Clinical trial NCT02428855
Conditions: Cholangiocarcinoma
Keywords: Cholangiocarcinoma
Sponsor: Massachusetts General Hospital
Start date: 2015-04-01; Completion date: 2018-02-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying Dasatinib as a possible treatment for cancer of bile ducts.

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The standard treatment for metastatic cholangiocarcinoma is combination chemotherapy with gemcitabine and cisplatin. The FDA (the U.S. Food and Drug Administration) has not approved dasatinib for your specific disease (Cholangiocarcinoma) but it has been approved for other uses (Chronic Myeloid Leukemia)

Arms: arm 1: Patients with advanced intrahepatic cholangiocarcinoma who have either IDH1 or IDH2 mutations and have received at least one prior platinum containing regimen

* Dasatinib, oral, daily, predetermined dosage per cycle
* Radiologic Response Assessment every 2 cycles
Interventions: intervention 1: Dasatinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 


.
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
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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
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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
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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
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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
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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
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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
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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:


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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.


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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)


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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


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
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:


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
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. 








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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:


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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.


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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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.