Clinical trial NCT02039726
Conditions: AML
Keywords: Acute Myeloid Leukemia AML FMS-like tyrosine kinase 3 FLT3-ITD Quizartinib Leukemia Tablets
Sponsor: Daiichi Sankyo
Start date: 2014-05-01; Completion date: 2020-09-08
Enrollment: 367 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.

Detailed description:

Arms: arm 1: Participants who were randomized to receive 20 or 30 mg quizartinib tablets administered orally once daily. arm 2: Participants who were randomized to receive salvage chemotherapy, such as low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA), were administered during 28-day cycles.
Interventions: intervention 1: Quizartinib intervention 2: Salvage Chemotherapy
Intervention descriptions: intervention 1: 20 or 30 mg quizartinib tablets administered orally once daily intervention 2: Low dose cytarabine (LoDAC); mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte colony stimulating factor (G-CSF) with idarubicin (FLAG-IDA) administered during 28-day cycles

Protocol documents:
Prot_SAP_000.pdf: 




Daiic hi Sa n k y o, I nc
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C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
S T U D Y S Y N O P SI S
N A M E O F S P O N S O R 
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U nite d States
N A M E O F 
FI NI S H E D 
P R O D U C T
Q uizarti ni b ta blets
N A M E O F A C TI V E 
I N G R E DI E N T
Q uizarti ni b 
TI T L E:   A P hase 3 O pe n -La bel Ra n d o mize d St u d y  of Q uizarti ni b M o n ot hera py Vers us 
Sal va ge C he m ot hera p y i n S u bjects wit h F L T 3 -I TD P ositi ve Ac ute M y el oi d Le u ke mia ( A M L) 
Refract or y  T o or Rela pse d After First-li ne Treat me nt Wit h or Wit h o ut He mat o p oietic Ste m Cell  
Tra ns pla ntati o n ( H S C T) C o ns oli dati o n
I N DI C A TI O N:  Rela pse d or refract or y F L T 3-I TD( +) A M L
S T U D Y P H A S E :  3
S T U D Y C E N T E R S:   A p pr o xi matel y  1 5 0 ce nters gl o ball y
N U M B E R O F S U B J E C T S P L A N N E D:   A p pr o xi matel y  3 6 3 s u bjects will be ra n d o mize d.
S T U D Y D U R A TI O N:   A p pr o xi matel y  3 6 m o nt hs
S T U D Y O B J E C TI V E S
T he pri mar y  o bjecti ve of t he st u d y is t o deter mi ne w het her q uizarti ni b m o n ot hera py pr ol o n gs 
o verall s ur vi val ( O S) c o m pare d t o sal va ge c he m ot hera p y i n s u bjects wit h F L T 3 -I TD p ositi ve 
A M L  w h o are refract or y t o or ha ve rela pse d wit hi n 6 m o nt hs, after first -li ne A M L t hera p y.
T he sec o n dar y  o bjecti ve is t o deter mi ne e ve nt-free s ur vi val ( E F S) wit h q uizarti ni b vers us 
sal va ge c he m ot hera py.
E x pl orat or y  o bjecti ves are:

t o c o m pare t he c o m p osite c o m plete re missi o n ( C Rc =  c o m plete re missi o n [ C R] + 
c o m plete re missi o n wit h i nc o m plete platelet rec o ver y  [ C R p] + c o m plete re missi o n 
wit h i nc o m plete he mat ol o gic rec o ver y  [ C Ri]) rate

t o c o m pare t he c o m plete re missi o n ( C R) rate

t o c o m pare t he d urati o n of c o m p osite c o m plete re missi o n  ( C Rc)

t o c o m pare t he d urati o n of c o m plete re missi o n ( C R)

t o deter mi ne le u ke mia-free s ur vi val ( L F S)

t o c o m pare t he tra ns pla ntati o n rate

t o deter mi ne t he Q Tc pr ol o n gi n g effects of q uizarti ni b i n relati o n t o plas ma dr u g 
c o nce ntrati o ns

t o deter mi ne t he p har maco ki netics ( P K) of q uizarti ni b a n d its acti ve meta b olite, 
A C 8 8 6

t o deter mi ne t he e x p os ure-res p o nse relati o ns hi p


Daiic hi Sa n k y o, I nc
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C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

t o deter mi ne res o urce utilizati o n i n t his st u d y p o p ulati o n

t o i de ntif y A M L-ass ociate d m utati o ns a n d t heir fre q ue ncies

p har mac o ge n o mic a n d p har mac o pr ote o mic deter mi nati o ns
S T U D Y D E SI G N
T his is a P hase 3, ra n d o mize d, o pe n -la bel, 2-ar m st u d y t o c o m pare t he effect of q uizarti ni b 
m o n ot hera p y a n d sal va ge c he m ot hera p y o n O S i n s u bjects wit h F L T 3 -I TD ( +) A M L t hat is 
refract or y or rela pse d wit hi n 6 m o nt hs, after first-li ne t hera p y wit h or wit h o ut c o ns oli dati n g 
he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T).
T he st u d y  will utilize a gr o u p se q ue ntial desi g n wit h 1 i nteri m a nal ysis at 0. 5 i nf or mati o n 
fracti o n (ie, a p pr o xi matel y 5 0 % of pla n ne d n u m ber of e ve nts). T he tar get sa m ple size will be 
a p pr o xi matel y 3 6 3 s u bjects, ra n d o mize d i n a 2: 1 rati o t o recei ve q uizarti ni b m o n ot hera p y ( 2 4 2 
s u bjects) or sal va ge c he m ot hera py ( 1 2 1 s u bjects). O ne f or mal i nteri m a nal y sis will be 
perf or me d b y a n i n de pe n de nt statistical a nal ysis ce nter ( S A C) a n d e val uate d b y a n i n de pe n de nt 
data m o nit ori n g c o m mittee ( D M C), acc or di n g t o statistical pr oce d ures defi ne d a pri ori. Base d 
o n t he res ults of t he i nteri m a nal y sis, t he D M C ma y rec o m me n d t hat t he st u d y be ter mi nate d 
earl y f or f utilit y  or f or efficac y, or c o nti n ue as pla n ne d. T he tas ks perf or me d b y  t he S A C a n d 
D M C are descri be d i n t he D M C c harter a n d I nteri m A nal ysis Pla n.
Pri or t o ra n d o mizati o n, t he I n vesti gat or will pre -select a sal va ge c he m ot hera p y re gi me n f or 
eac h s u bject; o pti o ns i ncl u de l o w d ose c y tara bi ne ( Lo D A C); mit o xa ntr o ne, et o p osi de, a n d 
i nter me diate-d ose c y tara bi ne ( M E C); or fl u dara bi ne, c ytara bi ne, a n d gra n ul oc yte c ol o n y 
sti m ulati n g fact or ( G-C S F) wit h i dar u bici n ( F L A G -I D A).
S cree ni n g
D uri n g t he 1 4 da y  scree ni n g peri o d, s u bjects will u n der g o me dical hist or y e val uati o n, p h ysical 
e xa mi nati o n, vital si g n deter mi nati o n, Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) 
perf or ma nce stat us assess me nt, c hest X- r a y, c o nc o mita nt me dicati o n assess me nt, bl o o d a n d 
uri ne sa m pli n g f or la b orat or y  tests, E C G m o nit ori n g, a n d b o ne marr o w as pirati o n/ bi o ps y t o 
c o nfir m F L T 3 -I T D stat us a n d c o nfir m dia g n osis.  S u bjects will u n der g o m ulti ple gate d 
ac q uisiti o n ( M U G A) sca ns or ec h ocar di o gra p h y ( E C H O).
S T U D Y P O P U L A TI O N
I ncl usi o n Criteri a
T o be a ble t o partici pate i n t his st u d y , ca n di dates m ust meet t he f oll o wi n g criteria at scree ni n g 
or ot her s pecifie d ti me p oi nt:
1.
Pr o visi o n of writte n i nf or me d c o nse nt a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d 
(IR B) or I n de pe n de nt Et hics C o m mittee (IE C) wit h pri vac y  la n g ua ge i n acc or da nce wit h 
nati o nal re g ula ti o ns [e g, Healt h I ns ura nce P orta bilit y  a n d Acc o u nta bilit y Act (HI P A A )
a ut h orizati o n f or U S sites] pri or t o a n y  st u d y-relate d pr oce d ures, i ncl u di n g wit h dra wal 
of pr o hi bite d me dicati o ns if a p plica ble.
2.
A ge ≥1 8 y ears or t he mi ni m u m le gal a d ult a ge ( w hic he ver is greater) at t he ti me of 
i nf or me d c o nse nt.


Daiic hi Sa n k y o, I nc
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C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
3.
M or p h ol o gicall y  d oc u me nte d pri mar y A M L or A M L sec o n dar y t o myel o d ys plastic 
s yn dr o me ( M D S), as defi ne d b y  W orl d Healt h Orga nizati o n criteria, as deter mi ne d b y  
pat h ol o g y  re vie w at t he st u d y site.
4. I n first rela pse ( wit h d urati o n of re missi o n of 6 m o nt hs or less) or refract or y after pri or 
t hera py, wit h or wit h o ut H S C T.  I n d ucti o n t hera p y  m ust ha ve i ncl u de d at least 1 c ycle 
of a n a nt hrac y cli ne/ mit o xa ntr o ne c o ntai ni n g i n d ucti o n bl oc k at a sta n dar d d ose.

Refract or y  is defi ne d as:
-
After 1 c y cle, a re d ucti o n i n b o ne marr o w blasts of less t ha n 5 0 % a n d fail ure t o 
ac hie ve a C R, C R p, or C Ri.
-
After 2 c y cles, lac k of ac hie ve me nt of C R, C R p, or C Ri

First rela pse ( wit h d urati o n of re missi o n of 6 m o nt hs or less) is defi ne d as:
-
Ac hie ve me nt of C R, C Ri, or C R p, as defi ne d b y 2 0 0 3 I nter nati o nal W or ki n g 
Gr o u p criteria after i nitial A M L  t hera p y wit h or wit h o ut c o ns oli dati o n or 
mai nte na nce, a n d wi t h or wit h o ut H S C T.
-
D urati o n of C R, C Ri or C R p is meas ure d fr o m t he date of t he b o ne marr o w 
assess me nt w hic h c o nfir me d res p o nse or t he date of all o ge neic tra ns pla ntati o n t o 
t he date of t he b o ne marr o w assess me nt t hat i de ntifie d rela pse or t he a p peara nce 
of peri p heral blasts.
5.
Prese nce of t he F L T 3 -I TD acti vati n g m utati o n i n b o ne marr o w or peri p heral bl o o d 
(allelic rati o as deter mi ne d b y a ce ntral la b orat or y wit h a c ut off of ≥3 % F L T 3 -I T D/t otal 
F L T 3).  If a s peci me n has bee n se nt f or F L T 3 -I TD testi n g at t he ce n tral la b orat or y b ut 
t he s u bject re q uires treat me nt f or A M L bef ore t he ce ntral F L T 3-I TD test res ult is 
a vaila ble, a l ocal test res ult ma y be acce pta ble f or ra n d o mizati o n after c o ns ultati o n wit h 
t he Me dical M o nit or.
6.
Eli gi bilit y  f or pre-selecte d sal va ge c he m ot hera py, acc or di n g t o t he I n vesti gat or’s 
assess me nt.
7.
E C O G perf or ma nce sc ore 0 - 2.
8.
Disc o nti n uati o n of pri or A M L  treat me nt bef ore t he start of st u d y treat me nt (e xce pt 
h y dr o x y u rea or ot her treat me nt t o c o ntr ol le u k oc yt osis) f or at least 2 wee ks f or c yt ot o xic 
age nts, or f or at least 5 half -li ves f or n o n-c yt ot o xic a ge nts.
9.
Ser u m creati ni ne ≤1. 5 × u p per li mit of n or mal ( U L N), or gl o mer ular filtrati o n rate 
> 2 5 m L / mi n, as calc ulate d wit h t he C oc kcr oft-Ga ult f or m ula.
1 0. Ser u m p otassi u m, ma g nesi u m, a n d calci u m (ser u m calci u m c orrecte d f or 
h y p oal b u mi ne mia) wit hi n i nstit uti o nal n or mal li mits.  S u bjects wit h electr ol y tes o utsi de 
t he n or mal ra n ge will be eli gi ble if t hese val ues are c orrecte d u p o n retesti n g f oll o wi n g 
a n y necessar y s u p ple me ntati o n.
1 1. T otal ser u m bilir u bi n ≤1. 5 × U L N.
1 2. Ser u m as partate tra nsa mi nase ( A S T) a n d/ or ala ni ne tra nsa mi nase ( A L T) ≤2. 5 × U L N.


Daiic hi Sa n k y o, I nc
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6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
E xcl usi o n Criteri a
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g criteria are met at 
scree ni n g or ot her s pecifie d ti me p oi nt:
1.
Ac ute pr o m yel oc yt ic le u ke mia ( A M L s u bty pe M 3).
2.
A M L  sec o n dar y t o pri or c he m ot hera py f or ot her ne o plas ms, e xce pt A M L sec o n dar y t o 
pri or M D S.
3.
Hist or y  of a n ot her mali g na nc y, u nless t he ca n di date has bee n disease-free f or at least 
5 ye ars.

Ca n di dates wit h treate d n o n- mela n o ma s ki n ca ncer, carci n o ma i n sit u, or cer vical 
i ntrae pit helial ne o plasia are eli gi ble re gar dless of t he ti me s pe nt disease-free, if t he y 
ha ve c o m plete d defi niti ve treat me nt.

Ca n di dates wit h or ga n -c o nfi ne d pr ostate ca ncer, wit h n o e vi de nce of rec urre nt or 
pr o gress i ve disease, are eli gi ble if h or m o nal t hera p y has bee n be g u n, or if t he t u m or 
has bee n s ur gicall y  re m o ve d or treate d wit h defi niti ve ra di ot hera p y.
4.
Persiste nt, cli nicall y  si g nifica nt > Gra de 1 n o n-he mat ol o gic t o xicit y  fr o m pri or 
A M L t hera p y.
5.
Cli nicall y  si g nifica nt G V H D or G V H D re q uiri n g i nitiati o n of treat me nt or treat me nt 
escalati o n wit hi n 2 1 da ys, a n d/ or > Gra de 1 persiste nt or cli nically si g nifica nt 
n o n -he mat ol o gic t o xicit y  relate d t o H S C T.
6.
Hist or y  of or c urre nt, ce ntral ner v o us sys te m i n v ol ve me nt wit h A ML.
7.
Cli nicall y  si g nifica nt c oa g ulati o n a b n or malit y, s uc h as disse mi nate d i ntra vasc ular 
c oa g ulati o n.
8.
Pri or treat me nt wit h q uizarti ni b or partici pate d i n a pri or q uizarti ni b st u d y .
9.
Pri or treat me nt wit h a F L T 3 tar gete d t hera p y i ncl u di n g s orafe ni b or i n vesti gati o nal 
F L T 3 i n hi bit ors ( n ot i ncl u di n g t he m ulti -ki nase i n hi bit or, mi d osta uri n).
1 0. Maj or s ur ger y  wit hi n 4 wee ks pri or t o scree ni n g.
1 1. Ra diati o n t hera p y wit hi n 4 wee ks pri or t o scree ni n g.
1 2. U nc o ntr olle d or si g nifica nt car di o vasc ular disease, i ncl u di n g:
 
Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula ( Q Tc F) i nter val > 4 5 0 msec 
(a vera ge of tri plicate deter mi nati o ns).

S u bject has bra d yc ar dia of less t ha n 5 0 B P M (as deter mi ne d b y ce ntral rea di n g) 
u nless t he s u bject has a pace ma ker.

Dia g n ose d or s us pecte d l o n g Q T s y n dr o me, or k n o w n fa mil y hist or y  of l o n g 
Q T s yn dr o me.

Hist or y  of cli nicall y rele va nt ve ntric ular arr hyt h mias, s uc h as ve ntric ular 


Daiic hi Sa n k y o, I nc
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7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
tac hycar dia, ve ntric ular fi brillati o n, or t orsa de de p oi ntes.

Hist or y  of sec o n d or t hir d de gree heart bl oc k.  Ca n di dates wit h a hist or y  of heart 
bl oc k ma y  be eli gi ble if t he y c urre ntl y ha ve pace ma kers, a n d ha ve n o hist or y of 
fai nti n g or cli nicall y rele va nt arr h yt h mia wit h pace ma kers.

M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o scree ni n g.

U nc o ntr olle d a n gi na pect oris wit hi n 6 m o nt hs pri or t o scree ni n g.

Ne w Y or k Heart Ass ociati o n ( N Y H A) Class 3 or 4 c o n gesti ve heart fail ure.

Left ve ntric ular ejecti o n fracti o n ( L V E F) ≤4 5 % or i nstit uti o nal l o wer li mit of 
n or mal.

U nc o ntr olle d h y perte nsi o n.

C o m plete left or ri g ht b u n dle bra nc h bl oc k.
1 3. Acti ve i nfecti o n n ot well c o ntr olle d b y  a nti bacterial, a ntif u n gal, a n d/ or a nti viral t hera p y.
1 4. K n o w n i nfecti o n wit h h u ma n i m m u n o deficie nc y vir us, or acti ve he patitis B or C, or 
ot her acti ve cli nicall y  rele va nt li ver disease.
1 5. U n willi n g ness t o recei ve i nf usi o n of bl o o d pr o d ucts acc or di n g t o t he pr ot oc ol.
1 6. I n a ma n w h ose se x ual part ner is a w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or 
i na bilit y of t he ma n or w o ma n t o use a hi g hly effecti ve c o ntrace pti ve met h o d f or t he 
e ntire st u d y treat me nt peri o d a n d f or at least 3 m o nt hs after st u dy treat me nt c o m pleti o n.

Male s u bjects m ust n ot freeze or d o nate s per m starti n g at Scree ni n g a n d t hr o u g h o ut 
t he st u d y peri o d a n d 1 0 5 da ys after t he fi nal st u d y dr u g a d mi nistrati o n.
1 7. I n a heter ose x uall y acti ve w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or i na bilit y  t o 
use a hi g hl y  effecti ve c o ntrace pti ve met h o d f or t he e ntire st u d y treat me nt peri o d a n d f or 
at least 3 m o nt hs after st u d y  treat me nt c o m pleti o n.  A d diti o nall y, f or w o me n 
ra n d o mize d t o c he m ot hera p y, u n willi n g ness t o a d here t o t he restricti o ns i n t he 
res pecti ve l ocall y esta blis he d g ui deli nes a n d l ocal a p pr o ve d la bel ( prescri bi n g 
i nf or mati o n, S u m mar y of Pr o d uct C haracteristics, or U S pr o d uct i nsert) fr o m t he 
ma n ufact urer a n d t he Patie nt I nf or mati o n Leaflet ( pac ka ge i nsert) as i nstr ucte d b y  t he 
I n vesti gat or.

W o me n are n ot re gar de d as of c hil d beari n g p ote ntial if t he y  are p ost-me n o pa usal (at 
least 2 years wit h o ut me nses) or are s ur gicall y  sterile (at least 1 m o nt h bef ore st u d y).

Hi g hl y effecti ve c o ntrace pti o n met h o ds i n cl u de: h or m o nal met h o ds ass ociate d wit h 
i n hi biti o n of o v ulati o n, i ntra- uteri ne de vice; s ur gical sterilizati o n (i ncl u di n g 
part ner’s vasect o m y) or se x ual a bsti ne nce if t his is t he preferre d a n d us ual lifest y le 
of t he s u bject.

Fe male s u bjects m ust n ot d o nate or retrie ve, f or t heir o w n use, o va fr o m t he ti me of 
Scree ni n g a n d t hr o u g h o ut t he st u d y  treat me nt peri o d, a n d f or 1 2 wee ks after t he 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
fi nal st u d y dr u g a d mi nistrati o n.
1 8. Pre g na nc y
1 9. Fe male s u bjects m ust a gree n ot t o breastfee d fr o m t he ti me of Scree ni n g a n d t hr o u g h o ut 
t he st u d y peri o d, a n d f or 2 5 da ys after t he fi nal st u d y dr u g a d mi nistrati o n.
2 0. Me dical c o n diti o n, seri o us i nterc urre nt ill ness, or ot her circ u msta nce t hat, i n t he 
I n vesti gat or’s j u d g me nt, c o ul d je o par dize t he ca n di date’s safet y as a st u d y s u bject, or 
t hat c o ul d i nterfere wit h st u d y o bjecti ves.
2 1. F or s u bjects i n t he U K o nl y :  Ref usal of per missi o n t o all o w t he s u bject’s Ge neral 
Practiti o ner t o be n otifie d of t heir partici pati o n i n t he st u d y .
S T U D Y T R E A T M E N T
Q uiz arti ni b
F or s u bjects ra n d o mize d t o q uizarti ni b t he starti n g d ose will be 3 0 m g/ da y  u nless t he s u bject is 
recei vi n g c o nc urre nt t hera p y wit h a str o n g C Y P 3 A 4 i n hi bit or, i n w hic h case t he starti n g d ose 
will be 2 0 m g/ da y .  T he d ose will be ta ke n i n t he m or ni n g wit h or wit h o ut f o o d o ver c o nti n u o us 
2 8- d a y  c ycles.  If t he s u bject o mits t o ta ke q uizarti ni b i n t he m or ni n g, it ma y be ta ke n later i n 
t he da y ( u ntil mi d ni g ht), ot her wise t he d ose is c o nsi dere d misse d.  If t he s u bject v o mits after 
ta ki n g q uizarti ni b, n o re place me nt d ose s h o ul d be gi ve n.
C Y C L E 1 D A Y 1 6
F or s u bjects n ot ta ki n g a str o n g C Y P 3 A 4 i n hi bit or t he d ose of q uizarti ni b will be i ncrease d 
fr o m 3 0 t o 6 0 m g/ da y starti n g o n Da y 1 6 base d o n t he f oll o wi n g criteria:

T he s u bject’ s a vera ge Q Tc F, base d o n tri plicate rea di n g, m ust be ≤ 4 5 0 msec o n a n d 
bef ore Da y  1 5.
F or s u bjects ta ki n g a str o n g C Y P 3 A 4 i n hi bit or, t he d ose of q uizarti ni b will be i ncrease d fr o m 
2 0 m g/ da y  t o 3 0 m g/ da y pr o vi di n g t he y meet t he a b o ve Q Tc F re q uire me nts.
C Y C L E 2 D A Y 1
S u bjects w h o fail t o ac hie ve a C R, C R p, or C Ri as defi ne d i n Secti o n 7. 2 after at least o ne 
2 8- d a y  c ycle of t hera p y ma y u n der g o d ose escalati o n if t he f oll o wi n g criteria are met:

S u bject has n ot ha d d ose i nterr u pti o n or d ose re d ucti o n f or a Gra de 3 or hi g her, 
n o n- he mat ol o gic, a n d relate d a d verse e ve nt.

N o i ncrease i n Q Tc F m ore t ha n 6 0 msec a b o ve baseli ne.

T he s u bject m ust n ot ha ve a plastic b o ne marr o w at t he ti me of t he pr o p ose d d ose 
escalati o n.
I n a d diti o n, s u bjects w h o ac hie ve d a res p o nse [ C R, C Ri, C R p or partial re missi o n ( P R)] at a n y 
ti me, a n d w h o ha ve s u bse q ue ntl y rela pse d, ma y u n der g o d ose escalati o n pr o vi de d t he y meet t he 
sa me criteria o utli ne d a b o ve.
F or s u bjects n ot ta ki n g a str o n g C Y P 3 A 4 i n hi bit or t he d ose of q uizarti ni b will be i ncrease d t o 
6 0 m g/ da y .


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
F or s u bjects ta ki n g a str o n g C Y P 3 A 4 i n hi bit or, t he d ose of q uizarti ni b will be i ncrease d t o 
3 0 m g/ da y  pr o vi di n g t he y meet t he a b o ve re q uire me nts.
F oll o wi n g d ose escalati o n, tri plicate E C G deter mi nati o ns s h o ul d be perf or me d at least o nce 
wee kl y f or 2 wee ks t o m o nit or Q Tc F pr ol o n gati o n.
If a ny of t he f oll o wi n g criteria are met, t he q uizarti ni b d ose will be re d uce d ste p wise fr o m 
6 0 m g/ da y  t o 3 0 m g/ da y or fr o m 3 0 m g / da y t o 2 0 m g/ da y or disc o nti n ue d.  N o f urt her d ose 
re d ucti o ns bel o w 2 0 m g/ da y will be all o we d.

Q Tc F pr ol o n g ati o n
o
Gra de 2 ( Q Tc F a vera ge of tri plicate rea di n gs > 4 8 0 msec) ( All t o xicit y  gra des 
acc or di n g t o Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y  Criteria f or 
A d verse E ve nts [ N CI  C T C A E] v 4. 0 3)

T he d ose will be re d uce d wit h o ut i nterr u pti o n.

If 2 0 m g/ da y  is t he c urre nt d ose, d osi n g will be i nterr u pte d f or u p t o 1 4 da ys.  
If Q Tc F ret ur ns t o wit hi n 3 0 msec of baseli ne or ≤ 4 5 0 msec wit hi n 1 4 da y s, 
treat me nt ma y be res u me d at 2 0 m g/ da y.
o
Gra de 3 ( Q Tc F a vera ge of tri plicate rea di n gs > 5 0 0 msec)

D osi n g wi ll be i nterr u pte d f or u p t o 1 4 da ys.  If Q Tc F ret ur ns t o wit hi n 
3 0 msec of baseli ne or ≤ 4 5 0 msec wit hi n 1 4 da y s, treat me nt ma y be 
res u me d at a re d uce d d ose.

If 2 0 m g/ da y is t he c urre nt d ose, d osi n g will be i nterr u pte d f or u p t o 1 4 da ys.  
If Q Tc F ret ur ns to wit hi n 3 0 msec of baseli ne or ≤ 4 5 0 msec wit hi n 1 4 da y s, 
treat me nt ma y be res u me d at 2 0 m g/ da y. If Gra de 3 e ve nt ret ur ns, treat me nt 
will be disc o nti n ue d.
o
Gra de 4 ( Q Tc F > 5 0 0 msec or > 6 0 msec c ha n ge fr o m baseli ne, a n d T orsa de de 
p oi ntes or p ol y m or p hic ve ntric ular tac h ycar dia or si g ns/s y m pt o ms of seri o us 
arr h yt h mia)

Treat me nt will be disc o nti n ue d.

N o n - he m at ol o gic t o xicit y
o
Gra de 3 or 4 relate d t o q uizarti ni b a n d persisti n g > 4 8 h o urs wit h o ut 
i m pr o ve me nt t o ≤ Gra de 2

D osi n g will be i nterr u pte d f or u p t o 1 4 da ys .

If t o xicit y i m pr o ves t o ≤ Gra de 1 wit hi n 1 4 da y s, treat me nt ma y be res u me d 
at t he re d uce d d ose.

M yel os u p pressi o n
o
I n a s u bject wit h C R p or C Ri, t he d ose ma y be re d uce d at t he I n vesti gat or’s 
discreti o n if:

T he s u bject has bee n treate d f or a mi ni m u m of 2 c ycles.

Platelet c o u nt is < 1 0 0 × 1 0 9/ L a n d a bs ol ute ne utr o p hil c o u nt ( A N C) is ≤ 
1 0 0 0 × 1 0 9/ L.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

Marr o w blasts < 5 %.

T here is n o e vi de nce of e xtra me d ullar y disease.

I niti ati o n of c o nc o mit a nt tre at me nt wit h a str o n g C Y P 3 A 4 i n hi bit or
o
T he d ose will be re d uce d fr o m eit her 6 0 m g/ da y t o 3 0 m g/ da y or fr o m 
3 0 m g/ da y  t o 2 0 m g/ da y.
o
A s u bject ta ki n g a str o n g C Y P 3 A 4 i n hi bit or at ti me of ra n d o mizati o n will 
i nitiate q uizarti ni b a d mi nistrati o n at 2 0 m g/ da y.
I n s u bjects recei vi n g a re d uce d d ose of q uizarti ni b, t he d ose ma y be re -escalate d ste p wise fr o m 
2 0 m g t o 3 0 m g t o 6 0 m g, e xce pt f oll o wi n g Gra de 3 Q Tc F pr ol o n gati o n.  If t he d ose was 
re d uce d d ue t o t o xicit y, all e ve nts res p o nsi ble f or d ose re d ucti o n m ust ha ve res ol ve d t o ≤Gra de 
1.  If t he d ose was re d uce d d ue t o a d mi nistrati o n of a str o n g C Y P 3 A 4 i n hi bit or, t he pri or d ose 
ca n be res u me d w he n t he i n hi bit or is wit h dra w n .
If a s u bject u n der g oes H S C T, q uizarti ni b s h o ul d be disc o nti n ue d 7 da ys bef ore t he start of a 
c o n diti o ni n g re gi me n.  F or a s u bject w h o was ra n d o mize d t o a n d recei ve d q uizarti ni b, treat me nt 
wit h q uizarti ni b ma y be res u me d at 3 0 t o 1 0 0 da y s after t he tra ns pla nt.  Q uizarti ni b ma y be 
restarte d if:

S u bject has a n A N C > 1 x 1 0 9/ L a n d platelet c o u nt > 5 0 × 1 0 9/ L wit h o ut platelet 
tra nsf usi o n s u p p ort wit hi n 1 wee k, or a platelet c o u nt > 2 5 × 1 0 9/ L wit h o ut platelet 
tra nsf usi o n s u p p ort wit hi n 2 wee ks pri or t o first d ose.

S u bject d oes n ot ha ve ( 1) acti ve ac ute, or ≥ Gra de 3 graft vers us h ost disease ( G V H D) 
or ( 2) acti ve G V H D t hera p y  ( n ot pr o p h yla xis) i nitiati o n i n t he prece di n g 2 1 da ys.
F oll o w -u p
After st u d y treat me nt is disc o nti n ue d, s u bjects will be f oll o we d f or 3 0 da ys f or safet y.  
Assess me nt of best res p o nse t o c he m ot hera p y s h o ul d be c o n d ucte d at Da y 2 9 ( ± 1 4 da ys) or 
pri or t o starti n g s u bse q ue nt A M L  t hera p y.  S u bjects will t he n e nter l o n g ter m f oll o w-u p e ver y  
3 m o nt hs f or c ollecti o n of i nf or mati o n o n s u bse q ue nt A M L  treat me nt, re missi o n stat us, a n d 
s ur vi val, i ncl u di n g t he ca use a n d date of deat h.
S al v a ge C he m ot her a p y
T he I n vesti gat or will pre -select t he s pecific sal va ge c he m ot hera p y re gi me n bef ore 
ra n d o mizati o n of eac h s u bject.  All sal va ge c he m ot hera py will be a d mi nistere d d uri n g 2 8 -d a y  
c ycles.  T he start of C ycl e 2 ( M E C, F L A G-I DA, or L o D A C) a n d s u bse q ue nt c y cles ( L o D A C) 
ma y  be dela ye d f or u p t o 1 4 da ys t o all o w f or rec over y  fr o m t o xicit y.  D ose re d ucti o ns are 
all o we d f or t o xicit y b ut m ust be d oc u me nte d i n t he s o urce rec or d.
L o w D ose C yt ar a bi ne ( L o D A C) 
C y tara bi ne ( 2 0 m g) will be a d mi nistere d t wice dail y b y s u bc uta ne o us i njecti o n f or 1 0 da ys 
( Da ys 1 t hr o u g h 1 0) o ver c o ntin u o us 2 8 -da y c y cles.  A dela y of u p t o 1 4 da ys bet wee n c ycles is 
all o we d f or rec o ver y fr o m t o xicit y.
M E C C he m ot her a p y 

Mit o xa ntr o ne ( 8 m g/ m
2/ da y) will be a d mi nistere d b y 5 mi n ute i ntra ve n o us (I V) 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
i njecti o n f or 5 da ys ( Da ys 1 t hr o u g h 5).

Et o p osi de ( 1 0 0 m g/ m 2/ da y) will be a d mi nistere d b y 1 h o ur I V i nf usi o n i m me diatel y 
after mit o xa ntr o ne f or 5 da ys ( Da ys 1 t hr o u g h 5).

C y tara bi ne ( 1 0 0 0 m g/ m2/ da y) will be a d mi nistere d b y 1 h o ur I V i nf usi o n 
i m me diatel y after et o p osi de f or 5 da ys ( Da ys 1 t hr o u g h 5).
F L A G- I D A C he m ot her a p y

G- C S F ( 3 0 0 μ g/ m 2/ da y) will be a d mi nistere d b y 2 h o ur I V i nf usi o n f or 5 da ys 
( Da ys 1 t hr o u g h 5) or alter nati vel y, G -C S F ( 5 µ g/ k g/ da y ) ma y be a d mi nistere d S C 
f or 5 da ys ( Da ys 1 t hr o u g h 5).  A d diti o nal G-C S F is rec o m me n de d 7 da y s after t he 
c o m pleti o n of c he m ot hera p y , u ntil A N C is > 0. 5 × 1 09/ L.

Fl u dara bi ne ( 3 0 m g/ m 2/ da y) will be a d mi nistere d b y 3 0 mi n ute I V i nf usi o n f or 
5 da y s ( Da ys 2 t hr o u g h 6).

C y tara bi ne ( 2 0 0 0 m g/ m2/ da y) will be a d mi nistere d b y 4 h o ur I V i nf usi o n, be gi n ni n g 
4 h o urs after t he fl u dara bi n e i nf usi o n, f or 5 da ys ( Da ys 2 t hr o u g h 6).

I dar u bici n ( 1 0 m g/ m 2/ da y) will be a d mi nistere d o ver 5 t o 1 0 mi n utes i n a fast-
r u n ni n g sali ne dri p f or 3 da ys ( Da ys 2 t hr o u g h 4).
I n s u bjects recei vi n g q uizarti ni b or L o D A C, treat me nt s h o ul d c o nti n ue u ntil t here is n o l o n ger 
cli nical be nefit fr o m t hera p y, or u ntil u nacce pta ble t o xicit y occ urs.  S u bjects t hat recei ve eit her 
q uizarti ni b or L o D A C will be assesse d f or res p o nse o n Da y 1 of C ycl e 2 a n d Da y 1 of Cycle 3 
as well as o n Da y 1 of eac h s u bse q ue nt c ycle u nless t he s u bject has alrea d y ac hie ve d C R, C R p, 
or C Ri.  I n t hat e ve nt, b o ne marr o w testi n g will be re peate d after e ver y  3 s u bse q ue nt c ycles, 
u nless t here is e vi de nce of rela pse.
S u bjects recei vi n g M E C or F L A G -I DA will recei ve 1 c y cle of t hera p y a n d be assesse d for 
res p o nse at Da y 2 9 ( ± 1 4 da ys).  Sal va ge c he m ot hera p y s h o ul d be gi ve n as 2 8 da y c ycles, 
alt h o u g h c ycles ma y be dela ye d f or rec o ver y fr o m t o xicit y or bl o o d c o u nt rec o ver y f or u p t o 
1 4 da y s.
S u bjects ac hie vi n g c o m plete re missi o n ( C R), c o m plete re missi o n w it h i nc o m plete he mat ol o gic 
rec o ver y ( C Ri), or c o m plete re missi o n wit h i nc o m plete platelet rec o ver y ( C R p) ( per 
I n vesti gat or assess me nt), ma y recei ve a sec o n d c ycle of t he sa me t hera py at t he In vesti gat or’s 
discreti o n.  Treat me nt s h o ul d be disc o nti n ue d if t h ere is n o e vi de nce of res p o nse or pr o gressi ve 
disease ( P D).  F or s u bjects w h o de m o nstrate s o me le vel of cli nical be nefit b ut d o n ot ac hie ve a 
re missi o n, t he decisi o n o n a d diti o nal treat me nt is at t he I n vesti gat or’s discreti o n.
C O N C O MI T A N T M E DI C A TI O N S
F or all s u bjects ( q uizarti ni b a n d sal va ge c he m ot hera p y):  A d mi nistrati o n of ot her a nti ne o plastic 
a ge nts d uri n g t he st u d y peri o d is pr o hi bite d wit h t he e xce pti o n of h y dr o x y urea w hic h is all o we d 
f or u p t o 1 4 da ys pri or t o or f or u p t o 4 da ys c o nc o mita ntl y wit h quizarti ni b or sal va ge 
c he m ot hera p y t o c o ntr ol t he peri p heral blast c o u nt, u p t o a ma xi m u m d ose of 5 g/ da y .
I n s u bjects recei vi n g q uizarti ni b, c o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc i nter val are 
pr o hi bite d e xce pt w he n re gar de d b y t he I n vesti gat or a s esse ntial f or s u bject care.  T he use of a 
str o n g C Y P 3 A 4 i n hi bit or s h o ul d be a v oi de d if p ossi ble, b ut is n ot pr o hi bite d alt h o u g h 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
q uizarti ni b d ose a dj ust me nts are re q uire d.  Wea k or m o derate C Y P 3 A 4 i n hi bit ors, s uc h as 
fl uc o naz ole ma y be use d wit h o ut a q uizarti ni b d ose re d ucti o n.
C o nc o mita nt str o n g or m o derate C Y P 3 A 4 i n d ucers are pr o hi bite d.
If q uizarti ni b is c o-a d mi nistere d wit h dr u gs t hat i n hi bit P -g p, i ncrease d c o nce ntrati o ns of 
q uizarti ni b are p ossi ble a n d ca uti o n s h o ul d be e xercise d.  T he c o -a d mi nistrati o n of 
P- g p i n hi bit ors a n d i n d ucers wit h q uizarti ni b s h o ul d be a v oi de d if p ossi ble.  If q uizarti ni b is 
c o-a d mi nistere d wit h dr u gs t hat are s u bstrates of P-g p, i ncrease d c o nce ntrati o ns of t he s u bstrate 
dr u gs are p ossi ble a n d ca uti o n s h o ul d be e xercise d.
S T U D Y V A RI A B L E S
Pri m ar y Effic ac y V ari a ble
T he pri mar y  efficac y varia ble is O S, defi ne d as t he ti me fr o m ra n d o mizati o n u ntil deat h fr o m 
a n y ca use.
Sec o n d ar y Effic ac y V ari a ble
T he sec o n dar y  varia ble is E F S, t he ti me fr o m ra n d o mizati o n u ntil d oc u me nte d refract or y 
disease, rela pse after C Rc, or deat h fr o m a n y ca use, w hic he ver is o bser ve d first.
A d diti o n al Effic ac y V ari a bles

Le u ke mia -free s ur vi val is t he ti me fr o m t he first d oc u me nte d res p o nse ( C R, C R p, or 
C Ri) u ntil d oc u me nte d rela pse or deat h fr o m a n y ca use.

C o m p osite c o m plete re missi o n ( C Rc) rate is t he perce nta ge of s u bjects ac hie vi n g a 
best res p o nse of C R, C R p, or C Ri.

C o m plete re missi o n ( C R) rate is t he perce nta ge of s u bjects ac hie vi n g a best res p o nse 
of C R.

D urati o n of c o m p osite c o m plete re missi o n ( C Rc) is t he ti me fr o m t he first 
d oc u me nte d C Rc ( C R + C R i + C R p) u ntil d oc u me nte d rela pse.

D urati o n of c o m plete re missi o n ( C R) is t he ti me fr o m t he first d oc u me nte d c o m plete 
re missi o n ( C R) u ntil d oc u me nte d rela pse.

Tra ns pla ntati o n rate ( bri d ge t o tra ns pla nt) is t he perce nta ge of s u bjects u n der g oi n g 
H S C T directl y  f oll o wi n g pr ot oc ol-s pecifie d treat me nt wit h n o i nter ve ni n g A M L 
t hera py.
S afet y V ari a bles

A d verse e ve nts

Vital si g ns

He mat ol o g y , ser u m c he mistr y, a n d uri nalys is res ults

P h y sical e xa mi nati o n res ults

E C G res ults

E C O G perf or ma nce sc ores


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
P h ar m ac o ki netic a n d E x p os ure -res p o nse V ari a bles

P har mac o ki netics of q uizarti ni b a n d its acti ve meta b olite, A C 8 8 6

C o nce ntrati o n -Q Tc F Relati o ns hi p

Ot her e x p os ure -res p o nse relati o ns hi ps wit h efficac y or safety varia bles
Ge n o mic a n d Pr ote o mic V ari a bles

F L T 3 -I TD stat us a n d allelic rati o

M utati o ns i n t he ki nase a n d j u xta me m bra ne d o mai ns of F L T 3 -I T D a n d ot her 
m utati o ns k n o w n t o be ass ociate d wit h A M L, deter mi ne d wit h b o ne marr o w or 
w h ole bl o o d sa m ples

P har mac o ge n o mics

P har mac o pr ote o mic e val uati o ns
P h ar m ac oec o n o mic V ari a bles

Res o urce utilizati o n
o
C o nc o mita nt me dicati o ns a n d pr oce d ures
o
H os pitalizati o ns
o
U nsc he d ule d cli nic visits
o
E mer ge nc y  r o o m visits
o
S kille d n ursi n g facilit y care
o
H os pice care
S T A TI S TI C A L M E T H O D S
S a m ple Size Deter mi n ati o n
Calc ulati o n of sa m ple size is base d o n c o m paris o n of O S, t he pri mar y  efficac y e n d p oi nt, i n t he 
2 treat me nt gr o u ps ( q uizarti ni b a n d sal va ge c he m ot hera py) at a 2-si de d si g nifica nce le vel 
of 0. 0 5, ass u mi n g t hat me dia n s ur vi val is 3. 9 m o nt hs i n t he sal va ge c he m ot hera p y gr o u p wit h 
a n i ncrease t o 6 m o nt hs, i n t he q uizarti ni b gr o u p ( hazar d rati o 0. 6 5).  A t otal of 2 8 0 e ve nts 
( deat hs) are necessar y t o meet a p o wer re q uire me nt of 9 0 %, gi ve n a n i nteri m a nal ysis pla n ne d 
at 1 4 0 e ve nts ( deat hs) wit h O’ Bria n -Fle mi n g b o u n dar y  f or s u peri or efficac y a n d a c o n diti o nal   
p o wer of 1 0 % f or f utilit y.  F or t he p ur p ose of sa m ple size calc ulati o n, s u bjects are ass u me d t o 
be accr ue d at a rate of 1 9. 2 per m o nt h wit h a dr o p -o ut rate of 1 0 %.  T he tar get accr ual is a t otal 
of a p pr o xi matel y  3 6 3 s u bjects ra n d o mize d i n a 2: 1 rati o ( 2 4 2 s u bjects i n t he q uizarti ni b gr o u p 
a n d 1 2 1 i n t he sal va ge c he m ot hera p y gr o u p) o ver 1 7 m o nt hs, t o reac h re q uire d n u m ber of 
e ve nts i n a reas o na ble ti mefra me a n d t o c o m pe nsate f or dr o p -o uts.  All cal c ulati o ns f or sa m ple 
size were perf or me d usi n g East ® 6. 3.
Ra n d o mizati o n will be stratifie d b y pri or t hera p y a n d res p o nse, a n d pre -selecte d sal va ge 
c he m ot hera p y:
Pri or t hera p y a n d res p o nse:

Rela pse d i n ≤6 m o nt hs ( n ot p ost H S C T)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

Refract or y

Rela pse d i n ≤6 m o n t hs p ost all o ge neic H S C T
Pre -selecte d c he m ot hera p y, e ve n f or s u bjects s u bse q ue ntl y ra n d o mize d t o q uizarti ni b:

Hi g h i nte nsit y  c he m ot hera p y ( M E C; F L A G-I D A)

L o w i nte nsit y c he m ot hera p y ( L o D A C)
Pri m ar y Effic ac y A n al ysis
Pri mar y  efficac y a nalys es will ta ke place after t he re q uire d n u m ber of e ve nts ( deat hs), 1 4 0 
e ve nts ( deat hs) at t he i nteri m a nal y sis or 2 8 0 e ve nts ( deat hs) at t he fi nal a nal ysis, has occ urre d.  
T he pri mar y  efficac y e n d p oi nt ( O S) a nalys is will be base d o n the stratifie d l o g -ra n k test.  T he 
stratificati o n fact ors will be t h ose use d f or ra n d o mizati o n.  A n o n-stratifie d l o g-ra n k test will be 
use d as s u p p orti ve e vi de nce of efficac y .  T hese a nal yses will be perf or me d o n t he i nte nt-t o-treat 
(I T T) a nalys is data set, c o nsisti n g of data fr o m all s u bjects ra n d o mize d.
Ka pla n - Meier met h o ds will be use d t o esti mate O S i n eac h treat me nt gr o u p, b ot h o verall a n d 
wit hi n s u bsets of s u bjects defi ne d b y t he stratificati o n fact ors.  Esti mates of me dia n s ur vi val 
will be pr o vi de d w it h 9 5 % c o nfi de nce i nter vals.  Hazar d rati o esti mates will als o be prese nte d.
O verall s ur vi val will be ce ns ore d at t he last date w he n s u bjects were k n o w n t o be ali ve.  F or 
pri mar y  a nalys is, O S will n ot be ce ns ore d at t he ti me of recei pt of s u bse q ue nt n o n pr ot oc ol 
A M L  t hera p y, i ncl u di n g tra ns pla ntati o n.
Sec o n d ar y Effic ac y A n al ysis
T he sec o n dar y  efficac y e n d p oi nt of E F S will be a nal yze d usi n g t he stratifie d l o g -ra n k test wit h 
c o variates t o c o ntr ol f or pri or t hera p y a n d res p o nse t o first -li ne A M L t hera p y a n d pre -selecte d 
sal va ge c he m ot hera py i n t he I T T p o p ulati o n.  T o mai ntai n t he o verall t y pe 1 err or rate at t he 
0. 0 5 si g nifica nce le vel, h y p ot hesis testi n g i n t he sec o n dar y  a nalys is will be perf or me d o nly if 
t he n ull h yp ot hesis i n t he pri mar y  a nalys is is rejecte d at t he o verall t w o-si de d 0. 0 5 si g nifica nce 
le vel.
T hese a nal y ses will be re peate d f or t he per pr ot oc ol set ( P P S). In a d diti o n, t he pri mar y  efficac y 
e n d p oi nt ( O S) a n d sec o n dar y efficac y e n d p oi nt ( E F S) will be a nalyz e d f or pre-defi ne d s u b -
gr o u ps.
A d diti o n al Effic ac y A n al yses
Statistical a nal y ses of e x pl orat or y efficac y e n d p oi nts i ncl u de:

Ka pla n -Meier a nal y sis of d urati o n of C Rc a n d C R.

C oc hra n -Ma ntel - Hae nszel ( C M H) test of C R rate

C M H test of C Rc rate

C M H test of tra ns pla ntati o n rate
S afet y A n al yses
T he sa fety a nal ys is set ( S A F) i ncl u des all s u bjects recei vi n g at least 1 d ose of st u d y treat me nt 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
( q uizarti ni b or sal va ge c he m ot hera py).
Safet y  e val uati o n will be base d mai nl y o n A Es, cli nical la b orat or y test res ults, p h ysical 
e xa mi nati o n res ults, vital si g ns, E C G res ults a n d E C O G perf or ma nce sc ores. Descri pti ve 
statistics will be use d t o s u m marize safety data. All safet y data will be s u m marize d b y treat me nt 
( q uizarti ni b or sal va ge c he m ot hera py). T he safet y data will als o be s u m marize d f or pre- defi ne d 
s u b-gr o u ps.
All s u m maries of A Es will i ncl u de o nl y  treat me nt-e mer ge nt e ve nts u nless ot her wise state d.  
A d verse e ve nts will be cate g orize d b y  sys te m or ga n class a n d preferre d ter m usi n g t he 
Me d D R A dicti o nar y  ( versi o n 1 4. 1), a n d will be gra de d acc or di n g t o N CI C T C A E v 4.0 3.
A d diti o nal safet y a nal ys is f or s u bjects i n p ost-H S C T q uizarti ni b ar m ma y  be perf or me d.
A d diti o n al A n al yses
A M L  m utati o ns, p har mac o ge n o mic, p har mac o pr ote o mic, a n d p har mac oec o n o mic a nalys es will 
be perf or me d.
I nteri m A n al ysis
T he st u d y  desi g n pr o vi des f or o ne f or mal i nteri m a nalys is w he n 5 0 % ( 1 4 0) of t he fi nal n u m ber 
of e ve nts ha ve bee n o bser ve d.  At t he discreti o n of t he D M C, o ne of t he f oll o wi n g acti o ns will 
occ ur at t his i nteri m a nal ysis:

Ter mi nati o n of t he st u d y f or f utilit y

Ter mi n ati o n of t he st u d y for efficac y

C o nti n ui n g t he st u d y  as pla n ne d


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1. 
T A B L E O F C O N T E N T S
I NV E S TI G A T O R’ S S T A T E M E N T ................................................................................................ 2
S T U D Y S Y N O P SI S ........................................................................................................................ 3
1. 
T A B L E O F C O N T E N T S ........................................................................................... 1 6
2. 
A B B R E VI A T I O N S .................................................................................................... 2 1
3. 
I NT R O D U C TI O N ...................................................................................................... 2 4
3. 1. 
Rati o nale f or De vel o p me nt of Q uizarti ni b ................................................................. 2 4
3. 2. 
N o ncli nical St u dies..................................................................................................... 2 4
3. 3. 
Cli nical St u dies ........................................................................................................... 2 4
4. 
S T U D Y O BJ E C TI V E S ..............................................................................................2 8
4. 1. 
Pri mar y  O bjecti ve....................................................................................................... 2 8
4. 2. 
Sec o n dar y  O bjecti ves ................................................................................................. 2 8
4. 3. 
E x pl orat or y  O bjecti ves...............................................................................................2 8
5. 
S T U D Y D E SI G N ....................................................................................................... 2 9
5. 1. 
O verall St u d y  Desi g n a n d Pla n................................................................................... 2 9
5. 1. 1. 
Scree ni n g .................................................................................................................... 2 9
5. 1. 2. 
Treat me nt .................................................................................................................... 2 9
5. 1. 3. 
F oll o w -u p.................................................................................................................... 3 1
5. 2. 
Rati o nale f or St u d y  Desi g n a n d D osi n g ..................................................................... 3 1
5. 2. 1. 
Rati o nale f or St u d y  Desi g n......................................................................................... 3 1
5. 2. 2. 
Selecti o n of ≥3 % F L T 3 -I T D Allelic Rati o as C ut off f or St u dy Eli gi bilit y ................ 3 2
5. 2. 3. 
Selecti o n of 3 0 m g Dail y f or t he Q uizarti ni b Starti n g D ose ...................................... 3 2
5. 2. 4. 
Q uizarti ni b D ose Re d ucti o n wit h Str o n g C Y P 3 A 4 I n hi bit ors ................................... 3 3
5. 2. 5. 
Treat me nt wit h Q uizarti ni b F oll o wi n g H S C T ............................................................ 3 4
5. 3. 
St u d y  D urati o n............................................................................................................3 5
5. 4. 
Selecti o n of St u d y  P o p ulati o n ....................................................................................3 5
5. 4. 1. 
I ncl usi o n Criteria................................ ........................................................................3 5
5. 4. 2. 
E xcl usi o n Criteria ....................................................................................................... 3 6
5. 4. 3. 
I ncl usi o n of W o me n, Mi n orities, a n d Ot her U n derre prese nte d P o p ulati o ns ..............3 8
5. 4. 4. 
Eli gi bilit y  t o Cr oss-O ver t o Q uizarti ni b fr o m Sal va ge C he m ot hera p y...................... 3 8
5. 4. 5.  
S u bject Wit h dra wal Criteria................................ .......................................................3 9
5. 5. 
St u d y  or Site Ter mi nati o n...........................................................................................4 1


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 6. 
St u d y  Treat me nt..........................................................................................................4 1
5. 6. 1. 
I de ntit y of I n vesti gati o nal Pr o d uct ............................................................................. 4 1
5. 6. 2. 
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps
................................................. 4 2
5. 6. 3. 
Selecti o n of D oses i n t he St u d y .................................................................................. 4 2
5. 6. 4. 
Selecti o n a n d Ti mi n g of D oses f or Eac h S u bject ....................................................... 4 2
5. 6. 5. 
Bli n di n g...................................................................................................................... 4 6
5. 6. 6. 
Pri or a n d C o nc o mita nt T hera p y................................ .................................................. 4 6
5. 6. 7. 
Treat me nt C o m plia nce ................................................................................................ 4 7
5. 7. 
St u d y  Varia bles........................................................................................................... 4 7
5. 7. 1. 
Pri ma r y Efficac y Varia ble.......................................................................................... 4 7
5. 7. 2. 
Sec o n dar y  Efficac y Varia ble...................................................................................... 4 7
5. 7. 3. 
A d diti o nal Efficac y  Varia bles .................................................................................... 4 7
5. 7. 4. 
Tra ns pla ntati o n rate ( bri d ge t o tra ns pla nt) is t he perce nta ge of s u bjects 
u n der g oi n g H S C T directl y  f oll o wi n g pr ot oc ol s pecifie d treat me nt wit h n o 
i nter veni n g A M L t hera p y . Safet y Varia bles................................................................ 4 7
5. 7. 5. 
P har mac o ki netic a n d E x p os ure -res p o nse Varia bles................................................... 4 8
5. 7. 6. 
A d diti o nal Varia bles ................................................................................................... 4 8
5. 7. 7. 
P har mac oec o n o mic Varia bles .................................................................................... 4 8
5. 8. 
St u d y  Sc he d ule ........................................................................................................... 4 8
6. 
S T U D Y VI SI T S A N D A C T I VI TI E S......................................................................... 5 6
6. 1. 
Acce pta ble Wi n d o ws f or Pr ot oc ol Assess me nts a n d F oll o w- u p Visits ...................... 5 6
6. 2. 
St u d y  Visits................................................................................................................. 5 7
6. 2. 1. 
Scree ni n g Acti vities .................................................................................................... 5 7
6. 2. 2. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Q uizarti ni b ............ 5 8
6. 2. 3. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Q uizarti ni b 
After H S C T ................................................................................................................. 6 1
6. 2. 4. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Sal va ge 
C he m ot hera p y ............................................................................................................. 6 3
6. 2. 5. 
Sc he d ule of Acti vities a n d Assess me nts after Treat me nt ........................................... 6 6
6. 2. 6. 
Earl y Ter mi nati o n/ E n d of St u d y .................................................................................6 8
7. 
E F FI C A C Y E V A L U A TI O N ......................................................................................7 0
Pri mar y  Efficac y Varia ble .............................................................................................................7 0
Sec o n d ar y Efficac y  Varia ble .........................................................................................................7 0
A d diti o nal Efficac y  Varia bles........................................................................................................7 0


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
7. 1. 
Met h o d of Assess me nt ................................................................................................7 0
7. 2. 
Res p o nse Defi niti o ns .................................................................................................. 7 1
7. 2. 1. 
C o m plete Re missi o n ( C R) .......................................................................................... 7 1
7. 2. 2. 
C o m plete Re missi o n wit h I nc o m plete Platelet Rec o ver y  ( C R p) ............................... 7 1
7. 2. 3. 
C o m plete Re missi o n wit h I nc o m plete He mat ol o gical Rec o ver y  ( C Ri)..................... 7 1
7. 2. 4. 
Partial Re missi o n ........................................................................................................ 7 2
7. 2. 5. 
R ela pse ........................................................................................................................ 7 2
7. 2. 6. 
Best Res p o nse ............................................................................................................. 7 2
7. 2. 7. 
N o E vi de nce of Res p o nse ( N R).................................................................................. 7 2
7. 3. 
O verall S ur vi val ( O S) ................................................................................................. 7 2
7. 4. 
E ve nt -Free S ur vi val ( E F S) ......................................................................................... 7 2
7. 5. 
Le u ke mia -Free S ur vi val ( L F S) ................................................................................... 7 2
7. 6. 
C o m p osite C o m plete Re missi o n ( C Rc) Rate ............................................................. 7 2
7. 7. 
C o m plete Re missi o n ( C R) Rate.................................................................................. 7 2
7. 8. 
D urati o n of C Rc .......................................................................................................... 7 3
7. 9. 
D urati o n of C R ........................................................................................................... 7 3
7. 1 0. 
Tra ns p la ntati o n Rate................................................................................................... 7 3
8. 
S A F E T Y E V A L U A TI O N .......................................................................................... 7 4
8. 1. 
Me dical Hist or y .......................................................................................................... 7 4
8. 2. 
P h y sical E xa mi nati o n ................................................................................................. 7 4
8. 3. 
Vital Si g ns .................................................................................................................. 7 4
8. 4. 
Electr ocar di o gra ms ..................................................................................................... 7 4
8. 5. 
Ma n a ge me nt of Q T Pr ol o n gati o n ............................................................................... 7 5
8. 6. 
Cli nical L a b orat or y E val uati o ns.................................................................................7 6
8. 7. 
Pre g na nc y  Testi n g a n d A d diti o nal E val uati o ns..........................................................7 7
8. 8. 
A d verse E ve nt Defi niti o ns .......................................................................................... 7 7
8. 9. 
Seri o us A d verse E ve nt Defi niti o ns ............................................................................. 7 8
8. 1 0. 
Pr oce d ures f or Rec or di n g a n d Re p orti n g A d verse E ve nts a n d Seri o us 
A d verse E ve nts Rec or di n g A Es a n d S A Es................................................................. 8 0
8. 1 0. 1. 
Disease -s pecific A Es a n d S A Es ................................................................................. 8 0
8. 1 0. 2. 
Assess me nt of Se verit y ...............................................................................................8 0
8. 1 0. 3. 
Assess me nt of Ca usalit y .............................................................................................8 1
8. 1 0. 4. 
S A E Re p orti n g ............................................................................................................8 1


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
9. 
P H A R M A C O KI N E TI C S ...........................................................................................8 3
1 0. 
P H A R M A C O G E N O MI C S A N D P H A R M A C O P R O T E O MI C S .............................. 8 4
1 0. 1. 
F L T 3 -I TD M utati o n Assa y ......................................................................................... 8 4
1 1. 
P H A R M A C O E C O N O MI C S ...................................................................................... 8 5
1 2. 
D A T A Q U A LI T Y A S S U R A N C E .............................................................................. 8 6
1 3. 
S T A TI S TI C A L M E T H O D S P L A N N E D I N T H E P R O T O C O L A N D 
D E T E R MI N A TI O N O F S A M P L E SI Z E ................................................................... 8 7
1 3. 1. 
Ge neral C o nsi derati o ns ...............................................................................................8 7
1 3. 2. 
S u bject Dis p ositi o n, De m o gra p hics, a n d Dr u g A d mi nistrati o n ................................. 8 7
1 3. 3. 
Sa m ple Size Deter mi nati o n ........................................................................................ 8 7
1 3. 4. 
Pri mar y  Efficac y A nalys is.......................................................................................... 8 9
1 3. 5. 
Sec o n dar y  Efficac y A nal ysis ...................................................................................... 8 9
1 3. 6. 
S u b -gr o u p A nal ys es .................................................................................................... 8 9
1 3. 7. 
A d diti o nal Efficac y  A nal yses ..................................................................................... 9 0
1 3. 8. 
Safet y  A nalys is........................................................................................................... 9 0
1 3. 9. 
A d diti o nal A nal y ses.................................................................................................... 9 1
1 3. 1 0. 
I nteri m A nalys is.......................................................................................................... 9 1
1 3. 1 1. 
Statistical Met h o ds f or P har mac o ki netics a n d E x p os ure- res p o nse A nalys es ............. 9 1
1 4. 
A D MI NI S T R A TI V E R E Q UI R E M E N T S A N D P R O C E D U R E S .............................. 9 3
1 4. 1. 
I nstit uti o nal Re vie w B oar d/In de pe n de nt Et hics C o m mittee A p pr o val ...................... 9 3
1 4. 2. 
Et hical C o n d uct of t he St u d y ...................................................................................... 9 3
1 4. 3. 
C ha n ges t o t he C o n d uct of t he St u d y  or Pr ot oc ol....................................................... 9 3
1 4. 4. 
St u d y  M o nit ori n g........................................................................................................ 9 3
1 4. 5. 
Data Ma na ge me nt ....................................................................................................... 9 3
1 4. 6. 
I n vesti gat or Res p o nsi bilities....................................................................................... 9 3
1 4. 6. 1. 
I nf or me d C o nse nt ....................................................................................................... 9 3
1 4. 6. 2. 
Case Re p ort F or ms .....................................................................................................9 4
1 4. 6. 3. 
S u bject C o nfi de ntialit y ...............................................................................................9 4
1 4. 6. 4. 
Rec or d Rete nti o n ........................................................................................................9 4
1 4. 7. 
Pr ot oc ol De viati o ns ....................................................................................................9 5
1 4. 8. 
C o ntr ol of Materials ....................................................................................................9 5
1 4. 8. 1.  
Recei pt of Cli nical S u p plies................................ .......................................................9 5
1 4. 8. 2. 
Dis p ositi o n of U n use d Cli nical S u p plies .................................................................... 9 5


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 4. 9. 
Fi na ncial Discl os ure ...................................................................................................9 5
1 4. 1 0. 
P u blicati o n P olic y ....................................................................................................... 9 5
1 5. 
R E F E R E N C E S ........................................................................................................... 9 7
A P P E N DI X 1: 
LI S T O F P O T E N TI A L Q T P R O L O N GI N G D R U G S, C Y P 3 A 4
I NHI BI T O R S /I N D U C E R S , A N D P-G L Y O P R O T EI N 
I NHI BI T O R S/I N D U C E R S ......................................................................................... 9 9
LI S T O F T A B L E S
Ta ble 1 
S u m mar y  of t he Efficac y Fi n di n gs Acr oss all 5 Dail y D oses St u die d i n t he 
P hase 2 Pr o gra m ......................................................................................................... 2 5
Ta ble 2 
S u m mar y  of t he Q Tc F Fi n di n gs Acr oss all 5 Daily D oses St u die d i n t he 
P hase 2 Pr o gra m ......................................................................................................... 2 5
Ta ble 3 
Sc he d ule of Acti vities a n d Ass ess me nts f or S u bjects Recei vi n g Q uizarti ni b ............ 4 9
Ta ble 4 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Q uizarti ni b 
Af ter H S C T................................................................................................................. 5 1
Ta ble 5 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Sal va ge 
C he m ot hera p y ............................................................................................................. 5 2
Ta ble 6 
Sc he d ule of Acti vities a n d Assess me nts After Treat me nt .......................................... 5 4
Ta ble 7 
Wi n d o ws f or Perf or mi n g Assess me nts a n d Sc he d uli n g F oll o w -U p Visits ................ 5 6
Ta ble 8 
Cli nical La b orat or y Deter mi nati o ns ........................................................................... 7 7
LI S T O F FI G U R E S
Fi g ure 1. 
Fl o w C hart of St u d y Acti vities ................................................................................... 3 1


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
2. 
A B B R E VI A TI O N S
A b bre vi ati o n 
Ter m
A E
A d verse e ve nt
A L L
Ac ute l y m p h oc ytic le u ke mia
A L T
Ala ni ne tra nsa mi nase
A M L
Ac ute m yel oi d le u ke mia
A N C
A bs ol ute ne utr o p hil c o u nt
A S T
As partate tra nsa mi nase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
A U C 0 -i nf
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y
C F R
C o de of Fe deral Re g ulati o ns
C ma x
Ma xi m u m plas ma c o nce ntrati o n
C M H
C oc hra n -Ma ntel -Hae nszel
C P
C o n diti o nal p o w er
C R
C o m plete re missi o n; c o m plete res p o nse
C R c
C o m p osite c o m plete re missi o n ( C R + C Ri + C R p)
C R F
Case re p ort f or m
C Ri
C o m plete re missi o n wit h i nc o m plete he mat ol o gic rec o ver y
C R O
Cli nical researc h or ga nizati o n; c o ntract researc h or ga nizati o n
C R p
C o m plete re missi o n wit h i nc o m plete platelet rec o ver y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C tr o u g h
Mi ni m u m plas ma c o nce ntrati o n
C V
C oefficie nt of variati o n
C Y P
C y t oc hr o me P 4 5 0 
D M C
Data m o nit ori n g c o m mittee
E C G
Electr ocar di o gra m
E C H O
Ec h ocar di o gra p h y
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
E F S
E ve nt -free s ur vi val
E M A
E ur o pea n Me dici nes A ge nc y
F D A
F o o d a n d Dr u g A d mi nistrati o n
F L A G -I D A 
Fl u dara bi ne, c ytara bi ne, a n d G -C S F wit h i dar u bici n
F L T 3
F M S -li ke t yr osi ne ki nase 3
G- C S F
Gra n ul oc yte -c ol o n y sti m ulati n g fact or
G C P
G o o d Cli nical Practice
G V H D
Graft vers us h ost disease
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
H S C T
He m at o p oietic ste m cell tra ns pla ntati o n
I C5 0
C o nce ntrati o n pr o d uci n g 5 0 % i n hi biti o n


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
A b bre vi ati o n 
Ter m
I C F
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C
I n de pe n de nt Et hics C o m mittee
I N R
I nter nati o nal n or malize d rati o
I R B
I nstit uti o nal Re vie w B oar d 
I T D
I nter nal ta n de m d u plicati o n
I T T
I nte nt-t o-treat
I V
I ntra ve n o us
L F S
Le u ke mia- free s ur vi val
L o D A C
L o w d ose c ytara bi ne
L V E F
Left ve ntric ular ejecti o n fracti o n
M D S
M y el o d ys plastic s y n dr o me
M E C
Mit o xa ntr o ne, et o p osi de, a n d i nter me diate -d ose c ytara bi ne
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
msec
Millisec o n d
M T D
Ma xi m u m t olerate d d ose
M U G A
M ulti ple gate d ac q uisiti o n
N CI
Nati o nal Ca ncer I nstit ute
N R
N o e vi de nce of res p o nse
N Y H A
Ne w  Y or k Heart Ass ociati o n
O S
O verall s ur vi val
P C R
P ol y merase c hai n reacti o n
P D
Pr o gressi ve disease
P G X
P har m ac o ge n o mic(s)
P K
P har m ac o ki netic(s)
P P S
Per pr ot oc ol set
P R
Partial re missi o n; partial res p o nse
P T
Pr ot hr o m bi n ti me
Q T
I nter val  bet wee n t he start of t he Q wa ve a n d t he e n d of t he T wa ve
Q T c
C orrecte d Q T i nter val 
Q Tc F
Q Tc w it h Fri dericia’s c orrecti o n fact or
R B C
Re d bl o o d cell(s)
R T K
Rece pt or t yr osi ne ki nase
S A C
Statistical a nal ysis ce nter
S A E
Seri o us a d verse e ve nt
S A F
Safet y a nal ysis set
S A P
Statistical a nal ysis pla n
S C
S u bc uta ne o us
S D
Sta ble disease; sta n dar d de viati o n


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
A b bre vi ati o n 
Ter m
S R C
St u d y re vie w c o m mittee
T d P
T orsa de de p oi ntes
T KI
T y r osi ne ki nase i n hi bit or
tma x
Ti m e t o ma xi m u m plas ma c o nce ntrati o n
U L N
U p per li mit of n or mal
U S
U nite d States 
W B C
W hite bl o o d cell(s)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
3. 
I N T R O D U C TI O N
Q uizarti ni b is a n o vel oral sec o n d -ge nerati o n Class III rece pt or t yr osi ne ki nase i n hi bit or wit h 
p ote nt acti vit y  a gai nst F M S-li ke t yr osi ne ki nase 3 ( F L T 3) b ot h i n vitr o a n d i n vi v o.  It is 
c urre ntl y u n der de vel o p me nt f or t he i n dicati o n of t he treat me nt of s u bjects 1 8 years of a ge or 
ol der wit h rela pse d (i ncl u di n g after he mat o p oie tic ste m cell tra ns pla ntati o n [ H S C T]) or 
refract or y F L T 3-i nter nal ta n de m d u plicati o n (I T D) p ositi ve ( +) ac ute myel oi d le u ke mia ( A M L), 
a n d has bee n gra nte d Fast Trac k Stat us i n t he U nite d States a n d a n Or p ha n Dr u g I n dicati o n i n t he 
U nite d States a n d E ur o pe.
F L T 3 is e x presse d i n he mat o p oietic pr o ge nit or cells, a n d si g nali n g t hr o u g h F L T 3 pr o m otes t hese 
cells’ pr oliferati o n a n d differe ntiati o n.  F L T 3 is m utate d i n a p pr o xi matel y  3 0 % of s u bjects wit h 
A M L ; t he m utati o ns i ncl u de I T D of t he j u xta me m bra ne d o mai n of FL T 3 a n d p oi nt m utati o ns, 
us uall y  i n t he ki nase d o mai n.  B ot h t ypes of m utati o ns c o nstit uti vel y  acti vate F L T 3 a n d 
c o ntri b ute t o le u ke mic tra nsf or mati o n of he mat o p oietic cells. 1
T here is a n u n met me dical nee d f or effecti ve treat me nt f or patie nts wit h rela pse d/refract or y  
A M L , a n d s pecifically f or t h ose wit h t he F L T 3 -I TD m utati o n.  T he F L T 3 -I T D m utati o n is 
ass ociate d wit h a s h orter d urati o n of res p o nse, a greater c u m ulati ve i nci de nce of rela pse, a n d 
s h orter s ur vi val after rela pse. 2  It has bee n i de ntifie d as t he w orst si n gle pr o g n ostic fact or i n 
A M L f or d urati o n of c o m plete re missi o n ( C R) a n d rela pse-free s ur vi val.3
3. 1. 
R ati o n ale f or De vel o p me nt of Q uiz arti ni b 
Q uizarti ni b selecti vel y  i n hi bits s ur vi val pat h wa ys t hat bl oc k a p o pt osis b y i n hi biti n g F L T 3.  
Q uizarti ni b i n hi bits pr oliferati o n of F L T 3 -de pe n de nt cell li nes, a n d is effecti ve i n h u ma n 
le u ke mia t u m or xe n o graft m o dels of A M L.  Data fr o m t he P hase 1 a n d P hase 2 st u dies ha ve 
s h o w n a hi g h res p o nse rate, e ve n i n patie nts w h o were refract or y t o pri or c he m ot hera p y.4, 5, 8
3. 2. 
N o ncli nic al St u dies
Please refer t o t he c urre nt q uizarti ni b I nvesti gat or’s Br oc h u re f or n o ncli nical data s u p p orti n g its 
use i n cli nical st u dies.
3. 3. 
Cli nic al St u dies
A brief s u m mar y  is gi ve n bel o w.  Refer t o t he c urre nt q uizarti ni b I nvesti gat or’s Br oc h ure f or 
a d diti o nal i nf or mati o n o n cli nical e x perie nce wit h q uizarti ni b.
As of 2 2 Ja n 2 0 1 6, a t otal of 1 2 8 9 s u bjects recei ve d q uizarti ni b i n 1 9 cli nical st u dies i ncl u di n g 
6 2 4 s u bjects wit h eit her A M L  or s oli d t u m ors, 4 7 2 healt h y v ol u nteers, a n d 1 9 3 s u bjects wit h 
A M L , A L L a n d M D S i n 4 i n vesti gat or s p o ns ore d trials.
Q uizarti ni b was st u die d i n 7 6 A M L  s u bjects i n a P hase 1 st u d y wit h i nter mitte nt d osi n g ( 1 4 da y s 
o n dr u g f oll o we d b y 1 4 da ys rest) fr o m 1 2 m g t o 4 5 0 m g, a n d c o nti n u o us d osi n g at 2 0 0 m g a n d 
3 0 0 m g. 8  Plas ma ta ke n fr o m s u bjects a n d assa y e d i n a n i n vitr o plas ma i n hi bit or y assa y, s h o we d 
ma xi mal i n hi biti o n of F L T 3 -I T D si g nali n g at 6 0 m g d ose as earl y as 2 h o urs after t he first d ose.  
A mar ke d re d ucti o n of F L T 3 -I T D p h os p h or ylati o n in vi v o was als o o bser ve d at 6 0 m g a n d 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
hi g her d oses.  T he o verall res p o nse rate was 5 3 % i n F L T 3 -I TD( +) s u bjects a n d 1 4 % i n 
F L T 3 -I TD( -) s u bjects.
T he res p o nse rate o bser ve d i n P hase 1 was c o nfir me d i n t he P hase 2, A C 2 2 0 -0 0 2 st u d y  of si n gle 
a ge nt q uizarti ni b i n rela pse d or refract or y A M L.  I n t his P hase 2 st u d y a t otal of 3 3 3 s u bjects 
were e nr olle d i n 2 c o h orts; C o h ort 1 i ncl u de d s u bjects 6 0 y ears or ol der w h o were rela pse d or 
refract or y t o 1 li ne of t hera p y a n d C o h ort 2 i ncl u de d s u bjects 1 8 years or ol der w h o were 
rela pse d or refract or y t o sal va ge t hera p y or rela pse d after H S C T.  I n C o h ort 1, t he C Rc rate was 
5 7 % i n F L T 3 -I T D( +) s u bjects wit h a me dia n s ur vi val of 2 5. 3 wee ks.4  C o h ort 2 s h o we d a C Rc 
rate of 4 6 % i n F L T 3-I T D( +) s u bjects wit h a me dia n s ur vi val of 2 4. 0 wee ks. 5  I mp orta ntl y , 3 5 % 
of C o h ort 2 F L T 3 -I T D( +) s u bjects were bri d ge d t o H S C T.  Al m ost all ( 9 4 %) s u bjects 
pr ocee di n g t o H S C T ha d ac hie ve d a C Rc or partial re missi o n ( P R) o n q uizarti ni b a n d t heir 1 year 
s ur vi val rate was 3 9 %.
T he ma xi m u m t olerate d d ose ( M T D) deter mi ne d i n t he P hase 1 st u d y was 2 0 0 m g c o nti n u o us 
dail y  d osi n g, b ut i n t he P hase 2, A C 2 2 0-0 0 2 St u d y  3 5 % of s u bjects i nitiall y d ose d wit h 2 0 0 m g 
e x perie nce d Gra de 3 Q T pr ol o n gati o n at t his d ose a n d t heref ore t he d ose was re d uce d t o 1 3 5 m g 
i n males a n d 9 0 m g i n fe males wit h t he d ose differe ntial bet wee n se xes d ue t o s us pecte d greater 
s usce pti bilit y of fe males t o Q T pr ol o n gati o n.  H o we ver, e x p os ure-res p o nse a nalys is of t he P hase 
2 st u d y , 2 6 8 9-C L -2 0 0 4, s u g gests n o si g nifica nt differe nce i n t he effect of q uizarti ni b 
c o nce ntrati o ns o n Q Tc F bet wee n me n a n d w o me n.  A si n gle case of Gra de 4 Q T pr ol o n gati o n, 
T orsa des de P oi ntes ( T d P), was re p orte d i n t he A C 2 2 0 -0 0 2 St u d y  i n a fe male s u bject recei vi n g 
t he 9 0 m g q uizarti ni b d ose a n d c o nc urre ntl y ta ki n g a str o n g C Y P 3 A 4 i n hi bit or.  A P hase 2 b 
St u d y  ( 2 6 8 9-C L -2 0 0 4) was s u bse q ue ntl y c o n d ucte d, w hic h e nr olle d 7 6 s u bjects wit h F L T 3 -
I TD( +) A M L ra n d o mize d t o 6 0 m g or 3 0 m g dail y , t o e xa mi ne efficac y a n d t o xicit y at t hese 
l o wer d oses.  B ot h males a n d fe males were ra n d o mize d at eac h d ose.  T he st u d y s h o we d t hat t he 
C Rc rate was si milar at b ot h l o wer d oses a n d t o t hat o bser ve d i n t he earlier A C 2 2 0 -0 0 2 St u d y
(Ta ble 1 ).  Q T pr ol o n gati o n was d ose de pe n de nt a n d was s u bsta ntiall y  re d uce d at t he l o wer 
d oses ( Ta ble 2 ).
T a ble 1 
S u m m ar y of t he Effic ac y Fi n di n gs Acr oss all 5 D ail y D oses St u die d i n t he 
P h ase 2 Pr o gr a m
St u d y
2 6 8 9- C L -2 0 0 4
A C 2 2 0 - 0 0 2
Q uiz arti ni b 
D ose
3 0 m g
( N = 3 8)
6 0 m g
( N = 3 8)
9 0 m g
( N = 5 7)
1 3 5 m g
( N = 6 7)
2 0 0 m g
( N = 1 2)
C Rc rate
4 7 %
4 7 %
4 7 %
4 5 %  
4 2 %
P R rate
1 3 %
2 4 %
2 5 %
2 8 %  
5 0 %
T a ble 2  
S u m m ar y of t he Q Tc F Fi n di n gs Acr oss all 5 D ail y D oses St u die d i n t he 
P h ase 2 Pr o gr a m
St u d y
2 6 8 9- C L -2 0 0 4
A C 2 2 0 - 0 0 2
Q uiz arti ni b D ose
3 0 m g
( N = 3 8)
6 0 m g
( N = 3 6)*
9 0 m g
( N = 5 7)
1 3 5 m g
( N = 6 7)
2 0 0 m g
( N = 1 2)
M a xi m u m v al ue of Q Tc F ( msec)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
> 4 8 0 t o ≤ 5 0 0 ( Gra de 2)
5 %
1 4 %  
2 1 %  
1 3 %  
3 3 %
> 5 0 0 ( Gra de 3 
[as y m pt o matic])
5 %
3 %  
2 1 %  
1 5 %  
4 2 %
M a xi m u m c h a n ge i n Q Tc F fr o m b aseli ne ( msec)
≤ 3 0 
5 0 %
4 4 %  
9 %  
9 %  
0 %
> 3 0 t o ≤ 6 0
4 7 %
3 6 %  
4 6 %  
5 1 %  
8 %
> 6 0
3 %
1 9 %  
4 6 %  
3 9 %  
9 2 %
* T w o s u bjects i n t he 6 0 m g/ da y gr o u p were ra n d o mize d b ut ne ver treate d wit h q uizarti ni b
C o m m o n a d verse e ve nts o bser ve d i n t he P hase 1 a n d 2 st u dies i ncl u de d gastr oi ntesti nal dis or ders 
( na usea, diarr hea, a n d v o miti n g), he mat ol o gic dis or ders (a ne mia, ne utr o pe nia, a n d 
t hr o m b oc yt o pe nia), fe brile ne utr o pe nia, fati g ue, a n d Q T pr ol o n gati o n.  Alt h o u g h he mat ol o gic 
t o xicit y is ass ociate d wit h u n derl yi n g disease, safet y re p orts fr o m St u d y A C 2 2 0-0 0 2 i n A M L  
i n dicate dela ye d rec o ver y or c o nti n ue d s u p pressi o n of a bs ol ute ne utr o p hil c o u nts ( A N C) a n d 
platelets as a c o nse q ue nce of c o nti n ue d treat me nt wit h q uizarti ni b.
T here are i ns ufficie nt data t o e xcl u de t he ris k of p h ot ot o xicit y / p h ot ose nsiti vit y reacti o ns d ue to 
q uizarti ni b.  E xcessi ve e x p os ure t o s u nli g ht a n d ot her U V li g ht e x p os ure s h o ul d be a v oi de d.  
S u bjects s h o ul d be a d vise d t o c o ntact t he I n vesti gat or if t he y  de vel o p a ras h or e xa g gerate d 
s u n b ur n i n e x p ose d areas of s ki n.
P har mac o ki netic data f or q uizarti ni b a n d A C 8 8 6 fr o m cli nical st u dies i n b ot h healt h y  s u bjects 
a n d A M L s u bjects ha ve bee n e val uate d.  P har mac o ki netic pr ofiles were si milar acr oss s u bjects, 
wit h q uizarti ni b plas ma le vels risi n g ra pi dl y (ti me t o ma xi m u m plas ma c o nce ntrati o n [t ma x ] 1 t o 
8 h o ur s d uri n g t he first da y of d osi n g).  Q uizarti ni b a n d A C 8 8 6 ha d l o n g effecti ve half-li ves of 
a p pr o xi matel y 3 da ys, res ulti n g i n a p pr o xi matel y 4-f ol d acc u m ulati o n at stea dy state.  Plas ma 
q uizarti ni b c o nce ntrati o ns were d ose pr o p orti o nal o ver a teste d d ose ra n ge of 3 0 m g t o 9 0 m g .  
O verall, C ma x a n d A U C s h o we d m o derate t o hi g h varia bilit y .  T he pri mar y r o ute of q uizarti ni b 
eli mi nati o n was n o n- re nal cleara nce, a n d b ot h q uizarti ni b a n d A C 8 8 6 were pri maril y 
meta b olize d b y  C Y P 3 A 4.  Q uizarti ni b has bee n s h o w n t o be a n i n hi bit or of h u ma n effl u x 
tra ns p orter P-gl yc o pr otei n ( P -g p) i n - vitr o.  I n a d diti o n, q uizarti ni b a n d its acti ve meta b olite 
A C 8 8 6 ha ve bee n s h o w n t o be i n vitr o s u bstrates of P- g p.
A f o o d -effect st u d y i n v ol vi n g si n gle d ose a d mi nistrati o n of a 3 0-m g  ta blet of q uizarti ni b t o 
healt h y  v ol u nteers u n der fasti n g c o n diti o ns or wit h a hi g h-fat meal i n dicate d t hat A U C was 
i ncrease d by a p pr o xi matel y 8 % w hile t he 9 0 % CI of t he C ma x rati o of fe d t o fasti n g c o n diti o n 
was c o ntai ne d wit hi n t he 8 0 t o 1 2 5 % i nter val. T his i ncrease i n e x p os ure is n ot cli nicall y  
si g nifica nt, a n d t heref ore q uizarti ni b ca n be ta ke n wit h or wit h o ut f o o d. H o we ver, f o o d di d 
pr ol o n g t he ti me t o pea k c o nce ntrati o ns, T ma x, b y  a p pr o xi matel y 2 h o urs. 
A dr u g -dr u g i nteracti o n ( D DI) st u d y  was c o n d ucte d wit h t he pr ot o n p u m p i n hi bit or la ns o praz ole. 
Healt h y s u bjects were ra n d o mize d t o recei ve q uizarti ni b 3 0 -m g ta blet al o ne or la ns o praz ole 6 0 -
m g a d mi nistere d o nce dail y  f or 5 da ys wit h a si n gle d ose of a 3 0-m g  ta blet of q uizarti ni b 
a d mi nistere d o n da y 5. A wea k P K dr u g-dr u g i nteracti o n was o bser ve d bet wee n q uizarti ni b a n d 
la ns o praz ole; Cma x a n d A U C decrease d 1 4 % a n d 5 %, res pecti vel y, f or q uizarti ni b. H o we ver 
t he decrease i n q uizarti ni b e x p os ure is n ot c o nsi dere d t o be cli nically si g nifica nt. Ot her t y pes of 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
ga stric p H m o difiers (e g, a ntaci ds a n d H 2 a nta g o nists) are als o n ot e x pecte d t o ha ve a cli nicall y 
si g nifica nt D DI wit h q uizarti ni b.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
4. 
S T U D Y O B J E C TI V E S
4. 1. 
Pri m ar y O bjecti ve
T he pri mar y  o bjecti ve of t he st u d y is t o deter mi ne w het her q uizarti ni b m o n ot hera py pr ol o n gs
o verall s ur vi val ( O S) c o m pare d t o sal va ge c he m ot hera p y i n s u bjects wit h F L T 3 -I TD( +) A M L 
w h o are refract or y  t o or ha ve rela pse d wit hi n 6 m o nt hs, after first-li ne A M L t hera p y.
4. 2. 
Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ve of t he st u d y is t o deter mi ne e ve nt-free s ur vi val ( E F S) f oll o wi n g 
treat me nt wit h q uizarti ni b vers us sal va ge c he m ot hera py.
4. 3. 
E x pl or at or y O bjecti ves
E x pl orat or y  o bjecti ves are:

t o c o m pare t he c o m p osite c o m plete re missi o n [ C Rc = c o m plete re missi o n ( C R) + 
c o m plete re missi o n wit h i nc o m plete platelet rec o ver y ( C R p) + c o m plete re missi o n 
wit h i nc o m plete he mat ol o gic rec o ver y  ( C Ri)] rate ( Res p o nse defi niti o ns pr o vi de d i n 
Secti o n 7. 2 )

t o c o m pare t he c o m plete re missi o n ( C R) rate

t o c o m pare t he d urati o n of C Rc

t o c o m pare t he d urati o n of C R 

t o deter mi ne le u ke mia-free s ur vi val ( L F S)

t o c o m pare t he tra ns pla ntati o n rate

t o deter mi ne t he Q Tc pr ol o n gi n g effects of q uizarti ni b i n relati o n t o plas ma dr u g 
c o nce ntrati o ns

t o deter mi ne t he p har mac o ki netics ( P K) of q uizarti ni b a n d its acti ve meta b olite, 
A C 8 8 6

t o deter mi ne t he e x p os ure-res p o nse relati o ns hi p

t o deter mi ne res o urce utilizati o n i n t his st u d y p o p ulati o n

t o i de ntif y A M L-ass ociate d m utati o ns a n d t heir fre que ncies

p har mac o ge n o mic a n d p har mac o pr ote o mic deter mi nati o ns


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
2 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 
S T U D Y D E SI G N
5. 1. 
O ver all St u d y Desi g n a n d Pl a n
T his is a P hase 3, ra n d o mize d, o pe n -la bel, 2-ar m st u d y t o c o m pare t he effect of q uizarti ni b 
m o n ot hera p y a n d sal va ge c he m ot hera p y o n O S i n s u bjects wit h F L T 3 -I TD( +) A M L t hat is 
refract or y or rela pse d wit hi n 6 m o nt hs, after first-li ne t hera p y wit h or wit h o ut c o ns oli dati n g 
H S C T.  T he c o ntr ol treat me nt is a li mite d c h oice of o ne of t hree sta n dar d c he m ot hera p y 
re gi me ns (l o w d ose c ytara bi ne [ Lo D A C]; mit o xa ntr o n e, et o p osi de, a n d i nter me diate -d ose 
c ytara bi ne [ M E C]; or fl u dara bi ne, c ytara bi ne, a n d gra n ul oc yte-c ol o n y sti m ulati n g fact or ( G -
C S F) wit h i dar u bici n [ F L A G -I D A]) w hic h are wi del y use d t o treat patie nts wit h A M L.  Pri or t o 
ra n d o mizati o n, t he In vesti gat or will pre -select o ne of t he t hree sal va ge c he m ot hera p y re gi me ns 
f or eac h s u bject; d oses a n d t he d urati o n of st u d y treat me nts are o utli ne d i n Secti o n 5. 6. 4. 2 .
T he st u d y  will utilize a gr o u p se q ue ntial desi g n wit h 1 i nteri m l o o k at 0. 5 i nf or mati o n fracti o n 
(ie, 5 0 % of pla n ne d n u m ber of e ve nts [ deat hs]).  T he tar get sa m ple size will be a p pr o xi matel y 
3 6 3 s u bjects, ra n d o mize d i n a 2: 1 rati o t o recei ve q uizarti ni b m o n ot hera p y  ( 2 4 2 s u bjects) or 
sal va ge c he m ot hera py ( 1 2 1 s u bjects).  O ne f or mal i nteri m a nal ysis will be perf or me d b y a n 
i n de pe n de nt statistical a nal ysis ce nter ( S A C) a n d e val uate d b y a n i n de pe n de nt data m o nit ori n g 
c o m mittee ( D M C), acc or di n g t o statisti cal pr oce d ures defi ne d a pri ori.  Base d o n t he res ults of 
t he i nteri m a nalys is, t he D M C ma y rec o m me n d t hat t he st u d y be ter mi nate d early f or f utilit y or 
f or efficac y, or c o nti n ue as pla n ne d.  T he tas ks perf or me d by t he S A C a n d D M C are descri be d i n 
t he D M C c harter a n d I nteri m A nal ys is Pla n. 
If t he st u dy is p ositi ve at t he pre -s pecifie d i nteri m or fi nal a nalys is, t he s p o ns or ma y all o w 
s u bjects w h o di d n ot recei ve q uizarti ni b t o cr oss-o ver t o t he q uizarti ni b m o n ot hera p y ar m after 
data base l oc k if t he safet y  para meters i n t he eli gi bilit y criteria are met (see Secti o n 5. 4 ).  T he 
st u d y will be u n bli n de d after data base l oc k.
5. 1. 1. 
Scree ni n g
D uri n g t he 1 4 da y  scree ni n g peri o d, s u bjects will u n der g o me dical hist or y e val uati o n, p h ysical 
e xa mi nati o n, vital si g n deter mi nat i o n, Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
perf or ma nce stat us assess me nt, c hest X- r a y, c o nc o mita nt me dicati o n assess me nt, bl o o d a n d 
uri ne sa m pli n g f or la b orat or y  tests, E C G m o nit ori n g, a n d b o ne marr o w as pirati o n or bi o ps y t o 
c o nfir m F L T 3 I T D stat us, m ulti ple gate d ac q uisiti o n ( M U G A) sca ns or ec h ocar di o gra p hy 
( E C H O).
5. 1. 2. 
Tre at me nt
A fl o w c hart of st u d y  acti vities is prese nte d i n Fi g ure 1 .
F or s u bjects ra n d o mize d t o q uizarti ni b t he starti n g d ose will be 3 0 m g/ da y  u nless t he s u bject is 
recei vi n g c o nc urre nt t hera p y wit h a str o n g C Y P 3 A 4 i n hi bit or, i n w hic h case t he starti n g d ose 
will be 2 0 m g/ da y .  T he d ose will be ta ke n i n t he m or ni n g wit h or wit h o ut f o o d o ver c o nti n u o us 
2 8- d a y  c ycles.  If t he s u bject o mits ta ki n g q uizarti ni b i n t he m or ni n g, it ma y  be ta ke n later i n t he 
da y  ( u ntil mi d ni g ht), ot her wise t he d ose s h o ul d be c o nsi dered misse d.  If t he s u bject v o mits after 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
ta ki n g q uizarti ni b, n o re place me nt d ose s h o ul d be gi ve n.  Detaile d i nf or mati o n o n q uizarti ni b 
d osi n g is pr o vi de d i n Secti o n 5. 6. 4. 1 .
T he d ose of q uizarti ni b will be i ncrease d at Da y  1 6 or C ycle 2 Da y 1 acc or di n g t o t he criteria 
s pecifie d i n Secti o n 5. 6. 4. 3 .  F oll o wi n g d ose escalati o n, tri plicate E C G deter mi nati o ns s h o ul d be 
perf or me d at least o nce wee kl y f or 2 wee ks t o m o nit or Q Tc F pr ol o n gati o n.
If necessar y, t he d ose of q uizarti ni b ma y be re d uce d acc or di n g t o t he criteria descri be d i n 
Secti o n 5. 6. 4. 4.
See als o Secti o n 8. 5 f or details of Q Tc F ma na ge me nt w he n pr ol o n gati o n is o bser ve d.
I n s u bjects recei vi n g q uizarti ni b or Lo D A C, treat me nt s h o ul d c o nti n ue u ntil t here is n o l o n ger 
cli nical be nefit fr o m t hera p y, or u ntil u nacce pta ble t o xicit y  occ urs.  F or s u bjects recei vi n g 
L o D A C t he i nitiati o n of c y cles ma y be dela ye d f or u p t o 1 4 da ys t o all o w f or rec o ver y fr o m 
t o xicit y.
S u bjects t hat recei ve eit her q uizarti ni b or L o D A C will be assesse d f or res p o nse o n Da y 1 of 
C y cle 2 a n d Da y 1 of C ycle 3 as well as o n Da y 1 of eac h s u bse q ue nt c ycle u nless t he s u bject 
has alrea d y ac hie ve d C R, C R p, or C Ri.  I n t hat e ve nt, b o ne marr o w testi n g will be re peate d after 
e ver y 3 s u bse q ue nt c ycles, u nless t here is e vi de nce of rela pse.
S u bje cts recei vi n g M E C or F L A G -I DA will recei ve 1 c y cle of t hera p y a n d be assesse d f or 
res p o nse at Da y 2 9 ( ± 1 4 da ys).  Sal va ge c he m ot hera p y s h o ul d be gi ve n as 2 8 da y c ycles, 
alt h o u g h c ycles ma y be dela ye d f or rec o ver y fr o m t o xicit y or bl o o d c o u nt rec o ver y f or u p t o 
1 4 da y s.  S u bjects ac hie vi n g c o m plete re missi o n ( C R), c o m plete re missi o n wit h i nc o m plete 
he mat ol o gic rec o ver y  ( C Ri), or c o m plete re missi o n wit h i nc o m plete platelet rec o ver y ( C R p) b y 
I n vesti gat or assess me nt, ma y recei ve a sec o n d c ycle of t he sa me t hera p y at t he I n vesti gat or’s 
discreti o n.  Treat me nt s h o ul d be disc o nti n ue d if t here is n o e vi de nce of res p o nse ( N R) or 
pr o gressi ve disease ( P D).  S u bjects classifie d as bei n g i n N R m ust ha ve at least o ne e val ua ble 
b o ne marr o w as pirate or bi o ps y  a n d n ot meet the criteria f or P R or better.
F or s u bjects w h o d o n ot ha ve e val ua ble b o ne marr o w as pirate or bi o ps y, b ut ha ve prese nce of 
le u ke mic blasts i n t he peri p heral bl o o d, t he res p o nse is c o nsi dere d as N R. F or s u bjects w h o 
de m o nstrate s o me le vel of cli nical be nefit b ut d o n ot ac hie ve a re missi o n, t he decisi o n o n 
a d diti o nal treat me nt is at t he In vesti gat or’s discreti o n.




Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
E nr oll me nt i n t he A C 2 2 0 -0 0 7 st u d y  is restricte d t o F L T 3-I TD( +) A M L s u bjects w h o are eit her 
refract or y t o i n d ucti o n c he m ot hera p y or ha ve rela pse d wit hi n 6 m o nt hs after ac hie vi n g C R 
i ncl u di n g after a pri or all o ge neic H S C T, as t hese s u bject p o p ulati o ns ha ve fe w treat me nt o pti o ns.  
I n t he P hase 2, A C 2 2 0-0 0 2 St u d y , t he C Rc rate, tra ns pla ntati o n rate a n d o verall s ur vi val of 
s u bjects recei vi n g q uizarti ni b as a sec o n d sal va ge treat me nt e xcee ded t hat re p orte d i n a rece nt 
st u d y of F L T 3-I TD( +) s u bjects recei vi n g first sal va ge c he m ot hera p y .6  A d diti o nall y , t he 
res p o nse rate, tra ns pla ntati o n rate a n d s ur vi val of s u bjects recei vi n g q uizarti ni b i n t he 
A C 2 2 0 -0 0 2 St u d y  als o e xcee de d t hat re p orte d i n a lar ge series of A ML s u bjects rece i vi n g sec o n d 
sal va ge.7
T he pla n ne d e nr oll me nt of 3 6 3 s u bjects was base d o n t he re q uire me nt f or 2 8 0 e ve nts t o pr o vi de 
9 0 % p o wer ass u mi n g a hazar d rat i o of 0. 6 5.  T his esti mate d hazar d rati o is base d o n data fr o m 
t he P hase 2, A C 2 2 0-0 0 2 st u d y  a n d hist orical data.  I n t he A C 2 2 0-0 0 2 st u d y, 
F L T 3 -I TD( +) s u bjects i n C o h ort 1 w h o were 6 0 years or ol der, rela pse d or refract or y after 1 li ne 
of A M L t hera p y ha d a me dia n s ur vi val of 2 5 wee ks.
4  P u blis he d data o n s ur vi val of a series of 
rela pse d F L T 3-I T D( +) patie nts s h o w a me dia n s ur vi val of 1 3 wee ks. 2  T h ose s u bjects i n t he 
A C 2 2 0 -0 0 2 st u d y  C o h ort 1 w h o rela pse d wit hi n 6 m o nt hs ha d a me dia n s ur vi val of 2 5 wee ks 
c o m pare d t o data fr o m a rece nt ra n d o mize d st u d y  w hic h s h o we d a me dia n s ur vi val of 1 4 wee ks 
f or F L T 3-I T D( +) s u bjects recei vi n g sal va ge t hera p y after a C R of less t ha n 6 m o nt hs.6  I n C o h ort 
2, s u bjects were 1 8 years or ol der rela pse d or refract or y after 1 li ne of sal va ge t hera p y or 
rela pse d after H S C T, ha d a me dia n s ur vi val of 2 4 wee ks.5  T his c o m pares t o a me dia n s ur vi val 
of 6 wee ks i n a lar ge series of A M L patie nts i ncl u di n g F L T 3 -I TD p ositi ve a n d ne gati ve patie nts 
w h o were rela pse d or refract or y  t o sal va ge t hera p y, a n d recei vi n g sec o n d sal va ge.7
5. 2. 2. 
Selecti o n of ≥3 % F L T 3 -I T D Allelic R ati o as C ut off f or St u d y Eli gi bilit y
I n pre vi o us P hase 2 st u dies wit h q uizarti ni b, s u bjects wit h a n allelic rati o of F L T 3-I TD t o t otal 
F L T 3 of > 1 0 % were defi ne d as I T D( +), h o we ver, f or t he P hase 3 st u d y  t he c ut off will be 
re d uce d t o ≥ 3 % base d o n t he li mit of q ua ntitati o n f or t he cli nical dia g n ostic assa y .  T he l o wer 
I TD rati o f or eli gi bilit y  will all o w t h ose s u bjects wit h a relia bly detecta ble a n d q ua ntifia ble 
I TD m utati o n t o be e nr olle d a n d t o deter mi ne t he p ote ntial be nefit fr o m q uizarti ni b.  A nal y sis of 
“I T D( -)” s u bjects fr o m t he A C 2 2 0-0 0 2 St u d y  s h o we d t hat t h ose s u bjects wit h a l o w 
le vel ( ≤1 0 %) of t he I T D m utati o n ha d si milar res p o nse rates t o p ositi ve ( > 1 0 %) s u bjects, w hile 
t h ose wit h n o detecta ble I T D m utati o n ( < 0. 3 %) ha d l o wer res p o nse rates.
5. 2. 3.  
Selecti o n of 3 0 m g D ail y f or t he Q uiz arti ni b St arti n g D ose
T he d ose of q uizarti ni b selecte d f or t he P hase 3 st u d y  is base d o n data fr o m t he P hase 1 
( C P 0 0 0 1) St ud y , a n d P hase 2 ( A C 2 2 0-0 0 2 a n d 2 6 8 9 -C L -2 0 0 4) St u dies i n a p pr o xi matel y  
4 8 0 s u bjects wit h rela pse d or refract or y A M L.
I n t he P hase 1 st u dy, 7 6 s u bjects were e nr olle d. A t otal of 5 1 s u bjects recei ve d q uizarti ni b o n a n 
i nter mitte nt sc he d ule (at dail y d oses of 1 2 m g t o 4 5 0 m g) a n d 2 5 s u bjects recei ve d q uizarti ni b o n 
a c o nti n u o us sc he d ule ( 2 0 0 m g t o 3 0 0 m g dail y ), of w hic h 1 7 s u bjects t otal were deter mi ne d t o 
be F L T 3 -I T D( +). Plas ma was c ollecte d fr o m s u bjects at s pecific ti me p oi nts f oll o wi n g i nitiati o n 
of q uizarti ni b a d mi nistrati o n a n d teste d f or t he a bilit y  of q uizarti ni b t o i n hi bit F LT 3 -I T D 
p h os p h or y lati o n i n a n i n vitr o plas ma i n hi bit or y assa y. C o m plete a n d s ustai ne d i n hi biti o n of 
p h os p h or y lati o n was o bser ve d i n t he 6 0 m g c o h ort as early as 2 h o urs after t he first d ose, a n d 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
re mai ne d at da y 2 8, w hereas at 1 8 m g o nl y partial i n hi biti o n was o bser ve d at 2 h o urs a n d t he 
i n hi biti o n was n ot as d ura ble.8 C o m pe ns at or y mec ha nis ms t hat will p ote ntiall y o verc o me F L T 3 
i n hi biti o n ca n re d uce t he effect of F L T 3 i n hi bit ors o n le u ke mic blasts. T hese mec ha nis ms 
i ncl u de o ver-e x pressi o n of F L T li ga n d a n d p h ys ical c o ntact wit h b o ne marr o w str o mal cells, 
w hic h b ot h i ncrease t he c o nce ntrati o n of i n hi bit or re q uire d t o bl oc k pr oliferati o n or i n d uce 
a p o pt osis b y a fact or of 3 t o 5 f ol d.9 T heref ore, selecti o n of a d ose t hat has c o m plete a n d 
l o n g-lasti n g i n hi biti o n of F L T 3-I TD si g nali n g is critical t o mai ntai n bl oc ka de of F L T 3 si g nali n g 
a n d f or s ustai ne d cli nical efficac y .
I n t he P hase 2 A C 2 2 0-0 0 2 St u d y , t he first 1 7 s u bjects e nr olle d recei ve d 2 0 0 m g/ da y (t he M T D 
fr o m t he P hase 1 st u d y) of q uizarti ni b as a starti n g d ose.  D ue t o Q Tc F pr ol o n gati o n, t he d ose 
was re d uce d a n d t he re mai ni n g 3 1 6 s u bjects recei ve d eit her 1 3 5 m g/ da y  ( pri maril y males) or 
9 0 m g/ da y  (all fe males).  In t he P hase 2 b 2 6 8 9 -C L -2 0 0 4 St u d y , b ot h males a n d fe males were 
ra n d o mize d t o eit her 3 0 m g/ da y or 6 0 m g/ da y.
W he n c o m pari n g t he efficac y  i n a si milar patie nt p o p ulati o n acr oss t he 5 dail y starti n g d oses 
st u die d i n t he P hase 2 st u dies [ A C 2 2 0-0 0 2 d oses of: 2 0 0 m g/ da y , 1 3 5 m g/ da y, a n d 9 0 m g/ da y; 
a n d i n 2 6 8 9-C L - 2 0 0 4 d oses of: 6 0 m g/ da y, a n d 3 0 m g/ da y] t here is n o o verall differe nce i n t he 
C Rc rates ( Secti o n 3. 3 ; Ta ble 1 ).  T he C Rc rates at eac h d ose were:  4 2 % at 2 0 0 m g/ da y; 4 5 % at 
1 3 5 m g/ da y ; 4 7 % at 9 0 m g/ da y; 4 7 % at 6 0 m g/ da y; a n d 4 7 % at 3 0 m g/ da y.  H o we ver, t he 
P R rates ( 1 3 % vs. 2 4 %, res pecti vely) were hi g her i n t he 6 0 m g/ da y gr o u p c o m pare d t o 3 0 m g 
gr o u p.  A d diti o nall y , t he perce nta ge of d ose m o dificati o ns was si milar f or d ose re d ucti o ns 
( 3 2 % a n d 3 1 % f or 3 0 m g a n d 6 0 m g d ose gr o u ps, res pecti vel y) b ut t here was a differe nce i n t he 
d ose i ncreases d ue t o lac k of res p o nse.  I n t he 3 8 s u bjects treate d at 3 0 m g/ da y as t he starti n g 
d ose, 2 4 ( 6 3 %) u n der we nt d ose escalati o n t o 6 0 m g/ da y c o m pare d t o 7 ( 1 9 %) w h o were d ose 
escalate d fr o m 6 0 m g t o 9 0 m g.
O verall t here were n o maj or differe nces i n a d verse e ve nts e x perie nce d b y  s u bjects i n t he 
3 0 m g/ da y  a n d 6 0 m g/ da y d ose gr o u ps.  T he Q Tc F pr ol o n gati o n f oll o wi n g a d mi nistrati o n of 
q uizarti ni b was clearl y d ose de pe n de nt i n t he A C 2 2 0 -0 0 2 St u d y  a n d t his was c o nfir me d i n t he 
P hase 2 b 2 6 8 9 -C L -2 0 0 4 St u d y  (Secti o n 3. 3 ; Ta ble 2 ).  T he Gra de 2 or greater Q Tc F 
pr ol o n gati o n was 1 1 % i n s u bjects ( 4/ 3 8) at 3 0 m g/ da y  a n d 1 7 % i n s u bjects ( 6/ 3 6) at 6 0 m g/ da y 
i n t he P hase 2 b 2 6 8 9-C L -2 0 0 4 St u d y .  I n a d diti o n, Gra de 3 Q Tc F pr ol o n gati o n was see n wit h a 
m uc h l o wer fre q ue nc y  i n t he P hase 2 b 2 6 8 9-C L -2 0 0 4 St u d y  at b ot h d oses ( 5 % a n d 3 % at 3 0 m g
a n d 6 0 m g res pecti vel y) c o m pare d t o t hat re p orte d at t he hi g her d oses i n St u d y A C 2 2 0- 0 0 2, 
w hic h s h o we d 4 2 % Gra de 3 Q Tc F pr ol o n gati o n at t he starti n g d ose of 2 0 0 m g/ da y , 1 5 % at 
1 3 5 m g/ da y , a n d 2 1 % ( w hic h i ncl u de d 1 case of Gra de 4 Q Tc F pr ol o n gati o n t hat res ol ve d after 
q uizarti ni b disc o nti n uati o n) at 9 0 m g/ da y.  Of i m p orta nce, t here were n o Gra de 4 Q T 
pr ol o n gati o n e ve nts i n t he P hase 2 b st u d y .
T he q uizarti ni b starti n g d ose f or t his st u d y will be 3 0 m g/ da y wit h d ose escalati o n t o 6 0 m g 
after 1 5 or 2 8 da y s accor di n g t o t he criteria s pecifie d i n  Secti o n 5. 6. 4. 3.   T his d ose was selecte d 
base d o n t he nee d t o mai ntai n a hi g h le vel of efficac y  i n a ver y a g gressi ve disease wit h a p o or 
o verall pr o g n osis, w hile at t he sa me ti me mi ni mizi n g t o xicit y .
5. 2. 4. 
Q uiz arti ni b D ose Re d ucti o n wit h Str o n g C Y P 3 A 4 I n hi bit ors
Data fr o m St u d y A C 2 2 0 -0 1 5, w hic h e xa mi ne d t he effect of str o n g a n d m o derate C Y P 3 A 4 
i n hi bit ors o n q uizarti ni b PK i n h u ma n v ol u nteers, s h o w t hat c o nc o mita nt ket oc o naz ole, a str o n g 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
C Y P 3 A 4 i n hi bit or, i ncrease d q uizarti ni b A U C 0- i nf a n d stea d y state C ma x (after re peat daily d osi n g) 
a p pr o xi matel y 2-f ol d, a n d c o nc o mita nt fl uc o naz ole, a m o derate C Y P 3 A 4 i n hi bit or,  i ncreased 
q uizarti ni b A U C 0 -i nf a n d stea d y state C ma x a p pr o xi matel y 1. 2-f ol d.  S u bjects recei vi n g 
c o nc o mita nt me dicati o n wit h a str o n g C Y P 3 A 4 i n hi bit or o n Da y  1, a n d w h o are ra n d o mize d t o 
q uizarti ni b, will ta ke 2 0 m g/ da y .  S u bjects w h o be gi n treat me nt wit h a str o n g C Y P 3 A 4 i n hi bit or 
w hile recei vi n g q uizarti ni b will be re q uire d t o be re d uce d fr o m eit her 6 0 m g/ da y  t o 3 0 m g/ da y or 
fr o m 3 0 m g/ da y t o 2 0 m g/ da y.  If t he s u bject disc o nti n ues t he str o n g C Y P 3 A 4 i n hi bit or, t he d ose 
of q uizarti ni b ca n be res u me d at t he pri or d o se.  N o d ose re d ucti o n of q uizarti ni b is re q uire d 
w he n s u bjects are c o -a d mi nistere d a m o derate or wea k C Y P 3 A 4 i n hi bit or.  See A p pe n di x 1 : List 
of P ote ntial Q T Pr ol o n gi n g Dr u gs, C Y P 3 A 4 I n hi bit ors/I n d ucers, a n d P - gl yc o pr otei n 
I n hi bit ors/I n d ucers.
5. 2. 5. 
Tre at me nt wit h Q uiz arti ni b F oll o wi n g H S C T
All o ge neic tra ns pla nt has bec o me a n acce pte d sta n dar d of care f or c o ns oli dati n g 
ne wl y dia g n ose d F L T 3 -I T D A M L s u bjects i n first re missi o n.1 0 ,1 1 ,1 2  A d diti o nall y , treat me nt 
c o nse ns us g ui deli nes rec o m me n d H S C T f or s u bjects wit h rela pse d A M L re gar dless of 
F L T 3 -I TD stat us w he ne ver feasi ble.  Base d o n data fr o m t he P hase 2 st u dies, a p pr o xi matel y  
3 5 % of s u bjects will li kel y be bri d ge d t o H S C T i n t he P hase 3 A C 2 2 0 -0 0 7 St u d y .
T he p ost -H S C T rela pse rate f or F L T 3- I T D p ositi ve A M L s u bjects is hi g her t ha n t hat o bser ve d 
f or ot her A M L s u b-gr o u ps u n der g oi n g c o ns oli dati o n H S C T, a n d t he le u ke mia cells at rela pse are 
t ypicall y hi g hl y a d dicte d t o F L T 3 -I TD si g nali n g. 1 3
T he use of a T KI t o i n d uce re missi o n a n d t he n as mai nte na nce p ost - H S C T has bee n esta blis he d 
i n B C R-A B L ac ute l y m p h oc y tic le u ke mia ( P h +-A L L).  I n a d ults with P h + A L L, H S C T is a n 
esta blis he d treat me nt sta n dar d of care ,1 4 a n d B C R -A B L T KIs are n ot o nl y use d t o bri d ge patie nts 
t o tra ns pla nt, t he y are r o uti nel y use d p ost-H S C T t o mai ntai n re missi o n a n d pr ol o n g s ur vi val. 1 5 ,1 6  
I n ter ms of A M L, a F L T 3 i n hi bit or (s orafe ni b) c urre ntly a p pr o ve d f or ot her o nc ol o g y i n dicati o ns 
has bee n re p orte d t o ha ve acti vit y  i n t he p ost-H S C T setti n g. 1 7  Gi ve n c urre nt sta n dar d practice 
wit h B C R - A B L T KIs i n P h + A L L, f or s u bjects ra n d o mize d t o t he q uizarti ni b treat me nt gr o u p, 
q uizarti ni b will be offere d t o t h ose s u bjects u n der g oi n g H S C T wit h t he ai m of re d uci n g t he hi g h 
ris k of rela pse p ost- H S C T a n d t o e val uate w het her a d mi nistrati o n of q uizarti ni b bef ore H S C T 
a n d as mai nte na nce f oll o wi n g H S C T, is of cli nical be nefit.
A p hase 1 st u d y ( A P hase 1 St u d y of A C 2 2 0 [ A S P 2 6 8 9] as Mai nte na nce T hera p y i n S u bjects 
wit h Ac ute M yel oi d Le u ke mia w h o Ha ve Bee n Treate d wit h a n All o ge neic He mat o p oietic Ste m 
Cell Tra ns pla nt: 2 6 8 9- C L - 0 0 1 1) e nr olle d 1 3 s u bjects w h o were i n re missi o n f oll o wi n g a n 
all o ge neic H S C T.  T hese s u bjects were i de ntifie d as F L T 3 -I T D( +) at dia g n osis, a n d after 
rec o ver y of bl o o d c o u nts p ost-H S C T were treate d wit h d oses of 4 0 m g/ da y ( n = 7) a n d 6 0 m g/ da y 
( n = 6) of q uizarti ni b.  Preli mi nar y data ha ve s h o w n t hat b ot h d oses are well t olerate d wit h 5/ 7 
( 7 1 %) s u bjects i n t he 4 0 m g c o h ort a n d 6/ 6 ( 1 0 0 %) s u bjects i n t he 6 0 m g c o h ort re mai ni n g o n 
q uizarti ni b wit h o ut disease rela pse.  T here were 8 s u bjects w h o disc o nti n ue d treat me nt: ( o ne d ue 
t o pr o gressi ve disease, t w o per t he I n vesti gat or’s discreti o n, f o ur d ue t o Seri o us A d verse E ve nts 
(S A Es ), a n d o ne f or reas o ns t hat were not s pecifie d), wit h 1 0 of 1 3 s u bjects recei vi n g q uizarti ni b 
f or m ore t ha n 1 ye ar.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 3. 
St u d y D ur ati o n
Ti me fr o m e nr oll me nt of first s u bject t o t he 2 8 0 t h e ve nt ( deat h) s h o ul d be a p pr o xi matel y  
3 6 m o nt hs.
5. 4. 
Selecti o n of St u d y P o p ul ati o n
5. 4. 1.  
I ncl usi o n Criteri a
T o be a ble t o partici pate i n t his st u d y, ca n di dates m ust meet t he f oll o wi n g criteria at scree ni n g or 
ot her s pecifie d ti me p oi nt:
1.
Pr o visi o n of writte n i nf or me d c o nse nt a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d (I R B) 
or I n de pe n de nt Et hics C o m mittee (I E C) wit h pri vac y la n g ua ge i n acc or da nce wit h 
nati o nal re g ulati o ns ( e g, HI P A A a ut h orizati o n f or U S sites) pri or t o a n y  st u d y-relate d 
pr oce d ures, i ncl u di n g wit h dra wal of pr o hi bite d me dicati o ns if a p plica ble.
2.
A ge ≥1 8 y ears or t he mi ni m u m le gal a d ult a ge ( w hic he ver is greater) at t he ti me of 
i nf or me d c o nse nt.
3.
M or p h ol o gicall y  d oc u me nte d pri mar y A M L or A M L sec o n dar y t o myel o d ys plastic 
s yn dr o me ( M D S), as defi ne d b y  W orl d Healt h Or ga nizati o n criteria, as deter mi ne d b y 
pat h ol o g y  re vie w at t he st u d y site.
4.
I n first rela pse ( wit h d urati o n of re missi o n of 6 m o nt hs or less) or refract or y after pri or 
t hera py, wit h or wit h o ut H S C T.  I n d ucti o n t hera p y  m ust ha ve i ncl u de d at least 1 c ycle of 
a n a nt hrac ycli ne/ mit o xa ntr o ne-c o ntai ni n g i n d ucti o n bl oc k at a sta n dar d d ose.

Refract or y  is define d as:
-
After 1 c y cle, a re d ucti o n i n b o ne marr o w blasts of less t ha n 5 0 % a n d fail ure 
t o ac hie ve a C R, C R p, or C Ri.
-
After 2 c y cles, lac k of ac hie ve me nt of C R, C R p, or C Ri.

First rela pse ( wit h d urati o n of re missi o n of 6 m o nt hs or less) is defi ne d as:
-
Ac hie v e me nt of C R, C Ri, or C R p, as defi ne d b y  2 0 0 3 Inter nati o nal W or ki n g 
Gr o u p criteria ( Secti o n 7. 2 ) after i nitial A M L t hera p y wit h or wit h o ut 
c o ns oli dati o n or mai nte na nce, a n d wit h or wit h o ut H S C T.
-
D urati o n of C R, C Ri or C R p is meas ure d fr o m t he date of t he b o ne marr o w 
assess me nt w hic h c o nfir me d res p o nse or t he date of all o ge neic 
tra ns pla ntati o n, t o t he date of t he b o ne marr o w assess me nt t hat i de ntifie d 
rela pse or t he a p peara nce of peri p heral blasts.
5.
Prese nce of t he F L T 3 -I TD acti vati n g m utati o n i n b o ne marr o w or peri p heral bl o o d 
(allelic rati o as deter mi ne d b y a ce ntral la b orat or y wit h a c ut off of 
≥3 % F L T 3 -I T D/t otal F L T 3).  If a s peci me n has bee n se nt f or F L T 3 -I T D testi n g at t he 
ce ntral la b orat or y b ut t he s u bject re q uires treat me nt f or A M L bef ore t he ce ntral F L T 3-
I TD test res ult is a vaila ble, a l ocal test res ult ma y  be acce pta ble f or ra n d o mizati o n after 
c o ns ultati o n wit h t he Me dical M o nit or.  


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
6.
Eli gi bilit y  f or pre-selecte d sal va ge c he m ot hera py, acc or di n g t o t he I n vesti gat or’s 
assess me nt.
7.
E C O G perf or ma nce sc ore 0 - 2.
8.
Disc o nti n uati o n of pri or A M L  treat me nt bef ore t he start of st u d y treat me nt (e xce pt 
h y dr o x y u rea or ot her treat me nt t o c o ntr ol le u k oc yt osis) f or at least 2 wee ks f or c yt ot o xic 
a ge nts, or f or at least 5 half- li ves f or n o n-c yt ot o xic a ge nts.
9.
Ser u m creati ni ne ≤1. 5 × u p per li mit of n or mal ( U L N), or gl o mer ular filtrati o n rate 
> 2 5 m L / mi n, as calc ulate d wit h t he C oc kcr oft-Ga ult f or m ula.
1 0. Ser u m p otassi u m, ma g nes i u m, a n d calci u m (ser u m calci u m c orrecte d f or 
h y p oal b u mi ne mia) wit hi n i nstit uti o nal n or mal li mits.  S u bjects wit h electr ol y tes o utsi de 
t he n or mal ra n ge will be eli gi ble if t hese val ues are c orrecte d u p o n retesti n g f oll o wi n g 
a n y necessar y s u p ple me ntati o n.
1 1. T otal ser u m bilir u bi n ≤1. 5 × U L N.
1 2. Ser u m as partate tra nsa mi nase ( A S T) a n d/ or ala ni ne tra nsa mi nase ( A L T) ≤2. 5 × U L N.
5. 4. 2.  
E xcl usi o n Criteri a
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g criteria are met at scree ni n g 
or ot her s pecifie d ti me p oi n t:
1.
Ac ute pr o m yel oc yt ic le u ke mia ( A M L s u bty pe M 3)
2.
A M L  sec o n dar y t o pri or c he m ot hera py f or ot her ne o plas ms, e xce pt A M L sec o n dar y 
t o pri or M D S
3.
Hist or y  of a n ot her mali g na nc y, u nless t he ca n di date has bee n disease-free f or at least 
5 y ears

Ca n di dates wit h treat e d n o n-mela n o ma s ki n ca ncer, carci n o ma i n sit u, or cer vical 
i ntrae pit helial ne o plasia are eli gi ble re gar dless of t he ti me s pe nt disease-free, if 
t he y ha ve c o m plete d defi niti ve treat me nt

Ca n di dates wit h or ga n -c o nfi ne d pr ostate ca ncer, wit h n o e vi de nce of rec urre nt or 
pr o gressi ve disease, are eli gi ble if h or m o nal t hera p y  has bee n be g u n, or if t he 
t u m or has bee n s ur gicall y re m o ve d or treate d wit h defi niti ve ra di ot hera py
4.
Persiste nt, cli nicall y  si g nifica nt > Gra de 1 n o n-he mat ol o gic t o xicit y  fr o m pri or A M L 
t hera py
5.
Cli nicall y  si g nifica nt G V H D or G V H D re q uiri n g i nitiati o n of treat me nt or treat me nt 
escalati o n wit hi n 2 1 da ys, a n d/ or > Gra de 1 persiste nt or cli nically si g nifica nt 
n o n -he mat ol o gic t o xicit y  relate d t o H S C T
6.
Hist or y  of or c urre nt, ce ntral ner v o us sys te m i n vol ve me nt wit h A M L
7.
Cli nicall y  si g nifica nt c oa g ulati o n a b n or malit y, s uc h as disse mi nate d i ntra vasc ular 
c oa g ulati o n
8.
Pri or treat me nt wit h q uizarti ni b or partici pate d i n a pri or q uizarti ni b st u d y


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
9.
Pri or treat me nt wit h a F L T 3 tar gete d t hera p y i ncl u di n g s orafe ni b or i n vesti gati o nal 
F L T 3 i n hi bit ors ( n ot i ncl u di n g t he m ulti -ki nase i n hi bit or, mi d osta uri n)
1 0. Maj or s ur ger y  wit hi n 4 wee ks pri or t o scree ni n g
1 1. Ra diati o n t hera p y wit hi n 4 wee ks pri or t o scree ni n g
1 2. U nc o ntr olle d or si g nifica nt car di o vasc ular disease, i ncl u di n g:

Q Tc F i nter val > 4 5 0 msec (a vera ge of tri plicate deter mi nati o ns)

S u bject has bra d yc ar dia of less t ha n 5 0 B P M (as deter mi ne d b y ce ntral rea di n g) 
u nless t he s u bject has a pace ma ker

Dia g n ose d or s us pecte d l o n g Q T s y n dr o me, or k n o w n fa mil y hist or y  of l o n g 
Q T s yn dr o me

Hist or y  of cli nicall y rele va nt ve ntric ular arr hyt h mias, s uc h as ve ntric ular 
tac hycar dia, ve ntric ular fi brillati o n, or t orsa de de p oi ntes

Hist or y  of sec o n d or t hir d de gree heart bl oc k.  Ca n di dates wit h a hist or y of heart 
bl oc k ma y  be eli gi ble if t he y c urre ntl y ha ve pace ma kers, a n d ha ve n o hist or y of 
fai nti n g or cli nicall y rele va nt arr h yt h mia wit h pace ma kers.

M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o scree ni n g

U nc o ntr olle d a n gi na pect oris wit hi n 6 m o nt hs pri or t o scree ni n g

Ne w Y or k Heart Ass o ciati o n ( N Y H A) Class 3 or 4 c o n gesti ve heart fail ure

Left ve ntric ular ejecti o n fracti o n ( L V E F) ≤4 5 % or i nstit uti o nal l o wer li mit of 
n or mal

U nc o ntr olle d h y perte nsi o n

C o m plete left or ri g ht b u n dle bra nc h bl oc k
1 3. Acti ve i nfecti o n n ot well c o ntr olle d b y  a nti bacterial, a ntif u n gal, a n d/ or a nti viral 
t hera py
1 4. K n o w n i nfecti o n wit h h u ma n i m m u n o deficie nc y vir us, or acti ve he patitis B or C, or 
ot her acti ve cli nicall y  rele va nt li ver disease
1 5. U n willi n g ness t o recei ve i nf usi o n of bl o o d pr o d ucts acc or di n g t o t he pr ot oc ol
1 6. I n a ma n w h ose se x ual part ner is a w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or 
i na bilit y of t he ma n or w o ma n t o use a hi g hly effecti ve c o ntrace pti ve met h o d f or t he 
e ntire st u d y treat me nt peri o d a n d f or at least 3 m o nt hs after st u d y treat me nt 
c o m pleti o n

Ma le s u bjects m ust n ot freeze or d o nate s per m starti n g at Scree ni n g a n d 
t hr o u g h o ut t he st u d y peri o d, a n d 1 0 5 da ys after t he fi nal st u d y dr u g 
a d mi nistrati o n.
1 7. I n a heter ose x uall y acti ve w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or i na bilit y 
t o use a hi g hly effecti ve c o ntrace pti ve met h o d f or t he e ntire st u d y treat me nt peri o d 
a n d f or at least 3 m o nt hs after st u d y treat me nt c o m pleti o n.  A d diti o nall y , f or w o me n 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
ra n d o mize d t o c he m ot hera p y, u n willi n g ness t o a d here t o t he restricti o ns res pecti ve 
l ocall y esta blis he d g ui deli nes a n d l ocal a p pr o ve d la bel ( prescri bi n g i nf or mati o n, 
S u m mar y  of Pr o d uct C haracteristics, or U S pr o d uct i nsert) fr o m t he ma n ufact urer a n d 
t he Patie nt Inf or mati o n Leaflet ( pac ka ge i nsert) as i nstr ucte d b y  t he I n vesti gat or.

W o me n are n ot re gar de d as of c hil d beari n g p ote ntial if t he y are p ost-me n o pa usal 
(at least 2 ye ars wit h o ut me nses) or are s ur gicall y sterile (at least 1 m o nt h bef ore 
st u d y).

Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de: h or m o nal met h o ds ass ociate d 
wit h i n hi biti o n of o v ulati o n, i ntra- uteri ne de vice; s ur gical sterilizati o n (i ncl u di n g 
part ner’s vasect o m y) or se x ual a bsti ne nce if t his is t he preferre d a n d us ual 
lifest yle of t he s u bject.

Fe male s u bjects m ust n ot d o nate or retrie ve, f or t heir o w n use, o va fr o m t he ti me 
of Scree ni n g a n d t hr o u g h o ut t he st u d y  treat me nt peri o d, a n d f or 1 2 wee ks after 
t he fi nal st u d y dr u g a d mi nistrati o n.
1 8. Pre g na nc y
1 9. Fe male s u bjects m ust a gree n ot t o breastfee d fr o m t he ti me of Scree ni n g a n d 
t hr o u g h o ut t he st u dy peri o d, a n d f or 2 5 da ys after t he fi nal st u d y dr u g a d mi nistrati o n.
2 0.
Me dical c o n diti o n, seri o us i nterc urre nt ill ness, or ot her circ u msta nce t hat, i n t he 
I n vesti gat or’s j u d g me nt, c o ul d je o par dize t he ca n di date’s safet y as a st u d y s u bject, or 
t hat c o ul d i nterfere wit h st u d y o bjecti ves.
2 1. F or s u bjects i n t he U K o nl y :  Ref usal of per missi o n t o all o w t he s u bject’s Ge neral 
Practiti o ner t o be n otifie d of t heir partici pati o n i n t he st u d y .
5. 4. 3. 
I ncl usi o n of W o me n, Mi n orities, a n d Ot her U n derre prese nte d P o p ul ati o ns
T his st u d y  is o pe n t o all s u b p o p ulati o ns of s u bjects w h o fulfill eli gi bilit y  criteria.
5. 4. 4.  
Eli gi bilit y t o Cr oss- O ver t o Q uiz arti ni b fr o m S al v a ge C he m ot her a p y
5. 4. 4. 1.  
I ncl usi o n Criteri a f or Cr oss- O ver 
T o be a ble t o cr oss -o ver t o q uizarti ni b t hera p y  fr o m sal va ge c he m ot hera p y, ca n di dates m ust meet 
t he f oll o wi n g criteria at scree ni n g or ot her s pecifie d ti me p oi nt:
1.
Pr o visi o n of writte n i nf or me d c o nse nt a p pr o ve d b y t he I R B or I E C wit h pri vac y la n g ua ge 
i n acc or da nce wit h nati o nal re g ulati o ns (e g, HIP A A a ut h orizati o n f or U S sites) pri or t o 
a n y st u d y-relate d pr oce d ures, i ncl u di n g wit h dra wal of pr o hi bite d me dicati o ns if 
a p plica ble.
2.
E C O G perf or ma nce sc ore 0 - 2.
3.
Ser u m creati ni ne ≤1. 5 × U L N, or gl o mer ular filtrati o n rate > 2 5 m L/ mi n, as calc ulate d wit h 
t he C oc kcr oft-Ga ult f or m ula.
4.
Ser u m p otassi u m, ma g nesi u m, a n d calci u m (ser u m calci u m c orr ecte d f or 
h y p oal b u mi ne mia) wit hi n i nstit uti o nal n or mal li mits.  S u bjects wit h electr ol y tes o utsi de 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
3 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
t he n or mal ra n ge will be eli gi ble if t hese val ues are c orrecte d u p o n retesti n g f oll o wi n g 
a n y necessar y s u p ple me ntati o n.
5.
T otal ser u m bilir u bi n ≤1. 5 × U L N.
6.
Ser u m A S T a n d/ or A L T ≤2. 5 × U L N.
5. 4. 4. 2. 
E xcl usi o n Criteri a f or Cr oss -O ver
Ca n di dates will be e xcl u de d fr o m cr oss -o ver t o q uizarti ni b if a n y  of t he f oll o wi n g criteria are 
met at S cree ni n g or ot her s pecifie d ti me p oi nt:
1.
Q Tc F i nter val > 4 5 0 msec (a vera ge of tri plicate deter mi nati o ns .)
2.
S u bject has bra d yc ar dia of less t ha n 5 0 B P M (as deter mi ne d b y ce ntral rea di n g) .
3.
U nc o ntr olle d h y perte nsi o n .
4.
Acti ve i nfecti o n n ot well c o ntr olle d b y  a nti bacterial, a ntif u n gal, a n d/ or a nti viral t hera p y.
5.
I n a ma n w h ose se x ual part ner is a w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or 
i na bilit y of t he ma n or w o ma n t o c o nti n ue t o use a hi g hly effecti ve c o ntrace pti ve met h o d 
f or t he e ntire st u dy treat me nt peri o d a n d f or at least 3 m o nt hs after st u d y treat me nt 
c o m pleti o n:

Male s u bjects m ust n ot
freeze or d o nate s per m starti n g at Scree ni n g a n d t hr o u g h o ut 
t he st u d y peri o d, a n d 1 0 5 da ys after t he fi nal st u d y dr u g a d mi nistrati o n.
6.
I n a heter ose x uall y acti ve w o ma n of c hil d beari n g p ote ntial, u n willi n g ness or i na bilit y t o 
c o nti n ue t o use a hi g hl y effecti ve c o ntrace pti ve met h o d f or t he e ntire st u d y treat me nt 
peri o d a n d f or at least 3 m o nt hs after st u d y  treat me nt c o m pleti o n.  

W o me n are n ot re gar de d as of c hil d bea ri n g p ote ntial if t he y are p ost-me n o pa usal (at 
least 2 years wit h o ut me nses) or are s ur gicall y sterile (at least 1 m o nt h bef ore st u d y).

Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de: h or m o nal met h o ds ass ociate d wit h 
i n hi biti o n of o v ulati o n, i ntra- uteri ne de vice; s ur gical sterilizati o n (i ncl u di n g part ner’s 
vasect o m y) ; or se x ual a bsti ne nce if t his i s t he preferre d a n d us ual lifestyl e of t he 
s u bject.

Fe male s u bjects m ust n ot d o nate or retrie ve, f or t heir o w n use, o va fr o m t he ti me of 
scree ni n g a n d t hr o u g h o ut t he st u d y  treat me nt peri o d, a n d f or 1 2 wee ks after st u d y 
treat me nt c o m pleti o n.
7.
Pre g na nc y
8.
Fe mal e s u bjects m ust a gree n ot t o breastfee d fr o m t he ti me of Scree ni n g a n d t hr o u g h o ut 
t he st u d y peri o d, a n d f or 2 5 da ys after t he fi nal st u d y dr u g a d mi nistrati o n.
9.
F or s u bjects i n t he U K o nl y :  Ref usal of per missi o n t o all o w t he s u bject’s Ge neral 
Prac titi o ner to be n otifie d of his or her partici pati o n i n t he st u d y .
5. 4. 5.  
S u bject Wit h dr a w al Criteri a
S u bjects are free t o wit h dra w c o nse nt a n d disc o nti n ue partici pati o n i n t he st u d y at a n y ti me a n d 
wit h o ut prej u dice t o f ut ure treat me nt.  A s u bject’s partici pati o n i n t he st u d y ma y  be disc o nti n ue d 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
at a n y ti me at t he I n vesti gat or’s discreti o n.  J ustifia ble r eas o ns f or a s u bject t o be wit h dra w n 
fr o m t he st u d y i ncl u de:

N o nc o m plia nce wit h st u d y  pr oce d ures or st u d y site r ules, i ncl u di n g fail ure t o ta ke 
st u d y me dicati o n or t o a p pear at 1 or m ore st u d y visits

Use of a n y pr o hi bite d c o nc o mita nt me dicati o n, s u p ple me nt, f o o d, or be vera ge 
wit h o ut pri or a p pr o val b y  t he I n vesti gat or a n d S p o ns or

Err o ne o us i ncl usi o n of t he s u bject i n t he st u d y

Maj or pr ot oc ol de viati o n prese nti n g a n u n necessar y  ris k t o t he s u bject’s healt h

L ost t o f oll o w - u p
St u d y  treat me nts m ust be wit h dra w n f or a n y of t he f oll o wi n g reas o ns:

I nt olera ble A E relate d t o st u d y treat me nt, i ncl u di n g Gra de 4 Q Tc F pr ol o n gati o n

Resti n g L V E F < 4 5 %

Pre g na nc y

Ter mi nati o n of t he st u d y b y  t he S p o ns or

Wit h dra wal of i nf or me d c o nse nt f or a n y reas o n

A n y  cli nical A E or a b n or mal la b orat or y test res ult i n dicati n g, i n t he I n vesti gat or’s 
o pi ni o n, t hat c o nti n ue d st u d y  dr u g d osi n g is n ot i n t he s u bject’s best i nterest
T he reas o n f or s u bject wit h dra wal s h o ul d be rec or de d o n t he a p pr o priate case re p ort f or m ( C R F).
O nl y  s u bjects w h o ref use all of t he f oll o wi n g met h o ds of f oll o w -u p will be c o nsi dere d t o ha ve 
wit h dra w n c o nse nt fr o m st u d y  partici pati o n:

Partici pati o n i n t he 3 0- Da y  F oll o w-u p Visit per pr ot oc ol, eit her i n cli nic or b y  
tele p h o ne; 

St u d y  pers o n nel c o ntacti n g t he s u bject b y tele p h one ( ma y  be q uarterly, bi -a n n uall y, 
a n n uall y, or o nl y at e n d of st u d y);

St u d y  pers o n nel c o ntacti n g a n alter nati ve pers o n (e g, fa mil y me m ber, s p o use, part ner, 
le gal re prese ntati ve, p hys icia n, or ot her healt hcare pr o vi der);

St u d y  pers o n nel accessi n g a n d re vie wi n g t he s u bject’s me dical i nf or mati o n fr o m 
alter nati ve s o urces (e g, d oct or’s n otes, h os pital rec or ds). 
If t he s u bject ref uses all of t he a b o ve met h o ds of f oll o w-u p, t he I n vesti gat or s h o ul d pers o nall y 
s pea k t o t he s u bject t o e ns ure t he s u bject u n dersta n ds all of t he p ote ntial met h o ds of f oll o w - u p.  
If t he s u bject c o nti n ues t o ref use all p ote ntial met h o ds of f oll o w-u p, t he I n vesti gat or will 
d oc u me nt t his as a wit h dra wal of c o nse nt i n t he me dical rec or d a n d i n t he C R F.
F or s u bjects w h o wit h dra w c o nse nt as defi ne a b o ve, st u d y  pers o n nel will use l ocal, re gi o nal, a n d 
nati o nal p u blic rec or ds (i n acc or da nce wit h l ocal la ws) t o m o nit or vital stat us.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 5. 
St u d y or Site Ter mi n ati o n
If t he S p o ns or, t he I n vesti gat or, t he cli nical m o nit or, U nite d States ( U S) F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) or ot her C o m pete nt A ut h orit y  officials disc o ver c o n diti o ns d uri n g t he 
st u d y i n dicati n g t hat t he site’s partici pati o n s h o ul d be ter mi nate d, t his acti o n ma y be ta ke n after 
a p pr o priate c o ns ultati o n bet wee n t he S p o ns or a n d t he I n vesti gat or .  C o n diti o ns t hat ma y warra nt 
ter mi nati o n of t he st u d y i ncl u de, b ut are n ot li mite d t o:

Disc o ver y  of a n u ne x pecte d, seri o us, or u nacce pta ble ris k t o s u bjects e nr olle d i n t he 
st u d y

S p o ns or’s decisi o n t o s us pe n d or disc o nti n ue testi n g, e val uati o n, or de vel o p me nt of 
t he st u d y dr u g

I n vesti gat or’s fail ure t o c o m pl y wit h perti ne nt U S F D A or re gi o nal Healt h A ut h orit y 
re g ulati o ns a n d I C H (I nter nati o nal C o nfere nce o n Har m o nisati o n of Tec h nical 
Re q uire me nts f or Re gistrati o n of P har mace uticals f or H u ma n Use) g ui deli n es

I ns ufficie nt c o m plia nce wit h pr ot oc ol re q uire me nts
5. 6. 
St u d y Tre at me nt
5. 6. 1. 
I de ntit y of I n vesti g ati o n al Pr o d uct
T he i n vesti gati o nal me dici nal pr o d uct is s u p plie d t o t he p har mac y as q uizarti ni b 3 0 m g y ell o w 
ta blets ( 2 6. 5 m g free base) or 2 0 m g w hite ta blets ( 1 7. 7 m g free base) of A C 0 1 0 2 2 0• 2 H Cl.  All 
pac ka ges are s hi p pe d at c o n diti o ns de picte d o n t he pr o d uct la bel.
5. 6. 1. 1.  
P ac k a gi n g a n d St or a ge
Q uizarti ni b dr u g will be pr o vi de d t o t he site i n n u m bere d b ottles.  S u bjects ra n d o mize d t o 
sal va ge c he m ot hera py will recei ve c o m me rcially a vaila ble c he m ot hera p y.
Q uizarti ni b ta blets m ust be st ore d a p pr o priatel y i n a l oc ke d ca bi net/r o o m wit h li mite d a n d 
c o ntr olle d access u n der t he rec o m me n de d st ora ge c o n diti o ns (st ore u p t o 2 5º C [ 7 7º F] a n d 
pr otecte d fr o m freezi n g).  T he st ora ge c o n diti o n of q uizarti ni b dr u g b ottles m ust be l o g ge d dail y.  
If t he st ora ge r o o m/ca bi net d oes n ot ha ve a n a ut o mate d c o nti n u o us te m perat ure rec or di n g sys te m 
t o rec or d t he dail y te m perat ure data, daily te m perat ure m ust be m o nit ore d a n d rec or de d o n a 
te m perat ure l og.
Detaile d i nstr ucti o ns f or t he ha n dli n g of q uizarti ni b ca n be f o u n d i n t he P har mac y  Ma n ual.
5. 6. 1. 2.  
St u d y Dr u g Acc o u nt a bilit y
T he i n vesti gati o nal p har mac y will mai ntai n a rec or d of st u d y  dr u g i n ve nt or y.
T he i n vesti gat or or desi g nee will mai ntai n s u bject I D, b ott le n u m ber, l ot n u m ber, date dis pe nse d, 
n u m ber of b ottles a n d ta blets dis pe nse d a n d ret ur ne d o n a s u bject st u d y dr u g dis pe nsi n g a n d 
acc o u nta bilit y l o g.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 6. 2. 
Met h o d of Assi g ni n g S u bjects t o Tre at me nt Gr o u ps
U p o n pr o vi di n g writte n i nf or me d c o nse nt a n d i nitiati o n o f scree ni n g pr oce d ures, a u ni q ue 
n u m ber will be assi g ne d t o eac h s u bject.  S u bjects will mai ntai n t his n u m ber t hr o u g h o ut t he 
st u d y.
S u bjects will be ra n d o mize d i nt o t he t w o treat me nt gr o u ps i n a 2: 1 rati o ( 2 4 2 q uizarti ni b a n d 
1 2 1 sal va ge c he m ot hera p y) a n d t he ra n d o mizati o n will be stratifie d b y pri or t hera p y a n d 
res p o nse, a n d pre-selecte d sal va ge c he m ot hera py:
Pri or t hera p y a n d res p o nse:

Rela pse d i n ≤ 6 m o nt hs ( n ot p ost H S C T)

Refract or y

Rela pse d i n ≤ 6 m o nt hs p ost all o ge neic H S C T
Pre -selecte d c he m ot hera p y, e ve n f or s u bjects s u bse q ue ntl y ra n d o mize d t o q uizarti ni b:

Hi g h i nte nsit y  c he m ot hera p y ( M E C; F L A G-I D A)

L o w i nte nsit y c he m ot hera p y ( L o D A C)
5. 6. 3. 
Selecti o n of D oses i n t he St u d y
T he f ull rati o nale is gi ve n i n Secti o n 5. 2. 3 .
5. 6. 4. 
Selecti o n a n d Ti mi n g of D oses f or E ac h S u bject
5. 6. 4. 1. 
Q uiz arti ni b
F or s u bjects ra n d o mize d t o q uizarti ni b t he starti n g d ose will be 3 0 m g/ da y  u nless t he s u bject is 
recei vi n g c o nc urre nt t hera p y with a str o n g C Y P 3 A 4 i n hi bit or, i n w hic h case t he starti n g d ose 
will be 2 0 m g/ da y .  T he d ose of q uizarti ni b will be ta ke n i n t he m or ni n g o ver c o nti n u o us 2 8-da y  
c ycles. Q uizarti ni b s h o ul d be ta ke n i n t he m or ni n g.
If t he s u bject o mits ta ki n g q uizarti ni b i n t he 
m or ni n g, it ma y  be ta ke n later i n t he da y ( u p t o mi d ni g ht) ot her wise t he d ose is c o nsi dere d 
misse d. If t he s u bject v o mits after ta ki n g q uizarti ni b, n o re place me nt d ose s h o ul d be gi ve n.
Criteria f or d ose escalati o n or d ose re d ucti o n are pr o vi de d i n  Secti o n 5. 6. 4. 3 a n d Secti o n 5. 6. 4. 4
respecti vel y .
Q uizarti ni b ca n be cr us he d a n d diss ol ve d i n water. T he res ulti n g s ol uti o n ca n be dra w n u p i n a 
dis p osa ble s y ri n ge a n d a d mi nistere d via p ol yvi n yl c hl ori de or silic o ne nas o gastric t u bes. Detail s 
ca n be f o u n d i n t he P har mac y Ma n ual.  
5. 6. 4. 2. 
S al v a ge C he m o t her a p y
T he I n vesti gat or will pre -select t he s pecific sal va ge c he m ot hera p y re gi me n bef ore ra n d o mizati o n 
of eac h s u bject.  All sal va ge c he m ot hera p y will be a d mi nistere d d uri n g 2 8 -da y c y cles.  T he start 
of C y cle 2 ( M E C; F L A G -I D A, or L o D A C) a n d s u bse q ue nt c ycles ( L o D A C) ma y be dela ye d f or 
u p t o 1 4 da ys t o all o w f or rec o ver y  fr o m t o xicit y.  D ose re d ucti o ns are all o we d f or t o xicit y a n d 
m ust be d oc u me nte d i n t he s o urce rec or d.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
L o w D ose C yt ar a bi ne ( L o D A C)
C y tara bi ne ( 2 0 m g) will be a d mi nistere d t wice dail y b y s u bc uta ne o us i njecti o n f or 1 0 da ys 
( Da ys 1 t hr o u g h 1 0) o ver c o nti n u o us 2 8 -da y  c ycles.  A dela y of u p t o 1 4 da ys bet wee n c ycles is 
all o we d f or rec o ver y fr o m t o xicit y.
M E C C he m ot her a p y

Mit o xa ntr o ne ( 8 m g/ m
2/ da y) will be a d mi nistere d b y 5 mi n ute i ntra ve n o us (I V) 
i njecti o n f or 5 d a y s ( Da ys 1 t hr o u g h 5).

Et o p osi de ( 1 0 0 m g/ m 2/ da y) will be a d mi nistere d b y 1 h o ur I V i nf usi o n i m me diatel y 
after mit o xa ntr o ne f or 5 da ys ( Da ys 1 t hr o u g h 5).

C y tara bi ne ( 1 0 0 0 m g/ m2/ da y) will be a d mi nistere d b y 1 h o ur I V i nf usi o n 
i m me diatel y after et o p osi de f or 5 da ys ( Da ys 1 t hr o u g h 5).
F L A G- I D A C he m ot her a p y

G- C S F ( 3 0 0 μ g/ m 2/ da y) will be a d mi nistere d b y 2 h o ur I V i nf usi o n f or 5 da ys 
( Da ys 1 t hr o u g h 5) or alter nati vel y, G -C S F ( 5 µ g/ k g/ da y ) ma y be a d mi nistere d S C f or 
5 da y s ( Da ys 1 t hr o u g h 5).  A d diti o nal G -C S F is rec o m me n de d 7 da y s after t he 
c o m pleti o n of c he m ot hera p y, u ntil A N C is > 0. 5 × 1 09/ L.

Fl u dara bi ne ( 3 0 m g/ m 2/ da y) will be a d mi nistere d b y 3 0 mi n ute I V i nf usi o n f or 5 da ys 
( Da ys 2 t hr o u g h 6).

C y tara bi ne ( 2 0 0 0 m g/ m2/ da y) will be a d mi nistere d b y 4 h o ur I V i nf usi o n, be gi n ni n g 
4 h o urs after t he fl u dara bi ne i nf usi o n, f or 5 da y s ( Da ys 2 t hr o u g h 6).

I dar u bici n ( 1 0 m g/ m 2/ da y) will be a d mi nistere d o ver 5 t o 1 0 mi n utes i n a fast-r u n ni n g 
sali ne dri p f or 3 da ys ( Da ys 2 t hr o u g h 4).
5. 6. 4. 3. 
Q uiz arti ni b D ose Es c al ati o n R ules a n d Defi niti o ns
C Y C L E 1 D A Y 1 6
F or s u bjects n ot ta ki n g a str o n g C Y P 3 A 4 i n hi bit or t he d ose of q uizarti ni b will be i ncrease d t o 
6 0 m g/ da y   starti n g o n Da y 1 6 if t he s u bject’s a vera ge Q Tc F ( Q T i nter val c orrecte d wit h 
Fri dericia’s f or m ula), base d o n tri plicate rea di n g, is ≤ 4 5 0 msec o n a n d bef ore Da y  1 5.
F or s u bjects ta ki n g a str o n g C Y P 3 A 4 i n hi bit or, t he d ose of q uizarti ni b will be i ncrease d t o 
3 0 m g/ da y  pr o vi di n g t he y meet t he a b o ve Q Tc F re q uire me nts.
C Y C L E 2 D A Y 1
S u bjects w h o fail t o ac hie ve a C R, C R p or C Ri as defi ne d i n Secti o n 7. 2 after at least o ne 2 8 -da y  
c ycle of t hera p y, a n d ma y u n der g o d ose escalati o n pr o vi di n g t he f oll o wi n g criteria are met:

T he s u bject has n ot ha d a Gra de 3 or hi g her, n o n - he mat ol o gic, a n d relate d a d verse 
e ve nt.

N o i ncrease i n Q Tc F m ore t ha n 6 0 msec a b o ve baseli ne.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

T he s u bject m ust n ot ha ve a plastic b o ne marr o w at t he ti me of t he pr o p ose d d ose 
escalati o n.
I n a d diti o n, s u bjects w h o ac hie ve d a res p o nse ( C R, C Ri, C R p, or P R) at a n y ti me a n d w h o 
s u bse q ue ntl y rela pse d ma y u n der g o d ose escalati o n pr o vi de d t he y meet t he sa me criteria as 
a b o ve.
F or s u bjects n ot ta ki n g a str o n g C Y P 3 A 4 i n hi bit or t he d ose of q uizarti ni b will be i ncrease d t o 
6 0 m g/ da y .
F or s u bjects ta ki n g a str o n g C Y P 3 A 4 i n hi bit or, t he d ose of q uizarti ni b will be i ncrease d t o 
3 0 m g/ da y  pr o vi di n g t he y meet t he a b o ve re q uire me nts.
F oll o wi n g d ose escalati o n, tri plicate E C G deter mi nati o ns s h o ul d be perf or me d at lea st o nce 
wee kl y f or 2 wee ks t o m o nit or Q Tc F pr ol o n gati o n.
5. 6. 4. 4. 
Q uiz arti ni b D ose Re d ucti o n R ules a n d Defi niti o ns
T he d ose of q uizarti ni b will be re d uce d ste p wise fr o m 6 0 m g/ da y  t o 3 0 m g/ da y or fr o m 
3 0 m g/ da y  t o 2 0 m g/ da y, base d o n t he f oll o wi n g criteria:
Q Tc F ( Q T i nter v al c orrecte d wit h Fri derici a’s f or m ul a) Pr ol o n g ati o n

Gra de 2 ( Q Tc F a vera ge of tri plicate rea di n gs > 4 8 0 msec)

T he d ose will be re d uce d wit h o ut i nterr u pti o n.

If 2 0 m g/ da y  is t he c urre nt d ose, d osi n g will be i nterr u pte d f or u p t o 1 4 da ys.  If 
Q Tc F ret ur ns t o wit hi n 3 0 msec of baseli ne or ≤ 4 5 0 msec wit hi n 1 4 da y s, treat me nt 
ma y  be res u me d at 2 0 m g/ da y. 

Gra de 3 ( Q Tc F a vera ge of tri plicate rea di n gs > 5 0 0 msec)

D osi n g w ill be i nterr u pte d f or u p t o 1 4 da ys.  If Q Tc F ret ur ns t o wit hi n 3 0 msec of 
baseli ne or ≤4 5 0 msec wit hi n 1 4 da y s, treat me nt ma y be res u me d at a re d uce d d ose.

If 2 0 m g/ da y is t he c urre nt d ose, d osi n g will be i nterr u pte d f or u p t o 1 4 da ys.  If 
Q Tc F ret ur ns to wit hi n 3 0 msec of baseli ne or ≤ 4 5 0 msec wit hi n 1 4 da y s, treat me nt 
ma y  be res u me d at 2 0 m g/ da y. If Gra de 3 e ve nt ret ur ns, treat me nt will be 
disc o nti n ue d. 

Gra de 4 ( Q Tc F > 5 0 0 msec or > 6 0 msec c ha n ge fr o m baseli ne, a n d T orsa de de p oi ntes or 
p ol y m or p hic ve ntric ular tac h y car dia or si g ns/s y m pt o ms of seri o us arr h yt h mia)

Treat me nt will be disc o nti n ue d.
See Secti o n 8. 5 f or cli nical g ui deli nes f or t he ma na ge me nt of Q T pr ol o n gati o n.
N o n -he m at ol o gic T o xicit y
Gra de 3 or 4 relate d t o q uizarti ni b a n d persisti n g > 4 8 h o urs wit h o ut i m pr o ve me nt t o ≤Gra de 2.

D osi n g will be i nterr u pte d f or u p t o 1 4 da y s.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

If t o xicit y i m pr o ves t o ≤Gra de 1 wit hi n 1 4 da y s, treat me nt ma y be res u me d at t he 
re d uce d d ose.
M yel os u p pressi o n
I n a s u bject wit h C R p or C Ri, t he d ose ma y be re d uce d at t he I n vesti gat or’s discreti o n if:

T he s u bject has bee n treate d f or a mi ni m u m of 2 c y cles.

Platelet c o u nt is < 1 0 0 × 1 0 9/ L a n d A N C is ≤1 0 0 0 × 1 0 9/ L.

Ma rr o w blast c o u nt is < 5 %.

T here is n o e vi de nce of e xtra me d ullar y disease.
I nitiati o n of c o nc o mita nt treat me nt wit h a str o n g C Y P 3 A 4 i n hi bit or is i de ntifie d i n A p pe n di x 1:  
List of P ote ntial Q T Pr ol o n gi n g Dr u gs, C Y P 3 A 4 I n hi bit ors/I n d ucers, a n d P -gl yc o pr otei n 
I n hi bit ors/I n d ucers.
T he d ose will be re d uce d o ne le vel ( 6 0 m g t o 3 0 m g or 3 0 m g t o 2 0 m g) w he n treat me nt wit h a 
str o n g C Y P 3 A 4 i n hi bit or is i nitiate d.

A s u bject ta ki n g a str o n g C Y P 3 A 4 i n hi bit or at e nr oll me nt will i nitiate q uizarti ni b 
a d mi nistrati o n at 2 0 m g/ da y.  T he d ose will be escalate d t o 3 0 m g/ da y at da y 1 6 if t he 
Q Tc F i nter val is less or e q ual t o 4 5 0 msec pri or t o or at t he da y  1 5 E C G e val uati o ns.
S u bjects recei vi n g a re d uce d q uizarti ni b d ose ma y be re- escalate d o ne le vel t o 3 0 m g/ da y or t o 
6 0 m g/ da y  e xce pt f or re d ucti o ns d ue t o Gra de 3 Q Tc F pr ol o n gati o n.  If t he d ose was re d uce d f or 
t o xicit y, all e ve nts res p o nsi ble f or d ose re d ucti o n m ust ha ve res ol ve d t o ≤ Gra de 1.  If t he d ose 
was re d uce d f or a str o n g C Y P 3 A 4 i n hi bit or, t he pri or d ose of q uizarti ni b ma y  be res u me d w he n 
t he i n hi bit or is wit h dra w n.
5. 6. 4. 5. 
Q uiz arti ni b D ose I nterr u pti o n f or H S C T
If a s u bject u n der g oes H S C T, q uizarti ni b s h o ul d be disc o nti n ue d 7 da ys bef ore t he start of a 
c o n diti o ni n g re gi me n.  F or s u bjects ra n d o mize d t o t he q uizarti ni b ar m w h o u n der g o H S C T, 
treat me nt wit h q uizarti ni b ma y be res u me d at 3 0 t o 1 0 0 da ys after t he tra ns pla nt.  A wi n d o w of 
+ 7 d a y s will be all o we d after da y 1 0 0.  Q uizarti ni b ma y be restarte d if:

S u bject has a n A N C > 1 x 1 0 9/ L a n d platelet c o u nt > 5 0 × 1 0 9/ L wit h o ut platelet 
tra nsf usi o n s u p p ort wit hi n 1 wee k, or a platelet c o u nt > 2 5 × 1 09/ L wit h o ut platelet 
tra nsf usi o n s u p p ort wit hi n 2 wee ks pri or t o first d ose.

S u bject d oes n ot ha ve ( 1) acti ve ac ute, or ≥Gra de 3 graft vers us h ost disease 
( G V H D) or ( 2) acti ve G V H D t hera p y ( n ot pr o p h yla xis) i nitiati o n wit hi n 2 1 da ys.
T he starti n g d ose of q uizarti ni b p ost- H S C T s h o ul d be 3 0 m g dail y  u nless t he s u bject is recei vi n g 
a str o n g C Y P 3 A 4 i n hi bit or, i n w hic h case t he starti n g d ose s h o ul d be 2 0 m g dail y.  S u bjects will 
d ose escala te starti n g o n Da y 1 6 if t he Q Tc F i nter val is less or e q ual t o 4 5 0 msec pri or t o or at 
t he da y 1 5 E C G e val uati o ns.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 6. 5. 
Bli n di n g
It is n ot feasi ble t o bli n d treat me nt all ocati o ns f or i n di vi d ual s u bjects beca use of differe nt r o utes 
of a d mi nistrati o n, differe nt treat me nt sc he d ules a n d differe nt a d verse e ve nt pr ofiles bet wee n 
q uizarti ni b a n d sal va ge c he m ot hera p y.  T he pri mar y e n d p oi nt of o verall s ur vi val is a r o b ust 
e n d p oi nt a n d bias d ue t o lac k of bli n di n g s h o ul d be mi ni mal.  T o f urt her re d uce a n y  p ote ntial 
bias, t he S p o ns or will n ot ha ve access t o a g gre gate efficac y data e xce pt w he n data fr o m b ot h 
treat me nt ( q uizarti ni b) a n d c o ntr ol (sal va ge c he m ot hera py) ar ms are c o m bi ne d.  Data relati n g t o 
t he pri mar y e n d p oi nt of s ur vi val will be restricte d s o t hat t he S p o ns or will n ot ha ve access t o 
l o n g- ter m f oll o w-u p data o n i n di vi d ual s u bjects, w hic h be gi ns 3 0 da y s after disc o nti n ui n g st u dy 
treat me nt i n eit her treat me nt ar m.  A p pr o xi matel y 8 0 % of t he pla n ne d e ve nts are e x pecte d t o 
occ ur d uri n g t his l o n g -ter m f oll o w-u p peri o d a n d t heref ore t he S p o ns or will be bli n de d t o f ull 
data s u p p orti n g t he pri mar y  e n d p oi nt of t he st u dy.
5. 6. 6.  
Pri or a n d C o nc o mit a nt T her a p y 
All c o nc o mita nt me dicati o ns a d mi nistere d fr o m t he Scree ni n g visit t hr o u g h t he 3 0 -Da y  
F oll o w -u p visit or u ntil t he start of a d diti o nal A M L t hera p y will be rec or de d o n t he a p pr o priate 
C R F.  Refer t o  Secti o n 5. 6. 6. 1 f or pr o hi bite d me dicati o ns a n d Secti o n 5. 6. 6. 2 f or all o we d 
s u p p orti ve t hera py.
5. 6. 6. 1. 
Pr o hi bite d Me dic ati o ns
F or all s u bjects ( q uizarti ni b a n d sal va ge c he m ot hera p y):  A d mi nistrati o n of ot her a nti ne o plastic 
a ge nts d uri n g t he st u d y peri o d is pr o hi bite d wit h t he e xce pti o n of hy d r o xy urea w hic h is all o we d 
f or u p t o 1 4 da ys pri or t o or f or u p t o 4 da y s c o nc o mita ntl y wit h q uizarti ni b or sal va ge 
c he m ot hera p y t o c o ntr ol t he peri p heral blast c o u nt, u p t o a ma xi m u m d ose of 5 g/ da y .
I n s u bjects recei vi n g q uizarti ni b:

C o nc o mita nt me dicati o ns t hat pr ol o n g t he Q T/ Q Tc i nter val are pr o hi bite d e xce pt 
w he n re gar de d b y t he I n vesti gat or as esse ntial f or s u bject care.

Str o n g C Y P 3 A 4 i n hi bit ors s h o ul d be a v oi de d b ut are n ot pr o hi bite d alt h o u g h re q uire 
a q uizarti ni b d ose a dj ust me nts are re q uire d.  Wea k or m o derate C Y P 3 A 4 i n hi bit ors, 
s uc h as fl uc o naz ole, ma y be use d with o ut d ose re d ucti o n.

C o nc o mita nt str o n g or m o derate C Y P 3 A 4 i n d ucers are pr o hi bite d.
If q uizarti ni b is c o-a d mi nistere d wit h dr u gs t hat i n hi bit P -g p, i ncrease d c o nce ntrati o ns of 
q uizarti ni b are p ossi ble a n d ca uti o n s h o ul d be e xercise d.  T he c o -a d mi nistrati o n of P -g p 
i n hi bit ors a n d i n d ucers wit h q uizarti ni b s h o ul d be a v oi de d if p ossi ble.  If q uizarti ni b is 
c o-a d mi nistere d wit h dr u gs t hat are s u bstrates of P- g p, i ncrease d c o nce ntrati o ns of t he s u bstrate 
dr u gs are p ossi ble a n d ca uti o n s h o ul d be e xercise d.
Pr o hi b ite d me dicati o ns a n d f o o ds are liste d i n A p pe n di x 1: Li st of P ote ntial Q T Pr ol o n gi n g 
Dr u gs, C Y P 3 A 4 I n hi bit ors/I n d ucers, a n d P -gl yc o pr otei n I n hi bit ors/I n d ucers.
5. 6. 6. 2.  
S u p p orti ve C are G ui deli nes
S u bjects will recei ve a p pr o priate best s u p p orti ve care t hr o u g h o ut t he st u d y.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 6. 7.  
Tre at me nt C o m pli a nce
Trai ne d me dical pers o n nel will a d mi nister M E C, a n d F L A G- I DA i n t he st u d y  site setti n g.  
Treat me nt wit h q uizarti ni b a n d L o D A C will be i nitiate d i n t he cli nic.  C o m plia nce m ust be 
m o nit ore d b y  re vie wi n g t he s u bject’s ret ur ne d st u d y treat me nt s u p pl y at e ver y visit a n d b y 
c o m pleti n g t he dr u g acc o u nta bilit y rec or d.
5. 7. 
St u d y V ari a bles
5. 7. 1. 
Pri m ar y Effic ac y V ari a ble
T he pri mar y  efficac y varia ble is o verall s ur vi val, defi ne d as t he ti me fr o m ra n d o mizati o n u ntil 
dea t h fr o m a ny ca use.  C o m plete defi niti o ns of efficac y  varia bles are gi ve n i n Secti o n 7. 2.
5. 7. 2. 
Sec o n d ar y Effic ac y V ari a ble
T he sec o n dar y  varia ble is E F S, defi ne d as t he ti me fr o m ra n d o mizati o n u ntil d oc u me nte d 
refract or y disease, rela pse after C Rc, or deat h fr o m a n y ca use, w hic he ver is o bser ve d first.  
C o m plete defi niti o ns of efficac y  varia bles are gi ve n i n Secti o n 7. 2 .
5. 7. 3. 
A d diti o n al Effic ac y V ari a bles
A d diti o nal efficac y  varia bles will be e val uate d as f oll o ws:

Le u ke mia -free s ur vi val is t he ti me fr o m t he first d oc u me nte d res p o nse ( C R, C R p, or 
C Ri) u ntil d oc u me nte d rela pse or deat h fr o m a n y ca use.

C o m p osite c o m plete re missi o n ( C Rc) rate is t he perce nta ge of s u bjects ac hie vi n g a 
best res p o nse of C R, C R p, or C Ri.

C o m plete re missi o n ( C R) rate is t he perce nta ge of s u bjects ac hie vi n g a best res p o nse 
of C R.

D ura ti o n of c o m p osite c o m plete re missi o n ( C Rc) is t he ti me fr o m t he first 
d oc u me nte d C Rc ( C R + C Ri + C R p) u ntil d oc u me nte d rela pse.

D urati o n of c o m plete re missi o n ( C R) is t he ti me fr o m t he first d oc u me nte d C R u ntil 
d oc u me nte d rela pse.
5. 7. 4. 
Tr a ns pl a nt ati o n r ate ( bri d ge t o tr a ns pl a nt) is t he perce nt a ge of s u bjects 
u n der g oi n g H S C T directl y f oll o wi n g pr ot oc ol s pecifie d tre at me nt wit h n o 
i nter ve ni n g A M L t her a p y. S afet y V ari a bles
Safet y  will be assesse d wit h p h y sical e xa mi nati o ns, vital si g n deter mi nati o ns, A E e val uati o ns, 
1 2- lea d E C Gs, E C O G perf or ma nce sc ores, a n d cli nical la b orat or y tests ( he mat ol o g y, ser u m 
c he mistr y, a n d uri nalys is res ults).
All A Es re p orte d fr o m Da y  1 t o t he 3 0-Da y  F oll o w-u p visit, or t o t he da y  of wit h dra wal of t he 
s u bject fr o m t he st u d y, will be e val uate d f or cli nical si g nifica nce b y t he I n vesti gat or.  A n A E 
will be c o nsi dere d cli nicall y  si g nifica nt if it res ults i n i na bilit y t o perf or m us ual acti vities, 
re q uires ac ute me dical i nter ve nti o n, or i n a ny ot her wa y s u g gests a si g nif ica nt hazar d t o t he 
s u bject.  A Es will be gra de d acc or di n g t o Versi o n 4. 0 3 of t he Nati o nal Ca ncer I nstit ute C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E v 4. 0 3) (htt p://cte p.i nf o. ni h. g o v ).


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
4 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
5. 7. 5. 
P h ar m ac o ki netic a n d E x p os ure -res p o nse V ari a bles
P har mac o ki netics a n d C o nce ntrati o n -Q Tc F Relati o ns hi p of q uizarti ni b a n d A C 8 8 6 will be 
e val uate d.  Ot her e x p os ure -res p o nse relati o ns hi ps wit h efficac y or safety varia bles ma y be 
e x pl ore d.
5. 7. 6. 
A d diti o n al V ari a bles
T he f oll o wi n g will be e val uate d:

F L T 3 -I TD stat us a n d allelic rati o

M utati o ns i n t he ki nase a n d j u xta me m bra ne d o mai ns of F L T 3 -I T D a n d ot her 
m utati o ns k n o w n t o be ass ociate d wit h A M L, deter mi ne d wit h b o ne marr o w or w h ole 
bl o o d sa m ples

P har mac o ge n o mics

P har mac o pr ote o mic e val uati o ns
5. 7. 7. 
P h ar m ac oec o n o mic V ari a bl es
Res o urce utilizati o n will be assesse d b y e val uati n g t he f oll o wi n g para meters:

C o nc o mita nt me dicati o ns a n d pr oce d ures

H os pitalizati o ns

U nsc he d ule d cli nic visits

E mer ge nc y  r o o m visits

S kille d n ursi n g facilit y care

H os pice care
5. 8. 
St u d y Sc he d ule
T he sc he d ule of st u d y  acti vities a n d assess me nts f or s u bjects recei vi n g q uizarti ni b is prese nte d i n 
Ta ble 3 ; t he sc he d ule of st u d y acti vities a n d assess me nts f or su bjects recei vi n g q uizarti ni b after 
H S C T is prese nte d i n  Ta ble 4 ; t he sc he d ule of st u d y acti vities a n d assess me nts f or s u bjects 
recei vi n g sal va ge c he mot hera p y is prese nte d  Ta ble 5 ; a n d t he sc he d ule of st u d y acti vities a n d 
assess me nts after treat me nt is prese nte d i n  Ta ble 6.




Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
b W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m test res ult ( mi ni m u m se nsiti vit y 2 5 I U/ L or e q ui vale nt u nits of h C G) at scree ni n g a n d a uri ne test o n Da y 1 of C ycle 
1 bef ore d osi n g, a n d e ver y 3 m o nt hs d uri n g t he treat me nt p hase.
c Tri plicate E C Gs t o be o btai ne d at scree ni n g; o n Da y 1 of C ycle 1 bef ore d osi n g a n d 2, 4 a n d 6 h o urs after d osi n g; o n Da y 2 a n d 8 of C ycle 1 bef ore d osi n g a n d 2 t o 4 h o urs after 
d osi n g; o n Da y 1 5 of C ycle 1 bef ore d osi n g a n d 2, 4 a n d 6 h o urs after d osi n g; o n Da y 1 of C y cles 2 a n d 3 bef ore d osi n g a n d 2 t o 4 h o urs after d osi n g; a n d o n Da y 1 of all 
s u bse q ue nt c ycles wit h n o ti me restricti o n.  F oll o wi n g d ose escalati o n, tri plicate E C G deter mi nati o ns s h o ul d be perf or me d at least o nce wee kl y f or 2 wee ks t o m o nit or Q Tc F 
pr ol o n g ati o n.
d O btai ne d bef ore d osi n g. Cli nical la b orat or y e val uati o ns are detaile d i n Secti o n 8. 6 , Ta ble 8 .
e M U G A sca ns or E C H O are t o be perf or me d at scree ni n g o n all s u bjects u nless
a M U G A sca n perf or me d wit hi n 1 m o nt h of scree ni n g re veale d L V E F ≥4 5 %.
f B o ne marr o w as pirati o n a n d bi o ps y f or m or p h ol o g y deter mi nati o n are preferre d, b ut bi o ps y ma y be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate.  B o ne marr o w sa m ples are 
re q uire d at scree ni n g f or ce ntral testi n g  ( wit hi n 1 4 da ys pri or t o ra n d o mizati o n; b o ne marr o w e xa mi nati o ns o utsi de t his wi n d o w ma y be acce pta ble if a gree d b y t he Me dical 
M o nit or), o n Da y 1 of C ycle 2 a n d C ycle 3, at t he earl y ter mi nati o n/e n d of treat me nt visit, a n d as cli nicall y i n dicate d.  B o n e marr o w assess me nts will be re peate d o n Da y 1 of 
eac h s u bse q ue nt c ycle u nless t he s u bject has alrea d y ac hie ve d C R, C R p, or C Ri.  I n t hat e ve nt, b o ne marr o w testi n g will be re peate d after e ver y 3 s u bse q ue nt c ycles, u nless 
t here is e vi de nce of rela pse.  A ce ntral la b orat or y will re vie w a scree ni n g s peci me n t o c o nfir m t he dia g n osis.
g T he f oll o wi n g s peci me ns m ust be c ollecte d a n d se nt t o Ge n o pti x f or ce ntral a nal ysis.  A b o ne marr o w a n d peri p heral bl o o d sa m p le s h o ul d be o btai ne d at scree ni n g (at 
a p pr o xi matel y t he sa me ti me) f or deter mi nati o n of F L T 3 -I T D stat us.  A b o ne marr o w sa m ple s h o ul d be o btai ne d at treat me nt disc o nti n uati o n or rela pse.  T he sa m ple ma y als o 
be teste d f or F L T 3 p oi nt m utati o ns a n d m utati o ns i n ot her A M L -ass ociate d ge nes.
h Bl o o d sa m ples f or P K deter mi nati o ns will be c ollecte d o n D a y 1 a n d Da y 1 5 of C ycle 1 bef ore d osi n g a n d 1, 2, 4, 6, a n d 2 4 h o urs after d osi n g.  T he 2 4 -h o ur sa m ples m ust be 
c ollecte d bef ore q uizarti ni b d osi n g o n Da y 2 a n d Da y 1 6.  Sa m ples will als o be c ollecte d o n Da y 8 of C ycle 1 bef ore d osi n g a n d 2 t o 4 h o urs (ta ke n i m me diatel y after E C G) 
after d osi n g.  T hereafter, sa m ples will be c ollecte d bef ore d osi n g a n d 2 t o 4 h o urs (ta ke n i m me diatel y after E C G) after d osi n g o n Da y 1 of C ycles 2 a n d 3.  At eac h ti me p oi nt, 
2 m L of bl o o d will be c ollecte d.  W he n a n E C G is perf or m e d at t he sa me st u d y ti me p oi nt, t he P K s peci me n s h o ul d be ta ke n i m me diatel y after war ds.
i If c o nse nt is pr o vi de d, bl o o d sa m ple ( Pa x ge ne D N A, Pa x ge ne R N A, a n d P B M C) a n d b uccal s wa b o n Da y 1 of C ycle 1 bef ore d osi n g.
j Q uizarti ni b m ust be ta ke n at t he cli nic o n C ycle 1: Da ys 1, 2, 8, 1 5, a n d 1 6; C ycle 2: Da y 1; a n d C ycle 3: Da y 1. O n ot her da ys t he s u bject ma y ta ke q uizarti n i b at h o me. 
Q uizarti ni b s h o ul d be ta ke n i n t he m or ni n g.  Please refer t o t he d osi n g g ui deli nes i n Secti o n 5. 6. 4. 3 re gar di n g re q uire d d ose escalati o n at Da y 1 6 if t he s u bject meets t he criteria 
f or d ose escalati o n.  A sec o n d o p p ort u nit y f or d ose escalati o n is a vaila ble after t he first 2 8-da y c ycle if t he s u bject has n ot ac hie ve d a C Rc.  I n a d diti o n, s u bjects w h o ac hie ve d a 
res p o nse ( C R, C Ri, C R p, or P R) at a n y ti me a n d w h o s u bse q ue ntl y rela pse d will be assesse d f or d ose escalati o n pr o vi de d t he y meet t he sa me criteria defi ne d i n  Se cti o n 5. 6. 4. 3 .






Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
a I ncl u des me dicati o ns recei ve d wit hi n 2 8 da ys pri or t o scree ni n g.
b W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m test res ult ( mi ni m u m se nsiti vit y 2 5 I U/ L or e q ui vale nt u nits of h C G) at scree ni n g a n d a uri ne test o n Da y 1 of C ycle 
1 bef ore d osi n g a n d e ver y 3 m o nt hs d uri n g t he treat me nt p hase.
c O btai ne d bef ore d osi n g.  S u bjects recei vi n g M E C or L o D A C will u n der g o E C Gs o n Da y 1 of eac h c ycle; F L A G -I D A will u n der g o E C Gs o n Da y 2 of eac h c ycle i nstea d of Da y 
1.  All sal va ge c he m ot hera p y s u bjects will ha ve E C G o n Da ys 8 a n d 1 5 C ycle 1 a n d Da y 1 5 C ycle 2.
d O btai ne d bef ore d osi n g.  Cli nical la b orat or y e val uati o ns are detaile d i n  Secti o n 8. 6 , Ta ble 8 .
e M U G A sca ns or E C H O are t o be perf or me d at scree ni n g u nless a M U G A sca n per f or me d wit hi n 1 m o nt h of scree ni n g re veale d L V E F ≥ 4 5 %.  S u bjects recei vi n g F L A G -I D A 
s h o ul d ha ve a M U G A sca n or E C H O bef ore d osi n g o n Da y 1 of C ycle 2, t o deter mi ne t heir eli gi bilit y f or a sec o n d c ycle.
f B o ne marr o w as pirati o n a n d bi o ps y f or m or p h ol o g y de ter mi nati o n are preferre d, b ut bi o ps y ma y be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate. B o ne marr o w sa m ples are 
re q uire d at scree ni n g ( wit hi n 1 4 da ys pri or t o ra n d o mizati o n; b o ne marr o w e xa mi nati o ns o utsi de t his wi n d o w ma y be acce pta ble if a greed b y t he Me dical M o nit or).  F or hi g h 
i nte nsit y c he m ot hera p y ( M E C or F L A G-I D A), b o ne marr o w sa m ples are als o re q uire d o n Da y 2 9 ( ± 1 4 da ys) of eac h c ycle of t hera p y, a n d at t he earl y ter mi nati o n/e n d of 
treat me nt visit, a n d as cli nicall y i n dicate d.  F or L o D AC, b o ne marr o w sa m ples are als o re q uire d o n Da y 1 of C ycle 2 a n d Da y 1 of C ycle 3.  If a s u bject c o nti n ues t o recei ve 
L o D A C past C ycle 2, b o ne marr o w assess me nts will be re peate d o n Da y 1 of eac h s u bse q ue nt c ycle u nless t he s u bject has alrea d y ac hie ve d a CR, C R p, or C Ri.  I n t hat e ve nt, 
b o ne marr o w testi n g will be re peate d after e ver y 3 s u bse q ue nt c ycles, u nless t here is e vi de nce of rela pse.  A d diti o nall y f or L o D A C, b o ne marr o w sa m ples are re q uire d at t he 
earl y ter mi nati o n/e n d of treat me nt visit, a n d as cli nicall y i n dicate d.
g A b o ne marr o w a n d peri p heral bl o o d sa m ple s h o ul d be o btai ne d at scree ni n g (at a p pr o xi matel y t he sa me ti me) f or deter mi nati o n of F L T 3 -I T D stat us.  A b o ne marr o w sa m ple 
s h o ul d be o btai ne d at treat me nt disc o nti n uati o n or rela pse.  T he sa mple ma y als o be teste d f or F L T 3 p oi nt m utati o ns a n d m utati o ns i n ot her A M L -ass ociate d ge nes.
h If c o nse nt is pr o vi de d, bl o o d sa m ple ( Pa x ge ne D N A, Pa x ge ne R N A, a n d P B M C) a n d b uccal s wa b o n Da y 1 of C ycle 1 bef ore d osi n g.
i A d diti o nal st u d y site visits are re q uire d f or s u bjects recei vi n g M E C ( Da ys 1 t hr o u g h 5) or F L A G- I D A ( Da ys 1 t hr o u g h 6).  M E C a n d F L A G-I D A are a d mi nistere d f or u p t o 2 
c ycles, de pe n di n g o n res p o nse a n d safet y assess me nts.
j Treat me nt wit h L o D A C ma y c o nti n ue past C ycle 2 a n d s u bse q ue nt c yc les will f oll o w sa me pr oce d ures as C ycle 2.  .  L o w d ose c ytara bi ne s h o ul d be a d mi nistere d f or 1 0 da ys i n a 
2 8 da y c ycle i n t he cli nic u nless arra n ge me nts ca n be ma de f or a d mi nistrati o n o utsi de of t he cli nic.  If d ose d o utsi de t he cl i nic, a re vie w of me dicati o n ret ur ne d a n d assess me nt 
of c o m plia nce m ust be c o n d ucte d at t he be gi n ni n g of eac h c ycle.




Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
e If c o nse nt is pr o vi de d, c ollecti o n of bl o o d ( Pa x ge ne R N A) at e n d of treat me nt visit
f Scree ni n g pr oce d ures ca n be c o m plete d wit hi n 3 da ys of t he e n d of treat me nt visit t o deter mi ne t hat s u bjects mee t i ncl usi o n 
criteria a n d d o n ot meet e xcl usi o n criteria .  T here is n o was h o ut peri o d re q uire d bet wee n st o p pi n g sal va ge c he m ot hera p y a n d 
starti n g treat me nt wit h q uizarti ni b. 
g F or t he Cr oss -o ver peri o d, o nl y he mat ol o g y a n d c he mistr y sa m ples will be c ollecte d.  Cli nical la b orat or y tests nee d n ot be 
re peate d if t he y were perf or me d wit hi n 3 da ys at t he E n d of Treat me nt visit, a n d 3 da ys pri or t o t he start of q uizarti ni b 
treat me nt.  
h Tele p h o ne c o ntact wit h t he s u bject is s ufficie nt u nless a n y assess me nt m ust be re peate d f or res ol uti o n of treat me nt -relate d A Es.
i Earl y Ter mi nati o n/ E n d of St u d y is f or s u bjects wit h dra wi n g c o nse nt, disc o nti n ui n g treat me nt a n d/ or f oll o w u p.  Re vie w of 
ret ur ne d me dicati o n is re q uire d f or s u bjects recei vi ng st u d y dr u g at ti me of wit h dra wal.
jTele p h o ne c o ntact e ver y 3 m o nt hs.




Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
6. 2. 
St u d y Visits
6. 2. 1. 
Scree ni n g Acti vities
Eli gi ble s u bjects will be scree ne d as o utli ne d bel o w.  U nless ot her wise s pecifie d, scree ni n g 
pr oce d ures m ust be c o m plete d wit hi n 1 4 da y s pri or t o ra n d o mizati o n t o deter mi ne t hat s u bjects 
meet i ncl usi o n criteria a n d d o n ot meet e xcl usi o n criteria.

Writte n i nf or me d c o nse nt

Me dical a n d disease hist or y  a n d de m o gra p hics

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Assess me nt of pri or a n d c o nc o mita nt me dicati o ns, i ncl u di n g me dicati o ns recei ve d 
wit hi n 2 8 da y s pri or t o scree ni n g.

Pre g na nc y  testi n g; w o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m 
( mi ni m u m se nsiti vit y 2 5 I U/ L or e q ui vale nt u nits of h C G).

Deter mi nati o n of c oa g ulati o n pr ofile ( pr ot hr o m bi n ti me [ P T]/i nter nati o nal n or malize d 
rati o [IN R])

C hest X -ra ys ( p osteri or/a nteri or a n d lateral)

1 2 -lea d E C G (tri plicate)

C ollecti o n of sa m ples f or cli nical la b orat or y  tests ( he matol o g y , c he mistr y, a n d 
uri nal y sis)

M U G A sca n or E C H O t o be perf or me d at scree ni n g o n all s u bjects u nless a sca n 
perf or me d wit hi n 1 m o nt h of scree ni n g re veale d L V E F ≥4 5 %.

B o ne marr o w as pirati o n a n d bi o ps y  f or ce ntral c o nfir mati o n of dia g n osis; bi o ps y ma y 
be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate.  If a s peci me n has bee n se nt 
f or ce ntral testi n g b ut t he s u bject re q uires treat me nt f or A M L bef ore t he ce ntral 
F L T 3 -I TD test res ult is a vaila ble, a l ocal test res ult ma y  be acce pta ble f or 
ra n d o mizati o n after c o ns ultati o n wit h t he Me dical M o nit or.  A Scree ni n g s peci me n 
m ust be se nt t o t he ce ntral la b orat or y f or c o nfir mati o n, a n d res ults c o m pare d t o t he 
l ocal test res ult.
I n cases w here s u bjects ha ve bee n ra n d o mize d a n d t he F L T 3-I T D l ocal a n d ce ntral 
la b orat or y res ults are disc or da nt t he s u bjects ma y c o nti n ue wit h q uizarti ni b d osi n g.

C ollecti o n of b o ne marr o w s peci me n a n d w h ole bl o o d (at a p pr o xi matel y  t he sa me 
ti me) f or F L T 3-I T D testi n g (a n d ot her A M L ass ociate d m utati o ns) b y ce ntral 
la b orat or y. If it is not feasi ble t o o btai n a b o ne marr o w s peci me n at Scree ni n g, 
peri p heral bl o o d o nl y  ma y be s u b mitte d t o Na vi gate Bi o P har ma Ser vices, I nc, a 
N o vartis C o m pa n y  ( Na vi gate).


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
o
T his test is a p pr o ve d b y  t he F D A f or i n vesti gati o nal use a n d is C E mar ke d.  It is 
n ot a p pr o ve d b y t he F D A or ot her re g ulat or y a ge ncies f or c o m mercial use . T he 
res ults of t he test will be use d t o s u p p ort t he de vel o p me nt of a c o m mercial 
c o m pa ni o n dia g n ostic test. T he F D A has re vie we d t he met h o d ol o g y  a n d assa y 
de vel o p me nt a n d vali dati o n of t he c o m pa ni o n dia g n ostic test, as d oc u me nte d b y  
I n vesti gati o nal De vice E xe m pti o n n u m ber G 1 4 0 0 1 2.
6. 2. 2. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Q uiz arti ni b
6. 2. 2. 1. 
C ycle 1, D a y 1
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Assess me nt of pri or a n d c o nc o mita nt me dicati o ns

A uri ne pre g na nc y test m ust be perf or me d pri or t o d osi n g a n d e ver y  3 m o nt hs d uri n g 
t he treat me nt p hase i n w o me n of c hil d-beari n g p ote ntial

1 2 -lea d E C G (tri plicate) bef ore d osi n g a n d 2, 4, a n d 6 h o urs after d osi n g

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n

C ollecti o n of bl o o d sa m ples f or P K deter mi nati o ns bef ore d osi n g a n d 1, 2, 4, a n d 
6 h o urs after d osi n g.  W he n a n E C G is perf or me d at t he sa me st u d y  ti me p oi nt, t he 
P K s peci me n s h o ul d be ta ke n i m me diatel y after war ds.

If c o nse nt is pr o vi de d, c ollecti o n of sa m ples ( bl o o d [ Pa x ge ne D N A, Pa x ge ne R N A, 
a n d P B M C] a n d b uccal s wa b) s h o ul d be o btai ne d bef ore d osi n g f or 
p har mac o ge n o mic a n d pr ote o mic deter mi nati o ns.

A d mi nistrati o n of q uizarti ni b at t he st u d y  site
6. 2. 2. 2. 
C ycle 1, D a y 2 a n d D a y 8 ( ± 1 d a y)
T he f oll o wi n g acti vi ties will ta ke place d uri n g t hese visits:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G bef ore d osi n g a n d 2 t o 4 h o urs after d osi n g

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
5 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

A E/ S A E e val uati o n

C ollecti o n of bl o o d sa m ples f or P K deter mi nati o ns o n Da y  2 bef ore d osi n g a n d o n 
Da y 8 bef ore d osi n g a n d 2 t o 4 h o urs after d osi n g.  W he n a n E C G is perf or me d at t he 
sa me st u d y ti me p oi nt, t he P K s peci me n s h o ul d be ta ke n i m me diatel y  after war ds.

A d mi nistrati o n of q uizarti ni b at t he st u d y  site
6. 2. 2. 3. 
C ycle 1, D a y 1 5 ( ± 1 d a y)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

1 2- lea d E C G bef ore d osi n g a n d 2, 4, a n d 6 h o urs after d osi n g

E C G re vie w t o deter mi ne if d ose escalati o n is re q uire d:

Please refer t o Secti o n 5. 6. 4. 3 f or d osi n g g ui deli nes t o deter mi ne if t he s u bject meets 
s pecifie d criteria f or d ose escalati o n; first i ncrease d d ose t o be a d mi nistere d C ycle 1 
Da y  1 6.

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a nd uri nal ys is)

A E/ S A E e val uati o n

C ollecti o n of bl o o d sa m ples f or P K deter mi nati o ns bef ore d osi n g a n d 1, 2, 4, a n d 
6 h o urs after d osi n g.  W he n a n E C G is perf or me d at t he sa me st u d y  ti me p oi nt, t he 
P K s peci me n s h o ul d be ta ke n i m me diatel y after war ds.

A d mi nistr ati o n of q uizarti ni b at t he st u d y  site

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 2. 4. 
C ycle 1, D a y 1 6 (t he d a y after D a y 1 5)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

C ollecti o n of bl o o d sa m ple f or P K deter mi nati o ns bef ore d osi n g

A d mi nistrati o n of q uizarti ni b at t he st u d y  site
6. 2. 2. 5. 
C ycle 2, D a y 1 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

1 2 -lea d E C G (tri plicate) bef ore d osi n g a n d 2 t o 4 h o urs after d osi n g

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

B o ne marr o w as pirati o n a n d bi o ps y  f or l ocal deter mi nati o n of res p o nse; bi o ps y ma y 
be o mitte d if as pirate s ufficie nt.

A E/ S A E e val uati o n

C ollecti o n of bl o o d sa m ples f or P K deter mi nati o ns bef ore d osi n g a n d 2 t o 4 h o urs 
after d osi n g.  W he n a n E C G is perf or me d at t he sa me st u d y ti me p oi nt, t he P K 
s peci me n s h o ul d be ta ken i m me diatel y after war ds.

A d mi nistrati o n of q uizarti ni b at t he st u d y  site

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce

C o nsi derati o n of w het her a d ose escalati o n is re q uire d if it di d n ot occ ur at Da y 1 6 
(f oll o wi n g res ults fr o m b o ne marr o w as pirati o n a n d m or p h ol o g y)
6. 2. 2. 6. 
C ycle 2, D a y 1 5 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 2. 7. 
C ycle 3, D a y 1 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G bef ore d osi n g a n d 2 t o 4 h o urs after d osi n g

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

B o ne marr o w as pirati o n a n d bi o ps y  f or l ocal deter mi nati o n of res p o nse; bi o ps y ma y 
be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

A E/ S A E e val uati o n

C ollecti o n of bl o o d sa m ples f or P K deter mi nati o ns bef ore d osi n g a n d 2 t o 4 h o urs 
after d osi n g.  W he n a n E C G is perf or me d at t he sa me st u d y  ti me p oi nt, t he P K 
s peci me n s h o ul d be ta ke n i m me diatel y after war ds.

A d mi nistrati o n of q uizarti ni b at t he st u d y  site

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 2. 8. 
C ycle 4 a n d S u bse q ue nt C ycles, D a y 1 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t hese visits:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

A uri ne pre g na nc y  test m ust be perf or me d e ver y 3 m o nt hs d uri n g t he treat me nt p hase 
i n w o me n of c hil d- beari n g p ote ntial

1 2 -lea d E C G (tri plicate)

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

B o ne marr o w as pirati o n a n d bi o ps y  f or l ocal deter mi nati o n of resp o nse; ( bi o ps y  ma y 
be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate) o n Da y  1 of Cycle 4 u nless 
s u bject has ac hie ve d a C R, C R p or C Ri, i n w hic h case b o ne marr o w e xa mi nati o n 
s h o ul d be e ver y 3 c ycles s u bse q ue ntl y, at t he e n d of treat me nt/e n d of st u d y visit, a n d 
as cli nicall y i n dicate d

A E/ S A E e val uati o n

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 3. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g Q uiz arti ni b After 
H S C T
6. 2. 3. 1. 
C ycle 1 ( P ost -H S C T), D a y 1
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate) bef ore d osi n g a n d 2 a n d 4 h o urs after d osi n g


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

Pre g na nc y  testi n g; w o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne 
pre g na nc y  test res ult bef ore t he start of st u d y treat me nt a n d e ver y 3 m o nt hs d uri n g t he 
treat me nt p hase.

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a nd uri nal ys is) ( bl o o d dra ws ma y be perf or me d t he pri or 
da y ; res ults s h o ul d be re vie we d bef ore d osi n g)

B o ne marr o w as pirati o n a n d bi o ps y  f or res p o nse deter mi nati o n; bi o ps y ma y be 
o mitte d if t he as pirate is c o nsi dere d t o be a de q uate

S peci me n c ollecti o n f or e x pl orat or y  assess me nt of F L T 3 m utati o ns usi n g b o ne 
marr o w ( or w h ole bl o o d if marr o w ca n n ot be c ollecte d); res ult of F L T 3 test n ot 
re q uire d f or s u bject t o start q uizarti ni b.

A E/ S A E e val uati o n

A d mi nistrati o n of q uizarti ni b at t he st u d y  site
6. 2. 3. 2. 
C ycle 1 ( P ost -H S C T ), D a y 8 ( ± 1 d a y)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate)

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n

A d mi nistrati o n of q uizarti ni b at t he st u d y  site

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 3. 3. 
C ycle 1 ( P ost -H S C T), D a y 1 5 ( ± 1 d a y)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate) bef ore d osi n g (i ncl u di n g a deter mi nati o n of w het her d ose 
escalati o n is a p pr o priate)

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cl i nical la b orat or y tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

A d mi nistrati o n of q uizarti ni b at t he st u d y  site

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 3. 4. 
C ycle 2 a n d S u bse q ue nt C ycles ( P ost -H S C T), D a y 1 ( ± 3 d a ys)
T h e f oll o wi n g acti vities will ta ke place d uri n g t hese visits:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate)

Pre g na nc y  testi n g; w o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne 
pre g na nc y  test res ult bef ore t he start of st u d y treat me nt a n d e ver y 3 m o nt hs d uri n g t he 
treat me nt p hase.

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is) 

B o ne marr o w assess me nt of res p o nse b y l ocal pat h ol o g y  is re q uire d o n Da y 1 of 
C y cle 4 a n d e ver y  3 c ycles s u bse q ue ntl y, a n d as cli nicall y i n dicate d

A E/ S A E e val uati o n

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce
6. 2. 4. 
Sc he d ule of Acti vities a n d Assess me nts f or S u bjects Recei vi n g S al v a ge 
C he m ot her a p y
6. 2. 4. 1. 
C ycle 1, D a y 1
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

1 2 -lea d E C G (tri plicate) bef ore d osi n g f or s u bjects recei vi n g M E C a n d L o D A C 
(s u bjects recei vi n g F L A G-I D A will ha ve tri plicate E C Gs o n Da y 2 of eac h c ycle, 
i nstea d of Da y 1)

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A uri ne pre g na nc y  test m ust be perf or me d pri or t o d osi n g a n d e ver y 3 m o nt hs d uri n g 
t he treat me nt p hase i n w o me n of c hil d-beari n g p ote ntial

Re vie w of c o nc o mita nt me dicati o ns


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

A E/ S A E e val uati o n

If c o nse nt is pr o vi de d, c ollecti o n of sa m ples ( bl o o d [ Pa x ge ne D N A, Pa x ge ne R N A, 
a n d P B M C] a n d b uccal s wa b) o btai ne d bef ore d osi n g f or p har mac o ge n o mic a n d 
pr ote o mic deter mi nati o ns

A d mi nistrati o n of M E C or F L A G -I DA at t he st u d y  site.
N ote:  A d diti o nal st u d y  site visits are re q uire d f or s u bjects recei vi n g M E C ( Da ys 1 
t hr o u g h 5) or F L A G-I DA ( Da ys 1 t hr o u g h 6).  M E C a n d F L A G-I D A are 
a d mi nistere d f or u p t o 2 c ycles.

L o D A C s h o ul d be a d mi nistere d f or 1 0 da y s i n a 2 8-da y c y cle i n t he cli nic u nless 
arra n ge me nts ca n be ma de f or a d mi nistrati o n o utsi de of t he cli nic.  If d ose d o utsi de 
t he cli nic a re vie w of me dicati o n ret ur ne d a n d assess me nt of c o m plia nce m ust be 
c o n d ucte d at t he be gi n ni n g of eac h c y cle.
6. 2. 4. 2. 
C ycle 1, D a y 2 a n d D a y 8 ( ± 1 d a y)
T he f oll o wi n g acti vities will ta ke place d uri n g t hese visits:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate) bef ore d osi n g f or s u bjects recei vi n g F L A G-I D A o n Da y 2.  .  
All c he m ot hera p y s u bjects will ha ve 1 2 -lea d E C Gs (tri plicate) o n Da y 8.

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n

A d mi nistrati o n of M E C or F L A G -I DA at t he st u d y  site.
N ote:  A d diti o nal st u d y  site visits are re q uire d f or s u bjects recei vi n g M E C ( Da ys 1 
t hr o u g h 5) or F L A G-I DA ( Da y s 1 t hr o u g h 6).  M E C a n d F L A G-I D A are 
a d mi nistere d f or u p t o 2 c ycles.

L o D A C s h o ul d be a d mi nistere d f or 1 0 da y s i n a 2 8-da y c y cle i n t he cli nic u nless 
arra n ge me nts ca n be ma de f or a d mi nistrati o n o utsi de of t he cli nic.  If d ose d o utsi de 
t he cli nic a re vie w of me dicati o n ret ur ne d a n d assess me nt of c o m plia nce m ust be 
c o n d ucte d at t he be gi n ni n g of eac h c y cle.
6. 2. 4. 3. 
C ycle 1, D a y 1 5 ( ± 1 d a y)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

1 2 -lea d E C G (tri plicate) bef ore d osi n g 

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y  tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n
6. 2. 4. 4. 
C ycle 1, D a y 2 9 ( ± 1 4 d a ys)

B o ne marr o w as pirati o n a n d bi o ps y  f or deter mi nati o n of res p o nse f or hi g h i nte nsit y 
c he m ot hera p y ( M E C or F L A G-I D A).
6. 2. 4. 5. 
C ycle 2, D a y 1 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate) bef ore d osi n g f or s u bjects recei vi n g M E C a n d L o D A C 
(s u bjects recei vi n g F L A G-I D A will ha ve tri plicate E C Gs o n Da y 2 of eac h c ycle, 
i nstea d of Da y 1)

C ollecti o n of sa m ples o btai ne d bef ore d osi n g f or cli nical la b orat or y tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

M U G A sca ns or E C H O t o be perf or me d i n s u bjects recei vi n g F L A G- I D A bef ore 
d osi n g t o deter mi ne eli gi bilit y  f or a sec o n d c ycle 

A E/ S A E e val uati o n

B o ne marr o w as pirati o n a n d bi o ps y  f or deter mi nati o n of res p o nse f or L o D A C.  B o ne 
marr o w sa m ples are als o re q uire d Da y  1 of Cycle 3.  If a s u bject c o nti n ues t o recei ve 
L o D A C past C y cle 2, b o ne marr o w assess me nts will be re peate d o n Da y  1 of eac h 
s u bse q ue nt c ycle u nless t he s u bject has alrea d y ac hie ve d a C R, C R p, or C Ri.  I n t hat 
e ve nt, b o ne marr o w testi n g will be re peate d after e ver y  3 s u bse q ue nt c ycles, u nless 
t here is e vi de nce of rela pse.

L o D A C s h o ul d be a d mi nistere d f or 1 0 da y s i n a 2 8 da y c ycle i n t he cli nic u nless 
arra n ge me nts ca n be ma de f or a d mi nistrati o n o utsi de of t he cli nic.  If d ose d o utsi de 
t he cli nic a re vie w of me dicati o n ret ur ne d a n d assess me nt of c o m plia nce m ust be 
c o n d ucte d at t he be gi n ni n g of eac h c y cle.  Treat me nt wit h Lo D A C ma y  c o nti n ue past 
C y cle 2.  S u bse q ue nt c ycles will f oll o w sa me pr oce d ur es as C ycl e 2.

A d mi nistrati o n of M E C or F L A G -I DA at t he st u d y  site.
N ote:  A d diti o nal st u d y  site visits are re q uire d f or s u bjects recei vi n g M E C ( Da ys 1 
t hr o u g h 5) or F L A G-I DA ( Da y s 1 t hr o u g h 6).  M E C a n d F L A G-I D A are 
a d mi nistere d f or u p t o 2 c ycles.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
6. 2. 4. 6. 
C ycle 2, D a y 1 5 ( ± 3 d a ys)
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

1 2 -lea d E C G (tri plicate) bef ore d osi n g 

C ollecti o n of sa m ple s o btai ne d bef ore d osi n g f or cli nical la b orat or y tests 
( he mat ol o g y, c he mistr y, a n d uri nalys is)

A E/ S A E e val uati o n
6. 2. 5.  
Sc he d ule of Acti vities a n d Assess me nts after Tre at me nt
6. 2. 5. 1. 
E n d of Tre at me nt Visit
T he e n d of treat me nt visit s h o ul d occ ur wit hi n 7 da y s of t he last d ose of q uizarti ni b or 
c orres p o n d t o Da y 2 9 f or t he last c ycle of sal va ge c he m ot hera p y.  F or M E C or F L A G -I DA t he 
e n d of treat me nt visit w o ul d be C y cle 1 Da y 2 9 or C ycle 2 Da y 2 9.
F or s u bjects o n q uizarti ni b w h o disc o nti n ue treat me nt wit h t he o bjecti ve of pr ocee di n g t o H S C T, 
a q uizarti ni b e n d of treat me nt visit s h o ul d occ ur.  A d diti o nall y  s u bjects m o vi n g o nt o H S C T m ust 
ha ve a 3 0 Da y  F oll o w-u p p h o ne c o ntact.  S u bse q ue ntl y , if s u bject u n der g oes H S C T, restarts 
q uizarti ni b a n d later disc o nti n ues treat me nt, a p o st-H S C T e n d of treat me nt visit s h o ul d als o 
occ ur.
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit:

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Re vie w of c o nc o mita nt me dicati o ns

Ser u m pre g na nc y  testi n g f or wo me n of c hil d beari n g p ote ntial

1 2 -lea d E C G (tri plicate)

C ollecti o n of sa m ples f or cli nical la b orat or y  tests ( he mat ol o g y, c he mistr y, a n d 
uri nal y sis)

B o ne marr o w as pirati o n a n d bi o ps y  f or l ocal res p o nse deter mi nati o n are preferre d, 
b ut bi o ps y  ma y be o mitte d if t he as pirate is c o nsi dere d t o be a de q uate.  F or s u bjects 
recei vi n g c he m ot hera py res p o nse assess me nt ma y be at Da y 2 9 ± 1 4 da ys.

C ollecti o n of s peci me n f or e x pl orat or y  assess me nt of F L T 3 m utati o ns usi n g b o ne 
marr o w or w h ole bl o o d will be perf or me d (f or su bjects i n t he q uizarti ni b ar m o nl y ).  


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

If c o nse nt is pr o vi de d, c ollecti o n of bl o o d ( Pa x ge ne R N A) f or p har mac o ge n o mic a n d 
pr ote o mic deter mi nati o ns

A E/ S A E e val uati o n

Re vie w me dicati o n a n d assess me nt of c o m plia nce
N ote:  P h y sical e xa mi nati o n, vital si g n deter mi nati o ns, E C O G perf or ma nce stat us deter mi nati o n, 
a n d cli nical la b orat or y tests nee d n ot be re peate d if t he y were perf or me d at a re g ularl y sc he d ule d 
visit wit hi n 3 da y s of t he e n d of treat me nt visit.
6. 2. 5. 2. 
Cr oss -O ver Pr oce d ures
I n t he e ve nt t hat t he st u d y o utc o me de m o nstrates a cli nical be nefit t o s u bjects o n t he q uizarti ni b 
ar m, s u bjects w h o were ra n d o mize d t o sal va ge c he m ot hera p y ma y be eli gi ble t o cr oss -o ver t o 
treat me nt wit h q uizarti ni b. 
Eli gi ble s u bjects will be scree ne d as o utli ne d bel o w bef ore a s u bject ca n cr oss -o ver t o 
q uizarti ni b.  U nless ot her wise s pecifie d, scree ni n g pr oce d ures ca n be c o m plete d wit hi n 3 da y s of 
t he e n d of treat me nt visit t o deter mi ne t hat s u bjects meet i ncl usi o n criteria a n d d o n ot meet 
e xcl usi o n crit eria.  

Writte n i nf or me d c o nse nt

P h y sical e xa mi nati o n

Vital si g n deter mi nati o ns

E C O G perf or ma nce stat us e val uati o n

Assess me nt of pri or a n d c o nc o mita nt me dicati o ns 

Deter mi nati o n of c oa g ulati o n pr ofile ( P T/I N R)

1 2 -lea d tri plicate electr ocar di o gra m (E C G )

C ol lecti o n of sa m ples f or cli nical la b orat or y tests ( he mat ol o g y a n d c he mistr y)

A E/ S A E e val uati o n

Deter mi nati o n of s ur vi val a n d s u bse q ue nt a ntile u ke mic treat me nts a n d t heir o utc o mes
N ote: Cli nical la b orat or y tests nee d n ot be re peate d if t he y  were perf or me d wit hi n 3 da y s at t he 
E n d of T reat me nt visit, a n d 3 da ys pri or t o t he start of q uizarti ni b treat me nt. T here is n o was h o ut 
peri o d re q uire d bet wee n st o p pi n g sal va ge c he m ot hera p y a n d starti n g treat me nt wit h q uizarti ni b.
6. 2. 5. 3.  
3 0 -D a y F oll o w -U p
T he f oll o wi n g acti vities will ta ke place d uri n g t his visit f or s u bjects o n q uizarti ni b or sal va ge 
c he m ot hera p y.
F or s u bjects w h o disc o nti n ue q uizarti ni b wit h t he o bjecti ve of pr ocee di n g t o H S C T, a q uizarti ni b 
3 0 -Da y  F oll o w-u p visit s h o ul d occ ur.  A d diti o nall y  t hese s u bjects will be f oll o we d i n l o n g -ter m 
f oll o w-u p u ntil t he y  res u me q uizarti ni b d osi n g.  S u bse q ue ntl y, if s u bject u n der g oes H S C T, ta kes 
q uizarti ni b a n d e n ds treat me nt, a p ost- H S C T 3 0 -Da y  F oll o w- u p visit s h o ul d als o occ ur.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
F or s u bjects w h o disc o nti n ue sal va ge c he m ot hera p y a n d d o n ot q ualif y f or cr oss -o ver t o 
q uizarti ni b treat me nt, a 3 0-Da y  F oll o w-u p visit s h o ul d occ ur.  A d diti o nall y t hese s u bjects will be 
f oll o we d i n Lo n g -Ter m F oll o w - u p.
Tele p h o ne c o ntact wit h t he s u bject is s ufficie nt u nless a n y  assess me nt m ust be re peate d f or 
res ol uti o n of treat me nt-relate d A Es:

A E e val uati o n; S A E i nf or mati o n will be c ollecte d at a mi ni m u m of 7 da y s after t he 
e n d of treat me nt visit if t he s u bject u n der g oes H S C T.

Deter mi nati o n of s ur vi val a n d s u bse q ue nt a ntile u ke mic treat me nts a n d t heir o utc o mes

Re vie w of c o nc o mita nt me dicati o ns use d u p t o 3 0 -Da y  F oll o w- u p
6. 2. 5. 4. 
L o n g -Ter m F oll o w -U p
T he f oll o wi n g acti vities will ta ke place d uri n g L o n g -Ter m F oll o w - u p:

Deter mi nati o n of s ur vi val a n d s u bse q ue nt a ntile u ke mic treat me nts a n d t heir 
o utc o mes, e val uate d b y tele p h o ne c o ntact e ver y 3 m o nt hs
o
S u bjects w h o st o p pe d q uizarti ni b t o m o ve o nt o H S C T will be f oll o we d u ntil t he y  
res u me q uizarti ni b d osi n g

If direct c o ntacts are n ot p ossi ble d ue t o wit h dra wal of c o nse nt or t he s u bject bec o mes 
l ost t o f oll o w- u p, t he site must ma ke e ver y  eff ort t o c ollect s ur vi val stat us fr o m p u blic 
rec or ds (e g, deat h certificates) i n acc or da nce wit h l ocal la ws. See Secti o n 5. 4. 4 f or
f urt her details o n h o w s u bjects will be f oll o we d f or vital stat us if t he y wit h dra w 
c o nse nt.
6. 2. 6. 
E arl y Ter mi n ati o n/ E n d of St u d y
E ver y  eff ort s h o ul d be ma de t o c o nti n ue t o f oll o w s u bjects after treat me nt disc o nti n uati o n 
i ncl u di n g if treat me nt is decli ne d by t he s u bject.  If t he s u bject decli nes st u d y treat me nt bef ore 
recei vi n g a ny t reat me nt, t he reas o n f or decli ni n g treat me nt, a n d i nf or mati o n o n a n y a d diti o nal 
A M L  t hera p y s h o ul d be c ollecte d.  S u bjects s h o ul d c o nti n ue t o be f oll o we d at 3 m o nt hl y 
i nter vals f or a dditi o nal treat me nt, re missi o n stat us a n d s ur vi val i nf or mati o n.
S u bjects wit h dra w n fr o m t he st u d y  a n d st u dy f oll o w u p, or w h o wit h dra w c o nse nt after recei vi n g 
at least 1 st u d y dr u g d ose s h o ul d ret ur n t o t he st u d y site f or t he early ter mi nati o n/e n d of st u d y 
visit wit hi n 7 da y s ( ± 1 da y ) of t he wit h dra wal decisi o n.  T he f oll o wi n g acti vities will ta ke place 
d uri n g t his visit:

Re vie w of c o nc o mita nt me dicati o ns

A E/ S A E assess me nt

Re vie w of ret ur ne d st u d y me dicati o n a n d assess me nt of c o m plia nce, f or s u bjects 
recei vi n g q uizarti ni b or L o D A C
E ver y  eff ort m ust be ma de t o c o ntact t he s u bject a n d ha ve hi m or her ret ur n t o t he st u d y site f or 
t he early ter mi nati o n/e n d of st u d y visit.  If t he s u bject ca n n ot ret ur n t o t he site, t he reas o n f or a n d 
date of ter mi nati o n of t he s u bject’s partici pati o n i n t he st u d y  m ust be rec or de d o n t he a p pr o priate 
C R F.  If t he s u bject is wit h dra w n or wit h dra ws c o nse nt m ore t ha n 3 0 da y s after st u d y treat me nt 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
6 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
disc o nti n uati o n, tele p h o ne c o ntact is s ufficie nt a n d if p ossi ble, reas o n f or wit h dra wal, r e missi o n 
stat us, a n d i nf or mati o n o n a n y a d diti o nal A M L t hera p y s h o ul d be c ollecte d.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
7. 
E F FI C A C Y E V A L U A TI O N
Pri m ar y Effic ac y V ari a ble
T he pri mar y  efficac y varia ble is o verall s ur vi val, defi ne d as t he ti me fr o m ra n d o mizati o n u ntil 
deat h fr o m a n y ca use.  S u bject s ali ve or l ost t o f oll o w-u p at t he ti me of a nal y sis will be ce ns ore d 
at t he date w he n t he y were last k n o w n t o be ali ve.
Sec o n d ar y Effic ac y V ari a ble
T he sec o n dar y  varia ble is E F S, defi ne d as t he ti me fr o m ra n d o mizati o n u ntil d oc u me nte d 
refract or y disease, rela pse after C Rc, or deat h fr o m a n y ca use, w hic he ver is o bser ve d first.  
S u bjects ali ve wit h o ut treat me nt fail ure or rela pse or l ost t o f oll o w -u p at t he ti me of a nal ys is will 
be ce ns ore d at t he date of t heir last res p o nse assess me nt.
A d diti o n al Effic ac y V ari a bles

Le u ke mia -free s ur vi val is t he ti me fr o m t he first d oc u me nte d res p o nse ( C R, C R p, or 
C Ri) u ntil d oc u me nte d rela pse or deat h fr o m a n y ca use.  S u bjects ali ve wit h o ut 
rela pse or l ost t o f oll o w-u p at t he ti me of a nal ys is will be ce ns ore d at t he date of t heir 
last res p o nse assess me nt.

C o m p osite c o m plete re missi o n ( C Rc) rate is t he perce nt of s u bjects ac hie vi n g a best 
res p o nse of C R, C R p, or C Ri.

C o m plete re missi o n ( C R) rate is t he perce nt of s u bjects ac hie vi n g C R.

D urati o n of C Rc is t he ti me fr o m t he firs t d oc u me nte d C Rc ( C R + C R p + C Ri) u ntil 
d oc u me nte d rela pse.  S u bjects ali ve wit h o ut rela pse, l ost t o f oll o w -u p, or w h o ha ve 
die d wit h o ut re p ort of rela pse as of t he ti me of a nal y sis will be ce ns ore d at t he date of 
t heir last res p o nse assess me nt.

D urati o n o f C R is t he ti me fr o m t he first d oc u me nte d C R u ntil d oc u me nte d rela pse.  
S u bjects ali ve wit h o ut rela pse, l ost t o f oll o w- u p, or w h o ha ve die d wit h o ut re p ort of 
rela pse as of t he ti me of a nalys is will be ce ns ore d at t he date of t heir last res p o nse 
assess me nt .

Tra ns pla ntati o n rate ( bri d ge t o tra ns pla nt) is t he perce nt of s u bjects u n der g oi n g H S C T 
directl y  f oll o wi n g pr ot oc ol s pecifie d treat me nt wit h n o i nter ve ni n g A M L t hera p y.
7. 1. 
Met h o d of Assess me nt
B o ne marr o w as pirati o n a n d bi o ps y  f or m or p h ol o g y are preferre d, but bi o ps y  ma y be o mitte d if 
t he as pirate is c o nsi dere d t o be a de q uate.
F or s u bjects recei vi n g q uizarti ni b, b o ne marr o w sa m ples are re q uire d d uri n g Scree ni n g ( wit hi n 
1 4 da y s pri or t o t he first d ose of st u d y dr u g), Cycl e 2 Da y 1, Cycle 3 Da y 1, at t he e n d of
treat me nt st u d y visit, a n d as cli nicall y i n dicate d.  If t he s u bject has alrea d y ac hie ve d a C R, C R p, 
or C Ri, b o ne marr o w testi n g will be re peate d after e ver y  3 s u bse q ue nt c ycles.  A ce ntral 
la b orat or y will re vie w t he scree ni n g s peci me n t o c o nfir m t he dia g nosis.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
F or s u bjects recei vi n g sal va ge c he m ot hera p y, b o ne marr o w sa m ples are re q uire d at scree ni n g 
( wit hi n 1 4 da ys pri or t o t he first d ose of c he m ot hera p y), o n Da y 2 9 ± 1 4 da ys of Cycl e 1, o n 
Da y 2 9 ± 1 4 da y s Cycle 2, or as cli nicall y i n dicate d.  If a s u bjec t c o nti n ues t o recei ve L o D A C 
past C y cle 2, b o ne marr o w assess me nts will be re peate d o n Da y  1 of eac h s u bse q ue nt c ycle 
u nless t he s u bject has alrea d y ac hie ve d a C R, C R p, or C Ri.  I n t hat e ve nt, b o ne marr o w testi n g 
will be re peate d after e ver y 3 s u bse q ue nt c ycl es.
7. 2. 
Res p o nse Defi niti o ns
Res p o nse t o treat me nt will be defi ne d per m o difie d C hes o n criteria 1 8 as o utli ne d bel o w.
7. 2. 1. 
C o m plete Re missi o n ( C R)
F or s u bj ects t o be classifie d as bei n g i n C R, t he y  m ust ha ve b o ne marr o w re ge nerati n g n or mal 
he mat o p oietic cells a n d ac hie ve a m or p h ol o gic le u ke mia -free state ( < 5 % b o ne marr o w blasts i n 
b o ne marr o w, n o blasts wit h A uer r o ds a n d n o persiste nce of e xtra me d ullar y  disease) a n d m ust 
ha ve a n A N C > 1 × 1 0 9/ L a n d platelet c o u nt ≥1 0 0 × 1 0 9/ L a n d t he y will be R B C a n d platelet 
tra nsf usi o n i n de pe n de nt ( defi ne d as 4 wee ks wit h o ut R B C tra nsf usi o ns a n d 1 wee k wit h o ut 
platelet tra nsf usi o n).
7. 2. 2. 
C o m plete Re missi o n wit h I nc o m plete Pl atel et Rec o ver y ( C R p)
F or s u bjects t o be classifie d as bei n g i n C R p, t he y  m ust ac hie ve C R e xce pt f or i nc o m plete 
platelet rec o ver y  ( < 1 0 0 × 1 09/ L).
7. 2. 3.   
C o m plete Re missi o n wit h I nc o m plete He m at ol o gic al Rec o ver y ( C Ri)
F or s u bjects t o be classifie d as bei n g i n C Ri, t he y  m ust f ulfill all t he criteria f or C R e xce pt f or 
i nc o m plete he mat ol o gical rec o ver y wit h resi d ual ne utr o pe nia < 1 × 1 09/ L a n d/ or platelet c o u nt 
< 1 0 0 × 1 0 9/ L.  R B C a n d platelet tra nsf usi o n i n de pe n de nce is n ot re q uire d.   


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
7. 2. 4. 
P arti al Re missi o n
F or s u bjec ts t o be classifie d as bei n g i n P R, t he y m ust meet t he criteria f or C Ri b ut o nl y re q uire a 
decrease of at least 5 0 % i n t he perce nta ge of blasts i n t he b o ne marr o w wit h t he t otal marr o w 
blasts bet wee n 5 % a n d 2 5 % i ncl usi ve.
7. 2. 5. 
Rel a pse
Rela pse after C R, C R p, or C Ri is defi ne d as a rea p peara nce of le u ke mic blasts i n t he peri p heral 
bl o o d or ≥5 % blasts i n t he b o ne marr o w as pirate or bi o ps y  n ot attri b uta ble t o a n y ot her ca use or 
rea p peara nce or ne w a p peara nce of e xtra me d ullar y le u ke mia.
Rela pse after P R is si milarl y  defi ne d wit h rea p peara nce of si g nifica nt n u m bers of peri p heral 
blasts a n d a n i ncrease i n t he perce nta ge of blasts i n t he b o ne marr o w as pirate t o > 2 5 % n ot 
attri b uta ble t o a n y ot her ca use or rea p peara nce or ne w a p peara nce of e xtra me d ullar y le u ke mia.
7. 2. 6. 
Best Res p o nse
Best res p o nse is defi ne d as t he best meas ure d res p o nse ( C R, C R p, C Ri, P R, N R or U n k n o w n) at 
a n y ti me p ost pr ot oc ol s pecifie d treat me nt.  Res p o nse will be assesse d b y t he I n vesti gat or a n d 
deri ve d per t he m o difie d C hes o n criteria.
7. 2. 7. 
N o E vi de nce of Res p o n se ( N R)
F or s u bjects t o be classifie d as bei n g i n N R, t he y  m ust ha ve at least o ne e val ua ble b o ne marr o w 
as pirate or bi o ps y a n d n ot meet t he criteria f or P R or better. F or s u bjects w h o d o n ot ha ve 
e val ua ble b o ne marr o w as pirate or bi o ps y, b ut ha ve prese nce of le u ke mic blasts i n t he peri p heral 
bl o o d, t he res p o nse is c o nsi dere d as N R.
7. 3. 
O ver all S ur vi v al ( O S)
O verall s ur vi val is t he ti me fr o m ra n d o mizati o n u ntil deat h fr o m a n y ca use.
7. 4. 
E ve nt -Free S ur vi v al ( E F S)
E ve nt -free s ur vi val is t he ti me fr o m ra n d o mizati o n u ntil d oc u me nte d refract or y  disease, rela pse 
after C Rc, or deat h fr o m a n y ca use, w hic he ver is o bser ve d first.
7. 5. 
Le u k e mi a-Free S ur vi v al ( L F S)
Le u ke mia -free s ur vi val is t he ti me fr o m t he first d oc u me nte d res p o nse ( C R, C R p, C Ri) u ntil 
d oc u me nte d rela pse or deat h fr o m a n y ca use.
7. 6. 
C o m p osite C o m plete Re missi o n ( C Rc) R ate
C o m p osite c o m plete re missi o n ( C Rc) rate is t he perce nta ge of s u bjects ac hie vi n g a best res p o nse 
of C R, C R p, or C Ri.
7. 7. 
C o m plete Re missi o n ( C R) R ate
C o m plete re missi o n ( C R) rate is t he perce nta ge of s u b jects ac hie vi n g C R.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
7. 8. 
D ur ati o n of C Rc 
D urati o n of C Rc is t he ti me fr o m t he first d oc u me nte d C Rc ( C R + C R p + C Ri) u ntil d oc u me nte d 
rela pse.
7. 9. 
D ur ati o n of C R 
D urati o n of C R is t he ti me fr o m t he first d oc u me nte d c o m plete re missi o n ( C R) u ntil d oc u me nte d 
rela pse.
7. 1 0. 
Tr a ns pl a nt ati o n R ate
Tra ns pla ntati o n rate is t he perce nta ge of s u bjects u n der g oi n g H S C T directl y  f oll o wi n g pr ot oc ol 
s pecifie d treat me nt wit h n o i nter ve ni n g A M L t hera p y.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
8. 
S A F E T Y E V A L U A TI O N
All s u bjects recei vi n g at least 1 d ose of q uizarti ni b or sal va ge c he m ot h era p y will be e val ua ble 
f or safet y a n d defi ne d as t he Safety A nal ys is Set. Safet y will be assesse d wit h p h ysical 
e xa mi nati o ns, vital si g n deter mi nati o ns, 1 2- lea d E C Gs, A E e val uati o ns, a n d cli nical la b orat or y 
tests ( he mat ol o g y, ser u m c he mistr y, a n d uri nalys is res ults). T he safety data will als o be 
s u m marize d f or pre-defi ne d s u b -gr o u ps.
St u d y  dr u g t o xicit y will be assesse d c o nti n u o usl y.  A Es will be e val uate d d uri n g t he st u d y 
acc or di n g t o N CI C T C A E v 4. 0 3 u ntil 3 0 da y s after t he last d ose of st u dy t reat me nt.
S u bjects s h o ul d be i nstr ucte d t o re p ort a n y ne w A E or w orse ni n g of a n e xisti n g A E i m me diatel y.
8. 1. 
Me dic al Hist or y
Eac h s u bject’s me dical hist or y  m ust be o btai ne d at scree ni n g.  I nf or mati o n o n a n y pri or or 
e xisti n g me dical c o n diti o ns a n d/ or s ur gical pr oce d ures will be rec or de d o n t he a p pr o priate C R F.
8. 2. 
P h ysic al E x a mi n ati o n
A c o m plete p h ys ical e xa mi nati o n will be perf or me d at scree ni n g t o esta blis h a baseli ne f or st u d y 
e ntr y, a n d at a d diti o nal ti mes s pecifie d i n t he st u d y sc he d ule (Secti o n 5. 8 ).  W he ne ver p ossi ble, 
t he sa me i n di vi d ual will perf or m s u bse q ue nt e xa mi nati o ns t o i de ntif y c ha n ges fr o m baseli ne.  
S y m pt o m -directe d p h y sical e xa mi nati o ns perf or me d d uri n g t he treat me nt peri o d will be base d o n 
t he s u bject’s me dical hist or y a n d A Es, a n d will i ncl u de wei g ht deter mi nati o n a n d a re vie w of 
b o d y  sys te ms.
8. 3. 
Vit al Si g ns
Vital si g ns, i ncl u di n g s ys t olic a n d diast olic bl o o d press ures, p ulse rate, res pirat or y rate, a n d b o dy 
te m perat ure will be deter mi ne d a n d rec or de d at t he ti mes s pecifie d i n t he st u d y  sc he d ule 
(Secti o n 5. 8 ).  All vital si g n meas ure me nts s h o ul d be o btai ne d wit h s u bject’s s u pi ne f or at least 
5 mi n utes bef ore deter mi nati o n.  W he ne ver m ulti ple assess me nts are sc he d ule d at t he sa me ti me, 
t he y s h o ul d occ ur i n t he or der of E C Gs, vital si g n deter mi nati o ns, a n d bl o o d sa m ple c ollecti o n.
8. 4. 
Electr oc ar di o gr a ms
S u pi ne tri plicate 1 2 -lead E C Gs will be o btai ne d at t he ti mes s pecifie d i n t he st u d y  sc he d ule 
(Secti o n  5. 8).  A d diti o nal E C Gs ma y be o btai ne d at t he In vesti gat or’s discreti o n.  S u bjects 
u n der g oi n g d ose escalati o n d ue t o lac k of res p o nse or l oss of res p o nse after c y cle 2 da y 1 s h o ul d 
be m o nit ore d caref ull y f or Q T pr ol o n gati o n w hic h s h o ul d i ncl u de at least wee kl y E C Gs f or 
2 wee ks.
Electr ocar di o gra ms will be rec or de d i n tri plic ate ( 3 se parate E C Gs at least 3 mi n utes a part b ut 
prefera bl y n o m ore t ha n 5 mi n utes a part; t he a vera ge of t he 3 Q Tc F deter mi nati o ns will be use d 
t o deter mi ne safet y para meters a n d d ose escalati o n at Da y 1 6 da y of q uizarti ni b a d mi nistrati o n) 
a n d tra ns mitte d electr o nicall y t o a ce ntral E C G la b orat or y.  Electr ocar di o gra ms will be re vie we d 
b y  a s uita bly -q ualifie d p h y sicia n at t he st u d y site t o all o w i m me diate decisi o ns a b o ut s u bject 
safety.  W he n a n E C G a b n or malit y of c o ncer n is s us pecte d (e g, Q Tc F > 4 8 0 msec), t he site will 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
c o ntact t he ce ntral E C G la b orat or y  t o o btai n a n e x pe dite d ( wit hi n 2 4 h o urs) e val uati o n, a n d t he 
site will use t he ce ntral la b orat or y’s a nalys is f or decisi o ns o n c ha n ges i n s u bject care a n d 
pr ot oc ol c o m plia nce.  T he E C G s h o ul d be re peate d i n t ri plicate wit hi n 2 h o urs o n t he sa me da y 
f or a nalys is b y t he ce ntral la b orat or y.  Res ults of t he ce ntral E C G la b orat or y a nalys is will be t he 
fi nal data f or t he E C G data base.  Electr ocar di o gra ms will be s u b mitte d t o t he F D A E C G 
ware h o use, if re q uire d b y t he F D A.  Q Tc F d urati o n will be use d t o ma ke all decisi o ns base d o n 
Q T criteria.
G ui deli nes f or E C G m o nit ori n g are as f oll o ws:

Electr ocar di o gra ms will be o btai ne d after t he s u bject has reste d q uietl y  a n d is a wa ke 
a n d f ull y s u pi ne f or 1 0 mi n utes bef ore t he first of t he tri plicate E C Gs.

A d diti o nal E C Gs ca n be o btai ne d at a n y ti me if cli nicall y  i n dicate d.  It is i m p orta nt t o 
rec or d act ual cl oc k ti me f or eac h assess me nt.  T he tri plicate E C Gs will be rec or de d 
a n d t he a vera ge Q Tc F i nter val will be deter mi ne d f or eac h ti me p oi nt.
If cli nically si g nifica nt E C G c ha n ges fr o m baseli ne at scree ni n g are n ote d, t he c ha n ges will be 
rec or de d as A Es o n t he a p pr o priate C R F.  Cli nicall y si g nifica nt c ha n ges will be defi ne d as a n y 
E C G variati o ns t hat are me dicall y  si g nifica nt a nd c o ul d ca use a c ha n ge i n me dical care.  T he 
I n vesti gat or m ust c o nti n ue t o m o nit or t he s u bject u ntil a n y E C G c ha n ges ret ur n t o n or mal.
8. 5. 
M a n a ge me nt of Q T Pr ol o n g ati o n
Q uizarti ni b is k n o w n t o be ass ociate d wit h pr ol o n gati o n of t he Q T i nter val.  T o re d uce t he ris k of 
car diac arr h yt h mias, it is i m p orta nt t o mai ntai n ser u m electr ol yt es ( K + , Ca+ + , a n d M g+ + ) wit hi n 
n or mal ra n ge a n d i deall y mai ntai n K + a b o ve 4. 0 m E q/ L.  S u bjects i n t he q uizarti ni b ar m w h o 
e x perie nce Q Tc F pr ol o n gati o n ≥ Gra de 2 s h o ul d be ma na ge d acc or di n g t o t he g ui deli nes bel o w.

Gra de 2 ( Q Tc F a vera ge of tri plicate rea di n gs > 4 8 0 msec)

Electr ol yt es ( p otassi u m, calci u m a n d ma g nesi u m) s h o ul d be c hec ke d a n d
s u p ple me ntati o n gi ve n t o c orrect a ny val ues o utsi de t he n or mal ra n ge

C o nc o mita nt me dicati o ns s h o ul d be re vie we d t o i de ntif y  a n d, if a p pr o priate, 
disc o nti n ue a n y  me dicati o n wit h k n o w n Q T pr ol o n gi n g effects

T he d ose of q uizarti ni b will be re d uce d o ne le vel wit h o ut i nterr u pti o n of d osi n g

Q uizarti ni b d ose ma y  be re-escalate d after 1 c ycle at re d uce d d ose if Q T pr ol o n gati o n 
has decrease d t o ≤ Gra de 1 b ut s u bject m ust be m o nit ore d cl osel y f or 
Q T pr ol o n gati o n f or first c y cle at t he i ncrease d d ose.

Gra de 3 ( Q Tc F a vera ge of tri plicate rea di n gs > 5 0 0 msec)

Electr ol yt es ( p otassi u m, calci u m a n d ma g nesi u m) s h o ul d be c hec ke d a n d 
s u p ple me ntati o n gi ve n t o c orrect a ny val ues o utsi de t he n or mal ra n ge

C o nc o mita nt me dicati o ns s h o ul d be re vie we d t o i de ntif y  a n d, if a p pr o priate,
disc o nti n ue a n y  me dicati o n wit h k n o w n Q T pr ol o n gi n g effects

Q uizarti ni b d osi n g will be i nterr u pte d f or u p t o 1 4 da y s.  If Q Tc F ret ur ns t o wit hi n 
3 0 ms ec of baseli ne or ≤4 5 0 msec wit hi n 1 4 da y s, treat me nt ma y be res u me d at a 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
re d uce d d ose.  Q uizarti ni b d ose ca n n ot be escalate d f oll o wi n g d ose re d ucti o n f or 
Gra de 3 Q Tc F pr ol o n gati o n.

Gra de 4 ( Q Tc F a vera ge of tri plicate rea di n gs > 5 0 0 msec or > 6 0 msec c ha n ge fr o m 
baseli ne, a n d T orsa de de p oi ntes or p ol y m or p hic ve ntric ular tac h y car dia or 
si g ns/s ym pt o ms of seri o us arr h yt h mia)

Electr ol yt es ( p otassi u m, calci u m a n d ma g nesi u m) s h o ul d be c hec ke d a n d 
s u p ple me ntati o n gi ve n t o c orrect a ny val ues o utsi de t he n or mal ra n ge

C o nc o mita nt me dicati o ns s h o ul d be re vie we d t o i de ntif y  a n d, if a p pr o priate, 
disc o nti n ue a n y  me dicati o n wit h k n o w n Q T pr ol o n gi n g effects

Q uizarti ni b d osi n g will be per ma ne ntl y  disc o nti n ue d.
S u bjects w h o e x perie nce Gra de 2 or hi g her Q Tc F pr ol o n gati o n a n d u n der g o d ose i nterr u pti o n 
a n d/ or re d ucti o n m ust be m o nit ore d cl osel y  wit h re peat E C Gs t o e ns ure res ol uti o n of t he Q Tc F 
pr ol o n gati o n.  Q Tc F pr ol o n gati o n ≥ Gra de 3, eit her seri o us or n o n -seri o us a n d w het her or n ot 
ca usall y relate d, m ust be rec or de d as A E or S A E a n d re p orte d o n a S A E re p orti n g f or m wit hi n 
2 4 h o urs of a ware ness, wit h t he i n vesti gat or’s assess me nt o f seri o us ness, ca usalit y, a n d a 
detaile d narrati ve.
8. 6. 
Cli nic al L a b or at or y E v al u ati o ns
Ser u m c he mistr y , uri nalysis a n d he mat ol o g y tests will be perf or me d at t he ti me s pecifie d i n t he 
st u d y sc he d ule (Secti o n 5. 8 ).  A ce ntral la b orat or y will perf or m all tests u nless t his is n ot 
feasi ble, i n w hic h case a l ocal la b orat or y m a y be use d.
T he deter mi nati o ns i de ntifie d i n Ta ble 8 will be d o ne.




Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

E xacer bati o n of a c hr o nic or i nter mitte nt pre- e xisti n g c o n diti o n (e g, ast h ma), 
i ncl u di n g a n i ncrease i n fre q ue nc y a n d/ or se verity

Ne w c o n diti o n (e g, dia betes) detec te d or dia g n ose d after a d mi nistrati o n of t he 
me dici nal pr o d uct, e ve n t h o u g h it ma y  ha ve bee n prese nt pri or t o t he start of t he st u d y

Si g ns, s y m pt o ms, or cli nical se q uelae of a s us pecte d dr u g i nteracti o n

Si g ns, s y m pt o ms, or cli nical se q uelae of a s us pecte d o ver d ose of eit her t he 
i n vesti gati o nal pr o d uct or a c o nc o mita nt me dicati o n.
I n t his st u dy, A Es i ncl u de p ost -treat me nt e ve nts o nl y.
T he f oll o wi n g are n ot e xa m ples of A Es:

Me dical or s ur gical pr oce d ure.  T he c o n diti o n necessitati n g t he pr oce d ure is a n A E.

Si t uati o n wit h o ut a n y u nt o war d me dical occ urre nce (e g, h os pitalizati o n f or s ocial 
reas o ns or reas o ns of c o n ve nie nce; res pite care).

A ntici pate d da y -t o-d a y  fl uct uati o ns of a pre-e xisti n g disease or c o n diti o n t hat d oes 
n ot w orse n (e g, fl uct uati o n of bl o o d s u ga r wit hi n a certai n ra n ge).
A d verse e ve nts t hat occ ur i n s u bjects after t he y ha ve disc o nti n ue d q uizarti ni b t o u n der g o H S C T 
or ot her treat me nt f or A M L  a n d w hic h are rec o g nize d as d ue t o tra ns pla ntati o n or t he a d diti o nal 
A M L  treat me nt are n ot re q uire d t o be rec or de d.  If t he s u bject restarts q uizarti ni b p ost -H S C T, 
t he n all a d verse e ve nts w hile recei vi n g q uizarti ni b m ust be rec or de d.
8. 9. 
Seri o us A d verse E ve nt Defi niti o ns
A n S A E is a n y  A E, occ urri n g at a n y st u d y dr u g d ose a n d re gar dless of ca usalit y, wit h a ny of t he
f oll o wi n g o utc o mes:

Deat h

Life -t hreate ni n g

T he ter m ‘life -t hreate ni n g’ refers t o a n e ve nt i n w hic h t he s u bject was at i m me diate 
ris k of deat h fr o m t he reacti o n as it occ urre d.  It d oes n ot i ncl u de a reacti o n w hic h 
h y p ot heticall y  mi g ht ha ve ca use d deat h had it occ urre d i n a m ore se vere f or m.

I n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

“ H os pitalizati o n” mea ns t hat t he s u bject has bee n a d mitte d t o a h os pital or e mer ge nc y  
facilit y f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n a 
p h y sicia n’s office or o ut patie nt setti n g.  H os pital a d missi o ns or s ur ger y pla n ne d 
bef ore a n y st u d y dr u g is a d mi nistere d are n ot t o be c o nsi dere d A Es u nless t here is 
u ne x pecte d deteri orati o n of t he s u bject’s c o n diti o n after st u d y dr u g t reat me nt (e g, 
s ur ger y m ust be perf or me d earlier t ha n pla n ne d).

C o m plicati o ns occ urri n g d uri n g h os pitalizati o n are A Es.  If a c o m plicati o n pr ol o n gs 
h os pitalizati o n or f ulfills a n y  ot her criteria f or seri o us ness, t he c o m plicati o n bec o mes 
a n S A E.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
7 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

If t here is d o u bt w het her h os pitalizati o n occ urre d or was necessar y , t he ass ociate d A E 
s h o ul d be c o nsi dere d seri o us.

H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat has n ot 
w orse ne d is n ot c o nsi dere d t o be a n A E.

Persiste nt or si g nifica nt disa bilit y /i nca pacity

Disa bilit y /i nca pacit y is defi ne d as s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o 
perf or m n or mal life f u ncti o ns.  T his defi niti o n is n ot i nte n de d t o i ncl u de e ve nts of 
relati vely mi n or me dical si g nifica nce, s uc h as u nc o m plicate d hea d ac he, na usea, 
v o miti n g, i nfl ue nza, or acci de ntal tra u ma, w hic h ma y  i nterfere wit h or pre ve nt n or mal 
life f u ncti o ns b ut are n ot s u bsta ntial disr u pti o ns.

C o n ge nital a n o mal y/ birt h defect

I m p orta nt me dical e ve nt

Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns.  A n i m p orta nt me dical e ve nt is a n e ve nt 
t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n, b ut t hat 
ma y  be c o nsi dere d a n S A E w he n, base d o n a p pr o priate me dical j u d g me nt, it ma y  
je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne 
of t he o utc o mes liste d a b o ve.  E xa m ples of s uc h me dical e ve nts i ncl u de aller gic 
br o nc h os pas m re q uir i n g i nte nsi ve treat me nt i n a n e mer ge nc y facilit y or at h o me, 
bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
A n S A E re q uires a d diti o nal detaile d re p orts a n d f oll o w- u p.  Detaile d re p orts m ust a d dress t he 
I n vesti gat or’s esti mate of ca usalit y a n d w het her or n ot t he A E is i de ntifie d i n nat ure, se verit y, 
a n d fre q ue nc y i n t he I n vesti gat or’s Br oc h ure or i n ot her ris k i nf or mati o n t hat has bee n s u p plie d 
t o t he I nvesti gat or (e x pecte d ness).  S A Es m ust be rec or de d o n t he a p pr o priate C R F pa ge .
T he ter ms “seri o us” a n d “se vere” are n ot s y n o n y m o us.

T he ter m “se vere” is use d t o descri be t he se verit y of a s pecific e ve nt (s uc h as a mil d, 
m o derate, or se vere m y o car dial i nfarcti o n); t he e ve nt itself, h o we ver, ma y be of 
relati vely mi n or me dical si g nifica nce (s uc h as a se vere hea dac he).  T his is n ot t he 
sa me as “seri o us,” w hic h is base d o n t he criteria a b o ve a n d is us uall y ass ociate d wit h 
e ve nts t hat t hreate n a s u bject’s life or f u ncti o ni n g.

A se vere A E is n ot al wa ys c o nsi dere d seri o us i n a cli nical st u d y .  A n e ve nt is 
c o nsi dere d seri o us w he n it meets at least o ne of t he defi niti o ns a b o ve.  F or e xa m ple, 
na usea lasti n g se veral h o urs ma y  be c o nsi dere d se vere b ut n ot a n S A E.  H o we ver, a 
str o ke res ulti n g i n o nly mi n or disa bilit y  ma y be c o nsi dere d mil d, b ut w o ul d be 
c o nsi dere d a n S A E base d o n t he criteria a b o ve.

Seri o us ness, n ot se verit y,  is a g ui de f or defi ni n g re g ulat or y re p orti n g o bli gati o ns.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
8. 1 0. 
Pr oce d ures f or Rec or di n g a n d Re p orti n g A d verse E ve nts a n d 
Seri o us A d verse E ve nts Rec or di n g A Es a n d S A Es
All A Es s p o nta ne o usl y  re p orte d b y s u bjects a n d/ or re p orte d i n res p o nse t o a n o pe n q uesti o n fr o m 
st u d y pers o n nel, or re veale d b y o bser vati o n, p h ysical e xa mi nati o n, or ot her dia g n ostic pr oce d ure, 
will be rec or de d o n t he a p pr o priate C R F.  F or b ot h seri o us a n d n o n- seri o us A Es, t he I n vesti gat or 
m ust deter mi ne, base d o n cli nical j u d g me nt, b ot h t he se verit y of t he e ve nts a n d t heir relati o ns hi p 
t o st u d y treat me nt.  All Gra de 3 or 4 Q Tc F pr ol o n gati o ns (a vera ge of tri plicate E C G 
deter mi nati o n b y  ce ntral rea di n g) m ust be re p orte d t o t he S p o ns or wit h t he i n vesti gat or’s 
assess me nt of seri o us ness, ca usalit y , a n d a detaile d narrati ve.  T hese e ve nts, re gar dless of 
seri o us ness, s h o ul d be re p orte d wit hi n 2 4 h o urs of In vesti gat or’s a ware ness of t he e ve nt.
W he n a n A E or S A E occ urs, it is t he I n vesti gat or’s res p o nsi bilit y  t o re vie w all d oc u me ntati o n 
rele va nt t o t he e ve nt (e g, h os pital pr o gress n otes; la b orat or y a n d dia g n ostic re p orts).  T he 
I n vesti gat or will t he n rec or d all rele va nt inf or mati o n re gar di n g t he e ve nt o n t he a p pr o priate C R F.  
All A Es a n d S A Es m ust be rec or de d, re gar dless of t heir relati o ns hi p t o st u d y  treat me nt.  It is n ot 
acce pta ble f or t he I n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical rec or ds t o t he 
S p o ns or i n place of pr o per C R F c o m pleti o n.  H o we ver, t here ma y  be i nsta nces w he n c o pies of 
me dical rec or ds are re q ueste d.  I n s uc h i nsta nces, all i nf or mati o n i de ntif y i n g t he s u bject will be 
re dacte d bef ore t heir s u b missi o n.
T he I n vesti gat or will als o atte m pt t o est a blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, 
a n d/ or ot her cli nical i nf or mati o n.  In s uc h cases, t he dia g n osis, a n d n ot t he si g ns or s y m pt o ms, 
s h o ul d be d oc u me nte d as t he A E or S A E.
8. 1 0. 1. 
Dise ase -s pecific A Es a n d S A Es
Disease pr o gressi o n/ w orse ni n g of A M L s h o ul d n ot be rec or de d as a n a d verse e ve nt.  H o we ver, 
e ve nts ass ociate d wit h disease pr o gressi o n, s uc h as t hr o m b oc y t o pe nia, ma y be rec or de d as A E.
Deat h d ue t o disease pr o gressi o n s h o ul d n ot be rec or de d as a d verse e ve nt or seri o us a d verse 
e ve nt a n d s h o ul d be rec or de d o n t he o utc o mes case re p ort f or m ( C R F).
8. 1 0. 2. 
Assess me nt of Se verit y
T he I n vesti gat or m ust deter mi ne t he se verit y  of b ot h seri o us a n d n o n-seri o us A Es, base d o n 
cli nical j u d g me nt.  T he se verit y of eac h A E, i ncl u di n g a n y a b n or mal la b orat or y test res ult, will 
be deter mi ne d usi n g C T C A E v 4. 0 3.  W he n C T C A E v 4. 0 3 criteria d o n ot a p pl y , se verity will be 
defi ne d acc or di n g t o t he f oll o wi n g criteria:
Mil d
T he e ve nt, si g n, a n d/ or s y m pt o m is easil y  t olerate d b y t he 
s u bject, ca usi n g mi ni mal disc o mf ort a n d n ot i nterferi n g wit h 
n or mal dail y acti vities ( Gra de 1)
M o derate
T he e ve nt ca uses s ufficie nt disc o mf ort t o i nterfere wit h n or mal 
dail y  acti vities ( Gra de 2)
Se vere
T he e ve nt pre ve nts t he s u bject fr o m perf or mi n g n or mal dail y  
acti vities ( Gra de 3)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
Life -t hreate ni n g 
T he e ve nt places t he s u bject at i m me diate ris k of deat h 
( Gra de 4)
Deat h
T he e ve nt res ults i n t he s u bject’s deat h ( Gra de 5)
8. 1 0. 3. 
Assess me nt of C a us alit y
T he I n vesti gat or m ust deter mi ne t he relati o ns hi p of eac h A E a n d S A E t o st u d y  treat me nt.  T he 
I nvesti gat or will use cli nical j u d g me nt t o deter mi ne t his relati o ns hi p.  Ot her ca uses, s uc h as 
c o nc urre nt me dicati o n or ill ness, ot her ris k fact ors, a n d t he e ve nt’s te m p oral relati o ns hi p t o st u d y  
treat me nt, will be c o nsi dere d.  T he I n vesti gat or will als o c o ns ult t he In vesti gat or’s Br oc h ure 
a n d/ or ot her pr o d uct la beli n g i nf or mati o n pr o vi de d b y  t he S p o ns or.
T here ma y  be sit uati o ns w he n a n S A E occ urs wit h mi ni mal i nf or mati o n f or t he i nitial re p ort.  
H o we ver, it is ver y  i m p orta nt t hat t he I n vesti gat or assess ca usalit y of e ver y S A E bef ore re p orti n g 
t he e ve nt.  T he I n vesti gat or ma y c ha n ge his or her o pi ni o n of ca usalit y i n li g ht of f oll o w- u p 
i nf or mati o n a n d a me n d t he S A E re p ort.  T he ca usalit y assess me nt is o ne of t he m ost i m p orta nt 
ite ms f or re g ulat or y re p orti n g a nd s h o ul d n ot be left u n d o ne.
Relati o ns hi p of a n A E or S A E t o st u d y  treat me nt will be defi ne d acc or di n g t o t he f oll o wi n g 
criteria:
Defi nite 
T here is a clear te m p oral relati o ns hi p t o st u d y  treat me nt, wit h n o ot her 
p ossi ble ca use.
P ossi ble 
A te m p oral relati o ns hi p t o st u d y treat me nt is n ot clear, a n d alter nati ve 
eti ol o gies are p ossi ble.
N ot Relate d 
T here is n o te m p oral relati o ns hi p t o st u d y  treat me nt, a n d/ or t here is 
e vi de nce of a n alter nati ve ca use s uc h as a c o nc urre nt me dicati o n or 
ill ness.
All u ne x pecte d e ve nts are e ve nts t hat are n ot i de ntifie d i n t he I nvesti gat or’s Br oc h ure .
8. 1 0. 4. 
S A E Re p orti n g
E ver y  S A E occ urri n g d uri n g t he st u d y, as defi ne d a b o ve, m ust be re p orte d b y t he I n vesti gat or t o 
t he S p o ns or’s desi g nate d c o ntact as s o o n as p ossi ble, b ut n o later t ha n wit hi n 1 w or ki n g da y  
fr o m t he ti me w he n t he I n vesti gat or bec o mes a ware of t he S A E.  All S A Es a n d deat hs m ust be 
re p orte d, w het her or n ot t he y are c o nsi dere d t o be ca usally relate d t o st u d y treat me nt.  S A E 
re p orti n g f or ms will be pr o vi de d t o eac h st u d y site.  A d diti o nall y , Q Tc F pr ol o n gati o n ≥ Gra de 3, 
eit her seri o us or n o n -seri o us a n d w het her or n ot ca usall y relate d m ust be re p orte d b y t he 
I n vesti gat or wit hi n 2 4 h o urs of a ware ness.  T he i nf or mati o n rec or de d o n t hese f or ms will i ncl u de 
at least t he f oll o wi n g:

S u bject n u m ber

I de ntit y of t he e ve nt

St u d y  dr u g na me a n d d ose


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

Narrati ve of t he e ve nt

I n vesti gat or’s assess me nt of t he e ve nt’s se verity a n d relati o ns hi p t o st u d y treat me nt

I n vesti gat or’s na me a n d si g nat ure
If seri o us, u ne x pecte d a d verse dr u g reacti o ns occ ur, t he S p o ns or will n otif y t he a p pr o priate 
re g ulat or y a ge nc y or a ge ncies a n d all partici pati n g I n vesti gat ors o n a n e x pe dite d basis.
All S A Es will be m o nit ore d u ntil t he y  ha ve res ol ve d or are clearly deter mi ne d t o res ult fr o m a 
c hr o nic or i nt erc urre nt c o n diti o n.
I n t he case of a n S A E , t he i n vesti gat or m ust c o ntact t he S p o ns or b y tele p h o ne or fa x i m me diatel y 
( wit hi n 2 4 h o urs of a ware ness).  T he i n vesti gat or s h o ul d c o m plete a n d s u b mit a n S A E 
W or ks heet c o ntai ni n g all i nf or mati o n t hat is re q uire d b y  t he Re g ulat or y A ut h orities t o t he 
S p o ns or or desi g nee b y fa x i m me diatel y  ( wit hi n 2 4 h o urs of a ware ness).
If t he fa xi n g of a n S A E W or ks heet is n ot p ossi ble or is n ot p ossi ble wit hi n 2 4 h o urs, t he l ocal 
dr u g safet y c o ntact s h o ul d be i nf or me d b y p h o ne.  F o r c o ntact details see t he St u d y Refere nce 
Ma n ual f or i nter nati o nal n u m ber access.  Please fa x or e mail t he S A E W or ks heet t o:
N o vella Cli nical Safet y Ma na ge me nt
U S safet y h otli ne:  
U S fa x n u m ber:  
E- mail:  
If t here are a ny q uesti o ns, or if clarificati o n is nee de d re gar di n g t he S A E, please c o ntact t he 
S p o ns or's Me dical M o nit or or desi g nee (see c o ntact details of ke y  S p o ns or’s Pers o n nel i n t he 
St u d y  Refere nce Ma n ual).  F oll o w-u p i nf or mati o n f or t he e v e nt s h o ul d be se nt pr o m ptl y 
( wit hi n 7 da y s) as necessar y.
T he S p o ns or or S p o ns or's desi g nee will s u b mit e x pe dite d safet y re p orts (ie, I N D Safet y Re p orts) 
t o t he Re g ulat or y A ge ncies (ie, F D A) as necessar y, a n d will i nf or m t he i n vesti gat ors of s uc h 
re g ulat ory re p orts.  I n vesti gat ors m ust s u b mit safet y re p orts as re q uire d b y t heir IR B /I E C wit hi n 
ti meli nes set b y re gi o nal re g ulati o ns (ie, E U H As, F D A).  D oc u me ntati o n of t he s u b missi o n t o 
a n d recei pt b y t he I R B / I E C of e x pe dite d safety re p orts s h o ul d be retai n e d b y t he site.
T he I n vesti gat or ma y  c o ntact t he S p o ns or's Me dical M o nit or f or a n y ot her pr o ble m relate d t o t he 
safety, welfare, or ri g hts of t he st u d y partici pa nt (s u bject/ patie nt).
F ull details of t he S A E s h o ul d als o be rec or de d o n t he me dical rec or ds a n d o n t he C R F.
T he f oll o wi n g mi ni m u m i nf or mati o n is re q uire d:

St u d y  n u m ber

S u bject n u m ber, se x a n d a ge

T he date of re p ort

A descri pti o n of t he S A E (e ve nt, seri o us ness of t he e ve nt)

Ca usal relati o ns hi p t o t he st u d y  dr u g


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
9. 
P H A R M A C O KI N E TI C S
Bl o o d sa m ples f or mea s ure me nt of q uizarti ni b a n d t he acti ve meta b olite, A C 8 8 6, plas ma 
c o nce ntrati o ns will be o btai ne d fr o m all s u bjects ra n d o mize d t o recei ve q uizarti ni b o n Da y 1 a n d 
Da y  1 5 of Cycle 1 bef ore d osi n g a n d 1, 2, 4, 6, a n d 2 4 h o urs after d osi n g.  T he 2 4 -h o ur sa m ple s 
m ust be c ollecte d bef ore q uizarti ni b d osi n g o n Da y  2 a n d Da y 1 6.  Sa m ples will als o be c ollecte d 
o n Da y  8 of Cycle 1 bef ore d osi n g a n d 2 t o 4 h o urs (ta ke n i m me diatel y after E C G) after d osi n g.  
T hereafter, sa m ples will be c ollecte d bef ore d osi n g a n d 2 t o 4 h o urs (ta ke n i m me diatel y  after 
E C G) after d osi n g o n Da y  1 of Cycl es 2 a n d 3.  At eac h ti me p oi nt, 2 m L of bl o o d will be 
c ollecte d.  Pre -d ose sa m ples s h o ul d be ta ke n wit hi n 0. 5 h o urs bef ore dr u g a d mi nistrati o n.
T he 1, 2, 4, a n d 6 h o ur p ost d ose sa m ples s h o ul d be ta ke n wit hi n ± 0. 5 h o urs of n o mi nal ti me.
T he 2 4 h o ur p ost d ose sa m ples s h o ul d be ta ke n wit hi n ± 3 h o urs of n o mi nal ti me a n d bef ore 
a d mi nistrati o n of t he ne xt d ose.
Bl o o d sa m pli n g, pr ocessi n g, st ora ge a n d s hi p me nt i nstr ucti o ns are pr o vi de d i n t he la b ma n ual.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 0. 
P H A R M A C O G E N O MI C S A N D P H A R M A C O P R O T E O MI C S
O n Da y  1, a b uccal s wa b a n d w h ole bl o o d sa m ples ( Pa x ge ne D N A, Pa x ge ne R N A, a n d P B M C) 
will be c ollecte d a n d s hi p pe d t o a ce ntral la b orat or y .  T he P G X/ P P X sa m ples will be st ore d f or 
u p t o 1 5 y ears, at w hic h ti me t he y will be destr o ye d.  P G X/ P P X researc h ma y  be c o n d ucte d t o 
e x pl ore P K a n d safet y e n d p oi nts d uri n g t his st u d y or after t he c o ncl usi o n of t his st u d y .  T he 
res ults of t he ge netic a n d pr ote o mic a nalys is will n ot be pr o vi de d t o s u bjects or t he I n vesti gat or.  
A n y  i nf or mati o n o btai ne d fr o m t he P G X/ P P X researc h will be t he pr o pert y of t he S p o ns or.  
C ollecti o n of t hese sa m ples is n ot ma n dat or y  f or partici pati o n i n t his st u d y.
1 0. 1. 
F L T 3 -I T D M ut ati o n Ass a y
Of n ote, a c o m pa ni o n dia g n ostic is bei n g de vel o pe d b y  Na vi gate f or t he U S a n d E ur o pea n U ni o n 
(E U ) t hat will all o w deter mi nati o n of F L T 3-I T D m utati o n stat us fr o m bl o o d a n d/ or b o ne marr o w 
sa m ples.  T he F L T 3 -I T D M utati o n Assa y is a p ol ymerase c hai n reacti o n ( P C R)-base d m olec ular 
assa y f or detecti n g F L T 3-I T D m utati o ns utilizi n g ge n o mic D N A is olate d fr o m bl o o d or b o ne 
marr o w.  T he I T D m utati o n al wa ys occ urs i n e x o ns 1 4 a n d 1 5 of t he F L T 3 ge ne, w hic h i ncl u des 
t he j u xta me mb ra ne d o mai n a n d t he N-ter mi nal part of the ki nase d o mai n.  T his re gi o n, w he n 
a m plifie d b y P C R usi n g a si n gle set of D N A pri mers t hat fla n k t he re gi o n, yiel ds I T D m uta nt 
reacti o n pr o d ucts t hat are greater i n size t ha n t he 3 3 0-base pair n o n -m uta nt (I T D wil d t y pe) 
pr o d uct.  T he F L T 3 -I TD M utati o n As sa y uses a fra g me nt size a nal ysis met h o d t o res ol ve a n d 
detect t he differe nt -size d P C R pr o d ucts b y ca pillar y electr o p h oresis.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 1. 
P H A R M A C O E C O N O MI C S
Res o urce all ocati o n will be s u m marize d a n d c o m pare d bet wee n st u d y ar ms.  T he f oll o wi n g 
varia bles will be meas ure d t o assess res o urce utilizati o n i n t his st u d y :

C o nc o mita nt me dicati o ns a n d pr oce d ures

H os pitalizati o ns

U nsc he d ule d cli nic visits

E mer ge nc y  r o o m visits

S kille d n ursi n g facilit y care

H os pice care


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 2. 
D A T A Q U A LI T Y A S S U R A N C E
T his st u d y  will be or ga nize d, perf or med, a n d re p orte d i n c o m plia nce wit h t he S p o ns or’s a n d t he 
cli nical researc h or ga nizati o n's ( C R O ’s) sta n dar d o perati n g pr oce d ures a n d w or ki n g practice 
d oc u me nts, a n d wit h I C H g ui deli nes. C o m plia nce will be ac hie ve d b y  st u d y-s pecific m o nit ori n g 
of st u d y  sites, a n d by re g ular a u dits of t he C R O's s yste ms f or ha n dli n g, re p orti n g, a n d arc hi vi n g 
data.
T he C R Fs will be c o m pare d t o s o urce d oc u me nts a n d re vie we d at t he st u d y site f or c o m plete ness 
b y  a cli nical m o nit or.  If necessar y, t he st u d y site will be c o ntacte d for c orrecti o ns a n d/ or 
clarificati o n.  All data will be mai ntai ne d i n a st u d y data base f or a nal ysis a n d re p orti n g.  Data 
ca pt ure d electr o nicall y will be electr o nicall y tra nsferre d t o t he data base.  T he data base will 
recei ve a q uality ass ura nce c hec k t o e ns ure acce pta ble acc urac y  a n d c o m plete ness.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 3. 
S T A TI S TI C A L M E T H O D S P L A N N E D I N T H E P R O T O C O L A N D 
D E T E R MI N A TI O N O F S A M P L E SI Z E
1 3. 1. 
Ge ner al C o nsi der ati o ns
T his st u d y  is desi g ne d t o c o m pare t he effect or q uizarti ni b m o n ot hera p y a n d sal va ge 
c he m ot hera p y o n o verall s ur vi v al i n s u bjects wit h F L T 3-I TD( +) A M L t hat is refract or y  or 
rela pse d wit hi n 6 m o nt hs after first-li ne t hera py wit h or wit h o ut c o ns oli dati n g H S C T.
1 3. 2. 
S u bject Dis p ositi o n, De m o gr a p hics, a n d Dr u g A d mi nistr ati o n
A n acc o u nti n g of all s u bjects ra n d o mize d t o t he st u d y will be re p orte d.  De m o gra p hics, 
dis p ositi o n i ncl u di n g reas o ns f or wit h dra wal, a d mi nistrati o n of q uizarti ni b a n d sal va ge 
c he m ot hera p y, a n d maj or pr ot oc ol vi olati o ns will be ta b ulate d a n d s u m marize d wit h descri pti ve 
statistics f or all ra n d o mize d s u bjects. Maj or pr ot oc ol vi olati o ns will be i de ntifie d i n listi n gs.
1 3. 3. 
S a m ple Size Deter mi n ati o n
Calc ulati o n of sa m ple size is base d o n c o m paris o n of O S, t he pri mar y  efficac y e n d p oi nt, i n t he 
2 treat me nt gr o u ps ( q uizarti ni b a n d sal va ge c he m ot hera py) at a 2-si de d si g nifica nce le vel 
of 0. 0 5, ass u mi n g t hat me dia n s ur vi val is 3. 9 m o nt hs i n t he sal va ge c he m ot hera p y gr o u p wit h a n 
i ncrease t o 6 m o nt hs, i n t he q uizarti ni b gr o u p ( hazar d rati o 0. 6 5).  A t otal of 2 8 0 e ve nts ( deat hs) 
are necessar y t o meet a p o wer re q uire me nt of 9 0%, gi ve n a n i nteri m a nal ysis pla n ne d at 1 4 0 
e ve nts ( deat hs) wit h O’ Bria n- Fle mi n g b o u n dar y  f or s u peri or efficac y a n d a c o n diti o nal p o wer 
( C P) of 1 0 % f or f utilit y.  F or t he p ur p ose of sa m ple size calc ulati o n, s u bjects are ass u me d t o be 
accr ue d at a rate of 1 9. 2 per m o nt h wit h a dr o p - o ut rate of 1 0 %.  T he tar get accr ual is a t otal of 
a p pr o xi matel y 3 6 3 s u bjects ra n d o mize d i n a 2: 1 rati o ( 2 4 2 s u bjects i n t he q uizarti ni b gr o u p a n d 
1 2 1 i n t he sal va ge c he m ot hera p y gr o u p) o ver 1 7 m o nt hs, t o reac h re q uire d n u m ber of e ve nts i n a 
reas o na ble ti mefra me a n d t o c o m pe nsate f or dr o p-o uts.  All calc ulati o ns f or sa m ple size were 
perf or me d usi n g East ® 6. 3. 
O ne f or mal i nteri m a nal ysis will be perf or me d b y a n i n de pe n dent S A C a n d e val uate d b y  a n 
i n de pe nde nt D M C acc or di n g t o statis tical pr oce d ures defi ne d a pri ori. At t he i nteri m a nalys is, 
t he D M C ma y rec o m me n d 3 p ote ntial st u d y o pti o ns:  ( 1) t he st u d y s h o ul d be st o p pe d d ue t o 
f utilit y; ( 2) t he st u d y s h o ul d be st o p pe d f or s u peri or efficac y i n t he q uizarti ni b ar m; or ( 3) t he 
st u d y s ho ul d c o nti n ue as pla n ne d t o t he t otal tar gete d n u m ber of 2 8 0 e ve nts.
It will be i m p ossi ble t o bli n d treat me nt all ocati o ns f or i n di vi d ual s u bjects beca use of differe nt 
treat me nt a d mi nistrati o n sc he d ules a n d a d verse e ve nts bet wee n t he 2 st u d y ar ms.  H o we ver, t he 
pri mar y  e n d p oi nt of s ur vi val is a r o b ust e n d p oi nt a n d n ot s usce pti ble t o bias res ulti n g fr o m lac k 
of bli n di n g.  A d diti o nall y, t he S p o ns or will n ot ha ve access t o a g gre gate efficac y  data e xce pt 
w he n data fr o m b ot h treat me nt a n d c o ntr ol ar ms are c o m bi ne d. I n a d diti o n, data relati n g t o t he 
pri mar y  e n d p oi nt of s ur vi val will be restricte d s o t hat t he S p o ns or will n ot ha ve access t o f oll o w 
u p data o n i n di vi d ual s u bjects after 3 0 da y s of disc o nti n ui n g st u d y treat me nt.  A p pr o xi matel y 
8 0 % of e ve nts will occ ur i n t his l o n g ter m f oll o w u p peri o d a n d s o t he S p o ns or will be bli n de d t o 
t he pri mar y e n d p oi nt of t he st u d y.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
Ra n d o mizati o n will be stratifie d b y pri or t hera p y a n d res p o nse, a n d pre -selecte d sal va ge 
c he m ot hera p y:
Pri or t hera p y a n d res p o nse:

Rela pse d i n ≤ 6 m o nt hs ( n ot p ost H S C T)

Refract or y

Rela pse d i n ≤ 6 m o nt hs p ost all o ge neic H S C T


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
8 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
Pre -selecte d c he m ot hera p y, e ve n f or s u bjects s u bse q ue ntl y ra n d o mize d t o q uizarti ni b:

Hi g h i nte nsit y  c he m ot hera p y ( M E C; F L A G-I D A)

L o w i nte nsit y c he m ot hera p y ( L o D A C)
1 3. 4. 
Pri m ar y Effic ac y A n al ysis
Pri mar y  efficac y a nalys is will ta ke place after t he re q uire d n u m ber of e ve nts ( deat hs), 1 4 0 e ve nts 
( deat hs) at t he i nteri m a nal ysis or 2 8 0 e ve nts ( deat hs) at t he fi nal a nal ysis, has occ urre d. 
T he pri mar y  efficac y e n d p oi nt ( O S) a nalys is will be base d o n t he stratifie d l o g-ra n k test.  T he 
stratificati o n fact ors will be t h ose use d f or ra n d o mizati o n.  A n o n-stratifie d l o g-ra n k test will be 
use d as s u p p orti ve e vi de nce of efficac y .  T hese a nal yses will be perf or me d o n t he i nte nt-t o-treat 
(I T T) a nal ys is data set, c o nsisti n g of data fr o m all s u bjects ra n d o mize d.
Ka pla n - Meier met h o ds will be use d t o esti mate O S i n eac h treat me nt gr o u p, b ot h o verall a n d 
wit hi n s u bsets of s u bjects defi ne d b y t he stratificati o n fact ors.  Esti mates of me dia n s ur vi val w ill 
be pr o vi de d wit h 9 5 % c o nfi de nce i nter vals.  Hazar d rati o esti mates will als o be prese nte d.
O verall s ur vi val will be ce ns ore d at t he last date w he n s u bjects were k n o w n t o be ali ve. F or 
pri mar y  a nalys is, o verall s ur vi val will n ot be ce ns ore d at t he ti me of s u bse q ue nt n o n pr ot oc ol 
A M L  t hera p y, i ncl u di n g tra ns pla ntati o n.
Se nsiti vit y  a nal yses of O S will be perf or me d b y i m ple me nti n g a n a d diti o nal ce ns ori n g r ule:  
ce ns ori n g at t he date of H S C T f or all s u bjects w h o ha ve u n der g o ne H S C T.  T he se nsiti vit y  
a nal ys es will be descri be d i n detail i n t he statistical a nal ys is pla n.  T he pri mar y efficac y a nalys is 
will be re peate d f or t he per pr ot oc ol set ( P P S), w hic h i ncl u des all s u bjects w h o are ra n d o mize d 
a n d ha ve n o maj or pr ot oc ol de viati o ns.
Pr ot oc ol de viati o ns will be re vie we d i n a bli n de d fas hi o n a n d cate g orize d as maj or or mi n or 
bef ore t he i nteri m a nal ys is a n d data base l oc k a n d will be d oc u me nte d i n a me m o.
1 3. 5. 
Sec o n d ar y Effic ac y A n al ysis
T he sec o n dar y  efficac y e n d p oi nt of E F S will be a nal yze d usi n g t he stratifie d l o g-ra n k test wit h 
c o variates t o c o ntr ol f or res p o nse t o first -li ne A M L t hera p y a n d pre-selecte d sal va ge 
c he m ot hera p y i n t he I T T.  T o mai ntai n t he o verall t ype 1 err or rate at t he 0. 0 5 si g nifica nce le vel, 
h y p ot hesis testi n g i n t he sec o n dar y  a nalys is will be perf or me d o nl y if t he n ull h y p ot hesis i n t he 
pri mar y  a nalys is is rejecte d at t he o verall t w o-si de d 0. 0 5 si g nifica nce le vel.
A nal y sis of t he sec o n dar y efficac y e n d p oi nt will be re peate d f or t he P P S.
1 3. 6. 
S u b -gr o u p A n al yses
T he pri mar y  efficac y e n d p oi nt ( O S) a nd sec o n dar y  efficac y e n d p oi nt ( E F S) will be a nalyz e d f or 
eac h s u b -gr o u p defi ne d acc or di n g t o t he f oll o wi n g:

A ge ( < 6 0, a n d ≥6 0 y ears)

A ge ( < 6 5 ye ars, ≥ 6 5 t o  < 7 5 years, a n d ≥ 7 5 years )

Se x at birt h ( male, a n d fe male)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

Race ( W hite, Blac k or Africa n A merica n, Asia n, a n d Ot her)

Et h nicit y  ( His pa nic or Lati n o, N o n-His pa nic or Lati n o)

Ge o gra p hical re gi o n ( N ort h A merica, E ur o pe a n d A ustralia, a n d Rest of W orl d) 

Stratificati o n fact ors fr o m ra n d o mizati o n (res p o nse t o pri or t hera p y a n d pre-selecte d 
sal va ge t hera py, s e paratel y)

F L T 3 -I TD allelic b ur de n ( usi n g ce ntral testi n g) at ra n d o mizati o n > 5 0 %, > 2 5 % t o 
5 0 %, a n d ≤2 5 %)

De n o v o A M L a n d sec o n dar y  A M L

Pri or all o ge neic H S C T ( y es a n d n o)

A M L  c yt o ge netic ris k sc ore (fa v ora ble, i nter me diate, u nfa v ora ble, a n d u n k n o w n ris k)

Blast c o u nt at baseli ne (less t ha n me dia n a n d greater t ha n or e q ual t o me dia n)
1 3. 7. 
A d diti o n al Effic ac y A n al yses
Statistical a nal y ses of e x pl orat or y efficac y e n d p oi nts i ncl u de:

Ka pla n -Meier a nal y sis of d urati o n of C Rc a n d C R

C oc hra n -Ma ntel -Hae nszel ( C M H) test of C R rate

C M H test of C Rc rate

C M H test of tra ns pla ntati o n rate
1 3. 8. 
S afet y A n al ysis
T he safet y a nal ys is set ( S A F) i ncl u des all s u bjects recei vi n g at least 1 d ose of st u d y treat me nt 
( q uizarti ni b or sal va ge c he m ot hera py).
Safet y  e val uati o n will be base d mai nl y o n A Es, cli nical la b orat or y test res ults, p h ysical 
e xa mi nati o n res ults, vital si g ns, E C G res ults a n d E C O G perf or ma nce sc ores.  Descri pti ve 
statistics will be use d t o s u m marize safety data.  All safet y data will be s u m marize d b y treat me nt.
All s u m maries of A Es will i ncl u de o nl y  treat me nt-e mer ge nt e ve nts u nless ot her wise state d.  
A d verse e ve nts will be cate g orize d b y  sys te m or ga n class a n d preferre d ter m usi n g t he m ost 
c urre nt Me d D R A dicti o nar y , a n d will be gra de d acc or di n g t o N CI C T C A E v 4. 0 3.
A d d iti o nal safety a nal ys is f or s u bjects i n p ost-H S C T q uizarti ni b ar m ma y  be perf or me d.
T he safet y data will als o be s u m marize d f or eac h s u b- gr o u p defi ne d acc or di n g t o t he f oll o wi n g:

A ge ( < 6 0 a n d ≥6 0 y ears)

A ge ( < 6 5, ≥6 5 t o  < 7 5, a n d ≥7 5 y ears)

Se x at birt h ( male a n d fe male)

Race ( Ca ucasia n, Blac k or Africa n A merica n, Asia n, a n d Ot her)

Et h nicit y  ( His pa nic or Lati n o, N o n-His pa nic or Lati n o)


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.

C o nc o mita nt use of str o n g C Y P 3 A 4 i n hi bit or ( y es a n d n o)

Baseli ne E C O G perf or ma nce sc ore ( 0, 1, ≥2)

Baseli ne b o d y m ass i n de x ( < 1 8. 5, 1 8. 5 t o < 2 5, 2 5 t o < 3 0, ≥3 0 k g/ m 2)

P ri or all o ge neic H S C T ( yes a n d no)
1 3. 9. 
A d diti o n al A n al yses
P har mac o ge n o mic a nal yses are descri be d i n  Secti o n  1 0 , a n d p har mac oec o n o mic a nalys es i n 
Secti o n 1 1.
1 3. 1 0. 
I nteri m A n al ysis
T he st u d y  desi g n pro vi des f or o ne f or mal i nteri m a nal ys is w he n 5 0 % ( 1 4 0) of t he fi nal n u m ber 
of e ve nts ha ve bee n o bser ve d.  At t he discreti o n of t he D M C, o ne of t he f oll o wi n g 
rec o m me n dati o ns will be ma de at t his i nteri m a nal ysis:

Ter mi nati o n of t he st u d y f or f utilit y.

Ter mi n ati o n of t he st u d y f or efficac y.

C o nti n ui n g t he st u d y  as pla n ne d.
T he D M C ma y  o nl y rec o m me n d t hat t he S p o ns or disc o nti n ue t he st u d y earl y o nly f or eit her 
efficac y or f utilit y.
T he efficac y  b o u n dar y will be base d o n t he O’ Brie n-Fle mi n g efficac y  b o u n dar y deri ve d fr o m t he 
La n a n d De Mets err or s pe n di n g f u ncti o n, a n d t he a p pr o priate a m o u nt of α will be s pe nt t o e ns ure 
t hat t he o verall 1-si de d ty pe 1 err or re mai ns at 0. 0 2 5.  T he f utilit y b o u n dar y will be base d o n C P.  
At t he ti me of t he i nteri m a nal ys is, s h o ul d t he C P cr oss t he f utilit y b o u n dar y of 1 0 %, t he D M C 
will deci de w het her t o rec o m me n d st o p pi n g t he st u d y .  T his decisi o n will be base d o n t he t otality 
of i nf or mati o n a vaila ble at t he i nteri m a nal ys is, i ncl u di n g res ults of se nsiti vit y a nalys es, 
sec o n dar y efficac y e n d p oi nt a nal yses, safety a nal yses, a n d be nefit -ris k a nal yses.
1 3. 1 1. 
St atistic al Met h o ds f or P h ar m ac o ki netics a n d E x p os ure -res p o nse 
A n al yses
P har mac o ki netic para meters f or q uizarti ni b a n d A C 8 8 6 will be esti mate d f or s u bjects fr o m 
w h o m s ufficie nt plas ma sa m ples ha ve bee n o btai ne d o n Da y 1 a n d Da y 1 5 of C ycle 1.  
Para meters t o be calc ulate d will i ncl u de area u n der t he c o nce ntrati o n -ti me c ur ve ( A U C), 
ma xi m u m plas ma c o nce ntrati o n ( C ma x ), mi ni m u m plas ma c o nce ntrati o n ( Ctr o u g h), a n d ti me t o 
ma xi m u m plas ma c o nce ntrati o n (t ma x ).  Sta n dar d n o n-c o m part me ntal a nal ys es will be perf or me d.
Plas ma c o nce ntrati o ns a n d P K para meters will be s u m marize d usi n g descri pti ve statistics, 
i ncl u di n g n u m ber of s u bjects, mea n, sta n dar d de viati o n, mi ni m u m, me dia n, ma xi m u m, 
ge o metr ic mea n, a n d c oefficie nt of variati o n ( C V) of t he mea n a n d ge o metric mea n.  T he ti me 
c o urse of dr u g c o nce ntrati o ns will be pl otte d as a p pr o priate.  T he relati o ns hi p bet wee n 
P K para meters a n d i ntri nsic (se x, a ge, race, wei g ht, etc.) or e xtri nsic (c o nc o mita n t me dicati o ns, 
etc.) fact ors ma y be e val uate d.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
P o p ulati o n P K m o deli n g will be perf or me d f or q uizarti ni b a n d A C 8 8 6 usi n g n o nli near mi xe d 
effects met h o d ol o g y.  Data fr o m t his st u d y ma y be p o ole d wit h data fr o m ot her st u dies f or 
a nal ys is.  A c o variate a nal ysis will be perf or me d t o relate t he effects of i ntri nsic a n d e xtri nsic 
s u bject fact ors t o e x p os ure.
T he relati o ns hi p bet wee n P K para meters a n d Q Tc i nter vals will be e xa mi ne d f or q uizarti ni b a n d 
A C 8 8 6 usi n g li near or n o nli near mi xe d effects met h o d ol o g y .  Data fr o m t his st u d y ma y be 
p o ole d wit h data fr o m ot her st u dies f or a nal ys is.  A c o variate a nalys is ma y be perf or me d t o 
relate t he effect of i ntri nsic a n d e xtri nsic s u bject fact ors t o Q Tc.
E x pl orat or y  assess me nt of e x p os ure-res p o nse relati o ns hi ps will be perf or me d.  Data fr o m t his 
st u d y ma y be p o ole d wit h data fr o m ot her st u dies f or a nalys is.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 4. 
A D MI NI S T R A TI V E R E Q UI R E M E N T S A N D P R O C E D U R E S
1 4. 1. 
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee A p pr o v al
T his pr ot oc ol a n d t he s u bject i nf or me d c o nse nt f or m (I C F) m ust be re vie we d a n d a p pr o ve d b y a n 
I RB/I E C c o m pl yi n g wit h t he re q uire me nts of 2 1 C F R Part 5 6 a n d l ocal re g ulat or y  re q uire me nts 
bef ore s u bject e nr oll me nt at eac h site. T he letter or certificate of a p pr o val fr o m t he I R B/I E C 
m ust be recei ve d b y t he S p o ns or or its desi g nee pri or t o deli ver y  of cli nical s u p plies. T he 
I RB/I E C will be n otifie d of a n y S A E or s us pecte d u ne x pecte d seri o us a d verse reacti o n i n 
acc or da nce wit h l ocal re g ulat or y re q uire me nts.
1 4. 2. 
Et hic al C o n d uct of t he St u d y
T his st u d y  was desi g ne d a n d will be c on d ucte d, a n d res ults will be rec or de d a n d re p orte d, i n 
c o m plia nce wit h t he pri nci ples of G o o d Cli nical Practice ( G C P).  T hese re q uire me nts are state d 
i n U S fe deral re g ulati o ns ( 2 1 C F R Parts 5 0, 5 4, 5 6, a n d 3 1 2) as well as t he I C H E 6 d oc u me nt 
title d “ G ui deli ne f or G o o d Cli nical Practice”.  State, l ocal, a n d fe deral re g ulati o ns m ust be 
f oll o we d i n t he c o n d uct of t his st u d y.
1 4. 3. 
C h a n ges t o t he C o n d uct of t he St u d y or Pr ot oc ol
N o c ha n ge t o t he pr ot oc ol s h o ul d be i nitiate d wit h o ut pri or writte n I R B/I E C a p pr o val, e xc e pt 
w he n necessar y  t o eli mi nate a n i m me diate hazar d t o a s u bject, or w he n t he c ha n ge i n v ol ves o nly 
l o gistic or a d mi nistrati ve as pects of t he st u dy.  O nl y t he S p o ns or ma y i nitiate pr ot oc ol 
a me n d me nts.
1 4. 4. 
St u d y M o nit ori n g
A re prese ntati ve of t he S p o ns or or its desi g nee will visit st u d y  sites peri o dicall y t o m o nit or t he 
pr o gress of t his st u d y  i n acc or da nce wit h G C P.  It is t he In vesti gat or’s res p o nsi bilit y  t o be 
prese nt or a vaila ble d uri n g m o nit ori n g visits.  D uri n g t hese r o uti ne visits, all data pertai ni n g t o a 
s u bject’s partici pati o n i n t he st u d y m ust be a vaila ble t o t he m o nit or.
1 4. 5. 
D at a M a n a ge me nt
Data ma na ge me nt will be c o or di nate d b y t he S p o ns or i n acc or da nce wit h t he sta n dar d o perati n g 
pr oce d ures ( S O Ps) f or data ma na ge me nt.  All st u d y  s pecific pr ocesses a n d defi niti o ns will be 
d oc u me nte d b y Data Ma na ge me nt.  A n electr o nic data ca pt ure ( E D C) s ys te m will be use d t o 
c ollect t he cli nical st u d y data.  C o di n g of me dical ter ms will be perf or me d usi n g Me d D R A a n d 
W H O Dr u g.
1 4. 6. 
I n vesti g at or Res p o nsi bilities
1 4. 6. 1. 
I nf or me d C o nse nt
W ritte n i nf or me d c o nse nt fr o m st u d y s u bjects is re q uire d pri or t o t heir e nr oll me nt i n t he st u d y.  
It is t he I n vesti gat or’s res p o nsi bilit y t o o btai n s uc h c o nse nt.  I n vesti gat ors m ust c o m pl y wit h 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 4
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
2 1 C F R Part 5 0, t he I C H G ui deli ne f or G o o d Cli nical Practice, a n d all l ocal re q uire me nts as 
a p plica ble w he n de vel o pi n g I C Fs.
I n vesti gat ors m ust pr o vi de t he S p o ns or or its desi g nee wit h a p h ot oc o py of t he pr o p ose d I C F 
pri or t o s u b mitti n g t his f or m t o t he I R B/I E C.  U p o n a p pr o val of t he I C F b y  t he I R B/I E C, 
I n vesti gat ors m ust pr o vi de t he S p o ns or or its desi g nee wit h a c o p y of t he a p pr o ve d I C F a n d t he 
I RB/I E C letter of f or mal a p pr o val.
1 4. 6. 2. 
C ase Re p ort F or ms
St u d y  data will be c ollecte d o n electr o nic C R Fs (e C R Fs).  I nc o m plete e C R F e ntries will be 
referre d t o I n vesti gat ors f or clarificati o n.
1 4. 6. 3. 
S u bject C o nfi de nti alit y
Data c ollecte d d uri n g t his st u d y  ma y be use d t o s u p p ort t he de vel o p me nt, re gistrati o n or 
mar keti n g of q uizarti ni b.  T he S p o ns or or its desi g nee ma y  re q uest c o pies of perti ne nt 
st u d y-relate d rec or ds, s uc h as s u bjects’ c harts a n d la b orat or y data, wit h d ue preca uti o ns f or 
pr otecti n g s u bjects’ pri vac y .
T he S p o ns or a n d its desi g nee will c o m pl y wit h all rele va nt data pr otecti o n la ws i n t he c ollecti o n 
of data fr o m t his cli nical st u d y .  S u bjects’ na mes a n d ot her i de ntif yi n g i nf or mati o n, s uc h as 
S ocial Sec urit y  n u m bers, will n ot be discl ose d o utsi de st u d y sites.  A u ni q ue n u m ber will be use d 
t o i de ntif y eac h s u bject.  S o me i nf or mati o n, s uc h as la b orat or y test res ults, will be ke pt i n a 
c o de d f or m a n d n ot attac he d t o s u bjects’ na me s d uri n g t he st u d y.  T he c o de will be st ore d i n a 
sec ure area, a n d o nly t he st u d y  site staff will ha ve access t o it.
After s u bjects ha ve c o nse nte d t o ta ke part i n t he st u d y , t heir me dical rec or ds a n d t he data 
c ollecte d d uri n g t he st u d y m a y be re vie we d b y re prese ntati ves of t he S p o ns or, its desi g nees, 
re g ulat or y a ut h orities, a n d pers o ns acti n g o n be half of t hese a ge ncies, t o perf or m q ualit y 
ass ura nce a u dits a n d t o c o nfir m t hat t he data c ollecte d are acc urate f or t he p ur p ose of a nal yz i n g 
t he res ults.  Pers o n nel of t he IR B/I E C a n d t he Q ualit y  Ass ura nce Office f or Cli nical Trials ma y 
als o re vie w t he data t o e ns ure t hat t he st u d y is safe a n d well ma na ge d.  T hese rec or ds a n d data 
ma y  a d diti o nall y be re vie we d b y i ntereste d c o m mercial parties.  T he res ults of t his st u d y m a y be 
use d i n c o u ntries t hr o u g h o ut t he w orl d.
1 4. 6. 4. 
Rec or d Rete nti o n
I n vesti gat ors m ust retai n st u d y dr u g dis p ositi o n rec or ds, c o pies of C R Fs, a n d s o urce d oc u me nts 
f or t he ma xi m u m peri o d re q uire d by a p plica ble re g ulati o ns a n d g ui deli nes or st u d y site 
pr oce d ures, or f or t he peri o d s pecifie d b y  t he S p o ns or, w hic he ver is l o n ger.  In vesti gat ors m ust 
c o ntact t he S p o ns or pri or t o destr o y i n g a ny rec or ds ass ociate d wit h t he st u d y.  T he S p o ns or will 
n otif y  In vesti gat ors w he n t he st u d y  rec or ds are n o l o n ger nee de d.  If a n I n vesti gat or wit h dra ws 
fr o m t he st u d y, t he rec or ds will be tra nsferre d t o a m ut uall y a gree d u p o n desi g nee, s uc h as 
a n ot her I n vesti gat or or t he IR B/I E C.  N otice of s uc h tra nsfer will be gi ve n i n writi n g t o t he 
S p o ns or.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 5
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 4. 7. 
Pr ot oc ol De vi ati o ns
Pr ot oc ol de viati o ns i ncl u de all i m p orta nt de viati o ns relate d t o st u d y  i ncl usi o n or e xcl usi o n 
criteria, st u d y c o n d uct, s u bject ma na ge me nt, or s u bject assess me nt.  Maj or pr ot oc ol de viati o ns 
m ust be re p orte d t o t he S p o ns or or its desi g nee a n d t o t he I R B/I E C.  E xa m ples of pr ot oc ol 
de viati o ns i ncl u de:

Ra n d o mizati o n of s u bjects n ot satisf y i n g e ntr y criteria

Fail ure t o wit h dra w s u bjects meeti n g wit h dra wal criteria

A d mi nistrati o n of t he wr o n g treat me nt or a n i nc orrect st u d y  dr u g d ose
1 4. 8. 
C o ntr ol of M ateri als
1 4. 8. 1.   
Recei pt of Cli nic al S u p plies
S hi p me nt of q uizarti ni b fr o m t he S p o ns or or desi g nee t o I n vesti gat ors will be acc o m pa nie d b y  a 
cli nical s u p pl y s hi p me nt a n d recei pt verificati o n f or m, w hic h will descri be t he d osa ge f or m a n d 
t he a m o u nt of cli nical s u p plies pr o vi de d f or t he st u d y.  I n vesti gat ors m ust e ns ure t hat st u dy dr u g 
is mai ntai ne d i n a sec ure area wit h restricte d access.
1 4. 8. 2. 
Dis p ositi o n of U n use d Cli nic al S u p plies
A cli nical s u p pl y  rec o nciliati o n f or m m ust be c o m plete d b y eac h I n vesti gat or or desi g nee u p o n 
c o m pleti o n or ter mi nati o n of t he st u d y .  All u n use d cli nical s u p plies will be rec or de d i n t he dr u g 
dis pe nsi n g a n d acc o u nta bilit y  rec or d f or q uizarti ni b a n d o n t he cli nical s u p pl y rec o nciliati o n 
f or m, a n d will be destr oye d at st u d y sites f oll o wi n g a p pr o ve d pr oce d ures, or ret ur ne d t o t he 
S p o ns or, after c o m pleti o n of t he st u d y .
1 4. 9. 
Fi n a nci al Discl os ure
Pri nci pal I n vesti gat ors, a n d all s u b -i n vesti gat ors liste d o n F D A F or m 1 5 7 2, will pr o vi de t he 
S p o ns or or desi g nee wit h i nf or mati o n o n a n y fi na ncial i nterests i n t he S p o ns or hel d or recei ve d 
b y  t he m, t heir s p o uses, or de pe n de nt c hil dre n, i n acc or da nce wit h US fe deral la w 
( 2 1 C F R Part 5 4).  T his discl os ure m ust be ma de at t he ti me of eac h I n vesti gat or’s first 
i n v ol ve me nt i n t he st u d y, t hr o u g h o ut t he st u d y, a n d f or 1 year after st u d y c o m pleti on.
1 4. 1 0. 
P u blic ati o n P olic y
T his is a m ulti -site st u d y, a n d res ults fr o m a n i n di vi d ual site will n ot be p u blis he d bef ore t he first 
m ulti -site p u blicati o n b y t he S p o ns or.  If t here is n o m ulti-site p u blicati o n wit hi n 1 8 m o nt hs after 
t he st u d y has bee n c o m plete d or ter mi nate d at all sites a n d all data ha ve bee n recei ve d, a n 
i n di vi d ual site will ha ve t he ri g ht t o p u blis h its res ults, s u bject t o t he f oll o wi n g re q uire me nts.  
Pri or t o s u b mitti n g or prese nti n g a ma n uscri pt or ot her st u d y -relate d material t o a p u blis her,
re vie wer, or ot her e xter nal party, t he I n vesti gat or or site will pr o vi de t he S p o ns or wit h a c o p y of 
t he ma n uscri pt or ot her material, a n d t he S p o ns or will ha ve 6 0 da ys fr o m recei pt of t he material 
t o re vie w it a n d c o m me nt.  At t he S p o ns or’s re q uest, t he In vesti gat or or site will re m o ve a n y  
c o nfi de ntial i nf or mati o n, ot her t ha n st u d y  res ults, pri or t o s u b mitti n g or prese nti n g t he material.  
T he I n vesti gat or or site will, at t he S p o ns or’s re q uest, f urt her dela y  p u blicati o n or prese ntati o n 


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 6
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
f or u p t o 1 2 0 da ys, t o all o w t he S p o ns or t o pr otect its i nterests i n a n y of its i n ve nti o ns descri be d 
i n t he material.


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 7
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 5. 
R E F E R E N C E S
1.
S mall D. F L T 3 m utati o ns: bi ol o g y  a n d treat me nt.  He mat ol o g y A mer. S oc.  He mat ol o g y 
E d uc. Pr o gra m 2 0 0 6; 1 7 8 - 1 8 4
2.
Ra va n di F, Ka ntarjia n H, Fa derl S, Garcia - Ma ner o G, O’ Brie n S, K oller C et al.  O utc o me of 
patie nts wit h F L T 3 - m utate d ac ute myel oi d le u ke mia i n first rela pse.  Le u k. Res. 
2 0 1 0; 3 4( 6): 7 5 2 - 7 5 6
3.
B oissel N, Ca y uela J M, Pre u d h o m me C, T h o mas X, Grar del N, F u n d X et al.  Pr o g n ostic 
si g nifica nce of F L T 3 i nter nal ta n de m re peat i n patie nts wit h de n o v o ac ute m y el oi d le u ke mia 
treate d wit h rei nf orce d c o urses of c he m ot hera py.  L e u ke mia 2 0 0 2; 1 6( 9): 1 6 9 9 - 1 7 0 4
4.
Marti nelli G, Perl A E, D o m bret H, Ka y ser S, Steffe n B, R o ussel ot P et al. Effect of 
Q uizarti ni b o n res p o nse rates a n d l o n g ter m s ur vi val i n el derl y patie nts wit h F L T 3 -I TD 
p ositi ve or ne gati ve rela pse d/refract or y  ac ute myel oi d le u ke mia. J Cli n O nc ol 2 0 1 3; 3 1 
(s u p pl): a bstr 7 0 2 1
5.
C ortes J E, Perl A E, D o m bret H, D o h ner H, Steffe n B, R o ussel ot P et al. Re s p o nse rate a n d 
bri d gi n g t o he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) wit h Q uizarti ni b i n patie nts wit h 
F L T 3 I T D p ositi ve or ne gati ve rela pse d/refract or y A M L after sec o n d li ne c he m ot hera p y or 
pre vi o us b o ne marr o w tra ns pla nt. J Cli n O nc ol 2 0 1 3; 3 1(s u p pl): a bstr 7 0 1 2
6.
Le vis M, Ra va n di F, Wa n g S, Baer M et al.  Res ults fr o m a ra n d o mize d trial of sal va ge 
c he m ot hera p y f oll o we d b y lesta urti ni b f or patie nts wit h F L T 3 m uta nt A M L i n first rela pse.  
Bl o o d 2 0 1 1; 1 1 7 ( 1 2): 3 2 9 4 - 3 3 0 1
7.
Giles F, O’ Brie n S, C ortes J, Ve rst o vse k S et al.  O utc o me of patie nts wit h ac ute 
m y el o ge n o us le u ke mia after sec o n d sal va ge t hera p y .  Ca ncer 2 0 0 5; 1 0 4 ( 3): 5 4 7- 5 5 4
8.
C ortes J E, Ka ntarjia n H, F ora n J M, G hir dala dze D et al.  P hase 1 st u d y  of q uizarti ni b 
a d mi nistere d dail y t o patie nts wit h re la pse d or refract or y ac ute myel oi d le u ke mia irres pecti ve 
of F M S -li ke tyr osi ne ki nase 3 -i nter nal ta n de m d u plicati o n stat us.  J Cli n O nc ol 2 0 1 3.  E- p u b 
a hea d of pri nt.
9.
Sat o T, Ya n g X, K na p per S, W hite P et al.  F L T 3 li ga n d i m pe des t he efficac y  of F L T 3 
i n hi bit ors i n vitr o a n d i n vi v o. Bl o o d 2 0 1 1; 1 1 7( 1 2): 3 2 8 6- 3 2 9 3
1 0. Sc hle n k R F, D ö h ner K, Kra uter J, Fr ö hli n g S et al. M utati o ns a n d treat me nt o utc o me i n 
c yt o ge netically n or mal ac ute m yel oi d le u ke mia. N E n gl J Me d 2 0 0 8; 3 5 8( 1 8): 1 9 0 9 - 1 9 1 8
1 1. Br u net S, Marti n o R, Sierra J. He mat o p oietic tra ns pla ntati o n f or ac ute m ye l oi d le u ke mia 
wit h i nter nal ta n de m d u plicati o n of F L T 3 ge ne ( F L T 3/I T D).  C urr O pi n O nc ol 2 0 1 3; 2 5: 1 9 5 -
2 0 4
1 2. St o ne R.  Ac ute m y el oi d le u ke mia i n first re missi o n: t o c h o ose tra ns pla ntati o n or n ot?  J Cli n 
O nc ol 2 0 1 3; 3 1( 1 0): 1 2 6 2 - 1 2 6 6
1 3. Pratz K W, Sat o T, M ur p h y  K M, Sti ne A et al.  F L T 3-m uta nt allelic b ur de n a n d cli nical stat us 
are pre dicti ve of res p o nse t o F L T 3 i n hi bit ors i n A M L .  Bl o o d 2 0 1 0; 1 1 5: 1 4 2 5- 1 4 3 2


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 8
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
1 4. Fiel di n g A K, R o we J M, Ric har ds S M, B uc k G et al.  Pr os pecti ve o utc o me o n 2 6 7 u nselecte d 
a d ult patie nts wit h P hila del p hia c hr o m os o me -p ositi ve ac ute l y m p h o blastic le u ke mia 
c o nfir ms s u peri orit y of all o ge neic tra ns pla ntati o n o ver c he m ot hera p y i n t he pre -i mati ni b era: 
res ults fr o m t he I nter nati o nal A L L Trail M R C U K A L L XII/E C O G 2 9 9 3.  Bl o o d 
2 0 0 9; 1 1 3: 4 4 8 9 - 4 4 9 6
1 5. Pfeifer H, Wass ma n B, Bet h ge W, De n gler J et al.  Ra n d o mize d c o m paris o n of pr o p h yl actic 
a n d mi ni mal resi d ual disease tri g gere d i mati ni b after all o ge neic ste m cell tra ns pla ntati o n f or 
B C R -A B 1 -p ositi ve ac ute l y m p h o blastic le u ke mia.  Le u ke mia 2 0 1 3; 2 7: 1 2 5 4 - 1 2 6 2
1 6. B ur ke M, Tr ozt B, L u o X, Ba ker K S et al.  All o -he mat o p oietic cell tra ns pla ntati o n f or P h -
c hr o m os o me- p ositi ve A L L: i m pact of i mati ni b o n rela pse a n d s ur vi val.  B o ne Marr o w 
Tra ns pla ntati o n 2 0 0 9; 4 3: 1 0 7- 1 1 3
1 7. Metzel der S K, S c hr oe der T, Fi nc k A, Sc h oll S et al.  Hi g h acti vit y  of s orafe ni b i n F LT 3 -I T D 
p ositi ve ac ute m y el oi d le u ke mia s yner gize d wit h all o -i m m u ne effects t o i n d uce s ustai ne d 
res p o nses.  Le u ke mia 2 0 1 2; 2 6: 2 3 5 3- 2 3 5 9
1 8. C hes o n B D, Be n nett J M, K o pec k y KJ, B uc h ner T, Will ma n C L , Este y E H et al.  Re vise d 
Rec o m me n dati o ns of t he I nter nati o nal W or ki n g Gr o u p f or Dia g n osis, Sta n dar dizati o n of 
Res p o nse Criteria, Treat me nt O utc o mes, a n d Re p orti n g Sta n dar ds f or T hera pe utic Trials i n 
Ac ute M yel oi d Le u ke mia.  J. Cli n. O nc ol. 2 0 0 3; 2 1( 2 4 ): 4 6 4 2- 4 6 4 9


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
9 9
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
A P P E N DI X 1: 
LI S T O F P O T E N TI A L Q T P R O L O N GI N G D R U G S, 
C Y P 3 A 4 I N HI BI T O R S /I N D U C E R S, A N D 
P- G L Y C O P R O T EI N I N HI BI T O R S/ I N D U C E R S
T his a p pe n di x lists me dicati o ns t hat p ote ntiall y  pr ol o n g Q T/ Q Tc a n d me dicati o ns a n d f o o ds t hat 
are c o m m o n i n hi bit ors of C Y P 3 A 4.  T his list s h o ul d n ot be c o nsi dere d all i ncl usi ve.  C o ns ult 
i n di vi d ual dr u g la bels f or s pecific i nf or mati o n o n a c o m p o u n d’s pr o pe nsit y t o pr ol o n g Q T/ Q Tc 
a n d/ or i n hi bit C Y P 3 A 4.
P ote nti al Q T/ Q Tc Pr ol o n gi n g Dr u gs
Dr u g T y pe
Ge neric Dr u g N a me
Class I A a ntiarr h yt h mics
q ui ni di ne
pr ocai na mi de
dis o p p yra mi de
Class I C a ntiarr h yt h mics
flecai ni de
pr o pafe n o ne
m oricizi ne
Class III a ntiarr h yt h mics
a mi o dar o ne
s otal ol
bret yli u m
i b utili de
d ofetili de
A nti ps yc h otics
t hi ori dazi ne
mes ori dazi ne
c hl or pr o mazi ne
pr oc hl or perazi ne
trifl u o perazi ne
fl u p he nazi ne
per p he nazi ne
pi m ozi de
ris peri d o ne
zi prasi d o ne
lit hi u m
hal o peri d ol
Tric yclic/tetrac yclic a nti de pressa nts
a mitri pt yli ne
desi pra mi ne
d o xe pi n
d os ule pi n h y dr oc hl ori de
i mi pra mi ne
ma pr otili ne
Selecti ve ser ot o ni n a n d n ore pi ne p hri ne re u pta ke 
i n hi bit ors ( S S N RIs)
ve nlafa xi ne
Macr oli de a nti bi otics
azit hr o m yci n
er yt hr o m yci n


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 0 0
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
clarit hr o m yci n
dirit hr o m yci n
r o xit hr o m yci n
t ulat hr o m yci n
Fl u or o q ui n ol o ne a nti bacterials
m o xifl o xaci n
gatifl o xaci n
Az ole a ntif u n gals
ket oc o naz ole
fl uc o naz ole
itrac o naz ole
p osac o naz ole
v oric o naz ole
A nti malarials
a m o dia q ui ne
at o va q u o ne
c hl or o q ui ne
d o x yc ycli ne
hal ofa ntri ne
mefl o q ui ne
pr o g ua nil
pri ma q ui ne
p yri met ha mi ne
q ui ni ne
s ul p ha d o xi ne
A nti pr ot oz oals
pe nta mi di ne
A ntie metics
dr o peri d ol
d olasetr o n
gra nisetr o n
o n da nsetr o n
A ntiestr o ge ns
ta m o xife n
I m m u n os u p presa nts
tacr oli m us


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 0 1
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
C Y P 3 A 4 I n hi bit ors
I n hi bit or T y pe
Ge neric Dr u g N a me
C o m me nts
Str o n g
b oce pre vir
clarit hr o m yci n
c o ni va pta n
gra pefr uit
gra pefr uit j uice
i n di na vir
itrac o naz ole
ket oc o naz ole
l o pi na vir
mi befra dil
nefaz o d o ne
nelfi na vir
p osac o naz ole
rit o na vir
sa q ui na vir
tela pre vir
telit hr o m yci n
v oric o naz ole
Use pr o hi bite d f or s u bjects 
recei vi n g q uiz arti ni b u nless 
necess ar y f or p atie nt c are i n 
w hic h c ase a d ose re d ucti o n 
of  q uiz arti ni b is re q uire d
M o derate
a m pre na vir
a pre pita nt
ataza na vir
ci pr ofl o xaci n
criz oti ni b
dar u na vir
diltiaze m
er yt hr o m yci n
fl uc o naz ole
f osa m pre na vir
i mati ni b
vera pa mil
Use all o we d.  N o 
re q uire me nt f or q uiz arti ni b 
d ose re d ucti o n
Wea k
al praz ola m
a mi o dar o ne
a ml o di pi ne
at or vastati n
bical uta mi de
cil ostaz ol
ci meti di ne
c ycl os p ori ne
fl u o xeti ne
fl u v o xa mi ne
gi n k g o
g ol de nseal
is o niazi d
la pati ni b
oral c o ntrace pti ves
Use all o we d.  N o 
re q uire me nt f or q uiz arti ni b 
d ose re d ucti o n


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 0 2
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
nil oti ni b
paz o pa ni b
ra niti di ne
ra n olazi ne
tica grel or
ti pra na vir
zile ut o n
C Y P 3 A 4 I n d ucers
I n d ucer T y pe
Ge neric Dr u g N a me
C o m me nts
Str o n g
a vasi mi be
car ba maze pi ne
p he n yt oi n
rifa m pi n
St. J o h n’s w ort
Use pr o hi bite d f or s u bjects 
recei vi n g q uiz arti ni b
M o derate
b ose nta n
efa vire nz
etra viri ne
m o dafi nil
nafcilli n
Use pr o hi bite d f or s u bjects 
recei vi n g q uiz arti ni b
Wea k
a m pre na vir
a pre pita nt
ar m o dafi nil
cl o baza m
ec hi nacea
pi o glitaz o ne
pre d nis o ne
r ufi na mi de
ve m urafe ni b
Use all o we d.
P- g l yc o pr otei n I n hi bit ors/I n d ucers
I n hi bit ors
I n d ucers
A m i o dar o ne
Azit hr o m yci n
Ca pt o pril
Car ve dil ol
Clarit hr o m yci n
C o ni va pta n
C ycl os p ori ne
Diltiaze m
Dr o ne dar o ne
Er yt hr o m yci n
Fel o di pi ne
Itrac o naz ole
A vasi mi be
Car ba maze pi ne
P he n yt oi n
Rifa m pi n
St. J o h n’s w ort
Ti pra na vir/rit o na vir


Daiic hi Sa n k y o, I nc
Pr ot oc ol A C 2 2 0 -0 0 7, Gl o bal A me n d me nt 6. 0
1 0 3
C o nfi de ntial
T his is a Daiic hi Sa n k y o, I nc d oc u me nt t hat c o ntai ns c o nfi de ntial i nf or mati o n.  It is
i nte n de d s olel y f or t he reci pie nt a n d m ust n ot be discl ose d t o a n y ot her part y.
Ket oc o naz ole
L o pi na vir
Rit o na vir
Q uerceti n
Q ui ni di ne
Ra n olazi ne
Tica grel or
Vera pa mil