Clinical trial NCT01755767
Conditions: Hepatocellular Carcinoma
Keywords: MET diagnostic-high Unresectable Hepatocellular Carcinoma c-Met inhibitor
Sponsor: Daiichi Sankyo
Start date: 2012-12-27; Completion date: 2017-07-31
Enrollment: 383 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if tivantinib (ARQ 197) is effective in treating patients with MET diagnostic-high hepatocellular carcinoma (liver cancer) who have already been treated once with another therapy.

Detailed description:
Expression of c-Met in tumors correlates with aggressive hepatocellular carcinoma (HCC) features. Overexpression of the receptor in tumor samples or high level of blood HGF in subjects is related to higher recurrence rate after surgery for HCC, while high c-Met expression correlates with shorter survival in HCC subjects. In summary, c-Met holds an important prognostic role in the natural history of HCC. This Phase 3 study in MET Diagnostic-High inoperable HCC subjects has been designed based on the results from the randomized, controlled Phase 2 study conducted by ArQule, Inc. with tivantinib versus placebo in subjects with MET Diagnostic-High inoperable HCC who have failed one prior systemic therapy, mentioned above. The purpose of this study is to confirm the efficacy of tivantinib in MET Diagnostic-High HCC subjects who were previously treated with one systemic therapy, and to further evaluate the safety profile of the experimental drug in this subject population.

Arms: arm 1: The tivantinib dosage of 240 mg tablets administered by mouth twice daily (BID), once in the morning and once in the evening, with food, for a total daily dose of 480 mg. arm 2: Tivantinib 120 mg is administered by oral tablet BID, once in the morning and once in the evening, with food, for a total daily dose of 240 mg (amended dosing group; primary analysis group). arm 3: Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food. arm 4: Matching placebo is administered by oral tablet(s) BID, once in the morning and once in the evening, with food.
Interventions: intervention 1: Tivantinib intervention 2: Placebo
Intervention descriptions: intervention 1: Tivantinib tablets intervention 2: Matching placebo tablets

Protocol documents:
Prot_SAP_000.pdf: 
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 
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C o nfi de ntial 
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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)  
 
 
 
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Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
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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)  
 
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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.  
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 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 
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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 ).     
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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, 
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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
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Pa ge 9
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Pr ot oc ol A R Q 1 9 7 - A- U 3 0 3 
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C o nfi de ntial 
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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
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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 
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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 
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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 
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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 
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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 %)  
 
 
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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. 
 
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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. 
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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 
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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. 
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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. 
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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 
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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. 
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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. 
 
 
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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.  
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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.  
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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)  
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 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) 
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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 
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 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)  
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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. 
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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. 
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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.  
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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.   
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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. 
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 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 . 
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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 . 
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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  
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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. 
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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 
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 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 ).   
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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 
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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. 
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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)  
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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. 
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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. 
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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).  
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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. 
 
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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.  
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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 
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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 
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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 
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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   
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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 )  
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 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.  
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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 
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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. 
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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. 
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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. 
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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 
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 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. 
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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.   
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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 
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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.  
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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 
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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.   
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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. 
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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.  
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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 
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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.  
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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 
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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. 
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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. 
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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. 
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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. 
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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 
 
 
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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.  
 
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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.  
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1 7.  
A P P E N DI C E S 
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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 
 
 
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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.  
 
 
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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  
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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  
 
 
 
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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  
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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 
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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 
 
 
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C o nfi de ntial 
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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  
 
 
 
 
 
 
 
 
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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 
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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   
  
  
  
  
 
 
 
 
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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 ). 
 
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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 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
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