Phase II Trial of Dasatinib in Patients With Isocitrate Dehydrogenase (IDH)-Mutant Advanced Intrahepatic Cholangiocarcinoma
Phase: PHASE2
Conditions: Cholangiocarcinoma
Sponsor: Massachusetts General Hospital



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A ge nt(s): Dasati ni b, ( N S C # _ _ _ _ _ _ _ _ _; I N D # _ _ _ _ _ _ _ _ _ _ _ _ _ _) – B M S
S C H E M A
Patie nts wit h a d va nce d i ntra he patic c h ola n gi ocarici n o ma 
w h o ha ve eit her I D H 1 or I D H 2 m utati o ns a n d ha ve 
recei ve d at least o ne pri or plati n u m c o ntai ni n g re gi me n  
 Dasati ni b orall y o nce dail y 
c o nti n u o usl y at 2 8 da ys/c ycle
Ra di ol o gic Res p o nse Assess me nts 
e ver y 2 c ycles ( 8 wee ks) b y 
R E CI S T v 1. 1 criteria

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
T A B L E O F C O N T E N T S
1.   
O B J E C TI V E S ...................................................................................................................................................... 1
1. 1  
St u dy Desi g n.................................................................................................................................................. 1
1. 2  
Pri m ary O bjectives........................................................................................................................................ 1
1. 3  
Sec o n d ary O bjectives.................................................................................................................................... 1
2.  
B A C K G R O U N D .................................................................................................................................................. 1
2. 1  
St u dy A ge nt.................................................................................................................................................... 1
2. 2  
St u dy Dise ase ................................................................................................................................................ 6
2. 3  
St u dy R ati o n ale ............................................................................................................................................. 6
2. 4  
C orrel ative St u dies B ack gr o u n d ................................................................................................................... 8
3.  
P A R TI CI P A N T S E L E C TI O N............................................................................................................................ 8
3. 1  
Eli gi bility Criteri a......................................................................................................................................... 8
3. 2  
E x cl usi o n Crit eri a ...................................................................................................................................... 9
3. 3  
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns .............................................. 1 1
4.   
R E GI S T R A TI O N P R O C E D U R E S.................................................................................................................. 1 1
4. 1   
Ge ner al G ui deli nes f or D F/ H C C a n d D F/ P C C I nstit uti o ns....................................................................... 1 1
4. 2  
R e gistr ati o n Pr o c ess f or D F/ H C C a n d D F/ P C C I nstit uti o ns................................................................... 1 2
5.  
T R E A T M E N T P L A N........................................................................................................................................ 1 2
5. 1  
Pr e-tr e at m e nt Crit eri a............................................................................................................................... 1 3
5. 2  
A g e nt A d mi nistr ati o n................................................................................................................................. 1 3
5. 3   
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p ortive C are G ui deli nes.......................................................... 1 3
5. 4   
D ur ati o n of T her a py..................................................................................................................................... 1 4
5. 5   
D ur ati o n of F oll o w U p................................................................................................................................ 1 4
5. 6  
Criteri a f or Re m ov al fr o m St u dy................................................................................................................. 1 5
6.  
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S..................................... 1 5
6. 1  
A ntici p ate d T oxicities.................................................................................................................................. 1 5
6. 2   
D ose Re d ucti o ns, I nterr u pti o ns, Re- Esc al ati o ns, a n d Del ays .................................................................... 1 5
6. 3  
T oxicity M a n a ge me nt.................................................................................................................................. 1 7
7.   
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N................................................................................... 2 1
7. 1   
D as ati ni b..................................................................................................................................................... 2 1
8.   
C O R R E L A TI V E/ S P E CI A L S T U DI E S ........................................................................................................... 2 3
8. 1  
P h ar m ac o dy n a mic St u dies.......................................................................................................................... 2 3
9.   
C LI NI C A L A N D L A B O R A T O R Y E V A L U A TI O N S A N D S T U D Y C A L E N D A R ............................... 2 3
9. 1  
Ev al u ati o ns.................................................................................................................................................. 2 4

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
9. 2  
St u dy C ale n d ar............................................................................................................................................ 2 6
1 0.   
M E A S U R E M E N T O F E F F E C T.................................................................................................................. 2 7
1 0. 1  
A ntit u m or Effect – S oli d T u m ors.................................................................................................................. 2 7
1 1.   
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S............................................................................ 3 4
1 1. 1   
Defi niti o ns................................................................................................................................................... 3 4
1 1. 2  
F oll o w- U p of A dverse Eve nts...................................................................................................................... 3 7
1 1. 3  
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g .............................................................................. 3 7
1 1. 4  
Re p orti n g Re q uire me nts.............................................................................................................................. 3 7
1 1. 5  
Re p orti n g t o t he St u dy S p o ns or................................................................................................................... 3 8
1 1. 6  
Re p orti n g t o t he I nstit uti o n al Revie w B o ar d (I R B)..................................................................................... 3 9
1 1. 7  
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistr ati o n ( F D A)............................................................................. 4 0
1 1. 8  
Re p orti n g t o H os pit al Risk M a n a ge me nt.................................................................................................... 4 0
1 1. 9   
M o nit ori n g of A dverse Eve nts a n d Peri o d of O bserv ati o n......................................................................... 4 0
1 2.   
D A T A A N D S A F E T Y M O NI T O RI N G....................................................................................................... 4 1
1 2. 1   
D at a Re p orti n g............................................................................................................................................ 4 1
1 2. 2  
S afety Meeti n gs ........................................................................................................................................... 4 2
1 2. 3   
M o nit ori n g................................................................................................................................................... 4 2
1 3.   
R E G U L A T O R Y C O N SI D E R A TI O N S....................................................................................................... 4 3
1 3. 1  
Pr ot oc ol Revie w a n d A me n d me nts.............................................................................................................. 4 3
1 3. 2  
I nf or me d C o nse nt........................................................................................................................................ 4 3
1 3. 3  
Et hics a n d G o o d Cli nic al Pr actice ( G C P).................................................................................................. 4 3
1 3. 4  
St u dy D oc u me nt ati o n .................................................................................................................................. 4 4
1 3. 5  
Rec or ds Rete nti o n ....................................................................................................................................... 4 4
1 4.  
S T A TI S TI C A L C O N SI D E R A TI O N S......................................................................................................... 4 4
1 4. 1  
St u dy Desi g n/ E n d p oi nts .............................................................................................................................. 4 5
1 4. 2  
S a m ple Size, Accr u al R ate, a n d E arly St o p pi n g R ule................................................................................. 4 5
1 4. 3  A n alysis of Sec o n d ary E n d p oi nts.................................................................................................................... 4 6
1 4. 4  Re p orti n g a n d Excl usi o ns ............................................................................................................................... 4 7
1 5.  
P U B LI C A TI O N P L A N................................................................................................................................. 4 7
1 6.   
R E F E R E N C E S .............................................................................................................................................. 4 8
A p pe n dix A - Perf or m a nce St at us Criteri a.............................................................................................................. 4 9
A p pe n dix B: C orrel ative St u dies.............................................................................................................................. 5 0

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1
1.
O BJ E C TI V E S
1. 1 
St u d y Desi g n
T his is a n o pe n-la bel, si n gle-ar m P hase II st u d y of dasati ni b i n patie nts w h o ha ve pr o gresse d o n 
first li ne s yste mic t hera p y f or a d va nce d i ntra he patic c h ola n gi ocarci n o ma (I C C) wit h eit her I D H 1 
or I D H 2  m utati o ns.  T he p hase II st u d y w o ul d ha ve a t w o-sta ge desi g n, wit h a tar get accr ual of 8 
e val ua ble patie nts f or t he first sta ge a n d a t otal of 1 9 patie nts f or t he w h ole st u d y.  If n o 
res p o nses see n i n t he first 8 patie nts, t he trial will be ter mi nate d.  If at least 1 patie nt i n t he first 
sta ge has res p o nse, t he trial w o ul d pr ocee d t o t he sec o n d sta ge.  Patie nts will be treate d wit h 
dasati ni b at 1 0 0 m g dail y a d mi nistere d orall y c o nti n u o usl y f or 2 8- da y c ycles. T u m or 
assess me nts will be perf or me d e ver y 8 wee ks u ntil d oc u me nte d disease pr o gressi o n b y R E CI S T 
criteria or dr u g i nt olera nce. T he esti mate d ti me f or acc r ual of t he patie nts is 1 2- 2 4 m o nt hs.
1. 2 
Pri mar y O bjecti ves
T he pri mar y o bjecti ve of t he st u d y is t o assess t he o bjecti ve res p o nse rate ( O R R) per 
R E CI S T v 1. 1 criteria.  
1. 3 
Sec o n dar y O bjecti ves
1. 3. 1 
E val uate t he safet y a n d t olera bilit y of dasati ni b i n patie nts wit h I D H- m uta nt 
a d va nce d I C C
1. 3. 2 
E val uate t he pr o gressi o n free s ur vi val ( P F S) a n d me dia n o verall s ur vi val ( O S) f or 
patie nts wit h I D H- m uta nt a d va nce d I C C
1. 3. 3 
E x pl ore m olec ular c orrelates of res p o nse a n d resista nce i ncl u di n g circ ulati n g 
bi o mar kers a n d t u m or tiss ue bi o mar kers
2. 
B A C K G R O U N D
2. 1 
St u d y A ge nt 
A s u m mar y of t he pr o perties of dasati ni b a n d t he cli nical a n d n o ncli nical e x perie nce wit h t he 
dr u g are c o ntai ne d i n t he I n vesti gat or’s Br oc h ure (I B) s u p plie d b y B M S. T he I B s h o ul d be 
re vie we d i n c o nj u ncti o n wit h t his st u d y pr ot oc ol.
2. 1. 1  S pectr u m of Dasati ni b Acti vit y
Dasati ni b p ote ntl y i n hi bits: S R C ki nases, B C R- A B L, c- KI T, P D G F R β  a n d E P H A a n d was less 
p ote nt a gai nst 1 6 ot her u nrelate d pr otei n t yr osi ne ki nases ( P T Ks) a n d seri ne/t hre o ni ne ki nases. 
I n vitr o, dasati ni b was acti ve i n le u ke mic cell li nes re prese nti n g varia nts of i mati ni b mes ylate 
se nsiti ve a n d resista nt disease. Dasati ni b i n hi bite d t he gr o wt h of c hr o nic m yel oi d le u ke mia 
( C M L) a n d ac ute l y m p h o blastic le u ke mia ( A L L) cell li nes o vere x pressi n g B C R- A B L. U n der t he 
c o n diti o ns of t he assa ys, dasati ni b was a ble t o o verc o me i mati ni b resista nce res ulti n g fr o m B C R-

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2
A B L ki nase d o mai n m utati o ns, acti vati o n of alter nate si g nali n g pat h wa ys i n v ol vi n g t he S R C 
fa mil y ki nases ( L Y N, H C K), a n d m ulti- dr u g resista nce ge ne o vere x pressi o n. Dasati ni b i n hi bits 
t he B C R- A B L ki nase wit h a n i n vitr o I C 5 0 of 3 n M, a p ote nc y 2 6 0-f ol d greater t ha n t hat of 
i mati ni b mes ylate (I C 5 0 = 7 9 0 n M). I n cell ular assa ys, dasati ni b kille d or i n hi bite d t he 
pr oliferati o n of all B C R- A B L de pe n de nt le u ke mic cell li nes teste d t o date.  Dasati ni b als o 
de m o nstrate d u n di mi nis he d a nti-t u m or acti vit y a gai nst se veral precli nicall y- a n d cli nicall y-
deri ve d m o dels of i mati ni b mes ylate resista nce. E vi de nce t hat S R C fa mil y ki nase o vere x pressi o n 
ma y pla y a r ole i n cli nical resista nce t o i mati ni b mes ylate was de m o nstrate d i n t hree C M L cell 
li nes esta blis he d fr o m patie nts w h o faile d i mati ni b mes ylate t hera p y. T hese cells re mai ne d 
hi g hl y se nsiti ve t o t he cell- killi n g effects of dasati ni b.  T hese res ults de m o nstrate t hat dasati ni b is 
effecti ve i n re d uci n g t he pr oliferati o n or s ur vi val of b ot h i mati ni b mes ylate-se nsiti ve a n d 
resista nt cells, a n d its i n hi bit or y acti vit y is n ot s olel y de pe n de nt o n B C R- A B L.
T he acti vit y of dasati ni b a gai nst C M L cells i n vitr o was re pr o d uce d i n viv o a gai nst se veral 
h u ma n C M L xe n o graft m o dels gr o w n s u bc uta ne o usl y i n S CI D mice. A gai nst t he K 5 6 2/i mati ni b 
mes ylate/ R C M L m o del, dasati ni b was c urati ve i n 1 0 0 % of t he treate d a ni mals. I n c o ntrast, at its 
o pti mal d ose a n d sc he d ule, i mati ni b mes ylate was i nacti ve.
2. 1. 2 
Dasati ni b Precli nical T o xic ol o g y
Si n gle or re peate d oral a d mi nistrati o n of dasati ni b pri nci pall y affecte d t he gastr o-i ntesti nal ( GI) 
tract, i ncl u di n g t he li ver, t he he mat o p oietic a n d l y m p h oi d s yste ms i n rats a n d m o n ke ys. Ot her 
pr o mi ne nt effects after si n gle oral a d mi nistrati o n of dasati ni b i ncl u de d re nal a n d car diac t o xicit y 
i n rats at let hal d oses, a n d c uta ne o us he m orr ha ge i n m o n ke ys. Dasati ni b ca n als o affect t he 
i m m u ne s yste m a n d b o ne t ur n o ver.
Dasati ni b i n vitr o acti vit y i n t he H E R G/I Kr a n d P ur ki nje-fi ber assa ys i n dicate d a m o derate
lia bilit y f or pr ol o n gati o n of car diac ve ntric ular re p olarizati o n ( Q T i nter val) i n t he cli nic.
H o we ver, t here were n o dasati ni b -relate d c ha n ges o bser ve d i n electr ocar di o gra ms, ner v o us 
s yste m f u ncti o n, res pirati o ns a n d heart rate, bl o o d press ure, or arterial o x y ge n sat urati o n i n 
si n gle- d ose, 1 0- da y, or 1- m o nt h oral t o xicit y st u dies i n m o n ke ys.
Dasati ni b was f o u n d t o e x hi bit a pr ofile of br oa d-s pectr u m platelet i n hi biti o n best t y pifie d
b y a nti- platelet a ge nts s uc h as t he G PII b/IIIa a nta g o nists, i nte greli n a n d a bci xi ma b.  Fi nall y, 
m o d ulati o n of S R C ki nase acti vit y c o ul d als o affect oste oclast m or p h ol o g y a n d f u ncti o n a n d 
b o ne re m o deli n g. T his effect c o ul d p ote ntiall y res ult i n a n i ncrease i n b o ne mi neral de nsit y a n d a 
p he n ot y pe a nal o g o us t o oste o petr osis.
A d diti o nal t o xic ol o g y i nf or mati o n ma y be f o u n d i n t he I n vesti gat or’s Br oc h ure.
2. 1. 3  Cli nical P har mac o ki netics
T he p har mac o ki netics of dasati ni b ha ve bee n e val uate d i n 2 2 9 healt h y s u bjects a n d i n 1 3 7
patie nts wit h le u ke mia ( C M L or P h + A L L) fr o m a P hase I cli nical st u d y ( C A 1 8 0 0 0 2).
A bs or pti o n
Ma xi m u m plas ma c o nce ntrati o ns ( C ma x) of dasati ni b are o bser ve d bet wee n 0. 5 a n d 6 h o urs 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3
( T ma x) f oll o wi n g oral a d mi nistrati o n. Dasati ni b e x hi bits d ose pr o p orti o nal i ncreases i n A U C a n d 
li near eli mi nati o n c haracteristics o ver t he d ose ra n ge of 1 5 m g t o 2 4 0 m g/ da y.  T he o verall mea n 
ter mi nal half-life of dasati ni b is 3 – 5 h o urs.  Data fr o m a st u d y of 5 4 healt h y s u bjects d mi nistere d 
a si n gle, 1 0 0- m g d ose of dasati ni b 3 0 mi n utes f oll o wi n g c o ns u m pti o n of a hi g h-fat meal res ulte d 
i n a 1 4 % i ncrease i n t he mea n A U C of dasati ni b. T he o bser ve d f o o d effects were n ot cli nicall y 
rele va nt.
Distri b uti o n
I n patie nts, dasati ni b has a n a p pare nt v ol u me of distri b uti o n of 2 5 0 5 L, s u g gesti n g t hat t he dr u g 
is e xte nsi vel y distri b ute d i n t he e xtra vasc ular s pace. Bi n di n g of dasati ni b a n d its acti ve 
meta b olite t o h u ma n plas ma pr otei ns i n vitr o was a p pr o xi matel y 9 6 % a n d 9 3 %, res pecti vel y, 
wit h n o c o nce ntrati o n de pe n de nce o ver t he ra n ge of 1 0 0 – 5 0 0 n g/ m L.
Met a b olis m
Dasati ni b is e xte nsi vel y meta b olize d i n h u ma ns, pri maril y b y t he c yt oc hr o me P 4 5 0 e nz y me 3 A 4. 
C Y P 3 A 4 was t he pri mar y e nz y me res p o nsi ble f or t he f or mati o n of t he acti ve meta b olite. Fla vi n-
c o ntai ni n g m o n o o x y ge nase 3 ( F M O- 3) a n d uri di ne di p h os p hate gl uc ur o n os yltra nsferase
( U G T) e nz y mes are als o i n v ol ve d i n t he f or mati o n of dasati ni b meta b olites. I n h u ma n li ver 
micr os o mes, dasati ni b was a wea k ti me- de pe n de nt i n hi bit or of C Y P 3 A 4.  T he e x p os ure of t he 
acti ve meta b olite, w hic h is e q ui p ote nt t o dasati ni b, re prese nts a p pr o xi matel y 5 % of t he dasati ni b 
A U C. T his i n dicates t hat t he acti ve meta b olite of dasati ni b is u nli kel y t o pla y a maj or r ole i n t he 
o bser ve d p har mac ol o g y of t he dr u g. Dasati ni b als o ha d se veral ot her i nacti ve o xi dati ve  
meta b olites.  Dasati ni b is a ti me- de pe n de nt i n hi bit or of C Y P 3 A 3. At cli nicall y rele va nt 
c o nce ntrati o ns, dasati ni b d oes n ot i n hi bit C Y P 1 A 2, 2 A 6, 2 B 6, 2 C 9, 2 C 1 9, 2 D 6, or 2 E 1. 
Dasati ni b is n ot a n i n d ucer of h u ma n C Y P e nz y mes. 1
Eli mi n ati o n
Eli mi nati o n is pri maril y via t he feces. F oll o wi n g a si n gle oral d ose of [ 1 4 C]-la bele d dasati ni b, 
a p pr o xi matel y 4 % a n d 8 5 % of t he a d mi nistere d ra di oacti vit y was rec o vere d i n t he uri ne a n d 
feces, res pecti vel y, wit hi n 1 0 da ys. U nc ha n ge d dasati ni b acc o u nte d f or 0. 1 % a n d 1 9 % of t he 
a d mi nistere d d ose i n uri ne a n d feces, res pecti vel y, wit h t he re mai n der of t he d ose bei n g 
meta b olites. 
2. 1. 4  
Cli nical Efficac y i n C M L
A P hase 2, ra n d o mize d, o pe n-la bel st u d y was c o n d ucte d i n patie nts wit h c hr o nic p hase C M L 
w h ose disease was resista nt t o pri or i mati ni b t hera p y at d oses of 4 0 0 or 6 0 0 m g. T he pri mar y 
e n d p oi nt was M C y R at 1 2 wee ks. O ne h u n dre d fift y patie nts were ra n d o mize d i n a 2: 1 rati o t o 
eit her dasati ni b 7 0 m g t wice dail y or i mati ni b 8 0 0 m g dail y ( 4 0 0 m g t wice dail y). Cr oss o ver t o 
t he alter nate t hera p y was per mitte d i n t he e ve nt of disease pr o gressi o n or i nt olera ble t o xicit y. 
Me dia n f oll o w- u p was 1 5 m o nt hs. Me dia n d urati o n of treat me nt pri or t o cr oss o ver was 1 4 
m o nt hs f or dasati ni b a n d 3 m o nt hs f or i mati ni b. Pri or t o cr oss o ver, 9 3 % of t he dasati ni b-treate d 
patie nts a n d 8 2 % of t he i mati ni b-treate d patie nts ac hie ve d a C H R. At 1 2 wee ks, M C y R was 
ac hie ve d i n 3 6 % of t he dasati ni b-treate d patie nts ( C C y R i n 2 2 %) a n d 2 9 % of t he i mati ni b-treate d 
patie nts ( C C y R i n 8 %).  Wit h l o n ger treat me nt a n d f oll o w- u p, M C y R was ac hie ve d i n 5 2 % of 
t he dasati ni b-treate d patie nts ( C C y R i n 4 0 %) a n d 3 3 % of t he i mati ni b-treate d patie nts ( C C y R i n 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
4
1 6 %) pri or t o cr oss o ver. Si nce t he me dia n f oll o w- u p was 1 5 m o nt hs, t here were t o o fe w 
pr o gressi o ns t o relia bl y esti mate t he d urati o n of M C y R.
I n t he p hase 3 D A SI SI O N trial, patie nts wit h ne wl y dia g n ose d c hr o nic- p hase ( C P) C M L were 
ra n d o mize d t o recei ve dasati ni b 1 0 0 m g ( n = 2 5 9) or i mati ni b 4 0 0 m g ( n = 2 6 0) o nce dail y. 
Pri mar y data s h o we d s u peri or efficac y f or dasati ni b c o m pare d wit h i mati ni b after 1 2 m o nt hs, 
i ncl u di n g si g nifica ntl y hi g her rates of c o m plete c yt o ge netic res p o nse ( C C y R), c o nfir me d C C y R 
( pri mar y e n d p oi nt), a n d maj or m olec ular res p o nse ( M M R).  T he 2 4- m o nt h f oll o w u p s h o we d 
si milar res ults ( Ka ntarijia n et al, Bl o o d, 2 0 1 2).
A P hase 3, ra n d o mize d, o pe n-la bel, d ose- o pti mizati o n st u d y was c o n d ucte d i n patie nts wit h 
c hr o nic p hase C M L, w h ose disease was resista nt t o or w h o were i nt olera nt t o i mati ni b, t o 
e val uate t he efficac y of dasati ni b a d mi nistere d o nce dail y c o m pare d wit h dasati ni b a d mi nistere d 
t wice dail y. Patie nts wit h si g nifica nt car diac diseases i ncl u di n g m y ocar dial i nfarcti o n wit hi n 6 
m o nt hs, c o n gesti ve heart fail ure wit hi n 3 m o nt hs, si g nifica nt arr h yt h mias, or Q Tc pr ol o n gati o n 
were e xcl u de d fr o m t he st u d y. T he pri mar y e n d p oi nt was M C y R i n patie nts wit h i mati ni b-
resista nt c hr o nic p hase C M L. T he mai n sec o n dar y e n d p oi nt was M C y R b y t otal dail y d ose le vel 
i n t he sa me p o p ulati o n. A t otal of 6 7 0 patie nts, of w h o m 4 9 8 ha d i mati ni b resista nt disease, were 
ra n d o mize d t o t he dasati ni b 1 0 0 m g o nce dail y, 1 4 0 m g o nce dail y, 5 0 m g t wice dail y, or 7 0 m g 
t wice dail y gr o u p. Mi ni m u m f oll o w- u p was 6 m o nt hs a n d me dia n d urati o n of treat me nt was 
a p pr o xi matel y 8 m o nt hs.  Res p o nse rates are prese nte d i n Ta ble 2. Efficac y was ac hie ve d acr oss 
all dasati ni b treat me nt gr o u ps wit h t he o nce dail y sc he d ule de m o nstrati n g c o m para ble efficac y 
( n o ni nferi orit y) t o t he t wice dail y sc he d ule o n t he pri mar y efficac y e n d p oi nt ( differe nce i n 
M C y R 2. 8 %; 9 5 % c o nfi de nce i nter val [- 6. 0 % – 1 1. 6 %]). T he mai n sec o n dar y e n d p oi nt of t he 
st u d y als o s h o we d c o m para ble efficac y ( n o n-i nferi orit y) bet wee n t he 1 0 0 m g t otal dail y d ose a n d 
t he 1 4 0 m g t otal dail y d ose ( differe nce i n M C y R - 0. 8 %; 9 5 % c o nfi de nce i nter val [- 9. 6 % – 8. 0 %]). 
Si nce t he mi ni m u m f oll o w- u p was o nl y 6 m o nt hs, t here were t o o fe w pr o gressi o ns t o esti mate 
t he d urati o n of M C y R.  L o n g-ter m f oll o w u p at 6 years c o nfir me d si milar res ults ( S ha h et al, 
Bl o o d, 2 0 1 4).
2. 1. 5  S afet y of D as ati ni b i n Cli nic al St u dies i n C M L a n d P h + A L L
T he data prese nte d i n Ta ble 3 reflect e x p os ure t o dasati ni b i n 2 1 8 2 patie nts wit h le u ke mia i n 
cli nical st u dies (starti n g d osa ge 1 0 0 m g o nce dail y, 1 4 0 m g o nce dail y, 5 0 m g t wice dail y, or 7 0 
m g t wice dail y). T he me dia n d urati o n of t hera p y was 1 1 m o nt hs (ra n ge 0. 0 3 – 2 6 m o nt hs). T he 
maj orit y of dasati ni b-treate d patie nts e x perie nce d a d verse reacti o ns at s o me ti me. Dr u g was 
disc o nti n ue d f or a d verse reacti o ns i n 9 % of patie nts i n c hr o nic p hase C M L, 1 0 % i n accelerate d 
p hase C M L, 1 5 % i n m yel oi d blast p hase C M L, a n d 8 % i n l y m p h oi d blast p hase C M L or P h +
A L L. I n a P hase 3 d ose- o pti mizati o n st u d y i n patie nts wit h c hr o nic p hase C M L, t he rate of 
disc o nti n uati o n f or a d verse reacti o n was l o wer i n patie nts treate d wit h 1 0 0 m g o nce dail y t ha n i n
patie nts treate d wit h 7 0 m g t wice dail y ( 4 % a n d 1 2 %, res pecti vel y).  T he m ost fre q ue ntl y 
re p orte d a d verse reacti o ns (re p orte d i n ≥2 0 %  of patie nts) i ncl u de d fl ui d rete nti o n e ve nts, 
diarr hea, hea dac he, s ki n ras h, na usea, he m orr ha ge, fati g ue, a n d d ys p nea. T he m ost fre q ue ntl y 
re p orte d seri o us a d verse reacti o ns i ncl u de d ple ural eff usi o n ( 9 %), p yre xia ( 3 %), p ne u m o nia 
( 3 %), i nfecti o n ( 2 %), fe brile ne utr o pe nia ( 4 %), gastr oi ntesti nal blee di n g ( 4 %), d ys p nea ( 3 %), 
se psis ( 1 %), diarr hea ( 2 %), c o n gesti ve heart fail ure ( 2 %), a n d pericar dial eff usi o n ( 1 %).

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
5
A ntici p ate d A d verse E ve nts
M yel os u p pressi o n
Treat me nt wit h dasati ni b is ass ociate d wit h se vere ( N CI C T C Gra de 3 or 4) t hr o m b oc yt o pe nia,
ne utr o pe nia, a n d a ne mia. T heir occ urre nce is m ore fre q ue nt i n patie nts wit h a d va nce d C M L or
P h + A L L t ha n i n c hr o nic p hase C M L. C o m plete bl o o d c o u nts s h o ul d be perf or me d wee kl y f or 
t he first 2 m o nt hs a n d t he n m o nt hl y t hereafter, or as cli nicall y i n dicate d. M yel os u p pressi o n was
ge nerall y re versi ble a n d us uall y ma na ge d b y wit h h ol di n g dasati ni b te m p oraril y or d ose 
re d ucti o n. I n a P hase 3 d ose- o pti mizati o n st u d y i n patie nts wit h c hr o nic p hase C M L, Gra de 3 or
4 m yel os u p pressi o n was re p orte d less fre q ue ntl y i n patie nts treate d wit h 1 0 0 m g o nce dail y t ha n
i n patie nts treate d wit h 7 0 m g t wice dail y.
Blee di n g Rel ate d E ve nts
I n a d diti o n t o ca usi n g t hr o m b oc yt o pe nia i n h u ma n s u bjects, dasati ni b ca use d platelet d ysf u ncti o n
i n vitr o. I n all cli nical st u dies, se vere ce ntral ner v o us s yste m ( C N S) he m orr ha ges, i ncl u di n g
fatalities, occ urre d i n < 1 % of patie nts recei vi n g dasati ni b. Se vere gastr oi ntesti nal he m orr ha ge
occ urre d i n 4 % of patie nts a n d ge nerall y re q uire d treat me nt i nterr u pti o ns a n d tra nsf usi o ns. Ot her
cases of se vere he m orr ha ge occ urre d i n 2 % of patie nts. M ost blee di n g e ve nts were ass ociate d 
wit h se vere t hr o m b oc yt o pe nia.
Patie nts were e xcl u de d fr o m partici pati o n i n dasati ni b cli nical st u dies if t he y t o o k me dicati o ns
t hat i n hi bit platelet f u ncti o n or a ntic oa g ula nts. I n s o me trials, t he use of a ntic oa g ula nts, as piri n,
a n d n o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) was all o we d c o nc urre ntl y wit h dasati ni b if
t he platelet c o u nt was > 5 0, 0 0 0. Ca uti o n s h o ul d be e xercise d if patie nts are re q uire d t o ta ke
me dicati o ns t hat i n hi bit platelet f u ncti o n or a ntic oa g ula nts.
Fl ui d Rete nti o n
Dasati ni b is ass ociate d wit h fl ui d rete nti o n. I n all cli nical st u dies, se vere fl ui d rete nti o n was
re p orte d i n 8 % of patie nts, i ncl u di n g ple ural a n d pericar dial eff usi o n re p orte d i n 5 % a n d 1 % of
patie nts, res pecti vel y. Se vere ascites a n d ge neralize d e de ma were eac h re p orte d i n < 1 % of
patie nts. Se vere p ul m o nar y e de ma was re p orte d i n 1 % of patie nts. Patie nts w h o de vel o p 
s y m pt o ms s u g gesti ve of ple ural eff usi o n s uc h as d ys p nea or dr y c o u g h s h o ul d be e val uate d b y
c hest X-ra y. Se vere ple ural eff usi o n ma y re q uire t h orace ntesis a n d o x y ge n t hera p y. Fl ui d
rete nti o n e ve nts were t y picall y ma na ge d b y s u p p orti ve care meas ures t hat i ncl u de di uretics or
s h ort c o urses of ster oi ds.
I n t he P hase 3 d ose- o pti mizati o n st u d y i n patie nts wit h c hr o nic p hase C M L, fl ui d rete nti o n
e ve nts were re p orte d less fre q ue ntl y i n patie nts treate d wit h 1 0 0 m g o nce dail y t ha n i n patie nts
treate d wit h 7 0 m g t wice dail y. 1
Q T Pr ol o n g ati o n
I n vitr o data s u g gest t hat dasati ni b has t he p ote ntial t o pr ol o n g car diac ve ntric ular re p olarizati o n
( Q T i nter val). I n si n gle-ar m cli nical st u dies i n patie nts wit h le u ke mia treate d wit h dasati ni b, t he
mea n Q Tc i nter val c ha n ges fr o m baseli ne usi n g Fri dericia’s met h o d ( Q Tc F) were 3 – 6 msec; t he
u p per 9 5 % c o nfi de nce i nter vals f or all mea n c ha n ges fr o m baseli ne were < 8 msec. Ni ne patie nts

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
6
ha d Q Tc pr ol o n gati o n re p orte d as a n a d verse e ve nt. T hree patie nts ( < 1 %) e x perie nce d a Q Tc F
> 5 0 0 msec.
Dasati ni b s h o ul d be a d mi nistere d wit h ca uti o n t o patie nts w h o ha ve or ma y de vel o p pr ol o n gati o n
of Q Tc. T hese i ncl u de patie nts wit h h y p o kale mia or h y p o ma g nese mia, patie nts wit h c o n ge nital
l o n g Q T s y n dr o me, patie nts ta ki n g a nti-arr h yt h mic me dici nes or ot her me dici nal pr o d ucts t hat
lea d t o Q T pr ol o n gati o n, a n d c u m ulati ve hi g h- d ose a nt hrac ycli ne t hera p y. H y p o kale mia or 
h y p o ma g nese mia s h o ul d be c orrecte d pri or t o dasati ni b a d mi nistrati o n.
2. 2 
St u d y Dise ase
Biliar y tract ca ncers ( B T Cs) i ncl u de a s pectr u m of i n vasi ve a de n ocarci n o mas e nc o m passi n g b ot h 
c h ola n gi ocarci n o ma arisi n g i n t he i ntra he patic, peri hilar, or distal biliar y tree, as well as 
carci n o ma arisi n g fr o m t he gall bla d der.  As a s u bset of B T Cs,  i ntra he patic c h ola n gi oci n o ma 
(I C C) is t he sec o n d m ost c o m m o n t y pe of pri mar y li ver t u m or a n d a m o n g t he m ost let hal of all 
h u ma n mali g na ncies. It carries a me dia n s ur vi val of < 1 year 1, a n d has bee n risi n g i n i nci de nce 
w orl d wi de f or t he past 3 deca des 2. A n esti mate d 8 0, 0 0 0 die per year die fr o m dia g n ose d I C C 
a n n uall y, alt h o u g h t he act ual rate is li kel y se veral ti mes hi g her disease, as rece nt m olec ular 
st u dies de m o nstrate t hat li ver “ca ncers- of- u n k n o w n pri mar y” are m ost c o m m o nl y biliar y i n 
ori gi n 3. I n m ost cases, I C C prese nts at a d va nce d sta ge disease wit h a p o or pr o g n osis. Des pite t he 
c urre nt sta n dar d c he m ot hera p y wit h ge mcita bi ne/cis plati n c o m bi nati o n f or patie nts wit h 
u nresecta ble or metastatic B T Cs, t he me dia n s ur vi val ti me re mai ns less t ha n o ne year 1. T here are 
n o sta n dar d treat me nts f or patie nts w h o faile d ge mcita bi ne/ plati n u m- base d c he m ot hera p y. 
Rece ntl y, t here ha ve bee n re ne we d i nterests i n de vel o pi n g m olec ularl y tar gete d t hera pies i n 
B T Cs 4, h o we ver, t here are n o st u dies tar geti n g a partic ular m olec ular si g nat ure f or I C C. Rece nt 
p hase II st u dies e val uati n g tar gete d a ge nts t hat i n hi bit E G F R or mit o ge n-acti vate d pr otei n 
ki nase/e xtracell ular si g nal –relate d ki nase ha ve de m o nstrate d e vi de nce of li mite d a ntit u m or 
acti vit y i n u nselecte d biliar y tract carci n o ma patie nts 5. Se veral tar gete d a ge nts i ncl u di n g 
la pati ni b a n d s orafe ni b, faile d t o de m o nstrate o bjecti ve res p o nses i n a d va nce d B T Cs6, 7. T h us, 
t here is a n i m me diate nee d t o u n dersta n d I C C bi ol o g y a n d t o de vel o p i m pr o ve d t hera pe utics. 
2. 3 
St u d y R ati o n ale
I m p orta nt a d va nces ha ve c o me fr o m rece nt ge n o me- wi de a n d ca n di date- base d se q ue nci n g 
st u dies. W or k b y o ur gr o u p a n d ot hers ha ve pr o vi de d a detaile d vie w of t he ge netics of I C C, a n d 
ha ve i m me diate cli nical i m plicati o ns f or tar gete d t hera pe utic a p pr oac hes i n defi ne d patie nt 
s u bsets. Base d o n o ur data a n d s u bse q ue nt st u dies b y ot her gr o u ps, s pecific “ h ot-s p ot” m utati o ns 
i n I D H 1 a n d I D H 2  (at I D H 1 R 1 3 2 a n d I D H 2 R 1 7 2) are n o w esta blis he d as t he m ost c o m m o n 
k n o w n ge netic lesi o ns i n I C C ( 2 0- 4 0 % of cases) 8- 1 1.
 
W hile pri or re p orts ha ve varie d i n t heir c o ncl usi o ns a b o ut t he p ote ntial pr o g n ostic si g nifica nce of 
I D H m utati o n i n I C C, o ur o w n lar ger scale st u d y of 2 0 0 patie nts i n dicate d t hat t he I D H m uta nt 
s u bset of I C C ha ve a c o m para ble a g gressi ve c o urse t o t he I D H wil d t y pe t u m ors 1 2. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
7
W hereas t he precise mec ha nis ms b y w hic h I D H 1 a n d 2 m utati o ns pr o m ote t u m ori ge nesis ha ve 
n ot bee n el uci date d, bi oc he mical st u dies s u g gest t hat t he y act t hr o u g h a n e ntirel y n o vel cell ular 
tra nsf or mati o n para di g m1 3. Ca ncer-ass ociate d I D H m utati o ns ca use a si n gle a mi n o aci d c ha n ge 
at a c o nser ve d ar gi ni ne resi d ue wit hi n t he is ocitrate bi n di n g site of I D H 1 ( R 1 3 2) or I D H 2 ( R 1 7 2, 
R 1 4 0), res ulti n g i n a n o vel e nz y matic f u ncti o n:  w hile t he wil d t y pe e nz y me catal yzes t he 
o xi dati ve decar b o x ylati o n of is ocitrate t o - ket o gl utarate (K G) m uta nt I D H lea ds t o t he 
N A D P H- de pe n de nt re d ucti o n of ( α K G) t o R ( –)- 2- h y dr o x y gl utarate ( 2- H G), a pr o p ose d 
‘ o nc o meta b olite’. 2- H G i n hi bits t he f u ncti o n of t he fa mil y of α K G- de pe n de nt  di o x y ge nase 
e nz y mes t hat utilize α K G  as a c ofact or, ma n y of w hic h f u ncti o n as e pi ge netic m o difiers, 
i ncl u di n g t he Tet fa mil y h y dr o x ylases, w hic h c o n vert 5- met h yl-c yt osi ne t o h y dr o x y met h yl-
c yt osi ne as a ste p i n D N A de met h ylati o n, a n d me m bers of t he J u m o mji fa mil y of hist o ne 
de met h ylases. C orres p o n di n gl y, I D H m uta nt t u m ors are c haracterize d b y hi g h le vels of D N A 
met h ylati o n a n d hist o ne l ysi ne met h ylati o n. T here are a t otal of ~ 7 0 α K G- de pe n de nt  
di o x y ge nases t hat are p ote ntial 2- H G tar gets, a n d a d diti o nal fa mil y me m bers ha ve di verse 
f u ncti o ns i n cell p h ysi ol o g y. N ota bl y, o ur gr o u p has s h o w n t hat circ ulati n g 2- H G is a s urr o gate 
bi o mar ker of I D H 1 or I D H 2 m utati o n stat us i n I C C a n d t hat circ ulati n g 2- H G le vels ma y 
c orrelate directl y wit h t u m or b ur de n 1 4.
O ur rece nt st u dies ha ve defi ne d mec ha nis ms f or I D H- dri ve n I C C pr o gressi o n a n d esta blis he d 
n o vel ge neticall y e n gi neere d m o use m o dels ( G E M Ms) of I C C 1 5. We f o u n d t hat m uta nt I D H 
i m pairs a d ult li ver pr o ge nit or cells fr o m u n der g oi n g he pat oc yte differe ntiati o n via s u p pressi o n of 
H N F 4 α  tra nscri pti o n fact or, a master re g ulat or of he pat oc yte i de ntit y a n d q uiesce nce. I n vi v o, 
t he I D H m uta nt li ver s h o ws a berra nt res p o nse t o i nj ur y, c haracterize d b y H N F 4 α  sile nci n g, 
ra m pa nt cell pr oliferati o n, a n d e x pa nsi o n of u n differe ntiate d pr o ge nit ors.  We ha ve als o 
esta blis he d a bi o ba n k of patie nt- deri ve d xe n o graft ( P D X) a n d earl y passa ge cell li ne m o dels.  
I n or der t o de vel o p n o vel strate gies a gai nst I C C, we ha ve perf or me d scree ns of o ur ne w 
c ollecti o n of I C C cell li nes t o 2 0 5 cli nicall y-rele va nt tar gete d a n d c he m ot hera pe utic a ge nts, 
c o nsisti n g of F D A a p pr o ve d dr u gs as well as i n n o vati ve t o ol c o m p o u n ds. I m p orta ntl y, t he 
scree ni n g of ~ 1 0 0 0 a d diti o nal cell li nes fr o m ot her ca ncers i n parallel e na bles us t o i de ntif y 
c o m p o u n ds or classes of c o m p o u n ds t o w hic h I C C’s i n ge neral s h o w se nsiti vit y relati ve t o ot her 
t u m or deri ve d cell li nes a n d c o m p o u n ds s pecific t o defi ne d m utati o nal s u bsets. M ost stri ki n gl y, 
t hese scree ns ha ve i de ntifie d o ne class of i n hi bit or t o w hic h I D H m uta nt I C Cs e x hi bite d e xtre me 
se nsiti vit y -- S R C fa mil y ki nase ( S F K) i n hi bit ors, Dasati ni b ( B M S- 3 5 4 8 2 5) a n d Saracati ni b 
( A Z D 0 5 3 0).  I m p orta ntl y, t hese t w o m olec ules are n ot str uct urall y relate d w hic h is c o nsiste nt 
wit h o n-tar get s pecificit y. Of all 2 0 5 c o m p o u n ds teste d, dasati ni b de m o nstrate d t he greatest 
differe ntial se nsiti vit y bet wee n o ur I D H m uta nt I C C li nes a n d all ot her ~ 1 0 0 0 cell li nes. T hese 
c o m pelli n g data s u g gest n o vel s y nt hetic let hal i nteracti o ns wit h t he I D H m uta nt ge n ot y pe.  
We ha ve defi ne d t he I C 5 0 of dasati ni b a n d f o u n d t he ra n ge of se nsiti vit y was 1- 1 0 n M i n h u ma n 
a n d m uri ne I D H m uta nt I C C li nes, ass ociate d wit h a hi g h de gree of cell deat h. B y c o ntrast, all 
I C C cell li nes wit h W T I D H were > 1 0 ti mes less se nsiti ve t o t he dr u g, wit h I C 5 0’s of greater 
1 5 0 n M. T he se nsiti vit y was c o m para ble t o t hat of C M L cell li nes teste d, a n d c orres p o n ds wit h a 
rea dil y ac hie va ble plas ma c o nce ntrati o n of t he dr u g i n h u ma ns ( plas ma c o nce ntrati o n wit h 
e xisti n g re gi me ns is 1 4 3 n M). We s u bse q ue ntl y teste d t he res p o nse of a n I D H m uta nt xe n o graft 
m o del of I C C t o dasati ni b a n d o bser ve d a dra matic a nti-t u m or effect, wit h dasati ni b treat me nt 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
8
lea di n g t o ra pi d a n d s ustai ne d t u m or re gressi o n ass ociate d wit h massi ve t u m or cell deat h.  
F urt her mec ha nistic st u dies re veale d a p ote nt a n d ra pi d decrease i n le vels of acti vate d beta-
cate ni n a n d t he p h os p h o- pa xilli n (a direct tar get of Src) wit hi n 3 0 mi n of treat me nt wit h 
dasati ni b. 
We pr o p ose t o assess t he i nitial safet y a n d efficac y of dasati ni b i n a p hase II st u d y i n patie nts 
wit h I D H m uta nt u nresecta ble or metastatic I C C base d o n t he f oll o wi n g rati o nale: 1) o ur i nitial 
dr u g scree n has i de ntifie d I D H m uta nt I C C cell li nes e xcee di n gl y se nsiti ve t o dasati ni b (I C 5 0 
c o m para ble t o C M L); 2) o ur xe n o graft e x peri me nts ha ve c o nfir me d t his fi n di n g i n vi v o; a n d 3) 
I D H m utati o n is t he m ost c o m m o n ge ne m utati o n i n I C C ( 2 0- 4 0 % of cases) a n d is r o uti nel y 
teste d usi n g o ur S Na Ps h ot platf or m.  De m o nstrati n g t he cli nical efficac y wit h n o vel a ge nts i n 
t his s u b gr o u p a n d i de ntif yi n g t he p ote ntial pre dict ors f or res p o nse a n d resista nce are esse ntial 
ste ps t o de vel o pi n g effecti ve treat me nts f or m olec ularl y selecte d patie nts wit h a d va nce d I C C.
2. 4 
C orrel ati ve St u dies B ac k gr o u n d
Base d o n o ur pri or a n d o n g oi n g fi n di n gs, we will pr o p ose t he f oll o wi n g c orrelati ve st u dies t o 
assess t he rele va nt p har mac o d y na mic e n d p oi nts, e x pl ore t he p ote ntial mec ha nis ms of acti o n of 
dasati ni b i n I C C, a n d i de ntif y p ote ntial mec ha nis m of resista nce: 
1) bl o o d sa m ples will be o btai ne d at baseli ne, 2 wee ks after treat me nt, a n d at t he be gi n ni n g of 
eac h c ycle, a n d teste d f or ser u m 2- H G a n d C A 1 9- 9 le vels; T hese c ha n ges will be c orrelate d wit h 
t u m or res p o nse b y i ma gi n g st u dies;  
2) patie nts will ha ve ma n dat or y c ore t u m or bi o psies at baseli ne, 8 wee ks f oll o wi n g dasati ni b 
treat me nt a n d at t he ti me of pr o gressi o n f or t h ose w h o ha d eit her S D or res p o nses f or m ore t ha n 
4 m o nt hs.  T u m or bi o psies will be teste d f or c ha n ges i n p h os p h o- pa xilli n ( Src ki nase tar get), 
acti vate d beta-cate ni n, Ki- 6 7 ( pr oliferati o n) a n d clea ve d-cas pase 3 (cell deat h).  
3. 
P A R TI CI P A N T S E L E C TI O N
3. 1 
Eli gi bilit y Criteria
Partici pa nts m ust meet t he f oll o wi n g criteria o n scree ni n g e xa mi nati o n t o be eli gi ble t o 
partici pate i n t he st u d y:

Partici pa nts m ust ha ve u nresecta ble or metastatic hist ol o gicall y c o nfir me d i ntra he patic 
c h ola n gi ocarci n o ma 

Patie nts m ust ha ve eit her I D H 1 or I D H 2 m utati o ns (a n y k n o w n m utati o ns) base d o n t he 
S Na Ps h ot platf or m or ot her m olec ular testi n g platf or m fr o m eit her arc hi ve d tiss ue or fres h 
bi o ps y (teste d i n C LI A-certifie d la b)

Patie nts wit h ot her biliar y tract ca ncers (e xtra he patic or gall bla d der ca ncers) wit h I D H 1 or 
I D H 2 m utati o ns are all o we d

Partici pa nts m ust ha ve meas ura ble disease, defi ne d as at least o ne lesi o n t hat ca n be 
acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter t o be rec or de d) as > 2 0 m m 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
9
wit h c o n ve nti o nal tec h ni q ues or as > 1 0 m m wit h s piral C T sca n. See secti o n 1 0 f or t he 
e val uati o n of meas urea ble disease.

P arti ci p a nts m ust h a v e r e c ei v e d at l e ast o n e pri or pl ati n u m- b as e d r e gi m e n f or a d v a n c e d 
c h ol a n gi o c ar ci n o m a a n d h a d pr o gr essi v e dis e as e or b e c o m e i nt ol er a bl e t o t h e r e gi m e n  

A ge ≥ 1 8 years. 

Life e x pecta nc y of ≥ 3 m o nt hs.

E C O G perf or ma nce stat us 0 or 1 (see A p pe n di x A).

Partici pa nts m ust ha ve a de q uate or ga n a n d marr o w f u ncti o n as defi ne d bel o w:

A bs ol ut e n e utr o p hil c o u nt > 1, 2 0 0/ mc L

Pl at el ets > 7 5, 0 0 0/ m c L

He m o gl o bi n ≥ 9 g/ d L

T ot al bilir u bi n ≤ 2. 5 x t he u p p er li mit of n or mal

A S T ( S G O T)/ A L T ( S G P T) ≤ 5 X i nstit uti o n al u p per li mit of n or m al

P T/ P T T ≤ 1. 5 x U L N

Cr e ati ni n e ≤ 1. 5 or G F R ≥ 6 0 m L/ mi n/ 1. 7 3 m2

Ser u m Al b u mi n ≥ 2. 8 g/ dl

Pri or c he m oe m b olizati o n, ra di ofre q ue nc y a blati o n, or ra diati o n t o t he li ver is all o we d as l o n g 
as t he patie nt has meas ura ble disease o utsi de of t he treate d area or meas ura ble pr o gressi o n at 
t he site of t he treate d area

A bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n i nf or me d c o nse nt d oc u me nt.

Se x uall y acti ve s u bjects ( me n a n d w o me n) m ust a gree t o use me dicall y acce pte d barrier 
met h o ds of c o ntrace pti o n (e g, male or fe male c o n d o m) d uri n g t he c o urse of 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), 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 barrier met h o d a n d a sec o n d 
met h o d of birt h c o ntr ol d uri n g t he c o urse of 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).

W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test at scree ni n g. W o me n 
of c hil d beari n g p ote ntial i ncl u de w o me n w h o ha ve e x perie nce d me narc he a n d w h o ha ve n ot 
u n der g o ne s uccessf ul s ur gical sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral 
o o p h orect o m y) or are n ot p ost me n o pa usal. P ost me n o pa use is defi ne d as a me n orr hea ≥ 1 2 
c o nsec uti ve m o nt hs.  N ote: w o me n w h o ha ve bee n a me n orr heic f or 1 2 or m ore m o nt hs are 
still c o nsi dere d t o be of c hil d beari n g p ote ntial if t he a me n orr hea is p ossi bl y d ue t o pri or 
c he m ot hera p y, a ntiestr o ge ns, o varia n s u p pressi o n or a n y ot her re versi ble reas o n.
3. 2 
E x cl usi o n Crit eri a
Partici pa nts w h o e x hi bit a n y of t he f oll o wi n g c o n diti o ns at scree ni n g will n ot be eli gi ble f or 
a d missi o n i nt o t he st u d y.

Pri or treat me nt wit h dasati ni b

peria m p ullar y t u m ors

C he m ot hera p y, wit hi n 4 wee ks pri or t o e nteri n g t he st u d y ( 6 w ee ks f or nitr os o ur eas or 
mit o m y ci n) or t h os e w h o h a v e n ot r e c o v er e d t o l ess t h a n or e q u al t o gr a d e 1 fr o m a d v ers e 
e v e nts d u e t o a g e nts a d mi nist er e d m or e t h a n 4 wee ks earlier.

T he s u bject has recei ve d ra diati o n t hera p y:

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 0
o
t o b o ne or brai n metastasis wit hi n 1 4 da ys of t he first d ose of st u d y treat me nt
o
t o a n y ot her site(s) wit hi n 2 8 da ys of t he first d ose of st u d y treat me nt

T he s u bject has acti ve brai n metastases or e pi d ural disease ( N ote: S u bjects wit h brai n 
metastases pre vi o usl y treate d wit h w h ole brai n ra diati o n or ra di os ur ger y or s u bjects wit h 
e pi d ural disease pre vi o usl y treate d wit h ra diati o n or s ur ger y w h o are as y m pt o matic a n d d o 
n ot re q uire ster oi d treat me nt f or at least 2 wee ks bef ore starti n g st u d y treat me nt are eli gi ble. 
Ne ur os ur gical resecti o n of brai n metastases or brai n bi o ps y is per mitte d if c o m plete d at least 
3 m o nt hs bef ore starti n g st u d y treat me nt.  ( Baseli ne brai n i ma gi n g wit h c o ntrast-e n ha nce d 
C T or M RI sca ns f or s u bjects wit h k n o w n brai n metastases is re q uire d t o c o nfir m eli gi bilit y.)

T he s u bject has u nc o ntr olle d, si g nifica nt i nterc urre nt or rece 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.
Car 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 Heart Ass ociati o n ( N Y H A) Class III 
( m o derate) or Class I V (se vere) at t he ti me of scree ni n g
ii.
C o nc urre nt u nc o ntr olle d h y perte nsi o n defi ne d as s ustai ne d B P > 1 4 0 m m H g s yst olic, 
or > 9 0 m m H g diast olic des pite o pti mal a nti h y perte nsi ve treat me nt wit hi n 7 da ys of 
t he first d ose of st u d y treat me nt
iii.
Dia g n ose d or s us pecte d c o n ge nital l o n g Q T s y n dr o me
i v.
A n y of t he f oll o wi n g wit hi n 6 m o nt hs bef ore t he first  d ose of st u d y treat me nt:

u nsta ble a n gi na pect oris

cli nicall y-si g nifica nt car diac arr h yt h mias

str o ke (i ncl u di n g 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 pe utic a ntic oa g ulati o n ( N ote: s u bjects 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)

A n y hist or y of cli nicall y si g nifica nt ve ntric ular arr h yt h mias (s uc h as ve ntric ular 
tac h ycar dia, ve ntric ular fi brillati o n, or T orsa des de p oi ntes)

Pr ol o n ge d Q Tc i nter val o n pre-e ntr y electr ocar di o gra m ( > 4 5 0 msec), ma y use 
eit her t he Fri dericia a n d Bazett’s c orrecti o n

H y p o kale mia or h y p o ma g nese mia t hat is n ot c orrecte d pri or t o dasati ni b 
a d mi nistrati o n

 Patie nts s h o ul d n ot be ta ki n g dr u gs t hat are ge nerall y acce pte d t o ha ve a ris k of 
ca usi n g T orsa des de P oi ntes. T he f oll o wi n g m ust be disc o nti n ue d at least 7 da ys 
pri or t o starti n g dasati ni b t o be eli gi ble: q ui ni di ne, pr ocai na mi de, dis o p yra mi de, 
a mi o dar o ne, s otal ol, i b utili de, d ofetili de, er yt hr o m yci ns, clarit hr o m yci n, 
c hl or pr o mazi ne, hal o peri d ol, mes ori dazi ne, t hi ori dazi ne, pi m ozi de, cisa pri de, 
be pri dil, dr o peri d ol, met ha d o ne, arse nic, c hl or o q ui ne, d o m peri d o ne, 
hal ofa ntri ne,le v o met ha d yl, pe nta mi di ne, s parfl o xaci n, li d oflazi ne

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 1
b.
Ot her cli nicall y si g nifica nt dis or ders s uc h as:
i.
acti ve i nfecti o n re q uiri n g s yste mic treat me nt wit hi n 2 8 da ys bef ore t he first d ose of 
st u d y treat me nt
seri o us n o n- heali n g w o u n d/ ulcer/ b o ne fract ure wit hi n 2 8 da ys bef ore t he first d ose of 
st u d y treat me nt
c.    Patie nts wit h k n o w n m o derate/se vere ple ural eff usi o ns t hat are u nrelate d t o mali g na nc y 
or esta blis he d dia g n osis of p ul m o nar y arterial h y perte nsi o n

C o nc urre nt mali g na nc y ( ot her t ha n a de q uatel y treate d n o n- mela n o ma s ki n ca ncer, s u perficial 
tra nsiti o nal cell carci n o ma of t he bla d der, a n d cer vical carci n o ma i n sit u) dia g n ose d wit hi n t he 
past 3 years or a n y c urre ntl y acti ve mali g na nc y

Ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts. 

T he s u bject has recei ve d a n y ot her t y pe of i n vesti gati o nal a ge nt wit hi n 2 8 da ys bef ore t he 
first d ose of st u d y treat me nt. 

T he s u bject is u na ble t o s wall o w ta blets

I n di vi d uals w h o are k n o w n t o be HI V- p ositi ve are e xcl u de d fr o m t his st u d y.  

Pre g na nt w o me n are e xcl u de d fr o m t his st u d y d ue t o t he p ote ntial f or terat o ge nic or 
a b ortifacie nt effects. Beca use t here is a n u n k n o w n b ut p ote ntial ris k of a d verse e ve nts i n 
n ursi n g i nfa nts sec o n dar y t o treat me nt of t he m ot her wit h dasati ni b, breastfee di n g s h o ul d be 
disc o nti n ue d if t he m ot her is treate d wit h dasati ni b. T hese p ote ntial ris ks ma y als o a p pl y t o 
ot her a ge nts use d i n t his st u d y.

S u bjects ma y n ot be recei vi n g a n y ot her st u d y a ge nts c o nc urre ntl y w hile o n t his st u d y
3. 3
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ulati o ns
T here are n o s pecific pr o visi o ns f or t his. B ot h me n a n d w o me n a n d me m bers of all races a n d 
et h nic gr o u ps are eli gi ble f or t his trial.
4. 
R E GI S T R A TI O N P R O C E D U R E S
4. 1 
Ge neral G ui deli nes f or D F/ H C C a n d D F/ P C C I nstit uti o ns
I nstit uti o ns will r e gist er eli gi bl e p arti ci p a nts wit h t h e D F/ H C C Q u alit y Ass ura n ce 
Offi c e f or Cli ni c al Tri als ( Q A C T) c e ntr al r e gistr ati o n s yst e m. R e gistr ati o n m ust 
o c c ur pri or t o t h e i niti ati o n of t h er a p y. A n y partici pa nt n ot r e gist er e d t o t h e pr ot o c ol 
b ef or e tr e at m e nt b e gi ns will b e c o nsi d er e d i n eli gi bl e a n d r e gistr ati o n will b e de nie d. 
A m e m b er of t h e st u d y t e a m will c o nfir m eli gi bilit y crit eri a a n d c o m pl et e t h e 
pr ot o c ol-s p e cifi c eli gi bilit y c h e c klist.
 
F oll o wi n g r e gistr ati o n, p arti ci p a nts m a y b e gi n pr ot o c ol tr e at m e nt. Iss u es t h at 
w o ul d c a us e tr e at m e nt d el a ys s h o ul d b e dis c uss e d wit h t h e Pri n ci p al I n vesti gat or. If 
a partici pa nt d oes n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he partici pa nt’s 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 2
pr ot oc ol stat us m ust be c ha n ge d. N otif y t he Q A C T Re gistrar of partici pa nt st at us 
c h a n g es as s o o n as p ossi bl e.
4. 2 
R e gistr ati o n Pr o c ess f or D F/ H C C a n d D F/ P C C I nstit uti o ns
T he Q A C T re gistrati o n staff is accessi ble o n M o n da y t hr o u g h Fri da y, fr o m 8: 0 0 A M t o 
5: 0 0 P M Easter n Sta n dar d Ti me. I n e mer ge nc y sit uati o ns w he n a partici pa nt m ust be gi n 
treat me nt d uri n g off- h o urs or h oli da ys, call t he Q A C T re gistrati o n li ne at 
 
a n d f oll o w t he i nstr ucti o ns f or re gisteri n g partici pa nts after h o urs.
  
T he re gistrati o n pr oce d ures are as f oll o ws:
1.   
O btai n writte n i nf or me d c o nse nt fr o m t he partici pa nt pri or t o t he perf or ma nce 
of a n y st u d y relate d pr oce d ures or assess me nts.
2.  
C o m plete t he pr ot oc ol-s pecific eli gi bilit y c hec klist usi n g t he eli gi bilit y 
assess me nt d oc u me nte d i n t he partici pa nt’s me dical/researc h rec or d. T o be 
eli gi ble f or re gistrati o n t o t he st u d y, t he partici pa nt m ust meet eac h i ncl usi o n 
a n d e xcl usi o n criteria liste d o n t he eli gi bilit y c hec klist.
 
Re mi n der: C o nfir m eli gi bilit y f or a ncillar y st u dies at t he sa me ti me as eli gi bilit y 
f or t he treat me nt st u d y. Re gistrati o n t o b ot h treat me nt a n d a ncillar y st u dies 
will n ot be c o m plete d if eli gi bilit y re q uire me nts are n ot met f or all st u dies.
 
3.  
Fa x t he eli gi bilit y c hec klist(s) a n d all pa ges of t he c o nse nt f or m(s) t o t he 
Q A C T at 
.
 
E xce pti o n: D F/ P C C Affiliate sites m ust fa x t he e ntire si g ne d c o nse nt f or m 
i ncl u di n g HI P A A Pri vac y A ut h orizati o n a n d t he eli gi bilit y c hec klist t o t he 
Net w or k Affiliate Office. T he Net w or k Affiliate Office will re gister t he 
partici pa nt wit h t he Q A C T.
 
4.  
T he Q A C T Re gistrar will (a) vali date eli gi bilit y, ( b) re gister t he partici pa nt o n 
t he st u d y, a n d (c) ra n d o mize t he partici pa nt w he n a p plica ble.
 
5.  
T he Q A C T Re gistrar will se n d a n e mail c o nfir mati o n of t he re gistrati o n 
a n d/ or ra n d o mizati o n t o t he pers o n i nitiati n g t he re gistrati o n i m me diatel y 
f oll o wi n g t he re gistrati o n a n d/ or ra n d o mizati o n.
 
5. 
T R E A T M E N T P L A N 
Treat me nt will be a d mi nistere d o n a n o ut patie nt basis. E x pecte d t o xicities a n d p ote ntial ris ks 
as well as d ose m o dificati o ns f or dasati ni b are descri be d i n Secti o n 6 of t his pr ot oc ol. N o 
i n vesti gati o nal or c o m mercial a ge nts or t hera pies ot her t ha n t h ose descri be d bel o w ma y be 
a d mi nistere d wit h t he i nte nt t o treat t he partici pa nt’s mali g na nc y.

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 3
Tr eat me nt D escri pti o n
A g e nt
Pr e- m e di c ati o ns; 
Pr e c a uti o ns
D ose 
R o ute 
Sc he d ule 
C y cle 
Le n gt h
d as ati ni b
N o n e
1 0 0 m g 
Oral 
Da ys 1- 2 8 
c o nti n u o usl y
2 8 da ys
5. 1 
Pr e-tr e at m e nt Crit eri a
S u bjects m ust meet eli gi bilit y criteria o n t he first da y of treat me nt.
5. 2 
A g e nt A d mi nistr ati o n 
C urre ntl y dasati ni b is a vaila ble o n st u d y fr o m Brist ol- M yers S q ui b b as pills of 2 0 m g or 5 0 m g. 
T he starti n g d ose of dasati ni b will be 1 0 0 m g b y m o ut h dail y ge nerall y f or eac h 2 8- da y c ycle.  
T he dasati ni b s h o ul d be ta ke n at a p pr o xi matel y t he sa me ti me i n t he m or ni n g eac h da y, b ut 
fasti n g bef ore a n d after d osi n g is n ot c o nsi dere d necessar y at t his ti me. S u bjects s h o ul d tr y t o 
a v oi d pr ot o n p u m p i n hi bit ors a n d H 2 a nta g o nists. S h ort-acti n g a ntaci d a ge nts ma y be ta ke n. If 
u nacce pta ble t o xicit y as defi ne d bel o w is e nc o u ntere d, t he d ose will be re d uce d t o 7 0 m g b y 
m o ut h dail y. If t his l o wer d ose still res ults i n u nacce pta ble t o xicit y, a sec o n d d ose re d ucti o n will 
be i nstit ute d at 4 0 m g b y m o ut h dail y. If t his d ose res ults i n u nacce pta ble t o xicit y, t he s u bject 
will be re m o ve d fr o m t he st u d y.  Sc he d ule d d oses t hat are misse d f or m ore t ha n 6 h o urs s h o ul d 
be o mitte d wit h o ut a n atte m pt t o “ ma ke it u p later.” A v o mite d d ose s h o ul d n ot be ma de u p 
u n der a n y circ u msta nces. T hese misse d a n d v o mite d d oses m ust be rec or de d, h o we ver, i n t he 
patie nt’s file.
S u bjects will be m o nit ore d c o nti n u o usl y f or a d verse e ve nts t hr o u g h 3 0 da ys ( + 7 da ys) after t he 
date of t he decisi o n t o disc o nti n ue st u d y 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 f or a n y a n d all t o xicities. S u bjects e x perie nci n g o ne or m ore A Es d ue t o 
t he st u d y treat me nt ma y re q uire a d osi n g dela y, or re d ucti o n(s), i n t heir d ose i n or der t o c o nti n ue 
wit h st u d y treat me nt. Assess me nt of ca usalit y (c hr o n ol o g y, c o nf o u n di n g fact ors s uc h as disease, 
c o nc o mita nt me dicati o ns, dia g n ostic tests, a n d pre vi o us e x perie nce wit h t he st u d y treat me nt) 
s h o ul d be c o n d ucte d b y t he PI w he n p ossi ble, bef ore a decisi o n is ma de t o m o dif y t he d ose or t o 
h ol d d osi n g te m p oraril y.
5. 3 
Ge neral C o nc o mita nt Me dicati o n a n d S u p p orti ve Care G ui deli nes
5. 3. 1 Dr u g- dr u g i nteracti o ns
Beca use t here is a p ote ntial f or i nteracti o n of Dasati ni b wit h ot her c o nc o mita ntl y a d mi nistere d 
dr u gs t hr o u g h t he c yt oc hr o me P 4 5 0 s yste m, t he case re p ort f or m m ust ca pt ure t he c o nc urre nt 
use of all ot her dr u gs, o ver-t he-c o u nter me dicati o ns, or alter nati ve t hera pies. T he Pri nci pal 
I n vesti gat or ( or Pr ot oc ol C hair) s h o ul d be alerte d if t he partici pa nt is ta ki n g a n y a ge nt k n o w n 
t o affect or wit h t he p ote ntial t o affect selecte d C Y P 4 5 0 is oe nz y mes.
5. 3. 2  S u p p orti ve me dicati o ns

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 4
5. 3. 2. 1   
A ntie metics
A ntie metics s h o ul d be prescri be d b y t he treati n g p h ysicia n as cli nicall y i n dicate d if a 
patie nt de vel o ps na usea a n d/ or v o miti n g. A ge nts classifie d as ha vi n g a hi g h t hera pe utic 
i n de x (s uc h as 5- H T 3 rece pt or a nta g o nists, or N K- 1 rece pt or a nta g o nists) per A S C O or 
M A S C C/ E S M O g ui deli nes f or a nti-e metics i n o nc ol o g y or de xa met has o ne are 
rec o m me n de d ( Hes ket h et al. 2 0 0 8, A S C O 2 0 0 6; R oila et al, A n nals of O nc ol o g y, 2 0 1 0). 
Ca uti o n is rec o m me n de d wit h t he use of a pre pita nt, f osa pre pita nt a n d na bil o ne beca use 
a pre pita nt a n d f osa pre pita nt are b ot h i n hi bit ors a n d i n d ucers of C Y P 3 A 4, a n d na bil o ne is a 
wea k i n hi bit or of C Y P 3 A 4; t h us c o nc o mita nt a d mi nistrati o n of a n y of t hese me dicati o ns 
wit h dasati ni b ca n affect dasati ni b e x p os ure.
5. 3. 2. 2   
A ntic oa g ula nts a n d A nti platelet t hera p y
See e xcl usi o n criteria secti o n.
5. 3. 2. 3   
Gr o wt h fact ors
Pr o p h ylactic use of a c ol o n y-sti m ulati n g fact or ( G- C S F or G M- C S F) is n ot per mitte d o n 
t his trial.  N o net heless, use of a c ol o n y-sti m ulati n g fact or f or t he treat me nt of fe brile 
ne utr o pe nia as per A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes is per missi ble 
( Be n nett et al.  J. Cli n O nc ol 1 9 9 6 Se p; 1 4( 9): 2 5 1 1- 2 5 2 0).  Use of er yt hr o p oieti n 
(i ncl u di n g Pr ocrit a n d Ara nes p) f or treat me nt of disease or treat me nt-relate d a ne mia is 
per mitte d.
5. 4 
D urati o n of T hera p y
D ur ati o n of t h er a p y will d e p e n d o n i n di vi d u al r es p o ns e, e vi d e n c e of dis e as e 
pr o gr essi o n a n d t ol er a n c e. I n t h e a bs e n c e of tr e at m e nt d el a ys d u e t o a d v ers e e v e nts, 
tr e at m e nt m a y c o nti n u e u ntil o n e of t h e f oll o wi n g crit eri a a p pli es:

Dis e as e pr o gr essi o n,

I nt er c urr e nt ill n ess t h at pr e v e nts f urt h er a d mi nistr ati o n of tr e at m e nt,

U n a c c e pt a bl e a d v ers e e v e nt(s),

P arti ci p a nt d e m o nstr at es a n i n a bilit y or u n willi n g n ess t o c o m pl y wit h t h e or al 
m e di c ati o n r e gi m e n a n d/ or d o c u m e nt ati o n r e q uir e m e nts,

P arti ci p a nt d e ci d es t o wit h dr a w fr o m t h e st u d y, or

G e n er al or s p e cifi c c h a n ges i n t he partici p a nt's c o n diti o n r e n d er t he p arti ci pa nt 
u nacce pta ble f or f urt her treat me nt i n t he o pi ni o n of t he treati n g i n vesti gat or.
5. 5 
D urati o n of F oll o w U p 
Partici pa nt s ur vi val i nf or mati o n will be c ollecte d, prefera bl y via office visit or tele p h o ne c o ntact, 
e ver y 1 2 wee ks ( ± 1 wee k) fr o m t he date of last d ose of st u d y dr u g u ntil 1) t he partici pa nt’s 
deat h, 2) t he partici pa nt is l ost t o f oll o w- u p, or 3) st u d y cl os ure (a p pr o xi matel y 6 m o nt hs after 
t he last partici pa nt ter mi nates treat me nt).  Partici pa nts re m o ve d fr o m st u d y f or u nacce pta ble 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 5
a d verse e ve nts will be f oll o we d u ntil res ol uti o n or sta bilizati o n of t he a d verse e ve nt, a n d t he y 
will be f oll o we d u p f or s ur vi val as a b o ve.
 
5. 6 
Criteria f or Re m o val fr o m St u d y 
Partici pa nts will be re m o ve d fr o m st u d y w he n a n y of t he criteria liste d i n Secti o n 
5. 4 a p plies .  T he reas o n f or st u d y re m o val a n d t he date t he partici pa nt was re m o ve d 
m ust be d oc u me nte d i n t he st u d y-s pecific case re p ort f or m ( C R F). Alter nati ve 
care o pti o ns will be disc usse d wit h t he partici pa nt.
I n t h e e v e nt of u n us u al or lif e-t hr e at e ni n g c o m pli c ati o ns, p arti ci p ati n g i n v esti g at ors 
m ust i m m e di at el y n otif y t h e Pri n ci p al I n v esti g at or ( or Pr ot o c ol C h air), Dr. Br u c e 
Gi a nt o ni o at p a g er 1 5 0 5 0
6. 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S 
T o xicit y assess me nts will be d o ne usi n g t he C T E P Acti ve Versi o n of t he N CI C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) w hic h is a vaila ble at: 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m . 
S u bjects will recei ve dasati ni b orall y at a (starti n g) d ose of 1 0 0 m g o nce dail y. D ose re d ucti o ns 
a n d dela ys t o ma na ge t o xicit y are all o we d u n der t he g ui deli nes bel o w.
All a d verse e ve nts ( A Es) e x perie nce d b y partici pa nts will be c ollecte d fr o m t he ti me of t he first 
d ose of st u d y treat me nt, t hr o u g h t he st u d y a n d u ntil t he fi nal st u d y visit. Partici pa nts c o nti n ui n g 
t o e x perie nce t o xicit y at t he off st u d y visit ma y be c o ntacte d f or a d diti o nal assess me nts u ntil t he 
t o xicit y has res ol ve d or is dee me d irre versi ble.
 
6. 1 
A ntici pate d T o xicities
 
Partici pa nts m ust be i nstr ucte d t o n otif y t heir p h ysicia n i m me diatel y f or a n y a n d all t o xicities. 
T he ge neral a d verse e ve nt pr ofile of dasati ni b i ncl u des ple ural eff usi o ns, pericar dial eff usi o ns, 
peri p heral e de ma, a n d se vere m yel os u p pressi o n.  Ot her t o xicities li kel y t o be e nc o u ntere d d ue t o 
dasati ni b are na usea, heart b ur n, diarr hea, ras h, li ver t o xicit y, a n d fati g ue. 
6. 2 
D ose Re d ucti o ns, I nterr u pti o ns, Re- Esc al ati o ns, a n d Del a ys
6. 2. 1 D ose Re d ucti o ns
Ta ble 6- 1 D ose Re d ucti o ns
D os e L e v el
D as ati ni b D os e
St arti n g D os e
1 0 0 m g d ail y
- 1
7 0 m g d ail y
- 2
4 0 m g d ail y

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 6
G ui deli nes f or t he ma na ge me nt of A Es (ie, d ose i nterr u pti o ns a n d d ose re d ucti o ns) are prese nte d 
i n t he ne xt secti o ns. Eac h d ose re d ucti o n of dasati 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 ucti o ns of m ore t ha n o ne d ose le vel are acce pta ble if a gree d t o b y t he 
I n vesti gat or. If st u d y treat me nt of dasati ni b is restarte d after bei n g wit h hel d or i nterr u pte d, t he 
s u bject s h o ul d be i nstr ucte d n ot t o ma ke u p t he misse d d oses of dasati ni b.  T he reas o n f or 
treat me nt dela y a n d re d uce d d ose m ust be rec or de d o n t he C R F.
6. 2. 2 D ose I nterr u pti o ns
D osi n g ma y nee d t o be i nterr u pte d f or A Es c o nsi dere d n ot relate d t o dasati ni b if t his is
cli nicall y i n dicate d or if ca usalit y is i nitiall y u ncertai n. St u d y treat me nt ma y be res u me d at t he
sa me d ose ( or a l o wer d ose per i n vesti gat or j u d g me nt) if t he A E is deter mi ne d n ot t o be relate d
t o dasati ni b o nce t he i n vesti gat or deter mi nes t hat retreat me nt is cli nicall y a p pr o priate a n d t he
partici pa nt meets t he pr ot oc ol re-treat me nt criteria.
If st u d y treat me nt is i nterr u pte d, t he partici pa nt s h o ul d be i nstr ucte d n ot t o ma ke u p t he wit h hel d 
d oses, a n d t he pla n ne d safet y a n d t u m or assess me nt sc he d ule are t o be mai ntai ne d.
6. 2. 3 D ose Re- Escalati o ns
D ose re-escalati o n is n ot all o we d f or d ose re d ucti o n tri g gere d treat me nt relate d t o xicities.
6. 2. 4 Disc o nti n uati o n of St u d y Dr u g
 
Reas o ns/e ve nts tri g geri n g per ma ne nt disc o nti n uati o n of dasati ni b:

If t he s u bject d oes n ot rec o ver fr o m his or her t o xicities t o t olera ble Gra de ≤ 2 or baseli ne 
wit hi n 6 wee ks

S u bjects w h o ca n n ot t olerate 4 0 m g dail y

A n ac ute m y ocar dial i nfarcti o n or a n y ot her cli nicall y si g nifica nt arterial t hr o m b oe m b olic 
c o m plicati o n

Patie nts wit h c o nfir me d p ul m o nar y arter y h y perte nsi o n

A n y treat me nt-relate d Gra de 4 n o n- he mat ol o gic t o xicit y. H o we ver, if t he patie nt is deri vi n g 
cli nical be nefit fr o m dasati ni b, t he t o xicit y m ust res ol ve t o Gra de ≤1  pri or t o restarti n g, a n d 
after a p pr o val b y t he pri nci pal i n vesti gat or, treat me nt at a re d uce d d ose ca n be c o nsi dere d.

Treat me nt-relate d Gra de 4 fe brile ne utr o pe nia.  H o we ver, if t he patie nt is deri vi n g cli nical 
be nefit fr o m dasati ni b, t he t o xicit y m ust res ol ve t o Gra de ≤1  pri or t o restarti n g, a n d after 
a p pr o val b y t he pri nci pal i n vesti gat or, treat me nt at a re d uce d d ose ca n be c o nsi dere d.

Necessit y f or treat me nt wit h ot her a ntica ncer treat me nt pr o hi bite 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 acce pte d barrier met h o ds of 
c o ntrace 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 c o urse of t he st u d y a n d f or  
4 m o nt hs f oll o wi n g disc o nti n uati o n of st u d y treat me nt

W o me n w h o bec o me pre g na nt or are breast fee di n g
T he reas o n f or st u d y treat me nt disc o nti n uati o n will be d oc u me nte d. F or s u bjects w h o 
disc o nti n ue or are wit h dra w n fr o m st u d y treat me nt, e ver y eff ort m ust be ma de t o u n derta ke 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
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pr ot oc ol-s pecifie d f oll o w- u p pr oce d ures a n d e n d- of-treat me nt assess me nts, if p ossi ble, u nless 
c o nse nt t o partici pate i n t he st u d y is als o wit h dra w n.
6. 3 
T o xicit y Ma na ge me nt
Ge neral G ui deli nes f or N o n- He mat ol o gic a n d He mat ol o gic A d verse E ve nts ( A Es)
Ge neral g ui deli nes f or t he ma na ge me nt of n o n- he mat ol o gic a n d he mat ol o gic t o xicities are 
pr o vi de d i n Ta ble 6- 2 a n d Ta ble 6- 3, res pecti vel y. As a ge neral a p pr oac h, it is s u g geste d t hat all 
A Es be ma na ge d wit h s u p p orti ve care w he n p ossi ble at t he earliest si g ns of t o xicit y. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
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Ta ble 6- 2 Ma na ge me nt of St u d y Treat me nt- Relate d N o n- He mat ol o gic T o xicities
C T C A E Versi o n 4 Gr a de 
G ui deli nes/I nter ve nti o n
Gr a de 1:
A d d s u p p orti ve care as i n dicate d.  C o nti n ue dasati ni b at t he c urre nt 
d ose le vel.
Gr a de 2:
Gra de 2 A Es c o nsi dere d relate d t o 
dasati ni b t hat are s u bjecti vel y t olera ble 
or easil y ma na ge d
A d d s u p p orti ve care as i n dicate d.  C o nti n ue dasati ni b at t he c urre nt 
d ose le vel. 
Gra de 2 A Es c o nsi dere d relate d t o 
dasati ni b t hat are i nt olera ble t o t he 
s u bject or dee me d u nacce pta ble i n t he 
i n vesti gat or’s j u d g me nt; or are n ot 
easil y ma na ge d or c orrecte d
D ose re d uce
 
If t he A E d ose n ot res ol ve t o Gra de ≤ 1 or baseli ne i n 7 t o 1 0 da ys 
or w orse ns at a n y ti me, dasati ni b d osi n g s h o ul d t he n be 
i nterr u pte d.  T he n u p o n res ol uti o n t o baseli ne or Gra de ≤ 1, t he 
re d uce d d ose s h o ul d be restarte d.
 
If t he A E d oes res ol ves t o res ol ves t o Gra de ≤ 1 or baseli ne 
wit h o ut a d ose i nterr u pti o n, c o nti n ue t he re d uce d d ose.
Gr a de 3:
Gra de 3 A Es c o nsi dere d relate d t o 
dasati ni b w hic h occ urre d wit h o ut 
o pti mal pr o p h yla xis or w hic h is easil y 
ma na ge d b y me dical i nter ve nti o n or 
res ol ve d q uic kl y
 
I nterr u pt dasati ni b a n d a d d s u p p orti ve care as i n dicate d
 
F or A Es t hat are easil y ma na ge d (e. g., c orrecti o n of electr ol ytes) 
wit h res ol uti o n t o baseli ne or Gra de ≤ 1 wit hi n 2 4 h o urs,  dasati ni b 
ma y be res u me d at eit her t he sa me d ose or wit h a d ose re d ucti o n at 
t he discreti o n of t he i n vesti gat or u nless t his is a rec urri n g e ve nt at 
w hic h ti me t he d ose s h o ul d be re d uce d
 
F or A Es t hat re q uire s u p p orti ve care, t he d ose s h o ul d be hel d 
w hile s u p p orti ve care is i nitiate d a n d o pti mize d.  T he n u p o n 
res ol uti o n of t he A E t o baseli ne or Gra de ≤ 1,  dasati ni b ma y be 
res u me d at eit her t he sa me d ose or wit h a d ose re d ucti o n at t he 
discreti o n of t he i n vesti gat or u nless t his is a rec urri n g e ve nt at 
w hic h ti me t he d ose s h o ul d be re d uce d
Gra de 3 A Es c o nsi dere d relate d t o 
st u d y treat me nt t hat occ urre d des pite 
o pti mal pr o p h yla xis or is n ot easil y 
ma na ge d b y me dical i nter ve nti o n 
I nterr u pt st u d y treat me nt u ntil rec o ver y t o ≤ Gra de 1 or baseli ne, a n d 
res u me treat me nt wit h a d ose re d ucti o n
Gr a de 4:
Gra de 4 A Es c o nsi dere d relate d t o 
st u d y treat me nt
Per ma ne ntl y disc o nti n ue st u d y treat me nt u nless deter mi ne d t hat t he 
s u bject is u ne q ui v ocall y deri vi n g cli nical be nefit.  I n t his case, u p o n 
rec o ver y t o Gra de ≤ 1 or baseli ne, t he s u bject ma y be re-treate d at a 
re d uce d d ose t hat is t o be deter mi ne d b y t he i n vesti gat or 
D ose re d ucti o ns or dela ys ma y occ ur i n t he setti n g of l o wer gra de t o xicit y t ha n defi ne d a b o ve if t he i n vesti gat or belie ves 
t hat it is i n t he i nterest of t he s u bject’s safet y.
Ta ble 6- 3: Ma na ge me nt of He mat ol o gic T o xicities

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
1 9
C T C A E Versi o n 4 Gr a de
I nter ve nti o n
Ne utr o pe ni a
Gra de 3 ne utr o pe nia wit h d oc u me nte d 
i nfecti o n
Gra de 3 ne utr o pe nia ≥ 5 da ys
Gra de 4 ne utr o pe nia 
I nterr u pt dasati ni b treat me nt u ntil res ol uti o n t o Gra de ≤ 1, a n d 
res u me dasati ni b treat me nt at a re d uce d d ose. 
T hr o m b oc yt o pe ni a
Gra de 3 t hr o m b oc yt o pe nia wit h 
cli nicall y si g nifica nt blee di n g or 
Gra de 4 t hr o m b oc yt o pe nia
I nterr u pt dasati ni b treat me nt u ntil platelet c o u nt is  ≥ 
7 5, 0 0 0/ m m 3, a n d res u me dasati ni b treat me nt at a re d uce d d ose
Fe brile Ne utr o pe ni a
Gra de 3 fe brile ne utr o pe nia
I nterr u pt dasati ni b treat me nt u ntil rec o ver y of A N C t o Gra de ≤ 1 
a n d te m perat ure t o ≤ 3 8. 0° C a n d res u me dasati ni b treat me nt at a 
re d uce d d ose.
Gra de 4 fe brile ne utr o pe nia
Per ma ne ntl y disc o nti n ue st u d y treat me nt u nless deter mi ne d t hat 
t he s u bject is u ne q ui v ocall y deri vi n g cli nical be nefit.  I n t his 
case, u p o n rec o ver y t o Gra de ≤ 1 or baseli ne, t he s u bject ma y be 
re-treate d at a re d uce d d ose t hat is t o be deter mi ne d b y t he 
i n vesti gat or 
Ot her Gr a de 4 He m at ol o gic T o xicities
Gra de 4 he mat ol o gic t o xicities 
ot her t ha n a ne mia
Per ma ne ntl y disc o nti n ue st u d y treat me nt u nless deter mi ne d t hat 
t he s u bject is clearl y deri vi n g cli nical be nefit. I n t his case, u p o n 
rec o ver y t o Gra de ≤ 1 or baseli ne, t he s u bject ma y be re-treate d 
at a re d uce d d ose t hat is t o be deter mi ne d b y t he i n vesti gat or a n d 
s p o ns or a n d o nl y wit h a p pr o val b y t he s p o ns or.
Gra de 4 a ne mia
Per ma ne nt disc o nti n uati o n f or Gra de 4 a ne mia is n ot ma n date d. 
D ose re d ucti o ns or d ose dela ys f or a ne mia s h o ul d be a p plie d as 
cli nicall y i n dicate d. S u p p orti ve care s uc h as re d bl o o d cell 
tra nsf usi o ns s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal 
g ui deli nes.
A N C, a bs ol ute ne utr o p hil c o u nt.
Ne utr o pe nia: Gra de 1 ( L L N ≤ A N C < 1. 5  1 09/ L; Gra de 2 ( 1  1 09/ L ≤ A N C < 1. 5 x 1 09/ L), 
Gra de 3 ( 0. 5  1 09/ L ≤ A N C < 1  1 09/ L), Gra de 4 ( A N C < 0. 5  1 09/ L).
Fe brile Ne ut or pe nia: Gra de 3 ( prese nt); Gra de 4 ( Life-t hreate ni n g c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d).
T hr o m b oc yt o pe nia: Gra de 1 ( < L L N – 7 5 x 1 0 9/ L); Gra de 2  ( < 7 5. 0 – 5 0. 0 x  1 09/ L);  Gra de 3 
( Platelet c o u nt ≤ 5 0 - 2 5  1 09/ L); Gra de 4 ( Platelet c o u nt < 2 5  1 09/ L).
D ose re d ucti o ns or dela ys ma y occ ur i n t he setti n g of l o wer gra de t o xicit y t ha n defi ne d a b o ve if 
t he i n vesti gat or belie ves t hat it is i n t he i nterest of t he s u bject’s safet y.
Treat me nt- E mer ge nt E de ma 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 0
If treat me nt-e mer ge nt e de ma bec o mes s y m pt o matic, dasati ni b d osi n g will be st o p pe d a n d n o 
restarte d u ntil t o xicit y is re d uce d t o a gra de 1 or less.
Treat me nt- E mer ge nt Ple ural Eff usi o n 
If treat me nt-e mer ge nt ple ural eff usi o n bec o mes s y m pt o matic, t he patie nt will u n der g o 
t h orace ntesis as nee de d f or s y m pt o matic relief a n d be treate d wit h pre d nis o ne 4 0 m g dail y ( or 
e q ui vale nt) f or 2 da ys, f oll o we d b y a ta per o ver 7 da ys.
Treat me nt- E mer ge nt C orrecte d Q T ( Q Tc) Pr ol o n gati o n
Treat me nt wit h dasati ni b has bee n ass ociate d wit h a mil d pr ol o n gati o n of t he Q Tc i nter val.  
Ot her fact ors w hic h ma y c o ntri b ute t o Q Tc pr ol o n gati o n i ncl u de

Treat me nt wit h ot her dr u gs ass ociate d wit h Q Tc pr ol o n gati o n (see 
htt p:// w w w. qt dr u gs. or g)

Treat me nt wit h C y P 3 A 4 i n hi bit ors ( w hic h ma y i ncrease dasati ni b dr u g le vels)

Electr ol yte c ha n ges ( h y p o kale mia, h y p ocalce mia, h y p o ma g nese mia)

Me dical c o n diti o ns w hic h ca n alter electr ol yte stat us e. g., se vere or pr ol o n ge d diarr hea
S u bjects ha vi n g a n y of t hese a d diti o nal ris k fact ors w hile o n dasati ni b m ust ha ve E C Gs 
perf or me d a p pr o xi matel y o ne wee k after t he o nset of t hese fact ors.
If at a n y ti me o n st u d y t here is a n i ncrease i n Q Tc i nter val t o a n a bs ol ute val ue > 5 0 0 msec, t w o 
a d diti o nal E C Gs s h o ul d be perf or me d wit hi n 3 0 mi n utes after t he i nitial E C G wit h i nter vals n ot 
less t ha n 3 mi n utes a part.  If t he a vera ge Q Tc F fr o m t he t hree E C Gs is > 5 0 0 msec, st u d y 
treat me nt m ust be wit h hel d a n d t he f oll o wi n g acti o ns s h o ul d be ta ke n:

C hec k electr ol ytes, es peciall y p otassi u m, ma g nesi u m a n d calci u m. C orrect a b n or malities 
as cli nicall y i n dicate d

If p ossi ble, disc o nti n ue a n y Q Tc- pr ol o n gi n g c o nc o mita nt me dicati o ns 

 Re peat E C G tri plets 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 car di ol o gist
T he S p o ns or s h o ul d be n otifie d i m me diatel y of a n y Q Tc pr ol o n gati o n e ve nt. 
S u bjects wit h Q Tc pr ol o n gati o n a n d s y m pt o ms m ust be m o nit ore d cl osel y u ntil t he Q Tc 
ele vati o n has res ol ve d. Car di ol o g y c o ns ultati o n is rec o m me n de d f or e val uati o n a n d s u bject 
ma na ge me nt. S y m pt o matic s u bjects m ust be treate d acc or di n g t o sta n dar d cli nical practice. N o 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 1
a d diti o nal st u d y treat me nt is t o be gi ve n t o t he s u bject u ntil after t he e ve nt has res ol ve d, t he 
s u bject has bee n t h or o u g hl y e val uate d, a n d f urt her treat me nt has bee n a gree d t o b y t he S p o ns or. 
If a n y a d diti o nal st u d y treat me nt is gi ve n (e g, after c orrecti o n of electr ol yte a b n or malities a n d 
n or malizati o n of Q Tc F), it will be at a re d uce d d ose as a gree d t o b y t he i n vesti gat or a n d t he 
S p o ns or.
7. 
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N 
7. 1 
Dasati ni b
D et ails c a n b e f o u n d i n t h e I n v esti g at or Br o c h ur e. 
7. 1. 1 
Descri pti o n
Dasati ni b ta blets are w hite t o off- w hite, bic o n ve x, fil m-c oate d ta blets c o ntai ni n g
dasati ni b, wit h t he f oll o wi n g i nacti ve i n gre die nts: lact ose m o n o h y drate, 
micr ocr ystalli ne cell ul ose, cr oscar mell ose s o di u m, h y dr o x y pr o p yl cell ul ose, a n d 
ma g nesi u m stearate. T he ta blet c oati n g c o nsists of h y pr o mell ose, tita ni u m 
di o xi de, a n d p ol yet h yle ne gl yc ol.
7. 1. 2 
F or m ulati o n
Dasati ni b is pr o vi de d i n t w o differe nt stre n gt hs:
2 0 m g fil m-c oate d ta blets, bic o n ve x, r o u n d, w hite t o off- w hite i n a p peara nce 
wit h“ B M S” de b osse d o n o ne si de a n d " 5 2 7" o n t he ot her si de
5 0 m g fil m-c oate d ta blets, bic o n ve x, o val, w hite t o off- w hite i n a p peara nce 
wit h“ B M S” de b osse d o n o ne si de a n d " 5 2 8" o n t he ot her si de
Dasati ni b is pac ka ge d i n b ottles as f oll o ws:
dasati ni b 2 0 m g fil m-c oate d ta blets, 3 0 ta bs/ b ottle
dasati ni b 5 0 m g fil m-c oate d ta blets, 3 0 ta bs/ b ottle
Eac h b ottle is la bele d i n a n o pe n la bel ma n ner. La bels c o ntai n, at a mi ni m u m, t he
f oll o wi n g i nf or mati o n: pr o d uct na me, ta blet stre n gt h, batc h n u m ber, directi o ns f or 
use, st ora ge c o n diti o ns, a n d a p pr o priate ca uti o n state me nts.
7. 1. 3 
St ora ge a n d Sta bilit y
D as ati ni b t a bl ets s h o ul d b e st ore d i n a sec ure area at 2 5° C ( 7 7° F); bet w ee n 1 5° –
3 0 C°.
7. 1. 4 
Ha n dli n g
Pr o ce d ur es f or pr o p er h a n dli n g a n d dis p os al of a ntic a ncer dr u gs s h o ul d be c o nsi der e d.

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 2
D as ati ni b t a bl ets c o nsist of a c or e ta blet (c o ntai ni n g t he acti ve dr u g s u bsta nc e), 
s urr o u n d e d b y a fil m c o ati n g t o pre ve nt e x p os ur e of p har m ac y a n d cli nical pers o n nel t o 
t h e a cti v e dr u g s u bst a n c e. If t a blets are cr us he d or br o ke n, p har mac y a n d cli nical 
p ers o n n el s h o ul d w e ar dis p os a ble c h e m ot hera p y gl o v es. P ers o n n el w h o are pre g na nt 
s h o ul d a v oi d e x p os ur e t o cr us he d a n d/ or br o k e n t a blets.
7. 1. 5 
A vaila bilit y
Dasati ni b ( S pr ycel ®) will be s u p plie d b y Brist ol- M yers S q ui b b free- of-c har ge.
7. 1. 6 
A d mi nistrati o n
T h e d as ati ni b s h o ul d b e t a k e n b y m o ut h wit h a gl ass of w at er at a p pr o xi m at el y 
t h e s a m e ti m e i n t h e m or ni n g e a c h d a y, b ut f asti n g b ef or e a n d aft er d osi n g is 
n ot c o nsi d er e d n e c ess ar y at t his ti m e.
S u bj e cts s h o ul d tr y t o a v oi d pr ot o n p u m p i n hi bit ors a n d H 2 a nt a g o nists.
7. 1. 7 
Acc o u nta bilit y
It is t h e r es p o nsi bilit y of t h e I n v esti g at or t o e ns ur e t h at a c urr e nt r e c or d of 
d as ati ni b dis p ositi o n is m ai nt ai n e d at e a c h st u d y sit e w h er e d as ati ni b is 
i n v e nt ori e d a n d dis p os e d.
R e c or ds or l o gs m ust c o m pl y wit h a p pli c a bl e r e g ul ati o ns a n d g ui d eli n es, a n d 
s h o ul d i n cl u d e:
A m o u nt r e c ei v e d a n d pl a c e d i n st or a g e ar e a.
A m o u nt c urr e ntl y i n st or a g e ar e a.
L a b el I D n u m b er or b at c h n u m b er a n d us e d at e or e x pir y d at e.
D at es a n d i niti als of p ers o n r es p o nsi bl e f or e a c h d as ati ni b
i n v e nt or y e ntr y/ m o v e m e nt.
A m o u nt dis p e ns e d t o a n d r et ur n e d b y e a c h s u bj e ct, i n cl u di n g
u ni q u e s u bj e ct i d e ntifi ers.
A m o u nt tr a nsf err e d t o a n ot h er ar e a/sit e f or dis p e nsi n g or st or a g e.
N o n-st u d y dis p ositi o n ( e. g., l ost, w ast e d, br o k e n).
A m o u nt r et ur n e d t o B M S, if a p pli c a bl e.
A m o u nt d estr o y e d at st u d y sit e, if a p pli c a bl e.
R et ai n s a m pl es s e nt t o t hir d p art y f or
bi o a v ail a bilit y/ bi o e q ui v al e n c e, if a p pli c a bl e.
D as ati ni b dis p e nsi n g r e c or d/i n v e nt or y l o gs a n d c o pi es of si g n e d p a c ki n g lists 
m ust b e m ai nt ai n e d at t h e i n v esti g ati o n al sit e. B at c h n u m b ers f or d as ati ni b 
m ust b e r e c or d e d i n t h e dr u g a c c o u nt a bilit y r e c or ds.
7. 1. 8 
Destr ucti o n a n d Ret ur n

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 3
At t h e e n d of t h e st u d y, u n us e d s u p pli es of d as ati ni b s h o ul d b e d estr o y e d 
a c c or di n g t o i nstit uti o n al p oli ci es. D estr u cti o n will b e d o c u m e nt e d i n t h e Dr u g 
A c c o u nt a bilit y R e c or d F or m.
8. 
C O R R E L A TI V E/ S P E CI A L S T U DI E S 
8. 1 
P har mac o d y na mic St u dies
8. 1. 1 
La b orat or y C orrelati ve St u dies
8. 1. 1. 1 Ser u m bi o mar kers f or dasati ni b
O ur gr o u p h as s h o w n t h at cir c ul ati n g 2- H G is a s urr o g at e bi o m ar k er of I D H 1 
or I D H 2 m ut ati o n st at us i n I C C a n d t h at cir c ul ati n g 2- H G l e v els m a y c orr el at e 
dir e ctl y wit h t u m or b ur d e n ( B or g er 2 0 1 4).
Bl o o d sa m ples will be o btai ne d at baseli ne, 2 wee ks after treat me nt, a n d at t he 
be gi n ni n g of eac h c ycle, at ti me of disease pr o gressi o n, a n d teste d f or ser u m 2-
H G a n d C A 1 9- 9 le vels; T hese c ha n ges will be c orrelate d wit h t u m or res p o nse b y 
i ma gi n g st u dies;  
8. 1. 2 
Tiss ue Bi o mar kers f or dasati ni b
8. 1. 2. 1 Tiss ue bi o mar kers f or dasati ni b
Patie nts will ha ve ma n dat or y t u m or c ore bi o psies at baseli ne.  P ost-treat me nt 
bi o psies at 8 wee ks f oll o wi n g dasati ni b treat me nt a n d at t he ti me of pr o gressi o n 
f or t h ose w h o ha d eit her S D or res p o nses f or m ore t ha n 4 m o nt hs are str o n gl y 
e nc o ura ge d b ut o pti o nal T u m or bi o psies will be teste d f or c ha n ges i n p h os p h o-
pa xilli n ( Src ki nase tar get), acti vate d beta-cate ni n, Ki- 6 7 ( pr oliferati o n) a n d 
clea ve d-cas pase 3 (cell deat h).  
9.
 C LI NI C A L A N D L A B O R A T O R Y E V A L U A TI O N S A N D S T U D Y C A L E N D A R
B as eli n e e v al u ati o ns ar e t o b e c o n d u ct e d wit hi n 2- w e e ks pri or t o st art of pr ot o c ol 
t h er a p y. S c a ns m ust b e d o n e < 4 w e e ks pri or t o t h e st art of t h er a p y. I n t h e e v e nt t h at t h e 
p arti ci p a nt's c o n diti o n is d et eri or ati n g, la b orat or y e val u ati o ns s h o ul d be re p eate d wit hi n 
4 8 h o urs pri or t o i niti ati o n of t h e n e xt c ycl e of t h era p y.
All ass ess m e nts m ust b e p erf or m e d pri or t o a d mi nistrati o n of a n y st u d y 
m e di c ati o n. All st u d y ass ess m e nts s h o ul d b e d o ne wit hi n + 3 da ys of t he pr ot oc ol-
s p e cifi e d d at e, u nl ess ot h er wis e n ote d. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 4
9. 1 
E v al u ati o ns
9. 1. 1 
Pretreat me nt e val uati o ns
E val uati o ns t hat m ust be perf or me d wit hi n 1 wee k pri or t o t he first d ose of dasati ni b:

Pre g na nc y test (ser u m or uri ne) f or w o me n of c hil d beari n g p ote ntial wit hi n 7 da ys pri or t o 
i nitiati o n of t hera p y.
E val uati o ns t hat m ust be perf or me d wit hi n 2 wee ks pri or t o t he first d ose of dasati ni b:

Me dical hist or y 

P h ysical e xa mi nati o n, i ncl u di n g vital si g ns, hei g ht, wei g ht, perf or ma nce stat us.

He mat ol o g y:  c o m plete bl o o d c o u nt ( C B C) wit h differe ntial.

Ser u m C he mistries: s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, creati ni ne, gl uc ose, t otal 
bilir u bi n, al kali ne p h os p hatase, L D H, t otal pr otei n, al b u mi n, S G O T( A S T), S G P T ( A L T), 
calci u m, p h os p h or us a n d T S H. 

C A 1 9- 9

P T/I N R

Uri nal ysis:  La b uri nal ysis will be o btai ne d. Patie nts wit h a p ositi ve uri nal ysis f or uri ne 
pr otei n (rea di n g of 2 + or greater) will t he n u n der g o a 2 4 h o ur uri ne c ollecti o n f or pr otei n.

Electr ocar di o gra m

He patitis B s urface a nti ge n, c ore a nti b o d y, a n d s urface a nti b o d y, a n d He patitis C a nti b o d y 
m ust be o btai ne d wit hi n 1 2 0 da ys of st u d y e nr oll me nt
*If t he scree ni n g la bs ha ve bee n c o m plete d wit hi n 7 da ys of C ycle 1 Da y 1, t hese la bs d o n ot 
nee d t o be re peate d.  H o we ver, baseli ne c orrelati ve st u dies nee d t o be dra w n o n C ycle 1 Da y 1 
pri or t o a d mi nistrati o n of dasati ni b.
E val uati o ns t hat m ust be perf or me d wit hi n 2 8 da ys pri or t o t he first d ose of dasati ni b: 

I ma gi n g: Baseli ne ra di ol o gic e val uati o n of t u m or b ur de n b y c hest/a b d o me n/ pel vis C T sca n.  
M RI of t he li ver ca n be use d if patie nts ha ve a n I V c o ntrast aller g y or t he C T sca n is s u b o pti mal 
base d o n t he p h ysicia n’s j u d g me nt.
 
9. 1. 2 
O n- Treat me nt E val uati o ns

S u bjects are defi ne d as e nr olle d u p o n recei pt of t he first d ose of st u d y treat me nt.

Eac h c ycle is defi ne d as 2 8 da ys.

D uri n g c ycle 1, assess me nts will be ma de o n da y 1, 8 a n d 1 5.

D uri n g c ycles 2- 3, assess me nts will be ma de o n da y 1, a n d 1 5.

I n s u bse q ue nt c ycles, assess me nts will be ma de o n da y 1.

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 5

All n o n-ra di ol o gical assess me nts ha ve a +/- 3 da y wi n d o w.

All ra di ol o gical assess me nts ha ve a +/- 7 da y wi n d o w.
If t he partici pa nt is u na ble t o ha ve a st u d y assess me nt ta 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 de of his or her c o ntr ol (e. g., cli nic 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 me d as cl ose as p ossi ble t o t he re q uire d 
sc he d ule.
See Ta ble 9- 1 f or details o n t he ti mi n g of assess me nts f or o n-treat me nt e val uati o ns. 

P h ysical e xa mi nati o n, i ncl u di n g vital si g ns, hei g ht, wei g ht, perf or ma nce stat us.

T o xicit y assess me nt

He mat ol o g y:  c o m plete bl o o d c o u nt ( C B C) wit h differe ntial.

Ser u m C he mistries: s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, creati ni ne, gl uc ose, t otal 
bilir u bi n, al kali ne p h os p hatase, L D H, t otal pr otei n, al b u mi n, S G O T( A S T), S G P T ( A L T), 
calci u m, p h os p h or us a n d T S H.

C A 1 9- 9

Uri nal ysis:  La b uri nal ysis will be o btai ne d.  Patie nts wit h a p ositi ve uri nal ysis  f or uri ne 
pr otei n (rea di n g of 2 + or greater) will t he n u n der g o a 2 4 h o ur uri ne c ollecti o n f or pr otei n.
9. 1. 3  P ost- Treat me nt E val uati o ns
S u bjects will ret ur n t o t he st u d y site bet wee n 3 0 – 3 7 da ys after t he last d ose of dasati ni b f or a n 
e n d- of-treat me nt assess me nt. La b orat or y a n d p h ysical e xa mi nati o ns will be perf or me d.
Re mai ni n g st u d y treat me nt will be ret ur ne d b y t he partici pa nt, a n d treat me nt c o m plia nce will be
d oc u me nte d. A d diti o nal f oll o w- u p will occ ur f or partici pa nts wit h A Es relate d t o st u d y treat me nt
t hat are o n g oi n g at t he ti me of t his visit, a n d f or partici pa nts wit h S A Es relate d t o st u d y treat me nt 
t hat occ ur after t he ti me of t his visit.
All Gra de 3 or 4 S A Es t hat are o n g oi n g 3 0 da ys after t he last d ose of st u d y treat me nt, a n d A Es 
assesse d t hat le d t o st u d y treat me nt disc o nti n uati o n t hat are o n g oi n g 3 0 da ys after t he last
d ose of st u d y treat me nt, are t o be f oll o we d u ntil:

t he A E has res ol ve d, or;

t he A E has i m pr o ve d t o Gra de 2 or l o wer, or;

t he i n vesti gat or deter mi nes t hat t he e ve nt has bec o me sta ble or irre versi ble.
T his re q uire me nt als o a p plies t o relate d S A Es t hat occ ur > 3 0 da ys after last d ose of st u d y
treat me nt.  T he stat us of all ot her A Es t hat are o n g oi n g 3 0 da ys after t he last d ose of st u d y 
treat me nt will be d oc u me nte d as of t he P ost- Treat me nt F oll o w- U p Visit.
After t he e n d- of-treat me nt assess me nt, li mite d partici pa nt s ur vi val i nf or mati o n ( me dical hist or y, 
E C O G perf or ma nce stat us, t o xicit y assess me nt) will be c ollecte d, prefera bl y via office visit or 
tele p h o ne c o ntact, e ver y 1 2 wee ks ( ± 1 wee k) fr o m t he date of last d ose of st u d y dr u g u ntil 1) t he 
partici pa nt’s deat h, 2) t he partici pa nt is l ost t o f oll o w- u p, or 3) st u d y cl os ure (a p pr o xi matel y 6 
m o nt hs after t he last partici pa nt ter mi nates treat me nt).

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 6
9. 2 
St u d y C ale n d ar
Ta ble 9- 1: S T U D Y C A L E N D A R
Scree ni n g
( wee ks)
C ycle 1
C ycle 2- 3
C ycle 4 a n d 
be y o n d
- 4 
- 2 
- 1
Da y 
1 5
Da y 
8 5
Da y 
1 5 5
Da y 1 of 
eac h c ycle 5
Da y 1 5 of 
eac h c ycle 5
Da y 1 of eac h 
c ycle 5 
E ver y 2 
c ycles 
( +/- 7 
da ys)
P ost-
Treat me nt
9 
I nf or me d 
c o nse nt
X
Me dical 
Hist or y
X 
X 
X 
X 
X
X
X
X
C o nc urre nt 
me ds
X 
X 
X 
X 
X
X
X
X
P h ysical e xa m 
(i ncl u di n g 
hei g ht, wei g ht, 
p ulse, bl o o d 
press ure, O 2 
sat urati o n)
X 
X 
X 
X 
X
X
X
X
E C O G 
Perf or ma nce 
Stat us
X 
X 
X 
X 
X
X
X
X
T o xicit y 
Assess me nt
X 
X 
X
X
X
X
Arc hi ve d 
T u m or Tiss ue
X
E K G
X
X
X
C B C 
w/ differe ntial
X 
X 6
X 
X 
X
X
X
X
Bilir u bi n, 
A L T, A S T, 
Al b u mi n, 
Al kali ne 
P h os p hatase
X 
X 6
X 
X 
X
X
X
X
Na, K, Cl, 
H C O 3, 
gl uc ose, B U N, 
Creati ni ne, 
M g, P O 4, Ca
X 
X 6
X 
X 
X
X
X
 L D H
X 
X 6
X
X
P T/ P T T/I N R
X 
X 6
T S H wit h 
refle x T 4
X 
X 6
X
X
X
Uri nal ysis 1 
X 
X 6
X
X
C A 1 9- 9
X 
X 6
X
X 
X 
X
H Bs A g, 
H Bs A b, 
H Bc A B, H C V 
A b 2
X
β- H C G 3
X
X
X
T u m or 
meas ure me nts
X
X
Ra di ol o gic 
e val uati o n 4
X
X
C orrelati ve 
Ser u m St u dies
X 7
X 7
X 7
X 7
C orrelati ve 
Tiss ue St u dies 8
X
1. Will ha ve 2 4- h o ur uri ne pr otei n c ollecti o n f or ≥ 2 + pr otei n o n uri nal ysis.
2. He patitis B a n d C ser ol o g y as liste d i n t he st u d y cale n dar m ust be o btai ne d wit hi n 1 2 0 da ys of 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 7
st u d y e nr oll me nt.
3. Ser u m or uri ne β- H C G  s h o ul d be perf or me d o n w o me n of c hil d beari n g p ote ntial.
4. Baseli ne meas ure me nts of t u m or b y ra di o gra p hic mea ns s h o ul d be c o m plete d wit hi n 2 8 da ys 
pri or t o treat me nt a n d s h o ul d i ncl u de f ull e val uati o n of t he e xte nt of metastatic disease.  
Assess me nts are re peate d e ver y 2 c ycles ( 8 wee ks).   Res p o nses m ust be c o nfir me d after 4- 8 
wee ks wit h re peat ra di ol o gical sca ns. If a b d o mi nal/ pel vic C T sca n or a b d o mi nal M RI is c h ose n 
as t he ra di o gra p hic mea ns of t u m or meas ure me nt, t he n t he sa me m o dalit y s h o ul d be use d 
c o nsiste ntl y f or all f ut ure assess me nts. 
5. Re q uire d n o n-ra di ol o gical assess me nts s h o ul d be perf or me d wit hi n +/- 3 da ys of t he sc he d ule d 
da y.
6. Scree n assess me nts nee d n ot be re peate d f or c ycle 1 da y 1.
7. C orrelati ve ser u m st u dies will be perf or me d at baseli ne, 2 wee ks after treat me nt, a n d at t he 
be gi n ni n g of eac h c ycle, a n d teste d f or ser u m 2- H G a n d C A 1 9- 9 le vels.
8. C orrelati ve tiss ue st u dies will be perf or me d o n t he bi o ps y tiss ues o btai ne d at baseli ne, 8 wee ks 
after dasati ni b treat me nt a n d at t he ti me of disease pr o gressi o n.  See A p pe n di x C f or details.
9. S u bjects will ret ur n t o t he st u d y site bet wee n 3 0 – 3 7 da ys after t he last d ose of dasati ni b f or 
a n e n d- of-treat me nt visit a n d u n der g o t he assess me nts i n t his c ol u m n.  After t hat, li mite d 
partici pa nt s ur vi val i nf or mati o n ( me dical hist or y, E C O G perf or ma nce stat us, t o xicit y 
assess me nt) will be c ollecte d, prefera bl y via office visit or tele p h o ne c o ntact, e ver y 1 2 wee ks ( ± 1 
wee k) fr o m t he date of last d ose of st u d y dr u g u ntil 1) t he partici pa nt’s deat h, 2) t he partici pa nt is 
l ost t o f oll o w- u p, or 3) st u d y cl os ure (a p pr o xi matel y 6 m o nt hs after t he last partici pa nt 
ter mi nates treat me nt).
1 0. M E A S U R E M E N T O F E F F E C T  
1 0. 1
A ntit u m or Effect – S oli d T u m ors
F or t he p ur p oses of t his st u d y, partici pa nts s h o ul d be re-e val uate d f or res p o nse e ver y 
8 wee ks. I n a d diti o n t o a baseli ne sca n, c o nfir mat or y sca ns s h o ul d als o be o btai ne d at 
least 4 wee ks f oll o wi n g i nitial d oc u me ntati o n of o bjecti ve res p o nse. Res p o nse a n d 
pr o gressi o n will be e val uate d i n t his st u d y usi n g t he ne w i nter nati o nal crit eri a 
pr o p os e d b y t h e R es p o ns e E v al u ati o n Crit eri a i n S oli d T u m ors ( R E CI S T) 
C o m mittee ( T herasse et al, 2 0 0 0). R E CI S T versi o n 1. 1 will be use d.  C h a n g es i n t h e 
di a m et er ( u ni di m e nsi o n al m eas ure me nt) of t he t u m or lesi o ns ar e us e d i n t he 
R E CI S T crit eri a.
1 0. 1. 1
Defi niti o ns
E v al u a bl e f or t o xi cit y. All p arti ci p a nts w h o r e c ei v e at l e ast o n e d os e of st u d y 
tr e at m e nt will b e e v al u a bl e f or t o xi cit y fr o m t h e ti m e of t h eir first tr e at m e nt.
E v al u a bl e f or o bj e cti v e r es p o ns e. O nl y t h os e p arti ci p a nts w h o h a v e 
m e as ur a bl e dis e as e pr es e nt at b as eli n e, h a v e r e c ei v e d at l e ast o n e c y cl e of 
t h er a p y, a n d h a v e h a d t h eir dis eas e re-e val uate d will be c o nsi der e d e val ua bl e 
f or r es p o ns e. T h es e p arti ci p a nts will h a v e t h eir r es p o ns e cl assifi e d a c c or di n g 
t o t h e d efi niti o ns st at e d b el o w. ( N ot e: P arti ci p a nts w h o e x hi bit o bj e cti v e 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 8
dis e as e pr o gr essi o n or di e pri or t o t h e e n d of c y cl e 1 will als o b e c o nsi d er e d 
e v al u a bl e. }
1 0. 1. 2
Disease Para meters
M e as ur a bl e dis e as e. M e as ur a bl e dis e as e is t h e pr es e n c e of at l e ast o n e 
( 1) l esi o n t h at c a n b e acc uratel y meas ure d i n at least o ne di me nsi o n wit h 
l o n gest dia meter  > 2 0 milli m et ers ( m m) usi n g c o n v e nti o n al t e c h ni q u es ( C T, 
M RI, x-r a y) or  > 1 0 m m wit h s pir al C T sca n. M eas ura ble lesi o ns m ust be at 
l e ast 2 ti m es t h e sli c e t hic k n ess i n m m. All t u m or meas ur e me nts m ust be 
r e c or d e d i n milli m et ers ( or d eci mal fracti o ns of ce nti meters). 
T u m or l esi o ns t h at ar e sit u at e d i n a pr e vi o usl y irr a di at e d or e m b oli z e d 
ar e as c a n b e c o nsi d er e d meas ura ble if t h er e is o bj e cti v e e vi d e n c e of 
pr o gr essi o n of t h e l esi o n pri or t o st u d y e nr oll m e nt. 
 
M ali g n a nt l y m p h n o d es. T o b e c o nsi d er e d p at h ol o gi c all y e nl ar g e d a n d 
m e as ur a bl e, a l y m p h n o d e m ust b e > 1 5 m m i n s h ort a xis w h e n ass ess e d b y C T 
s c a n ( C T s c a n sli c e t hi c k n ess r e c o m m e n d e d t o b e n o gr e at er t h a n 5 m m). At 
b as eli n e a n d i n f oll o w- u p, o nl y t h e s h ort a xis will b e m e as ur e d a n d f oll o w e d.
N o n- m e as ur a bl e dis e as e. All ot her lesi o ns ( or sit es of dis ease), i ncl u di n g s mall 
lesi o ns (l o n gest dia meter < 1 0 m m) or pat h ol o gical l y m p h n o des wit h > 1 0 t o < 
1 5 m m s h ort a xis, ar e c o nsi d er e d n o n- m e as ur a bl e dis e as e. B o n e l esi o ns, 
le pt o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis 
c utis/ p ul m o nis, i nfla m mat or y breast disease, a b d o mi nal masses i de ntifie d b y 
p h ysical e xa m t hat are n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues, a n d 
c ystic lesi o ns are all c o nsi dere d n o n- meas ura ble.
T ar g et l esi o ns. All m e as ur a bl e l esi o ns u p t o a m a xi m u m of 2 l esi o ns p er 
or g a n a n d 5 l esi o ns i n t ot al, r e pr es e nt ati v e of all i n v ol v e d or g a ns, s h o ul d b e 
i d e ntifi e d as t ar g et l esi o ns a n d r e c or d e d a n d m e as ur e d at b as eli n e. L esi o ns 
m ust b e a c c ur at el y m e as ur e d i n 1 di m e nsi o n wit h a mi ni m u m si z e of 1 0 m m 
b y C T or M RI (sli c e t hi c k n ess n o gr e at er t h a n 5 m m), 2 0 m m b y c h est  x-r a y. 
N o d es m ust h a v e a s h ort a xis > 1 5 m m. T h e s h ort a xis s h o ul d b e i n cl u d e d i n 
t h e s u m of t h e l esi o ns i n t h e c al c ul ati o n of r es p o ns e. N o d es t h at s hri n k t o < 1 0 
m m ar e c o nsi d er e d n or m al. T ar g et l esi o ns s h o ul d b e s el e ct e d o n t h e b asis of 
t h eir si z e, b e r e pr es e nt ati v e of all t h e i n v ol v e d or g a ns, a n d s h o ul d b e l esi o ns 
t h at c a n b e f oll o w e d wit h r e pr o d u ci bl e r e p e at e d m e as ur e m e nts. 
L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifi a ble s oft tiss ue 
c o m p o ne nts , t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as 
C T or M RI ca n be c o nsi dere d tar get lesi o ns if t he s oft tiss ue c o m p o ne nt meets 
t he defi niti o n of meas ura bilit y as defi ne d a b o ve. C ystic lesi o ns t h o u g ht t o 
re prese nt c ystic metastases ca n be c o nsi dere d as tar get lesi o ns. H o we ver, if n o n-
c ystic lesi o ns are prese nt, t hese are preferre d f or selecti o n as tar get lesi o ns. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
2 9
Lesi o ns i n pre vi o usl y irra diate d areas or areas s u bject t o ot her l oc o-re gi o nal 
t hera p y are us uall y n ot c o nsi dere d meas ura ble u nless t here has bee n 
de m o nstrate d pr o gressi o n of t hat lesi o n. 
N o n-tar get lesi o ns. All ot h er l esi o ns, i n cl u di n g s m all l esi o ns < 1 0 m m or 
p at h ol o gi c al l y m p h n o d es m e as uri n g > 1 0 m m t o < 1 5 m m i n s h ort a xis, as 
w ell as tr ul y n o n- m e as ur a bl e l esi o ns, w hi c h i n cl u d e l e pt o m e ni n g e al dis e as e, 
as cit es, pl e ur al or p eri c ar di al eff usi o n, i nfl a m m at or y br e ast dis e as e, 
l y m p h a n giti c i n v ol v e m e nt of s ki n or l u n g, a b d o mi n al m ass es i d e ntifi e d b y 
p h ysi c al e x a m t h at ar e n ot m e as ur a bl e b y r e pr o d u ci bl e i m a gi n g t e c h ni q u es. 
1 0. 1. 3
Met h o ds f or E val uati o n of Meas ura ble Disease
All meas ure me nts s h o ul d be ta ke n a n d rec or de d i n metric n otati o n, usi n g a r uler, 
cali pers, or di gital meas ure me nt t o ol. All baseli ne e val uati 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 treat me nt a n d ne ver m ore t ha n 4 wee ks 
bef ore t he be gi n ni n g of t he treat me nt.
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o 
c haracterize eac h i de ntifie d a n d re p orte 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 
w he n b ot h met h o ds ha ve bee n use d t o assess t he a nti-t u m or effect of a 
treat me nt.
Cli nical lesi o ns. Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are 
s u p erfi ci al ( e. g., s ki n n o d ul es a n d p al p a bl e l y m p h n o d es). F or t h e c as e of 
s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate 
t he size of t he lesi o n, is rec o m me n de d.
C hest x-ra y. Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns w he n 
t he y are clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g; h o we ver, C T is 
prefera ble.
C o n ve nti o nal C T a n d M RI. T hese tec h ni q ues s h o ul d be perf or me d wit h c uts of 
1 0 m m or less i n slice t hic k ness c o nti g u o usl y. S piral C T s h o ul d be perf or me d 
usi n g a 5 m m c o nti g u o us rec o nstr ucti o n al g orit h m. T his a p plies t o t u m ors of t he 
c hest, a b d o m e n, a n d p el vis. H e a d a n d n e c k t u m ors a n d t h os e of e xtr e miti es 
us u all y r e q uir e s p e cifi c pr ot oc ols.
Ultr as o u n d ( U S). U S is n ot a n a c c e pt a bl e m et h o d of dis e as e ass ess m e nt.
T u m or m ar k ers. T u m or m ar k ers al o n e c a n n ot b e us e d t o ass ess r es p o ns e. If 
m ar k ers ar e i niti all y a b o v e t h e u p p er n or m al li mit, t h e y m ust n or m ali z e f or 
a s u bj e ct t o b e c o nsi d er e d i n c o m pl et e cli ni c al r es p o ns e. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 0
C yt ol o g y, Hist ol o g y. T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n 
partial r es p o ns es ( P R) a n d c o m pl et e r es p o ns es ( C R) i n r ar e c as es ( e. g., r esi d u al 
l esi o ns i n t u m or t y p es, s u c h as g er m c ell t u m ors, w h er e k n o w n r esi d u al 
b e ni g n t u m ors c a n re mai n).
T h e c yt ol o gi c al c o nfir m ati o n of t h e n e o pl asti c ori gi n of a n y eff usi o n t h at 
a p p e ars or w ors e ns d uri n g tr e at m e nt w h e n t h e m e as ur a bl e t u m or h as m et 
crit eri a f or res p o nse or sta ble disease is ma n dat or y t o differe ntiate bet wee n 
res p o nse or sta ble dis e ase (a n eff usi o n ma y be a si de eff ect of t he treat m e nt) 
a n d pr o gr essi v e dis e as e.
1 0. 1. 4  Res p o nse Criteria 
1 0. 1. 4. 1  
E val uati o n of Tar get Lesi o ns
C o m plete R es p o ns e ( C R): Dis a p p e ar a n c e of all t ar g et l esi o ns. A n y 
p at h ol o gi c al l y m p h n o d e m ust h a v e r e d u cti o n i n s h ort a xis t o < 1 0 
m m.
Partial Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he 
di a m et ers of t ar g et l esi o ns, t a ki n g as r ef er e n c e t h e b as eli n e s u m 
di a m et ers.
Pr o gr essi v e Disease ( P D):  At le ast a 2 0 % i ncr eas e i n t he s u m of t h e 
di a m et ers of t ar g et l esi o ns, t a ki n g as r ef er e n c e t h e s m all e st s u m o n 
st u d y wit h at l e a st a 5 m m a b s ol ut e i n cr e a s e i n t h e s u m of 
all l e si o n s. T h e a p p e ar a n c e of o n e or m or e n e w l e si o n s * 
d e n ot e s di s e a s e pr o gr e s si o n. 
St a bl e Dis e as e ( S D): N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f or P R 
n or s uffi ci e nt i n cr e as e t o q u alif y f or P D, t a ki n g as r ef er e n c e t h e 
s m all est s u m di a m et ers w hile o n st u d y.
U n k n o w n ( U N): Assess me nt of tar get lesi o ns ca n n ot be ma de d ue t o 
i ns ufficie nt or u ne val ua ble data. I n t his case, a c o ncise e x pla nati o n m ust 
be gi ve n.
N ote: If t u m or res p o nse data is missi n g f or tar get lesi o ns, t he o verall 
assess me nt m ust be U N u nless t here is ne w disease t hat w o ul d res ult i n 
a n o verall assess me nt of P D. H o we ver, if t here is missi n g or 
u ne val ua ble data f or n o n-tar get lesi o ns, b ut data is a vaila ble f or all 
tar get lesi o ns, t he o verall res p o nse f or t hat ti me p oi nt will be assi g ne d 
base d o n t he s u m L D of all tar get lesi o ns. A d diti o nall y, t he assess me nt 
of C R ca n n ot be ma de if t here is missi n g or u ne val ua ble data f or n o n-
tar get lesi o ns. I n t his case, t he o verall assess me nt w o ul d be P R.

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 1
* Defi niti o n of Ne w Lesi o n: 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 ocal 
(i.e. n ot d ue t o differe nce i n sca n ni n g tec h ni q ue, i ma gi n g m o dalit y, or fi n di n gs 
t h o u g ht t o re prese nt s o met hi n g ot her t ha n t u m or (e x: ne w b o ne lesi o ns ma y be 
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 ot sca n ne d at baseli ne is 
c o nsi dere 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 ( beca use of 
s mall size, 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 
disease a n d if P D is c o nfir me d, pr o gressi o n s h o ul d be declare d usi n g t he date of 
t he i nitial sca n o n w hic h t he lesi o n was disc o vere d. 
1 0. 1. 4. 2  
E val uati o n of N o n- Tar get Lesi o ns
C o m pl et e R es p o ns e ( C R): Disa p peara nce of all n o n-tar get lesi o ns a n d
n or m ali z ati o n of t u m or mar ker le v el. All l y m p h n o d es m ust b e n o n-
p at h ol o gi c al i n si z e ( < 1 0 m m s h ort a xis). 
N ot e: If t u m or m ar k ers ar e i niti all y a b o v e t h e u p p er n or m al li mit, 
t h e y m ust n or m ali z e f or a s u bj e ct t o b e c o nsi d er e d i n c o m pl et e 
cli ni c al r es p o ns e.
I n c o m pl et e R es p o ns e/ St a bl e Dis e as e ( S D): Persiste nce of o ne or 
m ore n o n-tar get lesi o ns a n d/ or mai nte na nce of t u m or mar ker le vel 
a b o ve t he n or mal li mits.
Pr o gr essi v e Dis e as e ( P D): A p p e ar a n c e of o n e or m or e n e w 
l esi o ns * ( n e w l esi o ns 
m ust b e > sli c e t hi c k n ess) a n d/ or 
u ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get lesi o ns.
N ote:   I ncrease d u pta ke o n b o ne sca n al o ne is i ns ufficie nt 
e vi de nce of  
pr o gressi o n; a d diti o nal e vi de nce of pr o gressi ve 
disease w o ul d be prese nt   
t o declare u ne q ui v ocal pr o gressi o n.
U n k n o w n ( U N): Assess me nt of n o n-tar get lesi o ns ca n n ot be ma de d ue 
t o i ns ufficie nt or u ne val ua ble data. I n t his case, a c o ncise e x pla nati o n 
m ust be gi ve n.
* Defi niti o n of Ne w Lesi o n: 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 ocal 
(i.e. n ot d ue t o differe nce i n sca n ni n g tec h ni q ue, i ma gi n g m o dalit y, or fi n di n gs 
t h o u g ht t o re prese nt s o met hi n g ot her t ha n t u m or (e x: ne w b o ne lesi o ns ma y be 
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 ot sca n ne d at baseli ne is 
c o nsi dere 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 ( beca use of 
s mall size, 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 
disease a n d if P D is c o nfir me d, pr o gressi o n s h o ul d be declare d usi n g t he date of 
t he i nitial sca n o n w hic h t he lesi o n was disc o vere d. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 2
1 0. 1. 4. 3  
E val uati o n of ne w lesi o ns
N o:  T here are n o ne w lesi o ns.
Yes:  Ne w lesi o ns are prese nt.  N ote:  If ne w lesi o ns are prese nt, t he patie nt is 
c o nsi dere d t o ha ve pr o gressi ve disease o verall.
1 0. 1. 4. 4  
E val uati o n of Best O verall Res p o nse
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he 
tr e at m e nt u ntil dis e as e pr o gr essi o n/r e c urr e n c e (t a ki n g as r ef er e n c e f or 
pr o gressi ve disease t he s mallest 
meas ure me nts rec or de d si nce t he treat me nt 
st art e d). T h e p arti ci p a nt's b est r es p o ns e assi g n m e nt 
will d e p e n d o n t h e 
ac hie ve me nt of b ot h meas ure me nt a n d c o nfir mati o n criteria. O verall res p o nse 
will be deter mi ne d as ta b ulate d bel o w, base d o n t he e val uati o n of tar get, n o n-
tar get, a n d ne w lesi o ns:

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 3
F or Patie nts wit h Meas ura ble Disease (i.e., Tar get Disease)
Tar get 
Lesi o ns
N o n- Tar get
Lesi o ns
Ne w
Lesi o ns
O v er all 
Res p o nse
Best O verall Res p o nse f or 
w he n C o nfir mati 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
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
> 4 w ks c o nfir mati o n
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 me 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
A n y 
P D * 
Yes or N o 
P D
A n y 
A n y 
Y es
P D
N o pri or S D, P R or C R
* 
I n e xce pti o nal cir c u mst a n c es, u n e q ui v o c al pr o gr essi o n i n n o n-t ar g et l esi o ns m a y b e 
a c c e pt e d as dis e as e pr o gr essi o n.
N ote:   Partici pa nts wit h a gl o b al d et eri or ati o n of h e alt h st at us r e q uiri n g dis c o nti n u ati o n of 
tr e at m e nt wit h o ut o bj e cti v e e vi d e n c e of dis e as e pr o gr essi o n at t h at ti m e s h o ul d b e 
r e p ort e d as "sy m pt o m atic deteri or ati o n". E ver y eff ort s h o ul d be ma de t o d oc u me nt t he 
o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of treat me nt.
F or Patie nts wit h N o n- Meas ura ble Disease (i.e., N o n- Tar get Disease)
N o n- Tar get 
Lesi o ns
Ne w
Lesi o ns
O v er 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 uate 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 disease f or n o n-tar get disease si nce 
S D is i ncreasi n gl y use d 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 cate g or y w he n n o lesi o ns ca n be meas ure d is n ot a d vise d. 
I n t he case of sta ble disease ( S D), f oll o w- u p meas ure me nts m ust ha ve met t he S D 
criteria at least o nce after st u d y e ntr y at a mi ni m u m i nter val of 1 6 wee ks.

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
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E ver y eff ort s h o ul d be ma de t o d oc u me nt t u m or meas ure me nts a n d e xte nt of 
disease, e ve n after disc o nti n uati o n of t hera p y, i n or der t o classif y patie nts f or 
o verall res p o nse as descri be d a b o ve.  Patie nts w h o d o n ot ha ve t u m or res p o nse 
assess me nt d ue t o ra pi d pr o gressi o n or t o xicit y will be c o nsi dere d as n o n-
res p o n ders, will be i ncl u de d i n t he de n o mi nat or f or t he res p o nse rate, a n d will be 
classifie d i nt o o ne of t he f oll o wi n g cate g ories:
- 
deat h attri b ute d t o disease pr o gressi o n
- 
deteri orati o n attri b ute d t o disease pr o gressi o n
- 
deat h attri b ute d t o dr u g t o xicit y
- 
earl y disc o nti n uati o n attri b ute d t o dr u g t o xicit y
1 0. 1. 5
Defi niti o ns relate d t o res p o nse a n d pr o gressi o n:
D ur ati o n of o v er all r es p o ns e: T h e d urati o n of o verall res p o ns e is meas ure d 
fr o m t he ti me meas ure me nt criteria are met f or C R or P R ( w hic he ver is first 
rec or de d) u ntil t he first date t hat rec urre nce or P D is o bjecti vel y d oc u me nte d, 
t a ki n g as r ef er e n c e f or P D t h e s m all est m e as ur e m e nts r e c or d e d si nce t he 
treat me nt starte d. Patie nts w h o d o n ot rela pse will be ce ns ore d at t he da y of t heir 
last t u m or assess me nt.
Ti me t o res p o nse: Ti me fr o m date of i nitial treat me nt u ntil first o bjecti ve 
d oc u me ntati o n of res p o nse.
Ti me t o t u m or pr o gressi o n:  Ti me fr o m date of i nitial treat me nt t o first o bjecti ve 
d oc u me ntati o n of pr o gressi ve disease or deat h.  Patie nts w h o die wit h o ut a
re p orte d pri or pr o gressi o n will be c o nsi dere d t o ha ve pr o gresse d o n t he da y of 
t heir deat h. 
Ti me t o treat me nt fail ure:  Ti me fr o m date of i nitial treat me nt t o first o bjecti ve 
d oc u me ntati o n of pr o gressi ve disease, or off st u d y date, w hic he ver occ urs first.
Ti me t o deat h:  Ti me fr o m date of i nitial treat me nt t o date of deat h
Pr o gressi o n- Free S ur vi val:  Pr o gressi o n- Free S ur vi val ( P F S) is defi ne d as t he 
d urati o n of ti me fr o m start of treat me nt t o ti me of o bjecti ve disease pr o gressi o n or 
deat h fr o m a n y ca use wit h o ut e vi de nce of disease pr o gressi o n, w hic he ver c o mes first. 
O verall S ur vi val:  O verall S ur vi val ( O S) is defi ne d as t he d urati o n of ti me fr o m start 
of treat me nt t o ti me of deat h. 
1 1.
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S
1 1. 1
Defi niti o ns
1 1. 1. 1
A d verse E ve nt ( A E)

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
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3 5
A n a d verse e ve nt ( A E) is a n y u n desira ble si g n, s y m pt o m or me dical c o n diti o n or 
e x perie nce t hat de vel o ps or w orse ns i n se verit y after starti n g t he first d ose of 
st u d y treat me nt or a n y pr oce d ure s pecifie d i n t he pr ot oc ol, e ve n if t he e ve nt is n ot 
c o nsi dere d t o be relate d t o t he st u d y. 
All la b orat or y data re q uire d b y t his pr ot oc ol a n d a n y ot her cli nical i n vesti gati o ns 
s h o ul d be re vie we d. A n y a b n or mal val ue t hat lea ds t o a c ha n ge i n s u bject 
ma na ge me nt (e g, d ose re d ucti o n or dela y or re q uire me nt f or a d diti o nal  
 
me dicati o n or m o nit ori n g) or t hat is c o nsi dere d t o be of cli nical si g nifica nce b y 
t he i n vesti gat or s h o ul d be re p orte d as a n A E as a p pr o priate.
1 1. 1. 2 Seri o us a d verse e ve nt ( S A E)
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e ve nt, occ urri n g at a n y d ose a n d 
re gar dless of ca usalit y t hat: 

Res ults i n deat h

Is life-t hreate ni n g. Life-t hreate ni n g mea ns t hat t he pers o n was at 
i m me diate ris k of deat h fr o m t he reacti o n as it occ urre d, i.e., it d oes n ot 
i ncl u de a reacti o n w hic h h y p ot heticall y mi g ht ha ve ca use d deat h ha d it 
occ urre d i n a m ore se vere f or m.

Re q uires or pr ol o n gs i n patie nt h os pitalizati o n (i.e., t he e ve nt re q uire d at 
least a 2 4- h o ur h os pitalizati o n or pr ol o n ge d a h os pitalizati o n be y o n d t he 
e x pecte d le n gt h of sta y). H os pitalizati o n a d missi o ns a n d/ or s ur gical 
o perati o ns sc he d ule d t o occ ur d uri n g t he st u d y peri o d, b ut pla n ne d pri or t o 
st u d y e ntr y are n ot c o nsi dere d S A Es if t he ill ness or disease e xiste d bef ore 
t he pers o n was e nr olle d i n t he trial, pr o vi de d t hat it di d n ot deteri orate i n 
a n u ne x pecte d ma n ner d uri n g t he trial (e. g., s ur ger y perf or me d earlier t ha n 
pla n ne d).

Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y. Disa bilit y is 
defi ne d as a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal 
life f u ncti o ns.

Is a c o n ge nital a n o mal y or birt h defect; or

Is a n i m p orta nt me dical e ve nt w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, it ma y je o par dize t he partici pa nt a n d re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E xa m ples of 
s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me; bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
E ve nts n ot c o nsi dere d t o be seri o us a d verse e ve nts are h os pitalizati o ns f or:

r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d 
wit h a n y deteri orati o n i n c o n diti o n, or f or electi ve pr oce d ures

electi ve or pre- pla n ne d treat me nt f or a pre-e xisti n g c o n diti o n t hat di d n ot 
w orse n

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 6

e mer ge nc y o ut patie nt treat me nt f or a n e ve nt n ot f ulfilli n g t he seri o us 
criteria o utli ne d a b o ve a n d n ot res ulti n g i n i n patie nt a d missi o n

res pite care
1 1. 1. 3
Ot her Safet y C o nsi derati o ns
Pre g na nc y – If a s u bject bec o mes pre g na nt d uri n g t he st u d y, s he will be ta ke n off 
st u d y treat me nt a n d will be f oll o we d t hr o u g h t he e n d of her pre g na nc y. F or ms f or 
re p orti n g pre g na ncies 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 bject) a n d t he 
me dical c o n diti o n of a n y res ulta nt offs pri n g m ust be re p orte d t o B M S or 
desi g nee. A n y birt h defect or c o n ge nital a n o mal y m ust be re p orte d as a n S A E, 
a n d a n y ot her u nt o war d e ve nts occ urri n g d uri n g t he pre g na nc y m ust be re p orte d 
as A Es or S A Es, as a p pr o priate.
Me dicati o n Err ors/ O ver d ose – A n y st u d y dr u g a d mi nistrati o n err or or o ver d ose 
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 2 4 h o urs t o B M S or desi g nee.
1 1. 1. 4
E x pecte d ness
A d v ers e e v e nts c a n b e ' E x p e ct e d' or ' U n e x p e ct e d.' 
1 1. 1. 4. 1 
E x pecte d a d verse e ve nt
E x pecte d a d verse e ve nts are t h ose t hat ha ve bee n pre vi o usl y i de ntifie d as 
res ulti n g fr o m a d mi nistrati o n of t he a ge nt. F or t he p ur p oses of t his st u d y, 
a n a d verse e ve nt is c o nsi dere d e x pecte d w he n it a p pears i n t he c urre nt 
a d verse e ve nt list, t he I n vesti gat or’s Br oc h ure, t he pac ka ge i nsert or is 
i ncl u de d i n t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k.  
R ef er t o S e cti o n 6. 1 f or a listi n g of e x p e ct e d a d v ers e e v e nts ass o ci at e d 
wit h t h e st u d y a g e nt(s).
1 1. 1. 4. 2 
U ne x pecte d a d verse e ve nt
F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d u ne x pecte d 
w he n it varies i n nat ure, i nte nsit y or fre q ue nc y fr o m i nf or mati o n 
pr o vi de d i n t he c urre nt a d verse e ve nt list, t he I n vesti gat or’s Br oc h ure, 
t he pac ka ge i nsert or w he n it is n ot i ncl u de d i n t he i nf or me d c o nse nt 
d oc u me nt as a p ote ntial ris k.  
1 1. 1. 5
Attri b uti o n
Attri b uti o n is t he relati o ns hi p bet wee n a n a d verse e ve nt or seri o us a d verse e ve nt 
a n d t he st u d y treat me nt. Attri b uti o n will be assi g ne d as f oll o ws:

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
3 7

Defi nite – T he A E is clearl y relate d  t o t he st u d y treat me nt.

Pr o ba ble – T he A E is li kel y relate d  t o t he st u d y treat me nt.

P ossi ble – T he A E ma y be relate d  t o t he st u d y treat me nt. 

U nli kel y - T he A E is d o u btf ull y relate d  t o t he st u d y treat me nt.

U nr el at e d - T h e A E is clearl y N O T rel ate d  t o t he st u d y treat me nt.
1 1. 2
F oll o w- U p of A d verse E ve nts
A n y relate d S A Es or a n y A Es assesse d as relate 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 nifica nt a b n or mal la b orat or y val ues t hat meet t hese criteria, 
o n g oi n g 3 0 da ys after t he last d ose of st u d y treat me nt m ust be f oll o we 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 gat or t hat t he e ve nt has bec o me 
sta ble or irre versi ble. T his f oll o w- u p g ui da nce als o a p plies t o relate d S A Es t hat occ ur > 
3 0 d ays after t he l ast d ose of st u d y treat me nt. T he stat us of all ot her c o nti n ui n g A Es 
will be d oc u me nte d as of 3 0 da ys after t he last d ose of st u d y treat me nt.
1 1. 3
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g
Partici pati n g i n vesti gat ors will assess t he occ urre nce of A Es a n d S A Es at all partici pa nt 
e val uati o n ti me p oi nts d uri n g t he st u d y. 
All A Es a n d S A Es w het her re p orte d b y t he partici pa nt, disc o vere d d uri n g q uesti o ni n g, 
directl y o bser ve d, or detecte d b y p h ysical e xa mi nati o n, la b orat or y test or ot her mea ns, 
will be rec or de d i n t he partici pa nt’s me dical rec or d a n d o n t he a p pr o priate st u d y-
s pecific case re p ort f or ms. 
T he descri pti o ns a n d gra di n g scales f o u n d i n t he re vise d N CI C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0 will be utilize d f or A E re p orti n g. All 
a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 4. 0.
A c o p y of t he C T C A E versi o n 4. 0 ca n be d o w nl oa de d fr o m t he C T E P we bsite at:
 htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m . 
1 1. 4
Re p orti n g Re q uire me nts
F or m ulti-site trials w here a D F/ H C C i n vesti gat or is ser vi n g as t he pri nci pal 
i n vesti gat or, eac h partici pati n g i n vesti gat or is re q uire d t o a bi de b y t he re p orti n g 
re q uire me nts set b y t he D F/ H C C. T he st u d y m ust be c o n d ucte d i n c o m plia nce wit h 
F D A re g ulati o ns, l ocal safet y re p orti n g re q uire me nts, a n d re p orti n g re q uire me nts of t he 
pri nci pal i n vesti gat or. 
Eac h i n vesti gati ve site will be res p o nsi ble t o re p ort S A Es t hat occ ur at t hat i nstit uti o n 
t o t heir res pecti ve I R B. It is t he res p o nsi bilit y of eac h partici pati n g i n vesti gat or t o 
re p ort seri o us a d verse e ve nts t o t he st u d y s p o ns or a n d/ or ot hers as descri be d bel o w. 

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
4 1
re p ort f or m a n d rec or de d i n t he partici pa nt’s me dical rec or d t o facilitate s o urce data 
verificati o n. 
F or s o me S A Es, t he st u d y s p o ns or or desi g nee ma y f oll o w- u p b y tele p h o ne, fa x, a n d/ or 
m o nit ori n g visit t o o btai n a d diti o nal case details dee me d necessar y t o a p pr o priatel y 
e val uate t he S A E re p ort (e. g., h os pital disc har ge s u m mar y, c o ns ulta nt re p ort, or 
a ut o ps y re p ort). 
Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y seri o us p ost-st u d y e ve nt(s) t hat mi g ht 
reas o na bl y be relate d t o partici pati o n i n t his st u d y. Partici pati n g i n vesti gat ors s h o ul d 
n otif y t he D F/ H C C O verall Pri nci pal I n vesti gat or a n d t heir res pecti ve I R B of a n y 
u na ntici pate d deat h or a d verse e ve nt occ urri n g after a partici pa nt has disc o nti n ue d or 
ter mi nate d st u d y partici pati o n t hat ma y reas o na bl y be relate d t o t he st u d y.  
1 2.
D A T A A N D S A F E T Y M O NI T O RI N G
1 2. 1
Data Re p orti n g
1 2. 1. 1
Met h o d 
T h e Q A C T will c oll e ct, ma na ge, a n d m o nit or data f or t his st u d y. 
1 2. 1. 2
Data  S u b missi o n 
T he sc he d ule f or c o m pleti o n a n d s u b missi o n of case re p ort f or ms ( pa per or 
electr o nic) t o t he Q A C T is as f oll o ws:

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
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4 2
F or m
S u b missi o n Ti meli ne
Eli gi bilit y C h e c klist
C o m plete pri or t o re gistrati o n wit h Q A C T
O n St u d y F or m
Wit hi n 1 4 da ys of r e gistrati o n
B as eli n e Ass ess m e nt F or m 
Wit hi n 1 4 da ys of r e gistrati o n
Tr e at m e nt F or m
Wit hi n 1 0 da ys of t he last da y of t he c ycle
A d verse E ve nt Re p ort F or m 
Wit hi n 1 0 da ys of t he last da y of t he c ycle
Res p o nse Assess me nt F or m
Wit hi n 1 0 da ys of t he c o m pleti o n of t he c ycle 
re q uire d f or res p o nse e val uati o n
Off Treat me nt/ Off St u d y F or m
Wit hi n 1 4 da ys of c o m pleti n g treat me nt or 
bei n g ta ke n off st u d y f or a n y reas o n
F oll o w u p/ S ur vi val F or m 
Wit hi n 1 4 da ys of t he pr ot oc ol defi ne d f oll o w 
u p visit date or call
1 2. 2
Safet y Meeti n gs
T he D F/ H C C Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) will re vie w a n d m o nit or 
t o xicit y a n d accr ual data fr o m t his trial. T he c o m mittee is c o m p ose d of cli nical 
s pecialists wit h e x perie nce i n o nc ol o g y a n d w h o ha ve n o direct relati o ns hi p wit h t he 
st u d y. I nf or mati o n t hat raises a n y q uesti o ns a b o ut partici pa nt safet y will be a d dresse d 
wit h t he Pri nci pal I n vesti gat or a n d st u d y tea m.
T he D S M C will meet q uarterl y a n d/ or m ore ofte n if re q uire d t o re vie w t o xicit y a n d 
accr ual data.  I nf or mati o n t o be pr o vi de d t o t he c o m mittee ma y i ncl u de:  u p-t o- date 
partici pa nt accr ual; c urre nt d ose le vel i nf or mati o n; all gra de 2 or hi g her u ne x pecte d 
a d verse e ve nts t hat ha ve bee n re p orte d; s u m mar y of all deat hs occ urri n g wit hi n 3 0 da ys 
f or P hase I or II pr ot oc ols; f or ge ne tra nsfer pr ot oc ols, s u m mar y of all deat hs w hile 
bei n g treate d a n d d uri n g acti ve f oll o w- u p; a n y res p o nse i nf or mati o n; a u dit res ults, a n d 
a s u m mar y pr o vi de d b y t he st u d y tea m. Ot her i nf or mati o n (e. g. sca ns, la b orat or y 
val ues) will be pr o vi de d u p o n re q uest.  
1 2. 3 
M o nit ori n g 
I n v ol ve me nt i n t his st u d y as a partici pati n g i n vesti gat or i m plies acce pta nce of 
p ote ntial a u dits or i ns pecti o ns, i ncl u di n g s o urce data verificati o n, b y re prese ntati ves 
desi g nate d b y t he D F/ H C C O verall Pri nci pal I n vesti gat or ( or Pr ot oc ol C hair) or 
D F/ H C C. T he p ur p ose of t hese a u dits or i ns pecti o ns is t o e xa mi ne st u d y-relate d 

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acti vities a n d d oc u me nts t o deter mi ne w het her t hese acti vities were c o n d ucte d a n d 
data were rec or de d, a nal yze d, a n d acc uratel y re p orte d i n acc or da nce wit h t he pr ot oc ol, 
i nstit uti o nal p olic y, G o o d Cli nical Practice ( G C P), a n d a n y a p plica ble re g ulat or y 
re q uire me nts. 
All data will be m o nit ore d f or ti meli ness of s u b missi o n, c o m plete ness, a n d a d here nce 
t o pr ot oc ol re q uire me nts. M o nit ori n g will be gi n at t he ti me of partici pa nt re gistrati o n 
a n d will c o nti n ue d uri n g pr ot oc ol perf or ma nce a n d c o m pleti o n. 
1 3.
R E G U L A T O R Y C O N SI D E R A TI O N S
1 3. 1
Pr ot oc ol Re vie w a n d A me n d me nts
T his pr ot o c ol, t h e pr o p os e d i nf or m e d c o ns e nt a n d all f or ms of p arti ci p a nt 
i nf or m ati o n r el at e d t o t h e st u d y ( e. g., a d v ertis e m e nts us e d t o r e cr uit p arti ci p a nts) a n d 
a n y ot h er n e c ess ar y d o c u m e nts m ust b e s u b mitt e d, r e vi e w e d a n d a p pr o v e d b y a 
pr o p erl y c o nstit ut e d I R B g o v er ni n g e a c h st u d y l o c ati o n. 
A n y c h a n g es m a d e t o t h e pr ot o c ol m ust b e s u b mitt e d as a m e n d m e nts a n d m ust b e 
a p pr o v e d b y t h e I R B pri or t o i m pl e m e nt ati o n. A n y c h a n g es i n st u d y c o n d u ct m ust b e 
r e p ort e d t o t h e I R B. T h e D F/ H C C O v er all Pri n ci p al I n v esti g at or ( or Pr ot o c ol C h air) 
will diss e mi n at e pr ot o c ol a m e n d m e nt i nf or m ati o n t o all p arti ci p ati n g i n v esti g at ors. 
All d e cisi o ns of t h e I R B c o n c er ni n g t h e c o n d u ct of t h e st u d y m ust b e m a d e i n 
writi n g.
1 3. 2 I nf or me d C o nse nt
All p arti ci p a nts m ust b e pr o vi d e d a c o ns e nt f or m d es cri bi n g t his st u d y a n d 
pr o vi di n g s uffi ci e nt i nf or m ati o n f or p arti ci p a nts t o m a k e a n i nf or m e d d e cisi o n 
a b o ut t h eir p arti ci p ati o n i n t his st u d y. T h e f or m al c o ns e nt of a p arti ci p a nt, usi n g 
t h e I R B a p pr o v e d c o ns e nt f or m, m ust b e o bt ai n e d b ef or e t h e p arti ci p a nt is 
i n v ol v e d i n a n y st u d y-r el at e d pr o c e d ur e. T h e c o ns e nt f or m m ust b e si g n e d a n d 
d at e d b y t h e p arti ci p a nt or t h e p arti ci p a nt’s l e g all y a ut h ori z e d r e pr es e nt ati v e, a n d 
b y t h e p ers o n o bt ai ni n g t h e c o ns e nt. T h e p arti ci p a nt m ust b e gi v e n a c o p y of t h e 
si g n e d a n d d at e d c o ns e nt d o c u m e nt. T h e ori gi n al si g n e d c o p y of t h e c o ns e nt 
d o c u m e nt m ust b e r et ai n e d i n t he me dical rec or d or researc h file. 
1 3. 3
Et hics a n d G o o d Cli nical Practice ( G C P)
T his st u d y is t o b e c o n d u ct e d a c c or di n g t o t h e f oll o wi n g c o nsi d er ati o ns, w hi c h 
r e pr es e nt g o o d a n d s o u n d r es e ar c h pr a cti c e:
 
E 6 G o o d Cli ni c al Pr a cti c e: C o ns oli d at e d G ui d a n c e 
w w w.f d a. g o v/ d o w nl o a ds/ R e g ul at or yI nf or m ati o n/ G ui d a n c es/ U C M 1 2 9 5 1 5. p df  

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 
U S C o d e of F e d er al R e g ul ati o ns ( C F R) g o v er ni n g cli ni c al st u d y c o n d u ct a n d 
et hi c al pri n ci pl es t h at h a v e t h eir ori gi n i n t h e D e cl ar ati o n of H elsi n ki

Titl e 2 1 P art 1 1 – El e ctr o ni c R e c or ds; El e ctr o ni c Si g n at ur es 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 1 1 _ 0 2. ht ml

Titl e 2 1 P art 5 0 – Pr ot e cti o n of H u m a n S u bj e cts 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 5 0 _ 0 2. ht ml  

Titl e 2 1 P art 5 4 – Fi n a n ci al Dis cl os ur e b y Cli ni c al I n v esti g at ors 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 5 4 _ 0 2. ht ml  

Titl e 2 1 P art 5 6 – I nstit uti o n al R e vi e w B o ar ds 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 5 6 _ 0 2. ht ml  

Titl e 2 1 P art 3 1 2 – I n v esti g ati o n al N e w Dr u g A p pli c ati o n 
w w w. a c c ess. g p o. g o v/ n ar a/ cfr/ w aisi d x _ 0 2/ 2 1 cfr 3 1 2 _ 0 2. ht ml  
 
St at e l a ws
 
D F/ H C C r es e ar c h p oli ci es a n d pr o c e d ur es        
htt p:// w w w. df h c c. h ar v ar d. e d u/ cli ni c al-r es e ar c h-s u p p ort/ cli ni c al-r es e ar c h- u nit-
cr u/ p oli ci es- a n d- pr o c e d ur es/  
It is u n d erst o o d t h at d e vi ati o ns fr o m t h e pr ot o c ol s h o ul d b e a v oi d e d, e x c e pt w h e n 
n e c ess ar y t o eli mi n at e a n i m m e di at e h a z ar d t o a r es e ar c h p arti ci p a nt. I n s u c h c as e, 
t h e d e vi ati o n m ust b e r e p ort e d t o t h e I R B a c c or di n g t o t h e l o c al r e p orti n g p oli c y. 
1 3. 4
St u d y D oc u me ntati o n
T he i n vesti gat or m ust pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories 
desi g ne d t o rec or d all o bser vati o ns a n d ot her data perti ne nt t o t he st u d y f or eac h 
researc h partici pa nt. T his i nf or mati o n e na bles t he st u d y t o be f ull y d oc u me nte d a n d t he 
st u d y data t o be s u bse q ue ntl y verifie d.
Ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he case re p ort f or ms i ncl u de b ut are 
n ot li mite d t o h os pital rec or ds, cli nical c harts, la b orat or y a n d p har mac y rec or ds, 
rec or de d data fr o m a ut o mate d i nstr u me nts, micr ofic hes, p h ot o gra p hic ne gati ves, 
micr ofil m or ma g netic me dia, a n d/ or x-ra ys. 
1 3. 5
Rec or ds Rete nti o n
All st u d y-r el at e d d o c u m e nts m ust b e r et ai n e d f or t h e m a xi m u m p eri o d r e q uir e d b y 
a p pli c a bl e f e d er al r e g ul ati o ns a n d g ui d eli n es or i nstit uti o n al p oli ci es. 
1 4.
S T A TI S TI C A L C O N SI D E R A TI O N S 

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1 4. 1
St u d y Desi g n/ E n d p oi nts
1 4. 1. 1 St u d y Desi g n
T his is a n o pe n-la bel, si n gle-ar m, t w o sta ge, P hase II st u d y of dasati ni b i n patie nts w h o ha ve 
pr o gresse d o n first li ne s yste mic t hera p y f or a d va nce d i ntra he patic c h ola n gi ocarci n o ma (I C C) 
wit h eit her I D H 1 or I D H 2 m utati o ns.  
T his p hase II st u d y w o ul d ha ve a t w o-sta ge desi g n, wit h a tar get accr ual of 8 e val ua ble patie nts 
f or t he first sta ge a n d a t otal of 1 9 patie nts f or t he w h ole st u d y.  If n o res p o nses see n i n t he first 8 
patie nts, t he trial will be ter mi nate d.  If at least 1 patie nt i n t he first sta ge has res p o nse, t he trial 
w o ul d pr ocee d t o t he sec o n d sta ge. We h y p ot hesize d t hat dasati ni b w o ul d i m pr o ve t he res p o nse 
rate fr o m 2 % t o 2 0 %.  As desi g ne d, t he o verall st u d y wit h 1 9 e val ua ble patie nts  w o ul d ha ve a n 
8 0 % p o wer at a 0. 0 4 le vel of si g nifica nce t o detect a 1 8 % differe nce of res p o nse rate fr o m 2 % t o 
2 0 %.  At least 2 res p o nses m ust be o bser ve d a m o n g t he t otal st u d y p o p ulati o n of 1 9 patie nts at 
t he c o m pleti o n of sec o n d sta ge i n or der t o reject t he n ull h y p ot hesis ( O R R ≤ 2 %) i n fa v or of t he 
alter nati ve ( O R R ≥ 2 0 %).  Distri b uti o ns of o verall s ur vi val a n d P F S will be calc ulate d usi n g t he 
Ka pla n- Meier met h o d, a n d c o nfi de nce li mits f or s ur vi val esti mates will be calc ulate d usi n g t he 
Gree n w o o d f or m ula.
Base d o n t he pre vale nce of ~ 2 0 % of I D H 1/ 2 m utati o ns, a p pr o xi matel y 4 0- 5 0 or 9 0- 1 0 0 I C C 
patie nts will be scree ne d de pe n di n g o n w het her t he st u d y will be ter mi nate d after t he first sta ge 
wit h 8 patie nts e nr olle d or c o m plete d wit h t he tar gete d accr ual of 1 9 patie nts. 
1 4. 1. 1. 2 A nal ysis P o p ulati o n
T he a nal ysis p o p ulati o n will c o nsist of all partici pa nts w h o e nr oll i n t he st u d y.
1 4. 1. 1. 3 Safet y P o p ulati o n
T he safet y p o p ulati o n will c o nsist of all partici pa nts w h o recei ve a n y a m o u nt of st u d y 
treat me nt.
1 4. 1. 1. 4 Safet y A nal ysis
Safet y will be 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.
1 4. 1. 2 Pri mar y E n d p oi nt
T he pri mar y e n d p oi nt of t he st u d y is o bjecti ve res p o nse rate ( O R R) per R E CI S T v 1. 1 
criteria.  T he o bjecti ve res p o nse rate ( O R R) is defi ne d usi n g t he R E CI S T criteria as t he 
pr o p orti o n of t he p o p ulati o n wit h a c o nfir me d C R or c o nfir me d P R. T he p oi nt esti mate of 
t he O R R wit h a 9 0 % c o nfi de nce i nter val base d o n t he e xact bi n o mial distri b uti o n will be 
prese nte d.
  
1 4. 2
Sa m ple Size, Accr ual Rate, a n d Earl y St o p pi n g R ule
1 4. 2. 1  Sa m ple Size 

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T he pla n ne d sa m ple size f or Sta ge I is 8 a n d if t he st u d y pr ocee ds t o Sta ge II, a t otal 
of 1 9 patie nts will be e nr olle d.  
1 4. 2. 2  Accr ual Rate a n d F oll o w- u p after Ter mi nati o n of Accr ual
A n accr ual rate of 1- 2 patie nts/ m o nt h is e x pecte d.  Patie nts will be f oll o we d, as 
s pecifie d i n Secti o n 9, u ntil deat h or u ntil 6 m o nt hs after t he last e nr olle d patie nt 
ter mi nates treat me nt, w hic he ver c o mes first.
1 4. 2. 3  Rati o nale f or Sa m ple Size
We h y p ot hesize d t hat dasati ni b w o ul d i m pr o ve t he res p o nse rate fr o m 2 % t o 
2 0 %.  As desi g ne d, t he o verall st u d y wit h 1 9 e val ua ble patie nts  w o ul d ha ve a n 
8 0 % p o wer at a 0. 0 4 le vel of si g nifica nce t o detect a 1 8 % differe nce of res p o nse 
rate fr o m 2 % t o 2 0 %.   Pri or st u dies wit h la pati ni b a n d s orafe ni b ha ve pr o d uce d n o 
res p o nses i n t his p o p ulati o n.
1 4. 2. 4 Earl y St o p pi n g R ule
Of t he 8 patie nts e nr olle d i n Sta ge I, at least 1 patie nt nee ds t o ha ve res p o nse bef ore t he 
sec o n d sta ge ca n pr ocee d.  
1 4. 2. 5 O utc o me I n dicati n g Efficac y of t he Dr u g
T he o verall st u d y wit h 1 9 e val ua ble patie nts  w o ul d ha ve a n 8 0 % p o wer at a 0. 0 4 
le vel of si g nifica nce t o detect a 1 8 % differe nce of res p o nse rate fr o m 2 % t o 2 0 %. 
If t his pri mar y e n d p oi nt is met, t he dr u g warra nts f urt her i n vesti gati o n i n t his 
p o p ulati o n.
1 4. 3  A nal ysis of Sec o n dar y E n d p oi nts
1 4. 3. 1 Pr o gressi o n Free S ur vial ( P F S)
Pr o gressi o n Free S ur vial ( P F S) will be defi ne d as t he ti me fr o m t he start of treat me nt 
u ntil pr o gressi o n or deat h fr o m a n y ca use. Ka pla n- Meier esti mates of P F S will be 
calc ulate d al o n g wit h t heir c orres p o n di n g 9 5 % c o nfi de nce i nter vals. 
1 4. 3. 2 O verall S ur vi val
O verall s ur vi val ( O S) will be defi ne d as t he ti me fr o m t he start of treat me nt u ntil 
deat h fr o m a n y ca use. Ka pla n- Meier esti mates of o verall s ur vi val rates will be calc ulate d 
al o n g wit h t heir c orres p o n di n g 9 5 % c o nfi de nce i nter vals. C o x pr o p orti o nal hazar ds 
re gressi o n m o deli n g of O S will be use d t o assess t he effect of dasati ni b o n O S w hile 
c o ntr olli n g f or ot her c o nf o u n ders.
1 4. 3. 3  T olera bilit y a n d safet y a nal ysis
F or t he safet y a nal ysis, all e nr olle d patie nts w h o recei ve at least o ne d ose of 
dasati ni b will be i ncl u de d f or a nal ysis. A d verse e ve nt ter ms rec or de d o n t he C R Fs 
will be ma p pe d t o preferre d ter ms usi n g t he Me dical 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 de, a n d relati o ns hi p t o st u d y 

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treat me nt will be assesse d b y t he i n vesti gat or. Se verit y/ gra de will be defi ne d b y t he 
Nati o nal Ca ncer I nstit ute ( N CI) C T C A E v 4. 0. 
1 4. 3. 4 Bi ol o gic c orrelati ve st u dies of tar get i n hi biti o n (see a b o ve)
Ka pla n- Meier s ur vi val c ur ves a n d C o x Pr o p orti o nal Hazar d m o dels will be use d t o e x pl ore 
t he relati o ns hi p bet wee n t he bi o mar ker cate g ories a n d t he o verall res p o nse rate as well as 
pr o gressi o n-free s ur vi val.
1 4. 4  Re p orti n g a n d E xcl usi o ns
1 4. 4. 1
E val uati o n of t o xicit y.  All partici pa nts will be e val ua ble f or t o xicit y fr o m t he ti m e 
of t h eir first tr e at m e nt.
1 4. 4. 2
E val uati o n of res p o nse.  All partici pa nts i ncl u de d i n t he st u d y m ust be assesse d f or 
res p o nse t o treat me nt, e ve n if t here are maj or pr ot oc ol treat me nt de viati o ns or if t he y are 
i neli gi ble. Eac h partici pa nt s h o ul d be assi g ne d o ne of t he f oll o wi n g cate g ories: 1) c o m plete 
res p o nse, 2) partial res p o nse, 3) sta ble disease, 4) pr o gressi ve disease, 5) earl y deat h fr o m 
mali g na nt disease, 6) earl y deat h fr o m t o xicit y, 7) earl y deat h beca use of ot her ca use, or 9) 
u n k n o w n ( n ot assessa ble, i ns ufficie nt data). B y ar bitrar y c o n ve nti o n, cate g or y 9 us uall y 
desi g nates t he " u n k n o w n" stat us of a n y t y pe of data i n a cli nical data base.
             
1 5.
P U B LI C A TI O N P L A N
T he Pri nci pal I n vesti gat or ( Pr ot oc ol C hair) h ol ds t he pri mar y res p o nsi bilit y f or p u blicati o n of t he
st u d y res ults; pr o vi de d t hat t he PI will pr o vi de a n y s uc h p u blicati o n t o B M S, I nc. f or re vie w
at least si xt y ( 6 0) da ys pri or t o s u b missi o n a n d als o c o m pl y wit h a n y pr o visi o ns re gar di n g
p u blicati o n as are a gree d t o bet wee n t he PI’s i nstit uti o n (e g, Massac h usetts Ge neral H os pital) 
a n d B M S i n t he Cli nical Trial A gree me nt relate d t o t his st u d y. T he res ults will be ma de p u blic 
wit hi n 2 4 m o nt hs of t he e n d of data c ollecti o n. H o we ver, if a re p ort is pla n ne d t o be p u blis he d i n 
a peer-re vie we d j o ur nal, t he n t hat i nitial release ma y be a n a bstract t hat meets t he re q uire me nts 
of t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. I n a n y e ve nt, a f ull re p ort of t he 
o utc o mes s h o ul d be ma de p u blic n o later t ha n t hree ( 3) years after t he e n d of data c ollecti o n. 
A ut h ors hi p f or a bstracts a n d ma n uscri pts res ulti n g fr o m t his st u d y will be deter mi ne d acc or di n g 
t o g ui deli nes esta blis he d b y t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.

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1 6.
R E F E R E N C E S 
1   
Valle, J.  et al. Cis plati n pl us ge mcita bi ne vers us ge mcita bi ne f or biliar y tract ca ncer. N 
E n gl J Me d  3 6 2 , 1 2 7 3- 1 2 8 1, d oi: 1 0. 1 0 5 6/ N EJ M oa 0 9 0 8 7 2 1 ( 2 0 1 0).
2  
S hai b, Y. & El- Sera g, H. B. T he e pi de mi ol o g y of c h ola n gi ocarci n o ma. Se mi n ars i n liver 
dise ase  2 4 , 1 1 5- 1 2 5, d oi: 1 0. 1 0 5 5/s- 2 0 0 4- 8 2 8 8 8 9 ( 2 0 0 4).
3   
Hai ns w ort h, J. D.  et al. M olec ular ge ne e x pressi o n pr ofili n g t o pre dict t he tiss ue of ori gi n 
a n d direct site-s pecific t hera p y i n patie nts wit h carci n o ma of u n k n o w n pri mar y site: a 
pr os pecti ve trial of t he Sara h Ca n n o n researc h i nstit ute. J o ur n al of cli nic al o nc ol o gy : 
offici al j o ur n al of t he A meric a n S ociety of Cli nic al O nc ol o gy  3 1 , 2 1 7- 2 2 3, 
d oi: 1 0. 1 2 0 0/J C O. 2 0 1 2. 4 3. 3 7 5 5 ( 2 0 1 3).
4  
Z h u, A. X. & Hezel, A. F. De vel o p me nt of m olec ularl y tar gete d t hera pies i n biliar y tract 
ca ncers: reassessi n g t he c halle n ges a n d o p p ort u nities. He p at ol o gy  5 3 , 6 9 5- 7 0 4, 
d oi: 1 0. 1 0 0 2/ he p. 2 4 1 4 5 ( 2 0 1 1).
5  
Be kaii- Saa b, T.  et al. M ulti-i nstit uti o nal p hase II st u d y of sel u meti ni b i n patie nts wit h 
metastatic biliar y ca ncers. J o ur n al of cli nic al o nc ol o gy : offici al j o ur n al of t he A meric a n 
S ociety of Cli nic al O nc ol o gy  2 9 , 2 3 5 7- 2 3 6 3, d oi: 1 0. 1 2 0 0/J C O. 2 0 1 0. 3 3. 9 4 7 3 ( 2 0 1 1).
6  
El- K h o ueir y, A. B.  et al. S W O G 0 5 1 4: a p hase II st u d y of s orafe ni b i n patie nts wit h 
u nresecta ble or metastatic gall bla d der carci n o ma a n d c h ola n gi ocarci n o ma. 
I nvesti g ati o n al ne w dr u gs 3 0 , 1 6 4 6- 1 6 5 1, d oi: 1 0. 1 0 0 7/s 1 0 6 3 7- 0 1 1- 9 7 1 9- 0 ( 2 0 1 2).
7  
Ra ma nat ha n, R. K.  et al. A p hase II st u d y of la pati ni b i n patie nts wit h a d va nce d biliar y 
tree a n d he pat ocell ular ca ncer. C a ncer c he m ot her a py a n d p h ar m ac ol o gy  6 4 , 7 7 7- 7 8 3, 
d oi: 1 0. 1 0 0 7/s 0 0 2 8 0- 0 0 9- 0 9 2 7- 7 ( 2 0 0 9).
8  
B or ger, D. R.  et al. Fre q ue nt m utati o n of is ocitrate de h y dr o ge nase (I D H) 1 a n d I D H 2 i n 
c h ola n gi ocarci n o ma i de ntifie d t hr o u g h br oa d- base d t u m or ge n ot y pi n g. O nc ol o gist  1 7 , 
7 2- 7 9, d oi: 1 0. 1 6 3 4/t he o nc ol o gist. 2 0 1 1- 0 3 8 6 ( 2 0 1 2).
9  
Jia o, Y.  et al. E x o me se q ue nci n g i de ntifies fre q ue nt i nacti vati n g m utati o ns i n B A P 1, 
A RI D 1 A a n d P B R M 1 i n i ntra he patic c h ola n gi ocarci n o mas. N at Ge net  4 5 , 1 4 7 0- 1 4 7 3, 
d oi: 1 0. 1 0 3 8/ n g. 2 8 1 3 ( 2 0 1 3).
1 0   
Ki p p, B. R.  et al. Is ocitrate de h y dr o ge nase 1 a n d 2 m utati o ns i n c h ola n gi ocarci n o ma. 
H u m P at h ol  4 3 , 1 5 5 2- 1 5 5 8, d oi: 1 0. 1 0 1 6/j. h u m pat h. 2 0 1 1. 1 2. 0 0 7 ( 2 0 1 2).
1 1   
Wa n g, P.  et al. M utati o ns i n is ocitrate de h y dr o ge nase 1 a n d 2 occ ur fre q ue ntl y i n 
i ntra he patic c h ola n gi ocarci n o mas a n d s hare h y per met h ylati o n tar gets wit h gli o blast o mas. 
O nc o ge ne , d oi: 1 0. 1 0 3 8/ o nc. 2 0 1 2. 3 1 5 ( 2 0 1 2).
1 2  
Z h u, A. X.  et al. Ge n o mic Pr ofili n g of I ntra he patic C h ola n gi ocarci n o ma: Refi ni n g 
Pr o g n osis a n d I de ntif yi n g T hera pe utic Tar gets. A n n als of s ur gic al o nc ol o gy , 
d oi: 1 0. 1 2 4 5/s 1 0 4 3 4- 0 1 4- 3 8 2 8- x ( 2 0 1 4).
1 3  
L os ma n, J. A.  et al. ( R)- 2- h y dr o x y gl utarate is s ufficie nt t o pr o m ote le u ke m o ge nesis a n d 
its effects are re versi ble. Scie nce  3 3 9 , 1 6 2 1- 1 6 2 5, d oi: 1 0. 1 1 2 6/scie nce. 1 2 3 1 6 7 7 ( 2 0 1 3).
1 4  
B or ger, D. R.  et al. Circ ulati n g o nc o meta b olite 2- h y dr o x y gl utarate is a p ote ntial 
s urr o gate bi o mar ker i n patie nts wit h is ocitrate de h y dr o ge nase- m uta nt i ntra he patic 
c h ola n gi ocarci n o ma. Cli nic al c a ncer rese arc h : a n offici al j o ur n al of t he A meric a n 
Ass oci ati o n f or C a ncer Rese arc h  2 0 , 1 8 8 4- 1 8 9 0, d oi: 1 0. 1 1 5 8/ 1 0 7 8- 0 4 3 2. C C R- 1 3- 2 6 4 9 
( 2 0 1 4).
1 5  
Sa ha, S. K.  et al. M uta nt I D H i n hi bits H N F- 4al p ha t o bl oc k he pat oc yte differe ntiati o n 
a n d pr o m ote biliar y ca ncer. N at ure , d oi: 1 0. 1 0 3 8/ nat ure 1 3 4 4 1 ( 2 0 1 4).

P h ase II tri al of d as ati ni b f or a d v a nce d I D H- m ut a nt i ntr a he p atic c h ol a n gi oc arci n o m a
0 3/ 1 1/ 1 5
4 9
A P P E N DI C E S 
A p pe n di x A - Perf or m a nce St at us Criteri a
E C O G Perf or m a nce St at us Sc ale
Gra de
Descri pti o n
0
N or mal acti vit y. F ull y acti ve, a ble t o carr y o n all pre- disease perf or ma nce wit h o ut 
restricti o n.
1
S y m pt o ms, b ut a m b ulat or y. Restricte d i n p h ysicall y stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht or se de ntar y nat ure (e. g., li g ht 
h o use w or k, office w or k).
2
I n be d < 5 0 % of t he ti me. A m b ulat or y a n d ca pa ble of all self-care, b ut u na ble t o carr y 
o ut a n y w or k acti vities. U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.
3
I n be d > 5 0 % of t he ti me. Ca pa ble of o nl y li mite d self-care, c o nfi ne d t o be d or c hair 
m ore t ha n 5 0 % of wa ki n g h o urs.
4
1 0 0 % be dri d de n. C o m pletel y disa ble d. Ca n n ot carr y o n a n y self-care. T otall y 
c o nfi ne d t o be d or c hair.
5 
Dea d.