o m pl et e h e m at ol o g y a n d c or e s er u m c h e mi str y 
a n al y s e s c o ul d b e p erf or m e d wit hi n S cr e e ni n g p eri o d ( c a n b e 
u p t o 3 5 d a y s pri or t o t h e fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o n s). Pri or t o t h e a d mi ni str ati o n of st u d y 
i nt er v e nti o n s, t h e m o st r e c e nt c o m pl et e h e m at ol o g y a n d c or e 
s er u m c h e mi str y r e s ult s m u st b e a v ail a bl e a n d r e vi e w e d. S e e 
A p p e n di x 6 .
Di p sti c k Uri n al y si s
X 
X
X
Q 6 W  
St arti n g 
V i sit 1 3
F ull uri n al y si s ( di p sti c k +
mi cr o s c o pi c a n al y si s) s h o ul d b e 
p erf or m e d o nl y at S cr e e ni n g ( ca n b e u p t o 3 5 d a y s pri or t o t h e 
fir st a d mi ni str ati o n of st u d y i nt er v e nti o n s). If di p sti c k uri n al y si s 
at ot h er a s s e s s m e nt s i s a b n or m al, f ull a n al y si s s h o ul d b e 
p erf or m e d. S e e A p p e n di x  6.
Fr e e T 4, T S H
X
X
Q 6 W  
St arti n g 
V i sit 2
1 2 -L e a d r e sti n g E C G 
X 
X
X
T h e a s s e s s m e nt s h o ul d b e p erf or m e d aft er t h e p arti ci p a nt h a s 
b e e n i n s u pi n e p o siti o n br e at hi n g q ui etl y f or ≥5 mi n.
T u m or A s s e s s m e nt 
( R E CI S T v 1. 1)
X
T u m or i m a gi n g b y C T or M RI at B a s eli n e t o d o c u m e nt t u m or 
l e si o n b ur d e n. C a n b e u p t o 3 5 d a y s pri or t o tr e at m e nt st art.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 6 6
St u d y  P eri o d
S cr e e ni
n g
D L T E v al u ati o n P eri o d W e e k 1 t o 4
( M 3 8 1 4 + R T + a v el u m a b)
N ot e s
St u d y  Vi sit
1 
2 
3- 6 
7- 1 0 
1 1 
1 2 
1 3
St u d y  D a y
( ± Vi sit wi n d o w )
-3 5 t o - 1 
1
2- 5
(± 1)
8- 1 1
(± 1)
1 2
1 5
(± 1)
2 9
(± 1)
M 3 8 1 4
X 
X 
X 
X
M 3 8 1 4 Q D 5 d/ w k ( o nl y o n d a y s of r a di ati o n). S e e S e cti o n 
6. 6. 5. 2 .
R T 3 G y  × 1 0 ( 5 FD / W)
X 
X 
X 
X
R T 3 G y/fr a cti o n, 5 F D / w k. R T t o b e gi v e n 1. 5 h ( ± 3 0 mi n) 
aft er M 3 8 1 4 .
Pr e m e di c ati o n A v el u m a b
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b i nf u si o n s, a s n e e d e d 
t h er e aft er. S e e S e ctio n 6. 5 . 5.
A v el u m a b
X
X 
X
8 0 0 m g i v Q 2 W  u ntil P D; o n D a y 1 a v el u m a b will b e gi v e n pri or 
t o M 3 8 1 4. F or p o st -P D tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-
C R tr e at m e nt, s e e S e cti o n 4. 1. 1 . 2.
T u m or M at eri al
X
 
 
 
 
β- H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n, C R = c o m pl et e r e s p o n s e, C T = c o m p ut e d t o m o gr a p h y, d = d a y s, E C G = el e ctr o c ar di o gr a m, E C O G = E a st er n C o o p er ati v e 
O n c ol o g y Gr o u p, E o T = E n d of Tr e at m e nt V i sit, F S H =f olli cl e -sti m ul ati n g h or m o n e, F D/ W =fr a cti o n d a y s / w e e k, G y = Gr a y s, HI V = h u m a n i m m u n o d efi ci e n c y vir u s, 
i v =i ntra v e n o u s, m o = m o nt h s, M RI = m a g n eti c r e s o n a n c e i m a gi n g, P E = p h y si c al e x a m i n ati o n, P K = p h ar m a c o ki n eti c , P D = pr o gr e s si v e di s e a s e, Q D = o n c e d ail y, 
Q x W = e v er y x w e e k s, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s, R T = r a di ot h er a p y, fr e e 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 , 
w k = w e e k , WO C B P = w o m e n of c hil d b e ari n g p ot e nti al .
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 6 6
T a ble 3
Sc he d ule of Acti vities – S afet y F oll o w -u p Peri o d - P art B ( M 3 8 1 4 + R a di ot her a p y + A vel u m a b)
St u d y  P eri o d
R T S af et y  F U V i sit s a n d A v el u m a b T r e atm e nt
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
R T 
S h ort -t er m 
S af et y  F U
R T 
Mi d -t er m 
S af et y  F U
R T 
L o n g -t er m 
S af et y  F U
A v el u m a b 
Tr e at m e nt
E o T
3 0 -D a y
S af et y  F U
9 0 -D a y  
S af et y  F U

L o n g -
t er m 
F U
If p arti ci p a nt di s c o nti n u e s a v el u m a b pri or t o 
R T L o n g -t er m S af et y F U, R T L o n g -t er m 
S af et y F U c a n b e p erf or m e d b y t el e p h o n e.
St u d y  D a y
(± Vi sit 
wi n d o w )
4 3
(± 7)
9 9
(± 7)
3 5 1
(± 2)
n + 1 4 d
(± 2)
(Wit hi n 7 
d a y s of 
d e ci si o n t o 
di s c o nti n u e )
3 0 d a y s
(± 5)
9 0 d a y s
(± 5)
(Q 1 2 W)
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er g o 
a n E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3.
Pr e m e di c ati o n 
a v el u m a b
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X
X
X
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
β- H C G 
Pr e g n a n c y 
T e st
(if a p pli c a bl e)
Q 4 W
X
Uri n e β- H C G f or W O C B P. R e s ult s of m o st 
r e c e nt pr e g n a n c y t e st s h o ul d b e a v ail a bl e 
pri or t o a d mi ni str ati o n of st u d y i nt er v e nti o n.
Vit al Si g n s
X
X
X
X
X 
X
W e i g ht, t e m p er at ur e, di a st oli c a n d s y st oli c 
bl o o d pr e s s ur e, p ul s e, p ul s e o xi m etr y, a n d 
r e s pir at or y r at e Q 2 W, at t h e Eo T V i sit, a n d 
at 3 0 -d a y S af et y F U. O nl y r e q uir e d at E o T 
if p arti ci p a nt h a s n ot st art e d a n e w 
a ntit u m or tr e at m e nt.
P h y si c al E x a m
( P E)
X
X
X
Q 6 W
X 
X
A c o m pl et e P E will r e p ort fi n di n g s i n t h e 
irr a di at e d ar e a d uri n g all F U p eri o d s.
E v al u ati o n of 
all Ti s s u e s i n 
R T Ar e a
X
X
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 6 6
St u d y  P eri o d
R T S af et y  F U V i sit s a n d A v el u m a b T r e atm e nt
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
R T 
S h ort -t er m 
S af et y  F U
R T 
Mi d -t er m 
S af et y  F U
R T 
L o n g -t er m 
S af et y  F U
A v el u m a b 
Tr e at m e nt
E o T
3 0 -D a y
S af et y  F U
9 0 -D a y  
S af et y  F U

L o n g -
t er m 
F U
If p arti ci p a nt di s c o nti n u e s a v el u m a b pri or t o 
R T L o n g -t er m S af et y F U, R T L o n g -t er m 
S af et y F U c a n b e p erf or m e d b y t el e p h o n e.
St u d y  D a y
(± Vi sit 
wi n d o w )
4 3
(± 7)
9 9
(± 7)
3 5 1
(± 2)
n + 1 4 d
(± 2)
(Wit hi n 7 
d a y s of 
d e ci si o n t o 
di s c o nti n u e )
3 0 d a y s
(± 5)
9 0 d a y s
(± 5)
(Q 1 2 W)
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er g o 
a n E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3.
Pr e m e di c ati o n 
a v el u m a b
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X
X
X
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
E C O G P S
X
X
X
X
X 
X
A d v er s e E v e nt 
A s s e s s m e nt
X
X
X
X
X 
X 
X 
X
C o nti n u o u sl y, at all R T s af et y F U, E o T, a n d 
S af et y F U, o n g oi n g tr e at m e nt -e m er g e nt 
A E s s h o ul d b e e v al u at e d. At L o n g -t er m F U, 
o nl y n e e d e d if p arti ci p a nt h a s n ot st art e d a 
n e w a ntit u m or tr e at m e nt.
C o n c o mit a nt 
M e di c ati o n
X
X
X
X
X 
X 
X 
X
H e m at ol o g y
a n d S er u m 
C h e mi str y
X
X
X
Q 4 W 
X 
X
M o st r e c e nt c o m pl et e h e m at ol o g y a n d c or e 
s er u m c h e mi str y r e s ult s m u st b e a v ail a bl e 
a n d r e vi e w e d pri or t o t h e a d mi ni str ati o n of 
st u d y i nt er v e nti o n s. S e e A p p e n di x  6.
Di p sti c k 
Uri n al y si s 
Q 6 W
X
F ull uri n al y si s ( di p sti c k + mi cr o s c o pi c 
a n al y si s) s h o ul d b e p erf or m e d o nl y at E o T. 
Ot h er wi s e, d i p sti c k uri n al y si s Q 6 W . If 
di p sti c k uri n al y si s i s a b n or m al, a f ull 
a n al y si s s h o ul d b e p erf or m e d.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 6 6
St u d y  P eri o d
R T S af et y  F U V i sit s a n d A v el u m a b T r e atm e nt
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
R T 
S h ort -t er m 
S af et y  F U
R T 
Mi d -t er m 
S af et y  F U
R T 
L o n g -t er m 
S af et y  F U
A v el u m a b 
Tr e at m e nt
E o T
3 0 -D a y
S af et y  F U
9 0 -D a y  
S af et y  F U

L o n g -
t er m 
F U
If p arti ci p a nt di s c o nti n u e s a v el u m a b pri or t o 
R T L o n g -t er m S af et y F U, R T L o n g -t er m 
S af et y F U c a n b e p erf or m e d b y t el e p h o n e.
St u d y  D a y
(± Vi sit 
wi n d o w )
4 3
(± 7)
9 9
(± 7)
3 5 1
(± 2)
n + 1 4 d
(± 2)
(Wit hi n 7 
d a y s of 
d e ci si o n t o 
di s c o nti n u e )
3 0 d a y s
(± 5)
9 0 d a y s
(± 5)
(Q 1 2 W)
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er g o 
a n E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3.
Pr e m e di c ati o n 
a v el u m a b
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X
X
X
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
Fr e e T 4, T S H
X
Q 6 W
X
Q 6 W  u ntil P D.
1 2 -L e a d E C G
X
T u m or 
a s s e s s m e nt 
( R E CI S T v 1. 1)
D a y 5 6,
D a y 1 1 2, 
D a y 1 6 8, 
t h e n Q 1 2W
X 
X
X
At D 5 6, D 1 1 2, D 1 6 8 a n d t h e n Q 1 2 W , u ntil 
c o nfir m e d P D, t h e st art of s u b s e q u e nt 
s y st e mi c a nti c a n c er t h er a p y, or t h e e n d of 
t h e st u d y. At E o T/ L o n g -t er m F U, t u m or 
r e s p o n s e a s s e s s m e nt i s o nl y r e q uir e d if 
p arti ci p a nt h a s n ot pr o gr e s s e d or h a s n ot 
st art e d a n e w tr e at m e nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 6 6
St u d y  P eri o d
R T S af et y  F U V i sit s a n d A v el u m a b T r e atm e nt
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
R T 
S h ort -t er m 
S af et y  F U
R T 
Mi d -t er m 
S af et y  F U
R T 
L o n g -t er m 
S af et y  F U
A v el u m a b 
Tr e at m e nt
E o T
3 0 -D a y
S af et y  F U
9 0 -D a y  
S af et y  F U

L o n g -
t er m 
F U
If p arti ci p a nt di s c o nti n u e s a v el u m a b pri or t o 
R T L o n g -t er m S af et y F U, R T L o n g -t er m 
S af et y F U c a n b e p erf or m e d b y t el e p h o n e.
St u d y  D a y
(± Vi sit 
wi n d o w )
4 3
(± 7)
9 9
(± 7)
3 5 1
(± 2)
n + 1 4 d
(± 2)
(Wit hi n 7 
d a y s of 
d e ci si o n t o 
di s c o nti n u e )
3 0 d a y s
(± 5)
9 0 d a y s
(± 5)
(Q 1 2 W)
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er g o 
a n E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3.
Pr e m e di c ati o n 
a v el u m a b
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X
X
X
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st -P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
T u m or M at eri al
S e e n ot e s
 
 
 
 
 
 
 
 
S ur vi v al
X
X
X
X
X 
X 
X 
X
All p arti ci p a nt s will b e f oll o w e d u p f or 
s ur v i v al a n d u s e of s u b s e q u e nt a ntic a n c er 
t h er a p y b y p h o n e e v er y 1 2 w k s u ntil 1 y e ar
aft er l a st p arti ci p a nt h a s r e c ei v e d t h e l a st 
d o s e of st u d y i nt er v e nti o n s or t h e l a st 
p arti ci p a nt di e s, w hi c h e v er c o m e s fir st .
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 6 6
: p h o n e c all vi sit.
A E = a d v er s e e v e nt, β- H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n, d = d a y s, E C G = el e ctr o c ar di o gr a m, E C O G = E a st er n C o o p er ati v e O n c ol o g y Gr o u p, E o T = E n d of 
Tr e at m e nt V i sit, F U =f oll o w-u p, i v =i ntr a v e n o u s, m o = m o nt h s , P D = pr o gr e s si v e di s e a s e, Q x W = e v er y x w e e k s, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s, R T = r a di ot h er a p y, fr e e 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, w k = w e e k , WO C B P = w o m e n of c hil d b e ari n g p ot e nti al .
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 6 6
T a ble 4
Sc he d ule of Acti vities – P art F E ( M 3 8 1 4 + A vel u m a b)
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
Br e a kf a st at sit e
X
X
S e e S e cti o n 6. 6. 5 . 3 f or d et ail s o n 
br e a kf a st c o m p o siti o n.
Si g n e d I nf or m e d C o n s e nt
X
I n cl u si o n/ E x cl u si o n 
Crit eri a
X 
X
D e m o gr a p h y
X
M e di c al Hi st or y
X
β- H C G Pr e g n a n c y T e st 
(if a p pli c a bl e)
X 
X
X
Q 4 W
X
S er u m β- H C G at S cr e e ni n g ( c a n b e u p t o 
2 8 d a y s pri or t o t h e fir st a d mi ni str ati o n of 
st u d y i nt er v e nti o n s); uri n e β- H C G 
t h er e aft er f or WO C B P. R e s ult s of m o st 
r e c e nt pr e g n a n c y t e st s h o ul d b e a v ail a bl e 
pri or t o a d mi ni str ati o n of st u d y 
i nt er v e nti o n.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
F S H (if a p pli c a bl e)
X
S e e S e cti o n 8. 2. 5 , A p p e n di x  3 a n d 
A p p e n di x 6.
I nf e cti o n S cr e e n 
( H e p atiti s B a n d C), 
O pti o n al HI V T e st
X
H e p atiti s B a n d C t e st at S cr e e ni n g ( c a n 
b e u p t o 2 8 d a y s pri or t o t h e fir st st u d y 
i nt er v e nti o n s) u nl e s s d o n e ≤3 m o pri or t o 
S cr e e ni n g. HI V t e st p er l o c al pr a cti c e a n d 
l o c al r e g ul at or y g ui d a n c e.
Vit al Si g n s
X 
X 
X 
X 
X 
X 
X 
X 
X
All ti m e p oi nt s: w ei g ht, t e m p er at ur e, 
di a st oli c a n d s y st oli c B P, p ul s e, p ul s e 
o xi m etr y, a n d r e s pir at or y r at e. S cr e e ni n g 
o nl y: h ei g ht. 
T o b e p erf or m e d pri or t o t h e 
a d mi ni str ati o n of st u d y i nt er v e nti o n o n 
D a y 1. O nl y r e q uir e d at E o T if p arti ci p a nt 
h a s n ot st art e d a n e w a ntit u m or tr e at m e nt. 
S cr e e ni n g p eri o d: c a n b e u p t o 2 8 d a y s 
pri or t o t h e fir st st u d y i nt er v e nti o n s .
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
P h y si c al E x a m ( P E)
X 
X
X
P erf or m at 
Vi sit 6 
(W e e k 8 ) 
a n d t h e n 
Q 8 W
X 
X
C o m pl et e P E at S cr e e ni n g ( c a n b e u p t o 
2 8 d a y s pri or t o t h e fir st st u d y 
i nt er v e nti o n s), D a y 1 pri or t o t h e fir st 
a d mi ni str ati o n of st u d y i nt er v e nti o n s, a n d 
D a y 2 2. A P E o nl y r e q uir e d at E o T if 
p arti ci p a nt h a s n ot st art e d a n e w 
a ntit u m or tr e at m e nt. S y m pt o m -ori e nt e d 
P E at e a c h vi sit if d e e m e d n e c e s s ar y b y 
t h e I n v e sti g at or.
E C O G P erf or m a n c e 
St at u s
X
X 
X 
X 
X 
X 
X 
X
A E A s s e s s m e nt
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
C o nti n u o u sl y, at E o T, a n d S af et y F U, 
o n g oi n g tr e at m e nt - e m er g e nt A E s s h o ul d 
b e e v al u at e d. At L o n g -t er m F U, o nl y 
n e e d e d if p arti ci p a nt h a s n ot st art e d a n e w 
a ntit u m or tr e at m e nt.
C o n c o mit a nt M e di c ati o n s
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
H e m at ol o g y, S er u m 
C h e mi str y
X 
X
X 
X
Q 4 W
X 
X
B a s eli n e c o m pl et e h e m at ol o g y a n d c or e 
s er u m c h e mi str y a n al y s e s c o ul d b e 
p erf or m e d wit hi n t h e S cr e e ni n g p eri o d 
( c a n b e u p t o 2 8 d a y s pri or t o t h e fir st 
a d mi ni str ati o n of st u d y i nt er v e nti o n s). 
Pri or t o t h e a d mi ni str ati o n of st u d y 
i nt er v e nti o n s, t h e m o st r e c ent c o m pl et e 
h e m at ol o g y a n d c or e s er u m c h e mi str y 
r e s ult s m u st b e a v ail a bl e a n d r e vi e w e d. 
S e e A p p e n di x  6.
Di p sti c k Uri n al y si s
X 
X
X
P erf or m at 
Vi sit 6 
(W e e k 8 ) 
a n d t h e n 
Q 8 W
X
F ull uri n al y si s ( di p sti c k + mi cr o s c o pi c 
a n al y si s) s h o ul d b e p erf or m e d o nl y at 
S cr e e ni n g a n d E o T. If di p sti c k uri n al y si s at 
ot h er a s s e s s m e nt s i s a b n or m al, f ull 
a n al y si s s h o ul d b e p erf or m e d. S e e 
A p p e n di x  6.
Fr e e T 4, T S H
X 
X
X
Q 6 W
X
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
1 2 - L e a d E C G (i n cl u di n g 
Q T c F)
X 
X 
X 
X
X
P K -m at c h e d di git al 1 2 -l e a d r e sti n g E C G 
will b e p erf or m e d i n tri pli c at e at pr e d o s e, 1, 
2 a n d 6 h p o st - M 3 8 1 4 a d mi ni str ati o n 
b ef or e bl o o d c oll e cti o n f or P K, 
 
s a m pli n g, f oll o w e d b y vit al si g n s aft er t h e 
m or ni n g d o s e o nl y . T h e a s s e s s m e nt 
s h o ul d b e p erf or m e d aft er t h e p arti ci p a nt 
h a s b e e n i n s u pi n e p o siti o n br e at hi n g 
q ui etl y f or ≥5 mi n at pr e d o s e a n d all 
p o st d o s e s a m pli n g ti m e s.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
T u m or A s s e s s m e nt 
( R E CI S T v 1. 1)
X
D a y 5 6, 
D a y 1 1 2, 
D a y 1 6 8, 
t h e n 
Q 1 2 W
X 
X
X
T u m or i m a gi n g b y C T or M RI at B a s eli n e 
t o d o c u m e nt t u m or l e si o n b ur d e n. C a n b e 
u p t o 2 8 d a y s pri or t o fir st st u d y 
i nt er v e nti o n.
T h e n at D 5 6, D 1 1 2, D 1 6 8 a n d t h e n 
Q 1 2 W , u ntil c o nfir m e d P D, t h e st art of 
s u b s e q u e nt s y st e mi c a nti c a n c er t h er a p y, 
or t h e e n d of t h e st u d y. At E o T/ L o n g -t er m 
F U, t u m or r e s p o n s e a s s e s s m e nt i s o nl y 
r e q uir e d if p arti ci p a nt h a s n ot pr o gr e s s e d 
or h a s n ot st art e d a n e w tr e at m e nt.
T u m or M at eri al 
X
S e e N ot e s
A r c hi v al t u m or m at eri al s s a m pl e d b ef or e 
st art of tr e at m e nt n ot ol d er t h a n 6 m o
c a n 
b e c oll e ct e d if a v ail a bl e; if n o ar c hi v al 
t u m or m at eri al a v ail a bl e, no fr e s h bi o p s y
i s r e q uir e d. H o w e v er, a p pr o xi m at el y
1 0 m L w h ol e bl o o d s a m pl e f or pl a s m a 
ct D N A m u st b e t a k e n pri or t o t h e fir st d o s e 
of st u d y tr e at m e nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 6 6
St u d y  Peri o d
S cr e e ni n g
Tr e at m e nt P eri o d: M 3 8 1 4 + a v el u m a b 
E n d of Tr e at m e nt ( E o T)/ F U
N ot e s
D L T P eri o d
E o T
S af et y  F U
L o n g -t er m F U
Vi sit
- 1 
1 
2 
3 
4 
5 
n
Q 1 2 W
D uri n g o n -tr e at m e nt p eri o d, aft er D a y 2 9, 
vi sit s will b e e v er y 2 w k s o n d a y s of 
a v el u m a b i nf u si o n s u ntil E o T.
All p arti ci p a nt s di s c o nti n ui n g st u d y 
i nt er v e nti o n s f or a n y r e a s o n m u st u n d er go 
E o T Vi sit wit hi n 7 d a y s aft er d e ci si o n t o 
di s c o nti n u e st u d y i nt er v e nti o n s, b ut (if 
p o s si bl e) b ef or e a n y n e w a nti n e o pl a sti c 
t h er a p y i s st art e d.
T h e s af et y foll o w -u p p eri o d will b e 3 0 d a y s 
( ± 5 d a y s) a n d 9 0 d a y s (± 5 d a y s) aft er t h e 
l a st d o s e of a v el u m a b, s e e S e ct i o n 4. 1. 1 . 3
St u d y  D ay 
( ± Vi sit wi n d o w )
-2 8 t o - 1 
1
1 5
(± 1)
2 2
(± 1)
2 9
(± 1)
4 3
(± 1)
n +
1 4 d (± 2)
(Wit hi
n 7 
d a y s 
of 
d e ci si
o n t o 
di s c o n
ti n u e)
3 0 d 
(± 5)

9 0 d (± 5)
(± 7)
M 3 8 1 4
C o nti n u o u s BI D d o si n g ( 7 d a y s/ w k)
S e e S e cti o n 6. 6. 5 . 1 f or d et ail s. 
Pr e m e di c ati o n 
( a v el u m a b)
X 
X
X 
X
R e q uir e d o nl y f or fir st 4 a v el u m a b 
i nf u si o n s, a s n e e d e d t h er e aft er. S e e 
S e cti o n 6. 5 . 5.
A v el u m a b
X 
X
X 
X 
X
8 0 0 m g i v Q 2 W  u ntil P D. F or p o st-P D 
tr e at m e nt, s e e S e ctio n 6. 6 . 6. F or p o st-C R 
tr e at m e nt, s e e S e ctio n 4. 1. 1 . 2.
S ur vi v al
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
All p arti ci p a nt s will b e f oll o w e d u p f or 
s ur vi v al a n d u s e of s u b s e q u e nt a nti c a n c er 
tr e at m e nt ( b y p h o n e aft er E o T) e v er y 
1 2 w k s u ntil 1 y e ar aft er l a st p arti ci p a nt 
h a s r e c ei v e d t h e l a st d o s e of st u d y 
i nt er v e nti o n s or di e s, w hi c h e v er c o m e s 
fir st.
: p h o n e c all vi sit. A E = a d v er s e e v e nt, β- H C G = b et a h u m a n c h ori o ni c g o n a d otr o pi n, BI D =t wi c e d ail y, B P = bl o o d pr e s s ur e, C T = c o m p ut e d t o m o gr a p h y, 
ct D N A = cir c ul ati n g t u m or D N A, d = d a y s, E C G = el e ctr o c ar di o gr a m, E C O G = E a st er n C o o p er ati v e O n c ol o g y Gr o u p, E o T = E n d of Tr e at m e nt Vi s it, 
F S H =f olli cl e -sti m ul ati n g h or m o n e, F U =f oll o w -u p, HI V = h u m a n i m m u n o d efi ci e n c y vir u s, m o = m o nt h s, M RI = m a g n eti c r e s o n a n c e i m a gi n g, P E = p h y si c al e x a m i n ati o n; 
P K = p h ar m a c o ki n eti c, P D = pr o gr e s si v e di s e a s e, 
 Q T c F = Fri d eri ci a’s C orr e cti o n F or m ul a , Q xW = e v er y x w e e k s, R E CI S T = R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d T u m or s, fr e e 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, w k = w e e k, W O C B P = w o m e n of c hil d b e ari n g p ot e nti al.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 6 6
T a ble 5
P h ar m ac o ki netic a n d Bi o m ar ker Bl o o d S a m pli n g Sc he d ule – P art A ( M 3 8 1 4 + A vel u m a b)
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
W e e k ( D a y )
Ti m e ( h)
 
S ol u bl e 
F a ct or s
I m m u n e 
p h e n ot y pi n g
 
P K
P K
Bl o o d V ol u m e
( a p pr o xi m at e)
8 . 5 m L
9 m L
2 m L
3. 5 m L
W e e k 1 ( D a y 1)
P r e d o s e
( a p pr o xi m at e)
X
X 
X
)
X 
X
)
X
X
1
X
E oI
X
2
X
X
3
X
4
X
X
6
X
X
W e e k 3 ( D a y  1 5)
pr e d o s e
X
X
X
X
X
X
1
X
2
X
3
X
4
X
6
X
W e e k 4
( D a y 2 2)
pr e d o s e
X
2
X
6
X
W e e k 5 ( D a y  2 9)
pr e d o s e
X
X
X
X
X
E oI
X
W e e k 9 ( D a y  5 7)
pr e d o s e
X
X
X
X
X
W e e k 1 3 ( D a y  85)
pr e d o s e
X
X
X
X
W e e k s 2 5, 3 7, 4 9
pr e d o s e
X
X
X
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 6 6
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
W e e k ( D a y )
Ti m e ( h)
 
S ol u bl e 
F a ct or s
I m m u n e 
p h e n ot y pi n g
 
P K
P K
E o T f or M 3 8 1 4
( o nl y a p pli e s if M 3 8 1 4 
tr e at m e nt i s st o p p e d. If 
a v el u m a b a n d M 3 8 1 4 
tr e at m e nt ar e st o p p e d at 
t h e s a m e ti m e pri or t o 
W e e k 4 9, o nl y 1 s a m pl e f or 
im m u n e p h e n ot y pi n g a n d 
p l a s m a ct D N A s h o ul d b e 
c oll e ct e d) .
X
X
X
E o T f or a v el u m a b 
(if pri or t o W e e k 4 9)
X
X
X
X
3 0 -D a y  S af et y F U 
(if pri or t o W e e k 4 9)
X
X
, E oI = e n d of i nf u si o n; E o T = E n d of tr e at m e nt, F U =f oll o w -u p, 
, P K = p h ar m a c o ki n eti c, 
.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 6 6
T a ble 6
P h ar m ac o ki netic a n d Bi o m ar ker Bl o o d S a m pli n g Sc he d ule – P art B ( M 3 8 1 4 + R a di ot her a p y + A vel u m a b)
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
N ot e s
W e e k ( D a y )
Ti m e ( h)
 
S ol u bl e
F a ct or s
I m m u n e 
p h e n ot y
pi n g
 
P K
P K
P K a n d/ or P d s a m pli n g c oll e cti o n 
ti m e s m a y b e m o difi e d b a s e d o n 
e m er gi n g d at a fr o m pri or d o s e l e v el s 
b y t h e S M C. M 3 8 1 4 P K s a m pli n g 
s h o ul d b e p erf or m e d wit hi n ± 1 0 mi n
f or t h e fir st 2 h p o st d o s e s a m pl e 
c oll e cti o n s, a n d wit hi n ± 2 0 mi n
f or 
s u b s e q u e nt s a m pli n g at e a c h 
s a m pli n g d a y. T h e M 3 8 1 4 pr e d o s e 
s a m pl e s h o ul d b e t a k e n wit hi n 1 h
b ef or e d o si n g at e a c h s a m pli n g d a y.
A v el u m a b P K a n d A D A s a m pli n g 
s h o ul d b e p erf or m e d wit hi n 
1 2 0 mi n ut e s pri or t o d o s e a n d wit hi n 
1 5 mi n ut e s
b ef or e E oI.
Bl o o d v ol u m e
( a p pr o xi m at e)
8 . 5 m L
9 m L
2 m L
3. 5 m L
W e e k 1 
( D ay 1;  F D 1)
Pr e d o s e
( a p pr o xi m at e)
X 
X
 
1
X
P o st M 3 8 1 4 a d mi ni str ati o n.
E oI
X
2 
X 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
4
X 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
6 
X 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
W e e k 1 
D a y 2 ( F D 2)
Pr e d o s e
X 
X
F or M 3 8 1 4 p ar a m et er c al c ul ati o n s, t h e 
pr e d o s e v al u e will s er v e a s a n 
e sti m at e f or t h e 2 4 h p o st d o s e 
c o n c e ntr ati o n s of t h e pr e vi o u s fr a cti o n
d a y .
2 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 6 6
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
N ot e s
W e e k ( D a y )
Ti m e ( h)
 
S ol u bl e
F a ct or s
I m m u n e 
p h e n ot y
pi n g
 
P K
P K
P K a n d/ or P d s a m pli n g c oll e cti o n 
ti m e s m a y b e m o difi e d b a s e d o n 
e m er gi n g d at a fr o m pri or d o s e l e v el s 
b y t h e S M C. M 3 8 1 4 P K s a m pli n g 
s h o ul d b e p erf or m e d wit hi n ± 1 0 mi n
f or t h e fir st 2 h p o st d o s e s a m pl e 
c oll e cti o n s, a n d wit hi n ± 2 0 mi n
f or 
s u b s e q u e nt s a m pli n g at e a c h 
s a m pli n g d a y. T h e M 3 8 1 4 pr e d o s e 
s a m pl e s h o ul d b e t a k e n wit hi n 1 h
b ef or e d o si n g at e a c h s a m pli n g d a y.
A v el u m a b P K a n d A D A s a m pli n g 
s h o ul d b e p erf or m e d wit hi n 
1 2 0 mi n ut e s pri or t o d o s e a n d wit hi n 
1 5 mi n ut e s
b ef or e E oI.
W e e k 2 
( D ay 8;  F D 6)
Pr e d o s e
X
X
F or M 3 8 1 4 P K p ar a m et er c al c ul ati o n s, 
t h e pr e d o s e v al u e will s er v e a s a n 
e sti m at e f or t h e 2 4 h p o st d o s e 
c o n c e ntr ati o n s of t h e pr e vi o u s fr a cti o n 
d a y.
2
X
p o st M 3 8 1 4 a d mi ni str ati o n .
W e e k 2 
( D ay 1 2; 
F D 1 0)
Pr e d o s e
X 
X 
X 
X
X
F or M 3 8 1 4 P K p ar a m et er c al c ul ati o n s, 
t h e pr e d o s e v al u e will s er v e a s a n 
e sti m at e f or t h e 2 4 h p o st d o s e 
c o n c e ntr ati o n s of t h e pr e vi o u s fr a cti o n 
d a y. If D a y 1 2 ( F D 1 0) i s a Fri d a y, P K 
a n d P d s a m pli n g m u st b e d o n e o n D a y 
1 1 ( F D 9). F oll o wi n g D a y 1 2 ( F D 1 0), 
a v e l u m a b pr e d o s e P K s h o ul d b e 
c oll e ct e d pri or t o n e xt i nf u si o n, e v er y 6 
w k s u ntil w k 2 5 a n d t h e n at 1 2 -w k 
i nt er v al s w hil e o n a v el u m a b tr e at m e nt.
2
X 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
4
X 
X
P o st M 3 8 1 4 a d mi ni str ati o n.
6
X
P o st M 3 8 1 4 a d mi ni str ati o n.
W e e k 3 
( D ay 1 5)
pr e d o s e
X 
X 
X
X 
X
W e e k 5 
( D ay 2 9)
pr e d o s e
X 
X
X 
X
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 6 6
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
N ot e s
W e e k ( D a y )
Ti m e ( h)
 
S ol u bl e
F a ct or s
I m m u n e 
p h e n ot y
pi n g
 
P K
P K
P K a n d/ or P d s a m pli n g c oll e cti o n 
ti m e s m a y b e m o difi e d b a s e d o n 
e m er gi n g d at a fr o m pri or d o s e l e v el s 
b y t h e S M C. M 3 8 1 4 P K s a m pli n g 
s h o ul d b e p erf or m e d wit hi n ± 1 0 mi n
f or t h e fir st 2 h p o st d o s e s a m pl e 
c oll e cti o n s, a n d wit hi n ± 2 0 mi n
f or 
s u b s e q u e nt s a m pli n g at e a c h 
s a m pli n g d a y. T h e M 3 8 1 4 pr e d o s e 
s a m pl e s h o ul d b e t a k e n wit hi n 1 h
b ef or e d o si n g at e a c h s a m pli n g d a y.
A v el u m a b P K a n d A D A s a m pli n g 
s h o ul d b e p erf or m e d wit hi n 
1 2 0 mi n ut e s pri or t o d o s e a n d wit hi n 
1 5 mi n ut e s
b ef or e E oI.
E oI
X
W e e k 9 
( D ay 5 7)
pr e d o s e
X 
X 
X
X 
X
W e e k 1 3 
( D ay 8 5 )
pr e d o s e
X
X 
X
W e e k 2 5 , 3 7, 
4 9
pr e d o s e
X
X 
X
E o T f or 
M 3 8 1 4
X
E o T f or 
a v el u m a b 
X 
X 
X
X
If pri or t o W4 9.
3 0 -d a y  
S af et y  F U 
X 
X
If pri or t o W4 9 .
, E oI = e n d of i nf u si o n, E o T = E n d of Tr e at m e nt, F =fr a cti o n s, F D =fr a cti o n d a y, F U =f oll o w -u p, 
P K = p h ar m a c o ki n eti c s , S M C= S af et y M o nit ori n g C o m mitt e e .
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 6 6
T a ble 7
P h ar m ac o ki netic a n d Bi o m ar ker Bl o o d S a m pli n g Sc he d ule – P art F E ( M 3 8 1 4 + A vel u m a b)
M 3 8 1 4 a n d A v el u m a b
M 3 8 1 4
A v el u m a b
W e e k ( D a y)
Ti m e ( h)
 
S ol u bl e 
F a ct or s
I m m u n e 
p h e n ot y pi n g
 
P K
P K
Bl o o d V ol u m e
( a p pr o xi m at e)
8 . 5 m L
9 m L
2 m L
3. 5 m L
W e e k 1 ( D a y  1)
P r e d o s e
( a p pr o xi m at e)
X
X
1
X
E oI
X
2
X
X
4
X
X
6
X
X
W e e k 3 ( D a y  1 5)
pr e d o s e
X
X
X
X
X
X
1
X
2
X
3
X
4
X
6
X
W e e k 4 ( D a y  2 2)
pr e d o s e
X
2
X
4
X
6
X
W e e k 5 ( D a y  2 9)
pr e d o s e
X
X
W e e k 1 3 ( D a y  8 5)
pr e d o s e
X
X
W e e k s 2 5, 3 7, 4 9
pr e d o s e
X
X
E o T f or M 3 8 1 4
X
3 0 -D a y  S af et y F U 
(if pri or t o W e e k 4 9)
X
X
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 6 6
, 
 E oI = e n d of i nf u si o n; E o T = E n d of tr e at m e nt, F U =f oll o w -u p, 
 P K = p h ar m a c o ki n eti c, 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 6 6
2
I ntr o d ucti o n
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y, a n d safet y of a vel u ma b a n d 
M 3 8 1 4
is i n t he res pecti ve I n vesti gat or’s Br oc h ure s (I B) a n d i n t he a vel u ma b ( Bave nci o ®) U S 
Pr o d uct I nf or mati o n .
2. 1
St u d y R ati o n ale
T his st u d y  is part of a cli nical de vel o p me nt pr o gra m w hic h ai ms t o e val uate t he cli nical utilit y of 
M 3 8 1 4, a D N A da ma ge tar get a ge nt , wit h a vel u ma b , a n a nti-P D -L 1 t hera p y , wit h a n d wit h o ut R T
i n a br oa d ra n ge of ca ncers.
I n ad diti o n, t he f o o d effect ( F E) o n P K of M 3 8 1 4 will be i n vesti gate d t o e val uate t he effects of 
pra n dial state a n d fat c o nte nt of meals o n t he p har mac o ki netic ( P K) para meters of M 3 8 1 4 .
T he first part of t his st u d y ( Part A) will assess M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b i n partici pa nts 
wit h a d va nce d or metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, sta n dar d t hera p y 
has faile d, or partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera p y kn o w n t o pr o vi de 
cli nical be nefit f or t heir c o n diti o n.
T he sec o n d part of t his st u d y ( Part B) will assess M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b a n d R T i n 
partici pa nts wit h a d va nce d or metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, 
sta n dar d t hera py has faile d, or partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera py 
k n o w n t o pr o vi de cli nical be nefit f or t heir c o n diti o n a n d are a me na ble t o recei ve R T.
T he t hir d part of t his st u d y (Part F E ) will assess t he F E o n P K of M 3 8 1 4 w he n a d mi nistere d i n 
c o m bi nati o n wit h a vel u ma b u n der faste d a n d fe d c o n diti o ns i n partici pa nts wit h a d va nce d or 
metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, sta n dar d t hera py has faile d, or 
partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera py k n o w n t o pr o vi de cli nical be nefit 
f or t heir c o n diti o n. O nl y d oses of M 3 8 1 4 alrea d y declare d safe a n d t olera ble i n P art A b y  the 
Safet y  M o nit ori n g C o m mittee (S M C ) will be i ntr o d uce d i n t his part of t he st u d y.
2. 1. 1
C o m bi ni n g 
a D N A D a m a ge 
A ge nt wit h M 3 8 1 4, 
a D N A 
Re p air -T ar gete d T her a p y
M 3 8 1 4 is a D N A -P K i n hi bit or w hic h tar gets t u m or cell gr o wt h a n d s ur vi val b y  in hi biti n g a critical 
d o u ble -stra n d brea k (D S B ) D N A da ma ge re pair (D D R ) mec ha nis m . T he a ntit u m or effect of 
M 3 8 1 4 is de pe n de nt o n t he f u ncti o nalit y  of D N A re pair a n d c hec k p oi nt si g nali n g i n ca ncer cells, 
w hic h ha ve a l o were d a bilit y to c o pe wit h D S Bs, lea di n g t o cell deat h. He nce, t he rati o nale of 
D N A -P K i n hi biti o n is t o i ncrease t he a mo u nt of D S B D N A da ma ge ge nerate d b y D N A -da ma gi n g 
a ge nts i ncl u di n g direct D N A -da ma gi n g c he m ot hera p y a ge nts or I o nizi n g Ra diati o n (I R). 
 
 In c o m bi nati o n wit h et o p osi de a n d cis plati n i n t he
N CI -H 5 2 6
xe n o graft
m o del, 
M 3 8 1 4 
s h o we d 
a 
better 
t u m or c o ntr ol 
c o m pare d 
t o 
et o p osi de + cis plati n or M 3 8 1 4 
al o ne. 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 6 6
 
 
 
 
2. 1. 2
C o m bi ni n g R a di ati o n, a D N A D a m a ge A ge nt wit h M 3 8 1 4 , a D N A 
Re p air- T ar gete d T her a p y a n d I m m u n ot her a p y
I n ad diti o n t o t he p ote ntial of usi n g D D R i n hi bit ors i n c o m bi nati o n re gi me ns wit h ot her D D R 
i n hi bit ors or wit h D D R da ma gi n g a ge nts s uc h as sta n dar d-of -care c he m ot hera p y o r R T treat me nts, 
it is i ncreasi n gly rec o g nize d t hat s o me c o nsi derati o n mi g ht be gi ve n t o i de ntif yi n g o pti mize d 
a p pr oac hes t o usi n g D D R 
i n hi bit ors al o n gsi de i m m u n ot hera py a ge nts i ncl u di n g i m m u ne 
c hec k p oi nt i n hi bit ors. W hile 
ma n y  mec ha nis ms b y  whic h D D R da ma gi n g a ge nts ca n elicit 
a ntit u m or i m mu nit y  ha ve bee n i de ntifie d, t he mec ha nis ms b y  whic h D N A re pair- directe d a ge nts 
(s uc h as A T M, A T R, or D N A -P K catal ytic s u b u nit [ D N A-P Kcs] i n hi bit ors) m o d ulate t he t u m or 
i m m u ne e n vir o n me nt a n d affect se nsiti vit y t o i m m u ne c hec k p oi nt i n hi bit ors still nee d t o be f ull y  
el uci date d. H o we ver, it is reas o na ble t o h y p ot hesize t hat ge n o mic i nsta bilit y in d uce d b y  disr u pti o n 
of n or mal D N A re pair pat h wa y  fu ncti o n c o ul d res ult i n i ncrease d t u m or m utati o nal b ur de n, 
ne oa nti ge ns, a n d/ or S TI N G pat h wa y  acti vati o n, all of w hic h
c o ul d c o ntri b ute t o hei g hte ne d 
i m m u ne c hec k p oi nt i n hi bit ors se nsiti vit y ( Mc Gra na ha n 2 0 16 ; M o u w
2 0 1 7 ).
Te o
2 0 1 8
re p orte d i n s u bjects wit h 
metastatic 
ur ot helial 
ca ncer a n d treate d wit h 
a nti-P D -1/a nti -P D -L 1 a nti b o dies atez oliz u ma b a n d ni v ol u ma b, t hat t he prese nce of D D R 
alterati o ns was str o n gl y ass ociate d wit h a hi g her o bjecti ve res p o nse rate t ha n t h ose wit h o ut a n y 
D D R alterati o ns (6 7. 9 % v ers us 1 8. 8 %; p < 0 . 0 0 1). T he me dia n o verall s ur vi val (O S ) was n ot 
reac he d f or s u bjects wit h deleteri o us D D R alterati o ns, wit h 7 1. 5 % ali ve at 1 2 m o nt hs, w hereas t he 
me dia n O S f or t h ose wit h D D R alterati o ns of u n k n o w n si g nifica nce or n o detecta ble D D R 
alterati o ns were 2 3. 0 a n d 9. 3 m o nt hs, res pecti vel y.
Se veral cli nical st u dies are n o w u n der wa y t o test t he safety a n d  efficac y of c o m bi nati o ns of D N A 
re pair-tar gete d a ge nts wit h i m m u ne c hec k p oi nt i n hi bit ors i n b ot h D N A re pair- deficie nt a n d D N A 
re pair-pr ofi cie nt setti n gs (Ya p 2 0 1 5 ).
 
 
 
T he i nteracti o n bet wee n t he i m m u ne s yste m a n d I R has bee n a p preciate d f or ma n y deca des. 
T hera pe utic ra diati o n creates n u mer o us t ypes of D N A da ma ge, i ncl u di n g D S Bs a n d t he i m m u ne 
s yste m ca n i m pact ra diati o n-ass ociate d t u m or c o ntr ol b ot h l ocall y (wit hi n t he ra diati o n fiel d) a n d 
dista ntl y  (at u nirra diate d t u m or sites). 
 
 
 Ra diati o n i ncreases P D -L 1  ex pressi o n o n t u m or cells, a n d t his 
i n hi bit or y effect ca n be o verc o me wit h P D -L 1/ P D - 1 bl oc ka de res ulti n g i n a better t u m or c o ntr ol 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4 -0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 /1 6 6
a n d i m pr o ve me nt of s ur vi val c o m pare d t o eac h treat me nt re gi me n al o ne (De n g
2 0 1 4 ; 
D o ve di 2 0 1 4 ). 
A n ot her st u d y s h o we d t hat ra diati o n, a nti -c yt ot o xic T-l ym p h oc y te-ass ociate d pr otei n 4 (C T L A 4 ), 
a n d a nti -P D -1/ P D -L 1 a ge nts f u ncti o n i n n o n re d u n da nt wa ys t o acti vate t he i m m u ne s yste m. Data 
fr o m mela n o ma pa tie nts 
 s u g gest t hat alt h o u g h ra diati o n 
di versifies t he T cell re pert oire a n d a nti -C T L A 4 t hera py i n hi bits re g ulat or y T cells , a nti-P D -L 1  
t hera py is necessar y t o o verc o me resista nce dri ve n b y i ncrease d P D -L 1 e x pressi o n o n t u m o r cells 
(T w y ma n -Sai nt Vict or 2 0 1 5 ).
F urt her m ore, cli nical case re p orts a n d retr os pecti ve a nal ys es s u g gest t hat a treat me nt re gi me n 
c o m bi ni n g i m m u ne c hec k p oi nt bl oc ka de treat me nt a n d R T i n a variet y of s oli d t u m ors ma y res ult 
i n a better disease c o ntr ol a n d l o n ger s ur vi val t ha n t hat see n wit h i m m u ne c hec k p oi nt bl oc ka de 
treat me nt al o ne, wit h a n acce pta ble safety pr ofile (Hi ni ker 2 0 1 6 , A h me d 2 0 1 7 , Ols o n
2 0 1 5 , 
S ha ver dia n 2 0 1 7 ). Base d o n t hese fi n di n gs, cli nical st u dies c o m bi ni n g ra diati o n a n d i m m u ne 
c hec k p oi nt t hera pies are o n g oi n g i n a variety of t u m ors i n differ e nt cli nical setti n gs. 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 6 6
Ta ke n t o get her, t he e mer gi n g e x peri me ntal a n d cli nical e vi de nce s u g gests t hat D N A lesi o ns arisi n g 
fr o m differe nt bac k gr o u n ds (increase d D N A da ma ge e x p os ure [i.e. R T as e x o ge n o us s o urce of 
da ma ge a n d/ or decrease d D N A re pair ca pa cit y { D D R i n hi bit or a ge nt}]) ofte n lea ds t o i ncrease d 
m utati o nal l oa d a n d ne oa nti ge n b ur de n, b ot h of w hic h ha ve bee n c orrelate d wit h i m m u ne 
c hec k p oi nt bl oc ka de res p o nse i n a variet y of setti n gs. T heref ore, c o m bi ni n g a n i m m u ne c hec k p oi nt 
i n hi bit or s uc h as a vel u ma b wit h a D N A -da ma gi n g a ge nt s uc h as R T a n d a D N A re pair-tar gete d 
a ge nt s uc h as a 
 ma y be a usef ul t hera pe utic strate g y i n patie nts s ufferi n g fr o m 
ca ncer.
T he p ur p ose of t his P hase I st u d y is t o e val uate t he safet y, t olera bilit y, P K/ P d pr ofile a n d 
preli mi nar y  cli nical acti vit y of M 3 8 1 4, i n c o m bi nati o n wit h a vel u ma b wit h a n d wit h o ut R T i n 
partici pa nts wit h a d va nce d or metastatic select s oli d t u m ors. Part A of t he d ose escalati o n will 
esta blis h t he m a xi m u m tolerate d d ose (M T D)
a n d/ or rec o mme n de d P hase II d ose (R P 2 D ) of 
M 3 8 1 4 w he n a d mi nistere d i n c o m bi nati o n wit h a vel u ma b, w hile Part B will defi ne t he M T D 
a n d/ or R P 2 D of M 3 8 1 4 w he n a d mi nistere d i n c o m bi nati o n wit h a vel u ma b a n d R T. I n a d diti o n, 
t he Part F E will assess F E o n P K of M 3 8 1 4 w he n a dmi nistere d i n c o m bi nati o n wit h a vel u ma b 
u n der faste d a n d fe d c o n diti o ns .
2. 2
B ac k gr o u n d
2. 2. 1
Cli nic al Res p o nse a n d Resist a nce t o I m m u ne C hec k p oi nt 
I n hi bit ors
I m m u ne c hec k p oi nt i n hi bit ors tar geti n g C T L A 4 
a n d t he P D -1/ P D -L 1 a xis ha ve s h o w n 
u n prece de nte d cli nical acti vit y in se veral t y pes of ca ncer a n d are ra pi dl y tra nsf or mi n g t he practice 
of me dical o nc ol o g y (Par d oll 2 0 1 2 ; T o palia n 2 0 1 5; S har ma 2 0 1 7 ).
Pr o gra m me d deat h 1 ( P D-1) is a ne gati ve re g ulat or of T cell acti vit y t hat li mits t he acti vit y of 
T cells at a variet y of sta ges of t he i m m u ne res p o nse w he n it i nteracts wit h its 2 li ga n ds, P D -L 1  
a n d P D -L 2 (Is hi da 1 9 9 2 ; Keir
2 0 0 6 ; Free ma n 2 0 0 0 ). W he n 
e n ga ge d b y  a li ga n d, t hr o u g h 
p h os p hatase acti vit y, P D - 1 i n hi bits ki nase -si g nali n g p at h wa ys t hat n or mall y  lea d t o T cell 
acti vati o n. A n u m ber o f a nti b o dies t hat disr u pt t he P D -1 a xis ha ve e ntere d cli nical de vel o p me nt. 
P D -L 1  is als o c o nsi dere d t o e xert ne gati ve si g nals o n T cells b y  interacti n g wit h P D - 1 
(B utte 2 0 0 7 ), a n d P D -L 1 -bl oc ki n g a nti b o dies pre ve nt t his i nteracti o n. I mm u ne 
c hec k p oi nt 
i n hi bit ors als o e n ha nce t he f u ncti o n of t u m or-i nfiltrati n g l ym p h oc y tes ( TI Ls), a nd m ore 
s pecifically c yt ot o xic T 
cells, w hic h 
a u g me nts a ntit u m or i m m u nit y wit hi n 
t he t u m or 
micr oe n vir o n me nt. T he prese nce of TI Ls has bee n c orrelat e d t o i m pr o ve d pr o g n osis i n ma n y 
ca ncer t ypes, i ncl u di n g bla d der (Li p p o ne n
1 9 9 3 ; Ts uji has hi
1 9 8 8 ; S har ma
2 0 0 7 ), l u n g 
(Ge n g 2 0 1 5 ), breast (A da ms
2 0 1 4 ), c ol orectal (Ma b y
2 0 1 5 ), a n d es o p ha geal (Jia n g 2 0 1 7 ) 
carci n o mas. M ore o ver P D - 1 p ositi ve e x pressi o n as well as TI Ls ha ve bee n s h o w n t o be pre dicti ve 
bi o mar kers of res p o nse t o i m m u ne c hec k p oi nt bl oc ka de  (C urra n 2 0 1 0 ; Her bst
2 0 1 4 ). Se veral 
a nti b o dies t hat disr u pt t he P D - 1 or P D -L 1  axis i ncl u di n g a vel u ma b are a p pr o ve d a n d/ or are i n 
cli nical de vel o p me nt f or se veral t u m or i n dicati o ns.
Des pite r o b ust a n d d ura ble res p o nses t o i m m u ne c hec k p oi nt i n hi bit ors i n a s u bset of t u m ors 
(W olc h o k
2 0 1 3 ; P ost o w 2 0 1 5a ; P ost o w 2 0 1 5 b ; Her bst 2 0 1 6 ; Bra h mer 2 0 1 5 ), efficac y of im m u ne 
c hec k p oi nts i n hi bit ors varies wi del y. E ve n a m o n g t u m or t ypes s uc h as mela n o ma a n d n o n- s mall 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 6 6
cell l u n g ca ncer f or w hic h ma n y  of t he first im m u ne c hec k p oi nt i n hi bit ors st u dies were c o n d ucte d, 
o nl y  a s u bset of patie nts res p o n ds t o t hera py  (Bra h mer 2 0 1 2 ; Te o 2 0 1 8 ). As e vi de nce f or i m m u ne 
c hec k p oi nt i n hi bit or use acr oss cli nical setti n gs c o nti n ues t o gr o w, a maj or u n met nee d is t he 
i de ntificati o n of relia ble bi o mar kers t hat pre dict res p o nse t o i m m u ne c hec k p oi nt i n hi bit ors a n d/ or 
treat me nt c o m bi nati o ns w hic h all o w t o ac hie ve cli nical be nefit i n a lar ger pr o p orti o n of patie nts. 
N u mer o us li nes of e vi de nce n o w s u g gest t hat t he D N A re pair la n dsca pe has a n i m p orta nt r ole i n 
dri vi n g se nsiti vit y  a n d res p o nse t o i m m u ne c hec k p oi nt bl oc ka de.
2. 2. 2
D N A Re p air P at h w a ys Alter ati o ns ar e C a ncer Dri vers a n d 
Affect Res p o nse t o I m m u n ot her a p y
D N A da ma ge arises eit her beca use of a fail ure t o re pair e n d o ge n o us D N A da ma ge i n cells or d ue 
t o cell ular e x p os ure t o e x o ge n o us s o urces of da ma gi n g a ge nts s uc h as c he m ot hera p y or R T
(Jac ks o n a n d Barte k 2 0 0 9 ). Ra di ot he ra py ( R T) is wi del y  use d as sta n dar d- of-care treat me nt acr oss 
a ra n ge of t u m or t ypes wit h eit her a c urati ve i nte nt i n t he n o n metastatic setti n g or t o alle viate 
s ym pt o ms i n patie nts wit h metastatic ca nc ers. H o we ver, f or m ost patie nts, D N A -da ma gi n g a ge nts 
pr o vi de o nl y m o dest a n d li mite d be nefit o ver ti me d ue t o hi g hl y  pr oficie nt cell ular pr ocesses t hat 
ca n detect a n d re pair t he da ma ge d D N A. T heref ore, i n hi biti n g t he re pair of e n d o ge n o us or 
e x o ge n o us D N A d a ma ge is als o a n attracti ve a ntica ncer strate g y a n d se veral differe nt D N A re pair 
i n hi bit ors are i n n o ncli nical a n d cli nical de vel o p me nt  (Br o w n 2 0 1 7 ).
A m o n g t ypes of D N A da ma ge, D S Bs are o ne of t he m ost har mf ul lesi o ns t o a cell. Fail ure i n D S B 
re pair c o ul d lea d t o ge n o mic i nsta bilit y an d ca ncer. H o m ol o g o us rec o m bi nati o n ( H R) a n d 
n o n h o m ol o g o us e n d j oi ni n g are maj or D S B re pair pat h wa ys i n hi g her e u kar y otes. It is k n o w n t hat 
e x pressi o n of D S B re pair ge nes is altere d i n vari o us ca ncers. Als o, t he acti vati o n of D S B re pair 
ge nes is o ne of t he reas o ns f or c he m o - a n d ra di oresista nce. 
F urt her m ore, err o ne o us or dere g ulate d D N A re pair res ults i n c hr o m os o mal tra nsl ocati o ns, 
ge n o m ic rearra n ge me nts, hi g her m utati o n rates, a n d/ or i m m u n o ge nic cell deat h w hic h lea d t o 
pr o m oti n g i m m u n o ge nicit y an d m a y  pr o vi de s ur vi val a d va nta ges t o ca ncer cells (Li e ber ma n 2 0 0 8 ;
P o well a n d Bi n dra 2 0 0 9 ). T heref ore, patie nts wit h t u m ors deficie nt i n D N A da ma ge or mis matc h 
re pair m a y  res p o n d t o treat me nt wit h i m m u ne c hec k p oi nt i n hi bit ors (Le 2 0 1 5 ; Stric kla n d 2 0 16 ). 
I n a d diti o n, t here is i ncreasi n g e vi de nce t hat D D R
i n hi biti n g a ge nts c o m bi ne d wit h 
i m m u ne-c hec k p oi nt i n hi bit ors ma y e xert a pr o n o u nce d a ntit u m or acti vity  (M o u w
2 0 1 7 ). 
2. 3
Be nefit/ Ris k  Assess me nt
M ore 
detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bly 
e x pecte d a d verse e ve nts ( AE s) of M 3 8 1 4 
a n d a vel u ma b m a y  be f o u n d i n Secti o n Err or! 
Refere nce s o urce n ot f o u n d. ( Scie ntific Rati o nale f or St u d y  Desi g n) a n d t he res pecti ve I Bs a n d 
U S Pr o d uct I nf or mati o n f or a vel u ma b.
Base d o n t he a vaila ble data t o date, t he c o n d uct of t he st u d y, as s pecifie d i n t his pr ot oc ol, is 
c o nsi dere d j ustifia ble.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 6 6
2. 3. 1
S u m m ar y of M 3 8 1 4 D at a a n d P ote nti al B e nefits a n d R is ks
M 3 8 1 4 is a p ote nt a n d selecti ve i n hi bit or of t he A T P bi n di n g site of D N A -P K t hat tar gets t u m or 
cell gr o wt h a n d s ur vi val b y  in hi biti n g t he critical D D R mec ha nis m i n s oli d a n d he mat ol o gical 
mali g na ncies.
M 3 8 1 4 p ote ntiate s t he gr o wt h i n hi bit or y acti vit y of D N A -da ma gi n g a ge nts s uc h as et o p osi de a n d 
R T.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 6 6
 
 
A n u m ber of meas ures ha ve bee n i m ple me nte d i n t his st u d y to mi ni mize t he p ote ntial safet y ris k 
relate d t o st u d y inter ve nti o ns a n d e n ha nce t he safet y of partici pa nts, i ncl u di n g a d diti o nal e xcl usi o n 
criteria, S cree ni n g assess me nts i n partici pa nts wit h p ote ntial ris k fact ors, a d diti o nal c o nstrai nt t o 
t he v ol u me a n d d ose of irra diati o n t o be deli vere d t o t he es o p ha g us, a n d a L o n g -ter m F oll o w -u p 
of pa rtici pa nts at 1 ye ar after t he last d ose of R T t o e na ble t he detecti o n a n d t he ma na ge me nt of 
p ote ntial late t o xicities. Als o, clear i nf or mati o n a b o ut p ote ntial late t o xicities relate d t o st u d y 
i nter ve nti o ns will be pr o vi de d t o partici pa nts a n d I nvesti gat ors. T he S p o ns or c o nsi ders t hat t he 
o verall be nefit -ris k-bala nce of M 3 8 1 4 i n c o m bi nati o n wit h fracti o ne d R T ( 3 G y x 1 0; 5 fracti o ns 
per we e k f or 2 wee ks i n t otal) re mai ns p ositi ve.
 
 
M 3 8 1 4 was als o e val uate d i n c o m bi nati o n wit h cis plati n a n d et o p osi de i n 2 partici pa nt s wit h 
e x te nsi ve sta ge s mall cell l u n g ca ncer i n a P hase I b ( o pe n-la bel d ose escalati o n)/ P hase II 
( place b o-c o ntr olle d, ra n d o mize d) st u d y (M S 1 0 0 0 3 6 -0 0 2 2). E nr oll me nt i n t he st u d y 
was 
pre mat urel y ter mi nate d d ue t o recr uit me nt c halle n ges a n d n o t d ue t o c o ncer ns of safet y f or t he
partici pa nts .
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 / 1 6 6
2. 3. 2
S u m m ar y of P ote nti al B e nefits a n d R is ks of A vel u m a b
A vel u ma b ( M S B 0 0 1 0 7 1 8 C) is a f ull y h u ma n i m m u n o gl o b uli n G 1 (I g G 1) a nti -P D -L 1  mo n ocl o nal 
a nti b o d y that i n hi bits P D -L 1/ P D - 1 i nteracti o ns b ut lea ves i ntact t he P D -L 2 / P D- 1 pat h wa y 
(B o ye ri nas 2 0 1 5 ; G ulle y 2 0 1 5 ; Heer y 2 0 1 4 ; Heer y 2 0 1 5 ).
T o date, a vel u ma b has bee n a d mi nistere d at t he cli nicall y  acti ve t olera ble d ose of 1 0 m g/ k g Q 2 W
t o m ore t ha n 1 8 0 0 partici pa nts acr oss m ulti ple i n dicati o ns. It has bee n a p pr o ve d b y  FD A f or a d ults 
a n d pe diatric patie nts 1 2 years a n d ol der wit h metastatic Mer kel Cell Carci n o ma a n d f or a d ults 
wit h l ocall y ad va nce d or metastatic ur ot helial carci n o ma a n d is c urre ntl y bei n g e val uate d as 
m o n ot hera p y or i n c o m bi nati o n wit h c he m ot hera p y  an d tar gete d a ge nts acr oss a wi de ra n ge of 
ca ncers.
M ost of t he o bser ve d A Es were eit her i n li ne wit h t h ose e x pecte d i n partici pa nts wit h a d va nce d 
s oli d t u m ors or wit h class effects of m o n ocl o nal a nti b o d y bl oc ki n g t he P D -1/ P D -L 1  axis. 
I nf usi o n-relate d reacti o ns i ncl u di n g dr u g h y perse nsiti vit y  reacti o ns a n d i m m u ne-relate d a d verse 
e ve nts (ir A Es; i m m u ne-relate d p ne u m o nitis, i m m u ne-relate d c olitis, i m m u ne-relate d he patitis, 
i m m u ne-relate d e n d ocri n o pat hies [t h yr oi d dis or ders, a dre nal i ns ufficie nc y, Ty p e I dia betes 
mellit us, pit uitar y  dis or ders], i m m u ne-relate d ne p hritis a n d re nal d y sf u ncti o n a n d ot her ir A Es
[ m yositis, 
m y ocar ditis, 
G uillai n -Barrés y n dr o me, 
u veitis, 
pa ncreatitis, 
a n d 
m y ast he nia 
gra vis/ m y ast he nic s yn dr o me]) ha ve bee n i de ntifie d as i m p orta nt ris ks f or a vel u ma b. G ui deli nes 
f or t he ma na ge me nt of ir A Es a n d inf usi o n -relate d reacti o ns are i m ple me nte d i n all o n g oi n g cli nical 
st u dies wit h a vel u ma b (a vel u ma b I B V ersi o n 1 0. 0, 2 9 Ma y 2 0 2 0) .
2. 3. 3
S u m m ar y of P ote nti al B e nefits a n d R is ks of R a di ot her a p y
Ra di ot hera p y is a n i nte gral part of t he m ulti disci pli nar y  treat me nt of ca ncer, b ot h i n t he c urati ve 
a n d palliati ve setti n g. It is esti mate d t hat o ver 6 0 % of patie nts wit h s oli d t u m ors will ha ve R T as 
part of t heir t otal c o urse of treat me nt (Hal peri n 2 0 0 8 ).
Palliati ve R T is fre q ue ntl y use d f or patie n ts wit h a d va nce d or metastatic diseases . It offers a q uic k, 
i ne x pe nsi ve, a n d effecti ve w a y  of re d uci n g ma n y of t he f ocal s ym pt o ms of a d va nce d, i nc ura ble 
ca ncer, w het her t hese arise fr o m t he pri mar y  t u m or or fr o m metastatic lesi o ns. It ca n i m pr o ve 
q ualit y  of life w hile bei n g ass ociate d wit h li mite d treat me nt b ur de n i n ter ms of b ot h h os pital 
atte n da nces a n d si de effects (L u tz 2 0 1 4).
I n or der t o ac hie ve o pti mal patie nt care o utc o mes, a maj or g oal of ra diati o n t hera py i s t he deli ver y 
of t he desire d d ose distri b uti o n of I R t o tar get tiss ue w hile li miti n g t he ra diati o n d ose t o t he 
s urr o u n di n g n or mal tiss ues t o a n acce pta ble le vel. Wit h t he i ntr o d ucti o n of i nte nsit y-m o d ulate d 
ra diati o n t hera p y (I M R T) i n t he earl y 1 9 9 0s, it was rec o g nize d t hat d ose distri b uti o ns c o ul d be 
si g nifica ntly i m pr o ve d t o better ha n dle t his class of treat me nt pla n ni n g pr o ble ms (A C R Practic e 
P ara meter f or I M R T 2 0 1 6 ).
I nte nsity- m o d ulate d ra diati o n t hera py has bec o me wi del y  use d f or a variet y of cli nical i n dicati o ns, 
s uc h as t u m ors of t he ce ntral ner v o us s yste m, hea d a n d nec k, breast, pr ostate, gastr oi ntesti nal tract, 
l u n g, a n d g y nec ol o gic s yste m, as well as sites pre vi o usl y irra diate d (Bitt ner 2 0 1 5 ; Ba u ma n 2 0 1 2 ).
I n ge neral, t he a bilit y of I M R T t o deli ver d ose prefere ntially t o tar get str uct ures i n cl ose pr o xi mit y  
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 / 1 6 6
t o or ga ns at ris k a n d ot her n o ntar get tiss ues ma kes it a val ua ble t o ol e na bli n g t he ra diati o n 
o nc ol o gist t o deli ver d ose t o tar get v ol u mes w hile mi ni mizi n g d ose t o a djace nt n or mal tiss ues .
Alt h o u g h c urati ve treat me nt sc he mes ha ve bee n de vel o pe d t o deli ver dail y fracti o n sizes of 1. 8 t o 
2. 0 G y  t o d oses t otali n g bet wee n 4 0 a n d 8 0 Gy ( depe n di n g o n t u m or hist ol o g y), palliati ve c o urses 
are desi g ne d t o mi ni mize ti me a n d eff ort s pe nt i n tra vel a n d treat me nt f or patie nts s ufferi n g fr o m 
i nc ura ble diseases. I n a d diti o n, alt h o u g h h yp o fracti o nate d treat me nts ma y c orrelate wit h a hi g her 
ris k of late t o xicit y, caref ul selecti o n of palliati ve patie nts wit h li mite d life e x pecta ncies mi ni mizes 
t h ose ris ks. T h us, palliati ve treat me nt c o urses of 8 t o 3 0 G y  gi ve n i n 1 t o 1 0 fracti o ns ha ve bee n 
s h o w n t o be usef ul f or a wi de ra n ge of sce nari os (L utz 2 0 1 4 ). Als o, t he tec h ni q ue of si m ulta ne o us 
m ultisite palliati ve R T pr o vi des c ost be nefits t o patie nts w he n a nal yz e d i n ter ms of c ost per treate d 
site (We n dt 2 0 1 6 ).
T heref ore, i n a n attem pt t o mi ni mize R T relate d t o xicities a n d i m pr o ve pa rtici pa nt c o n ve nie nce i n 
t his st u d y, IM R T
has bee n c h ose n as a R T tec h ni q ue a n d 3 0 G y  t otal d ose deli vere d as 3 G y  dail y
fracti o n f or 1 0 da y s t otal treat me nt d urati o n has bee n ad o pte d as a treat me nt sc he me .
2. 3. 4
S u m m ar y of P ote nti al B e nefits a n d R is ks of t he T re at me nt 
C o m bi n 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 st u d y . 
 
 
 
Base d o n t he mec ha nis m s of acti o n of a vel u ma b a n d M 3 8 1 4, w hic h are well se parate d, a n d t he 
safet y pr ofile of M 3 8 1 4 a n d a vel u ma b m o n ot hera p y, t here are n o maj or o verla p pi n g t o xicities
e x pecte d w he n t he a ge nts are gi ve n i n c o m bi nati o n . Yet Part A of t his first i n h u ma n ( FI H) st u d y 
is pr o p ose d t o all o w f or a detaile d e val uati o n b y  an S M C of t he safety a n d t olera bilit y of t he 
c o m bi nati o n of M 3 8 1 4 a n d a vel u ma b, a n d t o ge nerate safety,  Pd, a n d P K data o n t his c o m bi nati o n ,
w hic h will be use d t o hel p defi ne t he starti n g d ose of M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b a n d 
R T i n Part B .
T he cli nical acti vit y an d safety of a nti-P D - 1 a n d a nti-P D -L 1 i n c o m bi nati o n wit h R T ha ve bee n 
i n vesti gate d retr os pecti vel y in a variet y  of s oli d t u m ors i ncl u di n g l u n g ca ncer, a n d t he res ults s h o w 
a cli nical be nefit i n O S a n d pr o gressi o n -free s ur vi val ( P F S) wit h o ut a n i ncrease i n t o xicities. T h us, 
n u mer o us pr os pecti ve cli nical st u dies t hat c o m bi ne ra diati o n wit h a nti-P D - 1 a n d a nti-P D -L 1  
i ncl u di n g a vel u ma b, are n o w u n der wa y  i n b ot h t he earl y a n d metastatic setti n gs t o c o nfir m t hese 
res ults. 
 
 He nce, f or Part B of t he c urre nt st u d y, w here t he tri plet of a vel u ma b, M 3 8 1 4 
a n d R T is t o be i n vesti gate d, a vaila ble safety data fr o m Part A of t his st u d y 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 / 1 6 6
2. 3. 5
S u m m ar y Be nefit/ R is k St ate me nt
I n s u m mar y, t he p ote ntial f or cli nical be nefit ass ociate d wit h t he c o m bi nati o n of t he P D-1/ P D -L 1  
pat h wa y  in hi bit or (a vel u ma b), D N A -da ma gi n g re pair i n hi bit or (M 3 8 1 4) 
wit h a n d wit h o ut a 
D N A -da ma gi n g a ge nt ( R T), 
 a n d o ut wei g hs t he 
p ote ntial ris ks base d o n t he A E s re p orte d i n partici pa nt s treate d eit her wit h M 3 8 1 4 m o n ot hera p y 
or i n c o m bi nati o n wit h R T as well as the well -k n o w n safety pr ofile of a vel u ma b. T h us, t he 
be nefit/ris k assess me nt fa v ors t he c o n d uct of t his pr o p ose d st u d y.
3
O bjecti ves a n d E n d p oi nts
T he o bjecti ves a n d e n d p oi nts of Part A a n d Part F E (M 3 8 1 4
i n c o m bi nati o n wit h a vel u ma b) are
s h o w n i n Ta ble 8 a n d Ta ble 1 0 a n d of Part B (M 3 8 1 4 i n c o m bi nati o n wit h a velu ma b a n d R T) i n 
Ta ble 9.
3. 1
P art A
T a ble 8
St u d y O bjecti ves a n d E n d p oi nts – P art A
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D a n d/ or t h e M T D
of M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b 
O c c urr e n c e of D L T s fr o m fir st tr e at m e nt t o pl a n n e d fi n al 
a s s e s s m e nt at t h e e n d of D L T p eri o d at 3 w e e k s
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s
a n d tr e at m e nt-r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI-C T C A E v 5. 0, a n d s eri o u s a d v e r s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S 
P h ar m a c o ki n eti c s
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of M 3 8 1 4 a n d 
a v el u m a b w h e n gi v e n a s c o m bi n ati o n t h er a p y

P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s, a s f e a si bl e 
( e. g. Cm a x, Cmi n , R a c c[ Cm a x], R a c c[ A U C] a n d t1/ 2 )

P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C m a x , tm a x, Cmi n , 
C a v g, fl u ct u ati o n i n d e x, A U C0-t , A U C0- ∞, R a c c[ Cm a x],
R a c c[ A U C], t 1/ 2 , V z/f, C L/f, a n d Λ z)
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n 
c o m bi n ati o n wit h M 3 8 1 4
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b i n 
p arti ci p a nt s wit h l o c all y a d v a n c e d or a d v a n c e d s oli d 
t u m or s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
E x pl or at or y
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A D A = a nti dr u g a nti b o d y, A D M E = a b s or pti o n, di stri b uti o n, m et a b oli s m, a n d e x cr eti o n, B O R = b e st o v er all r e s p o n s e, 
C R = c o m pl et e r e s p o n s e, D L T = d o s e -li miti n g t o xi cit y, D N A -P K = D N A -d e p e n d e nt pr ot ei n ki n a s e, D O R = d ur ati o n of 
r e s p o n s e, E C G = el e ctr o c ar di o gr a m, 
E C O G 
P S = E a st er n 
C o o p er ati v e 
O n c ol o g y 
Gr o u p 
P erf or m a n c e 
St at u s, 
F c R = F c r e c e pt or s f or I g G, M T D = m a xi m u m 
t ol er at e d d o s e, 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 s, 
P D = pr o gr e s si v e 
di s e a s e, 
 
P F S = pr o gr e s si o n -fr e e s ur vi v al, 
P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a 
I n S oli d T u m or s, 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 .
3. 2
P art B
T a ble 9
St u d y O bjecti ves a n d E n d p oi nts – P art B
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D a n d/ or t h e M T D
of M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b 
a n d r a di ot h er a p y
O c c urr e n c e of D L T s fr o m fir st tr e at m e nt t o pl a n n e d fi n al 
a s s e s s m e nt at t h e e n d of D L T p eri o d at 4 w e e k s
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b a n d 
r a di ot h er a p y

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI-C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S

I n ci d e n c e, s e v erit y a n d o ut c o m e s of R T-i n d u c e d 
t o xi cit y
P h ar m a c o ki n eti c s
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s of M 3 8 1 4 a n d 
a v el u m a b w h e n gi v e n i n c o m bi n ati o n wit h 
r a di ot h er a p y

P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s, a s f e a si bl e 
( e. g. Cm a x, Cmi n , R a c c[ Cm a x], R a c c[ A U C] a n d t1/ 2 )

P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C m a x , tm a x, Cmi n , 
C a v g, fl u ct u ati o n i n d e x, A U C 0-t , A U C0- ∞, R a c c[ C m a x],
R a c c[ A U C], t 1/ 2 , V z/f, C L/f, a n d Λ z)
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n 
c o m bi n ati o n wit h M 3 8 1 4 pl u s r a di ot h er a p y.
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b a n d 
r a di ot h er a p y i n p arti ci p a nt s wit h l o c all y a d v a n c e d a n d 
a d v a n c e d s oli d t u m or s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
E x pl or at or y
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
 
 
A D A = a nti dr u g a nti b o d y, A D M E = a b s or pti o n, di stri b uti o n, m et a b oli s m, a n d e x cr eti o n, B O R = b e st o v er all r e s p o n s e, 
C R = c o m pl et e r e s p o n s e, D L T = d o s e -li miti n g t o xi cit y, D N A -P K = D N A -d e p e n d e nt pr ot ei n ki n a s e, D O R = d ur ati o n of 
r e s p o n s e, E C G = el e ctr o c ar di o gr a m, 
E C O G 
P S = E a st er n 
C o o p er ati v e 
O n c o l o g y Gr o u p 
P erf or m a n c e 
St at u s, 
F c R = F c r e c e pt or s f or I g G, M T D = m a xi m u m 
t ol er at e d d o s e, 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 s, 
P D = pr o gr e s si v e 
di s e a s e, 
 
P F S = pr o gr e s si o n -fr e e s ur vi v al , 
, P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a 
I n S oli d T u m or s, 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, R T =r a di ot h er a p y.
3. 3
P art F E
T a ble 1 0
St u d y O bjecti ves a n d E n d p oi nts – P art F E
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
Pri m ar y
T o d et er mi n e a n d c o m p ar e t h e p h ar m a c o ki n eti c 
pr ofil e of M 3 8 1 4 u n d er f a st e d a n d f e d c o n diti o n s
Ar e a u n d er t h e M 3 8 1 4 pl a s m a c o n c e ntr ati o n -ti m e c ur v e 
( A U C) fr o m ti m e z er o t o t h e l a st q u a ntifi a bl e s a m pli n g 
ti m e ( A U C0-t ), a n d m a xi m u m M 3 8 1 4 pl a s m a 
c o n c e ntr ati o n o b s er v e d ( C m a x )
S e c o n d ar y
S af et y
T o e v al u at e t h e s af et y pr ofil e a n d t ol er a bilit y of 
M 3 8 1 4 i n c o m bi n ati o n wit h a v el u m a b
u n d er f a st e d 
a n d f e d c o n diti o n s

O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt-r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI- C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s

O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S
I m m u n o g e ni cit y
T o e v al u at e t h e i m m u n o g e ni cit y of a v el u m a b i n 
c o m bi n ati o n wit h M 3 8 1 4 u n d er f a st e d a n d f e d 
c o n diti o n s
I m m u n o g e ni cit y a s m e a s ur e d b y A D A
Effi c a c y
T o e v al u at e t h e pr eli mi n ar y a ntit u m or a cti vit y of 
M 3 8 1 4 w h e n gi v e n i n c o m bi n ati o n wit h a v el u m a b i n 
p arti ci p a nt s wit h l o c all y a d v a n c e d or a d v a n c e d s oli d 
t u m or s, u n d er f a st e d a n d f e d c o n diti o n s

C o nfir m e d B O R, D O R a s s e s s e d fr o m C R or P R u ntil 
P D, d e at h, or l a st t u m or a s s e s s m e nt, a n d P F S ti m e 
a c c or di n g t o R E CI S T v 1. 1 a s a s s e s s e d b y t h e 
I n v e sti g at or

T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1 fr o m t h e fir st 
st u d y i nt er v e nti o n s d o s e u ntil c o nfir m e d P D or st art of 
n e w c a n c er tr e at m e nt

O v er all S ur vi v al
E x pl or at or y
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 6 6
O bj e cti v e s
E n d p oi nt s ( O ut c o m e M e a s ur e s)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A D A = a nti dr u g a nti b o d y, A D M E = a b s or pti o n, di stri b uti o n, m et a b oli s m, a n d e x cr eti o n , B O R = b e st o v er all r e s p o n s e, 
C R = c o m pl et e r e s p o n s e, D O R = d ur ati o n of r e s p o n s e, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e 
O n c ol o g y Gr o u p P erf or m a n c e St at u s, F c R = F c r e c e pt or s f or I g 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 s, 
P D = pr o gr e s si v e 
di s e a s e, 
 
P F S = pr o gr e s si o n -fr e e s ur vi v al, 
 P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a 
I n S oli d T u m or s.
4
St u d y Desi g n
4. 1
O ver all Desi g n
T his is a P hase I , m ultice nter st u d y c o nsisti n g of 3 parts ( Part A, Part B , a n d Part F E) as s h o w n i n 
Fi g ure 1 a n d Fi g ure 2 .

Part A ai ms t o deter mi ne t he M T D a n d/ or t he R P 2 D of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h 
a vel u ma b.

Part B ai ms t o deter mi ne t he M T D a n d/ or t he R P 2 D of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h 
a vel u ma b a n d R T.

Part B will be i nitiate d o nce a first d ose le vel of Part A has bee n declare d as safe 
a n d t olera ble b y t he S M C

Part F E ai ms t o e val uate t he F E o n P K of M 3 8 1 4 f oll o wi n g a d mi nistrati o n of M 3 8 1 4 i n 
c o m bi nati o n wit h a vel u ma b u n der faste d a n d fe d co n diti o ns . O nl y  doses of M 3 8 1 4 alrea d y 
declare d as safe a n d t olera ble i n Part A b y  the S M C will be i n vesti gate d i n t his p art of t he st u d y.

T he ta blet f or m ulati o n of M 3 8 1 4 will be use d i n t his st u d y. Treat me nt after t he st u d y en ds is 
descri be d i n Secti o n 6. 7 .

A d diti o nal d osi n g re gi me ns of M 3 8 1 4 a n d a vel u ma b ( Part A a n d Part F E ) or M 3 8 1 4, a vel u ma b, 
a n d R T ( Part B) ma y be i ntr o d uce d b y pr ot oc ol a me n d me nt t o be e x pl ore d.

A n i ncrease i n t he sa m ple size f or Part A, Part B , a n d/ or Part F E of t he st u d y t o acc o m m o date 
a d diti o nal d ose le vels ma y be a d de d b y pr ot oc ol a me n d me nt.

I n a d diti o n, e x pa nsi o n c o h orts i n defi ne d a d va nce d s oli d t u m or i n dicati o ns ma y  be a d de d b y  
a me n d me nt t o e x pl ore preli mi nar y  efficac y of t he c o m bi nati o n re gi me ns st u die d i n Part A 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 6 6
a n d/ or Part B.
4. 1. 1
St u d y Peri o ds
Eac h p art of t he st u d y (Par t A , Part B, a n d Part F E ) will c o m prise 3 st u d y peri o ds : a S cree ni n g 
peri o d, a Treat me nt peri o d, a n d a F oll o w -u p peri o d. 
4. 1. 1. 1
Scree ni n g Peri o d 
After pr o vi di n g i nf or me d c o nse nt f or t he st u d y, t he eli gi bilit y of st u d y partici pa nts will be 
esta blis he d acc or di n g t o t he pr ot oc ol -defi ne d i ncl usi o n ( Secti on 5. 1 ) a n d e xcl usi o n criteria 
( Secti o n 5. 2 ) d uri n g a ma xi m u m 2 8 -da y  Scree ni n g p eri o d ( Scree ni n g a n d Baseli ne e val uati o ns)
f or Part A a n d F E a n d a ma xi m u m 3 5-da y  Scree ni n g p eri o d f or Part B . 
4. 1. 1. 2
Tre at me nt Peri o d
T he treat me nt peri o d will be gi n at t he first d ose of M 3 8 1 4 w hic h will be a d mi nistere d c o nti n u o usl y 
i n c o m bi nati o n wit h a vel u ma b f or Part A a n d Part F E, a n d wit h a vel u ma b a n d R T f or Part B.
P art A
a n d P art F E : M 3 8 1 4 
will be a d mi nistere d BI D c o nti n u o usl y,  in c o m bi nati o n wit h 
a vel u ma b Q 2 W starti n g o n Da y 1 u ntil P D or u nacce pta ble t o xicit y .
P art B : M 3 8 1 4 will be a d mi nistere d Q D. Ra di ot hera p y will be gi ve n at t he d ose of 3 G y  per da y. 
M 3 8 1 4 a n d R T will b ot h be gi ve n starti n g Da y  1 f or 5 d a y s/ wee k f or 2 wee ks. A vel u ma b will be 
a d mi nistere d Q 2 W starti n g o n Da y 1 u ntil P D or u nacce pta ble t o xicit y .
P art A a n d P art B:

D ose -li miti n g t o xicit y (D L T) Assess me nt Peri o d : will last 3 wee ks i n Part A a n d 4 wee ks i n 
Part B (after t he first a d mi nistrati o n of st u d y i nter ve nti o n) f or t he e val uati o n of ac ute s yste mic 
a n d l ocal t o xicit y i n all partici pa nts. T he D L T assess me nt peri o d i n Part B will be l o n ger t ha n 
f or P art A beca use t o xicities relate d t o ra diati o n i ncl u di n g Ra diati o n -I n d uce d L u n g T o xicities 
( RI L T) mi g ht occ ur wit h i n a fe w wee ks t o m o nt hs after ra diati o n. T heref ore, a d diti o nal R T 
S afet y F oll o w- u ps are sc he d ule d at 1, 3, a n d 1 2 m o nt hs after t he e n d of R T t o i n vesti gate t hese 
p ote ntial late t o xicities.
P art F E :

F E Assess me nt P eri o d: will last 3 wee ks (after t he first a d mi nistrati o n of st u d y inter ve nti o n)
f or t he e val uati o n of t he effect of f o o d c o n diti o ns (fasted /fe d) o n M 3 8 1 4 P K .
P art A, P art B , a n d P art F E : 

Partici pa nts w h o ha ve e x perie nce d a c o nfir me d 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 n t hs wit h a vel u ma b + M 3 8 1 4 i n Part A a n d Part F E or a vel u ma b i n Part B 
base d o n cli nical j u d g me nt of be nefit a n d/ or u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, 
after c o nfir mati o n of res p o nse as s pecifie d i n t he pr ot oc ol. W here
a partici pa nt 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 rei nitiati o n of treat me nt is all o we d at t he discreti o n of t he I n vesti gat or a n d 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 6 6
a gree me nt of t he Me dical M o nit or. T o be eli gi ble f or retreat me nt, t he partici pa nt 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 or M 3 8 1 4 
t hera py i n Part A a n d Part F E or a vel u ma b i n Part B. Partici pa nt s w h o rei nitiate treat me nt will 
sta y on t he 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 
pr o gressi o n” sc he d ule i n t he Sc he d ule of Acti vities  (Ta ble 1 , Ta ble 2 , Ta ble 3 , a nd Ta ble 4 ).
Pa rtici pa nts w h o rei nitiate treat me nt will n ot ha ve t o u n der g o a sec o n d S cree ni n g V isit.
4. 1. 1. 3
F oll o w -U p Peri o ds
Safet y  F oll o w- u p

P art A , P art B , a n d P art F E
T he Safet y  F oll o w-u p peri o d will be 3 0 d a y s a n d 9 0 d a y s after t he last d ose of a vel u ma b f or safety 
e val uati o n of t he c o m bi nati o n of st u d y i nter ve nti o ns . 

P art B
I n a d diti o n t o t he S afet y F oll o w -u p relati n g t o t he c o m bi nati o n of st u d y i nter ve nti o ns after t he last 
d ose of a vel u ma b, f or P art B, t he f oll o wi n g R T S afet y Foll o w - u p peri o ds are defi ne d t o assess 
p ote ntial t o xicit y  of R T w he n a d mi nistere d i n c o m bi nati o n wit h M 3 8 1 4 a n d a vel u ma b:
1.
S h ort -ter m R T Safet y  Foll o w - u p: 3 0 da y s after t he e n d of R T f or e val uati o n of 
safety.
2.
Mi d -ter m R T Safety F oll o w - u p: 3 m o nt hs after t he e n d of R T t o e val uate late si g ns 
of R T- i n d uce d t o xicit y o n n or mal s urr o u n di n g tiss ues.
3.
L o n g -ter m R T Safet y  Foll o w - u p: 1 2 m o nt hs after t he e n d of R T , t o e val uate 
R T -i n d uce d t o xicities, b y tele p h o ne call.
L o n g -Ter m F oll o w - u p

P art A, P art B , a n d P art F E
Partici pa nts will be f oll o we d f or s ur vi val a n d use of s u bse q ue nt a ntica ncer t hera py u ntil t he e n d 
of t he st u d y. Partici pa nts wit h o ut P D w h o are n ot recei vi n g s u bse q ue nt a ntica ncer t hera p y after 
t he E n d of Treat me nt Visit, will be f oll o we d e ver y 8 wee ks wit h ra di o gra p hic disease e val uati o n 
f or t he first 6 m o nt hs of t he st u d y an d t he n e ver y 12 wee ks t hereafter u ntil P D 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 V ersi o n 1. 1 ( R E CI S T v 1. 1), a n d for s ur vi val a n d 
use of s u bse q ue nt a ntica ncer t hera p y u ntil t he e n d of t he st u d y. 
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
T he d ose escalati o n desi g n pr o p ose d f or t his P hase I st u d y is dee me d a p pr o priate t o de fi ne t he 
M T D a n d/ or R P 2 D of M 3 8 1 4
( Part A a n d Part B) a n d f urt her i n vesti gate its safet y, t olera bilit y, 
P K/ P d pr ofile , preli mi nar y  antit u m or acti vit y a n d t he effect of hi g h -fat meal o n P K of M 3 8 1 4
w he n gi ve n i n c o m bi nati o n wit h a vel u ma b i n partici pa nts wit h metastatic or a d va nce d s oli d t u m ors 
( Part A
a n d Part F E ) a n d wit h a vel u ma b a n d R T i n partici pa nts wit h selecte d a d va nce d or 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 6 6
metastatic s oli d t u m ors ( Part B).
A n o pe n -la bel desi g n is c o nsi dere d a p pr o priate f or a d ose 
escalati o n st u d y.
T he decisi o n t o start Part B o nce t he first d ose le vel i n Part A is declare d safe a n d t olera ble, al o n g 
wit h usi n g a 2- f ol d l o wer starti n g d ose of M 3 8 1 4 c o m pare d wit h t he starti n g d ose le vel i n Part A, 
ai ms t o miti gate a p ote ntial i ncrease i n se verit y or fre q ue nc y of ra diati o n t o xicit y whic h c o ul d be 
relate d t o t he c o m bi nati o n of R T wit h a vel u ma b a n d/ or M 3 8 1 4. T his c o nser vati ve a p pr oac h ai ms 
t o mi ni miz e ris k t o st u d y participa nts i n t he i nitial c o h ort of P art B.
T he starti n g d ose i n P art F E will be 1 0 0 m g  BI D si nce t his d ose has bee n assesse d i n 4 pa rtici pa nts
i n Part A a n d alrea d y declare d safe a n d t olera ble. S u bse q ue nt d oses will be defi ne d base d o n P K 
a n d safety data ge nerate d i n pre vi o us c o h orts of Part A a n d Part F E a n d will be wit hi n t he ra n ge 
of d oses deter mi ne d as safe i n Part A. Data c ollecte d fr o m p artici pa nts i n Part F E will p ri marily
be use d t o i n vesti gate t he F E o n M 3 8 1 4 P K . I n a d diti o n, t he effects of pra n dial s tate o n t he safety
pr ofile of M 3 8 1 4 
al o n g wit h , t olera bilit y, P d pr ofile , a n d preli mi nar y  antit u m or acti vit y of 
escal ati n g d oses of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h a vel u ma b will als o be e val uate d .
A d diti o nal d osi n g re gi me ns of M 3 8 1 4 a n d a vel u ma b ( Part A a n d Part F E) or M 3 8 1 4, a vel u ma b, 
a n d R T ( Part B) ma y be i ntr o d uce d b y pr ot oc ol a me n d me nt t o be e x pl ore d.
A n i ncrease i n t he sa m ple size f or Part A, Part B, a n d/ or Part F E of t he st u d y t o acc o m m o date 
a d diti o nal d ose le vels ma y be a d de d b y pr ot oc ol a me n d me nt.
F ut ure d ose e x pa nsi o n c o h orts ma y  be i ncl u de d b y  ame n d me nt t o e x pl ore efficac y in selecte d 
t u m or i n dicati o ns i n Part A a n d/ or Part B.
P art A a n d P art B :
T he pri mar y  en d p oi nts of occ urre nce of D L Ts as well as t he sec o n dar y en d p oi nt of occ urre nce, 
se verity a n d d urati o n of treat me nt-e mer ge nt a d verse e ve nts (T E A Es ) a n d treat me nt-relate d A Es 
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 5. 0 are sta n dar d o bjecti ve meas ures of safet y. A 3- wee k ( Part A) a n d 4 -wee k 
( Part B) peri o d has bee n defi ne d as t he D L T assess me nt peri o d t o m o nit or D LT o ver 4 2 d oses of 
M 3 8 1 4 a n d 2 a d mi nistra ti o ns of a vel u ma b f or Part A a n d 1 0 a d mi nistrati o ns of M 3 8 1 4 a n d 
8 fracti o ns of R T ( 3 G y  eac h) a n d 3 a d mi nistrati o ns of a vel u ma b f or Part B. Sec o n dar y  en d p oi nts 
relati n g t o P K, i m m u n o ge nicit y, a n d c o nfir me d o bjecti ve res p o nse as assesse d b y t he I n vesti gat or 
usi n g R E CI S T v 1. 1 criteria are als o sta n dar d meas ure me nts. D urati o n of res p o nse, P F S a n d O S
will als o be deter mi ne d as sec o n dar y en d p oi nts a n d will ser ve t o assess w het her t he o bjecti ve 
res p o nse is ass ociate d wit h lasti n g cli nical a n d s ur vi val be nefit.
P art F E :
T he pr i m ar y en d p oi nt is t o e val uate t he F E (faste d/fe d state) o n P K of M 3 8 1 4 . A 3- wee k peri o d 
has bee n defi ne d as t he F E A ssess me nt Peri o d t o m o nit or t he e x p os ure b ot h after si n gle a n d 
re peate d a d mi nistrati o n of M 3 8 1 4
o ver 4 2 d oses of M 3 8 1 4 a n d 2 a d mi nistrati o ns of a vel u ma b. 
Sec o n dar y  en d p oi nts relati n g t o t he effects of pra n dial state o n t he safet y  pr ofile of M 3 8 1 4 al o n g 
wit h i m m u n o ge nicit y an d c o nfir me d o bjecti ve res p o nse as assesse d b y  the I nvesti gat or usi n g 
R E CI S T v 1. 1 criteria are als o sta n dar d meas ure me nts. D urati o n of res p o nse, P F S , a n d O S will 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 6 6
als o be deter mi ne d as sec o n dar y e n d p oi nts a n d will ser ve t o assess w het her t he o bjecti ve res p o nse 
is ass ociate d wit h lasti n g cli nical a n d s ur vi val be nefit. 
P art A, P art B , a n d P art F E :
T he e x pl orat or y  p har mac o d yna mic assess me nts were selecte d base d o n t he k n o w n mec ha nis m of 
acti o n a n d effects of M 3 8 1 4 
a n d are rele va nt t o t he res p o nse, safet y, or resista nce t o t he 
c o m bi nati o n. T hese assess me nts will c o ntri b ute t o t he u n dersta n di n g of A E s a n d hel p i n t he 
deter mi nati o n of t he R P 2 D.
Partici pa nts m ust ha ve hist ol o gicall y or c y t ol o gicall y pr o ve n a d va nce d or metastatic s oli d t u m ors 
( Part A a n d Part F E ) a n d ad va nce d or metastatic s oli d t u m ors eli gi ble f or fracti o nate d R T ( Part B) 
f or w hic h n o stan dar d t hera p y e x ists, sta n dar d t hera p y has faile d, or t he partici pa nt is i nt olera nt t o 
or has rejecte d esta blis he d t hera py k n o w n t o pr o vi de cli nical be nefit f or t heir c o n diti o n. 
Secti o n 5. 1 a n d Secti o n 5. 2 pr o vi de detaile d i ncl usi o n a n d e xcl usi o n criteria, res pecti vel y.
4. 3
J ustific ati o n f or D ose
4. 3. 1
M 3 8 1 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 6 6
P art A
T he selecti o n of 2 0 0 m g as t he starti n g t otal dail y  dose of t he M 3 8 1 4 ta blet f or m ulati o n gi ve n as 
1 0 0 m g BI D c o nc urre ntl y wit h a vel u ma b 8 0 0 m g Q 2 W
ta kes i nt o acc o u nt t he bi ol o gicall y 
effecti ve d ose ( B E D) of M 3 8 1 4 
m o n ot hera p y  whic h is esti mate d, base d o n m o deli n g a n d 
si m ulati o n res ults, t o be i n t he d ose ra n ge of 2 0 0 t o 8 0 0 m g t otal dail y  dose usi n g t he ca ps ule
f or m ulati o n. 
 
 
 
 
 
 
 
 
F urt her m ore, t he mec ha nis m of acti o n of M 3 8 1 4
( p ote nt a n d selecti ve s mall-m olec ule a de n osi ne 
tri p h os p hate-c o m petiti ve i n hi bit or of D N A -P K ) a n d a vel u ma b (a h u ma n a nti-P D -L 1  mo n ocl o nal 
a nti b o d y) are disti nct a n d t heir acce pta ble safety pr ofiles w he n gi ve n as si n gle a ge nts d o n ot pre dict 
maj or a d diti o nal safety t o xicities if c o m bi ne d. C
 
 
 
H o we ver, as t his is a n o vel c o m bi nati o n of a n i m m u ne-o nc ol o g y  age nt a n d a s mall-m olec ule 
ki nase i n hi bit or, a n a d diti o nal safety fact or of 2- f ol d has bee n c o nsi dere d t o acc o u nt f or a n y 
u ne x pecte d t o xicities w he n M 3 8 1 4 is gi ve n i n c o m bi nati o n wit h a vel u ma b.
 
 
 
 
 
 
P art B
T he starti n g d ose of M 3 8 1 4 i n t he first c o h ort of partici pa nts is e x pecte d t o be 1 0 0 m g t otal dail y 
d ose (i.e. 2-f ol d l o wer t ha n i n P art A), as rec o m me n de d b y t he S M C base d o n safet y, P K, a n d P d 
data ge nerate d d uri n g t he first d ose le vel i n Part A a n d/ or e mer gi n g safet y a n d p har mac ol o g y data 
fr o m t he o n g oi n g 
cli nical st u dies i n v ol vi n g M 3 8 1 4 
i n c o m bi nati o n wit h 
R T
(e. g.
. In Part B, M 3 8 1 4 will be a d mi nistere d Q D. M 3 8 1 4 a n d R T will b ot h be gi ve n 
starti n g Da y 1 f or 5 d a y s/ wee k f or 2 wee ks.
 
 i n t he d ose ra n ge of 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 / 1 6 6
5 0  t o 4 0 0 m g dail y wit h ca ps ule f or m ulati o n. 
 
 
 
 
T heref ore,  a starti n g d ose  of  1 0 0 m g  Q D  usi n g  t he ta blet f or m ulati o n has  bee n  defi ne d  t o all o w 
t he B E D t o be ac hie ve d w hile ta ki n g i nt o acc o u nt t he safety of partici pa nts i n t he first c o h ort.
I n t he c o nte xt of t his treat me nt c o m bi nati o n FI H cli nical st u d y, t he decisi o n t o c o n d uct t he 2  st u d y 
parts ( Part A a n d Part B) se q ue ntiall y  (i.e. Part B starti n g o nce t he first d ose i n Part A is declare d 
safe) an d i n o verla p pi n g fas hi o n (i.e. d ose escalati o n i n Part A c o nti n ui n g o nce Part B has starte d) 
will e na ble t he i nte grati o n of safet y, P K , a n d P d data ge nerate d d uri n g t he first d o se le vel i n Part  A 
al o n g wit h  e mer gi n g  safet y an d  p har mac ol o g y  d ata fr o m t he o n g oi n g  cli nical st u dies i n v ol vi n g 
M 3 8 1 4  a n d R T  i n t he decisi o n- ma ki n g  of  starti n g d ose  w hic h  is eit her c o nfir mi n g t he selecte d 
starti n g d ose of 1 0 0 m g  t otal dail y  d ose of M 3 8 1 4 or i nf or mi n g t he selecti o n of a n ot her d ose of 
M 3 8 1 4 t o be e val uate d as a starti n g d ose le vel, if dee me d a p pr o priate a n d safe b y  t he S M C. 
T heref ore, 
 a n d clinical e x perie nce  wit h M 3 8 1 4 , as well as t he st u d y desi g n, j ustif y 
t he starti n g d ose a p pr oac h a d o pte d i n Part B of t his st u d y.
I n Part B, t he Q D a d mi nistrati o n starti n g 1. 5  h o urs ( ± 3 0  mi n utes) bef ore R T a n d o nl y d u ri n g d a y s 
w he n R T is deli vere d is j ustified b y  t he mec ha nis m of acti o n of M 3 8 1 4 t hat is ai mi n g t o decrease 
t he re pair o f D S Bs  g e nerate d  b y  R T,  w hic h  mi g ht  occ ur  i m me diately  after R T  is a d mi nistere d 
(K w o k  a n d S ut herla n d 1 9 8 9 ; Sc h ulz  2 0 1 7 ).
P art F E 
A t otal dail y d ose of 2 0 0 m g gi ve n as 1 0 0 m g BI D M 3 8 1 4 ta blet f or m ulati o n has bee n selecte d as 
starti n g d ose  beca use  1 0 0  m g  BI D  has  alrea d y  bee n  d eclare d  safe a n d t olera ble i n c o m bi nati o n 
wit h a vel u ma b 8 0 0 m g Q 2 W i n t his st u d y. 
 
 
 
C o nse q ue ntl y , t he r o o m f or a n 
a d diti o nal i ncrease i n a bs or pti o n of ta blet f or m ulati o n d ue t o a p ositi ve F E  is e x pecte d t o be l o w. 
 
 
 
He nce, a starti n g t otal 
dail y  d ose of 2 0 0 m g M 3 8 1 4 a d mi nistere d as 1 0 0 m g BI D ta blet  f or m ulati o n is n ot e x pecte d t o 
affect t he safet y pr of ile of M 3 8 1 4.
S u bse q ue nt d ose le vels will be selecte d base d o n P K a n d safet y data ge nerate d i n b o t h Part A a n d 
Part F E.
4. 3. 2
R a di ot her a p y
Ra di ot hera p y is a s uccessf ul, ti me-efficie nt, well -t olerate d, a n d c ost-effecti ve i nter ve nti o n t hat is 
cr ucial f or t he a p pr o priate deli ver y  of palliati ve o nc ol o g y care.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 6 6
T o ac hie ve o pti mal patie nt care o utc o mes, o ne of t he maj or g oal s of ra diati o n t hera p y is t he 
deli ver y  of the desire d d ose distri b uti o n of I R t o tar get tiss ue w hile li miti n g t he ra diati o n d ose t o 
t he s urr o u n di n g n or mal tiss ues t o a n acce pta ble le vel. I nte nsity- m o d ulate d ra diati o n t hera py,
a m o n g ot her hi g hl y c o nf or mal tec h ni q ues, re prese nts a n i m p orta nt a d va nce i n ra diati o n t hera p y
a n d, beca use of its a bilit y t o ac hie ve a hi g hl y c o nf or mal d ose distri b uti o n w hile s pari n g a djace nt 
or ga ns at ris k , it has bec o me wi del y  use d f or a variet y of cli nical i n dicati o ns (C ha n dra 2 0 0 5; Y o m  
2 0 0 7 ; Nic oli ni 2 0 1 2 ; Etti n ger 2 0 1 8 ).
It is c urre ntl y wi del y a gree d t hat palliati ve R T c o urses s h o ul d be desi g ne d t o mi ni mize ti me a n d 
eff ort s pe nt i n tra vel a n d treat me nt f or patie nts s ufferi n g fr o m i nc ura ble diseases. T heref ore, 
treat me nt c o urses of 8 t o 3 0 G y gi ve n i n 1 t o 1 0 fracti o ns ha ve bee n s h o w n t o be usef ul f or a lar ge 
ra n ge of a d va nce d a n d metastatic s oli d t u m ors (L u tz 2 0 1 4 ). F urt her m ore , it is i ncreasi n gly 
rec o m me n de d t hat t he si m ulta ne o us m ultisite R T tec h ni q ue ca n be wi del y a d o pte d wit h t he ne w 
R T tec h n ol o gies s uc h as I M R T i n palliati ve setti n g i n or der t o o pti mize c ost-be nefits i n t his patie nt
p o p ulati o n . (We n dt 2 0 1 6 ).
T heref ore, Part B of t his st u d y will e nr oll partici pa nts wit h a d va nce d or metastatic s oli d t u m ors 
a me na ble t o recei ve 3 0 G y  t otal R T d ose gi ve n i n 1 0 fracti o ns ( 3 G y /fracti o n, 5 fracti o ns/ wee k, 
1 0 da y s t otal d urati o n of treat me nt) t o u p t o 3 pri mar y  an d/ or metastatic sites usi n g t he I MR T 
tec h ni q ue.
 
 
ot her palliati ve R T d ose a n d/ or 
fracti o nati o n sc he d ules ma y be i ncl u de d b y a me n d me nt.
4. 3. 3
A vel u m a b
T o date, a vel u ma b has bee n a d mi nistere d at t he cli nicall y  acti ve t olera ble d ose of 1 0 m g/ k g Q 2 W
t o m ore t ha n 1 8 0 0 patie nts acr oss m ulti ple i n dicati o ns. F urt her m ore, t his 1 0 m g/ k g e ver y  2-wee k 
a vel u ma b d osi n g re gi me n has bee n a p pr o ve d b y  the F D A as t he first treat me nt f or Mer kel Cell 
Carci n o ma a n d U C. A vel u ma b was ori gi nall y d ose d o n a m g / k g basis i n or der t o re d uce i nter 
partici pa nt varia bilit y  in dr u g e x p os ure. H o we ver, e mer gi n g data f or m o n ocl o nal a nti b o dies, 
i ncl u di n g t he mar kete d 
P D - 1 a n d P D -L 1  im m u ne 
c hec k p oi nt i n hi bit ors ni v ol u ma b, 
pe m br oliz u ma b , a n d atez oliz u ma b, re veal t hat b o d y  wei g ht base d d osi n g re gi me ns d o n ot res ult i n 
less varia bilit y  in meas ures of e x p os ure o ver fi xe d (i.e. b o d y  wei ght i n de pe n de nt) d osi n g re gi me ns 
(Wa n g 2 0 0 9 ; Fres h water 2 0 1 7 ; Z ha o 2 0 1 7 ). A d diti o nall y , fi xe d d osi n g offers t he a d va nta ges of 
less p ote ntial f or dis pe nsi n g err ors, s h orter d ose pre parati o n ti mes i n a cli nical setti n g, a n d greater 
ease of a d mi nistrati o n.
T he d ose re gi me n of a vel u ma b at 8 0 0 m g flat d ose Q 2 W has bee n a p pr o ve d b y  t he F D A. T he flat 
d ose re gi me n has bee n st u die d via m o deli n g a n d si m ulati o n a n d is c urre ntl y  bei n g i n vesti gate d i n 
a fe w cli nical st u dies i n c o m bi nati o n wit h ot her a ge nts. A vel u ma b was ori gi nall y  dose d o n a m g / k g 
basis t o re d uce i nter partici pa nt varia bilit y  in dr u g e x p os ure. H o we ver, t he P o p P K m o de l data, 
re veal t hat b o d y  wei g ht-base d d ose re gi me ns d o n ot res ult i n less varia bilit y  in meas ur es of 
e x p os ure o ver fi xe d (i .e. b o d y  wei g ht i n de pe n de nt) d ose re gi me ns.
Si m ulati o n s h o we d t hat e x p os ures t o a vel u ma b acr oss t he a vaila ble ra n ge of b o d y wei g hts are less 
varia ble wit h 8 0 0 m g  Q 2 W
c o m pare d wit h 1 0 m g/ k g Q 2 W ; e x p os ures were si milar near t he 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 / 1 6 6
p o p ulati o n me dia n wei g ht. F urt her m ore, t he 8 0 0 m g Q 2 W d ose re gi me n is e x pecte d t o res ult i n 
C tr o u g h > 1 m g/ m L  re q uire d t o mai ntai n a vel u ma b ser u m c o nce ntrati o ns at > 9 5 % tar get occ u pa nc y
t hr o u g h o ut t he e ntire Q 2 W d osi n g i nter val i n all wei g ht cate g ories .
T h e a d va nta ges of flat d osi n g are mi ni mizi n g 
dr u g wasta ge, facilitati n g pre parati o n a n d 
a d mi nistrati o n, a n d re d uci n g p har mac y  err ors (Wa n g 2 0 0 9 ).
T heref ore, i n t his cli nical st u d y, a fi xe d d osi n g re gi me n of 8 0 0 m g  ad mi niste re d as 1- h o ur I V 
i nf usi o n Q 2 W will be utilize d f or a vel u ma b.
4. 4
E n d of St u d y Defi niti o n
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y  parts, i ncl u di n g t he Safety 
F oll o w -u p Visit as s h o w n i n Secti o n 1. 3 ( Sc he d ule of Acti vities).
T he e n d of t he st u d y is defi ne d as t he date of 1 ye ar after t he last partici pa nt has recei ve d t he last 
d ose of st u d y  i nter ve nti o ns or t he last partici pa nt i n t his st u d y dies, w hic he ver c o mes first.
T his e n d of st u d y date will all o w s ufficie nt ti me t o c ollect da ta o n t he efficac y en d p oi nts ( O S, 
c o nfir me d B O R , d urati o n of res p o nse, P F S ti me, a n d t u m or size). 
T he S p o ns or ma y  ter mi nate t he st u d y at a n y t i me o nce access t o st u d y inter ve nti o n f or partici pa nts 
still be nefit i n g is pr o visi o ne d via a r oll o ver st u d y, e x pa n de d access, mar kete d pr o d uct or a n ot her 
mec ha nis m of access as a p pr o priate.
5
St u d y P o p ul ati o n
T he criteria i n Secti o ns 5. 1 a n d 5. 2 are desi g ne d t o e nr oll o nl y  partici pa nts, w h o are a p pr o priate 
f or t he st u d y; t her e b y, e ns uri n g t he st u d y fulfil s its o bjecti ves. All rele va nt me dical a n d n o n me dical 
c o n diti o ns s h o ul d be ta ke n i nt o c o nsi derati o n w he n deci di n g w het her a partici pa nt is s uita ble f or 
t his st u d y.
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef ore perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical care, 
t he I nvesti gat or will c o nfir m t hat t he partici pa nt or t he partici p a nt’s le gal re prese ntati ve has 
pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n A p pe n di x 2 ( St u d y G o ver na nce).
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteri a a p pl y:
A ge
1.
Are ≥1 8 ye ars of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 6 6
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
Partici pa nts m ust ha ve: 

P art A a n d P art F E ( M 3 8 1 4 + a vel u m a b): hist ol o gicall y o r c yt ol o gically pr o ve n a d va nce d or 
metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y exists, sta n dar d t hera py has faile d, or 
partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera py k n o w n t o pr o vi de cli nical 
be nefit f or t heir c o n diti o n. 

P art B ( M 3 8 1 4 + R T + a vel u m a b): hist ol o gicall y  or c yt ol o gicall y pr o ve n a d va nce d or 
metastatic s oli d t u m ors f or w hic h n o sta n dar d t hera p y  e xists, sta n dar d t hera p y has faile d, or 
partici pa nts are i nt olera nt t o or ha ve rejecte d esta blis he d t hera p y k n o w n t o pr o vi de be nefit f or 
t heir c o n diti o n a n d are a me na ble t o recei ve R T.
Lesi o ns t o be tar gete d wit h R T nee d t o f ulfil l t he f oll o wi n g criteria:

S h o ul d be of mali g na nt ori gi n

M ust n ot be arisi n g fr o m t he brai n or s pi nal ca nal

M ust n ot be es o p ha geal, g astric or s mall b o wel lesi o n

M ust n ot be pri mar y  li ver ca ncer ( he pat ocell ular carci n o ma [H C C ], i ntra he patic 
c h ola n gi ocarci n o ma [I CC], mi xe d H C C -I CC )

T he lesi o n or c o m p osite lesi o n tar get ma xi m u m l o n gest dia meter (s u m of ma xi m u m 
l o n gest dia meters f or all t u m or tar gets t o be irra diate d) m ust be at least 1 c m 
( ≥1 c m). F or i n di vi d ual t u m or w here t he l o n gest dia meter is > 5 c m, a tar get 
v ol u me c o ul d be create d wit hi n t he gr oss t u m or v ol u me t o li mit t he treate d t u m or 
t o 5 c m.
A d diti o nal details relate d t o ra di ati o n tar get selecti o n are o utli ne d in A p pe n di x 8 .
P art A , P art B , a n d P art F E
3.
Meas ura ble or e val ua ble disease acc or di n g t o R E CI S T v 1. 1.
4.
Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us ( E C O G P S) of 0 t o 1 at st u d y 
e ntr y.
5.
A de q uate b o ne marr o w f u ncti o n i ncl u di n g: A bs ol ute ne utr o p hil c o u nt ≥1, 5 0 0/ m m 3 or 
≥ 1. 5 × 1 0 9/ L; platelets ≥ 1 0 0, 0 0 0/ m m 3 or ≥ 1 0 0 × 1 0 9/ L; he m o gl o bi n ≥9 g/ d L ( may 
ha ve bee n tra nsf use d). Partici pa nts wit h d oc u me nte d be ni g n c yclical ne utr o pe nia are 
all o we d if w hite bl o o d cell c o u nt is ≥ 1. 5 × 1 0 9/ L wit h a bs ol ute ne utr o p hil c o u nt 
≥1. 0 × 1 0 9/ L.
6.
O nl y f or P art A a n d P art B: availa 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 bly 2 5) u n stai ne d t u m or sli des 
fr o m a rece ntl y o btai ne d ( wit hi n 6 m o nt hs bef ore D 1 ) bi o psy fr o m a n o nirra diate d area.
7.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤ 1. 5 × t he u p per li mit of 
n or mal ra n ge ( U L N), a n A S T le vel ≤ 3 × U L N, a n d a n A L T le vel ≤3 × U L N or, f or 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 6 6
partici pa nts wit h d oc u me nte d metastatic disease t o t he li ver, A S T a n d A L T le vels 
≤5 × U L N. P artici pa nt s wit h d oc u me nte d Gil bert disease are all o we d if t otal bilir u bi n 
is less t ha n 3 × U L N. 
8.
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 ≥ 3 0 m L / mi n 
acc or di n g t o t he C oc kcr oft -Ga ult f or m ula or b y 2 4 -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.
Se x
9.
Are male or fe male
a. Male partici pa nt s:
A gree t o t he f oll o wi n g d uri n g t he i nter ve nti o n peri o d a n d f or at least 9 0 d a y s (a s per mat o ge nesis 
c ycle) after t he last d ose of st u d y  i nter ve nti o n:

Refrai n fr o m d o nati n g s per m
P L U S, eit her:

A bstai n fr o m a n y acti vit y t hat all o ws f or e x p os ure t o ejac ulate
O R

Use a male c o n d o m :
o
W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial 
( W O C B P), w h o is n ot c urre ntl y pre g na nt, a n d a d vise her t o use a hi g hl y 
effecti ve c o ntrace pti ve met h o d wit h a fail ure rate of < 1 % per year, as 
descri be d i n  A p pe n di x 3 , si nce a c o n d o m ma y brea k or lea k.
o
W he n e n ga gi n g i n a n y acti vit y  t hat all o ws f or e x p os ure t o ejac ulate.
b. Fe male partici pa nts :

A re n ot pre g na nt or breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns 
a p plies:
o
N ot a W O C B P, as defi ne d i n A p pe n di x 3
O R
o
If a W O C B P, 
use a hi g hl y  effecti ve c o ntrace pti ve met h o d (i.e., wit h a 
fail ure rate of < 1 % per ye ar), prefera bl y wit h l o w user de pe n de nc y , as 
descri be d i n  A p pe n di x 3 f or t he f oll o wi n g ti me peri o ds:

Bef ore t he first d ose of t he st u d y i nter ve nti o n(s), if usi n g h or m o nal 
c o ntrace pti o n:

Has 
c o m plete d at least o ne 4- wee k 
c ycle of a n oral 
c o ntrace pti o n pill a n d eit her ha d or has be g u n her me nses
O R
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 / 1 6 6

Has use d a de p ot c o ntrace pti ve or e xte n de d-c ycle oral 
c o ntrace pti ve f or least 2 8 d a y s a n d has a d oc u me nte d 
ne gati ve pre g na nc y  test usi n g a hi g hl y se nsiti ve assa y.
A N D

A barrier met h o d, as descri be d i n A p pe n di x 3 .

D uri n g t he i nter ve nti o n peri o d

After t he st u d y inter ve nti o n peri o d (i.e., after t he last d ose of st u d y 
i nter ve nti o n is a d mi nistere d) f or at least 9 0 d a y s after t he last d ose 
of st u d y inter ve nti o n a n d a gree n ot t o d o nate e g gs ( o va, o oc y tes) f or 
re pr o d ucti o n d uri n g t his peri o d.
T he In vest i gat or e val uates t he effecti ve ness of t he c o ntrace pti ve met h o d i n relati o ns hi p t o t he first 
d ose of st u d y  i nter ve nti o n.

Ha ve a ne gati ve ser u m pre g na nc y  test, as re q uire d b y  local re g ulati o ns, wit hi n 
4 wee ks
bef ore t he first d ose of st u d y inter ve nti o n . A d di ti o nal re q uire me nts f or 
pre g na nc y testi n g d uri n g a n d after st u d y  i nter ve nti o n are i n Secti on 8. 2. 5.
T he In vesti gat or re vie ws t he me dical hist or y , me nstr ual hist or y , a n d rece nt se x ual acti vit y to 
decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y u n detecte d pre g na nc y .
1 0. Esti mate d life e x pecta nc y  of at least 3 m o nt hs.
I nf or me d C o nse nt
1 1. Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt, as i n dicate d i n A p pe n di x 2 ( St u d y 
G o ver na nce), w hic h i ncl u des c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d 
i n t he i nf or me d c o nse nt f or m (IC F) a n d t his pr ot oc ol.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y :
Me dic al C o n diti o ns
1.
Persisti n g t o xicit y relate d t o pri or t hera p y of N CI -C T C A E v 5. 0 Gra de > 1; h o we ver, 
al o pecia, se ns or y ne ur o pat h y Gra de ≤ 2, or ot her Gra de ≤ 2 A E s n ot c o nstit uti n g a safety 
ris k base d o n In vesti gat or’ s j u d g me nt are acce pta ble. 
2.
Cli nicall y  
si gnifica nt 
(i.e. acti ve) 
car di o vasc ular 
disease: 
cere bral 
vasc ular 
acci de nt/str o ke ( < 6 m o nt hs pri or t o e nr oll me nt), u nsta ble a n gi na, c o n gesti ve heart 
fail ure (≥ Ne w Y or k Heart Ass ociati o n Classificati o n Class II), or seri o us car diac 
arr h yt h mia re q uiri n g me dicati o n or u nc o ntr olle d c o n d ucti o n a b n or malities i ncl u di n g a 
hist or y  of l o n g Q Tc s yn dr o me [ Q Tc F > 4 8 0 ms] a n d/ or pace ma ker, or m y ocar dial 
i nfarcti o n ( < 6 m o nt hs pri or t o e nr oll me nt) .
3.
Hist or y  of u nc o ntr olle d i ntercurre nt ill ness i ncl u di n g b ut n ot li mite d t o:
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 / 1 6 6
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 %) 
4.
Pre vi o us mali g na nt disease ( ot her t ha n t he i n dicati o n f or t his st u d y) wit hi n t he last 
5 ye ars (exce pt a de q uatel y 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 ye ars pri or t o st u d y  entr y  an d t he partici pa nt 
was 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.
5.
All partici pa nts wit h brai n metastases, e xce pt t h ose meeti n g t he f oll o wi n g criteria:
a. Brai n metastases t ha t ha ve bee n treate d l ocall y a n d are cli nicall y sta ble f or ≥4 wee ks 
pri or t o ra n d o mizati o n
b. N o o n g oi n g ne ur ol o gical s ym pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he 
disease (se q uelae t hat are a c o nse q ue nce of t he treat me nt of t he brai n metastases are 
acce pta ble)
c. Partici pa nts m ust be eit her off ster oi ds or o n a sta ble or decreasi n g d ose of < 1 0 m g  
d ail y pre d nis o ne ( or e q ui vale nt).
6.
Hist or y  of diffic ult y s wall o wi n g, mala bs or pti o n, or ot her c hr o nic gastr oi ntesti nal 
disease or c o n diti o ns t hat m a y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he st u d y 
i nter ve nti o n.
7.
Hist or y  of a n y ot her si g nifica nt me dical disease, s uc h as maj or gastric or s mall b o wel 
s ur ger y, rece nt drai na ge of si g nifica nt v ol u mes of ascites or ple ural eff usi o n, or a 
ps y c hiatric c o n diti o n t hat mi g ht 
i m pair partici pa nt well -bei n g or precl u de f ull 
partici pati o n i n t he st u d y .
8.
Ot her 
se vere ac ute or c hr o nic me dical 
c o n diti o ns i ncl u di n g i m m u ne c olitis, 
i nfla m mat or y bo wel disease, i m m u ne p ne u m o nitis, p ul m o nar y  fi br osis or ps y c hiatric 
c o n diti o ns i ncl u din g rece nt ( wit hi n t he past year) or acti ve s uici dal i deati o n or be ha vi or ; 
or la b orat or y ab n or malities t hat m a y  increase t he ris k ass ociate d wit h st u d y partici pati o n 
or st u d y inter ve nti o n a d mi nistrati o n or m a y  interfere wit h t he i nter pretati o n of st u d y 
res ults a n d, i n t he j u d g me nt of t he I nvesti gat or, w o ul d 
ma ke 
t he partici pa nt 
i na p pr o priate f or e ntr y i nt o t his st u d y.
9.
I n i m m u n ot hera py pretreate d 
partici pa nt s, a n y hist or y of D L Ts
wit h 
pri or 
i m m u n ot hera p y a ge nts, i ncl u di n g G ra de 3/ 4 ir A Es; irre versi ble ir A Es; Gra de ≥3 ir A Es 
t hat di d n ot res p o n d t o ster oi d resc ue; or ne ur ol o gic ir A E wit h si g nifica nt cli nical 
se q uelae.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 / 1 6 6
N ote:
P ote ntial partici pa nts wit h ir A E re q uiri n g h or m o ne re place me nt t hera py (e. g. 
t h yr o xi ne, i ns uli n, or p h ysi ol o gic d ose of c ortic oster oi d re place me nt t hera p y for a dre nal 
or pit uitar y  ins ufficie nc y) are eli gi ble as l o n g as t he e n d ocri n o pat h y is well c o ntr olle d 
a n d t he partici pa nt
is n ot ot her wise s ym pt o matic 
fr o m h or m o ne i ns ufficie nc y. 
P h y si ol o gic c ortic oster oi d d ose is defi ne d as ≤ 1 0 m g dail y o f pre d nis o ne or e q ui vale nt.
1 0. 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 
hist or y  
of 
h u ma n 
i m m u n o deficie nc y 
vir us 
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 i nfecti o n at S cree ni n g ( p ositi ve h e patitis B vir us
s urface a nti ge n or he patitis C vir us R N A if a nti-he patitis C vir us a nti b o d y Scree ni n g 
test p ositi ve). Partici pa nts wit h hist or y  of i nfecti o n m ust ha ve a p ol y m erase c hai n 
reacti o n (P C R ) d oc u me ntati o n t hat i nfecti o n is cleare d.
1 1. Acti ve or hist or y  of 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 ne-sti m ulat or y age nt. Partici pa nts wit h dia betes t ype I, vitili g o, ps oriasis, h y p o- or 
h y pert h y r oi d disease n ot re q uiri n g i m m u n osu p pressi ve treat me nt are eli gi ble.
1 2. A n y  partici pa nt wit h p ossi ble area of o n g oi n g necr osis ( n o n-disease relate d), s uc h as 
acti ve ulcer, n o n heali n g w o u n d, or i nterc urre nt b o ne fract ure t hat m a y  be at ris k of 
dela y e d heali n g d ue t o pr ot oc ol t hera p y.
1 3. K n o w n pri or se vere h y perse nsiti vit y  to a n y of t he i n vesti gati o nal pr o d ucts or a n y 
c o m p o ne nt i n its f or m ulati o ns, i ncl u di n g k n o w n se vere h y perse nsiti vit y  reacti o ns t o 
m o n ocl o nal a nti b o dies ( N CI - C T C A E 5. 0 Gra de ≥ 3).
P art B o nl y:
1 4. I f t he partici pa nt has s ym pt o ms of o n g oi n g es o p ha gitis a n d t he treati n g I n vesti gat or 
esti mates t hat t he ra diati o n pla n ni n g tar get v ol u me ( P T V) will i ncl u de a n y porti o n of 
t he es o p ha g us , t he partici pa nt is n ot eli gi ble u nless a n es o p ha geal e n d osc o p y rules o ut 
t he prese nce of es o p ha gitis.
1 5. T he p artici pa nt will n ot be eli gi ble if m ore t ha n 1 0 % of t he t otal es o p ha g us v ol u me is 
esti mate d t o recei ve m ore t ha n 1 5 G y  (5 0 % of t he prescri be d R T d ose ).
1 6. I f he patic metastatic lesi o n is selecte d t o be irra diate d:

T he n o n -t u m or li ver v ol u me < 7 0 0 m L

C hil d -P u g h sc ore ≥ 8
1 7. If t he partici pa nt has a n ac ute or c hr o nic i nterstitial p ul m o nar y  disease a n d t he treati n g 
I n vesti gat or has selecte d a t h oracic lesi o n t o be irra diate d, t he partici pa nt is n ot eli gi ble.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 6 6
Pri or/ C o nc o mit a nt T her a p y
1 8. Recei ve d: 
a. C he m ot hera p y, h or m o nal a ntica ncer t hera py wit h 
t he e xce pti o n of l utei nizi n g 
h or m o ne -releasi n g h or m o ne a nal o gs, bi ol o gic t hera p y, or a n y ot her a ntica ncer t hera p y 
wit hi n 2 8 da y s of t he first d ose of st u d y inter ve nti o n a d mi nistrati o n ( 6 wee ks f or 
nitr os o ureas or mit o m yci n C). F or partici pa nts wit h ra pi dl y gr o wi n g t u m ors w here t he 
treati n g p h y sicia n ca n n ot wait f or 2 8 da y s or 6 wee ks , i ncl usi o n ma y  ta ke place if t he 
partici pa nt meets all t he ot her eli gi bilit y criteria a n d if t here is n o resi d ual t o xicit y 
relate d t o pre vi o u s treat me nt N CI-C T C A E Gra de > 1.
b. Maj or s ur ger y for a n y reas o n, e xce pt dia g n ostic bi o ps y , wit hi n 4 wee ks of t he st u d y 
i nter ve nti o n a n d/ or if t he partici pa nt has n ot f ull y rec o vere d fr o m t he s ur ger y wit hi n 
4 wee ks of t he st u d y i nter ve nti o n.
c. Treat me nt wit h a li ve atte n uate d vacci ne wit hi n 3 0 da ys of d osi n g.
1 9. Partici pa nts c urre ntl y recei vi n g ( or u na ble t o st o p usi n g pri or t o recei vi n g t he first d ose 
of st u d y  i nter ve nti o n) me dicati o ns or her bal s u p ple me nts k n o w n t o be str o n g i n hi bit ors 
of C Y P 3 A , C Y P 2 C 9, or C Y P 2 C 1 9 ( m ust st o p at least 1 wee k pri or) ; str o n g i n d ucers of 
C Y P 3 A , C Y P 2 C 9 , or C Y P 2 C 1 9 ( m ust st o p at least 3 wee ks pri or) ; or dr u gs mai nl y 
meta b olize d b y  CY P 3 A wit h a narr o w t hera pe utic i n de x ( m ust st o p at least 1 da y  pri or).
2 0. Partici pa nts 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 reas o n w h o 
ca n n ot be ta pere d off t hese dr u gs bef ore start of st u d y inter ve nti o n , wit h t he f oll o wi n g 
e xce pti o ns :
a. Partici pa nts wit h a dre nal i ns ufficie nc y, m a y  co nti n ue c ortic oster oi ds at p h y si ol o gic 
re placeme nt d ose, e q ui vale nt t o ≤ 1 0 m g pre d nis o ne dail y .
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 y s, or t hat t he d ose after 1 4 d a y s 
will be e q ui vale nt t o ≤ 1 0 m g pre d nis o ne dail y.
2 1. 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.
2 2. P art B o nl y: p ri or R T t o t he sa me re gi o n as i nte n de d t o be irra diate d i n t his st u d y wit hi n 
t he past 1 2 m o nt hs.
2 3. P art B o nl y: exte nsi ve pri or R T o n ≥ 3 0 % of b o ne marr o w reser ve as j u d ge d b y  th e 
In vesti gat or or pri or b o ne marr o w/ste m cell tra ns pla ntati o n wit hi n 5 y ears bef ore st u d y 
start.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 6 6
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 4. Partici pati o n i n a n y cli nical st u d y wit hi n 1 m o nt h or 5 half -li ves pri or t o S cree ni n g or 
d uri n g partici pati o n i n t hi s st u d y.
Di a g n ostic Assess me nts
2 5. O x y ge n sat urati o n < 9 0 % at rest, k n o w n p ul m o nar y  fi br osis, or acti ve/ hist or y of 
i nterstitial l u n g disease or p ne u m o nitis.
Ot her E xcl usi o ns
2 6. Pre g na nc y  or lactati o n.
2 7. Le gal i nca pacit y or li mite d le gal ca pacit y.
2 8. K n o w n alc o h ol or dr u g a b use as dee me d b y  t he I n vesti gat or.
2 9. A n y  ot her c o n diti o n or circ u msta nce t hat w o ul d, i n t he o pi ni o n of t he In vesti gat or, ma ke 
t he partici pa nt u ns uita ble f or partici pati o n i n t he st u d y .
5. 3
Lifest yle C o nsi der ati o ns
N o s pecific lifest yl e or dietar y restricti o ns are re q uire d t hr o u g h o ut t he st u d y.
5. 3. 1
Me als a n d Diet ar y Restricti o ns
Partici pa nts will be i nstr ucte d t o refrai n fr o m c o ns u m pti o n of re d wi ne, Se ville ora n ges, gra pefr uit 
or gra pefr uit j uice, (p o mel os, e x otic citr us fr uits, gra pefr uit h y bri ds, or fr uit j uices) fr o m 7 da ys 
bef ore t he start of st u d y i nter ve nti o n u ntil after t he fi nal d ose.
F o o d c o n diti o ns d uri n g M 3 8 1 4 
a d mi nistrati o n are prese nte d i n Secti o n 6. 6. 5. 1 ( f or Part A) , 
Secti o n 6. 6. 5. 2 (f or Part B) a n d Secti o n 6. 6. 5. 3 (f or Part F E).
See als o Secti o n 6. 8 .
5. 3. 2
C affei ne, Alc o h ol, a n d T o b acc o
N o s pecific restricti o ns o n caffei ne, alc o h ol or t o bacc o use a p ply d uri n g t he st u d y.
5. 3. 3
Acti vit y
N ot a p plica ble.
5. 4
Scree n F ail ures
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) m a y  be 
rescree ne d f or he mat ol o g y  an d c he mistr y para meters . Rescree ne d partici pa nts will be assi g ne d a 
ne w partici pa nt n u m ber.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 6 6
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u d y prot oc ol.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 6 6
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
T a ble 1 1
A d mi nistr ati o n of St u d y I nter ve nti o n(s)
St u d y  I nt er v e nti o n N a m e:
M 3 8 1 4
A v el u m a b
R a di ot h er a p y ( P art B o nly)
D o s e F or m ul ati o n:
 
 
E a c h si n gl e -u s e vi al c o nt ai n s
2 0 0 m g of a v el u m a b a s a
pr e s er v ati v e -fr e e 
a c et at e -b uff er e d s ol uti o n
( p H 5. 2) c o nt ai ni n g m a n nit ol, 
a n d p ol y s or b at e 2 0 ( T w e e n 2 0). 
F or a d mi ni str ati o n, a v el u m a b 
dr u g c o n c e ntr at e m u st b e 
dil ut e d wit h 0. 9 % s ali n e s ol uti o n 
( s o di u m c hl ori d e f or i nj e cti o n) 
s u p pli e d i n a n i nf u si o n b a g; 
alt er n ati v el y, a 0. 4 5 % s ali n e 
s ol uti o n c a n b e u s e d if n e e d e d.
I n t h e pl a n ni n g of R T, I M R T
m u st b e u s e d. T h e d o s e 
pl a n ni n g c a n b e C T or P E T- C T 
a c c or di n g t o i n stit uti o n al 
g ui d eli n e s.
T h e u s e of d ail y I G R T i s 
r e c o m m e n d e d. D et ail s o n 
t e c h ni c al f a ct or s t o c o n si d er 
i n cl u di n g I M R T tr e at m e nt 
pl a n ni n g will b e pr o vi d e d i n 
A p p e n di x  8.
U nit D o s e 
Str e n gt h s / D o s a g e L e v el s:
P art A a n d P art F E : A 5 0 m g t a bl et f or or al 
a d mi ni str ati o n i s u s e d d uri n g t h e tr e at m e nt p h a s e. T h e 
st arti n g d o s e will b e 1 0 0 m g BI D. S u b s e q u e nt d o s e s a n d 
s c h e d ul e s will b e d et er mi n e d :
- 
In P art A : b y t h e S M C.
-
I n P art F E: b y t h e S p o n s or b a s e d o n P K a n d 
s af et y d at a g e n er at e d i n pr e vi o u s c o h ort s of 
P art A a n d P art F E a n d will b e wit hi n t h e r a n g e 
of d o s e s d et er mi n e d a s s af e i n P art A .
P art B: A 5 0 m g t a bl et f or or al a d mi ni str ati o n i s u s e d 
d uri n g t h e tr e at m e nt p h a s e. T h e st arti n g d o s e of M 3 8 1 4 
i n t h e fir st c o h ort of p arti ci p a nt s i s e x p e ct e d t o b e 1 0 0 m g 
t ot al Q D . H o w e v er, t hi s st arti n g d o s e mi g ht b e a dj u st e d 
b y t h e S M C b a s e d o n s af et y, P K, a n d P d d at a g e n er at e d 
d uri n g t h e fir st d o s e l e v el i n P art A a n d/ or e m er gi n g d at a 
fr o m t h e o n g oi n g cli ni c al st u di e s i n v ol vi n g M 3 8 1 4. M 3 8 1 4 
will b e gi v e n st arti n g D a y 1 f or 5 d a y s/ w e e k f or 2 w e e k s. 
S u b s e q u e nt d o s e s a n d s c h e d ul e s will b e d et er mi n e d b y 
t h e S M C.
P art A a n d P art F E : Q 2 W
a s a 
fi x e d d o s e of 8 0 0 m g i n all d o s e 
l e v el s.
P art B: Q 2 W a s a fi x e d d o s e of 
8 0 0 m g i n all d o s e l e v el s .
R T f or s i n gl e a n at o mi c sit e: 
3 G y p er fr a cti o n p er d a y f or 
5 d a y s a w e e k t o a t ot al d o s e 
of 3 0 G y, st arti n g o n D a y 1 wit h 
M 3 8 1 4.
M ulti sit e R T
( up t o 3 a n at o mi c 
sit e s) : 3 G y p er fr a cti o n p er d a y 
p er sit e f or 5 d a y s a w e e k t o a 
t ot al d o s e of 3 0 G y, st arti n g o n 
D a y 1 wit h M 3 8 1 4.
All sit e s ( u p t o 3) s el e ct e d b y 
t h e I n v e sti g at or s h o ul d b e 
irr a di at e d o n t h e s a m e d a y. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 6 6
St u d y  I nt er v e nti o n N a m e:
M 3 8 1 4
A v el u m a b
R a di ot h er a p y ( P art B o nly)
R o ut e of A d mi ni str ati o n:
Or al
I ntr a v e n o u s i nf u si o n o v er 1 
h o ur .
D o si n g I n str u cti o n s:
S e e S e cti o n 6. 6. 5 .
S u p pli er/ M a n uf a ct ur er:
M 3 8 1 4 i s s u p pli e d b y t h e S p o n s or a n d p a c k a g e d, 
l a b el e d, a n d di stri b ut e d f or cli ni c al st u di e s b y a s uit a bl e 
s er vi c e pr o vi d er a n d fi n all y r el e a s e d b y a S p o n s or 
q u alifi e d p er s o n u n d er G o o d M a n uf a ct uri n g Pr a cti c e 
c o n diti o n s.
A v el u m a b will b e s u p pli e d b y t h e 
S p o n s or a n d p a c k a g e d, l a b el e d, 
a n d di stri b ut e d f or cli ni c al 
st u di e s b y a s uit a bl e s er vi c e 
pr o vi d er a n d fi n all y r el e a s e d b y 
a S p o n s or q u alifi e d p er s o n 
u n d er G o o d M a n uf a ct uri n g 
Pr a cti c e c o n diti o n s.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BI D =t wi c e d ail y, C T = c o m p ut e d t o m o gr a p h y, I G R T =i m a g e g ui d e d r a di ot h er a p y, I M P =i n v e sti g ati o n al m e di ci n al pr o d u ct, I M R T =i nt e n sit y- m o d ul at e d r a di ot h er a p y, 
P d = p h ar m a c o d y n a mi c, P E T - C T = p o sitr o n e mi s si o n t o m o gr a p h y-c o m p ut e d t o m o gr a p h y , P K = p h ar m a c o ki n eti c, P V A = p ol y vi n al al c o h ol, Q 2 W = o n c e e v er y 2 w e e k s, 
Q D = o n c e d ail y, R T = r a di ot h er a p y, S M C = s af et y m o nit ori n g c o m mitt e e.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 6 6
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he In vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(i. e., recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).

U p o n recei pt of t he st u d y inter ve nti o n(s), t he In vesti gat or or desi g nee m ust c o nfir m a ppr o priate 
te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g tra nsit a n d a ny discre pa ncies are re p orte d 
a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y . F urt her 
g ui da nce a n d i nf or mati o n f or st u d y inter ve nti o n acc o u ntabilit y  are pr o vi de d i n t he St u d y 
Refere nce Ma n ual.

O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter ve nti o n(s) a n d o nl y  aut h orize d 
site staff ma y  su p pl y it.
All 
st u d y inter ve nti o n(s) m ust 
be st ore d i n a sec ure, 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns, a n d wit h access li mite d t o t he In vesti gat or a n d a ut h orize d site staff.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y for ms s o t hat acc urate rec or ds 
wi ll be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:

C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  pr o vi de d f or t he cli nical st u dy a n d pre pare d at t he site.

T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.

T he 
dis p ositi o n 
(i ncl u di n g ret ur n, if a p plica ble) of 
a n y 
u n use d 
st u d y 
i nter ve nti o n(s).

Dates, q ua ntities, batc h n u m bers, c o ntai ner n u m bers 
 
e x pir y dates, f or m ulati o n, a n d t he partici pa nt n u m bers.

T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uatel y d oc u me nts t hat partici pa nts were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d were f ull y 
rec o ncile d.

U n use d st u d y inter ve nti o n(s) m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he 
prese nt st u d y . N o st u d y i nter ve nti o n t hat is dis pe nse d t o a partici pa nt ma y be re-dis pe nse d t o a 
differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y  c ollect t he st u d y i nter ve nti o n(s) acc o u nta bilit y f or ms.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y inter ve nti o n(s) are 
pr o vi de d i n t he St u d y  Refere nce Ma n ual.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 6 6
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
O nce a vaila ble, a n I nteracti ve V oice Res p o nse S y ste m will be e m pl o ye d t o assi g n st u d y 
i nter ve nti o n t o partici pa nts a n d facilitate res u p pl y of st u d y i nter ve nti o n at st u d y sites.
6. 3. 2
Bli n di n g
N ot a p plica ble.
6. 4
St u d y I nter ve nti o n C o m pli a nce
I n t his st u d y, partici pa nts will recei ve a vel u ma b a n d R T at t he i n vesti gati o nal site. M 3 8 1 4 will be 
ta ke n at h o me b y  the partici pa nt i n Part A a n d Part F E e xce pt f or d a y s wit h sc he d ule d P K c ollecti o n 
visits. M 3 8 1 4 will be ta ke n at t he i n vesti gati o nal site i n Part B. Well -trai ne d me dical staff will 
m o nit or a n d perf or m t he st u d y i nter ve nti o n a d mi nistrati o n. T he i nf or mati o n of eac h st u d y 
i nter ve nti o n a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d ose of st u d y i nter ve nti o n will be 
rec or de d o n t he electr o nic Case Re p ort F or m (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 st u d y inter ve nti o n a d mi nistrati o n is acc urate f or eac h 
partici pa nt. A n y reas 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 nc o m plia nce is defi ne d as a partici pa nt missi n g:

M ore t ha n 8 d oses of M 3 8 1 4 d uri n g t he D L T peri o d i n Part A, a n d t he F E Assess me nt P eri o d 
i n Part F E

T w o d oses of M 3 8 1 4 a n d R T d uri n g t he D L T peri o d i n Part B, 

F o ur wee ks of st u d y  i nter ve nti o n be yo n d t he D L T peri o d i n eit her Part A or Part B , or b e y o n d 
t he F E Assess me nt P eri o d i n Part F E .
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he eC R F all c o nc o mita nt t hera pies (e g. me dici nes or n o n dr u g i nter ve nti o ns) use d fr o m 
t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g a n y 
c ha n ges. F or prescri pti o n a n d o ver -t he-c o u nter me dici nes, 
vacci nes, vita mi ns, a n d her bal 
s u p ple me nts, rec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he st u d y an 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.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 6 6
6. 5. 1
Resc ue Me dici ne
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 nf usi o n -relate d reacti o ns. 
If h y perse nsiti vit y  reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical 
practice. Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y dela y e d reacti o ns t o t he 
I n vesti gat or i m me diately. I n a d diti o n, all h yperse nsiti vit y  reacti o ns are t o be re p orte d i n a ti mel y 
ma n ner.
6. 5. 2
Per mitte d Me dici nes
T he o nl y  per mitte d me dicati o ns are t he f oll o wi n g:

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 st u d y 
pr ot oc ol) t hat are c o nsi dere d necessar y  for t he partici pa nts’ welfare a n d will n ot i nterfere wit h 
t he st u d y me dicati o n ma y be gi ve n at t he I n vesti gat or’s discreti o n.

Ot her dr u gs t o be use d f or pr o p h y la xis, treat me nt of h y perse nsiti vit y  reacti 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. 9.

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 ntr o-oc ular, or i n halati o n) a n d a nti-i nfecti o us dr u gs are acce pta ble.

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 n y  me dici nes t hat are c o nsi dere d necessar y  to pr otect t he partici pa nt’s welfare i n e mer ge ncies
ma y  be give n at t he I n vesti gat or’s discreti o n , re gar dless if it res ults i n a pr ot oc ol de viati o n.
6. 5. 3
Pr o hi bite d Me dici nes
Pr o hi bite d me dici nes i ncl u de t h ose liste d i n t he e xcl usi o n criteria ( Secti o n 5. 2 ).

As state d i n Secti o n  5. 2 , c he m ot hera p y, h or m o nal a ntica ncer t hera p y wit h t he e xce pti o n of 
l utei nizi n g h or m o ne -releasi n g h or m o ne a nal o gs, bi ol o gic t hera py, or a n y ot her a ntica ncer 
t hera py wit hi n 2 8 da y s of t he first d ose of st u d y i nter ve nti o n a d mi nistrati o n ( 6 wee ks f or 
nitr os o ureas or mit o m y ci n C). T hese t hera pies are als o pr o hi bite d d uri n g t he treat me nt p eri o d 
(P a rt A, P a rt B, a n d P art F E) a n d u p t o 3 0 da ys after t he e n d of R T ( P a rt B). 

D uri n g t he treat me nt peri o d ( P a rt A, P a rt B, a n d P art F E) a n d u p t o 3 0 da ys after t he e n d of 
R T (P art B ), c he m ot hera p y, e xte nsi ve R T (i n v ol vi n g ≥ 3 0 % of b o ne marr o w) or a n y ot her 
a ntica ncer t hera p y (bi ol o gics or ot her tar gete d t hera py
or i n vesti gati o nal a ge nt) a n d 
a nti ne o plastic ster oi d t hera p y are als o pr o hi bite d.

Use of a n y ot her i n vesti gati o nal treat me nts, or partici pati o n i n a n y ot her i nter ve nti o nal st u dies,
d uri n g t he e ntire st u d y d urati o n ( P art A , P art B, a n d P art F E ) is n ot per mitte d. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 6 6
F urt her m ore, t he f oll o wi n g treat me nts m ust n ot be a d mi nistere d d uri n g t he st u d y :

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs (i.e. c he m ot hera p y or s yste mic c ortic oster oi ds )
e xce pt: 

W he n 
re q uire d 
f or 
t he 
treat me nt 
of 
ir A Es
or 
i nf usi o n-relate d 
reacti o ns/ h yperse nsiti vit y  

S y ste mic c ortic oster oi ds at p h y si ol o gic d oses ≤ 1 0 m g/ da y  of pre d nis o ne or 
e q ui vale nt

S y ste mic c ortic oster oi ds f or ma na ge me nt of partici pa nts wit h aller g y  t o c o m p ute d 
t o m o gra p hy ( C T ) I V ra di o gra p hic c o ntrast me dia.

A d mi nistrati o n of a li ve vacci ne wit hi n 3 0 da y s of st u d y i nter ve nti o n.

Gr o wt h fact ors (e.g. gra n ul oc y te 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: 
Gr o wt h 
fact ors are all o we d f or treat me nt of st u d y 
i nter ve nti o n-relate d m y el os u p pressi o n a n d f or pr o p h y la xis of re peat m y el os u p pressi o n after 
i nitial occ urre nce.

Her bal re me dies wit h i m m u n osti m ulati n g pr o perties (f or e xa m ple, mistlet oe e xtract) or k n o w n 
t o p ote ntiall y i nterfere wit h maj or or ga n f u ncti o n (f or e xa m ple, h yperici n).

Me dicati o ns or her bal s u p ple me nts k n o w n t o be str o n g i n hi bit ors or i n d ucers of C Y P 3 A , 
C Y P 2 C 9, or C Y P 2 C 1 9 .

Dr u gs mai nl y meta b olize d b y  C Y P 3 A or C Y P 2 C 9 wit h a narr o w t hera pe utic i n de x as j u d ge d 
b y  the I n vesti gat or (a n d after o pti o nal c o ns ultati o n wit h t he S p o ns or; f or details see S pecial 
Preca uti o ns bel o w ; Secti o n 6. 8 ).
T he s ol u bility of M 3 8 1 4 is p H de pe n de nt; t heref ore, a ntaci d dr u gs, H 2 -bl oc ker a n d p r ot o n p u m p 
i n hi bit ors ( P PI) mi g ht affect a bs or pti o n. P PI s s h o ul d be st o p pe d 5 da ys pri or t o t he first treat me nt
a n d a v oi de d d uri n g t he e ntire treat me nt peri o d wit h st u d y inter ve nti o n. A ntaci d dr u gs s h o ul d n ot 
be ta ke n 1 h o ur bef ore st u d y inter ve nti o n a d mi nistrati o n u ntil 2 h o urs after st u d y inter ve nti o n 
a d mi nistrati o n . H 2 bl oc kers ma y  be all o we d b ut s h o ul d be ta ke n at least 2 ho urs after M 3 8 1 4 d ose 
a n d st o p pe d at least 6 h o urs bef ore t h e ne xt d ose of M 3 8 1 4.
A n y  ad diti o nal c o nc o mita nt t hera py t hat bec o mes necessar y  duri n g t he st u d y an 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.
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he st u d y, e. g. 
beca use of A E s, s us pe nsi o n of t he partici pa nt fr o m treat me nt s h o ul d be perf or me d. T he 
re q uire me nt t o disc o nti n ue t he partici pa nt fr o m treat me nt s h o ul d be disc us se d wit h t he S p o ns or. 
I n case of disc o nti n uati o n a n d w here p ossi ble, t he E n d of Treat me nt V isit a n d Safet y  Foll o w - u p 
V isit a n d p h o ne call 3 0 a n d 9 0 d a y s after e n d of treat me nt s h o ul d be perf or me d as per Sc he d ule of 
Acti vities (Ta ble 1 , Ta ble 2 , Ta ble 3 , an d  Ta ble 4 ). F urt her m ore , i n partici pa nts w h o disc o nti n ue 
fr o m st u d y inter ve nti o n pri or t o disease pr o gressi o n t u m or assess me nts s h o ul d c o nti n ue acc or di n g 
t o t he Sc he d ule of Acti vities
u ntil c o nfir me d disease pr o gressi o n or start of a ne w a ntica ncer 
treat me nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 6 6
6. 5. 4
Ot her I nter ve nti o ns
S ur ger y  to a n y t u m or lesi o n f or s ym pt o m ma na ge me nt or t u m or c o ntr ol is per mitte d d uri n g t he 
st u d y i nter ve nti o n acc or di n g t o r ules defi ne d i n Secti o n 6. 6. 7 . F or a ny ot her s ur gical i nter ve nti o ns 
pla n ne d d uri n g t he st u d y, st u d y inter ve nti o n s h o ul d b e dela y e d f or u p t o a ma xi m u m of 4 wee ks 
t o all o w partici pa nt’s rec o ver y.
Palliati ve s h ort c o urse, li mite d fiel d (i.e. ≤ 1 0 fracti o ns a n d ≤ 3 0 % b o ne marr o w i n v ol ve me nt or 
per i nstit uti o nal sta n dar d) R T ma y  be a d mi nistere d at a n y ti me after t he e n d of t he DL T peri o d i n
P art A a n d P art B , a n d after t he F E A ssess me nt P eri o d i n P art F E . H o we ver, d osi n g of M 3 8 1 4 
m ust be s us pe n de d ≥2 4 h o urs pri or t o start of R T a n d m ust n ot be res u me d u ntil ≥2 4 h o urs after 
t he last R T d ose. T he assess me nt of P D will be ma de acc or di n g t o R E CI S T v 1. 1 a n d n ot base d o n 
t he necessity f or palliati ve R T .
Ra di ot hera p y ( P art A , P art B , a n d P art F E) is n ot per mitte d , wit h t he e xce pti o n of palliati ve R T
as descri be d a b o ve .
6. 5. 5
Pre m e dic ati o n f or A vel u m a b
Pre me dicate partici pa nts
wit h a n a nti hista mi ne a n d wit h aceta mi n o p he n pri or t o t he first 
4 i nf usi o ns of a vel u ma b. 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.
6. 6
D ose Selecti o n a n d M o dific ati o n
T his P hase I  o pe n-la bel st u d y c o nsists of 3 parts:

Part A a n d Part B wit h t he pri mar y  objecti ve t o esta blis h t he M T D a n d/ or R P 2 D of M 3 8 1 4
gi ve n res pecti vely , b y  BI D dosi n g i n c o m bi nati o n wit h a vel u ma b a n d b y  QD d osi n g wit h 
a vel u ma b a n d R T .

Part F E wit h t he pri mar y  objecti ve of deter mi ni n g t he F E o n P K of M 3 8 1 4
gi ve n b y  BI D d osi n g
i n c o m bi nati o n wit h a vel u ma b.
T he 3 parts f urt her i n vesti gate t he s af et y, t olera bilit y, P K/ P d a n d preli mi nar y  antit u m or acti vit y
of M 3 8 1 4 i n p artici pa nts wit h a d va nce d s oli d t u m ors ( Part A a n d Part F E ) a n d i n pa rtici pa nts
wit h selecte d a d va nce d s oli d t u m ors ( Part B)
T he criteria f or d ose escalati o n i n Part A a n d Part B are base d o n t he occ urre nce of A E s a n d/ or 
D L Ts d uri n g t he D L T peri o d i n e val ua ble partici pa nts i n eac h c o h ort. T he defi niti o n of a D L T is 
prese nte d i n Secti o n 6. 6. 3 . D ose escalati o n r ules are i n Secti o n 6. 6. 4. I n Part F E, t he d ose 
escalati o n is base d o n P K a n d safet y data ge nerate d i n pre vi o us c o h orts of Part A a n d Part F E a n d 
will be wit hi n t he ra n ge of d oses deter mi ne d as safe i n Part A.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 6 6
6. 6. 1
D ose Selecti o n ( P art A a n d P art B)
P art A:

T he starti n g d ose of M 3 8 1 4 will be 1 0 0 m g BI D. S u bse q ue nt d ose s a n d sc he d ules will be 
deter mi ne d b y t he S M C (see Secti o n 4. 3. 1 f or d ose rati o nale).

A vel u ma b will be a d mi nistere d Q 2 W as a n I V inf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d 
d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n Secti on 6. 5. 5 .
P art B: 

T he starti n g d ose of M 3 8 1 4 i n t he first c o h ort of partici pa nts will be 1 0 0 m g t otal dail y  dose
(i.e. 2-f ol d l o wer t ha n i n Part A) . H o we ver, t his starti n g d ose mi g ht be a dj uste d b y  the S M C 
base d o n safet y, P K a n d P d data ge nerate d d uri n g t he first d ose le vel i n Part A a n d/ or e mer gi n g 
data fr o m t he o n g oi n g cli nical st u dies i n v ol vi n g M 3 8 1 4.

A vel u ma b will be a d mi nistere d Q 2 W as a n I V inf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d 
d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n Secti o n 6. 5. 5.

Ra di ot hera p y:  3 G y per fracti o n per da y f or 5 da ys a wee k t o a t otal d ose of 3 0 G y, starti n g o n 
D a y 1 wit h M 3 8 1 4. 
T he S M C will re vie w t he safet y an d a n y a vaila ble P K/ P d data o n a re g ular basis. D uri n g Part A 
a n d Part B, t he S M C will deci de o n rele va nt D L Ts ( Secti o n 6. 6. 3 ) base d o n pr ot oc ol criteria. T he y
will deci de b y  co nse ns us o n d ose escalati o n or de -escalati o n of M 3 8 1 4, 
or 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 safe d ose (i .e. ma xi m u m a d mi nistere d d ose/ M T D ) 
a n d t he R P 2 D of M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b ( Part A) a n d wit h a vel u ma b a n d R T 
( Part B) .
F or P a rt A o nl y, i n t he e ve nt t hat a n A E w hic h meets t he defi niti o n of D L Ts as defi ne d per t he 
pr ot oc ol occ ur i n Part F E , after a hi g her d ose le vel has bee n o pe ne d i n Part A, t he data will be 
re vie we d b y  the S p o ns or a n d t he S M C t o deter mi ne t he best c o urse of acti o ns f or c urre ntl y 
e nr olli n g partici pa nts at t he hi g hest d ose le vel.
T he D L T peri o d is c o nsi dere d c o m plete d, a n d a partici pa nt e val ua ble f or d ose escalati o n decisi o ns, 
w he n t he mi ni m u m safet y  eval uati o ns ha ve bee n perf or me d ( he mat ol o g y, c he mistr y, a n d cli nical 
assess me nts), a n d t he partici pa nt has recei ve d: 

P art A: at least 8 0 % of t he pla n ne d d oses of M 3 8 1 4 (i.e. 3 4 of 4 2 d oses wit h BI D d osi n g 
re gi me n) a n d 1 0 0 % of t he pla n ne d a vel u ma b d oses ( 2 a d mi nistrati o ns) d uri n g t he D L T
assess me nt peri o d of 3 wee ks.

P art B: at least 8 0 % of t he pla ne d d oses of M 3 8 1 4 (i.e. 8 of 1 0 d oses wit h Q D d osi n g re gi me n), 
a n d R T ( 8 of 1 0 fracti o ns of 3 G y  eac h) a n d 1 0 0 % of t he pla n ne d a vel u ma b d oses 
( 3 a d mi nistrati o ns) d uri n g t he D L T assess me nt peri o d of 4 wee ks .
6. 6. 2
D ose Selecti o n ( P art F E)
T he starti n g d ose of M 3 8 1 4 w o ul d be 2 0 0 m g  t otal dail y dose gi ve n as 1 0 0 m g BI D . S u bse q ue nt 
d ose s a n d sc he d ules will be deter mi ne d b ase d o n t he P K a n d safet y data ge nerate d i n pre vi o us 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 6 6
c o h orts of Part A a n d Part F E a n d s h o ul d be wit hi n t he d ose ra n ges alrea d y declare d safe a n d 
t olera ble i n Part A. A vel u ma b will be a d mi nistere d Q 2 W as a n I V inf usi o n o ver 1 h o ur, starti n g 
o n D a y 1, at a fi xe d d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n 
Sect i o n 6. 5. 5 .
T he F E Assess me nt P eri o d is c o nsi dere d c o m plete d a n d a partici pa nt e val ua ble f or s u bse q ue nt 
d ose le vel decisi o n s, w he n t he P K a n d mi ni m u m safety e val uati o ns ha ve bee n perf or me d 
( he mat ol o g y, c he mistr y, a n d cli nical assess me nts), a n d t he partici pa nt has recei ve d:

at least 8 0 % of t he pla n ne d d oses of M 3 8 1 4 (i .e., 3 4 of 4 2 d oses wit h BI D d osi n g re gi me n) a n d 
1 0 0 % of t he pla n ne d a vel uma b d oses ( 2 a d mi nistrati o ns) d uri n g t he F E A ssess me nt P eri o d of 
3 wee ks.
T he res ults fr o m Part F E will be re vie we d a n d e val uate d b y  t he S p o ns or a n d if dee me d necessar y 
b y  t he S M C t o deter mi ne a p ote ntial i m pact o n t he st u d y dosi n g rec o m me n dati o ns f or M 3 8 1 4
a n d/ or safety pr ofile of M 3 8 1 4 w he n gi ve n i n c o m bi nati o n wit h a vel u ma b.
C o h orts of at least 3 partici pa nts eac h will be treate d at t he sa me d ose le vel of M 3 8 1 4 (starti n g 
d ose: 1 0 0 m g ta blet f or m ulati o n, BI D) i n c o m bi nati o n wit h a vel u ma b. O n t he d a y  of a vel u ma b 
a d mi nistrati o n, M 3 8 1 4 ca n be gi ve n pri or t o t he start or j ust after t he e n d of a vel u ma b i nf usi o n. 
A preselecte d set of acce pta ble d oses as descri be d in Ta ble 1 2 , will be c o nsi dere d o nce declare d 
as safe a n d t olera ble i n Part A, h o we ver, d oses w hic h are n ot part of t he pres pecifie d set m a y  b e 
c h ose n as well, as l o n g as t he y are wit hi n t he pres pecifie d d ose ra n ges base d o n c o nsi derati o ns of 
P K a n d safet y data ge nerate d i n pre vi o us c o h orts . If t he sa m ple size i n Part F E has t o be i ncrease d 
t o acc o m m o date a d diti o nal d ose le vels, a pr ot oc ol a me n d me nt wit h rati o nale will be s u b mitte d 
pri or t o i m ple me ntati o n. T he S p o ns or a n d/ or t he S M C ma y  deci de t o c o nti n ue or st o p t he 
assess me nt of F E i n s u bse q ue nt d ose le vel (s). T his decisi o n will be base d o n P K a n d safet y  data 
ge nerate d i n t he pre vi o us c o h orts i n Part A a n d/ or Part F E a n d/ or e mer gi n g data fr o m t he cli nical 
st u dies w hic h are c urre ntl y eval uati n g t he h u ma n p har mac ol o g y , safety, a n d t olera bilit y of M 3 8 1 4. 
It is a ntici pate d t hat 6 t o 1 2 partici pa nts ( 3 t o 6 partici pa nts at eac h d ose le vel ) ma y be nee de d. 
T a ble 1 2
E x a m ple of P ossi ble D ose 
Le vels of M 3 8 1 4 
i n C o m bi n ati o n wit h 
A vel u m a b i n P art F E 
D o s e L e v el
M 3 8 1 4 
S c h e d ul e
( m g; BI D)
T ot al D ail y  M 3 8 1 4 
D o s e
( m g)
A v el u m a b S c h e d ul e a
A v el u m a b D o s e 
( m g)
- 1b
5 0
1 0 0
Q 2 W
8 0 0
1 c
1 0 0
2 0 0
Q 2 W
8 0 0
2
2 0 0
4 0 0
Q 2 W
8 0 0
BI D =t wi c e d ail y, P K = p h ar m a c o ki n eti c s, Q 2 W = o n c e e v er y 2 w e e k s
D o s e e s c al ati o n will b e b a s e d o n t h e f o o d eff e ct d at a o n P K i n t h e pr e vi o u s c o h ort. A v ail a bl e s af et y d at a o n t h e 
pr e s e n c e/ a b s e n c e of st u d y i nt er v e nti o n -r el at e d cli ni c all y r el e v a nt a d v er s e e v e nt s will al s o b e t a k e n i nt o c o n si d er ati o n.
a 
A v el u m a b will b e a d mi ni st er e d Q 2 W a s a n I V i nf u si o n o v er 1 h o ur, st arti n g o n D a y 1, at a fi x e d d o s e of
8 0 0 m g i n all d o s e
l e v el s.
b
D o s e L e v el -1 c a n b e e v al u at e d u p o n c o n si d er ati o n of p h ar m a c o ki n eti c a n d s af et y d at a.
c
D o s e L e v el 1 i s t h e st arti n g d o s e.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 6 6
6. 6. 3
Defi niti o n of D ose -Li miti n g T o xicit y
P art A a n d P art B: 
A D L T is defi ne d as a n y Gra de ≥ 3 n o n he mat ol o gic A E or a n y Gra de ≥ 4 he mat ol o gic A E 
acc or di n g t o t he N CI -C T C A E v 5. 0, occ urri n g d uri n g t he D L T peri o d ( u p t o 3 wee ks f or Part A 
a n d u p t o 4 wee ks f or Part B) t hat is relate d t o a n y of t he st u d y  i nter ve nti o ns.
A D L T m ust be c o nfir me d b y  t he S M C. 
I n a d diti o n, a D L T is c o nsi dere d:

Gra de 3 t hr o m b oc y t o pe nia wit h me dicall y c o ncer ni n g blee di n g

A n y  fe brile ne utr o pe nia 

A st u d y inter ve nti o n -relate d T E A E t hat i n t he o pi ni o n of t he S M C is of p ote ntial cli nical 
si g nifica nce s uc h t hat f urt her d ose escalati o n w o ul d e x p ose partici pa nts t o u nacce pta ble ris k 

A n y  to xicit y  relate d t o st u d y i nter ve nti o n t hat ca uses t he partici pa nt t o recei ve less t ha n 8 0 % of 
M 3 8 1 4 d uri n g D L T peri o d
( 4 da ys treat me nt i n Part A a n d 2 da ys treat me nt i n Part B)

E vi de nce of st u d y treat me nt-relate d he pat ocell ular i nj ur y for m ore t ha n 3 da y s, s uc h as > 5- f ol d 
ele vati o ns a b o ve t he U L N of A L T or A S T ( C T C A E Gra de 3 or 4) wit h or wit h o ut ele vati o n of 
ser u m t otal bilir u bi n t o > 2 × U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os phatase) or ot her a p pare nt cli nical ca usalit y
T he f oll o wi n g treat me nt-relate d A E s are e xce pti o ns t o t he a b o ve me nti o ne d D L T defi niti o n a n d 
are n ot c o nsi dere d t o be D LTs:
P art A a n d B: 

Ne utr o pe nia of Gra de 4 lasti n g f or ≤ 5 da y s a n d n ot ass ociate d wit h fe ver

Is olate d Gra de 4 ly m p h oc y t o pe nia wit h o ut cli nical c orrelate

A n y  la b orat or y val ue of Gra de ≥ 3 o ut of t he n or mal ra n ge t hat ha ve n o cli nical si g nifica nce, 
a n d t hat res ol ve t o Gra de 2 or less wit h a de q uate ma na ge me nt wit hi n 6 da y s

Gra de 3 a ut oi m m u ne t h yr oi d -relate d t o xicit y t hat cli nicall y res ol ves t o ≤ Gra de 2 wit hi n 6 d a y s 
of i nitiati n g t hera p y

Gra de 3 diarr hea persisti n g ≤3 da y s after me dical ma na ge me nt

Gra de 3 na usea a n d v o miti n g persisti n g ≤3 d a y s wit h a de q uate a n d o pti mal t hera p y

Gra de 3 n o nrec u rre nt s ki n t o xicit y t hat res ol ves t o Gra de ≤ 1 i n less t ha n 1 4 da y s after me dical 
ma na ge me nt (e . g. i m m u n os u p pressa nt treat me nt) has bee n i nitiate d

Tra nsie nt (≤3 d a y s) Gra de 3 fati g ue, l ocal reacti o ns e xcl u di n g s ki n reacti o ns, fl u-li ke 
s ym pt o ms, fe ver, hea dac he, na usea, e mesis t hat res ol ves t o Gra de ≤1 wit h a de q uate treat me nt

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 t hat res ol ve t o Gra de ≤2 wit hi n 6 da y s
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 6 6
F or P art B o nl y:

M uc ositis 
( m uc osal i nfla m mati o n), i ncl u di n g oral m uc ositis (st o matitis) or es o p ha gitis of 
Gra de ≥ 3 lasti n g f or ≤ 4 wee ks after c o m pleti o n of t he st u d y  treat me nts

St o matitis ass ociate d t o xicities (e. g., s wall o wi n g d y sf u ncti o n [ o d yn o p ha gia, d y s p ha gia],
decrease d a p pe tite, or wei g ht l oss d ue t o diffic ult y or pai nf ul s wall o wi n g) of Gra de ≥3 lasti n g 
f or ≤ 4 wee ks after c o m pleti o n of t he st u d y  treat me nts

Ra diati o n der matitis a n d ass ociate d t o xicities of Gra de ≥ 3 lasti n g f or ≤ 4 wee ks after 
c o m pleti o n of t he st u d y treat me nts

F or partici pa nts s ufferi n g fr o m s q ua m o us cell carci n o ma of hea d a n d nec k a n d w h o recei ve R T 
i n t he hea d a n d nec k re gi o n: the d urati o n of fee di n g t u be ( F T) use ( nas o gastric t u be, 
perc uta ne o us e n d osc o pic gastr ost o m y) s h o ul d n ot defi ne t he se verity of t he t o xicit y (e. g., se vere 
s wall o wi n g d y sf u ncti o n, na usea, v o miti n g). A caref ul e val uati o n of t he partici pa nt ’s s ym pt o ms 
b y  the I n vesti gat or at eac h visit is re q uire d i n or der t o i de ntif y partici pa nts w h o are F T 
de pe n de nt (e. g. , partici pa nts w h o ref use/a v o i d s wall o wi n g, etc).
At a n y  ti me d uri n g t he st u d y, t he S M C ma y i de ntif y as a D L T a n y a d verse dr u g reacti o ns ( A D R) 
i n partici pa nts treate d wit h M 3 8 1 4 i n c o m bi nati o n wit h a vel u ma b ( Part A) a n d wit h a vel u ma b a n d 
R T i ncl u di n g i n -fiel d late ra diati o n t o xicities ( Part B).
6. 6. 4
D ose Esc al ati o n R ules
T he criteria f or d ose escalati o n are base d o n t he occ urre nce of A E s a n d/ or D L Ts d uri n g t he D L T 
peri o d i n e val ua ble partici pa nts i n eac h c o h ort. T he D L T assess me nt peri o d of 3 wee ks ( Part A) 
or 4 wee ks ( Part B) after t he start of M 3 8 1 4 treat me nt all o ws a n e val uati o n of ac ute t o xicit y. 
M 3 8 1 4 d ose escalati o n will n ot pr ocee d t o t he ne xt d ose le vel u ntil t he S M C has deci de d t o 
escalate. M ore o ver, R T a n d t he c o m bi nati o n of R T a n d M 3 8 1 4 a n d a vel u ma b ca n als o gi ve rise t o 
later t o xicities, es peciall y ra diati o n t o xicities. A 3 0- d a y a n d 9 0- d a y S afet y Foll o w -u p will be 
perf or me d i n all partici pa nts i n b ot h Parts ( A a n d B) of t he st u d y. O nce a vaila ble, t hese data ,
al o n gsi de wit h e mer gi n g safet y, P K , a n d P d data fr o m t he o n g oi n g cli nical pr ojects i n v ol vi n g 
M 3 8 1 4, 
will
als o g ui de s u bse q ue nt d ose escalati o n a n d t he esta blis h me nt of t he R P 2 D. 
F urt her m ore, R T S afet y F oll o w - u p Visits will be perf or me d i n all partici pa nts i n Part B 1 m o nt h
( S h ort-Ter m R T Safet y F oll o w -u p), 3 m o nt h s ( Mi d-Ter m R T Safet y F oll o w -u p), a n d 1 2 m o nt hs 
( Lo n g -Ter m R T Safet y F oll o w - u p, b y tele p h o ne) after t he last R T treat me nt, t o assess a n y l ate R T 
t o xicit y. T hese
data will be c o nsi dere d i n deter mi ni n g t he safety pr ofile of t he treat me nt 
c o m bi nati o n .
D ose Esc al ati o n P art A ( M 3 8 1 4 + a vel u m a b 8 0 0 m g Q 2 W )
A Ba yesia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose c o ntr ol will be use d t o assist 
t he S M C wit h d ose selecti o n d uri n g t he Part A d ose escalati o n. C o h orts of at least 3 partici pa nts 
eac h will be treate d at t he sa me d ose le vel of M 3 8 1 4 (starti n g d ose: 1 0 0 m g ta blet f or m ulati o n, 
BI D) i n c o m bi nati o n wit h a vel u ma b. O n t he da y of a vel u ma b a d mi nistrati o n, M 3 8 1 4 ca n be gi ve n 
pri or t o t he start or j ust after t he e n d of a vel u ma b i nf usi o n. T he m o del i nc or p orates a vaila ble 
 cli nical data a n d o bser ve d data fr o m eac h c o m plete d c o h ort (a n d data fr o m all 
pre vi o us c o h orts) t o pr o vi de a rec o m me n de d d ose f or t he ne xt c o h ort. A preselecte d set of 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 6 6
acce pta ble d oses are c o nsi dere d b y t he m o del as descri be d in Ta ble 1 3; h o we ver, d oses w hic h are 
n ot part of t he pres pecifie d set ma y  be c h ose n as well , as l o n g as t he y are wit hi n t he pres pecifie d 
d ose ra n ges base d o n c o nsi derati o n s of safet y, P K, a n d P d data ge nerate d i n pre vi o us c o h orts , a n d 
t he m o del . Yet, if t he sa m ple size i n P art A has t o be i ncrease d t o acc om m o date a d diti o nal d ose 
le vels, a pr ot oc ol a me n d me nt wit h rati o nale will be s u b mitte d pri or t o i m ple me ntati o n. M ore o ver, 
t he S M C or t he S p o ns or ma y  deci de t o st o p t he asce n di n g d ose pr ocess as s o o n as t he first d ose 
le vel is declare d safe a n d t olera ble. T his decisi o n will be base d o n safet y, P K a n d/ or P d data 
a vaila ble d uri n g t he first c o h ort a n d/ or e mer gi n g data fr o m t he cli nical st u dies w hic h are c urre ntl y 
e val uati n g t he h u ma n p har mac ol o g y , safet y an d t olera bilit y of M 3 8 1 4. It is a ntici pate d t hat 6 t o 
3 0 partici pa nts ( 3 t o 6 partici pa nts at eac h d ose le vel ) m a y  be nee de d . 
T a ble 1 3
E x a m ple of P ossi ble D ose 
Le vels of M 3 8 1 4 
i n C o m bi n ati o n wit h 
A vel u m a b ( P a rt A)
D o s e L e v el
M 3 8 1 4 
S c h e d ul e
( m g; BI D)
T ot al D ail y  M 3 8 1 4 
D o s e
( m g)
A v el u m a b S c h e d ul e a
A v el u m a b D o s e 
( m g)
- 1b
5 0
1 0 0
Q 2 W
8 0 0
1 c
1 0 0
2 0 0
Q 2 W
8 0 0
2
2 0 0
4 0 0
Q 2 W
8 0 0
3
4 0 0
8 0 0
Q 2 W
8 0 0
4
8 0 0
1 6 0 0
Q 2 W
8 0 0
BI D =t wi c e d ail y, D L T = d o s e -li miti n g t o xi cit y, I V =i ntr a v e n o u s, P d = p h ar m a c o d y n a mi c , P K =p h ar m a c o ki n eti c , 
Q 2 W = o n c e e v er y 2 w e e k s, S M C = S af et y M o nit ori n g C o m mitt e e .
D o s e e s c al ati o n will b e b a s e d o n t h e pr e s e n c e/ a b s e n c e of D L T s a n d st u d y i nt er v e nti o n -r el at e d cli ni c all y r el e v a nt 
a d v er s e e v e nt s d uri n g t h e D L T p eri o d. A v ail a bl e P K a n d P d d at a will al s o b e t a k e n i nt o c o n si d er ati o n.
a 
A v el u m a b will b e a d mi ni st er e d Q 2 W a s a n I V i nf u si o n o v er 1 h o ur, st arti n g o n D a y 1, at a fi x e d d o s e of
8 0 0 m g i n all d o s e l e v el s.
b
D o s e L e v el -1 c a n b e e v al u at e d u p o n d e ci si o n of t h e S M C.
c
D o s e L e v el 1 i s t h e st arti n g d o s e.
D ose Esc al ati o n P art B ( M 3 8 1 4 + r a di ot her a p y + a vel u m a b 8 0 0 m g Q 2 W)
Si milar t o Part A, a se parate Ba yesia n t w o-para meter l o gistic re gressi o n m o del wit h o ver d ose 
c o ntr ol will be use d i n Part B t o assist t he S M C. F oll o wi n g c o m pleti o n of t he first c o h ort (D ose 
le vel 1) i n Part A, partici pa nts wit h selecte d a d va nce d or metastatic will be e nr olle d i n t he first 
c o h ort a n d will recei ve M 3 8 1 4 ta blet f or m ulati o n, Q D, t o be gi ve n 1. 5 h o urs ( ± 3 0 mi n utes) pri or 
t o t he start of R T. O n t he d a y  of a vel u ma b a d mi nistrati o n, M 3 8 1 4 ca n be gi ve n at a n y ti me after 
t he e n d of t he a vel u ma b i nf usi o n. Ass u mi n g t hat t he first starti n g d ose le vel i n Part A is declare d 
safe a n d t olera ble, t he starti n g d ose of M 3 8 1 4 i n t he first c o h ort of partici pa nts will be 1 0 0 m g  
t otal dail y  d ose (i.e. 2-f ol d l o wer t ha n i n Part A). H o we ver, t his starti n g d ose mi g ht be a dj uste d by 
t he S M C, base d o n safet y, P K, a n d P d data ge nerate d d uri n g t he first d ose le vel i n Part A a n d/ or 
e mer gi n g data fr o m t he o n g oi n g cli nical st u dies i n v ol vi n g M 3 8 1 4 a n d R T t ha t ma y  justif y  a n ot her 
starti n g d ose.
Base d o n t he occ urre nce of A E s a n d/ or D L Ts , t he S M C will deci de if t he d ose ca n be escalate d or 
de- escalate d t o t he ne xt d ose le vel. T he m o del will i nc or p orate 
cli nical data 
a n d o bser ve d data fr o m eac h c o m plete d c o h ort t o pr o vi de a rec o m me n de d d ose f or t he ne xt c o h ort. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 6 6
A preselecte d set of acce pta ble d oses are c o nsi dere d b y  the m o del  (Ta b le 1 4 ), h o we ver, d oses 
w hic h are n ot part of t he pres pecifie d set ma y  be c h ose n as well , as l o n g as t he y are wit hi n t he 
pres pecifie d d ose ra n ges base d o n c o nsi derati o n s of safet y, P K, a n d P d data ge nerate d i n pre vi o us 
c o h orts, a n d t he m o del . Yet, if t he sa m ple size i n P art B has t o be i ncrease d t o acc om m o date 
a d diti o nal d ose le vels, a pr ot oc ol a me n d me nt 
wit h rati o nale will 
be s u b mitte d pri or t o 
i m ple me ntati o n. It is a ntici pate d t hat 6 t o 2 4 partici pa nts ( 3 t o 6 partici pa nts at eac h d ose le vel)
ma y  be nee de d.
T a b le 1 4
E x a m ple of P ossi ble D ose 
Le vels of M 3 8 1 4 
i n C o m bi n ati o n wit h 
R a di ot her a p y a n d A vel u m a b ( P art B)
D o s e L e v el
M 3 8 1 4 
S c h e d ul e a
( m g; Q D)
T ot al D ail y  M 3 8 1 4 
D o s e ( m g)
R a di ot h er a p y
S c h e d ul e b
A v el u m a b 
S c h e d ul e c
A v el u m a b 
D o s e ( m g)
- 1d
5 0
5 0
3 0 G y a s 
3 G y × 1 0 ( 5 F/ W )
Q 2 W
8 0 0
1 e
1 0 0
1 0 0
3 0 G y a s 
3 G y × 1 0 ( 5 F/ W )
Q 2 W
8 0 0
2
2 0 0
2 0 0
3 0 G y a s 
3 G y × 1 0 ( 5 F/ W )
Q 2 W
8 0 0
3
3 0 0
3 0 0
3 0 G y a s 
3 G y × 1 0 ( 5 F/ W )
Q 2 W
8 0 0
D L T = d o s e -li miti n g t o xi cit y, F/ W =fr a cti o n s/ w e e k, I V =i ntr a v e n o u s, P d = p h ar m a c o d y n a mi c , P K =p h ar m a c o ki n eti c , 
Q 2 W = o n c e e v er y 2 w e e k s, Q D = o n c e d ail y, R T =r a di ot h er a p y, S M C = S af et y M o nit ori n g C o m mitt e e.
D o s e e s c al ati o n will b e b a s e d o n t h e pr e s e n c e/ a b s e n c e of D L T s a n d st u d y i nt er v e nti o n -r el at e d cli ni c all y r el e v a nt 
a d v er s e e v e nt s d u ri n g t h e D L T p eri o d. A v ail a bl e r el e v a nt s af et y d at a w hi c h o c c ur d uri n g t h e R T S af et y F oll o w -u p at 
1, 3 , a n d 1 2 m o nt h s. A v ail a bl e P K a n d P d d at a will al s o b e t a k e n i nt o c o n si d er ati o n.
a
M 3 8 1 4 will b e a d mi ni st er e d o n c e a d a y f or 5 d a y s f oll o w e d b y 2 d a y s off
f or 1 0 d a y s i n t ot al (i. e. t o t h e s a m e 
s c h e d ul e a s R T).
b
R a di ot h er a p y, 3 0 G y i s d eli v er e d a s 3 G y p er fr a cti o n p er d a y f or 5 d a y s f oll o w e d b y 2 d a y s off f or 1 0 d a y s i n 
t ot al (i.e. t o t h e s a m e s c h e d ul e a s M 3 8 1 4) . 
c 
A v el u m a b will b e a d mi ni st er e d Q 2 W a s a n I V i nf u si o n o v er 1 h o ur, st arti n g o n D a y 1, at a fi x e d d o s e of
8 0 0 m g i n all d o s e l e v el s.
d
D o s e L e v el -1 c a n b e e v al u at e d u p o n d e ci si o n of t h e S M C. 
e
D o s e L e v el 1 i s t h e st arti n g d o s e.
6. 6. 5
D osi n g I nstr ucti o ns
6. 6. 5. 1
P art A ( M 3 8 1 4 + A vel u m a b)
M 3 8 1 4 : A 5 0 m g ta blet f or oral a d mi nistrati o n is use d d uri n g t he treat me nt p hase. T he starti n g 
d ose will be 1 0 0 m g BI D. S u bse q ue nt d oses a n d sc he d ules will be deter mi ne d b y  t he S M C. 
F or M 3 8 1 4 a d mi nistrati o ns, partici pa nts will be i nstr ucte d as f oll o ws:

F or all treat me nt da y s, fast at least 1 h o ur pri or t o M 3 8 1 4 d ose a n d c o nti n ue fasti n g f or at least 
1 h o ur p ost d ose f or b ot h m or ni n g a n d e ve ni n g M 3 8 1 4 d ose.

Ta ke t he prescri be d d ose of M 3 8 1 4 at a p pr o xi matel y  t he sa me ti me eac h da y.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 6 6
O n d a y s wit h sc he d ule d P K c ollecti o n visits, t he m or ni n g d ose s h o ul d n ot be ta ke n u ntil t he 
partici pa nt is a d mitte d t o t he cli nic/ h os pital a n d t he m or ni n g ( pre d ose) P K c ollecti o n has bee n 
c o m plete d.
If a partici pa nt misses ta ki n g a sc he d ule d d ose of M 3 8 1 4, it is acce pta ble t o ta ke t he misse d d ose 
wit hi n a wi n d o w of 5 h o urs. If m ore t ha n 5 h o urs has passe d after t he sc he d ule d d ose ti me, t he 
misse d d ose s h o ul d n ot be ta ke n, a n d t he partici pa nt s h o ul d be i nstr ucte d t o ta ke t he ne xt d ose at 
t he ne xt sc he d ule d ti me. A n y  cha n ge fr o m d osi n g sc he d ule, d ose i nterr u pti o ns, a n d d ose re d ucti o ns 
s h o ul d be rec or de d i n t he e C R F.
O n t he d a y  of a vel u ma b a d mi nistrati o n, M 3 8 1 4 ca n be a d mi nistere d at a n y t i me bef ore or after t he 
e n d of a vel u ma b i nf usi o n at h o me or cli nic e xce pt o n t he d a y s of M 3 8 1 4 P K c ollecti o n w here 
M 3 8 1 4 s h o ul d be o nl y  ta ke n i n cli nic after pre d ose P K sa m ple has bee n c ollecte d.
A vel u m a b: will be a d mi nistere d Q 2 W as a n I V i nf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d 
d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n Secti on 6. 5. 5.
6. 6. 5. 2
P art B ( M 3 8 1 4 + R a di ot her a p y + A vel u m a b)
M 3 8 1 4: 5 0 m g ta blets f or oral a d mi nistrati o n is use d d uri n g t he treat me nt p hase. T he starti n g d ose 
of M 3 8 1 4 i n t he first c o h ort of partici pa nts is e x pecte d t o be 1 0 0 m g t otal dail y  dose , gi ve n Q D
(i.e. 2-f ol d l o wer t ha n i n Part A). H o we ver, t his starti n g d ose mi g ht be a dj uste d b y t he S M C base d 
o n safety, P K , a n d P d data ge nerate d d uri n g t he first d ose le vel i n Part A a n d/ or e mer gi n g data 
fr o m t he o n g oi n g cli nical st u dies i n v ol vi n g M 3 8 1 4.
M 3 8 1 4 will be gi ve n starti n g D a y  1 for 
5 da y s/ wee k f or 2 wee ks.
F or M 3 8 1 4 a d mi nistrati o ns, partici pa nts will be i nstr ucte d as f oll o ws:

F or all treat me nt da y s, fast at least 1 h o ur pri or t o M 3 8 1 4 d ose a n d c o nti n ue fasti n g f or at least 
1 h o ur p ost d ose.

Ta ke t he prescri be d ta blets of M 3 8 1 4 1. 5 h o urs ( ± 3 0 mi n utes) bef ore eac h R T fracti o n is 
starte d.

O n t he da y  of a vel u ma b treat ment ( Da y 1), M 3 8 1 4 ca n be ta ke n at a n y ti me after t he e n d of 
a vel u ma b i nf usi o n as l o n g as t he a b o ve c o n diti o ns are met.

O n d a y s wit h serial P K c ollecti o n ( Da y 1 an d Da y  12), t he m or ni n g d ose s h o ul d n ot be ta ke n 
u ntil t he partici pa nt is a d mitte d t o t he cli nic/ h os pital a n d t he m or ni n g ( pre d ose) P K c ollecti o n 
has bee n c o m plete d.

O n t he da y  of a vel u ma b treat me nt ( Da y 1), M 3 8 1 4 ca n be ta ke n at a n y ti me after t he e n d of 
a vel u ma b i nf usi o n as l o n g as t he a b o ve c o n diti o ns are met.
A vel u m a b: t o be a d mi nistere d Q 2 W as a n I V inf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d 
d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n S ecti on 6. 5. 5.
R a di ot her a p y: 3 G y  per fracti o n per da y for 5 da y s a wee k f or 2 wee ks t o a t otal d ose of 3 0 G y, 
starti n g Da y 1 wit h M 3 8 1 4.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 6 6
M ultisite si m ulta ne o us R T is all o we d:

U p t o 3 pri mar y  a n d/ or metastatic lesi o ns c o ul d be irra diate d

If m ore t ha n o ne lesi o n is selecte d t o be irra diate d, s ym pt o matic or cli nicall y  rele va nt pri mar y 
t u m ors a n d/ or metastases s h o ul d be pri oritize d.

All selecte d lesi o ns s h o ul d be irra diate d t he sa me da y.
6. 6. 5. 3
P art F E
M 3 8 1 4 : A 5 0 m g ta blet f or oral a d mi nistrati o n is use d d uri n g t he treat me nt p hase. T he starti n g 
d ose will be 1 0 0 m g BI D. S u bse q ue nt d ose s a n d sc he d ules will be deter mi ne d base d o n P K a n d 
safety data. 
F or M 3 8 1 4 a d mi nistrati o ns, partici pa nts will be i nstr ucte d as f oll o ws:
O n Da y 1  a n d Day 2 2, partici pa nts will be i nstr ucte d t o fast o ver ni g ht f or at least 8 h o urs f oll o we d 
b y  t he meal pr o vi de d at t he site. M 3 8 1 4 s h o ul d be a d mi nistere d wit hi n 3 0 mi n utes after t he meal. 
T he dr u g s h o ul d be ta ke n wit h a p pr o xi matel y 2 4 0 m L  ( 8 fl ui d o u nces) of water. A d diti o nal water 
is all o we d a d li bit u m e xce pt for 1 h o ur bef ore a n d 1 h o ur after M 3 8 1 4 a d mi nistrati o n. 
O n D a y  15, partici pa nts will be i nstr ucte d t o fast o ver ni g ht f or at least 8 h o urs f oll o we d b y  th e 
M 3 8 1 4 a d mi nistrati o n at t he site. T he dr u g s h o ul d be ta ke n wit h a p pr o xi matel y 2 4 0 m L  (8 fl ui d 
o u nces) of water. A d diti o nal water is all o we d a d li bit u m e xce pt f or 1 h o ur bef ore a n d 1 h o ur after 
M 3 8 1 4 a d mi nistrati o n. Partici pa nts s h o ul d n ot c o ns u me a n y f o o d f or at least 4 h o urs after t he 
M 3 8 1 4 d ose.
C o m p ositi o n of a hi g h -fat diet: 8 0 0 t o 1 0 0 0 cal ories ( pr otei n [ 1 5 0 cal ories], car b o h y drates 
[ 2 5 0 cal ories], fat [ 5 0 0 t o 6 0 0 cal ories]). E x a m ple of hi g h -fat diet: T w o e g gs frie d i n b utter, t w o 
stri ps of bac o n, t w o slices of t oast wit h b utter, f o ur o u nces of has h br o w n p otat oes, ei g ht o u nces 
of w h ole mil k.
O n d a y s wit h sc he d ule d P K c ollecti o n visits, t he m or ni n g d ose s h o ul d n ot be ta ke n u ntil t he 
partici pa nt is a d mitte d t o t he cli nic/ h os pital a n d t he m or ni n g ( pre d ose) P K c ollecti o n has bee n 
c o m plete d.
If a partici pa nt misses ta ki n g a sc he d ule d d ose of M 3 8 1 4, it is acce pta ble t o ta ke t he misse d d ose 
wit hi n a wi n d o w of 5 h o urs. If m ore t ha n 5 h o urs has passe d after t he sc he d ule d d ose ti me, t he 
misse d d ose s h o ul d n ot be ta ke n, a n d t he partici pa nt s h o ul d be i nstr ucte d t o ta ke t he ne xt d ose at 
t he ne xt sc he d ule d ti me. A n y c ha n ge fr o m d osi n g sc he d ule, d ose i nterr u pti o ns, a n d d ose re d ucti o ns 
s h o ul d be rec or de d i n t he e C R F.
O n t he d a y  of a vel u ma b a d mi nistrati o n, M 3 8 1 4 ca n be a d mi nistere d at a n y t i me bef ore or after t he 
e n d of a vel u ma b i nf usi o n. 
A vel u m a b: will be a d mi nistere d Q 2 W as a n I V i nf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d 
d ose of 8 0 0 m g i n all d ose le vels. G ui da nce o n pre me dicati o n is gi ve n i n Secti o n 6. 5. 5.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 6 6
6. 6. 5. 4
P art A , P art B a n d P art F E
F or M 3 8 1 4
a d mi nistrati o ns, partici pa nts will be i nstr ucte d as f oll o ws:

Ta ke t he assi g ne d ta blets of M 3 8 1 4 wit h a f ull glass of water (a p pr o xi matel y 24 0 m L / 8 fl ui d 
o u nces).

S wall o w t he ta blets w h ole a n d n ot bite i nt o t he ta blets, brea k t he m, or atte m pt t o diss ol ve t he 
c o nte nts i n water pri or t o ta ki n g t heir assi g ne d d ose.

If t he partici pa nt v o mits wit hi n 1 h o ur of M 3 8 1 4 d ose , n o f urt her P K sa m pli n g s h o ul d be 
perf or me d. T he p artici pa nt s h o ul d be gi ve n a n a ntie metic, b ut n o f urt her d ose will be gi ve n t hat 
da y . Pr o p h y lactic a ntie metics s h o ul d t he n be gi ve n pri or t o s u bse q ue nt d oses of M 3 8 1 4 . A n y 
c ha n ge fr o m d osi n g sc he d ule, d ose i nterr u pti o ns, or d ose re d ucti o ns s h o ul d be rec or de d i n t he 
e C R F.
Eac h partici pa nt will sta y  on t he a vel u ma b assi g ne d d ose u ntil t he criteria f or disc o nti n uati o n are 
met ( Secti o n 7. 1 ). D osi n g m o dificati o ns (c ha n ges i n i nf usi o n rate a n d d ose dela y s) as a res ult of 
A Es are descri be d i n Secti o n  6. 9. 2. 1 . T here will be n o i ntrapartici pa nt d ose re d ucti o ns f or t o xicity 
reas o ns.
6. 6. 6
Tre at me nt Be y o n d Pr o gressi o n
6. 6. 6. 1
Tre at me nt B e y o n d Initi al P r o gressi o n
Partici pa nts will recei ve a vel u ma b wit h or wit h o ut M 3 8 1 4 i n Part A a n d Part F E a n d a vel u ma b i n 
Part B as o utli ne d i n t he Sc he d ule of Acti vities ( Secti on 1. 3 ) u ntil P D . A vel u ma b wit h or wit h o ut 
M 3 8 1 4 i n Part A a n d Part F E, a n d a vel u ma b i n Part B ma y c o nti n ue past t he i nitial deter mi nati o n 
of P D acc or di n g t o R E CI S T v 1. 1 as l o n g as t he f oll o wi n g criteria are met:

Treat me nt wit h a vel u ma b is o n g oi n g,

N o ne w u nacce pta ble treat me nt or disease -relate d t o xicity,

T olera nce of st u d y i nter ve nti o ns ,

Sta ble E C O G P S ,

Treat me nt b e y o n d pr o gressi o n 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 (f or e xa m ple, ce ntral ner v o us s ys te m metastases).
A ra di o gra p hic assess me nt s h o ul d be perf or me d wit hi n 4 t o 6 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 nti n ue d P D. 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 partici pa nt is cli nicall y
deteri orati n g a n d u nli kel y  t o recei ve a n y be nefit fr o m c o nti n ue d treat me nt wit h a vel u ma b wit h or 
wit h o ut M 3 8 1 4 i n Part A a n d Part F E, a n d a vel u ma b i n Part B.
6. 6. 6. 2
Tre at me nt B e y o n d C o nfir me d P r o gressi o n
Partici pa nts w h o 
e x perie nce P D m a y  co nti n ue treat me nt wit h
st u d y i nter ve nti o ns if t he 
I n vesti gat or belie ves t he partici pa nt will e x perie nce cli nical be nefit fr o m t he treat me nt a n d t here 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 6 6
is n o u nacce pta ble t o xicit y res ulti n g fr o m t he treat me nt. T he decisi o n t o c o nti n ue treat me nt be y o n d 
c o nfir me d P D s h o ul d be disc u sse d wit h t he Me dical M o nit or a n d d oc u me nte d i n t he st u d y rec or ds. 
If t he partici pa nt c o nti n ues wit h treat me nt after c o nfir me d P D, t he y sh o ul d re mai n o n t he st u d y 
a n d c o nti n ue t o recei ve m o nit ori n g acc or di n g t o t he Sc he d ule of Acti vities
( Secti on 1. 3 ). 
Partici pa nts w h o c o nti n ue be y o n d pr o gressi o n will be e val uate d f or f urt her t u m or res p o nse as per 
t he pr ot oc ol sc he d ule.
Treat me nt s h o ul d be disc o nti n ue d per ma ne ntl y u p o n d oc u me ntati o n of f urt her, u ne q ui v ocal, P D 
u nless t here are n o alter nati ve t hera pe utic o pti o ns a n d t he be nefit -ris k assess me nt is fa v ora ble i n 
c o ns ultati o n bet wee n t he I nvesti gat or a n d t he Me dical 
M o nit or. 
I n case of c o nti n uati o n of 
treat me nt b e y o n d P D, treat me nt will be disc o nti n ue d o nce a n y ot her criteria f or wit h dra wal are 
met (see Secti o n  7. 1 ).
6. 6. 7
C o nti n u ati o n of S t u d y Inter ve nti o n A fter L oc al T re at me nt of 
D ise ase P r o gressi o n
If P D is d ue t o brai n metastasis, partici pa nts ma y  co nti n ue st u d y inter ve nti o ns after t he l ocal 
treat me nt of t he brai n lesi o ns wit h res pect t o t he criteria defi ne d i n Secti on 6. 5. 4 a n d pr o vi de d t hat 
t he a b o ve criteria are met i n a d diti o n t o t he f oll o wi n g:

T u m or assess me nt s h o wi n g P D has bee n perf or me d a n d was d oc u me nte d acc or di n g t o 
R E CI S T v 1. 1. pri or t o t he pr oce d ure.

Brai n metastases ha ve bee n treate d l ocall y a n d are cli nicall y  sta ble f or at least 2 wee ks pri or t o 
rei nitiati o n of st u d y i nter ve nti o ns.

T here are n o o n g oi n g ne ur ol o gical s ym pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he 
di sease (se q uelae t hat are a c o nse q ue nce of t he treat me nt of t he brai n metastases are acce pta ble).

Partici pa nts m ust be eit her off ster oi ds or o n a sta ble or decreasi n g d ose of ≤ 1 0 m g dail y 
pre d nis o ne ( or e q ui vale nt).

Be nefit -ris k assess me nt t o c o nti n ue st ud y  i nter ve nti o n is fa v ora ble u n der c o nsi derati o n of a n y 
alter nati ve treat me nt o pti o ns as assesse d b y t he I nvesti gat or.
I n a d diti o n, if P D is mai nl y  d ue t o a metastatic lesi o n w hic h i n t he o pi ni o n of t he I n vesti gat or ma y 
be s ur gicall y re m o ve d, partici pa nts ma y  co nti n ue st u d y inter ve nti o ns after t he l ocal treat me nt of 
s uc h a lesi o n pr o vi de d t hat:

T u m or assess me nt s h o wi n g disease pr o gressi o n has bee n perf or me d a n d was d oc u me nte d 
acc or di n g t o R E CIS T v 1. 1. pri or t o t he pr oce d ure.

It has bee n at least 2 wee ks a nd t he partici pa nt has f ull y  rec o vere d fr o m t he s ur ger y.

Be nefit -ris k assess me nt t o c o nti n ue st u d y i nter ve nti o n is fa v ora ble u n der c o nsi derati o n of a n y 
alter nati ve treat me nt o pti o ns as assesse d b y t he I n vesti gat or.
6. 7
St u d y I nter ve nti o n A fter t he E n d of t he Stu d y
After a partici pa nt has c o m plete d t he st u d y 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 st u d y site’s sta n dar d- of-care a n d ge nerall y 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 6 6
acce pte d me dical practice a n d de pe n di n g o n t he partici pa nt’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 ad diti o nal care t o partici pa nts after t he y lea ve t he st u d y beca use s uc h 
care s h o ul d n ot differ fr o m w hat is n or mall y  ex pecte d f or partici pa nts wit h a d va nce d mali g na ncies.
6. 8
S peci al Prec a uti o ns
A vel u m a b
As a r o uti ne preca uti o n, partici pa nts e nr olle d i n t his st u d y must be o bser ve d f or 1- h o ur p ost 
i nf usi o n f or t he first 4 i nf usi o ns, i n a n area wit h res uscitati o n e q ui p me nt a n d e mer ge nc y age nts. 
At all ti mes d uri n g 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 hy perse nsiti vit y  reacti o n acc or di n g t o 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, f or i nsta nce, de xa met has o ne 1 0 m g a n d 
e pi ne p hri ne i n a 1: 1 0 0 0 dil uti o n or e q ui vale nts s h o ul d al wa ys be a vaila ble al o n g wit h e q ui p me nt 
f or assiste d ve ntilati o n. 
T he treat me nt rec o m me n dati o ns f or i nf usi o n -relate d reacti o ns are o utli ne d i n Secti on 6. 9. 2. 1. 
I n vesti gat ors s h o ul d als o m o nit or partici pa nts cl osel y for p ote ntial ir A Es, w hic h ma y  bec o me 
ma nifest at a n y ti me d uri n g treat me nt. S uc h e ve nts i ncl u de b ut are n ot li mite d t o p ne u m o nitis, 
he patitis, c olitis, e n d ocri n o pat hies ( hy p ot h yr oi dis m, h y pert h y r oi dis m, a dre nal i ns ufficie nc y, a n d 
t ype 1 dia betes mellit us), m y ocar ditis, m y ositis, a n d ras h. See Secti o n 6. 9. 2. 2 for details o n t he 
ma na ge me nt of ir A Es.
I n vesti gat ors s h o ul d als o m o nit or partici pa nts 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 persiste nt ras h, diarr hea a n d 
c olitis, a ut oi m m u ne he p atitis, art hritis, gl o mer ul o ne p hritis, car di o m y o 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 a nti b o dies or a nti ne utr o p hil c yt o plas mic a nti b o dies. See Secti o n 6. 9. 2. 2
f or details o n t he ma na ge me nt of ir A Es.
If a h y perse nsiti vit y reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical 
practice. Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y dela y e d reacti o ns t o t he 
I n vesti gat or i m me diately.
M 3 8 1 4
I n vitr o st u dies s u g gest t hat C Y P 3 A, C Y P 2 C 9, a n d C Y P 2 C 1 9 are i n v ol ve d i n t he meta b olis m of 
M 3 8 1 4. Usi n g p h ysi ol o gicall y  base d P K m o deli n g a n d si m ulati o n, p ote nt i n hi bit ors a n d i n d ucers 
of C Y P 3 A , C Y P 2 C 9, a n d C Y P 2 C 1 9 are pre dicte d t o ha ve a n i nfl ue nce o n t he P K of M 3 8 1 4. 
T heref ore, f o o ds (e. g. gra pefr uit a n d Se ville ora n ges) or c o nc o mita nt me dicati o ns t hat are p ote nt 
i n d ucers or i n hi bit ors of t hese e nz y m es s h o ul d be use d wit h ca uti o n. Partici pa nts will be i nstr ucte d 
t o a v oi d a n y i nta ke of gra pefr uit, gra pefr uit j uice, Se ville ora n ges, Se ville ora n ge mar mala de, or 
ot her pr o d ucts c o ntai ni n g gra pefr uit or Se ville ora n ges wit hi n 7 d a y s bef ore t he first a d mi nistrati o n 
of t he st u d y  i nter ve ntio n a n d d uri n g t he st u d y  i nter ve nti o n a d mi nistrati o n.
T he effect of M 3 8 1 4 o n C Y P 3 A -meta b olize d s u bstrates is c o m ple x d ue t o t he ti me de pe n de nt 
i n hi biti o n a n d i n d ucti o n. It ca n n ot be e xcl u de d t hat at hi g h c o nce ntrati o ns, M 3 8 1 4 affects t he P K 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 6 6
of se nsiti ve C Y P 3 A s u bstrates; t heref ore, se nsiti ve C Y P 3 A s u bstrates wit h a narr o w t hera pe utic 
i n de x s h o ul d als o be use d wit h ca uti o n a n d a v oi de d if p ossi ble, d uri n g treat me nt wit h M 3 8 1 4. 
Dr u gs mai nl y meta b olize d b y  CY P 2 C 9 wit h a narr o w t hera pe utic i n de x are t o be use d wi t h ca uti o n 
a n d if p ossi ble, a v oi de d d uri n g treat me nt wit h M 3 8 1 4.
T he s ol u bilit y of M 3 8 1 4 is p H de pe n de nt; t heref ore, a ntaci d dr u gs a n d pr ot o n p u m p i n hi bit ors 
mi g ht affect a bs or pti o n ( Secti o n  6. 5 ).
Dr u gs w hic h are s u bstrates of P- gl yc o pr otei n ( P-g p ) (e. g. da bi gatra n ete xilate, di g o xi n) , breast 
ca ncer resista nce pr otei n (B C R P ) (e. g. r os u vastati n, s ulfasalazi ne), or o r ga nic cati o n tra nsp orter 1
(O C T 1)
(e. g. metf or mi n) wit h a narr o w t hera pe utic i n de x are t o be use d wit h ca uti o n. T he 
I n vesti gat or m a y  deci de n ot t o i ncl u de a partici pa nt i n t he st u d y, if t he partici pa nt ca n n ot b e 
wit h dra w n fr o m t he dr u gs t hat ha ve a narr o w t hera pe utic i n de x a n d t hat are k n o w n t o be s u bstrates 
of P- g p, B C R P , or O C T 1; if t he I n vesti gat or deci des t o e nr oll a partici pa nt w h o is treate d wit h a 
dr u g t hat is k n o w n t o be s u bstrate of P- g p, B C R P , or O C T 1 a n d has a narr o w t hera pe utic ra n ge, 
cl ose safet y m o nit ori n g is a d vise d.
T he st u d y will be perf or me d i n a st u d y unit wit h direct access t o a H os pital E mer ge nc y  Unit. 
E q ui p me nt a n d me dicati o ns, s uc h as e pi ne p hri ne a n d pre d nis ol o ne e q ui vale nts, will be a vaila ble 
at t he st u d y site f or t he treat me nt of e mer ge ncies.
R a di ot her a p y
Refer t o  A p pe n di x 8 f or details of R T. 
6. 9
M a n a ge me nt of A d verse E ve nts of I nterest
6. 9. 1
A d verse 
Dr u g 
Re acti o ns 
Re q uiri n g 
M 3 8 1 4 
Tre at me nt 
Disc o nti n u ati o n or M o dific ati o ns
P art A a n d P art F E ( M 3 8 1 4 + A vel u m a b )
T here is n o d ose re d ucti o n all o we d f or M 3 8 1 4 or a vel u ma b d uri n g t he D L T peri o d or t he F E 
Assess me nt P eri o d. T he st u d y inter ve nti o n ca n o nl y  be disc o nti n ue d d ue t o t o xicit y. Details o n 
criteria f or disc o nti n uati o n of st u d y  i nter ve nti o ns are i n Secti on 7. 1 .
After t he D L T a n d t he F E Assess me nt P eri o d, if n ot t olerate d, treat me nt wit h M 3 8 1 4 ma y  be 
i nterr u pte d, m o difie d or st o p pe d at t he I n vesti gat or’s discreti o n.
W here a S A E ( Gra de ≥ 3) is belie v e d t o be d ue t o M 3 8 1 4, M 3 8 1 4 will be wit h hel d u ntil t he S A E 
has res ol ve d t o Gra de ≤2. O n s u bse q ue nt cases of t he sa me S A E, per ma ne nt d ose re d ucti o ns i n 
5 0 m g ste ps m ust be d o ne.
I n case of a n o nseri o us A E Gra de 3, assesse d b y  In vesti gat ors as relate d t o M 3 8 1 4, a d ose re d ucti o n 
s h o ul d be c o nsi dere d. 
In t he case of partici pa nts v o mit s wit hi n 1 h o ur of M 3 8 1 4 d ose , please see Secti on 6. 6. 5. 4. 
If M 3 8 1 4 5 0 m g BI D is n ot t olerate d, M 3 8 1 4 will be st o p pe d. A n y c ha n ge fr o m d osi n g sc he d ule, 
d ose i nterr u pti o ns, or d ose re d ucti o ns s h o ul d be rec or de d i n t he e C R F.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 6 6
If a vel u ma b treat me nt is disc o nti n ue d w hile M 3 8 1 4 treat me nt is o n g oi n g, M 3 8 1 4 treat me nt c o ul d
be c o nti n ue d if t he I nvesti gat or belie ves t he partici pa nt is e x perie nci n g cli nical be nefit fr o m 
M 3 8 1 4 treat me nt.
P art B ( M 3 8 1 4 + R a di ot her a p y + A vel u m a b)
T he f or mal criteria f or M 3 8 1 4 a n d R T d ose m o dificati o n are prese nte d i n Ta ble 1 5.
Earl y a n d late t o xicities relate d t o R T a n d/ or M 3 8 1 4 will be ma na ge d acc or di n g t o t he l ocal 
i nstit ute’s g ui deli nes.
T a ble 1 5
D ose M o dific ati o ns f or M 3 8 1 4 a n d R a di ot her a p y D uri n g P art B of t he 
St u d y
T o xi cit y
D o s e M o difi c ati o n s a
M 3 8 1 4
b
R a di ot h er a p y c
T o xi citi e s i n R a di ati o n Fi el d Gr a d e ≥3

M u c o siti s

R a di ati o n d er m atiti s
T e m p or aril y i nt err u pt tr e at m e nt.
R e s u m e tr e at m e nt o n c e s e v erit y
r e s ol v e s t o Gr a d e ≤2 
T e m p or aril y 
i nt err u pt tr e at m e nt. 
R e s u m e tr e at m e nt
o n c e s e v erit y 
r e s ol v e s t o 
Gr a d e ≤2
S y st e mi c T o xi citi e s

H e m at ol o gi c T o xi citi e s: 
-
A n y Gr a d e ≥ 4 t o xi cit y, e x cl u di n g:
o
Gr a d e 4 n e utr o p e ni a l a sti n g f or 
≤ 5 d a y s a n d n ot a s s o ci at e d 
wit h f e v er
o
I s ol at e d Gr a d e 4 
l y m p h o c yt o p e ni a wit h o ut cli ni c al 
c orr el at e

F e bril e n e utr o p e ni a

Gr a d e 3 t hr o m b o c yt o p e ni a wit h m e di c all y 
c o n c er ni n g bl e e di n g 
T e m p or aril y i nt err u pt tr e at m e nt. 
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e.
I n c a s e of a s e c o n d r e c urr e n c e, 
p er m a n e ntl y di s c o nti n u e st u d y 
i nt er v e nti o n.
N o a cti o n t o b e 
t a k e n.
S y st e mi c T o xi citi e s

N o n h e m at ol o gi c T o xi citi e s

A n y Gr a d e ≥ 3 t o xi cit y, e x cl u di n g:

Di arr h e a ( ≤3 d a y s d ur ati o n) f oll o wi n g 
a d e q u at e a n d o pti m al t h er a p y 

N a u s e a a n d v o miti n g ( ≤3 d a y s d ur ati o n) wit h 
a d e q u at e a n d o pti m al t h er a p y

F ati g u e or h e a d a c h e ( ≤7 d a y s d ur ati o n) 
f oll o wi n g i niti ati o n of a d e q u at e s u p p orti v e 
c ar e

A n y ot h er si n gl e l a b or at or y v al u e s o ut si d e of 
t h e n or m al r a n g e t h at h a v e n o cli ni c al 
si g nifi c a n c e, a n d t h at r e s o l v e t o Gr a d e ≤2 
wit h a d e q u at e m e a s ur e s wit hi n 7 d a y s .
T e m p or aril y i nt err u pt tr e at m e nt. 
R e s u m e tr e at m e nt ( at t h e s a m e 
d o s e) o n c e s e v erit y r e s ol v e s t o 
Gr a d e ≤ 1 or B a s eli n e.
I n c a s e of a s e c o n d r e c urr e n c e, 
p er m a n e ntl y di s c o nti n u e st u d y 
i nt er v e nti o n.
I n c a s e of Gr a d e ≥3 li v er 
e n z y m e v al u e s, t h e p arti ci p a nt 
m u st b e m o nit or e d at l e a st e v er y 
4 d a y s u ntil r e c o v er y t o Gr a d e 
≤2. 
N o a cti o n t o b e 
t a k e n.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 6 6
T o xi cit y
D o s e M o difi c ati o n s a
M 3 8 1 4
b
R a di ot h er a p y c

Tr e at m e nt -r el at e d h e p at o c ell ul ar i nj ur y f or m or e 
t h a n 3 d a y s, s u c h a s Gr a d e ≥ 3 A L T or A S T wit h 
or wit h o ut el e v ati o n of s er u m t ot al bilir u bi n t o 
> 2 × U L N, wit h o ut i niti al fi n di n g s of c h ol e st a si s 
( el e vat e d s er u m al k ali n e p h o s p h at a s e) or ot h er 
a p p ar e nt cli ni c al c a u s alit y .
A E = a d v er s e e v e nt, 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; C T C A 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 s, R T =r a di ot h er a p y, U L N = u p p er li mit of n or m al.
S e v erit y of A E s will b e gr a d e d u si n g t h e C T C A E ( v 5. 0) t o xi cit y gr a d e s.
a 
U p o n t h e I n v e sti g at or d e ci si o n a n d o n c e di s c u s s e d wit h t h e S p o n s or.
b
A s all tr e at m e nt s wit h M 3 8 1 4 will b e gi v e n i n c o m bi n ati o n wit h R T, a n i nt err u pti o n i n t h e a d mi ni str ati o n of R T 
w o ul d l e a d t o a n i nt err u pti o n i n tr e at m e nt wit h M 3 8 1 4.
c
A m a xi m u m R T d el a y of u p t o a n d i n cl u di n g 7 d a y s i n t ot al i s all o w e d wit hi n t h e c o m pl et e tr e at m e nt p e ri o d. If 
R T a n d M 3 8 1 4 tr e at m e nt h a v e t o b e d el a y e d b y m or e t h a n 7 d a y s, t h e p arti ci p a nt m u st b e di s c o nti n u e d 
fr o m M 3 8 1 4 ( u nl e s s t h e p arti ci p a nt d eri v e s a cli ni c al b e n efit fr o m t h e st u d y i nt er v e nti o n). 
Wit hi n Part B of t his st u d y , a ma xi m u m dela y of M 3 8 1 4 a n d/ or R T u p t o a n d i ncl u di n g 7 da y s i n 
t otal is all o we d wit hi n t he c o m plete treat me nt peri o d. If R T a n d M 3 8 1 4 treat me nt ha ve t o be 
dela y e d b y m ore t ha n 7 da ys, t he partici pa nt m ust be disc o nti n ue d fr o m st u d y i nter ve nti o n u nless 
t he I n vesti gat or feels t hat t he partici pa nt c o nti n ues t o ac hie ve cli nical be nefit b y  co nti n ui n g 
a vel u ma b acc or di n g t o t he st u d y sc he d ule, i n t his case t he partici pa nt s h o ul d be re place d f or D L T 
assess me nt b ut c o ul d re mai n o n t he st u d y an d c o nti n ue t o recei ve m o nit ori n g acc or di n g t o t he 
Sc he d ule of Acti vities ( Secti o n 1. 3 ).
If 5 0 m g Q D is n ot t olerate d, M 3 8 1 4 will be st o p pe d. A n y c ha n ge fr o m d osi n g sc he d ule, d ose 
i nterr u pti o ns, or d ose re d ucti o ns s h o ul d be rec or de d i n t he e C R F.
6. 9. 2
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
Treat me nt wit h a vel u ma b s h o ul d be per ma ne ntl y disc o nti n ue d, if a n y of t he f oll o wi n g A D Rs 
occ urs:

A n y  Gra de 4 A D Rs: 

Per ma ne ntl y  disc o nti n ue a vel u ma b e xce pt f or 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 y  Gra de 3 A D Rs: 

Wit h h ol d a vel u ma b e xce pt f or 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.

Per ma ne ntl y  disc o nti n ue a vel u ma b if t o xicit y does n ot res ol ve t o Gra de ≤ 1 or 
B aseli ne wit hi n 1 2 wee ks of last a d mi nistrati o n or if t he sa me Gra de 3 t o xicit y 
rec urs (c o nsi der c o ns ult wit h 
t he M e dical M o nit or 
bef ore 
per ma ne ntl y  
disc o nti n ui n g t he treat me nt).
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 6 6
If d osi n g is dela y e d m ore t ha n 4 wee ks, 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. A n y dela y i n d osi n g i n e xcess of 1 2 wee ks is n ot per mitte d.
I nf usi o n-relate d reacti o ns a n d ir A Es s h o ul d be ha n dle d acc or di n g t o g ui deli nes i n Secti on 6. 9. 2. 1 .
6. 9. 2. 1
M a n a ge me nt of I nf usi o n -Rel ate d Re acti o ns
T o miti gate 
i nf usi o n-relate d reacti o ns ass ociate d wit h 
a vel u ma b, partici pa nts ha ve t o b e 
pre me dicate d wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) pri or t o t he first 
4 i nf usi o ns of a vel u ma b. 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 t he prese nce/se verit y  of pri or i nf usi on reacti o ns.
Ma na ge me nt of s y m pt o ms s h o ul d f oll o w t he g ui deli nes s h o w n i n Ta ble 1 6 .
T a ble 1 6
Tre at me nt M o dific ati o n 
f or S y m pt o ms of I nf usi o n-rel ate d Re acti o ns 
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 – mi l 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 at 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 
(f or e x a m pl e, 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.
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 (f or e x a m pl e, 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 p arti ci p a nt.

P arti ci p a nt 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.
6. 9. 2. 2
I m m u ne-Rel ate d A d verse E ve nts
Si nce i n hi biti o n of P D -L 1 sti m ulates t he i m m u ne s yste m, ir A Es ma y occ ur. Treat me nt of ir A Es is 
mai nl y  de pe n de nt u p o n se verit y ( N CI-C T C A E gra de):

Gra de 1 t o 2: treat s y m pt o maticall y  or wit h m o derate d ose ster oi ds, m ore fre q ue nt m o nit ori n g

Gra de 1 t o 2 ( 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 as s h o w n i n Ta ble 1 7. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 6 6
T a ble 1 7  
M a n a ge me nt of I m m u ne- Rel 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
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
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 p arti ci p a nt 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 
Wi t h h ol d 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 ur s:
Tr e at a s Gr a d e 3 or 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; 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 g n 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 I V 
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 ni ti 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
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 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 (f or e x a m pl e, 
a nti hi st a mi n e s, t o pi c al st er oi d s) 
If Gr a d e 2 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 
C o n si d er 0. 5 - 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 en s: 
Tr e at a s Gr a d e 3 t o 4. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 6 6
Gr a d e 3 t o 4
Gr a d e 3: C o v eri n g > 3 0 % b o d y 
s urf a c e ar e a; 
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 
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 
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 
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; 
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).
P ul m o n ar y  ir A E s
Gr a d e of P n e u m o niti 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
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
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 
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 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 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 n g or f or r e c urr e nt Gr a d e 2 : 
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 di 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 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 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 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 
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 
(f or e x a m pl e, 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 buli 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
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
Gr a d e 1 A S T or A L T > U L N t o 
3. 0 × U L N a n d/ or T ot al bilir u bi n > U L N 
t o 1. 5 × 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. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 6 6
Gr a d e 2
A S T or A L T > 3. 0 t o ≤ 5 × U L N a n d/ or 
t ot al bilir u bi n > 1. 5 t o ≤ 3 × 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.
If r et ur n s t o Gr a d e ≤ 1:
R e s u m e r o uti n e m o nit ori n g; r e s u m e 
a v el u m a b t h er a p y.
If el e v ati o n p er si st s > 5 t o 7 d a y s or 
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
A S T or A L T > 5 × U L N a n d/ or t ot al 
bilir u bi n > 3 × 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 
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 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 r et ur n 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 
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 1 gr a m 
( g) 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 
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
Cr e ati ni n e i n cr e a s e 1. 5 × b a s eli n e or 
cr e ati ni n e i n cr e a s e d > U L N t o 
1. 5 × 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 ×
b a s eli n e a n d ≤ 6 x U L N or cr e ati ni n e 
i n cr e a s e d > 1. 5 a n d ≤6 × 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 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.
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 × 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 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.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 6 6
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 
c ar 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 ne- 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 g y 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
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.
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.
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 e . g. E S C or A H A g ui d eli n e s 
A H A g ui d eli n e s w e b sit e: 
E n d o cri n e ir A E s
E n d o cri n e Di s or d er
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 or Gr a d e 2 
e n d o cri n o p at hi e s 
( hy 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 yp e I di a b et e s 
m ellit u s)
C o nti n u e a v el u m a b t h er a p y
E n d o cri n ol o g y c o n s ult if n e e d e d
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 ntit 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 ut 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)
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.
Gl o bal Versi o n I D: C CI
C CI
C CI
P P D
P P D


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 6 6
Gr a d e 3 or Gr a d e 4 
e n d o cri n o p at hi e s 
( hy 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 yp 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 ntit 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 ut 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 t o 
Gr a d e ≤ 1 ( 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 al 
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 h yr o xi n e wit h 
i n a p pr o pri at el y l o w t h yr oi d-
sti m ul ati n g h or m o n e 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 dr e n o c orti c otr o pi c h or m o n e) 

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, 
P R L, 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) 

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 
s y m pt o m s wit h n or m al M RI. 
R e p e at t h e M RI i n 1 m o nt h .

Wi t h h ol d a v el u m a b if m o d er at e, 
s e v er e 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 
c orti c o st er oi d s ( 1 t o 2 m g/ k g/ d a y 
pr e d ni s o n e 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.

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 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 t o 
Gr a d e ≤ 1 ( 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/ C T 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.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 6 6
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 
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 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 A E 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 d i 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
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 ap y
S p e ci alt y c o n s ult
A D L = a cti viti e s of d ail y li vi n g , A H A = A m eri c a n H e art A s s o ci ati o n, 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 B , C T = c o m p ut e d t o m o gr a p h y ,
E S C = E ur o p e a n S o ci et y of C ar di ol o g 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 -li k e 
gr o wt h f a ct or 1 , ir A E =i m m u n e-r el at e d a d v er s e e v e nt, I V =i ntr a v e n o u s, 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 e r 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 s ,
P R L = pr ol a cti n , T 4 =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. 9. 3
R a di ot her a p y
6. 9. 3. 1
M a n a ge me nt of A d verse Dr u g Re acti o ns f or R a di ot her a p y
T o xicities relate d t o R T will be ma na ge d acc or di n g t o t he l ocal i nstit ute’s g ui deli nes. M ore details 
o n t he treat me nt of m ost fre q ue nt ra diati o n A Es are o utli ne d i n A p pe n di x 8 .
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 6 6
7
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n a n d 
P artici p a nt 
Disc o nti n u ati o n/ Wit h d r a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
T he partici pa nt m ust be wit h dra w n fr o m st u d y inter ve nti o n(s) i n t he e ve nt of a n y o f t he f oll o wi n g:

Partici pa nts 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 R E CI S T v 1. 1. 
(N ote: partici pa nts w h o e x perie nce c o nfir me d P D ma y  co nti n ue treat me nt wit h st u d y  dr u gs i n 
t he c o n diti o ns descri be d i n Secti o n 6. 6. 7 ). S uc h partici pa nts will be wit h dra w n fr o m t he 
treat me nt if a n y ot her criteria f or wit h dra wal are met or if alter nati ve treat me nt o pti o ns are 
a vaila ble a n d i n dicate d.

Occ urre nce of a n e xcl usi o n criteri o n w hic h is cli nicall y rele va nt a n d affects t he partici p a nt’s 
safety, if disc o nti n uati o n is c o nsi dere d necessar y  b y 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 t hera pe utic i nter ve nti o n (if a p plica ble, see 
all o wa ble l ocal treat me nt i n Secti o n 6. 5 ).

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w s ym 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.

Occ urre nce of A Es t hat re q uire disc o nti n uati o n of st u d y inter ve nti o n as j u d ge d b y  the 
I n vesti gat or a n d/ or t he partici pa nt (if a p plica ble).

Occ urre nce 
of 
a n y 
cli nicall y 
si g nifica nt a n d 
st u d y-i nter ve nti o n-relate d 
Gra de ≥3 
n o n he mat ol o gic or Gra de ≥ 4 he mat ol o gic A D Rs or as descri be d i n Secti o n 6. 6. 3.

Use of a n o n per mitte d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 5. 3 , w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he st u d y  i nter ve nti o n(s).

Ne w a p pr o ve d t hera p y t hat is c o nsi dere d m ore s uita ble acc or di n g t o t he Pri nci pal I nvesti gat or.

N o nc o m plia nce as defi ne d i n Secti on 6. 4 o nl y  if t he be nefit -ris k assess me nt f or c o nti n uati o n of 
st u d y i nter ve nti o ns is ne gati ve i n t he i n di vi d ual case as per I n vesti gat or j u d g me nt .

Re q uest of t he partici pa nt t o disc o nti n ue st u d y inter ve nti o n . Partici pa nts will be f oll o we d o n 
t he st u d y acc or di n g t o sc he d ule e xce pt i n case of wit h dra wal of c o nse nt.

If t he be nefit -ris k assess me nt f or c o ntin uati o n of treat me nt is ne gati ve acc or di n g t o I n vesti gat or 
assess me nt.

A d verse dr u g reacti o ns t hat ca use R T dela y s of > 7 da ys or disc o nti n uati o n of R T (f or P art B 
o nl y) .

Pre g na nc y .
Partici pa nts w h o c o me off treat me nt m ust be f oll o we d o n st u d y  i ncl u di n g c om pleti o n of all st u d y  
assess me nts, m ost i m p orta ntl y tu m or assess me nts u ntil c o nfir me d disease pr o gressi o n , a n d 
res ol uti o n of t o xicit y or disc o nti n uati o n of t he st u d y.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 6 6
Partici pa nts ma y  b e wit h dra w n fr o m o ne of t he st u d y inter ve nti o ns , e. g. i n case of i nt olera nce or 
t o xicit y clearly attri b uta ble t o a s pecific st u d y i nter ve nti o n. Partici pa nts
w h o are partiall y  
wit h dra w n fr o m o ne of t he st u d y inter ve nti o ns a n d c o nti n ue t o ac hie ve cli nical be nefit ma y 
c o nti n ue wit h t he ot her st u d y inter ve nti o ns acc or di n g t o sc he d ule u ntil t he pr ot oc ol -defi ne d criteria 
f or disc o nti n uati o n fr o m treat me nt are met.
If a vel u ma b treat me nt is disc o nti n ue d w hile M 3 8 1 4 treat me nt is o n g oi n g, M 3 8 1 4 treat me nt c o ul d 
be c o nti n ue d if t he I nvesti gat or belie ves t he partici pa nt is e x perie nci n g cli nical be nefit fr o m 
M 3 8 1 4 treat me nt.
T he Sc he d ule of Acti vities s pecifies t he data t o c ollect at st u d y inter ve nti o n disc o nti n uati o n a n d 
f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be c o m plete d.
7. 1. 1
Rec h alle n ge
Rec halle n ge wit h st u d y inter ve nti o n after disc o nti n uati o n d ue t o A E s is all o we d as defi ne d i n 
Secti o n  6. 9 . 
If partici pa nt s disc o nti n ue t he st u d y inter ve nti o n f or a c o nfir me d C R , o ne rei nitiati o n of st u d y 
i nter ve nti o n is per mitte d. If a partici pa nt d oes rei nitiate, st u d y inter ve nti o n s h o ul d res u me usi n g 
t he sa me treat me nt re gi me n t he partici pa nt was recei vi n g pri or t o disc o nti n uati o n, u nless t he 
In vesti gat or deci des t o rei nitiate a vel u ma b o nl y.
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
Partici pa nts are free t o disc o nti n ue t he st u d y  at a n y ti me wit h o ut gi vi n g t heir reas o ns. 
P art A, P art B, a n d P art F E:

A partici pa nt m a y  wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or m a y  be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safet y, be ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns

At t he ti me of disc o nti n ui n g fr o m t he st u d y, if p ossi ble, a disc o nti n uati o n visit will be 
c o n d ucte d, as liste d i n t he Sc he d ule of Acti vities . T he Sc he d ule of Acti vities s pecifies t he data 
t o c ollect at st u d y disc o nti n uati o n a n d f oll o w-u p, a n d a n y a d diti o nal e val uati o ns t hat nee d t o be 
c o m plete d.

If t he partici pa nt wit h dra ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y data c ollecte d u p 
t o t hat p oi nt ma y still be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gical sa m ples 
c ollecte d will be destr o ye d.

A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr ucti o n of a n y bi ol o gical sa m ples ta ke n. 
T he In vesti gat or m ust d oc u me nt t his i n t he site st u d y  rec or ds.
I n P art B o nl y , partici pa nts m ust be wit h dra w n pri or t o i nitiati o n of st u d y inter ve nti o n i n t he e ve nt 
of eit her of t he f oll o wi n g:

A partici pa nt wit h c o nfir me d es o p ha gitis f or w h o m t he ra diati o n P T V i ncl u des a n y porti o n of 
t he es o p ha g us. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 6 6

A partici pa nt f or w h o m m ore t ha n 1 0 % of t he t otal es o p ha g us v ol u me recei ves m ore t ha n 1 5 G y  
( 5 0 % of t he prescri be d R T d ose), base d o n t he ra diati o n P T V .
If a partici pa nt has faile d t o atte n d sc he d ule d st u d y acti vities, t he I n vesti gat or m ust deter mi ne t he 
reas o ns a n d t he circ u msta nces as c o m pletely a n d acc uratel y as p ossi ble.
I n case of pre mat ure wit h dra wal fr o m t he st u d y, t he i n vesti gati o ns sc he d ule d f or t he E n d of 
Treat me nt V isit s h o ul d be perf or me d, 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 C R F secti o n m ust be c o m plete d.
Partici pa nts s h o ul d be e x plicitl y as ke d 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 nses s h o ul d acc or di n gl y be ca pt ure d i n t he partici pa nt’s s o urce 
data a n d re p orte d i n t he e C R F acc or di n gl y.
Partici pa nts w h o are n ot D L T e val ua ble will n ot f or mall y  be re place d.
7. 3
L ost t o F oll o w U p
A partici pa nt will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule, 
a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y .

Bef ore a partici pa nt is dee me d “l ost t o f oll o w u p”, t he In vesti gat or or desi g nee m ust ma ke e ver y 
eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls; 2) if 
necessar y , se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last k n o w n 
maili n g a d dress , a n d 3) if a partici pa nt has gi ve n t he a p pr o priate c o nse nt, c o ntact t he 
partici pa nt’s ge neral practiti o ner f or i nf or mati o n. T hese c o ntact atte m pts s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d.

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he Sc he d ule of 
Acti vi ties.

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o n cer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y  i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Acti vities , is esse ntial a n d re q uire d f or st u dy c o n d uct.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 6 6

All 
Scree ni n g e val uati o ns m ust 
be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he In vesti gat or will mai ntai n a S cree ni n g l o g t o rec or d 
details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d reas o ns f or 
S cree ni n g fail ure.

Pri or t o perf or mi n g a n y s t u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d in A p pe n di x 2 ( St u d y 
G o ver na nce).

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e.g., bl o o d c o u nt) a n d 
o btai ne d bef ore si g ni n g of t he I C F m a y  be use d f or S cree ni n g or B aseli ne p ur p oses pr o vi de d 
t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me 
defi ne d i n t he Sc he d ule of Acti vities .
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
N o pri mar y  efficac y e n d p oi nts ha ve bee n pla n ne d f or t his st u d y. T he f oll o wi n g sec o n dar y efficac y 
e n d p oi nts will be assesse d: B O R, d urati o n of res p o nse , P F S, a n d O S.
8. 1. 1
Cli nic al A ssess me nts
8. 1. 1. 1
T u m or Res p o nse Assess me nt
C o m p ute d t o m o gra ph y  (C T)/ ma g netic res o na nce i ma gi n g ( M RI) sca ns will be perf or me d a n d 
c ollecte d u ntil c o nfir me d disease pr o gressi o n is assesse d b y  the I n vesti gat ors acc or di n g t o 
R E CI S T v 1. 1 or t he start of ne w ca ncer t hera p y. 
Ra di o gra p hic 
i ma ges a n d p h y sical fi n di n gs ( p hys ical assess me nts) will 
be u se d b y  the 
In vesti gat ors f or t he l ocal deter mi nati o n of disease pr o gressi o n a n d partici pa nt’s treat me nt 
decisi o ns. 
F or eac h partici pa nt, t u m or res p o nse assess me nt will be perf or me d b y C T sca n or M RI (if M RI is 
use d, c hest C T is ma n dat or y ) i ma gi n g of t he c hest/a b d o me n/ pel vis ( pl us ot her re gi o ns as 
s pecifically re q uire d) a n d ot her esta blis he d assess me nts of t u m or b ur de n if C T/ M RI  ima gi n g is 
i ns ufficie nt f or t he i n di vi d ual partici pa nt. All t he sca ns perf or me d at B aseli ne a n d ot her i ma gi n g 
perf or me d as cli nicall y re q uire d ( ot her s u p p orti ve i ma gi n g) nee d t o be re peate d at s u bse q ue nt 
visits. I n ge neral, lesi o ns detecte d at Baseli ne nee d t o be f oll o we d usi n g t he sa me i ma gi n g 
met h o d ol o g y  an d prefera bl y  the 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.
T u m or assess me nts will be perf or me d at Scree ni n g ( u p t o 2 8 d a y s bef ore start of st u d y inter ve nti o n 
treat me nt f or Part A a n d Part F E a n d u p t o 3 5 da ys bef ore start of st u d y i nter ve nti o n treat me nt f or 
Part B ), a n d t he n Q 8W f or
6 m o nt hs. After 6 m o nt hs, t u m or assess me nts will be Q 1 2 W u ntil P D 
or t he e n d of t he st u d y.
F or eac h partici pa nt, t he I n vesti gat or will desi g nate o ne or m ore of t he f oll o wi n g meas ures of 
t u m or stat us t o f oll o w f or deter mi ni n g res p o nse: C T or M RI i ma ges of pri mar y an d/ or metastatic 
t u m or masses, p h y sical e xa mi nati o n fi n di n gs, a n d t he res ults of ot her assess me nts. All a vaila ble 
i ma ges c ollecte d d uri n g t he st u d y peri o d will be c o nsi dere d. T he m ost a p pr o priate meas ures t o 
e val uate t he t u m or stat us of a partici pa nt s h o ul d be use d. T he meas ure(s) t o be c h ose n f or 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 6 6
se q ue ntial e val uati o n d uri n g t he st u d y must c orres p o n d t o t he meas ures use d t o d oc u me nt t he 
pr o gr essi ve t u m or stat us t hat q ualifies t he partici pa nt f or e nr oll me nt. T he t u m or res p o nse 
assess me nt will be assesse d a n d liste d acc or di n g t o t he Sc he d ule of Acti vities (Ta ble 1, Ta ble 2 , 
Ta ble 3 , a n d Ta ble 4 ).
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 v 1. 1 (all meas 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 v 1. 1).
At B aseli ne, t u m or lesi o ns will be cate g orize d i n tar get a n d n o ntar get lesi o ns as descri be d i n 
R E CI S T v 1. 1.
Res ults f or t hese e val uati o ns will be rec or de d wit h as m uc h s pecificity as p ossi ble s o t hat pre - a n d 
p ost -treat me nt res ults will pr o vi de t he best o p p ort u nit y f or e val uati n g t u m or res p o nse. 
A n y  CR or P R or P D s h o ul d be c o nfir me d, prefera bl y  at t he n e xt s u bse q ue nt sc he d ule d i ma gi n g 
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 C R or P R. C o nfir mati o n of 
P R ca n be c o nfir me d at a n assess me nt later t ha n t he ne xt assess me nt after t he i nitial d oc u me ntati o n 
of P R. 
T he I n vesti gat or m a y  perf or m sca ns i n a d diti o n t o a sc he d ule d st u d y s ca n f or me dical reas o ns or 
if t he In vesti gat or s us pects P D. Partici pa nts w h o wit h dra w fr o m t he st u d y i nter ve nti o n f or cli nical 
or s ym pt o matic deteri orati o n bef ore o bjecti ve d oc u me ntati o n of P D or w h o disc o nti n ue fr o m st u d y 
i nter ve nti o n f or reas o ns ot her t ha n o bjecti ve disease pr o gressi o n will be re q ueste d t o c o nti n ue 
a p pr o priate i ma gi n g acc or di n g t o t he st u d y sc he d ule u ntil deter mi nati o n of c o nfir me d P D or 
disc o nti n uati o n of t he st u d y, w h ic he ver occ urs earlier. E ver y  eff ort s h o ul d be ma de t o c o nfir m a 
cli nical dia g n osis of P D b y i ma gi n g.
8. 1. 1. 2
S ur vi v al F oll o w -u p
Partici pa nts wit h o ut P D acc or di n g t o R E CI S T v 1. 1 at t he E n d of Treat me nt Visit will be f oll o we d 
u p f or disease pr o gressi o n ( C T/ M RI sca ns Q 8 W calc ulate d fr o m Da y  1, a n d after 6 m o nt hs Q 1 2 W , 
usi n g t he sa me pr oce d ures a n d re vie w as w hile o n treat me nt) u ntil P D. I n t he case of P D wit h 
disc o nti n uati o n of treat me nt, a n y s u bse q ue nt l ocal t u m or assess me nts s h o ul d be d oc u me nte d. A n y 
s u 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.
At E o T/l o n g -ter m F U, t u m or assess me nt is n ot re q uire d if partici pa nt has pr o gresse d or h as starte d 
a ne w treat me nt.
Partici pa nts 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 a ntit u m or t hera p y). T he s ur vi val f oll o w- u p will c o nti n ue u ntil 1 ye ar after t he last 
partici pa nt recei ves t he last d ose of st u d y inter ve nti o n, or t he last partici pa nt dies, w hic he ver 
occ urs first. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 6 6
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of B aseli ne me dical 
c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, vital si g ns, 
electr ocar di o gra ms ( E C G), a n d la borat or y  tests.
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
In vesti gat or will re p ort a n y A Es, w het her o bser ve d b y  th e I n vesti gat or or re p orte d b y  th e 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n  8. 3. 1 ( Ti me Peri o d a n d Fre q ue nc y  for 
C ollecti n g A E a n d S A E I nf or mati o n). D ue t o t he c o m bi ne d a d mi nistrati o n of treat me nts i n t his 
st u d y, it is i m p orta nt t hat t he In vesti gat or caref ull y re vie w a n d atte m pt t o differe ntiate ca usalit y of 
A Es (f or a vel u ma b or M 3 8 1 4 i n Part A a n d Part F E, a n d f or a vel u ma b or M 3 8 1 4 or R T i n Part B) 
t o e ns ure a p pr o priate t o xicit y treat me nt rec o m me n dati o ns.
Bl o o d sa m ples f or t he tests liste d i n A p pe n di x 6 will be ta ke n fr o m n o nfaste d partici pa nts d uri n g 
t he Scree ni n g peri o d ( Da y - 2 8 t o D a y  -1) f or P art A/ Part F E a n d ( Da y -3 5 t o Da y  -1) f or Part B, 
t he Treat me nt peri o d, t he E o T V isit, a n d at t he 3 0- da y  Safet y F oll o w -u p at t he ti me p oi nts s pecifie d 
i n t he Sc he d ule of Acti vities f or eac h part of t he st u d y (Ta ble 1 , Ta ble 2 , Ta ble 3 , a nd Ta ble 4 ).
8. 2. 1
P h ysic al E x a mi n ati o ns
A c o m plete p h y sical e xa mi nati o n will be c o n d ucte d as i n dicate d i n t he Sc he d ule of Acti vities
( Secti o n 1. 3 ). At ot her visits, eit her a c o m plete p h y sical e xa mi nati o n or s ym pt o m -orie nte d p h y sical 
e xa mi nati o n if dee me d necessar y  by t he I n vestigat or will be c o n d ucte d as i n dicate d i n t he Sc he d ule 
of Acti vities (Secti o n 1. 3 ) 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 be reassesse d
at s u bse q ue nt visits.

A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he hea d/ nec k, 
e xtre mities, e yes, ears, n ose, t hr oat, c o g niti ve stat us, 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. Hei g ht (at Scree n) a n d wei g ht will als o be meas ure d a n d rec or de d.

A brief p h y sical e xa mi nati o n (i.e. a s ym pt o m -orie nte d p h y sical e xa mi nati o n) will i ncl u de, 
at a mi ni m u m, assess me nts of t h ose s yste ms t hat are tail ore d t o t he partici pa nt’s s ym pt o ms .

I n vesti gat ors s h o ul d pa y  special atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses.
I n a d diti o n, after t he Baseli ne visit i n P art B o nl y:

T he p h y sical e xa m will re p ort fi n di n gs i n t he irra diate d area d uri n g all R T F U peri o ds .
8. 2. 2
Vit al Si g ns

Vital si g ns will be meas ure d i n a se mi-s u pi ne p ositi o n after 5 mi n utes rest a n d will i ncl u de 
te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse , res pirat or y rate, a n d p ulse o xi metr y . 
T hree readi n gs of bl o o d press ure a n d p ulse will be ta ke n. T he first rea di n g s h o ul d be rejecte d. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 6 6
T he sec o n d a n d t hir d rea di n gs s h o ul d be a vera ge d t o gi ve t he meas ure me nt t o be rec or de d i n 
t he e C R F.
8. 2. 3
Electr oc ar di o gr a ms
1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he Sc he d ule of Acti vities usi n g a n E C G mac hi ne t hat 
a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, Q T, a n d Fri dericia's C orrecti o n 
F or m ula (Q Tc F) i nter vals. Refer t o Secti o n  7 f or Q Tc F wit h dra wal criteria a n d a n y a d diti o nal 
Q Tc F rea di n gs t hat ma y be necessary. 1 2- lea d E C Gs will be i n tri plicate i n Part A a n d Part F E b ut 
n ot Part B.
F or Part A a n d Part F E, at eac h ti me p oi nt at w hic h tri plicate E C G are re q uire d, 3 i n di vi d ual E C G 
traci n gs s h o ul d be o btai ne d as cl osely as  p ossi ble i n s uccessi o n, b ut n o m ore t ha n 2 mi n utes a part. 
T he f ull set of tri plicates s h o ul d be c o m plete d i n less t ha n 4 mi n utes.
Electr ocar di o gra ms will be rec or de d after t he partici pa nt has bee n i n a s u pi ne p ositi o n breat hi n g 
q uietl y  f or at least 5 mi n utes.
I n P art A a n d P art F E : Assess me nts s h o ul d be perf or me d pre d ose a n d 1, 2, a n d 6 h o urs p ost d ose 
bef ore bl o o d c ollecti o n f or P K, P d, a n d p har mac o ge n o mic sa m pli n g, wit h a tri plicate 1 2- lea d E C G 
bei n g perf or me d first, f oll o we d b y  vital si g ns after t he m or ni n g d ose o nl y. T he sc he d ule ti mes ma y 
be m o difie d base d o n e mer ge nt P K data.
8. 2. 4
Es o p h a ge al E n d osc o p y
I n P art B o nl y : If t he ra diati o n fiel ds i n v ol ve t he es o p ha g us, a n es o p ha geal e n d osc o p y m ust be 
perf or me d at Scree ni n g i n case of acti ve es o p ha gitis or cli nical si g ns of es o p ha gitis.
8. 2. 5
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y  tests liste d in A p pe n di x 6 , at 
t he ti me p oi nts liste d i n t he Sc he d ule of Acti vities .All sa m ples s h o ul d be clearl y ide ntifie d. F urt her 
details will be pr o vi de d i n t he La b orat or y  Ma n ual.
A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d necessar y  by t he 
In vesti gat or or re q uire d b y  l ocal re g ulati o ns.
T he tests will be perf or me d b y  t he l ocal la b orat or y.
T he S p o ns or m ust recei ve a list of t he l ocal la b orat or y n or mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y m ust be f or war de d t o t he S p o ns or.
T he In vesti gat or m ust re vie w eac h la b orat or y re p ort, d oc u me nt t heir re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he eC R F . T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts.
T he m ost rece nt res ults f or c o m plete he mat ol o g y  a n d c ore c he mistr y must be a vaila ble a n d 
re vie we d pri or t o a vel uma b d ose a d mi nistrati o n.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 6 6
I n case of li ver f u ncti o n test ele vati o ns ( A S T, A L T, a n d/ or t otal bilir u bi n) re q uiri n g a d diti o nal 
la b orat or y dra ws (acc or di n g t o g ui deli nes set f ort h in Ta ble 1 7 ), a n u nsc he d ule d la b orat or y dra w 
s h o ul d be se nt t o t he ce ntral la b orat or y f or a nalys is.
Bl o o d sa m ples will be dra w n, pr ocesse d, a n d st ore d i n acc or da nce wit h directi o ns pr o vi de d i n t he 
St u d y  Ma n ual a n d as per ti mi n g s h o w n i n t he Sc he d ules of Assess me nts  (Ta ble 1, Ta ble 2, Ta ble 3, 
a n d Ta ble 4 ).
T he re p ort of t he res ults m ust be retai ne d as a part of t he partici pa nt ’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 safety tests liste d i n A p pe n di x 6 will be ta ke n fr o m 
n o nfaste d partici pa nt s as detaile d i n t he Sc he d ules of Assess me nts  (Ta ble 1 , Ta ble 2, Ta ble 3 , a n d 
Ta ble 4 ). T he free T 4 , T S H, a n d uri nal y sis will o nl y  be assesse d at t he ti me p oi nts defi ne d i n 
Ta ble 1, Ta ble 2 , Ta ble 3 , a n d Ta ble 4 . If c o nfir mati o n of a partici pa nt ’s p ost me n o pa usal stat us is 
necessar y , a f ollicle-sti m ulati n g h or m o ne (F S H ) le vel will als o be perf or me d at S cree ni n g.
F or w o me n of c hil d beari n g p ote ntial, pre g na nc y testi n g (ser u m β -H C G) will be perf or me d d uri n g 
t he Scree ni n g p eri o d a n d pre g na nc y  testi n g ( uri ne β- H C G) at t he visits s pecifie d i n t he Sc he d ule 
of Acti vities ( Secti o n 1. 3 ). Partici pa nts after me n o pa use (a ge-relate d a me n orr hea ≥1 2 c o nsec uti ve 
m o nt hs
a n d a hi g h F S H le vel i n t he p ost me n o pa usal ra n ge m a y  be use d t o c o nfir m a 
p ost me n o pa usal
state i n w o me n n o t usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt 
t hera py. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is 
i ns ufficie nt) or partici pa nts w h o ha ve u n der g o ne h y sterect o my or bilateral o o p h orect o m y are 
e xe m pt fr o m pre g na nc y t esti n g.
If a partici pa nt has a cli nicall y si gnifica 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 an d t he partici pa nt will be f oll o we d u ntil t he test val ue 
has ret ur ne d t o t he n or mal ra n ge or t he I n ve sti 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.
8. 2. 6
Perf or m a nce St at us
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us will be assesse d at Scree ni n g t o assess 
eli gi bilit y (Secti o n 5 ), a n d t he n reassesse d acc or di n g t o t he Sc he d ule of Acti vities
(Ta ble 1,
Ta ble 2, Ta ble 3 , a n d Ta ble 4 ). 
8. 2. 7
S afet y M o nit ori n g C o m mittee
A n S M C will re g ularl y re vie w t he safety data of partici pa nts e nr olle d i n P art A a n d Part B of t his 
st u d y. It will deci de o n rele va nt D L Ts base d o n criteria defi ne d i n t he pr ot oc ol a n d will pr o vi de 
rec o m me n dati o n b y  co nse ns us o n d ose escalati o n, d ose de -escalati o n, or s us pe nsi o n of e nr oll me nt 
a n d/ or declarati o n of t he M T D a n d/ or t he R P 2 D. F u rt her details o n t he S M C ca n be f o u n d i n 
A p pe n di x 2 . Defi niti o ns of D L Ts are pr o vi de d i n Secti o n 6. 6. 3, d ose escalati o ns r ules are 
prese nte d i n Secti o n 6. 6. 4 , a n d a nalys is of D L Ts is descri be d i n Secti on 9. 4. 2 . 
I n a d diti o n, S M C will re vie w t he e ntire P K a n d safety d ata ge nerate d i n Part F E o nce t he last
pla n ne d d ose/ last c o h ort is c o m plete d.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 6 6
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o n s of a n A E a n d a n S A E are in A p pe n di x 4 , as is t he defi niti o n of a n A d verse E ve nt 
of S pecial I nterest ( A E SI).
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y  incl u de d i n 
t he st u d y (date of first si g nat ure of i nf or me d c o nse nt/ date of first si g nat ure of first i nf or me d 
c o nse nt) a n d c o nti n ues u ntil t he last Lo n g -ter m F oll o w - u p Visit.
A n y  S A E assesse d as relate d t o st u d y i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d i n 
A p pe n di x 4 , 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 i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es (i ncl u di n g S A Es) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n A p pe n di x 4 .
8. 3. 2
Met h o d 
of Detecti n g A d verse E ve nts a n d Seri o u s A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as A Es, 
re gar dless if re p orte d by t he partici pa nt 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 eC R F. 
All S A Es a n d all n o nseri o u s A Es of s pecial i nterest m ust be a d diti o nall y doc u me nte d a n d re p orte d 
usi n g t he a p pr o priate Re p ort F or m as s pecifie d i n A p pe n di x 4 .
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y thr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
( Ti me Peri o d a n d Fre q ue nc y  for C ollecti n g A d verse E ve nt a n d S A E I nf or mati o n) a n d are assesse d 
f or t heir o utc o me at t he last L o n g -ter m F oll o w -u p Visi t. All S A Es o n g oi n g at t he last L o n g -ter m 
F oll o w -u p Visit m ust be m o nit ore d a n d f oll o we d u p b y  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 partici pant 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 I nvesti 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. F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is gi ve n in A p pe n di x 4
(A Es : Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w-u p, a n d Re p orts) .
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 6 6
8. 3. 4
Re g ul at or y 
Re p orti n g 
Re q uire me nts 
f or Seri o us A d verse
E ve nts
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.
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 st u d y partici pa nts t o t he I n de pe n de nt Et hics 
C o m mittee (I EC)/ I nstit uti o nal Re vie w B oar d (I RB) t hat a p pr o ve d t he st u d y .
I n acc or da nce wit h I nter nati o nal C ou ncil o n Har m o nisati o n ( I CH ) G o o d Cli nical Practice ( 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 a ffect t he safety 
of partici pa nts, i m pact t he c o n d uct of t he st u d y 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 st u d y. I n li ne wit h res pecti ve re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he 
I n vesti gat or of A Es t hat are b ot h seri o us a n d u ne x pecte d a n d 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 re gar di n g Safet y Re p ort n otificati o ns t o In vesti gat ors will be c o nsi dere d.
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 st u dies c o vere d b y  the 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.
8. 3. 5
Pre g n a nc y
O nl y  pre g nancies t he I n vesti gat or c o nsi ders t o be relate d t o t he st u d y inter ve nti o n (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 met h o d) are 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 8. 3. 1 ( Ti me Peri o d a n d Fre q ue nc y 
f or C ollecti n g A E a n d S A E I nf or mati o n) m ust be rec or de d i n t he A E pa ge/secti o n of t he eC R F f or 
b ot h pre g na ncies i n fe male partici pa nts a n d pre g na ncies i n fe male part ners of male partici pa nts. 
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 p re g na nc y usi n g 
t he Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitte d b y  the sa me pr ocess s pecifie d f or S A E 
re p orti n g i n A p pe n di x 
4 , secti o n o n Re p orti n g S A Es
a n d A Es
of S pecial I nterest a n d 
D ose -Li miti n g T o xicities.
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 partici pa nts are wit h dra w n fr o m t he st u d y .
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 partici pa nt s ustai ns 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 6 6
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 a b n or mal o utc o me (e. g. s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y ) m ust 
be re p orte d i n a n e x pe dite d ma n ner, 
as s pecifie d i n 
Secti o n 8. 3. 1 , w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y.
I n t he e ve nt of a pre g na nc y  in a partici pa nt occ urri n g d uri n g t he st u d y, t he partici pa nt m ust be 
disc o nti n ue d fr o m st u d y inter ve nti o n. T he S p o ns or/ desi g nee m ust be n otifie d wit h o ut dela y  an d 
t he partici pa nt m ust be f oll o we d as i n dicate d a b o ve.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose of a vel u ma b greater t ha n 1 0 % a b o ve t he d ose f or t hat partic ular 
a d mi nistrati o n, a n d/ or a n y d ose of M 3 8 1 4 greater t ha n t hat s pecifie d i n t his cli nical st u d y pr ot oc ol,
will be c o nsi dere d a n o ver d ose.
T here are n o k n o w n s ym pt o ms of a vel u ma b or M 3 8 1 4 o ver d ose t o date. T he In vest i 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 st u d y i nter ve nti o n. E ve n if it n ot 
ass ociate d wit h a n A E or a S A E, a n y o ver d ose is rec or de d i n t he eC R F a n d re p orte d t o dr u g safet y 
i n a n e x pe dite d ma n ner. O ver d oses are re p ort e d o n a S A E Re p ort F or m, f oll o wi n g t he pr oce d ure 
i n A p pe n di x 4 , secti o n o n Re p orti n g S A Es a n d A Es of S pecial I nterest a n d D ose -Li miti n g 
T o xicities.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 6 6
8. 5
P h ar m ac o k i netics
T he f oll o wi n g P K para meters will be calc ulate d, w he n
a p pr o priate, f or M 3 8 1 4 a n d a vel u ma b, 
w here data per mit:
S y m b ol
D efi niti o n
A U C 0-t
A U C fr o m ti m e of d o si n g t o t h e ti m e of t h e l a st o b s er v ati o n
A U C 0- ∞
A U C fr o m ti m e of d o si n g t o i nfi nit y
C m a x
M a xi m u m s er u m ( a v el u m a b) / pl a s m a ( M 3 8 1 4) c o n c e ntr ati o n o b s er v e d p o st d o s e
C mi n
Mi ni m u m s er u m ( a v el u m a b) / pl a s m a ( M 3 8 1 4) c o n c e ntr ati o n o b s er v e d p o st d o s e
C a v g
A v er a g e s er u m ( a v el u m a b) / pl a s m a ( M 3 8 1 4) c o n c e ntr ati o n o b s er v e d p o st d o s e
tm a x
Ti m e t o m a xi m u m c o n c e ntr ati o n o b s er v e d p o st d o s e
t1/ 2
A p p ar e nt eli mi n ati o n h alf -lif e
Λ z
T er mi n al r at e c o n st a nt
C L/f
Or al cl e ar a n c e
V z/f
A p p ar e nt v ol u m e of di stri b uti o n d uri n g t er mi n al p h a s e
R a c c [ A U C]
A c c u m ul ati o n r ati o f or A U C
R a c c [ Cm a x ]
A c c u m ul ati o n r ati o f or C m a x
Fl u ct u ati o n 
i n d e x
Fl u ct u ati o n b et w e e n m a xi m u m a n d mi ni m u m c o n c e ntr ati o n s
F r el, F e d/ F a st e d
R el ati v e bi o a v ail a bilit y of M 3 8 1 4 aft er a br e a kf a st v er s u s aft er a n o v er ni g ht f a st ( o nl y f or P art 
F E )

W h ole bl o o d sa m ples of a p pr o xi matel y 2. 0 m L  will be c ollecte d f or meas ure me nt of plas ma
c o nce ntrati o ns of M 3 8 1 4, as s pecifie d i n t he Sc he d ule of Acti vities ( Secti on 1. 3). T he act ual 
date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.

T he q ua ntificati o n of M 3 8 1 4 
i n plas ma
will 
be perf or me d usi n g a vali date d li q ui d 
c hr o mat o gra p h y/ mass s pectr o metr y assa y. C o nce ntrati o ns will be use d t o e val uate t he P K of 
M 3 8 1 4. 

W h ole bl o o d sa m ples of a p pr o xi matel y 3. 5 m L  will be c ollecte d f or meas ure me nt of ser u m 
c o nce ntrati o ns of a vel u ma b, as s pecifie d i n t he Sc he d ule of Acti vities ( Secti on 1. 3 ). T he act ual 
date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will be rec or de d.

T he q ua ntificati o n of a vel u ma b i n ser u m will be perf or me d usi n g a vali date d i m m u n oassa y. 
C o nce ntrati o ns will be use d t o e val uate t he P K of a vel u ma b. 

Re mai ni n g sa m ples c ollecte d f or a nal ys is of a vel u ma b ser u m co nce ntrati o n ma y  als o be use d 
t o e val uate i m m u n o ge nicit y a n d safety or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or 
after t he st u d y.

Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y  Ma n ual. 
T he S p o ns or will st ore t he sa m ples i n a sec ure st ora ge s pace wit h a de q uate meas ures t o pr otect 
c o nfi de ntialit y. Rete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d of st u d y are 
s pecifie d i n t he res pecti ve IC F.

T hese sa m ples m a y  als o be use d f or e val uati o ns of met a b olites of M 3 8 1 4, f or f urt her e val uati o n 
of t he bi oa nal y tical met h o d, a n d f or a nal yses t hat pr o vi de i nf or mati o n o n t he meta b olic 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 6 6
pat h wa y s use d b y or affecte d b y. In a d diti o n, P K sa m ples ma y  be st ore d f or f ut ure a nal yses of 
pr otei n bi n di n g, ot her pr otei n relate d a nal ys es, bi oc he mistr y , bi o mar ker, a n d meta b olite 
pr ofili n g.

T he P K sa m pli n g sc he d ule m a y  be m o difie d u p o n a gree me nt of t he cli nical p har mac ol o gist a n d 
In vesti gat ors t o o pti mize t he sa m pli n g ti me f or M 3 8 1 4 dis p ositi o n (Ta ble 5, Ta ble 6, a nd Ta bl e 
7 ).

All eff orts will be ma de t o o btai n t he P K sa m ples wit hi n acce pta ble wi n d o w of e xact n o mi nal
ti me relati ve t o d osi n g (see Ta ble 1 8 a n d Ta ble 1 9 ). Act ual ti me of d osi n g a n d P K sa m ple 
c ollecti o n ti mes m ust be d oc u me nte d b y  the site. Details of t he sa m pli n g a n d pr ocessi n g 
pr oce d ures, st ora ge, a n d tra ns p ortati o n will be pr o vi de d i n a se parate La b orat or y  Ma n ual.

T he P K a n d a nti dr u g a nti b o d y (A D A ) sa m ples c ollecte d f or a vel u ma b at t he sa me pre d ose ti me 
p oi nts ma y  be use d i nterc ha n gea bly if t he de dicate d sa m ple has i ns ufficie nt q ua ntit y  as t he 
partici pa nts will ha ve c o nse nte d t o all c ollecti o ns a n d tests. 
T a ble 1 8
Acce pt a bl e P h ar m ac o ki netic Wi n d o ws f or A vel u m a b
S a m pli n g Ti m e
Ti m e Fr o m S c h e d ul e d S a m pli n g All o w e d
B ef or e B OI
Wi t hi n 1 2 0 mi n ut e s
pri or t o d o s e
E OI
Wi t hi n 1 5 mi n ut e s b ef or e E OI
B OI = b e gi n ni n g of i nf u si o n, E OI = e n d of i nf u si o n.
T a ble 1 9  
Acce pt a ble P h ar m ac o ki netic Wi n d o ws f or M 3 8 1 4
S a m pli n g Ti m e
Ti m e Fr o m S c h e d ul e d S a m pli n g All o w e d
Pr e d o s e
wit hi n 6 0 mi n ut e s pri or t o d o s e a d mi ni str ati o n
0. 5 t o 2 h o ur s p o st d o s e
± 2 0 mi n ut e s
> 2 h o ur s p o st d o s e
± 3 0 mi n ut e s
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 6 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 6 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 9
He alt h Ec o n o mics
N ot a p plica ble. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 6 6
8. 1 0
I m m u n o ge nicit y Assess me nts
W h ole bl o o d sa m ples of a p pr o xi matel y 3. 5 m L will be c ollecte d f or detecti o n of a nti b o dies a gai nst 
a vel u ma b i n ser u m, as s pecifie d i n t he Sc he d ule of Acti vities
( Secti on 1. 3). Sa m ples will be 
c ollecte d pri or t o a n y a vel u ma b a d mi nistrati o n o n t he sa me st u d y da y.
T he detecti o n of a nti b o dies t o a vel u ma b will be perf or me d usi n g a vali date d i m m u n oassa y met h o d .
C o nfir me d p ositi ve a nti b o dies ma y be f urt her c haracterize d. 
 
Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples are i n t he La b orat or y  Ma n ual .
R ete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d of st u d y are s pecifie d i n t he 
res pecti ve I CF.
9
St atistic al C o nsi der ati o ns
9. 1
St atistic al H y p ot hes es
N o f or mal statistical h y p ot hesis will be teste d, as t he st u d y  is desi g ne d t o be e x pl orat or y.
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 6 6
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a n y 
a nal ys is p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k.
A n al y s i s 
P o p ul ati o n
D e s cri pti o n
E nr oll e d
All p arti ci p a nt s w h o si g n i nf or m e d c o n s e nt
D o s e E s c al ati o n 
A n al y si s S et
P art A : All p arti ci p a nt s w h o h a v e r e c ei v e d at l e a st 3 4 of 4 2 d ail y d o s e s of M 3 8 1 4 a n d 
2 a d mi ni str ati o n s of a v el u m a b a n d c o m pl et e t h e D L T p eri o d . T h e D o s e E s c al ati o n 
A n al y si s S et will al s o i n cl u d e p arti ci p a nt s tr e at e d i n d o s e e s c al ati o n c o h ort s w h o 
e x p eri e n c e a D L T d uri n g t h e D L T p eri o d, r e g ar dl e s s of t h e a m o u nt of e a c h st u d y 
i nt er v e nti o n r e c ei v e d/ c o m pl eti o n of t h e D L T p eri o d.
P art B : All p arti ci p a nt s w h o h a v e r e c ei v e d at l e a st 8 of 1 0 d ail y d o s e s of M 3 8 1 4 a n d 
3 a d mi ni str ati o n s of a v el u m a b a n d 8 fr a cti o n s ( 2 4 G y) of R T a n d c o m pl et e t h e D L T 
p eri o d . T h e D o s e E s c al ati o n A n al y si s S et will al s o i n cl u d e p arti ci p a nt s tr e at e d i n d o s e 
e s c al ati o n c o h ort s w h o e x p eri e n c e a D L T d uri n g t h e D L T p eri o d, r e g ar dl e s s of t h e 
a m o u nt of e a c h st u d y i nt er v e nti o n r e c ei v e d/ c o m pl eti o n of t h e D L T p eri o d.
F ull A n al y si s S et 
/ S af et y A n al y si s S et
P art A , P art B , a n d P art F E : All p arti ci p a nt s w h o r e c e i v e at l e a st o n e d o s e of st u d y 
i nt er v e nti o n. 
P h ar m a c o ki n eti c
P art A a n d P art F E : All p arti ci p a nt s w h o c o m pl et e 1 a d mi ni str ati o n of M 3 8 1 4 a n d 
a v el u m a b st arti n g o n D a y 1 a n d w h o pr o vi d e at l e a st 1 p o st d o s e s a m pl e wit h m e a s ur a bl e 
c o n c e ntr ati o n s of M 3 8 1 4 .
P art B : All p arti ci p a nt s w h o h a v e r e c ei v e d at l e a st t h e fir st d o s e of M 3 8 1 4 a n d pr o vi d e d 
P K s a m pl e s a s p er pr ot o c ol f or at l e a st 6 h o ur s f oll o wi n g fir st d o si n g o n Fr a cti o n D a y 1.
 
 
 
 
 
 
 
 
 
 
 
 
I m m u n o g e ni cit y 
( A D A) P o p ul ati o n
P art A , P art B, a n d P art F E : All p arti ci p a nt s w h o c o m pl et e at l e a st 1 a d mi ni str ati o n of 
M 3 8 1 4 a n d a v el u m a b, a n d w h o h a v e at l e a st o n e v ali d A D A r e s ult. 
A D A = a nti d r u g a nti b o d y, A D M E = a b s or pti o n, di stri b uti o n, m et a b oli s m, a n d e x cr eti o n , 
 D L T = d o s e-li miti n g t o xi cit y, ct D N A= cir c ul ati n g t u m or D N A, 
 
P K = p h ar m a c o ki n eti c, R T =r a di ot h er a p y .
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 6 6
9. 4
St atistic al A n al yses
9. 4. 1
Effic ac y A n al ys es
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
N ot a p pli c a bl e
S e c o n d ar y
C o nfir m e d B O R r at e, d efi n e d a s t h e pr o p orti o n of p arti ci p a nt s h a vi n g a c hi e v e d 
c o nfir m e d C R or P R a s B O R , a c c or di n g t o R E CI S T v 1. 1 a s s e s s e d b y I n v e sti g at or 
(fr o m t h e fir st d o s e of st u d y i nt er v e nti o n u ntil di s e a s e pr o gr e s si o n, d e at h fr o m a n y 
c a u s e, or l a st t u m or a s s e s s m e nt).
P F S ti m e, d efi n e d a s t h e ti m e (i n m o nt h s) fr o m fir st tr e at m e nt d a y t o t h e d at e of t h e 
fir st d o c u m e nt ati o n of o bj e cti v e P D a c c or di n g t o R E CI S T v 1. 1 a s s e s s e d b y
I n v e sti g at or, or d e at h d u e t o a n y c a u s e, w hi c h e v er o c c ur s fir st.
O S ti m e, d efi n e d a s t h e ti m e fr o m fir st tr e at m e nt d a y t o t h e d at e of d e at h d u e t o a n y 
c a u s e. 
F or ti m e -t o- e v e nt a n al y s e s, t h e K a pl a n- M ei er e sti m at e s will b e pr o vi d e d. T h e 
c o nfi d e n c e i nt er v al f or t h e m e di a n will b e c al c ul at e d a c c or di n g t o 
Br o o k m e y er a n d Cr o wl e y 1 9 8 2 . 
All a n al y s e s f or s e c o n d ar y e n d p oi nt s will b e p erf or m e d o n t h e F ull A n al y si s S et u nl e s s 
ot h er wi s e s p e cifi e d.
B O R = b e st o v er all r e s p o n s e, C R = c o m pl et e r e s p o n s e, O S = o v er all s ur vi v al, P D = pr o gr e s si v e di s e a s e, 
P F S = pr o gr e s si o n -fr e e s ur vi v al, P R = p arti al r e s p o n s e, R E CI S T = R e s p o n s e E v al u ati o n Crit eri a I n S oli d T u m or s .
9. 4. 2
S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he Safet y  A nal ysis p o p ulati o n.
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
Pri m ar y
O c c urr e n c e of D L T s ( d e s cri pti v e t a b ul ati o n) – D o s e E s c al ati o n A n al y si s S et
S e c o n d ar y
O c c urr e n c e of T E A E s a n d tr e at m e nt -r el at e d A E s, tr e at m e nt-r el at e d Gr a d e ≥3 A E s,
irA E s , a n d R T -i n d u c e d t o xi cit y a c c or di n g t o N CI -C T C A E v 5. 0 , o c c urr e n c e of 
a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y t e st v al u e s, s eri o u s a d v er s e e v e nt s . 
( d e s cri pti v e t a b ul ati o n) – S af et y A n al y si s S et
T erti ar y/ E x pl or at or y
N ot a p pli c a bl e.
A E = a d v er s e e v e nt, D L T = d o s e -li miti n g t o xi cit y, ir A E s =i m m u n e-r el at e d a d v er s e e v e nt 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 s, T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 6 6
A n al ysis of Pri m ar y E n d p o i nt ( P art A a n d P art B)
F or t he d ose escalati o n part, t he a nal ysis will f oc us o n t he n u m ber of partici pa nts e x perie nci n g a 
D L T. T he S M C will recei ve res ults of a Ba ye sia n t w o-para meter l o gistic m o del wit h o ver d ose 
c o ntr ol u p date d wit h t he o bser ve d D L T data. 
T he rec o m me n de d d ose le vel fr o m t he Ba ye sia n m o del f or t he ne xt c o h ort is t he d ose wit h t he 
l o west l oss f u ncti o n: 
1 × P( u n der d osi n g ( 0 % t o 2 0 %) + 0 × P(tar get d osi n g ( > 2 0 % t o 3 3 %)) + 1 × P( o ver d osi n g 
( > 3 3 % t o 6 0 %) + 2 × P(e xcessi ve d osi n g ( > 6 0 %))
I n a d diti o n, o nl y  doses t hat ha ve a c orres p o n di n g pr o ba bilit y  of less t ha n 2 5 % t hat t he tr ue D L T 
rate is m ore t ha n 3 3 % ( o ver d ose c o ntr ol) are rec o m me n de d b y  the m o del. T his Ba yesia n escalati o n 
a p pr oac h will be use d t o assist t he S M C t o select t he ne xt d ose fr o m a pre dicte d set of acce pta ble 
d oses (Secti o n  2. 1). T he S M C ma y  ch o ose a differe nt d ose or d osi n g re gi me n t ha n s u g geste d b y  
t he Ba yesia n escalati o n a p pr oac h. 
If t he S M C deci des t o c ha n ge t he d osi n g re gi me n, a se parate m o del will be set u p or t he m o del 
e xte n de d t o a partial or der C o nti n ual Reassess me nt Met h o d.
O nl y  partici pa nts i ncl u de d i n t he D ose Escalati o n A nal ysis Set will be c o nsi dere d i n t he Ba yesia n 
m o del . Partici pa nts w h o are n ot D L T e val ua ble will n ot f or mall y  be re place d. T he S M C ca n still 
meet,
a n d t he Ba yesia n m o del will be u p date d wit h t he data fr o m t he e val ua ble partici pa nts. I n 
e xce pti o nal cases t he S M C ma y deci de ( base d o n a vaila ble data) u p o n e nr ol me nt a n d d ose f or t he 
ne xt d osi n g c o h ort bef ore all partici pa nts i n a c o h ort ha ve c o m plete d t he D L T peri o d. T he f ull data 
of s uc h dela y e d partici pa nt s will be c o nsi dere d at t he ne xt S M C. F or eac h S M C re vie w at least 
2 D L T e val ua ble partici pa nts s h o ul d be a vaila ble.
T he relati o ns hi p bet wee n d ose a n d t o xicit y  rate i n t he t w o-para meter l o gistic re gressi o n m o del is 
defi ne d b y:
      , ,   =
e x p   + e x p ( ) ∗l o g       1 + e x p   + e x p ( ) ∗l o g       w here d j is t he d ose at le vel i, dref t he refere nce d ose a n d ( α, β) are bi variate n or mall y  distri b ute d.
T he m o del f or Part A will be s pecifie d i n t he S M C c harter bef ore first patie nt i n (F PI ) a n d f or 
Part B after t he starti n g d ose f or t he sec o n d part of t his st u d y  is deter mi ne d (b ut als o bef o re F PI i n 
t he sec o n d part).
P osteri or distri b uti o n a n d t he rec o m me n de d ne xt d ose le vel will 
be calc ulate d usi n g 
R V ersi o n 3. 1. 2 or hi g her wit h li brar y  pac ka ge bcr m ( Bayesia n C o nti n ual Reassess me nt Met h o d) 
or pac ka ge C R M pac k or E A S T Versi o n 6. 4 or hi g her.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 6 6
A t i nteri m a nal ysis, after t he e n d of d ose escalati o n, a n d mai n a nal ysis, t he n u m ber a n d pr o p orti o n 
of partici pa nts e x perie nci n g D L Ts will be re p orte d b y  dose le vel, base d o n o bser vati o ns d uri n g 
t he D L T peri o d . P osteri or pr o ba bilities ( 2. 5 %, 2 5 %, 5 0 %, 7 5 %, a n d 9 7. 5 % q ui ntiles) f or D L T 
pr o ba bilities at selecte d d oses will be esti mate d fr o m t he m o del.
T he D ose Escalati o n A nal ysis Set will be use d f or t his a nal y sis.
Part F E: N ot a p plica ble.
A d verse E ve nts
All safet y a nal ys es will be perf or me d o n t he Safet y  A nalys is p o p ulati o n.
All A Es will be c o de d acc or di n g t o t he Me dical Dicti o nar y  f or Re g ulat or y Acti vities (Me d D R A ), 
V ersi o n 2 1. 0 or hi g her. T he se verity of A Es will be gra de d usi n g N CI -C T C A E v 5. 0 t o xicit y 
gra des. A d verse e ve nts relate d t o st u d y  i nter ve nti o n will be defi ne d as a n y A E c o nsi dere d relate d 
t o a n y st u d y i nter ve nti o n. I n ad diti o n, missi n g classificati o ns c o ncer ni n g st u d y i nter ve nti o n
relati o ns hi ps will be c o nsi dere d relate d t o t he st u d y i nter ve nti o n(s). 
A d verse 
e ve nts o bser ve d fr o m t he first d ose u ntil 3 0 da y s after last st u d y i nter ve nti o n
a d mi nistrati o n (i.e. T E A Es) will be s u m marize d acc or di n g t o Me d D R A s yste m or ga n classes a n d 
preferre d ter ms. T he i nci de nce a n d t y pe of t he f oll o wi n g will be a nal yz e d: 

T E A Es a n d S A Es

T E A Es a n d S A Es relate d t o st u d y  i nter ve nti o n

T E A Es wit h N CI -C T C A E Gra des ≥3

T E A Es relate d t o st u d y i nter ve nti o n wit h N CI - C T C A E Gra des ≥3 

A Es 
lea di n g t o wit h dra wal, 
d ose 
m o dificati o ns, 
or 
per ma ne nt 
st u d y i nter ve nti o n
disc o nti n uati o n

Deat hs.
Partici p a nts w h o ter mi nate treat me nt will be dis pla y e d i n a b y- partici pa nt listi n g a n d s u m marize d 
b y  pri mar y wit h dra wal reas o n. 
All re p orte d deat hs after first d ose of st u d y i nter ve nti o n as well as reas o ns f or deat h will be 
ta b ulate d (f or all partici pa nts e nr olle d). Deat hs wit hi n 3 0 da y s fr o m last d ose a d mi nistrati o n a n d 
deat hs be y o n d t his peri o d u p t o 9 0 da y s f oll o w-u p a n d reas o ns f or t he m will als o be ta b ulate d.
L a b or at or y V ari a bles
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 5. 0. T he w orst o n- st u d y 
gra des after t he f irst st u d y i nter ve nti o n will be s u m marize d. 
S hifts i n t o xicit y gra des fr o m first treat me nt t o hi g hest gra de will be dis pla y e d. Res ults f or 
varia bles t hat are n ot part of N CI -C T C A E will be prese nte d as bel o w, wit hi n, or a b o ve n or mal 
li mits. O nl y partici pa nts wit h p ost baseli ne la b orat or y  val ues will be i ncl u de d i n t hese a nalys es. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 6 6
P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n, i ncl u di n g vital si g ns ( b o d y te m perat ure, res pirat or y rate, heart rate, a n d 
bl o o d press ure), a n d 1 2 -lea d E C G, rec or de d at B aseli ne a n d after a d mi nistrati o n of st u d y 
i nter ve nti o n will be prese nte d. 
F urt her details will be pr o vi de d i n t he I nte grate d A nal ysis Pla n. 
9. 4. 3
Ot her A n al yses
Ge ner al C o nsi der ati o ns
T he f oll o wi n g statistics will be use d t o s u m marize t he st u d y data (e. g. Baseli ne C haracteristics) 
u nless ot her wise s pecifie d:

C o nti n u o us varia bles: n u m ber of n o n missi n g o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, 
mi ni m u m, a n d ma xi m u m, 9 5 % c o nfi de nce i nter vals f or t he mea n, as a p pr o priate.

Cate g orical varia bles: fre q ue ncies a n d perce nta ges.

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 partici pa nts i n t he a nal ys is set of 
i nterest, u nless ot her wise s pecifie d i n t he st u dy I nte grate d A nalys is Pla n.

Partici pa nts will be s u m marize d b y  d ose le vel f or Part A, Part B, a nd Part F E .
B aseli ne
I n ge neral, t he last n o n missi n g meas ure me nt pri or t o t he first st u d y i nter ve nti o n will ser ve as t he 
B aseli ne meas ure me nt. 
Esti m ati o n of I n di vi d u al P K P ar a meters:

P K, i m m u n o ge nicit y, p har mac o d y n a mic, a n d bi o mar ker e x pl orat or y a nal yses will be s pecifie d 
i n t he I nte grate d A nal ysis Pla n fi nalize d bef ore data base l oc k. I nte grate d a nal ys es acr oss 
st u dies, s uc h as t he p o p ulati o n P K a nal ysis a n d p har mac o d y n a mic a nal ys es will be prese nte d 
se paratel y fr o m t he mai n cli nical st u d y re p ort ( C S R).

N o nc o m part me ntal c o m p utati o n of P K para meters 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 ® V ersi o n 6. 3, 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). 

T he statistical s oft ware S A S ® ( Statistical A nal ysis S y ste m, S A S -I nstit ute, Car y  NC, U S A, 
wi n d o ws V ersi o n 9. 1 or hi g her) m a y  b e use d t o pr o d uce ta bles, listi n gs a n d fi g ures a n d i n t he 
calc ulati o n of P K Para meters if a p pr o priate.
P K c o nce ntrati o ns of a vel u ma b , M 3 8 1 4 , a n d/ or meta b olites will be s u m marize d descri pti vel y a n d 
ma y  be p o ole d wit h data fr o m ot her st u dies t o c o n d uct p o p ulati o n P K a nal ysis. 
F ull P K, p har mac o d y n a mic, a n d bi o mar ker e x pl orat or y an al y ses will be s pecifie d i n t he I nte grate d 
A nal y sis Pla n fi nalize d bef ore data base l oc k. T he p o p ulati o n P K a nal ysis, if c o n d ucte d, a n d 
p har mac o d y n a mic a nal ys es will be prese nte d se paratel y fr o m t he mai n C S R.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 6 6
A D A/I m m u n o ge nicit y 
I n di vi d ual partici pa nts will be cate g orize d acr oss all vali d A D A res ults as e ver -p ositi ve vers us 
ne ver -p ositi ve. A D A e ver-p ositi ve partici pa nts w ill be f urt her cate g orize d as pre-e xisti n g, 
i ncl u di n g treat me nt-b o oste d, vers us treat me nt-e mer ge nt. A D A treat me nt-e mer ge nt partici pa nts 
will be f urt her s u b di vi de d i nt o tra nsie nt p ositi ve a n d persiste nt p ositi ve.
9. 4. 4
Se q ue nce of A n al yses
I nteri m a n d A d diti o n al Pl a n ne d A n al yses 
T his is a n e x pl orat or y  st u d y. A vaila ble data will be e val uate d d uri n g t he st u d y b y t he S M C.
A nal y ses f or t he Ba yesia n d ose escalati o n will be perf or me d o n t he D L T a nal ys is set. Us uall y 
decisi o ns o n d ose escalati o n will be ta ke n o nce all partici pa nts of t he m ost rece nt c o h ort ha ve 
c o m plete d t he D L T peri o d or dr o p pe d o ut. I n e xce pti o nal cases, h o we ver, t he S M C ma y  deci de o n 
t he ne xt c o h ort earlier, i.e. bef ore t he last partici pa nt of a c o h ort has fi nis he d t he D L T peri o d 
(c o nsi deri n g t he m o del rec o m me n dati o n a n d ris k of o ver d ose). Per defi niti o n of t he D L T a nal ysis 
set, partici pa nts w h o ha ve n ot c o m plete d t he D L T peri o d are n ot i ncl u de d f or u p date of t he m o del, 
u nless t he y ex perie nce d a D L T. H o we ver, s uc h partici pa nts will be i ncl u de d at ne xt S M C (if 
criteria f or t he D L T a nal ysis set are f ulfille d).
T he c ut off f or a n e x pl orat or y mai n a nal ysis of t he safet y an d preli mi nar y  antit u m or acti vit y  data 
fr o m t he c o m plete d ose escalati o n will be tri g gere d w he n all partici pa nts i n Part A a n d Part B 
reac hes t he first o n- treat me nt t u m or assess me nt or e x perie nces deat h or pre mat ure wit h dra wal f or 
a n y reas o n, w hic he ver c o mes first. 
1 0
Refere nces 
A bratt R P, M or ga n G W. L u n g t o xicit y foll o wi n g c hest irra diati o n i n patie nts wit h l u n g ca ncer. 
L u n g Ca ncer. 2 0 0 2; 3 5 ( 2): 1 0 3-9.
A C R Practice Para meter f or I M R T - Re vise d 2 0 1 6 ( Res ol uti o n 4 0)
A da ms S, Gra y  RJ, De maria S, et al. Pr o g n ostic val ue of t u m or-i nfiltrati n g l ym p h oc y tes i n tri ple-
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Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 6 6
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Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 6 6
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Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 6 6
Lie ber ma n H B. D N A da ma ge re pair a n d res p o nse pr otei ns as tar gets f or ca ncer t hera p y. C urr Me d 
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i n de pe n de nt pr o g n ostic 
fact or i n tra nsiti o nal cell 
bla d der 
ca ncer. 
E ur 
J 
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Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 6 6
S ha ver dia n N, Lis ber g A E, B or naz ya n K, et al. Pre vi o us ra di ot hera p y a n d t he cli nical acti vit y a n d 
t o xicit y of pe m br oliz u ma b i n t he treat me nt of n o n -s mall-cell l u n g ca ncer: a sec o n dar y a nalys is of 
t he K E Y N O T E-0 0 1 p hase 1 trial. La ncet O nc ol. 2 0 1 7; 1 8( 7): 8 9 5 - 9 0 3.
Stric kla n d K C, H o witt B E, S h u kla S A, et al. Ass ociati o n a n d pr o g n ostic si g nifica nce of 
B R C A 1/ 2 -m utati o n stat us wit h ne oa nti ge n l oa d, n u m ber of t u m or-i nfiltrati n g l ym p h oc y tes a n d 
e x pressi o n of P D -1/ P D -L 1  in hi g h gra de ser o us o varia n ca ncer. O nc otar get. 
2 0 1 6 Mar 
2 2; 7( 1 2): 1 3 5 8 7 - 9 8.
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Cli n O nc ol. 2 0 1 8 d oi: 1 0. 1 2 0 0/J C O. 2 0 1 7. 7 5. 7 7 4 0. E p u b a hea d of pri nt
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Wa n g D D, Z h a n g S, Z h a o H, et al. Fi xe d d osi n g vers us b o d y  size-base d d osi n g of m o n ocl o nal 
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We n dt 
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Ya p T A, de Mi g uel 
L u ke n MJ, 
O' Carri ga n B, et al. P hase I trial of first-i n-class ata xia 
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c o m bi nati o n wit h car b o plati n ( C P) i n a d va nce d ca ncer patie nts ( pts) wit h preli mi nar y e vi de nce of 
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P R 1 4.
Y o m 
S S, Li a o Z, Li u H H, 
et al. I nitial e val uati o n of treat me nt-relate d p ne u m o nitis i n 
a d va nce d -sta ge n o n- s mall-cell l u n g ca ncer patie nts treate d wit h c o nc urre nt c he m ot hera p y a n d 
i nte nsit y-m o d ulate d ra di ot hera p y. I nt J Ra diat O nc ol Bi ol P h ys. 2 0 0 7; 6 8( 1): 9 4 - 1 0 2.
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O nc ol. 2 0 1 7; 2 8( 8): 2 0 0 2 - 2 0 0 8.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 6 6
1 1
A p pe n dices
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 6 6
A p pe n di x 1
A b bre vi ati o ns
A D A
A nti dr u g A nti b o d y
A D R
A d verse Dr u g Reacti o ns
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest
A L T  
Ala ni ne A mi n otra nsferase
A S T
As partate A mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
B C R P
B reast C a ncer Resista nce P r otei n
B E D
Bi ol o gicall y  Effecti ve D ose
BI D
T wice Dail y
B O R
Best o verall res p o nse
C R
C o m plete Res p o nse
C R O
C o ntract Researc h Or ga nizati o n
C R T
C he m ora di ot hera p y
C S R
Cli nical St u d y  Re p ort
C T
C o m p ute d T o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C T L A- 4
C y t ot o xic T-l ym p h oc y te-ass ociate d Pr otei n 4
D D R
D N A da ma ge re pair
D L T
D ose - Li miti n g T o xicit y
D S B
D o u ble- stra n d Brea k
E C O G P S
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us
E C G
Electr ocar di o gra m
e C R F
Electr o nic Case Re p ort F or m
F E
F o o d Effect
F F P E
F or mali n -fi xe d Paraffi n-e m be d de d
FI H
First I n H u ma n
F PI
First patie nt i n
F S H
F ollicle -sti m ulati n g H or m o ne
G C P
G o o d Cli nical Practice
H R
H o m ol o g o us rec o m bi nati o n
I B
I n vesti gat or’s Br oc h ure
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 M R T
I nte nsity- M o d ulate d Ra diati o n T hera p y
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 6 6
I R
I o nizi n g Ra diati o n
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
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
N CI -C T C A E
Nati o nal Ca ncer I nstit ute- C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nt
O C T 1  
O r ga nic C ati o n T ra ns p orter 1
O S
O verall S ur vi val
P E
P h y sical e xa mi nati o n
P D
Pr o gressi ve Disease
P D -L 1
Pr o gra m me d deat h -li ga n d 1
P F S
Pr o gressi o n -free S ur vi val
P- g p
P- gl yc o pr otei n
P K
P har mac o ki netics
P PI
Pr ot o n p u m p i n hi bit or
P R
Partial Res p o nse
P V T
P la n ni n g T ar get V ol u me
Q 2 W
O nce e ver y  2 wee ks
Q D
O nce Dail y
Q Tc F
Fri dericia's C orrecti o n F or m ula
R E CI S T v 1. 1
Res p o nse E val uati o n Criteria i n S oli d T u m ors V ersi o n 1. 1
RI L T
Ra diati o n -I nd uce d L u n g T o xicities
R P 2 D
Rec o m me n de d P hase II D ose
R T
Ra di ot hera p y
S A E
Seri o us A d verse E ve nt
S M C
Safet y  M o nit ori n g C o m mittee
T E A E
Treat me nt -e mer ge nt A d verse E ve nts
U L N
U p per li mit of n or mal
W O C B P  
W o ma n of C hil d beari n g P ote ntial
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 6 / 1 6 6
A p pe n di x 2
St u d y G o ver n a nce
Fi n a nci al Discl os ure
I n vesti gat ors a n d S u b -I nvesti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial certificati o n 
or discl os u re state me nts t o t he a p pr o priate re g ulat or y aut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y.
I nf or me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y t o t he partici pa nt 
or his/ her le gall y a ut h orize d re prese ntati ve a n d a ns wer all q uesti o ns o n t he st u d y.

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y .

Partici pa nts or t heir le gall y a ut h orize d re prese ntati ve (a n i n di vi d ual or j u dicial or ot her b o d y 
a ut h orize d t o c o nse nt o n be half of a pr os pecti ve partici pa nt u n der a p plica ble la w t o t he 
partici pa nt's partici pati o n i n t he pr oce d ure(s) i n v ol ve d i n t he researc h ) will be re q uire d t o si g n 
a state me nt of i nf or me d c o nse nt t hat meet s t he re q uire me nts of 2 1 C F R 5 0 ; l ocal re g ulati o ns; 
I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) g ui deli nes; Healt h I ns ura nce P orta bilit y  an d 
Acc o u nta bilit y  Act ( HI P A A) re q uire me nts, w here a p plica ble; a n d t he I nstit uti o nal Re vie w 
B oar d (I R B)/ I n de pe n de nt Et hics C o m mittee (I E C) or st u d y  ce nter.

T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he IC F.

If t he I C F is u p date d d uri n g t heir partici pati o n i n t he st u dy, partici pa nts m ust be rec o nse nte d t o 
t he m ost c urre nt, a p pr o ve d versi o n.

A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s le gall y  a uth orize d 
re prese ntati ve.

T he ori gi nal si g ne d a n d date d c o nse nt will re mai n at t he I nvesti gat or’s site a n d m ust be safel y 
arc hi ve d s o t hat it 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 partici pa nt w h o is rescree ne d is n ot re q uire d t o si g n a n o t her I C F.
D at a Pr otecti o n

T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir i nf or me d 
c o nse nt. All partici pa nt rec or ds or datasets tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier 
o nl y ; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot be tra nsferre d.

T he S p o ns or m ust i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d data will be use d per 
l ocal data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure m ust als o be e x plai ne d t o t he 
partici pa nt.
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 7 / 1 6 6

T he partici pa n t m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y  Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y  ap pr o priate 
I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect ors. All s uc h pers o ns will strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y .
St u d y A d mi nistr ati ve
A p pr o xi matel y  5 st u d y sites i n t he U S A will ta ke part i n t his st u d y. Sites i n t he E U m a y  als o be 
o pe ne d .
T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n vesti gat ors f or de cisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G o o d Cli nical Practice (G C P ). T he C o or di nati n g I n vesti gat or 
will pr o vi de e x pert me dical i n p ut a n d a d vice o n t he st u d y 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 C li nical S t u d y R ep ort (C S R ).
T he st u d y  will a p pear i n t he f oll o wi n g cli nical st u dies re gistries: Cli nical Trials. g o v .
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate O perati o ns Ma n ual, 
w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nica l St u d y Lea der.
S afet y M o nit ori n g C o m mittee
T he Safet y M o nit ori n g C o m mittee (S M C ) c o nsists of c ore ( v oti n g) me m bers fr o m t he S p o ns or 
( Gl o bal Patie nt Safety P r o d uct Lea der [ C hair], Me dical Res p o nsi ble, Cli nical P har mac ol o gist a n d 
Bi ostatisticia n), t he C o or di nati n g I n vesti gat or, a n d (if a p plica ble) t he Me dical M o nit or of t he 
C o ntract Res earc h Or ga nizati o n (C R O ). A d h oc me m bers m a y  be i n vite d as nee de d (if dee me d 
necessar y ).
T he S M C will re g ularl y  re vie w t he safety data of partici pa nts e nr olle d i n a n y  part of t his st u d y. It 
will deci de o n rele va nt D ose -Li miti n g T o xicit ies (D L Ts) base d o n c riteria defi ne d i n t he pr ot oc ol 
a n d will pr o vi de rec o m me n dati o n b y  co nse ns us o n d ose escalati o n, d ose de- escalati o n, or 
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 t he 
R P 2 D.
 
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nternati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G C P G ui deli nes

A p plica ble la ws a n d re g ulati o ns
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 6 6

T he I n vesti gat or m ust 
s u b mit the pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I CF, 
I n vesti gat or’s Br oc h ure, a n d ot her rele va nt d oc u me nts (e. g. a d vertise me nts) t o a n I R B/I E C a n d 
t he IR B/I E C m ust re vie w a n d a p pr o ve t he m bef ore t he st u d y is i nitiate d.

A n y  pr ot oc ol a me n d me nts (i.e. c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges necessar y  to 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica ble, a me n d me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities.

T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I RB/I E C a n n uall y or 
m ore fre q ue ntl y per t he I R B’s/I E C’s re q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I R B/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as re q uire d b y 
I RB/I E C pr oce d ures .

Pr o vi di n g o versi g ht of t he st u d y  c o n d uct at t he site a n d a d here nce t o re q uire me nts 
of 2 1 C F R, I C H g ui deli nes, t he I RB/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns.

T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n 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.
E mer ge nc y Me d ic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or use 
d uri n g t he st u d y. T hese pr o vi de t he mea ns 
f or partici pa nts t o i de ntif y the msel ves as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care p r o vi ders access t o a n y inf or mati o n 
a b o ut t his partici pati o n t hat m a 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 
partici pa nt. T he i nf or mati o n o n t he E mer ge nc y Me dical S u p p ort car d ma y incl u de t he pr ocess 
f or e mer ge nc y u n bli n di n g (if a p plica ble).

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y In vesti gat or cari n g f or 
t he partici pa nt. C o nse q ue ntl y , 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. If t he I n vesti gat or is a vailable w he n a n e ve nt occ urs, t he y  will a ns wer 
a n y questi o ns. A n y s u bse q ue nt acti o n (e. g. u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n vesti gat ors.
W he n 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 ( or desi g nee) p h y sicia n. T his i ncl u des 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 
( or desi g nee) p h y sicia n t o assist wit h t he me dical e mer ge nc y.
Cli nic a l St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
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 i n t he st u d y. 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.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 6 6
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or will write a C S R i n c o ns ultati o n wit h t he C o or di nati n g 
I n vesti gat or.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore s u b missi o n. 
T his all o ws Merc k t o pr otect pr o prietar y  i nf or mati o n a n d t o pr o vi de c o m me nts. 

T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical pr actice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y  in t heir e ntiret y an d n ot as i n di vi d ual site data. I n this case, a C o or di nati n g 
I n vesti gat or will be desi g nate d by a gree me nt.

A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
Disse mi n ati o n of Cli nic al St u d y D at a
After c o m pleti o n of t he st u d y, a C S R will be writte n b y  the 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 a n d will be s u b mitte d i n 
acc or da nce wit h l ocal re g ulati o ns.
A n y  an d all scie ntific, c o m mercial, a n d tec h nical i nf or mati o n discl ose d b y  the S p o ns or i n t his 
pr ot oc ol or else w here s h o ul d be c o nsi dere d t he c o nfi de ntial a n d pr o priet ar y pr o pert y of t he 
S p o ns or. T he I n vesti gat or s hall h ol d s uc h i nf or mati o n i n c o nfi de nce a n d s hall n ot discl ose t he 
i nf or mati o n t o a n y t hir d part y  exce pt t o s uc h of t he I n vesti gat or’s e m pl o yees a n d staff w h o ha d 
bee n ma de a ware t hat t he i nf or mati o n is c o nfide ntial a n d w h o are b o u n d t o treat it as s uc h a n d t o 
w h o m discl os ure is necessar y  to e val uate t hat i nf or mati o n. T he I nvesti gat or s hall n ot use s uc h 
i nf or mati o n f or a n y p ur p ose ot her t ha n f or deter mi ni n g m ut ual i nterest i n perf or mi n g t he st u d y 
a n d, if t he p arties deci de t o pr ocee d wit h t he st u d y, f or t he p ur p ose of c o n d ucti n g t he st u d y.
T he I n vesti gat or u n dersta n ds t hat t he i nf or mati o n de vel o pe d fr o m t his cli nical st u d y  will be use d 
b y  the S p o ns or i n c o n necti o n wit h t he de vel o p me nt of t he st u d y i nter ve nti o n a n d t heref ore ma y be 
discl ose d as re q uire d t o ot her cli nical I n vesti gat ors, t o t he U S F o o d a n d Dr u g A d mi nistrati o n, a n d 
t o ot her g o ver n me nt a ge ncies. T he I n vesti gat or als o u n dersta n ds t hat, t o all o w f or t he use of t he 
i nf or mati o n deri ve d fr o m t he cli nical st u d y, t he I nvesti gat or has t he o bli gati o n t o pr o vi de t he 
S p o ns or wit h c o m plete test res ults a n d all data de vel o pe d i n t he st u d y .
N o p u blicati o n or discl os ure of st u d y res ults will be per mitte d e xce pt u n der t he ter ms a n d 
c o n diti o ns of a se parate writte n a g ree me nt. 
D at a Q u alit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n pri nte d or electr o nic C R Fs or tra ns mitte d t o t he 
S p o ns or or desi g nee electr o nicall y (e. g. la b orat or y data). T he I n vesti gat or is res p o nsi ble f or 
verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y b y  ph y sically or 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 6 6
electr o nicall y si gni n g t he electr o nic Case Re p ort F or m (eC R F ). Details f or ma na gi n g eC R Fs 
are i n t he O perati o ns Ma n ual .

T he I n vesti gat or m ust 
mai ntai n 
acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he e C R F.

T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, q ualit y ass ura nce a u dits, I R B/I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d s o urce 
data.

T he S p o ns or or desi g nee is res p onsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y 
c hec ki n g of t he data a n d mai ntai ni n g a vali date d data base. Data base l oc k will occ ur o nce q ualit y 
c o 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 eC R Fs will be 
pr o vi d e d t o t he I n vesti gat ors at st u d y  c o m pleti o n.

St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n t he e C R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P , a n d all a p plica ble re g ulat or y re q uire me nts.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y  the I n vesti gat or f or 1 5 ye ars after st u d y co m pleti o n, u nless l ocal re g ulati o ns, 
i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y  be destr o ye d 
d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds m a y  be 
tra nsferre d t o a n ot her l ocati o n or part y wit h o ut t he S p o ns or’s writte n n otificati o n.
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.

T he I n vesti gat or m ust kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical rec or ds) 
at t he site f or eac h st u d y partici pa nt. T he file m ust i de ntif y eac h partici pa nt, c o ntai n t he 
f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d s h o ul d be as c o m plete
as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d 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 st u d y )

St u d y  i de ntifier (i.e. t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber

Dates of e ntr y  i nt o t he st u d y (i.e. si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h 
visit t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All A Es

Date t hat t he partici pa nt left t he st u dy, 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 st u d y or st u d y i nter ve nti o n, if a p plica ble.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 6 6

All s o urce data m ust be file d (e . g. C T or Ma g netic Res o na nce I ma gi n g [M R I] sca n i ma ges, 
E C G rec or di n gs, a n d la b orat or y res ults). Eac h d oc u me nt m ust ha ve t he p artici pa nt n u m ber 
a n d t he pr oce d ure date; i deall y, pri nte d b y  th e i nstr u me nt use d f or t he pr oce d ure. As 
necessar y , me dical e val uati o n of t hese rec or ds s h o ul d be perf or me d, d oc u me nte d, si g ne d 
a n d date d b y t he I n vesti gat or. 

Data rec or de d o n pri nte d or electr o nic C R Fs t hat are tra nscri be d fr o m s o urce d oc u me nts 
m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he 
I n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.

T he st u d y mo nit ors will use pri nt o uts of electr o nic files f or s o urce data verificati o n. T hese 
pri nt o uts m ust be si g ne d a n d date d b y  the I n vesti gat or, c o u ntersi g ne d b y  the M o nit or , a n d 
ke pt i n t he st u d y  file.

S o urce d o c u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y  the 
a p plica ble re g ulati o ns, a n d/ or as per I C H G C P g ui deli nes, w hic he ver is l o n ger. T he 
I n vesti gat or e ns ures 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 
S p o ns or’s writte n a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n t he e C R F g ui deli nes.
St u d y a n d Site St art a n d Cl os ure
First Act of Recr uit me nt

T he st u d y  start date is t he date w he n t he cli nical st u d y will be o pe n f or recr uit me nt.

T he first act of recr uit me nt is w he n t he first site is o pe ne d a n d will be t he st u d y  start date.
St u d y  Cl os ure a n d Site Ter mi nati o n

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me a n d 
f or a ny reas o n. St u dy sites wil l be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d 
cl ose d w he n all re q uire d d oc u me nts a n d st u d y su p plies ha ve bee n c ollecte d a n d a site cl os ure 
visit has bee n c o m plete d.

T he I n vesti gat or m a y  initiate site cl os ure at a n y t i me, pr o vi de d t here is reas o na ble ca use a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.

Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n vesti gat or ma y  i ncl u de:

Fail ure of t he I n vesti gat or t o c o m pl y  wit h t he pr ot oc ol, t he re q uire me nts of t he I RB/I E C 
or l ocal H ealt h A ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uit me nt of partici pa nts b y  t he I n vesti gat or

Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 6 6
A p pe n di x 3
C o ntr ace pti o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle can n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.
A W O C B P is n ot :
1. Pre me narc hal
2. A pre me n o pa usal fe male wit h o ne of t he f oll o wi n g:
D oc u me nte d h ys terect o m y
D oc u me nte d bilateral sal pi n gect o m y
D oc u me nte d bilateral o o p h orect o m y
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he fe male’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y  i nter vie w.
F or a fe male wit h per ma ne nt i nfertilit y due t o a n alter nate me dical ca use ot her t ha n t he a b o ve, 
(e. g., m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y), In vesti gat or discreti o n a p plies t o deter mi ne 
st u d y e ntr y.
3. A p ost me n o pa usal fe male

A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca use.

A hi g h f ollicle -sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y 
be use d t o c o nfir m a p ost me n o pa usal state i n a fe male n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o nal re place me nt t hera py ( H R T). H o we ver, i n t he a bse nce of 
1 2 m o nt hs of a me n orr hea, m ore t ha n 1 F S H meas ure me nt is re q uire d i n t he 
p ost me n o pa usal ra n ge.

A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne 
of t he n o n- estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if s he wis hes t o 
c o nti n ue her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  e nr oll me nt.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 6 6
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y  Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y

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 e 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

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 hi g hl y eff e cti v e c o ntr a c e pti v e 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 s e x u al 
p art n er of a 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. Ot h er wi s e, u s e 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. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y  Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt

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

Or al

I ntr a v a gi n al

Tr a n s d er m al

I nj e ct a bl e

Pr o g e st o g e n -o nl y h or m o n e 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

Or al

I nj e ct a bl e

S e x u al a b sti n e n c e: 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 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 i nt er v e nti o n. 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 ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a 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. T y pi c al 
u s e f ail ur e r at e s 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.
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 i nt er v e nti o n( s), 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. A s s u c h, m al e c o n d o m s m u st b e u s e d i n a d diti o n t o h or m o n al c o ntr a c e pti o n.
If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p ( C T F G) g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e 
m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c 
a b sti n e n c e 
( c al e n d ar, s y m pt ot h er m al, 
p o st -o v ul ati o n 
m et h o d s), 
wit h dr a w al 
( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h o e a m et h o d ( L A M) ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or t hi s 
st u d y. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri cti o n).
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 6 6
A p pe n di x 4
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
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 partici pa nt a d mi nistere d a p har mace utical pr o d uct, 
re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E ca n be a n y u nfa 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), s ym pt o m, or disease te m p orally 
ass ociate d wit h t he use of a me dici nal pr o d uct, re gar dless if it is 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 verit y or t o xicit y  of eac h A E.
I n vesti gat ors will refere nce 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 Es 
( C T C A E), V ersi o n 5. 0 ( p u blicati o n date: 2 7 N o v e m ber 2 0 1 7 ), 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 t he se verity f or a n A E is n ot s pecificall y gra de d b y NCI -C T C A E, t he I n vesti gat or is t o use t he 
ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi 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 
A n y  cli nical A E wit h se verit y 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 o ne of t he seri o us criteria s pecifie 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 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 6 6
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.
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 st u d y inter ve nti o n 
(i ncl u di n g a n y ot her n o n -st u d y inter ve nti o ns, ra diati o n t hera py, etc.) usi n g t he f oll o wi n g 
defi ni ti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o t he st u d y 
i nter ve nti o n(s) i ncl u de, b ut ma 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 
st u d y inter ve nti o n(s) , k n o w n si de effects of st u d y inter ve nti o n(s) , me d ical hist or y , c o nc o mita nt 
me dicati o n, c o urse of t he u n derl y i n g disease, a n d st u d y pr oce d ures.
U nrel ate d:
N ot reas o na bly relate d t o t he st u d y inter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y 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 st u d y inter ve nti o n. 
A E 
c o ul d 
me dicall y  
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n 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 ormal i n vesti gati o nal fi n di n gs (e . g. o n a n E C G trace) 
s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d w it h cli nical si g ns a n d s y m pt o ms, lea d t o 
st u d y inter ve nti o n disc o nti n uati o n or are c o nsi dere d ot her wise me dicall y  im p orta nt b y  the 
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 or i ncrease d A S 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.
Seri o us A d verse E ve nts
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. Life-t hreate ni n g refers t o a n e ve nt i n w hic h t he partici pa nt 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 pacit y

Is a c o n ge nital a n o maly or birt h defect

Is ot her wise c o nsi dere d t o be me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y  not res ult 
i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y  be c o nsi dere d as S A Es w he n, base d 
u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he partici pa nt or ma 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 r o o m 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.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 6 6
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 st u d y 
i nter ve nti o n is als o c onsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es.
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 st u d y inter ve nti o n or pr oce d ures (e. g. a n 
o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera py a p plicati o n) are n ot 
c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (i.e. u n desira ble effects of a n y a d mi nistere d treat me nt) 
m ust be d oc u me nte d a n d re p o rte 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 st u d y visit t hat d o n ot w orse n i n se verity or fre q ue nc y 
d uri n g t he st u d y are defi ne d as Baseli ne m e dical co 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 ul d n ot be re p orte d as a n ( S) A E, u nless t he partici pa nt ’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 d verse e ve nt re p orti n g peri o d, as defi ne d i n Secti o n 8. 3. 2 ( Met h o d of Detecti n g 
A d verse E ve nts a n d Seri o us A d verse E ve nts)
A d verse E ve nts of S peci al I nterest
A vel u ma b
I m m u ne-relate d a d verse reacti o ns (i m m u ne-relate d p ne u m o nitis, i m m u ne -relate d c olitis, 
i m m u ne-relate d he patitis, 
i m m u ne-relate d 
e n d ocri n o pat hies [t h yr oi d dis or ders, 
a dre nal 
i ns ufficie nc y, ne w o nset t ype I dia betes mellit us, pit uitar y  dis or ders]), i m m u ne-relate d ne p hritis 
a n d re nal d y sf u ncti o n a n d ot her i m m u ne-relate d A Es ( my osi tis, m y ocar ditis, G uillai n -Barré 
s yn dr o me, u veitis , pa ncreatitis, a n d m y ast he nia gra vis/ m y ast he nic s yn dr o me ) ha ve bee n i de ntifie d 
as A d verse E ve nt of S pecial I nterest ( A E SI ) f or a vel u ma b.
A n y  A E t hat is s us pecte d t o be a p ote ntial i m m u ne-relate d a d verse reacti o n will be c o nsi dere d a n 
A E SI . T hese A E SI d o n ot re q uire e x pe dite d re p orti n g u nless t he y are seri o us. S h o ul d t he A E SI be 
seri o us, a S A E f or m s h o ul d be fille d a n d t he re p orti n g pr ocess f or S A Es s h o ul d be f oll o we d.
M 3 8 1 4
N o A E SI  ha ve bee n defi ne d f or M3 8 1 4 t o date. 
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
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 als o o nset a n d res ol uti o n ti mes, w he n it is i m p orta nt t o assess t he ti me of A E 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 6 6
o nse t relati ve t o t he rec or de d st u d y inter ve nti o n a d mi nistrati o n ti me), its se verity, its ca usal 
relati o ns hi p wit h t he st u d y i nter ve nti o n, 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 ua ti o n of t he st u d y inter ve nti o n, a n d 
its o utc o me. I n a d diti o n, seri o us cases s h o ul d be i de ntifie d, a n d t he a p pr o priate seri o us ness criteria 
d oc u me nte d. If a n A E c o nstit utes a D L T t his is d oc u me nte d acc or di n gly.
S pecific g ui da nce is i n t he e C R F C o m pleti o n a nd M o nit ori n g 
C o n ve nti o ns pr o vi de d b y  th e 
S p o ns or.
Re p orti n g Seri o us A d verse E ve nts, A d verse E ve n ts of S peci al I nterest a n d D ose -Li m iti n g 
T o xicities
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I n vesti gat or m ust 
i m me diatel y (wit hi n a ma xi m u m of 2 4 H O U R S 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 i n writi n g. All writte n re p orts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort 
F or m, w hic h m ust be c o m plete d b y  t he I n vesti gat or 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 writte n re p ort m ust be se nt i m me diatel y thereafter b y  fa x or e-mail. Na mes, 
a d dresses, a n d tele p h o ne a n d fa x n u m ber s f or S A E re p orti n g will be i ncl u de d i n t he st u d y s pecific 
S A E Re p ort F or m. 
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e. g. me dical hist or y , c o nc o mita nt 
dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y  the I n vesti gat or, if a vaila ble (e.g. lab orat or y  
res ults, h os pital re p ort, a ut o ps y  re p ort). I n all cases, t he i nf or mati o n pr o vi de d o n t he S A E Re p ort 
F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he eC R F.
T he I n vesti gat or m ust 
res p o n d t o a n y re q uest f or f oll o w-u p i nf or mati o n (e. g. a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y q uesti o n t he 
S p o ns or/ 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 n t of t he e ve nt b y  the S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safety re p orti n g o bli gati o ns.
Re q uests f or f oll o w -u p will us uall y  be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e xce pti o nal 
circ u msta nces t he dr u g safety de part me nt m a y  co ntact t he I n vesti gat or directl y  to o btai n f urt her 
i nf or mati o n or t o disc uss t he e ve nt.
A d verse E ve nts of S peci al I nterest
A E SI  d o n ot re q uire e x pe dite d re p orti n g u nless t he y are seri o us. Na mes, a d dresses, a n d tele p h o ne 
a n d fa x n u m bers f or A E SI re p orti n g will be i ncl u de d o n t he Re p ort F or m. Seri o us A E SI s m ust be 
re p orte d i n a n e x pe dite d ma n ner as S A Es as o utli ne d a b o ve.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 6 6
D ose -Li m iti n g T o xicities
Eac h e ve nt meeti n g t he criteria of a D L T, as s pecifie d i n Secti o n 6. 6. 3 , m ust be rec or de d i n t he 
eC R F wit hi n 2 4 H O U R S after bec o mi n g a ware of t he e ve nt. Seri o us D L Ts m ust be re p orte d i n a n 
e x pe dite d ma n ner as S A Es, as o utli ne d a b o ve.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 6 6
A p pe n di x 5
Li ver S afet y: S u g geste d Acti o ns a n d F oll o w -u p Assess me nts 
D uri n g treat me nt wit h avel u ma b i m m u ne-relate d he patitis ma y  occ ur. See Secti o n 6. 9 f or details 
o n ma na ge me nt of he patic ir A Es. Mi n or li ver t o xicit y fi n di n gs o nl y  ha ve bee n re p orte d f or M 3 8 1 4. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 0 / 1 6 6
A p pe n di x 6
Cli nic al L a b or at or y Tests
T a ble 2 0
Pr ot oc ol -Re q uire d Cli nic al L a b or at or y Assess me nts
L a b or at or y  
A s s e s s m e nt s
P ar a m et er s
H e m at ol o g y
Pl at el et 
C o u nt
R B C I n di c e s :

M C V

M C H

M C H 
c o n c e ntr ati o n
% R eti c ul o c yt e s
W B C C o u nt wit h Diff er e nti al:

N e utr o p hil s

L y m p h o c yt e s

M o n o c yt e s

E o si n o p hil s
B a s o p hil s
R B C C o u nt
H e m o gl o bi n
H e m at o crit
Cli ni c al 
C h e mi str y
B l o o d ur e a 
nitr o g e n
P ot a s si u m
A s p art at e A mi n otr a n sf er a s e 
( A S T)/ S er u m Gl ut a mi c -
O x al o a c eti c Tr a n s a mi n a s e
( S G O T)
T ot al a n d dir e ct 
bilir u bi n
Cr e ati ni n e
S o di u m
Al a ni n e A mi n otr a n sf er a s e 
( A L T)/ S er u m Gl ut a mi c-
P yr u vi c Tr a n s a mi n a s e ( S G P T)
T ot al Pr ot ei n
N o nf a sti n g 
Gl u c o s e 
C al ci u m
Al k ali n e p h o s p h at a s e
G a m m a 
gl ut a m yltr a n sf er a s e
M a g n e si u m
Cr e ati n e 
p h o s p h o ki n a s e
Al b u mi n
L a ct at e 
d e h y dr o g e n a s e
P h o s p h or o u s
Uri c a ci d
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s a n d f oll o w -u p a s s e s s m e nt s aft er li v er st o p pi n g or 
m o nit ori n g e v e nt ar e gi v e n i n S e cti o n 7. 1 ( Di s c o nti n u ati o n of St u d y I nt er v e nti o n) a nd A p p e n di x 5 .
R o uti n e 
Uri n al y si s
F ull Uri n al y si s s h o ul d b e p erf or m e d o nl y at S cr e e ni n g a n d at E o T.

S p e cifi c gr a vit y

p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, l e u k o c yt e e st er a s e b y 
di p sti c k

Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al) .
Ot h er S cr e e ni n g 
T e st s

F olli cl e - sti m ul ati n g h or m o n e a n d e str a di ol ( a s n e e d e d i n w o m e n of n o n-c hil d b e ari n g 
p ot e nti al o nl y )

H u m a n c h ori o ni c g o n a d otr o pi n ( h C G) pr e g n a n c y t e st ( a s n e e d e d f or w o m e n of 
c hil d b e ari n g p ot e nti al).

I nf e cti o n S cr e e n:

H e p atiti s B

H e p atiti s C

H u m a n i m m u n o d efi ci e n c y vir u s ( a c c or di n g t o l o c al pr a cti c e a n d l o c al r e g ul at or y 
g ui d a n c e)

T S H

Fr e e T 4
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; h C G = h u m a n c h ori o ni c g o n a d otr o pi n; E o T = 
E n d of tr e at m e nt; M C H
=
m e a n c or p u s c ul ar h e m o gl o bi n; M C V = m e a n c or p u s c ul ar v ol u m e; R B C
= r e d bl o o d c ell; 
S G P T = S er u m Gl ut a mi c -P yr u vi c Tr a n s a mi n a s e ; fr e e 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; 
W B C = w hit e bl o o d c ell.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 1 / 1 6 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 2 / 1 6 6
A p pe n di x 8
R a di ati o n T her a p y
R a di ati o n T ar get Selecti o n 
F or partici pa nts i n Part B, t he ra diati o n t u m or tar get ma y i ncl u de bet wee n 1 a n d 3 sites of disease 
e xcl u di ng sites arisi n g fr o m t he brai n or s pi nal ca nal, es o p ha g us, gastric, s mall b o wel a n d m ust 
n ot be pri mar y  li ver ca ncer ( he pat ocell ular carci n o ma [ H C C], i ntra he patic c h ola n gi ocarci n o ma 
[IC C], mi xe d H C C -I CC) .
I n a d diti o n, t he ra diati o n t u m or tar get per a nat o mical site m a y  incl u de a si n gle pare nc h y mal t u m or 
O R a c o m p osite tar get i ncl u di n g i n v ol ve d l ym p h n o des wit h or wit h o ut a n ass ociate d pare nc h y m al 
t u m or. I ncl usi o n of i n v ol ve d l ym p h n o des i n a d diti o n t o a n i n v ol ve d pare nc h y mal lesi o n is at t he 
discreti o n of t he treati n g ra diati o n o nc ol o gist. 
T he lesi o n or c o m p osite lesi o ns tar get ma xi m u m l o n gest dia meter (i ncl usi ve of all tar get t u m ors 
t o be irra diate d) m ust be at least 1 c m. A ma xi m u m c o m p osite t u m or tar get d ia meter is n ot defi ne d; 
h o we ver, pr o p ose d ra diati o n treat me nt pla n m ust meet t he d ose c o nstrai nts (at least acce pta ble 
variati o n) o utli ne d i n  Ta ble 2 2 . 
I n t he e ve nt t hat i n t he sa me a nat o mical site, m ulti ple p ote ntial pare nc h y mal t u m or tar get lesi o ns 
e xist, i n ge neral t he lar gest lesi o n s h o ul d be selecte d u nless it is necessar y  to select a s maller tar get 
f or s ym pt o m palliati o n. I n s uc h cases w here pall iati ve ra diati o n is necessar y , s maller lesi o ns li kel y 
t o be nefit fr o m palliati ve ra diati o n m a y  be selecte d i nstea d of t he lar gest lesi o n as l o n g as t he 
ma xi m u m t u m or dia meter a d diti ve f or all i ncl u de d t u m or tar gets is at least 1 c m. H o we ver, f or 
i n di vi d ual t u m or w here t he l o n gest dia meter is > 5 c m, a tar get v ol u me c o ul d be create d wit hi n t he 
gr oss t u m or v ol u me t o li mit t he treate d t u m or t o 5 c m. A n y  questi o ns a b o ut tar get selecti o n ma y 
be re vie we d o n a case b y case basis wit h t he R a diati o n O nc ol o g y  Pri nci pal In vesti gat or.
Si m ulta ne o us m ultisite R T is all o we d. H o we ver, o wi n g t o li mitati o ns of I M R T pla n ni n g, n ot all 
pri mar y  or metastatic lesi o ns s h o ul d be tar gete d. T hree sites ma xi m u m c o ul d be selecte d t o be 
irra diate d pr o vi de d t hat all selecte d sites c o ul d b e irra diate d o n t he sa me d a y . W he n selecti n g 
metastases t o be irra diate d, s y m pt o matic or cli nicall y  rele va nt metastases c o ul d be pri oritize d.
R a di ati o n D ose S pecific ati o n
T he t otal d ose per selecte d site of 3 0 G y  will be gi ve n i n 1 0 dail y fracti o ns of 3 G y prescri be d t o 
t he P T V wit h at least 9 5 % of t he P T V recei vi n g 3 0 G y. A n acce pta ble variati o n is at least 9 0 % of 
t he P T V recei vi n g 3 0 Gy. T he ma xi m u m d ose f or a n y c o nti g u o us v ol u me of n o m ore t ha n 0. 0 3 cc 
i nsi de t he P T V m ust n ot e xcee d 1 2 0 % of t he prescri be d d ose. A n acce pta ble de viati o n is a 
ma xi m u m d ose i nsi de t he P T V of u p t o 1 2 5 % of t he prescri be d d ose. T he mi ni m u m d ose ( 0. 0 3 cc) 
t o t he P T V v ol u me s h o ul d be n o less t ha n 2 7 G y . All ra diati o n d oses will be calc ulate d wit h 
i n h o m o ge neity c orrecti o ns.
R a di ati o n Tre at me nt Sc he d ule
L ocalizati o n, Si m ulati o n, a n d I mm o bilizati o n f or ra diati o n treat me nt pla n ni n g, as o utli ne d i n 
“L o calizati o n, Si m ulati o n, a n d I m m o bilizati o n”, will be perf or me d n o m ore t ha n 3 5 d a y s a n d n o 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 3 / 1 6 6
less t ha n 1 d a y  bef ore t he first d a y  of ra diati o n treat me nt. T he partici pa nt ca n i nitiate treat me nt 
a n y da y of t he wee k. Treat me nt will be deli vere d dail y f or 1 0 w or ki n g da ys ( ge nerall y M o n da y t o 
Fri da y , wit h 2 d a y s off [ Sat ur da y an d S u n da y ]). Disr u pti o ns t o t he pla n ne d ra diati o n treat me nt 
sc he d ule s h o ul d be a v oi de d if at all p ossi ble. A n y  une x pecte d treat me nt brea k lasti n g > 2 d a y s 
s h o ul d be re p orte d t o t he I n vesti gat or.
T a ble 2 1
R a di ati o n Tre at me nt Sc he d ule
R T Pl a n ni n g Si m ul ati o n
R T Tr e at m e nt 
D a y 1- 5
R T Tr e at m e nt 
D a y 8- 1 2
N o. Fr a cti o n s a n d T ot al D o s e
B et w e e n D a y - 3 5 a n d D a y -1 
W e e k 1
W e e k 2
3 G y p er fr a cti o n p er irr a di at e d 
sit e f or all p arti ci p a nt s 
T o a t ot al d o s e of 3 0 G y i n 
1 0 fr a cti o n s f or e a c h sit e
U nif or m d o s e pr e s cri pti o n i n all 
p arti ci p a nt s a n d u nif or m d o s e t o 
all P T V s t hr o u g h o ut t h e R T 
c o ur s e
P T V = pl a n ni n g t ar g et v ol u m e, R T =r a di ot h er a p y.
D ose C alc ul ati o ns
All ra diati o n d oses will be calc ulate d wit h i n h o m o ge neit y correcti o ns t hat ta ke i nt o acc o u nt t he 
de nsit y  differe nces wit hi n t he irr a di ate d v ol u me .
Tec h nic al F act ors
Be a m E ner g y
Si x - t o 1 8- M V p h ot o ns are rec o m me n de d f or n o n -s u perficial t u m or tar gets; h o we ve r, bea m e ner g y 
a n d t y pe will be left t o t he discreti o n of t he treati n g ra diati o n o nc ol o gist i n or der t o o btai n t he best 
d ose distri b uti o n f or t he site bei n g treate d. 
Be a m S h a pi n g
M ulti leaf c olli mati o n ( M LC) or i n di vi d uall y sha pe d c ust o m bl oc ks s h o ul d be u se d t o pr otect 
n or mal tiss ues o utsi de of t he tar get v ol u me .
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n
A 
v ol u metric treat me nt pla n ni n g C T st u d y 
will be re q uire d f or treat me nt pla n ni n g. A 
f o ur-di me nsi o nal C T t o acc o u nt f or res pirat or y moti o n ma y  be be nefi cial a n d ca n be utilize d t o 
li mit t he o verall size of t he P V T . E val uati o n a n d/ or f usi o n (acc or di n g t o eac h i nstit uti o n’s sta n dar d 
practice) of a dia g n ostic P E T -C T or C T wit h I V c o ntrast ma y  assist wit h tar get deli neati o n. Eac h 
partici pa nt will be p ositi o ne d i n a n i m m o bilizati o n de vice i n t he treat me nt p ositi o n o n a flat ta ble. 
C o nti g u o us C T slices wit h a n o m ore t ha n 3- m m t hic k ness will be o btai ne d t hr o u g h t he re gi o ns 
har b ori n g tar get disease a n d t he e ntiret y of all or ga ns i n t he treat me nt fiel d. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 4 / 1 6 6
Tre at me nt Pl a n ni n g/ T ar get V ol u mes
T he defi niti o ns of v ol u mes will be i n acc or da nce wit h t he 1 9 9 3 I C R U Re p orts # 6 2:
Defi niti o n of G T V: Gr oss t u m or v ol u me ( G T V) will i ncl u de t he pla n ne d ra diati o n tar get t u m or(s) 
as deter mi ne d b y i ma gi n g st u dies a n d p h ys ical e xa mi natio n a n d selecte d acc or di n g t o  “ Ra diati o n 
Tar get Selecti o n ”.
Defi niti o n of C T V: T he cli nical tar get v ol u me ( C T V) will be defi ne d as t he c o nt o ure d G T V pl us 
0 t o 1 c m e x pa nsi o n v ol u me acc o u nti n g f or a nat o mic b o u n daries. C T Vs will
be la bele d t o 
c orres p o n d t o t he a p pr o priate G T V.
Defi niti o n of P T V: T he pla n ni n g tar get v ol u me ( P T V) is t he C T V pl us a mar gi n t o acc o u nt f or 
treat me nt set u p u ncertai nt y  an d or ga n m oti o n. T he m ost a p pr o priate P T V mar gi n is t o be 
deter mi ne d b y  t he treati n g ra diati o n o nc ol o gist a n d c o ul d ra n ge fr o m 0. 3 t o 1. 5 c m de pe n di n g o n 
t he use of res pirat or y m oti o n ma na ge me nt a n d i ma ge g ui de d ra diati o n t hera p y tec h ni q ues. 
Utilizati o n of a d va nce d pla n ni n g tec h ni q ues, I M R T t o mi ni mize d ose t o n or mal tiss ues is 
ma n dat or y i n t his cli nical st u d y. 
Res pirat or y  Moti o n Assess me nt a n d Ma na ge me nt: Utilizati o n of a d va nce d pla n ni n g tec h ni q ues t o 
acc o u nt f or res pirat or y moti o n ca n li mit t he v ol u me of n or mal tiss ue. B y utilizi n g res pirat or y 
m oti o n ma na ge me nt, t he P T V mar gi n t hat acco u nts f or or ga n m oti o n ca n be ma de s maller. 4 D -
C T base d pla n ni n g t o acc o u nt f or a n y resi d ual t u m or m oti o n as well as hilar - me diasti nal m oti o n 
is o ne f or m of res pirat or y m oti o n ma na ge me nt. Alter nati ve o pti o ns t o acc o u nt f or res pirat or y 
m oti o n 
i ncl u de b ut are n ot li mite d t o fi d ucial mar ker 
place me nt, gati n g a n d breat h h ol d 
a p pr oac hes. 
I nter nal Tar get V ol u me (I T V) A p pr oac h: If a 4 D- C T was c ollecte d at t he ti me of si m ulati o n f or 
res pirat or y moti o n ma na ge me nt, t he n a n I T V a p pr oac h ca n be utilize d t o acc o u nt f or i nter nal 
m oti o n. Utilizati o n of a n I T V a p pr oac h all o ws f or li miti n g P T V e x pa nsi o n as o utli ne d a b o ve. 
I M R T Treat me nt Pla n ni n g: I nstit uti o ns are i nte n de d t o use I M R T pla n ni n g a n d deli ver y  for a n y 
partici pa nt e ntere d o n t his st u d y. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 5 / 1 6 6
T a ble 2 2
E x a m ple of Ke y 
C o m p o ne nts of a n I nte nsit y-m o d ul ate d 
R a di ati o n 
T her a p y S yste m
C o m p o n e nt 
D e s cri pti o n
Wr itt e n tr e at m e nt dir e cti v e
Cl e ar c o m m u ni c ati o n fr o m p h y si ci a n t o d o si m etri st/ p h y si ci st 
r e g ar di n g tr e at m e nt pl a n ni n g g o al s i n cl u di n g t ar g et d o s e s 
a n d n or m al ti s s u e li mit s
Tr e at m e nt pl a n ni n g s y st e m ( T P S)
S oft w ar e u s e d t o cr e at e t h e r e pr e s e nt ati o n of t h e p arti ci p a nt , 
d efi n e v ol u m e s f or tr e at m e nt a n d a v oi d a n c e, p o siti o n a n d 
s h a p e b e a m s f or pl a n ni n g, o pti mi z e t h e i nt e n siti e s ( w ei g ht s) 
of s m all b e a ml et s, a n d c al c ul at e d o s e. I M R T tr e at m e nt 
pl a n ni n g i s t y pi c all y a n it er ati v e pr o c e s s t h at r e q uir e s 
i nt er a cti o n b et w e e n p h y si ci a n s, d o si m etri st s, a n d p h y si ci st s. 
T h e T P S m a y u s e a fl u e n c e -b a s e d a p pr o a c h b y cr e ati n g 
l ar g er s e g m e nt s fr o m t h e s m all b e a ml et s t o a c hi e v e m or e 
effi ci e nt d o s e d eli v er y
C o n v er si o n of d e sir e d fl u e n c e i nt o a fi el d 
c o n si sti n g of s e g m e nt s
F or fl u e n c e -b a s e d s y st e m s, t h e fl u e n c e i s c o n v ert e d i nt o a 
s eri e s of s e g m e nt s or s e q u e n c e s a s a f u n cti o n of ti m e ( a n d 
m o nit or u nit s) w hi c h c a n b e d e li v er e d b y t h e tr e at m e nt 
m a c hi n e. T h e n u m b er of M L C s e g m e nt s m a y r a n g e fr o m 5 t o 
gr e at er t h a n 1 0 0 f or a gi v e n fi el d. A p pr o xi m ati o n s i n t h e T P S 
m o d eli n g m a y r e s ult i n diff er e n c e s b et w e e n t h e o pti mi z e d 
a n d a ct u al d eli v er e d fl u e n c e. 
Pl a n tr a n sf er t o t h e tr e at m e nt m a n a g e m e nt 
s y st e m ( T M S)
T h e tr e at m e nt d at a ar e tr a n sf err e d fr o m t h e T P S t o t h e T M S 
f or d eli v er y. V erif yi n g t h e c orr e ct n e s s a n d i nt e grit y of all d at a, 
a s w ell a s c o nfir mi n g t h e d eli v er a bilit y of t h e l e af s e q u e n c e s 
t o b e u s e d, ar e a m o n g t h e m o st critic al st e p s t o b e c o nfir m e d 
i n t h e I M R T Q A pr o c e s s. 
P arti ci p a nt -s p e cifi c pr e tr e at m e nt q u alit y a s s ur a n c e
E q ui p m e nt f or I M R T t y pi c all y i n cl u d e s m ulti pl e 
c o m pl e m e nt ar y d et e ct or s a n d p h a nt o m s v erif y t h e a c c ur a c y 
of t h e d at a tr a n sf er a n d d o s e c al c ul ati o n s. S o m e c e nt er s 
m a y al s o h a v e m o nit or u nit c h e c k s oft w ar e of tr e at m e nt fi el d 
c al c ul ati o n s, a n d t hi s c a p a bilit y i s oft e n u s e d i n c o m bi n ati o n 
wit h m e a s ur e m e nt s.
A n al y si s of s oft w ar e
M a n y s y st e m s utili z e t h e g a m m a a n al y si s t e c h ni q u e t o 
c o m p ar e c al c ul ati o n s a n d m e a s ur e m e nt s. U s er s t y pi c all y 
s p e cif y t h e n u m b er of p oi nt s t h at ar e e x p e ct e d t o s ati sf y t h e 
crit eri a f or d o s e (i n G y or i n %) a n d di st a n c e (i n m m) f or 
a gr e e m e nt s w h e n t h e y e st a bli s h t h eir pr o gr a m.
Li n e ar a c c el er at or f or tr e at m e nt d eli v er y
T h e li n e ar a c c el er at or n e e d s t o b e c a p a bl e of a c c ur at el y 
d eli v eri n g i nt e n sit y -m o d ul at e d tr e at m e nt s. F or G a ntr y -b a s e d 
s y st e m s u si n g a n ar c d eli v er y t e c h ni q u e ( e . g. V M A T), 
a d diti o n al i nf or m ati o n r e g ar di n g t o a c c ur a c y of t h e g a ntr y 
i nf or m ati o n at m ulti pl e d eli v er y p oi nt s n e e d t o b e v ali d at e d a s 
w ell. F or t h e s e s y st e m s, d eri v ati o n of t h e d eli v er y i nf or m ati o n 
a s d e s cri b e d f or l e af s e q u e n ci n g a b o v e w o ul d al s o i n cl u d e 
v erifi c ati o n t h at t h e g a ntr y s e q u e n c e s, l e af p o siti o n s, d o s e 
d eli v er y, a n d ti m e i nf or m ati o n ar e c orr e ct a n d r e gi st er e d (i n 
ti m e a n d M U) c orr e ctl y. 
M or a n
et al. 2 0 1 1 .
G y = Gr a y s, I MR T =I nt e n sit y -m o d ul at e d R a di ati o n T h er a p y, M L C = m ultil e af c olli m at or, Q A = q u alit y a s s ur a n c e, 
T M S =tr e at m e nt m a n a g e m e nt s y st e m, T P S =tr e at m e nt pl a n ni n g s y st e m, V M A T = v ol u m etri c m o d ul at e d ar c t h er a p y.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 6 / 1 6 6
T ar get V ol u me a n d Critic al Str uct ure C o nstr ai nts wit h C o m pli a nce Criteri a
T a ble 2 3
T ar get V ol u me a n d Critic al Str uct ure C o nstr ai nts wit h C o m pli a nce 
Criteri a
Str u ct ur e 
D o s e C o n str ai nt
A c c e pt a bl e V ari ati o n
U n a c c e pt a bl e D e vi ati o n
P T V
3 0 G y ≥ 9 5 %
3 0 G y ≥ 9 0 %
3 0 G y < 9 0 %
Mi n ( 0. 0 3 c c) ≥ 2 7 G y
Mi n ( 0. 0 3 c c) ≥ 2 5. 5 G y
Mi n ( 0. 0 3 c c) < 2 5. 5 G y
M a x ( 0. 0 3 c c) ≤ 3 6 G y
M a x ( 0. 0 3 c c ) ≤ 3 7. 5 
G y
M a x ( 0. 0 3 c c ) > 3 7. 5 G y
T ot al P ar oti d Gl a n d s
M e a n < 1 7 G y
M e a n < 2 5 G y
M e a n > 2 5 G y 
P h ar y n g e al C o n stri ct or s
M e a n < 2 0 G y 
M e a n < 2 5 G y
M e a n > 2 5 G y
L ar y n x
D 2 c c < 3 0 G y
M e a n < 2 0 G y 
D 2 c c < 3 3 G y
M e a n < 2 5 G y 
D 2 c c > 3 3 G y
M e a n > 2 5 G y
Or al m u c o s a
M e a n < 2 0 G y
M e a n < 2 5 G y 
M e a n > 2 5 G y
L u n g s 
V 2 0 G y ≤ 2 0 % 
V 2 0 G y ≤ 3 5 %
V 2 0 G y > 3 5 %
M e a n ≤ 1 5 G y 
M e a n ≤ 2 0 G y
M L D > 2 0 G y
Li v er 
> 7 0 0 c c ≤ 1 0 G y 
> 7 0 0 c c ≤ 1 8 G y 
< 7 0 0 c c ≤ 1 8 G y 
S pi n al c a n al 
M a x ( 0. 0 3 c c) ≤ 3 3 G y 
N A
H e art 
M a x ( 0. 0 3 c c) ≤ 3 3 G y
M a x ( 0. 0 3 c c) > 3 6 G y
N A
V 3 0 G y ≤ 3 0 % 
V 3 0 G y > 3 0 %
Mi n ( 0. 0 3
c c ) > 3 0 G y
E s o p h a g u s / St o m a c h/ S m all 
b o w el
M a x ( 0. 0 3 c c) ≤ 3 3 G y
N A
V 1 5 G y < 1 0 c c
V 1 5 G y < 1 0 %
N A
V 1 5 G y > 1 0 %
Br a c hi al Pl e x u s / S a cr al 
Pl e x u s/
M a x ( 0. 0 3 c c) < 3 3 G y
M a x ( 0. 0 3 c c) < 3 6 G y
M a x > 3 6 G y 
Bl a d d er
M a x ( 0. 0 3 c c) < 3 3 G y
M a x ( 0. 0 3 c c) < 3 6 G y
M a x > 3 6 G y
T ot al Ki d n e y
V 1 8 G y < 3 3 %
V 1 8 G y < 5 0 %
V 1 8 G y > 5 0 %
N o n P T V
M a x ( 1 c c) < 3 6 G y
N A
Mi n = mi ni m u m, M a x = m a xi m u m, N A = n ot a p pli c a bl e (t h e d o s e c o n str ai nt m u st b e m et, ot h er wi s e t h e p arti ci p a nt 
s h o ul d b e wit h dr a w n) , P T V = pl a n ni n g t ar g et v ol u m e , R T =r a di ot h er a p y.
N ot e: All r e q uir e d str u ct ur e s m u st b e l a b el e d a s li st e d i n t h e t a bl e b el o w f or di git al R T d at a s u b mi s si o n. 
D oc u me nt ati o n Re q uire me nts
As I MR T is use d i n t his st u d y, p ortal i ma ges wi ll n ot be o btai ne d, b ut parti ci pa nt-s pecific Q A will 
be perf or me d pri or t o t he first fracti o n. 
C o ne bea m C T, k V i ma gi n g, or ot her i n- r o o m i ma gi n g f or set u p is all o we d.
Is o d ose pla ns f or I MR T pla n ni n g wit h d ose - v ol u me hist o gra m s of G T V, C T V, P T V, a n d critical 
str uct ures are re q uire d.
Acce pta ble variati o ns are all o we d o nl y w he n t he ge o metrical arra n ge me nt of t he tar get a n d critical 
str uct ures is c halle n gi n g. U nacce pta ble de viati o ns s h o ul d be a v oi de d w he ne ver p ossi ble a n d pla n 
m o dificati o ns s h o ul d be atte m pte d t o i m pr o ve res ults. T he de tails of eac h ra diati o n treat me nt pla n 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 7 / 1 6 6
are t o be c ollecte d b y t he st u d y S p o ns or a n d all acce pta ble variati o ns a n d u nacce pta ble de viati o ns 
will be a p pr o priatel y d oc u me nte d i n t he st u d y  rec or d.
R a di ati o n T her a p y Q u alit y Ass ur a nce Re vie ws
T he Ra diati o n O nc ol o g y Pri nci pal I n vesti gat or, or desi g nee, will re vie w all ra diati o n treat me nt 
pla ns wit hi n 3 m o nt hs after t he st u d y has reac he d t he tar get accr ual or as s o o n as c o m plete data 
f or all cases e nr olle d ha ve bee n recei ve d. I n a d diti o n, a di gital rec or d of t he ra diati o n treat me nt 
pla n can b e c ollecte d o n a case b y  case basis w he ne ver dee me d necessar y  t o be re vie we d b y  th e 
S p o ns or a n d t he Ra diati o n O nc ol o g y Pri nci pal In vesti gat or.
R a di ati o n T her a p y A d verse E ve nts
Si de effects of R T will var y  de pe n di n g o n t he l ocati on of disease, v ol u me of n or mal a n d 
ra di ose nsiti ve tiss ues i n or near t he ra diati o n pla n ni n g tar get v ol u me. E ve n t h o u g h, I M R T, t he R T 
tec h ni q ue use d i n t his st u d y, m a y  facilitate a better n or mal tiss ue s pari n g, all atte m pts s h o ul d be 
ma de t o mi ni mize t o xicit y t o s urr o u n di n g healt h y tiss ues b y  li miti n g t he n or mal tiss ue ra diati o n 
d ose as m uc h as p ossi ble a n d a d heri n g t o d ose v ol u me c o nstrai nts f or t he mai n or ga ns at ris ks as 
pr o vi de d i n  Ta ble 2 3 .
S h ort -ter m or ac ute a d verse effects occ ur d uri n g t hera p y or wit hi n 3 m o nt hs after R T w hile 
l o n g-ter m or late a d verse effects are o bser ve d t hereafter. Ac ute t o xicities (f or e xa m ple m uc ositis) 
g e nerall y heal wit hi n wee ks t o m o nt hs; late t o xicities, s uc h as fi br osis, are ge nerall y  co nsi dere d 
irre versi ble a n d pr o gressi ve o ver ti me.
P ote nti al R a di ot her a p y A d verse E ve nts
Ra di ot hera p y is ass ociate d wit h a wi de variet y of ac ute a n d late effects i n diff ere nt or ga ns. I n t his 
st u d y, t he N CI -C T C A E v 5. 0 gra di n g scale will be use d t o sta n dar dize defi niti o ns of a d verse e ve nts 
i ncl u di n g R T-i n d uce d t o xicities. 
M ost patie nts e x perie nce mil d t o m o derate fati g ue, s ki n t o xicit y  a n d m uc osal i nj ur y, w hic h ca uses 
m uc o sitis a n d diarr hea d uri n g treat me nt. T he maj orit y of patie nts rec o ver well fr o m ac ute effects. 
T he ac ute a n d late a d verse effects of R T are str o n gly de pe n de nt o n t he tiss ue tar gete d a n d ca n 
i ncl u de s ki n t o xicities, gastr oi ntesti nal da ma ge, l u n g i nj ur y, ca r diac t o xicit y, c o g niti ve 
i m pair me nt, re pr o d ucti ve dis or ders, def or mit y  an d i m pair me nts t o b o ne gr o wt h, he mat ol o gical 
dis or ders, hair l oss a n d sec o n dar y  mali g na nc y.
M a n a ge me nt of R a di ot her a p y A d verse E ve nts 
F oll o w -u p
F oll o w - u p is a n esse ntial c o m p o ne nt of R T ma na ge me nt. All partici pa nts dia g n ose d wit h R T 
t o xicit y sh o ul d be f oll o we d -u p wit h a tail ore d sc he d ule defi ne d b y t he t reati n g I n vesti gat or. Ac ute 
a d verse effects s h o ul d be treate d u ntil res ol uti o n. If late, c hr o nic a d verse effects are dia g n ose d, 
a n y un derl yi n g c o n diti o ns s h o ul d be treate d as t his ma y  i m pr o ve t he s ym pt o ms of partici pa nts.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 8 / 1 6 6
I n t his st u d y, i n a d diti o n t o t he Safet y  Foll o w - u p relati n g t o t he c o m bi nati o n of st u d y inter ve nti o ns 
pla n ne d after t he last d ose of a vel u ma b, f urt her Safet y F oll o w - u ps s h o ul d be sc he d ule d at 1, 3 a n d 
1 2 m o nt hs after t he e n d of R T i n or der t o i de ntif y, assess a n d ma na ge p ote ntial ac ute a n d late 
t o xicities relate d t o R T i n c o m bi nati o n wit h M 3 8 1 4 a n d a vel u ma b.
S y m pt o m atic M a n a ge me nt 
T he ma na ge me nt of ac ute a n d late ra dia ti o n t o xicit y is merel y sy m pt o matic. As i nfla m mati o n has 
a r ole i n ma n y  ra diati o n a d verse effects, a nti -i nfla m mat or y dr u gs are fre q ue ntly prescri be d. 
Fi br osis m a y  occ ur later, ca usi n g or ga n d y sf u ncti o n, a n d is m ostl y , b ut n ot al wa ys, irre versi ble. 
H o we ver, t he c o nse q ue nces of or ga n d y sf u ncti o n d ue t o R T ma y  be miti gate d b y  specific meas ures 
t hat i nterfere wit h t he p h ysi ol o g y of t he affecte d or ga n (e. g., i n hale d).
β- mi metics ma y  treat br o nc hial h y per -reacti vit y, a n d a n gi ote nsi n- c o n verti n g e nz y m e i n hi bit ors 
m a y be use d i n heart fail ure. U nf ort u natel y , m ost i nter ve nti o ns are base d lar gel y on e x pert o pi ni o n.
Gi ve n t he brea dt h of R T t o xicities, a fe w ke y e xa m ples of ma na ge me nt strate gies are pr o vi de d. I n 
t his st u d y, p artici p a nts e x perie nci n g a n a d verse e ve nt, s h oul d be e v al u ate d a n d tre ate d as 
a p pr o pri ate acc or di n g t o i nstit uti o n al g ui deli nes. All atte m pts s h o ul d be m a de t o li mit t he 
s y m pt o ms a n d t he o ver all i m p act of ac ute a n d l ate effects of r a di ati o n.
S ki n T o xicities
Ra diati o n der matitis is a c o m m o n a d verse effect of R T, partic ularl y  i n t he c o nte xt of s ki n, breast 
a n d hea d a n d nec k mali g na ncies, a m o n g ot hers (B ol derst o n 2 0 0 6 ) T he cli nical prese ntati o n 
escalates fr o m earl y er yt he ma, dr y  des q ua mati o n a n d m oist des q ua mati o n t o late a d verse effects 
i ncl u di n g pi g me ntati o n c ha n ges, tela n giectasias, al o pecia, fi br osis, atr o p h y , a n d ulcerati o n. T he 
ma na ge me nt of ra diati o n der matitis are lar gel y s ym pt o matic. E m ollie nts wit h t o pical ster oi ds a n d 
de x pa nt he n ol are ofte n p rescri be d f or ra diati o n der matitis, alt h o u g h t here is i ns ufficie nt e vi de nce 
t o fir ml y s u p p ort or ref ute t his rec o m me n dati o n (B ol derst o n 2 0 0 6 ).
U p per G astr oi ntesti n al Tr act M uc ositis
M uc ositis descri bes a cli nical c o n diti o n c haracterize d b y  oral eryt he ma, ulcerati o n a n d pai n a n d is 
a c o m m o n c o m plicati o n of R T, partic ularl y of t he hea d a n d nec k a n d gastr oi ntesti nal l u mi nal 
str uct ures (Blijle ve ns 2 0 0 0 ).
Ge neral be ha vi oral mea s ures are ofte n hel pf ul i n re d uci n g or miti gati n g m uc ositis. Partici pa nts 
s h o ul d be str o n gl y ad vise d a gai nst s m o ki n g, dri n ki n g alc o h ol a n d c o ns u mi n g aci dic or s pic y fo o ds 
d uri n g R T (Blijle ve ns 2 0 0 0 ; Bla nc har d 2 0 1 4 ). Pai n relate d t o m uc ositis s h o ul d be treate d i n a 
ste p-wise ma n ner, first usi n g t o pical a nest hetics, a n d t he n f or se vere pai n escalati n g t o usi n g 
ga ba pe nti n a n d o pi oi d a nal gesics (Bla nc har d 2 0 1 4 ).
Es o p h a gitis 
Ra diati o n -i n d uce d es o p ha gitis ( RI E) a n d pai nf ul s wall o wi n g o d yn o p ha gia are c o m m o n treat me nt 
t o xicities f or patie nts u n der g oi n g R T partic ularl y  for l u n g, breast, or hea d a n d nec k ca ncers.
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 9 / 1 6 6
T heref ore , t o mi ni mize t he ris k of ra diati o n es o p ha gitis w hic h c o ul d i ncrease wit h t he st u d y 
i nter ve nti o n, t he f oll o wi n g meas ures ha ve bee n a d o pte d:

If t he partici pa nt has s ym pt o ms of o n g oi n g es o p ha gitis a n d t he treati n g I n vesti gat or esti mates 
t hat t he ra diati o n pla n ni n g tar get v ol u me wi ll i ncl u de a n y p orti o n of t he es o p ha g us, t he 
partici pa nt is n ot eli gi ble u nless a n es o p ha geal e n d osc o p y r ules o ut t he prese nce of es o p ha gitis.

T he partici pa nt will n ot be eli gi ble if > 1 0 % of t he t otal es o p ha g us v ol u me is esti mate d t o recei ve 
m ore t ha n 1 5 G y  ( 5 0 % of t he prescri be d R T d ose).
I n ge neral, ac ute RI E occ urs t ypicall y  2 wee ks after treat me nt be gi ns a n d lasts u ntil 4 wee ks after 
treat me nt c o ncl u des, wit h pr o gressi vel y w orse ni n g o d y n o p ha gia, na usea, d y s p ha gia, a n d, if 
i neffecti vel y ma na ge d, a n ore xia (M urr o 2 0 1 5 ; Ba ker 2 0 1 6 ).  Late RI E occ urs m ore t ha n 3 m o nt hs 
after R T e n ds, wit h a n a vera ge ti me fr o m treat me nt t o s y m pt o m o nset of 6 m o nt hs.
Ra diati o n -i n d uce d es o p ha gitis d oes n ot c o nstit ute a reas o n t o i nterr u pt or dela y  RT or t he st u d y 
i nter ve nti o ns pr o vi de d oral i nta ke is s ufficie nt t o mai ntai n h ydrati o n. 
Ra diati o n -i n d uce d es o p ha gitis is treate d s ym pt o maticall y . Mil d 
t o m o derate o d y n o p ha gia is 
ma na ge d wit h t o pical a nal gesics s uc h as oral visc o us li d ocai ne (Ber ke y  20 1 0 ; Sass o 2 0 0 1 ). 
Treat me nt wit h n o nster oi dal a nti-i nfla m mat or y a ge nts has bee n pr o p ose d. Refl u x fre q ue ntl y 
ass ociate d wit h RIE ca n be treat e d wit h pr ot o n p u m p i n hi bit ors or H 2 rece pt or bl oc ker a n d dietar y 
m o dificati o ns. Pr o p h y lactic a ntif u n gal a ge nts are rec o m me n de d d ue t o a hi g h i nci de nce of t hr us h 
a n d ca n di da es o p ha gitis.
Partici pa nts s h o ul d als o be str o n gl y a d vise d t o a v oi d alc o h olic, aci d ic, or s pic y f o o ds or be vera ges 
d uri n g R T.
R a di ati o n -I n d uce d L u n g T o xicit y ( RI L T)
C o m m o n ra diati o n l u n g t o xicit y  i ncl u des ra diati o n p ne u m o nitis a n d fi br osis a n d ple ural eff usi o n.
Tra diti o nall y , RI L T, w hic h i ncl u des cli nical ra diati o n p ne u m o nitis a n d cli nical fi br osis s h o ul d 
o nl y  be dia g n ose d after e xcl usi o n of i nfecti o n, t u m or pr o gressi o n, a n d ot her eti ol o g y for t he 
cli nical s ym pt o ms.
Se veral st u dies ha ve e val uate d t he use of vari o us dr u g t hera pies t o miti gate ra diati o n p ne u m o nitis, 
b ut t here are n o ne o utsi de of ster oi d t hera p y  t hat are i n r o uti ne use (A bratt 2 0 0 2 ). Mi ni mizi n g t he 
v ol u me of irra diate d l u n g is partic ularl y i m p orta nt as se veral st u dies ha ve c orrelate d d ose a n d/ or 
v ol u me effects of R T wit h t he ris k of p ne u m o nitis  (De R u ys sc her 2 0 19 ).
S u p p orti ve care m a y  incl u de a ntit ussi ve t hera py t o s u p press c o u g hi n g, s u p ple me ntal o x y ge n a n d 
treat me nt of c o m or bi d diseases, s uc h as c hr o nic o bstr ucti ve p ul m o nar y  disease or heart fail ure, 
w h ic h ma y  co ntri b ute t o s ym pt o ms. M o derate t o hi g h -d ose ster oi d t hera p y is a c o m m o n a n d 
effecti ve t hera pe utic strate g y that is ge nerall y gi ve n f or a peri o d of se veral wee ks wit h a gra d ual 
ta per as t he s ym pt o ms settle (De R u y ssc her 2 0 1 9 ). H o we ver, ster oi ds are mi ni mall y  effecti ve i n 
t he late c o ns oli dati ve p hase of p ne u m o nitis, w he n p ul m o nar y  fi br osis is well esta blis he d 
(A bratt 2 0 0 2 ).
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 0 / 1 6 6
A p pe n di x 9
Pr ot oc ol A me n d me nt Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is o n t he title pa ge.
Pr ot oc ol Versi o n 2. 0 ( 2 6 J u ne 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
T he maj or p ur p ose of t his gl o bal pr ot oc ol a me n d me nt is t o i ncl u de t he assess me nt of t he f o o d 
effect ( F E) o n p har mac o ki netics ( P K) of M 3 8 1 4 
f oll o wi n g a d mi nistrati o n of M 3 8 1 4 
i n 
c o m bi nati o n wit h a vel u ma b u n der faste d a n d fe d c o n diti o ns. T he d ose -li mit t o xicit y (D L T) 
defi niti o n was als o re vise d as well as t he eli gi bilit y criteria of t he st u d y po p ulati o n, m ostl y  in 
Part B of t he st u d y. T he ke y c h a n ges are liste d bel o w.
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Titl e P a g e
U p d at e d t h e C o or di n ati n g 
I n v e sti g at or a n d t h e U S M e di c al 
M o nit or n a m e a n d c o nt a ct 
i nf or m ati o n
T o b e c o n si st e nt wit h c urr e nt i nf or m ati o n
Titl e P a g e,
1. 1 S y n o p si s,
1. 2 S c h e m a ,
1. 3 S c h e d ul e of A cti viti e s ,
2. 1 St u d y R ati o n al e ,
3. 3 P art F E ,
6. 6 D o s e S el e cti o n a n d 
M o difi c ati o n,
6. 6. 5. 3 P art F E
a n d t hr o u g h o ut d o c u m e nt, 
a s a p pli c a bl e
I n cl u d e d a t hir d c o h ort ( P art F E)
T o a s s e s s t h e F E o n P K of M 3 8 1 4 f oll o wi n g 
a d mi ni str ati o n of M 3 8 1 4 i n c o m bi n ati o n wit h 
a v el u m a b
1. 3 S c h e d ul e of A cti viti e s
C h a n g e d t h e E n d of Tr e at m e nt 
( E o T) p eri o d fr o m “- 1 t o 7” t o 
“ wit hi n 7 d a y s of d e ci si o n t o 
di s c o nti n u e” a n d a d d e d a 
cl arifi c ati o n n ot e
F or cl arit y a n d r e a d a bilit y
1. 3 S c h e d ul e of A cti viti e s,
a n d t hr o u g h o ut d o c u m e nt, 
a s a p pli c a bl e
I n cr e a s e d t h e s cr e e ni n g wi n d o w 
i n P art B fr o m 2 8 d a y s t o 3 5 d a y s
T o all o w t h e a s s e s s m e nt of t h e eli gi bilit y 
crit eri a r el at e d t o r a di ot h er a p y ( R T) w hi c h 
r e q uir e s a m ulti- di s ci pli n ar y t e a m
1. 3 S c h e d ul e of A cti viti e s,
a n d t hr o u g h o ut d o c u m e nt, 
a s a p pli c a bl e

C orr e ct e d t h e a p pr o xi m at e 
v ol u m e bl o o d f or s ol u bl e 
f a ct or s a n d i m m u n e 
p h e n ot y pi n g

A d d e d t h e i nf or m ati o n 
“ a p pr o xi m at el y” f or bl o o d 
v ol u m e
T o a d d cl arit y a n d t o b e c o n si st e nt wit h 
c urr e nt i nf or m ati o n
1. 3 S c h e d ul e of A cti viti e s
8. 5 P h ar m a c o ki n eti c s
U p d at e d t h e a c c e pt a bl e P K 
wi n d o w f or a v el u m a b a n d M 3 8 1 4
T o f a cilit at e P K s a m pli n g s c h e d ul e 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 1 / 1 6 6
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
2. 3. 1 S u m m ar y of M 3 8 1 4 
D at a a n d P ot e nti al B e n efit s 
a n d Ri s k s
2. 3. 1. 1 S u m m ar y of M 3 8 1 4 
T a bl et F or m ul ati o n a n d 
P ot e nti al B e n efit s a n d 
Ri s k s
R e vi s e d a c c or di n g t o t h e m o st 
u p d at e d i nf or m ati o n fr o m t h e 
I n v e sti g at or’ s Br o c h ur e
T o b e c o n si st e nt wit h t h e c urr e nt 
I n v e sti g at or’ s Br o c h ur e of M 3 8 1 4
2. 3. 3 S u m m ar y of P ot e nti al 
B e n efit s a n d Ri s k s of 
R a di ot h er a p y
4. 3. 2 R a di ot h er a p y 
a n d t hr o u g h o ut d o c u m e nt, 
a s a p pli c a bl e
U p d at e d i nf or m ati o n a b o ut t h e R T 
i n cl u di n g t h e r ol e of p alli ati v e R T 
i n s e v er al s oli d t u m or s b e y o n d 
t h or a ci c t u m or s a n d j u stifi c ati o n of 
m ulti sit e R T f or tr e ati n g m et a st ati c 
di s e a s e
T o pr o vi d e r ati o n al e s u p p orti n g t h e r e vi s e d 
eli gi bilit y crit eri a f or p arti ci p a nt s a n d R T 
s c h e d ul e
5. 1 I n cl u si o n Crit eri a,
5. 2 E x cl u si o n Crit eri a
a n d t hr o u g h o ut d o c u m e nt, 
a s a p pli c a bl e
R e vi s e d t h e eli gi bilit y crit eri a of 
t h e st u d y p o p ul ati o n i n P art B of 
t h e st u d y
T o r efl e ct b ot h P art B t ar g et e d p o p ul ati o n 
( s el e ct e d s oli d t u m or s) a n d m ulti sit e R T. 
T h e s e c h a n g e s will all o w t o a s s e s s s af et y of 
R T w h e n d eli v er e d t o diff er e nt s el e ct e d s oli d 
t u m or s t o eit h er o n e or m ulti pl e sit e s ( u p t o 
3 sit e s) i n c o m bi n ati o n wit h M 3 8 1 4 a n d 
a v el u m a b
5. 1 I n clu si o n Crit eri a,
A p p e n di x 3
R e vi s e d crit eri a f or c o ntr a c e pti o n
F or c o n si st e n c y wit h c urr e nt S p o n s or 
st a n d ar d s a n d c o n si st e n c y a cr o s s t h e 
d e v el o p m e nt pr o gr a m
5. 2 E x cl u si o n Crit eri a

R e vi s e d e x cl u si o n crit eri a # 2 

R e vi s e d e x cl u si o n crit eri a 
# 1 0 b

T o e x cl u d e d p arti ci p a nt s wit h hi st or y of 
l o n g Q T c F a s r e q u e st e d b y F D A

T o cl arif y t h e r e q uir e m e nt s of i n cl u si o n 
of p arti ci p a nt s wit h hi st or y of i nf e cti o n s
5. 3. 1 M e al s a n d Di et ar y 
R e stri cti o n s
U p d at e d t h e i nf or m ati o n f or m e al 
a n d di et ar y r e stri cti o n s
F or c o n si st e n c y wit h c urr e nt S p o n s or 
st a n d ar d s r e g ar di n g cli ni c al tri al s
6. 5. 3 Pr o hi bit e d M e di ci n e s
A d d e d a cl arifi c ati o n n ot e a b o ut 
t h e u s e of H 2 bl o c k er
T o pr o vi d e pr e c a uti o n s c o n si d eri n g t h e u s e 
of H 2
6. 6. 3 D efi niti o n of 
D o s e -Li miti n g T o xi cit y
U p d at e d t h e D L T d efi niti o n 
T o c o n si d er t h e k n o w n t o xi citi e s a s s o ci at e d 
wit h R T, s o t h at t h e a d v er s e e v e nt s ( A E s) 
r el at e d t o M 3 8 1 4 will b e m or e a c c ur at el y 
d et e ct e d, t h er e b y e n a bli n g a b ett er 
u n d er st a n di n g of t h e s af et y pr ofil e of M 3 8 1 4 
w h e n c o a d mi ni st er e d wit h a v el u m a b a n d R T
6. 9. 1 A d v er s e Dr u g 
R e a cti o n s R e q uiri n g 
M 3 8 1 4 Tr e at m e nt 
Di s c o nti n u ati o n or 
M o difi c ati o n s
R e vi s e d t h e d o s e m o difi c ati o n f or 
M 3 8 1 4 a n d R T i n P art B
T o b e c o n si st e nt wit h t h e n e w d efi niti o n s of 
D L T s i n P art B of t h e st u d y
A p p e n di x 8
S e ct i o n w a s u p d at e d t o a s si st 
I n v e sti g at or s i n d eli v eri n g 
a p pr o pri at e r a di ati o n o n c ol o g y 
c ar e t o t h e st u d y p arti ci p a nt s a s 
r e q uir e d p er t h e pr ot o c ol
T h e u p d at e d d o c u m e nt pr o vi d e s: 
G ui d a n c e o n tr e at m e nt pl a n ni n g a n d 
d eli v er y of I M R T t o d e cr e a s e t h e d o s e of 
r a di ati o n t o n or m al ti s s u e s i n t h e i nt e nt t o 
pr e v e nt t h e A E s of R T.  
Br o a d o v er vi e w of m o st c o m m o n R T 
r el at e d t o xi citi e s, a s w ell t h e s y m pt o m ati c 
tr e at m e nt of c ert ai n R T t o xi citi es ari si n g 
i n diff er e nt r e gi o n s of t h e b o d y. 
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 2 / 1 6 6
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
Y et, t h e ulti m at e j u d g e m e nt r e g ar di n g R T 
pr o c e d ur e or c o ur s e of a cti o n m u st b e m a d e 
b y t h e I n v e sti g at or i n li g ht of all t h e 
cir c u m st a n c e s pr e s e nt e d. T h e s ol e p ur p o s e 
of t hi s d o c u m e nt i s a s si sti n g I n v e sti g at or s 
a n d st u d y t e a m t o d eli v er eff e cti v e a n d s af e 
m e di c al c ar e t o p arti ci p a nt s t o t hi s st u d y   
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s
Mi n or t e xt r e vi si o n s ar e m a d e f or cl arit y, 
r e a d a bilit y, c o n si st e n c y of l a n g u a g e a cr o s s 
t h e d e v el o p m e nt pro gr a m, a n d c o m pli a n c e 
wit h c urr e nt S p o n s or g ui d eli n e s
Gl o bal Versi o n I D: C CI
C CI
C CI


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 3 / 1 6 6
A p pe n di x 1 0
S p o ns or Si g n at ure P a ge
St u d y Title:
A M ultice nter, 
O pe n -La bel, D ose Escalati o n P hase I 
St u d y  
to 
E val uate 
t he 
Safet y , 
T olera bilit y , 
P har mac o ki netics , a n d F o o d Effect o n P har mac o ki netics
of t he D N A -P K I nhi bit or M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b wit h a n d wit h o ut Palliati ve Ra di ot hera p y i n 
Partici pa nts wit h Selecte d A d va nce d S oli d T u m ors
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:
Cli nic al St u d y Pr ot oc ol Versi o n:
/ Versi o n 3. 0
I a p pr o ve t he desi g n of t he cli nical st u d y :
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D
P P D


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 4 / 1 6 6
A p pe n di x 1 1
C o or di n ati n g I n vesti g at or Si g n at ure P a ge
St u d y Title:
A M ultice nter, 
O pe n -La bel, D ose Escalati o n P hase I 
St u d y  
to 
E val uate 
t he 
Safet y , 
T olera bilit y , 
P har mac o ki netics , a n d F o o d Effect o n P har mac o ki netics
of t he D N A -P K I nhi bit or M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b wit h a n d wit h o ut Pa lliati ve Ra di ot hera p y i n 
Partici pa nts wit h Selecte d A d va nce d S oli d T u m ors
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:
Cli nic al St u d y Pr ot oc ol Versi o n:
/ Versi o n 3. 0
Site N u m ber:
I a p pr o ve t he desi g n of t he cli nical st u d y, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site 
a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y pr ot oc ol, a n y ap 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 Cli 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.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D
P P D


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 5 / 1 6 6
C o or di n ati n g I n vesti g at or Si g n at ure P a ge
St u d y Title:
A M ultice nter, 
O pe n -La bel, D ose Escalati o n P hase I 
St u d y  
to 
E val uate 
t he 
Safet y , 
T olera bilit y , 
P har mac o ki netics, a n d F o o d Effect o n P har mac o ki netics 
of t he D N A -P K I nhi bit or M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b wit h a n d wit h o ut P alliati ve Ra di ot hera p y i n 
Partici pa nts wit h Selecte d A d va nce d S oli d T u m ors
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:
Cli nic al St u d y Pr ot oc ol Versi o n:
/ Versi o n 3. 0
Site N u m ber:
I a p pr o ve t he desi g n of t he cli nical st u d y, a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site 
a n d u n dersta n d a n d will c o n d uct it per t he cli nical st u d y pr ot oc ol, a n y ap 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 Cli 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.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D
P P D


A vel u m a b a n d M 3 8 1 4
P h ase I St u d y of A vel u m a b -M 3 8 1 4
C o m bi n ati o n s
M S 2 0 1 9 6 4- 0 0 0 1
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 6 / 1 6 6
A p pe n di x 1 2
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A M ultice nter, 
O pe n -La bel, D ose Escalati o n P hase I 
St u d y  
to 
E val uate 
t he 
Safet y , 
T olera bilit y , 
P har mac o ki netics , a n d F o o d Effect o n P har mac o ki netics
of t he D N A -P K I nhi bit or M 3 8 1 4 i n C o m bi nati o n wit h 
A vel u ma b wit h a n d wit h o ut Pa lliati ve Ra di ot hera p y i n 
Partici pa nts wit h Selecte d A d va nce d S oli d T u m ors
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:
Cli nic al St u d y Pr ot oc ol Versi o n:
/ Versi o n 3. 0
Site N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u dy at t his site a n d u n dersta n d a n d will c o n d uct it per t he 
cli nical st u d y pr ot oc ol, a n y ap 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 
Cli 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 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 st u dies 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 n vesti 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 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p ply t he S p o ns or wit h a n y 
necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  sp 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  to meet 
Healt h 
A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a 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:
F a x n u m ber:
E- m ail a d dress:
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
P P D

SAP_001.pdf: 
M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 /6 5  
 
 
I nte gr ate d A n al ysis Pl a n 
Cli nic al St u d y  Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 1 9 6 4 -0 0 0 1  
Title  
A  M ultice nter,  O pe n -La bel,  D ose  Escalati o n  P hase  I  St u d y  t o 
E val uate  t he  Safet y,  T olera bilit y,  P har mac o ki netics,  a n d  t he  F o o d 
Effect  o n P har mac o ki netics  of  t he  D N A -P K  I n hi bit or  M 3 8 1 4  i n 
C o m bi nati o n  wit h  A vel u ma b  wit h  a n d  wit h o ut  Palliati ve 
Ra di ot hera p y i n Partici pa nts wit h Selecte d A d va nce d S oli d T u m ors  
St u d y P h ase  
P hase I 
I n vesti g ati o n al 
Me dici n al Pr o d uct(s)  
M S B 0 0 1 0 7 1 8 C (a vel u ma b), M S C 2 4 9 0 4 8 4 A ( M 3 8 1 4)  
Cli nic al St u d y  Pr ot oc ol 
Versi o n  
2 6 J u ne 2 0 1 9/ Versi o n 2. 0  
I nte gr ate d A n al ysis 
Pl a n A ut h or  
C o or di n ati n g A ut h or  
Bi o st ati sti c s, M er c k H e alt h c ar e K G a A  
 
 
  
 
,  
M er c k H e alt h c ar e K G a A  
 
I nte gr ate d A n al ysis 
Pl a n  D ate a n d Versi o n  0 5 N o ve m ber  2 0 2 0 / Versi o n 1. 0  
I nte gr ate d A n al ysis 
Pl a n Re vie wers  
F u n cti o n  
N a m e  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut e x press 
per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yr i g ht © 2 02 0  b y Merc k K G a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: 
C CI
C CI
P P D
P P D


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 /6 5  
 
 
A p pr o v al P a ge  
 
I nte gr ate d A n al ysis Pl a n: M S 2 0 1 9 6 4 -0 0 0 1   
A M ultice nter, O pe n -La bel, D ose Escalati o n P hase I St u d y t o E val uate t he Safet y, T olera bilit y, 
P har mac o ki netics, a n d t he F o o d Effect o n P har mac o ki netics of t he D N A -P K I n hi bit or M 3 8 1 4 i n 
C o m bi nati o n  wit h  A vel u ma b  wit h  a n d  wit h o ut  Palliati ve  Ra di ot hera p y  i n  Partici pa nts  wit h 
Selecte d A d va nce d S oli d T u m ors  
 
A p pr o val  of  t he  I A P  b y  all  Merc k  Healt hcare  K Ga A  Data  A nal ysis  R es p o nsi ble  has  t o  be 
d oc u me nte d wit hi n E L D O R A D O via e Si g nat ure. Wit h t he a p pr o val, t he Merc k  Healt hcare K Ga A  
res p o nsi ble  f or  eac h  of  t he  a nal ysis  als o  ta kes  res p o nsi bilit y  t hat  all  re vie wers’  c o m me nts  are 
a d dresse d a de q uatel y.  
B y usi n g e Si g nat ure, t he si g n at ure will a p pear at t he e n d of t he d oc u me nt.  
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 /6 5  
 
 
1  
T a ble of C o nte nts  
 
 
 
A p pr o val Pa ge  ......................................................................................2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b br e viati o ns a n d Defi niti o n of Ter ms  ....................................6  
3  
M o dificati o n Hist or y  ............................................................................8  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  ...............................................8  
5  
O bjecti ves a n d E n d p oi nts  .....................................................................9  
6  
O ver vie w of Pla n ne d A nal yses  ...........................................................1 3  
6. 1  
I nteri m A nal yses .................................................................................1 3  
6. 2  
Fi nal A nal ysis  .....................................................................................1 4  
7  
C ha n ges t o t he Pla n ne d A nal yses i n t he Cli nical St u d y Pr ot oc ol  ......1 4  
8  
Pr ot oc ol De viati o ns a n d A nal ysis P o p ulati o ns  ...................................1 5  
8. 1  
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ysis P o p ulati o ns  .............1 5  
8. 2  
Defi niti o n of A nal ysis P o p ulati o ns a n d S u b gr o u ps  ............................1 5  
9  
Ge neral S pecificati o ns f or Data A nal yses  ..........................................1 8  
9. 1  
Ge neral S pecificati o ns a n d Defi niti o ns f or A nal ysis  ..........................1 8  
9. 2  
Prese ntati o n of P har mac o ki netic Res ults  ............................................2 0  
9. 2. 1  
Prese ntati o n of P har mac o ki netic C o nce ntrati o n Data  ........................2 0  
9. 2. 2  
Prese ntati o n of P har mac o ki netic Para meter Data  ...............................2 0  
9. 3  
Visit Wi n d o wi n g  .................................................................................2 1  
9. 4  
Ha n dli n g of Missi n g Data a n d I m p utati o n R ules  ...............................2 4  
1 0  
St u d y Partici pa nts  ...............................................................................2 7  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................2 7  
1 0. 2  
C O VI D -1 9 I m pact  ..............................................................................2 8  
1 0. 3  
Re p orti n g of Pr ot oc ol De viati o ns  .......................................................2 9  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................3 0  
1 1. 1  
De m o gra p hics  .....................................................................................3 0  
1 1. 2  
Me dical His t or y ..................................................................................3 1  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................3 1  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................3 2  
1 2. 1  
Pri or A nti -Ca ncer Treat me nts  .............................................................3 2  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 /6 5  
 
 
1 2. 1  
Pre vi o us a n d C o nc o mita nt Me dicati o ns/ Pr oce d ures  ..........................3 3  
1 2. 2  
S u bse q ue nt A nti -Ca ncer T hera pies/ Pr oce d ures  .................................3 3  
1 3  
St u d y i nter ve nt i o n C o m plia nce a n d E x p os ure ...................................3 4  
1 4  
Efficac y A nal yses  ...............................................................................3 7  
1 4. 1  
Best O verall Res p o nse  ........................................................................3 7  
1 4. 2  
D urati o n of Res p o nse  .........................................................................4 0  
1 4. 3  
T u m or S hri n ka ge  ................................................................................4 0  
1 4. 4  
Pr o gressi o n Free S ur vi val  ...................................................................4 1  
1 4. 5  
O verall S ur vi val  ..................................................................................4 2  
1 5  
Safet y A nal yses  ..................................................................................4 3  
1 5. 1  
A d verse E ve nts  ...................................................................................4 3  
1 5. 1. 1  
All A d verse E ve nts  .............................................................................4 4  
1 5. 1. 2  
A d verse E ve nts Lea di n g t o St u d y I nter ve nti o n Disc o nti n uati o n  .......4 5  
1 5. 2  
D L Ts, Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her 
Si g nifica nt A d verse E ve nts  .................................................................4 6  
1 5. 2. 1  
Occ urre nce of D L Ts  ...........................................................................4 6  
1 5. 2. 2  
Deat hs  .................................................................................................4 6  
1 5. 2. 3  
Seri o us A d ver se E ve nts ......................................................................4 7  
1 5. 2. 4  
A d verse E ve nts of S pecial I nterest  .....................................................4 7  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................4 8  
1 5. 3. 1  
He mat ol o g y a n d Cli nical C he mistr y Para meters  ................................4 8  
1 5. 3. 2  
Ot her la b orat or y para meters  ...............................................................5 0  
1 5. 4  
Vital Si g ns  ..........................................................................................5 0  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................5 1  
1 5. 5. 1  
1 2 -Lea d Electr ocar di o gra m  ................................................................5 1  
1 5. 5. 2  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us  ................5 2  
1 6  
A nal yses of Ot her E n d p oi nts  ..............................................................5 2  
1 6. 1  
P har mac o ki netics  ................................................................................5 2  
 
 
 
 
1 6. 3  
I m m u n o ge nicit y ..................................................................................6 0  
1 7  
Refere nces  ...........................................................................................6 2  
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 /6 5  
 
 
1 8  
A p pe n dices  .........................................................................................6 3  
A p pe n di x I - Descri pti o n of t he Case Defi niti o n f or Assess me nt of ir A Es a n d I R Rs  .......6 3  
A p pe n di x II –  N CI -C T C Gra da ble a n d N o n -Gra da ble Safet y La b orat or y Test 
Para meters a n d Directi o n(s) of A b n or malit y  ......................................6 4  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 /6 5  
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms 
A D A  
A nti -Dr u g A nti b o d y  
A E  
A d verse E ve nt  
A E SI  
A d verse E ve nt of S pecial I nterest  
B MI  
B o d y Mass I n de x  
B O R  
Best O verall Res p o nse  
A T C  
A nat o mical T hera pe utic C he mical classificati o n  
C E OI  
O bser ve d c o nce ntrati o n at t he e n d of i nf usi o n peri o d  
CI  
C o nfi de nce I nter val  
C ma x  
Ma xi m u m O bser ve d C o nce ntrati o n  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R  
C o m plete Res p o nse  
(e) C R F 
(electr o nic) Case Re p ort F or m 
C S R  
Cli nical St u d y  Re p ort  
C tr o u g h 
C o nce ntrati o n  o bser ve d  i m me diatel y  bef ore  ne xt  d osi n g  (c orres p o n di n g  t o  pre -
d ose or tr o u g h c o nce ntrati o n f or m ulti ple d osi n g) 
C V  
C oefficie nt of Variati o n  
D L T  
D ose Li miti n g T o xicit y  
 
 
D O R  
D urati o n o f Res p o nse 
E C G  
Electr ocar di o gra m  
E C O G P S  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us  
e DI S H 
e val uati o n of Dr u g -I n d uce d Seri o us He pat ot o xicit y 
F A S  
F ull A nal ysis Set  
F E  
F o o d Effect  
Ge o C V  
Ge o metric C oefficie nt of Variati o n  
Ge o Mea n  
Ge o metric Mea n  
I A P 
I nte grate d A nal ysis Pla n 
irA E  
I m m u ne Relate d  A d verse E ve nt  
I P D 
I m p orta nt Pr ot oc ol De viati o n  
I R R 
I nf usi o n-Relate d Reacti o n  
L L N  
L o wer Li mit of N or mal  
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 /6 5  
 
 
L L O Q  
L o wer Li mit of Q ua ntificati o n  
Ma x  
Ma xi m u m  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
Mi n  
Mi ni m u m  
M T D  
Ma xi m u m T olerate d D ose  
N E  
N ot E val ua ble  
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  
O R R  
O bjecti ve Res p o nse Rate  
O S  
O verall S ur vi val  
 
 
P D  
Pr o gressi ve Disease  
 
 
 
 
P F S  
Pr o gressi o n -Free S ur vi val  
 
 
P K  
P har mac o ki netics  
P R  
Partial Res p o nse  
P T  
Preferre d Ter m  
R E CI S T  
Res p o nse E val uati o n Criteria I n S oli d T u m ors  
R P 2 D  
Rec o m me n de d P hase II D ose  
R T  
Ra di ot hera p y  
S A E  
Seri o us A d verse E ve nt  
S A F  
Safet y A nal ysis Set  
S C R  
Scree ni n g A nal ysis Set  
S D  
Sta ble Disease  
S D T M  
St u d y Data Ta b ulati o n M o del  
S M C  
Safet y M o nit ori n g C o m mittee  
St De v  
Sta n dar d De viati o n  
S O C  
S yste m Or ga n Class  
T 4  
T h yr o xi ne  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
tma x  
Ti me t o Ma xi m u m C o nce ntrati o n  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /6 5  
 
 
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per Li mit of N or mal  
W H O  
W orl d Healt h Or ga nizati o n  
 
3  
M o dific ati o n Hist or y  
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s 
V er si o n  
1. 0  
0 5  N o v  2 0 2 0  
 
 
N/ A –  Fir st  v er si o n  
 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n 
T he  p ur p ose  of  t his I nte grate d  A nal ysis  Pla n  (I A P) is  t o  d oc u me nt  tec h nical  a n d  detaile d 
s pecificati o ns f or t he fi nal a nal ysis of data c ollecte d f or  Parts A , B , a n d F E ( F o o d Effect) of t he 
C li nical T rial P r ot oc ol M S 2 0 1 9 6 4 -0 0 0 1 .  Res ults  of  t he  a nal yses  descri be d  i n  t his I A P will  b e 
i ncl u de d i n t he Cli nical St u d y  Re p ort ( C S R)  after st u d y c o m pleti o n/ data base l oc k . A d diti o nall y, 
t he pla n ne d a nal yses i de ntifie d i n t his I A P will be i ncl u de d i n re g ulat or y s u b missi o ns or f ut ure 
ma n uscri pts.  A n y  p ost -h oc  or  u n pla n ne d  a nal yses  perf or me d  a n d  i ncl u de d i n  t he  CS R , b ut  n ot 
i de ntifie d i n t his pr os pecti ve I A P, will be clearl y i de ntifie d as s uc h i n t he CS R.  
T he I A P is base d o n Secti o n 9 (St atistic al C o nsi der ati o ns ) of t he st u d y pr ot oc ol a n d is pre pare d i n 
c o m plia nce wit h I C H E 9.  
Details o n o ut p uts use d t o s u p p ort re vie w of t he st u d y b y a Safet y M o nit ori n g C o m mittee  ( S M C) 
are a vaila ble i n t he S M C C harter.  
 
 
 
Gl o bal Versi o n I D: C CI
P P D


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /6 5  
 
 
5  
O bjecti ves a n d E n d p oi nts  
P art A:  
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
Pri m ar y  
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D 
a n d/ or t h e M T D of M 3 8 1 4 w h e n gi v e n 
i n c o m bi n ati o n wit h a v el u m a b 
•  O c c urr e n c e of d o s e li miti n g t o xi citi e s ( D L T s )  
1 5. 1  
S e c o n d ar y  
T o e v al u at e t h e s af et y pr ofil e a n d 
t ol er a bilit y of M 3 8 1 4 i n c o m bi n ati o n 
wit h a v el u m a b.  
•  O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o 
t h e N CI-C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s  
•  O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n 
l a b or at or y t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S  
1 5. 2 –  1 5. 6  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s 
of M 3 8 1 4 a n d a v el u m a b w h e n gi v e n 
a s c o m bi n ati o n t h er a p y.  
•  P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s, a s f e a si bl e 
( e g, Cm a x , Cmi n , R a c c[ Cm a x ], R a c c[ A U C] a n d t1/ 2 )  
•  P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C
m a x , tm a x , 
C mi n , Ca v g , fl u ct u ati o n i n d e x, A U C0 -t, A U C0 -∞, 
R a c c [ Cm a x ], Ra c c [ A U C], t1/ 2 , V z/f, C L/f, a n d Λz) 
1 6. 1  
T o e v al u at e t h e i m m u n o g e ni cit y of 
a v el u m a b i n c o m bi n ati o n wit h M 3 8 1 4.  
•  I m m u n o g e ni cit y a s m e a s ur e d b y A D A 
1 6. 3  
T o  e v al u at e  t h e  pr eli mi n ar y  a ntit u m or 
a cti vit y  of  M 3 8 1 4  w h e n  gi v e n  i n 
c o m bi n ati o n  
wit h  
a v el u m a b  
i n 
p arti ci p a nt s  wit h  l o c all y  a d v a n c e d  or 
a d v a n c e d s oli d t u m or s.  
•   C o nfir m e d B O R  a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e I n v e sti g at or  
1 4. 1  
•   C o nfir m e d D O R  a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e I n v e sti g at or  
1 4. 2  
•   P F S ti m e  a c c or di n g t o R E CI S T v 1. 1, a s a s s e s s e d 
b y t h e I n v e sti g at or 
1 4. 4  
•   T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1  
1 4. 3  
•   O v er all S ur vi v al  
1 4. 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /6 5  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
P art B:  
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
Pri m ar y  
T o d et er mi n e a s af e, t ol er a bl e, R P 2 D 
a n d/ or t h e M T D of M 3 8 1 4 w h e n gi v e n 
i n  c o m bi n ati o n  wit h  a v el u m a b  a n d 
r a di ot h er a p y.  
•  O c c urr e n c e of D L T s  
1 5. 1  
S e c o n d ar y  
T o  e v al u at e  t h e  s af et y  pr ofil e  a n d 
t ol er a bilit y  of  M 3 8 1 4  i n  c o m bi n ati o n 
wit h a v el u m a b a n d r a di ot h er a p y.  
 
•  O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s 
a n d tr e at m e nt -r el at e d a d v er s e e v e nt s a c c or di n g t o t h e 
N CI -C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s  
•  O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s, cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S  
•  I n ci d e n c e, s e v erit y a n d o ut c o m e s of R T -i n d u c e d 
t o xi cit y 
1 5. 2 –  1 5. 6  
T o c h ar a ct eri z e t h e p h ar m a c o ki n eti c s 
of M 3 8 1 4 a n d a v el u m a b w h e n gi v e n 
i n c o m bi n ati o n wit h r a di ot h er a p y.  
 
•  P h ar m a c o ki n eti c pr ofil e of a v el u m a b i n t er m s of 
p h ar m a c o k i n eti c p ar a m et er e sti m at e s, a s f e a si bl e ( e g, 
C m a x , C mi n, R a c c[ Cm a x ], R a c c[ A U C] a n d t1/ 2 ) 
•  P h ar m a c o ki n eti c pr ofil e of M 3 8 1 4 i n t er m s of 
p h ar m a c o ki n eti c p ar a m et er e sti m at e s ( C m a x , t m a x, 
C mi n , Ca v g , fl u ct u ati o n i n d e x, A U C0 -t, A U C0 -∞, 
R a c c[ C m a x ], R a c c[ A U C], t 1/ 2 , V z/f, C L/f, a n d Λz) 
1 6. 1  
T o e v al u at e t h e i m m u n o g e ni cit y of 
a v el u m a b i n c o m bi n ati o n wit h M 3 8 1 4 
pl u s r a di ot h er a p y.  
•  I m m u n o g e ni cit y a s m e a s ur e d b y A D A 
1 6. 3  
T o e v al u at e t h e pr eli mi n ar y 
a ntit u m or a cti vit y of M 3 8 1 4 w h e n 
gi v e n i n c o m bi n ati o n wit h a v el u m a b 
a n d r a di ot h er a p y i n p arti ci p a nt s wit h 
•   C o nfir m e d B O R  a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e  I n v e sti g at or 
1 4. 1  
•   C o nfir m e d D O R a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e  I n v e sti g at or 
1 4. 2  
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /6 5  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
l o c all y a d v a n c e d a n d a d v a n c e d s oli d 
t u m or s 
•   P F S ti m e a c c or di n g t o R E CI S T v 1. 1, a s a s s e s s e d b y 
t h e I n v e sti g at or 
1 4. 4  
•   T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1  
1 4. 3  
•   O v er all S ur vi v al  
1 4. 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
P art F E:  
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
Pri m ar y  
T o  d et er mi n e  a n d  c o m p ar e  t h e 
p h ar m a c o ki n eti c  pr ofil e  of  M 3 8 1 4 
u n d er f a st e d a n d f e d c o n diti o n s  
Ar e a u n d er t h e M 3 8 1 4 pl a s m a c o n c e ntr ati o n -ti m e c ur v e 
( A U C) fr o m ti m e z er o t o t h e l a st q u a ntifi a bl e s a m pli n g 
ti m e ( A U C0 -t), a n d m a xi m u m M 3 8 1 4 pl a s m a 
c o n c e ntr ati o n  o b s er v e d ( C m a x ).  
1 6. 1  
S e c o n d ar y  
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /6 5  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
 
T o e v al u at e t h e s af et y pr ofil e a n d 
t ol er a bilit y of M 3 8 1 4 i n c o m bi n ati o n 
wit h a v el u m a b  u n d er f a st e d a n d f e d 
c o n diti o n s  
•  O c c urr e n c e of tr e at m e nt -e m er g e nt a d v er s e e v e nt s a n d 
tr e at m e nt-r el at e d a d v er s e e v e nt s a c c or di n g t o t h e N CI-
C T C A E v 5. 0, a n d s eri o u s a d v er s e e v e nt s  
•  O c c urr e n c e of a b n or m aliti e s ( Gr a d e ≥ 3) i n l a b or at or y 
t e st v al u e s, m ar k e dl y a b n or m al vit al si g n 
m e a s ur e m e nt s, m ar k e dl y a b n or m al p h y si c al 
e x a mi n ati o n m e a s ur e m e nt s,  cli ni c all y si g nifi c a nt 
a b n or m al E C G, m ar k e d c h a n g e s i n E C O G P S  
1 5. 2 –  1 5. 6  
T o e v al u at e t h e i m m u n o g e ni cit y of 
a v el u m a b i n c o m bi n ati o n wit h M 3 8 1 4  
•  I m m u n o g e ni cit y a s m e a s ur e d b y A D A 
1 6. 3  
T o e v al u at e t h e pr eli mi n ar y 
a ntit u m or a cti vit y of M 3 8 1 4 w h e n 
gi v e n i n c o m bi n ati o n wit h a v el u m a b 
a n d r a di ot h er a p y i n p arti ci p a nt s wit h 
l o c all y a d v a n c e d a n d a d v a n c e d s oli d 
t u m or s 
•  C o nfir m e d B O R  a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e  I n v e sti g at or 
1 4. 1  
•  C o nfir m e d D O R  a c c or di n g t o R E CI S T v 1. 1, a s 
a s s e s s e d b y t h e  I n v e sti g at or 
1 4. 2  
•   P F S ti m e  a c c or di n g t o R E CI S T v 1. 1, a s a s s e s s e d b y 
t h e I n v e sti g at or 
1 4. 4  
•   T u m or si z e m e a s ur e m e nt b a s e d o n I n v e sti g at or 
a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1  
1 4. 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /6 5  
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P s e cti o n 
 
 
 
 
 
 
 
 
 
 
 
 
6  
O ver vie w of Pl a n ne d A n al yses  
T his I A P c o vers t he a nal yses f or eff icac y a n d safet y base d o n t he data c ut-off date f or t he fi nal 
a nal ysis ; in a d diti o n, t his I A P descri bes t he i nteri m safet y a nal yses t o be c o n d ucte d f or eac h st u d y 
part , as well as a n i nteri m efficac y a nal ysis f or  Part A or B, w hic he ver is c o m plete d first. Statistical 
a nal yses will be perf or me d usi n g clea ne d  electr o nic case re p ort f or m  (e C R F) data as well as data 
c ollecte d  b y  e xter nal  ve n d ors,  i ncl u di n g 
 p har mac o ki netics  ( P K ) data,  
 a n d i m m u n o ge nicit y data . All data  will be i ncl u de d u p t o a cli nical 
c ut-off date w hic h will be deter mi ne d as descri be d i n t he secti o ns bel o w .  
A data re vie w meeti n g will be hel d pri or t o data base l oc k. I n a d diti o n, n o data base ca n be l oc ke d 
u ntil t his I A P has bee n a p pr o ve d.  
I n a d diti o n t o t he a nal yses descri be d i n t he f oll o wi n g secti o ns, an S M C will re vie w t he safet y a n d 
a n y a vaila ble P K/ P d data of partici pa nts e nr olle d i n a n y part of t he st u d y  o n a re g ular basis . D uri n g 
Part  A  a n d  Part  B,  t he  S M C  will  deci de  o n  rele va nt d ose  li miti n g  t o xi cities  ( D L Ts ) (Pr ot oc ol 
Secti o n 6. 6. 3) base d o n pr ot oc ol criteria. T he  S M C  will deci de b y c o nse ns us o n d ose escalati o n or 
de -escalati o n of M 3 8 1 4, or 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 safe d ose 
(i.e., ma xi m u m t olerate d d ose , M T D) a n d t he Rec o m me n de d P hase II D ose  ( R P 2 D) of M 3 8 1 4 i n 
c o m bi nati o n  wit h  a vel u ma b  ( Part  A)  a n d  wit h  a vel u ma b  a n d  ra di ot hera p y  ( R T) ( Part  B). 
 
 
 
 
6. 1  
I nteri m A n al yses  
T w o  i nteri m safet y  a nal yses,  o ne eac h f or  Part  A a n d Part  B , are  pla n ne d. T he i nteri m safet y 
a nal yses will be li mite d i n sc o pe a n d will i ncl u de a s u bset of t he safet y a nal yses descri be d i n t his 
I A P. Eac h i nteri m safet y a nal ys is will be c o n d ucte d after t he R P 2 D  f or t he gi ve n st u d y part is 
selecte d. T he D L T peri o d f or Part A is defi ne d as t he first 3 wee ks ( 2 1 da ys) of t he st u d y, f oll o wi n g 
t he start of t he st u d y i nter ve nti o n. T he D L T peri o d f or Part B is defi ne d as t he first 4 wee ks ( 2 8 
da ys) of t he st u d y, f oll o wi n g t he start of st u d y i nter ve nti o n.  T he i nteri m safet y a nal yses will be 
c o n d ucte d i n a d diti o n t o re g ularl y pla n ne d S M C meeti n gs.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /6 5  
 
 
O ne i nteri m efficac y a nal ysis f or Part A is pla n ne d. T he i nteri m efficac y a nal ysis will be li mite d 
i n sc o pe a n d will i ncl u de a s u bset of t he efficac y a nal yses descri be d i n t his I A P. T his a nal ysis will 
be c o n d ucte d after all s u bjects i n Part A  are eit her n o l o n ger acti vel y partici pati n g i n t he st u d y, or  
w o ul d be ass u me d t o ha ve c o m plete d at least t w o p ost -baseli ne t u m or assess me nts if still e nr olle d 
i n  t he  st u d y (i.e.,  c o m plete d  t he  pr ot oc ol-s pecifie d  assess me nt  at  t he  Da y  1 1 2  st u d y  visit). 
Alt h o u g h it is n ot a ntici pate d t hat Part B w o ul d be c o m plete d pri or t o Part A, t he i nteri m efficac y  
a nal ysis w o ul d be f or Part B i nste a d of Part A if t hat sce nari o were t o occ ur.  
As all a nal yses i n t his st u d y are c o nsi dere d e x pl orat or y, n o f or mal a dj ust me nt f or m ulti plicit y will 
be u n derta ke n t o acc o u nt f or t his i nteri m efficac y a nal ysis.  
6. 2  
Fi n al A n al ysis  
T he Fi nal A nal ysis of t he st u d y will i ncl u de all a nal yses descri be d i n t his I A P a n d will i ncl u de 
data fr o m partici pa nts i n Part A , Part B , a n d Part F E. Eac h st u d y part will be prese nte d i n a se parate 
set of o ut p uts, wit h se parate c ol u m ns f or eac h d ose le vel. 
All fi nal, pla n ne d a nal yses f or t he C S R t hat are i de ntifie d i n t he Cli nical Trial  Pr ot oc ol a n d i n t his 
I A P will be perf or me d o nl y after t he st u d y e n ds. T he st u d y will e n d w he n 1 year has passe d fr o m 
t he  da y  t he  last  partici pa nt i n a n y  of  t he  t hree  st u d y  parts  has  recei ve d  t he  last  d ose  of  st u d y 
i nter ve nti o n or all partici pa nts are n o l o n ger acti vel y partici pati n g i n t he st u d y , w hic he ver c o mes 
first.  
A data re vie w meeti n g will be hel d pri or t o data base l oc k  f or a n y a nal ysis. I n a d diti o n, n o data base 
ca n be l oc ke d a n d u n til t his I A P has bee n a p pr o ve d.  
 
7  
C h a n ges  t o  t he  Pl a n ne d  A n al yses  i n  t he 
Cli nic al 
St u d y  
Pr ot oc ol  
T he statistical met h o ds as descri be d i n t he pr ot oc ol were a d o pte d.  T he f oll o wi n g c ha n ges t o t he 
pla n ne d a nal yses  were ma de .  
M 3 8 1 4 a n d M 3 8 1 4 met a b olite ( 0 -de met h yl ate d pr o d uct M 4 6 7)  p h ar m ac o ki netic p ar a meters liste d i n 
pr ot oc ol n o l o n ger t o be c alc ul ate d  
A U C 0 -t 
Area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me of d osi n g t o t he ti me of 
t he last o bser vati o n 
A U C 0 -∞ 
A U C fr o m ti me of d osi n g t o i nfi nit y  
C mi n  
Mi ni m u m c o nce ntrati o n o bser ve d p ost d ose  
C a v g 
A vera ge c o nce ntrati o n at stea d y state  
C L/f  
Oral cleara nce  
V z/f 
A p pare nt v ol u me of distri b uti o n  
Fl uct uati o n i n de x  
Fl uct uati o n bet wee n ma xi m u m a n d mi ni m u m c o nce ntrati o ns  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /6 5  
 
 
Please refer t o Secti o n  1 6. 1  f or a c o m plete list of P K para meters w hic h will be re p orte d. 
 
8  
Pr ot oc ol De vi ati o ns  a n d A n al ysis P o p ul ati o ns  
8. 1  
Defi niti o n of Pr ot oc ol De vi ati o ns  a n d A n al ysis P o p ul ati o ns  
I m p orta nt pr ot oc ol de viati o ns (I P Ds) are pr ot oc ol de viati o ns t hat c o ul d  i m pact t he c o m plete ness, 
acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht a d versel y  affect a partici pa nt's ri g hts, 
safet y, or well-bei n g.  
I m p orta nt pr ot oc ol de viati o ns i ncl u de, b ut are n ot li mite d t o: 
•  Partici pa nts bei n g e nr olle d i n t he st u d y des pite  n ot satisf yi n g t he i ncl usi o n/e xcl usi o n criteria;  
•  Partici pa nts de vel o pi n g wit h dra wal criteria w hile o n t he st u d y b ut n ot bei n g wit h dra w n;  
•  Partici pa nts recei vi n g t he i nc orrect d ose  of st u d y treat me nt ; 
•  Partici pa nts recei vi n g a n e xcl u de d c o nc o mita nt me dicati o n;  
•  Partici pa nts  faili n g  t o  c o m plete  visits/st u d y  acti vities  o utli ne d  i n  t he  Sc he d ule  of 
Assess me nts wit h o ut a n a p pr o ve d reas o n ; 
•  De viati o ns fr o m G C P.  
A  c o m plete  list  of  pr ot oc ol  de viati o ns  pr os pecti vel y  defi ne d  f or  t his  st u d y  is  a vaila ble  i n  t he 
Pr ot oc ol  De viati o n  G ui da nce  d oc u me nt . All I P Ds will  be  d oc u me nte d  i n  t he  Cli nical  Trial 
Ma na ge me nt S yste m ( C T M S) a n d i n t he St u d y Data Ta b ulati o n M o del ( S D T M) datasets, w het her 
i de ntifie d t hr o u g h site m o nit ori n g, me dical re vie w, or data ma na ge me nt pr o gra m m i n g. 
Pr ot oc ol  de viati o ns  attri b ute d  t o  t he  i m pact  of  t he  n o vel  c or o na vir us  disease  ( C O VI D -1 9) 
pa n de mic  will  be  la bele d  acc or di n gl y.  B ot h  i m p orta nt  a n d  n o n -i m p orta nt  pr ot oc ol  de viati o ns 
attri b uta ble t o t he C O VI D -1 9 pa n de mic will be i ncl u de d i n t he S D T M data sets. 
Please refer t o Secti o n  1 0. 3  f or details o n re p orti n g of pr ot oc ol de viati o ns. 
8. 2  
Defi niti o n of A n al ysis P o p ul ati o ns  a n d S u b gr o u ps  
U nless ot her wise s pecifie d, partici pa nts will be a nal yze d acc or di n g t o t he treat me nt gr o u p/c o h ort 
assi g ne d at scree ni n g.  
Scree ni n g A n al ysis Set  ( S C R) 
T he Scree ni n g  A nal ysis S et i ncl u des all partici pa nt s w h o si g ne d t he i nf or me d c o nse nt f or m . 
F ull A n al ysis Set ( F A S)/ S afet y (S A F) A n al ysis Set  
T he F A S/ S A F  A nal ysis S et i ncl u des all partici pa nts w h o recei ve d at least o ne n o n -zer o d ose of  
a n y st u d y  i nter ve nti o n.  St u d y  i nter ve nti o n  i ncl u des  a vel u ma b,  M 3 8 1 4,  a n d  i n  t he  case  of 
partici pa nts i n Part B, R T . 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /6 5  
 
 
D ose Li miti n g T o xicit y ( D L T)  A n al ysis  Set  
T he D L T A nal ysis  S et is defi ne d f or t he d ose -escalati o n Parts A a n d B  a n d i ncl u des all partici pa nts 
w h o are D L T e val u able . T his p o p ulati o n is n ot defi ne d f or Part F E . 
•  P art A:  T he D L T A nal ysis S et i ncl u des all partici pa nts w h o ha ve recei ve d at least 3 4 of 
4 2 dail y d oses of M 3 8 1 4, 2 a d mi nistrati o ns of a vel u ma b, a n d c o m plete t he D L T peri o d . 
A d diti o nall y , partici pa nts treate d i n d ose escalati o n c o h orts w h o e x perie nce a D L T d uri n g 
t he D L T peri o d, re gar dless of t he a m o u nt of st u d y i nter venti o n recei ve d or c o m pleti o n of 
t he D L T peri o d are i ncl u de d . 
F or Part A, t he D L T  peri o d is defi ne d as t he first 3 wee ks  ( 2 1 da ys) of t he st u d y, f oll o wi n g 
t he start of a n y st u d y i nter ve nti o n. 
•  P art B : T he D L T A nal ysis S et i ncl u des all partici pa nts w h o ha ve r ecei ve d at least 8 of 1 0 
dail y  d oses  of  M 3 8 1 4  a n d  3  a d mi nistrati o ns  of  a vel u ma b  a n d  8  fracti o ns  of  R T  a n d 
c o m plete t he D L T  peri o d . A d diti o nall y, partici pa nts treate d i n d ose escalati o n c o h orts w h o 
e x perie nce a D L T d uri n g t he D L T peri o d, re gar dless of t he a m o u nt of st u d y i nter ve nti o n 
recei ve d or c o m pleti o n of t he D L T peri o d are i ncl u de d. 
F or Part B , t he DL T  peri o d is defi ne d as t he first 4 wee ks ( 2 8 da ys) of t he st u d y, f oll o wi n g 
t he start of a n y st u d y i nter ve nti o n. 
P h ar m ac o ki netic ( P K) A n al ysis Set  
T he P K A nal ysis Set  is defi ne d se paratel y f or Parts A/ F E a n d B. 
•  P art  A a n d P art F E : T he  P K A nal ysis S et  i ncl u des all  partici pa nts  w h o  c o m plete  1 
a d mi nistrati o n  of  M 3 8 1 4  a n d  a vel u ma b  starti n g  o n  Da y  1  a n d  w h o  pr o vi de  at  least  1 
p ost -d ose sa m ple wit h meas ura ble c o nce ntrati o ns of M 3 8 1 4.  
•  P art B:  T he P K A nal ysis S et i ncl u des all partici pa nts w h o ha ve recei ve d at least t he first 
d ose  of  M 3 8 1 4 a n d  w h o  pr o vi de  at  least  1  p ost -d ose  sa m ple  wit h  meas ura ble 
c o nce ntrati o ns of M 3 8 1 4 . 
  
 
 
  
 
 
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /6 5  
 
 
 
 
 
  
 
 
  
 
 
 
 
I m m u n o ge nicit y ( A D A) A n al ysis Set 
T he A D A A nal ysis Set i ncl u des all partici pa nts w h o c o m plete at least o ne  a d mi nistrati o n of b ot h 
M 3 8 1 4 a n d a vel u ma b a n d ha ve at least o ne vali d A D A res ult.
 
T a ble 1 : S u m m ar y of A n al ys es a n d Ass oci ate d A n al ysis Sets 
A n al y s e s  
S C R  
S A F  
F A S  
D L T  
P K  
M 3 8 1 4 -
B M -P d  
B M -
T u  
B M -
I P 
B M -
P d  
P Gt  
A D A  
Di s p o siti o n  
✓ 
 
 
 
 
 
 
 
 
 
 
B a s eli n e A s s e s s m e nt s  
 
✓ 
 
 
 
 
 
 
 
 
 
Pr e vi o u s a n d C o n c o mit a nt 
T h er a pi e s  
 
✓ 
 
 
 
 
 
 
 
 
 
C o m pli a n c e a n d E x p o s ur e  
 
✓ 
 
 
 
 
 
 
 
 
 
Effi c a c y  
 
 
✓ 
 
 
 
 
 
 
 
 
S af et y: D L T s a n d M T D/ 
R P 2 D  
 
 
 
✓ 
 
 
 
 
 
 
 
Ot h er S af et y a n d 
T ol er a bilit y  
 
✓ 
 
 
 
 
 
 
 
 
 
P h ar m a c o ki n eti c A n al y si s  
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I m m u n o g e ni cit y ( A D A) 
A n al y si s  
 
 
 
 
 
 
 
 
 
 
✓ 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /6 5  
 
 
 
9  
Ge ner al S pecific ati o ns f or D at a A n al yses  
U nless ot her wise i n dicate d, s u m mar y ta bles will be prese nte d se paratel y f or eac h st u d y part, b y 
d ose le vel  a n d o verall , base d o n t he a nal ysis set of i nterest; listi n gs will be prese nte d usi n g t he 
sa me a nal ysis sets as t he c orres p o n di n g ta bles.  Data fr o m t he t hree se parate st u d y parts will n ot be 
a g gre gate d f or a n y a nal yses.  
9. 1  
Ge ner al S pecific ati o ns a n d Defi niti o ns  f or A n al ysis 
P o oli n g of ce nters  
Data will be p o ole d acr oss ce nters.  
D at a h a n dli n g after i nteri m a n al ysis c ut -off d ate  
Data  after  t he  c ut -off  date  ma y  n ot  u n der g o  t he  clea ni n g  pr ocess  a n d  will  n ot  be  dis pla ye d  i n  a n y 
listi n gs or use d f or s u m mar y statistics, statistical a nal yses, or i m p utati o ns. F or e xa m ple, la b orat or y 
val ues of sa m ples ta ke n after data c ut -off, a d verse e ve nts ( A Es ) wit h o nset date after data c ut -off, 
etc. will n ot be i ncl u de d i n a n y a nal ysis or listi n g. St o p dates, h o we ver, are n ot affecte d b y t his 
r ule –  e. g. if a n A E starts pri or t o t he c ut -off, b ut st o ps after date of c ut -off, t he A E e n d date will 
be i nc l u de d i n listi n gs. 
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles  
C o nti n u o us  varia bles  will  be  s u m marize d  usi n g  descri pti ve  statistics  i.e.,  n u m ber  of  s u bjects 
c o nsi dere d a n d n u m ber of missi n g val ues, [i.e., n ( missi n g)], mea n, me dia n, sta n dar d de via ti o n 
( St De v), mi ni m u m, ma xi m u m a n d first a n d t hir d q uartile ( Q 1 a n d Q 3). As per ge neral re p orti n g 
c o n ve nti o ns, mea n, me dia n, Q 1, a n d Q 3  will be dis pla ye d wit h o ne m ore deci mal place t ha n t he 
ra w data; St De v will be dis pla ye d usi n g t w o m ore deci mal places tha n t he ra w data. Perce nta ges 
will be re p orte d t o o ne deci mal place. R o u n di n g will be perf or me d t o cl osest i nte ger/ deci mal usi n g 
t he c o m m o n mi d-p oi nt bet wee n t he t w o c o nsec uti ve val ues –  e. g., 5. 1 t o 5. 4 will be r o u n de d t o a n 
i nte ger of 5, a n d 5. 5 t o 5. 9 will be r o u n de d t o a n i nte ger of 6.  
Q ualitati ve varia bles will be s u m marize d b y fre q ue nc y c o u nts a n d perce nta ges. U nless ot her wise 
state d,  t he  calc ulati o n  of  pr o p orti o ns/ perce nta ges  f or  a  gi ve n  q ualitati ve  varia ble  will  i ncl u de 
s u bjects wit h missi n g val ues i n t he de n o mi nat or. W he n a p plica ble, c o u nts of missi n g o bser vati o ns 
f or a q ualitati ve varia ble will be prese nte d o n s u m mar y ta bles.  
U nless ot her wise s pecifie d, perce nta ges will be base d o n t he n u m ber of s u bjects i n t he a nal ysis set 
use d f or t he gi ve n s u m mar y.  
F or prese ntati o n of P K res ults please refer t o Secti o n 9. 2 . 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /6 5  
 
 
Defi niti o n of b aseli ne  
I n ge neral, t he last n o n-missi n g meas ure me nt pri or t o t he first st u d y i nter ve nti o n will ser ve as t he 
b aseli ne  meas ure me nt.  St u d y  i nter ve nti o n  i ncl u des  a vel u ma b,  M 3 8 1 4,  a n d  i n  t he  case  of 
partici pa nts i n Part B, R T . If t he ti me of a n assess me nt  a n d/ or t he ti me of  t he i nitial d osi n g are 
u n k n o w n  a n d d osi n g date a n d assess me nt d ate are t he sa me, t he f oll o wi n g r ule is use d: assess me nts 
i nte n de d t o be c o m plete d pri or t o d osi n g, as per pr ot oc ol, a n d c o m plete d o n sc he d ule d visits are 
ass u me d t o  ha ve  bee n  perf or me d pri or t o  d osi n g a n d ma y be selecte d as  baseli ne; assess me nts 
c o m plete d  o n u nsc he d ule d visits  are ass u me d t o ha ve  bee n perf or me d  after  d osi n g a n d are n ot 
eli gi ble f or selecti o n as baseli ne. U nsc he d ule d assess me nts w hic h occ ur u na m bi g u o usl y pri or t o 
t he start of a n y st u d y i nter ve nti o n are eli gi ble f or selecti o n as baseli ne.  
De fi niti o n of c h a n ge fr o m b aseli ne 
C ha n ge fr o m baseli ne = visit val ue –  baseli ne val ue  
Perce nt C ha n ge fr o m Baseli ne = 1 0 0 * ( visit val ue –  baseli ne val ue) / baseli ne val ue  
Si g nific a nce le vel  
All statistical tests me nti o ne d i n t his I A P are t o be re gar de d as e x pl orat or y. If c o nfi de nce i nter vals 
( CIs) are t o be calc ulate d, t hese will be t w o -si de d wit h a c o nfi de nce pr o ba bilit y of 9 5 %, u nless 
ot her wise s pecifie d i n t his I A P.  
C o n versi o n f act ors  
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years:  
1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.  
Details  f or deter mi nati o n of partici pa nt a ge a n d b o d y mass i n de x ( B MI ) are gi ve n i n Secti o n  1 1. 1. 
Defi niti o n of d ur ati o n  
D urati o n will be calc ulate d b y t he differe nce of start a n d st o p date + 1 . F or e xa m ple, A E d urati o n 
( da ys) = A E e n d date  –  A E start date  + 1  
U nless ot her wise s pecifie d, t he ti me si nce a n e ve nt will be calc ulate d as refere nce date mi n us date 
of e ve nt . F or e xa m ple, ti me si nce last d ose date will be calc ulate d as t he e ve nt date –  t he date of 
last d ose. 
Defi niti o n of tre at me nt d a y  
Treat me nt  da y  is  defi ne d  relati ve  t o  t he  date  of  first  d ose  of  a n y  st u d y  i nter ve nti o n.  St u d y 
i nter ve nti o n  i ncl u des  a vel u ma b,  M 3 8 1 4,  a n d  i n  t he  case  of  partici pa nts  i n  Part  B, R T .  Da y  1 
re prese nts t he first da y of treat me nt; t he da y bef ore is defi ne d as Da y -1 ( n o Da y 0 is defi ne d).  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /6 5  
 
 
Defi niti o n of o n -tre at me nt peri o d 
T he o n -treat me nt peri o d is defi ne d as t he ti me fr o m t he first d ose of st u d y treat me nt t hr o u g h t he 
mi ni m u m of ( last date of st u d y i nter ve nti o n + 3 0 da ys, start da y of ne w a nti-ca ncer dr u g t hera p y 
–  1 da y, deat h).  
Sc he d ule d a n d u nsc he d ule d visits  
Assess me nts fr o m u nsc he d ule d visits will be c o nsi dere d f or t he deri vati o n of baseli ne val ues a n d 
w orst o n -treat me nt val ues a n d gra des; t he y will als o be i ncl u de d i n listi n gs. Please see Secti o n  9.3  
f or details o n visit wi n d o wi n g. 
S oft w are  
All a nal yses will  be perf or me d usi n g S A S ®  S oft ware versi o n 9. 4 or hi g her , wit h t he e xce pti o n of 
M 3 8 1 4 a n d M 4 6 7 P K  para meters w hic h will be deri ve d usi n g n o nc o m part me ntal met h o ds wit h 
t he  vali date d  c o m p uter  pr o gra m  P h oe ni x®  Wi n N o nli n
®  8. 0  or  hi g her  ( Certara,  L. P.,  Pri ncet o n , 
Ne w Jerse y, U S A).  
9. 2  
Prese nt ati o n of P h ar m ac o ki netic Res ults  
9. 2. 1  
Prese nt ati o n of P h ar m ac o ki netic C o nce ntr ati o n D at a  
M 3 8 1 4 , 0 -de m et h ylate d  pr o d uct  M 4 6 7 (if  a vaila ble), a n d  a vel u ma b  c o nce ntrati o n  data  will  be 
descri pti vel y  s u m marize d  usi n g:  n u m ber  of  n o n -missi n g o bser vati o ns  ( n ),  arit h metic  mea n 
( Mea n),  sta n dar d  de viati o n  ( StDe v ),  c oefficie nt  of  variati o n  ( C V %),  mi ni m u m  ( Mi n),  me dia n 
( Me dia n) a n d ma xi m u m ( Ma x). I n cases wit h  n ≤ 2, o nl y n, Mi n, a n d Ma x will be re p orte d.  
Descri pti ve  statistics  of  P K  c o nce ntrati o n  data  will  be  calc ulate d  usi n g  val ues  wit h  t he  sa me 
precisi o n as t he s o urce data a n d r o u n de d f or re p orti n g p ur p oses o nl y. T he f oll o wi n g c o n ve nti o ns 
will be a p plie d w he n re p orti n g descri pti ve statistics of P K c o nce ntrati o n data:  
Mea n, Mi n, Me dia n, Ma x:  
3 si g nifica nt di gits  
St De v : 
4 si g nifica nt di gits  
C V %:  
1 deci mal place  
9. 2. 2  
Prese nt ati o n of P h ar m ac o ki netic P ar a meter D at a  
P har mac o ki netic para meter data will be descri pti vel y s u m marize d usi n g: n , Mea n, St De v , C V %, 
Mi n,  Me dia n,  Ma x,  ge o metric  mea n  ( Ge o Mea n), 
a n d t he  ge o metric  c oefficie nt  of  variati o n 
( Ge o C V). F or ti me t o reac h ma xi m u m o bser ve d c o nce ntrati o n (t ma x ), o nl y n, Mi n, Me dia n, a n d 
Ma x will be re p orte d.  I n cases wit h n ≤ 2, o nl y n, Mi n, a n d Ma x will be re p orte d. T he P K para meter 
ma xi m u m o bser ve d plas ma c o nce ntrati o n ( C ma x ) will be re p orte d wit h t he sa me precisi o n as t he 
s o urce data. All ot her P K para meters will be re p orte d t o 3 si g nifica nt fi g ures. I n e x p ort datasets, 
as well as i n t he S D T M P P d o mai n, P K para meters will be pr o vi de d wit h f ull precisi o n, a n d will 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /6 5  
 
 
n ot be r o u n de d. Descri pti ve statistics of P K para meter data will be calc ulate d usi n g f ull precisi o n 
val ues  a n d r o u n de d f or re p orti n g p ur p oses o nl y.  
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of P K para meter 
data:  
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n:  
3 Si g nifica nt di gits  
St De v : 
4 Si g nifica nt di gits  
C V %, Ge o C V %:  
1 d eci mal place   
9. 2. 3  
Visit Wi n d o wi n g  
T he assi g n me nt of visit wi n d o ws is descri be d i n  Ta ble 2  a n d Ta ble 3  f or Part A a n d Part F E  
s u bjects, a n d Ta ble 4  a n d Ta ble 5  f or Part B s u bjects f or t he p ur p ose of b y-visit a nal yses of 
la b orat or y assess me nts, vital si g ns ( V S), a n d electr ocar di o gra m ( E C G ) data. I n a d diti o n t o t h ose 
ta bles, t he f oll o wi n g r ules will be use d f or assi g n me nt of visits : 
•  Baseli ne will be deri ve d as descri be d i n Secti o n  9. 1. 
•  B ot h sc he d ule d a n d u nsc he d ule d assess me nts are c o nsi dere d i n  visit wi n d o wi n g.  
•  N o  visit  wi n d o wi n g  will  be  perf or me d  at  E n d -of -Treat me n t, S afet y  F oll o w -u p ,  or 
L o n g -T er m  F oll o w -u p  visits.  I nstea d,  t he  earliest  n o n -missi n g  o bser vati o n  a m o n g  t he 
u nsc he d ule d or sc he d ule d assess me nts f or eac h visit will be use d.  
•  If t here are m ulti ple assess me nts f or a n y s pecifie d visit a n d s o me of t he m are fr o m sc he d ule d 
visits wit h n o n -missi n g assess me nt res ults, t he assess me nt fr o m s c he d ule d visit t hat is cl osest 
t o t he pla n ne d st u d y da y will be use d f or a nal ysis. If t w o sc he d ule d visits are e q uall y s pace d 
ar o u n d t he assi g ne d st u d y da y, t he earlier of t he t w o will be use d.  
•  If t here are m ulti ple assess me nts f or a n y s pecifie d visit a n d n o ne of t he m are fr o m sc he d ule d 
visits, t he assess me nt wit h n o n -missi n g res ults a n d cl osest t o t he pla n ne d st u d y da y will be 
use d.  
•  If t here are t w o or m ore u nsc he d ule d assess me nts wit h n o n-missi n g res ults a n d t he sa me 
dista nce t o t he pla n ne d st u d y da y, t h e assess me nt pri or t o t he pla n ne d st u d y da y will be use d 
i n deri vi n g visit wi n d o w. F or e xa m ple, if t he la b assess me nt was d o ne o n b ot h St u d y Da y -1 
a n d 1, t he n t he assess me nt o n St u d y Da y -1 will be use d f or visit wi n d o wi n g.  
 
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /6 5  
 
 
T a ble 2 : Visit Wi n d o w Defi niti o n f or L a b Assess me nts f or P art A & F E P artici p a nts  
Assi g n e d St u d y D a y (I ncl usi v e)  
Pl a n n e d St u d y 
D a y ( A W T A R G E T)  
A n al ysis Visit 
( N) ( A VI SI T N) 
A n al ysis Visit ( A VI SI T)  
Fr o m ( A WL O)  
T o ( A W HI)  
-2 8  
-1  
-1  
1 0 0  
Scree ni n g  
~  
1  
 
1  
Baseli ne  
1  
4  
1  
1 0 1  
Visit 1 Da y 1  
5  
2 5  
2 2  
1 0 3  
Visit 3 Da y 2 2  
2 6  
3 2  
2 9  
1 0 4  
Visit 4 Da y 2 9  
3 3  
6 0  
5 7  
1 0 6  
Visit 6 Da y 5 7  
6 1  
8 8  
8 5  
1 0 8  
Visit 8 Da y 8 5  
F urt her la b visits are sc he d ule d f or e ve n visit n u m bers ( X = 1 2, 1 4, …), a n d t he f oll o wi n g al g orit h m ca n be a p plie d: 
Y -2 4  
Y + 3  
Y  =  ( X-2) * 1 4 + 1  
1 0 0 + X  
Visit X Da y Y  
 
T a ble 3 : Visit  Wi n d o w  Defi niti o n  f or  Vit al  Si g n  &  E C G  Assess me nts  f or  P art  A  &  F E 
P artici p a nts  
Assi g n e d St u d y D a y (I ncl usi v e)  
Pl a n n e d St u d y 
D a y ( A W T A R G E T) 
A n al ysis Visit 
( N) ( A VI SI T N) 
A n al ysis Visit ( A VI SI T)  
Fr o m ( A WL O)  
T o ( A W HI)  
-2 8  
-1  
-1  
1 0 0  
Scree ni n g *  
~  
1  
 
1  
Baseli ne *  
1  
4  
1  
1 0 1  
Visit 1 Da y 1 *  
5  
1 8  
1 5  
1 0 2  
Visit 2 Da y 1 5 *  
1 9  
2 5  
2 2  
1 0 3  
Visit 3 Da y 2 2 *  
2 6  
3 2  
2 9  
1 0 4  
Visit 4 Da y 2 9  
3 3  
4 6  
4 3  
1 0 5  
Visit 5 Da y 4 3  
4 7  
6 0  
5 7  
1 0 6  
Visit 6 Da y 5 7  
6 1  
7 4  
7 1  
1 0 7  
Visit 7 Da y 7 1  
7 5  
8 8  
8 5  
1 0 8  
Visit 8 Da y 8 5  
* Visit als o i ncl u des E C G assess me nt.  
F urt her vital si g n assess me nts are sc he d ule d at eac h bi wee kl y visit, a n d t he f oll o wi n g al g orit h m ca n be a p plie d: 
Y -1 0  
Y + 3  
Y  =  ( X-2) * 1 4 + 1  
1 0 0 + X  
Visit X Da y Y  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /6 5  
 
 
 
T a ble 4 : Visit Wi n d o w Defi niti o n f or L a b  Assess me nt s f or P art B P artici p a nts  
Assi g n e d St u d y D a y (I ncl usi v e)  
Pl a n n e d St u d y 
D a y ( A W T A R G E T)  
A n al ysis Visit 
( N) ( A VI SI T N) 
A n al ysis Visit ( A VI SI T)  
Fr o m ( A WL O)  
T o ( A W HI)  
-3 5  
-1  
-1  
1 0 0  
Scree ni n g  
~  
1  
 
1  
Baseli ne  
1  
1  
1  
2 0 2  
Part B Visit 2 Da y 1  
2  
7  
5  
2 0 6  
Part B Visit 6  Da y 5  
8  
1 5  
1 2  
2 1 1  
Part B Visit 1 1  Da y 1 2  
1 6  
4 3  
2 9  
2 1 3  
Part B Visit 1 3 Da y 2 9  
 
T a ble 5 : Visit Wi n d o w Defi niti o n f or Vit al Si g n & E C G Assess me nts f or P art B P artici p a nts  
Assi g n e d St u d y D a y (I ncl usi v e)  
Pl a n n e d St u d y 
D a y ( A W T A R G E T)  
A n al ysis Visit 
( N) ( A VI SI T N) 
A n al ysis Visit ( A VI SI T)  
Fr o m ( A WL O)  
T o ( A W HI)  
-3 5  
-1  
-1  
2 0 0  
Scree ni n g  
~  
1  
 
1  
Baseli ne  
1  
1  
1  
2 0 2  
Part B Visit 2 Da y 1 *  
2  
2  
2  
2 0 3  
Part B Visit 3 Da y 2  
3  
3  
3  
2 0 4  
Part B Visit 4 Da y 3  
4  
4  
4  
2 0 5  
Part B Visit 5 Da y 4  
5  
5  
5  
2 0 6  
Part B Visit 6 Da y 5  
8  
8  
8  
2 0 7  
Part B Visit 7 Da y 8  
9  
9  
9  
2 0 8  
Part B Visit 8 Da y 9  
1 0  
1 0  
1 0  
2 0 9  
Part B Visit 9 Da y 1 0  
1 1  
1 1  
1 1  
2 1 0  
Part B Visit 1 0 Da y 1 1  
1 2  
1 3  
1 2  
2 1 1  
Part B Visit 1 1 Da y 1 2  
1 4  
1 6  
1 5  
2 1 2  
Part B Visit 1 2  Da y 1 5  
1 7  
3 0  
2 9  
2 1 3  
Part B Visit 1 3 Da y 2 9 *  
* Visit als o i ncl u des E C G assess me nt.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /6 5  
 
 
9. 3  
H a n dli n g of Missi n g D at a a n d I m p ut ati o n R ules  
H a n dli n g of missi n g d at a:  
U nless ot her wise s pecifie d, missi n g data will n ot be re place d.  
I n all partici pa nt data listi n gs, i m p ute d val ues will be prese nte d a n d fla g ge d as s uc h.  
Missi n g statistics, e. g. , w he n t he y ca n n ot be calc ulate d, s h o ul d be prese nte d as “ n d” ( n ot d o ne).  
F or e xa m ple, if n = 1, t he meas ure of varia bilit y ( St De v) ca n n ot be c o m p ute d a n d will be prese nte d 
as “ n d”. 
U nless  ot her wise  s pecifie d,  t he  n u m ber  of  s u bjects  c o u nte d  as  “ missi n g”  is  t he  n u m ber  of 
partici pa nts i n t he rele va nt a nal ysis p o p ulati o n mi n us t he n u m ber of n o n -missi n g res ults f or t he 
gi ve n a nal ysis.  
Ha n dli n g of missi n g data f or P K para meter calc ulati o ns is disc usse d u n der Secti o n  1 6. 1. 
L a b or at or y d at a o utsi de t he li mit of q u a ntit ati o n  
F or la b orat or y assess me nts i n dicati n g t hat t he sa m ple teste d bel o w t he l o wer li mit of q ua ntitati o n 
( L L O Q) f or t he a nal yte i n q uesti o n, half t he l o wer li mit of q ua ntitati o n ( ½ * L L O Q) will be use d as 
t he  a nal ysis  val ue.  F or  la b orat or y  assess me nts  testi n g  a b o ve  t he  u p per  li mit  of  q ua ntitati o n 
( U L O Q), t he a nal ysis val ue will be i m p ute d as { U L O Q + 1 *(t he le vel of precisi o n of U L O Q) }. 
F or e xa m ple, if a n assess me nt tests at a val ue “ > 7. 0”, t he le vel of precisi o n is 0. 1 a n d t he a nal ysis 
val ue will be 7. 1. T he i m p ute d a nal ysis val ues will be use d i n all a nal yses (e. g. , s u m mar y statistics) 
a n d will be use d f or deter mi nati o n of t o xicit y gra di n g. Listi n gs will prese nt t he sta n dar dize d u nit 
val ues  as  pr o vi de d  i n  t he  ra w  data,  i n dicati n g  t he  assess me nt  val ue  was  n ot  q ua ntifia ble  (e. g. , 
“ > 7. 0”). 
Partial dates will be i m p ute d as f oll o ws:  
Dise ase hist or y  
I nc o m plete  dates  f or  disease  hist or y  (e. g., i nitial  dia g n osis  date,  date  of  d oc u me nte d,  l ocall y 
a d va nce d,  i n o pera ble  or  metastati c  disease  dia g n osis,  date  of res p o nse  or pr o gressi o n t o pri or 
treat me nt) will be i m p ute d as f oll o ws:  
•  If t he da y is missi n g, it will be i m p ute d t o t he 1 5t h da y of t he m o nt h.  
•  If  b ot h  da y  a n d  m o nt h  are  missi n g  a n d  t he  year  is  pri or  t o  t he  year  of  t he  first st u d y 
treat me nt, t he m o nt h a n d da y will be i m p ute d as J ul y 1st.  
•  If  b ot h  da y  a n d  m o nt h  are  missi n g  a n d  t he  year  is  sa me  as  t he  year  of  t he  first  st u d y 
treat me nt, t he m o nt h a n d da y will be i m p ute d as Ja n uar y 1st.  
•  If t he date is c o m pletel y missi n g, n o i m p utati o n will be perf or me d.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /6 5  
 
 
A d verse E ve nts  
I nc o m plete A E-relate d dates will be i m p ute d as f oll o ws:  
•  If t he A E o nset date is missi n g c o m pletel y, t he n t he o nset date will be re place d b y t he start 
of st u d y i nter ve nti o n.  
•  If o nl y t he da y part of t he A E o nset date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he 
start of st u d y i nter ve nti o n, t he n t he A E o nset date will be re place d b y t he start of st u d y 
i nter ve nti o n. F or e xa m ple, if t he A E o nset date is --/J A N/ 2 0 1 5, a n d st u d y i nter ve nti o n start 
date is 1 5/J A N/ 2 0 1 5, t he n t he i m p ute d A E o nset date will be 1 5/J A N/ 2 0 1 5.  
•  If b ot h t he da y a n d m o nt h of t he A E o nset date are missi n g b ut t he o nset year is e q ual t o 
t he start of st u d y i nter ve nti o n, t he n t he o nset date will be re place d b y t he mi ni m u m o f t he 
start of st u d y i nter ve nti o n a n d A E st o p date . F or e xa m ple, if A E o nset date is --/---/ 2 0 1 4, 
a n d st u d y i nter ve nti o n start date is 1 9/ N O V/ 2 0 1 4, t he n t he i m p ute d A E o nset date will be 
1 9/ N O V/ 2 0 1 4.  
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1.  
•  I nc o m plete st o p date will be re place d b y t he last da y of t he m o nt h (if da y is missi n g o nl y), 
if n ot res ulti n g i n a date later t ha n t he date of s u bject's deat h. I n t he latter case t he date of 
deat h will be use d t o i m p ute t he  i nc o m plete st o p date.  
•  I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d. 
Pri or/ C o nc o mit a nt Me dic ati o n  
I nc o m plete pri or/c o nc o mita nt me dicati o n dates will be i m p ute d as f oll o ws:  
•  If t he me dicati o n date is missi n g c o m pletel y, t he n t he me dicati on date will be re place d b y t he 
start date of t he first st u d y i nter ve nti o n . 
•  If t he da y of me dicati o n date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start date of  
t he first st u d y i nter ve nti o n, t he n t he me dicati o n date will be re place d b y t he start date of  t he 
first  st u d y  i nter ve nti o n.  F or  e xa m ple,  if  t he  me dicati o n  start  date  is --/J A N/ 2 0 1 5,  a n d st u d y 
i nter ve nti o n start  date  is  1 5/J A N/ 2 0 1 5,  t he n  t he  i m p ute d  me dicati o n  start  date  will  be 
1 5/J A N 2 0 1 5.  
•  If b ot h t he da y a n d m o nt h of me dicati o n start date are missi n g b ut t he start year is e q ual t o t he 
start date of  t he first st u d y i nter ve nti o n, t he n t he me dicati o n date will be re place d b y t he start 
date of  t he first st u d y i nter ve nti o n. F or e xa m ple, if t he me dicati o n start date is --/---/ 2 0 1 4, a n d 
st u d y i nter ve nti o n start date is 1 9/ N O V/ 2 0 1 4, t he n t he i m p ute d me dicati o n start date will be 
1 9/ N O V/ 2 0 1 4.  
•  I n all ot her cases, t he missi n g me dicati o n da y or m o nt h will be re place d b y 1. 
•  I n t he case t hat t he i mp ute d start date occ urs after t he me dicati o n e n d date, t he me dicati o n e n d 
date will be use d as t he start date.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /6 5  
 
 
•  I nc o m plete e n d date will be re place d b y t he last da y of t he m o nt h (if da y is missi n g o nl y), if n ot 
res ulti n g i n a date later t ha n t he date of s u bject's deat h. I n t he latter case, t he date of deat h will 
be use d t o i m p ute t he i nc o m plete e n d date.  
•  I n all ot her cases, t he i nc o m plete me dicati o n e n d date will n ot be i m p ute d.  
S u bse q ue nt A nti -C a ncer T her a p y  
I nc o m plete dates f or start date of s u bse q ue nt a nti-ca ncer t hera p y ( dr u g t hera p y, ra diati o n, s ur ger y) 
will be i m p ute d as f oll o ws a n d will be use d f or deter mi ni n g ce ns ori n g dates f or efficac y a nal yses 
a n d i n t he deri vati o n of t he e n d of o n -treat me nt peri o d.   
If  o nl y  da y  is  missi n g,  it  will  be  i m p ute d  as  the  last  da y  of  t he  m o nt h  u nless  t he  e n d  date  of 
s u bse q ue nt a nti-ca ncer t hera p y is bef ore t hat date. I n t hat case, t he i nc o m plete a nti -ca ncer t hera p y 
start date will be i m p ute d as t he e n d date of t he a nti-ca ncer t hera p y. If b ot h da y a n d m o nt h are 
missi n g, n o i m p utati o n will be perf or me d, a n d t he date of s u bse q ue nt a nti -ca ncer t hera p y will n ot 
be use d f or a n y calc ulati o ns.  
E x p os ure  
F or eac h treat me nt  c o m p o ne nt , i n case t he last a d mi nistrati o n date is i nc o m plete , t he date of last 
a d mi nistrati o n of st u d y i nter ve nti o n will be ta ke n fr o m t he “ Treat me nt T er mi nati o n ” e C R F pa ges.  
D ate of L ast C o nt act  
T he last ali ve date will be deri ve d f or s u bjects n ot k n o w n t o ha ve die d at t he a nal ysis c ut -off usi n g 
t he latest c o m plete date a m o n g t he f oll o wi n g: 
•  All s u bject  assess me nt dates ( bl o o d dra ws (la b orat or y, P K), vital si g ns, perf or ma nce stat us, 
E C G, t u m or assess me nts)  
•  Start  a n d  e n d  dates  of  a nti -ca ncer  t hera pies  a d mi nistere d  after  st u d y  treat me nt 
disc o nti n uati o n  
•  A E start a n d e n d dates  
•  Date last k n o w n t o be ali ve c ol lecte d o n t he e C R F pa ge  “ S u bject Stat us / S ur vi val F oll o w -
u p”  
•  St u d y i nter ve nti o n start a n d e n d dates 
•  Date of disc o nti n uati o n fr o m t he “ St u d y Ter mi nati o n” e C R F pa ge ( n ot use d if reas o n f or 
disc o nti n uati o n is l ost t o f oll o w -u p)  
O nl y dates ass ociate d wit h ac t ual e xa mi nati o ns of t he s u bject will be use d i n t he deri vati o n. Dates 
ass ociate d wit h a tec h nical o perati o n u nrelate d t o s u bject stat us s uc h as t he date a bl o o d sa m ple 
was pr ocesse d will n ot be use d.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /6 5  
 
 
De at h d ate  
Missi n g or partial deat h dates will be i m p u te d base d o n t he last c o ntact date: 
•  If t he date is missi n g it will be i m p ute d as da y after date of last c o ntact fr o m t he eC R F 
“S u bject Stat us / S ur vi val F oll o w -u p”  pa ge  
•  If t he da y or b ot h da y a n d m o nt h are missi n g, deat h will be i m p ute d t o t he ma xi m u m of 
the f ull ( n o n -i m p ute d) da y after t he date of last c o ntact a n d t he f oll o wi n g: 
–  Missi n g da y: 1st da y of t he m o nt h a n d year of deat h  
–  Missi n g da y a n d m o nt h: Ja n uar y 1
st of t he year of deat h  
If t he da y is missi n g fr o m t he date of last c o ntact, it will be i m p ute d t o 1st da y of t he m o nt h a n d 
year of last c o ntact o nl y if deri ve d fr o m t he s ur vi val pa ge.  
T u m or assess me nts  
All i n vesti gati o n dates (e. g. , X -ra y, C T sca n) m ust be c o m plete d wit h da y, m o nt h a n d year. 
If t here are m ulti ple sca n dates ass ociate d wit h a n e val uati o n, i.e., ra di ol o gical assess me nts occ ur 
o ver a series of da ys rat her t he sa me da y, t he c h oice of date of assess me nt c o ul d i m pact t he date 
of  pr o gressi o n  a n d/ or  date  of  res p o nse.  If  t here  are  m ulti ple  sca n  dates  ass ociate d  wit h  a n 
e val uati o n, t he earliest of t he sca n dates ass ociate d wit h t he e val uati o n will be use d as t he date of 
assess me nt.  
If o ne or m ore i n vesti gati o n dates f or a n e val uati o n are i nc o m plete b ut ot her i n vesti gati o n dates 
are a vaila ble, t he i nc o m plete date(s) are n ot c o nsi dere d f or calc ulati o n of t he assess me nt date a n d 
assess me nt date is calc ulate d as t he earliest of all i n vesti gati o n dates (e. g. , X -ra y, C T-sca n). 
If all meas ure me nt dates f or a n e val uati o n ha ve n o da y rec or de d, t he 1st of t he m o nt h is use d.  
If  t he m o nt h  is  n ot  c o m plete d,  f or  a n y  of  t he  i n vesti gati o ns  f or  a n  e val uati o n,  t he  res pecti ve 
assess me nt  will  be  c o nsi dere d  t o  be  at  t he  date  w hic h  is  e xactl y  bet wee n  t he  pre vi o us  a n d  t he 
f oll o wi n g  assess me nt.  If  b ot h  a  pre vi o us  a n d  f oll o wi n g  assess me nts  are  n ot  a vaila ble,  t his 
assess me nt will n ot be use d f or a n y calc ulati o ns.  
 
1 0  
St u d y P artici p a nt s 
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns 
A n alysis set: S cree ni n g 
T he f oll o wi n g i nf or mati o n will be s u m marize d b y d ose le vel a n d o verall  wit hi n eac h st u d y part : 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /6 5  
 
 
•  N u m ber of partici pa nts scree ne d  
•  N u m ber  of  partici pa nts  w h o  disc o nti n ue d  t he st u d y pri or  t o st u d y  i nter ve nti o n, a n d b y 
reas o n (e. g., s u bject di d n ot meet all eli gi bilit y criteria, wit h dre w i nf or me d c o nse nt , die d 
pri or t o recei vi n g treat me nt ) 
•  N u m ber of parti ci pa nts w h o recei ve d at least o ne d ose of a n y st u d y i nter ve nti o n 
•  N u m ber a n d perce nta ge of partici pa nts wit h at least o ne st u d y i nter ve nti o n o n g oi n g  
•  N u m ber a n d perce nta ge of  partici pa nts w h o recei ve d at least o ne d ose of  st u d y i nter ve nti o n, 
dis pla ye d b y s pecific st u d y i nter ve nti o n c o m p o ne nt  
•  N u m ber  a n d  perce nta ge  of  partici pa nts  wit h st u d y i nter ve nti o n o n g oi n g ,  dis pla ye d  b y 
s pecific st u d y i nter ve nti o n c o m p o ne nt  
•  N u m ber a n d perce nta ge of partici pa nt s w h o disc o nti n ue d  st u d y inter ve nti o n , o verall a n d 
b y reas o n, dis pla ye d b y s pecific st u d y i nter ve nti o n c o m p o ne nt  
•  N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d all st u d y i nter ve nti o n, o verall a n d 
b y mai n reas o n (reas o n f or disc o nti n uati o n of last st u d y i nter ve nti o n) 
•  N u m ber a n d perce nta ge of  partici pa nts w h o re -i nitiate d st u d y i nter ve nti o n 
•  N u m ber  a n d  perce nta ge  of  partici pa nts  w h o  disc o nti n ue d st u d y  i nter ve nti o n after  re-
i nitiati o n,  o verall  a n d  b y  pri mar y  reas o n,  dis pla ye d  b y  s pecific st u d y  i nter ve nti o n 
c o m p o ne nt 
•  N u m ber a n d perce nta ge of partici pa nts w h o recei ve d s u bse q ue nt a nti -ca ncer t hera p y  
•  N u m ber of partici pa nts w h o disc o nti n ue d t he st u d y a n d mai n reas o n  
T he  n u m ber  a n d  perce nta ge  of  partici pa nts  i n  eac h  of  t he  a b o ve  dis p ositi o n  cate g ories  will  be 
prese nte d b y assi g ne d st u d y i nter ve nti o n gr o u p a n d o verall. Perce nta ges will be prese nte d wit h 
res pect t o t he n u m ber of S A F A nal ysis Set partici pa nts.  
T he n u m ber of partici pa nts  i n t he a nal ysis p o p ulati o ns o utli ne d i n Secti o n 8. 2  will be s u m marize d 
b y st u d y i nter ve nti o n gr o u p a n d b y site.  
T he n u m ber a n d perce nta ge of partici pa nts e nr olle d b y re gi o n  a n d b y c o u ntr y wit hi n re gi o n will 
be s u m marize d.  
All rele va nt partici pa nt dis p ositi o n data will be prese nte d i n data listi n gs.  
1 0. 2  
C O VI D -1 9 I m p act  
N o c ha n ges t o t he per -pr ot oc ol pla n ne d a nal yses of safet y or efficac y e n d p oi nts will be ma de d ue 
t o t he i m pact of cor o na vir us disease 2 0 1 9  ( C O VI D-1 9) o ut brea k.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /6 5  
 
 
A d diti o nal o ut p uts (s u m mar y ta ble a n d listi n g) will be ge nerate d i n or der t o descri be a n d q ua ntif y 
t he i m pact of C O VI D-1 9 pa n de mic o n t he f oll o wi n g para meters:  
•  S u bjects p ote ntiall y affecte d b y C O VI D -1 9  
•  A d verse E ve nts   
•  Pr ot oc ol de viati o ns (i m p orta nt a n d n o n -i m p orta nt) 
•  Misse d Visits  
•  Misse d efficac y e val uati o ns  
•  Tele -Visits perf or me d  
•  Dr u g A d mi nistrati o n: misse d d oses  
•  Dr u g A d mi nistrati o n: d ose dela ys  
•  Treat me nt Disc o nti n uati o n  
•  St u d y Disc o nti n uati o n  
•  Deat h  
P ote ntiall y affecte d s u bjects are defi ne d as:  
a) Patie nts w h o starte d treat me nt after start of t he C O VI D -1 9 pa n de mic, or  
b)  Patie nts w h o starte d treat me nt pri or t o start of t he C O VI D -1 9 pa n de mic a n d are still 
o n g oi n g after t he start of t he pa n de mic.  
T he start of C O VI D -1 9 pa n de mic will be defi ne d b y c o u ntr y as t he earliest date of eit her : ( 1) t he 
date of t he first deat h attri b ute d t o C O VI D -1 9 i n t he patie nt’s c o u ntr y , acc or di n g t o t he p u blis he d 
data b y E ur o pea n Ce ntre f or Disease Pre ve nti o n a n d C o ntr ol o n 2 6t h J u ne 2 0 2 0  or  ( 2) 1 1t h Marc h 
2 0 2 0 ( w he n t he W H O declare d C O VI D -1 9 pa n de mic).  
A  fre q ue nc y ta ble will be pr o d uce d f or t he S A F a nal ysis set t o prese nt t he n u m ber of s u bjects wit h 
a n y of t he a b o ve -liste d st u d y e ve nts attri b uta ble t o C O VI D-1 9.  
A d d iti o nal  C O VI D-1 9 -relate d  o ut p uts  will  als o  be  pr o d uce d  f or  pr ot oc ol  de viati o ns,  a d verse 
e ve nts, a n d e x p os ure. Please refer t o t h ose secti o ns of t his d oc u me nt f or f urt her details.  
1 0. 3  
Re p orti n g of Pr ot oc ol De vi ati o ns  
A n alysis set: S A F  
Please see Secti o n  8. 1 f or details o n t he defi niti o n a n d c ollecti o n of pr ot oc ol de viati o ns. 
T he f oll o wi n g s u m mar y ta bles a n d listi n gs of pr ot oc ol de viati o ns  will be pr o vi de d : 
•  Fre q ue nc y ta ble b y  reas o n of I P Ds 
•  Fre q ue nc y ta ble o f I P Ds attri b ute d t o t he i m pact of t he C O VI D -1 9 pa n de mic  
•  Listi n g of I P Ds  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /6 5  
 
 
•  Listi n g of pr ot oc ol de viati o ns attri b ute d t o t he i m pact of C O VI D -1 9, i ncl u di n g se verit y le vel 
of t he de viati o n (i m p orta nt vs. n o n -i m p orta nt) 
 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acte ristics 
1 1. 1  
De m o gr a p hics  
A n alysis set: S A F  
De m o gra p hic c haracteristics will be liste d a n d s u m marize d b y d ose le vel a n d o verall as f oll o ws:  
•  De m o gra p hic c haracteristics  
•  Ge n der: male, fe male  
•  Race : W hite, B lac k or Africa n A merica n,  A sia n, A merica n I n dia n or Alas ka Nati ve , Nati ve 
Ha waiia n or Ot her Pacific Isla n der, N ot c ollecte d at t his sit e, ot her  
•  Et h nicit y: His pa nic or Lati n o, N ot His pa nic or Lati n o  
•  A ge ( years)  
•  A ge cate g ories:  
-  < 6 5 years, ≥ 6 5 years  
-  6 5 -7 4, 7 5 -8 4, ≥8 5  
•  Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us ( E C O G P S)  
•  P h ysical meas ure me nts  
-  Hei g ht (c m)  
-  Wei g ht ( k g)  
-  B MI  ( k g/ m2) 
S pecificati o ns f or c o m p utati o n:  
•  A ge [ years]  
-  ( date of gi ve n i nf or me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5   
-  I n case of missi n g da y f or at least o ne date, b ut m o nt h a n d year a vaila ble f or b ot h dates , 
t he da y of i nf or me d c o nse nt a n d t he da y of birt h will be set t o 1 a n d t he f or m ula a b o ve will 
be use d . 
-  I n case of missi n g m o nt h f or at least o ne date, b ut year a vaila ble f or b ot h dates, t he da y 
a n d t he m o nt h of i nf or me d c o nse nt a n d  t he da y a n d m o nt h of  birt h will be set t o 1 a n d  t he 
f or m ula a b o ve will be use d. 
•  Site c o des will be use d f or t he deter mi nati o n of t he partici pa nt ’s p o ole d  re gi o n. 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /6 5  
 
 
•  B MI ( k g/ m²) = wei g ht ( k g) / [ hei g ht (c m) x hei g ht (c m)] x 1 0 0 0 0  
A listi n g s h o wi n g t he rele va nt de m o gra p hic data will als o be pr o d uce d. 
1 1. 2  
Me dic al Hist or y  
A n alysis set: S A F  
T he me dical hist or y will be s u m marize d fr o m t he “ Me dical Hist or y Details”  e C R F pa ge s, usi n g 
t he latest versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), preferre d ter m ( P T) 
as e ve nt cate g or y a n d Me d D R A s yste m or ga n class ( S O C) b o d y ter m as b o d y s yste m cate g or y.  
Me dical hist or y will be dis pla ye d i n ter ms of fre q ue nc y ta bles: or dere d b y pri mar y S O C a n d P T 
i n al p ha betical or der. 
A s u p p orti ve listi n g of me dical h ist or y data b y partici pa nt will i ncl u de all t he rele va nt data fiel ds 
as c ollecte d o n t he “ Me dical Hist or y” eC R F pa ge.  
1 1. 3  
Ot her B aseli ne C h ar acteristics  
Dise ase C h ar acteristics  
A n alysis set: S A F  
I nf or mati o n re gar di n g disease c haracteristics c ollecte d o n t he “ Disease Hist or y” C R F pa ge will be 
s u m marize d a n d liste d as f oll o ws: 
•  T y pe  of  ca ncer:  Breast  ca ncer,  ser o us  e pit helial  o var y  ca ncer,  bla d der  ca ncer,  c ol o n  ca ncer, 
n o n -s mall cell l u n g ca ncer, castrati o n resista nt pr ostate ca ncer, st o mac h ca ncer, uteri ne ca nc er, 
mela n o ma, s mall cell l u n g ca ncer, rectal ca ncer, pr ostate ca ncer, ot her ca ncers  
•  T u m or hist o pat h ol o gic/ c yt ol o gic gra de: G X: Gra de ca n n ot be assesse d ( u n deter mi ne d gra de), 
G 1: Well differe ntiate d (l o w gra de), G 2: M o deratel y differe ntiate d (i nter me diate gra de), G 3: 
P o orl y differe ntiate d ( hi g h gra de), G 4: U n differe ntiate d ( hi g h gra de)   
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs), defi ne d as ( date of first st u d y treat me nt –  date of 
i nitial dia g n osis)/ 3 0. 4 3 7 5 
•  Ti me si nce d oc u me nte d l ocall y a d va nce d, i n o pera ble, or metastatic disease dia g n osis ( m o nt hs), 
defi ne d as ( date of first st u d y treat me nt –  date of d oc u me nte d l ocall y a d va nce d, i n o pera ble, or 
metastatic disease dia g n osis)/ 3 0. 4 3 7 5  
•  Sta ge at i nitial dia g n osis  
•  Sta ge at st u d y e ntr y  
•  T N M classificati o n at i nit ial dia g n osis 
•  T N M classificati o n at st u d y e ntr y  
Site of pri mar y t u m or a n d s u bsites will be prese nte d i n a listi n g.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 2 /6 5  
 
 
 
1 2  
P re vi o us  or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures  
A n alysis set: S A F  
1 2. 1  
Pri or A nti -C a ncer Tre at me nts  
T he  pri or  a nti -ca ncer  treat me nts  a n d pr oce d ures  are  c ollecte d  fr o m  t he  “ Pri or  A nti -ca ncer 
S ur geries  Details”,  “ Pri or  A nti -ca ncer  Dr u g  T hera pies  Details”,  a n d  “ Pri or  A nti -ca ncer 
Ra di ot hera p y Details” e C R F pa ges.  
T he n u m ber a n d perce nta ge of s u bjects i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y  cate g ories will 
be ta b ulate d:  
•  S u bjects wit h at least o ne t y pe of pri or a nti -ca ncer treat me nt  
•  S u bjects wit h at least o ne pri or a nti -ca ncer dr u g t hera p y  
•  S u bjects wit h at least o ne pri or a nti -ca ncer ra di ot hera p y  
•  S u bjects wit h at least o ne pri or a nti -ca nc er s ur ger y  
•  T y pe of pri or a nti -ca ncer dr u g t hera p y: C yt ot o xic t hera p y / E n d ocri ne t hera p y / M o n ocl o nal 
a nti b o d y t hera p y / S mall m olec ules / I m m u n ot hera p y / Ot her  
•  I nte nt of T hera p y: Ne oa dj u va nt / A dj u va nt / Metastatic or L ocall y a d va nce d 
•  F or Metastatic/ L oc all y a d va nce d i nte nt, n u m ber of t hera p y li nes: 1 / 2 / 3 / ≥4  
•  Best res p o nse: C o m plete Res p o nse ( C R) / Partial Res p o nse ( P R) / Sta ble Disease ( S D) / N o n -
C R/ N o n -P D  /  Pr o gressi ve  Disease  ( P D)  /  N ot E val ua ble  ( N E) /  U n k n o w n. Best  res p o nse  is 
deri ve d fr o m t he l ast treat me nt re gi me n .  
T he pri or a nti -ca ncer dr u gs will als o be e xte nsi vel y detaile d wit h t he n u m ber a n d perce nta ge of 
s u bjects b y t he dr u g class a n d P T i n a se parate ta ble. A s u bject will be c o u nte d o nl y o nce wit hi n a 
gi ve n dr u g class a n d wit hi n a gi ve n dr u g na me, e ve n if t he s u bject recei ve d t he sa me me dicati o n 
at differe nt ti mes. T he s u m mar y ta bles will be s orte d o n decreasi n g fre q ue nc y of dr u g class a n d 
decreasi n g fre q ue nc y of dr u g na me i n a gi ve n dr u g class, base d o n t he i nci de nce i n t he “ O verall” 
c ol u m n. I n case of e q ual fr e q ue nc y, al p ha betical or der will be use d.  
T he listi n gs of pri or a nti -ca ncer treat me nts a n d pr oce d ures will als o be pr o vi de d:  
•  listi n g of pri or a nti-ca ncer dr u g t hera pies  
•  listi n g of pri or a nti-ca ncer ra di ot hera p y  
•  listi n g of pri or a nti-ca ncer s ur geries  
T h ese will i ncl u de d ose le vel, s u bject i de ntifier, a n d all t he rele va nt c ollecte d data  fiel ds o n t he 
c orres p o n di n g e C R F pa ges ( or dere d b y d ose le vel, s u bject i de ntifier a n d t hera p y start date).  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /6 5  
 
 
1 2. 1  
Pre vi o us a n d C o nc o mit a nt Me dic ati o ns/ Pr oce d ures  
Pre vi o us  a n d  c o n c o mita nt  me dicati o ns  are  c ollecte d  o n  t he  " Rele va nt P re vi o us M e dicati o ns 
D etails" a n d “ C o nc o mita nt M e dicati o ns D etails” e C R F pa ge s. Pri or  a n d c o nc o mita nt pr oce d ures 
are c ollecte d o n t he “ C o nc o mita nt pr oce d ures details” e C R F pa ge.   
Pre vi o us  me dic ati o ns  are  me dicati o ns,  ot her  t ha n  st u d y  me dicati o ns  a n d  pre -me dicati o ns  f or 
st u d y i nter ve nti o n, w hic h are starte d bef ore first a d mi nistrati o n  of  a n y st u d y i nter ve nti o n.  
C o nc o mit a nt me dic ati o ns  are me dicati o ns, ot her t ha n st u d y me dicati o ns a n d pre -me dicati o ns f or 
st u d y i nter ve nti o n, w hic h starte d pri or t o first d ose date of st u d y i nter ve nti o n a n d c o nti n ue d d uri n g 
t he o n -treat me nt peri o d as well as t h ose starte d d uri n g t he o n-treat me nt peri o d.  
Pre vi o us me dicati o ns a n d c o nc o mita nt me dicati o ns will be s u m marize d se paratel y s h o wi n g t he 
n u m ber  of  s u bjects  a n d  perce nta ge  of  s u bjects  ha vi n g  ta ke n  a  gi ve n  dr u g,  s u m marize d  b y 
A nat o mical T hera pe utic C he mical classificati o n  class ( A T C-2 n d le vel) a n d  P T , dis pla ye d b y d ose 
le vel a n d o verall. A T C a n d P T will be s u m marize d as gi ve n fr o m t he W orl d Healt h Or ga nizati o n 
(W H O ) dicti o nar y c urre nt versi o n.  I n case m ulti ple A T Cs are assi g ne d t o a dr u g, all A T C -2 n d 
le vel will be use d f or re p orti n g. I n case t he date val ues will n ot all o w f or u ne q ui v ocal  classificati o n 
of  a me dicati o n as c o nc o mita nt , t he me dicati o n will be c o nsi dere d as a c o nc o mita nt me dicati o n.  
A s u bject will be c o u nte d o nl y o nce wit hi n a gi ve n dr u g class a n d wit hi n a gi ve n dr u g na me,  e ve n 
if t he  s u bject recei ve d  t he sa me me dicati o n at differe nt  ti mes or  m ulti ple me dicati o ns  wit hi n a 
gi ve n dr u g class.  
T he s u m mar y ta bles will be s orte d o n decreasi n g fre q ue nc y of dr u g class a n d decreasi n g fre q ue nc y 
of dr u g na me i n a gi ve n dr u g class, bas e d o n t he i nci de nce i n t he “ O verall” c ol u m n. I n case of 
e q ual fre q ue nc y re gar di n g dr u g class (res pecti vel y dr u g na me), al p ha betical or der will be use d.  
Pre vi o us a n d c o nc o mita nt me dicati o n data will be liste d se paratel y. T he f oll o wi n g varia bles will 
be i ncl u de d i n t he listi n gs: c o h ort d ose le vel, s u bject i de ntifier, a n d all c orres p o n di n g c ollecte d 
data  fiel ds o n  t he  c orres p o n di n g  e C R F  pa ge s.  T he  listi n gs will  be  s orte d  b y c o h ort d ose  le vel, 
s u bject i de ntifier, a n d t he start date of t he me dicati o n. 
Pri or a n d c o nc o mita nt pr oce d ures data  c ollecte d o n t he  “ Pri or A nti -ca ncer S ur geries Details” a n d  
“C o nc o mita nt Pr oce d ures Details ” e C R F pa ge s will be liste d. C o h ort d ose le vel, s u bject i de ntifier, 
a n d all c ollecte d data  fiel ds o n t he c orres p o n di n g e C R F pa ge s will be i ncl u de d i n t he listi n gs. T he 
listi n gs will be s orte d b y c o h ort d ose le vel, s u bject i de ntifier, a n d t he start date of t he pr oce d ure.  
Pre me dicati o n data (re p orte d o n t he “ Pre me dicati o n D etails” e C R F pa ge) gi ve n bef ore eac h st u d y 
i nter ve nti o n a d mi nistrati o n will be liste d.  
1 2. 2  
S u bse q ue nt A nti -C a ncer T her a pies/ Pr oce d ures  
T he  n u m ber  of  s u bjects w h o recei ve d  treat me nt  after  disc o nti n uati o n  will  be  s u m marize d  as 
re p orte d  o n  t he  “ A nti-ca ncer  Treat me nt  after  Disc o nti n uati o n  Details”,  “ Ra di ot hera p y  after 
Disc o nti n uati o n Details” a n d “ S ur ger y after Disc o nti n uati o n Details” e C R F pa ges.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /6 5  
 
 
T he n u m ber a n d perce nta ge of s u bjects i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y cate g ories will 
be ta b ulate d:  
•  S u bjects wit h at least o ne t y pe of s u bse q ue nt a nti -ca ncer treat me nt  
•  S u bjec ts wit h at least o ne s u bse q ue nt a nti-ca ncer dr u g t hera p y  
•  S u bjects wit h at least o ne s u bse q ue nt a nti -ca ncer ra di ot hera p y  
•  S u bjects wit h at least o ne s u bse q ue nt a nti -ca ncer s ur ger y  
•  T y pe  of  s u bse q ue nt  a nti -ca ncer  t hera p y:  C yt ot o xic  t hera p y  / E n d ocri ne  t hera p y  / 
M o n ocl o nal a nti b o d y t hera p y / S mall m olec ules / I m m u n ot hera p y / Ot her  
•  Best res p o nse: C o m plete Res p o nse ( C R) / Partial Res p o nse ( P R) / Sta ble Disease ( S D) / 
N o n -C R/ N o n -P D / Pr o gressi ve Disease ( P D) / N ot E val ua ble  / U n k n o w n. Best res p o ns e is 
deri ve d fr o m t he last treat me nt re gi me n .  
A nti -ca ncer treat me nt after disc o nti n uati o n will be pr o vi de d i n a listi n g wit h data retrie ve d fr o m 
“ A nti -Ca ncer  Treat me nt  after  Disc o nti n uati o n  Details”,  “ Ra di ot hera p y  after  Disc o nti n uati o n 
Details” a n d “ S ur ge r y after Disc o nti n uati o n Details” e C R F pa ges. 
 
1 3  
St u d y i nter ve nti o n C o m pli a nce a n d E x p os ure  
A n alysis set: S A F  
All d osi n g calc ulati o ns a n d s u m maries, as well as t he listi n gs of st u d y dr u g a d mi nistrati o n , will be 
base d  o n  t he  “ M 3 8 1 4 A d mi nistrati o n 
D etails”,  “ M 3 8 1 4 
A cc o u nta bilit y”  “ A vel u ma b 
A d mi nistrati o n D etails,”  “ Ra di ot hera p y A d mi nistrati o n”  “ M 3 8 1 4 T er mi nati o n”,  “ A vel u ma b 
T er mi nati o n” a n d “ Ra di ot hera p y T er mi nati o n” e C R F pa ges.  
•  P art  A a n d P art F E :  M 3 8 1 4 will be a d mi nistere d t wice daily, wit h o ut i nterr u pti o n , i n 
c o m bi nati o n wit h a vel u ma b, a d mi nistere d o nce e ver y t w o wee ks, starti n g o n Da y 1 u ntil 
P D or u nacce pta ble t o xicit y.  
•  P art B : M 3 8 1 4 will be a d mi nistere d o nce a da y. R T  will be gi ve n at t he d ose of 3 G y per 
da y. M 3 8 1 4 a n d R T  will b ot h be gi ve n starti n g Da y 1 f or 5 da ys/ wee k f or 2 wee ks , at w hic h 
p oi nt, b ot h M 3 8 1 4 a n d R T are disc o nti n ue d.  A vel u ma b will be a d mi nistere d o nce e ver y 
t w o wee ks starti n g o n Da y 1 u ntil P D or u nacce pta ble t o xicit y. 
 
D ur ati o n of t her a p y  
St u d y i nter ve nti o n  d urati o n will be calc ulate d base d o n t he  n u m ber of pla n ne d  a d mi nistrati o n da ys 
e x pecte d  f or eac h treat me nt c o m p o ne nt . D urati o n of t hera p y is defi ne d as f oll o ws: 
Part s A  a n d F E: 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /6 5  
 
 
D urati o n of a vel u ma b ( wee ks) =  
(
d at e  of  l a st d o s e −d at e  of  fi r st d o s e  + 1 4
7
)  
D urati o n of M 3 8 1 4 ( wee ks) =  
(
d at e  of  l a st d o s e −d at e  of  fi r st d o s e  + 1
7
)  
Part B:  
D urati o n of a vel u ma b ( wee ks) =  
(
d at e  of  la st  d o s e −d at e  of  fi r st d o s e  + 1 4
7
)  
D urati o n of M 3 8 1 4 ( wee ks) =  
(
d at e  of  l a st d o s e −d at e  of  fi r st d o s e  + 3
7
)  
D urati o n of R T  ( wee ks) = 
  
(
d at e  of  l a st d o s e −d at e  of  fi r st d o s e  + 3
7
)  
D urati o n of t hera p y will be s u m marize d o n a ta ble wit h s u m mar y statistics f or eac h tre at me nt b y 
c o h ort d ose le vel. Details will als o be i ncl u de d i n a listi n g.  
C u m ul ati ve d ose  
T he o verall c u m ulati ve d ose per s u bject acr oss all c ycles is t he s u m of act ual d oses t he s u bject 
recei ve d (i.e., t otal d ose a d mi nistere d). 
C u m ulati ve d ose is meas ure d i n m g f or a vel u ma b a n d M 3 8 1 4 a n d G y f or ra di ot hera p y.  
C u m ulati ve act ual d ose will be s u m m arize d o n a ta ble wit h s u m mar y statistics f or eac h treat me nt, 
b y c o h ort d ose le vel. Details will als o be i ncl u de d i n a listi n g.  
D ose I nte nsit y  
Eac h c ycle is defi ne d b y a 2 -wee k peri o d . M 3 8 1 4 will be a d mi nistere d o nce a da y f or 5 da ys 
f oll o we d b y 2 da ys off f or 1 0 da ys i n t otal (i.e., o n t he sa me sc he d ule as t he R T). A vel u ma b will 
be a d mi nistere d Q 2 W as a n I V i nf usi o n o ver 1 h o ur, starti n g o n Da y 1, at a fi xe d d ose of 8 0 0 m g 
i n all d ose le vels. 
T he d ose i nte nsit y  will be calc ulate d f or eac h s u bject acr oss al l c ycles.  
D ose  i nte nsit y  is  defi ne d  f or  a vel u ma b  ( m g/c ycle),  M 3 8 1 4  ( m g/c ycle),  a n d R T  ( G y/c ycle)  as 
f oll o ws: 
D os e  I nt e nsit y = (
act u al  c u m ul ati v e  d os e
d ur ati o n  of  t h er a p y (w e e ks )
2  w e e ks / c ycl e
)  
D ose i nte nsit y will be s u m marize d o n a ta ble wit h s u m mar y statistics f or eac h treat me nt, b y c o h ort 
d ose le vel. Details will als o be i ncl u de d i n a listi n g.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /6 5  
 
 
Rel ati ve D ose I nte nsit y  
T he  relati ve  d ose  i nte nsit y  is  defi ne d  as  t he  act ual  d ose  i nte nsit y  di vi de d  b y  t he per -pr ot oc ol  
pla n ne d d ose  le vel per c ycle a n d is e x presse d as a perce nta ge.   
R el ati v e  D os e  I nt e nsit y = (
D os e  I nt e nsit y
pl a n n e d  d os e  l e v el p er  c ycl e)  
Relati ve d ose i nte nsit y  f or eac h treat me nt will be i ncl u de d i n a listi n g a n d will be s u m marize d i n 
t he f oll o wi n g cate g ories, b y c o h ort d ose le vel: 
o  < 5 0 %  
o  5 0 %  t o < 8 0%  
o  8 0 %  t o < 9 0 %  
o  9 0 %  t o 1 1 0 %  
o  > 1 1 0 %  
D ose Re d ucti o ns  
F or a vel u ma b, a d ose re d ucti o n is defi ne d as a n act ual n o n-zer o d ose < 9 0 % of t he per -pr ot oc ol  
d ose  wit hi n a gi ve n c ycl e. 
F or  M 3 8 1 4,  a d ose  re d ucti o n  is  defi ne d  as  a n  act ual  n o n -zer o  c u m ulati ve  d ose  <  9 0 %  of  t he 
pla n ne d ( per -pr ot oc ol)  c u m ulati ve d ose  f or a gi ve n treat me nt c ycle (i.e., t w o-wee k peri o d) . A n y 
s ki p pe d d oses wit hi n t he c ycle will c o ntri b ute t o t he calc ulati o n o f t he d ose re d ucti o n (i.e., will be 
i ncl u de d i n t he de n o mi nat or of t he calc ulati o n). If a s u bject per ma ne ntl y disc o nti n ues treat me nt 
bef ore  c o m pleti n g  a  f ull  c ycle,  t he  pla n ne d  c u m ulati ve  d ose  will  be  calc ulate d  as  pla n ne d 
c u m ulati ve d ose e x pecte d bet wee n t he first d ose of treat me nt o n t he c ycle a n d t he last. 
D ose re d ucti o ns are c o u nte d o n a per -c ycle basis a n d d o n ot c o nsi der w het her pre vi o us d oses were 
re d uce d. 
N u m ber a n d perce nta ge of s u bjects wit h at least o ne d ose re d ucti o n , as well as a brea k d o w n of 
c ycles wit h d ose re d ucti o ns ( 1 / 2 / 3 / ≥4) will be s u m marize d b y  c o h ort  d ose le vel.  
T her a p y  Del a ys  
T hera p y dela ys are o nl y defi ne d f or a vel u ma b a d mi nistrati o n a n d  are defi ne d as i nf usi o ns gi ve n 
≥3 da ys fr o m t he pla n ne d a d mi nistrati o n date . Dela ys are o nl y defi ne d f or s u bjects w h o recei ve at 
least  t w o  a d mi nistrati o ns  of  a vel u ma b  a n d will  be  deri ve d  base d  o n t he  ti me  bet wee n  t w o 
a d mi nistrati o n s: 
T h er a p y  D el a y = [d at e  of  c urr e nt a d mi nistr ati o n ] − [d at e  of  pr e vi o us  a d mi nistr ati o n ] − 1 4  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /6 5  
 
 
Dela ys  will be gr o u pe d i nt o t he  f oll o wi n g cate g ories: 
•  N o dela y (i ncl u di n g dela y of 1 -2 da ys ) 
•  Dela y of 3 -6  da ys  
•  Dela y of 7 -1 3  da ys  
•  Dela y of 1 4 -2 0  da ys  
•  Dela y of ≥2 1 da ys  
T he n u m ber a n d perce nta ge of s u bjects wit h dela ye d a vel u ma b a d mi nistrati o n a n d t he l o n gest 
o bser ve d  dela y  ( da ys) per s u bject will be s u m marize d b y c o h ort d ose le vel.  If p ossi ble, t he 
n u m ber a n d perce nta ge of s u bjects wit h t hera p y dela ys attri b uta ble t o t he C O VI D -1 9 pa n de mic 
will als o be prese nte d.  
T her a p y  I nterr u pti o ns 
A  t hera p y  i nterr u pti o n  is  defi ne d  as  o missi o n  of  a  f ull  c ycle  of  a  pla n ne d  st u d y  i nter ve nti o n. 
T hera p y i nterr u pti o ns are o nl y defi ne d if t he i nter ve nti o n is later restarte d.    
A vel u ma b: A t hera p y dela y of greater t ha n 1 3  da ys is c o nsi dere d a t hera p y i nter r u pti o n. 
M 3 8 1 4  ( Parts A a n d F E o nl y) : f o urtee n c o nsec uti ve da ys of misse d M 3 8 1 4 is c o nsi dere d a t hera p y 
i nterr u pti o n.  
T he n u m ber a n d perce nta ge of s u bjects wit h a n i nterr u pti o n i n  st u d y dr u g a d mi nistrati o n a n d t he 
l o n gest o bser ve d i nterr u pti o n (c ycles) per s u bject will be s u m marize d b y c o h ort d ose le vel.  If 
p ossi ble, t he n u m ber a n d perce nta ge of s u bjects wit h t hera p y i nterr u pti o ns attri b uta ble t o t he 
C O VI D -1 9 pa n de mic will als o be prese nte d.  
 
1 4  
Effic ac y A n al yses  
1 4. 1  
Best O ver all Res p o nse  
A n alysis sets: F A S  
T he c o nfir me d Best O verall Res p o nse ( B O R) is defi ne d as t he best c o nfir me d res p o nse o btai ne d 
a m o n g  all  t u m or  assess me nt s after  t he start  of  st u d y  i nter ve nti o n u ntil  d oc u me nte d  disease 
pr o gressi o n  or start of s u bse q ue nt a nti -ca ncer treat me nt , ta ki n g re q uireme nts f or c o nfir mati o n i nt o 
acc o u nt  as  detaile d  bel o w . C o nfir me d B O R  will  be  e val uate d  acc or di n g  t o t he Res p o nse 
E val uati o n  Criteria in  S oli d  T u m ors  (R E CI S T ) v 1. 1  base d  o n  t he  I n vesti gat or’s  assess me nt  of 
disease . 
O nl y t u m or assess me nts perf or me d o n or bef ore 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  as 
d oc u me nte d disease pr o gressi o n.  If a t u m or assess me nt was perf or me d o n t he sa me da y  as start of 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /6 5  
 
 
ne w a nti -ca ncer  t hera p y, it will be ass u me d t hat t he t u m or assess me nt was perf or me d pri or t o t he 
start  of  t he  ne w  a nti-ca ncer  t hera p y , t heref ore t he  t u m or  assess me nt will  be  i ncl u de d  i n  t he 
assess me nt of B O R.  
Ta ble 6  s u m marizes  t he  deri vati o n  r ules  descri be d  b y Eise n ha uer,  et  al . f or  t he  B O R  w he n 
c o nfir mati o n fr o m s u bse q ue nt assess me nt is nee de d.  F or s u bjects w h o ha ve n o n -tar get lesi o ns o nl y 
at baseli ne, t he ti me-p oi nt t u m or assess me nt of “ N o n -C R/ n o n -P D” will be e val uate d wit h t he sa me 
criteria as S D ( mi ni m u m criteria f or S D d urati o n)  i n deri vi n g t he o verall B O R.  
T a ble 6 : Best O ver all Res p o nse W he n C o nfir m ati o n of C R/ P R Is Re q uire d  
O ver all res p o nse  
1st ti me p oi nt  
O ver all res p o nse  
s u bse q ue nt ti me 
p oi nt  
Best o ver all res p o nse ( B O R)  
C R  
C R  
C R  
C R  
P R  
S D, P D or P R a 
C R  
S D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met; ot her wise, P D  
C R  
P D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met; ot her wise, P D  
C R  
N E  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise N E  
P R  
C R  
P R  
P R  
P R  
P R  
P R  
S D  
S D  
P R  
P D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, P D  
P R  
N E  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise N E  
N E  
N E  
N E  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve disease, N E =  n ot e val ua ble . 
a If a C R is tr ul y met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease meeti n g P R 
criteria relati ve t o baseli ne, ma kes t he disease P D at t hat p oi nt (si nce disease m ust ha ve rea p peare d after C R). Best 
res p o nse w o ul d de pe n d o n w het her mi ni m u m d urati o n f or S D was met. H o we ver, s o meti mes ‘ C R’ ma y be clai me d w he n 
s u bse q ue nt sca ns s u g gest s mall lesi o ns were li kel y still prese nt a n d i n fact t he patie nt ha d P R, n ot C R at t he first ti me 
p oi nt. U n der t hese circ u msta nces, t he ori gi na l C R s h o ul d be c ha n ge d t o P R a n d t he best res p o nse is P R.   
B O R base d o n c o nfir me d res p o nses:  
•  C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a part ( wit h n o P D i n bet wee n)  
•  P R = at least t w o deter mi nati o ns of P R or better ( P R f oll o we d b y P R or P R f oll o we d b y 
C R) at least 4 wee ks a part (a n d n ot q ualif yi n g f or a C R), wit h n o P D i n bet wee n  
•  S D  (a p plica ble o nl y t o partici pa nt wit h meas ura ble disease at baseli ne) = at least o ne S D 
assess me nt ( or better) ≥ 8  wee ks after start date (a n d n ot q ualif yi n g f or C R or P R).  
•  N o n -C R/ n o n -P D (a p plica ble o nl y t o partici pa nts wit h n o n -meas ura ble disease at basel i ne) 
= at least o ne n o n -C R/ n o n -P D assess me nt ( or better) ≥ 8  wee ks after start date (a n d n ot 
q ualif yi n g f or C R or P R).  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /6 5  
 
 
•  P D = P D ≤ 1 6  wee ks  after start date (a n d n ot q ualif yi n g f or C R, P R, n o n -C R/ n o n -P D or 
S D).  
•  N ot E val ua ble ( N E):  all ot her cases.  
S D ca n f o ll o w P R o nl y i n t he rare case t hat t u m or i ncreases b y less t ha n 2 0 % fr o m t he na dir, b ut 
e n o u g h t hat a pre vi o usl y d oc u me nte d 3 0 % decrease fr o m baseli ne n o l o n ger h ol ds.  If t his occ urs 
t he se q ue nce P R-S D -P R is c o nsi dere d a c o nfir me d P R.  A se q ue nce of P R –  S D –  S D –  P D w o ul d 
be a best res p o nse of S D if t he mi ni m u m d urati o n f or S D defi niti o n has bee n met.  
O bjecti ve Res p o nse ( O R) is defi ne d as a c o nfir me d B O R of c o m plete res p o nse ( C R) or partial 
res p o nse ( P R) acc or di n g t o R E CI S T v 1. 1.  
T he n u m ber a n d perce nta ge of s u bjects wit h B O R of C R, P R, S D, P D, n o n -C R/ n o n -P D (a p plica ble 
o nl y t o s u bjects wit h n o n -meas ura ble disease at baseli ne), a n d N E will be ta b ulate d. S u bjects  wit h 
B O R of N E will be s u m marize d b y reas o n f or ha vi n g N E stat us. T he f oll o wi n g reas o ns will be 
use d:  
•  N o Baseli ne Assess me nt  
•  N o p ost -baseli ne assess me nts d ue t o deat h wit hi n 8  wee ks after treat me nt start 
•  N o p ost -baseli ne assess me nts d ue t o ot her reas o ns  
•  All p ost -baseli ne assess me nts ha ve o verall res p o nse N E  
•  Ne w a nti -ca ncer t hera p y starte d  bef ore first p ost -baseli ne assess me nt  
•  S D of i ns ufficie nt d urati o n ( < 6 wee ks after treat me nt start wit h o ut f urt her e val ua ble t u m or 
assess me nt)  
•  P D t o o late (i.e. , t u m or assess me nt of P D was > 16  wee ks after treat me nt start a n d t here 
was n o t u m or assess me nt i n bet wee n)  
S pecial a n d rare cases w here B O R is N E d ue t o b ot h earl y S D a n d late P D will be classifie d as 
‘ S D t o o earl y’. 
O bjecti ve Res p o nse  
T he c o nfir me d  o bjecti ve  res p o nse  rate ( O R R)  is  defi ne d  as t he  pr o p orti o n  of  s u bjects  ha vi n g 
reac he d a c o nfir me d  B O R  of  C R  or  P R  acc or di n g  t o  R E CI S T  v 1. 1 ,  as  e val uate d  b y  t he 
In vesti gat or . S u bjects wit h B O R of n o n -C R/ n o n -P D are n ot c o nsi dere d t o ha ve ac hie ve d o bjecti ve 
res p o nse. S u bjects w h o d o n ot ha ve a p ost -bas eli ne 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 nti -ca ncer  treat me nts ot her t ha n t he st u d y i nter ve nti o n 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 a s n o n-res p o n ders i n t he assess me nt of OR R.  
O R R will be ta b ulate d b y c o h ort d ose le vel al o n g wit h t he t w o -si de d 9 5 % CI usi n g t he Cl o p per-
Pears o n met h o d (e xact CI f or a bi n o mial pr o p orti o n as c o m p ute d b y defa ult b y t he S A S F R E Q 
pr oce d ure usi n g t he E X A C T o pti o n).  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
  P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns  
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /6 5  
1 4. 2  
D ur ati o n of Res p o nse  
A n alysis sets: F A S  
D urati o n of Res p o nse ( D O R) is defi ne d o nl y f or s u bjects wit h a n O R . DO R is calc ulate d as t he 
ti me fr o m first d oc u me ntati o n of O R  ( C R or P R acc or di n g t o R E CI S T 1. 1, as e val uate d b y t he 
In vesti gat or) t o t he date of first d oc u me ntati o n of o bjecti ve  pr o gressi o n of disease or deat h d ue t o 
a n y ca use.  F or s u bjects wit h a n  O R  b ut neit her d oc u me nte d disease pr o gressi o n n or deat h  as of 
t he  cut -off  date  f or  t he  a nal ysis, D O R  will  be  ce ns ore d  at  t he  date  of  t he  last a de q uate t u m or 
assess me nt.  T he  ce ns ori n g  r ules  f or  D O R  are  t he  sa me  as  t h ose  descri be d  f or pr o gressi o n -free 
s ur vi val (P F S ) i n Secti o n  14. 4 . 
D O R ( m o nt hs) = ( date of P D or deat h –  date of 1 st o bjecti ve res p o nse  + 1)/ 3 0. 4 3 7 5 
Ka pla n -Meier (i.e. , pr o d uct -li mit) esti mates of me dia n D O R ti me will be prese nte d b y c o h ort d ose 
le vel t o get her wit h t w o-si de d 9 5 % CIs calc ulate d acc or di n g t o Br o o k me yer a n d Cr o wle y  (3 ). T he 
n u m ber  of  s u bjects  at  ris k  (i.e., wit h  o n g oi n g  res p o nse)  vs.  faile d  al o n g  wit h  Ka pla n -Meier 
esti mates  of o n g oi n g  res p o nse  pr o ba bilit y  at  3,  6, an d  1 2  m o nt hs  will  be  est i mate d  wit h 
c orres p o n di n g  t w o -si de d  9 5 %  CIs deri ve d  usi n g  t he  l o g -l o g tra nsf or mati o n  acc or di n g  t o 
Kal bfleisc h  a n d  Pre ntice  (4 ) (i.e., C O N F T Y P E =l o gl o g  defa ult  o pti o n  i n  S A S  LI F E T E S T 
pr oce d ure).  T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g Gree n w o o d’s f or m ula.   
If t he n u m ber of s u bjects wit h O R is s mall, t he Ka pla n-Meier met h o d ma y n ot pr o vi de relia ble 
esti mates. I n t his case, o nl y descri pti ve statistics or listi n gs will be pr o vi de d.  
1 4. 3  
T u m or S hri n k a ge  
A n alysis sets : F A S  
T u m or  s hri n ka ge is  defi ne d o nl y  f or  s u bjects  wit h  b ot h  a  baseli ne  a n d p ost- baseli ne  t u m or 
assess me nt  a n d  is  deri ve d  as  t he  perce nt  c ha n ge  fr o m  baseli ne  i n  tar get  lesi o ns  (s u m  of 
l o n gest dia meter f or n o n- n o dal lesi o ns a n d s h ort a xis f or n o dal lesi o ns) at eac h ti me p oi nt. See 
Secti o n 9. 1  f or t he defi niti o n of baseli ne a n d perce nt c ha n ge fr o m baseli ne.  
T he perce nt c ha n ge fr o m baseli ne i n tar get lesi o ns as well as t he first occ urre nce of a ne w lesi o n 
a n d s u bject  off  treat me nt will  be dis pla ye d a gai nst  ti me p oi nt ( wee ks) i n a li ne/s pi der  pl ot.  T he 
li nes of t he pl ot will be c ol or c o de d acc or di n g t o c o h ort d ose le vel. 
T he ma xi m u m  perce nt  re d ucti o n i n tar get lesi o ns fr o m baseli ne  will  be  i de ntifie d acr oss  all t he 
p ost- baseli ne assess me nts u ntil d oc u me nte d P D  or start of s u bse q ue nt a nti-ca ncer treat me nt. T he 
ma xi m u m perce nt re d ucti o n is e q ui vale nt t o t he s mallest perce nt c ha n ge fr o m baseli ne.  
A water fall pl ot of t he ma xi m u m perce n t re d uctio n i n tar get lesi o ns fr om baseli ne will als o be 
create d. Bars i n t he waterfall pl ot will be c ol or c o de d acc or di n g t o c o h ort d ose le vel. 
F or Part B, a listi n g wit h details of t he irra diate d lesi o ns will be pr o vi de d. 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /6 5  
 
 
1 4. 4  
Pr o gressi o n  Free S ur vi v al  
A n alysis sets: F A S  
Pr o gressi o n  free s ur vi val ( P F S) ti me is defi ne d as t he ti me (i n m o nt hs) fr o m treat me nt da y 1  u ntil  
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  v 1. 1  as  deter mi ne d  b y  t he 
I n vesti gat or or deat h d ue t o  a n y ca use , w hic he ver occ urs first .  
P F S ti me ( m o nt hs) = ( Date of e ve nt or ce ns ori n g  –  Treat me nt start date  + 1)/ 3 0. 4 3 7 5   
If a t u m or assess me nt was perf or me d o n t he sa me da y  as start of ne w a nti -ca ncer t hera p y, it will 
be  ass u me d  t hat  t he  t u m or  assess me nt  was  perf or me d  pri or  t o  t he  start  of  t he  ne w  a nti -ca ncer 
t hera p y; t heref ore, t he t u m or assess me nt will be i ncl u de d i n t he deri vati o n of t he P F S ti me.  
A n  a de q uate t u m or assess me nt is def i ne d as a res ult t hat is n ot “ N E” or “ N A” ( N ot A p plica ble). 
T he ce ns ori n g a n d e ve nt date o pti o ns f or t he P F S a n d D O R  anal ys es are prese nte d i n Ta ble 7 . 
T a ble 7 : O utc o me a n d E ve nt D ates f or P F S a n d D O R A n al yses  
Sce n ari o  
D ate of e ve nt / ce ns ori n g  
O utc o me  
N o  a de q uate  baseli ne assess me nt  
Treat me nt d a y 1 
Ce ns ore d a 
If t he last t u m or assess me nt is be y o n d 6 m o nt hs 
fr o m t he first d ose: 
Pr o gressi o n or deat h ≤ 2 4  wee ks after last t u m or 
assess me nt  
Date of pr o gressi o n or deat h  
E ve nt  
If t he last t u m or assess me nt is wit hi n 6 m o nt hs 
fr o m t he first d ose: 
Pr o gressi o n or deat h ≤ 1 6  wee ks after last t u m or 
assess me nt or ≤ 1 6  wee ks after treat me nt d a y 1 
Date of pr o gressi o n or deat h  
E ve nt  
If t he last t u m or assess me nt is be y o n d 6 m o nt hs 
fr o m t he first d ose: 
Pr o gressi o n or deat h > 2 4  wee ks after last t u m or 
assess me nt  
Date of last e val ua ble assess me nt  
Ce ns ore d  
If t he last t u m or assess me nt is wit hi n 6 m o nt hs 
fr o m t he first d ose: 
Pr o gressi o n or deat h > 1 6  wee ks after last t u m or 
assess me nt  
Date of last e val ua ble assess me nt  
Ce ns ore d  
N o pr o gressi o n  
Date of last e val ua ble assess me nt  
Ce ns ore d  
Treat me nt disc o nti n uati o n d ue t o ‘ Disease 
pr o gressi o n’ wit h o ut d oc u me nte d pr o gressi o n  
N ot a p plica ble.  
I nf or mati o n is i g n ore d. 
O utc o me is deri ve d 
base d o n d oc u me nte d 
pr o gressi o n o nl y.  
Ne w a nti -ca ncer t hera p y gi ve n  
Date of last e val ua ble t u m or assess me nt 
bef ore a nti -ca ncer t hera p y is gi ve n  
Ce ns ore d  
a H o we ver if t he s u bject dies ≤ 1 6 wee ks after treat me nt da y 1 , t he deat h is c o nsi dere d a n e ve nt wit h date o n deat h date.     
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 /6 5  
 
 
P F S will be s u m marize d f or t he F A S b y d ose le vel usi n g t he Ka pla n -Meier met h o d a n d dis pla ye d 
gra p hicall y w he n a p pr o priate. Me dia n e ve nt ti mes a n d t w o -si de d 9 5 % CIs f or eac h me dia n will be 
pr o vi de d.  
T he P F S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a s u bject 
listi n g. 
Fre q ue nc y ( n u m ber a n d p erce nta ge) of s u bjects wit h eac h e ve nt t y pe ( P D or deat h) a n d ce ns ori n g 
reas o ns will be prese nte d b y treat me nt gr o u p. Reas o ns f or ce ns ori n g will be s u m marize d acc or di n g 
t o t he cate g ories i n Ta ble 8  f oll o wi n g t he hierarc h y s h o w n. 
T a ble 8 : P F S Ce ns ori n g Re as o ns a n d Hier arc h y  
Hier arc h y  
C o n diti o n  
Ce ns ori n g Re as o n  
1  
N o a de q uate baseli ne assess me nt  
N o a de q uate baseli ne assess me nt  
2  
Start of ne w a nti -ca ncer t hera p y bef ore e ve nt  
Start of ne w a nti -ca ncer t hera p y  
3  
E ve nt m ore t ha n 1 6 ( or 2 4 if be y o n d 6 m o nt hs fr o m t he first d ose of 
st u d y treat me nt) wee ks after last a de q uate p ost-baseli ne t u m or 
assess me nt / date of first d ose of st u d y treat me nt (see als o Ta ble 7 ) 
E ve nt after missi n g assess me nts  a 
4  
N o e ve nt a n d [ wit h dra wal of c o nse nt date ≥ date of first d ose of 
st u d y treat me nt O R e n d of st u d y ( E O S) = s u bject ref use d f urt her 
F U]  
Wit h dra wal of c o nse nt  
5  
N o e ve nt a n d l ost t o f oll o w -u p i n a n y dis p ositi o n e C R F pa ge  
L ost t o f oll o w -u p  
6  
N o e ve nt a n d E O S prese nt a n d n o a de q uate p ost -baseli ne t u m or 
assess me nt  
N o a de q uate p ost -baseli ne t u m or 
assess me nt  
7  
N o e ve nt a n d n o ne of t he c o n diti o ns i n t he pri or hierarc h y are met  
O n g oi n g wit h o ut a n e ve nt  
a M ore t ha n 1 6 ( or 2 4) wee ks after last a de q uate t u m or assess me nt (see als o  Ta ble 7 ) 
1 4. 5  
O ver all S ur vi v al  
O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m treat me nt start t o t he date of deat h, re gar dless of 
t he act ual ca use of t he s u bject’s deat h. F or s u bjects w h o are still ali ve at t he ti me of t he data  c ut-
off f or t he  a nal ysis or w h o are l ost t o f oll o w u p, O S ti me will be ce ns ore d at t he last rec or de d date 
t hat t he s u bject is k n o w n t o be ali ve as s pecifie d i n Secti o n  9. 4.  
O S (i n m o nt hs) = ( Date of deat h –  Date of first st u d y treat me nt a d mi nistrati o n + 1) / 3 0. 4 3 7 5  
Ka pla n -Meier (i.e. , pr o d uct -li mit) esti mates of me dia n O S ti me will be prese nte d b y c o h ort d ose 
le vel t o get her wit h t w o-si de d 9 5 % CIs calc ulate d acc or di n g t o Br o o k me yer a n d Cr o wle y ( 1) . T he 
n u m ber of s u bjects at ris k vs. faile d al o n g wit h Ka pla n -Meier esti mates of s ur vi val pr o ba bilit y at 
3,  6, an d  1 2  m o nt hs (as  well  as  f urt her  ti me p oi nts  as  a p pr o priate) will  be  esti mate d  wit h 
c orres p o n di n g  t w o -si de d  9 5 %  CIs deri v e d  usi n g  t he  l o g -l o g tra nsf or mati o n  acc or di n g  t o 
Kal bfleisc h  a n d  Pre ntice  ( 2)  (i.e., C O N F T Y P E =l o gl o g  defa ult  o pti o n  i n  S A S  LI F E T E S T 
pr oce d ure).  T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g Gree n w o o d’s f or m ula.   
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
  P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns  
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /6 5  
Fre q ue nc y ( n u m ber a n d perce nta ge) of s u bjects wit h a n e ve nt ( deat h) a n d ce ns ori n g reas o ns will 
als o be prese nte d b y treat me nt ar m. Ce ns ori n g reas o ns are as f oll o ws:  
•
O n g oi n g i n t he st u d y wit h o ut a n e ve nt
•
Wit h dra wal of c o nse nt
•
L ost t o f oll o w -u p
T he O S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a s u bject 
listi n g. 
1 5  
S afet y A n al yses  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y e n d p oi nts t hat are 
c o m m o n acr oss cli nical trials s uc h as A Es, la b orat or y tests a n d vital si g ns.  
1 5. 1  
A d verse E ve nts  
A n alysis set: S A F 
T he se verit y of A Es will be gra de 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 5 . If  a  partic ular  A E’s se verit y  is  n ot  s pecificall y 
gra de d  b y  t his  g ui da nce,  t he  I n vesti gat or  uses  t he  ge neral  N CI -C T C A E  defi niti o ns  of  Gra de  1 
t hr o u g h Gra de 5 f oll o wi n g his or her best me dical j u d g me nt. T he latest Me d D R A versi o n at t he 
ti me of data c ut-off will be use d t o c o de  A Es  acc or di n g t o S O C a n d P T . 
•
Tre at me nt  E mer ge nt  A d verse  E ve nts  ( T E A Es)  are  e ve nts  wit h  o nset  dates  occ urri n g
d uri n g  t he  o n -treat me nt  peri o d,  or  t h ose  t hat  w orse n  i n  se verit y  d uri n g  t he  o n-treat me nt
peri o d. All a nal yses will be base d o n T E A Es u nless ot her w ise s pecifie d.
•
Rel ate d A d verse E ve nts  ha ve  a  relati o ns hi p  t o st u d y treat me nt of  “ Relate d ”, or  missi n g
relate d ness, as re p orte d  b y  t he In vesti gat or  o n  t he “A d verse  E ve nts  Details”  eC R F  pa ge .
Relate d ness is defi ne d se paratel y f or eac h st u d y i nter ve nti o n c o m po ne nt .
•
Seri o us A d verse E ve nts ( S A Es) are t h ose rec or de d o n t he “A d verse E ve nts  Details”  eC R F
pa ge as  Seri o us A d verse E ve nt = “Yes ”.
•
A d verse  E ve nts  Le a di n g  t o  Tre at me nt  Disc o nti n u ati o n  are  t h ose rec or de d  o n  t he
“A d verse  E ve nts  Details”  eC R F  pa ge  as  Acti o n(s )  ta ke n  wit h  M 3 8 1 4/ avel u ma b /
ra di ot hera p y = “ Dr u g wit h dra w n”.
•
A d verse  E ve nts  Le a di n g  t o  De at h  are  t h ose rec or de d  o n  t he “A d verse  E ve nts  Details”
eC R F pa ge as  O utc o me = “Fatal ” as well as A Es of Gra de 5 .
•
A d verse E ve nts of S peci al I nterest ( A E SIs) f or t his st u d y i ncl u de i nf usi o n relate d reacti o ns
(I R Rs) / h y perse nsiti vities a n d i m m u ne-relate d A Es (i rA Es ) / a ut oi m m u ne dis or ders. I R Rs
a n d ir A Es  are i de ntifie d base d o n a list of Me d D R A P Ts a n d ot her q ualif yi n g  criteria, as
s pecifie d i n A p pe n di x I.
Details o n t he ha n dli n g of i nc o m plete A E-relate d dates are s pecifie d i n Secti o n  9. 4. 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /6 5  
 
 
1 5. 1. 1  
All A d verse E ve nts  
A d verse e ve nts will be s u m marize d b y w orst se verit y per s u bject, usi n g Me d D R A P T as e ve nt 
cate g or y a n d S O C as s u m mar y cate g or y, i n al p ha betical or der. If a n A E is re p orte d f or a gi ve n 
s u bject m ore t ha n o nce d uri n g treat me nt, t he w orst se verit y a n d t he w orst relati o ns hi p t o st u d y 
treat me nt will be ta b ulate d. 
A n  o verall s u m mar y  ta ble of A Es will be pre pare d a n d will ta b ulate t he n u m ber a n d perce nta ge of 
partici pa nts wit h A Es i n t he f oll o wi n g cate g ories: 
•  A n y T E A E  
•  T E A Es relate d t o st u d y i nter ve nti o n (ta b ulate d b y relate d ness t o a n y st u d y i nter ve nti o n, 
a n d i n di vi d ual st u d y i nter ve nti o n c o m p o ne nts ) 
•  A n y seri o us T E A Es 
•  Seri o us  T E A Es relate d  t o  st u d y  i nter ve nti o n  (ta b ulate d  b y  relate d ness  t o  a n y  st u d y 
i nter ve nti o n, a n d i n di vi d ual st u d y i nter ve nti o n c o m p o ne nts ) 
•  T E A Es wit h N CI -C T C A E se verit y Gra de  3  
•  T E A Es  relate d t o st u d y i nter venti o n  wit h N CI -C T C A E se verit y Gra de  3  (ta b ulate d b y 
relate d ness t o a n y st u d y i nter ve nti o n, a n d i n di vi d ual st u d y i nter ve nti o n c o m p o ne nts ) 
•  T E A Es lea di n g t o deat h  
•  T E A Es relate d t o st u d y i nter ve nti o n lea di n g t o deat h (ta b ulate d b y relate d ness t o a n y st u d y 
i nter ve nti o n, a n d i n di vi d ual st u d y i nter ve nti o n c o m p o ne nts ) 
•  Treat me nt -e mer ge nt A E SIs o verall a n d b y cate g or y (see Secti o n  1 5. 2. 4 f or m ore details o n 
s u m maries of A E SIs) 
I n a d diti o n, ta bles s u m marizi n g t he fre q ue nc y of s u bjects wit h A Es, prese nte d b y S O C a n d P T, i n 
t he f oll o wi n g cate g ories will be pre pare d. Ta bles s u m marizi n g T E A Es relate d t o st u d y i nter ve nti o n 
will  be create d  t o  s u m marize  T E A Es relate d  t o  a n y  st u d y  i nter ve nti o n a n d  will  be  re peate d  t o 
s u m marize T E A Es relate d t o s pecific st u d y i nter ve nti o n c o m p o ne nts  ( M 3 8 1 4, a vel u ma b, a n d, f or 
Part B, R T).  
•  A n y T E A E  
•  T E A E s b y w orst gra de  
•  T E A Es relate d t o st u d y i nter ve nti o n 
•  Seri o us T E A Es  
•  Seri o us T E A Es relate d t o st u d y i nter ve nti o n 
•  T E A Es relate d t o st u d y i nter ve nti o n b y w orst g ra de 
•  T E A Es lea di n g t o deat h  
•  T E A Es relate d t o st u d y i nter ve nti o n lea di n g t o deat h 
Cli nic al tri al. g o v a n d E u dr a C T re q uire me nts  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /6 5  
 
 
S u m mar y ta bles f or n o nseri o us A Es, a p pl yi n g fre q ue nc y t hres h ol d of 5 %  i n a n y d ose le vel w he n 
e xcl u di n g S A Es, b y S O C a n d P T, will be pr o vi de d.   
Details  of  t he  A E SIs  will  be  prese nte d  i n  a  listi n g  s orte d  b y  S O C  a n d  P T,  i ncl u di n g:  S u bject 
n u m ber, S O C, P T, A E SI cate g or y, relati o ns hi p t o avel u ma b, seri o us ness, gra de, start date, c o h ort 
d ose le vel, a n d ti me si nce last a n d first a d mi nistrati o n of avel u ma b.  
A listi n g of all A Es will als o be pre pare d, i ncl u di n g all rele va nt details fr o m t he “ A d verse E ve nts 
Details”  e C R F pa ge.  A fla g will be i ncl u de d i n t he listi n g, i de ntif yi n g A Es attri b ute d t o C O VI D -
1 9 . 
1 5. 1. 2  
A d verse  
E ve nts  
Le a di n g  
t o 
St u d y  
I nter ve nti o n 
Disc o nti n u ati o n  
A n  o verall s u m mar y  ta ble of A Es lea di n g t o per ma ne nt  st u d y i nter ve nti o n disc o nti n uati o n will be 
pre pare d a n d will t a b ulate t he n u m ber a n d perce nta ge of partici pa nts wit h A Es i n t he f oll o wi n g 
cate g ories : 
•  A n y T E A E lea di n g t o per ma ne nt disc o nti n uati o n of at least o ne st u d y i nter ve nti o n  
•  T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of M3 8 1 4  
•  T E A Es lea di n g t o per ma ne n t disc o nti n uati o n of a vel u ma b  
•  T E A E s lea di n g t o per ma ne nt disc o nti n uati o n of R T  ( Part B o nl y ) 
•  T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of b ot h M 3 8 1 4 a n d a vel u ma b  
•  T E A Es relate d t o M 3 8 1 4  lea di n g t o its per ma ne nt disc o nti n uati o n  
•  T E A Es relate d t o a vel u ma b lea di n g t o its per ma ne nt disc o nti n uati o n  
•  T E A E relate d t o b ot h lea di n g t o per ma ne nt disc o nti n uati o n  
•  T E A Es relate d t o R T  lea di n g t o its per ma ne nt disc o nti n uati o n 
•  A E SIs lea di n g t o per ma ne nt disc o nti n uati o n of a vel u ma b , b y cate g or y 
 
In a d diti o n, ta bles s u m marizi n g t he fre q ue nc y of s u bjects wit h T E A Es, prese nte d b y S O C a n d P T, 
i n t he f oll o wi n g cate g ories will be pre pare d. 
•  T E A Es lea di n g per ma ne nt disc o nti n uati o n of a vel u ma b  
•  T E A Es lea di n g per ma ne nt disc o nti n uati o n of M 3 8 1 4  
•  T E A Es lea di n g per ma ne nt disc o nti n uati o n of R T  ( Part B o nl y) 
•  T E A Es lea di n g per ma ne nt disc o nti n uati o n of M 3 8 1 4 a n d a vel u ma b  
•  T E A Es relate d t o a vel u ma b lea di n g t o its per ma ne nt disc o nti n uati o n  
•  T E A Es relate d t o M 3 8 1 4  lea di n g to its per ma ne nt disc o nti n uati o n  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 /6 5  
 
 
As acti o n ta ke n wit h st u d y i nter ve nti o n will be detaile d i n t he f ull listi n g of A Es, n o se parate listi n g 
of A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n will be pr o d uce d.  
 
1 5. 2  
D L Ts, De at hs,  Ot her  Seri o us  A d vers e  E ve nts,  a n d  Ot her 
Si g nific a nt A d verse E ve nts  
1 5. 2. 1  
Occ urre nce of D L Ts  
A n alysis set: D L T  
T he occ urre nce of D L Ts  d uri n g t he D L T e val uati o n peri o d is a pri mar y e n d p oi nt f or b ot h Parts A 
a n d B of t he st u d y.  T he D L T peri o d f or Part A is defi ne d as t he first 3 wee ks of t he st u d y, f oll o wi n g 
t he start of t he st u d y i nter ve nti o n. T he D L T peri o d f or Part B is defi ne d as t he first 4 wee ks of t he 
st u d y, f oll o wi n g t he start of st u d y i nter ve nti o n. T he D L T A nal ysis S et will be use d f or t he a nal ysis 
of t he pri mar y e n d p oi nt. Please refer t o Secti o n 6. 6 .3  of t he Cli nical Trial  Pr ot oc ol M S 2 0 1 9 6 4 -
0 0 0 1  f or t he detaile d defi niti o n of a DL T. Deter mi nati o n of w het her a n A E is c o nsi dere d a D L T is 
ma de  b y  t he In vesti gat or  a n d  s pecifie d  o n  t he “A d verse  E ve nt s Details ” e C R F  pa ge ;  t his 
assess me nt is s u bse q ue ntl y c o nfir me d b y t he S M C . 
A s u m mar y ta ble of D L Ts will i ncl u de t he f oll o wi n g s u m maries: 
•  N u m ber a n d perce nta ge of s u bjects w h o e x perie nce d a D L T d uri n g t he D L T e val uati o n 
peri o d  
•  N u m ber  a n d  perce nta ge  of  s u bjects  e x perie nci n g  a n y  A E  d uri n g  t he  D L T  e val uati o n 
peri o d.  
•  N u m ber of D L Ts e x perie nce d per s u bject: 1 / 2 / ≥3  
•  D L T s b y S O C a n d P T  
A listi n g of D L T s will i ncl u de s u bject i de ntifier, d ose le vel, a n d all rele va nt varia bles fr o m t he 
“ A d verse E ve nts Details”  e C R F pa ge.  
I n a d diti o n, a D L T pr ofile pl ot of all s u bjects i n t he Safet y A nal ysis Set will be pr o d uce d. T his 
will s h o w a cl ose d s q u are f or all s u bjects w h o were c o nsi dere d e val ua ble ( i.e. i ncl u de d i n D L T 
A nal ysis  S et)  a n d  di d  n ot  ha ve  a  D L T  d uri n g t he  D L T  peri o d,  a n  o pe n  s q uare  f or  t h ose  w h o 
e x perie nce d a D L T d uri n g t he D L T peri o d, a n d a n o pe n circle f or t h ose w h o were e xcl u de d fr o m 
the D L T A nal ysis Set. T his pl ot will ha ve co h ort n u m ber o n t he x -a xis a n d d ose le vel ( m g) o n t he 
y -a xis. 
1 5. 2. 2  
De at hs  
A n alysis set: S A F  
All deat hs after first st u d y i nter ve nti o n  will be ta b ulate d base d o n i nf or mati o n fr o m t he “ Deat h” 
e C R F pa ge . T he s u m mar y will b e dis pla ye d b y c o h ort d ose le vel a n d will i ncl u de:  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 /6 5  
 
 
•  N u m ber of d eat hs o verall a n d b y pri mar y reas o n  
•  N u m ber of d eat hs wit hi n 3 0 da ys after last d ose of st u d y i nter ve nti o n 
•  N u m ber of d eat hs wit hi n 6 0 da ys after first d ose of st u d y i nter ve nti o n  
I n  a d diti o n,  date  a n d  ca use  of  deat h  will  be  pr o vi de d  i n a n i n di vi d ual  partici pa nt  data  listi n g 
t o get her wit h selecte d d osi n g i nf or mati o n, prese nte d se paratel y f or eac h i nter ve nti o n ( date of first 
/  last  a d mi nistrati o n, d ose , n u m ber  of  c ycles/  fracti o n  da y s,  a n d  relate d ness  t o  eac h  st u d y 
i nter ve nti o n). T he listi n g will i ncl u de c ol u m ns f or: 
•  A Es wit h fatal o utc o me  
•  Fla g f or deat h wit hi n 3 0 da ys of last st u d y i nter ve nti o n  
•  Fla g f or deat h wit hi n 6 0 da ys of first st u d y i nter ve nti o n  
•  Fla g f or deat h relate d t o C O VI D -1 9  
1 5. 2. 3  
Seri o us A d verse E v e nts  
A n alysis set: S A F  
Please refer t o Secti o n  1 5. 1. 1 f or details o n S A E s u m maries.  
T he listi n gs of all S A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or S A Es 
wit h o nset o utsi de of t he o n -treat me nt peri o d. 
1 5. 2. 4  
A d verse E ve nts of S peci al I nterest  
A n alysis set: S A F  
T he fre q ue nc y ( n u m ber a n d perce nta ge) of s u bjects wit h eac h of t he f oll o wi n g will be prese nte d 
f or treat me nt e mer ge nt ir A Es, b y d ose le vel: 
•  ir A Es lea di n g t o deat h, b y S O C a n d P T  
•  ir A Es, b y S O C a n d P T  
•  ir A Es lea di n g t o disc o nti n uati o n, b y S O C a n d P T 
•  ir A Es, Gra de ≥ 3, b y S O C a n d P T 
•  ir A Es b y S O C a n d P T a n d w orst gra de 
•  Seri o us ir A Es b y S O C a n d P T  
T he listi n g of all ir A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or ir A Es 
wit h o nset o utsi de of t he o n -treat me nt peri o d. A se parate listi n g of ir A Es wit h o nset after t he o n-
treat me nt peri o d will als o be pr o vi de d. 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /6 5  
 
 
T he fre q ue nc y ( n u m ber a n d perce nta ge) of s u bjects wit h eac h of t he f oll o wi n g will be prese nte d 
f or treat me nt e mer ge nt I R Rs, b y d ose le vel:  
•  I R Rs lea di n g t o deat h, b y S O C a n d P T 
•  I R Rs lea di n g t o disc o nti n uati o n , b y S O C a n d P T 
•  I R Rs, b y S O C a n d P T 
•  I R Rs, Gra de ≥ 3, b y S O C a n d P T 
•  Seri o us I R Rs, b y S O C a n d P T  
Ti mi n g  of  first  o nset  of  a n  I R R  (i nf usi o n  1,  i nf usi o n  2,  i nf us i o n  3,  i nf usi o n  4  or  later)  will  be 
pr o vi de d.  
T he listi n g of all I R Rs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or I R Rs 
wit h o nset o utsi de of t he o n -treat me nt peri o d. 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n  
A n alysis set: S A F  
1 5. 3. 1  
He m at ol o g y a n d Cli nic al C he mistr y P ar a meters  
All statistical a nal yses of la b orat or y val ues will be perf or me d usi n g SI u nits.  
A n y  s u bject  wit h  a n  a b n or mal  he mat ol o g y  or  c he mistr y  res ult  will  ha ve  all  rec or ds  f or  t he 
para meter wit h t he a b n or mal res ult i ncl u de d i n a listi n g. Perti ne nt details, i ncl u di n g val ue, c ha n ge 
fr o m baseli ne, n or mal ra n ge i n dicat or, a n d t o xicit y gra de ( w here a p plica ble) will be pr o vi de d. 
Q ua ntitati ve data will be e xa mi ne d f or tre n ds i n act ual val ues a n d t he c ha n ge fr o m baseli ne t hr o u g h 
prese nt ati o n of b o x pl ots s h o w n o ver ti me , at eac h visit. I n a d diti o n, a b o x pl ot of t he c ha n ge fr o m 
baseli ne t o t he w orst o n -treat me nt rec or d f or eac h para meter will be pr o d uce d. 
Listi n gs will i ncl u de all t he he mat ol o g y a n d c he mistr y la b orat or y para meters as a vaila ble i n t he 
data base wit h t he all c orres p o n di n g rele va nt i nf or mati o n.  
P ar a meters wit h C T C A E gr a de defi ne d  
Please  see A p pe n di x II –  N CI -C T C  Gra da ble  a n d  N o n -Gra da ble  Safet y  La b orat or y  Test 
Para meters a n d Directi o n(s) of A b n or malit y f or a list of t he C T C A E-gra da ble para meters.  
La b orat or y t o xicities will be ta b ulate d  (c o u nt a n d perce nta ge) f or eac h gra da ble para meter b y t he 
w orst o n -treat me nt C T C A E  gra de .  Shift s fr o m  baseli ne t o  w orst C T C A E  gra de  d uri n g  t he  o n -
treat me nt peri o d will als o be ta b ulate d . F or s o me para meters (i n dicate d i n A p pe n di x I I), t he o n-
treat me nt  gra di n g  is  de pe n de nt  u p o n  t he  baseli ne  gra di n g;  i n  s uc h  cases,  t he  baseli ne  gra di n g 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /6 5  
 
 
( n or mal  vs.  a b n or mal)  will  be  dis pla ye d  t o get her  wit h  t he  o n-treat me nt  gra di n g i n  t he  ta b ular 
s u m maries.  
T he de n o mi nat or t o calc ulate perce nta ges f or eac h la b orat or y para meter is t he n u m ber of patie nts 
i n t he c o h ort d ose le vel. S u bjects wit h o ut baseli ne or p ost -baseli ne res ults f or a gi ve n para meter 
will be prese nte d i n t he “ Missi n g” cate g or y a n d will c o ntri b ute t o t he de n o mi nat or.    
P ar a meters wit h n o C T C A E gr a de defi ne d    
La b orat or y  a b n or malities  will  be  ta b ulate d  (c o u nt  a n d  perce nta ge)  f or  eac h  n o n -gra da ble 
para meter  b y  t he  w orst  o n -treat me nt  a b n or malit y.  S hifts  fr o m  baseli ne  t o  w orst  a b n or malit y 
(se paratel y f or hi g h a n d l o w criteria) d uri n g t he o n -treat me nt peri o d will als o be ta b ulate d. T he 
de n o mi nat or t o calc ulate perce nta ges f or eac h la b orat or y para meter is t he n u m ber of patie nts i n 
t he c o h ort d ose le vel. S u bjects wit h o ut baseli ne or p ost-baseli ne res ults f or a gi ve n para meter will 
be prese nte d i n t he “ Missi n g” cate g or y a n d will c o ntri b ute t o t he de n o mi na t or. 
Li ver F u ncti o n Ele v ati o n a n d P ossi ble H y's L a w C ases d uri n g O n -Tre at me nt Peri o d  
A L T, A S T a n d T otal Bilir u bi n are use d t o assess p ossi ble dr u g i n d uce d li ver t o xicit y.  T he rati os 
of test res ult o ver u p per li mit of n or mal ( U L N) will be calc ulate d a n d cl assifie d f or t hese t hree 
para meters d uri n g t he o n -treat me nt peri o d. 
A  s u m mar y  of  li ver  f u ncti o n  tests  will  i ncl u de  t he  f oll o wi n g  cate g ories.  T he  n u m ber  a n d 
perce nta ge  of  s u bjects  wit h  eac h  of  t he  f oll o wi n g  d uri n g  t he  o n -treat me nt  peri o d  will  be 
s u m marize d o verall a n d b y d ose le vel:  
•  A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 1 0 × U L N, A L T ≥ 2 0 × U L N  
•  A S T ≥ 3 × U L N, A S T ≥ 5 x U L N, A S T ≥ 1 0 × U L N, A S T ≥ 2 0 × U L N  
•  ( A L T or A S T) ≥ 3 × U L N, ( A L T or A S T)  ≥ 5 × U L N, ( A L T or A S T)  ≥ 1 0 × U L N, ( A L T or A S T)  ≥ 
2 0 × U L N  
•  T otal Bilir u bi n ≥ 2 × U L N  
•  C o nc urre n t A L T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N 
•  C o nc urre nt A S T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt ( A L T or A S T)  ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt ( A L T or A S T)  ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d A L P > 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d A L P ≤ 2 × U L N or missi n g  
C o nc urre nt meas ure me nts are t h ose occ urri n g o n t he sa me date.  
Cate g ories will be c u m ulati ve, i.e., a s u bject wit h a n ele vati o n of A S T ≥1 0 × U L N will als o a p pear 
i n t he cate g ories ≥5 × U L N a n d ≥3 × U L N.  
A n  e val uati o n  of  Dr u g -I n d uce d  Seri o us  He pat ot o xicit y  (e DI S H)  pl ot  will  als o  be  create d  b y 
gra p hicall y  dis pla yi n g  pea k  ser u m  A L T  (/ U L N)  vs  pea k  T otal  Bilir u bi n  (/ U L N)  i ncl u di n g 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /6 5  
 
 
refere nce  li nes  at  A L T  ≥3 x U L N  a n d  bilir u bi n  ≥2 x U L N.  T he  dis pla y  will  be  di vi de d  i nt o  4 
q ua dra nts  b y  t he  li nes  t hr o u g h  A L T  ≥  3 × U L N  a n d  T otal  Bilir u bi n  ≥2 × U L N.  T he  left  l o wer 
q ua dra nt is t he n c o nsi dere d n or mal or i nsi g nifica nt ele vati o ns i n li ver c he mistries, t he left u p per 
q ua dra nt  i n dicates  patie nts  wit h  p ossi ble  Gil bert’s  c h olestasi s; t he  ri g ht  u p per  q ua dra nt  are  t he 
p ossi ble H y’s La w patie n ts; t he ri g ht l o wer q ua dra nt is p ossi ble Te m ple’s C or ollar y ( patie nts wit h 
A L T ≥ 3 x U L N b ut n ot satisf yi n g H y’s La w). Differe nt s y m b ol will be use d f or differe nt c o h ort 
d ose le vel s. 
1 5. 3. 2  
Ot her l a b or at or y p ar a meters  
All  ot her  para meters  c ollecte d  o n  t he  e C R F  will  be  liste d  i n  de dicate d  listi n gs  prese nti n g  all 
c orres p o n di n g c ollecte d data -fiel ds o n t he e C R F.  
•  Uri nal ysis: all uri nal ysis para meters  
•  H or m o nes: free 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) 
•   Ser ol o g y: HI V a n d he patitis  
•  Pre g na nc y test  
1 5. 4  
Vit al Si g ns  
A n alysis set: S A F  
T he ma xi m u m c ha n ges of  vital si g n meas ure me nts fr o m baseli ne t o ma xi m u m c ha n ge d uri n g t he 
o n -treat me nt peri o d will be gr o u pe d as f oll o ws:  
T a ble 9 : Vit al Si g ns S u m m ar y C ate g ories 
Vit al Si g n B aseli ne C ate g or y  
C h a n ge fr o m B aseli ne C ate g or y  
B o d y te m perat ure i ncrease 
< 1 C, 1 -< 2 C, 2 -< 3 C,    3 C  
Heart rate i ncrease fr o m baseli ne  
< 1 0 0 b p m ; ≥ 1 0 0 b p m  
2 0 b p m, > 2 0 –  4 0 b p m, > 4 0 b p m  
Heart rate decrease fr o m baseli ne  
< 1 0 0 b p m ; ≥ 1 0 0 b p m  
2 0 b p m, > 2 0 –  4 0 b p m, > 4 0 b p m  
S B P i ncrease fr o m baseli ne  
< 1 4 0 m m H g ; ≥ 1 4 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
S B P decrease fr o m baseli ne  
< 1 4 0 m m H g ; ≥ 1 4 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
D B P i ncrease fr o m baseli ne  
< 9 0 m m H g; ≥ 9 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
D B P decrease fr o m baseli ne  
< 9 0 m m H g; ≥ 9 0 m m H g  
2 0 m m H g, > 2 0 –  4 0 m m H g, > 4 0 m m H g  
Res pirati o n rate i ncrease fr o m baseli ne < 2 0 b p m; ≥ 2 0 b p m  
5 b p m, > 5 –  1 0 b p m, > 1 0 b p m  
Res pirati o n rate decrease fr o m baseli ne < 2 0 b p m; ≥ 2 0 b p m  
5 b p m, > 5 –  1 0 b p m, > 1 0 b p m  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /6 5  
 
 
T he f oll o wi n g s u m maries will be pre pare d f or vital si g n para meters as gr o u pe d a b o ve c o nsi deri n g 
o nl y partici pa nts wit h p ost -baseli ne val ues:  
•  Ma xi mal shifts (c ha n ges i n cate g ories)  
•  Listi n g of hi g hest c ha n ge per partici pa nt  
A n a d diti o nal  partici pa nt  data  listi n g  will  prese nt  all  perti ne nt  vital  si g ns  details  c ollecte d 
t hr o u g h o ut t he c o urse of t he st u d y. 
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns  
A n alysis set: S A F   
1 5. 5. 1  
1 2 -Le a d Electr oc ar di o gr a m  
T he  i nci de nce  a n d  perce nta ge  of  s u bjects wit h  p ote ntiall y  cli nicall y  si g nifica nt  a b n or malities 
( P C S A)  f or  1 2-lea d E C G  para meters  will  be  s u m marize d  d uri n g  t he  o n -treat me nt  peri o d.  T he 
P C S A criteria are pr o vi de d i n t he Ta ble 1 0 . 
T a ble 1 0 : P ote nti all y Cli nic all y Si g nific a nt A b n or m alities Criteri a f or E C G 
Test  
P ote nti all y Cli nic all y Si g nific a nt A b n or m alities ( P C S A) Criteri a  
Heart Rate  
≤ 5 0 b p m a n d decrease fr o m baseli ne ≥ 2 0 b p m  
≥ 1 2 0 b p m a n d i ncrease d fr o m baseli ne ≥ 2 0 b p m  
Q R S  
 ≥ 1 2 0 ms  
Q Tc F a bs ol ute  (a) 
> 4 5 0 ms - < = 4 8 0 ms                             
> 4 8 0 ms - < = 5 0 0 ms                        
> 5 0 0 ms                               
Q Tc F c ha n ge fr o m baseli ne  (a) 
I ncrease:                                                                                             
> 3 0 ms  - < = 6 0 ms  
> 6 0 ms  
Q Tc F c ha n ge fr o m baseli ne  
D ecrease:                                                                                             
> 3 0 ms  - < = 6 0 ms  
> 6 0 ms  
  
(a) 𝑄𝑇𝑐𝐹 (Fri d erici a’s  C orr ecti o n ) =   𝑄𝑇/ ∛𝑅𝑅 (R R -i nter val is meas ure d i n sec o n ds) will be s u m marize d as 
c ollecte d i n e C R F.  
 
Listi n gs of E C G para meters will be pr o vi de d i ncl u di n g t he data c ollecte d i n e C R F a n d t he c ha n ge 
fr o m baseli ne. A se parate listi n g f or P C S A  will be create d.  
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 /6 5  
 
 
1 5. 5. 2  
E aster n C o o per ati ve O nc ol o g y Gr o u p  P erf or m a nce St at us  
Easter n C o o perati ve O nc ol o g y Gr o u p  Perf or ma nce Stat us  (E C O G  P S)  will be s u m marize d usi n g 
a s hift ta ble s h o wi n g baseli ne vers us w orst  p ost -treat me nt val ue. T he i nf or mati o n will c o me fr o m 
t he “ E C O G P erf or ma nce S tat us” e C R F pa ge. 
Listi n gs of eac h partici p a nt’s E C O G P S  o ver ti me will be pr o vi de d.  
 
1 6  
A n al yses of Ot her E n d p oi nts  
1 6. 1  
P h ar m ac o ki netics  
P o p ul ati o n: P K a n alysis set  
N o n -c o m part me ntal c o m p utati o n of M 3 8 1 4  a n d 0 -de m et h ylate d pr o d uct M 4 6 7 (if a vaila ble) P K 
para meters 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
®  V ersi o n 8. 0, or 
hi g her  ( P harsi g ht  C or p orati o n,  a  Certara  C o m pa n y,  Pri ncet o n,  Ne w  Jerse y).  T he  statistical 
s oft ware S A S ®  ( Statistical A nal ysis S yste m, S A S-I nstit ute, Car y N ort h Car oli na), V ersi o n 9. 2 , or 
hi g her , will be use d t o pr o d uce ta bles, listi n gs , a n d fi g ures. Fi g ures will  be pre pare d wit h S A S 
Versi o n 9. 2, or hi g her.  
A vel u ma b  ta bles, listi n gs, fi g ures, a n d para meters will be c o m p ute d usi n g S A S . 
P har mac o ki netic para meters will be calc ulate d usi n g sta n dar d n o n -c o m part me ntal met h o ds , t he 
act ual a d mi nistere d d ose , a n d act ual ela pse d ti me fr o m d osi n g .  
P har mac o ki netic  c o nce ntrati o ns  of  M 3 8 1 4 w o ul d be  p o ole d  wit h  data  fr o m  ot her  st u dies  t o 
c o n d uct a p o p ulati o n  P K  a nal ysis.  A n o n -li near  mi xe d  effect  a p pr oac h w o ul d  be  use d  t o 
c haracterize  t he bl o o d c o nce ntrati o n  ti me  pr ofile  of  M 3 8 1 4  f oll o wi n g  m ulti ple  d oses  a n d  t o 
e val uate t he P K i nter -i n di vi d ual varia bilit y a n d t he c o variates t hat are pre dicti n g t his varia bilit y. 
Pr o vi de d s ufficie nt a m o u nt of data, t he F E will als o be tes te d as a c o variate i n t he m o del. S uc h 
a nal ysis will be s pecifie d i n a se parate  P har mac o metr y  a nal ysis pla n .  Res ults will be prese nte d 
se paratel y fr o m t he mai n C S R . 
Bl o o d  will  be  c ollecte d  f or  M 3 8 1 4  (a n d 0 -de m et h ylate d  pr o d uct  M 4 6 7) a n d  a vel u ma b 
deter mi nat i o n acc or di n g t o t he f oll o wi n g sc he d ules: 
 
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /6 5  
 
 
T a ble 1 1 : P h ar m ac o ki netic S a m pli n g Ti mes f or P art A a n d P art F E  
W e e k ( D a y)  
Ti m e ( h)  
M 3 8 1 4  
( P art A) 
M 3 8 1 4  
( P art F E) 
A v el u m a b   
( b ot h p art s) 
W e e k 1 ( D a y 1) a n d  
W e e k 3 ( D a y 1 5)  
Pr e d o s e  
X  
X  
X  
1  
X  
X  
 
E oI  
 
 
X ( D a y 1 o nl y)  
2  
X  
X  
 
3  
X  
X  ( D a y 1 5 o nl y) 
 
4  
X  
X  
 
6  
X  
X  
 
W e e k 4 ( D a y 2 2)  
Pr e d o s e  
X  
X  
 
2  
X  
X  
 
4  
 
X  
 
6  
X  
X  
 
W e e k 5 ( D a y 2 9)  
Pr e d o s e  
X  
 
X  
E oI  
 
 
X  ( P art A o nl y) 
W e e k 9 ( D a y 5 7)  
Pr e d o s e  
 
 
X  ( P art A o nl y) 
W e e k 1 3 ( D a y 8 5)  
Pr e d o s e  
 
 
X  
W e e k s 2 5, 3 7, 4 9  
Pr e d o s e  
 
 
X  
E o T * 
 
X  
X  
X  ( P art A o nl y) 
3 0 -D a y S af et y F U (if pri or t o 
W e e k 4 9)  
 
 
 
X  
F or b ot h P art A a n d P art F E, M 3 1 4 will b e a d mi ni st er e d t wi c e d ail y , wit h o ut i nt err u pti o n, i n c o m bi n ati o n wit h 
a v el u m a b  ( 1 h o ur i nf u si o n), a d mi ni st er e d o n c e e v er y t w o w e e k s, st arti n g o n D a y 1 u ntil P D or u n a c c e pt a bl e t o xi cit y. 
I n P art F E, s u bj e ct s will b e f e d a hi g h f at m e al o n D a y 1 a n d D a y 2 2 a n d will b e f a st e d o n D a y 1 5. 
E oI = e n d of i nf u si o n; E o T = e n d of tr e at m e nt; F U = f oll o w -u p  
*  F or M 3 8 1 4, o nl y a p pli e s if M 3 8 1 4 tr e at m e nt i s st o p p e d.  F or a v el u m a b if pri or t o W e e k 4 9.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /6 5  
 
 
T a ble 1 2 : P h ar m ac o ki netic S a m pli n g Ti mes f or P art B  
W e e k ( D a y)  
Ti m e ( h)  
M 3 8 1 4  
A v el u m a b  
W e e k 1 ( D a y 1; F D 1)  
 
Pr e d o s e  
X  
X  
1  
X  
 
E oI  
 
X  
2  
X  
 
4  
X  
 
6  
X  
 
W e e k 1 ( D a y 2; F D 2)  
Pr e d o s e  
X  
 
2  
X  
 
W e e k 2 ( D a y 8; F D 6)  
Pr e d o s e  
X  
 
2  
X  
 
W e e k 2 ( D a y 1 2; F D 1 0)  
Pr e d o s e  
X  
 
2  
X  
 
4  
X  
 
6  
X  
 
W e e k 3 ( D a y 1 5)  
Pr e d o s e  
 
X  
W e e k 5 ( D a y 2 9)  
Pr e d o s e  
 
X  
E oI  
 
X  
W e e k 9 ( D a y 5 7) 
Pr e d o s e  
 
X  
W e e k 1 3 ( D a y 8 5)  
Pr e d o s e  
 
X  
W e e k s 2 5, 3 7, 4 9  
Pr e d o s e  
 
X  
E o T*  
 
X  
X  
3 0 -d a y S af et y F U  
 
 
X  
M 3 8 1 4 will b e a d mi ni st er e d o n c e a d a y. R T will b e gi v e n at t h e d o s e of 3 G y p er d a y. M 3 8 1 4 a n d R T will b ot h b e 
gi v e n st arti n g D a y 1 f or 5 d a y s/ w e e k f or 2 w e e k s, at w hi c h p oi nt b ot h M 3 8 1 4 a n d R T ar e di s c o nti n u e d. A v el u m a b ( 1 
h o ur i nf u si o n) will b e a d mi ni st er e d o n c e e v er y t w o w e e k s, st arti n g o n D a y 1 u ntil P D or u n a c c e pt a bl e t o xi cit y.  
E oI = e n d of i nf u si o n; E o T = e n d of tr e at m e nt; F D = fr a cti o n d a y; F U = f oll o w -u p.  
* F or a v el u m a b, if pri or t o W e e k 4 9. 
T a ble 1 3 : Acce pt a ble P h ar m ac o ki netic Wi n d o w f or A vel u m a b  
S a m pli n g Ti m e  
Ti m e Fr o m S c h e d ul e d S a m pli n g All o w e d  
B ef or e B oI  
Wit hi n 1 2 0 mi n ut e s pri or t o d o s e  
E oI  
Wit hi n 1 5 mi n ut e s b ef or e E oI  
B oI = b e gi n ni n g of i nf u si o n; E oI = e n d of i nf u si o n  
T a ble 1 4 : Acce pt a ble P h ar m ac o ki netic Wi n d o w f or M 3 8 1 4  
S a m pli n g Ti m e  
Ti m e Fr o m S c h e d ul e d S a m pli n g All o w e d  
Pr e d o s e  
Wit hi n 6 0 mi n ut e s pri or t o d o s e a d mi ni str ati o n  
0. 5 t o 2 h o ur s p o st d o s e  
± 2 0 mi n ut e s  
 2 h o ur s p o st d o s e  
± 3 0 mi n ut e s  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /6 5  
 
 
Sa m ples t hat are c ollecte d o utsi de t he s pecifie d ti me wi n d o ws will be i ncl u de d i n t he P K para meter 
esti mati o n ( N C A) b ut will be e xcl u de d fr o m t he c o nce ntrati o n s u m mar y a n d mea n c o nce ntrati o n 
pl ots.  
P K  c o nce ntrati o ns  w hic h  are  err o ne o us  d ue  t o  a  pr ot oc ol  vi olati o n  (as  defi ne d  i n  t he  C S P), 
sa m pli n g  pr ocessi n g  or  a nal ytical  err or  (as  d oc u me nte d  i n  t he  bi oa nal ytical  re p ort)  ma y  be 
e xcl u de d fr o m t he P K a nal ysis if a gree d b y t he S p o ns or. I n t his case t he rati o nale f or e xcl usi o n 
m ust be pr o vi de d i n t he Cli nical St u d y Re p ort ( C S R ). A n y ot her P K c o nce ntrati o ns t hat a p pear 
i m pla usi ble t o t he Cli nical P har mac ol o gist/Cli nical P K /P D Scie ntist will n ot be e xcl u de d fr o m t he 
a nal ysis. A n y i m pla usi ble data will be d oc u me nte d i n t he Cli nical St u d y Re p ort ( C S R).  
A n y P K c o nce ntrati o ns or P K para meters e xcl u de d fr o m s u m mar y statistics will be i ncl u de d i n 
s u bject listi n gs a n d fla g ge d; a reas o n f or e xcl usi o n will be detaile d i n t he C S R (e. g. a fo ot n ote or 
a ta ble of e xcl usi o ns) . A n y fla gs s h o ul d be i ncl u de d i n t he st u d y s pecific S D T M a n d A Da M data 
sets. 
T he f oll o wi n g P K para meters will be re p orte d f or M 3 8 1 4 a n d 0 -de m et h ylate d pr o d uct M 4 6 7 (if 
a vaila ble) o n Da y 1 ( D 1) , Da y 1 5 ( D 1 5) , a n d Da y 2 2 ( D 2 2) a n d i n Part A a n d Part F E w here data 
per mit . A p pr o priate a dj ust me nts will be ma de f or differe nces i n m olec ular wei g ht ( M W) ( M 3 8 1 4 
M W = 4 8 1. 9 2 g m ol
-1; 0 -de met h ylate d pr o d uct M 4 6 7 M W = 4 6 7. 1 2 g m ol -1). C o nce ntrati o n res ults 
c ollecte d o n Da y 2 2, Da y 2 9 ( Part A), a n d E o T will be s u m marize d descri pti vel y.  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n . 
C ma x / D ose 
T he d ose -n or malize d ma xi m u m o bser ve d c o nce ntrati o n  ( Part A o nl y). N or malize d 
usi n g t he act ual d ose, a n d t he f or m ula C ma x / D ose. 
C tr o u g h 
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt  d osi n g o n  D 1 5 , D 2 2 , a n d D 2 9, 
( D 2 9 is Part A o nl y ). 
C tr o u g h/ D ose 
T he d ose -n or malize d tr o u g h c o nce ntrati o n. N or malize d usi n g t he act ual d ose, a n d 
t he f or m ula C tr o u g h / D ose o n D 1 5, D 2 2 , a n d D 2 9, ( D 2 9 is Part A o nl y ). 
A U C 0 -6  
Area  u n der  t he  c o nce ntrati o n -ti me  c ur ve  ( A U C)  fr o m  ti me  zer o  t o  ti me 6  h o urs 
p ost d ose. A U C 0 -6  will be base d o n t he esti mate d c o nce ntrati o n at 6  h o urs a n d n ot 
t he c o nce ntrati o n at t he act ual o bser vati o n ti me. 
A U C 0 -6/ D ose T he d ose -n or mal ize d  A U C  fr o m  ti me  zer o  t o 6  h o urs  p ost d ose  ( Part  A  o nl y). 
N or malize d usi n g t he act ual d ose, usi n g t he f or m ula A U C 0 -6/ D ose.  
A U C 0 -1 2  
A U C fr o m ti me zer o t o ti me 1 2 h o urs p ost d ose . A U C 0 -1 2, D 1 will be base d o n t he 
esti mate d c o nce ntrati o n at 1 2  h o urs after d osi n g . A U C 0 -1 2 , D 15  fr o m zer o t o 1 2 h o urs 
p ost d ose  wit h  pre d ose  D 1 5  c o nce ntrati o n  use d  f or  esti mate d  c o nce ntrati o n  at 
1 2  h o urs ( Part A o nl y).  
A U C 0 -1 2/ D ose  T he  d ose -n or malize d  A U C 0 -1 2 ( Part  A o nl y).  N or malize d  usi n g  t he  act ual  d ose, 
usi n g t he f or m ula A U C 0 -1 2/ D ose.  
tma x  
Ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n C ma x . 
R acc( C ma x) 
Acc u m ulati o n rati o f or C ma x , calc ulate d as Cma x, D 1 5/ Cma x, D 1 ( Part A o nl y). 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /6 5  
 
 
F rel( C ma x) 
Relati ve 
bi oa vaila bilit y  of  C ma x  of  fe d  ( D 2 2)  c o m pare d  t o  faste d  ( D 1 5) 
C ma x, fe d/ Cma x, faste d a n d C ma x  of fe d ( D 1) c o m pare d t o faste d ( D 1 5) C ma x, fe d/ Cma x, faste d  
( Part F E o nl y). 
R acc( A U C 0 -1 2 ) 
Acc u m ulati o n rati o f or A U C 0 -1 2  calc ulate d as A U C 0 -1 2 , D 15/ A U C0 -1 2 , D 1 ( Part A o nl y ). 
F rel(A U C 0 -6 ) 
Relati ve  bi oa vaila bilit y  f or A U C 0 -6 of  fe d  ( D 2 2)  c o m pare d  t o  faste d  ( D 1 5) 
A U C 0 -6 ,fe d/ A U C 0 -6 ,faste d a n d as se nsiti vit y a nal ysis A U C 0 -6 of fe d ( D 1) c o m pare d t o 
faste d ( D 1 5) A U C 0 -6 ,fe d/ A U C 0 -6 ,faste d ( Part F E o nl y). 
λ z 
Ter mi nal first or der eli mi nati o n rate c o nsta nt. 
t½  
A p pare nt ter mi nal half -life, t½   = l n 2/ λ z. 
 
  
 
 
 
  
T he f oll o wi n g P K para meters will be re p orte d f or M 3 8 1 4 o n Da y 1 ( F D 1) a n d Da y 1 2 ( F D 1 0) i n 
Part  B w here data per mit. C o nce ntrati o n res ults c ollecte d o n Da y 2 ( F D 2), Da y 8 ( F D 6), a n d E o T 
will be s u m marize d descri pti vel y.  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n  
C ma x / D ose 
T he  d ose -n or malize d  ma xi m u m  o bser ve d  c o nce ntrati o n.  N or malize d  usi n g  t he 
act ual d ose, a n d t he f or m ula C ma x / D ose. 
C tr o u g h 
T he c o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g o n F D 1 0 o nl y.  
C tr o u g h/ D ose 
T he d ose -n or malize d tr o u g h c o nce ntrati o n. N or mali ze d usi n g t he act ual d ose, a n d 
t he f or m ula C tr o u g h / D ose o n F D 1 0 o nl y. 
A U C 0 -6  
Area  u n der  t he  c o nce ntrati o n -ti me  c ur ve  ( A U C)  fr o m  ti me  zer o  t o  ti me  6  h o urs 
p ost d ose. A U C 0 -6  will be base d o n t he esti mate d c o nce ntrati o n at 6 h o urs a n d n ot 
t he c o nce ntrati o n at t he act ual o bser vati o n ti me.  
A U C 0 -6/ D ose  T he d ose -n or malize d A U C fr o m ti me zer o t o 6 h o urs p ost d ose. N or malize d usi n g 
t he act ual d ose, usi n g t he f or m ula A U C 0 -6/ D ose.  
A U C 0 -2 4  
Area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me zer o t o ti me 2 4 h o urs 
p ost d ose. A U C 0 -2 4, F D 1 will be base d o n t he esti mate d c o nce ntrati o n at 2 4  h o urs after 
d osi n g a n d n ot t he c o nce ntrati o n at t he act ual o bser vati o n ti me . A U C0 -2 4, F D 1 0 fr o m 
zer o  t o  2 4  h o urs  p ost d ose  wit h  pre d ose  F D 1 0  c o nce ntrati o n  use d  f or  esti ma te d 
c o nce ntrati o n at 2 4 h o urs.  
A U C 0 -2 4/ D ose  T he d ose -n or malize d A U C fr o m ti me zer o t o 2 4 h o urs p ost d ose f or F D 1 a n d F D 1 0. 
N or malize d  usi n g  t he  act ual  d ose,  usi n g  t he  f or m ula 
A U C 0 -2 4, F D 1/ D ose  a n d 
A U C 0 -2 4, F D 1 0/ D ose.  
tma x  
Ti me t o reac h t he ma xi m u m o bser ve d c o nce ntrati o n C ma x  
R acc( C ma x) 
Acc u m ulati o n rati o f or C ma x , calc ulate d as Cma x, F D 1 0/ Cma x, F D 1  
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /6 5  
 
 
R acc( A U C 0 -6 ) 
Acc u m ulati o n rati o f or A U C 0 -6  calc ulate d as A U C 0 -6 ,F D 1 0/ A U C0 -6 ,F D 1  
R acc( A U C 0 -2 4 ) 
Acc u m ulati o n rati o f or A U C 0 -2 4  calc ulate d as A U C 0 -2 4 ,F D 1 0/ A U C0 -2 4 ,F D 1  
t½  
A p pare nt ter mi nal half -life, t½  = l n 2/ λ z 
 
 
 
 
 
 
 
 
 
 
T he f oll o wi n g P K para meters will be re p orte d f or a vel u ma b w here data per mit.  
C E OI  
 
C o nce ntrati o n o bser ve d at t he e n d of i nf usi o n peri o d.  
C tr o u g h 
 C o nce ntrati o n o bser ve d i m me diatel y bef ore ne xt d osi n g (c orres p o n di n g t o pre -d ose 
o r tr o u g h c o nce ntrati o n f or m ulti ple d osi n g). 
R acc(Ce oi ) 
Acc u m ulati o n rati o f or C E O I, calc ulate d as CE OI , D2 9/ CE OI , D 1 ( Part A a n d Part B). 
R acc(Ctr o u g h ) 
Acc u m ulati o n rati o f or C tr o u g h, calc ulate d as C tr o u g h, D5 7/ Ctr o u g h, D 15  ( Part A a n d Part B) 
T he f oll o wi n g P K para meters will be calc ulate d f or M 3 8 1 4 or M 4 6 7 f or dia g n ostic p ur p oses a n d 
liste d, b ut will n ot be s u m marize d: 
•  λ z 
Ter mi nal first or der eli mi nati o n rate c o nsta nt 
•  First ( λ z l o w) a n d last (λ z u p) ti me p oi nt of t he ti me of t he l o g-li near re gressi o n t o deter mi ne 
λ z.  
•  N u m ber of data p oi nts i ncl u de d i n t he l o g -li near re gressi o n a nal ysis t o deter mi ne λz. 
•  G o o d ness of fit statistic ( Rs q,a dj) f or calc ulati o n of λ z.    
T he calc ulati o n of t he A U C will be perf or me d usi n g t he mi xe d li near -l o g tra pez oi dal met h o d. T he 
act ual ti me of bl o o d sa m pli n g ( 1 4 si g nifica nt di gits or t he S A S f or mat Best 1 2 ) will be use d f or P K 
para meter  calc ulati o n. I n  cases  w here  t he  act ual  sa m pli n g ti me  is  missi n g,  calc ulati o ns  will  be 
perf or me d usi n g t he sc he d ule d ti m e.  
Val ues  bel o w  t he  l o wer  li mit  of  q ua ntificati o n  of  t he  assa y  ( L L O Q)  will  be  ta ke n  as  zer o  f or 
s u m mar y  statistics  of  P K  c o nce ntrati o n  data,  P K  para meter  esti mati o n,  a n d  f or  gra p hical 
prese ntati o ns. I n case B L Q c o nce ntrati o ns occ ur at t he e n d of t he d osi n g i nter val ( 2 4 h), t hese will 
be e xcl u de d fr o m t he calc ulati o n of t he A U C 0 -2 4.   
T he re gressi o n a nal ysis s h o ul d c o ntai n data fr o m at least 3 differe nt ti me p oi nts i n t he ter mi nal 
p hase  c o nsiste nt  wit h  t he  assess me nt  of  a  strai g ht  li ne  o n  t he  l o g -tra nsf or med  scale. P h oe ni x 
Gl o bal Versi o n I D: C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /6 5  
 
 
Wi n N o nli n  “ best  fit”  met h o d ol o g y  will  be  use d  as  sta n dar d. 
H o we ver,  i n  s o me  cases,  f urt her 
a dj ust me nt  ma y  be  ma de  b y  t he  p har mac o ki neticist,  if  warra nte d,  after  a gree me nt wit h  t he 
S p o ns or.  T he last q ua ntifia ble c o nce ntrati o n s h o ul d al wa ys be i ncl u de d i n t he re gressi o n a nal ysis, 
w hile  t he  c o nce ntrati o n  at  t ma x  a n d  a n y  c o nce ntrati o ns  < L L O Q  w hic h  occ ur  after  t he  last 
q ua ntifia ble data p oi nt s h o ul d n ot be use d.   
T he c oefficie nt of c orrelati o n ( R s q,a dj) s h o ul d be ≥0. 80 0 0  a n d t he o bser vati o n peri o d o ver w hic h 
t he re gressi o n li ne is esti mate d s h o ul d be at least t w of ol d t he res ulti n g t1/ 2 itself. If t hese criteria 
are n ot met, t he n t he rate c o nsta nt  a n d t 1/ 2 will be i ncl u de d i n t he para meter o ut p uts a n d descri pti ve 
statistics b ut will be fla g ge d  a n d disc usse d a p pr o priatel y . A n y fla gs will be i ncl u de d i n t he st u d y 
s pecific S D T M a n d A D aM data sets .  
T he  f oll o wi n g  listi n gs  a n d  s u m mar y  statistics  of M 3 8 1 4 , 0 -de m et h ylate d  pr o d uct  M 4 6 7, a n d 
a vel u ma b P K c o nce ntrati o n a n d M 3 8 1 4 a n d 0 -de m et h ylate d pr o d uct M 4 6 7 para meter data will be 
pr o vi de d:  
•  Listi n g of i n di vi d ual P K c o nce ntrati o n data b y  a nal yte,  part, d ose, a n d sc he d ule d ti me p oi nt  
•  Listi n g of i n di vi d ual si n gle d ose P K para meters b y a nal yte, part, d ose, a n d da y  
•  Listi n g of i n di vi d ual m ulti ple d ose P K para meters b y a nal yte, part, d ose,  a n d da y  
•  Descri pti ve s u m mar y ta ble of P K c o nce ntrati o n data b y a nal yte, part, d ose, da y, a n d sc he d ule d 
ti me p oi nt 
•  I n di vi d ual c o nce ntrati o n-ti me pr ofiles (li near a n d se mi-l o garit h mic scales) will be pl otte d b y 
a nal yte, d ose  le vel  a n d  da y  as  s pa g hetti  pl ots,  usi n g  act ual  ti me  p oi nts  ( w here  a vaila ble). 
Se parate pr ofiles f or fe d a n d faste d treat me nts, Part F E.  
•  A d diti o nal s pa g hetti  pl ots  will  be  pr o d uce d  ( o n  b ot h  li near  a n d  se mi-l o g  scale)  t o  s h o w  t he 
c o nce ntrati o n -ti me data per d ose le vel o ver t he e ntire-ti me c o urse. Se parate pr ofiles f or fe d a n d 
faste d treat me nts, Part  F E.  
•  Arit h metic mea n c o nce ntrati o ns will be pl otte d o n  b ot h li near ( ± S t De v) a n d se mi-l o garit h mic 
scales usi n g sc he d ule d ti me p oi nts –  wit h all d ose le vels o verlai d per da y, a n d wit h all da ys 
o verlai d per d ose le vel. A d diti o nal mea n pl ots will be pr o d uce d ( o n b ot h li near ( ± S t De v) a n d 
se mi-l o g scale) t o s h o w t he mea n c o nce ntrati o n -ti me data per d ose le vel o ver t he e ntire-ti me 
c o urse. A d diti o nal  i n di vi d ual  pr ofiles a n d  mea n  pl ots f or  fe d  a n d  faste d  treat me nts:  o verla y 
pl ots D 1/ D 1 5 a n d D 1 5/ D 2 2  f or Part F E.  
•  Scatter pl ots of d ose -n or malize d C ma x , d ose -n or malize d A U C 0 -6, a n d d ose -n or malize d A U C 0 -1 2  
or d ose -n or malize d A U C 0 -2 4 (as a p plica ble) a gai nst d ose (all da ys).  
•  Paire d data  pl ots of C ma x  a n d A U C 0 -6 a gai nst fe d a n d faste d, Da y 2 2  a n d Da y 1 5, Da y 1 a n d 
Da y 1 5 res pecti vel y, f or Part F E. 
All descri pti ve s u m maries of P K data will be perf or me d usi n g t he P K A nal ysis Set. I n di vi d ual P K 
data will be liste d usi n g t he Safet y A nal ysis Set. T he mea n c o nce ntrati o n -ti me pr ofiles a n d P K 
para meter pl ots will be pl otte d usi n g t he P K A nal ysis Set a n d t he i n di vi d ual s u bj ect c o nce ntrati o n -
ti me pr ofiles will use t he Safet y A nal ysis Set.  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 9 /6 5  
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 0 /6 5  
 
 
1 6. 3  
 I m m u n o ge nicit y 
Bl o o d  sa m ples  f or a nti-dr u g  a nti b o d y  ( A D A ) a nal ysis  will  be  c ollecte d  per  t he  Sc he d ule  of 
Assess me nts  i n  t he  Cli nical  Trial  Pr ot oc ol  a n d  teste d  f or  prese nce  of  a nti -a vel u ma b  A D A.  All 
sa m ples  will  be  scree ne d  f or  t he  detecti o n  of  A D A  a n d  t h ose  detecte d  will  be  s u bse q ue ntl y 
e val uate d f or a c o nfir mat or y si g nal. If t he sa m ple is c o nfir me d p ositi ve f or A D A, it will be re -
a nal yze d  t o  deter mi ne  t he  titer. I n de pe n de ntl y  f or  eac h  assa y,  t he  A D A  res ults  will  be  deri ve d 
base d o n t he al g orit h m i n  Ta ble 1 6 . 
S u bjects will be c haracterize d b y i m m u n o ge nicit y stat us  base d o n t he criteria i n  Ta ble 1 7 . 
T a ble 1 6 : Al g orit h m f or t he Deri v ati o n of A D A Res ults  
S a m ple Scree n Res ult  
C o nfir m at or y  
Titer  
Deri ve d A D A Res ult  
Ne gati ve  
N A  
N A  
Ne gati ve  
N R  
N A  
N A  
N R  
P ositi ve  
Ne gati ve  
N A  
Ne gati ve  
P ositi ve  
N R  
N A  
N R  
P ositi ve  
P ositi ve  
N u m ber  
N u m ber  
P ositi ve  
P ositi ve  
N R  
P ositi ve -T N R  
N R = n o res ult, N A = n ot a p plica ble, T N R = titer n o res ult.  
Ne gati ve, n u m ber, or p ositi ve -T N R are vali d res ults, w hile n u m ber a n d p ositi ve -T N R are c o nsi dere d as p ositi ve.  
T a ble 1 7 : S u bject C h ar acteriz ati o n B ase d o n A D A Res ults  
C ate g or y  
Defi niti o n  
S u bject at Ris k ( De n o mi n at or f or I nci de nce) 
Ne ver 
p ositi ve  
N o p ositi ve res ults at a n y ti me p oi nt  
N u m ber of s u bjects wit h at least o ne vali d res ult at 
a n y ti me p oi nt  
E ver 
p ositi ve  
At least o ne p ositi ve res ult at a n y ti me p oi nt  
N u m ber of s u bjects wit h at least o ne vali d res ult at 
a n y ti me p oi nt 
Pre -e xisti n g 
A p ositi ve A D A res ult pri or t o treat me nt wit h a vel u ma b  
N u m ber of s u bjects wit h vali d baseli ne res ult  
Treat me nt 
b o oste d  
A p ositi ve A D A res ult pri or t o treat me nt wit h a vel u ma b 
a n d t he titer ≥ 8 * baseli ne titer w hile o n a vel u ma b 
treat me nt 
N u m ber of s u bjects wit h vali d baseli ne a n d at least 
o ne vali d p ost -baseli ne res ult  
Treat me nt 
e mer ge nt  
N ot p ositi ve pri or t o treat me nt wit h a vel u ma b a n d wit h 
at least o ne p ositi ve p ost -baseli ne res ult  
N u m ber of s u bjects wit h at least o ne vali d p ost -
baseli ne res ult a n d wit h o ut p ositi ve baseli ne res ults 
(i ncl u di n g missi n g, N R) 
Tra nsie nt 
p ositi ve  
If treat me nt e mer ge nt s u bjects ha ve (a si n gle p ositi ve 
e val uati o n, or d urati o n bet wee n first a n d last p ositi ve 
res ult < 1 6 wee ks) a n d last assess me nt n ot p ositi ve.  
N u m ber of s u bjects wit h at least o ne vali d p ost -
baseli ne res ult a n d wit h o ut p ositi ve baseli ne res ults 
(i ncl u di n g missi n g, N R) 
Persiste nt 
p ositi ve  
If treat me nt e mer ge nt s u bjects ha ve d urati o n bet wee n 
first a n d last p ositi ve res ult ≥1 6 wee ks or a p ositi ve 
e val uati o n at t he last assess me nt  
N u m ber of s u bjects wit h at least o ne vali d p ost -
baseli ne res ult a n d wit h o ut p ositi ve baseli ne res ults 
(i ncl u di n g missi n g, N R) 
N R: N ot re p orte d;  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 1 /6 5  
 
 
T he fre q ue nc y a n d perce nta ge of s u bjects i n eac h cate g or y will be s u m marize d b y c o h ort d ose 
le vel a n d o verall. A listi n g will be pre pare d b y d ose le vel f or s u bject I Ds e ver p ositi ve. 
A D A res ults f or e ver p ositi ve s u bjects will be liste d b y c o h ort d ose le vel:  
•  O ver vie w o n A D A stat us: S u bject I D, a ge, ge n der, A D A Stat us, S t u d y Da y of Start of A D A 
res p o nse, D urati o n of A D A i m m u n o ge nicit y res p o nse ( wee ks) 
•  Listi n g of A D A a n d C tr o u g h c o nce ntrati o ns: S u bject I D, Visit a n d Visit Date, A D A res ult, Date 
of  last  pri or  a vel u ma b  i nf usi o n,  Da ys  si nce  last  a vel u ma b  i nf usi o n,  Date  of  las t  a vaila ble 
pre d ose dr u g c o nce ntrati o n at or bef ore A D A assess me nt a n d c orres p o n di n g dr u g c o nce ntrati o n  
•  Listi n g of all P K c o nce ntrati o ns,  S u bject I D, Visit na me a n d Visit Date, ti me p oi nt, o bser ve d 
a vel u ma b ser u m c o nce ntrati o n, Act ual date/ti me; H o urs si nc e last a vel u ma b i nf usi o n.  
•  Listi n g  of  i m m u n o ge nicit y  data  a n d  a d verse  e ve nts  ( A Es):  S u bject  I D,  a ge,  ge n der,  st u d y 
treat me nt  start  a n d  st o p  date,  all  dates  wit h  p ositi ve  A D A  res ult,  A E  start  date,  st o p  date, 
preferre d ter m,  C T C A E t o xicit y gra de, seri o us ness , a n d a p plica ble fla gs f or i m m u ne-relate d 
a d verse e ve nt (ir A E), i nf usi o n relate d reacti o n (I R R), seri o us a d verse e ve nt ( S A E), or reas o n 
f or per ma ne nt treat me nt disc o nti n uati o n. 
 
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 2 /6 5  
 
 
1 7  
Refere nces  
1.  Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 -4 7.  
2.  Cl o p per, C. J., & Pears o n, E. S. ( 1 9 3 4). T he Use of C o nfi de nce or Fi d ucial Li mits Ill ustra te d 
i n t he Case of t he Bi n o mial. Bi o metri ka, 2 6, 4 0 4– 4 1 3.  
3.  Br o o k me yer R, Cr o wle y J. A C o nfi de nce I nter val f or t he Me dia n S ur vi val Ti me. Bi o metrics 
1 9 8 2; 3 8: 2 9 -4 1.  
4.  Kal b ﬂeisc h J D, Pre ntice R L. T he Statistical A nal ysis of Fail ure Ti me Data, Ne w Y or k: J o h n 
Wile y  & S o ns 1 9 8 0.  
 
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 3 /6 5  
 
 
1 8  
A p pe n dices  
A p pe n di x I - Descri pti o n of t he C ase Defi niti o n f or Assess me nt  of irA Es a n d I R R s 
 
I m m u ne-Rel ate d A d verse E ve nts  
I m m u ne-relate d a d verse e ve nts (ir A Es) will be i de ntifie d pr o gra m maticall y . A Es w hic h satisf y all 
of  t he f oll o wi n g criteria will be fla g ge d as i m m u ne-relate d: 
1) T he A E preferre d ter m matc hes a preferre d ter m o n t he list of pre -selecte d Me d D R A ter ms. 
2) T he A E o nset occ urs after  t he first st u d y dr u g a d mi nistrati o n a n d n o m ore t ha n 9 0 da ys after 
last d ose. 
3)  O n  t he  A E  e C R F  pa ge,  t he  q uesti o n  “ Is  t his  a n  a d verse  e ve nt  of  s pecial  i nterest?” has  t he 
res p o nse “i m A Es / a ut oi m m u ne dis or ders” selecte d. 
 
I R Rs 
I nf usi o n relate d reacti o ns are i de ntifie d base d o n a list of Me d D R A P Ts a n d criteria o n t he ti mel y 
relati o ns hi p acc or di n g t o Ta ble 1 8 Ta ble 1 8 . 
 
T a ble 1 8 : Criteri a f or i nf usi o n rel ate d re acti o ns  
I nf usi o n relate d reacti o ns 
Re acti o ns - C o nsi dere d w he n o nset is o n t he d a y of st u d y dr u g i nf usi o n 
( d uri n g or after t he i nf usi o n) or t he d a y after t he st u d y dr u g i nf usi o n 
(irres pecti ve of res ol uti o n d ate): 
•  
I nf usi o n relate d reacti o n 
•  
Dr u g h y perse nsiti vit y  
•  
A na p h ylactic reacti o n  
•  
H y perse nsiti vit y  
•  
T y pe 1 h y perse nsiti vit y  
 
Si g ns a n d S y m pt o ms - occ urri n g o n t he d a y of st u d y dr u g i nf usi o n ( d uri n g or 
after t he i n f usi o n) a n d res ol ve d wit h e n d d ate wit hi n 2 d a ys after o nset 
•  
P yre xia  
•  
C hills  
•  
Fl us hi n g  
•  
H y p ote nsi o n  
•  
D ys p n oea  
•  
W heezi n g  
•  
Bac k pai n  
•  
A b d o mi nal pai n  
•  
Urticaria  
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 /6 5  
 
 
A p pe n di x II –  N CI -C T C Gr a d a ble a n d N o n -Gr a d a ble S afet y L a b or at or y Test 
P ar a meters a n d Directi o n(s) of A b n or m alit y  
T a ble 1 9 : N CI -C T C gr a d a ble p ar a meters  
C at e g or y  
P ar a m et er  
N a m e i n N CI -C T C  
Dir e cti o n( s) of 
a b n or m alit y  
S er u m c h e mi str y  
El e ctr ol yt e s  
C al ci u m  
H y p o c al c e mi a/ H y p er c al c e mi a  
L o w/ Hi g h  
El e ctr ol yt e s  
M a g n e si u m  
H y p o m a g n e s e mi a/ H y p er m a g n e s e mi a  
L o w/ Hi g h  
El e ctr ol yt e s  
P ot a s si u m  
H y p o k al e mi a/ H y p er k al e mi a  
L o w/ Hi g h  
El e ctr ol yt e s  
S o di u m  
H y p o n atr e mi a/ H y p er n atr e mi a  
L o w/ Hi g h  
E n z y m e s/ c ar di n al  
Cr e ati ni n e P h o s p h o ki n a s e  
C P K i n cr e a s e d  
Hi g h  
E n z y m e s/ c ar di n al  
L a ct at e d e h y dr o g e n a s e  
Bl o o d l a ct at e d e h y dr o g e n a s e i n cr e a s e d  
Hi g h  
E n z y m e s/li v er  
Al a ni n e A mi n otr a n sf er a s e  
Al a ni n e A mi n otr a n sf er a s e i n cr e a s e d  * 
Hi g h  
E n z y m e s/li v er  
Al k ali n e P h o s p h at a s e  
Al k ali n e P h o s p h at a s e i n cr e a s e d  * 
Hi g h  
E n z y m e s/li v er  
A s p art at e A mi n otr a n sf er a s e  
A s p art at e A mi n otr a n sf er a s e i n cr e a s e d  * 
Hi g h  
E n z y m e s/li v er  
G a m m a -gl ut a m yl tr a n sf er a s e  
G G T i n cr e a s e d  * 
Hi g h  
E n z y m e s/li v er  
T ot al bilir u bi n  
Bl o o d bilir u bi n i n cr e a s e d  * 
Hi g h  
M et a b oli s m  
Gl u c o s e  
H y p o gl y c e mi a  
L o w  
M et a b oli s m  
Ur at e  ( uri c a ci d) 
H y p er uri c e mi a  
Hi g h  
Pl a s m a pr ot ei n s  
Al b u mi n  
H y p o al b u mi n e mi a  
L o w  
R e n al/ ki d n e y  
Cr e ati ni n e  
Cr e ati ni n e i n cr e a s e d  * 
Hi g h  
H e m at ol o g y  
Pl at el et s  
Pl at el et s C o u nt  
Pl at el et c o u nt d e cr e a s e d  
L o w  
R e d bl o o d c ell s  
H e m o gl o bi n  
A n e mi a/ H e m o gl o bi n i n cr e a s e d  
L o w/ Hi g h  
W hit e bl o o d 
c ell s/ diff er e nti al  
W hit e Bl o o d C ell C o u nt  
W hit e bl o o d c ell 
d e cr e a s e d/ L e u k o c yt o si s  
L o w/ Hi g h  
W hit e bl o o d 
c ell s/ diff er e nti al  
A b s ol ut e L y m p h o c yt e s C o u nt  
L y m p h o c yt e c o u nt d e cr e a s e d/i n cr e a s e d  
L o w/ Hi g h  
W hit e bl o o d 
c ell s/ diff er e nti al  
A b s ol ut e N e utr o p hil s C o u nt  
N e utr o p hil c o u nt d e cr e a s e d  
L o w  
W hit e bl o o d 
c ell s/ diff er e nti al  
E o si n o p hil s  
E o si n o p hili a  * 
Hi g h  
* i n di c at e s p ar a m et er s f or w hi c h t h e o n-tr e at m e nt gr a di n g d e p e n d s u p o n t h e b a s eli n e gr a di n g.  
 
 
 
Gl o bal Versi o n I D: C CI


M 3 8 1 4  
                P h ase I St u d y of A vel u m a b -M 3 8 1 4 C o m bi n ati o ns   
M S 2 0 1 9 6 4 -0 0 0 1  Versi o n 1  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 5 /6 5  
 
 
T a ble 2 0 : N CI -C T C n o n -gr a d a ble p ar a meters  
C at e g or y  
P ar a m et er ( L B T E S T)  
Dir e cti o n ( s) of a b n or m alit y  
S er u m c h e mi str y  
El e ctr ol yt e s  
P h o s p h at e  
L o w  
M et a b oli s m  
Gl u c o s e  
Hi g h  
Pl a s m a pr ot ei n s  
T ot al pr ot ei n  
L o w  
R e n al/ ki d n e y  
Bl o o d Ur e a Nitr o g e n  
Hi g h  
H e m at ol o g y  
R e d bl o o d c ell s  
H e m at o crit  
Hi g h/ L o w  
R e d bl o o d c ell s  
M e a n C or p u s c ul ar H e m o gl o bi n  
Hi g h/ L o w  
R e d bl o o d c ell s  
M e a n C or p u s c ul ar H e m o gl o bi n C o n c e ntr ati o n  
Hi g h/ L o w  
R e d bl o o d c ell s  
M e a n C or p u s c ul ar V ol u m e  
Hi g h/ L o w  
R e d bl o o d c ell s  
R e d bl o o d c ell s ( Er yt hr o c yt e s)  
Hi g h/ L o w  
R e d bl o o d c ell s  
R eti c ul o c yt e s  
Hi g h/ L o w  
W hit e bl o o d c ell s/ diff er e nti al  
B a s o p hil s  
Hi g h  
W hit e bl o o d c ell s/ diff er e nti al  
M o n o c yt e s  
Hi g h/ L o w  
 
 
Gl o bal Versi o n I D: C CI