An Open-Label, Multicenter, Phase 1b/2 Study of E7386 in Combination With Pembrolizumab in Previously Treated Subjects With Selected Solid Tumors
Phase: PHASE1
Conditions: Melanoma, Carcinoma, Hepatocellular, Colorectal Neoplasms
Sponsor: Eisai Inc.



Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 of 2 1 0
d oc u m e nt atio n will be arc hi ve d as re q uire d b y re g ulat or y  
a ut h orities.
C o nfi de nti alit y 
St ate me nt:
T his d oc u me nt is c o nfi de nt ial.  It c o ntai ns pr o prietar y inf or mati o n 
of  Eisai (t he S p o ns or ).  A n y vie wi n g or discl os ure of s uc h 
i nf or mat i on t hat i s n ot a ut h orize d i n writ i n g b y t he S p o ns or is 
strict l y pr o hi bite d.  S uc h i nf or mati on ma y be use d s olel y f or t he 
p ur p ose of re vie wi n g or perf or mi n g t his st u d y .

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 3 of 2 1 0
R E VI SI O N HI S T O R Y
Pr ot oc ol A me n d me nt 0 4
D ate: 2 5 J a n 2 0 2 3
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 4 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 5 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 6 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 8 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 9 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 0 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 1 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 3 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 4 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 0 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 1 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 2 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 3 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 4 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 5 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 6 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 7 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 8 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 9 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 3 0 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 3 1 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 3 2 of 2 1 0
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 3 3 of 2 1 0
2
C L I NI C A L P R O T O C O L S Y N OP SI S
C o m p o u n d N o.:   E 7 3 8 6; M K - 3 4 7 5; E 7 0 8 0
N a me of Acti ve I n gre die nt:
( 6S , 9aS )-N -Be nz yl - 8-( { 6-[ 3-( 4-et h yl pi perazi n - 1-yl)azeti di n - 1-yl] p yri di n - 2-yl } met h yl) - 6-( 2-fl u or o-
4 -h y dr o x y be nz yl) -4, 7 -di o x o - 2-( pr o p- 2-e n- 1-yl) he xa h y dr o - 2H -p yrazi n o[ 2, 1 -c][ 1, 2, 4]triazi ne-
1( 6 H )-car b o xa mi de; p e mbr oliz u ma b ; le n vati ni b
St u d y Pr ot oc ol Title:
A n O pe n -La b el, M ultice nter, P hase 1 b/ 2 St u d y of E 7 3 8 6 i n C o m bi nati o n Wit h Pe m br oliz u ma b i n 
Pre vi o usl y Treate d S u bjects Wit h Selecte d S oli d T u m ors
Sites:
M ulti nati o nal wit h a p pr o xi matel y 4 0 i n vesti gati o nal sites i n N ort h A merica, E ur o pe, a n d Asia -
Pacific ( A P A C) re gi o ns.
St u d y Peri o d a n d P h ase of De vel o p me nt
T otal st u d y peri o d: A p pr o xi matel y 5 0 m o nt hs; P hase 1 b/ 2 parts
O bjecti ves
Pri m ar y O bjecti ves
P h ase 1 b p art :

T o assess t he safet y a n d t olera bilit y of E 7 3 8 6 i n c o m bi nati o n wit h pe m br oliz u ma b i n s u bjects 
wit h pre vi o usl y treate d selecte d s oli d t u m ors

T o deter mi ne t he rec o m me n de d P hase 2 d ose ( R P 2 D) of E 7 3 8 6 i n c o m bi nati o n wit h 
pe m br oliz u ma b
P h ase 2 p art :

T o assess t he o bjecti ve res p o nse rate ( O R R) of E 7 3 8 6 i n c o m bi nati o n wit h pe m br oliz u ma b
( mela n o ma, c ol orectal ca ncer [ C R C], he pat ocell ular carci n o ma [ H C C]) or of E 7 3 8 6 i n 
c o m bi nati o n wit h pe m br oliz u ma b pl us le n vati ni b (H C C ) 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 ( R E CI S T ) 1. 1
Sec o n d ar y O bjecti ves
P h ase 1 b p art o n l y:

T o assess t u m or res p o nse acc or di n g t o R E CI S T 1. 1
P h ase 1 b a n d P h ase 2 p art s:

T o assess d urati o n of res p o nse ( D O R) acc or di n g t o R E CI S T 1. 1 per t u m or c o h ort

T o assess t he disease c o ntr ol rate ( D C R: t he pr o p orti o n of s u bjects wit h c o m plete res p o nse 
[ C R], partial res p o nse [ P R], or sta ble disease [ S D] after ≥5 wee ks fr o m t he first d ose) 
acc or di n g t o R E CI S T 1. 1 per t u m or c o h ort

T o assess t he cli nical be nefit rate ( C B R: t he pr o p orti o n of s u bjects wit h C R, P R, or d ura ble 
S D [ d urati o n of S D ≥2 3 wee ks]) ac c or di n g t o R E CI S T 1. 1 per t u m or c o h ort

T o assess t he safet y a n d t olera bilit y of E 7 3 8 6 i n c o m bi nati o n wit h pe m br oliz u ma b a n d E 7 3 8 6 
i n c o m bi nati o n wit h pe m br oliz u ma b pl us le n vati ni b

T o e val uate t he p har mac o ki netic ( P K) pr ofile of E 7 3 8 6 w he n c o -a d mi nistere d eit her wit h 
pe m br oliz u ma b or wit h t he c o m bi nati o n of pe m br oliz u ma b pl us le n vati ni b 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 4 3 of 2 1 0
2.
Male or fe male, a ge ≥1 8 years ( or a n y a ge ≥1 8 years as deter mi ne d b y c o u ntr y le gisla ti o n) at 
t he ti me of i nf or me d c o nse nt. 
3.
Life e x pecta nc y of ≥1 2 wee ks.
4.
Ha ve a hist ol o gicall y or c yt ol o gicall y -d oc u me nte d, a d va nce d ( metastatic a n d/ or u nresecta ble) 
selecte d s oli d t u m or f or w hic h pri or sta n dar d s yste mic t hera p y has faile d.  Selecte d t u m or 
t yp e s: mela n o ma (e xcl u di n g u veal mela n o ma), C R C, H C C .
5.
F or Mel a n o m a C o h ort o nl y
( P h ase 2 p art), s u bject m ust ha ve:
a.
U nr es ecta ble Sta ge III or Sta ge I V mela n o ma, per A merica n J oi nt C o m mittee o n Ca ncer 
sta gi n g s yste m versi o n 8, n ot a me na ble t o l ocal t hera p y.
b.
At least o ne meas ura ble lesi o n b y c o mp uter t o m o gra p h y (C T ) or ma g net ic res o na nce 
i mager y ( M RI ) base d o n R E CI S T 1. 1 (c uta ne o us lesi o ns a n d ot her s u perficial lesi o ns are 
n ot c o nsi dere d meas ura ble lesi o ns f or t he p ur p oses of t his pr ot oc ol b ut ma y be c o nsi dere d 
as n o ntar get lesi o ns).
◦
Lesi o ns i n a pre vi o usl y irra diate d area s h o ul d n ot be c o nsi dere d meas ura ble u nless 
t here has bee n d oc u me nte d gr o wt h of t he lesi o ns si nce t he c o m pleti o n of ra di ot hera p y.
c.
Pr o gresse d o n or after pri or treat me nt wit h o ne a nti -P D -1/ P D -L 1 m A b a d mi nistere d eit her 
as mo n ot hera p y or i n c o m bi nati o n wit h ot her c hec k p oi nt i n hi bit ors or ot her t hera pies.  
P D -1 pr o gressi o n is defi ne d as: 
◦
Has recei ve d at least 2 d oses of a n a p pr o ve d a nti -P D -1/ P D -L 1 m A b (e g, 
pe m br oliz u ma b, ni v ol u ma b, ni v ol u ma b pl us i pili m u ma b) a n d
◦
Has de m o nstrate d disease pr o gressi o n after P D -1/ P D -L 1 as defi ne d b y R E CI S T v 1. 1.  
Pr o gressi ve disease has bee n d oc u me nte d wit hi n 1 2 wee ks fr o m t he last d ose of a nti -
P D -1/ P D -L 1 m A b (refract or y disease).  T he i nitial e vi de nce of disease pr o gr essi o n is 
t o be c o nfir me d b y a sec o n d assess me nt n o less t ha n 4 wee ks fr o m t he date of t he first 
d oc u me nte d pr o gressi ve disease, i n t he a bse nce of ra pi d cli nical pr o gressi o n.
◦
T his deter mi nati o n is ma de b y t he i n vesti gat or.  O nce pr o gressi ve disease is 
c o nf irme d, t he i nitial date of disease pr o gressi o n d oc u me ntati o n will be c o nsi dere d t he 
date of disease pr o gressi o n.
d.
Recei ve d o nl y 1 or, if B R A F m ut ati o n p ositi ve, 2 li nes of t hera p y i n t he l ocall y a d va nce d 
or metastatic setti n g pri or t o st u d y e nr ol lme nt . N ot e: A dj u va nt a nti-P D -1/ P D -L 1 m A b / 
B R A F i n hi bit or treat me nt will be c o u nte d as pri or li ne of treat me nt if rela pse occ urre d 
d uri n g acti ve treat me nt or wit hi n 1 2 wee ks of treat me nt disc o nti n uati o n. 
e.
N o restricti o n wit h re gar ds t o P D -L 1 a n d B R A F stat us
f.
I n case mela n o ma is k n o w n t o be B R A F m ut ati o n p ositi ve, s u bjects m ust ha ve pr o gresse d 
o n o ne pri or B R A F i n hi bit or.
6.
F or C R C C o h ort o nl y ( P h ase 2 p art), s u bjects m ust ha ve r ecei ve d at least t w o pri or s yste mic 
t hera pies fr o m t he f oll o wi n g, i n a dj u va nt a n d/ or metastatic setti n g , if a p pr o ve d a n d l ocall y 
a vaila ble (n ot e xcee di n g 4 li nes of t hera pies i n t he metastatic setti n g, pr o gr esse d o n at least 1 
pri or re gi me n i n t he metastatic setti n g or c o ul d n ot t olerate sta n dar d treat me nt ):
N ote: A dj u va nt c he m ot hera p y c o u nts as pri or s yste mic treat me nt i n t he metastatic setti n g if 
t here is d oc u me nte d disease pr o gressi o n wit hi n 6 m o nt hs of treat me nt c o m pleti o n.
N ote:
If a s u bject is deter mi ne d t o be i nt olera nt t o pri or sta n dar d treat me nt, t he s u bject must 
ha ve recei ve d at least of 2 c ycles of t hat t hera p y.
a.
Fl u or o p yri mi di ne, iri n oteca n a n d o xali plati n
N ote: Ca pecita bi ne is acce pta ble as e q ui vale nt t o fl u or o p yri mi di ne i n pri or treat me nt.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 4 4 of 2 1 0
N ote: S u bjects w h o ha ve pre vi o usl y recei ve d fl u or o p yri mi di ne, o xali plati n, a n d iri n oteca n 
as part of t he sa me a n d o nl y c he m ot hera p y re gi me n, e g, fl u or o uracil, le uc o v ori n, 
o xali plati n, a n d iri n oteca n (F O L F O XI RI ) or fl u or o uracil, le uc o v ori n, iri n oteca n a n d 
o xali plati n (F O L FI RI N O X ), ma y be eli gi ble after disc ussi o n wit h t he S p o ns or.
b.
C he m ot hera p y wit h or wit h o ut a n a nti - vasc ular e n d ot helial gr o wt h fact or (V E G F ) m A b 
(e g, be vaciz u ma b)
c.
C he m ot hera p y wit h a nti -e n d ot helial gr o wt h fact or rec pt or ( E G F R ) m A b (cet u xi ma b or 
pa nit u m u ma b) f or s u bjects wit h R A S ( K R A S/ N R A S) wil d t y pe ( W T) C R C
N ote: R A S ( K R A S/ N R A S) W T s u bjects wit h ri g ht or left C R C lesi o ns w h o ma y ha ve n ot 
bee n treate d wit h a nti -E G F R m A b base d o n l ocal g ui deli nes are eli gi ble
d.
B R A F i n hi bit or (i n c o mbi nati o n wit h cet u xi ma b ± bi ni meti ni b) f or B R A F V 6 0 0 E m utate d 
t u m ors.
7.
S u bjects wit h H C C ( P h ase 2 p art) m ust ha ve:
a.
A dia g n osis of H C C t hat is hist ol o gicall y or c yt ol o gicall y c o nfir me d (e xcl u di n g 
fi br ola mellar, sarc o mat oi d or mi xe d c ola n gi o- H C C t u m ors) or cli nicall y c o nfir me d 
acc or di n g t o A merica n Ass ociati o n f or t he St u d y of Li ver Disease criteria i n cirr h otic 
s u bjects. S u bjects wit h o ut cirr h osis re q uire hist ol o gical c o nfir mati o n of dia g n osis.
b.
Sta ge B ( n ot a me na ble t o l oc ore gi o nal t hera p y or refract or y t o l oc ore gi o nal t hera p y, a n d 
n ot a me na ble t o a c urati ve treat me nt ) or sta ge C base d o n Barcel o na Cli nic Li ver Ca ncer 
sta gi n g S yste m a n d C hil d-P u g h class A o nl y.
c.
S u bjects m ust ha ve recei ve d o nl y o ne pri or li ne of s yste mic t hera p y i n t he l ocall y a d va nce d 
or m etastatic setti n g, a n d m ust ha ve pr o gresse d o n treat me nt wit h a n a nti-P D -1/ P D -L 1 
m A b a d mi nistere d eit her as m o n ot hera p y, or i n c o m bi nati o n wit h ot her c hec k p oi nt 
i n hi bit ors or ot her t hera pies. N ote: S u bjects m ust ha ve recei ve d at least 2 d oses of t he
a nti- P D -1/ P D -L 1 m A b . 
8.
F or s u bjects wit h H C C :
a.
I n case of he patitis B s urface a nti ge n (H Bs A g ) ( +) s u bjects: A nti viral t hera p y f or he patitis 
B vir us ( H B V) m ust be gi ve n f or at least 3 m o nt hs pri or t o t he first d ose of st u d y dr u g, a n d 
H B V viral l oa d m ust be less t ha n 1 0 0 I U/ m L pri or t o t he first d ose of st u d y dr u g
◦
S u bjects w h o are H Bs A g ( +) a n d o n acti ve H B V t hera p y wit h viral l oa ds u n der 1 0 0 
I U/ m L s h o ul d sta y o n t he sa me t hera p y w hile o n st u d y dr u g .
◦
S u bjects wit h o ut H B V pr o p h yla xis w h o are a nti -he patitis B c ore a nti b o d y (H Bc A b )
( +) a n d/ or a nti- H Bs A b ( +) b ut ne gati ve f or H Bs A g a n d H B V D N A d o n ot re q uire 
pr o p h yla xis.
◦
S u bjects wit h H B V pr o p h yla xis w h o are a nti -H Bc A b ( +) a n d/ or a nti - H Bs A b ( +) b ut 
ne gati ve f or H Bs A g a n d H B V D N A s h o ul d c o nti n ue t he pr o p h yla xis.
◦
All t he s u bjects a b o ve nee d m o nit ori n g wit h H B V D N A e ver y 3 wee ks w hile o n st u d y 
dr u g .
b.
T hera p y f or he patitis C vir us ( H C V ) m ust be c o m plete d at least 4 wee ks pri or t o first d ose 
of st u d y dr u g i n case of he patitis C s u bjects w h o are o n acti ve H C V treat me nt.  He p atitis C 
s u bjects w h o are u ntreate d or u nc ure d ma y als o be e nr olle d
9.
Tri plet treat me nt c o h orts o nl y:   A de q uatel y c o ntr olle d bl o o d press ure ( B P) wit h or wit h o ut 
a nti h y perte nsi ve me dicati o ns, defi ne d as B P ≤1 5 0/ 9 0 m m H g at Scree ni n g/ Baseli ne a n d n o 
c ha n ge i n a nti h y perte nsi ve me dicati o ns wit hi n 1 wee k bef ore starti n g treat me nt i n t his st u d y.  
1 0. E C O G P S of 0 t o 1.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 6 3 of 2 1 0
3
T A B L E O F C O N T E N T S
1
TI T L E P A G E ................................................................................................................1
R E VI SI O N HI S T O R Y ..........................................................................................................3
2 
C LI NI C A L P R O T O C O L S Y N O P SI S ..........................................................................3 3
3
T A B L E O F C O N T E N T S .............................................................................................6 3
4
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ................................6 9
5
E T HI C S .......................................................................................................................7 3
5. 1
I nstituti o nal  Re vie w B oar ds/I n de pe n de nt Et hics C o m mittees.............................7 3
5. 2
Et hical C o n d uct of t he St u d y ..............................................................................7 4
5. 3
S u bject I nf or mat i on a n d I nf or me d C o nse nt ........................................................7 4
6
I N V E S TI G A T O R S A N D S TU D Y P E R S O N N E L .......................................................7 5
7
I N T R O D U C TI O N .......................................................................................................7 6
7. 1
C o m p o u n d O ver vie w .........................................................................................7 6
7. 1. 1
Bac k gr o u n d of E 7 3 8 6 ...............................................................................7 6
7. 1. 2
Bac k gr o u n d of Pe m br oliz u ma b ................................................................. 7 6
7. 1. 3
Bac k gr o u n d of Le n vat i ni b ........................................................................7 7
7. 1. 4
Mela n o ma, C ol orectal Ca ncer, a n d He pat ocell ular Carci n o ma ..................7 8
7. 2
N o ncli nical e vi de nce ..........................................................................................7 9
7. 3
Cli nical E x perie nce ............................................................................................8 0
7. 3. 1
E 7 3 8 6 .......................................................................................................8 0
7. 4
St u d y  Ratio nale ..................................................................................................8 1
7. 5
Ris k / Be nefit Assess me nt....................................................................................8 2
8
S T U D Y O BJ E C TI V E S ................................................................................................8 3
8. 1
Pri mar y O bject i ves.............................................................................................8 3
8. 2
Se c o n dar y O bjecti ves.........................................................................................8 3
8. 3
E x pl or at or y  O bjecti ves.......................................................................................8 4
9
I N V E S TI G A TI O N A L P L A N ......................................................................................8 4
9. 1
O v erall St u d y Desi g n a n d Pla n ...........................................................................8 4
9. 1. 1
P hase 1 b Part ............................................................................................8 6
9. 1. 1. 1
Defi nit i on o f D ose -li miti n g T o xicit y.................................................8 8
9. 1. 2
P hase 2 Part ..............................................................................................9 0
9. 1. 3
E xte nsi o n Part ..........................................................................................9 4
9. 1. 4
St u d y  P hases ............................................................................................9 4
9. 1. 4. 1
Pr etreat me nt P hase ............................................................................9 4
9. 1. 4. 2
Treat me nt P hase ...............................................................................9 4
9. 1. 4. 3
F o ll ow- U p P hase ..............................................................................9 5
9. 1. 4. 4
....................................................9 5
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 6 4 of 2 1 0
9. 1. 5
E n d of St u d y .............................................................................................9 6
9. 2
Di sc ussio n of  St u d y Desi g n................................................................................9 6
9. 3
S el ect i on of St u d y  P o p ulatio n ............................................................................9 7
9. 3. 1
I ncl usi on Cri t eria ......................................................................................9 7
9. 3. 2
E xcl usi o n Cri t eria ...................................................................................1 0 1
9. 3. 3
Re m o v al  of S u bjects fr o m T hera p y or Assess me nt ................................. 1 0 6
9. 4
Treat me nts .......................................................................................................1 0 7
9. 4. 1
Treat me nts A d mi nistere d ........................................................................1 0 7
9. 4. 1. 1
Cri teria f or D ose M o dificati on ........................................................1 0 9
9. 4. 1. 1. 1
D ose M o dificat i on a n d T o xi cit y Ma na ge me nt G ui da nce f or 
E 7 3 8 6 .......................................................................................1 1 1
9. 4. 1. 1. 2
D ose M o dificat i on a n d T o xi cit y Ma na ge me nt G ui da nce f or 
Pe m br oliz u ma b .........................................................................1 1 4
9. 4. 1. 1. 3
D ose M o dificat i on a n d T o xi cit y Ma na ge me nt f or Le n vati ni b....1 2 2
9. 4. 2
I de ntity of  I n vesti gati onal Pr o d ucts ........................................................1 2 9
9. 4. 2. 1
C he mical Na me o f E 7 3 8 6 ...............................................................1 2 9
9. 4. 2. 2
I nf or mat i on o n Pe m br oliz u ma b .......................................................1 2 9
9. 4. 2. 3
I nf or mat i on o n Le n vati ni b ..............................................................1 3 0
9. 4. 2. 4
C o m parat or Dr u g ............................................................................1 3 0
9. 4. 2. 5
La beli n g f or St u d y  Dr u g................................................................. 1 3 0
9. 4. 2. 6
St ora ge C o n dit i ons ..........................................................................1 3 0
9. 4. 3
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps ...............................1 3 0
9. 4. 4
S el ect i on of D oses i n t he St u d y ..............................................................1 3 1
9. 4. 4. 1
J ustificati o n f or D ose f or t he C o m bi nati on of E 7 3 8 6 Wit h 
Pe m br oliz u ma b ...............................................................................1 3 1
9. 4. 4. 1. 1
E 7 3 8 6 .......................................................................................1 3 1
9. 4. 4. 1. 2
Pe m br oliz u ma b .........................................................................1 3 1
9. 4. 4. 2
J ustificati o n f or D ose f or t he C o m bi nati on of E 7 3 8 6 Wit h 
Pe m br oliz u ma b Pl us Le n vati ni b ......................................................1 3 1
9. 4. 4. 2. 1
E 7 3 8 6 .......................................................................................1 3 1
9. 4. 4. 2. 2
Pe m br oliz u ma b .........................................................................1 3 2
9. 4. 4. 2. 3
Le n vat i ni b.................................................................................1 3 2
9. 4. 5
S el ect i on a n d Ti mi n g o f D ose f or Eac h S u bject ......................................1 3 2
9. 4. 6
Bli n di n g ................................................................................................. 1 3 3
9. 4. 7
Pri or a n d C o nc o mi ta nt T hera p y..............................................................1 3 3
9. 4. 7. 1
Dr u g -Dr u g I nteracti o ns ...................................................................1 3 3
9. 4. 7. 2
Pr o hi bite d C o nc o mit a nt T hera pies a n d Dr u gs ................................. 1 3 3
9. 4. 7. 3
Resc ue Me dicat i ons a n d S u p p orti ve Care ........................................1 3 5

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 6 6 of 2 1 0
9. 5. 4. 3. 3
Re p orti n g of St u d y -S pecific E ve nts ...........................................1 6 8
9. 5. 4. 4
E x pe dite d Re p orti n g .......................................................................1 6 8
9. 5. 4. 5
Brea ki n g t he Bli n d ..........................................................................1 6 8
9. 5. 4. 6
Re g ulat or y  Re p orti n g of A d verse E ve nts ........................................1 6 8
9. 5. 5
C o m plet i on/ Disc o nti n uati o n of S u bjects .................................................1 6 8
9. 5. 6
A b use or Di versi o n of St u d y  Dr u g..........................................................1 6 9
9. 5. 7
C o nfir mati o n o f Me dical Care b y A n ot her P h y sicia n ..............................1 6 9
9. 6
Data Q ualit y Ass ura nce ....................................................................................1 6 9
9. 6. 1
Data C ollect i on .......................................................................................1 6 9
9. 6. 2
Cli nical Data Ma na ge me nt .....................................................................1 7 0
9. 7
Stati stical Met h o ds...........................................................................................1 7 0
9. 7. 1
Stati stical a n d A nal ytical Pla ns...............................................................1 7 0
9. 7. 1. 1
St u d y  E n d p oi nts..............................................................................1 7 0
9. 7. 1. 1. 1
Pri mar y E n d p o i nts ....................................................................1 7 0
9. 7. 1. 1. 2
Sec o n dar y  E n d p oi nts................................................................. 1 7 0
9. 7. 1. 1. 3
E x pl or at or y  E n d p oi nts ..............................................................1 7 1
9. 7. 1. 2
Defi nit i ons of A nal ysis Sets ............................................................1 7 1
9. 7. 1. 3
S u bject Dis p osit i on .........................................................................1 7 1
9. 7. 1. 4
D e m o gra p hic a n d Ot her Baseli ne C haracterist ics............................1 7 2
9. 7. 1. 5
Pri or a n d C o nc o mi ta nt T hera p y ......................................................1 7 2
9. 7. 1. 6
Efficac y A nal yses ...........................................................................1 7 2
9. 7. 1. 6. 1
Pri mar y Efficac y  A nal ysis.........................................................1 7 3
9. 7. 1. 6. 2
Sec o n dar y  Efficac y A nal yses....................................................1 7 3
9. 7. 1. 6. 3
E x pl or at or y  Efficac y A nal yses..................................................1 7 3
9. 7. 1. 7
P har mac o ki net ic, P har mac o d y na mic, P har mac o ge n omic, a n d 
Ot her Bi o mar ker A nal yses ..............................................................1 7 3
9. 7. 1. 7. 1
P har mac o ki net ic A nal yses ........................................................1 7 3
9. 7. 1. 7. 2
P har mac o d y na mic, P har mac o ge n o mic, a n d Ot her Bi o mar ker 
A nal yses ...................................................................................1 7 4
9. 7. 1. 8
S af et y A nal yses ..............................................................................1 7 4
9. 7. 1. 8. 1
E xte nt of E x p os ure ....................................................................1 7 4
9. 7. 1. 8. 2
A d verse E ve nts .........................................................................1 7 4
9. 7. 1. 8. 3
La b orat or y  Val ues.....................................................................1 7 5
9. 7. 1. 8. 4
Vi t al Sig ns................................................................................ 1 7 6
9. 7. 1. 8. 5
Electr ocar di o gra ms ...................................................................1 7 6
9. 7. 1. 8. 6
Ot her Safet y A nal yses ...............................................................1 7 6
9. 7. 2
Deter mi nat i on of Sa m ple Size ................................................................1 7 6
9. 7. 3
I nteri m A nal ysis .....................................................................................1 7 7

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 6 9 of 2 1 0
4
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
A b bre vi ati o n
Ter m
1 L
first-li ne
2 L
sec o n d-li ne
A E
a d verse e ve nt
A EI
a d verse e ve nts of  int erest
AJ C C
A merica n J o i nt C o m mittee o n Ca ncer
A D A
a nt i-dr u g a nt i b o d y
A L T
ala ni ne a mi n otra nsferase
A N C
a bs o l ute ne utr o p hil c o u nt
A nt i-H Bc
a nt i-he pat itis B c ore a nti b o d y
A nt i-H Bs
a nt i-he pat itis B s urface a nti b o d y
A P C
a de n o mat o us p ol y p osis c o li
A S T
as partate a mi n otra nsferase
B C L C
Barcel o na Cli nic Li ver Ca ncer
BI C R
bli n de d i n de pe n de nt ce ntral re vie w
BI D
t wice dail y
B M D
b o ne mi neral de nsit y
B W
b o d y  wei g ht
C A
C o m pete nt A ut h ori t y
C B P
C R E B -bi n di n g pr otei n
C N S
ce ntral ner v o us s yste m
C R
c o mplete res p o nse
C R A
cli nical researc h ass ociate
C R E B
c A M P res p o nse ele me nt bi n di n g pr otei n
C R C
c olorectal  ca ncer
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C T
c o mp ut e d t o mo gra p h y
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 0 of 2 1 0
A b bre vi ati o n
Ter m
C T L A - 4
c yt ot o xic T -l y m p h oc yte ass ociate d pr otei n- 4
C Y P 3 A
c yt oc hr o m e P 4 5 0 3 A
D L T
d ose -li miti n g t o xicity
d M M R
D N A mis matc h re pair -deficie nt
D O R
d urati o n of  res p o nse
E CI
e ve nts of cli nical i nterest
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
E O T
E n d of Treat me nt
F G F
fi br o blast gr o wt h fact or
G- C S F
gra n ul oc y t e c olo n y -sti m ulati n g fact or
H Bc A b
he pat itis B c ore a nti b o d y
H Bs A g
he pat itis B s urface a nti ge n
H B V
he pat itis B vir us
H C C
he pat ocell ular carci n o ma
H C V
he pat itis C vir us
H C V A b
he pat itis C vir us a nt i b o d y
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or’s Br oc h ure
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati on of  Tec h nical Re q uire me nts 
f or P har mace uticals f or H u ma n Use
I CI
i m m u ne c hec k p oi nt i n hi bit or
I C L
I ma gi n g C ore La borat or y
I E C
I n de pe n de nt Et hics C o m mittee
I N R
i nter nat i onal n or m alize d ratio
I R B
I nstituti o nal  Re vie w B oar d
I V
int ra ve n o us
I B
i n vesti gat or’s br oc h ure
C CI
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 2 of 2 1 0
A b bre vi ati o n
Ter m
R P 2 D
rec o m me n de d P hase 2 d ose
R T K
rece pt or t yr osi ne ki nase
S A E
serio us a d verse e ve nt
S A P
statistical a nal ysis pla n
S D
sta ble disease
S O C
s yste m or ga n class or s ta n dar d of care
S O P
sta n dar d o perati n g pr oce d ure
S U S A R
s us pecte d u ne x pecte d seri o us a d verse e ve nt
T B L
t otal bilir u bi n
T E A E
treat me nt -e mer ge nt a d verse e ve nt
U L N
u p per li mit of n or mal
V E G F
Vasc ular e n d ot helial gr o wt h fact or
W H O D D
W o rld Heal t h Or ga nizati on Dr u g Di rect or y
W T
wil d t y pe

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 3 of 2 1 0
5
E T HI C S
5. 1
In stit uti o n al R e vi e w B o ar d s/I n d e p e n d e nt Et hi c s C o m mitt e e s
T he pr ot oc ol, i nf or me d c o nse nt f or m (I C F), a n d a p pr o priate relate d d oc u me nts m ust be 
re vie we d a n d a p pr o ve d b y a n I nstituti o nal  Re vie w B oar d (I R B) or I n de pe n de nt Et hics 
C o m mittee (I E C) c o nstit ute d a n d f u ncti oni n g i n acc or da nce wit h t he I nter nati o nal C o u ncil 
f or H ar m o nisat i on of  Tec h nical R e q uire me nts f or P har mace uticals f or H u ma n Use (I C H) E 6 
(G C P ), Secti o n 3, a n d a n y  lo c al  re g ulati ons .  A n y pr ot oc ol  a me n d me nt or re visio n  t o t he I C F 
will be res u b mitte d t o t he I R B/I E C f or re vie w a n d a p pr o val , e xce pt f or c ha n ges i n v ol vi n g 
o nl y  lo gistical  or a d mi nistrati ve as pects of t he st u d y (e g, c ha n ge i n cli nical researc h ass ociate 
(C R As ), c ha n ge of tele p h o ne n u m ber[s]).  D oc u me ntati o n of I R B/I E C c o m plia nce wit h t he 
I C H E 6 a n d a n y l ocal re g ulati o ns re gar di n g c o nst ituti o n a n d re vie w c o n d uct will be pr o vi de d 
t o t he S p o ns or .
D oc u m e nte d st u d y a p pr o val fr o m t he I R B/I E C c hair ma n m ust be se nt t o t he pri nci pal 
i n vesti gat or (or if re gi o nall y re q uire d, t he hea d of t he me dical i nst ituti o n) wi t h a c o p y t o t he 
S p o ns or be f ore st u d y start a n d t he release of a n y st u d y dr u g t o t he site b y t he S p o ns or or i ts 
desi g nee (I C H E 6, Secti o n 4. 4).  If t he I R B/I E C deci des t o s us pe n d or ter mi nate t he st u d y , 
t he i n vest i gat or (or if re gi o nall y  r e q uire d, t he hea d of t he me dical i nst ituti o n ) will 
i m me diatel y se n d t he n otice of st u d y s us pe nsio n  or ter mi nati on b y t he I R B/I E C t o t he 
S p o ns or .
St u d y  pr o gress is t o be re p orte d t o I R B/I E Cs a n n uall y (or as re q ui re d) b y t he i n vesti gat or or 
S p o ns or , de pe n di n g o n l ocal re g ulat or y o bli gati o ns.  If t he in vest i gat or is re q uire d t o re p ort t o 
t he I R B/I E C, he/s he will f or war d a c o p y t o t he S p o ns or at t he ti me of eac h peri o dic re p ort.  
T he i n vest i gat or(s) or t he S p o ns or will s u b mit, de pe n di n g o n l ocal re g ulati o ns, peri o dic 
re p orts a n d i nf or m t he I R B/I E C (or if r e gio n all y r e q uire d, t he i n vesti gat or a n d t he rele va nt 
I R B via t he hea d of t he me dical i nstituti o n) of  a n y re p orta ble a d verse e ve nts (A Es) per I C H 
g ui deli nes a n d l ocal I R B/I E C sta n dar ds of practice.  U p o n c o m plet i on of t he st u d y , t he 
i n vesti gat or will pr ovi de t he I R B/I E C wit h a brief re p ort of t he o utc o me of t he st u d y, if 
re q uire d.
A t the e n d of t he st u d y , t he S p o ns or s h o ul d n otif y t he I R B/I E C a n d C o m pete nt A ut h orit y 
(C A) wit hi n 9 0 d a ys.   T he e n d of t he st u d y will be t he ti me o f data c ut -off f or t he fi nal 
a nal ys is or t he date of t he last st u d y visit or l ast st u d y assess me nt f or t he last s u bject i n t he 
st u d y, w hic he ver occurs later .  T he S p o ns or s h o ul d als o pr o vi de t he I R B/I E C wit h a 
s u m mar y of t he st u d y’s o utc o me.
I n t he case of earl y ter mi nati on/te m p or ar y  halt of t he st u d y , t he i n vesti gat or or desi g nee, as 
a p pr o priate, s h o ul d n otif y t he I R B/I E C a n d C A wit hi n 1 5 cale n dar da ys, a n d a detaile d 
wri tte n e x pla nati o n of t he reas o ns f or t he ter mi nati o n/ halt s h o ul d be gi ve n.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 4 of 2 1 0
5. 2
E t hi c al C o n d u ct of t h e St u d y
T his st u d y  will be c o n d ucte d i n acc or da nce wit h sta n dar d o perati n g pr oce d ures ( S O Ps) of  t he 
S p o ns or (or desi g nee), w hic h are desi g ne d t o e ns ure a d here nce t o G C P g ui deli nes as re q uire d 
b y t he f o ll owi n g:

Pri nci ples of t he W orl d Me dical Ass ociat i on Declarati o n of  Helsi nki 2 0 1 3

I C H E 6 G uideli ne f or G C P (C P M P/I C H/ 1 3 5/ 9 5) of t he E ur o pea n A ge nc y f or t he 
E val uat i on of Me dici nal Pr o d ucts, C o m mittee f or Pr o prietar y  Me dici nal Pr o d ucts, 
I nter nati o nal C ou ncil f or Har m o nisat i on of Tec h nical Re q uire me nts f or P har mace ut icals 
f or H u m a n Use

Ti tle 2 1 of t he U nite d States C o de of Fe deral Re g ulat i ons (U S 2 1 C F R) re gar di n g cli nical 
st u dies, i ncl u di n g Part 5 0 a n d Part 5 6 c o ncer ni n g i nf or me d s u bject c o nse nt a n d I R B 
re g ulat i ons a n d a p plica ble secti on s of U S 2 1 C F R Part 3 1 2

E ur o pea n G o o d Cl i nical Practice Directi ve 2 0 0 5/ 2 8/ E C a n d Cli nical Trial Directi ve 
2 0 0 1/ 2 0/ E C f or st u dies c o n d ucte d wit hi n a n y  E U c o u ntr y.  All s us pecte d u ne x pecte d 
serio us a d verse e ve nt ( S U S A Rs ) will be re p orte d, as re q uire d, t o t he C o m pete nt 
A ut h ori ties of all in v o l ve d EU m e m ber states

Ot her a p plica ble re g ulat or y  a ut h orities ’ re q uire me nts or directi ves
5. 3
S u bj e ct I nf or m ati o n a n d I nf or m e d C o n s e nt
As part of a d mi nisteri n g t he i nf or me d c o nse nt d oc u me nt, t he i n vest i gat or m ust e x plai n t o 
eac h s u bject (or t he s u bject’s legall y  a ut hori ze d re prese ntati ve), t he nat ure of t he st u d y, its 
p ur p ose, t he pr oce d ures i n v ol ve d, t he e x pecte d d urati o n, t he p ote n tial ris ks a n d be nefits 
i n v ol ve d, a n y p ote ntial disc o mf ort, p ote ntial alter nati ve pr oce d ure(s) or c o urse(s) of 
treat me nt a vaila ble t o t he s u bject, a n d t he e xte nt of mai ntai ni n g c o nfi de ntialit y of t he 
s u bject’s rec or ds.  Eac h s u bject m ust be i nf or me d t hat partici pat i on i n t he st u d y is v ol unt ar y, 
t hat he/s he ma y wit hdra w fr o m  t he st u d y at a n y time, a n d t hat wit h dra wal of c o nse nt will n ot 
affect his/ her s u bse q ue nt me dical treat me nt or relati o ns hi p wit h t he treati n g p h ysicia n.
T his i nf or me d c o nse nt s h o ul d be gi ve n b y mea ns of a sta n dar d writte n state me nt or el ectr o nic 
versi o n, if all o we d per c o u ntr y -s pecific re g ulati ons , wri tte n i n n o ntec h nical la n g ua ge.  T he 
s u bject (or t he s u bject’s le gall y a ut h orize d re prese ntati ve) s h o uld u n dersta n d t he state me nt 
bef ore si g ni n g a n d dat i n g it a n d will be gi ve n a c o p y of t he si g ne d d oc u me nt.  If a s u bject is 
u na ble t o rea d or if a le gall y a ut h orize d re prese ntati ve is u na ble t o rea d, a n i m partial wi t ness 
s h o uld be prese nt d uri n g t he e nt ire i nf or me d c o nse nt disc ussi o n. A fter t he I C F a n d a n y ot her 
wri tte n i nf or mat i on t o be pr o vi de d t o s u bjects is rea d a n d e x plai ne d t o t he s u bject (or t he 
s ubject’s l e gall y a ut h orize d re prese ntati ve), a n d after t he s u bject (or t he s u bject’s le gall y 
a ut h orize d re prese ntati ve) has orall y  c o nse nte d t o t he s u bject’s partici pat i on i n t he st u d y a n d, 
if ca pa ble of d oi n g s o, has si g ne d a n d pers o nall y date d t he I C F, t he wit ness s h o uld si g n a n d 
pers o nall y date t he c o nse nt f or m.  T he s u bject will be as ke d t o si g n a n I C F at t he Scree ni n g 
Vi sit bef ore a n y st u d y -s pecific pr oce d ures are perf or me d.  N o s u bject ca n e nter t he st u d y 
bef ore his/ her i nf or me d c o nse nt has bee n o btai n e d.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 5 of 2 1 0
I n t he case of a s u bject lac ki n g ca pacity t o c o nse nt i n t he i n vesti gat or's o pi ni on, s u bject's 
asse nt plus wri tte n i nf or me d c o nse nt of a le gall y a ut h orize d re prese ntative s h o ul d be 
o btai ne d, if re q uire d i n acc or da nce wit h l ocal la ws, re g ulati ons, a n d c ust o ms.  I n c o u ntries 
w here l ocal la ws/re g ulati o ns a n d c ust o ms d o n ot per mit s u bjects lac ki n g ca pacit y t o co nse nt 
t o partici pate i n t his st u d y (e g, Ger ma n y a n d S pai n), t he s u bjects will n ot be e nr olle d.  
Ca pacit y t o co nse nt a n d defi nit i on of le gall y a ut h orize d re prese ntati ve s h o ul d be deter mi ne d 
i n acc or da nce wit h a p plica ble l ocal la ws a n d re g ulati o ns.  T he i n vesti gat or s hall reassess 
c o nse nt ca pacit y at perio dic i nter vals d uri n g t he s u bject’s i n v o l ve me nt i n t he st u d y, a n d w he n 
a s u bject's fa mil y me m ber e x pr esses c o ncer n a b o ut t he s u bject's st u d y partici pat i on.  T he 
met h o d a n d fre q ue nc y o f reassess me nt of ca pacity is at t he i n vesti gat or’s discreti on (ta ki n g 
i nto acc o u nt a n y  rele va nt lo c al  la ws a n d re g ulat i ons).  D uri n g t he st u d y , s h o uld a s u bject 
decli ne t o t he p oi nt of lac ki n g ca pacit y i n t he i n vesti gat or's o pi ni on, t he i n vest i gat or s h o ul d 
o btai n t he asse nt of t he s u bject a n d c o nse nt of a legall y  a ut h orize d re prese ntati ve i n 
acc or da nce wit h l ocal la ws/re g ulat i ons a n d c ust o ms f or t he s u bject t o c o nti n ue i n t he st u d y.  
I n c o u ntries w here lo c al  la ws/re g ulatio ns d o n ot per mit s u bjects lac ki n g ca pacit y t o c o nse nt 
t o c o nti n ue i n t his st u d y (e g, Ger ma n y), t he n s u bjects w h o ha ve decli ne d t o t he p oi nt of 
lac ki n g ca pacity t o c o nse nt d uri n g t he st u d y  will be disc o nti n ue d.  
A n elect ro nic c o nse nt (e C o nse nt) pr ocess ma y be use d, if all o we d per c o u ntr y re g ulat i ons, 
a gree d b y S p o ns or a n d a p pr o ve d b y I R B/ E C.  
A n u nsi g ne d c o p y  of a n I R B/I E C-a p pr o ve d I C F m ust be pre pare d i n acc or da nce wit h I C H 
E 6, Secti o n 4, a n d all a p plica ble l ocal re g ulati o ns . Eac h s u bject m ust si g n a n a p pr o ve d I C F 
bef ore st u d y  p artici pat i on.  T he f or m m ust be si g ne d a n d date d b y  t he a p pr o priate parties.  
T he ori gi nal , si g ne d I C F f or eac h s u bject will be verifie d b y t he S p o ns or a n d ke pt o n file 
acc or di n g t o l ocal pr oce d ures at t he site.   
T he s u bjec t ( or t he s u bject’s le gall y a ut h orize d re prese ntati ve) s h o uld be i nf or m e d i n a 
ti mel y ma n ner if ne w i nf or mati o n bec o me s a vaila ble t hat ma y be rele va nt t o t he s u bject’s 
willi n g ness t o c o nti n ue parti ci pat i on i n t he st u d y.  T he c o m m u nicati on of t his i nf or mat i on 
s h o uld be d oc u m e nte d.
Wit h re gar d t o t he p har mac o ge n o mic ( P G) assess me nts descri be d i n Secti o n 9. 5. 1. 3. 2 , a n 
i nf or me d c o nse nt f or c ollect i on of sa m ples d uri n g t he st u d y  for P G a nal ysis will be pre pare d 
se paratel y.  S u bjects ma y st ill partici pate i n t he st u d y if t he y d o n ot gi ve i nf or me d c o nse nt 
f or P G a nal ysis.
6
I N V E S TI G A T O R S A N D S TU D Y P E R S O N N E L
T hi s st u d y will be c o n d ucte d b y q ualifie d i n vesti gat ors u n der t he S p o ns or s hi p of Eisai (t he 
S p o ns or ) at a p pr o xi matel y 4 0 i n vesti gati onal sites i n N ort h A merica, E ur o pe, a n d Asia-
Pacific ( A P A C) re gi o ns.
T he na me a n d tele p h o ne a n d fa x n u m bers of t he me dical m o nit or a n d ot her c o ntact pers o n nel 
at t he S p o ns or a n d of t he c o ntract researc h or ga nizati o ns (C R Os) are liste d i n t he I n vesti gat or 
St u d y  File pr o vi de d t o eac h site.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 6 of 2 1 0
7
I N T R O D U C TI O N
7. 1
C o m p o u n d O v er vi e w
7. 1. 1
B a c k gr o u n d of E 7 3 8 6
E 7 3 8 6 i s a p ote ntial first i n class W nt/ β-cate ni n si g nali n g pat h wa y m o d ulat or.  E 7 3 8 6 
i n hi bits pr otei n-pr otei n i nteract i on bet wee n a tra nscri pt i onal c o -acti vat or, c A M P res p o nse 
ele me nt bi n di n g pr otei n (C R E B )-bi n di n g pr otei n (C B P ) a n d β-cate ni n, res ult i n g i n t he 
m o d ulat i on of W nt/ β - cate ni n si g nali n g pat h wa y-de pe n de nt ge ne e x pressi o n.  E 7 3 8 6 ca n 
i n hi bit n ot o nl y li ga n d-de pe n de nt acti vati o n b ut als o a de n o mat o us p ol y p osis c o li (A P C ) or β-
cate ni n m utati o n-de pe n de nt acti vat i on of W nt/ β- cate ni n si g nali n g beca use o f t he d o w nstrea m 
actio n of  E 7 3 8 6 o n A P C a n d β-cate ni n i n t he W nt/ β-cate ni n si g nali n g casca de.  T heref ore, 
E 7 3 8 6 i s c o nsi dere d t o be p ote ntiall y acti ve i n t u m ors wit h a berra nt W nt/ β-cate ni n si g nali n g 
acti vat i on.  I n a d di tio n, E 7 3 8 6 als o has t he p ote ntial t o eli mi nate dr u g -resista nt ca ncer ste m 
cells a n d t u m or -i nitiati n g cells via f orce d differe ntiati o n, a n d t o se nsitize or re-se nsitize 
resista nt t u m ors t o c o n ve nti onal t hera p y  as a mo n ot hera p y , a n d i n c om bi nat i on wi t h 
c he m ot hera p y a n d ot her a ge nts ( Ka h n, 2 0 1 4 ).  I n vi v o, oral a d mi nistrati o n of E 7 3 8 6 
sig nifica nt l y i n hi bite d i ntesti nal p ol y p f or mat i on i n A pcMi n/ + mice (a n e n gi neere d m o use 
m o d el  w here a berra nt activati o n of  t he W nt/ β-cate ni n pat h wa y ge nerates s p o nta ne o us 
p ol y p osis i n i n testi ne).  T his de m onstrates t hat E 7 3 8 6 m o d ulate d t he W nt/ β -cate ni n pat h wa y 
i n vi v o.  E 7 3 8 6 als o de m o nstrate d a ntit u m or acti vit y  a gai nst mo use ma m mar y t u m ors 
de vel o pe d i n m o use ma m mar y t u m or vir us ( M M T V) -W nt 1 tra ns ge nic mice. 
T hese i n vi v o 
n o ncli nical res ults s u g gest t hat E 7 3 8 6 ma y  pr o vi de a n o vel a ntica ncer t hera p y a gai nst 
mali g na ncies wit h a berra nt acti vat i on of W nt/ β -cate ni n pat h wa y (Ya ma da, et al ., 2 0 2 1).
7. 1. 2
B a c k gr o u n d of P e m br oli z u m a b
Pe m br oliz u ma b is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nt i b o d y 
( mA b) wi t h hi g h s pecificity of  bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D-1) rece pt or, t h us 
i n hi biti n g its i nteractio n wi t h pr o gra m me d cell deat h li ga n d 1 ( P D-L 1) a n d pr o gra m me d cell 
deat h li ga n d 2 ( P D -L 2). Base d o n n o n cli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y 
a n d p ote nt rece pt or bl oc ki n g act i vity f or P D-1. Pe m br oliz u ma b has a n acce pta ble 
n o n cli nical safet y pr ofile a n d is i n cli nical de vel o p me nt as a n i ntra ve n o us (I V) 
i m m u n ot hera p y for a d va nce d m ali g na ncies. Ke ytr u da ® ( pe m br oliz u ma b) is i n dicate d f or t he 
treat me nt of patie nts acr oss a n u m ber of i n dicat i ons. F or m ore details o n s pecific i n dicati o ns 
refer t o t he I n vesti gat or’s Br oc h ure (I B)/a p pr o ve d la beli n g f or detaile d bac k gr o u n d 
i nf or mat i on o n M K - 3 4 7 5.
T he i m p orta nce of i ntact i m m u ne s ur veilla nce f u ncti o n i n c o ntr olli n g o ut gr o wt h of ne o plastic 
tra nsf or mati o ns has bee n k n o w n f or deca des (Di sis, 2 0 1 0). Acc u m ulat i n g e vi de nce s h o ws a 
c orrelat i on bet wee n t u m or -i nfiltrati n g l y m p h oc ytes i n ca ncer tiss ue a n d fa v ora ble pr o g n osis 
i n v ari o us m ali g na ncies. I n partic ular, t he prese nce of C D 8 + T-cells a n d t he rati o of C D 8 + 
effect or T cells/ F o x P 3 + re g ulat or y T-cells c orr elates wit h im pr o ve d pr o g n osis a n d l o n g -t er m 
s ur vi val i n s oli d mali g na ncies, s uc h as o varia n, c ol orectal, a n d pa ncreat ic ca ncer; 
he pat ocell ular carci n o ma ( H C C); mali g na nt mela n o ma; a n d re nal cell carci n o ma. T u m or -

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
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FI N A L: 2 5 Ja n 2 0 2 3
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Pa ge 7 7 of 2 1 0
i nfiltrati n g l y m p h oc ytes ca n be e x pa nde d e x vi v o a n d rei nf use d, i n d uci n g d ura ble o bjecti ve 
t u mor res p o nses i n ca ncers s uc h as mela n o ma (D u dl e y, et al., 2 0 0 5; H u n der , et al., 2 0 0 8).
T he pr o gra m me d cell deat h pr otei n 1 (P D - 1) rece pt or-li ga n d i nteracti o n is a maj or pat h wa y 
hijac ke d b y  t u mors t o s u p press i m m u ne c o ntr ol. T he n or m al fu n cti o n of  P D-1, e x presse d o n 
t he cell s urface of acti vate d T cells u n der healt h y c o n dit i ons, i s t o d o w n-m o d ul ate u n wa nte d 
or e xcessi ve i m m u ne res p o nses, i ncl u di n g a ut oi m m u ne react i ons. E nc o de d b y  t he ge ne 
P dc d 1, P D -1 is a n i m m u n o gl o b uli n s u perfa mil y me m ber relate d t o cl uster of differe ntiati on 
2 8 ( C D 2 8) a n d c y t ot o xic T -l y m p h oc yt e-ass ociate d pr otei n 4 ( C T L A-4) t hat has bee n s h o w n 
t o ne gati vel y re g ulate a nti ge n rece pt or si g nali n g u p o n e n ga ge me nt of its li ga n ds ( P D L 1 
a nd/ or P D -L 2) (Gree n wal d , et al., 2 0 0 5; O kaza ki , et al., 2 0 0 1).
T he str uct ure of m uri ne P D -1 has bee n res o l ve d (Z ha n g , et al., 2 0 0 4). P D -1 a n d its fa mil y 
me m bers are t y pe I tra ns m e m bra ne gl yc o pr otei ns c o ntai ni n g a n I g -varia ble – t yp e d o m ai n 
res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic tail res p o nsi ble f or t he bi n di n g of si g nali n g 
m o lec ules. T he c y t o plas mic tail of P D-1 c o ntai ns 2 t y r osi ne-base d si g nali n g m otifs, a n 
i m m u n orece pt or t yr osi ne-base d i n hi bit i on m o tif, a n d a n i m m u n orece pt or t yr osi ne-base d 
s witc h motif . F o ll owi n g T -cell st i m ulati on, P D -1 recr uits t he t yr osi ne p h os p hatases, S H P - 1 
a n d S H P -2, t o t he i m m u n orece pt or t y r osi ne-base d s witc h m otif wit hi n its c yt o plas mic tail, 
lea di n g t o t he de p h os p h or ylati on of effect or m o lec ules s uc h as C D 3 zeta ( C D 3ζ), pr otei n 
ki nase C -t heta ( P K C θ), a n d zeta-c hai n-ass ociate d pr otei n ki nase ( Z A P 7 0), w hic h are 
i n v ol ve d i n t he C D 3 T-cell si g nali n g casca de (O kaza ki , et al., 2 0 0 1; C he m nit z, et al., 2 0 0 4; 
S he p par d , et al., 2 0 0 4; a n d Rile y , 2 0 0 9). T he m ec ha nis m b y w hic h P D- 1 d o w n -m o d ul ates T 
cell res p o nses is si milar t o, b ut dist i nct fr om,  t hat of C T L A-4, beca use b ot h m o lec ules 
re g ulate a n o verla p pi n g set of si g nali n g pr otei ns (Parr y , et al., 2 0 0 5; Fra ncisc o , 2 0 1 0). As a 
c o nse q ue nce, t he P D 1/ P D -L 1 pat h wa y is a n attracti ve t ar get f or t hera pe utic i nter ve nt i on i n 
mela n o ma, H C C , a n d c o l orectal ca ncer (C R C ).
7. 1. 3
B a c k gr o u n d of L e n v ati ni b
Le n vat i ni b is a p ote nt m ulti ple-rece pt or t yr osi ne ki nase i n hi bit or t hat selecti vel y i n hi bits 
vasc ular e n d ot helial gr o wt h fact or ( V E G F ) rece pt ors ( V E G F R 1 [ F L T 1], V E G F R 2 [ K D R], 
V E G F R 3 [ F L T 4]) i n a d dit i on t o ot her pr o -a n gi o ge nic a n d o nc o ge nic pat h wa y- relate d 
rece pt or t yr osi ne ki nases (R T Ks) , i ncl u di n g fi br o blast gr o wt h fact or ( F G F) rece pt ors F G F R 1
t o 4, platelet -deri ve d gr o wt h fact or ( P D G F) rece pt or α rece pt or-α ( P D G F R α), ste m cell fact or 
rece pt or ( KI T), a n d ret pr ot o-o nc o ge ne ( R E T).
I n t he C T 2 6 s y n ge neic m o del, le n vati ni b si g nifica nt l y decrease d t he T A M p o p ulat i on a n d 
i ncrease d t he perce nta ge of acti vate d C D 8 + T cells (Ki m ura, et al., 2 0 1 8; Kat o , et al., 2 0 1 9; 
A dac hi, et al., 2 0 2 2 ).  T h us, i n a d dit i on t o t he direct a nti -a n gio ge nic effects of l e n vat i ni b, t he 
i m m u ne-m o d ul at i n g effect of le n vat i ni b ma y als o res ult i n p ote nt c o m bi nati on effect wit h 
P D -1 si g nal i n hi bit ors i n m ult i ple s y n ge neic t u mor m o dels .  T he effect of c o m bi ni n g 
le n vati ni b wi t h P D-1/ L 1 ( pr o gra m me d deat h, li ga n d 1) m o n ocl o nal a nt i b o dies ( m A bs) has 
bee n i n vest i gate d a n d was m ore effect i ve t ha n either c o mp o u n d al o ne.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 8 of 2 1 0
Le n vat i ni b alo n e or i n c o m bi nat i on wi t h pe m br oliz u ma b is a p pr o ve d f or se veral i n dicat i ons 
i n ma n y re gi o ns (r efer t o t he I n vest i gat or's Br oc h ure [I B] f or s pecific details).  Le n vat i ni b 
m o n ot hera p y  is a p pr o ve d as first-li ne ( 1 L) treat me nt i n H C C i n ma n y parts of t he w orl d .  I n 
a d ditio n, le n vat i ni b is c urre ntl y bei n g i n vesti gate d i n c o m bi nat i on wi t h E 7 3 8 6 i n t he o n g oi n g 
S t u d y E 7 3 8 6-J 0 8 1- 1 0 2 ( St u d y 1 0 2).
E 7 3 8 6 has bee n s h o w n t o e n ha nce t he a nt itu m or acti vit y of  le n vati ni b a n d/ or s u p press
le n vati ni b resista nce i n n o ncli nical st u dies (Oza wa , et  al., 2 0 1 7; Ya m a da, et al., 2 0 1 8).
7. 1. 4
M el a n o m a, C ol or e ct al C a n c er , a n d H e p at o c ell ul ar C ar ci n o m a
T he i m m u ne c hec k p o i nt i n hi bit ors (I CIs), s uc h as a nti b o dies ( A b) t hat bl oc k ( C T L A-4), t he 
pr o gra m me d cell deat h pr otei n 1 ( P D -1), P D li ga n d 1 ( P D-L 1), a n d P D - L 2 is wi del y 
a p pr o ve d i n ma n y t y p es of ca ncers as t he sta n dar d of care ( S O C).  Alt h o u g h si g nifica nt 
i m pr o ve me nt has bee n ma de i n patient s’ o utc o mes, t he efficac y of t hese dr u gs is still li mite d 
a n d pri mar y or ac q uire d resista nce t o I CIs re mai n a n iss ue, es peciall y i n 3 differe nt ca ncer 
i n dicati ons: me la n oma a n d H C C after faili n g I CI t hera p y a n d pri mar y resista nce i n 
micr osatellite sta ble ( M S S) C R C.  Ta ke n t o get her, t hese li mitat i ons u n derli ne t he nee d t o 
de vel o p better t hera pies or c o m bi nat i on strate gi es t hat ca n a d dress t his ke y u n m et m e dical 
nee d i n s u bjects wit h metastatic mela n o ma, H C C, a n d M S S C R C.
I n 2 0 2 0, 3 2 4, 6 3 5 ne w dia g n oses of mela n oma a n d 5 7, 0 4 3 deat hs f or t his disease were 
esti mate d gl o ball y (S u n g , et al., 2 0 2 1).  T he ma na ge me nt of metastatic mela n oma has 
c ha n ge d dra maticall y si nce t he i ntr o d uctio n of  tar gete d t hera p y a n d i m mu n ot hera p y .  I n 
parti c ular, A bs tar geti n g P D -1, s uc h as pe m br o liz u ma b a n d ni v ol u ma b al o ne or ni v ol uma b i n 
c o m bi nat i on wi t h a C T L A- 4 i n hi bit or (i pili m u ma b) ha ve bee n s h o w n t o i m pr o ve o bjecti ve 
res p o nse a n d pr o gressi o n free s ur vi val ( P F S) (W o lc h o k, et al., 2 0 1 7; R o bert , et al., 2 0 1 9).  
T u m or re gressi o n after t hera pe utic P D -1 bl oc ka de re q ui res pre-e xist i n g C D 8+ T- cells t hat are 
ne gat i vel y re g ulate d b y P D-1/ P D -L 1 -me d iate d a da pti ve i m m u ne resista nce (T u me h , et al., 
2 0 1 4 ).  T here is n o sta n dar d of care after faili n g t hese t hera pies.  T he res p o nse rates i n 
pati e nts wit h a d va nce d me la n oma w h o e x perie nce d disease pr o gressi o n o n i m m u n ot hera p y 
a n d w h o ha d bee n treate d wit h a vaila ble t hera p y s uc h as c he mot h era p y, C T L A - 4 i n hi bit or, 
a n d c o m bi nat i on of C T L A - 4 i n hi bit or wit h P D - 1 bl o c ka de are a p pr o xi matel y 1 0 % t o 2 1 % 
(Lar ki n , et al., 2 0 1 8; Zi m mer , et al., 2 0 1 7 ).
T heref ore , t here re mai ns a n u n met m e dical nee d f o r patie nts after i m m u n ot hera p y fail ure. I n 
a d ditio n, pri mar y or ac q uire d resista nce t o a nti -P D -1 t hera p y  r e mai ns a n iss ue.  I n partic ular, 
o ne m ec ha nis m of i n nate resista nce t o P D-1/ P D -L 1 i n hi bit ors is t he acti vat i on of t he W nt/ β -
cate ni n si g nali n g pat h wa y, w hic h res ults i n T -cell e xcl usi o n ( S pra n ger, et  al., 2 0 1 5).  
T heref ore, m o d ulat i on of t his i ntri nsic W nt/ β -cate ni n si g nali n g i n mela n o ma ma y offer a n 
o p p ort u nit y t o o verc o me resista nce t o a nti-P D -L 1 A b t hera p y . 
F or C R C, o ver 1. 9 milli o n ne w C R C cases a n d 9 3 5, 0 0 0 deat hs were esti mate d t o occ ur 
gl o ball y  in 2 0 2 0 ( S u n g , et al., 2 0 2 1).  T he sta n dar d of care i n t he metastatic setti n g i ncl u des 
c yt ot o xic a ge nts s uc h as f oli nic aci d a n d 5 -fl u or o uracil c om bi ne d wit h eit her o xali plati n 
( F O L F O X) or wit h iri n oteca n ( F O L FI RI), bi ol ogi c al tar gete d a ge nts i n co m bi nat i on wi t h 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 7 9 of 2 1 0
c he m ot hera p y a ge nts a n d m ult i ki nase i n hi bit ors s uc h as re g orafe ni b. Alt h o u g h re g orafe ni b 
a n d trifl uri di ne/ti piracil (T A S - 1 0 2) are a p pr o ve d i n patie nts wit h pre vi o usl y  treate d 
metastati c C R C base d o n s ur vi val be nefit data , t he o bj ect i ve res p o nse r at es (O R R ) i n t hese 
pati e nts are ≤2 % f or b ot h a ge nts ( Gr ot he y , et al., 2 0 1 3 ; Ma ye r, et al., 2 0 1 5 ). I m m u ne 
c hec k p oi nt i n hi bit ors are effect i ve i n patient s wit h t he h y per m utate d s u bt yp e of  C R C, 
s pecificall y t h ose wit h micr osatellite i nsta bilit y hi g h ( M SI H)/ D N A mis matc h re pair -
deficie nt ( d M M R) C R C or t h ose wit h here ditar y  mutati o ns ( A n dre , et al., 2 0 2 0; Di az, et al., 
2 0 1 5; Gr ot he y , 2 0 2 0; Le , 2 0 1 5 ).  H o we ver, o nl y a s mall pr o p ortio n of  patie nts wit h C R C 
ha ve M SI -H t u m ors.  Pati e nts wit h M S S C R C d o n ot be nefit fr om si n gle a ge nt I CI t hera p y 
(Her mel a n d Sig al , 2 0 1 9).  I n partic ular, > 9 0 % of C R C e x hi bit m utatio ns i n t he A P C ge ne 
a n d i n ot her W nt si g nali n g c o m p o ne nts t hat res ult i n h y peracti vati o n of t he W nt pat h wa y, 
a n d t hese m utati o ns are t he earliest k n o w n ge net ic alt er atio ns, i n dicat i n g t hat t he y re prese nt 
t he i nit iati n g e ve nt i n t he pat h t o C R C (B u gte r, et al. , 2 0 2 1; T he Ca ncer Ge n o me At las 
Net w or k , 2 0 1 2; Sil va, et al., 2 0 1 4). T heref ore , effecti ve tr e at me nt i n patie nts wit h M S S C R C
still r e mai ns a n u n met m e dical nee d. P RI -7 2 4, a sec o n d-ge nerat i on C R E B/ β -cate ni n 
a nta g o nist, i n hi bits t he i nteracti o n bet wee n C B P a n d β -cate ni n ( Ta ke mar u a n d M o o n , 2 0 0 0).  
I n a n eff ort t o i ncrease t he a nti-t u mor efficac y  of P D -1/ P D -L 1 A b, c o m bi nat i on of P RI 7 2 4 
a n d P D-L 1 A b has bee n teste d i n a m o use m o del of c o l on ca ncer li ver metastasis.  T his 
a p pr oac h has s h o w n re gressi o n of t u m o r gr o wt h c o m pare d t o m o n ot hera p y alo ne.  T his st u d y  
s h o ws a ne w p ote ntial t hera pe utic strate g y for treati n g t his disease ( Osa wa , et al. , 2 0 1 9).
F or li ver ca ncer, a p pr o xi matel y 9 0 6, 0 0 0 ne w cases a n d 8 3 0, 0 0 0 deat hs were esti mate d t o 
occ ur gl o ball y i n 2 0 2 0 (S u n g , et al., 2 0 2 1).  He pat ocell ular carci n o ma is t he m ost c o m m on 
pri mar y  li v er mali g na nc y w orl d wi de a n d lea di n g ca use of deat h a n d re prese nts 7 5 % -8 5 % of 
pri mar y  li ver ca ncer (S u n g , et al., 2 0 2 1).  Besi de se veral tar gete d t yr osi ne ki nase i n hi bit ors 
i ncl udi n g l e n vati ni b, treat me nt o ptio ns i ncl u de I CIs w hic h ha ve s h o w n a nt itu m or acti vit y.   
C o m bi nat i on of atez oliz u ma b a n d be vaciz u ma b has s h o w n a s ur vi val be nefit r elat i ve t o 
s orafe ni b i n t he first li ne setti n g a n d is wi del y use d (Fi n n , et al., 2 0 2 0). I n t his st u d y, 2 8 % of  
pati e nt s teste d p ositi ve f or treat me nt-e mer ge nt a nt i-dr u g a nti b o d y  (A D A ) a n d ha d a l o wer 
s yste mic atez oliz u ma b e x p os ure as c o m pare d t o patie nts w h o were A D A-ne gat i ve 
(At ez oliz u ma b [ T E C E N T RI Q® ] Pac ka ge I nsert). Alt h o u g h se veral vasc ular e n d ot helial 
gr o wt h fact or ( V E G F ) i n hi bit ors are a vaila ble as sec o n d -li ne treat me nt o pti o n s, s uc h as 
re g orafe ni b a n d ca b oza nt i ni b, t he O R R < 1 0 % f or t hese treat me nts a n d ma n y o f t hese 
treat me nts are li mite d t o use after s orafe ni b (Br ui x , et al., 20 1 7; A b o u -Alfa , et al., 2 0 1 8 ). 
T heref ore , t here is n o sta n dar d of care a n d t here is a n u n met me d ical nee d f or effecti ve 
treat me nt aft er I CI-base d re gi me ns.  Rece ntl y, ne xt ge nerati o n se q ue nci n g st u dies ha ve 
s h o w n t hat t he prese nce of a n acti vate d W nt/ β-cate ni n si g nali n g was ass ociate d wit h i n nate 
resista nce t o I CIs (Har di n g , et al., 2 0 1 9).  Base d o n rece nt n o ncli nical data descri be d bel o w, 
t he W nt/ β-cate ni n si g nali n g pat h wa y is als o a ke y pat h wa y in le n vati ni b resista nce 
de vel o p me nt.  T heref ore, t he W nt/ β -cate ni n si g nali n g pat h wa y is ke y i n I CIs a n d le n vat i ni b 
resista nce a n d tar geti n g t his si g nal ma y o verc ome resista nce t o t hese a ge nts .
7. 2
N o n cli ni c al e vi d e n c e
I n n o ncli nical st u dies, E 7 3 8 6 i n d uce d i nfiltrati o n of C D 8+ cells i nt o t u m or tiss ues i n 
i m m u n o hist oc he mistr y e x peri me nts.  F urt her m ore, E 7 3 8 6 s h o we d s y ner gistic a ntitu m or 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 8 0 of 2 1 0
acti vit y a gai nst M M T V-W nt 1 t u m or i n c o m bi nati o n wit h a n a nt i- m o use P D -1 A b i n 
n o n cli nical t u mor is o graft e x peri me nts ( Ya ma da , et al., 2 0 2 1).
Re gar di n g pe m br o liz u ma b, t hera pe utic st u dies i n mo us e m o d el s ha ve s h o w n t hat
a d mi nistrati o n of a nti b o dies bl oc ki n g P D-1/ P D -L 1 i nteracti o n e n ha nces i nfiltrati o n of t u m or -
s pecific C D 8 + T cells a n d ult i matel y lea ds t o t u m or rejecti on, ei t her as a mo n ot hera p y  or i n 
c o m bi nat i on wi t h ot her treat me nt mo dali ties (Hi ra n o, et  al.,2 0 0 5 ; Bl a nk, et al., 2 0 0 4; We ber , 
2 0 1 0; Str o m e, et al., 2 0 0 3 ; S pra n ger , et al., 2 0 1 4; C urra n , et al., 2 0 1 0 ; Pi l on , et al., 2 0 1 0 ).  
A nt i-m o use P D -1 or a nti -m o use P D -L 1 a nt i b o dies ha ve de m onstrate d a ntit u m or res p o nses i n 
m o dels o f s q ua m o us cell carci n oma, pa ncreat ic carci n oma, me la n oma, ac ute m yel o i d 
le u ke mia a n d c ol orectal carci n oma (Str o m e, et al., 2 0 0 3 ; C urra n , et al., 2 0 1 0; Pil o n , et al., 
2 0 1 0 ; N o mi , et al., 2 0 0 7; Z ha n g , et al., 2 0 0 4 ).  I n s uc h st u dies, t u m or i nfiltrati o n b y C D 8+ T 
cells a n d i ncrease d i nterfer o n-γ (I F N-γ), gra nz y me B a n d perf ori n e x pressi on were o bser ve d, 
i n dicati n g t hat t he mec ha nis m u n derl yi n g t he a nt itu m or acti vit y of  P D-1 c hec k p o i nt 
i n hi biti on i n v ol ve d l ocal i nfiltrati on a n d acti vat i on of effect or T cell f u nct i on i n vi v o (C urra n,
et al., 2 0 1 0). E x peri me nts ha ve c o nfir me d t he i n vi v o efficac y of a nt i-m o use P D -1 a nt i b o d y 
as a m o n ot hera p y, as well as i n c o m bi nat i on wi t h c he mot h era p y, i n s y n ge neic mo us e t u m or 
m o dels (see t he I B/a p pr o ve d la beli n g).
I n n o ncli nical st u dies, le n vati ni b i n hi bits b ot h V E G F- a n d F G F-dri ve n a n gi o ge nesis i n vitr o 
a n d i n vi v o.  Le n vat i ni b de m onstrate d a ntit u m or acti vit y a g a i nst a wi de variet y of xe n o graft 
at h y mic m o use m o dels i n w hic h ca ncer cells (s uc h as differe nt iate d t h yr oid ca ncer, re nal cell 
ca ncer, H C C) are tra ns pla nte d.  Le n vati ni b als o s h o we d a ntit u m or acti vit y i n a muri ne H C C 
is o graft m o del i n at h y mic mice.  Le n vat i ni b m o n ot hera p y si g nifica ntl y decrease d 
micr o vessel de nsit y i n t u mors i n a n i s o graft mo del of 4 T 1 m uri ne breast ca ncer cells.  I n 
t u mors treate d wit h len vat i ni b, t he ratio of  t u mor vessels c o vere d wit h peric y tes, w hic h are 
k n o w n t o be resista nt a gai nst V E G F i n hi bit ors, were i ncrease d.  T he c o m bi nat i on of E 7 3 8 6 
wi t h le n vati ni b s h o we d e n ha nce d a ntitu m or acti vit y a n d res ulte d i n a sig nifica nt decrease i n 
t he micr o ve ssel de nsity a n d greater re d ucti o n i n t he rate of t u m or vessels c o vere d wit h 
p eri c yt es c o mpare d wi t h E 7 3 8 6 a n d le n vati ni b i n di vi d ual treat me nts i n H C C xe n o graft t u m or 
m o dels .  T hese data s u g gest E 7 3 8 6 s u p presses le n vati ni b-resista nt vasc ularizati on a n d 
e n ha nces a nt i-a n gi o ge nesis act i vity b y le n vat i ni b (Oza wa , et al., 2 0 1 7; Ya ma da , et al., 2 01 8 ).  
M ore rece nt l y, triple t treat me nt of E 7 3 8 6 wit h a nti-m o use P D -1 a nti b o d y  plus le n vat i ni b i n 
sy n ge neic m o use H C C a n d R C C m o d el s s h o we d i ncrease d a ntit u mor acti vit y of  triplet 
treat me nt c o m p are d wit h eit her a nti-P D -1 pl us len vat i ni b or E 7 3 8 6 pl us len vati ni b 
c o m bi nat i on (data o n file ).
7. 3
Cli ni c al E x p eri e n c e
7. 3. 1
E 7 3 8 6
T w o P hase 1 st u dies ( St u d y E 7 3 8 6 -G 0 0 0 - 1 0 1 [St u d y  1 0 1] a n d St u d y  E 7 3 8 6 -J 0 8 1- 1 0 3 
[St u d y 1 0 3] ) ar e o n g oi n g t o e val uate t he safet y a n d t olera bilit y of E 7 3 8 6 m o n ot hera p y , a n d 
t o deter mi ne t he ma xi m u m t olerate d d ose a n d rec o m me n de d P hase 2 d ose (R P 2 D ) i n 
s u bjects wi t h s pecific ty pes o f a d va nce d s o li d t u m ors.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 9 8 of 2 1 0
5.
F or Mel a n o m a C o h ort o nl y
( P h ase 2 p art), s u bject must ha ve: 
a.
U nresecta ble Sta ge III or Sta ge I V me la n oma, per A merica n J o i nt C o m mittee o n 
Ca ncer ( AJ C C) sta gi n g s yste m versi o n 8, n ot a me na ble t o l ocal t hera p y.
b.
At  least o ne meas ura ble lesi on b y c o m p uter t o m o gra p h y ( C T ) or ma g net ic i ma gi n g 
res o na nce (M RI ) base d o n R E CI S T 1. 1 (c uta ne o us lesi o ns a n d ot her s u perficial 
lesio ns are n ot c o nsi dere d meas ura ble lesi o ns f or t he p ur p oses of t his pr ot oc ol b ut 
ma y be c o nsi dere d as n o ntar get lesi o ns).

Lesi o ns i n a pre vi o usl y irra diate d area s h o ul d n ot be c o nsi dere d meas ura ble 
u nless t here has bee n d oc u me nte d gr o wt h of t he lesio ns si nce t he c o m plet i on of 
r a diot h era p y.
c.
Pr o gresse d o n or after pri or treat me nt wit h o ne a nti- P D -1/ P D -L 1 m A b a d mi nistere d 
eit her as mo n ot hera p y  or i n c o m bi nati on wi t h ot her c hec k p oi nt i n hi bit ors or ot her 
t hera pies.  P D-1 pr o gressi o n is defi ne d as : 

Has recei ve d at least 2 d oses of a n a p pr o ve d a nt i-P D -1/ P D -L 1 m A b ( e g, 
pe m br o liz u ma b, ni v ol u ma b, ni v ol uma b pl us i pili m u ma b) a n d

Has de m o nstrate d disease pr o gressi o n after P D -1/ P D -L 1 as defi ne d b y R E CI S T 
v 1. 1.  Pr o gressi ve disease has bee n d oc u me nte d wit h i n 1 2 wee ks fr o m t he last 
d ose of a nt i-P D -1/ P D -L 1 m A b (refract or y  disease).  T he i nitial e vi de nce of 
di sease pr o gressio n is t o be c o nfir me d b y a sec o n d assess me nt n o less t ha n 4 
wee ks fr o m t he date of t he first d oc u me nte d pr o gressi ve disease, i n t he a bse nc e of 
r a pid cli nical pr o gressi o n.

T his deter mi nat i on is ma d e b y t he i n vesti gat or.  O nce pr o gressi ve disease is 
c o nfir me d, t he i nit ial date of disease pr o gressi o n d oc u me ntati o n will be 
c o nsi dere d t he date of disease pr o gressi o n.
d.
Recei ve d o nl y 1 or, if B R A F m ut atio n p osi ti ve, 2 li nes of t hera p y in t he l ocall y 
a d va nce d or met astatic setti n g prior t o st u d y  e nr o llme nt . N ote: A dj u va nt a nt i-P D -
1/ P D -L 1 m A b / B R A F i n hi bit or treat me nt will be c o u nte d as pri or li ne of treat me nt if 
r ela pse occ urre d d uri n g act i ve treat me nt or wit hi n 1 2 wee ks of treat me nt 
di sc o nti n uati on. 
e.
N o restricti o n wit h re gar ds t o P D -L 1 a n d B R A F stat us
f.
I n case mela n oma is k n o w n t o be B R A F m ut atio n p osi tive , s u bjects m ust ha ve 
pr o gresse d o n o ne pri or B R A F i n hi bit or 
6.
F or C R C C o h ort o nl y ( P h ase 2 p art), s u bjects m ust ha ve recei ve d at least t w o prior 
s yste mic t hera pies fr om t he f o ll owi n g, i n a dj u va nt a n d/ or m etastatic setti n g, if a p pr o ve d 
a n d l ocall y a vaila ble ( n ot e xceedi n g 4 li nes of t hera pies i n t he metastatic setti n g, 
pr o gresse d o n at least 1 pri or re gi me n i n t he metastatic setti n g or c o ul d n ot t olerate 
sta n dar d treat me nt):
N ote: A d j uva nt c he m ot hera p y  c o u nts as prior s y ste mic treat me nt i n t he metastatic setti n g
if t here is d oc u me nte d disease pr o gressi o n wit hi n 6 m o nt hs of treat m e nt c o mplet i on.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 9 9 of 2 1 0
N ote: If a s u bject is deter mi ne d t o be i nt olera nt t o pri or sta n dar d treat me nt, t he s u bject 
m ust ha ve recei ve d at least of 2 c y cles of t hat t hera p y.
a. Fl u or o p y ri mi di ne, irin otec a n a n d o xali plat i n
N ote: Ca pecita bi ne is acce pta ble as e q ui vale nt t o fl u or o p y rimi di ne i n pri or treat me nt.
N ote:
S u bjects w h o ha ve pre vi o usl y recei ve d fl u or o p yri mi di ne, o xali plat i n, a n d 
iri n oteca n as part of t he sa me a n d o nl y c he m ot hera p y re gi me n, e g, fl uor o uracil , 
le uc o v ori n, o xali plati n, a n d iri n oteca n (F O L F O XI RI ) or fl u or o uracil, le uc o v ori n, 
iri n oteca n a n d o xali plati n (F O L FI RI N O X ), ma y be eli gi ble after disc ussi o n with t he 
S p o ns or.
b.
C he m ot h era p y wit h or wit ho ut a n a nti -V E G F m A b (e g, be vaciz u ma b)
c.
C he m ot h er a p y wit h a nti-E G F R m A b (cet u xi ma b or pa nit u m u ma b) f or s u bjects wit h 
R A S ( K R A S/ N R A S) wil d t y pe ( W T) C R C
N ote: R A S ( K R A S/ N R A S) W T s u bjects wit h ri g ht or left C R C lesi o ns w h o ma y 
ha ve n ot bee n treate d wit h a nt i-E G F R m A b base d o n l o c al  g ui deli nes are eli gi ble
d.
B R A F i n hi bit or (i n c o m bi nati on wi t h cet u xi ma b ± bi ni meti ni b) f or B R A F V 6 0 0 E 
m utate d t u m ors.
7.
S u bjects wit h H C C ( P h ase 2 p art) m ust ha ve:
a.
A dia g n osis o f H C C t hat i s hist olo gi call y or c yt olo gi call y c o nfir me d (e xcl u di n g 
fi br olamellar, sarc o mat oi d or mi xe d c h ola n gi o- H C C t u m ors) or cli nicall y c o nfir me d 
acc or di n g t o A merica n Ass ociat i on f or t he St u d y of Li ver Disease crit eria i n cirr h otic 
s u bjects.  S u bjects wit h o ut cirr h osis re q uire hist ol ogi cal c o nfir mat i on of dia g n osis.
b.
Sta ge B ( n ot a me na ble t o l oc ore gi o nal t hera p y or refract or y t o l oc ore gi o nal t hera p y, 
a n d n ot a me na ble t o a c urati ve treat me nt ) or sta ge C base d o n Barcel o na Cli nic Li ver 
Ca ncer ( B C L C) sta gi n g S yste m a n d C hil d -P u g h class A o nl y .
c.
S u bjects m ust ha ve recei ve d o nl y o ne pri or li ne of s yste mic t hera p y  in t he l ocall y  
a d va nce d or metastatic setti n g , a n d m u st ha ve pr o gresse d o n treat me nt wit h a n a nti-
P D -1/ P D -L 1 m A b a d mi nistere d eit her as m o n ot hera p y , or i n c o m bi nati on wi t h ot her 
c hec k p oi nt i n hi bit ors or ot her t hera p ies. N ote:  S u bjects m ust ha ve recei ve d at least 
2 d oses of t he a nt i- P D -1/ P D -L 1 m A b .
8.
F or s u bjects wit h H C C :
a.
I n case of he pat itis B s urface a nti ge n (H Bs A g ) ( +) s u bjects:  A nti viral t hera p y for 
he pat itis B vir us ( H B V) m ust be gi ve n f or at least 3 m o nt hs pr i or t o t he first d ose of 
st u d y dr u g, a n d H B V viral l oa d m ust be less t ha n 1 0 0 I U/ m L pri or t o t he first d ose of 
st u d y dr u g.
◦
S u bjects w h o are H Bs A g ( +) a n d o n acti ve H B V t hera p y wit h viral l oa ds u n der 
1 0 0 I U/ m L s h o ul d sta y  o n t he sa me t hera p y w hile o n st u d y dr u g.
◦
S u bjects wit h o ut H B V pr o p h yla xis w h o are a nti -he pati tis B c ore a nti b o d y 
(H Bc A b ) ( +) a n d/ or a nti- H Bs A b ( +) b ut ne gati ve f or H Bs A g a n d H B V D N A d o 
n ot re q uire pr o p h yla xis.
◦
S u bjects wit h H B V pr o p h yla xis w h o are a nti -H Bc A b ( +) a n d/ or a nti - H Bs A b ( +) 
b ut ne gat i ve f or H Bs A g a n d H B V D N A s h o ul d c o nti n ue t he pr o p h yla xis.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 0 3 of 2 1 0
9.
S u bjects wit h C N S met astases are n ot eli gi ble u nless t he y  are pre vi o usl y  treate d, are 
r a diol o gicall y  sta ble, ie, wit ho ut e vi de nce of pr o gressi o n f or at least 4 wee ks b y re peat 
i ma gi n g ( n ote t hat t he re peat i magi n g s h o ul d be perf or m e d d uri n g st u d y scree ni n g), a n d 
cli nicall y sta ble a n d wit h o ut re q uire me nt of ster oi d treat me nt f or at least 1 4 da y s prior t o 
first d ose of st u d y treat me nt .
1 0. Di a g n ose d me ni n geal carci n omat osis
1 1. Has se vere h y perse nsit i vity ( Gra de ≥3) t o s t u d y dr u gs a n d/ or a n y of its e xci pie nts 
i ncl u di n g pre vi o us cli nicall y-si g nifica nt h yperse nsi tivi t y reacti on t o treat m e nt wit h 
a n ot her m A B .
1 2. Has a n act i ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n t he past 2 years 
(ie, wit h use of disease m o dif yi n g a ge nts, c ortic oster oi ds or i m m u n os u p pressi ve dr u gs).  
Re place me nt t hera p y  ( e g, t h yr o xi ne, i ns uli n, or p h ysi ol ogic c orti c oster oid re pl ace me nt 
t hera p y for a dre nal  or pit uit ar y ins ufficie nc y ) is n ot c o nsidere d a f or m  of s yste mic 
treat me nt a n d is allo we d.
1 3. Has a hist or y  of ( n o n-i nfecti o us) p ne u m onit is t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nit is.
1 4. Act i ve i nfecti o n re q uiri n g s yste mic treat me nt.
1 5. Act i ve viral he pat itis ( B or C) as de m o nstrate d b y p ositi ve ser ol og y f or s u bjects wit h 
mel a n o m a a n d C R C .
F or s u bj ects wit h H C C :  
-
Has d ual act i ve H B V i nfecti o n ( H Bs A g [ +] a n d / or detecta ble H B V D N A) a n d H C V 
i nfecti on (a nt i-H C V A b [ +] a n d detecta ble H C V R N A) at st u d y e ntr y.
1 6. K n o w n t o be h u ma n i m m u n o deficie nc y vir us ( HI V) p ositi ve. ( N ote: the S p o ns or has 
e val uate d w het her t o i ncl u de s u bject wit h HI V.  Gi ve n t hat t his is t he first c o m bi nati on 
st u d y of E 7 3 8 6 wit h pe m br oliz u ma b a n d t hat t he mai n mec ha nis m of acti on of E 7 3 8 6 is 
i m m u n om o d ulati o n o f t he t u m or micr oe n vir o n me nt al o n g wit h t he fact t hat se veral a nt i-
retro vi r al t h er a pies ha ve dr u g -dr u g i nteracti o n wit h c yt oc hr o m e P 4 5 0 3 A 4 (C Y P 3 A )
s u bstrates, t he S p o ns or has deci de d n ot t o i ncl u de t hese s u bjects at t he c urre nt ti me.  
H o we ver, f urt her c o nsi derat i ons will be ma de m o vi n g f or war d base d o n ne w e mer gi n g 
data ). 
1 7. E vi de nce of c urre nt C O VI D -1 9 i nfect i on or o n g oi n g u nrec o vere d se q uelae of C O VI D - 1 9 
i nfecti on.
1 8. Has a hist or y  or c urre nt e vi de nce of a n y c o n ditio n, t hera p y , or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he st u d y, i nterfere wit h t he s u bject's partici pat i on f or 
t he f ull d urat i on of t he st u d y , or is n ot i n t he best i nterest of t he s u bject t o partici pate, i n 
t he o pini o n of t he treati n g i n vest i gat or.
1 9. Has a k n o w n ps yc hiatric or s u bsta nce a b use dis or der t hat w o ul d i nterfere wit h t he 
s u bject’s a bility t o co o perate wi t h t he re q uire me nts of t he st u d y.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 0 6 of 2 1 0
c.
hist or y  of he pat ic e nce p hal o pat h y wit hi n 6 m o nt hs pri or starti n g st u d y dr u g
u nres p o nsi ve t o t hera p y wit hi n 3 da ys. S u bjects o n rifa xi mi n or lact ul ose d uri n g 
scree ni n g t o c o ntr ol t h eir he patic e nce p hal o pat h y are n ot all o we d
3 1. F or s u bjects i n t he tri plet tre at me nt co h orts o nl y :  
a.
P r otei n uria > 1 + o n uri ne di pstic k testi n g will u n der g o 2 4 -h o ur uri ne c ollect i on f or 
q ua nt itati ve assess me nt of pr otei n uria. S u bjects wit h uri ne pr otei n ≥1 g/ 2 4 h o urs will 
be i neli gi ble
b.
Bl ee di n g or t hr o m b otic dis or ders or use of a nt ic oa g ula nts re q uirin g t hera pe ut ic I N R 
m o nit ori n g (e g, warfari n or si milar a ge nts). Treat me nt wit h l o w m o lec ular wei g ht 
he pari n a n d fact or X i n hi bit ors is per mitte d 
c.
Cli nicall y si g nifica nt he m o pt ysis fr o m a n y s o urce or t u m or blee di n g wit hi n 3 wee ks
pri or t o t he first d ose of st u d y  dr u g
d.
P ree xisti n g ≥Gra de 3 gastr oi ntesti nal or n o n -gastr oi ntest i nal fist ula
9. 3. 3
R e m o v al of S u bj e ct s fr o m T h er a p y or A s s e s s m e nt
T he i n vest i gat or ma y with dra w t he s u bject fr o m t he st u d y  at a n y time f or safety or 
a d mi nistrati ve reas o ns.  T he s u bject ma y st o p st u d y dr u g or wit h dra w fr o m  t he st u d y at a n y 
ti me f or a n y reas o n.
S u bjects will c o nt i n ue t o recei ve st u d y dr u g u nt il a n y of t h e fol l owi n g occ ur (s):  

Ra di ol o gi c al Disease P r o gressio n

Cli nical Disease Pr o gressi o n

Treat me nt disc o nt i n ue d d ue t o a d verse e ve nt

S u bject c h o ice t o disc o nt i n ue treat me nt

L ost t o f oll o w - u p

Wit h dra wal o f c o nse nt fr o m t he st u d y

St u d y  Ter mi nate d b y S p o ns or

Ot her
T he i n vesti gat or ma y disc o nti n ue treati n g a s u bject wit h st u d y dr u g or wi t hdra w t he s u bject 
fr om t he st u d y at a n y ti me f or safety or a d mi nistrati ve reas o ns.  T he s u bject ma y deci de t o 
di sc o nti n ue st u d y dr u g or wi t hdra w fr o m  t he st u d y at a n y time f or a n y reas o n.  T he reas o n 
f or disc o nti n uati on will be d oc u me nte d. 
After c o m plet i on of s pecifie d E O T Visit, t he s u bject will e nter t he F o ll ow- U p P hase a nd 
s ur vi val f oll ow- u p u nless t he s u bject wit h dra ws c o nse nt.   T he i n vest i gat or s h o ul d c o nfir m 
w het her a s u bject will wit h dra w fr o m st u d y dr u g b ut a gree t o c o nti n ue pr ot oc ol -s pecified, 
off -tr e at me nt st u d y visits, pr oce d ures, a n d s ur vi val f oll ow- u p, or w het her t he s u bject will 
wi t hdra w c o nse nt.  If a s u bject wit h dra ws c o nse nt, t he date will be d oc u me nt e d i n t he s o urce 
d oc u m e nts.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 0 9 of 2 1 0
T a bl e 5
Tr e at m e nt s A d mi ni st er e d
Dr u g N a me
Stre n gt h
D ose F or m
D ose, Fre q ue nc y, R o ute
D ur ati o n
.
9. 4. 1. 1
Crit eri a f or D o s e M o difi c ati o n
D ose re d ucti o n a n d i nterr u pti o ns f or s u bjects w h o e x perie nce c o m bi nat i on t hera p y -relate d 
t o xicit y will be ma na ge d as descri be d i n Ta bles 6 t o 1 3. I n vesti gat ors will deci de t he 
pr o ba bilit y o f t he e ve nt bei n g relate d t o o ne or m ore dr u gs as t o w het her d ose m o dificat i on of 
o ne or m ore dr u gs i s re q uire d. 
Base d o n t he k n o w n t o xicit y pr ofiles of pe m br o liz u ma b a n d le n vati ni b, certai n treat me nt-
r elate d A E s are u ni q uel y ass o ciat e d wit h 1 dr u g vers us t he ot her. F or e xa m ple, h y perte nsi o n, 
arterial t hr o m b otic e ve nts, pr otei n uria, a n d he m orr ha gic e ve nts are k n o w n ris ks f or le n vat i ni b 
treat me nt, w hile i m m u ne-relate d A Es are ris ks f or pe m br oliz u ma b treat me nt.  N a usea a n d 
v o mit i n g ha ve bee n t he m ost c o m m on treat me nt -relate d t o xicities ass ociate d wit h E 7 3 8 6 t h us 
far. H o we ver, certai n A Es, s uc h as diarr hea, h y p ot h yr o i dis m, a n d li ver e nz y me ele vati on, 
ma y be i nit iall y c o nsi dere d attri b uta ble t o eit her st u d y dr u g. T heref ore, e val uat i on of 
attri b uti o n is i m p orta nt f or deter mi ni n g t he st u d y dr u g most li kel y  relate d t o t he A E, or a n 
alter nati ve eti ol og y , a n d s u bse q ue ntl y pr o per cli nical ma na ge me nt. T he f oll o wi n g as pects 
s h o uld be c o nsi dere d:
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 1 0 of 2 1 0
1.
Ti mi n g of A E o nset
Si nce le n vat i ni b is a d mi nistere d dail y a n d c o nti n u o usl y d ue t o a relati vel y s h ort half-life 
( ~ 2 8 h o urs), E 7 3 8 6 i s a d mi nistere d BI D a n d c o nti n u o usl y als o d ue t o a relati vel y s h ort half -
life ( ~ 5 h o urs), a n d pe m br oliz u ma b is a d mi nistere d Q 3 W d ue t o a l o n g half-life, len vati ni b
a n d E 7 3 8 6 ca n be i nterr u pte d t o assess w het her a n A E i m pr o ves/res o l ves wit h dec halle n ge 
(ie, i nterr u ptio n of  treat me nt) base d o n t he f o ll owi n g 2 sce nari os:

If a n A E is ide ntifie d d uri n g a treat me nt c y cle (ie, bet wee n 2 pe m br oliz u ma b d oses), o nl y 
le n vati ni b a n d/ or E 7 3 8 6 i nterr u pti o n is nee de d

If a n A E is ide ntifie d at t he be gi n ni n g of a treat me nt c y cle, le n vat i ni b a n d/ or E 7 3 8 6 ca n 
be i nterr u pte d a n d d osi n g of pe m br o liz u ma b s h o ul d be hel d
If t he s u bject rec o vers fr o m a n A E i n res p o nse t o le n vati ni b or E 7 3 8 6 i nterr u pti o n (ie, 
p osi tive dec halle n ge), t he e ve nt is m ore li kel y t o be relate d t o le n vat i ni b or E 7 3 8 6 . 
Ot her wi se, after e xcl u di n g ot her alter nat i ve e x pla nati o ns, a n i m m u ne-r elate d A E s h o uld be 
c o nsi dere d.
2.
S e verit y of  A E
If a n A E is s us pecte d t o be treat me nt relate d a n d is se vere/life t hreate ni n g at t he ti me of o nset 
or i s ra pi dl y w orse ne d, actio n i ncl u di n g i nterr u pti n g all dr u gs a n d i nit iati n g treat me nt wit h a 
c ortic oster oid ( wi t h e xce pti on of h y p ot h y r oidis m , T1 D M) a n d ot her s u p p orti ve care s h o ul d 
be ta ke n pr o m pt l y.
I n case of a n y u ncertai nty re gar di n g t he e ve nt or ca usality,  t he i n vestigat ors s h o ul d use 
cli nical j u d ge me nt a n d c o nsi der pr o m pt c o m m u nicati o n wit h a n a gree me nt b y  t he S p o ns or.  
Attri b uti o n of T oxicity 
W he n st u d y  dr u gs are a d mi nistere d i n c o m bi nati on, attri b ut i on of a n A E t o a si n gle 
c o mp o n e nt i s li kel y t o be diffic ult.  T heref ore, w hile t he i n vesti gat or ma y attri b ute a t o xicity 
e ve nt t o t he c o m bi nat i on, or t o E 7 3 8 6 al o ne, or t o pe m br o liz u ma b al o ne f or A Es liste d i n 
Ta ble 9 , int er ve nt i ons m ust be hel d acc or di n g t o t he criteria i n  Ta ble 9.
H ol di n g St u dy I nterve nti o ns 
W he n st u d y  dr u gs are a d mi nistere d i n c o m bi nati on, if t he A E is c o nsi dere d i m m u ne -relate d 
ot her t ha n  Ta ble 9 a n d n ot part of k n o w n refere nce safet y i nf or mati o n of pe m br o liz u ma b 
t he n all st u d y dr u gs s h o uld be hel d acc or di n g t o rec o m me n de d d ose m o dificati o ns. 
I n case of a n y u ncertai nty re gar di n g t he e ve nt or ca usality,  t he i n vestigat ors s h o ul d use 
cli nical j u d ge me nt a n d c o nsi der pr o m pt c o m m u nicati o n wit h a n a gree me nt b y  t he S p o ns or.  

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 4 of 2 1 0
T a bl e 1 2
M a n a g e m e nt of L e n v ati ni b Tr e at m e nt -R el at e d T o xi cit y
Tre at me nt -Rel ate d T o xicit y a, b
M a n a ge me nt
D ose A dj ust me nt
Gr a de 1 or T oler a ble Gr a de 2
C o nti n ue treat me nt
N o c ha n ge
I nt oler a ble Gr a de 2 c, d or Gr a de 3 e,f
1 st occ urre nce
I nterr u pt le n vati ni b u ntil res ol ve d t o 
Gra de 0 – 1 , or t olera ble Gra de 2
O n e -le vel re d ucti o n
2 n d occ urre nce
(sa me t o xicit y or ne w o ne)
I nterr u pt le n vati ni b u ntil res ol ve d t o 
Gra de 0 – 1 , or t olera ble Gra de 2
O n e -le vel re d ucti o n
3r d occ urre nce
(sa me t o xicit y or ne w o ne)
I nterr u pt le n vati ni b u ntil res ol ve d t o 
Gra de 0 – 1 , or t olera ble Gra de 2
O n e -le vel re d ucti o n
4t h occ urre nce
(sa me t o xicit y or ne w o ne)
I nterr u pt le n vati ni b
Disc uss wit h S p o ns or
Gr a de 4 g
Disc o nti n ue le n vati ni bh
B MI = b o d y mass i n de x; 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.
N ote: F or gra di n g see C T C A E versi o n 5. 0.  C ollect all C T C gra des of a d verse e ve nts, decreasi n g a n d i ncreasi n g gra de. 
a: A n i nterr u pti o n of st u d y treat me nt f or m ore t ha n 2 1 da ys will
re q uire S p o ns or’s a p pr o val bef ore treat me nt ca n be 
res u me d. 
b: I nitiate o pti mal me dical ma na ge me nt f or na usea, v o miti n g, h y p ot h yr oi dis m, or diarr hea pri or t o a n y le n vati ni b 
i nterr u pti o n or d ose re d ucti o n. 
c: A p plica ble o nl y t o Gra de 2 t o xicities j u d ge d b y t he s u bject a n d/ or p h ysicia n t o be i nt olera ble.
d: O bese s u bjects wit h wei g ht l oss d o n ot nee d t o ret ur n t o t he baseli ne wei g ht or 1 0 % of baseli ne wei g ht (ie, Gra de 1 
wei g ht l oss).  T hese s u bjects will restart t he st u d y dr u g(s) at a l o wer d ose o nce t heir wei g ht re mai ns sta ble f or at least 
1 wee k a n d t he y reac he d t he n or mal B M I (if t he wei g ht l oss occ urre d b ut it is still a b o ve n or mal B MI, t he y ca n restart 
t he st u d y treat me nt at a l o wer d ose o nce t he wei g ht has bee n sta ble f or at least 1 wee k).  N or mal B MI s h o ul d be use d 
as t he ne w baseli ne f or f urt her d ose re d ucti o ns. 
e: F or as ym pt o matic la b orat or y a b n or malities, s uc h as Gra de ≥3 ele vati o ns of a m ylase a n d li pase t hat are n ot c o nsi dere d 
cli nicall y rele va nt b y t he i n vesti gat or, c o nti n uati o n of treat me nt s h o ul d be disc usse d wit h t he S p o ns or. 
f: F or Gra de 3 t hr o m b oe m b olic e ve nts, per ma ne ntl y disc o nti n ue le n vati ni b.  Refer t o secti o n bel o w o n ma na ge me nt of 
t hr o m b oe m b olic e ve nts.
g: E xcl u di n g la b orat or y a b n or malities j u d ge d t o be n o n -life-t hreate ni n g, i n w hic h case ma na ge as Gra de 3. 
h: If le n vati ni b is disc o nti n ue d d ue t o a n a d ver se e ve nt, t he i n vesti gat or ca n c o nti n ue wit h E 7 3 8 6 a n d p e m br oliz u ma b i n 
t he tri plet treat me nt co h ort s.
M a n a g e m e nt of H y p ert e n si o n
H y perte nsi o n is a rec o g nize d si de effect of treat me nt wit h dr u gs i n hi biti n g V E G F si g nali n g.  
I n vesti gat ors s h o ul d t heref ore e ns ure t hat s u bjects e nr olle d t o recei ve treat me nt wit h 
le n vati ni b ha ve bl o o d press ure ( B P) of ≤1 5 0/ 9 0 m m H g at t he ti me of st u d y  e ntr y a n d, if 
k n o w n t o be h y perte nsi ve, ha ve bee n o n a sta ble d ose of a nt i h y perte nsi ve t hera p y for at l east 
1 wee k bef ore C 1 D 1.  Earl y detecti o n a n d effecti ve ma na ge me nt of h y perte nsi o n are 
i m p orta nt t o mi ni mize t he nee d f or le n vati ni b d ose i nterr u pti o ns a n d re d ucti o ns.
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 5 of 2 1 0
Re g ular assess me nt of B P s h o ul d be as detaile d i n t he Sc he d ule of Pr oce d ures/ Assess me nts
(Ta ble 1 5 , Ta ble 1 6 , a n d Ta ble 1 7 ).  H yperte nsi o n  will be gra de d usi n g C T C A E v 5. 0, base d 
o n B P m eas ure me nts o nl y (a n d n ot o n t he n u m ber of a nt i h y perte nsi ve me dicati ons).
If t he s u bject’s first B P meas ure me nt of t he c urre nt assess me nt is ele vate d (ie, s yst olic B P 
≥1 4 0 m m H g or diast olic B P ≥9 0 m m H g), t he B P meas ure me nt s h o ul d be re peate d at least 
5 mi n utes later.  O ne B P assess me nt is defi ne d as t he mea n val ue of 2 meas ure me nts at least 
5 mi n utes a part.  If t he B P assess me nt ( ie, t he mea n of t he 2 B P meas ure me nts o btai ne d at 
least 5 mi n utes a part) is ele vate d (s yst olic B P ≥1 4 0 m m H g or diast olic B P ≥9 0 m m H g), a 
c o nfir mat or y assess me nt s h o ul d be o btai ne d at least 3 0 mi n utes later b y p erfor m i n g 
2 meas ure me nts (at least 5 mi n utes a part) t o yiel d a mea n val ue. 
A nt i h y perte nsi ve a ge nts s h o ul d be starte d as s o o n as ele vate d B P (s yst olic B P ≥1 4 0 m m H g 
or di ast olic B P ≥9 0 m m H g) is c o nfir me d o n 2 assess me nts at least 3 0 mi n utes a part.  T he 
c h o ice of a nt i h y perte nsi ve treat me nt s h o ul d be i n di vi d ualize d t o t he s u bject’s cli nical 
circ u msta nces a n d f oll o w sta n dar d me dical practice.  For pre vi o usl y  nor m ote nsi ve s u bjects, 
a p pr o priate a nti h y perte nsi ve t hera p y s h o ul d be starte d w he n s yst olic B P ≥1 4 0 m m H g or 
di ast olic B P ≥9 0 m m H g is first o bser ve d o n 2 assess me nts at least 3 0 mi n utes a part.  F or 
t hose s u bjects alrea d y  o n a nti h y perte nsi ve me dicati o n, treat me nt m o dificati on ma y be 
necessar y  if h y perte nsi o n persists.  
Le n vat i ni b s h o uld be wi t h hel d i n a n y insta nce w here a s u bject is at i m mi ne nt ris k t o de vel o p 
a h y perte nsi ve crisis or has u nc o ntr olle d h y perte nsi o n (e g, B P ≥1 6 0/ 1 0 0 m m H g) wit h 
sig nifica nt ris k fact ors f or se vere c o m plicati o ns, si g nifica nt ris k fact ors f or car diac disease, 
i ntracere bral he morr ha ge, or ot her si g nifica nt c o -m o r bidi ties.   O nce t he s u bject has bee n o n 
t he sa me a nt i h y perte nsi ve me dicati ons f or at least 4 8 h o urs a n d t he B P is c o ntr olle d, 
le n vati ni b s h o uld be res u me d as descri be d bel o w.
S u bjects w h o ha ve ha d s yst olic B P ≥1 6 0 m m H g or diast olic B P ≥1 0 0 m m H g m ust ha ve 
t heir B P m o nit ore d o n Da y  1 5 ( or mor e f re q ue ntl y as cli nicall y i n dicate d) u ntil s yst olic B P 
has bee n ≤1 5 0 m m H g a n d diast olic B P has bee n ≤9 5 m m H g f or 2 c o nsec uti ve treat me nt 
c ycles.  If a re peat e ve nt of s yst olic B P ≥1 6 0 m m H g or diast olic B P ≥1 0 0 m m H g occ urs, t he 
s u bject m ust res u me t he Da y 1 5 e val uati on u nt il s yst olic B P has bee n ≤1 5 0 m m H g a n d 
di ast olic B P has bee n ≤9 5 m m H g f or 2 c o nsec uti ve treat me nt c y cles.  A diar y ma y be 
pr o vi de d t o t he s u bject t o ca pt ure t he bl o o d press ure e val uat i ons bet wee n st u d y  visits.
T he f o ll owi n g g ui deli nes s h o ul d b e f ol l owe d f or t he m a na ge me nt of s yst olic B P ≥1 6 0 m m 
H g or di ast olic B P ≥1 0 0 m m H g c o nfir me d o n 2 B P assess me nts at least 3 0 mi n utes a part:
1.
C o nti n ue st u d y  dr u g a n d i nstitut e a nti h y perte nsi ve t hera p y for s u bjects n ot alr ea d y 
recei vi n g t his.
2.
F or t h ose partici pa nts alrea d y  o n a nti h y perte nsi ve me dicati on, t he d ose of t he c urre nt 
a ge nt ma y be i ncrease d, if a p pr o priate, or 1 or m ore a ge nts of a differe nt class of 
a nt i h y perte nsi ve s h o ul d be a d de d. St u d y treat me nt ca n be c o nti n ue d wit ho ut d ose 
m o dificati o n.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 6 of 2 1 0
3.
If s yst olic B P ≥1 6 0 m m H g or di ast olic B P ≥1 0 0 m m H g persists des pite ma xi mal 
a nt i h y perte nsi ve t hera p y, t he n le n vati ni b a d mi nistrati o n s h o ul d be i nterr u pte d a n d 
restarte d at 1 d ose le vel re d ucti on o nl y  w he n s yst olic B P ≤1 5 0 m m H g a n d diast olic B P 
≤9 5 m m H g a n d t he partici pa nt has bee n o n a sta ble d ose of a nt i h y perte nsi ve me dicati on 
f or at least 4 8 h o urs.
-
If s yst olic B P ≥1 6 0 m m H g or di ast olic B P ≥1 0 0 m m H g rec urs o n t he first d ose 
re d uctio n des pi te o pti mal ma na ge me nt of h y perte nsi o n with a nt i h y perte nsi ve 
me dicat i ons (ei t her b y d ose i ncrease or t he a d ditio n of  a differe nt class of 
a nt i h y perte nsi ve), t he n len vat i ni b a d mi nistrati o n s h o ul d be i nterr u pte d a n d restarte d 
at a n a d dit i onal d ose re d ucti o n o nl y w he n s yst olic B P ≤1 5 0 m m H g a n d diast olic 
B P ≤9 5 m m H g a n d t he s u bject has bee n o n a sta ble d ose of a nt i h y perte nsi ve 
me dicat i on f or at least 4 8 h o urs 
-
If s yst olic B P ≥1 6 0 m m H g or di ast olic B P ≥1 0 0 m m H g rec urs o n t he sec o n d d ose 
re d uctio n des pi te o pti mal ma na ge me nt of h y perte nsi o n with a nt i h y perte nsi ve 
me dicat i ons (ei t her b y d ose i ncrease or t he a d ditio n of  a differe nt class of 
a nt i h y perte nsi ve), t he n le n vat i ni b a d mi nistrati o n s h o ul d be i nterr u pte d a n d restarte d 
at a t hir d d ose re d uctio n o nl y w he n s yst olic B P ≤1 5 0 m m H g a n d diast olic B P ≤9 5 
m m H g a n d t he s u bject has bee n o n a sta ble d ose of a nt i h y perte nsi ve me dicati on f or 
at least 4 8 h o urs
-
A d dit i onal d ose re d ucti o n s h o ul d be disc usse d wit h t he S p o ns or
T he f o ll owi n g g ui deli nes s h o ul d b e f ol l owe d f or t he m a na ge me nt of Gra de 4 h yperte nsi o n 
(life t hreate ni n g c o nse q ue nces):
1.
I nstitute a p pr o priate me dical ma na ge me nt.
2.
Di sc o nti n ue st u d y dr u g.
M a n a g e m e nt of Pr ot e i n uri a
Re g ular assess me nt of pr otei n uria s h o ul d be c o n d ucte d as detaile d i n t he Sc he d ule of 
Pr oce d ures/ Assess me nts (Ta ble 1 5 , Ta ble 1 6 , a n d Ta ble 1 7 ).  G ui deli nes f or assess me nt a n d 
ma na ge me nt of pr otei n uria are as f o ll ows:
D et e cti o n a n d C o nf ir m ati o n
1.
Perf or m  uri ne dipsti c k testi n g or uri nal ysis per t he Sc he d ule of Pr oce d ure/ Assess me nts .  
Uri ne di pstic k testi n g is t he preferre d met h o d f or testi n g f or uri nar y pr otei n, h o we ver, 
uri nal ysis ma y be use d if t he use of uri ne di pst ic ks is n ot feasi ble.
2.
A 2 4 -h o ur uri ne c o llecti on i nitiate d as s o o n as p ossi ble a n d at least wit hi n 7 2 h o urs ( or a n 
i m me diate s p ot U P C R test) is re q uire d i n t he f oll owi n g sit uat i ons:
-
T he first (i nit ial) occ urre nce of 
 pr otei n uria o n uri ne dipsti c k ( or 
uri nal ys is) w hile t he s u bject is recei vi n g le n vati ni b
-
A s u bse q ue nt i ncrease i n se verit y of  uri ne di pstic k or uri nal ysis pr otei n uria 
occ urri n g o n t he sa me le n vati ni b d ose le vel
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 7 of 2 1 0
-
W he n t here has bee n a le n vat i ni b d ose re d ucti o n a n d at t he ne w d ose le vel t he uri ne 
pr otei n di pst ic k res ult is 
3.
A 2 4 -h o ur uri ne c o llecti on (i nit iate d as s o o n as p ossi ble a n d at least wit hi n 7 2 h o urs) t o 
verif y t he gra de of pr otei n uria is re q uire d w he n U P C R is ≥2. 4 .
Gr a di n g of Pr ot ei n uri a
Gra di n g acc or di n g t o N CI C T C A E v 5. 0 will be base d o n t he 2 4 -h o ur uri nar y pr otei n res ult if 
o ne has bee n o btai ne d.  If t he s u bject has 4 + pr otei n uria b y di pst ic k (≥1 0 0 0 m g/ d L b y  
uri nal ysis), a 2 4 -h o ur uri nar y pr otei n res ult is re q uire d t o c o nfir m Gra de 3 pr otei n uria.  
Ma na ge me nt of le n vat i ni b a d mi nistrati o n will be base d o n t he gra de of pr otei n uria acc or di n g 
t o Ta ble 1 2 .
M o nit ori n g
Uri ne di pstic k or uri nal ysis testi n g f or s u bjects wit h pr otei n uria 
 s h o uld be 
perf or m e d o n Da y 1 5 ( or mor e f re q ue ntl y as cli nicall y in dicate d) u ntil  t he res ults ha ve bee n 
1 + ( 3 0 m g/ d L) or ne gat i ve f or 2 c o nsec uti ve treat me nt c ycles.  
Pr ote i n uria m onit ori n g ca n be perf or me d at t he l ocal la b orat or y  or i n vesti gat or site b ut m ust 
be ma na ge d b y  t he site p h ysicia n.
I n t he e ve nt of ne p hr otic s y n dr ome, len vat i ni b m ust be di sc o nti n ue d.
M a n a g e m e nt of Di arr h e a
A n a nt i-di arr heal a ge nt s h o uld be rec o m me n de d t o t he s u bject at t he start of st u d y treat me nt, 
a n d s u bjects s h o ul d be i nstr ucte d a n d e d ucate d t o i nit iate a nti-diarr heal  tr e at me nt at t he first 
o nset of s oft b o wel m o ve me nts.  T he c h o ice of a nti-diarr heal a ge nt s h o ul d be i n di vi d ualize d 
t o t he s u bject’s cli nical circ u msta nces a n d f oll ow sta n dar d m e dical practice.  If 
sig ns/s y m pt o m s of diarr hea persist des pite o pti mal me dical ma na ge me nt, i nstr ucti o ns 
c o ntai ne d i n  Ta ble 1 2 s h o uld b e f ol l owe d.
M a n a g e m e nt of H e p at ot o xi cit y
Li ver f u ncti o n tests (ala ni ne tra nsa mi nase [ A L T], as partate tra nsa mi nase [ A S T], bilir u bi n 
le vels) s h o ul d be c o n d ucte d as detaile d i n t he Sc he d ul e of Pr oce d ure/ Assess me nts a n d as 
cli nicall y i n dicate d. If si g ns/s y m pt o ms i n dicati n g li ver i nj ur y occ ur, i nstr ucti o ns c o ntai ne d 
i n Ta ble 1 2 s h o uld be f o ll owe d.  A p pr o pri ate s u p p ortive care s h o ul d be pr o vi de d t o get her 
wi t h clos e m o ni t orin g.  If he pat ic fail ure (a n y gra de per C T C A E v 5. 0) occ urs, le n vati ni b 
m ust be disc o nt i n ue d.
M a n a g e m e nt of T hr o m b o e m b oli c E v e nt s
S u bjects s h o ul d be a d vise d t o pa y  atte ntio n t o s y m pt o m s s u g gesti ve of ve n o us 
t hr o mb oe m b o lic e ve nts w hic h i ncl u de ac ute o nset of s h ort ness of breat h, d ys p nea, c hest pai n, 
c o u g h, he m o pt ysis, tac h yp nea, tac h ycar dia, c y a n osis, D V T sig ns i ncl u di n g l ower e xtre mit y
s welli n g, a n d war mt h t o t o uc h or te n der ness.  I n case a n y of t hese s y m pt o ms a p pear, s u bjects 
s h o uld be i nstr uc te d t o re p ort s uc h s y m pt o ms pr o m ptl y t o t he treati n g p h ysicia n.  If a 
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 8 of 2 1 0
t hr o mb oe m b o lic e ve nt is c o nfir me d, i nstr ucti o ns c o ntai ne d i n Ta ble 1 2 s h o uld be f ol l owe d.  
A p pr o p riate s u p p orti ve care s h o ul d be pr o vi de d t o get her wit h cl ose m o nit ori n g.  If a s u bject 
e x perie nces a Gra de 3 or a life t hreate ni n g ( Gra de 4) t hr o m b oe m b o lic reacti o n, i ncl u di n g 
p ul m o nar y  e m b olis m, le n vati ni b m ust be disc o nti n ue d.
Arterial t hr o m b oe m b o lic e vent s (e g, ne w o nset, w orse ni n g, or u nsta ble a n gi na, m y ocar dial 
i nfarcti o n, tra nsie nt isc he mic attac k, a n d cere br o vasc ular acci de nt) of a n y gra de re q uire st u d y 
treat me nt disc o nt i n uati on. 
M a n a g e m e nt of P o st eri or R e v er si bl e E n c e p h al o p at h y S y n dr o m e/ R e v er si bl e 
E n c e p h al o p at h y S y n dr o m e/ R e v er si bl e P o st eri or L e u k o e n c e p h al o p at h y S y n dr o m e
P os t erior Re versi ble E nce p hal o pat h y S y n dr o me/ Re versi ble E nce p hal o pat h y  S y n dr o me/ 
Re versi ble P osteri or Le u k oe nce p hal o pat h y S y n dr o me ( P R E S/ R P L S) is a ne ur ol o gical 
di s or der t hat ca n prese nt wit h hea dac he, seiz ure, let har g y, c o nfusi o n , altere d me nt al fu ncti o n, 
bli n d ness, a n d ot her vis ual or ne ur ol o gical dist ur ba nces.  Mil d t o se vere h y perte nsi o n ma y be 
prese nt.  Ma g netic res o na nce i ma gi n g ( M RI) is necessar y t o c o nfir m t he dia g n osis of 
P R E S/ R P L S.  A p pr o priate meas ures s h o ul d be ta ke n t o c o ntr ol B P.  I n s u bjects wit h si g ns or 
s y m pt o ms of P R E S/ R P L S, i nstr ucti o ns i n Ta ble 1 2 s h o uld be f ol l owe d.
M a n a g e m e nt of H y p o c al c e mi a
S er u m  c alci u m s h o uld b e m o ni t ore d per t he Sc he d ule of Pr oce d ures/ Assess me nts (Ta ble 1 5,
Ta ble 1 6 , a n d Ta ble 1 7 ).  C orrecte d ser u m calci u m s h o ul d be use d t o assess t he gra de of 
h y p ocalce mia per C T C A E v 5. 0, usi n g t he f o ll owi n g f or m ula: 
C orrecte d calci u m = ([ 4 – ser u m al b u mi n i n g/ d L] × 0. 8 + ser u m calci u m)
T he f or m ula is n ot a p plica ble w he n ser u m al b u mi n c o nce ntrati o n i s n or mal (˃ 4 g/ d L); i n 
s uc h sit uati o ns, t he t otal ( u nc orrecte d) ser u m calci u m s h o ul d be use d i nstea d. 
H y p ocalce mia s h o ul d be treate d per i nst itut i onal g ui deli nes (e g, usi n g a p pr o priate calci u m, 
ma g nesi u m, a n d Vita mi n D s u p ple me ntati o n) u n til res oluti o n.
M a n a g e m e nt of H e m orr h a g e
I nstr uctio ns i n  Ta ble 1 2 s h o uld b e f ol l owe d f or t he ma na ge me nt of he m orr ha ge.  Eit her 
res u me at a re d uce d d ose or disc o nti n ue len vat i ni b de pe n di n g o n t he se verity a n d persiste nce 
of  he m orr ha ge.
M a n a g e m e nt of G a str oi nt e sti n al P erf or ati o n or Fi st ul a F or m ati o n
Le n vat i ni b s h o uld be disc o nt i n ue d i n a n y s u bjects w h o de vel o p gastr oi ntesti nal perf orati o n 
of  a n y gra de or Gra de 4 fist ula.
M a n a g e m e nt of Q T Pr ol o n g ati o n
Le n vat i ni b s h o uld be wi t h hel d i n t he e ve nt of de vel o p me nt of Q T i nter val pr ol o n gati o n 
greater t ha n 5 0 0 msec.  Le n vat i ni b s h o ul d be res u me d at a re d uce d d ose w he n Q Tc 
pr ol o n gati o n is res ol ve d t o < 4 8 0 m sec or t o baseli ne val ue. M o ni t or p otassiu m , calci u m a n d 
ma g nesi u m, a n d re ple nis h as a p pr o priate.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 2 9 of 2 1 0
M a n a g e m e nt of O st e o n e cr o si s of t h e J a w
Perf or m  a n oral e xa mi nati on pri or t o treat m e nt wit h le n vat i ni b a n d peri o dicall y d uri n g 
le n vati ni b tr e at me nt.  A d vise s u bjects re gar di n g g o o d oral h y gie ne practices.  A v oi d i n vasi ve 
de ntal  pr oce d ures, if p ossi ble, w hile o n le n vati ni b treat me nt, partic ularl y i n s u bjects at hi g her 
ris k.  F or s u bjects re q uiri n g i n vasi ve de ntal pr oce d ures, disc o nt i n uati on of  bis p h os p h o nate 
treat me nt ma y re d uce t he ris k of oste o necr osis of t he ja w ( O NJ).  Wit h h ol d le n vat i ni b if O NJ 
de vel o ps a n d restart base d o n cli nical j u d ge me nt of a de q uate res ol uti o n.
9. 4. 2
I d e ntit y of I n v e sti g ati o n al Pr o d u ct s
E 7 3 8 6 i s s u p plie d as ta blets i n stre n gt hs of  
 a n d  
.  E 7 3 8 6 will be a d mi nistere d 
orall y   
 c o nti n u o usl y i n 
.  T he ta blets s h o ul d be ta ke n wit h water e ver y 
1 2 h o urs at t he sa me ti mes of t he da y  wit ho ut re gar d t o f o o d i nta ke.  E 7 3 8 6 wi ll be 
a d mi nistere d a p pr o xi matel y 3 0- 6 0 mi n utes p ost a d mi nistrati o n of  pe m br oliz u ma b o n Da y 1 
of  t he c ycle. 
N ote: if t he s u bject v omit s after E 7 3 8 6 a d mi nistrati o n, t his will be re gar de d as c o m pleti on of 
a d mi nistrati o n, a n d E 7 3 8 6 s h o ul d n ot be re -a d mi nist ere d.
Pe m br oliz u ma b will be pr o vi de d as a sterile, preser vat i ve-free, clear t o sli g ht l y o palesce nt, 
c olorl ess t o sli g ht l y yell o w s o l uti on t hat re q uires dil ut i on f or I V i nf usi on. Eac h vial c o ntai ns 
1 0 0 m g of  pe m br oliz u ma b i n 4 m L of s ol uti on. Eac h 1 m L of s ol uti on c o ntai ns 2 5 m g of 
pe m br o liz u ma b. 
Le n vat i ni b is s u p plie d as ca ps ules i n stre n gt hs of 1 m g a n d 4 m g.  Le n vat i ni b will be 
a d mi nistere d orall y Q D c o nti n u o usl y i n 
.  Le n vati ni b ca ps ules ma y be ta ke n 
wi t h or wit ho ut f o o d .
9. 4. 2. 1  
C h e mi c al N a m e of E 7 3 8 6
Test dr u g c o de:  E 7 3 8 6
Ge neric na me:  N ot a p plica ble
C he mical na me:
( 6S , 9aS)- N- Be nz yl - 8-( { 6-[ 3-( 4-et h yl pi perazi n -1- yl)azet i di n-1 -yl] p y ridi n - 2-
yl } met h yl) - 6-( 2-fl u or o-4- h y dr o x y be nz yl) -4, 7 -di o x o - 2-( pr o p- 2-e n- 1-yl) he xa h y dr o -2 H-
p y razi n o[ 2, 1- c][ 1, 2, 4]triazi ne-1( 6 H)- car b o xa mi de
M olec ular f or m ula: 
C 3 9H 4 8F N 9O 4
M olec ular wei g ht:
7 2 5. 8 7 (free f or m)
9. 4. 2. 2
I nf or m ati o n o n P e m br oli z u m a b
Pe m br oliz u ma b is a h u ma nize d m A b t hat bloc ks t he i nteracti o n bet wee n P D -1 a n d i ts 
li ga n ds, P D-L 1 a n d P D -L 2.  Pe m br o liz u mab is a n I g G 4 ka p pa i m m u n o gl o b uli n with a n 
a p pr o xi mate m o lec ular weig ht of 1 4 9 k Da.
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 3 6 of 2 1 0

Wr itte n pr o of of a p pr o val of t he pr ot oc ol, t he I C Fs, a n d a n y ot her i nf or mati on pr o vi de d 
t o t he s u bjects b y t he I R B/I E C f or t he i nstit uti o n w here t he st u d y is t o be c o n d ucte d

A c o p y  of t he I R B/I E C-a p pr o ve d I C F a n d a n y ot her d oc u me ntati o n pr o vi de d t o t he 
s u bjects t o be use d i n t his st u d y

T he I R B/I E C me m bers hi p list a n d stat utes or Healt h a n d H u ma n Ser vices Ass ura nce 
n u m ber

A c o p y  of t he certificati o n a n d a ta ble of  t he n or mal la b orat or y ra n ges f or t he refere nce 
la b orat or y c o n d ucti n g t he cli nical la b orat or y tests re q uire d b y t his pr ot oc ol

A n i n vesti gat or-sig ne d a n d date d F or m  F o o d a n d Dr u g A d mi nistrati o n ( F D A) 1 5 7 2 , or a 
c o mplete d I n vest i gat or a n d Site I nf or mat i on F or m

Fi na ncial Discl o s ure f or m(s) for t he pri nci pal i n vesti gat or (PI) a n d all s u bi n vest i gat ors 
liste d o n F or m  F D A 1 5 7 2 or I n vesti gat or a n d Site I nf or mat i on F or m

A si g ne d a n d date d c urric ul u m vitae (C V) of t he PI i ncl u di n g a c o p y  of t he PI’s c urre nt 
m e dical lice nse (re q uire d i n t he U S) or m e dical re gistr atio n n u m ber o n t he C V

A si g ne d a n d date d cli nical st u dies a gree me nt

A c o p y  of t he re g ulat or y a ut h orit y a p pr o val for t he c o u ntr y  in w hic h t he st u d y  is bei n g 
c o n d ucte d (if re q uire d), a n d t he I m p ort Lice nse (if re q uire d)
T he i n vest i gat or a n d t he st u d y staff (or if re gi o nall y  re q uire d, t he hea d of t he me dical 
i nstituti o n or t he desi g nate d p har macist) will be res p o nsi ble f or t he acc o u nta bilit y of  all st u d y 
dr u gs /st u d y s u p plies (di s pe nsi n g, i n ve nt or y, a n d recor d kee pi n g) f o ll owi n g t he S p o ns or ’s 
i nstr uctio ns a n d a d here nce t o G C P g ui deli nes, as well as l ocal or re gi o nal re q uire me nts.   
U n der n o circ u msta nces will t he i n vest i gat or all o w t he st u d y dr u gs/st u d y s u p plies t o be use d 
ot her t ha n as directe d b y  t his pr oto c ol .  St u d y dr u gs/st u d y s u p plies will n ot be di s pe nse d t o 
a n y i n di vi d ual w h o is n ot e nr olle d i n t he st u d y.  
T he site m ust mai ntai n a n acc urate a n d ti mel y rec or d of t he f oll o wi n g:  recei pt of all st u d y  
dr u gs, dis pe nsi n g of st u d y  dr u gs t o t he s u bject, c ollect i on a n d rec o nciliat i on of u n use d st u d y  
dr u gs t hat are eit her ret ur ne d b y t he s u bjects or s hi p pe d t o site b ut n ot dis pe nse d t o s u bjects, 
a n d ret ur n of rec o ncile d st u d y dr u gs t o t he S p o ns or or (w here a p plica ble) destr ucti o n of 
rec o ncile d st u d y dr u gs at t he site.  T his i nclu des, b ut m a y n ot be li mite d t o:  
(a) d oc u me ntati o n of recei pt of st u d y  dr u gs, (b) st u d y dr u gs dis pe nsi n g/ret ur n rec o nciliat i on 
l og, (c) st u d y dr u gs acc o u nta bility l og, (d) all s hi p pi n g ser vice recei pts, (e) d oc u me ntati o n of 
ret ur ns t o t he S p o ns or , a n d (f) certificates of destr ucti o n f or a n y destr ucti o n of st u d y dr u gs
that occ urs at t he site .  All f or ms will be pr o vi de d b y t he S p o ns or .  A n y c o mpara ble f or m s 
t hat t he site wis hes t o use m ust be a p pr o ve d b y t he S p o ns or .   
T he st u d y  dr u gs a n d i n ve nt or y rec or ds must be ma de a vaila ble, u p o n re q uest, f or i ns pect i on 
b y a desi g nate d re prese ntati ve of t he S p o ns or or a re prese ntati ve of a healt h a ut h orit y (e g, 
F D A, M H R A) .  As a p plica ble, all u n use d st u d y dr u gs a n d e m pty a n d partiall y e m pty 
c o ntai ners fr o m use d st u d y  dr u gs are t o be ret ur ne d t o t he i n vesti gat or (or if re gi o nall y 
re q uire d, t he hea d of t he me dical i nst ituti o n or t he desi g nate d p har macist) b y t he s u bject a n d ,
t o get her wit h u n use d st u d y dr u gs t hat were s hi p pe d t o t he site b ut n ot dis pe nse d t o s u bjects,

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 3 7 of 2 1 0
are t o be ret ur ne d t o t he S p o ns or ’s desi g nate d ce ntral or l ocal de p ot(s) d uri n g t he st u d y or at 
t he c o nclusi o n  of t he st u d y, u nless pr o visio n  is ma de b y t he S p o ns or f or destr ucti o n of st u d y 
dr u gs a n d c o ntai ners at t he site.   Destr ucti o n at t he site will o nl y occ ur u n der circ u msta nces 
w here re g ulati o n or s u p pl y t y pe pr o hi bits t he ret ur n of st u d y dr u gs t o t he ce ntral or l ocal 
de p ot (s).  A p pr o val f or destr ucti o n t o occ ur at t he site m ust be pr o vi de d b y t he S p o ns or i n 
a d va nce.  U p o n c o m plet i on of dr u g acc o u nta bilit y a n d rec o nciliat i on pr oce d ures b y  t he site’s 
pers o n nel a n d d oc u me ntati o n pr oce d ures b y  t he S p o ns or ’s pers o n nel, st u d y dr u gs t hat are t o 
be ret ur ne d t o t he S p o ns or ’s desi g nate d ce ntral or l ocal de p ot(s) must be b o xe d , seale d, a n d 
s hi p pe d bac k t o t he ce ntral or l ocal de p ot(s) f oll owi n g all l o c al  re g ulat or y re q uire me nts.  I n 
s o me re gio ns, st u d y  dr u gs ma y be re mo v e d fr o m t he site a n d ha n d deli vere d t o t he ce ntral or 
l ocal de p ot b y S p o ns or re prese ntati ves.  W here st u d y dr u gs are a p pr o ve d f or destr ucti o n at 
t he site, destr uctio n will occ ur f oll o wi n g t he site’s sta n dar d pr oce d ures a n d certificates of 
destr ucti o n will be pr o vi de d t o t he S p o ns or .
Dr u g acc o u nta bilit y will  be re vie we d d uri n g site visits a n d at t he c o m plet i on of t he st u d y.
9. 5
St u d y A s s e s s m e nt s
9. 5. 1
A s s e s s m e nt s
9. 5. 1. 1
S cr e e ni n g a n d B a s eli n e A s s e s s m e nt s
Scree ni n g a n d b aseli ne assess me nts will be perf or me d as desi g nate d i n t he Sc he d ule of
Pr oce d ures/ Assess me nts (Ta ble 1 5 , Ta ble 1 6 , a n d Ta ble 1 7 ).  T he res ults of all scree ni n g 
assess me nt a n d e val uat i ons m u st be c o mplete d a n d re vi e we d b y t he i n vest i gat or pri or t o t he 
Baseli ne Visit.
9. 5. 1. 1. 1
D E M O G R A P H Y 
S u bject de m o gra p h y  inf or mat i on will be c ollecte d at t he Scree ni n g Visit.  De m o gra p h y 
i nf or matio n i ncl u des a ge, se x, race/et h nicit y . Baseli ne c haracterist ics will incl u de E C O G P S
(A p pe n di x 2 ), N Y H A car diac disease classificat i on ( A p pe n di x 5 ), t u mor sta gi n g s uc h as 
T N M (A p pe n di x 8 ). F or s u bjects wit h H C C, B C L C sta gi n g (A p pe n di x 6 ), macr osc o pic 
i n vasi o n, e xtrahe patic s prea d, a n d C hil d P u g h sc ore (A p pe n di x 4 ) will als o be i ncl u de d.
9. 5. 1. 1. 2
M E DI C A L H I S T O R Y
Me dical a n d s ur gical hist or y  a n d c urre nt me dical c o n ditio ns will be rec or de d at t he Scree ni n g 
Vi sit.  All me dical a n d s ur gical hist or y  c o nsi dere d b y t he i n vestigat ors t o affect t he efficac y, 
safety,  a n d P K e val uati ons a n d all c urre nt a n d cli nicall y si g nifica nt me dical c o n dit i ons 
c o nfir me d at t he Scree ni n g a n d Baseli ne Visit m ust be rec or de d o n t he case re p ort f or m 
(C R F ).  
9. 5. 1. 1. 3
P RI O R C A N C E R H I S T O R Y
D uri n g Scree ni n g, t he f oll owi n g c haracteristics will i ncl u de t he detaile d me d ical hist or y  of  
s u bjects wit h carci n o ma i ncl u di n g, b ut i s n ot li mite d t o:

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 3 8 of 2 1 0

Pat h ol o g y

Date of i nitial dia g n osis a n d m et h o d of dia g n osis [ hist olo g y / c yt olo g y ]

T N M sta gi n g classificat i on b y AJ C C sta gi n g s yste m versi o n 8

S pecif y  w het her disease is locall y a d va nce d or metastatic, a n d if metastatic, t o w hic h 
or ga ns

A n y s ur gical pr oce d ures

Ra di ot h era p y

Pri or a nt ica ncer t hera p y

Pri or treat m e nts a d mi nistere d (i ncl u di n g dates a n d m o dalit y)

K n o w n g e ne alt er atio n a n d mut ati o n stat us

Arc hi val t u m or tiss ue sa m ple m ust be ac q uire d pri or t o fi rst d ose.  If arc hi val t u m or 
tiss ue sa m ple is n ot a vaila ble, please c o ns ult S p o ns or
S u bjects wit h me la n oma o nl y:

B R A F m ut ati o n stat us
S u bjects wit h C R C o nl y :

Pri mar y site of disease

Hi st or y of L y nc h s y n dr o me

K R A S m utati o n stat us

B R A F m ut ati o n stat us

M SI/ M M R m utati o n stat us
S u bjects wi t h H C C o nl y :

Ca use of H C C ( he pat itis B, he pat itis C, al c o h o l, n o n-alc o h o lic steat o he patitis (N A S H ), 
ot her, u n k n o w n)

Macr o vasc ular i n vasi o n i ncl u di n g p ortal vei n i n vasi o n

E xt ra he patic s prea d 

B C L C sta gi n g 

A F P (alp ha- fet o pr otei n)
9. 5. 1. 2
Effi c a c y A s s e s s m e nt s
T u m or assess me nts will be perf or me d b y i n vest i gat ors base d o n R E CI S T 1. 1.  T u m or 
assess me nt will be perf or me d b y C T/ M RI e ver y 6 wee ks ( ±1 wee k c o u nti n g fr o m C 1 D 1) 
u nt il Wee k 2 4, t he n e ver y  9 wee ks ( ± 1 wee k) , at t he E O T visit , a n d if cli nicall y i n dicate d.  
I n vesti gat or-deter mi ne d res p o nse assess me nts will be perf or me d at eac h assess me nt ti me 
p oi nt.  C o pi es of all t u m or assess me nt sca ns will be se nt t o a n I ma gi n g C ore La b (I C L) 
desi g nate d b y  t he S p o ns or f or arc hi val a n d p ote ntial bli n de d i n de pe n de nt ce ntral re vie w 
(BI C R ) assess me nt.  After t he pri mar y a nal ysis, t he S p o ns or ma y disc o nt i n ue re q uirin g 
c o pies of t u mor assess me nt sca ns t o be se nt t o t he I C L.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 4 3 of 2 1 0
r elat i ons h i p wit h t he me dici nal pr o d uct.  F or t his st u d y, t he st u d y dr u gs are E 7 3 8 6 a n d 
pe m br o liz u ma b. 
T he cri t eria for i de nt if yi n g A Es i n t his st u d y are:

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 y m pt o m, or disease te mp orall y  ass ociate d wit h t he use of a n i n vesti gati onal pr o d uct , 
w het her or n ot c o nsi dere d relate d t o t he i n vesti gati o nal pr o d uct (N ote:  E ver y  si g n or 
s y m pt o m s h o uld n ot be liste d as a se para te A E if t he a p plica ble disease [ dia g n osis] is 
bei n g re p orte d as a n A E)

A n y ne w disease or e xacer bat i on of a n e xisti n g disease . H o we ver, w orse ni n g of t he 
pri mar y  disease s h o uld ge nerall y be ca pt ure d u n der efficac y assess me nts a n d n ot as a n 
A E (see  Secti o n 9. 5. 1. 4. 2 ).

A n y deteri orati o n i n n o n pr ot oc ol -re q uir e d meas ure me nts of a la b orat or y val ue or ot her 
cli nical test (e g, E C G or x-ra y) t hat res ults i n sy m pt o m s, a c ha n ge i n treat me nt, or 
di sc o nti n uati on of st u d y  dr u g

Rec urre nce of a n i nter mitte nt me dical c o n dit i on ( e g, hea dac he) n ot prese nt pretreat me nt 
(Baseli ne)

A n a b n or mal la b orat or y  test res ult s h o uld be c o nsi dere d a n A E if t he i de nt ifie d la b orat or y 
ab n or m alit y lea ds t o a n y t yp e of  int er ve nt i on , wit hdra wal  of st u d y dr u g, or wit h h oldi n g 
of  st u d y dr u g, w het her prescri be d i n t he pr ot oc ol or n ot
All A Es, re gar dless of relati o ns hi p t o st u d y  dr u g or pr oce d ure, s h o ul d be rec or de d be gi n ni n g 
fr om t he ti me t he s u bject si g ns t he st u d y I C F t hr o u g h t he last visit a n d f or 3 0 da y s after t he 
s u bject’s last d ose.  Refer t o  Secti o n 9. 5. 4. 1 f or t he ti me peri o d after t he E O T f or S A E
c ollect i on.
A b n or m al la b orat or y val ues s h o uld n ot be liste d as se parate A Es if t he y are c o nsi dere d t o be 
part of t he cli nical s y n dr o me t hat is bei n g re p orte d as a n A E.  It is t he res p o nsi bility of  t he 
i n vestigat or t o re vi e w all la b orat or y fi n di n gs i n all s u bjects a n d deter mi ne if t he y c o nstit ut e 
a n A E.  Me dical a n d scie nt ific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her a n is olate d 
la b orat or y a b n or malit y s h o uld be classifie d as a n A E.  A n y la b orat or y a b n or malit y
c o nsi dere d t o c o nstit ute a n A E s h o ul d be re p orte d o n t he A d verse E ve nt C R F. 
A b n or m al E C G (Q Tc F ) res ults, if not ot her wi se c o nsi dere d part of a cli nical s y m pt o m t hat is 
bei n g re p orte d as a n A E, s h o ul d be c o nsi dere d a n A E if t he Q Tc F i nter val is m o re t ha n 
4 5 0 ms a n d t here is a n i ncrease of m o re t ha n 6 0 ms fr o m baseli ne.  A n y E C G a b n or malit y 
t hat t he i n vesti gat or c o nsi ders as a n A E s h o ul d be re p orte d as s uc h.
All A Es m ust be f o ll owe d f or 3 0 da ys after t he s u bject’s last d ose, or u ntil res o l uti on, 
w hic he ver c o mes first.  All S A Es m ust be f o ll owe d t o res ol ut i on or, if res o l uti on is u nli kel y, 
t o sta bilizati on.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 4 4 of 2 1 0
E ver y eff ort m ust be m a de b y t he i n vesti g at or t o c ate g orize e ac h A E acc or di n g t o its 
se verit y a n d its rel ati o ns hi p t o t he st u d y dr u g .
A s s e s si n g S e v erit y of A d v er s e E v e nt s
A d verse e ve nts will be gra de d o n a 5 -p oi nt scale acc or di n g t o C o m m o n Ter mi n o l og y  Criteria 
f or A d verse E ve nts (C T C A E v 5. 0 ) (Ca n cer T hera p y E val uat i on Pr o gra m , 2 0 1 7).  
I n vesti gat ors will re p ort C T C A E gra des f or all A E s (f or b ot h i ncreasi n g a n d decreasi n g 
se verity ).  
A s s e s si n g R el ati o n s hi p t o St u d y D r u g
It e ms t o be c o nsi dere d w he n assessi n g t he relati o ns hi p of a n A E t o t he st u d y dr u g are:

T e m p oral  r el atio ns hi p of t he o nset of t he e ve nt t o t he i nit iati on of t he st u d y  dr u g

T he c o urse of t he e ve nt, es peciall y t he effect of disc o nti n uat i on of st u d y  dr u g or 
rei ntr o d ucti o n of st u d y dr u g , as a p plica ble

W het her t he e ve nt is k n o w n t o be ass ociate d w ith t he st u d y  dr u g or wi t h ot her si milar 
treat me nts

T he prese nce of ris k fact ors i n t he st u d y  s u bject k n o w n t o i ncrease t he occ urre nce of t he 
e ve nt

T he prese nce of n o nst u d y , treat me nt -relate d fact ors t hat are k n o w n t o be ass ociate d wit h 
t he occ urre nce of t he e ve nt
Cl a s sifi c ati o n of C a u s alit y
T he rel at i ons hi p of eac h A E t o t he st u d y  dr u g will  be rec or de d o n t he C R F i n res p o nse t o t he 
f oll owi n g q uesti o n:
Is t here a reas o na ble p ossi bility t hat t he st u d y  dr u g ca use d t he A E?
Yes (rel ate d)
A ca usal relat i ons hi p b et wee n t he st u d y dr u g a n d t he A E is a reas o na ble 
p ossi bilit y.
N o ( n ot relate d)
A ca usal relat i ons hi p bet wee n t he st u d y  dr u g a n d t he A E is n ot a 
reas o na ble p ossi bility.
9. 5. 1. 4. 2
D I S E A S E-R E L A T E D E V E N T S A N D /O R D I S E A S E-R E L A T E D O U T C O M E S N O T Q U A LI F YI N G 
A S A E S O R S A E S
Di sease pr o gressio n s h o ul d n ot be rec or de d as a n A E or S A E ter m.  Fatal e ve nts, e ve n if d ue 
t o disease pr o gressi o n, s h o ul d al wa ys be rec or de d as a n S A E a n d s h o ul d be re p orte d i n 
acc or da nce wit h  Secti on 9. 5. 4. 1 . Als o , disease pr o gressi o n S A Es, t hat are c o nsi dere d as 
“ Relate d” t o st u d y dr u g b y t he i n vest i gat or m ust als o be re p orte d i n acc or da nce wit h 
Secti o n 9. 5. 4. 1 .  

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 4 8 of 2 1 0
A la b orat or y a b n or malit y ma y meet t he crit eria t o q ualif y as a n A E as descri be d i n t his 
pr ot oc ol  (see Secti o n 9. 5. 1. 4. 1 a n d t he CR F C o m pleti o n G ui deli nes ).  I n t hese i nsta nces, t he 
A E c orres p o n di n g t o t he la b orat or y  a b n or malit y will be rec or de d o n t he A d verse E ve nt  C R F.
9. 5. 1. 4. 6
V I T A L S I G N S A N D W
EI G H T M E A S U R E M E N T S
Vi t al si g n meas ure me nts (ie, s yst olic a n d diast olic bl o o d press ure [ B P] [ m m H g], p ulse [ beats 
per mi n ute], res pirat or y  rate [ per mi n ute], b o d y te m perat ure [i n ce nti gra de]), a n d wei g ht (k g) 
will be o btai ne d at t he visits desi g nate d in t he Sc he d ule of Pr oce d ures/ Assess me nts 
(Ta ble 1 5 , Ta ble 1 6 , a n d Ta ble 1 7 ) b y a vali date d met h o d.  Bl o o d press ure a n d p ulse will be 
meas ure d after t he s u bject has bee n s u pi ne f or 5 mi n utes.  All B P m eas ure me nts s h o uld be 
perf or m e d o n t he sa me ar m, pr efera bl y b y t he sa me pers o n.
9. 5. 1. 4. 7
P H Y SI C A L E X A MI N A TI O N S
P h ysical e xa mi nat i ons will be perf or me d as desi g nate d in t he Sc he d ule of 
Pr oce d ures/ Assess me nts (Ta ble 1 5 , Ta ble 1 6, a n d Ta ble 1 7 ).  
A c o m pre he nsi ve p h ysical e xa mi nat i on will i ncl u de e val uat i ons o f t he hea d, e yes, ears, n ose, 
t hr oat, nec k, c hest (i ncl u di n g heart a n d l u n gs), a b d o me n, li m bs, s ki n, a n d a c o m plete 
ne ur o l ogi cal e xa mi natio n. I n a d ditio n, asci tes a n d e nce p hal o pat h y will  be assesse d f or C hil d 
P u g h assess me nt f or t he s u bject s wi t h H C C (A p pe n di x 4 ).  A ur o ge nital e xa mi nat i on will  
o nl y  b e r e q uire d i n t he prese nce of cli nical s y m pt o ms relate d t o t his re gi o n. Starti n g fr o m 
C 3 D 1 a n d o n war ds, o nl y C X D 1 visit will be perf or me d o nsite .   D o c u me ntati o n of t he 
p h ysical e xa mi nat i on will be i ncl u de d i n t he s o urce d oc u me ntati o n at t he site.  O nl y c ha n ges 
fr om scree ni n g p h ysical e xa mi nat i on fi n di n gs t hat meet t he defi niti on of a n A E will be 
rec or de d o n t he A d verse E ve nts C R F.
9. 5. 1. 4. 8
E L E C T R O C A R DI O G R A M S
Electr ocar di o gra ms will be o bt ai ne d as desi g nate d in t he Sc he d ule of 
Pr oce d ures/ Assess me nts (Ta ble 1 5 , Ta ble 1 6, a n d Ta ble 1 7 ).  C o mplete, sta n dar dize d, 
1 2- lea d E C G rec or di n gs t hat per mit all 1 2 lea ds t o be dis playe d o n a si n gle pa ge wit h a n 
acc o m pa n yi n g lea d II r h yt hm strip bel o w t he c ust o mar y  3 × 4 lea d f or mat are t o be use d.  I n 
a d ditio n t o a r h y t h m strip, a mi ni m u m of 3 f ull c o m ple xes s h o ul d be rec or de d fr o m eac h lea d 
si m ulta ne o usl y.  S u bjects must be i n t he re c u m be nt p ositio n f or a peri o d of  5 mi n utes prior t o 
t he E C G.
A n E C G a b n or malit y ma y meet t he criteria o f a n A E as descri be d i n t his pr ot oc ol (see
Secti o n 9. 5. 1. 4. 1 ) a n d t he C R F C om p leti on G ui deli nes.  I n t hese i nsta nces, t he A E 
c orres p o n di n g t o t he E C G a b n or malit y will  be rec or de d o n t he A d verse E ve nts C R F.
Q T c i nter vals will be e val uate d via 1 2 - Si n gle, 1 2 -Lea d E C G.
S u bjects m ust be i n 
rec u m be nt p ositi on f or a peri od of  5 mi n prior t o E C G. 1 2- Lea d E C Gs will be c o llecte d at 
Scree ni n g (si n gle) a n d Baseli ne (si n gle u nless a b n or malit ies are o bser ve d or if cli nicall y
i n dicate d, t he n i n tri plicate at 2-mi n ute i nter vals); Da y 1 of C ycle: 2, 3, a n d 6 . Aft er t hat, 
D a y 1 o f e ver y 3 C ycles s uc h as C ycle 9, C ycle 1 2, u p t o C ycle 1 8, a n d t he n e ver y 6 mo nt hs 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 2 of 2 1 0
T a bl e 1 5
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y :  P h a s e 1 b a n d P h a s e 2 P art s
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 3 of 2 1 0
T a bl e 1 5
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y :  P h a s e 1 b a n d P h a s e 2 P art s
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 4 of 2 1 0
T a bl e 1 5
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y :  P h a s e 1 b a n d P h a s e 2 P art s
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 7 of 2 1 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
C
C
I

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 8 of 2 1 0
T a bl e 1 6
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y:  E xt e n si o n P art
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 5 9 of 2 1 0
T a bl e 1 6
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y:  E xt e n si o n P art
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 0 of 2 1 0
T a bl e 1 6
S c h e d ul e of Pr o c e d ur e s/ A s s e s s m e nt s i n E 7 3 8 6 -G 0 0 0 -2 0 1 St u d y:  E xt e n si o n P art
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 2 of 2 1 0
 
 
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 4 of 2 1 0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 5 of 2 1 0
9. 5. 3
A p pr o pri at e n e s s of M e a s ur e m e nt s
All cli nical assess me nts are sta n dar d meas ure me nts c o m m o nl y  use d i n st u dies of me la n oma, 
H C C, a n d C R C.
T he safety assess me nts t o be perf or me d i n t his st u d y, i ncl u di n g he mat ol o g y a nal yses, bl o o d 
c he mistr y tests, uri nal ysis, a n d assess me nt of A Es, are sta n dar d e val uati ons t o e ns ure s u bject 
safety.
9. 5. 4
R e p orti n g of S eri o u s A d v er s e E v e nt s, Pr e g n a n c y, a n d E v e nt s A s s o ci a t e d 
wit h S p e ci al Sit u ati o n s
9. 5. 4. 1
R e p orti n g of S eri o u s A d v er s e E v e nt s
All S E RI O U S A D V E R S E E V E N T S, re g ar dless of t heir rel ati o ns hi p t o st u d y dr u g , m ust 
be re p orte d o n a c o m plete d S A E f or m b y e m ail or f a x as s o o n as p ossi ble b ut n o l ater 
t h a n 2 4 h o urs fr o m t he d ate t he i n vesti g at or bec o mes a w are of t he e ve nt.
S eri o us a d verse e ve nts, re gar dless of ca usalit y assess me nt, m ust be c ollecte d f or 9 0 d a y s 
after t he s u bject’s last d ose, or u p t o 3 0 da ys f oll owi n g cessat i on of st u d y  dr u g if t he s u bject 
i nitiates ne w a nt ica ncer t hera p y, w hic he ver is earlier.  All S A Es m ust be f o ll owe d t o 
res olut i on or, if res o l uti on is u nli kel y, t o sta bilizati o n.  A n y S A E j u d ge d b y t he i n vesti gat or 
t o be relate d t o t he st u d y dr u g or a n y  pr ot oc ol-re q uire d pr oce d ure s h o ul d be re p orte d t o t he 
S p o ns or re gar dless of t he le n gt h of ti me t hat has passe d si nce st u d y c om p leti on.
T he detaile d c o ntact i nf or mat i on f or re p ortin g of S A Es is pr o vi de d i n t he I n vest i gat or St u d y 
File.
F or ur ge nt s afet y iss ues , pl ease e ns ure all a p pr o priate me dical care is a d mi nistere d t o t he 
s u bject a n d c o ntact t he a p pr o priate st u d y tea m me m ber liste d i n t he I n vest i gat or St u d y 
File.
It is ver y i m p orta nt t hat t he S A E re p ort f or m be fille d o ut as c o m pletel y as p ossi ble at t he 
ti me of t he i nitial re p ort.  T his i ncl u des t he i n vesti gat or’s assess me nt of ca usality.
A n y rele va nt f oll ow- u p i nf or m at i on recei ve d o n S A Es s h o ul d be f or war de d wit hi n 2 4 h o urs
of  its receipt.  If t he rele va nt f oll ow- u p i nf or m at i on c ha n ges t he i n vest i gat or’s assess me nt of 
ca usalit y,  t his s h o uld als o be n ote d o n t he f o ll ow- u p S A E f or m .
Preli mi nar y S A E re p orts s h o ul d be f o ll owe d as s o o n as p ossi ble b y  detaile d descri ptio ns 
i ncl u di n g c o pies of h os pital case re p orts, a ut o ps y re p orts, a n d ot her d oc u me nts re q ueste d b y 
t he S p o ns or .
T he i n vest i gat or m ust n otif y his/ her I R B/I E C of t he occ urre nce of t he S A E i n writi n g, if 
re q uire d b y t heir i nstituti o n .  A c o p y of t his c o m m u nicati on m u st be f or war de d t o t he 
S p o ns or t o be file d i n t he S p o ns or ’s Trial Master File.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 6 9 of 2 1 0
S u bjects w h o di sc o nti n ue earl y fr om t he st u d y will be disc o nti n ue d f or 1 of  t hese pri mar y 
reas o ns: A E(s), l ost t o f o ll ow- u p, s u bject c h o ice, pr o gressi o n of disease, wit h dra wal of 
c o nse nt,  
 st u d y ter mi nate d b y S p o ns or or ot her.   I n a d diti o n t o t he pri mar y reas o n, 
t he s u bject ma y in dicate 1 or m ore sec o n dar y reas o n(s) f or disc o nti n uatio n.  St u d y 
di s p ositio n i nf or mat i on will be c ollecte d o n t he S u bject Dis p osit i on C R F.   
A s u bject re m o ve d fr o m t he st u d y  for a n y  reas o n d uri n g P hase 2 will n ot be re place d.
9. 5. 6
A b u s e or Di v er si o n of St u d y Dr u g
N ot a p plica ble .
9. 5. 7
C o nfir m ati o n of M e di c al C ar e b y A n ot h er P h y si ci a n
T he i n vest i gat or will i nstr uct s u bjects t o i nf or m site pers o n nel w he n t he y are pla n ni n g t o 
recei ve me dical care b y a n ot her p h ysicia n.  At eac h visit, t he i n vesti gat or will as k t he s u bject 
w het her he/s he has recei ve d me dical care b y a n ot her p h ysicia n si nce t he last visit or is 
pl a n ni n g t o d o s o i n t he f ut ure.  W he n t he s u bject is g oi n g t o recei ve me dical care b y  a not her 
p h ysicia n, t he i n vesti gat or, wit h t he c o nse nt of t he s u bject, will i nf or m t he ot her p h ysicia n 
t hat t he s u bject is part ici pati n g i n t he cli nical st u d y.
9. 6
D at a Q u alit y A s s ur a n c e
T his st u d y  will b e or g a nize d, perf or me d, a n d re p orte d in c o m p lia nce with t he pr ot oc ol, 
S O Ps, w or ki n g practice d oc u me nts, a n d a p plica ble re g ulat i ons a n d g ui deli nes.  Si te a u dits 
will be ma de peri o dicall y b y t he S p o n s or’s or t he C R O’s q ualifie d c om p lia nce a u diti n g tea m, 
w hic h is a n i n de pe n de nt f u nct i on fr o m t he st u d y tea m res p o nsi ble f or c o n d uct of t he st u d y.  
9. 6. 1
D at a C oll e cti o n
Data re q ui re d b y t he pr ot oc ol will be c ollecte d o n t he C R Fs a n d e ntere d i nt o a vali date d data 
ma na ge me nt s yste m t hat is c o m p lia nt wit h all re g ulat or y re q uire me nts.  As defi ne d b y I C H 
g ui deli nes, t he C R F is a pri nte d, o ptical, or electr o nic d oc u me nt desi g ne d t o rec or d all o f t he 
pr ot oc ol -re q uire d i nf or matio n t o be re p orte d t o t he S p o ns or o n eac h s t u d y s u bject.
Data c ollect i on o n t he C R F m ust f o ll ow t he i nstr ucti o ns descri be d i n t he C R F C o m p leti on 
G ui deli nes.  T he i n vest i gat or has ulti mate res p o nsi bility f or t he c ollecti on a n d re p orti n g of all 
cli nical data e ntere d o n t he C R F.  T he i n vest i gat or or desig nee as i de nt ifie d o n F or m F D A 
1 5 7 2 or I n vest i gat or a n d Site In f or mat i on F or m m ust si g n t he c o m plete d C R F t o attest t o its 
acc urac y, a ut he nticity,  a n d c o mplete ness.
C o m plete d, ori gi nal  C R Fs are t he s ole pr o pert y of Eisai a nd s h o ul d n ot be m a de a vaila ble i n 
a n y f or m t o t hir d parties wit ho ut wri tte n per missi on fr om Ei sai, e xce pt f or a ut h orize d 
re prese ntati ves of Eisai or a p pr o priate re g ulat or y a ut h orities.
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 0 of 2 1 0
9. 6. 2
Cli ni c al D at a M a n a g e m e nt
All s oft ware a p plicati ons use d i n t he c ollect i on of data will be pr o perl y va li date d f oll owi n g 
sta n dar d c o m p uter s yst e m vali datio n t hat is c o m plia nt wi t h all re g ulat or y re q uire me nts.  All 
data, b ot h C R F a n d e xter nal data (e g, la b orat or y data), will be e ntere d i nt o a cli nical s yste m.
9. 7
St ati sti c al M et h o d s
S t atistical a nal yses will be p erf or me d b y t he S p o ns or or desi g nee after t he st u d y  is c om p lete d 
a n d t he data base is l oc ke d a n d release d.  A n earlier data base l oc k ma y als o be perf or me d f or 
t he p ur p ose of writ i n g a cli nical st u d y re p ort. Statistical a nal yses will be perf or me d usi n g 
S A S s oft ware or ot her vali date d statistical s oft ware as re q uire d.  Details of t he statistical 
a nal yses will be i ncl u de d i n a se parate statistical a nal ysis pla n (S A P).
9. 7. 1
St ati sti c al a n d A n al yti c al Pl a n s
T he stati stical a nal yses of st u d y data are descri be d i n t his secti on .  F urt her details of t he 
a nal yt ical pla n will be pr o vi de d i n t he S A P, w hic h will be fi nalize d bef ore data base l oc k.
9. 7. 1. 1
St u d y E n d p oi nt s
F or t he t u m or res p o nse relate d e n d p oi nts, t he t u m or assess me nts b y BI C R (if c o n d ucte d) ma y
be use d i n t he pri mar y a nal ysis f or t he c o h orts i n P hase 2 part .  Ot her wise, t u m or assess me nts 
b y t he i n vesti gat or will be use d f or t he a nal ysis.
9. 7. 1. 1. 1
P RI M A R Y E N D P OI N T S

P hase 1 b part : Safet y r elate d e n d p oi nts i ncl u di n g D L T s

P hase 2 part : O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ha ve best o verall 
res p o nse ( B O R) of c o nfir me d C R or P R per R E CI S T 1. 1
9. 7. 1. 1. 2
S E C O N D A R Y E N D P OI N T S

B O R per R E CI S T 1. 1 (f or P hase 1 b part ) 

D O R i s defi ne d as t he ti me fr o m t he first d oc u me ntati o n of C R or P R t o t he first 
d oc u m e nt atio n of  disease pr o gressio n or deat h d ue t o a n y ca use ( w hic he ver occ urs first), 
i n s u bjects wit h c o nfir me d C R or P R per R E CI S T 1. 1

D C R is defi ne d as t he pr o p orti o n of s u bjects w h o ha ve a B O R of c o nfir me d C R or P R, or 
S D: aft er ≥5 wee ks fr o m t he first d ose) per R E CI S T 1. 1

C B R is defi ne d as t he pr o p ortio n of  s u bjects w h o ha ve a B O R of c o nfir me d C R or P R, or 
d ura ble S D ( d urati o n of S D ≥2 3 wee ks) per R E CI S T 1. 1

S af et y a n d t olera bilit y (e g , treat me nt -e mer ge nt a d verse e ve nts , treat me nt-relate d a d verse 
e ve nts) f or E 7 3 8 6 i n c o m bi nat i on wi t h p e mbr oliz u ma b a n d safet y a n d t olera bilit y 
i ncl u di n g D L Ts f or E 7 3 8 6 i n c o m bi nat i on wi t h pe m br oliz u ma b pl us le n vati ni b 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 2 of 2 1 0
T he n u m ber ( perce nta ge) of s u bjects w h o were treate d, c o nti n ue d , or di sc o nt i n ue d st u d y dr u g 
at data c ut off date, al o n g wit h t he pri mar y reas o n f or disc o nti n uatio n f r o m t he st u d y dr u g will 
be prese nte d. T he n u m ber ( perce nta ge) of s u bjects w h o disc o nti n ue d treat me nt b ut were o n 
s ur vi val f oll ow- u p at data c ut off date will als o be pr o vi de d.
T he n u m ber ( perce nta ge) of s u bjects w h o were o n st u d y  or off st u d y (ie, disc o nt i n ue d fr o m 
t he st u d y) at data c ut off date a n d t he pri mar y reas o n f or disc o nti n uati on fr o m st u d y will be 
prese nte d.
9. 7. 1. 4
D e m o gr a p hi c a n d Ot h er B a s eli n e C h ar a ct eri sti c s
D e m o gra p hic a n d ot her baseli ne c haracterist ics for t he Efficac y A nal ysis Set will be 
s u m marize d f or eac h d ose le vel/t u m or c o h ort, a n d f or p hase/ o verall (as nee de d) usi n g 
descri pt i ve statistics.  C o nti n u o us de m o gra p hic a n d baseli ne varia bles i ncl u de a ge, we i ght , 
a n d hei g ht ; cate g orical varia bles i ncl u de se x, a ge gr o u p, race, et h nicit y , r e gio n /c o u ntr y, 
E C O G P S a n d N Y H A car diac disease classificat i on .  
9. 7. 1. 5
Pri or a n d C o n c o mit a nt T h er a p y
All i n vesti gat or ter ms f or me dicati o ns rec or de d i n t he C R F will be c o de d t o an 1 1 -di git c o de 
usi n g t he W orl d Healt h Or ga nizati o n Dr u g Dict i on ar y  ( W H O D D). T he n u m ber 
( perce nta ge) of s u bjects w h o t o o k pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d o n 
t he Efficac y A nal ysis Set b y A nat o mical T hera pe utic C he mical class (ie, A nat o mical class, 
P har mac o l ogi cal class), a n d W H O D D preferre d ter m ( P T). Pri or m e dicat i ons will be 
defi ne d as me dicat i ons t hat starte d bef ore t he first d ose of st u d y  dr u g re gar dless if t he y were 
eit her st o p pe d bef ore t he first d ose of st u d y dr u g or c o nti n ue d d uri n g t he st u d y .  C o nc o mit a nt 
me dicat i ons will be defi ne d as me dicat i ons t hat ( 1) starte d bef ore t he first d ose of st u d y  dr u g 
a n d were c o nti n ui n g at t he ti me of t he first d ose of st u d y dr u g, or ( 2) starte d o n or after t he 
date of t he first d ose of st u d y  dr u g u p t o 3 0 da ys after t he s u bject’s last d ose. T he s u m mar y 
will be prese nte d f or eac h d ose le vel/t u m or c o h ort, a n d f or p hase/ o verall (as nee de d) . A 
me dicat i on t hat ca n n ot be deter mi ne d as pri or/c o nc o mita nt/ p ost treat me nt d ue t o 
missi n g/i nc o m plete date s will be re gar de d as a c o nc o mita nt me dicat i on. All me dicat i ons will 
be prese nte d i n s u bject data list i n gs.
9. 7. 1. 6
Effi c a c y A n al y s e s
All efficac y a nal yses (e xce pt f or D O R) will be perf or me d wit hi n eac h c o h ort/t u m or t y pe o n 
t he Efficac y A nal ysis Set.  T he a nal ysis for D O R will  be perf or me d i n t he s u bjects w h o s h o w 
a c o nfir me d C R or P R wit hi n eac h c o h ort/t u m or t y pe o n t he Efficac y A nal ysis Set.
B O R is C R, P R, S D, P D, or n ot e val ua ble ( N E) / U n k n o w n, w here S D has t o be ac hie ve d at 
≥5 wee ks after t he first d ose.  T he B O R of C R a n d P R re q uires c o nfir mat i on b y a s u bse q ue nt 
assess me nt of res p o nse at least 2 8 da ys later.  H o we ver, f or t he c o nsi derati on of c o h ort 
e x pa nsi o n i n t he i nteri m data re vie w, res p onse c o nfir mat i on will n ot be re q uire d.
Data c ut off of t he pri mar y a nal ysis i n t he P hase 2 part f or eac h t u m or c o h ort ma y be 
perf or m e d base d o n t he Efficac y A nal ysis Set w he n all s u bjects i n t hat c o h ort ha ve 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 4 of 2 1 0
treat me nt c o h orts) will be ta b ulate d a n d s u m marize d b y d ose le vel, d a y , a n d ti me.  T he 
pri mar y  P K para meters of E 7 3 8 6 will be calc ulate d usi n g n o nc o m part me ntal a nal ysis f or t he 
P hase 1 b part.  Plas ma c o nce ntrati o n data f or E 7 3 8 6 a n d le n vati ni b i n t he P hase 2 part will be 
use d t o c o n d uct p o p ulat i on P K a nal ysis a n d/ or gra p hical prese ntati o n b y i nte grat i n g plas ma 
c o nce ntrati o n data fr o m t he P hase 1 b part a n d / or ot her st u di es. P K/ P D r elatio ns hi ps (i e, 
e x p os ure-efficac y, e x p os ure-safety,  a n d e x p os ure-bi o mar ker rel at i ons hi ps) will be m o dele d, 
if p ossi ble, usi n g a mec ha nistic a p pr oac h, f or effects of st u d y tr e at me nt. Efficac y e nd p oi nts 
will i ncl u de pri mar y e n d p o i nt of O R R ( base d o n R E CI S T 1. 1) a n d ot her efficac y-relate d 
m etri cs i ncl u di n g b ut n ot li mite d t o D O R . Safet y e n d p o i nt will be m ost fre q ue nt A Es a n d 
d ose re d ucti o ns o f E 7 3 8 6. E x pl orat or y / gra p hical a nal yses will be c o n d ucte d f or P K/P D
e val uat i ons, a n d, if p ossi ble, will be f o ll owe d b y  m o d el-base d a nal yses f or E 7 3 8 6.
F o r 
p o p ul at i on P K a n d P K/ P D a nal ys es, t he details will be descri be d i n a se paratel y pre pare d 
a nal ysis pla n a n d its re p ort, a n d t he res ults will n ot be i ncl u de d i n t he cli nical st u d y re p ort.
9. 7. 1. 7. 2
P H A R M A C O D Y N A MI C , PH A R M A C O G E N O MI C , A N D O T H E R B I O M A R K E R A N A L Y S E S
Details o f t he P D a n d ot her bi o mar ker a nal yses will be pr o vi de d i n a se parate a nal ysis pla n.
9. 7. 1. 8
S af et y A n al y s e s
All t olera bilit y a nal yses will b e p erfor m e d b y d ose le vel (if a p plica ble) o n t he D L T A nal ysis 
Set.  T he n u m ber a n d perce nta ge of s u bjects wit h D L T will be calc ulate d.
T he Safet y A nal ysis Set will be use d f or all ot her safet y a nal yses.  Safet y a nal yses will be
assesse d wit hi n eac h c o h ort/t u m or t y pe , a n d f or p hase/ o verall (as nee de d) o n a n “as treate d” 
basis usi n g descri pti ve statist ics (e g, n, mea n, sta n dar d de viati o n, me dia n, q uartiles , 
mi ni m u m, ma xi m u m f or c o nti n u o us varia bles; n [ %] f or cate g orical varia bles ).  Safet y 
varia bles i ncl u de T E A Es , cli nical la b orat or y para meters, vit al si g ns, T- sc ore
, 
L V E F a n d 1 2 -lea d E C G para meters.  If nee de d, t he c ha n ges fr o m baseli ne will als o be 
s u m marize d. St u d y  D a y 1 for all safet y a nal yses will be defi ne d as t he date of t he first d ose 
of  st u d y dr u g.
9. 7. 1. 8. 1
E X T E N T O F E X P O S U R E
T he n u m ber of c ycles/ da ys o n treat me nt, q ua ntit y of  st u d y dr u g a d mi nistere d, a n d t he 
n u m ber of s u bjects re q uiri n g d ose re d ucti o ns a n d / or treat me nt i nterr u ptio n will be 
s u m marize d f or the Safet y A nal ysis Set.
9. 7. 1. 8. 2
A D V E R S E E V E N T S
T he A E ver bat i m descri pti ons (i n vesti gat or ter ms fr o m t he C R F) will be classifie d i nt o 
sta n dar dize d me dical ter mi n o l og y usi n g t he Me dical Dict i onar y  for Re g ul at or y Acti vities 
(Me d D R A).  
A T E A E i s defi ne d as a n A E t hat e mer ges d urin g treat me nt ( o n or after t he first d ose of st u d y 
dr u g u p t o 3 0 d a y s after t he s u bject’s last d ose), ha vi n g bee n a bse nt at pretreat me nt 
(Baseli ne) or :
C CI

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 5 of 2 1 0

Ree mer ges d uri n g treat me nt, ha vi n g bee n prese nt at pretreat me nt (Baseli ne) b ut st o p pe d 
bef ore treat me nt, or 

W o rse ns i n se verity d uri n g treat me nt relat i ve t o t he pretreat me nt state w he n t he A E is 
c o nti n u o us
O nl y t h ose A Es t hat are treat me nt-e mer ge nt will be i ncl u de d i n s u m mar y ta bles.  All A Es, 
treat me nt - e mer ge nt or ot her wise, will be prese nte d i n s u bject data listi n gs.
T he T E A Es will be s u m marize d.  T he i nci de nce o f T E A Es will be re p orte d as t he n u m ber 
(perce nta ge) of s u bjects wit h T E A Es b y s yste m or ga n class (S O C ) a n d P T.  A s u bject will be 
c o u nte d o nl y o nce wi t hi n an S O C a n d P T, e ve n if t he s u bject e x perie nce d m ore t ha n 1 T E A E 
wi t hi n a s pecific S O C a n d P T.  T he n u m ber (perce nta ge) of s u bjects wit h T E A Es will als o be 
s u m marize d b y hi g hest C T C A E gra de acc or di n g t o t he C T C A E v 5. 0 .
T he n u m ber (perce nta ge) of s u bjects wit h treat me nt-relate d T E A Es will be s u m marize d b y 
S O C a n d P T.  Treat me nt -relate d T E A Es i ncl u de t h ose e ve nts c o nsi dere d b y t he i n vesti gat or 
t o be relate d t o st u d y dr u g .  T he n u m ber (perce nta ge) of s u bjects wit h treat me nt -r elate d 
T E A Es will als o b e s u m marize d b y hi g hest C T C A E gra de.
T he n u m ber (perce nta ge) of s u bjects wit h T E A Es lea di n g t o deat h will be s u m marize d b y 
Me d D R A S O C a n d P T.  A s u bject data listi n g of  all AEs lea di n g t o deat h will be pr o vi de d.
T he n u m ber (perce nta ge) of s u bjects wit h tre at me nt -e mer ge nt S A Es will be s u m marize d b y 
Me d D R A S O C a n d P T.  A s u bject data listi n g of  all S A Es will be pr o vide d.
T he n u m ber ( perce nta ge) of s u bjects wit h T E A Es lea di n g t o disc o nti n uati o n fr o m st u d y dr u g 
will be s u m marize d b y  Me d D R A S O C a n d P T. A s u bjec t data listi n g of  all A Es lea di n g t o 
di sc o nti n uati on fr om st u d y dr u g will be pr o vi de d.
9. 7. 1. 8. 3
L A B O R A T O R Y V A L U E S
La b orat or y  res ults will be s u m marize d usi n g S ystè me I nter nati onal (SI) u ni ts, as a p pr o priate.  
F or all q ua ntitati ve para meters liste d i n  Sect i on 9. 5. 1. 4. 5 , t he act ual val ue a n d t he c ha n ge 
fr om baseli ne t o eac h p ost baseli ne visit a n d t o t he E O T (defi ne d as t he last o n-treat me nt 
val ue i ncl u di n g assess me nt ) will be s u m marize d b y visit usi n g descript i ve statistics.  
Q ualitat i ve para meters liste d i n Sect i on 9. 5. 1. 4. 5 will be s u m marize d usi n g fre q ue ncies 
(n u m ber a n d perce nta ge of s u bjects), a n d c ha n ges fr o m ba seli ne t o eac h p ost baseli ne visit 
a n d t o E O T will be re p orte d usi n g s hift ta ble s.  Perce nta ges will be base d o n t he n u m ber of 
s u bjects wit h b ot h n o n-missi n g baseli ne a n d rele va nt p ost baseli ne res ult s.
La b orat or y  para meters will be cate g orize d acc or di n g t o C T C A E v 5. 0 a n d s hifts fr om 
baseli ne C T C A E gra des t o w orst p ost baseli ne gra des will be assesse d. T he n u m ber 
(perce nta ge ) of  s u bjects wit h p ost baseli ne val ues w orse ne d fr o m baseli ne ( wit h at l east 1 
C T C A E gra de i ncrease) will be prese nte d. Li ke wise, s u bjects wit h p ost baseli ne val ues of  
C T C A E gra des 3 or 4 w orse ne d fr o m baseli ne will als o be s u m marize d.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 8 of 2 1 0
9. 7. 4
Ot h er St ati sti c al/ A n al yti c al I s s u e s
N ot a p plica ble
9. 7. 5
Pr o c e d ur e f or R e vi si n g t h e St ati sti c al A n al y si s Pl a n
If t he S A P nee ds t o be re vise d after t he st u d y starts, t he S p o ns or will deter mi ne h o w t he 
re visi on i m pacts t he st u d y a n d h o w t he re visi on s h o ul d be i m ple me nte d.  T he deta ils of t he 
re visi on will be d oc u me nte d a n d descri be d i n t he C S R .

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 7 9 of 2 1 0
1 0
R E F E R E N C E LI S T
A b o u -Alfa G, Me yer T, C he n g A -L, El -K h o uei r y A, Ri massa L, R yo o B -Y, et al. 
Ca b oza nt i ni b i n patie nts wit h a d va nce d a n d pr o gressi n g he pat ocell ular carci n oma. N E n gl  J 
Me d . 2 0 1 8; 3 7 9: 5 4 - 6 3.
A dac hi Y, Ka mi ya ma H, Ic hi ka wa K, F u k us hi ma S, Oza wa Y, Ya ma g uc hi S, et al. I n hi bit i on 
of  F G F R reacti vates I F Nγ si g nali n g i n t u m or cells t o e n ha nce t he c o m bi ne d a ntitu m or 
acti vit y of  le n vat i ni b with a nti -P D -1 a nt i b o dies. Ca ncer Res. 2 0 2 2;8 2( 2): 2 9 2 – 3 0 6.
A n dre T, S hi u K -K, Ki m T, Je nse n B, Je nse n L, P u nt C, et al. Pe m br o liz u ma b i n 
micr osatellite -i nsta bility -hi g h a d va nce d c o l orectal ca ncer. N E n gl J Me d. 2 0 2 0; 3 8 3: 2 2 0 7 - 1 8.
At ez oliz u ma b (T E C E N T RI Q ® ) [ prescri bi n g i nf or mati on]. S o ut h Sa n Fra ncis c o, C A:
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Res. 2 0 0 4; 6 4: 1 1 4 0 - 5.
B u gter J, Fe n deric o N, Ma urice M. M utati o ns a n d mec ha nis ms of Wnt  pat h wa y t u mo ur 
s u p press ors i n ca ncer. Nat ure Re vie ws Ca ncer. 2 0 2 1; 2 1: 5 -2 1. 
Br ui x J, Qi n S, Merle P, Gra nit o A, H ua n g Y -H, B o d o k y  G, et al. Re g orafe ni b f or patie nts 
wi t h he pat ocell ular carci n oma w h o pr o gresse d o n s orafe ni b treat me nt ( R E S O R C E): a 
ra n d omise d d o u ble -bli n d, pl ace b o -c o nt r olle d, p hase 3 trial. La ncet. 2 0 1 7 ; 3 8 9: 5 6-6 6.
C he m nitz J M, Parr y R V, Nic h o ls K E, J u ne C H, a n d Rile y J L. S H P-1 a n d S H P -2 ass ociate 
wi t h im m u n orece pt or t y r osi ne-base d s witc h m otif of pr o gra m me d deat h 1 u p o n pri mar y 
h u ma n T cell  sti m ulati on, b ut o nl y rece pt or li gat i on pre ve nts T cell act i vati on. J I m m u n ol. 
2 0 0 4; 1 7 3: 9 4 5 - 5 4.
C urra n M A, M o ntal v o W, Ya gita H, a n d Allis o n J P. P D -1 a n d C T L A -4 c o m bi nat i on 
bl oc ka de e x pa n ds i nfiltrati n g T cells a n d re d uces re g ulat or y  T a n d m yel oi d cells wit hi n B 1 6 
mela n o ma t u m ors. Pr oc Natl Aca d Sci U S A. 2 0 1 0; 1 0 7: 4 2 7 5 - 8 0.
Di az L A a n d Le D T. P D -1 bl oc ka de i n t u m ors wit h mis matc h -re pair deficie nc y. N E n gl J 
Me d. 2 0 1 5; 3 7 3: 1 9 7 9.
Di sis M L. I m m u ne re g ulat i on of ca ncer. J Cli n O nc ol. 2 0 1 0; 2 8( 2 9): 4 5 3 1- 8.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 0 of 2 1 0
D u dl e y M E, W u n derlic h J R, Ya n g J C, S herr y  R M, T o palia n S L, Restif o N P, et al. A d o pti ve 
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treat me nt of patie nts wit h refract or y metastatic mela n o ma. J Cli n O nc o l. 2 0 0 5;2 3: 2 3 4 6- 5 7.
Eise n ha ue r E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, et al. Ne w 
res p o nse e val uati on cri teria i n s oli d t u m o urs: re vise d R E CI S T g ui deli ne (versi o n 1. 1). E ur J 
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Fi n n R, Qi n S, I ke da M, Galle P, D ucre u x M, Ki m T -Y, et al. Atez oliz u ma b pl us 
be vaciz u ma b i n u nresecta ble he pat ocell ular carci n o ma. N E n gl J Me d . 2 0 2 0; 3 8 2: 1 8 9 4 - 1 9 0 5.
Fra ncisc o L M, Sa ge P T, a n d S har pe A H. T he P D -1 pat h wa y  in t ol era nce a n d a ut oi m m u nit y.  
I mm u n o l Re v. 2 0 1 0; 2 3 6: 2 1 9 - 4 2.
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2 0 0 5; 2 3: 5 1 5 - 4 8.
Gr ot he y A, Va n C utse m E, S o brer o A, Sie na S, Falc o ne A, Yc h o u M, et  al. C O R R E C T 
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Har di n g J, Na n da k u mar S, Ar me nia J, K halil D, Al ba n o M, L y  M, et al. Pr os pecti ve 
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H u n der N N, Walle n H, Ca o J, He n dric ks D W, Reill y  J Z, R o d m yre R, et al. Treat me nt of 
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2 0 0 8; 3 5 8: 2 6 9 8 -7 0 3. 
Ka h n M. Ca n we safel y tar get t he W nt pat h wa y? Nat Re v Dr u g Disc o v. 2 0 1 4; 1 3( 7): 5 1 3 - 3 2.
Kat o Y, Ta bata K, Ki m ura T, Yac hie -Ki n o s hita A, Oza wa Y, Ya ma da K, et al. Le n vati ni b 
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2 0 1 9; 1 4( 2):e 0 2 1 2 5 1 3.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 1 of 2 1 0
Ki m ura T, Kat o Y, Oza wa Y, K o da ma K, It o J, Ic hi ka wa K, et al. I m m u n o m o d ul at or y 
acti vit y of  le n vat i ni b c o ntri b utes t o a ntit u m or acti vity i n t he h e pa 1-6 he pat ocell ular 
carci n o ma m o d el . Ca ncer Sci. 2 0 1 8; 1 0 9( 1 2): 3 9 9 3– 4 0 0 2.
K o ba yas h i Y, Ue hara S, U da ga wa N, Ta ka has hi N. Re g ulati o n of b o ne meta b olis m b y W nt 
sig nals. J Bi oc he m. 2 0 1 6; 1 5 9: 3 8 7 – 9 2.
Kr is h na n V, Br y a nt H U, Mac D o u gald O A. Re g ulati o n of  b o ne mass b y W nt sig nali n g. J Cli n 
I n vest. 2 0 0 6; 1 1 6: 1 2 0 2 – 9.
Lar ki n J, Mi n or D, D' A n gel o S, Ne y ns B, S m ylie M, Miller W H Jr, et al. O verall sur vi val  in 
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O nc o l. 2 0 1 8; 3 6: 3 8 3- 9 0.
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Ma yer
RJ, Va n C utse m  E, Falc o ne A, Y os hi n o T, Garcia -Car b o ner o R, Mi z u n u ma N, et al.
R E C O U R S E St u d y  Gr o u p. Ra n d o mize d trial of T A S-1 0 2 f or refract or y  metastatic c olorectal  
ca ncer. N E n gl J Me d. 2 0 1 5; 3 7 2: 1 9 0 9 - 1 9.
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t hera pe utic p ote ntial of t he pr o gra m me d deat h-1 li ga n d/ pr o gra m me d deat h -1 pat h wa y  in 
h u ma n pa ncreat ic ca ncer. Cli n Ca ncer Res. 2 0 0 7; 1 3: 2 1 5 1- 7.
O kaza ki T, Mae da A, Nis hi m ura H, K ur osa ki T, a n d H o nj o T. P D -1 i m m u n orece pt or i n hi bi ts 
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1 9 8 2; 5( 6): 6 4 9 - 5 5.
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cell deat h li ga n d 1 ( P D -L 1) bl oc ka de atte n uates metastatic c ol o n ca ncer gr o wt h i n c A M P -
res p o nse ele me nt bi n di n g pr otei n ( C R E B)-bi n di n g pr otei n ( C B P)/ β -cate ni n i n hi bit or -treate d 
li vers. O nc otar get. 2 0 1 9; 1 0: 3 0 1 3 - 2 6.
Oza wa Y, H ori Y, Ya ma da K, F u na has hi Y, Mats ui J, Mats us hi ma T, et al. E 7 3 8 6, a n orall y  
acti ve C B P/ beta-cate ni n mo d ulat or, effects t u m or micr oe n vir o n me nt, res ult i n g t o t he 
e n ha nce me nt of a ntit u m or acti vit y of le n vat i ni b Ca ncer Res . 2 0 1 7; 7 7( 1 3 _ S u p pl e me nt): 5 1 7 6.
Parr y R V, C he m ni tz J M, Fra u wirt h K A, La nfra nc o A R, Bra u nstei n I, K o ba yas hi S V, et al. 
C T L A - 4 a n d P D- 1 rece pt ors i n hi bit T-cell act i vati o n b y disti nct mec ha nis ms. M ol Cell  Biol . 
2 0 0 5; 2 5: 9 5 4 3 - 5 3.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 2 of 2 1 0
Pi l on- T h o mas S, Mac ka y A, V o hra N, a n d M ulé JJ. Bl oc ka de of pr o gra m me d deat h li ga n d 1 
e n ha nces t he t hera pe utic efficac y of c o m bi nati on i m m u n ot hera p y a gai nst mela n o m a. J 
I mm u n o l. 2 0 1 0; 1 8 4: 3 4 4 2- 9.
Rile y J L. P D-1 si g nali n g i n pri mar y T cells. I mm u n o l Re v. 2 0 0 9; 2 2 9: 1 1 4 - 2 5.
R o bert C, Ri bas A, Sc hac hter J, Ara nce A, Gr o b J -J, M ortier L, et al. Pe m br oliz u ma b vers us 
i pili m u ma b i n a d va nce d mela n oma ( K E Y N O T E -0 0 6): p ost -h oc 5 - year res ults fr o m a n o pe n-
la bel, mul tice ntre, ra n d o mise d, c o ntr olle d, p hase 3 st u d y. La ncet O nc ol. 2 0 1 9; 2 0: 1 2 3 9- 5 1.
S he p par d K A, Fitz LJ, Lee J M, Be na n der C, Ge or ge J A, W o oters J, et al. P D -1 i n hi bits 
T- cell rece pt or i n d uce d p h os p h or ylat i on of t he Z A P 7 0/ C D 3 zeta si g nal os o me a n d 
d o w nstrea m si g nali n g t o P K Ct heta. F E B S Lett. 2 0 0 4; 5 7 4: 3 7 - 4 1.
Si l va A L, Da ws o n S, Are n ds M, G utt ula K, Hall N, Ca mer o n E, et al. B o osti n g W nt acti vit y 
d uri n g c ol orectal ca ncer pr o gressi o n t hr o u g h selecti ve h y per met h ylat i on of W nt si g nal i n g 
a nta g o nists. B M C Ca ncer. 2 0 1 4; 1 4: 8 9 1.
S pra n ger S, Ba o R, Gaje ws ki T. Mela n o ma -i ntrinsic b -cate ni n si g nali n g pre ve nts a nt itu m or 
i m m u nity,  Nat ure pre ve nts a nti-t u mor i m m u ni t y. N at ur e. 2 0 1 5; 5 2 3: 2 3 1 - 5.
S pra n ger S, K o blis h H K, H ort o n B, Sc herle P A, Ne wt o n R , a n d Gaje ws ki T F. Mec ha nis m of 
t u mor r ej ect i on wi t h d o u blets of C T L A-4, P D -1/ P D - L 1, or I D O bl oc ka de i n v ol ves rest ore d 
I L-2 pr o d ucti o n a n d pr oliferat i on of C D 8( +) T cells direct l y withi n t he t u m or 
micr oe n vir o n me nt. J I m m u n ot her Ca ncer. 2 0 1 4; 2: 3.
Str o m e S E, D o n g H, Ta m ura H, V oss S G, Flies D B, Ta ma da K, et al. B 7 -H 1 bl oc ka de 
a u g me nts a d o pti ve T -cell i m m u n ot hera p y for s q ua m o us cell  carci n o ma. Ca ncer Res. 
2 0 0 3; 6 3: 6 5 0 1 - 5.
S u n g H, Ferl a y J, Sie gel R, La versa n ne M, S oerj o matara m I, Je mal A, et al. Gl o bal  Ca ncer 
S t atistic 2 0 2 0: G L O B O C A N Esti mates of I nci de nce a n d M ortality W o rld wi d e f or 3 6 
Ca ncers i n 1 8 5 C o u ntries. C A Ca ncer J Cli n . 2 0 2 1; 7 1( 3) : 2 0 9- 4 9.
Ta ke m ar u K a n d M o o n R. T he tra nscri pt i onal c oacti vat or C B P i nteracts wit h beta -cate ni n t o 
acti vate ge ne e x pressi o n. J. Cell Bi o l. 2 0 0 0; 1 4 9: 2 4 9– 5 4.
T he Ca ncer Ge n o me At las Net w or k. C o m pre he nsi ve m olec ular c haracterizati on of h u ma n 
c olo n a n d rectal  ca ncer. Nat ure. 2 0 1 2; 4 8 7; 3 3 0 – 7. 
T u me h P, Har vi e w C, Yearle y J, S hi nta k u I, Ta yl o r E, R o bert L, et al. P D-1 bl oc ka de 
i n d uces res p o nses b y i n hi biti n g a da pti ve i m m u ne resista nce. Nat ure. 2 0 1 4; 5 1 5: 5 6 8 -7 1. 
We ber
J. I m m u ne c hec k p oi nt pr otei ns: a ne w t hera pe utic para di g m f or ca ncer --precli nical 
bac k gr o u n d: C T L A - 4 a n d P D-1 bl oc ka de. Se mi n O nc o l. 2 0 1 0; 3 7: 4 3 0- 9.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 3 of 2 1 0
W o lch o k J, C hiari o n-Si le ni V, G o nzalez R, R ut k o ws ki P, Gr o b J-J, C o we y L, et al. O verall 
s ur vi val wit h c om bi ne d ni v o l uma b a n d i pili m u ma b i n a d va nce d mela n o ma. N E n gl J
Me d.
2 0 1 7; 3 7 7: 1 3 4 5 - 5 6.
Y a m a da K, H ori Y, Ka mi ya ma H, Ki m ura T, F u na has hi Y, Mats ui J, et al. A nti-t u mor a n d 
a nt i-a n gio ge nesis act i vities of E 7 3 8 6, a n orall y acti ve C B P/ beta-cate ni n m o d ulat or, as a 
si n gle a ge nt a n d i n c om bi nat i on wi t h le n vat i ni b i n h u ma n H C C xe n o graft m o dels. Ca ncer 
Res . 2 0 1 8; 7 8 ( 1 3 _ S u p pl e me nt): 2 9 2 7.
Y a m a d a K, H ori  Y, I n o ue S, Ya ma mot o Y, Is o K, Ka mi ya ma H, et al. E 7 3 8 6, a selecti ve 
i n hi bit or of t he i nteracti o n bet wee n β-cate ni n a n d C B P, e xerts a ntit u m or acti vit y i n t u mor 
m o dels wi t h acti vated ca n o nical W nt si g nali n g. Ca ncer Res. 2 0 2 1; 8 1 : 1 0 5 2- 6 2.
Y o o C, Ki m J H, R y u M H, Par k S R, Lee D, Ki m K M, et al. Cli nical O utc o mes wit h 
M ul tiki nase I n hi bit ors after Pr o gressi o n o n First -Li ne Atez oliz u ma b pl us Be vaciz u ma b i n 
P ati e nts wit h A d va nce d He pat ocell ular Carci n o ma : A M ulti nati onal M ult ice nter 
Retr os pecti ve St u d y . Li ver Ca ncer. 2 0 2 1 ; 1 0( 2): 1 0 7– 1 4.
Z ha n g X, Sc h wartz J C, G u o X, B hat ia S, Ca o E, L ore nz M, et al. Str uct ural a n d f u ncti onal 
a nal ysis of t he c osti m ulat or y rece pt or pr o gra m me d deat h-1. I m m u nity.  2 0 0 4; 2 0: 3 3 7 -4 7.
Z h u A X, Ka n g Y K, Ye n CJ, Fi n n R S, Galle P R, Ll o vet J M, et al. Ra m ucir u ma b after 
s orafe ni b i n patient s wit h a d va nce d he pat ocell ular carci n oma a n d i ncrease d α- feto pr otei n 
c o nce ntrati o ns ( R E A C H -2): a ra n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olled, p hase 3 tri al. 
La ncet O nc o l. 2 0 1 9; 2 0( 2): 2 8 2– 9 6. 
Zi m mer L, A p uri S, Er o gl u Z, K ottsc ha de L A, F orsc h ner A, G utz mer R, et al. I pili m u ma b 
alo ne or i n c o m bi nat i on wi t h ni v ol u ma b after pr o gressi on o n a nt i-P D -1 t hera p y  in a d va nce d 
mela n o ma. E ur J Ca ncer . 2 0 1 7; 7 5: 4 7- 5 5.
C T C A E Refere nce
Ca ncer T hera p y  E val uati on Pr o gra m, C o m m o n Ter mi n o l og y  Crit eria for A d verse E ve nts 
(C T C A E) versi o n 5. 0 [ p u blis he d 2 7 N o v 2 0 1 7 ].  A vaila ble fr om : 
ht t ps://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati ons/ctc. ht m.

Cli nical St u d y  Pr ot oc ol
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C o nfi de ntial
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1 1
P R O C E D U R E S A N D I N S T R U C TI O N S (A D MI NI S T R A TI V E 
P R O C E D U R E S)
1 1. 1
C h a n g e s t o t h e Pr ot o c ol
A n y c ha n ge t o t he pr ot oc ol re q uires a writte n pr ot oc ol a me n d me nt or a d mi nistrati ve c ha n ge 
t hat must be a p pr o ve d b y  t he S p o ns or bef ore i m ple me ntati o n.  A me n d me nts s pecificall y 
a ffecti n g t he safety of  s u bjects, t he sc o pe of t he i n vesti gati o n, or t he scie ntific q uality of  t he 
st u d y r e q uire s u b missio n  t o healt h or re g ulat or y a ut h orities as well as a d ditio nal a p pr o val  b y 
t he a p plica ble I R Bs/I E Cs.  T hese re q uire me nts s h o ul d i n n o wa y  pre ve nt a n y  i m me diate 
actio n f r o m bei n g ta ke n b y t he i n vesti gat or, or b y t he S p o ns or , in t he i nterest of preser vi n g 
t he safet y of  all s u bjects i ncl u de d i n t he st u d y.  If t he i n vesti gat or deter mi nes t hat a n 
i m me diate c ha n ge t o or de viati on fr om t he pr ot oc ol is necessar y  for s af et y reas o ns t o 
eli mi nate a n i m me diate hazar d t o t he s u bjects, t he S p o ns or ’s me dical m onit or (or a p pr o priate 
st u d y t e a m me m ber) a n d t he I R B/I E C f or t he site m ust be n otifie d i m me diatel y.  T he 
S p o ns or m u st n otif y t he healt h or re g ulat or y a ut h orit y as re q uire d per lo c al  re g ulati ons.
Pr ot oc ol  a me n d me nts t hat affect o nl y a d mi nistrati ve as pects of t he st u d y ma y n ot re q uire 
s u b missi on t o healt h or re g ulat or y  a ut h orit y or t he I R B/I E C, b ut t he health or re g ulat or y  
a ut h orit y a n d I R B/I E C (or if re gi o nall y re q ui re d, t he hea d of t he me dical i nstituti o n) s h o uld 
be ke pt i nf or me d of s uc h c ha n ges as re q uire d b y l o cal re g ulatio ns.  I n t hese cases, t he 
S p o ns or ma y be re q uire d t o se n d a letter t o t he I R B/I E C a n d t he C o m pete nt A ut h orit ies (or, 
if re gi onall y  re q uire d, t he hea d of t he me dical i nstit uti o n) detaili n g s uc h c ha n ges.
1 1. 2
A d h er e n c e t o t h e Pr ot o c ol
T he i n vest i gat or will c o n d uct t he st u d y i n strict acc or da nce wit h t he pr ot oc ol (refer t o 
I C H E 6, Secti o n 4. 5).
1 1. 3
M o nit ori n g Pr o c e d ur e s
T he S p o ns or ’s/C R O’s C R A wi ll mai ntai n c o ntact wit h t he i n vest i gat or a n d desi g nate d staff 
b y tele p h o ne, letter, or e mail etc. bet wee n st u d y  visits.  M o nit ori n g visits t o eac h site will be 
c o n d ucte d b y t he assi g ne d C R A as descri be d i n t he m o nit ori n g pla n.  T he i n vesti gat or (or if 
re gi onall y  re q uire d, t he hea d of t he me dical i nstituti o n) will all o w t he C R A t o i ns pect t he 
cli nical, la b orat or y, a n d p har mac y facilities t o ass ure c o mplia nce wi t h G C P a n d lo c al  
re g ulat or y r e q uire me nts.  T he C R Fs a n d s u bject’s c orres p o n di n g ori gi nal me dical rec or ds 
(s o urce d oc u me nts) are t o be f ull y a vaila ble f or re vie w b y t he S p o ns or ’s re prese ntati ves at 
re g ular i nter vals.  T hese re vie ws verif y a d here nce t o st u d y pr ot oc ol a n d data acc urac y in 
acc or da nce wit h l ocal re g ulat i ons.  All rec or ds at t he site are s u b ject t o ins pect i on b y t he 
l ocal a u ditin g a ge nc y  a n d t o I R B/I E C re vie w.
I n acc or da nce wit h I C H E 6, Secti o n 1. 5 2, s o urce d oc u me nts i ncl u de, b ut are n ot li mite d t o ,
t he f o ll owi n g:

Cli nic, office, or h os pital c harts

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 5 of 2 1 0

C o pi es or tra nscri be d healt h care pr o vi der n otes t hat ha ve bee n certifie d f or acc urac y 
after pr o d uctio n

Rec or de d data fr o m a ut o mate d i nstr u me nts s uc h as I x R S, x -r a ys, a n d ot her i ma gi n g 
re p orts (e g, s o n o gra ms, C T sca ns, ma g netic res o na nce i ma ges, ra di oacti ve i ma ges, E C Gs, 
r h yt hm strips, E E Gs, p ol ys o m n o gra p hs, p ul m o nar y  fu nct i on tests) re gar dless of h o w 
t hese i ma ges are st ore d, i ncl u di n g micr o fic he a n d p h ot o gra p hic ne gati ves

Rec or ds of tele p h o ne c o nt acts

Di aries or e valuat i on c hec klists

Dr u g distri b ut i on a n d acc o u nta bilit y l ogs mai ntai ne d i n p har macies or b y  researc h 
pers o n nel

La b orat or y  res ults a n d ot her la b orat or y test o ut p uts 
 

C orr es p o n de nce re gar di n g a st u d y s u bject’s treat me nt bet wee n p h ysicia ns or me m ora n da 
se nt t o t he I R Bs/I E Cs

C R F c o m p o ne nts (e g, q uesti o n naires) t hat are c o m plete d directl y b y s u bjects a n d ser ve as 
t heir o w n s o urce

Electr o nic Cli nical O ut c o m e Assess me nt (e C O A)
1 1. 4
R e c or di n g of D at a
A C R F is re q uire d a n d m ust be c o m p lete d f or eac h s u bject b y q ualifie d a n d a ut h orize d 
pers o n nel.  All data o n t he C R F m ust reflect t he c orres p o n di n g s o urce d oc u me nt, e xce pt 
w he n a secti on of  t he C R F itself is use d as t he s o urce d oc u me nt.  An y c orrecti o n t o e ntries 
ma de o n t he C R F m ust be d oc u me nte d i n a vali d a u dit trail w here t he c orrecti o n is date d, t he 
i n di vi d ual ma ki n g t he c orrect is i de ntifie d, t he reas o n f or t he c ha n ge is state d, a n d t he 
ori gi nal  data are n ot o bsc ure d.  O nl y data re q uire d b y t he pr ot oc ol for t he p ur p oses of t he 
st u d y s h o uld be c ollecte d.
T he in vest i gat or m ust si g n eac h C R F.  T he i n vesti gat or will re p ort t he C R Fs t o t he S p o ns or
a n d retai n a c o p y of t he C R Fs.
1 1. 5
I d e ntifi c ati o n of S o ur c e D at a
All data t o be rec or de d o n t he C R F m u st reflect t he c orres p o n di n g s o urce d oc u me nts. F or t he 
f oll owi n g ite m (s), t he data rec or de d direct l y o n t he C R F are t o be c o nsi dere d s o urce data:

St u d y  dr u g c o mplia nce (e g, t he reas o n f or a n y  c ha n ge of d osa ge)

I n dicati on f or prior/c o nc o mita nt m e dicat i on ( dr u g/t hera p y )

Di sc o nti n uatio n i nf or mat i on (e g, i n t he case of l ost t o f oll o w -u p d ue t o t he s u bject 
c h o ice)

S a m pli n g date a n d ti me f or t he dr u g c o nce ntrati o n

S a m pli n g date f or t he cli nical la b orat or y  t est
C CI

Cli nical St u d y  Pr ot oc ol
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Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 6 of 2 1 0

C o m me nts a n d ot her i nf or mat i on o n A Es (e g, se verit y, relati ons hi p t o st u d y  dr u g, 
o utc o m e)
1 1. 6
R et e nti o n of R e c or d s
T he ci rc u msta nces of c o mplet i on or ter mi nat i on of t he st u d y  not wi t hsta n di n g, t he 
i n vesti gat or (or if re gi o nall y re q uire d, t he hea d of t he me dical i nst ituti o n or t he desi g nate d 
re prese ntative) is res p o nsi ble f or retai ni n g all st u d y d oc u me nts, i ncl u di n g b ut n ot li mite d t o 
t he pr ot oc ol, c o pies of C R Fs, t he I n vest i gat or's Br oc h ure, a n d re g ulat or y a ge nc y re gistrati o n 
d oc u m e nts (e g, F or m F D A 1 5 7 2 f or U S sites), I n vesti gat or a n d Site I nf or mati o n F or m  (for 
n o n- U S si tes), I C Fs, a n d I R B/I E C c orres p o n de nce. T he site s h o ul d pla n t o retai n st u d y 
d oc u m e nts, u nless ot her wise i nstr ucte d b y t he S p o ns or , for at least 1 5 y e ars fol l owi n g t he 
c o mplet i on of t he st u d y .
It is re q ueste d t hat at t he c o m pleti o n of t he re q uire d rete nti o n peri o d, or s h o ul d t he 
i n vesti gat or retire or rel ocate, t he i n vesti gat or c o ntact t he S p o ns or , all o wi n g t he S p o ns or t he 
o pti o n of  p er ma ne nt l y retai ni n g t he st u d y rec or ds.
1 1. 7
A u diti n g Pr o c e d ur e s a n d I n s p e cti o n
I n a d diti on t o r o uti ne m o nit ori n g pr oce d ures, t he S p o ns or ’s Cli nical Q uality Ass ura nce 
de part m e nt c o n d ucts a u dits of cli nical researc h acti vities i n acc or da nce wit h t he S p o ns or ’s 
S O Ps t o e val uate c o m plia nce wit h t he pri nci ples of I C H G C P a n d all a p plica ble l ocal 
re g ulat i ons.  If a g o ver nme nt re g ulat or y  a ut h orit y re q uests a n i ns pecti on d uri n g t he st u d y  or 
aft er its c o mplet i on, t he i n vest i gat or m ust i nf or m t he S p o ns or i m me diatel y.
1 1. 8
H a n dli n g of St u d y Dr u g
All st u d y dr u g will be s u p plie d t o t he pri nci pal i n vesti gat or (or a desi g nate d p har m acist) b y 
t he S p o ns or . Dr u g s u p plies m ust be ke pt i n a n a p pr o priate sec ure area (e g, l oc ke d ca bi net) 
a n d st ore d acc or di n g t o t he c o n dit i ons s pecifie d o n t he dr u g la bels.  T he i n vest i gat or (or a 
desi g nate d p har macist) m ust mai ntai n a n a cc urate rec or d of t he s hi p me nt a n d dis pe nsi n g of 
t he st u d y dr u g i n a dr u g acc o u nta bility le d ger, a c o p y of w hic h must be gi ve n t o t he S p o ns or
at t he e n d of t he st u d y.  A n acc urate rec or d of t he date a n d a m o u nt of st u d y dr u g dis pe nse d t o 
eac h s u bject m ust be a vaila ble f or i ns pect i on at a n y t i me.  T he C R A will visit t he site a n d 
re vie w t hese d oc u me nts al o n g wit h all ot her st u d y c o n d uct d oc u me nts at a p pr o priate 
i nter vals o nce st u d y dr u g has bee n recei ve d b y t he site.
All dr u g s u p plies are t o be use d o nl y f or t his st u d y a n d n ot f or a n y ot her p ur p ose.  T he 
i n vesti gat or (or si te pers o n nel) m ust n ot destr o y a n y dr u g la bels or a n y partl y use d or u n use d 
dr u g s u p pl y bef ore a p pr o val t o d o s o b y  t he S p o ns or .  At t he c o ncl usi on of t he st u d y  a n d as 
a p pr o priate d uri n g t he st u d y, t he i n vesti gat or (or a desi g nate d p har macist) will ret ur n all use d 
a n d u n use d dr u g c o ntai ners, dr u g la bels, a n d a c o p y of t he c o mplete d dr u g di s p ositio n  for m  
t o t he S p o ns or ’s C R A (or desi g nate d c o ntract or) or, w he n a p pr o val is gi ve n b y  t he S p o ns or , 
will destr o y  s u p plies a n d c o ntai ners at t he site.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 7 of 2 1 0
1 1. 9
P u bli c ati o n of R e s ult s
All ma n uscri pts, a bstracts, or ot her m o des of prese ntati o n arisi n g fr o m t he res ults of t he 
st u d y must be re vie we d a n d a p pr o ve d i n writ i n g b y t he S p o ns or i n a d va nce of s u b missi on 
p urs u a nt t o t he ter ms a n d c o n dit i ons set f ort h i n t he e xec ute d Cli nical Trial A gree me nt 
bet wee n t he S p o ns or / C R O a n d t he i nstituti o n/i n vesti gat or.  T he re vie w is ai me d at pr otecti n g 
t he S p o ns or 's pr o prietar y inf or m at i on e xist i n g eit her at t he date of t he c o m me nce me nt of t he 
st u d y or ge nerate d d uri n g t he st u d y.
T he detaile d o bli gat i ons re gar di n g t he p u blicat i on of  a n y data, mat erial r es ults, or ot her 
i nf or mat i on ge nerate d or create d i n relati o n t o t he st u d y  s hall be set o ut i n t he a gree me nt 
bet wee n eac h i n vesti gat or a n d t he S p o ns or or C R O, as a p pr o priate.
1 1. 1 0 Di s cl o s ur e a n d C o nfi d e nti alit y
T he c o nte nts of t his pr ot oc ol a n d a n y a me n d me nts a n d res ults o btai ne d d uri n g t he st u d y  
s h o uld be ke pt c o nfi de nt ial b y t he i n vest i gat or, t he i n vesti gat or’s staff, a n d t he I R B/I E C a n d 
will n ot be discl ose d i n w h o le or i n part t o ot hers, or use d f or a n y p ur p ose ot her t ha n 
re vie wi n g or perf or mi n g t he st u d y, wit ho ut t he writte n c o nse nt of t he S p o ns or .  N o data 
c ollecte d as part of t his st u d y will be use d i n a n y writte n w or k, i ncl u di n g p u blicati ons, 
wi t ho ut t he wri tte n c o nse nt of t he S p o ns or .  T hese o bli gati ons of c o nfi de nt iality a n d n o n -use 
s hall i n n o wa y di mi nis h s uc h o bli gati ons as set f ort h i n eit her t he C o nfi de ntialit y A gree me nt 
or Cli nical Trial A gree me nt e xec ute d bet wee n t he S p o ns or / C R O a n d t he 
i nstituti o n/i n vest i gat or.
All pers o ns assist i n g i n t he perf or ma nce of t his st u d y must be b o u n d b y t he o bli gat i ons of 
c o nfi de nt iality a n d n o n-use set f ort h i n eit her t he C o nfi de ntialit y A gree me nt or Cli nical Trial 
A gree me nt e xec ute d bet wee n t he i nstit uti o n/i n vesti gat or a n d t he S p o ns or / C R O.
1 1. 1 1 Di s c o nti n u ati o n of St u d y
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y for m e dical reas o ns or a n y ot her 
reas o n at a n y ti me.  If a st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or will 
pr o m ptl y i nf or m t he i n vest i gat ors/i nstit uti o ns a n d re g ulat or y a ut h orities of t he ter mi nat i on or 
s us pe nsi o n a n d t he reas o n(s) for t he ter mi nat i on or s us pe nsi o n.  T he I R B/I E C will als o be 
i nf or me d pr o mpt l y a n d pr o vi de d t he reas o n(s) f or t he ter mi nati on or s us pe nsi o n b y t he 
S p o ns or or b y  t he i n vesti gat or/i nstitut i on, as s pecifie d b y  t he a p plica ble re g ulat or y 
re q uire me nt(s).
T he i n vest i gat or reser ves t he ri g ht t o disc o nti n ue t he st u d y s h o uld his/ her j u d g me nt s o 
di ctate.  If t he i n vesti gat or ter mi nates or s us pe n ds a st u d y wit ho ut pri or a gree m e nt of t he 
S p o ns or , t he i nvest i gat or s h o ul d i nf or m t he i nstituti o n w here a p plica ble, a n d t he 
i n vesti gat or/i nstituti o n s h o ul d pr o m ptl y i nf or m t he S p o ns or a n d t he I R B/I E C a n d pr o vi de t he 
S p o ns or a n d t he I R B/I E C wit h a detaile d writte n e x pla nat i on of t he ter mi nat i on or 
s us pe nsi o n.  Stu d y rec or ds m ust be retai ne d as n ote d a b o ve.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 8 8 of 2 1 0
1 1. 1 2 S u bj e ct I n s ur a n c e a n d I n d e m nit y
T he S p o ns or will pr o vi de i ns ura nce f or a n y s u bjects partici pat i n g i n t he st u d y i n acc or da nce 
wi t h all a p plicable la ws a n d re g ulat i ons.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 0 of 2 1 0
A p p e n di x 2
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
Sc ale
E C O G Perf or m a nce St at us
0
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n
1
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se de ntar y nat ure (e g, li g ht h o use w or k, office w or k)
2
A m b ulat or y a n d ca pa ble of all self -care, b ut u na ble t o carr y o ut a n y w or k 
acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs
4
C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or 
c hair.
5
Dea d
E C O G = Easter n C o o perati ve Gr o u p.
A da pte d f r om O ke n M M, Creec h R M, T or me y D C, H ort o n J, Da vis T E, Mc Fa d de n T, et al. T o xicit y a n d 
res p o nse criteria of t he Easter n C o o perati ve O nc ol o g y Gr o u p, et al. A m J Cli n O nc ol. 1 9 8 2; 5( 6): 6 4 9-5 5.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 1 of 2 1 0
A p p e n di x 3
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 1. 1
T u m or res p o nse assess me nts i n t his cli nical st u d y will use Res p o nse E val uat i on Cri t eria i n 
S oli d T u m o u rs ( R E CI S T 1. 1) base d o n t he 2 0 0 9 article b y Ei se n ha uer, et al. e nt itle d, Ne w 
Res p o nse E val uat i on Cri t eria i n S oli d T u m ors:  re vise d R E CI S T g ui deli ne ( vers i on 1. 1).
T he s o le m o dificat i on t o R E CI S T 1. 1 t o be i m ple me nte d i n t his st u d y  is t hat c hest x-r a ys 
ma y n ot be use d t o f o ll ow disease; o nl y  C T sca ns ma y be use d t o f oll o w c hest disease.  As 
re q uire d b y R E CI S T 1. 1, t he pr ot oc ol states t hat t he mi ni m u m d uratio n of  S D is 7 wee ks 
f oll owi n g t he date of first d ose of st u d y  dr u g.   
T he Ei se n ha uer article, a vaila ble o nli ne at: Ei se n ha uer E A, T herasse P, B o gaerts J, Sc h wartz 
L H, Sar ge nt D, F or d R, et al. Ne w res p o nse e val uati o n criteria i n s o li d t u m o urs: Re vise d 
R E C I S T g uideli ne ( versi o n 1. 1). E u J Ca ncer . 2 0 0 9; 4 5( 2): 2 2 8- 4 7. Retrie ve d at 
ht t p://li n ki n g h u b.else vier.c om/retrie ve/ pii/ S 0 9 5 9 8 0 4 9 0 8 0 0 8 7 3 3 .

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 2 of 2 1 0
A p p e n di x 4  
C hil d- P u g h Cl a s sifi c ati o n
P ar a meter
Sc ore a
1
2
3
Ascite s
A bse nt
Mil d
( Res p o n d t o treat me nt)
M o derate
( Refract or y)
Ser u m bilir u bi n ( m g/ d L)
< 2. 0
2. 0 – 3. 0
> 3. 0
Ser u m al b u mi n ( g/ d L)
> 3. 5
2. 8 – 3. 5
< 2. 8
I N R
< 1. 7
1. 7 – 2. 3 0
> 2. 3 0
E nce p hal o pat h y b
0
1 – 2
3 – 4
I N R = i nter nati o nal n or malize d rati o.
a: C hil d -P u g h A: 5 or 6 p oi nts; C hil d -P u g h B: 7 – 9 p oi nts; C hil d -P u g h C: > 9 p oi nts.
b: E nce p hal o pat h y gra des defi ne d as f oll o ws:
G ra de 0: n or mal c o nsci o us ness, pers o nalit y, ne ur ol o gical e xa mi nati o n, electr oe nce p hal o gra m 
G ra de 1: restless, slee p dist ur be d, irrita ble/a gitate d, tre m or, i m paire d ha n d writi n g, 5 c ps (c ycles per sec o n d) 
wa ves 
G ra de 2: let har gic, ti me-dis orie nte d, i na p pr o priate, asteri xis, ata xia, sl o w tri p hasic wa ves 
G ra de 3: s o m n ole nt, st u p or o us, place-dis orie nte d, h y peracti ve refle xes, ri gi dit y, sl o wer wa ves
Gra de 4: u nr o usa ble, c o ma, n o pers o nalit y/ be ha vi or, de cere brate, sl o w 2 – 3 c ps delta acti vit y

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 3 of 2 1 0
A p p e n di x 5  
N e w Y or k H e art A s s o ci ati o n C ar di a c Di s e a s e 
Cl a s sifi c ati o n
T he Ne w Y or k Heart Ass ociat i on Car diac Disease Classificat i on pr o vi des a f u ncti onal a n d 
t hera pe utic classificati o n f or t he prescri pt i on of  p h ysical acti vit y for c ar di ac s u bjects.  Base d 
o n N Y H A defi nit i ons, s u bjects are t o be classifie d as f o ll ows:
Cl ass
N Y H A St at us
Class I:
S u bjects wit h n o li mitati o n of acti vities; t he y s uffer n o s y m pt o ms fr o m or di nar y 
acti vities.
Class II:
S u bjects wit h sli g ht, mil d li mitati o n of acti vit y; t he y are c o mf orta ble wit h rest or wit h 
mil d e xerti o n.
Class III:
S u bjects wit h mar ke d li mitati o n of acti vit y; t he y are c o mf orta ble o nl y at rest.
Class I V:
S u bjects w h o s h o ul d b e  at c o m plete r est, c o nfi ne d t o be d or c ha ir; a n y p h ysical 
acti vit y bri n gs o n disc o mf ort a n d s y m pt o ms occ ur at rest.
N Y H A = Ne w Y or k Heart Ass ociati o n.
A da pte d fr o m T he Criteria C o m mittee of t he N Y H A .  N o me nclat ure a n d criteria f or dia g n osis of diseases of 
t he heart a n d great vessels.  9t h e d. Ne w Y or k: Little Br o w n; 1 9 9 4. p. 2 5 3 -6.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 4 of 2 1 0
A p p e n di x 6
B ar c el o n a Cli ni c Li v er C a n c er St a gi n g S y st e m 
E ur o pea n Ass ociati o n f or T he St u d y of t he Li ver; E ur o pea n Or ga nisati o n f or Researc h an d Treat me nt o f 
Ca ncer .  E A S L C li nical P ractice G ui deli nes: M a na ge me nt of he pat ocell ular carci n o ma.  J He pat ol. 2 0 18
A pr; 5 6( 4): 9 0 8 -4 3.  Errat u m t o: ‘‘ E A S L – E O R T C Cli nical Practice G ui deli nes: Ma na ge me nt of he pat ocell ular 
carci n o ma’’ [J He pat ol 2 0 1 2; 5 6: 9 0 8 -4 3]. J He pat ol. 2 0 1 2.  I n press.  htt p:// w w w.easl.e u/ _cli nical -practice -
g ui deli ne/iss ue - 7-A pril -2 0 1 2 -ma na ge me nt -of -he pat ocell ular -carci n o ma

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 5 of 2 1 0
A p p e n di x 7
P h ar m a c o d y n a mi c, P h ar m a c o g e n o mi c, a n d Ot h er 
Bi o m ar k er R e s e ar c h
O bjecti ve
S u bjects e nr o lle d i n t his cli nical st u d y will ha ve bi ol o gic sa m ples c ollecte d f or P D , P G, a n d 
ot her bi o mar ker a nal ysis.  T hese sa m ples ma y be use d f or disc o ver y a n d vali dati o n t o 
i de ntif y bi o mar kers t hat ma y be use d f or e x pl orat or y  e valu ati o n of  res p o nse a n d/ or safety-
r elate d o utc o mes as well as f or use i n dia g n ostic de vel o p me nt.
T he P G sa m ples ma y be use d t o i de nt if y ge netic fact ors t hat ma y i nfl ue nce a s u bject’s 
e x p os ure t o t he st u d y dr u g, as well as ge netic fact ors t hat ma y ha ve an effect o n cli nical 
res p o nse or p ote ntial A Es r elate d t o st u d y dr u g , a n d t o e x pl ore t he r ole of ge netic varia bility 
i n res p o nse.  Sa m ples ma y be a nal yze d t o deter mi ne a s u bject’s ge n ot ypes or se q ue nce f or a 
n u m ber of ge nes or n o n -c o di n g re g ulat or y re gi o ns .  T he researc h ma y i ncl u de t he 
i n vesti gati on of p o l y m or p his ms i n ge nes t hat are li kel y t o i nfl ue nce t he st u d y dr u g P K or 
t hera pe utic res p o nse.
C ollect i on of t he P D , P G, a n d ot her bi omar ker sa m ples will be b o u n d b y t he sa m ple 
pri nci ples a n d pr ocesses o utli ne d i n t he mai n st u d y pr ot oc ol.  Sa m ple c o llecti on f or P D , P G, 
a n d ot her bi o mar ker a nal ysis is re q uire d as per t he st u d y pr ot oc ol u nless t he c ollect i on a n d 
use of t he sa m ples is pr o hi bite d b y s pecific c o u ntr y la ws.
S a m pl e C oll e cti o n a n d H a n dli n g
T he sa m ple s will be c ollecte d acc or di n g t o t he st u d y fl ow c hart.  If, f or o perati o nal or 
me dical reas o ns, t he ge n o mic D N A bl o o d sa m ple ca n n ot be o btai ne d at t he pres pecifie d visit, 
t he sa mple ca n be ta ke n at a n y  st u d y ce nter visit at t he discreti o n of t he i n vesti gator a n d site 
staff.
S e c urit y of t h e S a m pl e s, U s e of t h e S a m pl e s, R et e nti o n of t h e S a m pl e s
S a m ple pr ocessi n g, f or e xa m ple D N A a n d/ or R N A e xtracti o n, ge n ot y pi n g, se q ue nci n g, or 
ot her a nal ysis will be perf or me d b y a la b orat or y  u n der t he directi on of t he S p o ns or .  
Pr ocessi n g, a nal ysis, a n d st ora ge will be perf or me d at a sec ure la b orat or y facilit y t o pr otect 
t he vali dit y of  t he data a n d mai ntai n s u bject pri vac y.
S a m ples will  o nl y be use d f or t he p ur p oses descri be d i n t his pr ot oc ol.  La b orat ories 
c o ntracte d t o perf or m t he a nal ysis o n be half of t he S p o ns or will n ot retai n ri g hts t o t he 
sa m ples be yo n d t h ose necessar y  t o perf or m t he s pecifie d a nal ysis a n d will n ot tra nsfer or sell 
t hose sa m ples.  T he S p o ns or will n ot sell t he sa m ples t o a t hir d part y .
S a m ples wi ll be st ore d f or u p t o 1 5 y ears after t he c o m plet i on of t he st u d y  ( defi ne d as 
s u b missi on of t he cli nical st u d y  re p ort t o t he a p pr o priate re g ulat or y a ge ncies).  At t he e n d of 
t he st ora ge peri o d, sa m ples will be destr o ye d.  Sa m ples ma y be st ore d lo n ger if a healt h 
a ut h orit y ( or me dici nal pr o d uct a p pr o val a ge nc y) has acti ve q uestio ns a b o ut t he st u d y .  I n 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 6 of 2 1 0
t his s pecial circ u msta nce, t he sa mples will  be st ore d u ntil t he q uest i ons ha ve bee n a de q uatel y 
a d dresse d.
It is p ossi ble t hat f ut ure researc h a n d tec h n ol o gical a d va nces ma y i de ntif y ge n omic varia nts 
of  int erest, or all o w alter nat i ve t y pes of ge n omic a nal ysis n ot f oresee n at t his t i me.  Beca use 
it is n ot p ossi ble t o pr os pecti vel y defi ne e ver y a ve n ue of f ut ure testi n g, all sa m ples c ollecte d 
will be si n gle or d o u b le c o de d (acc or di n g t o t he I C H E 1 5 g ui deli nes) i n or der t o mai ntai n 
s u bject pri vac y. 
Ri g ht t o Wit h dr a w
If, d uri n g t he ti me t he sa m ples are st ore d, a s u bject w o ul d li ke t o wi t hdra w his/ her c o nse nt 
f or p articip ati o n i n t his researc h, Eisai will destr o y t he sa m ples.  I nf or mati o n fr om a n y assa ys 
t hat ha ve alrea d y bee n c o m p lete d at t he ti me of wit h dra wal of c o nse nt will c o nti n ue t o be 
use d as necessar y  t o pr otect t he i nte grit y of t he researc h pr oject.
S u bj e ct Pri v a c y a n d R et ur n of D at a
N o s u bj ect -i de ntif yi n g i nf or mat i on (e g, i nit ials, date of birt h, g o ver n me nt i de ntif yi n g 
n u m ber) will be ass ociate d wit h t he sa m ple.  All P D a n d ot her bi o mar ker sa m ples will be 
si n gle c o de d.  Ge n o mic D N A sa m ples use d t o e x pl ore t he effects o n P K, treat me nt res p o nse, 
a n d safet y will be si n gle c o de d.  Ge n o mic D N A sa m ples t hat will be st ore d f or l o n g -t er m use 
( defi ne d as 1 5 years after t he c o m plet i on of t he st u d y ) will be d o u ble c o de d.  
D o u bl e c o di n g i n v o l ves re m o vi n g t he i nitial c o de (s u bject I D) a n d re placi n g wit h a n ot her 
c o de s uc h t hat t he s u bject ca n be re-i de ntifie d b y use of 2 c o de ke ys.  T he c o de ke ys are 
us uall y hel d b y differe nt parties.  T he ke y  li n ki n g t he sa m ple I D t o t he s u bject n u m ber will 
be mai ntai ne d se paratel y fr o m t he sa mple.  At t hi s p oi nt, t he sa m ples will be d o u ble- c o de d, 
t he first c o de bei n g t he s u bject n u m ber.  La b orat or y pers o n nel perf or mi n g ge net ic a nal ysis 
will n ot ha ve access t o t he “ ke y.”  Cli nical data c ollecte d as part of t he cli nical trial will be 
clea ne d of s u bject i de nt if yi n g i nf or mati o n a n d li n ke d b y use of t he sa m ple I D “ ke y. ”
T he S p o ns or will ta ke ste ps t o e ns ure t hat data are pr otecte d acc or di n gl y a n d c o nfi de ntialit y 
is mai ntai ne d as far as p ossi ble.  Data fr o m s u bjects e nr o lle d i n t his st u d y ma y be a nal yze d 
w orl d wi de, re gar dless o f l ocatio n of  c ollect i on.
T he S p o ns or a n d its re prese ntati ves a n d a ge nts ma y s hare c o de d data wit h pers o ns a n d 
or ga ni zat i ons i n v ol ve d i n t he c o n d uct or o versi g ht of t his researc h.  T hese i ncl u de:

Me dical i nst ituti o ns

Cli nical researc h or ga nizat i ons retai ne d b y t he S p o ns or

IE Cs or I R Bs t hat ha ve res p o nsi bilit y f or t his researc h st u d y 

Nati o nal re g ulat or y  a ut h orities or e q ui vale nt g o ver n me nt a ge ncies
At  t he e n d of t he a nal ysis, res ults ma y be prese nte d i n a fi nal re p ort w hic h ca n i ncl u de part or 
all o f t he c o de d data, i n listi n g or s u m mar y for m at.  Ot her p u blicat i on (e g, i n peer -re vie we d 

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 7 of 2 1 0
scie ntific j o ur nals) or p u blic prese ntati o n of t he st u d y res ults will o nl y incl u de s u m maries of 
t he p o p ulatio n i n t he st u d y , a n d n o ide nt ifie d i n di vi d ual res ults will be discl ose d.
Gi ve n t he researc h nat ure of t he P D , P G, a n d ot her bi omar ker a nal ysis, it will n ot be p ossi ble 
t o ret ur n i n di vi d ual data t o s u bjects.  T he res ults t hat ma y be ge nerate d are n ot c urre ntl y 
a nt ici pate d t o ha ve cli nical rele va nce t o t he s u bjects or t hei r fa mil y me m bers.  T heref ore, 
t hese res ults will n ot be discl ose d t o t he s u bjects or t heir p h ysicia ns.
If at a n y time, P D , P G, a n d/ or ot her bi omar ker res ults are o btai ne d t hat ma y ha ve cli nical 
r ele va nce, I R B re vie w a n d a p pr o val will be s o u g ht t o deter mi ne t he m ost a p pr o pri at e ma n ner 
of  dis clos ure a n d t o deter mi ne w het her or n ot vali dati o n i n a Cli nical La b orat or y  
I mpr o ve m e nt A me n d me nts ( C LI A)- certifie d setti n g will be re q uire d.  S hari n g of researc h 
data wi t h in di vi d ual s u bjects s h o uld o nl y  occ ur w he n data ha ve bee n validate d b y  mul tiple 
st u dies a n d testi n g has bee n d o ne i n C LI A-a p pr o ve d la b orat ories.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 8 of 2 1 0
A p p e n di x 8
T u m or, N o d e, a n d M et a st a si s St a gi n g of H e p at o c ell ul ar 
C ar ci n o m a, C ol or e ct al C a n c er a n d M el a n o m a 
T he T N M (t u m or - n o de-met astasis) classificat i on f or sta gi n g of he p at ocell ul ar c arci n o m a
per t he AJ C C is pr o vi de d bel o w:
Pri m ar y t u m or ( T)
T X
Pri mar y  t u m or ca n n ot be assesse d
T 0
N o e vi de nce of pri mar y t u m or
T 1
S olitar y t u m or ≤2 c m, or > 2 c m wit h o ut vasc ular i n vasi o n
T 1a
S olitar y t u m or ≤2 c m
T 1 b
> 2 c m wit h o ut vasc ular i n vasi o n
T 2
S olitar y t u m or > 2 c m wit h vasc ular i n vasi o n, or m ulti ple t u m ors, n o ne > 5 c m
T 3
M ulti ple t u m ors, at least o ne of w hic h > 5 c m
T 4
Si n gle t u m or or m ulti ple t u m ors of a n y size i n v ol vi n g a maj or bra nc h of t he p ortal or he patic vei n, or
t um or(s) wit h direct i n vasi o n of a djace nt or ga ns ot her t ha n t he gall bla d der or wit h perf orati o n of 
visceral perit o ne u m
Re gi o n al l y m p h n o des ( N)
N X
Re gi o nal l y m p h n o des ca n n ot be assesse d
N 0
N o re gi o nal l y m p h n o de metastasis
N 1
Re gi o nal l y m p h n o de metastasis
Dist a nt met ast asis ( M)
M 0
N o dista nt metastasis
M 1
Dista nt metastasis
A n at o mic st a ge/ pr o g n ostic gr o u ps
St a ge
T
N
M
I A
T 1a
N 0
M 0
I B
T 1 b
N 0
M 0
II
T 2
N 0
M 0
III A
T 3
N 0
M 0
III B
T 4
N 0
M 0
I V A
A n y  T
N 1
M 0
I V B
A n y  T
A n y  N
M 1
T he T N M (t u m or - n o de-met astasis) classificat i on f or sta gi n g of c ol o rect al c a ncer per t he 
A merica n J o i nt C o m mittee o n Ca ncer ( AJ C C) is pr o vi de d bel o w:

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 1 9 9 of 2 1 0
Pri m ar y t u m or ( T)
T X
Pri mar y  t u m or ca n n ot be assesse d
T 0
N o e vi de nce of pri mar y t u m or
Tis
Carci n o ma i n sit u, i ntra m uc osal carci n o ma (i n v ol ve me nt of la mi na pr o pria wit h n o e xte nsi o n 
t hr o u g h m usc ularis m uc osae)
T 1
T u m o r i n va des t he s u b m uc osa (t hr o u g h t he m usc ularis m uc osa b ut n ot i nt o t he m usc ularis pr o pria)
T 2
T u m o r i n va des t he m usc ularis pr o pria
T 3
T u m o r i n va des t hr ou g h t h e m usc ularis pr o pria i nt o peric ol orectal tiss ues
T 4
T u m o r i n va des t he visceral perit o ne u m or i n va des or  a d heres t o a djace nt or ga n or str uct ure
T 4a
T u m o r i n va des t hr o u g h t he visceral perit o ne u m (i ncl u di n g gr oss perf orati o n of t he b o wel t hr o u g h 
t u m or a n d c o nti n u o us i n vasi o n of t u m or t hr o u g h areas of i nfla m mati o n t o t he s urface of t he visceral 
perit o ne u m) 
T 4 b
T u m o r direct i n va des or a d heres t o a djacent or ga ns or str uct ures
Re gi o n al l y m p h n o des ( N)
N X
Re gi o nal l y m p h n o des ca n n ot be assesse d
N 0
N o re gi o nal l y m p h n o de metastasis
N 1
O ne t o t hree re gi o nal l ym p h n o de s are p ositi ve (t u m or i n l y m p h n o des meas uri n g ≥0. 2 m m), or a n y 
n u m ber of t u m or de p osits are prese nt a n d all i de ntifia ble l y m p h n o des are ne gati ve
N 1a
O ne re gi o nal l ym p h n o de is p ositi ve
N 1 b
T w o or  t hree re gi o nal l y m p h n o des are p ositi ve
N 1c
N o re gi o nal l y m p h n o des are p ositi ve, b ut t here are tu m or de p osits i n t he s u bser osa mese nter y or  
n o n p erit onea lize d peric olic, or perirectal /mes orectal tiss ues
N 2
F o ur or m o re re gi o nal l ym p h n o des are p ositi ve
N 2a
F o ur t o si x re gi o nal l y m p h n o des are p ositi ve
N 2 b
S e ve n or m ore re gi o nal l ym p h n o des are p ositi ve
Dist a nt met ast asis ( M)
M 0
N o dista nt metastasis b y i ma gi n g, etc . ; n o e vi de nce of t u m or i n dista nt sites or or ga ns (this
cate g or y is n ot assi g ne d b y pat h ol o gists)
M 1
Dista nt metastasis t o o ne or m ore dista nt sites or or ga ns or perit o neal metastasis is i de ntifie d
M 1a
Metastasis t o o ne site or or ga n is i de ntifie d wit h o ut perit o neal metastasis
M 1 b
Metastasis t o t w o or m ore sites or or ga ns is i de ntifie d wit h o ut perit o neal metastasis
M 1c
Metastasis t o t he perit o neal s urface is i de ntifie d al o ne or wit h ot her site or or ga n metastasis
A n at o mic st a ge/ pr o g n ostic gr o u ps
St a ge
T
N
M
0
Tis
N 0
M 0
I
T 1 , T 2
N 0
M 0
II A
T 3
N 0
M 0
II B
T 4a
N 0
M 0
II C
T 4 b
N 0
M 0
III A
T 1 -T 2
N 1/ N 1c
M 0
III A
T 1
N 2a
M 0

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 0 0 of 2 1 0
St a ge
T
N
M
III B
T 3 -T 4a
N 1/ N 1c
M 0
III B
T 2 -T 3
N 2a
M 0
III B
T 1 -T 2
N 2 b
M 0
III C
T 4a
N 2a
M 0
III C
T 3 -T 4a
N 2 b
M 0
III C
T 4 b
N 1 -N 2
M 0
I V A
A n y  T
A n y  N
M 1a
I V B
A n y  T
A n y  N
M 1 b
I V C
A n y  T
A n y  N
M 1c
T he T N M (t u m or - n o de-met astasis) classificat i on f or sta gi n g of mel a n o m a per t he AJ C C is 
pr o vi de d bel o w:
Pri m ar y t u m or ( T)
C ate g or y
T hic k ness
Ulcer ati o n st at us
T X: pri mar y t u m or ca n n ot be assesse d
N ot A p plica ble
T 0: N o e vi de nce of pri mar y t u m or
N ot A p plica ble
Tis ( mela n o ma i n sit u)
N ot A p plica ble
T 1
≤1. 0 m m
U n k n o w n or  u ns pecifie d
  T 1a
≤0. 8 m m
W it h o ut ulcerati o n
  T 1 b
≤0. 8 m m
0. 8 -1. 0 m m
W it h ulcerati on
W it h or wit h o ut ulcerati o n
T 2
> 1. 0 -2. 0 m m
U n k n o w n or  u ns pecifie d
  T 2a
> 1. 0 -2. 0 m m
W it h o ut ulcerati o n
  T 2 b
> 1. 0 -2. 0 m m
W it h ulcerati on
T 3
> 2. 0 -4. 0 m m
U n k n o w n or  u ns pecifie d
  T 3a
> 2. 0 -4. 0 m m
W it h o ut ulcerati o n
  T 3 b
> 2. 0 -4. 0 m m
W it h ulcerati on
T 4
> 4. 0 m m
U n k n o w n or  u ns pecifie d
  T 4a
> 4. 0 m m
W it h o ut ulcerati o n
  T 4 b
> 4. 0 m m
W it h ulcerati on
Re gi o n al l y m p h n o des ( N)
C ate g or y
N u m ber of t u m or -i n v ol ve d
Prese nce of i n -tr a nsit, s atellite, 
a n d/ or micr os atellites met ast as es
N X
Re gi o nal l y m p h n o des ca n n ot be assesse d
E xce pti o n: pat h ol o gical N cate g or y is n ot re q uire d 
f or T 1 mela n o mas , use c N, if re gi o nal l ym p h n o des 
n ot assesse d f or s u bject wit h T 1 mela n o ma
N o
N 0
N o re gi o nal l y m p h n o de metastasis
N o
N 1
O ne t u m o r-i n v ol ve d n o de or a n y n u m ber of i n-
tra nsit, satellite, a n d/ or micr osatellite metastases 
wit h n o t u m or -i n v ol ve d n o des

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 0 1 of 2 1 0
  N 1a
O ne cli nicall y occ ult
N o
  N 1 b
O ne cli nicall y detecte d
N o
  N 1c
N o re gi o nal l ym p h n o de disease
Yes
N 2
T w o or  t hree t u m or-i n v ol ve d n o des or a n y n u m ber 
of i n -tra nsit, satellite, a n d/ or
micr osatellite metastases wit h o ne t u m or -i n v ol ve d 
n o de
  N 2a 
T w o or  t hree cli nicall y occ ult
N o
  N 2 b
T w o or  t hree, at least o ne of w hic h was cli nicall y 
detecte d
N o
  N 2c
O ne cli nicall y occ ult or cli nicall y detecte d
Yes
N 3
F o ur or m ore t u m or -i n v ol ve d n o des or a n y n u m ber 
of i n -tra nsit, satellite, a n d/ or micr osatellite 
metastases wit h t w o or m ore t u m or -i n vol ve d n o des, 
or  a n y n u m ber of
matte d n o des wit h o ut or wit h i n -tra nsit, satellite, 
a n d/ or micr osatellite metastases
  N 3a
F o ur or m ore cli nicall y occ ult
N o
  N 3 b
F o ur or m ore, at least o ne of w hic h was cli nicall y 
detecte d, or prese nce of a n y n u m ber
of matte d n o des
N o
  N 3c
T w o or  m ore cli nicall y occ ult or cli nicall y detecte d 
a n d/ or prese nce of a n y n u m ber of
matte d n o des
Yes
Dist a nt met ast asis ( M)
C ate g or y
A n at o mic site
L D H le vel
M 0
N o e vi de nce of dista nt metastasis
N ot a p plica ble
M 1
E vi de nce of dista nt metastasis
See bel o w
  M 1a
Dista nt metastasis t o s ki n, s oft
tiss ue i ncl u di n g m uscle, a n d/ or
n o nre gi o nal l y m p h n o de
N ot rec or de d or u ns peci fie d
    M 1a( 0)
N ot ele vate d
    M 1a( 1)
Ele vate d
  M 1 b
Dista nt metastasis t o l u n g wit h or wit h o ut M 1a sites 
of disease
N ot rec or de d or u ns peci fie d
    M 1 b( 0)
N ot ele vate d
    M 1 b( 1)
Ele vate d
  M 1c
Dista nt metastasis t o n o n -C N S
visceral sites wit h or wit h o ut M 1a or  M 1 b sites of 
disease
N ot rec or de d or u ns peci fie d
    M 1c( 0)
N ot ele vate d
    M 1c( 1)
Ele vate d
  M 1 d
Dista nt metastasis t o C N S wit h or wit h o ut M 1a, 
M 1 b, or M 1c sites of
disease
N ot rec or de d or u ns peci fie d
    M 1 d( 0)
N ot ele vate d
    M 1 d( 1)
Ele vate d
C N S – ce ntral ner v o us s yste m

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 0 2 of 2 1 0
A n at o mic st a ge/ pr o g n ostic gr o u ps
St a ge
T
N
M
I A
T 1a
N 0
M 0
I B
T 1 b or  T 2a
N 0
M 0
II A
T 2 b or T 3a
N 0
M 0
II B
T 3 b or T 4a
N 0
M 0
II C
T 4 b
N 0
M 0
III
A n y  T, Tis
≥N 1
M 0
I V
A n y  T
A n y  N
M 1
S o urce: AJ C C Ca ncer sta gi n g Ma n ual Ei g ht h E di tio n , E di t ors: A mi n, M B, E d ge, S, Gree ne 
F, B y r d D R, Br o o kla n d R K, Was hi n gt o n, M K . S pri n ger: 2 0 1 7.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 0 3 of 2 1 0
A p p e n di x 9
Attri b ut e s M e a s ur e d b y A d v er s e E v e nt s C oll e ct e d b y 
t h e P ati e nt-R e p ort e d O ut c o m e s -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
S y m pt o m/ T o xicit y
Attri b utes
H oarse ness
S
Decrease d A p petite
S, I
Na usea
F, S
V o miti n g
F, S
C o nsti pati o ns
S
Diarr hea 
F
Ha n d -F o ot S y n dr o me
S
Ge neral Pai n
F, S, I
Fati g ue
S, I
Ras h
P
Pai n a n d S welli n g at I njecti o n Site
P
F or eac h attri b ute t here is a se parate q uesti o n f or eac h s y m pt o m/t o xicit y e val uate d.
F = fre q ue nc y; I = i nterfere nce; P = prese nce/a bse nce; S = se verit y.

Cli nical St u d y  Pr ot oc ol
i nc or p orati n g A me n d me nt 0 4
E 7 3 8 6 -G 0 0 0 -2 0 1
Eisai
FI N A L: 2 5 Ja n 2 0 2 3
C o nfi de ntial
Pa ge 2 1 0 of 2 1 0
I N V E S TI G A T O R SI G N A T UR E P A G E
St u d y Pr ot oc ol N u m ber:
E 7 3 8 6 -G 0 0 0 - 2 0 1
St u d y Pr ot oc ol Title:
A n O pe n -La bel, M ult ice nter, P hase 1 b/ 2 St u d y of E 7 3 8 6 i n 
C o m bi nat i on Wit h Pe m br oliz u ma b i n Pre vi o usl y Treate d 
S u bjects Wit h Sel ecte d S oli d T u mors
I n vesti g ati o n al Pr o d uct
N a me :
E 7 3 8 6
I N D N u m ber:
1 3 6 7 9 9 
E u dr a C T N u m ber:
2 0 2 1- 0 0 1 5 6 8- 1 0
I ha ve rea d t his pr ot oc ol a n d a gree t o c o n d uct t his st u d y i n acc or da nce wit h all sti p ulati o ns of 
t he pr ot oc ol a n d i n acc or da nce wit h I nter nat i onal C o u ncil f or Har m o nisat i on of Tec h nical 
Re q ui re me nts f or P har mace uticals f or H u ma n Use (I C H) a n d all a p plica ble l ocal G o o d 
Cli nical Practice (G C P) g ui deli nes, i ncl u di n g t he Declarati o n of Helsi n ki.
Me dical I nst ituti o n
I n vesti gat or
Si t e 
N u m ber
Si g nat ure
Date
As re gi o nall y  re q uire d.
< Ti tle of si g nat or y 
f or Ja pa n/ Asia 
cli nical researc h >
Si g nat ure
Date