A Prospective Randomized Clinical Trial on 90Yttrium Trans-arterial Radio-Embolization (TheraSphere®) vs. Standard of Care (Sorafenib) for the Treatment of Advanced Hepatocellular Carcinoma (HCC) With Portal Vein Thrombosis (PVT)
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Sponsor: Boston Scientific Corporation

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1  
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
Pr ot oc ol N u m b er:  
T S -1 0 4  
Pr ot oc ol S h ort Titl e:  
Y E S -P  
Pr ot oc ol N a m e:  
A  pr os p ecti v e  ra n d o miz e d  cli nic al  tri al  o n  9 0Y ttri u m  tr a ns-art eri al  r a di o -
E m b oliz ati o n  ( T h er a S p h er e ®)  vs.  S t a n d ar d  of  c ar e  (sor af e ni b ) f or  t h e  
tr e at m e nt  of  a d v a nc e d  H e p at oc ell ul ar  C arci n o m a  ( H C C)  wit h  P ort al  V ei n  
T hr o m b osis ( P V T)  
Gl o b al  S p o ns or:  
Bi oc o m p ati bl es U K Lt d  
C h a p m a n H o us e  
F ar n h a m B usi n ess P ar k  
W ey d o n L a n e, F ar n h a m  
S urr ey G U 9 8 QL, U K  
( Bi oc o m p ati bl es) 
Gl o b al Pri nci p al 
I n v esti g at ors 
 
 
 
 It al y
 
 
 
 
 
U S A  
M e dic al M o nit or:  
 
T h e or e m Cli nic al R es e arc h, I nc.  
3 5 Ni ekl a ns k a St.  
0 3- 9 5 4 W arsz a w a, P ol a n d  
D evic e:  
T h er a S p h er e ® , Yttri u m-9 0 Gl ass Micr os p h er es  
C E M ar k f or E U sit es o nl y  
C E 0 0 8 6  
H D E #  f or U S sit es o nl y: 
H D E H 9 8 0 0 0 6  
Pr ot oc ol D at e Acti v at e d:  
2 0 1 2/ 0 6 /2 2  ( Y Y Y Y/ M M/ D D) 
A m e n d m e nts:  
V ersi o n 1. 1  D at e d  2 0 1 2 /0 9 /2 8  
V ersi o n 2. 0 D at e d 2 0 1 3/ 0 9/ 1 3 
V ersi o n 3. 0 D at e d 2 0 1 4/ 0 8/ 0 8  
T his d oc u m e nt is t h e c o nfi d e nti al pr o p ert y of t h e S p o ns or.  N o p art of it m a y b e tr a ns mitt e d, r e pr o d uc e d, 
p u blis h e d, or us e d b y ot h er p ers o ns wit h o ut pri or writt e n a ut h oriz ati o n.  
T h er a S p h er e ® is a tr a d e m ar k of T h er a g e nics C or p or ati o n us e d u n d er lic e ns e b y B T G I nt er n ati o n al C a n a d a I nc. 
B T G a n d t h e B T G r o u n d el l o g o ar e tr a d e m ar ks of B T G I nt er n ati o n al Lt d, a n d ar e r e gist er e d tr a d e m ar ks i n t h e 
U S, E U a n d c ert ai n ot h er t errit ori es. All ri g hts r es er v e d.  
N C T #: N C T 0 1 8 8 7 7 1 7

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
P R O T O C OL  A P P R O V AL  A N D  R EL E A S E  SI G N A T U R E  P A G E  
 
Pr ot o c ol Titl e:  
A pr os p ecti v e r a n d o miz e d cli nic al tri al o n 9 0Y ttri u m tr a ns-art eri al 
r a di o-E m b oliz ati o n ( T h er a S p h er e ®) vs. S t a n d ar d of c ar e (s or af e ni b ) 
f or t h e tr e at m e nt of a d v a nc e d H e p at oc ell ul ar C arci n om a ( H C C) wit h 
P ort al V ei n T hr o m b osis ( P V T)  
Pr ot o c ol #:   
 
T S -1 0 4  
 
Pr ot o c ol A p pr o v al D at e:  
V er si o n 1. 0 2 0 1 2 -0 6 -0 7    ( Y Y Y Y/ M M/ D D)  
  
  
  
 
V er si o n 1. 1  2 0 1 2 - 0 9-2 3    
  
 
  
  
  
 
V er si o n 2. 0 2 0 1 3 -0 9 -1 3    
  
 
  
  
  
 
V er si o n 3. 0  2 0 1 4 -0 8 -0 8  
T h e a b o v e -r ef er e n c e d pr ot o c ol w a s r e vi e w e d a n d a p pr o v e d f or r el e a s e b y t h e f oll o wi n g:   
  
  
 
  
  
 
 
Pri n ci p al I n v e sti g at ors 
 
 
 
  
  
  
  
  
 
                      
  
  
 
                  
  
  
  
  
 
Si g n at ur e   
  
 
          D at e ( Y Y Y Y/ M M/ D D)  
 
 
 
 
  
  
  
  
  
 
                     
  
  
 
                  
  
  
  
  
 
Si g n at ur e   
  
 
          D at e ( Y Y Y Y/ M M/ D D)  
  
  
 
  
  
 
 
 
Bi o c o m p ati bl e s U K  Lt d.  
 
  
  
  
  
  
 
                      
  
  
 
                   
 
  
  
  
  
 
Si g n at ur e   
  
  
 
D at e ( Y Y Y Y/ M M/ D D)  
 
    
  
 
                     
  
  
 
                   
 
  
  
  
  
 
Si g n at ur e   
  
 
          D at e ( Y Y Y Y/ M M/ D D)  
 
 
 

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
3 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
INVESTIGATOR’S PROTOCOL REVIEW STATEMENT 
 
By my signature, I confirm that my staff and I have carefully read and understand the protocol, A 
prospective randomized clinical trial on 90Yttrium trans-arterial radio-Embolization (TheraSphere®) vs. 
Standard of care (sorafenib) for the treatment of advanced Hepatocellular Carcinoma (HCC) with Portal 
Vein Thrombosis (PVT), and agree to conduct the trial in accordance with the protocol, the appropriate 
regulations specified in the protocol, and the stipulations of the clinical study agreement 
 
 
__________________________________________ 
 
________________ 
Investigator  
 
 
 
 
 
Date (YYYY/MM/DD) 
 
__________________________________________ 
Investigator Printed Name 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
4  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
T A BL E O F C O N T E N T S  
P R O T O C O L A P P R O V A L A N D R E L E A S E SI G N A T U R E P A G E  ............................................................ 2  
I N V E S TI G A T O R’ S P R O T OC O L R E VI E W S T A T E M E N T  ...................................................................... 3  
T A B L E O F C O N T E N T S  ................................................................................................................................. 4  
1  
P R O T O C O L S Y N O P SI S  ........................................................................................................................ 7  
2  
T RI A L S C H E M A  ................................................................................................................................... 1 4  
3  
S C H E D U L E O F E V E N T S  .................................................................................................................... 1 5  
3. 1  
S C H E D U L E O F E V E N T S : C O N T R O L A R M  ............................................................................................ 1 5  
3. 1. 1  
R a n d o mize  ............................................................................................................................... 1 5  
3. 1. 2  
Pr o gressi o n  .............................................................................................................................. 1 5  
3. 1. 3  
E n d of St u dy  ............................................................................................................................ 1 5  
3. 2  
S C H E D U L E O F E V E N T S : T R E A T M E N T A R M  ........................................................................................ 1 6  
4  
LI S T O F A B B R E VI A TI O N S  ................................................................................................................ 1 7  
5  
B A C K G R O U N D A N D R A TI O N A L E  .................................................................................................. 1 9  
5. 1  
G E N E R A L D E VI C E D E S C RI P TI O N  ....................................................................................................... 1 9  
5. 2  
G L O B A L R E G U L A T O R Y S T A T U S O F T H E R A S P H E R E  ........................................................................... 1 9  
5. 3  
R A TI O N A L E F O R T H E T R E A T M E N T O F H E P A T O C E L L U L A R C A R CI N O M A  ............................................ 1 9  
6  
S T U D Y O B J E C TI V E S  .......................................................................................................................... 2 2  
7  
S T U D Y D E SI G N  .................................................................................................................................... 2 2  
8  
S T U D Y P O P U L A TI O N A N D E LI GI BI LI T Y  C RI T E RI A  ................................................................ 2 2  
8. 1  
E LI GI BI LI T Y C RI T E RI A ....................................................................................................................... 2 2  
9  
S T U D Y VI SI T S, E V A L U A TI O N S A N D P R O C E D U R E S  ................................................................. 2 3  
9. 1  
S T U D Y V I SI T S ................................................................................................................................... 2 4  
9. 1. 1  
Scree ni n g/ R a n d o miz ati o n ( D ays -1 4 t o D ay 0)  ........................................................................ 2 4  
9. 1. 2  
P atie nts r a n d o mize d t o t he C o ntr ol Ar m  .................................................................................. 2 4  
9. 1. 3  
P atie nts r a n d o mize d t o t he Tre at me nt Ar m  .............................................................................. 2 5  
9. 1. 4  
P atie nt C o m pleti o n or E arly Wit h dr a w al  ................................................................................. 2 7  
9. 2  
S T U D Y E V A L U A TI O N S A N D P R O C E D U R E S  ......................................................................................... 2 7  
9. 2. 1  
P ote nti ally Eli gi ble P atie nts a n d I nf or me d C o nse nt ................................................................ 2 7  
9. 2. 2  
De m o gr a p hics  .......................................................................................................................... 2 7  
9. 2. 3  
Me dic al Hist ory  ........................................................................................................................ 2 7  
9. 2. 4  
P hysic al Ex a mi n ati o n  ............................................................................................................... 2 8  
9. 2. 5  
Cl assific ati o n of P V T ................................................................................................................ 2 8  
9. 2. 6  
E C O G Perf or m a nce St at us ....................................................................................................... 2 8  
9. 2. 7  
C hil d P u g h St at us  ..................................................................................................................... 2 9  
9. 2. 8  
Me dic ati o n a n d Pri or Tre at me nt Hist ory  ................................................................................. 2 9  
9. 2. 9  
Liver T u m or V ol u me Deter mi n ati o n ......................................................................................... 2 9  
9. 2. 1 0  
Cli nic al L a bs  ........................................................................................................................... 2 9  
9. 2. 1 1  
Pre g n a ncy Test  ......................................................................................................................... 2 9  
9. 2. 1 2  
Revie w Eli gi bility Criteri a  ........................................................................................................ 3 0  
9. 2. 1 3  
H C C T u m or Bi o m arker ( A F P)  ................................................................................................. 3 0  
9. 2. 1 4  
P atie nt Re p orte d O utc o me  ....................................................................................................... 3 0  
9. 2. 1 5  
R a n d o miz ati o n ( D ay 0)  ............................................................................................................ 3 0  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
9. 2. 1 6  
St u dy Tre at me nts  ...................................................................................................................... 3 1  
9. 2. 1 7  
Effic acy I m a gi n g –  C T/ M RI ...................................................................................................... 3 8  
9. 2. 1 8  
St u dy Tre at me nt Me dic ati o n Rec or d  ........................................................................................ 3 8  
9. 2. 1 9  
C o nc urre nt Me dic ati o n Rec or d  ................................................................................................ 3 9  
9. 2. 2 0  
Defi niti o n of Pr o gressi o n F or P atie nt m a n a ge me nt Decisi o n -M aki n g  .................................... 3 9  
9. 2. 2 1  
St u dy c o m pleti o n  ...................................................................................................................... 3 9  
9. 2. 2 2  
P atie nt Wit h dr a w al ................................................................................................................... 3 9  
1 0  S T A TI S TI C S  .......................................................................................................................................... 3 9  
1 0. 1  
S A M P L E S I Z E E S TI M A T E  .................................................................................................................... 4 0  
1 0 . 2 
S T A TI S TI C A L A N A L Y SI S P L A N ........................................................................................................... 4 0  
1 0. 2. 1  
P o p ul ati o ns a n d S u b -Ar ms  ....................................................................................................... 4 0  
1 0. 2. 2  
Tri al E n d p oi nts  ......................................................................................................................... 4 0  
1 0. 2. 3  
Effic acy A n alysis  ...................................................................................................................... 4 1  
1 0. 2. 4  
S afety A n alysis  .......................................................................................................................... 4 3  
1 0. 2. 5  
Ot her A n alyses  ......................................................................................................................... 4 3  
1 0. 2. 6  
I n de pe n de nt D at a M o nit ori n g C o m mittee ................................................................................ 4 4  
1 1  D A T A C O L L E C TI O N A N D M A N A G E M E N T  .................................................................................. 4 4  
1 1. 1  
E L E C T R O NI C D A T A C O L L E C TI O N ( E D C) ........................................................................................... 4 4  
1 1. 2  
D A T A M A N A G E M E N T  ........................................................................................................................ 4 4  
1 2  A D V E R S E E V E N T S  .............................................................................................................................. 4 4  
1 2. 1  
D E FI NI TI O N S O F A E/ S A E  F O R D R U G S  ............................................................................................... 4 4  
1 2. 2  
D E FI NI TI O N S O F A D E/ S A D E/ U A D E  F O R D E VI C E S  ........................................................................... 4 5  
1 2. 3  
R E C O R DI N G A D V E R S E E V E N T S  ......................................................................................................... 4 6  
1 2. 3. 1  
C a us ality ( Rel ati o ns hi p t o Me dic al Device) Assess me nt  .......................................................... 4 6  
1 2. 4  
S U B MI T TI N G E X P E DI T E D S A F E T Y R E P O R T S  ...................................................................................... 4 6  
1 2. 5  
P E RI O DI C S A F E T Y R E P O R TI N G  .......................................................................................................... 4 7  
1 2. 6  
E X P E C T E D A D V E R S E E V E N T S ............................................................................................................ 4 7  
1 2. 6. 1  
T her a S p here A dverse Eve nt Pr ofile  ......................................................................................... 4 7  
1 2. 6. 2  
S or afe ni b A dverse Eve nt Pr ofile  .............................................................................................. 4 8  
1 3  I N V E S TI G A T O R A N D SI TE Q U A LI FI C A TI O N A N D O B LI G A TI O N S  ...................................... 4 8  
1 3. 1  
S T U D Y S I T E A N D IN V E S TI G A T O R Q U A LI FI C A TI O N  ............................................................................. 4 8  
1 3. 2  
IN S TI T U TI O N A L A P P R O V A L A N D D O C U M E N T A TI O N O F T H E P R O T O C O L  ............................................ 4 9  
1 3. 3  
R E G U L A T O R Y D O C U M E N T S  .............................................................................................................. 4 9  
1 3. 4  
S O U R C E R E C O R D S A N D S T U D Y D O C U M E N T A TI O N  ............................................................................ 5 0  
1 3. 5  
E T HI C A L C O N D U C T O F T H E S T U D Y  .................................................................................................... 5 1  
1 3. 6  
R E S P O N SI B L E C O N D U C T O F R E S E A R C H  ............................................................................................. 5 1  
1 3. 7  
IN F O R M E D C O N S E N T  ......................................................................................................................... 5 2  
1 3. 8  
P A TI E N T M E DI C A L R E C O R D S  ............................................................................................................. 5 2  
1 3. 9  
P A TI E N T P RI V A C Y A N D C O N FI D E N TI A LI T Y  ....................................................................................... 5 3  
1 3. 1 0  
A D DI TI O N A L IN V E S TI G A T O R R E S P O N SI BI LI TI E S  ............................................................................ 5 3  
1 4  P R O T O C O L D E VI A TI O N S  ................................................................................................................. 5 3  
1 5  P R O T O C O L VI O L A TI O N S ................................................................................................................. 5 4  
1 6  S T U D Y M O NI T O RI N G  ........................................................................................................................ 5 4  
1 7  S T U D Y T E R MI N A TI O N  ...................................................................................................................... 5 4  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
A P P E N DI C E S  ................................................................................................................................................ 5 6  
R E F E R E N C E S  ............................................................................................................................................... 6 0  
 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
7  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1  P R O T O C OL S Y N O P SI S  
Pr ot oc ol Titl e  
A pr os p ecti v e r a n d o miz e d cli nic al tri al o n 9 0Y ttri u m tr a ns-art eri al r a di o -E m b oliz ati o n 
(T h er a S p h er e ®)  vs.  S t a n d ar d  of  c ar e  (sor af e ni b ) f or  t h e  tr e at m e nt  of  a d v a nc e d  
H e p at oc ell ul ar C arci n o m a ( H C C) wit h P ort al V ei n T hr o m b osis ( P V T)  
T y p e of Pr ot oc ol  
P h as e III pr ot oc ol t o c oll ect effic ac y  a n d s af et y d at a  
Pr ot oc ol D esi g n  
T his is a t w o -ar m , o p e n-l a b el, pr os p ecti v e, m ulti-c e nt er, r a n d o miz e d, acti v e -c o ntr oll e d 
cli nic al tri al. 
St u d y  O bj ecti v e  
T o ass ess  effic ac y a n d s af et y of T h er a S p h er e  i n c o m p aris o n t o st a n d ar d of c ar e t h er a p y 
(s or af e ni b) i n t h e tr e at m e nt of p ati e nts wit h p ort al v ei n t hr o m b osis ass oci at e d wit h 
u nr es ect a bl e h e p at oc ell ul ar c arci n o m a. 
Pri m ar y E n d p oi nt  
O v er all S ur vi v al ( O S)  fr o m ti m e of r a n d o miz ati o n 
S ec o n d ar y E n d p oi nts  
•  
Ti m e t o pr o gr essi o n ( T T P) fr o m ti m e of r a n d o miz ati o n b as e d o n i n v esti g at or 
ass ess m e nt acc or di n g  t o R E CI S T v 1. 1   
•  
Ti m e t o pr o gr essi o n ( T T P) fr o m ti m e of r a n d o miz ati o n b as e d o n i n v esti g at or 
ass ess m e nt acc or di n g  t o m o difi e d R E CI S T  
•  
Ti m e t o pr o gr essi o n ( T T P) fr o m ti m e of r a n d o miz ati o n b as e d o n i n v esti g at or 
ass ess m e nt acc or di n g  t o E A SL r es p o ns e crit eri a  
•  
Ti m e t o w ors e ni n g of P V T  fr o m ti m e of r a n d o miz ati o n t o t h e ti m e of a n y 
c h a n g e i n t h e cl assific ati o n of P V T t y p e b y at l e ast o n e s u b-t y p e (s e e S ecti o n 
9. 2. 5 ) b as e d o n i n v esti g at or ass ess m e nt    
•  
Ti m e t o sy m pt o m atic pr o gr e ssi o n ( T T S P) fr o m t h e ti m e of r a n d o miz ati o n t o 
ass ess m e nt of E C O G p erf or m a nc e st at us ≥2  wit h or wit h o ut t u m or 
pr o gr essi o n b as e d o n i m a gi n g. D et eri or ati o n i n p erf or m a nc e st at us  is t o b e 
c o nfir m e d at o n e s u bs e q u e nt ev al u ati o n 8 w e ek s lat er.  
•  
T u m or r es p o ns e acc or di n g t o  R E CI S T v 1. 1  crit eri a b as e d o n i n v esti g at or 
ev al u ati o ns  
•  
T u m or r es p o ns e acc or di n g t o m o difi e d R E CI S T  crit eri a ba s e d o n i n v esti g at or 
ev al u ati o ns  
•  
T u m or r es p o ns e acc or di n g t o E A SL  r es p o ns e crit eri a b as e d o n i n v esti g at or 
ev al u ati o ns  
•  
P ati e nt r e p ort e d o utc o m e ( P R O) as ass ess e d b y t h e F u ncti o n al Ass ess m e nt of 
C a nc er T h er a p y –  H e p at o bili ar y Q u esti o n n air e (F A C T -H e p)  q u esti o n n air e  
•  
A d v ers e ev e nts  ( N CI-C T A E v 4 . 0) 
Tri al P o p ul ati o n  
P ati e nts di a g n os e d wit h p ort al v ei n t hr o m b osis ass oci at e d wit h u nr es ect a bl e a d v a nc e d 
H C C , w h o ar e n ot eli gi bl e f or a n y c ur ati v e pr oc e d ur e.  
N u m b er of p ati e nts  
A p pr oxi m at el y 3 2 0  p ati e nts r a n d o miz e d pl a n n e d, wit h u p t o a m axi m u m of 5 0 0  p ati e nts 
r a n d o miz e d b as e d o n s a m pl e siz e r e -esti m ati o n  
N u m b er of sit es  
U p t o 2 5  sit es i n E ur o p e , Asi a a n d N ort h A m eric a  
Pr ot oc ol Tr e at m e nts  
•  
T h e C o ntr ol ar m  will r ec ei v e st a n d ar d -of -c ar e ( S O C) t h er a p y s or af e ni b i n 
acc or d a nc e wit h t h e a p pr o v e d pr o d uct l a b eli n g.  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
8  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
•  
T h e Tr e at m e nt  ar m  will r ec ei v e T h er a S p h er e  i n acc or d a nc e wit h t h e a p pr o v e d 
pr o d uct l a b eli n g.    
St u d y D ur ati o n  
A p pr oxi m at el y  4 2   m o nt hs of accr u al a n d 1 y e ar a d diti o n al f oll o w -u p ar e pl a n n e d 
( wit h u p t o a m axi m u m of 7 2  m o nt hs of accr u al b as e d o n s a m pl e siz e r e -
esti m ati o n).  
Eli gi bilit y Crit eri a  
1.  P ati e nts o v er 1 8 y e ars of a g e, r e g ar dl ess of r ac e or g e n d er  
2.  A d v a nc e d st a g e H C C c o nfir m e d b y hist ol o g y ( m a n d at or y i n n o n cirr h otic p ati e nts) 
or n o n -i n v asi v e crit eri a ( E A SL/ A A SL D) wit h br a nc h P V T . 
o  
Eit h er  n aï v e or  r ec urr e nt H C C aft er c ur ati v e tr e at m e nt ( mi nim u m 3 m o nt hs fr o m 
c ur ati v e tr e at m e nt - mi n or r es ecti o n or  l oc al a bl ati o n) is acc e pt a bl e.  
o  
 Br a nc h P V T cl assifi e d as Ty p e I, Ty p e II or Ty p e III a  (s e e S ecti o n 9. 2. 5 ).  
3.  U nil o b ar dis e as e  as d efi n e d i n S ecti o n 8. 1 . 
4.  T u m or v ol u m e ≤ 7 0 % of li v er v ol u m e  (d et er mi n e d b y vis u al esti m ati o n)  
5.  C hil d -P u g h A  
6.  At l e ast o n e u ni -di m e nsi o n al H C C  t ar g et l esi o n ass ess a bl e acc or di n g t o t h e R E CI S T  
v 1. 1  crit eri a b y C T-sc a n or M RI 
7.  N o c o nfir m e d extr a h e p atic m et ast as es . P ati e nts wit h i n d et er mi n at e h e p atic hil ar 
l y m p h n o d es u p t o 2. 5 c m i n gr e at est di m e nsi o n, or wit h i n d et er mi n at e l u n g 
n o d ul es (si n gl e l esi o n b et w e e n 1 -1. 5c m, or m ulti pl e s m all er l esi o ns wit h a t ot al 
di a m et er ≤ 2 c m) m a y b e i ncl u d e d if  m et ast atic dis e as e is d e e m e d u nli k el y  
8.  N o  k n o w n  c o ntr ai n dic ati o ns  t o  st a n d ar d -of -c ar e  s or af e ni b  i ncl u di n g  all er gic  
r e acti o n, pill s w all o wi n g diffic ult y, u nc o ntr oll e d h y p ert e nsi o n or hist or y of c ar di ac 
dis e as e ( acc or di n g t o s or af e ni b p ac k a g e i ns ert a n d c o u ntry -s p ecific p olici es, m a y 
i ncl u d e e vi d e nc e of s ev er e or u nc o ntr oll e d syst e mic dis e as es, c ar di ac arr h yt h mi as 
(r e q uiri n g a nti-arr h yt h mic t h er a p y or p ac e m a k er), c o n g esti v e c ar di ac f ail ur e > N e w 
Y or k H e art Ass oci ati o n cl ass 2,  my oc ar di al i nf arct wit hi n 6 m o nt hs, pr ol o n g e d 
Q T/ Q Tc > 4 5 0 ms ), or l a b or at or y fi n di n g t h at i n t h e vi e w of t h e i n v esti g at or m a k es it 
u n d esir a bl e f or t h e p ati e nt t o p artici p at e i n t h e tri al  , si g nific a nt GI bl e e d wit hi n 3 0 
d a ys ,  r e n al f ail ur e r e q uiri n g di al ysis 
9.  N o evi d e nc e of h e p atic v ei n i n v asi o n or  c a v al t hr o m b osis  
1 0.  C a nc er -r el at e d sy m pt o ms wit hi n t h e E C O G 0-1 c at e g or y  
1 1.  PL T ≥ 5 0 x 1 0 3/ µL 
1 2.  W B C ≥ 1. 5 x 1 0
3/ µL  
1 3.  A S T/ AL T ≤ 5 ti m es t h e u p p er li mit of n or m al ( U/L)  
1 4.  Cr e ati ni n e ≤  2. 0 m g / dL  
1 5.  N o  evi d e nc e of p ul m o n ar y i ns uffici e nc y or cli nic all y evi d e nt c hr o nic o bstr ucti v e 
p ul m o n ar y dis e as e.  
1 6.  N o  i n dic ati o n  f or  a n y  p ossi bl e  c ur ati v e  tr e at m e nt  aft er  m ulti disci pli n ar y  
ass ess m e nt (s ur g er y, a bl ati o n, tr a ns pl a nt ati o n)  
1 7.  N o pr evi o us tr e at m e nt wit h S or af e n i b f or m or e t h a n 4 we e ks d uri n g t h e 2 pr evi o us 
m o nt hs ; n o pri or s or af e ni b-r el at e d t oxicit y at a n y d os e a n d/ or d ur ati o n d efi n e d as 
d oc u m e nt e d s or af e ni b -r el at e d gr a d e 3 or 4 a d v ers e e v e nts t h at l e d t o s or af e ni b 
disc o nti n u ati o n  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
9  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1 8.  N o  i niti ati o n  of 
a n y  ot h er  a nti -t u m or  t h er a p y  i ncl u di n g  c h e m ot h er a p y, 
r a di o e m b oliz ati o n ( m axi m u m l u n g s h u nt of 2 0 % f or pri or r a di o e m b oliz ati o n) or 
i n v esti g ati o n al dr u g tr e at m e nt wit hi n 3 0 d a ys b ef or e t h e b e gi n ni n g of t h e st u d y  
1 9.  I n c as e of p ati e nts pr o gr essi n g fr o m a n i nt er m e di at e t o a n a d v a nc e st a g e b ec a us e 
of occ urr e nc e of P V T, e nr ol m e nt is all o w e d if pr e vi o us c o n v e nti o n al or dr u g el uti n g 
T A C E w as p erf or m e d at l e ast 3  m o nt hs pri or t o scr e e ni n g p h as e  
2 0.  P ati e nts c a n n ot b e o n a li v er tr a ns pl a nt ati o n list  
2 1.  N o h ist or y of or g a n all o gr aft 
2 2.  N o co ntr ai n dic ati o n t o a n gi o gr a p h y or s el ecti v e visc er al c at h et eriz ati o n  
2 3.  N o h ist or y of s e v er e all er g y or i nt ol er a nc e t o c o ntr ast a g e nts, n arc otics, s e d ati v es 
or atr o pi n e t h at c a n n ot b e m a n a g e d m e dic all y  
2 4.  N o p r evi o us ext er n al b e a m r a di ati o n tr e at m e nt t o t h e liv er  
2 5.  N o e vi d e nc e of  c o nti n ui n g a d v ers e eff ect of pri or t h er a p y  
2 6.  N o a cti v e GI bl e e di n g a n d a n y bl e e di n g di at h esis or c o a g ul o p at h y t h at is n ot 
c orr ect a bl e b y us u al t h er a p y or h e m ost atic a g e nts ( e. g., cl os ur e d e vic e)  
2 7.  N o evi d e nc e of a n y dis e as e or c o n diti o n t h at w o ul d pl ac e t h e p ati e nt at u n d u e risk 
a n d pr ecl u d e s af e us e of micr os p h er es ( T h er a S p h er e ®) tr e at m e nt  
2 8.  N e g ati v e  s er u m pr e g n a nc y t est i n f e m al es of c hil d-b e ari n g p ot e nti al ; p ati e nts w h o 
ar e br e ast -f e e di n g c a n n ot p artici p at e i n t his tri al 
2 9.  Lif e ex p ect a nc y of gr e at er t h a n 3 m o nt hs  
3 0.  N o p artici p ati o n i n c o nc urr e nt i nt er v e nti o n al cli nic al tri als  
3 1.  Si g n e d i nf or m e d c o ns e nt f or m  
I m a gi n g 
R e q uir e m e nts  
•  
Tri pl e P h as e C T a b d o m e n/ p el vis  –  p erf or m e d wit h c uts of 1 0 m m or l ess i n slic e 
t hic k n ess c o nti g u o usl y i n t h e axi al pl a n e . T o ass ess dis e as e ext e nsi o n a n d t o 
d et er mi n e li v er v ol u m e m e as ur e m e nt  a n d  i d e ntify h e p atic v asc ul ar a n at o my. 
•  
S pir al C T C h est  – ( wit h c o ntr ast m e di a i n c as e of C T a b d o m e n/ p el vis a n d wit h o ut 
c o ntr ast m e di a i n c as e of M RI a b d o m e n/ p el vis) p erf or m e d wit h c uts of 1 0 m m or 
l ess i n slic e t hic k n ess c o nti g u o usl y i n t h e axi al pl a n e. T o ass ess ext r a-h e p atic 
l esi o ns acc or di n g t o t h e R E CI S T crit eri a v 1. 1. 
•  
M RI c a n r e pl ac e C T sc a ns  a b d o m e n/ p el vis ; h o w ev er, t h e s a m e i m a gi n g m o d alit y 
s h o ul d b e us e d  f or all i m a g es i n a n i n di vi d u al p ati e nt t hr o u g h o ut t h e st u d y  
•  
H e p atic a n gi o gr a p h y a n d 9 9 m T C -M A A  –  s el ecti v e c eli ac a n d s u p eri or m es e nt eric 
art eri o gr a ms ar e n e e d e d t o e v al u at e t h e h e p atic art eri al a n at o my f or t h e w h ol e 
li v er, as w ell as e v al u ati o n of p ot e nti al s o urc es of extr a-h e p atic bl o o d s u p pl y t o 
t u m ors. R e p e at 9 9 mT C -M A A  m a y b e n e e d e d t o esti m at e c u m ul ati v e l u n g s h u nt or 
r e-ass es GI fl o w.  
•  
B o n e sci nti gr a p h y t o ass ess m et ast atic dis e as e i n p ati e nts wit h A F P > 4 0 0 n g/ mL  
•  
S P E C T i m a gi n g m a y b e p erf or m e d acc or di n g t o st a n d ar d of c ar e pr actic es f or 
cli nic al m a n a g e m e nt b ut is n ot a st u d y r e q uir e m e nt.  
S a m pl e Siz e 
C alc ul ati o n  a n d 
St atistic al Pl a n  
T his st u d y is  a n a d a pti v e tri al usi n g a gr o u p s e q u e nti al d esi g n  wit h o v er all s ur vi v al ( O S) 
as t h e pri m ar y effic ac y e n d p oi nt . 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
T h e st u d y is d esi g n e d  t o  d et ect  a  4 m o nt hs i ncr e as e i n  m e di a n  O S ti m e,  fr o m a n 
a ntici p at e d v al u e of 9 . 0 m o nt hs i n t h e s or af e ni b ar m t o 1 3 . 0 m o nt hs  i n t h e T h er a S p h er e  
ar m  (i e, h az ar d r ati o = 0. 6 9 ), usi n g a l o g r a n k t est.   D u e t o u nc ert ai nt y i n t h e ex p ect e d 
tr e at m e nt eff ect, a s a m pl e siz e r e-esti m ati o n is pl a n n e d, w hic h w o ul d all o w t h e s a m pl e 
siz e t o i ncr e as e t o d et ect a 3  m o nt h i m pr o v e m e nt i n m e di a n O S  i n t h e T h er a S p h er e ar m 
as c o m p ar e d t o t h e c o ntr ol ar m (i e, H R = 0. 7 5).  
A  m axi m u m of 2 5 0  d e at hs will yi el d 8 0 % p o w er t o d et ect t h e t ar g et diff er e nc e i n m e di a n 
O S (h az ar d r ati o =  0. 6 9 ) wit h a t w o-si d e d al p h a of 0. 0 5 usi n g a gr o u p s e q u e nti al d esi g n 
wit h 2 i nt eri m a n al ys es . It is esti m at e d t h at a m axi m u m of 3 2 0  p ati e nts will n e e d t o b e 
r ecr uit e d o v er 4 2  m o nt hs, wit h a 1 y e ar a d diti o n al f oll o w -u p p eri o d.  T his i ncl u d es a n 
a dj ust m e nt t o t a k e acc o u nt of a n ass u m e d 5 % of p ati e nts w h o will b e l ost t o f oll o w -u p 
a n d f or w h o m a d at e of d e at h is n ot r ec or d e d.  
A n al ysis of pri m ar y e n d p oi nt  
O S will b e c o m p ar e d b et w e e n tr e at m e nt ar ms usi n g a lo g -r a n k t est.  T h e h az ar d r ati o 
a n d c orr es p o n di n g t w o -si d e d 9 5 % c o nfi d e nc e i nt er v al (CI) f or t h e tr e at m e nt eff ect will 
b e c o m p ut e d.  K a pl a n -M ei er c ur v es will als o b e pr o d uc e d.  
I nt eri m a n al ys e s of pri m ar y e n d p oi nt : T h e first i nt eri m a n al ysis will b e p erf or m e d w h e n 
a p pr oxi m at el y, b ut n o l ess t h a n,  1 2 5  d e at hs  h a v e occ urr e d, wit h a t w o-si d e d p-v al u e 
≤0. 0 1 7 7  all o wi n g t h e st u d y t o b e st o p p e d e arl y f or effic ac y .  A s ec o n d i nt eri m a n al ysis 
will b e p erf or m e d w h e n a p pr oxi m at el y, b ut n o l ess t h a n,  1 8 8  d e at hs  h a v e occ urr e d , wit h 
a t w o-si d e d p-v al u e ≤0. 0 2 2 8  all o wi n g t h e st u d y t o b e st o p p e d e arl y f or effic ac y .  A 
co n diti o n al p o w er of l ess t h a n or e q u al t o 1 5 % at e ac h of t h e i nt eri m a n al ys es will r es ult 
i n t h e st u d y st o p pi n g e arl y f or f utilit y. 
S a m pl e siz e m o dific ati o n will b e c o nsi d er e d at t h e s ec o n d i nt eri m a n al ysis f oll o wi n g t h e 
a p pr o ac h d escri b e d i n M e ht a & P oc oc k ( 2 0 1 1 ) , w hic h e m pl o ys a n u n -w ei g ht e d t est 
st atistic at t h e fi n al a n al ysis as r ec o m m e n d e d b y B ur m a n & S o n n es o n ( 2 0 0 6).  
Fi n al a n al ysis  of pri m ar y e n d p oi nt :  T h e fi n al a n al ysis, wit h o ut a s a m pl e siz e m o dific ati o n , 
will b e p erf or m e d w h e n a p pr oxi m at el y, b ut n o l ess t h a n,  2 5 0  d e at hs  h a v e occ urr e d .  A 
t w o-si d e d p-v al u e ≤0. 0 3 2 2  is r e q uir e d t o d ecl ar e a st atisticall y si g nific a nt i m pr o v e m e nt 
i n m e di a n O S at t h e fi n al a n al ysis . 
If t h e s a m pl e siz e is i ncr e as e d aft er t h e s ec o n d i nt eri m a n al ysis, t h e fi n al a n al ysis will b e 
p erf or m e d w h e n a p pr oxi m at el y, b ut n o l ess t h a n,  4 3 0  d e at hs  h a v e occ urr e d , w hic h will 
r es ult i n 8 0 % p o w er t o d et ect a n i m pr o v e m e nt i n m e di a n O S fr o m 9  t o 1 2  m o nt hs usi n g 
a l o g r a n k t est wit h a fi n al t w o-si d e d al p h a of 0. 03 2 2 . 
A n al ysis of s ec o n d ar y effic ac y e n d p oi nts  
C o m p aris o n b et w e e n tr e at m e nt gr o u ps f or all s ec o n d ar y e n d p oi nt s will b e c o n d uct e d at 
t h e fi n al a n al ysis wit h a t w o -si d e d al p h a of 0. 0 5. 
Ti m e t o e v e nt e n d p oi nts (i e, T T P, T T S P, Ti m e t o w ors e ni n g of P V T ) will b e c o m p ar e d 
b et w e e n tr e at m e nt ar ms usi n g a l o g -r a n k t est.  T u m or r es p o ns e r at es will b e c o m p ar e d  
b et w e e n tr e at m e nt ar ms usi n g t h e  c o nti n uit y a dj ust e d N e wc o m b e -Wils o n t est .  T h e 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
F A C T -H e p sc or e will b e c o m p ar e d b et w e e n tr e at m e nt ar ms usi n g a mix e d li n e ar m o d el 
wit h b as eli n e sc or e  a n d t h e r el ati v e ti m e fr o m b as eli n e as c o v ari at es.  
S af et y A n al ysis : All p ati e nts w h o r ec ei v e d st u d y tr e at m e nts at l e ast o nc e will b e i ncl u d e d 
i n t h e s af et y a n al ysis. All a d v ers e ev e nts will b e r e p ort e d acc or di n g t o t h e N ati o n al 
C a nc er I nstit ut 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 v 4. 0 ( C T C A E)  gr a d es 
a n d  c o d e d  u si n g t h e M e dic al  Dicti o n ar y  f or  R e g ul at or y  Acti viti es  ( M e d D R A ).  T h e  
i nci d e nc e of tr e at m e nt-e m er g e nt a d v ers e e v e nts ( e v e nts w hic h w er e n ot pr es e nt at 
b as eli n e or w ors e n e d i n s e v erit y f oll o wi n g t h e st art of tr e at m e nt) will b e s u m m ariz e d 
acc or di n g t o M e d D R A p ri m ar y syst e m-or g a n cl ass ( S O C) a n d pr ef err e d t er m . L a b or at or y 
v al u es will b e s u m m ariz e d b y tr e at m e nt gr o u p o v er ti m e a n d o v er all.  
P o ol a bilit y a n d Ot h er A n al ysis:  M ulti v ari at e C ox r e gr essi o n a n al ysis of ti m e -t o-ev e nt 
effic ac y e n d p oi nts will b e c o n d uct e d o n str atific ati o n crit eri a a n d ot h er f act ors s uc h as 
a g e, g e n d er, d ur ati o n of dis e as e pri or t o r a n d o miz ati o n.  
As a s e nsiti vit y a n al ysis, t o a d dr ess t h e p o ol a bilit y of d at a acr oss r e gi o ns (i e, E ur o p e , 
N ort h A m eric a , Asi a), st u d y sit es a n d g e n d er, a C ox r e gr essi o n a n al ysis of t h e pri m ar y 
effic ac y e n d p oi nt, O S, will b e c o n d uct e d wit h f act ors of r e gi o n, st u d y sit e a n d g e n d er, 
a n d t o d et er mi n e t h e i m p act of t h es e f act ors o n O S.  N ot e: r e gi o n a n d st u d y sit e will n ot 
b e i ncl u d e d si m ult a n e o usl y i n t h e m o d el d u e t o c olli n e arit y.  
S h o ul d t h e i m p act of r e gi o n, sit e or g e n d er o n O S b e st atistic all y a n d cli nic all y r el e v a nt, 
t h e r e as o ns f or t h e o bs er v e d diff er e nti al tr e at m e nt eff ect, s uc h as p ati e nt d e m o gr a p hic 
or cli nic al c h ar act eristics, will b e i n v esti g at e d a n d r e p ort e d.   If t h e p o ol a bilit y of O S 
r es ults ar e i n dir ect q u esti o n as a r es ult of t his s e nsiti vit y a n al ysis, t h e pri m ar y e n d p oi nt 
( O S) will als o b e a n al yz e d s e p ar at el y b y r e gi o n, sit e or g e n d er.   
Scr e e ni n g P eri o d  
T h e f oll o wi n g scr e e ni n g a n d e nr oll m e nt e v al u ati o ns s h o ul d b e p erf or m e d  wit hi n 1 4 d a ys 
pri or t o r a n d o miz ati o n : (  
•  
I C F ( b ef or e a n y st u d y r e q uir e d t ests ar e p erf or m e d, i m a g es a n d t est r es ults 
o bt ai n e d f or cli nic al p ati e nt m a n a g e m e nt wit hi n  t h e n u m b er of d a ys b ef or e  
r a n d o miz ati o n s p ecifi e d i n S ecti o n 9. 1. 1  a n d b ef or e si g ni n g of 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 ass ess m e nt ),  
•  
D e m o gr a p hics  
•  
P h ysic al ex a mi n ati o n  
•  
M e dic al hist or y  
•  
C at e g o riz ati o n of  P V T b as e d o n d y n a mic i m a gi n g st u di es  
•  
C hil d -P u g h ass ess m e nt of c hr o nic li v er dis e as e  
•  
E C O G P erf or m a nc e St at us ass ess m e nt  
•  
A b d o m e n/ p el vis s pir al C T / M RI t o ass ess li v er t u m or pr es e nt ati o n, c alc ul at e 
li v er v ol u m e a n d ass ess t u m or b ur d e n i n t h e li v er. 
•  
C h est C T t o r ul e o ut extr a -h e p atic m et ast as es  
•  
B o n e sci nti gr a p h y  if A F P > 4 0 0 n g/ mL  
•  
B as eli n e F A C T -H e p  P ati e nt R e p ort e d O utc o m e  q u esti o n n air e  
•  
R e q uir e d l a b or at or y bl o o d w or k pl us alf a p h et o pr ot ei n  ( A F P) 
T h e d at e of scr e e ni n g is t h e d at e all scr e e ni n g pr oc e d ur es ar e c o m pl et e d.  
R a n d o miz ati o n  
U p o n  m e eti n g  eli gi bilit y  f or  st u d y  p artici p ati o n  i n  acc or d a nc e  wit h  t h e  
I ncl usi o n/ Excl usi o n crit eri a, pati e nts will b e r a n d o miz e d 1: 1  t o Tr e at m e nt a n d C o ntr ol 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 2  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
Ar ms .  I n  or d er  t o  b al a nc e  t h e  tr e at m e nt  ar m s,  p ati e nts will  b e  str atifi e d  at  
r a n d o miz ati o n o n t h e b asis of  
•  
S er u m l ev el of alf a p h et o p r ot ei n ( A F P) (≤ 4 0 0 n g/ ml  vs > 4 0 0 n g/ ml )  
•  
P artici p ati n g tri al  sit e 
C o ntr ol Ar m  St u d y 
Tr e at m e nt( S or af e ni b)  
All p ati e nts r a n d o miz e d t o t h e C o ntr ol ar m  s h o ul d st art tr e at m e nt wit h st a n d ar d of c ar e 
s or af e ni b wit hi n 2 w e eks fr o m r a n d o miz ati o n. 
P ati e nt s will  f oll o w  st a n d ar d  d osi n g  f or  s or af e ni b  acc or di n g  t o  t h e  pr o d uct  l a b el  
i nf or m ati o n as pr escri b e d b y t h e i n v esti g at or. M e dic all y a p pr o pri at e d os e a dj ust m e nts  
a n d dr u g h o li d ays d u e t o  a d v ers e e v e nts a n d t oxicit y  ar e all o w a bl e . 
Tr e at m e nt  Ar m  St u d y 
Tr e at m e nt  
(T h er a S p h er e ) 
W it hi n 2 w e eks fr o m r a n d o miz ati o n, h e p atic a n gi o gr a p h y will b e p erf or m e d t o ass ess 
h e p atic v asc ul ar a n at o my a n d t u m or h y p er v asc ul arit y, f oll o w e d b y a 9 9 mTc -M A A sc a n t o 
r ul e-o ut  g astr oi nt esti n al  fl o w  or  u n acc e pt a bl e  l u n g  s h u nti n g.  E m b oliz ati o n  m a y  b e  
p erf or m e d,  if  n ec ess ar y,  t o  cl os e  off  g astr oi nt esti n al  fl o w  or  t o  p erf or m  t u m or  
r e distri b uti o n s o t h at t h e p ati e nt c a n m e et eli gi bilit y crit eri a.  
P ati e nts wil l n ot b e eli gi bl e f or T h er a S p h er e  i nf usi o n if t h e p ot e nti al r a di ati o n d os e t o 
t h e l u n gs exc e e ds 3 0 Gy f or a si n gl e tr e at m e nt or c u m ul ati v e 5 0 Gy or  e m b oliz ati o n 
c a n n ot b e p erf or m e d t o eff ecti v el y bl oc k GI bl o o d fl o w fr o m t h e h e p atic art eri al syst e m.  
If r adi ati o n ex p os ur e t o t h e l u n gs exc e e ds 3 0 Gy, d os e r e d ucti o n of T h er a S p h er e is 
p er mitt e d ( mi ni m u m d os e all o w e d is 8 0 Gy ± 1 0 %).   T h es e p ati e nts will b e eli gi bl e t o 
r ec ei v e s or af e ni b S O C t h er a p y a n d will  b e i n cl ud e d i n t h e Tr e at m e nt Ar m  I nt e nt-t o-Tr e at 
a n al y sis, b ut n ot i n t h e Tr e at m e nt Ar m  P er -Pr ot oc ol a n al ysis.  
T h er a S p h er e  Tr e at m e nt :   T h er a S p h er e  tr e at m e nt s h o ul d  occ ur  wit hi n  2 8  d a ys  of  
r a n d o miz ati o n. T h e n u m b er of i nf usi o ns r e q uir e d t o ac hi ev e l o b ar tr e at m e nt will b e 
d et er mi n e d b y t h e I n v esti g at or, b as e d o n t h e h e p atic v asc ul ar a n at o my.   
P ati e nts will r ec ei v e T h er a S p h er e, at a d os e c o nsist e nt wit h t h e a p pr o v e d pr o d uct l a b el , 
t o t h e tr e at e d l o b e of t h e li v er. A t ar g et d os e of 1 2 0 Gy ± 1 0 % is a d vis e d.T h er a S p h er e  
R e -tr e at m e nt: R e -tr e at m e nt of t h e s a m e p ati e nt/l o b e wit h f urt h er c ycl es of T h er a S p h er e  
is p er mitt e d if a tr e at a bl e pr o gr essi o n is d et ect e d d uri n g f oll o w-u p ev al u ati o ns. A n y r e -
tr e at m e nt s h o ul d t a k e pl ac e at l e ast 2 8 d a ys fr o m t h e l ast T h er a S p h er e  tr e at m e nt 
a d mi nist er e d  t o  t h at  l o b e.   P ati e nts  c a n  r ec ei v e  a  s u bs e q u e nt  T h er a S p h er e  
a d mi nistr ati o n  i n  t h e  a bs e nc e  of  r a di ol o gic al  pr o gr essi o n  crit eri a  at  i n v esti g at or  
discr eti o n . P ati e nts  m ust  m e et  i niti al  eli gi bilit y  crit eri a  t o  r ec ei v e  s u bs e q u e nt  
tr e at m e nts. A m axi m u m of t hr e e ( 3) T h er a S p her e a d mi nistr ati o ns ar e p er mitt e d i n t ot al . 
St u d y Visits a n d 
F oll o w -u p  
St u d y visits t h at t a k e pl ac e aft er t h e scr e e ni n g/r a n d o miz ati o n p eri o d s h o ul d occ ur wit hi n 
+/ - 7 d a ys of t h e d esi g n at e d ti m e i nt er v al f or t h at st u d y visit.  
Scr e e ni n g e v al u ati o ns  will b e c o m pl et e d wit hin 1 4 d a ys pri or t o r a n d o miz ati o n . Im a g es 
a n d t est r es ults o bt ai n e d f or cli nic al p ati e nt m a n a g e m e nt a n d b ef or e si g ni n g of i nf or m e d 
c o ns e nt d o n ot n e e d t o b e r e p e at e d a n d m a y b e us e d f or scr e e ni n g ass ess m e nt  pr o vi d e d 
i m a g es w er e t a k e n wit hi n 2 8 d a ys a n d t ests c o n d uct e d wit hi n 1 4 d a ys of r a n d o miz ati o n . 
T h es e e v al u ati o ns will b e t h e b as eli n e v al u es f or p ati e nts r a n d o miz e d t o t h e tri al.  
F or p ati e nts r a n d o miz e d t o  St a n d ar d of c ar e  S or af e ni b , st u d y visits will t a k e pl ac e at l e ast 
o nc e ev er y 4  w e eks u ntil pr o gr essi o n  t h e n ev er y 8 w e eks f or as l o n g as t h e p ati e nt 
r e m ai ns o n t h e tri al.  A d diti o n al p ati e nt cli nic al m a n a g e m e nt visits m a y b e sc h e d ul e d 
b et w e e n Q 4  w e ek visits as n e e d e d w h e n i niti ati n g s or af e ni b tr e at m e nt, t o m a n a g e a n y 
a d v ers e ev e nts  a n d a dj ust m e nts of s or af e ni b d osi n g or t o a d h er e t o l oc al st a n d ar d of 
c ar e tr e at m e nt r e q uir e m e nts.  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 3  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
F or  P ati e nts  r a n d o miz e d  t o  T h er a S p h er e ,  t h e  pr e-tr e at m e nt  e v al u ati o ns  a n d  
T h er a S p h er e  tr e at m e nt  s h o ul d  t a k e  pl ac e  wit hi n  t h e  first  4  w e eks  f oll o wi n g  
r a n d o miz ati o n. Aft er T h er a S p h er e  tr e at m e nt, s u bs e q u e nt st u d y visits will t a k e pl ac e at 
l e ast o nc e e v er y 4  w e eks fr o m r a n d o miz ati o n u ntil pr o gr essi o n  t h e n e v er y 8 w e e ks 
t h er e aft er. 
R e -tr e at m e nt of t h e s a m e p ati e nt/t u m or wit h f urt h er c ycl es of T h er a S p h er e  is all o w e d 
i n c as e of d et ecti o n d uri n g f oll o w-u p of a still tr e at a bl e t u m or pr o gr essi o n.  P ati e nts c a n 
r ec ei v e  a  s u bs e q u e nt  T h er a S p h er e  a d mi nistr ati o n  i n  t h e  a bs e nc e  of  r a di ol o gic al  
pr o gr essi o n crit eri a at i n v esti g at or discr eti o n P ati e nts m ust m e et i niti al  eli gi bilit y crit eri a 
t o r ec ei v e s u bs e q u e nt tr e at m e nts. A m axi m u m of t hr e e ( 3) T h er a S p h er e a d mi nistr ati o ns 
ar e p er mitt e d i n t ot al  
 
F oll o w -u p visits  f or r es p o ns e ass ess m e nt: I n b ot h ar ms , t h e first f oll o w-u p visit will t a k e 
pl ac e at 2 w e eks. T h er e aft er foll o w -u p visits t a k e pl ac e at l e ast o nc e  ev er y 4  w e e ks fr o m 
r a n d o miz ati o n t o w e ek 2 4 or pr o gr essi o n.  Aft er w e ek 2 4, i n t h e a bs e nc e of pr o gr essi o n, 
f oll o w u p visits will occ ur e v er y 8 w e eks fr o m r a n d o miz ati o n t o dis e as e pr o gr essi o n  a n d 
i ncl u d e: 
o  
E C O G P erf or m a n c e St at us ass ess m e nt 
o  
St a n d ar d l a b or at or y bl o o d dr a w f or C B C, diff er e nti al, el ectr ol yt es, B U N, 
gl uc os e, li v er f u ncti o n t est, c o a g ul ati o n p a n el, a n d α -f et o pr ot ei n bi o m ar k er 
o  
Q OL q u esti o n n air e  ( F A C T-H e p)  
o  
A d v ers e ev e nt r e p orti n g   
o  
C o nc urr e nt m e dic ati o n  
o  
A b d o m e n/ p el vic C T sc a n / M RI ( ev er y 8 w e eks fr o m r a n d o miz ati o n) 
o  
C h est C T sc a n (e v er y 1 6 w e eks  fr o m r a n d o miz ati o n) 
o  
B o n e sci nti gr a p h y at w e ek 1 6, ev er y 6 m o nt hs t h er e aft er  
Pr o gr essi o n  f or p ati e nt m a n a g e m e nt d ecisi o n-m a ki n g : F or t h e p ur p os es of t his tri al, 
d efi niti o n of pr o gr essi o n f or p ati e nt m a n a g e m e nt d ecisi o ns will i ncl u d e ass ess m e nt of 
c h a n g e i n P V T st at us a n d t u m or pr o gr essi o n a n d is d efi n e d as:    
•  
R a di ol o gic al  pr o gr essi o n  as  d efi n e d  b y  R E CI S T  v  1. 1  ( aft er  r ec ei vi n g  all  
all o w a bl e T h er a S p h er e tr e at m e nts as s p ecifi e d b y t h e pr ot oc ol)  A n d/ Or  
•  
D ev el o p m e nt  of  extr a -h e p atic  dis e as e  b ey o n d  t h e  li mits  d efi n e d  i n  t h e  
eli gi bilit y crit eri a  
•  
W ors e ni n g of P V T fr o m b as eli n e d efi n e d as c h a n g e i n cl assific ati o n of P V T  ( p er 
S hi et al)  u p t o Ty p e III a;  P V T Ty p e III b or Ty p e I V  m a y n ot b e tr e at e d  
•  
E C O G P erf or m a nc e St at us ≥2  
F oll o w u p visits  f oll o wi n g pr o gr essi o n: In b ot h ar ms , aft er  W e ek 2 4 or aft er  pr o gr essi o n 
h as b e e n c o nfir m e d a n d p ati e nts h a v e r ec ei v e d all tr e at m e nts all o w e d u n d er t h e 
pr ot oc ol , st u d y visits will t a k e pl ac e o nc e e v er y 8  w e eks u ntil d e at h. T h es e visits c a n b e 
c o n d uct e d b y t el e p h o n e at t h e i n v esti g at or’s discr eti o n, if a P S ≥ 2 (sy m pt o m atic 
pr o gr essi o n) is ass ess e d a n d w h e n e v er i n t h e b est i nt er est of t h e p ati e nt, a n d will 
d oc u m e nt:  
o  
E C O G P erf or m a nc e St at us (i ncl u di n g d at e of d e at h if a p plic a bl e)  
o  
A d v ers e ev e nt r e p orti n g   
o  
C o nc urr e nt m e dic ati o n (f or tr e at m e nt of H C C o nl y, r ec or di n g of m e dic ati o ns 
or t h er a pi es us e d i n s u p p orti v e c ar e is n ot r e q uir e d).  
I n d e p e n d e nt D at a 
M o nit ori n g 
C o m mitt e e  
T his st u d y will h a v e o v ersi g ht b y a n I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e  w h o  will 
m e et as d et er mi n e d t o r evi e w t h e e nr oll m e nt, pr ot oc ol d evi ati o ns, a n d s af et y ev e nts.  
T h ey will e v al u at e t h e d at a at i nt eri m a n al ys es f or c o nsi d er ati o n of st o p pi n g t h e st u d y 
f or o v er w h el mi n g effic ac y or f utilit y a n d f or s a m pl e siz e r e-esti m ati o n at t h e s ec o n d 
i nt eri m a n al ysis.   T h e I D M C  will e v al u at e t h e fi n al st u d y r e p ort . 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 4  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
2  T RI AL S C H E M A  
 
1. Y 9 0 tr e at m e nt m a y b e pl a n n e d i n o n e or t w o s essi o ns a n d s h o ul d b e st art e d wit hi n 4 w e eks fr o m r a n d o miz ati o n  
2. A t ot al of n o m or e t h a n 3 s essi o ns of Y 9 0 r a di o e m b oliz ati o n ar e all o w e d f or e ac h p ati e nt  
 
 
 
 
 
Eli gi bl e p ati e nt s  
- H C C wit h pr e s e n c e of P V T  
- C hil d P u g h : A, P S: 0-1  
R a n d o mi z ati o n 1: 1  
Tr e at m e nt Ar m  
C o ntr ol Ar m  
Pr e -tr e at m e nt 
e v al u ati o n   
St a n d ar d -of -c ar e 
S or af e ni b 4 0 0 m g b d  
T h er a S p h er e Tr e at m e nt 1  
Fr o m r a n d o mi z ati o n tr e at m e nt w it hi n 4 
w e e k s
 
N o n tr e at a bl e  
St a n d ar d -of -c ar e 
s or af e ni b   
F oll o w -u p  
 
 
  
 
F oll o w -u p  
  
  
  
 
P D  
B e st a v ail a bl e c ar e  
P D  
T h er a S p h er e R etr e at m e nt 2  
i n c a s e of i ntr a h e p ati c P D 
U p t o 2 r etr e at m e nt s ar e all o w e d  
Str atifi c ati o n  
A F P ≤ 4 0 0/ A F P > 4 0 0 n g/ m L  
B e st a v ail a bl e c ar e  
A s s e s s m e nt of r e s p o n s e  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 5  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
 
3  S C H E D UL E O F E V E N T S  
3. 1  S C H E D UL E O F E V E N T S : C O N T R O L A R M  
St u d y P eri o d & E v e nts  
Scr e e ni n g   
 
R a n d o miz e  
C o ntr ol Ar m Tr e at m e nt & R es p o ns e 
Ass ess m e nt  
 
Pr o gr essi o n  
F oll o w 
u p 1  
 
E n d of St u d y  
Ti mi n g:  
 St u d y Visits  ( +/- 7 d a ys) or E v e nts  
D  
-1 4 t o 0 2 
D 
0  
W
2  
W
4  
W
8  
W 
1 2  
W 
1 6  
W 
2 0  
W   
2 4  
W 
Q 8  
 
W  
Q 8  
 
I nf or m e d C o ns e nt 
x 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hics  
x 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al Hist or y  
x 
 
 
 
 
 
 
 
 
 
 
 
 
P hysic al Ex a m ( P E)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
C at e g oriz ati o n of P V T  
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
E C O G P erf or m a nc e St at us  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
C hil d P u g h St at us  
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
M e dic ati o n  & Pri or Tr e at m e nt Hist or y  
x 
 
 
 
 
 
 
 
 
 
 
 
 
H e m at ol o gy  
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
C o a g ul ati o n  
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
C h e mistry p a n el, liv er f u ncti o n t ests  
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
S er u m Pr e g n a nc y 3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or m a rk er ( A F P)  
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
B o n e Sci nti gr a p hy 4 
x 
 
 
 
 
 
x 
 
 
 
 
( Q 6 m o) 
 
Liv er V ol u m e/ T u m or m ass 
x 
 
 
 
 
 
 
 
 
 
 
 
 
R evi e w Eli gi bilit y Crit eri a  
x 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o miz e P ati e nt  
 
x 
 
 
 
 
 
 
 
 
 
 
 
F A C T -H e p q u esti o n n air e 5 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
I niti at e S or af e ni b6 t h er a py 
 
 
x 
 
 
 
 
 
 
 
 
 
 
S pir al C T of a b d o m e n/ p elvis  
x 7 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
S pir al C T of c h est 8  
x 5  
 
 
 
 
 
x 
 
 
x 
 
 
 
Ass ess/ R e p ort A dv ers e E v e nts  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
R evi e w/ R ec or d St u dy Tr e at m e nt  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
R ec or d C o nc urr e nt M e dic ati o n  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 9 
x  
Fi n al E n d p oi nt Effic ac y/ S af et y 
d oc u m e nt ati o n  & exit p ati e nt  
 
 
 
 
 
 
 
 
 
 
 
 
x  
 
                                                                
1 Visits c a n b e c o n d uct e d by t el e p h o n e at t h e i nv esti g at or’s discr eti o n, if a P S ≥ 2 (sy m pt o m atic pr o gr essi o n) is ass ess e d a n d w h e n ev er 
i n t h e b est i nt er est of t h e p ati e nt 
2 R es ults fr o m t ests a n d ex a mi n ati o ns d o n e as p art of cli nic al p ati e nt m a n a g e m e nt wit hi n 1 4 d a ys of r a n d o miz ati o n m a y b e us e d t o 
s atisfy scr e e ni n g r e q uir e m e nts t o av oi d u n n ec ess ar y d u plic ativ e p ati e nt t esti n g  
3 F e m al e p ati e nts of c hil d b e ari n g p ot e nti al o nl y  
4 R e q uir e d f or p ati e nts wit h A F P > 4 0 0 n g/ mL t o ass ess m et ast atic dis e as e at scr e e ni n g, W e ek 1 6 t h e n ev er y 6 m o nt hs  
5 S u bj ects t o c o m pl et e q u esti o n n air e at e ac h st u dy visit; c o m pl eti o n n ot r e q uir e d f or t el e p h o n e f oll o w -u p visits  
6 Acc or di n g t o s or af e ni b p a c k a g e i ns ert b e gi n ni n g at W e ek 2 f or C o ntr ol Ar m p ati e nts o nly  
7 I m a g es t a k e n u p t o 2 8 d a ys i n a dv a nc e of r a n d o miz ati o n c a n b e us e d f or b as eli n e i m a g es 
8 I m a gi n g t o b e sc h e d ul e d ev ery 1 6 w e eks fr o m r a n d o miz ati o n at alt er n at e Q 8 w e ek f oll o w u p visits  
9 D oc u m e nt liv er tr e at m e nt m e dic ati o ns o nly; m e dic ati o ns us e d f or s u p p ortiv e c ar e d o n ot r e q uir e d oc u m e nt ati o n  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
1 6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
3. 2  S C H E D UL E O F E V E N T S : T R E A T M E N T A R M  
St u d y P eri o d & E v e nts  
Scr e e ni n g  
R a n d o miz e  
Tr e at m e nt Ar m Tr e at m e nt & 
R es p o ns e Ass ess m e nt  
Pr o gr essi o n  
F oll o w 
u p 1 
E n d of St u d y  
Ti mi n g : 
 St u d y Visits ( +/- 7 d a ys)  or E v e nts  
D  
-1 4  t o 0 2 
D 
0  
W
2  
W
4  
W
8  
W 
1 2  
W 
1 6  
W 
2 0  
W   
2 4  
W 
Q 8  
 
W  
Q 8  
 
I nf or m e d C o ns e nt 
x 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p hics  
x 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al Hist or y  
x 
 
 
 
 
 
 
 
 
 
 
 
 
P hysic al Ex a m ( P E)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
C at e g oriz ati o n of P V T  
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
E C O G P erf or m a nc e St at us  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
C hil d P u g h St at us  
x 
 
 
 
x 
 
x 
 
x 
x 
 
x 
 
M e dic ati o n  & Pri or Tr e at m e nt Hist or y  
x 
 
 
 
 
 
 
 
 
 
 
 
 
H e m at ol o gy  
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
C o a g ul ati o n  
x 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
C h e mistry p a n el, liv er f u ncti o n t ests  
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
S er u m Pr e g n a nc y 3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or m a rk er ( A F P)  
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
B o n e Sci nti gr a p hy 4 (if A F P  > 4 0 0 n g/ mL) 
x 
 
 
 
 
 
x 
 
 
 
 
( Q 6 m o) 
 
Liv er V ol u m e/ T u m or m ass  
x 
 
 
 
 
 
 
 
 
 
 
 
 
R evi e w Eli gi bilit y Crit eri a  
x 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o miz e P ati e nt  
 
x 
 
 
 
 
 
 
 
 
 
 
 
F A C T -H e p q u esti o n n air e 5 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
H e p atic A n gi o gr a m 6, Tc M A A sc a n6, T S 
D os e C alc ul ati o n  
 
 
x 
 
 
 
 
 
 
 
 
 
 
Or d er T S  
 
 
x 
 
 
 
 
 
 
 
 
 
 
A d mi nist er T S tr e at m e nt 7 
 
 
 
x 
 
 
 
 
 
 
 
 
 
S pir al C T of a b d o m e n/ p elvis  
x 8 
 
 
 
x 
 
x 
 
x 
x 
 
 
 
S pir al C T of c h est 9 
X 8  
 
 
 
 
 
x 
 
 
x 
 
 
 
Ass ess/ R e p ort A dv ers e E v e nts  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
R evi e w/ R ec or d St u dy Tr e at m e nt  
 
 
x 
x 
 
 
 
 
 
 
 
x 
 
R ec or d C o nc urr e nt M e dic ati o n  
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 1 0 
x  
O pti o n al T h er a S p h er e R etr e at m e nt 6 ,1 1  
 
 
 
 
 
 
 
 
 
 
 
x 
 
Fi n al E n d p oi nt Effic ac y/ S af et y 
d oc u m e nt ati o n & exit p ati e nt  
 
 
 
 
 
 
 
 
 
 
 
 
x  
                                                                
1 Visits c a n b e c o n d uct e d by t el e p h o n e at t h e i nv esti g at or’s discr eti o n, if a P S ≥ 2 (sy m pt o m atic pr o gr essi o n) is ass ess e d a n d w h e n ev er 
i n t h e b est i nt er est of t h e p ati e nt 
2 R es ults fr o m t ests a n d ex a mi n ati o ns d o n e as p art of cli nic al p ati e nt m a n a g e m e nt wit hi n 1 4 d a ys of r a n d o miz ati o n m a y b e us e d t o 
s atisfy scr e e ni n g r e q uir e m e nts t o av oi d u n n ec ess ar y d u plic ativ e p ati e nt t esti n g  
3 F e m al e p ati e nts of c h il d b e ari n g p ot e nti al o nl y – c a n b e r e p e at e d at p hysici a n discr eti o n b ef or e r e p e at T h er a S p h er e tr e at m e nts  
4 R e q uir e d f or p ati e nts wit h A F P > 4 0 0 n g/ mL t o ass ess m et ast atic dis e as e at scr e e ni n g, W e ek 1 6 t h e n ev er y 6 m o nt hs  
5 S u bj ects t o c o m pl et e q u esti o n n air e at e ac h st u dy visit; c o m pl eti o n n ot r e q uir e d f or t el e p h o n e f oll o w -u p visits  
6 Pr e -tr e at m e nt ev al u ati o n is al w a ys d o n e b ef or e t h e first T h er a S p h er e tr e at m e nt a n d pri or t o s u bs e q u e nt tr e at m e nts as n e e d e d  
7 T h er a S p h er e  m ust b e a d mi nist er e d wit hi n 4 w e eks of r a n d o miz ati o n  
8 I m a g es t a k e n u p t o 2 8 d a ys i n a dv a nc e of r a n d o miz ati o n c a n b e us e d f or b as eli n e i m a g es 
9 I m a gi n g t o b e sc h e d ul e d ev ery 1 6 w e eks fr o m r a n d o miz ati o n at alt er n at e Q 8 w e ek f oll o w u p visits 
1 0 D oc u m e nt liv er tr e at m e nt m e dic ati o ns o nly; m e dic ati o ns  us e d f or s u p p ortiv e c ar e d o n ot r e q uir e d oc u m e nt ati o n  
1 1 A m axi m u m of 2 r e -tr e at m e nts wit h T h er a S p h er e ar e all o w e d f oll o wi n g h e p atic pr o gr essi o n f or l esi o ns a m e n a bl e t o T h er a S p h er e 
tr e at m e nt 

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
17 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
4 LIST OF ABBREVIATIONS 
AE - Adverse Event 
AFP - Alphafetoprotein 
ALT – Alanine Transaminase 
AST – Aspartate Transaminase 
BUN – Blood Urea Nitrogen 
CBC – Complete Blood Count 
COPD – Chronic Obstructive Pulmonary Disease 
CP- Child-Pugh 
CRC – Colorectal Cancer 
Cr – Chromium 
CR – Complete Response 
CT – Computed Tomography 
CTCAE – Common Toxicity Criteria for Adverse Events 
EASL- European Association for the Study of the Liver  
ECOG – Eastern Cooperative Oncology Group 
eCRF – electronic Case Report Form 
FACT-Hep - Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire 
FHSI8 – Functional Assessment of Cancer Therapy – Hepatobiliary Symptom Index 8 
GBq - gigabecquerel 
GI – gastrointestinal 
Gy – Gray, a measure of irradiation dose 
HBV- Hepatitis B Virus  
HCC – Hepatocellular Carcinoma 
HCV – Hepatitis C Virus 
HDE – Humanitarian Device Exemption 
ICF – Informed Consent Form 
INR – International Normalized Ratio for prothrombin time 
IRB – Institutional Review Board 
ITT – Intent–to-Treat 
LFT – Liver Function Tests 
mRECIST- modified RECIST 
MRI – Magnetic Resonance Imaging 
NCI – National Cancer Institute 
PD – Progressive Disease 

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
18 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
PE – Physical Exam 
PFS – Progression Free Survival 
PLT – Platelet Count 
PPP – Per Protocol Population 
PR – Partial Response 
PRO – Patient Reported Outcome 
PS – Performance Status 
PT - Prothrombin Time 
PTT – Partial Thromboplastin Time 
PVT- Portal Vein Thrombosis 
PVTT – Portal Vein Tumor Thrombosis 
RECIST – Response Evaluation Criteria in Solid Tumor 
SAE – Serious Adverse Event 
SD – Stable Disease 
SOC – Standard of Care 
99mTC-MAA – Technetium-99m Magroaggregated Albumin 
TEAE – Treatment emergent adverse events 
TS – TheraSphere 
TTDQoL - Time to deterioration in QoL  
TTP – Time-to-Progression 
TTSP - Time to symptomatic progression 
UADE – Unanticipated Adverse Device Effect 
US - Ultrasound 
WBC – White Blood Cells 
Y-90 (Y-88, Y-91) – Ytrium-90 and isotopes 
Y90-TARE– 90Yttrium trans-arterial radioembolization 
 
 

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
19 
 
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CONFIDENTIAL  8 August 2014 
5 BACKGROUND AND RATIONALE 
5.1 GENERAL DEVICE DESCRIPTION 
TheraSphere® consists of insoluble glass microspheres in which yttrium-90 is an integral component of the 
glass. The sphere diameter ranges from 20 to 30 µm with 22,000 to 73,000 microspheres per milligram. 
TheraSphere is available in dose sizes ranging from 3 GBq to 20 GBq, each supplied in 0.6 mL of sterile, 
pyrogen-free water contained in a 1.0 mL vial secured within a clear acrylic vial shield. A pre-assembled single-
use TheraSphere Administration Set is provided for each dose. Each user site is provided with a re-useable 
TheraSphere Administration Accessory Kit that provides both radiation protection for the user and physical 
support of the dose vial and Administration Set during administration of the product. 
Yttrium-90 is a pure beta emitter which decays to stable zirconium-90 with a physical half-life of 64.1 hours. 
The average energy of the beta emissions from yttrium-90 is 0.9367 MeV with mean tissue penetration of 
approximately 2.5 mm.  
TheraSphere is administered through the hepatic artery which supplies blood to tumor tissue (the portal vein 
supplies blood to the normal hepatic tissue). The microspheres are trapped in the vasculature of the tumor 
due to arteriolar capillary blockage where they exert a local radiotherapeutic effect. In clinical use, the glass 
microspheres remain permanently trapped in the vasculature where the isotope decays to infinity leaving 
background radiation with no therapeutic value.  
5.2 GLOBAL REGULATORY STATUS OF THERASPHERE 
TheraSphere received a Humanitarian Device Exemption (HDE) from the United States Food and Drug 
Administration (FDA) in 1999 (HDE H980006) and is currently approved for use in radiation treatment or as a 
neoadjuvant to surgery or transplantation in patients with unresectable hepatocellular carcinoma (HCC) who 
can have placement of appropriately positioned hepatic arterial catheters. The device is also indicated for HCC 
patients with partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the 
treatment.  The US package insert is provided in Appendix 1(a). 
TheraSphere is approved for use in Europe for the treatment of hepatic neoplasia. TheraSphere is approved in 
Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial catheters. 
In addition, TheraSphere is available in Russia, India, South Africa, Turkey and Kuwait for the treatment of 
hepatic neoplasia. The current package insert for Canada is provided in Appendix 1 (b); current Instructions for 
Use document for Europe is provided in Appendix 1(c). 
5.3 RATIONALE FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA 
According to the American Cancer Society1, primary liver cancer is a major health problem worldwide.  
Globally, it is the fifth most commonly diagnosed cancer in men and eighth most common in women, with 
more than 700,000 new cases in 2007. It is the third leading cause of cancer death in men and sixth among 
women. Hepatocellular carcinoma is associated with known risk factors2 including chronic viral hepatitis 
(types B and C), alcohol intake and aflatoxin exposure, the presence of which vary geographically. In North 
America and Europe, chronic hepatitis C is a major risk factor while chronic hepatitis B is a major risk factor 
worldwide. 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
I n 2 0 0 7, t h e F D A3 a n d E M E A 4 a p pr o v e d s or af e ni b t osyl at e ( N ex a v ar ® - a r e gist er e d tr a d e m ar k of O n yx 
P h ar m ac e utic als, I nc. a n d B ay er H e alt h C ar e P h ar m ac e utic als, I nc. ), a s m all m ol ec ul e R af ki n as e a n d V E G F 
r ec e pt or ki n as e i n hi bit or, f or t h 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 ( H C C).  
T h e a p pr o v al w as b as e d o n t h e r es ults of a n i nt er n ati o n al, m ultic e nt er, r a n d o miz e d, d o u bl e -bli n d, pl ac e b o -
c o ntr oll e d tri al ( S H A R P 5  tri al) i n p ati e nts wit h u nr es ect a bl e, bi o psy-pr o v e n h e p at oc ell ul ar c arci n o m a.  O v er all 
s ur vi v al w as t h e pri m ar y effic ac y e n d p oi nt. A t ot al of 6 0 2 p ati e nts r ecr uit e d pri m aril y fr o m E ur o p e a n d N ort h 
A m eric a w er e r a n d o miz e d; 2 9 9 t o s or af e ni b 4 0 0 m g t wic e d ail y a n d 3 0 3 t o m atc hi n g pl ac e b o.  
D e m o gr a p hics a n d b as eli n e dis e as e c h ar act eristics w er e si mil ar b et w e e n t h e s or af e ni b a n d pl ac e b o ar m s. 
Pri o r tr e at m e nts i ncl u d e d s ur gic al r es ecti o ns ( 2 0 p erc e nt), l oc or e gi o n al t h er a pi es (i ncl u di n g r a di ofr e q u e nc y 
a bl ati o n , p erc ut a n e o us et h a n ol i nj ecti o n  a n d tr a ns art eri al c h e m o em b oliz ati o n  i n 4 0 p erc e nt), r a di ot h er a p y 
( 5 p erc e nt), a n d syst e mic t h er a p y ( 4 p erc e nt). Dis e as e eti ol o g y w as b al a nc e d i n b ot h s or af e ni b a n d pl ac e b o 
gr o u ps: H C V i nf ecti o n ( 2 9 % vs 2 7 %), alc o h ol -ass oci at e d li v er dis e as e ( 2 6 % b ot h ar ms) a n d H B V i nf ecti o n ( 1 9 % 
vs 1 8 %).  
T h e tri al w as st o p p e d f oll o wi n g a pr e -s p ecifi e d s ec o n d i nt eri m a n al ysis f or s ur vi v al discl osi n g a st atistic all y 
si g nific a nt a d v a nt a g e f or s or af e ni b [ m e di a n 1 0. 7 vs. 7. 9 m o nt hs; H R: 0. 6 9 ( 9 5 %  CI: 0. 5 5, 0. 8 7), p = 0. 0 0 0 5 8]. 
T h e fi n al a n al ysis of ti m e -t o-t u m or pr o gr essi o n ( T T P) b y i n d e p e n d e nt r a di ol o gic r e vi e w w as b as e d o n d at a 
fr o m a n e arli er ti m e p oi nt a n d d e m o nstr at e d a st atistic all y si g nific a nt i mpr o v e m e nt i n T T P i n t h e s or af e ni b 
ar m  [ m e di a n 5. 5 vs. 2. 8 m o nt hs; H R: 0. 5 8 ( 9 5%  CI: 0. 4 5, 0. 7 4),  p = 0. 0 0 0 0 0 7].  I n a s u bs et a n al ysis, p ati e nts wit h 
m acr o v asc ul ar i n v asi o n , t h e h az ar d r ati o f or O S f a v or e d s or af e ni b o v er pl ac e b o: H R 0. 6 8 ( 9 5 % CI 0. 4 9 –  0. 9 3).  
T o o bt ai n r e g ul at or y a p pr o v al i n C hi n a a p ar all el st u d y of s or af e ni b w as u n d ert a k e n i n t h e Asi a -P acific 6 r e gi o n, 
w h er e c hr o nic h e p atitis B vir us i nf ecti o n is a n i m p ort a nt eti ol o g y f act or. I n 2 3 sit es i n C hi n a, T ai w a n a n d 
K or e a, C hil d P u g h A st at us p ati e nts  w er e r a n d o miz e d i n a 2: 1 r ati o t o r ec ei v e s or af e ni b ( 4 0 0 m g) or pl ac e b o 
t wic e d ail y i n 6 w e e k c ycl es. Of t h e 2 7 1 e nr oll e d p ati e nts, 2 2 6 w er e r a n d o miz e d t o r ec ei v e pl ac e b o ( N = 7 6) or 
s or af e ni b ( N = 1 5 0).  D e m o gr a p hic a n d b as eli n e c h ar act eristics w er e si mil ar i n b ot h ar ms as w as h e p atitis vir us 
st at us:  H B V i nf ecti o n w as m or e c o m m o n ( 7 0. 7 % s or af e ni b v.s 7 7. 6 % pl ac e b o) t h a n H C V i nf ecti o n ( 1 0. 7 % 
s or af e ni b vs. 3. 9 % pl ac e b o). 
M e di a n o v er all s ur vi v al w as 6. 5 m o nt hs ( 9 5 % CI 5. 5 6 –  7. 5 6) wit h s or af e ni b c o m p ar e d t o 4. 2  m o nt hs ( 9 5 % CI 
3. 7 5 –  5. 4 6) wit h a h az ar d r ati o of 0. 6 8 ( 9 5 % CI 0. 5 –  0. 9 3)[ p = 0. 0 1 4]. M e di a n T T P w as 2· 8 m o nt hs ( 9 5 % CI 
2· 6 3 — 3· 5 8) i n t h e s or af e ni b gr o u p c o m p ar e d wit h 1· 4 m o nt hs ( 9 5 % CI 1· 3 5 — 1· 5 5) i n t h e pl ac e b o gr o u p ( H R 
0· 5 7 [ 9 5 % CI 0· 4 2 — 0· 7 9]; p = 0· 0 0 0 5).  A d v ers e ev e nts a n d effic ac y e n d p oi nt h az ar d r ati os w er e c o nsist e nt wit h 
t h os e r e p ort e d i n t h e S H A R P st u d y, i n dic ati n g si mil ar acti o n of s or af e ni b i n b ot h p o p ul ati o ns. S u bs e q u e nt 
ex pl or at or y s u b -s et a n al ys es 7 i n p ati e nts wit h m acr o v asc ul ar i n v asi o n a n d extr a h e p atic m et ast as es, s h o w e d 
m e di a n O S of 5. 6 m o nt hs wit h s or af e ni b vs. 4. 1 m o nt hs wit h pl ac e b o; H R 0. 7 5 ( 9 5 % CI 0. 5 4 –  1. 0 5) a n d m e di a n 
T T P of 2. 7 m o nt hs wit h s or af e ni b vs. 1. 3 m o nt hs pl ac e b o; H R 0. 5 8 ( 9 5 % CI 0. 4 1 -0. 8 3).  
S or af e ni b is  n o w  c o nsi d er e d th e st a n d ar d of c ar e t h er a p y 8  f or p ati e nts wit h a d v a nc e d H C C, t h e p ati e nts 
cl assifi e d as B CL C C acc or di n g t o t h e B arc el o n a  Cli nic Li v er C a nc er ( B CL C) cl assific ati o n syst e m.  T h es e a ut h ors 
als o s u g g est usi n g s or af e ni b as t h e c o ntr ol ar m  f or r a n d o miz e d cli nic al tri als of first-li n e  syst e mic  a g e nts.   
S or af e ni b is i n cl u d e d i n t h e N C C N Cli nic al Pr actic e G ui d eli n es i n O nc ol o g y 9  ( N C C N–  H e p at o bili ar y c a nc ers 
V. 2 .2 0 1 2 –  H C C 6 ) a n d t h e E A SL -E O R T C Cli nic al Pr actic e G ui d eli n es 2 as o n e of t h e p ossi bl e tr e at m e nts f or 
p ati e nts wit h u nr es ect a bl e H C C a n d ext e nsi v e li v er dis e as e w h o ar e n ot c a n di d at es f or tr a ns pl a nt ati o n.  
Alt h o u g h s or af e ni b is a st a n d ar d of c ar e i n t h e tr e at m e nt of p ati e nts wit h H C C, it is ass oci at e d wit h o nl y a 
m o d est i m pr o v e m e nt i n m e d i a n s ur vi v al as c o m p ar e d t o best s u p p orti v e c ar e.  F urt h er, s or af e ni b tr e at m e nt 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
is ass oci at e d wit h si g nific a nt t oxicit y. T h e m ost c o m m o n a d v ers e r e acti o ns4 , 5 ( ≥2 0 p erc e nt) c o nsi d er e d r el at e d 
t o s or af e ni b w er e f ati g u e, w ei g ht l oss, r as h/ d es q u a m ati o n, h a n d-f o ot ski n r e acti o n, al o p eci a, di arr h e a, 
a n or exi a, n a us e a a n d a b d o mi n al p ai n. Di arr h e a w as r e p ort e d i n 5 5 p erc e nt of s or af e ni b p ati e nts ( gr a d e 3 i n 
1 0 p erc e nt). H a n d -f o ot sy n dr o m e ( 2 1 p erc e nt o v er all; gr a d e 3 i n 8 p erc e nt) a n d r as h ( 1 9 p erc e nt o v er all; 
gr a d e 3 i n 1 p erc e nt) w er e t h e m ost c o m m o n d er m at ol o gic a d v ers e r e acti o ns t o s or af e ni b.  S or af e ni b d os e 
r e d ucti o ns a n d dr u g h oli d a ys ar e oft e n r e q uir e d t o m a n a g e t h es e t oxiciti es.   
S u bs e q u e nt s u bs et a n al ysis of t h e S H A R P tri al d at a 1 0 i n dic at ed  t h at t h e effic acy of S or af e ni b is r e d uc e d i n a n 
i m p ort a nt s u bs et of p ati e nts wit h a d v a nc e d H C C.  I n p ati e nts wit h extr a h e p atic s pr e a d or m acr osc o pic 
v asc ul ar i n v asi o n, t h e m e di a n s ur vi v al w as 8. 9 m o nt hs i n p ati e nts tr e at e d wit h s or af e ni b as c o m p ar e d t o 6. 7 
m o nt hs i n p ati e nts tr e at e d wit h pl ac e b o.  
S al e m et al d e m o nstr at e d t h e t ol er a bilit y of T h er a S p h er e i n tr e at m e nt of p ati e nts wit h H C C a n d br a nc h P V T 1 1 
a n d p ati e nts wit h u nr es ect a bl e H C C 1 2.    S al e m et al 1 3  r ec e ntl y p u blis h e d t h eir l o n g-t er m ex p eri e nc e of 
T h er a S p h er e  i n t h e tr e at m e nt of p ati e nts wit h H C C. I n t his r e p ort, p ati e nts wit h H C C ( n = 2 9 1) w er e tr e at e d 
wit h T h er a S p h er e  as p art of a si n gl e -c e nt er, pr os p ecti v e, l o n git u di n al c o h ort st u d y. T oxiciti es w er e r ec or d e d 
usi n g t h e C o m m o n T er mi n ol o g y Crit eri a v ersi o n 3. 0. R es p o ns e  r at e a n d ti m e t o pr o gr essi o n ( T T P) w er e 
d et er mi n e d usi n g W orl d H e alt h Or g a niz ati o n ( W H O) a n d E ur o p e a n Ass oci ati o n f or t h e St u d y of t h e Li v er 
( E A SL) g ui d eli n es. S ur vi v al b y st a g e w as ass ess e d. U ni v ari at e/ m ulti v ari at e a n al ys es w er e p erf or m e d. A t ot al 
of 5 2 6  tr e at m e nts w er e a d mi nist er e d ( m e a n, 1. 8; r a n g e, 1-5). T oxiciti es i ncl u d e d f ati g u e ( 5 7 %), p ai n ( 2 3 %), 
a n d n a us e a/ v o miti n g ( 2 0 %); 1 9 % ex hi bit e d gr a d e 3/ 4 bilir u bi n t oxicit y. T h e 3 0 -d a y m ort alit y r at e w as 3 %. 
R es p o ns e r at es w er e 4 2 % a n d 5 7 % b as e d o n W H O a n d E A SL crit eri a, r es p ecti v el y. T h e o v er all T T P w as 7. 9 
m o nt hs ( 9 5 % c o nfi d e nc e i nt er v al, 6 -1 0. 3). S ur vi v al ti m es diff er e d b et w e e n p ati e nts wit h C hil d -P u g h A a n d B 
dis e as e ( A, 1 7. 2 m o nt hs; B, 7. 7 m o nt hs; P = . 0 0 2). P ati e nts wit h C hil d -P u g h B dis e as e w h o h a d p o rt al v ei n 
t hr o m b osis ( P V T) s ur vi v e d 5. 6 m o nt hs ( 9 5 % c o nfi d e nc e i nt er v al, 4. 5-6. 7). B as eli n e a g e; g e n d er ; p erf or m a nc e 
st at us;  pr es e nc e  of  p ort al  h y p ert e nsi o n;  t u m or  distri b uti o n;  l ev els  of  bilir u bi n,  al b u mi n,  a n d  al p h a -
f et o pr ot ei n; a n d W H O/ E A SL r es p o ns e r ate pr e dict e d s ur vi v al. T h es e i n v esti g at ors c o ncl u d e d t h at p ati e nts 
wit h C hil d -P u g h A dis e as e, wit h or wit h o ut P V T, b e n efit e d m ost fr o m tr e at m e nt. P ati e nts wit h C hil d -P u g h B 
dis e as e w h o h a d P V T h a d p o or o utc o m es. T T P a n d o v er all s ur vi v al v ari e d b y p ati e nt st a g e at b as eli n e.  
T h e  cli nic al  ex p eri e nc e  of  S al e m  et  al 1 1 , 1 2, 1 3 a n d  a  r ec e nt  m et a -a n al ysis  of  yttri u m -9 0  micr os p h er e 
r a di o e m b oliz ati o n 1 4 i n dic at es t h at T h er a S p h er e is v er y w ell t ol er at e d w h e n a p pr o pri at e p ati e nt s el ecti o n 
crit eri a ar e us e d. E arl y r e p orts 1 5 of s eri o us a d v ers e e v e nts p ossi bl y ass oci at e d wit h t h e us e of T h er a S p h er e,  as 
d escri b e d i n t h e p ac k a g e l a b eli n g d oc u m e nts i n A p p e n dix 1, i ncl u d e d d e at h, h e p at or e n al f ail ur e, li v er a bsc ess, 
h e p atic e nc e p h al o p at h y, h e p atic d ec o m p e ns ati o n, r a di ati o n h e p atiti s, r a di ati o n p n e u m o nitis, d u o d e n al ulc er, 
g astr oi nt esti n al bl e e di n g a n d c h ol ec ystitis.  T h es e m or e s e v er e e v e nts  ar e n o w u nc o m m o n as p ati e nts wit h t h e 
hi g h risk f act ors ass oci at e d wit h t h e occ urr e nc e of t h es e e v e nts ar e t y pic all y excl u d e d fr o m tr e at m e nt wit h 
T h er a S p h er e. P ati e nts i n w h o m T h er a S p h er e  s h o ul d b e us e d wit h c a uti o n i ncl u d e t h os e wit h i nfiltr ati v e t u m or 
t y p e, b ul k dis e as e (t u m or v ol u m e > 7 0 % or n o d ul es t o o n u m er o us t o c o u nt), A S T or AL T > fi v e ti m es t h e u p p er 
li mit of n or m al, bilir u bi n > 2 m g/ dL, tu m or v ol u m e > 5 0 % i n t h e pr es e nc e of a n al b u mi n < 3 g/ dL , a n d t h os e i n 
w h o m extr a -h e p atic s h u nti n g t o t h e l u n gs or g astr oi nt esti n al tr act c a n n ot b e m a n a g e d t hr o u g h st a n d ar d 
a n gi o gr a p hic t ec h ni q u es.  
R ec e nt cli nic al d at a i n p ati e nts wit h H C C a n d P V T i n dic at e t his gr o u p of p ati e nts m a y h a v e a b ett er o utc o m e 
f oll o wi n g T h er a S p h er e tr e at m e nt as c o m p ar e d t o s or af e ni b tr e at m e nt. S al e m et al 1 3 i n dic at es t h at m e di a n 
s ur vi v al i n t his gr o u p of p ati e nts f oll o wi n g T h er a S p h er e tr e at m e nt r a n g es fr o m 7. 7 m o nt hs ( m ai n P V T) t o  1 6. 6 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 2  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
m o nt hs ( br a nc h P V T) wit h a n o v er all a v er a g e of 1 0. 4 m o nt hs. A r ec e nt  p a p er  b y M azz af err o et al 1 6 r e p ort e d 
a m e di a n o v er all s ur vi v al of 1 3 m o nt hs  i n a c o h ort of 3 5 p ati e nts wit h P V T tr e at e d wit h T h er a S p h er e. 
6  S T U D Y O BJ E C TI V E S  
T h e o bj ecti v e  of t his p h as e III, pr os p ecti v e r a n d o miz e d tri al is t o d et er mi n e w h et h er T h er a S p h er e  pr o vi d es a 
m e a ni n gf ul b e n efit i n s ur vi v al i n c o m p aris o n wit h t h e st a n d ar d of c ar e (s or af e ni b) i n p ati e nts wit h g o o d 
h e p atic f u ncti o n a n d a d v a nc e d h e p at oc ell ul ar c arci n o m a ( H C C) ass oci at e d wit h p ort al v ei n t hr o m b osis ( P V T). 
7  S T U D Y D E SI G N  
T his is a n o p e n -l a b el pr os p ecti v e, m ulti -c e nt er, r a n d o miz e d, c o ntr oll e d cli nic al tri al t h at will ev al u at e t h e us e 
of T h er a S p h er e  c o m p ar e d t o st a n d ar d-of -c ar e s or af e ni b al o n e.  U p t o 2 5  st u d y c e nt ers will p artici p at e a n d 
r ecr uit p ati e nts f or t h e pr ot oc ol. P artici p ati n g st u d y sit es m a y b e i n E ur o p e , Asi a or  N ort h A m eric a.  All p ati e nts 
will b e f oll o w e d pr os p ecti v el y fr o m r a n d o miz ati o n t o d e at h.  
8  S T U D Y  P O P UL A TI O N  A N D E LI GI BILI T Y C RI T E RI A 
P ati e nts d i a g n os e d wit h u nr es ect a bl e H C C a n d P V T wit h a d e q u at e li v er r es er v e w h o  ar e n ot eli gi bl e f or a n y 
c ur ati v e pr oc e d ur es m a y b e scr e e n e d f or e li gi bilit y crit eri a. 
8. 1  E LI GI BILI T Y C RI T E RI A  
P ati e nts m ust m e et t h e f oll o wi n g eli gi bilit y  crit eri a: 
1.  
P ati e nts o v er 1 8 y e ars of a g e, r e g ar dl ess of r ac e or  g e n d er  
2.  
A d v a nc e d st a g e H C C c o nfir m e d b y hist ol o g y ( m a n d at or y i n n o n cirr h otic p ati e nts) or n o n -i n v asi v e 
crit eri a ( E A SL/ A A SL D) wit h br a nc h P V T .  
o  
Eit h er n aï v e or r ec urr e nt H C C aft er c ur ati v e tr e at m e nt ( mi nim u m 3  m o nt hs fr o m c ur ati v e 
tr e at m e nt - mi n or r es ecti o n or l oc al a bl ati o n) is acc e pt a bl e 
o  
Br a nc h P V T cl assifi e d p er m o difi e d S hi et al 2 0 1 0 1 6 as Ty p e I, Ty p e II or Ty p e III a  (s e e S ecti o n 
9. 2. 5 ).  
3.  
U nil o b ar dis e as e  w hic h c a n i ncl u d e m ultif oc al t u m ors if u nil o b ar  a n d if all n o d ules (i ncl u di n g n o d ul e 
ass oci at e d wit h P V T) ar e tr e at a bl e wit hi n a si n gl e T h er a S p h er e tr e at m e nt s essi o n  
4.  
T u m or v ol u m e ≤ 7 0 % of li v er v ol u m e  ( d et er mi n e d b y vis u al esti m ati o n) 
5.  
C hil d -P u g h A  
6.  
At l e a st o n e u ni-di m e nsi o n al H C C  t ar g et l esi o n ass ess a bl e acc or di n g t o t h e R E CI S T v 1. 1 crit eri a b y C T -
sc a n or M RI 
7.  
N o c o nfir m e d extr a h e p atic m et ast as es . P ati e nts wit h i n d et er mi n at e h e p atic hil ar l y m p h n o d es u p t o 2. 5 
c m i n gr e at est di m e nsi o n, or wit h i n d et er mi n at e l u n g n o d ul es (si n gl e l esi o n b et w e e n 1 –  1. 5 c m, or 
m ulti pl e s m all er l esi o ns wit h a t ot al di a m et er ≤ 2 c m) m a y b e i ncl u d e d if m et ast atic dis e as e is d e e m e d 
u nli k el y   
8.  
N o k n o w n c o ntr ai n dic ati o ns t o st a n d ar d -of -c ar e s or af e ni b i ncl u di n g all er gic r e acti o n, pill s w all o wi n g 
diffic ult y, u nc o ntr oll e d h y p ert e nsi o n or hist or y of c ar di ac dis e as e ( acc or di n g t o s or af e ni b p ac k a g e i ns ert 
a n d c o u ntr y -s p ecific p olici es, m a y i ncl u d e e vi d e nc e of s ev er e or u nc o ntr oll e d syst e mic dis e as es, c ar di ac 
arr h yt h mi as (r e q uiri n g a nti -arr h yt h mic t h er a p y or p ac e m a k er), c o n g esti v e c ar di ac f ail ur e > N e w Y or k 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 3  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
H e art Ass oci ati o n cl ass 2,  my oc ar di al i nf arct wit hi n 6 m o nt hs, pr ol o n g e d Q T/ Q Tc > 4 5 0 ms ), or l a b or at or y 
fi n di n g t h at i n t h e vi e w of t h e i n v esti g at or m a k es it u n d esir a bl e f or t h e p ati e nt t o p artici p at e i n t h e tri al, 
si g nific a nt GI bl e e d wit hi n 3 0 d a ys,  r e n al f ail ur e r e q uiri n g di al ysis 
9.  
N o evi d e nc e of h e p atic v ei n i n v asi o n or  c a v al t hr o m b osis  
1 0.  C a nc e r-r el at e d sy m pt o ms wit hi n t h e E C O G 0-1 c at e g or y  
1 1.  PL T ≥ 5 0 x 1 0 3/ µL 
1 2.  W B C ≥ 1. 5 x 1 0
3/ µL  
1 3.  A S T/ AL T ≤ 5 ti m es t h e u p p er li mit of n or m al ( U/L)  
1 4.  Cr e ati ni n e ≤  2. 0 m g / dL  
1 5.  N o evi d e nc e of p ul m o n ar y i ns uffici e nc y or cli nic all y e vi d e nt c hr o nic o bstr ucti v e p ul m o n ar y dis e as e. ) 
1 6.  N o i n dic ati o n f or a n y p ossi bl e c ur ati v e tr e at m e nt aft er m ulti disci pli n ar y ass ess m e nt (s ur g er y, a bl ati o n, 
tr a ns pl a nt ati o n) 
1 7.  N o pr evi o us tr e at m e nt wit h S or af e ni b f or m or e t h a n 4 w e e ks d uri n g t h e 2 pr evi o us m o nt hs ; n o pri or 
s or af e ni b-r el at e d t oxicit y at a n y d os e a n d/ or d ur ati o n d efi n e d as d oc u m e nt e d s or af e ni b -r el at e d gr a d e 
3 or 4 a d v ers e e v e nts t h at l e d t o s or af e ni b disc o nti n u ati o n  
1 8.  N o i niti ati o n  of a ny ot h er a nti -t u m or t h er a p y i ncl u di n g c h e m ot h er a p y, r a di o e m b oliz ati o n ( m axi m u m 
l u n g s h u nt of 2 0 % f or pri or r a di o e m b oliz ati o n) or i n v esti g ati o n al dr u g tr e at m e nt wit hi n 3 0 d a ys b ef or e 
t h e b e gi n ni n g of t h e st u d y  
1 9.  I n c as e of p ati e nts pr o gr essi n g fr o m a n i nt er m e di at e t o a n a d v a nc e st a g e b ec a us e of occ urr e nc e of P V T, 
e nr ol m e nt is all o w e d if pr evi o us c o n v e nti o n al or d r u g el uti n g T A C E w as p erf or m e d at l e ast 3  m o nt hs 
pri or t o scr e e ni n g p h as e  
2 0.  P ati e nts c a n n ot b e o n a li v er tr a ns pl a nt ati o n list  
2 1.  N o h ist or y of or g a n all o gr aft 
2 2.  N o c o ntr ai n dic ati o n t o a n gi o gr a p h y or s el ecti v e visc er al c at h et eriz ati o n  
2 3.  N o h ist or y of s ev er e all er g y or i nt ol er a nc e t o c o ntr ast a g e nts, n arc otics, s e d ati v es or atr o pi n e t h at 
c a n n ot b e m a n a g e d m e dic all y  
2 4.  N o p r evi o us ext er n al b e a m r a di ati o n tr e at m e nt t o t h e li v er 
2 5.  N o e vi d e nc e of  c o nti n ui n g a d v ers e eff ect of pri or t h er a p y  
2 6.  N o a cti v e GI bl e e di n g a n d a n y bl e e din g di at h esis or c o a g ul o p at h y t h at is n ot c orr ect a bl e b y us u al 
t h er a p y or h e m ost atic a g e nts ( e. g., cl os ur e d e vic e)  
2 7.  N o evi d e nc e of a n y dis e as e or c o n diti o n t h at w o ul d pl ac e t h e p ati e nt at u n d u e risk a n d pr ecl u d e s af e 
us e of micr os p h er es ( T h er a S p h er e ®) tr e at m e nt  
2 8.  N e g ati v e s er u m pr e g n a nc y t est  i n f e m al es of c hil d-b e ari n g p ot e nti al ; p ati e nts w h o ar e br e ast-f e e di n g 
c a n n ot p artici p at e i n t his tri al 
2 9.  Lif e ex p ect a nc y of gr e at er t h a n 3 m o nt hs 
3 0.  N o p artici p ati o n i n c o nc urr e nt i nt er v e nti o n al cli nic al tri als 
3 1.  Si g n e d i nf or m e d c o ns e nt 
 
9  S T U D Y V I SI T S, E V AL U A TI O N S A N D P R O C E D U R E S  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 4  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
9. 1  S T U D Y V I SI T S 
St u d y tr e at m e nt visits s h o ul d occ ur at t h e ti m e i nt er v als o utli n e d b el o w a n d i n t h e st u d y visit sc h e d ul e i n 
S ecti o n  3 .  All s t u d y visits t h at t a k e pl ac e aft er t h e scr e e ni n g/ r a n d o miz ati o n p eri o d s h o ul d occ ur wit hi n +/- 7 
d a ys of t h e d esi g n at e d ti m e i nt er v al f or t h at st u d y visit.  
9. 1. 1  S C R E E NI N G / R A N D O MI Z A TI O N ( DA Y S -1 4  T O D A Y 0)  
All scr e e ni n g a n d b as eli n e ev al u ati o ns m ust b e c o m pl et e d wit hi n 1 4 d a ys pri or t o r a n d o miz ati o n. C T/ M RI 
sc a ns o bt ai n e d f or cli nic al m a n a g e m e nt pri or t o si g ni n g of t h e 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 
a n d b as eli n e e v al u ati o ns pr o vi di n g  t h es e sc a ns w er e t a k e n wit hi n 2 8 d a y s b ef or e r a n d o miz ati o n a n d c o nf or m 
t o t h e pr ot oc ol i m a g e s p ecific ati o ns i n S ecti o n 9. 2. 1 7 . Ext er n al i m a gi n g will b e acc e pt e d as l o n g as p erf or m e d 
wit h t h e n ec ess ar y s p ecific ati o ns, di git aliz e d, a n d r etri ev a bl e fr o m i nt er n al r a di ol o gic al arc hi v e syst e m. T h e 
q u alit y of ext er n al i m a gi n g h as t o b e a d e q u at e i n or d er t o c a pt ur e li v er v ol u m e m e as ur e m e nt a n d m ass 
c alc ul ati o ns r e q uir e d at b as eli n e. T est r es ults o bt ai n e d f or cli nic al p ati e nt m a n a g e m e nt a n d b ef or e si g ni n g of 
i nf or m e d c o ns e nt d o n ot n e e d t o b e r e p e at e d a n d m a y b e us e d f or scr e e ni n g ass ess m e nt pr o vi d e d t ests w er e 
c o n d uct e d wit hi n 1 4 d ays of r a n d o miz ati o n.  T h e d at e of scr e e ni n g is t h e d at e all scr e e ni n g pr oc e d ur es  ar e 
c o m pl et e d. 
T h e f oll o wi n g acti viti es will b e c o m pl et e d d uri n g t h e scr e e ni n g p eri o d wit hi n 1 4 d a ys pri or t o r a n d o miz ati o n.   
1.  Inf or m e d C o ns e nt m ust b e si g n e d as d escri b e d i n S ecti o n 9. 2. 1 . 
2.  P ati e nt d e m o gr a p hic i nf or m ati o n will b e c oll ect e d as d escri b e d i n S ecti o n 9. 2. 2 . 
3.  M e dic al Hist or y i nf or m ati o n will b e c oll ect e d as d escr i b e d i n S ecti o n 9. 2. 3 . 
4.  A p h ysic al ex a mi n ati o n as d escri b e d i n S ecti o n 9. 2. 4  will b e d o n e . 
5.  C at e g oriz ati o n of t y p e of P V T as d escri b e d i n S ecti o n 9. 2. 5  will b e d o n e.  
6.  E C O G P erf or m a nc e St at us will b e ass ess e d as d escri b e d i n S ecti o n  9. 2. 6 . 
7.  C hil d P u g h will b e ass ess e d as d escri b e d i n S ecti o n 9. 2. 7 . 
8.  M e dic ati o n hist or y  & Pri or tr e at m e nt hist or y will b e o bt ai n e d as d escri b e d i n S ecti o n 9. 2. 8 .  
9.  T h e li v er t u m or v ol u m e c alc ul ati o n will b e c o m pl et e d as d escri b e d i n S ecti o n 9. 2. 9 . 
1 0.  B as eli n e cli nic al l a b or at or y t ests , bl o o d c h e mistr y, h e m at ol o g y  a n d c o a g ul ati o n , as d escri b e d i n 
S ecti o n 9. 2. 1 0  will b e d o n e.  
1 1.  A s er u m pr e g n a nc y t est as d escri b e d i n S ecti o n  9. 2. 1 1  will b e a d mi nist er e d f or all f e m al e p ati e nts 
of c hil d b e ari n g p ot e nti al.  
1 2.  T h e p ati e nt’s eli gi bilit y t o p artici p at e will b e ass ess e d as d escri b e d i n S ecti o n 9. 2. 1 2 . 
1 3.  A b as eli n e A F P  l e v el will b e dr a w n as d escri b e d i n S ecti o n 9. 2. 1 3 . 
1 4.  B as eli n e i m a g es f or effic ac y e v al u ati o n ( S pir al C T of a b d o m e n/ p el vis a n d S pir al  C T of c h est ) will b e 
t a k e n as d escri b e d i n S ecti o n  9. 2. 1 7 . I m a g es t a k e n wit hi n 2 8 d a ys pri or t o r a n d o miz ati o n m a y b e 
us e d as b as eli n e i m a g es.   
1 5.  B as eli n e P ati e nt R e p ort e d O utc o m e  ass ess m e nts will b e m a d e as d escri b e d i n S ecti o n  9. 2. 1 4 . 
1 6.  B o n e sci nti gr a p h y as d escri b e d i n S ecti o n  9. 2. 1 7 .  
 
F oll o wi n g Scr e e ni n g, p ati e nts m e eti n g t h e  eli gi bilit y  crit eri a will b e r a n d o miz e d as d escri b e d i n S ecti o n 9. 2. 1 5 .  
9. 1. 2  P A TI E N T S R A N D O MI Z E D T O T H E C O N T R O L A R M  
9. 1. 2. 1  W E E K 2  F O L L O WI N G R A N D O MI Z A TI O N   
T h e f oll o wi n g st u d y-r el at e d acti viti es will b e c o m pl et e d  as a p pr o pri at e .  P ati e nts m a y n e e d s ev er al visits 
d uri n g t his p eri o d t o a dj ust t h e d os e of s or af e ni b . 
1.  I niti at e s or af e ni b tr e at m e nt as d escri b e d i n S ecti o n  9. 2. 1 6. 2 . 
2.  R ec or d d et ails o n t h e cli nic al ass ess m e nts a n d  a d mi nistr ati o n of s or af e ni b. 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 5  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
3.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
9. 1. 2. 2  Q 4  W E E K S F O L L O WI N G R A N D O MI Z A TI O N T O P R O G R E S SI O N  
A d diti o n al cli nic al m a n a g e m e nt visits ar e p er mitt e d t o m e et l oc al st a n d ar d of c ar e tr e at m e nt r e q uir e m e nts. 
I n a d diti o n t o t h e a d mi nistr ati o n of s or af e ni b a n d t h e e v al u ati o ns ass oci at e d wit h t h at t h er a p y, at ev er y 4  
w e e k visit  f oll o wi n g r a n d o miz ati o n t o w e ek 2 4 or pr o gr essi o n t h e f oll o wi n g acti viti es  will b e c o m pl et e d .  I n 
t h e a bs e nc e of pr o gr essi o n aft er 2 4 w e eks t h e f oll o w u p visit sc h e d ul e will c h a n g e t o e v er y 8 w e eks fr o m 
r a n d o miz ati o n u ntil d et er mi n ati o n of pr o gr essi o n f or t h e p ur p os es of cli nic al m a n a g e m e nt ( S ecti o n 9. 2. 2 0 ). 
1.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
2.  E C O G P erf or m a nc e St at us will b e ass ess e d as d escri b e d i n S ecti o n 9. 2. 6  
3.  Cli nic al l a b or at or y t ests, b l o o d c h e mistr y, h e m at ol o g y  a n d c o a g ul ati o n, A F P, as d escri b e d i n S ecti o n 
9. 2. 1 0  will b e d o n e . 
4.  P ati e nt R e p ort e d O utc o m e  ass ess m e nts will b e o bt ai n e d as d escri b e d i n S ecti o n 9. 2. 1 4 . 
 
9. 1. 2. 3  Q 8  W E E K S F O L L O WI N G R A N D O MI Z A TI O N T O P R O G R E S SI O N   
1.  C T/ M R i m a g es will b e t a k e n a s d escri b e d i n S ecti o n 9. 2. 1 7  f or effic ac y ass ess m e nt 
2.  C h est C T/ M RI i m a g es will b e t a k e n ev er y 1 6 w e eks as d escri b e d i n S ecti o n 9. 2. 1 7 . 
3.  B o n e sci nti gr a p h y f or s el ect e d p ati e nts at w e ek 1 6 t h e n ev er y 6 m o nt hs t h er e aft er as d escri b e d i n 
S ecti o n 9. 2. 1 7  
 
9. 1. 2. 4  Q 8  W E E K S F O L L O WI N G P R O G R E S SI O N T O D E A T H  
E v er y 8 w e e ks f oll o wi n g d et er mi n ati o n of pr o gr essi o n ( S ecti o n 9. 2. 2 0 ), u ntil d e at h, a cli nic visit or t el e p h o n e 
f oll o w-u p ( at t h e i n v esti g at or’s discr eti o n, if a P S ≥ 2 (sy m p t o m atic pr o gr essi o n) is ass ess e d a n d w h e n ev er i n 
t h e b est i nt er est of t h e p ati e nt) will b e c o n d uct e d. T h e f oll o wi n g acti viti es will t a k e pl ac e:  
1.  E C O G P erf or m a nc e St at us (i ncl u di n g d at e of d e at h, if a p plic a bl e) will b e ass ess e d as d escri b e d i n 
S ecti o n 9. 2. 6 . 
2.  R ec or d  a n y  tr e at m e nt  a n d  c o nc urr e nt  m e dic ati o ns t o  tr e at  h e p at oc ell ul ar  c arci n o m a a n d  a ny  
a d v ers e e v e nts as d escri b e d i n S ecti o n s 9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . M e dic ati o ns a n d t h er a pi es us e d i n 
s u p p orti v e c ar e will n ot b e r ec or d e d. 
3.  P ati e nt R e p ort e d O utc o m e  ass ess m e nts will b e o bt ai n e d as d escri b e d i n S ecti o n 9. 2. 1 4  at cli nic visits 
o nl y.  
4.  C hil d P u g h st at us will b e ass ess e d as d escri b e d i n S ecti o n 9. 2. 7  
 
 
9. 1. 3  P A TI E N T S R A N D O MI Z E D T O T H E T R E A T M E N T A R M  
9. 1. 3. 1  W E E K S 1 -4  F O L L O WI N G R A N D O MI Z A TI O N  
T h e f oll o wi n g st u d y-r el at e d acti viti es will b e c o m pl et e d : 
1.  C o m pl et e a p pr o pri at e cli nic al l a b or at or y t ests, i ncl u di n g A F P , as d escri b e d i n S ecti o n 9. 2. 1 0  wit hi n 
7 d a ys  pri or t o T h er a S p h er e a d mi nistr ati o n . 
2.  C o n d uct pr e -T h er a S p h er e  ev al u ati o n wit h i n W e ek 2, as d escri b e d i n S ecti o n 9. 2. 1 6. 1. 2 , a n d 
a d mi nist er T h er a S p h er e  b y t h e e n d of W e ek 4  t o p ati e nts a bl e t o r ec ei v e T h er a S p h er e tr e at m e nt 
as d escri b e d i n S ecti o n 9. 2. 1 6. 1. 7 . F or p ati e nts w h o ar e d et er mi n e d t o b e n ot tr e at a bl e wit h 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
T h er a S p h er e f oll o wi n g t h e pr etr e at m e nt ev al u ati o n, p ati e nts m a y  b e gi n s or af e ni b t h er a p y as s o o n 
as p ossi bl e .  
3.  R ec or d d et ails o n t h e cli nic al ass ess m e nts a n d  a d mi ni str ati o n of T h er a S p h er e . 
4.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
9. 1. 3. 2  T H E R A S P H E R E  R E -T R E A T M E N T   
P ati e nts c a n r ec ei v e a s u bs e q u e nt T h er a S p h er e a d mi nistr ati o n i n t h e a bs e nc e of r a di ol o gic al pr o gr essi o n 
crit eri a  at  i n v esti g at or  discr eti o n  P ati e nts  m ust  m e et  i niti al  eli gi bilit y  crit eri a  t o  r ec ei v e  s u bs e q u e nt  
tr e at m e nts.  A m axi m u m of t hr e e ( 3) T h er a S p h er e a d mi nistr ati o ns ar e p er mitt e d  i n  t ot al. T h er a S p h er e  
tr e at m e nts m a y b e a d mi nist er e d aft er h e p atic pr o gr essi o n if t h e l esi o ns ar e a m e n a bl e t o tr e at m e nt. A n y r e -
tr e at m e nt s h o ul d t a k e pl ac e at l e ast 2 8 d a ys fr o m t h e l ast T h er a S p h er e tr e at m e nt. T h es e o pti o n al tr e at m e nts 
ar e n ot r e q uir e d pr ot oc ol tr e at m e nts a n d ar e a d mi n ist er e d at t h e discr eti o n of t h e i n v esti g at or. T h e f oll o wi n g 
acti viti es will t a k e pl ac e:  
1.  C o m pl et e a p pr o pri at e cli nic al l a b or at or y t ests, as d escri b e d i n S ecti o n 9. 2. 1 0 . 
2.  C o n d uct pr e -T h er a S p h er e  ev al u ati o n as  wit h i nt er v e nti o ns as i n dic at e d  a n d a d mi nist er 
T h er a S p h er e  as d escri b e d i n S ecti o ns 9. 2. 1 6. 1. 2  a n d 9. 2. 1 6. 1. 7 . 
3.  R ec or d d et ails o n t h e cli nic al ass ess m e nts a n d  a d mi nistr ati o n of T h er a S p h er e . 
4.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
5.  R ec or d C hil d P u g h st at us as d escri b e d i n S ecti o n 9. 2. 7  
9. 1. 3. 3  Q 4  W E E K S F O L L O WI N G R A N D O MI Z A TI O N  T O P R O G R E S SI O N   
A d diti o n al cli nic al m a n a g e m e nt visits ar e p er mitt e d t o m e et l oc al st a n d ar d of c ar e tr e at m e nt r e q uir e m e nts. 
At  ev er y 4  w e e k visit  f oll o wi n g r a n d o miz ati o n t o w e ek 2 4 or pr o gr essi o n, t h e f oll o wi n g acti viti es will b e 
c o m pl et e d. I n t h e a bs e nc e of pr o gr essi o n aft er 2 4 w e eks t h e f oll o w u p visit sc h e d ul e will c h a n g e t o e v er y 8 
w e e ks fr o m r a n d o miz ati o n u ntil d et er mi n ati o n of pr o gr essi o n f or t h e p ur p os es of cli nic al m a n a g e m e nt 
( S ecti o n 9. 2. 2 0 ). 
1.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
2.  E C O G P erf or m a nc e St at us will b e ass ess e d as d escri b e d i n S ecti o n  9. 2. 6 . 
3.  Cli nic al l a b or at or y t ests, b l o o d c h e mistr y, h e m at ol o g y  a n d c o a g ul ati o n,  A F P  as d escri b e d i n S ecti o n 
9. 2. 1 0  will b e d o n e . 
4.  P ati e nt R e p ort e d O utc o m e  ass ess m e nts will b e o bt ai n e d as d escri b e d i n S ecti o n 9. 2. 1 4 . 
9. 1. 3. 4  Q 8  W E E K S F O L L O WI N G R A N D O MI Z A TI O N  
1.  C T/ M R i m a g es will b e t a k e n ( as d escri b e d i n S ecti o n 9. 2. 1 7  f or effic ac y ass ess m e nt). 
2.  C h est C T/ M RI i m a g es will b e t a k e n ev er y 1 6 w e eks as d escri b e d i n S ecti o n 9 . 2. 1 7. 
3.  B o n e sci nti gr a p h y f or s el ect e d p ati e nts at w e ek 1 6 t h e n ev er y 6 m o nt hs t h er e aft er as d escri b e d i n 
S ecti o n 9. 2. 1 7   
4.  R ec or d C hil d P u g h st at us as d escri b e d i n S ecti o n 9. 2. 7  
 
9. 1. 3. 5  Q 8  W E E K S F O L L O WI N G P R O G R E S SI O N T O D E A T H  
E v er y 8  w e e ks f oll o wi n g d et er mi n ati o n of pr o gr essi o n  ( S ecti o n 9. 2. 2 0 ), u ntil d e at h, a cli nic visit or t el e p h o n e 
f oll o w-u p (at t h e i n v esti g at or’s discr eti o n, if a P S ≥2 (sy m pt o m atic pr o gr essi o n) is ass ess e d a n d w h e n ev er i n 
t h e b est i nt er est of t h e p ati e nt) will b e c o n d uct e d . T h e f oll o wi n g acti viti es will t a k e pl ac e:  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 7  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1.  E C O G P erf or m a nc e St at us (i ncl u di n g d at e of d e at h, if a p plic a bl e) will b e ass ess e d as d escri b e d i n 
S ecti o n 9. 2. 6 . 
2.  R ec or d  a n y  tr e at m e nt  a n d  c o nc urr e nt  m e dic ati o ns t o  tr e at  h e p at oc ell ul ar  c arci n o m a a n d  a ny  
a d v ers e e v e nts as d escri b e d i n S ecti o n s 9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . M e dic ati o ns a n d t h er a pi es us e d i n 
s u p p orti v e c ar e will n ot b e r ec or d e d. 
3.  P ati e nt R e p ort e d O utc o m e  ass ess m e nts will b e o bt ai n e d as d escri b e d i n S ecti o n 9. 2. 1 4  at cli nic visits 
o nl y.  
F or p ati e nts u n d er g oi n g r etr e at m e nt pr oc e d ur es, st u d y visits will occ ur Q 8 w e ek s, u ntil d et er mi n ati o n of 
s u bs e q u e nt h e p atic pr o gr essi o n, d uri n g w hic h t h e pr oc e d ur es d escri b e d i n S e cti o ns 9. 1. 3. 3  a n d 9. 1. 3. 4  will 
b e c o m pl et e d.   
9. 1. 4  P A TI E N T C O M P L E TI O N O R E A RL Y W I T H D R A W A L 
If a p ati e nt c o m pl et es t h e tri al or wit h dr a ws e arl y, t h e f oll o wi n g acti viti es will b e c o m pl et e d  at st u d y exit as 
a p pr o pri at e : 
1.  R ec or d t h e d at e a n d r e as o n f or st u d y exit, as d escri b e d i n s ecti o n 9. 2. 2 0 .  
2.  R ec or d t h e E C O G st at us as d escri b e d i n S ecti o n  9. 2. 6 , as a p pr o pri at e.  
3.  C o m pl et e, as a p pr o pri at e, a n y cli nic al l a b or at or y t ests, i ncl u di n g A F P, as d escri b e d i n S ecti o n 
9. 2. 1 0 . 
4.  R ec or d a n y tr e at m e nt a n d c o nc urr e nt m e dic ati o ns a n d a n y a d v ers e e v e nts as d escri b e d i n S ecti o n s 
9. 2. 1 8 , 9. 2. 1 9  a n d 1 2. 3 . 
5.  C o m pl et e a n y  C T/ M R i m a g es , as a p pr o pri at e,  f or effic ac y ass ess m e nt.  
6.  C o m pl et e t h e P ati e nt  R e p ort e d O utc o m e  ass ess m e nts , as a p pr o pri at e, as d escri b e d i n S ecti o n 
9. 2. 1 4 . 
9. 2  S T U D Y E V AL U A TI O N S A N D P R O C E D U R E S  
9. 2. 1  P O T E N TI AL L Y E LI GI BL E P A TI E N T S A N D IN F O R M E D C O N S E N T  
A n y p ati e nt w h o a p p e ars t o m e et t h e eli gi bilit y crit eri a  m a y b e off er e d t h e o p p ort u nit y t o b e ev al u at e d f or 
p artici p ati o n i n t his cli nic al tri al. All s uc h p ati e nts m ust si g n a n I R B / E C a p pr o v e d i nf or m e d c o ns e nt f or m, a n d 
h a v e t h e o p p ort u nit y t o ask t h e I n v e sti g at or a n y q u esti o ns r e g ar di n g t h e tri al, a n d t h eir ri g hts a n d o bli g ati o ns 
as a tri al p artici p a nt b ef or e a n y  pr ot oc ol r el at e d  ev al u ati o ns c a n  b e p erf or m e d. T h e d et ails r e g ar di n g  
i nf or m e d c o ns e nt ar e d escri b e d i n S ecti o n 1 3. 7 . 
9. 2. 2  D E M O G R A P HI C S   
D e m o gr a p hic d at a ( d at e of birt h, a g e, g e n d er, f e m al e c hil d b e ari n g p ot e nti al, r ac e, a n d et h nicit y) will b e 
o bt ai n e d.  
9. 2. 3  M E DI C AL H I S T O R Y 
M e dic al hist or y d e e m e d cli nic all y si g nific a nt  b y t h e I n v esti g at or will b e c oll ect e d p er b o d y syst e m ( e. g. 
all er g y/i m m u n ol o g y,
 a u dit or y/ e ar,
 bl o o d/ b o n e
 m arr o w,
 c ar di ac
 arr h yt h mi a,
 c ar di ac
 g e n er al,
 
d er m at ol o g y/ski n, e n d ocri n e m et a b olic, g astr oi nt esti n al, h e m orr h a g e/ bl e e di n g, h e p at o bili ar y / p a ncr e atic, 
inf ecti o n, m usc ul osk el et al/s oft tiss u e, n e ur ol o gic, oc ul ar/ visi o n, psyc hi atric, p ul m o n ar y/ u p p er r es pir at or y, 
s ex u al r e pr o d ucti v e f u ncti o n, v asc ul ar). 
T h e d i a g n os es a n d hist or y of H C C  will b e r ec or d e d s e p ar at el y fr o m ot h er m e dic al hist or y.  
All o n -g oi n g m e di cal c o n diti o ns a n d a d v ers e ev e nts arisi n g fr o m tr e at m e nt of t h os e c o n diti o ns pr es e nt f or 
≥3 0 d a ys ar e g e n er all y c o nsi d er e d a p art of t h e p ati e nt’s m e dic al hist or y a n d m ust b e r ec or d e d at b as eli n e.  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 8  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
9. 2. 4  P H Y SI C A L E X A MI N A TI O N  
A p h ysic al ex a mi n ati o n will als o b e p er f or m e d, w hic h will c o v er t h e f oll o wi n g: 
•  
V it al si g ns:  h e art r at e ( H R ), r es pir at or y r at e (R R ), bl o o d pr ess ur e ( B P ), a n d t e m p er at ur e  ( T) 
•  
H ei g ht a n d w ei g ht  
•  
C h est , a b d o m e n 
•  
H e art  
•  
Extr e miti es  
•  
Bri ef n e ur ol o gic al ex a mi n ati o n (l ev el of c o nsci o us n ess, ori e nt ati o n, s e ns ati o n, a n d m ot or f u ncti o n) 
 
9. 2. 5  C L A S SI FI C A TI O N O F P V T   
T h e  r ef er e nc e st a n d ar d f or c h ar act erizi n g P V T i n cirr h otic p ati e nts wit h or wit h o ut H C C is a  hist o p at h ol o gic 
ex a mi n ati o n. H o w e v er i n t h e pr es e nt tri al f or pr actic al r e as o ns, c o ntr ast e n h a nc e d C T sc a n o r M RI a n d cli nic al 
a n d l a b or at ory fi n di n gs c a n b e r eli e d o n f or c at e g oriz ati o n of P V T a d a pt e d fr o m S hi et al 2 0 1 0 1 7 (s e e A p p e n dix 
2 ). P ort al v ei n t u m or t hr o m b osis ( P V T T) i n H C C is d efi n e d as ex p a nsi o n of t h e t hr o m b osis wit hi n t h e i n v ol v e d 
p ort al v ei n a dj ac e nt t o t h e pri m ar y t u m or a n d e n h a nc e m e nt of t h e t hr o m b us its elf d ur i n g t h e art eri al p h as e 
o n c o ntr ast e n h a nc e d C T or M RI. 1 8 ,1 9  
T h e m a n d at or y r e q uir e m e nts q u alifyi n g p ati e nts f or t h e pr es e nt st u d y is t h e c o nfir m ati o n, acc or di n g t o 
st a n d ar d crit eri a ( hist ol o g y or E A SL/ A A SL D g ui d eli n es) of a d v a nc e d st a g e  H C C ass oci at e d wit h br a nc h P V T.  
F or t h e p ur p os e of t his st u d y, br a nc h P V T is d efi n e d as Ty p e I a or I b, Ty p e II a or II b or Ty p e III a as n ot e d b el o w.  
Pr es e nc e of P V T i n a bs e nc e of f oc al li v er l esi o ns or ass oci at e d o nl y wit h hi g h l ev els of A F P, is n ot eli gi bl e f or 
t h e st u d y b ec aus e of t h e l ac k of a t ar g et l esi o n.  
At t h e scr e e ni n g visit a n d s u bs e q u e nt Q 8 w e ekl y visits : 
•  
v e n o us l oc ati o n of t h e P V T  will b e  r ec or d e d o n t h e e C R F  
•  
t u m or l oc ati o n (l o b e/s e g m e nt) will b e r ec or d e d o n t h e e C R F 
•  
P V T will b e c at e g oriz e d b as e d o n d y n a mic i m a gi n g st u di es as:  
- 
Ty p e I: s e g m e nt al, t o b e d e m o nstr at e d at i m a gi n g i n at l e ast o n e of t h e ei g ht s e g m e nt al 
br a nc h es of t h e p ort al v ei n ( p eri p h er al or s u b -s e g m e nt al v e n o us i n v asi o n ar e n ot eli gi bl e) 
- 
Ty p e II: br a nc h e d (l eft or ri g ht br a nc h es of t h e p ort al v ei n) 
- 
Ty p e III h as b e e n m o difi e d o n t h e b asis of ext e nsi o n of t h e t u m or t hr o m b us r at h er t h a n o n t h e 
l e n gt h of t h e t u m or t hr o m b us; i n p artic ul ar: 
o  
Ty p e III a, eli gi bl e t o t h e st u d y: t hr o m b us i n v ol vi n g t h e m ai n p ort al tr u n k alt h o u g h 
a ll o wi n g bl o o d fl o w t o t h e c o ntr al at er al l o b e ( wit h n o t hr o m b osis) 
o  
Ty p e III b, N O T eli gi bl e t o t h e st u d y: t hr o m b us i n t h e m ai n p ort al tr u n k occl u di n g bl o o d 
fl o w t o t h e c o ntr al at er al l o b e; i ncl u d es p ort al c a v er n o m as ass oci at e d wit h m ai n tr u n k 
t hr o m b osis  
- 
Ty p e I V: m ai n P V T –  N O T eli gi bl e t o t h e st u d y; ext e n d e d ( m es e nt eric or s pl e nic v ei ns a n d/ or 
s o vr a-h e p atic v ei ns)  
 
9. 2. 6  E C O G  P E R F O R M A N C E S T A T U S  
P erf or m a nc e St at us will b e ass ess e d acc or di n g t o 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
2 0 p erf or m a nc e 
st at us c h ar act eristic (s e e A p p e n dix 3 ). 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
2 9  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
 
9. 2. 7  C HIL D P U G H S T A T U S  
S ev erit y of li v er dis e as e will b e ass ess e d acc or di n g t o t h e C hil d P u g h Cl assific ati o n of S e v erit y of Li v er Dis e as e 
(s e e A p p e n dix 4 ) at scr e e ni n g a n d at ev er y 8 w e ek visit . 
9. 2. 8  M E DI C A TI O N A N D P RI O R T R E A T M E N T H I S T O R Y 
T h e us e of c o nc urr e nt m e dic ati o ns ( m e d ic ati o ns t a k e n wit hi n 3 0 d a ys of scr e e ni n g a n d d uri n g t h e c o n d uct of 
t h e st u d y) will b e o bt ai n e d a n d d oc u m e nt e d o n t h e r el e v a nt e C R F .  
Pri or tr e at m e nts  f or H C C will b e r ec or d e d s e p ar at el y fr o m tr e at m e nt f or ot h er m e dic al c o n diti o ns.  
T h e st art a n d st o p d at e s f or all s uc h pri or tr e at m e nts f or H C C or ot h er c a nc er tr e at m e nts as w ell as pri or 
tr e at m e nt of ot h er m e dic al c o n diti o ns s h o ul d b e r ec or d e d. 
9. 2. 9  L I V E R T U M O R V OL U M E D E T E R MI N A TI O N  
Tri pl e P h as e C T is  t h e f ast est a n d m ost r e pr o d uci bl e m et h o d of c a pt uri n g li v er v ol u m e m e as ur e m e nt a n d 
m ass c alc ul ati o ns r e q uir e d at B as eli n e . Tri pl e p h as e C T will b e us e d  i n acc or d a nc e wit h sit e st a n d ar ds f or 
d osi m etr y d et er mi n ati o n. I n a d diti o n C T or M RI b as eli n e i m a g es s h o ul d b e t a k e n f or d et er mi n ati o n of 
pr o gr essi o n. S u bs e q u e nt i m a g es t o d et er mi n e effic ac y o utc o m es m ust b e t a k e n usi n g t h e s a m e m o d alit y a n d 
s etti n gs us e d f or t h e b as eli n e i m a g e. Acc ur at e i m a gi n g a n d v ol u m e c alc ul ati o n ar e ess e nti al f or c alc ul ati o n of 
T h er a S p h er e  d osi m etr y.  
Usi n g i nstit uti o n al st a n d ar d e q ui p m e nt a n d t ec h ni q u es, l o b ar a n d t u m or r e gi o ns of i nt er est will b e dr a w n 
a n d t h e l o b ar a n d t u m or v ol u m es d et er mi n e d . T u m or r e pl ac e m e nt, ex pr ess e d as a p er c e nt of t ot al li v er 
v ol u m e, will b e r ec or d e d o n t h e  r el e v a nt e C R F.  
9. 2. 1 0  C LI NI C A L L A B S   
T h e f oll o wi n g cli nic al l a b or at or y ass ess m e nts will b e c o m pl et e d at st u d y visits d uri n g t h e tri al a n d m ust b e 
d oc u m e nt e d as d escri b e d i n S ecti o n 1 3. 4 . 
•  
H e m at ol o g y: c o m pl et e bl o o d c ell ( C B C) c o u nt,  diff er e nti al w hit e bl o o d c o u nt ( W B C) c o u nt, pl at el et 
c o u nt, h e m at ocrit, h e m o gl o bi n  
•  
C o a g ul ati o n: P arti al T hr o m b o pl asti n Ti m e ( P T T) ; Pr ot hr o m bi n Ti m e ( P T) or  I nt er n ati o n al N or m aliz e d 
r ati o f or pr ot hr o m bi n ti m e (I N R)  
•  
C h e mistr y p a n el: s er u m cr e ati ni n e, bl o o d ur e a nitr o g e n ( B U N), gl uc os e, as p art at e a mi n otr a nsf er as e 
( A S T), al a ni n e a mi n otr a nsf er as e ( AL T), al b u mi n, t ot al bilir u bi n, a n d al k ali n e p h os p h at as e. 
•  
Al p h af et o pr ot ei n ( A F P ) 
9. 2. 1 1  P R E G N A N C Y T E S T  
A s er um  pr e g n a nc y t est f or f e m al es  of c hil d -b e ari n g p ot e nti al will b e p erf or m e d  at t h e scr e e ni n g visit .  
P ati e nts d et er mi n e d t o b e pr e g n a nt ar e n ot eli gi bl e t o p artici p at e i n t his cli nic al tri al.  
F e m al e p ati e nts of c hil d b e ari n g p ot e nti al m ust b e a d vis e d t h at t h e y s h o ul d n ot b ec o m e pr e g n a nt w hil e 
p artici p ati n g i n t his cli nic al tri al. A d e q u at e m et h o ds of c o ntr ac e pti o n m ust b e us e d b y t h es e p ati e nts w hil e 
t h ey ar e e nr oll e d i n t his cli nic al tri al. P ati e nts s h o ul d n ot b e br e astf e e di n g w hil e p artici p ati n g o n t his tri al . 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
9. 2. 1 2  R E VI E W E LI GI BILI T Y C RI T E RI A  
D at a d et aili n g D e m o gr a p hic, M e dic al Hist or y, P h ysic al Ex a mi n ati o n, P V T Cl assific ati o n, E C O G P erf or m a nc e 
St at us, C hil d P u g h St at us, M e dic ati o n a n d Pri or O nc ol o gic Tr e at m e nt, T u m or a n d Li v er v ol u m e a n d Cli nic al 
L a bs will b e r e vie w e d t o d et er mi n e eli gi bilit y  i n acc or d a nc e wit h t h e eli gi bilit y crit eri a. T h e d et er mi n ati o n will 
b e r ec or d e d o n t h e r el e v a nt c as e r e p ort f or m ( e C R F ). 
9. 2. 1 3  H C C  T U M O R B I O M A R K E R ( A F P) 
Bl o o d will b e c oll ect e d pri or t o a n d at t h e Q 8 w e eks  st u d y f oll o w-u p visits f oll o wi n g r a n d o miz ati o n t o 
d et er mi n e t h e b as eli n e a n d s u bs e q u e nt A F P  v al u es.   
9. 2. 1 4  P A TI E N T R E P O R T E D O U T C O M E  
F u ncti o n al  Ass ess m e nt  of  c a nc er  T h er a p y  –  H e p at o bili ar y  Q u esti o n n air e  ( F A C T -H E P ) P ati e nt  R e p ort e d  
O utc o m e  i nstr u m e nt s uit a bl e f or p ati e nts b ei n g tr e at e d f or h e p at oc ell ul ar c arci n o m a  will b e a d mi nist er e d at 
st u d y visits t hr o u g h o ut t h e tri al ( ev er y 4 w e eks t o W e ek 2 4 or pr o gr essi o n, w hic h e v er is e arli est) , t h e n ev er y 
8 w e e ks t h er e aft er . T h e b as eli n e Q u alit y of Lif e (Q OL ) F A C T -H E P ass ess m e nt s will b e o bt ai n e d d uri n g t h e 
Scr e e ni n g p eri o d aft er t h e I nf or m e d C o ns e nt is si g n e d a n d b ef or e t h e first tr e at m e nt i n eit h er ar m  is 
a d mi nist er e d.  If t h e p ati e nt c a n n ot att e n d f oll o w-u p visits,  F A C T -H E P q u esti o n n air es will n ot  b e c o m pl et e d .  
. 
9. 2. 1 5  R A N D O MI Z A TI O N ( DA Y 0 ) 
Acc or di n g t o a n i nt e nti o n -t o-tr e at (I T T) m et h o d ol o g y, r a n d o miz ati o n will b e p erf or m e d u pfr o nt, b ef or e a n y 
f urt h er i n v asi v e t u m or ass ess m e nt ( a n gi o gr a m) or tr e at m e nt pl a n ni n g. 
P ati e nts will b e r a n d o miz e d 1: 1 t o st u d y tr e at m e nt, eit h er t h e C o ntr ol ar m  or t h e Tr e at m e nt  ar m .   
If a p ati e nt is d et er mi n e d t o b e eli gi bl e t o p artici p at e i n t h e tri al, t h e st u d y sit e will c o nt act t h e c e ntr al 
r a n d o miz ati o n offic e vi a t el e p h o n e or b y i nt er n et  w h er e r a n d o miz ati o n will b e d et er mi n e d usi n g assi g n m e nt 
b y a c o m p ut er -g e n er at e d r a n d o miz ati o n sc h e m e.  U p o n r a n d o miz ati o n, e ac h p ati e nt will b e assi g n e d a 
s u bj ect i d e ntit y c o d e c o nsisti n g of t h e pr ot oc ol n u m b er, t h e sit e n u m b er ( e .g . 0 1)  a n d a p ati e nt i d e ntifi er 
n u m b er ( e. g.  0 0 1) .  
In or d er t o cr e at e a b al a nc e b et w e e n st u d y ar m s, p ati e nts will b e str atifi e d at r a n d o miz ati o n b as e d o n t h e 
f oll o wi n g:  
•  
A F P ≤ 4 0 0 n g/ mL or > 4 0 0 n g/ mL  
•  
P artici p ati n g tri al sit e  
Alt h o u g h t his will n ot b e c o nsi d er e d as str atific ati o n crit eri a u pfr o nt , e ac h p ati e nt will b e r e gist er e d as n aï v e 
or r ec urr e nt, i. e. w h et h er or n ot t h e H C C di a g n osis pr es e nts at first di a g n osis, wit h n o pr evi o us tr e at m e nt, or 
as a r ec urr e nt t u m or.  
P ati e nts r a n d o miz e d t o t h e C o ntr ol ar m  or t h e Tr e at m e nt  ar m,  u n a bl e t o r ec ei v e t h eir pl a n n e d st u d y 
tr e at m e nt, will c o nti n u e t o b e f oll o w e d u n d er t h eir assi g n e d st u d y ar m  f or t h e p ur p os e of t h e i nt e nt-t o-tr e at 
a n al ysis.   
P ati e nt s w h o d o n ot m e et t h e eli gi bilit y crit eri a s h o ul d n ot b e r a n d o miz e d a n d t h e r e as o n f or tr e at m e nt 
i n eli gi bilit y s h oul d b e d oc u m e nt e d o n t h e Scr e e n F ail ur e L o g.   
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
 
9. 2. 1 6  S T U D Y T R E A T M E N T S  
9. 2. 1 6. 1  T H E R A S P H E R E   
T h er a S p h er e  will b e a d mi nist er e d t o all dis e as e pr es e nt at r a n d o miz ati o n.  
9. 2. 1 6. 1. 1  R E -T R E A T M E N T  
P ati e nts c a n r ec ei v e a s u bs e q u e nt T h er a S p h er e a d mi nistr ati o n i n t h e a bs e nc e of r a di ol o gic a l pr o gr essi o n 
crit eri a  at  i n v esti g at or  discr eti o n.  D uri n g  f oll o w -u p,  f or  p ati e nts  i n  t h e  Tr e at m e nt  ar m  w h o  h a v e  
d e m o nstr at e d  h e p atic  pr o gr essi o n  wit h  h e p atic  l esi o ns  a m e n a bl e  t o  T h er a S p h er e ., r e-tr e at m e nt wit h 
T h er a S p h er e  is all o w e d.  A n y r e-tr e at m e nt s h o ul d t a k e pl ac e at l e ast 2 8 d a ys fr o m t h e l ast T h er a S p h er e 
tr e at m e nt.  
P ati e nts m ust m e et i niti al eli gi bilit y crit eri a  f or T h er a S p h er e tr e at m e nt (S ecti o n 8. 1 ) t o r ec ei v e s u bs e q u e nt 
tr e at m e nts. A m axi m u m of t hr e e ( 3) T h er a S p h er e a d mi nistr ati o ns ar e p er mitt e d i n t ot al. 
P ati e nts  will  u n d er g o  a d diti o n al  pr e -tr e at m e nt  e v al u ati o ns  as  d escri b e d  i n  S ecti o n  9. 2. 1 6. 1. 2  at  t h e  
i n v esti g at or’s discr eti o n pri or t o a d mi nistr ati o n of s u bs e q u e nt T h er a S p h er e  tr e at m e nts t o ass ess a n d a d dr ess 
a n y c h a n g es i n extr a -h e p atic s h u nti n g  t h at m a y h a v e d ev el o p e d. 
9. 2. 1 6. 1. 2  T H E R A S P H E R E  P R E -T R E A T M E N T E V A L U A TI O N  
P ati e nts r a n d o miz e d t o t h e Tr e at m e nt  ar m  m ust u n d er g o t h e f oll o wi n g ev al u ati o n s t o d et er mi n e eli gi bilit y 
t o r ec ei v e t h e T h er a S p h er e . T h es e  i ncl u d e: 
•  
H e p atic A n gi o gr a p h y : s el ecti v e c eli ac a n d s u p eri or m es e nt eric art eri o gr a ms ar e n e e d e d t o ev al u at e 
t h e h e p atic art eri al a n at o my f or t h e w h ol e li v er, as w ell as e v al u ati o n of p ot e nti al s o urc es of extr a-
h e p atic bl o o d s u p pl y t o t u m ors.  T h e g o al is t o i d e ntify, wit hi n t h e h e p atic  v asc ul ar a n at o my, a 
c at h et er pl ac e m e nt l oc ati o n t h at all o ws a si n gl e T S i nf usi o n t hr o u g h o ut t h e l o b ar t u m or v ol u m e 
wit h o ut a d mi nistr ati o n of micr os p h er es t o extr a -h e p atic str uct ur es.   
•  
A  t ec h n eti um -9 9 m m acr o a g gr e g at e d al b u mi n ( 9 9 mTc -M A A) sc a n is us e d t o ass ess t h e p ot e nti al f or 
s h u nti n g micr os p h er es t o t h e l u n gs as w ell as t h e p ot e nti al f or t h e d e p ositi o n of micr os p h er es t o 
t h e g astr oi nt esti n al ( GI) tr act. R e p e at 9 9 mTc -M A A m a y b e n e e d e d  f or s u bs e q u e nt tr e at m e nts t o 
esti m at e c u m ul ati v e l u n g s h u nt or r e -ass es GI fl o w.   N ot e t h at 3 t ec h nic al f act ors (ti m e b et w e e n 
a d mi nistr ati o n of 9 9 mTc -M A A  a n d t h e sc a n, 9 9 mTc -M A A  p articl e siz e a n d t h e pr es e nc e of fr e e 9 9 mTc -
M A A ) c a n l e a d t o a n o v er-esti m ati o n of s h u nti n g t o t h e l u n gs.  
T h er a S p h er e  s h o ul d n ot b e a d mi nist er e d t o a p ati e nt r a n d o miz e d t o t h e Tr e at m e nt ar m if:  
•  
D e p ositi o n of micr os p h er es t o t h e GI tr act t h at c a n n ot b e c orr ect e d b y pl ac e m e nt of t h e c at h et er 
dist al t o c oll at er al v ess els or t h e a p plic ati o n of st a n d ar d a n gi o gra p hic t ec h ni q u es, s uc h as c oil 
e m b ol iz ati o n t o pr ev e nt d e p ositi o n of micr os p h er es i n t h e GI tr act. 
 
•  
Ex p os ur e  of r a di ati o n t o t h e l u n gs of 3 0 Gr a y ( Gy) f or a si n gl e i nf usi o n or a c u m ul ati v e 5 0 G y li mit f or 
all i nf usi o ns of T h er a S p h er e  t h at c a n n ot b e c orr ecte d b y d os e r e d ucti o n of T h er a S p h er e.  
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 2  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
I n t h e ev e nt t h at a  p ati e nt  r a n d o miz e d t o t h e T h er a S p h er e ar m is d et er mi n e d n ot t o b e s uit a bl e f or a n d/ or 
c a n n ot b e s af el y tr e at e d wit h T h er a S p h er e , t h at p ati e nt will n ot r ec ei v e T h er a S p h er e a n d m a y pr oc e e d t o 
tr e at m ent wit h S O C s or af e ni b  r e gi m e n as d escri b e d i n S ecti o n 9. 2. 1 6. 2 .  
9. 2. 1 6. 1. 3  T H E R A S P H E R E  A D MI NI S T R A TI O N S T R A T E G Y  
F or p ati e nts eli gi bl e t o r ec ei v e T h er a S p h er e , t h e a d mi nistr ati o n str at e g y (c h oic e of art er y p ositi o n t o i nf us e 
t h e t ar g et v asc ul ar b e d; s el ecti o n of pl ac e m e nt of c oil e m b oliz ati o n or ot h er t ec h ni q u es us e d t o pr ev e nt 
micr os p h er e d e p ositi o n t o t h e GI tr act) s h o ul d b e d et er mi n e d . D osi m etr y is b as e d o n t h e v ol u m e of t h e t ar g et 
v asc ul ar b e d s u p pli e d b y t h e art er y s el ect e d f or i nf usi o n.  P ati e nts r e q uiri n g c oil e m b oliz ati o n t o pr ev e nt 
micr os p h er e dis p ositi o n t o t h e GI tr act s h o ul d u n d er g o t his pr oc e d ur e d uri n g T h er a S p h er e  w or k -u p.    
Si nc e t h e tr e at m e nt a p pr o ac h f or Y 9 0 is l o b ar, pr o p er i m a gi n g a n d v ol u m e c alc ul ati o n is ess e nti al f or 
d osi m etr y p ur p os es.  T h e a bilit y t o u n d erst a n d h e p atic a n at o my r eli es o n t h e s o u n d u n d erst a n di n g of t h e 
C o ui n a u d h e p atic s e g m e nts 2 1.  A n at o mic all y, t h e mi d dl e h e p atic v ei n s e p ar at es t h e ri g ht a n d l eft l o b es.  W h e n 
dr a wi n g r e gi o ns of i nt er est a n d c alc ul ati n g l o b ar v ol u m es, it is t h e mi d dl e h e p atic v ei n t h at s h o ul d b e us e d 
as t h e a n at o mic d eli n e at or b et w e e n t h e ri g ht a n d l eft l o b es.  If t h e mi d dl e h e p atic v ei n c a n n ot b e s e e n, t h e n 
t h e g all bl a d d er a n d its axis r el ati v e t o t h e li v er c a n b e us e d.  T his t ec h ni q u e ass u m es st a n d ar d art eri al 
a n at o my wit h si n gl e ri g ht a n d l eft h e p atic art eri es.  If v ari a nts ar e o bs er v e d a n gi o gr a p hic all y, f or ex a m pl e, a n 
acc ess or y ri g ht h e p atic art er y, t h e n acc ur at e a n gi o gr a p hic c orr el ati o ns m ust b e p erf or m e d w h e n dr a wi n g t h e 
r e gi o ns of i nt er est f or l o b ar or s e g m e nt al l o b ar v ol u m es.  T his will e ns ur e t h at acc ur at e v ol u m es ar e o bt ai n e d 
a n d 3 or m or e i nf usi o ns ar e a d mi nist er e d.  T h e v ol u m e t h at n e e ds t o b e us e d f o r Y 9 0 d osi m etr y is t h at v ol u m e 
of li v er t h at is p erf us e d b y t h e v ess el t h at will b e i nf us e d.  
Art eri al r e distri b uti o n t ec h ni q u es ar e p er mitt e d f or i ntr a -t u m or al a n d/ or l ess t h a n o n e li v er s e g m e nt. 
T ar g et li v er m ass is d et er mi n e d b y t h e p ositi o ni n g of t h e d e li v er y c at h et er i n t h e h e p atic v asc ul at ur e a n d t h e 
r es ulti n g li v er ar e a (s e g m e nts) i nf us e d.  Si nc e t h er e is c o nsi d er a bl e i n di vi d u al v ari ati o n i n h e p atic v asc ul ar 
a n at o my, t h e d et er mi n ati o n of t ar g et li v er m ass will d e p e n d o n t h e v ari a nt e nc o u nt er e d.  T h e T a bl e b el o w 
pr es e nts t h e m ost c o m m o nl y e nc o u nt er e d v ari a nts wit h t h e c orr es p o n di n g s e g m e nts ass oci at e d t o t h e m.   
 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 3  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
 
S T A N D A R D  A N D  V A RI A N T  H E P A TI C  V A S C U L A R  A N A T O M Y  A N D  C O R R E S P O N DI N G  
C O UI N A U D  S E G M E N T S  
H e p atic V asc ul ar A n at o m y a: A n gi o gr a p hic 
Fi n di n gs  
T ar g et S e g m e nts 
–  I nf usi o n 1b ,c 
T ar g et S e g m e nts 
–  I nf usi o n 2 
T ar g et S e g m e nts –
A d diti o n al I nf usi o n  
St a n d ar d ri g ht a n d l eft h e p ati c art eri e s  
1, 5, 6, 7, 8  
2, 3, 4  
 
R e pl a c e d  ri g ht  h e p ati c  wit h  fl o w  t o  m e di al  
s e g m e nt l eft l o b e  
1, 4, 5, 6, 7, 8  
2, 3  
 
R e pl a c e d 
ri g ht  h e p ati c  art er y  wit h o ut  fl o w  t o  
mi d dl e l o b e, l eft h e p ati c art er y wit h fl o w t o m e di al 
a n d l at er al s e g m e nt s l eft l o b e  
1, 5, 6, 7, 8  
2, 3, 4  
 
R e pl a c e d l eft h e p ati c art er y  wit h o ut fl o w t o m e di al 
l o b e 
1, 4, 5, 6, 7, 8  
2, 3  
 
R e pl a c e d l eft  h e p ati c  art er y  w it h  fl o w t o m e di al 
l o b e 
1, 5, 6, 7, 8  
2, 3, 4  
 
A c c e s s or y ri g ht h e p ati c art er y  
6, 7  
2, 3, 4  
1, 5, 8  
Ri g ht  h e p ati c  art er y  i n  t h e  pr e s e n c e  of  a n  
a c c e s s or y ri g ht h e p ati c  
5, 8  
2, 3, 4  
1, 6, 7  
Mi d dl e h e p ati c art er y  (irr e s p e cti v e of ori gi n) 
1, 5 , 6, 7, 8  
4  
2, 3  
N ot es:  
a) v asc ul ar a n at o m y s u bj ect t o v ari ati o n  
b) ass u m es c a u d at e l o b e (s e g m e nt 1) d eriv es bl o o d s u p pl y fr o m ri g ht h e p atic art er y  
c) c a u d at e l o b e (s e g m e nt 1), ri g ht a nt eri or l o b e (s e g m e nts 5/ 8), ri g ht p ost eri or l o b e  
(s e g m e nts 6/ 7), l eft m e di al l o b e ( 4), l eft l at er al l o b e ( 2, 3) 
9. 2. 1 6. 1. 4  T H E R A S P H E R E  D O S E D E T E R MI N A TI O N  
T h e scr e e ni n g a n gi o gr a m a n d 9 9 mT C -M A A  sc a n ar e us e d t o d et er mi n e l o b ar li v er v ol u m e fr o m C T or M R 
i m a g es, t o i d e ntify v asc ul ar s h u nti n g t o t h e g astr oi nt esti n al tr act r e q uiri n g us e of a n gi o gr a p hic occl usi o n 
t ec h ni q u es a n d t o d et er mi n e t h e l u n g s h u nt fr acti o n. P ati e nts will r ec ei v e T h er a S p h er e at a d os e c o nsist e nt 
wit h t h e a p pr o v e d pr o d uct l a b el . T h e t ar g et d os e is 1 2 0 Gy ± 1 0 %.  D os e r e d ucti o n is p er mitt e d w h e n r e q uir e d 
t o e ns ur e r a di ati o n ex p os ur e t o t h e l u n g is l ess t h a n 3 0 Gy f or a si n gl e tr e at m e nt or 5 0 G y c u m ul ati v e. D os e 
r e d ucti o n b el o w 8 0 Gy p er tr e at m e nt is n ot p er mitt e d.  
C alc ul ati o n of L u n g S h u nt F act or :  L u n g s h u nt f act or is d et er mi n e d fr o m t h e 9 9 mTc -M A A  sc a n usi n g t h e 
f oll o wi n g e q u ati o n:  
Lu n g s h u nt Fr acti o n ( F) = t ot al l u n g c o u nts/(t ot al l u n g + li v er c o u nts)  
C alc ul ati o n of T ar g et Li v er M ass:  C o n v ert t h e t ar g et li v er v ol u m e t o m ass ass u mi n g a c o n v ersi o n f act or of 
1. 0 3 g/c m 3.   
 
C alc ul ati o n of Acti vit y r e q uir e d t o d eli v er a  d esir e d d os e of 1 2 0 G y : 
T h e a m o u nt of r a di o acti vit y r e q uir e d t o d eli v er a  d esir e d t ar g et d os e ( 1 2 0 Gy) t o t h e s el ect e d li v er t ar g et , 
a dj ust e d f or t h e esti m at e d fr acti o n t h at will b e s h u nt e d t o t h e l u n g, is c alc ul at e d usi n g t h e f oll o wi n g f or m ul a:  
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 4  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
Acti vit y R e q uir e d ( G B q) = [ D esir e d D os e  ( Gy)] [ M ass of S el ect e d Li v er T ar g et ( k g)][ 1 + F] 
5 0  
C alc ul ati o n of esti m at e d l u n g r a di ati o n ex p os ur e ( Gy) : 
  
L u n g D os e ( Gy) p er i nf usi o n = 5 0 * C alc ul at e d Acti vit y i n gi g a b ec q u er el  ( G B q) * F 
C u m ul ati v e ex p os ur e is t h e s u m of esti m at e d ex p os ur e p er i nf usi o n f or all pl a n n e d i nf usi o ns.  
 
9. 2. 1 6. 1. 5  T H E R A S P H E R E  D O S E V I A L S E L E C TI O N  
S el ecti o n of t h e d os e vi al siz e t o s u p pl y t h e  r e q uir e d acti vit y ( G B q) f or d eli v er y of t h e d esir e d t ar g et d os e t o 
t h e s el ect e d t ar g et li v er v ol u m e vi a t h e s el ect e d v asc ul ar r o ut e is d e pe n d e nt o n t h e d a y a n d ti m e of t h e 
sc h e d ul e d p ati e nt tr e at m e nt a n d m ust acc o u nt f or t h e ti m e z o n e i n w hic h t h e h os pit al is l oc at e d a n d t h e 
d ec a y i n r a di o acti vit y o v er ti m e. T h e i m p act of ti m e f or a v ail a bl e d os e siz es is ill ustr at e d i n t h e d ec a y c ur v e 
b el o w.  
T h e T h er a S p h er e  Tr e at m e nt  Wi n d o w  Ill ustr at or  c a n  b e  us e d  t o  s el ect  t h e  a p pr o pri at e  d os e  vi al  or  
c o m bi n ati o n of d os e vi al(s) r e q uir e d t o d eli v er t h e c alc ul at e d acti vit y r e q uir e d.  
 
N ot e: T h e n u m b er of micr os p h er es d o es n ot c h a n g e ov er ti m e.  
 
 
9. 2. 1 6. 1. 6  T H E R A S P H E R E  O R D E RI N G  
Or d ers m ust b e pl ac e d usi n g t h e or d er f or m pr o vi d e d b y t h e s p o ns or. St a n d ar d d os e vi al siz es ( 3 G B q, 5 G B q, 
7 G B q, 1 0 G B q, 1 5 G B q a n d 2 0 G B q) ar e m a d e t o st oc k a n d c a n b e or d er e d at a n yti m e. Or d ers f or c ust o m siz e 
d os e vi als m ust b e r ec ei v e d at T h er a S p h er e C ust o m er S er vic e  b y 1 2 n o o n E ast er n Ti m e  o n t h e T u es d a y b ef or e 
t h e d esir e d C ali br ati o n D at e ( a p pr oxi m at el y D a y 7 -1 0  p ost -r a n d o miz ati o n). T h er a S p h er e  will b e d eli v er e d t o 
t h e i nstit uti o n’s d esi g n at e d r a di o p har m ac y  a n d h a n dl e d acc or di n g t o i nstit u ti o n al pr actic es.  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 5  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
E ac h vi al of T h er a S p h er e  will b e s hi p p e d wit h a p ac ki n g sli p, a c o p y of w hic h m ust b e tr a nsf err e d t o t h e st u d y 
c o or di n at or f or d evic e acc o u nt a bilit y s o t h at t h e vi als us e d c a n b e tr ac k e d t o t h e s p ecific i nf usi o n(s) f or e ac h 
p ati e nt.  Dis p os al of us e d or a n y u n us e d vi als will b e h a n dl e d i n acc or d a nc e wit h h os pit al st a n d ar d pr actic es 
f or dis p os al of r a di o acti v e m at eri als. 
9. 2. 1 6. 1. 7  T H E R A S P H E R E  A D MI NI S T R A TI O N  
T h er a S p h er e  will b e a d mi nist er e d at a d os e c o nsist e nt wit h t h e a p pr o v e d pr o d uct l a b el.  A t ar g et d os e of 1 2 0 
+  1 0 % Gy t o t h e t ar g et li v er tiss u e is r ec o m m e n d e d. D os e r e d ucti o n t o a mi ni m u m d os e of 8 0 +  1 0 % Gy is 
p er mitt e d t o m a n a g e r a di ati o n ex p os ur e t o t h e l u n gs wit hi n t h e li mits of 3 0 Gy f or a si n gl e i nf usi o n a n d 5 0 
Gy c u m ul ati v e.    
D uri n g f oll o w -u p, f or p ati e nts i n t h e Tr e at m e nt ar m  w h o h a v e d e m o nstr at e d h e p atic pr o gr essi o n wit h h e p atic 
l esi o ns a m e n a bl e t o T h er a S p h er e , r e-tr e at m e nt wit h T h er a S p h er e  is all o w e d.  
T h er a S p h er e  s h o ul d b e a d mi nist er e d b y a p pr o pri at el y tr ai n e d or d esi g n at e d p ers o n n el fr o m t h e d e p art m e nts 
of R a di ol o g y, N ucl e ar M e dici n e, a n d/ or I nt er v e nti o n al R a di ol o g y.  
T h er a S p h er e  a d mi nistr ati o n is g e n er all y c o nsi d er e d t o b e a n o ut p ati e nt pr oc e d ur e i n N ort h A m eric a . It is 
g e n er all y c o nsi d er e d t o b e a n i n p ati e nt pr oc e d ur e i n so m e c o u ntri es i n E ur o p e. T h e p h ysic al l oc ati o n f or 
aft er -c ar e a n d r ec o v er y will b e d et er mi n e d b y i n di vi d u al i nstit uti o n al p olici es a n d f acilit y c o nfi g ur ati o ns.  T h e 
l oc ati o n  a n d  s e q u e nci n g  of tr e at m e nt  pr oc e d ur e m a y  v ar y  d e p e n di n g  o n  t h e p h ysic al  l oc ati o n  of  t h e  
a n gi o gr a p h y a n d n ucl e ar m e dici n e s uit es, t h e a v ail a bilit y  of p ort a bl e g a m m a c a m er as, a n d t h e cli nic al 
j u d g m e nt of t h e p h ysici a n r es p o nsi bl e f or t h e tr e at m e nt pl a n. 
O n t h e d a y of tr e at m e nt, a n art eri al c at h et er will b e pl ac e d p erc ut a n e o usl y vi a t h e f e m or al or br ac hi al art er y 
u n d er i m a g e g ui d a nc e.  T h e i nt er v e nti o n al r a di ol o gist p erf or ms t his pr oc e d ur e.  T h e p at e nc y of t h e c at h et er 
is m ai nt ai n e d  b y  a n  i nf usi o n  of n or m al  s ali n e a n d  a  c o a g ul ati o n  i n hi bit or  ( p er  i nstit uti o n al  pr ot oc ols)  
a d mi nist er e d vi a a  c o nti n u o us i nf usi o n p u m p. Pr o p er c at h et er p ositi o ni n g i n t h e s el ect e d l oc ati o n i n t h e 
h e p atic art er y will b e v erifi e d o n a n gi o gr a p h y b ef or e T h er a S p h er e  a d mi nistr ati o n.  
St a n d ar d m e dic ati o n pr ot oc ol f or s e d ati o n, p ai n a n d i nf ecti o n pr o p h yl axis s h o ul d b e i m pl e m e nt e d p er 
est a blis h e d i nstit uti o n al pr ot oc ols. Pr o p h yl axis wit h a g astric i n hi bit or ( H 2 bl oc k er  or pr ot o n p u m p i n hi bit or ) 
is r ec o m m e n d e d t o mi ni miz e risk of p ost-tr e at m e nt g astr oi nt esti n al si d e eff ects.  Alt h o u g h r ec o m m e n d e d 
f or  all  p ati e nts u n d er g oi n g tr e at m e nt,  t his pr o p h yl axis is  es p eci all y  i m p ort a nt  f or  p ati e nts u n d er g oi n g  
T h er a S p h er e  tr e at m e nt t o t h e l eft l o b e of t h e li v er, d u e t o t h e pr oxi mit y of t h e g astr oi nt esti n al or g a ns, a n d 
f or p ati e nts wit h a pri or hist or y of p e ptic ulc er dis e as e.  T h er a p y sh o ul d b e gi n o n t h e d a y of T h er a S p h er e  
tr e at m e nt a n d c o nti n u e f or 1 4-2 1 d a ys f oll o wi n g e ac h T h er a S p h er e  tr e at m e nt. 
T h e T h er a S p h er e  l a b eli n g d oc u m e nts ( A p p e n dix 1) d escri b es t h e s p ecific pr oc e d ur e us e d t o a d mi nist er 
T h er a S p h er e .   
9. 2. 1 6. 1. 8  T H E R A S P H E R E  A D MI NI S T R A TI O N D O C U M E N T A TI O N  
A n y t ec h nic al pr o bl e ms or c o m plic ati o ns r el at e d t o t h e d eli v er y of T h er a S p h er e  tr e at m e nt t o t h e p ati e nt 
m ust b e d oc u m e nt e d i n t h e m e dic al r ec or d.  T h e d et ails of a n y ev e nt a n d its i m p act o n t h e p ati e nt s h o ul d b e 
d oc u m e nt e d o n a n A d v ers e E v e nt  e C R F . P ati e nts i n t h e Tr e at m e nt  ar m  m ust c ertify c o nti n u e d eli gi bilit y pri or 
t o a d mi nistr ati o n of T h er a S p h er e . A n e w bl o o d dr a w f or l a bs a n d pr e g n a nc y a n d a n E C O G P erf or m a nc e St at us 
t est m a y  b e p erf or m e d wit hi n 7 d a ys  b ef or e T h er a S p h er e a d mi nistr ati o n  at p h ysici a n discr eti o n t o c o nfir m 
b as eli n e r es ults . 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
Usi n g  i nstit uti o n al  pr actic es,  t h e  acti vit y  of  e ac h  vi al  of  T h er a S p h er e  will  b e  d et er mi n e d  pri or  t o  
a d mi nistr ati o n. T his acti vit y will b e us e d t o c alc ul at e t h e act u al d os e d eli v er e d t o t h e li v er a n d l u n g w hic h 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 . 
 
C alc ul ati o n of t h e li v er d os e ( Gy) d eli v er e d : 
C alc ul ati o n of t h e d eli v er e d d os e p er  i nf usi o n t a k es i nt o acc o u nt t h e acti vit y l ost t o l u n g s h u nti n g pl us acti vit y 
ass oci at e d wit h r esi d u al micr os p h er es i n t h e  a d mi nistr ati o n syst e m a n d is pr o vi d e d b y t h e f oll o wi n g f or m ul a: 
D os e ( Gy) =  
5 0[I nj ect e d Acti vit y ( G B q)][ 1 -F][ 1 -R]  
M ass of S el ect e d Li v er T ar g et ( k g)  
w h er e  F = l u n g s h u nt fr acti o n  ( d et er mi n e d i n S ecti o n 9. 2.1 4. 1 . 3) 
R =  r esi d u al acti vit y  fr acti o n  
C alc ul a ti o n of r esi d u al acti vit y fr acti o n f or micr os p h er es: 
T h e fr acti o n of micr os p h er es r e m ai ni n g i n t h e d e vic e  ( R) is c alc ul at e d usi n g t h e f oll o wi n g f or m ul a: 
R = ( W -b’)/(I -b)  
W h er e  R   = r esi d u al acti vit y fr acti o n  
             b = b ac k gr o u n d d os e r at e pri or t o s o urc e vi al m e as ur e m e nt 
I = m e as ur e d d os e r at e of s o urc e vi al p ositi o n e d gr e at er t h a n 3 0 c m fr o m i o niz ati o n c h a m b er ( or 
ot h er m e as uri n g d evic e)  a n d a dj ust e d f or r a di o acti v e d ec a y t o t h e ti m e of w ast e m e as ur e m e nt  
b’ = b ac k gr o u n d d os e r at e pri or t o w ast e m e as ur e m e nt  
W = a v er a g e d os e r at e of s hi el d e d w ast e c o nt ai n er (c o nt ai ni n g disc ar d e d vi al, micr oc at h et er, t u bi n g) 
p ositi o n e d wit h c e nt er i n s a m e l oc ati o n as I  
 
C alc ul ati o n of Act u al L u n g R a di ati o n Ex p os ur e:  
C alc ul ati o n of t h e l u n g d os e ( Gy) d eli v er e d i n e ac h i nf usi o n is pr o vi d e d b y t h e f oll o wi n g f or m ul a:  
L u n g d os e ( Gy) = 5 0 * acti vit y d eli v er e d ( G B q) * F  
9. 2. 1 6. 1. 9  T H E R A S P H E R E  P O S T -T R E A T M E N T P A TI E N T M A N A G E M E N T  
I m m e di at el y f oll o wi n g tr e at m e nt, t h e p ati e nt s h o ul d r e m ai n u n d er o bs er v ati o n c o nsist e nt wit h i nstit uti o n al 
st a n d ar d of c ar e g ui d eli n es f or aft erc ar e i n pr oc e d ur es i n v ol vi n g f e m or al or br ac hi al art er y c at h et eriz ati o n.  
T h es e aft erc ar e g ui d eli n es ar e u ni q u e a n d s u bj ect t o t h e p olici es a n d pr oc e d ur es dict at e d b y t h e r es p ecti v e 
r a di ol o g y a n d r a di ati o n s af et y d e p art m e nts at e ac h i nstit uti o n.  Pr o p h yl actic tr e at m e nt usi n g g astric i n hi bit or 
( H 2 bl oc k er or pr ot o n p u m p i n hi bit or ) s h o ul d c o nti n u e f or 1 4 –  2 1 d a ys p ost tr e at m e nt. I n a d diti o n, st er oi ds 
( e. g., M e dr ol D os e P ac k) m a y b e t a k e n ( wit h f o o d) o v er t h e first six d a ys p ost-tr e at m e nt. 
Pri or t o disc h ar g e, p ati e nts s h o ul d b e i nstr uct e d r e g ar di n g aft er -c ar e a n d pr o vi d e d wit h a 2 4-h o ur t el e p h o n e 
n u m b er t h at t h ey m a y us e t o c o nt act t h e Sit e I n v esti g at or if t h ey d ev el o p a pr o bl e m or h a v e q u esti o ns a b o ut 
t h eir tr e at m e nt.  
A n y c o nc u rr e nt m e dic ati o n or t h er a p y d e e m e d n ec ess ar y, i ncl u di n g g astric pr o p h yl axis, t o pr o vi d e a d e q u at e 
s u p p orti v e c ar e t o t h e p ati e nt i n t h e i m m e di at e p ost -tr e at m e nt p eri o d m a y b e a d mi nist er e d acc or di n g t o 
i nstit uti o n al st a n d ar d of cli nic al c ar e a n d s h o ul d b e d oc u m e nt e d o n t h e C o nc urr e nt M e dic ati o ns e C R F . 
 
9. 2. 1 6. 1. 1 0  
R A DI A TI O N S A F E T Y I N T H E IM M E DI A T E P O S T -T R E A T M E N T P E RI O D  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 7  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
S p eci al r a di ati o n is ol ati o n pr oc e d ur es f or Tr e at m e nt ar m  p ati e nts ar e n ot n ec ess ar y f oll o wi n g T h er a S p h er e  
Tr e at m e nt. T h e exist e nc e of a s m all a m o u nt of l o n g -li v e d r a di o acti v e b y pr o d ucts i n T h er a S p h er e  is a f u ncti o n 
of t h e pr o d ucti o n m et h o d 2 2. T h e pr e d o mi n a n t b y pr o d ucts ar e Y-9 1 , Y-8 8 a n d Cr -5 1 wit h r es p ecti v e h alf -li v es 
of 5 9, 1 0 7 a n d 2 8 d a ys. T h e 3 y e ar acc u m ul at e d d os e t o t h e p ati e nt’s li v er is esti m at e d t o b e 1/ 1 0 0 0 of t h e 
pl a n n e d tr e at m e nt d os e.  
S h o ul d a p ati e nt di e or r e q uir e s ur g er y i n t h e p eri o d i m m e di at el y f oll o wi n g -T h er a S p h er e  tr e at m e nt t h e 
h os pit al r a di ati o n s af et y offic er s h o ul d b e c o ns ult e d. At 6 0 d a ys aft er t h e T h er a S p h er e  c ali br ati o n d at e, a 
s urg e o n ex pl a nti n g a tr e at e d li v er i n a pr oc e d ur e l asti n g o n e h o ur w o ul d b e ex p os e d t o a n esti m at e d d os e t o 
t h e h a n ds of < 0. 6 mr e m. T his is si mil ar t o esti m at e d b ac k gr o u n d d os es fr o m n at ur al r a di ati o n s o urc es w hic h 
r a n g e fr o m 0. 5 t o 0. 8 mr e m/ d a y.  I nstit uti o nal r a di ati o n s af et y g ui d eli n es f or h a n dli n g of t h e b o d y a n d/ or 
b o d y tiss u es s h o ul d b e f oll o w e d.    
9. 2. 1 6. 2  S O C  S O R A F E NI B T R E A T M E N T  
C o ntr ol ar m p ati e nts will st art S O C s or af e ni b t h er a p y wit hi n 2 w e eks aft er r a n d o miz ati o n.  
All p ati e nts i n t h e C o ntr ol gr o u p will r ec ei v e S O C tr e at m e nt wit h s or af e ni b i n acc or d a nc e wit h t h e p ac k a g e 
i ns ert.  I n acc or d a nc e wit h t h e s or af e ni b p ac k a g e i ns ert a n d c o u ntr y-s p ecific p olici es, sp eci al att e nti o n s h o ul d 
b e p ai d t o p ati e nts wit h h y p ert e nsi o n or pr ol o n g e d Q T or at risk of d e v el o pi n g Q T pr ol o n g ati o n ( p ati e nts wit h 
a c o n g e nit al l o n g Q T sy n dr o m e, p ati e nts tr e at e d wit h a hi g h c u m ul ati v e d os e of a nt hr ac ycli n e t h er a p y, 
p ati e nts t a ki n g c ert ai n a nti -arr h yt h mic m e dici n es or ot h er m e dici n al pr o d ucts t h at l e a d t o Q T pr ol o n g ati o n, 
a n d t h os e wit h el ectr ol yt e dist ur b a nc es s uc h as h y p o k al e mi a, h y p oc alc e mi a, or h y p o m a g n es e mi a) . I n t h e 
U nit e d Ki n g d o m, b l o o d pr ess ur e m o nit ori n g pl us el ectr oc ar di o gr a m wit h m a g n esi u m a n d c alci u m l a b or at or y 
t ests  d o n e  at  scr e e ni n g  a n d  first  p ost-t h er a p y  visit  t h e n ev er y  6 -8  w e eks  ar e  r ec o m m e n d e d  as  S O C  
m o nit ori n g .   
A b n or m al r es ults or a d v ers e e v e nts r el at e d t o t h es e c o n diti o ns o bs er v e d i n st u d y s u bj ects s h o ul d b e r ec or d e d 
as a d v ers e e v e nts. T h er a pi es us e d t o m a n a g e s uc h a d v ers e ev e nts s h o ul d b e r ec or d e d i n t h e C o n c o mit a nt 
M e dic ati o n e C R F.  
D os a g e a dj ust m e nts a n d dr u g h oli d a ys will b e d et er mi n e d t o b e i n t h e p ati e nt’s b est i nt er est at t h e discr eti o n 
of t h e p h ysici a n. I n t h os e c o u ntri es w h er e m o nit ori n g b y E C G is r e q uir e d, co nsi d er disc o nti n ui n g sor af e ni b if 
Q T/ Q Tc i n cr e as es o v er 5 0 0 ms or i ncr e as es t o 6 0 ms a b o v e t h e b as eli n e r e a di n g.  All d os a g e a dj ust m e nts m ust 
b e l o g g e d o n t h e Tr e at m e nt M e dic ati o n e C R F.  
C a uti o n is r ec o m m e n d e d w h e n c o nsi d eri n g c o nc o mit a nt a d mi nistr ati o n of t h e f oll o wi n g m e dic ati o ns; pl e as e 
c o ns ult t h e s or af e ni b s u m m ar y of pr o d uct c h ar act eristics f or d et ails: 
•  
W arf ari n,  p h e m pr oc o u m o n  or  C Y P 2 B 6,  C Y P 2 C 8  a n d  C Y P 2 C 9  s u bstr at es  ( m o nit or  r e g ul arl y  f or  
c h a n g es i n pr ot hr o m bi n ti m e, I N R or e pis o d es of cli nic al bl e e di n g)  
•  
I n d uc ers of m et a b olic e nz y m es s uc h as rif a m pici n, St. J o h n’s w ort, p h e n yt oi n, c ar b a m ez e pi o n e, 
p h e n o b ar bit al,  d ex a m et h as o n e  m a y  i ncr e as e   s or af e ni b  m et a b olis m  a n d  d ecr e as e  s or af e ni b  
c o nc e ntr ati o ns 
•  
U G T 1 A 1 or U G T 1 A 9 p at h w a ys m et a b oliz e d c o m p o u n ds d u e t o gl uc ur o ni d ati o n i n hi biti o n  
9. 2. 1 6. 3  P O S T -P R O G R E S SI O N T R E A T M E N T :B E S T A V AI L A B L E C A R E  
All p ati e nts w h o m e et t h e crit eri a f or pr o gr essi o n s p ecifi e d i n S ecti o n 9. 2. 2 0  a n d r ec ei v e d t h e tr e at m e nts as 
d escri b e d f or eit h er ar m of t h e tri al c a n r ec ei v e i nstit uti o n al b est a v ail a bl e c ar e. P ati e nts i n t h e c o ntr ol ar m 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 8  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
w h o h a v e pr o gr ess e d ar e n ot all o w e d t o cr oss -o v er t o t h e tr e at m e nt ar m. B est a v ail a bl e c ar e is b as e d o n 
p h ysici a n j u d g m e nt a n d c urr e nt st a n d ar d of c ar e pr actic es , i ncl u di n g s or af e ni b. 
 F or p ati e nts i n t h e c o ntr ol ar m : I n t h e c as e of r ec urr e nt u nif oc al l esi o n, r es ecti o n or r a di ofr e q u e nc y a bl ati o n 
ar e all o w e d pr o vi di n g t h e l esi o n(s) tr e at e d wit h s or af e ni b d e m o nstr at es  t u m or r es p o ns e ( P R or C R) b y R E CI S T 
v 1. 1. F or a n y ot h er pr o gr essi o n, if r es ecti o n or a bl ati o n is n ot a p pr o pri at e, p ati e nts m a y r ec ei v e b est a v ail a bl e 
c ar e. 
F or p ati e nts i n t h e tr e at m e nt ar m:  I n c as e of a pr e vi o usl y tr e at e d t u m or wit h pr o gr essi o n p er R E CI S T v 1. 1 
d et ect e d d uri n g f oll o w u p e v al u ati o ns, r e -tr e at m e nt wit h T h er a S p h er e is all o w e d if it d o es n ot exc e e d t h e 
m axi m u m  all o w a bl e  t hr e e  Y 9 0  tr e at m e nts.  I n  t h e  c as e  of  a  tr e at a bl e  m ultif oc al  pr o gr essi o n  (i psi  or  
c o ntr al at er al), a Y 9 0 r e -tr e at m e nt is all o we d if t h e l esi o n(s) tr e at e d wit h T h er a S p h er e d e m o nstr at e t u m or 
r es p o ns e ( P R or C R) b y R E CI S T v 1. 1, t h e l esi o n is a m e n a bl e t o T h er a S p h er e tr e at m e nt a n d t h e r e-tr e at m e nt 
pr oc e d ur e d o es n ot exc e e d t h e p er mit e d m axi m u m t hr e e tr e at m e nts.  
9. 2. 1 7  E F FI C A C Y IM A GI N G –  C T / M RI    
B as eli n e effic ac y i m a gi n g sc a ns will b e o bt ai n e d d uri n g scr e e ni n g a n d effic ac y ass ess m e nt sc a ns will b e t a k e n 
ev er y 8 w e e ks p ost r a n d o miz ati o n u ntil pr o gr essi o n  is c o nfir m e d (s e e S ecti o n 9. 2. 2 0 ). M ost p ati e nts will b e 
ev al u at e d b y C T i m a g es. M RI i m a g es ar e als o p er mitt e d. T h e i m a gi n g m o d alit y us e d at b as eli n e m ust c o nti n u e 
t o b e us e d f or all effic ac y i m a g es t hr o u g h o ut t h e st u d y. Tri pl e p h as e C T will b e us e d  i n acc or d a nc e wit h sit e 
st a n d ar ds at b as eli n e f or d osi m etr y d et er mi n ati o n . S P E C T i m a gi n g m a y b e p erf or m e d acc or di n g t o st a n d ar d 
of c ar e pr actic es f or cli nic al m a n a g e m e nt b ut is n ot a st u d y r e q uir e m e nt.  
S pir al C T  a b d o m e n/ p el vis –  m ust b e p erf or m e d wit h c uts of 1 0 m m or l ess i n slic e t hic k n ess c o nti g u o usl y i n 
t h e axi al pl a n e.  Fr o m t h es e i m a g es, h e p atic a n d extr a-h e p atic l esi o ns will b e r e a d .  
S pir al C T C h est  –  m ust b e p erf or m e d wit h c uts of 1 0 m m or l ess i n slic e t hic k n ess c o nti g u o usl y i n t h e axi al 
pl a n e.  Fr o m t h es e i m a g es, extr a -h e p atic l esi o ns will b e r e a d.  
T o e n a bl e a n al ysis of s ec o n d ar y st u d y e n d p oi nts usi n g r a di ol o gic al ass ess m e nt, i n v esti g at ors will i de ntify, 
r e a d a n d us e bi di m e nsi o n al m e as ur e m e nts of t ar g et l esi o ns f or siz e a n d will r ec or d evi d e nc e of e n h a nc e m e nt 
a n d i ncr e as e i n di m e nsi o n of a pr e-existi n g t hr o m b us f or all i m a g e ti m e p oi nts. T h es e d at a will b e c a pt ur e d 
o n t h e e C R F . C o m p aris o n b et w e e n b a s eli n e a n d s u bs e q u e nt i m a g es of q u a ntit ati v e a n d q u alit ati v e fi n di n gs  
will d et er mi n e r es p o ns e acc or di n g t o R E CI S T v 1. 1 2 3, m R E CI S T2 4 a n d E A SL w hic h ar e ass ess e d s e p ar at el y i n 
s ec o n d ar y e n d p oi nt a n al ys es. 
B o n e Sci nti gr a p h y  –  B o n e sci nti gr a p h y t o ass ess s pr e a d  of m et ast atic dis e as e will b e p erf or m e d acc or di n g t o 
i nstit uti o n al st a n d ar ds. F or p ati e nts wit h A F P > 4 0 0 n g/ mL at scr e e ni n g, res ults of b o n e sci nti gr a p h y will b e 
r ec or d e d at t h e scr e e ni n g visit  a n d s u bs e q u e nt st u d y visits acc or di n g t o t h e sit e st a n d ar d p r actic e ( w e e k 1 6 
st u d y visit a n d 6 m o nt hs t h er e aft er (i. e. m o nt hs 1 0, 1 6, 2 2 , etc.)  ). B o n e sci nti gr a p h y  is s u g g est e d w h e n ev er 
t h er e is a n u nj ustifi e d i ncr e as e i n A F P or t h e p ati e nt ex p eri e nc es b o n e p ai n or sy m pt o m atic d et eri or ati o n a n d 
r e p e at e d at a fr eq u e nc y acc or di n g t o sit e st a n d ar d pr actic e.  
9. 2. 1 8  S T U D Y T R E A T M E N T M E DI C A TI O N R E C O R D  
T h e a d mi nistr ati o n of st u d y tr e at m e nt will b e r ec or d e d t hr o u g h o ut t h e tri al o n t h e a p pr o pri at e e C R F .  
S t art/st o p d at es, d at es of c h a n g e of d os a g e , a n d a n y dr u g h oli d a ys  will b e r ec or d e d . 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
3 9  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
9. 2. 1 9  C O N C U R R E N T M E DI C A TI O N R E C O R D  
At ev er y st u d y visit n e w or c h a n g es i n c o nc urr e nt m e dic ati o ns will b e d oc u m e nt e d o n t h e a p pr o pri at e 
c o nc urr e nt m e dic ati o n e C R F .  D oc u m e nt ati o n will i ncl u d e d os a g e, st art/st o p d at es, d at e of c h a n g e of d os a g e 
a n d a n y dr u g h oli d a ys .  
F oll o wi n g d et er mi n ati o n of pr o gr essi o n a n d r ec ei pt of tr e at m e nt o pti o ns i n eit h er ar m of t h e st u d y, r ec or d 
o nl y  m e dic ati o ns us e d s p ecific all y f or t h e tr e at m e nt of H C C. Ot h er m e dic ati o n s d o n ot n e e d t o b e r ec or d e d.  
9. 2. 2 0  D E FI NI TI O N O F P R O G R E S SI O N  F O R P A TI E N T M A N A G E M E N T D E CI SI O N -M A KI N G  
F or t h e p ur p os es of t his tri al, d efi niti o n of cli nic al pr o gr essi o n f or p ati e nt m a n a g e m e nt d ecisi o ns will 
i ncl u d e ass ess m e nt of c h a n g e i n P V T st at us a n d t u m or pr o gr essi o n a n d is d efi n e d as:    
•  
R a di ol o gic al pr o gr essi o n as d efi n e d b y R E CI S T v 1. 1 ( aft er r ec ei vi n g all all o w a bl e T h er a S p h er e 
tr e at m e nts as s p ecifi e d b y t h e pr ot oc ol)  
A n d/ O R  
•  
D ev el o p m e nt of extr a -h e p atic dis e as e b ey o n d t h e li mits d efi n e d i n t h e eli gi bilit y crit eri a  
•  
W ors e ni n g of P V T  fr o m b as eli n e d efi n e d as c h a n g e i n cl assific ati o n of P V T ( p er S hi et al) u p t o Ty p e 
III a; Ty p e III b or Ty p e I V  m a y n ot b e r etr e at e d  
•  
E C O G P erf or m a nc e St at us ≥2  
9. 2. 2 1  S T U D Y C O M PL E TI O N  
P ati e nts c o m pl et e t h e tri al u p o n r e ac hi n g t h e pri m ar y effic ac y e n d p oi nt of d e at h.   
9. 2. 2 2  P A TI E N T W I T H D R A WAL  
A p ati e nt m a y d eci d e h e/s h e n o l o n g er wis h es t o p artici p at e i n t h e tri al. I n acc or d a nc e wit h t h e D ecl ar ati o n 
of H elsi n ki, a n d a p plic a bl e st at e a n d f e d er al r e g ul ati o ns, a tri al s u bj ect h as t h e ri g ht t o wit h dr a w fr o m t h e 
st u d y at a n y ti m e a n d f or a n y r e aso n. E v er y eff ort s h o ul d b e m a d e t o h a v e p ati e nts c o m pl et e t h e st u d y wit hi n 
t h e pr o visi o ns of i nf or m e d c o ns e nt. H o w e v er, t h e p artici p ati o n of t h e p ati e nt m a y b e disc o nti n u e d at a n y 
ti m e d uri n g t h e st u d y w h e n, i n t h e j u d g m e nt of t h e i n v esti g at or, s p o ns or or s u bj ect, it is a p pr o pri at e.  
T h e r e as o ns f or s t u d y wit h dr a w al  i ncl u d e: 
•  
D e at h of t h e p ati e nt  
•  
P ati e nt’s d esir e f or a n y r e as o n t o wit h dr a w c o ns e nt 
•  
A d mi nistr ati v e r e as o ns ( e. g. st u d y t er mi n ati o n) 
•  
It is c o nsi d er e d n ec ess ar y b y t h e i n v esti g at or or s p o ns or, f or a n y r e as o n  
L ost t o f oll o w-u p is n ot a n a d e q u at e r e as o n f or wit h dr a w al.  P ati e nts s h o ul d b e e nc o ur a g e d t o att e n d st u d y 
visits u ntil c o m pl eti o n of t h e st u d y or u ntil a d ecisi o n is t a k e n t o wit h dr a w f or o n e of t h e a b ov e -n ot e d r e as o ns.  
If t h e p ati e nt is r e m o v ed d u e t o pr e g n a nc y or b ec a us e of i nt ol er a nc e t o t h e st u d y tr e at m e nt, h e/s h e s h o ul d 
b e u n d er m e dic al s u p er visi o n f or as l o n g as d e e m e d a p pr o pri at e b y t h e tr e ati n g p h ysici a n.  If t h e p ati e nt is 
disc o nti n u e d d u e t o a n A E, t h e ev e nt will b e f oll o w e d u ntil it r es ol v es t o t h e I n v esti g at or’s s atisf acti o n or is 
c o nsi d er e d st a bl e. T h e d et ails a n d r e as o ns f or disc o nti n u ati o n m ust b e c ar ef ull y a n d c o m pl et el y d oc u m e nt e d.   
1 0  S T A TI S TI C S  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
4 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1 0. 1  S A M PL E S I Z E E S TI M A T E 
T his is a r a n d o miz e d o p e n l a b el m ulti -c e nt er P h as e III a d a ptiv e  tri al usi n g a gr o u p s e q u e nti al d esi g n wit h  a 
pri m ar y e n d -p oi nt of O S .  
T h e st u d y is d esi g n e d t o d et ect a 4 m o nt hs i ncr e as e i n m e di a n O S ti m e  fr o m 9  m o nt hs i n t h e c o ntr ol ar m t o 
1 3  m o nt hs i n t h e T h er a S p h er e ar m (i. e., h az ar d r ati o = 0. 6 9 ), usi n g a l o g r a n k t est.  
A m axi m u m of 2 5 0  d e at hs will yi el d 8 0 % p o w er t o d et ect t h e t ar g et diff er e nc e i n m e di a n O S (i. e., H R  =  0. 6 9 ) 
wit h a t w o-si d e d al p h a of 0. 05 usi n g a gr o u p s e q u e nti al d esi g n wit h 2 i nt eri m a n al ys es a n d st o p pi n g b o u n d ary 
d efi n e d b y t h e r h o f a mil y err or s p e n di n g f u ncti o n wit h r h o= 1. 5  (J e n nis o n a n d T ur n b ull, 2 0 0 0 2 5).  It is 
esti m at e d t h at a m axi m u m of 3 2 0  p ati e nts will n e e d t o b e r ecr uit e d o v er 4 2  m o nt hs, wit h a 1 y e ar a d diti o n al 
f oll o w-u p p eri o d.  T his i ncl u d es a n a dj ust m e nt t o t a k e acc o u nt of a n ass u m e d 5 % of p ati e nts w h o will b e l ost 
t o f oll o w-u p a n d f or w h o m a d at e of d e at h is n ot r ec or d e d.  
S a m pl e siz e m o dific ati o n will b e c o nsi d er e d at t h e s ec o n d i nt eri m a n al ysis usi n g t h e a p pr o ac h d escri b e d i n 
M e ht a a n d P oc oc k
2 6 ( 2 0 1 1), w hic h e m pl o ys a n u n -w ei g ht e d t est  st atistic at t h e fi n al a n al ysis as r ec o m m e n d e d 
b y B ur m a n a n d S o n n es o n 2 7 ( 2 0 0 6).  If t h e s a m pl e siz e is i ncr e as e d aft er t h e s ec o n d i nt eri m a n al ysis, t h e fi n al 
a n al ysis is pl a n n e d w h e n a p pr oxi m at el y, b ut n o l ess t h a n, 4 3 0  d e at hs  h a v e occ urr e d , w hic h will r esult i n 8 0 % 
p o w er t o d et ect a n  i m pr o v e m e nt i n m e di a n O S fr o m 9 t o 1 2 m o nt hs usi n g a l o g r a n k t est wit h a fi n al t w o-
si d e d al p h a of 0. 03 2 2 .  It is esti m at e d t h at a p pr oxi m at el y 50 0  p ati e nts will n e e d t o b e  r ecr uit e d o v er 7 2  
m o nt hs, wit h a 1 y e ar a d diti o n al f oll o w-u p p eri o d, i n or d er t o o bs er v e 4 3 0  d e at hs.  T his i ncl u d es a n 
a dj ust m e nt t o t a k e acc o u nt of a n ass u m e d 5 % of p ati e nts w h o will b e l ost t o f oll o w -u p a n d f or w h o m a d at e 
of d e at h is n ot r ec or d e d.  
1 0. 2  S T A TI S TI C AL A N AL Y SI S P L A N 
T h e st atistic al a n al ysis pl a n will b e writt e n b as e d o n t h e fi n al pr ot oc ol a n d will b e u p d at e d, as r e q uir e d, i n 
ass oci ati o n wit h a n y pr ot oc ol a m e n d m e nts.  T h e pl a n will i ncl u d e t a bl es, listi n gs a n d gr a p hs a n d d escri b e 
st atistic al pr o gr a m mi n g c o nsi d er ati o ns.  
1 0. 2. 1  P O P U L A TI O N S A N D S U B -A R M S  
 
I nt ent t o Tr e at p o p ul ati o n  
 
All  r a n d o miz e d p ati e nts will b e a n al yz e d acc or di n g t o t h e tr e at m e nt gr o u p t o w hic h t h ey ar e 
assi g n e d.   
 
P er Pr ot oc ol P o p ul ati o n ( P P P)  
All r a n d o miz e d p ati e nts will b e a n al yz e d acc or di n g t o t h e tr e at m e nt act u all y r ec ei v e d a n d a d h er e nc e t o 
t h e prot oc ol.  P ati e nts w h o ar e d et er mi n e d t o h a v e m aj or pr ot oc ol vi ol ati o ns as d efi n e d i n S ecti o n 1 4 
will b e ex cl u de d fr o m t h e P P P a n al ysis  
 
S af et y A n al ysis P o p ul ati o n ( S A P)  
All r a n d o miz e d p ati e nts w h o r ec ei v e d st u d y tr e at m e nts at l e ast o nc e will b e a n al yz e d acc or di n g t o t h e 
tr e at m e nt act u all y r ec ei v e d.  
 
1 0. 2. 2  T RI AL E N D P OI N T S  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
4 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1 0. 2. 2. 1  P RI M A R Y E F FI C A C Y E N D P OI N T  
T h e pri m ar y st u d y e n d p oi nt is o v er all  sur vi v al  ( O S) ti m e, w hic h will b e c alc ul at e d as t h e i nt er v al b et w e e n t h e 
r a n d o miz ati o n d at e a n d t h e d at e of d e at h f or a n y c a us e, wit h c e ns ori n g at t h e d at e of l ast c o nt act f or p ati e nts 
ali v e at l ast c o nt act.   
1 0. 2. 2. 2  S E C O N D A R Y S T U D Y E N D P OI N T S  
Ti m e -t o-pr o gr essi o n  will b e c o m p ar e d b et w e e n tr e at m e nt  a n d c o ntr ol  ar m s fr o m ti m e of r a n d o miz ati o n t o 
r a di ol o gic al pr o gr essi o n (i ncl u di n g n e w li v er l esi o ns a n d extr a-h e p atic l esi o ns) acc or di n g t o R E CI S T v 1. 1 , 
m o difi e d R E CI S T a n d E A SL  crit eri a (s e e A p p e n dix 5) , ass ess e d s e p ar at el y b y i n v esti g at or d et er mi n ati o n.   
Ti m e -t o-sy m pt o m atic-pr o gr essi o n  will  b e  c o m p ar e d  b et w e e n  tr e at m e nt  a n d  c o ntr ol  ar m s  fr o m  
r a n d o miz ati o n t o sy m pt o m atic pr o gr essi o n . S y m pt o m atic pr o gr essi o n is d efi n e d as cli nic al pr o gr essi o n t o 
E C O G p erf or m a nc e st at us ≥2. S uc h d et eri or ati o n i n P S s h o ul d b e o bs er v e d  at o n e  s u bs e q u e nt ev al u ati o n 8 
w e e ks l at er.  
T u m or R es p o ns e  acc or di n g t o R E CI S T v 1. 1 , m o difi e d R E CI S T a n d E A SL r es p o ns e crit eri a b as e d o n 
i n v esti g at or ass ess m e nt.  At B as eli n e, t ar g et t u m ors ar e i d e ntifi e d, a n d q u a ntit ati v e a n d q u alit ati v e 
(e n h a nc e m e nt , n ecr osis) c h ar act eristics r ec or d e d.  At all s u bs e q u e nt f oll o w-u p visits, t h e i m a g es ( usi n g t h e 
s a m e m o d alit y) f or t h e s a m e t ar g et l esi o ns will b e r e a d, a n d q u a ntit ati v e a n d q u alit ati v e  c h ar act eristics 
r ec or d e d. C o mp ari n g t h es e fi n di n gs f or f oll o w u p visits t o t h e b as eli n e fi n di n gs, t u m or r es p o ns e acc or di n g 
t o R E CI S T v 1. 1, m o difi e d R E CI S T or E A SL crit eri a will b e d et er mi n e d  u n d er s e p ar at e a n al ys es . A p p e n dix 5 
pr o vi d es a s u m m ar y of t h es e crit eri a.   
P ati e nt R e p ort e d O utc o m e  Ass ess m e nts (i ncl u di n g F u ncti o n al Ass ess m e nt of C a nc er T h er a p y –  
H e p at o bili ar y Q u esti o n n air e –  F A C T -H e p). P ati e nts will b e ask e d t o c o m pl et e t h e q u esti o n n air e at B as eli n e 
a n d e ac h of t h e 8 w e e k st u d y visits.  
S af et y  will b e ass ess e d at all visits f o r e nr oll e d p ati e nts usi n g v 4. 0 of t h e N ati o n al C a nc er I nstit ut e’s 
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 ( N CI: C T A E). All a d v ers e ev e nts, s eri o us  a d v ers e ev e nts , a n d 
u n a ntici p at e d a d v ers e d e vic e eff ects  as d efi n e d b y t h e st u d y pr ot oc ol will b e c oll ect e d t h r o u g h o ut t h e 
d ur ati o n of t h e st u d y .  T h es e ev e nts will b e d oc u m e nt e d a n d r ec or d e d o n t h e A d v ers e E v e nt e C R F  usi n g t h e 
N CI C o m m o n T oxicit y Crit eri a f or A d v ers e E v e nts; C T C A E v.  4. 0 st a n d ar ds , a n d will b e c o d e d usi n g t h e 
M e dic al Dicti o n ar y f or R e g ul at or y Act i viti es ( M e d D R A). 
1 0. 2. 3  E F FI C A C Y A N A L Y SI S  
T h e effic ac y a n al ys es will b e p erf or m e d o n t h e I T T a n d P P P p o p ul ati o ns.  
1 0. 2. 3. 1  P RI M A R Y E N D P OI N T S T A TI S TI C A L A N A L Y SI S P L A N  
T h e K a pl a n -M ei er m et h o d will b e us e d t o esti m at e t h e O S c ur v es i n t h e t w o tr e at m e nt ar ms; c o m p aris o n 
b et w e e n t h e c ur v es will b e p erf or m e d usi n g t h e l o g -r a n k t est.  
I nt eri m A n al yse s: T w o  i nt eri m a n al yse s of O S ar e pl a n n e d t o b e p erf or m e d b y t h e I n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e (I D M C)  b as e d o n gr o u p s e q u e nti al st o p pi n g r ul es usi n g a n al p h a b o u n d ar y d efi n e d  b y 
t h e r h o f a mil y err or s p e n di n g f u ncti o n wit h r h o = 1. 5. T h e first i nt eri m a n al ysis is pl a n n e d at a p pr oxi m at el y, 
b ut n o l ess t h a n, 1 2 5  d e at hs, wit h a t w o-si d e d p-v al u e ≤0. 0 1 7 7  all o wi n g t h e st u d y t o b e st o p p e d e arl y f or 
effic ac y.  A s ec o n d i nt eri m a n al ysis is pl a n n e d at a p pr oxi m at el y, b ut n o l ess t h a n, 1 8 8  d e at hs, wit h a t w o-
si d e d p-v al u e ≤0. 0 2 2 8  all o wi n g t h e st u d y t o b e st o p p e d e arl y f or effic ac y.   
A c o n diti o n al p o w er of l ess t h a n or e q u al t o 1 5 % at e ac h of t h e i nt eri m a n al ys es will r es ult i n t h e st u d y 
st op pi n g e arl y f or f utilit y , usi n g t h e m et h o d d escri b e d i n Pr osc h a n et al 2 8 ( 2 0 0 6) . 

H C C P h as e III Pr ot oc ol T S -1 0 4  
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C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
S a m pl e siz e m o dific ati o n  will b e c o nsi d er e d at t h e s ec o n d i nt eri m a n al ysis usi n g t h e a p pr o ac h d escri b e d i n 
M e ht a a n d P oc oc k ( 2 0 1 1).   T h e ex act crit eri a t o all o w s a m pl e siz e m o dific ati o n will b e pr o vi d e d i n t h e I D M C 
c h art er. 
Fi n al A n al ysis : T h e fi n al a n al ysis, wit h o ut a s a m pl e siz e m o dific ati o n, is pl a n n e d w h e n a p pr oxi m at el y, b ut n o 
l ess t h a n, 2 5 0  d e at hs  h a v e occ urr e d .  A t w o-si d e d p-val u e ≤0. 0 3 2 2  is r e q uir e d t o d ecl ar e a st atistic all y 
si g nific a nt i m pr o v e m e nt i n m e di a n O S at t h e fi n al a n al ysis. 
If  t h e  s a m pl e  siz e  is  i ncr e as e d  aft er  t h e  s ec o n d  i nt eri m  a n al ysis,  t h e  fi n al  a n al ysis  is  pl a n n e d  w h e n 
a p pr oxi m at el y, b ut n o l ess t h a n,  4 3 0  d e at h s h a v e occ urr e d , w hic h will r es ult i n 8 0 % p o w er t o d et ect a n 
i m pr o v e m e nt i n m e di a n O S fr o m 9 t o 1 2  m o nt hs usi n g a l o g r a n k t est wit h a fi n al t w o-si d e d al p h a of 0. 03 2 2 . 
1 0. 2. 3. 2  S E C O N D A R Y E N D P OI N T S T A TI S TI C A L A N A L Y SI S P L A N  
F or s ec o n d ar y  effic ac y e n d p oi nts, e ac h c o m p aris o n b et w e e n tr e at m e nt gr o u ps will b e c o n d uct e d at t h e fi n al 
a n al ysis wit h α = 0. 0 5 ( t w o-si d e d).  S ec o n d ar y st u d y e n d p oi nts will b e a n al yz e d o nl y at t h e fi n al a n al ysis t o 
d et er mi n e t h e st atistic al si g nific a nc e, if a n y b et w e e n, t h e Tr e at m e nt a n d C o ntr ol gr o u ps.   
•  
Ti m e t o pr o gr essi o n ( T T P) will b e c alc ul at e d as t h e i nt er v al b et w e e n t h e r a n d o miz ati o n d at e  a n d t h e 
d at e of first dis e as e pr o gr essi o n  as d efi n e d b y t h e r es p ecti v e crit eri a n ot e d b el o w , d e at h f or a n y 
c a us e or of l ast c o nt act f or p ati e nts ali v e. T h e K a pl a n -M ei er m et h o d will b e us e d t o esti m at e t h e T T P 
c ur v es i n t h e t w o tr e at m e nt ar ms; c o m p aris o n b et w e e n t h e c ur v es will b e p erf or m e d usi n g t h e 
l o g-r a n k t est. M e di a n T T P will b e r e p ort e d. Pr o gr essi o n will b e ass ess e d s e p ar at el y usi n g:  
 
R E CI S T v 1. 1 crit eri a  
 
m R E CI S T crit eri a  
 
E A SL r es p o ns e crit eri a  ( ass ess e d bi di m e nsi o n all y o n e n h a nci n g tiss u e) 
•  
Ti m e t o sy mpt o m atic pr o gr essi o n  ( T T S P) will b e c alc ul at e d as t h e i nt er v al b et w e e n t h e 
r a n d o miz ati o n d at e a n d sy m pt o m atic pr o gr essi o n, d efi n e d as ass ess m e nt of E C O G p erf or m a nc e 
st at us ≥2 wit h or wit h o ut t u m or pr o gr essi o n b as e d o n i m a gi n g. D et eri or ati o n i n p erf or m a nc e 
st at us is t o b e o bs er v e d at o n e s u bs e q u e nt ev al u ati o n 8 w e eks l at er. F or s u bj ects w h o h a d n ot 
pr o gr ess e d sy m pt o m atic all y at t h e ti m e of a n al ysis, T T S P will b e c e ns or e d at t h eir l ast d at e of P S 
ass ess m e nt. T h e K a pl a n -M ei er m et h o d will b e us e d t o esti m at e t h e T T S P c ur v es i n t h e t w o 
tr e at m e nt ar ms; c o m p aris o n b et w e e n t h e c ur v es will b e p erf or m e d usi n g t h e l o g-r a n k t est.M e di a n 
T T S P will b e r e p ort e d.  
•  
T u m or r es p o ns e r at e. T h e r es p o ns e pr o b a bilit y will b e esti m at e d i n e ac h of t h e t w o tr e at m e nt 
ar ms as pr o p orti o n o f C R + P R o v er t h e t ot al n u m b er of I T T or P P P p ati e nts. T h e dis e as e c o ntr ol r at e 
(i e, C R + P R + S D ) will als o b e c o m p ar e d b et w e e n t h e tr e at m e nt ar ms.  T h e mi ni m u m ti m e  b et w e e n 
i m a g e ac q uisiti o ns is 6 -8 w e e ks.  T u m or r es p o ns e r at e will b e ass ess e d s e p ar at el y usi n g:  
 
R E CI S T v 1. 1  
 
m R E CI S T  
 
E A SL   
T u m or r es p o ns e will b e c o m p ar e d usi n g t h e c o nti n uit y a dj ust e d N e wc o m b e -Wils o n t est, a n d th e 
9 5 % c o nfi d e nc e li mits will b e c alc ul at e d  

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Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
•  
P ati e nt r e p ort e d o utc o m e ( P R O). T h e t ot a l sc or e F A C T-H e p will b e c alc ul at e d, t h e sc or es of e ac h 
d o m ai n a n d e ac h q u esti o n at e ac h ti m e -p oi nt a n d t h eir diff er e nc es fr o m b as eli n e will b e 
s u m m ariz e d f or e ac h tr e at m e nt ar m . T h e t w o tr e at m e nt ar m s will b e c o m p ar e d a p pl yi n g a mix e d 
li n e ar m o d el wit h t he tr e at m e nt as f act ors, t h e b as eli n e sc or e a n d t h e r el ati v e ti m e fr o m b as eli n e 
as c o v ari at es. A d et eri or ati o n i n Q oL is d efi n e d as a 7-p oi nt d ecli n e i n t h e t ot al sc or e o r d e at h 
w hic h e v er occ urs first. T h e ti m e t o d et eri or ati o n i n Q oL ( T T D Q oL) will b e c alc u l at e d as t h e i nt er v al 
b et w e e n t h e r a n d o miz ati o n d at e a n d d et eri or ati o n  i n Q oL.  T h e K a pl a n -M ei er m et h o d will b e us e d 
t o esti m at e t h e T T D Q oL  c ur v es i n t h e t w o tr e at m e nt ar ms a n d will b e c o m p ar e d usi n g a l o g -r a n k 
t est. 
A d et ail e d d escri pti o n of d at a c e ns ori n g h a n dli n g f or p ati e nts will b e d efi n e d i n t h e St atistic al A n al ysis Pl a n.  
1 0. 2. 4  S A F E T Y A N A L Y SI S  
T h e s af et y a n al ys es will b e p erf or m e d o n t h e S A P p o p ul ati o n.  
All tr e at m e nt e m er g e nt ad v ers e e v e nts ( T E A Es) , ( d efi n e d as e v e nts w hic h w er e n ot pr es e nt at b as eli n e or 
w ors e n e d i n s e v erit y f oll o wi n g t h e st art of tr e at m e nt)  will b e r e p ort e d acc or di n g t o N CI Crit eri a. T h e i nci d e nc e 
of T E A E s will b e s u m m ariz e d acc or di n g t o t h e M e d D R A c o d e d pri m ar y syst e m -or g a n cl ass ( S O C) a n d pr ef err e d 
t er m.T h e  s u m m ari es will b e pr es e nt e d o v er all (s e v erit y gr a d es 1 -5 ) a n d f or gr a d e ≥3 e v e nts a n d b y tr e at m e nt 
disc o nti n u ati o n.  T h es e s u m m ari es will pr es e nt t h e n u m b er a n d p erc e nt a g e of p ati e nts r e p orti n g a n a d v ers e 
ev e nt f or e ac h cl assific ati o n l e v el as w ell as t h e n u m b er of e v e nts r e p ort e d.  
S eri o us a d v ers e e v e nts ( S A E s) will b e t a b ul at e d b y tr e at m e nt gr o u p.  
L a b or at or y v al u es will b e s u m m ariz e d b y tr e at m e nt gr o u p o v er ti m e a n d o v er all.  
 
1 0. 2. 5  O T H E R A N AL Y S E S  
T h e n u m b er of r a n d o miz e d  p ati e nts , t h e n u m b er of p ati e nts tr e at e d, t h e n u m b er of p ati e nts i n e ac h a n alysis 
p o p ul ati o n  will b e s u m m ariz e d. Als o t h e n u m b er of p ati e nts disc o nti n ui n g fr o m acti v e tr e at m e nts a n d 
r e as o ns f or disc o nti n u ati o n will b e s u m m ariz e d. I n t h e s a m e m a n n er t h e n u m b er of p ati e nts disc o nti n ui n g 
f oll o w u p a n d r e as o ns f or disc o nti n u ati o ns will b e r e p ort e d.  
Listi n gs of r e as o ns f or disc o nti n u ati o n fr o m acti v e tr e at m e nts, fr o m f oll o w u p, a n d r e as o ns effic ac y d at a 
c a n n ot b e ev al u a t e d i n P P P will b e als o pr o vi d e d.   
D ur ati o n of f oll o w u p will b e d escri b e d b y d escri pti v e st atistics s uc h as m e di a n a n d i nt er q u artil e r a n g e.  
D e m o gr a p hic, p ati e nt a n d dis e as e c h ar act eristics will b e list e d a n d s u m m ariz e d usi n g a p pr o pri at e d escri pti v e 
st atistics.  
M ulti -v ari a t e C ox r e gr essi o n a n al ysis  of ti m e-t o-ev e nt effic ac y e n d p oi nts  will b e c o n d uct e d o n A F P l ev el , a g e, 
g e n d er, n aï v e or r ec urr e nt dis e as e, H C C di a g n osis pr es e nt at first o nc ol o g y di a g n osis, pri or tr e at m e nt , 
g e o gr a p h y  t o d et er mi n e t h e i m p act of t h es e f act ors o n tri al e n d p oi nts.  
As a s e nsiti vit y a n al ysis, t o a d dr ess t h e p o ol a bilit y of d at a acr oss r e gi o ns (i e, E ur o p e, N ort h A m eric a  or Asi a ), 
st u d y sit es a n d g e n d er, a C ox r e gr essi o n a n al ysis of t h e pri m ar y effic ac y e n d p oi nt, O S, will b e c o n d uct e d wit h 
f act ors of r e gi o n, st u d y sit e a n d g e n d er, a n d t o d et er mi n e t h e i m p act of t h es e f act ors o n O S.  N ot e: r e gi o n 
a n d st u d y sit e will n ot b e i ncl u d e d si m ult a n e o usl y i n t h e m o d el d u e t o c olli n e arit y.  
S h o ul d t h e i m p act of r e gi o n, sit e or g e n d er o n O S b e st atistic all y a n d cli nic all y r el ev a nt, t h e r e as o ns f or t h e 
o bs er v e d  diff er e nti al  tr e at m e nt  eff ect,  s uc h  as  p at i e nt  d e m o gr a p hic  or  cli nic al  c h ar act eristics,  will  b e  
i n v esti g at e d a n d r e p ort e d.  If t h e p o ol a bilit y of O S r es ults ar e i n dir ect q u esti o n as a r es ult of t his s e nsiti vit y 
a n al ysis, t h e pri m ar y e n d p oi nt ( O S) will als o b e a n al yz e d s e p ar at el y b y r e gi o n, sit e o r g e n d er.  T h e s p ecific 

H C C P h as e III Pr ot oc ol T S -1 0 4  
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Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
m ec h a nis m of m er gi n g l o w e nr olli n g st u d y sit es i nt o virt u al sit es f or p ur p os es of a n al ysis will b e d et ail e d i n 
t h e St atistic al A n al ysis Pl a n. 
A F P l e v els at Q 8 w e e k visits f or p ati e nts wit h A F P >4 0 0 n g/ mL at scr e e ni n g will b e c o m p ar e d , i n s e p ar at e 
a n al ys es, t o R E CI S T v 1. 1, m R E CI S T a n d E A SL r es p o ns e crit eri a t o c orr el at e bi ol o gic al a n d r a di ol o gic al r es p o ns e 
t o ex pl or e t h e us e of v ari ati o ns  i n A F P as a c o nfir m ati o n of r a di ol o gic al r es p o ns e. 
A n al ys es of all pri m ar y a n d s ec o n d ar y e n d p oi nt s will b e p erf or m e d i n a d escri pti v e m a n n er o nl y usi n g t h e 
f oll o wi n g s u b gr o u ps: 
•  
Ri g ht  vs l eft vs b ot h  br a nc h P V T  
•  
I psil at er al vs c o ntr al at er al t u m or/ P V T l oc ati o n 
1 0. 2. 6  IN D E P E N D E N T D A T A M O NI T O RI N G C O M MI T T E E  
A n  I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e  (I D M C) will b e est a blis h e d t o o v ers e e t h e c o n d uct of t h e st u d y , 
will f oll o w t h e F D A’s G ui d a nc e o n I D M Cs/D S M Bs  a n d c o m pl y wit h I S O 1 4 1 5 5: 1 1: 4. 9 .  T h e I D M C will m e et 
p eri o dic all y d uri n g t h e st u d y t o r evi e w e nr oll m e nt, pr ot oc ol d evi ati o ns, a n d s af et y e v e nts f or t h e st u d y.  I n 
a d diti o n t h e  I D M C will e v al u at e t h e d at a at i nt eri m a n al ys es f or c o nsi d er ati o n of st o p pi n g t h e st u d y f or 
o v er w h el mi n g effic ac y or f utilit y a n d f or s a m pl e siz e r e -esti m ati o n at t h e s ec o n d i nt eri m a n al ysis  a n d will 
m a k e f or m al r ec o m m e n d ati o ns t o t h e st u d y  S p o ns or at t h e ti m e of t h e i nt eri m a n al ys e s a n d d uri n g t h e 
c o n d uct of t h e st u d y b as e d o n d et ail e d d ecisi o n r ul es s p ecifi e d i n t h e I D M C c h art er . A n I D M C m e m b er or 
d esi g n at e m a y act as t h e st u d y i n d e p e n d e nt m e dic al m o nit or.  T h e I D M C  will ev al u at e t h e fi n al st u d y r e p ort. 
1 1  D A T A C OLL E C TI O N A N D M A N A G E M E N T  
1 1. 1  E L E C T R O NI C D A T A C OLL E C TI O N ( E D C) 
D at a fr o m t his tri al will b e c a pt ur e d o n el ectr o nic c as e r e p orti n g f or ms ( e C R F s), a n d will b e e nt er e d i nt o a 
v ali d at e d cli nic al d at a b as e.  A n a u dit tr ail will b e m ai nt ai n e d t o d o c u m e nt all d at a c h a n g es i n t h e d at a b as e.  
Pr oc e d ur es will b e f oll o w e d t o e ns ur e t h e v ali dit y a n d acc ur ac y of t h e cli nic al d at a b as e.  
T h e i n v esti g at or will si g n a n d d at e all i n dic at e d pl ac es o n t h e e C R F s.  T his si g n at ur e will i n dic at e t h at t h or o u g h 
i ns p ectio n of t h e d at a h as b e e n m a d e a n d will c ertify t h at t h e Sit e I n v esti g at or h as r e vi e w e d a n d a p pr o v e d 
t h e d at a c o nt ai n e d o n t h e f or ms. 
1 1. 2  D A T A M A N A G E M E N T  
T h e i n v esti g at or will e ns ur e t h at tri al d at a q u alit y is m ai nt ai n e d t o c urr e nt st a n d ar ds of G o o d Cli nic al Pr a ctic e 
a n d t h at d at a ar e s u b mitt e d i n a ti m el y m a n n er as o utli n e d i n t h e pr ot oc ol a n d s u p p orti n g d oc u m e nt ati o n, 
i ncl u di n g r es p o ns es t o d at a q u eri es, u ntil t h e tri al is t er mi n at e d. T h e in v esti g at or m ust si g n a n affir m ati o n 
st at e m e nt v erifyi n g t h e c o nt e nt of all s u bj ects' e C R F s. 
Err ors m ust b e c orr ect e d i n acc or d a nc e wit h E D C d at a e ntr y g ui d eli n es. 
1 2  A D V E R S E E V E N T S  
A d v ers e ex p eri e nc e will b e c o nsi d er e d sy n o n y m o us wit h t h e t er m a d v ers e e v e nt a n d vic e v ers a.  
1 2. 1  D E FI NI TI O N S O F A E/ S A E  F O R D R U G S  

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C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
A d v ers e E v e nt ( A E)  
A n A E is a ny u nt o w ar d m e dic al occ urr e nc e or u n d esir a bl e ev e nt(s) ex p eri e nc e d i n a s u bj ect or cli nic al 
i n v esti g ati o n s u bj ect t h at b e gi ns or w ors e ns f oll o wi n g a d mi nistr ati o n of t h e st u d y dr u g, w h et h er or n ot 
c o nsi d er e d r el at e d t o t h e tr e at m e nt b y t h e in v esti g at or.  
A n u n d esir a bl e e v e nt(s) c a n b e, b ut is n ot li mit e d t o, sy m pt o ms ex p eri e nc e d b y a s u bj ect or o bj ecti v e fi n di n gs, 
s uc h as si g nific a nt cli nic al l a b or at or y a b n or m aliti es. 
S eri o us A d v ers e E v e nt ( S A E)  
A n y u nt o w ar d m e dic al occ urr e nc e t h at at a n y d os e:  
•  
r es ults i n d e at h; 
•  
is lif e-t hr e at e ni n g (“lif e-t hr e at e ni n g” r ef ers t o a n ev e nt i n w hic h t h e s u bj ect w as at risk of d e at h at 
t h e ti m e of t h e ev e nt; it d o es n ot r ef er t o a n ev e nt w hic h h y p ot h etic all y mi g ht h a v e c a us e d d e at h 
if it w er e m or e s ev er e); 
•  
r e q uir es 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; 
•  
r es ults i n a p ersist e nt or si g nific a nt dis a bilit y/i nc a p acit y; or 
•  
is a c o n g e nit al a n o m al y/ birt h d ef ect. 
 
M e dic al a n d sci e ntific j u d g m e nt s h o ul d b e ex ercis e d i n d eci di n g w h et h er m e dic al e v e nt s t h at m a y n ot b e 
i m m e di at el y lif e-t hr e at e ni n g or r es ult i n d e at h or h os pit aliz ati o n b ut m a y j e o p ar diz e t h e s u bj ect or m a y 
r e q uir e i nt er v e nti o n t o pr ev e nt o n e of t h e ot h er o utc o m es list e d i n t h e d efi niti o n a b o v e, s h o ul d als o b e 
c o nsi d er e d s eri o us.  
1 2. 2  D E FI NI TI O N S O F A D E/ S A D E/ U A D E  F O R D E VI C E S 
A d v ers e D e vic e Eff ect ( A D E)  
A n a d v ers e d e vic e eff ect is a n a d v ers e ev e nt ( A E –  pr evi o usl y d efi n e d) r el at e d t o a m e dic al d evic e a n d i ncl u d es 
a n y ev e nt r es ulti n g fr o m i ns uffici e nci es or i n a d e q u aci es i n t h e i nstr ucti o ns f or us e or t h e d e pl o y m e nt, 
i m pl a nt ati o n, i nst all ati o n or m alf u ncti o n of t h e d evic e; a n y ev e nt t h at is t h e r es ult of us er err or; or a n y 
p ot e nti al  a d v ers e  d evic e  eff ect  w hic h  mi g ht  h a v e  occ urr e d  i f s uit a bl e  acti o n  h a d  n ot  b e e n  t a k e n  or  
i nt er v e nti o n h a d n ot b e e n m a d e or if circ u mst a nc es h a d b e e n l ess f ort u n at e.  
S eri o us A d v ers e D e vic e Eff ect ( S A D E)  
A S eri o us A d v ers e D e vic e Eff ect is a n a d v ers e d evic e eff ect t h at h as r es ult e d i n a ny of t h e c o ns e q u e nc es 
c h ar act eristic of a s eri o us a d v ers e ev e nt ( S A E –  pr e vi o usl y d efi n e d) or mi g ht h a v e l e d t o a n y of t h es e 
c o ns e q u e nc es if s uit a bl e acti o n h a d n ot b e e n t a k e n; i nt er v e nti o n h a d n ot b e e n m a d e or circ u mst a nc es h a d 
b e e n l ess f ort u n at e.  
U n a ntici p at e d A d v ers e D e vic e E v e nt ( U A D E)  
A n u n a ntici p at e d a d v ers e d e vic e eff ect is a n y s eri o us a d v ers e eff ect w hic h b y its n at ur e, i nci d e nc e, s e v erit y 
a n d o utc o m e h as n ot b e e n i d e ntifi e d i n t h e risk ass ess m e nt, t h e i nf or m e d c o ns e nt f or m as w ell as t h e 
pr ot oc ol.  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
4 6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
1 2. 3  R E C O R DI N G A D V E R S E E V E N T S  
All  a d ve rse  e ve nts  a n d  a d ve rse  d e vic e e ffe cts w ill b e  d o cu m e nt e d  fr o m th e  d at e  of  i nf or m e d c o ns e nt 
u ntil  stu d y  exit  f or r a n d o miz e d p ati e nts. 
I n t his st u d y, p ati e nts s h o ul d b e e nc o ur a g e d t o r e p ort a d v ers e e v e nts s p o nt a n e o usl y or i n r es p o ns e t o 
g e n er al, n o n -dir ect e d q u esti o ns.  At a n y ti m e d uri n g t h e st u d y, t h e p ati e nt m a y v ol u nt e er i nf or m ati o n t h at 
r es e m bl es a n a d v ers e e v e nt. O nc e it is d et er mi ne d t h at a n a d v ers e ev e nt h as occ urr e d, t h e I n v esti g at or 
s h o ul d o bt ai n all t h e i nf or m ati o n r e q uir e d t o c o m pl et e t h e a d v ers e ev e nt f or m.  A n y m e dic al m a n a g e m e nt 
of a n ev e nt a n d t h e d at e of r es ol uti o n of t h e ev e nt  m ust b e r ec or d e d i n t h e s o urc e d oc u m e nt a n d o n t h e 
a p pr o pri at e c as e r e p orts f or m(s) usi n g m e dic al t er mi n ol o g y acc or di n g t o s p o ns or i nstr ucti o ns.  
F or e ac h A E , t h e f oll o wi n g i nf or m ati o n will b e r ec or d e d:  
•  
A d v ers e ev e nt  
•  
S eri o us/ n o n -S eri o us  
•  
S ev erit y  ( T oxicit y Gr a d e) 
•  
Acti o n t a k e n  
•  
R el ati o ns hi p t o st u d y tr e at m e nt 
•  
Ex p ect e d/ U n ex p ect e d  
•  
D at e a n d ti m e of o ns et  
•  
D at e a n d ti m e of r es ol uti o n  
A n ex p ect e d a d v ers e ev e nt is a n y A E, t h e n at ur e or s e v erit y of w hic h is i d e ntifi e d i n t h e r el e v a nt P ac k a g e 
I ns ert. 
A n y A E ex p eri e nc e d b y a s u bj ect will b e  f oll o w e d u ntil t h e AE h as r es ol v e d t o t h e i n v esti g at or's or p h ysici a n 
s u b-i n v esti g at or's s atisf acti o n.  If a pr o bl e m still exists, t h e n t h e i n v esti g at or or p h ysici a n s u b-i n v esti g at or at 
his/ h er discr eti o n will ask t h e s u bj ect t o c o m e b ac k t o t h e cli nic f or f urt h er ev al u ati o n.  A n y s eri o us a d v ers e 
ev e nts s h o ul d b e m a n a g e d as disc uss e d i n S ecti o n 1 2. 3. 
O nc e t h e s u bj ect h as b e e n disc h ar g e d fr o m t h e st u d y, t h e i n v esti g at or h as n o o bli g ati o n t o s e ek f urt h er 
f oll o w-u p wit h t h e s u bj ect i n or d er t o i d e ntify n e w A Es. A Es o n g oi n g at st u d y exit will b e f oll o w e d t o 
r es ol uti o n. H o w e v er, if t h e i n v esti g at or b ec o m es a w ar e of a n S A E t h at h as occ urr e d f oll o wi n g t h e s u bj ect's 
disc h ar g e fr o m t h e st u d y a n d t h e i n v esti g at or c o nsi d ers t h e S A E p ossi bl y, pr o b a bl y, or d efi nit el y r el at e d t o a 
st u d y dr u g or d evic e, t h e n t h e i n v esti g at or s h o ul d r e p ort t h e S A E as d escri b e d i n t h e pr ot oc ol.  
1 2. 3. 1  C A U S ALI T Y ( RE L A TI O N S HI P T O M E DI C A L  D E VI C E ) A S S E S S M E N T  
T h e i n v esti g at or or p h ysici a n s u b -i n v esti g at or m ust i n dic at e w h et h er h e/s h e  b eli e v e s t h e A E  is n ot r el at e d, 
u nli k el y r el at e d, p ossi bl y r el at e d ( r e as o n a bl e p ossi bilit y t h at t h e m e dic al d evic e c a us e d t h e A E ), pr o b a bly 
r el at e d, or d efi nit el y r el at e d t o t h e m e dic al d e vic e .  
A n a d v ers e ev e nt  b ec o m es a n a d v ers e d e vic e eff ect w h e n t h e a d v ers e e v e nt  is c o nsi d er e d ass oci at e d wit h 
t h e us e of t h e t est d e vic e if t h e attri b uti o n is P ossi bl y, Pr o b a bl y or D efi nit el y R el at e d.  R el ati o n t o T h er a S p h er e  
(scr e e ni n g, pr oc e d ur e, e m b oliz ati o n or r a di ati o n) is n ot a p pr o pri at e f or t h e C o ntr ol Ar m .   
1 2. 4  S U B MI T TI N G E X P E DI T E D S A F E T Y R E P O R T S  

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
47 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
Any SAE, SADE or UADE (defined previously) must be reported by telephone or fax to Biocompatibles or its 
designate as specified in the study procedures within 24 hours of learning of the event.  In the event of an 
emergency, the Investigator will contact the CRO using the coordinates specified by study procedures. 
The SAE form provided by the sponsor should be completed and signed by the investigator or physician sub-
investigator. The entire SAE form needs to be completed, if possible, to keep requests for additional 
information to a minimum. Patients experiencing SAE, SADE or UADE should be followed clinically and with 
laboratory studies, if appropriate, until medical treatment and/or medical monitoring of the event is no 
longer required because the event resolves or stabilizes, returns to baseline if a baseline value is available, 
can be attributed to agents other than the study treatments or a referral for appropriate follow-up care 
has been made. 
The Investigator must promptly inform the IRB/EC of all unexpected SAE or UADE. These events will be 
reported by the sponsor as appropriate to the regulatory authorities according to relevant jurisdictional 
regulations. The Investigator will receive notification of these events across all study centers from the 
sponsor.  
Each AE reported on an SAE form must also be reported in the adverse event section of the eCRF. 
12.5 PERIODIC SAFETY REPORTING 
Adverse events will be recorded on the AE form and coded using NCI CTCAE v 4.0.  The investigator or 
physician sub-investigator will judge the severity of each AE and whether or not it is treatment-related.   All 
AEs that occur after the initiation of trial treatment, including events likely to be related to the underlying 
disease or likely to represent concurrent illness, will be reported, including events present at Baseline which 
worsened during the trial.   
Periodic safety reports prepared by the sponsor will be distributed across all study centers. The Investigator 
will be responsible for informing the IRB/EC. 
12.6 EXPECTED ADVERSE EVENTS  
12.6.1 THERASPHERE ADVERSE EVENT PROFILE 
TheraSphere has been approved for the treatment of HCC since 1999. Adverse events known to be related 
to the device or the procedure listed in the current package insert (Appendix 1). Those adverse events 
identified in clinical trials investigating treatment with TheraSphere of liver lesions metastatic to non-HCC 
primary cancers are listed below in decreasing order of frequency. 
Frequency 
Description of Adverse Event (per NCI-CTCAE v 3.0) 
Common - >10% 
Fatigue, pain, nausea, vomiting, anorexia and laboratory value abnormalities 
including increased alkaline phosphatase, AST, ALT, bilirubin and decrease albumin 
Infrequent - <10% 
Lymphopenia with no clinical sequellae; constipation, heartburn, weight loss, fever, 
ascites, muscle weakness, variations in hemoglobin, neutrophils and leukocytes, GI 
ulcer, dyspnea, arrhythmia, diarrhea, liver dysfunction, hypotension, insomia, 
rigors/chills, sweating, distension, GI obstruction, hematoma, GI hemorrhage, pleural 
effusion  

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
48 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
Rare – < 1% 
Alopecia, bruising, pruritis, rash, hot flashes, dehydration, taste alteration, 
hemorrhage, infection, dizziness, mood alteration, sensory neuropathy, somnolence, 
cough, urine color change, intraoperative injury, flu-like symptoms, tumor lysis 
syndrome, 
thrombosis, 
metabolic/laboratory 
abnormalities 
– 
creatinine, 
hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, lipase 
 
In addition, the following events, which may or may not be related to the use of TheraSphere or the 
administration procedure, have been reported in clinical trials of treatment of primary or secondary liver 
cancer: 
Abdominal pain, dyspnoea, abdominal distention, anxiety, blurred vision, chills, hot flashes, bladder infection, 
lower extremity edema, gastrointestinal stoma complication including mild pain, hepatic encephalopathy, 
hepatorenal failure, edema, malaise, hepatic decompensation, hepatitis, duodenal ulcer, hypertension, 
hypertension, aspiration pneumonia, fall, gastrointestinal bleeding, elevated AFP, elevated LDH, elevated 
prothrombin time, elevated BUN, bacterial sepsis, hypoglycemia, abnormal platelets and electrolyte 
disturbances including hypercalcemia, hyperkalemia, hypomagnesemia, hyponatremia, low serum 
bicarbonate and low serum chloride. 
12.6.2 SORAFENIB ADVERSE EVENT PROFILE 
Sorafenib has been approved for treatment of HCC since 2007 and adverse events known to be related to 
this therapy are listed in the current package insert. Safety updates to the commercial package insert by the 
manufacturer automatically apply to this trial. 
13 INVESTIGATOR AND SITE QUALIFICATION AND OBLIGATIONS 
13.1 STUDY SITE AND INVESTIGATOR QUALIFICATION 
This study will be performed by qualified investigators at multiple research centers that may be located in 
Europe, Asia or North America.  
All participating study sites will be reviewed by the study Sponsor or designee in order to verify that they are 
able to conduct the trial.  Each participating institution must have an established IRB/EC and clinical protocol 
review process in compliance with the appropriate regulations (21 CFR 56 or ISO 14155:11:3) so the clinical 
protocol can be adequately evaluated and approved at the institutional level.     
The institution must have appropriately qualified investigators, and clinical and administrative support staff 
in place to adequately conduct the trials according to GCP in general, and must have adequate expertise and 
staff in the treatment of patients with hepatocellular carcinoma and the ability to adequately conduct clinical 
research under Good Clinical Practice Standards (GCP) consistent with the regulations of 21 CFR 812, 
Investigational Device Exemptions, and ISO 14155. 
In addition, all participating study sites must be appropriately experienced in the use of Y-90 microspheres 
for the treatment of liver tumors, and must have completed adequate training in order to use the 
TheraSphere Y-90 microsphere product.  The required training will be specified by Biocompatibles.  Generally, 
an adequate level of experience consists of a minimum of 5 TheraSphere administrations for sites without 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
4 9  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
r a di o e m b oliz ati o n  ex p eri e nc e a n d  at  l e ast  3  a d mi nistr ati o ns  of T h er a S p h er e  f or  sit es  ex p eri e nc e d  i n  
r a di o e m b oliz ati o n wit h a diff er e nt r a di o acti v e micr os p h er e pr o d uct. 
1 3. 2  IN S TI T U TI O N AL A P P R O V AL A N D D O C U M E N T A TI O N O F T H E P R O T O C OL  
Pri or  t o  i niti ati n g  t h e  cli nic al  st u d y,  e ac h  p artici p ati n g  i nstit uti o n  m ust  h a v e  d oc u m e nt ati on  t h at  t h e  
I nstit uti o n R evi e w B o ar d (I R B) or Et hics C o m mitt e e ( E C) h as r e vi e w e d a n d a p pr o v e d t h e pr ot oc ol a n d t h e 
I nf or m e d C o ns e nt F or m (I C F).  
T h e fi n al I R B / E C a p pr o v e d pr ot oc ol, c o ns e nt f or m, d oc u m e nt ati o n of I R B / E C a p pr o v al of t h e c o ns e nt a n d 
pr ot oc ol, St u d y  C o ntr act, St at e m e nt of I n v esti g at or, C Vs of all i n v esti g at ors a n d st u d y c o or di n at ors, r ec or ds 
of pr ot oc ol tr ai ni n g, a n d all  ot h er  st u d y-r el at e d r e q uir e d r e g ul at or y d oc u m e nt ati o n as d escri b e d i n t h e 
S ecti o ns b el o w m ust als o b e m ai nt ai n e d i n t h e cli nic al st u d y fil es f or t his tri al. 
T h e Sit e  Pri nci p al I n v esti g at or is ulti m at el y r es p o nsi bl e f or e ns uri n g t h at r e q uir e d st u d y d oc u m e nt ati o n h as 
b e e n o bt ai n e d, t h at all st u d y pr oc e d ur es ar e pr o p erl y f oll o w e d, a n d t h at all e nr oll e d p ati e nts m e et t h e 
eli gi b ilit y crit eri a pri or t o e nr oll m e nt u n d er t his pr ot oc ol.  
T h e I n v esti g at or is r es p o nsi bl e f or s u b missi o n of t h e pr ot oc ol, i nf or m e d c o ns e nt f or m, a n y p ati e nt e d uc ati o n 
m at eri als, a n d a n y r ecr uit m e nt or a d v ertisi n g m at eri als t o t h e i nstit uti o n’s I R B/ E C.  
•  
Writt e n a p pr o v al of t h e pr ot oc ol a n d I nf or m e d C o ns e nt F or m m ust b e o bt ai n e d pri or t o r ecr uit m e nt 
of p ati e nts i nt o t h e tri al at e ac h sit e a n d pri or t o a d mi nistr ati o n of a n y pr ot oc ol tr e at m e nt .   
•  
R ecr uit m e nt a n d a d v ertisi n g m at eri als m ust h a v e  writt e n  I R B/ E C a p pr o v al b ef or e us e.   
•  
T h e I n v esti g at or is r es p o nsi bl e f or o bt ai ni n g a n d m ai nt ai ni n g I R B / E C a p pr o v al at his f acilit y a n d 
pr o vi di n g c o pi es of all I R B / E C c orr es p o n d e nc e t o t h e S p o ns or or d esi g n e e.   
T his pr ot oc ol is a m ulti -c e nt er pr ot oc ol a n d as s uc h m ust r e m ai n c o nsist e nt wit h all ot h er sit es.  
1 3. 3  R E G UL A T O R Y D O C U M E N T S  
T h e f oll o wi n g d oc u m e nt ati o n ( wit h t h e exc e pti o n of Fi n al R e p ort ) m ust  b e o bt ai n e d b ef or e st u d y e nr oll m e nt 
c a n b e gi n. A d diti o n all y, i n E ur o p e a n or Asi a n C o u ntri es, all t h os e d oc u m e nts r e q uir e d as p er I C H/ G C P a n d 
l oc al l a ws f or sit e acti v ati o n n e e d t o b e o bt ai n e d/ pr o vi d e d t o Bi oc o m p ati bl es  or its d esi g n e e b ef or e t h e 
e nr ol m e nt c a n b e gi n at sit es.  
•  
I nstit uti o n al R evi e w B o ar d/ Et hics C o m mitt e e A p pr o v al  
A c o p y of t h e pr ot oc ol a n d a n y a m e n d m e nts, t h e pr o p os e d i nf or m e d c o ns e nt f or m (I C F), ot h er writt e n s u bj ect 
i nf or m ati o n a n d a n y pr o p os e d a d v ertisi n g m at eri al m ust b e s u b mitt e d b y t h e I n v esti g at or t o t h e I R B/ E C f or 
writt e n a p pr o v al.  A c o p y of t h e writt e n a p pr o v al of t h e pr ot oc ol a n d I C F m ust b e r ec ei v e d b y t h e sp o ns or or 
d esi g n e e b ef or e r ecr uit m e nt of s u bj ects i nt o t h e st u d y a n d a d mi nistr ati o n of pr ot oc ol tr e at m e nt . 
T h e in v esti g at or m ust s u b mit a n d, w h er e n ec ess ar y, o bt ai n a p pr o v al fr o m t h e I R B / E C f or all s u bs e q u e nt 
pr ot oc ol a m e n d m e nts a n d c h a n g es t o t h e I C F.  T h e in v esti g at or s h o ul d n otify t h e I R B / E C of d evi ati o ns fr o m 
t h e pr ot oc ol a n d  S A Es  as r e q uir e d b y  l oc al pr oc e d ur es. 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
T h e in v esti g at or will b e r es p o nsi bl e f or u p d ati n g t h e I R B/ E C a b o ut t h e st at us of t h e tri al at l e ast a n n u all y a n d 
o bt ai ni n g  a n y  r e q uir e d  a p pr o v als  r e n e w al  t hr o u g h o ut  t h e  d ur ati o n  of  t h e  st u d y.   C o pi es  of  a n y 
c orr es p o n d e nc e a n d ot h er d oc u m e nt ati o n b et w e e n t h e i n v esti g at or a n d t h e I R B / E C m ust b e r et ai n e d as p art 
of t h e sit e d oc u m e nt ati o n of t h e st u d y. C o pi es of all s uc h d oc u m e nts  m ust b e s e nt t o t h e sp o ns or or d esi g n e e.  
•  
I nstit uti o n al R evi e w B o ar d/ Et hics C o m mitt e e M e m b ers hi p R ost er  
As r e q uir e d i n acc or d a nc e wit h j uris dicti o n r e g ul ati o ns, t h e in v esti g at or m ust s u b mit a c o m pl et e  a n d  c urr e nt 
r ost er  of  t h e  I R B/E C  t o  t h e  s p o ns or  (Bi oc o m p ati bl es )  or  d esi g ne e.   S o m e  i nstit uti o ns,  o n  gr o u n ds  of  
c o nfi d e nti alit y, m a y n ot r el e as e t h e I R B / E C r ost er.  I n s uc h i nst a nc es, t h e i nstit uti o n’s G e n er al Ass ur a nc e 
N u m b er,  assi g n e d  b y  t h e  U nit e d  St at es  D e p art m e nt  of  H e alt h  a n d  H u m a n  S er vic es,  is  a n  acc e pt a bl e  
s u bstit ut e. 
•  
St at e m e nt of I n v esti g at or  
T h e i n v esti g at or will b e r e q uir e d t o si g n a n d d at e a St at e m e nt of i n v esti g at or f or m pr o vi d e d t o t h e m b y 
Bi oc o m p ati bl es .  A c o p y of t his f or m will b e gi v e n t o t h e i n v esti g at or f or t h eir fil es.  T h e ori gi n al f or m will b e 
m ai nt ai n e d b y  Bi oc o m p ati bl es . 
•  
C urric ul u m Vit a e  
T h e i n v esti g at or will pr o vi d e Bi oc o m p ati bl es  or d esi g n e e wit h his/ h er u p -t o-d at e c urric ul u m vit a e a n d t h os e 
of a n y s u b -i n v esti g at ors or st aff p ers o n n el wit h si g nific a nt tri al r es p o nsi biliti es. 
•  
L a b or at or y C ertific ati o n a n d N or m al V al u es  
T h e I n v esti g at or will pr o vi d e Bi oc o m p ati bl es  wit h t h e n a m e a n d l oc ati o n of t h e cli nic al l a b or at or y t o b e 
utiliz e d f or d et er mi n ati o n of l a b or at or y ass a ys, c o p y of c ertific ati o n a n d a list of t h e n or m al r a n g e of v al u es 
of all l a b or at or y t ests.  A n y c h a n g es i n l a b or at or y, c ertific ati o n or n or m al r a n g es will b e c o m m u nic at e d 
pr o m ptl y t o Bi oc o m p ati bl es  or d esi g n e e.  
•  
Fi n a nci al Discl os ur e  
Fi n a nci al d iscl os ur e st at e m e nts will b e c o m pl et e d f or t h e in v esti g at or a n d all s u b-i n v esti g at ors t o discl os e 
p ot e nti al c o nflicts of i nt er est ( p er 2 1 C F R 5 4 a n d I S O 1 4 1 5 5: 1 1: 9. 2) .  T h e i n v esti g at or is r es p o nsi bl e f or 
e ns uri n g c o m pl et e d a n d si g n e d fi n a nci al discl os ur e f or ms, w hic h ar e pr o vi d e d b y Bi oc o m p ati bl es  or d esi g n e e.  
A c o p y of t h e f or m(s) will b e gi v e n t o t h e i n v esti g at or f or t h eir fil es.  T h e ori gi n al f or m(s) will b e m ai nt ai n e d 
b y Bi oc o m p ati bl es  Fi n a nci al discl os ur e i nf or m ati o n will b e c oll ect e d b y t h e s p o ns or b ef or e t h e st art of t h e 
st u d y a n d m ai nt ai n ed f or o n e y e ar aft er st u d y c o m pl eti o n.  
•  
Fi n al R e p ort  
U p o n c o m pl eti o n of t h e cli nic al tri al, a  fi n al st u d y r e p ort will b e pr o vi d e d b y t h e s p o ns or. T h e I n v esti g at or will 
pr e p ar e a n d s u b mit t o t h e I R B / E C a fi n al r e p ort, i ncl u di n g fi n al st u d y r e p ort.   
    
1 3. 4  S O U R C E R E C O R D S A N D S T U D Y D O C U M E N T A TI O N  

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
I n v esti g at ors ar e r e q uir e d t o pr e p ar e a n d m ai nt ai n a d e q u at e s o urc e d oc u m e nt ati o n.  S o urc e d oc u m e nt ati o n 
i ncl u d es: 
•  
d oc u m e nts r el ati v e t o t h e p ati e nt’s m e dic al hist or y t h at v erify t h e eli gi bilit y  crit eri a  
•  
r ec or ds c o v eri n g t h e p atie nt’ p artici p ati o n i n t h e st u d y w hic h  i ncl u d e b ut ar e n ot li mit e d t o b asic 
i d e ntific ati o n i nf or m ati o n, r es ults of p h ysic al ex a mi n ati o ns a n d di a g n ostic t ests, t h er a p y, d evic e 
a d mi nistr ati o n, c o n c urr e nt m e dic ati o n i nf or m ati o n a n d visit/c o ns ult n ot es.  
T h e I n v esti g at or will i niti al a n d d at e all l a b or at or y r e p orts or i niti al a n d d at e st at e m e nts at e ac h st u d y visit 
t h at all cli nic al l a b or at or y d at a w as r e vi e w e d. 
F e d er al or n ati o n al  r e g ul ati o ns c o nc er ni n g t h e p eri o d d uri n g w hic h st u d y r ec or ds m ust b e m ai nt ai n e d b y t h e 
I n v esti g at or v ar y fr o m c o u ntr y t o c o u ntr y. I n v esti g at ors ar e r e q uir e d t o c o m pl y wit h t h eir l oc al r e g ul at or y 
a ut h orit y f or st or a g e of st u d y d oc u m e nt ati o n.  F or t h e p ur p os es of t his st u d y t h e mi ni m u m r et e nti o n f or St u d y 
D oc u m e nt ati o n is a p eri o d of t w o ( 2) y e ars aft er t h e d at e o n w hic h t h e St u d y is t er mi n at e d or c o m pl et e d.  
 
C o m pl et e d e C R F s t h at ar e d at e d a n d si g n e d b y t h e i n v esti g at or m ust b e m a d e a v ail a bl e f or r e vi e w a n d 
r etri e v al b y Bi oc o m p ati bl es  or d esi g n e e at t h e ti m e t h e s u bj ect c o m pl et es t h e st u d y.  Bi oc o m p ati bl es  or 
d esi g n e e will pr o vi d e t h e i n v esti g at or wit h a c o p y of c o m pl et e d e C R F s f or t h eir fil es. 
I n or d er t o e ns ur e t h e acc ur ac y of d at a c oll ect e d i n t h e e C R F s, it is m a n d at or y t h at r e pr es e nt ati v es of 
Bi oc o m p ati bl es , as w ell as r e pr es e nt ati v es of a r e g ul at or y a g e nc y ( e.g . t h e F o o d a n d Dr u g A d mi nistr ati o n) or 
t h e i nstit uti o n al r evi e w b o ar d/ et hics c o m mitt e e (I R B/ E C), h a v e acc ess t o s o urc e d oc u m e nts (i.e . s u bj ect 
r ec or ds, s u bj ect c h arts, a n d l a b or at or y r e p orts).  D uri n g t h e r evi e w of t h es e d oc u m e nts, t h e a n o n y mit y of 
t h e  s u bj ect  will  b e  m ai nt ai n e d  wit h  strict  a d h er e nc e  t o  pr of essi o n al  st a n d ar ds  of  c o nfi d e nti alit y.   
Bi oc o m p ati bl es  r es er v es t h e ri g ht t o t er mi n at e t h e st u d y at a n y sit e  f or r ef us al of t h e i n v esti g at or t o s u p pl y 
s o urc e d oc u m e nt ati o n of w or k p erf or m e d i n t his cli nic al tri al.  
1 3. 5  E T HI C AL C O N D U C T O F T H E S T U D Y  
T his st u d y will b e c o n d uct e d i n c o m pli a nc e wit h st a n d ar d o p er ati n g pr oc e d ur es of t h e sp o ns or or d esi g n e e, 
w hic h ar e d esi g n e d t o e ns ur e a d h er e nc e t o g o o d cli nic al p r actic e (G C P) g ui d eli n es as r e q uir e d b y t h e 
f oll o wi n g:  
1.  W orl d M e dic al Ass oci ati o n ( W M A), D ecl ar ati o n of H elsi n ki, Et hic al Pri nci pl es f or M e dic al R es e arc h 
I n v ol vi n g H u m a n S u bj ects, A d o pt e d b y t h e 1 8t h W M A G e n er al Ass e m bl y, H elsi n ki, Fi nl a n d, J u n e 
1 9 6 4, a n d as a m e n d e d at s u bs e q u e nt W M A G e n er al Ass e m bl y m e eti n gs.  
 
2.  E 6 G o o d Cli nic al Pr actic e: C o ns oli d at e d G ui d a nc e (I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n of 
P h ar m ac e utic als f or H u m a n Us e [I C H], A pril 1 9 9 6 g o v er ni n g dr u gs a n d I S O 1 4 1 5 5 g o v er ni n g 
d evic es.  
 
3.  Titl e 2 1 of t h e U S C o d e of F e d er al R e g ul ati o ns ( 2 1 C F R) P arts 5 0, 5 4, a n d 5 6 . 
 
 
1 3. 6  R E S P O N SI BL E C O N D U C T O F R E S E A R C H  

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
52 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
The Sponsor will ensure that this trial is conducted in full conformity with the current revision of the 
‘Declaration of Helsinki’, ISO 14155, the U.S. Code of Federal Regulations 21 CFR 812, and applicable state 
and federal regulations, whichever affords the greatest protection to the patient.  The Sponsor is responsible 
for providing monitoring oversight for the study to ensure the involvement of the Investigator in the trial, to 
ensure the rights, safety and well-being of the patients, compliance to the protocol and to all applicable laws, 
and to oversee the completeness, accuracy and consistency of the data collected in support of a premarket 
approval application.  
The procedures defined in the protocol and the eCRFs will be carefully reviewed by the Sponsor with the 
Investigator and staff prior to time of trial initiation to ensure appropriate interpretation and implementation.  
No deviations from the protocol may be made without advance approval from Biocompatibles and the IRB/EC 
as required by the policies of the IRB/EC. 
Monitors from the Sponsor, or their designees, will periodically visit the site to review case report forms, the 
Regulatory Binder, patient medical records including electronic records, imaging files, laboratory reports, 
device accountability, site training and authorization of delegation and any other records related to the study 
conduct.  Investigator will maintain and release the records for review, provide access to the records and 
copies as needed, and will meet with the monitor as needed to discuss study progress and needs.  The 
Investigator should maintain the files suitable for inspection at any time by a trial monitor from 
Biocompatibles, or the appropriate regulatory authority, or designate representing these organizations. 
13.7 INFORMED CONSENT 
An IRB/EC approved signed informed consent form (ICF) must be obtained from a patient before that patient 
can enter the trial, and before any study related evaluations can be performed on that patient. 
The investigator is responsible for the creation of the ICF and must ensure that the informed consent adheres 
to the U.S Code of Federal Regulations 21 CFR 50, ISO 14155:11:3.7 or equivalent, as appropriate to his/her 
country.  The Investigator will ensure that the local IRB/EC has approved the protocol and the informed 
consent prior to the initiation of the trial.  The signed informed consent from each patient must be kept in 
the patient’s study file.   
The investigator or designee will review the treatment plan with the patient and the patient will have an 
opportunity to ask questions regarding study procedures, the required visit schedule, risks/benefits of the 
use of the approved device (TheraSphere), and alternative treatment options prior to signing the ICF.  The 
patient will receive a copy of the signed informed consent to keep for their records.  Periodically during the 
study, revisions to the informed consent form may be needed.  Patients will be informed of such revisions 
and any revisions must be signed and kept in the patients study file.   
The acquisition of informed consent should be documented in the subject’s medical record and the ICF should 
be signed and personally dated by the subject and by the person who conducted the informed consent 
discussion (not necessarily by the investigator).   
Patients for whom English is not their first language may need a written translation of the document and/or 
a patient advocate, according to the policies of the IRB/EC.  The Investigator will provide Biocompatibles a 
copy of the IRB/EC approved translation, if any. 
13.8 PATIENT MEDICAL RECORDS 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 3  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
T h e I n v esti g at or m ust m ai nt ai n a d e q u at e m e dic al r ec or ds r e g ar di n g t h eir c ar e of t h e p ati e nt, i ncl u di n g c as e 
hist ori es, t o s u p p ort t h e cli nic al d at a i n t h e c as e r e p ort f or ms.  T h es e r ec or ds m ust b e m ai nt ai n e d a n d m a d e 
a v ail a bl e f or m o nit ori n g a n d a u diti n g b y t h e S p o ns or, or t h eir d esi g n e e, a n d t h e a p pr o pri at e r e g ul at or y 
a g e nc y .  All C T/ M RIs will b e m ai nt ai n e d or arc hi v e d al o n g wit h t h e m e dic al c h art f or r evi e w f or at l e ast 2 y e ars 
aft er st u d y t er mi n ati o n .  
1 3. 9  P A TI E N T P RI V A C Y A N D C O N FI D E N TI ALI T Y  
All c oll ect e d p ati e nt d at a will b e tr e at e d c o nfi d e nti all y a n d i d e ntifi e d o nl y b y a p ati e nt i d e ntific ati o n n u m b er 
a n d  p ati e nt  i niti als  ( w h er e  all o w e d).   M e dic al  r ec or ds  r el ati n g  t o  t his  tri al,  i ncl u di n g  t h os e  t h at  ar e  
el ectr o nic all y m ai nt ai n e d a n d t h os e t h at m a y c o nt ai n i nf or m ati o n t h at w o ul d i d e ntify a n i n di vi d u al p ati e nt 
will r e m ai n c o nfi d e nti al, b ut m a y b e r e vi e w e d b y, r el e as e d, a n d/ or tr a ns mitt e d t o r e pr es e nt ati v es of t h e 
h os pit al, t h e a p pr o pri at e r e g ul at or y a g e nc y, Bi oc o m p ati bl es  (t h e S p o ns or) or its a g e nts, a n d t h e D at a S af et y 
M o nit ori n g B o ar d w h e n r e as o n a bl e a n d a p pr o pri at e f or t h e c o n d uct of t h e tri al.  
As p art of t h e r e q uir e d c o nt e nt of t h e i nf or m e d c o ns e nt, t h e p ati e nt m ust b e i nf or m e d t h at his/ h er r ec or ds 
will b e r e vi e w e d b y Bi oc o m p ati bl es  a n d/ or a r e pr es e nt ati v e of t h e a p pr o pri at e r e g ul at or y a g e nc y a n d t h e 
D at a S af et y M o nit ori n g B o ar d. T h e i nf or m e d c o ns e nt or r el at e d d oc u m e nt will als o st at e t h at p ati e nt pri v ac y 
will b e m ai nt ai n e d p urs u a nt t o t h e H e alt h I ns ur a nc e P ort a bilit y a n d Acc o u nt a bilit y Act ( HI P A A) , 2 1 C F R 2 1  or 
e q ui v al e nt f or c o u ntri es ot h er t h a n t h e U nit e d St at es.  S h o ul d acc ess  t o t h e m e dic al r ec or d r e q uir e a s e p ar at e 
HI P A A w ai v er or a ut h oriz ati o n p er i nstit uti o n al c o nfi d e nti all y p olici es, it is t h e I n v esti g at or’s r es p o nsi bilit y t o 
o bt ai n s uc h p er missi o n fr o m t h e p ati e nt i n writi n g b ef or e  t h e p ati e nt is e nt er e d i nt o t h e tri al. 
1 3. 1 0  A D DI TI O N AL IN V E S TI G A T O R R E S P O N SI BILI TI E S  
A d diti o n al I n v esti g at or r es p o nsi biliti es ar e n ot e d i n C o u ntr y -s p ecific g ui d eli n es a n d l a ws, i n I S O 1 4 1 5 5:1 1  a n d 
i n S ecti o n 1 1 of t h e U S 2 1 C F R 8 1 2. 1 0 0, 8 1 2. 1 1 0 a n d r es p o nsi biliti es f or r e p orti n g of u n a ntici p at e d a d v ers e 
d evic e e v e nts a n d d e vi ati o ns fr o m t h e i n v esti g ati o n al pl a n p er 8 1 2. 1 5 0 as w ell as t h e f oll o wi n g:  
•  
E ns ur e  c o m pli a nc e  wit h  i nstit uti o n al  a n d  a p pr o pri at e  r el e v a nt  j uris dicti o n al R a di ati o n  S af et y  
p olici es a n d pr oc e d ur es  
•  
Ass e m bl e a n d c o or di n at e a t e a m t h at i ncl u d es a d esi g n at e d c o -i n v esti g at or i n all of t h e m e dic al 
disci pli n es n ec ess ar y f or t h e effici e nt c o n d uct of t h e pr ot oc ol ( o nc ol o g y, i nt er v e nti o n al r a di ol o g y, 
n ucl e ar m e dici n e,  di a g n ostic r a di ol o g y, etc).  
•  
Pr o vi d e a tri al c o or di n at or w h o will b e r es p o nsi bl e f or assisti n g t h e I n v esti g at or i n m e eti n g d at a 
c oll ecti o n  a n d  r e p orti n g  r e q uir e m e nt  a n d  f or  sc h e d uli n g,  m a n a g e m e nt  a n d  f oll o w -u p  of  tri al  
p ati e nts.  
•  
Pr o vi d e a d e q u at e acc ess t o st u d y m at eri als f or Bi oc o m p ati bl es  t o m o nit or t h e tri al at a p pr o pri at e 
a n d c o n v e ni e nt i nt er v als a n d pr o vi d e a n a d e q u at e, s ec ur e ar e a, wit hi n t h e st u d y sit e f acilit y f or a 
Bi oc o m p ati bl es  r e pr es e nt ati v e t o c o n d uct t h es e m o nit ori n g acti viti es. 
1 4  P R O T O C OL D E VI A T I O N S 
It is vit al t o t h e s ucc ess of t h e st u d y t h at t h e in v esti g at or a d h er es t o t h e d et ails of t h e pr ot oc ol .  All d evi ati o ns 
fr o m t h e pr ot oc ol m ust b e a p pr o v e d b y t h e s p o ns or b ef or e i m pl e m e nt ati o n.   

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 4  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
Pr ot oc ol d evi ati o ns will b e tr ac k e d acc or di n g t o t h e f oll o wi n g c at e g ori es: 
1.  I nf or m e d C o ns e nt pr oc ess n ot f oll o w e d 
2.  Scr e e ni n g t ests or pr oc e d ur es o ut of wi n d o w or n ot d o n e  
3.  I m a gi n g t ests n ot p erf or m e d as r e q uir e d 
4.  I ncl usi o n/ Excl usi o n crit eri a vi ol ati o n 
5.  T h er a S p h er e  d os e d eli v er y o utsi d e r a n g e of 8 0 t o 1 5 0  Gy  
6.  L u n g d os e exc e e ds 3 0 Gy si n gl e tr e at m e nt, 5 0 Gy c u m ul ati v e  
7.  St u d y visits , t ests or pr oc e d ur es c o n d uct e d o ut of wi n d o w or n ot d o n e  
8.  Li v er-dir ect e d tr e at m e nt of H C C  ot h er t h a n T h er a S p h er e  
 
1 5  P R O T O C OL V I OL A TI O N S 
M aj or pr ot oc ol vi ol ati o ns ar e d efi n e d as:  
 
•  
E nr oll m e nt Vi ol ati o ns:   
o  
Eli gi bilit y crit eri a d e vi ati o ns  
o  
N o i nf or m e d c o ns e nt  
  
•  
P ost -Tr e at m e nt Vi ol ati o ns:  
o  
A d mi nistr ati o n of li v er -dir ect e d l oc al r e gi o n al t h er a p y  ot h er t h a n t h at s p ecifi e d i n t h e 
pr ot oc ol  f oll o wi n g i ntr a-h e p atic pr o gr essi o n  
o  
P ati e nts wit h dis e as e pr o gr essi o n w h o h a v e t u m or r es p o ns e d at a missi n g f or 2 f oll o w -u p 
visits pri or t o pr o gr essi o n . 
 
1 6  S T U D Y M O NI T O RI N G  
T h e st u d y will b e m o nit or e d b y q u alifi e d p ers o n n el fr o m t h e sp o ns or or a c o ntr act r es e arc h or g a niz ati o n 
( C R O) c o ntr act e d to pr o vi d e s uc h m o nit ori n g b y t h e sp o ns or .  D at a m a n a g e m e nt a n d st atistic al a n al ys es will 
b e  t h e r es p o nsi bilit y of t h e sp o ns or  w h o will c o ntr act wit h o n e or m or e or g a niz ati o ns t o m a n a g e t h es e 
f u ncti o ns.  
B ef or e i niti ati o n of t h e tri al, r e pr es e nt ati v es fr o m t h e s p o ns or will, t o g et h er wit h t h e i n v esti g at or, r e vi e w t h e 
pr ot oc ol a n d t h e f aciliti es.  At tri al i niti ati o n, t h e s p o ns or's r e pr es e nt ati v e will t h or o u g hl y r evi e w t h e pr ot oc ol 
a n d g o o v er t h e e C R F s a n d el ectr o nic d at a e ntr y pr oc e d ur es wit h t h e i n v esti g at or(s) a n d ot h er a ut h oriz e d 
st aff.   
D uri n g t h e c o urs e of t h e tri al, a st u d y m o nit or 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 will c o n d uct 
r e m ot e m o nit ori n g a n d visit t h e i n v esti g at or at s uit a bl e i nt er v als.  T h e p ur p os e of t h es e visits will b e t o v erify 
c o m pli a nc e  wit h  a p plic a bl e  g o v er n m e nt  r e g ul ati o ns  a n d  a d h er e nc e  t o  t h e  pr ot oc ol,  e ns ur e  c orr ect  
c o m pl eti o n of t h e e C R F s. 
I n  or d er  t o  p erf or m  his/ h er  r ol e  eff ecti v el y,  t h e  st u d y  m o nit or(s)  m ust  b e  gi v e n  acc ess  t o  s o urc e  
d oc u m e nt ati o n (e g,  cli nic c h arts, ori gi n al l a b or at or y r ec or ds), w hic h s u p p ort d at a o n t h e e C R F , a n d i nf or m e d 
c o ns e nt f or ms.  T h e m o nit or m ust b e a bl e t o v erify d at a a p p e ari n g i n t h e e C R F s a g ai nst d at a i n t h e s u bj ect's 
cli nic c h art (e g,  c h art n ot es) or i n pri nt o ut f or ms ( e g, l a b or at or y r es ults). 
1 7  S T U D Y T E R MI N A TI O N  

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
55 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
Biocompatibles reserves the right to discontinue this study for administrative reasons at any time.  The End 
of Trial is defined as database hard lock.   
The manuscript reporting the outcome of this trial will be authored by the Principal Investigators with input 
from investigators and submitted to a peer-reviewed scientific journal for publication. 
 
 
 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 6  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
A P P E N DI C E S  
 
1.  T h er a S p h er e  Pr o d uct L a b eli n g  
a.  U S P ac k a g e I ns ert  
htt p:// w w w.t h er as p h er e.c o m/ p h ysici a ns -p ac k a g e -i ns ert/ p ac k a g e-i ns ert-
us. p df p  
b.  C A P ac k a g e I ns ert  
    htt p:// w w w.t h er as p h er e.c o m/ p h ysici a ns -p ac k a g e -i ns ert/ p ac k a g e-i ns ert-c a. p df 
c. E U I nstr ucti o ns f or Us e  
htt p:// w w w.t h er as p h er e.c o m/ p h ysici a ns -p ac k a g e -i ns ert/ p ac k a g e-i ns ert-e u -
e n. p df p  ( ot h er l a n g u a g es ar e a v ail a bl e at t his w e bsit e 
 
 
 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 7  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
 
2.  P V T Cl assific ati o n: T a bl e 1 a n d Fi g ur e 1 a d a pt e d  fr o m S hi J et al., A n n S ur g O nc ol 2 0 1 0 . 
 
T a bl e 1 Cl assific ati o n of P V T  
Ty p es  
S u bt y p es  
Ty p e  1 0:  T u m or  t hr o m bi  f or m ati o n  
f o u n d u n d er micr osc o p y 
 
Ty p e  1:  T u m or  t hr o m bi  i n v ol vi n g  
s e g m e nt al br a nc h es of p ort al v ei n or 
a b o v e  
Ty p e I a: T u m or t hr o m bi i n v ol vi n g s e g m e nt al br a nc h es 
of p ort al v ei n or a b o v e  
Ty p e I b: T u m or t hr o m bi i n v ol vi n g s e g m e nt al br a nc h es 
of p ort al v ei n ext e n di n g t o s ect or al br a nc h  
Ty p e  II:  T u m or  t hr o m bi  i n v ol vi n g  
ri g ht/l eft p ort al v ei n 
Ty p e II a: t u m or t hr o m bi i n v ol vi n g ri g ht/l eft p ort al v ei n  
Ty p e II b: T u m or t hr o m bi i n v ol vi n g b ot h l eft a n d ri g ht 
p ort al v ei n  
Ty p e III: T u m or t hr o m bi i n v ol vi n g t h e 
m ai n p ort al tr u n k *   
Ty p e III a: T u m or t hr o m bi i n v ol vi n g t h e m ai n p ort al v ei n 
tr u n k all o wi n g bl o o d fl o w t o t h e c o ntr al at er al l o b e ( wit h 
n o t hr o m b osis)  
Ty p e III b: T u m or t hr o m bi i n v ol vi n g t h e m ai n p ort al v ei n 
tr u n k als o occl u di n g blo o d fl o w t o t h e c o ntr al at er al l o b e 
( wit h n o t hr o m b osis) 
Ty p e I V: T u m or t hr o m bi i n v ol vi n g t h e 
s u p eri or m es e nt eric v ei n 
 
N ot e: p ati e nts wit h P V T cl assific ati o ns T y p e III b a n d T y p e I V n ot e d a b ov e ar e n ot eli gi bl e u n d er t his pr ot oc ol.  
* m o difi e d o n t h e b asis of ext e nsi o n of t h e t u m or t hr o m b us r at h er t h a n o n t h e l e n gt h of t h e t hr o m b us  
 
 

HCC Phase III Protocol TS-104 
YES-P, Version 3.0 
58 
 
Biocompatibles 
CONFIDENTIAL  8 August 2014 
3. ECOG Performance Status 
Score 
Characteristics 
0 
Asymptomatic and fully active 
1 
Symptomatic; fully ambulatory; restricted in physically strenuous activity 
2 
Symptomatic; ambulatory; capable of self-care; more than 50% of waking hours 
are spent out of bed. 
3 
Symptomatic; limited self-care; more than 50% of waking hours are spent in bed 
4 
Completely disabled; no self-care; bedridden. 
 
4. Child Pugh Classification 
Assess severity of liver disease by assigning points for each of the five parameters in the 
table below and adding the points to obtain a total score. Record the resulting Child Pugh 
Grade: A (well compensated disease) 5-6 points; B (functional compromise, worsening 
disease) 7-9 points and C (decompensated disease) 10-15 points. 
Parameter 
1 point 
2 points 
3 points 
Bilirubin 
<34 µmol/L 
34–50 µmol/L 
>50 µmol/L 
Albumin 
>35 g/L 
28-35 g/L 
<28 g/L 
Prothrombin Time 
<1.8 (INR) or <4 secs 
(Seconds over control) 
1.8-2.2 (INR) or 4-6 
secs 
>2.2 (INR) or >6 
secs 
Ascites 
absent 
Slight 
(medically 
controlled) 
Moderate (poorly 
controlled) 
Encephalopathy* 
None 
Grade 1-2 
Grade 3-4 
 
*Grades of Encephalopathy 
Grade 1 – Inverted sleep pattern; forgetfulness, agitation, irritability, apraxia 
Grade 2 – Lethargy; Disorientation for time or place, Subtle personality change; Asterixis, 
ataxia 
Grade 3 – Somnolence but rousability; Disorientation as regards place; Asterixis, 
hyperactive reflexes, Babinski signs, muscle rigidity 
Grade 4 – Coma (unresponsive to verbal or noxious stimuli) 
 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
5 9  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
5.  Bri ef S u m m ar y of R es p o ns e Crit eri a M et h o ds  
R E CI S T v 1. 1 d et er mi n ati o n of ti m e -p oi nt r es p o ns e  
 
 
Ass ess m e nt of R es p o ns e acc or di n g t o E A SL, m R E CI S T  
 
E A SL  
m R E CI S T  
 
 
B E S T 
R E S P O N S E  
Esti m ati o n  of  r e d ucti o n  
i n vi a bl e t u m or v ol u m e  
( n ecr osis = n o n e n h a nc e d 
ar e a at C T)  
C h a n g e  i n  t h e  s u m  of  
di a m et er
 of
 vi a bl e
 
( e n h a nc e m e nt
 i n
 t h e
 
art eri al
 p h as e)
 t ar g et
 
l esi o nsΔ  
C R  
Dis a p p e ar a nc e of all  
e n h a nc e d t u m or ar e as  
Dis a p p e ar a nc e
 of
 a n y
 
i ntr at u m or al 
art eri al 
e n h a nc e m e nt  i n  all  t ar g et  
l esi o ns 
P R  
D ecr e as e > 5 0 % of  
e n h a nc e d ar e as  
≥3 0 % d ecr e as e i n t h e s u m of 
di a m et ers  of  vi a bl e  t ar g et  
l esi o ns 
S D  
N eit h er C R n or P R n or P D  
N eit h er C R n or P R  
n or P D  
P D  
a n i ncr e as e > 2 5 % i n t h e 
siz e  of  ≥1  m e as ur a bl e 
l esi o n(s)  
≥2 0 % i ncr e as e i n t h e s u m of 
t h e  di a m et er  of  vi a bl e  of  
t ar g et l esi o n 
Δ  D o es n ot i ncl u d e s u m m ariz ati o n of i m p act of n e w a n d  n o n -t ar g et l esi o ns o n r es p o ns e ass ess m e nt –  s e e n e w a n d  n o n -t ar g et l esi o n 
r es p o ns e i n R E CI S T v 1. 1  a b ov e  f or m or e d et ails 
 

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
6 0  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
R E F E R E N C E S  
 
1 htt p:// w w w.c a nc er. or g/ d o w nl o a ds/S T T/ Gl o b al _ F acts _ a n d _ Fi g ur es _ 2 0 0 7 _r ev 2. p df   acc ess e d J u n e 2 2, 2 0 1 0 at 1 1  : 1 0 E T  
 
2 E ur o p e a n Ass oci ati o n F or T h e St u d y Of T h e Liv er; E u r o p e a n Or g a nis ati o n F or R es e arc h A n d Tr e at m e nt Of C a nc er. E A SL -E O R T C  cli nic al 
pr actic e  g ui d eli n es: m a n a g e m e nt of h e p at oc ell ul ar c arci n o m a.  J H e p at ol. 2 0 1 2 A pr; 5 6( 4): 9 0 8-4 3.  
 
3 htt p:// w w w.f d a. g ov/ A b o ut F D A/ C e nt ers Offic es/ C D E R/ uc m 1 2 9 2 3 4. ht m , acc ess e d J u n e 2 2, 2 0 1 0 at 0 9: 3 0 E T 
 
4 htt p:// w w w. n ex av ar.c o m/scri pts/ p a g es/ e n/ h o m e/ p df/ N ex av ar S m P C E U M ar 2 0 1 3. p df  
 
5 Ll ov 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 Oliv 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 or t 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 ä ussi n g er D, Gi a n n aris T, S h a n M, M osc ovici M, V oli otis D, Br uix J; S H A R P 
I nv esti g at ors St u dy Ar m. S or af e ni b i n a dv a nc e d h e p at oc ell ul ar c arci n o m a. N E n gl J M e d. 2 0 0 8 J ul 2 4; 3 5 9( 4): 3 7 8-9 0. P u b M e d P MI D: 
1 8 6 5 0 5 1 4.  
 
6 C h e n AL, et al Effic acy a n d s af ety of s or af e ni b i n p ati e nts i n t h e Asi a -P acific r e gi o n wit h a dv a nc e h e p at oc ell ul ar c arci n o m a: a p h as e III 
r a n d o miz e d, d o u bl e bli n d, pl ac e b o-c o ntr oll e d tri al. L a nc et O nc ol 2 0 0 9; 1 0: 2 5 -3 4  
 
7 C h e n g  AL et al Effic acy a n d s af ety of s or af e ni b i n p ati e nts w it h a dv a nc e d h e p at oc ell ul ar c arci n o m a acc or di n g t o b as eli n e st at us: s u bs et 
a n alys es of t h e p h as e III S or af e ni b Asi a -P acific tri al. EJ C 2 0 1 2 J a n 1 0 [ e p u b a h e a d of pri nt] d oi: 1 0. 1 0 1 6/j. ejc a. 2 0 1 1. 1 2. 0 0 6  
 
8 Ll ov et J M, Di Bisc e gli e A M, Br uix J, Kr a m er B S, L e ncio ni R, Z h u A X, S h er m a n M, Sc h w artz M, L otz e M, T al w alk ar J, G or es GJ; P a n el of 
Ex p erts i n H C C -D esi g n Cli nic al Tri als. D esi g n a n d e n d p oi nts of cli nic al tri als i n h e p at oc ell ul ar c arci n o m a. J N atl C a nc er I nst. 2 0 0 8 M a y 
2 1; 1 0 0( 1 0): 6 9 8 -7 1 1. E p u b 2 0 0 8 M a y 1 3. R e vi e w. P u b M e d P MI D: 1 8 4 7 7 8 0 2.  
 
9 htt p:// w w w. ncc n. or g/ pr of essi o n als/ p hysici a n _ gls/ P D F/ h e p at o bili ar y. p df  acc ess e d Oct o b er 2 8, 2 0 1 1  at 0 9: 3 1  E T  
 
1 0 htt p:// w w w. asc o. or g/ A S C Ov 2/ M e eti n gs/ A bstr acts ? & v m vi e w = a bst _ d et ail _vi e w &c o nfI D = 5 5 & a bstr actI D = 3 4 5 5 2  acc ess e d J u n e 2 3, 
2 0 1 0 at 1 0: 0 1 E T    M. S h er m a n, V. M azz af err o, D. A m a d ori, J. S eitz, M. M osc ovici, M. S h a n, A. N a d el, D. V oli otis, J. M. Ll ov et, J. Br uix, 
o n b e h alf of t h e S H A R P i nv esti g at ors st u dy ar m Effic acy a n d s af ety of s or af e ni b i n p ati e nts wit h a dv a nc e d h e p at oc ell ul ar c arc i n o m a 
a n d v asc ul ar i nv asi o n or extr a h e p atic s pr e a d: A s u b a n alysis fr o m t h e S H A R P tri al. J Cli n O nc ol 2 6: 2 0 0 8 ( M a y 2 0 s u p pl; a bstr 4 5 8 4)  
 
1 1 S al e m R, L e w a n d o ws ki RJ, R o b erts C et al. Us e of Yttri u m -9 0 Gl ass Micr os p h er es ( T h er a S p h er e) f or t h e Tr e at m e nt of U nr es ect a bl e 
H e p at oc ell ul ar C arci n o m a i n P ati e nts wit h P ort al V ei n T hr o m b osis. J V as e I nt erv R a di ol 2 0 0 4;  1 5: 3 3 5-3 4 5 . 
1 2 S al e m R, L e w a n d o ws ki RJ, At assi B, et al. Tr e at m e nt of U nr es ect a bl e H e p at oc ell ul ar C arci n o m a wit h Us e of 9 0 Y Micr os p h er es 
( T h er a S p h er e): S af ety, T u m or R es p o ns e, a n d S urviv al. J V as e I nt erv R a di ol 2 0 0 5; 1 6: 1 6 2 7-1 6 3 9  
 
1 3 S al e m R, L e w a n d o ws ki RJ, M ulc a hy M F, Ri az A, Ry u R K, I br a hi m S, At assi B, B a k er T, G at es V, M ill er F H, S at o K T, W a n g E, G u pt a R, 
B e ns o n A B, N e w m a n S B, O m ary R A, A b ec assis M, K ulik L. R a di o e m b oliz ati o n f or h e p at oc ell ul ar c arci n o m a usi n g Yttri u m -9 0 
micr os p h er es: a c o m pr e h e nsiv e r e p ort of l o n g -t er m o utc o m es. G astr o e nt er ol o g y. 2 0 1 0 J a n; 1 3 8( 1): 5 2-6 4. E p u b 2 0 0 9 S e p 1 8. P u b M e d 
P MI D: 1 9 7 6 6 6 3 9.  
 
1 4 V e nt e M A, W o n d er g e m M, v a n d er T w e el I et al. Yttri u m -9 0 micr os p h er e r a di o e m b oliz ati o n f or t h e tr e at m e nt of liv er m ali g n a nci es: a 
str uct ur e d m et a-a n alysis. E ur R a di ol. 2 0 0 8 N ov 7  
 
1 5 G esc h wi n d J F, S al e m R, C arr B e t al. Yttri u m -9 0 Micr os p h er es f or t h e Tr e at m e nt of H e p at oc ell ul ar C arci n o m a. G astr o e nt er ol o g y 
2 0 0 4; 1 2 7: S 1 9 4 -S 2 0 5 . 
1 6 M azz af err o et al Yttri u m -9 0 r a di o e m b oliz ati o n f or i nt er m e di at e -a dv a nc e d h e p at oc ell ul ar c arci n o m a  : A P h as e 2 st u dy H e p at ol o g y 
2 0 1 3  ; 5 7 : 1 8 2 6-1 8 3 7   
1 7 S hi J, L ai E C, Li N et al. S ur gic al Tr e at m e nt of H e p at oc ell ul ar C arci n o m a wit h P ort al V ei n T u m or T hr o m b us. A n n S ur g O nc 2 0 1 0  [ E p u b 
a h e a d of pri nt  
 
1 8 S h a h Z K, Mc K er n a n M G, H a h n P F, S a h a ni D V. E n h a nci n g a n d ex p a nsil e p ort al v ei n t hr o m b osis: v al u e i n t h e di a g n osis of h e p at oc el l ul ar 
c arci n o m a i n p ati e nts wit h m ulti pl e h e p atic l esi o ns. AJ R A m J R o e nt g e n ol 2 0 0 7; 1 8 8: 1 3 2 0 -1 3 2 3   
1 9 R ossi S et al . C o ntr ast-e n h a nc e d ultr as o n o gr a p hy a n d s pir al c o m p ut e d t o m o gr a p hy i n t h e d et ecti o n a n d c h ar act eriz ati o n of p ort al v ei n 
t hr o m b osis c o m plic ati n g h e p at oc ell ul ar c arci n o m a. E ur R a di o 2 0 0 8; 1 8: 1 7 4 9-1 7 5 6.  
                                                                

H C C P h as e III Pr ot oc ol T S -1 0 4  
Y E S -P , V ersi o n 3. 0  
6 1  
 
Bi oc o m p ati bl es  
C O N FI D E N TI AL  8 A u g ust 2 0 1 4  
                                                                                                                                                                                                  
 
2 0  htt p:// ec o g. dfci. h arv ar d. e d u/ g e n er al/ p erf _st at. ht ml acc ess e d 3/ 2 4/ 2 0 1 0 ; Ok e n, M. M., Cr e ec h, R. H., T or m ey, D. C. et al. 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 g y Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2.  
 
2 1 Fisc h er L, et al.  T h e s e g m e nts of t h e h e p atic v ei ns –  is t h er e a s p ati al c orr el ati o n t o t h e C o ui n a u d liv er s e g m e nts ?  E ur J R a di ol 
5 3( 2): 2 4 5 -2 5 5, 2 0 0 5.  
 
2 2 D at a o n Fil e –  N or di o n T h er a S p h er e R ef er e nc e Bi n d er 2 0 1 0  
 
2 3 Eis e n h a u er E A , T h er ass e P , B o g a erts J , Sc h w artz L H , S ar g e nt D , F or d R , D a nc ey J , Ar b uck S , G w yt h er S , M o o n ey M , R u bi nst ei n L , 
S h a n k ar L , D o d d L , K a pl a n R , L ac o m b e D, V er w eij J . N e w r es po ns e ev al u ati o n crit eri a i n s oli d t u m o urs: r evis 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. d oi: 1 0. 1 0 1 6/j. ejc a. 2 0 0 8. 1 0. 0 2 6.)  
 
2 4 L e nci o ni R, Ll ov et J M. M o difi e d R E CI S T ( m R E CI S T) ass ess m e nt f or h e p at oc ell ul ar c arci n o m a. S e mi n Liv er Dis.  2 0 1 0 F e b; 3 0( 1): 5 2 -6 0. 
d oi: 1 0. 1 0 5 5/s -0 0 3 0 -1 2 4 7 1 3 2. E p u b 2 0 1 0 F e b 1 9.  
 
2 5 J e n nis o n, C. a n d T ur n b ull, B. W. ( 2 0 0 0), Gr o u p S e q u e nti al M et h o ds wit h A p plic ati o ns t o Cli nic al Tri als, N e w Y ork: C h a p m a n & Hall. 
2 6 M e ht a, C.  R. a n d P oc oc k, S. J. ( 2 0 1 1), A d a ptiv e i ncr e as e i n s a m pl e siz e w h e n i nt eri m r es ults ar e pr o misi n g: A pr actic al g ui d e wit h 
ex a m pl es. St atist. M e d., 3 0: 3 2 6 7 – 3 2 8 4. d oi: 1 0. 1 0 0 2/si m. 4 1 0 2  
 
2 7 B ur m a n a n d S o n ess o n ( 2 0 0 6), Ar e fl exi bl e d esi g ns s o u n d ? Bi o m etrics., 6 2: 6 6 4 -6 8 3  
 
2 8 Pr osc h a n M A, L a n K K G, Witt es J T ( 2 0 0 6), St atistic al M o nit ori n g of Cli nic al Tri als: A U nifi e d A p pr o ac h. 1st e d n. S pri n g er: U S A