Phase 1b, Open-label, Dose Escalation Study of Quizartinib in Combination With Induction and Consolidation Chemotherapy in Japanese Patients With Newly Diagnosed Acute Myeloid Leukemia (AML)
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Sponsor: Daiichi Sankyo Co., Ltd.

 
 
 
 
 
1 
 
Pr ot o c ol N o.: A C 2 2 0 - A-J 1 0 2 
 
 
 
 
 
 
Cli nical St u d y Pr ot oc ol  
 
A P hase 1 b Cli ni cal St u d y of Q ui zarti ni b ( A C 2 2 0)  
– E val uati o n of t he Safet y a n d P h ar mac o ki netics of 
Q uizarti ni b i n C o m bi nati o n wit h St a n dar d I n d ucti o n a n d 
C o ns oli dati o n T hera p y i n Ja pa nese Patie nts w it h I nitiall y 
Dia g n ose d Ac ut e M y el oi d Le u k e mia – 
 
C o nfi d e nti al I nf or mati o n  
 
T his cli ni cal st u d y pr ot o c ol is c o nfi d e nti al i nf or mati o n pr o vi d e d t o t h e i n vesti gat ors, 
s u bi n vesti gat ors, st u d y st aff, st u d y dr u g ma n a gers, st u d y ce nt ers, a n d i nstit uti o n al 
r e vie w bo ar ds i n v ol ve d i n t h e st u d y.   It s h o ul d n ot b e dis cl ose d t o a t hir d part y or us e d 
f or a n y ot her p ur p os e t ha n t h at of t h e st u d y wit h o ut t h e writt e n p er missi o n fr o m 
Daii c hi Sa n k y o C o., Lt d. e xce pt w h e n it is us e d t o e x pl ai n t h e d et ails of t he st u d y t o 
s u bj ects. 
 
S p o ns or: Daiic hi S a n k y o C o., Lt d.  
 
Versi o n 0 1. 0 0. 0 0 0 / Dat e of Pre p arati o n : 1 7 M a y 2 0 1 6 

 
 
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P R O T O C O L S Y N O P SI S  
Pr ot o c ol n u m ber 
A C 2 2 0 - A-J 1 0 2 
I n vesti gati o n al 
s u bst a n ce c o d e 
A C 2 2 0  
Ge n eri c n a me  
(r-I N N) 
Q uizarti ni b  
St u d y titl e  
A P h as e 1 b Cli nical St u d y of Q uizarti ni b ( A C 2 2 0)  
– E val u ati o n of t h e Safet y a n d P har mac o ki n etics of Q ui zarti ni b 
i n C o m bi n ati o n wit h St a n d ar d I n d u cti o n a n d C o ns oli d ati o n 
T h er a p y i n J a p a n es e P ati e nts wit h I niti all y Di a g n os e d Ac ut e 
M yel oi d Le u ke mi a – 
P has e of d e vel o p me nt  P has e 1 b  
Pla n n e d  i n di cati o n 
Ac ut e m yel oi d l e u ke mi a ( A M L)  
St u d y o bj ecti ves  
P ri mar y o bj ecti ve: 
To e val u at e t h e s afet y a n d p h ar mac o ki n eti cs of q ui zarti ni b  i n 
c o m bi n ati o n wit h st a n d ar d i n d u cti o n a n d c o ns oli dati o n t h era p y 
i n J a p a n es e p atie nts wit h initi all y  di a g n os e d A M L , a n d  t o 
det er mi n e t h e d os e f or s u bse q u e nt p h as es of d e v el o p me nt . 
S ec o n dar y o bj ecti ve s: 
• 
E x pl or at or y st u d y of q ui zarti ni b -relat e d bi o mar k ers 
• 
E x pl or at or y e val u ati o n of a ntit u m or effect  
Ty p e of st u d y o bj ecti ves : 
Saf et y / p h ar mac o d y n a mics  / p h ar mac o ki n eti cs  / t ol era bilit y / 
p h ar mac o ge n o mi cs  
St u d y d esi g n  
Ty p e of st u d y: I nt er ve nti o n al 
Ty p e of i nt er ve nti o n: P h ar mace uti cal dr u gs  
Ty p e of pr o p os e d i n di cati o ns : Treat me nt 
St u d y d esi g n: Si n gl e ar m  
Le vel of bli n di n g: O p e n -la b el 
T y p e a n d pres e n ce/ a bs e n ce of c o m parat or: A bs e nt  
Pres e n ce/ a bs e n ce of  ra n d o mi zati o n: A bs e nt 
S u bject o bs er vati o n p eri o d: Fr o m i nf or me d c o ns e nt t o t h e e n d 
of t h e p ost -treat me nt o bs er vati o n p eri o d  
Pres e n ce/ a bs e n ce of  a d d-o n t o st a n d ar d t h era p y: Pres e nt  
Re gi me n  of st a n d ar d t hera p y: C yt ara bi n e a n d a n a nt hrac ycli ne  

 
 
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dr u g 
Pla n n e d st u d y p eri o d  
1 J ul 2 0 1 6 t o 3 1 Dec 2 0 1 7  
St u d y c o u ntr y  
Ja p a n 
St u d y ce nt er  
To b e d et er mi n e d  
Pla n n e d s a m pl e si ze  
Si x t o t wel ve p ati e nts ( mi ni m u m of 3 p ati e nt s at eac h l e vel, a 
t ot al of 6 p ati e nts) 
St u d y p o p ul ati o n  
(I n cl usi o n a n d 
e xcl usi o n crit eri a)  
< I n cl usi o n criteri a> 
1)  Pr o visi o n of writt e n i nf or me d c o nse nt f or p arti ci p ati o n i n 
t h e st u d y. 
2)  A ge ≥ 2 0 years a n d ≤ 7 5 years at t h e ti me of re gistrati o n i n 
t h e st u d y 
3)  A M L p ati e nts (i n cl u di n g t h os e wit h a hist or y of 
m yel o d ys pl asti c s y n dr o me  [ M D S]) wh o h a ve n ot 
p r e vi o usl y recei ve d ot h er treat me nts (i n cl u di n g 
q ui zarti ni b ) t h a n t h os e list e d b el o w 
• 
Le u ka p heresis  
• 
Tr eat me nt wit h h y dr o x ycar b a mi d e f or c o ntr ol of t h e 
w hit e bl o o d cell c o u nt  
• 
Cr a ni al ra di ati o n f or t h e treat me nt of i n vasi o n of t h e 
ce ntral n er v o us s yst e m 
• 
Pr o p h yl acti c i ntrat h ecal c h e m ot h era p y 
• 
S u p p orti ve treat me nt wit h gr o wt h fact or pr o d u cts or 
c yt o ki n e  
4)  East er n C o o p erati ve O n c ol o g y Gr o u p  p erf or ma n ce st at us 
( E C O G P S) s c ore 2 or l ess at t h e ti me of re gistrati o n i n t h e 
st u d y (refer t o “ A p p e n di x 1”). 
5)  La b o r at or y t est res ults o bt ai n e d wit hi n 1 4 d a ys b ef ore 
r e gistr ati o n i n t h e st u d y meet all of t h e f oll o wi n g 
r e q uir e me nts: 
La b or at or y P ar a met er  
Re q uir e me nt  
A S T  
≤ 2. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al 
refer e n c e r a n g e 
A L T  
≤ 2. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al 
refer e n c e r a n g e 
Tot al bilir u bi n  
≤ 1. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al 
refer e n c e r a n g e 

 
 
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Ser u m cr e ati ni n e  
≤ 1. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al 
refer e n c e r a n g e, or esti mat e d gl o mer ular 
filtr ati o n r ate (e G F R) c al c ulat ed t o b e 
≥ 5 0  m L/ mi n/ 1. 7 3  m2 b y t h e M o difi c ati o n of 
Di et i n R e n al Dis eas e ( M D R D) e q u ati o n  
Ser u m K  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge *  
Ser u m C a ( c orr ect e d f or al b u mi n)  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge *  
Ser u m M g  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge * 
*  P ati e nts wit h el e ctr ol yt es o utsi d e t h e  i nstit uti o n al r efer e n c e ra n g e will b e eli gi ble if 
t h es e v al u es ar e c orr e ct e d u p o n r et esti n g f oll o wi n g a n y n e c ess ar y s u p pl e me nt ati o n. 
6)  P ati e nts w h o  ca n recei ve q ui zarti ni b orall y. 
7)  P ati e nts w h o  ca n b e h os pit ali ze d d uri n g t h e d os e- li miti n g 
t o xi cit y ( D L T) ass ess me nt p eri o d. 
< E x cl usi o n criteri a >  
1)  Di a g n osis of ac ut e pr o m yel o c yti c l e u ke mi a  
2)  C hr o ni c m yel oi d l e u ke mia i n bl ast crisis ( p ati e nts wit h 
B C R -A B L  [brea k p oi nt cl ust er re gi o n - c-A b els o n ] f usi o n 
ge n e)  
3)  Di a g n osi s of treat me nt-rel at e d m yel oi d t u m or 
4)  Ha vi n g recei ve d ot h er i n vesti gati o n al pr o d u cts or h a vi n g 
us e d a n y i n vesti gati o n al me di cal d e vi ce s wit hi n 3 0 da ys 
bef or e re gistrati o n i n t he st u d y. 
5)  Hist or y of mali g n a nt t u m or e xce pt f or t h e f oll o wi n g  
• 
A d e q u at el y treat e d n o n -mela n o ma s ki n ca n cer  
• 
C urati vel y treat e d m u c os al carci n o ma or c arci n o ma i n 
sit u wit h n o e vi d e n ce of rel a ps e f or ≥ 2 years  aft er t h e 
l o cal treat me nt 
6)  Hist or y of or c urre nt car di o vas c ul ar diseas e as s p ecifi e d 
bel o w:  
• 
Heart rat e  < 5 0  b eats/ mi n , d et er mi n e d as t h e a ver a ge 
of t hree meas ure me nts t a ke n al o n g wit h 1 2 -l ea d E C G 
wit hi n 1 4 d a ys b ef ore re gistrati o n i n t h e st u d y 
( e xcl u di n g p atie nts h a vi n g a car diac p ace ma ker)  
• 
Q T c orrect e d f or heart rate usi n g Fri d eri ci a’s met h o d 
( Q Tc F) of ≥ 4 5 0 ms, d et er mi n e d as t h e a vera ge of 
t hree meas ure me nts t a ke n wit hi n 1 4 d a ys b ef ore 
r e gistrati o n i n t he st u d y 
• 
Di a g n os e d or s us p ect e d c o n ge nital l o n g Q T s y n dr o me  
• 
S yst olic bl o o d press ure l e vel ≥ 1 8 0  m m H g or di ast oli c 

 
 
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bl o o d press ure l e vel ≥ 1 1 0  m m H g wit hi n 7 d a ys 
bef ore re gistrati o n i n t he st u d y 
• 
Hist or y of cli ni call y si g nifi ca nt ve ntri c ul ar arr h yt h mi a 
( ve ntri c ul ar tac h ycar di a, ve ntri c ul ar fi brill ati o n, 
t ors a de de p oi nt es [ T d P], et c.) 
• 
Hist or y of  M o bit z II  atri o ve ntri c ul ar bl o c k or t hir d 
de gree atri o ve ntri c ul ar bl o c k ( P ati e nts w h o h a ve a 
car di ac p ace ma ker b ut h a ve n ot e x p eri e n ce d s y n c o p e 
or cli ni call y si g nifi ca nt arr h yt h mi a d uri n g t h e p eri o d 
of us e are a ll o we d t o t a ke p art i n t h e st u d y.) 
• 
Hist or y of u n c o ntr oll e d a n gi n a p ect oris or m y o car di al 
i nfarcti o n wit hi n 6 m o nt hs b ef ore re gistrati o n i n t he 
st u d y 
• 
Hist or y of Cl ass 3 or m ore s e vere h eart fail ure 
acc or di n g t o “ A p p e n di x 2 Ne w Yor k Heart 
Ass o ci ati o n ( N Y H A) F u ncti o n al Cl assifi cati o n ”  
• 
Hist or y of  l eft ve ntri c ul ar ejecti o n fracti o n b el o w 4 5 % 
or t h e l o wer li mit of t h e i nstit uti o n al refere n ce ra n ge, 
w hic h e ver is l o wer  
• 
C o m pl et e l eft or ri g ht b u n dl e bra n c h bl o c k  
7)  Ac ut e a n d acti ve i nfecti o n u n c o ntr oll e d b y a nti bact eri al or 
a nti vir al a ge nts or c hr o ni c a n d s yst e mi c i nfecti o n  
8)  Acti ve a n d cli ni call y si g nifi ca nt li ver dis eas e ( h e patitis B, 
he p atitis C, et c.)  
9)  Test e d p ositi ve f or h u ma n i m m u n o d efi ci e n c y vir us ( HI V ) 
a nti b o d y wit hi n 1 4 d a ys bef ore re gistrati o n i n t he st u d y  
1 0)  Wo me n c o nfir me d  t o b e pre g n a nt b y a pre g n a n c y test 
perf or me d wit hi n 1 4 d a ys b ef ore re gistrati o n i n t h e st u d y , 
or br eastfee di n g w o me n  
1 1)  U n willi n g n ess t o practi ce a p pr o pri at e c o ntrace pti o n usi n g 
eff ecti ve c o ntrace pti ve met h o ds (e g, b arri er c o ntrace pti ves 
c o m bi n e d wi t h s p er mi ci des, i ntra ut eri n e d e vi ce, et c.) f or 
t h e e ntire st u d y p eri o d a n d 3 m o nt hs aft er t h e l ast d os e of 
t h e st u d y dr u g 
1 2)  P ati e nts w h o are ot h er wise c o nsi d ere d i n eli gi bl e f or t h e 

 
 
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st u d y i n t h e i n vesti gat or’s or s u bi n vesti gat or’s o pi ni o n 
St u d y  dr u g  
Q uizarti ni b will b e orall y a d mi nist ere d at t h e d os e list e d b el o w 
o n ce d ail y e ver y m or ni n g u n d er fasti n g c o n diti o ns (at l east 1 
h o ur b ef ore or at l east 2 h o urs aft er brea kfast).  
Le v el  
D os e  
1 
2 0 m g 
2  
4 0  m g  
Re missi o n i n d u cti o n t h era p y a n d c o ns oli d ati o n t h era p y wil l b e 
gi ve n f or u p t o 2 c ycl es a n d 4 c ycl es, res p ecti vel y, eac h of 
w hic h is 2 8 d a ys l o n g.  
T h e d os e- li miti n g t o xi cit y (D L T) ass ess me nt p eri o d  is t h e 
i n d u cti o n p h as e.  
< R e missi o n i n d u cti o n t her a p y > 
* 
As  a n a nt hrac ycli n e  dr u g, eit h er d a u n or u bi ci n or 
i d ar u bi ci n will b e c h os e n, a n d t h e s a me dr u g will be us e d 
i n C ycl e 1 a n d C ycl e 2. 
C ycl e 1  ( “7 + 3 ”) 
• 
C yt ar a bi n e : 1 0 0 m g/ m2/ d a y o n Da y 1  t o Da y 7  
• 
Da u n or u bi ci n : 6 0 m g/ m2/ d a y o n Da y 1  t o Da y 3  
• 
I d ar u bi ci n: 1 2 m g/ m2/ d a y o n Da y 1  t o Da y 3  
• 
Q uizarti ni b: 2 0 m g/ d a y or 4 0  m g/ d a y o n Da y 8  t o Da y 2 1  
C ycl e 2  
* 
T h e tr eat me nt will b e a d mi nist ere d  usi n g t h e sa m e 
r e gi me n as i n C ycl e 1 (“7 + 3 ”) or as s h o w n b el o w (“ 5 + 
2 ”).  
• 
C yt ar a bi n e : 1 0 0 m g/ m2/ d a y o n Da y 1  t o Da y 5  
• 
Da u n or u bi ci n : 6 0 m g/ m2/ d a y o n Da y 1  t o Da y 2  
• 
I d ar u bi ci n: 1 2 m g/ m2/ d a y on Da y 1  t o Da y 2  
• 
Q uizarti ni b: 2 0  m g/ d a y  or 4 0 m g/ d a y o n Da y 6  t o Da y 1 9  
< C o ns oli d ati o n t her a p y > 
• 
C yt ar a bi n e : 3. 0 g/ m 2/ 1 2 h o urs f or p ati e nt s of  < 6 0 years  
ol d a n d 1. 5  g/ m 2/ 1 2 h o urs f or p ati e nt s of ≥ 6 0 years ol d  o n 
Da y 1,  Da y 3, a n d Da y 5  (a ge at t h e ti me of  re gistrati o n i n 
t h e st u d y) 
• 
Q uizarti ni b: 2 0  m g/ d a y  or 4 0 m g/ d a y o n Da y 6  t o Da y 1 9  

 
 
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Pr o hi bit e d 
c o n c o mit a nt dr u gs 
a n d t h er a pi es, 
r estri ct e d 
c o n c o mit a nt dr u gs , 
a n d d r u gs t o b e 
c o a d mi nist er e d wit h 
car e  
< Pr o hi bit e d c o n c o mit a nt d r u gs a n d t her a pi es >  
C o n c o mit a nt us e of t h e f oll o wi n g dr u gs , et c. is pr o hi bite d 
d uri n g t h e q ui zarti ni b treat me nt p eri o d.  
As a n e xce pti o n, t h e dr u gs list e d i n 1) a n d 2) ma y b e us e d o nl y 
w h e n t h e i n vesti gat or or s u bi n vesti gat or c o nsi d ers t h at t h es e 
dr u gs ar e me di call y ess e nti al t o pre ve nt o r treat i nfecti o n.    I n 
t his cas e, oral treat me nt wit h q ui zarti ni b s h o ul d b e i nt err u pte d 
fr o m t h e st art t o t h e e n d of us e of t h e dr u gs list e d i n 1) a n d 2), 
a n d b e r es u me d o n t h e f oll o wi n g d a y of t h e e n d of us e of t h e 
dr u gs.    At t h e ti me of res u m pti o n, n o d os e re d u cti o n of 
q ui zarti ni b will b e n ecessar y u nl ess t h e i n vesti gat or or 
s u bi n vesti gat or c o nsi d ers it n ecess ar y. 
1)  Dr u gs t h at ma y p ot e nti all y pr ol o n g t he Q T/ c orrecte d Q T 
( Q Tc) i nt er val 
2)  Str o n g c yt o c hr o me P 4 5 0  ( C Y P) 3 A 4 i n hi bit ors 
3)  Str o n g or m o d erat e C Y P 3 A 4 i n d u cers  
4)  Cr u d e dr u g s a n d f o o d pr o d ucts wit h C Y P 3 A 4 -i n hi biti n g 
or - i n d u ci n g pr o p erti es (e g, f o o ds a n d b e vera ges 
c o nt ai ni n g St. J o h n’s w ort or gra p efr uit) 
5)  A nti ca n cer treat me nts ot her t h a n q ui zarti ni b (e xce pt 
h y dr o x ycar b a mi d e)  
6)  I n vesti gati o n al dr u gs ot h er t h a n q ui zarti ni b, a n d 
i n vesti gati o n al d e vi ces 
7)  D o n or l y m p h o c yt es  
< R est ri ct e d c o nc o mit a nt d r u gs > 
T h e f oll o wi n g treat me nts s h o ul d b e restri ct e d d uri n g oral 
tr eat me nt wit h q ui zarti ni b: 
• 
Tr eat me nt wit h h y dr o x ycar b a mi d e f or  c o ntr ol of t h e  w hit e 
bl o o d cell c o u nt : Restri ct e d t o a d ail y d os e of 2 g f or  u p t o 
a t ot al of 1 4 d a ys  
< D r u gs t o b e c o a d mi nistere d wit h c a re >  
D uri n g or al treat me nt wit h q ui zarti ni b,  us e of s u bstrat es a n d 
i n hi bit ors of P- gl yc o pr ot ei n s h o ul d b e a v oi d e d as far as 
p ossi bl e. 
St u d y  pr o ce d ur es 
Ref er t o p a ges 1 0  a n d 1 3 . 

 
 
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E n d p oi nts 
Pri mar y  
Saf et y:  
A d vers e e ve nt ( A Es ), l a b orat or y d at a, vit al si g n s, b o d y wei g ht , 
1 2- l ea d E C G  
P har mac o ki n eti c s: 
P har mac o ki n eti c p ara meters of q ui zarti ni b a n d its acti ve 
meta b olit e A C 8 8 6 i n pl as ma  
Sec o n dar y  P har mac o d y n a mi cs : 
F M S -li ke t yr osi n e ki n as e ( F L T) 3-i nt er n al t a n d e m d u pli cati o n 
(I T D) st at us, c- v-kit Har d y -Z u c ker ma n 4 feli n e s arc o ma viral 
o n c o ge n e h o m ol o g ( KI T ) m utati o n st at us , p h os p h or yl at e d 
F L T 3 pr ot ei n l e vels i n bl o o d, p h os p h or yl at e d si g n al tra ns d u cer 
a n d acti vat or of tra ns cri pti o n 5  ( S T A T 5 ) pr ot ei n l e vels  i n 
bl o o d, p h os p h or yl at e d c- KI T  pr ot ei n l e vels  i n bl o o d, i n hi bit or y 
acti vit y of pl as ma q ui zarti ni b o n p h os p h or yl at e d F L T 3 pr ot ei n  
Effi cac y:  
C o m pl et e r e missi o n  ( C R), C R wit h i n c o m pl et e pl at el et 
r ec o ver y ( C R p), C R wit h i n c o m pl et e h e mat ol o gi cal rec o ver y  
( C Ri), p arti al re missi o n  ( P R), n o res p o ns e  ( N R), c o m p osit e 
C R ( C Rc: C R + C R p + C Ri), res p o ns e rat e ( C Rc + P R) 
Pri mar y st atisti cal 
a n al ys es  
Saf et y e val u ati o n:  
F or A Es  t h at o cc ur  or w ors e n aft er t h e st art of st u d y treat me nt, 
fr e q u e n c y t a bl es will b e pre p are d b y e ve nt, ca us alit y wit h t h e 
st u d y dr u g or a c oa d mi nist ere d  dr u g ( c yt ara bi n e or a n 
a nt hr ac ycli ne dr u g) , a n d gra d e acc or di n g t o t h e C o m m o n 
Ter mi n ol o g y Crit eri a f or A d vers e E ve nts  ( C T C A E).  D L Ts  
will b e ass ess e d b y fre q u e n c y t a bl es.    C o n cer ni n g l a b orat or y 
dat a, vit al si g n meas ure me nts, b o d y wei g ht, a n d 1 2 -l ea d E C G 
fi n di n gs, fre q u e n c y t a bl es or s hift t a bl es will b e pre p are d f or 
cat e g ori cal d at a, a n d s u m mar y st atisti cs will b e cal c ul at e d f or 
q u a ntit ati ve d at a.    F or Q Tc F, s u m mar y st atisti cs will b e 
cal c ul at e d, a n d fre q u e n c y t a bl es acc or di n g t o t h e pre d efi n e d 
cat e g ori es will b e pre p are d.  
P har mac o ki n eti c e val u ati o n: 
C o n cer ni n g pl as ma c o n ce ntrati o ns of q ui zarti ni b a n d its acti ve 
meta b olit e A C 8 8 6, s u m mar y st atisti cs will b e calc ul at e d b y 

 
 
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d ose l e vel at eac h ti me p oi nt, a n d c h a n ges i n t h e 
c o n ce ntr ati o ns will b e d e pi ct e d i n fi g ures.    S u m mar y 
st atisti cs of p h ar mac o ki n etic para met ers will als o be 
cal c ul at e d.  
P har mac o d y n a mi c  e val u ati o n:  
Fr e q u e n c y  t a bl es will b e pre p are d f or t h e F L T 3-I T D st at us a n d 
c-KI T m ut ati o n st at us.  F or p h os p h or yl at e d F L T 3, S T A T 5, 
a n d c -KI T pr ot ei n l e vels i n bl o o d  a n d t h e i n hi bit or y acti vit y of 
pl as ma q ui zarti ni b o n p h os p h or yl at e d F L T 3 pr ot ei n, t h e 
meas ur e d val u es will b e s u m mari ze d at eac h ti me p oi nt.  
Effi cac y  e val u ati o n: 
Fr e q u e n c y t a bl es f or C R, C R p, C Ri, P R, a n d N R will b e 
pr e p are d.    T h e C Rc rat e, t h e res p o nse rat e, a n d t heir 9 5 % 
c o nfi d e n ce i nter vals will b e cal c ul at e d.  
 
 

 
 
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Da y 1 
Da y 2 
Da y 3
Da y 5
Da y 6 
Da y 7
Da y 8
Da y 1 5
Da y 1 9 
Da y 2 1
Da y 2 8
Q ui zarti ni b
C yt ar a bi ne
Da u n or u bi ci n or i dar u bi ci n
 
 

Q ui zarti ni b
C yt ar a bi ne
Da u n or u bi ci n or i dar u bi ci n
 

a)!
5 + 2 c)
7 + 3 c)

5 + 2 
7 + 3  
e)
a)!
e)
a)!
5 + 2 
7 + 3 
5 + 2 
7 + 3  
e)
a)!
5 + 2 c)
7 + 3 c)

5 + 2 
7 + 3  
e)
a)!
5 + 2 
7 + 3  

5 + 2 
7 + 3  
e)
T he da y 
P har mac o ki neti cs
F L T3-I T D a n d c- KI T m ut ati o ns
P h os p h or yl at e d pr ot ei n l e vels i n bl o o d, i ncl u di n g F L T3
I n hi bit or y acti vit y of pl as ma q ui zarti ni b o n
p h os p h or yl at e d F L T3 pr ot ei n
Ass ess me nt of c o nc o mit a nt dr u gs a n d t her a pi es
M o nit ori n g of A Es
HI V a nti b o d y t ests
Ce ntral
m e as ure m e nt
La b or at or y t ests ( he mat ol o g y, bl o o d c he mistr y, uri nal ysis) * *
Pr e g na nc y t est
Ass ess me nt of b o ne marr o w fi n di n gs ( a ntit u m or eff e ct)
B o d y wei g ht
E C O G P S ass ess me nt
1 2-l e a d E C G * *
Bas eli ne s u bj e ct c har act eristi cs
Me di c al hist or y/ c o m pli c ati o ns
Vit al si g n me as ur e me nt * *
Ad mi nistr ati o n of t he st u d y dr u g a n d c o a d mi nist er e d dr u gs *
7
+
3
5
+
2
C ycle 2
I nf or me d c o ns e nt
Re gistr ati o n of pati e nts
 

 
 
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● Ma n d at or y, ○ To b e p erf or me d o nl y i n s el e ct e d p ati e nt s 
 
a)  Bef or e t h e st art of a d mi nistr ati o n  of c yt ara bi n e a n d t h e a nt hr a c ycli n e dr u g  
b)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, 4 h o urs ( ± 1 0 mi n ut es) p ost -d ose, a n d 6 h o urs ( ± 1 0 mi n utes) p ost -d os e  
c)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -d os e  
d)   Pre-d os e, 3 0 mi n ut es ( ± 1 0 mi n ut es) p ost -d os e, 1 h o ur ( ± 1 0 mi n ut es) p ost -d os e, 2 h o urs ( ± 1 0 mi n utes) p ost -d os e, 4 h o urs ( ± 1 0 mi n utes) p ost -d os e, a n d 6 h o urs ( ± 1 0 
mi n utes) p ost -d os e  
e)  −3 d a ys t o t h e d a y  
 
* Re missi o n i n d u cti o n t h er a p y i n C ycl e 2 will b e gi v e n usi n g t h e s a me r e gi me n as i n C ycl e 1 (“ 7 + 3 ”) or o n t h e d osi n g s c h e d ule  ( “ 5 + 2 ”) s h o w n i n t h e t a bl e. 
 
* *  If dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er v al or str o n g C Y P 3 A 4 i n hi bit ors ar e us e d aft er  t h e st art of q ui z arti ni b tr eat me nt, q ui z arti ni b tr eat me nt s h o ul d b e 
i nt err u pt e d fr o m t h e st art t o t h e e n d of us e of t h es e dr u gs. 
Aft er t h e d a y w h e n q ui z arti ni b is r es u me d, t h e f oll o wi n g pr o c e d ur es will b e p erf or me d at t h e ti me p o i nts liste d b el o w: 
 
[ 1]  Pre-d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt, 1 2 -l e a d E C G, a n d la b or at or y t ests 
[ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 3]  Pre-d os e of q ui z arti ni b o n D a y 4 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 4]  Pre-d os e of q ui z arti ni b o n D a y 8 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 5]  Pre-d os e of q ui z arti ni b o n D a y 1 1 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 6]  Pre-d os e of q ui z arti ni b o n D a y 1 5  ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
 
! 
If C ycl e 2 is st arte d wit hi n + 7 d a ys re c k o n e d fr o m D a y 2 8 of C ycl e 1, t h e pr o ce d ur es s c h e d ule d o n D a y 1 of C ycl e 2 ar e n ot n e c ess ar y. 

 
 
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● Ma n d at or y, ○ To b e p erf or me d o nl y i n s el e ct e d p ati e nt s 
 
a)   Bef or e t h e st art of c yt ar a bi n e  a d mi nistr ati o n  
b)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, 4 h o urs ( ± 1 0 mi n ut es) p ost -d ose, a n d 6 h o urs ( ± 1 0 mi n utes) p ost -d os e  
c)  Pre- d os e, 2 h o urs ( ± 1 0 mi n ut es)  p ost -d os e, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -d os e  
d) 
−3 d a ys t o t h e d a y  
e)   Da y w h e n st u d y t er mi n ati o n is d e ci d e d ( −3 d a ys t o + 7 d a ys)  
f) 
2 8t h d a y ( ± 7 d a ys) r e c k o n e d fr o m t h e d a y of t h e l ast d os e of t h e st u d y dr u g 
 
* *  If dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er v al or str o n g C Y P 3 A 4 i n hi bit ors ar e us e d aft er  t h e st art of q ui z arti ni b tr eat me nt, q ui z arti ni b tr eat me nt s h o ul d b e 
i nt err u pt e d fr o m t h e st art t o t h e e n d of us e of t h es e dr u gs. 
Aft er t h e d a y w h e n q ui z arti ni b is r es u me d, t h e f oll o wi n g pr o c e d ur es  will b e p erf or me d at t h e ti me p oi nts liste d b el o w:  
 
[ 1]  Pre-d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt, 1 2 -l e a d E C G, a n d la b or at or y t ests 
[ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 3]  Pre-d os e of q ui z arti ni b o n D a y 4 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 4]  Pre-d os e of q ui z arti ni b o n D a y 8 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y  w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 5]  Pre-d os e of q ui z arti ni b o n D a y 1 1 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 6]  Pre-d os e of q ui z arti ni b o n D a y 1 5  ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
 
! 
If t h e n e xt c ycl e is st arte d wit hi n + 7 d a ys r e c k o n e d fr o m D a y 2 8 of ea c h c ycl e, t h e pr o c e d ur es sc h e d ule d o n Da y 1 of t h e n e xt c ycl e ar e n ot n e c ess ar y.  
 

 
 
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Ta bl e of C o nte nts  
P R O T O C O L S Y N O P SI S  ................................................................................................... 2 
Ta bl e of C o nt e nts  .............................................................................................................. 1 6 
List of Ta bl es  ..................................................................................................................... 1 8 
List of Fi g u res  ................................................................................................................... 1 9 
List of A b b re vi ati o ns a n d Defi niti o ns of Ter ms  ............................................................ 2 0 
1.  I N T R O D U C TI O N ...................................................................................................... 2 2 
1. 1  Bac k gr o u n d of T his St u d y  ......................................................................................... 2 2 
1. 2  N o n cli ni cal St u d y Dat a  .............................................................................................. 2 3 
1. 3  Cli ni cal St u d y Dat a  .................................................................................................... 2 6 
1. 4  K n o w n a n d F or es eea ble Ris ks  ................................................................................... 3 0 
1. 5  Rati o n al e f or t h e D os a ge  ............................................................................................ 3 1 
2.  S T U D Y O B J E C TI V E S  .............................................................................................. 3 4 
3.  S T U D Y D E SI G N  ........................................................................................................ 3 5 
4.  S T U D Y P O P U L A TI O N  ............................................................................................. 3 7 
4. 1  Sel ecti o n of P ati e nts  ................................................................................................... 3 7 
4. 2  S u bject Wit h dr a wal Crit eri a a n d Pr o ce d ures  ............................................................. 4 1 
5.  M E T H O D O L O G Y  ..................................................................................................... 4 2 
5. 1  St u d y Dr u g  ................................................................................................................. 4 2 
5. 2  C o a d mi nist er e d Dr u gs ( C yt ar a bi n e a n d A nt hrac ycli n e Dr u gs) ................................. 4 2 
5. 3  Tr eat me nt M et h o d of t h e St u d y Dr u g a n d C o a d mi nist ere d Dr u gs ( C yt ara bi ne a n d 
A nt hrac ycli n e Dr u gs)  ................................................................................................. 4 3 
5. 4  Ass ess me nt of D os e -li miti n g To xi cit y ....................................................................... 4 7 
5. 5  Crit eri a f or Te m p or ar y Dis c o nti n u ati o n, D os e Re d ucti o n, a n d Res u m pti o n of 
Q uizarti ni b  .................................................................................................................. 5 0  
5. 6  Wit h dr a wa l Criteria .................................................................................................... 5 1  
5. 7  Pr o hi bit e d C o n c o mit a nt Dr u gs a n d T h era pi es, Restri ct e d C o n c o mit a nt Dr u gs, a n d 
Dr u gs t o Be C o a d mi nist er e d wit h Care  ..................................................................... 5 1  
5. 8  S y m pt o mati c T h er a p y  ................................................................................................ 5 3  
5. 9  Ma n a ge me nt of P ati e nts  ............................................................................................. 5 3  
6.  S T U D Y P R O C E D U R E S  ............................................................................................ 5 4 
6. 1  I nf or me d C o nse nt t o P ati e nt Re gistrati o n ................................................................. 6 1 
6. 2  Re missi o n I n d u cti o n T h er a p y  .................................................................................... 6 3 
6. 3  C o ns oli d ati o n T h e r a p y ............................................................................................... 6 8  
6. 4  At t h e Ti me of Wit h dr a wal fr o m t h e St u d y  ............................................................... 7 2 

 
 
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6. 5  P ost- tr eat me nt O bs er vati o n P eri o d ............................................................................ 7 2 
6. 6  P ost Tr eat me nt  ............................................................................................................ 7 3 
6. 7  P har mac o ki n eti cs  ....................................................................................................... 7 3 
6. 8  Bi o mar ker St u d y  ........................................................................................................ 7 4 
6. 9  A n o n y mi zati o n, St or a ge, a n d Dis p os al of S p eci m e ns f or t h e Bi o mar ker St u d y  ...... 7 5  
7.  P H A R M A C O KI N E TI C E N D P OI N T S  .................................................................... 7 8 
8.  P H A R M A C O D Y N A MI C E N D P OI N T S  ................................................................. 7 9 
9.  S A F E T Y E N D P OI N T S  .............................................................................................. 8 0 
9. 1  Defi niti o n of A d vers e E v e nts  ..................................................................................... 8 0  
9. 2  Defi niti o n of Seri o us A d vers e E ve nts ........................................................................ 8 0  
9. 3  A d vers e E ve nt I nf or mati o n t o Be Re p ort e d  .............................................................. 8 0  
9. 4  Defi niti o n of A d vers e Dr u g Reacti o ns  ...................................................................... 8 3  
9. 5  Acti o ns t o Be Ta ke n f or A d vers e E ve nts  ................................................................... 8 3  
9. 6  Acti o ns t o Be Ta ke n i n t he E ve nt T h at I nf or mati o n o n Pre g n a nc y, Pre g n a nt a n d 
P art uri e nt Wo me n, a n d Deli ver y Is O bt ai n e d  ............................................................ 8 3  
1 0.  E F FI C A C Y E N D P OI N T S  ......................................................................................... 8 4 
1 0. 1  Defi niti o n of Efficac y E n d p oi nts ............................................................................... 8 4  
1 0. 2  Best Res p o ns e  ............................................................................................................ 8 4  
11.  S T A TI S TI C A L A N A L Y S E S  ...................................................................................... 8 5 
1 1. 1  A n al ysis Sets  .............................................................................................................. 8 5  
1 1. 2  Dat a Ha n dli n g  ............................................................................................................ 8 6  
1 1. 3  St atisti cal A n al ysis It e ms a n d M et h o ds  ..................................................................... 8 6  
1 1. 4  C h a n ges t o t h e A n al ysis Pla n  ..................................................................................... 8 9  
1 1. 5  Pla n n e d Sa m pl e Size  .................................................................................................. 8 9  
1 2.  Q U A L I T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ........................................ 9 0 
1 3.  P A Y M E N T F O R P A R TI CI P A TI O N, C O M P E N S A TI O N F O R 
S T U D Y -R E L A T E D I N J U RI E S, A N D I N S U R A N C E  ............................................. 9 1 
1 3. 1  P a y me nt f or P arti ci p ati o n  .......................................................................................... 9 1 
1 3. 2  C o m p e ns ati o n f or St u d y -r el at e d I nj uries ................................................................... 9 1 
1 3. 3  I ns ur a n ce .................................................................................................................... 9 1 
1 4.  P U B LI C A TI O N P O LI C Y  ......................................................................................... 9 2 
1 5.  S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N  ..................................................... 9 3 
1 5. 1  Et hi cs  .......................................................................................................................... 9 3 
1 5. 2  S u bject C o nfi d e nti alit y  .............................................................................................. 9 3 
1 5. 3  Pr oce d ur es f or I nf or me d C o ns e nt  .............................................................................. 9 3 

 
 
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1 5. 4  I nf or me d C o nse nt f or P har mac o ge n o mics/ Bi o mar ker St u d y ................................... 9 5  
1 5. 5  Pr o visi o n of Ne w I nf or mati o n Affecti n g t h e C o n d uct of t h e St u d y  ......................... 9 6 
1 5. 6  Pla n n e d St u d y P eri o d ................................................................................................. 9 6  
1 5. 7  Pr ot o c ol A me n d me nt  .................................................................................................. 9 6 
1 5. 8  P er ma n e nt or Te m p or ar y Dis c o nti n u ati o n of t he St u d y  ............................................ 9 7 
1 5. 9  Pr oce d ur es f or Pr e p ari n g t h e Cas e Re p ort F or m a n d Re mar ks  ................................. 9 7 
1 5. 1 0  Ret e nti o n of S o ur ce D o c u me nts a n d Ot h er Rec or ds  ............................................. 9 9 
1 5. 1 1  S o ur ce D o c u me nt Verifi cati o n  ............................................................................. 1 0 0 
1 5. 1 2  Or ga ni zati o n  ......................................................................................................... 1 0 0 
1 5. 1 3  E mer ge n c y C o nt act I nf or mati o n  .......................................................................... 1 0 5  
1 6.  R E F E R E N C E S  ......................................................................................................... 1 0 6 
1 7.  A P P E N DI C E S  .......................................................................................................... 1 0 8 
Att a c h me nts  .................................................................................................................... 1 0 9 
 
List of Ta bl es  
Ta bl e 1. 3- 1    M a xi m u m Val u es of Q T C orrect e d f or Heart Rate Usi n g Fri d eri ci a’s 
Met h o d ( Q Tc F) a n d M a xi m u m C h a n ges fr o m  Bas eli n e i n Q Tc F i n T w o P has e 
2 St u di es  ........................................................................................................... 2 8  
Ta bl e 1. 3- 2    C o m p osit e C o m pl et e Re missi o n a n d P artial Res p o ns e Rat es i n T w o P h as e 2 
St u di es  .............................................................................................................. 2 8  
Ta bl e 5. 1 -1    I nf or mati o n Dis pl a ye d o n t h e St u d y Dr u g La b el  ........................................ 4 2 
Ta bl e 5. 3 -1   Q ui zarti ni b  D os e  .......................................................................................... 4 3 
Ta bl e 5. 4 -1   Criteria  f or Pr o cee di n g t o Le vel 2 ............................................................... 4 8  
Ta bl e 5. 4 -2    Criteria f or Ass essi n g M a xi m u m Tolerat e d D os es ( M T Ds) at Le vel 2  ...... 4 9 
Ta bl e 6 -1   Sc h e d ul e of St u d y Pr o ce d ures  ........................................................................ 5 5  
Ta bl e 6 -2    Sc h e d ul e of St u d y Pr o ce d ures  ........................................................................ 5 8  
Ta bl e 6. 7- 1    Bl o o d C oll ecti o n P oi nts f or P har mac o ki n eti c Ass ess me nt  ......................... 7 3 
Ta bl e 6. 8 -1    Bl o o d C oll ecti o n P oi nts ( P h os p h or ylate d Pr ot ei n Le vels i n Bl o o d)  .......... 7 5  
Ta bl e 6. 8 -2   Bl o o d  C oll ecti o n  P oi nts  (I n hi bit or y Acti vit y of Pl as ma Q uizarti ni b o n 
P h os p h or yl at e d F L T 3 Pr ot ei n) ......................................................................... 7 5  
Ta bl e 9. 3- 1    I n vesti gati o n It e ms f oll o wi n g O ns et of A d vers e E ve nts ............................. 8 2  
Ta bl e 1 0. 1- 1    Defi niti o n of Effi cac y E n d p oi nts  .............................................................. 8 4  
Ta bl e 1 5. 9 -1    E D C S yst e m  ............................................................................................... 9 8  
 

 
 
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List of Fi g u res  
Fi g ur e 3 -1   St u d y  Fl o w  .................................................................................................... 3 6 
Fi g ur e 4. 1- 1    P ati e nt Re gistr ati o n Pr o ce d ure  .................................................................. 4 1 
Fi g ur e 5. 3 -1    S u m mar y of St u d y Tr eat me nt Sc h e d ul e  .................................................... 4 6 
 

 
 
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List of A b b re vi ati o ns a n d Defi niti o ns of Ter ms  
List of A b b re vi ati o ns  
A b br e vi ati o n  
F ull E x pr essi o n  
A K T  
pr ot ei n  ki n as e B  
A L P  
al k ali n e p h os p h at as e  
A L T  
L -al a ni n e a mi n otr a nsfer as e  
A M L  
a c ut e m yel oi d l e u k e mi a  
A N C  
a bs ol ut e n e utr o p hil c o u nt  
A S T  
L -as p art at e a mi n otr a nsfer as e  
B C R -A B L  
bre a k p oi nt cl uster re gi o n - c-A b els o n  
B U N  
bl o o d ur e a nitr o g e n  
C R  
c o m pl et e r e missi o n 
C R c  
c o m p osit e C R  
C Ri  
C R wit h i n c o m plet e h e mat ol o gic al r e c o ver y  
C R p  
C R wit h i n c o m plet e pl at elet re c o v er y  
C R P  
C -re a cti v e pr ot ei n 
C S F 1 R  
c ol o n y sti m ul ati n g fa ct or 1 r e c e pt or  
C T C A E  
C o m m o n Ter mi n ol o g y Criteri a f or A d v ers e E v e nts  
C Y P  
c yt o c hr o me P 4 5 0  
D D R  
dis c oi di n d o mai n r e ce pt or t yr osi n e ki n as e  
D F S  
di s e as e fre e s ur vi v al 
D L T  
d os e -li miti n g t o xi cit y 
E C O G  
East er n C o o p er ati v e O n c ol o g y Gr o u p  
E D C  
el e ctr o ni c d at a c a pt uri n g  
e G F R  
esti mat e d gl o mer ul ar filtr ati o n r ate  
F L T  
F M S -li k e t yr osi n e ki n as e 
G C P  
G o o d Cli ni cal Pr acti c e  
γ-G T  
γ-gl ut a m yl tr a nsferas e  
h E R G  
h u ma n  et h er-à -g o -g o r el ate d g e n e  
HI V  
h u ma n i m m u n o d efi ci e n c y vir us  
H S C T  
h e mat o p oi eti c  st e m c ell tra ns pl a nt 
I C5 0 
5 0 % i n hi bit or y c o n c e ntr ati o n  
IC a -L  
l o n g-l asti n g c al ci u m c urr e nt 
I C H 
Int er n ati o n al C o nfer e n c e o n  Har m o ni sati o n of T e c h ni c al R e q uir e me nts f or R e gistr ati o n 
of P h ar ma c e uti c als f or H u ma n U s e 
IKr  
p otassi u m c urr e nt c arrie d b y c h a n n el f or me d fr o m h E R G s u b u nits  
IKs  
p otassi u m c urr e nt c arrie d b y c h a n n el f or me d fr o m K V L Q T 1 ( K C N Q 1) s u b u nits  
a n d mi n K ( K C N E 1) b -s u b u nits 
IN a  
so di u m c urr e nt  
I R B 
I nstit uti o n al R e vi e w B o ar d 
I T D 
i nt er n al t a n d e m d u plic ati o n 
K D M  
ki n as e  d o mai n m ut ati o n  
KI T  
v -kit H ar d y -Z u c k er ma n 4 feli n e s ar c o ma vir al o n c o g e n e h o m ol o g  
L D H  
la cti c aci d (l a ct at e) d e h y dr o g e n as e 
M A P K  
mit o ge n -a cti v ate d pr otei n ki n as e  
M D S  
m yel o d ys pl astic s y n dr o me  
Me d D R A  
Me di c al Di cti o n ar y f or R e g ul at or y Acti vities  
M T D  
ma x im u m  t ol er at e d d os e 

 
 
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A b br e vi ati o n  
F ull E x pr essi o n  
N C C N  
T h e N ati o n al C o m pr e h e nsi v e Ca n c er N et w or k  
N Y H A  
N e w Yor k H e art Ass o ci ati o n  
N R  
n o r es p o ns e  
P D G F R  
platel et -d eri v e d gr o wt h fa ct or r e c e p t or 
PI 3 K  
p h os p h ati d yli n osit ol 3 -ki n as e  
P R  
p arti al  r e missi on  
P S  
p erf or ma n c e st at us  
P T  
pr ot hr o m bi n ti me  
P T -I N R 
pr ot hr o m bi n ti me -i nt er n ati o n al n or mali z e d r ati o 
Q T  
int er v al b et we e n t h e st art of t h e Q  wa v e a n d t h e e n d of t h e T wa v e  
Q Tc  
c orr ect e d Q T i nter v al 
Q Tc F  
Q T c orr ect e d f or h e art rat e  usi n g Fri d eri ci a’s met h o d  
R T K  
re c e pt or t yr osi n e ki n as e 
S A V E R  
Seri o us A d verse E v e nt R e p ort  
S T A T 5  
si g n al tr a ns d u c er a n d a cti v at or of tr a ns cri pti o n 5 
T d P  
t orsa d es d e p oi nt es  
T E A E  
tr eat me nt e mer g e nt a d v ers e e v e nt 
V E G F R  
v asc ul ar e n d ot h eli al gr o wt h fa ct or  r e c e pt or 
W H O  
Worl d H e alt h Or g a ni z ati o n  
W T  
wil d  t y p e 
 
List of P h ar m a c o ki n eti c P a r a met ers  
A b br e vi ati o n  
F ull E x pr essi o n  
A U C  
ar e a u n d er t h e pl as ma  c o n c e ntrati o n -ti me c ur v e 
A U Ci nf  
ar e a u n d er t h e pl as ma  c o n c e ntrati o n -ti me c ur v e u p t o  i nfi nit y 
A U Ct a u  
ar e a u n d er t h e pl as ma  c o n c e n trati o n-ti me c ur v e d uri n g d osi n g i nter val  
A U Ct a u, ss  
ar e a u n d er t h e pl as ma  c o n c e ntrati o n -ti me c ur v e d uri n g d osi n g i nter val at ste a d y stat e  
C ma x  
m a xi m u m plas ma  c o n ce ntr ati o n  
C ma x, ss  
m a xi m u m plas ma  c o n ce ntr ati o n  at ste a d y stat e  
Ctr o u g h 
tr o u g h plas ma c o n c e ntrati o n  
T ma x  
ti me t o r ea c h ma xi m u m pl as ma  c o n c e ntrati o n  
T ma x, ss  
ti me t o r ea c h ma xi m u m pl as ma  c o n c e ntrati o n  at st e a d y st at e  
 
List of Ter ms  
Ter m  
D efi niti o n  
A C 2 2 0  
D e vel o p me nt c o d e of q ui z arti ni b  
A C 8 8 6  
A cti v e met a b olit e of q ui zarti ni b  
 

 
 
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1.  
I N T R O D U C TI O N 
1. 1  
B a c k g r o u n d of T his St u d y  
Ac ut e m yel oi d l e u ke mi a ( A M L) is a h e mat ol o gi cal mali g n a nt t u m or  c h aract eri ze d b y 
a ut o n o m o us gr o wt h of m yel oi d bl ast cells ( m yel o bl asts) t h at are u n a bl e t o differe nti at e or 
f urt h er d e vel o p i nt o mat ur e w hit e bl o o d cells, a n d its cli nical pres e nt ati o n is di vers e. 1)  
Acc or di n g t o “ Ca n cer R e gistr ati o n a n d St atisti cs ” of t h e Ca n cer I nf or mati o n Ser vi ce, 
Nati o n al Ca n cer Ce nt er, t h e cr u d e pr e vale n ce rat e of l e u ke mi a is 9. 6 ( 1 1. 4 f or mal e s a n d 
7. 9 f or f e mal e s) p er 1 0 0 0 0 0 p e o pl e i n 2 0 1 1 a n d it is i n creasi n g eac h year.2)  T h e 
pr e val e n ce r at e of A M L b y its elf  is u n k n o w n; h o we ver, ac ut e l e u ke mi a acc o u nts f or 
a b o ut 8 0 % of all l e u ke mias, a n d A M L acc o u nts f or a p pr o xi mat el y 8 0 % of a d ult ac ut e 
le u ke mi a cases a n d 2 0 % of p e di atric ac ut e l e u ke mi a cas es.   W hil e A M L h as b ec o me a 
dis ease t h at is c o nsi d er e d c ur a bl e i n rece nt years, t h e l o n g -t er m s ur vi val rat e aft er 
c o m pl et e r e missi o n ( C R) wit h c h e m ot h era p y i n A M L p ati e nts  re mai ns l o w at a b o ut 
4 0 %. 3)  T his is attri b ut a bl e t o fr e q u e nt rel a ps e after re missi o n.    H o w t o pre ve nt rel a ps e 
is a maj or pr o bl e m of c h e m ot h er a p y.    To s ol ve t his pr o ble m, ma n y res earc h st u di es ha ve 
i d e ntifi e d po or pr o g n osti c f act ors i n att e m pts t o stratif y A M L.    I n pati e nts wit h p o or 
pr o g n ostic f act ors, i nt e nsifi e d treat me nt d o es n ot necess aril y i m pr o ve t h e pr o g n osis.   
T h er ef or e, it is n ecessar y t o d e vel o p m ol ec ul ar t ar geti n g dr u gs i n li ne wit h t h e m ol ec ul ar 
pl a tf or m t h at pla ys a ke y r ol e i n A M L.4) -6) 
F M S -li ke t yr osi n e ki n as e ( F L T) 3 m ut ati o ns, w hi c h are f o u n d i n a p pr o xi mat el y 3 0 % of 
A M L p ati e nts, r e pr es e nt a n i m p ort a nt p o or  pr o g n osti c fact or a n d are list e d as ge n e 
a b n or maliti es t hat ca n b e s ear c h e d i n t h e Worl d Healt h Or ga nizati o n ( W H O) 
cl assifi cati o n versi o n 4. 5) ,6)  F L T 3 is a Cl ass II I rece pt or t yr osi n e ki n as e ( R T K), li ke 
v- kit Har d y -Z u c ker ma n 4 f eli n e s arc o ma viral o n c o ge n e h o m ol o g  (KI T), c ol o n y 
sti m ul ati n g f act or 1 r ece pt or (C S F 1 R ), a n d pl at el et -d eri ve d gr o wt h fact or rece pt or  
(P D G F R ), a n d c o ntai ns a n i ntr acell ul ar t yr osi n e ki nas e d o m ai n s plit i n t w o b y t h e 
j u xt a me m br a n e d o mai n.  F L T 3 is  pri maril y e x pr ess e d o n h e mat o p oi eti c pr o ge nit or  cells 
a n d is di meri ze d a n d acti vat e d  b y li ga n d bi n di n g, a n d t h e n i n v ol ve d i n h e m at o c yt e 
diff er e nti ati o n a n d pr olif er ati o n as well as s elf -re pli cati o n of h e mat o p oi eti c st e m cells. 7)  
F L T 3 m ol ec ul es ar e e x pr ess e d o n t h e  l e u ke mi a cell s urface i n m ost cas es of A M L a n d 
ac ut e l y m p h o c yti c l e u ke mi a, a n d pl a y a r ol e i n t h e s ur vi val a n d pr oliferati o n of l e u ke mi a 
cells.   T h er e are t w o mai n t y p es of F L T 3 m ut ati o ns: F L T 3 -i nter n al t a n d e m d u pli cati o n 
( F L T 3-I T D), w hi c h i n v ol ves r e p etiti o n of p art of t he j u xt a me m bra n e d o mai n, a n d ki n as e 
d o mai n m ut ati o n ( K D M), w hi c h i n v ol ves  p oi nt m ut ati o n or d el eti o n of t h e as p arti c aci d 
r esi d ue at p ositi o n 8 3 5 ( D 8 3 5) i n t h e t yr osi n e ki n as e d o mai n or s urr o u n di n g resi d u es. 7)  

 
 
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T h es e ge n e m utati o ns ca us e F L T 3 li ga n d -i n d e p e n de nt, c o nst a nt acti vati o n of F L T 3 
m ol ec ul es a n d c o ntri b ut e t o t h e pr o m oti o n of l e u ke mia cell pr oliferati o n vi a acti vati o n of 
d o w nstr ea m si g n ali n g p at h wa ys, i n cl u di n g si g n al tra ns d u cer a n d acti vat or of 
tr a ns cri pti o n 5 ( S T A T 5), mit o ge n -acti vat e d pr ot ei n ki n as e  ( M A P K), a n d 
p h os p h ati d yli n osit ol 3- ki nas e ( PI 3 K)/ pr ot ei n  ki n ase  B  ( A K T).   T h eref o re, m ut at e d 
F L T 3 m ol ec ul es ar e r ec o g ni ze d as pr o misi n g t ar g et m ol ec ules f or t h e treat me nt of 
A M L. 6) 
Q uizarti ni b  ( De vel o p me nt C o d e: A C 2 2 0 ) is a n F L T 3 i n hi bit or d e vel o p e d b y A m bit 
Bi osci e n ces C or p or ati o n  t h at h as hi g h er s el ecti vit y a n d affi nit y  f or F L T 3 t ha n first 
ge n er ati o n F L T 3 i n hi bit ors ( l est a uriti ni b, ta n d uti ni b, mi d ost a uri n,  s orafe ni b, s u niti ni b, 
et c.).   N o n cli ni cal d at a  ha ve d e m o nstrat e d t h at q ui zarti ni b is a p ot e nt a n d s p ecifi c 
i n hi bit or of F L T 3 ki n ase a n d s e ver al ot h er C l ass III R T Ks (KI T,  C S F 1 R/ F M S,  R E T,  a n d 
P D G F R α/ β) a n d t h at it h as a ntit u m or acti vit y a gai nst F L T 3-I T D p ositi ve h u ma n l e u ke mi a 
cells.  O vers eas P has e 2 st u di es h a ve als o d e m o nstrat e d hi g h effi cac y of q ui zarti ni b i n 
r el a ps e d or r efr act or y A M L p ati e nts.    It is t heref ore e x p ect e d t hat q ui zarti ni b  will 
be c o me  a n e w tr eat me nt o pti o n n ot o nl y f or p ati e nts wit h rel a ps e d or refract or y A M L, 
b ut als o f or p ati e nts  wit h initi all y  di a g n os e d A M L.    D u e t o its s el ecti ve F L T 3 i n hi bit or y 
acti vit y, q ui zarti ni b  is als o e x p ect e d t o i m pr o ve t h e treat me nt res ults i n a s el ecte d 
p o p ul ati o n of F L T 3 -I T D p ositi ve A M L p atie nts, w h o are k n o w n t o h a ve p o or pr o g n osis.   
A gai nst t his b ac k gr o u n d, q ui zarti ni b  recei ve d fast trac k d esi g n ati o n i n N o ve m b er 2 0 1 0 i n 
t h e U S.    At pr es e nt, a gl o b al P h as e 3 st u d y is o n g oi n g mai nl y i n E ur o p e a n d t h e U S . 
I n J a p a n, r el a ps e d or r efr act or y A M L p ati e nts are treat e d wit h m o n ot h era p y or 
c o m bi n ati o n t h er a p y wit h  c yt ar a bi n e, mit o xa ntr o ne, et o p osi d e , fl u d ara bi n e, acl ar u bi ci n , 
ge mt u z u ma b o z o ga mi ci n, a n d ot h ers.    N o n e of t hes e t h era pi es, h o we ver, pr o vi d e a n 
a d e qu at e t h er a p e uti c eff ect.    N o st a n d ar d treat me nt h as b ee n est a blis h e d f or t h es e 
pati e nts. 8)  T her e ar e als o n o m ol ec ul ar t ar geti n g dr u gs t h at ca n b e us e d f or 
i niti all y-di a g n os e d A M L p ati e nts, i n w h o m a hi g h rel a p s e rat e is still a pr o bl e m.    I n 
vi e w of t his sit u ati o n, Daii c hi Sa n k y o d eci d e d t o parti ci p at e i n t he J a p a n es e d e vel o p me nt 
of q ui zarti ni b f or A M L p atie nts.  
 
1. 2  
N o n cli ni c al St u d y D at a  
1. 2. 1  
P h a r m a c ol o g y  
In a bi o c h e mi cal bi n di n g ass a y  usi n g a p a nel of 4 4 1 ki n as es, q ui zarti ni b a n d its 
meta b olit e , A C 8 8 6,  e x hi bit e d th e hi g h est bi n di n g affi nit y f or F L T 3  ( diss o ci ati o n 
c o nst a nt : 1. 3 n M f or q ui zarti ni b  a n d 0. 5 4  n M f or A C 8 8 6 ).  T h e bi n di n g affi nit y f or ot h er 

 
 
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Class  III R T Ks ( e g, KI T, C S F 1 R/ F M S, P D G F R β, a n d R E T ) was wit hi n 1 0 -f ol d l o wer 
t h a n t h at f or F L T 3 , a n d t he bi n di n g affi nit y f or 4 a d diti o n al ki n as es ( F L T 1, F L T 4, 
dis c oi di n d o mai n r ece pt or t yr osi n e ki n ase  [D D R ] 1, P D G F R α , a n d vas c ul ar e n d ot h eli al 
gr o wt h f act or r ece pt or  [V E G F R ] 2) was  wit hi n 1 0 0 -f old l o wer t h a n t h at f or F L T 3.   O n 
t h e ot h er h a n d, q ui zarti ni b s h o we d a wea k i n hi bit or y acti vit y a gai nst 1 1 8 differe nt 
e n z y mes, r ece pt or c h a n n els, a n d tr a ns p ort ers , a n d t h e 5 0 % i n hi bit or y c o n ce ntrati o n  (I C5 0) 
was hi g h er t h a n 1  μ M.  
I n h u ma n M V 4 -1 1 l e u ke mi a cel l li n e wit h F L T 3 -I T D m ut ati o ns treat e d wit h q ui zarti ni b 
a n d A C 8 8 6 , t h es e c o m p o u n ds i n hi bit e d F L T 3 -I T D a ut o p h os p h or yl ati o n, as well as 
F L T 3 -d e pe n d e nt cell pr olif er ati o n (I C 5 0: a p pr o xi matel y 0. 3 n M  f or q uizarti ni b a n d 
0. 2 6 n M  f or A C 8 8 6 ).   F oll o wi n g 2 8 -d a y ( o n ce d ail y) re p eat e d oral d osi n g  of q ui zarti ni b 
i n mi ce wit h  fla n k s oli d t u m ors est a blis h e d b y s u b c ut a n e o usl y i m pl a nte d M V 4 -1 1 cells, 
q ui zarti ni b i n hi bit e d t u m or gr o wt h at 1 m g/ k g a n d i n d u ce d t u m or re gressi o n at 3 m g/ k g 
a n d 1 0 m g/ k g.   At 1 0  m g/ k g, t u m ors did n ot re gr o w t hr o u g h o ut t h e e ntire 3 2 -d a y 
f oll o w-u p p eri o d aft er q uizarti ni b d osi n g .   Q uizarti ni b a d mi nist ere d  i n c o m bi n ati o n wit h 
c h e m ot h er a p y ( c yt ar a bi n e a n d d a u n or u bi ci n) was als o c o nfir me d t o h a ve s u p eri or 
a ntit u m or acti vit y a n d b e well t ol er at e d i n t h e a b o ve -me nti o n e d m o us e m o del.  
I n a t el e metr y st u d y i n c y n o m ol g us m o n ke ys, q ui zarti ni b d os e-d e p e n d e ntl y pr ol o n ge d t h e 
c orr ect e d Q T i nt er val ( Q Tc) a n d tra nsi e ntl y i n creas e d s yst e mi c bl o o d press ure at 
≥ 1 0  m g/ k g; h o we ver, n o h e m o d y n a mi c or E C G  c ha n ges were s ee n at 3  m g/ k g.    I n t h e 
ass ess me nt  of p ot e ntial eff ects of q ui zarti ni b a n d A C 8 8 6  o n p ot assi u m c urre nt carri e d b y 
c h a n n el f or me d fr o m h E R G s u b u nits ( IKr ) c ha n n el-c o d e d b y h E R G u si n g a p at c h cl a m p 
a p pr o ac h i n H E K 2 9 3  cells o ver e x pr essi n g h u ma n et h er -à- g o-g o rel at e d ge ne  (h E R G ), 
q ui zarti ni b di d n ot i n hi bit t h e IKr  c h a n n el, w h ereas A C 8 8 6  i n hi bit e d t h e IKr  c h a n n el 
c o n ce ntr ati o n -i n d e p e n d e ntl y ( ma xi mal i n hi biti o n: 3 0 % t o 4 0 %).   I n t h e ass ess me nt of 
p ot e nti al eff ects of q ui zarti ni b a n d A C 8 8 6  o n s o di u m c urre nt  (IN a ), p ot assi u m c urre nt 
carri e d b y t h e c h a n n el f or me d b y  K V L Q T 1 (K C N Q 1 ) s u b u nits a n d mi n K (K C N E 1 ) 
b-s u b u nits (I Ks ), a n d l o n g-l asti n g cal ci u m c urre nt (ICa - L), q uizarti ni b i n hi bite d IKs , a n d 
A C 8 8 6  i n hi bit e d IN a , IKs , a n d ICa - L.  I n e x vi v o st u di es usi n g ra b bit h eart pre p arati o ns, 
q ui zarti ni b a n d A C 8 8 6 ca us e d i n cr eas es i n Q Tc i nt er val at c o nce ntrati o ns of > 3 μ M .   It  
was t h us s u g gest e d t h at t he eff ects  of t he t w o c o m p o u n ds  o n p ot assi u m c urre nts (I Ks  + 
IKr ) w o ul d pl a y a r ol e i n Q Tc pr ol o n gati o n.  
 
1. 2. 2  
P h a r m a c o ki n eti cs  a n d D r u g Met a b olis m  
Plas ma e x p os ur e of q uizar ti ni b was a p pr o xi mat el y d ose pr o p orti o n al  i n mice, rats, d o gs, 

 
 
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a n d m o n ke ys.   I n all e xa mi n e d s p eci es, q ui zarti ni b was  c o n vert e d t o t he acti ve 
meta b olit e, A C 8 8 6 .   Bi oa vaila bilit y of q ui zarti ni b acr oss s p eci es ra n ge d fr o m 1 6 % i n 
m o n ke ys t o 4 0 % i n d o gs .   Th e l o w bi o a vail a bilit y of  q ui zarti ni b  i n m o n k e ys was 
c o nsi d er e d t o b e r el ate d t o t h e hi g h met a b oli c cleara n ce of q ui zarti ni b t o  t h e active 
meta b olit e A C 8 8 6.  T h e pr es e n ce of f o o d was s u g gest e d t o e n h a n ce t h e fracti o n of 
a d mi nist er e d q ui zarti ni b d ose a bs or b e d i n rats.   I n rats gi ve n re p eat e d d oses , t h ere was 
e vi d e n ce of acc u m ul at e d  q ui zarti ni b, b ut n o e vi d e nce of s elf-i n d u ce d  met a b olis m.    
Q uizarti ni b a n d A C 8 8 6 wer e s h o w n t o b e hi g hl y b o u n d t o pl as ma pr ot ei ns ( >  9 9 % i n all 
s p eci es t est e d), a n d q ui zarti ni b was s h o w n t o p o orl y p e n etrat e t h e brai n i n rats.  
Q uizarti ni b  was c o nfir m e d t o b e n eit h er a n i n hi bit or ( 1 A 2 , 2 B 6 , 2 C 8 , 2 C 9 , 2 C 1 9, 2 D 6 , 
a n d 3 A 4 ) n or a n i n d u cer ( 3 A 4 a n d 1 A) of maj or h u ma n c yt o c hr o me  P 4 5 0 ( C Y P ) 
is o e n z y mes.   A C 8 8 6  s h o we d wea k i n hi bit or y acti vit y a gai nst C Y P 2 C 8, b ut h a d n o 
i n hi bit or y acti vit y a gai nst t h e ot h er is o e n z y mes, w hic h s u g gests t h at A C 8 8 6  is u nli kel y t o 
s h o w i n hi bit or y acti vit y a gai nst C Y Ps at p h ysi ol o gi c c o n ce ntrati o ns.    Q ui zarti ni b a n d 
A C 8 8 6  ar e s u bstr ates f or C Y P 3 A 4  a n d P -gl yc o pr ot ei n, a n d q uizarti ni b  is meta b oli ze d b y 
C Y P 3 A 4  t o A C 8 8 6 .    O n t h e ot h er ha n d, C Y P 2 B 6 , 2 C 8,  2 C 9,  2 C 1 9,  2 D 6, a n d 1 A 2  are 
f o u n d t o b e b ar el y i n v ol ve d i n t h e met a b olis m of q ui zarti ni b . 
 
1. 2. 3  
To xi c ol o g y  
Q uizarti ni b was t est e d i n si n gl e -d os e a n d re p eat e d -d os e t o xi cit y st u di es ( 2 8 -d a y a n d 
9 0- d a y st u dies i n rats, d o gs, a n d m o n ke ys), ge n eti c t o xi cit y st u di es  (i n vitr o a n d i n vi v o), 
r e pr o d u cti ve a n d d e vel o p me nt al t o xi cit y st u di es (rat), a n d i n vitr o n e utral re d u pt a ke 
p h ot ot o xi cit y ass a y usi n g a m uri n e fi br o bl ast li n e ( 3 T 3).  
I n r e p eat e d-d os e t o xi cit y st u di es,  t h e pri nci p al or ga ns affect e d were t he l y m p h oi d a n d 
he mat o p oi eti c or ga ns  i n all s p eci es  t est e d.   In a d d iti o n, t o xi c ol o gi c effects were 
o bser ve d i n t h e ki d n e ys , li ver, a n d ge nit al or ga ns (o var y, va gi na, a n d t estis ).  
Tar get -or ga n t o xi cit y a p pear e d t o b e q ui zarti ni b d ose- a n d ti me -d e p e n d e nt, a n d m ost 
t o xi c ol o gi c fi n di n gs wer e r e versi bl e f oll o wi n g a 2 8 - or 3 0- d a y rec o ver y p eri o d; h o we ver, 
sli g ht d ecr eas es i n r e d bl o o d cell ( R B C) a n d w hit e bl o o d cell ( W B C) p ara meters, 
mi ni mal b o n e marr o w h y p o cell ul arit y, a n d li ver cr yst al d e p ositi o n ( o nl y i n d o gs) 
persist e d  aft er t h e e n d of t h e r ec o ver y p eri o d .  I n 9 0-d a y st u die s, t o xi c ol o gi c fi n di n gs 
wer e e vi d e nt i n hi g h-d os e r ats a n d d o gs at 1 0  m g/ k g a n d 1 5  m g/ k g, res p ecti vel y, a n d 
i n cl u d e d d ecr eases i n h e mat ol o g y p ara met ers, i n creas e d li ver e n z y mes, a n d 
hist o p at h ol o gi cal  c h a n ges i n b o n e marr o w a n d l y m p h oi d or ga ns.   I n 9 0-da y s t u di es i n 
m o n ke ys, t h e m ort alit y a n d t o xi c si g ns were re p ort e d at 1 0 m g/ k g/ d a y, res ulti n g i n a d os e 

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
2 6 
 
r e d u cti o n t o 6 m g/ k g/ d a y d uri n g t h e d osi n g peri o d; t h es e t o xi c ol o gi c  fi n di n gs o bs er ve d i n 
m o n ke ys wer e  c o nsist e nt wit h  t h os e s ee n i n rats a n d/ or d o gs.    Th e n o a d v ers e effect 
le vel ( N O A E L) fr o m 9 0-da y r e p eat e d oral d os es was est a blis h e d a t 3 m g/ k g/ d a y i n rats 
a n d m o n ke ys a n d 5  m g/ k g/ d a y i n d o gs.    T h e C ma x a n d A U C of q ui zarti ni b at t h e 
N O A E L wer e 0. 8 2  μ g/ m L a n d 1 2. 1 μ g· h/ m L i n rats, 0. 1 1  μ g/ m L  a n d 0. 7 2 7  μ g· h/ m L i n 
m o n ke ys, a n d 0. 4 2  μ g/ m L a n d 3. 9 3 μ g· h/ m L i n d o gs, res p ecti vel y.  
Q uizarti ni b was e val uat e d f or ge n ot o xi c p ot e nti al; q ui zarti ni b was p ositi ve i n b acteri al 
r e vers e m ut ati o n ass a y, b ut was n ot ge n ot o xi c i n c hr o m os o mal a b errati o n ass a y i n h u ma n 
l y m p h o c yt es, ma m mali a n cell m ut a ge ni cit y ass a y, or micr o n u cl e us ass a y i n  rats.    I n t h e 
ma m mali a n cell m ut a ge nicit y ass a y, it was e val u ate d w h et h er t h e p ositi ve res ult o bt ai n e d 
fr o m t h e b act eri al r e vers e m ut ati o n assa y c o ul d b e re pr o d u ce d or n ot.    I n m o us e 
l y m p h o ma L 5 1 7 8 Y T K +/ − cells i n c u b at e d wit h q uizarti ni b , n o s u bst a nti al i ncreases i n 
m ut ati o n fre q u e n c y wer e o bs er ve d at d oses u p t o t h e c yt ot o xi cit y  li mit.   C o ns e q u e ntl y,  
q ui zarti ni b is c o nsi d er e d t o h a ve a l o w ge n ot o xic ris k. 
I n e m br y o -f et al t o xi cit y st u di es i n r ats, s yst emi c e d e ma was f o u n d i n fet uses at t h e 
ma xi m u m d os e of 6  m g/ k g/ d a y, i n a d diti o n t o d ecreas e d fet al wei g ht a n d del a ye d s kel etal 
ossifi cati o n .   Th e N O A E L f or e m br y o -fet al de v el o p me nt was c o nsi d ere d t o b e 
2 m g/ k g/ d a y. 
I n t h e n e utr al r e d u pt a ke p h ot ot o xi cit y ass a y, q ui zarti ni b h a d a p h ot o irrit ati o n fact or of 
3. 1 3 a n d a mea n p h ot o eff ect of 0. 1 2 2.    T h es e res ults s u g gest e d t h at t h e c o m p o u n d 
w o ul d h a ve a “ p h ot ot o xi c p ot e nti al ” acc or di n g t o t h e g ui d eli n es at t h e ti m e of t h e 
ass a y. 9) ,1 0) ,1 1)  H o we ver, a r e vie w of t h e ass a y d ata i n acc or d a n ce wit h t h e g ui d a n ce o n 
p h ot os af et y e val u ati o n of p h ar mace uti cals iss u e d o n 2 1 M a y 2 0 1 4 1 2) res ult e d i n t h e 
c o n cl usi o n  t h at q ui zarti ni b is n ot p h ot ot o xi c. 
 
1. 3  
Cli ni c al St u d y D at a 
1. 3. 1  
P h as e 1 St u d y ( St u d y C P 0 0 0 1 ) 
Q uizarti ni b was t est e d i n 7 6 A M L p ati e nt s wit h treat me nt c ycl es of i nt er mitt e nt d osi n g 
( 1 4 d a ys o n t h e d r u g f oll o we d b y 1 4 d a ys of rest) at d os es of  1 2  m g / d a y t o 4 5 0 m g/ d a y , 
a n d 2 8 -d a y c o nti n u o us d osi n g at 2 0 0 a n d 3 0 0  m g / d a y. 
D os e -li miti n g t o xi citi es ( D L Ts) wer e p yre xi a i n 1 of 5 p ati e nt s o n i nt er mitt e nt d osi n g at 
1 3 5  m g/ d a y, Gr a d e 3 Q Tc pr ol o n gati o n i n 1 of  1 7 p ati e nt s o n c o nti n u o us d osi n g at 
2 0 0 m g/ d a y, a n d Gr a d e 3 Q Tc pr ol o n gati o n i n 3 of 8 p ati e nt s o n c o nti n u o us d osi n g at 
3 0 0 m g/ d a y.    T h e ma xi m u m t ol erat e d d os e ( M T D) was d et er mi n e d t o b e 2 0 0  m g/ d a y 
c o nti n u o us d osi n g. 

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
2 7 
 
T h e o ver all r es p o ns e r at e ( C R + p arti a l re missi o n [ P R]) was 5 3 % i n F L T 3 -I T D p ositi ve 
pati e nt s a n d 1 4 % i n F L T 3 -I T D n e gati ve p ati e nt s. 
I n t his st u d y, pl as ma s p eci me ns wer e c oll ect e d fr o m q ui zarti ni b-treat e d p atie nt s a n d were 
test e d i n a n e x vi v o ass a y of pl as ma i n hi bit or y acti vit y  of q ui zarti ni b  o n F L T 3 
p h os p h or yl ati o n.   Pl as ma fr o m t h e p ati e nt s s u p press e d F L T 3 -I T D a n d wil d-t y p e F L T 3 
( F L T 3-W T) a ut o p h os p h or yl ati o n acti vit y .   I n cells e x pressi n g F L T 3-W T, hi g h er d os es 
a n d l o n ger e x p os ur es of q ui zarti ni b were n ecess ar y t o eli mi n at e d et ect a bl e 
p h os p h o r yl at e d F L T 3 as c o m p ar e d wit h F L T 3 -I T D-e x pressi n g cells . 
M or e o ver, a  s u bs et of 2 0 A M L p ati e nts i n t h e st u d y were e val u at e d f or t h e effect of 
q ui zarti ni b o n p h os p h or ylate d S T A T 5  (p S T A T 5) , usi n g a w h ol e bl o o d-b as e d ass a y.   
Q uizarti ni b tr eat me nt d ecr eas e d p S TA T 5 l e vels i n 1 0  of 1 1 F L T 3 -I T D p ositi ve p ati e nts 
a n d 7  of 9 F L T 3 -I T D n e gati ve pati e nts.   Th ere was a n e n ha n ce d effect o n p S T A T 5 
i n hi biti o n i n F L T 3-I T D p ositi ve p ati e nts.  T h es e dat a s u g gest t h at q ui zarti ni b i n hi bit s 
p S T A T 5 pr o d ucti o n re gar dl ess of F L T 3 -I TD m ut ati o n st at us i n A M L p ati e nts . 
 
1. 3. 2  
P h as e 2 St u di es  (St u d i es A C 2 2 0 - 0 0 2 a n d 2 6 8 9 -C L -2 0 0 4 ) 
I n St u d y A C 2 2 0 - 0 0 2 c o n d u ct e d i n 3 3 3 p ati e nts wit h rel a ps e d or refract or y A M L, 1 2 
pati e nt s r ecei ve d 2 8-d a y c o nti n u o us d osi n g at 2 0 0  m g/ d a y, w hi c h is t h e M T D d et er mi ne d 
i n St u d y C P 0 0 0 1, a n d Gr a d e 3 Q Tc pr ol o n gati o n was re p orte d at t his d os e i n 4 2 % of 
pati e nt s i n St u d y A C 2 2 0 - 0 0 2.    T h e st u d y d e m o nstrat e d t h at t h e i n ci d e n ce of Q Tc 
pr ol o n gati o n t e n d e d t o b e hi g h er i n f e mal es t h a n i n mal es.    To a d dress t his iss u e, t h e 
d ose of q ui zarti ni b was r e d u ce d t o 1 3 5  m g/ d a y f or mal es a n d 9 0  m g/ da y f or fe mal es 
d uri n g t h e c o urs e of St u d y A C 2 2 0 -0 0 2.    Aft er d ose re d u cti o n, 1 fe mal e p ati e nt  o n 
c o nti n u o us d osi n g at 9 0  m g/ d a y, c o n c o mit a ntl y  wit h a str o n g C Y P 3 A 4  i n hi bit or, 
e x p eri e n ce d Gr a d e 4 Q Tc  pr ol o n gati o n ( t ors a d es de p oi nt es [T d P ]). 
I n St u d y A C 2 2 0- 0 0 2, p atie nt s wer e di vi d e d i nt o 2 c o h orts acc or di n g t o a ge a n d pre vi o us 
tr eat me nt st at us.    S p ecifi call y, A M L p ati e nts  of  ≥ 6 0 years ol d wit h rel a pse d or 
r efr act or y A M L aft er 1 first-li ne c h e m ot h era p y re gi me n were e nr oll e d i n C o h ort 1, w hil e 
A M L p ati e nts of ≥ 1 8 ye ars ol d wit h rel a ps e d or refract or y A M L aft er s al v a ge re gi me n , 
or r el a ps e d A M L  aft er h e mat o p oi eti c st e m cell tra ns pl a nt ( H S C T ) were e nr oll e d i n 
C o h ort 2.    I n C o h ort 1, t h e c o m p osit e C R ( C Rc = C R + [ C R wit h i n c o m pl et e 
he mat ol o gi cal r ec o ver y; C Ri] + [ C R wit h i n c o m plete pl at el et rec o ver y; C R p]) rat e was 
5 2 % i n a s u bs et of F L T 3 -I T D p ositi ve p ati e nt s, wit h a me di a n o verall s ur vi val of 2 5. 3 
wee ks.    I n C o h ort 2, t h e C Rc r at e was 4 5 % i n a s u bset of F L T 3 -I T D p ositi ve p ati e nt s, 
wit h a me di a n o ver all s ur vi val of 2 2. 9 wee ks.    I n C o h ort 2, 3 5 % of F L T 3 -I T D p ositi ve 

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
2 8  
 
pati e nt s pr o cee d e d t o H S C T, a n d al m ost all ( 9 4 %) of t h os e pr ocee din g t o H S C T ac hi e ve d 
C Rc or P R wit h q ui zarti ni b tr eat me nt, wit h a 1 -year s ur vi val rat e of 3 9 %.  
St u d y 2 6 8 9 -C L -2 0 0 4 was c o n d u ct e d i n 7 6 F L T 3 -I T D p ositi ve A M L p ati e nts, w h o were 
assi g n e d t o 2 8 -d a y c ycl es of 3 0 or 6 0  m g/ d a y c o nti n u o us d osi n g of q ui zarti ni b (f or  b ot h 
males a n d f e mal es) t o e v al u at e t h e effi cac y a n d safet y of q ui zarti ni b at l o w er d os es t h a n 
t h os e test e d i n St u d y A C 2 2 0-0 0 2.    I n t h e st u d y, t he i n ci de n ce of Q Tc pr ol o n gati o n was 
m u c h l o wer t ha n t h at o bser ve d i n St u d y A C 2 2 0 -0 0 2, i n di cati n g t h at t h e ris k  of Q Tc 
pr ol o n gati o n was d os e- d e p e n d e nt  (Ta bl e 1. 3- 1 ).    T h e st u d y als o d e m o nstrat e d t h at t h e 
C Rc r at es wer e c o m p ar a bl e t o t h os e o bs er ve d i n St u d y A C 2 2 0 - 0 0 2 (Ta bl e 1. 3- 2 ).  I n 
St u d y 2 6 8 9 -C L -2 0 0 4 as well, 3 4 % of p ati e nt s pr o cee d e d t o H S C T, a n d t h e p ati e nt s w h o 
u n der we nt H S C T t e n d e d t o h a ve a l o n ger s ur vi val t h a n t h os e w h o di d n ot. 
C o m m o n a d vers e e ve nts ( A Es) r e p ort e d i n St u di es A C 2 2 0 - 0 0 2 a n d 2 6 8 9 -C L -2 0 0 4 were 
gastr oi nt esti n a l dis or d ers ( e g, n a us ea, di arr h ea, a n d v o miti n g), h e mat ot o xi cit i es (e g, 
a n e mi a, n e utr o p e ni a, a n d t hr o m b o c yt o p e ni a) , fe bril e n e utr o p e ni a, fe ver, fati g u e, a n d Q Tc 
pr ol o n gati o n.   Alt h o u g h t h e h e mat ol o gic t o xi cit ies a p p ear t o b e  ass o ci at e d wit h  t h e 
u n derl yi n g dis eas e , A M L, d at a s u g gest d el a ye d rec o ver y or c o nti n u e d s u p pressi o n of 
a bs ol ute ne utr o p hil c o u nt ( A N C) a n d pl at elets as a c o ns e q u e n ce of c o nti n ue d treat me nt 
wit h q ui zarti ni b. 
 
Ta bl e 1. 3- 1   M a xi m u m Val u es of Q T C orrect e d f or Heart Rate Usi n g Fri d eri ci a ’s 
Met h o d (Q Tc F ) a n d M a xi m u m C h a n ges fr o m Bas eli n e i n  Q Tc F  i n T w o P has e 2 St u di es  
 
St u d y A C 2 2 0 -0 0 2  
St u d y 2 6 8 9 -C L -2 0 0 4  
D ail y D os e of Q ui z arti ni b  
9 0  m g/ d a y  
( N = 5 7) 
†  Fe mal e  
1 3 5  m g/ d a y  
( N = 6 7) 
†  Mal e  
2 0 0  m g/ d a y  
( N = 1 2 ) 
3 0  m g/ d a y  
( N = 3 8 ) 
6 0  m g/ d a y  
( N = 3 6 ) * 
Ma xi m u m Q Tc F ( ms)  
> 4 8 0, ≤ 5 0 0  ( Gr a d e 2) 
2 1 %  
1 3 %  
3 3 %  
5 %  
1 4 %  
> 5 0 0 ( Gr a d e 3) †  A s y m pt o mati c 
2 1 %  
1 5 %  
4 2 %  
5 %  
3 %  
Ma xi m u m c h a n g e i n Q Tc F fr o m b aseli n e ( ms)  
≤ 3 0  
9 %  
9 %  
0 %  
5 0 %  
4 4 %  
>  3 0, ≤ 6 0  
4 6 %  
5 1 %  
8 %  
4 7 %  
3 6 %  
>  6 0  
4 6 %  
3 9 %  
9 2 %  
3 %  
1 9 %  
* T w o p atie nts i n t h e 6 0  m g/ d a y gr o u p wer e r a n d o mi z e d b ut n e v er tre ate d wit h q ui z arti ni b . 
 
Ta bl e 1. 3- 2   C o m p osit e C o m pl et e Re missi o n a n d P artial Res p o ns e Rat es i n T w o P h as e 2 
St u di es  
 
St u d y A C 2 2 0 -0 0 2  
St u d y 2 6 8 9 -C L -2 0 0 4  
D ail y D os e of Q ui z arti ni b  
9 0  m g/ d a y  
( N = 5 7) 
† Fe mal e  
1 3 5  m g/ d a y  
( N = 6 7) 
† Mal e  
2 0 0  m g/ d a y  
( N = 1 2 ) 
3 0  m g/ d a y  
( N = 3 8 ) 
6 0  m g/ d a y  
( N = 3 8 ) 
C R c r at e  
4 7 %  
4 5 %  
4 2 %  
4 7 %  
4 7 %  
P R rat e  
2 5 %  
2 8 %  
5 0 %  
1 3 %  
2 4 %  

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
2 9 
 
 
1. 3. 3  
P h as e 1 b St u d y ( St u d y 2 6 8 9- C L - 2 0 05)  
I n t his st u d y, q ui zarti ni b  was a d mi nist ere d  i n c o m bi n ati o n wit h i n d u cti o n a n d 
c o ns oli d ati o n c h e m ot h er a p y i n i niti all y di a g n os e d A M L p ati e nts a n d t h e s afet y a n d 
p h ar mac o ki n eti cs  wer e ass ess e d.    D uri n g t he i n d ucti o n p h as e, c yt ara bi n e 
( 2 0 0 m g/ m2/ d a y o n Da y 1  t o Da y 7 ), d a u n or u bi ci n ( 6 0  m g/ m2/ d a y o n Da y 1  t o Da y 3 ), 
a n d q ui zarti ni b  (4 0  m g/ d a y or 6 0  m g/ d a y o n Da y 4  t o Da y 1 0 or Da y 4  t o Da y 1 7 ) were 
a d mi nist er e d  f or u p t o 2 c ycl es.    D uri n g t h e c o ns oli d ati o n p h as e, c yt ara bi n e 
( 3. 0 g/ m2/ 1 2 h o urs o n Da y 1, Da y 3, a n d Da y 5) a n d q ui zarti ni b  (4 0  m g/ d a y or 6 0  m g/ d a y 
o n Da y 4  t o Da y 1 0 or D a y 4  t o Da y 1 7 ) were a d mi nist ere d f or u p t o 3 c ycl es. 
A E s fr e q u e ntl y r e p ort e d i n t h e st u d y were na us ea,  di arr h ea, co nsti p ati o n,  hy p o kal e mi a,  
h y p o ma g n es e mi a,  n e utr o pe ni a, vo miti n g,  fati g u e, hea d ac h e , h y p o p h os p h at e mia , 
h y p ot e nsi o n, p yr e xi a,  a n d r as h.   O n e  p ati e nt  h a d a fat al o ut c o me d u e t o c ar diac arrest  
aft er e x p eri e n ci n g s eri o us A E s ( S A Es) ( m u c os al i nfl a m mati o n, pl e ural eff usi o n, a n d 
p ericar di al eff usi o n); h o we ver, t h e ca us alit y b et wee n car di ac arrest a n d q ui zarti ni b was 
r ul e d o ut. 
 
1. 3. 4  
P h a r m a c o ki n eti cs  
P har mac o ki n eti c d at a of  q ui zarti ni b a n d its acti ve met a b olit e A C 8 8 6 fr o m cli ni cal st u di es 
i n A M L p atie nts a n d h ealt h y v ol u nt eers h a ve bee n e val u at e d.    Aft er a d mi nistrati o n of 
q ui zarti ni b, t h e pl as ma c o n ce ntrati o ns of q ui zarti ni b a n d A C 8 8 6 i n crea s e d ra pi dl y ( Tma x  
of q ui zarti ni b , 2 t o 8 h o urs p ost q uizarti ni b d osi n g d uri n g t h e first d a y of d osi n g) .   
Q uizarti ni b  a n d A C 8 8 6 h a d t er mi n al eli mi n ati o n h alf -li ves of a p pr o xi matel y 3 d a ys, 
r es ulti n g i n a p pr o xi mat el y 4-f ol d acc u m ulati o n fr o m t h e first d a y of d osi n g  f or e x p os ure 
at t h e st ea d y st at e aft er d ail y d osi n g.   Plas ma e x p os ure t o b ot h q ui zarti ni b  a n d A C 8 8 6 
was  ge n er all y pr o p orti o n al wit h t h e d os e i n t h e t est e d d os e ra n ge of 3 0  m g/ d a y  t o 
9 0 m g/ d a y .  O ver all, C ma x a n d A U C s h o we d m o d erat e t o hi g h vari a bil it y.   Plas ma 
c o n ce ntr ati o ns  of A C 8 8 6 at t h e st ea d y st at e p arall el e d q uizarti ni b  l e vels wit h a  pl as ma 
c o n ce ntr ati o n r ati o of A C 8 8 6 t o q ui zarti ni b ( A C 8 8 6/ q ui zarti ni b)  of 0. 5.  A C 8 8 6 is t h e 
o nl y maj or met a b olit e of q ui zarti ni b i n t h e circ ulati o n.  Q ui zarti ni b  was mai nl y 
eli mi n at e d b y n o n -r e n al cl ear a n ce.    T h e pres e n ce of c o n c o mit a nt ket o c o naz ol e, a str o n g 
C Y P 3 A 4 i n hi bit or, i ncr eas e d t h e o bs er ve d A U Ci nf of q ui zarti ni b  a p pr o xi matel y 2 -f ol d.  
T h e pr es e n ce of c o n c o mita nt fl u c o n az ol e, a m o d erat e C Y P 3 A 4 i n hi bit or, i ncrease d t h e 
o bser ve d A U Ci nf of q ui zarti ni b  a p pr o xi mat el y 1. 2 -f ol d. 
 

 
 
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1. 4  
K n o w n a n d F o res ee a bl e Ris ks  
A Es t h at wer e p arti c ul arl y fr e q u e ntl y re p ort e d i n pre vi o us cli nical st u di es were b o d y as a 
w h ol e ge ner al dis or d ers  ( e g, p yr e xi a  a n d fati g u e) a n d gastr oi nt esti n al dis or ders  (e g, 
na us ea, di arr h ea , a n d v o miti n g ).   I n  a d diti o n, bl o o d dis or d ers  (e g, a n emi a , n e utr o p e ni a , 
a n d t hr o m b o c yt o p e ni a), eff ects of c yt o pe ni a (e g, i n creas e d ris k of i nfecti o n a n d 
he m orr h a ge ), a n d Q Tc pr ol o n gati o n h a ve als o b ee n re p ort e d. 
Alt h o u g h t h e h emat ot o xi cit i es ma y b e ass o ciat e d wit h A M L, s afet y re p orts fr o m St u d y 
A C 2 2 0 -0 0 2 i n di cat e d ela ye d r ec o ver y of A N C a n d pl at el ets as a c o ns e q u e nce of 
c o nti n u e d tr eat me nt wit h q ui zarti ni b  i n ma n y p ati e nts. 
S A Es  r elat e d t o b o n e marr o w d e pr essi o n  (e g, fe bril e b o n e marr o w a plasi a, b o ne marr o w 
h y p o cell ul arit y,  l y m p h o p e ni a, a n e mi a , h e m orr h a g e, t hr o m b oc yt o p e ni a , a n d 
pa n c yt o p e nia), a n d/ or i nf ecti o ns  ( p arti c ul arl y, b ut n ot e xcl usi vel y, f u n gal a n d ot h er 
o p p ort u nisti c i nf ecti o ns, Gr a m n e gati ve b act erial i nfecti o ns,  a n d b act eremi a/s e psis) h a ve 
bee n r e p ort e d i n q ui zarti ni b cli ni cal  st u di es.  Re p orts of i nfecti o n s h a ve oft e n b ee n i n 
t h e c o nte xt of n e utr o p e ni a, p yr e xi a, or b ot h.  I n v esti gat ors s h o ul d rec o g ni ze t h at A M L  
ma y r ais e t h e ris k of i nf ecti o n.   Atte nti o n s h o ul d als o b e p ai d t o  infecti o ns fr o m di verse 
pat h o ge ns i n diff ere nt or ga n s yst e ms (i n cl u di n g s e psis  a n d b act er emi a) . 
T h er e ar e als o r e p orts of S A Es r elat e d t o h e m orr h a ge  (e g, e pist a xis, h e m o pt ysis , mel en a, 
gastr oi nt esti n al h e m orr h a ge , a n d i ntracra ni al hem orr h a g e). 
Q Tc pr ol o n gati o n is as st at e d i n “ 1. 3. 2  P has e 2 St u di es  (St u d i es A C 2 2 0 -0 0 2 a n d 
2 6 8 9 -C L -2 0 0 4) . ”  Tr eat me nt wit h q ui zarti ni b ma y i n d u ce T d P  d e pe n di n g o n  t h e e xt e nt 
of Q Tc pr ol o n gati o n, c o n c o mit a nt a d mi nistrati o n of Q Tc pr ol o n gi n g dr u gs, a hist or y of 
T d P, pr ee xisti n g Q Tc pr ol o n gati o n, c o n ge nit al l o n g Q T s y n dr o me, c o n gesti ve h eart 
f ail ur e, or ot h er cli nical states of p h ysi ol o gi c stress (e g, p n e u m o ni a a n d ot h er i nfecti o ns), 
a d mi nistr ati o n of p ot assi u m -wasti n g di ureti cs, or ot h er c o n diti o ns t h at res ult i n 
h y p o kal e mi a or h y p o ma g n es e mi a . 
C h e m ot h er a p y use d i n t his st u d y c o nsists of re missi o n i n d u cti o n t h era p y a n d 
c o ns oli d ati o n t h er a p y gi ve n f or u p t o 2 c ycl es a n d 4 c ycl es, res pecti vel y, eac h of w hi c h is 
2 8 d a ys l o n g.  
D uri n g t h e i n d u cti o n p h ase, q ui zarti ni b will b e a d mi nist ere d  i n c o m bi n ati o n wit h 
c yt ar a bi n e a n d a n a nt hr ac ycli ne  dr u g (eit h er da u n or u bi ci n or i d ar u bi ci n will b e c h ose n).   
I n C ycl e 1, t h e tr eat me nt will b e a d mi nist er e d as c yt ara bi n e at a d os e of 1 0 0 m g/ m 2/ d a y 
o n Da y 1 t o Da y 7 , da u n or u bi ci n at a d os e of 6 0 m g/ m 2/ d a y or i d ar u bi ci n at a d os e of 
1 2 m g/ m 2/ d a y o n Da y 1  t o Da y 3, a n d q ui zarti ni b at a d ose of 2 0  m g/ d a y or 4 0 m g/ da y o n 
Da y 8 t o Da y 2 1.   I n C ycl e 2, t h e treat me nt will be a d mi nist ere d  b y  t h e s a me d osi n g 

 
 
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sc h e d ul e as i n C ycl e 1 or as c yt ar a bi n e  at a d os e of 1 0 0 m g/ m 2/ d a y o n Da y 1 t o Da y 5, 
da u n or u bi ci n at a d os e of 6 0 m g/ m 2/ d a y or i d ar u bi ci n at a d os e of 1 2 m g/ m 2/ d a y o n Da y 
1 t o Da y 2, a n d q uizarti ni b o n Da y 6 t o Da y 1 9 .   T h e a nt hrac ycli n e  dr u g us e d i n C ycl e 2 
has t o b e t h e s a me as t h at  i n C ycl e 1.    T h e d ail y d ose of d a u n or u bi ci n us e d i n t his st u d y 
e xcee ds t he d ail y d ose a p pr o ve d i n J a p a n (t h e d osa ge a p pr o ve d i n J a p a n is 0. 4  m g/ k g/ d a y 
t o 1. 0 m g/ k g/ d a y gi ve n f or 3 to 5 c o ns ec uti ve d a ys or e ver y ot h er d a y, w hi c h is cal c ul at e d 
t o b e 2 4 m g  t o 6 0  m g/ d a y f or p ati e nts wei g hi n g 6 0 k g; h o we ver, t h e d ail y d ose i n t his 
st u d y is 9 6 m g  p er 1. 6 m 2).   It h as n ot b ee n re p ort e d t o d at e w h et h er  t h ere is a n y 
diff er e n ce i n t h e s af et y b et wee n t h e d os e us e d i n t his st u d y a n d t h e d os e rec o m me n d e d i n 
Ja p a n. 
D uri n g t h e c o ns oli d ati o n p has e, c yt ara bi n e a n d q ui zarti ni b will b e a d mi nist ere d .   T h e  
c yt ar a bi n e d os e is 3. 0 g/ m 2/ 1 2 h o urs f or A M L p ati e nts of < 6 0 years ol d ( 1. 5 g/ m2/ 1 2 
h o urs f or A M L p ati e nts of ≥ 6 0 years ol d) gi ve n o n Da y 1, Da y 3, a n d Da y 5.   
Q uizarti ni b  will b e a d mi nist er e d  at a d os e of 2 0 m g/ d a y or 4 0  m g/ d a y o n Da y 6 t o Da y 
1 9 .   C yt ar a bi n e, w hi c h  is us e d as c o ns oli d ati o n t hera p y i n Ja p a n, will b e a d mi nist ere d  
o n Da y 1  t o Da y  5  at a  d os e of 2. 0 g/ m 2/ 1 2 h o urs f or y o u n g A M L p ati e nts a n d at a l o wer 
d ose f or el d erl y A M L p ati e nts at t h e i n vesti gat or’s dis creti o n.    T his is b eca us e 
c yt ar a bi n e h as b ee n c o nfir me d t o b e effecti ve at a d os e of 3. 0 g/ m 2 i n p ati e nts of <  6 0 
years  ol d; h o we ver, t h e r e gi me n is c o nsi dere d t o i n v ol ve fre q u e nt ce ntral n er v o us s yst e m 
( C N S)-r el at e d c o m pli cati o ns ( att ac ks, cere bral d ysf u n cti o n, a n d ac ut e cere bell ar 
s y n dr o me).1), 1 3)  C yt ar a bi n e  ma y ca us e C N S c o m pli cati o ns, a n d ca uti o n is t h eref ore 
r e q uir e d i n t his st u d y. 
 
1. 5  
R ati o n ale f o r t h e D os a g e  
T his st u d y will b e c o n d u ct e d t o c o nfir m t h e s afet y of q ui zarti ni b  i n c o m bi nati o n wit h 
st a n d ar d c h e m ot her a p y, w hic h is s p ecifi e d i n a gl o b al P has e 3 st u d y t h at is c urre ntl y 
u n der wa y a br o a d i n p ati e nts wit h i niti all y di a g n ose d F L T 3 -IT D -p ositi ve A M L 
(A C 2 2 0 - A-U 3 0 2: Q u A N T U M -First ), i n J a p a n es e A M L p ati e nts, a n d t h e n t o ass ess a n d 
det er mi n e w h et h er J a p a n’s p arti ci p ati o n i n t h e a b o ve st u d y is p ossi bl e or n ot.    F or t his 
r eas o n, t h e d os a ge r e gi m e n of c h e m ot h era p y a n d q ui zarti ni b use d i n t his st u d y was s et 
bas e d o n t h e d os a ge r e gi me n of i n d u cti o n a n d c o ns oli d ati o n t h era p y us e d i n 
Q u A N T U M -First . 
T h e  g ui d eli ne f or t he ma na ge me nt of A M L ( Ve r s i o n  1 , 2 0 1 5 ) b y T h e Nati o nal 
C o m pr e h e nsi ve Ca n cer Net w or k (N C C N ) rec o m me n ds, as o n e of t h e re missi o n i n d u cti o n 
r e gi me ns, t h e us e of c yt ar a bi n e ( 1 0 0 m g/ m2/ d a y t o 2 0 0 m g/ m2/ d a y) f or 7 c o nsec uti ve 

 
 
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da ys a n d a n a nt hrac ycli n e dr u g ( d a u n or u bi ci n at 4 5  m g/ m2/ d a y t o 9 0 m g/ m2/ d a y or 
i d ar u bi ci n at 1 2 m g/ m 2/ d a y) f or 3 c o ns ec uti ve d a ys.    As far as t h e d a u n or u bi ci n d os e is 
c o n cer n e d, t h er e is a r e p ort t h at c o m pl et e re missi o n ( C R) rat e a n d o verall s ur vi val were 
m or e f a v ora bl e wit h 9 0 m g/ m 2/ d a y gi ve n f or 3 d a ys t h a n wit h 4 5 m g/ m2/ da y gi ve n f or 3 
da ys  i n i niti all y dia g n os e d A M L p ati e nts of <  6 0 years  ol d.1 4)  O n t h e ot h er h a n d, i n a 
cli ni cal st u d y i n w hi c h c yt ar a bi n e ( 1 0 0 m g/ m2/ 1 2 h o urs) was a d mi nist ere d  c o ns ec uti vel y 
o n Da y 1 t o Da y 1 0 a n d da u n or u bi ci n ( 9 0 m g/ m2/ da y or 6 0 m g/ m 2/ d a y) w as a d mi nistere d  
f or 3 d a ys o n Da y 1, Da y 3, a n d Da y 5  i n u ntreat e d A M L p ati e nts or hi g h-ris k 
m yel o d ys pl asti c s y n dr o me ( M D S ) p ati e nts, n o differe n ce i n t h e C R rat e was o bs er ve d 
bet wee n t h e 9 0  m g/ m2/ d a y a n d 6 0  m g/ m2/ d a y gr o u ps; h o we ver, t h e 6 0 -d a y m ortalit y was 
hi g h er i n t h e 9 0  m g/ m2/ d a y gr o u p ( 1 0 % vs 5 %).   T h e 2 -year s ur vi val was al m ost t h e 
sa me b et wee n t h e tr eat me nt gr o u ps ( 5 9 % vs 6 0 % ).1 5)  Bas e d o n t h es e, Q u A N T U M -First  
a d o pt e d r e missi o n i n d u cti o n t h er a p y as c yt ara bi n e  ( 1 0 0 m g/ m2/ d a y) gi ve n c o nti n u o usl y 
o n Da y 1  t o Da y 7 a n d a n a nt hr ac ycli ne  dr u g ( d a u n or u bi ci n at 6 0  m g/ m2/ da y or 
i d ar u bi ci n at 1 2 m g/ m 2/ d a y) gi ve n c o nsec uti vel y o n Da y 1 t o Da y 3 .    T h e d os a ge of 
da u n or u bi ci n a p pr o ve d i n J a p a n is 0. 4 m g/ k g/ d a y t o 1. 0 m g/ k g/ d a y gi ve n f or 3 t o 5  
c o ns ec uti ve d a ys or e ve r y ot h er d a y, a n d t he dail y d ose is cal c ul at e d t o b e 2 4  m g/ d a y t o 
6 0 m g/ d a y  f or p ati e nts wei g hi n g 6 0 k g.    T he d os e of 6 0 m g/ m 2/ d a y us e d i n t his st u d y is 
9 6 m g/ d a y  p er 1. 6 m 2. 
T h e  N C C N  g ui d eli n e f or t h e ma na ge me nt of A M L ( Versi o n 1, 2 0 1 5) rec o m me n ds , as o n e 
of t h e p ostr e missi o n r e gi me ns, hi g h - d os e c yt ara bi ne ( 2 g/ m2/ 1 2 h o urs  t o 3 g/ m 2/ 1 2 h o urs 
f or p ati e nts of < 6 0 years  ol d a n d 1 g/ m2/ 1 2 h o urs  t o 1. 5  g/ m2/ 1 2 h o urs f or pati e nts of ≥ 
6 0 years ol d ) gi ve n a t ot al of 6 ti mes o n Da y 1, Da y 3 a n d Da y 5.    O n t he ot h er h a n d, 
E ur o p ea n Le u ke mi a Net  r ec o m me n ds t h e us e of hi g h- d os e c yt ara bi n e as c o ns oli d ati o n 
t h era p y i n cli ni cal st u di es o nl y.1 6)  At pres e nt, c o ns oli d ati o n t h era p y rec o m me n d e d f or 
A M L p ati e nts wit h F L T 3 -I T D m ut ati o ns h as n ot b ee n cl arifi e d.   T h e  N C C N  g ui d eli n e 
r ec o m me n ds p arti ci p ati o n i n cli ni cal st u dies, w h ereas E ur o p ea n Le u ke mi a Net  
r ec o m me n ds H S C T  f or p atie nts of  1 8 t o 6 0 years ol d a n d l o w - d os e c yt ara bi n e as 
c o ns oli d ati o n t h er a p y f or p ati e nts of ≥ 6 0 years ol d .1 6)  I n a cli ni cal st u d y i n w hi c h 
r e missi o n i n d u cti o n t h er a p y wit h c yt ara bi n e a n d da u n or u bi ci n was gi ve n t o i niti all y 
di a g n os e d A M L p ati e nts, a n d t hr ee d osa ge re gi me ns of c yt ara bi n e  ( 5-d a y c o nti n u o us 
tr eat me nt at a d ose of 1 0 0  m g/ m2/ d a y, 5-d a y c o nti n u o us treat me nt at a d os e of 
4 0 0 m g/ m 2/ d a y, or a t ot al of 6-d ose treat me nt at 3 g/ m 2/ 1 2 h o urs o n Da y 1, Da y 3, a n d 
Da y 5 ) wer e c o m p are d i n pati e nts ac hie vi n g C R, dis ease-free s ur vi val ( D F S) i n pati e nt s 
o f < 6 0 years ol d was si g nifi ca ntl y hi g h er i n t h e 3 g/ m 2/ 1 2 h o urs gr o u p t h a n i n t h e 

 
 
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1 0 0 m g/ m 2/ d a y a n d  4 0 0 m g/ m2/ d a y gr o u ps.1 3)  T heref ore, Q u A N T U M -First  a d o pt e d, as 
c o ns oli d ati o n t h er a p y, c ytar a bi n e  gi ve n at a d o s e of 3 g/ m 2/ 1 2 h o urs a t ot al of 6 ti mes o n 
Da y 1, Da y 3, a n d Da y 5 f or p ati e nt s of < 6 0 years ol d a n d c yt ara bi n e gi ve n at a d os e of 
1. 5  g/ m2/ 1 2 h o urs a t ot al of 6 ti mes o n Da y 1, Da y 3, a n d Da y 5 f or p ati e nt s of ≥ 6 0 years 
ol d .   Th e c yt ar a bi n e  d osa ge a p pr o ve d f or p ati e nt s of <  6 0 years ol d i n J a pa n is 2 g/ m 2 
gi ve n e ver y 1 2 h o urs f or a ma xi m u m of 6 c o nsec uti ve d a ys, a n d t h e d ail y d os e of 
c yt ar a bi n e us e d i n t his st u d y e xcee ds t h e d ail y d ose of c yt ara bi ne a p pr o ve d i n J a p a n. 
 

 
 
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2.  
S T U D Y O B J E C TI V E S  
Pri mar y o bj ecti ve : 
To e val u at e t h e s af et y a n d p h ar mac o ki n eti cs of q ui zarti ni b  i n c o m bi n ati o n wit h st a n d ar d 
i n d u cti o n a n d c o ns oli d ati o n t h er a p y i n J a p a n es e pati e nts wit h i niti all y di a g n os e d A M L , 
a n d t o d et er mi ne t h e d os e f or s u bs e q u e nt p h as es of d e vel o p me nt. 
Sec o n dar y o bj ec ti ves: 
• 
E x pl or at or y st u d y of q ui zarti ni b -relat e d bi o mar k ers 
• 
E x pl or at or y e val u ati o n of a ntit u m or effect  
 

 
 
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3.  
S T U D Y D E SI G N  
T his  st u d y is d esi g n e d as a m ulti ce nt er, o p e n-l a b el, P h as e 1 cli ni cal st u d y of q ui zarti ni b  
at 2 0 m g or 4 0  m g a d mi nist er e d  i n c o m bi n ati o n wit h c h e m ot h era p y. 
Q uizarti ni b  will b e a d mi nist er e d  at a d os e of 2 0  m g at Le vel 1 a n d 4 0  m g at Le vel 2.   
D os e escal ati o n wit hi n a si n gl e p ati e nt  is n ot all o we d.    T h e c h e m ot h era p y re gi me n 
c o a d mi nist er e d wit h q ui zarti ni b  is s h o w n i n “Fi g ure 3- 1  St u d y Fl o w . ” 
T h e pr es e n ce or a bs e n ce  of d os e-li miti n g t o xi cit y (D L T ) of q ui zarti ni b  will b e c h ec ke d at 
eac h l e vel b as e d o n t he d efi niti o n pr o vi d e d i n “ 5. 4. 1  Defi niti o n of D ose -li miti n g 
To xi citi es ,” a n d t he M T D will b e d et er mi n e d usi n g t h e al g orit h m of a 3 + 3 d esi g n (refer 
t o Secti o n “5. 4. 2  A ss ess me nt M et h o d ”).  
T h e D L T ass ess me nt  p eri o d is t h e i n d u cti o n p has e; t h e pres e n ce or a bs e n ce  o f D L T 
d uri n g t h e a b o ve peri o d will b e c o nfir me d i n a mi ni m u m of 3 p ati e nt s (i n cl u di n g at l east 
1 pati e nt of <  6 0 years  ol d at t h e ti me of re gistrati o n i n t h e st u d y) at eac h l e vel.    If D L T 
occ urs, a d diti o n al p ati e nt s will b e e nr olle d at t h e c o n cer n e d le vel i n acc or d a n ce wit h 
“ Ta bl e 5. 4 - 1 Crit eri a f or Pr ocee di n g  t o Le vel 2” or “ Ta bl e 5. 4 - 2 Crit eri a f or Ass essi n g 
Ma xi m u m Toler ate d D os es ( M T Ds) at Le vel 2 ,” or q ui zarti ni b d os e es cal ati o n will b e 
dis c o nti n u e d .    If D L T c a n n ot b e ass ess e d a p pr o pri at el y i n a n y p atie nt , a d diti o nal 
pati e nt s will be e nr oll e d i n acc or d a n ce wit h “5. 4. 4  E nr oll me nt of A d diti o n al P ati e nts . ” 
 

 
 
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Fi g ure 3- 1   St u d y Fl o w  
 
R e missi o n i n d u cti o n t h er a p y  
 
< C y cl e 1 > 
D a y 1 t o D a y 7 :  C o nti n u o u s i ntr a ve n o us i nf usi o n of c yt ar a bi n e  (1 0 0  m g/ m 2/ d a y) 
D a y 1 t o D a y 3 :  I ntr a v e n o us i nf usi o n of d a u n or u bici n ( 6 0 m g/ m 2/ d a y) or i d ar u bi ci n (1 2  m g/ m 2/ d a y) 
D a y 8  t o D a y 2 1 :  Or al a d mi nistr ati o n  (o n c e d ail y ) of q ui z arti ni b ( 2 0  m g/ d a y or 4 0  m g/ d a y)  
B o ne marr o w as pir ati o n or bi o ps y will b e p erf or me d o n D a y 2 1 of C ycl e 1; if m yel o bl asts a c c o u nt f or  < 5 %, t h e 
tr eat me nt will pr o ce e d t o C ycl e 1 of c o ns oli d ati o n t h era p y; if m yel o blasts a c c o u nt f or  ≥ 5 %, r e missi o n i n d u cti o n 
t her a p y i n C ycl e 2 will b e gi v e n. 
< C y cl e 2 >  
Tr e at me nt will b e gi v e n usi n g t h e s a me r e gi me n as i n C ycl e 1 or as s h o w n  b el o w. 
D a y 1 t o D a y 5:  C o nti n u o us i ntr a ve n o us i nf usi o n of c yt ar a bi n e  ( 1 0 0 mg/ m 2/d a y ) 
D a y 1 t o D a y 2:  I ntr a v e n o us i nf usi o n of d a u n or u bici n ( 6 0 m g/ m 2/ d a y) or i d ar u bi ci n (1 2  m g/ m 2/ d a y) 
D a y 6 t o D a y 1 9:  Or al a d mi nistr ati o n  (o n c e d ail y ) of q ui z arti ni b ( 2 0  m g/ d a y or 4 0  m g/ d a y)  
 
 
 
C o ns oli d ati o n t h er a p y  
 
< C y cl e  1 > 
D a y 1 , 3, 5:   
Intr a v e n o us i nf usi o n of c yt ar a bi n e ( 3. 0 g/ m 2/ 1 2 h o urs f or p ati e nts of < 6 0 ye ars ol d a n d 
1. 5  g/ m 2/ 1 2 h o urs f or p atie nts of ≥ 6 0 ye ars ol d)  
D a y 6 t o D a y 1 9:  Or al a d mi nistr ati o n  (o n c e d ail y ) of q ui z arti ni b ( 2 0  m g/ d a y or 4 0  m g/ d a y)  
C o ns oli d ati o n t h er a p y will b e gi v e n f or u p t o 4 c ycl es i n p ati e nts wit h c o nfir me d t ol er a bilit y. 
< C y cl e 2 a n d t here aft e r >  
Sa me re gi me n as i n C ycl e 1.  
P ati e nt s a c hi e vi n g C R, C R p, or C Ri i n C ycl e 2 or l at er ar e all o we d t o t er mi n at e c o ns oli d ati o n t h era p y a n d u n d er g o 
he mat o p oi eti c st e m c ell tra ns pl a nt.  
 
 
< R ati o n al e > 
I n or d er t o c o nfir m t h e t ol era bilit y of re missi o n i n d ucti o n t hera p y a n d c o ns oli d ati o n 
t h erap y, w hi c h ar e  s p ecifie d i n Q u A N T U M -First,  w hic h  is c urre ntl y u n d er wa y i n p ati e nts 
wit h i niti all y di a g n ose d F L T 3 -I T D-p ositi ve A M L, i n J a p a n es e p ati e nts wit h i niti all y 
di a g n os e d A M L, it was d eci d e d t o us e t h e s a me re missi o n i n d u cti o n t h era p y a n d 
c o ns oli d ati o n t h er a p y as i n Q u A N T U M -First i n t his st u d y t o o . 
I n Q u A N T U M-First, q ui zarti ni b  is a d mi nist ere d  at 2 0 m g t o 4 0  m g i n c o m bi n ati o n wit h 
st a n d ar d re missi o n i n d ucti o n a n d c o ns oli d ati o n t h era p y.   T h e  q ui zarti ni b d ose was 
t h eref or e set as 2 0 m g at Le vel 1 a n d 4 0  m g at Le vel 2 i n t his st u d y.  
I n t his st u d y, D L T of q ui zarti ni b  will b e ass ess e d d uri n g t h e i n d u cti o n p h ase; h o we ver, 
saf et y d at a c oll ect e d fr o m eac h p ati e nt  d uri n g t h e c o ns oli dati o n p h as e will als o b e us e d t o 
deci d e w h et h er J a p a n  ca n parti ci p at e i n Q u A N T U M -First  or n ot.  
 

 
 
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4.  
S T U D Y P O P U L A TI O N  
4. 1  
S el ecti o n of P ati e nts  
P ati e nts w h o meet all of t h e i n cl usi o n criteri a a n d d o n ot fit a n y of t h e f oll o wi n g 
e xcl usi o n crit eri a ar e eli gi bl e f or t h e st u d y.  
 
4. 1. 1  
I n cl usi o n C rit eri a 
1)  Pr o visi o n of writt e n i nf or me d c o nse nt f or p arti ci p ati o n i n t h e st u d y.  
2)  A ge ≥ 2 0 years a n d ≤ 7 5 years at t h e ti me of re gistrati o n i n t h e st u d y  
3)  A M L p ati e nts (i n cl u di n g t h os e wit h a hist or y of M D S ) w h o ha ve n ot p re vi o usl y 
r ecei ve d ot h er tr eat me nts (i n cl u di n g q ui zarti ni b ) t h a n t h os e list e d b el o w 
• 
Le u ka p her esis  
• 
Tr eat me nt wit h h y dr o x ycar b a mi d e f or c o ntr ol of t h e w hit e bl o o d cell c o u nt  
• 
Cr a ni al r a di ati o n f or t h e tr eat me nt of i n vasi o n of t h e ce ntral n er v o us s yst e m  
• 
Pr o p h yl acti c i ntr at h ecal c h e m ot h era p y 
• 
S u p p orti ve tr eat me nt wit h gr o wt h fact or pr o d u cts or c yt o ki n e  
4)  East er n C o o p er ati ve O n c ol o g y Gr o u p  p erf or ma n ce st at us ( E C O G P S) s c ore 2  or l ess 
at t h e ti me of r e gistr ati o n i n t h e st u d y (refer t o “ A p p e n di x 1 ”). 
5)  La b or at or y t est r es ults o bt ai n e d wit hi n 1 4 d a ys b ef ore re gistrati o n i n t h e st u d y meet 
all of t h e f oll o wi n g r e q uir e me nts:  
La b or at or y P ar a met er  
Re q uir e me nt  
A S T  
≤ 2. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al r efer e n ce r a n g e  
A L T  
≤ 2. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al r efer e n ce r a n g e  
Tot al bilir u bi n  
≤ 1. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al r efer e n ce r a n g e  
Ser u m cr e ati ni n e  
≤ 1. 5 ti mes t h e u p p er li mit of t h e i nstit uti o n al r efer e n ce r a n g e , or 
esti mat e d gl o mer ul ar filtr ati o n r ate ( e G F R ) c al c ul at e d t o b e 
≥ 5 0  m L/ mi n/ 1. 7 3  m2 b y t h e M o difi c ati o n of Di et i n R e n al Dise as e 
( M D R D) e q u ati o n 
Ser u m K  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge * 
Ser u m C a ( c orr ect e d f or 
al b u mi n)  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge *  
Ser u m M g  
Wit hi n t h e i nstit uti o n al r efer e n c e r a n ge *  
*  P ati e nts wit h el e ctr ol yt es o utsi d e t h e  i nstit uti o n al r efer e n c e ra n g e will b e eli gi ble if t h ese v al u es ar e 
c orr ect e d  u p o n r et esti n g f oll o wi n g a n y n e c ess ar y s u p pl e me nt ati o n . 
6)  P ati e nts w h o  ca n r ecei ve q ui zarti ni b orall y. 
7)  P ati e nts w h o  ca n b e h os pit ali ze d d uri n g t h e D L T ass ess me nt p eri o d.  
 
< R ati o n al e > 
1) 
To e ns ur e t h e eli gi bilit y as a st u d y p ati e nt a n d f or et hi cal c o nsi dera ti o ns. 
2) 
T we nt y is c o nsi d er e d t h e mi ni m u m a ge f or p ati e nt s t o b e a bl e t o pr o vi d e a p pr o pri at e 
i nf or me d c o ns e nt bas e d o n t h eir o w n d ecisi o n.   T h e u p p er a ge li mit was set at 7 5 
years as i n Q u A N T U M -First . 

 
 
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3), 4), 6), 7)  To e val u at e t h e s af et y of q ui zarti ni b i n a n a p pr o priate ma n n er.  
5)  To e ns ur e t h at or ga n f u n cti o ns all o wi n g t h e a p pr o pri at e e val u ati o n of pati e nt  s afet y 
ha ve b ee n mai nt ai n e d b ase d o n t h e G ui d eli n es f or t h e Cli ni cal E val u ati o n of 
A nti c a n cer Dr u gs .1 7) 
 
4. 1. 2  
E x cl usi o n C rit eri a  
1)  Di a g n osis of ac ut e pr o m yel o c yti c l e u ke mi a  
2)  C hr o ni c m yel oi d l e u ke mia i n bl ast crisis ( p ati e nts wit h B C R -A B L [ brea k p oi nt 
cl uster r e gi o n - c-A b els o n] f usi o n ge ne)  
3)  Di a g n osis of tr eat me nt-r el at e d m yel oi d t u m or 
4)  Ha vi n g r ecei ve d ot h er i n vesti gati on al  pr o d u cts or h a vi n g us e d a n y i n vesti gati o n al 
me di cal d e vi ce s wit hi n 3 0 da ys b ef ore re gistrati o n i n t h e st u d y.  
5)  Hist or y of mali g n a nt t u m or e xce pt f or t h e f oll o wi n g  
• 
A d e q u at el y tr eat e d n o n -mela n o ma s ki n ca n cer  
• 
C urati vel y tr eat e d m u c os al carci n o ma or c arci n o ma i n sit u wit h n o e vi de nce of 
r el a ps e f or ≥ 2 years  aft er t h e l o cal treat me nt  
6)  Hist or y of or c urr e nt car di o vas c ul ar diseas e as s p ecifi e d b el o w:  
• 
Heart r at e  < 5 0  b eats/ mi n , d et er mi n e d as t h e a ver a ge of t hree meas ure me nts 
ta ke n al o n g wit h 1 2-l ea d E C G wit hi n 14 d a ys b ef ore re gistrati o n i n t h e st u d y 
( e xcl u di n g p atie nts h a vi n g a car diac p ace ma ker) 
• 
Q T c orr ect e d f or heart r ate usi n g Fri d eri ci a’s met h o d ( Q Tc F) of ≥ 4 5 0  ms, 
det er mi n e d as t h e a ver a ge of t hree meas ure me nts ta ke n wit hi n 1 4 d a ys b ef ore 
r e gistr ati o n i n t he st u d y 
• 
Di a g n os e d or s us p ect e d c o n ge nital l o n g Q T s y n dr o me  
• 
S yst olic bl o o d pr ess ur e l e vel ≥ 1 8 0  m m H g or di ast oli c bl o o d press ure le v el ≥ 
1 1 0  m m H g wit hi n 7 d a ys b ef ore re gistrati o n i n t h e st u d y  
• 
Hist or y of cli ni call y si g nifi ca nt ve ntri c ul ar arr h yt h mi a ( ve ntri c ul ar t ac h yc ar dia, 
ve ntri c ul ar fi brill ati o n, T d P, et c.) 
• 
Hist or y of  M o bit z II  atri o ve ntri c ul ar bl o c k or t hir d de gree atri o ve ntric ul ar bl o c k 
( P atie nts w h o h a ve a car di ac p ace ma ker b ut h a ve n ot e x p eri e n ce d s y n c o p e or 
cli ni call y si g nifi ca nt arr h yt h mi a d uri n g t h e p eri o d of us e are all o we d t o t a k e p art 
i n t h e st u d y.) 
• 
Hist or y of  u n c o ntr oll e d a n gi n a p ect oris or m y o car di al i nfarcti o n wit hi n 6 m o nt hs 
bef or e r e gistr ati o n i n t he st u d y 
• 
Hist or y of  Cl ass 3 or m or e s e vere h eart fail ure acc or di n g t o “ A p p e n di x 2 Ne w 

 
 
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Yo r k  He a rt Ass o ci ati o n ( N Y H A) F u ncti o n al Cl assifi cati o n ” 
• 
Hist or y of  l eft ve ntri c ul ar ejecti o n fracti o n b el o w 4 5 % or t h e l o wer li mit of t h e 
i nstit uti o n al r ef er e n ce r a n ge, w hi c h e ver is l o wer 
• 
C o m pl et e l eft or ri g ht b u n dl e bra n c h bl o c k  
7)  Ac ut e a n d acti ve i nfecti o n u n c o n tr oll e d b y a nti bact eri al or a nti viral a ge nts or c hr o ni c 
a n d s yst e mi c i nf ecti o n  
8)  Acti ve a n d cli ni call y si g nifi ca nt li ver dis eas e ( h e patitis B, h e p atitis C, etc.)  
9)  Test e d p ositi ve f or h u ma n i m m u n o d efi ci e n c y vir us ( HI V ) a nti b o d y wit hi n 1 4 d a ys 
bef or e r e gistr ati o n i n t he st u d y 
1 0)  Wo me n c o nfir me d  t o b e pr e g n a nt b y a pre g n a n c y test p erf or me d wit hi n 1 4 d a ys 
bef or e r e gistr ati o n i n t he st u d y, or breastfee di n g w o me n  
1 1)  U n willi n g n ess t o pr acti ce a p pr o pri at e c o ntrace pti o n usi n g effecti ve c o ntrace pti ve 
met h o ds ( e g, b arri er c o nt r ace pti ves c o m bi n e d wit h s p er mi ci d es, i ntra ut eri ne d e vi ce, 
et c.) f or t he e ntir e st u d y peri o d a n d 3 m o nt hs aft er t h e l ast d os e of t h e st u d y dr u g  
1 2)  P ati e nts w h o ar e ot h er wise c o nsi d ere d i n eli gi bl e f or t h e st u d y  i n t h e i n vesti gat or’s or 
s u bi n vesti gat or’s o pi ni o n 
 
< R ati o n al e > 
1) t o 9) 
To e val u at e t h e s af et y of q ui zarti ni b i n a n a p pr o priate ma n n er.  
1 0), 1 1)  Est a blis h e d b eca us e eff ects of q ui zarti ni b o n t h e fet us a n d n ursi n g b a bi es 
ca n n ot b e r ul e d o ut.  
1 2) Est a blis h e d s o t h at t h e i n vesti gat or or s u bi n vesti gat or ca n  det er mi n e t h e eli gi bilit y 
f or p arti ci p ati o n i n t h e st u d y fr o m a c o m pre h e nsi ve st a n d p oi nt wit h caref ul 
c o nsi d er ati o n f or p ati e nt  saf et y. 
 
4. 1. 3  
R e gist r ati o n of P ati e nts  
P ati e nt s will b e r e gist er e d i n t h e st u d y acc or di n g  t o t h e pr oce d ures d es cri b e d b el o w. 
 
4. 1. 3. 1  
P ati e n t Re gistr ati o n Pr oce d u re 
Aft er o btai ni n g writt e n i nf or me d c o ns e nt fr o m eac h p ati e nt, t h e i n vesti gat or or 
s u bi n vesti gat or will assi g n a s u bj ect i d e ntificati o n c o d e t o t h e p ati e nt .    If t h e 
a b o ve -st at e d p ati e nt  is assess e d t o b e eli gi bl e f or t he st u d y, t h e i nvesti gat or or 
s u bi n vesti gat or will e nt er t h e n ecess ar y i nf or mati o n o n t h e p atie nt  i n t h e s u bj ect 
r e gistr ati o n f or m ( Attac h me nt 1) a n d s e n d it t o t h e s p o ns or b y fa x. 
T h e s p o ns or will c h ec k t he eli gi bilit y of t h e p ati e nt  i n t he li g ht of t h e i ncl usi o n a n d 

 
 
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e xc l usi o n crit eri a f or t h e st u d y b as e d o n t h e e ntri es i n t h e recei ve d s u bj ect re gistrati o n 
f or m.    If t h er e ar e a n y q uesti o ns a b o ut t h e e ntri es i n t h e re gistrati o n f or m, t h e s p o ns or 
s h o ul d i m me di at el y c o nt act t he i n vesti gat or or s u bi n vesti gat or t o ma ke i n q uiries.   W h e n  
t h e s p o ns or d et er mi n es t hat t h e p ati e nt  is eli gi bl e f or t he st u d y, t h e s p o ns or will re gist er 
t h e p ati e nt a n d assi g n t h e s u bj ect n u m b er.  
T h e s p o ns or will i m me di at el y f a x t h e re gistrati o n c o nfir mati o n f or m t o get her wit h t h e 
r es ult of t he eli gi bility assess me nt t o t h e i n vesti gat or; t h e c o nfir mati o n f or m s h o ul d 
i n cl u d e t h e d at e of r e gistr ati o n, s u bj ect n u m b er, a n d d os e of t h e st u d y dr u g f or p ati e nt s 
ass ess e d t o b e eli gi bl e, a n d t h e f act t h at t h e p ati e nt  is n ot eli gi bl e a n d t he reas o n f or it f or 
pati e n ts ass ess e d t o b e i n eli gi bl e.    T h e i n vesti gat or or s u bi n vesti gat or will e x pl ai n t h e 
r eas o n f or i n eli gi bilit y t o p ati e nt s ass ess e d t o b e i neli gi bl e b y t h e s p o ns or. 
 
A d d ress f o r s e n di n g t h e s u bject re gistr ati o n f or m  
(t h e s p o ns o r’s a d d ress) 
Wor ki n g h o urs: M o n d a y t o Fri d a y, 9: 0 0 t o 1 7: 3 0   
( cl os e d o n Sat ur d a y s, S u n d a ys, a n d p u bli c h oli d a ys) 
F A X : 
 
T E L : 
 
 
T h e i n vesti gat or or s u bi n vesti gat or ma y n ot dis p e ns e t h e st u d y dr u g t o a p atie nt  u ntil t h e 
pati e nt is r e gist er e d. 
If a n y p ati e nt  pr o vi des i nf or me d c o ns e nt b ut is n ot re gist ere d, t h e i n vesti gat or or 
s u bi n vesti gat or will d escri b e t h e r eas o n w h y t h e p atie nt  is n ot re gist ere d i n t h e me di cal 
r ec or d.   T h e  p ati e nt  will n ot b e i ncl u d e d i n t h e n u m b er of p ati e nt s e nr oll e d i n t h e st u d y. 
E ve n if a p a ti e nt is c o nsi der e d i n eli gi bl e b y t h e i n vesti gat or or s u bi n vesti gat or at t h e ti me 
of eli gi bilit y c h ec k aft er pr o vi di n g i nf or me d c o ns e nt, a n d t h e s u bj ect re gistrati o n f or m of 
t h e p ati e nt is n ot f a xe d t o t h e s p o ns or, if t h e i n vesti gat or or s u bi n vesti gat or l at er c o nfir ms 
t h at t h e p ati e nt  meets t h e eli gi bilit y crit eri a, t h e i n vesti gat or or s u bi n vesti gat or ma y a gai n 
o bt ai n c o ns e nt f or parti ci pati o n i n t h e st u d y fr o m t h e p ati e nt  a n d fa x t h e s u bj ect 
r e gistr ati o n f or m t o t he s p o ns or. 
 
P P D
P P D

 
 
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Fi g ur e 4. 1- 1   P ati e nt Re gistrati o n Pr o ce d ure  
 
 
4. 1. 3. 2  
N otif yi n g A n y Ot h er P h ysi ci a ns Tre ati n g P ati e nts of T h ei r St u d y 
P a rti ci p ati o n  
T h e i n vesti gat or or s u bi n vesti gat or will as k p ati e nt s w h o h a ve pr o vi d e d i nf or me d c o ns e nt 
w h et h er t h e y ar e b ei n g tr eat e d b y a n ot her p h ysi ci a n (e g, a p h ysi ci a n i n a n ot h er 
de p art me nt of t h e st u d y ce nt er or at a n ot h er me di cal i nstit uti o n) or n ot.    If t h e p ati e nt  is 
r ecei vi n g tr eat me nt b y a n ot h er p h ysi ci a n, t h e i n v esti gat or or s u bi n vesti gat or will i nf or m 
t h e p h ysi ci a n of t he pati e nt’ s p arti ci p ati o n i n t h e st u d y wit h t h e p ati e nt’ s a p pr o val a n d 
r ec or d t h e i nf or mati o n i n t h e me di cal rec or d. 
 
4. 2  
S u bj ect Wit h d r a w al C rit eri a a n d Pr o ce d u res  
If a p ati e nt  meets t h e crit eri a s p ecifi e d i n “5. 6  Wit h dra wal Crit eri a , ” t h e i n vesti gat or or 
s u bi n vesti gat or will wit h dr a w t h e p ati e nt  fr o m st u d y treat me nt a n d p erf or m t h e 
e xa mi nati o ns a n d ass ess me nts acc or di n g t o “6. 4  At t h e Ti me of Wit h dra wal fr o m t h e 
St u d y . ”  T h e i n vesti gat or or s u bi n vesti gat or will rec or d t h e d at e of wit h dra wal, reas o n 
f or wit h dr a wal, a n d e xa mi n ati o n/ ass ess me nt res ults i n t h e case re p ort f or m ( C R F).  
 
O bt ai n  c o ns e nt . 
Assi g n t h e s u bj e ct i d e ntific ati o n c o d e.  
C h e c k eli gi bilit y.  
( F or eli gi bl e p atie nt s) C o m pl et e t h e 
s u bj e ct r e gistr ati o n f or m. 
Se n d t h e s u bj e ct r e gistrati o n f or m.  
Re c ei v e t h e s u bj e ct r e gistrati o n f or m.  
Ass ess e li gi bilit y. 
( F or eli gi bl e p atie nt s) Assi g n t h e s u bj e ct 
n u m b er.  
C o m pl et e t h e r e gistr ati o n c o nfir mati o n f or m.  
Se n d t h e r e gis tr ati o n c o nfir mati o n f or m. 
Re c ei ve t h e r e gistr ati o n c o nfir mati o n f or m.  
F or eli gi ble p atie nt s, start t h e st u d y treat me nt. 
St u d y ce nt er  
S p o ns o r  
F A X  
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5.  
M E T H O D O L O G Y  
5. 1  
St u d y D r u g  
F or t h e d et ails of t h e st u d y dr u g a n d its h a n dli n g, s ee t h e “I n vesti gat or’s Br o c h ure” a n d 
“ St u d y Dr u g M a n a ge me nt Pr o ce d ures. ”  
1)  I n vesti gati o n al s u bst a n ce c o d e: A C 2 2 0  
2)  Ge n eri c n a me (r-I N N): 
Q uizarti ni b  
3)  C o nt e nt a n d d os a ge f or m:  
W hit e fil m -c o at e d t a bl ets, eac h of w hi c h c o nt ai ns 
2 0 m g A C 0 1 0 2 2 0 ·H Cl . 
4)  L ot n u m b er:  
L ot n u m b ers are list e d i n t h e “ St u d y Dr u g 
Ma n a ge me nt Pr o ce d ures.”  
 
5. 1. 1  
L a b eli n g a n d P a c k a gi n g  
T h e p ac ka gi n g f or m a n d i nf or mati o n dis pla ye d o n t h e l a bel of t h e st u d y dr u g will b e 
pr o vi d e d i n  t h e “ St u d y Dr u g M a n a ge me nt Pr o ce d ures. ” 
T hirt y st u d y dr u g t a blets ar e p ac ka ge d i n a pl asti c b ottle (f or 1 p ati e nt ). 
T h e i nf or mati o n dis pl a ye d o n t h e l a bel is s h o w n i n “Ta bl e 5. 1 - 1 I nf or mati o n Dis pl a ye d 
o n t h e St u d y Dr u g La b el .” 
 
Ta bl e 5. 1 - 1  I nf or mati o n Dis pl a ye d o n t h e St u d y Dr u g La b el  
Stat e me nt, “F or cli nic al st u d y ”  
N a me of t h e st u d y dr u g  
P r ot o c ol nu m b er  
L ot n u m b er of t h e st u d y dr u g  
St or a ge c o n diti o ns  
Stat e me nt, “D o n ot dis c ar d b ut st ore a n y u n use d st u d y dr u g t a blets; t h e y will b e c oll e ct e d l ater. ”  
N a me of t h e s p o ns or  
A d dr ess of t h e s p o ns or  
 
5. 1. 2  
St o r a g e of t he St u d y D r u g  
Aft er c o n cl u di n g t h e cli nical st u d y c o ntract wit h t he st u d y ce nter, t h e s p o ns or will 
distri b ut e t h e st u d y dr u g t o t h e st u d y ce nt er.   T h e st u d y dr u g ma n a ger will st ore a n d 
ma n a ge t h e st u d y dr u g at ≤ 2 5° C wit h o ut freezi n g.    T h e st u d y dr u g will b e ma n a ge d a n d 
r etri e ve d i n acc or d a n ce wit h t h e “ St u d y Dr u g M a n a ge me nt Pr o ce d ures. ” 
 
5. 2  
C o a d mi nist ere d  D r u g s (C yt a r a bi ne a n d A nt h r ac y cli n e  D r u gs)  
I n t his st u d y, c yt ar a bi n e a n d a nt hr ac ycli n e dr u gs ( d a u n or u bi ci n or i d ar u bi ci n) will b e 
us e d as c o a d mi nist er e d  dr u gs.    F or t h e d et ails a n d ha n dli n g of c o a d mi nist ere d  dr u gs, 

 
 
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r efer t o t h e p ac ka ge i nsert  ( Pr ot o c ol Att ac h me nt), et c.  
 
5. 2. 1  
C yt a r a bi n e  
1)  C o nt e nt a n d d os a ge f or m:  A cl ear c ol orless a q u e o us s ol uti o n f or i nj ecti o n ( C yl o ci d e 
I nj ecti o n: p H 7. 5  t o 9. 0; C yl o ci d e N I nj ecti o n: p H 8. 0  t o 
9. 3 ).    T h e c o nt e nt is s h o w n b el o w. 
 
S pe cifi c ati o n  
C o nt e nt  
1 m L  a m p o ul e  
2 0  m g of c yt ar a bi n e a n d 9  m g of s o di u m c hl ori d e  
2  m L  a m p o ul e  
4 0  m g  of c yt ar a bi n e a n d 1 8  m g  of s o di u m c hl ori d e  
3  m L  a m p o ul e  
6 0  m g  of c yt ar a bi n e a n d 2 7  m g  of s o di u m c hl ori d e  
5  m L  a m p o ul e  
1 0 0  m g  of c yt ar a bi n e a n d  4 5  m g  of s o di u m c hl ori d e  
1 0  m L  a m p o ul e  
2 0 0  m g  of c yt ar a bi n e a n d 9 0  m g  of s o di u m c hl ori d e  
2 0  m L  a m p o ul e  
4 0 0  m g  of c yt ar a bi n e a n d 1 8 0  m g  of s o di u m c hl ori d e  
5 0  m L  vi al  
1  g  of c yt ar a bi n e a n d 4 5 0  m g  of s o di u m c hl ori d e  
* S o di u m c hl ori d e is a n i n a cti ve i n gr e di e nt.  
 
5. 2. 2  
D a u n o r u bi ci n  
1)  C o nt e nt a n d d os a ge f or m:  Re d l y o p hilize d f or m ul ati o n ( p H  5. 0  t o 6. 5 ) t h at c o nt ai ns 
2 0 m g of d a u n or u bi ci n h y dr o c hl ori d e a n d 1 0 0  m g of 
D- M a n nit ol as a n i n acti v e i n gre di e nt p er vi al.  
 
5. 2. 3  
I d a r u bi ci n 
1)  C o nt e nt a n d d os a ge f or m:  Ye l l o w -re d l y o p hilize d f or m ulati o n (p H 5. 0  t o 7. 0 ) t h at 
c o nt ai ns 5 m g of i d ar u bi ci n h y dr o c hl ori d e a n d 5 0  m g  of 
lact os e h y drat e as a n i n acti ve i n gre di e nt p er vi al.  
 
5. 3  
Tre at me nt Met h o d of t he St u d y D r u g a n d C o a d mi nistere d  D r u gs ( C yt ar a bi ne 
a n d A nt h r a c ycli n e  D r u gs)  
5. 3. 1  
D os e a n d R e g i me n 
Q uizarti ni b  will b e or all y a d mi nist er e d  at t h e d os e list e d b el o w o n ce d ail y e ver y m or ni n g 
u n der f asti n g c o n diti o ns ( at l east 1 h o ur bef ore or at l east 2 h o urs aft er brea kfast ). 
 
Ta bl e 5. 3 - 1  Q ui zarti ni b  D os e  
Le v el  
D os e  
1  
2 0  m g  
2  
4 0  m g  
 
If a p ati e nt v o mits aft er t a ki n g a d os e of q ui zarti ni b , a re pl ace me nt d os e ma y  n ot b e gi ve n 
o n t h e s a me da y.    A p ati e nt  w h o di d n ot t a ke q ui zarti ni b  at t h e us u al h o ur of d osi n g (e g, 

 
 
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f or g ot t o t a ke t h e d os e) will b e all o we d t o t a ke t he miss e d d os e at l east 1 h o ur b ef ore or 
at l east 2 h o urs aft er a m eal wit hi n a b o ut 1 0 h o urs aft er t h e us u al h o ur of d osi n g (f or 
e xa m ple, if t h e p ati e nt  us uall y t a kes t h e dr u g at 7: 0 0 or 8: 0 0, h e/s h e ma y t a ke it u ntil 
ar o u n d 1 8: 0 0).   A p ati e nt  w h o di d  n ot t a ke t he misse d d os e wit hi n a b o ut 1 0 h o urs aft er 
t h e us u al h o ur of d osi n g s h o ul d n ot t a ke q ui zarti ni b o n t h at d a y, a n d res u m e t a ki n g 
q ui zarti ni b o n t h e f oll o wi n g d a y.   T h e p ati e nt  ma y n ot t a ke t w o d os es at o n ce o n t h e d a y 
w h e n t h e dr u g is res u m e d. 
 
Re missi o n i n d u cti o n t h er a p y a n d c o ns oli d ati o n t h era p y will b e gi ve n f or u p t o 2 c ycl es 
a n d 4 c ycl es, r es p ecti vel y, eac h of w hi c h is 2 8 d a ys l o n g. 
 
R e missi o n I n d u cti o n T her a p y  
* 
As  a n a nt hr ac ycli n e  dr u g, eit h er d a u n or u bi ci n or i dar u bi ci n will b e c h ose n, a n d t h e 
sa me dr u g will b e us e d i n C ycl e 1 a n d C ycl e 2. 
C ycl e 1 ( “ 7 + 3 ”)  
• 
C yt ar a bi n e : 
C yt ar a bi n e, w hi c h is dil ute d wit h 5 % gl u c os e s ol uti o n or 5 % 
n or mal s ali n e t o ma ke a t ot al v ol u me of 2 5 0  m L  t o 5 0 0  m L , will b e 
a d mi nist er e d at a d ail y d os e of 1 0 0  m g/ m2 by 2 4 -h o ur c o nti n u o us 
i ntr a ve n o us i nf usi o n f or 7 c o ns ec uti ve d a ys o n D a y 1 t o Da y 7. 
• 
Da u n or u bi ci n:  
Da u n or u bi ci n , w hi c h is diss ol ve d i n 1 0 m L of J a pa n es e 
P har mac o p o ei a (J P) st erile wat er f or i nj ecti o n p er vi al, will b e 
a d mi nist er e d at a d ail y d os e of 6 0 m g/ m 2 b y i ntra ve n o us i nf usi o n 
o ver a p eri o d of 3 0 t o 6 0 mi n utes o n Da y 1 t o Da y 3.  
• 
I d ar u bi ci n: 
I d ar u bi ci n, w hi c h is diss ol ve d i n 5  m L of J P steril e wat er f or 
i nj ecti o n p er vi al, will b e a d mi nist ere d at a d ail y d os e of 1 2 m g/ m 2 
b y i ntra ve n o us i nf usi o n o ver a p eri o d of 3 0 t o 6 0 mi n utes o n Da y 1 
t o Da y 3.  
• 
Q uizarti ni b:  
Aft er t h e e n d of c yt ara bi ne a d mi nistrati o n , q ui zarti ni b will b e 
or all y a d mi nist ere d  at a d ose of 2 0  m g or 4 0  m g o n ce d ail y o n Da y 
8 t o Da y 2 1.  
C ycl e 2  
* 
T h e tr eat me nt will b e a d mi nist ere d  usi n g t h e s a m e re gi me n as i n C ycl e 1 (“ 7 + 3 ”) or 
as s h o w n b el o w ( “ 5  + 2”).  
• 
C yt ar a bi n e : 
C yt ar a bi n e, w hi c h is dil ute d wit h 5 % gl u c os e s ol uti o n or 5 % 
n or mal s ali n e t o ma ke a t ot al v ol u me of 2 5 0  m L  t o 5 0 0  m L , will b e 

 
 
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a d mi nist er e d at a d ail y d os e of 1 0 0  m g/ m2 b y 2 4 - h o ur c o nti n u o us 
i ntr a ve n o us i nf usi o n f or 5  c o ns ec uti ve d a ys o n D a y 1 t o Da y 5 . 
• 
Da u n or u bi ci n:  
Da u n or u bi ci n , w hi c h is diss ol ve d i n 1 0 m L of J P st eril e wat er f or 
i nj ecti o n p er vi al, will b e a d mi nist ere d at a d ail y d os e of 6 0 m g/ m 2 
b y i ntra ve n o us i nf usi o n o ver a p eri o d of 3 0 t o 6 0 mi n utes o n Da y 1 
t o Da y 2 . 
• 
I d ar u bi ci n: 
I d ar u bi ci n, w hi c h is diss ol ve d i n 5  m L of J P steril e wat er f or 
i nj ecti o n p er vi al, will b e a d mi nist ere d at a d ail y d os e of 1 2 m g/ m 2 
b y i ntra ve n o us i nf usi o n o ver a p eri o d of 3 0 t o 6 0 mi n utes o n Da y 1 
t o Da y 2 . 
• 
Q uizarti ni b:  
Aft er t h e e n d of c yt ara bi ne a d mi nistrati o n , q ui zarti ni b will b e 
or all y a d mi nist ere d  at a d ose of 2 0  m g or 4 0  m g o n ce d ail y o n Da y 
6 t o Da y 1 9 . 
 
C o ns oli d ati o n T h er a p y  
• 
C yt ar a bi n e : 
C yt ar a bi n e, w hi c h is dil ute d wit h 5 % gl u c os e s ol uti o n or  5 % 
n or mal s ali n e t o ma ke a t ot al v ol u me of 3 0 0  m L  t o 5 0 0  m L , will b e 
a d mi nist er e d at a d os e of 3. 0 g/ m 2 f or p ati e nts of <  6 0 years ol d or 
1. 5  g/ m2 f or p ati e nts of ≥ 6 0 years ol d (a ge at t h e ti me of 
r e gistr ati o n i n t h e st u d y) b y i ntra ve n o us i nf usi o n o ver a p eri o d of 3 
h o urs a t ot al of 6 ti mes e ver y 1 2 h o urs o n Da y 1, Da y 3, a n d Da y 5.  
• 
Q uizarti ni b:  
Aft er t h e e n d of t h e 6t h d ose of c yt ara bi n e, q ui zarti ni b will b e 
or all y a d mi nist ere d  at a d ose of 2 0  m g or 4 0  m g o n Da y 6 t o Da y 
1 9. 
 

 
 
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pr ol o n gati o n was s ee n i n 1 of 1 7 pati e nt s o n c o nti n u o us d osi n g at 2 0 0 m g/ da y a n d i n 3 of 
8 pati e nt s o n c o nti n u o us d osi n g at 3 0 0 m g / d a y. 
 
5. 3. 3  
E mer g e n c y Pr o ce d u res  a n d M a n a ge me nt  i n t h e E v e nt of C yt a r a bi n e a n d 
A nt h r a c y cli n e  O v er d os es  
I n t h e e ve nt of o ver d os e of c yt ar a bi n e or a n a nt hrac ycli n e dr u g, t h e i n vesti gat or or 
s u bi n vesti gat or s h o ul d i m me di at el y ass ess t h e p ati e nt’ s c o n diti o n, a n d if a n y s y m pt o ms 
ar e f o u n d, i m me di at el y pr o vi d e a p pr o pri at e i nt er ve nti o n a n d s u p p orti ve t h era p y.   T h e 
i n vesti gat or a n d s p o ns or will dis c uss a n d d eci d e w h et h er t h e p ati e nt  ma y c o nti n u e st u d y 
parti ci p ati o n or n ot, t a ki n g t h e st at us of o ver d ose a n d t h e s u bs e q u e nt c o urse of t h e pati e nt 
i nt o c o nsi d er ati o n. 
 
5. 3. 4  
R a n d o mi z ati o n a n d Bli n di n g  
Neit h er r a n d o mi zati o n or bli n di n g will b e us e d i n t h e st u d y.  
 
5. 4  
Ass ess me nt  of D os e -li miti n g To xi cit y 
5. 4. 1  
D efi niti o n of D os e -li miti n g To xi citi es 
T h e D L T  ass ess me nt  p eri o d is fr o m t h e st art d a y of q ui zarti ni b  a d mi nistrati o n  i n C ycl e 1 
of r e missi o n i n d u cti o n t h er a p y t o t h e prece di n g d a y of Da y 1 of C ycl e 1 of  c o ns oli d ati o n 
t h era p y (i n d u cti o n p h as e), a n d a D L T is d efi n e d as a n y t o xi city a m o n g A E s t h at o cc ur 
d uri n g t h e a b o ve peri o d t hat ar e ass ess e d t o b e “relate d ” t o q ui zarti ni b , as list e d bel o w.   
T h e s e verit y gr a d e will b e ass ess e d acc or di n g t o t he C o m m o n Ter mi n ol o g y Crit eri a f or 
A d vers e E ve nts ( C T C A E) v 4. 0 J a p a n es e versi o n.  
• 
≥ Gr a d e 3 n o n -h e mat ol o gi cal t o xi citi es ( e xce pt f or t h e f oll o wi n g ) 
• 
Al o p ec i a, an or e xi a , a n d f ati g u e 
• 
G r a d e 3 q ueas y, v o miti n g, or  di arr h ea  t h at h a s i m pr o ve d t o ≤ Gra d e 2 wit hi n 7 
da ys aft er t h e o ns et aft er tr eat me nt wit h a nti e meti c or a nti di arr h eal dr u gs  
• 
G r a d e 3 m u c ositis t h at  h a s i m pr o ve d t o ≤ Gra d e 2 wit hi n 7 d a ys aft er t h e o ns et  
• 
G r a d e 3 i nf ecti o ns 
• 
Fe bril e n e utr o p e ni a  
• 
He mat ol o gi cal t o xi citi es t h at h a ve n ot res ol ve d b ef ore Da y 1 of C ycl e 1 of 
c o ns oli d ati o n t h er a p y, as list e d b el o w  
• 
P eri p h er al n e utr o p e ni a  ( < 5 0 0/ m m 3) 
• 
T hr o m b o c yt o p e ni a r es ulti n g fr o m b o ne marr o w a pl asia or h y p o pl asi a  
( < 2 0 0 0 0/ m m 3)  

 
 
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• 
≥ Gr a d e 3 t hr o m b o c yt o p e ni a ass oci at e d wit h bl ee di n g ( < 5 0  0 0 0/ m m3) 
• 
Gr a d e 4 t hr o m b o c yt o p e nia  re q uiri n g bl o o d tra nsf usi o n (< 2 5  0 0 0/ m m 3) 
 
If t h er e is a d a y w h e n q uizarti ni b ca n n ot b e t a ke n d ue t o a n y t o xicit y d uri n g t h e D L T 
ass ess me nt p eri o d, t h e i n vesti gat o r a n d t h e s p o ns or will dis c uss a n d d eci d e w h et h er t o 
ha n dl e t h e t o xi cit y as a D L T or n ot.  
 
5. 4. 2  
A ss ess me nt Met h o d  of D os e -li miti n g To xi cit y 
Q uizarti ni b  will b e a d mi nist er e d  at a d os e of 2 0  m g at Le vel 1 a n d 4 0  m g at Le vel 2.   
D os e escal ati o n wit hi n a si n gl e p ati e nt  is n ot all o we d.    F or t h e d ose of c yt ara bi n e a n d 
t h e a nt hr ac ycli n e dr u g us e d f or re missi o n i n d u cti o n t h era p y, refer t o Secti o n “ 5. 3. 1  D os e 
a n d Re gi me n . ” 
D L T ass ess me n t at eac h le vel will first b e c o n d u cte d i n 3 p ati e nt s (i n cl u di n g at l east 1 
pati e nt of  < 6 0 years ol d at t h e ti me of re gistrati o n i n t h e st u d y).   D L T assess me nt  f or 
eac h p ati e nt  will b asicall y b e c o n d u ct e d aft er t h e e n d of t h e D L T ass ess me nt  p eri o d  f or 
t he p ati e nt ; h o we ver, if b ot h t h e i n vesti gat or a n d t he s p o ns or d eci de it n ecess ar y t o 
ter mi n at e t h e p ati e nt’s p arti ci p ati o n i n t he st u d y, e g, ≥ Gra de  3 n o n-h e mat ol o gi cal 
t o xi cit y o cc urs d uri n g t h e D L T ass ess me nt  p eri o d a n d is ass ess e d t o b e “relate d ” t o 
q ui zarti ni b , a n d pr e mat ur e ter mi n ati o n of t h e st u d y is c o nsi d ere d n ecess ar y t o e ns ure t h e 
pati e nt ’s saf et y, it is all o we d t o ass ess D L Ts bef ore t h e e n d of t h e D L T ass ess me nt  p eri o d.  
If D L T s d o n ot o cc ur i n t he first 3 p ati e nt s at Le v el 1, t h e treat me nt will pr o cee d t o Le vel 
2.   If D L T s o cc u r i n t he first 3 p ati e nt s at Le vel 1, a n a d diti o n al 3 p ati e nt s will b e 
e nr oll e d at Le vel 1 or q uizarti ni b  d os e es cal ati o n will b e dis c o nti n u e d i n acc or d a n ce wit h  
“ Ta bl e 5. 4 - 1 Crit eri a f or Pr ocee di n g t o Le vel 2 .”    If t he treat me nt pr o cee ds t o Le vel 2, 
t h e M T D will b e d eter mi ne d i n acc or d a n ce wit h  “Ta bl e 5. 4 - 2 Crit eri a f or Ass essi n g 
Ma xi m u m Toler ate d D os es ( M T Ds) at Le vel 2 . ” 
 
Ta bl e 5. 4 - 1  Criteria f or P r o cee di n g t o Le vel 2 
I nci d e nc e of D L Ts i n t h e first 3 p atie nt s at Le v el 1, 
a n d t he de cisi o n  
I n ci d e n c e of D L Ts w h e n 3 p ati e nt s are a d diti o n all y e nr oll e d 
at Le v el 1 ( a t ot al of 6 p ati e nt s), a n d t h e d e cisi o n  
0  of 3  p ati e nt s: Pr o c e e d t o Le v el 2 . 
—  
1 of 3 p at i e nts: A d diti o n all y e nr oll 3 p ati e nt s at Le v el 
1. 
1 of 6 p ati e nt s or 2 of 6 p ati e nt s: Pr o ce e d t o Le v el 2 . 
3 of 6 p ati e nt s or 4 of 6 p ati e nt s: St o p i n cr e asi n g t h e d ose of 
q uiz arti ni b (st u d y t er mi n ati o n) . 
2  of 3  p ati e nt s or 3  of 3  p ati e nt s: St o p i n cr e asi n g t h e 
d os e of q ui z arti ni b (st u d y t er mi n ati o n) . 
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Ta bl e 5. 4 - 2  Criteria f or Ass essi n g M a xi m u m Tolerat e d D os es ( M T Ds) at Le vel 2  
I nci d e nc e of D L Ts i n t h e first 3 p atie nt s at Le v el 2, 
a n d t he de cisi o n  
I n ci d e n c e of D L Ts w h e n 3 p ati e nt s are a d diti o n all y e nr oll e d 
at Le v el 2 ( a t ot al of 6 p ati e nt s), a n d t h e d e cisi o n  
0  of 3 p ati e nt s: Ter mi n at e t h e st u d y ( M T D: 4 0  m g) . 
—  
1 of 3 p ati e nt s: A d diti o n all y e nr oll 3 p ati e nt s at Le v el 
2. 
1 of 6 p ati e nt s or 2 of 6 p ati e nt s: Te r mi n at e t h e st u d y ( M T D: 
4 0 m g). 
3 of 6 p ati e nt s or 4 of 6 p ati e nt s: Ter mi n at e t h e st u d y ( M T D: 
2 0  m g ). 
2  of 3  p ati e nt s or 3  of 3  p ati e nt s: Ter mi n at e t h e st u d y 
( M T D: 2 0  m g ). 
— 
 
If a n y of t h e crit eri a pr o vi d e d i n “5. 4. 4  E nr oll me nt of A d diti o n al P ati e nts ” is met at Le vel 
1 a n d a n y p ati e nt  is e xcl u d e d fr o m D L T ass ess me nt , i nf or mati o n o n A E s occ urri n g i n t h e 
c o n cer n e d p ati e nt , et c. s h o ul d b e t a ke n i nt o c o nsi derati o n t o assess  w h et h er t o pr ocee d t o 
Le vel 2 or n ot.  
W het h er it is n ecess ar y or n ot t o est a blis h a n e w l e vel, i n a d diti o n t o Le vel 1 a n d Le vel 2, 
will b e d et er mi n e d t hr o u g h dis c ussi o n b et wee n t h e i n vesti gat or a n d t h e s p o ns or.   T h e 
me di cal e x p ert  will b e c o ns ult e d  as n eed e d. 
 
5. 4. 3  
D et er mi n ati o n of M a xi m u m Tol er ate d D os es  
T h e M T D will b e d et er mi n e d i n acc or d a n ce wit h  t he ass ess me nt  criteria gi ve n i n Ta bl e 
5. 4 - 2. 
 
5. 4. 4  
E n r oll me nt of A d diti o n al P ati e nt s 
If a n y of t h e f oll o wi n g a p pl y, t h e n ee d t o e nr oll a d diti o n al p ati e nts at t h e l e vel or n ot will 
be d et er mi n e d t hr o u g h disc ussi o n b et wee n t h e i n v esti gat or a n d t h e s p o ns or.   T h e 
me di cal e x p ert  will b e c o ns ult e d  as n ee d e d.    If e nr oll me nt of a d diti o n al pati e nt s is 
det er mi n e d, t h e p ati e nt s meeti n g a n y of t he f oll o wi n g will b e e xcl u de d fr o m D L T 
ass ess me nt . 
• 
A p ati e nt is f o u n d t o b e i neli gi bl e aft er re gistrati o n.  
• 
A p ati e nt h as t a ke n q ui zarti ni b  f or t h e f oll o wi n g n u m b er of d a ys d uri n g t h e D L T 
ass ess me nt  p eri o d.  
• 
T h e n u m b er of d a ys of q ui zarti ni b a d mi nistrat i o n is ≤ 9 f or p atie nt s w h o h a ve 
c o m pl et e d r e missi o n i n d ucti o n t h era p y i n C ycl e 1  
• 
T h e n u m b er of d a ys of q ui zarti ni b a d mi nistrati o n  is ≤ 9 b ot h i n C ycl e 1 a n d 
C ycl e 2 f or p ati e nt s w h o ha ve pr o cee de d t o re missi o n i n d u cti o n t h era p y i n C ycl e 
2. 
• 
A p ati e nt t a kes q ui zar ti ni b at a hi g h er d os e at o n ce t h a n t h e d os e gi ve n at t he 
parti ci p ati n g l e vel d uri n g t h e D L T ass ess me nt  peri o d. 

 
 
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• 
T h e i n vesti gat or or t h e s p o ns or c o nsi d ers  it diffi c ult t o ass ess D L Ts i n a p atie nt 
beca us e s o me pr o ce d ur es d uri n g t h e D L T ass ess me nt  p eri o d h a ve  n ot b ee n 
perf or me d a p pr o pri at el y.  
• 
A p ati e nt is wit h dr a w n fr o m t h e st u d y b eca us e t h e p ati e nt meets t h e crit eri a s p ecifi e d 
i n “5. 6  Wit h dr a wal Crit eri a ” d uri n g t h e D L T ass ess me nt p eri o d (e xce pt i n cas e t he 
st u d y is t er mi n ate d d u e t o D L Ts). 
• 
E nr oll me nt of a d diti o nal pati e nts is ot h er wis e c o nsi d ere d necess ar y f or s afet y 
e val u ati o n. 
 
5. 5  
C rit eri a f o r Te m p o r a r y Dis c o nti n u ati o n, D os e R e d u cti o n, a n d R es u m pti o n of 
Q ui z a rti ni b  
• 
W he n t h e n ee d aris es t o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val 
or str o n g C Y P 3 A 4 i n hi bit ors b y n ecessit y d uri n g t he q ui zarti ni b  treat me nt peri o d: 
Q uizarti ni b  a d mi nistr ati o n s h o ul d b e t e m p oraril y dis c o nti n u e d fr o m t h e st art t o t h e 
e n d of us e of t h e a b o ve - me nti o n e d dr u gs.    O n t he d a y w h e n t he q ui zarti ni b is 
r es u me d aft er i nt err u pti o n, vit al si g n meas ure me nt , 1 2-l ea d E C G, a n d l a b orat or y t ests 
will b e p erf or me d b ef ore t h e start of q ui zarti ni b a d mi nistrati o n (refer t o “6. 2  
Re missi o n I n d u cti o n T h er a p y ” a n d “6. 3  C o ns oli d ati o n T h era p y ”) . 
• 
W he n ≥ Gr a d e 3 Q Tc F pr ol o n gati o n  o cc urs i n a p atie nt  at Le vel 2:  
Q uizarti ni b  a d mi nistr ati o n  s h o ul d b e t e m p oraril y dis c o nti n u e d  fr o m t h e o nset ti me of 
t h e a b o ve e ve nt. 
If t h e i n cr eas e i n Q Tc F r ec o vers t o ≤ 3 0  ms , c o m pare d wit h t he val u e at re gistrati o n, 
wit hi n 1 4 d a ys aft er t h e o nset, q ui zarti ni b a d mi nistrati o n will b e res u me d at a d os e 
r e d u ce d t o 2 0 m g/ d a y . 
If t h e i n cr eas e i n Q Tc F d oes n ot rec o ver t o ≤ 3 0  ms , c o m p are d wit h t h e val u e at 
r e gistr ati o n, wit hi n 1 4 d a ys after t h e o ns et, t h e st u d y f or t h e rel e va nt p atie nt will be 
dis c o nti n u e d . 
* 
If ≥ Gr a d e 3 Q Tc F pr ol o n gati o n  o cc urs i n a p ati e nt  at Le vel 1, t h e st u d y f or t h e 
pati e nt s h o ul d b e dis c o nti n u e d (refer t o “5. 6  Wit h dra wal Crit eri a ”). 
• 
W he n a D L T o cc urs (i n cl u di n g cas es i n w hi c h it t a kes ti me t o ass ess t h e ca us alit y 
wit h q ui zarti ni b, c yt ar a bi ne , or t h e a nt hrac ycli n e  dr u g b ut t h e t o xi cit y ca n p ot e nti all y 
be ass o ciat e d wit h q uizarti ni b ): 
If Gr a d e 3 n o n- h e mat ol o gi cal t o xi cit y  (e xcept Q Tc F  pr ol o n gati o n) o cc urs d uri n g t h e 
i n d u cti o n p h as e a n d it is ass ess e d t o b e “rel at e d” t o q ui zarti ni b, q ui zarti ni b 
a d mi nistr ati o n  will b e t e m p or aril y dis c o nti n ue d fr o m t h e o ns et ti me of t h e e ve nt.    If 

 
 
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t h e e ve nt r es ol ves t o Gr a de 1 wit hi n 2 8 d a ys aft er t h e o ns et of t h e e ve nt a n d t h e 
i n vesti gat or or s u bi n vesti gat or d eci d es it p ossi bl e t o res u me q ui zarti ni b 
a d mi nistr ati o n , q uizarti ni b  a d mi nistrati o n  will b e res u me d.  
If a Gr a d e 4 n o n- h e mat ol o gi cal t o xi cit y  (e xce pt Q Tc F  pr ol o n gati o n) o cc urs d uri n g 
t h e i n d u cti o n p h as e, t he st u d y f or t h e rel e va nt p atie nt will b e dis c o nti n u e d . 
 
O n ce t h e d os e of q ui zarti ni b is r e d u ce d, t h e d os e s h o ul d n ot b e i n creas e d a gai n t o t h e 
ori gi n al d os e. 
 
5. 6  
Wit h d r a w al C rit eri a  
T h e s t u d y tr eat me nt m ust b e wit h dr a w n f or a n y of t h e f oll o wi n g r eas o ns:  
1)  O vert dis eas e pr o gr essi o n  
2)  I nt oler a bl e A Es i n cl u di n g t h e f oll o wi n g: 
• 
Gr a d e 4 n o n -h e mat ol o gi cal t o xi cit y f or w hi c h t h e relati o ns hi p t o t h e st u d y dr u g 
is ass ess e d as “r el at e d” 
• 
( F or p ati e nt s at Le vel 1) Gr a d e 3 or hi g h er Q Tc F pr ol o n gati o n o r D L T  
• 
( F or p a ti e nts at Le vel 2) A n y A E t hat d o es n ot l ea d t o a sit u ati o n all o wi n g t h e 
r es u m pti o n of st u d y tr eat me nt, as s p ecifi e d i n “5. 5  Crit eri a f or Te m p orar y 
Disc o nti n u ati o n, D ose Re d u cti o n, a n d Res u m pti o n of Q uizarti ni b . ” 
3)  T h e n ee d of t h e s ec o n d d os e r e d u cti o n i n p ati e nts wit h a d os e re d u cti o n of t h e st u d y 
dr u g 
4)  Ac hi e ve me nt of C R,  C R p,  or C Ri  i n C ycl e 2 or l at er of c o ns oli d ati o n t h era p y, 
lea di n g t o t h e d ecisi o n of t h e i n vesti gat or or s u bi n vesti gat or t o i ntr o d u ce H S C T  
5)  P ati e nt ’s wit h dr a wal of c o nse nt f or st u d y p arti ci p ati o n 
6)  I n eli gi bilit y f o u n d aft er r e gistr ati o n i n t h e st u d y 
7)  P ati e nt  f o u n d t o b e pr e g na n t aft er re gistrati o n i n t his st u d y  
8)  P o or p ati e nt c o m pli a n ce wit h st u d y pr o ce d ures, i nc l u di n g fail ure t o visit t he st u d y 
ce nt er as s c h e d ul e d i n t h e pr ot o c ol  
9)  Ot her cir c u mst a n ces w h y t h e st u d y ca n n ot b e c o nti n u e d i n t h e i n vesti gat or ’s or 
s u bi n vesti gat or’s o pi ni o n 
 
5. 7  
Pr o hi bite d C o nc o mit a nt D r u gs a n d T her a pi es, R estri cte d C o n c o mit a nt D r u gs, 
a n d D r u gs t o B e Co a d mi nist ere d wit h C a re  
Pr o hi bit e d c o n c o mit a nt dr u gs a n d t h era pi es:  
C o n c o mit a nt us e of t h e f oll o wi n g dr u gs , et c. is pr o hi bite d d uri n g t h e q ui zarti ni b  

 
 
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tr eat me nt p eri o d.  
As a n e xce pti o n, t h e dr u gs list e d i n 1) a n d 2) ma y b e us e d o nl y w h e n t h e i n ve sti gat or or 
s u bi n vesti gat or c o nsi d ers t h at t h es e dr u gs are me di call y ess e nti al t o pre ve nt or treat 
i nf ecti o n.    I n t his cas e, or al tr eat me nt wit h q ui zarti ni b s h o ul d b e i nt err u pt e d fr o m t h e 
st art t o t he e n d of us e of t h e dr u gs list e d i n 1) a n d 2), a n d b e resu me d o n t he f oll o wi n g 
da y of t h e e n d of us e of t he dr u gs.    At t h e ti me of res u m pti o n, n o d os e re d u cti o n of 
q ui zarti ni b will b e n ecessar y u nl ess t h e i n vesti gat or or s u bi n vesti gat or c o nsi d ers it 
necess ar y.  
1)  Dr u gs t h at ma y p ot e nti all y pr ol o n g t he Q T/ Q Tc i nt er v al  
2)  Str o n g C Y P 3 A 4 i n hi bit ors  
3)  Str o n g or m o d er at e C Y P 3 A 4 i n d u cers  
4)  Cr u d e dr u g s a n d f o o d pr o d ucts wit h C Y P 3 A 4 -i n hi biti n g or -i n d u ci n g pr o perti es (e g, 
f o o ds a n d b e ver a ges c o ntai ni n g St. J o h n’s w ort or gra p efr uit) 
5)  A nti ca n cer treat me nts ot her t h a n q ui zarti ni b (e xc e pt h y dr o x ycar b a mi de)  
6)  I n vesti gati o n al dr u gs ot h er t h a n q ui zarti ni b, a n d i n vesti gati o n al d e vi ces 
7)  D o n or l y m p h o c yt es  
 
Restri ct e d c o n c o mita nt dr u gs:  
T h e f oll o wi n g tr eat me nts s h o ul d b e restri ct e d d uri n g oral treat me nt wit h q ui zarti ni b:  
• 
Tr eat me nt wit h h y dr o x ycar b a mi d e f or  c o ntr ol of t h e  w hit e bl o o d cell c o u nt : 
Restri ct e d t o a dail y d os e of 2  g f or  u p t o a t ot al of 1 4 d a ys 
 
[ Dr u gs t o b e c o a d mi nist er e d wit h care] 
D uri n g or al tr eat me nt wit h q ui zarti ni b,  us e of s u bstrat es a n d i n hi bit ors of P- gl yc o pr ot ei n 
s h o ul d b e a v oi d e d as f ar as p ossi bl e. 
 
< R ati o n al e > 
T h es e s p ecifi cati o ns ar e pr o vi d e d f or pr o p er s afet y e val u ati o n of q ui zarti ni b.  
Q uizarti ni b a n d A C 8 8 6 ar e mai nl y met a b oli ze d b y C Y P 3 A 4.    If t h e nee d aris es t o us e 
dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nter val or str o n g C Y P 3 A 4 i n hi bit ors b y 
necessit y f or t h e pr e ve nti o n or tr eat me nt of i nfecti o n, c o n c o mit a nt us e of t hes e dr u gs 
wit h q ui zarti ni b s h o ul d b e a v oi d e d.  
I n a d diti o n, i n vitr o d at a i n di cat e t h at q ui zarti ni b is a s u bstrat e of P- gl yc o pr ot ei n  a n d t h at 
it i n hibits P- gl yc o pr ot ei n .    F or t his reas o n, c o n c o mit a nt us e of q ui zarti ni b wit h 
s u bstr at es a n d i n hi bit ors of P- gl yc o pr ot ei n s h o ul d b e a v oi d e d as far as p ossi bl e.   

 
 
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C o n c o mit a nt us e of q ui zarti ni b  wit h P -gl yc o pr ot ei n s u bstrat es ma y i n creas e t h e bl o o d 
c o n ce ntr ati o n s of t h e P -gl yc o pr ot ei n  s u bstrat es.   C o n c o mit a nt  us e  of  q ui zarti ni b  wit h 
P- gl yc o pr ot ei n i n hi bit ors ma y i n cr eas e t h e bl o o d c o n ce ntrati o n  of q ui zarti ni b a n d A C 8 8 6 . 
 
5. 8  
S y m pt o m ati c T h er a p y  
N o s p ecifi cati o ns o n s y m pt o matic t h era p y are esta blis h e d i n t he st u d y.  
 
5. 9  
M a n a g e me nt of P atie nt s 
T h e i n vesti gat or or s u bi n vesti gat or will stri ve t o e ns ure t h e ma xi m u m s afet y of p ati e nts 
t hr o u g h o ut t he st u d y p eri o d.    P ati e nts m ust b e h os pit ali ze d d uri n g t h e D L T ass ess me nt 
peri o d ( r efer t o “5. 4. 1  D efi niti o n of D os e -li miti n g To xi citi es”).    P ati e nts will b e all o we d 
t o ma ke a t e m p or ar y o ver ni g ht st a y o utsi d e t h e h os pit al d uri n g t h e h os pit alizati o n p eri o d 
if t he i n vesti gat or or s u bi n vesti gat or c o nsi ders it p ossi ble aft er caref ul e xa mi n ati o n of t h e 
pati e nt.    If a pati e nt ma kes a n o ver ni g ht st a y o utsi d e t he h os pit al, t h e st u d y st aff at t h e 
st u d y ce nter will i nstr u ct t h e p ati e nt h o w t o c o nt act t h e st u d y ce nter i n t h e e ve nt of a n 
e mer ge n c y, pri or t o ma ki n g a n o ver ni g ht st a y o utsi d e t h e h os pit al. 
If a n A E o cc urri n g  d uri n g h os pit ali zati o n d o es n ot res ol ve or is n ot reli e ve d u ntil t h e 
pl a n n e d d a y of dis c h ar ge, t h e i n vesti gat or or s u bi n vesti gat or will d eci d e t he n ee d t o 
c o nti n u e h os pit ali zati o n or n ot i n c o nsi d erati o n of p ati e nt s afet y ass ura n ce.  
 

 
 
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6.  
S T U D Y P R O C E D U R E S  
St u d y pr o ce d ur es s p ecifi e d i n t h e pr ot o c ol are s h o w n i n “Ta bl e 6- 1  a n d Ta bl e 6- 2  
Sc he d ul e of St u d y Pr o ce d ur es . ” 
I n t h e st u d y, t h e p eri o d fr o m t h e d a y of i nf or me d c o ns e nt t hr o u g h t h e e n d da y of 
p ost- tr eat me nt o bs er vati o n is d efi n e d as t h e “st u d y p eri o d” f or  eac h  p ati e nt.   H o we ver,  
if a p ati e nt h as diffi c ult y t o att e n d t h e f oll o w-u p at t h e st u d y ce nt er f or reas o ns i n cl u di n g 
tr a nsf er t o a n ot h er h os pit al or h e/s h e ref us es t o visit t h e st u d y ce nt er aft er t h e fi n al d osi n g 
of q ui zarti ni b, t h e n t h e st u d y p eri o d f or t h e p ati e nt will be t er mi n at e d o n t h e rel e va nt d a y.  
 

 
 
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Da y 1 
Da y 2 
Da y 3
Da y 5
Da y 6 
Da y 7
Da y 8
Da y 1 5
Da y 1 9 
Da y 2 1
Da y 2 8
Q ui zarti ni b
C yt ar a bi ne
Da u n or u bi ci n or i dar u bi ci n
 
 

Q ui zarti ni b
C yt ar a bi ne
Da u n or u bi ci n or i dar u bi ci n
 

a)!
5 + 2 c)
7 + 3 c)

5 + 2 
7 + 3  
e)
a)!
e)
a)!
5 + 2 
7 + 3 
5 + 2 
7 + 3  
e)
a)!
5 + 2 c)
7 + 3 c)

5 + 2 
7 + 3  
e)
a)!
5 + 2 
7 + 3  

5 + 2 
7 + 3  
e)
T he da y 
P har mac o ki neti cs
F L T3-I T D a n d c- KI T m ut ati o ns
P h os p h or yl at e d pr ot ei n l e vels i n bl o o d, i ncl u di n g F L T3
I n hi bit or y acti vit y of pl as ma q ui zarti ni b o n
p h os p h or yl at e d F L T3 pr ot ei n
Ass ess me nt of c o nc o mit a nt dr u gs a n d t her a pi es
M o nit ori n g of A Es
HI V a nti b o d y t ests
Ce ntral
m e as ure m e nt
La b or at or y t ests ( he mat ol o g y, bl o o d c he mistr y, uri nal ysis) * *
Pr e g na nc y t est
Ass ess me nt of b o ne marr o w fi n di n gs ( a ntit u m or eff e ct)
B o d y wei g ht
E C O G P S ass ess me nt
1 2-l e a d E C G * *
Bas eli ne s u bj e ct c har act eristi cs
Me di c al hist or y/ c o m pli c ati o ns
Vit al si g n me as ur e me nt * *
Ad mi nistr ati o n of t he st u d y dr u g a n d c o a d mi nist er e d dr u gs *
7
+
3
5
+
2
C ycle 2
I nf or me d c o ns e nt
Re gistr ati o n of pati e nts
 

 
 
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● Ma n d at or y, ○ To b e p erf or me d o nl y i n s el e ct e d p ati e nt s 
 
a)  Bef or e t h e st art of a d mi nistr ati o n  of c yt ara bi n e a n d t h e a nt hr a c ycli n e dr u g 
b)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, 4 h o urs ( ± 1 0 mi n ut es) p ost -d ose, a n d 6 h o urs ( ± 1 0 mi n utes) p ost -d os e  
c)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -d os e  
d)   Pre-d os e, 3 0 mi n ut es ( ± 1 0 mi n ut es) p ost -d os e, 1 h o ur ( ± 1 0 mi n ut es) p ost -d os e, 2 h o urs ( ± 1 0 mi n utes) p ost -d os e, 4 h o urs ( ± 1 0 mi n utes) p ost -d os e, a n d 6 h o urs ( ± 1 0 
mi n utes) p ost -d os e  
e)  −3 d a ys t o t h e d a y  
 
* Re missi o n i n d u cti o n t h er a p y i n C ycl e 2 will b e gi v e n usi n g t h e s a me r e gi me n as i n C ycl e 1 (“ 7 + 3 ”) or o n t h e d osi n g s c h e d ule  ( “ 5 + 2 ”) s h o w n i n t h e t a bl e. 
 
* *  If dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er v al or str o n g C Y P 3 A 4 i n hi bit ors ar e us e d aft er  t h e st art of q ui z arti ni b tr eat me nt, q ui z arti ni b tr eat me nt s h o ul d b e 
i nt err u pt e d fr o m t h e st art t o t h e e n d of us e of t h es e dr u gs. 
Aft er t h e d a y w h e n q ui z arti ni b is r es u me d, t h e f oll o wi n g pr o c e d ur es will b e p erf or me d at t h e ti me p o i nts liste d b el o w: 
 
[ 1]  Pre-d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt, 1 2 -l e a d E C G, a n d la b or at or y t ests 
[ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 3]  Pre-d os e of q ui z arti ni b o n D a y 4 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 4]  Pre-d os e of q ui z arti ni b o n D a y 8 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 5]  Pre-d os e of q ui z arti ni b o n D a y 1 1 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 6]  Pre-d os e of q ui z arti ni b o n D a y 1 5  ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
 
! If C ycl e 2 is st arte d wit hi n + 7 d a ys re c k o n e d fr o m D a y 2 8 of C ycl e 1, t h e pr o ce d ur es s c h e d ule d o n D a y 1 of C ycl e 2 ar e n ot n e c ess ar y. 
 

 
 
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● Ma n d at or y, ○ To b e p erf or me d o nl y i n s el e ct e d p ati e nt s 
 
a)   Bef or e t h e st art of c yt ar a bi n e  a d mi nistr ati o n  
b)   Pre-d os e, 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e, 4 h o urs ( ± 1 0 mi n ut es) p ost -d ose, a n d 6 h o urs ( ± 1 0 mi n utes) p ost -d os e  
c)  Pre- d os e, 2 h o urs ( ± 1 0 mi n ut es)  p ost -d os e, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -d os e  
d) 
−3 d a ys t o t h e d a y  
e)   Da y w h e n st u d y t er mi n ati o n is d e ci d e d ( −3 d a ys t o + 7 d a ys)  
f) 
2 8t h d a y ( ± 7 d a ys) r e c k o n e d fr o m t h e d a y of t h e l ast d os e of t h e st u d y dr u g 
 
* *  If dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er v al or str o n g C Y P 3 A 4 i n hi bit ors ar e us e d aft er  t h e st art of q ui z arti ni b tr eat me nt, q ui z arti ni b tr eat me nt s h o ul d b e 
i nt err u pt e d fr o m t h e st art t o t h e e n d of us e of t h es e dr u gs. 
Aft er t h e d a y w h e n q ui z arti ni b is r es u me d, t h e f oll o wi n g pr o c e d ur es  will b e p erf or me d at t h e ti me p oi nts liste d b el o w:  
 
[ 1]  Pre-d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt, 1 2 -l e a d E C G, a n d la b or at or y t ests 
[ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost -d os e of q ui z arti ni b o n t h e d a y w h e n t h e dr u g is r es u me d:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 3]  Pre-d os e of q ui z arti ni b o n D a y 4 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 4]  Pre-d os e of q ui z arti ni b o n D a y 8 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y  w h e n t h e dr u g is r es u me d as D a y 1:  
Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 5]  Pre-d os e of q ui z arti ni b o n D a y 1 1 ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
[ 6]  Pre-d os e of q ui z arti ni b o n D a y 1 5  ( ± 1 d a y ) w h e n d efi ni n g t h e d a y w h e n t h e dr u g is r es u me d as D a y 1:  Vit al si g n me as ure me nt a n d 1 2 -l e a d E C G 
 
! If t h e n e xt c ycl e is st arte d wit hi n + 7 d a ys r e c k o n e d fr o m D a y 2 8 of ea c h c ycl e, t h e pr o c e d ur es sc h e d ule d o n Da y 1 of t h e n e xt c ycl e ar e n ot n e c ess ar y. 
 
 

 
 
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6. 1  
I nf or me d C o ns e nt t o P ati e nt  R e gistr ati o n  
T h e pr o ce d ur es list e d b el o w will be perf or me d, a n d t h e res ults will b e rec or d e d i n t he 
C R F.  
F or eac h ass ess me nt it e m, d at a o bt ai n e d b ef ore i nf or me d c o ns e nt wit hi n t he all o wa ble 
ti me li mits f or eac h it e m ma y als o be us e d. 
 
1)  It e ms t o b e c oll ect e d or ass ess e d aft er i nf or me d c o nse nt is o bt ai n e d b ut bef ore t h e 
st art of t h e p atie nt r e gistr ati o n pr o ce d ure 
• 
Dat e of i nf or me d c o ns e nt f or p arti ci p ati o n i n t he st u d y  
• 
S u bject i d e ntifi cati o n c o de  
• 
D at e of birt h  
• 
Se x  
• 
Race  
• 
Hei g ht 
• 
E li gi bilit y 
• 
Me di cal hist or y a n d c o m pli cati o ns:  
Ass ess t h e pr es e n ce or a bs e n ce of me di cal hist or y a n d c o m pli cati o ns, t h e 
pr es e n ce or a bs e n ce of s y m pt o ms at t h e ti me of i nf or me d c o ns e nt (if a n y 
s y m pt o ms ar e pr es e nt, it s h o ul d b e h a n dl e d as a c o m pli cati o n), fin di n gs, a n d t h e 
di a g n osis. 
Re gar di n g me di cal hist or y, rec or d o nl y t h e s y m pt o ms/ dis eas es t h at h a ve b ee n 
c ur e d b y t h e ti me of i nf or me d c o nse nt a n d are c o nsi d ere d n ecess ar y t o b e 
r e p ort e d i n t h e i n vesti gat or’s or s u bi n vesti gat or’s o pi ni o n. 
• 
I nf or mati o n o n t h e u n d erl yi n g dis eas e ( A M L): 
T h e d at e w h e n t h e pati e nt was di a g n os e d wit h A M L a n d W H O classifi cati o n will 
be c o nfir me d.  
• 
A Es  
T h e o cc urr e nce  of A Es aft er t h e d a y of i nf or me d c o ns e nt will b e m o nit ore d 
acc or di n g t o “9 . S A F E T Y E N D P OI N T S . ” 
• 
C o n c o mit a nt dr u gs a n d t her a pi es 
C oll ect dat a o n t h e f oll o wi n g it e ms c o n cer ni n g dr u gs a n d t h era pi es use d aft er t h e 
da y of i nf or me d c o ns e nt:  
• 
Na me of dr u g (t h er a p y), d ose, u nit, m o de of a d mi nistrati o n, fre q u e n c y  
• 
St art a n d st o p d at es of dr u g (t h era p y)  
• 
Reas o n f or us e ( a p pli cati o n)  

 
 
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T h e f oll o wi n g it e ms d o n ot h a ve t o b e rec or d e d i n t h e C R F u nl ess a rel ati o ns hi p 
of t h e m wit h t h e A Es occ urri n g d uri n g st u d y p artici p ati o n ca n n ot b e r ul e d o ut:  
• 
A ntis e pti c s ol uti o ns 
• 
He p ari n f or he p ari n l o c k fl us h 
• 
Test or pr o ce d ur al a ge nts us e d f or t ests i n cl u di n g b o ne marr o w as pirati o n or 
bi o ps y 
• 
Tr a nsf usi o n  
T h e  f oll o wi n g i nf or mati o n o n tra nsf usi o ns p erf or me d aft er t h e d a y of i nf or me d 
c o ns e nt will b e c o nfir me d.  
Ty p e of bl o o d pr o d u cts ( w h ol e bl o o d, re d bl o o d cells, pl as ma, pl atel ets, ot hers), 
st art d at e, e n d d at e, a m o u nt of us e ( u nit), a n d reas o n f or us e 
 
2)  It e ms t o b e c oll ect e d or ass ess e d b et wee n Da y −7 a n d Da y 0 ( = d a y of re gistrati o n)  
• 
Vit al si g n meas ur e me nt  
A xill ar y  b o d y t e m p er at ur e, p uls e rat e, s yst oli c bl o o d press ure, a n d di ast olic 
bl o o d pr ess ur e will b e meas ure d i n t h e resti n g st ate.  
• 
B o d y wei g ht  
• 
E C O G P S ass ess me nt  
“ A p p e n di x 1 E C O G P erf or ma n ce St at us ( P S )” s h o ul d b e f oll o we d f or 
ass ess me nt.  
 
3)  It e ms t o b e c oll ect e d or ass ess e d b et wee n Da y −1 4 a n d Da y 0 ( = d a y of re gistrati o n) 
( c oll ect e d or ass ess e d o n a d a y as cl ose as p ossi bl e t o t h e d a y of re gistrati o n) 
• 
1 2- l ea d E C G (i n cl u di n g Q Tc F ass ess me nt) 
E C G wi ll b e p erf or me d i n pati e nts aft er a 1 0-mi n ut e rest i n t he s u pi n e p ositi o n.   
F or Q Tc F ass ess me nt, t ri pli cat e E C G rec or di n gs will b e o btai n e d at a b o ut 
2- mi n ut e i nt er vals.    If 1 2 -l ea d E C G a n d bl o o d c oll ecti o n f or l a b orat or y t ests, 
et c. ar e c o n d u ct e d o n t h e s a me d a y, t h e 1 2 -l ea d E C G will b e f oll o we d b y bl o o d 
c oll ecti o n.  

 
 
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• 
La b or at or y t ests  
 
La b or at or y P ar a met er  
H e mat ol o g y test  
Re d bl o o d c ell c o u nt, r eti c ul o c yt e, me a n c or p us c ul ar v ol u me  ( M C V), me a n 
c or p us c ul ar h e m o gl o bi n  ( M C H), me a n c or p us c ul ar h e m o gl o bi n  c o n c e ntr ati o n 
( M C H C), h e m o gl o bi n, h e mat o crit, w hit e bl o o d c ell c o u nt, w hit e bl o o d cell 
differ e nti al c o u nt  ( n e utr o p hils, b as o p hils, e osi n o p hils, l y m p h o c yt es, 
m o n o c yt e s), pl at el et c o u nt, pr ot hr o m bi n ti me (P T ), a n d pr ot hr o m bi n 
ti me-i nter n ati o n al n or mali z e d r ati o ( P T-I N R) 
Bl o o d c h e mistr y t est  
Tot al pr ot ei n , al b u mi n, t ot al bilir u bi n, dir e ct bilir u bi n, i n dir e ct bilir u bi n, A S T, 
A L T, A L P, γ-G T, L D H, li p ase, B U N, ser u m cr e ati ni n e, cr e ati n e ki n ase, uri c 
a ci d, gl u c ose, bi c ar b o n at e , el e ctr ol yt es ( K, N a, Cl, C a, P, M g), a n d C R P 
Uri n al ysis  
A p p ear a n ce, c ol or, s p e cifi c gr a vit y, p H, o c c ult bl o o d , gl u c os e , pr otei n , 
bilir u bi n, a n d k et o n e b o dies  
• 
Ass e ss me nt of b o ne marr o w fi n di n gs 
B o n e marr o w fi n di n gs a n d n e utr o p hil a n d pl at el et c o u nts i n t h e p eri p h eral bl o o d 
will b e ass ess e d as s p ecifi e d i n “1 0. 1  Defi niti o n of Effi ca c y E n d p oi nts . ” 
• 
Pre g n a n c y t est 
A uri n e or s er u m pr e g n a nc y t est will b e p erf or me d i n fe mal e p ati e nts.  
A pr e g n a nc y t est is n ot n ecess ar y i n  w o me n w h o ha ve b ee n a me n orr h ei c f or at 
least 1 2 m o nt hs aft er t h e last me nstr u ati o n a n d w h o are  c o nsi dere d t o h a ve n o 
chil d b eari n g p ot e nti al , or w o me n w h o are n ot of c hil d b eari n g p ot e nti al aft er 
per ma n e nt s ur gi cal sterilizati o n, et c.    I n t his cas e, t h e i nf or mati o n a n d reas o n 
will b e r ec or d e d i n t h e C R F.  
A pr e g n a nc y t est m ust b e p erf or me d i n  w o me n w h o h a ve bee n a me n orr h ei c f or 
at l east 1 2 m o nt hs  f or me di cal reas o ns ot h er t h a n s ur gi cal st erili zati o n (e g, 
me di cati o n) b eca us e t h e y ar e c o nsi d ere d t o h a ve c hil d b eari n g p ot e nti al.  
• 
HI V a nti b o d y 
 
6. 2  
R e missi o n I n d u cti o n T her a p y  
Re missi o n i n d u cti o n t h er a p y will b e gi ve n f or u p t o 2 c ycl es , eac h of w hi c h is 2 8 d a ys 
l o n g. 
T h e pr o ce d ur es list e d b el o w will be perf or me d, a n d t h e res ults will b e rec or d e d i n t he 
C R F.  
T h e d et ails of t he pr o ce d ur es ar e t h e s a me as t h os e s p ecifi e d  i n “6. 1  I nf or me d C o ns e nt t o 
P ati e nt  Re gistrati o n. ” 
B o n e marr o w as pir ati o n or bi o ps y will b e p erf or me d o n Da y 2 1 of C ycl e 1; if 
m yel o bl asts acc o u nt f or  < 5 %, t h e treat me nt will pr o cee d t o C ycl e 1 of c o ns oli d ati o n 
t h era p y ( C ycl e 2 of r e missi o n i n d u cti o n t h era p y will b e s ki p pe d); if m yel o bl asts acc o u nt 
f or ≥ 5 %, r e missi o n i n d u cti o n t h er a p y i n C ycl e 2 will b e gi ve n.  
T h e s t art of C ycl e 2 ca n be p ost p o n e d wit hi n a ra n ge of + 5 6 d a ys fr o m Da y 1 of C ycl e 1.   

 
 
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If C ycl e 2 is st art e d wit hi n + 7 d a ys reck o ne d fr o m  Da y 2 8 of C ycl e 1, t h e pr o ce d ures 
( vit al si g ns meas ur e me nt, b o d y wei g ht meas ure m e nt, E C O G P S  ass ess me nt , 1 2-l ea d 
E C G meas ur e me nt, a n d l a b or at or y t ests) s c h e d ul e d o n Da y 1 of C ycl e 2  are n ot 
necess ar y. 
 
1)  C o nfir mati o n of t h e st at us of a d mi nistrati on of t h e st u d y dr u g a n d c o a d mi nist ere d  
dr u gs ( c yt ar a bi n e a n d t h e a nt hrac ycli n e dr u g)  
• 
Pres cri b e d d os es a d mi nist ere d  or n ot a d mi nist ere d  
• 
Dat es of d os es a d mi nist er e d  
• 
Ti mi n g of d osi n g  
• 
A m o u nt of d os e a d mi nister e d  
• 
Pres e n ce or a bs e n ce of t e m p orar y dis c o nti n u ati o n  a n d d os e re d u cti o n (if pres e nt, 
t h e d et ails a n d r eas o n f or it) 
P ati e nt s ar e i nstr u ct e d t o r ec or d t h e pres e n ce or a bs e n ce  of q ui zarti ni b  a d mi nistrati o n , 
a n d t h e ti me of a d mi nistr ati o n , et c. i n t h e d osi n g diar y.    T h e i n vesti gat or or 
s u bi n vesti gat or will c h ec k t h e st at us of q ui zarti ni b  a d mi nistrati o n b ase d o n t h e 
i nf or mati o n i n t h e d osi n g di ar y. 
 
2)  Vit al si g n meas ur e me nt  
C ycl e 1  
D a y 1  
Bef or e  t h e st art of a d mi nistr ati o n  of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e  dr u g  
D a y 8  
* First d a y of q ui z arti ni b  
a d mi nistr ati o n  
Be f or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 9  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 2 1  
* Last  d a y of q ui z arti ni b  
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 2 2  
—  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “7 + 3 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “5 + 2 ”  
D a y 1  
Bef or e t h e st art of a d mi n istr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  

 
 
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D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val or str o n g 
C Y P 3 A 4 i n hi bit ors, vit al si g ns will b e meas ure d at t h e f oll o wi n g ti me p oi nts: [ 1] 
pr e- d os e of q ui zarti ni b o n t h e f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e 
da y w h e n q ui zarti ni b is r es u me d); [ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost- d os e o n t h e d a y 
w h e n q ui zarti ni b is r es u me d; [ 3] pre -d os e o n Da y 4 ( ± 1 d a y) if t h e d a y w he n 
q ui zarti ni b is r es u me d is defi n e d as Da y 1; [ 4] pre -d os e o n Da y 8 ( ± 1 d a y) if t h e d a y 
w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; [ 5] pre -d os e o n Da y 1 1 ( ± 1 d a y) if 
t h e d a y w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; a n d [ 6] pre-d os e o n Da y 1 5 
( ±1 d a y) if t h e d a y w h e n q ui zarti ni b is res u me d is defi n e d as Da y 1.  
 
3)  B o d y wei g ht  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “7 + 3 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “5 + 2 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
th e a nt hr a c ycli n e dr u g  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
 
4)  E C O G P S ass ess me nt  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “7 + 3 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z ar ti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
Bef or e a d mi nistrati o n of q uiz arti ni b  

 
 
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* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “5 + 2 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ar a bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
 
5)  1 2- l ea d E C G 
If 1 2- l ea d E C G a n d bl o o d c oll ecti o n f or l a b orat or y t ests, et c. are s c h e d ul e d at t h e 
sa me ti me, t h e 1 2-l ea d E C G will b e f oll o we d b y bl o o d c oll ecti o n. 
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 9  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 2 2  
—  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “7 + 3 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “5 + 2 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val or str o n g 
C Y P 3 A 4 i n hi bit ors, 1 2- l ea d E C G will b e meas ure d at t he f oll o wi n g ti me p oi nts: [ 1] 
pr e- d os e of q ui zarti ni b o n t h e f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e 

 
 
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da y w h e n q ui zarti ni b is r es u me d); [ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost- d os e o n t h e d a y 
w h e n q ui zarti ni b is r es u me d; [ 3] pre -d os e o n Da y 4 ( ± 1 d a y) if t h e d a y w he n 
q ui zarti ni b is r es u me d is defi n e d as Da y 1; [ 4] pre -d os e o n Da y 8 ( ± 1 d a y) if t h e d a y 
w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; [ 5] pre -d os e o n Da y 1 1 ( ± 1 d a y) if 
t h e d a y w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; a n d [ 6] pre-d os e o n Da y 1 5 
( ±1 d a y) if t h e d a y w h e n q ui zarti ni b is res u me d is defi n e d as Da y 1.  
 
6)  La b or at or y t ests  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z a rti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “7 + 3 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2  
* I n c as e of “5 + 2 ” 
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e a n d 
t h e a nt hr a c ycli n e dr u g  
D a y 6  
* Firs t d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 5  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val or str o n g 
C Y P 3 A 4 i n hi bit ors, l a b or at or y t ests will b e p erf or me d pre -d os e of q ui zarti ni b o n t h e 
f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e d a y w h e n q uizarti ni b is 
r es u me d). 
 
7)  Ass ess me nt of a ntit u m or eff ect  
B o n e marr o w fi n di n gs a n d n e utr o p hil a n d pl at el et c o u nts i n t h e p eri p h eral bl o o d will 
be ass esse d as s p ecifi e d i n “1 0. 1  Defi niti o n of Efficac y E n d p oi nts . ” 
It is d esir a bl e t o o bt ai n b o n e marr o w s p eci me ns b y b o n e marr o w as pirati o n a n d 
bi o ps y.    If t h e i n vesti gat or or s u bi n vesti gat or c o nsi d ers t h at t h e a ntit u m or effect of 

 
 
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q ui zarti ni b ca n b e ass ess e d a d e q u at el y usi n g s p eci me ns o bt ai n e d b y b o n e marr o w 
as pir ati o n  al o n e, b o n e m arr o w bi o ps y ma y b e o mitt e d.  
C ycl e 1  
D a y 2 1  
O n t h e s p e cifi e d d a y  
C ycl e 2  
* I n c as e of “7 + 3 ”  
D a y 2 1  
O n t h e s p e cifi e d d a y  
C ycl e 2  
* I n c as e of “5 + 2 ”  
D a y 2 1  
O n t h e s p e cifi e d d a y  
 
8)  M o nit ori n g of A Es  
 
9)  Ass ess me nt of c o n c o mit a nt dr u gs a n d t h er a pi es  
 
1 0)  C oll ecti o n of s p eci me ns f or  p h ar mac o ki neti c ass ess me nt a n d t h e bi o mar ker st u d y  
Ref er t o “6. 7  P har mac o ki n eti cs ” a n d “6 . 8 Bi o mar ker St u d y . ” 
 
6. 3  
C o ns oli d ati o n T h er a p y  
Re missi o n i n d u cti o n t h er a p y will b e gi ve n f or u p t o 4 c ycl es, eac h of w hi c h is 2 8 d a ys 
l o n g. 
T h e s t art of C ycl e 2 a n d s u bs e q u e nt c ycl es ca n b e p ost p o n e d wit hi n a ra n ge of + 5 6 d a ys 
fr o m Da y 1 of t he pr ece di n g c ycl e if t he i n vesti gat or or s u bi n vesti gat or c o nsi d ers  it 
necess ar y.   P ati e nt s w h o ha ve ac hi e ve d C R,  C R p, or C Ri  i n C ycl e 2 or l at er are all o we d 
t o t er mi nat e c o ns oli d ati o n t h er a p y a n d u n d er g o H S C T.    I n s u c h a cas e, ho we ver, t h e 
st u d y tr eat me nt f or t h e r el e va nt p ati e nt  s h o ul d b e dis c o nti n u e d (refer t o “5. 6  Wit h dra wal 
Crit eri a ”).  
T h e pr o ce d ur es list e d b el o w will be perf or me d, a n d t h e res ults will b e rec or d e d i n t he 
C R F.  
T h e d et ails of t he pr o ce d ur es ar e t h e s a me as t h os e s p ecifi e d i n “6. 1  I nf or me d C o ns e nt t o 
P ati e nt  Re gistrati o n. ” 
If t h e n e xt c ycl e is st art e d wit hi n + 7 d a ys rec k o n e d fr o m Da y 2 8 of eac h c ycl e, t h e 
pr o ce d ur es ( vit al si g ns meas ur e me nt, b o d y wei g ht meas ure me nt, E C O G P S  ass ess me nt , 
1 2- l ea d E C G meas ur e me nt, a n d l a b orat or y t ests) s c h e d ul e d o n Da y 1 of t h e n e xt c ycl e 
ar e n ot n ecess ar y. 
 
1)  C o nfi r mati o n of t h e st at us of a d mi nistrati o n of t h e st u d y dr u g a n d c o a d mi nist ere d  
dr u gs ( c yt ar a bi n e a n d t h e a nt hrac ycli n e dr u g)  
• 
Pres cri b e d d os es a d mi nist ere d  or n ot a d mi nist ere d  
• 
Dat es of d os es a d mi nist er e d  

 
 
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• 
Ti mi n g of d osi n g  
• 
A m o u nt of d os e a d mi nister e d  
• 
Pres e n ce o r a bs e n ce of t e m p orar y dis c o nti n u ati o n a n d d os e re d u cti o n (if pres e nt, 
t h e d et ails a n d r eas o n f or it) 
P ati e nt s ar e i nstr u ct e d t o r ec or d t h e pres e n ce or a bs e n ce  of q ui zarti ni b  a d mi nistrati o n , 
a n d t h e ti me of a d mi nistr ati o n , et c. i n t h e d osi n g diar y.    T h e i nvesti gat or or 
s u bi n vesti gat or will c h ec k t h e st at us of q ui zarti ni b a d mi nistrati o n b ase d o n t h e 
i nf or mati o n i n t h e d osi n g di ar y. 
 
2)  Vit al si g n meas ur e me nt  
C ycl e 1  
D a y 1  
B ef or e t h e st art of c yt ar a bi n e  a d mi nistr ati o n  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 3  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
— 
C ycl e 2 a n d t h er e after  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nist rati o n of q uiz arti ni b 
 
D a y 1 3  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc int er val or str o n g 
C Y P 3 A 4 i n hi bit ors, vit al si g ns will b e meas ure d at t h e f oll o wi n g ti me p oi nts: [ 1] 
pr e- d os e of q ui zarti ni b o n t h e f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e 
da y w h e n q ui zarti ni b is r es u me d); [ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost- d os e o n t h e d a y 
w h e n q ui zarti ni b is r es u me d; [ 3] pre -d os e o n Da y 4 ( ± 1 d a y) if t h e d a y w he n 
q ui zarti ni b is r es u me d is defi n e d as Da y 1; [ 4] pre -d os e o n Da y 8 ( ± 1 d a y) if t he d a y 
w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; [ 5] pre -d os e o n Da y 1 1 ( ± 1 d a y) if 
t h e d a y w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; a n d [ 6] pre-d os e o n Da y 1 5 
( ±1 d a y) if t h e d a y w h e n q ui zarti ni b is res u me d is defi n e d as Da y 1.  
 

 
 
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3)  B o d y wei g ht  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2 a n d t h er e after  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
 
4)  E C O G P S ass ess me nt  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d ministr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2 a n d t h er e after  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
 
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
 
5)  1 2- l ea d E C G 
If 1 2-l ea d E C G a n d bl o o d c oll ecti o n f or l a b orat or y t ests, et c. are s c h e d ul e d at t h e 
sa me ti me, t h e 1 2-l ea d E C G will b e f oll o we d b y bl o o d c oll ecti o n. 
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 3  
Bef or e a d mi nistrati o n of q uiz arti ni b  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Be f or e a d mi nistrati o n of q uiz arti ni b 
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
C ycl e 2 a n d t h er e after  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
 
D a y 1 3  
Bef or e a d mi ni strati o n of q uiz arti ni b 
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  

 
 
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I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val or str o n g 
C Y P 3 A 4 i n hi bit ors, 1 2- l ea d E C G  will b e meas ure d at t he f oll o wi n g ti me p oi nts: [ 1] 
pr e- d os e of q ui zarti ni b o n t h e f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e 
da y w h e n q ui zarti ni b is r es u me d); [ 2] 2 h o urs ( ± 1 0 mi n ut es) p ost- d os e o n t h e d a y 
w h e n q ui zarti ni b is r es u me d; [ 3] pr e-d os e o n Da y 4 ( ± 1 d a y) if t h e d a y w he n 
q ui zarti ni b is r es u me d is defi n e d as Da y 1; [ 4] pre -d os e o n Da y 8 ( ± 1 d a y) if t he d a y 
w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; [ 5] pre -d os e o n Da y 1 1 ( ± 1 d a y) if 
t h e d a y w h e n q ui zarti ni b is r es u me d is d efi n e d as Da y 1; a n d [ 6] pre-d os e o n Da y 1 5 
( ±1 d a y) if t h e d a y w h e n q ui zarti ni b is res u me d is defi n e d as Da y 1.  
 
6)  La b or at or y t ests  
C ycl e 1  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistra ti o n of q uiz arti ni b 
D a y 1 3  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
— 
C ycl e 2 a n d t h er e after  
D a y 1  
Bef or e t h e st art of a d mi nistr ati o n of c yt ara bi n e  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
 
D a y 1 3  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 1 9  
* Last d a y o f q ui z arti ni b 
a d mi nistr ati o n  
Bef or e a d mi nistrati o n of q uiz arti ni b  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
—  
I n p ati e nts w h o us e dr u gs t h at ma y p ot e nti all y pr ol o n g t h e Q T/ Q Tc i nt er val or str o n g 
C Y P 3 A 4 i n hi bit ors, l a b or at or y t ests will b e p erf or me d pre -d os e of q ui zar ti ni b o n t h e 
f oll o wi n g d a y of t h e e n d of us e of t h e dr u gs (i e, t h e d a y w h e n q uizarti ni b is 
r es u me d). 
 
7)  Pre g n a n c y t est 
P ati e nt s w h o h a ve u n d er g o ne a pre g n a n c y t est ( uri n e or s er u m t est) b ef ore 
r e gistr ati o n i n t h e st u d y ar e r e q uire d t o u n d er g o a pre g n a n c y t est a gai n b ef ore t h e 
st art of tr eat me nt wit h c o a d mi nist ere d  dr u gs o n D a y 1 of C ycl e 1 ( −7 d a ys t o t h e 
da y).    If t h e r es ult is p ositi ve, t h e st u d y  f or t he rel e va nt p ati e nt will b e disc o nti n u e d 
(r ef er t o “5. 6  Wit h dr a wal Criteria ”).  
 
8)  Ass ess me nt of a ntit u m or e ff ect 
B o n e marr o w fi n di n gs a n d n e utr o p hil a n d pl at el et c o u nts i n t h e p eri p h eral bl o o d will 

 
 
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be ass esse d as s p ecifi e d i n “1 0. 1  Defi niti o n of Efficac y E n d p oi nts . ” 
It is d esir a bl e t o o bt ai n b o n e marr o w s p eci me ns b y b o n e marr o w as pirati o n a n d 
bi o ps y.    If t h e i n vesti gat or or s u bi n vesti gat or c o nsi d ers t h at t h e a ntit u m or effect of 
q ui zarti ni b ca n b e ass ess e d a d e q u at el y usi n g s p eci me ns o bt ai n e d b y b o n e marr o w 
as pir ati o n al o n e, b o n e m arr o w bi o ps y ma y b e o mitt e d.  
C ycl e 1  
D a y 2 1  
O n t h e s p e cifi e d d a y  
C ycl e 2 a n d t h er e after  
D a y 2 1  
O n t h e s p e cifi e d d a y  
 
9)  M o nit ori n g of A Es  
 
1 0)  Ass ess me nt of c o n c o mit a nt dr u gs a n d t h era pi es  
 
1 1)  C oll ecti o n of s p eci me ns f or  p h ar mac o ki neti c ass ess me nt a n d t h e bi o ma r ker st u d y 
Ref er t o “6. 7  P har mac o ki n eti cs ” a n d “6. 8  Bi o mar ker St u d y . ” 
 
6. 4  
At t h e Ti me  of Wit h dr a w al f r o m t h e St u d y  
T h e pr o ce d ur es list e d b el o w will be perf or me d wit hi n t h e d a y of t h e i n vesti gat or ’s or 
s u bi n vesti gat or’s d ecisi o n t o wit h dr a w a p ati e nt fr o m t h e st u d y (−3 d a ys t o + 7 da ys) . 
T h e d et ails of t he pr o ce d ur es ar e t h e s a me as t h os e s pecifi e d i n “6. 1  I nf or me d C o ns e nt t o 
P ati e nt  Re gistrati o n. ” 
• 
Dat e of a n d r eas o n f or wit h dra wal  
• 
Vit al si g n meas ur e me nt  
• 
B o d y wei g ht  
• 
E C O G P S ass ess me nt  
• 
1 2- l ea d E C G 
• 
La b or at or y  t ests 
• 
Ass ess me nt of a ntit u m or eff ect  
• 
M o nit ori n g of A Es  
• 
Ass ess me nt of c o n c o mit a nt dr u gs a n d t h era pi es  
 
6. 5  
P ost- t re at me nt O bs er v ati o n P eri o d  
T h e pr o ce d ur es list e d b el o w will be perf or me d at 2 8 d a ys ( ± 7 d a ys) rec k o n e d fr o m t h e 
da y of t h e l ast d os e of t h e st u d y dr u g.   If a n y A E h as n ot res ol ve d at t h e ti me p oi nt w h e n 
t h e pr o ce d ur es are p erf or me d, f oll o w-u p s h o ul d b e c o nti n u e d as far as p ossi bl e u ntil t h e 
A E is c o nfir me d t o h a ve r es ol ve d or b e res ol vi n g. 
• 
C o nfir mati o n of s ur vi val or d eat h ( T h e “ d at e of fi nal c o nfir mati o n ” w h e n t he p ati e nt  

 
 
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is ali ve a n d t h e “ d at e of deat h ” w h e n t h e p ati e nt  is d ea d will b e rec or d e d i n t h e C R F.)  
• 
Vit al si g n meas ur e me nt  
• 
B o d y wei g ht  
• 
E C O G P S ass ess me nt  
• 
1 2- l ea d E C G 
• 
La b or at or y t ests  
• 
M o nit ori n g of A Es  
• 
Ass ess me nt of c o n c o mit a nt dr u gs a n d t h era p i es ( C o n c o mit a nt dr u gs a n d t hera pi es 
us e d f or A Es , if a n y, will b e r ec or d e d i n t h e C R F.) 
• 
C o nfir mati o n of t h e pr es e n ce or a bse n ce  of p ost treat me nt (If treat me nt m eeti n g t h e 
defi niti o n s p ecifi e d i n “ 6. 6  P ost Treat me nt ” is st arte d aft er t h e f oll o wi n g d a y of t h e 
last d os e of t h e st u d y dr u g, t h e treat me nt re gi me n a n d t h e start d at e will b e rec or de d 
i n t h e C R F.) 
 
6. 6  
P ost Tre at me nt  
Tr eat me nt us e d f or A M L after t h e d a y of t h e l ast d ose of t h e st u d y dr u g (e g, 
c h e m ot h er a p y, i m m u n ot her a p y, r a di ati o n t h era p y, a n d s ur gi cal t h era p y) is defi n e d as 
“p ost tr eat me nt. ” 
 
6. 7  
P h a r m a c o ki n eti cs  
Aft er 2  m L of bl o o d is c oll ect e d fr o m eac h p ati e nt , as s p ecifi e d i n “Ta bl e 6. 7- 1  Bl o o d 
C oll ecti o n P oi nts f or P h ar mac o ki n eti c Ass ess me nt , ” t h e pl as ma s p eci me ns will 
i m me di at el y b e st or e d i n a fr o ze n st at e at −9 0 ° C t o −7 0 ° C.    T he s p eci me ns i n a fr o ze n 
st at e will b e s u b mitt e d t o t h e a ge n c y c o ntract e d b y t h e s p o ns or t o c oll ect t he s p eci me ns.   
Det ails i n cl u di n g t h e h a n dli n g of s p eci me ns will be s p ecifi e d i n s e p arat e pr o ce d ures.   
T h e d at e a n d ti me of bl o o d c oll ecti o n will b e rec or d e d i n t h e C R F.  
 
Ta bl e 6. 7- 1   Bl o o d C oll ecti o n P oi nts f or P har mac o ki n eti c Ass ess me nt  
Tr e at me nt C ycl e  
Tr e at me nt D a y  
Bl o o d C olle cti o n P oi nt ( Ac c e pta ble Li mit) 
Re missi o n i n d u cti o n 
t her a p y 
C ycl e 1 
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre- d os e  
3 0 mi n ut es ( ± 1 0 mi n ut es) p ost -d os e  
1 h o ur ( ± 1 0 mi n ut es) p ost -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 9  
Pre -d os e  
D a y 1 5  
Pre -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  

 
 
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D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
3 0 mi n ut es ( ± 1 0 mi n ut es) p ost -d os e  
1 h o ur ( ± 1 0 mi n ut es) p ost -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 2 2  
O n t h e s p e cifi e d d a y  
D a y 2 8  
O n t h e s p e cifi e d d a y  
C o ns oli d ati o n t h er a p y  
C ycl e 1  
D a y 6  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 7  
Pre- d os e 
D a y 1 3  
Pre -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 1 9  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
D a y 2 8  (−3 d a ys t o t h e d a y ) 
O n t h e s p e cifi e d d a y  
 
6. 8  
Bi o m a r k er St u d y  
Q uizarti ni b -r el at e d bi o mar kers a n d bi o mar kers t h at all o w t h e pre di cti o n of effi cac y a n d 
ot h ers of q ui zarti ni b will b e e x pl or e d.    Det ails i n cl u di n g t h e h a n dli n g of s peci me ns f or 
eac h st u d y it e m will b e s pecifi e d i n se p arat e pr o ce d ures.    T h e d at e a n d ti me of s p eci me n 
c oll ecti o n will b e r ec or d e d i n t h e  C R F.  
 
6. 8. 1  
F L T 3 -I T D St at us a n d c -KI T M ut ati o ns  
T h e f oll o wi n g s p eci me ns will b e c oll ect e d  bef ore t h e st art of a d mi nistrati o n  of 
c o a d mi nist er e d  dr u gs ( c ytar a bi n e  a n d t h e a nt hrac ycli n e  dr u g) : 1 m L of b o n e marr o w 
li q ui d or 2 m L of p eri p h er al bl o o d f or a n al ysis of t he F L T 3-I T D st at us, a n d 1 m L of b o n e 
marr o w li q ui d or 7  m L of p eri p h er al bl o o d f or a n al ysis of c -KI T  m ut ati o ns.   T h e  
s p eci me ns u n d er refri ger ati o n  will b e s u b mitt e d t o t h e a ge n c y c o ntract e d b y t h e s p o ns or 
t o c oll ect t h e s p eci me ns. 
 
6. 8. 2  
P h os p h o r yl at e d F L T 3 , S T A T 5, a n d c-KI T  Pr otei n L e vels i n Bl o o d 
Aft er 2  m L of bl o o d is c oll ect e d fr o m eac h p ati e nt as s p ecifi e d i n “Ta bl e 6. 8 - 1 Bl o o d 
C oll ecti o n P oi nts ( P h os p h or yl at e d Pr ot ei n Le vels  i n Bl o o d), ” t h e pl as ma s peci me ns will 
i m me di at el y b e st or e d i n a fr o ze n st at e at −9 0 ° C t o −7 0 ° C.    T he s p eci me ns i n a fr o ze n 
st at e will b e s u b mitt e d t o t h e a ge n c y c o ntract e d b y t h e s p o ns or t o c oll ect t he s p eci me ns.  
 

 
 
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Ta bl e 6. 8 - 1  Bl o o d C oll ecti o n P oi nts ( P h os p h or ylate d Pr ot ei n Le vels i n Bl o o d) 
Tr e at me nt C ycl e  
Tr e at me nt D a y  
Bl o o d C olle cti o n P oi nt  ( Ac c e pta ble Li mit) 
Re missi o n i n d u cti o n 
t her a p y 
C ycl e 1  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre- d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 9  
Pre -d os e  
D a y 1 5  
Pre -d os e  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
 
6. 8. 3  
I n hi bit o r y A cti vit y of Pl as m a Q ui z a rti ni b o n P h os p h o r yl ate d F L T 3 Protei n 
Aft er 5  m L of bl o o d is c oll ect e d fr o m eac h p ati e nt as s p ecifi e d i n “Ta bl e 6. 8 - 2 Bl o o d 
C oll ecti o n P oi nts ( I n hi bit or y Acti vit y of Plas ma Q uizarti ni b o n P h os p h or yl at e d F LT 3 
Pr ot ei n ), ” t h e s p eci me ns will b e pre p are d a n d i m me di at el y b e st ore d i n a fr o ze n st at e at 
−9 0 ° C t o −7 0 ° C.    T h e s peci me ns i n a fr o ze n st at e will b e s u b mitt e d t o t h e a ge n c y 
c o ntr act e d b y t h e s p o ns or t o c oll ect t h e s p eci me ns.  
 
Ta bl e 6. 8 - 2  Bl o o d C oll ecti o n P oi nts ( I n hi bit or y Acti vit y of Pl as ma Q uizarti ni b o n 
P h os p h or yl at e d F L T 3 Pr ot ei n) 
Tr e at me nt C ycl e  
Tr e at me nt D a y  
Bl o o d C olle cti o n P oi nt  ( Ac c e pta ble Li mit) 
Re missi o n i n d u cti o n 
t her a p y 
C ycl e 1  
D a y 8  
* First d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
2 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
4 h o urs ( ± 1 0 mi n ut es ) p ost-d os e  
6 h o urs ( ± 1 0 mi n ut es) p ost -d os e  
D a y 9  
Pre -d os e  
D a y 1 5  
Pre -d os e  
D a y 2 1  
* Last d a y of q ui z arti ni b 
a d mi nistr ati o n  
Pre -d os e  
 
6. 9  
A n o n y mi z ati o n , St o r a g e, a n d Dis p os al of S p eci me ns f o r t h e Bi o m a r k er St u d y 
6. 9. 1  
A n o n y mi z ati o n  of S p eci me ns  
T h e s peci me ns w ill b e a n o n y mi ze d b y eac h of t h e st u d y ce nt ers a n d t h e s peci me n 
c oll ecti o n a ge n c y acc or di n g t o t h e pr o ce d ure d es cri b e d b el o w.  
T h e st u d y ce nt er will n e ver pr o vi d e i nf or mati o n t hat ca n i d e ntif y i n di vi d u al p ati e nts t o 
t h e s p eci me n c oll ecti o n a ge n c y.    T he a n o n y mit y n u m b er s will b e stri ctl y st ore d b y t he 
s p eci me n st ora ge ma n a g er at t h e s p eci me n c oll ecti o n a ge n c y a n d will n ot be pr o vi d e d t o 
t h e st u d y ce nt er. 
1)  T h e st u d y ce nt er will assi g n a “ s u bj ect i de ntifi cati o n c o de” t o eac h p ati e nt.    T h e 
c orr es p o n de n ce t a bl e b e t wee n t h e “me di cal rec or d n u m b er ” a n d t h e “s u bj ect 
i d e ntifi cati o n c o d e” t h at ca n i d e ntif y p ers o n al i nf or mati o n will be st ore d at t h e st u d y 

 
 
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ce nt er.  
2)  T h e s peci me n c oll ecti o n a ge n c y will assi g n a n “a n o n y mit y n u m b er ” t o t h e c oll ect e d 
s p eci me ns of eac h p atie nt an d att ac h a la b el dis pl a yi n g t h e “a n o n y mit y n u m b er, ” i n 
pl ace of t h e “ s u bj ect i d e ntifi cati o n c o d e,” t o eac h s p eci me n.    T h e c orres p o n de n ce 
ta bl e b et wee n “s u bj ect i d e ntifi cati o n c o d e” a n d “ a n o n y mit y n u m b er ” will be 
pr e p are d b y t h e s p eci me n c oll ecti o n a ge n c y a n d be st ore d b y t h e s p o ns or.  
 
6. 9. 2  
St o r a g e a n d Dis p os al of S p eci me ns  
T h e s p o ns or will b e r es p o nsi bl e f or dis p os al of t h e s p eci me ns as re q u est e d b y p ati e nts vi a 
t h e i n vesti gat or a n d dis p os al aft er t h e e n d of t he st ora ge p eri o d.    S p eci me ns will b e 
st or e d f or a ma xi m u m of u p t o 3 years aft er c o m pleti o n of t h e st u d y.  
At t h e e x pir ati o n of t h e st or a ge p eri o d , t h e s p eci me n c oll ecti o n a ge n c y a n d t h e ce ntral 
la b or at or y will dis p os e of t h e s p eci me ns acc or di n g t o t h e s p o ns or’s directi o ns.    F or 
s p eci me ns t h at t h e s p o ns or co nsi d ers are n ot n ecess ar y t o be st ore d a n y l o n ger, e ve n 
d uri n g t h e s p eci me n st or a ge p eri o d, t h e s p eci me n c oll ecti o n a ge nc y a n d t h e ce ntral 
la b or at ori es will dis p os e of t h e s p eci me ns acc or di n g t o t h e s p o ns or’s directi o ns. 
If a p ati e nt wit h dr a ws c o ns e nt f or t h e st u d y a n d re q u ests t h e st u d y ce nt er t o dis p os e of 
t h e bi o mar ker s p eci me ns d uri n g t h e s peci me n st ora ge p eri o d, t h e s p eci me ns will b e 
dis p os e d of, d e p e n di n g o n t h e l o cati o n of t h e s p eci me ns at t h e ti me of t h e re q u est, 
acc or di n g t o t h e f oll o wi n g pr o ce d ur e:  
1)  I n cas es w h er e t h e s p eci me ns are t e m p oraril y st ore d at t h e st u d y ce nt er: 
T h e i n vesti gat or or s u bi n vesti gat or will i d e ntif y t he s p eci me ns of t he p ati e nt a n d 
dis p os e of t h e m.  
2)  I n cas e t h e s p eci me ns ar e st ore d at t h e s peci me n c oll ecti o n a ge n c y or t h e ce ntral 
la b or at or y: 
T h e i n vesti gat or or s u bi n vesti gat or will re p ort t h e s u bj ect i d e ntifi cati o n c o de of t h e 
perti n e nt p ati e nt t o t h e s p o ns or.    T h e s p o ns or will i d e ntif y t h e s p eci me ns of t h e 
pati e nt b as e d o n t h e c orr es p o n d e n ce ta bl e li n ki n g t h e s u bj ect i d e ntifi cat i o n c o d e wit h 
t h e a n o n y mit y n u m b er, i nf or m t h e s p eci me n c oll ecti o n a ge n c y or t h e ce ntral 
la b or at or y of t h e a n o n y mit y n u m b er, a n d direct t he a ge n c y or l a b orat or y t o dis p os e 
of t h e s p eci me ns.    T h e s p eci me n c oll ecti o n a ge n c y or t h e ce ntral l a b orat or y will 
dis p os e of t h e s p eci me ns acc or di n g t o t h e s p o ns or ’s directi o ns. 
S p eci me ns c oll ect e d f or t h e ass ess me nt  o f F L T 3 -I T D st at us a n d c-KI T m ut ati o ns of a 
pati e nt w h o wit h dr a ws c o nse nt s h o ul d b e dis p os e d of pr o m ptl y i n acc or d a nce wit h t h e 
Et hi cal  G ui deli n es f or H u ma n  Ge n o me / Ge n e A n al ysis Res earc h .1 8)   Re gar di n g t h e ot h er 

 
 
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s p eci me ns of t he pati e nt, t h e s p o ns or will d eci de o n t h e ti mi n g of dis p os al. 
S p eci me ns of a p ati e nt w h o wit h dr a ws c o ns e nt s h o ul d b e ma n a ge d stri ctl y b y s e p arati n g 
t h e m fr o m t h e s p eci me ns of ot h er pati e nts u ntil t h e y are dis p os e d of.    T h e s p o ns or is 
r es p o nsi bl e f or t h e ma na ge me nt of t h e s p eci me ns. 
 

 
 
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7.  
P H A R M A C O KI N E TI C E N D P OI N T S  
T h e f oll o wi n g p h ar mac o ki n eti c p ar a met ers will b e calc ul ate d b y a n o n- c o m p art me nt 
m o d el a p pr o ac h usi n g pl as ma c o n ce ntrati o n d at a of q ui zarti ni b  a n d its acti ve meta b olit e 
A C 8 8 6  o bt ai n e d o n Da y 8 of C ycl e 1 a n d Da y 2 1 of C ycl e 1 d uri n g t h e i n d ucti o n p h as e.  
Da y 8  of C ycl e 1  d uri n g t h e i n d u cti o n p h as e : C m a x , T ma x , A U Ct a u  
Da y 2 1  of C ycl e 1  d uri n g  t h e i n d u cti o n p h as e: C ma x,ss, Ctr o u g h , Tma x,ss , A U Ct a u,ss  
T h e d et ails of t he met h o d of cal c ul ati o n of p h ar mac o ki n etic para met ers are s p ecifi e d i n 
t h e St atistical A n al ysis Pla n.  
 

 
 
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8.  
P H A R M A C O D Y N A MI C  E N D P OI N T S  
T h e f oll o wi n g e n d p oi nts will b e meas ure d:  
• 
F L T 3 -I T D st at us a n d c-KI T m ut ati o ns ( b o n e marr o w li q ui d or bl o o d s p eci me ns)  
• 
P h os p h or yl at e d F L T 3 , S T A T 5, a n d c-KI T  pr ot ei n l e vels i n bl o o d  ( bl o o d s peci me ns) 
• 
I n hi bit or y acti vit y of pl as ma quizarti ni b  o n p h os p h or yl at e d F L T 3 pr ot ei n ( pl as ma 
s p eci me ns) 
 

 
 
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9.  
S A F E T Y E N D P OI N T S  
Saf et y e n d p oi nts ar e d efi ne d as A Es, l a b orat or y d at a, b o d y wei g ht, vit al si g n s, a n d 
1 2- l ea d E C G.  
 
9. 1  
D efi niti o n of A d v ers e E ve nts  
A n A E is a n y u nt o war d or u ni nt e n d e d si g n ( i n cl u di n g a n a b n or mal c h a n ge i n l a b orat or y 
fi n di n gs or vital si g ns), s y m pt o m, or dis eas e n ot e d bet wee n t h e d a y of i nf or me d c o ns e nt 
f or t he st u d y a n d t h e e n d d a y of p ost-treat me nt o bser vati o n, w h et h er it is c o nsi d ere d t o b e 
r el at e d t o t h e st u d y dr u g or n ot. 
A s y m pt o m or dis eas e pr ee xisti n g b ef ore i nf or me d c o ns e nt f or t h e st u d y is o bt ai n e d will 
be h a n dl e d as a c o m pli cati o n, n ot as a n A E.    A n y c o m pli cati o n t h at is e xacer b at e d  aft er 
i nf or me d c o ns e nt f or t he st u d y is o bt ai n e d s h o ul d b e h a n dl e d as a n A E, a n d t h e d at e 
w h e n t h e e xacer b ati o n is d et ect e d will b e rec or d e d as t h e d at e of o ns et of t he A E . 
T h e pr o gr essi o n of t h e u n d erl yi n g dis eas e ( A M L) will b e h a n dle d as d es cri b e d b el o w:  
• 
T u m or pr o gr essi o n will n ot b e h a n dl e d as a n A E, i n pri n ci pl e.    H o we ver, t u m or 
pr o gr essi o n l ea di n g t o t h e o ut c o me of d eat h d uri n g t h e A E c oll ecti o n p eri o d  s h o ul d 
be h a n dl e d as a n S A E ( wit h t he n a me a n d o ut c o m e of t h e e ve nt rec or d e d as “ dis eas e 
pr o gr essi o n ” a n d “ f at al,” r es p ecti vel y). 
• 
T u m or pr o gr essi o n r es ulti n g i n e xacer b at e d si g ns or s y m pt o ms will be ha n dl e d as a n 
A E.  
 
9. 2  
D efi niti o n of S eri o us A d v ers e E v e nts  
A n S A E is a n y A E  t h at: 
• 
r es ults i n d eat h, 
• 
is lif e-t hr eat e ni n g, 
• 
r e q uir es i n p ati e nt h os pit alizati o n or pr ol o n gati o n of e xisti n g h os pit ali zati o n f or 
tr eat me nt, 
• 
is a dis a bilit y or i n ca p acit y, 
• 
ma y l ea d t o a disa bilit y or i n ca pacit y,  
• 
r e pr es e nts ot her me di call y i m p ort a nt c o n diti o n, or 
• 
is a c o n ge nit al a n o mal y or birt h d efect. 
 
9. 3  
A d v ers e E v e nt I nf o r m ati o n t o B e R e p o rte d  
If a n A E  o cc urs d uri n g t he st u d y, t h e it e ms s h o w n i n “ Ta bl e 9. 3- 1  I n vesti gati o n It e ms 
foll o wi n g O ns et of A d vers e E ve nts ” will b e i n vesti gat e d a n d rec or d e d i n t he C R F, et c.   

 
 
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O nl y t h e hi g h est gr a d e o bs er ve d i n t h e c o urs e of eac h A E s h o ul d b e rec or de d as t h e 
se verit y i n t he C R F. 
 

 
 
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Ta bl e 9. 3- 1   In vesti gati o n It e ms foll o wi n g O ns et of A d vers e E ve nts  
It e m 
D et ails t o Be I n v esti gat e d  
A E  
N a me of A E , d at e of o nset 
I nt er ve nti o n f or A E  
Pres e n c e or a bs e n c e of i nt er v e nti o n (i n cl u di n g c h a n g es i n st u d y dr u g a d mi nistr ati o n), 
a n d if pr es e nt, t h e c o nt e nt of t h e  i nt er v e nti o n 
O ut c o me  
O ut c o me c at e g or y, d at e of o ut c o me ass ess me nt, d at e of r es ol uti o n  
 
O ut c o me 
c at e g or y  
Re c o v ere d/  
Res ol v e d  
T h e A E  h as r es ol v e d, a n d t h e p atie nt h as r e c o v er e d t o t h e pr e -e v e nt 
c o n diti o n.  
Re c o v eri n g/  
Res ol vi n g  
T h e A E  h as al m ost r es ol v ed, a n d t h e p ati e nt h as n e arl y r ec o v er e d t o 
t h e pr e-e v e nt c o n diti o n.  
N ot r ec o ver e d/  
N ot res ol v e d  
T h e A E  h as n ot res ol ve d, a n d t h e c o n diti o n of t h e p ati e nt is si mil ar 
t o t h at at o ns et ( u n c h a n g e d). 
Re c o v ere d/  
Res ol v e d wit h 
s e q u el ae/r esi d u al 
effe ct(s) pr ese nt  
T h e A E  h as r es ol v e d, b ut t h e p ati e nt h as s e q u el a e.  
Fat al  
T h e e v e nt o ut c o me is fatal o nl y w h e n t h e i n v esti g at or c o nsi d ers t h at 
t h e A E  a n d t h e p ati e nt’s d e at h ar e rel at e d or t h at a r elati o ns hi p  
c a n n ot b e r ul e d o ut.    D e at h d u e t o w orse ni n g of t h e u n d erl yi n g 
dis e as e is n ot a p pli c a bl e t o t his c at e g or y.  
U n k n o w n  
O ut c o me is u n k n o w n b e c a use of la c k of i nf or mati o n.  
Se verit y  
To b e ass ess e d a c c or di n g t o t h e C T C A E v 4. 0 J a p a n es e v ersi o n.  
T h e s e v erit y of A Es n ot i n cl u d e d i n t h e C T C A E v 4. 0 Ja p a n es e v ersi o n wil l b e ass ess e d 
a cc or di n g t o t h e f oll o wi n g gr a d es:  
Gr a d e 1  
Mil d; as y m pt o mati c or mil d s y m pt o ms; cli nic al or di a g n osti c 
o bs er v ati o ns o nl y; i nter v e nti o n n ot i n di c at e d.  
Gr a d e 2  
M o d erat e; mi ni mal, l o cal or n o ni n v asi v e i nt er v e nti o n i n di cat e d; 
li miti n g a g e-a p p r o pri ate i nstr u m e nt al A D L. 
Gr a d e 3  
Se v er e or me di c all y si g nifi c a nt b ut n ot i m me diat el y 
life-t hr e at e ni n g; h os pit ali z ati o n or pr ol o n g ati o n of h os pit aliz ati o n 
i n di cat e d; dis a bli n g; li miti n g s elf c ar e A D L. 
Gr a d e 4  
Life -t hr e at e ni n g c o nse q u e n c es; ur g e nt i nt er v e nti o n i n di c at e d. 
Gr a d e 5  
D eat h r elat e d t o A E.  
Seri o us n ess  
Seri o us/ N o nseri o us  
Ca us alit y wit h t h e st u d y 
dr u g a n d c o a d mi nist er e d  
dr u gs  (c yt ara bi n e a n d 
t he a nt hr a c ycli n e dr u g ) 
Cl assifi c ati o n of t h e r el ati o ns hi p (i n a c c or d a n c e wit h t h e f oll o wi n g cl assifi c ati o n of t h e 
relati o ns hi p) 
 
Ca us alit y c at e g or y  
Rel at e d  
• T h er e is a r eas o n a bl e t e m p or al r elati o ns hi p b et we e n t h e o ns et of 
t h e A E  a n d a d mi nistr ati o n of t h e st u d y dr u g, it is n ot r e as o n a bl e 
t o ass ess t h at t h e A E  is attri b ut a ble t o t h e p ati e nt’s c o n diti o n or 
ot h er fa ct ors t h a n t h e st u d y dr u g ( u n d erl yi n g dis e as e, 
c o m pli c ati o ns, c o n c o mit a nt dr u gs, et c.), a n d a r elati o ns hi p wit h 
t h e st u d y dr u g ca n n ot b e r ul e d o ut. 
• T h er e is a r eas o n a bl e t e m p or al r elati o ns hi p b et we e n t h e o ns et of 
t h e A E  a n d a d mi nistr ati o n of t h e st u d y dr u g, a n d t h e A E  c a n b e 
e x pl ai n e d b y k n o w n a cti o ns or t h e p h ar ma c ol o gi cal a cti o n of t h e 
st u d y dr u g or si mil ar a n al o g u es. 
 
 
U nr el ate d  
• T h er e is n o r e as o n a ble t e m p or al r el ati o ns hi p b et we e n t h e o ns et 
of t h e A E  a n d a d mi nistrati o n of t h e st u d y dr u g, it is r e as o n a bl e 
t o ass ess t h at t h e A E  is attri b ut a ble t o t h e p ati e nt’s c o n diti o n or 
ot h er fa ct ors t h a n t h e st u d y dr u g ( u n d erl yi n g dis e as e, 
c o m pli c ati o ns, c o n c o mit a nt dr u gs), a n d a rel ati o ns hi p wit h t h e 
st u d y dr u g c a n b e r ul e d o ut. 
 

 
 
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9. 4  
D efi niti o n of A d v ers e D r u g R e a cti o ns  
A E s t h at ar e ass ess e d as “r el at e d ” t o t h e st u d y dr u g will b e h a n dle d as a d vers e dr u g 
r eacti o ns. 
 
9. 5  
A cti o ns t o B e Ta k e n f o r A d v ers e E v e nts  
9. 5. 1  
R ec o m me n de d A cti o n f o r A d v ers e E ve nts  
If a n y A E  has o cc urr e d, t he i n vesti gat or or s u bi n v esti gat or will t a ke a p pr o pri at e acti o ns, 
n otif y t h e s p o ns or as r e q uir e d, a n d c o nti n u e f oll o w - u p u ntil t he p ati e nt  rec o vers t o t h e 
pr e- e ve nt c o n diti o n wit h r es ol uti o n or reli ef of t h e A E  as far as p ossi bl e , e ve n aft er t h e 
e n d of t h is st u d y.   H o w e ver,  e ve n  if t h e A E  is n ot c o nfir med t o h a ve res ol ve d or relie ve d, 
if it is j u d ge d t h at t h e p atie nt ’s c o n diti o n re mai ns st a ble a n d t h e s afet y ca n be ass ure d, t h e 
i n vesti gat or or s u bi n vesti gat or will e x pl ai n t he matter t o t h e p atie nt , a n d t he f oll o w-u p of 
t h e st u d y will b e c o m pl ete d (tr eat ment of t h e rel e va nt s y m pt o m will b e c o nti n u e d).  
 
9. 5. 2  
A cti o n  f o r S eri o us A d v ers e E v e nts  
If a n S A E h as o cc urr e d, t h e i n vesti gat or or s u bi n vesti gat or will t a ke a p pr o pri at e acti o ns, 
a n d r e p ort t h e d et ails of t he S A E t o t h e s p o ns or b y t el e p h o n e or fa x wit hi n 2 4 h o urs of 
lear ni n g of t h e o cc urr e nce.   T h e i n vesti gat or will s u bs e q u e ntl y e nt er t h e n ecess ar y 
i nf or mati o n i n t h e Seri o us A d vers e E ve nt Re p ort ( S A V E R) F O R M ( A p p e n di x 3) a n d 
s u b mit t h e f or m wit h t he d at e of c o nfir mati o n a n d a si g n at ure t o t he s p o ns or wit h o ut 
del a y.   A writte n r e p ort t o t h e h ea d of t h e st u d y c e nt er will b e ma d e i n acc or d a n ce wit h 
t h e pr o ce d ur es a n d f or m at s p ecifi e d b y t h e st u d y ce nt er. 
 
9. 6  
A cti o ns t o B e Ta k e n i n t h e E v e nt T h at I nf o r m ati o n o n Pre g n a n c y, Pre g n a nt 
a n d P a rt u ri e nt Wo me n, a n d D eli v er y Is O b t ai n e d 
If i nf or mati o n o n t h e pr e g n a n c y of a p ati e nt or a pati e nt ’s fe mal e p art n er is o bt ai n e d 
d uri n g t h e st u d y p eri o d or wit hi n 6 m o nt hs aft er t he l ast d os e of t h e st u d y dr u g , t h e 
i n vesti gat or or s u bi n vesti gat or will i n vesti gat e t h e i nf or mati o n o n t h e pre gn a n c y t hr o u g h 
deli ver y, a n d r e p ort it t o t h e s p o ns or usi n g t h e f or mat  pr o vi d e d b y t h e s p o ns or  ( A p p e n di x 
4) .   Pr e g n a n c y  will n ot be h a n dl e d as a n A E ; h o we ver, if t h e o ut c o me of t h e pre g n a nt 
w o ma n f alls u n d er t he defi niti o n of S A E s (c o n ge nit al a n o mal y i n t h e fet us [i n cl u di n g 
s us p ect e d cas es], still birt h, a n d a b orti o n), t h e i n vesti gat or or s u bi n vesti gat or m ust re p ort 
it t o t h e s p o ns or i n acc or da n ce wit h t h e pr o ce d ures f or re p orti n g S A E s s p ecifi e d i n “9. 5. 2  
Acti o n  f or Seri o us A d verse E ve nts ,” i n de p e n d e nt of w h et h er it is d uri n g t h e st u d y p eri o d 
or n ot. 

 
 
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1 0.  E F FI C A C Y E N D P OI N T S  
T h e a ntit u m or eff ect of q ui zarti ni b will b e ass ess e d bas e d o n b o n e marr o w fi n di n gs a n d 
ne utr o p hil a n d pl at e l et c o u nts i n t h e p eri p h eral bl o o d, as s p ecifi e d i n “1 0. 1  Defi niti o n of 
Effi cac y E n d p oi nts . ” 
 
1 0. 1  D efi niti o n of Effi c a c y E n d p oi nts  
T h e effi cac y e n d p oi nts ar e d efi n e d as f oll o ws:  
 
Ta bl e 1 0. 1 - 1  Defi niti o n of Effi cac y E n d p oi nts  
C o m pl et e re missi o n  ( C R) 
F or p atie nts t o b e cl assifi e d as C R, t h e y m ust ac hi e v e a 
m or p h ol o gi c l e u ke mi a -fr e e st at e, m ust h a v e < 5 % b o n e marr o w 
blasts i n t h e b o n e marr o w , a n e utr o p hil c o u nt ≥ 1 0 0 0  / m m3, a n d 
a pl atel et c o u nt ≥ 1 0 0  0 0 0  / m m3, m ust b e i n d e p e n d e nt of  R B C 
a n d plat el et tr a nsf usi o n s ( d efi n e d as 4 we e ks wit h o ut R B C 
tr a nsf usi o n a n d 1 we e k wit h o ut platel et tr a nsf usi o n), a n d ma y 
n ot  h a ve e xtr a me d ullar y le u k e mi a.  
C R w it h i n c o m plet e pl at elet re c o v er y ( C R p) 
F or p atie nts t o b e cl assifi e d as C R p , t h e y m ust f ulfill all t h e 
crit eri a f or C R, e xc e pt f or i n c o m plete pl at el et  r e c o v er y (< 
1 0 0  0 0 0  / m m3). 
C R wit h i n c o m plet e h e mat ol o gic al r e c o ver y  
( C Ri) 
F or p atie nts t o b e cl assifi e d  as C Ri, t h e y m ust f ulfill all t h e 
crit eri a f or C R, e xc e pt f or i n c o m plete h e mat ol o gi c al r e c o v er y 
wit h r esi d u al n e utr o p e nia < 1 0 0 0  / m m3.   P l at el et r e c o v er y 
st at us a n d R B C a n d pl at el et tra nsf usi o n i n d e p e n d e n c e ar e n ot 
re q uir e d. 
P arti al r e missi o n  ( P R) 
F or p a tie nts t o b e cl assifi e d as P R, t h e y m ust h a v e b o n e 
marr o w r e g e n er ati n g n or mal h e m at o p oieti c c ells, n o or mi ni mal 
resi d u al bl ast c ells i n t h e p eri p h eral bl o o d, a d e cr e ase of at l e ast 
5 0 % i n t h e p er ce nt a g e of bl asts i n t h e b o n e marr o w as pir at e , 
a n d  t ot al marr o w bl asts b et we e n 5 % a n d 2 5 % i n cl usi v e. 
N o r es p o ns e  ( N R) 
N R is d efi n e d as a c o n diti o n n ot re a c hi n g a n y of C R, C R p , 
C R i, or  P R.  
C o m p osit e C R r at e ( C R c r ate)  
C o m p osit e C R r at e ( C R c r ate)  is d efi n e d as t h e pr o p orti o n of 
p atie nts w h os e b est r es p o ns e is a n y of C R,  C R p, a n d C Ri . 
Res p o ns e r ate  
Res p o ns e r ate  is d efi n e d as t h e pr o p orti o n of p ati e nts w h os e 
b est r es p o ns e is a n y of C R,  C R p,  C Ri,  a n d P R . 
Rel a ps e  
Rel a ps e aft er C R, C R p, or C Ri : 
D efi n e d as t h e r e a p p e ar a n c e of l e u k e mi c blasts i n t h e 
p eri p h er al bl o o d or  a n i n cr e as e i n t h e p er c e nt a g e of  bl asts i n 
t h e bo n e marr o w as pir at e t o ≥ 5 % , or t h e r e a p p e ar a n c e or 
n e w a p p ear a n c e of e xtr a me d ull ar y le u ke mi a.  
Rel a ps e aft er P R: 
D efi n e d as t h e r e a p p e ar a n c e of si g nifi c a nt n u m b ers of bl asts 
i n t h e p eri p h er al bl o o d or a n i n cr e as e i n t h e p er c e nt a g e of 
blasts i n t h e b o n e mar r o w as pir at e t o > 2 5 %, or t h e 
re a p p e ar a n c e or n e w a p p e ar a n c e of e xtra me d ull ar y 
le u k e mi a. 
 
1 0. 2  B est R es p o ns e  
Best r es p o ns e is d efi n e d as t h e b est meas ure d res p o ns e ( C R, C R p, C Ri, P R, or N R) o ver 
all r es p o ns e assess me nts at all ti me p oi nts aft er t h e st art of st u d y treat me nt.  
 

 
 
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1 1.  S T A TI S TI C A L A N A L Y S E S  
A n o utli n e of t h e st atisti cal a n d p h ar mac o ki n etic a n al ys es is pr o vi d e d bel o w.   Det ails 
will b e s p ecifi e d i n t h e Statisti cal A n al ysis Pla n.  
 
1 1. 1  A n al ysis S ets 
T h e s p o ns or will fi n ali ze t h e p o p ul ati o n fl a g of i n di vi d u al p atients f or eac h a n al ysis s et 
aft er C R F l o c k.   P ati e nts wit h maj or G o o d C li ni cal P racti ce ( G C P) vi ol ati o ns (e g, a 
vi ol ati o n of t he i nf or me d c o ns e nt pr o ce d ure, a maj or vi ol ati o n of st u d y pr o ce d ures) will 
be e xcl u d e d fr o m all a n al ysis s ets a n d b e ass ess e d i n di vi d u all y.   P ati e nts wit h a 
q ui zarti ni b d os e r e d u cti o n f or a n y r eas o n aft er t h e st art of st u d y treat me nt will b e 
a n al yze d as p ati e nt s at t h e d osi n g l e vel at t h e st art of st u d y treat me nt. 
T h e s p o n s or will als o fi n alize t h e p o p ul ati o n fl a g  of p ati e nt s w h o are n ot s pecifi e d i n t h e 
pr ot o c ol or t h e St atisti cal A n al ysis Pla n  b as e d o n t he a d vi ce of t h e me di cal e x p ert as 
nee d e d.  
 
1 1. 1. 1  S af et y A n al ysis S et  
T h e Saf et y A n al ysis Set is d efi n e d as p ati e nt s w h o recei ve d at l east 1 d os e of a n y of t h e 
st u d y dr u g, c yt ar a bi n e, a n d t he a nt hrac ycli n e  dr u g.  
 
1 1. 1. 2  Effi c a c y  A n al ysis S et  
T h e Effi cac y A n al ysis S et is defi n e d as pati e nt s w h o recei ve d at l east 1 d os e of t h e st u d y 
dr u g a n d w h o h a ve a vail a bl e d at a of t h e a ntit u m or effect assess e d at l east at 1 ti me p oi nt 
aft er t h e st art of st u d y tr eat me nt. 
 
1 1. 1. 3  M T D A n al ysis S et  
T h e M T D A n al ysis Set is d efi n e d as  p ati e nts w h o recei ve d at l east 1 d os e of a n y of t h e 
st u d y dr u g, c yt ar a bi n e , a n d t h e a nt hrac ycli n e  dr u g , b ut e xcl u d es t h e p ati e nts list e d b el o w.  
• 
P ati e nts w h os e D L T ass ess me nt h as n ot b ee n p erf or me d  a p pr o pri at el y b eca us e s o me 
of t h e pr o ce d ur es d uri n g t h e D L T ass ess me nt peri o d are missi n g f or ot h er reas o ns 
t h a n a d vers e dr u g r eacti o ns ( e g, w ors e ni n g of t h e cli ni cal c o n diti o n d u e t o 
pr o gr essi o n of t h e pri mar y dis eas e, A Es t h at are ass ess e d as  n ot rel at e d t o t he st u d y 
dr u g) 
• 
P ati e nts w h o h a ve t a ke n q ui zarti ni b f or t h e f oll o wi n g n u m b er of d a ys d uri n g t h e D L T 
ass ess me nt  p eri o d  
• 
T h e n u m b er of d a ys of q ui zarti ni b a d mi nistrati o n  is ≤ 9 f or p atie nts w h o h a ve 

 
 
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c o m pl et e d r e missi o n i n d ucti o n t h era p y i n C ycl e 1  
• 
T h e n u m b er of d a ys of q ui zarti ni b a d mi nistrati o n  is ≤ 9 b ot h i n C ycl e 1 a n d 
C ycl e 2 f or p ati e nts w h o ha ve pr o cee de d t o re missi o n i n d u cti o n t h era p y i n C ycl e 
2. 
 
1 1. 1. 4  P h a r m a c o ki n eti c A n al ysis S et  
T h e P har mac o ki n etic A n al ysis Set is defi n e d as p atie nt s w h o recei ve d at least 1 d os e of 
t h e st u d y dr u g, w h o pr o vi d e d s p eci me ns f or p h ar mac o ki n etic ass ess me nt, a n d w h o h a ve 
a vail a bl e meas ur e me nt d at a o bt ai n e d wit h t h e s p eci me ns.  
 
1 1. 1. 5  P h a r m a c o d y n a mi c ( Bi o m a r k er) A n al ysis S et  
T h e P har mac o d y n a mi c ( Bi o mar ker) A n al ysis Set is d efi n e d as p ati e nt s w h o recei ve d at 
least 1 d os e of t h e st u d y dr u g, w h o pr o vi d e d s p eci me ns f or t h e bi o mar ker st u d y, a n d w h o 
ha ve a vail a bl e d at a o n F L T 3 -I T D st at us o bt ai n e d wit h t h e s p eci me ns. 
 
1 1. 2  D at a H a n dli n g  
T h e s p o ns or will d eci d e t h e h a n dli n g of i n di vi d u al d at a  in c o ns ult ati o n wit h t h e me di cal 
e x p ert  a n d l o c k d at a . 
 
1 1. 3  St atisti c al A n al ysis It e ms a n d Met h o ds  
1 1. 3. 1  B as eli n e S u bj ect C h a r a ct eristi c s 
To a n al yze b as eli n e s u bj ect c h ar act eristi cs ( d e m o gra p hi c vari a bl es a n d o t h er b as eli n e 
ch ar act eristi cs ), fr e q u e n c y t a bl es will b e prep are d f or cat e g ori cal d at a a n d s u m mar y 
st atisti cs will b e calc ul at e d f or q u a ntit ati ve d at a.   An al ys es will b e p erf or me d o n t h e 
Saf et y A n al ysis Set , Effi cac y A n al ysis Set, M T D A n al ysis  Set, P h ar mac o ki n eti c A n al ysis 
Set , a n d P h ar mac o d y n a mi c ( Bi o mar ker) A n al ysis Set. 
 
1 1. 3. 2  S af et y A n al ysis  
Ot her s af et y a n al ys es t h a n D L T a n al ys es will b e p erf or me d o n t h e Safet y A nal ysis Set, 
w h er eas D L T a n al ys es will b e p erf or me d o n t h e M T D A n al ysis Set.  
A Es t h at o cc ur  or w ors e n r el ati ve t o t h e pre -treat me nt st ate aft er t h e st art of st u d y 
tr eat me nt (tr eat me nt e mer ge nt A Es [ T E A Es]) will b e t a b ul at e d.    A Es c oll ect e d i n t h e 
st u d y will b e c o d e d usi n g t h e M e dical Di cti o n ar y f or Re g ul at or y Acti viti es ( M e d D R A) 
ter mi n ol o g y d e vel o p e d b y t h e I nt er n ati o n al C o nfere n ce o n Har m o nis ati o n of Tec h ni ca l 
Re q uir e me nts f or Re gistr ati o n of P har mace uti cals f or H u ma n Us e  (I C H), a n d b e 

 
 
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ta b ul at e d b y b o d y or ga n gr o u p usi n g t h e M e d D R A syst e m or ga n c lass ( S O C) a n d b y A E 
ter m usi n g pr ef err e d t er ms ( P T). 
 
1 1. 3. 2. 1  
A d vers e E v e nts  
F or all T EA Es  a n d T E A Es ass ess e d as “rel at e d” t o t h e st u d y dr u g or  a c o a d mi nist ere d  
dr u g ( c yt ar a bi ne or t h e a nt hr ac ycli n e dr u g) , fre q u e n c y t a bl es will b e pre p are d f or p atie nts 
wit h T E A Es as cl assifie d bel o w.  
T h e gr a d e of eac h A E will b e ass ess e d acc or di n g t o t h e C T C A E v 4. 0 J a p a nes e versi o n.  
• 
T E A Es ( b y gr a d e; i n cl u di n g cl assifi cati o n i nt o ≥ Gra d e 3 e ve nts a n d ot hers)  
• 
S eri o us T E A Es  
• 
P ati e nts w h o h a ve p ost p o n e d a d mi nistrati o n  of t h e st u d y dr u g d u e t o T E A Es  
• 
P ati e nts w h o h a ve p ost p o n e d a d mi nistrati o n  of a c o a d mi nist ere d  dr u g ( c yt ara bi n e or 
t h e a nt hr ac ycli n e dr u g) d ue t o T E A Es 
• 
P ati e nts wit h tr eat me nt dis c o nti n u ati o n b eca us e of T E A E  
 
1 1. 3. 2. 2  
I n di vi d u al A d vers e E v e nts 
F or all T EA Es  a n d T E A Es ass ess e d as “rel at e d” t o t h e st u d y dr u g or  a c o a d mi nist ere d  
dr u g ( c yt ar a bi ne or t h e a nt hr ac ycli n e dr u g) , fre q u e n c y t a bl es will b e pre p are d acc or di n g 
t o t h e f oll ow i n g cat e g ori es.   If a p ati e nt  re p orts t he s a me e ve nt s e veral ti mes, o nl y t h e 
hi g h est- gr a d e e ve nt will be c o u nt e d f or t a b ul ati o n  b y gra d e.  
• 
T E A Es  
• 
T E A Es b y gr a d e (i n cl u di n g cl assifi cati o n i nt o ≤ Gra d e 2 e ve nts a n d ≥ Gr a d e 3 
e ve nts) 
• 
T E A E s l ea di n g t o p ost p o ne me nt of a d mi nistrati o n  of t h e st u d y dr u g  
• 
T E A E s l ea di n g t o p ost p o ne me nt of a d mi nistrati o n  of a c o a d mi nist ere d  dr u g 
(c yt ar a bi n e or t h e a nt hr ac ycli ne  dr u g)  
• 
T E A Es ca usi n g tr eat me nt dis c o nti n u ati o n  
 
1 1. 3. 2. 3  
D os e -li miti n g To xi cit y 
D L Ts will be s u m mari ze d b y fr e q u e n c y t a bl es. 
 
1 1. 3. 2. 4  
L a b or at o r y D at a  
F or he mat ol o g y a n d bl o o d c h e mistr y t ests, s u m m ar y statisti cs of meas ure d val u es a n d 
c h a n ges fr o m b as eli n e  will b e calc ul ate d at eac h ti me p oi nt.    F or uri n al ysis  (e xce pt 
s p ecifi c gr a vit y), s hift t a bl es of meas ure d val u es at b as eli n e a n d t h os e at  eac h ti me p oi nt 

 
 
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will b e pre p ar e d .    F or s pecifi c gr a vit y, s u m mar y st atisti cs will b e cal c ul at e d at eac h ti me 
p oi nt. 
 
1 1. 3. 2. 5  
Vit al Si g ns  a n d B o d y Wei g ht  
F or bl o o d pr ess ur e (s yst oli c a n d di ast oli c), p uls e rat e, b o d y t e m p erat ure, a n d b o d y wei g ht, 
s u m mar y st atisti cs of meas ur e d val u es a n d c h a n g es fr o m b as eli n e  will b e cal c ul at e d at 
eac h ti me p oi nt.  
 
1 1. 3. 2. 6  
1 2- l e a d El ect r o c a r di o g r a m 
F or 1 2 -l ea d E C G fi n di n gs, s hift t a bles of n or mal- a b n or mal ass ess me nts bef ore t h e first 
d ose of t h e st u d y dr u g a n d at eac h ti me p oi nt will be pre p are d .    F or P R, Q R S, R R, Q T, 
a n d Q Tc F i nt er vals a n d h eart r ate, s u m mar y st atistics of meas ure d val u es a n d c h a n ges 
fr o m bas eli n e  will b e cal c ul at e d at eac h ti me p oi nt.   F or Q Tc F, fre q u e n c y ta bl es will b e 
pr e p are d acc or di n g t o t h e f oll o w i n g cat e g ori es. 
I n cr eas e i n a bs ol ut e Q Tc F: 
• 
Q Tc F > 4 5 0 ms 
• 
Q Tc F > 4 8 0 ms 
• 
Q Tc F > 5 0 0 ms 
C h a n ges i n Q Tc F fr o m b as eli n e : 
• 
I n cr eas e i n Q Tc F fr o m b as eli n e > 3 0 ms  
• 
I n cr eas e i n Q Tc F fr o m b as eli n e > 6 0 ms  
 
1 1. 3. 3  Effi c a c y  A n al ysis  
I n t h e Effi cac y A n al ysis Set, fr e q u e n c y t a bles will b e pre p are d f or C R,  C R p,  C Ri,  P R,  
a n d N R at eac h ti me p oi nt as well as f or b est res p o ns e.    T h e C Rc rat e ( C R + C R p + 
C Ri), r es p o ns e r at e ( C Rc + P R), a n d t heir 9 5 % c o nfi d e n ce i nt er vals will b e cal c ul ate d.  
 
1 1. 3. 4  P h a r m a c o ki n eti c A n al ysis  
I n t h e P h ar mac o ki n eti c A n al ysis Set , s u m mar y statisti cs of t he pl as ma c o nce ntrati o ns of 
q ui zarti ni b a n d A C 8 8 6  will b e calc ul ate d b y d os e at eac h ti me p oi nt, a n d  plas ma 
c o n ce ntr ati o n -ti me pr ofil es will b e pre p are d.  S u m mar y st atisti cs of p h ar mac o ki n etic 
par a met ers will als o b e cal c ul at e d.  
 
1 1. 3. 5  P h a r m a c o d y n a mi c ( Bi o m a r k er) A n al ysis  
I n t h e P h ar mac o d y n a mi c ( Bi o mar ker) A n al ysis Set, fre q u e n c y t a bl es will be pre p are d f or 

 
 
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t h e F L T3- I T D st at us a n d t h e c -KI T m ut ati o n  st at us.   F or p h os p h o r yl ate d F L T 3, S T A T 5, 
a n d c -KI T pr ot ei n l e vels i n bl o o d a n d t h e i n hi bit or y acti vit y of pl as ma q ui zarti ni b o n 
p h os p h or yl at e d F L T 3 pr ot ei n, t h e meas ure d val u es will b e s u m mari ze d at eac h ti me 
p oi nt. 
 
1 1. 4  C h a n g es t o t h e A n al ysis Pl a n  
If it is c o nsi d er e d n ecess ar y t o c h a n ge t h e pl a n n e d a n al ys es, t h e s p o ns or will e xa mi n e t h e 
a p pr o pri at e n ess  of t h e c h a n ge a n d p ot e nti al effects o n t h e st u d y res ults, a n d det er mi n e 
w h et h er t o ma ke t h e c ha n ge or n ot.    T h e s p o ns or will cl earl y d o c u me nt a n d ret ai n t h e 
c o nt e nt of e xa mi n ati o n  of  t h e c h a n ge i n t h e pl a n n e d a n al ys es, t h e pres e n ce or a bs e n ce of 
t h e c h a n ge, a n d if t h e c h a n ge is ma d e, t h e reas o n.    If a c h a n ge i n t h e pl a n ne d a n al ys es is 
ma d e , t he det ails of a n d t he r eas o n f or t h e c h a n ge will b e d o c u me nt e d i n t h e cli ni cal 
st u d y r e p ort. 
 
1 1. 5  Pl a n n e d S a m pl e Si ze  
Si x t o t wel ve p ati e nts ( mi ni m u m of 3 p ati e nt s at eac h l e vel, a t otal of 6 p atie nt s) 
 
< R ati o n al e > 
T h e s a m pl e si ze was s et as a mi ni m u m of 3 p ati e nt s at eac h l e vel a n d it was pl a n n e d t o 
a d diti o n all y e nr oll u p t o 6 pati e nt s b as e d o n t h e st at us of o cc urre n ce of D L Ts i n refere n ce 
t o t h e G ui d eli n es f or t h e Cli ni cal E val u ati o n of A nti ca ncer Dr u gs .1 7) 
 

 
 
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1 2.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T h e s p o ns or will i m pl e me nt t h e q u alit y ass ura n ce a n d q u alit y c o ntr ol s yst e m i n 
acc or d a n ce wit h t h e st a n dar d o p er ati n g pr o ce d ures s p ecifi e d b y t h e s p o ns or t o e ns ure t h at 
t h e i m pl e me nt ati o n of t h e st u d y a n d t h e ge n erati o n, rec or di n g, a n d re p orti n g of d at a are 
i n c o m pli a n ce wit h t h e f oll o wi n g: 
1)  T h e cli ni cal st u d y pr ot o c ol 
2)  St a n d ar ds sti p ul ate d i n Arti cl e 1 4, P ara gra p h 3 a n d Arti cl e 8 0 -2 of t h e Act o n 
Sec uri n g Q u alit y, Effi cac y a n d Safet y of P har mace uti cals, M e di cal De vi ces, 
Re ge n er ati ve a n d Cell ul ar T h er a p y Pr o d u cts, Ge n e T h era p y Pr o d ucts, a n d C os meti cs 
( h er ei n aft er, t he P M D A ct)  
3)  G C P  or di n a n ce 
I n a d diti o n, t h e s p o ns or will p erf or m q ualit y c o ntr ol at eac h st a ge of d at a ha n dli n g t o 
e ns ur e t he r eli a bilit y a n d pr o p er pr o cessi n g of all st u d y -rel at e d d at a.    T h e met h o ds f or 
q u alit y c o ntr ol will b e pr e p ar e d i n a d va n ce i n acc or d a n ce wit h t h e st a n d ar d o p erati n g 
pr o ce d ur e s p ecifi e d b y t he s p o ns or, a n d t h e i m pl e me nt ati o n will b e rec or de d.  
T h e s p o ns or’s r es p o nsi bl e a u dit or will p erf or m G C P a u diti n g as p art of q u alit y ass ura nce 
o p er ati o ns t o d et er mi n e w h et h er t h e st u d y is c o n d u ct e d i n c o m plia n ce wit h G C P, t h e 
cli ni cal st u d y pr ot o c ol, a n d t h e writt e n pr o ce d ures i n d e p e n d e ntl y a n d s e p arat el y fr o m t h e 
r e g ul ar m o nit ori n g a n d st u d y q u alit y c o ntr ol o p erati o ns. 
 

 
 
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1 3.  P A Y M E N T F O R P A R TI CI P A TI O N, C O M P E N S A TI O N F O R 
S T U D Y -R E L A T E D I N J U RI E S, A N D I N S U R A N C E  
1 3. 1  P a y me nt f o r P a rti ci p ati o n 
As p a y me nts f or r e d u ci n g t h e s u bj ect ’s b ur d e n, th e st u d y ce nt er will p a y s u bj ects fr o m 
t h e f u n ds p ai d b y t h e s p o ns or t o t h e st u d y ce nt er acc or di n g t o t h e s e p arat el y s p ecifi e d 
r e g ul ati o ns of t h e st u d y ce nt er. 
 
1 3. 2  C o m p e ns ati o n f o r St u d y -rel ate d I nj u ri es  
If a s u bj ect e x p eri e nces a n y st u d y-r el at e d i nj ur y res ulti n g fr o m p arti ci p ati o n i n t h e st u d y, 
t h e i n vesti gat or or s u bi n vesti gat or will t a ke t h e n ecess ar y acti o ns, i n cl u di n g treat me nt.   
If t h e s u bj ect ma kes a cl ai m f or st u d y-rel at e d i nj ur y, t h e s p o ns or will b e pr o m ptl y 
n otifi e d.  
T h e s p o ns or will s p ecif y t h e pr o ce d ures f or c o m p e ns ati o n f or st u d y -rel at e d i nj ur y 
r es ulti n g fr o m p arti ci p ati o n i n t h e st u d y a n d t a ke acti o ns s u c h as p urc h as e of a n i ns ura n ce 
p oli c y.   I n t h e e ve nt of a n y st u d y-r el at e d i nj ur y occ urri n g  i n a s u bj ect, th e s p o ns or will 
bear t he e x p e ns es t hat ar e p ai d b y t h e s u bj ect f or treat me nt of  t h e i nj ury, e xcl u di n g t he 
a m o u nt c o ver e d b y h ealt h i ns ur a n ce , et c.   F or i nj uri es t h at are as s e vere as re q uiri n g 
h os pit ali zati o n, t he s p o ns or w ill als o p a y a me di cal all o wa n ce b as e d o n t h e a m o u nt set i n 
t h e Reli ef S yst e m f or S uff er ers fr o m A d vers e Dr u g Reacti o ns.    H o we ver, t h e s p o ns or 
will n ot a gr ee t o i n d e m nif y t h e s u bj ect f or st u d y-r el at e d i nj uri es arisi n g u n der t h e 
f oll o wi n g cir c u mst a n ces: 
1)  If th ere is cl ear e vi d e n ce of a n y ot h er ca us e of st u d y -rel at e d i nj ur y. 
2)  If th ere is n o r eas o n a bl e te m p or al rel ati o ns hi p b et wee n a d mi nistrati o n of t he st u d y 
dr u g a n d t h e o cc urr e n ce of t h e st u d y-rel at e d i nj ur y. 
3)  If a p er p etr at or h as bee n i d e ntifi e d (f or i nst a nce,  traffi c acci d e nt). 
4)  If t h er e wer e n o t her a p e uti c b e n efits b eca us e of l ac k of effi cac y. 
5)  If a s u bj ect or a s u bj ect’s p art n er is f o u n d t o be pre g n a nt d uri n g t h e st u d y. 
6)  If th ere is a n y pr ot o c ol vi ol ati o n wit h o ut d u e reas o n.  
If a st u d y-r el at e d i nj ur y is ca us e d b y a n i nt e nti o nal act or gr oss n e gli ge n ce o n t h e p art of 
t h e st u d y ce nt er or t h e s u bj ect, c o m p e ns ati o n ma y n ot b e p ai d or ma y b e re d u ce d. 
 
1 3. 3  I ns u r a n ce 
I n cas e of c o m p e ns ati o n f or st u d y-r el at e d i nj ur y, t he s p o ns or will p urc h as e a n i ns ura nce 
p oli c y as r e q uir e d.    I n cas e of st u d y- rel at e d i nj ur y d u e t o me di cal mal practi ce, t h e st u d y 
ce nt er will p ur c h as e a n i ns ur a n ce p oli c y a n d ta ke ot h er meas ures as re q uire d.  

 
 
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1 4.  P U B LI C A TI O N P O LI C Y  
1)  N o i nf or mati o n o bt ai n e d fr o m t h e st u d y ma y  b e p u blis h e d p artiall y or e ntirel y 
wit h o ut pri or c o ns ult ati o n wit h t h e s p o ns or.    T h e met h o ds of p u bli cati o n will b e 
det er mi n e d b y t h e s p o ns or.    Ut m ost ca uti o n s h o ul d b e e xercis e d t o pr ot ect t h e 
pri vac y of s u bj ects w h e n i nf or mati o n is p u blis h e d.  
2)  T h e s p o ns or will us e i nf or mati o n o bt ai n e d fr o m t he st u d y f or t h e p ur p os e of 
a p pli cati o n f or ma n uf act uri n g/ mar keti n g a p pr o val of t he i n vesti gati o n al dr u g.    If t h e 
i n vesti gati o n al dr u g is a p pr o ve d, i nf or mati o n a b o ut t h e st u d y ma y b e p arti all y 
dis cl os e d i n acc or d a n ce wit h t h e “ Act o n Access t o I nf or mati o n Hel d b y 
A d mi nistr ati ve Or ga ns ( Act N o. 4 2, d at e d 1 4 M a y 1 9 9 9),” “ Act o n Access t o 
I nf or mati o n Hel d b y I n d e p e n d e nt A d mi nistrati ve A ge n ci es ( Act N o. 1 4 0, dat e d 5 
Dec 2 0 0 1),” a n d “ N otifi cati o n c o n cer ni n g p u bli cati o n of i nf or mati o n o n n e w dr u g 
a p pr o vals ( P F S B/ E L D N o tifi cati o n N o. 0 4 2 2 0 0 1, dat e d 2 2 A pr 2 0 0 5). ”  Ut m ost 
ca uti o n s h o ul d b e e xer cise d t o pr ot ect t h e pri vac y of s u bj ects w h e n dis cl osi n g 
i nf or mati o n. 
 

 
 
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1 5.  S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N  
1 5. 1  Et hi cs  
1 5. 1. 1  Et hi c al C o n d u ct of t h e St u d y  
T his st u d y will b e c o n d u ct e d i n c o m pli a n c e wit h t h e st a n d ar ds sti p ul at e d i n Arti cl e 1 4, 
P ar a gr a p h 3 a n d Arti cl e 8 0 -2 of t h e P M D Act a n d t h e “ Or di n a n ce o n G o o d Cli ni cal 
Practi ce” ( M H W Or di na nce N o. 2 8, d at e d 2 7 M ar 1 9 9 7) ( h erei n aft er , t h e G C P or di n a n ce).   
It will als o b e c o n d u ct e d i n c o m pli a n ce wit h t h e et hi cal pri n ci pl es of t h e D ecl arati o n of 
Helsi n ki t o e ns ur e t hat t h e h u ma n ri g hts, well b ei n g, a n d safet y of s u bj ects are pr ot ecte d 
t o t h e ma xi m u m e xt e nt. 
T h e ge n o me/ ge n e a n al ysis t o b e p erf or me d d uri n g  t h e st u d y will b e p erf or me d i n 
acc or d a n ce wit h t h e “ Et hical G ui d eli n es f or H u ma n Ge n o me/ Ge n e A n al ysis Res earc h 1 8)” 
a n d t h e  “Et hi cal G ui d eli nes f or Cli ni cal St u di es 1 9)” i n a d diti o n t o t h e a b o ve- me nti o n e d 
r e g ul ati o ns. 
 
1 5. 1. 2  I nstit uti o n al R e vi e w B o ar d 
Pri or t o t h e start of t h e st u d y, it m ust b e re vi e we d a n d a p pr o ve d b y t h e I nstit uti o n al 
Re vi e w B o ar d (I R B) s p ecifi e d i n Secti o n 2 7 of t h e G C P or di n a nce.    D uri n g t h e c o urs e 
of t h e st u d y, t h e a p pr o pri at e n ess of st u d y c o nti n u ati o n will b e re vi e we d a n n u all y, or m ore 
fr e q u e ntl y u p o n t h e I R B’s r e q u est.    T h e a p pr o pri at e n ess of st u d y c o nti n u ati o n will als o 
be r e vie we d if a n y i nf or mati o n t h at ma y affect t h e s afet y of s u bj ects or t h e c o n d u ct of t h e 
st u d y is o btai n e d. 
 
1 5. 2  S u bj ect C o nfi d e nti a lit y 
To pr ot ect t h e pri vac y of i n di vi d u al s u bj ects, t h e s u bj ect i d e ntificati o n c o de  a n d s u bj ect 
n u m b er, rat h er t h a n t h e n a me or me di cal c h art n u m b er t h at ma y l ea d t o p ers o n al 
i d e ntifi cati o n, will b e us e d t o i d e ntif y s u bj ects i n t h e d o c u me nts s u b mitte d o utsi d e t h e 
st u d y ce nter.    A n y p ers o n al i nf or mati o n o bt ai n e d  i n t h e c o urs e of t h e st u d y will b e ke pt 
c o nfi d e nti al.  
 
1 5. 3  Pr o ce d u res f o r I nf o r me d C o nse nt  
T h e i n vesti gat or or s u bi n vesti gat or will e x pl ai n t h e d et ails of t h e st u d y list e d b el o w t o 
s u bj ect ca n did at e s i n a r ea dil y u n d erst a n d a bl e wa y usi n g t h e i nf or me d c o nse nt 
d o c u me nts , b ef or e a n y i n vasi ve pr o ce d ures rel at e d t o t h e st u d y are p erf or me d i n eac h 
s u bj ect, a n d o bt ai n writt e n i nf or me d c o ns e nt t o p arti ci p at e i n t h e st u d y  b y t h eir free will .  
Bef or e o bt ai ni n g c o ns e nt, t h e i n vesti gat or or s u bi n vesti gat or s h o ul d gi ve t he s u bj ect 

 
 
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ca n di d at es a m pl e ti me a n d o p p ort u nit y t o as k q u esti o ns t o d eci de w h et h er t o p arti ci p at e 
i n t h e st u d y, a n d s h o ul d a ns wer t h e q u esti o ns i n a n a p pr o pri at e ma n n er.  
Bef or e t h e st art of st u d y dr u g a d mi nistrati o n  i n C ycl e 1 of c o ns oli d ati o n t hera p y, writt e n 
i nf or me d c o ns e nt t o c o nti n u e p arti ci p ati o n i n t h e st u d y aft er t h e e n d of t h e D L T 
ass ess me nt  p eri o d will b e o bt ai ne d a gai n fr o m t h e s u bj ects.    F or s u bj ects w h o 
e x p eri e n ce d a n y D L Ts d uri n g t h e D L T ass ess me nt p eri o d , writt e n i nf or me d c o ns e nt t o 
c o nti n u e p arti ci p ati o n i n t h e st u d y will b e o bt ai n e d a gai n b ef ore res u mi n g t h e st u d y dr u g 
a d mi nistr ati o n  aft er r ec o ver y fr o m t h e t o xi cit y. 
T h e i n vesti gat or or s u bi n vesti gat or w h o h a s pr o vi de d a n e x pl a n ati o n a n d  t he s u bj ect w h o 
has gi ve n c o ns e nt will si g n a n d d at e t h e c o ns e nt f or m.    If st u d y st aff p ers o n nel pr o vi d e a 
s u p pl e me nt ar y e x pl a n ati o n t o t h e s u bj ect ca n di d ate s, t he st u d y st aff s h o ul d si g n a n d d at e 
t h e f or m.    T he i n vesti gat or or s u bi n vesti gat or will pr o vi de a c o p y of t h e c o nse nt f or m 
al o n g wit h t h e s u bj ect i nf or mati o n f or m t o t h e s u bj ect, a n d retai n th e ori gi nal c o ns e nt 
f or m at  t h e st u d y ce nt er.    T h e i n vesti gat or or s u bi n vesti gat or will d o c u m e nt (e g, i n t h e 
ori gi n al c o ns e nt f or m or me di cal rec or d) t h at a c o p y of t h e c o ns e nt f or m a n d s u bj ect 
i nf or mati o n f or m h a ve b ee n pr o vi d e d t o t h e s u bject.  
[It e ms t o b e e x pl ai n e d t o t h e s u bj ects] 
1)  T h at t h e st u d y i n v ol ves r es ear c h  
2)  St u d y o bj ecti ves  
3)  St u d y met h o ds ( i ncl u di n g t h e r esearc h as p ects of t h e st u d y a n d t h e i n cl usi o n a nd 
e xcl usi o n crit eri a of t h e st u d y)  
4)  T h e e x p ect e d d urati o n of eac h s u bj ect’s p arti ci p ati o n i n t h e st u d y  
5)  Pla n n e d n u m b er of s u bj ects i n t h e st u d y  
6)  F ores eea bl e p h ysi cal a n d me nt al b e n efits a n d ris ks ass o ciat e d wit h t h e st u d y dr u g  
7)  Pres e n ce or a bs e n ce of ot h er tr eat me nt met h o ds a n d e x p ect e d i m p ort a nt b e n efits a n d 
ris ks of t h e met h o ds 
8)  C o m p e ns ati o n a n d tr eat me nt t h at t h e s u bj ect ca n recei ve if a n y st u d y -rel ate d i nj ur y 
occ urs as a r es ult of p arti ci p ati o n i n t h e st u d y  
9)  St at e me nt s t h at p arti ci p ati o n i n t h e st u d y is bas e d  o n  t h e s u bj ect’s o w n free will; t h at 
t h e s u bj ect ca n r ef us e t o parti ci p at e i n, or wit h dra w fr o m, t h e st u d y at a n y ti me; t hat 
he/s h e will n ot b e disa d va nt a ge d e ve n if h e/s h e ref us es t o parti ci p at e i n or wit h dra w 
fr o m t h e st u d y; a n d t h at he/s h e will n ot l ose a n y be n efits t h at w o ul d h a ve bee n gi ve n , 
e ve n if h e/s h e d o es n ot p arti ci p at e i n t h e st u d y  
1 0)  A stat e me nt t h at t h e s u bj ect will b e pr o m ptl y i nf or me d if a n y i nf or mati o n t h at ma y 
aff ect his / her willi n g n ess t o c o nti n ue parti ci p at i o n i n t h e st u d y is o bt ai n e d 

 
 
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1 1)  C o n diti o ns or r eas o ns f or wit h dr a wal fr o m t h e st u d y  
1 2)  St at e me nts t h at t h e cli ni cal res earc h ass o ci at es, res p o nsi bl e a u dit ors, I R B, a n d 
r e g ul at or y a ut h oriti es ca n access s o urce d o c u me nts; t h at i n s uc h a cas e, t h e s u bj ect’s 
pri vac y will b e pr ot ecte d; a n d t h at t h e  s u bj ect is d ee me d t o h a ve c o ns e nt e d t o s u c h 
access b y writi n g his / h er n a me a n d affi xi n g his / h er s eal o n or si g ni n g t h e c o ns e nt 
f or m 
1 3)  A stat e me nt t h at t h e s u bj ect’s pri vac y will b e pr ot ect e d e ve n if t h e res ults of t h e 
st u d y ar e p u blis h e d 
1 4)  Det ails of e x p e ns es  t h e s u bj ect nee ds t o p a y, if a n y 
1 5)  Det ails of p a y me nt t o t h e s u bj ect, if a n y  
1 6)  Na me, titl e, a n d c o nt act i nf or mati o n of t h e i n vesti gat or or s u bi n vesti gat or  
1 7)  C o nt act i nf or mati o n of  t he st u d y ce nter i n t h e e v e nt t h at t h e s u bj ect re q uires f urt h er 
i nf or mati o n r e gardi n g t h e st u d y or t h e ri g hts of s u bj ects, or i n t h e e ve nt of 
st u d y-r el at e d i nj ur y 
1 8)  Res p o nsi biliti es of s u bj ects  
1 9)  T h e t y p e of I R B t h at e val u at es a n d re vi e ws t h e a p pr o priat e n ess of t h e st u d y, it e ms t o 
be e val u at e d a n d r e vi e w e d b y t h e I R B, a n d ot h er matt ers re g ar di n g t h e I R B i n 
r el ati o n t o t h e st u d y 
 
1 5. 4  I nf or me d C o ns e nt f o r P h a r m a c o ge n o mi cs/ Bi o m a r k er St u d y 
T h e i n vesti gat or or s u bi n vesti gat or will e x pl ai n t h e d et ails of t h e st u d y list e d b el o w t o 
s u bj ect ca n di d at es i n a r ea dil y u n d erst a n d a bl e wa y t o c o nfir m t h eir wil li n g n ess t o pr o vi de 
c o ns e nt t o p arti ci p at e i n t h e bi o mar ker st u d y  b y t heir free will , a n d o bt ai n t h e res ult i n 
writi n g .  T h e i nf or me d c o ns e nt f or ms f or t h e c ore cli ni cal st u d y a n d t h e bi o mar ker st u d y 
will b e pre p ar e d i n a o ne -u nit f or mat.    T h e i n vesti gat or  or s u bi n vesti gat or will e ns ure 
t h at t h e s u bj ect’s d ecisi o n o n t h e c o ns e nt h as bee n e nt ere d i n t h e c o n cer n e d s ecti o n of t h e 
i nf or me d c o ns e nt f or m. 
1)  C h ar act eristi cs a n d pr o p erti es of ge n eti c i nf or mati o n 
2)  St u d y o bj ecti ves  
3)  St u d y met h o ds  
4)  F ores eea bl e p h ysi cal a n d  me nt al b e n efits  a n d ris ks ass o ciat e d wit h  t h e st u d y 
5)  St at e me nts t h at p arti ci p ati o n i n t h e p h ar mac o ge n o mi cs  st u d y is b as e d o n t he 
s u bj ect’s o w n fr ee will a n d t h at t h e s u bj ect ca n ref us e t o p arti ci p at e i n, or wit h dra w 
fr o m, t h e st u d y at a n y ti me; t h at h e/s h e will n ot be dis a d va nt a ge d e ve n if h e/s h e 
wit h dr a w s his/ h er c o ns e nt; t hat p arti ci p ati o n i n t he c ore st u d y will n ot b e affect e d b y 

 
 
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r ef usal t o p artici p ate i n t he bi o mar ker  st u d y. 
6)  Ha n dli n g of s p eci me ns a n d d at a aft er wit h dra wal of c o ns e nt  
7)  Matt ers o n t h e met h o d of h a n dli n g, d urati o n of st ora ge, a n d dis p os al of s p eci me ns  
8)  C o m p e ns ati o n a n d tr eat me nt t h at t h e s u bj ect ca n recei ve  
9)  Discl os ur e of st u d y r es ults a n d t o w h o m t h e res ults b el o n g  
1 0)  Det ails of e x p e ns es t h e s u bj ect nee ds t o p a y, if a n y  
1 1)  A stat e me nt t h at n o p a y me n t is ma d e f or s p eci me ns pr o vi d e d b y t h e s u bj ect 
1 2)  Pr ot ecti o n of h u ma n ri g hts, i n cl u di n g t h e s u bj ect ’s pri vac y 
 
1 5. 5  Pr o visi o n of N e w I nf o r m ati o n Affecti n g t h e C o n d u ct of t h e St u d y  
If a n y i nf or mati o n t h at ma y aff ect t he s u bj ect’s willi n g ness t o p arti ci p at e  i n t h e st u d y is 
o bt ai n e d, t h e i n vesti gat or or s u bi n vesti gat or will pr o m ptl y i nf or m t h e s u bj ect a n d 
c o nfir m t h e s u bj ect’s willi n g n ess t o c o nti n ue parti ci p at i o n i n t h e st u d y.    T he i n vesti gat or 
or s u bi n vesti gat or will als o d oc u me nt  t h e d at e of e x pl a n ati o n, t h e p ers on w h o h as gi ve n 
t h e e x pla n ati o n, t h e d et ails of t h e e x pl a n ati o n, t h e s u bj ect’s d ecisi o n , a n d t he d at e of 
c o nfir m i n g t h e s u bj ect’s willi n g ness i n t h e me di cal rec or d, etc .   T h e i n vesti gat or will 
pr o m ptl y r e vis e t h e c o ns e nt f or m  a n d s u bj ect i nf or mati o n f or m , as n ecess ar y, a n d s u b mit 
t h e m t o t h e s p o ns or.   T he i n vesti gat or will als o re p ort t h e re vis e d f or ms t o t h e h ea d of 
t h e st u d y ce nt er a n d gai n a p pr o val b y t he I R B.    W he n a n y s u bj ects are alrea d y 
parti ci p ati n g i n t h e st u d y  as of t h e ti me of a p pr o v al b y t h e I R B, t h e i n vesti gat or or 
s u bi n vesti gat or will o bt ai n t h eir c o ns e nt t o c o nti n ue p arti ci p ati o n i n t he st u d y a gai n i n t h e 
sa me ma n n er as t h e a b o ve-me nti o n e d pr o ce d ure usi n g t h e re vis e d c o ns e nt f or m  a n d 
s u bj ect i nf or mati o n f or m.    A c o p y of t h e c o ns e nt f or m a n d s ubj ect i nf or mati o n f or m will 
be pr o vi d e d t o t h e s u bj ects.    T h e ori gi n al i nf or me d c o ns e nt f or m will b e ret ai n e d at t he 
st u d y ce nter.  T h e i n vesti gat or or s u bi n vesti gat or will d o c u me nt (e g, i n t h e ori gi n al 
c o ns e nt f or m or me di cal r ec or d) t h at a c o p y of t h e c o ns e nt f or m a n d s u bject i nf or mati o n 
f or m ha ve b ee n pr o vi d e d t o t h e s u bj ect. 
 
1 5. 6  Pl a n n e d St u d y Peri o d 
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1 5. 7  Pr ot o c ol A me n d me nt  
If a n a me n d me nt t o t h e cli ni cal st u d y pr ot o c ol is c o nsi d ere d aft er t h e st art of t h e st u d y, 
t h e s p o ns or will e xa min e t h e a p pr o pri at e n ess  of t he a me n d me nt a n d p ot e nti al i nfl u e n ces 
o n t h e st u d y r es ults t hr o u g h dis c ussi o n wit h t h e me di cal e x p ert, et c., if n ecess ar y, a n d 

 
 
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det er mi n e w h et h er t o ma ke t h e a me n d me nt  or n ot.    T h e s p o ns or will cl earl y d o c u me nt 
a n d r etai n t h e c o nt e nt of t h e disc ussi o n, t h e pres e nce or a bs e n ce of t h e a me n d me nt, a n d 
t h e r eas o n, et c. 
T h e s p o ns or will pr o m ptl y n otif y t h e i n vesti gat or of t h e s p ecifi c d et ails of t h e 
a me n d me nt t o t h e pr ot o c ol.    If t h e pr ot o c ol is u p dat e d t o a n e w versi o n, t he s p o ns or will 
ne wl y o bt ai n writt e n a gr ee me nt of t h e i n vesti gat or a n d i m pl e me nt t h e pr o ce d ures 
s p ecifi e d b y t h e st u d y ce nt er. 
 
1 5. 8  Per m a ne nt o r Te m p o r a r y Dis c o nti n u ati o n of t he St u d y  
If a n y of t h e f oll o wi n g o cc ur a n d t h e s p o ns or j u d ges t h at c o nti n u ati o n of t he st u d y is 
diff i c ult, t h e s p o ns or will t e m p or aril y dis c o nti n u e t h e st u d y.    T h e s p o ns or will t h e n 
det er mi n e w h et h er t o p er ma n e ntl y dis c o nti n u e t h e e ntire st u d y, a n d d o c u me nt t h e 
decisi o n. 
1)  If a n y n e w s afet y i nf or mati o n r e gar di n g t h e st u d y dr u g, or i nf or mati o n re g ar di n g 
S A E s is o bt ai n e d 
2)  If a n y maj or G C P vi ol ati o n or si g nifi ca nt pr ot o c ol d e vi ati o n is c o m mitte d b y t h e 
s p o ns or, t h e st u d y ce nt er, or t h e i n vesti gat or 
3)  If a n y ot h er n e w i nf or mati o n of s u c h rel e va n ce is o bt ai n e d d uri n g t h e st u d y 
If t h e s p o ns or d eci d es t o dis c o nti n u e t h e st u d y e ntirel y aft er c o ns ult ati o n wit h t he 
me di cal e x p ert  etc., t h e s p o ns or will pr o m ptl y n otif y t h e h ea d of t h e st u d y ce nt er i n 
writi n g a n d t h e r eas o n f or t h e dis c o nti n uati o n.   T he h ea d of t h e st u d y ce nt er will 
pr o m ptl y n otif y t h e i n vesti gat or a n d t h e I R B i n writi n g of t h e i nf or mati o n o bt ai n e d fr o m 
t h e s p o ns or. 
If t h e st u d y is dis c o nti n u e d p er ma n e ntl y or t e m p oraril y, t h e i n vesti gat or will pr o m ptl y 
n otif y t h e s u bj ects p arti ci p ati n g i n t h e st u d y of t h e fact, a n d t a ke a p pr o pri at e acti o ns a n d 
perf or m t h e necess ar y t ests t o verif y t h e s afet y of s u bj ects. 
 
1 5. 9  Pr o ce d u res f o r Pre p a ri n g t h e C as e Re p o rt F o r m a n d R e m a r ks  
I n t h e st u d y, th e C R F will b e pr e p ar e d b y t h e i n vesti gat or,  a n d t he meas ure me nt re p orts 
of 1 2- l ea d E C G, p h ar ma c o ki n eti cs, a n d bi o mar kers will be pre p are d  b y ea c h ce ntral 
la b or at or y.  T h e pr o ce d ur e f or pr e p arati o n of meas ure me nt re p orts b y eac h meas ure me nt 
f acilit y will b e s p ecifi e d se p ar at el y. 
 
1 5. 9. 1  St yl e of t h e C ase R e p o rt F o r m  
I n t his st u d y, a n el ectr o ni c C R F will b e rec or d e d usi n g t h e el ectr o ni c d at a capt uri n g  

 
 
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(E D C ) s yst e m ( “Ta bl e 1 5. 9 - 1 E D C S yst e m ”), w hic h is d esi g n e d t o pre p are el ectr o ni c 
C R Fs.    T h e C R F (i n cl u di n g a n a u dit trail) will b e pre p are d f or eac h s u bj ect a n d t h e o ne 
t h at was si g n e d b y t h e i n vesti gat or will b e h a n dl e d as t h e ori gi n al.    A vali dat e d E D C 
s yst e m will b e us e d i n t h e st u d y. 
 
Ta bl e 1 5. 9 - 1  E D C S yst e m  
E D C s yste m n a me  
Me di d ata R a v e
®  
E D C s yste m d e v el o p me nt 
cor p or ati o n  
Me di d ata S ol uti o ns , I n c. 
H o w t o e nter d at a  
D at a e ntr y vi a t h e we b i nterfa c e  
Ter mi nal f or d ata e ntr y  
P C at t h e st u d y c e nt er  
O S pr o hi bit e d  
N o n e  
Br o ws er  
Me di d ata R a v e
®  s u p p orts a n y br o ws er t h at c o nf or ms t o H T M L 5, a n d C S S 2.   
J a va Scri pt n e e ds t o b e e n a bl e d i n t h e br o ws er.  
Re c o m me n d e d scr e e n 
res ol uti o n 
1 0 2 4 ×  7 6 4  r es ol uti o n or hi g h er 
Re c o m me n d e d c o n n ecti o n 
s p ee d 
1 2 8  k b ps  or hi g h er  
Ot h ers  
A d o b e Fl as h Pl a yer: v er. 1 0  or hi g h er  
 
1 5. 9. 2  C o m pl eti o n of t h e C as e R e p o rt F o r m s 
T h e i n vesti gat or will t a k e a n el ectr o ni c si g n at ure trai ni n g pr o gra m pri or t o pre p arati o n of 
t h e C R F a n d t h e tr ai ni n g r ec or d will s u p ers e d e t h e list of si g n at ures a n d pri nti n g of s eals. 
1)  T h e C R F will b e c o m pl ete d f or s u bj ects w h o pr o vi d e i nf or me d c o nse nt.  
2)  T h e i n vesti gat or or s u bi n vesti gat o r will c o m pl et e t h e C R F i n acc or d a n ce wit h t he 
“ G ui d a n ce f or C o m pl eti n g a n d Ma ki n g C orrecti o ns t o t h e Cas e Re p ort F or m” 
pr o vi d e d b y t h e s p o ns or.  
3)  T h e st u d y st aff will f oll o w t h e i nstr ucti o ns of t h e i n vesti gat or or s u bi n vesti gat or 
w h e n assisti n g wit h t h e c o mpl eti o n of t he C R F.  
4)  T h e i n vesti gat or will s u b mit t h e C R F t o t h e s p o ns or a n d ret ai n a c o p y of t h e C R F.  
5)  If t h er e ar e a n y i n c o nsist e n c i es b et wee n t h e d at a i n t h e C R F a n d t h e s o urce 
d o c u me nts, t h e i n vesti gat or will s e p arat el y pre p are a rec or d e x pl ai ni n g t h e re as o n 
a n d s u b mit it t o t h e s p o ns or, a n d ret ai n a c o p y of t h e rec or d.  
 
1 5. 9. 3  Si g n at u re o r Se al wit h Pri nte d N a me A p pli e d t o t h e C as e R e p o rt F o r m  
T h e i n vesti gat or will c h ec k all C R Fs pre p are d at t he st u d y ce nter, a n d affi x his/ h er 
el ectr o nic si g n at ur e t o t h e m.  
 
1 5. 9. 4  C h a n g es o r C orrecti o ns t o t h e C as e R e p o rt F o r m  
1)  A n y c orr ecti o n s t o t h e C R F will b e ma d e b y t h e i n vesti gat or, s u bi n vesti gat or, or 

 
 
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st u d y st aff i n acc or d a n ce wit h t h e “ G ui d a n ce f or C o m pl eti n g a n d M a ki n g 
C orr ecti o ns t o t h e Cas e Re p ort F or m” pr o vi d e d b y t h e s p o ns or . 
2)  T h e i n vesti gat or is r es p o nsi bl e f or t h e d es cri pti o ns i n t h e C R F, a n d will ret ai n c o pies 
of all r ec or ds, i n cl u di n g c h a n ges or c orrecti o ns.  
 
1 5. 1 0  R et e nti o n of S o u rce D o c u me nts a n d Ot h er R ec or ds  
1 5. 1 0. 1  D efi niti o n of S o u rce D o c u me nts  
S o ur ce d o c u me nts s h all r ef er t o ori g i n al d o c u me nts, d ata, a n d rec or ds s et f ort h i n 
I C H-G C P 1. 5 2, or t h eir certifie d c o pi es, a n d i n cl u de rec or ds (s o urce dat a) necess ar y t o 
r e pr o d u ce a n d e val u at e t he f act u al pr o gress of t h e cli ni cal st u d y.    S o urce d oc u me nts 
i n cl u d e h os pit al r ec or ds, me di cal rec or ds, t est rec or ds, me m ora n d a, s u bj ect di ar y or 
c h ec k lists f or e val uati o n, a d mi nistrati o n rec or ds, dat a rec or d e d b y a ut o mate d meas uri n g 
i nstr u me nts, r e pr o d u cti o ns or tra ns cri pts verifi e d as precis e c o pies, micr ofic h es, 
p h ot o gr a p hi c n e gati ves, mi cr ofil ms or ma g n eti c me di a, X -ra y fil ms, s u bj ect fil es, a n d 
r ec or ds ke pt at eit h er a p har mac y, l a b orat or y, or me di cal t ec h n ol o g y d e p art me nt i n v ol ve d 
i n t h e st u d y. 
 
1 5. 1 0. 2  R ec o r d Kee pi n g  
1 5. 1 0. 2. 1  I nstit uti o n al R e vi e w B o ar d 
T h e f o u n der of t he I R B will r et ai n t h e sta n dar d o perati n g pr o ce d ures, me m b er list, 
d o c u me nts s u b mitt e d, mi n ut es a n d s u m mari es of meeti n gs, l ett ers, et c., u ntil t h e d at e 
s p ecifi e d i n 1) or 2) b el o w, w hi c h e ver is l at er.    H o we ver, if l o n ger ret e nti o n is re q u est e d 
b y t h e s p o ns or, t he d ur ati o n a n d met h o d of ret e nti o n will b e dis c uss e d wit h t h e s p o ns or.  
1)  Dat e of a p pr o val of q ui zarti ni b ( or if cli ni cal d e v el o p me nt is dis c o nti n u e d, 3 years 
aft er t h e d at e of n otifi cati o n of t h e dis c o nti n u ati o n b y  t h e s p o ns or) 
2)  T hr ee years after dis c o nti n u ati o n or c o m pl eti o n of t h e st u d y  
 
1 5. 1 0. 2. 2  St u d y C e nt er  
T h e h ea d of t h e st u d y ce nt er or t h e p ers o n res p o nsi bl e f or rec or d kee pi n g will ret ai n t h e 
“ d o c u me nts or r ec or ds r elate d t o t h e cli nical st u d y” t o b e ret ai ne d b y t h e st u d y ce nt er 
u ntil t h e d ate s p ecifi e d i n 1) or 2) b el o w, w hi c h e ver is l at er.    H o we ver, if l o n ger 
r et e nti o n is r e q u est e d b y t h e s p o ns or, t h e d urati o n a n d met h o d of ret e nti o n will b e 
dis c uss e d wit h t h e s p o ns or.   A p ers o n res p o nsi bl e f or rec or d kee pi n g will b e d esi g n at e d 
f or eac h s et of r ec or ds. 
T h e h ea d of t h e st u d y ce nt er or t h e p ers o n r es p o nsi bl e f or rec or d kee pi n g will ta ke 

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De p art me nt  
Cli ni cal St u d y Lea d:  
O n c ol o g y Cli ni cal  De vel o p me nt De p art me nt  
Deli ver y Lea d:  
 O n c ol o g y Cli ni cal De vel o p me nt De p art me nt  
1- 2- 5 8 Hir o mac hi, S hi n a ga wa -k u, To k y o 1 4 0 -8 7 1 0 , J a p a n 
  
 
 
P ers o n r es p o nsi bl e f or st u d y dr u g ma n a ge me nt:  
 C M C Pl a n ni n g De p art me nt  
P ers o n  r es p o nsi bl e f or bi ost atisti cal a n al ysis: 
 Cli nical Dat a & Bi ost atisti cs De p art me nt 
P ers o n r es p o nsi bl e f or p har mac o ki n eti c a n al ysis:  
 Tra nsl ati o n al M e di ci n e & Cli ni cal 
P har mac ol o g y De p art me nt  
P ers o n r es p o nsi bl e f or c o n ce ntrati o n meas ure me nt:  
 Tra nsl ati o n al M e dici n e & Cli ni cal 
P har mac ol o g y De p art me nt  
P ers o n r es p o nsi bl e f or d at a ma n a ge me nt:  
 Cli nical Dat a & Bi ost atisti cs De p art me nt 
P ers o n r es p o nsi bl e f or q ualit y ma n a ge me nt:  
 De vel o p me nt F u n cti o n 
P ers o n r es p o nsi bl e f or s af et y i nf or mati o n : 
 P h ar m ac o vi gil a n ce De p art me nt 
P ers o n r es p o nsi bl e f or m eas ur es f or h a n dli n g of s afet y i nf or mati o n:  
 P h ar m ac o vi gil a n ce De p art me nt 
P ers o n r es p o nsi bl e f or g e n o me/ ge n e a n al ysis:  
 Tra nsl ati o n al M e dici n e & Cli ni cal 
P har mac ol o g y De p art me nt  
 
1 5. 1 2. 2  Me di c al E x pert  
 O n c ol o g y Cli ni cal De vel o p me nt De p art me nt , Daii c hi Sa n k y o C o., Lt d. 
1- 2- 5 8 Hir o mac hi, S hi n a ga wa -k u, To k y o 1 4 0 -8 7 1 0 , J a p a n 
  
 
D uti es:  T h e me di cal e x p ert will gi ve a d vi ce o n me di cal iss u es d uri n g pl a n ni n g a n d 
c o n d u ct of t he st u d y, a n d pre p arati o n of t h e cli ni cal st u d y re p ort.    T h e me di cal 
e x p ert will affi x his / h er si g n at ure t o t h e cli ni cal st u d y re p ort if h e/s h e is assess e d 
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t o b e a p pr o pri ate as a n a ut h ori zer of t h e re p ort. 
 
1 5. 1 2. 3  E D C S yst e m D e v el o p me nt  
Me di d at a S ol uti o ns, I n c.  
P ers o n r es p o nsi bl e:  
C h air ma n &  C hief E xec uti ve Officer  
3 5 0 H u ds o n Str eet, 9t h Fl o or, Ne w Yor k, Ne w Yor k 1 0 0 1 4, U S A  
  
 
D uti es:  T h e c o m p a n y will p erf or m o p erati o n, ma n a ge me nt, a n d mai nt e n a n ce of t he E D C 
s yst e m acc or di n g t o t h e c o nsi g n me nt c o ntract. 
 
1 5. 1 2. 4  E D C  S yst e m S u p p o rt  
F ujits u S yst e ms East Li mit e d  
P ers o n r es p o nsi bl e: 
 
S hi na ga wa Seas o n Terr ace , 1- 2-7 0 K o n a n, Mi n at o -k u, To k y o 1 0 8 -0 0 7 5 , J a p a n 
  
 
D uti es:  T h e c o m p a n y will p erf or m E D C s yst e m s u p p ort acti viti es acc or di n g t o t h e 
c o nsi g n me nt c o ntr act.  
 
1 5. 1 2. 5  C o nt r a ct R es e a rc h O r g a ni z ati o n  
Me dis ci e n ce Pla n ni n g I n c. 
P ers o n r es p o nsi bl e: 
 Direct or, Ni nt h De p art me nt of Cli ni cal 
De vel o p me nt  
1- 1 1 -4 4 A kas a ka, Mi n at o -k u, To k y o 1 0 7 -0 0 5 2 , J a p a n 
  
 
 
1 5. 1 2. 6  St u d y C e nt er a n d I n v esti g at or 
Ref er t o Att ac h me nt 2.  
D uti es:  To a gr ee o n t h e pr ot o c ol, t h e i n vesti gat or will pre pare a n d re vis e t he i nf or me d 
c o ns e nt f or m, s el ect s u bj ects a n d o bt ai n t h eir c o nse nt, i nstr u ct a n d s u p er vise t h e 
s u bi n vesti gat ors a n d st u d y st aff, pr o vi d e mat eri als a n d i nf or mati o n, c o o p erat e 
wit h  m o nit ori n g a n d a u diti n g, re p ort d e vi ati o ns of or c h a n ges fr o m t h e pr ot o c ol 
a n d A E s, c o m pl et e t h e C R Fs, a n d ret ai n t he “d o c u me nts or rec or ds rel at e d t o t h e 
cli ni cal st u d y” i n c o ns ult ati o n wit h t h e s p o ns or. 
 
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1 5. 1 2. 7  C e nt r al L a b o r at o r y  
1 5. 1 2. 7. 1  Me as u re me nt of D r u g C o n ce ntr ati o ns  
B A Si c or p or at e  
P ers o n r es p o nsi bl e:
 
2 7 0 1 K e nt Ave n u e, West Laf a yett e, I N 4 7 9 0 6, U S A  
  
 
D uti es:  T h e c o m p a n y will meas ur e a n d st ore t h e s peci me ns s e nt fr o m eac h st u d y ce nt er 
acc or di n g t o  t h e c o nsi g n me nt c o ntract. 
 
1 5. 1 2. 7. 2  Me as u re me nt of P h a r m a c o d y n a mi c E n d p oi nts  
1)  A n al ysis of F L T 3 -I T D st at us a n d c-KI T m ut ati o ns  
S R L, I n c.  
P ers o n r es p o nsi bl e: 
 
2- 1- 1 Nis hi -s hi nj u k u, S hi nj u k u-k u, To k y o 1 6 3 -0 4 0 9, Ja p a n  
  
 
D uti es:  T h e c o m p a n y will p erf or m a n al ys es of F L T 3 -I T D st at us a n d c-KI T m ut ati o ns.  
 
2)  Meas ur e me nt of p h os p h or yl at e d F L T 3 , S T A T 5, a n d c-KI T  pr ot ei n l e vels i n bl o o d 
S hi n Ni p p o n Bi o me di cal La b or at ori es, Lt d.  
P ers o n r es p o nsi bl e: 
 
2 4 3 8 Mi ya n o ur a -c h o, K a g os hi ma- s hi, K a g os hi ma 8 9 1 -1 3 9 4 , Ja p a n 
  
 
D uti es:  T h e c o m p a n y will meas ur e p h os p h or yl at e d F L T 3 , S T A T 5, a n d c-KI T  pr ot ei n 
le vels i n t h e bl o o d acc or di n g t o t h e c o ntract wit h t h e s p o ns or.  
 
3)  Meas ur e me nt of i n hi bit or y acti vit y of pl as ma q ui zarti ni b o n p h os p h or yl at e d F L T 3 
pr ot ei n 
S hi n Ni p p o n Bi o me di cal La b or at ori es, Lt d.  
P ers o n r es p o nsi bl e: 
 
2 4 3 8 Mi ya n o ur a -c h o, K a g os hi ma- s hi, K a g os hi ma 8 9 1 -1 3 9 4 , Ja p a n 
  
 
D uti es:  T h e c o m p a n y will meas ur e t h e i n hi bit or y acti vit y of pl as ma q ui zarti ni b o n 
p h os p h or yl at e d F L T 3 pr ot ei n acc or di n g t o t h e c o ntract wit h t h e s p o ns or.  
 
4)  C o nfir mati o n of 1 2 -l ea d E C G meas ure me nt res ults, et c. 
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e Res ear c h Tec h n ol o g y, I n c.  
P ers o n r es p o nsi bl e: 
 
1 8 1 8 M ar ket Str eet, S uit e 1 0 0 0,  P hil a d el p hi a, P A 1 9 1 0 3, U nit e d St at es  
  
 
D uti es:  T h e c o m p a n y will c o nfir m t h e E C G meas ure me nt res ults s u b mitte d b y eac h 
st u d y ce nter, etc. acc or di n g t o t h e c o ntract wit h t h e s p o ns or. 
 
1 5. 1 2. 7. 3  A g e n c y t o C oll ect S p eci me ns f o r Me as u re me nt of D r u g C o n ce ntr ati o ns 
a n d P h a r m a c o d y n a mi c E n d p oi nts, etc.  
1)  L SI Me di e n ce C or p orati o n  
P ers o n r es p o nsi bl e: 
 
3- 3 0- 1 S hi m ur a, It a bas hi -k u, To k y o 1 7 4 -8 5 5 5 , J a pa n 
  
 
D uti es:  C o n cer ni n g s p eci me ns f or dr u g c o n ce ntrati o n me as ure me nt a n d t he bi o mar ker 
st u d y ( ph os p h or yl at e d F L T 3 , S T A T 5, a n d c-KI T  pr ot ei n l e vels i n bl o o d , a n d t h e 
i n hi bit or y acti vit y of pl as ma q uizarti ni b o n p h os p h or yl at e d F L T 3 pr ot ei n), t h e 
c o m p a n y will c oll ect t he s p eci me ns fr o m t h e st u d y ce nt er, st ore a n d a n o n y mi ze 
t h e s p eci me ns, a n d se n d t h e m t o eac h l a b orat or y acc or di n g t o t h e c o ntract wit h 
t h e s p o ns or. 
 
2)  S R L M e dis ear c h I n c.  
P ers o n r es p o nsi bl e: 
 
6- 5 -1 Nis hi -s hi nj u k u, S hi nj u k u-k u, To k y o 1 6 3 -1 3 1 0, Ja p a n  
  
 
D uti es:  C o n cer ni n g s p eci me ns f or t h e bi o mar ker st u d y ( F L T 3 -I T D st at us a n d c-KI T 
m ut ati o ns), t h e c o m p a n y will c oll ect t h e s p eci me ns fr o m t h e st u d y ce nt er, st ore 
a n d a n o n y mi ze t h e s p eci me ns, a n d s e n d t he m t o eac h l a b orat or y acc or di n g t o t h e 
c o ntr act wit h t h e s p o ns or. 
 
1 5. 1 2. 8  D e p a rt me nt R es p o nsi bl e f o r A u dit  
P ers o n r es p o nsi bl e: 
 R & D & P V Q u alit y Ass ura n ce De p art me nt, Q u alit y 
& Saf et y M a n a ge me nt Di visi o n, Daii c hi Sa n k y o C o., Lt d.  
1- 2- 5 8  Hir o mac hi, S hi n a ga wa -k u, To k y o 1 4 0 -8 7 1 0 , J a p a n 
   
 
D uti es:  T h e d e part me nt will p erf or m G C P a u diti n g.  
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1 5. 1 3  E mer g e n c y C o nt a ct I nf or m ati o n  
1)  Ni g ht h o urs ( 1 8: 0 0 t o 9: 0 0) a n d Sat ur d a ys, S u n d a ys, a n d h oli d a ys (all d a y):  
 O n c ol o g y Cli ni cal De vel o p me nt De p art me nt , Daii c hi Sa nk y o C o., Lt d.  
 
 
2)  Da yti me ( 9: 0 0 t o 1 8: 0 0) fr o m M o n d a y t hr o u g h Fri d a y (e xce pt h oli d a ys):  
 O n c ol o g y Cli ni cal De vel o p me nt De p art me nt , Daii c hi Sa n k y o C o., Lt d. 
  
 
 
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1 6.  R E F E R E N C E S  
1)  
Ja p a n es e S o ci et y of He m at ol o g y . G ui d eli n e o n He mat o p oi eti c M ali g n a nt T u m or s 
( 2 0 1 3 E diti o n). K a n e h ar a & C o., Lt d.  (1 1 Oct 2 0 1 3) . 
htt p:// w w w.js h e m. or.j p/ g ui- h e mali/ 1 _ 1. ht ml # c q 6  
2)  
Mats u d a A, M ats u d a T, S hi bat a A, et al. Ca n cer I nci d e n ce a n d I n ci d e n ce Rat es i n 
Ja p a n i n 2 0 0 8: A St u d y of 2 5 P o p ul ati o n-b as e d Ca n cer Re gistri es f or t h e 
M o nit ori n g of Ca n cer I n ci d e n ce i n J a p a n ( M CIJ) Pr oj ect. J p n J Cli n O n c ol.  
2 0 1 3; 4 4( 4): 3 8 8 - 9 6. 
3)  
O hta ke S, Mi ya wa ki S, Ki y oi H, et al. Ra n d o mi ze d tri al of res p o ns e -ori e nte d 
i n di vi d uali ze d vers us fi x e d -s c h e d ul e i n d u cti o n c h e m ot h era p y wit h i d ar u bi ci n a n d 
c yt ar a bi n e i n a d ult ac ut e  m yel oi d l e u ke mi a: t h e J A L S G A M L 9 5 st u d y. I nt J 
He mat ol . 2 0 1 0; 9 1 ( 2): 2 7 6-8 3.  
4)  
D ö h n er H, Weis d orf DJ, Bl o o mfi el d C D. Ac ut e M yel oi d Le u ke mi a. N E n gl J M e d.  
2 0 1 5; 3 7 3( 1 2): 1 1 3 6 -5 2.  
5)  
Var di ma n J W, T hi el e J, Ar b er D A, et al. T h e 2 0 0 8 re visi o n of t h e Worl d Healt h 
Or ga ni zati o n  ( W H O) cl assifi cati o n of m yel oi d n e o pl as ms a n d ac ut e l e u ke mi a: 
r ati o n al e a n d i m p ort a nt c ha n ges. Bl o o d. 2 0 0 9; 1 1 4( 5): 9 3 7 -5 1.  
6)  
Ki y oi H. Feasi bilit y of F L T 3 -t ar geti n g treat me nt f or l e uke mi a. T h e J a p a n ese 
J o ur n al of Cli ni cal He mat ol o g y. 2 0 0 5; 4 6( 3): 1 8 7 - 9 7. 
7)  
Ki y oi H. F L T 3 i n hi bit ors a n d a nti -F L T 3 a nti b o di es. J o ur n al of Cli ni cal a n d 
E x p eri me nt al M e di ci n e . 2 0 0 7; 2 2 0( 9): 7 5 9-6 4.  
8)  
O h ta ke S, Mi ya wa ki S. Tr eat me nt pr ot o c ol f or ac ut e m yel oi d le u ke mi a ( A M L). 
Mi ya wa ki S, Na ka o S , e dit ors. T h era pe utic ma n u al of l e u ke mi a. 3r d re v. e d. 
Na n k o d o. 2 0 0 9; 2 7 - 4 1. 
9)  
Ce nt er f or Dr u g E val u ati o n a n d Res earc h  ( C D E R). G ui d a n ce f or I n d ustr y: 
p h ot os af et y t esti n g. ( Ma y 2 0 0 3) . 
1 0)  Or ga nis ati o n f or Ec o n o mi c C o -o p erati o n a n d D e vel o p me nt  ( O E C D). O E C D 
g ui d eli n e f or t esti n g of c he mi cals. I n vitr o 3 T 3 N R U p h ot ot o xi cit y t est, N o. 4 3 2 
secti o n 4 Healt h Eff ects ( Pi n k p a ges). (a d o pt e d  1 3  A pr 2 0 0 4 ). 
1 1)  C o m mitt ee f or Pr o priet ar y M e di ci n al Pr o d u cts  ( C P M P). N ot e f or g ui d a n ce o n 
p h ot os af et y t esti n g . C P M P/ S W P/ 3 9 8/ 0 1. ( 2 7 J u n 2 0 0 2). 
1 2)  G ui d a nce o n P h ot os af et y E val u ati o n of P h ar mace uti cals.  P F S B/ E L D N otificati o n 
N o. 0 5 2 1 -1 ( 2 1 M a y 2 0 1 4). 
1 3)  Ma yer RJ, Da vis R B, Sc hiff er C A, et al. I nt e nsi ve p ostre missi o n c h e m ot h era p y i n 
a d ults wit h ac ut e m yel oi d l e u ke mi a. Ca n cer a n d Le u ke mi a Gr o u p B.  N E n gl J M e d. 

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
1 0 7 
 
1 9 9 4; 3 3 1( 1 4): 8 9 6 -9 0 3.  
1 4)  Fer n a n d ez H F, S u n Z, Ya o X, et al. A nt hrac ycli n e d ose i nt e nsifi cati o n i n ac ut e 
m yel oi d l e u ke mi a. N E n gl J M e d. 2 0 0 9; 3 6 1( 1 3): 1 2 4 9 -5 9.  
1 5)  B ur n ett A K, R uss ell N H, Hills R K, et al. A ra n d o mi ze d c o m p ari s o n of 
da u n or u bi ci n 9 0 m g/ m 2 vs 6 0 m g/ m 2 i n A M L i n d ucti o n: res ults fr o m t h e U K N C RI 
A M L 1 7 tri al i n 1 2 0 6 p atie nts. Bl o o d. 2 0 1 5; 1 2 5( 2 5): 3 8 7 8 -8 5.  
1 6)  D ö h n er H, Est e y E H, A ma d ori S , et al. Di a g n osis a n d ma n a ge me nt of ac ut e 
m yel oi d l e u ke mi a i n a d ults: r ec o m me n d ati o ns fr o m a n i nt er n ati o n al e x p ert p a n el, 
o n b e half of t h e E ur o p ea n Le u ke mi a Net. Bl o o d. 2 0 1 0; 1 1 5( 3): 4 5 3 -7 4.  
1 7)  Re visi o n  of t h e G ui d eli n es f or t h e Cli nical E val u ati o n of A nti ca n cer Dr u gs.  
P F S B/ E L D N otificati o n N o. 1 1 0 1 0 0 1 ( 1 N o v 2 0 0 5). 
1 8)  Mi nistr y of E d u cati o n, C ult ure, S p orts, Sci e n ce a n d Tec h n ol o g y ; Mi nistr y of 
Healt h, La b o ur a n d Welf ar e ; Mi nistr y of Ec o n o m y, Tra d e a n d I n d ustr y . Et hi cal 
G ui d eli n es f or H u ma n G e n o me/ Ge n e A n al ysis Researc h . (est a blis h e d o n 2 9 Mar 
2 0 0 1, f ull y r e v. o n 2 8 De c 2 0 0 4, p artiall y  re v. o n 2 9 Ju n 2 0 0 5, p arti all y re v.  o n 1 
Dec 2 0 0 8, f ull y r e v. o n 8 Fe b 2 0 1 3).  
1 9)  Mi nistr y of Healt h, La b o ur a n d Welfare . Et hi cal G ui d eli n es f or Cli ni cal St u di es  
( est a blis he d o n 3 0 J ul 2 0 0 3, f ull y re v. o n 2 8 Dec 2 0 0 4, f ull y re v. o n 3 1 J ul 2 0 0 8).  
 

 
 
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Versi o n 0 1. 0 0. 0 0 0 
 
1 0 8  
 
1 7.  A P P E N DI C E S  
A p p e n di x 1  
E C O G P erf or ma n ce St at us  ( P S) 
A p p e n di x 2 
Ne w Yor k Heart Ass o ci ati o n ( N Y H A) F u ncti o n al Cl assifi cati o n  
A p p e n di x 3 
S A V E R F O R M  
A p p e n di x 4 
E x p os ur e i n Ut er o Re p orti n g F or m  
 

 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
Versi o n 0 1. 0 0. 0 0 0 
 
1 0 9 
 
Att ac h me nts  
Att ac h me nt 1 
S u bject Re gistr ati o n F or m  
Att ac h me nt 2 
List of St u d y Ce nt ers a n d I n vesti gat ors 
Att ac h me nt 3 
C yl o ci d e ®  I nj ecti o n 2 0 m g /  4 0 m g / 6 0 m g / 1 0 0 mg / 2 0 0 m g [ p ac ka ge 
i ns ert]. Ni p p o n S hi n ya k u C o.,  Lt d .; Dec 2 0 1 4 . 
Att ac h me nt 4 
C yl o ci d e ® N I nj ecti o n 4 0 0 m g / 1 g [ p ac ka ge i ns ert ]. Ni p p o n S hi n ya k u 
C o., Lt d .; Dec 2 0 1 4 . 
Att ac h me nt 5   
Da u n o m yci n ®  f or I nj ecti o n 2 0 m g [p ac ka ge i ns ert ]. M eiji Sei ka P h ar ma 
C o., Lt d .; A pr  2 0 1 1. 
Att ac h me nt 6 
I d a m yci n®  f or I ntr a ve n o us Us e 5  m g [p ac ka ge i nsert ]. Pfi zer J a p a n I n c. ; 
J u n 2 0 0 9. 
 

 
 
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Versi o n 0 1. 0 0. 0 0 0 
 
 
 
[A p p e n di x 1]  
 
E C O G P erf or ma n ce St at us  ( P S) 
 
Sc or e  
E C O G P erf or ma n ce S t at us 
0 
F ull y acti ve, a bl e t o carr y o n all pre -dis eas e  p erf or ma n ce 
wit h o ut r estri cti o n.  
1 
Restri ct e d i n p h ysi call y stre n u o us acti vit y,  b ut a m b ul at or y a n d 
a bl e t o carr y o ut w or k of  a li g ht or s e d e nt ar y n at ure (e g, li g ht  
h o us e w or k, offi ce w or k).  
2 
A m b ul at or y a n d ca p a bl e of all s elf -care, b ut  u n a bl e 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 h a n 5 0 % of wa ki n g 
h o urs.  
3 
Ca p a bl e of o nl y li mit e d self -care, c o nfi ne d t o  b e d or c h air m ore 
t h a n 5 0 % of wa ki n g h o urs. 
4 
C o m pl et el y dis a bl e d.  Ca n n ot carr y o n a n y  s elf-care.  Tot all y 
c o nfi n e d t o be d or c h air.  
 

 
 
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[A p p e n di x 2]  
 
Ne w Yor k Heart Ass o ci ati o n  ( N Y H A) F u ncti o n al Cl assifi cati o n  
 
Class  
S y m p t o ms 
Class  0 
P ati e nts wit h o ut car di ac dis ease a n d wit h n o li mit ati o n of p h ysi cal 
acti vit y.  
Class  I 
P ati e nts wit h c ar di ac dis eas e b ut wit h o ut res ulti n g li mit ati o n of p h ysi cal 
acti vit y.  Or di n ar y p h ysical acti vit y d o es n ot ca use u n d u e fati g u e, 
pal pit ati o n, d ys p n ea, or a n gi n al p ai n.  
Class  II 
P ati e nts wit h car di ac dis eas e res ulti n g i n sli g ht li mit ati o n of p h ysi cal 
acti vi t y.  T h e y ar e c o mf ort a bl e at rest.  Or di n ar y p h ysi cal acti vit y 
r es ults i n fati g u e, p al pit ati o n, d ys p n ea, or a n gi n al p ai n. 
Class  III 
P ati e nts wit h car di ac dis eas e res ulti n g i n mar ke d li mitati o n of p h ysi cal 
acti vit y.  T h e y ar e c o mf ort a bl e at rest.  Less t h a n or di n ar y acti vit y 
ca us es fati g u e, p al pit ati o n, d ys p n ea, or a n gi n al p ai n.  
Class  I V 
P ati e nts wit h car di ac dis eas e res ulti n g i n i n a bilit y t o carr y o n a n y 
p h ysi cal acti vit y wit h o ut dis c o mf ort.  S y m pt o ms of h eart fail ure or t h e 
a n gi n al s y n dr o me ma y b e pres e n t e ve n at rest.  If a n y p h ysi cal acti vit y 
is u n d ert a ke n, dis c o mf ort is i n creas e d. 
 

 
 
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[A p p e n di x 3] S A V E R F O R M  
 

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
 
Pr ot oc ol #:        
Sit e #:  
      
S u bj e ct I n iti als:       
 
 
 
 
 
 
 
 
 
W h e n c o m plet e d, s e n d t o D aii c hi -S a n k y o . 
S u p pl e me ntal p a g es us e d ( M ar k all t h at a p ply): 
 S A E  
 La b R es ults  
 C o n c o mit a nt M e di c ati o ns  
Re p ort Ty p e:  
  I nitial 
 F oll o w -u p #           
1. S o u rc e  
I n vesti g at or N a me: 
          
C o u nt r y:  
          
 
A d dress:  
          
 
P h o ne #:  
          
F a x #:  
          
 
 
 
 
 
 
2. S u bje ct a n d St u d y I nf or m ati o n  
Sc re e ni n g #/ S u bj e ct #:            
R a n d o mi z ati o n #:  
          
S u bj e ct I niti als:            
 
Birt h D at e: ( d d M m m y y yy) 
          
 
G e n de r:  
 Mal e  
 Fe mal e  
Wei g ht:  
 k g  
 l b           
 
H ei g ht:  
 c m  
 i n           
 
Et h ni cit y: 
 His p a ni c or Lati n o  
 N ot His p a ni c or Lati n o  
R ace:  
 Asi a n  
 Bl a c k  
 Ca u c asi a n  
 A meri c a n I n di a n/ Al as k a n N ati v e  
 
 N ati v e H a waii a n/ P a cifi c Isl a n d er  
 Ot h er            
 
P h as e of St u d y at ti me of S A E:  
 Scre e ni n g  
 Was h o ut  
 Plac e b o/ R u n -i n 
 
 Ra n d o mi z e d  
 P ost St u d y  
 O p e n -l a b el 
D at e of I nf or me d C o ns e nt: ( d d M m m y y y y) 
      
 
 
 
 
3. P ri m a r y Se ri o us A d ve rse E v e nt  
( Us e a p pr o pri ate me dic al t er mi n ol o g y, s y m pt o ms s h o ul d b e gr o u p e d t o g et h er as s y n dr o m es a n d di a g n osis.)  
If a d diti o n al e ve nts ar e r e p ort e d, us e s u p pl e me nt al p a g e.    If s u p pl e me nt al S A E p a g es were us e d, m ar k h er e: 
 
S A E ( E ve nt/ Di a g n osis) :       
 
D ate E v e nt Bec a me Seri o us: ( d d M m m yyyy) 
      
 D ate E ve nt St o p pe d  or : ( d d M m m yyyy) 
      
 
 
 
 
 
 
 
C o nti n ui n g  
N CI C T C A E Se verit y 
Gr a di n g  
O utc o me  
Seri o us n ess Criteri a  
(see pr ot oc ol f or S A E defi niti o ns) 
 Ye s 
 N o  
 1 = Mil d  
 2 = M o derat e  
 3 = S e ver e  
 4 = Lif e -t hr eat e ni n g 
or disa bli n g  
 5 = D eat h  
 Rec o ver e d/ R es ol ve d  
 Rec o veri n g/ R es ol vi n g  
 N ot R ec o ver e d/ N ot R es ol ve d  
 Rec o ver e d/ R es ol ve d wit h s e q uela e  
   /resi d ual eff ect(s) pr es e nt 
 Fatal  
 U n k n o w n  
 D eat h  
 Lif e -t hr eat e ni n g 
 H o s pitali zati o n-i nitial or pr ol o n ge d 
 Disa bilit y or P er ma n e nt Da ma ge  
 C o n ge nital a n o mal y/ Birt h D ef ect  
 I m p ort a nt M e dical E ve nt 
St u d y Dr u g C a us alit y  ( C o m plete o n e li ne f or e ac h st u dy dr u g) 
Dr u g N a me  
Rel at e d  
N ot Rel ate d  
          
 
 
          
 
 
          
 
 
          
 
 
4. I n C ase of D e at h  
D at e: ( d d M m m y y y y)           
 A ut o ps y:  
 Ye s  
 N o  
 
 
 C ertifi c at e:  
 Ye s  
 N o  
C a use:            
 
 
 
 
 
 
 
 
 
 

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
 
Pr ot oc ol #:        
Sit e #:  
      
S u bj e ct I n iti als:       
 
 
 
 
 
 
 
 
 
5. St u d y D r u g D osi n g  
Re c or d o nly d ose gi v e n t o s u bj ect at ti m e of S A E.   C o m pl et e all  pre vi o us d osi n g re gi m es i n cl u di n g pl a ce b o r u n -i n 
Se cti o n 6.  
St u d y Dr u g D osi n g  
St u d y Dr u g Acti o n 
Ta ke n  
St u d y Dr u g  
U nit D ose  
Fre q u e nc y  
R o ute  
St a rt D at e  
( d d M m m y y y y) 
St o p D at e  
( d d M m m y y y y) 
N o n e  
Dis c o nti n u e d  
R e d u c e d  
I nt e r r u pt e d 
I n cre as e d 
          
          
          
          
          
          
 
 
 
 
 
          
          
          
          
          
          
 
 
 
 
 
          
          
          
          
          
          
 
 
 
 
 
Was t he s u bj ect wit h dr a w n d u e t o S A E?  
 Ye s  
 N o  
Was St u d y Dr u g C o d e br o ke n d u e t o S A E ?  
 Ye s  
 N o  
If Yes, D ate: ( d d M m m y y y y) 
          
 
W h o:        
Dr u g:  
      
D osi n g:        
 
 
 
 
 
 
 
 
6. P re vi o us St u d y D r u g D osi n g R e gi me ns p e r P r ot o c ol, i ncl u di n g pl ac e b o r u n -i n. 
St u d y dr u g d osi n g at t h e ti m e of S A Es is c a pt ure d i n S e cti o n 5.   D o N O T c o m pl et e wit h “ S e e Att a c h e d ”.  
If n ot a p plic a ble mar k h ere: 
 
Dr u g N a me  
U nit D ose  
Fre q u e nc y  
R o ute  
St art D ate  
( d d M m m yy yy) 
St o p D ate  
( d d M m m yy yy) 
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
7. Rele v a nt C o n c o mit a nt M e di c ati o ns  
(I n cl u d e t h os e t a k e n b ef ore t h e o ns et of t h e e v e nt, n ot t a ke n as a tre at m e nt f or t h e e v e nt.)   D o N O T c o m plete wit h 
“ Se e Att ac h e d ”.   If S u p pl e me nt al C o n c o mita nt M e di c ati o n p a g e is us e d, mar k h er e: 
 
Ge neri c/ Br a n d N a me  
D ose  
Fre q u e nc y  
R o ute  
St art D ate  
( d d M m m yy yy) 
St o p D ate  
( d d M m m yy yy)  
I n dic ati o n 
C o nti n ui n g ?  
      
            
      
      
      
      
 
      
            
      
      
      
      
 
      
            
      
      
      
      
 
      
            
      
      
      
      
 
      
            
      
      
      
      
 
          
                    
          
          
          
          
 
8. Rele v a nt L a b R es ults  
D o N O T c o m pl et e wit h “ S e e Att a c h e d. ”   If s u p pl e me ntal La b Res ults p a g es wer e us e d, mar k h er e: 
 
L a b Test  
D ate  
( d d M m m yy yy) 
Res ults  
Ref ere nc e N or m al R a n ge 
( U nits) 
          
          
          
          
          
          
          
          
          
          
          
          
      
      
      
      
      
      
      
      

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
 
Pr ot oc ol #:        
Sit e #:  
      
S u bj e ct I n iti als:       
 
 
 
 
 
 
 
 
 
9. Rele v a nt M e di c al Hist or y I n cl u di n g Alle r gies  
D o N O T c o m pl et e wit h “ S e e Att a c h e d. ”  
D ate of O nset  
( d d M m m yy yy) 
C urre nt  
P ast  
Descri pti o n  
( M ark o ne o nly) 
      
 
 
      
      
 
 
      
          
 
 
          
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
      
 
 
      
1 0. N a rr ati v e  
Re c or d a det aile d d es cri pti o n of t h e e v e nt i n cl u di n g t h e c o urs e of  t h e e v e nt, e v al u ati o n, ass ess m e nt a n d tre at me nt. 
          
11. Pe rs o n C o m pl eti n g T his F or m  
 
          
 
 
 
 
 
 
N a me  
 
Si g n at ure  
 
D ate  
 
 
      
 
      
 
 
 
 
Title  
 
P h o ne N u m b er  
 
 
 
 
      
 
 
 
 
 
 
I n vesti g at or N a me 
 
Si g n at ure  
 
D ate  
 
 

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
( S u p pl e me nt al S A E) 
 
Pr ot oc ol #:        
Sit e #:        
S u bj e ct I niti als:        
 
 
 
 
 
 
 
 
 
S A E ( E ve nt/ Di a g n osis) #: 2  
          
 
D ate E v e nt Bec a me Seri o us:  ( d d M m m yyyy)       
 
D ate E ve nt St o p pe d  or : ( d d M m m yyyy)       
 
 
 
 
 
 
 
C o nti n ui n g  
N CI C T C A E Se verit y 
Gr a di n g  
O utc o me  
Seri o us n ess Criteri a  
(see pr ot oc ol f or S A E defi niti o ns)  
 Yes  
 N o  
 1 = Mil d  
 2 = M o derat e  
 3 = S e ver e  
 4 = Lif e -t hr eat e ni n g 
or disa bli n g  
 5 = D eat h  
 Rec o ver e d/ R es ol ve d  
 Rec o veri n g/ R es ol vi n g  
 N ot R ec o ver e d/ N ot R es ol ve d  
 Rec o ver e d/ R es ol ve d wit h s e q uela e  
   /resi d ual eff ect(s) pr es e nt 
 Fatal  
 U n k n o w n  
 D eat h  
 Li f e-t hr eat e ni n g 
 H os pitali zati o n -i nitial or pr ol o n ge d 
 Disa bilit y or P er ma n e nt Da ma ge  
 C o n ge nital a n o mal y/ Birt h D ef ect  
 I m p ort a nt M e dical E ve nt 
St u d y Dr u g C a us alit y ( C o m plete o n e li ne f or e ac h st u dy dr u g)  
Dr u g N a me  
Rel at e d  
N ot Rel ate d  
      
 
 
      
 
 
          
 
 
S A E ( E ve nt/ Di a g n osis) #: 3  
          
 
D ate E v e nt Bec a me Seri o us:  ( d d M m m yyyy)       
 
D ate E ve nt St o p pe d  or : ( d d M m m yyyy)       
 
 
 
 
 
 
 
C o nti n ui n g  
N CI C T C A E Se verit y 
Gr a di n g  
O utc o me  
Seri o us n ess Criteri a  
(see pr ot oc ol f or S A E defi niti o ns) 
 Yes  
 N o  
 1 = Mil d  
 2 = M o derat e  
 3 = S e ver e  
 4 = Lif e -t hr eat e ni n g 
or disa bli n g  
 5 = D eat h  
 Rec o ver e d/ R es ol ve d  
 Rec o veri n g/ R es ol vi n g  
 N ot R ec o ver e d/ N ot R es ol ve d  
 Rec o ver e d/ R es ol ve d wit h s e q uela e  
   /resi d ual eff ect(s) pr es e nt 
 Fatal  
 U n k n o w n  
 D eat h  
 Lif e -t hr eat e ni n g 
 H os pitali zati o n -i nitial or pr ol o n ge d 
 Disa bilit y or P er ma n e nt Da ma ge  
 C o n ge nital a n o mal y/ Birt h D ef ect  
 I m p ort a nt M e dical E ve nt 
St u d y Dr u g C a us alit y ( C o m plete o n e li ne f or e ac h st u dy dr u g) 
Dr u g N a me  
Rel at e d  
N ot Rel ate d  
      
 
 
      
 
 
      
 
 
S A E ( E ve nt/ Di a g n osis) #: 4  
      
 
D ate E v e nt Bec a me Seri o us: ( d d M m m yyyy)       
 
D ate E ve nt St o p pe d  or : ( d d M m m yyyy)       
 
 
 
 
 
 
 
C o nti n ui n g  
N CI C T C A E Se verit y 
Gr a di n g  
O utc o me  
Seri o us n ess Criteri a  
(see pr ot oc ol f or S A E defi niti o ns) 
 Yes  
 N o  
 1 = Mi l d 
 2 = M o derat e  
 3 = S e ver e  
 4 = Lif e -t hr eat e ni n g 
or disa bli n g  
 5 = D eat h  
 Rec o ver e d/ R es ol ve d  
 Rec o veri n g/ R es ol vi n g  
 N ot R ec o ver e d/ N ot R es ol ve d  
 Rec o ver e d/ R es ol ve d wit h s e q uela e  
   /resi d ual eff ect(s) pr es e nt 
 Fatal  
 U n k n o w n  
 D eat h  
 Lif e -t hr eat e ni n g 
 H os pitali zati o n -i nitial or pr ol o n ge d 
 Disa bilit y or P er ma n e nt Da ma ge  
 C o n ge nital a n o mal y/ Birt h D ef ect  
 I m p ort a nt M e dical E ve nt 
St u d y Dr u g C a us alit y ( C o m plete o n e li ne f or e ac h st u dy dr u g) 
Dr u g N a me  
Rel at e d  
N ot Rel ate d  
          
 
 
          
 
 
          
 
 
 

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
( S u p pl e me nt al C o n c o mit a nt Me di c ati o ns) 
 
Pr ot oc ol #:        
Sit e #:  
      
S u bj e ct I niti als:        
 
 
 
 
 
 
 
 
 
7. Rele v a nt C o n c o mit a nt M e di c ati o ns ( C o nti n ue d)  
(I n cl u d e t h os e t a k e n b ef ore t h e o ns et of t h e e v e nt, n ot t a ke n as a tre at m e nt f or t h e e v e nt.)   D o N O T c o m plete wi t h 
“ Se e Att ac h e d ”.  
Ge neri c/ Br a n d N a me  
D ose  
Fre q u e nc y  
R o ute  
St art D ate  
( d d M m m yy yy) 
St o p D ate  
( d d M m m yy yy) 
I n dic ati o n 
C o nti n ui n g ?  
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
          
                    
                    
          
          
 
      
            
            
      
      
 
 

 
 
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S E RI O U S A D V E R S E E V E N T R E P O R T ( S A V E R) F O R M -O N C O L O G Y S T U DI E S  
( S u p pl e me nt al L a b R es ults) 
 
Pr ot oc ol #:        
Sit e #:  
      
S u bj e ct I niti als:  
      
 
 
 
 
 
 
 
 
 
8. Rele v a nt L a b R es ults ( C o nti n ue d)  
D o N O T c o m pl ete wit h “ S e e Att a c h e d. ”  
L a b Test  
D ate  
( d d M m m yy yy) 
Res ults  
Ref ere nc e N or m al R a n ge 
( U nits) 
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
 

 
 
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[A p p e n di x 4] E x p os ure i n Ut er o Re p orti n g F or m  
 

 
 
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Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
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