Clinical trial NCT03542877
Conditions: Colorectal Cancer
Keywords: Cabozantinib Progression Free Survival Metastatic Colorectal Cancer Tumor
Sponsor: Academic Thoracic Oncology Medical Investigators Consortium
Start date: 2018-06-01; Completion date: 2022-03-07
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study seeks to use Cabozantinib to treat those with Metastatic Colorectal Cancer who have not previously responded to treatment.

Detailed description:
This is a phase II clinical trial that seeks to use Cabozantinib to treat those with Metastatic Colorectal Cancer who have not previously responded to treatment. This study is a two stage study that will first measure (up to) 16 patients' progression free survival (PFS). Stage two will, again, measure PFS, but in a population (up to) 28 patients.

Arms: arm 1: Patients will be enrolled to take 60mg of cabozantinib, by mouth, once a day, every day, for 12 weeks. If less than three patients have Progression Free Survival (PFS) lasting at least 12 weeks, the study will be terminated.
Interventions: intervention 1: Oral Tablet: Cabozantinib
Intervention descriptions: intervention 1: Patients will take 60mg cabozantinib, by mouth, once daily, every day for 12 weeks. This medication should be taken on an empty stomach. Patients should not eat 2 hours before or 1 hour after taking cabozantinib. Only water is permitted during this 3 hour time frame.

Protocol documents:
Prot_SAP_000.pdf: 
 
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E xeli xis I n v esti g at or S p o ns ore d C LI NI C A L S T U D Y P R O T O C O L  
A n o pe n -l a bel, si n gle-ar m, t w o -st a ge p h ase II st u d y i n vesti g ati n g 
c a b oz a nti ni b i n p ati e nts wit h ref r act or y met ast ati c c ol orect al c a ncer  
P R O T O C O L N U M B E R:  A GI C C 1 7 C R C 0 1/ E X E LI X I S I S T5 6  
 
S T U D Y D R U G:  C a b oza nti ni b ( X L 1 8 4)  
 
I N D N U M B E R: 1 3 8 2 7 7  
 
S P O N S O R:  Criteri u m  
 
P ri nci p al I n vesti g at or (s): 
 
Wells A M ess ers mit h M D  
U ni versit y of C ol ora d o C a ncer C e nt er  
M ailst o p 8 1 1 7  
1 2 8 0 1 E 1 7 t h A ve, L 1 8 -8 1 2 4  
A ur ora, C O 8 0 0 4 5  
( p) 3 0 3-7 2 4 -0 7 4 7  
(f) 3 0 3-7 2 4 -3 8 8 9  
Wells. mess ers mit h @ u c d e n ver.e d u  
 
C o -P ri nci p al I n vesti g at or a n d T r a nsl ati o n al P ri nci p al I n vesti g at or : 
 
Aar o n J S c ott M D  
U ni versit y of Ariz o na C a ncer C e nt er  
1 5 1 5 N C a m p bell A ve, R o o m 1 9 1 6  
T u cs o n, A Z 8 5 7 2 4  
( p) 5 2 0-6 2 6 -2 2 2 4  
(f) 5 2 0-6 2 6 -2 2 2 5  
ajs c ott @ e mail.ari z o na. e d u  
 
 
 
M E DI C A L M O NI T O R:   
Aar o n J S c ott  M D  
 
V E R S IO N 1. 9  D A T E FI N A L:  1 0/ 2 5/ 1 7  
V E R SI O N 2. 0 D A T E FI N A L : 1 0/ 2 7/ 1 8  
 
 


 
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S Y N O P SI S  
TI T L E : A n o pe n -l a bel, si n gle-ar m, t w o -st a ge p h as e 2 st u d y i n vesti g ati n g c a b oz a nti ni b i n p atie nts 
wit h ref r act or y m et ast atic c ol orect al c a ncer  
 
P R O T O C O L N U M B E R :  1 7 C R C 0 1  
C LI NI C A L P H A S E  II 
 
R A TI O N A L E :  
C ol or ectal ca ncer ( C R C) is t he t hir d m ost c o m m o n ca ncer dia g n os e d a n n uall y i n t h e U nit e d Stat es.  
M etastatic C R C is t he s ec o n d l ea di n g ca us e of ca ncer -r elate d deat h wit h a n esti mate d 5 0, 0 0 0 deat hs i n t he 
U nite d Stat es a n d o ver 5 0 0, 0 0 0 d eat hs w orl d wi d e a n n u all y.  D es pite s u bsta ntial i m pr o ve m e nts i n treat m e nt 
o ver t he past deca de, m etastatic dis eas e r e mai ns i n c ura bl e wit h a me dia n o verall s ur vi val of a p pr o xi mat el y 
3 0 m o nt hs wit h o pti mal c o m bi nati o n c he m ot hera p y a n d bi ol o gical a g e nts, i n cl u di n g a nti -V E G F a n d a nti -
E G F R a nti b o d y t h era pies.  W hile re g orafe ni b a n d T A S -1 0 2 h a ve bee n a p pr o ve d f or r efra ct or y m etastatic 
C R C bas e d o n p has e III data, t hes e a g e nts are ass ociate d wit h o nl y m o d est 1 -2 m o nt h i m pr o ve m e nts i n 
o verall s ur vi val w h e n c o m par e d t o b est s u p p orti ve c ar e.  N e w dr u g de vel o p m e nt f or m etastatic C R C is a n 
ur ge nt pri orit y.  
 
C a b oza nti ni b ( X L 1 8 4) is a p ote nt, orall y -bi oa vaila bl e s mall -m ol ec ul e i n hi bit or of 
m ulti ple r ece pt or 
t yr osi n e ki nas es, w hi c h has de m o nstrat e d earl y e vi d e n ce of a cti vit y i n a vari et y of s oli d t u m ors. T his a gent 
is c urr e ntl y F D A-a p pr o ve d  f or treat m e nt of m e d ullar y t h yr oi d ca ncer a n d r e nal cell car ci n o ma .  T he 
pri nci pal tar gets of ca b oza nti ni b ar e pr ot ei ns ce ntral t o ca ncer cell gr o wt h a n d t u m or a n gi o g e nesis:  
V E G F R 2/ K D R, M E T, R E T, A X L, TI E 2,  a n d KI T.  It is t h o u g ht t hat t he c o n c urr e nt i n hi biti o n of M E T a n d 
V E G F R 2 u n d erli e t h e pri mar y a cti vit y of ca b oza nti ni b s ee n i n s oli d t u m ors, differi n g fr o m t h e m ulti -ki nas e 
acti vit y of r e g orafe ni b, w hic h d oes n ot i n hi bit M E T.  Bas e d o n t he t h e or y t hat d ua l M E T a n d V E G F R 2 
i n hi biti o n ma y w or k s y ner gisticall y, ca b oza nti ni b d e m o nstrat e d s u peri or s ur vi val c o m par e d t o e ver oli m us 
i n a rece ntl y p u blis he d p has e III cli ni cal trial i n patie nts wit h r ela ps e d/refra ct or y r e nal cell car ci n o ma. 
 
Precli ni cal data has s h o w n  t hat ca b oza nti ni b e x hi bits gr o wt h i n hi bit or y a n d a nti-t u m or effects i n h u ma n 
C R C cell li nes as well as i n patie nt -deri ve d t u m or xe n o graft ( P D T X) m o us e m o d els, res pecti vel y.  M ore 
rece ntl y, ass ess me nt of tr eat me nt effects of ca b oza nti ni b vers us re g orafe ni b i n 1 0 h u ma n C R C t u m or 
e x pla nts s h o w e d t hat ca b oza nti ni b ha d gr eater a nti -t u m or acti vit y i n 9 o ut of 1 0 e x pla nts. A nal ysis of t u m or 
gr o wt h i n hi biti o n i n d e x ( T GII) d e m o nstrat e d t hat ca b oza nti ni b was si g nifica ntl y m ore effecti ve t ha n 
re g orafe ni b at i n hi biti ng t u m or gr o wt h (a vera ge T GII 3. 2 0 2 vers us 4 8. 4 8, res p ecti vel y; P = 0. 0 0 7).  
I m p orta ntl y, M E T i n hi biti o n ma y b e t h e ca us e f or t his differ e nce i n effi ca c y as t he H C T 1 1 6 par e ntal cell 
li ne was s e nsiti ve t o b ot h c o m p o u n ds; h o we ver, r e g orafe ni b was i nacti ve i n t h e M E T ki nas e a cti ve is o g e nic 
cell li n e. T h es e fi n di n gs s u g gest t hat ca b oza nti ni b ma y fill a n u n met n ee d b y pr o vi di n g a s afe a n d effecti ve 
treat m e nt o n ce sta n dar d of car e o pti o ns ar e n o l o n ger a vaila ble f or patie nts wit h m etastatic C R C.  
 
We h yp ot hesi ze t hat ca b oza nti ni b, t hr o u g h d ual i n hi biti o n of M E T a n d V E G F R 2, will l ea d t o i m pr o ve d 
cli ni cal acti vit y i n pati e nts wit h metastatic C R C r efra ct or y t o st a n dar d of car e t h era p y.  
 
O B J E C TI V E S  
T h e o bj ecti ves of t his st u d y ar e:  


 
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P ri m ar y O bjecti ve:  
1)  T o d et er mi n e t h e c li ni cal acti vit y of ca b oza nti ni b i n patie nts wit h r efract or y m etastatic C R C usi n g 
pr o gressi o n fr ee s ur vi val ( P F S) as pri mar y e n d p oi nt . 
Sec o n d ar y O bjecti ve s: 
1)  T o d eter mi n e t h e res p o ns e rat e ( R R) i n patie nts wit h r efract or y 
metastatic C R C tr eate d wit h 
ca b oza n ti ni b. 
2)  T o d eter mi n e t h e o verall s ur vi val ( O S) i n pati e nts wit h r efract or y m etastatic C R C treat e d wit h 
ca b oza nti ni b.  
3)  T o d es cri b e s afet y a n d t ol era bilit y of ca b oza nti ni b i n t his gr o u p of h ea vil y pr etreat e d pati e nts.  
4)  T o r etr os pecti vel y e x pl ore t h e P F S a n d R R i n patie nts bas e d o n R A S, B R A F, a n d PI K 3 C A m utati o n 
stat us. 
E x pl or at or y O bjecti ve s: 
1)  E x pl orat or y a nal ysis of pre di cti ve a n d p har ma c o d y na mic mar k ers . 
 
S T U D Y D E SI G N  
T his is a n o pe n -label, si n gle -ar m, 2 -sta ge P has e II st u d y of ca b oza nti ni b, a s mall m ol ec ul e i n hi bit or of 
m ulti ple r ece pt or t yr osi n e ki nas es ( R T Ks) i ncl u di n g M E T, V E G F R 2, R E T, A X L, a n d KI T, i n patie nts wit h 
refract or y m etastatic C R C. U p t o 4 4 e val ua ble patie nts will be treat e d wit h ca b oza nti ni b at a d os e of 6 0 m g 
da il y.  O n e c ycl e is defi n e d as 2 1 da ys.  
 
T h e pri mar y e n d p oi nt is 1 2 -w ee k pr o gr essi o n -fr ee s ur vi val ( P F S). T h e st u d y will u n d er g o o n e i nt eri m 
m o nit ori n g f or f utilit y w h e n 1 6 e val ua ble patie nts ha ve b ee n accr u e d  a n d  d os e d , a n d at l east  3 patie nts ha v e 
met t h e 1 2 w ee k P F S ti m e p oi nt . If 2  or fe wer patie nts ha ve a P F S of  1 2 w ee ks, t he n t h e st u d y will b e 
ter mi nat e d. If 3  or m ore patie nts ha ve a P F S of  1 2 wee ks, a n a d diti o nal 2 8 pati e nts will b e e nr olle d f or a 
t otal a ccr ual of 4 4 pati e nts. 
 
Ass ess me nt  of t u m or r es p o ns e will b e perf or me d e ver y 6 w ee ks f or t h e first 1 2 wee ks o n st u d y. Aft er 1 2 
wee ks, ass ess me nt of r es p o ns e will b e e ver y 9  wee ks. T he m o difie d R es p o ns e E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T v 1. 1) will b e us e d t o esta blis h dis eas e r es p o ns e or pr o gressi o n.  
 
All patie nts will b e e val uate d a n d gra de d f or a d vers e e ve nts a cc or di n g t o t h e N CI C o m m o n Ter mi n ol o g y 
f or A d vers e E ve nts, versi o n 4. 0 ( C T C A E). 
 


 
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N U M B E R O F S U B J E C T S  
A p pr o xi mat el y 4 4  s u bj ects will b e eli gi bl e f or t his st u d y . 
( 1 6 patie nts i n sta ge 1 + 2 8 patie nts i n sta ge 2 = 4 4 t otal pati e nts) 
T A R G E T P O P U L A TI O N  
C ol or ectal c a n cer pati e nts will be eli gi ble f or e nr oll m e nt as defi ne d b y t h e i ncl usi o n a n d e xcl usi o n 
crit eria as f oll o ws:  
I ncl usi o n crit eria - A s u bj ect m ust f ull y m eet all t h e f oll o wi n g criteria t o be eli gi ble f or t h e st u d y:  
1.  T h e s u bj ect has a hist ol o gi c or c yt ol o gi c dia g n osis of c ol or ectal a de n ocarci n o ma t hat is metastatic 
or u nr es ecta bl e , a n d t h e patie nt eit h er di d n ot t ol erat e, is r efra ct or y t o or pr o gress e d ( or r ela ps e d) 
f oll o wi n g a fl u or o p yri mi di n e, iri n ot eca n, o xali plati n, a n d b e vaciz u ma b; pri or e pi d er mal gr o wt h 
fa ct or i n hi bit or t hera p y is re q uir e d f or patie nts wit h left-si d e d, R A S wil d -t y pe t u m ors; pri or F D A-
a p pr o ve d P D -1 i n hi bit or t hera p y is r e q uir e d f or pati e nts wit h 
M SI -H c ol or ectal ca n cer. Pri or 
re g orafe ni b or T A S-1 0 2 tr eat me nt is n ot re q uir e d;  
2.  M eas ura ble dis eas e p er R E CI S T 1. 1 as d et er mi n e d b y t h e i n vesti gat or;  
3.  T h e s u bj ect has ha d a n ass ess me nt of all k n o w n dis eas e sites e. g., b y c o m p ut erize d t o m o gra p h y 
( C T) s ca n a n d/ or ma g netic r es o na n ce i ma gi n g ( M RI) wit hi n 2 8 da ys b ef or e t he first d os e of 
ca b oza nti ni b;  
1 6  P a tie n ts Tre a te d  
w ith  ca b o za n tin ib
6 0  m g  P O  d a ily
A sse ssm e n t fo r 
re sp o n se  e ve ry  6  
w e e ks fo r first 1 2  
w e e ks, th e n  e ve ry  9  
w e e k s th e re a fte r
A d d itio n a l P a tie n ts 
E n ro lle d  
S tu d y  Te rm in a te d
3  o r m o re  p a tie n ts h a ve  
P FS  ≥ 1 2  w e e k s
2 8  a d d itio n a l p a tie n ts 
Tre a te d  w ith  ca b o za n tin ib
6 0  m g  P O  d a ily
A sse ssm e n t o f re sp o n se  
e ve ry  6  w e e ks fo r first 1 2  
w e e ks, th e n  e ve ry  9  w e e ks 
th e re a fte r
W o rth y  o f fu rth e r e xp lo ra tio n  
(e sp if p re d ictive  b io m a rke r 
id e n tifie d )
D ru g  is 
R e je cte d
A t le a st 1 0  p a tie n ts (o u t o f 4 4  
to ta l) h a ve  P FS  ≥ 1 2  w e e ks
2  o r fe w e r p a tie n ts h a ve  
P FS  ≥ 1 2  w e e k s 
P re d ictiv e
B io m a rke r
D e ve lo p m e n t
3 4  o r m o re  p a tie n ts h a ve  
P FS  <  1 2  w e e k s 


 
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4.  T h e s u bj ect is ≥ 1 8  years o l d o n t he da y of c o ns e nt; 
5.  T h e s u bj ect has a n Easter n C o o p erati ve O n c ol o g y Gr o u p ( E C O G) p erf or ma n ce stat us of 0 or 1;  
6.  R ec o ver y t o bas eli n e or ≤ Gra d e 1 C T C A E v. 4. 0 fr o m t o xi cities r elate d t o a n y pri or tr eat m e nts, 
u nless A E(s) are cli ni call y n o nsi g nifi ca nt a n d/ or sta bl e o n s u p p orti ve t h era p y;  
7.  A de q uate ar c hi val fr oze n or fi xe d tiss ue a vaila ble fr o m pri mar y or m etastatic site f or ge n ot y pic 
a nal ysis (at least 1 5 u nstai ne d sli des a n d/ or t u m or bl oc k);  
8.  T h e s u bject has or ga n a n d marr o w f u n cti o n a n d la b orat or y val ues  as f oll o ws wit hi n 7  da ys bef or e 
t he first d os e of ca b oza nti ni b: 
a. 
T h e A N C ≥ 1 5 0 0/ m m 3 wit h o ut c ol o n y sti m ulati n g fact or s u p p ort;  
b.  Platel ets ≥ 1 0 0, 0 0 0/ m m 3; 
c.  
He m o gl o bi n ≥ 9  g/ d L;  
d.  Bilir u bi n ≤ 1. 5   t h e U L N. F or s u bjects wit h k n o w n Gil b ert’s dis eas e, bilir u bi n ≤ 3. 0 
m g/ d L;  
e.  
Ser u m al b u mi n ≥ 2. 8 g/ dl;  
f. 
Ser u m creati ni ne ≤ 1. 5   U L N or cr eati ni n e cl eara nce ( Cr Cl) ≥ 4 0  m L/ mi n. F or cr eati ni ne 
cl eara nce esti mati o n, t he C oc k cr oft a n d Ga ult e q uati o n s h o ul d be us e d:  
i. 
M ale: Cr Cl ( m L/ mi n) = ( 1 4 0 - a ge) × wt ( k g) / (s er u m cr eati ni n e ×  7 2);  
ii. 
Fe mal e: M ulti pl y a b o ve res ult b y 0. 8 5;  
g.  A L T a n d A S T ≤ 3. 0   U L N;  
h.  Li pas e < 2. 0 x t h e u p p er li mit of n or mal a n d n o ra di ol o gi c or cli ni cal e vi d e n ce of 
pa ncr eatitis;  
i. 
U P C R ≤ 1;  
j. 
Ser u m p h os p h or us, calci u m, ma g nesi u m a n d p otassi u m ≥ L L N.  
9.  T h e s u bj ect is ca pa ble of u n dersta n di n g a n d c o m pl yi n g wit h t he pr ot oc ol r e q uir e m e nts a n d has 
si g ne d t he i nf or m e d c o ns e nt d oc u m e nt;  
1 0.  Se x uall y a cti ve s u bj ects ( me n a n d w o m e n) m ust a gr ee t o us e me di call y a cce pt e d barrier m et h o ds 
of c o ntrace pti o n ( e g,  mal e or fe mal e c o n d o m) d uri n g  t h e st u d y a n d f or 4 m o nt hs after t h e last d os e 
of st u d y dr u g(s), e ve n if oral c o ntrace pti ves are als o us e d. All s u bjects of r e pr o d u cti ve p ot e ntial 
m ust a gree t o us e b ot h a barrier m et h o d a n d a s ec o n d m et h o d of birt h c o ntr ol  or pra cti ce 
a bs ti ne nce d uri n g  t h e st u d y a n d f or 4 m o nt hs aft er t h e last d os e of st u d y dr u g(s);  
E xcl usi o n Crit eria - A s u bj ect w h o meets a n y of t h e f oll o wi n g criteria is i neli gi bl e f or t h e st u d y:  
1.  T h e s u bj ect 
has r ecei ve d 
c yt ot o xi c 
c he m ot hera p y (i n cl u di n g 
i n vesti gati o nal 
c yt ot o xi c 
c h e m ot hera p y) 
or 
bi ol o gi c 
a ge nts 
(e g,  c yt o ki n es 
or 
a nti b o di es) 
wit hi n 
3  wee ks, 
or 
nitr os o ur eas/ mit o m yci n  C wit hi n 6  wee ks b ef or e t h e first d os e of st u d y tr eat m e nt;  
2.  Pri or tr eat m e nt wit h ca b oza nti ni b;  


 
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3.  R a diati o n t hera p y f or b o n e meta stasis wit hi n 2 wee ks, a n y ot h er e xt er nal ra diati o n t h era p y wit hi n 
4 wee ks b ef or e t h e first d os e of st u d y tr eat m e nt. S yst e mi c tr eat me nt wit h ra di o n u cli d es wit hi n 6 
wee ks b ef or e t h e first d os e of st u d y tr eat m e nt. S u bj ects wit h cli ni call y r el e va nt o n g oi n g 
c om pli cati o ns fr o m pri or ra diati o n t h era p y ar e n ot eli gi bl e;  
4.  R ecei pt of a n y t y p e of s mall m ol ec ul e ki nas e i n hi bit or (i ncl u di n g i n vesti gati o nal ki nas e i n hi bit or) 
wit hi n 1 4 da ys b ef or e t he first d os e of st u d y treat m e nt. N ot e: S u bj ects wit h pr ostat e ca ncer 
c urr e ntl y recei vi n g L H R H or G n R H a g o nists ma y b e mai ntai ne d o n t h es e a g e nts;  
5.  T h e s u bject has r ecei ve d a n y ot her t y p e of i n vesti gati o nal a g e nt wit hi n 2 8  da ys b ef or e t h e first 
d os e of st u d y tr eat me nt;  
6.  K n o w n brai n m etastas es or cra nial e pi d ural dis eas e u nl ess a de q uatel y tr eat e d wit h ra di ot h era p y 
a n d/ or s ur ger y (i n cl u di n g ra di os ur g er y) a n d sta ble f or at l east 4  wee ks b ef or e t he first d os e of 
st u d y tr eat m e nt. Eli gi ble s u bj ects m ust be ne ur ol o gi call y as y m pt o mati c a n d wit h o ut c orti c oster oi d 
treat m e nt at t h e ti m e of t he start of st u d y tr eat m e nt;  
7.  T h e s u bject has pr ot hr o m bi n ti m e ( P T)/I N R or partial t hr o m b o plasti n ti me ( P T T) t est ≥ 1. 3  t he 
la b orat or y U L N wit hi n 7 da ys b ef ore t h e first d os e of st u d y tr eat me nt; 
8.  C o nc o mita nt a nti c oa g ulati o n  at t hera pe uti c d os es  wit h oral a n tic oa g ula nts ( e g, warfari n, dir ect 
t hr o m bi n a n d Fact or Xa i n hi bit ors) or plat el et i n hi bit ors (e g,  cl o pi d o gr el);  
N ot e: L o w -d os e as piri n f or car di o pr ot ecti o n ( p er l ocal a p pli ca ble g ui d eli n es), l o w -d os e warfari n 
( < 
1 
m g/ da y), 
a n d 
l o w 
d os e, 
l o w 
m olec ular 
wei ght 
h e pari ns 
( L M W H) 
ar e 
per mitte d.  A nti c oa g ulati o n wit h t h era p e uti c d os es of L M W H is all o we d i n s u bj ects wit h o ut 
ra di o gra p hic e vi de n ce of brai n metastasis, w h o are o n a sta ble d os e of L M W H f or at least 1 2 
wee ks bef or e ra n d o mi zati o n, a n d w h o ha ve ha d n o c o m p li cati o ns fr o m a t hr o m b oe m b oli c e ve nt or 
t he a nti c oa g ulati o n r e gi m e n. ; 
9.  T h e s u bj ect has e x peri e nce d a n y of t h e f oll o wi n g:  
a. 
cli ni call y-si g nifi ca nt 
GI bl ee di n g wit hi n 6 
m o nt hs b ef or e t he first d os e of st u d y 
treat m e nt; 
b.  he m o pt ysis of ≥ 0. 5 teas p o o n ( 2. 5 ml) of r e d bl o o d wit hi n 3 m o nt hs b ef ore t h e first d os e 
of st u d y tr eat m e nt;  
c.  
a n y ot h er si g ns i n dicati ve of p ul m o nar y h e m orr ha ge wit hi n 3 m o nt hs b ef or e t he first d os e 
of st u d y tr eat m e nt.  
1 0.  T h e s u bj ect has ra di o gra p hi c e vi d e nce of ca vitati n g p ul m o nar y lesi o n(s);  
1 1.  T h e s u b j ect has t u m or i n va di n g or e n casi n g a n y maj or bl o o d vess els; 
1 2.  T h e s u bj ect has e vi d e n ce of cli ni call y si g nifi ca nt bl ee di n g fr o m t u m or i n va di n g t h e GI tract 
(es o p ha g us, st o mac h, s mall or lar g e b o wel, r ect u m or a n us), or a n y e vi d e n ce of e n d otra c h eal or 
e n d o br on c hial t u m or wit hi n 2 8 da ys b ef or e t h e first d os e of ca b oza nti ni b;  
1 3.  T h e s u bject has u nc o ntr oll e d, si g nifi ca nt i nterc urr e nt or rece nt ill ness i ncl u di n g, b ut n ot li mit e d t o, 
t he f oll o wi n g c o n diti o ns: 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 7  of 9 6  
a. 
C ar di o vas c ular dis or d ers i n cl u di n g:  
i. 
C o n gesti ve h eart fail ur e ( C H F): Ne w Y or k Heart Ass ociati o n ( N Y H A) Class III 
( m o d erate) or Class I V (s e ver e) at t h e ti me of s cr ee ni n g; 
ii. 
C o nc urr e nt u n c o ntr olle d h y p erte nsi o n d efi n e d as s ustai ne d bl o o d pr ess ure ( B P) 
>  1 5 0  m m  H g  
s yst oli c  
or  
>  1 0 0  m m  H g  
diast oli c  
des pite  
o pti mal  
a nti h yp ert e nsi ve tr eat me nt wit hi n 7 da ys of t h e first d os e of st u d y tr eat m e nt;  
iii. 
A n y hist or y of c o n g e nital l o n g Q T s y n dr o m e;  
i v. 
A n y of t h e f oll o wi n g wit hi n 6 m o nt hs bef or e t h e first d os e of st u d y tr eat m e nt:  
•  
u nsta ble a n gi na pect oris;  
•  
cli ni call y-si g nifi ca nt car diac arr h yt h mias; 
•  
str o k e (i n cl u di n g tra nsie nt is c h e mi c attac k ( TI A), or ot her is c he mi c 
e ve nt);  
•  
m y ocar dial i nfar cti o n;  
•  
t hr o m b oe m b olic e ve nt re q uiri n g t hera pe uti c a ntic oa g ulati o n ( N ot e: 
s u bjects wit h a ve n o us filt er ( e g, ve na ca va filt er) are n ot eli gi ble f or  
t his st u d y). 
b.  GI dis or d ers parti c ularl y t h os e ass ociat e d wit h a hi g h ris k of perf orati o n or fist ula 
f or mati o n i n cl u di n g: 
i. 
A cti ve pe ptic ulcer dis eas e, i nfla m mat or y b o wel dis eas e ( e g, Cr o h n’s dis eas e), 
di verti c ulitis, c h olec ystitis, s y m pt o mati c c h ola n gitis o r a p pe n di citis, ac ute 
pa ncr eatitis or a c ut e o bstr u cti o n of t h e pa ncreati c d u ct or c o m m o n bil e d uct, or 
gastric o utl et o bstr ucti o n  
ii. 
A b d o mi nal fist ula, GI perf orati o n, b o w el o bstr u cti o n, i ntra -a b d o mi nal a bs cess 
wit hi n 6 m o nt hs b ef or e ra n d o mi zati o n ,  
N ot e: C o m plete h eali n g of a n i ntra -a b d o mi nal a bs cess m ust be c o nfir m e d pri or 
t o ra n d o mi zati o n 
c.  
Ot her cli ni call y si g nifi ca nt dis or d ers t hat w o ul d precl u d e s afe st u d y parti ci pati o n;  
1 4.  M aj or s ur g er y wit hi n 1 2 w ee ks bef or e t h e first d os e of st u d y treat m e nt. C o m pl et e w o u n d  h eali n g 
fr o m maj or s ur g er y a n d/ or ra diati o n m ust ha ve occ urre d 1 m o nt h b ef or e t h e first d os e of st u d y 
treat m e nt. Mi n or s ur g er y (i ncl u di n g u nc o m plicat e d t o ot h e xtr acti o ns) wit hi n 2 8 da ys b ef or e t he 
first d os e of st u d y treat m e nt wit h c o m pl et e w o u n d h eali n g at l east 1 0 da ys bef or e t h e first d os e of 
st u d y tr eat m e nt. S u bj ects wit h cli ni call y r el e va nt o n g oi n g c o m plicati o ns fr o m pri or s ur g er y ar e n ot 
eli gi bl e;  
1 5.  Q Tc F >  5 0 0  ms ec wit hi n 1 m o nt h bef or e t h e first d os e of st u d y treat m e nt:  
a. 
T hr ee E C Gs m ust be perf or m e d f or eli gi bilit y d et er mi nati o n. If t he a vera g e of t hes e t hr ee 
c o ns ec uti ve r es ults f or Q Tc F is ≤ 5 0 0 ms ec, t h e s u bject m eets eli gi bilit y i n t his r e gar d.  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8  of 9 6  
1 6.  Pre g na nt or lactati n g fe mal es;  
1 7.  I na bilit y t o s wall o w i nta ct ta bl ets; 
1 8.  Pre vi o usl y i d e ntifi e d aller g y or h y p ers e nsiti vit y t o c o m p o n e nts of t h e st u d y tr eat me nt 
f or m ulati o ns; 
1 9.  Dia g n osis of a n ot h er mali g na nc y wit hi n 2  years b ef or e t h e first d os e of st u d y treat m e nt, e xce pt f or 
s u perfi cial s ki n ca ncers, or l ocali ze d, l o w gra de t u m ors dee m e d c ur e d a n d n ot trea t e d wit h 
s yste mi c t h era p y; 
E S TI M A T E D L E N G T H O F S U B J E C T P A R TI CI P A TI O N  
S u bjects ma y c o nti n u e t o recei ve st u d y tr eat me nt u ntil t h e y e x p eri e n ce u na cce pta ble dr u g -r elat e d 
t o xi cit y or dis eas e pr o gressi o n. S p o ns or or i n vesti gat or ma y t er mi nate t h e st u d y at a n y ti m e.  
E S TI M A T E D S T U D Y D A T E S  
First q uarter  of 2 0 1 8  t o First q uarter  of 2 0 2 0  (last st u d y f oll o w-u p visit) . 
I N V E S TI G A TI O N A L R E GI M E N D O S E/ R O U T E/D U R A TI O N  
C a b oza nti ni b is s u p pli e d as 2 0 -m g  a n d a d mi nister e d orall y at a d os e of 6 0 m g/ da y.  
S A F E T Y  A S S E S S M E N T S  
Safet y  will b e m o nit or e d o n a n o n g oi n g basis.  La b orat or y t esti n g (c h e mistr y, h e mat ol o g y t ests) 
a n d uri nal ysis  will b e p erf or me d e ver y 3  wee ks . Ot her s afet y  e val uati o ns i ncl u di n g E K Gs will b e 
perf or m e d  e ver y 6 w ee ks . 
A d vers e e ve nt s eri o us ness, s e verit y gra de, a n d r elati o ns hi p t o st u d y tr eat m e nt will b e ass ess e d b y 
t he i n vesti gat or. S e verit y gra de will b e defi ne d b y t h e Nati o n al C a ncer I nstit ut e ( N CI) C o m m o n 
Ter mi n ol o g y Crit eria f or A d vers e E ve nts ( C T C A E) versi o n 4. 0.  
T U M O R  A S S E S S M E N T S  
T u m ors will be ass ess e d b y C T or M RI met h o ds  at a fre q u e n c y of e ver y 6  wee ks  f or t he first 1 2 
wee ks, t h e n e ver y 9  wee ks t her eaft er . 
BI O M A R K E R A S S E S S M E N T S  
W h ol e bl o o d  s a m pl es will b e o btai n e d pr etreat m e nt a n d +/ - 5  da ys of C ycle 3 Da y 1 fr o m 
c o ns e nti n g pati e nts , w hic h will t he n be s hi p pe d a n d st or e d i n a re p osit or y f or f ut ure a nal ysis at 
T h e U ni versit y of Ari z o na . P e n di n g f u n di n g a vaila bilit y, arc hi val t u m or s peci m e ns will b e 
ge n ot y p e d at  T h e U ni versit y of Ari z o na Ge netics C ore, a C LI A -certifi e d cli ni cal la b orat or y. Ot her 
bi o mar k ers ma y be e val uat e d bas e d o n o n g oi n g pr ecli nical e x peri m e nts as well as t h e s ci e ntifi c 
literat ure. 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9  of 9 6  
O T H E R A S S E S S M E N T S  
Pe n di n g f u n di n g a vaila bil it y, M E T c o p y n u m b er a nal ysis a n d e x pr essi o n will be ass ess e d b y 
fl u or es ce nt i n sit u h y bri di zati o n ( FI S H) a n d i m m u n o hist oc h e mistr y (I H C), t o e x pl or e ass ociati o n 
wit h li keli h o o d of res p o ns e a n d/ or P F S at 1 2 wee ks i n patie nts wit h 
metastatic refra ct or y 
c ol or ectal ca ncer tr eat e d wit h ca b oza nti ni b.   Ot h er bi o mar k ers ma y b e e val uat e d bas e d o n o n g oi n g 
precli ni cal e x peri m e nts as well as t he s ci e ntific literat ur e.  
S T A TI S TI C A L M E T H O D S  
1.  Defi niti o n of pri mar y o ut c o m e/ e n d p oi nt:  
a) 
P F S will b e defi n e d as t he ti m e fr o m a d mi nistrati o n of t h e i nitial d os e of ca b oza nti ni b t o 
e vi d e nce of ra di o gra p hi c pr o gr essi o n as defi n e d b y R E CI S T crit eria or deat h fr o m a n y 
ca us e wit h o ut e vi d e nce of dis eas e pr o gressi o n, w hic h e ver occ urs first.  
2.  Defi niti o n of s ec o n dar y o ut c o m es/e n d p oi nts:  
a) 
R R  is defi n e d usi n g t he R E CI S T 1. 1 crit eria as t he pr o p orti o n of s u bjects wit h a c o nfir m e d 
C R or c o nfir m e d P R.  
b)  
O S will b e defi n e d as t he ti m e fr o m a d mi nistrati o n of t he i niti al d os e of ca b oza nti ni b u ntil 
deat h fr o m a n y ca us e.  
c)  
Safet y a n d t ol era bilit y a nal ysis  of ca b oza nti ni b s u m mari ze d b y d os e a n d s e verit y as 
ass ess e d b y t h e C o m m o n T o xicit y Crit eria f or A d vers e E ve nts  ( C T C A E) versi o n 4. 0 a n d 
relati o ns hi p t o st u d y dr u g. 
d)  
R etr os pecti ve a nal ysis of t h e P F S a n d R R i n patie nts bas e d o n R A S, B R A F, a n d PI K 3 C A 
m utati o n  stat us t hr o u g h a s e parate a nal ysis a nal yzi n g R R a n d P F S b y R A S, B R A F, a n d 
PI K 3 C A m utati o n stat us t o t h os e wit h o ut s uc h m utati o ns.  
3. Defi niti o n of e x pl orat or y o ut c o m es/e n d p oi nts:  
a) 
E x pl orat or y a nal ysis of pr e dicti ve a n d p har mac o d y na mi c mar kers b y o btai ni n g pre - a n d 
p ost -tr eat m e nt w h ole bl o o d s a m ples pretreat m e nt  a n d +/ - 5  da ys of C ycl e 3 Da y 1  of 
treat m e nt f or ea c h pati e nt a n d arc hi ve d f or f ut ure st u di es a n d a nal ysis. 
4.  A nal yti c pla n f or pri mar y o bj ecti ve:  
a) 
P F S –  eac h pati e nt will b e e xa mi n e d f or P F S at 1 2 w ee ks a n d dic h ot o mi ze d as eit h er ha vi n g 
pr o gressi o n or n ot.  Usi n g a n o pti mal Si m o n 2 -sta ge d esi g n t he first 1 6 patie nts will be 
e nr oll e d a n d 1 2 -w ee k P F S will b e deter mi n e d. St u d y e nr oll m e nt will c o nti n u e aft er t he 1 6 t h 
patie nt is a ccr ue d a n d d os e d , a n d at  least 3 patie nts ha ve m et t h e 1 2 w ee k P F S ti m e p oi nt . If 
3  or m or e  of t h es e patie nts ha ve n ot pr o gr ess e d b y 1 2 wee ks, t he trial will a ccr u e a n 
a d diti o nal 2 8 patie nts f or a t otal of 4 4 patie nts.  If 1 0 or m ore (t otal) of t h es e 4 4 patie nts are 
free of pr o gressi o n at 1 2 wee ks, t he n t h e N ull H y p ot hesis will be r ej ect e d i n fa v or of t he 
alter nati ve s u g gesti n g t hat t h e tr eat m e nt has s uffi ci e nt effica c y t o warra nt f ut ur e st u d y.  
i. 
P F S –  Ka pla n -M eier esti mates of pr o gressi o n -free s ur vi val rat es will als o b e calc ulated 
al o n g wit h t h eir c orres p o n di n g 9 5 % c o nfi de n ce i nt er vals.  
5.  A nal yti c pla n f or s ec o n dar y o bjecti ves:  
a) 
R R - defi n e d usi n g t h e R E CI S T crit eria as t he pr o p orti o n of s u bjects wit h a c o nfir m e d C R 
or c o nfir m e d P R. T h e p oi nt esti mate of t he R R wit h a 9 5 % c o nfi d e n ce i nt er val bas e d o n t he 
e xact bi n o mial distri b uti o n will b e pr es e nte d.  
b)  
O S –  Ka pla n -M ei er esti mates of pr o gressi o n -fr ee s ur vi val rates will be calc ulat e d al o n g 
wit h t heir c orr es p o n di n g 9 5 % c o nfi d e nce i nt er vals.  
c)  
Safet y a n d t ol era bilit y a nal ysis - all e nr oll e d patie nts w h o r ecei ve at l east o n e d os e of 
ca b oza nti ni b will ha ve i nf or mati o n c oll ect e d o n a d vers e e ve nts, w hic h will b e s u m marize d 
b y d os e a n d s e verit y as ass ess e d b y t h e C o m m o n T o xi cit y Crite ria f or A d vers e E ve nts 
( C T C A E) v. 4. 0 a n d r elati o ns hi p t o St u d y Dr u g.  
d)  
R etr os pecti ve a nal ysis of t h e P F S a n d R R i n patie nts bas e d o n R A S, B R A F, a n d PI K 3 C A 
m utati o n stat us - p oi nt esti mates wit h 9 5 % c o nfi de n ce i nter vals will be pr o vi d e d f or eac h 
gr o u p, a n d c o m paris o ns will be ma d e usi n g a stratifie d l o g -ra n k test. 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
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Pa ge 1 0  of 9 6  
6.  A nal yt i c pla n f or e x pl orat or y a nal ysis: 
a) 
E x pl orat or y a na l ysis –  peri p heral bl o o d c oll ecti o ns pr etr eat m e nt a n d +/ - 5  da ys of  C ycl e 3 
Da y 1 
will be o btai ne d a n d arc hi ve d f or f ut ur e i n vesti gati o n of pr e di cti ve a n d 
p har mac o d y na mics bi o mar k ers.  
7.  Sa m ple size j ustificati o n:  
Fr o m t h e r ece nt p has e III C O R R E C T trial i n vesti gati n g r e g orafe ni b vers us best s u p p orti ve 
car e, t he me dia n P F S f or patie nts wit h r efract or y c ol or ectal ca n cer was 1. 7 m o nt hs i n t h e 
place b o ar m. T h er ef or e, t h e P F S at 1 2 wee ks w o ul d be a p pr o xi matel y 1 3 %, w hi c h will 
s er ve as t h e r es p o ns e rate i n t he n ull h y p ot h esis. We ha ve d esi g ne d t h e trial t o ha ve at least 
9 0 % p o w er t o d et ect a n i m pr o ve m e nt i n t h e 1 2 -w ee k P F S rate of at l east 2 0 %, t h er ef or e t h e 
alter nati ve h y p ot h esis is t hat t he 1 2 -wee k P F S rat e is 3 3 %.  T h e o pti mal d esi g n pr o vi di n g at 
least 9 0 % p o wer t o detect t h e alt er nati ve w hil e c o ntr olli n g t h e t y p e I err or rat e at 0. 0 5 us es 
at m ost 4 4 patie nts. T his desi g n has a n act ual t yp e I err or rat e of 0. 0 4 4 1 (i. e. if t h e tr u e 1 2 -
wee k P F S rat e is l ess t ha n or e q u al t o 0. 1 3, t h er e is o nl y a 4. 4 % pr o ba bilit y of c o ncl u di n g 
t hat t he P F S rat e is great er t ha n or e q ual t o 0. 3 3).  T his desi g n h as p o wer of 0. 9 0 6  t o detect 
t he alt er nati ve h y p ot h esize d 1 2-w ee k P F S rat e of 0. 3 3.  T his tri al desi g n us es a n a vera ge of 
2 5. 7 pati e nts. 
 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
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Pa ge 1 1  of 9 6  
T A B L E O F C O N T E N T S  
S Y N O P SI S  ...........................................................................................................................2  
T A B L E O F C O N T E N T S  ...................................................................................................1 1  
1  
B A C K G R O U N D A N D R A TI O N A L E  .....................................................................1 8  
1. 1  
Bac k gr o u n d:  .....................................................................................................1 8  
1. 2  
Ca b oz a nti ni b ( X L 1 8 4)  .....................................................................................1 8  
1. 2. 1  
P har m ac ol o g y  ......................................................................................1 8  
1. 2. 2  
Ca b o z a nti ni b N o ncli nic al T o xic ol o g y  .................................................2 1  
1. 2. 3  
Cli nic al E x p erie nce  ..............................................................................2 1  
1. 2. 3. 1  
Cli nic al S u m m ar y  .......................................................................2 1  
1. 2. 3. 2  
Cli nic al Safet y Pr ofile  .................................................................2 3  
1. 2. 3. 3  
Cli nic al P har m ac o ki netics  ..........................................................2 7  
1. 2. 3. 4  
Cli nic al Acti vit y  ..........................................................................3 0  
1. 3  
Rati o nale  ..........................................................................................................3 2  
1. 3. 1  
Rati o nale f or t he St u d y, D ose, a n d Sc he d ule  .......................................3 2  
2  
S T U D Y O BJ E C TI V E S A N D  D E SI G N  ...................................................................3 3  
2. 1  
St u d y O bje cti ves  ..............................................................................................3 3  
2. 2  
St u d y Desi g n  ....................................................................................................3 4  
2. 2. 1  
O ver vie w of St u d y De si g n ...................................................................3 4  
2. 3  
Treat me nt Assi g n me nt  .....................................................................................3 4  
2. 4  
Bli n di n g a n d r a n d o miz ati o n  .............................................................................3 4  
2. 5  
St u d y Sit es  .......................................................................................................3 4  
2. 6  
Wit h dra wals  .....................................................................................................3 4  
3  
T R E A T M E N T S  ........................................................................................................3 6  
3. 1  
C o m p ositi o n, F or m ulati o n, a n d St ora ge  ..........................................................3 6  
3. 1. 1  
I n vesti gati o nal Treat me nt ....................................................................3 6  
3. 1. 2  
Ca b oz a nti ni b T a blets  ...........................................................................3 6  
3. 2  
D ose, Sc he d ule a n d R o ut e  ...............................................................................3 7  
3. 3  
Ca b oz a nti ni b D ose M o dific ati o ns, I nt err u pti o ns, a n d Disc o nti n uati o n ...........3 7  
3. 3. 1. 1  
Ca b oz a nti ni b D os e Rei nstit uti o n a n d Re escalati o n  ....................4 0  
3. 3. 2  
War ni n gs a n d Prec a uti o ns a n d G ui deli nes f or t he Ma na g e me nt of 
A d verse E ve nts  ....................................................................................4 0  
3. 3. 2. 1  
G ui deli nes f or Ma na g e me nt of P ote ntial A d verse E ve nts  ..........4 1  
3. 3. 2. 2  
Gastr oi ntesti nal Dis or ders  ...........................................................4 2  
3. 3. 2. 3  
He pat o biliar y Dis or ders  ..............................................................4 4  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 2  of 9 6  
3. 3. 2. 4  
He mat ol o gical Dis or d ers  ............................................................4 5  
3. 3. 2. 5  
Fati g ue, A n ore xia, a n d Wei g ht L oss ...........................................4 6  
3. 3. 2. 6  
S ki n Dis or ders  .............................................................................4 6  
3. 3. 2. 7  
W o u n d He ali n g a n d S ur ger y  .......................................................4 7  
3. 3. 2. 8  
H y pert e nsi o n  ...............................................................................4 7  
3. 3. 2. 9  
T hr o m b oe m b olic E ve nts  .............................................................4 9  
3. 3. 2. 1 0  
Pr otei n uria  ...................................................................................4 9  
3. 3. 2. 1 1  
C orre cte d Q T c Pr ol o n gati o n  .......................................................5 0  
3. 3. 2. 1 2  
H y p o p h os p hate mia  .....................................................................5 2  
3. 3. 2. 1 3  
T h yr oi d F u ncti o n Dis or ders  ........................................................5 2  
3. 3. 2. 1 4  
He m orr ha gic E ve nts ....................................................................5 2  
3. 3. 2. 1 5  
GI Perf orati o n/ Fist ula a n d N o n -GI Fist ula F or mati o n ................5 3  
3. 3. 2. 1 6  
Oste o ne cr osis of t he Ja w  .............................................................5 4  
3. 3. 2. 1 7  
A n gi oe d e ma  ................................................................................5 5  
3. 3. 2. 1 8  
M usc ul os keletal a n d C o n ne cti ve Tiss ue Dis or ders  ....................5 5  
3. 3. 2. 1 9  
Res pir at or y, T h or acic a n d Me diasti nal Dis or ders  ......................5 5  
3. 4  
C o nc o mit a nt Me dicati o ns a n d T hera pies .........................................................5 6  
3. 4. 1  
A ntica nc er T hera p y  ..............................................................................5 6  
3. 4. 2  
Ot her Me dicati o ns  ................................................................................5 6  
3. 4. 3  
All o we d T hera pies  ...............................................................................5 6  
3. 4. 4  
Pr o hi bite d or Restrict e d T hera pies .......................................................5 7  
3. 4. 5  
P ote ntial Dr u g I ntera cti o ns  ..................................................................5 8  
3. 5  
C o m plia nce  ......................................................................................................6 0  
3. 6  
St u d y Dr u g A cc o u nt a bilit y  ..............................................................................6 1  
4  
S T U D Y P O P U L A TI O N  ...........................................................................................6 1  
4. 1  
I ncl usi o n Crit eria .............................................................................................6 1  
4. 2  
E xcl usi o n Criteria  ............................................................................................6 3  
5  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ....................................................6 6  
5. 1  
Pre -Treat me nt Peri o d  .......................................................................................6 6  
5. 1. 1  
De m o gr a p hics  ......................................................................................6 6  
5. 1. 2  
C o nc o mit a nt m e dic ati o ns .....................................................................6 6  
5. 1. 3  
Vit al Si g ns  ............................................................................................6 7  
5. 1. 4  
Hei g ht a n d wei g ht  ................................................................................6 7  
5. 1. 5  
P h ysical E xa mi nati o n ...........................................................................6 7  
5. 1. 6  
La b orat or y Assess me nt  ........................................................................6 7  
5. 1. 7  
Pre g na nc y test  ......................................................................................6 7  
5. 1. 8  
Electr ocar di o gra m ( E C G)  ....................................................................6 7  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 3  of 9 6  
5. 1. 9  
Arc hi val t u m or tiss ue  ...........................................................................6 8  
5. 1. 1 0  
W h ole bl o o d c ollecti o n  ........................................................................6 8  
5. 2  
Treat me nt Peri o d  ..............................................................................................6 8  
5. 3  
P ost -Tre at m e nt Peri o d  .....................................................................................7 0  
5. 4  
La b orat or y Assess me nts  ..................................................................................7 1  
5. 5  
T u m or Assess me nt  ...........................................................................................7 2  
5. 5. 1  
Res p o nse Criteria  .................................................................................7 4  
5. 5. 1. 1  
E val uati o n of T ar get L esi o ns  ......................................................7 4  
5. 5. 1. 2  
E val uati o n of N o n -Tar get Lesi o ns  ..............................................7 4  
5. 5. 1. 3  
E val uati o n of Ne w Lesi o ns  .........................................................7 5  
5. 5. 1. 4  
E val uati o n of Best O ver all R es p o nse  .........................................7 5  
6  
S A F E T Y  ...................................................................................................................7 6  
6. 1  
A d verse E ve nts a n d L a b orat or y A b n or malities  ...............................................7 6  
6. 1. 1  
A d verse E ve nts  ....................................................................................7 6  
6. 1. 2  
Se ri o us A d verse E ve nts .......................................................................7 7  
6. 1. 3  
Relati o ns hi p t o St u d y Tr eat me nt  .........................................................7 8  
6. 1. 4  
Seri o us A d verse E ve nt Re p orti n g  ........................................................7 9  
6. 1. 5  
Re g ulat or y R e p orti n g  ...........................................................................7 9  
6. 2  
Ot her Safet y C o nsi der ati o ns  ............................................................................8 0  
6. 2. 1  
La b orat or y Data  ...................................................................................8 0  
6. 2. 2  
Pre g na nc y/ L act ati o n E x p os ure  ............................................................8 0  
6. 2. 3  
Me dicati o n Err ors/ O ver d ose  ................................................................8 0  
6. 2. 4  
F oll o w -U p of A d verse E ve nts  .............................................................8 0  
7  
S T A TI S TI C A L C O N SI D E R A TI O N S ......................................................................8 1  
7. 1  
A nal ysis P o p ulati o n  .........................................................................................8 1  
7. 1. 1  
Safet y P o p ulati o n  .................................................................................8 1  
7. 2  
Safet y A nal ysis  ................................................................................................8 1  
7. 2. 1  
A d verse E ve nts  ....................................................................................8 1  
7. 3  
Sa m ple Siz e  ......................................................................................................8 1  
7. 3. 1  
Sa m ple Siz e J ustific ati o n  .....................................................................8 1  
8  
O T H E R A N A L Y S E S  ...............................................................................................8 2  
8. 1  
A nal ytic Pla n Pri mar y, Se c o n dar y, a n d E x pl orat or y E n d p oi nts  ......................8 2  
8. 1. 1  
Pri m ar y E n d p oi nt:  ................................................................................8 2  
8. 1. 2  
Sec o n d ar y E n d p oi nts:  ..........................................................................8 2  
8. 1. 2. 1  
Res p o nse Rate ( R R)  ....................................................................8 2  
8. 1. 2. 2  
O verall S ur vi val ( O S)  .................................................................8 2  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 4  of 9 6  
8. 1. 2. 3  
T olera bilit y a n d Safet y  ................................................................8 3  
8. 1. 2. 4  
P F S a n d R R Base d o n M olec ular Stat us  .....................................8 3  
8. 1. 3  
E x pl orat or y E n d p oi nt  ...........................................................................8 3  
8. 1. 3. 1  
Bi o mar ker A nal ysis  ....................................................................8 3  
8. 2  
Bi o mar ker, C orr elati ve, a n d S pe cial St u dies  ...................................................8 3  
8. 2. 1  
La b orat or y C orr elati ve St u dies  ............................................................8 3  
8. 2. 2  
Arc hi val T u m or Tiss ue  ........................................................................8 3  
8. 2. 3  
W h ole Bl o o d  ........................................................................................8 4  
9  
D A T A S A F E T Y M O NI T O RI N G .............................................................................8 4  
1 0  
D A T A Q U A LI T Y A S S U R A N C E  ............................................................................8 5  
1 1  
M U L TI C E N T E R G UI D E LI N E S A N D S T U D Y C O M MI T T E E S ...........................8 5  
1 2  
E T HI C A L A S P E C T S  ...............................................................................................8 6  
1 2. 1  
L ocal R e g ulati o ns  ............................................................................................8 6  
1 2. 2  
I nf or m e d C o nse nt.............................................................................................8 6  
1 2. 3  
I nstit uti o nal Re vie w B oar d/ Et hics C o m mitte e ................................................8 6  
1 2. 4  
F ut ure Use of Patie nt Sa m ples  .........................................................................8 7  
1 3  
C O N DI TI O N S F O R M O DI F YI N G T H E P R O T O C O L ...........................................8 7  
1 4  
C O N DI TI O N S F O R T E R MI N A TI N G T H E S T U D Y  .............................................8 7  
1 5  
S T U D Y D O C U M E N T A TI O N A N D R E C O R D K E E PI N G  .....................................8 7  
1 5. 1  
I n vesti gat or’s Files a n d Ret e nti o n of D oc u me nts ............................................8 7  
1 5. 2  
S o urce D oc u me nts a n d B ac k gr o u n d Data  .......................................................8 8  
1 5. 3  
A u dits a n d I ns pe cti o ns  .....................................................................................8 8  
1 5. 4  
Case Re p ort F or ms  ...........................................................................................8 8  
1 6  
M O N I T O RI N G T H E S T U D Y ..................................................................................8 9  
1 7  
C O N FI D E N TI A LI T Y O F T RI A L D O C U M E N T S A N D S U BJ E C T R E C O R D S  ...8 9  
1 8  
P U B LI C A TI O N O F D A T A A N D P R O T E C TI O N O F T R A D E S E C R E T S ............8 9  
1 9  
R E F E R E N C E S  .........................................................................................................9 1  
 
LI S T O F T A B L E S  
Ta ble 3 -1:  
Ca b oz a nti ni b T a blet C o m p o ne nts a n d C o m p ositi o n  ................................ 3 6  
Ta ble 3 -2:  
D ose Re d ucti o ns of Ca b oz a nti ni b  ............................................................. 3 8  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 5  of 9 6  
Ta ble 3 -3:  
D ose M o dific ati o ns of Ca b oz a nti ni b f or Tre at m e nt -Relat e d A Es  ............ 3 9  
Ta ble  3 -4:  
Ma na g e me nt of Treat me nt -E m er ge nt Ha n d -F o ot S y n dr o m e ( P P E S)  ...... 4 7  
Ta ble 3 -5:  
Ma na g e me nt of H y p erte nsi o n Relat e d t o Ca b oz a nti ni b  ........................... 4 8  
Ta ble 3 -6:  
Ma na g e me nt of Treat me nt -e m er ge nt Pr ot ei n uria  ..................................... 5 0  
Ta ble 5 -1:  
St u d y Assess me nts  .................................................................................... 6 9  
Ta ble 5 -2:  
Partici p a nts wit h Meas ura ble Disease ( T ar get Dise ase)  ........................... 7 5  
Ta ble 5 -3:  
Partici p a nts wit h N o n -Meas ura ble Disease ( N o n -Tar get Disease)  .......... 7 6  
 
LI S T O F A P P E N DI C E S  
A p pe n di x  A:  Perf or m a nce St at us Crit eria  ...................................................................... 9 3  
A p pe n di x  B:  Dr u g Diar y  ................................................................................................ 9 4  
A p pe n di x  C:  E x pl orat or y bi o mar kers  ............................................................................ 9 6  
 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 6  of 9 6  
LI S T O F A B B R E VI A TI O N S  
A E  
a d vers e e ve nt  
A L T  
ala ni ne a mi n otra nsferas e  
A N C  
a bs ol ute n e utr o p hil c o u nt  
A S C O  
A meri ca n S oci et y of Cli ni cal O nc ol o g y  
A S T  
as partate a mi n otra nsferas e  
A U C  
area u n der t h e plas ma dr u g c o n ce ntrati o n ti m e c ur ve  
B P  
bl o o d pr ess ure  
B U N  
bl o o d ur ea nitr o g e n  
C H F  
c o n g esti ve h eart fail ure  
Cr Cl  
cr eati ni n e cleara n ce  
C R F  
cas e r e p ort f or m  
C T  
c o m p ut eri ze d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y Crit eria f or A d vers e E ve nts  
C Y P  
c yt oc hr o m e P 4 5 0  
D B P  
diast oli c bl o o d pr ess ure  
D L T  
d os e -li miti n g t o xicit y 
D V T  
dee p vei n t hr o m b osis  
E C  
et hi cs c o m mittee  
E C G  
el ectr ocar di o gra m  
E C O G  
Easter n C o o perati ve O n c ol o g y Gr o u p  
E S C  
E xeli xis Safet y C o m mittee  
E S M O  
E ur o p ea n S oci et y of M e di cal O nc ol o g y  
E S R  
er yt hr oc yt e s e di me ntati o n rate  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle-sti m ulati n g h or m o n e 
G A B A  
γ -a mi n o b ut yric a ci d  
G C P  
G o o d Cli ni cal Pra cti ce  
GI  
gastr oi nt esti nal  
G G T  
γ -gl uta m yl tra nsferas e  
G n R H  
g o na d otr o pi n -r el easi n g h or m o n e 
I C H 
I nter nati o nal C o nfer e n ce o n Har m o nis ati o n 
I M E 
i m p orta nt me dical e ve nt 
I N R 
I nter nati o nal N or malize d R ati o 
I R B 
I nstit uti o nal R e vi e w B oar d 
L F T  
li ver f u ncti o n test 
L H R H  
l utei ni zi n g h or m o ne-r el easi n g h or m o n e 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 7  of 9 6  
L M W H  
l o w m ol ec ular w ei g ht h e pari n 
L L N  
l o w er li mit of n or mal 
M e d D R A  
M e dical Di cti o nar y f or R e g ulat or y A cti vities  
M RI  
ma g neti c r es o na n ce i ma gi n g  
M T C  
me d ullar y t h yr oi d ca n cer  
N CI  
Nati o nal C a ncer I nstit ut e  
N S AI D  
n o n -st er oi dal a nti-i nfla m mat or y dr u g 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
P D  
pr o gressi ve dis eas e  
P E  
p ul m o nar y e m b olis m  
PI  
pri nci pal i n vesti gat or  
P P E  
pal mar -pla ntar er yt hr o d ys est h esia  
P T  
pr ot hr o m bi n ti m e  
P T T  
partial t hr o m b o plasti n ti me  
q d  
o n ce dail y  
O NJ  
oste o n ecr osis of t h e ja w  
Q Tc  
c orr ect e d Q T i nt er val 
Q Tc F  
Q Tc calc ulate d b y t h e Fri deri ca f or m ula  
R B C  
re d bl o o d cell 
R P L S  
re versi bl e p osteri or l e u k oe nce p hal o pat h y s yn dr o m e 
S A E  
s eri o us a d vers e e ve nt 
S B P  
s yst oli c bl o o d press ur e 
T F T  
t h yr oi d f u n cti o n t est 
TI A  
tra nsie nt is c h e mi c attac k 
T S H  
t h yr oi d sti m ulati n g h or m o n e 
U L N  
u p per li mit of n or mal  
U P C R  
uri ne pr otei n / uri n e cr eati ni ne rati o  
V E G F( R)  
vas c ular e n d ot h elial gr o wt h fa ct or (r ece pt or)  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 8  of 9 6  
1  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
B ac k gr o u n d:  
C ol or ect al ca nc er  ( C R C) is t he f o urt h m ost c o m m o n ca ncer dia g n ose d ea c h year i n t he U nite d 
States, wit h nearl y 1 3 5 , 0 0 0 ne w cases esti mat e d t o occ ur i n 2 0 16 ( Sie g el, 2 0 1 6) .  Metast atic 
C R C  is t he se c o n d le a di n g ca use of ca ncer deat h, wit h a n esti m ate d 5 0, 0 0 0 deat hs i n t he U nit e d 
States a n d o ver 5 0 0, 0 0 0 d eat hs w orl d wi d e a n n u all y. F or a d va nce d disease, F O L F O X ( 5 -
fl u or o ur acil ( 5-F U), le uc o v ori n, o xali plati n) or F O L FI RI ( 5 -F U, le uc o v ori n, iri n ote ca n) ar e 
sta n d ar d c he m ot hera p y r e gi m e ns rec o m me n de d i n t he first- a n d sec o n d -li ne tr eat me nt setti n gs, 
al o ne or i n c o m bi nati o n wit h bi ol o gic a g e nts  t ar geti n g eit her a n gi o g e nesis (be vaciz u ma b , zi v-
afli ber ce pt, re g or afe ni b) 
or 
E G F R  (cet u xi ma b 
or 
pa nit u m u ma b). Des pit e si g nific a nt 
i m pr o ve m e nts wit h t he e mer ge nce of t hese ne w treat m e nts o ver t he past deca d e, m etastatic 
dise ase re mai ns i nc ura ble wit h a me dia n o ver all s ur vi val of a p pr o xi m atel y 3 0 m o nt hs  wit h 
o pti mal c o m bi nati o n c he m ot hera p y.  Pri mar y refra ct or y dis ease, ac q uire d c he m oresist a nce, a n d 
treat me nt-li miti n g t o xicities lea ve m a n y ot her wise fit patie nts wit h o ut a st a n dar d tre at m e nt 
o pti o n at s o me p oi nt i n t heir dise ase traject or y. 
W hile r e g orafe ni b a n d T A S -1 0 2 ha ve bee n  
a p pr o ve d f or refract or y C R C  base d o n ra n d o miz e d p hase III d at a, t here was o nl y m o dest  
i m pr ove m e nt i n o verall s ur vi val see n as c o m p are d t o bes t s u p p orti ve c are ( Gr ot he y, 2 0 1 3; 
Ma yer, 2 0 1 5 ).  N e w dr u g de vel o p me nt f or a d va nce d C R C  is a n ur g e nt pri orit y. 
1. 2  
C a b oz a nti ni b ( X L 1 8 4)  
1. 2. 1  
P h ar m ac ol o g y  
Ca b oz a nti ni b is a m ulti -t ar get e d i n hi bit or of R T Ks. T he t ar gets of c a b oz a nti ni b i ncl u de se ver al 
R T Ks k n o w n t o pla y i m p ort a nt r oles i n t u m or cell pr oliferati o n a n d/ or t u m or ne o vasc ulariz ati o n, 
na mel y M E T, V E G F R 2 (als o k n o w n as K D R), A X L, a n d R E T. Ot her re c o g niz e d tar gets of 
ca b oz a nti ni b i ncl u de R O S 1, T R K A, T R K B, TI E 2,  T Y R O 3, a n d M E R, t w o a d diti o nal me m bers 
of t he V E G F R fa mil y ( V E G F R 1, V E G F R 3), a n d t he cl osel y relat e d R T Ks KI T a n d F L T -3. T he 
m o d e of acti o n f or c a b oz a nti ni b is si milar t o ot her dr u gs tar geti n g R T Ks: bi n di n g i n a f ull y 
re versi ble m a n ner t o a re gi o n of t he ki nase d o m ai n (i ncl u di n g t he A T P -bi n di n g site) w hic h 
f orc es t he ki nase acti vati o n l o o p i nt o a pse u d o-i nacti ve c o nf or m ati o n, t here b y i n hi biti n g 
s u bse q ue nt catal ytic acti vit y. T he c ell-b ase d tar g et i n hi biti o n pr ofile of c a b oz a nti ni b is s h o w n i n 
Ta ble 1 -1.   
 
  T a ble 1 -1 : 
I n hi biti o n of K e y P r otei n Ki n ases b y C a b oz a nti ni b i n Cells  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 1 9  of 9 6  
 
 
T he I C 5 0 val ues i n bi oc he mical ki nase assa ys ( Ta ble 1 -2) d o n ot al wa ys tra nslate e ve nl y i n vi v o. 
F or e xa m ple, ca b oz a nti ni b e x hi bits c o m para ble p ot e nc y a gai nst M E T a n d V E G F R 2 i n cell ular 
a n d i n vi v o assa ys, i n s pite of its a p par e nt gr eater p ot e nc y f or i n hi biti o n of V E G F R 2 i n 
bi oc he mical ki nase assa ys.  
 
 
 
 
 
 
 
 
 
   T a ble 1 -2 : K e y Pr o tei n Ki n ase I n hi biti o n b y C a b oz a nti ni b i n Bi oc he mic al Ass a ys 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 0  of 9 6  
 
Data fr o m p har mac o d y na mic e x peri me nts ha ve s h o w n t hat ca b oz a nti ni b i n hi bits 
M E T a n d 
V E G F R 2 i n vi v o. 
Oral a d mi nistrati o n of c a b oz a nti ni b res ulte d i n bl oc ka de of 
M E T 
p h os p h or ylati o n i n h u m a n l u n g  t u m or xe n o grafts gr o w n i n n u de mice, bl oc ka d e of 
M E T 
p h os p h or ylati o n i n li vers of mic e, a n d bl oc ka de of V E G F R 2 p h os p h or ylati o n i n m o use l u n g 
tiss ue. F or b ot h t ar gets, t he d urati o n of acti o n f or ca b oz a nti ni b was s ustai ne d, wit h > 5 0 % 
i n hi biti o n o bser ve d f or > 8 h p ost-d ose at a si n gle d ose le vel of 1 0 0 m g/ k g ( Ya kes et al. 2 0 1 1). I n 
a d diti o n, or al a d mi nistr ati o n of ca b oz a nti ni b res ulte d i n bl oc ka d e of p h os p h or ylati o n of 
m utati o nall y a cti vate d R E T i n T T h u ma n M T C xe n o grafts gr o w n i n n u de mice ( Be ntzie n et al.  
2 0 1 3).  
Treat me nt wit h ca b oz a nti ni b res ults i n a nti -a n gi o ge nic effects i n xe n o gr aft t u m ors, wit h 
disr u pti o n of t he vasc ulat ure b e gi n ni n g wit hi n 2 4 h after a d mi nistrati o n, a n d is ass ociate d wit h 
pr o -a p o pt otic effe cts. T hese effects tra nslate i nt o si g nifica n t t u m or gr o wt h i n hi biti o n or t u m or 
re gressi o n aft er ca b oz a nti ni b treat me nt i n m ulti ple t u m or m o d els i ncl u di n g M T C, breast c a ncer, 
l u n g carci n o ma, a n d G B ( Ya kes et al. 2 0 1 1). 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 1  of 9 6  
1. 2. 2  
C a b oz a nti ni b  N o n cli nic al T o xic ol o g y 
T o xicit y ass ociat e d wit h oral a d mi nistr ati o n of c a b oz a nti ni b was c har act eriz e d i n defi niti ve 
( G L P-c o m plia nt) si n gle -d ose a n d re peat -d ose st u dies i n mice, r ats, a n d d o gs; a fertilit y st u d y i n 
rats; e m br y ot o xicit y/ter at o ge nicit y st u dies i n rats a n d ra b bits; j u ve nile t o xicit y st u dies i n rats; i n 
vitr o a n d i n vi v o ge n ot o xicit y bi oassa ys; a n d a n i n vitr o p h ot ot o xicit y st u d y. Tar get tiss ues f or 
ca b oz a nti ni b -r elat e d t o xicit y i de ntifie d i n t hese st u dies i ncl u de GI tract, b o ne marr o w, l y m p h oi d 
tiss ues, re pr o d u cti ve tr act tiss ues, e n d ocri ne tiss ues, ki d ne y a n d s ki n. Hist o pat h ol o gic c ha n ges 
were als o prese nt i n b o ne, ce ntral ner v o us s yste m ( C N S) tiss ues a n d li ver/ g all bla d der. A d verse 
fi n di n gs ass ociate d wit h ca b oz a nti ni b a d mi nistrati o n were: ( 1) ge nerall y d ose-relate d; ( 2) ofte n 
c orr elati ve 
wit h c li nic al si g ns a n d/ or cli nic al p at h ol o g y para met er c ha n ges reflecti ve of 
ass ociate d tar g et tiss ue hist o p at h ol o gic fi n di n gs; ( 3) ge nerall y re versi ble u p o n disc o nti n uati o n of 
treat me nt; a n d ( 4) oft e n o bser ve d i n b ot h r o d e nt a n d n o n-r o de nt s pecies. I n defi nitive 
re pr o d u cti ve a n d de vel o p me ntal t o xicit y st u dies, ca b oz a nti ni b re d uc e d fertilit y i n male a n d 
fe male rats, was e m br y ot o xic i n r ats, pr o d uc e d a fet al s oft-tiss ue malf or mati o n (s mall s ple e n) i n 
ra b bits a n d pr o d uc e d fetal e xter nal malf or mati o ns (cleft palate/li p, der m al a plasia a n d ki n ke d or 
r u di me nt ar y tail) i n rats. Ca b oz a nti ni b was ne g ati ve i n i n vitr o bacterial a n d ma m malia n 
ge n ot o xicit y, clast o ge nicit y, a n d p h ot ot o xicit y bi oassa ys. T he meta b olite prese nt at hi g hest 
plas ma c o nce ntrati o ns i n h u m a ns a d mi nis t ere d ca b oz a nti ni b, E X E L-1 6 4 4, was ne gati ve i n a n i n 
vitr o bact erial g e n ot o xicit y bi oassa y a n d c a use d n o s yst e mic tiss ue t o xicit y i n rats d ose d 
s u bc uta ne o usl y wit h E X E L-1 6 4 4 f or t w o wee ks.   
T he carci n o g e nic p ot e ntial of c a b oz a nti ni b is bei n g e val uat e d i n a n o n g oi n g t w o -year bi oassa y i n 
rats. N o carci n o ge nic si g nal was o bser ve d i n t he ras H 2 tra ns ge nic m o use m o d el f oll o wi n g 
ca b oz a nti ni b d osi n g f or 2 6 w ee ks.  
1. 2. 3  
Cli ni c al E x perie nce  
1. 2. 3. 1  
Cli ni c al S u m m ar y  
Ca b oz a nti ni b ( X L 1 8 4) is a n i n hi bit or of m ulti ple rec e pt or t yr osi ne ki nases ( R T Ks). It is pr o vi de d 
as b ot h c a ps ules a n d ta blets, b ut t he t w o f or m ulati o ns are n ot i nter c ha n gea ble. C o m etri q ® 
(ca b oz a nti ni b ca ps ules, 1 4 0 
m g) 
was a p pr o ve d b y t he 
U nite d Stat es F o o d a n d 
Dr u g 
A d mi nistrati o n ( F D A) o n 2 9 N o ve m ber 2 0 1 2 f or t he tr eat m e nt of patie nts wit h pr o gressi ve, 
metast atic me d ullar y t h yr oi d ca nc er ( M T C). O n 2 1 Marc h 2 0 1 4, c a b oz a nti ni b c a ps ules were 
a p pr o ve d b y t he E ur o pea n C o m missi o n f or t he tr eat m e nt of a d ult patie nts wit h pr o gressi ve, 
u nrese cta ble l ocall y a d va nc e d or 
me tastatic 
M T C. 
O n 2 5 
A pril 2 0 1 6, 
Ca b o met y x ™ 
(ca b oz a nti ni b ta blets, 6 0 m g) was a p pr o ve d b y F D A f or patie nts wit h a d va nc e d re nal c ell 
carci n o ma ( R C C) 
w h o 
ha ve rec ei ve d 
pri or a nti -a n gi o ge nic t hera p y. 
C a b oz a nti ni b is 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 2  of 9 6  
c o m mer ciall y a vaila ble as b ot h c a ps ules a n d ta bl ets i n t he U nit e d States a n d is c urr e ntl y 
a vaila ble o nl y as ca ps ules i n t he E ur o p ea n U ni o n.   
T he tar g ets of c a b oz a nti ni b i ncl u d e se ver al R T Ks k n o w n t o pla y i m p orta nt r oles i n t u m or cell 
pr oliferati o n a n d/ or t u m or ne o vasc ulariz ati o n, na m el y M E T ( he p at oc yt e gr o wt h fa ct or [ H G F] 
rece pt or), vasc ular e n d ot helial gr o wt h fact or rece pt or 2 ( V E G F R 2, als o k n o w n as K D R), A X L, 
a n d R E T. Ot her rec o g niz e d tar g ets of ca b oz a nti ni b i ncl u d e R O S 1, T R K A, T R K B, T Y R O 3, 
M E R, t w o a d diti o nal m e m bers of t he V E G F R fa mil y ( V E G F R 1, V E G F R 3), a n d t he cl os el y -
relat e d R T Ks KI T a n d F L T-3. I n vi v o p har mac o d y na mic acti vit y of ca b oz a nti ni b a g ai nst M E T, 
V E G F R 2, A X L, a n d R E T has be e n de m o nstrat e d i n precli nic al st u dies a n d has b ee n ass ociat e d 
wit h t u m or gr o wt h i n hi biti o n a n d t u m or re gr essi o n. I n precli nic al st u dies, ca b oz a nti ni b tre at m e nt 
has als o b ee n s h o w n t o i n hi bit t u m or a n gi o g e nesis a n d t u m or i n vasi ve ness a n d metastasis.   
I n vesti gat or Br oc h ure versi o n 1 2 (I B v 1 2) i ncl u des a nal ysis of 1 7 cli nical st u dies of c a b oz a nti ni b 
f or o nc ol o g y i n dic ati ons i ncl u di n g f o ur P hase 1 st u dies, o ne P hase 1 b/ 2 st u d y, f o ur P hase 2 
st u dies, fi ve P hase 3 st u dies (a plac e b o-c o ntr olle d st u d y i n s u bjects wit h M T C, t w o a cti ve -
c o ntr olle d st u dies i n s u bjects wit h c astrati o n -resista nt pr ost ate ca ncer [ C R P C], o ne o n g oi n g 
o p e n-la bel, acti ve-c o ntr olle d st u d y i n s u bjects wit h R C C, a n d o ne o n g oi n g a n d e nr olli n g d o u ble -
bli n de d place b o -c o ntr olle d st u d y i n s u bje cts wit h he pat ocell ular carci n o ma [ H C C]), o ne o n g oi n g 
a n d e nr olli n g P hase 4 st u d y i n 
M T C, o ne o n g oi n g mai nte na nc e “r oll -o v er” st u d y, a n d o ne 
e x pa n de d acc ess st u d y ( See Ta ble 5 -1  of I B v 1 2 ). I n a d diti o n, t here are ele ve n cli nic al 
p har mac ol o g y st u dies ( See T a ble 5 -2  of I B v 1 2 ); ni ne were c o n d uct e d i n healt h y s u bje cts al o ne, 
o ne st u d y was c o n d ucte d t hat i ncl u de d healt h y s u bjects a n d s u bjects wit h re nal i m pair me nt, a n d 
o ne st u d y was c o n d ucte d t hat i ncl u de d he alt h y s u bje cts a n d s u bje cts wit h he patic i m p air me nt. I n 
a d diti o n t o t hese c o m pa n y -s p o ns ore d cli nic al st u di es, t we nt y-si x i n vesti gat or-s p o ns ore d trials 
(I S Ts) a n d si xtee n Nati o nal Ca nc er I nstit ut e ( N CI) -Ca ncer T hera p y E val uati o n Pr o gr a m ( C T E P) 
trials ha ve e nr olle d s u bjects i n o nc ol o g y i n dic ati o ns.  
A p o ole d a nal ysis of safet y data i n 2 4 1 0 s u bje cts wit h ca ncer tr eate d wit h ca b oz a nti ni b i n 
c o m pa n y-s p o ns or e d si n gle-a ge nt stu dies ( X L 1 8 4 -0 0 1, X L 1 8 4 -0 0 8, X L 1 8 4 -2 0 1, X L 1 8 4 -2 0 3, 
X L 1 8 4 -2 0 5, X L 1 8 4 -3 0 1, X L 1 8 4 -3 0 6, X L 1 8 4 -3 0 7, X L 1 8 4 -3 0 8, a n d X L 1 8 4 -4 0 1) has bee n 
perf or me d. F or o n g oi n g st u dies, seri o us a d verse e ve nt ( S A E) dat a are  prese nte d t hr o u g h 2 9 
Fe br uar y 2 0 1 6. A d verse e ve nt ( A E) da ta c ut offs are a vaila ble a n d s h o w n i n Ta ble 5-1  of I B v 1 2 .  
Ca b oz a nti ni b is a d mi nist ere d as eit her ca ps ules or t a blets. I n a bi oe q ui vale nce st u d y c o m pari n g 
ca ps ules wit h ta blets i n healt h y a d ult s u bjects ( St u d y X L 1 8 4 -0 1 0), t he g e o metric me a n rati os f or 
b ot h  A U C para met ers ( A U C 0 -t a n d A U C 0 -i nf) c o m pari n g 1 4 0 m g ca b oz a nti ni b d oses of t he 
ta blet f or m ulati o n wit h t he ca ps ule f or m ulati o n w ere 1 0 8 % ( 9 0 % c o nfi d e nce i nt er val [ CI] %: 
1 0 1, 1 1 7). T he rati o of g e o metric m ea ns f or C ma x ( 1 1 9 %; 9 0 % CI %: 1 0 7, 1 3 2) ha d a 9 0 % CI 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 3  of 9 6  
u p per b o u n d t hat sli g htl y e xc ee ds t he st a n dar d acce pte d li mit of 1 2 5 %. 
T heref ore, 
bi oe q ui vale nc e of t he ca b oz a nti ni b ca ps ule a n d ta blet f or m ulati o ns ca n n ot be c o ncl u de d, a n d t he 
t w o f or m ulati o ns are n ot i nterc ha n gea ble.  
T he si n gle -a ge nt ma xi m u m t olerat e d d ose ( M T D) of t he c a ps ule i n a d ail y d osi n g sc he d ule base d 
o n 2 8 da ys of d osi n g i n St u d y X L 1 8 4 -0 0 1 was d et er mi ne d t o be 1 4 0 m g. T he 1 4 0 m g ca ps ule 
d ose le vel was e val uate d i n plac e b o -c o ntr olle d P has e 3 St u d y X L 1 8 4 -3 0 1 i n s u bje cts wit h M T C. 
D ose m o difica ti o ns (re d ucti o ns or i nt err u pti o ns) oc c urre d fre q u e ntl y i n t he ca b oz a nti ni b ar m of 
t his st u d y. L o wer d oses of ca b oz a nti ni b ha ve be e n e x pl or e d i n ot her i n dicati o ns. A t a blet d ose of 
6 0 m g o nce d ail y ( q d) was e val uate d i n t w o P hase 3 st u dies i n pr ostate ca nc er, a n d t w o o n g oi n g 
P hase 3 st u dies, o ne i n R C C a n d o ne i n H C C, are als o e val uati n g t his d ose. O n g oi n g d o u ble -
bli n d St u d y X L 1 8 4 -4 0 1 c o m p ares t he efficac y a n d safet y of ca b oz a nti ni b 1 4 0 m g q d (ca ps ule 
f or m ulati o n) wit h ca b oz a nti ni b 6 0 m g q d (t a blet f or m ulati o n). C o m m o n t o all st u dies is t he 
titrati o n of t he d ose t o i n di vi d ual patie nt t olera bilit y.  
1. 2. 3. 2  
Cli ni c al S afet y P r ofil e  
A p o ole d a nal ysis of safet y data i n 2 4 1 0 s u bjects treat e d wit h c a b oz a nti ni b i n c o m pa n y -
s p o ns or e d si n gle-a ge nt st u dies ( X L 1 8 4 -0 0 1, X L 1 8 4 -0 0 8, X L 1 8 4 -2 0 1, X L 1 8 4 -2 0 3, X L 1 8 4 -2 0 5, 
X L 1 8 4 -3 0 1, X L 1 8 4 -3 0 6, X L 1 8 4 -3 0 7, X L 1 8 4 -3 0 8, a n d X L 1 8 4 -4 0 1 [ bli n de d c o m p aris o n of t w o 
ca b oz a nti ni b d ose le vels]) has be e n perf or me d. F or o n g oi n g st u dies, S A E d ata are prese nt e d 
t hr o u g h 2 9 Fe br uar y 2 0 1 6. A d verse e ve nt data c ut offs f or ea c h of t he st u dies are s h o w n i n Ta ble 
5 -1  of I B v 1 2 .  
S u m maries of safet y data fr o m P hase 3 st u dies i n R C C ( St u d y X L 1 8 4 -3 0 8), 
M T C ( St u d y 
X L 1 8 4 -3 0 1), a n d C R P C ( St u d y X L 1 8 4 -3 0 7) are als o pr o vi d e d  i n I B v 1 2. All st u d y e n d p oi nts 
ha ve bee n det er mi ne d f or St u dies X L 1 8 4 -3 0 1 a n d X L 1 8 4 -3 0 7. A nal yses f or t he pri m ar y 
e n d p oi nt a n d sec o n dar y e n d p oi nts of St u d y X L 1 8 4 -3 0 8 ha ve be e n perf or me d; t he st u d y is still 
o n g oi n g a n d s u bjects are c o nti n ui n g t o recei ve st u d y treat me nt. Safet y s u m maries of t hese t hree 
st u dies are base d o n d ata re p orte d i n t he cli nic al st u d y re p orts ( C S Rs).  
A d verse e ve nts/ a n d or S A Es are pr o vi de d f or s o m e a d diti o nal select e d st u dies. T hese i ncl u de a 
P hase 2 st u d y i n G B ( X L 1 8 4 -2 0 1; n = 2 2 2), a st u d y c o n d ucte d i n Ja p a nese ca ncer s u bjects 
( X L 18 4 -0 1 4; n = 4 3), a n o n g oi n g d o u ble -bli n d plac e b o -c o ntr olle d st u d y i n H C C ( X L 1 8 4 -3 0 9, 
n = 4 5 0), t hree P hase 2 st u dies e val uati n g ca b oz a nti ni b i n c o m bi nati o n wit h a n ot her dr u g ( X L 1 8 4 -
0 0 2; n = 2 6, X L 1 8 4 -2 0 2; n = 7 7, a n d X L 1 8 4 -2 1 0; n = 4 0), a mai nt e na nce “r oll o ver” st u d y ( X L 1 8 4 -
9 0 0; n = 3 7), a n d t we nt y -si x I S Ts (t otal n = 5 9 2) a n d si xt ee n N CI-C T E P st u dies (t otal n = 6 1 9). 
S A Es are als o pr o vi d e d f or c o m pa n y -s p o ns ore d cli ni cal p har m ac ol o g y st u dies c o n d uct e d i n n o n -
ca ncer s u bjects .  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 4  of 9 6  
1. 2. 3. 2. 1  A d verse E ve nts  
T he A E data s u m marize d i n t he f o ll o wi n g secti o ns i nclu de t h ose re p orte d a n d e ntere d i n t he cli nical 
data base as of t he dates prese nte d i n Ta ble 1 -1. F or acti ve cli nical st u dies wit h a “ Data T hr o u g h” date 
of 2 9 Fe br uar y 2 0 1 6, t he A E data fr o m t he cli nical da ta base ma y n ot yet i nclu de all S A Es. A 
s u m mar y of p o ole d S A Es fr o m c o m pa n y-s p o ns ore d cli nical st u dies wit h si n gle-a ge nt ca b oza nti nib is 
pr o vi de d i n Secti o n 5. 4. 1. 4  of t he I B v 1 2 . 
T he se verit y of A Es was assesse d usi n g t he C o m m o n Ter mi n ol o g y Criteria f or A d ver se E ve nts 
( C T C A E) versi o n 4. 0, a n d A E a n d S A E P Ts were c o de d wit h t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) versi o n 1 7. 0 f or all st u dies. F or A Es a n d S A Es, m ultiple occ urre nces of t he 
sa me e ve nt i n a n y in di vi d ual s u bject are c o u nte d o nce at t he hi g hest gra de re p orte d. E ve nts t hat were 
assesse d as p ossi bl y relate d or pr o ba bl y relate d t o ca b oza nti ni b are re p orte d as “relate d,” a n d e ve nts 
t hat were assesse d as n ot relate d or u nli kel y relate d t o ca b oza nti ni b are re p orte d as “ n ot relate d.”  
A d verse e ve nts t hat occ urre d i n ≥ 1 0 % of t he 2 4 1 0 s u bjects i n t he p o ole d si n gle -a g e nt st u dies are 
prese nte d i n Ta ble 1 -3.  
T a ble  1 -3 : 
S u m m ar y of A d verse E ve nts E x perie nc e d b y ≥ 1 0 %  of  S u bjects  T re ate d 
wit h Si n gle -A ge nt C a b oz a nti ni b, N =  2 4 1 0  
All A Es  
Rel ate d A Es  
 
 
 
M e d D R A P referre d Ter m  
 
 
S u bjects 
wit h A E  
n ( %)  
S u bjects 
wit h  
≥ G r a de 3 
A E  
n ( %)  
 
 
S u bjects 
wit h A E  
n ( %)  
S u bjects 
wit h  
≥ G r a de 3 
A E  
n ( %)  
N u m ber of s u bj ects wit h at least o ne e ve nt 
2 4 0 4 ( 9 9. 8)  
1 9 7 9 ( 8 2. 1)  
2 3 2 4 ( 9 6. 4)  
1 5 1 2 ( 6 2. 7)  
Diarr h oea  
1 4 7 1 ( 6 1. 0)  
2 5 1 ( 1 0. 4)  
1 3 0 0 ( 5 3. 9)  
2 2 6 ( 9. 4)  
Fati g ue  
1 4 5 8 ( 6 0. 5)  
3 6 9 ( 1 5. 3)  
1 2 8 1 ( 5 3. 2)  
3 1 2 ( 1 2. 9)  
Na us ea  
1 2 9 0 ( 5 3. 5)  
1 1 8 ( 4. 9)  
1 0 6 2 ( 4 4. 1)  
8 9 ( 3. 7)  
Decreas e d a p petit e  
1 2 8 3 ( 5 3. 2) 
1 3 6 ( 5. 6)  
1 0 8 0 ( 4 4. 8)  
1 0 4 ( 4. 3)  
V o miti n g  
8 6 1 ( 3 5. 7)  
9 5 ( 3. 9)  
6 1 2 ( 2 5. 4)  
5 9 ( 2. 4)  
Wei g ht decreas e d  
8 6 0 ( 3 5. 7)  
9 7 ( 4. 0)  
6 7 1 ( 2 7. 8)  
7 5 ( 3. 1)  
Pal mar -pla ntar er yt hr o d ys aest h esia s yn dr o m e  
8 3 5 ( 3 4. 6)  
1 8 6 ( 7. 7)  
8 1 9 ( 3 4. 0)  
1 8 5 ( 7. 7)  
C o nsti pati o n  
7 7 9 ( 3 2. 3)  
3 1 ( 1. 3)  
3 4 5 ( 1 4. 3)  
1 1 ( 0. 5)  
H y p ert e nsi o n  
7 0 8 ( 2 9. 4)  
3 3 0 ( 1 3. 7)  
6 0 3 ( 2 5. 0)  
2 8 4 ( 1 1. 8)  
D ys ge usia  
6 3 7 ( 2 6. 4)  
2 ( 0. 1)  
6 0 5 ( 2 5. 1)  
2 ( 0. 1)  
D ys p h o nia  
6 1 0 ( 2 5. 3)  
5 ( 0. 2)  
5 2 0 ( 2 1. 6)  
4 ( 0. 2)  
Ast he nia  
5 5 7 ( 2 3. 1)  
1 6 5 ( 6. 8)  
4 3 4 ( 1 8. 0)  
1 2 4 ( 5. 1)  
D ys p n oea  
4 9 7 ( 2 0. 6)  
7 6 ( 3. 2)  
1 8 7 ( 7. 8)  
2 2 ( 0. 9)  
A nae mia  
4 7 9 ( 1 9. 9)  
2 0 0 ( 8. 3)  
2 1 7 ( 9. 0)  
7 0 ( 2. 9)  
St o matitis  
4 7 4 ( 1 9. 7)  
4 2 ( 1. 7)  
4 4 6 ( 1 8. 5)  
4 1 ( 1. 7)  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 5  of 9 6  
A b d o mi nal pai n  
4 5 6 ( 1 8. 9)  
9 5 ( 3. 9)  
2 3 2 ( 9. 6)  
2 2 ( 0. 9)  
As partate a mi n otra nsferas e i ncreas e d  
4 4 6 ( 1 8. 5)  
6 9 ( 2. 9)  
3 8 2 ( 1 5. 9)  
4 6 ( 1. 9)  
Bac k pai n  
4 4 4 ( 1 8. 4)  
9 0 ( 3. 7)  
5 6 ( 2. 3)  
6 ( 0. 2)  
M uc os al i nfla m mati o n  
4 4 4 ( 1 8. 4)  
4 6 ( 1. 9)  
4 2 3 ( 1 7. 6)  
4 4 ( 1. 8)  
Pai n i n e xtr e mit y  
4 2 2 ( 1 7. 5)  
5 3 ( 2. 2)  
1 8 0 ( 7. 5)  
1 5 ( 0. 6)  
Hea dac h e  
4 1 5 ( 1 7. 2) 
3 0 ( 1. 2)  
1 4 9 ( 6. 2)  
3 ( 0. 1)  
Ala ni ne a mi n otra nsferas e i n cr eas e d  
3 8 9 ( 1 6. 1)  
7 4 ( 3. 1)  
3 4 3 ( 1 4. 2)  
5 8 ( 2. 4)  
R as h  
3 6 7 ( 1 5. 2)  
1 5 ( 0. 6)  
3 0 0 ( 1 2. 4)  
1 3 ( 0. 5)  
H y p ot h yr oi dis m  
3 5 9 ( 1 4. 9)  
6 ( 0. 2)  
3 0 1 ( 1 2. 5)  
3 ( 0. 1)  
C o u g h  
3 5 4 ( 1 4. 7)  
7 ( 0. 3)  
8 4 ( 3. 5)  
1 ( 0. 0) 
Oe de ma peri p h eral  
3 3 5 ( 1 3. 9)  
1 5 ( 0. 6)  
1 0 1 ( 4. 2)  
4 ( 0. 2)  
Dizzi ness  
3 0 7 ( 1 2. 7)  
1 2 ( 0. 5)  
1 5 4 ( 6. 4)  
3 ( 0. 1)  
Art hral gia  
3 0 3 ( 1 2. 6)  
3 0 ( 1. 2)  
7 6 ( 3. 2)  
4 ( 0. 2)  
D ys pe psia  
3 0 0 ( 1 2. 4)  
4 ( 0. 2)  
2 2 4 ( 9. 3)  
4 ( 0. 2)  
H y p o kalae mia  
3 0 0 ( 1 2. 4)  
9 0 ( 3. 7)  
1 3 6 ( 5. 6) 
4 2 ( 1. 7)  
Dr y m o ut h  
2 7 9 ( 1 1. 6)  
0  
2 3 1 ( 9. 6)  
0  
Uri nar y tract i nfecti o n  
2 6 9 ( 1 1. 2)  
3 5 ( 1. 5)  
3 1 ( 1. 3)  
3 ( 0. 1)  
Dr y s ki n  
2 6 4 ( 1 1. 0)  
0  
2 1 9 ( 9. 1)  
0  
H y p o ma g n es ae mia  
2 6 2 ( 1 0. 9)  
2 4 ( 1. 0)  
1 7 0 ( 7. 1)  
1 7 ( 0. 7)  
De h y drati o n  
2 5 5 ( 1 0. 6)  
7 9 ( 3. 3)  
1 3 9 ( 5. 8)  
4 2 ( 1. 7) 
M us cle s pas ms  
2 5 5 ( 1 0. 6)  
1 ( 0. 0)  
1 4 7 ( 6. 1)  
1 ( 0. 0)  
Hair c ol o ur c ha n g es  
2 5 1 ( 1 0. 4)  
2 ( 0. 1)  
2 4 3 ( 1 0. 1)  
2 ( 0. 1)  
P yre xia  
2 5 0 ( 1 0. 4)  
1 6 ( 0. 7)  
4 4 ( 1. 8)  
2 ( 0. 1)  
I ns o m nia 
2 4 4 ( 1 0. 1)  
0  
8 2 ( 3. 4)  
0  
A E, a d verse e ve nt; Me d D R A, Me dical Dicti o nar y f or Re g ulat or y Acti vities.  
At eac h le vel of s u bject s u m marizati o n, a s u bject is c o u nte d o nce if t h e s u bject re p orte d o ne or m ore e ve nts. A d verse 
e ve nts were c o de d base d o n Me d D R A versi o n 1 7. 0.  
N ote: T his ta ble s u m marizes p o ole d data i n t he cli nical data base f o r si n gle-a ge nt ca b oza nti ni b st u dies ( X L 1 8 4 -0 0 1,  
X L 1 8 4 -0 0 8, X L 1 8 4 -2 0 1, X L 1 8 4 -2 0 3, X L 1 8 4 -2 0 5, X L 1 8 4 -3 0 1 ca b oza nti ni b ar m, X L 1 8 4 -3 0 6 ca b oza nti ni b ar m, 
X L 1 8 4 -3 0 7 ca b oza nti ni b ar m, X L 1 8 4 -3 0 8 ca b oza nti ni b ar m, a n d X L 1 8 4 -4 0 1).  
T he m ost c o m m o n A Es ( ≥ 5 % i nci de nce ) re p orte d at se verit y of Gra de 3 a n d a b o ve were fatig ue 
( 1 5. 3 %), h y perte nsi o n ( 1 3. 7 %), diarr hea ( 1 0. 4 %), a ne mia ( 8. 3 %), P P E S ( 7. 7 %), ast he nia ( 6. 8 %), 
p ul m o nar y e m b olis m ( 6. 1 %), a n d decrease d a p petite ( 5. 6 %).  
T he m ost fre q ue ntl y ( ≥ 2 0 % i nci de nce) o bser ve d A Es re p orte d as relate d t o ca b oza nti nib, were 
diarr hea ( 5 3. 9 %), fati g ue ( 5 3. 2 %), decrease d a p petite ( 4 4. 8 %), na usea ( 4 4. 1 %), P P E S ( 3 4. 0 %), 
wei g ht decrease d ( 2 7. 8 %), v o miti n g ( 2 5. 4 %), d ys ge usia ( 2 5. 1 %),  h y perte nsi o n ( 2 5. 0 %), a n d 
d ys p h o nia ( 2 1. 6 %).  
1. 2. 3. 2. 2  Seri o us A d verse E ve nts  
T he m ost c o m m o nl y r e p orte d S A Es ( ≥ 1 % i nci de nc e) e xcl u di n g e ve nts of dise ase pr o gr essi o n 
are s h o w n i n Ta ble 1-4.  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 6  of 9 6  
T a ble  1 -4 : 
S u m m ar y of Seri o us A d verse E ve nts E x perie nc e d b y ≥ 1 %  of  S u bjects  
Tre ate d wit h Si n gl e -A ge nt C a b oz a nti ni b E xcl u di n g E ve nts of Dise ase 
Pr o gressi o n, N =  2 4 1 0  
 
All S A Es  
Rel ate d S A Es  
 
 
M e d D R A P referre d Ter m  
S u bjects wit h 
S A E  
n ( %)  
S u bjects wit h  
≥ G r a de 3 S A E 
n ( %)  
S u bjects wit h 
S A E  
n ( %)  
S u bjects wit h  
≥ G r a de 3 S A E 
n ( %)  
S u bjects re p orti n g at le ast o ne S A E  
1 3 3 2 ( 5 5. 3)  
1 2 2 1 ( 5 0. 7)  
6 0 2 ( 2 5. 0)  
5 1 6 ( 2 1. 4)  
P ul m o nar y e m b olis m  
1 2 0 ( 5. 0)  
1 1 9 ( 4. 9)  
8 5 ( 3. 5)  
8 4 ( 3. 5)  
V o miti n g  
8 1 ( 3. 4)  
4 8 ( 2. 0)  
4 0 ( 1. 7)  
2 7 ( 1. 1)  
Na us ea  
7 2 ( 3. 0)  
4 4 ( 1. 8)  
4 7 ( 2. 0)  
3 1 ( 1. 3)  
Ge neral p h ysi cal h ealt h det eri orati o n  
7 1 ( 2. 9)  
6 5 ( 2. 7)  
1 3 ( 0. 5)  
9 ( 0. 4)  
De h y drati o n  
6 9 ( 2. 9)  
5 4 ( 2. 2)  
4 1 ( 1. 7)  
3 2 ( 1. 3)  
P ne u m o nia  
6 9 ( 2. 9)  
5 8 ( 2. 4)  
5 ( 0. 2)  
4 ( 0. 2)  
A nae mia  
5 9 ( 2. 4)  
4 9 ( 2. 0)  
1 7 ( 0. 7)  
1 3 ( 0. 5)  
A b d o mi nal pai n  
5 3 ( 2. 2)  
4 3 ( 1. 8)  
1 3 ( 0. 5)  
9 ( 0. 4) 
Diarr h oea  
5 2 ( 2. 2)  
3 6 ( 1. 5)  
4 2 ( 1. 7)  
3 1 ( 1. 3)  
Dee p vei n t hr o m b osis  
4 6 ( 1. 9)  
3 6 ( 1. 5)  
2 1 ( 0. 9)  
1 6 ( 0. 7)  
Fati g ue  
4 3 ( 1. 8)  
3 6 ( 1. 5)  
2 7 ( 1. 1)  
2 5 ( 1. 0)  
Ast he nia  
4 1 ( 1. 7)  
3 0 ( 1. 2)  
2 0 ( 0. 8)  
1 3 ( 0. 5)  
Bac k pai n  
4 1 ( 1. 7)  
3 6 ( 1. 5)  
1 ( 0. 0)  
1 ( 0. 0)  
D ys p n oea  
3 9 ( 1. 6)  
2 6 ( 1. 1)  
7 ( 0. 3)  
5 ( 0. 2)  
P yre xia  
3 6 ( 1. 5)  
9 ( 0. 4)  
5 ( 0. 2)  
2 ( 0. 1)  
Uri nar y tract i nfecti o n  
3 5 ( 1. 5)  
2 5 ( 1. 0)  
4 ( 0. 2)  
3 ( 0. 1)  
H y p o natra e mia  
3 1 ( 1. 3)  
2 9 ( 1. 2)  
1 5 ( 0. 6)  
1 4 ( 0. 6)  
Ple ural eff usi o n  
3 0 ( 1. 2)  
2 2 ( 0. 9)  
6 ( 0. 2)  
5 ( 0. 2)  
R e nal fail ur e ac ut e  
3 0 ( 1. 2)  
2 4 ( 1. 0)  
7 ( 0. 3)  
5 ( 0. 2)  
C o n v ulsi o n  
2 9 ( 1. 2)  
1 8 ( 0. 7)  
5 ( 0. 2)  
2 ( 0. 1)  
Decreas e d a p petit e  
2 8 ( 1. 2)  
2 0 ( 0. 8)  
1 9 ( 0. 8)  
1 4 ( 0. 6)  
B o ne pai n  
2 7 ( 1. 1)  
2 3 ( 1. 0)  
0  
0  
Se psis  
2 7 ( 1. 1)  
2 7 ( 1. 1)  
5 ( 0. 2)  
5 ( 0. 2)  
M etastatic pai n  
2 6 ( 1. 1) 
2 0 ( 0. 8)  
1 ( 0. 0)  
0  
C o nf usi o nal state  
2 5 ( 1. 0)  
1 7 ( 0. 7)  
7 ( 0. 3)  
5 ( 0. 2)  
C o nsti pati o n  
2 5 ( 1. 0)  
9 ( 0. 4)  
9 ( 0. 4)  
4 ( 0. 2)  
S pi nal c or d c o m pr essi o n  
2 3 ( 1. 0)  
2 2 ( 0. 9)  
1 ( 0. 0)  
1 ( 0. 0)  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 7  of 9 6  
Me d D R A, Me dical Dicti o nar y f or Re g ulat or y Acti vities; S A E, seri o us a d verse e ve nt. 
N ote: Re p orte d S A Es were c o de d usi n g Me d D R A versi o n 1 7. 0. At eac h le vel of s u bject s u m marizati o n, a s u bject is 
c o u nte d o nce if t he s u bject re p orte d o ne or m ore e ve nts.  
N ote: T his ta ble s u m marizes p o ole d data fr o m t he safet y data base f or si n gle-a ge nt ca b oza nti ni b st u dies ( X L 1 8 4 -0 0 1, 
X L 1 8 4 -0 0 8, X L 1 8 4 -2 0 1, X L 1 8 4 -2 0 3, X L 1 8 4 -2 0 5, X L 1 8 4 -3 0 1 ca b oza nti ni b ar m, X L 1 8 4 -3 0 6 ca b oza nti ni b ar m 
X L 1 8 4 -3 0 7 ca b oza nti ni b ar m, X L 1 8 4 -3 0 8 ca b oza nti ni b ar m, a n d X L 1 8 4 -4 0 1).  
N ote: Disease pr o gressi o n is e x pect e d f or s u bjects wit h a d va nce d ca nc er o n ca b oza nti ni b cli nical trials, a n d as s uc h, 
e ve nts of pr o gressi o n of u n derl yi n g ca ncer are n ot i ncl u de d.  
a T we nt y ( 2 0) o ut of 2 9 of t he o bser ve d c o n v ulsi o n e ve nts were re p orte d i n s u bjects wit h gli o blast o ma ( G B) e nr ol le d 
i n St u dies X L 1 8 4-2 0 1 or X L 1 8 4 -2 0 5. F or m ore i nf or mati o n o n safet y o bser ve d i n s u bjects wit h G B, see  
Secti o n 5. 4. 3. 1.  
 
1. 2. 3. 2. 3  De at hs  
P o ole d Gra de 5 A E data i ncl u de t h ose re p orte d i n s u bjects wit h ca ncer treate d wit h ca b oza nti ni b as a 
si n gle a ge nt o n c o m pa n y-s p o ns ore d st u dies (see Secti o n 5. 4 f or a list of t he st u dies i ncl u de d i n t his 
p o ol). As of 2 9 Fe br uar y 2 0 1 6, t he i nci de nce of Gra de 5 A Es fr o m t he p o ole d si n gle -a ge nt st u dies was 
1 0. 5 % ( 2 5 4 s u bjects). Gra de 5 A Es re p orte d i n p o ole d si n gle -a ge nt st u dies, i ncl u di n g e ve nts of 
disease pr o gressi o n, are s u m marize d i n A p pe n dix F  of t he I B v 1 3 . 
T he Gra de 5 e ve nts t hat occ urre d at t he hi g hest fre q ue nc y ( ≥ 1 % i nci de nce) were pr ostate ca ncer 
( 2. 9 %) a n d ge neral p h ysical healt h deteri orati o n ( 1. 0 %). Per c o n ve nti o n, pr ostate ca ncer was t he P T 
f or disease pr o gressi o n of t he ca ncer u n der st u d y f or St u dies X L 1 8 4- 2 0 3 ( C R P C c o h orts), X L 1 8 4 -
3 0 6, a n d X L 1 8 4 -3 0 7. O nl y o ne e ve nt of ge neral p h ysical healt h deteri orati o n ( o n St u d y X L 1 8 4 -3 0 7) 
was assesse d as relate d t o st u d y treat me nt; n o e ve nts of pr ostate ca ncer were assesse d as relate d t o 
st u d y treat me nt. 
T hirt y -t hree ( 3 3) of t he 2 5 4 s u bjects wit h Gra de 5 A Es ha d e ve nts assesse d as relate d t o t he st u d y 
treat me nt. T he o nl y relate d Gra de 5 A Es t hat occ urre d m ore t ha n o nce were p ul m o nar y e m b olis m 
( n = 4), deat h ( u ns pecifie d; n = 3), he m orr ha ge ( n = 2), res pirat or y fail ure ( n = 2), a n d s u d de n deat h ( n = 2). 
1. 2. 3. 3  
Cli ni c al P h ar m ac o ki netic s 
A P o p P K a nal ysis of c a b oz a nti ni b was perf or m e d usi n g data c ollecte d fr o m 2 8 9 c a b oz a nti ni b -
treat e d s u bjects wit h s oli d t u m ors fr o m st u dies X L 1 8 4-3 0 1 ( M T C), X L 1 8 4 -0 0 1 ( M T C a n d ot her 
t u m or t y p es), a n d X L 1 8 4-2 0 1 ( G B) f oll o wi n g or al a d mi nistrati o n of 1 4 0 -m g c a ps ule dail y d oses. 
T he pre dict e d effecti ve half -life is a p pr o xi m atel y 5 5 h, V/ F is a p pr o xi matel y 3 4 9 L, a n d C L/ F at 
stea d y-stat e is esti m ate d t o be 4. 4 L/ h. T he t er mi nal half -life (f or pre dicti n g dr u g was h o ut) is 
a p pr o xi matel y 1 2 0 h. F oll o wi n g or al a d mi ni str ati o n of c a b oz a nti ni b, Tma x ra n g e d fr o m 2 t o 5 h 
p ost -d ose. Re p eat d ail y d osi n g of ca b oz a nti ni b at 1 4 0 m g f or 1 9 da ys res ult e d i n 4 - t o 5-f ol d 
hi g her 
me a n ca b oz a nti ni b a cc u m ulati o n ( base d o n 
A U C) c o m par e d 
wit h a si n gle d ose 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 8  of 9 6  
a d mi nistr ati o n; stea d y st ate was ac hie ve d b y Da y 1 5. Ca b oz a nti ni b is hi g hl y pr otei n b o u n d i n 
h u m a n plas ma ( ≥ 9 9. 7 %). T his P o p P K a nal ysis di d n ot i d e ntif y cli nicall y rele va nt differe nc es i n 
clear a nce of ca b oz a nti ni b bet wee n fe m ales a n d m ales or bet wee n W hites ( 8 9 %) a n d n o n -W hites 
( 1 1 % [ < 4 % were Asia n]). C a b oz a nti ni b P K was n ot affect e d b y a ge ( 2 0-8 6 ye ars).   
A sec o n d P o p P K a nal ysis was c o n d ucte d usi n g plas ma c o nce ntrati o ns of ca b oz a nti ni b fr o m 3 1 8 
s u bje cts wit h R C C i n St u d y X L 1 8 4-3 0 8 a n d 6 3 he alt h y s u bje cts i n St u d y X L 1 8 4 -0 2 0. T he R C C 
su bje cts rec ei ve d a 6 0 m g c a b oz a nti ni b ta blet d ose q d; a si n gle P K bl o o d sa m ple was ta ke n pre -
d ose o n Da y 2 9 a n d Da y 5 7 a p pr o xi matel y 8 or m ore h o urs after t he pri or e ve ni n g d ose. D ose 
re d ucti o ns t o dail y d oses of 4 0 m g or 2 0 m g were per mitte d per pr ot oc ol. T he he alt h y s u bje cts 
( n = 2 1/t a blet stre n gt h) rec ei ve d a si n gle ca b oz a nti ni b d ose at a ta blet stre n gt h of 2 0 m g, 4 0 m g, 
or 6 0 m g; P K bl o o d sa m ples were ta ke n pre -d ose a n d at 2 0 ti me p oi nts t hr o u g h 5 0 4 h p ost -d ose.   
Res ults fr o m t his sec o n d P o p P K a nal ysis i n dicat e d t hat f or a W hite male s u bject t he pre dict e d 
ter mi nal plas ma half-life of c a b oz a nti ni b was a p pr o xi mat el y 9 9 h; t he ter mi nal p hase v ol u m e of 
distri b uti o n ( V z ) was a p pr o xi matel y 3 1 9 L; a n d t he C L/ F at ste a d y-stat e was esti mate d t o be 
a p pr o xi matel y 2. 2 L/ h. I nter -i n di vi d u al varia bilit y i n cleara nc e ( perce nt c oefficie nt of variati o n 
[ % C V] of C L/ F) was esti mate d t o be 4 6 %. Fe m ale ge n der a n d Asia n ra ce were si g nifica nt 
c o variates o n C L/ F, w her e fe m ale s u bjects ha d 2 1 % l o wer C L/ F c o m pare d wit h m ale s u bject s 
a n d Asia n s u bje cts ha d 2 7 % l o wer C L/ F c o m par e d wit h W hite s u bjects. W hile t he attri b utes of 
Asia n race a n d fe m ale ge n der were statistic all y si g nifica nt, t he y wer e n ot dee me d cli nic all y 
mea ni n gf ul gi ve n t he ma g nit u de of t he effects. C o variat es det er mi ne d t o ha ve a n o n-si g nifica nt 
effect o n C L/ F were a ge, baseli ne b o d y mass i n de x ( B MI), baseli ne he m o gl o bi n, baseli ne t otal 
bilir u bi n, baseli ne A L T, b aseli ne ser u m al b u mi n, b aseli ne calc ulate d cre ati ni ne cle ara nc e, a n d 
p o p ulati o n ( healt h y s u bjects or s u bjects w it h R C C).  
T he s maller plas m a cleara nce val u e ( 2. 2 L/ h) a n d l o n ger plas ma t er mi nal eli mi nati o n half -life 
( 9 9 h) d eter mi ne d i n t he se c o n d ( R C C) P o p P K a nal ysis, c o m p are d t o res pecti ve val ues of 4. 4 L/ h 
a n d 5 5 h esti mate d i n t he first ( M T C) P o p P K a nal ysis was  e val uate d f urt her. A d diti o nal a nal ysis 
re veale d t hat c o m pare d wit h ot her c a ncer patie nt gr o u ps (ie, R C C, C R P C, G B), M T C s u bje cts 
clear e d ca b oz a nti ni b faster a n d t h us ha d l o wer d ose -n or m aliz e d stea d y -st ate plas ma e x p os ures. 
Se ver al p ossi ble fact ors ma y u n d erlie t he hi g her ca b oz a nti ni b cleara nce o bser ve d i n 
M T C 
patie nts i n t he first P o p P K a nal ysis; h o we ver, a n e x act c a use has yet t o b e i d e ntifie d. A P o p P K 
a nal ysis has bee n perf or m e d f or a n ot her T KI ( m otes a ni b) i n t h yr oi d c a ncer patie nts a n d s h o we d, 
si milar to c a b oz a nti ni b, t hat 
M T C patie nts ha d a hi g her ( 6 7 % gre ater) or al clear a nce t ha n 
patie nts wit h D T C ( L u et al. 2 0 1 0). T he m ec ha nistic basis f or t he differe nc e i n m otesa ni b C L/ F 
bet wee n M T C a n d D T C p atie nts was als o n ot i de ntifie d.   


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 2 9  of 9 6  
I n a n N CI-C T E P st u d y perf or me d i n pe diatric s u bje cts wit h rela pse d or refr act or y s oli d t u m ors, 
i ncl u di n g C N S t u m ors, t he m ea n st ea d y-state A U C0 -2 4 ( ± sta n d ar d de viati o n) at d ose le vels of 
3 0, 4 0, a n d 5 5 m g/ m 2 / da y were 3 1. 9 ± 7. 8, 3 3. 3 ± 1 1. 3, a n d 3 3. 7 ± 1 5 μ g * h/ m L, res pecti vel y. 
T he a vera g e e x p os ure ( A U C, C ma x , mi ni m u m plas ma c o nce ntrati o n [ Cmi n ]) val u es at stea d y-
state acr oss 3 d ose gr o u ps were i n t he ra n ge of t he e x p os ure at stea d y -st ate o bser ve d f or a 1 4 0 
m g dail y d ose i n a d ult s u bjects wit h me d ullar y t h yr oi d ca nc er.   
Wit hi n a 4 8 -da y c ollecti o n peri o d aft er a si n gle d ose of 1 4 C -c a b oz a nti ni b i n healt h y s u bjects, 
a p pr o xi matel y 8 1 % of t he t otal a d mi nist ere d ra di oacti vit y was re c o vere d wit h   
5 4 % i n feces a n d 2 7 % i n uri ne. R es ults fr o m a P K st u d y of c a b oz a nti ni b i n s u bjects wit h r e nal  
i m pair me nt ( X L 1 8 4-0 1 7) i n dicat e d t hat t he rati os of ge o metric L S mea n f or plas m a ca b oz a nti ni b 
C ma x a n d A U Cs ( A U C 0 -t a n d A U C 0 -i nf) were 1 9 % a n d 3 0 % hi g her, res pecti vel y, f or s u bjects 
wit h mil d re nal i m pair me nt c o m par e d t o s u bjects wit h n or mal re nal f u ncti o n. F or s u bjects wit h 
m o d erat e re nal i m p air m e nt, b ot h C ma x a n d A U Cs a p peare d t o be si milar w he n c o m pare d t o 
s u bje cts wit h n or mal re nal f u ncti o n ( differ e nces: < 3 % a n d < 7 %, res pecti vel y). Res ults fr o m a 
P K e val uati o n of ca b oz a nti ni b i n s u bjects wit h he p atic  i m pair me nt ( X L 1 8 4-0 0 3) i n dicat e d t hat 
e x p os ure ( A U C 0 -i nf) t o ca b oz a nti ni b was i ncrease d b y a b o ut 8 1 % a n d 6 3 % i n s u bjects wit h mil d 
a n d m o derate he patic i m pair me nt, res pecti vel y.   
A hi g h -fat meal i ncre ase d Cm a x a n d A U C val u es b y 4 1 % a n d 5 7 %, res pecti vel y, relati ve t o 
fast e d c o n diti o ns i n healt h y s u bje cts a d mi nistere d a si n gle 1 4 0 m g oral ca b oz a nti ni b d ose 
( X L 1 8 4-0 0 4).   
Ca b oz a nti ni b is a s u bstrat e of C Y P 3 A 4 i n vitr o. I n vitr o i n hi biti o n of C Y P 3 A 4 re d uc e d t he 
f or m ati o n of t he ca b oz a nti ni b N-o xi de m eta b olite b y > 8 0 %. I n hi biti o n of C Y P 2 C 9 ha d a 
mi ni m al effect o n ca b oz a nti ni b meta b olite f or mati o n (ie, a < 2 0 % re d ucti o n). I n hi biti o n of 
C Y P 1 A 2, C Y P 2 A 6, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 1 9, C Y P 2 D 6 a n d C Y P 2 E 1 ha d n o effect o n 
ca b oz a nti ni b meta b olite f or mati o n. I n he alt h y s u bj ect s, c a b oz a nti ni b A U C was i ncr ease d 3 8 % 
wit h c oa d mi nistrati o n of t he str o n g C Y P 3 A 4 i n hi bit or ket oc o naz ole ( X L 1 8 4 -0 0 7) a n d de crease d 
7 7 % wit h c oa d mi nistrati o n of t he str o n g C Y P 3 A 4 i n d uc er rifa m pi n ( X L 1 8 4 -0 0 6) i n healt h y 
s u bje cts.  
Ca b oz a nti ni b is a n o nc o m petiti ve i n hi bit or of C Y P 2 C 8 ( K ia p p = 4. 6 μ M), a mi xe d -t y pe i n hi bit or 
of b ot h C Y P 2 C 9 ( K ia p p = 1 0. 4 μ M) a n d C Y P 2 C 1 9 ( K ia p p = 2 8. 8 μ M), a n d a wea k c o m petiti ve 
i n hi bit or of C Y P 3 A 4 (esti m ate d Kia p p = 2 8 2 μ M) i n H L M pre parati o ns. T he I C 5 0 val ue was 
1 0. 1 μ M f or C Y P 2 B 6 a n d I C 5 0 val ues were > 2 0 μ M f or C Y P 1 A 2, C Y P 2 D 6, a n d C Y P 3 A 4 
is oz y mes. Ca b oz a nti ni b at stea d y-state plas m a c o nc e ntrati o ns ( ≥ 1 0 0 m g/ d a y dail y d osi n g f or a 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 3 0  of 9 6  
mi ni m u m of 2 1 da ys) s h o we d n o effect o n si n gle -d ose r osi glit az o ne ( a C Y P 2 C 8 s u bstra te) 
plas ma e x p os ure ( C ma x a n d A U C) i n s u bjects wit h s oli d t u m ors ( X L 1 8 4 -0 0 8).   
Ca b oz a nti ni b is a n i n d ucer of C Y P 1 A 1 m R N A i n h u ma n he pat oc yte i nc u b ati o ns (ie, 7 5 -1 0 0 % of 
C Y P 1 A 1 p ositi ve c o ntr ol β -na p ht h ofla v o ne i n d ucti o n), b ut n ot of C Y P 1 A 2, C Y P 2 B 6, C Y P 2 C 8,  
C Y P 2 C 9, C Y P 2 C 1 9 or C Y P 3 A 4 m R N A or is oz y me -ass ociate d e nz y me acti vities.   
C o nc o mit a nt a d mi nistrati o n of t he P PI es o m e praz ol e res ulte d i n n o cli nic all y -r ele va nt effect o n 
ca b oz a nti ni b plas ma P K i n healt h y s u bje cts ( X L 1 8 4 -0 1 8).   
Ca b oz a nti ni b is a n i n hi bit or (I C5 0 = 7. 0 μ M), b ut n ot a s u bstrate, of P -g p tra ns p ort acti vities i n a 
bi -directi o nal assa y s yst e m usi n g M D C K -M D R 1 cells. T her ef ore, c a b oz a nti ni b ma y ha ve t he 
p ot e ntial t o i ncrease plas ma c o nce ntrati o ns of c o -a d mi nister e d s u bstrat es of P -g p. I n a d diti o n, 
ca b oz a nti ni b was s h o w n t o be a s u bstrat e of dr u g tra ns p orter 
M R P 2 i n a n i n vitr o assa y. 
A d mi nistrati o n of M R P 2 has t he p ote ntial t o i ncreas e plas ma c o nce ntrati o ns of c a b oz a nti ni b.   
1. 2. 3. 4  
Cli ni c al Acti vit y  
Ca b oz a nti ni b has bee n st u die d i n a br oa d selecti o n of t u m or t y pes. A s u m mar y  of t he a vaila ble 
cli nical acti vit y r es ults f or ca b oz a nti ni b i n t hese t u m or t y p es is pr o vi de d i n Ta ble 1 -5.  
T a ble  1 -5 : 
Assess m e nt of C a b oz a nti ni b See n i n M ulti ple T u m or  T y pes  
 
T u m or T y pe  
 
St u d y  
Me di a n P F S 
( m o nt hs) 
Wee k 1 2 D C R
a 
( %) 
D T C  
X L 1 8 4 -0 0 8  
n ot r ea c he d  
8 0 b  
R C C  
X L 1 8 4 -0 0 8  
1 2. 9  
7 2 b  
 
O varia n C a ncer  
X L 1 8 4 -2 0 3 R D T  
5. 5  
5 0  
X L 1 8 4 -2 0 3 N R E  
4. 0  
N A  
 
X L 1 8 4 -2 0 3 R D T  
6. 8  
6 6  
C R P C  
X L 1 8 4 -2 0 3 N R E  
4. 6 c  
N A  
 
X L 1 8 4 -2 0 3 N R E  
6. 5 d  
N A  
H C C  
X L 1 8 4 -2 0 3 R D T  
5. 2  
6 6  
Br east C a ncer  
X L 1 8 4 -2 0 3 R D T  
4. 3  
4 7  
M ela n o ma  
X L 1 8 4 -2 0 3 R D T  
2. 8  
4 3  
N S C L C  
X L 1 8 4 -2 0 3 R D T  
4. 0  
3 8  
S C L C  
X L 1 8 4 -2 0 3 R D T  
3. 4  
4 3  
Pa ncr eati c C a ncer  
X L 1 8 4 -2 0 3 R D T  
2. 7  
3 5  
Gastri c/ G EJ C a ncer  
X L 1 8 4 -2 0 3 R D T  
1. 4  
3 3  
G B  
X L 1 8 4 -2 0 1  
3. 7 e  
N A  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 3 1  of 9 6  
C R P C, castrati o n -resista nt pr ostate ca ncer; D C R, disease c o ntr ol rate; D T C, differe ntiate d t h yr oi d ca ncer; G B, 
gli o blast o ma; G EJ, gastr oes o p ha geal j u ncti o n; H C C, he pat ocell ular carci n o ma; P F S, pr o gressi o n -free s ur vi val; N A, n ot 
a vaila ble; N R E, n o n-ra n d o mize d e x pa nsi o n; N S C L C, n o n-s mall cell l u n g ca ncer; R C C; re nal cell carci n o ma; R D T, 
ra nd o mize d disc o nti n uati o n trial; S C L C, s mall-cell l u n g ca ncer.  
N ote: Data re p orte d i n t his ta ble is fr o m t he fi nal e n d p oi nt a nal yses.  
a   D C R = (c o nfir me d res p o nse [ C R] + partial res p o nse [ P R] + sta ble disease [ 1]) 
b   D C R at Wee k 1 7  
c   F or t he C R P C c o h ort t hat was assi g ne d a d ose of 4 0 m g q d  
d   F or t he C R P C c o h ort t h at was assi g ne d a d ose of 1 0 0 m g q d  
e   F or Treat me nt Gr o u p C ( 1 0 0 m g q d). See Secti o n 5. 5. 2. 2 f or f urt her details. 
 
1. 2. 3. 5  
Tr a nsl ati o n al Me dici ne  
I n hi biti o n of t he V E G F si g nali n g p at h wa y al o ne was pre vi o usl y s h o w n t o res ult i n m ore i n vasi ve 
t u m ors i n t he tr a ns ge nic RI P-Ta g 2 m o use m o del of ne ur oe n d ocri ne p a ncre atic ca ncer t hat 
s p o nta ne o usl y d e vel o ps a g gressi ve t u m ors ( Pàez -Ri b es et al. 2 0 0 9). Treat me nt wit h ca b oz a nti ni b 
f or 3 we e ks, fr o m a g e 1 4 t o 1 7 wee ks, si g nifica ntly pre ve nt e d f or m ati o n of li ver m etast ases 
( Fi g ure 1-1 A) i n t he RI P -Ta g 2 m o del c o m p are d wit h a nti -V E G F tre at m e nt or ve hicle al o ne. T he 
n u m b er of li ver m etast ases was 5 -f ol d greater i n a nti-V E G F a nti b o d y -treate d a ni mals c o m pare d 
wit h ve hicle -tre ate d a ni mals, a n d n o li ver met ast ases were detect e d i n ca b oz a nti ni b -tre ate d 
a ni mals ( Fi g ure 4 -1 A). I n a d diti o n, tre at m e nt wit h ca b oz a nti ni b fr o m a ge 1 4 t o 2 0 wee ks 
i m pr o ve d s ur vi val ( Fi g ure 4-1 B). Me dia n s ur vi val w as 1 4. 7 wee ks f or ve hicle -tr eat e d a ni mals ( n 
= 1 2) a n d 1 6. 4 wee ks f or a nti -V E G F a nti b o d y -tr eat e d a ni mals ( n = 7; P < 0. 0 5 vs ve hicle), a n d 
all ca b oz a nti ni b -tr eat e d a ni m als s ur vi ve d f or t he f ull 2 0 wee ks of o bser vati o n ( n = 6; P < 0. 0 5 vs 
ve hicle a n d a nti-V E G F a nti b o d y; Fi g ure 1 -1 B).  
Fi g ure 1 -1:  
RI P -T a g 2 M o del : S ur vi v al, C a b oz a nti ni b ve rs us Ve hicle  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 3 2  of 9 6  
O ne of 7 mice i n t he ca b oza nti ni b gr o u p t hat die d fr o m a ga va ge i nj ur y at 3. 5 wee ks was e xcl u de d.  
* P < 0. 0 5 a nti -V E G F a nti b o d y vs ve hicle  
# P < 0. 0 5 ca b oza nti ni b vs a nti -V E G F a nti b o d y 
T hese res ults are a da pte d fr o m Se n ni n o et al. 2 0 1 2.  
T hese data s u g gest t hat d ual i n hi biti o n of M E T a n d V E G F R 2 wit h ca b oza nti nib lea ds t o p ote nt 
a ntit u m or efficac y, i ncl u di n g pr otecti o n fr o m metastatic t u m or esca pe, w hic h tra nslates i nt o s ur vi val 
a d va nta ges. 
1. 3  
R ati o n ale  
1. 3. 1  
R ati o n ale f o r t he St u d y , D ose, a n d Sc he d ul e   
Ca b oza nti ni b is a p ote nt, orall y bi oa vaila ble s mall -m olec ule i n hibit or of m ultiple rece pt or t yr osi ne 
ki nases w hic h has de m o nstrate d earl y e vide nce of acti vit y i n a variet y of s oli d  t u m ors. T he pri ncipal 
tar gets of ca b oza nti ni b are pr otei ns ce ntral t o ca ncer cell gr o wt h a n d t u m or a n gi o ge nesis:  
V E G F R 2/ K D R, M E T, R E T, a n d KI T. Ca b oza nti nib is F D A a p pr o ve d f or t he treat me nt of pr o gressi ve 
metastatic 
me d ullar y t h yr oi d ca ncer, 
w here a 
statisticall y sig nifica nt P F S pr ol o n gati o n 
was 
de m o nstrate d i n t he ca b oza nti ni b ar m c o m pare d t o place b o [ 1 1. 2 vs. 4 m o nt hs; H R 0. 2 8 ( 9 5 % CI: 
0. 1 9, 0. 4 0); p < 0. 0 0 0 1].  Ca b oza nti ni b als o de m o nstrate d a hig her res p o nse rate as c o m pare d t o 
place b o ( 2 7 % vers us 0 %; p < 0. 0 0 0 1) ( Elisei, 2 0 1 3). Ca b oza nti ni b has als o bee n F D A a p pr o ve d f or 
metastatic re nal cell carci n o ma base d o n res ults fr o m t he M E T E O R trial, w hic h s h o we d a sig ni fica nt 
i m pr o ve me nt i n me dia n pr o gressi o n free s ur vi val wit h ca b oza nti nib vers us e ver oli m us ( 7. 4 m o nt hs vs 
3. 8 m o nt hs, res pecti vel y). T he rate of pr o gressi o n or deat h was re d uce d b y 4 2 % wit h ca b oza nti ni b 
c o m pare d t o e ver oli m us ( H R 0. 5 8; 9 5 % CI, 0. 5 1 t o 0. 8 9 ; P < 0. 0 0 1). T he o bjecti ve res p o nse rate was 
als o si g nifica ntl y i m pr o ve d wit h ca b oza nti ni b c o m pare d t o e ver oli m us ( 2 1 % vs 5 %, res pecti vel y; 
P < 0. 0 0 1).  
W hile m utati o ns i n t he R E T ge ne u n derlie m uc h of t he efficac y of t he dr u g i n me d ullar y t h yr oid 
ca ncer, it is e x pecte d t hat t he c o nc urre nt i n hi biti o n of M E T a n d V E G F R 2 ma y be effecti ve i n ma n y 
s oli d t u m ors.  I n c ol orectal ca ncers, M E T o vere x pressi o n was de m o nstrate d i n 1 1/ 1 2 h u ma n t u m or 
s peci me ns, a n d de m o nstrate d i n vitr o t hat sile nci n g of M E T b y si R N A le d t o d ecreases i n c ol o n 
ca ncer cell li ne pr oliferati o n, mi grati o n, a n d i n vasi o n ( H olgre n, 2 0 1 0).  I n a n ot her st u d y of 2 8 6 h u ma n 
c ol orectal ca ncer s peci me ns, M E T o vere x pressi o n as assesse d b y i m m u n o hist oc he mistr y was see n i n 
7 9 % ( 2 3 6/ 2 8 6) of s peci me ns.  F urt her m o re, M E T o vere x pressi o n c orrelate d wit h p o or pr o g n osis ( De 
Oli veira, 2 0 0 9). T he pr oa n gi o ge nic li ga n d, vasc ular e n d ot helial gr o wt h fact or ( V E G F) bi n ds t o at least 
3 rece pt ors: V E G F R 1 ( F L T 1), V E G F R 2 ( K D R), a n d V E G F R 4 ( F L T 4). T he V E G F rece pt ors, 
V E G F R 1 a n d V E G F R 2 ( K D R) are e x presse d o n t he s urface of vasc ular e n d ot helial cells, a n d o n 
s o me b o ne marr o w-deri ve d cells.  
W he n acti vate d b y li ga n d bi n di n g, V E G F rece pt ors me diate 
e n d ot helial cell i n vasi o n, pr oliferati o n, a n d s ur vi val.  Cli nicall y, i n hibiti o n of V E G F b y be vaciz u ma b 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 3 3  of 9 6  
i n c o m bi nati o n wit h I F L yiel de d i m pr o ve d pr o gressi o n-free s ur vi val a n d o verall s ur vi val c o m pare d t o 
c he m ot hera p y al o ne i n a d va nce d C R C, de m o nstrati n g t he p ote ntial f or a ntia n gi o ge nic a p pr oac hes t o 
t he treat me nt of ca ncer ( H ur witz, 2 0 0 4). T her e is e vide nce t hat M E T a n d V E G F R pat h wa ys c o o perate 
t o acti vate d o w nstrea m effect ors re g ulati n g t u m or gr o wt h ( S ulpice, 2 0 0 9; 
Gerritse n, 2 0 0 3).  
E x pressi o n of M E T is re g ulate d b y t he sa me h y p o xia -i n d ucible fact or s yste m t hat g o ver ns V E G F 
e x pressi o n le vels.  T heref ore, b ot h M E T a n d V E G F are i n d uce d i n res p o nse t o t u m or h y p o xia.  T he 
d o w nstrea m mec ha nis ms i n v ol ve d i n 
M E T a n d V E G F R sig nali n g are c o m ple x a n d ma y var y 
de pe n di n g o n c o nte xt; h o we ver, i n hi biti o n of t hese tar gets wit h si n gle -a ge nt ca b oza nti ni b a p pears t o 
ha ve t he p ote ntial t o s hri n k t u m ors.  I n xe n o graft a ni mal st u dies, treat me nt wit h ca b oza nti ni b res ulte d 
i n brea k d o w n of t u m or e n d ot heli u m be gi n ni n g 2 4 h o urs after a d mi nistrati o n, t h us s u g gesti n g p ote nt 
a nti-a n gi o ge nic effects of ca b oza nti ni b.  T his, i n t ur n, le d t o sig nifica nt t u m or gr o wt h i n hibiti o n after 
ca b oza nti ni b treat me nt i n m ulti ple t u m or m o dels i ncl u di n g h u ma n me d ullar y t h yr oid ca ncer, h u ma n 
breast ca ncer, h u ma n l u n g carci n o ma, a n d rat gli o blast o ma ( Ya kes, 2 0 1 1).  I n C R C patie nt -deri ve d 
xe n o gr aft m o dels, ca b oza nti ni b res ulte d i n sig nifica ntl y decrease d gr o wt h i n all t u m ors, i nclu di n g 
re gressi o n of 2/ 1 2 t u m ors after 2 8 da ys of treat me nt. Treat me nt wit h ca b oza nti ni b sig nifica ntl y 
decrease d b ot h t he n u m ber pr oliferati n g cells ( KI 6 7 e x pressi o n) a n d  a n gi o ge nesis ( C D 3 4 stai ni n g) 
w he n c o m pare d t o u ntreate d t u m ors ( Atre ya, 2 0 1 3).  
W hile a d diti o nal la b orat or y -b ase d t esti n g will b e critical t o better u n d ersta n d t he mec ha nis m of 
acti vit y of ca b oz a nti ni b, h u m a n testi n g i n t he c o nte xt of a cli nical trial is r e q uir e d t o deter mi ne 
its effic ac y i n a n u nselect e d C R C p o p ulati o n.  Base d u p o n t he pr ecli nic al e vi de nc e a b o ve 
s u g gesti n g t hat M E T a n d t he V E G F pat h wa y ar e pr o misi n g t hera p e utic t ar gets i n c ol orectal 
ca ncers, as well as t he preli mi nar y cli nic al e vi de nce f or  b ot h a nti -t u m or efficac y a n d safet y 
acr oss a br oa d ra n g e of a de n oc arci n o mas, it is a p pr o priate t o pr ocee d wit h a cli nical trial of 
ca b oz a nti ni b i n patie nts wit h a d va nce d c ol ore ctal ca nc ers.  T he e x perie nc e wit h V E G F -directe d 
t hera p y wit h b e vaciz u m a b, afliberce pt, a n d re g or afe ni b i n t he tr eat me nt of a d va nc e d C R C 
hi g hli g hts t he i m p ort a nce of a n gi o g e nesis i n t his dis ease.  I n a d diti o n, a r ole f or M E T si g nali n g 
i n C R C is s u p p orte d b y precli nic al a n d cli nic al data, a n d b y t he p ot e ntial f or t he cl os e i nter pla y 
b et wee n M E T a n d V E G F R pat h wa ys.  F urt her m ore, it is li kel y t hat as -yet u nrec o g niz e d tar g ets 
i n a d diti o n t o 
M E T a n d V E G F R c o ntri b ute t o t he br oa d s pectr u m of a ntic a ncer acti vit y 
de m o nstrat e d i n t he precli nic al m o d els . 
2  
S T U D Y O B J E C TI V E S A N D D E SI G N  
2. 1  
St u d y O bject i ves 
T he o bje cti ves of t his st u d y are as f oll o ws:  
Pri m ar y O bjecti v e:  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
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1)  T o det er mi ne t he cli nical a cti vit y of c a b oz a nti ni b i n patie nts wit h refr act or y metastatic C R C 
usi n g pr o gressi o n fre e s ur vi val ( P F S) as pri mar y e n d p oi nt.  
Sec o n d ar y O bje cti ves:  
1)  T o deter mi ne t he r es p o nse rate ( R R) i n patie nts wit h refra ct or y metastatic C R C tr eat e d wit h 
ca b oz a nti ni b.  
2)  T o det er mi ne t he o ver all s ur vi val ( O S) i n patie nts wit h refr act or y metastatic C R C tr eat e d 
wit h ca b oz a nti ni b.  
3)  T o descri b e safet y a n d t olera bilit y of ca b oz a nti ni b i n t his gr o u p of hea vil y pretreat e d 
patie nts.  
4)  T o retr os pecti vel y e x pl ore t he P F S a n d R R i n patie nts base d o n R A S, B R A F, a n d PI K 3 C A 
m utati o n stat us.  
E x pl or at or y O bjecti ves:  
1)  E x pl orat or y a nal ysis of pre dicti ve a n d p har mac o d y n a mic mar kers.  
2. 2  
S t u d y Desi g n  
2. 2. 1  
O ver vi e w of St u d y Desi g n  
T his is a P hase 2, si n gle -ar m, o p e n-la b el st u d y of ca b oz a nti ni b i n s u bjects wit h metastatic 
c ol orectal ca ncer refract or y t o  sta n dar d of c are o pti o ns.  T he pri mar y e n d p oi nt is pr o gressi o n-
fre e s ur vi val at 1 2 wee ks.  A Si m o n 2-sta ge o pti m al  desi g n will be use d.  
2. 3  
Tre at m e nt Assi g n m e nt  
It is t he r es p o nsi bilit y of t he i n vesti g at or t o assi g n a s u bje ct n u m b er bef ore  treati n g e ac h su bje ct 
wit h ca b oz a nti ni b . 
2. 4  
Bli n di n g a n d r a n d o miz ati o n  
T his is a n o pe n -la bel, si n gle-ar m st u d y w hic h re q uir es n o bli n di n g or ra n d o miz ati o n.  
2. 5  
St u d y Sites  
T his st u d y will be c o n d uct e d at u p t o  a p pr o xi matel y 8 sit es. 
2. 6  
Wit h dr a w al s 
S u bje cts ma y dis c o nti n u e st u d y tre at m e nt or wit h dra w t heir c o nse nt t o partici p ate i n t he st u d y at 
a n y ti me wit h o ut pr ej u dice. T he i n vesti g at or ma y wit h dr a w a s u bject fr o m st u d y tre at m e nt or 
fr o m t he st u d y if, i n his or her cli nic al j u d g me nt, it is i n t he best i nter est of t he s u bject or if t he 
s u bje ct c a n n ot c o m pl y wit h t he pr ot oc ol.  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
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I n a d diti o n, a n y of t he f oll o wi n g c o n diti o ns re q uir e disc o nti n uati o n of t he s u bje ct fr o m st u d y 
treat me nt: 
•  A n A E or i nterc urr e nt ill ness t hat i n t he o pi ni o n of t he i n vesti g at or warr a nts t he s u bject’s 
wit h dr a wal fr o m  st u d y treat me nt; 
•  T he i n vesti gat or b elie ves it is n ot i n t he best i nterest of t he s u bject t o c o nti n ue st u d y 
•  S pecific c o n diti o ns descri be d i n t he Ma na ge me nt of A d verse E ve nts  S ecti o ns 3. 3. 2  a n d 
3. 3. 2. 1 ; 
•  Necessit y f or tre at me nt wit h ot h er a ntica ncer tr eat me nt pr o hi bit e d b y pr ot oc ol ; 
•  Se x uall y acti ve s u bjects w h o ref use t o use me dicall y a cce pte d b arrier met h o ds of 
c o ntrac e pti o n (e g,  male c o n d o m, fe male c o n d o m ) d uri n g  t he st u d y a n d f or 4  m o nt hs after  
disc o nti n uati o n of st u d y tr eat me nt ; 
•  W o me n w h o bec o me pre g na nt  or are br eastfe e di n g;  
•  If t he s u bject d oes n ot re c o ver fr o m his or her t o xicities t o t olera ble Gra d e ≤ 2 wit hi n 6 
wee ks, t he s u bje ct will ha ve st u d y treat me nt disc o nti n ue d u nless t here is u ne q ui v ocal 
e vi de nc e t hat t he s u bje ct is be nefitti n g. I n t his sit u ati o n, a s u bject m a y be a ble t o r estart 
t hera p y wit h a d ose re d u cti o n u p o n res ol uti o n of t he t o xicit y a n d wit h a gr ee m e nt of t he 
pri nci pal i n vesti gat or / S p o ns or;  
•  Re q uest b y r e g ulat or y a g e ncies f or  ter mi nati o n of tre at me nt of a n i n di vi d ual s u bje ct or all 
s u bje cts u n der t he pr ot oc ol; 
•  Si g nifica nt n o nc o m plia nce wit h t he pr ot oc ol sc he d ule i n t he o pi ni o n of  t he i n vesti gat or; 
•  T he mi ni m u m d ose of st u d y treat me nt will b e 2 0  m g o nce d ail y ( q d ). S u bje cts w h o 
ca n n ot t olerate 2 0  m g q d will ha ve st u d y treat me nt disc o nti n ue d;  
•  Pr o gressi ve disease ( P D) or t he s u bject n o l o n ger e x perie nc es cli nical be nefit as 
deter mi ne d b y t he i n vesti gat o r 


 
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3  
T R E A T M E N T S  
3. 1  
C o m p ositi o n, F or m ul ati o n , a n d S t or a ge 
At st u d y sit es, all st u d y me dicati o n will b e st ore d as descri be d i n t he p har mac y ma n ual a n d 
i n ve nt orie d i n a cc or da nc e wit h a p plic a ble st ate a n d fe deral r e g ulati o ns. 
3. 1. 1  
I n vesti g ati o n al Tr e at m e nt  
 
C he mic al Na m e:  
C he mic al 
Na m e: 
N -{ 4 -[( 6, 7-di met h o x y q ui n oli n -4 -yl) o x y] p he n yl } -N ’-( 4-
fl u or o p he n yl)c ycl o pr o pa ne-1, 1 -dicar b o x a mi d e, ( 2 S) -h y dr o x y b ut a ne di oate  
 
3. 1. 2  
C a b oz a nti ni b  T a blets   
E xeli xis i nter nal n u m b er: X L 1 8 4  
Ca b oz a nti ni b ta blets are s u p plie d as fil m c oat e d 
ta blets c o ntai ni n g ca b oz a ntini b 
malate 
e q ui vale nt t o 2 0 m g  of c a b oz a nti ni b a n d c o ntai n  micr ocr ystalli ne cell ul ose, la ct ose a n h y dr o us, 
h y d o x y pr o p yl cell ul ose, cr oscar mell os e s o di u m, c oll oi dal silic o n di o xi de, ma g nesi u m stearate 
a n d O pa dr y ® yell o w. 
All ta ble t stre n gt hs are pre pare d fr o m a c o m m o n ble n d a n d are 
disti n g uis he d b y s ha pe. T he 2 0 m g t a blets are r o u n d a n d t he 6 0  m g ta blets ar e o val . T he 
c o m p o ne nts of t he ta blets are liste d i n  Ta ble 3 -1 . 
T a ble 3 -1 : 
C a b oz a nti ni b T a blet C o m p o ne nts a n d C o m p ositi o n  
I n gre die nt  
F u ncti o n  
% w/ w  
C a b oza nti ni b malat e ( 2 5 % dr u g l oa d as ca b oza nti ni b ) 
Acti ve I n gr e di e nt  
3 1. 7  
Micr ocr ystalli ne C ell ul os e ( A vi cel P H -1 0 2)  
Filler  
3 8. 9  
La ct os e A n h y dr o us ( 6 0 M)  
Filler  
1 9. 4  
H y dr o x y pr o p yl C ell ul os e ( E X F)  
Bi n d er  
3. 0  
Cr os car mell os e S o di u m ( Ac -Di -S ol)  
Dis e ne gra nt  
6. 0  
C oll oi dal Sili c o n Di o xi d e,  
Gli da nt  
0. 3  
M a g nesi u m Stearat e  
L u bri ca nt  
0. 7 5  
O pa dr y Y ell o w Fil m C oati n g w hi c h i n cl u des:  
- 
H P M C 2 9 1 0/ H y pr o m ell os e 6 c p  
- 
Tita ni u m di o xi d e  
- 
Triaceti n  
- 
Ir o n O xi de Y ell o w 
Fil m C oati n g  
4. 0 0  
 


 
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Pa ge 3 7  of 9 6  
3. 2  
D ose , Sc he d ul e  a n d R o ut e  
S u bje cts will  r ecei ve ca b oz a nti ni b orall y at a (starti n g) d ose of 6 0  m g o nce dail y .  
Ca b oz a nti ni b  m ust  be t a ke n o n  a n e m pt y st o ma c h.  S u bje cts m ust be i nstr ucte d n ot t o eat f or at 
least 2 h o urs bef ore a n d at least 1 h o ur aft er t a ki n g ca b oz a nti ni b.  S u bje cts m a y dri n k water 
d uri n g t his ti me. S u bje cts  s h o ul d be i nstr uct e d t o ta ke t heir ca b oz a nti ni b d ose at a p pr o xi mat el y 
t he sa m e ti me e ver y da y.  If a s u bje ct misses a d ose, t he d ose m a y be ta ke n later o nl y if it is 
wit hi n 1 2 h o urs of w he n t he misse d d ose s h o ul d ha ve bee n ta ke n.  T he misse d d ose s h o ul d n ot  
be ma de u p if it is wit hi n 1 2 h o urs of t he ne xt  sc he d ule d d ose.   
Ca b oz a nti ni b t a blets s h o ul d b e s wall o we d w h ole wit h at least 8 o u nces of wat er.  T he ta blets 
s h o ul d n ot be cr us he d. Gra pefr uit, gra pefr uit j uic e, Se ville ora n g es a n d t heir pr o d ucts s h o ul d  be 
a v oi de d b y s u bje cts ta ki n g ca b oz a nti ni b.  
I n all s u bjects, d ose re d ucti o ns a n d dela ys t o ma na ge t o xicit y ar e all o we d u n der t he g ui deli nes i n 
S ecti o n 3. 3  bel o w.  
3. 3  
C a b oz a nti ni b D ose M o dific ati o ns, I nte rr u pti o ns, a n d Disc o nti n u ati o n  
S u bje cts will be m o nit or e d f or A Es fr o m t he ti me of si g ni n g i nf or me d c o nse nt t hr o u g h t heir last 
f oll o w-u p visit ( 3 0  da ys after t he dat e of t he last d ose of c a b oz a nti ni b treat me nt .) S u bjects will 
be i nstr ucte d t o n otif y t heir p h ysicia n i m me diatel y at t he o nset of a n y A E. Ca usalit y assess me nt 
of A Es will be d eter mi ne d b y t he i n vesti g at or . A E  se verit y will be gra d e d b y t he i n vesti gat or i n 
acc or da nce wit h C T C A E v. 4. 0.  
T he f oll o wi n g s h o ul d be t a ke n i nt o c o nsi der ati o n i n decisi o ns re gar di n g d ose m o dificati o ns 
(re d ucti o ns or i nterr u pti o n): 
•  As a ge neral a p pr oac h , all A Es s h o ul d be ma na g e d wit h s u p p orti ve care at t he earliest si g ns 
of t o xicit y  c o nsi d ere d  relat e d t o the st u d y tr eat me nt . S h o ul d t his be i neffecti ve, d ose 
i nterr u pti o ns a n d/ or re d u cti o ns s h o ul d be c o nsi dere d t o pr e ve nt w orse ni n g of t o xicit y.  
•  D ose  m o dificati o n crit eria f or ca b oz a nti ni b are s h o w n i n Ta ble 3 -3 . D ose i nterr u pti o ns a n d/ or 
re d ucti o ns s h o ul d be i m ple me nte d f or u nacc e pta ble t o xicit y. D oses ma y b e m o difie d at a n y 
ti me w hile a s u bject is o n treat me nt. 
•  T he assi g ne d st arti n g d ose f or ca b oz a nti ni b is 6 0  m g/ da y. T w o ( 2 ) d ose re d u cti o n le vels of 
ca b oz a nti ni b are per mitt e d (see T a ble 3 -2 ). 


 
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•  D ose re d ucti o ns or i nterr u pti o ns  ma y als o occ ur i n t h e setti n g of l o w er gra de t o xicit y t ha n 
defi ne d i n  T a ble 3 -3 , if t he i n vesti gat or fe els it is i n t he i nterest of a s u bje ct’s safet y a n d will 
o pti miz e dr u g t olera bilit y . 
•  I nt err u pti o n of ca b oz a nti ni b  tre at m e nt f or ca b oz a nti ni b -relate d A Es  ma y occ ur at a n y ti me 
per i n vesti g at or discreti o n.  If tre at m e nt is i nterr u pte d d ue t o relat e d A Es f or m or e t ha n 
6  wee ks, ca b oz a nti ni b s h o ul d be disc o nti n ue d  u nless t here is u ne q ui v ocal e vi de nce t hat t he 
s u bje ct is be nefitti n g. I n t his sit u ati o n, a s u bject ma y be a ble t o restart t hera p y wit h a d ose 
re d ucti o n u p o n r es ol uti o n of t he t o xicit y per t he dis creti o n of t he i n vesti gat or . 
•  D ose i nt err u pti o ns f or r eas o n(s) ot her t ha n relat e d A Es (e g, s ur gical pr oce d ures) ca n be 
l o n g er t ha n 6 we e ks per t he discr eti o n of t he i n vesti g at or.  
G ui deli nes f or t he ma na ge me nt of s pecific A Es are pr o vi d e d i n Secti o n  3. 3. 2 .  
T a ble 3 -2 : 
D ose Re d ucti o ns of C a b oz a nti ni b  
Assi g ne d d ose  
First D ose Le vel Re d ucti o n  
Se c o n d D ose Le vel Re d ucti o n  
6 0 -m g ca b oz a nti ni b oral q d  
4 0 -m g ca b oz a nti ni b oral q d  
2 0 -m g ca b oz a nti ni b oral q d  
q d, o n ce dail y  
C a b oza nti ni b s h o ul d b e dis c o nti n u e d if a dail y  d os e of 2 0 -m g ca b oza nti ni b ( mi ni m u m d os e) is n ot t ol erat e d  
 


 
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Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 3 9  of 9 6  
T a ble 3 -3 : 
D ose M o dific ati o ns of C a b oz a nti ni b f or Tr e at m e nt -Rel ate d A Es  
C T C A E  v. 4. 0 Gr a de  
Rec o m m e n de d G ui deli nes f or M a n a ge m e nt a 
Gr a de 1 A Es  
A d d s u p p orti ve care as i n dicat e d. C o nti n ue ca b oz a nti ni b 
treat me nt at t he c urre nt d os e l e vel if A E is ma na gea ble 
a n d t ol era ble.  
Gr a de 2 A Es  w hi c h are t olera ble 
a n d ar e easil y ma na ge d  
 
Gr a de 2 A Es w hi c h are i nt ole r a ble 
a n d c a n n ot be a de q u atel y 
m a n a ge d   
C o nti n ue ca b oz a nti ni b tr eat me nt at t he c urre nt d os e l e vel 
wit h s u p p orti ve care.  
 
At t he dis creti o n of t he i n vesti gat or, ca b oz a nti ni b s h o ul d 
be d ose re d uce d or i nterr u pte d.  
N ot e: It is re c o m me n de d t hat d os e h ol ds b e as brief as 
p ossi ble.  
Gr a de 3 A Es (e x c e pt cli nicall y 
n o n -rel e va nt la b orat or y 
a b n or malities)  
Ca b oz a nti ni b  s h o ul d be i nterr u pt e d u nless t he t o xicit y 
ca n b e easil y ma na ge d wit h a d ose r e d ucti o n a n d o pti mal 
me di cal care.  
N ot e: It is re c o m me n de d t hat d os e h ol ds b e as brief as 
p ossi ble.  
Gr a de 4 A Es (e x c e pt cli nicall y 
n o n -rel e va nt la b orat or y 
a b n or malities)  
S u bje cts s h o ul d ha ve ca b oz a nti ni b  i nterr u pte d 
i m me diat el y.  
Disc o nti n ue ca b oz a nti ni b u nless t he f oll o wi n g criteria ar e 
met:  
•  
S u bje ct is deri vi n g clear cli nical be nefit as 
deter mi ne d b y t he i n vesti gat or a n d a gr ee d b y t he 
S p o ns or  
•  
T o xi cit y ca n b e ma na ge d wit h a d os e re d ucti o n 
f oll o wi n g re c o ver y t o Gra de 1 ( or baseli ne) a n d 
o pti mal me di cal care  
A E, a d vers e e ve nt.  
N ot e : T h e d os e d ela y a n d m o difi cati o n crit eria f or s pecific me dical c o n diti o ns are pr o vi de d i n S ecti o n 
3. 3. 2 . F or r e -tr eat m e nt crit eria of st u d y treat m e nt aft er a d os e h ol d s ee S ecti o n 3. 3. 1. 1 . 
a St u d y tr eat m e nt d os e a dj ust me nt is o nl y n ee de d if t h e t o xi cit y was dee m e d r elate d t o ca b oza nti ni b  
treat m e nt or ha d a n u n clear r elati o ns hi p t o ca b oza nti ni b  tr eat m e nt. 
  


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
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3. 3. 1. 1  
C a b oz a nti ni b D ose Rei nstit uti o n a n d Reesc al ati o n  
If t he s u bject rec o vers fr o m his or her t o xicities t o C T C A E v. 4. 0 Gra de   1 or t o t he baseli ne 
val ue ( or l o w er) a n d t he t o xicit y was u nrelat e d t o st u d y treat me nt, t he n st u d y tre at m e nt ma y b e 
restarte d wit h n o c ha n ge i n d ose.  
If t he s u bje ct rec o vers fr o m his or her t o xicities t o Gra de  1 or t o t he baseli ne val ue ( or l o wer) 
t he t o xicit y was dee me d p ossi bl y relat e d t o st u d y tre at m e nt, t he n st u d y tr eat me nt m a y b e 
restarte d at a re d u ce d d ose (see Ta ble 3 -2  f or t he sc he d ule of d ose re d u cti o ns).  
S u bje cts re cei vi n g a dail y d ose of 2 0  m g m a y be restarte d at t he sa m e d ose  if de e me d safe at t he 
discr eti o n of t he i n vesti gat or.  S u bjects u na ble t o t olerate a dail y d ose of 2 0 
m g s h o ul d 
disc o nti n ue st u d y treat m e nt.  
Re -escalati o n t o t he pre vi o us d ose, ( b ut n ot hi g her t ha n 6 0 m g/ da y ) m a y b e all o we d at t he 
discr eti o n of t he i n vesti gat or a n d a gr ee m e nt of t he S p o ns or f or A Es w hic h ha ve res ol ve d or 
rec o vere d t o Gra de 1 ( or baseli ne val ue) a n d de e me d t olera ble a n d e asil y ma na g e d b y o pti miz e d 
s u p p orti ve treat me nt. D ose re-escalati o n is n ot all o w e d f or a dr u g -relate d d ose re d ucti o n 
tri g gere d b y Gra de 4 he mat ol o gic t o xicities or b y Gra de 4 A Es affe cti n g maj or or g a ns (e g, 
ce ntral ner v o us s yst e m, car diac, he patic, re nal).  
3. 3. 2  
W a r ni n gs a n d P rec a uti o ns a n d G ui deli nes f or t he M a n a ge m e nt of A d verse 
E ve nts  
T he m ost fr e q u e nt a d vers e e ve nts e x p erie nc e d b y ≥ 2 0 % of s u bjects tr eate d wit h ca b oza nti ni b wer e 
diarr hea, fati g u e, na us ea, decr eas e d a p petit e, v o miti n g, wei g ht decr eas e d, P P E S, c o n sti pati o n, 
h y p ert e nsi o n, d ys ge usia, d ys p h o nia, a n d ast he nia.  
A d vers e e ve nts ass ociate d wit h la b or at or y a b n or malities e x p erie nc e d b y ≥ 5 % of s u bjects tr eat e d 
wit h ca b oza nti ni b i ncl u de a ne mia, A S T i ncr ease d, A L T i ncr eas e d, h y p ot h yr oi dis m, h y p o kale mia, 
h y p o ma g nes e mia, t hr o m b oc yt o p e nia, h y p ocalc e mia, h y p o p h os p hate mia, li pas e i ncr eas e d, la ctate 
de h y dr o ge nas e ( L D H) i ncr eas e d, ne utr o p e nia, A L P i ncr ease d, h y p o natr e mia, a n d le u k o p e nia.  Mil d t o 
m o der ate Q T c i nt er val pr ol o n gati o n ( 1 0 -1 5 ms) has als o b ee n o bs er ve d wit h a Q T i nt er val calc ulat e d 
b y t he Fri dericia f or m ula ( Q T c F ) n ot e xc ee di n g 5 0 0 ms.  
S u bjects ma y als o e x p erie nc e me dicall y i m p orta nt b ut less fr e q u e nt a d vers e e ve nts i ncl u di n g arterial 
a n d ve n o us t hr o m b otic A Es ( e g, D V T, p ul m o nar y e m b olis m [ P E], tr a nsie nt isc he mic atta c k [ TI A], 
a n d 
m y ocar dial i nfar cti o n [ MI]), se ver e 
he m orr ha gic e ve nts, 
p r ot ei n uria, 
w o u n d 
heali n g 


 
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c o m plicati o ns, GI perf or ati o n, a bscess es i ncl u di n g i ntr a -a b d o mi nal a n d pel vic a bsc ess, GI a n d n o n -
GI fist ula e f or mati o n, ost e o necr osis, a n d r e vers e p ost eri or le u k oe nc e p hal o pat h y s y n dr o me (R P L S ). 
Ca b oza nti ni b tr eat me nt s h o ul d b e pe r ma ne ntl y disc o nti n u e d f or t he f oll o wi n g a d vers e e ve nts: 
visc er al p erf or ati o n or fist ula f or mati o n, se ver e he m orr ha ge, s eri o us arterial t hr o m b oe m b olic e ve nts, 
ne p hr otic s y n dr o me, 
mali g na nt h y p ert e nsi o n, h y p erte nsi ve e mer ge nc y, p ersist e nt u nc o ntr olle d 
h y p er t e nsi o n des pit e o pti mal me dical ma na ge me nt, ost e o necr osis of t he ja w ( O NJ), a n d R P L S. 
G ui deli nes f or t he m a na ge me nt of A E s (ie, d ose i nterr u pti o ns a n d d ose re d u cti o ns) ar e prese nte d 
i n t he ne xt secti o ns. Ea c h d ose re d ucti o n of ca b oz a nti ni b  s h o ul d be t o o ne d ose le vel  l o wer t hat 
t he c urre nt d ose. D ose re d u cti o ns of m ore t ha n o ne d ose le vel are a cce pta ble per I n vesti gat or 
j u d g me nt. All A Es s h o ul d als o be ma na g e d wit h s u p p orti ve care at t he e arliest si g ns of t o xicit y .   
A d verse re acti o ns are pres u me d t o be att ri b uta ble t o st u d y dr u g. A d verse e ve nts classifie d as 
“ n ot relat e d” are d efi ne d as A Es t hat are, wit h o ut q uesti o n, n ot ass ociate d wit h t he st u d y 
treat me nt a n d attri b uta ble t o a n ot her ca use. 
T he pre dicte d effe cti ve plas ma half -life of c a b oz a nti ni b is 5 5  h o u rs. T h us, w he n i nitiati n g 
t hera p y wit h ca b oz a nti ni b, it will ta ke m ost s u bje cts 2 t o 3  wee ks t o rea c h ste a d y stat e. If A Es 
attri b uta ble t o ca b oz a nti ni b  oc c ur wit hi n t he i nitial 3 -wee k peri o d of d osi n g, earl y i nt er ve nti o n 
wit h d ose m o dificati o ns ma y be j ustifie d f or A Es t hat, if w orse ne d, c o ul d p ote ntiall y be 
da n g er o us or de bilit ati n g, be ca use  wit h o ut a d ose a dj ust me nt , s yst e mic e x p os ure of c a b oz a nti ni b 
mi g ht be e x pecte d t o i ncrease  after t he o nset of t he A E.    
E ve nts t hat ge ner all y ha ve a n earl y o ns et i ncl u de h y p ocalc e mia, h y p o kale mia, t hr o m b oc yt o p e nia, 
h y p ert e nsi o n, P P E S, a b d o mi nal pai n, m uc osal i nfla m mati o n, c o nsti pati o n, diarr hea a n d v o miti n g. I n 
a d diti o n, earlier o ns et f or e ve nt s of de h y dr ati o n was o bser ve d i n s u bjects wit h C R P C w he n c o m par e d 
wit h s u bjects wit h ot her t u m or t y p es.  
3. 3. 2. 1  
G ui deli nes f or M a n a ge m e nt of P ote nti al  A d verse E ve nts  
Secti o ns 3. 3. 2. 2  –  3. 3. 2. 1 9  prese nt m a na ge m e nt g ui d eli nes or war ni n gs/ prec a u ti o ns f or t he 
f oll o wi n g ca b oz a nti ni b tr eat m e nt -e mer ge nt a d ver se e ve nts/seri o us a d verse e ve nts of i nterest: 
•  Gastr oi ntesti nal dis or ders ( diarr hea, na use a a n d v o miti n g, de h y dr ati o n [ pr ost ate ca ncer 
st u dies], st o matitis a n d m uc ositis) 
•  H e pat o biliar y dis or ders (ele vat e d A L T a n d A S T)   
•  He mat ol o gical dis or ders  


 
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•  F ati g ue, an or e xia , a n d wei g ht l oss  
•  S ki n dis or ders ( pal mar -pla nt ar er yt hr o d ysest hesia s y n dr o m e [ P P E S ] a n d r as h)  
•  W o u n d heali n g  a n d s ur ger y  
•  H y pert e nsi o n  
•  T hr o m b oe m b olic e ve nts  ( ve n o us a n d arterial) 
•  P r otei n uria 
•  Q Tc pr ol o n gati o n  
•  H y p o p h os p hate mia  
•  T h yr oi d f u ncti o n dis or ders   
•  H e m orr ha gic e ve nts  
•  Oste o ne cr osis of t he ja w ( O NJ ) 
•  A n gi oe d e ma  
•  M usc ul os keletal a n d c o n necti ve tiss ue d is or ders 
•  Res pir at or y, th or acic, a n d m e diasti nal dis or ders  
 
Ple ase refer t o t he I n vesti gat or’s Br oc h ur e f or a d diti o nal pr actice g ui d eli nes a n d ma na ge m e nt 
rec o m m e n dati o ns f or t hese a n d ot her A Es p ote ntiall y relate d t o ca b oz a nti ni b tre at m e nt ( e. g. 
i ntra-a b d o mi nal a n d pel vic a bscess; ner v o us s yst e m dis or ders; i nfecti o ns a n d i nfestati o ns;  a n d 
res pir at or y t h oracic a n d me diasti nal dis or d ers) use  i n s pecific p o p ulati o ns, a n d o ver d ose a n d first 
ai d me as ures f or acci d e ntal ca b oz a nti ni b e x p os ure . 
As wit h all i n vesti gati o nal pr o d ucts, u n k n o w n A Es ma y oc c ur. S u bjects s h o ul d be m o nit ore d 
cl osel y f or all A Es. As wit h ot he r a ge nts i n de vel o p me nt, a d diti o nal A Es are u n k n o w n .  
3. 3. 2. 2  
G astr oi nt esti n al Dis or ders  
T he m ost c o m m o n n o n -he pat o biliar y  GI A Es re p ort e d i n cli nical st u dies wit h ca b oz a nti ni b  
re gar dless of ca usalit y are diarr hea, na usea, d ecre ase d a p petite, v o miti n g,  c o nsti p ati o n,  st o matitis 
a n d a b d o mi nal pai n.  
Diarr hea  
S u bje cts s h o ul d be i nstr ucte d t o n otif y t heir p h ysicia n i m m e diatel y at t he first si g ns of p o orl y 
f or m e d or l o ose st o ol or a n i ncrease d fre q u e nc y of b o wel m o ve me nts. A d mi nistrati o n of 
a nti diarr heal /a nti m otilit y a g e nts is r ec o m me n de d at t he first si g n of diarr hea as i nitial 
ma na ge me nt. S o me s u bje cts m a y re q uire c o nc o mita nt tre at m e nt wit h m ore t ha n o ne a nti diarr heal 


 
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a ge nt. W he n t hera p y wit h a nti diarr he al a ge nts d oes n ot c o ntr ol t he diarr hea t o t oler a ble l e vels, 
st u d y tr eat me nt s h o ul d b e te m p oraril y i nterr u pte d or d ose re d u ce d per  T a ble 3 -4 . 
Ta ble 3 -4 :  
Ma na g e me nt of Diarr hea Ass ociate d wit h  C a b oz a nti ni b  
St at us  
M a n a ge me nt  
T olera ble Gra d e 1 -2 ( d urati o n 
<  4 8  h)  
•  
C o nti n u e wit h st u d y tr eat me nt a n d c o nsi der d os e r e d u cti o n  
•  
I nitiate treat m e nt wit h a n a nti diarr heal a g e nt ( e g, l o p era mi d e 4 m g f oll o we d b y 
2 m g aft er ea c h e pis o d e of diarr hea [ ma xi m u m: 1 6 m g l o p era mi de p er da y])  
•  
Dietar y m o dificati o ns ( e g, s mall lact os e-free m eals, ba na nas a n d rice) 
•  
I nta ke of is ot o ni c fl ui ds ( 1-1. 5 L/ da y)  
•  
R e -ass ess after 2 4 h o urs:  
o  
Diarr hea r es ol vi n g t o bas eli n e b o w el ha bits: gra d uall y a d d s oli d f o o ds 
a n d dis c o nti n u e or d ecr eas e a nti diarr heal treat m e nt aft er 1 2  h 
diarr hea -fr ee i nter val 
o  
Diarr hea n ot r es ol vi n g: C o nti n u e/r es u me a nti diarr h eal tr eat me nt  
I nt olera ble Gra d e 2, 
Gra d e 2 > 4 8 h,  
or ≥ Gra d e 3  
•  
I nterr u pt st u d y tr eat m e nt 
•  
As k s u bject t o att e n d cli nic  
•  
R ule o ut i nfecti o n ( e g, st o ol s a m ple f or c ult ur e)  
o  
A d mi nister a nti bi oti cs as nee d e d (e g, if fe ver or Gra d e 3 -4 
ne utr o p e nia p ersists >  2 4  h)  
•  
A d mi nister fl ui ds ( 1 -1. 5 L/ da y orall y or I V, as a p pr o priate) f or h ydrati o n or t o 
c orr ect el ectr ol yt e a b n or maliti es  
•  
F or Gra de 3 -4 or c o m pli cate d l o wer gra de diarr h ea c o nsi der h os pitalizati o n 
a n d I V  h ydrati o n  
•  
R e -ass ess after 2 4 h  
o  
Diarr hea r es ol vi n g t o bas eli n e b o w el ha bits or Gra de ≤ 1: c o nsi der 
restarti n g st u d y tr eat m e nt at r e d uce d d os e 
o  
Diarr hea n ot r es ol vi n g: Start a n d or c o nti n ue a nti diarr h eal tr eat me nt 
(e g, l o p era mi d e 4 m g f oll o we d b y 2 m g after ea c h e pis o d e of di arr hea 
[ ma xi m u m: 1 6 m g l o p era mi d e per da y]). C o nsi der starti n g s ec o n d li ne 
a nti diarr heal or r eferral t o gastr oe nt er ol o gist  
 
I n a d diti o n, g e neral s u p p orti ve m eas ures s h o ul d b e i m ple m e nte d i ncl u di n g h y dr ati o n, c orre cti o n 
of fl ui d a n d ele ctr ol yt e a b n or malities, s mall fre q u e nt me als, a n d st o p pi n g lact ose-c o ntai ni n g 
pr o d ucts, hi g h fat meals , a n d alc o h ol.  
Rec urre nt or pr ol o n g e d diarr hea ca n b e ass ociate d wit h a nal or peria nal s ki n er osi o ns w hic h 
i ncrease t he ris k f or a nal a bscesses, fist ulas, or pr octitis. G o o d pers o nal h y gie ne s h o ul d be 
e m p hasiz e d. Re g ular e xa mi nati o ns of t he p eria nal re gi o n s h o ul d b e perf or m e d w he ne ver diarr he a 


 
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has occ urr e d d uri n g tre at m e nt wit h c a b oz a nti ni b. I nfe cti o ns of t he peria nal r e gi o n s h o ul d be 
treat e d per l ocal g ui d eli nes.  
Na usea a n d V o miti n g  
A ntie metic a ge nts are rec o m me n d e d as cli nicall y a p pr o priat e at t he first si g n of na usea a n d 
v o miti n g or as pr o p h yla xis t o pre ve nt e mesis, al o n g wit h s u p p orti ve c are i n ac c or da nc e t o 
cli nical practic e g ui d eli nes.  T h e 5 -H T 3 r ece pt or a nt a g o nists are rec o m me n d e d o ver c hr o nic use 
of N K -1 rece pt or a nta g o nists a n d de x a met has o ne ( N K -1 rece pt or a nta g o nists ca n i n d uce or 
i n hi bit C Y P 3 A 4, a n d gl uc oc ortic oi ds i n d uce C Y P 3 A 4 a n d t h us c o ul d l o wer c a b oz a nti ni b 
e x p os ure (see Secti o ns  3. 4. 4 ). Ca uti o n is als o rec o m me n de d wit h t he use of na bil o ne, w hic h is a 
wea k i n hi bit or of C Y P 3 A 4.  W he n t hera p y wit h a nti e metic a g e nts d oes n ot c o ntr ol t he na usea,  or 
v o miti n g t o t oler a ble le vels, st u d y treat me nt s h o ul d be t e m p oraril y i nterr u pte d or d ose re d u ce d 
per  Ta ble 3 -3 . 
De h y drati o n ma y b e ass ociate d wit h v o miti n g a n d m o nit ori n g f or a n d c orrecti o n of fl ui d  a n d 
electr ol yt e dist ur ba nc es s h o ul d b e i m ple m e nte d.  
St o m atitis a n d M uc ositis  
Pr e ve nti ve meas ur es ma y i ncl u de a c o m pr e he nsi ve or al e xa mi nati o n t o i de ntif y a n d tr eat a n y 
p ot e ntial ris k f or c o m plicati o ns b ef or e st u d y tr eat me nt is i nitiate d. A p pr o priate c orr ecti o n of l ocal 
fa ct ors s h o ul d b e i nstit ut e d as i n dicate d, s uc h as m o dificati o n of ill-fitti n g de nt ur es a n d a p pr o priate 
car e of gi n gi vitis.  
D uri n g tre at m e nt wit h ca b oz a nti ni b g o o d or al h y gie ne a n d sta n dar d l ocal tr eat me nts s uc h as 
n o n tr a u matic clea nsi n g a n d or al ri nses (e g, wit h a wea k s ol uti o n of salt a n d b a ki n g s o d a) s h o ul d 
be mai ntai ne d.  T he or al c a vit y s h o ul d be ri nse d after meals, a n d de n t ures s h o ul d b e clea ne d a n d 
br us he d ofte n t o re m o ve pla q ue.  L ocal tr eat me nt s h o ul d be i nstit ute d at t he earliest o nset of 
s y m pt o ms. O btai n bacterial/ viral c ult ure if or al i nfe cti o n is s us pect e d a n d treat i nfe cti o n as 
i n dicate d b y l oc al g ui deli nes. 
W he n st om atitis i nterferes wit h a d e q uat e n utriti o n a n d l ocal 
t hera p y is n ot a d e q uat el y effecti ve, d ose re d ucti o n or te m p orar y wit h h ol di n g of ca b oz a nti ni b 
s h o ul d be c o nsi dere d p er  Ta ble 3 -2  a n d T a ble 3 -3 . 
3. 3. 2. 3  
He p at o bili ar y Dis or de rs  
Ele vati o ns of A L T, A S T, a n d bilir u bi n  ha ve bee n o bser ve d d uri n g tr eat me nt wit h c a b oz a nti ni b . 
It is r ec o m me n de d t hat s u bjects wit h ele vati o n of A L T, A S T, a n d/ or bilir u bi n ha ve m or e 


 
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fre q u e nt la b or at or y 
m o nit ori n g of t hese para m et ers. If p ossi ble, he p at ot o xic c o nc o mit a nt 
me dic ati o ns s h o ul d be disc o nti n ue d i n s u bje cts w h o de vel o p i ncrease d val ues of A L T, A S T, or 
bilir u bi n .  
S u bje cts o n t his st u d y ma y e nter wit h i ncr ease d A L T/ A S T ser u m le vels u p t o 3  U L N. D ose 
re d ucti o ns of st u d y tre at m e nt s h o ul d be c o nsi d ere d i n a n y s u bject w h o de vel o ps dr u g-relate d 
Gra de  2 ele vate d A L T, A S T, or bilir u bi n lasti n g l o n ger t ha n 1 wee k. A s u bject w h o de vel o ps 
Gra de ≥ 3 ele vat e d A L T, A S T, or bilir u bi n s h o ul d ha ve st u d y tr eat me nt hel d a n d restart e d at a 
re d uce d d ose (see Ta ble 3 -2 ) aft er A L T, A S T, a n d bilir u bi n le vels res ol ve t o at le ast Gra de ≤ 1 or 
baseli ne. I n s u bje ct s wit h rec urre nce of dr u g-relate d Gra de ≥ 3 ele vate d A L T, A S T, or bilir u bi n 
at t he l o west d ose le vel, st u d y treat me nt s h o ul d be disc o nti n ue d. I n s u bjects w h o de vel o p 
A L T/ A S T ele vati o ns > 3  U L N i n c o m bi nati o n wit h a bilir u bi n ele vati o n > 2  U L N wit h o ut 
reas o na ble ot her e x pla nati o n, dr u g -i n d uce d li ver i nj ur y s h o ul d be s us pecte d a n d c a b oz a nti ni b 
treat me nt i nterr u pte d. Rei nstit uti o n of st u d y tr eat me nt after r ec o ver y of A L T, A S T, a n d bilir u bi n 
t o Gra d e 1 or baseli ne le vel is at t he dis creti o n of t he i n vesti gat or. 
3. 3. 2. 4  
He m at ol o gic al Dis or ders  
He mat ol o gical t o xicities (ie, ne utr o p e nia a n d t hr o m b oc yt o pe nia) a n d ass ociate d c o m plicati o ns 
ha ve bee n o bser ve d after a d mi nistr ati o n of ca b oz a nti ni b a n d ma y b e ma na ge d wit h d ose 
i nterr u pti o ns a n d/ or d ose re d ucti o ns.  Use of gra n ul oc yt e c ol o n y -sti m ulati n g fact or s u p p ort f or 
ne utr o p hil rec o ver y is all o w e d per i n vesti gat or discreti o n a n d i n acc or da nce wit h acc e pte d 
g ui d eli nes  after t he first i nci de nce of cli nic all y rele va nt c yt o p e nia. 
C o m plet e bl o o d c o u nts wit h differe ntials a n d pla telets s h o ul d be perf or me d re g ularl y. S u bje cts 
wit h he mat ol o gic t o xicities ma y re q uire a d diti o nal or m or e fr e q ue nt la b orat or y tests ac c or di n g t o 
i nstit uti o nal g ui d eli nes. Res ults of s uc h tests are t o be f or war d e d t o t he l ocal la b orat or y data 
ma na ge me nt ve n d or.  
Fe brile ne utr o pe nia or e vi de nce of i nfecti o n ass ociat e d wit h ne utr o pe nia m ust be assesse d 
i m me diat el y a n d treate d a p pr o priatel y a n d i n a ti mel y 
m a n ner acc or di n g t o i nstit uti o nal 
g ui d eli nes.  
D ose re d ucti o ns or d ose i nterr u pti o ns f or a ne mia are n ot ma n date d b ut c a n be a p plie d as 
cli nicall y i n dicat e d. S u p p orti ve car e s uc h as re d bl o o d cell tr a nsf usi o ns ma y  be ma na g e d 
acc or di n g t o i nstit uti o nal g ui d eli nes.  


 
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3. 3. 2. 5  
F ati g ue, A n or e xi a, a n d Wei g ht L oss  
Fati g ue has bee n r e p orte d d uri n g tr eat me nt wit h c a b oz a nti ni b. C o m m o n ca uses of fati g ue s uc h as 
a ne mia, dec o n diti o ni n g, e m oti o nal distr ess ( de pressi o n a n d/ or a n xiet y), p o or n utriti o n, sle e p 
dist ur b a nce, a n d h y p ot h yr oi dis m s h o ul d be r ule d o ut a n d / or t hese ca uses treat e d i n acc or d a nce t o 
sta n d ar d of car e. I n di vi d ual n o n-p ha r mac ol o gic al a n d/ or p har mac ol o gic i nt er ve nti o ns dire cte d t o 
t he c o ntri b uti n g a n d tre ata ble fa ct ors s h o ul d be gi ve n. N ote : Chr o nic use of m o dafi nil s h o ul d be 
a v oi de d bec a use of its p ote ntial t o re d uce c a b oz a nti ni b e x p os ure (see I n vesti gat or’s Br oc h ure ).  
Refer t o T a ble 3 -3  f or ge neral ma na g e me nt g ui deli nes. 
A n ore xia a n d wei g ht l oss  s h o ul d b e ma na ge d i n ac c or d a nce t o l oc al sta n d ar d of car e incl u di n g 
n utriti o nal s u p p ort.  If fati g u e, a n or e xia, or wei g ht l oss ca n n ot be a d e q uatel y ma na g e d, st u d y 
treat me nt s h o ul d b e te m p oraril y i nterr u pte d or d ose r e d uce d per  Ta ble 3 -2  a n d Ta ble 3 -3 . 
3. 3. 2. 6  
S ki n Dis or ders  
Pal mar -pla ntar er yt hr o d ys est hesia s y n dr o me ( P P E S; als o k n o w n as ha n d -f o ot s y n dr o me), s ki n 
ras h (i ncl u di n g blisters, er yt he mat o us ras h, ma c ular ras h, s ki n e xf oliati o n, der matitis ac neif or m, 
a n d pa p ular ras h), pr urit us, dr y s ki n, er yt he ma , pi g me ntar y c ha n ges, a n d al o p ecia  ha ve b ee n 
re p orte d i n ca b oz a nti ni b-tre ate d s u bjects. 
All s ubjects o n st u d y s h o ul d be a d vise d o n 
pr o p h yla ctic s ki n c are. T his i ncl u des t he use of h y p oaller g e nic m oist urizi n g cre a ms, oi nt m e nt f or 
dr y s ki n, a n d s u nscree n wit h s u n pr otecti o n fact or ≥ 3 0 , a v oi da nce of e x p os ure of ha n ds a n d fe et 
t o h ot water, re m o val of c all uses, pr ot ecti o n of pr ess ure -se nsiti ve are as of ha n ds a n d feet, a n d 
use of t hic k c ott o n gl o ves a n d s oc ks t o pre ve nt i nj ur y a n d t o kee p t he pal ms a n d s oles dr y. 
S u bje cts wit h s ki n dis or ders s h o ul d b e caref ull y m o nit ore d f or si g ns of i nfecti o n (e g, a bsc ess, 
cell ulitis, or i m peti g o).  
Earl y si g ns of ha n d -f o ot s y n dr o me c o ul d b e ti n gli n g, n u m b ness, a n d sli g ht re d ness or mil d 
h y per kerat osis. Earl y ma nifestati o ns i ncl u de p ai nf ul, s y m metric al re d a n d s w olle n ar eas o n t he 
pal ms a n d s oles. T he lateral si des of t h e fi n gers or peri -u n g ual z o nes ma y als o be affe cte d. 
A de q uate i nter ve nti o ns are re q uire d t o pre ve nt w orse ni n g of s ki n s y m pt o ms s uc h as blist ers, 
des q ua mati o ns, ulcer ati o ns, or necr osis of affe cte d areas. A g gr essi ve ma na ge m e nt of s y m pt o ms 
is rec o m me n de d, i ncl u di n g earl y d er mat ol o g y r eferral. Treat me nt g ui d eli nes f or P P E relate d t o 
st u d y tr eat me nt are prese nt e d i n T a ble  3 -5 . 
I n t he c ase of st u d y tre at m e nt-relat e d s ki n c ha n ges (e g, ras h, ha n d-f o ot s y n dr o me), t he 
i n vesti gat or m a y re q uest t hat a d diti o nal assess me nts be c o n d ucte d wit h t he s u bject’s c o nse nt. 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 4 7  of 9 6  
T hese assess me nts ma y i ncl u de di git al p h ot o gr a p hs of t he s ki n c ha n ges a n d/ or a bi o ps y of t he 
affect e d s k i n a n d ma y b e re pe ate d u ntil t he s ki n c ha n ges res ol ve.  
T a ble  3 -5 : 
M a n a ge m e nt of T re at m e nt -E m er ge nt H a n d -F o ot  S y n dr o m e  ( P P E S) 
C T C A E v. 4. 0 Gr a de  
Acti o n T o B e T a k e n  
Gra d e 1  
St u d y tr eat me nt ma y b e c o nti n u e d at t he c urr e nt d os e if P P E S  is cli nicall y 
i nsi g nifi ca nt a n d t ol era bl e. Ot her wis e, st u d y tr eat m e nt s h o ul d b e r e d u ce d t o t he 
ne xt l o w er d os e l e vel a Start ur ea 2 0 % cr ea m t wi ce dail y A N D cl o b etas ol 0. 0 5 % 
cr ea m o nce dail y. R eass ess at least wee kl y; if  P P E S  w ors e ns at a n y ti m e or d oes 
n ot i m pr o ve after 2 wee ks, pr ocee d t o t h e i nt er ve nti o n g ui deli n es f or Gra d e  2.  
Gra d e 2  
St u d y tr eat me nt ma y b e c o nti n u e d if P P E S  is t ol erat e d. St u d y tr eat me nt s h o ul d b e 
d os e re d u ce d or i nt err u pt e d if P P E S  is i nt ol era bl e. C o nti n u e ur ea 2 0 % cr ea m t wi ce 
dail y A N D cl o betas ol 0. 0 5 % cr ea m o n ce dail y a n d a d d a nal gesi cs 
(e g, N S AI Ds/ ga m ma -a mi n o b ut yric a ci d a g o nists) f or pai n c o ntr ol if nee d e d. 
R eass ess at least wee kl y; if P P E S  w ors e ns or affects s elf -care, pr ocee d t o t h e 
i nter ve ntio n g ui d eli n es f or Gra de  3.  
Gra d e 3  
I nterr u pt st u d y tr eat m e nt u ntil s e verit y decr eas es t o Gra d e 1 or 0. C o nti n u e 
treat m e nt of s ki n r ea cti o n wit h cl o b etas ol 0. 0 5 % crea m t wi ce d ail y A N D 
a nal gesics. R es u me st u d y dr u g at a r e d u ce d d os e if P P E S  rec o vers t o Gra de ≤ 1. 
Dis c o nti n ue s u bj ect fr o m st u d y tr eat m e nt if P P E S  d oes n ot i m pr o ve wit hi n 
6  wee ks.  
C T C A E, C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; N S AI D,  n o n -ster oi dal a nti-i nfla m mat or y dr u g; P P ES , pal mar 
pla ntar er yt hr o d ysest hesia  s y n dr o me. 
a Per mitte d d ose le vels are defi ne d b y i n di vi d ual pr ot oc ols.  
 
3. 3. 2. 7  
W o u n d H e ali n g a n d S ur ge r y  
V E G F R  i nhi bit ors  ca n c a use w o u n d heali n g c o m plicati o ns a n d w o u n d  de hisce nce w hic h ma y  
oc c ur e ve n l o n g after a w o u n d has be e n c o nsi dere d he ale d. T heref ore, s ur gical a n d tra u m atic 
w o u n ds m ust ha ve c o m pletel y heale d bef ore  starti n g ca b oz a nti ni b tre at m e nt a n d be m o nit ore d 
f or w o u n d de hisc e nce or w o u n d i nfecti o n w hile t he s u bje ct is bei n g tr eat e d wit h ca b oz a nti ni b. If 
p ossi ble, ca b oz a nti ni b treat me nt s h o ul d be st o p pe d f or at le ast 2 8 da ys pri or t o maj or s ur ger y.  
3. 3. 2. 8  
H y perte nsi o n  
H y pert e nsi o n is a c o m m o n class effe ct of dr u gs t hat i n hi bit V E G F pat h wa ys a n d has bee n 
re p orte d a m o n g  s u bjects treat ed wit h c a b oz a nti ni b.  
Treat me nt g ui deli nes f or h y perte nsi o n de e me d relate d t o ca b oz a nti ni b  ar e prese nt e d i n Ta ble 3 -6 . 
Bl o o d press ure s h o ul d be m o nit or e d i n a c o nst a nt p ositi o n at e ac h visit  (eit her sitti n g or s u pi ne ). 
I n general, s u bjects wit h k n o w n h y perte nsi o n s h o ul d be o pti m all y ma na g e d bef ore  st u d y e ntr y. 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 4 8  of 9 6  
Decisi o ns t o de crease or h ol d t he d ose of st u d y treat m e nt m ust be base d o n bl o o d pr ess ure  
rea di n gs t a ke n b y a m e dic al pr ofessi o nal a n d m ust be c o nfir me d wit h a se c o n d m eas ure me nt at 
least 5 mi n utes after  t he first me as ure me nt.  Ot her t ha n f or h y perte nsi o n re q uiri n g i m m e diate 
t hera p y, t he prese nce of ne w or w orse ne d h y perte nsi o n s h o ul d b e c o nfir me d at a sec o n d visit 
bef or e ta ki n g t hera p e utic acti o n. It is r ec o m me n de d t hat t his sec o n d visit oc c ur s wit hi n 1  wee k.  
Ca b oz a nti ni b s h o ul d be dis c o nti n u e d i n s u bje cts wit h h y p erte nsi ve crises or h y perte nsi ve 
e nce p hal o pat h y.  
T a ble 3 -6 : 
M a n a ge m e nt of H y perte nsi o n Rel ate d t o C a b oz a nti ni b  
Criteri a f or D os e M o dific ati o ns  
T re at m e nt/ C a b oz a nti ni b D os e M o dific ati o n  
S u bjects N O T recei vi n g o pti mize d a nti -h y perte nsi ve t her a p y  
> 1 5 0 m m H g (s yst oli c) a a n d <  1 6 0 m m H g  
O R  
> 1 0 0 m m H g ( diast oli c) a n d < 1 1 0 m m H g  
 
•  
O pti mize a nti h y p ert e nsi ve m e di cati o ns b y a d di n g n e w or 
a d diti o nal a nti h y p ert e nsi ve m e di cati o ns a n d/ or i n cr eas e d os e 
of e xisti n g m e di cati o ns.  
•  
R e d uce st u d y tr eat m e nt b y o ne d os e l e vel if o pti mal 
a nti h yp ert e nsi ve t h era p y ( us uall y t o i n cl u d e 3 a g e nts) d oes 
n ot r es ult i n B P < 1 5 0 m m H g s yst oli c or < 1 0 0  m m  H g 
diast oli c  
•  If s u bject is s y m pt o matic i nt err u pt st u d y tr eat m e nt 
≥ 1 6 0 m m H g (s yst oli c)  
O R  
≥ 1 1 0 m m H g ( diast oli c)  
•  
R e d uce ca b oza nti ni b b y o n e d os e l e vel b or i nterr u pt st u d y 
treat m e nt p er i n vesti gat or dis creti o n 
•  
A d d ne w or a d diti o nal a nti -h y p ert e nsi ve me di cati o ns a n d/ or 
i ncr eas e d os e of e xisti n g me di cati o ns a n d m o nit or s u bject 
cl os el y f or h y p ot e nsi o n. If o pti mize d a nti h y p ert e nsi ve t hera p y 
( us ually t o i n cl u d e 3  a ge nts) d oes n ot r es ult i n B P 
<  1 5 0  m m  H g s yst oli c or <  1 0 0  m m  H g diast olic, st u d y 
treat m e nt s h o ul d be d os e r e d u ce d f urt h er or i nt err u pt e d 
•  
St u d y tr eat me nt s h o ul d b e d os e i nt err u pt e d if u p p er li mits of 
s yst oli c B P ( ≥ 1 6 0 m m H g) ar e s ustai ne d a n d n ot a d e q uat el y 
ma na gea ble or if s yst oli c B P is >  1 8 0  m m H g or diast oli c B P 
>  1 1 0 m m H g, or if s u bj ect is s y m pt o mati c  
•  R e -start st u d y treat m e nt at t h e m ost t ol era bl e d os e a n d 
re-es calat e o nl y if B P falls t o a n d is s ustai ne d at <  1 5 0  m m  H g 
s yst oli c a n d < 1 0 0  m m  H g diast oli c  
H y p ert e nsi ve e m er g e n c y c 
•  
Dis c o nti n ue st u d y tr eat m e nt  
B P, bl o o d press ure.  
a T he i n vesti gat or ma y deci de t o i nitiate or a dj ust a nti h y perte nsi ve treat me nt at a l o wer t hres h ol d t ha n s yst olic B P  > 1 5 0 or 
diast olic B P > 1 0 0 base d o n t heir cli nical j u d g me nt a n d assess me nt of t he i n di vi d ual s u bject.  
b Per mitte d d ose le vels are defi ne d  b y i n di vi d ual pr ot oc ols.  
c H y perte nsi ve e mer ge nc y is defi ne d as u nc o ntr olle d ele vate d bl o o d press ure wit h cli nical e vi de nce of pr o gressi ve or i m pe n di n g 
e nd -or ga n da ma ge ( e g, m y ocar dial i nfarcti o n/isc he mia, i ntracra nial he m orr ha ge, cere bral isc he mia, p ul m o nar y e de ma, 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 4 9  of 9 6  
Criteri a f or D os e M o dific ati o ns  
T re at m e nt/ C a b oz a nti ni b D os e M o dific ati o n  
e nce p hal o pat h y, ki d ne y da ma ge).  
 
3. 3. 2. 9  
T hr o m b oe m b olic E ve nts  
T hr o m b oe m b olic c o m plicati o ns ar e fr e q ue nt i n c a nc er patie nts d ue t o pr oc oa g ula nt c ha n g es 
i nd u ce d b y t he mali g na nc y or a nti ca ncer t hera p y i n cl u di n g i n hi bit ors of V E G F pat h wa ys. Dee p 
vei n t hr o m b osis a n d P E ha ve bee n o bser ve d i n cli ni cal st u dies wit h ca b oz a nti ni b; i ncl u di n g fatal 
e ve nts ( please r efer t o t he I n vesti gat or’s Br oc h ure).  S u bje cts w h o de vel o p a P E or D V T s h o ul d 
ha ve ca b oz a nti ni b treat me nt hel d u ntil t her a pe uti c a ntic oa g ulati o n wit h he p ari ns (e g, l o w 
m olec ular wei g ht he pari n [L M W H ]) is esta blis he d. L M W H are t he preferr e d m a na ge m e nt f or 
t hr o m b otic e ve nts, warfari n is n ot re co m m e n de d. Ca b oz a nti ni b tr eat me nt ma y b e res u me d i n 
s u bje cts w h o ar e sta ble a n d ha ve u nc o m plicat e d P E or D V T a n d are d eri vi n g cli nical b e nefit 
fr o m c a b oz a nti ni b tr eat me nt a n d t hat a ntic oa g ulati o n d oes n ot pla c e t he m at a si g nifica nt ris k t hat 
o ut wei g hs t he b e nefit of r es u mi n g tr eat me nt p er discr eti o n of t he i n vesti gat or/ S p o ns or . D uri n g 
a ntic oa g ulati o n tre at m e nt, s u bjects ne e d t o be m o nit or e d o n a n o n g oi n g basis f or ble e di n g ris k 
a n d si g ns of blee di n g w hic h m a y re q uire a d diti o nal or m ore fre q ue nt la b or at or y t ests i n 
acc or da nce  t o i nstit uti o nal g ui deli nes. If t her e ar e a n y si g ns of cli nic all y si g nifica nt ble e di n gs, 
ca b oz a nti ni b treat me nt s h o ul d b e per m a ne ntl y  disc o nti n ue d.  
Arterial t hr o m b otic e ve nts (e g, tra nsie nt  isc he mic att ac k, m y ocar dial i nfar cti o n) ha ve bee n 
o bser ve d i n st u dies wit h ca b oz a nti ni b. S u bjects s h o ul d b e e val uate d f or pre e xisti n g ris k fact ors 
f or arterial t hr o m b otic e ve nts s uc h as dia bet es mellit us, h y p erli pi de mia, h y perte nsi o n, c or o nar y 
arter y dis e ase, hist or y of t o bac c o use, a n d c ar diac or t hr o m b oe m b olic e ve nts t hat oc c urre d b ef ore  
i nitiati o n of st u d y treat me nt. Ca b oz a nti ni b treat me nt s h o ul d b e disc o nti n ue d i n s u bjects w h o 
de vel o p a n ac ute m y oc ar dial i nfarcti o n , cer e bral i nfarcti o n or a n y ot her cli nic all y rele va nt 
arterial t hr o m b oe m b olic c o m plicati o n.  
3. 3. 2. 1 0  
Pr otei n uri a  
Pr otei n uria is a n a ntici p ate d A E wit h t he i n hi biti o n of V E G F pat h wa ys a n d has be e n o bser ve d i n 
ca b oz a nti ni b cli nic al st u dies, a n d ne p hr otic s y n dr o me has bee n re p orte d wit h c a b oz a nti ni b a n d 
ot her i n hi bit ors of V E G F pat h wa ys.  Ma na ge me nt g ui d eli nes are pr o vi d e d i n Ta ble 3 -7 .   
Ca b oz a nti ni b s h o ul d be  p er ma ne ntl y dis c o nti n u e d  i n s u bje cts w h o d e vel o p ne p hr otic s y n dr o me 
( pr ot ei n uria > 3. 5 gra ms per da y i n c o m bi nati o n wit h h y p oal b u mi ne mia a n d peri p heral e de ma 
[ h y perli pi d e mia a n d t hr o m b otic disease m a y als o be prese nt ]) or a n y ot her rele va nt re nal dise ase.  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 5 0  of 9 6  
T a ble 3 -7 : 
M a n a ge m e nt of T re at m e nt -e m er ge nt  Pr ot ei n uri a  
Se verit y of P r otei n uri a 
( U P C R) 
M a n a ge m e nt of P r otei n uri a  
≤ 1 m g/ m g  
( ≤ 1 1 3. 1 m g/ m m ol) 
•  
N o c ha n ge i n ca b oza nti ni b tr eat m e nt or m o nit ori n g 
> 1 a n d < 3. 5 m g/ m g  
( > 1 1 3. 1 a n d < 3 9 5. 9 
m g/ m m ol)  
•  
C o nsi der c o nfir mi n g wit h a 2 4 -h o ur pr ot ei n ass ess me nt wit hi n 7 da ys  
•  
N o c ha n ge i n ca b oza nti ni b tr eat m e nt r e q uir e d if U P C R ≤ 2 m g/ m g or uri n e 
pr ot ei n ≤ 2 g/ 2 4 h o urs o n 2 4 -h o ur uri n e c oll ecti o n.  
•  
D os e re d u ce or i nt err u pt ca b oza nti ni b treat m e nt i f U P C R > 2 m g/ m g o n 
re p eat U P C R testi n g or uri ne pr ot ei n > 2 g/ 2 4 h o urs o n 2 4-h o ur uri ne 
c oll ecti o n. C o nti n ue ca b oza nti ni b o n a r e d uce d d os e if U P C R decr eas es t o < 
2 m g/ m g. C o nsi der h ol di n g ca b oza nti ni b tr eat me nt if U P C R re mai ns > 2 
m g/ m g des pit e a d os e r e d u cti o n u ntil U P C R decr eas es t o < 2 m g/ m g. R estart 
ca b oza nti ni b tr eat me nt at a r e d u ce d d os e aft er a d os e h ol d u nl ess ot her wis e 
a p pr o ve d b y s p o ns or.  
•  
R e peat U P C R wit hi n 7 da ys a n d o n ce p er w ee k. If U P C R < 1 m g/ m g o n 2 
c o ns ec uti ve r ea di n gs, U P C R m o nit ori n g ca n r e vert t o pr ot oc ol -s pecific ti mes. 
( Sec o n d r ea di n g is c o nfir mat or y a n d ca n b e d o ne wit hi n 1 wee k of first 
rea di n g.) If U P C R re mai ns > 1 m g/ m g a n d < 2 m g/ m g f or 1 m o nt h or is 
det er mi n e d t o b e sta ble ( < 2 0 % c ha n g e) f or 1 m o nt h, c h ec k uri ne 
pr ot ei n/ cr eati ni n e p er pr ot oc ol or as cli ni call y i n di cat e d.  
≥ 3. 5 m g/ m g  
( ≥ 3 9 5. 9 m g/ m m ol)  
•  
H ol d ca b oza nti ni b tr eat me nt p e n di n g re p eat U P C R wit hi n 7  da ys a n d/ or 
2 4 -h o ur uri n e pr ot ei n.  
•  
If ≥ 3. 5 m g/ m g o n r e p eat U P C R, c o nti n u e t o h ol d ca b oza nti ni b treat m e nt a n d 
c h ec k U P C R e ver y 7 da ys. If U P C R decr eas es t o <  2 m g/ m g, restart 
ca b oza nti ni b tr eat me nt at a r e d u ce d d os e a n d m o nit ori n g of uri ne 
pr ot ei n/ cr eati ni n e s h o ul d c o nti n u e wee kl y u ntil t h e U P C R decr eas es t o <  1 
m g/ m g. If U P C R r e mai ns > 1 m g/ m g a n d < 2 m g/ m g f or 1  m o nt h or is 
det er mi n e d t o b e sta ble ( <  2 0 % c ha n g e) f or 1 m o nt h, c h ec k uri ne 
pr ot ei n/ cr eati ni n e p er pr ot oc ol or as cli ni call y i n di cat e d.  
Ne p hr oti c s y n dr o m e  
•  
Dis c o nti n ue all st u d y tr eat m e nt 
U P C R, uri ne pr otei n/creati ni ne rati o.  
 
3. 3. 2. 1 1  
C orrecte d Q Tc Pr ol o n g ati o n  
T he effect of orall y a d mi nistere d c a b oz a nti ni b 1 4 0 m g q d o n Q Tc i nter val was e val u ate d i n a 
place b o -c o ntr olle d st u d y i n s u bjects wit h M T C. A mea n i ncrease i n Q Tc F of 1 0 -1 5  ms was 
o bser ve d aft er 4 wee ks after i nitiati n g ca b oz a nti ni b treat me nt. A c o nce ntrati o n -Q Tc r elati o ns hi p 
c o ul d n ot be defi niti vel y est a blis he d. C ha n g es i n c ar diac wa ve f or m m or p h ol o g y or ne w r h yt h ms 
were n ot o bser ve d. N o ca b oz a nti ni b -tre ate d s u bjects i n t his st u d y ha d a Q T c F > 5 0 0 ms. 


 
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U nless ot her wise s pecifie d i n c ertai n pr ot oc ols, o nl y s u bje cts wit h a baseli ne Q Tc F ≤ 5 0 0  msec 
are eli gi ble f or c a b oz a nti ni b resear c h st u dies. Ca b oz a nti ni b s h o ul d be use d wit h ca uti o n i n 
s u bje cts wit h Q T pr ol o n g ati o n ris k, a hist or y of Q T i nter val pr ol o n gati o n, or w h o ar e ta ki n g 
a ntiarr h yt h mics or dr u gs k n o w n t o pr ol o n g t he Q T i nter val. C o nc o mita nt treat me nt wit h str o n g 
C Y P 3 A 4 i n hi bit ors, w hic h ma y i ncrease ca b oz a nti ni b plas ma c o nce ntr ati o ns, s h o u l d be a v oi de d.  
If at a n y ti me o n st u d y t her e is a n i ncre ase i n Q Tc F t o a n a bs ol ute val ue > 5 0 0 ms or a n i ncre ase 
of >  6 0 ms a b o ve baseli ne, t w o a d diti o nal E C Gs m ust be perf or me d wit h i nter vals n ot less t ha n 
3  mi n a part wit hi n 3 0 mi n after t he i nitial E C G.  
If t he a ver a ge Q Tc F fr o m t he t hree E C Gs is > 5 0 0 ms or i ncreased b y  >  6 0 ms a b o ve b aseli ne, 
t he f oll o wi n g acti o ns m ust be t a ke n: 
•  Wit h h ol d st u d y treat me nt  
•  I m me diatel y n otif y t he S p o ns or 
•  H os pitaliz e s y m pt o m atic s u bjects (e g, wit h pal pitati o ns, diz zi ness, s y nc o pe, ort h ostatic 
h y p ot e nsi o n, a si g nifica nt ve ntric ular arr h yt h mia o n E C G) f or a t h or o u g h car di ol o g y 
e val uati o n a n d ma na ge me nt  
•  C o nsi der car di ol o g y c o ns ult ati o n f or as y m pt o matic s u bjects f or e val uati o n a n d m a na ge me nt  
•  C he c k electr ol ytes, es peciall y ma g nesi u m, p ot assi u m a n d c alci u m; c orre ct a b n or malities as 
cli nicall y i n dicat e d  
•  C he c k c o nc o mita nt 
me dicati o ns f or a n y 
me dicati o n t hat 
ma y ha ve c o ntri b ut e d t o Q T 
pr ol o n g ati o n, a n d if p ossi ble, dis c o nti n u e t hese me dicati o ns ( htt p:// w w w. qt dr u gs. or g ) 
•  Re peat E C G tri plic ates h o url y u ntil t he a vera ge Q Tc F is ≤ 5 0 0 
msec, or ot her wise 
deter mi ne d b y c o ns ultati o n wit h a c ar di ol o gist or a p pr o priate e x pert.  
S u bje cts wit h Q Tc pr ol o n g ati o n a n d s y m pt o ms 
m ust be m o nit or e d cl osel y u ntil t he Q Tc 
ele vati o n a n d s y m pt o ms ha ve res ol ve d. St u d y tre at m e nt m a y b e rest arte d at a re d uc e d d ose le vel 
if all of t he f oll o wi n g c o n diti o ns are met: 
•  S y m pt o ms are deter mi ne d t o b e u nrelate d t o t he Q T i nt er val pr ol o n gati o n  
•  T he Q Tc F val u e > 5 0 0 ms or i ncrease of > 6 0 ms a b o ve baseli ne is n ot c o nfir me d a cc or di n g 
t o pr ot oc ol pr oce d ures 
•  St u d y tre at m e nt has bee n i nterr u pte d t hr o u g h a mi ni m u m of 1 wee k f oll o wi n g t he ret ur n of 
t he Q Tc F t o ≤ 5 0 0 msec or ret ur n t o ≤ 6 0 ms a b o ve b aseli ne. 
•  Q T pr ol o n gati o n ca n be u ne q ui v ocall y ass ociate d wit h a n e ve nt ot her t ha n ca b oz a nti ni b 
a d mi nistr ati o n a n d is tre ata ble/ has be e n res ol ve d  
•  S p o ns or has r e vie we d all a vaila ble i nf or m ati o n a n d has a gre e d t o t he c o nti n uati o n of st u d y 
treat me nt 


 
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F oll o wi n g rei nitiati o n of st u d y tr eat m e nt, E C Gs m ust be re p eat e d wee kl y f or 2 wee ks, t he n e ver y 
2 wee ks f or 1 m o nt h, t he n acc or di n g t o t he pr ot oc ol -defi ne d ti me p oi nts.  
All st u d y treat me nt m ust be p er ma ne ntl y disc o nti n ue d if eit her of t he f oll o wi n g a p plies:  
•  Car diac e val u ati o n c o nfi r ms t hat s y m pt o ms ar e t he c o nse q ue nce of Q T i nter val pr ol o n gati o n 
•  Rec urre nc e of Q T c F pr ol o n gati o n aft er rei nitiati o n of st u d y tr eat me nt at a re d u ce d d ose  
3. 3. 2. 1 2  
H y p o p h os p h ate mi a  
H y p o p h os p hate mia has bee n re p ort e d d uri n g tre at me nt wit h c a b oz a nti ni b . Ser u m p h os p h or us 
s h o ul d b e m o nit or e d fre q u e ntl y w hile rec ei vi n g ca b oz a nti ni b . Ot her ca uses of h y p o p h os p hat e mia 
s h o ul d be r ule d o ut a n d/ or t hese c a uses treate d i n a cc or da nce t o st a n dar d of c are. Mil d t o 
m o d erat e h y p o p h os p ha te mia s h o ul d be ma na ge d b y oral re place m e nt i ncl u di n g f o o d t hat are 
hi g h i n p h os p hate ( diar y ite ms, meats, bea ns) a n d/ or oral p h os p hate s u p ple m e nts i n ac c or da nce 
t o st a n dar d cli nic al pra ctice g ui d eli nes.  
Cli nic all y rele va nt h y p o p h os p hate mia s h o ul d be m a na g e d i n ac c or da nc e t o t he d ose m o dificati o n 
g ui d eli nes as o utli ne d i n T a ble 3 -2  a n d Ta ble 3 -3  or as cli nicall y i n dicat e d.  
3. 3. 2. 1 3  
T h yr oi d F u ncti o n Dis or ders  
C ha n g es i n t h yr oi d f u ncti o n tests ( T F Ts) a n d h y p ot h yr oi dis m ha ve be e n re p orte d 
wit h  
ca b oz a nti ni b t hera p y  a n d ot her t yr osi ne ki nase i n hi bit ors as a res ult of alt ere d t h yr oi d h or m o ne 
re g ulati o n b y m ec ha nis ms t hat see m t o b e s pecific f or ea c h a ge nt ( T ori n o et al. 2 0 0 9). C urre ntl y 
a vaila ble dat a are i ns ufficie nt t o deter mi ne t he m e c ha nis m of T F T alterati o ns a n d its cli nical 
rele va nce. R o uti ne m o nit ori n g of t h yr oi d f u ncti o n a n d assess me nts f or si g ns a n d s y m pt o ms 
ass ociate d wit h t h yr oi d d ysf u ncti o n is re c o m m e n de d bef ore i nitiati o n a n d d uri n g tre at m e nt wit h 
ca b oz a nti ni b. 
Ma na g e me nt of t h yr oi d d ysf u ncti o n (e g, s y m pt o m atic h y p ot h yr oi dis m) s h o ul d 
f oll o w acc e pte d cli nical practice g ui deli nes a n d d ose m o dific ati o n g ui deli nes as o utli ne d i n Ta ble 
3 -2  a n d Ta ble 3 -3 .  
3. 3. 2. 1 4  
He m orr h a gi c E ve nts  
He m orr ha gic e ve nts ha ve bee n re p ort e d 
wit h ca b oz a nti ni b. 
T o  miti gat e ris k of se vere 
he m orr ha ge, s u bjects s h o ul d be e val u ate d f or p ote n tial blee di n g ris k fact ors bef ore  i nitiati n g 
ca b oz a nti ni b tr eat me nt a n d m o nit or e d f or blee di n g e ve nts wit h serial c o m plete bl o o d c o u nts a n d 
p h ysic al e xa mi nati o n w hile o n st u d y. Ris k fa ct ors f or he m orr ha gic e ve nts ma y i ncl u d e ( b ut ma y 
n ot b e li mit e d t o) t he  f oll o wi n g: 


 
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•  T u m or of t he l u n g wit h c a vit ar y lesi o ns or t u m or lesi o ns w hic h i n va des, e nc ases, maj or bl o o d 
vessels. T he a nat o mic l ocati o n a n d c hara cteristics of t u m or as well as t he m e dical hist or y 
m ust be car ef ull y r e vie we d i n t he selecti o n of s u bjects f or tr eat me nt wit h ca b oz a nti ni b; 
•  Rece nt or c o nc urre nt r a diati o n t o t he t h or acic ca vit y ; 
•  Acti ve pe ptic ulcer dise ase, i nfla m m at or y GI diseases i ncl u di n g Cr o h n’s disease a n d 
ulcerati ve c olitis ; 
•  U n derl yi n g me dical c o n diti o ns w hic h affe ct n or m al he m ostasis (e g, de ficie ncies i n cl otti n g 
fa ct ors a n d/ or plat elet f u ncti o n, or t hr o m b oc yt o pe nia); 
•  C o nc o mit a nt m e dic ati o n wit h a ntic oa g ula nts or ot her dr u gs w hic h affect n or mal he m ostasis ; 
•  Hist or y of cli nic all y si g nifica nt he m o pt ysis . 
T he ris k of he m orr ha g e i n ca b oz a nti ni b -tre ate d s u bjects wit h brai n metastases has n ot be e n 
t h or o u g hl y a nal yz e d. T h o u g h t he i nci d e nce of C N S he m orr ha g e e ve nts i n a st u d y of s u bjects 
wit h G B was hi g her t ha n o bser ve d i n ge neral p o p ulati o n of s u bjects wit h c a ncer tr eat e d wit h 
ca b oz a ntini b, it is n ot cle ar h o w t he ris k of he m orr ha ge i n G B tra nslates t o a ris k of he m orr ha g e 
f or s u bjects 
wit h brai n 
met astases. 
C urre ntl y, brai n 
met astases of c arci n o mas are n ot 
c o ntrai n dicati o ns t o t he use of c a b oz a nti ni b, b ut s u bjects wit h br ai n met astases s h o ul d be 
m o nit ore d wit h a hi g h i n de x of s us pici o n if s y m pt o ms t hat c o ul d be d u e t o a C N S he m orr ha ge 
oc c ur.  
C o m plet e heali n g fr o m r a diati o n -i n d uc e d si de effects s h o ul d ha ve occ urre d bef or e i nitiati n g 
ca b oz a nti ni b treat me nt, a n d ca b oz a nti ni b  s h o ul d be disc onti n ue d i n s u bjects wit h seri o us a n d 
life-t hr eat e ni n g ble e di n g e ve nts or rec e nt he m o pt ysis ( ≥ 2. 5  m L of re d bl o o d).  
3. 3. 2. 1 5  
GI Perf or ati o n/ Fist ul a a n d N o n -GI Fist ul a F o r m ati o n  
Gastr oi ntesti nal perf or ati o n /GI fist ula:  Pri or t o i nitiati o n of tr eat me nt wit h ca b oz a nti ni b, s u bjects 
s h o ul d be c aref ull y e val uate d f or p ote ntial ris k fa ct ors i ncl u di n g ( b ut n ot li mite d t o) t he 
f oll o wi n g: 
•  T u m ors i n va di n g GI or res pir at or y tra cts  
•  Acti ve pe ptic ulcer dise ase, i nfla m m at or y b o wel dis e ase ( e g, ulc erati ve c olitis, Cr o h n’s 
dise ase ), di vertic ulitis, c h olec ystitis or s y m pt o matic c h ola n gitis, or a p pe n dicitis  
•  Hist or y of a b d o mi nal fist ula, GI p erf orati o n, b o wel o bstr ucti o n, or i ntra -a b d o mi nal a bscess  
•  O n g oi n g visc eral c o m plicati o ns fr o m pri or ra diati o n t hera p y  


 
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•  Pri or GI s ur ger y ( partic ularl y w he n ass ociate d wit h d ela ye d or i nc o m plete heali n g) 
C o m plet e heali n g f oll o wi n g a b d o mi nal s ur ger y a n d/ or res ol uti o n of i ntra -a b d o mi nal a bscess 
m ust be c o nfir me d pri or t o i nitiati n g tre at m e nt wit h ca b oz a nti ni b.  
After starti n g ca b oz a nti ni b, s u b je cts s h o ul d be m o nit or e d f or earl y si g ns of GI perf or ati o n s uc h 
as a b d o mi nal pai n, na use a, e mesis, c o nsti pati o n, a n d fe ver  es pe ciall y if k n o w n ris k fa ct ors f or 
de vel o pi n g GI perf orati o n or fist ula ar e pres e nt.  
Disc o nti n ue ca b oz a nti ni b tre at m e nt i n s u bjects 
w h o 
ha ve 
bee n 
dia g n ose d 
wit h 
GI 
perf or ati o n/fist ula.  
N o n -GI fist ula f or m ati o n : C o m plicati o ns fr o m ra diati o n t hera p y has be e n i de ntifie d as a p ossi ble 
pre dis p osi n g ris k fact or f or fist ula f or m ati o n i n s u bje cts u n d er g oi n g tr eat me nt wit h ca b oz a nti ni b.  
S u bje cts wit h a n y cli nicall y rele va nt o n g oi n g c o m plicati o ns fr o m pri or r a diati o n t hera p y (ie, 
ra diati o n es o p ha gitis or ot her i nfla m mati o n of t he visc era) s h o ul d n ot be treate d 
wit h 
ca b oz a nti ni b.  
Ra diati o n t her a p y t o t he t h ora cic ca vit y (i ncl u di n g me diasti n u m) s h o ul d be a v oi de d wit hi n 
3  m o nt hs of starti n g treat me nt wit h ca b oz a nti ni b ( e x cl u di n g l ocal ra diati o n f or b o ne m etast ases).  
F ist ula s h o ul d b e r ule d o ut as a p pr o priate i n cases of o nset of se vere m uc ositis or diffic ult y 
s wall o wi n g after st art of t hera p y. Disc o nti n ue c a b oz a nti ni b a n d i nitiate a p pr o priat e ma na ge m e nt 
i n s u bjects w h o ha ve b ee n dia g n ose d wit h a n o n-GI fist ula.  
Disc o n ti n ue c a b oz a nti ni b treat me nt i n s u bjects w h o ha ve bee n dia g n ose d wit h n o n -GI fist ula.  
3. 3. 2. 1 6  
Oste o ne cr osis of t he J a w  
Oste o ne cr osis of t he ja w ( O NJ) has bee n r e p ort e d 
i n s u bjects tr eat e d wit h ca b oz a nti ni b. 
A d diti o nal ris k fact ors f or O NJ ha ve be e n i d e ntifie d i nclu di n g t he use of bis p h os p h o nates a n d 
de n os u m a b,  c he m ot hera p y, c ortic ost er oi ds, l ocal ra di ot hera p y, a n d d e ntal or or ofa cial s ur ger y 
pr oc e d ures .   
Oste o ne cr osis of t he ja w ca n ma nifest as ja w pai n, oste o m yelitis, osteitis, b o ne er osi o n, t o ot h or 
peri o d o ntal i nfecti o n, t o ot ha c he, gi n gi val ulcer ati o n, or gi n gi val er osi o n. Persiste nt pai n or sl o w 
he ali n g of t he m o ut h or ja w aft er de nt al s ur ger y m a y als o b e ma nifestati o ns of O NJ.  


 
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Perf or m a n or al e x a mi nati o n pri or t o i nitiati o n of ca b oz a nti ni b a n d peri o dicall y d ur i n g 
ca b oz a nti ni b t hera p y as cli nic all y i n dicat e d . A d vis e s u bje cts re gar di n g oral h y gie ne pra ctice a n d 
t o q uic kl y r e p ort s y m pt o ms t o i n vesti g at or. Ca uti o n s h o ul d be use d i n s u bjects recei vi n g 
bis p h os p h o nat es.  
I n vasi ve de ntal pr oce d ures s h o ul d be a v oi de d. I n cas es w here de nt al pr oce d ur es are u na v oi da ble, 
treat me nt wit h ca b oz a nti ni b s h o ul d be hel d f or at least 4 wee ks pri or t o t he pr oce d ur e a n d 
res u me d aft er c o m plet e w o u n d heali n g has occ urre d. B o ne heali n g 
m a y ofte n r e q uire a 
pr otr act e d ti me.  
If O NJ oc c urs, ca b oz a nti ni b treat me nt s h o ul d be hel d a n d s h o ul d n ot be rest arte d u ntil t he 
c o n diti o n has s ufficie ntl y he ale d a n d t he S p o ns or has a p pr o ve d t he r e -i nitiati o n of t her a p y.  
3. 3. 2. 1 7  
A n g i oe de m a 
A n gi oe d e ma s h o ul d be m a na ge d acc or di n g t o st a n d ar d practice. T he s u bject s h o ul d be o bser ve d 
u ntil s y m pt o ms res ol ve, wit h att e nti o n t o mai ntai ni n g a n o p e n air wa y.  
3. 3. 2. 1 8  
M usc ul os kelet al a n d C o n ne cti ve Tiss ue Dis or ders  
Ca b oz a nti ni b a p p ears t o re pr ese nt mi ni mal ris k of a d verse m usc ul os kelet al effects base d o n 
n o ncli nic al 
G L P -c o m plia nt t o xic ol o g y st u dies. T he de vel o p m e nt of ne w or pr o gr essi ve, 
u ne x plai ne d 
m usc ul os keletal s y m pt o ms s uc h as pai n or wea k ness s h o ul d be assesse d f or 
u n derl yi n g c a uses.  
R ha b d o m y ol ysis has b e e n re p orte d. C a b oz a nti ni b s h o ul d be disc o nti n ue d i n s u bjects wit h seri o us 
a n d life-t hreate ni n g r ha b d o m y ol ysis a n d i nterr u pte d if less se vere f or ms occ ur w he n t here are n o 
ot her clear c a uses. Rei nitiati o n of ca b oz a nti ni b tr eat me nt m ust be disc usse d wit h a n d  a p pr o ve d 
b y t he s p o ns or. T hera p y of r ha b d o m y ol ysis s h o ul d i ncl u de s u p p orti ve care a n d sta n dar d me dical 
i nter ve nti o n. 
3. 3. 2. 1 9  
Res pir at or y, T h or a cic a n d Me di asti n al Dis or de rs  
D ys p nea has bee n r e p orte d i n cli nic al st u dies wit h c a b oz a nti ni b . S y m pt o ms s h o ul d be ma na ge d 
acc or di n g t o l ocall y acce pte d cli nical pra ctice i ncl u di n g a n assess me nt f or u n d erl yi n g ca uses. 
P ul m o nar y e m b olis m s h o ul d be c o nsi dere d as p ossi ble ca uses f or ne w o nset d ys p ne a gi ve n t he 
ris k of t hr o m b osis ass ociate d wit h i n hi biti o n of V E G F si g nali n g. F ur t her m ore, fist ula f or mati o n 
( Secti o n 0 ) a n d p ne u m o nia ha ve b ee n re p orte d i n s u bjects treat e d wit h ca b oz a nti ni b a n d s h o ul d 
be c o nsi dere d as cli nicall y i n dicat e d i n s u bje cts pres e nti n g wit h p ul m o nar y s y m pt o ms.  


 
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3. 4  
C o nc o mit a nt Me di c ati o ns a n d T her a pies  
3. 4. 1  
A ntic a nce r T her a p y  
L ocal i nter ve nti o n is disc o ura ge d u nless 
me dicall y u na v oi da ble. S u bjects recei vi n g l ocal 
i nter ve nti o n (e g, palliati ve ra diati o n) c a n c o nti n ue t o recei ve st u d y treat me nt at t he i n vesti gat or’s 
discr eti o n.  
3. 4. 2  
Ot he r Me di c ati o ns  
All c o nc o mit a nt me dicati o ns use d b y t he s u bject (i ncl u di n g prescri pti o n a n d  o ver -t he-c o u nter 
me dic ati o ns, tra nsf usi o ns, vit a mi ns, her bal re m e dies, a n d n utriti o nal s u p ple me nts) d uri n g t he 
peri o d fr o m 2 8  da ys bef or e t he first d ose of st u d y tr eat m e nt t hr o u g h 3 0  da ys after t he dat e of t he 
last d ose of st u d y tre at m e nt are t o be re c or de d i n t he case re p ort f or ms.  
3. 4. 3  
All o we d T her a pi es  
•  A nti e metics a n d a nti diarr heal me dicati o ns are all o we d pr o p h yla cticall y i n acc or da nce t o 
sta n d ar d cli nic al practic e if cli nic all y i n dicat e d;  
•  G ra n ul oc yte c ol o n y-sti m ulati n g fact ors ( G-C S F or G M -C S F)  are all o w e d if use d per cli n ical 
g ui d eli nes (e g, A merica n S ociet y of Cli nical O nc ol o g y [ A S C O ] or [ E ur o p ea n S ociet y f or 
Me dical O nc ol o g y] E S M O g ui d eli nes) ;  
•  Dr u gs use d t o c o ntr ol b o ne l oss (e g, bis p h os p h o nat es  a n d d e n os u ma b) ar e all o we d if start e d 
bef or e  scree ni n g acti vities b ut m a y not be i nitiat e d or e xc ha n ge d d uri n g  t he st u d y a n d r e q uire 
S p o ns or a p pr o val ; 
•  Tra nsf usi o ns, h or m o ne re place m e nt, a n d s h ort ter m hi g her d oses of c ortic oster oi ds s h o ul d be 
utiliz e d as i ndicate d b y sta n dar d cli nical  practic e ; 
•  I n di vi d ualiz e d a ntic oa g ulati o n t hera p y wit h he pari n is all o w e d if it ca n b e pr o vi de d safel y 
a n d effecti vel y u n der t he f oll o wi n g circ u mst a nces:  
o  L o w d ose  he p ari ns f or pr o p hyl actic use  are all o we d if cli nic all y i n dicat e d a n d t he 
be nefit o ut wei g hs t he ris k p er t he i n vesti gat or’s discr eti o n.  
o  T her a pe utic d oses  of l o w m ol ec ul ar wei g ht he p ari ns ( L M W H)  at t he ti me of first d ose 
are all o w e d if t he s u bject has n o e vi de nce of brai n m etastasis,  has be e n o n a sta ble 
d ose of L M W H f or at least 1 2 wee ks, a n d has ha d n o c o m plicati o ns fr o m a 
t hr o m b oe m b olic e ve nt or t he a ntic oa g ulati o n re gi me n.  


 
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o  T her a pe utic d oses  of l o w m ol ec ul ar wei g ht he p ari ns ( L M W H)  after first d ose  are 
all o we d if cli nicall y i n dicat e d (e g, f or t he tre at m e nt of de e p ve n o us t hr o m b osis), a n d 
t he be nefit o ut wei g hs t he ris k per t he i n vesti gat or’s discr eti o n. F or m a na ge me nt of 
t hr o m b oe m b olic c o m plicati o ns w hile o n st u d y, refer t o Se cti o n 3. 3. 2. 9 .  
o  Acc e pte d cli nical g ui deli nes re gar di n g a p pr o priate m a na ge m e nt w hile recei vi n g 
a ntic oa g ulati o n t hera p y wit h he p ari ns m ust be f oll o we d. T his i n cl u d es, b ut is n ot 
li mite d t o, s u bject e d ucati o n re gar di n g p ote ntial a d verse dr u g reacti o ns, m o nit ori n g 
la b orat or y p ara meters, d ose a dj ust me nts (e g, d u e t o ki d ne y d ysf u ncti o n);  
o  F or restricti o ns o n oral a ntic oa g ula nts see Secti o n 3. 4. 4 . 
•  A d mi nistrati o n of t he P PI es o me pr az ole res ulte d i n n o cli nic all y -rele va nt effect o n 
ca b oz a nti ni b plas ma P K i n healt h y v ol u nteers ( St u d y X L 1 8 4 -0 1 8). T heref ore, c o nc o mita nt 
use of gast ric p H m o dif yi n g a ge nts (ie, P PIs, H 2 rece pt or a nta g o nists, a n d a nt aci ds) is n ot 
c o ntrai n dicate d i n s u bjects a d mi nister e d ca b oz a nti ni b .  Ci meti di ne s h o ul d b e a v oi d e d d ue t o 
p ot e ntial C Y P i nter acti o ns.  
P ote ntial dr u g i nt eracti o ns wit h c a b oz a nti ni b ar e s u m ma riz e d i n Se cti o n 3. 4. 5 . 
3. 4. 4  
Pr o hi bite d or Restri cte d T her a pies  
T he f oll o wi n g t her a pies are pr o hi bite d  w hile t h e s u bj ect is o n st u dy : 
•  A n y i n vesti gati o nal a ge nt or i n vesti g ati o nal me dical de vice ; 
•  A n y dr u g or her bal pr o d uct use d s pecific all y f or t he treat m e nt of c ol orect al c a ncer ; 
•  T hera pe utic d oses  of oral a ntic oa g ula nts (e g, warfari n or ot her c o u m ari n -relate d a ge nts, 
dir ect t hr o m bi n or direct F Xa i n hi bit ors, or a nti p latel et a ge nts s uc h as cl o pi d o gr el, or c hr o nic 
use of as piri n a b o ve l o w d ose le vels f or c ar di o pr ot ecti o n per l ocal a p plica ble g ui deli nes) ; 
•  A n y ot her s yste mic a ntica ncer treat me nt (e g, c he m ot her a p y, i m m u n ot her a p y, ra di o n ucli des) 
a n d l ocal a ntica nc er tre at m e nt s uc h as s ur ger y, a blati o n, or e m b oliz ati o n.   
T he f oll o wi n g t her a pies s h o ul d be a v oi de d  if p ossi bl e, w hile t he s u bje ct is o n st u dy : 


 
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•  Palliati ve e xter nal ra diati o n t o b o ne m etast asis f or b o ne p ai n s h o ul d n ot b e perf or m e d w hile 
o n st u d y. S u bje cts w h o ha ve s uc h a n i nter ve nti o n ma y be c o nsi dere d n ot e val ua ble ( a n d ma y 
be assi g ne d a c e ns ori n g or pr o gr essi o n d ate) f or cert ai n efficac y e n d p oi nts ; 
•  Er yt hr o p oietic sti m ulati n g a ge nts (e g, e p oeti n alfa  a n d dar be p oeti n alfa) s h o ul d n ot be use d 
base d o n a re p ort of i ncrease d ris k of t u m or re c urre nce  a n d/or pr o gr essi o n ass ociate d wit h 
er yt hr o p oieti n ( Wri g ht 2 0 0 7) ; 
•  C hr o nic c o -a d mi nistr ati o n of ca b oz a nti ni b wit h str o n g i n d u cers of t he C Y P 3 A 4 fa mil y 
(e g, p he n yt oi n, car ba maz e pi ne, rifa m pi n, rifa b uti n, rifa p e nti n e, p he n o bar bital, a n d St. J o h n’s 
W ort) ma y si g nific a ntl y d ecrease ca b oz a nti ni b c o nc e ntr ati o ns a n d s h o ul d b e 
a v oi de d.  Selecti o n of alter nat e c o nc o mit a nt m e dic ati o ns wit h n o or mi ni m al C Y P 3 A 4 
e nz y me i n d ucti o n p ote ntial is  rec o m me n de d; 
•  Ca uti o n m ust b e use d w he n disc o nti n ui n g tr eat me nt wit h a str o n g C Y P 3 A 4 i n d uc er i n a 
s u bje ct w h o has bee n c o nc urre ntl y rec ei vi n g a sta ble d ose of c a b oz a nti ni b, b eca use  t his c o ul d 
si g nifica ntl y i ncrease t he e x p os ure t o ca b oz a nti ni b;  
•  C o -a d mi nistr ati o n of ca b oz a nti ni b wit h str o n g i n hi bit ors of t he C Y P 3 A 4 fa mil y 
(e g, ket oc o naz ole, itra c o naz ole, clarit hr o m yci n, i n di na vir, nefaz o d o ne, nelfi na vir, a n d 
rit o na vir) ma y i ncrease c a b oz a nti ni b c o nce ntrati o ns a n d s h o ul d be a v oi d e d. Gra pefr uit a n d 
Se ville or a n ges ma y als o i ncre ase plas m a c o nc e ntrati o ns of ca b oz a nti ni b a n d s h o ul d b e 
a v oi de d.  
A d diti o nal i nf or mati o n o n p ot e ntial dr u g i nteracti o ns wit h ca b oz a nti ni b  is pr o vi de d i n Secti o n 
3. 4. 5 . 
3. 4. 5  
P ote nti al Dr u g I nte r acti o ns  
Cyt oc hr o me P 4 5 0  ( C Y P): D ata fr o m a cli nic al dr u g i nteracti o n st u d y ( St u d y  X L 1 8 4 -0 0 8) s h o w 
t hat cli nic all y rele va nt ste a d y-stat e c o nce ntrati o ns of ca b oz a nti ni b a p pear t o ha ve n o m ar ke d 
effect o n t he area u n d er t he plas ma dr u g c o nc e ntr ati o n ti me c ur ve ( A U C ) of c o -a d mi nist ere d 
r osi glitaz o ne, a C Y P 2 C 8 s u bstrate. T heref or e, ca b oz a nti ni b is n ot a ntici pat e d t o mar ke dl y i n hi bit 
C Y P 2 C 8 i n t he cli nic, a n d b y i nfere nce, is n ot a nti ci pate d t o m ar ke dl y i n hi bit ot her C Y P 4 5 0 
is oz y mes t hat ha ve l o wer [I]/ Ki val ues c o m p are d wit h  C Y P 2 C 8 (ie,  C Y P 2 C 9, C Y P 2 C 1 9, 
C Y P 2 D 6, C Y P 1 A 2, a n d C Y P 3 A 4). I n vitr o data i n dicat e t hat ca b oz a nti ni b is u nli kel y t o i n d uce 


 
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c yt oc hr o m e P 4 5 0 e nz y mes, e xc e pt f or p ossi ble i n d ucti o n of C Y P 1 A 1 at hi g h ca b oz a nti ni b 
c o nce ntr ati o ns ( 3 0  μ M).   
Ca b oz a nti ni b is a C Y P 3 A 4 s u bstrate a n d a wea k s u bstrate f or  C Y P 2 C 9  ( b ut n ot a C Y P 2 D 6, 
C Y P 2 C 8, C Y P 2 C 1 9, C Y P 2 B 6, or C Y P 1 A 2 s u bstrate), base d o n data fr o m i n vitr o st u dies.  
R es ults fr o m a c li nic al p har mac ol o g y st u d y, X L 1 8 4-0 0 6, s h o we d t hat c o nc urr e nt a d mi nistrati o n 
of ca b oz a nti ni b wit h t he str o n g C Y P 3 A 4 i n d u cer, rifa m pi n, res ulte d i n a n a p pr o xi matel y 7 7 % 
re d ucti o n i n ca b oz a nti ni b e x p os ure ( A U C val u es) aft er a si n gle d ose of ca b oz a nti ni b i n healt h y 
v ol u nteers. C hr o nic c o -a d mi nistrati o n of ca b oz a nti ni b wit h str o n g i n d uc ers of t he C Y P 3 A 4 
fa mil y ( e g, p he n yt oi n, car ba maz e pi ne, rifa m pi n, rifa b uti n, rifa pe nti n e, p he n o bar bital, a n d St. 
J o h n’s W ort) m a y si g nific a ntl y d ecre ase ca b oz a nti ni b c o nce ntrati o ns. T he c hr o nic use of str o n g 
C Y P 3 A 4 i n d uc ers s h o ul d be a v oi de d. Ot her dr u gs t hat i n d uc e C Y P 3 A 4 s h o ul d be use d wit h 
ca uti o n b eca use t hese dr u gs ha ve t he p ot e ntial t o decrease e x p os ure ( A U C) t o ca b oz a nti ni b. 
Selecti o n of alter nate c o nc o mit a nt me dic ati o ns wit h n o or mi ni mal C Y P 3 A 4 e nz y m e i n d u cti o n 
p ot e ntial is re c o m m e n de d .  
R es ults fr o m a cli nic al p har mac ol o g y st u d y, X L 1 8 4 -0 0 7, s h o we d t hat c o nc urr e nt a d mi nistrati o n 
of ca b oz a nti ni b wit h t he str o n g C Y P 3 A 4 i n hi bit or, ket oc o naz ole, r es ulte d i n a 3 8 % i ncrease i n 
t he c a b oz a nti ni b e x p os ure ( A U C val ues) after a si n gle d ose of c a b oz a nti ni b i n he alt h y 
v ol u nteers. C o -a d mi nistrati o n of c a b oz a nti ni b wit h str o n g i n hi bit ors of t he C Y P 3 A 4 fa mil y 
(e g, ket oc o naz ole, itr ac o naz ole, clarit hr o m yci n, i n di na vir, nefaz o d o n e, nelfi na vir, a n d rit o na vir) 
ma y i ncrease c a b oz a nti ni b c o nce ntrati o ns. Gra pefr uit a n d Se ville ora n g es ma y als o i ncrease 
plas ma c o nce ntrati o ns of ca b oz a nti ni b  a n d s h o ul d b e a v oi d e d . Str o n g C Y P 3 A 4 i n hi bit ors s h o ul d 
be a v oi de d a n d ot her dr u gs t hat i n hi bit C Y P 3 A 4 s h o ul d b e use d wit h ca uti o n bec a use t hese dr u gs 
ha ve t he p ote ntial t o i ncrease e x p os ure ( A U C) t o ca b oz a nti ni b. Selecti o n of alter nate 
c o nc o mita nt 
m e dic ati o ns 
wit h n o or 
mi ni mal 
C Y P 3 A 4 e nz y me i n hi biti o n p ote ntial is 
rec o m m e n de d.  
I n a d diti o n, ci meti di ne s h o ul d be a v oi de d be ca use of its p ote ntial t o i nterfere wit h C Y P 3 A 4 
me di ate d m eta b olis m of ca b oz a nti ni b . 
Dr u g i nteracti o n ta bles ca n b e f o u n d o n t he F D A w e bsite u n der “ Dr u g De vel o p me nt a n d Dr u g 
I nt eracti o ns” a n d at I n dia na 
U ni versit y 
we bsite i n “ De p art m ent of 
Me dici ne”, “ Cli nic al 
P har m ac y”, “ Dr u g I ntera cti o ns”. T he f oll o wi n g we bsit es  bel o w c a n be use d  f or lists of 
s u bstrates, i n d ucers, a n d i n hi bit ors of select e d C Y P 4 5 0 is oz y me pat h wa ys : 


 
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H tt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/t a ble.as p x 
htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr oc ess/ De vel o p m e nt Res o urces/ Dr u g I nt eracti o
ns La b eli n g/ uc m 0 8 0 4 9 9. ht m    
Pr ot ei n Bi n di n g : Ca b oz a nti ni b is hi g hl y b o u n d ( ≥ 9 9. 7 %)  t o h u ma n plas m a pr otei ns. T her ef ore, 
hi g hl y pr otei n b o u n d dr u gs s h o ul d be use d wit h c a uti o n wit h ca b oz a nti ni b bec a use t her e is a 
p ot e ntial dis pla ce m e nt i nt eracti o n  t hat c o ul d i ncr eas e fre e c o nce ntrati ons of ca b oz a nti ni b a n d/ or 
a c o-ad mi nistere d hi g hl y pr otei n -b o u n d dr u g (a n d a c orr es p o n di n g i ncre ase i n p har m ac ol o gic 
effect) . 
Ot her I nter acti o ns :  
F o o d  ma y i ncr ease e x p os ure le vels of ca b oz a nti ni b  b y 5 7 % , fasti n g re c o m m e n dati o ns s h o ul d be 
f oll o w e d. S u bje cts s h o ul d fast ( wit h t he e xce pti o n of water) f or at least 2 h o urs after eati n g t he 
e ve ni n g meal bef or e t a ki n g t heir d ose of ca b oz a nti ni b. After t he 2 -h o ur fast a n d bef or e g oi n g t o 
be d, s u bjects are t o t a ke c a b oz a nti ni b wit h a f ull glass of wat er ( mi ni m u m of 8 oz or 2 4 0 m L) 
wit h n o m ore f o o d i nta ke f or o ne h o ur p ost -d ose.  
I n vitr o data s u g gest t hat ca b oz a nti ni b is u nli kel y t o be a s u bstrate f or P-gl yc o pr ot ei n, b ut it d oes 
a p pear t o ha ve t he p ote ntial  t o i n hi bit t he P-g l yc op r otei n tr a ns p ort acti vit y. T heref ore,  
ca b oz a nti ni b m a y ha ve t he p ot e ntial t o i ncr ease plas m a c o nce ntrati o ns of c o -a d mi nist ere d  
s u bstrates of P -g l yc op r otei n.  
Ca b oz a nti ni b was s h o w n t o be a s u bstrate of dr u g tra ns p ort er 
M R P 2 i n a n i n vitr o assa y. 
A d mi nistrati o n of M R P 2 i n hi bit ors t o s u bjects ma y r es ult i n i ncr eases i n ca b o z a nti ni b plas ma 
c o nce ntr ati o ns.  
A d diti o nal d etails re gar di n g p ote ntial dr u g i ntera cti o ns wit h ca b oz a nti ni b c a n be f o u n d i n t he 
i n vesti gat or br oc h ure. 
3. 5  
C o m pli a nce  
Dr u g acc o u nta bilit y a n d s u bject c o m plia nc e will b e assesse d wit h dr u g dis pe nsi n g a n d ret ur n 
rec or ds.  


 
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3. 6  
St u d y Dr u g Acc o u nt a bilit y  
T he i n vesti g at or will m ai nt ai n ac c urat e  rec or ds of r ecei pt of all ca b oz a nti ni b, i ncl u di n g dat es of 
recei pt. I n a d diti o n, acc ur ate r ec or ds will be ke pt re g ar di n g w he n a n d h o w m uc h st u d y treat me nt 
is dis pe nse d a n d use d b y e ac h s u bject i n t he st u d y. Reas o ns f or d e viati o n fr o m t he e x pecte d 
dis pe nsi n g r e gi m e n m ust als o be r ec or de d. At c o m pleti o n of t he st u d y, t o satisf y re g ulat or y 
re q uire m e nts re gar di n g dr u g ac c o u nta bilit y, all u n use d ca b oz a nti ni b  will be re c o ncile d a n d 
destr o ye d i n a cc or da nc e wit h a p plic a ble st ate a n d fe deral re g ulati o ns.  
4  
S T U D Y P O P U L A TI O N  
4. 1  
I ncl usi o n Criteri a 
A s u bject m ust f ull y me et all t he f oll o wi n g criteria t o be eli gi ble f or t he st u d y: 
1.  T he s u bje ct has a hist ol o gic or c yt ol o gic dia g n osis of c ol orectal a de n ocarci n o ma t hat is 
metast atic or u nrese cta ble , a n d t he patie nt eit her di d n ot t oler ate,  is refra ct or y t o or 
pr o gresse d  ( or r ela pse d) f oll o wi n g a fl u or o p yri mi di ne, iri n oteca n, o xali plati n, a n d 
be vaciz u ma b; pri or e pi d er mal gr o wt h fact or i n hi bit or t hera p y is  re q uire d f or patie nts wit h 
left-si de d, R A S wil d -t y pe t u m ors; pri or F D A-a p pr o ve d P D-1 i n hi bit or t hera p y is re q uire d 
f or patie nts wit h M SI-H c ol ore ctal ca nc er.  Pri or re g orafe ni b or T A S -1 0 2 tre at m e nt is n ot 
re q uire d; 
2.  Meas ura ble dise ase per R E CI S T 1. 1 as deter mi ne d b y t he i n vesti gat or ; 
3.  T he s u bje ct has ha d a n assess me nt of all k n o w n disease sites e g, b y c o m p uteriz e d 
t o m o gra p h y ( C T) sc a n a n d/ or ma g netic r es o n a nce i ma gi n g ( M RI)  wit hi n 2 8 da ys bef ore 
t he first d ose of c a b oz a nti ni b; 
4.  T he s u bject is ≥ 1 8  ye ars ol d  o n t he d a y of c o nse nt;  
5.  T he s u bject has a n Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C OG) perf or ma nce st at us of 
0 or 1;  
6.  Rec o ver y t o baseli ne or ≤ Gra de 1 C T C A E v. 4. 0 fr o m t o xicities relate d t o a n y pri or 
treat me nts, u nless A E(s) are cli nic all y n o nsi g nifica nt a n d/ or sta ble o n s u p p orti ve t hera p y; 
7.  A de q uate ar c hi val fr oz e n or fi x e d tiss ue a va ila ble fr o m pri mar y or met astatic site f or 
ge n ot y pic a nal ysis (at least 1 5 u nstai ne d sli des a n d/ or t u m or bl oc k) ; 


 
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8.  T he s u bje ct has or ga n a n d marr o w f u ncti o n a n d la b orat or y val u es as f oll o ws  wit hi n 
7  da ys bef or e t he first d ose of ca b oz a nti ni b : 
a. T he A N C ≥ 1 5 0 0/ m m 3  wit h o ut c ol o n y sti m ulati n g fa ct or s u p p ort;  
b.  Platelets ≥ 1 0 0, 0 0 0/ m m 3; 
c. He m o gl o bi n ≥ 9  g/ d L ; 
d.  Bilir u bi n ≤ 1. 5   t he U L N. F or s u bje cts wit h k n o w n Gil bert’s dise ase, bilir u bi n 
≤ 3. 0 m g/ d L;  
e. Ser u m al b u mi n ≥ 2. 8 g/ dl;  
f. Ser u m cre ati ni ne ≤ 1. 5   U L N or creati ni ne cleara nc e ( Cr Cl) ≥ 4 0  m L/ mi n.  F or 
creati ni ne clear a nce  esti m ati o n, t he C oc kcr oft a n d G a ult e q u ati o n s h o ul d b e use d:  
iii. 
Male: Cr Cl ( m L / mi n) = ( 1 4 0 - a g e) × wt ( k g)  / (ser u m creati ni ne × 7 2) ; 
i v. 
Fe male: M ulti pl y a b o ve r es ult b y 0. 8 5 ; 
g.  A L T a n d A S T ≤ 3. 0   U L N;  
h.  Li pase < 2. 0 x t he u p per li mit of n or m al a n d n o ra di ol o gic or cli nical e vi d e nce of 
pa ncreatitis;  
i. U P C R ≤ 1;  
j. Ser u m p h os p h or us, calci u m, ma g nesi u m a n d p otassi u m ≥ L L N.  
9.  T he s u bject is ca pa ble of u n derst a n di n g a n d c o m pl yi n g wit h t he pr ot oc ol re q uir e m e nts 
a n d has si g ne d t he i nf or me d c o nse nt d oc u m e nt ; 
1 0.  Se x uall y a cti ve s u bje cts ( me n a n d w o me n) m ust a gr ee t o use me dicall y  ac ce pt e d barrier 
met h o ds of c o ntra ce pti o n ( e g,  male or  fe male c o n d o m) d uri n g  t he st u d y a n d f or 4  m o nt hs 
after t he last d ose of st u d y d r u g(s), e ve n if oral c o ntrace pti ves are als o use d. All s u bjects 
of re pr o d ucti ve p ote ntial m ust a gree t o use b ot h a b arrier met h o d a n d a sec o n d met h o d of 
birt h c o ntr ol  or practic e a bsti ne nc e d uri n g  t he st u d y a n d f or 4  m o nt hs after  t he last d ose 
of st u d y dr u g(s).  


 
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4. 2  
E xcl usi o n Crit eri a   
A s u bject w h o meets a n y of t he f oll o wi n g criteria is i neli gi ble f or t he st u d y:  
1.  T he s u bject has rec ei ve d c yt ot o xic c he m ot hera p y (i ncl u di n g i n vesti gati o nal c yt ot o xic 
c he m ot hera p y) or bi ol o gic a ge nts (e g,  c yt o ki nes or a nti b o dies) wit hi n 3  wee ks, or 
nitr os o ur eas/ mit o m yci n  C wit hi n 6  wee ks bef ore t he first d ose of st u d y treat me nt ; 
2.  Pri or tr eat me nt wit h ca b oz a nti ni b;  
3.  Ra diati o n t hera p y f or b o ne met astasis wit hi n 2 wee ks, a n y ot her e xter nal ra diati o n 
t hera p y wit hi n 4 wee ks bef ore t he first d ose of st u d y tre at m e nt. S yst e mic treat me nt wit h 
ra di o n ucli des wit hi n 6 wee ks bef ore t he first d os e of st u d y tr eat me nt. S u bje cts wit h 
cli nicall y rele va nt o n g oi n g c o m plicati o ns fr o m pri or ra diati o n t her a p y are n ot eli gi ble ; 
4.  Recei pt of a n y t y pe of s mall m ole c ule ki nase i n hi bit or (i ncl u di n g i n vesti gati o nal ki nase 
i n hi bit or) wit hi n 1 4 da ys bef ore t he first d ose of st u d y treat me nt . N ote: S u bjects wit h 
pr ostate c a ncer c urre ntl y rec ei vi n g L H R H or G n R H a g o nists ma y b e mai ntai ne d o n t hese 
a ge nts;  
5.  T he s u bje ct has re cei ve d a n y ot her t y pe of i n vesti g ati o nal a ge nt wit hi n 2 8 da ys b ef ore t he  
first d ose of st u d y treat me nt; 
6.  K n o w n brai n 
met astases or cra nial e pi d ural dise ase u nless a de q u atel y tr eat e d wit h 
ra di ot her a p y a n d/ or s ur ger y (i ncl u di n g ra di os ur ger y) a n d sta ble f or at least 4  wee ks 
bef or e t he first d ose of st u d y tr eat me nt. Eli gi ble s u bjects 
m ust be ne ur ol o gicall y 
as y m pt o matic a n d wit h o ut c ortic oster oi d tr eat me nt at t he ti me of t he st art of st u d y 
treat me nt; 
7.  T he s u bject has pr ot hr o m bi n ti me ( P T)/I N R or partial t hr o m b o p lasti n ti m e ( P T T) t est 
≥ 1. 3  the la b orat or y U L N  wit hi n 7 da ys bef ore  t he first d ose of st u d y treat me nt; 
8.  C o nc o mit a nt a ntic oa g ulati o n  at t hera pe utic d oses  wit h oral a ntic oa g ula nts (e g, warfari n, 
dir ect t hr o m bi n  a n d Fact or Xa i n hi bit ors) or platelet i n hi bit ors (e g,  cl o pi d o gr el) ;  
N ote: L o w -d ose as piri n f or c ar di o pr ot ecti o n ( per l o cal a p plica ble g ui deli nes), l o w -d ose 
warfari n ( < 1 m g/ da y), a n d l o w d ose, l o w m olec ular wei g ht he pari ns ( L M W H) are 
per mitte d.  A ntic oa g ulati o n wit h t hera p e utic d oses of L M W H is all o w e d i n s u bjects 


 
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Pa ge 6 4  of 9 6  
wit h o ut ra di o gr a p hic e vi de nce of br ai n m etast asis,  w h o are o n a st a ble d ose of L M W H 
f or at least 1 2 wee ks b ef or e ra n d o miz ati o n, a n d w h o ha ve ha d n o c o m plicati o ns fr o m a 
t hr o m b oe m b olic e ve nt or t he a ntic oa g ulati o n re gi me n; 
9.  T he s u bject has e x p erie nce d a n y of t he f oll o wi n g:  
a. C li nic all y-si g nific a nt GI ble e di n g  wit hi n 6 m o nt hs bef or e t he first d ose of st u d y 
treat me nt; 
b.  H e m o pt ysis of ≥ 0. 5 t eas p o o n  ( 2. 5 ml) of re d bl o o d  wit hi n 3 m o nt hs bef ore t he 
first d ose of st u d y treat me nt; 
c. A n y ot her si g ns i n dicati ve of p ul m o nar y he m orr ha g e wit hi n 3 m o nt hs bef ore t he 
first d ose of st u d y treat me nt. 
1 0.  T he s u bject has r a di o gra p hic e vi de nc e of ca v itati n g p ul m o nar y lesi o n(s); 
1 1.  T he s u bject has t u m or i n va di n g or e ncasi n g a n y maj or bl o o d vessels ; 
1 2.  T he s u bject has e vi de nce of cli nic all y si g nific a nt blee di n g fr o m  t u m or i n va di n g t he GI 
tract (es o p ha g us, st o m ac h, s m all or lar ge b o wel, r ect u m or a n us), or a n y e vi de nce of 
e n d otrac heal or e n d o br o nc hial t u m or wit hi n 2 8 da ys bef or e t he first d ose of ca b oz a nti ni b ; 
1 3.  T he s u bject has u nc o ntr olle d, si g nific a nt i nterc urr e nt  or r ece nt  ill ness i ncl u di n g, b ut n ot 
li mite d t o, t he f oll o wi n g c o n diti o ns: 
a. C ar di o vasc ular dis or ders i ncl u di n g:  
i. 
C o n gesti ve heart fail ure ( C H F ): Ne w Y or k He art Ass ociati o n ( N Y H A) 
Class III ( m o d erat e) or Class I V (se ver e) at t he ti me of scre e ni n g; 
ii. 
C o nc urr e nt u nc o ntr olle d h y pert e ns i o n defi ne d as s ustai ne d bl o o d press ure 
( B P) > 1 5 0  m m  H g s yst olic  or >  1 0 0  m m  H g diast olic des pite o pti mal 
a nti h y perte nsi ve tr eat me nt wit hi n 7 da ys of t he first d ose  of st u d y 
treat me nt; 
iii. 
A n y hist or y of c o n g e nit al l o n g Q T s y n dr o m e;  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
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Pa ge 6 5  of 9 6  
i v. 
A n y of t he f oll o wi n g wit hi n 6 m o nt hs bef or e t he first d ose of st u d y 
treat me nt: 
•  u nsta ble a n gi na pe ct oris;  
•  cli nicall y-si g nifica nt car dia c arr h yt h mias; 
•  str o ke (i ncl u di ng tr a nsie nt isc he mic att ac k ( TI A), or ot her isc he mic 
e ve nt);  
•  m y ocar dial i nfarcti o n ; 
•  t hr o m b oe m b olic e ve nt re q uiri n g t hera p e utic a ntic oa g ulati o n ( N ote: 
s u bje cts wit h a ve n o us filter (e g, ve na ca va filter) are n ot eli gi ble 
f or t his st u d y). 
b.  GI dis or ders p artic ularl y t h ose ass ociate d wi t h a hi g h ris k of perf or ati o n or fist ula 
f or m ati o n i ncl u di n g: 
i. 
A cti ve p e ptic ulcer dis ease, i nfla m mat or y b o wel dise ase (e g, Cr o h n’s 
dise ase), 
di vertic ulitis, 
c h ole c ystitis, 
s y m pt o m atic 
c h ola n gitis 
or 
a p pe n dicitis, ac ut e pa ncr eatitis or ac ute o bstr u cti o n of t he p a ncreatic d uct 
or c o m m o n bile d uct, or gastric o utlet o bstr ucti o n  
ii. 
A b d o mi nal fist ula, GI perf orati o n, b o wel o bstr ucti o n, i ntra -a b d o mi nal 
a bscess wit hi n 6 m o nt hs bef or e ra n d o miz ati o n ,  
N ote: C o m plete he ali n g of a n i ntra -a b d o mi nal a bscess m ust be c o nfir me d 
pri or t o ra n d o miz ati o n  
c. Ot her cli nicall y si g nifica nt dis or ders t hat w o ul d pr ecl u d e safe st u d y partici pati o n; 
1 4.  Maj or s ur ger y wit hi n 1 2 wee ks  b ef ore t he first d ose of st u d y tr eat me nt. C o m plete w o u n d 
he ali n g fr o m maj or s ur ger y  a n d/ or ra diati o n  m ust ha ve occ urr e d 1 m o nt h b ef ore t he first 
d ose of st u d y tr eat m e nt . 
Mi n or s ur ger y (i ncl u di n g u nc o m plicat e d t o ot h e xtracti o ns) 
wit hi n 2 8 d a ys bef ore t he first d ose of st u d y tre at m e nt wit h c o m plet e w o u n d heali n g  at 
least 1 0 da ys bef or e t he first d ose of st u d y tr eat m e nt. S u bje cts wit h cli nic all y rele va nt 
o n g oi n g c o m plicati o ns fr o m pri or s ur ger y ar e n ot eli gi ble ; 
1 5.  Q Tc F >  5 0 0  msec wit hi n 1 m o nt h bef or e t he first d ose of st u d y tr eat me n t: 


 
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Pa ge 6 6  of 9 6  
a. T hr ee E C Gs m u st be perf or me d f or eli gi bilit y d et er mi nati o n. If t he a vera ge of 
t hese t hree c o nsec uti ve res ults f or Q Tc F is ≤ 5 0 0 msec, t he s u bject me ets 
eli gi bilit y i n t his r e gar d.  
1 6.  Pre g na nt or la ctati n g fe m ales;  
1 7.  I na bilit y t o s wall o w i ntact ta blets; 
1 8.  Pre vi o usl y i d e ntifie d aller g y or h y p erse nsiti vit y t o c o m p o ne nts of t he st u d y treat me nt 
f or m ulati o ns; 
1 9.  Dia g n osis of a n ot her m ali g na nc y wit hi n 2  ye ars bef ore t he first d ose of st u d y treat me nt, 
e xce pt f or s u perficial s ki n ca ncers, or l ocaliz e d, l o w gra de t u m ors dee m e d c ur e d a n d n ot 
treat e d wit h s yste mic t hera p y; 
5  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
5. 1  
Pre -Tr e at m e nt Peri o d  
D uri n g t he Pre -Tre at me nt Peri o d, s u bje cts are c o nse nt e d a n d q ualifie d (scree ne d) f or t he st u d y. 
I nf or m e d c o nse nt m ust be o bt ai ne d bef or e i nitiati o n of a n y cli nical scree ni n g pr oce d ure t hat is 
perf or me d s olel y f or deter mi ni n g eli gi bilit y f or t his st u d y. E val u ati o ns perf or me d as part of 
r o uti ne c are bef ore i nf or me d c o nse nt c a n be c o nsi d er e d  as scree ni n g e val uati o ns if d o ne wit hi n 
t he defi ne d scree ni n g p eri o d, a n d if per mitt e d b y t he sit e’s i nstit uti o nal re vie w b oar d 
(I R B)/et hics c o m mitt ee ( E C ) p olicies.  
St u d y eli gi bilit y is base d o n m eeti n g all t he st u d y i ncl usi o n crit eria a n d n o ne of t he e xcl usi o n 
criteria at scree ni n g a n d o n St u d y Da y 1 bef ore st u d y treat me nt a d mi nistrati o n.  T he f oll o wi n g 
assess me nts will be c o n d u cte d b ef ore  s u bjects recei vi n g t heir first d ose of ca b oz a nti ni b o n t his 
pr ot oc ol:  
5. 1. 1  
De m o gr a p hics  
M e dical a n d ca nc er hist or y, a n d d e m o gra p hics s h o ul d be rec or de d d uri n g t he pre -
treat me nt p eri o d. 
5. 1. 2  
C o nc o mit a nt m e dic ati o ns  
C o nc o mit a nt m e dic ati o ns will be c ollecte d d uri n g t he pretre at m e nt peri o d a n d at eac h 
st u d y visit. 


 
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5. 1. 3  
Vit al Si g ns  
Vit al si g ns ( b o d y t e m per at ure, res pirat or y r ate, bl o o d press ure , a n d p ulse) o btai ne d at 
eac h st u d y visit . Bl o o d press ure a n d p ulse will b e m eas ure d after t he s u bject has bee n 
sitti n g f or at le ast 5 mi n utes. 
W he n vit al si g ns are sc he d ule d at t he sa m e ti me as bl o o d dr a ws, t he bl o o d dr a ws will 
be o btai ne d at t he sc he d ule d ti me p oi nt, a n d t he vitals will b e o btai ne d as cl ose t o t he 
sc he d ule d bl o od dr a w as p ossi ble  ( pre- or p ost -dra w) . 
5. 1. 4  
Hei g ht a n d wei g ht  
Hei g ht of s u bject s h o ul d be re c or de d d uri n g t he pre -treat m e nt peri o d. Wei g ht s h o ul d 
be re val u ate d at ea c h st u d y visit.  
5. 1. 5  
P h ysic al E x a mi n ati o n  
A p h ysical e xa mi nati o n will i ncl u de assess me nts of E C O G pe rf or ma nc e stat us, 
ge neral 
a p pe ara nc e, s ki n, 
H E E N T, t h ora x/l u n gs, 
car di o vasc ular, 
a b d o mi nal, 
ge nit o uri nar y, m usc ul os kelet al , a n d ne ur ol o gic al fi n di n gs. A n y perti ne nt fi n di n gs 
s h o ul d b e d oc u m e nte d eit her i n t he s u bject’s me di cal hist or y (if d eter mi ne d t o be 
pri or t o t he first d ose of ca b oz a nti ni b) or as a n A E (if ne w or w orse ni n g after t he first 
d ose of c a b oz a nti ni b).  
5. 1. 6  
L a b or at or y Assess m e nt  
L ocal la b orat ories will perf or m all la b orat or y tests, a n d res ults will be pr o vi de d t o t he 
I n vesti gat or. F or a d etaile d d escri pti o n of t he la b orat or y assess me nts, ple ase see 
Secti o n 5. 4 . Bl o o d a n d uri ne sa m ples f or he mat ol o g y, ser u m c he mistr y, c oa g ulati o n 
pa nel, T F Ts, C E A  a n d uri nal ysis  a n d uri ne pr otei n/ uri ne cre ati ni ne rati o n ( U P C R)  
will be pre par e d usi n g sta n dar d pr oce d ur e s a n d a nal yz e d d uri n g t he pretr eat m e nt 
peri o d . L a b orat or y res ults 
will b e re vie we d b y t he I n vesti gat or f or cli nical 
si g nifica nce. 
5. 1. 7  
Pre g n a nc y test  
A pre g na nc y test  ( uri ne or ser u m) will be c olle cte d d uri n g pr etre at m e nt peri o d a n d 
wit hi n 7 da ys of st u d y tre at m e nt start. It will be re pe ate d  e ver y O d d C ycle  if fe male 
patie nt  of c hil d -beari n g p ote ntial r e mai n s o n st u d y. 
5. 1. 8  
Electr o c ar di o gr a m ( E C G)  
E C G assess me nts will be p erf or me d wit h st a n dar d 1 2 -lea d E C G e q ui p me nt a cc or di n g 
t o st a n dar d pr oc e d ures. Pre -treat me nt E C Gs s h o ul d be perf or me d after vital si g ns ar e 


 
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o bt ai ne d a n d b ef ore a n y bl o o d dr a ws. A b n or malities i n t he E C G t hat lea d t o a c ha n g e 
i n s u bject ma na g e me nt (e.g ., d ose re d u ce d or wit h hel d, re q uir e me nt f or a d diti o nal 
me dic ati o n or m o nit ori n g) or res ult i n cli nical si g ns a n d s y m pt o ms are c o nsi der e d 
cli nicall y si g nific a nt f or t he p ur p oses of t his st u d y a n d will b e rec or de d o n t he A E 
C R F. If val ues me et crit eria defi ni n g t he m as seri o us, t he y m ust b e re p orte d as 
S A Es). 
W he n a n E C G ti m e p oi nt c oi nci de s wit h ot her acti vities, t he E C G will be 
c olle cte d first, f oll o we d b y vital si g ns.  
5. 1. 9  
Arc hi v al t u m or tiss ue  ( o pti o n al) 
A de q uate ar c hi val fr oz e n or fi x e d tiss ue a vaila ble fr o m pri mar y or met astatic sit e f or 
ge n ot y pic a nal ysis (at least 1 5 u nstai ne d sli des a n d/ or t u m or bl oc k). 
5. 1. 1 0  
W h ole bl o o d c olle cti o n  ( o pti o n al) 
W h ole bl o o d will be c ollecte d a n d ba n ke d  f or f ut ure c orr elati ve /e x pl orat or y a nal ysis 
a n d will be o btai ne d C ycle 1 Da y 1 ( -7 d a y wi n d o w)  a n d a gai n +/ - 5  da ys of  C ycle 3 
Da y 1 . 
F or ea c h s u bject, t he Pre -Tr eat me nt Peri o d e n ds u p o n re cei pt of t he first d ose of st u d y treat me nt 
or fi nal deter mi nati o n t hat t he s u bje ct is i neli gi ble f or t he st u d y.  
5. 2  
Tre at m e nt Pe ri o d   
D uri n g t he T reat me nt P eri o d s u bje cts will re cei ve c a b oz a nti ni b u ntil eit her disease pr o gre ssi o n, 
t he occ urre nce of u nacc e pta ble dr u g -relate d t o xicit y or f or ot her reas o n(s) f or s u bje ct wit h dra wal 
as descri b e d i n Secti o n 2. 6 . S u bjects s h o ul d be i nstr ucte d t o i m m e diatel y i nf or m t he pri nci pal 
i n vesti gat or (PI ) of a n y A Es. S u bjects e x perie nci n g diz zi ness, slee pi ness, or ot her s y m pt o ms t hat 
c o ul d i nfl u e nce alert ness or c o or di nati o n s h o ul d be a d vis e d n ot t o dri ve or o per ate ot her he a v y 
mac hi ner y.  
T he f oll o wi n g sc he d ule of assess me nts  a p plies t o all s u bjects  (T a ble  5 -1 ). M or e fre q ue nt 
assess me nts s h o ul d be o btai ne d if cli nic all y i n dic ate d.  


 
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T a ble  5 -1 : 
St u d y Assess m e nts  
 
St u d y T re at m e nt P eri o d  
1 C ycle = 2 1 d a ys  
P ost -T re at m e nt P eri o d  
Wit hi n 2 8 d a ys 
b ef ore  1 st D os e of 
St u d y T re at m e nt  
C ycle 1 D a y 1  
(-7 d a y wi n d o w)  
D a y 1 of e ac h  
s u bs e q ue nt C ycle  
( ± 5 d a ys) 
3 0 - 3 7  D a ys  after l ast 
d os e  
I nf or m e d c o ns e nt  
X  
 
 
 
De m o gra p hi cs  
X  
 
 
 
M e dical a n d ca ncer 
h ist or y/ d e m o gra p hi cs 
X  
 
 
 
P h ysi cal e xa mi nati o n  
X  
X  
X  
X  
Hei g ht  
X  
 
 
 
Wei g ht  
X  
X  
X  
X  
Vital si g ns  
X  
X  
X  
X  
E C O G p erf or ma nce 
stat us 
X  
X  
X  
X  
He mat ol o g y ( C B C w 
diff a n d platel ets  
X  
X  
X  
X  
C he mistr y ( C M P, 
ma g nesi u m, L D H, 
p h os p h or us  
X  
X  
X  
X  
A m ylas e/ Li pas e  
X  
X  
X  
X  
G G T  
 
X  
 
 
Uri nal ysis  a n d U P C R  
X  
 
X  
X  
P T/I N R, P T T  
X  
 
X 1 
 
T F Ts ( T S H, fr ee T 3, 
free T 4)  
X  
 
X 1 
 
1 2 -lea d E C G 
X 2  
 
X 1 
X  
C a b oza nti ni b  
a d mi nistrati o n  
 
X ( dail y)  
X ( dail y)  
 
Pre g na n c y t est  
X  
X  
X 1 
X  
T u m or ass ess me nt 3  
X  
 
X  (e ver y 6 w ee ks  
f or first 1 2 w ee ks, 
t he n e ver y 9 wee ks ) 
 
C E A  
X  
 
X (e ver y 3  w ee ks)  
 
Arc hi val t u m or tiss ue  
X 3  
 
 
 
W h ol e bl o o d 
c oll ecti o n f or 
c orr elati ve a nal ysis  
 
X 4 
(C ycl e 3 Da y 1 )4  
 
C o nc o mita nt 
me di cati o ns   
X  
 
X  
X  
A d vers e e ve nts  
C o nti n u o us  
X  
I nteri m a nal ysis 
 
 
X 5  
 
F oll o w -u p / E O S 
 
 
 
X 6  
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; P T/I N R, pr ot hr o m bi n ti me/I nter nati o nal N or malize d 
Rati o; P T T, partial pr ot hr o m bi n ti me, T F T, t h yr oi d f u ncti o n test; U P C R, uri ne pr otei n/ uri ne creati ni ne rati o ; E O S e n d-of -st u d y 
1O d d c ycle as sess me nts 


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
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2E C G d o ne i n tri plicate t o assess a vera ge Q Tc f or scree ni n g  
3All sites of k n o w n disease m ust be assesse d  
4A de q uate arc hi val fr oze n or fi xe d tiss ue a vaila ble fr o m pri mar y or metastatic site f or ge n ot y pic a nal ysis (at least 1 5 u nstai ne d 
sli des a n d/ or t u m or bl oc k) . W h ole bl o o d f or c orrelati ve/e x pl orat or y a nal ysis will be o btai ne d C ycle 1 Da y 1 ( -7 da y wi n d o w) a n d 
C ycle 3 Da y 1 ( +/ - 5 da ys)  
5U p o n e nr olli n g t he 1 6 t h patie nt, a n i nteri m a nal ysis will be perf or me d t o e val uate P F S  o nce 3 patie n ts ha ve met t he 1 2 wee k P F S 
mar k.  A n a d diti o nal safet y D M S C re vie w will occ ur o nce 1 6 patie nts ha ve bee n d ose d t hr o u g h 1 2 wee ks.  
6Patie nts  will be f oll o we d f or u p t o 1 2 m o nt hs t o rec or d t heir healt h a n d disease stat us  after E O S assess me nt  
 
If t he s u bject is u na ble t o ha ve a st u d y assess me nt t a ke n wit hi n t he defi ne d ti me wi n d o w d ue t o 
a n e ve nt o utsi d e of his or her c o ntr ol ( e. g., cli ni c cl os ure, pers o nal e mer ge nc y, i ncle me nt 
weat her, vacati o n), t he assess me nt s h o ul d be perf or m e d as cl ose as p os si ble t o t he re q uir e d 
sc he d ule. 
Re g ular t u m or assess me nts s h o ul d be perf or m e d i n a cc or da nc e t o t he g ui d eli nes i n S ecti o n 5. 5  t o 
deter mi ne if P D  is present . 
T he Tre at m e nt Peri o d e n ds w he n a s u bject rec ei ves his or her last d ose of st u d y treat me nt; t he 
s u bje ct t he n e nt ers t he P ost-Treat me nt Peri o d . 
5. 3  
P ost -Tre at m e nt Peri o d  
S u bje cts will ret ur n t o t he st u d y site 3 0 t o 3 7 da ys after t heir last d ose of c a b oz a nti n i b t o 
c o m plete e n d -of -st u d y ( E O S) assess me nts . 
La b orat or y a n d p h ysical e x a mi nati o ns will be perf or m e d. Re mai ni n g st u d y tre at m e nt will be 
ret ur ne d b y t he s u bje ct, a n d treat me nt c o m plia nce will be d oc u me nt e d. A d diti o nal f oll o w -u p will 
oc c ur f or s u bjects wit h  A Es relate d t o st u d y tr eat m e nt t hat are o n g oi n g at t he ti me of t his visit, 
a n d f or s u bjects wit h S A Es relate d t o st u d y treat me nt t hat occ ur after t he ti m e of t his visit.   
A d diti o nal f oll o w -u p t o re c or d healt h a n d disease st at us will b e d o ne f or u p t o 1 2 m o nt hs after 
E O S.  S ur vi val i nf or m ati o n ca n b e c ollecte d via t ele p h o ne a n d  s h o ul d oc c ur e ver y 9 0 da ys  ( +/- 3 0 
da ys)  u p t o 1 2 m o nt hs aft er E O S.  


 
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5. 4  
L a b or at or y Assess m e nts  
La b orat or y p a nels are c o m p ose d of t he f oll o wi n g:  
He m at ol o g y  
•  
W B C c o u nt wit h 
differ e ntial (i n cl u di n g at 
mi ni m u m: ne utr o p hils, 
bas o p hils, e osi n o p hils, 
l y m p h oc yt es, 
m o n oc yt es)  
•  
he mat ocrit  
•  
platel et c o u nt  
•  
R B C c o u nt  
•  
he m o gl o bi n  
 
 
Ser u m c he mistr y  
•  
al b u mi n 
•  
A L P  
•  
a m ylas e  
•  
A L T  
•  
A S T  
•  
bicar b o nat e  
•  
B U N  
•  
c hl ori d e  
•  
cr eati ni n e  
•  
G G T  ( da y 1 o nl y) 
•  
g l uc os e ( n o n-fasti n g 
per mitte d ) 
•  
i o ni ze d cal ci u m or 
t otal a n d c orr ect e d 
calci u m  
•  
lactate d e h y dr o g e nas e  
•  
li pas e 
•  
ma g nesi u m  
•  
p h os p h or us  
•  
p otassi u m  
•  
s o di u m 
•  
t otal bilir u bi n 
•  
t otal pr otei n 
 
Uri n al ysis  
•  
a p peara nce  
•  
c ol or  
•  
p H  
•  
s pecific gra vit y 
•  
ket o n es  
•  
pr ot ei n  
•  
U P C R  
•  
gl uc os e  
•  
bilir u bi n  
•  
nitrit e  
•  
cr eati ni n e  
•  
ur o bili n o ge n  
 
•  
occ ult bl o o d 
( micr os c o pi c 
e xa mi nati o n of 
s e di me nt will be 
perf or m e d o nl y if t h e 
res ults of t h e uri nal ysis 
di pstic k e val uati o n ar e 
p ositi ve)  
Ot her  
•  
T S H , Fr ee T 3 a n d T 4 
•  
Pre g na n c y t e st ( uri n e or 
s er u m) f or w o me n of 
c hil d-b eari n g p ot e ntial  
 
 
•  
P T/I N R  or P T T  
•  
2 4 -h o ur uri n e c oll ecti o n 
f or pr ot ei n 
A L P, al kali ne p h os p hatase ; A L T, ala ni ne a mi n otra nsferase; A S T, as partate a mi n otra nsferase; B U N, bl o o d urea nitr o ge n ; G G T, 
-gl uta m yltra nsferase ; I N R, I nter nati o nal N or malize d Rati o; P T, pr ot hr o m bi n ti me; P T T partial t hr o m b o plasti n ti me; R B C, re d 
bl o o d cell ; T S H, t h yr oi d sti m ulati n g h or m o ne ; U P C R, uri ne pr otei n/cr eati ni ne rati o; W B C, w hite bl o o d cell . 
 
A b n or malities i n cli nic al la b orat or y tests t hat le a d t o a c ha n ge i n s u bject ma na g e me nt (e g,  d ose 
dela ye d [wit h hel d ] or re d u ce d, re q uire m e nt f or a d diti o nal me dicati o n , tr eat me nt or m o n it ori n g) 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
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Pa ge 7 2  of 9 6  
are c o nsi der e d cli nicall y si g nifica nt f or t he p ur p oses of t his st u d y, a n d will b e  rec or d e d o n t he 
A d verse E ve nts Case Re p ort F or m ( C R F ). If la b orat or y val ues c o nstit ute p art of a n e ve nt t hat 
meets criteria defi ni n g it as seri o us, t he e ve nt (a n d as s ociate d la b orat or y val ues) m ust b e re p ort e d 
as a n S A E.  
5. 5  
T u m or  Assess m e nt  
F or t he p ur p oses of t his st u d y, partici p a nts s h o ul d b e re -e val uat e d f or r es p o nse e ver y  6  wee ks  f or 
t he first 1 2 wee ks, f oll o w e d b y e ver y 9 wee ks t hereaft er . 
Res p o nse a n d pr o gressi o n w ill be e val uat e d i n t his st u d y usi n g t he ne w i nter nati o nal crit eria 
pr o p ose d b y t he R E CI S T v 1. 1  g ui deli ne [ E ur J C a  4 5: 2 2 8 -2 4 7, 2 0 0 9].  C ha n ges i n t he lar gest 
dia meter ( u ni di m e nsi o nal me as ure me nt) of t he t u m or lesi o ns a n d t he s h ortest dia m eter i n t he 
case of mali g na nt l y m p h n o d es are use d i n t he R E CI S T criteria.  
All meas ure me nts s h o ul d be t a ke n a n d re c or de d i n metric n otati o n usi n g a r uler, cali pers, or a 
di gital m eas ure me nt t o ol.  All baseli ne e val u ati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o 
t he be gi n ni n g of tre at m e nt a n d ne ver m ore t ha n 4 we e ks bef or e t he b e gi n ni n g of t he tre at m e nt. 
T he sa m e met h o d of assess m e nt a n d t he sa me tec h ni q u e s h o ul d b e use d t o c har act eriz e ea c h 
i d e ntifie d a n d re p ort e d lesi o n at baseli ne a n d d uri n g f oll o w-u p. I ma gi n g -base d e val uati o n is 
preferre d t o e val uati o n b y cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d c a n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xa m.  
Cli ni c al lesi o ns:  Cli nical lesi o ns will o nl y be c o nsi dere d me as ura ble w he n t he y are s u perficial 
(e. g., s ki n n o d ules a n d pal p a ble l y m p h n o des) a n d ≥1 0 m m i n dia met er as assesse d usi n g c ali p ers 
(e. g., s ki n n o d ules).  I n t he c ase of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gr a p h y, i ncl u di n g a 
r uler t o esti mate t he siz e of t he lesi o n, is r ec o m me n d e d.  
C o n ve nti o n al C T a n d M RI:  T his g ui d eli ne has d efi ne d meas ura bilit y of lesi o ns o n C T sc a n 
base d o n t he ass u m pti o n t hat C T t hic k ness is 5 m m or less. If C T sca ns ha ve slic e t hic k ness 
greater t ha n 5 m m, t he mi ni m u m siz e of a me as ura ble lesi o n s h o ul d be t wic e t he slice t hic k ness. 
M RI is als o a cce pta ble i n certai n sit uati o ns ( e. g. f or b o d y sca ns). 
Use of 
M RI re mai ns a c o m ple x iss ue.  
M RI has e xcelle nt c o ntrast, s patial, a n d te m p oral 
res ol uti o n; h o we ver, t her e are ma n y i ma ge ac q uisiti o n varia bles i n v ol ve d i n M RI, w hic h greatl y 
i m pact i ma g e q ualit y, lesi o n c o ns pic uit y, a n d meas ure me nt.  F urt her m ore, t he a vaila bilit y of 
M RI is varia ble gl o ball y.  As wit h C T, if a n M RI is perf or me d, t he tec h nical s pecificati o ns of t he 
sca n ni n g se q ue nces use d s h o ul d be o pti miz e d f or t he e val uati o n of t he t y pe a n d site of disease.  
F urt her m ore, as wit h C T, t he m o dalit y use d at f oll o w -u p s h o ul d b e t he sa me as was use d at 
baseli ne a n d t he lesi o ns s h o ul d be m eas ure d/ assesse d o n t he sa me p ulse se q ue nce.  It is be y o n d 


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
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Pa ge 7 3  of 9 6  
t he sc o pe of t he R E CI S T g ui deli nes t o prescri be s pe cific M RI p uls e se q ue nc e para met ers f or all 
sca n ners, b o d y parts, a n d dis eases.  I d eall y, t he sa me t y p e of sc a n ner s h o ul d be use d a n d t he 
i ma ge ac q uisiti o n pr ot oc ol s h o ul d be f oll o w e d as cl osel y as p ossi ble t o pri or sca ns.  B o d y sc a ns 
s h o ul d be p erf or me d wit h breat h-h ol d sca n ni n g tec h ni q u es, if p ossi ble.  
F D G -P E T : W hile F D G -P E T res p o nse as sess me nts nee d a d diti o nal st u d y, it is s o m eti mes 
reas o na ble t o i nc or p or ate t he use of F D G-P E T sca n ni n g t o c o m ple me nt C T sca n ni n g i n 
assess me nt of pr o gressi o n ( partic ularl y p ossi ble ' ne w' disease).  Ne w lesi o ns base d o n F D G -P E T 
i ma gi n g ca n be i de ntifie d a ccor d i n g t o t he f oll o wi n g al g orit h m: 
(a)  Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w -u p is a si g n of P D base d 
o n a ne w lesi o n.  
( b) N o F D G-P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w -u p:  If t he p ositi ve F D G -P E T at 
f oll o w-u p c orres p o n ds t o a ne w sit e of dise ase c o nfir me d b y C T, t his is P D.  If t he p ositi ve 
F D G -P E T at f oll o w -u p is n ot c o nfir me d as a ne w sit e of disease o n C T, a d diti o nal f oll o w -u p 
C T sca ns are nee de d t o det er mi ne if t here is tr ul y pr o gressi o n oc c urri n g at t hat sit e (if s o, t he 
date of P D will be t he dat e of t he i nitial a b n or mal F D G -P E T sca n).  If t he p ositi ve F D G -P E T 
at f oll o w -u p c orr es p o n ds t o a pre -e xisti n g sit e of dis ease o n C T t hat is n ot pr o gr essi n g base d 
o n t he a nat o mic i m a ges, t his is n ot P D.  
(c)  F D G-P E T ma y be u se d t o u p gra de a r es p o nse t o a C R i n a m a n ner li ke a bi o ps y i n cases 
w here a resi d u al ra di o gr a p hic a b n or malit y is t h o u g ht t o re pr ese nt fi br osis or scarri n g.  T he 
use of F D G -P E T i n t his circ u mst a nce s h o ul d be pr os pecti vel y descri b e d i n t he pr ot oc ol a n d 
s u p porte d b y dise ase -s pecific me dical lit erat ur e f or t he i n dic ati o n.  H o we ver, it m ust b e 
ac k n o wle d ge d t hat b ot h a p pr oa c hes ma y lea d t o fals e p ositi ve C R d ue t o li mitati o ns of F D G -
P E T a n d bi o ps y res ol uti o n/se nsiti vit y.  
N ote :  A ‘ p ositi ve’ F D G-P E T sca n lesi o n m ea ns o ne w hic h is F D G a vi d wit h a n u pta ke 
greater t ha n t wice t hat of t he s urr o u n di n g tiss ue o n t he att e n uati o n c orrecte d i ma ge.  
P E T -C T:  At prese nt, t he l o w d ose or atte n u ati o n c orrecti o n C T p orti o n of a c o m bi ne d P E T -C T 
is n ot al w a ys of o pti mal dia g n ostic CT q ualit y f or use wit h R E CI S T meas ure me nts.  H o we ver, if 
t he sit e c a n d oc u me nt t hat t he C T perf or m e d as p art of a P E T-C T is of i de ntic al dia g n ostic 
q ualit y t o a dia g n ostic C T ( wit h I V a n d oral c o ntrast), t he n t he C T p orti o n of t he P E T -C T ca n be 
use d f or R E CI S T meas ure me nts a n d c a n be use d i nter c ha n ge a bl y wit h c o n ve nti o nal C T i n 
acc uratel y m eas uri n g ca ncer lesi o ns o ver ti me.  N ot e, h o we ver, t hat t he P E T p orti o n of t he C T 
i ntr o d uces a d diti o nal data w hic h ma y bias a n I n vesti gat or if it is n ot r o uti nel y or seriall y 
perf or me d.   


 
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T u m or m ar kers:  T u m or mar kers al o ne c a n n ot b e use d t o assess res p o nse. If mar kers are 
i nitiall y a b o ve t he u p p er n or mal li mit, t he y m ust n or maliz e f or a partici p a nt t o be c o nsi dere d i n 
c o m plete cli nic al res p o nse.  
5. 5. 1  
Res p o nse Criteri a  
5. 5. 1. 1  
E v al u ati o n of T ar g et Lesi o ns  
C o m plet e Res p o nse ( C R) :  Disa p pe ara nce of all t ar get lesi o ns.  A n y pat h ol o gical 
l y m p h n o des ( w het her tar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 
m m.  
Partial Res p o nse ( P R) :  At le ast a 3 0 % decre ase i n t he s u m of t he dia m eters of tar g et 
lesi o ns, ta ki n g as refere nc e t he b aseli ne s u m dia met ers. 
Pr o gressi ve Disease ( P D) :  At le ast a 2 0 % i ncre ase i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as refere nc e t he s m allest s u m o n st u d y (t his i ncl u d es t he 
baseli ne s u m if t h at is t he s mallest o n st u d y).  I n a d diti o n t o t he relati ve i ncr ease of 
2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ut e i ncrease of at least 5 m m.  ( N ote:  
t he a p pe ara nce of o ne or m ore ne w lesi o ns is als o c o nsi der e d pr o gressi o ns). 
Sta ble Disease ( S D) :  Neither s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncrease t o q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia m eters w hile o n 
st u d y. 
5. 5. 1. 2  
E v al u ati o n of N o n -T a r get Lesi o ns  
C o m plet e Res p o nse ( C R) :  Disa p peara nce of all n o n-tar get lesi o ns a n d n or maliz ati o n 
of t u m or mar ker le vel.  All l y m p h n o des m ust b e n o n -pat h ol o gical i n siz e ( < 1 0 m m 
s h ort a xis). 
N ote :  If t u m or mar kers are i nitiall y a b o ve t he u p per n or m al li mit, t he y m ust 
n or m aliz e f or a patie nt t o be c o nsi dere d i n c o m plet e cli nical r es p o nse . 
N o n -C R/ N o n -P D:   Persiste nc e 
of 
o ne or 
m ore n o n -t ar get lesi o n(s) a n d/ or 
mai nt e na nc e of t u m or mar ker le vel a b o ve t he n or mal li mits.  
Pr o gressi ve 
Disease ( P D) :  
A p pear a nce of o ne or 
m or e ne w lesi o ns a n d/ or 
u ne q uiv oc al pr o gressi o n  of e xisti n g n o n -tar get lesi ons.  U ne q uiv o c al pr o gressi o n  
s h o ul d n ot n or mall y tr u m p t ar get lesi o n stat us.  It m ust be re pr ese ntati ve of o verall 
dise ase stat us c ha n ge, n ot a si n gle lesi o n i ncr ease.     
 


 
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Alt h o u g h a clear pr o gr essi o n of “ n o n -t ar get ” lesi o ns o nl y is e xc e pti o nal, t he o pi ni o n 
of t he tre ati n g p h ysicia n  s h o ul d pre vail i n s uc h cir c u msta nc es, a n d t he pr o gressi o n 
stat us s h o ul d b e c o nfir me d later b y t he re vie w pa nel ( or S p o ns or ). 
5. 5. 1. 3  
E v al u ati o n of N e w Lesi o ns  
T he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v oc al (i.e. n ot d ue t o differe nce i n 
sca n ni n g te c h ni q ue, i magi n g m o dalit y, or fi n di n gs t h o u g ht t o re pr ese nt s o met hi n g 
ot her t ha n t u m or (f or e xa m ple, s o m e ‘ ne w’ b o ne lesi o ns m a y be si m pl y heali n g or 
flare of pre-e xisti n g lesi o ns). H o we ver, a lesi o n i de ntifie d o n a f oll o w -u p sca n i n a n 
a nat o mical l ocati o n t hat was n o t sca n ne d at baseli ne is c o nsi d ere d ne w a n d will 
i n dicate P D. If a ne w lesi o n is e q ui v ocal ( bec a use of s mall siz e etc.), f oll o w-u p 
e val uati o n will clarif y if it tr ul y re prese nts ne w dise ase a n d if P D is c o nfir me d, 
pr o gressi o n s h o ul d be declar e d usi n g t he d ate of t he i nitial sca n o n w hic h t he lesi o n 
was disc o ver e d.  
5. 5. 1. 4  
E v al u ati o n of B est O ver all Res p o nse  
T he best o verall res p o nse is t he best r es p o nse rec or d e d fr o m t he start of t he tre at m e nt 
u ntil disease pr o gr essi o n/rec urre nce (t a ki n g as refer e nce f or pr o gressi v e disease t he 
s mallest meas ure me nts r ec or de d si nce t he tr eat m e nt start e d).  T he patie nt's best 
res p o nse assi g n m e nt will d e pe n d o n t he ac hie ve me nt of b ot h m eas ure m e nt a n d 
c o nfir mati o n criteria.  
T a ble 5 -2 : 
P arti ci p a nts wit h Me as ur a ble Dise ase ( T ar g et Dise ase ) 
T ar get 
Lesi o ns  
N o n -T ar get 
Lesi o ns  
Ne w 
Lesi o ns  
O ver all 
Res p o nse  
B est O ver all Res p o nse w he n 
C o nfir m ati o n is Re q uire d *  
C R  
C R  
N o  
C R  
> 4 w ks C o nfir mati o n * *  
C R  
N o n -C R/ N o n -
P D  
N o  
P R  
> 4 w ks C o nfir mati o n * *  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -C R/ N o n -
P D/ n ot 
e val uate d  
N o  
P R  
S D  
N o n -C R/ N o n -
P D/ n ot 
e val uate d  
N o  
S D  
D oc u m e nte d at least o nce > 4 
w ks fr o m baseli ne * *  
P D  
A n y  
Yes or N o  
P D  
n o pri or S D, P R or C R  
A n y  
P D * * *  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
 
See R E CI S T 1. 1 ma n uscri pt f or f urt her details o n w hat is e vi d e nce of a ne w lesi o n.  
* *        O nl y f or n o n -ra n d o miz e d trials wit h res p o nse as pri mar y e n d p oi nt. 


 
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* * *      I n e x ce pti o nal circ u mst a nces, u ne q ui v ocal pr o gressi o n i n n o n -tar get lesi o ns m a y be 
            acce pte d as disease pr o gr essi o n.  
N ote :  Partici pa nts wit h a gl o b al deteri orati o n of he alt h st at us re q uiri n g disc o nti n uati o n of 
treat me nt wit h o ut o bjecti ve e vi d e nce of dis ease pr o gressi o n at t hat ti me s h o ul d be 
re p orte d as “sy m pt o m atic det eri or ati o n. ”  E ver y eff ort s h o ul d b e ma d e t o d oc u me nt t he 
o bjecti ve pr o gressi o n e ve n after dis c o nti n u ati o n of tr eat m e nt.  
 
T a ble 5 -3 : 
P artici p a nts wit h N o n -Me as ur a ble Dise ase ( N o n -T ar get Dise ase)  
N o n -T ar get Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
N o  
C R  
N o n -C R/ n o n -P D  
N o  
N o n -C R/ n o n -P D *  
N ot all e val uate d  
N o  
n ot e val u ate d  
U ne q ui v ocal P D  
Yes or N o  
P D  
A n y  
Yes  
P D  
 
‘ N o n-C R/ n o n -P D’ is preferre d o ver ‘sta ble dis ease’ f or n o n -t ar get dis ease si nce S D is 
i ncreasi n gl y use d as a n e n d p oi nt f or assess me nt of efficac y i n s o me trials s o t o assi g n 
t his cat e g or y w he n n o lesi o ns c a n be me as ure d is n ot a d vis e d 
 
6  
S A F E T Y  
6. 1  
A d verse E ve nts a n d L a b or at or y A b n o r m alities  
6. 1. 1  
A d verse E ve nts  
A n A E  is a n y u nt o war d m e dic al occ urr e nce i n a patie nt or cli nic al trial s u bje ct a d mi nister e d a 
me dici nal pr o d uct a n d w hic h d oes n ot ne cessaril y ha ve a ca usal relati o ns hi p wit h t his treat me nt. 
A n a d verse e ve nt ca n t heref or e b e a n y u nfa v ora ble a n d u ni nt e n de d si g n  (e. g. a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or dise ase te m p oraril y ass ociat e d wit h t he use of a me dici nal 
pr o d uct, w het her or n ot c o nsi d ere d relat e d t o t he m e dici nal pr o d uct. A n a d verse e ve nt ca n arise 
fr o m a n y use of t he dr u g (e. g. off-la b el use, use i n c o m bi nati o n wit h a n ot her dr u g) a n d wit h a n y 
r o ut e of a d mi nistrati o n, f or m ulati o n, or d ose, i ncl u di n g a n o ver d ose. T his defi niti o n als o i ncl u des 
A Es ass ociate d wit h me dic ati o n err ors a n d uses of t he i n vesti gati o nal pr o d uct o utsi de w hat is i n 
t he pr ot oc ol, i ncl u di n g mis use a n d a b use. Pre -e xisti n g me dic al c o n diti o ns t hat w orse n d uri n g t he 
stu d y s h o ul d be r ec or de d as A Es. A b n or mal la b or at or y val ues, E C G fi n di n gs, or vital si g ns ar e t o 
be rec or de d as A Es if t he y meet t he criteria descri b e d i n t his pr ot oc ol. All u nt o war d e ve nts t hat 
oc c ur fr o m ti m e of first st u d y dr u g d ose t hr o u g h 3 0 da ys after t he decisi o n t o disc o nti n ue st u d y 
treat me nt ( or t he date t he s u bject is dee me d t o be a scree n fail ur e) are t o be re c or de d b y t he 
i n vesti gati o nal sit e. T his re q uire m e nt i ncl u d es A Es fr o m u nsc he d ule d as well as sc he d ule d visits  
a n d i ncl u d es t he ne w o nset of or i ncrease i n pai n d uri n g t his peri o d.  


 
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6. 1. 2  
Seri o us A d verse E ve nts  
T he S A E defi niti o n a n d re p orti n g re q uire m e nts are i n a cc or da nce wit h t he I nt er nati o nal 
C o nfer e nce of Har m o nisati o n (I C H) G ui d eli ne f or Cli nic al Safet y Data Ma na ge m e nt: Defi niti o ns 
a n d St a n dar ds f or E x pe dite d R e p orti n g, T o pic  E 2 A.  
A n S A E is d efi ne d as a n y u nt o war d m e dical occ urr e nc e t hat at a n y d ose:  
•  Res ult i n de at h;  
•  Is life-t hr eat e ni n g (i.e., i n t he o pi ni o n of t he i n vesti g at or, t he A E pla ces t he s u bject at ris k 
of d eat h; it d oes n ot i ncl u d e a n e ve nt t hat, ha d it oc c urre d i n a m or e se vere f or m, mi g ht 
ha ve ca use d d eat h) ; 
•  R e q uires i n patie nt h os pitaliz ati o n or res ults i n pr ol o n ga ti o n of a n e xisti n g h os pitaliz ati o n; 
o  N ote: 
W hile 
m ost h os pitaliz ati o ns necessit ate r e p orti n g of a n S A E, s o me 
h os pit aliz ati o ns d o n ot re q uire S A E re p orti n g, as f oll o ws: ele cti ve or pre vi o usl y 
sc he d ule d s ur geries or pr oce d ures f or pre-e xisti n g c o n diti o ns t ha t ha ve n ot 
w orse ne d after i nitiati o n of tre at m e nt (e. g., a pre vi o usl y sc he d ule d ve ntral her nia 
re pair); pre-s pe cifie d st u d y h os pitaliz ati o ns f or o bser vati o n; or e ve nts t hat res ult 
i n h os pit al sta ys of fe wer t ha n 2 4 h o urs a n d t hat d o n ot re q uire a d missi o n (e. g., a n 
E R visit f or he m at uria t hat res ults i n a dia g n osis of c ystitis a n d dis c har ge h o me o n 
oral a nti bi otics).  S A Es m ust, h o we ver, be r e p orte d f or a n y s ur gical c o m plic ati o n 
res ulti n g i n pr ol o n gati o n of t he h os pitaliz ati o n. 
•  Res ults i n persiste nt or si g ni fica nt dis a bilit y or i nca p acit y: 
o  N ote: T he ter m “ dis a bilit y” refers t o e ve nts t hat res ult i n a s u bsta ntial disr u pti o n 
of a s u bject’s a bilit y t o c o n d u ct n or mal life f u ncti o n.  
•  Is a c o n g e nit al a n o mal y or birt h defe ct; 
•  Is a n i m p orta nt me dical e ve nt (I M E):  


 
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o  N ot e: T he t er m “i m p orta nt me dical e ve nt” refers t o a n e ve nt t hat, base d u p o n 
a p pr o priat e me dic al j u d g me nt, ma y n ot be i m me diatel y life -t hreate ni n g or res ult 
i n de at h or h os pitaliz ati o n, b ut ma y je o par diz e t he s u bject or re q uir e i nter ve nti o n 
t o pre ve nt o ne of t he ot her seri o us o ut c o mes liste d. E xa m ples of I M Es i ncl u d e 
i nte nsi ve tr eat me nt i n a n e mer g e nc y r o o m or at h o me f or aller gic br o nc h os pas m; 
bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot r es ult i n h os pit aliz ati o n; or 
de vel o p m e nt of pr o d uct de pe n de nc y or pr o d u ct a b use.  
6. 1. 3  
Rel ati o ns hi p t o St u d y Tre at m e nt  
Assess me nt of t he relati o ns hi p of t he A E t o t he st u d y tre at m e nt b y t he i n vesti g at or is base d o n 
t he f oll o wi n g t w o d efi niti o ns: 
•  N ot Relat e d: A n ot -relat e d A E is defi ne d as a n A E t hat is n ot ass ociat e d wit h t he st u d y 
treat me nt a n d is attri b uta ble t o a n ot her c a use or t her e is n o e vi d e nce t o s u p p ort a ca usal 
relati o ns hi p; 
•  Relat e d: A r elate d A E is defi ne d as a n A E w here a c a usal relati o ns hi p bet wee n t he e ve nt 
a n d t he st u d y tr eat me nt is a reas o na ble p ossi bilit y. A reas o na ble c a usal relati o ns hi p is 
mea nt t o c o n ve y t hat t here are fa cts (e. g., e vi de nce s uc h as dec halle n g e/re c halle n ge) or 
ot her cli nic al ar g u m e nts t o s u g gest a ca usal relati o ns hi p b et wee n t he A E a n d st u d y 
treat me nt. P ossi bl y a n d pr o b a bl y relate d A Es s h o ul d be d oc u me nte d as relate d.  


 
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6. 1. 4  
Seri o us A d verse E ve nt Re p orti n g  
As s o o n as a n i n vesti gat or be c o mes a ware of a n A E t hat meets t he defi niti o n of ‘seri o us,’ t his 
m ust be d oc u me nt e d o n a n S A E Re p ort F or m or i n a n ele ctr o nic data base a n d i ncl u de t he 
f oll o wi n g: (i) all S A Es t hat occ ur after st arti n g c a b oz a nti ni b a n d t hr o u g h 3 0 da ys after t he 
decisi o n t o disc o nti n ue st u d y treat me nt a n d (ii) a n y S A Es assesse d as relat e d t o st u d y tr eat me nt 
or st u d y pr oc e d ures, fr o m t he ti me of  first st u d y dr u g d ose, e ve n if t he S A E occ urs m or e t ha n 3 0 
da ys after t he decisi o n t o disc o nti n ue st u d y tr eat me nt.  
All S A Es t hat are assesse d b y t he PI as 
rel ate d  t o dr u g or st u d y pr oce d ure a n d all 
pre g na nc y/lactati o n re p orts re g ar dless of o ut c o me m ust be se nt t o E x eli xis wit hi n o ne ( 1 ) 
b usi ness 
da y 
of t h e 
PI’s 
k n o wle d ge 
of t he e ve nt. 
T he r e p orts 
m ust 
be se nt t o 
dr u gsafet y @e xeli xis.c o m or fa x 6 5 0 -8 3 7 -7 3 9 2.  
•  T he PI 
will p erf or m a de q u ate d ue dili g e nce 
wit h re gar d t o o bt ai ni n g f oll o w -u p 
i nf or mati o n o n i nc o m plet e re p orts. All f oll o w-u p i nf or m ati o n m ust b e se nt t o E xeli xis 
wit hi n o ne ( 1 ) b usi ness da y of t he PI’s rec ei pt of t he ne w i nf or m ati o n. U p o n E xeli xis 
re q uest, t he PI will q uer y f or f oll o w-u p i nf or mati o n.  
6. 1. 5  
Re g ul at or y Re p orti n g  
T he I n vesti gat or will assess t he e x pe cte d ness of e ac h relat e d S A E. T he c urr e nt ca b oz a nti ni b 
Refere nc e Safet y I nf or mati o n ( A p pe n di x K of t he m ost re ce nt a p pr o ve d I n vesti g at or Br oc h ure) 
will b e use d as t he refere nc e d oc u me nt f or assessi n g t he e x pecte d ness of t he e ve nt wit h re g ar d t o 
ca b oz a nti ni b . All seri o us u ne x pe cte d a d verse dr u g reacti o ns ( u ne x p ect e d relate d S A Es) m ust be 
re p orte d t o all a p pr o priate re g ulat or y a ut h orities a n d Et hics C o m mitt ees b y t he i n vesti gat or as 
re q uire d b y 2 1 C F R 3 1 2. 3 2 or b y Directi ve 2 0 1 1/ 2 0/ E C:  
•  T hese re p orts are t o be file d utilizi n g t he F or m F D A 3 5 0 0 A ( Me d Wat c h F or m)  or a 
CI O M S -1 f or m;  
•  E xeli xis reser ves t he ri g ht t o u p gra de t he I n vesti gat or assess me nt of a n S A E base d o n 
E xeli xis assess me nt.  
•  I nstit uti o ns a n d PIs s hall pr o m ptl y pr o vi de all i nf or mati o n re q u este d b y E xeli xis 
re gar di n g all a d verse e ve nts oc c urri n g d uri n g t he co n d uct of t he st u d y.  
•  T he PI is r es p o nsi ble f or c o m pl yi n g wit h all re g ulat or y a ut h orit y re p orti n g re q uire m e nts 
f or t he st u d y t hat are a p plic a ble t o t he s p o ns or of a cli nic al trial. T he PI s hall pr o vi de a 


 
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c o p y of all r es p o nses t o re g ulat or y a ge nc y re q u ests,  peri o dic re p orts, a n d fi nal st u d y 
re p orts t o E xeli xis wit hi n o ne ( 1) b usi ness da y of t he s u b missi o n.   
•  E xeli xis will pr o vi d e rele va nt pr o d u ct safet y u p dat es a n d n otificati o ns, as necessar y. I n 
t he c ase of m ulti-c e nter st u dies, it is t he r es p o nsi bilit y of t he s p o ns ori n g PI/I nstit uti o n t o 
disse mi nat e t hese u p d ates t o p artici pati n g PIs.  
6. 2  
Ot he r S afet y C o nsi der ati o ns  
6. 2. 1  
L a b or at or y D at a  
All la b or at or y d ata re q uir e d b y t his pr ot oc ol a n d a n y ot her cli nic al i n vesti g ati o ns s h o ul d be 
re vie we d. A n y a b n or mal val ue t hat leads t o a c ha n g e i n s u bje ct ma na ge m e nt (e g,  d ose re d ucti o n 
or dela y or re q uire m e nt f or a d diti o nal m e dic ati o n or m o nit ori n g) or t hat is of cli nical si g nifica nc e 
b y t he i n vesti gat or s h o ul d b e re p orte d as a n A E or S A E as a p pr o priat e.  
6. 2. 2  
Pre g n a nc y / L act ati o n E x p os ure  
If a s u bje ct bec o mes pre g na nt d uri n g t he st u d y, s he will be t a ke n off st u d y tr eat me nt a n d will be 
f oll o w e d t hr o u g h t he e n d of her pre g na nc y. Pre g na nc y (i n s u bject or part ner)  or lactati o n 
e x p os ure, alt h o u g h n ot a n S A E, s h o ul d be r e p orte d t o E x eli xis. F or ms will be pr o vi de d t o t he 
st u d y sites u p o n re q uest. T he o utc o me of a pre g na nc y (f or a s u bject or f or t he part ner of a 
s u bje ct) a n d t he m e dic al c o n diti o n of a n y res ult a nt offs pri n g m ust be re p ort e d t o E xeli xis. A n y 
birt h defect or c o n g e nit al a n o mal y m ust b e re p ort e d as a n  S A E , a n d a n y ot her u nt o war d e ve nts 
oc c urri n g d uri n g t he pre g na nc y m ust be r e p orte d as A Es or S A Es, as a p pr o priat e.  
6. 2. 3  
Me dic ati o n Er r ors/ O v er d ose  
A n y o ver d ose , or st u d y dr u g a d mi nistrati o n err or t hat res ults i n a n A E, e ve n if it d oes n ot meet 
t he defi niti o n of seri o us, re q uires re p orti n g wit hi n o ne ( 1) b usi ness da y  t o E xeli xis. 
6. 2. 4  
F oll o w -U p of A d verse E ve nts  
A n y relat e d S A Es or a n y A Es assesse d as r elate d t hat le d t o treat me nt disc o nti n uati o n, i ncl u di n g 
cli nicall y si g nific a nt a b n or m al la b or at or y v al ues t hat meet t hese criteria, o n g oi n g 3 0  da ys after 
t he decisi o n t o disc o nti n ue st u d y tr eat me nt m ust be f oll o w e d u ntil eit her res ol uti o n of t he e ve nt 
or deter mi nati o n b y t he i n vesti g at or t hat t he e ve nt has bec o me sta ble or irr e versi ble. T his f oll o w-
u p g ui d a nce als o a p p lies t o relat e d S A Es t hat oc c ur m or e t ha n 3 0 d a ys after t he de cisi o n t o 
disc o nti n ue st u d y tre at m e nt. T he stat us of all ot her c o nti n ui n g A Es will be d oc u m e nte d as of 3 0 
da ys after t he decisi o n t o disc o nti n ue  st u d y tr eat me nt. 


 
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7  
S T A TI S TI C A L C O N SI D E R A TI O N S  
7. 1  
A n al ysis P o p ul ati o n  
7. 1. 1  
S afet y P o p ul ati o n  
T he safet y p o p ulati o n will c o nsist of all s u bjects w h o re cei ve a n y a m o u nt of st u d y tre at m e nt.  
7. 2  
S afet y A n al ysis  
Safet y will b e assesse d b y e val uati o n of A Es . All safet y a nal yses will be perf or me d usi n g t he 
safet y p o p ulati o n.  
7. 2. 1  
A d verse E ve nts  
A d verse e ve nt ter ms rec or d e d o n t he C R Fs will be ma p pe d t o preferr e d ter ms usi n g t he Me dic al 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). Seri o us ness, se verit y  gra d e a n d re lati o ns hi p t o 
st u d y tr eat me nt will be assesse d b y t he in vesti g at or. Se verit y  gra d e will be d efi ne d b y t he 
Nati o nal C a ncer I nstit ut e ( N CI) C T C A E v 4 . 0. Listi n gs of A Es will be pr o vi de d.  
7. 3  
S a m ple Size  
T he  sta g e I sa m ple siz e will c o nsist of 1 6  s u bjects f or i nteri m a nal ysis, t he n a n a d diti o nal 2 8 
s u bje cts f or sta ge II f or a t otal of 4 4 s u bjects. 
7. 3. 1  
S a m ple Size J ustific ati o n  
Base d o n t he p hase III C O R R E C T trial i n vesti gati n g re g orafe ni b vers us best 
s u p p orti ve care, t he me dia n P F S f or patie nts wit h refract or y c ol or ect al ca nc er was 1. 7 
m o nt hs i n t he place b o ar m. T heref ore, t he P F S at 1 2  wee ks w o ul d be a p pr o xi matel y 
1 3 %, w hic h  will ser ve as t he  res p o nse rate i n t he n ull h y p ot hesis. We ha ve desi g ne d 
t he trial t o ha ve at least 90 % p o wer t o dete ct a n i m pr o ve me nt i n t he 1 2 -wee k P F S rat e 
of at least 2 0 %, t her ef ore t he alter nati ve h y p ot hesis is  t hat t he 1 2-wee k P F S rat e is 
3 3 %.  T he o pt i mal desi g n pr o vi di n g at least 90 % p o wer t o detect t he alter nati ve w hile 
c o ntr olli n g t he t y pe I err or rat e at 0. 0 5 uses at m ost 4 4  p atie nts. T his desi g n has a n 
act ual t y pe I err or r ate of 0. 0 4 4 1 (i. e. if t he tr ue 1 2 -w ee k P F S rate is less t ha n or e q u al 
t o 0. 1 3, t here is o nl y a 4. 4 % pr o ba bilit y of c o ncl u di n g t hat t he P F S rate is gr eat er t ha n 
or e q ual t o 0. 3 3).   T his desi g n has p o wer of 0. 9 0 6  t o detect t he alter nati ve 
h y p ot hesiz e d 1 2 -wee k P F S rate of 0. 3 3.  T his trial desi g n uses a n a ver a ge of 2 5. 7 
patie nts.  


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
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Pa ge 8 2  of 9 6  
8  
O T H E R A N A L Y S E S  
8. 1  
A n al ytic Pl a n Pri m ar y, Sec o n d ar y, a n d E x pl or at o r y E n d p oi nts  
8. 1. 1  
Pri m ar y E n d p oi nt : 
Pr o gressi o n -free s ur vi val will b e defi ne d as t he ti me fr o m a d mi nistrati o n of t he i nitial 
d ose of ca b oz a nti ni b t o e vi d e nce of ra di o gra p hic pr o gressi o n as defi ne d b y R E CI S T 
criteria or deat h fr o m a n y c a use wit h o ut e vi de nc e of dise ase pr o gr essi o n, w hic he ver 
oc c urs first. E ac h patie nt will be e xa mi ne d f or P F S at 1 2 wee ks a n d dic h ot o miz e d as 
eit her ha vi n g pr o gressi o n or n ot.  Usi n g a n o pti mal Si m o n 2 -sta ge desi g n, t he first 1 6 
patie nts will be e nr olle d a n d 1 2 -wee k P F S will be d eter mi ne d.  If 3  or m or e  of t hese 
patie nts ha ve n ot pr o gresse d b y 1 2 wee ks, t he tri al will a ccr ue a n a d diti o nal 2 8 
patie nts f or a t otal of 4 4 patie nts.  If 1 0 or m ore (t ot al) of t hese 4 4 patie nts are fre e of 
pr o gressi o n at 1 2 wee ks t he n t he N ull H y p ot hesis will b e reje cte d i n fa v or of t he 
alter nati ve s u g gesti n g t hat t he tre at m e nt has s uf ficie nt effica c y t o warra nt f ut ur e 
st u d y. 
Ka pla n -Meier esti ma tes 
of 
P F S rates 
will be calc ulate d al o n g 
wit h t heir 
c orr es p o n di n g 9 5 % c o nfi d e nce i nter vals.  
E v al u a ble f o r Res p o nse  
O nl y t h ose partici pa nts w h o ha ve re cei ve d at le ast 2 c ycles  of t hera p y, a n d ha ve ha d t heir dise ase 
re-e val u ate d will b e c o nsi dere d e val ua ble f or res p o nse. N ote: Partici p a nts w h o e x hi bit o bje cti ve 
dise ase pr o gressi o n or die pri or t o C ycle 3  will als o be c o nsi der e d e val ua ble. Partici pa nts w h o d o 
n ot m eet t he crit eri a f or bei n g e val ua ble f or res p o nse defi ne d a b o ve ma y be re plac e d t o reac h t he 
sa m ple siz e nec essar y f or i nteri m a nal ysis.  
8. 1. 2  
S ec o n d a r y E n d p oi nts : 
8. 1. 2. 1  
Res p o nse R ate ( R R)  
Res p o nse rate is defi ne d usi n g t he R E CI S T v 1. 1 crit eria as t he pr o p orti o n of s u bjects 
wit h a c o nfir m e d C R or c o nfir m e d P R. T he p oi nt esti mate of t he R R wit h a 9 5 % 
c o nfi de nc e i nt er val base d o n t he e x act bi n o mial distri b uti o n will be e val uate d.  
8. 1. 2. 2  
O ver all S ur vi v al ( O S)  
O verall s ur vi val will be defi ne d as t he ti m e fr o m a d mi nistrati o n of t he i nitial d ose  of  
ca b oz a nti ni b u ntil d eat h fr o m a n y ca use.  P F S is defi ne d a b o ve. Ka pla n -Meier 
esti mates of o verall s ur vi val a n d pr o gressi o n -free s ur vi val r ates will be calc ulate d 
al o n g wit h t heir c orr es p o n di n g 9 5 % c o nfi de nce i nter val.  


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 3  of 9 6  
8. 1. 2. 3  
T oler a bilit y a n d S afet y  
F or t he saf et y a nal ysis, all e nr olle d patie nts w h o r ecei ve at le ast o ne d ose of 
ca b oz a nti ni b will ha ve i nf or mati o n c ollecte d o n a d verse e ve nts, w hic h will be 
s u m mariz e d b y d ose a n d se verit y as assesse d b y t he C o m m o n T o xicit y Criteria f or 
A d verse E ve nts ( C T C A E), v. 4. 0  a n d relati o ns hi p t o ca b oz a nti ni b.  
8. 1. 2. 4  
P F S a n d R R B ase d o n M olec ul ar St at us  
A nal ysis of  t he PF S a n d R R i n patie nts base d o n R A S, B R A F, a n d PI K 3 C A m utati o n 
stat us will be d o ne wit h p oi nt esti mat es of  9 5 % c o nfi d e nce i nter vals  pr o vi de d f or 
eac h gr o u p, a n d c o m p aris o ns will be ma d e usi n g a stratifie d l o g-ra n k t est.  Ot her 
bi o mar kers m a y b e e val uat e d base d o n o n g oi n g pre cli nic al e x peri me nts as well as t he 
scie ntific liter at ure. 
8. 1. 3  
E x pl or at or y E n d p oi nt  
8. 1. 3. 1  
Bi o m ar ker A n al ysis  
E x pl orat or y a nal ysis of pre dicti ve a n d p har ma c o d y n a mic bi o mar kers 
will b e 
perf or me d b y c ollecti n g pre - a n d p ost-treat me nt p eri p heral bl o o d c ollecti o n d uri n g 
pretreat me nt pe ri o d a n d a gai n o n C ycle 3 Da y 1 +/ - 5  da ys . Sa m ples will be arc hi ve d 
f or f ut ur e i n vesti gati o n. See A p pe n di x C f or list of bi o m ar kers. 
8. 2  
Bi o m ar ker, C orrel ati ve, a n d S peci al St u dies  
8. 2. 1  
L a b or at or y C orrel ati ve St u di es  
W h ole bl o o d  sa m ples will be o btai ne d at C ycle 1 D a y 1 ( -7 d a y wi n d o w) a n d o n C ycle 3 Da y 1  
( +/- 5  da ys)  fr o m c o nse nti n g patie nts, w hic h will t he n be s hi p pe d a n d st or e d i n a re p osit or y f or 
f ut ur e a nal ysis at T he U ni versit y of Ariz o na. Pe n di n g f u n di n g a vaila bilit y, ar c hi val t u m or 
s peci me ns will b e ge n ot y p e d at T he U ni versit y of Ariz o na Ge netics C or e, a C LI A -certifie d 
cli nical la b orat or y. Ot her bi o mar kers m a y be e val uat e d base d o n o n g oi n g pre cli nical e x peri me nts 
as well as t he scie ntific liter at ure.  
8. 2. 2  
Arc hi v al T u m or Tiss ue  
Pe n di n g f u n di n g a vaila bilit y, M E T c o p y n u m ber a nal ysis a n d e x pr essi o n will b e assesse d b y 
fl u or esce nt i n sit u h y bri diz ati o n ( FI S H) a n d i m m u n o hist oc he mistr y (I H C), t o e x pl or e ass ociati o n 
wit h li keli h o o d of res p o nse a n d/ or P F S at 1 2 wee ks i n p atie nts wit h metastatic refr act or y 
c ol orectal ca nc er tr eat e d wit h ca b oz a nti ni b.  Ot her bi o mar kers ma y be e val u ate d base d o n 
o n g oi n g pr ecli nic al e x peri me nts as we ll as t he scie ntific liter at ure. 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 4  of 9 6  
8. 2. 3  
W h ole Bl o o d  
P ote ntial ca n di dat e mar kers f or f ut ure st u d y i ncl u de s ol u ble me m b ers of t he M E T/ H G F a n d 
V E G F  pat h wa ys ( Please se e A p p e n di x C ). 
9  
D A T A S A F E T Y M O NI T O RI N G  
T he s p o ns or i n vesti gat or will be res p o nsi ble f or m o nit ori n g t he trial per t he trial m o nit ori n g pla n, 
i n a d diti o n t o o verseei n g t he safet y a n d effica c y of t he trial i ncl u di n g a n y s pe ci m e ns c ollecte d, 
e xec uti n g t he data a n d safet y 
m o nit ori n g ( D S M) pla n, a n d c o m pl yi n g wit h all re p orti n g 
re q uire m e nts t o l ocal a n d fe d eral a ut h orities. T his o versi g ht will b e ac c o m plis he d t hr o u g h 
a d diti o nal o versi g ht fr o m t he Data a n d Safet y M o nit ori n g C o m mitt ee ( D S M C) at t he U ni versit y 
of C ol ora d o Ca nc er Ce nter ( C U Ca nc er Ce nter).   T he D S M C is res p o nsi ble f or e ns uri n g dat a 
q ualit y a n d st u d y p artici pa nt safet y f or all cli nic al st u dies at t he C U Ca ncer Ce nter, w hic h is t he 
c o or di nati n g i nstit uti o n of t his trial.    A s u m mar y of t h e D S M C’s acti vities is as f oll o ws:  
• C o n d uct of i nter nal a u dits 
• O n g oi n g re vie w of all seri o us a d verse e ve nts ( S A Es), u na ntici pate d pr o ble ms ( U A Ps) a n d 
re p orta ble a d verse e ve nts ( A Es) 
• Has t he a ut h orit y t o cl ose a n d/ or s us pe n d trials f or safet y or trial c o n d u ct iss ues  
• Ma y s u b mit rec o m m e n dati o ns f or c orrecti ve acti o ns t o t he C U Ca ncer Ce nter’s E xec uti ve 
C o m mittee  
Per t he C U Ca nc er Ce nter I nstit uti o nal D S M Pla n, S A Es, U A Ps a n d re p orta ble A Es are re p orte d 
t o t he D S M C, I R B a n d t he s p o ns or i n vesti gat or per pr ot oc ol.  All S A Es, U A Ps a n d r e p orta ble 
A Es are t o be r e p orte d t o t he D S M C wit hi n 5 b usi ness da ys of t he s p o ns or i n vesti gat or re cei vi n g 
n otific ati o n of t he oc c urre nce.  
Eac h s u bject’s treat me nt o utc o mes will be disc usse d b y t he site PI a n d a p pr o priat e staff  at 
re g ularl y s c he d ule d me eti n gs.  Data r e gar di n g n u m ber of s u bjects, si g nifica nt t o xicities, d ose 
m o dific ati o ns, a n d tre at me nt res p o nses will be disc usse d a n d d oc u me nte d i n t he meeti n g’s 
mi n utes.  
T he s p o ns or i n vesti g at or is r es p o nsi ble f or or g a nizi n g a n d c o n d ucti n g re g ularl y s c he d ule d 
tele c o nfere nc es wit h all p artici pati n g sites.  T he s p o ns or i n vesti g at or will als o be res p o nsi ble f or 
i ncl u di n g data fr o m all of t he partici p ati n g sit es t o i ncl u de t he mi n utes fr o m t hese re g ularl y 
sc he d ule d tele c o nfere nces betwee n t he s p o ns or i n vesti gat or a n d t he sit es wit hi n t he o verall trial’s 
si x m o nt h D S M re p ort. 


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
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Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 5  of 9 6  
T he s p o ns or i n vesti gat or will pr o vi de a D S M re p ort t o t he C U Ca ncer Ce nter D S M C o n a si x 
m o nt h basis. T he D S M re p ort will i ncl u de a pr ot oc ol s u m mar y; c urr e nt e nr ol l me nt n u m bers; 
s u m mar y of t o xicit y d ata t o i ncl u d e s pecific S A Es, U A Ps a n d A Es; a n y d ose m o dific ati o ns; all 
pr ot oc ol de viati o ns; a n d pr ot oc ol a me n d m e nts. T he D S M re p ort s u b mitte d t o t he D S M C will 
als o i ncl u d e, if a p plica ble, t he res ults of a n y effi cac y dat a a nal ysis c o n d u cte d.   Res ults a n d 
rec o m m e n dati o ns fr o m t he r e vie w of t his si x m o nt h re p ort b y t he D S M C will t he n be pr o vi d e d t o 
t he s p o ns or i n vesti gat or i n a D S M C re vie w letter.  T he s p o ns or i n vesti gat or is t he n res p o nsi ble 
f or e ns uri n g t his letter is s u bmitte d t o t he sit e’s I R B of rec or d at t he ti m e of I R B c o nti n ui n g 
re vie w. 
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  
Sit e m o nit ori n g visits will b e perf or me d b y t he s p o ns or i n vesti g at or’s a ut h oriz e d re prese ntati ve 
o n a re g ular basis, p urs ua nt t o t he M o nit ori n g P la n. D uri n g t hese visits, i nf or mati o n re c or de d o n 
t he C R Fs will be verifie d a gai nst s o urc e d oc u me nts.  A d diti o nal c o m p uter pr o gra ms t hat i de ntif y 
select e d pr ot oc ol de viati o ns, o ut-of -ra n ge d ata, a n d ot her data err ors wit hi n t he electr o nic d ata 
e ntr y ma y als o be use d t o hel p m o nit or t he st u d y.  As necessar y, re q uests f or dat a clarific ati o n or 
c orr ecti o n will b e se nt t o t he a p pr o priate site PI.  
I n de p e n de nt a u dit ors fr o m t he s p o ns or i n vesti gat or’s a ut h oriz e d re pr ese ntati ve will be all o we d 
b y t he site’s PI t o a u dit.   I n a d diti o n, a u dits m a y be c o n d u cte d at a n y ti me b y a p pr o priate 
re g ulat or y a ut h orities a n d/ or t he I R B. 
1 0  
D A T A Q U A LI T Y A S S U R A N C E  
Acc ur ate a n d relia ble d ata c ollecti o n will b e e ns ure d b y verific ati o n a n d cr ossc hec k of t he C R Fs 
a gai nst t he i n vesti gat or’s  rec or ds b y t he st u d y m o nit or (s o urce d oc u me nt verificati o n) a n d b y t he 
mai nt e na nc e of a dr u g – dis pe nsi n g l o g b y t he i n vesti gat or . 
1 1  
M U L TI C E N T E R G UI D E LI N E S A N D S T U D Y C O M MI T T E E S  
T his pr ot oc ol will a d here t o t he p olicies a n d re q uire me nts of t he A GI C C M ulti -Ce nt er Data a n d 
Safet y M o nit ori n g Pla n.  T he s pecific res p o nsi bilities of t he S p o ns or , C o or di nati n g Ce nt er, a n d 
Partici p ati n g I nstit uti o ns are liste d bel o w.  
•  T he S p o ns or / C o or di nati n g C e nter is res p o nsi ble f or distri b uti n g all I N D Acti o n Letters or 
Safet y Re p orts t o all p artici pati n g i nstit uti o ns f or s u b missi o n t o t heir i n di vi d ual I R Bs f or 
acti o n as re q uire d.  
•  Mec ha nis ms will b e i n place t o e ns ure q ualit y ass ura nce, pr ot oc ol c o m plia n c e, a n d 
a d verse e ve nt re p orti n g at e ac h sit e.  


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
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Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 6  of 9 6  
•  E xce pt i n ver y u n us ual circ u msta nces, ea c h partici p ati n g i nstit uti o n will or der t he st u d y 
a ge nt(s) directl y fr o m s u p plier.  A partici pati n g site ma y or d er t he a g e nt(s) o nl y aft er t he 
i nitial I R B a p pr o val f or t he site has bee n f or war de d t o t he C o or di nati n g Ce nter.  
1 2  
E T HI C A L A S P E C T S  
1 2. 1  
L oc al Re g ul ati o ns  
T he st u d y m ust f ull y a d here t o t he pri nci ples o utli ne d i n “ G ui deli ne f or G o o d Cli nic al Practice ” 
( G C P) I C H E 6 Tri partite G ui d eli ne (Ja n u ar y 1 9 9 7). T he i n vesti gat or will  e ns ure t hat t he c o n d uct 
of t he st u d y c o m plies wit h t he basic pri nci ples of G C P as o utli ne d i n t he c urre nt versi o n of 
2 1  C o de of Fe deral 
Re g ulati o ns, s u b part  D, Part  3 1 2, “ Res p o nsi bilities of S p o ns ors a n d 
I n vesti gat ors” Part 5 0, “ Pr otecti o n of H u ma n S u bjec ts” a n d Part 5 6, “I nstit uti o nal Re vie w 
B oar ds.”  
1 2. 2  
I nf or m e d C o nse nt 
It is t he r es p o nsi bilit y of t he i n vesti g at or, or a pers o n desi g nate d b y t he i n vesti g at or, t o o btai n 
writte n i nf or me d c o nse nt fr o m eac h s u bject partici p ati n g i n t his st u d y after a de q uate e x pla nati o n 
of t he ai ms, met h o ds, a ntici p ate d b e nefits, a n d p ote ntial haz ar ds of t he st u d y. I n t he c ase w here 
t he s u bject is u na ble t o rea d, a n i m p artial wit ness s h o ul d b e prese nt d uri n g t he e ntire i nf or me d 
c o nse nt disc ussi o n. After t he s u bject has orall y c o nse nte d t o p artici pati o n i n t he trial, t he 
wit ness’ s si g nat ure o n t he f or m will att est t hat t he i nf or mati o n i n t he c o nse nt f or m was 
acc uratel y e x plai ne d a n d u n derst o o d.  
T he C R F f or t his st u d y c o ntai ns a secti o n f or d oc u me nti n g i nf or m e d s u bje ct c o nse nt, a n d t h is 
m ust be c o m plete d a p pr o priatel y. If ne w safet y i nf or mati o n r es ults i n si g nific a nt c ha n ges i n t he 
ris k/ b e nefit assess me nt, t he c o nse nt f or m s h o ul d be re vie we d a n d u p date d as necessar y. All 
s u bje cts (i ncl u di n g t h ose alr ea d y b ei n g treate d) s h o ul d be i nf or m e d of t he ne w i nf or mati o n, 
s h o ul d be gi ve n a c o p y of t he re vise d f or m, a n d s h o ul d gi ve t heir c o nse nt t o c o nti n ue i n t he 
st u d y. 
1 2. 3  
I nstit uti o n al Re vie w B o ar d/Et hics C o m mittee  
T his st u d y is bei n g c o n d ucte d u n der a U nite d Stat es I n vesti g ati o nal Ne w Dr u g a p plica ti o n or 
ot her Cli nic al Trial A p plicati o n, as a p pr o priat e . T his pr ot oc ol ( a n d a n y m o dific ati o ns) a n d 
a p pr o priat e c o nse nt pr oce d ur es m ust b e re vie we d a n d a p pr o ve d b y a n I R B/ E C. T his b oar d m ust 
o per ate i n acc or da nce wit h c urr e nt l oc al, re gi o nal, a n d fe der al r e g ulati o ns. T he i n vesti g at or will 
se n d a letter or c ertificate of I R B/ E C a p pr o val t o E x eli xis ( or desi g ne e) bef ore s u bject e nr oll me nt 
a n d w he ne ver s u bse q ue nt m o dific ati o ns t o t he pr ot oc ol are ma de.  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
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Pa ge 8 7  of 9 6  
1 2. 4  
F ut ure Use of P atie nt S a m ples  
N o sa m ples f or a n yt hi n g ot he r t ha n safet y t esti n g will b e c ollecte d d uri n g t his st u d y.  
1 3  
C O N DI TI O N S F O R M O DI F Y I N G T H E P R O T O C O L 
Pr ot oc ol 
m o dificati o ns 
ma y b e 
ma d e a n d will be pre pare d, r e vie we d, a n d a p pr o ve d b y 
re prese ntati ves of t he i n vesti g at or. Pr ot oc ol m o dific ati o ns or a m e n d me nts m ust be re vie we d a n d 
a p pr o ve d b y E xeli xis pri or t o i m ple m e ntati o n.  
All pr ot oc ol m o dific ati o ns m ust be s u b mitt e d t o t he I R B/ E C f or i nf or mati o n a n d a p pr o val i n 
acc or da nce wit h l oc al re q uir e me nts a n d t o re g ulat or y a ge ncies if re q uir e d. A p pr o val m ust be 
o bt ai ne d bef ore a n y c ha n g es ca n be i m ple me nt e d, e xce pt f or c ha n ges ne cessar y t o eli mi nat e a n 
i m me diat e haz ar d t o st u d y s u bjects or t h ose t hat i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects 
of t he trial (e g,  c ha n ge i n m o nit or or c ha n ge of tele p h o ne n u m ber).  
1 4  
C O N DI TI O N S F O R T E R MI N A T I N G T H E S T U D Y 
E xeli xis reser ves t he ri g ht t o ter mi nat e t he st u d y, a n d i n vesti gat ors reser ve t he ri g ht t o ter mi nate 
t heir partici pati o n i n t he st u d y, at a n y ti m e. S h o ul d t his be necessar y, E x eli xis a n d t he 
i n vesti gat or 
will arr a n ge t he pr oc e d ures o n a n i n di vi d ual st u d y basis after re vie w a n d 
c o ns ultati o n. I n ter mi nati n g t he st u d y, E xeli xis a n d t he i n vesti gat or will e ns ure t hat a de q u ate 
c o nsi d erati o n is gi ve n t o t he pr otecti o n of t he s u bjects’ i nt erests.  
1 5  
S T U D Y D O C U M E N T A TI O N A N D R E C O R D K E E PI N G  
1 5. 1  
I n vesti g at or’s Files a n d Rete nti o n of D oc u m e nts  
T he i n vesti g at or m ust m ai nt ai n a de q u ate a n d a cc urate rec or ds t o e na ble t he c o n d u ct of t he st u d y 
t o be f ull y d oc u m e nte d a n d t he st u d y d ata t o b e s u bse q ue ntl y verifie d. T hese d oc u me nts s h o ul d 
be c lassifie d i nt o t w o se p arat e cate g ories as f oll o ws: ( 1) t he i n vesti g at or’s st u d y file, a n d 
( 2) s u bje cts’ cli nic al s o urce d oc u me nts.  
T he i n vesti gat or’s st u d y file will c o nt ai n t he pr ot oc ol a n d pr ot oc ol a m e n d me nts, C R Fs, q uer y 
f or ms, I R B/ E C a n d g o ver n me nt al a p pr o vals wit h c orr es p o n d e nce, sa m ple i nf or m e d c o nse nt, 
dr u g rec or ds, staff c urric ul u m vitae a n d a ut h oriz ati o n f or ms, a n d ot her a p pr o priate d oc u m e nts 
a n d c orres p o n de nce.  
S u bje cts’ cli nic al s o ur ce d oc u me nts i ncl u de t he s u bjects’ h os pit al/cli nic r ec or ds; p h ysicia ns’ a n d 
n urses ’ n ot es; t he a p p oi nt me nt b o o k; ori gi nal la b orat or y, E C G, electr oe nce p hal o gra m, X -ra y, 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 8  of 9 6  
pat h ol o g y a n d s pecial assess me nt r e p orts; si g ne d i nf or m e d c o nse nt f or ms; c o ns ult a nt letters; a n d 
s u bje ct scre e ni n g a n d e nr oll m e nt l o gs.  
T he i n vesti g at or m ust kee p t hese t w o c ate g ories of d oc u m e nts o n file f or at le ast t he latest of 
2  ye ars f oll o wi n g t he 
m ar keti n g a p plicati o n a p pr o val dat e f or t he st u d y tr eat me nt i n t he 
i n dicati o n b ei n g i n vesti g ate d, 2  years after t he i n vesti gati o n is  c o m plete d or disc o nti n ue d , or f or 
a ti m e c o nsiste nt wit h l ocal re g ulat or y re q uir e me nts . After t hat peri o d, t he d oc u m e nts ma y be 
destr o ye d s u bject t o l oc al re g ulati o ns wit h pri or writte n p er missi o n fr o m E x eli xis. If t he 
i n vesti gat or wa nts t o assi g n t he st u d y r ec 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, 
E xeli xis m ust be n otifie d i n a d va nce.  
If t he i n vesti gat or ca n n ot g uara nt ee t he arc hi vi n g re q uir e me nt at t he st u d y sit e f or a n y or all t he 
d oc u me nts, s pecial arr a n ge m e nts m ust be m a de bet wee n t he i n vest i gat or a n d E xeli xis t o st ore 
t hese i n a seale d c o ntai ner o utsi de of t he st u d y sit e s o t hat t he y ca n be r et ur ne d seale d t o t he 
i n vesti gat or i n c ase of a r e g ulat or y a u dit. W he n s o ur ce d oc u me nts are re q uir e d f or t he c o nti n ue d 
care of t he s u bject, a p pr o priate c o pies s h o ul d be m a d e f or st ori n g o utsi de of t he st u d y sit e.  
1 5. 2  
S o urce D oc u m e nts a n d B ac k gr o u n d D at a  
U p o n re q uest, t he i n vest i g at or will s u p pl y its lic e nsees a n d c olla b orat ors wit h a n y re q uire d 
bac k gr o u n d data fr o m t he st u d y d oc u me ntati o n or cli nic rec or ds. T his is partic ularl y i m p ort a nt 
w he n C R Fs are ille gi ble or w he n err ors i n dat a tra nscri pti o n are s us pect e d. I n case of s pe cial 
pr o ble ms or g o ver n me ntal q u eries or re q uests f or a u dit i ns pecti o ns, it is als o necessar y t o ha ve 
access t o t he c o m plete st u d y r ec or ds, pr o vi de d t hat s u bject c o nfi de ntialit y is pr otect e d.  
1 5. 3  
A u dits a n d I ns pecti o ns  
T he i n vesti g at or s h o ul d u n d ersta n d t hat s o urc e d oc u me nts f or t his st u d y s h o ul d be ma d e 
a vaila ble, after a p pr o priat e n otificati o n, t o q ualifie d pers o n nel fr o m t he E x eli xis Q ualit y 
Ass ura nce U nit ( or desi g ne e) or t o healt h a ut h orit y i ns pe ct ors. T he verificati o n of t he C R F dat a 
m ust be b y dire ct i ns pe cti o n of s o urce d oc u me nts.  
1 5. 4  
C ase Re p ort F or ms  
F or e nr olle d s u bjects, all a n d o nl y data fr o m t he pr oc e d ures a n d assess me nts s pecifie d in t his 
pr ot oc ol a n d re q uire d b y t he C R Fs s h o ul d be e ntere d o n t he a p pr o priate C R F. Data fr o m s o m e 
pr oc e d ures re q uire d b y t he pr ot oc ol, s uc h as p h ysic al e xa mi nati o ns  a n d la b orat or y res ults , will 
be rec or de d o nl y o n t he s o urc e d oc u me nts a n d will n ot be tr a ns cri be d t o C R Fs. A d diti o nal 


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 8 9  of 9 6  
pr oc e d ures a n d assess me nts ma y be perf or m e d as part of t he i n vesti g at or’s i nstit uti o n or m e dic al 
practice sta n d ar d of care  a n d ma y n ot be re q uire d f or C R F e ntr y .  
F or e ac h s u bje ct e nr olle d, t he C R F ( pa per or electr o nic) m ust be c o m plete d a n d si g ne d b y t he PI 
or a ut h oriz e d dele gate fr o m t he st u d y st aff.  
All p a per f or ms s h o ul d b e t y pe d or fille d o ut usi n g i n d eli ble i n k a n d m ust b e le gi ble. Err ors 
s h o ul d be cr osse d o ut b ut n ot o bliterate d, t he c orre cti o n i nserte d, a n d t he c ha n ge i nit iale d a n d 
date d b y t he i n vesti gat or or his or her a ut h oriz e d del e gate.  
T he i n vesti g at or s h o ul d e ns ure t he acc ura c y, c o m pl ete ness, le gi bilit y, a n d ti meli ness of t he data 
i n t he C R Fs a n d i n all re q uire d re p orts.  
1 6  
M O NI T O RI N G T H E S T U D Y  
It will be t he m o nit or’s res p o nsi bilit y t o i ns pe ct t he C R Fs 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 b ot h a d her e nce t o t he pr ot oc ol a n d t he c o m plete ness, c o nsiste nc y, a n d acc ur ac y 
of t he data bei n g e nt ere d o n t he m. T he m o nit or s h o ul d ha ve access t o la b orat or y test re p o rts a n d 
ot her s u bje ct r ec or ds ne e de d t o verif y t he e ntries o n t he C R F. T he i n vesti g at or ( or desi g ne e) 
m ust a gree t o c o o perate wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms det ect e d d uri n g  t hese 
m o nit ori n g visits are r es ol ve d.  
1 7  
C O N FI D E N TI A LI T Y O F T R I A L D O C U M EN T S A N D S U B J E C T R E C O R D S  
T he i n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y will be mai ntai ne d a n d t hat t heir i de ntities 
are pr otecte d fr o m u na ut h oriz e d partie s. O n C R Fs or ot her d oc u me nts, s u bje cts s h o ul d be 
i d e ntifie d b y i d e ntificati o n c o d es a n d n ot b y t heir na mes. T he i n vesti gat or s h o ul d kee p a s u bject 
e nr oll m e nt l o g s h o wi n g c o des, na mes, a n d a d dresses. T he i n vesti gat or s h o ul d 
mai ntai n 
d oc u me nts n ot f or s u b missi o n t o E xeli xis or desi g nees (e g,  s u bjects’ writte n c o nse nt f or ms) i n 
strict c o nfi de nc e. 
All t u m or sca ns, researc h sa m ples, p h ot o gra p hs, a n d res ults fr o m e xa mi nati o ns, tests, a n d 
pr oc e d ures ma y be se nt t o E xeli xis a n d its part ners or d esi g nees f or st or a ge a n d ce ntral re vie w. 
E xeli xis ma y a ccess data a n d/ or re cei ve dat a tra nsfer u p o n st u d y c o m pleti o n.  
1 8  
P U B LI C A TI O N O F D A T A A N D P R O T E C TI O N O F T R A D E S E C R E T S  
T he Pri nci pal I n vesti gat or ( Pr ot oc ol C hair) h ol ds t he pri mar y r es p o nsi bilit y f or p u blic ati o n of t he 
st u d y res ults; pr o vi d e d t hat t he PI  will pr o vi de E xeli xis wit h a c o p y of a n y pr o p ose d p u blicati o n 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 0  of 9 6  
or rele ase: (a) f or a bstr acts, sli de prese ntati o ns or p osters, at le ast fi ve ( 5) b usi ness da y pri or t o  
s u b missi o n (i n t he case of a bstr acts) or first p u blic prese ntati o n (i n t he c ase of sli de prese nt ati o ns 
a n d p osters); a n d ( b) at least t hirt y ( 3 0) da ys i n a d va nc e of first s u b missi o n a n d ea c h s u bse q ue nt 
s u b missi o n i n t he c ase of ma n uscri pts a n d als o c o m pl y wit h  a n y pr o visi o ns r e gar di n g p u blicati o n 
t hat are a gre e d t o bet wee n t he PI ’s i nstit uti o n (e g, i nstit uti o n na m e.) a n d E x eli xis, I nc. i n t he 
Cli nic al  
Trial  
A gr ee m e nt  
r elat e d  
t o  
t his  
st u d y.


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 1  of 9 6  
1 9  
R E F E R E N C E S  
Atre ya C, S o n g E -K, Messers mit h W, et al.  P ot e nt a ntit u m or acti vit y of X L 1 8 4 
(ca b oz a nti ni b), a  c-M E T a n d V E G F R 2 i n hi bit or, i n c ol orectal c a ncer  patie nt -
deri ve d t u m or e x pla nt m o d els. A A C R; A bstract L B 3 0 2.  
De Oli veira  A T, Mat os D, L o g ull o A F, et al. M E T Is hi g hl y e x presse d i n a d va nce d sta ges 
of c ol orectal ca nce r a n d i n dicat es w orse pr o g n osis a n d m ortalit y. A ntica nc er 
Res. 2 0 0 9 N o v; 2 9( 1 1): 4 8 0 7 -1 1.  
Elisei R, Sc hl u m ber g er MJ, M uller S P, et al.  C a b oz a nti ni b i n pr o gressi ve m e d ullar y 
t h yr oi d ca ncer.  J Cli n O nc ol 2 0 1 3; 3 1( 2 9): 3 6 3 9-3 6 4 6.  
Gerritse n M E, T o mli ns o n J E, Zl ot C, Zi ma n M, H wa n g S. Usi n g g e ne e x pr essi o n 
pr ofili n g t o i de ntif y t he m ole c ular basis of t he s y ner gistic a cti o ns of 
he p at oc yt e gr o wt h fact or a n d vasc ular e n d ot helial gr o wt h fa ct or i n  h u ma n 
e n d ot helial cells. Br J P har m ac ol. 2 0 0 3 Oct; 1 4 0( 4 ): 5 9 5-6 1 0.  
Gr ot he y  A, et al.  R e g orafe ni b m o n ot her a p y f or pre vi o usl y treate d m etast atic c ol ore ctal 
ca ncer ( C O R R E C T):  a n i nter nati o nal m ultic e ntre, r a n d o miz e d, plac e b o-
c o ntr olle d, p hase 3 trial.  La ncet 2 0 1 3; 3 8 1( 9 8 6 3): 3 0 3 -3 1 2.  
H ol gre n C, D o u g hert y U, E d w i n F, Cerasi D, Ta yl or I, Fic hera A, J ose p h L, Biss o n nett e 
M,  K hare S. S pr o ut y -2 c o ntr ols c -Met e x pressi o n a n d m etastatic p ote ntial of 
c ol o n  
ca ncer cells: s pr o ut y/c -Met u pr e g ulati o n i n h u ma n c ol o nic 
a de n ocar ci n o mas.  O nc o ge ne. 2 0 1 0 Se p 2 3; 2 9( 3 8): 5 2 4 1 -5 3.  
H ur witz  H, Fe hre n b ac her L, N o v ot n y W, et al. Be va ciz u ma b pl us  iri n otec a n, 
fl u or o ur acil, a n d le uc o v ori n f or m etast atic c ol or ect al ca ncer. N E n gl J Me d. 
2 0 0 4 J u n 3; 3 5 0( 2 3): 2 3 3 5 -4 2.  
Ma yer RJ , Va n C utse m E, Falc o ne A, Y os hi n o T, Garcia-Car b o ner o R, Miz u n u ma N , 
Ya maz a ki K, S hi ma da Y, Ta b er ner o J, K o mats u Y, S o brer o A, B o uc her E, 
Peeters M, Tra n B, L e nz HJ, Za ni b o ni A, H oc hster H, Cle ar y J M, Pre ne n H, 
Be ne detti F, Miz u g uc hi H, Ma kris L, It o M, O hts u A .  Ra n d o miz e d trial of 
T A S -1 0 2 f or refra ct or y metastatic c ol ore ctal ca ncer.   N E n gl J Me d. 2 0 1 5 
Ma y 1 4; 3 7 2( 2 0): 1 9 0 9 -1 9  


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 2  of 9 6  
Pàez -Ri bes M, Alle n E, H u d oc k J, Ta ke da T, O k u ya ma H, Vi ñ als F, I n o u e M, Ber gers G, 
Ha na ha n D, Casa n o vas O.  A ntia n gi o ge nic  t hera p y elicits  m ali g na nt  
pr o gressi o n  of  t u m ors t o i ncr ease d l oc al i n vasi o n a n d dist a nt  
metast asis.  Ca ncer C ell. 2 0 0 9 Mar 3; 1 5( 3): 2 2 0 -3 1.  
Sie g el , R D, Nas ha d ha m D, a n d Je mal A.  Ca nc er statistics.  C A C a ncer J  Cli n 2 0 1 6 ; 66 : 
7 -3 0.  
S ul pice  E, Di n g S, M uscat elli-Gr o u x B, et al. Cr oss -tal k bet we e n t he V E G F-A a n d H G F 
si g nalli n g p at h wa ys i n e n d ot helial cells. Bi ol Cell. 2 0 0 9 Se p; 1 0 1( 9): 5 2 5 -3 9.  
T ori n o F, C orsell o S M, L o n g o R, Bar na b ei A, Gas pari ni G. H y p ot h yr oi dis m relat e d t o 
t yr osi ne ki nase i n hi bit ors: a n e mer gin g t o xic effect of t ar get e d t hera p y. Nat 
Re v Cli n O nc ol. 2 0 0 9 ; 6( 4): 2 1 9-2 8.  
Wri g ht J R, U n g Y, J ulia n  J, et al. Ra n d o miz e d, d o u ble-bli n d, plac e b o -c o ntr olle d trial of 
er yt hr o p oieti n i n n o n-s m all-cell l u n g ca ncer wit h dis ease -relate d a ne mia. J 
Cli n O nc ol. 2 0 0 7 ;2 5: 1 0 2 7 -3 2.  
Ya kes  F M, C he n J, Ta n J, Ya ma g u c hi K, S hi Y, Y u P, et al. Ca b oz a nti ni b ( X L 1 8 4), a 
n o vel  M E T a n d V E G F R 2 i n hi bit or, si m ulta ne o usl y s u p presses metastasis, 
a n gi o ge nesis, a n d t u m or gr o wt h. M ol Ca ncer T her. 2 0 1 1; 1 0: 2 2 9 8 -3 0 8.  
 
 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 3  of 9 6  
A p pe n di x  A : Perf or m a nc e St at us Criteri a  
E C O G P erf or m a nce St at us Sc ale  
K ar n ofs k y P erf or m a nce Sc ale  
Gra d e  
Des cri pti o ns  
Per ce nt  
Des cri pti o n  
0  
N or mal a cti vit y. F ull y a cti ve, a bl e t o 
carr y o n all pr edis eas e perf or ma nce 
wit h o ut restri cti o n.  
1 0 0  
N or mal, n o c o m plai nts, n o e vi de n ce of 
dis eas e.  
9 0  
A ble t o carr y o n n or mal a cti vit y; mi n or 
si g ns or s y m pt o ms of dis eas e. 
1  
S y m pt o ms, b ut a m b ulat or y. 
R estrict e d i n p h ysi call y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a bl e t o 
carr y o ut w or k of a li g ht or s e de ntar y 
nat ure ( e. g., li g ht h o us e w or k, office 
w or k).  
8 0  
N or mal a cti vit y wit h eff ort; s o m e si g ns 
or s y m pt o ms of dis eas e.  
7 0  
C ares f or s elf, u na bl e t o carr y o n 
n or mal a cti vit y or t o d o acti ve w or k.  
2  
I n be d < 5 0 % of t h e ti m e. 
A m b ulat or y a n d ca pa ble of all 
s elf-car e, b ut u na ble t o carr y o ut a n y 
w or k a cti viti es. U p a n d a b o ut m ore 
t ha n 5 0 % of wa ki n g h o urs. 
6 0  
R e q uir es occasi o nal assista nce, b ut is 
a ble t o care f or m ost of his/ h er n ee ds.  
5 0  
R e q uir es c o nsi dera ble assista nce a n d 
fre q u e nt m e di cal care. 
3  
I n be d > 5 0 % of t h e ti m e. C a pa ble of 
o nl y li mite d s elf-car e, c o nfi n e d t o b e d 
or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs.  
4 0  
Dis a ble d, re q uires s pecial car e a n d 
assista nce.  
3 0  
Se ver el y dis a ble d, h os pitali zati o n 
i n dicat e d. Deat h n ot i m mi ne nt. 
4  
1 0 0 % be dri d de n. C o m pl et el y 
dis a ble d. C a n n ot carr y o n a n y 
s elf-car e. T otall y c o nfi n e d t o b e d or 
c hair.  
2 0  
Ver y sic k, h os pitali zati o n i n di cat e d. 
Deat h n ot i m mi n e nt.  
1 0  
M ori b u n d, fatal pr ocess es pr o gr essi n g 
ra pi dl y. 
5  
Dea d  
0  
Dea d  
E C O G , Easter n C o o perati ve O nc ol o g y Gr o u p  
 
1.  
K w o n g L N, C ostell o J C, Li u H, Jia n g S, Hel ms T L, La n gs d orf A E, J a k u b os k y D, Ge n o vese G, M uller F L, 
J e o ng J H et al: O nc o ge nic N R A S si g n ali n g differe nti all y re g ul ates s ur vi v al a n d pr olifer ati o n i n 
mel a n o m a . N at ure me dici ne 2 0 1 2, 1 8 ( 1 0): 1 5 0 3-1 5 1 0.  
 
 
 
 
 
 


 
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P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
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Pa ge 9 4  of 9 6  
A p pe n di x  B : Dr u g Di ar y  
Pr ot oc ol #:  
St u d y Partici p a nt Dr u g Diar y  
 
 
C a b o z a nti ni b Dr u g T a bl et s  
 
Dir e cti o n s f or U s e  
 
 
I m m e di at el y c all y o ur d o ct or if y o u h a v e a n y q u e sti o n s a b o ut ta ki n g t h e 
t a bl et s or a b o ut a n y r e a cti o n s or si d e eff e ct s.  
 
 
Dir e cti o n s  
 
D O  
•  T a k e t h e t a bl et o n a n e m pt y st o m a c h wit h a f ull gl a s s of w at er ( 8 o u n c e s).  
•  T a k e t h e t a bl et s at a p pr o xi m at el y t h e s a m e ti m e e a c h d o si n g d a y.  
 
 
D O N O T  
•  D O N O T  e at 2 h o ur s b ef or e a n d  1 h o ur aft er e a c h d o s e ( e x c e pt f or w at er).  
•  D O N O T  m a k e u p mi s s e d d o s e s.  
•  D O N O T m a k e u p v o mit e d d o s e s.  
 
 
St or a g e of Dr u g  
C a b o z a nti ni b s h o ul d b e st or e d a t c o ntr oll e d r o o m t e m p er at ur e ( 2 0◦C t o 2 5 ◦C, 
6 8 ◦F t o 7 7 ◦F). D o n ot r efri g er at e or fr e e z e. K e e p a w a y fr o m c ol d or h e at s o ur c e s.  
 
 
 
 
 
 
 
 
 
 
 
St u d y P arti ci p a nt Dr u g Di ar y  


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 5  of 9 6  
 
Pr ot o c ol:  
 
 
 
 
     P arti ci p a nt N a m e:   
St u d y Dr u g: C a b o z a nti ni b   
 
     P arti ci p a nt M R N:  
 
St u d y Dr u g I n str u cti o n s  
 
H o w M u c h:  
 6 0 m g  
4 0 m g  
2 0 m g  
H o w Oft e n:  O n c e d ail y  
 
 
 
•  
F or a d diti o n al d o si n g i n str u cti o n s, s e e “ Dir e cti o n s f or U s e” s h e et  
•  
Pl e a s e c all wit h a n y q u e sti o n s: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D o si n g L o g : C y cl e # _ _ _ _ W e e k #  _ _ _ _  D a y # _ _ _ _  
 
 
D at e  
Ti m e of D o s e  
A m o u nt T a k e n  
C o m m e nt s  
E x:  
6/ 1/ 2 0 1 2  
8 a m  
1 pill / 6 0 m g  
V o mit e d pill  
D a y 1  
 
 
 
 
D a y 2  
 
 
 
 
D a y 3  
 
 
 
 
D a y 4  
 
 
 
 
D a y 5  
 
 
 
 
D a y 6  
 
 
 
 
D a y 7  
 
 
 
 
D a y 8  
 
 
 
 
D a y 9  
 
 
 
 
D a y 1 0  
 
 
 
 
D a y 1 1  
 
 
 
 
D a y 1 2  
 
 
 
 
D a y 1 3  
 
 
 
 
D a y 1 4  
 
 
 
 
D a y 1 5  
 
 
 
 
D a y 1 6  
 
 
 
 
D a y 1 7  
 
 
 
 
D a y 1 8  
 
 
 
 
D a y 1 9  
 
 
 
 
D a y 2 0  
 
 
 
 
D a y 2 1  
 
 
 
 
 
N a m e of p er s o n c o m pl eti n g t hi s f or m: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Si g n at ur e of p er s o n c o m pl eti n g t hi s f or m: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D at e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 


 
©  2 0 1 7 A GI C C/ Criteri u m I nc.  
P R O P RI E T A R Y & C O N FI D E N TI A L  
Te m pl ate Fi n al Ver. 2 5 O C T 2 0 1 7  
 
Pr ot oc ol 1 7 C R C 0 1/ E X E LI XI S I S T 5 6/ Versi o n 2. 0 1 0/ 2 7 / 18  
Pa ge 9 6  of 9 6  
A p pe n di x  C : E x pl or at or y bi o m ar kers  
 
Pre dicti ve a n d p har mac o d y na mics bi o mar ker a nal ysis ma y i ncl u d e b ut n ot li mite d t o  t he 
f oll o wi n g: 
 
H G F  
M E T  
A ut o p ha g y mar kers ( L C 3 a n d 
S Q S T M 1/ p 6 2)  
V E G F  
V E G F R -2  
A K T  
P D -L 1  
cfD N A a n d cf R N A  
E pi ge netic h y p er met h ylati o n/ m o dific ati o ns