A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Sponsor: Daiichi Sankyo

C LI NI C A L S T U D Y P R O T O C O L 
A P H A S E 3, R A N D O MI Z E D, D O U B L E- B LI N D S T U D Y O F 
TI V A N TI NI B ( A R Q 1 9 7) I N S U B J E C T S WI T H M E T 
DI A G N O S TI C- HI G H I N O P E R A B L E H E P A T O C E L L U L A R 
C A R CI N O M A ( H C C) T R E A T E D WI T H O N E P RI O R S Y S T E MI C 
T H E R A P Y 
A R Q 1 9 7- A- U 3 0 3  
E u dr a C T N U M B E R 2 0 1 2- 0 0 3 3 0 8- 1 0  
 
V E R SI O N 6. 0 , 1 5  M A R 2 0 1 6  
S u perse de d Versi o n: 
Versi o n 5. 0, 1 7 D E C 2 0 1 3 
Versi o n 4. 0, 1 3 S E P T 2 0 1 3 
Versi o n 3. 0, 2 9 A U G 2 0 1 3 
Versi o n 2. 0, 1 1 J U N 2 0 1 3 
Versi o n 1. 0, 2 1 S E P  2 0 1 2 
D AII C HI S A N K Y O P H A R M A D E V E L O P M E N T 
3 9 9 T H O R N A L L S T R E E T 
E DI S O N, N J 0 8 8 3 7 
 
A R Q U L E, I N C.  
O N E W A L L S T R E E T 
B U R LI N G T O N, M A 0 1 8 0 3 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
I nf or mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n k y o a n d Ar Q ule, I nc.  T he i nf or mati o n is 
pr o vi de d t o y o u i n c o nfi de nce w hic h is re q ueste d u n der a n a gree d u p o n a n d si g ne d C o nfi d e ntialit y a n d Discl os ure 
A gree me nt.  D o n ot gi ve t his d oc u me nt or a n y c o p y of it or re veal a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y 
t hir d part y ( ot her t ha n t h ose i n y o ur or ga nizati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d b y t he 
C o nfi de ntialit y a n d Discl os ure A gree me nt) wit h o ut t he pri or writte n per missi o n of a n a ut h orize d re prese ntati ve of 
Daiic hi Sa n k y o, I nc a n d Ar Q ule, I nc. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 of 1 1 3 
I N V E S TI G A T O R A G R E E M EN T  
A P hase 3, Ra n d o mi ze d, D o u ble- Bli n d St u d y of Ti va nti ni b ( A R Q 1 9 7) i n S u bject s wit h 
M E T Dia g n ostic- Hi g h I n o pe ra ble H e pat ocell ular Carci n o ma ( H C C) Treate d wit h O ne 
Pri or S yste mic T hera p y  
S p o ns or A p pr o v al:  
T his cli nical st u d y pr ot oc ol has bee n re vie we d a n d a p pr o ve d b y t he Daiic hi Sa n k y o , 
I n c a n d Ar Q ule, I n c re prese ntati ves liste d bel o w. 
 
 
   
  
 
 
Pri nt N a me  
 
Si g n at ure  
 
 
E x ec uti ve Direct or, - Cli nical 
De vel o p me nt  O nc ol o g y ,  
Daiic hi  Sa n k y o  P har ma De vel o p me nt    
 
 
Title  
 
D ate ( D D M M M Y Y Y Y)  
 
 
 
  
 
 
Pri nt N a me  
 
Si g n at ure  
 
 
V P Cli nical De vel o p me nt ,  
Ar Q ule , I n c  
  
 
 
Title  
 
D ate ( D D M M M Y Y Y Y)  
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 of 1 1 3 
I n vesti g at or’s Si g n at ure: 
I h a ve f ull y disc usse d t he o bjecti ves of t his st u d y a n d t he c o nte nts of t his pr ot oc ol wit h 
t he S p o ns or’s re prese ntati ve. 
I u n d ersta n d t hat i nf or m ati o n c o ntai ne d i n or pertai ni n g t o t his pr ot oc ol is c o nfi de ntial 
a n d s h o ul d n ot be discl ose d, ot her t ha n t o t h ose dir ectl y i n v ol ve d i n t he e x ec uti o n or 
t he et hical re vi e w of t he st u d y, wit h o ut writte n a ut h orizati o n fr o m Daiic hi Sa n k y o 
P har ma De vel o p me nt ( D S P D ) or Ar Q ule , I n c.  It is, h o we ver, per missi ble t o pr o vi de 
i nf or mati o n t o a s u bject i n or der t o o btai n c o nse nt. 
I a gree to c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its 
re q uire me nts, s u bject t o et hical a n d safet y c o nsi d erati o ns a n d g ui deli nes, a n d t o 
c o n d uct t he st u d y i n acc or da nce wit h t he Decl arati o n of Helsi n ki, I nter nati o nal 
C o nfere nce o n Har m o ni sati o n g ui deli nes o n G o o d Cli nical Practice (I C H E 6), a n d 
a p plica ble re gi o nal re g ul at or y re q uir e me nts.  
I a gree t o ma ke a vaila ble t o S p o ns or pers o n nel, t heir re prese ntati ves, a n d rele va nt 
re g ulat or y a ut h orities, m y s u bjects’ st u d y rec or ds i n or der t o verif y th e data t hat I h a ve 
e ntere d i nt o t he case re p ort f or ms.  I a m a ware of m y res p o nsi bilities as a Pri nci pal 
I n v esti gat or as pr o vi de d b y t he S p o ns or. 
I u n d ersta n d t hat t he S p o ns or ma y d eci de t o s us pe n d or pre mat urel y t er mi n ate t he 
st u d y at a n y ti me f or w hate ver reas o n; s uc h a d ecisi o n will be c o m m u nicate d t o me i n 
writi n g.  C o n vers el y, s h o ul d I deci de t o wit h dra w fr o m e xec uti o n of t he st u d y, I will 
c o m m u nicate m y i nte nti o n i m me diatel y i n writi n g t o t he S p o ns or.  
  
  
 
 
Pri nt N a me  
 
Si g n at ure  
 
  
  
 
 
Title  
 
D ate ( D D M M M Y Y Y Y)  
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 of 1 1 3 
P R O T O C O L S Y N O P SI S 
E u dra C T/I N D N u m b er:  
2 0 1 2 -0 0 3 3 0 8 -1 0  / 1 1 4 6 4 2 
Pr ot oc ol N u m ber:  
A R Q  1 9 7 -A -U 3 0 3  
I n v esti gati o nal Pr o d uct: 
Ti va nti ni b  ( A R Q 1 9 7) 
Acti ve I n gre die nt(s)/I N N:  
( 3R, 4 R )-3 -( 5, 6-D i h y dr o-4 H -p yrr ol o[ 3, 2, 1 -ij] q ui n oli n-1 -yl) -
4 -( 1H -i n d ol-3 -yl) p yrr oli di ne -2, 5 -di o ne  
I n v esti gati o nal de vice t o 
prescree n f or M E T Hi g h 
Stat us :  
La b C or p M E T  I m m u n o hist oc he mistr y (I H C) C o m pa ni o n 
Dia g n ostic Assa y  
St u d y Title:  
A P hase 3 , Ra n d o mize d, D o u ble-Bli n d  St u d y  of Ti va nti ni b 
( A R Q 1 9 7) i n S u bject s wit h M E T  Dia g n ostic -Hi g h  
I n o p era bl e He p at ocell ular Carci n o ma ( H C C) Treate d wit h 
O ne Pri or S yste mic T h era p y  
St u d y P has e:  
P hase 3  
I n dic ati o n U n der 
I n v esti gati o n: 
Ti va nti ni b is i n dicate d f or t he treat me nt of s u bj ects wit h 
in o pera ble , M E T Di a g n ostic -Hi g h  h e pat ocell ular 
carci n o ma w h o pr o gress o n or ca n n ot t olerate pri or t hera p y   
St u d y O bjecti ves:  
Pri mar y:  
 E val uate o verall s ur vi val ( O S) a m o n g all s u bjects i n 
t he i nte nt-t o-treat (I T T) p o p ulati o n c o m pare d t o 
place b o . 
Sec o n dar y:  
 E val uate pr o gressi o n free s ur vi val ( P F S) b y ce ntral , 
i n de pe n de nt ra di ol o g y re vie w a m o n g all s u bjects i n 
t he i nte nt-t o-treat (I T T) p o p ulati o n c o m pare d t o 
place b o.  
 E val uate safet y of  ti va nti ni b i n t he treate d H C C 
s u bjects. 
E x pl orat or y : 
 E val uate o bjecti ve res p o nse rate ( O R R) , disease 
c o ntr ol rate ( D C R), ti me t o pr o gressi o n ( T T P) , a n d 
t y pe of pr o gressi o n, b y ce ntral , i n de pe n d e nt 
ra di ol o g y re vie w a m o n g all s u bjects i n t he i nte nt-t o-
treat (I T T) p o p ulati o n c o m pare d t o place b o.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 of 1 1 3 
 E val uate p har mac o ki neti cs of ti va nti ni b a n d its 
meta b olites i n H C C s u bjects a n d e x pl ore t he 
fact ors, i ncl u di n g C Y P 2 C 1 9 ge n ot y pe, a n d maj or 
str o n g C Y P 3 A 4/ C Y P 2 C 1 9 i n hi bit ors w hic h ma y 
affect ti va nt i ni b p har mac o ki netics  (P K ) i n H C C 
s u bjects. 
 E x pl ore t he e x p os ure -res p o nse relati o ns hi p of 
ti va nti ni b t o bi o mar kers  a n d t o safet y a n d effi cac y 
e n d p oi nts .  
 E val uate F u n cti o nal Assess me nt of Ca ncer 
T hera p y -He pat o biliar y ( F A C T -He p) -b ase d F H SI -3 
Pai n Sc ore ( pai n, pai n i n bac k, pai n/ disc o mf ort i n 
st o mac h); F A C T-He pat o biliar y S y m pt o m I n d e x 
( F H SI-8) sc ore, E m oti o nal Well Bei n g ( E W B) 
sc ore, a n d t h e F A C T -H e p t otal sc ore. 
 E val uate ti me -t o-h os pitalizati o n (all -ca use) a n d 
ti me-t o-h os pitalizati o n ( H C C -relate d). 
St u d y Desi g n:  
Gl o bal , m ulti-ce nter, ra n d o mize d, place b o-c o ntr olle d, 
d o u ble -bli n d  P hase 3 st u d y desi g n e d t o c o m pare treat me nt 
of ti va nti ni b vers us place b o i n s u bjects wit h M E T  
Dia g n ostic -Hi g h  (M E T -Hi g h ) (≥ 5 0 % of t u m or cells wit h a 
stai ni n g i nte nsit y of ≥ 2 + f or M E T  as ass esse d b y  
i m m u n o hist oc he mistr y i n a ce ntr al la b) i n o pera bl e H C C  
(w here s ur ger y is n ot i n dicate d d ue t o diseas e e xte n si o n, 
c o-m or bi dities , or ot her t ec h nical r eas o ns) . S u bjects m ust 
ha ve  ha d ra di o gra p hi c disease pr o gressi o n aft er o ne 
s orafe ni b c o nt ai ni n g s yst e mic first li ne t hera p y or were 
u na ble t o t olerate s orafe ni b. 
S u bjects are ra n d o mize d t o recei ve eit her ti va nti ni b or 
place b o i n a 2: 1 rati o  a n d  are stratifi e d base d o n v asc ular 
i n vasi o n ( prese nt or n ot), e xtra-he patic s prea d  i ncl udi n g 
dista nt metastasis a n d/ or i n v ol ve d re gi o nal (= p eri -he patic, 
m ust be ≥2 0  m m  i n s h ortest dia meter) or dista nt l y m p h 
n o des (pres e nt or n ot ), a n d Al p ha fet o pr otei n (A F P ) 
(less/e q ual or greater t ha n 2 0 0  n g/ m L) .  
I n A u g ust 2 0 1 3, f oll o wi n g a hi g h er t ha n e x pecte d i nci de nce 
of ne utr o pe nia -rel ate d a d verse e v e nts, t he st u d y D M C 
e val uate d all a vaila ble data i ncl u di n g preli mi nar y 
p har mac o ki netics, a n d rec o m me n de d t he re d uce d starti n g 
d ose of 1 2 0 m g BI D.  T h eref ore t he 1 2 0  m g BI D re gi me n 
will be t he i nte n de d d ose re gi me n s h o ul d mar keti n g 
a p pr o val  be gra nte d . T h e s u bjects will nee d t o be gr o u pe d 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 of 1 1 3 
t o 2 c o h orts: t he 1 2 0 m g c o h ort (all s u bjects w h o are 
ra n d o mize d t o a starti n g d ose of  1 2 0 m g BI D  vers us 
Place b o ) a n d t he 2 4 0 m g c o h ort (all s u bjects w h o are 
ra n d o mize d t o a starti n g d ose of 2 4 0 m g BI D vers us 
Place b o ).  Dat a fr o m s u bjects i n t he 1 2 0 m g c o h ort will be 
use d f or t he pri mar y a nal ysis of efficac y re gar di n g p ote ntial 
mar keti n g a p pr o val  of t he 1 2 0 m g BI D d os e re gi me n . 
A n i nteri m a nal ysis is pla n ne d w he n a p pr o xi matel y 1 5 4 
( ~ 6 0 %) of t h e 2 5 7 O S e ve nts are d o c u me nte d. T h e st u d y 
ma y b e ter mi nate d f or s u peri orit y at t he i nteri m a n al ysis i n 
acc or d a nce wit h t he statistical a nal ysis pla n.  If t h e st u d y is 
p ositi ve at t he pres pec ifie d i nteri m or fi nal a n al ysis, t he 
s p o ns or will all o w patie nts w h o are recei vi n g place b o 
treat me nt t o recei ve acti ve ti va nti ni b treat me nt , aft er 
data base l oc k  if t he safet y para meters i n t he eli gi bilit y 
criteria are met (s ee secti o n 4. 1 ).  T he st u d y will be 
u n bli n de d after data base l oc k. Data p ost data b ase l oc k will 
be use d t o ca pt ur e a d diti o nal safet y i nf or m ati o n.  
St u d y D urati o n:  
S u bject s are t o c o nti n ue t hera p y wit h st u d y dr u g  u ntil deat h 
or ra di o gra p hi c pr o gressi ve disease ( P D ) if c o nfir me d b y 
re peat C T/ M RI sca n 4  wee ks aft er first s us pecte d 
ra di o gra p hic pr o gressi o n (see g ui deli nes i n Ta bl e 4. 1 ), or 
u ntil a n ot her  of t he s pecifie d criteri a is met f or st o p pi n g 
t hera p y. 
A vera ge esti mate d d urati o n of s u bject partici pati o n 
(scree ni n g/ e nr oll me nt t hr o u g h f ollo w -u p) : 1 -7 m o nt hs.  
A vera ge esti mate d d urati o n of s u bject treat me nt (fr o m first 
t o last d ose of st u d y dr u g): 1 -5  m o nt hs  (s o me s u bjects ma y 
sta y o n tr eat me nt e ve n less or m ore). 
T he e n d of t he tri al will be defi ne d as t he date t h e last visit 
i n t he st u d y is c o m plete d f or a n y ra n d o mize d s u bject.  
 
St u d y Sites a n d L o cati o n:  
A p pr o xi matel y  1 2 0  ce nters i n E ur o pe, t he A mericas, a n d 
Asia  Pacific  
Pla n ne d Sa m ple Siz e:  
A p pr o xi matel y 3 0 3 s u bj ects ra n d o mize d i n a 2: 1 rati o t o 
eit her ti va nti nib ( ~ 2 0 2 s u bjects) or place b o ( ~ 1 0 1 s u bjects)  
i n 1 2 0 m g c o h ort. T he i nitial 4 3 s u bjects w h o were  
ra n d o mize d t o t he starti n g d ose of  2 4 0 m g BI D vers us 
Place b o pri or t o t h e d ose re d ucti o n will be a nal yze d 
se parat el y as descri be d i n statistical a nal ysis secti o n 
( Secti o n 1 1. 2 ).     
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 of 1 1 3 
S u bject Eli gi bilit y Criteri a:  
I n cl usi o n Criteria: 
1.  Writte n i nf or me d c o nse nt gra nt e d pri or t o i nitiati o n 
of a n y st u d y -s pecific scree ni n g pr oce d ures 
2.  1 8 year s of a ge or ol d er  
3.  Hist ol o gicall y c o nfir m e d H C C  t hat is i n o pera ble 
( w here s ur ger y is n ot i n dicate d d ue t o diseas e 
e xte nsi o n, c o -m or bi dities, or ot her tec h ni cal 
reas o ns) a n d n ot eli gi ble f or l ocal t hera p y  
4.  M E T  Dia g n ostic -Hi g h  tiss ue re p orte d b y t h e ce ntral 
a ut h orize d la b orat or y usi n g  arc hi val or rece nt 
bi o ps y t u m or sa m ples  (see la b ma n ual a n d 
Secti o n  6. 1  of pr ot oc ol f or tiss ue pre parati o n  
details).   
5.  Recei ve d at least 4 wee ks of o ne pri or s orafe ni b 
c o ntai ni n g s yste mic t hera p y a n d t h e n e x perie nce d 
d oc u me nte d ra di o gra p hic disease pr o gressi o n ; or 
i na bilit y t o t olerate pri or t hera p y recei v e d f or at 
least a mi ni m u m peri o d of ti me. For t he p ur p os e of 
t his st u d y, i nt olera nce t o s orafe ni b is deter mi ne d as 
f oll o ws: 
 T he s u bject m ust ha ve tri e d t o ta ke s orafe ni b 
f or a peri o d of at least 2 8 da ys (e ve n 
i nter mitte ntl y)  
 T he s u bject m ust ha ve tri e d t o d ose re d u ce 
s orafe ni b at ≤5 0 % of t he f ull d ose f or a 
peri o d of at least 1 4 da ys (e ve n 
i nter mitte ntl y) a n d still ha ve a d o c u me nte d 
G ra de ≥2 t o xicit y  
 A  peri o d of e v e n less t ha n 1 4  da ys o n 
s orafe ni b is acce pt a ble i n case of: 
i. U nc o ntr olle d G ra de 3  - 4 arterial 
h y perte nsi o n  
ii. Pa ncreatitis, car diac e ve nt, 
e nce p h al o pat h y relat e d t o s orafe ni b  
iii. ≥ G ra de 2 Ha n d -f o ot s y n dr o me 
tri g gere d e v e n at 5 0 % of t he 
s orafe ni b d ose 
6.  Disc o nti n ue d pri or s yste mic treat me nt or a n y 
i n vesti gati o nal dr u g f or at least 2 wee ks ( 1 4 da ys) 
or f or at least 3 wee ks f or I V a nti-ca ncer dr u gs , 
pri or t o t he st u d y ra n d o mizati o n  
7.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
Perf or ma nce Stat us ( P S) ≤ 1 ( A p pe n di x 1 7. 2 ) 
8.  L ocal or l oc o -re gi o nal t h era p y (i. e., s ur ger y, 
ra diati o n t hera p y, h e patic arterial e m b olizati o n, 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 of 1 1 3 
c he m oe m b olizati o n, ra di ofre q ue n c y a blati o n, 
perc uta ne o us et ha n ol i njecti o n, or cr y oa bl ati o n) 
m ust ha ve bee n c o m plet e d ≥ 4  wee ks pri or t o 
ra n d o mizati o n a n d are all o we d .   
9.  Meas ura ble dis ease as defi ne d b y t h e Res p o nse 
E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 
versi o n 1. 1. T u m or lesi o ns pre vi o usl y tr eate d wit h 
l ocal t hera p y s h o ul d de m o nstrate clear di me nsi o nal 
i ncreas e b y ra di o gra p hic assess me nt i n or der t o be 
selecte d as t ar get lesi o n(s) at baseli ne.  Bas eli ne 
ra di o gra p hic assess me nt nee ds t o be d o ne wit hi n 
2 1  da ys  pri or t o ra n d o mi zati o n.  
1 0.  A de q uate b o ne marr o w, li ver, a n d re nal f u ncti o ns at 
Scree ni n g  Visit, defi ne d as: p latelet c o u nt 
≥ 6 0  ×  1 0 9/ L; h e m o gl o bi n ≥ 9 . 0 g/ d L; abs ol ute 
ne utr o p hil c o u nt ( A N C) ≥ 1. 5 × 1 0 9/ L; total 
bilir u bi n ≤ 2 m g/ d L; Ala ni ne tra nsa mi nase ( A L T) 
a n d as part ate  a mi n otra nsferas e  ( A S T) ≤ 5 × u p per 
li mit of n or mal ( U L N); ser u m creati ni ne ≤ 1. 5 × 
U L N ; al b u mi n ≥ 2. 8 g/ d L ; inter n ati o nal n or malize d  
rati o (I N R) 0. 8 t o U L N or ≤ 3 f or s u bjects recei vi n g 
a ntic oa g ula nt s uc h as c o u ma di n or he pari n. S u bject s 
w h o are t hera p e uticall y a ntic oa g ul ate d are all o we d 
t o partici pate pr o vi de d t h at pri or t o a ntic oa g ula nt 
t hera p y n o e vi de nce of u n derl yi n g d efect i n 
c oa g ulati o n e xists  
1 1.  W o me n
 of c hil d beari n g p ote ntial m ust ha ve a 
ne gati ve ser u m pre g na n c y test perf or me d wit hi n 
1 4  da ys pri or t o t he ra n d o mizati o n ( where 
de ma n de d b y l ocal re g ul ati o ns, test ma y be re q uir e d 
wit hi n 7 2  h o u rs pri or t o ra n d o mizati o n) 
1 2.  Male a n d fe male s u bjects of c hil d -beari n g p ot e ntial 
m ust a gree t o use d o u ble -barrier c o ntr ace pti ve 
meas ures, oral c o ntrace pti o n, or a v oi da nce of 
i nterc o urse d uri n g t h e st u d y a n d f or 9 0 da ys after 
last st u d y dr u g d ose recei ve d  
1 3.  Lif e e x pecta nc y of at least 1 2  wee ks  
 
 
E x cl usi o n Criteria:  
1.  > 1 pri or s yste mic re gi me n ( pri or M E T  
i n hi bit ors/a nti b o dies are n ot all o we d; e x peri me ntal 
s yste mic t hera p y f or i n o p era ble H C C gi ve n bef ore 
or after s orafe ni b c o u nts as se parate re gi me n a n d is 
n ot all o we d ) 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 of 1 1 3 
2.  C hil d -P u g h B -C cirr h otic stat us base d  o n cli nical 
fi n di n gs a n d la b orat or y res ults d uri n g scree ni n g 
peri o d (see A p pe n di x 1 7 . 4 f or C hil d-P u g h 
Classificati o n a n d i nter pretati o n of ascites at 
p h ysical e x a mi nati o n a n d Pr ot hr o m bi n Ti me ( P T )/ 
I nter nati o nal N or m alize d Rati o (I N R)) 
3.  Pre vi o us or c o nc urre nt ca ncer t h at is disti nct fr o m 
H C C i n pri mar y site or hist ol o g y, E X C E P T cer vical 
carci n o ma i n sit u, treate d basal cell carci n o ma, a n d 
s u perficial bla d der t u m ors ( Ta, Tis & T 1). A n y 
ca ncer c urati vel y treate d >  3  years pri or t o 
e nr oll me nt is per mitte d . 
4.  Hist or y of c o n gesti ve heart fail ure d efi ne d as 
Class  II t o I V per Ne w Y or k Heart Ass ociati o n 
( N Y H A) classificati o n  (see A p pe n di x 1 7. 5 ) wit hi n 
6 m o nt hs pri or t o st u d y e ntr y; acti ve c or o n ar y arter y 
disease ( C A D); cli nicall y si g nifica nt br a d ycar dia or 
ot her u nc o ntr olle d, car di ac arr h yt h mia defi ne d as 
≥ Gra de  3 acc or di n g t o N ati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E), versi o n 4. 0 3 , or u nc o ntr olle d 
h y perte nsi o n; m y o car dial i nfarcti o n occ urri n g 
wit hi n 6 m o nt hs pri or t o st u d y e ntr y ( m y o car di al 
i nfarcti o n occ urri n g > 6 m o nt hs pri or t o st u d y e ntr y 
is per mitte d) 
5.  Acti ve cli nicall y seri o us i nfecti o ns defi ne d  as 
≥ Gra de 3 acc or di n g t o N CI C T C A E, versi o n 4. 0 3  
6.  A n y me di cal, ps yc h ol o gi cal , or s ocial c o n diti o ns , 
partic ularl y if u nsta ble, i ncl u di n g s u bsta nce a b use,  
t hat ma y, i n t he o pi ni o n of t he I n vesti gat or, i nterfere 
wit h t he s u bject’s safet y or partici pati o n i n t he 
st u d y, pr ot oc ol c o m plia n ce, or e v al uati o n of t he 
st u d y res ults 
7.  K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) 
i nfecti o n 
8.  Bl o o d or al b u mi n  tra nsf usi o n wit hi n 5 da ys pri or t o 
t he bl o o d dra w bei n g use d t o c o nfir m eli gi bilit y 
9.  C o nc o mita nt i nterfer o n t hera p y  or t h era pies  f or 
acti ve He p atitis C Vir us ( H C V ) infecti o n  
1 0.  Pre g n a nc y or breast -fee di n g 
1 1.  Hist or y of li ver tra ns pla nt  
1 2.  I n a bilit y t o s wall o w oral me dicati o ns 
1 3.  Cli nicall y si g nifica nt gastr oi ntesti nal blee di n g 
occ urri n g ≤ 4 wee ks pri or t o ra n d o mizati o n  
1 4.  Ple ural eff usi o n or cli nicall y e vi d e nt ( visi ble or 
pal pa ble) as cites  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 of 1 1 3 
 
Patie nts o n t he place b o ar m bei n g c o nsi dere d f or cr oss o ver 
t o ti va nti ni b after data bas e l oc k m ust meet t he safet y 
eli gi bilit y criteria at t he ti me of cr oss o ver:  I ncl usi o n # 6, 8, 
1 0, 1 1, 1 2, a n d E x cl usi o n # 2, 4, 5, 6, 7, 8, 9, 1 0, 1 1, 1 2, 1 3, 
a n d 1 4.  
D osa ge F or m, D ose a n d 
R o ute of A d mi nistrati o n:  
T he i n vesti gati o nal dr u g ti va nti ni b a n d its matc hi n g 
place b o are s u p plie d as t a blets. A d ose of 1 2 0  m g ( 1  ta blet 
of 1 2 0 m g) of ti va nti ni b will be a d mi nistere d b y m o ut h  
t wice dail y (BI D ), o n ce i n t he m or ni n g a n d o n ce i n t he 
e ve ni n g wit h meals, f or a t otal dail y d ose of 2 4 0  m g.  
After dat a base l oc k a n d u n bli n di n g, all eli gi ble p atie nts 
w h o ha ve bee n ra n d o mize d t o place b o will be all o we d t o 
recei v e ti vanti ni b.  
St u d y E n d p oi nts:  
Pri m ar y:  
 O verall s ur vi val ( O S)  i n I T T p o p ul ati o n 
Sec o n d ar y:  
 Pr o gressi o n free s ur vi val ( P F S) b y ce ntr al , 
i n de pe n de nt ra di ol o g y re vie w 
 S afet y 
E x pl or at or y : 
 O bjecti ve res p o ns e rat e ( O R R) , disease c o ntr ol rate 
( D C R), ti me t o pr o gressi o n ( T T P), a n d t y pe of 
pr o gressi o n,  b y ce ntral , i n de pe n de nt ra di ol o g y 
re vie w 
 P o p ulati o n p har mac o ki netic  ( P K) para meters  
 F u ncti o nal Assess me nt of Ca ncer T hera p y -
He pat o biliar y ( F A C T -He p) -base d F H SI -3 Pai n 
Sc ore ( pai n, p ai n i n bac k, pai n/ disc o mf ort i n 
st o mac h); F A C T-He pat o biliar y S y m pt o m I n d e x 
( F H SI-8) sc ore, E m oti o nal Well Bei n g ( E W B) 
sc ore, a n d t h e F A C T-He p t otal sc ore  
 Ti me -t o-h os pitalizati o n (all -ca use) a n d ti me -t o-
h os pitalizati o n ( H C C -relate d) 
Statistical A nal yses:  
T he f or mal a n al ysis of efficac y e n d p oi nts will be 
perf or me d o nl y f or t he 1 2 0 m g c o h ort.  
T he fi nal a n al ysis of O S will re q uire 2 5 7 e v e nts t o  e ns ure a 
9 0 % p o wer t o det ect t he differe n ce i n O S b y stratifie d l o g-
ra n k test at a 1-si d e d t y p e 1 err or rat e of α = 0. 0 2 5, w ith  a n 
u n derl yi n g tr u e hazar d rati o of 0. 6 5 ( or 5 4 % i m pr o ve me nt 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 1 of 1 1 3 
i n me dia n s ur vi val fr o m 5 m o nt hs f or t he place b o ar m t o 
7. 7 m o nt hs f or t he ti va nti ni b ar m).   A p pr o xi matel y 3 0 3 
t otal s u bjects are re q uire d t o be e nr olle d i n t he 1 2 0 m g 
c o h ort o ver  a p pr o xi matel y 2 8  m o nt hs of accr ual  peri o d  
wit h  3 8 m o nt hs ma xi m u m f oll o w -u p st u d y peri o d a n d 1 0 % 
dr o p -off rate.   A n i nteri m a nal ysis is pla n ne d w he n a b o ut 
6 0 % of t he t otal n u m ber of e ve nts (i.e., a p pr o xi matel y 
1 5 4  t otal e ve nts) i n t he 1 2 0 m g c o h ort will be  
d oc u me nte d.   T he  O' Bri e n -Fle mi n g  al p ha s p e n di n g 
f u ncti o n will be use d t o defi ne t he st o p pi n g b o u n d ar y f or 
t he p ossi ble earl y st o p pi n g f or s u peri or effi cac y.   If t he 
i nteri m a nal ysis is base d o n e x actl y 1 5 4 e v e nts, t he effi cac y 
b o u n dar y w o ul d be cr oss e d if  t he stratifie d lo g -ra n k test t o 
s h o w a 1-si de d n o mi nal p-val ue of 0. 0 0 3 8 or less.  If t he 
st u d y meets s uc h criteria at t he i nteri m a nal ysis, t he Data 
M o nit ori n g C o m mittee ( D M C) a n d select e d re prese ntati ve s 
fr o m t he S p o ns or ma y re q uest  a c o ns ult ati o n wit h H ealt h 
A ut h orities pri or t o a fi nal D M C rec o m me n dati o n; t he 
st u d y tea m will re m ai n bli n de d d uri n g t his pr ocess . If t he 
D M C d oes n ot rec o m me n d earl y ter mi nati o n at t h e ti me of 
t he i nteri m a nal ysis, t he trial will c o nti n ue u ntil t he fi nal 
2 5 7  e ve nts are d oc u me nt e d.   T he fi nal a nal ysis of O S will 
re q uire a 1-si de d n o mi nal p-val ue of 0. 0 2 3 8 or less f or t he 
st u d y t o be p ositi ve.  It is rec o g nize d t hat t he e x act n u m ber 
of e ve nts at t he i nteri m a nal ysis ma y n ot be 1 5 4 .  T he 
b o u n daries will be u p dat e d wit h t he act ual n u m be r of 
e ve nts at t he i nteri m a nal ysis.  After data base l oc k, 
a d diti o nal data will be re vie we d via dat a listi n gs.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 2 of 1 1 3 
T A B L E O F C O N T E N T S 
I N V E S TI G A T O R A G R E E M EN T  ................................................................................... 2 
P R O T O C O L S Y N O P SI S .................................................................................................. 4  
T A B L E O F C O N T E N T S ................................................................................................ 1 2  
L I S T O F I N- T E X T T A B L E S ......................................................................................... 1 8 
L I S T O F I N- T E X T FI G U R E S ....................................................................................... 1 9 
L I S T O F A B B R E VI A TI O N S ......................................................................................... 2 0 
1.  
I N T R O D U CTI O N A N D B A C K G R O U N D I N F O R M A TI O N .................. 2 4 
1. 1.  
I n v esti gati o nal Pr o d ucts .................................................................................. 2 4 
1. 1. 1.  
Ti va nti ni b ........................................................................................................ 2 4  
1. 1. 2  
La b C or p M E T I m m u n o hist oc he mistr y (I H C) C o m pa ni o n Dia g n ostic 
Assa y ............................................................................................................... 2 5  
1. 1. 3.  
N o ncli nical St u dies  ......................................................................................... 2 5 
1. 1. 4.  
Cli nical E x perie nce ......................................................................................... 2 6  
1. 2.  
St u d y R ati o nale ............................................................................................... 2 6  
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects ............................................................ 2 7  
1. 4.  
P o p ulati o n, R o ute, D osa ge, D osa ge Re g i me n, Treat me nt Peri o d .................. 2 9 
1. 5.  
C o m plia nce State me nt, Et hics a n d Re g ul at or y C o m plia nc e .......................... 3 0  
1. 5. 1.  
S u bject C o nfi de ntialit y ................................................................................... 3 0  
1. 5. 2.  
I nf or me d C o nse nt Pr oce d ure .......................................................................... 3 0 
1. 5. 3.  
Re g ulat or y C o m plia nce .................................................................................. 3 1  
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  ........................................... 3 3 
2. 1.  
St u d y O bjecti ves ............................................................................................. 3 3  
2. 1. 1.  
Pri mar y O bj ecti ves ......................................................................................... 3 3  
2. 1. 2.  
Sec o n dar y O bj ecti ves ................................ ..................................................... 3 3 
2. 1. 3.  
E x pl orat or y O bjecti ves ................................ ................................................... 3 3 
2. 2.  
St u d y H y p ot hesis ............................................................................................ 3 3  
3.  
S T U D Y D E SI G N .......................................................................................... 3 4  
3. 1.  
O verall Pla n .................................................................................................... 3 4  
3. 1. 1.  
St u d y T y pe ...................................................................................................... 3 4  
3. 1. 2.  
Treat me nt Gr o u ps ........................................................................................... 3 4  
3. 1. 3.  
St u d y E n d p oi nts  .............................................................................................. 3 5 
3. 1. 4.  
D urati o n of  t he St u d y ...................................................................................... 3 5 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 3 of 1 1 3 
3. 1. 5.  
D urati o n of S u bject Parti ci pati o n ................................................................... 3 5  
3. 1. 6.  
St o p pi n g R ules ................................................................................................ 3 6  
3. 2.  
Selecti o n of D oses .......................................................................................... 3 6  
3. 2. 1.  
E x peri me n tal Treat me nts ................................................................................ 3 6  
4.  
S T U D Y P O P U L A TI O N ............................................................................... 3 9  
4. 1.  
E nr oll me nt ...................................................................................................... 3 9  
4. 1. 1.  
I n cl usi o n Criteria ............................................................................................ 3 9 
4. 1. 2.  
E x cl usi o n Criteria ........................................................................................... 4 0  
4. 2.  
R e m o val of S u bjects Fr o m T hera p y ............................................................... 4 1  
4. 2. 1.  
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n ............................................. 4 1  
4. 2. 2.  
Wit h dra wal/ Disc o nti n uati o n Pr oce d ures ........................................................ 4 3  
4. 2. 3.  
S u bject Re- scree ni n g Pr oce d ures ................................................................... 4 3 
5.  
T R E A T M E N T S A D MI NI S T E R E D ............................................................ 4 5  
5. 1.  
I n v esti gati o nal Pr o d ucts .................................................................................. 4 5 
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g ........................... 4 5  
5. 1. 2.  
Met h o d of Assessi n g Treat me nt C o m plia nce ................................................. 4 5  
5. 1. 3.  
La b eli n g a n d Pac k a gi n g .................................................................................. 4 6  
5. 1. 4.  
Pre parati o n ...................................................................................................... 4 6 
5. 1. 5.  
St ora ge ............................................................................................................ 4 6  
5. 1. 6.  
Dr u g Acc o u nta bilit y ....................................................................................... 4 7  
5. 2.  
C o nc o mita nt Me dicati o ns  ............................................................................... 4 7 
6.  
S T U D Y P R O C E D U R E S  .............................................................................. 4 9 
6. 1.  
Pre- Scree ni n g T u m or Sa m ple C ollecti o n ....................................................... 4 9  
6. 2.  
Scree ni n g Visit ( Da ys - 1 4 t o 0) ...................................................................... 5 0  
6. 3.  
R a n d o mizati o n ................................................................................................ 5 1  
6. 4.  
C ycle 1 Da y 1 Visit ......................................................................................... 5 1  
6. 5.  
Treat me nt Peri o d ............................................................................................ 5 2  
6. 5. 1.  
C ycle 1, Da ys 5, 9, 1 3, 1 7, a n d 2 5 ( ± 1 da y) ................................................... 5 2  
6. 5. 2.  
C ycle 1, Da y 2 1 ( ± 1 da y) ................................................................................ 5 2  
6. 5. 3.  
C ycles 2 +, Da y 1 ( ± 2 da ys) ............................................................................ 5 2 
6. 5. 4.  
C ycle 2, Da ys 8, 1 5 a n d 2 2 ( ± 2 da ys) ................................ ............................. 5 3 
6. 5. 5.  
C ycle 3 +, Da y 1 5 ( ± 2 da ys)  ............................................................................ 5 3 
6. 5. 6.  
T u m or Assess me nt Sca ns ............................................................................... 5 3  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 4 of 1 1 3 
6. 5. 7.  
Cr oss o ver Visits ( p ositi ve st u d y a n d p ost data base l oc k) ............................... 5 3  
6. 6.  
E n d of Treat me nt ............................................................................................ 5 4  
6. 7.  
3 0- Da y Safet y F oll o w- u p ............................................................................... 5 4  
6. 8.  
S ur vi val F oll o w u p (e ver y 3 m o nt hs ± 1 4 da ys) .............................................. 5 5  
6. 9.  
Pr ot oc ol De viati o ns ........................................................................................ 5 5  
7.  
E F FI C A C Y A S S E S S M E N T S ...................................................................... 5 6  
7. 1.  
Pri mar y V aria ble(s) ........................................................................................ 5 6  
7. 2.  
Sec o n dar y V aria ble(s) .................................................................................... 5 6  
7. 3.  
E x pl orat or y Varia ble(s) .................................................................................. 5 6  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C 
A S S E S S M E N T S ............................................................................................ 5 7  
8. 1.  
P har mac o ki netic ( P K) Varia ble(s) .................................................................. 5 7  
8. 2.  
P har mac o d y na mic ( P D) Varia ble(s) ............................................................... 5 7  
8. 3.  
Bi o mar ker a n d E x pl orat or y Varia bl e(s) ......................................................... 5 8  
8. 4.  
P har ma c o ge n o mics a n d O pti o nal P har mac o ge n o mic Sa m pl e Ba n ki n g ......... 5 9  
8. 4. 1.  
P har mac o ge n o mic T esti n g .............................................................................. 5 9  
8. 4. 2.  
P har mac o ge n o mic Sa m ple C ollecti o n ............................................................ 5 9  
8. 4. 3.  
O pti o nal P har mac o ge n o mic Sa m ple Ba n ki n g ................................................ 5 9  
9.  
S A F E T Y A S S E S S M E N T S ........................................................................... 6 1  
9. 1.  
A d verse E v e nts ............................................................................................... 6 1  
9. 1. 1.  
Defi niti o ns ...................................................................................................... 6 2  
9. 2.  
Seri o us A d verse E v e nt Re p orti n g – Pr oce d ure f or I n vesti gat ors ..................... 6 4  
9. 2. 1.  
I nitial Re p orts ................................................................................................. 6 4 
9. 2. 2.  
F oll o w- u p Re p orts .......................................................................................... 6 5  
9. 2. 3.  
N otif yi n g I n v esti gat ors or Et hics C o m mittee/I nstit ut i o nal Re vie w 
B oar d ............................................................................................................... 6 5  
9. 2. 4  
E ve nts of S pecial I nterest  ............................................................................... 6 5 
9. 3.  
E x p os ure I n Uter o D uri n g Cli nical St u dies .................................................... 6 6  
9. 4.  
Cli nical La b ora t or y E val uati o ns ..................................................................... 6 6 
9. 5.  
Vital Si g ns  ...................................................................................................... 6 7 
9. 6.  
Electr ocar di o gra ms ......................................................................................... 6 7  
9. 7.  
P h ysical Fi n di n gs ............................................................................................ 6 7  
9. 8.  
Ot her Safet y Ass e ss me nts ............................................................................... 6 7 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 5 of 1 1 3 
1 0.  
O T H E R A S S E S S M E N T S ............................................................................ 6 8  
1 0. 1.  
Patie nt- Re p orte d O utc o mes ( P R Os) ............................................................... 6 8  
1 0. 1. 1.  
F u ncti o nal Assess me nt of Ca ncer T hera p y – He p at o biliar y ( F A C T-
He p) ................................................................................................................ 6 8  
1 0. 1. 2.  
E U R O Q O L 5- D ( E Q- 5 D) ............................................................................... 6 8  
1 0. 1. 3.  
H os pitalizati o n (all-ca use a n d H C C-rel ate d) .................................................. 6 9  
1 0. 1. 4.  
A nal gesic, Di ureti c, a n d A nti bi otic Use ......................................................... 6 9  
1 1.  
S T A TI S TI C A L M E T H O D S ........................................................................ 7 0  
1 1. 1.  
A nal ysis Sets ................................................................ ................................... 7 0 
1 1. 1. 1.  
I nte nt-t o- Treat (I T T) A n al ysis Set .................................................................. 7 0 
1 1. 1. 2.  
Per- Pr ot oc ol A nal y sis Set ............................................................................... 7 0 
1 1. 1. 3.  
Sa fet y A nal ysis Set ......................................................................................... 7 0 
1 1. 1. 4.  
Patie nt- Re p orte d O utc o me ( P R O) A nal ysis Set ............................................. 7 0  
1 1. 1. 5.  
Bi o mar ker A nal ysis Set .................................................................................. 7 0  
1 1. 1. 6.  
P har mac o ge n o mic A n al ysis Set ..................................................................... 7 0  
1 1. 2.  
Ge nera l Statistical C o nsi derati o ns .................................................................. 7 0 
1 1. 3.  
St u d y P o p ulati o n Dat a .................................................................................... 7 1  
1 1. 4.  
Efficac y A nal yses ........................................................................................... 7 2  
1 1. 4. 1.  
Pri mar y Efficac y A nal ys es ............................................................................. 7 2 
1 1. 4. 2.  
Sec o n dar y Efficac y A nal ys es ......................................................................... 7 2  
1 1. 5.  
E x pl orat or y A nal yses ...................................................................................... 7 3  
1 1. 5. 1.  
E x pl orat or y Effi c ac y A nal yses ....................................................................... 7 3  
1 1. 5. 2.  
Ot her Assess me nts .......................................................................................... 7 6  
1 1. 6.  
P har mac o ki netic/ P har mac o d y n a mi c A nal yses ............................................... 7 8  
1 1. 6. 1.  
P har mac o ki netic A n al ys es  .............................................................................. 7 8 
1 1. 6. 2.  
P har ma c o d y na mic/ Bi o mar ker A nal yses ......................................................... 7 8  
1 1. 6. 3.  
P ha r mac o ge n o mic A n al yses ........................................................................... 7 8 
1 1. 7.  
Safet y A nal yses .............................................................................................. 7 8  
1 1. 7. 1.  
A d verse E v e nt A nal yse s ................................................................................. 7 9 
1 1. 7. 2.  
Cli nical La b orat or y E val ua ti o n A nal ys es ....................................................... 7 9 
1 1. 7. 3.  
Vital Si g n A nal y ses ........................................................................................ 7 9 
1 1. 7. 4.  
Electr ocar di o gra m A n al yses ........................................................................... 7 9  
1 1. 7. 5.  
P h ysical Fi n di n g A n al ys es  .............................................................................. 8 0 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 6 of 1 1 3 
1 1. 7. 6.  
Ot her Safet y A n al yses .................................................................................... 8 0  
1 1. 8.  
I nteri m A nal yses ............................................................................................. 8 0 
1 1. 9.  
Data M o nit ori n g C o m mittee ........................................................................... 8 1  
1 1. 1 0.  
S a m ple Siz e Deter mi nati o n ............................................................................ 8 1  
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E .............................. 8 3  
1 2. 1.  
M o nit ori n g a n d I ns p ecti o ns ............................................................................ 8 3  
1 2. 2.  
C o m p uter S yste ms .......................................................................................... 8 3 
1 2. 3.  
Data C ollecti o n ............................................................................................... 8 3  
1 2. 4.  
Data Ma na ge me nt ........................................................................................... 8 4 
1 2. 4. 1.  
Data Vali dati o n ............................................................................................... 8 4  
1 2. 5.  
St u d y D oc u me ntati o n a n d S t ora ge ................................................................. 8 4 
1 2. 6.  
Rec or d Kee pi n g .............................................................................................. 8 5  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  ............................................................... 8 6 
1 3. 1.  
Fi na nces .......................................................................................................... 8 6  
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura n ce .................................................... 8 6 
1 4.  
P U B LI C A TI O N P O LI C Y ............................................................................ 8 7  
1 5.  
S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N ....................................... 8 8  
1 5. 1.  
Pr ot oc ol A me n d me nts .................................................................................... 8 8  
1 5. 2.  
A d dress L ist .................................................................................................... 8 8 
1 5. 2. 1.  
S p o ns ors .......................................................................................................... 8 8  
1 5. 2. 2.  
Gl o bal Me dical M o nit or  .................................................................................8 8  
1 5. 2. 3.  
Dr u g Safet y ..................................................................................................... 8 8  
1 5. 2. 4.  
Safet y R e p orti n g: ............................................................................................ 8 8  
1 5. 2. 5.  
Pri nci pal I n v esti gat ors  ....................................................................................8 9  
1 6.  
R E F E R E N C E S ............................................................................................. 9 0  
1 7.  
A P P E N DI C E S ............................................................................................... 9 2  
1 7. 1.  
Sc he d ule of E ve nts ......................................................................................... 9 3  
1 7. 2.  
E C O G Perf or ma n ce Stat us ............................................................................. 9 7  
1 7. 3.  
E x a m ples of i n vi v o S u bstra tes, I n hi bit ors, a n d I n d ucers f or s pecifi c 
C Y P e nz y m es f or st u d y ................................ .................................................. 9 8 
1 7. 4.  
Li ver Stat us –  C hil d- P u g h Classificati o n ....................................................... 9 9  
1 7. 5.  
T he Criteria C o m mittee of t he Ne w Y or k Heart Ass ociati o n. ..................... 1 0 0  
1 7. 6.  
P har mac o ki netics .......................................................................................... 1 0 1  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 7 of 1 1 3 
1 7. 7.  
Patie nt re p orte d o utc o mes q uesti o n naires i nf or mati o n s he et – F A C T-
He p a n d E Q- 5 D ............................................................................................ 1 0 2  
1 7. 8.  
H os pit aliz ati o n S u b- F or m  .......................................................................... 1 1 2 
1 7. 8. 1. O ut pati e nt S u b- F or m ........................................................................................... 1 1 3  
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 8 of 1 1 3 
LI S T O F I N- T E X T T A B L E S 
Ta ble 1. 1 M ost C o m m o n ( > 5 % of all S u bjec ts) Ad verse E ve nts a n d Se vere 
( Gra d e 3 or hi g her) A d verse E ve nts See n i n t he Ra n d o mize d-
C o ntr olle d P hase 2 H C C St u d y, A R Q 1 9 7- 2 1 5 ......................................... 2 8  
Ta ble 3. 1 D ose Dela ys/ Re d ucti o ns f or Dr u g- Relat e d N o n- H e mat ol o gical 
T o xicit y ...................................................................................................... 3 7  
Ta ble 3. 2 D ose Dela ys/ Re d ucti o ns f or Dr u g- Relat e d He mat ol o gical T o xici t y ................ 3 8 
Ta ble 4. 1 P ossi ble Sce nari os a n d Acti o ns at Ra di o gra p hic Pr o gr essi o n ........................... 4 2  
Ta ble 1 1. 1 Statistical G ui deli nes f or St o p pi n g B o u n daries ............................................... 8 1  
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 9 of 1 1 3 
LI S T O F I N- T E X T FI G U R E S 
Fi g u re 1. 1 Ti va nti ni b Str uct ural Dia gra m .......................................................................... 2 4 
Fi g ure 3. 1 Sc h e matic of Treat me nt Gr o u ps ....................................................................... 3 4  
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 0 of 1 1 3 
LI S T O F A B B R E VI A TI O N S 
A B B R E VI A TI O N  
D E FI NI TI O N  
A E  
A d verse E v e nt  
A F P  
Al p ha fet o pr otei n  
A L T  
Ala ni ne tra nsa mi nase  
A N C  
A bs ol ute ne utr o p hils c o u nt  
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n d er t he ti me -c o nce ntrati o n c ur v e  
BI D  
T wice dail y  
b p m  
Beats p er mi n ute  
B U N  
Bl o o d urea nitr o ge n  
C A D  
C or o nar y Arter y Diseas e  
C A P  
C olle ge of A merica n Pat h ol o gists  
C B C  
C o m plete bl o o d c o u nt  
C D x  
C o m pa ni o n Dia g n ostic  
C D F  
C u m ulati ve distri b uti o n f u ncti o n  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
C D R H  
Ce nter f or De vices a n d Ra di ol o gic Healt h  
C F R  
C o de of  Fe d eral Re g ul ati o ns  
CI  
C o nfi de nce I nter val  
C LI A  
Cli nical La b orat or y I m pr o ve me nt A me n d me nts  
C ma x  
Ma xi m u m plas ma dr u g c o nce ntrati o n  
c-Met  
c-Met rece pt or t yr osi n e ki nase  
C R  
C o m plete Res p o nse  
C R F  
Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga nizati o n  
C S P V  
Cli nical Safet y a n d P har mac o vi gila n ce  
C S R  
Cli nical St u d y Re p ort  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
D A G  
Data A nal ysis Gr o u p  
D C R  
Disease C o ntr ol Rate  
D M C  
Data M o nit ori n g C o m mittee  
D N A  
De o x yri b o n ucleic aci d  
D S P D  
Daiic hi Sa n k y o P har ma De vel o p me nt  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 1 of 1 1 3 
A B B R E VI A TI O N  
D E FI NI TI O N  
EI U  
E x p os ure i n uter o  
E LI S A  
E nz y m e -li n ke d i m m u n os or be nt assa y 
E Q -5 D  
E ur o Q ol 5 -D  
E S A  
Er yt hr o p oiesis Sti m ulati n g A ge nt  
E U  
E ur o pea n U ni o n  
E W B  
E m oti o nal well bei n g  
F A C T -H e p  
F u ncti o nal Assess me nt of Ca ncer T hera p y -He pat o biliar y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F F P E  
F or mali n Fi x e d, Paraffi n E m be d de d  
F H SI  
F A C T -H e p S y m pt o m I n de x  
F N A  
Fi ne nee dle as pir ate  
F W B  
F u ncti o nal well -b ei n g  
F W E R  
Fa mil y -wise t y pe I err or rate  
G C P  
G o o d Cli nical Practice (refers t o I C H a n d C F R)  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
GI 5 0 
Dr u g c o nce ntrati o n t hat i n hi bits t he gr o wt h of ca n cer cells b y 
5 0 %  
H B V  
He patitis B Vir us  
H Be A g  
He patitis B “e” a nti ge n  
H Bs A g  
s urface a nti ge n of t h e he patitis B vir us 
H C C  
He pat oc ell ular carci n o m a  
H C S  
He pat o biliar y A d diti o nal C o ncer ns S u bscale  
H C V  
He patitis C Vir us  
H C V A b  
He patitis C a nti b o d y  
H G B  
He m o gl o bi n  
H G F  
He pat oc yte Gr o wt h Fact or  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
H R  
Hazar d Rati o  
I C5 0 
I n hi bit or c o n ce ntr ati o n re q uire d f or 5 0 % i n hi biti o n 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee  
I H C 
I m m u n o hist oc he mistr y 
I N D 
I n v esti gati o nal Ne w Dr u g 
I N N 
I nter nati o nal N o n pr o prietar y Na me 
I N R 
I nter nati o nal N or m alize d Rati o 
I P 
I n v esti gati o nal Pr o d uct 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 2 of 1 1 3 
A B B R E VI A TI O N  
D E FI NI TI O N  
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-t o-treat 
I X R S 
I nteracti ve V oice/ We b R es p o nse S yste m  
L D H  
Lactate d e h y dr o ge n ase  
L L N  
L o w er Li mit of N or mal  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M E T  
N -Met h yl -N' -nitr o -N -nitr os o -g u a ni di ne h u ma n ste o ge ni c 
sarc o ma cell li ne tra nsf or mi n g pr otei n ( ge ne) 
M E T -hi g h  
≥ 5 0 % of t u m or cells wit h a stai ni n g i nte nsit y of ≥ 2 +  f or M E T 
as assesse d b y i m m u n o hist oc he mistr y i n a ce ntr al la b  
N B F  
Ne utral b uffere d f or mali n  
N CI  
Nati o nal Ca ncer I nstit ute  
N O A E L  
N o o bser va ble a d verse effect le vel  
N O E L  
N o o bser va ble effect le v el  
N S C L C  
N o n -s mall cell l u n g ca n cer  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
N Y S D O H  
Ne w Y or k State De part me nt of Healt h  
O R R  
O bjecti ve Res p o nse Rate  
O S  
O verall S ur vi val  
O T C  
O ver -t he-c o u nter  
P D  
Pr o gressi ve Diseas e  
P F S  
Pr o gressi o n Free S ur vi val  
P K  
P har mac o ki netics  
P O  
B y m o ut h  
P O P P K  
P o p ulati o n P har mac o ki netics  
P R  
Partial Res p o nse  
P R O  
Patie nt -re p orte d o utc o m es 
P S  
Perf or ma nce Stat us  
P T  
Pr ot hr o m bi n ti me  
P W B  
P h ysical w ell -bei n g  
Q D  
O nce per da y  
Q O D  
E ver y ot her d a y  
R B C  
Re d bl o o d cell c o u nt  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors 
S A E  
Seri o us A d verse E v e nt  
S A P  
Statistical A nal ysis Pla n  
S A V E R  
Seri o us A d verse E v e nt Re p ort  
S D  
Sta ble Disease  
S D  
Sta n dar d de viati o n  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 3 of 1 1 3 
A B B R E VI A TI O N  
D E FI NI TI O N  
S O P  
Sta n dar d O perati n g Pr oce d ure  
S W B  
S ocial well -bei n g  
T A O  
T r olea n d o m yci n 
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T T P  
Ti me t o pr o gressi o n  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
V A S  
Vis ual A nal o g Scale  
W B C  
W hite bl o o d cell c o u nt  
W H O  
W orl d Healt h Or ga nizati o n  
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 5 of 1 1 3 
1. 1. 2  
L a b C or p M E T  I m m u n o hist oc he mistr y (I H C) C o m p a ni o n Di a g n ostic Ass a y 
La b C or p has de vel o pe d a n d vali date d a n i m m u n o hist oc he mistr y assa y f or M E T i n H C C 
f or mali n-fi x e d, paraffi n- e m be d de d ( F F P E) tiss ues t o meet t he re q uir e me nts of t he 
Cli nical La b orat or y I m pr o ve me nt A me n d me nts ( C LI A), t he C olle ge of A merica n 
Pat h ol o gists ( C A P) C o m missi o n o n La b orat or y Accre ditati o n, a n d t h e Ne w Y or k State 
De part me nt of Healt h ( N Y S D O H).  
T he assa y has b ee n re vie we d b y t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) Ce nter f or 
De vices a n d R a di ol o gic al Healt h ( C D R H) u n der I D E s u b missi o n # G 1 2 0 1 8 3 a n d is 
a p pr o ve d f or i n vesti gati o nal use i n t his st u d y.    C E mar ki n g f or t he assa y was o btai ne d i n 
acc or d a nce wit h E U directi ve 9 8/ 7 9/ E C. 
It is i nte n de d t hat t his La b C or p I H C Assa y will be use d as a C o m pa ni o n Di a g n ostic 
( C D x) t o select s u bjects wit h hi g h M E T e x pressi o n w h o w o ul d be ca n di d ates f or t hera p y 
wit h ti va nti ni b.    
1. 1. 2. 1  
I nte n de d Use 
T he La b C or p M E T I H C C o m pa ni o n Dia g n ostic Assa y is i nte n de d f or use i n t he detecti o n 
of M E T pr otei n e x pressi o n i n F F P E tiss ues. 
1. 1. 2. 2  
I n dic ati o ns f or Use 
T he i n dicati o n f or use f or t he La b C or p M E T I H C C o m pa ni o n Dia g n ostic Assa y is t o 
select s u bjects f or t h era p y wit h ti va nti ni b f or t he treat me nt of i n o pera ble M E T 
Dia g n ostic- Hi g h he pat o cell ular carci n o ma w h o pr o gress o n or ca n n ot t olerate pri or 
t hera p y.    
It is i nte n de d t hat t his cli nical st u d y will s u p p ort t he re gistrati o n of t he assa y. 
1. 1. 3.  
N o ncli nic al St u dies 
Ti va nti ni b has de m o nstrate d i n viv o a n d i n vitro  a nti-t u m or acti vit y acr oss a wi de ra n ge 
of h u ma n t u m or cell li nes, i ncl u di n g t h ose deri v e d fr o m breast, c ol o n, l u n g, pa n creas, a n d 
st o mac h.  T he p ote nc y of ti va nti ni b i n ca ncer cells e x pressi n g detecta ble c- Met i n a nti-
pr oliferati o n assa ys yi el d i n hi bit or c o nce ntrati o n re q uire d f or 5 0 % i n hi biti o n  (I C5 0) 
va l ues fr o m 0. 1 t o 0. 6 μ M,7 c o nce ntr ati o ns l o wer t ha n t he e x p os ures o bser ve d i n h u ma n 
P K st u dies. At e ve n l o wer d oses, a n i n viv o st u d y s h o we d i n hi biti o n of metastatic 
acti vit y. 8 
Ti va nti ni b i n hi bits c- Met acti vati o n i n a ra n ge of t u m or cell li nes.  T he dr u g 
c o nce ntr ati o n t hat i n hi bits t he gr o wt h of ca ncer c ells b y 5 0 %  (GI 5 0) of  ti va nti ni b has bee n 
e val uate d i n 1 2 H C C cell li nes b y t he S p o ns or a n d b y aca d e mic c olla b orat ors.  All of t he 
GI 5 0 val ues are bel o w 1. 7 0 µ M, wit h t he e x ce pti o n of t w o cell li nes.9 ,1 0   
T he c o m p o u n d has de m o nstrate d efficac y i n m uri ne xe n o graft m o dels of h u ma n c ol o n, 
pa ncreas, a n d breast c a ncers. A seri es of  i n vitr o e x peri me nts de m o nstrate t hat ti va nti ni b 
is a p ote nt a n d s pecific i n hi bit or of c- Met, w hic h c orrelates wit h t he a bilit y of ti va nti ni b 
t o kill ca ncer cells a n d i n hi bit metastasis i n vitr o.  Si n gle- a n d re peat- d ose t o xic ol o g y 
st u dies ha ve bee n p erf or me d i n d o gs a n d rats.  I n b ot h s pecies, si n gle- d ose escalati o n 
st u dies f oll o we d b y 7- a n d 2 8- da y re p eat- d os e st u dies were p erf or me d wit h d oses 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 6 of 1 1 3 
a d mi nistere d via oral ga v a ge.  I n t he 2 8- da y re peat- d ose st u dies, a n o o bser va ble effect 
le vel ( N O E L) of 1 0 m g/ k g f or d o gs a n d a n o o bs er va ble a d verse effect le vel ( N O A E L) of 
1 5 m g/ k g f or rats were i d e ntifie d.  T o xicit y was o bser ve d i n a d os e- de p e n d e nt ma n ner i n 
b ot h s pecies.  Pri mar y cli nical o bser vati o ns i n cl u d e d re d uce d f o o d c o ns u m pti o n a n d l oss 
of b o d y wei g ht at d oses > 3 0 m g/ k g/ da y (rat) a n d at 4 5 m g/ k g/ da y ( d o g) i n t he 2 8- da y 
st u dies; e mesis a n d e x cessi ve sali vati o n at d oses > 1 0 0 m g/ k g/ da y i n t he d o g st u dies.  
N o n-f or me d or li q ui d feces at d oses > 1 0 0 m g/ k g / da y were n ote d i n t he rat st u dies.   
I n b ot h s pecies, t o xic o ki netic res ults fr o m t he re peat- d ose st u dies s h o w e d t hat e x p os ure 
t o ti va nti ni b ge nerall y i n creas e d as d ose l e vels i ncrease d. H o we v er, i ncreas es i n 
ma xi m u m plas ma dr u g c o nce ntrati o n ( C ma x ) a n d area u n der t he ti me-c o n ce ntrati o n c ur ve 
( AU C) val ues were n ot c o nsiste ntl y d os e pr o p orti o nal.  Pri mar y cli nical pat h ol o gic 
o bser vati o ns c o nsiste d of decrease d retic ul oc yte c o u nt a n d l o wer a bs ol ute re d cell mass at 
t he ma xi m u m d oses: 4 5 m g/ k g/ da y f or rats a n d 3 0 m g/ k g/ da y f or d o gs i n t he 2 8- da y 
re peat- d ose st u dies. T hes e effects were re versi ble wit hi n a 1 4- da y rec o ver y peri o d.  
T hese sa me effects were o bser ve d i n b ot h s pecies at hi g her d oses i n t he si n gle- a n d 7- d a y 
re peat- d ose st u dies.  N o treat me nt-relate d gr oss or hist o pat h ol o gic effects were o bs er ve d 
i n t he 2 8- da y re p eat- d os e st u dies. 
Base d o n t h ese o bser vati o ns, t he N O A E L f or rats a d mi nistere d ti va nti ni b  dail y b y oral 
g a v a ge f or a 2 8- d a y peri o d was 1 5 m g/ k g/ da y a n d t he N O E L i n d o gs a d mi nistere d 
ti va nti ni b dail y b y ca ps ul e f or a 2 8- da y peri o d was 1 0 m g/ k g/ da y 
A d diti o nal i nf or mati o n ca n be f o u n d i n t he I n v esti gat or’s Br oc h ur e.  
1. 1. 4.  
Cli nic al E x perie nce 
Ti va nti ni b is c urre ntl y u n der j oi nt gl o bal cli nical de vel o p me nt i n t he U nite d States ( U S ) 
a n d E ur o pea n U ni o n ( E U ) b y Daiic hi Sa n k y o, I nc, a n d Ar Q ule, I nc.  O ver 7 8 0 s u bjects 
ha ve bee n e x p ose d t o ti va nti ni b pri or t o t he i nitiat i o n of t his st u d y.1 1 Ti va nti ni b is 
curre ntl y bei n g d e vel o pe d as a treat me nt f or a v ari et y of ca n cers, s electe d b y m olec ul ar 
a n d bi ol o gic al c haracteristics, i ncl u di n g t he pres e nce of t he c- Met rece pt or ki nase. 
Ti va n ti ni b has s h o w n pr o misi n g res ults i n H C C i n P hase 1 a n d 2 st u dies as m o n ot hera p y 
a n d i n c o m bi nati o n wit h s orafe ni b.  I n earl y P has e 1 st u dies e m pl o yi n g ti va nti ni b 
ca ps ules, t he d ose li miti n g t o xicities were  f o u n d t o be le u k o pe nia, ne utr o pe nia, 
t hr o m b oc yt o pe ni a, v o miti n g, de h y drati o n, fati g ue, m uc ositis, ha n d-f o ot s y n dr o me, a n d 
fe brile ne utr o p e nia.1 2 , 1 3 I n P hase 1 st u dies e nr olli n g H C C s u bjects b ot h wit h ti va nti ni b 
ca ps ules as m o n ot hera p y a n d i n c o m bi nati o n wit h s orafe ni b, t he ti va nti ni b 3 6 0 m g BI D 
d ose has pr o d uce d a ma n a gea ble s afet y pr ofile, wi t h hi g her rate of n e utr o pe nia. M ore 
e xte nsi ve disc ussi o n of t he safet y pr ofile i n H C C s u bjects is i n Secti o n 1. 3  of t his 
pr ot oc ol. Ti va nti ni b has als o be e n st u die d i n a P h ase 3 cli nical st u d y i n n o n-s q ua m o us 
N S C L C, e m pl o yi n g t he t a blet f or m ulati o n. 
F urt her i nf or mati o n ca n be f o u n d i n t he I n vesti gat or’s Br oc h ure. 
1. 2.  
St u d y R ati o n ale 
E x pressi o n of c- Met i n t u m ors c orrel ates wit h a g gressi ve H C C feat ur es. O vere x pressi o n 
of t he rece pt or i n t u m or s a m ples or hi g h l e vel of bl o o d H G F  i n s u bjects is relate d t o 
hi g her rec urre nce rate aft er s ur ger y f or H C C, w hil e hi g h c- Met e x pressi o n c orrel ates wit h 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 7 of 1 1 3 
s h orter s ur vi val i n H C C s u bjects. I n s u m mar y, c- Met h ol ds a n i m p orta nt pr o g n ostic r ole 
i n t he nat ural hist or y of H C C.1 4 , 1 5 , 1 6 , 1 7 , 1 8 , 1 9 , 2 0 , 2 1 , 2 2  
A ra n d o mize d, c o ntr olle d P hase 2 st u d y wit h ti va nti ni b vers us place b o i n s u bjects wit h 
i n o pera ble H C C w h o ha v e faile d o ne pri or s yste mic t hera p y h as pr o vi de d p ositi ve res ults 
a n d bi ol o gic al i nsi g hts o n t he acti vit y of ti va nti ni b i n t his disease. T his st u d y e m pl o ye d 
t he ca ps ule f or m ulati o n of ti va nti ni b. W hile t he st u d y met its pri mar y e n d p oi nt b y 
i m pr o vi n g ti me t o pr o gressi o n (T T P ) i n t he i nte nt-t o-treat (I T T) p o p ulati o n ( 6. 9 vs 6. 0 
we e ks, hazar d rati o ( H R ) 0. 6 4, 9 0 % C o nfi de nce I nter val (CI ) 0. 4 3- 0. 9 4, p = 0. 0 4), 
re gar dl ess of t he starti n g d ose, t he hi g h est be nefit was o btai ne d b y M E T Di a g n ostic- Hi g h 
s u bjects. Efficac y a n al ysis b y M E T stat us was a pre- pla n ne d st u d y e n d p oi nt a n d s u bjects 
were d efi ne d as “ M E T Dia g n ostic- Hi g h ” if ≥ 5 0 % of t u m or cells ha d a stai ni n g i nte nsit y 
of  ≥ 2 + f or M E T as assesse d b y i m m u n o hist oc he mistr y. I n ME T Dia g n ostic- Hi g h 
s u bjects, me dia n T T P was 1 1. 7 vers us 6. 1 wee ks ( H R = 0. 4 3, 9 5 % CI 0. 1 9- 0. 9 7, p = 0. 0 3), 
me dia n pr o gressi o n free s ur vi val ( P F S) was 9. 6 v ers us 6. 0 wee ks ( H R = 0. 4 5, 
9 5 % CI  0. 2 1- 0. 9 5, p = 0. 0 2), a n d diseas e c o ntr ol rate ( D C R) was 5 0 % vers us 2 0 %. I n t his 
p o p ulati o n, f i nal me dia n o verall s ur vi val (O S ) at t he A pril 2 0 1 2 u p date was 7. 2 vs 3. 8 
m o nt hs, H R = 0. 3 8 , 9 5 % CI 0. 1 8- 0. 8 1, p = 0. 0 2). I n M E T Dia g n ostic- L o w s u bjects, T T P 
a n d O S were statisticall y si milar o n ti va nti ni b a n d place b o. Aft er 5 7 s u bject s were 
e nr olle d, d ue t o hi g h ( 2 1 %) i nci de nce of dr u g-rel ate d G ≥ 3 ne utr o p e nia, t he ti va nti ni b 
starti n g d ose of 3 6 0 m g BI D was m o difie d t o 2 4 0 m g BI D a n d a m o difie d d ose re d ucti o n 
sc he ma was i m ple me nt e d. At t he latter d ose, t he rate of G ≥ 3 ne utr o p e nia dr o p pe d t o 6 % 
an d a pre di cta ble a n d m a na gea ble s afet y pr ofile e mer ge d. Efficac y was si milar i n b ot h of 
t he teste d d ose le vels, 3 6 0 m g BI D a n d 2 4 0 m g BI D. Res ults fr o m t he st u d y als o s h o we d 
t hat c- Met is a n i n de pe n d e nt pr o g n ostic fact or i n t he e nr olle d H C C s u bjects, si nce O S f or 
M E T  Dia g n ostic- Hi g h s u bjects o n place b o a p pears t o be w orse t ha n t hat of M E T 
Dia g n ostic- L o w s u bjects o n place b o ( 3. 8 v ers us 9. 0 m o nt hs, H R = 2. 9 4, 9 5 % CI 1. 1 6-
7. 4 3, p = 0. 0 2), c o nfir mi n g t he pr o g n ostic r ole of M E T i n H C C. S uc h res ults warra nt 
f urt her st u d y i n t he p o p ul ati o n selecte d f or t his P hase 3 st u d y: ME T Dia g n ostic- Hi g h 
H C C s u bjects w h o ha ve faile d o ne pri or s yste mic t hera p y.  
T his P hase 3 st u d y i n M E T Dia g n ostic- Hi g h i n o p era ble H C C s u bjects has bee n desi g ne d 
base d o n t he res ults fr o m t he ra n d o mize d, c o ntr olle d P hase 2 st u d y c o n d uct e d b y Ar Q ule, 
I n c. wit h ti va nti ni b vers us place b o i n s u bjects wit h M E T Dia g n ostic- Hi g h i n o pera ble 
H C C w h o ha ve faile d o n e pri or s yste mic t hera p y, me nti o ne d a b o ve . T he p ur p ose of t his 
st u d y is t o c o nfir m t he efficac y of ti va nti ni b i n M E T Dia gn ostic- Hi g h H C C s u bjects w h o 
were pre vi o usl y treat e d wit h o ne s yste mic t hera p y, a n d t o f urt her e val uate t he safet y 
pr ofile of t he e x peri me nt al dr u g i n t his s u bject p o p ulati o n. F or ma n ufact uri n g reas o ns, 
t his st u d y e m pl o ys t he ta blet f or m ulati o n of ti va nti ni b. 
 
 
1. 3.  
Ris k s a n d Be nefits f or St u d y S u bjects 
A ti va nti ni b ta blet d ose of 2 4 0 m g  BI D (a t otal dail y d ose of 4 8 0 m g) was s electe d f or 
t his P hase 3 st u d y o n t he basis of efficac y a n d t olera bilit y esta blis he d i n P h ase 1 a n d 
P hase 2 st u dies wit h ca ps ules.   I n A u g ust 2 0 1 3, f oll o wi n g a hi g her t h a n e x pecte d 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 8 of 1 1 3 
i nci de nce of ne utr o pe ni a-relate d t o xicities, t he st u dy D M C e val uate d all a v aila ble data 
i ncl u di n g preli mi nar y p h ar mac o ki netics. Bas e d o n t his re vie w, t he D M C rec o m me n de d 
t he starti n g d ose of 1 2 0 m g BI D (f or a t otal dail y d ose of 2 4 0 m g).  T he D M C re q ueste d 
t o c o n d uct a detaile d s afet y re vi e w of a pre- deter mi ne d c o h ort of patie nts treate d at 1 2 0 
m g BI D.  B y 1 5 N o ve m b er 2 0 1 3, 2 9 s u bjects w ere treate d at 1 2 0 m g BI D.  Of t hese, 2 6 
were tr eate d fr o m bet w ee n 1 a n d 2 ½ m o nt hs a n d 3 were  tr eate d f or at least 3 wee ks.  
After re vie wi n g t he A bs ol ute Ne utr o p hil C o u nt ( A N C) data pr o vi de d o n 1 5 N o ve m ber 
2 0 1 3, t he D M C a d vise d t hat t he st u d y e nr oll me nt ca n c o nti n ue. 
T he res ults of t he ra n d o mize d c o ntr olle d P hase 2 trial A R Q 1 9 7- 2 1 5 de m o nstrate d t hat 
ti va nti ni b offere d be n efits i n T T P, P F S, O S, a n d D C R, as s h o w n i n Secti o n 1. 2  of t his 
pr ot oc ol.  T he be n efits w ere e v e n m ore r o b ust i n t he M E T Dia g n ostic- Hi g h s u b gr o u p, 
w here t he i m pr o v e me nt i n T T P was 1 3 3 % a n d t he i m pr o ve me nt i n O S was 1 6 3 %. 
Efficac y was si milar i n b ot h of t he teste d d ose le vels, 3 6 0 m g BI D a n d 2 4 0 m g BI D. 
T a ble 1. 1 M ost C o m m o n ( > 5 % of all S u bjects) A d verse E ve nts a n d Se vere ( Gr a de 3 
or hi g her) A d verse E v e nts  See n i n t he R a n d o mize d- C o ntr olle d P h ase 
2 H C C St u d y, A R Q 1 9 7- 2 1 5  
 
A d verse E ve nts  
Se vere A d verse E ve nts  
Pri m ar y S yste m Or g a n Cl ass  
      Preferre d Ter m  
A R Q 1 9 7 
2 4 0  m g  
( N = 3 3) 
n ( %) 
Pl ace b o  
 
( N = 3 6) 
n ( %)  
A R Q 1 9 7 
2 4 0  m g  
( N = 3 3) 
n ( %)  
Pl ace b o  
 
( N = 3 6) 
n ( %)  
Bl o o d a n d l y m p hatic s yste m 
dis or ders  
 
 
 
 
    Ne utr o pe nia  
7 ( 2 1. 2 %)  
2 ( 5. 6 %)  
2 ( 6. 1 %)  
0  
    A nae mia  
7 ( 2 1. 2 %)  
2 ( 5. 6 %)  
3 ( 9. 1 %)  
0  
    T hr o m b oc yt o pe nia  
3 ( 9. 1 %)  
0  
2 ( 6. 1 %)  
0  
    Le u k o pe nia  
2 ( 6. 1 %)  
1 ( 2. 8 %)  
1 ( 3. 0 %)  
0  
Car diac dis or ders  
 
 
 
 
    Bra d ycar dia  
3 ( 9. 1 %)  
1 ( 2. 8 %)  
 
 
Gastr oi ntesti nal dis or ders  
 
 
 
 
    Diarr h oea  
3 ( 9. 1 %)  
9 ( 2 5. 0 %)  
 
 
    Ascites  
1 0 ( 3 0. 3 %)  
5 ( 1 3. 9 %)  
 
 
    A b d o mi nal pai n  
3 ( 9. 1 %)  
7 ( 1 9. 4 %)  
 
 
    Na usea  
3 ( 9. 1 %)  
5 ( 1 3. 9 %)  
 
 
    A b d o mi nal pai n u p per  
6 ( 1 8. 2 %)  
3 ( 8. 3 %)  
 
 
    C o nsti pati o n  
4 ( 1 2. 1 %)  
4 ( 1 1. 1 %)  
 
 
    D ys pe psia  
2 ( 6. 1 %)  
2 ( 5. 6 %)  
 
 
Ge neral dis or ders a n d 
a d mi nistrati o n site c o n diti o ns  
 
 
 
 
    Ast he nia  
1 4 ( 4 2. 4 %)  
7 ( 1 9. 4 %)  
 
 
    Fati g ue  
4 ( 1 2. 1 %)  
1 0 ( 2 7. 8 %)  
1 ( 3. 0 %)  
2 ( 5. 6 %)  
    Oe d e ma peri p heral  
8 ( 2 4. 2 %)  
6 ( 1 6. 7 %)  
 
 
    P yre xia  
3 ( 9. 1 %)  
5 ( 1 3. 9 %)  
 
 
He p at o biliar y dis or ders  
 
 
 
 
    He p atic fail ure  *  
2 ( 6. 1 %)  
0  
2 ( 6. 1 %)  
0  
I n vesti gati o ns 
 
 
 
 
    W ei g ht d ecrease d  
4 ( 1 2. 1 %)  
1 ( 2. 8 %)  
 
 
Meta b olis m a n d n utriti o n dis or ders  
 
 
 
 
    Decrease d a p petite  
9 ( 2 7. 3 %)  
6 ( 1 6. 7 %)  
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 2 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 2 9 of 1 1 3 
 
A d verse E ve nts  
Se vere A d verse E ve nts  
Pri m ar y S yste m Or g a n Cl ass  
      Preferre d Ter m  
A R Q 1 9 7 
2 4 0  m g  
( N = 3 3) 
n ( %) 
Pl ace b o  
 
( N = 3 6) 
n ( %)  
A R Q 1 9 7 
2 4 0  m g  
( N = 3 3) 
n ( %)  
Pl ace b o  
 
( N = 3 6) 
n ( %)  
Res pirat or y, t h oracic a n d 
me diasti nal dis or ders  
 
 
 
 
    C o u g h  
4 ( 1 2. 1 %)  
5 ( 1 3. 9 %)  
 
 
    D ys p n oea  
2 ( 6. 1 %)  
3 ( 8. 3 %)  
 
 
    Ple ural eff usi o n  
1 ( 3. 0 %)  
3 ( 8. 3 %)  
 
 
*  N ot see n i n > 5 % of all s u bj ects.  
Pr ot oc ol A R Q 1 9 7- 2 1 5 was i nitiate d wit h a ti va nti ni b d ose of 3 6 0 m g BI D. I n t h is st u d y, 
t he safet y pr ofile of t he e x peri me ntal dr u g was ma na gea ble, wit h si milar rates of a d verse 
e ve nts ( A Es) i n t he tr eat me nt a n d place b o ar ms; h o we ver, t he o bser v e d rate of ≥ Gra d e 3 
ne utr o pe nia at 3 6 0 m g BI D was 2 1 % c o m p are d t o < 5 % i n s u bjects i n ot her ti va nti ni b 
st u dies, a n d i ncl u de d 3 s u bjects wit h ne utr o pe nia w h o die d wit hin 3 0 da ys of treat me nt 
wit h t he st u d y dr u g. A m ore a g gressi ve d ose re d u cti o n sc he ma was t h e n i m ple me nte d, 
a n d t he d ose w as re d u ce d t o 2 4 0 m g B I D f or all s u bjects a n d b ot h meas ures are a p plie d 
i n t his P hase 3 st u d y.  S u c h meas ures re d u ce d t he i nci de nce of ≥ Gra d e 3 n e utr o pe nia t o 
6 %; h o we ver, t h e re was 1 deat h i n a s u bject ass o ciate d wit h ne utr o pe nia e v e n at t he 
re d uce d d os e. At t he 2 4 0 m g BI D d ose, t he m ost fre q ue nt dr u g-relate d s eri o us a d verse 
e ve nt (A E ) i n t he A R Q 1 9 7- 2 1 5 st u d y was ne utr o pe nic se psis ( 3 %). P K a n al ysis 
i n dicate d t hat dr u g e x p os ure was a p pr o xi matel y 3 f ol d hi g her i n s u bjects wit h H C C 
c o m pare d t o ot her ca n cers.  T o f urt her ma na ge s uc h ris ks ass ociate d wit h se vere 
ne utr o pe nia (rare, at t he 2 4 0 m g  BI D d ose), t his P hase 3 st u d y m a n dates m ore fre q ue nt 
bl o o d c o u nts a n d treat me nt wit h a nti bi otics a n d c ol o n y-sti m ulati n g gr o wt h fact ors i n 
s u bjects de vel o pi n g Gra d e 4 ne utr o pe nia. S uc h a g gressi ve pr o p h yla xis of ne utr o pe nic 
se psis, n ot i n place i n t he A R Q 1 9 7- 2 1 5 st u d y, is e xpecte d t o f urt her i m pr o ve t he safet y 
pr ofile of ti va nti ni b i n H C C s u bjec ts treate d wit h ti va nti ni b.   
1. 4.  
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d 
T he st u d y p o p ulati o n c o nsists of s u bjects wit h M E T Dia g n ostic- Hi g h  i n o pera ble 
he pat ocell ular carci n o ma ( H C C) treate d wit h o ne pri or s yste mic t h era p y. T he 
e x peri me ntal dr u g will be gi v e n orall y, at t he starti n g d ose of 1 2 0 m g t wice a da y ( BI D ) 
o nce i n t he m or ni n g, o nce i n t he e ve ni n g , wit h f o o d ( 2 4 0 m g/ da y), c o nti n u o usl y. F or 
a d mi nistrati ve reas o ns, t he trea t me nt peri o d is di vi de d i nt o 4- wee k c ycles ( 2 8 da ys). 
At t he start of eac h c ycl e, s u bjects will recei ve a de q uate s u p plies of ti va nti ni b or place b o 
ta blets f or o ne f ull c ycle of t hera p y, at a d ose of 1 2 0 m g BI D (i. e., 2 4 0 m g per da y). See 
Secti o n 3  f or f urt her details.  Acti ve ta blets will eac h c o ntai n 1 2 0 m g of ti va nti ni b. 
F or i n di vi d ual s u bjects, treat me nt will c o nti n ue u ntil u nacce pta ble t o xicit y or a n ot her 
disc o nti n uati o n criteri o n is met.  It is e x pecte d t hat m ost s u bjects will recei ve 
ti va nti ni b/ place b o f or at l east 1 t o 5 treat me nt m o nt hs. 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 0 of 1 1 3 
1. 5.  
C o m pli a nce St ate m e nt, Et hics a n d Re g ul at or y C o m pli a nce 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter n ati o nal C o nfere n ce o n 
Har m o nisati o n (I C H) c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( G C P) 
( C P M P/I C H/ 1 3 5/ 9 5), a n d t he f oll o wi n g a p plica bl e re g ulat or y re q uir e me nt(s): 
 E ur o pea n C o m missi o n Directi ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1) 
 E ur o pea n C o m missi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) 
 F D A G C P Re g ulati o ns: C o de of Fe d eral Re g ul ati o ns Title 2 1, parts 1 1, 5 0, 5 4, 
5 6, a n d 3 1 2 as a p pr o priat e 
 Ot he r a p plica bl e l ocal r e g ulati o ns 
1. 5. 1.  
S u bject C o nfi de nti alit y 
T he I n vesti gat ors a n d t h e S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g 
part i n t he st u d y, i n a cc or da nce wit h G C P a n d l ocal re g ul ati o ns. 
F or E U sit es, D aiic hi Sa n k y o a n d d esi g nees will o bser ve t he r ul es lai d d o w n i n t he 
E ur o pea n D ata Pr otecti o n Directi ve  9 5/ 4 6/ E C o n t he pr otecti o n of i n di vi d uals wit h 
re gar d t o t he pr ocessi n g of pers o nal dat a a n d t he free m o ve me nt of s uc h data. 
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he Case 
Re p ort F or ms or ot her d oc u me nts s u b mitte d t o Daiic hi Sa n k y o a n d d esi g n ees, s u bjects 
s h o ul d be i de ntifie d b y a u ni q ue s u bject i de ntifier as desi g n ate d b y t he S p o ns or.  
D oc u me nts t hat are n ot f or s u b missi o n t o Daiic hi Sa n k y o a n d d esi g nees (i.e., si g ne d 
I nf or me d C o nse nt F or ms [I C F]) s h o ul d be ke pt i n strict c o nfi de nce b y t he I n vesti gat or. 
I n c o m plia nce wit h Fe deral re g ulati o ns/I C H G C P G ui deli nes, it is re q uire d t hat t he 
I n v esti gat or a n d i nstit uti o n per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he 
re g ulat or y a ge nc y(s), a n d t he In d e pe n d e nt Et hics C o m mittee (I E C) or I nstit uti o nal 
Re vie w B o ar d (I R B) direct access t o re vie w t h e s u bject’s ori gi nal me dical r ec or ds f or 
verificati o n of st u d y-relat e d pr oce d ures a n d data.  T he I n vesti gat or is o bli gate d t o i nf or m 
t he s u bject t hat his/ her st u d y-relate d rec or ds will be re vie we d b y t he a b o v e na me d 
re pres e ntati ves wit h o ut vi olati n g t he c o nfi d e ntialit y of t he s u bj ect. 
1. 5. 2.  
I nf or me d C o nse nt Pr oce d ure 
Bef ore a s u bj ect’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o 
o btai n freel y gi ve n c o nse nt, i n writi n g, fr o m t he s u bject after a de q u ate e x pla nati o n of t he 
ai ms, met h o ds, a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d bef ore a n y 
pr ot oc ol-s pecifi c scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  T he writte n 
I C F s h o ul d be pre p are d i n t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n. 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hical 
pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y 
re visi o n(s) s h o ul d be a p pr o ve d b y t he I E C or I R B pri or t o bei n g pr o vi de d t o p ote ntial 
s u bjects. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 1 of 1 1 3 
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or  t o his/ her partici pati o n i n 
t he st u d y, a n d s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y 
2 1 C o de of Fe d eral Re g ulati o ns ( C F R) Part 3 1 2. 6 2.  T he I C F s h o ul d be si g ne d a n d 
pers o nall y date d b y t he s u bject a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt 
disc ussi o n ( n ot necessaril y t he I n v esti gat or).  T h e ori gi nal si g ne d I C F s h o ul d be retai ne d 
i n acc or d a nce wit h i nstit uti o nal p olic y, a n d a c o p y of t he si g n e d c o nse nt f or m s h o ul d be 
pr o vi de d t o t he s u bject or le gal re prese ntati ve.  T he date t hat i nf or m e d c o ns e nt was gi ve n 
s h o ul d be rec or de d o n t h e Case Re p ort F or m. 
If t he s u bject c a n n ot rea d, t he n acc or di n g t o I C H G C P G ui deli ne, Secti o n 4. 8. 9, a n 
i m partial wit ness s h o ul d be prese nt d uri n g t he e ntire i nf or me d c o nse nt disc ussi o n.  T his 
wit ness s h o ul d si g n t he I C F after t h e s u bject or t h e le gall y acce pta ble re prese ntati ve has 
orall y c o nse nte d t o t he s u bject’s partici pati o n a n d, if p ossi ble, si g ne d t he I C F.  B y 
si g ni n g t he I C F, t he wit ness attests t hat t he i nf or m ati o n i n t he I C F a n d a n y ot her writte n 
i nf or mati o n was a de q u at el y e x plai ne d t o a n d a p pare ntl y u n d erst o o d b y t he s u bject or t he 
le gall y acce pta ble re pres e ntati ve a n d t hat i nf or me d c o nse nt was freel y gi ve n b y t he 
s u bject or t he le gall y acce pta ble re prese nt ati ve. 
S u g geste d m o del te xt f or t he I C F f or t h e st u d y a n d a n y a p plica ble s u b p arts (s uc h as 
pre-scree ni n g, t u m or sa m ple c ollecti o n, p har mac o ge n o mic, p h ar mac o ki netic, a n d 
o pti o nal t u m or bi o ps y) are pr o vi de d i n t he Daiic hi Sa n k y o P har m a De v el o p me nt ( D S P D) 
I C F te m plate f or t he I n vesti gat or t o pre p are t he d oc u me nts t o be use d at his or her site.  
U p dates t o a p plica ble f or ms will be c o m m u nicate d via letter fr o m t he Cli nical St u d y 
Ma na ger. 
F or sites i n t he U nite d St ates ( U S), a d diti o nal c o nse nt is re q uir e d f or t he Healt h I ns ura nce 
P orta bilit y a n d Acc o u nta bilit y A ct ( HI P A A). 
1. 5. 3.  
Re g ul at or y C o m pli a nce 
T he st u d y pr ot oc ol, s u bje ct i nf or mati o n a n d c o nse nt f or m, t he I n vesti gat or Br oc h ure, a n y 
s u bject diar y car d or writte n i nstr ucti o ns t o be gi v e n t o t he s u bject, a vaila bl e safet y 
i nf or mati o n, s u bject recr uit me nt pr oce d ures (i.e., a d vertise me nts), i nf or mati o n a b o ut 
pa y m e nts a n d c o m pe ns ati o n a vaila ble t o t he s u bjects, a n d d oc u me ntati o n e vi de nci n g t h e 
I n v esti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o t he I E C or I R B f or et hi cal re vie w a n d 
a p pr o val a cc or di n g t o l ocal re g ulati o ns, pri or t o t h e st u d y start.  T he writte n a p pr o val 
s h o ul d i de ntif y all d oc u me nts re vie we d b y n a me a n d versi o n. 
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he St atistical A nal ysis Pla n ( S A P). 
T he I n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he I E C or I R B 
a n d/ or S p o ns or ( or desi g nee) f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he 
i nf or me d c o nse nt d oc u m e nt or c ha n ges of t he i n v estigati o nal site, facilities or pers o n nel.  
T he I n vesti gat or s h o ul d n otif y t he I E C or I R B of de viati o ns fr o m t he pr ot o c ol or seri o us 
a d verse e ve nts oc c urri n g a t t he site a n d ot her a d verse e ve nt r e p orts recei v e d fr o m t he 
S p o ns ors or Cli nical Researc h Or ga nizati o n ( C R O ), i n acc or da n ce wit h l o cal pr oce d ures. 
As r e q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p will 
e ns ure all le gal as pects are c o vere d, a n d a p pr o val of t he a p pr o pri ate re g ulat or y b o dies 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 2 of 1 1 3 
o btai ne d, pri or t o st u d y i nitiati o n, a n d t hat i m ple me nta ti o n of c ha n ges t o t he i nitial 
pr ot oc ol a n d ot her rele va nt st u d y d oc u me nts ha p p e n o nl y after t h e a p pr o priate 
n otificati o n of or a p pr o val b y t he rele va nt re g ulat or y b o dies. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 3 of 1 1 3 
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S 
2. 1.  
St u d y O bjecti ves 
2. 1. 1.  
Pri m ar y O bjecti ves 
E val uate t he o verall s ur vi val ( O S) a m o n g all  s u bjects i n t he i nte nt-t o-treat (I T T) 
p o p ulati o n c o m pare d t o place b o. 
2. 1. 2.  
Sec o n d ar y O bjecti ves 
E val uate pr o gressi o n free s ur vi val ( P F S) b y ce ntral, i n de pe n de nt ra di ol o g y re vie w a m o n g 
all s u bject s i n t he i nte nt-t o-treat (I T T) p o p ulati o n c o m pare d t o place b o. 
E val uate t he safet y of ti v a nti ni b i n t he treate d H C C s u bject s. 
2. 1. 3.  
E x pl or at or y O bjecti ves 
E val uate t he o bje cti ve res p o nse rate ( O R R), disease c o ntr ol rate ( D C R), ti me t o 
pr o gressi o n ( T T P), a n d t y p e of pr o gressi o n, b y ce ntral, i n de pe n de nt ra di ol o g y re vie w 
a m o n g all s u bject s i n t he i ntent- t o-treat (I T T) p o p ulati o n c o m pare d t o place b o. 
E val uate t he p har mac o ki netics of ti va nti ni b  a n d its meta b olites i n H C C s u bjects a n d 
e x pl ore t he fact ors, i ncl u di n g C Y P 2 C 1 9 ge n ot y p e a n d maj or str o n g C Y P 3 A 4/ C Y P 2 C 1 9 
i n hi bit ors, w hic h ma y affect ti va nti ni b P K i n H C C s u bjects. 
E x pl ore t he e x p os ure-res p o nse relati o ns hi p of  ti va nti ni b t o bi o mar kers a n d t o safet y a n d 
effic ac y e n d p oi nts.  
E val uate t he  F u ncti o nal Assess me nt of Ca ncer T hera p y- He pat o biliar y ( F A C T- He p) 
base d F H SI- 3 Pai n Sc ore ( pai n, pai n i n bac k, p ai n/ disc o mf ort i n st o mac h); F A C T-
He pat o biliar y S y m pt o m I n de x ( F H SI- 8) sc ore, E m oti o nal Well Bei n g ( E W B) sc ore, a n d 
t he F A C T- He p t otal sc ore. 
E va l uate t he ti me-t o- h os pitalizati o n (all-ca use) a n d t he ti me-t o- h os pitalizati o n ( H C C-
relate d). 
2. 2.  
St u d y H y p ot h esis 
Treat me nt wit h ti va nti ni b will i m pr o ve O S relati ve t o place b o i n s u bjects wit h M E T 
Dia g n ostic- Hi g h i n o pera ble H C C treate d wit h o ne pri or s yste mic t h era p y. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 4 of 1 1 3 
3.  
S T U D Y D E SI G N 
3. 1.  
O ver all Pl a n 
3. 1. 1.  
St u d y T y pe 
T his is a P hase 3, gl o bal, m ultice nter, d o u ble- bli n d, ra n d o mize d, stratifie d, place b o-
c o ntr olle d st u d y. S u bject s are e nr olle d base d o n pr ot oc ol i ncl usi o n/e xcl usi o n criteria; 
t he y are ra n d o mize d t o ti va nti ni b or place b o i n a 2: 1 rati o; t he y are str atifie d base d o n 
vasc ular i n vasi o n ( prese nt or n ot), e xtra- he pati c s prea d i ncl u di n g dista nt metastasis 
a n d/ or i n v ol ve d re gi o nal or dista nt l y m p h n o des ( prese nt or n ot , usi n g R E CI S T 1. 1 
criteria, b ut re gi o nal n o d es are c o nsi dere d i n v ol ve d if ≥ 2 0 m m i n s h ortest dia meter), a n d 
A F P (less/e q ual or greater t ha n 2 0 0 n g/ m L). Pri or pr o gressi o n or i nt olera n ce t o s orafe ni b 
nee ds t o be d oc u me nt e d as per pr ot oc ol. O ver 1 2 0 ce nters will be i n v ol ve d i n t he st u d y i n 
E ur o pe, t he A mericas, a n d Asia Pacific. A p p r o xi matel y 3 0 3 a d ult s u bjects wit h M E T 
Dia g n ostic- Hi g h  i n o pera ble H C C w h o pr o gresse d or di d n ot t olerate s orafe ni b (see 
i ncl usio n/e x cl usi o n criteria f or detaile d i nf or mati o n) will be e nr olle d ( a p pr o xi matel y 
2 0 2 o n ti va nti ni b a n d a p pr o xi matel y 1 0 1 o n place b o)  i n 1 2 0 m g c o h ort. T he 4 3 s u bjects 
w h o  were ra n d o mize d t o t he starti n g d ose of 2 4 0 m g BI D vers us Place b o pri or t o t he 
d ose re d ucti o n will be a n al yze d se p arat el y as descri be d i n statistical a nal ysis secti o n 
( Secti o n 1 1. 2 ). Cr oss o ver fr o m place b o after disease pr o gressi o n is n ot all o we d. 
A n i nteri m a nal ysis is pla n ne d w he n a p pr o xi m atel y 1 5 4 ( ~ 6 0 %) of t h e 2 5 7 O S e ve nts are 
d oc u me nte d. T he st u d y ma y b e ter mi nate d f or s u peri orit y at t he i nteri m a n al ysis i n 
acc or d a nce wit h t he statistical a nal ysis pla n.  If t h e st u d y is p ositi ve at t he pres pecifi e d 
i nteri m or fi nal a nal ysis, t he s p o ns or will all o w patie nts w h o are recei vi n g place b o 
treat me nt t o recei ve acti ve ti va nti ni b treat me nt aft er data base l oc k if t he s afet y 
para meters i n t he eli gi bilit y criteria ar e met (see s ecti o n 4. 1 ).  T he st u d y will be 
u n bli n de d after data base l oc k.  
3. 1. 2.  
Tre at me nt Gr o u ps 
Fi g ure 3. 1 Sc he m atic of Tre at me nt Gr o u ps 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 5 of 1 1 3 
Detaile d i nf or mati o n o n i ncl usi o n/e xcl usi o n criteria, st u d y pr oce d u res, stratificati o n, a n d 
sc he d ule of e ve nts, are i n Secti o ns 4. 1. 1 , 4. 1. 2 , 6 , 1 1. 5. 1. 1 , a n d A p pe n di x 1 7. 1 , 
res pecti vel y.   
3. 1. 3.  
St u d y E n d p oi nts 
3. 1. 3. 1. Pri m ar y E n d p oi nt  
 O verall s ur vi val ( O S) i n I T T p o p ul ati o n  
3. 1. 3. 2. Sec o n d ar y E n d p oi nts  
 Pr o gressi o n free s ur vi val ( P F S) b y ce ntr al, i n de pe n de nt ra di ol o g y re vie w  
 S afet y 
3. 1. 3. 3. 
E x pl or at or y E n d p oi nts 
 O bjecti ve res p o ns e rat e ( O R R), disease c o ntr ol rate ( D C R), ti me t o pr o gressi o n 
( T T P), a n d t y pe of pr o gressi o n, b y ce ntral, i n de pe n de nt ra di ol o g y re vie w 
 P o p ulati o n p har mac o ki netic para m eters of ti va nti ni b a n d its meta b olites a n d 
e x pl ore t he fact ors, i ncl u di n g C Y P 2 C 1 9 ge n ot y p e a n d maj or  str o n g 
C Y P 3 A 4/ C Y P 2 C 1 9 i n hi bit ors w hic h ma y affec t ti va nti ni b P K 
 E va l uate F u n cti o nal Assess me nt of Ca ncer T h era p y He pat o biliar y bas e d ( F A C T-
He p ) F H SI- 3 Pai n Sc ore ( pai n, pai n i n bac k, p ai n/ disc o mf ort i n st o mac h); F A C T-
He pat o biliar y S y m pt o m I n de x ( F H SI- 8) sc ore, F A C T- He p E m oti o nal Well Bei n g 
( E W B) sc ore, a n d t he F A C T- He p t otal sc ore 
 E va l uate ti me-t o- h os pitaliz ati o n (all-ca use) a n d ti me-t o- h os pitaliz ati o n ( H C C-
relate d). 
3. 1. 4.  
D ur ati o n of t he St u d y 
T his st u d y will last a p pr o xi matel y 3 8 m o nt hs fr o m First S u bject First Visit t o Last 
S u bject Last F oll o w- u p.  
3. 1. 5.  
D ur ati o n of S u bje ct P a rtici p ati o n 
S u bjec ts are t o c o nti n ue t hera p y wit h st u d y dr u g u ntil deat h, ra di o gra p hic disease 
pr o gressi o n (c o nfir me d b y re peat C T/ M R I sca n 4 wee ks after ra di o gra p hic pr o gressi o n 
first s us pecte d.  Refer t o secti o n 4. 2. 1  f or details.), or a n ot her disc o nti n uati o n criteri o n is 
met. It is e x pecte d t hat m ost s u bjects will rec ei ve bet wee n at least 1 a n d 5 m o nt hs ( 4 t o 
2 0 wee ks) of treat me nt.  
O nce a s u bjec t disc o nti n ues fr o m t he st u d y, t he y an d/ or t heir fa mil y will be c o ntact e d f or 
l o n g ter m s ur vi val f oll o w u p e ver y 3 m o nt hs u ntil deat h, l ost t o f oll o w u p, or wit h dra wal 
of c o nse nt f or l o n g ter m f oll o w u p. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 6 of 1 1 3 
3. 1. 6.  
St o p pi n g R ules 
St o p pi n g r ules f or i n di vi d ual s u bjects are s p ecifie d i n Secti o n 4. 2 . G ui deli nes f or efficac y 
base d o n st o p pi n g b o u n d aries, wit h w hic h t he Dat a  M o nit ori n g C o m mittee ( D M C) will 
be ma ki n g t h eir rec o m me n dati o n per t he D M C c ha rter ta ki n g safet y i nt o o verall 
c o nsi derati o ns, are s pecifie d i n Secti o n 1 1. 8 .  I n a d diti o n, t he st u d y ma y b e ter mi nate d at 
a n y ti me at t he S p o ns or’s discreti o n.  
3. 2.  
Selecti o n of D oses 
3. 2. 1.  
E x peri me n t al Tre at me nts 
3. 2. 1. 1. 
Ti v a nti ni b Tre at me nt 
T he ti va nti ni b d osa ge of 2 4 0 m g a d mi nistere d b y m o ut h ( P O) o nce i n t he m or ni n g a n d 
o nce i n t he e v e ni n g, wit h f o o d f or a t otal  dail y d os e of 4 8 0 m g, was sel ecte d o n t he basis 
of effic ac y a n d t olera bilit y esta blis he d i n P hase 1 a n d P hase 2 st u dies.   I n A u g ust 2 0 1 3, 
f oll o wi n g a hi g her t ha n e x pecte d i nci de nce of neutr o pe nia-relate d t o xicities, t he st u d y 
D M C e val uate d all a v aila ble data i ncl u di n g preli mi nar y p h ar mac o ki netics. Base d o n t his 
re vie w, t he D M C rec o m me n de d t he starti n g d ose of 1 2 0 m g BI D (f or a t otal dail y d ose of 
2 4 0 m g).  
3. 2. 1. 2. 
C o ntr ol Tre at me nt 
T he c o ntr ol ar m will r ecei ve matc hi n g pl ace b o ta blets, o nce i n t he m or ni n g a n d o nce i n 
t he e ve ni n g, wit h f o o d, c o nti n u o usl y. 
If t he st u d y is p ositi ve at t he i nteri m or fi nal a nal ysis, all eli gi ble patie nts w h o ha ve bee n 
ra n d o mize d t o place b o will be all o we d t o recei ve ti va nti ni b after data base l oc k a n d 
u n bli n di n g.  N o place b o will be dis pe nse d b y t h e I X R S s yste m f or a s u bject o nce t hat 
s u bject recei ves acti ve tr eat me nt. 
3. 2. 1. 3. 
Misse d or V o mite d D os es 
A m isse d or v o mite d d ose s h o ul d n ot be re place d. T he patie nt s h o ul d be i nstr ucte d t o ta ke 
t he ne xt sc he d ule d d ose at t he re g ularl y sch e d ule d ti me. 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 7 of 1 1 3 
3. 2. 1. 4. 
D ose M o dific ati o ns 
W he n a dr u g  relat e d t o xicit y is o bser ve d, d ose del a ys a n d/ or re d u cti o ns i n 
ti va nti ni b/ place b o a d mi nistrati o n are all o we d as d escri be d b el o w.  I n t he e ve nt of a d ose 
re d ucti o n, t he d ose c ha n ge(s) m ust be ca pt ure d i n t he electr o ni c data ca pt ur e ( E D C) 
s yste m. If q uesti o ns or c o nsi derati o ns re gar di n g d ose m o dificati o n arise or a s pecific d os e 
m o dificati o n is nee de d, t he S p o ns or’s Me dical M o nit or or desi g n ee s h o ul d be c o ns ulte d. 
In ge neral, o nce t h e d ose of ti va nti ni b/ place b o has bee n re d u ce d f or a s u bject, all 
s u bse q ue nt c ycles s h o ul d be a d mi nistere d t o t hat s u bject at t he m o difie d d ose u nless 
f urt her re d ucti o n is re q uire d. T he re d uce d d ose will be c o nsi dere d t he m a xi m u m d ose f or 
all s u bse q ue nt c ycles f or t hat s u bject ( d ose re-es calati o n is n ot per mitte d).  
D ose a d mi nistrati o n ma y be dela ye d t o all o w f or rec o ver y fr o m t o xicit y  
D ose re d u cti o ns are t o be ma de i n t he f oll o wi n g or der acc or di n g t o t he f oll o wi n g d ose 
le vels:  
 1 2 0 m g  o nce a da y ( Q D), i n t he m or ni n g or i n t he e ve ni n g  
 1 2 0 m g  e v er y ot her d a y ( Q O D) i n t he m or ni n g or i n t he e ve ni n g 
 1 2 0 m g o nce e ver y t hree da ys i n t he m or ni n g or i n t he e ve ni n g (ie: o ne d a y of 
d osi n g f oll o we d b y t w o d a ys off) 
If a s u bject is d osi n g at t he l o west le vel (i.e., 1 2 0 m g o nce e ver y t hree da ys) a n d has a 
rele va nt a d v erse e ve nt (s ee ta bles bel o w), t his w o ul d res ult i n t he s u bject ta ki n g p a uses i n 
dr u g a d mi nistrati o n or bei n g disc o nti n ue d fr o m t h e st u d y at t he dis creti o n of t he 
I n v esti gat or a n d after dis c ussi o n wit h t he Me dical M o nit or of t he st u d y. 
F urt her i nstr ucti o ns f or m o dif yi n g t he ti va nti ni b/ place b o d ose d u e t o n o n- he mat ol o gical 
or he mat ol o gi cal t o xicities are liste d i n t he f oll o wi n g ta bles. 
T a ble 3. 1 D ose Del a ys/ Re d ucti o ns f or Dr u g- Rel ate d N o n- He m at ol o gi c al T o xicit y 
E ve nt Gr a de  
Acti o n  
Gr a de 1 or 2  
C o nti n ue c urre nt d ose le vel  
Gr a de 3  
 
Wit h h ol d ti va nti ni b / place b o u ntil rec o ver y t o Gra de 1 or baseli ne.  A d mi nister 
ti va nti ni b / place b o at t he ne xt l o wer d ose f or s u bse q ue nt d osi n g, u nless f urt her d ose 
re d ucti o n is re q uire d.  
Gr a de 4  
 
Wit h h ol d ti va nti ni b / place b o u ntil rec o ver y t o Gra de 1 or baseli ne.  C o ns ult wit h t he 
Me dical M o nit or or desi g nee pri or t o restarti n g ti va nti ni b / place b o.  If t he I n vesti gat or 
a n d Me dical M o nit or c o nc ur, a d mi nister ti va nti ni b / place b o at t he ne xt l o wer d ose f or 
s u bse q ue nt d osi n g, u nless f urt her d ose re d ucti o n is re q uire d.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 8 of 1 1 3 
 
T a ble 3. 2 D ose Del a ys/ Re d ucti o ns f or Dr u g- Rel ate d He m at ol o gic al T o xicit y 
E ve nt/se verit y  
Acti o n  
Ne utr o pe ni a (abs ol ute 
ne utr o p hil c o u nt ( A N C ) 
<  L o wer li mit of  n or mal 
(L L N ) t o ≥ 1. 5 × 1 0 9/ L) 
 
T hr o m b oc yt o pe ni a 
( Platelets <  L L N t o 
≥ 6 0 × 1 0 9/ L) 
 
A ne mi a  
(h e m o gl o bi n (H g b ) <  
L L N t o ≥ 9  g/ d L ) 
C o nti n ue c urre nt d ose le vel  
Ne utr o pe ni a  A N C 
<  1. 5  t o ≥ 1. 0 × 1 0 9/ L) 
 
T hr o m b oc yt o pe ni a 
(Platelets  <  6 0  t o 
≥ 5 0  × 1 0 9/ L) 
 
A ne mi a  
( H g b <  9  a n d ≥ 8  g/ d L ) 
Wit h h ol d ti va nti ni b/ place b o a n d m o nit or he mat ol o g y a n d/ or c he mistr y wee kl y 
(e ver y 2 da ys i n case of A N C  < 1. 5 × 1 0 9/ L)  u ntil rele va nt la b val ue(s) rec o ver 
t o t he val ues o utli ne d bel o w: 
 I n case of ne utr o pe nia, res u me treat me nt at t he ne xt l o wer  d ose o nce A N C 
val ues rec o ver t o ≥ 1. 5 × 1 0 9/ L a n d test he mat ol o g y t wice wee kl y f or t he 
re mai n der of t he c ycle.   
 I n case of t hr o m b oc yt o pe nia/a ne mia:   
o  If t he rele va nt la b val ue rec o vers wit hi n 7 da ys t o ≥ 9  g/ d L  f or 
he m o gl o bi n, or ≥ 6 0 × 1 0 9/ L f or platelet, res u me ti va nti ni b/place b o 
treat me nt at t he sa me d ose le vel.   
o  If t he rele va nt la b val ue ta kes m ore t ha n 7 da ys  t o rec o ver t o t he le vel 
descri be d a b o ve, restart ti va nti ni b/ place b o a d mi nistrati o n at t he ne xt 
l o wer d ose. 
o  If a sec o n d h ol d is re q uired f or t he sa me e ve nt, a d mi nister 
ti va nti ni b/ place b o at t he ne xt l o wer d ose. 
 
Ne utr o pe ni a  
( A N C <  1. 0 t o 
≥ 0. 5 × 1 0 9/ L)  
 
T hr o m b oc yt o pe ni a  
( Platelets <  5 0 × 1 0 9/ L) 
 
A ne mi a  
( H g b < 8 g/ d L ) 
Wit h h ol d ti va nti ni b/ place b o a n d m o nit or he mat ol o g y a n d/ or c he mistr y wee kl y  
(e ver y 2 da ys i n case of A N C < 1. 0 × 1 0 9/ L) u ntil t he rele va nt la b val ue(s) 
rec o ver t o t he val ues o utli ne d bel o w.  I n case of ne utr o pe nia, co nti n ue t o test 
he mat ol o g y t wice wee kl y f or t he re mai n der of t he c urre nt c ycle a n d t he 
f oll o wi n g ( 1) c ycle.  
If t he rele va nt la b val ue rec o vers t o: ≥ 1. 5 × 1 0 9/ L f or A N C, 9 g/ d L  f or 
he m o gl o bi n, or ≥ 6 0 × 1 0 9/ L f or platelet s, res u me treat me nt at t he ne xt l o wer 
d ose o nce la b val ues all o w d oi n g  s o, u nless f urt her d ose re d ucti o n is re q uire d.  
Treat me nt wit h gr o wt h fact ors is rec o m me n de d f or Gra de 3 ne utr o pe nia 
persisti n g f or > 7 da ys . 
Ne utr o pe ni a  
( A N C <  0. 5 × 1 0 9/ L)  
 
Or  
 
Fe brile Ne utr o pe ni a  
 
Wit h h ol d ti va nti ni b/ place b o a n d m o nit or he mat ol o g y a n d/ or c he mistr y e ver y 2 
da ys  u ntil rele va nt la b val ue(s) rec o ver.   C o nti n ue t o test he mat ol o g y t wice 
wee kl y f or  t he re mai n der of t he c urre nt c ycle a n d t he f oll o wi n g ( 1) c ycle.   
A d mi nister a nti bi otics a n d gr o wt h fact ors e ve n if s u bject is afe brile a n d 
as y m pt o matic.  
If t he rele va nt la b val u e rec o vers t o ≥ 1. 5 × 1 0 9/ L f or A N C, res u me treat me nt at 
ne xt l o wer d ose o nce la b val ues all o w d oi n g  s o, u nless f urt her d ose re d ucti o n is 
re q uire d.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 3 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 3 9 of 1 1 3 
4.  
S T U D Y P O P U L A TI O N 
4. 1.  
E nr oll me nt 
I n v esti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects ( p ossi bl y i nitials, a ge, s e x) a n d t he date 
a n d o utc o me of scree ni n g pr ocess (i.e., e nr oll me nt i n t he st u d y, reas o n f or i neli gi bilit y, 
ref use d t o partici pate). 
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n 
t he st u d y i n dicati n g t heir assi g ne d st u d y n u m ber. 
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his 
c o nfi de ntial list of na mes of all s u bjects all ocate d t o st u d y n u m bers o n e nr olli n g i n t he 
st u d y, all o ws t he I n v esti gat or t o re veal t he i de ntit y of a n y s u bject w h e n necessar y. 
A s u bject is c o nsi dere d e nr olle d at t he ti me of ra n d o mizati o n. All s u bjects m ust 
pers o nall y si g n a n d date ( u nless i nca pa ble of d oi n g s o; see Secti o n 1. 5. 2 ) t he I nf or me d 
C o nse nt F or m pr o vi de d b y t he site bef or e pre-s cree ni n g or scree ni n g pr oce d ures are 
perf or me d. F or a d diti o nal i nf or mati o n o n I nf or me d C o nse nt, see Secti o n 1. 5. 2 . 
A n i nteri m a nal ysis is pla n ne d w he n a p pr o xi ma tel y 1 5 4 ( ~ 6 0 %) of t h e 2 5 7 O S e ve nts are 
d oc u me nte d. T he st u d y ma y b e ter mi nate d f or s u peri orit y at t he i nteri m a n al ysis i n 
acc or d a nce wit h t he statistical a nal ysis pla n.  If t h e st u d y is p ositi ve at t he pres pecifi e d 
i nteri m or fi nal a nal ysis, t he s p o ns or will all o w patie nts w h o are recei vi n g place b o 
treat me nt t o recei ve acti ve ti va nti ni b treat me nt aft er data base l oc k. T h e st u d y will be 
u n bli n de d after data base l oc k.  Patie nts o n t he pla ce b o ar m b ei n g c o nsi dere d f or 
cr oss o ver m ust meet t he safet y eli gi bilit y criteria:  I n cl usi o n # 6, 8, 1 0, 1 1, 1 2, a n d 
E x cl usi o n # 2, 4, 5, 6, 7, 8, 9, 1 0, 1 1, 1 2, 1 3, a n d 1 4.    
4. 1. 1. 
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteri a t o be i ncl u de d i n t he st u d y: 
1.  W ritte n i nf or me d c o nse nt gra nt e d pri or t o i nitiati o n of a n y st u d y-s pecific 
scree ni n g pr oce d ures 
2.  1 8 years of a ge or ol d er 
3.  Hist ol o gicall y c o nfir m e d H C C t hat is i n o pera ble ( w here s ur ger y is n ot i n dicate d 
d ue t o disease e xte nsi o n, c o- m or bi dities, or ot her t e c h nical r eas o ns), a n d n ot 
eli gi ble f or l ocal t hera p y 
4.  M E T Dia g n ostic- Hi g h tiss ue re p orte d b y t h e ce ntral a ut h orize d la b orat or y usi n g 
arc hi val or rece nt bi o ps y t u m or sa m ples; (see t he l a b ma n ual a n d Secti o n 6. 1  of 
t he pr ot oc ol f or tiss ue pre parati o n det ails)  
5.  R ecei ve d at least 4 wee ks of o ne pri or s orafe ni b c o ntai ni n g s yste mic t hera p y a n d 
t he n e x perie nce d d o c u me nte d ra di o gra p hic disease pr o gressi o n; or i na bilit y t o 
t olerate pri or t hera p y recei ve d for at least a mi ni m u m peri o d of ti me.  F or t he 
p ur p ose of t his st u d y, i nt olera n ce t o s orafe ni b is deter mi ne d as f oll o ws: 
 T he  s u bject m ust ha ve tri e d t o ta ke s orafe ni b f or a peri o d of at least 
2 8 da ys (e ve n i nter mitte ntl y)  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 0 of 1 1 3 
 T he  s u bject m ust ha ve tri e d t o d ose re d u ce s orafe ni b at ≤5 0 % of t he f ull 
d ose f or a p eri o d of at least 1 4 da y s (e ve n i nter mitt e ntl y) a n d still ha ve a 
d oc u me nte d Gra de ≥ 2 t o xicit y 
 A pe ri o d of e v e n less t ha n 1 4 da ys o n s orafe ni b is acce pta ble i n cas e of: 
i. U nc o ntr olle d Gra de 3- 4 arterial h y p erte nsi o n 
ii. Pa ncreatitis, car diac e ve n t, e nce p hal o p at h y relate d t o s orafe ni b 
iii. ≥ Gra de 2 H a n d-f o ot s y n dr o me tri g gere d e ve n at 5 0 % of t he 
s orafe ni b d ose 
6.  Disc o nti n ue d pri or s yste mic treat me nt or a n y i n v esti gati o nal dr u g f or at least 
2 wee ks ( 1 4 d a ys) or f or at least 3 wee ks f or I V a n ti-ca ncer dr u gs, pri or t o t he 
st u dy ra n d o mizati o n  
7.  Ea ster n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us ( P S) ≤ 1 (see 
A p pe n di x 1 7. 2 ) 
8.  L ocal or l oc o-re gi o nal t h era p y (i. e., s ur ger y, ra diati o n t hera p y, h e patic arterial 
e m b oliz ati o n, c he m oe m b olizati o n, ra di ofre q ue nc y a blati o n, perc uta ne o us et ha n ol 
i njecti o n, or cr y oa bl ati o n) m ust ha ve bee n c o m plete d ≥ 4 wee ks pri or t o 
ran d o mizati o n   
9.  Mea s ura ble dis ease as defi ne d b y t h e Res p o nse E v al uati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v ersi o n 1. 1. T u m or lesi o ns pre vi o usl y treat e d wit h l ocal 
t hera p y s h o ul d de m o nstr ate clear di me nsi o nal i ncrease b y ra di o gra p hic 
assess me nt i n or der t o be selecte d as t ar get lesi o n(s) at baseli ne.  Baseli ne 
ra di o gra p hic assess me nt nee ds t o be d o ne wit hi n 2 1 da ys pri or t o ra n d o mi zati o n.  
1 0.  A de q uate b o n e marr o w, li ver, a n d re nal f u ncti o ns at Scree ni n g Visit, defi ne d as: 
platelet c o u nt ≥ 6 0 × 1 0 9/ L; he m o gl o bi n ≥ 9. 0 g/ d L; a bs ol ute n e utr o p hil c o u nt 
( AN C) ≥ 1. 5 × 1 0 9/L; t ot al bilir u bi n ≤ 2 m g/ d L; Ala ni ne tra nsa mi nase ( A L T) a n d 
as partate a mi n otra nsferas e ( A S T) ≤ 5 × u p p er li mit of n or mal ( U L N); ser u m 
creati ni ne ≤ 1. 5 × U L N; al b u mi n ≥ 2. 8 g/ d L; i nter nati o nal n or malize d rati o (I N R) 
0. 8 t o U L N or ≤ 3 f or s u bjects recei vi n g a ntic oa g ula nt s uc h as c o u ma di n or 
he pari n. S u bjects w h o are t hera p e uticall y a ntic oa g ulate d are all o we d t o partici pate 
pr o vi de d t hat pri or t o a ntic oa g ula nt t hera p y n o e vi de nce of u n d erl yi n g defect i n 
c oa g ulati o n e xists  
1 1.  W o me n  of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g na n c y test 
perf or me d wit hi n 1 4 da ys pri or t o t he ra n d o mi zati o n ( w here de ma n de d b y l ocal 
re g ulati o ns, test ma y b e re q uire d wit hi n 7 2 h o urs pri or t o ra n d o mizati o n) 
1 2.  Male  a n d fe male s u bjects of c hil d- beari n g p ot e ntial m ust a gree t o use d o u bl e-
barrier c o ntrace pti ve me as ures, oral c o ntrace pti o n, or a v oi da nce of i nterc o urse 
d uri n g t he st u d y a n d f or 9 0 da ys after l ast i n vesti gati o nal dr u g d os e recei ve d 
1 3.  L if e e x pecta nc y of at least 1 2 wee ks 
4. 1. 2.  
E xcl usi o n Criteri a 
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be dis q ualifie d fr o m e nteri n g t he 
st u d y: 
1.  > 1 pri or s yste mic re gi me n ( pri or M E T i n hi bit ors/a nti b o dies are n ot all o we d ; 
ex peri me ntal s yste mic t h era p y  f or i n o pera ble H C C gi ve n bef ore or after s orafe ni b 
c o u nts as se parate re gi me n a n d is n ot all o we d) 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 1 of 1 1 3 
2.  C hil d- P u g h B- C cirr h otic stat us base d o n cli nical fi n di n gs a n d la b orat or y res ults 
d uri n g scree ni n g p eri o d (see A p pe n di x 1 7. 4  f or C hil d- P u g h Classificati o n a n d 
i nter pretati o n of as cites at p h ysical e xa mi nati o n a n d P T/I N R) 
3.  P re vi o us or c o nc urre nt c a ncer t h at is disti nct fr o m H C C i n pri mar y site or 
hist ol o g y, E X C E P T cer vical carci n o ma i n sit u, treate d basal cell carci n o ma, a n d 
s u perficial bla d d er t u m ors ( Ta, Tis, a n d T 1). A n y ca ncer c urati vel y treate d 
> 3 years pri or t o e nr oll me nt is per mitte d. 
4.  Hist or y of c o n gesti ve heart fail ure d efi ne d as Class II t o I V per Ne w Y or k Heart 
Ass ociati o n ( N Y H A) classificati o n (see A p p e n di x 1 7. 5 ) wit hi n 6 m o nt hs pri or t o 
st u d y e ntr y; a cti ve c or o n ary art er y diseas e ( C A D); cli nicall y si g nifica nt 
bra d ycar dia or ot her u nc o ntr olle d, car diac arr h yt h mia defi ne d as ≥ Gra de 3 
acc or di n g t o N ati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteri a f or 
A d verse E v e nts ( C T C A E), versi o n 4. 0 3, or u nc o ntr olle d h y p erte nsi o n; 
m y ocar dial i nfarcti o n occ urri n g  wit hi n 6 m o nt hs pri or t o st u d y e ntr y ( m y o car dial 
i nfarcti o n occ urri n g > 6 m o nt hs pri or t o st u d y e ntr y is per mitte d) 
5.  Ac ti ve cli nicall y seri o us i nfecti o ns defi ne d as ≥ Gra de 3 acc or di n g t o N CI 
C T C A E, versi o n 4. 0 3 
6.  A n y me di cal, ps yc h ol o gi cal, or s ocial c o n diti o ns, partic ularl y if u nsta ble, 
i ncl u di n g s u bsta nce a b us e, t hat ma y, i n t he o pi nio n of t he I n vesti gat or, i nterfere 
wit h t he s u bject’s safet y or partici pati o n i n t he st u d y, pr ot o c ol c o m plia nce, or 
e val uati o n of t he st u d y res ults 
7.  K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n 
8.  B l o o d or al b u mi n tra nsf usi o n wit hi n 5 da ys pri or t o t he bl o o d dra w bei n g use d t o 
co nfir m eli gi bilit y 
9.  C o nc o mita nt i nterfer o n t hera p y or t h era pies f or acti ve H C V i nfecti o n 
1 0.  P re g n a nc y or breast-fee di n g 
1 1.  Hist or y of li ver tra ns pla nt 
1 2.  In a bilit y t o s wall o w oral me dicati o ns 
1 3.  Cli nicall y si g nifica nt gastr oi ntesti nal blee di n g occ urri n g ≤ 4 wee ks pri or t o 
ran d o mizati o n  
1 4.  Ple ural eff usi o n or cli nicall y e vi d e nt ( visi ble or pal pa ble) ascites  
4. 2.  
Re m o v al of S u bjects Fr o m T her a p y 
4. 2. 1.  
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n 
S u bjects ma y be dis c o nti n ue d pri or t o ra n d o mizati o n b ut after si g ni n g i nf or me d c o nse nt 
i n case of: 
 S cree n Fail ure 
 A d verse E v e nt 
 Wit h dra wal b y S u bject 
 P h ysicia n D ecisi o n 
 L ost t o f oll o w u p 
S u bjects ma y be dis c o nti n ue d fr o m treat me nt after ra n d o mizati o n, d uri n g t he treat me nt 
p hase of t he trial, i n c ases of: 
 De at h 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 2 of 1 1 3 
 P r o gressi ve Diseas e if c o nfir me d b y re p eat C T/ M RI sca n 4 wee ks aft er 
ra di o gra p hic pr o gressi o n first s us pecte d(see g ui deli nes i n Ta ble 4. 1) 
 N o nc o m plia nce wit h a n y part of t he st u d y, as e val uate d b y t he I n vesti gat or a n d 
S p o ns or’s Me dical M o nit or or desi g nee 
 Cli nicall y u n acce pt a ble t o xicities 
 W it h dra wal of c o nse nt t o treat me nt 
 L ost t o F oll o w- u p 
 P h ysicia n D ecisi o n 
 S t u d y Ter mi nate d b y S p o ns or 
A n y s u bject w h o disc o nti n ues fr o m t he st u d y treat me nt f or a n y reas o n will ha ve t heir 
st u d y treat me nt disc o nti n uati o n rec or d e d. Disc o nti n ue d s u bjects will still be f oll o we d f or 
s ur vi val eit her t hr o u g h direct c o ntacts or c ollecti o n of p u blic rec or ds (i.e., a deat h 
certificate) i n a cc or d a nce t o l ocal la ws. 
U n bli n di n g f or ra di o gra p hic pr o gressi o n will n ot be all o we d.  U n bli n di n g will o nl y b e 
per mitte d f or me dical e m er ge nc i es w here k n o wi n g t he treat me nt ar m will affect h o w t he 
p h ysicia n w o ul d treat t he s u bject. A n y s u bject w h ose treat me nt has b ee n u n bli n de d 
bef ore d ata bas e l oc k m ust be disc o nti n ue d i m me diatel y fr o m t he treat me nt. S u bjects 
disc o nti n ue d fr o m t he st u d y beca use of c o ns e nt wit h dra wal will be f oll o we d f or s ur vi val 
t hr o u g h c ollecti o n of p u blic recor ds (i.e., a d eat h certificate) u nless pr o hi bite d b y l o cal 
la ws. 
T a ble 4. 1 P ossi ble Sce n ari os a n d Acti o ns at R a di o gr a p hic Pr o gressi o n  
Sce n ari o : 
A cti o n:  
Ra di o gra p hic s us pici o n of  t u m or 
pr o gressi o n   
Perf or m c o nfir mat or y C T/ M RI sca n 4 
wee ks after ra di o gra p hic pr o gressi o n first 
s us pecte d.  ( A n y n e w lesi o ns < 1 0 m m t o 
be c o nfir me d b y  o bs er vati o n of c o nti n ue d  
gr o wt h or de vel o p me nt of a t y pi cal H C C 
patter n).     F or t he p ur p os e of t u m or 
assess me nt, ascites a n d/ or ple ural eff usi o n 
s h o ul d n ot be re gistered as disease 
pr o gressi o n  u nless t heir mali g na nt ori gi n 
is pr o ve n b y p at h ol o g y.   
 
Ra d i o gra p hic re-assess m e nt c o nfir ms 
t u m or pr o gressi o n 
 
St o p t he e x peri me ntal t hera p y  
Ra di o gra p hic re -assess m e nt d oes N O T 
c o nfir m t u m or pr o gressi o n  
 
C o nti n ue t he e x peri me ntal t hera p y  u ntil 
ne w ra di o gra p hic s us pici o n of t u m or 
pr o gressi o n (re peat as a b o ve)  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 3 of 1 1 3 
If a s u bject wit h dra ws fr o m t he st u d y treat me nt, t he I n vesti gat or will c o m plete a n d re p ort 
t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of wit h dr a wal i ncl u di n g t he dat e 
of last treat me nt a n d t he reas o n f or wit h dra wal. S u bjects w h o disc o nti n ue fr om t he st u d y 
f or reas o ns ot her t ha n d eat h will still be f oll o we d f or s ur vi val, eit her t hr o u g h visits/ p h o ne 
calls or t hr o u g h c ollecti o n of p u blic rec or ds (i.e., deat h certificate) i n acc or da nce wit h 
l ocal la ws. 
If t he s u bject is disc o nti n ue d d ue t o a n a d verse e v e nt, t he I n vesti gat or will f oll o w t he 
s u bject u ntil t he a d verse e ve nt has res ol ve d or sta bilize d. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol s p ecifie d 
wit h dra wal pr o ce d ures (s ee Secti o n 4. 2. 2 ). 
4. 2. 2.  
Wit h dr a w al/ Disc o nti n u ati o n Pr o ce d ures 
If a s u bject wit h dra ws fr o m st u d y treat me nt, t he d ate a n d reas o n f or wit h dra wal will be 
rec or d e d o n t he el ectr o ni c Case Re p ort F or m (e C R F).  T he I n v esti gat or will c o m plete a n d 
re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra wal, i ncl u di n g 
t he date of last treat me nt.  All pr oce d ures a n d t u m or assess me nt s pecifie d f or t he E n d of 
Treat me nt visit ( Secti o n  6. 6) will be c o n d ucte d.  See S ecti o n 6  f or s pecific f oll o w- u p 
pr oce d ures de pe n di n g o n t he reas o n f o r wit h dra wal fr o m treat me nt.   
If t he s u bject is disc o nti n ue d fr o m st u d y treat me nt d ue t o a n A E, t he I n v esti gat or will 
f oll o w t he s u bject u ntil t he A E has res ol ve d or sta bilized. 
S u bjects w h o disc o nti n ue fr o m st u d y tr eat me nt f or reas o ns ot her t h a n deat h will be 
f oll o we d f or s ur vi v al after t he E n d of Treat me nt visit u ntil deat h or st u d y cl os ure (i.e., 
w he n t he pre-s pecifie d n u m ber of e v e nts ha ve occ urre d), eit her t hr o u g h visits/ p h o ne calls 
or t hr o u g h c ollecti o n of p u blic rec or ds (i.e., a d eat h certificate) u nless t he y s pecificall y 
wit h dra w c o nse nt f or s ur vi val f oll o w u p.  S ur vi val ma y still  be assesse d t hr o u g h 
c ollecti o n of p u blic rec or ds, i n a cc or d a nce wit h l ocal la ws. 
4. 2. 3.  
S u bject Re-scree ni n g Pr oce d ures 
S u bjects ca n be re-scree n e d if t he y were dee me d a scree n fail ure f or tec h nical reas o ns 
(i.e., t u m or sa m ples were i na de q uate t o det er mi ne M E T  stat us, or ME T  stat us was 
dee me d t o be L o w a n d a bi o ps y  nee ds t o be re- d o ne, or perf or mi n g scree ni n g pr oce d ures 
t o o k lo n ger t ha n t h e all o we d wi n d o w) or d u e t o i na de q uate l a b val ues t hat rec o vere d 
wit h o ut me dical i nter ve nti o n. H o we ver, scree ni n g pr oce d ures m ust be restarte d wit hi n 
2 8 da ys fr o m t he scree n fail ure ( or t he c o m m u nicati o n of t he res ults t o t he site, i n case of 
scree n fail ures relate d t o t he tiss ue sa m ple). S uc h ti me wi n d o w d oes n ot a p pl y t o s u bjects 
scree n faile d beca us e M E T stat us e val uati o n was n ot p ossi ble.  If t he ori gi nall y s u b mitte d 
sa m ple is dee me d t o be M E T- L o w, t u m or sa m ples fr o m a ne w bi o ps y (if safe f or t he 
s u bject) ca n b e s u b mitte d f or M E T e val u ati o n wit hi n 2 8 da ys fr o m t he c o m m u nicati o n of 
t he res ults t o t he site; if t he tiss ue fr o m t he ne w bi o ps y is f o u n d t o be M E T- Hi g h a n d t he 
s u bject has pr o gresse d or is i nt olera nt t o s orafe ni b, t he s u bject m ust start scree ni n g 
pr oce d ures (e. g. l a bs, vital si g ns, etc.) as s o o n as p ossi ble b ut n o later t ha n 1 4 da ys fr o m 
t he c o m m u nicati o n of t he M E T- Hi g h res ult t o t he site. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 4 of 1 1 3 
T he Pri nci pal I n vesti gat or wil l c o ns ult wit h t he S p o ns ors or t he C R O bef ore ma ki n g t h e 
re-scree n d ecisi o n.   
Re -screene d s u bjects will kee p t he sa me i d e ntificati o n n u m ber t he y were assi g ne d at first 
scree ni n g. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 5 of 1 1 3 
5.  
T R E A T M E N T S A D MI NI S T E R E D 
5. 1.  
I n vesti g ati o n al Pr o d ucts 
T he I n vesti gat or m ust e ns ure t hat t he i n vesti gati o nal pr o d uct will be use d o nl y i n 
acc or d a nce wit h t he pr ot oc ol. 
Ti va nti ni b is a n i n vesti gati o nal oral dr u g s u p plie d as 1 2 0 m g re d- ora n ge, fil m-c oate d 
ta blets.  Place b o ta blets will be i de ntical i n a p peara nce.  If t he st u d y is p ositi ve at t he 
i nteri m or fi nal a nal ysis, all eligi ble patie nts w h o ha ve bee n ra n d o mize d t o place b o will 
be all o we d t o recei ve ti v a nti ni b after data base l oc k a n d u n bli n di n g.  N o place b o will be 
dis pe nse d b y t h e I X R S s yste m f or a s u bject o n ce t hat s u bject has recei ve d acti ve 
treat me nt.  
5. 1. 1. Met h o d of Assi g ni n g S u bjects t o Tr e at me nts a n d Bli n di n g 
T his st u d y will be d o u ble bli n d: t he s u bject, t he I n vesti gat or, a n d site staff will be bli n de d 
t o t he treat me nt a d mi nistere d. If t he st u d y is p ositi ve at t he i nteri m or fi nal a nal ysis, all 
eli gi ble patie nts w h o h a v e bee n ra n d o mize d t o place b o will be all o we d t o r ecei ve 
ti va nti ni b after data bas e l oc k a n d u n bli n di n g. 
T he ra n d o mizati o n sc he d ule will be ge nerate d b y t he I nteracti ve V oice/ We b Res p o nse 
S yste m (I X R S) f oll o wi n g t he ra n d o miz ati o n s pecificati o ns bef ore t he start of t he st u d y. 
After o btai ni n g i nf or me d c o nse nt a n d c o nfir mi n g eli gi bilit y via t he M e dical M o nit or, t he 
I n v esti gat or will ra n d o mi ze t he s u bject usi n g t he I X R S.  T he I X R S will ra n d o mize t he 
s u bject t o o ne of t he t w o treat me nt ar ms.   
S u bjects will be stratifie d b y: vasc ular i n vasi o n ( prese nt or n ot), e xtra- he p atic s prea d 
i ncl u di n g dista nt metastasis a n d/ or i n v ol ve d re gi onal or dista nt l y m p h n o des ( prese nt or 
n ot, usi n g R E CI S T 1. 1 criteria b ut re gi o nal n o de s are c o nsi d ere d i n v ol ve d if ≥ 2 0 m m i n 
s h ortest dia meter), a n d A F P (less/e q ual or greater t ha n 2 0 0 n g/ m L).   
Eli gi ble s u bjects will be a ssi g ned ra n d o ml y o n a 2: 1 basis t o eit her ti va nti ni b ( 1 2 0 m g 
BI D) or place b o.   
Ti va nti ni b/ place b o will be  dis pe nse d usi n g t he I X R S.  T he s u bject s h o ul d be gi n treat me nt 
as s o o n as p ossi ble after ra n d o mizati o n; prefera bl y o n t he s a me da y. 
E mer ge nc y u n bli n di n g f or safet y reas o ns will ta ke place usi n g t he I X R S.  I n case of 
e mer ge n c y, t he I n v esti gat or m ust ma ke e ver y eff ort t o c o ntact a n d c o ns ult wit h t he 
Me dical M o nit or pri or t o brea ki n g t he bli n d.  If t h e bli n d is br o ke n wit h o ut c o ns ulti n g t he 
Me dical M o nit or, a f ull e x pla nati o n f or t his e ve nt m ust be pr o vi de d wit hi n 2 4 h o urs.  
C o ntact i nf or mati o n is liste d i n Secti o n 1 5. 2  of t he pr ot oc ol. 
5. 1. 2. 
Met h o d of Assessi n g Tre at me nt C o m pli a nce 
All d oses gi ve n d uri n g t h e s u bject’s visit wit h t he I n v esti gat or will be a d mi nistere d u n der 
t he s u per visi o n of cli nical st u d y pers o n nel.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 6 of 1 1 3 
T he s u bjects will be i nstr ucte d t o ret ur n all u n use d st u d y dr u g at t he n e xt visit.  
C o m plia nce t o t he st u d y dr u g re gi me n will be e v al uate d b y c o u nti n g u n us e d ta blets a n d 
ma y i ncl u d e t he use of s u bjects’ diaries: 
% c o m plia nce =  
N u m ber of ta blets dis pe nse d –  N u m ber of ta blets ret ur ne d  
× 1 0 0  
 
N u m ber of ta blets prescri be d per da y a × N u m ber of da ys b i n t he d osi n g i nter val 
 
a: N u m ber of ta blets prescri be d (i.e.  2 , or as deter mi ne d per t he d ose re d ucti o n g ui deli nes f or t o xicit y 
c o nsi dere d relate d t o ti va nti ni b a n d s pecifie d i n t he e C R F) 
b:  N u m ber of da ys d uri n g t hat i nter val t hat t he s u bj ect s h o ul d ha ve d ose d (i.e.,  e xcl u di n g a n y da ys t hat 
t he s u bj ect was i nstr ucte d t o h ol d d osi n g d ue t o a n a d verse e ve nt 
D uri n g t h e treat me nt p eri o d, if c o m plia nce is n ot b et wee n 8 0 % a n d 1 2 0 %, i ncl usi ve, t he 
s u bject will be c o u nsele d a b o ut t he i m p orta nce of a d here n ce t o t he ma n date d r e gi me n.  If 
t he s u bject c o nti n ues t o b e n o n-c o m plia nt i n ter ms of d osi n g, t he s u bject ma y h a ve t o be 
disc o nti n ue d fr o m t he st u d y treat me nt. 
A d mi nistrati o n of I n v esti gati o nal Pr o d uct ( I P) will be rec or de d i n t he Dr u g 
Acc o u nta bilit y L o g a n d e C R F.  S u bjects m ust ret ur n e m pt y b ottles a n d re m ai ni n g ta blets.  
Ret ur ne d ta blets m ust be rec or d e d i n t he Dr u g Acc o u nta bilit y L o g w hic h is s u p plie d t o 
t he site.  S u bjects nee d t o kee p rec or d of t h eir dail y I P d osi n g.  
At eac h visit after st u d y treat m e nt is i nitiate d, t he I n v esti gat or or desi g nee m ust rec or d 
t he date, i nter val b et wee n visits, q ua ntit y a n d stre n gt hs, a n d a n y d ose 
c ha n ges/i nterr u pti o ns of st u d y dr u g dis pe nse d/ a d mi nistere d. 
5. 1. 3.  
L a beli n g a n d P ac k a gi n g 
T he a p peara n ce a n d pac k a gi n g of ti va nti ni b a n d pl ace b o are t he s a me.  Ti va nti ni b a n d 
matc hi n g pla ce b o are s u p plie d as ta blets i n b ottles a n d la bele d i n t he l ocal la n g u a ges as 
i n vesti gati o nal a ge nt, acc or di n g t o r ele va nt g ui deli nes.  T he S p o ns or will pr o vi de 
ti va nti ni b a n d place b o re q uire d f or c o m pleti o n of t his st u d y.  T h e y will be s hi p pe d t o t he 
p har macist/st u d y p ers o n nel  at t he cli nical sites d uri n g t he st u d y t hr o u g h t h e I X R S. 
5. 1. 4.  
Pre p ar ati o n 
T here is n o pre parati o n re q uire d f or ti va nti ni b a n d matc hi n g place b o.   
5. 1. 5.  
St or a ge 
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area.   Ti va nti ni b ta blets 
an d matc hi n g place b o are sta ble w he n st ore d at r o o m te m perat ure. T h e st or a ge 
re q uire me nt a p plica ble t o a s pecific regi o n is reflecte d i n t he la bel.  
If st ora ge c o n diti o ns de viate fr o m t he a b o ve st ora ge re q uir e me nts, t he I n vesti gat or will 
d oc u me nt t he de viati o n a n d i nf or m t he st u d y m o nit or wit hi n 2 4 h o ur s of disc o ver y of t h e 
de viati o n.  T he s u p plies s h o ul d be hel d a n d n ot dis pe nse d u ntil t he de viati o n has bee n 
re vie we d b y t h e S p o ns or's Q uality Ass ura nce or desi g nee.  If it is deter mi ne d t hat t he 
pr o d uct is n o l o n ger s uita ble f or use, t he b ottl es m ust be re p orte d as da ma ge d i n t he 
I X R S.   
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 7 of 1 1 3 
5. 1. 6.  
Dr u g Acc o u nt a bilit y 
W he n a dr u g s hi p me nt is recei v e d, t he I n v esti gat or or desi g nee will c hec k t he a m o u nt 
a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l o cal la n g ua ge i n t he la bel, dr u g 
e x pirati o n date, si g n t he Recei pt of S hi p me nt F or m pr o vi de d, a n d ac k n o wle d ge recei pt of 
t he s hi p me nt i n I X R S.  T he Recei pt of S hi p me nt F or m s h o ul d be ret ur ne d as i nstr ucte d 
o n t he f or m.  T he ori gi nal will be retai ne d at t he  site.  I n a d diti o n, t he I n vesti gat or or 
desi g nee s hall c o ntact t he S p o ns or as s o o n as p ossi ble if t here is a pr o ble m wit h t he 
s hi p me nt. 
A Dr u g Acc o u nta bilit y R e c or d will be pr o vi d e d f or t he I P a n d place b o c o ntr ol 
T he rec or d m ust be ke pt c urre nt a n d s h o ul d c o ntai n t he dates a n d q ua ntities of dr u g 
recei v e d, s u bject’s i de ntificati o n n u m ber (a n d/ or i nitials or s u p pl y n u m b er as a p plica ble) 
f or w h o m t he i n vesti gati o nal pr o d uct was dis pe nse d, t he date a n d q ua ntit y of I P 
dis pe nse d a n d re mai ni n g, if fr o m i n di vi d ual s u bject dr u g u nits, as w ell as t he i nitials of 
t he dis pe nser. 
At t he e n d of t he st u d y , or as direct e d, all st u d y dr u g (ti va nti ni b a n d place b o), i ncl u di n g 
u n use d, partiall y use d, or e m pt y c o ntai ners, will be ret ur ne d t o a desi g nee as i nstr ucte d 
b y t he S p o ns or.  I n vesti gati o nal Pr o d uct will be ret ur ne d o nl y after t he st u d y m o nit or has 
c o m plete d a fi nal i n ve nt or y t o v erif y t h e q ua ntit y t o b e ret ur ne d.  T h e ret ur n of I P m ust 
be d oc u me nte d a n d t h e d oc u me ntati o n i ncl u de d i n t he s hi p me nt. D os a g e f or m (i. e. 
t a bl et) sit e l e v el a c c o u nt a bilit y d o c u m e nt ati o n is t o b e i n cl u d e d wit h e a c h dr u g s u p pl y 
r et ur n s hi p m e nt ( or ot h er r et ur ni n g f a cilit y, s u c h as a n ot h er d e p ot). T his is r e q uir e d as 
p art of t h e r e c ei vi n g r e c or ds f or r et ur n s hi p m e nts.     
U n use d dr u g s u p plies ma y be d estr o ye d b y t h e I n vesti gat or w he n a p pr o ve d i n writi n g b y 
t he S p o ns or a n d t he S p o ns or has recei ve d c o pies of t h e site’s dr u g ha n dli n g a n d 
dis p ositi o n Sta n dar d O perati o n Pr oce d ures ( S O Ps) or e q ui v ale nt. D osa ge f or m (i.e. 
ta blet) site le vel acc o unta bilit y d oc u m e ntati o n is re q uire d as part of t he dis p ositi o n 
rec or ds of I P. T h e d os a ge f or m site le vel acc o u nta bilit y d oc u me ntati o n s h o ul d be 
a p pe n de d t o t he Certificate of Destr ucti o n. 
At t he e n d of t he st u d y, a fi nal I P rec o n ciliati o n state me nt m ust be c o m plet e d b y t h e 
I n v esti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.   
All I P i n ve nt or y f or ms m ust be ma de a vaila bl e f or i ns pecti o n b y a S p o ns or a ut h orize d 
repres e ntati ve or d esi g n ee a n d re g ul at or y a ge nc y i ns pect ors.  T he I n vesti gat or is 
res p o nsi ble f or t he acc o u nta bilit y of all use d a n d u n use d st u d y s u p plies at t he site. 
5. 2.  
C o nc o mit a nt Me dic ati o ns 
Treat me nts per mitte d bef ore a n d d uri n g st u d y treat me nt i ncl u de t he f oll o wi n g: 
 Sta n dar d n o ns ur gical t hera pies f or c o nc urre nt me dical c o n diti o ns 
 Er yt hr o p oiesis sti m ulati n g a ge nts ( E S As): Please f oll o w A merica n S ociet y of 
Cli nical O nc ol o g y ( A S C O) g ui deli nes f or  t he us e of E S As i n s u bjects dia g n ose d 
wit h ca ncer; see dr u g l a b els a n d F D A alerts. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 8 of 1 1 3 
 He mat o p oietic gr o wt h f act ors i ncl u di n g fil grasti m ( Ne u p o ge n
® ), le u ki n e 
( Sar gra m osti m® ), or ot her c ol o n y-sti m ulati n g fact ors as per pr ot oc ol ( See Secti o n 
3. 2 . 1. 4 o n t hera pies i n case of ne utr o pe nia)   
 P r o p h yla ctic a ntie metics ma y b e a d mi nistere d acc or di n g t o sta n dar d practice 
 A p pr o priate treat me nt f or H B V if necessar y (e x ce pt f or i nterfer o n) 
 Me ge str ol acetate ( M e gace ® ) as s u p p orti ve care. Use of t o pical c ortic oster oi ds, 
t o pical a nti bi otics, a n d s yste mic a nti bi otics acc or di n g t o i nstit uti o nal g ui deli nes  
 Tr eat me nt wit h n o n-c o n v e nti o nal t hera pies (i. e., h er bs or ac u p u nct ur e), a n d 
vita mi n/ mi neral s u p ple me nts are acce pta ble, pr o vi de d t hat t he y d o n ot i nterfere 
wit h t he st u d y e n d p oi nts, i n t he o pi ni o n of t he I n v esti gat or 

Bis p h os p h o nates f or b o ne metastases 
 P alliati ve ra di ot hera p y f or n o n- he patic l o cal pai n c o ntr ol pr o vi de d t hat, i n t he 
o pi ni o n of t he I n v esti gat or, t he s u bject d oes n ot meet t he criteri a f or e xiti n g t he 
st u d y (i.e. clear pr o gressi o n of disease)  
 P re ve nti o n of variceal bl ee di n g as per relati ve g ui deli nes 
Pr o hi bite d Treat me nts i ncl u de t he f oll o wi n g: 
 A n y c o nc urre nt a nti-ca ncer t hera p y i ncl u di n g c he m ot hera p y, ra di ot hera p y f or 
tar get lesi o ns, s ur ger y, h or m o nal t hera p y (ex ce pt me gestr ol acetate as s u p p orti ve 
care), or i m m u n ot hera p y 
 Ot he r i n vesti gati o nal a ge nts 
 Im m u n os u p pr essi ve t hera pies i ncl u di n g i nterfer o n a n d s yste mic c ortic oster oi ds 
(e x ce pt u p t o a 2 5 m g/ da y pre d nis o ne-eq ui vale nt d ose or w he n us e d i nter mitte ntl y 
i n a n a ntie metic re gi me n or pre me dicati o n f or i magi n g st u dies)  
 T he ra pies f or acti ve H C V i nfecti o n i ncl u di n g i nt erfer o n, pr otease a n d p ol y m erase 
i n hi bit ors 
 Bl o o d or al b u mi n tra nsf usi o n wit hi n 5 da ys pri or t o t he bl o o d dra w bei n g use d t o 
c o nfir m eli gi bilit y 
Ca uti o n s h o ul d be a p plie d w he n beta- bl o c kers (i.e. ate n ol ol, pr o pra n ol ol, m et o pr ol ol, etc) 
or C Y P 2 C 1 9 i n hi bit ors s uc h as o me praz ole, fl u v o x a mi ne, m ocl o be mi de, fl uc o naz ole, 
ticl o pi di ne, ra be praz ole, a n d fl u o x eti ne or str o n g C Y P 3 A 4 i n hi bit ors s uc h as ata naza vir, 
clarit hr o m yci n, i n di na vir, itrac o naz ole, ket oc o n az ole, nefaz o d o ne, nelfi na vir, rit o na vir, 
sa q ui na vir, ci pr ofl o x aci n, telit hr o m yci n, tr olea n d o m yci n ( T A O), or v oric o n az ole are use d 
as c o nc o mita nt t hera p y. La b orat or y p ara m eters m ust be m o nit ore d as descri be d i n t he 
pr ot oc ol.  Detaile d g ui deli nes o n d ose re d u cti o n a n d/ or i nterr u pti o n are pr o vi de d i n 
Secti o n 3. 2. 1. 4  i n re gar d t o a n y p ote ntial h e mat ol o gic or n o n-he mat ol o gic a d verse 
reacti o n o bser ve d f or a n i n di vi d ual s u bject. A d diti o nal details ma y b e f o u n d i n 
A p pe n di x 1 7. 3 . 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 4 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 4 9 of 1 1 3 
6.  
S T U D Y P R O C E D U R E S 
A st u d y visit sc he d ule i n ta b ular f or mat is pr o vi de d i n A p pe n di x 1 7. 1 .  After writte n 
i nf or me d c o nse nt is o btai ne d, a s u bject’s eligi bilit y f or t he st u d y a n d bas eli ne disease 
stat us will be assesse d. A s u bject m ust si g n t he c o nse nt f or m pri or t o starti n g a n y st u d y 
relate d pr oce d ures or ass ess me nts; b ut the i nf or me d c o nse nt ca n be si g ne d greater t ha n 
1 4 da ys pri or t o d osi n g, a n d d oes n ot ha ve t o be re-si g ne d pri or t o d osi n g u nless s pecific 
reas o ns a p pl y (i. e. a ne w a p pr o ve d co ns e nt versi o n has bee n iss ue d). 
6. 1.  
Pre- Scree ni n g T u m or S a m ple C ollecti o n 
I n or der t o facilitate tra nsiti o n fr o m t he s orafe ni b treat me nt t o t his e x peri me ntal st u d y, t he 
pre-scree ni n g p h ase ca n ta ke place e v e n bef ore or w hile t he s u bject is treate d wit h 
s orafe ni b; ass ess me nt of M E T m ust be perf orme d b y t he ce ntral a ut h orize d la b orat or y, 
a n d t he res ult will be c o m m u nicate d t o t he I n vesti gat or’s staff if/ w h e n t he s u bject 
e x perie nces d oc u m e nte d t u m or pr o gressi o n or i nt olera nce t o s orafe ni b. T he f oll o wi n g 
acti vities a n d/ or assess m e nts will be perf or m e d d uri n g t he pre-s cree ni n g t u m or sa m ple 
c ollecti o n p hase: 
 
Arc hi val or rece nt t u m or sa m ple c ollecti o n ( bi o ps y n ot ol der t ha n t h e ma xi m u m 
ti me s pecifie d i n t he la b ma n ual; Fi ne nee dle as pirate ( F N A) is n ot acce pta ble 
u nless it ca n be pre p are d as per t he la b m a n ual ; f or mali n fi x e d, paraffi n e m b e d de d 
( F F P E) t u m or tiss ue bl oc k is preferre d (s p eci me ns s h o ul d be fi x e d i n 1 0 % ne utral 
b uff ere d f or mali n ( N B F) a n d s h o ul d n ot be st ore d i n fi x a ti ve f or m ore t ha n 
7 2 h o urs bef ore pr ocessi n g i nt o paraffi n bl oc ks.); if F F P E sli des are se nt, t he re 
m ust  be at least 7 (refer t o c urre nt la b m a n ual), pre pare d fr o m F F P E tiss ue, o n 
p ositi vel y c har ge d sl i des; t he ti me bet wee n sli de pre parati o n a n d s u b missi o n f or 
a nal ysis ca n n ot be l o n ger t ha n t he ti mefra me ma n date d b y t he la b ma n ual  
 O bta i n writte n i nf or me d c o nse nt fr o m t he s u bject or t he s u bject’s le gal 
re pres e ntati ve t o a nal yze arc hi val sam ples f or t he p ur p ose of t he st u d y 
 If a t u m or bi o ps y is nee d e d, o btai n writte n i nf or m e d c o nse nt t o perf or m t he 
bi o ps y a n d a nal yze s a m ples f or t he p ur p os e of t he st u d y 
Me dical hist or y (i ncl u di n g Pri mar y Ca n cer Hist or y) 
 R ec or d a n y seri o us a d verse e ve nts ( S A Es) dir ectl y relate d t o a pre-s cree ni n g 
pr oce d ur e (i.e., a t u m or bi o ps y).  D o n o t r ec or d A Es or u nrelate d S A Es u nl ess t his 
is ma n date d b y l o cal la ws.  
 
If t he t u m or tiss ue is f o u n d t o be M E T- Hi g h a n d t he s u bject has pr o gresse d or is 
i nt olera nt t o s orafe ni b, t h e s u bject m ust start scree ni n g pr oce d ures (e. g. la bs, vital si g ns, 
etc.) as s o o n as p ossi ble b ut n o later t ha n 1 4 da ys fr o m t he c o m m u nicati o n of t he M E T-
Hi g h res ult t o t he site.  If t he t u m or ti ss ue is n ot a de q uate f or testi n g or is f o u n d t o be 
M E T L o w pl ease refer t o secti o n 4. 2. 3 . 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 0 of 1 1 3 
6. 2.  
Scree ni n g Visit ( D a ys - 1 4 t o 0)  
T he f oll o wi n g acti vities a n d/ or assess me nts wil l be perf or me d at/ d uri n g Scree ni n g: 
 If n ot alrea d y pr o vi de d, o btai n writte n i nf or me d c o nse nt fr o m t he s u bject or t he 
s u bject’s le gal r e pres e ntati ve (s u bjects m ust si g n t he c o nse nt f or m pri or t o starti n g 
an y st u d y relate d pr oce d ures or ass ess me nts, b ut t he i nf or me d c o ns e nt ca n be 
si g ne d greater t ha n 1 4 da ys pri or t o e nr oll me nt a n d d oes n ot ha ve t o be re-si g ne d 
pri or t o d osi n g u nless s pecific reas o ns a p pl y) 
 Me dic al hist or y (i ncl u di n g Pri mar y Ca n cer Hist or y) 
 P h ysical e x a mi nati o n i ncl u di n g hei g ht 
 E C O G P S  
 Vital si g ns a n d w ei g ht, i ncl u di n g te m perat ur e 
 B l o o d sa m ple f or S urface a nti ge n of t he h e patitis B vir us (H Bs A g), He patitis B 
“e” a nti ge n ( H Be A g), H B V De o x yri b o n ucleic aci d ( D N A ) *, d elta vir us; He patitis 
C a nti b o d y ( H C V A b) 
 He mat ol o g y  
 C oa g ulati o n tests 
 B l o o d c he mistr y  
 B l o o d sa m ple f or A F P testi n g  
 S er u m pre g na n c y test, if a p plica ble * *  
 C hil d- P u g h stat us assess me nt 
 1 2 -lea d ele ctr ocar di o gra ms ( Tri plicate E C Gs a p pr o xi matel y 2 mi n utes a p art) 
 P ri or a n d C o nc o mita nt me dicati o ns (i ncl u di n g Pre vi o us Ca ncer T hera p y) 
 T u m or a ssess me nt b y C T or M RI s ca n (ca n be u p t o - 2 1 da ys bef ore 
ra n d o mizati o n) re p orti n g als o vasc ular i n vasi o n st at us.     
 T u m or sa m ple c ollecti o n ( bi o ps y if n ecess ar y), if n ot d o ne at pre-s cree ni n g. Ca n 
be perf or me d e v e n earlier t ha n 1 4 da ys pri or t o e nr oll me nt * * * 
 R ec or d a n y S A Es directl y relate d t o a s cree ni n g pr oce d ure ( e. g.  a t u m or bi o ps y).  
D o n ot rec or d A Es or S A Es t hat are u nrelate d t o a scree ni n g pr oce d ure u nless t his 
is ma n date d b y l o cal la ws.  
* If acti ve H B V re plicati o n is disc o vere d, t he s u bject m ust be i m me diatel y treate d wit h 
co n ve nti o nal a nti- viral t h era p y ( n ot i ncl u di n g i nterfer o n) as per sta n d ar d of care 
* * 
W here de ma n de d b y l o cal re g ul ati o ns, a pre g n a nc y test ma y be re q uir e d wit hi n 
7 2 h o urs pri or t o ra n d o miz ati o n 
* * * Ar c hi val or rece nt t u m or sa m ple c ollecti o n ( bi o ps y n ot ol der t ha n t he ma xi m u m ti me 
s pecifie d i n t he la b ma n u al; F N A is n ot acce pta ble u nless it ca n be pre p are d as per t he 
la b ma n ual; f or mali n fi x e d, paraffi n e m be d ded ( F F P E) t u m or tiss ue bl oc k is preferre d 
(s peci me ns s h o ul d be fi x e d i n 1 0 % ne utral b uffere d f or mali n ( N B F) a n d s h o ul d n ot 
be st ore d i n fi x ati ve f or m ore t ha n 7 2 h o urs bef ore pr ocessi n g i nt o paraffi n bl oc ks.); 
if F F P E sli des are se nt, t he re m ust be at least 7 (refer t o c urre nt la b ma n ual), pre pare d 
fro m F F P E tiss ue, o n p ositi vel y c har ge d sli des; t he ti me bet wee n sli de pre p arati o n 
an d s u b missi o n f or a nal ysis ca n n ot be l o n ger t ha n t he ti mefra me ma n d ate d b y t he la b 
ma n ual  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 1 of 1 1 3 
6. 3.  
R a n d o miz ati o n 
T he ra n d o mizati o n sc he d ule will be ge nerate d b y a n I X R S per ra n d o mizati o n 
s pecificati o ns bef ore t he start of t he st u d y.  After all scree ni n g pr oce d ures are perf or m e d 
a n d res ults of scree ni n g t ests are a v aila ble (i.e., bet wee n t he scree ni n g visit a n d t he 
C ycle 1, Da y 1 visit), eli gi ble s u bjects will be assi g ne d ra n d o ml y o n a 2: 1 rati o t o t he 
ti va nti ni b or place b o treat me nt gr o u ps. 
R a n d o mizati o n will be perf or me d b y t h e I X R S.  S u bjects will be stratifie d base d o n 
vasc ular i n vasi o n ( prese nt or n ot), e xtra- he patic s prea d i ncl u di n g dista nt metastasis 
a n d/ or i n v ol ve d dista nt or re gi o nal l y m p h n o des ( prese nt or n ot , per R E CI S T 1. 1 criteria, 
b ut re gi o n al n o des are c o nsi dere d i n v ol ve d if ≥ 2 0 m m i n s h ortest dia meter), a n d A F P 
(less/e q ual or greater t ha n 2 0 0 n g/ mL).  
St u d y treat me nt s h o ul d b e i ni tiate d as s o o n as p ossi ble after ra n d o mizati o n, prefera bl y o n 
t he sa me da y, n o later t ha n 2 da ys fr o m ra n d o mizati o n. 
6. 4.  
C ycle 1 D a y 1 Visit 
T he f oll o wi n g acti vit ies a n d/ or assess me nts will be perfor me d at/ d uri n g 
Ra n d o mizati o n/ C ycle 1 Da y 1, a n d, ot her t ha n A Es a n d P K sa m pli n g, will be d o ne pri or 
t o t he first d ose of st u d y dr u g: 
 F u ncti o nal Assess me nt of Ca ncer T hera p y- He pat o biliar y ( F A C T- He p) a n d 
E ur o Q ol- 5 D ( E Q - 5 D) q u esti o n naires ( bef ore m eeti n g wit h t he p h ysicia n or 
ha vi n g a n y ot her ass ess me nt perf or m e d) 
 P h ysical e x a mi nati o n  
 E C O G P S  
 Vital si g ns a n d w ei g ht, i ncl u di n g te m perat ur e 
 He mat ol o g y  
 C oa g ulati o n tests  
 B l o o d c he mistr y  
 If n ot restricte d b y l o cal r e g ul ati o n, c ollect a bl o o d sa m ple f or p har mac o ge n o mic 
( C Y P 2 C 1 9) a nal ysis fr o m all s u bjects.   If per mitte d a n d t he s u bject c o ns e nts, 
s o me of t his sa m ple ma y be ba n ke d f or f ut ur e p har mac o ge n o mic a n al ysis (see 
Secti o n 8. 4. 3 ) 
 B l o o d sa m ple f or H G F t esti n g  
 C hil d- P u g h stat us assess me nt 
 C o nc o mita nt me dicati o ns (a n y me dicati o n t he s u bject t o o k wit hi n 3 0 da ys fr o m 
ra n d o mizati o n) 
 Dis pe nse st u d y dr u g (t o be ta ke n wit h meals) 
 A Es  
 1 2 -lea d ele ctr ocar di o gra ms ( Tri plicate E C Gs a p pr o xi matel y 2 mi n utes a p art) at 
t he sa me ti me as eac h of t he bl o o d dra ws f or p h armac o ki netics ( P K).  E C Gs t o be 
perf or me d ± 3 0 mi n utes fr o m t he ti me of eac h P K c ollecti o n. 
 B l o o d sa m ples f or p h ar m ac o ki netics bet w ee n 1 a n d 3 h o urs p ost first d ose a n d 
bet wee n 4 a n d 8 h o urs p ost first d ose (as descri be d i n A p pe n di x 1 7. 6 ).  D ose a n d 
P K sa m pli n g ti me s h o ul d be rec or de d. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 2 of 1 1 3 
6. 5.  
Tre at me nt Peri o d 
All vi sits are base d o n t h e date of t he first d ose at C ycle 1 Da y 1 re gar dless of dr u g h ol ds.  
If a s u bject visit de viates fr o m t he pr ot ocol per mitte d wi n d o w, t he ne xt visit m ust be d o ne 
at t he c orrect ti me base d o n t he date of C ycle 1 Da y 1. 
6. 5. 1.  
C ycle 1, D a ys 5, 9, 1 3, 1 7, a n d 2 5 ( ±1 d a y) 
 He mat ol o g y 
 A Es  
 C o nc o mita nt Me dicati o ns 
6. 5. 2.  
C ycle 1, D a y 2 1 ( ±1 d a y) 
 He mat ol o g y 
 1 2 -lea d ele ctr ocar di o gra ms ( Tri plicate E C Gs a p pr o xi matel y 2 mi n utes a p art) at 
t he sa me ti me as t he bl o o d dra w f or pre- d ose p harmac o ki netics ( P K).  E C Gs t o be 
perf or me d ± 3 0 mi n utes fr o m t he ti me of t he pre- d ose P K c ollecti o n. 
 B l o o d sa m ples f or p h ar m ac o ki netics bef ore t he m or ni n g d ose a n d at least o ne 
h o ur after t h e m or ni n g d ose (as descri be d i n A p p e n di x 1 7. 6).  T he m or ni n g d ose 
(t o be ta ke n wit h a meal) s h o ul d be a d mi nistere d at t he cli nic.  D ose a n d P K 
sa m pli n g ti me s h o ul d be rec or d e d.  Ti me f or t h e t w o prece di n g d oses m ust als o be 
rec or d e d. 
 Vital si g ns a n d w ei g ht, i ncl u di n g te m perat ur e 
 A Es  
 C o nc o mita nt Me dicati o ns 
 O pt i o nal c ore nee dle t u m or bi o ps y (after Da y 2 2 a n d prefera bl y bef ore Da y 3 0).  
See Secti o n 6. 1  f or det ails o n tiss ue pre parati o n. 
6. 5. 3.  
C ycles 2 +, D a y 1 ( ± 2 d a ys) 
 F u ncti o nal Assess me nt of Ca ncer T hera p y – He p at o biliar y ( F A C T- He p) a n d 
E Q -5 D q uesti o n nair es ( bef ore m eeti n g wit h t he p h ysicia n or ha vi n g a n y ot her 
assess me nt perf or me d) 
 P h ysical e x a mi nati o n  
 E C O G P S   
 Vital si g ns a n d w ei g ht, i ncl u di n g te m perat ur e 
 He mat ol o g y  
 C oa g ulati o n tests  
 Bl o o d c he mistr y 1  
 W here m o nt hl y pre g na nc y testi n g is re q uir e d b y l ocal re g ulati o ns f or s u bjects of 
c hil d beari n g p ote ntial, a pre g na nc y t est will be perf or me d 
 Bl o o d sa m ples f or H G F a n d A F P testi n g (at c ycles 2, 3, a n d 4)  
                                                 
1 If a re mar ka ble s u d de n i ncrease i n A S T/ A L T val ues is f o u n d, a n d s u bj ect is H B V p ositi ve, H B V 
re plicati o n m ust b e assesse d; if acti ve H B V re plicati o n is disc o vere d, s u bj ect m ust be i m me diatel y treate d 
wit h c o n ve nti o nal a nti- viral t hera p y ( n ot i ncl u di n g i nt erfer o n) as per sta n dar d of care 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 3 of 1 1 3 
 B l o o d sa m ple(s) f or p har mac o ki netics as descri be d i n Secti o n 8  a n d 
A p pe n di x 1 7. 6 .  T he m or ni n g d ose s h o ul d be a d mi nistere d at t he cli nic 
(e x peri me ntal dr u g is ta k e n wit h a meal). Dos e a n d P K sa m pli n g ti mes, a n d t he 
ti me w he n t he t w o prece di n g d oses w ere t a ken, m ust be rec or d e d.   
 C hil d- P u g h stat us assess me nt 
 T u m or assess me nt (as p er fre q u e nc y o utli ne d i n secti o n 6. 5. 5) 
 E C G  –  si n gle E C G (at C ycl e 2 O N L Y.  If heart rate d uri n g first c ycle is ≤ 5 0 
beats per mi n ute ( b p m) t he n E C G will als o be  perf or me d o n Da y 1 of e v er y c ycle 
t hereafter) 
 A Es  
 C o nc o mita nt me dicati o ns 
 Dis pe nse Dr u g  
 C ollect ret ur ne d dr u g/ Assess treat me nt c o m plia nce   
6. 5. 4.  
C ycle 2, D a ys 8, 1 5 a n d 2 2 ( ± 2 d a ys) 
 He mat ol o g y: sa m ples ca n be teste d l ocall y (cl ose t o t he s u bject’s h o me) a n d 
res ults nee d t o be re vie we d ra pi dl y b y t he h os pital st u d y tea m  
 A Es 
 C o nc o mita nt me dicati o ns 
6. 5. 5.  
C ycle 3 +, D a y 1 5 ( ± 2 d a ys) 
 He mat ol o g y: sa m ples ca n be teste d l ocall y (cl ose t o t he s u bject’s h o me) a n d 
res ults nee d t o be re vie we d ra pi dl y b y t he h os pital st u d y tea m  
 A Es  
 C o nc o mita nt me dicati o ns 
6. 5. 6.  
T u m or Assess me nt Sc a ns 
D uri n g t h e st u d y, t u m or a ssess me nt will be perf or me d i n 8- wee k i nter vals ( ± 3 da ys) fr o m 
t he date of first d ose.  Dates of all p ost d ose sca ns are bas e d o n t he dat e of first d ose.  If 
f or a n y reas o n a s ca n is p erf orme d o ut of wi n d o w, t he s u bse q ue nt sca n m ust be 
perf or me d at t he c orrect ti me.  T he sa me i ma gi n g m o dalit y (e. g. C T or M RI) m ust be 
use d t hr o u g h o ut t he st u d y t o f oll o w lesi o ns f or eac h s u bject, u nless c o ntrai n dicate d f or 
safet y reas o ns (e. g. d e vel o p me nt of aller g y t o c o ntrast me di u m). 
N ote: S u bjects w h o disc o nti n ue t heir assi g n e d tre at me nt f or a reas o n ot her t ha n 
c o nfir me d ra di o gra p hic disease pr o gressi o n, wit h dra wal of c o nse nt, deat h, or l oss t o 
f oll o w- u p s h o ul d c o nti n ue t u m or e val uati o n visits at 8- wee k i nter vals if p ossi ble u ntil 
t he y start a n ot her a nti-ca ncer t herap y, diseas e pr o gressi o n, wit h dra wal of c o nse nt, deat h, 
or are l ost t o f oll o w- u p. 
6. 5. 7.  
Cr oss o ver Visits ( p ositi ve st u d y a n d p ost d at a b ase l oc k) 
If t he st u d y is p ositi ve at t he pres pecifie d i nteri m or fi nal a nal ysis, t he s p o ns or will all o w 
patie nts w h o are recei vi n g pla ce b o treat me nt t o cr oss o ver t o t he acti ve ti va nti ni b 
treat me nt ar m after data b ase l oc k if t he safet y para meters i n t he eli gi bilit y criteria are met 
(see secti o n 4. 1 ).   
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 4 of 1 1 3 
F or t he first m o nt h o n ti va nti ni b, he mat ol o g y  will be teste d e ver y 4 da ys a n d f or t he 
sec o n d m o nt h, he mat ol o g y will be teste d wee kl y.  A si n gle E C G m ust be perf or me d pri or 
t o t he first d ose of ti va nti ni b a n d a gai n o n Da y 1 of t he f oll o wi n g c ycle ( o ne m o nt h after 
starti n g d osi n g wit h ti va nti ni b).  If h eart rate is ≤ 5 0 beats per mi n ute ( b p m) t he n a n E C G 
will als o be perf or m e d o n Da y 1 of e v er y c ycle t h ereafter.  
6. 6.  
E n d of Tre at me nt 
S u bjects w h o st o p a n y assi g ne d tr eat me nt s h o ul d be see n wit hi n 7 da ys after last d ose of 
ti va nti ni b/ place b o f or t he f oll o wi n g ass ess me nts: 
 F u ncti o nal Assess me nt of Ca ncer T hera p y - He pat o biliar y ( F A C T- He p) a n d 
E Q - 5 D q uesti o n nair es ( bef ore m eeti n g wit h t he p h ysicia n or ha vi n g a n y ot her 
assess me nt perf or me d) 
 P h ysical e x a mi nati o n 
 E C O G pe rf or ma nce stat us 
 Vital si g ns a n d w ei g ht, i ncl u di n g te m perat ure  
 S er u m pre g na n c y test (if a p plica ble) 
 He mat ol o g y  
 Bl o o d c he mistr y 2 a n d c oa g ulati o n 
 Bl o o d sa m ples f or H G F a n d A F P testi n g   
 C hil d- P u g h assess me nt 
 T u m or assess me nt (if n ot d o ne wit hi n 1 4 da ys) 
 E C G  (si n gle E C G) 
 R ec or d c o n c o mita nt me dicati o ns 
 Assess a d vers e e ve nts 
 C ollect ret ur ne d dr u g/ Assess treat me nt c o m plia nce 
 De acti vat e t he s u bject i n t he I X R S 
 O pti o nal c ore nee dle t u m or bi o ps y.  See Secti o n 6. 1  f or details o n tiss ue 
pre parati o n.   
6. 7.  
3 0 - D a y S af et y F oll o w-u p  
All s u bjects m ust ha ve a f oll o w- u p visit or p h o ne call 3 0 da ys f oll o wi n g t heir last d ose of 
assi g ne d treat me nt.  S u bjects wit h u nres ol ve d pr ot oc ol-t hera p y relate d A Es at t he ti me of 
treat me nt disc o nti n uati o n or t hat occ ur wit hi n 3 0 da ys after dis c o nti n uati o n of assi g n e d 
treat me nt will be f oll o we d f or a mi ni m u m of 3 0 da ys f oll o wi n g t he l ast d ose of pr ot oc ol 
desi g nat e d t hera p y or u ntil all st u d y relate d t o xicities ha ve, i n o pi ni o n of t he I n vesti gat or, 
res ol ve d t o baseli ne, sta biliz e d, or are deeme d t o b e irre v ersi ble. If a s u bject recei v es 
ot her a nti-ca ncer t hera p y wit hi n t he 3 0- da y f oll o w- u p peri o d, t he f oll o w- u p a n d rec or di n g 
f or A Es will cease be gi n ni n g t he first da y of t he n e w t hera p y.  
                                                 
2 If a re mar ka ble s u d de n i ncrease i n A S T/ A L T val ues is f o u n d, a n d s u bj ect is H B V p ositi ve, H B V 
re plicati o n m ust b e assesse d; if acti ve H B V re plicati o n is disc o vere d, s u bj ect m ust be i m me diatel y treate d 
wit h c o n ve nti o nal a nti- viral t hera p y ( n ot i ncl u di n g i nterfer o n) as per sta n dar d of care 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 5 of 1 1 3 
6. 8.  
S ur vi v al F oll o w u p (e ver y 3 m o nt hs ± 1 4 d a ys)  
S ur vi val f oll o w- u p will start t he da y of t he E n d of Treat me nt visit. All s u bjects a n d/ or 
fa mil y will be c o nt acte d at 3- m o nt h i nter vals ( ± 2 wee ks) a n d rec or d t he s u bject stat us as 
Ali ve ( date); D ea d ( date); Ali ve, b ut wit h dre w c o nse nt; L ost t o F oll o w U p.  T he s ur vi val 
f oll o w- u p peri o d will c o nti n ue u ntil at least t he re q uire d n u m ber of e ve nts ha ve bee n 
re p orte d. S ur vi val f oll o w- u p will als o c o nti n ue wit h s u bjects w h o wit h dra w fr o m 
treat me nt, u nless s pecifi call y n otifie d, i n writi n g, b y t he s u bject. I n t hat case, p u blic 
rec or ds (i.e., deat h certifi cates) will be use d f or s ur vi val a nal ysis. 
6. 9.  
Pr ot oc ol D e vi ati o ns 
T he I n ve sti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y 
t he S p o ns ors a n d, if re q uire d, b y t h e re g ul at or y a ut h orit y(ies), a n d w hic h was gi ve n 
a p pr o val/fa v ora ble o pi ni o n b y t he I R B/I E C. 
A de viati o n t o a n y pr ot oc ol pr oce d ure, or wai ver t o a n y  stat e d criteria will n ot be all o we d 
i n this st u d y e x ce pt w h er e necessar y t o eli mi nate i m me diate hazar d(s) t o t h e s u bject.  
S p o ns ors m ust be n otifie d of all i nte n de d or u ni nt e n de d de viati o ns t o t he pr ot oc ol (i.e., 
i ncl usi o n/e x cl usi o n criteria, d osi n g, misse d st u d y visits) o n a n e x pe dite d basis. 
T he I n vesti gat or, or d esi g nee s h o ul d d oc u me nt all pr ot oc ol de viati o ns a n d e x plai n (if 
p ossi ble) a n y de viati o n fr o m t he a p pr o ve d pr ot o c ol. 
A n y d ata rec or d e d o n t he st u d y  Case Re p ort F or m will be c ollecte d a n d i ncl u de d i n t he 
data base acc or di n g t o Cli nical Data I nt erc h a n ge St a n dar ds C o ns orti u m ( C DI S C) 
sta n dar ds a n d s u bjecte d t o t he sa me pr oce d ures as ot her data.  If a s u bje ct was i neli gi ble 
or recei ve d t he i nc orrect d ose or i n vesti gati o nal treat me nt, a n d ha d at least o ne 
a d mi nistrati o n of i n vesti gati o nal pr o d u ct, data s h o ul d be c ollecte d f or safet y p ur p oses. 
T he I n vesti gat or s h o ul d n otif y t he I E C or I R B of de viati o ns fr o m t he pr ot o c ol i n 
acc or d a nce wit h l ocal pr oc e d ures. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 6 of 1 1 3 
7.  
E F FI C A C Y A S S E S S M E N T S 
7. 1.  
Pri m ar y V a ri a ble(s) 
 O ve rall s ur vi val ( O S) i n t he I T T p o p ulati o n 
7. 2.  
Sec o n d ar y V ari a ble(s) 
 Pr o gressi o n free s ur vi val ( P F S) 
7. 3.  
E x pl or at or y V ari a ble(s) 
 Ti me t o pr o gressi o n ( T T P), t y pe of pr o gressi o n, o verall res p o ns e rate ( O R R), a n d 
disease c o ntr ol r ate ( D C R) e val uate d b y  i n de pe n de nt ra di ol o g y re vie w 
 F A C T - H e p- bas e d F H SI- 3 pai n sc ore, F A C T- He p at o biliar y S y m pt o m I n de x 
( F H SI- 8) sc ore, F A C T- H e p E m oti o nal Well Bei n g ( E W B) sc ore, F A C T- He p t otal 
sc ore, E Q- 5 D 
 Ti me -t o- h os pitaliz ati o n (all-ca use) a n d ti me-t o- h os pitalizati o n ( H C C-relate d)  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 7 of 1 1 3 
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S 
8. 1.  
P h ar m a c o ki netic ( P K ) V ari a ble(s) 
Bl o o d sa m ples will be c ollecte d o n Da y 1 a n d Da y 2 1 of C ycl e 1 a n d Da y 1 of C ycl es 2 
a nd 3 t o f urt her e val uate p har mac o ki netics of ti va nti ni b a n d its meta b olites a n d t heir 
c orrel ati o n wit h bi o mar kers a n d cli nical e n d p oi nts. S uc h a nal ysis will be c o n d ucte d usi n g 
a p o p ulati o n p har mac o ki netic/ p har mac o d y n a mic a p pr oac h.  
D ose a n d P K sa m pli n g ti mes m ust be rec or d e d.  T he date a n d ti me t hat t he 2 prece di n g 
d oses were ta ke n m ust als o be rec or de d. 
Bl o o d sa m ples f or p h ar m ac o ki netic a n al ysis will b e c ollecte d as per t he f oll o wi n g ti me 
p oi nts: 
 C ycle 1, Da y 1: t w o sa m ples 
o  O ne  bl o o d dra w b et wee n 1 a n d 3 h o urs aft er t he first d ose of 
ti va nti ni b/ place b o 
o  O ne  bl o o d dra w b et wee n 4 a n d 8 h o urs aft er t he first d ose of 
ti va nti ni b/ place b o 
 C ycle 1, Da y 2 1: t w o sa m ples 
o  O ne  bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
o  O ne  bl o o d dra w at least 1 h o ur after t h e m or ni n g d ose of 
ti va nti ni b/ place b o 
 C ycle 2, Da y 1: o ne sa m ple 
o  O ne  bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
 C ycle 3, Da y 1: o ne sa m ple 
o  O ne  bl o o d dra w at a n y ti me after t h e m or ni n g d os e of ti va nti ni b/ place b o 
If t he s u bject starts r ecei vi n g a C Y P 2 C 1 9 a n d/ or C Y P 3 A 4 i n hi bit or/i n d ucer at a n y c ycle 
after C ycle 3, 2 bl o o d s a m ples s h o ul d be c ollecte d, if p ossi ble, w hile t he s u bject is o n t he 
c o nc urre nt me dicati o n: 
 O ne bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
 O ne  bl o o d dra w at least 1 h o ur after t h e m or ni n g d ose of ti va nti ni b/ place b o 
If a s u bject e x perie nces Gra de ≥ 2  n e utr o pe nia, if p ossi ble, c ollect 1 p har mac o ki netic 
bl o o d sa m ple at a n yti me d uri n g t he d osi n g peri o d b ut bef ore a n y d ose s us p e nsi o n or 
re d ucti o n is a p plie d.  D o  n ot dela y d ose s us pe nsi o n or re d ucti o n. 
8. 2.  
P h ar m a c o d y n a mi c ( P D) V ari a ble(s) 
Bl o o d sa m ples will be c ollecte d at pre- d ose o n Da y 1 of C ycl es 1, 2, 3, a n d 4 a n d at t he 
e n d of treat me nt f or t he a na l ysis of d y n a mic c ha n ges i n he pat oc yte gr o wt h fact or (H G F).  
B l o o d sa m ples will be c ollecte d at pre- d ose at Scree ni n g a n d o n Da y 1 of C ycles 2, 3, 
an d 4 a n d at t he e n d of tr eat me nt f or t he a nal ysis of d y n a mic c ha n ges i n A F P.  H G F a n d 
A F P will be meas ur e d usi n g a n a p pr o ve d e nz y me-li n ke d i m m u n os or be nt assa y ( E LI S A) 
kit. 
A d diti o nal bi o mar kers ma y als o be e v al uate d o n bl o o d sa m ples as ne w data ma y s u g gest. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 8 of 1 1 3 
8. 3.  
Bi o m ar ker a n d E x pl or a t or y V ari a ble(s) 
T u m or sa m ples of arc hi v al or rece nt bi o ps y m ust be c ollecte d at baseli ne f or all s u bject s 
(f or mali n fi x e d, paraffi n- e m be d de d bl oc ks or at least 7 (refer t o c urre nt la b ma n ual) 
f or mali n fi x e d, paraffi n e m be d de d u nstai ne d, u n ba ke d, p ositi vel y c h ar ge d sli des of 4 t o 5 
micr o n t hic k ness ; s peci m e ns s h o ul d be fi x e d i n 1 0 % ne utral b uffere d f or mali n ( N B F) a n d 
s h o ul d n ot be st ore d i n fi x ati ve f or m ore t ha n 7 2 h o urs bef ore pr ocessi n g i nt o paraffi n 
bl oc k) as descri be d i n t he relate d la b ma n u al.  If sli des are se nt, t he y m ust h a ve bee n 
pre pare d fr o m f or mali n- fi x e d paraffi n-e m b e d de d tiss ue; t he ti me bet wee n sli de 
pre para ti o n a n d s u b missi o n f or a nal ysis ca n n ot be l o n ger t h a n t he ti mefra me ma n date d b y 
t he la b ma n ual. Rece nt bi o ps y (als o pr o vi di n g f or mali n fi x e d, paraffi n-e m be d de d bl oc ks 
or at least 7 (refer t o c urre nt la b ma n ual) u nstai ne d sli des) is preferre d.  Fi ne Nee dl e 
As pirate ( F N A) is n ot a cce pta ble u nless it ca n be pre pare d as per t he la b m a n ual. Bi o ps y 
sa m ples c ollecte d wit hi n 3 0 da ys b ef ore t he first d a y of treat me nt are c o nsi dere d rece nt. 
C ollecte d sa m ples will be e val uat ed pri maril y f or t he e x pressi o n of t otal M E T b y 
i m m u n o hist oc he mistr y.  T he sa m ples will be s hi p pe d t o a desi g nate d ce ntr al la b orat or y 
w here t he y will be teste d.  Tiss ue sa m ples will be c o nsi dere d M E T  Dia g n ostic- Hi g h 
w he n ≥ 5 0 % of t u m or cells ha ve a stai ni n g i nte nsit y of ≥ 2 + f or M E T i n a si n gle sli de as 
assessed b y  i m m u n o hist oc he mistr y usi n g a si n gle vali date d assa y. 
If a n arc hi val sa m ple is d ee me d t o be M E T Di a g n ostic- L o w, t u m or sa m ples fr o m a ne w 
bi o ps y ca n be s u b mitte d f or M E T e va l u ati o n, if safe f or t he s u bj ect; re-scree ni n g 
pr oce d ures m ust be starte d wit hi n 2 8 da ys fr o m t he c o m m u nicati o n of t he res ults t o t he 
site.  If t h e ne w b aseli ne bi o ps y pr o vi des a M E T Dia g n ostic- Hi g h sa m ple, t he s u bject will 
be eli gi ble f or t he st u d y.  S hi p me nt of pre-scree ni n g sa m ples will be all o we d u p o n 
si g nat ur e of i nf or me d c o nse nt. 
In a d diti o n, if dee me d safe f or t he s u bj ects a n d wit h t heir c o nse nt, o pti o nal t u m or 
bi o psies will be perf or me d at baseli ne, p ost-treat me nt (after Da y 2 2 a n d prefera bl y b ef ore 
Da y 3 0 of C ycle 1), a n d at t he e n d of tr eat me nt.  C ollecte d sa m ples ma y b e e val uat e d, if 
p ossi ble, f or t he e x pressi o n of M E T, p- M E T, d o w nstrea m mar kers of M E T si g nali n g, cell 
pr oliferati o n, a n d a d diti o nal ( n o n g e netic) bi o mar kers ma y als o be e val uat e d o n t u m or 
sa m ples as ne w d ata ma y s u g gest. 
Sa m ples will be la bele d b y pers o n nel fr o m t he i nstit uti o n wit h t he s u bjects’ st u d y I D a n d 
t heir i de ntit y will n ot be ma de k n o w n t o e m pl o yees fr o m t he c o m pa n y, a d diti o nal 
c olla b orat ors, or ot h er I n vesti gat ors. Sa m ples will o nl y be us e d f or t he p ur p oses of t he 
pr ot oc ol a n d will o nl y be use d b y S p o ns ors’ p ers o n nel or b y a n e xter nal la b orat or y 
ch ose n b y t he S p o ns ors t o o uts o urce t he a n al ysis acc or di n g t o i nter n al g ui deli nes.  Tiss ue 
sa m ples c ollecte d f or t he p ur p ose of t his st u d y will be utilize d t o c o m plete all necessar y 
a nal ys es t o s u p p ort t he re g ulat or y a p pr o val f or t he i n dicati o n.  A d diti o nal a nal ysis ma y 
be perf or me d t o gai n a b etter u n dersta n di n g of t he tar get ( M E T) a n d/ or effect of t he st u d y 
dr u g u nless restricte d b y l ocal re g ulati o ns.  T hes e sa m ples will be st ore d f or t he peri o d 
re q uire d b y t he a nal yzi n g la b, u nless ot her wise s pecifie d b y a p plica bl e l ocal re g ulati o ns.  
After c o m pleti o n of t he pr ot oc ol-relat e d a nal yses, u n use d or re m ai ni n g tiss ue sa m ples 
will be destr o ye d per t h e La b orat or y sta n d ar d practice u nless t he sites/s u bjects re q ueste d 
t he sa m ples t o be ret ur n e d. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 5 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 5 9 of 1 1 3 
8. 4.  
P h ar m a c o ge n o mics a n d  O pti o n al P h ar m a c o ge n o mi c S a m ple B a n ki n g  
8. 4. 1.  
P h ar m a c o ge n o mic Testi n g 
If n ot restricte d b y l o cal r e g ul ati o ns, after si g nat ur e of i nf or me d c o nse nt, a bl o o d sa m ple 
will be c ollecte d fr o m eac h s u bject o n Da y 1 of C ycl e 1 as part of t his st u d y, pri maril y 
f or ge n ot y pi n g of c o m m o nl y k n o w n varia nts i n C Y P 2 C 1 9.   
C Y P 2 C 1 9  is t he c yt o c hr o me P4 5 0 e nz y me pri maril y res p o nsi ble f or t he met a b olis m of 
ti va nti ni b.  S u bjects carr yi n g c o m m o n ge n etic varia nts i n C Y P 2 C 1 9 ha ve altere d 
p ha r mac o ki netics a n d s u b o pti mal o utc o mes f oll o wi n g treat me nt wit h cl o pi d o grel, 2 3 
a n ot her dr u g pri maril y m eta b oliz e d b y C Y P 2 C 1 9.    
T hese res ults ma y pr o vi d e i nf or mati o n o n h o w differe nt i n di vi d uals meta b olize a n d react 
t o t he st u d y dr u g.  
If t he s u bject has als o pr o vi de d a s pecifi c c o nse nt f or p har mac o ge n o mic b a n ki n g, a n d if 
n ot restricte d b y l ocal re g ulati o ns, t he n t he sa m ple will be st ore d f or f ut ur e a nal ysis.  
Sa m ples f or t h ose s u bjects w h o d o n ot c o nse nt t o ge n e tic ba n ki n g will be d estr o ye d aft er 
all t he assess me nts ha ve bee n perf or me d.   
8. 4. 2.  
P h ar m a c o ge n o mic S a m ple C ollecti o n 
O n Da y 1 of C ycle 1, if n ot restricte d b y l ocal re g ul ati o n, a bl o o d sa m ple s h o ul d be 
c ollecte d a n d fr oze n as s o o n as it is p ossi ble.  Sa m ple v ol u mes a n d ha n dli n g pr oce d ures 
are pr o vi d e d i n t he la b orat or y m a n ual.   
T o e ns ure s u bject c o nfi d e ntialit y, eac h sa m ple t u b e will be i de ntifie d o nl y b y a b arc o d e.  
T his barc o de will be li n ke d t o t he s u bject’s st u d y i de ntificati o n n u m ber. 
T he sa m ples will be s hi p pe d t o desi g n ate d ce ntral la b or at or y.  Sa m ple c ollecti o n, 
ha n dli n g, st ora ge, a n d s hi p pi n g i nstr ucti o ns are d escri be d i n t he la b ma n u al. 
8. 4. 3.  
O pti o n al P h ar m a c o ge n o mic S a m ple B a n ki n g 
T he re mai n d er of t he p h ar mac o ge n o mic s a m ples fr o m eac h c o nse nti n g s u bject, if n ot 
restricte d b y l oc al re g ulati o n a n d if t he s u bject c o nse nts, ma y b e retai n e d f or p ossi ble 
f ut ure res earc h as n e w i nf ormati o n re gar di n g t he s afet y a n d effi cac y of ti va nti ni b ma y 
e mer ge.  
All s u bjects s h o ul d be pr o v i de d wit h t he o p p ort u nit y t o c o nse nt se p aratel y t o 
p har mac o ge n o mic sa m pl e ba n ki n g at e nr oll me nt.  Partici pati o n i n t his p orti o n of t he 
st u d y is o pti o nal f or all s u bjects.  T h us, a s u bject w h o c h o os es n ot t o all o w rete nti o n of 
his/ her p har mac o ge n o mic sa m ple be y o n d t he i nitial testi n g ma y still partici pate i n t he 
mai n p orti o n of t he st u d y.  P har mac o ge n o mic s a m ples fr o m all s u bjects w h o c h o ose n ot 
t o partici pate i n t he ba n ki n g p orti o n of t he st u d y will be destr o ye d at t he e n d of t he st u d y. 
Beca use it is i m p ossi ble t o k n o w w hat ne w s cie ntific i nf or mati o n ma y arise i n t he f ut ure, 
n o a nal ysis pla n e xists f or t hese sa m ples.  H o we ver, t he sc o pe of t he a nal ysis will be 
li mite d t o ge nes s us pect e d t o c o ntri b ute t o t he safet y a n d efficac y of ti va nti ni b.  Sa m ples 
will be retai ne d u ntil t he D N A has bee n e x ha uste d or u ntil t he S p o ns or i nstr ucts t he 
ge n ot y pi n g c o ntr act or t o destr o y t h e sa m ple (i n acc or da nce wit h la b orat or y pr oce d ures).  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 0 of 1 1 3 
T he rete nti o n peri o d will n ot e x ce e d 1 0 years.  D uri n g t he peri o d of st ora ge, t he D N A 
sa m ple will n ot be i m m ortalize d or s ol d t o a n y o ne.  
S u bjects will ha ve t he ri g ht t o wit h dra w c o nse nt a n d ha ve t heir sa m ples destr o ye d at a n y 
ti me. 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 1 of 1 1 3 
9.  
S A F E T Y A S S E S S M E N T S 
9. 1.  
A d verse E ve nts 
A d verse e ve nts ( A Es) will be c ollecte d fr o m t he date of ra n d o mizati o n u ntil t he e n d of 
t he treat me nt wit h t he st u d y dr u g.  Seri o us a d verse e ve nts ( S A Es) relate d t o st u d y-
s pecific pr oce d ures will be re p ort e d fr o m t he d ate of si g ni n g t he i nf or m e d c o nse nt; all 
S A Es will be re p orte d fr o m t he date of ra n d o mizati o n t o 3 0 da ys aft er t he l ast d ose of 
st u d y dr u g.  If ma n date d b y l oc al la w, A Es a n d/ or S A Es as a p pr o priat e will be rec or de d 
f or ti me of c o nse nt. If a s u bject recei ves a n y ot h er a nti-ca ncer t hera p y wit hi n t he 3 0- da y 
f oll o w- u p peri o d, t he f oll o w- u p a n d rec or di n g f or A Es will cease b e gi n ni n g t he first da y 
of t he ne w t hera p y. 
A n y fi n di n gs n ote d d uri n g bas eli ne assess me nt will be rec or d e d as part of me dical 
hist or y.  All seri o us a d v erse e ve nts ( S A Es) are t o be re p ort e d acc or di n g t o t he pr oce d ures 
i n Secti o n 9. 2  S A E Re p orti n g- Pr oce d ure f or I n vesti gat ors.  Re p ort t he di a g n osis as t he 
A E or S A E ter m; w he n t he dia g n osis is u na vaila ble, re p ort si g ns a n d s y m pt o ms as 
i n di vi d ual e ntries of t he A E or S A E u ntil t he dia g n osis bec o mes a vaila ble.  F or e v e nts 
t hat are seri o us d ue t o h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust be re p ort e d as 
t he seri o us a d verse e v e nt ( dia g n osis or s y m pt o m r e q uiri n g h os pitalizati o n).  A pr oce d ure 
is n ot a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y be a n A E or S A E.  Pre-
pla n ne d ( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) pr oc e d ures or treat m e nts re q uiri n g 
h os pitaliz ati o n f or pre-e xisti n g c o n diti o ns w hi c h d o n ot w orse n i n se verit y s h o ul d n ot be 
re p orte d as S A Es (see Secti o n 9. 1. 1  f or Defi niti o ns).  F or d eat hs, t he u n derl yi n g or 
i m me diate ca use of deat h s h o ul d al wa ys b e re p orte d as a n S A E.  Diseas e pr o gressi o n is a 
st u d y e n d p oi nt a n d c o ns e q ue ntl y, s h o ul d n ot be re p orte d as a n A E/ S A E.  H o we ver, w he n 
a s u bject dies fr o m dise ase pr o gressi o n wit h n o ot her i m me diate ca uses, “ disease 
pr o gressi o n” s h o ul d be re p orte d as a n S A E. I n a d diti o n, a n y u nt o war d e ve nt t hat ma y 
occ ur s u bse q u e nt t o t he re p orti n g p eri o d t hat t he I n vesti gat or assesses as relate d t o st u d y 
dr u g s h o ul d als o b e re p orte d a n d ma na ge d as a n A E.   
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y a d v erse e ve nts h a ve occ urre d 
b y e v al uati n g t he s u bject.  A d verse e ve nts ma y be directl y o bs er ve d, re p ort e d 
s p o nta ne o usl y b y t he s u bject, or b y q uesti o ni n g t h e s u bj ect at eac h st u d y visit.  S u bjects 
s h o ul d be q uesti o ne d i n a ge n eral w a y, wit h o ut as ki n g a b o ut t he o cc urre nce of a n y 
s pecific s y m pt o ms.  All la b orat or y v al ues m ust be a p praise d b y t he I n vesti gat or as t o 
cli nical si g nifica nce.  All p ost- baseli ne a b n or m al la b orat or y v al ues c o nsi dere d cli nicall y 
si g nifica nt b y t he I n vesti gat or m ust be rec or de d i n t he a d verse e ve nt p a ge of t he Case 
Re p ort F or m ( C R F), a n d if seri o us, re p ort as a n S A E f oll o wi n g t he pr oce d ures i n 
Secti o n 9. 2 . 
T he I n vesti gat or s h o ul d f oll o w s u bjects wit h a d verse e ve nts u ntil t he e ve nt has res ol ve d 
or t he c o n diti o n has sta bilize d. S u bjects wit h u nres ol ve d pr ot oc ol-t hera p y relate d A Es at 
t he ti me of treat me nt disc o nti n uati o n or t hat occ ur wit hi n 3 0 da ys after disc o nti n uati o n of 
assi g ne d treat me nt will b e f oll o we d f or a mi ni m u m of 3 0 da ys f oll o wi n g t he last d ose of 
pr ot oc ol desi g n ate d t hera p y or u ntil all st u d y relat e d t o xicities ha ve, i n o pi ni o n of t he 
I n v esti gat or, res ol ve d t o baseli ne, sta bilized, or are dee me d t o b e irre v ersi ble.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 2 of 1 1 3 
9. 1. 1.  
Defi niti o ns 
9. 1. 1. 1. 
A d verse E ve n t ( A E) 
A n a d vers e e ve nt ( A E) is a n y u nt o w ar d me dical o cc urre nce i n a s u bject or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har m ace utical pr o d uct a n d w hic h d oes n ot 
necessaril y h a ve t o ha v e a ca usal relati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ( A E) 
ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n d e d si g n (i ncl u di n g a n a b n or m al la b orat or y 
fi n di n g, f or e x a m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal pr o d uct, w het h er or n ot c o nsi dere d relat e d t o t he me dici nal pr o d u ct (I C H E 2 A 
G ui deli ne.  Cli nical Safet y D ata Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d 
Re p orti n g, O ct 1 9 9 4). 
It is t he res p o nsi bilit y of I n v esti gat ors, base d o n t h eir k n o wle d ge a n d e x peri e nce, t o 
deter mi ne t h ose cir c u msta nces or a b n or mal la b fi n di n gs w hic h s h o ul d be c o nsi dere d 
a d verse e ve nts. 
9. 1. 1. 2. Seri o us A d verse E ve nt ( S A E) 
A seri o us a d verse e v e nt ( S A E) is a n y u nt o w ar d m e dical occ urre nce t hat at a n y d os e: 
 R es ults i n deat h 
 Is life-t hreate ni n g 
 R e q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
 R es ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y 
 Is a c o n ge nital a n o mal y/ birt h defect 
 Is a n i m p orta nt me dical e ve nt 
N ote: T he ter m “lif e-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h 
t he s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot hetic all y mi g ht ha v e ca use d d eat h if it were m ore se vere (I C H E 2 A G ui deli ne.  
Cli nical Safet y D ata Ma n a ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, 
Oct 1 9 9 4). 
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uir e i nter ve nti o n t o pre v e nt o ne of t he ot her o ut c o mes liste d i n t he 
defi niti o n a b o ve.  E x a m ples i ncl u de aller gic br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d 
d yscrasias or d e vel o p me nt of dr u g d e pe n d e nc y or dr u g a b use. 
N ote: 
 A pr oce d ure is n ot a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y b e a n A E 
 Pre- pla n ne d ( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) s ur geries or 
h os pitaliz ati o ns f or pre-e xisti n g c o n diti o ns w hic h d o n ot w orse n i n se verit y are 
n ot S A Es 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 3 of 1 1 3 
9. 1. 1. 3. 
A E Se verit y 
All A Es will be gra de d ( 1 t o 5; see bel o w) b y t he I n v esti gat or, acc or di n g t o t he 
N CI C T C A E, V ersi o n 4. 0 3, ( p u blis h date: 1 4 J u n 2 0 1 0). 2 4 
Se verit y v ers us Seri o us n ess: Se verit y is use d t o d escri be t he i nte nsit y of a s pecific e v e nt 
w hile t he e ve nt itself, h o we ver, ma y b e of relati vel y mi n or me dical si g nifica nce (s u c h as 
se vere h ea d ac he).  T his is n ot t he sa me as “seri o us ness,” w hic h is base d o n s u bject/e ve nt 
o utc o me at t he ti me of t h e e ve nt.  F or e x a m ple, t he N CI C T C A E Gra d e 4 (life-
t hreate ni n g or disa bli n g A E) is assesse d based o n u ni q ue cli nical descri pti o ns of se verit y 
f or eac h A E, a n d t h ese criteria ma y be differe nt fr o m t h ose use d f or t he ass ess me nt of A E 
seri o us ness.  A n A E ass esse d as Gra d e 4 bas e d o n t he N CI C T C A E gra des ma y or m a y 
n ot be assesse d as s eri o us base d o n t he seri o us n ess criteria . 
9. 1. 1. 4. 
C a us alit y Assess me nt 
T he relati o ns hi p bet wee n a n a d vers e e v e nt a n d t he st u d y pr o d uct will be deter mi ne d b y 
t he I n v esti gat or o n t he basis of his/ her cli nical j u d g me nt a n d t h e f oll o wi n g defi niti o ns: 
 1 =  Relate d: 
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g 
a d mi nistrati o n, a n d ca n n ot be reas o n a bl y e x plai ne d b y t he s u bject’s cli nical 
state or ot her fact ors (i. e., disease u n der st u d y, c o nc urre nt dise ases, a n d 
c o nc o mita nt me dicati o ns) 
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g 
a d mi nistrati o n, a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its c he mical 
gr o u p, or is pre dicte d b y k n o w n p har mac ol o g y. 
 2 =  N ot Relate d: 
 T he A E d oes n ot f oll o w a reas o n a ble se q u e nce fr o m st u d y pr o d uct 
a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s cli nical stat e 
or ot her fact ors (i.e., dise ase u n der st u d y, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns). 
9. 1. 1. 5. 
Acti o n T a ke n Re g ar di n g t he St u d y Pr o d uct 
 1 =  N o ne  
− N o c ha n ge i n st u d y dr u g d osa ge was ma d e 
 2 =  Disc o nti n ue d P er ma n e ntl y  
− T he st u d y pr o d uct was p er ma ne ntl y st o p pe d 
 3 =  Re d uce d  
− T he d osa ge of st u d y pr o d uct was re d u ce d (i n cl u di n g if dr u g was i nterr u pte d 
a n d re d uce d) 
 4 =  I nterr u pte d  
− T he st u d y pr o d uct was h el d te m p oraril y 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 4 of 1 1 3 
9. 1. 1. 6. 
A d verse E ve nt O utc o me 
 1 =  Rec o vere d/ Res ol ve d 
 T he s u bject f ull y rec o vere d fr o m t he a d v erse e ve nt wit h n o resi d ual effect 
o bser ve d 
 2 =  Rec o vere d/ Res ol ve d wit h S e q uelae 
 T he resi d ual effects of t h e a d verse e v e nt are still prese nt a n d o bs er va ble 
 I d e ntif y se q uela e/resi d ual effects 
 3 =  N ot Rec o vere d/ N ot Res ol ve d 
 T he a d verse e v e nt itself is still prese nt a n d o bser va ble 
 4 =  Fat al 
 5 =  U n k n o w n 
9. 1. 1. 7. 
Ot her Acti o n T a ke n f or E ve nt 
 1 =  N o ne 
 N o treat me nt was re q uir e d 
 2 = Me dicati o n was re q uire d 
 Prescri pti o n a n d/ or o ver-t he-c o u nter ( O T C) me dicati o n was re q uir e d t o treat 
t he a d vers e e ve nt 
 3 =  H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n was re q uir e d 
 H os pitalizati o n was re q uire d or pr ol o n ge d d ue t o t he a d verse e v e nt, w het her 
or n ot me dicati o n was r e q uire d 
 4 =  Ot her 
9. 2.  
Seri o us A d verse E ve nt Re p orti n g – Pr oce d ure f or I n vesti g at ors 
9. 2. 1. 
I niti al Re p orts 
Wit hi n 2 4 h o urs of recei vi n g a n S A E re p ort: 
 C o m plete a Daiic hi Sa n k y o Seri o us A d verse E v e nt Re p ort ( S A V E R) f or m, si g n 
a n d fa x t he f or m t o C o va nce usi n g t he desi g nate d fa x tra ns mittal f or m.  C o va nce 
will re vie w a n d f or war d t he S A V E R f or m t o Daiic hi Sa n k y o Cli nical Safet y a n d 
P har mac o vi gila nce ( C S P V)  
 Call t he C o va nce S A E H otli ne f or a n y q uesti o ns re gar di n g S A E r e p orti n g 
 C o va nce S A E H ot Li ne t ele p h o ne n u m ber a n d fa x: 
 
 
 
 P lace t he i nitial versi o n of t he S A E Re p ort F or m i n t he s u bject’s file 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 5 of 1 1 3 
9. 2. 2.  
F oll o w- u p Re p orts 
T his is N E W i nf or mati o n  recei v e d o n a pre vi o usl y re p orte d S A E. 
Wit hi n 2 4 h o urs of t he recei pt of ne w i nf or mati o n f or a re p orte d S A E: 
 C o m plete a Daiic hi Sa n k y o Seri o us A d verse E v e nt Re p ort ( S A V E R) f or m wit h 
t he ne w i nf or mati o n.  Ple ase c o m plete Secti o ns 1 t hr o u g h 3 e ve n if t he y c o ntai n 
n o ne w i nf or mati o n.  F or Secti o ns 4 t hr o u g h 1 0, pr o vi de o nl y t he ne w 
i nf or mati o n.  Si g n a n d fa x t he f or m t o C o va nce usi n g t he fa x tra ns mittal f or m. 
 F a x, e- mail, or se n d b y e x press mail, c o pies of s u p p orti n g d oc u me nts (i. e. , 
h os pital disc har ge s u m maries, la b test res ults wit h n or mal ra n g es, a ut o ps y or 
bi o ps y re p orts) t o C o va n ce 
 T he  C R O will re vie w a n d f or war d t he f oll o w- u p S A V E R f or m a n d s u p p orti n g 
d oc u me nts t o Daiic hi Sa n k y o Cli nical Safet y a n d P har mac o vi gila nce 
 
 P lace t he f oll o w- u p v ersi o n of t he S A V E R f or m a n d all s u p p orti n g d oc u me ntati o n 
i n t he s u bject’s file 
9. 2. 3.  
N otif yi n g I n vesti g at ors or Et hics C o m mittee/I nstit uti o n al Re vie w B o ar d 
Daiic hi Sa n k y o a n d/ or C R O will u n derta ke t o i nf or m I n v esti gat ors of a n y seri o us, 
u ne x pecte d ( n ot liste d i n t he I n v esti gat or’s Br oc h ure) a n d relate d A Es occ urri n g i n ot her 
st u d y sites or ot her Daiic hi Sa n k y o st u dies of t he i n vesti gati o nal pr o d u ct, as a p pr o priate. 
De pe n di n g o n t he c o u ntr y/re gi o n, eit her D aiic hi Sa n k y o or t he I n v esti gat or will i nf or m 
t he Et hics C o m mittee/I nstit uti o nal Re vie w Boar d of seri o us u ne x pecte d a n d relate d A Es 
rep orte d wit h D aiic hi Sa n k y o’s i n vesti gati o nal pr o d uct. 
9. 2. 4 
E ve nts of S peci al I nterest 
9. 2. 4. 1 C o m bi ne d Ele v ati o ns of A mi n otr a nsfer ases a n d Bilir u bi n 
C o m bi ne d ele vati o ns of a mi n otra nsferases a n d bilir u bi n, e it her seri o us or n o n-seri o us a n d 
w het her or n ot ca usall y relate d, meeti n g t he criteri a of a p ote ntial H y’s La w case 
[ T B L ≥ 2 x U L N wit h si m ulta ne o us A L T or A S T ≥ 3 x U L N f or s u bjects starti n g fr o m a 
ba seli ne n or mal val u e, or wit h si m ulta ne o us AL T or A S T ≥ 5 × U L N f or s u bjects starti n g 
wit h a hi g her t ha n U L N baseli ne val ue] s h o ul d a l wa ys be re p orte d t o t he S p o ns or usi n g a 
S A V E R f or m, wit h t he I n vesti gat or’s assess me nt of seri o us ness, c a usalit y, a n d a detaile d 
narrati ve.  ( F D A’s G ui da nce f or I n d ustr y: Dr u g-I n d uce d Li ver I nj ur y: Pre m ar keti n g 
Cli nical E val uati o n; J ul y 2 0 0 9; 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui d a nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ U C M 0 7 2 2 7 8. p df ).  T hese e v e nts s h o ul d be re p orte d as s o o n as p ossi ble f oll o wi n g 
t he pr oce d ures o utli ne d i n Secti o n 9. 2  f or S A E re p orti n g. 
If t he s u bject disc o nti n ues st u d y dr u g d ue t o li ver e nz y me a b n or malities, t he s u bject m ust 
perf or m all t he e val uati o ns i ncl u de d i n t he e n d of treat me nt per t he S c he d ule of E ve nts i n 
A p pe n di x 1 7. 1 . I n a d diti o n, if t he s u bject is H B V p ositi ve, H B V re plicati o n m ust be   
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 6 of 1 1 3 
teste d a n d if acti ve re plicati o n is disc o vere d t he s u bject m ust be treate d per sta n dar d 
g ui deli nes ( n ot i ncl u di n g i nterfer o n). 
9. 3.  
E x p os ure I n Uter o D uri n g Cli nic al St u dies 
Daiic hi Sa n k y o m ust be n otifie d of a n y s u bject w h o bec o mes pre g na nt w hile recei vi n g or 
wit hi n 3 0 da ys of disc o nti n ui n g t he i n vesti gati o nal pr o d uct.  Alt h o u g h pre g na nc y is n ot 
tec h nicall y a n a d v erse e v e nt, all preg na n cies m ust be f oll o we d t o c o ncl usi o n t o deter mi ne 
t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g safet y a n d p u blic healt h 
c o ncer ns.  It is t he res p o nsi bilit y of t he I n vesti gat or, or desi g nee, t o re p ort a n y pre g na nc y 
i n a s u bject usi n g t he E x p os ure I n Uter o ( EI U) Re p orti n g f or m.  Please c o ntact y o ur 
st u d y m o nit or t o recei ve t he EI U Re p orti n g F or m u p o n lear ni n g of a pre g n a nc y.  T he 
I n v esti gat or s h o ul d ma ke e ver y eff ort t o f oll o w t h e s u bject u ntil c o m pleti o n of t he 
pre g na nc y.  If t he o utc o me of t he pre g n a nc y meets t he criteria f or i m me diate 
classificati o n as a S A E (i.e., p ost- part u m c o m plicati o ns, s p o nta ne o us a b orti o n, still birt h, 
ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat i n a n a b orte d fet us), t he 
I n v esti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es. 
9. 4.  
Cli nic al L a b or at or y E v al u ati o ns 
La b orat or y assess me nts will i ncl u de he mat ol o g y, bl o o d c he mistr y, c oa g ulati o n, H G F , 
an d A F P.  All testi n g ot h er t ha n he mat ol o g y will be perf or me d b y a ce ntr al la b. I n case 
c oa g ulati o n res ults fr o m t he ce ntral la b are altere d d ue t o s hi p me nt-relate d iss ues, l ocal 
c oa g ulati o n res ults ma y be use d t o deter mi ne a s u bject’s eli gi bilit y. He mat ol o g y will be 
teste d at t he st u d y site la b orat or y.  F or s u bjects li vi n g m ore t ha n a p pr o xi matel y 1 h o ur 
fr o m t he st u d y site, a la b l ocal t o t he s u bject’s l ocati o n ca n be c o nsi dere d f or C ycl e 1, 
Da ys 5, 9, 1 3, 1 7, a n d 2 5, f or C ycl e 2, Da ys 8 a n d 2 2, f or C ycle 2 + Da y 1 5 a n d f or 
u nsc he d ule d visit he mat ol o g y testi n g.  A la b l ocal t o t he s u bject’s l ocati o n ca n als o be 
co nsi dere d f or a n y pla ce b o patie nts w h o cr oss o ver t o ti va nti ni b f oll o wi n g data base l oc k 
f or t he e xtra he mat ol o g y testi n g re q uir e d d uri n g t h eir first t w o m o nt hs o n ti va nti ni b (see 
secti o n 6. 5. 7 ). 
Eac h l ocal la b m ust be a p pr o ve d i n a d va n ce of bei n g use d f or t his st u d y b y pr o vi di n g t o 
t he C R O all a p plica ble re g ulat or y d o c u me nts (i ncl u di n g la b n or mal ra n ges a n d la b 
certificati o n at mi ni m u m). 
 He mat ol o g y: c o m plete bl o o d c o u nt ( C B C) i ncl u di n g he m o gl o bi n, he mat o crit, 
w hite bl o o d cell c o u nt ( W B C) wit h 5- part differe ntial, re d bl o o d cell c o u nt 
( R B C), a n d platel et c o u nt 
T he  res ults of u nsc h e d ule d he mat ol o g y tests perf or me d at a l ocal la b orat or y 
or dere d b y t h e I n vesti gat or i n or der t o ma na ge a s u bjects’ c o n diti o n will be 
c ollecte d as a part of t h e safe t y la b orat or y assess m e nt of t he s u bject. 
 C oa g ulati o n: pr ot hr o m bi n ti me, i nter nati o nal n or malize d rati o, a n d partial 
t hr o m b o plasti n ti me  
 Bl o o d c he mistr y: cal ci u m, p h os p h or us, ma g n esi u m, al b u mi n, s o di u m, p otassi u m, 
c hl ori de, gl uc ose, ser u m creati ni ne, uric aci d, t otal pr otei n, a n d bl o o d urea 
nitr o ge n ( B U N), A S T, A L T, lactate de h y dr o ge n as e ( L D H), al kali ne p h os p h atase, 
t otal a n d direct bilir u bi n, a n d ga m ma- gl uta m yl tra ns pe pti dase (G G T )  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 7 of 1 1 3 
 S er u m pre g na n c y test f or fe male s u bjects of c hil d beari n g p ote ntial 
 A F P bl o o d sa m ple 
 H G F  bl o o d sa m ple 
 H B s A g, H Be A g, H B V D N A, delta vir us, H C V A b  
9. 5.  
Vit al Si g ns 
Hei g ht ( o n scree ni n g  visit o nl y), wei g ht, vital si g ns (t o i ncl u de bl o o d press ure, heart rate, 
res pirat or y rate, a n d t e m perat ur e [ oral, a xillar y or t y m pa nic]) a n d E C O G P erf or ma nce 
Stat us ( A p pe n di x 1 7. 2 ).  S u bject is t o be i n t he sa me p ositi o n eac h ti me vital si g ns are 
assesse d (i.e., s u pi ne, etc) o ver t he co urse of t he st u d y . 
9. 6.  
Electr oc a r di o gr a ms 
Tr i plicate E C Gs s h o ul d be c o n d ucte d at t he scree ni n g visit, at C ycl e 1 Da y 1 a n d at C ycl e 
1 Da y 2 1.  A 1 2-le a d E C G (si n gle) s h o ul d be c o n d ucte d at C ycle 2 D a y 1, a n d t he e n d of 
treat me nt visit. A d diti o nal E C G(s) may be c o n d u cte d if cli nicall y i n dicate d. Bra d ycar di c 
s u bjects wit h a heart rate ≤ 5 0 beats per mi n ute d uri n g t he first c ycle s h o ul d ha ve a n E C G 
d o ne  o n Da y 1 of e ver y c ycl e. 
F or patie nts t hat w ere cr osse d fr o m place b o t o ti va nti ni b f oll o wi n g data bas e l oc k, a si n gle 
E C G m ust be perf or me d pri or t o t he first d ose of ti va nti ni b a n d a gai n o n D a y 1 of t he 
f oll o wi n g c ycl e ( o n e m o nt h after starti n g d osi n g wit h ti va nti ni b).  If heart rate is ≤ 5 0 
beats per mi n ute ( b p m) t he n a n E C G will als o be perf or me d o n Da y 1 of e ver y c ycl e 
t hereafter. 
9. 7.  
P h ysic al Fi n di n gs 
C o m plete p h ysical e x a mi nati o n of t he maj or b o d y s yste ms.  
9. 8.  
Ot her S afet y Assess me nts 
N ot a p plica ble.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 8 of 1 1 3 
1 0.  
O T H E R A S S E S S M E N T S 
1 0. 1.  
P at i e nt- Re p orte d O utc o mes ( P R Os)  
Patie nt-re p orte d o utc o m es ( P R Os) will be e val uate d base d o n t he a d mi nistrati o n of:  
a)  T he F u ncti o nal Ass ess me nt of Ca ncer T hera p y  – He pat o biliar y ( F A C T- He p) 
scale  
b)  T he E ur o Q ol 5- D  
1 0. 1. 1. 
F u ncti o n al Ass ess me nt of C a ncer T her a p y – He p at o bili ar y ( F A C T- He p )  
T he F A C T- He p c o nt ai ns 4 ge n eral s u bs cales (t otal 2 7 ite ms) meas uri n g p h ysical well-
bei n g ( P W B), f u ncti o nal well- bei n g ( F W B), s ocial well- bei n g ( S W B), e m oti o nal well-
bei n g ( E W B), a n d a he p at o biliar y- ca ncer s y m pt o m-s pecific s u bscale – t he 1 8-ite m 
He pat o biliar y A d diti o nal C o ncer ns S u bscale ( H C S).  F urt her, wit hi n t he o verall 4 5-ite m 
F A C T- H e p, c o m bi ni n g 3 pai n-relat e d ite ms – “I h a ve pai n” ( P W B ite m 4), “I ha ve p ai n 
i n my bac k ” ( A d diti o nal C o ncer ns ite m 8), a n d “I ha ve disc o mf ort/ pai n i n m y st o mac h 
area” ( A d diti o nal C o ncer ns ite m 1 8) – yiel ds a 3-ite m F A C T He p at o biliar y Pai n 
S y m pt o m I n d e x ( F H SI- 3).  Als o, wit hi n t he 4 5-ite m F A C T- He p, c o m bi ni n g 8 ite ms t hat 
meas ure s pecific s y m pt o ms a n d si de effects yi el ds t he 8-ite m F H SI- 8. 2 4  All q uesti o ns 
ha ve 5 p ossi ble sc ores f or res p o nses, ra n gi n g fr o m 0 = n ot at all t o 4 = ver y m uc h; hi g her 
sc ores r e pres e nt m ore fa v ora ble patie nt-re p orte d o utc o mes.   
S pecificall y, 4 s pecifi c s u m mar y s c ores will be e val uate d base d o n t h e F A C T- He p scal e 
 F H SI- 3 pai n s u bscale sc ore  
 F H SI- 8 s y m pt o m i n de x sc ore 
 E W B sc ore 
 F A C T - H e p t otal sc ore    
1 0. 1. 2. 
E U R O Q O L 5- D ( E Q- 5 D) 
T he E Q- 5 D, a ge n eric m eas ure of sta n dar dize d healt h stat us, c o nsists of: 
(i) T he E Q- 5 D d escri pti ve s yste m w hic h c o ntai ns 5 d o mai ns: m o bilit y, self-care, 
us ual acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n  
(ii) T he E Q- 5 D Vis ual A nal o g Scale ( V A S)2 5   
F or t he f or mer, eac h of t he 5 di me nsi o ns has 3 res p o nses: n o pr o ble m, s o me pr o ble ms, 
a n d se vere pr o ble ms.  T h e set of res p o ns es t o eac h of t he 5 di me nsi o ns will yi el d a 5- di git 
n u m ber w hic h re pres e nts a u ni q ue healt h state (f or e x a m ple, 1 1 1 1 1 re prese nts t he best 
p ossi ble res p o nse t o all 5 di me nsi o ns); t hese will be c o n vert e d i nt o a si n gl e s u m mar y 
wei g ht e d i n de x base d u p o n t he E Q- 5 D al g orit h m 2 5 (f urt her details will be pr o vi de d i n t he 
S A P).  Base d u p o n t he E Q- 5 D V A S assess me nt, a meas ure of o verall self-rate d healt h 
stat us2 5 will be ge nerate d.  Fi nall y, t h e distri b uti o n of res p o nses o n t he E Q- 5 D descri pti ve 
s yste m will be use d t o ge nerate a healt h pr ofile, 2 5 i n partic ular, t he pr o p orti o n of s u bjects 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 6 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 6 9 of 1 1 3 
wit h “e xtre me pr o ble ms” o n eac h di me nsi o n.  All of t he E Q - 5 D a nal yses will be 
c o n d ucte d i n de p e n de nt of treat me nt gr o u p, i.e., o n p o ole d data, wit h o ut a n y c o m paris o n 
acr oss treat me nt gr o u ps, b y bas eli ne, o n-st u d y, a n d e n d of treat me nt assess me nt o nl y 
(f urt her d etails will be pr o vi de d i n t he S A P). 
1 0. 1. 3. 
H os pit aliz ati o n ( all-c a u se a n d H C C-rel ate d) 
Ti me- t o- h os pitaliz ati o n, f or a n y ca use a n d f or reas o ns relate d t o H C C, will be e val uat e d. 
A d diti o nal details i ncl u di n g le n gt h of sta y ( base d o n dates of a d missi o n a n d disc har ge), 
pri mar y reas o n f or h os pit alizati o n, a n d s u bject disc har ge st at us ( deat h, n ursi n g h o me, 
h o me, or ot her facilit y) will  be ca pt ure d o n a n el ectr o nic C R F.  F urt her d etails will be 
pr o vi de d i n t he S A P. 
1 0. 1. 4. 
A n al gesic, Di uretic, a n d A nti bi otic Use 
Base d o n c o nc o mita nt m e dicati o n rec or ds a n d a pre-s pecifie d list of a nal gesics, di uretics, 
an d a nti bi otic use will be ca pt ure d i ncl u di n g dat es of use. T he use of a n al gesics, 
di uretics, a n d a nti bi otics (f or  t he o ne wee k prece di n g eac h sc he d ule d visit) will be 
c o m pare d acr oss tr eat me nt gr o u ps i n or d er t o e ns ure t hat t he patie nt-re p ort e d pai n 
e n d p oi nt is n ot c o nf o u n de d b y differe ntial use of a nal gesics, di uretics, a n d a nti bi otics 
acr oss treat me nt gr o u ps.   Details will be pr o vi de d i n t he S A P. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 0 of 1 1 3 
1 1.  
S T A TI S TI C A L M E T H O D S  
1 1. 1.  
A n al ysis Sets 
1 1. 1. 1. 
I nte nt- t o- Tre at (I T T) A n al ysis Set  
T he I T T A n al ysis Set will i ncl u de all ra n d o mize d s u bjects. 
1 1. 1. 2. 
Per- Pr ot oc ol A n al ysis Set  
T he Per- Pr ot oc ol A n al ysi s Set will i ncl u de all s u bjects i n t he I T T a n al ysis s et w h o meet 
all of t he f oll o wi n g criteria: 
 N o maj or vi olati o n occ urs i n t he eli gi bilit y criteria f or ra n d o mizati o n 
 C o m pleti o n of at least o ne c ycle of treat me nt 
Maj or vi olati o ns of eli gi bilit y criteria will be defi ne d a n d d oc u me nt e d i n a me m o pri or t o 
t he u n bli n di n g of t he dat a base. 
1 1. 1. 3. 
S afet y A n al ysis Set 
T he Safet y A n al ysis  Set will i ncl u de all s u bjects w h o recei ve d a n y a m o u nt of st u d y dr u g. 
1 1. 1. 4. 
P ati e nt- Re p orte d O utc o me ( P R O) A n al ysis Set 
T he P R O A nal ysis Set wil l i ncl u de all s u bjects i n t he I T T a nal ysis set w h o c o m plete t he 
rele va nt P R O assess me nt  at scree ni n g, at least partiall y i n a ma n n er t hat per mits 
i m p utati o n of missi n g res p o nses.  F urt her details will be pr o vi de d i n t he S A P.  
1 1. 1. 5. 
Bi o m ar ker A n al ysis Set 
T he Bi o mar ker A n al ysis  Set will i ncl u de all s u bjects w h o recei ve d at least o ne d ose of 
st u d y dr u g a n d h a d at least o ne pre- d ose a n d at least o ne p ost- d ose bi o mar ker assess me nt. 
1 1. 1. 6. 
P h ar m a c o ge n o mic A n al ysis Set 
T he P har mac o ge n o mic A nal ysis Set will i ncl u de all s u bjects f or w h o m C Y P 2 C 1 9 
ge n ot y pi n g w as d o ne at t he ce ntr al ge n ot y pi n g d esi g nate d la b orat or y. 
1 1. 2.  
Ge ner al St atistic al C o nsi der at i o ns 
T he ra n d o mizati o n will be stratifie d b y vas c ular i n vasi o n ( prese nt or n ot), e xtra- he patic 
s prea d i ncl u di n g dista nt metastasis a n d/ or i n v ol ve d re gi o nal or dista nt l y m p h n o des 
( prese nt or n ot, usi n g R E CI S T 1. 1 criteria, b ut re gi o nal n o des are c o nsi dere d i n v ol ve d if 
≥ 2 0 m m i n s h ortest dia meter), a n d A F P (less/e q ual or greater t ha n 2 0 0 n g/ m L). 
S u m mar y statistics will be pre se nt e d as f oll o ws.  F or c o nti n u o us varia bles, n u m ber of 
a vaila ble o bser vati o ns ( n), mea n, sta n dar d de viati o n ( S D), me dia n, a n d ra n ge will be 
pr o vi de d. T he distri b uti o n b y a cli nicall y rele va nt discretizati o n als o will be pr o vi de d. 
F or cate g oric al varia bl es, t he n u m ber a n d perce nta ge i n eac h cate g or y will be dis pla ye d. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 1 of 1 1 3 
I n A u g ust 2 0 1 3, f oll o wi n g a hi g h er t ha n e x pecte d i nci de nce of ne utr o pe ni a-relate d 
a d verse e ve nts, t he st u d y D M C e val uate d all a v aila ble data i ncl u di n g preli mi nar y 
p har mac o ki netics, a n d rec o m me n de d t he re d uce d starti n g d ose of 1 2 0 m g BI D.  
T heref ore t he 1 2 0 m g BI D re gi me n will be t he i nt e n de d d ose re gi me n s h o ul d mar keti n g 
a p pr o val be gra nte d.  
T he s u bjec ts will nee d t o be gr o u pe d t o 2 c o h orts: t he 1 2 0 m g c o h ort (all s u bjects w h o 
are ra n d o mize d t o a starti n g d ose of  1 2 0 m g BI D v ers us Place b o) a n d t he 2 4 0 m g c o h ort 
(all s u bjects w h o are ra n d o mize d t o a starti n g d ose of 2 4 0 m g BI D vers us Place b o).  Data 
fr o m s u bjects i n t he 1 2 0 m g c o h ort will be use d f or t he pri mar y a n al ysis of efficac y 
re gar di n g t he p ot e ntial mar keti n g a p pr o val of t he 1 2 0 m g BI D d ose re gi me n. 
F or mal efficac y a n al ys e s will be perf or me d usi n g o nl y t he 1 2 0 m g c o h ort. T he pri mar y 
a nal ysis will use t he I T T A nal ysis  Set, w hile s o me of t he descri pti ve a nal ysis will use t he 
Per- Pr ot oc ol A nal ysis Set.  Sa fet y a nal ysis will be perf or me d usi n g t he Safet y A nal ysis 
Set.  T he data fr o m t he 2 4 0 m g c o h ort will be vie we d as a pil ot st u d y w here all a nal yses 
of t h ose data will be des cri pti ve. 
T he pri mar y a n al ysis of t he pri mar y  efficac y e n d p oi nt of O S will be base d o n t h e I T T 
A nal ysis Set f or t h e 1 2 0 m g c o h ort.  C o m paris o n of O S bet wee n treat me nt gr o u ps will be 
base d o n t he stratifie d  l o g-ra n k test a n d t he hazar d rati o ( H R).  T he H R will be esti mate d 
usi n g t he stratifie d C o x pr o p orti o nal haza r ds re gressi o n m o del. 
T he effi cac y a nal yse s will be perf or m e d acc or di n g t o t he treat me nt gr o u ps assi g ne d at 
ra n d o mizati o n.  F or safet y a n al ys es, s u bjects will be a nal yz e d acc or di n g t o act ual 
treat me nt recei ve d. As wit h efficac y, t he e val u ati o n of safet y will be perf or me d 
se parat el y f or t he 1 2 0 m g c o h ort a n d t he 2 4 0 m g c o h ort. 
Assess me nts of c ha n ge fr o m baseli ne t o p ost- baseli ne or t he rati o of p ost- b aseli ne t o 
baseli ne will i ncl u de o nl y t h ose s u bjects wit h b ot h baseli ne a n d p ost- bas eli ne 
meas ure me nts.  T h e last assess me nt ta ke n bef ore t he first d ose of st u d y dr u g will be use d 
as t he baseli ne, u nless ot her wise s pecifie d.   
In ge neral, missi n g or dr o p o ut data will n ot be i m p ute d f or t he p ur p ose of data a n al ysis. 
Si nce a n y statistical a p pr oac h f or h a n dli n g missi n g dat a w o ul d rel y o n u ntesta ble 
ass u m pti o ns t hat li kel y w o ul d be i n vali d, t he f oc us will be t o i m ple me nt creati ve 
a p pr oac h es t o pre v e nt missi n g ness 2 7. 
1 1. 3.  
St u d y P o p ul ati o n D at a 
S u bject dis p ositi o n will be s u m marize d b y d ose c o h ort f or eac h ra n d o mize d treat me nt 
gr o u p a n d i n t otal f or t he differe nt A nal ysis Sets.  T he I T T A nal ysis Set will be use d f or 
t he s u m mar y. 
T he de m o gra p hi c a n d ba seli ne c haracteristics s uc h as baseli ne E C O G disease stat us will 
be s u m mariz e d descri pti vel y b y d os e c o h ort a n d treat me nt gr o u p f or t he I T T, Per -
P r ot oc ol, a n d Safet y A nal ysis Sets.  
S t u d y dr u g e x p os ure (a m o u nt a n d d urati o n) will be s u m marize d usi n g des cri pti ve 
statistics b y d os e c o h ort a n d treat me nt gr o u p f or t he Safet y A nal ysis Set. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 2 of 1 1 3 
1 1. 4.  
Effic ac y A n al yses 
As state d i n secti o n 1 1. 2 , f or mal a nal yses of efficac y e n d p oi nts will be perf or me d o nl y 
f or t he 1 2 0 m g c o h ort as t his is n o w t he i nte n ded d ose re gi me n s h o ul d mar keti n g 
a p pr o val gra nte d.  
1 1. 4. 1. 
Pr i m ar y Effic ac y A n al yses 
T he  o verall s ur vi val ( O S) will be t he pri mar y effi cac y e n d p oi nt f or t his st u d y.  O S is 
defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of deat h fr o m a n y ca use.  If 
t here is n o deat h r e p orte d f or a s u bject b ef ore t he c ut- off date f or O S a nal ysis, O S will be 
ce ns ore d at t he last c o nta ct date at w hic h t h e s u bject is k n o w n t o be ali ve. 
T he a nal yses f or O S will be base d o n t he I T T a n al ysis set.  T he distri b uti o n of O S will be 
c o m pare d b et wee n t h e t w o treat me nt gr o u ps usi n g a str atifie d l o g-ra n k test a dj usti n g f or 
vasc ular i n vasi o n, e xtra- he patic s prea d a n d A F P at o ne-si de d 2. 5 % si g nifica nce le vel.   
T he distri b uti o n f u ncti o n of O S will be esti mate d usi n g  t he Ka pla n- Meier met h o d.  T he 
me dia n O S al o n g wit h t he 9 5 % c o nfi d e nce i nter va ls b y Br o o k me yer a n d Cr o wle y will be 
prese nte d b y tr eat me nt gr o u p.  T he stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o del 
i n w hic h t he treat me nt gr o u p is i ncl u de d as m o del fact or will be use d t o esti mate t he 
hazar d rati o ( H R) of O S, al o n g wit h t he 9 5 % c o nfi de nce i nter val. S A S P R O C LI F E T E S T 
a n d P R O C P H R E Q will be use d i n t he a nal ysis. 
T w o a nal yses are pla n n e d f or O S as f oll o ws:  
1)  A n i nteri m a nal ysis at t he ti me w he n at least 1 5 4 ( 6 4 % of t he 2 5 7) d eat hs are 
d oc u me nte d i n t he 1 2 0 m g c o h ort 
2)  T he fi nal a n al ysis f or O S w he n at least 2 5 7 deat hs ha ve bee n rec or de d i n t h e 1 2 0 
m g c o h ort (e x pecte d ar o u n d 3 8. 0 m o nt hs fr o m t he date of t he first s u bject 
ra n d o mize d t o t he 1 2 0 m g c o h ort), if t he trial c o nti n ues after t he i nteri m a n al ysis  
T he t y p e I err or rate f o r t hese a nal ys es i n t he 1 2 0 m g c o h ort will be c o ntr olle d b y usi n g a 
o ne-si de d 2-l o o k gr o u p- seq ue ntial desi g n. S pecifi call y, La n De M ets met h o d ( La n 1 9 8 3 ) 
wit h O’ Bri e n -Fl e mi n g t y pe st o p pi n g b o u n dar y (as i m ple me nte d i n E A S T 5. 0) will be 
use d t o mai ntai n t he c u m ulati ve t y pe -I err or rate at 2. 5 %. 
1 1. 4. 2. 
Sec o n d ar y Effic ac y A n al yses 
T he sec o n d ar y effica c y e n d p oi nts i ncl u de P F S i n t he I T T p o p ulati o n i n t he 1 2 0 m g 
c o h ort.   
P F S is defi ne d as t he ti me fr o m t he ra n d o miza ti o n date t o t he date of first o bjecti ve 
d oc u me ntati o n of disease pr o gressi o n via ce ntral r e vie w per R E CI S T, Versi o n 1. 1, or 
deat h res ulti n g fr o m a n y ca use, w hic he ver c o mes first. O bjecti ve d oc u me nt ati o n of 
disease pr o gressi o n is base d u p o n t u m or assess me nts rec or de d as “ pr o gressi ve disease ” 
f or “ o verall t u m or assess me nt”. 
T he r ules f or ce ns ore d cases of  P F S are d efi ne d as f oll o ws: 
 S u bjects w h o are ali ve a n d pr o gressi o n-free at t he ti me of t he a nal yses will be 
ce ns ore d at t he date of t he last t u m or e val uati o n 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 3 of 1 1 3 
 S u bjects w h o disc o nti n ue fr o m t he st u d y pri or  t o t he first p ost- baseli ne t u m or 
e val uati o n f or a reas o n ot her t ha n diseas e pr o gressi o n or deat h will be ce ns ore d at 
t he date of ra n d o mizati o n 
 S u bjects w h o disc o nti n ue fr o m t he st u d y d u e t o reas o ns ot her t ha n diseas e 
pr o gressi o n or deat h (i.e. c o nsi dere d n ot t o ha v e die d or pr o gresse d) will be ce ns ore d 
at t he date of t he l ast t u m or e val uati o n 
 S u bjects w h o start ot her a nti-ca ncer t hera p y pri or t o disease pr o gressi o n will be 
ce ns ore d at t he date of t he last t u m or e val uati o n pri or t o starti n g ne w a nti-ca ncer 
t hera p y 
 S u bjects w h o pr o gress or die after missi n g ≥2 c o nsec uti ve sc he d ul e d t u m or 
assess me nts will be ce ns ore d at t he dat e of t he last t u m or e val uati o n pri or t o 
pr o gressi o n or deat h 
 S u bjects w h o ha ve s ur gic al i nter ve nti o n f or c urati ve reas o n wit h o ut c o nfir mati o n of 
pr o gressi o n will be ce ns ore d at t he dat e of t he last t u m or e val uati o n pri or t o t heir 
s ur gic al i nter ve nti o n 
 S u bjects wit h o ut  baseli ne t u m or assess me nt will be ce ns ore d at t he d ate of 
ra n d o mizati o n 
Si milarl y t o t he pri mar y effic ac y a n al ysis, c o m paris o ns of P F S bet wee n treat me nt gr o u ps 
will be ma de usi n g t he stratifie d l o g- ra n k test base d o n t he I T T A nal ysis Set i n t he 1 2 0 
m g c o h ort.  T h e me dia n P F S will be c alc ulate d base d o n Ka pla n- M eier esti mates a n d t he 
c orres p o n di n g 9 5 % c o nfi de nc e i nter val ( CI) will b e calc ul ate d usi n g t h e met h o d pr o vi de d 
b y Br o o k me yer a n d Cr o wle y.  T h e se statistics will be calc ulate d usi n g P R O C LI F E T E S T 
i n S A S s oft ware.  I n a d diti o n, t he stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o del 
wit h t he treat me nt gr o u p as t he o nl y fact or will be perf or me d t o o btai n p oi nt esti mates of 
hazar d rati os a n d t w o-si d e d 9 5 % CI base d o n t h e I T T A nal ysis Set.   
T o c o ntr ol f or t he fa mil y- wise t y p e  I err or rate ( F W E R) f or pri mar y a n d sec o n dar y 
effic ac y e n d p oi nts, t he st a ge wise hierarc hical gr o u p-se q ue ntial testi n g str ate g y is 
i m ple me nte d (t he details are s pecifie d i n t he Statistical A nal ysis Pla n).  T h e pri mar y 
assess me nt of O S i n t he I T T p o p ulati o n will be e val uate d first, a n d if si g nifica nt at a o ne-
si de d al p ha of 0. 0 2 5, a st atistical e val uati o n of P F S i n t he I T T p o p ulati o n will be 
perf or me d.   
1 1. 5.  
E x pl or at or y A n al ys es 
E x pl orat or y a nal ys es i n t he 1 2 0 m g c o h ort i ncl u de e x pl orat or y efficac y a n al yses a n d 
patie nt re p orte d o ut c o me ( P R O) a nal ysis.  
1 1. 5. 1. 
E x pl or at or y Effic ac y A n al yses 
T he e x pl orat or y effi cac y a nal ys es f or t h e 1 2 0 m g c o h ort i ncl u de a d diti o nal s u p p orti ve 
a nal ys es a n d s u b gr o u p a nal yses of t he pri mar y a n d sec o n dar y e n d p oi nts, a n d a nal ys es of 
e x pl orat or y effic ac y e n d p oi nts. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 4 of 1 1 3 
1 1. 5. 1. 1.  A d diti o n al S u p p orti ve A n al yses 
As a se nsiti vit y a nal ysis, u nstratifie d l o g-ra n k test a n d u nstratifie d C o x pr o p orti o nal 
hazar ds re gressi o n a nal ysis wit h o ut a dj usti n g f or stratificati o n fact ors will be perf or me d 
o nl y f or t h e 1 2 0 m g c o h ort usi n g t he I T T A nal ysis Set f or ti me-t o e ve nt e n d p oi nts O S, 
P F S a n d T T P.  A n y a d diti o nal a nal ysis  will be a d d e d t o t he Statistical A nal ysis Pla n. 
All pri mar y a n d sec o n d ar y a n al ys es, i ncl u di n g t he s u p p orti ve a nal yses s pecifie d a b o ve, 
will als o be re peate d f or t he Per- Pr ot oc ol Set. 
1 1. 5. 1. 2.  S u b gr o u p A n al yses 
T he a nal yses s p ecifie d i n Secti o ns 1 1. 4. 1  a n d 1 1. 4. 2  will be perf or me d b y t he f oll o wi n g 
s u b gr o u ps: 
 Va sc ular i n v asi o n: Prese nt, N ot 
 R eas o n of disc o nti n uati o n of pri or s yste mic t hera p y: P D, Ot her 
 P ri or s yste mic t hera p y d urati o n: ≤ 6 0 da ys, > 6 0 da ys 
 E x tra- he patic s prea d at b aseli ne: Prese nt, N ot  
 E C O G a t baseli ne: 0, 1 
 A F P at baseli ne: less/e q u al t o 2 0 0 n g/ m L, greater t ha n 2 0 0 n g/ m L 
 He patitis: H B V p ositi ve, H C V p ositi ve (e x cl u di n g H B V p ositi ve), H B V n e gati ve 
a n d H C V ne gati ve 
 A S T/ A L T at baseli ne: bel o w U L N, Bet wee n U L N a n d 3 x U L N, a b o v e 3 x U L N 
 Platelets at baseli ne: < 1 0 0 x 1 0 9/ L, ≥1 0 0 x 1 09/ L 
 B est res p o ns e t o pri or s orafe ni b t hera p y: P D, Ot her 
 A ge  gr o u p: less t ha n 6 5 yrs, greater t ha n/e q ual t o 6 5 yrs 
 R ace: Ca ucasia n, Bl ac k, Asia n, A merica n I n dia n or Alas ka n Nati ve, Nati v e 
Ha waiia n/ Pacifi c Isla n der, Ot her 
 S e x: Fe male, Male 
 C Y P 2 C 1 9 i n hi bit or use: Yes, N o 
 C Y P 3 A 4 i n hi bit or use: Yes, N o 
 Re gi o n: Asia, U S/ Ca na d a/ A ustralia/ West E ur o pe, Rest of W orl d 
1 1. 5. 1. 3.  A n al ysis of E x pl or at or y Effic ac y E n d p oi nts 
T he e x pl orat or y effi cac y e n d p oi nts i ncl u de o bjecti ve res p o nse rate ( O R R), disease 
c o ntr ol rate ( D C R), ti me t o pr o gressi o n ( T T P), a n d t y pe of pr o gressi o n, b y ce ntral, 
i n de pe n de nt ra di ol o g y re vie w a m o n g all s u bjects treate d wit h ti va nti ni b c o m pare d t o 
place b o.   
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 5 of 1 1 3 
O R R is defi ne d as t he pr o p orti o n of s u bjects w h ose p ost- base li ne t u m or res p o nses 
i ncl u de at least o ne c o m plete res p o nse (C R ) or partial res p o nse (P R ). 
T he O R R f or eac h treat me nt gr o u p will be esti mate d base d o n bi n o mial distri b uti o n.  T he 
as y m pt otic 9 5 % c o nfi de n ce i nter vals f or t he O R Rs will be calc ulate d base d o n n or mal 
a p pr o xi mati o n.  T he c o m paris o n of O R Rs bet wee n treat me nt gr o u ps a n d t h e o d ds rati o 
esti mate will be base d o n l o gistic re gressi o n m o del wit h l o git li n k f u ncti o n.  T he Wal d 
statistic will be use d t o o btai n t he p- val ue of t h e test a n d t he 9 5 % c o nfi de n ce li mit of t he 
o d ds rati o.  T he a nal ys es will be perf or me d usi n g P R O C L O GI S TI C i n S A S s oft ware. 
D C R is defi ne d as t he pr o p orti o n of s u bjects w h ose p ost baseli ne t u m or res p o nses 
i ncl u de at least o ne C R, P R, or S D. 
T he  D C R f or eac h treat me nt gr o u p will be esti mate d base d o n bi n o mial distri b uti o n.  T he 
as y m pt otic 9 5 % c o nfi de n ce i nter vals f or t he D C Rs will be calc ulate d base d o n n or mal 
a p pr o xi mati o n.  T he c o m paris o n of D C Rs bet wee n treat me nt gr o u ps a n d t h e o d ds rati o 
esti mate will be base d o n l o gistic re gressi o n m o del wit h l o git li n k f u ncti o n.  T he Wal d 
statistic will be use d t o o btai n t he p- val ue of t h e test a n d t he 9 5 % c o nfi de n ce li mit of t he 
o d ds rati o.  T he a nal ys es will be perf or me d usi n g P R O C L O GI S TI C i n S A S s oft ware. 
T T P  is defi ne d as t he ti me fr o m t he dat e of ra n d o mizati o n t o t he date of t he first o bjecti ve 
d oc u me ntati o n of disease pr o gressi o n per R E CI S T, Versi o n 1. 1, criteria.  T he r ules f or 
ce ns ore d cases are d efi ne d as f oll o ws: 
 S u bjects w h o are ali ve a n d pr o gressi o n-free at t he ti me of t he T T P  a nal yses will 
be  ce ns or e d at t he d ate of t he last t u m or e val uati o n   
 S u bjects w h o die d or disc o nti n ue fr o m t he st u d y d ue t o reas o ns ot her t ha n disease 
pr o gressi o n will be ce ns ore d (i.e., c o nsi dere d n ot t o ha ve pr o gresse d) at t he date 
of t he last t u m or e val uati o n 
 S u bjects w h o die d or disc o nti n ue fr o m t he st u d y pri or t o t he first p ost- bas eli ne 
t u m or e val uati o n f or a reas o n ot her t ha n diseas e pr o gressi o n will be ce ns ore d at 
t he date of ra n d o mizati o n 
 S u bjects w h o start ot her a nti-ca ncer t hera p y pri or t o pr o gressi o n will be ce ns ore d 
at t he date of t he l ast t u m or e val uati o n pri or t o starti n g ne w a nti-ca n cer t h era p y 
 S u bjects w h o pr o gress after ≥ 2 c o nsec uti ve misse d visits will be ce ns ore d at t he 
da te of t he last t u m or e v al uati o n pri or t o pr o gressi o n 
 S u bjects w h o ha ve s ur gic al i nter ve nti o n f or c urati ve reas o n wit h o ut c o nfir mati o n 
of pr o gressi o n will be ce ns ore d at t he dat e of t he l ast t u m or e val uati o n 
 S u bjects wit h n o baseli ne t u m or assess me nt will be ce ns ore d at t he d ate of 
ra n d o mizati o n 
Si milarl y t o t he pri mar y effic ac y a n al ysis, c o m paris o ns of T T P  bet wee n treat me nt gr o u ps 
will  be ma de usi n g t he stratifie d l o g-ra n k test base d o n t he I T T A nal ysis Set i n t he 1 2 0 
m g c o h ort.  T h e me dia n T T P  will be calc ulate d base d o n Ka pla n- Meier esti mates a n d t he 
corres p o n di n g 9 5 % c o nfi de nce i nter val ( CI) will b e calc ul ate d usi n g t h e met h o d pr o vi de d 
b y Br o o k me yer a n d Cr o wle y.  T h e se statistics will be calc ulate d usi n g P R O C LI F E T E S T 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 6 of 1 1 3 
i n S A S s oft ware.  I n a d diti o n, t he stratified C o x pr o p orti o nal hazar ds re gressi o n m o del 
wit h t he treat me nt gr o u p as t he o nl y fa ct or will be perf or me d t o o btai n p oi nt esti mates of 
hazar d rati os a n d t w o-si d e d 9 5 % CI base d o n t h e I T T A nal ysis Set.   
T y pe of pr o gressi o n will a na l yze reas o ns f or pr o gressi o n (i ncl u di n g cli nical, ra di o gra p hic 
d ue t o ne w lesi o ns or ne w vasc ular i n v asi o n or i ncreas e i n t u m or di me nsi o ns) i n t he I T T. 
1 1. 5. 2. 
Ot her Assess me nts 
1 1. 5. 2. 1 
P ati e nt Re p orte d O utc o mes: F A C T- H e p 
T he F A C T- He p T otal Sc ore is t he s u m of t he sc ores of 4 5 ite ms o n t he q uesti o n naire.  
T he F A C T- He p T otal Sc ore ra n ges fr o m 0- 1 8 0. T he E m oti o nal Well- Bei n g ( E W B) 
S u bscale is t he s u m of t he sc ores of G E 1, G E 2, G E 3, G E 4, G E 5, a n d G E 6. T he 
E m oti o nal Well- Bei n g S c ore ra n ges fr o m 0- 2 4. T he F H SI- 8 s c ore is t he s u m of 8 ite ms 
( wit hi n t he F A C T- H e p) re prese nti n g vari o us s y m pt o ms a n d si de effects; t he F H SI- 8 
sc ore ra n ges fr o m 0- 3 2. T he FH SI- 3 Pai n S u bscale Sc ore is t he s u m of 3 p ai n ite ms 
( wit hi n t he F A C T- H e p) a n d its score ra n ges fr o m 0- 1 2. T he F A C T- He p t ot al sc ore, 
E m oti o nal Well Bei n g sc ore, F H SI- 8 sc ore, a n d t h e F H SI- 3 Pai n s c ores will be a nal yz e d 
as e x pl orat or y e n d p oi nts.  
All a nal ys es o n t he F A C T- He p t otal sc ore, t he F A C T- He p E W B sc ore, t h e F A C T- He p 
F H SI- 3 sc ore, a n d t h e F A C T- He p F H SI- 8 sc ore will be c o n d ucte d i n t he 1 2 0 m g c o h ort 
se parat el y f or (i) all s u bjects, (ii) s u bjects wit h sc ore < me dia n of t he c orres p o n di n g 
s u bscales, a n d (iii) s u bjects wit h a sc ore ≥ me di a n of t he c orres p o n di n g s u bscales, 
c o m pare d acr oss tr eat me nt gr o u ps, i n all a n al ys es (i) t o (iii).  
F or eac h e v al uati o n of tr eat me nt gr o u p differe n ces o n t he F H SI- 3 Pai n sc ores, 
a p pr o priate statistical a dj ust me nt f or meas ure d us e of c o nc o mita nt a n al gesics, di uretics, 
a n d a nti bi otics will be a p plie d; details will be pr o vi de d i n t he S A P.  
T he st u d y a n d c o ntr ol ar ms will be c o m pare d as f oll o ws:  
1.  F re q u e nc y distri b uti o n of c ha n ge fr o m baseli ne t o eac h visit, f or eac h of t he 
F A C T- H e p t otal sc ore, t h e F A C T- He p E W B sc ore, t he F A C T- He p F H SI- 3 sc ore, 
an d t he F A C T- He p F H SI- 8 sc ore. 
2.  In ter ms of ti me- t o- det eri orati o n fr o m baseli ne, w here s u bject-le vel det eri orati o n 
f or eac h sc ore is defi ne d as f oll o ws:  
 F H SI- 3 pai n s u bscale sc ore decrease ≥ 2 
 F H SI- 8 s y m pt o m i n de x sc ore decrease ≥ 4 2 6  
 E W B sc ore d ecrease ≥ 3  
 F A C T- H e p t otal sc ore d ecreas e ≥ 1 0  
N ote: Ka pla n- M eier a n al ysis a n d stratifie d C o x pr o p orti o nal hazar ds re gressi o n 
a nal ys es will be perf or m e d f or eac h of t h e ti me- t o- deteri or ati o n a nal yses n ote d 
a b o ve. F urt her details i ncl u di n g alter nati ve r ules f or ce ns ori n g, will be pr o vi de d 
i n t he S A P.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 7 of 1 1 3 
3.   I n ter ms of t he c u m ulati ve distri b uti o n f u ncti o n ( C D F) of c ha n ge fr o m bas eli ne, 
f or eac h visit ( w here at least 2 5 % of ra n d o mize d s u bjects ha ve n o n- missi n g 
o bser vati o ns) b y treat me nt gr o u p, f or t he F A C T- He p t otal sc ore, t h e F A C T- He p 
E m oti o nal Well Bei n g ( E W B) sc ore, t h e F A C T- He p Pai n S y m pt o m I n de x ( F H SI-
3) sc ore, a n d t he F A C T- He p F H SI- 8 sc ore. F urt her details o n a p pr o priate 
statistical tests f or c o m paris o ns of t he C D F c ur ves acr oss treat me nt gr o u ps will be 
pr o vi de d i n t he S A P.  
F or rele va nt a n al ys es o n t he F H SI- 3 p ai n s u bscale, a nal gesic use, di ur etic use, a n d 
a nti bi otic use i n t he o ne- wee k prece di n g t he assess me nt of t he F A C T- He p will be treate d 
as c o vari ates i n c o m paris o n of treat me nt gr o u ps, usi n g stratifie d C o x Pr o p orti o nal Hazar d 
m o deli n g (as i n [i] a b o ve). F urt her details of a ll a n al yses, i n cl u di n g h a n dli n g of missi n g 
data, will be pr o vi de d i n t he S A P. 
1 1. 5. 2. 2. 
P ati e nt Re p orte d O utc o mes: E Q- 5 D 
T he E Q- 5 D a nal yses will be c o n d ucte d i n d e pe n de nt of treat me nt gr o u p, i.e., o n p o ole d 
data, wit h o ut a n y c o m paris o n acr oss treat me nt gr o u ps, b y bas eli ne, o n-st u d y, a n d e n d of 
treat me nt assess me nt o nl y. If data warra nts, t he E Q- 5 D healt h stat us will be s u m marize d 
o verall (i.e. f or c o m bi ne d treat me nt gr o u ps, wit h o ut a n y c o m paris o ns acr oss treat m e nt 
gr o u ps), b y disease stat e ( baseli ne, pre- pr o gressi o n, p ost- pr o gressi o n, a n d d uri n g 
Gra de 2 - 4 a d verse e v e nts). S pecificall y, E Q- 5 D will be s u m marize d f or all s u bjects f or 
eac h of t h e a b o ve dis ease  states defi ne d as f oll o ws:  
 F or bas eli ne, t he C ycle 1 Da y 1 assess me nt will be use d  
 F or t he pre- pr o gressi o n disease state, t he w orst E Q- 5 D sc ore ( o ver p ote nti al 
m ulti ple assess me nts of E Q- 5 D pri or t o pr o gressi o n, a n d n ot i ncl u di n g a n y 
assess me nts attri b uta ble t o gra de 2- 4 A Es, see b el o w) will be s u m marize d 
 F or t he p ost- pr o gressi o n disease state, t he e n d- of-treat me nt visit- base d 
assess me nt ( w here e n d of treat me nt is attri b uta ble t o pr o gressi o n) will be 
s u m marize d 
 F or t he disease state re prese nti n g Gra d e 2 - 4 a d v erse e v e nts, t he w orst 
assess me nt f oll o wi n g t he A E will be s u m marize d  
 In t he cas e of m ulti ple Gra de 2 - 4 A Es, t he w orst E Q- 5 D sc ore i m me diatel y 
f oll o wi n g t he e v e nt will be selecte d.  
Re peate d or u ns c he d ule d tests will n ot be s u m marize d f or eac h s c he d ule d visit, b ut will 
be i ncl u de d f or s u m maries of ma xi m u m a n d mi ni m u m p ost-treat me nt val ues. All 
sc he d ule d visits ha vi n g a mi ni m u m of 5 % of t he t otal n u m ber of ra n d o mize d s u bjects 
wit h n o n- missi n g o bser vati o ns will be s u m marize d.  F urt her d etails will be pr o vi de d i n 
t he S A P. 
1 1. 5. 2. 3. 
He alt h C are Utiliz ati o n A n al yses  
S p o nta ne o us utiliz ati o n of healt h care ser vices u nrelate d t o pr ot oc ol- ma n date d visits: 
e mer ge n c y r o o m use, o ut patie nt cli nic use, la b orat or y tests ( u ns c he d ule d), a n d 
h os pitaliz ati o n will be assesse d. A se parate case re p ort f or m ( C R F) has bee n de vel o pe d 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 8 of 1 1 3 
f or t his p ur p ose. I n t he 1 2 0 m g c o h ort, t he treat m e nt gr o u ps will be c o m pare d i n ter ms of 
ti me-t o- h os pitaliz ati o n (all-ca use a n d H C C-relate d), usi n g Ka pla n- Mei er a n d stratifie d 
C o x pr o p orti o nal hazar d m o del a p pr oac h es. T he me dia n ti me- t o- h os pitalizati o n (all-
ca use a n d H C C-relate d) al o n g wit h t he 9 5 % c o nfi de nce i nter vals b y Br o o k me yer a n d 
Cr o wle y will be prese nt e d b y treat me nt gr o u p. T h e stratifie d C o x pr o p orti o nal hazar ds 
re gressi o n m o del i n w hic h t he treat me nt gr o u p is i ncl u de d as m o del f act or will be use d t o 
esti mate t he hazar d rati o ( H R) of ti me- t o- h os pitalizati o n (all-ca use a n d H C C-relate d), 
al o n g wit h t he 9 5 % c o nfi de nce i nter val.  F urt her details will be pr o vi de d i n t he S A P. 
1 1. 6.  
P h ar m a c o ki netic/ P h ar m a c o d y n a mic A n al yses 
1 1. 6. 1. 
P h ar m a c o ki netic A n al yses 
P har mac o ki netics of ti va nti ni b a n d its f o ur  maj or meta b olites will be e val u ate d usi n g t he 
res pecti ve pl as ma c o nce ntratio ns b y usi n g P o p ulati o n p har mac o ki netic a nal ysis. T his will 
be c o n d ucte d s e paratel y i n t he 1 2 0 m g c o h ort, wit h p ossi ble p o oli n g of dat a fr o m ot her 
cli nical st u dies of ti va nti ni b.  T his a nal ysis will n ot be part of t he statistical a nal ysis pla n 
f or t his st u d y.  T he res ults will be pr o vi de d i n a se parate p har mac o ki netics re p ort o utsi de 
t he cli nical st u d y re p ort ( C S R) f or t his st u d y.  F or t he C S R, p ur p ose c o nce ntrati o n of 
ti va nti ni b a n d its meta b olites will be liste d. 
1 1. 6. 2. 
P h ar m a c o d y n a mi c/ Bi o m a r ker A n al yses 
If p ossi ble, e x pl orat or y a nal ysis ma y be c o n d ucte d t o e xa mi ne relati o ns hi ps of ti va nti ni b 
e x p os ure t o circ ulati n g l e vels of H G F a n d cli nical o utc o me meas ures.  T hes e a nal yses 
ma y b e pres e nte d i n a se parate re p ort.  A d diti o nall y, t he relati o ns hi p bet wee n e x p os ure 
a n d res p o nse m a y be e x pl ore d as a part of t he p o p ulati o n p har mac o ki netic/ 
p har mac o d y n a mic a nal ysis.  T hese a nal yses ma y b e pr o vi de d i n a se parat e re p ort. 
A d diti o nall y, f or bi o mar kers, H G F  a n d A F P c ha n ge fr o m baseli ne at eac h visit will be 
calc ulate d a n d will be s u m marize d b y visit a n d treat me nt ar m. Ma xi m u m c ha n ge fr o m 
baseli ne will als o be calc ulate d f or i n di vi d ual s u bjects a n d will be s u m mari ze d b y 
treat me nt ar ms. D escri pti ve statistics i ncl u di n g mea n, sta n dar d de viati o n, c oefficie nt of 
variati o n, ge o metric mea n, me dia n, mi ni m u m, a n d ma xi m u m will be c o m p ute d b y 
e val uati o n ti me f or bi o mar kers. 
1 1. 6. 3. 
P h ar m a c o ge n o mic A n al yses 
T he relati o ns hi p bet wee n c o m m o n ge n e tic vari a nts i n C Y P 2 C 1 9 (i.e., e xte nsi ve 
meta b olizers vs p o or meta b olizers) o n selec t safet y e n d p oi nts will be e x pl ore d.  Details of 
t hese a nal yses will be pr o vi de d i n t he S A P.  A d diti o nall y, t he rel ati o ns hi p bet wee n 
C Y P 2 C 1 9 ge n ot y p e a n d e x p os ure a n d res p o nse m a y b e e x pl ore d as a part of t he 
p o p ulati o n p har mac o ki netic/ p har mac o d y na mic a n al ysis. 
1 1. 7.  
S afet y A n al yses 
Safet y a nal ysis will be perf or me d b y d ose c o h ort a n d treat me nt gr o u p wit hi n d ose c o h ort.   
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 7 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 7 9 of 1 1 3 
1 1. 7. 1. 
A d verse E ve nt A n al yses 
Tre at me nt- e mer ge nt A Es ( T E A Es) are defi ne d as t h ose A Es t hat occ ur, ha vi n g bee n 
a bse nt bef ore t he st u d y, or w orse n i n se v erit y after t he i nitiati o n of st u d y tr eat me nt 
a d mi nistrati o n  a n d start n o later t ha n 3 0 da ys after t he e n d of treat me nt .   
A Es w ill be c o de d usi n g Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) a n d 
assi g ne d gra d es base d o n N C I C T C A E, Versi o n 4. 0 3.  
T he n u m ber a n d p erce nta ge o f s u bjects r e p orti n g T E A Es will b e ta b ulate d b y t he w orst 
C T C A E gra de, s yste m or ga n class, a n d preferre d ter m, wit h a brea k d o w n b y d ose c o h ort 
a n d treat me nt gr o u p.  Si milarl y, t he n u m ber a n d perce nt a ge of s u bjects re p orti n g 
treat me nt-e mer ge nt S A Es will be ta b ulate d, as well as T E A Es lea di n g t o disc o nti n uati o n 
of st u d y dr u gs.  
A b y-s u bj ect A E (i n cl u di n g treat me nt-e mer ge nt) d ata listi n g i ncl u di n g, b ut n ot li mite d t o, 
ver bati m ter m, preferre d ter m, s yste m or ga n class, C T C A E gra de, a n d relati o ns hi p t o 
st u d y dr u g will be pr o vi d e d.  Deat hs, ot her S A Es, a n d ot her si g nifica nt A Es, i ncl u di n g 
t h ose lea di n g t o disc o nti n uati o n of st u d y dr u gs, will be liste d. 
1 1. 7. 2. 
Cli nic al L a b or at or y E v al u ati o n A n al yses 
Descri pti ve statistics will be pr o vi de d f or t he cli nical la b orat or y res ults, as well as f or t he 
c ha n ge fr o m baseli ne, b y sc he d ule d ti me of e v al uati o n a n d b y d ose c o h ort a n d treat me nt 
gr o u p usi n g t he Safet y A nal ysis  Set.  T he bas eli ne val ue is defi ne d as t he last n o n-
missi n g val ue bef ore t he i nitial a d mi nistra ti o n of st u d y treat me nt.  I n a d diti o n, mea n 
c ha n ge fr o m baseli ne will be prese nte d b y tr eat me nt gr o u p f or t he ma xi m u m a n d 
mi ni m u m p ost-treat me nt val ues a n d t he val u es at t he E n d of Treat me nt visit. A b n or mal 
la b orat or y res ults will be grade d acc or di n g t o N CI C T C A E versi o n 4. 0 3, if a p plica ble, 
a n d t he gra d e will be prese nte d i n a b y-s u bject d ata listi n g.  A s hift ta ble, prese nti n g b y -
treat me nt gr o u p t he t w o- wa y fre q ue nc y t a b ulati o n f or baseli ne a n d t he w orst p ost-
treat me nt val ue acc or di n g t o t he N CI C T C A E gra de, will be pr o vi de d f or cli nical 
la b orat or y tests.  A b n or m al cli nical la b orat or y t est res ults dee me d of cli nical si g nifica n ce 
or of Gra de 3 or 4 will be liste d. 
1 1. 7. 3. 
Vit al Si g n  A n al yses 
Descri pti ve statistics will be pr o vi de d f or t he vital si g ns meas ure me nts, as well as f or t he 
c ha n ge fr o m baseli ne, b y sc he d ule d ti me of e v al uati o n a n d b y d ose c o h ort a n d treat me nt 
gr o u p usi n g t he Safet y A nal ysis  Set.  T he bas eli ne val ue is defi ne d as t he last n o n-
missi n g val ue bef ore t he i nitial a d mi nistra ti o n of st u d y treat me nt.  I n a d diti o n, mea n 
c ha n ge fr o m baseli ne will be prese nte d b y tr eat me nt gr o u p f or t he ma xi m u m a n d 
mi ni m u m p ost-treat me nt val ues a n d t he val u es at t he E n d of Treat me nt visit. 
1 1. 7. 4. 
Electr oc a r di o gr a m A n al yses 
T he  E C G fi n di n gs ( n or m al/a b n or mal a n d o utliers) will be s u m marize d b y d ose c o h ort 
a n d treat me nt gr o u p a n d visit/ ti me p oi nts.  A listi n g of E C G e x a mi nati o n data will als o be 
pr o vi de d. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 0 of 1 1 3 
1 1. 7. 5. 
P h ysic al Fi n di n g A n al yses 
T he  a b n or mal fi n di n gs fr o m t he p h ysical e x a mi nati o ns at baseli ne will be s u m marize d b y 
d ose c o h ort a n d tr eat me nt gr o u p.  A listi n g of ne w or w orse ni n g a b n or malities f o u n d at 
p h ysical e x a mi nati o n will als o be pr o v i de d. 
1 1. 7. 6. 
Ot her S afet y A n al yses 
C o nc o mita nt me dicati o ns will be c o de d usi n g t h e W orl d Healt h Or ga nizati o n ( W H O) 
dr u g dicti o nar y ( m ost rece nt versi o n).  N u m ber a n d perce nt a ge of s u bjects ta ki n g 
c o nc o mita nt me dicati o ns will be s u m marize d b y d ose c o h ort a n d tr eat me nt gr o u p. 
S u b gr o u p a n al ys es of a d verse  e v e nts will als o be perf or me d usi n g s u b gr o u ps base d o n 
se x, a ge, E C O G stat us, C Y P 2 C 1 9 ge n ot y pi n g, a n d C Y P 3 A 4 i n hi bit or usa ge.   
1 1. 8.  
I nteri m A n al yses 
A si n gle i nteri m eff ic ac y a nal ysis will be p erf or m e d f or t he 1 2 0 m g c o h ort w he n a b o ut 
6 0 % of t he pla n ne d n u m ber of e v e nts (i.e., 1 5 4 e v e nts) are o bs er ve d i n t hat c o h ort.  T he 
pri mar y i nte nt of t he i nteri m a nal y sis is to st o p earl y f or s u p eri or efficac y.  T he st o p pi n g 
criteria f or efficac y will be base d o n t he α- s pe n di n g f u n cti o n met h o d ol o g y of La n-
De Mets fa mil y wit h O’ Brie n- Fl e mi n g p ara met ers as s h o w n i n Ta ble 1 1. 1  b el o w.  At t he 
i nteri m a nal ysis of O S, t he trial w o ul d b e st o p pe d t o reject n ull h y p ot h esis if a n o bser ve d 
z-statistic is greater t ha n 2. 6 6 9 if t he i nteri m a nal ysis is base d o n e x actl y 1 5 4 e ve nts. T he 
pr o ba bilit y of st o p pi n g f or s u peri or effic ac y is a p pr o xi matel y 0. 4 % u n der t he n ull 
h y p ot hesis (i.e., n o differe nce i n relati ve ris k bet w ee n t he t w o treat me nt ar ms, a n d 
a p pr o xi matel y 4 4. 1 % u n der t he alter nati ve h y p ot hesis t hat t he tr ue hazar d rati o is 0. 6 5). 
If t he st u d y meets criteria of s u peri or efficac y at t h e i nteri m a nal ysis a n d, t h e Data 
M o nit ori n g C o m mittee ( D M C) rec o m me n ds ter mi nati o n of t he trial, t he n  selecte d 
re pres e ntati ves fr o m t he S p o ns or may re q uest a c o ns ultati o n wit h Healt h A ut h orities 
pri or t o reac hi n g t h eir fi n al de cisi o n a b o ut w het her t o acce pt t he D M C rec o m me n dati o n; 
t he st u d y tea m will r e mai n bli n de d d uri n g t his pr ocess. A de dicate d Data A nal ysis Gr o u p 
( D A G) at a n i n de pe n d e nt C R O (se parat e C R O fr o m t he o ne f or t he fi n al data a nal ysis) 
will perf or m t he i nteri m a nal ysis.  T h e c o m p ositi o n of t he D A G will be descri be d i n a 
Data M o nit ori n g C o m mittee ( D M C) c h arter.  T he act ual i de ntities of t he treat me nt 
assi g n me nts will o nl y b e re veal e d t o t he D M C a n d t o t his gr o u p, w hic h s u p p orts t he 
D M C.  T his gr o u p will st ore all files t hat are p ote nti all y u n bli n de d i n nat ure i n a sec ure 
direct or y o n a file ser ver.  T he access t o t his direct or y will be li mite d t o t his gr o u p a n d a 
net w or k a d mi nistrat or.  Data st ore d i n t his direct or y w o ul d i ncl u de, b ut n ot be li mite d t o, 
S A S pr o gra ms, S A S datasets, o ut p ut pr o d uce d b y S A S pr o gra ms, a n d s u m mar y 
d oc u me nts/c orres p o n d e n ce descri bi n g t h e u n bli n de d res ults.  T he sec urit y a n d access t o 
t his direct or y will be mai ntai ne d b y a net w or k a d mi nistrat or.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 1 of 1 1 3 
T a ble 1 1. 1 St atistic al G ui deli nes f or St o p pi n g B o u n d aries 
 
A n al ysis 
Ti me  
 
# of E ve n ts 
( O S) 
 
E x pecte d 
Ti me of 
A n al ysis 
( m o nt hs) 
 
E x pecte d 
Accr u al  
Effic ac y  
P -v al ue  
( o ne-si de d) 
Cr ossi n g 
B o u n d ar y  
( Z-sc ore) 
I nteri m 
1 5 4  
2 4  
2 6 0  
0. 0 0 3 8  
2. 6 6 9  
Fi nal  
2 5 7  
3 8  
3 0 3  
0. 0 2 3 8  
1. 9 8 1  
It is rec o g niz e d t hat t he e x act n u m ber of e ve nts at t he i nteri m a nal ysis ma y n ot be 1 5 4.  
T he b o u n daries will be u p date d wit h t he act u al n u m ber of e v e nts at t he i nteri m a nal ysis. 
A d diti o nall y, t he i nteri m a nal ysis will als o i ncl u de a nal ysis t o e x pl ore t he effects of 
C Y P 2 C 1 9 ge n ot y p e a n d c o nc o mita nt me dicati o ns s uc h as C Y P 2 C 1 9 i n hi bit ors a n d 
str o n g C Y P 3 A 4 i n hi bit ors o n ne utr o pe nia, a n d als o e x p os ure res p o nse ( n e utr o pe nia a n d 
ne utr o pe nia- relate d t o xicit y) re lati o ns hi ps usi n g p o p ulati o n p har mac o ki netics 
( P O P P K)/ P D. 
1 1. 9.  
D at a M o nit ori n g C o m mittee 
A Data M o nit ori n g C o m mittee ( D M C) will be esta blis he d f or peri o dic re vi e w of 
u n bli n de d safet y a n d/ or efficac y data i n t his st u d y.  T he D M C will re vie w all data 
rele va nt t o safet y (i.e., A Es, S A Es, cli nical la b orat or y val u es, e x p os ure, ge n ot y pi n g, a n d 
c o nc o mita nt me dicati o n i nf or mati o n o n i n hi bit ors of C Y P 2 C 1 9 a n d C Y P 3 A 4) as well as 
data rele v a nt t o effi cac y a n d q ualit y of trial c o n d uct.  T he c o m p ositi o n a n d tas ks of t he 
D M C are des cri be d i n detail i n t he D M C C harte r f or t his st u d y.  
1 1. 1 0.  
S a m ple Size D eter mi n ati o n 
T he effi cac y a nal ysis will be perf or m e d o nl y f or t he 1 2 0 m g c o h ort, a n d t h us t he sa m ple 
siz e deter mi nati o n is f or t he 1 2 0 m g c o h ort.  
T he pri mar y e n d p oi nt of t his trial is O S i n t he IT T.  O S is defi ne d as t he ti me fr o m date 
of ra n d o mizati o n t o t he date of deat h d ue t o a n y ca use.  T he fi nal a n al ysis of O S will 
re q uire 2 5 7 O S e v e nts, w hic h is t he n u m ber of O S e ve nts need e d f or a o ne-si de d 
stratifie d l o g-ra n k test at 0. 0 2 5 si g nifica n ce le v el t o ha ve 9 0 % p o wer t o ac hie ve  a 
statisticall y si g nifica nt differe nce i n O S distri b uti o n w he n t he tr ue h azar d rati o is 0. 6 5 
(i.e., w he n t he me di a n O S i n ti va nti ni b is 7. 7 m o nt hs a n d t he me dia n O S i n place b o is 
5 m o nt hs, c orres p o n di n g t o a 5 4 % i m pr o ve me nt).  
A p pr o xi matel y 3 0 3 s u bj ects will be  ra n d o mize d i n a 2: 1 rati o i nt o t he 2 treat me nt ar ms 
( 20 2 s u bjects i n t he ti va nti ni b treat me nt ar m a n d 1 0 1 s u bjects i n t he c o ntr ol ar m) i n 
a p pr o xi matel y 2 8 m o nt hs. T he 2 5 7 O S e ve nts are  e x pecte d t o ha ve occ urre d b y 
a p pr o xi matel y 3 8 m o nt hs fr o m t he ra n d o mi zati o n date of t he first s u bject i n t he 1 2 0 m g 
c o h ort, ass u mi n g 8 s u bjects/ m o nt h e nr oll me nt f or t he first 6 m o nt hs a n d 1 2 
s u bjects/ m o nt h e nr oll me nt t hereafter. 
T he desi g n acc o u nts f or o ne i nteri m l o o k u n der a 2-l o o k gr o u p s e q ue ntial desi g n. T h e 
pri mar y i nte nt of t he i nteri m a nal ysis is t o a d dress p ote ntial earl y ter mi nati o n f or s u peri or 
effic ac y.  A n α-s pe n di n g f u ncti o n acc or di n g t o La n- De Mets gr o u p s e q ue nti al desi g n wit h 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 2 of 1 1 3 
a n O’ Brie n- Fle mi n g t y pe st o p p i n g b o u n dar y (as i m ple me nte d i n E A S T versi o n 5. 3) is 
use d t o c o nstr uct t he st o p pi n g b o u n daries.  T he i nt eri m a nal ysis is pla n ne d w he n 
a p pr o xi matel y 1 5 4 (a b o ut 6 0 %)  of t he 2 5 7 O S e ve nts are d oc u me nt e d. If t h e i nteri m 
a nal ysis of O S is base d o n e x actl y 1 5 4 e v e nts, t he  efficac y b o u n dar y w o ul d be cr osse d if 
t he z-statistics are great er t ha n 2. 6 6 9, acc or di n g t o a 1-si de d n o mi nal p- val u e of 0. 0 0 3 8 or 
less.  T he pr o ba bilit y of ter mi nati o n f or s u peri orit y at i nteri m a n al ysis is a p pr o xi matel y 
4 4. 1 % u n der t he alter nati ve h y p ot h esis (i.e., H R = 0. 6 5) a n d less t ha n 0. 4 % u n der t he n ull 
h y p ot hesis.  T he s a m ple siz e deri va ti o n is base d o n t he f oll o wi n g met h o d: S ur vi val 
S u peri orit y Tri als: T w o Sa m pl e Test – L o gra n k T est: Gi ve n Accr ual D urati o n a n d 
E nr oll me nt Rate i n t he E A S T versi o n 5. 3, ass u m i n g a n accr ual peri o d of 2 8 m o nt hs, 
e nr oll me nt rates of 8 s u bj ects per  m o nt h f or t h e first 6 m o nt hs a n d of 1 2 s u bjects per 
m o nt h t hereafter, a n d a dr o p- o ut rate o f 1 0 %. If t he D M C d oes n ot rec o m m e n d earl y 
ter mi nati o n at ti me of t he i nteri m a nal ysis, t he trial will c o nti n ue u ntil t he fi nal 2 5 7 O S 
e ve nts are d oc u me nte d.  T he fi nal a n a l ysis of O S will re q uire a 1-si d e d n o mi nal p- val ue 
of 0. 0 2 3 8 or less f or t he st u d y t o be p ositi ve.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 3 of 1 1 3 
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E 
T he I n vesti gat or/i n vesti gati o na l site will per mit st u d y-relate d m o nit ori n g, a u dits, 
I R B/I E C re vie w, a n d re g ulat or y i ns pe cti o ns b y pr o vi di n g direct acc ess t o s o urce 
data/ d oc u me nts.  Direct a cce ss i ncl u des p er missi o n t o e x a mi ne, a nal yze, v erif y, a n d 
re pr o d uce a n y rec or ds a n d re p orts t hat are i m p orta nt t o t he e val uati o n of a cli nical st u d y. 
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns 
T he m o nit ors a n d desi g n ee a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or 
c o ntacti n g a n d visiti n g t h e I n vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, 
u p o n re q uest, i ns pecti n g t he vari o us rec or ds of t he st u d y (i.e., case re p ort f or ms, s o urce 
data, a n d ot her p erti ne nt d oc u me nts). 
T he m o nit ors are res p o nsi ble f or visiti n g sites at re g ular i nter vals t hr o u g h o ut t he st u d y t o 
verif y a d h ere n ce t o t he p r ot oc ol (as defi ne d i n t he m o nit ori n g pla n); c o m pl ete ness, 
acc urac y, a n d c o nsiste nc y of t he data; a n d a d here nce t o I C H G C P a n d l ocal re g ul ati o ns 
o n t he c o n d uct of cli nic al researc h.  T h e m o ni t ors are res p o nsi ble f or i ns pecti n g t he case 
re p ort f or ms a n d e ns uri n g c o m plet e ness of t he st u d y ess e ntial d oc u me nts.  T he m o nit ors 
s h o ul d ha ve access t o s u bject s o urce m e dical r ec or ds a n d ot her st u d y-relate d rec or ds 
nee de d t o verif y t he e ntri es o n t he cas e re p ort f or ms. 
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, I C H G C P, a n d 
a p plica ble re g ulati o ns t o t he In v esti gat or a n d will e ns ure t hat a p pr o priate acti o n desi g ne d 
t o pre ve nt rec urre nce of t he detect e d de viati o ns is ta ke n a n d d oc u m e nte d. 
T he I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms 
detecte d i n t he c o urse of t hese m o nit ori n g visits are  a d dress e d a n d d o c u me nte d. 
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be s electe d 
f or a u dit b y re prese ntati v es fr o m D S P D.  I ns pecti o n of site facilities (i.e., p har mac y, dr u g 
st ora ge areas, la b orat ories, etc) a n d re vie w of st u d y relate d rec or ds will occ ur i n or der t o 
e val uate t he st u d y c o n d u ct a n d c o m plia nce  wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble 
re g ulat or y re q uire me nts. 
1 2. 2.  
C o m p uter S yste ms 
A p pr o priatel y vali dat e d sta n dar d c o m p uter s yst e ms will be use d b y t he C R O i n v ol ve d i n 
t his st u d y. 
1 2. 3.  
D at a C ollecti o n 
All data c ollecte d d uri n g t he st u d y will be rec or d e d i n t he i n di vi d ual, s u bject s pecific 
e C R F.  I nstr ucti o ns will be pr o vi de d f or t he c o m pleti o n of t he e C R F a n d a n y c orrecti o ns 
ma de will be a ut o maticall y d oc u me nt e d via t he E D C s oft ware’s “a u dit trail”. 
T he  e C R F s h o ul d be ke pt c urre nt t o e n a ble t he m o nit or t o re vie w t he s u bject’s stat us 
t hr o u g h o ut t he c o urse of t he st u d y.  T here will be D M C re vie ws d uri n g t he c o n d uct of 
t his st u d y.  T h e i nf or mati o n s h o ul d be e ntered i nt o t he e C R F wit hi n 4 8 h o urs of t he visit 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 4 of 1 1 3 
f or t he ge n erati o n of t he re p ort for D M C re vie w, a n d s h o ul d be c o m plete d, re vie we d a n d 
si g ne d off b y t he I n v esti gat or. 
A n e C R F m ust be c o m pl ete d f or eac h s u bject w h o si g ns a n I C F, a n d u n der g oes a n y pre-
scree ni n g or s cree ni n g pr oce d ures.  If a s u bj ect is n ot treate d, t he reas o n m ust be rec or d e d 
o n t he e C R F. 
All data ge nerate d fr o m e xter nal s o urces (i.e., ce ntral la b orat or y, p h ar mac o ki netic 
pr ocessi n g, p har m ac o d y n a mic pr ocessi n g, a n d ge n ot y pi n g la b orat or y) will be i nte grate d 
wit h t he s u bject’s e C R F data i n ac c or da n ce wit h t he Data Ma n a ge me nt Pla n. 
T he I n vesti gat or will si g n a n d date t he i n dicate d places o n t he e C R F vi a t he E D C 
s yste m’s el ectr o nic si g nat ure.  T hese si g nat ur es will i n dicate t hat t he I n v esti gat or 
i ns pecte d or re vie we d t h e data o n t he e C R F, t he data q ueries, a n d t he site n otificati o ns 
a n d a grees wit h t he c o nte nt. 
All writte n i nf or mati o n a n d ot her material t o be us e d b y s u bj ects a n d i n vesti gati ve staff 
m ust use v oca b ular y a n d la n g u a ge  t hat are cl earl y u n derst o o d. 
1 2. 4.  
D at a M a n a ge me nt 
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject i de ntifier as defi ne d b y 
t he S p o ns or. 
All a d verse e ve nts ( A Es) will be c o de d usi n g t h e c urre nt Me d D R A ( Me dical Dicti o nar y 
f or Re g ulat or y A cti vities).   
Pri or a n d c o nc o mita nt m e dicati o n will be c o de d b y W H O ( W orl d Healt h Or ga nizati o n) 
Dr u g Dicti o nar y.  A Es a n d c o nc o mita nt me dicati o ns will be c o de d i n t he latest versi o n of 
b ot h dicti o naries at t he ti me of fi nal pr ot oc ol. 
1 2. 4. 1. 
D at a V ali d ati o n 
T o e ns ure t he q u alit y of cli nical data acr oss all s u bjects a n d sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pe cifi cati o ns gi ve n 
t o t he C R O.  Data will be vette d b ot h electr o nicall y a n d m a n uall y f or e C R Fs a n d t he data 
will be electr o nicall y v ette d b y pr o gra m me d d ata r ules wit hi n t he a p plicati o n, as 
descri be d i n t he D ata Ma na ge me nt Pla n.  Q ueri es ge n erat e d b y r ules a n d raise d b y 
re vie wers will be ge nerat e d wit hi n t he E D C a p plicati o n.  D uri n g t his re vi e w, s u bject data 
will be c hec k e d f or c o nsiste nc y, o missi o ns, a n d a n y a p p are nt discre pa n cies.  
1 2. 5.  
St u d y D oc u me nt ati o n a n d St or a ge 
T he I n vesti gat or will mai ntai n a Si g nat ur e List of a p pr o priatel y q u alifie d p ers o ns t o 
w h o m he/s he has dele gat e d st u d y d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or 
c orrecti o ns o n case re p ort f or ms will be i ncl u de d o n t he Si g nat ure List. 
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s 
case re p ort f or m d ata are o btai ne d.  T hese i ncl u d e b ut are n ot li mite d t o h os pital rec or ds, 
cli nical a n d office c h arts, la b orat or y a n d p h ar mac y rec or ds, diaries, micr ofic hes, X-ra ys, 
a n d c orres p o n de n ce. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 5 of 1 1 3 
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m ( Trial Master File) of all st u d y-relate d (esse ntial) 
d oc u me ntati o n, s uita ble f or i ns pecti o n at a n y ti me b y re pres e ntati ves fr o m D S P D a n d/ or 
a p plica ble re g ulat or y a ut h orities.  Esse ntial d oc u me nts i ncl u de: 
 S u bject files c o ntai ni n g c o m plete d case re p ort f or ms, i nf or me d c o nse nts, a n d 
s u p p orti n g c o pies of s o urce d oc u me nt ati o n (if ke pt) 
 S t u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I n v esti gat or’s Br oc h ure, 
c o pies of rel e va nt esse nti al d oc u me nts re q uir e d pri or t o c o m me nci n g a cli nical 
st u d y, a n d all c orres p o n d e nce t o a n d fr o m t he I E C/I R B a n d D S P D 
 R ec or ds rel ate d t o t he I n vesti gati o nal Pr o d uct(s) i ncl u di n g ac k n o wle d g me nt of 
recei pt at site, acc o u nta bilit y rec or ds a n d fi n al rec o nciliati o n a n d a p plica bl e 
c orres p o n d e nce 
I n a d diti o n, all ori gi nal so urce d oc u m e nts s u p p orti n g e ntries i n t he case re p ort f or ms m ust 
be mai ntai ne d a n d b e rea dil y a vaila ble. 
All esse ntial d oc u me ntati o n will be retai ne d b y t he I n v esti gat or u ntil at least 2 years after 
t he last a p pr o val of a mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o 
pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 2 years ha v e 
la pse d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p m e nt of t he i n vesti gati o nal 
pr o d uct.  T hese d o c u me nts s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y 
t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he S p o ns or.  It is t he 
res p o nsi bilit y of t he S p o ns or t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t hese 
d oc u me nts n o l o n ger nee d t o be retai ne d. 
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt b et wee n D S P D 
a n d t he I n vesti gat or.  S h o ul d t he I n v esti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her 
part y or m o ve t he m t o a n ot her l ocati o n, he/s he m ust n otif y D S P D i n writi n g of t he n e w 
res p o nsi ble pers o n a n d/ or t he ne w l ocati o n. 
1 2. 6.  
Rec or d Kee pi n g 
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, dat a c orrecti o n f or ms, Case 
Re p ort F or ms ( C R Fs), i n ve nt or y of st u d y pr o d uct, re g ulat or y d oc u m e nts (i.e., pr ot oc ol 
a n d a me n d me nts, I R B/ E C c orres p o n de n ce a n d a p pr o vals, a p pr o v e d a n d si g ne d i nf or me d 
c o nse nt f or ms, I n v esti gat or’s A gree me nt, cli nical s u p plies recei pts, distri b uti o n a n d 
ret ur n rec or ds), a n d ot her S p o ns or c orres p o n d e nce pertai ni n g t o t he st u d y m ust be ke pt i n 
a p pr o priate st u d y files at t he sit e.  S o urce d oc u me nts i ncl u de all rec or di n gs a n d 
o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p orts a n d rec or ds n ecessar y f or 
t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hes e rec or ds will be retai ne d i n a 
sec ure file f or t he p eri o d re q uire d b y t he i nstit uti o n or site p olic y.  Pri or t o tra nsfer or 
destr ucti o n of t hese rec or ds D S P D  m ust be n otifie d i n writi n g a n d be gi v e n t he 
o p p or t u nit y t o f urt her st ore s uc h rec or ds. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 6 of 1 1 3 
1 3.  
FI N A N CI N G A N D I N S U R A N C E  
1 3. 1.  
F i n a nces 
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical 
st u d y a gree me nt wit h D S P D a n d/ or desi g n ee.  T his a gree m e nt will i ncl u de t he fi na ncial 
i nf or mati o n a gree d u p o n b y t he p arties. 
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce 
Rei m b urse me nt, i n de m nit y, a n d i ns ura nce s h all be a d dresse d i n a se parate a gree me nt o n 
ter ms a gree d u p o n b y t he parties. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 7 of 1 1 3 
1 4.  
P U B LI C A TI O N P O LI C Y 
A st u d y sit e ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter 
p u blicati o n has bee n s u b mitte d f or p u blicati o n or u ntil o ne year after t he st u d y has e n de d, 
w hic he ver occ urs first.  T heref ore, t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t he 
res ults of t he st u d y, pr o vi de d t hat Ar Q ule a n d Daii c hi Sa n k y o h a ve ha d t h e o p p ort u nit y 
t o re vie w a n d c o m me nt o n t he st u d y site’s pr o p os e d p u blicati o n pri or t o its bei n g 
s u b mitte d f or p u blicati o n wit h t he pri or a d vice of Ar Q ule a n d Daiic hi Sa n k y o Le gal 
Affairs (i ntellect ual pr o p ert y c o u ncil) a n d wit h pr o per re gar d t o t he pr ot ecti o n of 
s u bjects’ i de ntities. 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 8 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 8 9 of 1 1 3 
 
 
 
F or sites i n t he E ur o pea n U ni o n: 
 
 
 
F or sites i n Asia- Pacific: 
 
 
1 5. 2. 5. 
Pri nci p al I n vesti g at ors 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 0 of 1 1 3 
1 6.  
R E F E R E N C E S 
                                                 
1 G herar di E, Birc h meier W, Birc h meier C, Va n de W o u de G. T ar geti n g M E T i n ca ncer: rati o nale a n d 
pr o gress. N at Rev C a ncer . 2 0 1 2; 1 2( 2): 8 9- 1 0 3. d oi: 1 0. 1 0 3 8/ nrc 3 2 0 5. Re vie w. 
2 T a ka ya ma H, La R oc helle WJ, S har p R, et al. Di verse t u m ori ge nesis ass ociate d wit h a berra nt 
de vel o p me nt i n mice o ver e x pressi n g he p at oc yte gr o wt h fact or/scatter fact or. Pr oc N at Ac a d Sci.  
1 9 9 7; 9 4: 7 0 1- 6.  
3 F ur ge K A, Z ha n g Y W, Va n d e W o u de G F. Met rece pt or t yr osi ne ki nase: e n ha nce d si g nali n g 
t hr o u g h a d a pter pr otei ns. O nc o ge n e . 2 0 0 0; 1 9: 5 5 8 2-9.  
4 C hriste nse n J G, Sc hrec k R, B urr o ws J, et al. A selecti ve s mall m olec ule i n hi bit or of c- Met ki nase i n hi bits 
c-Met - de p e n de nt p he n ot y pes i n vitr o a n d e x hi bits c yt ore d ucti ve a ntit u m or acti vit y i n vi v o. C a ncer Res . 
2 0 0 3; 6 3: 7 3 4 5- 5 5.  
5 Tr us oli n o L, B ert otti A, C o m o gli o P M. Asi g nali n g a da pter f u ncti o n f or al p ha 6 beta 4 i nte gri n i n 
t he c o ntr ol of H G F- de p e n de nt i n vasi ve gr o wt h. Cell . 2 0 0 1; 1 0 7: 6 4 3- 5 4. 
6 T a via n D, De P G, B e netti A, et al. u _ P A a n d c- Met m R N A e x pressi o n is c o- or di natel y e n ha nce d w hile 
he p at oc yte gr o wt h fact or m R N A is d o w n-re g ulate d i n h u ma n he pat ocell ular carci n o ma. I nt J C a ncer . 
2 0 0 0; 8 7: 6 4 4- 9.  
7 A R Q 1 9 7 I n vesti gat or’s Br oc h ure. Ar Q ule, I nc. Versi o n 7: 2 6 J a n 2 0 1 2. 
8 Pre vi di S, A b ba d essa G, Dal ò F, Fra nce D S, Br o g gi ni M. Breast ca ncer- deri ve d b o ne metastasis ca n be 
effecti vel y re d uce d t hr o u g h s p ecific c- M E T i n hi bit or ti va nti ni b ( A R Q 1 9 7) a n d s h R N A c- M E T 
k n oc k d o w n. M ol C a ncer T her . 2 0 1 2; 1 1( 1): 2 1 4-2 3.  
9 Ar Q ule I nter nal data. T ec h nical Re p ort i n pre parati o n. 
1 0 L ü S, Rizza ni A, K olli gs F, G ö ke B, Ger bes A, De T o ni E. P 5. 3 1 A ntit u m or efficac y of t he c- met 
i n hi bit or ti va nti ni b ( A R Q- 1 9 7) i n li ver ca ncer cells: effects o n a p o pt osis a n d cell c ycle. A bstract t o be 
prese nte d at t he 2 0 1 2 G A S L  c o nfere nce. 
1 1 A R Q 1 9 7 I n vesti gat or’s Br oc h ure. Ar Q ule, I nc. Versi o n 7: 2 6 J a n 2 0 1 2. 
1 2 R ose n L S, Se nzer N, Me k hail T, et al. A p hase I d ose-escalati o n st u d y of Ti va nti ni b ( A R Q 1 9 7) i n a d ult 
patie nts wit h metastatic s oli d t u m ors. Cli n C a ncer Res . 2 0 1 1; 1 7( 2 4): 7 7 5 4-6 4.  
1 3 Ya p T A, Ol m os D, Br u nett o A T, et al. P hase I trial of a selecti ve c -M E T i n hi bit or A R Q 1 9 7 
i nc or p orati n g pr o of of mec ha nis m p har mac o d y na mic st u dies. J Cli n O nc ol . 2 0 1 1; 2 9( 1 0): 1 2 7 1-9.  
1 4 Nati o nal C o m pre he nsi ve Ca ncer Net w or k, Cli nical Practice G ui deli nes i n O nc ol o g y, He p at o biliar y 
Ca ncers, Versi o n 2. 2 0 1 2, 1 0/ 2 8/ 2 0 1 1, fr o m N C C N we bsite. 
1 5 Birc h meier C, G herar di E. De vel o p me ntal r oles of H G F/ S F a n d its rece pt or, t he c- Met t yr osi ne ki nase.     
Tre n ds Cell Bi ol.  1 9 9 8 Oct; 8( 1 0): 4 0 4-1 0.  
1 6 Birc h meier C, Birc h meier W, G herar di E, Va n de W o u de G F. Met, metastasis, m otilit y a n d m ore. N at 
Rev M ol Cell Bi ol . 2 0 0 3; 4( 1 2): 9 1 5-2 5.  
1 7 F ur ge K A, Z ha n g Y W, Va n d e W o u de G F. Met rece pt or t yr osi ne ki nase: e n ha nce d si g nali n g t hr o u g h 
a d a pter pr otei ns. O nc o ge n e . 2 0 0 0; 1 9( 4 9): 5 5 8 2- 9.  
1 8 Ke A W, S hi G M, Z h o u J, et al. R ole of o vere x pressi o n of C D 1 5 1 a n d/ or c- Met i n pre dicti n g pr o g n osis of 
he p at ocell ular carci n o ma. He p at ol . 2 0 0 9; 4 9( 2): 4 9 1- 5 0 3. 
1 9 Osa da S, Ka ne mats u M, I mai H, G os hi ma S. Cli nical si g nifi ca nce of ser u m H G F a n d c- M et e x pressi o n 
i n t u m or tiss ue f or e val uati o n of pr o perties a n d treat me nt of he pat ocell ular carci n o ma. 
He p at o g astr oe nter ol o gy . 2 0 0 8; 5 5( 8 2- 8 3): 5 4 4- 9.  
2 0 O ka n o J, S hi ota G, Ka wasa ki H. E x pressi o n of he pat oc yte gr o wt h fact or ( H G F) a n d H G F rece pt or (c-
met) pr otei ns i n li ver diseases: a n i m m u n o hist oc he mical st u d y. Liver . 1 9 9 9; 1 9( 2): 1 5 1-9.  
2 1 Ue ki T, F uji m ot o J, S uz u ki T, Ya ma m ot o H, O ka m ot o E. E x pressi o n of he pat oc yte gr o wt h fact or a n d its 
rece pt or, t he c- Met pr ot o- o nc o ge ne, i n He p at ocell ular carci n o ma. He p at ol . 1 9 9 7; 2 5( 3): 6 1 9- 2 3.  
2 2 W a n g Z L, Lia n g P, D o n g B W, Y u X L, Y u de J. Pr o g n osti c fact ors a n d rec urre nce of s mall 
He p at ocell ular carci n o ma after he p atic resecti o n or micr o wa ve a blati o n: a retr os pecti ve st u d y. J 
G astr oi ntest S ur g . 2 0 0 8; 1 2( 2) 3 2 7-3 7.  
2 3 Me ga J L, Cl ose S L, Wi vi ott S D, et al. C yt oc hr o me P -4 5 0 p ol y m or p his ms a n d res p o nse t o cl o pi d o grel.  N 
E n gl J Me d . 2 0 0 9; 3 6 0: 3 5 4– 6 2.  
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 1 of 1 1 3 
                                                                                                                                                 
2 4 Y o u nt S, Cella D, W e bster K, et al. Assess me nt of patie nt-r e p orte d cli nical he pat o biliar y ca ncers: T he 
F A C T He p at o biliar y S y m pt o m I n de x.  J P ai n a n d Sy m pt o m M a n a ge me nt . 2 0 0 2; 2 4: 3 2-4 4.  
2 5 E ur o Q ol Gr o u p. E ur o Q ol - a ne w facilit y f or t he meas ure me nt of healt h-relate d q ualit y of life.  Healt h 
P olic y 1 9 9 0; 1 6: 1 9 9- 2 0 8.  
2 6 Y o u nt S, Cella D, W e bster K, et al. Assess me nt of patie nt-r e p orte d cli nical o utc o me i n pa ncreatic a n d 
ot her he p at o biliar y ca ncers: T he F A C T He p at o biliar y S y m pt o m I n de x.  J o ur nal of P ai n a n d S y m pt o m 
Ma na ge me nt 2 0 0 2; 2 4: 3 2- 4 4. 
2 7 Fle mi n g T R. A d dressi n g Missi n g Data i n Cli nical Trials.  A n n I nter n Me d. 2 0 1 1; 1 5 4: 1 1 3-1 1 7.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7- A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
 
C o nfi de ntial 
Pa ge 9 2 of 1 1 3 
 
1 7.  
A P P E N DI C E S 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7- A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 6 of 1 1 3 
9.  He mat ol o g y sa m ples will be teste d l ocall y (eit her at site or at la b near t he s u bj ect’s l ocati o n) wit h res ults re vie we d b y t he site st u d y tea m. F or t he first 
2 c ycles, res ults m ust b e re vie we d t he sa me da y t he test is d o ne a n d pri or t o t he s u bj ect c o nti n ui n g t o d ose. 
1 0.  If n ot restricte d b y l ocal re g ul ati o n; ma y i ncl u de o pti o nal ba n ki n g of sa m ples ( per i nf or me d c o nse nt) 
1 1.  Da y 1 of C ycles 2, 3, a n d 4  
1 2.  Da y 1 of C ycles 2 a n d 3 
1 3.  Refer t o Secti o n 8. 1 .  N o a d diti o nal sa m ple nee de d if c oi nci des wit h sc he d ule d P K sa m pli n g 
1 4  
P erf or me d at ± 3 0 mi n utes fr o m ti me of 1- 3 h o urs a n d 4- 8 h o urs p ost d ose P K sa m ples o n C 1 D 1 a n d at ± 3 0 mi n utes fr o m ti me of pre d ose P K sa m ple o n 
C 1 D 2 1.  
1 5. At C ycle 2 o nl y.  H o we ver, s u bj ects wit h heart rate < 5 0 b p m d uri n g t he first c ycle will als o ha ve E C G teste d at e ver y c ycle t hereafter.   If after data b ase 
l oc k a n d st u d y u n bli n di n g a patie nt ori gi nall y ra n d o mize d t o place b o cr osses o ver t o ti va nti ni b, t he y will ha ve a n E C G pri or t o t he first d ose a n d a gai n 
o n Da y 1 of t he f oll o wi n g c ycl e. S uc h s u bj ects wit h heart rat e < 5 0 b p m d uri n g t he first m o nt h o n ti va nti ni b will als o ha ve E C G teste d at e ver y c ycle 
t hereafter 
1 6. 
Wit hi n 2 1 da ys of ra n d o mizati o n 
1 7. I n 8- wee k i nter vals fr o m C 1 D 1 u ntil c o nfir me d ra di o gra p hic pr o gressi ve disease (- refer t o Secti o n 4. 2. 1 ), s u bj ect deat h, or l oss t o f oll o w- u p. Wi n d o w 
of  ± 3 da ys per mitte d f or t he t u m or assess me nt sca ns. 
1 8. If n ot d o ne wit hi n 1 4 da ys. S u bj ects w h o disc o nti n ue t heir assi g ne d treat me nt f or a reas o n ot her t ha n disease pr o gressi o n, wit h dra wal of c o nse nt, deat h, 
or l oss t o f oll o w- u p s h o ul d c o nti n ue t u m or e val uati o n visits at 8- wee k i nter vals if p ossi ble u ntil disease pr o gressi o n, wit h dra wal of c o nse nt, deat h, start 
of s u bse q ue nt a nti-ca ncer t her a p y, or l oss t o f oll o w- u p . 
1 9. O pti o nal Bi o ps y after Da y 2 2 a n d prefera bl y bef ore Da y 3 0 a n d a gai n at E n d of Treat me nt. F N A is n ot acce pta ble u nless it ca n be pre p are d as per t he 
la b ma n ual. 
2 0 . A n y me dicati o n t he s u bj ect t o o k wit hi n 3 0 da ys fr o m ra n d o mizati o n 
2 1. Ca n be d o ne eit her i n pers o n or o ver t he p h o ne 
2 2. He mat ol o g y res ults m ust b e verifie d pri or t o dis pe nsi n g st u d y dr u g t o s u bj ect 
2 3 .  If after data b ase l oc k a n d st u d y u n bli n di n g a patie nt ori gi nall y ra n d o mize d t o place b o cr osses o ver t o ti va nti ni b, he mat ol o g y will be teste d e ver y 4 da ys 
for t he first m o nt h a n d wee kl y f or t he sec o n d m o nt h after starti n g ti va nti ni b 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7- A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
 
C o nfi de ntial 
Pa ge 9 7 of 1 1 3 
 
1 7. 2.  
E C O G Perf or m a nc e St at us  
 
Gr a de  
Descri pti o n  
0  
N or mal acti vit y.  F ull y acti ve, a ble t o carr y o n all pre -diseas e perf or ma nce wit h o ut 
restricti o n. 
1  
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y 
a n d a ble t o carr y o ut w or k of a li g ht or se de ntar y nat ure (e. g., li g ht h o use w or k, office 
w or k).  
2  
I n be d < 5 0 % of t he ti me.  A m b ulat or y a n d ca pa ble of all self-care, b ut u na ble t o carr y 
o ut a n y w or k acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.  
3  
I n be d > 5 0 % of t he ti me.  Ca p a ble of o nl y li mite d self-care, c o nfi ne d t o be d or c hair 
m ore t ha n 5 0 % of wa ki n g h o urs.  
4  
1 0 0 % be dri d de n.  C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y 
c o nfi ne d t o be d or c hair.  
5  
Dea d.  
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 8 of 1 1 3 
1 7. 3.  
E x a m ples of i n vi v o S u bstr ates, I n hi bit ors, a n d I n d ucers f or s pecific C Y P e nz y mes 
f or st u d y 
 
C Y P  
S u bstr ate  
I n hi bit or 
I n d ucer 
2 C 1 9  o me praz ole, es o praz ole,  
la ns o praz ole, pa nt o praz ole  
o me praz ole, fl u v o xa mi ne, 
m ocl o be mi de, fl uc o naz ole, 
ticl o pi di ne, ra be praz ole, fl u o xeti ne 
 
rifa m pi n  
3 A 4/  
3 A 5  
   
mi daz ola m, b us pir o ne,  
fel o di pi ne,  
l o vastati n, 
eletri pta n, 
sil de nafil, 
si m vastati n, 
triaz ola m  
ataza na vir, clarit hr o m yci n, 
i n di na vir, 
itrac o naz ole, 
ket oc o naz ole, 
nefaz o d o ne, 
nelfi na vir, 
rit o navir, 
sa q ui na vir, 
telit hr o m yci n  
rifa m pi n, 
car ba maze pi ne  
* N ote t hat t his is n ot a n e x ha usti ve list (create d Ma y 1, 2 0 0 6).  
A d o pte d fr o m: htt p:// w w w.f da. g o v/ C der/ dr u g/ dr u gI nteracti o ns/ta ble S u bstrates. ht m #classI n hi bit 
S u bstrates f or a n y p artic ular C Y P e nz y me liste d i n t his ta ble are t h ose wit h plas ma A U C val ues 
i ncreas e d b y 2-f ol d or hi g her w he n c o-a d mi nistere d wit h i n hi bit ors of t hat C Y P e nz y m e; f or 
C Y P 3 A, o nl y t h ose wit h plas ma A U C i ncrease d b y 5-f ol d or hi g her are list e d. I n hi bit ors liste d 
are t h ose t hat i ncreas e pl as ma A U C val ues of s u bstrates f or t hat C Y P e nz y me b y 2-f ol d or 
hi g her. F or C Y P 3 A i n hi bit ors, o nl y t h ose t hat i ncrease A U C of C Y P 3 A s u bstrates b y 5-f ol d or 
hi g her are liste d. I n d ucers liste d are t h ose t hat d ecrease pl as ma A U C val ues of s u bstrates f or t hat 
C Y P e nz y m e b y 3 0 % or hi g her.  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 9 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 9 9 of 1 1 3 
1 7. 4.  
L i ver St at us –  C hil d- P u g h Cl assific ati o n 
 
P ar a meter  
P oi nts assi g ne d  
1  
2  
3  
Ascites *  
A bse n t 
Sli g ht  
M o derate  
Bilir u bi n, m g/ d L  
< 2  
2 -3  
> 3  
Al b u mi n, g/ d L  
> 3. 5  
2. 8 -3. 5  
< 2. 8  
P r ol o n ge d pr ot hr o m bi n ti me, 
sec o n ds  **  
(or I N R ) 
  
1 -3   
( < 1. 7) 
  
4 -6   
( 1. 7-2. 3)  
  
> 6   
( > 2. 3) 
E nce p hal o pat h y * * *  
N o ne  
Gra de 1 -2  
Gra de 3 -4  
 
* Ascites as per p h ysical e xa mi nati o n assess me nt ( m ust be pal pa ble), n ot per ra di o gra p hic assess me nt, i n a s u bj ect 
ta ki n g n o m ore t ha n 1 0 0 m g s pir o n olact o ne ( or e q ui vale nt di uretic) per da y; s u bj ects w h o nee d m ore t ha n 1 0 0 m g 
s pir o n olact o ne ( or e q ui vale nt di uretic) per da y t o c o ntr ol ascites m ust be assi g ne d 1 e xtra p oi nt. 
* *   F or s u bj ects o n a ntic oa g ul a nt t hera p y s uc h as warfari n/ he pari n use t he P T val ue a n d detract o ne p oi nt fr o m t he 
P T  sc ore if P T is pr ol o n ge d b y m ore t ha n 3 sec o n ds a b o ve t he u p per li mit of n or mal.  
* * * E nce p hal o pat h y gra d es: 
 
Gra d e 0: n or mal c o nsci o us ness, pers o nalit y, ne ur ol o gical e xa mi nati o n, electr oe nce p hal o gr a m 
 
Gra d e 1: restless, slee p dist ur b e d, irrita ble/a gitate d, tre m or, i m paire d ha n d writi n g, 5 c ps wa ves 
 
Gra d e 2: let har gic, ti me- dis ori e nte d, i na p pr o priate, asteri xis, ata xia, sl o w tri p hasic wa ves 
 
Gra d e 3: s o m n ole nt, st u p or o us, place- dis orie nte d, h y peracti ve refle xes, ri gi dit y, sl o wer wa ves 
 
Gra d e 4: u nr o usa ble c o ma, n o pers o nalit y/ be ha vi or, decere brate, sl o w 2- 3 c ps delta acti vit y  
 
Assess me nt as g o o d o perati ve ris k ( A) if 5 or 6 p oi nts; m o derate ris k ( B) if 7 t o 9 p oi nts, a n d p o o r 
o perati ve ris k ( C) if 1 0 t o 1 5 p oi nts ( de vel o pe d f or s ur gical e val uati o n of alc o h olic cirr h otics).  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 0 of 1 1 3 
1 7. 5.  
T he Criteri a C o m mittee of t he Ne w Y or k He art Ass oci ati o n.  
 
N o me nclat ure a n d Criteri a f or Dia g n osis of Diseas es of t he Heart a n d Great Vessels. 9t h e d. 
B ost o n, Mass: Little, Br o w n & C o; 1 9 9 4: 2 5 3- 2 5 6. 
 
F u ncti o n al C a p acit y   
O bjecti ve Assess me nt   
Cl ass I. P atie nts wit h car diac disease b ut wit h o ut res ulti n g li mitati o n of p h ysical 
acti vit y. Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue fati g ue, pal pitati o n, 
d ys p nea, or a n gi nal pai n.  
A.  N o o bj ecti ve e vi de nce of 
car di o vasc ular disease.  
Cl ass II.  P atie nts wit h car diac disease res ulti n g i n sli g ht li mitati o n of p h ysical 
acti vit y. T he y are c o mf orta ble at rest. Or di nar y p h ysical acti vit y res ults i n fati g ue, 
pal pitati o n, d ys p nea, or a n gi nal pai n.  
B.  O bj ecti ve e vi de nce of 
mi ni mal car di o vasc ular 
disease.  
Cl ass III.  P atie nts wit h car diac disease res ulti n g i n mar ke d li mitati o n of p h ysical 
acti vit y. T he y are c o mf orta ble at rest. Less t ha n or di nar y acti vit y ca uses fati g ue, 
pal pitati o ns, d ys p nea, or a n gi nal pai n.  
C.  O bj ecti ve e vi de nce of 
m o deratel y se vere 
cardi o vasc ular disease.  
Cl ass I V.  P atie nts wit h car diac disease res ulti n g i n i na bilit y t o carr y o n a n y p h ysical 
acti vit y wit h o ut disc o mf ort. S y m pt o ms of heart fail ure or t he a n gi nal s y n dr o me ma y 
be prese nt e ve n at rest. If a n y p h ysical acti vit y is u n derta ke n , disc o mf ort is 
i ncrease d. 
D.  O bj ecti ve e vi de nce of 
se vere car di o vasc ular disease. 
 
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 1 of 1 1 3 
1 7. 6.  
P h ar m a c o ki netics  
 

C ycle 1, Da y 1: t w o sa m ples 
o  O ne  bl o o d dra w b et wee n 1 a n d 3 h o urs aft er t he first d ose of ti va nti ni b/ place b o 
o  O ne  bl o o d dra w b et wee n 4 a n d 8 h o urs aft er t he first d ose of ti va nti ni b/ place b o 
 C ycle 1, Da y 2 1: t w o sa m ples 
o  O ne  bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
o  O ne  bl o o d dra w at least o ne h o ur aft er t he m or ni n g d ose of ti va nti ni b/ place b o 
 C ycle 2, Da y 1: o ne sa m ple 
o  O ne  bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
 C ycle 3, Da y 1: o ne sa m ple 
o  O ne  bl o o d dra w at a n y ti me after t h e m or ni n g d os e of ti va nti ni b/ place b o 
 
If t he s u bject starts recei vi n g a C Y P 2 C 1 9 a n d/ or C Y P 3 A 4 i n hi bit or/i n d ucer at a n y c ycle after 
cycle 3, 2 bl o o d sa m ples s h o ul d be c ollecte d, if p ossi ble, w hile t he s u bject is o n t he c o nc urre nt 
st u d y dr u g: 
 O ne bl o o d dra w b ef ore t he m or ni n g d os e of ti va nti ni b/ place b o 
 O ne bl o o d dra w at least 1 h o ur after t h e m or ni n g d ose of ti va nti ni b/ place b o 
If a s u bject e x perie nces Gra de ≥ 2  n e utr o pe nia, if p ossi ble, c ollect 1 p har mac o ki netic bl o o d 
sa m ple at a n yti me d uri n g t he d osi n g peri o d b ut bef ore a n y d os e s us pe nsi o n or re d ucti o n is 
a p plie d.  D o n ot dela y d ose s us pe nsi o n or re d u cti o n. 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 2
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 2 of 1 1 3 
1 7. 7.  
P ati e nt re p orte d o utc o mes q uesti o n n aires i nf or m ati o n s heet –  F A C T- He p a n d 
E Q -5 D 
F u ncti o n al Assess me nt of C a ncer T her a p y  He p at o bili ar y ( F A C T- He p) Q uesti o n n aire - 
G ui deli nes f or A d mi nistr at i o n3 
T hese g ui deli nes ass u me t hat a n a p pr o pri ate pers o n has bee n desi g n ate d t o facilitate t he self-
a d mi nistrati o n of t he q uesti o n naire. 
W he n a n d h o w s h o ul d t he q uesti o n n aire be a d mi nistere d ? 
T he F A C T- He p s h o ul d b e c o m plete d b y t he s u bject wit h o ut assista nce d uri n g his or her 
sc he d ule d visits at t he cli nic. T he F A C T- Hep s h o ul d be a d mi nistere d at t he start of t he visit, 
bef ore t h e s u bject sees t he p h ysici a n, s o t hat a n y i nteracti o n bet w ee n t he s u bject a n d p h ysicia n 
will n ot i nfl ue nce t he s u bject’s res p o ns es t o t he q uesti o n naire.  T he q u esti o n naires s h o ul d als o be 
a d mi nistere d bef ore t he s u bject is as ke d a b o ut a d verse e x perie n ces a n d c o n c urre nt ill nesses, 
a gai n s o t hat a n y disc ussi o ns of healt h pr o ble ms d o n ot i nfl ue nce t he s u bject’s res p o nses.  T h e 
F A C T- H e p is t o be a d mi nistere d o n Da y 1 of e ver y c ycle a n d at E n d of Treat me nt.  
A q uiet place s h o ul d be pr o vi de d f or t he s u bject t o c o m plete t he q uesti o n naire. It is i m p orta nt 
t hat t he s u bject c o m pletes t he q uesti o n naire al o ne, wit h o ut a n y a d vi ce fr o m fa mil y me m bers or 
frie n ds w h o ma y acc o m p a n y t he m. O n a vera ge, it ta kes less t ha n 1 0 mi n utes t o c o m plete t he 
q uesti o n naire. 
S u bjects m ust ha ve basic fl ue nc y i n t he la n g ua ge of t heir c o u ntr y i n or d er t o c o m plete t he 
F A C T- H e p. If a s u bject is n ot a ble t o s pea k/rea d t he la n g ua ge of his/ her c o u ntr y, c h ec k if t h e 
s u bject has basic fl u e nc y i n a ny of t h e la n g ua ges i n w hic h t he q uesti o n nair e is c urre ntl y a v aila ble 
a n d w hic h has b ee n a p pr o ve d b y t h e sites I R B/I E C.  
H o w s h o ul d t he q uesti o n n aire be i ntr o d uce d ? 
A sa m ple scri pt f or i ntr o d uci n g t he q u esti o n naire is gi ve n bel o w. 
“ Y o ur d oct or w o ul d li ke t o better u n dersta n d h o w y o u feel, h o w well y o u are a ble t o d o y o ur 
us ual acti vities, a n d h o w y o u rate y o ur healt h. T o hel p us better u n derst a n d t hese t hi n gs a b o ut 
y o u, ple ase c o m plete t his q uesti o n naire a b o ut y o ur healt h.  T he q uesti o n nair e is eas y t o fill o ut. 
T he i nstr ucti o ns are o n t h e fr o nt c o v er ( p oi nt t o t he m). Y o u s h o ul d rea d eac h q uesti o n a n d t he n 
circle t he a p pr o priat e n u m ber t hat matc hes y o ur a ns wer. Re me m ber t h at t his is n ot a test a n d 
t here are n o ri g ht or wr o n g a ns wers.  C h o ose t he a ns wer t hat b est descri bes t he wa y y o u feel.  I 
will q uic kl y re vie w t he q uesti o n naire w he n y o u are fi nis he d t o ma ke s ure t hat all of t he q uesti o ns 
ha ve bee n a ns were d. Y o u s h o ul d a ns wer t hese q u esti o ns b y y o urself.  Y o ur s p o use or ot her 
fa mil y me m bers s h o ul d n ot hel p y o u w he n y o u a ns wer t he q uesti o n nair e.  I will be near b y i n 
case y o u w a nt t o as k me a n y q u esti o ns.  Please ret ur n t he q uesti o n naire t o me w he n y o u ha v e 
fi nis he d.” 
                                                 
3 T hese g ui deli nes are a da pte d fr o m q uesti o n naire a d mi nistrati o n g ui deli nes d e vel o pe d b y t he De part me nt of Q ualit y Ass ess me nt, Ne w E n gla n d 
Me dical Ce nter H os pitals  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 3 of 1 1 3 
W h at t o d o if t he s u bject as ks f or cl arific ati o n ? 
S o me s u bjects ma y as k t he mea ni n g of s pecific q uesti o ns. If t his ha p pe ns, t he staff me m ber ca n 
assist t he s u bject b y re-rea di n g t he q u esti o n f or t he m ver bati m.  If t he s u bject as ks w hat 
s o met hi n g mea ns, d o n ot tr y t o e x plai n w hat t he q uestio n mea ns, b ut tactf ull y s u g gest t hat t he 
s u bject use his/ her o w n i nter pretati o n of t he q u esti o n.  All s u bjects s h o ul d a ns wer t he q u esti o ns 
base d o n w hat t he y t hi n k t he q uesti o ns mea n, or t he st u d y res ults ma y b e biase d. 
Q uesti o n n aire c o m pleti o n:  
W he n t he s u bject ret ur ns t he q uesti o n naire, c h ec k t hat all of t he q uesti o ns ha ve bee n a ns were d. If 
t he q uesti o n naire is n ot c o m plete, p oi nt o ut t o t he s u bject t hat s o me of t he q uesti o ns were n ot 
a ns were d.  If t he s u bj ect d oes n ot q uic kl y v ol u nteer t o a ns wer t hese ite ms, as k hi m/ her w het her 
s he ha d a n y diffic ult y c o m pleti n g t he q uesti o n nair e. If t he s u bject sa ys t hat he/s he ha d tr o u ble 
u n dersta n di n g a q uesti o n, as k hi m/ her w h y he/s he ha d diffic ult y wit h t hat ite m.  Re-rea d t he 
q uesti o n f or hi m/ her ver bati m, b ut d o n ot atte m pt t o e x plai n or re w or d t he q uesti o n, as e x plai ne d 
bef ore.  If t he s u bject is still u na ble t o a ns wer t he q uesti o n, acce pt t he q u esti o n naire as is. 
S o me s u bjects ma y b e c o nf use d b y t he res p o nse c h oices.  T he y ma y wa nt t o res p o n d wit h “I 
d o n’t k n o w” or s o me ot h er res p o ns e c h oice t hat is n ot a vaila ble.  If t his ha p pe ns, tr y t o h el p t he 
s u bject c h o ose o ne of t he res p o nse cate g ories b y s a yi n g s o met hi n g li ke: “I k n o w t hat it ma y be 
diffic ult f or y o u t o c h o os e a n a ns w er, b ut w hic h o f t hese a ns w ers d o y o u t hi n k c o mes cl osest t o 
t he wa y t hat y o u are t hi n ki n g or feeli n g? ”  If t he s u bject still ca n n ot select a n a ns wer, acce pt t he 
q ue sti o n naire as is. 
Occasi o nall y, s u bjects ma y n ot r e p ort ha vi n g diffic ult y wit h a q uesti o n or t he res p o ns e c h oices, 
b ut still ma y hesitate or ref use t o a ns wer a n ite m or ite ms.  If t his ha p pe ns, acce pt t he 
q uesti o n naire as is. 
If a s u bject as ks f or i nter pretati o n of his/ her res p o nses or as ks f or his/ her sc ores o n t he 
q uesti o n naire, tell hi m/ her t hat y o u are n ot trai ne d t o sc ore or i nter pret t he q uesti o n naire.  
E m p hasiz e t hat t heir a ns wers will be ke pt c o nfi de ntial. 
C o m plete d q uesti o n n aire: 
T ha n k t he s u bject o nce h e/s he has c o m plete d t h e q uesti o n naire a n d y o u h a ve c hec ke d it f or 
c o m plete ness. 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 4
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 4 of 1 1 3 
F A C T - He p ( versi o n 4) Q uesti o n n aire  
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are i m p orta nt . 
Ple ase circle or m ar k o ne n u m ber per li ne t o i n dic ate y o ur res p o nse as it a p plies t o 
t he p ast 7 d a ys. 
 
 
 
P H Y SI C A L W E L L -B EI N G  
 
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
G P 1  
I h a ve a l ac k of e ner g y .....................................
  
0  
1  
2  
3  
4  
G P 2  
I h a ve na us ea ....................................................
  
0  
1  
2  
3  
4  
G P 3  
Beca use of m y p h ysic al c o n diti o n, I ha ve 
tr o u ble meeti n g t h e nee ds of m y fa mil y ...........
  
 
0  
 
1  
 
2  
 
3  
 
4  
G P 4  
I h a ve pai n ........................................................
  
0  
1  
2  
3  
4  
G P 5  
I a m b ot here d b y si de effects of treat me nt .......
  
0  
1  
2  
3  
4  
G P 6  
I feel ill .............................................................
  
0  
1  
2  
3  
4  
G P 7  
I a m f orce d t o s pe n d ti me i n be d ......................
  
0  
1  
2  
3  
4  
 
 
S O CI A L/ F A MI L Y W E L L -B EI N G  
 
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
G S 1  
I feel cl ose t o m y frie n ds  ..................................
  
0  
1  
2  
3  
4  
G S 2  
I get e m oti o nal s u p p ort fr o m m y fa mil y ..........
  
0  
1  
2  
3  
4  
G S 3  
I get s u p p ort fr o m m y fri e n ds ...........................
  
0  
1  
2  
3  
4  
G S 4  
M y fa mil y has acce pte d m y ill ness  ..................
  
0  
1  
2  
3  
4  
G S 5  
I a m satisfie d wit h fa mil y c o m m u nicati o n 
a b o ut m y ill ness ................................................
  
 
0  
 
1  
 
2  
 
3  
 
4  
G S 6  
I feel cl ose t o m y p art ner ( or t he pers o n w h o 
is m y mai n s u p p ort) ..........................................
  
 
0  
 
1  
 
2  
 
3  
 
4  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 5
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 5 of 1 1 3 
 
Q 1  
Re g ar dless of y o ur c urre nt level of sex u al 
activity, ple ase a ns wer t he f oll o wi n g q uesti o n. If 
y o u prefer n ot t o a ns wer i  le ase m ar k t his b ox           
a n d g o t o t he next secti o n. 
 
 
 
 
 
G S 7  
I a m satisfie d wit h m y s e x life .........................
  
0  
1  
2  
3  
4  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 6
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 6 of 1 1 3 
Ple ase circle or m ar k o ne n u m ber per li ne t o i n dic ate y o ur res p o nse as it a p plies t o 
t he p ast 7 d a ys. 
 
 
 
E M O TI O N A L W E L L -B EI N G  
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
G E 1  
I feel sa d ..............................................................
  
0  
1  
2  
3  
4  
G E 2  
I a m satisfie d wit h h o w I a m c o pi n g wit h m y 
ill ness ...................................................................
  
0  
1  
2  
3  
4  
G E 3  
I a m l osi n g h o pe i n t he fi g ht a gai nst m y ill ness ..
  
0  
1  
2  
3  
4  
G E 4  
I feel n er v o us .......................................................
  
0  
1  
2  
3  
4  
G E 5  
I w orr y a b o ut d yi n g .............................................
  
0  
1  
2  
3  
4  
G E 6  
I w orr y t hat m y c o n diti o n will get w ors e  ............
  
0  
1  
2  
3  
4  
 
 
 
 
F U N C TI O N A L W E L L -B EI N G  
 
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
G F 1  
I a m a ble t o w or k (i ncl u d e w or k at h o me) ..........
  
0  
1  
2  
3  
4  
G F 2  
M y w or k (i ncl u de w or k at h o me) is f ulfilli n g  .....
  
0  
1  
2  
3  
4  
G F 3  
I a m a ble t o e nj o y life  ..........................................
  
0  
1  
2  
3  
4  
G F 4  
I h a ve acce pte d m y ill ness ...................................
  
0  
1  
2  
3  
4  
G F 5  
I a m slee pi n g well ...............................................
  
0  
1  
2  
3  
4  
G F 6  
I a m e nj o yi n g t h e t hi n gs I us u all y d o f or f u n ......
  
0  
1  
2  
3  
4  
G F 7  
I a m c o nte nt wit h t he q ualit y of m y life ri g ht 
 
  
0  
1  
2  
3  
4  
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 7
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 7 of 1 1 3 
 
Ple ase circle or m ar k o ne n u m ber per li ne t o i n dic ate y o ur res p o nse as it a p plies t o 
t he p ast 7 d a ys. 
 
 
 
A D DI TI O N A L C O N C E R N S  
 
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
C 1  
I h a ve s w elli n g or cra m ps i n m y st o mac h 
 
 
0  
1  
2  
3  
4  
C 2  
I a m l osi n g w ei g ht  ...........................................
 
0  
1  
2  
3  
4  
C 3  
I h a ve c o ntr ol of m y b o w els ............................
 
0  
1  
2  
3  
4  
C 4  
I ca n di gest m y f o o d w ell ................................
 
0  
1  
2  
3  
4  
C 5  
I h a ve diarr hea ( diarr h oea) ..............................
 
0  
1  
2  
3  
4  
C 6  
I h a ve a g o o d a p petite ......................................
 
0  
1  
2  
3  
4  
He p
1  
I a m u n ha p p y a b o ut a c h a n ge i n m y 
 
 
0  
1  
2  
3  
4  
C N S
7  
I h a ve pai n i n m y bac k ....................................
 
0  
1  
2  
3  
4  
C x 6  
I a m b ot here d b y c o nsti pati o n .........................
 
0  
1  
2  
3  
4  
H 1 7  
I feel f ati g u e d ...................................................
 
0  
1  
2  
3  
4  
A n 7  
I a m a ble t o d o m y us ual acti vities ..................
 
0  
1  
2  
3  
4  
He p
2  
I a m b ot here d b y j a u n dic e or yell o w c ol or t o 
m y s ki n  
 
0  
1  
2  
3  
4  
He p 
3  
I h a ve ha d fe v ers (e pis o d es of hi g h b o d y 
 
 
0  
1  
2  
3  
4  
He p 
4  
I h a ve ha d itc hi n g ............................................
 
0  
1  
2  
3  
4  
He p 
5  
I h a ve ha d a c h a n ge i n t h e wa y f o o d tast es .....
 
0  
1  
2  
3  
4  
He p 
6  
I h a ve ha d c hills ...............................................
 
0  
1  
2  
3  
4  
H N 
2  
M y m o ut h is dr y  ..............................................
 
0  
1  
2  
3  
4  
He p 
8  
I h a ve disc o mf ort or pai n i n m y st o mac h 
 
 
0  
1  
2  
3  
4  
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 8
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 8 of 1 1 3 
P ati e nt Re p orte d  O utc o mes ( P R O) Q uesti o n n aire I nf or m ati o n S heet – F A C T- He p 
In str u cti o n s: 
- T hi s i nf or m ati o n s h e et i s t o b e c o m pl et e d b y t h e st u d y n ur s e/i n v e sti g at or.  
- T hi s i nf or m ati o n s h e et m u st b e c o m pl et e d f or all s u bj e ct s at e a c h vi sit i n w hi c h t h e 
pr ot o c ol r e q uir e s P ati e nt -R e p ort e d O ut c o m e a s s e s s m e nt, w h et h er or n ot t h e 
q u e sti o n n air e h a s b e e n c o m pl et e d b y t h e s u bj e ct . 
- W h e n t h e s u bj e ct  r et ur n s t h e q u e sti o n n air e 
 
 
C o m pl et e t h e i nf or m ati o n s h e et.  
 
 
Pl e a s e c h e c k t h at t h e s u bj e ct  h a s a n s w er e d all q u e sti o n s a n d n o q u e sti o n h a s 
m or e t h a n o n e a n s w er.  
 
1. W a s t h e q u e sti o n n air e pr o vi d e d t o t h e s u bj e ct  at t hi s  
    vi sit ?  
     1  N o  
 
      2  Y e s  
If Y E S, c o nti n u e a n d a n s w er Q. 2- 4 
If N O, g o t o Q. 5 
 
2. D at e q u e sti o n n air e a n s w er e d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d  d  m  m  y  y  y  y  
 
3. W a s t h e q u e sti o n n air e a n s w er e d pri or t o cli ni c al  
    e x a mi n ati o n ?  
     1  N o  
 
        2  Y e s  
 
4. W er e all q u e sti o n s a n s w er e d ?  
     1  N o  
 
        2  Y e s  
If Y E S, st o p 
If N O, c o nti n u e 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 0 9
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 0 9 of 1 1 3 
5. If N o, s p e cif y  r e a s o n q u e sti o n n air e w a s n ot a n s w er e d: 
 
S u bj e ct  w a s o n -sit e b ut f elt t o o ill  
 
S u bj e ct  r ef u s e d t o c o m pl et e q u e sti o n n air e f or r e a s o n ot h er t h a n ill n e s s 
 
S u bj e ct  di d n ot k e e p a p p oi nt m e nt - If t hi s i s t h e r e a s o n a n d t h e vi sit w a s 
r e s c h e d ul e d, a n s w er Q. 6  
 
Q u e sti o n n air e n ot a d mi ni st er e d ( alt h o u g h t h e s u bj e ct  w a s o n -sit e)  d u e t o i n stit uti o n 
err or - If t hi s i s t h e r e a s o n. N ot e t h at if t h e q u e sti o n n air e w a s n ot a d mi ni st er e d d u e 
t o i n stit uti o n err or, n o att e m pt c a n b e m a d e t o s u b s e q u e ntl y a d mi ni st er t h e 
q u e sti o n n air e vi a t el e p h o n e, e m ail, dir e ct m ail or ot h er m e a n s, o n c e t h e s u bj e ct  h a s 
l eft t he sit e, o n t h at vi sit.  
 
Ot h er, pl e a s e s p e cif y:  
 
 
 
6. If s u bj e ct di d n ot k e e p hi s/ h er a p p oi nt m e nt or q u e sti o n n air e n ot a d mi ni st er e d d u e t o 
i n stit uti o n al err or: 
 
W a s t h e q u e sti o n n air e c o m pl et e d at a r e s c h e d ul e d 
vi sit t h at o c c urr e d wit hi n 7 d a y s of t h e ori gi n all y 
s c h e d ul e d vi sit d a y ?  
     N o  
 
      Y e s  
If N O, st o p 
If Y E S, c o nti n u e 
N ot e: t h e q u e sti o n n air e m u st b e c o m pl et e d i n p er s o n at t h e r e- s c h e d ul e d vi sit 
 
D at e q u e sti o n n air e w a s c o m pl et e d  at t h e r e s c h e d ul e d vi sit:  
 
 
 
 
 
 
 
 
                                                                                     
 
 
 
 
 
 
 
 
 
d  d  m  m  y  y  y  y  
 
 
 
 
 
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 1 0
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 1 0 of 1 1 3 
P ati e nt Re p orte d  O utc o mes ( P R O) Q uesti o n n aire I nf or m ati o n S heet – E Q -5 D 
B y placi n g a c hec k mar k i n o ne b o x i n eac h gr o u p bel o w, please i n dicate w hic h state me nts best 
descri be y o ur o w n healt h state t o da y. 
 
M o bilit y 
I h a ve n o pr o bl e ms i n wal ki n g a b o ut              
  
  
 
 
I h a ve s o me pr o ble ms i n wal ki n g a b o ut   
  
  
  
 
 
I a m c o nfi ne d t o b e d   
  
  
  
  
  
  
  
  
 
 
 
Self- C are  
I h a ve n o pr o bl e ms wit h self-care  
  
  
  
  
  
 
 
I h a ve s o me pr o ble ms was hi n g or dressi n g m yself   
 
 
I a m u na ble t o was h or dress m yself   
  
  
  
  
 
 
 
Us u al Acti vities (e. g. w ork, st u dy, h o use w ork, f a mily or 
leis ure activities) 
I h a ve n o pr o bl e ms wit h perf or mi n g m y us ual acti vities  
 
I h a ve s o me pr o ble ms wit h perf or mi n g m y us u al acti vities  
I a m u na ble t o perf or m m y us ual a cti vities   
  
  
 
 
 
P ai n/ Disc o mf ort 
I h a ve n o pai n or disc o mf ort   
  
  
  
  
  
  
 
 
I h a ve m o derate p ai n or disc o mf ort   
  
  
  
  
 
 
I h a ve e xtre me p ai n or disc o mf ort 
  
  
  
  
  
 
 
 
A n xiet y/ De pressi o n  
I a m n ot a n xi o us or de presse d  
  
  
  
  
  
  
 
 
I a m m o derat el y a n xi o us or de press e d 
  
  
  
  
 
 
I a m e xtre mel y a n xi o us or de press e d   
  
  
  
  
 
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 1 1
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 1 2 of 1 1 3 
1 7. 8. 
H os p it aliz ati o n S u b- F or m 
 
H os pit aliz ati o n  
# 1  
H os pit aliz ati o n #  2  
H os pit aliz ati o n  
# 3  
D ate a n d Ti me of 
A d missi o n  
Date:  
D D/ M M/ Y Y Y Y  
 
Date: D D/ M M/ Y Y Y Y  
 
Date: 
D D/ M M/ Y Y Y Y  
 
Fi n al A dj u dic ate d 
Re as o n f or 
H os pit aliz ati o n  
C hec k O N E:  
- Gra d e >  3 ne utr o pe nia/fe ver  
- Ras h/ Ha n d -f o ot s y n dr o me 
- Ne w/ metastatic mali g na nc y (s pecif y 
site) 
- S p o nta ne o us B acterial 
P erit o nitis/ ot her i nfecti o n (s pe cif y)  
- U nc o ntr olle d ascites  
- Ot her (s pecif y) _ _ _ _  
 
 
N at ure of 
h os pit aliz ati o n  
C hec k O N E  
-    Ur ge nt/ E mer ge nc y  
- Sc he d ule d/ Pla n ne d  
- Pr ol o n gati o n of e xisti n g 
h os pitalizati o n  
 
 
D ate of Disc h ar g e  
Date:  
D D/ M M/ Y Y Y Y  
Date: D D/ M M/ Y Y Y Y  
Date: 
D D/ M M/ Y Y Y Y  
S u bject Disc h ar g e d 
t o: 
 
C hec k O N E:  
- H o me w/ o ut s u p p orti ve n ursi n g care  
- H o me wit h s u p p orti ve n ursi n g care  
- H os pice  
- L o n g ter m care facilit y  
- A n ot her ac ute care h os pital  
- Dea d  
- Ot her, s pecif y _ _ _ _ _  
C hec k O N E:  
- H o me w/ o ut 
s u p p orti ve n ursi n g 
care  
- H o me wit h 
s u p p orti ve n ursi n g 
care  
- H os pice  
- L o n g ter m care 
facilit y 
- A n ot her ac ute care 
h os pital  
- Dea d  
-  Ot her, s pecif y _ _ _ _ _  
C hec k O N E:  
- H o me w/ o ut 
s u p p orti ve n ursi n g 
care  
- H o me wit h 
s u p p orti ve n ursi n g 
care  
- H os pice  
- L o n g ter m care 
facilit y 
- A n ot her ac ute care 
h os pital  
- Dea d  
-   Ot her, 
s pecif y _ _ _ _ _ 
1)  Was t he pri mar y reas o n f or h os pitalizati o n relate d t o a seri o us 
a d verse e ve nt (if s o, c o m plete t he a p pr o priate S A E f or m ). 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 1 3
Pr o prietar y a n d C o nfi de ntial

Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
Versi o n 6. 0, 1 5 Mar 2 0 1 6 
C o nfi de ntial 
Pa ge 1 1 3 of 1 1 3 
1 7. 8. 1. O ut p atie nt S u b- F or m 
 
1)  Di d t he s u bject ha ve  a n y u nsc he d ule d ( n ot r elate d t o st u d y 
pr ot oc ol) o ut patie nt e val uati o ns si nce t he last visit? 
Y E S (c hec k all t hat a p pl y): 
(i) 
E mer ge nc y r o o m visits N O T res ulti n g i n h os pitalizati o n 
                  N u m ber of visits _ _ _ _ _ _ _ _ _ _ 
(ii) 
O ut patie nt p h ysicia n visits N O T relate d t o st u d y pr ot oc ol 
                  N u m ber of visits _ _ _ _ _ _ _ _ _ _ _ 
(iii) 
S kille d n ursi n g facilit y –  N u m ber of da ys i n s kille d n ursi n g 
facilit y/ n ursi n g h o me _ _ _ _ _ _ _ _ 
(i v) 
H o me healt h n ursi n g care – N u m ber of d a ys of h o me healt h 
care _ _ _ _ _ _ _ _ _ _ _ _ 
( v) 
H os pice care – N u m b er of da ys of h os pice care _ _ _ _ _ _ _ 
( vi) 
Dia g n ostic tests ( N O T relate d t o st u d y pr ot oc ol): 
                  List tests c o n d ucte d _ _ _ _ _ _ 
( vii) 
Ot her o ut patie nt e val u ati o ns ( please s pecif y): n u m ber of 
visits _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
A b bre viate d Cli nical St u d y Re p ort A R Q 1 9 7- A- U 3 0 3, Versi o n 1. 0
1 6. 1 St u d y I nf or mati o n
Pa ge 1 1 4
Pr o prietar y a n d C o nfi de ntial