Lenvatinib in Recurrent Hepatocellular Carcinoma After Liver Transplantation
Phase: PHASE2
Conditions: Recurrent Hepatocellular Carcinoma, Stage III Hepatocellular Carcinoma AJCC v8, Stage IIIA Hepatocellular Carcinoma AJCC v8, Stage IIIB Hepatocellular Carcinoma AJCC v8, Stage IV Hepatocellular Carcinoma AJCC v8, Stage IVA Hepatocellular Carcinoma AJCC v8, Stage IVB Hepatocellular Carcinoma AJCC v8, Unresectable Hepatocellular Carcinoma
Sponsor: Emory University

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
P R O T O C OL TI TL E: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er Tr a ns pl a nt ati o n 
WI N S HI P P R O T O C OL #: Wi ns hi p 5 3 8 1- 2 1
C O O R DI N A TI N G C E N T E R:  
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y  
P RI N CI P AL I N V E S TI G A T O R:
Ol u mi d e G b ol a h a n, M. D.
Assist a nt Pr of ess or, D e p art m e nt of H e m at ol o g y a n d M e dic al O nc ol o g y
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y
1 3 6 5 Clift o n R o a d N E
Atl a nt a, G A 3 0 3 2 2
P h o n e: 4 0 4- 7 7 8- 8 0 2 5
o g b ol a h @ e m or y. e d u
C O-I N V E S TI G A T O R S:
Gr e g or y L esi ns ki, P h D, M P H
Pr of ess or, D e p art m e nt of H e m at ol o g y a n d M e dic al O nc ol o g y
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y
e m ail a d dr ess: Gr e g or y. B.L esi ns ki @ e m or y. e d u  
Ol at u nji Al es e, M. D.
Assist a nt Pr of ess or, D e p art m e nt of H e m at ol o g y a n d M e dic al O nc ol o g y
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y
e- m ail a d dr ess: Ol at u nji. al es e @ e m or y. e d u                  
       
S T A TI S TI CI A N:  
J effr e y S witc h e n k o P h. D., M. S.
E m or y U ni v ersit y
js witc h @ e m or y. e d u
E X T E R N AL ( N O N- E M O R Y) C OLL A B O R A T O R S            
U ni v ersit y of Al a b a m a at Bir mi n g h a m

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
O` N e al C o m pr e h e nsi v e C a nc er C e nt er, U ni v ersit y of Al a b a m a at Bir mi n g h a m: M e h m et A kc e, M D
U ni v ersit y of Al a b a m a at Bir mi n g h a m I R B n e e ds t o r e vi e w t h e pr ot oc ol
N a m e, Titl e(s), I nstit uti o n, a n d D e p art m e nt of Ext er n al C oll a b or at ors
( F or e ac h e ntr y, pl e as e i n dic at e w h et h er t h at i nstit uti o n’s I R B will r e vi e w ( or h as alr e a d y r evi e w e d) 
t h at i n di vi d u al’s e n g a g e m e nt i n h u m a n p artici p a nts r es e arc h acti viti es) 
V E R SI O N: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5  
F U N DI N G S O U R C E: Eis ai
I N V E S TI G A TI O N AL P R O D U C T (I P): L e n v ati ni b, Eis ai
O T H E R A G E N T( S):  N o n e
I N D #: 1 5 7 5 9 0
R E VI SI O N HI S T O R Y
R e visi o n #
V ersi o n 
D at e
S u m m ar y of C h a n g es
1
6/ 7/ 2 0 2 2
PI C h a n g e, St aff u p d at es o n p a g es 1 & 2, c h a n g e i n l a b o n 
p a g e 1 9, ct D N A t o r e pl ac e circ ul ati n g t u m or c ells o n p a g es 
8, 1 9 & 2 0, u p d at e d s ecti o n 1 1
2
6/ 1 0/ 2 0 2 2
E nr oll m e nt n u m b er u p d at e d i n v ersi o n 6/ 7/ 2 0 2 2 i n err or; 
e nr oll m e nt n u m b er b ei n g u p d at e d b ac k t o t h e ori gi n al 1 7 
3
3/ 2 8/ 2 0 2 3
A d di n g U A B as a m ulti-sit e, c h a n gi n g t h e l a b a d dr ess fr o m 
E m or y t o U A B, a d di n g U A B t hr o u g h o ut d oc u m e nt w h er e 
a p plic a bl e, c h a n g e d e nr oll m e nt n u m b ers 
4
0 3/ 0 4/ 2 0 2 4
C h a n g e pr ot oc ol a n d l a b m a n u al t o s p ecif y L esi ns ki 
L a b or at or y is t h e sit e of bl o o d s a m pl e c oll ecti o n o n P a g e 
1 8 a n d i n L a b or at or y M a n u al
5. 
0 3/ 2 8/ 2 0 2 4
U p d at e pr ot oc ol sc h e d ul e of acti viti es t o r efl ect c h a n g e 
fr o m e v e n c ycl es C ycl e 1 0 t o C ycl e 8- 2 4
6.
1/ 1 4/ 2 0 2 5
U p d at e t o t h e sc h e d ul e of ass ess m e nts a n d r e m o vi n g 
M a y o as a sit e.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
T a bl e of C o nt e nts
1. 
St u d y S u m m ar y....................................................................................................................................... 5
1. 1  S y n o ps ys ....................................................................................................................................................... 5
1. 2  Sc h e m a ......................................................................................................................................................... 6
1. 3  Sc h e d ul e of Ass ess m e nts.............................................................................................................................. 7
2. 
O bj ecti v es ( a n d E n d p oi nts) ..................................................................................................................... 8
3. 
B ac k gr o u n d............................................................................................................................................. 8
3. 1 St u d y R ati o n al e.............................................................................................................................................. 9
3. 2 Cli nic al Ex p eri e nc e......................................................................................................................................... 9
4. 
St u d y I nt er v e nti o n/I n v esti g ati o n al A g e nt.............................................................................................. 1 0
4. 1 D escri pti o n................................................................................................................................................... 1 0
4. 2 Dr u g/ D evic e H a n dli n g.................................................................................................................................. 1 0
4. 3 Acc o u nt a bilit y.............................................................................................................................................. 1 0
5. 
Pr oc e d ur es I n v ol v e d.............................................................................................................................. 1 1
5. 1 St u d y D esi g n................................................................................................................................................ 1 1
5. 2 D osi n g a n d A d mi nistr ati o n.......................................................................................................................... 1 2
5. 3 D efi niti o n of D os e-Li miti n g T oxicit y............................................................................................................. 1 2
5. 4 D os e M o dific ati o n ....................................................................................................................................... 1 2
5. 5 C o nc o mit a nt m e dic ati o n............................................................................................................................. 1 4
5. 6 St u d y Pr oc e d ur es......................................................................................................................................... 1 5
5. 7 D escri pti o n of St u d y Pr oc e d ur es................................................................................................................. 1 7
6. 
D at a a n d S p eci m e n B a n ki n g.................................................................................................................. 1 9
7. 
S h ari n g of R es ults wit h P artici p a nts ...................................................................................................... 2 0
8. 
St u d y Ti m eli n es..................................................................................................................................... 2 0
8. 1 D ur ati o n of t h er a p y..................................................................................................................................... 2 0
8. 2 D ur ati o n of f oll o w- u p.................................................................................................................................. 2 1
9. 
I ncl usi o n a n d E xcl usi o n Crit eri a............................................................................................................. 2 2
1 0.
V ul n er a bl e P o p ul ati o ns......................................................................................................................... 2 4
1 1.
L oc al N u m b er of P artici p a nts ................................................................................................................ 2 4
1 2.
R ecr uit m e nt M et h o ds ........................................................................................................................... 2 5
1 3.
Wit h dr a w al of P artici p a nts.................................................................................................................... 2 6
1 4.
Ris ks t o P artici p a nts.............................................................................................................................. 2 6
1 5.
P ot e nti al B e n efits t o P artici p a nts.......................................................................................................... 2 7
1 6.
D at a M a n a g e m e nt a n d C o nfi d e nti alit y.................................................................................................. 2 7
1 6. 1 St atistic al c o nsi d er ati o n s ecti o n: Bi ost atistici a n ....................................................................................... 2 7
1 6. 2 D at a/s p eci m e ns:........................................................................................................................................ 2 9
1 7.
Pr o visi o ns t o M o nit or t h e D at a t o E ns ur e t h e S af et y of P artici p a nts...................................................... 3 0
1 8.
Pr o visi o ns t o Pr ot ect t h e Pri v ac y I nt er ests of P artici p a nts..................................................................... 3 7
1 9.
Ec o n o mic B ur d e n t o P artici p a nts........................................................................................................... 3 8
2 0.
C o ns e nt Pr oc ess.................................................................................................................................... 3 8
2 1.
S etti n g .................................................................................................................................................. 3 9
2 2.
R es o urc es A v ail a bl e .............................................................................................................................. 4 0
2 3.
M ulti- Sit e R es e arc h w h e n E m or y is t h e L e a d Sit e .................................................................................. 4 1
2 4.
R ef er e nc es............................................................................................................................................ 4 2
A P P E N DI X A 
P E R F O R M A N C E S T A T U S C RI T E RI A ....................................................................................... 4 5
A P P E N DI X B  
Dr u g Di ar y........................................................................................................................... 4 6
A P P E N DI X C         R E CI S T crit eri a v 1. 1 ............................................................................................................. 4 7

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A P P E N DI X D         C hil d P u g h Cl assific ati o n .................................................................................................... 4 7
1. St u d y S u m m ar y
1. 1 S y n o psis
Titl e:
L e n v ati ni b i n r ec urr e nt h e p at oc ell ul ar c arci n o m a aft er li v er tr a ns pl a nt ati o n 
St u d y 
D escri pti o n:
T his r es e arc h st u d y is a n o p e n l a b el, si n gl e ar m, P h as e II st u d y, d esi g n e d t o e v al u at e t h e 
s af et y a n d t ol er a bilit y/ effic ac y of l e n v ati ni b i n s u bj ects wit h r ec urr e nt h e p at oc ell ul ar 
c arci n o m a aft er li v er tr a ns pl a nt ati o n. P ati e nts wit h bi o ps y pr o v e n r ec urr e nt H C C aft er 
li v er tr a ns pl a nt ati o n will b e st art e d o n l e n v ati ni b. R est a gi n g sc a ns will b e p erf or m e d 
e v er y 8 w e e ks. P eri p h er al bl o o d s a m pl es will b e c oll ect e d pri or t o tr e at m e nt, o n c ycl e 3 
d a y 1, a n d at pr o gr essi o n f or c orr el ati v e r es e arc h.  Tr e at m e nt will b e c o nti n u e d u ntil 
pr o gr essi o n, exc essi v e t oxicit y, or p ati e nt wit h dr a w al fr o m pr ot oc ol t h er a p y.
O bj ecti v es:
Pri m ar y O bj ecti v e :   
T o ev al u at e t h e a nti-t u m or acti vit y of l e n v ati ni b b y ass essi n g t h e o v er all r es p o ns e 
r at e ( O R R) b y R E CI S T v ersi o n 1. 1. 
S ec o n d ar y O bj ecti v es:

T o e v al u at e t h e s af et y a n d t ol er a bilit y of l e n v ati ni b i n p ati e nts wit h r ec urr e nt H C C 
aft er li v er tr a ns pl a nt ati o n 

T o ev al u at e t h e a nti-t u m or acti vit y of l e n v ati ni b b y ass essi n g pr o gr essi o n fr e e 
s urvi v al ( P F S) a n d o v er all s ur vi v al ( O S) a n d d ur ati o n of r es p o ns e.
E x pl or at or y O bj ecti v e:

T o ev al u at e t h e eff ect of tr e at m e nt o n s el ect e d bi o m ar k ers i n s yst e mic circ ul ati o n.
E n d p oi nts:
Pri m ar y E n d p oi nt:  

Effic ac y
O R R ( C o m pl et e r es p o ns e + p arti al r es p o ns e) p er R E CI S T v ersi o n 1. 1 
S ec o n d ar y E n d p oi nts: 
S af et y: a d v ers e ev e nts, vit al si g n m e as ur e m e nts, p h ysic al ex a mi n ati o ns, a n d cli nic al 
l a b or at or y t est.
Effic ac y: Pr o gr essi o n fr e e s urvi v al ( P F S) a n d o v er all s urvi v al ( O S), d ur ati o n of r es p o ns e
Ex pl or at or y: C h a n g es i n s el ect e d bi o m ar k ers i n circ ul ati o n b ef or e a n d aft er tr e at m e nt 
wit h l e n v ati ni b .
St u d y 
P o p ul ati o n:

T h e p ati e nt p o p ul ati o n c o nsists s u bj ects ≥1 8  y e ars of a g e wit h bi o ps y pr o v e n 
r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n. Eli gi bl e p ati e nts m ust h a v e/ h a v e n ot 
r ec ei v e d a n y s yst e mic t h er a p y f or H C C i n t h e p ost-tr a ns pl a nt s etti n g.
P h as e:
II

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 5 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
1. 2  Sc h e m a
R e gistr ati o n
↓
L e n v ati ni b
1 2 m g d ail y f or p ati e nts ≥6 0  k g
8 m g d ail y f or p ati e nts < 6 0 k g 
R est a g e ev er y 8 w e e ks
↓
E v e nts at a n y ti m e:
Dis e as e Pr o gr essi o n
I nt ol er a bl e a d v ers e eff ects
P ati e nt wit h dr a w al/r ef us al fr o m 
pr ot oc ol t h er a p y
↓
S ur vi v al F oll o w- u p ev er y 9 0 d a ys 
f or u p t o 2 y e ars
C ycl e = 2 8 d a ys 
Tr e at m e nt u ntil pr o gr essi o n, exc essi v e t oxicit y, or p ati e nt wit h dr a w al fr o m pr ot oc ol t h er a p y.
S ur vi v al f oll o w- u p, e v er y 9 0 d a ys u ntil d e at h or 2 y e ars fr o m r e gistr ati o n.
D escri pti o n of 
Sit es/ F aciliti es 
E nr olli n g 
P artici p a nts:
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y ( Atl a nt a, G A).  
M a y o Cli nic Ariz o n a ( Ariz o n a)
M a y o Cli nic R oc h est er ( Mi n n es ot a)
U ni v ersit y of Al a b a m a at Bir mi n g h a m ( Bir mi n g h a m, AL)
D escri pti o n 
of 
St u d y 
I nt er v e nti o n:
P ati e nts will r ec ei v e t h e f oll o wi n g tr e at m e nt: L e n v ati ni b 1 2 m g d ail y f or p ati e nts ≥6 0  k g, 
8 m g d ail y f or p ati e nts < 6 0 k g. St u d y dr u gs will b e gi v e n P O o n D a ys 1- 2 8. Tr e at m e nt 
c ycl es ar e 2 8 d a ys.
St u d y D ur ati o n:
P ati e nts will b e tr e at e d u ntil u n acc e pt a bl e t oxicit y, p ati e nt wit h dr a w al fr o m pr ot oc ol 
t h er a p y or dis e as e pr o gr essi o n p er R es p o ns e E v al u ati o n Crit eri a I n S oli d T u m ors V ersi o n 
1. 1 ( R E CI S T v 1. 1).

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 6 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
1. 3 Sc h e d ul e of Ass ess m e nt
W hil e p ati e nts ar e r ec ei vi n g tr e at m e nt ( u p t o 2 4 c ycl es), pl e as e us e t h e f oll o wi n g T a bl e 1:
Scr e e ni
n g 
Acti v e m o nit ori n g p h as e 
Pr oc e d ur es
D a y  -
2 8 t o - 1
C ycl
e 
1 
D a y 
1
C ycl
e 1 
D a y 
7
C ycl
e 
1 
D a y 
1 4
C ycl e 
2 D a y 
1
C ycl
e 
2 
D a y 
1 4
C ycl
e 
3 
D a y 
1
C ycl
e 
4 
D a y 
1
C ycl
e  5 
D a y 
1
C ycl
e 
6 
D a y 
1
O d d 
c ycl e
s 
7-
2 3 
D a y 
1
E v e n 
c ycl e
s  8-
2 4 
D a y 1
E n d 
of 
tr e at
m e nt
S af et
y 
f oll o
w u p
L o n g  t er m 
f oll o w  
u p 
e v er y  
9 0 
d a ys ( +/- 1 4 
d a ys)
I nf or m e d c o ns e nt1
X
D e m o gr a p hics
X
M e dic al hist ory
X
A d mi nist er st u dy i nt erv e nti o n
X
X
X
X
X
X
X
X
X
X
X
C o n. m e dic ati o n r evi e w
X
X
X--------------------------------------------------------------------------------------------- X
P hysic al ex a m ( i ncl u di ng h eig ht a n d w eig ht)2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vit al si g ns 3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P erf or m a nc e st at us
X
X
X
X
X
X
X
X
X
X
X
X
X
X
H e m at ol o gy 4
X
X
X
X
X
X
X
X
X
X
X
X
X
S er u m c h e mistry 5
X
X
X
X
X
X
X
X
X
X
X
X
X
Uri n e a n alysis 
X
X
X
X
X
X
X
X
TS H, Fr e e T 4 a n d T 3
X
X
X
X
X
AF P
X
X
X
X
X
X
X
X
X
X
C o a g ul ati o n st u di es ( P T, I N R, 
a P T T)
X
H e p atitis a n d HI V scr e e ni n g 6
X
Pr e g n a ncy t est 7
X
X
X
X
X
X
X
X
X
X
X
E K G  8
X
A Es r evi e w a n d ev al u ati o n
X
X
X--------------------------------------------------------------------------------------------- X
X
S urviv al st at us 
X
X
R a di ol o gic/I m a gi n g 
ass ess m e nt 9
X
X 9
X 9
X 9
X
Ot h er  
ass ess m e nts 
( C orr el ati v e bl o o d s a m pl es)1 0
X
X
X
C o m pl et e C as e R e p ort F or ms 
( C RFs)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1 If l a b or at or y or i m a gi n g pr oc e d ur es w er e p erf or m e d f or alt er n at e r e as o ns pri or t o si g ni n g c o ns e nt, t h es e c a n b e us e d f or scr e e ni n g p ur p os es 
wit h c o ns e nt of t h e p ati e nt. H o w ev er, all scr e e ni n g l a b or at or y a n d i m a gi n g r es ults m ust h a v e b e e n o bt ai n e d wit hi n 2 8 d a ys of C ycl e 1 
D a y 1.
2 H ei g ht o nl y at scr e e ni n g
3 Bl o o d pr ess ur e s h o ul d b e m o nit or e d aft er 1 w e e k of tr e at m e nt wit h l e n v ati ni b, t h e n e v er y 2 w e e ks f or t h e first 2 m o nt hs a n d m o nt hl y 
t h er e aft er w hil e o n tr e at m e nt. If a p ati e nt d e v el o ps s yst olic B P ≥1 4 0  m m H g or di ast olic B P ≥9 0  m m H g acti v e m a n a g e m e nt is i n dic at e d.
4 C B C wit h diff er e nti al. If scr e e ni n g h e m at ol o g y ass ess m e nt p erf or m e d wit hi n 3 d a ys pri or t o d a y 1, t h e y d o n ot n e e d t o b e r e p e at e d o n d a y 1. 
5 Al b u mi n, al k ali n e p h os p h at as e, t ot al bilir u bi n, bic ar b o n at e, B U N, c alci u m, c hl ori d e, cr e ati ni n e, gl uc os e, L D H, p h os p h or us, p ot assi u m, t ot al 
pr ot ei n, A S T, AL T, s o di u m. If scr e e ni n g cli nic al c h e mistr y ass ess m e nt p erf or m e d wit hi n 3 d a ys pri or t o d a y 1, t h e y d o n ot n e e d t o b e r e p e at e d 
o n d a y
6 H e p atitis B s urf ac e a nti g e n, H e p atitis C a nti b o di es, HI V a nti b o di es
7 F or w o m e n of c hil d b e ari n g p ot e nti al o nl y.  Uri n e pr e g n a nc y t est wit h p ositi v e v erifi e d vi a bl o o d s er u m pr e g n a nc y t est. W o m e n of 
c hil d b e ari n g p ot e nti al ar e r e q uir e d t o h a v e a s er u m or uri n e pr e g n a nc y t est wit hi n 7 2 h o urs  pri or t o t h e first d os e of st u d y dr u g a n d t h e n 
e v er y 4 w e e ks. Pr e g n a nc y t est m a y occ ur o n D a y 1, b ut r es ults m ust b e a v ail a bl e a n d r e vi e w e d b y t h e tr e ati n g p h ysici a n or I n v esti g at or pri or 
t o c o m m e nci n g a n i nf usi o n
8 A n y cli nic all y si g nific a nt a b n or m aliti es d et ect e d r e q uir e tri plic at e E C G r es ults o bt ai n e d o v er a bri ef p eri o d ( wit hi n 3 0 mi n ut es) t o c o nfir m t h e 
fi n di n g
9 I m a gi n g will b e ev al u at e d f or r a di o gr a p hic r es p o ns e usi n g R E CI S T v 1. 1 o n i m a g es fr o m C T or M RI, e ac h pr ef er a bl y wit h I V c o ntr ast of t h e 
c h est, a b d o m e n (i ncl u di n g li v er a n d a dr e n al gl a n ds) a n d p el vis. A d diti o n al a n at o m y s h o ul d b e i m a g e d b as e d o n si g ns a n d s y m pt o ms of 
i n di vi d u al p ati e nts at b as eli n e a n d f oll o w- u p. I m a gi n g will b e p erf or m e d at 8 w e e ks ( +/- 7 d a ys) of i niti ati o n of pr ot oc ol tr e at m e nt, a n d 
r e p e at e d e v er y 8 w e e ks ( +/- 7 d a ys). S a m e i m a gi n g m o d alit y utiliz e d i n t h e scr e e ni n g s h o ul d b e p erf or m e d i n s u bs e q u e nt sc a ns u nl ess 
d e e m e d n ot s uit a bl e or s af e b y t h e pri nci p al i n v esti g at or.
1 0  Bl o o d f or c orr el ati v e st u di es will b e c oll ect e d at b as eli n e pri or t o s yst e mic t h er a p y, o n c ycl e 3 d a y 1, a n d at off pr ot oc ol tr e at m e nt  

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 7 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
2.
O bj ecti v es ( a n d E n d p oi nts)
O BJ E C TI V E S
E N D P OI N T S
Pri m ar y
3.
T o e v al u at e a nti-t u m or acti vit y of t h e l e n v ati ni b 
b y ass essi n g t h e o v er all r es p o ns e r at e ( O R R) b y 
R es p o ns e E v al u ati o n Crit eri a i n S oli d T u m ors 
( R E CI S T v 1. 1).

Effic ac y:

O R R  
p er  
R E CI S T  
v 1. 1  
( T u m or 
m e as ur e m e nts will b e p erf or m e d e v er y 8 
w e e ks ± 7 d a ys  
S ec o n d ar y

T o ev al u at e t h e s af et y a n d t ol er a bilit y of 
l e n v ati ni b i n p ati e nts wit h r ec urr e nt H C C 
aft er li v er tr a ns pl a nt ati o n.

T o ev al u at e t h e a nti-t u m or acti vit y of t h e 
l e n v ati ni b 
b y ass essi n g 
pr o gr essi o n-fr e e 
s urvi v al ( P F S) a n d o v er all s urvi v al ( O S) a n d 
d ur ati o n of r es p o ns e

S af et y: a d v ers e e v e nts, vit al si g n, E C G, 
p h ysic al ex a mi n ati o ns, cli nic al l a b or at or y 
t est.

Pr o gr essi o n-fr e e 
S ur vi v al 
( P F S) 
usi n g 
R E CI S T 1. 1

O v er all S ur vi v al

D ur ati o n of r es p o ns e 
T erti ar y/ Ex pl or at or y 

T o ass ess t h e eff ects of t h e l e n v ati ni b o n 
circ ul ati n g t u m or D N A a n d bi o m ar k ers 

C h a n g es i n circ ul ati n g t u m or D N A a n d 
bi o m ar k ers aft er tr e at m e nt l e n v ati ni b 
a n d t h eir r el ati o ns hi p wit h effic ac y.
3. B ac k gr o u n d
H e p at oc ell ul ar c arci n o m a ( H C C) is t h e s ec o n d l e a di n g c a us e of c a nc er r el at e d m ort alit y i n t h e w orl d.( 1) H C C is 
t h e f ast est i ncr e asi n g c a us e of c a nc er-r el at e d m ort alit y i n t h e U S a n d 5 y e ar s urvi v al is l ess t h a n 1 2 %.( 2) A b o ut 
4 0 % of p ati e nts wit h H C C c a n b e c a n di d at es f or c ur ati v e tr e at m e nts ( a bl ati o n, s ur gic al r es ecti o n, li v er 
tr a ns pl a nt ati o n)( 3) b ut 
m ost pr es e nt at a d v a nc e d st a g e. Li v er tr a ns pl a nt ati o n is a c ur ati v e o pti o n i n 
h e p at oc ell ul ar c arci n o m a wit h 5 y e ars o v er all s urvi v al b et w e e n 6 5 %- 8 5 %.( 4) H o w ev er, u p t o 2 0 % of p ati e nts 
d e v el o p r ec urr e nt dis e as e i n 5 y e ars a n d pr o g n osis r e m ai ns p o or.( 4- 6) H C C r ec urr e nc e p ost-tr a ns pl a nt is us u all y 
extr a h e p atic ( u p t o 6 7 %) h e nc e r e q uir es eff ecti v e s yst e mic t h er a p y o pti o ns.( 6, 7) R ec urr e nt H C C aft er 
tr a ns pl a nt ati o n is d efi n e d as m et ast asis fr o m t h e n ati v e li v er t h at c o ul d occ ur d u e t o u n d et ect e d extr a h e p atic 
m et ast asis t h at w as pr es e nt b ef or e li v er tr a ns pl a nt ati o n or d u e t o circ ul ati n g H C C c ell cl o n es e n gr afti n g i nt o 
t ar g et or g a n.( 5, 6) C urr e nt F D A- a p pr o v e d s yst e mic tr e at m e nt o pti o ns i n a d v a nc e d H C C i ncl u d e s or af e ni b, 
l e n v ati ni b, at ez oliz u m a b/ b e v aciz u m a b i n t h e first li n e s etti n g, r e g or af e ni b, c a b oz a nti ni b, ni v ol u m a b, 
p e m br oliz u m a b, r a m ucir u m a b, ni v ol u m a b/i pili m u m a b i n t h e s ec o n d li n e s etti n g.( 8- 1 4) N o n e of t h es e a g e nts 
w er e st u di e d i n p ati e nts wit h pri or li v er tr a ns pl a nt ati o n t h er ef or e s yst e mic t h er a p y is n ot est a blis h e d i n 
p ati e nts wit h r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n.  Alt h o u g h s yst e mic tr e at m e nt of a d v a nc e d H C C h as 
s e v er al o pti o ns, m a n a g e m e nt of p ati e nts wit h r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n p os es a u ni q u e c h all e n g e 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 8 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
f or r o uti n e cli nic al pr actic e d u e t o t h e a bs e nc e of cl e ar g ui d a nc e fr o m i nt er n ati o n al g ui d eli n es. L ac k of 
pr os p ecti v e cli nic al tri al d at a a n d li mit e d d at a fr o m r etr os p ecti v e c as e s eri es i n dic at es a n ar e a of u n m et n e e d i n 
tr e at m e nt of r ec urr e nt H C C p ost li v er tr a ns pl a nt ati o n. L ac k of pr os p ecti v e cli nic al tri al d at a t o s u p p ort 
r ec o m m e n d ati o ns i n i nt er n ati o n al g ui d eli n es c a n cr e at e c h all e n g es t o ac q uir e n e wl y a p pr o v e d s yst e mic t h er a p y 
a g e nts i n t his s p eci al s u b gr o u p of H C C p ati e nts i n t h e cli nic al pr actic e.( 1 5)  
3. 1 St u d y R ati o n al e
T h e d at a f or s yst e mic t h er a p y a g e nts i n r ec urr e nt H C C p ost-tr a ns pl a nt is li mit e d t o r etr os p ecti v e c as e s eri es.( 5, 
1 6)  Si nc e s or af e ni b w as t h e o nl y a p pr o v e d s yst e mic t h er a p y a g e nt i n a d v a nc e d H C C f or al m ost a d ec a d e m aj orit y 
of t h e d at a is li mit e d t o r etr os p ecti v e st u di es wit h s or af e ni b i n p ost-tr a ns pl a nt H C C.( 5, 1 7- 1 9) I n a s yst e m atic 
r e vi e w of lit er at ur e i ncl u di n g 1, 0 2 1 p ati e nts wit h r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n s or af e ni b w as utiliz e d 
i n 2 0 % of p ati e nts, 4 2. 1 % of t h e p ati e nts r e q uir e d d os e r e d ucti o ns, 4 6. 5 % ac hi e v e d st a bl e dis e as e.( 6) R e g or af e ni b 
w as st u di e d i n 2 8 p ati e nts w h o pr o gr ess e d o n s or af e ni b i n r ec urr e nt H C C p ost-tr a ns pl a nt s etti n g a n d r e v e al e d 
m e di a n O S of 1 2. 9 m o nt hs.( 2 0) D es pit e t h es e r etr os p ecti v e d at a wit h s or af e ni b a n d r e g or af e ni b, b ot h a g e nts 
h a v e b e e n ass oci at e d wit h i ncr e as e d t oxiciti es w h e n c o m bi n e d wit h i m m u n os u p pr essi o n i n p ost-tr a ns pl a nt 
r ec urr e nt H C C.( 1 8, 2 0) R e g or af e ni b w as ass oci at e d wit h i ncr e as e d pl as m a l e v els of i m m u n os u p pr ess a nt a g e nts 
i n a r etr os p ecti v e st u d y ( 2 0) a n d s or af e ni b w as ass oci at e d wit h fr e q u e nt d os e r e d ucti o ns a n d disc o nti n u ati o n 
d u e t o a d v ers e e v e nts i n ot h er r etr os p ecti v e st u di es i n p ost-tr a ns pl a nt s etti n g.( 1 7) As m or e n o v el a n d b ett er 
t ol er at e d a g e nts e m er g e i n a d v a nc e d H C C tr e at m e nt it is w arr a nt e d t o ex pl or e t h es e a g e nts i n r ec urr e nt H C C 
aft er li v er tr a ns pl a nt ati o n i n a pr os p ecti v e m a n n er. 
T h er e ar e n o evi d e nc e- b as e d r ec o m m e n d ati o ns fr o m i nt er n ati o n al g ui d eli n es i n r e g ar d t o s yst e mic t h er a p y i n 
t his u ni q u e s u b p o p ul ati o n of H C C. Gi v e n t ol er a bilit y a n d effic ac y of l e n v ati ni b i n a d v a nc e d H C C a n d e nc o ur a gi n g 
d at a fr o m r es p ecti v e r e p orts i n r ec urr e nt H C C aft er li v er tr a ns pl a nt w e pr o p os e a pr os p ecti v e m ultic e nt er ( E m or y, 
U A B a n d M a y o Cli nic) p h as e II st u d y wit h si n gl e a g e nt l e n v ati ni b i n r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n.  
3. 2 Cli nic al E x p eri e nc e
L e n v ati ni b is a m ulti ki n as e i n hi bit or t ar g eti n g V E G F R 1- 3, F G F R 1- 4, KI T, P D G F R α,  a n d R E T s el ecti v el y h e nc e pl a ys 
a si g nific a nt r ol e i n a nti- a n gi o g e n esis as w ell as dir ect i n hi biti o n of t u m or c ell pr olif er ati o n.( 2 1) I n r a n d o miz e d 
n o n-i nf eri orit y p h as e III R E FL E C T tri al l e n v ati ni b w as n o n-i nf eri or t o s or af e ni b i n first li n e tr e at m e nt of 
u nr es ect a bl e H C C.( 1 1) B as e d o n r es ults of t his tri al o n A u g ust 1 6 t h, 2 0 1 8 t h e F D A a p pr o v e d l e n v ati ni b f or t h e first-
li n e tr e at m e nt of p ati e nts wit h u nr es ect a bl e H C C. I n R E FL E C T tri al 9 5 4 eli gi bl e p ati e nts wit h u nr es ect a bl e H C C 
w er e r a n d o miz e d t o l e n v ati ni b ( 1 2 m g [ b as eli n e b o d y w ei g ht ≥6 0  k g] or 8 m g [ b as eli n e b o d y w ei g ht < 6 0 k g]) 
gi v e n or all y o nc e d ail y or s or af e ni b 4 0 0 m g gi v e n or all y  t wic e d ail y. P ati e nts w er e r e q uir e d t o h a v e a hist ol o gic all y 
or c yt ol o gic all y c o nfir m e d  di a g n osis of a d v a nc e d H C C, or a cli nic all y c o nfir m e d di a g n osis of H C C acc or di n g t o t h e 
A m eric a n  Ass oci ati o n f or t h e St u d y of Li v er Dis e as es crit eri a, i ncl u di n g cirr h osis of a n y eti ol o g y, or  wit h c hr o nic 
h e p atitis B or C i nf ecti o n. P ati e nts h a d at l e ast 1 m e as ur a bl e t ar g et h e p atic or  n o n h e p atic l esi o n acc or di n g t o 
m R E CI S T, a n d a d e q u at e li v er, b o n e m arr o w, bl o o d  c o a g ul ati o n, r e n al, a n d p a ncr e atic f u ncti o n. P ati e nts w er e 
str atifi e d b y r e gi o n, pr es e nc e or a bs e nc e of m acr osc o pic p ort al v ei n i n v asi o n or extr a h e p atic s pr e a d or b ot h, 
E C O G P S 0 or 1,  a n d b o d y w ei g ht ( < 6 0 k g or ≥6 0  k g). T h e m aj orit y of p ati e nts i n b ot h tr e at m e nt ar ms h a d a n 
E C O G P S of 0 at B as eli n e ( 6 3 %), C hil d- P u g h sc or e of 5 ( 7 6 %), a n d w ei g h e d ≥6 0  k g ( 6 9 %). T h e m e di a n a g e w as 6 2 
y e ars, 8 4 % w er e m al e, 1 6 % w er e f e m al e, 6 9 % w er e Asi a n, 1 % w er e  bl ac k, a n d 2 9 % w er e w hit e. L e n v ati ni b w as 
n o ni nf eri or f or O S t o s or af e ni b 4 0 0 m g t wic e d ail y. M e di a n O S w as  1 3. 6 m o nt hs c o m p ar e d t o 1 2. 3 m o nt hs f or 
s or af e ni b wit h H R = 0. 9 2 [ 9 5 % CI ( 0. 7 9, 1. 0 6)]. B as e d o n i n v esti g at or ass ess m e nt ev al u at e d acc or di n g t o m R E CI S T, 
l e n v ati ni b tr e at m e nt r es ult e d i n st atistic all y si g nific a nt ( P < 0. 0 0 0 0 1) a n d cli nic all y m e a ni n gf ul i m pr o v e m e nt o v er 
s or af e ni b i n t h e s ec o n d ar y e n d p oi nts of P F S a n d O R R. L e n v ati ni b tr e at m e nt si g nific a ntl y pr ol o n g e d T T P c o m p ar e d 
t o s or af e ni b, wit h a m e di a n T T P t h at w as m or e t h a n t wic e as l o n g as t h at of s or af e ni b. R etr os p ecti v e i n d e p e n d e nt 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 9 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
r e vi e w of i m a gi n g c orr o b or at e d t h e s ec o n d ar y e n d p oi nts of P F S, T T P a n d O R R. O bj ecti v e r es p o ns e r at e w as 2 4. 1 % 
vs 9. 2 %, r es p ecti v el y b y m R E CI S T a n d 1 8. 8 % a n d 6. 5 % b y R E CI S T v ersi o n 1. 1. P ati e nts wit h pri or or g a n 
tr a ns pl a nt ati o n w er e excl u d e d i n t h e R E FL E C T tri al li miti n g a p plic a bilit y of l e n v ati ni b i n t his s p eci al s u b gr o u p of 
H C C p ati e nts. Y a n g et al. ev al u at e d t h e effic ac y of v ari o us tr e at m e nts f or r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n 
i n a C hi n es e p ati e nt p o p ul ati o n. Of t h e 6 4 p ati e nts wit h r ec urr e nt H C C aft er L T. M e di a n O S i n s or af e ni b-t ol er a nt 
p ati e nts tr e at e d wit h L e n v ati ni b w as 1 9. 5 m o nt hs, si g nific a ntl y exc e e di n g t h e p ati e nts t h at disc o nti n u e d 
s or af e ni b or w er e tr e at e d wit h r e g or af e ni b aft er s or af e ni b f ail ur e.( 7) D es pit e li mit e d r etr os p ecti v e d at a wit h 
diff er e nt t yr osi n e ki n as e i n hi bit ors wit h v ari o us s ucc ess r at es i n m ostl y si n gl e c e nt er st u di es t h er e is n o 
pr os p ecti v e d at a o n s af et y a n d effic ac y of l e n v ati ni b i n r ec urr e nt H C C aft er li v er tr a ns pl a nt ati o n. 
4. St u d y I nt er v e nti o n/I n v esti g ati o n al A g e nt
4. 1 D escri pti o n
L e n v ati ni b  
4-[ 3- C hl or o- 4-(N ’-c ycl o pr o p yl ur ei d o) p h e n ox yl]-  
7- m et h ox y q ui n oli n e-  
6-c ar b ox a mi d e 
m et h a n es ulf o n at e (l e n v ati ni b m esil at e) is a n or al, p ot e nt m ulti pl e r ec e pt or t yr osi n e ki n as e ( R T K) i n hi bit or t h at 
s el ecti v el y i n hi bits v asc ul ar e n d ot h eli al gr o wt h f act or ( V E G F) r ec e pt ors ( V E G F Rs), V E G F R 1 ( FL T 1), V E G F R 2 ( K D R), 
a n d V E G F R 3 ( FL T 4), i n a d diti o n t o ot h er pr o- a n gi o g e nic a n d o nc o g e nic p at h w a y-r el at e d R T Ks i ncl u di n g fi br o bl ast 
gr o wt h f act or ( F G F) r ec e pt ors ( F G F Rs) 1- 4, pl at el et- d eri v e d gr o wt h f act or r ec e pt or ( P D G F R) α, KI T, a n d R E T. 
N o ncli nic al st u di es s h o w e d l e n v ati ni b t o b e a p ot e nt a nti a n gi o g e n esis a g e nt wit h a ntit u m or acti vit y v ers us 
v ari o us h u m a n c a nc er x e n o gr aft m o d els i n at h y mic mic e a n d m uri n e t u m or is o gr aft m o d els i n i m m u n oc o m p et e nt 
mic e. L e n v ati ni b dr u g s u bst a nc e is a w hit e t o p al e y ell o w p o w d er t h at is b ei n g us e d i n t h e c a ps ul e f or m ul ati o n 
f or t h e cli nic al st u di es e v al u ati n g l e n v ati ni b. It is sli g htl y s ol u bl e i n w at er a n d h as a m ol ec ul ar w ei g ht of 5 2 2. 9 6 
a n d a p K a of 5. 2 7 ( m esil at e s alt).
4. 2 Dr u g/ D e vic e H a n dli n g
L e n v ati ni b c a ps ul es ar e p ac k a g e d i n c ol d f or m blist ers or hi g h- d e nsit y p ol y et h yl e n e b ottl es wit h a
p ol y pr o p yl e n e c a p a n d d esicc a nt. T h e blist ers a n d b ottl es s h o ul d b e st or e d u n d er r o o m
t e m p er at ur e. T h e r ec o m m e n d e d d ail y d os e of l e n v ati ni b is 8 m g (t w o 4 m g c a ps ul es) o nc e d ail y f or p ati e nts wit h 
a b o d y w ei g ht of < 6 0 k g a n d 1 2 m g (t hr e e 4 m g c a ps ul es) o nc e d ail y f or p ati e nts wit h a b o d y w ei g ht of ≥6 0  k g 
( T a bl e 2). T h e d ail y d os e is t o b e m o difi e d, as n e e d e d, acc or di n g t o t h e d os e/t oxicit y m a n a g e m e nt pl a n ( T a bl e 3). 
4. 3 Acc o u nt a bilit y
T h e st u d y dr u g pr o vi d e d f or t his st u d y will b e us e d o nl y as dir ect e d i n t h e st u d y pr ot oc ol. T h e I D S  (I n v esti g ati o n al 
Dr u g S er vic e) p ers o n n el at Wi ns hi p, U A B a n d M a y o Cli nics will acc o u nt f or all st u d y dr u gs. Dr u g acc o u nt a bilit y 
s h o ul d b e p erf or m e d u ntil t h e p ati e nt st o ps st u d y tr e at m e nt c o m pl et el y. St u d y sit e p ers o n n el will acc o u nt f or all 
st u d y dr u gs r ec ei v e d at t h e sit e.
St u d y dr u g s u p pli es m ust b e k e pt i n a n a p pr o pri at e, s ec ur e l oc k e d ar e a a n d st or e d i n acc or d a nc e wit h t h e 
c o n diti o ns s p ecifi e d o n t h e l a b els. T h e I n v esti g at or, p h ar m acist, or d esi g n e e m ust m ai nt ai n a n acc ur at e r ec or d 
of dis p e nsi n g t h e st u d y dr u g/s i n a Dr u g Acc o u nt a bilit y L o g.
T h e Dr u g Acc o u nt a bilit y L o g m a y r ec or d s p ecifics t o st u d y dr u g dis p e ns ati o n s uc h as: 
• R ec or ds of pr o d uct d eli v er y, i n v e nt or y, t e m p er at ur e m o nit ori n g, d estr ucti o n, a n d r et ur n.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 0 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
• D os a g es pr e p ar e d, ti m e pr e p ar e d, d os es dis p e ns e d. 
• D os es a n d/ or vi als d estr o y e d. 
• T h e Dr u g Acc o u nt a bilit y L o g m a y b e r e vi e w e d b y t h e m o nit or d uri n g sit e visits a n d at t h e c o m pl eti o n of t h e 
st u d y.
Dr u g acc o u nt a bilit y m a y b e n ot e d b y t h e i nt er n al m o nit or d uri n g sit e visits a n d at t h e c o m pl eti o n of t h e st u d y. 
P ati e nts will b e as k e d t o r et ur n all u n us e d st u d y tr e at m e nt a n d p ac k a gi n g o n a r e g ul ar b asis, at t h e e n d of t h e 
st u d y or at t h e ti m e of st u d y tr e at m e nt disc o nti n u ati o n.
T h e st u d y dr u g s u p pl y will b e dis p os e d of p er i nstit uti o n al’ s I n v esti g ati o n al Dr u g S er vic e (I D S) S O P.
C o m pli a nc e will b e ass ess e d b y t h e i n v esti g at or a n d/ or st u d y p ers o n n el at e ac h p ati e nt visit a n d i nf or m ati o n 
pr o vi d e d b y t h e p ati e nt a n d/ or c ar e gi v er (c oll ecti o n of dr u g di ar y a n d pill c o u nts) will b e c a pt ur e d i n t h e Dr u g 
Acc o u nt a bilit y F or m. T his i nf or m ati o n m ust b e c a pt ur e d i n t h e s o urc e d oc u m e nt at e ac h p ati e nt visit. 
T h e p ati e nt mi g ht b e r e q u est e d t o m ai nt ai n a m e dic ati o n di ar y of e ac h d os e of m e dic ati o n.  T h e m e dic ati o n 
di ar y ( A p p e n dix B) will b e r et ur n e d t o cli nic st aff at t h e e n d of e ac h c ycl e.
D os e c h a n g es a n d i nt err u pti o ns of st u d y dr u g m ust b e s p ecific all y d oc u m e nt e d i n t h e p ati e nt s o urc e 
d oc u m e nts a n d e C R F.
5. Pr oc e d ur es I n v ol v e d
5. 1 St u d y D esi g n
T his cli nic al tri al is a P h as e II st u d y, d esi g n e d t o ev al u at e t h e s af et y a n d t ol er a bilit y/ effic ac y of l e n v ati ni b i n 
s u bj ects wit h r ec urr e nt h e p at oc ell ul ar c arci n o m a aft er li v er tr a ns pl a nt ati o n.
T h e st u d y is di vi d e d i nt o a Scr e e ni n g p eri o d, Tr e at m e nt p eri o d, E n d of Tr e at m e nt ( E O T) p eri o d, a n d F oll o w- u p 
p eri o d.
D uri n g t h e Scr e e ni n g p eri o d p ati e nts will pr o vi d e writt e n i nf or m e d c o ns e nt t o p artici p at e i n t h e st u d y b ef or e 
c o m pl eti n g a n y pr ot oc ol-s p ecifi e d pr oc e d ur es or e v al u ati o ns n ot c o nsi d er e d t o b e p art of t h e p ati e nt’s st a n d ar d 
c ar e.  Pr oc e d ur es t h at w er e p erf or m e d f or st a n d ar d of c ar e pri or t o si g ni n g i nf or m e d c o ns e nt m a y b e us e d f or 
scr e e ni n g p ur p os es ( e. g., f ull p h ysic al ex a m) as l o n g as t h e pr oc e d ur es w er e c o m pl et e d wit hi n t h e 2 8- d a y 
scr e e ni n g p eri o d.  Aft er si g ni n g t h e I C F, p ati e nts will b e ev al u at e d f or e ntr y crit eri a d uri n g t h e scr e e ni n g p eri o d 
wit hi n 2 8 d a ys b ef or e a d mi nistr ati o n of st u d y dr u g(s).  R escr e e ni n g aft er scr e e n f ail ur e will b e all o w e d.
Tr e at m e nt will c o nti n u e u ntil u n acc e pt a bl e t oxicit y, d e at h, dis e as e pr o gr essi o n p er R E CI S T 1. 1, I n v esti g at or’s 
d ecisi o n t o disc o nti n u e tr e at m e nt, t h e p ati e nt wit h dr a ws c o ns e nt, is l ost t o f oll o w- u p, or I nstit uti o n d eci d es t o 
t er mi n at e t h e tri al.
P ati e nts wit h P D p er R E CI S T 1. 1 b ut wit h ot h er wis e st a bl e or i m pr o v e d p erf or m a nc e a n d cli nic al st at us m a y 
c o nti n u e t o b e tr e at e d i n t h e e v e nt of a p erc ei v e d b e n efit p er I n v esti g at or; s e e S ecti o n “ Tr e at m e nt b e y o n d 
pr o gr essi o n”.  I n v esti g at ors h a v e t o disc uss wit h sit e PI pri or t o c o nti n ui n g tr e at m e nt b e y o n d pr o gr essi o n. 
P ati e nts wit h a P R or S D will c o nti n u e t o r ec ei v e tr e at m e nt u ntil ac hi e v e m e nt of a c o nfir m e d c o m pl et e r es p o ns e 
( C R), dis e as e pr o gr essi o n, or i nt ol er a bilit y t o t h er a p y.  It is at t h e discr eti o n of t h e I n v esti g at or t o c o nti n u e 
tr e ati n g p ati e nts wit h a c o nfir m e d C R.
5. 2 D osi n g a n d A d mi nistr ati o n

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 1 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
I niti al d os e r e gi m e n
T h e r ec o m m e n d e d d ail y d os e of l e n v ati ni b is 8 m g (t w o 4 m g c a ps ul es) o nc e d ail y f or p ati e nts wit h a b o d y w ei g ht 
of < 6 0 k g a n d 1 2 m g (t hr e e 4 m g c a ps ul es) o nc e d ail y f or p ati e nts wit h a b o d y w ei g ht of ≥6 0  k g. T h e d ail y d os e is 
t o b e m o difi e d, as n e e d e d, acc or di n g t o t h e d os e/t oxicit y m a n a g e m e nt pl a n. 
T h e tr e at m e nt t o b e us e d i n t his tri al is o utli n e d b el o w i n T a bl e 2
T a bl e 2:   Tri al Tr e at m e nt
Dr u g
D os e/ P ot e nc y
D os e 
Fr e q u e nc y
C ycl es
R o ut e of 
A d mi nistr ati o n
≥6 0  k g B W 
1 2 m g (t hr e e 4 
m g 
C a ps ul es) 
O nc e d ail y
ALL
or al
L e n v ati ni b
< 6 0 k g B W 
8 m g (t w o 4 m g 
C a ps ul es) 
O nc e d ail y
ALL
or al
5. 3 D efi niti o n of D os e-Li miti n g T o xicit y 
N/ A
5. 4 D os e M o dific ati o n
T h e i n v esti g at or will d eci d e w h et h er a n y A E t h at occ urs is r el at e d t o st u d y dr u g a n d d et er mi n e w h et h er d os e 
m o dific ati o n or disc o nti n u ati o n of st u d y dr u g is r e q uir e d p er t h e g ui d a nc e b el o w. M a n a g e m e nt of s o m e a d v ers e 
r e acti o ns m a y r e q uir e d os e i nt err u pti o n, a dj ust m e nt, or disc o nti n u ati o n of l e n v ati ni b t h er a p y. Mil d t o m o d er at e 
a d v ers e r e acti o ns ( e g, Gr a d e 1 or 2) g e n er all y d o n ot w arr a nt i nt err u pti o n of l e n v ati ni b, u nl ess i nt ol er a bl e t o t h e 
p ati e nt d es pit e o pti m al m a n a g e m e nt. 
R e d uc e d os e, wit h h ol d d os e, or disc o nti n u e S T U D Y D R U G t o m a n a g e a d v ers e r e acti o ns as d escri b e d i n T a bl e 3 
b el o w a n d ar e b as e d o n crit eri a i n t h e p ac k a g e i ns ert. 
T a bl e 3 : D os e M o dific ati o n f or A d v ers e E v e nts Ass oci at e d wit h L e n v ati ni b
St arti n g D os e
≥6 0  k g B W 
1 2 m g (t hr e e 4 m g 
c a ps ul es or all y o nc e 
d ail y)
< 6 0 k g B W 
8 m g (t w o 4 m g 
c a ps ul es or all y o nc e 
d ail y)
P ersist e nt a n d I nt ol er a bl e Gr a d e 2 or Gr a d e 3 T o xiciti es a
A d v ers e R e acti o n 
M o dific ati o n 
A dj ust e d D os e b  
( ≥6 0 k g B W) 
A dj ust e d D os e b  ( < 6 0 k g 
B W) 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 2 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
First occ urr e nc e c 
I nt err u pt u ntil r es ol v e d 
t o Gr a d e 0- 1 or 
b as eli n e d 
8 m g 
(t w o 4 m g c a ps ul es) 
or all y o nc e d ail y 
4 m g 
( o n e 4 m g c a ps ul e) 
or all y o nc e d ail y 
S ec o n d occ urr e nc e 
(s a m e r e acti o n or n e w 
r e acti o n)
I nt err u pt u ntil r es ol v e d 
t o Gr a d e 0- 1 or 
b as eli n e d  
4 m g 
( o n e 4 m g c a ps ul e) 
or all y ev er y d a y 
4 m g 
( o n e 4 m g c a ps ul e) 
or all y ev er y ot h er d a y 
T hir d occ urr e nc e (s a m e 
r e acti o n or n e w 
r e acti o n) 
I nt err u pt u ntil r es ol v e d 
t o Gr a d e 0- 1 or 
b as eli n e  d 
4 m g 
( o n e 4 m g c a ps ul e) 
or all y ev er y ot h er d a y 
Disc o nti n u e 
Lif e-t hr e at e ni n g t oxiciti es ( Gr a d e 4): Disc o nti n u e  e
a I niti at e m e dic al m a n a g e m e nt f or n a us e a, v o miti n g, or di arr h e a pri or t o i nt err u pti o n or d os e 
r e d ucti o n 
b R e d uc e d os e i n s ucc essi o n b as e d o n t h e pr e vi o us d os e l ev el ( 1 2 m g, 8 m g, 4 m g or 4 m g e v er y ot h er 
d a y) 
c H e m at ol o gic t oxicit y or pr ot ei n uri a - n o d os e a dj ust m e nt r e q uir e d f or first occ urr e nc e 
d F or h e m at ol o gic t oxicit y or pr ot ei n uri a c a n r est art w h e n r es ol v e d t o Gr a d e 2 
e Excl u di n g l a b or at or y a b n or m aliti es j u d g e d t o b e n o n lif e-t hr e at e ni n g, w hic h s h o ul d b e m a n a g e d as 
Gr a d e 3
P ati e nts wit h H y p ert e nsi o n
Bl o o d pr ess ur e s h o ul d b e w ell c o ntr oll e d pri or t o tr e at m e nt wit h l e n v ati ni b a n d s h o ul d b e r e g ul arl y m o nit or e d 
d uri n g tr e at m e nt. W h e n n ec ess ar y, m a n a g e h y p ert e nsi o n as r ec o m m e n d e d i n T a bl e 4 b el o w:
T a bl e 4: R ec o m m e n d e d M a n a g e m e nt of H y p ert e nsi o n
Bl o o d Pr ess ur e L e v el
R ec o m m e n d e d Acti o n
S yst olic B P ≥1 4 0  m m H g u p t o 1 6 0 m m H g or di ast olic 
B P ≥9 0  m m H g u p t o 1 0 0 m m H g
C o nti n u e l e n v ati ni b a n d i niti at e a nti h y p ert e nsi v e 
t h er a p y, if n ot alr e a d y r ec ei vi n g
O R
C o nti n u e l e n v ati ni b a n d i ncr e as e t h e d os e of t h e 
c urr e nt a nti h y p ert e nsi v e t h er a p y or i niti at e 
a d diti o n al a nti h y p ert e nsi v e t h er a p y
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
d es pit e o pti m al a nti h y p ert e nsi v e t h er a p y
Wit h h ol d l e n v ati ni b
W h e n s yst olic B P ≤1 5 0  m m H g, di ast olic B P ≤9 5  
m m H g, a n d p ati e nt h as b e e n o n a st a bl e d os e of 
a nti h y p ert e nsi v e t h er a p y f or at l e ast 4 8 h o urs, 
r es u m e l e n v ati ni b at a r e d uc e d d os e
Lif e-t hr e at e ni n g c o ns e q u e nc es ( m ali g n a nt 
h y p ert e nsi o n, n e ur ol o gic al d eficit, or h y p ert e nsi v e 
crisis)
Ur g e nt i nt er v e nti o n is i n dic at e d. Disc o nti n u e 
l e n v ati ni b a n d i nstit ut e a p pr o pri at e m e dic al 
m a n a g e m e nt
B P = Bl o o d pr ess ur e 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 3 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
5. 5 C o nc o mit a nt m e dic ati o n
M e dic ati o ns or v acci n ati o ns s p ecific all y pr o hi bit e d i n t h e excl usi o n crit eri a ar e n ot all o w e d d uri n g t h e o n g oi n g 
tri al.  If t h er e is a cli nic al i n dic ati o n f or o n e of t h es e or ot h er m e dic ati o ns or v acci n ati o ns s p ecific all y pr o hi bit e d 
d uri n g t h e tri al, disc o nti n u ati o n fr o m tri al t h er a p y or v acci n ati o n m a y b e r e q uir e d.
Acc e pt a bl e M e dic ati o ns
All tr e at m e nts t h at t h e i n v esti g at or c o nsi d ers n ec ess ar y f or a s u bj ect’s w elf ar e m a y b e a d mi nist er e d at t h e 
discr eti o n of t h e i n v esti g at or i n k e e pi n g wit h t h e c o m m u nit y st a n d ar ds of m e dic al c ar e.  All c o nc o mit a nt 
m e dic ati o n will b e r ec or d e d o n t h e c as e r e p ort f or m ( C R F) i ncl u di n g all pr escri pti o n, o v er-t h e-c o u nt er ( O T C), 
h er b al s u p pl e m e nts, a n d I V m e dic ati o ns a n d fl ui ds.  If c h a n g es occ ur d uri n g t h e tri al p eri o d, d oc u m e nt ati o n of 
dr u g d os a g e, fr e q u e nc y, r o ut e, a n d d at e m a y als o b e i ncl u d e d o n t h e C R F. All c o nc o mit a nt m e dic ati o ns r ec ei v e d 
wit hi n 2 8 d a ys b ef or e t h e first d os e of tri al tr e at m e nt a n d 3 0 d a ys aft er t h e l ast d os e of tri al tr e at m e nt s h o ul d b e 
r ec or d e d.  C o nc o mit a nt m e dic ati o ns a d mi nist er e d aft er 3 0 d a ys aft er t h e l ast d os e of tri al tr e at m e nt s h o ul d b e 
r ec or d e d. I n g e n er al, c o nc o mit a nt m e dic ati o ns a n d t h er a pi es d e e m e d n ec ess ar y f or t h e s u p p orti v e c ar e ( e. g. 
s uc h as a nti- e m etics, a nti- di arr h e a) a n d s af et y of t h e p ati e nt ar e all o w e d. 
• M e dic ati o ns t o pr e v e nt or tr e at n a us e a or v o miti n g. • A nti- di arr h e al m e dic ati o ns ( e. g., l o p er a mi d e) f or p ati e nts 
w h o d e v el o p di arr h e a. • P ai n m e dic ati o n t o all o w t h e p ati e nt t o b e as c o mf ort a bl e as p ossi bl e. • Tr e at m e nt wit h 
bis p h os p h o n at es or d e n os u m a b f or pr e- existi n g, p ai nf ul b o n e/li v er m et ast as es, a n d li mit e d-fi el d p alli ati v e 
r a di ot h er a p y or s ur g er y is p er mitt e d. P ati e nts r e q uiri n g i niti ati o n of s uc h tr e at m e nt d uri n g t h e c o urs e of t h e 
st u d y m ust b e e v al u at e d f or dis e as e pr o gr essi o n; r a di ot h er a p y li k e a n y c o nc o mit a nt m e dic ati o n m ust b e list e d 
o n t h e C R F. 
• H e m at o p oi etic c ol o n y-sti m ul ati n g gr o wt h f act ors ( e. g. G- C S F, G M- C S F, M- C S F), t hr o m b o p oi eti n mi m etics or 
er yt hr oi d sti m ul ati n g a g e nts as p er l oc al or p u blis h e d g ui d eli n es; i n c as e of a n e mi a, t hr o m b oc yt o p e ni a or 
n e utr o p e ni a, p ot e nti al i m m u n e m e di at e d eti ol o g y s h o ul d b e r ul e d o ut • N utriti o n al s u p p ort or a p p etit e 
sti m ul a nts ( e. g. m e g estr ol). • Ox y g e n t h er a p y a n d bl o o d pr o d ucts or tr a nsf usi o ns. • I n acti v at e d v acci n es.  • T h e 
p ati e nt m ust b e t ol d t o n otif y t h e i n v esti g ati o n al sit e a b o ut a n y n e w m e dic ati o ns h e/s h e t a k es aft er t h e st art of 
t h e st u d y dr u g. All m e dic ati o ns ( ot h er t h a n st u d y dr u g) a n d si g nific a nt n o n- dr u g t h er a pi es (i ncl u di n g p h ysic al 
t h er a p y, h er b al/ n at ur al m e dic ati o ns a n d bl o o d tr a nsf usi o ns) a d mi nist er e d d uri n g t h e st u d y m ust b e list e d o n 
t h e C o nc o mit a nt M e dic ati o ns
Pr o hi bit e d c o nc o mit a nt m e dic ati o ns 
D uri n g t h e c o urs e of t h e st u d y, p ati e nts m ust n ot r ec ei v e ot h er a nti n e o pl astic t h er a pi es ( e. g. i n v esti g ati o n al 
dr u gs, d e vic es, c h e m ot h er a p y, i m m u n ot h er a pi es).  H o w e v er, li mit e d-fi el d p alli ati v e r a di ot h er a p y m a y b e all o w e d 
as c o nc o mit a nt t h er a p y (s e e a b o v e).  T h e us e of li v e v acci n es is n ot all o w e d t hr o u g h t h e w h ol e d ur ati o n of t h e 
st u d y. I n acti v at e d v acci n es ar e all o w e d. T h er e ar e n o pr o hi bit e d t h er a pi es d uri n g t h e p ost-tr e at m e nt f oll o w- u p 
p eri o d.
R esc u e M e dic ati o ns & S u p p orti v e C ar e
P ati e nts w h os e tr e at m e nt is i nt err u pt e d or p er m a n e ntl y disc o nti n u e d d u e t o a n a d v ers e e v e nt or cli nic all y 
si g nific a nt l a b or at or y v al u e, m ust b e f oll o w e d u p at l e ast o nc e e v er y 2 w e e ks ( or m or e fr e q u e ntl y if r e q uir e d b y 
i nstit uti o n al pr actic es, or if cli nic all y i n dic at e d) f or 4 w e e ks, a n d s u bs e q u e ntl y at a p pr oxi m at el y 4- w e e k i nt er v als, 
u ntil r es ol uti o n or st a biliz ati o n of t h e ev e nt, w hic h e v er c o m es first. A p pr o pri at e cli nic al ex p erts s uc h as 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 4 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
o p ht h al m ol o gist, e n d ocri n ol o gist, d er m at ol o gist, ps yc hi atrists etc. s h o ul d b e c o ns ult e d as d e e m e d n ec ess ar y.  All 
p ati e nts m ust b e f oll o w e d u p f or a d v ers e e v e nts a n d s eri o us a d v ers e e v e nts u ntil st art of n e w a nti n e o pl astic 
m e dic ati o n f or 2 8 d a ys aft er disc o nti n u ati o n of st u d y dr u gs, w hic h e v er is s o o n er.  
S us p ect e d S A Es will c o nti n u e t o b e c oll ect e d b e y o n d t h e 1 5 0- D a y s af et y visit. T his will b e d o n e b y r et ur n cli nic 
visits, l a b or at or y c h ec ks, a n d p h o n e c alls
5. 6 St u d y Pr oc e d ur es
B ef or e st u d y e ntr y, t hr o u g h o ut t h e st u d y, a n d f oll o wi n g st u d y dr u g disc o nti n u ati o n, v ari o us cli nic al a n d 
di a g n ostic l a b or at or y e v al u ati o ns ar e o utli n e d.  T h e p ur p os e of o bt ai ni n g t h es e d et ail e d m e as ur e m e nts is t o 
e ns ur e a d e q u at e s af et y a n d t ol er a bilit y ass ess m e nts.  Cli nic al ev al u ati o ns a n d l a b or at or y st u di es m a y b e 
r e p e at e d m or e fr e q u e ntl y if cli nic all y i n dic at e d.  T h e Sc h e d ul es of Ass ess m e nts d uri n g t h e scr e e ni n g a n d 
tr e at m e nt p eri o d is pr o vi d e d f oll o wi n g t h e Pr ot oc ol S y n o psis. 
Scr e e ni n g P h as e
Scr e e ni n g pr oc e d ur es will b e p erf or m e d u p t o 2 8 d a ys pri or t o i niti ati o n of pr ot oc ol t h er a p y as a p plic a bl e.  All 
s u bj ects m ust first r e a d, u n d erst a n d, a n d si g n t h e I R B- a p pr o v e d I C F b ef or e a n y st u d y-s p ecific scr e e ni n g 
pr oc e d ur es ar e p erf or m e d.  Aft er si g ni n g t h e I C F, c o m pl eti n g all scr e e ni n g pr oc e d ur es, a n d b ei n g d e e m e d eli gi bl e 
f or e ntr y, s u bj ects will b e e nr oll e d i n t h e st u d y.  Pr oc e d ur es t h at ar e p erf or m e d pri or t o t h e si g ni n g of t h e I C F 
a n d ar e c o nsi d er e d st a n d ar d of c ar e m a y b e us e d as scr e e ni n g ass ess m e nts if t h e y f all wit hi n t h e scr e e ni n g 
wi n d o w. 
T h e f oll o wi n g pr oc e d ur es will b e p erf or m e d d uri n g t h e Scr e e ni n g Visit :

I nf or m e d C o ns e nt

R e vi e w of eli gi bilit y crit eri a

M e dic al hist or y a n d d e m o gr a p hics

C o m pl et e p h ysic al ex a m 

E C O G P erf or m a nc e St at us

Vit als si g ns, w ei g ht a n d h ei g ht 

1 2-l e a d E C G

R e vi e w of pri or/c o nc o mit a nt m e dic ati o ns 

I m a gi n g b y C T/ M RI ( wit hi n 2 8 d a ys)

Cli nic al l a b or at or y t ests f or:
o
H e m at ol o g y 
o
Cli nic al c h e mistr y 
o
T S H, fr e e T 4, T 3
o
C o a g ul ati o n ( P T, I N R, a P T T)
o
Cr e ati ni n e or Cr e ati ni n e Cl e ar a nc e
o
S er u m or uri n e pr e g n a nc y t est (f or w o m e n of c hil d b e ari n g p ot e nti al)
o
H e p atitis B s urf ac e a nti g e n, H e p atitis C a nti b o di es, HI V a nti b o di es 
o
Uri n al ysis 
o
Al p h a f et o pr ot ei n ( A F P)
Tr e at m e nt P h as e 
Pr oc e d ur es t o b e c o n d uct e d d uri n g t h e tr e at m e nt p h as e of t h e st u d y ar e pr es e nt e d i n t h e Sc h e d ul e of 
Ass ess m e nts ( S ecti o n 1. 3). Scr e e ni n g pr oc e d ur es p erf or m e d wit hi n 7 2 h o urs of C ycl e 1 D a y 1 ( C 1 D 1) d o n ot n e e d 
t o b e r e p e at e d o n C 1 D 1.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 5 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5

Bri ef m e dic al hist or y

S y m pt o m- dir ect e d p h ysic al ex a m 

E C O G P erf or m a nc e St at us

Vit als si g ns, w ei g ht 

R e vi e w of pri or/c o nc o mit a nt m e dic ati o ns 

Cli nic al l a b or at or y t ests f or:
o
H e m at ol o g y 
o
Cli nic al c h e mistr y
o
T S H, Fr e e T 4 a n d T 3
o
A F P
o
S er u m or uri n e pr e g n a nc y t est (f or w o m e n of c hil d b e ari n g p ot e nti al)
o
Uri n al ysis (s e e Uri n e a n al ysis t ests)
Dr u g Tr e at m e nt d escri pti o n
Dr u g
D os e/ P ot e nc y
D os e 
Fr e q u e nc y
C ycl es
R o ut e of 
A d mi nistr ati o n
≥6 0  k g B W 
1 2 m g (t hr e e 4 
m g 
c a ps ul es 
O nc e d ail y
ALL
or al
L e n v ati ni b
< 6 0 k g B W 
8 m g (t w o 4 m g 
c a ps ul es 
O nc e d ail y
ALL
or al
E n d of Tr e at m e nt
o
E n d of tr e at m e nt is d efi n e d as t h e l ast pl a n n e d d osi n g visit wit hi n t h e d osi n g p eri o d. F or s u bj ects w h o 
disc o nti n u e dr u g tr e at m e nt, e n d of tr e at m e nt is c o nsi d er e d t h e l ast visit w h er e t h e d ecisi o n is m a d e t o 
disc o nti n u e tr e at m e nt. All r e q uir e d pr oc e d ur es m a y b e c o m pl et e d wit hi n ± 7 d a ys  of t h e e n d of tr e at m e nt 
visit. R e p e at dis e as e ass ess m e nt is n ot r e q uir e d if p erf or m e d wit hi n 2 8  d a ys pri or t o t h e e n d of tr e at m e nt 
visit.
o
Ass ess m e nts f or s u bj ects w h o h a v e c o m pl et e d tr e at m e nt a n d ac hi e v e d dis e as e c o ntr ol or h a v e disc o nti n u e d 
tr e at m e nt d u e t o t oxicit y i n t h e a bs e nc e of c o nfir m e d pr o gr essi v e dis e as e ar e pr o vi d e d i n t h e Sc h e d ul e of 
E v e nts.   
o
All s u bj ects will b e f oll o w e d f or s ur vi v al u ntil t h e e n d of t h e st u d y r e g ar dl ess of f urt h er tr e at m e nts, or u ntil 
t h e s p o ns or e n ds t h e st u d y.
5. 7 D escri pti o n of St u d y Pr oc e d ur es

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 6 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
M e dic al hist or y
Fi n di n gs fr o m m e dic al hist or y ( o bt ai n e d at scr e e ni n g) a n d p h ysic al ex a mi n ati o n s h all b e gi v e n a b as eli n e gr a d e 
acc or di n g t o t h e pr oc e d ur e f or A Es. I ncr e as es i n s e v erit y of pr e- existi n g c o n diti o ns d uri n g t h e st u d y will b e 
c o nsi d er e d A Es, wit h r es ol uti o n occ urri n g w h e n t h e gr a d e r et ur ns t o t h e pr e-st u d y gr a d e or b el o w.
P h ysic al e x a mi n ati o n
P h ysic al ex a mi n ati o ns s h o ul d b e c o n d uct e d acc or di n g t o t h e Sc h e d ul e of E v e nts.  F ull p h ysic al ex a mi n ati o ns 
s h o ul d b e c o n d uct e d at scr e e ni n g/ b as eli n e, D a y 1 of c ycl e 2 a n d b e y o n d, a n d E O T ( e v al u at e all m aj or or g a n 
s yst e ms, i ncl u di n g t h e f oll o wi n g c at e g ori es:  g e n er al, h e a d, e y es, e ars, m o ut h/t hr o at, n ec k, h e art, l u n gs, 
a b d o m e n, l y m p h n o d es, j oi nts, extr e miti es, i nt e g u m e nt ar y, n e ur ol o gic, a n d ps yc hi atric). Ot h er ex a mi n ati o ns m a y 
b e f oc us e d, at t h e discr eti o n of t h e I n v esti g at or, t o i d e ntif y c h a n g es fr o m b as eli n e or e v al u at e c h a n g es b as e d o n 
t h e p ati e nt’s cli nic al s y m pt o ms.  W ei g ht is t o b e r ec or d e d at e ac h visit, h ei g ht at scr e e ni n g/ b as eli n e visit o nl y.  
Vit al si g ns
Vit al si g ns ( bl o o d pr ess ur e [ B P], p uls e, t e m p er at ur e, a n d r es pir ati o n r at e) will b e ev al u at e d acc or di n g t o t h e 
ass ess m e nt sc h e d ul es.  B o d y w ei g ht is als o r ec or d e d al o n g wit h vit al si g ns.  
T h e d at e a n d ti m e of c oll ecti o n a n d m e as ur e m e nt will b e r ec or d e d o n t h e a p pr o pri at e e C R F.  A d diti o n al 
m o nit ori n g wit h ass ess m e nt of vit al si g ns is at t h e discr eti o n of t h e I n v esti g at or p er st a n d ar d cli nic al pr actic e or 
as cli nic all y i n dic at e d.  
El ectr oc ar di o gr a ms
R esti n g 1 2-l e a d E C Gs will b e r ec or d e d at scr e e ni n g a n d as cli nic all y i n dic at e d t hr o u g h o ut t h e st u d y.  E C Gs s h o ul d 
b e o bt ai n e d aft er t h e p ati e nt h as b e e n i n a s u pi n e p ositi o n f or 5 mi n ut es a n d r ec or d e d w hil e t h e p ati e nt r e m ai ns 
i n t h at p ositi o n.
At Scr e e ni n g, a si n gl e E C G will b e o bt ai n e d o n w hic h Q Tc F m ust b e ≤4 8 0  ms.  
I n c as e of cli nic all y si g nific a nt E C G a b n or m aliti es, i ncl u di n g a Q Tc F v al u e > 4 8 0 ms, 2 a d diti o n al 1 2-l e a d E C Gs 
s h o ul d b e o bt ai n e d o v er a bri ef p eri o d ( e. g., 3 0 mi n ut es) t o c o nfir m t h e fi n di n g.  
T h e I n v esti g at or or q u alifi e d S u b-I n v esti g at or will r e vi e w all E C G i nt er pr et ati o ns a n d i nt er v al d ur ati o n 
m e as ur e m e nts f or cli nic al si g nific a nc e.  A n y E C G i nt er pr et ati o n d e e m e d t o b e cli nic all y si g nific a nt will b e r e p ort e d 
as a n A E.   
Cli nic al l a b or at or y t ests
T h e f oll o wi n g cli nic al l a b or at or y t ests will b e p erf or m e d (s e e t h e Sc h e d ul e of Ass ess m e nts)

H e m at ol o g y a n d Cli nic al C h e mistr y

Uri n al ysis

C o a g ul ati o n p ar a m et ers: Acti v at e d p arti al t hr o m b o pl asti n ti m e  a n d I nt er n ati o n al n or m aliz e d r ati o  t o b e 
ass ess e d at b as eli n e a n d as cli nic all y i n dic at e d 

Pr e g n a nc y t est (f e m al e s u bj ects of c hil d b e ari n g p ot e nti al o nl y)
o
S er u m or Uri n e h u m a n c h ori o nic g o n a d otr o pi n

T h yr oi d Sti m ul ati n g H or m o n e
o
T S H, Fr e e T 3 a n d fr e e T 4 

Ot h er l a b or at or y t ests
o
H e p atitis B s urf ac e a nti g e n, h e p atitis C a nti b o d y
o
HI V a nti b o d y
H e m at ol o g y L a b or at or y T ests

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 7 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
B as o p hils
M e a n c or p usc ul ar v ol u m e
E osi n o p hils
M o n oc yt es
H e m at ocrit
N e utr o p hils
H e m o gl o bi n
Pl at el et c o u nt
L y m p h oc yt es
R e d bl o o d c ell c o u nt
M e a n c or p usc ul ar h e m o gl o bi n
T ot al w hit e c ell c o u nt
M e a n c or p usc ul ar h e m o gl o bi n c o nc e ntr ati o n
Cli nic al c h e mistr y (s er u m or pl as m a) L a b or at or y T ests
Al b u mi n
Gl uc os e
Al k ali n e p h os p h at as e
L act at e d e h y dr o g e n as e
Al a ni n e a mi n otr a nsf er as e
Li p as e
A m yl as e
M a g n esi u m
As p art at e a mi n otr a nsf er as e
P ot assi u m
Bic ar b o n at e
S o di u m
C alci u m 
T ot al bilir u bi n a
C hl ori d e
T ot al pr ot ei n
Cr e ati ni n e
Ur e a or bl o o d ur e a nitr o g e n, d e p e n di n g o n l oc al pr actic e
G a m m a gl ut a m yltr a nsf er as e
Uric aci d
a   If T ot al bilir u bi n is ≥2x UL N  ( a n d n o e vi d e nc e of Gil b ert’s s y n dr o m e) t h e n fr acti o n at e i nt o dir ect a n d i n dir ect  bilir u bi n
Uri n al ysis T ests
Bilir u bi n
p H
Bl o o d
Pr ot ei n
Gl uc os e
S p ecific gr a vit y
K et o n es
C ol o ur a n d a p p e ar a nc e

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 8 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
5. 8 T u m or a n d R a di o gr a p hic Ass ess m e nts 
T u m or ass ess m e nts f or all p ati e nts will b e p erf or m e d at Scr e e ni n g a n d aft er 8 w e e ks ( ± 7 d a ys) of pr ot oc ol 
tr e at m e nt. Ass ess m e nts will b e p erf or m e d e v er y 8 w e e ks d uri n g t h e l o n g-t er m f oll o w- u p p eri o d. T u m or r es p o ns e 
will b e e v al u at e d usi n g R E CI S T v 1. 1. ( A p p e n dix C )
R a di o gr a p hic ass ess m e nts (c h est/ a b d o m e n/ p el vis, a n d ot h er k n o w n aff ect e d a n at o mic al ar e as) ar e r e q uir e d f or 
all p ati e nts f or t u m or m e as ur e m e nts.  A d diti o n al sc a n ass ess m e nts m a y b e c oll ect e d b as e d o n cli nic al s y m pt o ms, 
as a p pr o pri at e. D oc u m e nt e d t u m or m e as ur e m e nts ar e r e q uir e d usi n g C T sc a ns, M RI, p h ysic al ex a mi n ati o n, 
a n d/ or di git al p h ot o gr a p h y, as a p pr o pri at e.  A n y i m a gi n g us e d t o ass ess dis e as e at a n y ti m e p oi nt will b e 
s u b mitt e d f or a n i n d e p e n d e nt r a di ol o g y r e vi e w. T h e s a m e m et h o d of ass ess m e nt ( C T or M RI a n d/ or di git al 
p h ot o gr a p h y) a n d t h e s a m e t ec h ni q u e f or ac q uisiti o n of i m a g es m ust b e us e d f or all st u d y ass ess m e nts (c o ntr ast 
m ust b e us e d u nl ess m e dic all y c o ntr ai n dic at e d).  B as eli n e i m a gi n g s h o ul d b e d o n e at t h e s a m e i nstit uti o n/f acilit y 
w hic h will b e us e d t o m e as ur e r es p o ns e d uri n g t h e p ati e nt’s p artici p ati o n i n t h e st u d y.  R a di o gr a p hic ass ess m e nts 
a n d effic ac y a n al ys es will b e c o n d uct e d b y t h e I n v esti g at or sit e.
5. 9 C orr el ati v e St u di es
Pr e a n d p ost tr e at m e nt p eri p h er al bl o o d f or c orr el ati v e st u di es i ncl u di n g circ ul ati n g t u m or D N A ( all p ati e nts), 
a n d bi o m ar k er a n al ysis. P eri p h er al bl o o d will b e c oll ect e d at b as eli n e, o n c ycl e 3 d a y 1 a n d at 
pr o gr essi o n.  A p pr oxi m at el y 2 0 mL t u b es of bl o o d will b e o bt ai n e d f or c orr el ati v e st u di es at e ac h of t h es e ti m e 
p oi nts. Bl o o d s a m pl es will b e c oll ect e d, pr oc ess e d, st or e d a n d s hi p p e d t o L esi ns ki L a b as p er l a b m a n u al.
L esi ns ki L a b or at or y
S uit e C 3 0 5 4, B a y 1 7
1 3 6 5- C Clift o n R d. N E
Wi ns hi p C a nc er I nstit ut e of E m or y U ni v ersit y
Atl a nt a, G A 3 0 3 2 2
6.
D at a a n d S p eci m e n B a n ki n g 
Bl o o d s a m pl es  will b e o bt ai n e d a n d us e d f or m e dic al r es e arc h b y t h e i n v esti g at ors of t his st u d y. D at a a n d 
s p eci m e ns fr o m t his st u dy m ay b e us ef ul f or ot h er r es e arc h b ei n g d o n e by i nv esti g at ors at E m ory or els e w h er e. 
T o h el p f urt h er sci e nc e, I nv esti g at ors m ay pr ovi d e d e-i d e ntifi e d d at a a n d/ or s p eci m e ns t o ot h er r es e arc h ers. A ny 
i nf or m ati o n t h at c o ul d i d e ntify p artici p a nts will n ot b e i ncl u d e d. If d at a or s p eci m e ns ar e l a b el e d wit h st u dy I D, 
w e will n ot all o w ot h er i nv esti g at ors t o li n k t h at I D t o i d e ntifi a bl e i nf or m ati o n.
S a m pl es a n d d at a c oll ect e d u n d er t his pr ot oc ol m a y b e us e d t o st u d y H C C . Acc ess t o st or e d s a m pl es will b e 
li mit e d t o I R B- a p pr ov e d i nv esti g at ors. S a m pl es a n d d at a will b e st or e d usi n g c o d es assi g n e d b y t h e i n v esti g at ors 
or t h eir d esi g n e es. D at a will b e k e pt i n p ass w or d- pr ot ect e d c o m p ut ers. O nly i n v esti g at ors will h a v e acc ess t o t h e 
s a m pl es a n d d at a.
All st or e d s a m pl es will b e m ai nt ai n e d i n t h e l a b or at or y t o w hic h it w as s e nt i niti all y f or a n al ysis. St u d y p artici p a nts 
w h o r e q u est d estr ucti o n of s a m pl es will b e n otifi e d of c o m pli a nc e wit h s uc h r e q u est a n d all s u p p orti n g d et ails 
will b e m ai nt ai n e d f or tr ac ki n g.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 1 9 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
T h e r es ults of s o m e st u d y t ests a n d pr oc e d ur es will b e us e d o nl y f or r es e arc h p ur p os es a n d will n ot b e pl ac e d 
i n s u bj ect’s m e dic al r ec or d.  F or t his st u d y, t h os e it e ms i ncl u d e r es e arc h bl o o d c oll ecti o n. 
C orr el ati v e p eri p h er al bl o o d s a m pl es will b e c oll ect e d pri or t o st u d y dr u g all ot m e nt, pri or t o tr e at m e nt o n c ycl e 
3  d a y 1, a n d at pr o gr essi o n t o ass ess eff ects l e n v ati ni b o n circ ul ati n g t u m or D N A. 
7. S h ari n g of R es ults wit h P artici p a nts
I n g e n er al, st u dy st aff will n ot pr ovi d e a ny i n divi d u al r es ults t o s u bj ects ( ex. o utc o m e tri al r es ults or r es ults fr o m 
s u bj ect’s s a m pl es st u di es). If s o m et hi n g of ur g e nt m e dic al i m p ort a nc e t o t h e p artici p ati n g s u bj ects will b e f o u n d, 
t h e PI ( or c o-Is) will i nf or m t h e s u bj ect, alt h o u g h w e ex p ect t h at t his will b e a v ery r ar e occ urr e nc e. S a m pl es a n d 
d at a will o nl y b e us e d f or r es e arc h.
8. St u d y Ti m eli n es
8. 1 D ur ati o n of t h er a p y
I n t h e a bs e nc e of tr e at m e nt d el a ys d u e t o a d v ers e ev e nt(s), p ati e nts will b e tr e at e d u ntil a n y o n e of t h e f oll o wi n g: 
• T u m or pr o gr essi o n p er R E CI S T 1. 1 
• D e at h 
• U n acc e pt a bl e t oxicit y 
• S y m pt o m atic d et eri or ati o n 
• Ac hi e v e m e nt of m axi m al r es p o ns e 
• I n v esti g at or’s d ecisi o n t o disc o nti n u e tr e at m e nt 
• P ati e nt d ecisi o n t o disc o nti n u e tr e at m e nt 
• P ati e nt wit h dr a ws c o ns e nt 
• L ost t o f oll o w u p
S p o ns or or Ei asi t er mi n at e t h e st u d y 
I n t h e e v e nt of a p ati e nt’s wit h dr a w al, t h e I n v esti g at or will m a k e ev er y eff ort t o c o m pl et e t h e E n d of Tr e at m e nt 
pr oc e d ur es s p ecifi e d i n t h e Sc h e d ul e of E v e nts.
Tr e at m e nt B e y o n d Pr o gr essi o n
P ati e nts will b e p er mitt e d t o c o nti n u e o n tr e at m e nt b e y o n d i niti al R E CI S T 1. 1- d efi n e d P D as l o n g as t h e y m e et 
t h e f oll o wi n g crit eri a: 
• 
I n v esti g at or- ass ess e d cli nic al b e n efit a n d wit h o ut r a pi d dis e as e pr o gr essi o n. 
• 
C o nti n u e t o m e et all ot h er st u d y pr ot oc ol eli gi bilit y crit eri a. 
• 
P ati e nt t ol er at es st u d y dr u g(s). 
• 
P ati e nt h as st a bl e E C O G p erf or m a nc e st at us of 0 or 1. 
• 
Tr e at m e nt b e y o n d pr o gr essi o n will n ot d el a y a n i m mi n e nt i nt er v e nti o n t o pr e v e nt s eri o us c o m plic ati o ns 
of dis e as e pr o gr essi o n ( e. g., c e ntr al n erv o us s yst e m m et ast as es). T h e ass ess m e nt of cli nic al b e n efit 
s h o ul d t a k e i nt o acc o u nt w h et h er t h e p ati e nt is cli nic all y d et eri or ati n g a n d u nli k el y t o r ec ei v e f urt h er 
b e n efit fr o m c o nti n u e d tr e at m e nt.  
All d ecisi o ns t o c o nti n u e tr e at m e nt b e y o n d i niti al pr o gr essi o n m ust b e disc uss e d wit h t h e sit e Pri nci p al 
I n v esti g at or a n d a n ass ess m e nt of t h e ris k/ b e n efit of c o nti n ui n g wit h st u d y dr u g(s) m ust b e d oc u m e nt e d i n t h e 
st u d y r ec or ds. F or p ati e nts w h o st a y o n tr e at m e nt b e y o n d R E CI S T 1. 1- d efi n e d P D, all st u d y pr oc e d ur es s h o ul d 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 0 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
c o nti n u e t o b e p erf or m e d, i ncl u di n g r a di o gr a p hic ass ess m e nt b y c o m p ut e d t o m o gr a p h y ( C T) ( pr ef err e d) or 
m a g n etic r es o n a nc e i m a gi n g ( M RI).  
P ati e nts will b e disc o nti n u e d fr o m tr e at m e nt u p o n f urt h er evi d e nc e of dis e as e pr o gr essi o n, d efi n e d as a n 
a d diti o n al 1 0 % or gr e at er i ncr e as e i n t h e t ot al t u m or b ur d e n fr o m t h e ti m e of i niti al dis e as e pr o gr essi o n.  T h e 
t ot al t u m or b ur d e n is c alc ul at e d as t h e s u m of t h e l o n g est di a m et ers ( SL D) of all t ar g et t u m ors a n d SL D of all 
n e w m e as ur a bl e l esi o ns.  A n e w l esi o n is m e as ur a bl e if t h e l o n g est di a m et er is at l e ast 1 0 m m.  A n y n e w l esi o ns 
t h at ar e n o n- m e as ur a bl e at t h e ti m e of i niti al a p p e ar a nc e a n d b ec o m e m e as ur a bl e l at er will b e i ncl u d e d i n t h e 
c alc ul ati o n of t ot al t u m or b ur d e n.  T h e t ot al t u m or b ur d e n fr o m t h e ti m e of i niti al R E CI S T 1. 1- d efi n e d 
pr o gr essi o n will b e us e d as t h e r ef er e nc e b as eli n e f or c o m p aris o n wit h all p ost- pr o gr essi o n ass ess m e nts
8. 2 D ur ati o n of f oll o w- u p 
P ati e nts will b e f oll o w e d f or a p pr oxi m at el y 3 0 d a ys ( S af et y F oll o w- u p) aft er t h e l ast d os e of st u d y dr u g or b ef or e 
i niti ati o n of n e w a nti n e o pl astic or i n v esti g ati o n al t h er a p y w hic h ev er occ urs first.  P ati e nts r e m o v e d fr o m st u d y 
f or u n acc e pt a bl e a d v ers e e v e nt(s) will b e f oll o w e d u ntil r es ol uti o n or st a biliz ati o n of t h e a d v ers e e v e nt.
L o n g-t er m f oll o w- u p s h o ul d c o nti n u e u ntil t h e p ati e nt’s wit h dr a w al of c o ns e nt or l oss t o f oll o w u p, d e at h, or 
st u d y t er mi n ati o n. 
P ati e nts i n l o n g t er m f oll o w- u p c a n b e s e e n b y m e dic al o nc ol o g y, h a v e c h art r e vi e w e d, or p h o n e c all t o d et er mi n e 
c urr e nt st at us e v er y 1 2 w e e ks ( +/- 1 4 d a ys) as i n dic at e d i n t h e S ecti o n 1. 3 Sc h e d ul e of Ass ess m e nts . 
A p artici p a nt will b e c o nsi d er e d l ost t o f oll o w- u p if h e f ails t o r et ur n f or t hr e e sc h e d ul e d visits a n d is u n a bl e t o 
b e c o nt act e d b y t h e st u d y sit e st aff aft er t hr e e att e m pts at c o nt act b y p h o n e. 
T h e f oll o wi n g acti o ns m ust b e t a k e n if a p artici p a nt f ails t o r et ur n t o t h e cli nic f or a r e q uir e d st u d y visit:

T h e sit e will att e m pt t o c o nt act t h e p artici p a nt a n d r esc h e d ul e t h e miss e d visit a n d c o u ns el t h e 
p artici p a nt o n t h e i m p ort a nc e of m ai nt ai ni n g t h e assi g n e d visit sc h e d ul e a n d asc ert ai n if t h e p artici p a nt 
wis h es t o a n d/ or s h o ul d c o nti n u e i n t h e st u d y.

B ef or e a p artici p a nt is d e e m e d l ost t o f oll o w- u p, t h e i n v esti g at or or d esi g n e e will m a k e e v er y eff ort t o 
r e g ai n c o nt act wit h t h e p artici p a nt ( w h er e p ossi bl e, 3 t el e p h o n e c alls a n d, if n ec ess ar y, a c ertifi e d l ett er 
t o t h e p artici p a nt’s l ast k n o w n m aili n g a d dr ess or l oc al e q ui v al e nt m et h o ds). T h es e c o nt act att e m pts 
s h o ul d b e d oc u m e nt e d i n t h e p artici p a nt’s m e dic al r ec or d or st u d y fil e. 
S h o ul d t h e p artici p a nt c o nti n u e t o b e u nr e ac h a bl e, h e will b e c o nsi d er e d t o h a v e wit h dr a w n fr o m t h e st u d y wit h 
a pri m ar y r e as o n of l ost t o f oll o w- u p. 
Disc o nti n u ati o n fr o m st u d y i nt er v e nti o n d o es n ot m e a n disc o nti n u ati o n fr o m t h e st u d y, a n d r e m ai ni n g st u d y 
pr oc e d ur es s h o ul d b e c o m pl et e d as i n dic at e d b y t h e st u d y pr ot oc ol.   If a cli nic all y si g nific a nt fi n di n g is i d e ntifi e d 
(i ncl u di n g, b ut n ot li mit e d t o c h a n g es fr o m b as eli n e) aft er e nr oll m e nt, t h e i n v esti g at or or q u alifi e d d esi g n e e will 
d et er mi n e if a n y c h a n g e i n p artici p a nt m a n a g e m e nt is n e e d e d. A n y n e w cli nic all y r el ev a nt fi n di n g will b e r e p ort e d 
as a n a d v ers e ev e nt ( A E).
P ati e nts m a y c h o os e t o disc o nti n u e t h e tri al at a n y ti m e, f or a n y r e as o n, a n d wit h o ut pr ej u dic e t o f urt h er 
tr e at m e nt.  T h e E O T visit will occ ur 3 0 d a ys aft er t h e l ast d os e of t h e st u d y dr u g or b ef or e a n e w a nti n e o pl astic 
r e gi m e n h as b e e n i niti at e d f or p ati e nts e nr oll e d.
T h e d at a t o b e c oll ect e d at t h e E O T visit will i ncl u d e t h e f oll o wi n g:

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 1 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
Vit al si g ns, p erf or m a nc e st at us, w ei g ht, p h ysic al ex a m, pr e g n a nc y t est, h e m at ol o g y a n d cli nic al c h e mistr y, 
t h yr oi d f u ncti o n p a n el, uri n al ysis, a n d ass ess m e nt of a d v ers e e v e nts.
R e pl ac e m e nt of S u bj ects
S u bj ects w h o si g n t h e i nf or m e d c o ns e nt f or m a n d ar e assi g n e d b ut d o n ot r ec ei v e t h e st u d y i nt er v e nti o n m a y 
b e r e pl ac e d. S u bj ects w h o si g n t h e i nf or m e d c o ns e nt f or m, a n d ar e assi g n e d a n d r ec ei v e t h e st u d y 
i nt er v e nti o n, a n d s u bs e q u e ntl y wit h dr a w, or ar e wit h dr a w n or disc o nti n u e d fr o m t h e st u d y, will n ot b e 
r e pl ac e d.
9. I ncl usi o n a n d E xcl usi o n Crit eri a
A s u bj ect m ust f ull y m e et all of t h e f oll o wi n g crit eri a t o b e eli gi bl e f or t h e st u d y:
I ncl usi o n Crit eri a
1.
M al e or F e m al e 
2.
A g e ≥1 8  y e ars.  
3.
E C O G p erf or m a nc e st at us ≤1  ( K ar n ofs k y ≥6 0 %,  s e e A p p e n dix A).  
4.
P ati e nts m ust h a v e r ec urr e nt hist ol o gic all y or c yt ol o gic all y c o nfir m e d h e p at oc ell ul ar c arci n o m a t h at h as 
r ec urr e d aft er li v er tr a ns pl a nt ati o n a n d n ot a m e n a bl e f or s ur gic al r es ecti o n. 
5.
C hil d P u g h Cl ass A
6.
Pri or ort h otr o pic li v er tr a ns pl a nt ati o n f or c ur ati v e i nt e nt
7.
M e as ur a bl e dis e as e p er R E CI S T v ersi o n 1. 1
8.
Lif e ex p ect a nc y > 1 2 w e e ks as d et er mi n e d b y t h e I n v esti g at or
9.
P ati e nts m ust h a v e a d e q u at e or g a n a n d m arr o w f u ncti o n, wit hi n 2 8 d a ys of C ycl e 1 D a y 1, as d efi n e d 
b el o w:
H e m at ol o g y
H e m o gl o bi n
≥ 8. 0 g/ dl 
A bs ol ut e n e utr o p hil c o u nt ( A N C)
≥ 1, 5 0 0/ mcL ( aft er at l e ast 7 d a ys wit h o ut gr o wt h f act or 
s u p p ort or tr a nsf usi o n)
Pl at el ets
≥ 7 5, 0 0 0/ mcL 
C o a g ul ati o n
I nt er n ati o n al N or m aliz e d R ati o (I N R)
≤2. 3
C h e mistr y
T ot al bilir u bi n
≤3  ti m es t h e i nstit uti o n al u p p er li mit of n or m al ( UL N)
A S T/ AL T
≤ 5. 0 ti m es t h e UL N. 
Al b u mi n 
≥2. 8  g/ dL
S er u m cr e ati ni n e
≤ 1. 5 × UL N or 
cr e ati ni n e cl e ar a nc e ≥6 0  mL/ mi n/ 1. 7 3 m2 f or p ati e nts wit h 
cr e ati ni n e l e v els > 1. 5 x UL N. Cr e ati ni n e cl e ar a nc e s h o ul d b e 
c alc ul at e d p er i nstit uti o n al st a n d ar d
Uri n ar y pr ot ei n
≤1 +  o n di pstic k or r o uti n e uri n al ysis or 2 4- h o ur uri n e 
d e m o nstr ati n g < 1 gr a m of pr ot ei n

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 2 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
1 0. T h e eff ects of l e nv ati ni b o n t h e d e v el o pi n g h u m a n f et us ar e u n k n o w n.  F or t his r e as o n f e m al e of c hil d-
b e ari n g p ot e nti al ( F C B P) m ust h a v e a n e g ati v e s er u m or uri n e pr e g n a nc y t est 7 2 h o urs pri or t o st arti n g 
pr ot oc ol t h er a p y. 
N ot e:  F e m al es of c hil d b e ari n g p ot e nti al ar e d efi n e d as t h os e w h o ar e n ot s ur gic all y st eril e (i e, bil at er al 
s al pi n g ect o m y, bil at er al o o p h or ect o m y, or c o m pl et e h yst er ect o m y) or p ost- m e n o p a us al.  
W o m e n will b e c o nsi d er e d p ost- m e n o p a us al if t h e y h a v e b e e n a m e n orr h eic f or 1 2 m o nt hs wit h o ut a n 
alt er n ati v e m e dic al c a us e.  T h e f oll o wi n g a g e-s p ecific r e q uir e m e nts a p pl y: 
W o m e n < 5 0 y e ars of a g e w o ul d b e c o nsi d er e d p ost- m e n o p a us al if t h e y h a v e 
b e e n a m e n orr h eic f or 1 2 m o nt hs or m or e f oll o wi n g c ess ati o n of ex o g e n o us 
h or m o n al tr e at m e nts a n d if t h e y h a v e l ut ei nizi n g h or m o n e a n d f ollicl e-sti m ul ati n g 
h or m o n e l e v els i n t h e p ost- m e n o p a us al r a n g e f or t h e i nstit uti o n.
W o m e n ≥5 0  y e ars of a g e w o ul d b e c o nsi d er e d p ost- m e n o p a us al if t h e y h a v e b e e n a m e n orr h eic f or 1 2 m o nt hs 
or m or e f oll o wi n g c ess ati o n of all ex o g e n o us h or m o n al tr e at m e nts, h a d r a di ati o n-i n d uc e d m e n o p a us e wit h l ast 
m e ns es > 1 y e ar a g o, h a d c h e m ot h er a p y-i n d uc e d m e n o p a us e wit h l ast m e ns es > 1 y e ar a g o
1 1. F C B P a n d m e n m ust a gr e e t o us e a d e q u at e c o ntr ac e pti o n ( h or m o n al or b arri er m et h o d of birt h c o ntr ol; 
a bsti n e nc e) pri or t o st u d y e ntr y, f or t h e d ur ati o n of st u d y tr e at m e nt, a n d f or 6 0 d a ys aft er t h e l ast d os e 
of pr ot oc ol t h er a p y.  S h o ul d a w o m a n b ec o m e pr e g n a nt or s us p ect s h e is pr e g n a nt w hil e s h e or h er 
p art n er is p artici p ati n g i n t his st u d y or f or 6 0 d a ys aft er t h e l ast d os e of pr ot oc ol t h er a p y, s h e s h o ul d 
i nf or m t h e pri nci p al i n v esti g at or i m m e di at el y.  M e n tr e at e d or e nr oll e d o n t his pr ot oc ol m ust als o a gr e e 
t o us e a d e q u at e c o ntr ac e pti o n pri or t o t h e st u d y, f or t h e d ur ati o n of st u d y p artici p ati o n, a n d 6 0 d a ys 
aft er l ast d os e of pr ot oc ol t h er a p y.  
1 2. P ati e nts wit h k n o w n hist or y or c urr e nt s y m pt o ms of c ar di ac dis e as e, or hist or y of tr e at m e nt wit h 
c ar di ot oxic a g e nts, s h o ul d h a v e a cli nic al ris k ass ess m e nt of c ar di ac f u ncti o n usi n g t h e N e w Y or k H e art 
Ass oci ati o n F u ncti o n al Cl assific ati o n.  T o b e eli gi bl e f or t his tri al, p ati e nts s h o ul d b e cl ass 2 B or b ett er.
1 3. Willi n g n ess a n d a bilit y of t h e s u bj ect t o c o m pl y wit h sc h e d ul e d visits, dr u g a d mi nistr ati o n pl a n, pr ot oc ol-
s p ecifi e d l a b or at or y t ests, ot h er st u d y pr oc e d ur es, a n d st u d y r estricti o ns.  
1 4. E vi d e nc e of a p ers o n all y si g n e d i nf or m e d c o ns e nt i n dic ati n g t h at t h e s u bj ect is a w ar e of t h e n e o pl astic 
n at ur e of t h e dis e as e a n d h as b e e n i nf or m e d of t h e pr oc e d ur es t o b e f oll o w e d, t h e ex p eri m e nt al n at ur e 
of t h e t h er a p y, alt er n ati v es, p ot e nti al ris ks a n d disc o mf orts, p ot e nti al b e n efits, a n d ot h er p erti n e nt 
as p ects of st u d y p artici p ati o n.
E xcl usi o n crit eri a
A n i n di vi d u al w h o m e ets a n y of t h e f oll o wi n g crit eri a will b e excl u d e d fr o m p artici p ati o n i n t his st u d y:
1. 
Pri or s yst e mic t h er a p y wit h l e n v ati ni b or a n ot h er F D A a p pr o v e d s yst e mic t h er a p y f or h e p at oc ell ul ar 
c arci n o m a i n t h e p ost-tr a ns pl a nt s etti n g.
2. 
Pri or li v er dir ect e d t h er a p y is all o w e d, s h o ul d b e at l e ast > 2 8 d a ys pri or t o t h e st u d y e nr oll m e nt. S h o ul d 
h a v e at l e ast o n e m e as ur a bl e u ntr e at e d l esi o n b y R E CI S T 1. 1 
3. 
P ati e nts w h o h a v e h a d r a di ot h er a p y wit hi n 4 w e e ks pri or t o e nt eri n g t h e st u d y or t h os e w h o h a v e n ot 
r ec o v er e d fr o m a d v ers e ev e nts d u e t o a g e nts a d mi nist er e d m or e t h a n 4 w e e ks e arli er (i. e., h a v e r esi d u al 
t oxiciti es > Gr a d e 1).
4. 
P ati e nts w h o ar e r ec ei vi n g a n y ot h er i n v esti g ati o n al a g e nts or a n i n v esti g ati o n al d e vic e wit hi n 2 1 d a ys 
b ef or e a d mi nistr ati o n of first d os e of st u d y dr u gs.
5. 
Hist or y of all er gic r e acti o ns attri b ut e d t o c o m p o u n ds of si mil ar c h e mic al or bi ol o gic c o m p ositi o n t o 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 3 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
l e n v ati ni b.
6. 
P ati e nts wit h k n o w n br ai n m et ast as es s h o ul d b e excl u d e d fr o m t his cli nic al tri al b ec a us e of t h eir p o or 
pr o g n osis a n d b ec a us e t h e y oft e n d ev el o p pr o gr essi v e n e ur ol o gic d ysf u ncti o n t h at w o ul d c o nf o u n d t h e 
e v al u ati o n of n e ur ol o gic a n d ot h er a d v ers e e v e nts.
7. 
U nc o ntr oll e d i nt erc urr e nt ill n ess i ncl u di n g, b ut n ot li mit e d t o, o n g oi n g or acti v e i nf ecti o n, s y m pt o m atic 
c o n g esti v e h e art f ail ur e, u nst a bl e a n gi n a p ect oris, c ar di ac arr h yt h mi a, or ps yc hi atric ill n ess/s oci al 
sit u ati o ns t h at w o ul d li mit c o m pli a nc e wit h st u d y r e q uir e m e nts. S u bj ects wit h acti v e h e p atitis vir us 
i nf ecti o n c o ntr oll e d wit h a nti vir al t h er a p y ar e eli gi bl e.
8. 
Si g nific a nt c ar di o v asc ul ar i m p air m e nt: hist or y of c o n g esti v e h e art f ail ur e gr e at er t h a n N e w Y or k H e art 
Ass oci ati o n ( N Y H A) Cl ass II, u nst a bl e a n gi n a, m y oc ar di al i nf arcti o n or str o k e wit hi n 6 m o nt hs of t h e first 
d os e of st u d y dr u g, or c ar di ac arr h yt h mi a r e q uiri n g m e dic al tr e at m e nt at Scr e e ni n g.
9. 
Q Tc i nt er v al > 4 8 0 ms.  
1 0. 
U nc o ntr oll e d bl o o d pr ess ur e ( S yst olic B P > 1 4 0 m m H g or di ast olic B P > 9 0 m m H g) i n s pit e of a n o pti miz e d 
r e gi m e n of a nti h y p ert e nsi v e m e dic ati o n.
1 1. 
Bl e e di n g or t hr o m b otic dis or d ers or s u bj ects at ris k f or s e v er e h e m orr h a g e. T h e d e gr e e of t u m or 
i n v asi o n/i nfiltr ati o n of m aj or bl o o d v ess els ( e. g. c ar oti d art er y) s h o ul d b e c o nsi d er e d b ec a us e of t h e 
p ot e nti al ris k of s e v er e h e m orr h a g e ass oci at e d wit h t u m or s hri n k a g e/ n ecr osis f oll o wi n g l e n v ati ni b 
t h er a p y.
1 2. 
S u bj ects h a vi n g > 1 + pr ot ei n uri a o n uri n e di pstic k t esti n g u nl ess a 2 4- h o ur uri n e c oll ecti o n f or 
q u a ntit ati v e ass ess m e nt i n dic at es t h at t h e uri n e pr ot ei n is < 1 g/ 2 4 h o urs.
1 3. 
S u bj ects w h o h a v e n ot r ec o v er e d a d e q u at el y fr o m a n y t oxicit y fr o m ot h er a nti- c a nc er tr e at m e nt 
r e gi m e ns a n d/ or c o m plic ati o ns fr o m m aj or s ur g er y pri or t o st arti n g t h er a p y. Wit h h ol d l e n v ati ni b f or at 
l e ast 1 w e e k pri or t o el ecti v e s ur g er y. D o n ot a d mi nist er f or at l e ast 2 w e e ks f oll o wi n g m aj or s ur g er y a n d 
u ntil a d e q u at e w o u n d h e ali n g.
1 4. 
F e m al es w h o ar e br e astf e e di n g or pr e g n a nt at Scr e e ni n g or B as eli n e ( as d oc u m e nt e d b y a p ositi v e b et a-
h u m a n c h ori o nic g o n a d otr o pi n [ ß- h C G] ( or h u m a n c h ori o nic g o n a d otr o pi n [ h C G]) t est wit h a mi ni m u m 
s e nsiti vit y of 2 5 I U/L or e q ui v al e nt u nits of ß- h C G [ or h C G]).
1 5. 
F e m al es of c hil d- b e ari n g p ot e nti al m ust b e willi n g t o us e eff ecti v e c o ntr ac e pti o n d uri n g st u d y a n d f or 6 0 
d a ys aft er t h e l ast d os e. 
1 6. 
T h e p artici p a nt h as s e v er e h y p ers e nsiti vit y ( ≥Gr a d e 3) t o l e n v ati ni b a n d/ or a n y of its exci pi e nts.
1 7. 
P ati e nts wit h k n o w n HI V i nf ecti o n. 
1 8. 
P artici p a nt wit h di a g n osis, d et ecti o n, or tr e at m e nt of a n ot h er t y p e of c a nc er ≤2  y e ars pri or t o i niti ati n g 
pr ot oc ol t h er a p y ( exc e pt b as al or s q u a m o us c ell c arci n o m a of t h e s ki n a n d c ervic al c a nc er t h at h as b e e n 
d efi niti v el y tr e at e d)
1 0. V ul n er a bl e P o p ul ati o ns
N/ A

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 4 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
1 1.L oc al N u m b er of P artici p a nts
W e pl a n t o h a v e 1 7 p artici p a nts c o m pl et e t h e pr ot oc ol r e q uir e d r es e arc h pr oc e d ur es a n d esti m at e t o 
e nr oll 2 6 p artici p a nts acr oss all sit es i n or d er t o acc o u nt f or scr e e n f ail ur es. 
E m or y: T h e n u m b er of p artici p a nts w h o ar e ex p ect e d t o b e e nr oll e d a n d scr e e n e d at Wi ns hi p is 1 2, a n d 
t h e n u m b er of p artici p a nts n e e d e d t o c o m pl et e t h e r es e arc h pr oc e d ur es (i. e., n u m b ers of p artici p a nts 
excl u di n g scr e e n f ail ur es) is 8. 
M a y o Cli nic: T h e n u m b er of p artici p a nts w h o ar e ex p ect e d t o b e e nr oll e d a n d scr e e n e d at M a y o Cli nic 
is 6, a n d t h e n u m b er of p artici p a nts n e e d e d t o c o m pl et e t h e r es e arc h pr oc e d ur es (i. e., n u m b ers of 
p artici p a nts excl u di n g scr e e n f ail ur es.) is 4. 
U A B: T h e n u m b er of p artici p a nts w h o ar e ex p ect e d t o b e e nr oll e d a n d scr e e n e d at U A B is 8, a n d t h e 
n u m b er of p artici p a nts n e e d e d t o c o m pl et e t h e r es e arc h pr oc e d ur es (i. e., n u m b ers of p artici p a nts 
excl u di n g scr e e n f ail ur es.) is 5.
1 2. R ecr uit m e nt M et h o ds
I n v esti g at ors, n urs es, a n d/ or d at a m a n a g ers r e vi e w lists of c a nc er p ati e nts w h o h a v e c a nc er a n d will d et er mi n e 
if t h er e ar e p ati e nts w h o mi g ht b e eli gi bl e f or a cli nic al tri al. T h e n urs e/ d at a m a n a g er r evi e ws acc essi bl e m e dic al 
r ec or ds t o scr e e n f urt h er f or eli gi bilit y. T h e n urs e r e vi e ws t h e eli gi bilit y wit h t h e p h ysici a n.  
S u bj ects will b e i d e ntifi e d b y t h eir tr e ati n g p h ysici a ns. Cli nic al c ar e t e a m at Wi ns hi p will i nf or m p ot e nti al s u bj ects 
a b o ut t h e k n o w n b e n efits a n d p ot e nti al ris ks of a cli nic al tri al as w ell as ot h er a v ail a bl e tr e at m e nt o pti o ns.
S o m e of t h e s u bj ects r ecr uit e d f or t his pr ot oc ol will b e p ati e nts b ei n g tr e at e d at E m or y a n d u n d er t h e c ar e of 
o n e or m or e of t h e st u d y i n v esti g at ors. S o m e p ot e nti al s u bj ects will b e i d e ntifi e d b y t h eir tr e ati n g p h ysici a n a n d 
r ef err e d t o E m or y f or p ossi bl e p artici p ati o n i n t h e pr ot oc ol.
N o i nc e nti v es ar e pr o vi d e d t o p ati e nts f or tri al p artici p ati o n.
St u d y p ers o n n el will n otif y Wi ns hi p C e ntr al S u bj ect R e gistr ati o n ( W C S R) b y e m ail at wi ns hi pcsr @ e m or y. e d u , 
o nc e s u bj ect h as b e e n c o ns e nt e d f or a tri al. 
E m ail n otific ati o n m ust b e d o n e wit hi n 2 4 h o urs aft er c o ns e nt h as b e e n o bt ai n e d a n d it will i ncl u d e sc a n n e d 
c o pi es of:

Si g n e d p ati e nt c o ns e nt f or m

HI P A A a ut h oriz ati o n f or m

       E m or y R es e arc h M a n a g e m e nt S yst e m ( E R M S; htt ps:// er ms. e m ory. e d u) E nr oll m e nt F ax C o v er 
T h e W C S R will e nt er t h e s u bj ect i nt o t h e O n C or e R es e arc h M a n a g e m e nt S yst e m, w hic h is t h e s yst e m of r ec or d 
f or Wi ns hi p C a nc er I nstit ut e Cli nic al Tri als.
P artici p ati n g Sit e (s)
A sit e- s p ecific C e ntr al S u bj ect R e gistr ati o n ( C S R) f or m will b e pr o vi d e d t o e ac h P artici p ati n g Sit e.
Aft er e ac h s u bj ect si g ns c o ns e nt, t h e C e ntr al S u bj ect R e gistr ati o n f or m is t o b e c o m pl et e d a n d s e nt t o Wi ns hi p 
wit hi n 2 4 h o urs of c o ns e nt. T his f or m, al o n g wit h t h e v ali d, si g n e d i nf or m e d c o ns e nt f or m/ HI P A A a ut h oriz ati o n 
f or m, is t o b e f ax e d or e m ail e d t o Wi ns hi p’s C e ntr al S u bj ect R e gistr ar p er i nstr ucti o ns o n t h e f or m. O nc e a s u bj ect 
is r e gist er e d, e ac h p artici p ati n g sit e will b e n otifi e d vi a e- m ail.
E nr olli n g a s u bj ect r e q uir es c ar ef ul scr e e ni n g a n d d et er mi n ati o n of eli gi bilit y. 
S u bj ects w h o ar e c o ns e nt e d t o p artici p at e i n t h e cli nic al tri al, w h o d o n ot m e et o n e or m or e crit eri a r e q uir e d f or 
p artici p ati o n i n t h e tri al d uri n g t h e scr e e ni n g pr oc e d ur es, will n ot b e e nr oll e d i nt o t h e st u d y a n d ar e c o nsi d er e d 
scr e e n f ail ur es. All s u bj ects w hic h h a v e si g n e d i nf or m e d c o ns e nt, a n d w er e d e e m e d i n eli gi bl e will b e r ec or d e d 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 5 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
i n a l o g wit h t h e r e as o n of i n eli gi bilit y a n d t h eir e nr oll m e nt st at us will b e u p d at e d i n O n C or e. A mi ni m al s et of 
scr e e n f ail ur e i nf or m ati o n is r e q uir e d t o e ns ur e tr a ns p ar e nt r e p orti n g of scr e e n f ail ur e p artici p a nts a n d t o 
r es p o n d t o q u eri es fr o m r e g ul at or y a ut h oriti es. Mi ni m al i nf or m ati o n i ncl u d es d e m o gr a p h y, i nf or m e d c o ns e nt 
d at e, scr e e n f ail ur e d et ails, eli gi bilit y crit eri a, st u d y disc o nti n u ati o n d at e, a d v ers e ev e nts a n d a n y s eri o us a d v ers e 
e v e nt ( S A E).
Eli gi bl e p ati e nts will b e e nr oll e d o n st u d y c e ntr all y at Wi ns hi p C a nc er I nstit ut e b y t h e St u d y C o or di n at or.  
W h e n all r e q uir e d t est r es ults ar e a v ail a bl e, c o m pl et e t h e eli gi bilit y c h ec klist a n d pr o vi d e t h e c h ec klist a n d t h e 
s u p p orti n g d oc u m e nt ati o n t o t h e I R B a p pr o v e d i n v esti g at or f or r evi e w a n d si g n- off. O nc e t h e i n v esti g at or (s u b-
i n v esti g at or, C o-I n v esti g at or) h as si g n e d t h e eli gi bilit y c h ec klist, r a n d o miz ati o n a n d or e nr oll m e nt m a y pr oc e e d. 
O nc or e a n d E R M S m ust b e u p d at e d t o r efl ect eli gi bilit y a n d o n tr e at m e nt st at us. 
F oll o wi n g e nr oll m e nt, p ati e nts s h o ul d b e gi n pr ot oc ol tr e at m e nt wit hi n 1 4 b usi n ess d a ys. Iss u es t h at w o ul d c a us e 
tr e at m e nt d el a ys s h o ul d b e disc uss e d wit h t h e Pri nci p al I n v esti g at or.
T h e Eli gi bilit y c h ec klist is t o b e pri nt e d fr o m O n C or e a n d v erifi e d b y 2 p e o pl e, of w hic h o n e m ust b e a cli nic al 
i n v esti g at or or c o-i n v esti g at or. T h e c o m pl et e d a n d si g n e d eli gi bilit y c h ec klist al o n g wit h all r e d act e d s u p p orti n g 
s o urc e d oc u m e nt ati o n m ust b e s u b mitt e d t o t h e Wi ns hi p M ulti-sit e C o or di n at or ( M S C) or d esi g n e e (f ax 4 0 4- 7 7 8-
0 4 1 7) wit hi n 1 4 d a ys aft er pr e-r e gistr ati o n b ut n o l at er t h a n 2 b usi n ess d a ys b ef or e t h e sc h e d ul e d tr e at m e nt 
visit. Eli gi bilit y will b e c o nfir m e d b y t h e sit e i n v esti g at or or c o-i n v esti g at or a n d t h e M S C or d esi g n e e wit hi n 1 
b usi n ess d a y of r ec ei pt of all eli gi bilit y d oc u m e nt ati o n a n d c o nfir m ati o n will b e s e nt t o t h e p artici p ati n g sit e al o n g 
wit h c o h ort assi g n m e nt, if s u bj ect m e ets crit eri a. T h e P artici p ati n g Sit e will e nt er all d at a i n O n C or e f oll o wi n g 
eli gi bilit y c o nfir m ati o n, i ncl u di n g s u bj ect ‘ o n tr e at m e nt d at e’. If a c o ns e nt e d s u bj ect d o es n ot m e et eli gi bilit y 
crit eri a (scr e e n f ail ur e), t h e M S C will u p d at e t h e e nr oll m e nt st at us i n O n C or e. T h e P artici p ati n g Sit e is r es p o nsi bl e 
f or e nt eri n g d at a f or all pr oc e d ur es s u bj ect c o m pl et e d pri or t o eli gi bilit y d et er mi n ati o n.
1 3. Wit h dr a w al of P artici p a nts
P artici p a nts ar e fr e e t o wit h dr a w fr o m p artici p ati o n i n t h e st u d y at a n y ti m e u p o n r e q u est.
A n i n v esti g at or m a y disc o nti n u e or wit h dr a w a p artici p a nt fr o m t h e st u d y f or t h e f oll o wi n g r e as o ns:

Pr e g n a nc y

Si g nific a nt st u d y i nt erv e nti o n n o n-c o m pli a nc e 

If a n y cli nic al a d v ers e ev e nt ( A E), l a b or at or y a b n or m alit y, or ot h er m e dic al c o n diti o n or sit u ati o n occ urs 
s uc h t h at c o nti n u e d p artici p ati o n i n t h e st u d y w o ul d n ot b e i n t h e b est i nt er est of t h e p artici p a nt

Dis e as e pr o gr essi o n w hic h r e q uir es disc o nti n u ati o n of t h e st u d y i nt er v e nti o n

If t h e p artici p a nt m e ets a n excl usi o n crit eri o n ( eit h er n e wl y d ev el o p e d or n ot pr evi o usl y r ec o g niz e d) t h at 
pr ecl u d es f urt h er st u d y p artici p ati o n

P artici p a nt u n a bl e t o r ec ei v e st u d y i nt er v e nti o n f or 8 w e e ks .

S p o ns or or Eis ai t er mi n at e t h e st u d y
T h e r e as o n f or p artici p a nt disc o nti n u ati o n or wit h dr a w al fr o m t h e st u d y will b e r ec or d e d o n t h e C as e R e p ort 
F or m ( C R F). S u bj ects w h o si g n t h e i nf or m e d c o ns e nt f or m a n d ar e e nr oll e d b ut d o n ot r ec ei v e t h e st u d y 
i nt er v e nti o n m a y b e r e pl ac e d.  S u bj ects w h o si g n t h e i nf or m e d c o ns e nt f or m, a n d ar e e nr oll e d a n d r ec ei v e t h e 
st u d y i nt er v e nti o n, a n d s u bs e q u e ntl y wit h dr a w, or ar e wit h dr a w n or disc o nti n u e d fr o m t h e st u d y, will n ot b e 
r e pl ac e d.
1 4. Ris ks t o P artici p a nts

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 6 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
T h e A d v ers e E v e nt a n d P ot e nti al Ris ks list pr o vi d es a si n gl e list of r e p ort e d a n d/ or p ot e nti al a d v ers e e v e nts ( A E) 
ass oci at e d wit h a n a g e nt usi n g a u nif or m pr es e nt ati o n of e v e nts b y b o d y s yst e m.  
R ef er t o t h e p ac k a g e i ns erts f or t h e c o m pr e h e nsi v e list of a d v ers e ev e nts.
A d diti o n al Ris ks:

A d diti o n al bl o o d dr a ws  - T h e p h ysic al ris k of dr a wi n g bl o o d is l oc al p ai n a n d br uisi n g at t h e sit e of 
v e ni p u nct ur e. Q u alifi e d p hl e b ot o mists or d esi g n e e will dr a w bl o o d s a m pl es. C ar e will b e t a k e n t o o bt ai n 
t h es e s p eci m e ns i n a s af e a n d h y gi e nic m a n n er. A s m all n u m b er of p e o pl e ex p eri e nc e li g ht h e a d e d n ess or 
f ai nti n g. T h er e is a sli g ht ris k of i nf ecti o n. T o mi ni miz e t h es e ris ks, att e m pts will b e m a d e t o dr a w st u d y bl o o d 
s a m pl es at t h e s a m e ti m e as bl o o d dr a ws n e e d e d f or r o uti n e cli nic al c ar e ar e o bt ai n e d. R e p e at e d bl o o d 
dr a wi n g m a y b e ass oci at e d wit h ir o n d efici e nc y a n e mi a.

E v e nts of ost e o n ecr osis of t h e j a w ( O NJ)  h a v e b e e n o bs erv e d wit h l e n v ati ni b. I n v asi v e d e nt al pr oc e d ur es 
ar e a n i d e ntifi e d ris k f act or f or t h e d ev el o p m e nt of O NJ. A n or al d e nt al ex a mi n ati o n a n d a p pr o pri at e 
pr e v e nti v e d e ntistr y s h o ul d b e c o nsi d er e d pri or t o i niti ati o n of l e n v ati ni b. P ati e nts s h o ul d b e a d vis e d 
r e g ar di n g p eri o dic d e nt al ex a mi n ati o ns a n d or al h y gi e n e pr actic e d uri n g l e n v ati ni b t h er a p y. A v oi d i n v asi v e 
d e nt al pr oc e d ur es d uri n g l e n v ati ni b tr e at m e nt, if p ossi bl e. Us e c a uti o n i n p ati e nts r ec ei vi n g a g e nts 
ass oci at e d wit h O NJ, s uc h as bis p h os p h o n at es a n d d e n os u m a b. 

D at a s ec urit y- S u bj ects will b e as k e d t o pr o vi d e p ers o n al h e alt h i nf or m ati o n ( P HI). All att e m pts will b e m a d e 
t o k e e p t his P HI c o nfi d e nti al wit hi n t h e li mits of t h e l a w. H o w ev er, t h er e is a c h a nc e t h at u n a ut h oriz e d 
p ers o ns will s e e t h e s u bj ects’ P HI. All r ec or ds will b e k e pt i n a l oc k e d fil e c a bi n et or m ai nt ai n e d i n a l oc k e d 
r o o m at t h e p artici p ati n g sit es. El ectr o nic fil es will b e p ass w or d pr ot ect e d b e hi n d a n ac a d e mic i nstit uti o n al 
fir e w all. O nl y p e o pl e w h o ar e i n v ol v e d i n t h e c o n d uct, o v ersi g ht, m o nit ori n g, or a u diti n g of t his st u d y will b e 
all o w e d acc ess t o t h e P HI t h at is c oll ect e d. A n y p u blic ati o ns fr o m t his st u d y will n ot us e i nf or m ati o n t h at will 
i d e ntif y s u bj ects. Or g a niz ati o ns t h at 
m a y i ns p ect a n d/ or c o p y r es e arc h r ec or ds 
m ai nt ai n e d at t h e 
p artici p ati n g sit es f or q u alit y ass ur a nc e a n d d at a a n al ysis i ncl u d e gr o u ps s uc h as t h e N ati o n al C a nc er I nstit ut e 
( N CI) a n d F o o d a n d Dr u g A d mi nistr ati o n ( F D A).
1 5. P ot e nti al B e n efits t o P artici p a nts
T h er e is n o g u ar a nt e e of b e n efit t o s u bj ects w h o e nr oll i n t his pr ot oc ol.
1 6. D at a M a n a g e m e nt a n d C o nfi d e nti alit y
1 6. 1
St atistic al C o nsi d er ati o n D at a/s p eci m e ns:
St u d y d esi g n
T his is a P h as e II, si n gl e ar m, m ulti-i nstit uti o n al tri al of l e n v ati ni b i n p ati e nts wit h r ec urr e nt H C C aft er li v er 
tr a ns pl a nt.  T h e st u d y will pr oc e e d usi n g a Si m o n 2-st a g e Mi ni m ax d esi g n.
S a m pl e siz e c o nsi d er ati o ns

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 7 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A Si m o n’s 2-st a g e ( Mi ni m ax) d esi g n will b e a d o pt e d f or a p ossi bl e e arl y t er mi n ati o n f or f utilit y.  O v er all r es p o ns e 
r at e ( O R R) (c o m pl et e r es p o ns e + p arti al r es p o ns e) will b e t h e pri m ar y e n d p oi nt.  T h e o bj ecti v e r es p o ns e r at e wit h 
si n gl e a g e nt L e n v ati ni b w as 2 4. 1 % b y m R E CI S T a n d 1 8. 8 % b y R E CI S T v ersi o n 1. 1 i n R E FL E C T tri al 1 1; h o w e v er, t h e 
o bj ecti v e r es p o ns e r at e i n p ost-tr a ns pl a nt r ec urr e nt H C C is n ot k n o w n.  W e h y p ot h esiz e t h at t h er e is > 2 4 % o v er all 
r es p o ns e r at e a n d a r at e < 5 % will b e c o nsi d er e d as f utilit y.  T h e T y p e I err or r at e is s et at 5 % a n d p o w er of t his 
st u d y will b e at l e ast 8 0 %.  I n t h e first st a g e, 1 1 p ati e nts will b e accr u e d, a n d if t h er e is n o o bj ecti v e r es p o ns e 
a m o n g t h e m, t h e st u d y will b e st o p p e d f or f utilit y. Ot h er wis e, a d diti o n al 6 p ati e nts will b e accr u e d f or a t ot al of 
1 7 p ati e nts. T h e tr e at m e nt will b e d et er mi n e d t o b e i n eff ecti v e if t h er e ar e 2 or f e w er r es p o ns es i n 1 7 p ati e nts 
at t h e e n d of t h e s ec o n d st a g e e nr oll m e nt. W e r e q uir e 3 or m or e p ati e nts o ut of t h e t ot al of 1 7 s u bj ects t o 
ac hi e v e o bj ecti v e r es p o ns e f or t h e i n v esti g ati o n al t h er a p y t o b e d e e m e d t o h a v e s uffici e ntl y i m pr o v e d cli nic al 
acti vit y t o j ustif y f urt h er cli nic al d e v el o p m e nt. W e a ntici p at e e nr olli n g 1 p ati e nt p er m o nt h. All p ati e nts will 
u n d er g o b as eli n e st a gi n g sc a n a n d r est a gi n g sc a n e v er y 8 w e e ks. T h e tr e at m e nt will c o nti n u e u ntil dis e as e 
pr o gr essi o n ( usi n g R E CI S T v ersi o n 1. 1 crit eri a), i nt ol er a bl e si d e eff ects or c o ns e nt wit h dr a w al.  Gi v e n a n 
a ntici p at e d attriti o n r at e of a p pr oxi m at el y 1 0 %, w e ex p ect t o e nr oll a n a d diti o n al 2 p ati e nts, f or a t ot al of 1 9 
p ati e nts.
Effic ac y a n al ysis
Pri m ar y e n d p oi nt
O v er all r es p o ns e r at e ( O R R):  
O v er all r es p o ns e r at e 
will b e ass ess e d p er R E CI S T v ersi o n 1. 1 ( T u m or 
m e as ur e m e nts will b e p erf or m e d ev er y 8 w e e ks).  O R R will b e c alc ul at e d as a pr o p orti o n (c o m pl et e r es p o ns es + 
p arti al r es p o ns es / t ot al p ati e nts) al o n g wit h a 9 5 % c o nfi d e nc e i nt erv al usi n g t h e Cl o p p er- P e ars o n m et h o d.  C hi-
s q u ar e t ests or Fis h er’s ex act t ests will b e us e d t o c o m p ar e t h e effic ac y i n t er m of r es p o ns e r at e acr oss diff er e nt 
gr o u ps str atifi e d b y bi o m ar k ers or ot h er f act ors, r es p ecti v el y .
S ec o n d ar y e n d p oi nts
Pr o gr essi o n Fr e e s ur vi v al ( P F S): Pr o gr essi o n-fr e e s urvi v al is d efi n e d as ti m e fr o m di a g n osis t o dis e as e pr o gr essi o n 
or d e at h.  P ati e nts will b e c e ns or e d at ti m e of l ast f oll o w- u p.  P F S will b e esti m at e d usi n g t h e K a pl a n- M ei er 
m et h o d a n d c o m p ar e d b et w e e n diff er e nt gr o u ps usi n g t h e l o g-r a n k t est, r es p ecti v el y. T h e P F S of e ac h p ati e nt 
gr o u p at s p ecific ti m e p oi nts, s uc h as 6 m o nt hs, 1 y e ar, 3 y e ar, a n d 5 y e ar, etc. will b e als o esti m at e d al o n e wit h 
9 5 % CI usi n g t h e Gr e e n w o o d f or m ul a.  C ox pr o p orti o n al h az ar ds m o d els will b e f urt h er us e d i n t h e m ulti v ari a bl e 
a n al ys es t o ass ess t h e a dj ust e d eff ect of r es p o ns e o n t h e p ati e nts’ P F S aft er a dj usti n g f or ot h er f act ors.  
I nt er acti o n t er ms b et w e e n t h es e f act ors will als o b e t est e d f or st atistic al si g nific a nc e.  T h e pr o p orti o n al h az ar ds 
ass u m pti o n will b e e v al u at e d gr a p hic all y a n d a n al ytic all y wit h r e gr essi o n di a g n ostics.  Vi ol ati o ns of t h e 
pr o p orti o n al h az ar ds ass u m pti o ns will b e a d dr ess e d b y us e of ti m e- d e p e n d e nt c o v ari at es or ext e n d e d C ox 
r e gr essi o n m o d els. 
O v er all s ur vi v al ( O S): O v er all s ur vi v al is d efi n e d as ti m e fr o m di a g n osis t o d e at h.  P ati e nts will b e c e ns or e d at ti m e 
of l ast f oll o w- u p.  O S will b e esti m at e d usi n g t h e K a pl a n- M ei er m et h o d a n d c o m p ar e d b et w e e n diff er e nt gr o u ps 
usi n g t h e l o g-r a n k t est, r es p ecti v el y. T h e O S of e ac h p ati e nt gr o u p at s p ecific ti m e p oi nts, s uc h as 6 m o nt hs, 1 
y e ar, 3 y e ar, a n d 5 y e ar, etc. will b e als o esti m at e d al o n e wit h 9 5 % CI usi n g t h e Gr e e n w o o d f or m ul a.  C ox 
pr o p orti o n al h az ar ds m o d els will b e f urt h er us e d i n t h e m ulti v ari a bl e a n al ys es t o ass ess t h e a dj ust e d eff ect of 
r es p o ns e o n t h e p ati e nts’ O S aft er a dj usti n g f or ot h er f act ors.  I nt er acti o n t er ms b et w e e n t h es e f act ors will als o 
b e t est e d f or st atistic al si g nific a nc e.  T h e pr o p orti o n al h az ar ds ass u m pti o n will b e e v al u at e d gr a p hic all y a n d 
a n al ytic all y wit h r e gr essi o n di a g n ostics.  Vi ol ati o ns of t h e pr o p orti o n al h az ar ds ass u m pti o ns will b e a d dr ess e d b y 
us e of ti m e- d e p e n d e nt c o v ari at es or ext e n d e d C ox r e gr essi o n m o d els. 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 8 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
D ur ati o n of r es p o ns e ( D R): D ur ati o n of r es p o ns e is d efi n e d as ti m e fr o m c o nfir m ati o n of a p arti al r es p o ns e ( P R), 
c o m pl et e r es p o ns e ( C R) or st a bl e dis e as e ( S D), u ntil t h e dis e as e h as b e e n s h o w n t o pr o gr ess f oll o wi n g 
tr e at m e nt ( pr o gr essi v e dis e as e or P D).  S u m m ar y st atistics will b e r e p ort e d f or D R i ncl u di n g m e a n, m e di a n, 
st a n d ar d d e vi ati o n, a n d r a n g e.
E x pl or at or y a n al ysis
F or t h e bi o m ar k er st u d y, d escri pti v e st atistics will b e first us e d t o s u m m ariz e bi o m ar k er e n d p oi nts, i ncl u di n g 
p eri p h er al bl o o d s a m pl es.  Bi o m ar k er d at a will als o b e dis pl a y e d gr a p hic all y, w h er e a p pr o pri at e.  D e p e n di n g o n 
w h et h er d at a is n or m all y distri b ut e d, a t-t est or Wilc ox o n r a n k s u m t est will b e us e d t o c o m p ar e e ac h bi o m ar k er 
b et w e e n a n y t w o gr o u ps str atifi e d b y r es p o ns e or ot h er f act ors, r es p ecti v el y.  G e n er al li n e ar m o d els ( GL M) will 
b e us e d t o c o m p ar e e ac h bi o m ar k er b et w e e n r es p o n d ers a n d n o n-r es p o n d ers wit h a n d wit h o ut a dj usti n g f or 
ot h er f act ors.  L o gistic r e gr essi o n m o d els will b e f urt h er e m pl o y e d t o t est t h e a dj ust e d eff ect of bi o m ar k er o n 
t h e r es p o ns e r at e aft er a dj usti n g f or ot h er f act ors.
S af et y a n al ysis
S af et y will b e ass ess e d t hr o u g h a d v ers e e v e nts, vit al si g n m e as ur e m e nts, p h ysic al ex a mi n ati o ns, a n d cli nic al 
l a b or at or y t ests.  S u m m ar y st atistics will b e pr es e nt e d f or all s af et y a n al ys es.  D at a f or c o nti n u o us p ar a m et ers 
will b e pr es e nt e d usi n g d escri pti v e st atistics i ncl u di n g s a m pl e siz e, m e a n, a n d m e di a n; st a n d ar d d evi ati o n; a n d 
mi ni m u m a n d m axi m u m.  C at e g oric al p ar a m et ers b e dis pl a y e d usi n g c o u nts a n d p erc e nt a g es.  T oxiciti es will b e 
pr es e nt e d as w orst t oxicit y p er p ati e nt a n d will b e r e p ort e d as p erc e nt t oxicit y.
A n al ysis p o p ul ati o ns
T h e Effic ac y a n d S af et y P o p ul ati o ns i ncl u d e all s u bj ects e nr oll e d i n t h e st u d y a n d w h o r ec ei v e l e n v ati ni b.  T h e 
Effic ac y P o p ul ati o n will b e us e d f or a n al ysis of t h e pri m ar y a n d s ec o n d ar y e n d p oi nts.  All s af et y a n al ys es will b e 
p erf or m e d o n t h e S af et y P o p ul ati o n.
I nt eri m a n al ysis
Si m o n’s 2-st a g e a p pr o ac h will b e utiliz e d, a n d a n i nt eri m a n al ysis f or f utilit y will occ ur. T h e n ull h y p ot h esis t h at 
t h e tr u e r es p o ns e r at e is 5 % will b e t est e d a g ai nst a o n e-si d e d alt er n ati v e. I n t h e 1st st a g e, 1 1 p ati e nts will b e 
accr u e d.  If t h er e ar e n o r es p o ns es, t h e st u d y will b e st o p p e d.  Ot h er wis e, 6 a d diti o n al p ati e nts will b e accr u e d 
f or a t ot al of 1 7. T his d esi g n yi el ds a T y p e I err or r at e of 5 % wit h 8 0 % p o w er w h e n t h e tr u e r es p o ns e r at e is 
2 4 %.  
1 6. 2 D at a/s p eci m e ns:
P artici p a nt c o nfi d e nti alit y is strictl y h el d i n tr ust b y t h e p artici p ati n g i n v esti g at ors, t h eir st aff, a n d t h e s p o ns or(s) 
a n d t h eir a g e nts. T h er ef or e, t h e st u d y pr ot oc ol, d oc u m e nt ati o n, d at a, a n d all ot h er i nf or m ati o n g e n er at e d will 
b e h el d i n strict c o nfi d e nc e. N o i nf or m ati o n c o nc er ni n g t h e st u d y or t h e d at a will b e r el e as e d t o a n y u n a ut h oriz e d 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 2 9 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
t hir d p art y wit h o ut pri or writt e n a p pr o v al of t h e Pri nci p al I n v esti g at or. T h e st u d y p artici p a nt’s c o nt act 
i nf or m ati o n will b e s ec ur el y st or e d at e ac h cli nic al sit e f or i nt er n al us e d uri n g t h e st u d y. At t h e e n d of t h e st u d y, 
all r ec or ds will c o nti n u e t o b e k e pt i n a s ec ur e l oc ati o n f or as l o n g a p eri o d as dict at e d b y l oc al I R B a n d 
I nstit uti o n al r e g ul ati o ns.
D at a a n d/ or d at a f or ms will b e s u b mitt e d i n t h e cli nic al m a n a g e m e nt s yst e m - O nli n e C oll a b or ati v e R es e arc h 
E n vir o n m e nt ( O N C O R E)- p er Wi ns hi p S O P 4. 2 D at a C o m pl eti o n M etrics.
All i nf or m ati o n i n ori gi n al r ec or ds a n d c ertifi e d c o pi es of ori gi n al r ec or ds or cli nic al fi n di n gs, o bs er v ati o ns, or 
ot h er acti viti es n ec ess ar y f or t h e r ec o nstr ucti o n a n d ev al u ati o n of t h e tri al is c o nsi d er e d s o urc e d at a. S o urc e d at a 
ar e c o nt ai n e d i n s o urc e d oc u m e nts, w hic h c a n b e ori gi n al r ec or ds or c ertifi e d c o pi es of h os pit al r ec or ds, cli nic al 
a n d offic e c h arts, l a b or at or y n ot es, m e m or a n d a, s u bj ects' di ari es of ev al u ati o n c h ec klists, p h ar m ac y dis p e nsi n g 
r ec or ds, r ec or d e d d at a fr o m a ut o m at e d i nstr u m e nts, c o pi es or tr a nscri pti o ns c ertifi e d aft er v erific ati o n as b ei n g 
acc ur at e a n d c o m pl et e, micr ofic h es, p h ot o gr a p hic n e g ati v es, micr ofil m or m a g n etic m e di a, x-r a ys, s u bj ect fil es, 
a n d r ec or ds k e pt at t h e p h ar m ac y, at t h e l a b or at ori es, a n d at m e dic o-t ec h nic al d e p art m e nts i n v ol v e d i n t h e 
cli nic al tri al. C as e R e p ort F or ms ( C R Fs) - S o urc e d at a m a y b e c oll ect e d i n t h e s o urc e d oc u m e nts or e nt er e d dir ectl y 
o nt o t h e c as e r e p ort f or ms.
All d oc u m e nt ati o n of a d v ers e ev e nts, r ec or ds of st u d y dr u g r ec ei pt a n d dis p e ns ati o n, a n d all I R B c orr es p o n d e nc e 
will b e m ai nt ai n e d f or at l e ast 2 y e ars aft er t h e i n v esti g ati o n is c o m pl et e d.
St u d y p artici p a nt r es e arc h d at a, w hic h is f or p ur p os es of st atistic al a n al ysis a n d sci e ntific r e p orti n g, will b e st or e d. 
T his will n ot i ncl u d e t h e p artici p a nt’s c o nt act or i d e ntif yi n g i nf or m ati o n. R at h er, i n di vi d u al p artici p a nts a n d t h eir 
r es e arc h d at a will b e i d e ntifi e d b y a u ni q u e st u d y i d e ntific ati o n n u m b er. T h e st u d y d at a e ntr y a n d st u d y 
m a n a g e m e nt s yst e ms us e d b y cli nic al sit es a n d r es e arc h st aff will b e s ec ur e d a n d p ass w or d pr ot ect e d. At t h e 
e n d of t h e st u d y, all st u d y d at a b as es will b e d e-i d e ntifi e d a n d arc hi v e d.
S a m pl es a n d d at a c oll ect e d u n d er t his pr ot oc ol m a y b e us e d t o st u d y h e p at oc ell ul ar c arci n o m a Acc ess t o 
st or e d s a m pl es will b e li mit e d t o I R B- a p pr o v e d i n v esti g at ors. S a m pl es a n d d at a will b e st or e d usi n g c o d es 
assi g n e d b y t h e i n v esti g at ors or t h eir d esi g n e es. D at a will b e k e pt i n p ass w or d- pr ot ect e d c o m p ut ers. O nl y 
i n v esti g at ors will h a v e acc ess t o t h e s a m pl es a n d d at a.
All st or e d s a m pl es will b e m ai nt ai n e d i n t h e l a b or at or y t o w hic h it w as s e nt i niti all y f or a n al ysis. St u d y 
p artici p a nts w h o r e q u est d estr ucti o n of s a m pl es will b e n otifi e d of c o m pli a nc e wit h s uc h r e q u est a n d all 
s u p p orti n g d et ails will b e m ai nt ai n e d f or tr ac ki n g.
1 7. Pr o visi o ns t o M o nit or t h e D at a t o E ns ur e t h e S af et y of P artici p a nts
A d v ers e e v e nt ( A E) m o nit ori n g a n d r e p orti n g is a r o uti n e p art of e v er y cli nic al tri al.  T h e c h ar act eristics of a n 
o bs er v e d A E will d et er mi n e w h et h er t h e e v e nt r e q uir es ex p e dit e d r e p orti n g i n a d diti o n t o r o uti n e r e p orti n g.
D efi niti o n of A d v ers e E v e nts ( A E)
A d v ers e e v e nt m e a ns a n y u nt o w ar d m e dic al occ urr e nc e ass oci at e d wit h t h e us e of a n i nt er v e nti o n i n h u m a ns, 
w h et h er or n ot c o nsi d er e d i nt erv e nti o n-r el at e d ( 2 1 C F R 3 1 2. 3 2 ( a)).
D efi niti o n of S eri o us A d v ers e E v e nts ( S A E) 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 0 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A n a d v ers e ev e nt ( A E) or s us p ect e d a d v ers e r e acti o n is c o nsi d er e d "s eri o us" if, i n t h e vi e w of eit h er t h e 
i n v esti g at or or s p o ns or, it r es ults i n a n y of t h e f oll o wi n g o utc o m es: 

D e at h

Lif e-t hr e at e ni n g a d v ers e e v e nt 

I n p ati e nt h os pit aliz ati o n or pr ol o n g ati o n of existi n g h os pit aliz ati o n

A p ersist e nt or si g nific a nt i nc a p acit y or s u bst a nti al disr u pti o n of t h e a bilit y t o c o n d uct n or m al lif e 
f u ncti o ns, or a c o n g e nit al a n o m al y/ birt h d ef ect. 

I m p ort a nt m e dic al e v e nts t h at m a y n ot r es ult i n d e at h, b e lif e-t hr e at e ni n g, or r e q uir e h os pit aliz ati o n m a y 
b e c o nsi d er e d s eri o us w h e n, b as e d u p o n a p pr o pri at e m e dic al j u d g m e nt, t h e y m a y j e o p ar diz e t h e 
p artici p a nt a n d m a y r e q uir e m e dic al or s ur gic al i nt er v e nti o n t o pr ev e nt o n e of t h e o utc o m es list e d i n t his 
d efi niti o n. ( Ex a m pl es of s uc h 
m e dic al ev e nts i ncl u d e all er gic br o nc h os p as m r e q uiri n g i nt e nsi v e 
tr e at m e nt i n a n e m er g e nc y r o o m or at h o m e, bl o o d d yscr asi as or c o n v ulsi o ns t h at d o n ot r es ult i n 
i n p ati e nt h os pit aliz ati o n, or t h e d ev el o p m e nt of dr u g d e p e n d e nc y or dr u g a b us e).
Cl assific ati o n of a n A d v ers e E v e nt
S e v erit y of E v e nt
F or a d v ers e e v e nts ( A Es) n ot i ncl u d e d i n t h e pr ot oc ol d efi n e d gr a di n g s yst e m, t h e f oll o wi n g g ui d eli n es will b e 
us e d t o d escri b e s e v erit y. 
•
Mil d – E v e nts r e q uir e mi ni m al or n o tr e at m e nt a n d d o n ot i nt erf er e wit h t h e p artici p a nt’s d ail y acti viti es. 
•
M o d er at e – E v e nts r es ult i n a l o w l ev el of i nc o n v e ni e nc e or c o nc er n wit h t h e t h er a p e utic m e as ur es. 
M o d er at e ev e nts m a y c a us e s o m e i nt erf er e nc e wit h f u ncti o ni n g.
•
S e v er e – E v e nts i nt err u pt a p artici p a nt’s us u al d ail y acti vit y a n d m a y r e q uir e s yst e mic dr u g t h er a p y or 
ot h er tr e at m e nt. S e v er e e v e nts ar e us u all y p ot e nti all y lif e-t hr e at e ni n g or i nc a p acit ati n g.  Of n ot e, t h e 
t er m “s ev er e” d o es n ot n ec ess aril y e q u at e t o “s eri o us”.
R el ati o ns hi p t o St u d y I nt er v e nti o n
All a d v ers e e v e nts ( A Es) m ust h a v e t h eir r el ati o ns hi p t o st u d y i nt erv e nti o n ass ess e d b y t h e cli nici a n w h o 
ex a mi n es a n d e v al u at es t h e p artici p a nt b as e d o n t e m p or al r el ati o ns hi p a n d his/ h er cli nic al j u d g m e nt. T h e 
d e gr e e of c ert ai nt y a b o ut c a us alit y will b e gr a d e d usi n g t h e c at e g ori es b el o w. I n a cli nic al tri al, t h e st u d y 
pr o d uct m ust al w a ys b e s us p ect. 
•
D efi nit el y R el at e d – T h er e is cl e ar evi d e nc e t o s u g g est a c a us al r el ati o ns hi p, a n d ot h er p ossi bl e 
c o ntri b uti n g f act ors c a n b e r ul e d o ut. T h e cli nic al ev e nt, i ncl u di n g a n a b n or m al l a b or at or y t est r es ult, 
occ urs i n a pl a usi bl e ti m e r el ati o ns hi p t o st u d y i nt erv e nti o n a d mi nistr ati o n a n d c a n n ot b e ex pl ai n e d b y 
c o nc urr e nt dis e as e or ot h er dr u gs or c h e mic als. T h e r es p o ns e t o wit h dr a w al of t h e st u d y i nt er v e nti o n 
( d ec h all e n g e) s h o ul d b e cli nic all y pl a usi bl e. T h e e v e nt m ust b e p h ar m ac ol o gic all y or p h e n o m e n ol o gic all y 
d efi niti v e, wit h us e of a s atisf act or y r ec h all e n g e pr oc e d ur e if n ec ess ar y.
•
Pr o b a bl y R el at e d – T h er e is evi d e nc e t o s u g g est a c a us al r el ati o ns hi p, a n d t h e i nfl u e nc e of ot h er f act ors 
is u nli k el y. T h e cli nic al ev e nt, i ncl u di n g a n a b n or m al l a b or at or y t est r es ult, occ urs wit hi n a r e as o n a bl e 
ti m e aft er a d mi nistr ati o n of t h e st u d y i nt erv e nti o n, is u nli k el y t o b e attri b ut e d t o c o nc urr e nt dis e as e or 
ot h er dr u gs or c h e mic als, a n d f oll o ws a cli nic all y r e as o n a bl e r es p o ns e o n wit h dr a w al ( d ec h all e n g e). 
R ec h all e n g e i nf or m ati o n is n ot r e q uir e d t o f ulfill t his d efi niti o n.
•
P ot e nti all y R el at e d – T h er e is s o m e e vi d e nc e t o s u g g est a c a us al r el ati o ns hi p ( e. g., t h e e v e nt occ urr e d 
wit hi n a r e as o n a bl e ti m e aft er a d mi nistr ati o n of t h e tri al m e dic ati o n). H o w ev er, ot h er f act ors m a y h a v e 
c o ntri b ut e d t o t h e e v e nt ( e. g., t h e p artici p a nt’s cli nic al c o n diti o n, ot h er c o nc o mit a nt e v e nts). Alt h o u g h 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 1 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
a n A E m a y r at e o nl y as “ p ossi bl y r el at e d” s o o n aft er disc o v er y, it c a n b e fl a g g e d as r e q uiri n g m or e 
i nf or m ati o n a n d l at er b e u p gr a d e d t o “ pr o b a bl y r el at e d” or “ d efi nit el y r el at e d”, as a p pr o pri at e.
•
U nli k el y t o b e r el at e d – A cli nic al e v e nt, i ncl u di n g a n a b n or m al l a b or at or y t est r es ult, w h os e t e m p or al 
r el ati o ns hi p t o st u d y i nt er v e nti o n a d mi nistr ati o n m a k es a c a us al r el ati o ns hi p i m pr o b a bl e ( e. g., t h e e v e nt 
di d n ot occ ur wit hi n a r e as o n a bl e ti m e aft er a d mi nistr ati o n of t h e st u d y i nt erv e nti o n) a n d i n w hic h ot h er 
dr u gs or c h e mic als or u n d erl yi n g dis e as e pr o vi d es pl a usi bl e ex pl a n ati o ns ( e. g., t h e p artici p a nt’s cli nic al 
c o n diti o n, ot h er c o nc o mit a nt tr e at m e nts).
•
N ot R el at e d – T h e A E is c o m pl et el y i n d e p e n d e nt of st u d y i nt er v e nti o n a d mi nistr ati o n, a n d/ or e vi d e nc e 
exists t h at t h e e v e nt is d efi nit el y r el at e d t o a n ot h er eti ol o g y. T h er e m ust b e a n alt er n ati v e, d efi niti v e 
eti ol o g y d oc u m e nt e d b y t h e cli nici a n.
A d v ers e E v e nt a n d S eri o us A d v ers e E v e nt R e p orti n g 
Ex p ect e d n ess 
S p o ns or I n v esti g at or will b e r es p o nsi bl e f or d et er mi ni n g w h et h er a n a d v ers e e v e nt ( A E) is ex p ect e d or 
u n ex p ect e d.  A n A E will b e c o nsi d er e d u n ex p ect e d if t h e n at ur e, s ev erit y, or fr e q u e nc y of t h e e v e nt is n ot 
c o nsist e nt wit h t h e ris k i nf or m ati o n pr e vi o usl y d escri b e d f or t h e st u d y i nt erv e nti o n.
A d v ers e E v e nt R e p orti n g 
Fr o m t h e ti m e of tr e at m e nt all oc ati o n t hr o u g h 3 0  d a ys f oll o wi n g c ess ati o n of tr e at m e nt, all a d v ers e e v e nts, t h at 
b e gi n or w ors e n aft er i nf or m e d c o ns e nt, m ust b e r ec or d e d  b y t h e i n v esti g at or or d esi g n e e at e ac h ex a mi n ati o n 
o n t h e A d v ers e E v e nt c as e r e p ort f or ms/ w or ks h e ets.  
T h e i n v esti g at or will m a k e e v er y att e m pt t o f oll o w all s u bj ects wit h n o n-s eri o us a d v ers e e v e nts f or o utc o m e.
C o n diti o ns t h at w er e alr e a d y pr es e nt at t h e ti m e of i nf or m e d c o ns e nt s h o ul d b e r ec or d e d i n t h e M e dic al Hist or y 
p a g e of t h e p ati e nt’s C R F/ w or ks h e et.
A d v ers e e v e nts will b e ass ess e d a n d gr a d e d acc or di n g t o t h e C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts 
( C T C A E) v ersi o n 5. 0. Gr a d e 1 t o 5 will b e us e d t o c h ar act eriz e t h e s e v erit y of t h e A d v ers e E v e nt. 
If C T C A E gr a di n g d o es n ot exist f or a n a d v ers e ev e nt, t h e s e v erit y of mil d, m o d er at e, s ev er e, a n d lif e-t hr e at e ni n g, 
d e at h r el at e d t o t h e A E c orr es p o n di n g r es p ecti v el y t o Gr a d es 1 - 5, will b e us e d. I nf or m ati o n a b o ut a n y d e at hs 
(r el at e d t o a n A d v ers e E v e nt or n ot) will als o b e c oll ect e d t hr o u g h a D e at h f or m ( or E O T/ S E C/ S ur vi v al I nf or m ati o n 
i n N O V D D). T h e occ urr e nc e of a d v ers e ev e nts s h o ul d b e s o u g ht b y n o n- dir ecti v e q u esti o ni n g of t h e p ati e nt 
( p ati e nt) d uri n g t h e scr e e ni n g pr oc ess aft er si g ni n g i nf or m e d c o ns e nt a n d at e ac h visit d uri n g t h e st u d y. A d v ers e 
e v e nts als o m a y b e d et ect e d w h e n t h e y ar e v ol u nt e er e d b y t h e p ati e nt ( p ati e nt) d uri n g t h e scr e e ni n g pr oc ess or 
b et w e e n visits, or t hr o u g h p h ysic al ex a mi n ati o n, l a b or at or y t est, or ot h er ass ess m e nts. As f ar as p ossi bl e, e ac h 
a d v ers e e v e nt s h o ul d b e e v al u at e d t o d et er mi n e: 
1. T h e s e v erit y gr a d e ( C T C A E Gr a d e 1- 5) 
2. Its d ur ati o n ( St art a n d e n d d at es)  
3. Its r el ati o ns hi p t o t h e st u d y tr e at m e nt ( R e as o n a bl e p ossi bilit y t h at A E is r el at e d: N o, Y es) or Its r el ati o ns hi p t o 
t h e st u d y tr e at m e nt ( R e as o n a bl e p ossi bilit y t h at A E is r el at e d: N o, Y es, i n v esti g ati o n al tr e at m e nt, Y es, t h e st u d y 
tr e at m e nt ( n o n-i n v esti g ati o n al), Y es, b ot h a n d/ or i n disti n g uis h a bl e) 
4. Acti o n t a k e n wit h r es p ect t o st u d y or i n v esti g ati o n al tr e at m e nt ( n o n e, d os e a dj ust e d, t e m p or aril y i nt err u pt e d, 
p er m a n e ntl y disc o nti n u e d, u n k n o w n, n ot a p plic a bl e) 
5. 
W h et h er m e dic ati o n or t h er a p y w as gi v e n ( n o c o nc o mit a nt m e dic ati o n/ n o n- dr u g t h er a p y, c o nc o mit a nt 
m e dic ati o n/ n o n- dr u g t h er a p y) 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
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P a g e 3 2 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
6. W h et h er it is s eri o us, w h er e a s eri o us a d v ers e ev e nt ( S A E) is d efi n e d as i n S ecti o n 9. 2 a n d w hic h s eri o us n ess 
crit eri a h a v e b e e n m et (i ncl u d e f or N C D S tri als).
7. O utc o m e ( n ot r ec o v er e d/ n ot r es ol v e d, r ec o v er e d/r es ol v e d, r ec o v eri n g/r es ol vi n g, r ec o v er e d/r es ol v e d wit h 
s e q u el a e, f at al, u n k n o w n)  
 
If t h e e v e nt w ors e ns t h e e v e nt s h o ul d b e r e p ort e d a s ec o n d ti m e i n t h e C R F n oti n g t h e st art d at e w h e n t h e e v e nt 
w ors e ns i n t oxicit y. F or gr a d e 3 a n d 4 a d v ers e e v e nts o nl y, if i m pr o v e m e nt t o a l o w er gr a d e is d et er mi n e d a n e w 
e ntr y f or t his ev e nt s h o ul d b e r e p ort e d i n t h e C R F n oti n g t h e st art d at e w h e n t h e e v e nt i m pr o v e d fr o m h a vi n g 
b e e n Gr a d e 3 or Gr a d e 4.   F or p h as e I st u di es a n y A E t h at c o nstit ut es a DL T s h o ul d b e r e p ort e d li k e a gr a d e 3 
a n d 4 a d v ers e e v e nt.  All a d v ers e ev e nts s h o ul d b e tr e at e d a p pr o pri at el y. If a c o nc o mit a nt m e dic ati o n or n o n-
dr u g t h er a p y is gi v e n, t his acti o n s h o ul d b e r ec or d e d o n t h e A d v ers e E v e nt C R F.
O nc e a n a d v ers e ev e nt is d et ect e d, it s h o ul d b e f oll o w e d u ntil its r es ol uti o n or u ntil it is j u d g e d t o b e p er m a n e nt, 
a n d ass ess m e nt s h o ul d b e m a d e at e ac h visit ( or m or e fr e q u e ntl y, if n ec ess ar y) of a n y c h a n g es i n s e v erit y, t h e 
s us p ect e d r el ati o ns hi p t o t h e st u d y tr e at m e nt, t h e i nt erv e nti o ns r e q uir e d t o tr e at it, a n d t h e o utc o m e. 
Pr o gr essi o n of m ali g n a nc y (i ncl u di n g f at al o utc o m es), if d oc u m e nt e d b y us e of a p pr o pri at e m et h o d (f or ex a m pl e, 
as p er R E CI S T crit eri a f or s oli d t u m ors), s h o ul d n ot b e r e p ort e d as a s eri o us a d v ers e ev e nt. 
A d v ers e e v e nts s e p ar at e fr o m t h e pr o gr essi o n of m ali g n a nc y ( ex a m pl e, d e e p v ei n t hr o m b osis at t h e ti m e of 
pr o gr essi o n or h e m o pt ysis c o nc urr e nt wit h fi n di n g of dis e as e pr o gr essi o n) will b e r e p ort e d as p er us u al 
g ui d eli n es us e d f or s uc h e v e nts wit h pr o p er attri b uti o n r e g ar di n g r el at e d n ess t o t h e dr u g.
L a b or at or y a b n or m aliti es t h at c o nstit ut e a n A d v ers e e v e nt i n t h eir o w n ri g ht ( ar e c o nsi d er e d cli nic all y si g nific a nt, 
i n d uc e cli nic al si g ns or s y m pt o ms, r e q uir e c o nc o mit a nt t h er a p y or r e q uir e c h a n g es i n st u d y tr e at m e nt), s h o ul d 
b e r ec or d e d o n t h e A d v ers e E v e nts C R F.
L a b or at or y a b n or m aliti es, t h at d o n ot m e et t h e d efi niti o n of a n a d v ers e ev e nt, s h o ul d n ot b e r e p ort e d as a d v ers e 
e v e nts. A Gr a d e 3 or 4 ev e nt (s e v er e) as p er C T C A E d o es n ot a ut o m atic all y i n dic at e a S A E u nl ess it m e ets t h e 
d efi niti o n of s eri o us as d efi n e d b el o w a n d/ or as p er i n v esti g at or’s discr eti o n. A d os e h ol d or m e dic ati o n f or t h e 
l a b a b n or m alit y m a y b e r e q uir e d b y t h e pr ot oc ol i n w hic h c as e t h e l a b a b n or m alit y w o ul d still, b y d efi niti o n, b e 
a n a d v ers e e v e nt a n d m ust b e r e p ort e d as s uc h.
R e p orti n g t o st u d y s u p p ort er/I R B a n d or F D A .
S eri o us A d v ers e E v e nt R e p orti n g 
F or t h e ti m e p eri o d b e gi n ni n g at tr e at m e nt all oc ati o n t hr o u g h 3 0 d a ys f oll o wi n g c ess ati o n of tr e at m e nt, or 3 0  
d a ys f oll o wi n g c ess ati o n of tr e at m e nt if t h e s u bj ect i niti at es n e w a ntic a nc er t h er a p y, w hic h e v er is e arli er, a n y 
s eri o us a d v ers e ev e nt, or f oll o w u p t o a s eri o us a d v ers e e v e nt, i ncl u di n g d e at h d u e t o a n y c a us e w h et h er or n ot 
r el at e d t o t h e st u d y dr u g, m ust b e s u b mitt e d o n a n S A E f or m a n d ass ess e d b y PI i n or d er t o d et er mi n e r e p orti n g 
crit eri a t o I R B, D S M C, F D A, s u p p ort er or I N D S p o ns or. 
All S A Es will b e f oll o w e d u ntil s atisf act or y r es ol uti o n or u ntil t h e sit e i n v esti g at or d e e ms t h e e v e nt t o b e c hr o nic 
or t h e a d h er e nc e t o b e st a bl e. Ot h er s u p p orti n g d oc u m e nt ati o n of t h e e v e nt m a y b e r e q u est e d b y t h e I N D 
s p o ns or a n d s h o ul d b e pr o vi d e d as s o o n as p ossi bl e. T h e I N D s p o ns or will b e r es p o nsi bl e f or n otif yi n g F D A of a n y 
u n ex p ect e d f at al or lif e-t hr e at e ni n g s us p ect e d a d v ers e r e acti o n as s o o n as p ossi bl e b ut i n n o c as e l at er t h a n 7 
c al e n d ar d a ys aft er t h e s p o ns or's i niti al r ec ei pt of t h e i nf or m ati o n.
All s u bj ects wit h s eri o us a d v ers e e v e nts m ust b e f oll o w e d u p f or o utc o m e.
A n y a d diti o n al i nf or m ati o n f or t h e S A E i ncl u di n g c o m plic ati o ns, pr o gr essi o n of t h e i niti al S A E, a n d r ec urr e nt 
e pis o d es m ust b e r e p ort e d as f oll o w- u p t o t h e ori gi n al e pis o d e. 
A n S A E occ urri n g at a diff er e nt ti m e i nt er v al or ot h er wis e c o nsi d er e d c o m pl et el y u nr el at e d t o a pr e vi o usl y 
r e p ort e d o n e s h o ul d b e r e p ort e d s e p ar at el y as a n e w e v e nt. 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 3 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A n y S A Es ex p eri e nc e d aft er t h e r e p orti n g p eri o d d escri b e d a b o v e s h o ul d o nl y b e r e p ort e d t o F D A/I R B if t h e 
i n v esti g at or s us p ects a c a us al r el ati o ns hi p t o t h e st u d y tr e at m e nt.   
All S A E's w h er e t h e i n v esti g at or s us p ects a c a us al r el ati o ns hi p t o t h e st u d y tr e at m e nt will b e r e p ort e d t o t h e 
st u d y s u p p ort er.
I nf or m ati o n a b o ut all S A Es is c oll ect e d a n d r ec or d e d o n t h e S eri o us A d v ers e E v e nt R e p ort F or m ; all a p plic a bl e 
s ecti o ns of t h e f or m m ust b e c o m pl et e d i n or d er t o pr o vi d e a cli nic all y t h or o u g h r e p ort. T h e i n v esti g at or m ust 
ass ess a n d r ec or d t h e r el ati o ns hi p of e ac h S A E t o e ac h s p ecific st u d y tr e at m e nt (if t h er e is m or e t h a n o n e st u d y 
tr e at m e nt), c o m pl et e t h e S A E R e p ort F or m, a n d s u b mit t h e c o m pl et e d f or m.  
E ac h r e occ urr e nc e, c o m plic ati o n, or pr o gr essi o n of t h e ori gi n al ev e nt s h o ul d b e r e p ort e d as a f oll o w- u p t o t h at 
e v e nt r e g ar dl ess of w h e n it occ urs. T h e f oll o w- u p i nf or m ati o n s h o ul d d escri b e w h et h er t h e e v e nt h as r es ol v e d 
or c o nti n u es, if a n d h o w it w as tr e at e d, w h et h er t h e bli n d w as br o k e n or n ot, a n d w h et h er t h e p ati e nt c o nti n u e d 
or wit h dr e w fr o m st u d y p artici p ati o n. 
All S A Es f or dr u g st u di es m ust b e r ec or d e d o n a M e d W atc h 3 5 0 0 F or m. S A E r e p orts a n d a ny ot h er r el ev a nt s af ety 
i nf or m ati o n ar e t o b e f or w ar d e d t o t h e f oll o wi n g 
M e d W atc h 3 5 0 0 R e p orti n g G ui d eli n es:
N ot e:  
M e d W atc h 3 5 0 0 f or ms a n d ot h er i nf or m ati o n r el at e d t o 
M e d W atc h r e p orti n g ar e a v ail a bl e at 
htt p:// w w w.f d a. g o v/ m e d w atc h/i n d ex. ht ml .
A c o p y of all 1 5 D a y R e p orts a n d A n n u al Pr o gr ess R e p orts is s u b mitt e d t o Eis ai  as r e q uir e d b y F D A. I n v esti g at ors 
will cr oss r ef er e nc e t his s u b missi o n acc or di n g t o l oc al r e g ul ati o ns t o t h e I n v esti g ati o n al C o m p o u n d N u m b er (I N D, 
C S A, etc.) at t h e ti m e of s u b missi o n. 
A n i n v esti g at or w h o is a q u alifi e d p h ysici a n will ev al u at e all a d v ers e e v e nts acc or di n g t o t h e N CI C o m m o n 
T er mi n ol o g y f or A d v ers e E v e nts ( C T C A E), v ersi o n 4. 0. A n y a d v ers e ev e nt w hic h c h a n g es C T C A E gr a d e o v er t h e 
c o urs e of a gi v e n e pis o d e will h a v e e ac h c h a n g e of gr a d e r ec or d e d o n t h e a d v ers e ev e nt c as e r e p ort 
f or ms/ w or ks h e ets. All a d v ers e ev e nts r e g ar dl ess of C T C A E gr a d e m ust als o b e e v al u at e d f or s eri o us n ess.
R e p orti n g R e q uir e m e nts f or I N D h ol d er
F or I n v esti g at or-s p o ns or e d I N D st u di es, r e p orti n g r e q uir e m e nts f or t h e F D A a p pl y i n acc or d a nc e wit h t h e 
g ui d a nc e s et f ort h i n 2 1 C F R, P art 3 1 2. 3 2.  E v e nts m e eti n g t h e f oll o wi n g crit eri a n e e d t o b e s u b mitt e d t o t h e F D A 
as Ex p e dit e d I N D S af et y R e p orts.
7 C al e n d ar- D a y T el e p h o n e or F ax R e p ort
T h e S p o ns or-I n v esti g at or is r e q uir e d t o n otif y t h e F D A of a f at al or lif e-t hr e at e ni n g a d v ers e e v e nt t h at is 
u n ex p ect e d a n d ass ess e d b y t h e i n v esti g at or t o b e p ossi bl y r el at e d t o t h e us e of i nv esti g ati o n al a g e nts.  A n 
u n ex p ect e d a d v ers e ev e nt is o n e t h at is n ot alr e a d y d escri b e d i n t h e m ost r ec e nt G ui d a nc e f or I n v esti g at or 
s ecti o n of t h e I n v esti g at or’s Br oc h ur e.  S uc h r e p orts ar e t o b e t el e p h o n e d or f ax e d t o t h e F D A, wit hi n 7 c al e n d ar 
d a ys of t h e first l e ar ni n g of t h e ev e nt.
1 5 C al e n d ar- D a y Writt e n R e p ort
T h e S p o ns or-I n v esti g at or is als o r e q uir e d t o n otif y t h e F D A a n d all p artici p ati n g i n v esti g at ors, i n a writt e n I N D 
S af et y R e p ort, of a n y s eri o us u n ex p ect e d a d v ers e ev e nt t h at is c o nsi d er e d r e as o n a bl y or p ossi bl y r el at e d t o t h e 
us e of i n v esti g ati o n al a g e nt.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 4 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
Writt e n I N D S af et y R e p orts wit h a n al ysis of si mil ar e v e nts ar e t o b e s u b mitt e d t o t h e F D A, wit hi n 1 5 c al e n d ar 
d a ys of first l e ar ni n g of t h e e v e nt.  T h e F D A pr ef ers t h es e r e p orts o n a M e d W atc h 3 5 0 0 F or m b ut alt er n ati v e 
f or m ats ( e. g., s u m m ar y l ett er) ar e acc e pt a bl e.
F D A F ax n u m b er of I N D S af et y R e p orts: 1-( 8 0 0)- F D A- 1 0 7 8.
T h e I N D s p o ns or will als o m a k e a n ass ess m e nt of w h et h er t h e ev e nt c o nstit ut es a n u n a ntici p at e d pr o bl e m p osi n g 
ris ks t o s u bj ects or ot h ers ( U P). T his ass ess m e nt will b e pr o vi d e d t o t h e E m or y U ni v ersit y I R B, w hic h, i n t ur n will 
m a k e a fi n al d et er mi n ati o n.  If t h e E m or y I R B d et er mi n es a n e v e nt is a U P it will n otif y t h e a p pr o pri at e r e g ul at or y 
a g e nci es a n d i nstit uti o n al offici als.
All A d v ers e E v e nts will b e r e p ort e d t o r e g ul at or y a ut h oriti es, I R Bs a n d i n v esti g at ors i n acc or d a nc e wit h all 
a p plic a bl e gl o b al l a ws a n d r e g ul ati o ns. 
F or p artici p ati n g s u bsit es, a d v ers e ev e nts c oll ect e d at tr e at m e nt visits ar e t o b e e nt er e d i nt o O n C or e n o l at er 
t h a n 1 4 c al e n d ar d a ys aft er d at a c oll ecti o n. 
Sit e i n v esti g at ors m ust r e p ort all S A Es a n d u n a ntici p at e d pr o bl e ms t o t h e s p o ns or-i n v esti g at or wit hi n 2 4 h o urs 
of t h e p artici p ati n g sit e b ec o mi n g a w ar e of t h e e v e nt. T h e p artici p ati n g sit e will s u b mit t h e M e d W atc h F or m 
3 5 0 0 A t o t h e Wi ns hi p r e g ul at or y st aff a n d will als o e nt er t h e d at a i nt o O n C or e wit hi n t h e s p ecifi e d ti m eli n es 
a b o v e. T h e E m or y s p o ns or m ust r evi e w a n d si g n off o n t h e ev e nt a n d r et ur n t o t h e Wi ns hi p r e g ul at or y st aff. 
R e g ul at or y will r evi e w t h e ass ess m e nt t o d et er mi n e I R B a n d/ or F D A r e p orti n g r e q uir e m e nts. 
As a p plic a bl e i n m ulti-sit e st u di es, i n v esti g ati v e sit es at e ac h i nstit uti o n s h o ul d r e p ort s eri o us a d v ers e e v e nts t o 
t h eir r es p ecti v e I R B p er l oc al I R B p olici es a n d pr oc e d ur es.  T h e s u bsit e Pri nci p al I n v esti g at or will s u b mit S A E 
r e p orts fr o m o utsi d e i nstit uti o ns t o his/ h er i nstit uti o n’s I R B p er i nstit uti o n al g ui d eli n es.
S u bsit e S A E R e p orti n g R e q uir e m e nts 
S u bsit es ar e n ot p er mitt e d t o r e p ort dir ectl y t o t h e c o or di n ati n g c e nt er I R B or F D A.  All ext er n al sit e S A Es ar e t o 
b e r e p ort e d t o t h e c o or di n ati n g c e nt er.  T h e c o or di n ati n g c e nt er m ulti-sit e c o or di n at or will f acilit at e s u b missi o n 
of ext er n al sit e S A Es t o t h e c o or di n ati n g c e nt er I R B a n d F D A.
All s eri o us a d v ers e ev e nts ( S A Es) a n d ot h er a d v ers e e v e nts m ust b e r ec or d e d o n c as e r e p ort f or ms. I n a d diti o n, 
all S A Es m ust b e r e p ort e d t o t h e c o or di n ati n g c e nt er pri nci p al i n v esti g at or a n d c o or di n ati n g c e nt er m ulti-sit e 
c o or di n at or wit hi n 2 4 h o urs of k n o wl e d g e of t h e e v e nt usi n g t h e F D A M e d W atc h 3 5 0 0 A m a n d at or y r e p orti n g 
f or m.
C o pi es of d e-i d e ntifi e d s o urc e d oc u m e nt ati o n p ert ai ni n g t o t h e S A E m ust b e s u b mitt e d t o t h e c o or di n ati n g 
c e nt er. If a p ati e nt is p er m a n e ntl y wit h dr a w n fr o m t h e st u d y b ec a us e of a S A E, t his i nf or m ati o n m ust b e i ncl u d e d 
i n t h e i niti al or f oll o w- u p f or m.
All S A Es m ust b e s u b mitt e d t o t h e l oc al I R B p er l oc al I R B a n d i nstit uti o n al p olic y.
U p o n r e q u est of a d diti o n al d at a or i nf or m ati o n t h at is d e e m e d n ec ess ar y m ust b e r e p ort e d t o t h e c o or di n ati n g 
c e nt er as s o o n as p ossi bl e b ut n o l at er t h a n 5 c al e n d ar d a ys.
S p o ns or I n v esti g at or r e p orti n g t o t h e F o o d a n d Dr u g a d mi nistr ati o n ( F D A)

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 5 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
T h e S p o ns or I n v esti g at or, as h ol d er of t h e I N D ( as a p plic a bl e), will b e r es p o nsi bl e f or all c o m m u nic ati o n wit h t h e 
F D A. T h e S p o ns or I n v esti g at or [ or d esi g n e e] will r e p ort t o t h e F D A, r e g ar dl ess of t h e sit e of occ urr e nc e, a n y 
a d v ers e e v e nt t h at is s eri o us, u n ex p ect e d a n d r e as o n a bl y r el at e d (i. e., p ossi bl e, pr o b a bl e, d efi nit e) t o t h e st u d y 
tr e at m e nt. 
U n ex p ect e d f at al or lif e-t hr e at e ni n g ex p eri e nc es ass oci at e d wit h t h e us e of t h e st u d y tr e at m e nt will b e r e p ort e d 
t o F D A as s o o n as p ossi bl e b ut n o l at er t h a n 7 c al e n d ar d a ys aft er i niti al r ec ei pt of t h e i nf or m ati o n. 
All ot h er s eri o us u n ex p ect e d ex p eri e nc es ass oci at e d wit h t h e us e of t h e st u d y tr e at m e nt will b e r e p ort e d t o F D A 
as s o o n as p ossi bl e b ut i n n o e v e nt l at er t h a n 1 5 c al e n d ar d a ys aft er i niti al r ec ei pt of t h e i nf or m ati o n. E v e nts will 
b e r e p ort e d t o t h e F D A b y t el e p h o n e ( 1- 8 0 0- F D A- 1 0 8 8) or b y f ax ( 1- 8 0 0- F D A- 0 1 7 8) usi n g M E D W A T C H F or m F D A 
3 5 0 0 A 
( M a n d at or y 
R e p orti n g 
F or m 
f or 
i n v esti g ati o n al 
a g e nts). 
F or ms 
ar e 
a v ail a bl e 
at 
htt p:// w w w.f d a. g o v/ m e d w atc h/ g etf or ms. ht m . 
A n a n n u al s af et y r e p ort c o nt ai ni n g all S A Es, ex p ect e d a n d u n ex p ect e d, will b e s e nt t o t h e F D A a n d ot h er 
a p plic a bl e r e g ul at or y a ut h oriti es. 
S ec o n d a n d s ec o n d ar y m ali g n a nc y
A s ec o n d ary m ali g n a ncy is a c a nc er c a us e d b y tr e at m e nt f or a pr e vi o us m ali g n a nc y (e. g. , tr e at m e nt wit h 
i n v esti g ati o n al a g e nt/i nt erv e nti o n, r a di ati o n or c h e m ot h er a p y). A s ec o n d ar y m ali g n a nc y is n ot c o nsi d er e d a 
m et ast asis of t h e i niti al n e o pl as m. 
All s ec o n d ar y m ali g n a nci es t h at occ ur f oll o wi n g tr e at m e nt wit h a n a g e nt u n d er a n I N D/I D E m ust b e r e p ort e d 
t hr o u g h O n C or e.  
T hr e e o pti o ns ar e a v ail a bl e t o d escri b e t h e ev e nt: 

L e u k e mi a s ec o n d ar y t o o nc ol o g y c h e m ot h er a p y ( e. g. , ac ut e m y el oc ytic l e u k e mi a [ A ML]) 

M y el o d ys pl astic s y n dr o m e ( M D S) 

Tr e at m e nt-r el at e d s ec o n d ar y m ali g n a nc y 
A n y m ali g n a nc y p ossi bl y r el at e d t o c a nc er tr e at m e nt (i ncl u di n g A ML/ M D S) s h o ul d als o b e r e p ort e d vi a t h e 
r o uti n e r e p orti n g m ec h a nis ms o utli n e d i n e ac h pr ot oc ol.
A s ec o n d m ali g n a nc y is o n e u nr el at e d t o t h e tr e at m e nt of a pri or m ali g n a nc y ( a n d is N O T a m et ast asis fr o m t h e 
i niti al m ali g n a nc y).  
D efi niti o n of u n a ntici p at e d pr o bl e ms ( U P) a n d r e p orti n g r e q uir e m e nts
T h e Offic e f or H u m a n R es e arc h Pr ot ecti o ns ( O H R P) c o nsi d ers u n a ntici p at e d pr o bl e ms i n v ol vi n g ris ks t o 
p artici p a nts or ot h ers t o i ncl u d e, i n g e n er al, a n y i nci d e nt, ex p eri e nc e, or a n o utc o m e t h at m e ets all  t h e f oll o wi n g 
crit eri a:  U n ex p ect e d i n t er ms of n at ur e, s e v erit y, or fr e q u e nc y gi v e n ( a) t h e r es e arc h pr oc e d ur es t h at ar e 
d escri b e d i n t h e pr ot oc ol-r el at e d d oc u m e nts, s uc h as t h e I R B- a p pr o v e d r es e arc h pr ot oc ol a n d i nf or m e d c o ns e nt 
d oc u m e nt; a n d ( b) t h e c h ar act eristics of t h e p artici p a nt p o p ul ati o n b ei n g st u di e d; R el at e d or p ossi bl y r el at e d t o 
p artici p ati o n i n t h e r es e arc h (“ p ossi bl y r el at e d” m e a ns t h er e is a r e as o n a bl e p ossi bilit y t h at t h e i nci d e nt, 
ex p eri e nc e, or o utc o m e m a y h a v e b e e n c a us e d b y t h e pr oc e d ur es i n v ol v e d i n t h e r es e arc h); a n d S u g g ests t h at 
t h e r es e arc h pl ac es p artici p a nts or ot h ers at a gr e at er ris k of h ar m (i ncl u di n g p h ysic al, ps yc h ol o gic al, ec o n o mic, 
or s oci al h ar m) t h a n w as pr evi o usl y k n o w n or r ec o g niz e d.  T his st u d y will us e t h e O H R P d efi niti o n of u n a ntici p at e d 
pr o bl e ms. I nci d e nts or ev e nts t h at m e et t h e O H R P crit eri a f or U Ps r e q uir e t h e cr e ati o n a n d c o m pl eti o n of a U P 
r e p ort f or m. It is t h e sit e i n v esti g at or’s r es p o nsi bilit y t o r e p ort U Ps t o t h eir I R B a n d t o t h e D C C/st u d y s p o ns or. 
T h e U P r e p ort will i ncl u d e t h e f oll o wi n g i nf or m ati o n:  Pr ot oc ol i d e ntif yi n g i nf or m ati o n: pr ot oc ol titl e a n d n u m b er, 
PI’s n a m e, a n d t h e I R B pr oj ect n u m b er; A d et ail e d d escri pti o n of t h e ev e nt, i nci d e nt, ex p eri e nc e, or o utc o m e; A n 
ex pl a n ati o n of t h e b asis f or d et er mi ni n g t h at t h e ev e nt, i nci d e nt, ex p eri e nc e, or o utc o m e r e pr es e nts a n U P; A 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 6 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
d escri pti o n of a n y c h a n g es t o t h e pr ot oc ol or ot h er c orr ecti v e acti o ns t h at h a v e b e e n t a k e n or ar e pr o p os e d i n 
r es p o ns e t o t h e U P.  T h e I N D s p o ns or will m a k e a n ass ess m e nt of w h et h er t h e ev e nt c o nstit ut es a n u n a ntici p at e d 
pr o bl e m p osi n g ris ks t o s u bj ects or ot h ers ( U P). T his ass ess m e nt will b e pr o vi d e d t o t h e E m or y U ni v ersit y I R B.  If 
t h e E m or y I R B d et er mi n es a n ev e nt is a U P it will n otif y t h e a p pr o pri at e r e g ul at or y a g e nci es a n d i nstit uti o n al 
offici als. 
T h e D at a a n d S af et y M o nit ori n g C o m mitt e e ( D S M C)
T h e D at a a n d S af et y M o nit ori n g C o m mitt e e ( D S M C) of t h e Wi ns hi p C a nc er I nstit ut e will pr o vi d e o v ersi g ht f or t h e 
c o n d uct of t his st u d y.  T h e D S M C f u ncti o ns i n d e p e n d e ntl y wit hi n Wi ns hi p C a nc er I nstit ut e t o c o n d uct i nt er n al 
m o nit ori n g f u ncti o ns t o e ns ur e t h at r es e arc h b ei n g c o n d uct e d b y 
Wi ns hi p C a nc er I nstit ut e I n v esti g at ors 
pr o d uc es hi g h- q u alit y sci e ntific d at a i n a m a n n er c o nsist e nt wit h g o o d cli nic al pr actic e ( G C P) a n d a p pr o pri at e 
r e g ul ati o ns t h at g o v er n cli nic al r es e arc h.    D e p e n di n g o n t h e ris k l e v el of t h e pr ot oc ol, t h e D S M C r e vi e w m a y 
occ ur e v er y 6 m o nt hs or a n n u all y.  F or st u di es d e e m e d Hi g h Ris k, i niti al st u d y m o nit ori n g will occ ur wit hi n 6 
m o nt hs fr o m t h e d at e of t h e first s u bj ect accr u e d, wit h 2 of t h e first 5 s u bj ects b ei n g r e vi e w e d.  F or st u di es 
d e e m e d M o d er at e Ris k, i niti al st u d y m o nit ori n g will occ ur wit hi n 1 y e ar fr o m t h e d at e of t h e first s u bj ect accr u e d, 
wit h 2 of t h e first 5 s u bj ects b ei n g r e vi e w e d.  S u bs e q u e nt m o nit ori n g will occ ur i n r o uti n e i nt er v als p er t h e 
Wi ns hi p D at a a n d S af et y M o nit ori n g Pl a n ( D S M P) . 
T h e D S M C will r evi e w p erti n e nt as p ects of t h e st u d y t o ass ess s u bj ect s af et y, c o m pli a nc e wit h t h e pr ot oc ol, d at a 
c oll ecti o n, a n d ris k- b e n efit r ati o. S p ecific all y, t h e Wi ns hi p C a nc er I nstit ut e I nt er n al M o nit ors assi g n e d t o t h e 
D S M C m a y v erif y i nf or m e d c o ns e nt, eli gi bilit y, d at a e ntr y, acc ur ac y a n d a v ail a bilit y of s o urc e d oc u m e nts, 
A Es/ S A Es, a n d ess e nti al r e g ul at or y d oc u m e nts.  F oll o wi n g t h e m o nit ori n g r evi e w, m o nit ors will pr o vi d e a 
pr eli mi n ar y r e p ort of m o nit ori n g fi n di n gs t o t h e PI a n d ot h er p erti n e nt i n di vi d u als i n v ol v e d i n t h e c o n d uct of t h e 
st u d y.  T h e PI is r e q uir e d t o a d dr ess a n d r es p o n d t o all t h e d efici e nci es n ot e d i n t h e pr eli mi n ar y r e p ort.  Pri or t o 
t h e c o m pl eti o n of t h e fi n al s u m m ar y r e p ort, m o nit ors will disc uss t h e pr eli mi n ar y r e p ort r es p o ns es wit h t h e PI 
a n d ot h er t e a m m e m b ers ( w h e n a p pr o pri at e).  A fi n al m o nit ori n g s u m m ar y r e p ort will t h e n b e pr e p ar e d b y t h e 
m o nit or.  Fi n al D S M C r evi e w will i ncl u d e t h e fi n al m o nit ori n g s u m m ar y r e p ort wit h c orr es p o n di n g PI r es p o ns e, 
s u b mitt e d C A P A ( w h e n a p plic a bl e), PI S u m m ar y st at e m e nt, a n d a v ail a bl e a g gr e g at e t oxicit y a n d s af et y d at a.  
T h e D S M C will r e n d er a r ec o m m e n d ati o n a n d r ati n g b as e d o n t h e o v er all tri al c o n d uct.  T h e PI is r es p o nsi bl e f or 
e ns uri n g t h at i nst a nc es of e gr e gi o us d at a i ns uffici e nci es ar e r e p ort e d t o t h e I R B.  C o nti n ui n g R e vi e w s u b missi o ns 
will i ncl u d e t h e D S M C r ec o m m e n d ati o n l ett er.  S h o ul d a n y r e visi o ns b e m a d e t o t h e pr ot oc ol-s p ecific m o nit ori n g 
pl a n aft er i niti al D S M C a p pr o v al, t h e PI will b e r es p o nsi bl e f or n otif yi n g t h e D S M C of s uc h c h a n g es.  T h e 
C o m mitt e e r es erv es t h e ri g ht t o c o n d uct a d diti o n al a u dits if n ec ess ar y.   
M ultisit e M o nit ori n g Pl a n 
 At t h e ti m e of st u d y i niti ati o n at a n o n- E m or y sit e, t h e E m or y S p o ns or, Wi ns hi p r e g ul at or y s p eci alist, a n d Wi ns hi p 
r es e arc h c o or di n at ors will p erf or m a sit e i niti ati o n t el ec o nf er e nc e. D uri n g t his t el ec o nf er e nc e, t h e E m or y t e a m 
will r e vi e w t h e st u d y, e nr oll m e nt, r e p orti n g, a n d r e g ul at or y c o m pli a nc e. T h e p artici p ati n g sit e will h a v e i nt er n al 
m o nit ori n g m e eti n gs. T h es e m e eti n gs, w hic h will i ncl u d e t h e p artici p ati n g sit e i n v esti g at or, t h e cli nic al r es e arc h 
c o or di n at or a n d t h e r e g ul at or y aff airs c o or di n at or, will m e et at l e ast o n a m o nt hl y b asis t o r evi e w a n d disc uss 
st u d y d at a t o e ns ur e s u bj ect s af et y. T h e r es e arc h c o or di n at ors will m ai nt ai n a s pr e a ds h e et w hic h will b e d e-
i d e ntifi e d a n d will s u m m ariz e all t h e p ati e nt d at a f or s u bj ects acti v el y b ei n g tr e at e d o n t h e tri al as w ell as a 
r o a d m a p d et aili n g p e n di n g t ests/tr e at m e nts f or e ac h i n di vi d u al s u bj ect. T h e s pr e a ds h e et will b e s h ar e d wit h t h e 
E m or y PI vi a e- m ail.  M ulti- Sit e Wi ns hi p’s M S C will p erf or m a n o n-sit e or r e m ot e m o nit ori n g visit wit hi n t h e first 
t hr e e m o nt hs of e nr oll m e nt of t h e first s u bj ect. Q u art erl y m o nit ori n g visits will occ ur ( o nc e a n n u all y o nsit e a n d 
t hr e e ti m es r e m ot el y) u ntil s u bj ect f oll o w- u p is t er mi n at e d. M o nt hl y r evi e ws of d at a i n O n C or e will b e c o n d uct e d 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 7 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
t o e ns ur e c o m pli a nc e or i d e ntif y discr e p a nci es. At l e ast m o nt hl y t el ec o nf er e nc es b et w e e n E m or y PI a n d 
p artici p ati n g sit e T el ec o nf er e nc es will b e c o n d uct e d at l e ast o nc e m o nt hl y b et w e e n t h e PI at E m or y a n d t h e 
r es e arc h t e a m at t h e p artici p ati n g sit e(s). T h e p ur p os e of t h e m e eti n gs is t o disc uss t h e e nr oll m e nt, r e g ul at or y 
u p d at es, m o nit or t oxiciti es, a n d e v al u at e t h e pr o gr ess of t h e tri al. Sc h e d ul e d t el ec o nf er e nc es m a y st o p aft er all 
p ati e nts h a v e c o m pl et e d assi g n e d pr ot oc ol t h er a p y. T h e PI at E m or y will c o m m u nic at e wit h p artici p ati n g sit es 
vi a m o nt hl y e m ail. T h e mi n ut es fr o m t h e t el ec o nf er e nc e will b e m ai nt ai n e d i n t h e r e g ul at or y bi n d er f or t h e st u d y. 
I n a d diti o n el ectr o nic c o pi es will b e s e nt vi a e m ail t o t h e pri nci p al i n v esti g at ors at e ac h sit e.  
1 8.  Pr o visi o ns t o Pr ot ect t h e Pri v ac y I nt er ests of P artici p a nts
P artici p a nts will b e ass ur e d of t h eir v ol u nt ar y p artici p ati o n i n t h e st u d y, t h eir c h oic e t o a ns w er or n ot a ns w er 
a n y q u esti o n, a n d t h e pr ot oc ol f or m ai nt ai ni n g c o nfi d e nti alit y.
P artici p a nt c o nfi d e nti alit y is strictl y h el d i n tr ust by t h e p artici p ati n g i n v esti g at ors, t h eir st aff, a n d t h e s p o ns or(s) 
a n d t h eir a g e nts. T his c o nfi d e nti alit y is ext e n d e d t o c o v er t esti n g of bi ol o gic al s a m pl es a n d g e n etic t ests i n 
a d diti o n t o t h e cli nic al i nf or m ati o n r el ati n g t o p artici p a nts. T h er ef or e, t h e st u d y pr ot oc ol, d oc u m e nt ati o n, d at a, 
a n d all ot h er i nf or m ati o n g e n er at e d will b e h el d i n strict c o nfi d e nc e. N o i nf or m ati o n c o nc er ni n g t h e st u d y or t h e 
d at a will b e r el e as e d t o a n y u n a ut h oriz e d t hir d p art y wit h o ut pri or writt e n a p pr o v al of t h e s p o ns or.
T h e st u d y m o nit or, ot h er a ut h oriz e d r e pr es e nt ati v es of t h e s p o ns or, r e pr es e nt ati v es of t h e I R B or p h ar m ac e utic al 
c o m p a n y s u p pl yi n g st u d y pr o d uct m a y i ns p ect all d oc u m e nts a n d r ec or ds r e q uir e d t o b e 
m ai nt ai n e d by t h e 
i n v esti g at or, i ncl u di n g b ut n ot li mit e d t o, m e dic al r ec or ds ( offic e, cli nic, or h os pit al) a n d p h ar m ac y r ec or ds f or 
t h e p artici p a nts i n t his st u d y. T h e cli nic al st u dy sit e will p er mit acc ess t o s uc h r ec or ds.
T h e st u d y p artici p a nt’s c o nt act i nf or m ati o n will b e s ec ur el y st or e d at e ac h cli nic al sit e f or i nt er n al us e d uri n g t h e 
st u d y. At t h e e n d of t h e st u d y, all r ec or ds will c o nti n u e t o b e k e pt i n a s ec ur e l oc ati o n f or as l o n g a p eri o d as 
dict at e d b y l oc al I R B a n d I nstit uti o n al r e g ul ati o ns.
St u d y p artici p a nt r es e arc h d at a, w hic h is f or p ur p os es of st atistic al a n al ysis a n d sci e ntific r e p orti n g, will b e 
tr a ns mitt e d t o a n d st or e d. T his will n ot i ncl u d e t h e p artici p a nt’s c o nt act or i d e ntif yi n g i nf or m ati o n. R at h er, 
i n di vi d u al p artici p a nts a n d t h eir r es e arc h d at a 
will b e i d e ntifi e d b y a u ni q u e st u d y i d e ntific ati o n n u m b er. T h e 
st u dy d at a e ntr y a n d st u d y m a n a g e m e nt s yst e ms us e d b y cli nic al sit es a n d r es e arc h st aff will b e s ec ur e d a n d 
p ass w or d pr ot ect e d. At t h e e n d of t h e st u d y, all st u dy d at a b as es will b e d e-i d e ntifi e d a n d arc hi v e d
1 9.   Ec o n o mic B ur d e n t o P artici p a nts
L e n v ati ni b will b e fr e e of c h ar g e t o t h e p artici p a nts. T h e st u d y s p o ns or will p a y f or c ert ai n it e ms a n d s er vic es 
t h e s u bj ect m a y r ec ei v e i n t his st u d y.  S u bj ects will h a v e t o p a y f or t h e it e ms or s ervic es f or w hic h t h e st u d y 
s p o ns or d o es n ot p a y. T h e s p o ns or will n ot p a y f or r e g ul ar m e dic al c ar e. If s u bj ects h a v e i ns ur a nc e, E m or y will 
s u b mit cl ai ms t o t h e i ns ur a nc e f or it e ms a n d s ervic es t h at t h e s p o ns or d o es n ot c o v er.  E m or y will s e n d i n o nl y 
t h os e cl ai ms f or it e ms a n d s ervic es t h at it r e as o n a bl y b eli e v es t h e i ns ur a nc e will p a y a n d t h at t h e s p o ns or h as 
n ot p ai d. T h e act u al a m o u nt t h at p artici p a nts h a v e t o p a y d e p e n ds o n w h et h er or n ot t h e y h a v e h e alt h i ns ur a nc e 
a n d w h et h er or n ot t h at i ns ur a nc e will p a y f or a n y r es e arc h st u d y c osts. G e n er all y, i ns ur a nc e c o m p a ni es will n ot 
p a y f or it e ms a n d s er vic es t h at ar e r e q uir e d j ust f or a r es e arc h st u d y. S o m e i ns ur a nc e c o m p a ni es will n ot p a y 
f or r e g ul ar m e dic al tr e at m e nt or tr e at m e nt f or c o m plic ati o ns if i n a st u d y.  If s u bj ect d o n ot h a v e i ns ur a nc e, 
E m or y will r evi e w t h at p artic ul ar c as e as p art of its pr o gr a m f or l o w-i nc o m e p ati e nt c ar e.  T h e st a n d ar d p olici es 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 8 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
of t h at pr o gr a m will a p pl y.  T h e pr o gr a m will fi g ur e o ut if s u bj ects h a v e t o p a y a n y c osts f or t a ki n g p art i n t h e 
st u d y a n d w h at t h os e c osts will b e

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 3 9 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
2 0.  C o ns e nt Pr oc ess
T h e i niti al i nf or m e d c o ns e nt disc ussi o n will occ ur i n Wi ns hi p C a nc er I nstit ut e or t h e E m or y Cli nic.
At Wi ns hi p C a nc er I nstit ut e, t h e i nf or m e d c o ns e nt is a n o n g oi n g, i nt er acti v e pr oc ess r at h er t h a n a o n e-ti m e 
i nf or m ati o n s essi o n. T h e c o ns e nt f or m d oc u m e nt is d esi g n e d t o b e gi n t h e i nf or m e d c o ns e nt pr oc ess, w hic h 
pr o vi d es t h e p ati e nt wit h o n g oi n g ex pl a n ati o ns t h at will h el p t h e m m a k e e d uc ati o n al d ecisi o ns a b o ut w h et h er 
t o b e gi n or c o nti n u e p artici p ati n g i n t h e tri al. T h e r es e arc h t e a m k n o ws t h at a writt e n d oc u m e nt al o n e m a y n ot 
e ns ur e t h at t h e p ati e nt f ull y u n d erst a n ds w h at p artici p ati o n m e a ns. T h er ef or e, t h e r es e arc h t e a m will disc uss 
wit h t h e p ati e nt t h e tri al's p ur p os e, pr oc e d ur es, ris ks a n d p ot e nti al b e n efits, a n d t h eir ri g hts as a p artici p a nt. T h e 
t e a m will c o nti n u e t o u p d at e t h e p ati e nt o n a n y n e w i nf or m ati o n t h at m a y aff ect t h eir sit u ati o n.
C o ns e nt will b e o bt ai n e d pri or t o a n y r es e arc h- dri v e n pr oc e d ur es. T h e i n v esti g at or will ass ess t h e p ati e nt’s 
c a p acit y d uri n g his/ h er e nc o u nt ers wit h hi m or h er. T h e i n v esti g at or will gi v e t h e p ers o n pr o vi di n g c o ns e nt 
a d e q u at e o p p ort u nit y t o r e a d t h e c o ns e nt d oc u m e nt b ef or e it is si g n e d a n d d at e d.
It will b e ex pl ai n e d t o pr os p ecti v e p artici p a nts t h at t h e st u d y i n v ol v es r es e arc h, t h e p ur p os e of t h e r es e arc h, t h e 
ex p ect e d d ur ati o n of p artici p ati o n, as w ell as t h e a p pr oxi m at e n u m b er of p artici p a nts t o b e e nr oll e d. T h e st u d y 
pr oc e d ur es, a n d i d e ntific ati o n of r es e arc h pr oc e d ur es v. n o n-r es e arc h will als o b e t h or o u g hl y disc uss e d. It will 
b e ex pl ai n e d t o p artici p a nts t h at p artici p ati o n is v ol u nt ar y a n d t h at t h e s u bj ect m a y disc o nti n u e at a n y ti m e.
R ef us al t o p artici p at e or wit h dr a w will n ot i n v ol v e a p e n alt y or l oss of b e n efits t o w hic h t h e p artici p a nt is 
ot h er wis e e ntitl e d. R ef us al will i n n o w a y aff ect t h e p artici p a nt's f ut ur e ar e. T h e p artici p a nt will als o b e t ol d of 
t h e p ossi bl e c o ns e q u e nc es of t h e d ecisi o n t o wit h dr a w fr o m t h e r es e arc h, a n d pr oc e d ur es f or or d erl y 
t er mi n ati o n of p artici p ati o n.
A n y si g nific a nt n e w fi n di n gs d e v el o p e d d uri n g t h e c o urs e of t h e r es e arc h t h at m a y aff ect t h e p artici p a nt's 
willi n g n ess t o c o nti n u e t o p artici p at e will b e pr o vi d e d. Als o ex pl ai n e d will b e a ntici p at e d circ u mst a nc es u n d er 
w hic h t h e s u bj ect's p artici p ati o n m a y b e t er mi n at e d b y t h e i n v esti g at or wit h o ut t h e p artici p a nt's c o ns e nt.
Pr os p ecti v e p artici p a nts will b e pr o vi d e d wit h a d escri pti o n of a n y r e as o n a bl y f ors e e a bl e ris ks or disc o mf orts as 
w ell as a d escri pti o n of a n y b e n efits t o t h e p artici p a nt or t o ot h ers t h at mi g ht b e r e as o ns ex p ect e d fr o m t h e 
r es e arc h. Alt er n ati v e pr oc e d ur es or c o urs es of tr e at m e nt will als o b e t h or o u g hl y disc uss e d.
Pr os p ecti v e p artici p a nts will als o b e gi v e n d et ail e d i nf or m ati o n d escri bi n g t h e ext e nt t o w hic h c o nfi d e nti alit y of 
r ec or ds i d e ntif yi n g t h e p artici p a nt will b e m ai nt ai n e d a n d w h at r ec or ds m a y b e ex a mi n e d b y t h e r es e arc h st aff, 
I R Bs, s p o ns or, t h eir r e pr es e nt ati v es, a n d p ossi bl y t h e F D A or O H R P.
Als o c o m m u nic at e d t o t h e p artici p a nt will b e a n ex pl a n ati o n t h at e m er g e nc y m e dic al c ar e will b e arr a n g e d f or a 
st u d y-r el at e d ill n ess or i nj ur y, a n d a n ex pl a n ati o n of w h et h er f u n ds ar e s et asi d e t o p a y f or t his c ar e a n d/ or 
c o m p e ns ati o n, a n d if s o b y w h o m ( e. g., s p o ns or, s u bj ect, i ns ur er). T h e p artici p a nt is t ol d t h e s o urc e of t h e st u d y's 
f u n di n g.
All p artici p a nts will b e t ol d of a n y a d diti o n al c osts t h at m a y r es ult fr o m p artici p ati o n i n t h e r es e arc h.
N o n- E n glis h- S p e a ki n g P artici p a nts   
A c ertifi e d tr a nsl at or/i nt er pr et er will b e pr es e nt d uri n g t h e c o ns e nti n g pr oc ess a n d all q u esti o ns a n d c o nc er ns 
will b e a ns w er e d b y t h e tr e ati n g p h ysici a n. 
A S h ort F or m i n t h at s p ecific l a n g u a g e will b e us e d. A c ertifi e d tr a nsl at or/i nt er pr et er will b e pr es e nt d uri n g t h e 
c o ns e nti n g pr oc ess a n d t his will b e d oc u m e nt e d. W e will us e w h at's a v ail a bl e o n E m or y I R B w e bsit e. F or t h e 
l a n g u a g es t h at ar e n ot a v ail a bl e, w e will h a v e t h e s h ort f or m tr a nsl at e d t o t h at l a n g u a g e a n d s u b mit t h e I R B f or 
r e vi e w a n d a p pr o v al pri or t o us e. Pr oc ess t o D oc u m e nt C o ns e nt i n Writi n g: Wi ns hi p S O P 2. 1:” O bt ai ni n g I nf or m e d 
c o ns e nt f or I nt erv e nti o n al cli nic al tri al” will b e f oll o w e d.
P artici p a nts w h o ar e n ot y et a d ults (i nf a nts, c hil dr e n, t e e n a g ers):  N/ A
C o g niti v el y I m p air e d A d ults:  N/ A

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 0 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A d ults U n a bl e t o C o ns e nt:  N/ A
W ai v er or Alt er ati o n of C o ns e nt Pr oc ess (c o ns e nt will n ot b e o bt ai n e d, r e q uir e d i nf or m ati o n 
will n ot b e discl os e d, or t h e r es e arc h i n v ol v es d ec e pti o n) N/ A
2 1.   S etti n g
T h e r es e arc h will b e c o n d uct e d at E m or y U ni v ersit y, M a y o Cli nic t w o sit es ( M a y o Cli nic Ariz o n a a n d M a y o Cli nic 
R oc h est er) a n d t h e U ni v ersit y of Al a b a m a at Bir mi n g h a m.
P ot e nti al p artici p a nts will b e i d e ntifi e d i n m e dic al o nc ol o g y cli nics, m ulti disci pli n ar y c a nc er cli nic, s ur gic al 
o nc ol o g y cli nics, m ulti disci pli n ar y t u m or b o ar d at E m or y U ni v ersit y, M a y o Cli nic a n d t h e U ni v ersit y of Al a b a m a 
at Bir mi n g h a m.
2 2.  R es o urc es A v ail a bl e
E m or y U ni v ersit y w as f o u n d e d i n 1 8 3 6 a n d is a n ati o n al c e nt er f or t e ac hi n g, r es e arc h, a n d s er vic e. E m or y 
U ni v ersit y h as b e e n n a m e d as o n e of t h e n ati o n’s t o p 2 5 u ni v ersiti es f or m or e t h a n a d ec a d e b y t h e U. S. N e ws 
a n d W orl d R e p ort. E m or y U ni v ersit y r es e arc h p art n ers i ncl u d e t h e G e or gi a I nstit ut e of T ec h n ol o g y, t h e U ni v ersit y 
of G e or gi a, M or e h o us e Sc h o ol of M e dici n e, t h e U S C e nt ers f or Dis e as e C o ntr ol a n d Pr e v e nti o n, C hil dr e n's 
H e alt hc ar e of Atl a nt a, a n d t h e G e or gi a Cli nic al a n d Tr a nsl ati o n al Sci e nc e Alli a nc e ( G A C T S A). E m or y U ni v ersit y 
r es e arc h ers r ec ei v e d $ 7 3 4 milli o n fr o m ext er n al f u n di n g a g e nci es i n fisc al y e ar 2 0 1 8, i ncl u di n g a p pr oxi m at el y 
$ 4 4 1 milli o n i n f u n di n g fr o m f e d er al a g e nci es, $ 3 5 9 milli o n of t his fr o m t h e N ati o n al I nstit ut es of H e alt h ( NI H).
Wi ns hi p C a nc er I nstit ut e ( Wi ns hi p)  is G e or gi a's first a n d o nl y N ati o n al C a nc er I nstit ut e ( N CI)- d esi g n at e d 
C o m pr e h e nsi v e C a nc er C e nt er ( P 3 0 C A 1 3 8 2 9 2) a n d is d e dic at e d t o t h e i nt e gr ati o n of i n n o v ati v e cli nic al a n d b asic 
sci e nc e r es e arc h wit h o utst a n di n g p ati e nt c ar e f or t h e pr ev e nti o n, tr e at m e nt a n d c o ntr ol of c a nc er. First 
d esi g n at e d i n 2 0 0 9, Wi ns hi p’s N CI d esi g n ati o n w as r e n e w e d i n 2 0 1 2 a n d 2 0 1 6, ac hi e vi n g a n “ o utst a n di n g” r ati n g. 
Wi ns hi p e ar n e d t h e pr esti gi o us C o m pr e h e nsi v e C a nc er C e nt er d esi g n ati o n fr o m t h e N CI i n 2 0 1 6, aft er 
d e m o nstr ati n g t h at its o utst a n di n g pr o gr a ms ar e r e d uci n g t h e c a nc er b ur d e n o n t h e st at e of G e or gi a t hr o u g h 
r es e arc h c o n d uct e d i n its l a b or at ori es, its cli nic al tri al pr o gr a m, a n d its p o p ul ati o n- b as e d sci e nc e. T h e 
i nstit uti o n al s u p p ort f or Wi ns hi p w as r at e d as ‘ exc e pti o n al’ b y t h e r e vi e w p a n el.
T h e Wi ns hi p Cli nic B uil di n g C  h o us es t h e pri m ar y offic es a n d cli nic al s p ac e f or c a nc er s ervic es i ncl u di n g t h e 
m e dic al o nc ol o g y, h e m at ol o g y, a n d s ur gic al o nc ol o g y cli nics, t h e r a di ati o n o nc ol o g y pr o gr a m, a n d t h e Wi ns hi p 
A m b ul at or y I nf usi o n C e nt er.  I n s u m m er 2 0 1 7, E m or y H e alt hc ar e c o m pl et e d t h e ex p a nsi o n of E m or y U ni v ersit y 
H os pit al T o w er  o n Clift o n R o a d. T his ni n e-fl o or f acilit y a d ds 1 4 4 i n p ati e nt b e ds t o t h e h os pit al, of w hic h m or e 
t h a n 8 0 % ar e d e dic at e d t o c a nc er c ar e. T h e h os pit al ex p a nsi o n als o acc o m m o d at es c a nc er p ati e nt-s p ecific 
i nt e nsi v e c ar e u nits, a n ex p a n d e d B M T U nit wit h p eri-tr a ns pl a nt cli nics t o f acilit at e c o nti n uit y of c ar e, a n d a 2 4-
h o ur c a nc er ur g e nt c ar e c e nt er, w hic h s er v es as b ot h a tri a g e f acilit y a n d s h ort st a y tr e at m e nt c e nt er f or p ati e nts 
wit h c a nc er-r el at e d m e dic al c o nc er ns. 
T h e Wi ns hi p P h as e I U nit , o n t h e f o urt h fl o or of t h e E m or y U ni v ersit y H os pit al T o w er, is t h e l ar g est u nit i n G e or gi a 
d e dic at e d t o t h e e arli est a n d m ost critic al p h as e of n e w c a nc er t h er a p y ev al u ati o n. T h er e is s p ac e f or 1 5 pri v at e 
tr e at m e nt b a ys, f o ur cli nic r o o ms, its o w n l a b f or d oi n g p ati e nt bl o o d w or k, a d e dic at e d s ec ur e m e dic ati o n r o o m, 
c o m p ut er w or ks p ac e f or r es e arc h a n d ot h er s u p p ort st aff, a n d a "f ast tr ac k" b a y wit h t hr e e c h airs f or r a pi d us e 
i n p ati e nts w h o, f or ex a m pl e, mi g ht n e e d o nl y a r es e arc h l a b t est d o n e.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 1 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
M a y o Cli nic  is t h e first a n d l ar g est i nt e gr at e d, n ot-f or- pr ofit gr o u p pr actic e i n t h e w orl d. M a y o Cli nic h as 6 5, 2 1 4 
t ot al e m pl o y e es c o nsisti n g of 4, 8 7 8 p h ysici a ns a n d sci e ntists a n d 6 0, 3 3 6 alli e d a n d a d mi nistr ati v e st aff ( n ot 
i ncl u di n g st u d e nts, f ell o ws, a n d r esi d e nts), wit h m ai n c a m p us es i n R oc h est er, Mi n n es ot a; J ac ks o n vill e, Fl ori d a; 
a n d Sc otts d al e/ P h o e nix, Ariz o n a; as w ell as m or e t h a n 7 0 s m all er h os pit als a n d f aciliti es (t h e M a y o Cli nic H e alt h 
S yst e m) acr oss 6 st at es. 
M a y o Cli nic C a nc er C e nt er  is t h e o nl y N CI- d esi g n at e d C o m pr e h e nsi v e C a nc er C e nt er wit h t hr e e g e o gr a p hic 
sit es. It w as o n e of t h e first c a nc er c e nt ers t o r ec ei v e t h e N CI d esi g n ati o n i n 1 9 7 3. M or e t h a n 1 2 2, 0 0 0 c a nc er 
p ati e nts c o m e t o M a y o Cli nic C a nc er C e nt er e ac h y e ar, w h er e p h ysici a ns, c ar e pr o vi d ers a n d r es e arc h ers – 
m or e t h a n 1, 0 0 0 of t h e m – h el p p ati e nts fi n d i n di vi d u aliz e d s ol uti o ns t o a d dr ess all as p ects of t h eir c a nc er 
j o ur n e ys. P ati e nts ar e c ar e d f or b y a t e a m of ex p erts w h o a d dr ess n ot o nl y t h eir c a nc er di a g n os es, b ut t h eir 
h e alt hc ar e n e e ds b e y o n d c a nc er. M a y o Cli nic C a nc er C e nt er p ati e nts h a v e acc ess t o h u n dr e ds of cli nic al tri als 
l e d b y M a y o Cli nic p h ysici a ns a n d sci e ntists. M or e tri als ar e a v ail a bl e t hr o u g h c o o p er ati v e r es e arc h a gr e e m e nts 
wit h t h e N CI a n d cli nic al tri al st u d y gr o u ps.
M a y o Cli nic i n R oc h est er , M N ( M C R) is a p pr ox. 1, 0 1 7, 7 8 7 s q ft a n d R es e arc h l a b or at or y s p ac e is a p pr oxi m at el y 
3 9 0, 2 5 0 s q. ft. P ati e nt- ori e nt e d r es e arc h is c o n d uct e d i n t h e M a y o a n d G o n d a B uil di n gs, a n d l a b or at or y r es e arc h 
is pri m aril y c o n d uct e d i n t h e G u g g e n h ei m, Hilt o n, a n d St a bil e B uil di n gs. Dr y l a b or at or y r es e arc h is c o n d uct e d i n 
t h e C h arlt o n B uil di n g, t h e Pl u m m er B uil di n g, a n d t h e H ar wic k B uil di n g. T h e C a nc er C e nt er c o ntr ols m or e t h a n 
8 4, 0 0 0 t ot al s q ft o n t h e R oc h est er c a m p us i n t h e G u g g e n h ei m, C h arlt o n, G o n d a, a n d Pl u m m er B uil di n gs, a n d 
t h e M a y o S u p p ort C e nt er.
M a y o Cli nic i n Ariz o n a  o p e n e d i n 1 9 8 7 a n d is n o w l oc at e d o n 2 s e p ar at e c a m p us es. T h e r es e arc h f aciliti es a n d 
a d mi nistr ati o n ar e l oc at e d i n Sc otts d al e, A Z, a s u b ur b of P h o e nix, a m aj or m etr o p olit a n ar e a of n e arl y 4 milli o n 
p e o pl e. T h e h os pit al f aciliti es a n d t h e c a nc er c e nt er ar e l oc at e d wit hi n t h e P h o e nix cit y li mits a b o ut 1 5 mil es 
a w a y. T h e h os pit al h as a d e dic at e d h e m at ol o g y/ o nc ol o g y i n p ati e nt u nit. T h e c a nc er c e nt er b uil di n g at t h e 
P h o e nix c a m p us h o us es m e dic al o nc ol o g y, r a di ati o n o nc ol o g y, r a di ol o g y, a n d n ucl e ar m e dici n e t o e ns ur e t h e 
m ulti- disci pli n ar y c ar e. 
T h e O` N e al C o m pr e h e nsi v e C a nc er C e nt er at U ni v ersit y of Al a b a m a at Bir mi n g h a m  off ers a f ull arr a y of 
tr e at m e nt o pti o ns fr o m m ulti disci pli n ar y cli nics fill e d wit h ex p erts fr o m acr oss c a nc er fi el ds t o t h e l at est st at e-
of-t h e- art t ec h n ol o g y. T h e c e nt er is h o m e t o a n o utst a n di n g f ac ult y of r o u g hl y 4 0 0 cli nici a ns, sci e ntists a n d 
cli nici a n-sci e ntists, m a n y of w h o m ar e i nt er n ati o n all y a n d n ati o n all y r ec o g niz e d f or t h eir ex p ertis e i n o nc ol o g y. 
T h e O' N e al C a nc er C e nt er tr e ats a p pr oxi m at el y 2 0, 0 0 0 p ati e nts a n n u all y, wit h a n esti m at e d 5, 0 0 0 n e w p ati e nts 
e ac h y e ar.
2 3.  M ulti- Sit e R es e arc h w h e n E m or y is t h e L e a d Sit e 
All sit es will h a v e t h e c urr e nt pr ot oc ol d oc u m e nt a n d e ac h I R B will r e vi e w e ac h sit e’s c o ns e nt f or m a n d all 
r e q uir e d a p pr o v als will b e o bt ai n e d at e ac h sit e.  A n y pr ot oc ol m o dific ati o ns will b e c o m m u nic at e d t o all sit es 
wit h t h e a p pr o pri at e r e g ul at or y a g e nci es n otifi e d f or t h eir r es p ecti v e r e vi e ws a n d a p pr o v als.  All e n g a g e d 
p artici p ati n g sit es will s af e g u ar d d at e, i ncl u di n g s ec ur e tr a ns missi o n of d at a, as r e q uir e d b y l oc al i nf or m ati o n 
s ec urit y p olici es.  All l oc al sit e i n v esti g at ors will c o n d uct t h e st u d y i n acc or d a nc e wit h a p plic a bl e f e d er al 
r e g ul ati o ns a n d l oc al l a ws.  All n o n-c o m pli a nc e wit h t h e st u d y pr ot oc ol or a p plic a bl e r e q uir e m e nts will b e 
r e p ort e d i n acc or d a nc e wit h l oc al p olic y.  
Sit e i niti ati o n at s u bsit es

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 2 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
At t h e ti m e of st u d y i niti ati o n at a s u bsit e, t h e c o or di n ati n g c e nt er m ulti-sit e c o or di n at or ( wit h a d diti o n al st aff 
as n e e d e d) will p erf or m a sit e i niti ati o n t el ec o nf er e nc e. D uri n g t his t el ec o nf er e nc e, t h e E m or y t e a m will r e vi e w 
t h e st u d y, e nr oll m e nt, r e p orti n g, a n d r e g ul at or y c o m pli a nc e. 
S u bsit e d at a c oll ecti o n
S u bsit e d at a m ust b e s u b mitt e d t o t h e c o or di n ati n g c e nt er m ulti-sit e c o or di n at or as o utli n e d i n t h e pr ot oc ol-
s p ecific m o nit ori n g pl a n. T h e pr ot oc ol-s p ecific m o nit ori n g pl a n will b e pr o vi d e d b y t h e c o or di n ati n g c e nt er m ulti-
sit e c o or di n at or t o ext er n al p artici p ati n g pri or t o sit e acti v ati o n. Acc ess t o t h e c o or di n ati n g c e nt er O n C or e 
d at a b as e will b e pr o vi d e d t o ext er n al p artici p ati n g sit es f or dir ect el ectr o nic d at a e ntr y. All d at a s u b mitt e d m ust 
b e acc o m p a ni e d b y s u p p orti n g s o urc e d oc u m e nts, w h er e a p plic a bl e a n d as o utli n e d i n t h e pr ot oc ol-s p ecific 
m o nit ori n g pl a n. All d at a m ust b e e nt er e d i n t h e ti m efr a m e r e q uir e d at e ac h sit e, b ut n o l at er t h a n 1 4 d a ys 
f oll o wi n g r e gistr ati o n a n d e ac h visit c o m pl eti o n. All q u eri es ar e t o b e r es ol v e d wit hi n 4 w e e ks of iss u e. T h e 
c o or di n ati n g c e nt er m ulti-sit e c o or di n at or will pr o vi d e O n C or e tr ai ni n g a n d r e q u est acc ess t o t h e a p pr o pri at e 
st aff at t h e p artici p ati n g sit e.
M o nt hl y i n v esti g at or c o nf er e nc e c alls
T h e s u bsit e r es e arc h c o or di n at ors will m ai nt ai n a s pr e a ds h e et w hic h will b e d e-i d e ntifi e d a n d will s u m m ariz e 
p ati e nt d at a f or s u bj ects acti v el y b ei n g tr e at e d o n t h e tri al w ell as a r o a d m a p d et aili n g p e n di n g t ests/tr e at m e nts 
f or e ac h i n di vi d u al s u bj ect. T h e s pr e a ds h e et will b e s h ar e d wit h t h e c o or di n ati n g c e nt er PI / I N D s p o ns or ( or 
d esi g n e e) vi a e- m ail. T el ec o nf er e nc es will b e c o n d uct e d at l e ast o nc e m o nt hl y b et w e e n t h e PI ( or d esi g n e e) at 
E m or y a n d t h e r es e arc h t e a m at t h e p artici p ati n g sit e(s). 
T h e p ur p os e of t h e m e eti n gs is t o disc uss t h e e nr oll m e nt, r e g ul at or y u p d at es, m o nit or t oxiciti es, a n d e v al u at e 
t h e pr o gr ess of t h e tri al. Sc h e d ul e d t el ec o nf er e nc es m a y st o p aft er all p ati e nts h a v e c o m pl et e d assi g n e d pr ot oc ol 
t h er a p y. T h e c o or di n ati n g c e nt er ( or d esi g n e e) will c o m m u nic at e wit h p artici p ati n g sit es vi a m o nt hl y e m ail. 
T h e mi n ut es fr o m t h e t el ec o nf er e nc e will b e m ai nt ai n e d i n t h e r e g ul at or y bi n d er f or t h e st u d y. I n a d diti o n 
el ectr o nic c o pi es will b e s e nt vi a e m ail t o t h e r es e arc h t e a ms at s u bsit e.  
M o nit ori n g
Cli nic al sit e m o nit ori n g is c o n d uct e d t o e ns ur e t h at t h e ri g hts a n d w ell- b ei n g of h u m a n s u bj ects ar e pr ot ect e d, 
t h at t h e r e p ort e d tri al d at a ar e acc ur at e, c o m pl et e, a n d v erifi a bl e, a n d t h at t h e c o n d uct of t h e tri al f oll o ws t h e 
c urr e ntl y a p pr o v e d pr ot oc ol/ a m e n d m e nt(s), wit h G C P, a n d wit h a p plic a bl e r e g ul at or y r e q uir e m e nt(s).
S u bsit e s elf- m o nit ori n g: T h e p artici p ati n g sit e will h a v e i nt er n al m o nit ori n g m e eti n gs. T h es e m e eti n gs w hic h will 
i ncl u d e t h e p artici p ati n g sit e i n v esti g at or ( or d esi g n e e), t h e cli nic al r es e arc h c o or di n at or a n d t h e r e g ul at or y 
aff airs c o or di n at or as a p plic a bl e, will m e et at l e ast o n a m o nt hl y b asis t o r e vi e w a n d disc uss st u d y d at a t o e ns ur e 
s u bj ect s af et y. C h art r evi e ws will b e p erf or m e d o n s el ect e d c as es b y p artici p ati n g sit e st aff t o c o nfir m t h at t h e 
d at a c oll ecti o n is acc ur at e r e g ar di n g st u d y c o n d uct, d at a c oll ecti o n, d oc u m e nt ati o n a n d c o m pl eti o n. 
C e ntr al m o nit ori n g: St u d y-s p ecific m o nit ori n g pl a ns ar e s p ecifi e d p er sit e, wit h t h e o nl y diff er e nc e b et w e e n sit es 
w h et h er t h e sit e s u b mits s o urc e d at a o n p a p er or pr o vi d es t h e c o or di n ati n g c e nt er m ulti-sit e t e a m r e m ot e acc ess 
t o t h at sit e’s l oc al el ectr o nic m e dic al r ec or d.  C e ntr aliz e d m o nit ori n g will occ ur mi ni m all y q u art erl y, n o m or e 
fr e q u e ntl y t h a n 
m o nt hl y. 
M o nit ori n g will b e c e ntr aliz e d, i ncl u di n g d at a r e p orti n g a n d r es e arc h s a m pl e 
ac q uisiti o n. T h e c o or di n ati n g c e nt er m ulti-sit e c o or di n at or will p erf or m o n-sit e a n d/ or r e m ot e m o nit ori n g visit 
wit hi n t h e first t hr e e m o nt hs of e nr oll m e nt of t h e first s u bj ect. Q u art erl y m o nit ori n g visits will occ ur ( o n sit e u p 
t o o nc e p er y e ar a n d at l e ast t hr e e ti m es r e m ot el y) u ntil s u bj ect f oll o w- u p is t er mi n at e d. M o nt hl y r e vi e ws of 
d at a will b e c o n d uct e d t o e ns ur e c o m pli a nc e or i d e ntif y discr e p a nci es; s p ecific all y, t o ass ess c o m pli a nc e wit h t h e 
pr ot oc ol, v erif y i nf or m e d c o ns e nt f or ms, v erif y c o m pli a nc e wit h S A E r e p orti n g pr oc e d ur es, m o nit or t h e tr ac ki n g 
of st u d y dr u g ( p h ar m ac y visit, st or a g e a n d acc o u nti n g of st u d y dr u g), r etri ev e r e g ul at or y d oc u m e nt ati o n, a n d 
p erf or m q u alit y c o ntr ol b y c o m p ari n g d at a fr o m t h e C R F t o t h e s o urc e d oc u m e nts of t h e c e nt er.
A u diti n g

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 3 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
F or sit es wit h a n a u diti n g m ec h a nis m i n pl ac e t h at ar e a bl e t o s h ar e d oc u m e nt ati o n of t h eir a u diti n g st a n d ar ds 
a n d pr oc ess es f oll o w e d, a n a gr e e m e nt m a y b e r e q u est e d f or t h e sit e t o p erf or m l oc al a u diti n g a n d pr o vi d e f or m al 
a u dit r e p orts t o t h e c o or di n ati n g c e nt er.
2 4.  R ef er e nc es
1. 
F erl a y J, S o erj o m at ar a m I, Di ks hit R, Es er S, M at h ers C, R e b el o M, P ar ki n D M, F or m a n D, Br a y F. C a nc er 
i nci d e nc e a n d m ort alit y w orl d wi d e: s o urc es, m et h o ds a n d m aj or p att er ns i n GL O B O C A N 2 0 1 2. I nt er n ati o n al 
j o ur n al of c a nc er. 2 0 1 5; 1 3 6( 5): E 3 5 9- 8 6. E p u b 2 0 1 4/ 0 9/ 1 6. d oi: 1 0. 1 0 0 2/ijc. 2 9 2 1 0. P u b M e d P MI D: 2 5 2 2 0 8 4 2.
2.  
Mitt al S, El- S er a g H B. E pi d e mi ol o g y of h e p at oc ell ul ar c arci n o m a: c o nsi d er t h e p o p ul ati o n. J Cli n 
G astr o e nt er ol. 2 0 1 3; 4 7 S u p pl: S 2- 6. d oi: 1 0. 1 0 9 7/ M C G. 0 b 0 1 3 e 3 1 8 2 8 7 2f 2 9. P u b M e d P MI D: 2 3 6 3 2 3 4 5; P M CI D: 
P M C 3 6 8 3 1 1 9.
3. 
Ll o v et J M, Br uix J. M ol ec ul ar t ar g et e d t h er a pi es i n h e p at oc ell ul ar c arci n o m a. H e p at ol o g y. 
2 0 0 8; 4 8( 4): 1 3 1 2- 2 7. d oi: 1 0. 1 0 0 2/ h e p. 2 2 5 0 6. P u b M e d P MI D: 1 8 8 2 1 5 9 1; P M CI D: P M C 2 5 9 7 6 4 2.
4. 
D u v o ux C, Ki uc hi T, P est al ozzi B, B us uttil R, Mi ks a d R. W h at is t h e r ol e of a dj u v a nt t h er a p y aft er li v er 
tr a ns pl a nt ati o n f or h e p at oc ell ul ar c arci n o m a ? Li v er tr a ns pl a nt ati o n : offici al p u blic ati o n of t h e A m eric a n 
Ass oci ati o n f or t h e St u d y of Li v er Dis e as es a n d t h e I nt er n ati o n al Li v er Tr a ns pl a nt ati o n S oci et y. 2 0 1 1; 1 7 S u p pl 
2( S u p pl 2): S 1 4 7- 5 8. E p u b 2 0 1 1/ 0 6/ 3 0. d oi: 1 0. 1 0 0 2/lt. 2 2 3 6 7. P u b M e d P MI D: 2 1 7 1 4 0 6 5; P M CI D: P M C 3 4 1 7 8 0 9.
5. 
A u K P, C h o k K S H. M ulti disci pli n ar y a p pr o ac h f or p ost-li v er tr a ns pl a nt r ec urr e nc e of h e p at oc ell ul ar 
c arci n o m a: A pr o p os e d m a n a g e m e nt al g orit h m. W orl d j o ur n al of g astr o e nt er ol o g y. 2 0 1 8; 2 4( 4 5): 5 0 8 1- 9 4. E p u b 
2 0 1 8/ 1 2/ 2 1. d oi: 1 0. 3 7 4 8/ wj g. v 2 4.i 4 5. 5 0 8 1. P u b M e d P MI D: 3 0 5 6 8 3 8 6; P M CI D: P M C 6 2 8 8 6 5 3.
6. 
d e' A n g elis N, L a n di F, C arr a M C, Az o ul a y D. M a n a g e m e nts of r ec urr e nt h e p at oc ell ul ar c arci n o m a aft er 
li v er tr a ns pl a nt ati o n: A s yst e m atic r e vi e w. W orl d j o ur n al of g astr o e nt er ol o g y. 2 0 1 5; 2 1( 3 9): 1 1 1 8 5- 9 8. E p u b 
2 0 1 5/ 1 0/ 2 7. d oi: 1 0. 3 7 4 8/ wj g. v 2 1.i 3 9. 1 1 1 8 5. P u b M e d P MI D: 2 6 4 9 4 9 7 3; P M CI D: P M C 4 6 0 7 9 1 6.
7. 
Y a n g Z, W a n g S, Ti a n X Y, Xi e Q F, Z h u a n g L, Li Q Y, C h e n C Z, Z h e n g S S. I m p act of tr e at m e nt m o d aliti es o n 
p ati e nts wit h r ec urr e nt h e p at oc ell ul ar c arci n o m a aft er li v er tr a ns pl a nt ati o n: Pr eli mi n ar y ex p eri e nc e. 
H e p at o bili ar y P a ncr e at Dis I nt. 2 0 2 0; 1 9( 4): 3 6 5- 7 0. E p u b 2 0 2 0/ 0 6/ 2 0. d oi: 1 0. 1 0 1 6/j. h b p d. 2 0 2 0. 0 6. 0 0 2. 
P u b M e d P MI D: 3 2 5 5 3 7 7 4.
8. 
Ll o v et J M, Ricci S, M azz af err o V, Hil g ar d P, G a n e E, Bl a nc J F, d e Oli v eir a A C, S a nt or o A, R a o ul JL, F or n er 
A, Sc h w artz M, P ort a C, Z e uz e m S, B ol o n di L, Gr et e n T F, G all e P R, S eitz J F, B or b at h I, H a ussi n g er D, Gi a n n aris T, 
S h a n M, M osc o vici M, V oli otis D, Br uix J. S or af e ni b i n a d v a nc e d h e p at oc ell ul ar c arci n o m a. T h e N e w E n gl a n d 
j o ur n al of m e dici n e. 2 0 0 8; 3 5 9( 4): 3 7 8- 9 0. E p u b 2 0 0 8/ 0 7/ 2 5. d oi: 1 0. 1 0 5 6/ N EJ M o a 0 7 0 8 8 5 7. P u b M e d P MI D: 
1 8 6 5 0 5 1 4.
9. 
Br uix J, Qi n S, M erl e P, Gr a nit o A, H u a n g Y H, B o d o k y G, Pr ac ht M, Y o k os u k a O, R os m or d uc O, Br e d er V, 
G er ol a mi R, M asi G, R oss PJ, S o n g T, Br o n o wic ki J P, Olli vi er- H o ur m a n d I, K u d o M, C h e n g AL, Ll o v et J M, Fi n n R S, 
L e B err e M A, B a u m h a u er A, M ei n h ar dt G, H a n G. R e g or af e ni b f or p ati e nts wit h h e p at oc ell ul ar c arci n o m a w h o 
pr o gr ess e d o n s or af e ni b tr e at m e nt ( R E S O R C E): a r a n d o mis e d, d o u bl e- bli n d, pl ac e b o-c o ntr oll e d, p h as e 3 tri al. 
L a nc et (L o n d o n, E n gl a n d). 2 0 1 7; 3 8 9( 1 0 0 6 4): 5 6- 6 6. E p u b 2 0 1 6/ 1 2/ 1 0. d oi: 1 0. 1 0 1 6/s 0 1 4 0- 6 7 3 6( 1 6) 3 2 4 5 3- 9. 
P u b M e d P MI D: 2 7 9 3 2 2 2 9.
1 0. 
El- K h o u eir y A B, S a n gr o B, Y a u T, Cr oc e nzi T S, K u d o M, Hs u C, Ki m T Y, C h o o S P, Tr oj a n J, W elli n g T H R, 
M e y er T, K a n g Y K, Y e o W, C h o pr a A, A n d ers o n J, D el a Cr uz C, L a n g L, N e el y J, T a n g H, D ast a ni H B, M el er o I. 
Ni v ol u m a b i n p ati e nts wit h a d v a nc e d h e p at oc ell ul ar c arci n o m a ( C h ec k M at e 0 4 0): a n o p e n-l a b el, n o n-
c o m p ar ati v e, p h as e 1/ 2 d os e esc al ati o n a n d ex p a nsi o n tri al. L a nc et (L o n d o n, E n gl a n d). 2 0 1 7; 3 8 9( 1 0 0 8 8): 2 4 9 2-
5 0 2. E p u b 2 0 1 7/ 0 4/ 2 5. d oi: 1 0. 1 0 1 6/s 0 1 4 0- 6 7 3 6( 1 7) 3 1 0 4 6- 2. P u b M e d P MI D: 2 8 4 3 4 6 4 8.
1 1. 
K u d o M, Fi n n R S, Qi n S, H a n K H, I k e d a K, Pisc a gli a F, B ar o n A, P ar k J W, H a n G, J ass e m J, Bl a nc J F, V o g el 
A, K o m o v D, E v a ns T RJ, L o p ez C, D utc us C, G u o M, S ait o K, Kr alj e vic S, T a m ai T, R e n M, C h e n g AL. L e n v ati ni b 
v ers us s or af e ni b i n first-li n e tr e at m e nt of p ati e nts wit h u nr es ect a bl e h e p at oc ell ul ar c arci n o m a: a r a n d o mis e d 

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 4 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
p h as e 3 n o n-i nf eri orit y tri al. L a nc et (L o n d o n, E n gl a n d). 2 0 1 8; 3 9 1( 1 0 1 2 6): 1 1 6 3- 7 3. E p u b 2 0 1 8/ 0 2/ 1 3. d oi: 
1 0. 1 0 1 6/s 0 1 4 0- 6 7 3 6( 1 8) 3 0 2 0 7- 1. P u b M e d P MI D: 2 9 4 3 3 8 5 0.
1 2. 
Z h u A X, K a n g Y K, Y e n CJ, Fi n n R S, G all e P R, Ll o v et J M, Ass e n at E, Br a n di G, Pr ac ht M, Li m H Y, R a u K M, 
M ot o m ur a K, O h n o I, M erl e P, D a ni el e B, S hi n D B, G er k e n G, B or g C, Hiri art J B, O k us a k a T, M ori m ot o M, Hs u Y, 
A b a d a P B, K u d o M. R a m ucir u m a b aft er s or af e ni b i n p ati e nts wit h a d v a nc e d h e p at oc ell ul ar c arci n o m a a n d 
i ncr e as e d al p h a-f et o pr ot ei n c o nc e ntr ati o ns ( R E A C H- 2): a r a n d o mis e d, d o u bl e- bli n d, pl ac e b o-c o ntr oll e d, p h as e 
3 tri al. T h e L a nc et O nc ol o g y. 2 0 1 9; 2 0( 2): 2 8 2- 9 6. E p u b 2 0 1 9/ 0 1/ 2 3. d oi: 1 0. 1 0 1 6/s 1 4 7 0- 2 0 4 5( 1 8) 3 0 9 3 7- 9. 
P u b M e d P MI D: 3 0 6 6 5 8 6 9.
1 3. 
Fi n n R S, Qi n S, I k e d a M, G all e P R, D ucr e ux M, Ki m T- Y, K u d o M, Br e d er V, M erl e P, K as e b A O, Li D, 
V err et W, X u D- Z, H er n a n d ez S, Li u J, H u a n g C, M ull a S, W a n g Y, Li m H Y, Z h u A X, C h e n g A-L. At ez oliz u m a b pl us 
B e v aciz u m a b i n U nr es ect a bl e H e p at oc ell ul ar C arci n o m a. N e w E n gl a n d J o ur n al of M e dici n e. 2 0 2 0; 3 8 2( 2 0): 1 8 9 4-
9 0 5. d oi: 1 0. 1 0 5 6/ N EJ M o a 1 9 1 5 7 4 5. P u b M e d P MI D: 3 2 4 0 2 1 6 0.
1 4. 
Y a u T, K a n g Y- K, Ki m T- Y, El- K h o u eir y A B, S a nt or o A, S a n gr o B, M el er o I, K u d o M, H o u M- M, M atill a A, 
T o v oli F, K n ox JJ, H e A R, El- R a y es B F, Ac ost a- Ri v er a M, N e el y J, S h e n Y, B acc a n C, Cr uz C M D, Hs u C. Ni v ol u m a b 
( NI V O) + i pili m u m a b (I PI) c o m bi n ati o n t h er a p y i n p ati e nts ( pts) wit h a d v a nc e d h e p at oc ell ul ar c arci n o m a 
( a H C C): R es ults fr o m C h ec k M at e 0 4 0. J o ur n al of Cli nic al O nc ol o g y. 2 0 1 9; 3 7( 1 5 _s u p pl): 4 0 1 2-. d oi: 
1 0. 1 2 0 0/J C O. 2 0 1 9. 3 7. 1 5 _s u p pl. 4 0 1 2.
1 5. 
Cl a vi e n P A, L es urt el M, B oss u yt P M, G or es GJ, L a n g er B, P erri er A. R ec o m m e n d ati o ns f or li v er 
tr a ns pl a nt ati o n f or h e p at oc ell ul ar c arci n o m a: a n i nt er n ati o n al c o ns e ns us c o nf er e nc e r e p ort. T h e L a nc et 
O nc ol o g y. 2 0 1 2; 1 3( 1): e 1 1- 2 2. E p u b 2 0 1 1/ 1 1/ 0 4. d oi: 1 0. 1 0 1 6/s 1 4 7 0- 2 0 4 5( 1 1) 7 0 1 7 5- 9. P u b M e d P MI D: 
2 2 0 4 7 7 6 2; P M CI D: P M C 3 4 1 7 7 6 4.
1 6. 
Pi ñ er o F, T h o m ps o n M, M arí n JI, Sil v a M. L e n v ati ni b as first-li n e t h er a p y f or r ec urr e nt h e p at oc ell ul ar 
c arci n o m a aft er li v er tr a ns pl a nt ati o n: Is t h e c urr e nt evi d e nc e a p plic a bl e t o t h es e p ati e nts ? W orl d J Tr a ns pl a nt. 
2 0 2 0; 1 0( 1 1): 2 9 7- 3 0 6. E p u b 2 0 2 0/ 1 2/ 1 5. d oi: 1 0. 5 5 0 0/ wjt. v 1 0.i 1 1. 2 9 7. P u b M e d P MI D: 3 3 3 1 2 8 9 1; P M CI D: 
P M C 7 7 0 8 8 7 7.
1 7. 
I n v er nizzi F, I a v ar o n e M, Z a v a gli a C, M azz a S, M a g gi U, C es ari ni L, A nt o n elli B, Air ol di A, M a ni ni M A, 
S a n gi o v a n ni A, R ossi G, D o n at o M F, S a v eri o B elli L, L a m p ertic o P. Ex p eri e nc e Wit h E arl y S or af e ni b Tr e at m e nt 
Wit h m T O R I n hi bit ors i n H e p at oc ell ul ar C arci n o m a R ec urri n g Aft er Li v er Tr a ns pl a nt ati o n. Tr a ns pl a nt ati o n. 
2 0 2 0; 1 0 4( 3): 5 6 8- 7 4. E p u b 2 0 1 9/ 0 9/ 1 4. d oi: 1 0. 1 0 9 7/t p. 0 0 0 0 0 0 0 0 0 0 0 0 2 9 5 5. P u b M e d P MI D: 3 1 5 1 7 7 8 1.
1 8. 
H uss a arts K, v a n D o or n L, Bi ns S, S pr e n g ers D, d e Br uij n P, v a n L e e u w e n R W F, K o ol e n SL W, v a n G el d er 
T, M at hijss e n R HJ. C o m bi ni n g S or af e ni b a n d I m m u n os u p pr essi o n i n Li v er Tr a ns pl a nt R eci pi e nts wit h 
H e p at oc ell ul ar C arci n o m a. P h ar m ac e utic als ( B as el, S witz erl a n d). 2 0 2 1; 1 4( 1). E p u b 2 0 2 1/ 0 1/ 1 4. d oi: 
1 0. 3 3 9 0/ p h 1 4 0 1 0 0 4 6. P u b M e d P MI D: 3 3 4 3 5 3 2 1; P M CI D: P M C 7 8 2 6 9 7 8.
1 9. 
K a n g S H, C h o H, C h o EJ, L e e J H, Y u SJ, Ki m YJ, Yi NJ, L e e K W, S u h K S, Y o o n J H. Effic ac y of S or af e ni b f or 
t h e Tr e at m e nt of P ost- Tr a ns pl a nt H e p at oc ell ul ar C arci n o m a R ec urr e nc e. J o ur n al of K or e a n m e dic al sci e nc e. 
2 0 1 8; 3 3( 4 5): e 2 8 3. E p u b 2 0 1 8/ 1 1/ 0 8. d oi: 1 0. 3 3 4 6/j k ms. 2 0 1 8. 3 3. e 2 8 3. P u b M e d P MI D: 3 0 4 0 2 0 4 8; P M CI D: 
P M C 6 2 0 9 7 6 9.
2 0. 
I a v ar o n e M, I n v er nizzi F, Cz a u d er n a C, S a n d uzzi- Z a m p ar elli M, B h o ori S, A m a d d e o G, M a ni ni M A, L ó p ez 
M F, A n d ers M, Pi nt er M, R o drí g u ez MJ B, Crist ó b al M R, S ot er as G A, Pi ñ er o F, Vill a ds e n G E, W ei n m a n n A, Cr es p o 
G, M azz af err o V, R e g n a ult H, Gi or gi o M, G o nz ál ez- Di é g u ez ML, D o n at o M F, V ar el a M, W ör ns M A, Br uix J, 
L a m p ertic o P, R ei g M. Pr eli mi n ar y ex p eri e nc e o n s af et y of r e g or af e ni b aft er s or af e ni b f ail ur e i n r ec urr e nt 
h e p at oc ell ul ar c arci n o m a aft er li v er tr a ns pl a nt ati o n. A m J Tr a ns pl a nt. 2 0 1 9; 1 9( 1 1): 3 1 7 6- 8 4. E p u b 2 0 1 9/ 0 8/ 0 1. 
d oi: 1 0. 1 1 1 1/ ajt. 1 5 5 5 1. P u b M e d P MI D: 3 1 3 6 5 1 7 7.
2 1. 
S u y a m a K, I w as e H. L e n v ati ni b: A Pr o misi n g M ol ec ul ar T ar g et e d A g e nt f or M ulti pl e C a nc ers. C a nc er 
c o ntr ol : j o ur n al of t h e M offitt C a nc er C e nt er. 2 0 1 8; 2 5( 1): 1 0 7 3 2 7 4 8 1 8 7 8 9 3 6 1. E p u b 2 0 1 8/ 0 7/ 2 4. d oi: 
1 0. 1 1 7 7/ 1 0 7 3 2 7 4 8 1 8 7 8 9 3 6 1. P u b M e d P MI D: 3 0 0 3 2 6 4 3; P M CI D: P M C 6 0 5 6 7 9 5.

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 5 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A P P E N DI X A
P E R F O R M A N C E S T A T U S C RI T E RI A
E C O G P erf or m a nc e St at us Sc al e
K ar n ofs k y P erf or m a nc e Sc al e
Gr a d e
D escri pti o ns
P erc e nt
D escri pti o n
1 0 0
N or m al, n o c o m pl ai nts, n o evi d e nc e of 
dis e as e.
0
N or m al acti vit y.  F ull y acti v e, a bl e t o 
c arr y o n all pr e- dis e as e p erf or m a nc e 
wit h o ut r estricti o n.
9 0
A bl e t o c arr y o n n or m al acti vit y; mi n or 
si g ns or s y m pt o ms of dis e as e.
8 0
N or m al acti vit y wit h eff ort; s o m e si g ns 
or s y m pt o ms of dis e as e.
1
S y m pt o ms,  
b ut  
a m b ul at or y.  
R estrict e d i n 
p h ysic all y str e n u o us 
acti vit y, b ut a m b ul at or y a n d a bl e t o 
c arr y o ut w or k of a li g ht or s e d e nt ar y 
n at ur e ( e. g. , li g ht h o us e w or k, offic e 
w or k).
7 0
C ar es f or s elf, u n a bl e t o c arr y o n n or m al 
acti vit y or t o d o acti v e w or k.
6 0
R e q uir es occ asi o n al assist a nc e, b ut is 
a bl e t o c ar e f or m ost of his/ h er n e e ds.
2
I n b e d < 5 0 % of t h e ti m e.  A m b ul at or y 
a n d c a p a bl e of all s elf-c ar e, b ut u n a bl e 
t o c arr y o ut a n y w or k acti viti es.  U p 
a n d a b o ut m or e t h a n 5 0 % of w a ki n g 
h o urs.
5 0
R e q uir es c o nsi d er a bl e assist a nc e a n d 
fr e q u e nt m e dic al c ar e.
4 0
Dis a bl e d, r e q uir es s p eci al c ar e a n d 
assist a nc e.
3
I n b e d > 5 0 % of t h e ti m e.  C a p a bl e of 
o nl y li mit e d s elf-c ar e, c o nfi n e d t o b e d 
or c h air m or e t h a n 5 0 % of w a ki n g 
h o urs.
3 0
S e v er el y  
dis a bl e d,  
h os pit aliz ati o n 
i n dic at e d.  D e at h n ot i m mi n e nt.
2 0
V er y sic k, 
h os pit aliz ati o n i n dic at e d. 
D e at h n ot i m mi n e nt.
4
1 0 0 %  
b e dri d d e n.  
  
C o m pl et el y 
dis a bl e d.  C a n n ot c arr y o n a n y s elf-
c ar e.  T ot all y c o nfi n e d t o b e d or c h air.
1 0
M ori b u n d, f at al pr oc ess es pr o gr essi n g 
r a pi dl y.
5
D e a d.
0
D e a d.
As p u blis h e d i n A m. J. Cli n. O nc ol.:  O k e n, M. M., Cr e ec h, R. H., T or m ey, D. C., H ort o n, J., D avis, T. E., Mc F a d d e n, E. T., 
C ar b o n e, P. P.: T oxicity A n d R es p o ns e Crit eri a Of T h e E ast er n C o o p er ativ e O nc ol o gy Gr o u p. A m J Cli n O nc ol 5: 6 4 9- 6 5 5, 
1 9 8 2. T h e E ast er n C o o p er ati v e O nc ol o g y Gr o u p, R o b ert C o mis M. D., Gr o u p C h air

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 6 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A P P E N DI X B  
Dr u g Di ar y
St u d y I D:
[Dr u g ] Pill Di ar y
 S u bj ect I niti als: _ _ _          S u bj ect I D: _ _ _ _ _                   C ycl e: _ _ _ _ _                                                                                                 
I nstr ucti o ns:
 
 
 
 
 
 
 
 
 
Pl a n n e d D ail y D os e:  _ _ m g
 
R E MI N D E R S:
1. 
2.
D a y
D at e 
Ti m e
# of T a bl ets t a k e n
C o m m e nts
1
 
 
 
2
 
 
 
3
 
 
 
4
 
 
 
5
 
 
 
6
 
 
 
7
 
 
 
8
 
 
 
9
 
 
 
1 0
 
 
 
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
2 3
2 4
2 5
2 6
2 7
2 8

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 7 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
 
R ec or d all m e dic ati o ns t a k e n d uri n g t his c ycl e f or e x a m pl e pr escri pti o ns a n d o v er t h e c o u nt er 
i ncl u di n g vit a mi ns.
Pl e as e si g n at t h e c o m pl eti o n of t his c ycl e a n d r et ur n wit h pill b ottl e t o t h e st u d y t e a m.
P ati e nt’s                     
Si g n at ur e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D at e _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
If y o u h a v e a n y q u esti o ns, pl e as e c all: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
N a m e 
of 
 M e dic ati o n
W h y di d y o u t a k e t h e 
m e dic ati o n ?
D at e
 M e dic ati o n
 St art e d
D at e  
M e dic ati o n 
St o p p e d

Pr ot oc ol Titl e : Wi ns hi p 5 3 8 1- 2 1: L e n v ati ni b i n R ec urr e nt H e p at oc ell ul ar C arci n o m a Aft er Li v er 
Tr a ns pl a nt ati o n   
P a g e 4 8 of 4 8
Pr ot oc ol V ersi o n: V ersi o n 7. 0; 1/ 1 4/ 2 0 2 5
A P P E N DI X C ( R E CI S T Crit eri a v. 1. 1)   
R E CI S T v ersi o n 1. 1 * will b e us e d i n t his st u d y f or ass ess m e nt of t u m or r es p o ns e. W hil e eit h er C T or M RI m a y b e 
utiliz e d, as p er R E CI S T 1. 1, C T is t h e pr ef err e d i m a gi n g t ec h ni q u e i n t his st u d y.
* As p u blis h e d i n t h e E ur o p e a n J o ur n al of C a nc er:
E. A. Eis e n h a u er, P. T h er ass e, J. B o g a erts, L. H. Sc h w artz, D. S ar g e nt, R. F or d, J. D a nc e y, S. Ar b uc k, S. 
G w yt h er, M. M o o n e y, L. R u bi nst ei n, L. S h a n k ar, L. D o d d, R. K a pl a n,
D. L ac o m b e, J. V er w eij. N e w r es p o ns e ev al u ati o n crit eri a i n s oli d t u m ors: R e vis e d R E CI S T g ui d eli n e ( v ersi o n 1. 1). 
E ur J C a nc er. 2 0 0 9 J a n; 4 5( 2): 2 2 8- 4 7.
A p p e n di x D C HIL D- P U G H CL A S SI FI C A TI O N 
C hil d P u g h Sc or e
Sc or e
P oi nts
C hil d- P u g h A
5- 6
C hil d P u g h B
7- 9
C hil d P u g h C
> 9
M e as ur e
1 p oi nt
2 p oi nts
3 p oi nts
Ascit es
A bs e nt
Sli g ht
M o d er at e
S er u m Al b u mi n ( g/ dL)
> 3. 5
2. 8- 3. 5
< 2. 8
S er u m bilir u bi n 
( m g/ dL)
< 2
2. 0- 3. 0
> 3
I N R or Pr ot hr o m bi n 
ti m e pr ol o n g ati o n
< 1. 7
< 4 s ec
1. 7- 2. 2
4- 6 s ec
> 2. 2
> 6 s ec
E nc e p h al o p at h y 
N o n e
Gr a d e I-II
Gr a d e III-I V
E nc e p h al o p at h y gr a d e: 

Gr a d e 0: n or m al c o nsci o us n ess, p ers o n alit y, n e ur ol o gic al ex a mi n ati o n, el ectr o e nc e p h al o gr a m

Gr a d e 1: r estl ess, sl e e p dist ur b e d, irrit a bl e/ a git at e d, tr e m or, i m p air e d h a n d writi n g, 5 c ps w a v es

Gr a d e 2: l et h ar gic, ti m e- dis ori e nt e d, i n a p pr o pri at e, ast erixis, at axi a, sl o w tri p h asic w a v es

Gr a d e 3: s o m n ol e nt, st u p or o us, pl ac e- dis ori e nt e d, h y p er acti v e r efl ex es, ri gi dit y, sl o w er w a v es

Gr a d e 4: u nr o us a bl e c o m a, n o p ers o n alit y/ b e h a vi or, d ec er e br at e, sl o w 2- 3 c ps d elt a acti vit y