Conditions: Acute Myeloid Leukemia
Keywords: AML phase 1 hematology malignancy newly diagnosed
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a phase 1b, dose escalation, study of quizartinib to evaluate the safety profile, the pharmacokinetics, and the recommended dose of quizartinib for subsequent clinical studies of the combination of quizartinib and induction and consolidation chemotherapy.

Detailed description:

Arms:
arm 1: Participants who received 20 mg quizartinib once daily in the morning under fasting conditions.

For the Induction phase, cytarabine (100 mg/m\^2/day IV) and either idarubicin (12 mg/m\^2/day IV infusion) or daunorubicin (60 mg/m\^2/day IV) were co-administered with quizartinib.

For the Consolidation phase, cytarabine (3.0 g/m\^2/12 hours IV) was co-administered with quizartinib. arm 2: Participants who received 40 mg quizartinib once daily in the morning under fasting conditions.

For the Induction phase, cytarabine (100 mg/m\^2/day IV) and either idarubicin (12 mg/m\^2/day IV infusion) or daunorubicin (60 mg/m\^2/day IV) were co-administered with quizartinib.

For the Consolidation phase, cytarabine (3.0 g/m\^2/12 hours IV) was co-administered with quizartinib.

Interventions: intervention 1: Quizartinib intervention 2: Cytarabine intervention 3: Idarubicin intervention 4: Daunorubicin
Intervention descriptions: intervention 1: \[Induction period, Cycle 1\] Once-daily repeated oral administration Day 8 to Day 21.

\[Induction period, Cycle 2\] Once-daily repeated oral administration Day 6 to Day 19.

\[Consolidation period\] Once-daily repeated oral administration Day 6 to Day 19. intervention 2: \[Induction period, Cycle 1\] Once-daily intravenous injection of 100 mg/m\^2 cytarabine on Day 1 to 7.

\[Induction period, Cycle 2\] Once-daily intravenous injection of 100 mg/m\^2 cytarabine on Day 1 to 5.

\[Consolidation period\] Twice-daily intravenous injection of 3.0 g/m\^2 cytarabine at 12-hour intervals on Days 1, 3, and 5. intervention 3: Either Idarubicin or Daunorubicin will be used \[Induction period, Cycle 1\] Once-daily intravenous injection of 12 mg/m\^2 idarubicin on Day 1 to 3.

\[Induction period, Cycle 2\] Once-daily intravenous injection of 12 mg/m\^2 idarubicin on Day 1 and 2. intervention 4: Either Idarubicin or Daunorubicin will be used \[Induction period, Cycle 1\] Once-daily intravenous injection of 60mg/m\^2 daunorubicin on Day 1 to 3.

\[Induction period, Cycle 2\] Once-daily intravenous injection of 60mg/m\^2 daunorubicin on Day 1 and 2.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
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 


 
 
Cli nical St u d y Pr ot oc ol A C 2 2 0- A-J 1 0 2 
 
 
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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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Versi o n 0 1. 0 0. 0 0 0 
 
2 5  
 
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  
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 
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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  
• 
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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 .  
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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  
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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. 


 
 
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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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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  
 


 
 
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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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[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) 
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
      
      
      
      
          
          
          
          
 


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


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