A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)
Phase: PHASE1
Conditions: Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Sponsor: Daiichi Sankyo

 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1  
C LI NI C A L S T U D Y P R O T O C O L  
 
A P H A S E 1 S T U D Y O F MI L A D E M E T A N ( D S -3 0 3 2 b ), A N 
O R A L M D M 2 I N HI BI T O R, I N D O S E E S C A L A TI O N A S A 
SI N G L E A G E N T A N D I N D O S E 
E S C A L A TI O N/ E X P A N SI O N I N C O M BI N A TI O N WI T H 
5 -A Z A CI TI DI N E I N S U B J E C T S WI T H A C U T E 
M Y E L O G E N O U S L E U K E MI A ( A M L) O R HI G H -RI S K 
M Y E L O D Y S P L A S TI C S Y N D R O M E ( M D S)  
D S 3 0 3 2 -A -U 1 0 2  
 
I N D N U M B E R:  1 1 8 1 2 5  
 
V E R SI O N 5 . 0, 0 6  M ar  2 0 2 0  
 
 
D AII C HI S A N K Y O, I N C.  
2 1 1 M T. AI R Y R O A D  
B A S KI N G RI D G E, N J 0 7 9 2 0 -2 3 1 1  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
I nf or mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n k y o, I n c.  T he i nf or mati o n is 
pr o vi de d t o y o u i n c o nfi d e nce w hi c h is re q ueste d u n der a n a gree d u p o n a n d si g ne d 
C o nfi de ntialit y a n d Discl os ure A gree me nt.  D o n ot gi ve t his d oc u me n t or a n y c o p y of it or re v eal 
a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her t ha n t h ose i n y o ur 
or ga nizati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d b y t he C o nfi de ntialit y a n d 
Discl os ure A gree me nt) wit h o ut t he pri or writte n per missi o n of a n a ut h orize d re prese ntati ve of 
Daiic hi Sa n k y o, I nc . 

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D O C U M E N T HI S T O R Y  
Versi o n N u m ber  
Versi o n D ate  
4. 0  
2 1 Oct 2 0 1 9  
3. 0  
1 0 Ma y 2 0 1 8  
2. 0  
2 4 A u g 2 0 1 7  
1. 0  
3 0 Ma y 2 0 1 4  

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S U M M A R Y O F C H A N G E S  
A me n d me nt R ati o n ale:  
T he mai n p ur p ose of t his a me n d me nt is t o clarif y s u bject visits f or assess me nts a n d sa m ple 
c ollecti o ns i n t he alter nati ve ( 5 + 2) A Z A d osi n g s c he d ule . 
C h a n ges t o t he Pr ot oc ol:  
Please refer t o t he c o m paris o n d oc u me nt f or pr ot o c ol Versi o n 5 . 0 ( date d 0 6  Mar  2 0 2 0 ) vers us  
pr ot oc ol Versi o n 4. 0 ( d ate d 2 1 Oct 2 0 1 9) f or act ual c ha n ges i n-t e xt.  T he s u m mar y of c ha n ges 
bel o w is a t o p -li ne s u m mar y of maj or c ha n ges i n t he D S 3 0 3 2-A -U 1 0 2 cli nical st u d y pr ot oc ol 
( Versi o n 5 . 0) b y s ecti o n. 
C O N V E N TI O N S U S E D I N T HI S S U M M A R Y O F C H A N G E S  
All l ocati o ns ( Secti o n n u m bers a n d/ or para g ra p h/ b ullet n u m bers) refer t o t he c urre nt pr ot oc ol versi o n, 
w hic h  i nc or p orates t he ite ms s pecifie d i n t his S u m mar y of C ha n ges. 
Mi n or e dits, s uc h as u p dates t o la n g ua ge t hat d o n ot alter ori gi nal mea ni n g, u p date t o versi o n n u m beri n g, 
f or matti n g, c ha n ge i n f o nt c ol or, c orrecti o ns t o t y p o gra p hical err ors, use of a b bre viati o ns, m o vi n g 
ver bia ge wit hi n a secti o n or ta ble, c ha n ge i n st yle, or c ha n ges i n case, are n ot n ote d i n t he ta ble bel o w.  
 
Secti o n # a n d Title  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Pr ot oc ol S y n o psis ( St u d y Desi g n - 
Part 1 A [D ose escalati o n of 
mila de meta n i n c o m bi nati o n wit h 
A Z A ]) 
Secti o n 3. 1. 2. 2.  Part 1 A ( D ose 
Escalati o n of Mila de meta n i n 
C o m bi nati o n wit h A Z A)  
Fi g ure 3. 2 D osi n g Sc he d ule of 
Mila de meta n i n C o m bi nati o n wit h 5 -
Azaciti di n e 
Fi g ure 3. 3 Alter nati ve 5 Azaciti di ne 
D osi n g Sc he d ule i n C o m bi nati o n 
wit h Mila de meta n at R D E  
Secti o n 5. 1. 4 A d mi nistrati o n  
U p date d/a d de d la n g ua ge 
re gar di n g t he alter nati ve 
sc he d ule a n d w he n t he d osi n g 
sc he d ules ma y be e val uate d. 
Clarificati o n  
Secti o n 3. 1. 3 Part 2 ( D ose 
E x pa nsi o n of Mila de meta n i n 
C o m bi nati o n wit h A Z A)  
A d de d state me nt, “If t he safet y 
a n d efficac y data fr o m t he ’1 t o 
7 ’ a n d ’5 + 2 ’ sc he d ules of A Z A 
are c o m para ble i n t he D ose 
Escalati o n, b ot h A Z A sc he d ules 
will be all o we d i n D ose 
E x pa nsi o n. ” 
Clarificati o n  
Secti o n 6. 4. 3 Bl o o d Sa m ple f or 
Ba n ki n g Plas ma  
Ta ble 1 7. 2:  Sc he d ule of E ve nts Part 
1 A ( D ose Escalati o n) a n d Part 2 
( D ose E x pa nsi o n) –  wit h 
A d de d t hat assess me nts/sa m ple 
c ollecti o n f or C ycle 1/ Da y 7 will 
be d o ne o n Da y 8 a n d Da y  1 4 
will be d o ne o n Da y 1 5 , f or 
s u bj ects o n t he alternati ve ( 5 + 2) 
Clarifie d t he s u bject vis its f or 
assess me nts a n d sa m ple 
c ollecti o ns" i n t he alter nati ve 
( 5 + 2) d osi n g sc he d ule, i n 
c o m bi nati o n wit h 

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Pr o prietar y a n d C o nfi de ntial  
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Secti o n # a n d Title  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Mila de meta n o n Da ys 5 t o 1 4 
( Sc he d ule E) –  f o ot n otes e, t a n d v 
Ta ble 1 7. 3:  Sc he d ule of E ve nts Part 
1 A ( D ose Escalati o n) a n d Part 2 
( D ose E x pa nsi o n) –  wit h 
Mila de meta n o n Da ys 8 t o 1 4 
( Sc he d ule F) –  f o ot n ote e a n d t 
A Z A sc he d ule  
T a ble 1 7. 2 A d de d f o ot n ote ‘e’ t o 
C ycle  1/ Da y 1 4, C ycle  2/ Da ys 
5 -7, C ycle  3/ Da ys  5 -7, a n d 
C ycle  4 +/ Da ys 5 -7  
T a ble 1 7. 3 A d de d f o ot n ote ‘e’ t o 
C ycle  1/ Da y 1 4, C ycle  2/ Da y  7, 
C ycle 3/ Da y 7, a n d 
C ycle  4 +/ Da y 7  
mila de meta n at R D E ( o nl y at 
t he R D E d ose a n d d ose 
sc he d ule) t o pr o vi de a n 
alter nati ve sc he d ule f or sites 
t hat are n ot o pe n o n t he 
wee ke n ds or s u bjects  w h o 
ca n n ot c o me t o t he st u d y site 
o n t he wee ke n ds.  
Ta ble 8. 1 C ycle 1 Bl o o d Sa m ple 
C ollecti o n f or P har mac o ki netics 
D uri n g D ose Escalati o n ( Part 1 A, 
Sc he d ule E)  
Ta ble 8. 2:  C ycle 1 Bl o o d Sa m ple 
C ollecti o n f or P har mac o ki netics 
D uri n g D ose Escalati o n ( Part 1 A, 
Sc he d ule F)  
Ta ble 8. 4:  C ycle 1 S parse Sa m ple 
C ollecti o n f or Mila de meta n 
P har mac o ki netics D uri n g D ose 
E x pa nsi o n f or All S u bj ects  
Secti o n 1 1. 5. 1 P har mac o ki netic 
A nal yses  
A d de d t hat P K sa m ples will n ot 
be c ollecte d f or s u bj ects o n t he 
alter nati ve ( 5 + 2) A Z A sc he d ule  
Clarificati o n  
Secti o n 1 1. 1 0.  Sa m ple Size 
Deter mi nati o n  
A d de d ‘e val ua ble’ t o t he 
para gra p h disc ussi n g “ D ose 
Escalati o n ( Part 1 a n d Part 1 A).”  
Clarificati o n  
Secti o n 1 5. 3. 1. 3 S p o ns or’s Cli nical 
St u d y Ma na ger/ Deli ver y Lea d  
Secti o n 1 5. 3. 1. 5 S p o ns or’s 
Bi ostatisticia n  
Re vise d st u d y me m ber 
i nf or mati o n 
U p date d ue t o c ha n ges i n 
tea m me m bers 
Ta ble 1 7. 2:  Sc he d ule of E ve nts Part 
1 A ( D ose Escalati o n) a n d Part 2 
( D ose E x pa nsi o n) –  wit h 
Mila de meta n o n Da ys 5 t o 1 4 
( Sc he d ule E) 
Se parate d o ut bl o o d sa m ple 
c ollecti o n f or P K of mila de meta n 
a n d A Z A  
M o ve d MI C -1 ser u m sa m ple 
fr o m C ycle 1/ Da y 5  0. 5 h o urs t o 
Pre -d ose  
F o ot n ote p - delete d “ T he b o ne 
marr o w sa m ple o n 
C ycle  1/ Da y  5 is o pti o nal. ” 
Clarificati o n/c orrecti o n  
Ta ble 1 7. 3:  Sc he d ule of E ve nts Part 
1 A ( D ose Escalati o n) a n d Part 2 
( D ose E x pa nsi o n) –  wit h 
Mila de meta n o n Da ys 8 t o 1 4 
( Sc he d ule F) 
Delete d MI C -1 ser u m sa m ple 
fr o m C ycle 2 Da ys 1-6 a n d 
Da y  7  
F o ot n ote o - delete d “ A b o ne 
marr o w sa m ple o n 
C ycle  1/ Da y  8 is o pti o nal.  
C orrecti o n  

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P R O T O C O L S Y N O P SI S  
I N D N um ber:  
1 1 8 1 2 5  
Pr ot oc ol N u m ber:   
D S 3 0 3 2 -A -U 1 0 2  
I n v esti gati o nal Pr o d ucts: Mila de meta n ( D S -3 0 3 2 b ) 
5 -Azac iti di ne ( A Z A) (for c o m bi nati o n treat me nt wit h mila de meta n ) 
Acti ve I n gre die nt(s)/I N N:  Mila de meta n  
( 3'R , 4'S , 5'R )-N -[( 3R , 6S )-6 -Car ba m o yltetra h y dr o -2 H -p yra n -3 -yl] -6'' -
c hl or o-4' -( 2-c hl or o -3 -fl u or o p yri di n-4 -yl) -4, 4 -di met h yl -2'' -o x o -1'', 2'' -
di h y dr o dis pir o[c ycl o he xa ne -1, 2' -p yrr oli di ne -3', 3'' -i n d ole]-5' -
car b o xa mi de m o n o( 4 -met h yl be nze nes ulf o n ate) m o n o h y drate  
A Z A  
4 -a mi n o-1 -β -D -ri b of ura n os yl-s-tri azi n-2( 1 H) -o n e  
St u d y Title:  
A P hase 1 St u d y of Mila de meta n ( D S -3 0 3 2 b ), a n Oral M D M 2  
I n hi bit or, i n D ose Es calati o n as a Si n gle A ge nt a n d i n D ose 
Escalati o n/ E x pa nsi o n i n C o m bi nati o n wit h 5 -Azac itidi ne i n S u bjects 
wit h Ac ute M yel o ge n o us Le u k e mia ( A M L)  or Hi g h -Ris k 
M yel o d ys plastic S y n dr o me ( M D S)  
St u d y P has e:  
P hase 1  
I n dicati o n St u die d : 
Mila de meta n  will be e val uate d i n s u bjects wit h rel a pse d or refract or y 
( R/ R) A M L  or hi g h -ris k M D S i n Part s 1  a n d 1 A ( D ose Escalati o n), 
a n d R/ R  A M L , ne wl y dia g n ose d A M L u nfit f or i nt e nsi ve 
c he m ot hera p y,  or hi g h -ris k M D S i n Part 2 ( D ose E x pa nsi o n). 
St u d y O bjecti ves:  
St u d y O bjecti ves  
Pri m ar y O bjecti ves  
Part 1 a n d Part 1 A  
 T o assess t he safet y a n d t olera bilit y of m ila de m eta n as a 
si n gle a ge nt ( Part 1) a n d i n c o m bi nati o n wit h A Z A  ( Part 1 A). 
 T o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) of 
m ila de meta n as si n gle a ge nt a n d i n c o m bi nati o n wit h A Z A 
a n d t o i de ntif y a  rec o m me n de d d ose f or a n e x pa nsi o n c o h ort 
( R D E) of m ila de meta n pl us A Z A . 
Part 2  

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 T o c o nfir m t he safet y a n d t olera bilit y of mila de m eta n i n 
c o m bi nati o n wit h A Z A at t he R D E a n d i de ntif y t h e 
rec o m me n de d P has e 2 d ose ( R P 2 D). 
 T o e val uate t he effi cac y of mila de meta n i n c o m bi nati o n wit h 
A Z A i n s u bjects wit h A M L or hi g h -ris k M D S. 
Sec o n d ar y O bjecti ves  
Part 1 a n d Part 1 A  
 T o e val uate t he p h ar mac o ki netics ( P K) of m ila de meta n 
f oll o wi n g si n gle a n d m ulti ple d osi n g. 
Part 2  
 T o e val uate t he P K of mila de meta n at t he R D E . 
O utc o me Me as ures  
Pri m ar y O utc o me Me as ures  
Part 1 a n d Part 1 A  
1.  N u m ber of s u bjects wit h D L Ts b y t h e e n d of t he D ose 
Escalati o n part  (ti mefra m e:  wit hi n 5 years of first s u bject 
e nr olle d). 
Part 1, Part 1 A, a n d Part 2  
1.  N u m ber of s u bjects wit h treat me nt -e mer ge nt a d verse e ve nts 
( T E A Es) (ti mefra me:  wit hi n 6 years of first s u bject e nr olle d). 
Part 2  
1.  N u m ber of s u bjects w h o ac hie ve d C R, C Ri or  M L F S f or 
A M L a n d w h o attai ne d C R, marr o w C R ( m C R) or P R f or 
hi g h -ris k M D S as t he best res p o nse (ti mefra me:  wit hi n 6 
years  of first s u bject e nr olle d). 
Sec o n d ar y O utc o me Me as ures  
Part 1, Part 1 A, a n d Part 2  
 Plas ma c o nce ntrati o ns a n d P K  para meters of mila de meta n  
(ti mefra me: wit hi n 6 years of first s u bject e nr olle d ). 
St u d y Desi g n :  
T his will be a P hase 1, o pe n -la bel st u d y of m ila de meta n as a si n gle 
a ge nt ( Part 1) a n d i n c o m bi nati o n wit h A Z A ( Part  1 A) t o assess its 
safet y a n d t olera bilit y a n d i de ntif y t he M T D  a n d R D E (i n D ose 
Escalati o n)  i n s u bjects wit h R/ R A M L or hi g h -ris k M D S a n d t o 
c o nfir m t he safet y a n d t olera bilit y of R D E a n d i de ntif y a R P 2 D (i n 
D ose E x pa nsi o n  [ Part 2]) i n s u bjects wit h R/ R  A M L , ne wl y 
dia g n ose d A M L u nfit f or i nte nsi ve c he m ot hera p y,  or hi g h -ris k M D S. 

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D ose re gi me n  
I n Part 1, m ila de meta n will be a d mi nistere d o nce dail y ( Q D) o n 
Da ys  1  t o 2 1  of a 2 8 -d a y  c ycle (q d  2 1 / 2 8) i n c o h orts of i ncreasi n g 
d oses, starti n g fr o m 6 0 m g  ( Sc h e d ule a).  Alter nati ve , less fre q u e nt, 
dr u g a d mi nistrati o n sc he d ule s of q d o n Da ys 1 t o 7 of a 2 8 -da y c ycle 
(q d  7/ 2 8)  ( Sc he d ule b ), q d f or 3 of 1 4 da ys re peate d t wice i n a 2 8-da y 
c ycle (q d  3/ 1 4  × 2 ) ( Sc he d ule c), a n d q d o n Da ys 1 t o 1 4 of a 2 8-da y 
c ycle ( q d 1 4/ 2 8) ( Sc he d ule d)  will als o be e val u ate d i n  D ose 
E scalati o n, starti n g fr o m t he M T D deter mi ne d i n t he q d  2 1/ 2 8 
sc he d ule. 
T he d osi n g s c he d ules f or t he d ose escalati o n i n Part 1 A i n 
c o m bi nati o n wit h A Z A will be i de ntifie d base d o n safet y, P K , PD y , 
a n d cli nical  res p o ns e dat a c ollecte d d uri n g d os e escalati o n of 
m ila de meta n as a si n gle a ge nt  a n d re vie we d b y t h e Pri nci pal  
I n v esti gat ors a n d S p o ns or. 
P art 1 ( D ose esc al ati o n of m il a de met a n si n gle a ge nt) 
D ose  escalati o n of m ila de meta n t o deter mi ne t h e M T D  will be g ui de d 
b y a Ba yesia n l o gistic re gressi o n m o del ( B L R M) f oll o wi n g es c alati o n 
wit h o ve r d ose c o ntr ol ( E W O C) pri nci ple wit h a starti n g d os e of 6 0 
m g base d o n safet y a n d t olera bilit y dat a o btai ne d i n  t he s oli d t u m or or 
l y m p h o ma first-i n-h u ma n st u d y of m ila de met a n (S t u d y D S 3 0 3 2-A -
U 1 0 1) . 
D ose  le vel i ncre me nt d uri n g D ose E s calati o n b y B L R M wit h E W O C  
T he d ose i ncre me nt s f or mila de meta n g ui de d b y B L R M wit h  E W O C  
will als o a d here t o t he f oll o wi n g restricti o ns : 
 T he d ose le vel i ncre me nt s h o ul d be n o less t ha n 3 0 % i n  or der 
t o ha ve disti ncti o n a m o n g d ose le vels c o nsi deri n g t he i nter-
s u bject varia bilit y i n e x p os ure, b ut fle xi bilit y ma y be a p plie d 
i n selecti n g t he d ose t o acc o m m o date t he a vaila bl e d osa ge 
f or m stre n gt hs. 
 T he d ose le vel i ncre me nt s h o ul d be n o m ore t ha n 1 0 0 % e ve n 
if t he m o del s u g gests a hi g her d ose t ha n 1 0 0 % f or t he ne xt 
c o h ort. 
 I n t he e ve nt of a d ose -li miti n g t o xicit y (D L T ), t he ne xt 2 
s u bjects i n t he c urre nt  c o h ort will recei ve m ila de meta n 
treat me nt starti n g at least 1 wee k a p art. 
C o h orts of 3 t o 6 s u bjects will be e nr olle d a n d ass es se d f or D L Ts 
bef ore escal ati o n t o a ne w hi g her d ose.   If 2 e val u a ble s u bjects i n a 
c o h ort e x perie nce a D L T bef ore t h e e nr oll me nt of t he ne xt  s u bject, 
t he m o del  will be re -e val uate d bef ore e nr oll me nt of a n y a d diti o nal 
s u bjects t o t he c o h ort.  E nr oll me nt of s u bjects t o a ne w c o h ort 

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re q uires c o m pleti o n of D L T e val uati o n of at least 3 s u bjects treate d i n 
t he c urre nt c o h ort.  S u bjects w h o ha ve n eit her c o m plete d a D L T 
e val uati o n n or e x perie n ce d a D L T will be ce ns ore d a n d n ot i ncl u de d 
i n t he B L R M u p d ate.  I n t he e ve nt t hat s u bjects i n t he pre vi o us c o h ort 
e x perie nce a D L T after t he e nr oll me nt of s u bjects t o a ne w c o h ort has 
be g u n, d os e le vel assi g n me nt of t he ne xt s u bject i n t he ne w c o h ort 
will be base d o n a n u p dat e d B L R M usi n g D L T o ut c o me data fr o m all 
assesse d d oses. 
F or a s u bject t o be c o nsi dere d e v al ua ble f or d ose escalati o n de cisi o ns, 
t he s u bject m ust ha ve recei ve d at least 7 5 % of t he d oses d uri n g  
C ycle  1 or e x perie nce d a D L T i n C ycle  1.   T he fi nal M T D  will be 
deci de d bas e d o n c o nsi derati o ns of t he res p e cti ve M T D  esti mate d b y 
t he B L R M a n d o n a n o v erall assess me nt of safet y data fr o m 
s u bse q ue nt c ycles a n d P K /P D y i nf or mati o n c ollecte d at all d oses 
teste d.  F or d os e  deter mi nati o n, t he f oll o wi n g st o p pi n g r ules will be 
i m ple me nte d f or t he D ose Escalati o n  part : (a) at least 6  e val ua bl e 
s u bjects ha ve bee n e nr oll e d at t he M T D  le vel wit h at least 
1 8  e val ua ble s u bjects i n t otal e nr olle d i n t he D ose Escalati o n  part , 
( b) at least 9  e v al ua ble s u bjects ha ve bee n e nr olle d at a d ose le vel 
w hic h is t he m o del’s rec o m me n dat i o n f or t he ne xt d ose c o h ort a n d 
f or w hic h t he p osteri or pr o ba bilit y of tar gete d t o xicit y is at least 5 0 %, 
or  (c) d ose le vel -1 is t o o t o xic.  
A d diti o nal s u bjects f or t he c haracterizati o n of safet y, P K, or P D y  ma y 
be a d de d t o a n y D ose Es calati o n c o h ort bel o w t h e M T D d ose le vel or 
at t he M T D i n parallel wit h o n g oi n g escalati o n u p t o a ma xi m u m of 
1 2 s u bjects i n eac h c o h ort.  
T he sa me d ose escal ati o n met h o d a p plies t o t he ot her d osi n g 
sc he d ules of m ila de met a n as a si n gl e a ge nt a n d i n c o m bi nati o n wit h 
A Z A ( Part 1 A).  
D ose escalati o n usi n g alt er nati ve si n gle a ge nt mila de meta n dr u g 
a d mi nistrati o n sc he d ule  
Base d o n s afet y, P K , a n d P D y  data c ollecte d d uri n g D ose Escalati o n 
usi n g t he q d  2 1/ 2 8 sc he d ule of m ila de meta n o ver 5  d ose le vels  a n d 
re vie we d b y t h e Pri nci pal I n vesti gat ors a n d S p o ns or, alter nati ve, less 
fre q ue nt d osi n g sc h e d ules were e val uate d f or d ose escalati o n .  
Starti n g fr o m t he M T D d ose le vel ( 1 6 0  m g) est a blis he d f or t he 
q d  2 1/ 2 8 sc he d ule, d ose escalati o n usi n g t h e f oll o wi n g rec o m me n de d 
alter nati ve d osi n g sc he d ules were  p erf or me d i n lie u of t he q d  2 1/ 2 8 
sc he d ule all o wi n g parallel  e val uati o n : 
 q d  7/ 2 8 sc he d ule  ( Sc he d ule b) 
 q d  3/ 1 4 × 2 sc he d ule ( Sc he d ule c) 

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 q d  1 4/ 2 8 sc he d ule  ( Sc he d ule d ) 
N ote :  After t he fi nalizati o n of V ersi o n 3. 0 of t his pr ot oc ol o n 1 0 Ma y 
2 0 1 8, St u d y D S -3 0 3 2 -A -U 1 0 2 c o m plete d e nr oll m e nt i n Part 1, w hic h 
e val uate d mila de met a n as a si n gle a ge nt t hera p y i n 4  differe nt d os e 
sc he d ules ( Sc h e d ules a t o d).  Alt h o u g h n o D L Ts were o bs er ve d i n 
t he si n gle c o h orts of 1 6 0 m g sc he d ules b ( q d 7/ 2 8) a n d c ( q d 3/ 1 4 × 
2), res pecti vel y, n eit her sc he d ule was a ble t o c o ntr ol le u ke mia a n d 
neit her was p urs ue d f urt h er.  I n Sc he d ul e d ( q d 1 4/ 2 8), w he n t he d ose 
was escalate d fr o m 1 6 0 m g wit h n o D L Ts i n 3 s u bjects t o t he ne xt 
h i g her d ose of 2 2 0 m g, D L Ts bas e d o n Gra de 3 n a usea were o bser ve d 
i n t he first 2 s u bjects.  T he d ose was t heref ore d e-escalate d t o 
1 6 0  m g.  H o we ver, n o f urt her e nr oll me nt w as p urs ue d at 1 6 0 m g i n 
t his d ose sc he d ule si nce t he d ose was s a me as t he M T D deter mine d i n 
t he m ore fre q ue nt d ose s c he d ule ( Sc h e d ule a; q d 2 1/ 2 8). 
P art 1 A ( D ose es c al ati o n of m il a de met a n i n c o m bi n ati o n wit h 
A Z A ) 
I n Part 1 A, s u bjects will be treate d wit h A Z A at 7 5 m g/ m 2 
s u bc uta ne o usl y ( S Q) or i ntra ve n o usl y (I V) i n c o m bi nati o n wit h 
escalatin g d oses of m ila d e meta n.  T w o d osi n g sc h e d ules f or 
m ila de meta n will be e val uate d.  I n S c he d ule e, A Z A will be 
a d mi nistere d o n Da ys 1 t o 7 a n d m ila de meta n will be a d mi nistere d q d 
o n Da ys  5 t o 1 4 ( wit h a n o verla p of b ot h dr u gs a d mi nist ere d o n Da ys 
5 t o 7) i n  eac h 2 8-d a y c ycle.  I n S che d ule  f, A Z A will be  
a d mi nistere d o n D a ys 1 t o 7 a n d m ila de meta n will be a d mi nistere d q d 
o n Da ys 8 t o 1 4 (se q ue ntial treat me nt) i n eac h 2 8 -da y c ycle.   After 
t he R D E (ie, t he o pti mal d ose a n d sc he d ul e of mila de meta n) is 
i de ntifie d, a n alter nati ve sc he d ule of A Z A will be teste d i n 
c o m bi nati o n wit h mila de meta n at R D E ( o nl y at t h e R D E d ose a n d 
d ose sc he d ule) .  I nstea d of t he 7-da y c o nsec uti ve a d mi nistrati o n fr o m 
Da ys 1 t o 7, A Z A will be a d mi nistere d o n Da ys 1 t o 5 a n d t he n fr o m 
Da ys 8  t o 9 (“ 5 + 2 ”), wit h A Z A d osi n g i nterr u pti o n d uri n g t he 
wee ke n d (e g, f or l o gistic c halle n ges s uc h as cl os ur e of st u d y sites or 
i n vesti gati o nal p har mac y d uri n g t he wee k e n d).  B ot h of t he d osi n g 
sc he d ules of mila de met a n (sc he d ules e a n d f) ma y  be e val uat e d i n  
parallel  d uri n g d ose escal ati o n .  T he starti n g d os e f or m ila de meta n i n 
c o m bi nati o n wit h A Z A will be 1 6 0 m g (t he M T D of si n gle a ge nt 
m ila de meta n treat me nt i n t he q d  2 1 /2 8  sc he d ule) a n d will f oll o w d ose 
escalati o n per t he B L R M wit h t he E W O C pri nci ple . 
S u bjects s h o ul d a v oi d a str o n g C Y P 3 A 4 i n hi bit or s w hile e nteri n g t he 
st u d y.  H o we ver, if a s u bject has a me dical  c o n diti o n  w hic h t he 
I n v esti gat or belie ves is b est treate d b y a str o n g C Y P 3 A 4 i n hi bit or, t he 
str o n g C Y P 3 A 4 i n hi bit or ca n be i ntr o d uce d a n d t h e mi la de meta n 
d ose will be re d uce d b y 5 0 %.   N o d ose m o dificati o n f or A Z A is 
re q uire d wit h t he c o nc o mita nt a d mi nistrati o n of a str o n g C Y P 3 A 

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i n hi bit or. 
Mila de meta n  ca n b e a d mi nist ere d wit h o ut re gar ds t o t he ti mi n g of 
f o o d (e x ce pt f or s u bjects i n Part  1 , w h o were  re q uire d t o a v oi d f o o d 
f or 2 h o urs bef ore a n d 1 h o ur after mila de meta n a d mi nistrati o n).  If 
t he d ose of 1 6 0 m g  ( 8 0 m g f or s u bj ects recei vi n g a str o n g C Y P 3 A 4 
i n hi bit or) is n ot well t olerate d, t he n a l o w er d ose of 1 2 0 m g ( 6 0 m g 
f or s u bjects recei vi n g a str on g C Y P 3 A 4 i n hi bit or) will be e val uate d.   
B ot h of t he d osi n g sc he d ules ma y b e e val u ate d i n parallel.  
D ose -li miti n g to xicit y d efi niti o n 
A D L T is defi ne d as a n y T E A E n ot attri b uta ble t o disease or disease -
relate d pr ocesses t hat o cc urs d uri n g t h e o bser vati o n peri o d (C ycle  1) 
i n eac h d ose -le vel c o h ort a n d is Gra de 3 or hi g her acc or di n g t o 
Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E ) Versi o n 5. 0  (Versi o n 4. 0 3 bef ore  0 1 A pr 
2 0 1 8) , wit h t he e x ce pti o ns as defi ne d b el o w. 
F or ele vati o ns i n he patic f u ncti o n e nz y mes, a D L T is defi ne d as 
f oll o ws: 
 Gra de ≥3  as partat e a mi n otra nsferase ( A S T)/ala ni ne 
a mi n otra nsferase ( A L T) l e vels  lasti n g > 3 da ys . 
 A S T/ A L T  > 5 ×  U L N if acc o m pa nie d b y  ≥G ra de 2 ele vati o n i n 
bilir u bi n . 
T he f oll o wi n g e ve nts a re classifie d as D L Ts: 
 S u bjects w h o are u n a ble t o c o m plete at least 7 5 % of t he 
prescri be d d os e of m ila d e meta n or A Z A  i n C ycl e 1  as a result 
of n o n -disease -rel ate d Gra de ≥2 e ve nts will be c o nsi dere d t o 
ha ve a D L T.  
 Persiste nt b o ne marr o w a plasia i n t he a bse nce of mali g na nt 
cell i nfiltrati o n, per i nstit uti o nal g ui deli nes, a n d fail ure t o 
rec o ver a p eri p heral a bs ol ute ne utr o p hil c o u nt ≥0. 5 ×  1 0 9/ L 
a n d platelets ≥2 0  ×  1 0 9/ L w hile wit h h ol di n g st u d y dr u g, 
res ulti n g i n a > 2-wee k dela y i n i nitiati n g C ycle 2.  
T he f oll o wi n g a d verse e v e nts ( AE s) are N O T c o nsi dere d D L Ts:  
 Gra de 3 fati g ue lasti n g  < 3 da ys . 
 Gra de 3 n a usea or v o miti n g t hat has res ol ve d t o ≤Gra de 2 
wit hi n 4 8 h o urs f oll o wi n g a d mi nistrati o n of pre ve nti ve, as 
well as a d di ti o nal t hera p e utic a ntie metic a ge nts f or ma na gi n g 
esta blis he d na usea or v o miti n g.  
 Gra de 3 diarr h ea t hat has res ol ve d t o G ra de ≤2 wit hi n 
4 8  h o urs  after st a n dar d a nti diarr heal t hera pies . 

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 Is olat e d la b orat or y fi n di n gs n ot ass oci ate d wit h si g ns or 
s y m pt o ms i ncl u di n g Gra de 3/ 4 al kali ne p h os p hatase, uric 
aci d, a m ylase, a n d li pase ele vati o ns, a n d  G ra de 3 
h y p o natre mia lasti n g  < 7 2  h o urs  de vel o pe d fr o m G ra de 1 at 
baseli ne . 
 D ue t o t he nat ure of A M L a n d M D S, si g nifica nt a b n or malities 
of he mat ol o gi cal para met ers are e x pecte d fr o m t he u n derl yi n g 
disease or as p art of a ntica ncer  t h era p y.  T heref ore, n o 
he mat ol o gical D L Ts are defi ne d f or t his pr ot oc ol.  
 Al o pecia.  
 Gra de ≥3 electr ol yte a b n or malities t hat are c orrecte d t o  
≤Gra de 1 wit hi n 2 4 h o urs.  
P art 2 ( D ose E x p a nsi o n ) 
U p o n c o m pleti o n of Part 1 a n d Part 1 A  wit h esta blis he d R D E a n d 
dr u g a d mi nistrati o n sc he d ule, t he D ose E x pa nsi o n part will be gi n t o 
c o nfir m t he safet y a n d t olera bilit y of m ila de m eta n i n c o m bi nati o n 
wit h A Z A , t o d eter mi n e t he P D y  i n bl o o d a n d/ or b o ne marr o w 
bi o psies/as pirates , a n d t o e val uate preli mi nar y efficac y a n d i de ntif y 
t he R P 2 D . 
T hree c o h orts of a p pr o xi matel y 4 0 s u bjects  per c o h ort  wit h A M L or 
hi g h -ris k M D S will be c o nc urre ntl y e nr olle d a n d treate d i n D ose 
E x pa nsi o n (t otal of a p pr o xi matel y 1 2 0 s u bjects) as f oll o ws: 
1.  C o h ort 1:  S u bjects wit h R/ R  A M L.  
2.  C o h ort 2:  S u bjects wit h ne wl y di a g n ose d A M L a n d are u nfit 
f or i nte nsi ve c he m ot hera p y. 
3.  C o h ort 3:  S u bjects wit h hi g h -ris k M D S. 
N ote :  F or C o h orts 1 a n d 3 of Part 2 ( D ose E x pa nsi o n), m ore 
stri n ge nt eligi bilit y criteria re gar di n g pri or A M L or M D S t hera pies 
will be a p plie d i n or der t o creat e a m ore h o m o ge n o us s u bject 
p o p ulati o n (as n ote d i n t he S u bject Eli gi bilit y Crit eria secti o n bel o w).  
St u d y D urati o n:   
T he st u d y d urati o n is e x pecte d t o last a p pr o xi mate l y 6  years fr o m t he 
ti me t he first s u bject is e nr olle d i n Part 1 of t he st u d y.  T he n u m ber of 
treat me nt c ycl es is n ot fi x e d i n t his st u d y.  S u bjects w h o c o nti n ue t o 
deri ve cli nical b e nefit fr o m treat me nt i n t he a bse n ce of wit h dra wal of 
s u bject c o nse nt, dis eas e pr o gressi o n, or u nacce pta ble t o xicit y ma y 
c o nti n ue treat me nt.  
St u d y Sites a n d L o cati o n:  A p pr o xi matel y  1 2 U S sites are pl a n ne d f or Part 1 a n d Part 1 A (D ose 
Escalati o n ). 

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A p pr o xi matel y  1 2 U S sites are pl a n ne d f or Part 2 ( D ose E x pa nsi o n ). 
Pla n ne d Sa m ple  Size:   
T he D ose Escalati o n p arts of t his st u d y ( Part 1  a n d Part 1 A ) will 
f oll o w a B L R M  +  E W O C desi g n wit h at least 3  D L T -e val u a ble 
s u bjects per d ose le vel .  I n D ose Escalati o n Parts 1 a n d 1 A, 
ap pr o xi matel y 8 0  s u bjects ma y  be e nr olle d t o esti mate t he M T Ds of 
m ila de meta n as a si n gle a ge nt  a n d i n c o m bi nati o n wit h A Z A a n d t o 
i de ntif y R D E . 
T he D ose E x pa nsi o n  p art  ( Part 2) will e nr oll s u bjects i n t he f oll o wi n g  
3 c o h orts : (1 ) R/ R  A M L  (a p pr o xi matel y 4 1 s u bjects), ( 2) ne wl y 
dia g n ose d A M L u nfit f or i nte nsi ve c he m ot hera p y (a p pr o xi matel y 3 9 
s u bjects), or ( 3) hi g h-ris k M D S (a p pr o xi matel y 3 9 s u bjects). 
S u bject Eli gi bilit y 
Criteria:  
I ncl usi o n Criteri a ( P a rt 1/ 1 A a n d P art 2) 
1.  S u bjects wit h hist ol o gical c o nfir mati o n of pri mar y or sec o n dar y 
A M L acc or di n g t o t he 2 0 1 6 W orl d Healt h Or ga nizati o n criteria 
classificati o n, or hi g h -ris k M D S ( defi ne d b y Re vise d I nter nati o nal 
Pr o g n ostic Sc ori n g S yst e m sc ore of Hi g h or Ver y Hi g h . 
 Part 1 a n d 1 A ( D ose Escalati o n)  
o  S u bjects wit h R/ R ( R/ R) A M L, O R  
o  S u bjects wit h u ntreate d, hi g h -ris k MD S or s u bjects 
w h o ha ve recei v e d pri or M D S treat me nt re gi me ns . 
o  S u bjects ≥1 8 years ol d . 
N ote :  T here is n o mi ni m u m or ma xi m u m n u m ber of pri or 
A M L or M D S treat me nt re gi me ns f or Part 1 a n d 1 A . 
 Part 2 ( D ose E x pa nsi o n)  
o  C o h ort 1:  R/ R A M L  
 S u bjects w h o ha ve treat me nt fail ure t o pri or 
A M L t hera p y ( defi ne d as fail ure t o ac hie ve at 
least C Ri) or ha ve rela pse d after pri or A M L 
t hera p y, A N D 
 S u bjects ha ve recei ve d 1 t o 3 pri or 
treat me nt re gi me ns f or A M L if pri or 
treat me nts i ncl u de d a n i nte nsi ve 
c he m ot hera p y (e g, a nt hrac ycli ne-bas e d 
t hera p y a n d/ or i nter me di ate or hi g h 
d ose of c ytara bi ne) , O R 
S u bjects w h o ha ve recei v e d 1 t o 2 pri or 
treat me nt re gi me ns f or A M L if pri or 
treat me nts di d n ot i ncl u de a n i nte nsi ve 

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c he m ot hera p y. 
 S u bject s ≥1 8 years ol d. 
o  C o h ort 2:  N e wl y dia g n ose d A M L  
 S u bjects wit h ne wl y dia g n ose d A M L w h o are 
i neli gi ble f or i nte nsi ve i n d ucti o n c he m ot hera p y 
(e g, c o m bi nati o n of a n a nt hrac ycli ne a n d 
c yt ara bi ne ).  S u bjects m ust ha ve ha d n o pri or 
A M L treat me nt, wit h t he e x ce pti o ns of t hera p y 
f or a ntece de nt h e mat ol o gic mali g na n cies (e g, 
azaciti di ne f or M D S) or h y dr o x y urea.  
 S u bjects ≥7 5 years ol d, O R  
S u bjects bet wee n 1 8 a n d 7 4 years ol d 
(i ncl usi ve) wit h at least o ne of t he f oll o wi n g 
c o m or bi dities:  
 E C O G Perf or ma nce Stat us of 3;  
 Car diac hist or y of c o n gesti ve heart 
fail ure ( C H F) re q uiri n g treat me nt, or 
left ve ntric ular ejecti o n fracti o n (L V E F) 
≤5 0 %, or c hr o nic sta bl e a n gi n a;  
 Diff usi n g ca p acit y of t he l u n g f or 
car b o n m o n o xi de ( D L C O) ≤6 5 % or 
f orce d e x pirat or y v ol u me i n 1 sec o n d 
( F E V 1) ≤6 5 %; 
 A n y ot her c o m or bi dit y t hat t he 
I n v esti gat or j u d ges t o be i nc o m pati ble 
wit h i nte nsi ve c he m ot hera p y m ust be 
re vie we d b y t h e S p o ns or Me dical 
M o nit or d uri n g Scree ni n g a n d b ef ore 
st u d y e nr oll me nt. 
o  C o h ort 3:  H i g h-ris k M D S 
 S u bjects wit h u ntreate d, hi g h -ris k M D S or w h o 
recei v e d u p t o 2 pri or M D S treat me nt 
re gi me ns.  Pri or M D S t hera p y here e x cl u des 
s u p p orti ve care s uc h as tr a nsf usi o n, or 
er yt hr o p oiesis -sti m ulati n g a ge nt. 
2.  Has a 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 n ce stat us 0 t o 2 . 
 As a n e x ce p ti o n, s u bjects wit h ne wl y dia g n os e d A M L 
bet wee n 1 8 a n d 7 4 years ol d (i ncl usi ve) i n Part 2 C o h ort 2 

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wit h E C O G Perf or ma n ce Stat us of 3 will be eli gi ble.  
3.  Has a de q u ate re nal f u ncti o n, defi ne d as:  
 Creati ni ne cleara n ce  ≥6 0 m L/ mi n, as cal c ula te d usi n g t he 
m o difie d C oc kcr oft -Ga ult e q uati o n,  ([ { 1 4 0 –  a ge i n years } ×  
{act ual wei g ht i n k g }] di vi de d b y [ { 7 2 ×  ser u m creati ni ne i n 
m g/ d L } ] m ulti pl y b y 0. 8 5 if fe male), O R  creati ni ne cleara nce 
5 0 -6 0 m L/ mi n A N D h as ser u m creati ni ne ≤1. 5 × U L N.   I n 
o bese s u bjects, t he lea n b o d y wei g ht ca n be us e d i n t he 
e q uati o n i nstea d of act ual b o d y wei g ht . 
4.  Has a de q u ate he p atic f u ncti o n, defi ne d as:  
 A S T/ A L T  ≤2. 5  ×  U L N  (≤5  U L N if dee me d ele vate d d ue t o 
le u ke mia), a n d 
 Ser u m t otal b ilir u bi n ≤1. 5 ×  U L N  (≤3  U L N if dee me d 
ele vate d d ue t o le u ke mia or i n s u bjects wit h d oc u me nte d 
Gil bert’s S y n dr o me ). 
5.  S u bject  ( or le gall y acce pt a ble re prese ntati ve) is a ble t o pr o vi de 
writte n i nf or me d c o ns e nt, c o m pl y wit h pr ot oc ol visits a n d 
pr oce d ures, a n d ta ke oral me dicati o n, a nd d oes n ot ha ve a n y 
acti ve i nfecti o n or c o m or bi dit y t h at w o ul d i nterfere wit h t hera p y.  
6.  S u bject, i f fe male of c hil d beari n g p ote ntial , m ust ha ve a n e gati ve 
ser u m pre g na nc y test u p o n e ntr y i nt o t his st u d y a n d m ust be 
willi n g t o use hi g hl y effecti ve birt h c o ntr ol d uri n g t he peri o d of 
t hera p y a n d f or 6 m o nt hs f oll o wi n g t he last i n vesti gati o nal dr u g 
d ose.   A fe mal e is c o nsi dere d of c hil d beari n g p ote ntial f oll o wi n g 
me narc h e a n d u ntil bec o mi n g p ost me n o pa usal ( n o me nstr ual 
peri o d f or a mi ni m u m of  1 2 m o nt hs), u nless per ma ne ntl y sterile 
( u n der g o ne a h ysterect o m y, bilateral sal pi n gect o m y, or bilateral 
o o p h orect o m y).  
If male, m ust be s ur gicall y sterile or be willi n g t o use 1 f or m of 
hi g hl y effecti ve c o ntrace pti o n met h o d u p o n e nr oll me nt, d uri n g 
t he c o urse of t he st u d y, a n d f or 6 m o nt hs f oll o wi n g t he last 
i n vesti gati o nal dr u g d ose. 
7.  S u bject m ust be f ull y i nf or me d a b o ut t heir ill ness a n d t he 
i n vesti gati o nal nat ure of t he st u d y pr ot oc ol (i n cl u di n g f oreseea ble 
ris ks a n d p ossi ble si de effects). 
8.  S u bject m ust s i g n a n d date a n I nstit uti o nal Re vie w B oar d-
a p pr o ve d i nf or me d c o nse nt f or m (i ncl u di n g Healt h I ns ura nce 
P orta bilit y a n d Acc o u nta bilit y Act a ut h orizati o n, if a p plica ble) 
bef ore p erf or ma nce of a n y st u d y -s pecific pr oce d ures or tests. 
9.  A ble a n d willi n g t o pr o vi de b o ne marr o w bi o psies /as pirates as 

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re q ueste d b y t he pr ot oc ol. 
1 0.  Is willi n g t o u n der g o mali g na n c y ge n ot y pi n g f or T P 5 3 m utati o n , 
i nserti o n, or deleti o n at S cree ni n g.  
 
E xcl usi o n Criteri a  
1.  Has a dia g n osis of ac ute pr o m yel o c yti c le u ke mia.  
2.  Has a mali g na nc y t h at is  k n o w n t o c o ntai n a n o n -s y n o n y m o us 
m utati o n, i nserti o n, or deleti o n i n t he T P 5 3 ge ne d eter mi ne d 
pre vi o usl y or at Scree ni n g . 
3.  Prese nce of ce ntral ner v o us s yste m ( C N S) i n v ol ve me nt of 
le u ke mia.  Patie nts wit h a hist or y of C N S le u ke mia ma y be 
eli gi ble if t he C N S le u ke mia is a de q uatel y c o ntr olle d ( defi ne d as 
n o acti ve cli nical s y m pt o ms of C N S disease a n d at least 
2  c o nsec uti ve l u m bar p u nct ures wit h n o e vi de n ce of disease pri or 
t o st u d y e nr oll me nt) after disc ussi o n wit h  t he S p o ns or Me dical 
M o nit or . 
4.  Has ot her c o n c urre nt pri mar y m ali g n a nc y t hat re q uire d s yst e mic 
a nti-ne o plastic  treat me nt wit hi n t he pre vi o us 2 years, e x ce pt f or 
l ocalize d ca ncers t hat ha ve a p pare ntl y b ee n c ure d, s uc h as n o n-
mela n o ma s ki n ca ncer, s u perficial bla d d er ca ncer, or carci n o ma i n 
sit u of t he cer vi x or breast. 
5.  A n y c o n diti o n t hat w o ul d precl u de a de q uat e a bs or pti o n of 
m ila de meta n, i ncl u di n g refract or y na us ea a n d v o miti n g, 
mala bs or pti o n, biliar y s h u nt, si g nifica nt b o w el res ecti o n, a n d / or 
graft -vers us -h ost disease ( G V H D) affecti n g t he g ut.  
6.  Has a n u nc o ntr olle d i nfecti o n re q uiri n g I V a nti bi otics, a nti virals, 
or a ntif u n gals . 
7.  Has k n o w n h u ma n i m m u n o deficie nc y vir us i nfecti o n  wit h 
e vi de nce of acti ve i nfecti o n b y HI V R N A viral l oa d , or acti ve 
he patitis B or C i nfecti o n  base d o n p ositi ve tests d uri n g 
Scree ni n g . 
8.  Has a c o n c o mita nt me dical c o n diti o n t hat w o ul d i ncreas e t he ris k 
of t o xicit y.  
9.  Has u nres ol ve d t o xicities fr o m pre vi o us a ntica ncer t hera p y, 
defi ne d as t o xicities ( ot her t ha n al o pecia) n ot y et res ol ve d t o N CI-
C T C A E Gra de  ≤1, or b as eli ne.  S u bjects wit h c hr o nic Gra de  2 
t o xicities ma y be eli gi ble per discreti o n of t h e I n v esti gat or a n d 
S p o ns or (e g, Gra d e 2 c h e m ot hera p y -i n d uce d ne ur o pat h y). 
1 0.  Has recei ve d h e mat o p oietic cell tra ns pla ntati o n (H C T ) wit hi n 
6 0  da ys of t he first d ose of st u d y dr u gs. 

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1 1.  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 
s yste mic treat me nt or s yste mic treat me nt escalati o n wit hi n 
2 1  da ys pri or t o Scree ni n g a n d/ or > Gra de 1 p ersiste nt or cli nicall y 
si g nifica nt G V H D or oth er n o n -he m at ol o gic t o xicit y relat e d t o 
H C T.  
1 2.  Is recei vi n g c o nc o mita nt treat me nt wit h a str o n g i n d ucer of 
c yt o c hr o me P 4 5 0 3 A 4/ 5  or c o ns u m pti o n of St. J o h n’s W ort 
( h y p erici n) wit hi n 3 da ys pri or t o t he first d ose a n d d uri n g 
treat me nt. 
1 3.  Recei ve d a nti-A M L t hera p y (e x ce pt f or h y dr o x y urea) or 
a nti-M D S t hera p y wit hi n t he f oll o wi n g was h o ut peri o ds bef ore 
starti n g st u d y me dicati o n. 
 Se ve n da ys O R 5 half -li v es, w hic he ver is l o n ger, f or s mall 
m olec ule dr u gs.  
 T we nt y -o ne d a ys O R 5 half -li ves, w hic he v er is s h orter, f or 
a nti b o d y-b ase d, i m m u ne -base d, bi ol o gic, or cell ular t hera pies.  
 H y dr o x y urea  m ust be disc o nti n ue d at least 4 8  h o urs pri or t o 
st u d y treat me nt. 
1 4.  Ha d maj or s ur ger y wit hi n 4 wee ks pri or t o st u d y dr u g treat me nt.  
1 5.  Partici pate d i n a t hera pe utic cli nical st u d y wit hi n a w as h o ut ti me 
of 2  wee ks or 5 half -li ves of t he dr u g/ bi ol o gic ( w hic he ver is 
l o n ger) bef ore starti n g st u d y dr u g treat me nt u n der t his pr ot oc ol, or 
c urre nt p artici pati o n i n ot her t hera pe utic i n vesti gati o nal 
pr oce d ures.  
1 6.  U nc o ntr olle d or si g nifica nt car di o vasc ul ar  diseas e, i ncl u di n g:  
a. Pr ol o n gati o n of c orrecte d Q T i nter val usi n g Fri dericia’s 
met h o d ( Q Tc F) at rest, w here t he mea n Q Tc F i nter val is 
> 4 8 0  ms base d o n tri plicate electr ocar di o gra ms ( E C Gs).  
b.  Bra d ycar dia of less t ha n 5 0 b p m u nless t he s u bject has a 
pace ma ker.  
c. Dia g n os e 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 y n dr o me.  
d.  Hist or y of cli nicall y rele va nt ve ntric ular arr h yt h mias, s uc h as 
ve ntric ular tac h ycar dia, v e ntric ular fi brillati o n, or t orsa de de 
p oi ntes.  
e. Hist or y of sec o n d or t hir d de gre e h eart bl oc k.  S u bjects wit h a 
hist or y of heart bl oc k ma y be eli gi ble if t h e y c urre ntl y ha ve 
pace ma kers a n d h a 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. 

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f. M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o Scree ni n g.  
g.  U nc o ntr oll e d a n gi na pect oris wit hi n 6 m o nt hs pri or t o 
Scree ni n g.  
h.  N Y H A Class III or I V c o n gesti ve h eart fail ure.  
i. K n o w n L V E F ≤5 0 % or i nstit uti o nal l o wer li mit of n or mal . 
 As a n e x ce pti o n, s u bjects wit h ne wl y dia g n os e d A M L 
bet wee n 1 8 a n d 7 4 years ol d i n Part 2 C o h ort 2 wit h L V E F 
≤5 0 % or i nstit uti o nal l o wer li mit of n or mal will be 
eli gi ble.  
j. U nc o ntr olle d h y perte nsi o n.  
k.  Left b u n dle bra n c h bl oc k.  
1 7.  K n o w n D L C O ≤6 5 % or F E V 1 ≤6 5 %.  
 As a n e x ce pti o n, s u bjects wit h ne wl y dia g n os e d A M L 
bet wee n 1 8 a n d 7 4 years ol d i n Part 2 C o h ort 2 wit h D L C O 
≤6 5 % or F E V 1 ≤6 5 % will be eli gi ble.  
1 8.  Pre g n a nt or breastfee di n g.  
1 9.  S u bsta nce a b use or me dical, ps yc h ol o gical, or s o cial c o n diti o ns 
t hat, i n t he o pi ni o n of t he I n v esti gat or, ma y i nterfere wit h t he 
s u bject’s partici pati o n i n t he cli nical st u d y or e val uatio n of t he 
cli nical st u d y res ults.  
2 0.  Pri or treat me nt wit h a n M D M 2 i n hi bit or.  
D osa ge F or m, D ose , a n d 
R o ute of A d mi nistrati o n:  
Mila de meta n  will be a d mi nistere d as a si n gle oral ca ps ule or as a 
c o m bi nati o n of m ulti ple oral ca ps ule s c o ntai ni n g 5  m g, 2 0  m g, 
8 0  m g, a n d / or 2 0 0  m g  m ila de meta n, w hic h will be  i n di vi d uall y 
pac ka ge d i n desicca nt -e m be d de d al u mi n u m blisters , a n d 3 0 m g, 
8 0  m g,  a n d/ or 1 0 0 m g ca ps ules t hat are pac ka ge d i n hi g h de nsit y 
p ol yet h yle ne b ottles . 
A Z A  will be a d mi nistere d at 7 5 m g/ m 2 S Q or I V i n c o m bi nati o n wit h 
m ila de meta n i n t he select e d d osi n g sc h e d ule.  A Z A  is c o m merciall y 
a vaila ble as a l y o p hilize d p o w der i n 1 0 0 m g si n gle-d ose vials, 
pac ka ge d i n cart o ns of 1 vial,  t o be rec o nstit ute d i n sterile water f or 
use acc or di n g t o t he pac k a ge i nsert.  
St u d y E n d p oi nts:  
S afet y E n d p oi nt  
Safet y is t he pri mar y e n d p oi nt a n d will i ncl u de seri o us a d verse e ve nts 
( S A Es), T E A Es, D L Ts, p h ysical e x a mi nati o n fi n di n gs (i ncl u di n g 
E C O G perf or ma nce stat us), vital si g n meas ure me nts, cli nical 
la b orat or y para meters (ser u m c he mistr y  a n d he mat ol o g y), a n d E C G 
para meters  (i ncl u di n g Q Tc F ).  A d verse e ve nts will be cate g orize d 

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usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A)  
V ersi o n 1 7. 0.  A d verse e ve nts a n d la b orat or y t est res ults will be 
gra de d acc or di n g t o t he N CI -C T C A E Versi o n 5. 0 ( Versi o n 4. 0 3 
bef ore 0 1 A pr 2 0 1 8).  
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic E n d p oi nts  
T he P K para m eters f or m ila de meta n will i ncl u de ma xi m u m plas ma 
c o nce ntr ati o n (C ma x ), ti me t o reac h m a xi m u m plas ma c o nce ntrati o n  
( Tma x) , tr o u g h plas ma c o nce ntrati o n  ( Ctr o u g h), a n d area u n d er t he 
plas ma c o nce ntrati o n -ti me c ur ve u p  t o ti me 2 4 h o urs ( A U C 2 4h ).  I n 
a d diti o n, p o p ulati o n P K  ( P o p P K) a nal ysis  ma y b e use d t o assess t he 
P K of m ila de meta n a n d t he relati o ns hi p t o res p o nse or bi o mar kers. 
T he P K para m eters f or A Z A will i ncl u de C ma x, T ma x, a n d area 
u n der t he plas ma c o nce ntrati o n -ti me c ur ve u p  t o ti me 6 h o urs 
(A U C 6 h ). 
I n d u cti o n of ser u m MI C-1 will be assesse d as a P D y  bi o mar ker.  
Ser u m  sa m ples will be c ollecte d at m ulti ple ti me p oi nts i n t he st u d y 
t o assess t he effect of m il a de meta n treat me nt o n MI C-1 i n d ucti o n.  
Ot her e x pl orat or y P D y  bi o mar kers ma y i ncl u d e , b ut are n ot li mite d 
t o, e x pressi o n le vels of p 5 3 a n d its tar get ge nes  a n d D N A a nal ysis t o 
deter mi ne ge n e m utati o ns, c o p y n u m b er variati o n s, a n d C p G 
met h ylati o n stat us .  A d diti o nal bi o mar kers b ot h i nsi de a n d/ or o utsi de 
of t he p 5 3 pat h wa y ma y be i ncl u de d i n or der t o better u n dersta n d t h e 
res p o nsi ve ness t o t hera p y. 
Effic ac y E n d p oi nts  
T he cli nical acti vit y of t h e treat me nt will be ass esse d  usi n g t he 2 0 1 7 
E ur o pea n Le u ke mia  Net rec o m me n dati o ns f or A M L a n d t h e 2 0 0 6 
I W G res p o nse criteria f or M D S. 
F or s u bjects wit h  A M L, t he effi cac y e n d p oi nts will be C R, C R i, 
M L F S, P R , a n d sta ble disease ( S D).  C o m plete re missi o n  wit h partial 
he mat ol o gical rec o ver y ( C R h) will be e val uate d s e parat el y.  
F or s u bjects wit h M D S, t he effi cac y e n d p oi nts will be C R, m C R, P R, 
c yt o ge netic res p o nse (c o m plete or partial), S D, a n d he mat ol o gic 
i m pr o ve me nt. 
Statistical A nal yses:   
T he pri mar y a n al ysis will occ ur after all s u bjects ha ve eit her 
disc o nti n ue d t he st u d y or c o m plete d at least 6  m o nt hs of treat me nt.  
After t he pri mar y a n al ysis, t he mai n st u d y will be cl ose d.  S u bjects 
w h o c o nti n ue t o deri ve cli nical be nefit fr o m treat me nt i n t he a bse nce 
o f wit h dra wal of s u bject c o nse nt, disease pr o gressi o n, or 
u nacce pta ble t o xicit y m a y c o nti n ue treat me nt.  
Descri pti ve statistics will be pr o vi de d f or select e d de m o gra p hic, 
safet y, P K , a n d P D y  data b y d ose c o h ort at eac h ti mep oi nt  as 

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a p pr o priate.  Descri pti ve statistics o n c o nti n u o us data will i ncl u de 
mea ns, me dia ns, sta n dar d de viati o ns, a n d ra n ges, w hile cate g orical 
data will be s u m marize d usi n g fre q ue n c y c o u nts a n d perce nt a ges.  
Gra p hical s u m mari es of t he data ma y b e pres e nte d.  
Safet y A nal yses  
Safet y a nal yses i n ge n eral will be descri pti ve a n d will be prese nte d i n 
ta b ular f or mat wit h t he a p pr o priate s u m mar y statistics.  T he Safet y 
A nal ysis Set will i ncl u de a ll e nr olle d s u bjects w h o recei ve d at least 1 
d ose  of m ila de meta n or A Z A . 
P har mac o ki netic  A nal ys es  
Plas ma c o nce ntrati o n data  f or m ila de meta n a n d/ or A Z A  will be 
s u m marize d usi n g descri pti ve  statistics b y d os e c o h ort at eac h 
ti mep oi nt .  T he P K A nal ysis Set will i ncl u de all s u bjects i n t he Safet y 
A nal ysis Set w h o ha d m eas ura ble plas ma c o nce ntrati o ns of 
mila de meta n a n d/or A Z A.  
A P o p P K a nal ysis a n d e x p os ure -res p o nse a n al ys es f or vari o us 
e n d p oi nts ma y be d e vel o pe d.  If de v el o pe d, t he n t he P o p P K pla n a n d 
t he Tec h nical Re p ort will be pr o vi de d se p aratel y. 
P har mac o d y n a mic A nal yses  
C ha n ges i n MI C -1 l e vels i n ser u m a n d ot her P D y  para meters , if 
a vaila ble, will be liste d a n d s u m marize d f or t he Safet y A nal ysis Set 
usi n g descri pti ve statistics b y d ose le vel c o h ort.  
Efficac y A nal yses  
T he effi cac y e n d p oi nts will be liste d a n d s u m marize d usi n g 
descri pti ve statistics base d o n t he F ull A nal ysis Set b y d ose f or t he 
c o m bi ne d D ose Escalati o n a n d D ose E x pa nsi o n parts .  F or res p o nse 
rate, p oi nt esti mates a n d 9 5 % e x act bi n o mial c o nfi de nce i nter vals will 
be pr o vi de d.  Ti me t o e v e nt e n d p oi nt (D o R ) will be s u m marize d 
descri pti vel y usi n g t he Ka pla n -Meier met h o d . 

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T A B L E O F C O N T E N T S  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................2  
D O C U M E N T HI S T O R Y .................................................................................................................3  
S U M M A R Y O F C H A N G E S  ...........................................................................................................4  
P R O T O C O L S Y N O P SI S  ................................................................................................................6  
LI S T O F A B B R E VI A TI O N S  ........................................................................................................3 0  
1.  
I N T R O D U C TI O N A N D B A C K G R O U N D IN F O R M A TI O N  .......................................3 4  
1. 1.  
I n v esti gati o nal Pr o d ucts ..................................................................................................3 4  
1. 1. 1.  
Mila de meta n  ....................................................................................................................3 4  
1. 1. 2.  
5 -Azaci ti di ne ...................................................................................................................3 4  
1. 2.  
I nte n de d Use U n der I n vesti gati o n ...................................................................................3 4  
1. 3.  
P har mac ol o gical T ar get(s)  ...............................................................................................3 4  
1. 4.  
Data S u m mar y  .................................................................................................................3 5  
1. 4. 1.  
Cli nical E x perie nce  .........................................................................................................3 7  
1. 5.  
St u d y R ati o nale  ...............................................................................................................3 7  
1. 6.  
Ris ks a n d Be nefits f or St u d y S u bjects  .............................................................................3 8  
1. 6. 1.  
P ote ntial Ris k of Dr u g -Dr u g I nteracti o n  .........................................................................3 9  
1. 6. 2.  
P ote ntial Be nefit Ass oci ate d wit h Mila de meta n as a Si n gle A ge nt a n d i n 
C o m bi nati o n wit h 5 -Azaciti di ne  .....................................................................................3 9  
2.  
S T U D Y O BJ E C TI V E S A N D  H Y P O T H E S E S  ...............................................................4 1  
2. 1.  
St u d y O bjecti ves  ..............................................................................................................4 1  
2. 1. 1.  
Pri ma r y O bj ecti ves ..........................................................................................................4 1  
2. 1. 2.  
Sec o n dar y O bj ecti ves  ......................................................................................................4 1  
2. 1. 3.  
E x pl orat or y O bjecti ves  ....................................................................................................4 1  
2. 2.  
O utc o me Meas ures  ..........................................................................................................4 2  
2. 2. 1.  
Pri mar y O ut c o me Meas ures  ............................................................................................4 2  
2. 2. 2.  
Sec o n dar y O ut c o me Meas ures  ........................................................................................4 2  
2. 2. 3.  
E x pl orat or y O utc o me M eas ures  ......................................................................................4 2  
2. 3.  
St u d y E n d p oi nts  ...............................................................................................................4 3  
2. 3. 1.  
Safet y E n d p oi nts  ..............................................................................................................4 3  
2. 3. 2.  
P har mac o ki netic a n d P har mac o d y na mic E n d p oi nts  .......................................................4 3  
2. 3. 3.  
Efficac y E n d p oi nts  ..........................................................................................................4 3  

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2. 3. 3. 1.  A M L  ................................................................................................................................4 3  
2. 3. 3. 2.  Hi g h -ris k M D S ................................................................................................................4 4  
2. 3. 3. 3.  A d diti o nal Efficac y E n d p oi nts  ........................................................................................4 4  
2. 4.  
St u d y H y p ot hesis  .............................................................................................................4 5  
3.  
S T U D Y D E SI G N  ............................................................................................................4 6  
3. 1.  
O verall Pla n  .....................................................................................................................4 6  
3. 1. 1.  
St u d y T y p e .......................................................................................................................4 6  
3. 1. 2.  
D ose Escalati o n  ...............................................................................................................4 7  
3. 1. 2. 1.  Part 1 ( D ose Escalati o n of Mila de meta n as a Si n gl e A ge nt)  ...........................................4 8  
3. 1. 2. 2.  Part 1 A ( D ose Es calati o n of Mila de meta n i n C o m bi nati o n wit h A Z A)  .........................5 0  
3. 1. 2. 3.  D ose M o dificati o n of Mila de meta n d ue t o T hr o m b oc yt o p e nia a n d/ or 
Ne utr o pe nia ( C ycl e 2 a n d Lat er)  .....................................................................................5 2  
3. 1. 3.  
Part 2 ( D ose E x pa nsi o n of Mila d e meta n i n C o m bi nati o n wit h A Z A)  ............................5 2  
3. 1. 3. 1.  I ntr as u bject D os e Escal ati o n ...........................................................................................5 2  
3. 2.  
D urati o n of t he St u d y  ......................................................................................................5 3  
3. 2. 1.  
D urati o n of S u bject Parti ci pati o n  ....................................................................................5 3  
3. 2. 2.  
St o p pi n g R ules  .................................................................................................................5 3  
3. 3.  
St o p pi n g R ule f or Ma xi m u m T olerate d D ose Det er mi nati o n  .........................................5 3  
3. 4.  
D ose -li miti n g T o xicities ..................................................................................................5 3  
3. 5.  
Ma xi m u m T olerate d D ose a n d Rec o m me n d e d D ose f or E x pa nsi o n  ..............................5 4  
3. 6.  
Ma na ge me nt of S u bjects wit h A d verse E ve nts  ...............................................................5 4  
3. 7.  
D ose I nterr u pti o ns a n d Re d ucti o ns of St u d y Dr u g (s)  ....................................................5 5  
3. 7. 1.  
D ose Re d ucti o ns Wit h C o nc o mita nt A d mi nistrati o n of a Str o n g C Y P 3 A 
I n hi bit or ...........................................................................................................................5 5  
3. 7. 2.  
D ose I nterr u pti o ns a n d Re d ucti o ns f or N o n -h e mat ol o gic T o xicities  ..............................5 5  
3. 7. 3.  
D ose I nterr u pti o ns a n d Re d ucti o ns f or He mat ol o gi c T o xicities  .....................................5 5  
3. 7. 3. 1.  Mila de meta n  ....................................................................................................................5 6  
3. 7. 3. 2.  5 -Azaciti di ne  ...................................................................................................................5 6  
3. 7. 4.  
D osa ge M o dificati o ns f or 5 -Azaciti di ne Base d o n Re nal F u ncti o n a n d Ser u m 
Electr ol yt es  ......................................................................................................................5 7  
4.  
S T U D Y P O P U L A TI O N  ..................................................................................................5 8  
4. 1.  
E nr oll me nt  .......................................................................................................................5 8  
4. 1. 1.  
I n cl usi o n Criteria ( Part 1/ 1 A a n d Part 2) .........................................................................5 8  

Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 3  
4. 1. 2.  
E x cl usi o n Criteria  ............................................................................................................6 1  
4. 2.  
Disc o nti n uati o n  ................................................................................................................6 3  
4. 2. 1.  
St u d y Treat me nt Disc o nti n uati o ns  ..................................................................................6 3  
4. 2. 2.  
St u d y Disc o nti n uati o n  .....................................................................................................6 4  
4. 2. 3.  
S u bject Re place me nt  .......................................................................................................6 4  
4. 2. 4.  
S u bject Re -scree ni n g Pr oce d ures ....................................................................................6 4  
5.  
T R E A T M E N T S A D MI NI S T E R E D  ................................................................................6 5  
5. 1.  
I n v esti gati o nal Pr o d ucts ..................................................................................................6 5  
5. 1. 1.  
Ra n d o mizati o n a n d Bli n di n g  ...........................................................................................6 5  
5. 1. 2.  
La b eli n g a n d Pac k a gi n g  ..................................................................................................6 5  
5. 1. 3.  
Pre parati o n  .......................................................................................................................6 5  
5. 1. 4.  
A d mi nistrati o n  .................................................................................................................6 5  
5. 1. 5.  
St ora ge  .............................................................................................................................6 5  
5. 1. 6.  
Dr u g Acc o u n ta bilit y ........................................................................................................6 6  
5. 1. 7.  
Rete nti o n Sa m ples  ...........................................................................................................6 6  
5. 2.  
Met h o d of Assessi n g Treat me nt C o m plia nce  ..................................................................6 6  
5. 3.  
C o nc o mita nt Me dicati o ns  ................................................................................................6 7  
5. 3. 1.  
Pr o hi bite d C o nc o mita nt Me dicati o ns/ Acti vities  .............................................................6 7  
6.  
S T U D Y P R O C E D U R E S  .................................................................................................6 8  
6. 1.  
Scree ni n g/ S u bject Eli gi bilit y Pr oce d ures  ........................................................................6 8  
6. 1. 1.  
I nf or me d C o nse nt ............................................................................................................6 8  
6. 1. 2.  
Ge neral Me dical Hist or y a n d Bas eli ne C o n diti o ns  .........................................................6 8  
6. 1. 3.  
Left Ve ntric ul ar Ejecti o n Fracti o n  ...................................................................................6 8  
6. 1. 4.  
Q ualif yi n g B o ne M arr o w E val uati o n  ..............................................................................6 8  
6. 2.  
Efficac y Pr oce d ures  .........................................................................................................6 9  
6. 3.  
Safet y Pr oce d ures  ............................................................................................................6 9  
6. 3. 1.  
A d v erse E v e nts a n d C o n c o mita nt Me dicati o ns  ...............................................................6 9  
6. 3. 2.  
Vital Si g ns  .......................................................................................................................6 9  
6. 3. 3.  
Cli nical La b orat or y Assess me nts  ....................................................................................6 9  
6. 3. 4.  
1 2 -lea d Electr ocar di o gra m ..............................................................................................6 9  
6. 3. 5.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us  ............................................6 9  
6. 4.  
P har mac o ki netic/ P har mac o d y n a mic Pr oce d ures  .............................................................6 9  

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6. 4. 1.  
P har mac o ki netic Bl o o d Sa m ples  .....................................................................................6 9  
6. 4. 2.  
Bi o mar ker A nal ysis Usi n g Bl o o d or B o ne Marr o w Sa m ples  .........................................6 9  
6. 4. 3.  
Bl o o d Sa m ple f or Ba n ki n g Plas ma  ..................................................................................7 0  
6. 4. 4.  
B uccal S wa b f or P har mac o ge n o mics  ..............................................................................7 0  
6. 5.  
E n d -of -treat me nt - Part 1/ Part 1 A a n d Part 2 ( P ost -c ycle)  ..............................................7 0  
6. 5. 1.  
E n d -of -treat me nt B o n e Marr o w Re-bi o ps y ( Part 1/ Part 1 A a n d Part 2)  .........................7 0  
6. 6.  
F oll o w -u p P hase  ..............................................................................................................7 0  
6. 6. 1.  
F oll o w -u p 3 0 Da ys After E n d -of -treat me nt ....................................................................7 0  
6. 6. 2.  
L o n g -t er m S ur vi val F oll o w-u p  ........................................................................................7 1  
6. 7.  
Pr ot oc ol De viati o ns  .........................................................................................................7 1  
7.  
E F FI C A C Y A S S E S S M E N T S  .........................................................................................7 3  
7. 1.  
Efficac y Varia ble(s)  .........................................................................................................7 3  
7. 1. 1.  
B o ne Marr o w Bi o psies/ As pirates ( S u bjects wit h A M L) .................................................7 3  
7. 1. 2.  
B o ne Marr o w Bi o psies/ As pirates ( S u bjects wit h Hi g h -ris k M D S) ................................7 4  
7. 1. 3.  
B o ne Marr o w Sa m ples f or Tra nslati o nal Researc h ( A M L a n d Hi g h -ris k M D S)............7 6  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S  ...........................7 7  
8. 1.  
P har mac o ki netic Varia bl es  ..............................................................................................7 7  
8. 2.  
P har mac o d y na mic a n d Pre dicti ve Bi o mar ker Varia ble(s)  ..............................................7 8  
8. 2. 1.  
T u m or Pr otei n p 5 3 Stat us  ................................................................................................7 8  
8. 2. 2.  
P har mac o d y na mic Varia bles  ...........................................................................................7 9  
8. 2. 3.  
E x pl orat or y Bi o mar ker A nal ysis  .....................................................................................7 9  
8. 3.  
Ge netic a n d P har mac o ge n o mic Testi n g  ..........................................................................7 9  
9.  
S A F E T Y A S S E S S M E N T S  .............................................................................................8 0  
9. 1.  
A d verse E v e nts  ................................................................................................................8 0  
9. 2.  
E ve nts of  S pecial I nterest  ................................................................................................8 0  
9. 3.  
Defi niti o ns  .......................................................................................................................8 1  
9. 3. 1.  
A d verse E v e nt  .................................................................................................................8 1  
9. 3. 2.  
Seri o us A d verse E v e nt  ....................................................................................................8 1  
9. 3. 3.  
A d verse E v e nt Se verit y  ...................................................................................................8 2  
9. 3. 4.  
Ca usalit y Assess me nt  ......................................................................................................8 2  
9. 3. 5.  
Acti o n Ta ke n Re gar di n g t he St u d y Dr u g  ........................................................................8 2  
9. 3. 6.  
A d verse E v e nt O utc o me  ..................................................................................................8 3  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 5  
9. 3. 7.  
Ot her Acti o n Ta k e n f or E ve nt  .........................................................................................8 3  
9. 4.  
Seri o us A d verse E v e nt Re p orti n g Pr oce d ure f or I n vesti gat ors  .......................................8 3  
9. 4. 1.  
I nitial Re p orts ..................................................................................................................8 3  
9. 4. 2.  
F ol l o w-u p Re p orts  ...........................................................................................................8 4  
9. 4. 3.  
N otif yi n g Re g ulat or y A ut h orities, I n vesti gat ors, a n d I nstit uti o nal Re vie w 
B oar d/ Et hics C o m mittees  ................................................................................................8 4  
9. 5.  
E x p os ure I n Uter o D uri n g Cli nical St u dies  .....................................................................8 4  
9. 6.  
Cli nical La b orat or y E val uati o ns  ......................................................................................8 5  
9. 7.  
Vital Si g ns  .......................................................................................................................8 5  
9. 8.  
Electr ocar di o gra ms  ..........................................................................................................8 5  
9. 9.  
P h ysical Fi n di n gs  .............................................................................................................8 5  
9. 1 0.  
Ot he r Safet y Ass ess me nts ...............................................................................................8 5  
1 0.  
O T H E R A S S E S S M E N T S  ...............................................................................................8 6  
1 1.  
S T A TI S TI C A L M E T H O D S  ...........................................................................................8 7  
1 1. 1.  
A nal ysis Sets  ...................................................................................................................8 7  
1 1. 2.  
Ge neral Statistical C o nsi derati o ns  ...................................................................................8 7  
1 1. 3.  
St u d y P o p ulati o n Dat a  .....................................................................................................8 8  
1 1. 4.  
Efficac y A nal yses  ............................................................................................................8 8  
1 1. 5.  
P har mac o ki netic/ P har mac o d y n a mic A nal yses  ................................................................8 8  
1 1. 5. 1.  P har mac o ki netic A n al ys es  ...............................................................................................8 8  
1 1. 5. 2.  P har mac o d y na mic A nal yses  ............................................................................................8 9  
1 1. 5. 3.  Bi o mar ker a n d E x pl orat or y A nal yses  .............................................................................8 9  
1 1. 6.  
Safet y A nal yses  ...............................................................................................................8 9  
1 1. 6. 1.  A d verse E v e nt A nal yses  ..................................................................................................8 9  
1 1. 6. 2.  Cli nical La b orat or y E val uati o n A nal ys es  ........................................................................9 0  
1 1. 6. 3.  Vital Si g ns A nal yses  ........................................................................................................9 0  
1 1. 6. 4.  Electr ocar di o gra m A n al yses  ............................................................................................9 0  
1 1. 6. 5.  P h ysical E x a mi nati o n Fi n di n g A nal ys es  .........................................................................9 0  
1 1. 6. 6.  Ot her Safet y A nal yses  .....................................................................................................9 0  
1 1. 7.  
Ot her A nal yses  ................................................................................................................9 0  
1 1. 8.  
I nteri m A nal yses ..............................................................................................................9 1  
1 1. 9.  
Data  a n d Safet y M o nit ori n g B oar d  ..................................................................................9 1  
1 1. 1 0.  
Sa m ple Size Deter mi nati o n  .............................................................................................9 1  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 6  
1 1. 1 1.  
S pecificati o n of Ba yesi a n L o gistic Re gressi o n M o del wit h Escalati o n wit h 
O ver d ose C o ntr ol  .............................................................................................................9 2  
1 1. 1 1. 1.  Ba yesi a n L o gistic Re gressi o n M o del Wit h Escalati o n Wit h O ver d ose C o ntr ol  .............9 2  
1 1. 1 1. 2.  Pri or S pecificati o n f or Ba yesia n L o gistic Re gressi o n M o del Para meters  .......................9 2  
1 1 . 1 1. 3. Escalati o n wit h O ver d ose C o ntr ol Pri nci ple  ...................................................................9 2  
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ..................................................9 4  
1 2. 1.  
M o nit ori n g a n d I ns p ecti o ns  .............................................................................................9 4  
1 2. 2.  
Data C ollecti o n  ................................................................................................................9 4  
1 2. 3.  
Data Ma na ge me nt  ............................................................................................................9 5  
1 2. 4.  
St u d y D oc u me ntati o n a n d St ora ge  ..................................................................................9 5  
1 2. 5.  
Rec or d Kee pi n g  ...............................................................................................................9 6  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  ..................................................................................9 7  
1 3. 1.  
Fi na nces  ...........................................................................................................................9 7  
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura n ce  .....................................................................9 7  
1 4.  
P U B LI C A TI O N P O LI C Y  ...............................................................................................9 8  
1 5.  
E T HI C S A N D S T U D Y A D M I NI S T R A TI V E I N F O R M A TI O N ...................................9 9  
1 5. 1.  
C o m plia nce State me nt, Et hics, a n d Re g ul at or y C o m plia nce  ..........................................9 9  
1 5. 1. 1.  S u bject C o nfi de ntialit y  ....................................................................................................9 9  
1 5. 1. 2.  I nf or me d C o nse nt Pr oce d ure ...........................................................................................9 9  
1 5. 1. 3.  Re g ulat or y C o m plia nce  .................................................................................................1 0 0  
1 5. 2.  
Pr ot oc ol A me n d me nts  ...................................................................................................1 0 1  
1 5. 3.  
A d dress List  ...................................................................................................................1 0 1  
1 5. 3. 1.  S p o ns o r ..........................................................................................................................1 0 1  
1 5. 3. 1. 1.  S p o ns or’s Me dical M o nit or  ...........................................................................................1 0 1  
1 5. 3. 1. 2.  S p o ns or’s Cli nical Scie ntist  ...........................................................................................1 0 1  
1 5. 3. 1. 3.  S p o ns or’s Cli nical St u d y Ma na ger/ Deli ver y Lea d  ........................................................1 0 2  
1 5. 3. 1. 4.  S p o ns or’s Safet y C o ntact  ..............................................................................................1 0 2  
1 5. 3. 1. 5.  S p o ns or’s Bi ostatisticia n  ...............................................................................................1 0 2  
1 5. 3. 2.  C R O  ...............................................................................................................................1 0 2  
1 5. 3. 2. 1.  C R O Me dica l M o nit or ...................................................................................................1 0 2  
1 5. 3. 2. 2.  C R O Pr oject Ma na ger  ...................................................................................................1 0 2  
1 5. 3. 2. 3.  C R O Dr u g Safet y  ..........................................................................................................1 0 2  
1 5. 3. 2 . 4. C R O Data Ma na ge me nt  ................................................................................................1 0 2  

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1 5. 3. 3.  Bi ol o gical S peci me ns  ....................................................................................................1 0 3  
1 5. 3. 4.  Bi oa nal ytical La b orat or y  ...............................................................................................1 0 3  
1 6.  
R E F E R E N C E S  ..............................................................................................................1 0 4  
1 7.  
A P P E N DI C E S  ...............................................................................................................1 0 6  
1 7. 1.  
Sc he d ule of E ve nts  ........................................................................................................1 0 6  
1 7. 2.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us Scale 1 4 ..............................1 1 4  
1 7. 3.  
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, 
Versi o n 5. 0 ( Versi o n 4. 0 3 bef ore 0 1  A pr  2 0 1 8)  ............................................................1 1 5  
1 7. 4.  
Res p o nse Criteria f or A M L  ...........................................................................................1 1 6  
1 7. 4. 1.  2 0 1 7 E ur o pea n Le u ke mi a Net Rec o m me n d ati o ns f or Ac ute M yel o ge n o us 
Le u k e mia wit h M o dificati o ns ( Part 2 O nl y) 1 6 ...............................................................1 1 6  
1 7. 4. 2.  He mat ol o gi c Rec o ver y Re q uire me nts f or C R a n d C Ri ( All Parts)  ...............................1 1 7  
1 7. 4. 3.  C R h ( A d diti o nal Defi niti o ns/ Res p o nse Criteria) ( All Parts) 1 7 ......................................1 1 8  
1 7. 4. 4.  2 0 0 3 I nter nati o nal W or ki n g Gr o u p Res p o nse Criteria f or Ac ute M yel o ge n o us 
Le u k e mia wit h M o dificati o ns ( Part 1 a n d Part 1 A O nl y) 1 5 ...........................................1 1 9  
1 7. 5.  
Res p o nse Criteria f or M D S  ...........................................................................................1 2 0  
1 7. 5. 1.  2 0 0 6 I nter nati o nal W or ki n g Gr o u p Res p o nse Criteria f or M yel o d ys plastic 
S y n dr o me 1 6 ....................................................................................................................1 2 0  
1 7. 6.  
Re vise d I nter nati o nal Pr o g n ostic Sc ori n g S yste m 1 9 ......................................................1 2 3  
1 7. 7.  
C yt o c hr o me P 4 5 0 3 A I n d ucers a n d I n hi bit ors  ..............................................................1 2 4  
1 7. 8.  
Ne w Y or k Heart Ass ociati o n ( N Y H A) F u ncti o nal Classificati o ns  ...............................1 2 5  
1 7. 9.  
Hi g hl y Effecti ve M et h o ds of Birt h C o ntr ol  ...................................................................1 2 6  
 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 8  
LI S T O F T A B L E S  
Ta ble  3. 1:  St u d y Desi g n  ...............................................................................................................4 7  
Ta ble  3. 2:  D osi n g Sc he d ul e of Mila de meta n as a Si n gle A ge nt ( Part 1)  ....................................4 9  
Ta ble  3. 3:  D osi n g Sc he d ul e of Mila de meta n i n C o m bi nati o n wit h 5 -Azaciti di ne  ......................5 1  
Ta ble  3. 4:  5 -Azaci ti di ne D osa ge A dj ust me nts Base d o n Na dir C o u nts ......................................5 6  
Ta ble  3. 5:  5 -Azaciti di ne D osa ge A dj ust me nts Base d o n Na dir C o u nts  ......................................5 7  
Ta ble  8. 1:  C ycle 1 Bl o o d Sa m ple C ollecti o n f or P har mac o ki netics D uri n g D ose 
Escalati o n ( Part 1 A, Sc h e d ule E)  ................................................................................7 7  
Ta ble  8. 2:  C ycle 1 Bl o o d Sa m ple C ollecti o n f or P har mac o ki netics D uri n g D ose 
Escalati o n ( Part 1 A, Sc h e d ule F)  ................................................................................7 7  
Ta ble  8. 3:  C ycle 1 Bl o o d Sa m ple C ollecti o n f or P har mac o ki netics of 5 -Azaciti di ne 
D uri n g D ose Escalati o n ( n = 6, Mila de meta n o n Da ys 5 t o 1 4 –  Part 1 A, 
Sc he d ule E)  .................................................................................................................7 8  
Ta ble  8. 4:  C ycle 1 S parse Sa m ple C ollecti o n f or Mila de meta n P har mac o ki netics 
D uri n g D ose E x pa nsi o n f or All S u bjects  ....................................................................7 8  
Ta ble  1 7. 1:  Sc he d ule of E ve nts Part 1 ( D ose Escalati o n) –  Mila de meta n as a Si n gle 
A ge nt  .........................................................................................................................1 0 7  
Ta ble  1 7. 2:  Sc he d ule of E ve nts Part 1 A ( D ose Escalati o n) a n d Part 2 ( D ose E x pa nsi o n) 
–  wit h Mila de meta n o n Da ys  5  t o 1 4 ( Sc he d ule E)  ..................................................1 0 9  
Ta ble  1 7. 3:  Sc he d ule of E ve nts Part 1 A ( D ose Escalati o n) a n d Part 2 ( D ose E x pa nsi o n) 
–  wit h Mila de meta n o n Da ys  8  t o 1 4 ( Sc he d ule F)  ..................................................1 1 2  
Ta ble  1 7. 4:  Res p o nse Criteria  ......................................................................................................1 2 0  
Ta ble  1 7. 5:  He mat ol o gi c I m pr o ve m e nt  .......................................................................................1 2 2  
Ta ble  1 7. 6:  T he I nter n ati o nal Pr o g n ostic Sc ori n g S yste m –  Re vise d Para meters a n d 
Sc ore Val ues  .............................................................................................................1 2 3  
Ta ble  1 7. 7:  T he I nter n ati o nal Pr o g n ostic Sc ori n g S yste m –  Re vise d Ris k Gr o u ps  ....................1 2 3  
 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 9  
LI S T O F FI G U R E S  
Fi g ure  1. 1:  Tar gete d M ec ha nis m of Mila de meta n A ntit u m or Acti vit y  ........................................3 5  
Fi g ure  1. 2:  Effects of Mila de meta n a n d 5 -Azaciti di ne o n Esti mate d T u m or V ol u me i n 
M O L M -1 3 -Beari n g N o n -O bese Di a betic Se vere C o m bi ne d 
I m m u n o deficie nt Mice ................................................................................................3 6  
Fi g ure  3. 1:  D osi n g Sc he d ul e of Mila de meta n as a Si n gle A ge nt ( Part 1)  ....................................4 9  
Fi g ure  3. 2:  D osi n g Sc he d ul e of Mila de meta n i n C o m bi nati o n wit h 5 -Azaciti di ne  ......................5 1  
Fi g ure  3. 3:  Alter nati ve 5 -Azaciti di ne D osi n g Sc he d ul e i n C o m bi nati o n wit h 
Mila de meta n at R D E  ..................................................................................................5 2  
Fi g ure  7. 1:  B o ne Marr o w Bi o ps y/ As pirate Sc he d ule  f or A M L ....................................................7 4  
Fi g ure  7. 2:  B o ne Marr o w Bi o ps y/ As pirate Sc he d ule f or Hi g h -ris k M D S ....................................7 5  
Fi g ure  1 7. 1:  He mat ol o gi c Rec o ver y Re q uire me nts f or C R a n d C Ri ( All Parts)  ......................1 1 7  
Fi g ure  1 7. 2:  He mat ol o gi c Rec o ver y Re q uire me nts f or C R a n d C R h ( All Parts)  .....................1 1 8  
 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 0  
LI S T O F A B B R E VI A TI O N S  
A B B R E VI A TI O N  
D E FI NI TI O N  
A E  
A d verse e ve nt  
A L T  
Ala ni ne ami n otra nsferase  
A M L  
Ac ute m yel o ge n o us le u ke mia  
A N C  
A bs ol ute ne utr o p hil c o u nt  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase 
A U C 6 h  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve u p  t o ti me 6 h o urs  
A U C 2 4 h  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve u p  t o ti me 2 4 h o urs  
A U Ci nf  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve u p t o i nfi nit y 
A Z A  
5 -Azac iti di ne 
B C R P  
Breast ca ncer resista nce pr otei n  
B L R M  
Ba yesia n l o gistic re gressi o n m o del  
B U N  
Bl o o d urea nitr o ge n  
C D K N 2 A  
C ycli n -de pe n de nt ki nase i n hi bit or 2 A  
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 N S  
Ce ntral ner v o us s yste m  
C R  
C o m plete re missi o n  
C Rc  
C o m p osite c o m plete re missi o n  
C R h  
C o m plete re missi o n wit h partial he mat ol o gical rec o ver y  
C Ri  
C o m plete re missi o n wit h i nc o m plete bl o o d c o u nt rec o ver y  
C R O  
C o ntract researc h or ga nizati o n  
C S P V  
Cli nical Safet y a n d P har mac o vi gila nce  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
Ctr o u g h  
Tr o u g h plas ma c o nce ntrati o n  
C Y P  
C yt oc hr o me P 4 5 0  
D DI  
Dr u g -dr u g i nteracti o n  
D L T  
D ose -li miti n g t o xicit y(ies) 
D N A  
De o x yri b o n ucleic aci d  
D o R  
D urati o n of c o m p osite c o m plete remissi o n  

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Pa ge 3 1  
A B B R E VI A TI O N  
D E FI NI TI O N  
D S -3 0 3 2a  
T he free f or m of D S -3 0 3 2 b  
D SI  
Daiic hi Sa n k y o, I nc.  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E D C  
Electr o nic data ca pt ure  
EI U  
E x p os ure I n U ter o 
E L N  
E ur o pea n Le u ke mia Net  
E W O C  
Escalati o n wit h o ver d ose c o ntr ol  
G C P  
G o o d Cli nical Practice  
G V H D  
Graft -vers us -h ost disease  
H C T  
He mat o p oietic  cell tra ns pla ntati o n  
h E R G  
H u ma n et her -a -g o -g o relate d ge ne  
HI  
He mat ol o gic i m pr o ve me nt  
H N S T D  
Hi g hest n o nse verel y t o xic d ose  
I B 
I n vesti gat or’s Br oc h ure 
I C 5 0 
Half ma xi mal i n hi bit or y c o nce ntrati o n  
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 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 V 
I ntra ve n o us(l y)  
I W G 
I nter nati o nal W or ki n g Gr o u p 
m C R  
Marr o w c o m plete re missi o n  
M D M 2  
M uri ne d o u ble mi n ute 2  
M D M 4  
M uri ne d o u ble mi n ute 4  
M D S  
M yel o d ys plastic s y n dr o me 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
MI C -1  
Macr o p ha ge i n hi bit or y c yt o ki ne -1  
M L F S  
M or p h ol o gic le u ke mia -free state 
M O L M -1 3  
Le u ke mia cell li ne  
M T D  
Ma xi m u m t olerate d d ose  

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Pa ge 3 2  
A B B R E VI A TI O N  
D E FI NI TI O N  
N CI  
Nati o nal Ca ncer I nstit ute  
O S  
O verall s ur vi val  
P D  
Pr o gressi ve disease  
P D y  
P har mac o d y na mic(s)  
P -g p  
P -gl yc o pr otei n  
P G x  
P har mac o ge n o mics  
P K  
P har mac o ki netic(s)  
P o p P K  
P o p ulati o n p har mac o ki netics  
P R  
Partial re missi o n  
q d  
O nce dail y  
q d 3/ 1 4  × 2   
O nce dail y f or 3 of 1 4 da ys re peate d t wice i n a 2 8 -da y c ycle  
q d 7/ 2 8  
O nce dail y o n Da ys 1 t o 7 of a 2 8 -da y c ycle  
q d 1 4/ 2 8  
O nce dail y o n Da ys 1 t o 1 4 of a 2 8 -da y c ycle  
q d 2 1/ 2 8  
O nce dail y o n Da ys  1 t o 2 1 of a 2 8 -da y c ycle  
q d 2 8/ 2 8  
O nce dail y o n Da ys  1 t o 2 8 of a 2 8 -da y c ycle  
Q Tc F  
C orrecte d Q T i nter val usi n g Fri dericia’s f or m ula  
R B C  
Re d bl o o d cell  
R D E  
Rec o m me n de d d ose f or a n e x pa nsi o n c o h ort  
R N A  
Ri b o n ucleic aci d  
R P 2 D  
Rec o m me n de d P hase 2 d ose  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S A V E R  
Seri o us A d verse E ve nt Re p ort  
S D  
Sta ble disease  
SI D  
S u bj ect i de ntificati o n n u m ber  
SJ S A -1  
Oste osarc o ma cell li ne  
S O C  
S yste m Or ga n Class  
S O P  
Sta n dar d o perati n g pr oce d ure  
S Q  
S u bc uta ne o us(l y)  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse e ve nt reacti o n  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T ma x  
Ti me t o reac h ma xi m u m plas ma c o nce ntrati o n 

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Pa ge 3 3  
A B B R E VI A TI O N  
D E FI NI TI O N  
T P 5 3  
T he ge ne e nc o di n g p 5 3  
U L N  
U p per li mit of n or mal  
W B C  
W hite bl o o d cell  

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1.   
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N 
1. 1.   
I n vesti g ati o n al Pr o d ucts 
1. 1. 1.   
Mil a de met a n  
D S -3 0 3 2 b (I nter n ati o nal N o n pr o prietar y Na me  [I N N]:  Mila de meta n ) 
Mila de meta n is a n orall y a vaila ble a n d hi g hl y selecti ve i n hi bit or of t he m uri ne d o u ble mi n ute  2 
( M D M 2)-p 5 3 i nteracti o n.  
Mila de meta n ( D S -3 0 3 2a) is t he free base a n d t he acti ve m oiet y of t he salt f or m ( D S -3 0 3 2 b).  
T he salt f or m ( D S -3 0 3 2 b) is t he acti ve p ha r mace utical i n gre die nt of t he oral ca ps ule f or m ulati o n.  
T hr o u g h o ut t he re mai n der of t his d oc u me nt, D S -3 0 3 2a a n d D S -3 0 3 2 b will be referre d t o as 
“ mila de meta n” u nless i n dicate d ot her wis e.  
1. 1. 2.   
5 -Az aciti di ne  
5 -Azaciti di ne (I N N:  Azaciti di ne ) 
5 -Azaciti di ne ( A Z A) is a p yri mi di ne n ucle osi d e a nal o g of c yti di ne a n d is i n dicate d f or t he 
treat me nt of patie nts wit h m yel o d ys plastic s y n dr o me ( M D S).1 
1. 2.   
Inte n de d Use U n der I n vesti g ati o n  
Mila de meta n  will be e val uate d i n s u bjects wit h rel a pse d or refract or y (R/ R)  ac ute m yel o ge n o us 
le u ke mia ( A M L) or hi g h -ris k m yel o d ys plastic s y n dr o me ( M D S) as a si n gle a ge nt i n Part 1 a n d i n 
c o m bi nati o n wit h A Z A i n Part 1 A .  I n Part 2, mila de meta n i n c o m bi nati o n wit h A Z A will be 
e val uate d i n s u bjects wit h R/ R  A M L , n e wl y dia g n ose d A M L u nfit f or i nte nsi ve c he m ot hera p y, 
or hi g h -ris k M D S. 
1. 3.   
P h ar m ac ol o gi c al T ar get(s) 
Mila de meta n , a n o vel, s p ecific, s mall-m olec ul e i n hi bit or of M D M 2, disr u pts i nt eracti o ns 
bet wee n M D M 2 a n d t he t u m or s u p press or pr otei n p 5 3 i n t u m or cells a n d is bei n g d e vel o pe d as 
a n oral dr u g f or t he treat me nt of ca ncer .  T he t u m or s u p press or pr ot ei n p 5 3 pla ys a n esse ntial 
r ole i n pre ve nti n g ne o pl asia b y i n d uci n g cell c ycle arrest o r a p o pt osis i n cells u n der g oi n g v ari o us 
t y pes of p h ysi ol o gical stress.  H o we ver, i nacti vati o n of p 5 3 b y m utati o n occ urs i n a si g nifica nt 
perce nt a ge of h u m a n t u m ors, res ulti n g i n a l oss of t u m or s u p press or acti vit y a n d t here b y 
re m o vi n g a pi v otal barri er t o ne o plastic de vel o p m e nt.  
Mila de meta n e x erts a ntit u m or acti vit y b y i n hi biti n g i nteracti o ns bet wee n M D M 2 a n d p 5 3 a n d 
pre ve nti n g p 5 3 de gra dati o n.  T he res ulti n g i n creas e i n wil d -t y pe p 5 3 acti vit y acti vates 
tra nscri pti o nal pat h wa ys i m p orta nt i n i n d uci n g cell c ycl e arrest, a p o pt osis, a n d/ or se nesce nce i n 
t u m or cells. 
T he mec ha nis m of acti o n of m ila de meta n is s u m marize d i n Fi g ure  1 .1 . 

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Pa ge 3 5  
Fi g ure  1 .1 : 
T ar gete d Mec h a nis m of Mil a de met a n  A ntit u m or Acti vit y  
 
Ba x  =  Bcl -2 -ass ociate d X pr otei n; M D M 2 = m uri ne d o u ble mi n ute 2; p u ma = p 5 3 u pre g ul ate d m o d ulat or of 
a p o pt osis; U b  =  u bi q uiti n  
I n h u ma n t u m ors t hat ret ai n wil d-t y pe p 5 3 pr otei n, p 5 3  acti vit y is fre q ue ntl y i n hi bite d b y 
i nter m olec ular i nteracti o ns bet wee n p 5 3 a n d M D M 2.  M D M 2 a n d p 5 3 f or m a n  a ut ore g ulat or y 
fee d bac k l o o p i n w hic h M D M 2 mai ntai ns l o w le vels of p 5 3 acti vity i n n or mal, u nstresse d cells, 
b y pr o m oti n g e x p ort of p 5 3 o ut of t he n ucle us a n d pr oteas o me -me di ate d de gra dati o n of p 5 3 
t hr o u g h its E 3 u bi q uiti nati o n  li gase acti vit y.1  I n t he prese n ce of stress, p 5 3 bec o mes acti vate d 
a n d s u bse q ue ntl y acts as a tra nscri pti o n fact or t hat m o d ulates t he e x pressi o n of a variet y of 
ge n es, i ncl u di n g M D M 2. 3  T he M D M 2 bi n di n g d o mai n o n p 5 3 o verla ps wit h t he tra nscri pti o nal 
acti vati o n d o mai n of p 5 3, t here b y i n hi biti n g t he acti vit y of p 5 3 .  T h us, i n h u ma n t u m ors , 
disr u pti o n of M D M 2/ p 5 3 bala nce t hr o u g h o v ere x pressi o n a n d/ or o nc o ge nic acti vati o n of M D M 2 
all o ws t u m ori ge n esis a n d t u m or gr o wt h b y pre ve nti n g p 5 3 f u n cti o n.  P har mac ol o gic i n hi biti o n of 
t he i nteracti o n bet w ee n M D M 2 a n d wil d-t y p e p 5 3 i n t u m or cells c o ul d res ult i n s ustai ne d 
i ncreas es i n p 5 3 acti vit y a n d s u bse q ue nt a ntit u m or effects.4 ,5  T heref ore, p har mac ol o gic 
rest orati o n of t he p 5 3 pat h wa y c o ul d be a n effecti ve strate g y f or ca n cer t hera p y tar geti n g t he 
wi de arra y of h u ma n ca n cers t hat r etai n wil d -t y pe p 5 3.6 
1. 4.   
D at a S u m m ar y  
N o n cli nical p har mac o l o g y st u dies were c o n d ucte d t o de mo nstrate t he r ole of m ila de meta n i n 
s u p pressi o n of t u m or gr o wt h.  I n vitr o st u dies e v al uate d t he p ote nc y of m ila de meta n f or 
i n hi biti o n of t he M D M 2-p 5 3 i nteracti o n, t he i n d ucti o n of p 5 3 -i n d uce d ge n e e x pressi o n, a n d t he 
i n hi biti o n of t u m or gr o wt h i n 6 h u ma n ca ncer cell li nes.  I n a d diti o n, i n vi v o st u dies were 
c o n d ucte d i n a m o use m o del t o de m o nstrate a ntit u m or acti vit y of m ila de m eta n after oral 
a d mi nistrati o n.  

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T he effects of m ila de m eta n o n h u ma n A M L as si n gle a ge nt a n d i n c o m bi nati o n wit h a 
h y p o met h ylati n g a ge nt, A Z A, were e v al uate d b y treati n g t h e x e n o graft A M L m o del ( M O L M -1 3)  
wit h wil d -t y pe ge n e e n c o di n g p 5 3 ( T P 5 3) i n i m m un o deficie nt mice.  N o n -o bese dia betic s e vere 
c o m bi ne d i m m u n o deficie nt mice beari n g M O L M -1 3 x e n o grafts were treate d wit h m ila de meta n 
at 2 5 or 5 0 m g/ k g/ da y f or 1 1 da ys orall y a n d wit h A Z A at 4  m g/ k g/ da y f or 5 da ys, eit her as 
si n gle a ge nts or i n c o m bi nati o n.  A ntit u m or effects were assesse d bas e d o n esti mate d t u m or 
v ol u mes o n Da y 1 1.  As ca n be see n i n Fi g ure  1 .2 , si g nifica nt t u m or gr o wt h i n hi biti o n c o m pare d 
t o t he u ntreate d c o ntr ol were s ee n b y treat me nt wit h t he t w o d ose le vels of m ila de meta n al o ne 
( 4 6. 4 % a n d 8 0. 3 % f or t h e 2 5 m g a n d 5 0 m g d os es, res pecti vel y), a n d wit h A Z A al o ne ( 4 9. 6 %).  
T he c o m bi nati o n treat me nt f urt her i ncrease d t h e t u m or gr o wt h i n hi biti o n ( 7 5. 4 % a n d 9 4. 8 %, 
res pecti vel y, f or t he 2 5 a n d 5 0 m g m ila de meta n gr o u p i n c o m bi nati o n  wit h 4  m g A Z A).  I n t his 
e x peri me nt, t he mice were treate d wit h m ila de meta n a n d A Z A c o nc o mita ntl y (starti n g fr o m t he 
sa me da y) f or 1 1 a n d 5 d a ys, res pecti vel y. 
Fi g ure  1 .2 : 
Effects of Mil a de met a n  a n d 5 -Az ac iti di ne o n Esti m ate d T u m o r V ol u me i n 
M O L M -1 3 -B e ari n g No n -O bese D i a betic S e vere C o m bi ne d Im m u n o deficie nt  
Mice  
 
M C = met h ylcell ul ose  
N ote:  D ata p oi nts re prese nt t he mea n f or 1 0 a ni mals .  T he vertical bars re prese nt sta n dar d err or. 
S o urce :  Mila d e meta n  I n vesti gat or’s Br oc h ure 7 
Safet y p h ar mac ol o g y st u dies were c o n d ucte d i n c o m plia nce  w it h G o o d La b orat or y Practice 
re g ulati o ns a n d e v al uate d t he effect of m ila de met a n o n t he car di o vas c ular s yste m, ce ntral 
ner v o us  s yst e m ( C N S), a n d p ul m o nar y s yste m. 

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Pa ge 3 7  
In vitr o a n d i n vi v o data  fr o m t hese st u dies s u g gest a l o w ris k p ote ntial o n car di o vasc ular 
f u ncti o n i n h u ma ns at m ila de meta n e x p os ures e x pecte d t o be ass ociate d wit h cli nical efficac y . 
Effects o n t he C N S a n d p ul m o nar y s yste m were e val uate d as part of a 4 -wee k re p eate d d ose 
t o xicit y st u d y, i n w hic h n o a d verse effects o n m ot or acti vit y a n d n o fi n di n gs of p h ysi ol o gical 
c o ncer n f or effects o n t he p ul m o nar y s yste ms w ere n ote d . 
Mila de meta n is a s u bstrate f or C Y P 3 A a n d P -g p.   A P hase 1 st u d y i n healt h y s u bjects w as 
c o n d ucte d t o e v al uate t he effect of c o -a d mi nistrati o n of str o n g C Y P 3 A 4 i n hi bit ors (itrac o naz ole 
a n d p osac o naz ole) o n mila de meta n P K ( St u d y D S 3 0 3 2 -A -U 1 0 7).  C o -a d mi nistrati o n of 
mila de meta n 1 0 0 m g wit h itrac o naz ole 2 0 0 m g , a n antif u n gal a n d a str o n g C Y P 3 A i n hi bit or,  at 
stea d y st ate i ncrease d mila de meta n ge o metric mea n ma xi m u m plas ma c o nce ntrati o n ( C ma x ) a n d 
area u n d er t he pl as ma c o nce ntrati o n -ti me c ur ve u p t o i nfi nit y (A U Ci nf ) b y 8 % a n d 1 1 5 % , 
res pecti vel y.  Si milarl y, p osac o naz o le 2 0 0 m g at stea d y st ate i ncrease d mila de meta n mea n C ma x 
b y a p pr o xi matel y 1 9 % a n d mea n A U Ci nf b y a p pr o xi matel y 1 4 9 %.  T heref ore, it is 
rec o m me n de d t h at t he d ose of mila de meta n b e re d uce d t o 5 0 %  w he n it is c o nc o mita ntl y 
a d mi nistere d wit h a str o n g C Y P 3 A 4 i nhi bit ors.  
T he direct i n hi bit or y p ote ntial of m ila de meta n o n h u ma n  C Y P is oe nz y mes was st u die d i n  vitr o 
a n d mila de meta n s h o we d direct i n hi biti o n o n C Y P 2 A 6, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, 
C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5, b ut n ot o n C Y P 1 A 2, a n d C Y P 2 E 1 (I C 5 0 ra n ge: 7. 8  µ M t o 
2 7. 0  µ M).  Mila de meta n  als o s h o we d mil d -t o-m o derate, met a b olis m -de pe n de nt i n hi biti o n o f 
C Y P 3 A 4/ 5 ( b ot h test oster o ne 6 β -h y dr o x ylase a n d mi daz ola m 1 '-h y dr o x ylase), b ut n ot o n t h e 
o t her C Y P is oe nz y m es e x a mi ne d.  H o we ver, t hes e le vels (I C 5 0 val u es) of mi la de meta n are 
m uc h hi g her t ha n plas ma c o nce ntr ati o ns at e x pecte d t hera p e utic d oses i n s u bjects a n d 
c o nc o mita nt use of C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5 
s u bstrates will t heref ore be per mitte d. 
A d diti o nal i nf or mati o n  f or o n g oi n g st u dies an d t h e m ost c urre nt safet y a n d n o ncli nical 
i nf or mati o n f or mila de m eta n ca n b e f o u n d i n t he I n vesti gat or’s Br oc h ure  (I B).7 
1. 4. 1.   
Cli nic al E x perie nce  
A P hase 1 m ulti ple asce n di n g d ose st u d y ( D S 3 0 3 2-A -U 1 0 1) of m ila de meta n i n s u bjects wit h 
a d va nce d s oli d t u m ors  or l y m p h o mas  is c urre ntl y o n g oi n g.  A n ot her P hase 1 st u d y of 
m ila de meta n ( D S 3 0 3 2-A -J 1 0 3) i n s u bjects wit h a d va nce d s oli d t u m ors or l y m p h o mas is als o 
c urrentl y o n g oi n g.  I n a d diti o n, a n ot her P hase 1 st u d y of mila de m eta n i n c o m bi nati o n wit h 
q uizarti ni b ( D S 3 0 3 2-A -U 1 0 5) i n s u bjects wit h F L T 3-I T D m uta nt A M L a n d a P hase 1 st u d y of 
mila de meta n i n s u bjects wit h A M L i n J a pa n ( D S 3 0 3 2 -A -J 1 0 4) are o n g oi n g. 
A d diti o nal i nf or mati o n o n o n g oi n g a n d c o m plete d  st u dies ca n be f o u n d i n t he I B.7 
1. 5.   
St u d y R ati o n ale  
T he t u m or s u p press or p 5 3 is a tra nscri pti o n fact or t hat pla ys a ce ntral r ole i n pre ve nti n g t u m or 
de vel o p me nt a n d pr o gressi o n b y i n d uci n g cell c ycle arrest, a p o pt osis, or se nesce nce.  T P 5 3 
s uffers disa bli n g s o matic m utati o ns or deleti o ns i n a b o ut 5 0 % of all mali g n a nt t u m ors ; p 5 3 
m utati o ns are less fre q ue nt i n le u ke mia, b ut are m ore c o m m o n i n a n a b erra nt kar y ot y p e .8  I n 
t u m ors e x pressi n g wil d -t y p e pr otei n, t he t u m or s u p press or f u n cti o n of p 5 3 ma y b e atte n uate d b y  
ot her mec ha nis ms, s uc h as o ver -e x pressi o n of M D M 2 , a ne gati ve re g ulat or of p 5 3.  M D M 2  

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bi n ds p 5 3 wit h hi g h affi nit y a n d ne gati vel y m o d ulates t he tra nscri pti o nal acti vit y a n d sta bilit y of 
t he t u m or s u p press or.  I n le u ke mia wit h f u ncti o nal p 5 3, i n hi biti o n of t he M D M 2 -p 5 3 i nteracti o n 
ca n rest or e p 5 3 acti vit y a n d is e x pecte d t o offer a n o ve l strate g y for t hera p y.  
A Z A  is a c yti di ne a n al o g ue t hat e xerts its a nti-le u ke mic acti vit y b y 2  mec h a nis ms:   direct 
c yt ot o xicit y b y i nc or p orati o n i nt o ri b o n ucleic aci d ( R N A) a n d d e o x yri b o n ucleic aci d ( D N A) 
(after c o n versi o n i nt o t he de o x yri b on ucle oti de), a n d b y i n hi bit i n g D N A met h yl tra nsferase 1 
res ulti n g i n D N A h y p o m et h ylati o n, t h us re v ersi n g t he D N A h y per met h yl ati o n of C p G isla n ds 
re p orte d i n M D S, A M L, a n d ot her mali g na nci es .9 
Si nce A Z A  is m ost t o xic d uri n g S p hase t hr o u g h i nc or p orati o n i nt o D N A a n d m ila de meta n 
ca uses cell c ycle arrest d uri n g  G 1 p h ase , mec ha nisticall y, t he ma xi mal effect of t he c o m bi nati o n 
is e x pecte d w he n t he treat me nt is a d mi nistere d se q ue ntiall y , wit h A Z A  first f oll o we d b y 
m ila de meta n. 
T his P hase 1 , m ulti ple asce n di n g d ose  st u d y will be c o n d ucte d t o assess t he safet y a n d 
t olera bilit y of m ila de met a n as a si n gle a ge nt  a n d i n c o m bi nati o n wit h A Z A , as well as t o 
deter mi ne t he P K /p har m ac o d y na mic ( P D y ) res p o nse pr ofile a n d preli mi nar y efficac y of t he dr u g  
i n s u bjects wit h A M L a n d M D S. 
1. 6.   
Ris ks a n d Be nefits f or St u d y S u bjects  
T he safet y, t olera bilit y, a n d P K of A Z A ha ve b ee n e val uate d i n h u ma ns.  T he m ost c o m m o n 
reacti o ns f or A Z A b y s u b c uta ne o us ( S Q) r o ute are na usea, a n e mia, t hr o m b o c yt o p e nia, v o miti n g, 
p yre xia, le u k o pe nia, diarr hea, i njecti o n site er yt h e ma, c o nsti pati o n, ne utr o p e nia, a n d ecc h y m osis.  
T he m ost c o m m o n a d verse reacti o ns b y i ntra ve n o us (I V) r o ute als o i ncl u de d petec hiae, ri g ors, 
wea k ness , a n d h y p o kale mia.  
Base d o n earl y cli nical st u dies t hat ha ve bee n c o n d ucte d wit h mila de meta n, t he a d verse e ve nts 
( AE s) a ntici pat e d wit h mila de meta n are pri maril y relate d t o t he gastr oi ntesti nal tract (e g, n a usea, 
v o miti n g, diarr hea, a n d p o or a p petite), m yel o s u p pressi o n ( pri maril y t hr o m b oc yt o p e nia), 
electr ol yte dist ur ba n ces, a n d D DIs wit h str o n g C Y P 3 A i n hi bit ors.  
As of 0 2 Ma y 2 0 1 9 , a t ot al of 6 0 s u bjects wit h A M L or hi g h-ris k M D S ha ve recei ve d treat me nt 
as si n gle a ge nt u n der t his pr ot oc ol ( D S 3 0 3 2 -A -U 1 0 2).  T he  s u bjects w ere treate d i n a q d 2 1/ 2 8 
d osi n g sc he d ul e at d oses starti n g fr o m 6 0 m g a n d at i ncreasi n g d oses of 9 0, 1 2 0, 1 6 0 , a n d 
2 1 0  m g.  T he M T D was deter mi ne d t o be 1 6 0 m g i n t he q d 2 1/ 2 8 d osi n g sc he d ule i n t hese 
s u bjects.  A t otal of 5 7 o f t he 6 0 s u bjects ha ve disc o nti n ue d t he st u d y.  Base d o n t he i ncreas e d 
t olera nce a n d cli nical b e nefit of t he less fre q ue nt d osi n g sc he d ul e o bser ve d i n t he 
D S 3 0 3 2 -A -U 1 0 1 st u d y i n s oli d t u m ors, 1 5  s u bjects were treate d u n der alter nati ve d osi n g 
sc he d ules as of 0 8 Ja n 2 0 1 8:  7 s u bjects at 1 6 0 m g q d 7/ 2 8, 3 s u bjects at 1 6 0 m g q d 3/ 1 4  × 2 , 4 
s u bjects at 1 6 0 m g q d f or 1 4 of eac h 2 8-da y c ycle  (q d 1 4/ 2 8 ), a n d 1 s u bject at 2 2 0 m g q d 1 4/ 2 8.  
Ei g ht of t he 6 0 s u bjects ha ve e x perie nce d D L Ts:  
q d 2 1/ 2 8 d osi n g sc he d ule:  
 1 s u bject a t 6 0 m g ( v o miti n g) 
 2 s u bjects at 1 6 0 m g ( h y p o kale mia a n d diarr hea; 1 s u bject eac h)  

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 3 s u bjects at 2 1 0 m g mil a de meta n ( na usea, fati g u e, cell ulitis, a n d re nal fail ure; 1 s u bject 
eac h)  
q d 1 4/ 2 8 d osi n g sc he d ule:  
 2 s u bjects at 2 2 0 m g ( na usea)  
All 6 0 ( 1 0 0 %) s u bjects wh o recei v e d treat me nt i n t he D S 3 0 3 2 -A -U 1 0 2 st u d y e x perie n ce d at 
least 1  T E A E.  O verall, t he m ost c o m m o n T E A Es of a n y gra d e re gar dless  of ca usalit y were 
na usea ( 4 2 [7 0 % ] s u bjects); diarr hea ( 3 3 [5 5 % ] s u bjects); v o miti n g ( 2 4 [4 0 % ] s u bjects); fati g u e 
( 2 1 [3 5 % ] s u bjects); decrease d a p p etite , e de m a peri p heral, a n d t hr o m b o c yt o pe nia ( 1 4 [ 2 3. 3 % ] 
s u bjects eac h); a ne mia ( 1 3 [2 1. 7 % ] s u bjects); h y p o kale mia ( 1 2 [2 0. 0 % ] s u bjects); h y p ot e nsi o n, 
l u n g i nfecti o n, a n d p ne u m o nia ( 1 1 [ 1 8. 3 % ] s u bjects eac h); h yp o m a g nese mia, ne utr o pe nia, 
d ys p nea, a n d se psis ( 9 [ 1 5. 0 % ] s u bjects eac h); a n d a b d o mi nal pai n, ast he nia, a n d dizzi ness 
(7  [1 1. 7 % ] s u bjects eac h).  
1. 6. 1.   
P ote nti al Ris k of Dr u g -Dr u g I nter acti o n  
Mila de meta n is a s u bstrate f or C Y P 3 A a n d P -g p.  A st u d y i n healt h y s u bj ects was c o n d ucte d t o 
e val uate t he effect of c o -a d mi nistrati o n of t he str o n g C Y P 3 A 4 i n hi bit ors (itrac o naz ole a n d 
p osac o naz ole) o n mila de meta n P K ( St u d y D S 3 0 3 2 -A -U 1 0 7).  C o -a d mi nistrati o n of mila de meta n 
1 0 0 m g wit h itrac o n az ole 2 0 0 m g at stea d y st ate i n crea s e d mila de meta n ge o metric mea n C ma x 
a n d (A U Ci nf ) b y 8 % a n d 1 1 5 %.   Si milarl y, p osac o naz ole 2 0 0 m g at stea d y state i ncrease d 
mila de meta n ge o metric mea n C ma x b y a p pr o xi matel y 1 9 % a n d A U Ci nf b y a p pr o xi matel y 
1 4 9 %.  T heref ore, it is rec o m me n de d t hat t he d ose of  mila de meta n be re d uce d t o 5 0 % w he n it is 
c o nc o mita ntl y a d mi nistere d wit h a str o n g C Y P 3 A 4 i n hi bit ors.  
N o f or mal cli nical dr u g i nteracti o n st u dies wit h A Z A ha ve bee n c o n d u cte d.  
In vitr o st u dies s h o w t hat A Z A  is n ot a n i n hi bit or or i n d ucer of t h e C Y Ps  teste d ( C Y P 2 B 6, 
C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, C Y P 2 D 6, C Y P 1 A 2, C Y P 2 E 1 , a n d C Y P 3 A 4); t heref ore, 
cli nicall y rele va nt P K D DI  are u nli kel y t o o cc ur bet wee n A Z A  a n d c o-a d mi nistere d s u bstrates of 
t hese C Y P is oz y mes.1  T here a p p ears t o be li mite d p ote ntial f or a D DI  bet wee n m ila de meta n a n d 
A Z A.   H o we v er, t o xic o ki netics i n mice x e n o graft m o dels s u g gest l o wer P K f or m ila de meta n 
w he n c o -a d mi nistere d wit h A Z A, a n d t he P K of m ila de meta n will be assess e d.   I n a d diti o n, a 
s u bst u d y ( n =  6) t o e x cl u de a p ote ntial effect of m ila de meta n o n A Z A P K d ue t o tra ns p orter 
i n hi biti o n (ie, P-gl yc o pr otei n  [ P-g p]  a n d breast ca ncer resista nce pr otei n  [ B C R P]) will be 
c o n d ucte d.  
1. 6. 2.   
P ote nti al Be nefit Ass oci ate d wit h Mil a de met a n  as a Si n gle A ge nt  a n d i n 
C o m bi n ati o n wit h 5 -Az ac iti di ne 
N o n cli nical data d e m o nstrate d t hat m ila de meta n i n hi bite d cell gr o wt h i n a 
c o nce ntr ati o n -de pe n d e nt ma n ner a n d i n d uce d a p o pt osis, a n d was m ore p ot e nt t ha n t he well -
c haracterize d M D M 2 i n hi bit or N utli n -3a.   I n vi v o st u dies de m o nstrate d t hat m ulti ple d oses of 
m ila de meta n pr o d uce d statisticall y si g nifica nt d os e -rel ate d a ntit u m or res p o nses, wit h the hi g hest 
d ose of m ila de meta n yiel di n g a 9 3 % t u m or re d ucti o n relati ve t o t he c o ntr ol gr o u p.  T hese d ata 
de m o nstrate t hat i n t u m ors wit h wil d -t y pe p 5 3, i n hi biti o n of M D M 2 -p 5 3 i nteracti o n ca n rest or e 
p 5 3 acti vit y a n d is e x pect e d t o offer a n o vel strat e g y f or ca n cer t hera p y.   N o n cli nical i n vi v o 

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ex peri me nts usi n g m ila de meta n i n c o m bi nati o n wit h A Z A de m o nstrate d e n ha nce d b e nefit of t he 
c o m bi nati o n treat me nt c o m pare d t o t he si n gle -a ge nt acti vities.  
It is e x pecte d t hat t he c o m bi nati o n treat me nt of m ila de meta n wit h A Z A  ma y i ncreas e t he a nti -
le u ke mic acti vit y b y t ar geti n g 2  differe nt mali g na nt pat h wa ys  base d o n t he mec ha nis m of acti o n 
of t hese dr u gs, na m el y c yt ot o xic a n d h y p o met h yl ati n g effect of A Z A a n d i ncreas e d p 5 3 acti vit y 
b y mila de met a n . 

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2.   
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  
2. 1.   
S t u d y O bjecti ves 
2. 1. 1.   
Pri m ar y O bjecti ves  
Part 1 a n d Part 1 A  
 T o assess t he safet y a n d t olera bilit y of m ila de m eta n as a si n gl e a ge nt ( Part 1) a n d i n 
c o m bi nati o n wit h A Z A  ( Part 1 A). 
 T o deter mi ne t he M T D  of m ila de meta n as si n gle a ge nt a n d i n c o m bi nati o n wit h A Z A a n d 
t o i de ntif y a rec o m me n de d d ose f or a n e x pa nsi o n c o h ort  ( R DE ) of m ila d e meta n pl us 
A Z A . 
Part 2  
 T o c o nfir m t he safet y a n d t olera bilit y of m ila de m eta n i n c o m bi nati o n wit h A Z A at t he 
R D E a n d i de ntif y t h e rec o m me n de d P hase 2 d ose (R P 2 D ). 
 T o e val uate t he effi cac y of m ila de meta n i n c o m bi nati o n  wit h A Z A  i n s u bjects wit h A M L 
or  hi g h -ris k M D S. 
2. 1. 2.   
Sec o n d ar y O bjecti ves  
Part 1 a n d Part 1 A  
 T o e val uate t he P K  of m ila de meta n f oll o wi n g si n gle a n d m ulti ple d osi n g. 
Part 2  
 T o e val uate t he P K of m ila de meta n at t he R DE . 
2. 1. 3.   
E x pl or at or y O bjecti ves  
Part 1 a n d Part 1 A  
 T o e val uate efficac y of  m ila de meta n as a si n gle a ge nt  ( Part 1) a n d i n c o m bi nati o n wit h 
A Z A ( Part 1 A) i n R/ R A M L  a n d hi g h -ris k M D S. 
 T o e val uate t he relati o ns hi p bet wee n le u ke mia res p o nse t o m ila de meta n as a si n gle a ge nt  
a n d i n c o m bi nati o n wit h A Z A  a n d t he pre dicti ve bi o mar kers st u die d i n pre -treat me nt 
b o ne marr o w bi o psies/as pirates a n d/ or bl o o d sa m ples . 
 T o e val uate i n ser u m t he P D y effect of mila de met a n as a si n gle a ge nt a n d i n c o m bi nati o n 
wit h A Z A o n m acr o p ha ge i n hi bit or y c yt o ki ne -1 ( MI C -1) le v els.  
 T o assess o t her P D y effect s of m ila de meta n as a si n gle a ge nt  a n d i n c o m bi nati o n wit h 
A Z A o n  e x pressi o n le vels of p 5 3 d o w nstrea m ge n es, a p o pt osis mar kers, a n d/ or ot her 
bi o mar kers i n pre - a n d p ost -treat me nt b o ne marr o w  sa m ples, if a vaila ble. 
 T o assess t he p ote ntial D DI  of m ila de meta n o n A Z A P K i n a s u bst u d y ( n  =  6).  

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Part 2  
 T o e val uate t he relati o ns hi p bet wee n res p o nse t o mila de meta n i n c o m bi nati o n wit h A Z A 
i n R/ R A M L, n e wl y dia g n ose d A M L  u nfit f or i nte nsi ve c he m ot hera p y , or hi g h -ris k M D S 
a n d bi o mar kers. 
 T o e val uate i n ser u m t he P D y effect of mila de met a n i n c o m bi nati o n wit h A Z A o n 
macr o p ha ge i n hi bit or y c yt o ki ne -1 ( MI C -1) le v els.  
 T o a ssess o t her P D y effect s of m ila de meta n i n c o m bi nati o n  wit h A Z A  o n  e x pressi o n of 
p 5 3  d o w nstrea m ge n es , a p o pt osis mar kers, a n d/ or ot her bi o mar kers i n pre - a n d 
p ost -treat me nt le u ke mic sa m ples, if a vaila ble. 
 A d diti o nal assess me nts of efficac y. 
2. 2.   
O utc o me Me as ures  
2. 2. 1.   
Pri m ar y O utc o me Me as ures  
Part 1 a n d Part 1 A  
 N u m ber of s u bjects wit h D L Ts b y t h e e n d of t he D ose Escalati o n part (ti mefra m e:  wit hi n 
5 years  of first s u bject e nr olle d). 
Part 1, Part 1 A, a n d Part 2  
 N u m ber of s u bjects wit h treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ) (ti mefra me:  wit hi n 
6  years  of first s u bject e nr olle d). 
Part 2  
 N u m ber of s u bjects w h o ac hie ve d C R, C Ri or M L F S f or A M L a n d w h o att ai ne d C R, 
marr o w C R ( m C R) or P R f or hi g h -ris k M D S as t he best res p o nse (ti mefra me:  wit hi n 
6  years  of first s u bject e nr olle d). 
2. 2. 2.   
Sec o n d ar y O utc o me Me as ures  
Part 1, Part 1 A, a n d Part 2  
 Plas ma c o nce ntr ati o ns a n d P K p ara meters of mila de meta n (ti mefra me: wit hi n 6  years  of 
first s u bject e nr olle d ). 
2. 2. 3.   
E x pl or at or y O utc o me Me as ures  
Part 1 a n d Part 1 A  
 P har mac o ki netic para met ers  of t he c o m bi nati o n of mila de meta n a n d A Z A.  
Part 1, Part 1 A, a n d Part 2  
 P har mac o d y na mic a n d ot her bi o mar ker meas ure m e nts.  
 A d diti o nal efficac y meas ure me nts . 

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2. 3.   
St u d y E n d p oi nts  
2. 3. 1.   
S afet y E n d p oi nts  
T he e n d p oi nts f or safet y will i ncl u de seri o us a d verse e ve nts ( S A Es), T E A Es, D L Ts, p h ysical 
e x a mi nati o n fi n di n gs (i ncl u di n g E C O G perf or ma nce stat us), vital si g n m eas u re me nts, cli nical 
la b orat or y para meters (ser u m c he mistr y a n d he mat ol o g y), a n d electr ocar di o gra m ( E C G) 
para meters, partic ularl y t he c orrecte d Q T i nter val usi n g Fri dericia’s met h o d ( Q Tc F ).  A d verse 
e ve nts will be cate g orize d usi n g Me dical Dicti o nar y f or Re g u lat or y Acti vities ( Me d D R A) 
V ersi o n 1 7. 0.  A d verse e ve nts a n d la b orat or y t est res ults will be gra de d acc or di n g t o t he Nati o nal 
Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d v erse E ve nts ( C T C A E) Versi o n 5. 0 
(Versi o n 4. 0 3 bef ore 0 1 A pr 2 0 1 8).  
2. 3. 2.   
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic E n d p oi nts  
T he P K para m eters f or mila de meta n will i ncl u de C ma x,  ti me t o reac h ma xi m u m plas ma 
c o nce ntr ati o n (T ma x ), tr o u g h plas ma c o nce ntrati o n (Ctr o u g h ), a n d area u n der t he plas ma 
c o nce ntr ati o n -ti me c ur ve u p t o ti me 2 4 h o urs ( A U C 2 4 h).  Plas ma sa m ples f or P K assess me nts 
will be ta ke n at m ulti ple ti me p oi nts i n t he st u d y.  I n a d diti o n, p o p ulati o n P K ( P o p P K) a nal ysis 
ma y b e use d t o assess t he P K of mila de meta n a n d t he relati o ns hi p t o res p o nse or bi o mar kers . 
P K para meters f or A Z A will i ncl u de C ma x, T ma x, a n d area u n der t he plas ma c o nce ntrati o n -ti me 
c ur ve u p t o ti me 6 h o urs ( A U C 6 h) o n C ycle 1/ Da y 1 ( A Z A al o ne) a n d C ycle 1/ Da y 7 ( wit h 
mila de meta n starti n g o n Da y 5) f or t he first 6 s u bj ects  i n Sc he d ule e of Part 1 A. 
I n d u cti o n of ser u m MI C -1 will be assesse d as a P D y bi o mar ker.  Ser u m sa m ples will be 
c ollecte d at m ulti ple ti me p oi nts i n t he st u d y t o ass ess t he effect of mila de m eta n treat me nt o n 
MI C -1 i n d ucti o n.  Ot her e x pl orat or y P D y bi o mar kers i ncl u di n g, b ut are n ot li mite d t o, 
e x press i o n le vels of p 5 3, p 2 1, M D M 2, M D M 4, a p o pt osis mar kers, a n d/ or ot her bi o mar kers will 
als o be assesse d i n b o n e marr o w sa m ples, if a vail a ble.  
2. 3. 3.   
Effic ac y E n d p oi nts  
T he effi cac y e n d p oi nts will i ncl u de t he f oll o wi n g assess me nts.  T he res p o nse rate will be 
s u m marize d base d o n t he I n v esti gat or-ass esse d best res p o nse after t he first d ose of st u d y 
treat me nt a n d bef ore t h e last disease assess me nt d uri n g t he st u d y ( Secti o n 7 ). 
2. 3. 3. 1.  
A M L  
T he A M L res p o ns e i n Part 1 a n d Part 1 A will be assesse d acc or di n g t o t he 2 0 03  I nter nati o nal 
W or ki n g Gr o u p ( I W G) res p o nse criteria (Secti o n  1 7. 4 . 4), w hile i n Part 2, t he 2 0 1 7 E ur o pea n 
Le u k e mia Net ( E L N) rec o m me n dati o ns will be a p plie d (Secti o n  1 7. 4. 1 ): 
 C R rate  
 C Ri rate  
 C o m p osite c o m plete re missi o n ( C Rc ) rate ( C R + C Ri) 
 D O R ( d urati o n of c o m p osite c o m plete re missi o n):  Ti me fr o m t he first o bjecti ve e vi de nce 
of C Rc t o t he first o bjecti ve e vi de nce of rela pse or deat h  

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 M L F S rate  
 P R rate  
 O R R ( C R c + M L F S + P R)  
 S D rate  ( Part 2 o nl y) 
 Treat me nt f ail ure ( Part 1 a n d Part 1 A o nl y)  
 C R h rate  
o  C R h will be e val uate d se paratel y fr o m t he ot her res p o nse criteria  
2. 3. 3. 2.  
Hi g h -ris k M D S 
T he res p o nse f or hi g h -ris k M D S i n all st u d y p arts will be assesse d acc or di n g t o t he 2 0 0 6 I W G 
res p o nse criteria ( Secti o n 1 7. 4. 4 ): 
 C R rate  
 m C R rate 
 P R rate  
 C yt o ge netic res p o nse (c o m plete or partial) rates  
N ote :  St u d y sites s h o ul d re p ort C R, m C R, P R, or c yt o ge netic res p o nse at eac h assess me nt b y 
i g n ori n g d urati o n of res p o nse.  H o we v er, C R, m C R, P R, or c yt o ge netic res p o nse w hic h persists 
f or at least 4 w ee ks will be s u m marize d f or t he efficac y a nal ysis. 
C yt o ge netic res p o nse (c o m plete or partial)  are n ot m ut uall y e x cl usi ve t o C R, m C R or P R rates.  
I n ot her w or ds, c yt o ge netic res p o nse (c o m plete or partial) ca n be re p orte d w he n C R, m C R or P R 
is re p orte d. 
 S D rate  
 He mat ol o gi c i m pr o ve me nt ( HI) rate  
N ote :  St u d y sites s h o ul d re p ort S D or HI at eac h assess me nt b y i g n ori n g d urati o n of res p o ns e.  
H o we ver, S D or HI w hi c h persists f or at least 8 w ee ks will be s u m marize d f or t he efficac y 
a nal ysis.  
2. 3. 3. 3.  
A d diti o n al Effic ac y E n d p oi nts  
A d diti o nal efficac y e n d p oi nts ma y i ncl u de t he f oll o wi n g ass ess me nts:  
 Tra ns pla nta ti o n rat e:  Perce nt of s u bjects u n der g oi n g all o ge n eic H C T directl y f oll o wi n g 
pr ot oc ol -s pecifi e d treat m e nt wit h n o i nter ve ni n g A M L t hera p y or n o i nter ve ni n g M D S 
t hera p y 
 E ve nt -free s ur vi val ( E F S) f or A M L:  D efi ne d as ti me fr o m first d ose dat e u ntil rela pse 
after C R or C Ri, refract or y disease, or deat h fr o m a n y ca use, w hic he v er is o bser ve d first 

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 Pr o gressi o n -free s ur vi val ( P F S) f or hi g h -ris k M D S:  D efi ne d as ti me fr o m first d ose date 
u ntil rela pse, disease pr o gressi o n, pr o gressi o n t o A M L, or deat h fr o m a n y ca us e, 
w hic he ver is o bs er ve d first  
 O verall s ur vi val ( O S):  Ti me fr o m first d ose date u ntil deat h fr o m a n y ca use  
 Tra nsf usi o n i n de pe n d e nce  
2. 4.   
St u d y H y p ot hesis  
Mila de meta n  as a si n gle a ge nt  a n d i n c o m bi nati o n wit h A Z A  will be safe a n d well t olerate d a n d 
will s h o w cli nical be nefit i n s u bjects wit h R/ R  A M L, ne wl y di a g n ose d A M L  u nfit f or i nte nsi ve 
c he m ot hera p y, or hi g h -ris k M D S.  T he st u d y dr u gs  will ma nifest acti vit y as e vi de nce d b y 
res p o nse i n s u bjects wit h R/ R  A M L  a n d ne wl y dia g n ose d A M L  acc or di n g t o t he 2 0 0 3 I W G 
res p o nse criteria ( Part 1 a n d Part 1 A) a n d t he 2 0 1 7 E L N rec o m me n d ati o ns ( Part 2), a n d i n 
s u bjects wit h hi g h-ris k M D S acc or di n g t o t he 2 0 0 6 I W G res p o nse criteria (all parts). 

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3.   
S T U D Y D E SI G N  
3. 1.   
O ver all Pl a n  
3. 1. 1.   
St u d y T y pe  
T his will be a P ha se 1, o pe n -la bel st u d y of m ila de meta n as a si n gle a ge nt ( Part 1) a n d i n 
c o m bi nati o n wit h A Z A ( Part  1 A) t o assess its safet y a n d t olera bilit y a n d i d e ntif y t he M T D a n d 
R D E (i n D ose Escal ati o n) i n s u bjects wit h R/ R  A M L or hi g h -ris k M D S a n d t o c o nfir m t he safet y 
a n d t olera bilit y of R D E a n d i de ntif y a R P 2 D (i n D ose E x pa nsi o n [ Part 2]) i n s u bjects wit h R/ R  
A M L, n e wl y dia g n ose d A M L u nfit f or i nte nsi ve c he m ot hera p y,  or hi g h -ris k M D S. 
A p pr o xi matel y  1 2 U S sites are pl a n ne d f or Part 1 an d Part 1 A  ( D ose Escal ati o n).  A p pr o xi matel y 
1 2  U S sites are pla n ne d f or Part 2 ( D ose E x pa nsi o n).  
T his 2 -part st u d y will i ncl u de b ot h a d ose escalati o n p orti o n, t o i de ntif y t h e M T D of 
m ila de meta n as a si n gle a ge nt  a n d i n c o m bi nati o n wit h A Z A a n d t he rec o m m e n de d d ose a n d 
sc he d ule of m ila de m eta n a n d A Z A c o m bi nati o n f or d ose ex pa nsi o n  c o h orts ( R D E) , f oll o we d b y 
a d ose ex pa nsi o n  p orti o n, t o c o nfir m t he safet y a n d t olera bilit y of m ila de m eta n a n d A Z A 
c o m bi nati o n , t o deter mi n e t he P D y i n bl o o d a n d/ or  b o ne marr o w  bi o psies/as pirates , a n d t o 
e val uate preli mi nar y efficac y i n s u bjects wit h R/ R  A M L , n e wl y dia g n ose d A M L u nfit f or 
i nte nsi ve c he m ot hera p y, or  hi g h -ris k M D S. 
Mila de meta n  as a si n gle a ge nt will be a d mi nistere d o n a q d  2 1 / 2 8 sc he d ule.  A n alter nati ve dr u g 
a d mi nistrati o n sc he d ule f or d ose escalati o n ma y b e c o nsi dere d t o e val uat e t he m ila de meta n 
e x p os ure relati o ns hi p t o P D y a n d t o xicit y .  If t he res ults i n dicate t hat usi n g a n alter nati ve d osi n g 
sc he d ule ma y pr o vi d e less t o xicit y (e g, m yel o s u p pressi o n) w hile offeri n g P D y  b e nefits base d o n 
a vaila ble bi o mar k ers, d ose escal ati o n usi n g t his rec o m me n de d alter nati ve d osi n g sc he d ul e will 
be perf or me d i n lie u of, or i n parallel wit h , t he q d  2 1/ 2 8  sc he d ule.  T he m il a de meta n d ose will 
als o be e val uat e d i n c o m bi nati o n wit h A Z A i n D ose Escalati o n ( Part 1 A) f oll o we d b y D ose 
E x pa nsi o n ( Part  2)  (Ta ble  3 .1 ). 

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C o h orts of 3 t o 6 s u bjects will be e nr olle d a n d ass esse d f or D L T s bef ore es calati o n t o a ne w 
hi g her d ose.   If 2 e val ua ble s u bjects i n a c o h ort e x perie nce a D L T bef ore t h e e nr oll me nt of t he 
ne xt  s u bject, t he m o del  will be re -e v al uate d bef ore e nr oll me nt of a n y a d diti o nal s u bjects t o t he 
c o h ort.  E nr oll me nt of s u bjects t o a ne w c o h ort re q uires c o m pleti o n of D L T e val uati o n of at least 
3 s u bjects treate d i n t he c urre nt c o h ort.  S u bjects w h o ha ve neit her c o m plete d a D L T e v al uati o n 
n or e x perie nce d a D L T will be ce ns ore d a n d n ot i ncl u de d i n t he B L R M u p date .  I n t he e v e nt t hat 
s ubjects i n t he pre vi o us c o h ort e x perie nce a D L T after t he e nr oll me nt of s u bjects t o a ne w c o h ort 
has be g u n, d ose le vel assi g n me nt of t he ne xt s u bject i n t he ne w c o h ort will be base d o n a n 
u p date d B L R M usi n g D L T o utc o m e data fr o m all assesse d d oses.  
F or a s u bject t o be c o nsi dere d e v al ua ble f or d ose escalati o n decisi o ns, t he s u bject m ust ha ve 
recei v e d at least  7 5 % of t he d oses d uri n g C ycle 1 or e x perie nce d a D L T i n C ycle  1.  T he fi nal 
M T D  will be deci de d base d o n c o nsi derati o ns of t he res pecti ve M T D  esti m ate d b y t he B L R M 
a n d o n a n o verall assess me nt of safet y dat a fr o m s u bse q ue nt c ycles a n d P K / P D y i nf or mati o n 
c ollecte d at all d oses test e d.  
A d diti o nal s u bjects f or t he c haracterizati o n of safet y, P K, or P D y ma y be a d de d t o a n y D ose 
E scalati o n c o h ort bel o w t he M T D d ose le vel or at t he M T D i n parallel wit h o n g oi n g es calati o n 
u p t o a ma xi m u m of 1 2 s u bjects i n eac h c o h ort.  F urt her details ca n be f o u n d i n t he C o h ort 
Ma na ge me nt Pla n.  
3. 1. 2. 1.  
P art 1 ( D os e Esc al ati o n of Mil a de met a n as a Si n gle A ge nt ) 
3. 1. 2. 1. 1.  Mil a de met a n St arti n g D ose a n d D ose Sc he d ule  
I n a n o n g oi n g P hase 1 d ose escal ati o n st u d y ( St u d y D S 3 0 3 2-A -U 1 0 1), mil a de meta n was gi ve n 
as a si n gl e a ge nt o n a sc h e d ule of q d  2 1/ 2 8 t o s u bjects wit h a d va nce d s oli d t u m ors or 
l y m p h o mas.  T he M T D i n t his sc he d ule was deter mi ne d t o be 1 2 0 mg.  
Base d o n t h e data fr o m t he D S 3 0 3 2 -A -U 1 0 1 st u d y, t he D S 3 0 3 2 -A -U 1 0 2 st u d y i n s u bjects wit h 
A M L or hi g h -ris k M D S was starte d at a mila de m eta n d ose of 6 0 m g i n t he q d 2 1/ 2 8 sc he d ule 
a n d t he d ose was escalate d t hr o u g h 9 0 m g, 1 2 0 m g, 1 6 0  m g, a n d 2 1 0 m g.  
T he M T D i n t he q d  2 1/ 2 8 sc he d ule has b ee n det er mi ne d t o be 1 6 0  m g.  
Fi g ure  3 .1  a n d Ta ble  3 .2  s u m marize t he d osi n g sc he d ule fi n di n gs f or mila de meta n as a si n gle 
a ge nt d ose es calati o n  i n Part 1. 

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3. 1. 2. 1. 2.  D ose Esc al ati o n U si n g Alter n ati ve M il a de met a n as a Si n gle A ge nt  S c he d ule 
Base d o n s afet y, P K , a n d P D y data c ollecte d d uri n g D ose Escalati o n usi n g  t he q d  2 1/ 2 8 sc he d ule 
of m ila de meta n o ver 5  d ose le vels  a n d re vie we d b y t he Pri nci pal I n vesti gat ors a n d S p o ns or , 
alter nati ve, less fre q ue nt d osi n g sc he d ul es were e v al uate d f or d os e escalati o n.  Starti n g fr o m t he 
M T D d ose le vel ( 1 6 0 m g) est a blis he d f or t he q d  2 1/ 2 8 sc he d ule,  d ose es cal ati o n usi n g t he 
f oll o wi n g rec o m me n de d alter nati ve d osi n g sc he d ules were  p erf or me d i n lie u of t he 
q d  2 1/ 2 8  sc he d ule all o wi n g parallel  e v al uati o n : 
 q d 7/ 2 8 sc he d ule  ( Sc he d ule b) 
 q d 3/ 1 4 × 2 sc he d ule ( Sc he d ule c) 
 q d 1 4/ 2 8 sc he d ule  ( Sc he d ule d) 
D ose escalati o n/ de -es cal ati o n will f oll o w t he B L R M met h o d as descri be d a b o ve.  
N ote:   After t he fi nalizati o n of V ersi o n 3. 0 of t his pr ot oc ol o n 1 0 Ma y 2 0 1 8, 
St u d y  D S 3 0 3 2 -A -U 1 0 2  c o m plete d e nr oll me nt i n Part 1, w hic h e v al uate d m ila de meta n as a si n gl e 
a ge nt t hera p y i n 4  differe nt d ose sc he d ules ( Sc h e d ules a t o d).  Alt h o u g h n o D L Ts were o bser ve d 
i n t he si n gle c o h orts of 1 6 0 m g sc h e d ules b ( q d 7/ 2 8) a n d c ( q d 3/ 1 4 × 2), res pecti vel y, neit her 
sc he d ule was a ble t o c o ntr ol le u ke mia a nd neit her was p urs ue d f urt her.  I n Sc he d ule d 
( q d 1 4/ 2 8), w he n t he d os e was es calate d fr o m 1 6 0 m g wit h n o D L Ts i n 3 s u bjects t o t he ne xt 
hi g her d ose of 2 2 0 m g, D L Ts bas e d o n Gra de 3 n a usea were o bser ve d i n t h e first 2 s u bjects.  T he 
d ose was t heref ore de -es calate d t o 1 6 0 m g.  H o we ver, n o f urt her e nr oll me nt was p urs ue d at 
1 6 0  m g i n t his d ose sc he d ule si nce t he d ose was s a me as t he M T D deter mi ne d i n t he m ore 
fre q ue nt d ose s c he d ule ( Sc he d ule a; q d 2 1/ 2 8).  
3. 1. 2. 2.  
P art 1 A ( D ose E sc al ati o n of Mil a de met a n  i n Co m bi n ati o n wit h A Z A)  
I n Part 1 A, s u bjects will be treate d wit h A Z A at 7 5 m g/ m 2 S Q or I V i n c o m bi nati o n wit h 
escalati n g d oses of mila d e meta n.  T w o d osi n g sc h e d ules f or mila de met a n will be e val uate d  
(Fi g ure  3 .2  a n d Ta ble  3 .3 ).  T he starti n g d ose f or mila de meta n i n c o m bi nati o n wit h A Z A will be 
1 6 0 m g bas e d o n t he M T D of mila de meta n as a si n gle a ge nt i n t he q d 2 1/ 2 8 sc he d ule a n d will 
f oll o w d ose escalati o n per t he B L R M wit h t he E W O C pri nci ple. 
I n Sc h e d ule e, A Z A will be a d mi nistere d o n Da ys 1 t o 7 a n d mila de meta n will be a d mi nistere d 
q d o n Da ys 5 t o 1 4 ( wit h a n o verla p of b ot h dr u gs a d mi nistere d o n Da ys 5 t o 7) i n eac h 2 8-da y 
c ycle. 
I n Sc h e d ule f, A Z A will be a d mi nistere d o n Da ys 1 t o 7 a n d mila de meta n will be a d mi nistere d 
q d o n Da ys 8 t o 1 4 i n eac h 2 8 -da y c ycl e.  
B ot h of t he d osi n g sc he d ules of mila de meta n ma y  be e val uat e d i n parallel.  

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Fi g ure  3 .2 : 
D osi n g Sc he d ule of Mil a de met a n i n C o m bi n ati o n wit h 5 -Az aciti di ne  
 
A Z A = 5 -azaciti di ne; I V = i ntra ve n o us; q d = o nce dail y; S Q = s u bc uta ne o us  
N ote: A n alter nati ve A Z A sc he d ule ( Fi g ure  3 .3 ) will be teste d i n c o m bi nati o n wit h mila de meta n at R D E ( d ose a n d 
d ose sc he d ule of R D E) . 
T a ble  3 .3 :  
D osi n g Sc he d ule of Mil a de met a n i n C o m bi n ati o n wit h 5 -Az aciti di ne  
C o h ort   
D osi n g 
Sc he d ule  
A Z A  
( 7 5 m g/ m2) 
Mil a de met a n D ose 
Le vel  
Mil a de met a n 
Sc he d ule  
C o h ort 1 0  
e 
Da ys 1 t o 7  
1 6 0 m g  
q d 1 0/ 2 8  
( Da ys 5 t o 1 4) 
C o h ort 1 1  
f 
Da ys 1 t o 7  
1 6 0 m g  
q d 7/ 2 8  
( Da ys 8 t o 1 4) 
C o h ort 1 2  
e 
Da ys 1 t o 7  
2 0 0 m g  
q d 1 0/ 2 8  
( Da ys 5 t o 1 4) 
C o h ort 1 3  
f 
Da ys 1 t o 7  
2 0 0 m g  
q d 7/ 2 8  
( Da ys 8 t o 1 4) 
A Z A = 5 -azaciti di ne; q d = o nce dail y  
After t he R D E (ie, t he o pti mal d ose a n d sc he d ule of mila de meta n) is i de ntifie d, a n alter nati ve 
sc he d ule of A Z A will be teste d i n c o m bi nati o n wit h mila de meta n at R D E ( o nl y at t he R D E d ose 
a n d d ose sc he d ul e) .  I nst ea d of t he 7-da y c o ns ec uti ve a d mi nistrati o n fr o m Da ys 1 t o 7, A Z A will 
be a d mi nistere d o n Da ys 1 t o 5 a n d t he n fr o m Da ys 8 t o 9 (“ 5 + 2”), wit h A Z A d osi n g i nterr u pti o n 
d uri n g t he wee k e n d (e g, f or l o gistic c h alle n ges s u c h as cl os ure of st u d y sites or i n vesti gati o nal 
p har m ac y d uri n g t h e wee ke n d)  (Fi g ure  3 .3 ). 
B ot h of t he d osi n g sc he d ules of mila de meta n (sc h e d ules e a n d f) ma y be e v al uate d i n parallel  
d uri n g d ose escalati o n . 

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Fi g ure  3 .3 : 
Alter n ati ve 5 -Az a citi di ne D osi n g Sc he d ule i n C o m bi n ati o n wit h 
Mil a de met a n at R D E  
 
A Z A = 5 -azaciti di ne; I V = i ntra ve n o us; q d = o nce dail y; S Q = s u bc uta ne o us  
3. 1. 2. 3.  
D ose M o dific ati o n of Mil a de met a n d ue t o T hr o m b oc yt o pe ni a a n d/ or 
Ne utr o pe ni a ( C ycle 2 a n d L ater)  
If a s u bject e x perie nces pr ol o n ge d t hr o m b oc yt o pe nia ( platelets < 5 0 × 1 0 9/ L) a n d/ or ne utr o pe nia 
( A N C < 0. 5 × 1 09/ L) t hat is dr u g-relate d i n t he I n vesti gat or’s cli nical j u d ge me nt bef ore starti n g 
t he s u bse q ue nt mila de meta n c ycle, t he n t he I n vesti gat or after c o ns ultati o n wit h t he S p o ns or 
Me dical M o nit or ma y re d uce t he d ose fre q u e nc y of mila de meta n (e g, 1 0/ 2 8 da ys  t o 7/ 2 8 da ys, 
7/ 2 8 da ys t o 5/ 2 8 da ys, et c) i n s u bse q ue nt c ycl es w hile mai ntai ni n g t he sa m e dail y d os e of 
mila de meta n.  
3. 1. 3.   
P art 2 ( D os e E x p a nsi o n  of Mil a de met a n i n C o m bi n ati o n wit h A Z A ) 
U p o n c o m pleti o n of Part 1 a n d Part 1 A  wit h a n est a blis he d R D E a n d dr u g a d mi nistrati o n 
sc he d ule, t he D os e E x pa nsi o n part will be gi n t o c o nfir m t he safet y a n d t olera bilit y of 
m ila de meta n i n c o m bi nati o n wit h A Z A , t o deter mi n e t he P D y i n bl o o d a n d/ or b o ne marr o w  
bi o psies/as pirates , a n d t o e val uate preli mi nar y efficac y  a n d i de ntif y t he R P 2 D .  If t he safet y a n d 
efficac y dat a fr o m t he " 1 t o 7" a n d " 5 + 2" sc h e d ules of A Z A are c o m para ble i n t he D ose 
Escalati o n, b ot h A Z A sc he d ules will be all o we d i n D ose E x pa nsi o n.  
T hree c o h orts of a p pr o xi matel y 4 0 s u bjects  per c o h ort  wit h A M L or hi g h -ris k M D S will be 
c o nc urre ntl y e nr olle d a n d treate d i n D ose E x pa nsi o n (t otal of a p pr o xi matel y 1 2 0  s u bjects) as 
f oll o ws (see Secti o n 4. 1. 1 ): 
 C o h ort 1:  S u bjects wit h R/ R  A M L.  
 C o h ort 2:  S u bjects wit h ne wl y di a g n ose d A M L a n d are u nfit f or i nte nsi ve c he m ot hera p y.  
 C o h ort 3:  S u bjects wit h hi g h -ris k M D S. 
N ote :  F or C o h orts 1 a n d 3 of Part 2 ( D ose E x pa nsi o n), m ore stri n ge nt eli gi bilit y criteria 
re gar di n g pri or A M L or M D S t hera pies will be a p plie d i n or der t o create a m ore  h o m o ge n o us 
s u bject p o p ulati o n  ( Secti o n 4. 1 ). 
3. 1. 3. 1.  
I ntr as u bject D ose Esc al ati o n 
N o i ntras u bject d ose es calati o n will be per mitte d.  

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3. 2.   
D ur ati o n of t he St u d y  
T he st u d y d urati o n is e x pecte d t o last a p pr o xi matel y 6  years fr o m t he ti me t he first s u bject is 
e nr olle d i n Part 1 of t he st u d y.  
3. 2. 1.   
D ur ati o n of S u bject P a rtici p ati o n  
T he scree ni n g peri o d is u p t o 1 4 da ys.  E ac h c ycle of treat me nt will be 2 8 da ys.  T he n u m ber of 
treat me nt c ycl es is n ot fi x e d i n t his st u d y.  S u bjects w h o c o nti n ue t o deri ve cli nical be nefit fr o m 
treat me nt i n t he a bse n ce of wit h dra wal of s u bject c o nse nt, disease pr o gressi o n, or u nacce pta ble 
t o xicit y ma y c o nti n ue tr eat me nt. 
3. 2. 2.   
St o p pi n g R ules  
T he st u d y ma y b e ter mi n ate d at a n y ti me a n d f or a n y reas o n at t he S p o ns or’s discreti o n.  
3. 3.   
St o p pi n g R ule f or M a xi m u m T oler ate d D ose Deter mi n ati o n  
T he fi nal M T D will be d eci de d bas e d o n c o nsi derati o ns of t he res pecti ve M T D esti mate d b y t h e 
B L R M a n d o n a n o v erall assess me nt of safet y dat a fr o m s u bse q ue nt c ycles a n d P K / P D y 
i nf or mati o n c ollecte d at all differe nt d os es teste d.  F or d ose d eter mi nati o n, t he f oll o wi n g 
st o p pi n g r ules will be i m ple me nte d f or t he D ose Escalati o n part: (a) at least 6 e val ua ble s u bjects 
ha ve bee n e nr olle d at t he M T D  le vel wit h at least 1 8 e val ua ble s u bjects i n t otal e nr olle d i n t he 
D ose Escalati o n part, ( b) at least 9  e val ua bl e s u bjects ha ve bee n e nr olle d at a d ose le vel w hic h is 
t he m o del’s rec o m me n d ati o n f or t he ne xt d ose c o h ort a n d f or w hi c h t he p osteri or pr o ba bilit y of 
tar gete d t o xicit y is at least 5 0 %, or (c) d ose le vel -1 is t o o t o xic.  
3. 4.   
D ose -li miti n g T o xicities 
A D L T is defi n e d as a n y T E A E n ot attri b uta ble t o disease or disease -relate d pr ocesses t hat 
occ urs d uri n g t he o bs er vati o n peri o d ( C ycle  1) i n  eac h d ose -le vel c o h ort a n d is Grade  3 or hi g h er 
acc or di n g t o N CI-C T C A E Versi o n 5. 0  (Versi o n 4. 0 3 bef ore  0 1 A pr 2 0 1 8) , wit h t he e x ce pti o ns 
as defi ne d b el o w . 
F or ele vati o ns i n he patic f u ncti o n e nz y mes, a D L T is defi ne d as f oll o ws:  
 Gra de ≥3 A S T/ala ni n e a mi n otra nsferas e ( A L T) le vels lasti n g > 3 d a ys.  
 A S T/ A L T > 5 × U L N if acc o m pa nie d b y ≥Gra de  2 ele vati o n i n bilir u bi n . 
T he f oll o wi n g e ve n ts are classifie d as D L Ts: 
 S u bjects w h o are u n a ble t o c o m plete at least 7 5 % of t he prescri be d d ose of m ila de meta n 
or A Z A  i n C ycle 1  as a res ult of n o n -disease -relat e d Gra d e ≥2 e ve nts will be c o nsi dere d 
t o ha ve a D L T. 
 Persiste nt b o ne marr o w a plasia i n t he a bse nce of mali g na nt cell i nfiltrati o n, per 
i nstit uti o nal g ui deli nes, a n d fail ure t o rec o ver a peri p heral a bs ol ute ne utr o p hil c o u nt 
(A N C ) ≥0. 5 × 1 0 9/ L a n d platelets ≥2 0 ×  1 0 9/ L w hile wit h h ol di n g st u d y dr u g, res ulti n g i n 
a > 2 -wee k del a y i n i nitiati n g C ycle 2.  

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T he f oll o wi n g A Es  are N O T c o nsi dere d D L Ts:  
 Gra de 3 fati g ue lasti n g < 3 da ys . 
 Gra de 3 n a usea or v o miti n g t hat has res ol ve d t o ≤Gra de 2 wit hi n 4 8 h o urs f oll o wi n g 
a d mi nistrati o n of pre ve nti ve, as well as a d diti o nal t hera pe utic a ntie metic a ge nts f or 
ma na gi n g  esta blis he d na usea or v o miti n g . 
 Gra de 3  diarr hea t hat has res ol ve d t o G ra de ≤2 wit hi n 4 8 h o urs after sta n d ar d 
a nti diarr heal t hera pies . 
 Is olat e d la b orat or y fi n di n gs n ot ass oci ate d wit h si g ns or s y m pt o ms i ncl u di n g G ra de 3/ 4 
al kali ne p h os p hatase, uric aci d, a m ylas e, a n d li pas e ele vati o ns, a n d G ra d e 3 
h y p o natr e mia lasti n g  < 7 2  h o urs de vel o pe d fr o m G ra de 1 at b aseli ne . 
 D ue t o t he nat ure of A M L  a n d M D S , si g nifica nt a b n or malities of he mat ol o gical 
para meters are e x pecte d fr o m t he u n derl yi n g disease or as p art of a ntica ncer t hera p y.  
T heref ore, n o h e mat ol o gi cal D L Ts are defi ne d f or t his pr ot oc ol.  
 Al o pecia.  
 Gra de ≥3 electr ol yte a b n or malities t hat are c orrecte d t o ≤Gra de 1 wit hi n 2 4  h o urs.  
3. 5.   
M a xi m u m T oler ate d D ose  a n d Rec o m me n de d D ose f or E x p a nsi o n  
O nce t he st o p pi n g cr iteria are m et, t he M T D  esti mate d b y B L R M a n d  E W O C is t he d ose wit h 
t he hi g hest p osteri or pr o ba bilit y of t he D L T rate i n t he tar get D L T rate i nter val of [ 1 6 %, 3 3 %] 
a m o n g all d oses f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt (t here is less t ha n 2 5 % pr o ba bilit y f or 
t he D L T rate > 3 3 % [pr o ba bilit y f or e x cessi ve or u nacce pta ble t o xicit y ]) (S ecti o n  3. 1. 2 ).  Si nce 
a n alter nati ve mila de met a n  a d mi nistrati o n sc he d ule ma y b e e x pl ore d i n lie u of or i n parallel wit h 
t he ori gi nal q d  2 1/ 2 8 sc h e d ule  a n d als o i n t he c o m bi nati o n of mila de meta n pl us A Z A , s e parate 
M T Ds ma y b e i de ntifie d f or eac h re gi me n .  T he fi nal M T D f or eac h d osi n g sc he d ule will be 
deci de d bas e d o n c o nsi derati o ns of t he res p ecti ve M T Ds esti mate d b y t h e B L R M a n d o n a n 
o verall assess me nt of s afet y d ata fr o m s u bse q u e nt c ycles a n d P K / P D y i nfor mati o n c ollecte d at 
all differe nt d os es teste d . 
3. 6.   
M a n a ge me nt of S u bjects w it h A d verse E ve nts 
Treat me nt -relate d t o xicities meeti n g t he D L T defi niti o n (see Secti o n 3. 4 ) occ urri n g d uri n g t he 
st u d y will res ult i n i nterr u pti o n a n d/ or disc o nti n uati o n of t hera p y.  F or s u bjects deri vi n g cli nical 
be nefit fr o m treat me nt, a n o pti o n t o res u me t he t hera p y at 1  d os e le vel bel o w t hat at w hic h t he 
t o xicit y occ urre d m a y be c o nsi dere d after t he t o xicit y ret ur ns t o N CI -C T C A E G ra de ≤1 or t o 
baseli ne val ues.  H o we ver, s u bjects re q uiri n g m ore t ha n 2 8 da ys  t o rec o ver fr o m ac ute t o xicities 
s h o ul d be wit h dra w n fr o m t he treat me nt.  If a s u bject e x perie nces N CI -C T C A E G ra de 3 or 4 
t o xicit y or a n S A E t hat is u ne q ui v ocall y attri b uta ble t o t he u n derl yi n g m ali g na n c y, m ila de meta n 
treat me nt ma y be p ost p o ne d u ntil t he t o xicit y h as res ol ve d t o N CI-C T C A E G ra de ≤1 , or ret ur ns 
t o baseli ne val ues. 

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3. 7.   
D ose I nterr u pti o ns a n d Re d ucti o ns of St u d y D r u g (s) 
3. 7. 1.   
D ose Re d ucti o ns Wit h C o nc o mit a nt A d mi nistr ati o n of a Str o n g C Y P 3 A 
I n hi bit or 
N o d ose m o dificati o n f or A Z A is re q uire d wit h t he c o nc o mita nt a d mi nistrati o n of a str o n g 
C Y P 3 A i n hi bit or.  
T he m ila de meta n d ose will be re d uce d w he n t he c o nc o mita nt a d mi nistrati o n of a str o n g C Y P 3 A 
i n hi bit or is re q uire d: 
 Mila de meta n d ose will b e re d uce d t o half of t he prescri be d d os e (ie, 1 2 0 m g a n d 1 6 0 m g 
d oses of mila de meta n will be re d uce d t o 6 0 m g a n d 8 0 m g, res pecti vel y) . 
 Re g ularl y s c he d ule d d os es of mila de meta n after disc o nti n uati o n of str o n g C Y P 3 A 
i n hi bit or s h o ul d be res u me d after a 3-da y was h o ut peri o d f oll o wi n g disc o nti n uati o n . 
3. 7. 2.   
D ose I nterr u pti o ns a n d Re d ucti o ns f or N o n -he m at ol o gic T o xicities  
T he f oll o wi n g g ui d eli nes s h o ul d be f oll o we d f or s u bjects w h o de vel o p a Gra de 3 or 4 
n o n -he mat ol o gi c t o xicit y t hat is at least p ossi bl y relate d t o mila de meta n a n d/ or A Z A a n d w hic h 
persists > 4 8 h o urs wit h o ut i m pr o ve me nt t o ≤Gra d e 2 ( or wit h o ut waiti n g 4 8 h o urs if i n t he 
I n v esti gat ors j u d g m e nt t he A E p oses a s eri o us ris k t o t he s u bject).  T his will n ot a p pl y f or 
Gra de  3 fati g ue lasti n g < 4 8 h o urs.  
 D osi n g will be i nterr u pt e d f or u p t o 2 8 da ys.  
o  If t o xicit y i m pr o ves t o ≤Gra de 1 wit hi n 2 8 da ys, treat me nt ma y be res u me d at t he 
pre vi o us d ose.  
o  If t o xicit y i m pr o ves t o Gra de 2 wit hi n 2 8 da ys, treat me nt ma y b e res u m e d at a 
re d uce d d os e ( 1 le v el bel o w) f or mila de met a n a n d/ or A Z A o nl y after t he t o xicit y 
has res ol ve d t o ≤Gra de 1.  Alter nati vel y , f or mila de meta n, t he I n v esti gat or after 
c o ns ultati o n wit h t he S p o ns or Me dical M o nit or ma y re d uce t he d ose fre q u e nc y 
(e g, q d 1 0/ 2 8 da ys  t o q d 7/ 2 8 da ys , q d 7/ 2 8 da ys t o q d 5/ 2 8 da ys, etc) i n 
s u bse q ue nt c ycles w hile mai ntai ni n g t he sa me dail y d ose of mila d e meta n.  
o  F or ot her Gra d e ≥2 la b orat or y a b n or malities t hat d o  n ot meet t he criteria f or 
D L Ts, tr eat me nt c o nti n u ati o n wit h mila de meta n will be at t he discreti o n of t he 
I n v esti gat or. 
 If t o xicit y d o es n ot i m pr o ve/res ol ve wit hi n 2 8 da ys, t he n treat me nt ma y be disc o nti n ue d 
after disc ussi o n bet w ee n t he I n v esti gat or a n d S p o ns or Me dical M o nit or.  
3. 7. 3.   
D ose I nter r u pti o ns a n d Re d ucti o ns f or He m at ol o gic T o xicities  
Ne utr o pe nia a n d/ or t hr o m b oc yt o pe ni a are a ntici p ate d he mat ol o gic t o xicities f or b ot h 
mila de meta n a n d A Z A.  Eit her or b ot h of t he st u d y dr u gs ca n be i nterr u pte d a n d/ or d ose  re d uce d 
per t he I n v esti gat or’s cli nical o pi ni o n of attri b uti o ns  t o t he disease or t he st u d y dr u g(s).  T he 
I n v esti gat or s h o ul d c o ns ult t he S p o ns or Me dical M o nit or if attri b uti o ns are n ot clear. 

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3. 7. 3. 1.  
Mil a de met a n  
Acti ve m o nit ori n g a n d a p pr o priate treat me nt s h o ul d be e m pl o ye d f or n e utr o pe nia a n d 
t hr o m b oc yt o pe ni a.  F or m yel os u p pressi o n n ot relate d t o u n derl yi n g A M L ( A N C < 0. 5 × 1 0 9/ L 
a n d/ or platelet c o u nt < 5 0 × 1 0 9/ L): 
 U p o n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or, t he I n v esti gat or ma y : 
o  R e d uce t he mila de met a n d ose fre q u e nc y (e g, q d 1 0/ 2 8 da ys t o q d 7/ 2 8 da ys, q d 
7/ 2 8 da ys t o q d 5/ 2 8 da ys, etc ) w hile kee pi n g t he sa me d ose le vel, O R 
o  R e d uce t he d ose of mila de meta n b y 1 d ose le vel w hile kee pi n g t he sa me d osi n g 
sc he d ule. 
 If t o xicities persist, t he I n vesti gat or s h o ul d disc uss wit h t he S p o ns or pri or t o an y 
a d diti o nal d ose re d ucti o ns of eit her A Z A or mila de meta n.  
W he n t he s u bject is n o l o n ger m yel os u p press e d, b ot h st u d y dr u gs ma y be res u me d at t he 
pre vi o us d ose a n d/ or d osi n g sc he d ule.  
3. 7. 3. 2.  
5 -Az aciti di ne  
F or s u bjects wit h o ut re d u ce d baseli ne bl o o d c o u nt (e g, W B C  ≥3. 0 × 1 0 9/ L, A N C ≥1. 5 × 1 09/ L, 
a n d platelets ≥7 5. 0 × 1 0 9/ L) pri or t o t he st u d y dr u g treat me nt, t he d ose will be a dj uste d per 
Ta ble  3 .4 , base d o n n a dir c o u nts f or a n y gi ve n c ycle.  
T a ble  3 .4 :  
5 -Az aciti di ne D os a ge A dj ust me nts B ase d o n N a dir C o u nts  
N a dir C o u nts  
% D ose i n t he Ne xt C o urse  
A N C ( × 1 0 9/ L)  
Pl at elets ( × 1 0 9/ L) 
 
< 0. 5  
< 2 5. 0  
5 0 %  
0. 5 –  1. 5  
2 5. 0 –  5 0. 0  
6 7 %  
> 1. 5  
> 5 0. 0  
1 0 0 %  
A N C = a bs ol ute ne utr o p hil c o u nt  
S o urce = Vi daza ®  (azaciti di ne f or i nj ecti o n) pac ka ge i nsert 1 
F or s u bjects wit h re d uce d baseli ne bl o o d c o u nt (e g, W B C < 3. 0 × 1 0 9/ L, A N C < 1. 5 × 1 09/ L, a n d 
platelets < 7 5. 0 × 1 0 9/ L) pri or t o t he st u d y dr u g treat me nt, d ose a dj ust me nts s h o ul d be base d o n 
na di r c o u nts a n d b o ne m arr o w bi o ps y cell ularit y at t he ti me of t he na dir as n ote d i n Ta ble  3 .5 , 
u nless t here is clear i m pr o ve me nt i n differe ntiati o n ( perce nta ge of mat ure gra n ul oc ytes is hi g h er 
a n d A N C is hi g her t ha n at o nset of t hat c o urse) at t he ti me of t he ne xt c ycl e, i n w hic h case t he 
d ose of t he c urre nt treat me nt s h o ul d be c o nti n ue d.  
If a na dir as defi n e d i n T a ble  3 .4  has occ urre d, t he ne xt c o urse of treat me nt s h o ul d be gi ve n 
2 8  da ys after t h e start of t he prece di n g c o urse, pr o vi de d t hat b ot h t he W B C a n d t he platelet 
c o u nts are > 2 5 % a b o v e t he na di r a n d are risi n g.  If a > 2 5 % i n crease a b o v e t he na dir is n ot see n 
b y Da y  2 8, c o u nts s h o ul d be reass esse d e v er y 7 da ys.  If a > 2 5 % i ncrease is n ot see n b y Da y  4 2, 
t he n t he patie nt s h o ul d be treate d wit h 5 0 % of t he sc he d ule d d ose. 

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T a ble  3 .5 :  
5 -Az aciti di ne D os a ge A dj ust me nts B ase d o n N a dir C o u nts  
W B C or Pl atelet N a dir  
% Decre ase i n C o u nts fr o m B aseli ne  
B o ne M arr o w Bi o ps y Cell ul arit y at Ti me of N a dir  
3 0 % –  6 0 %   
1 5 % –  3 0 %   
< 1 5 %  
5 0 % –  7 5 %  
% D ose i n t he Ne xt C ycle  
1 0 0 %  
5 0 %  
3 3 %  
> 7 5 %  
7 5 %  
5 0 %  
3 3 %  
W B C = w hite bl o o d cell  
S o urce = Vi daza ®  (azaciti di ne f or i nj ecti o n) pac ka ge i nsert 1 
3. 7. 4.   
D os a ge M o dific ati o ns f or 5 -Az a citi di ne B ase d o n Re n al F u ncti o n a n d Ser u m 
Electr ol ytes  
If u ne x plai ne d re d ucti o ns i n ser u m bicar b o nat e le vels t o < 2 0 m E q/ L occ ur, t he d osa ge s h o ul d be 
re d uce d b y 5 0 % o n t he ne xt c o urse.  Si milarl y, if u ne x plai ne d ele vati o ns of bl o o d urea nitr o ge n 
( B U N) or ser u m creati ni ne occ ur, t h e ne xt c ycl e s h o ul d be dela ye d u ntil val ues ret ur n t o n or mal 
or baseli ne, a n d t h e d ose s h o ul d be re d uce d b y 5 0 % o n t he ne xt treat me nt c o urse.  

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Pa ge 5 8  
4.   
S T U D Y P O P U L A TI O N  
S u bjects wit h R/ R  A M L or hi g h -ris k M D S will be e nr olle d i n Part 1 ( D ose Escalati o n) f or 
mila de meta n as a si n gle a ge nt  a n d i n Part 1 A ( D ose Escalati o n) f or mila de meta n i n c o m bi nati o n 
wit h A Z A.  Part 2 ( D ose E x pa nsi o n) will e x a mi ne mila de meta n i n c o m bi nati o n wit h A Z A i n 
s u bjects wit h R/ R  A M L, ne wl y di a g n ose d A M L u nfit f or i nte nsi ve c he m ot hera p y, or hi g h -ris k 
M D S.  S pecific  i ncl usi o n a n d e x cl usi o n criteria are a vaila ble i n Secti o n 4. 1. 1  a n d Secti o n 4. 1. 2 . 
4. 1.   
E nr oll me nt  
I n v esti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates t hat 
i ncl u des li mite d i nf or mati o n of t he s u bjects (i nitials, a ge, se x), a n d date a n d o utc o me of 
scree ni n g pr ocess ( e g, e nr oll i n t he st u d y, reas o n f or i neli gi bilit y, ref use d t o partici pate).  
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n t he st u d y 
i n dicati n g t heir assi g n e d st u d y n u m ber. 
I n v esti gat ors will mai ntai n a c onfi de ntial s u bject i de ntificati o n c o de list.  T his c o nfi de ntial list of 
na mes of all s u bjects w h o ha ve bee n all ocate d t o st u d y n u m bers u p o n e nr olli n g i n t he st u d y 
all o ws t he I n vesti gat or t o re veal t he i d e ntit y of a n y s u bject w he n necessar y.  
Eac h s u bject or  l e gall y acce pta bl e re prese ntati ve will be pr o vi de d wit h i nf or mati o n a b o ut t he 
st u d y, will ha ve all q uesti o ns a ns were d t o t heir s atisfacti o n, a n d will si g n a n d date a n i nf or m e d 
c o nse nt f or m ( I C F).  T his will be c o m plete d bef ore a n y st u d y -s pecific pr oce d ures are perf or me d.  
A d diti o nal i nf or mati o n a b o ut i nf or me d c o nse nt pr oce d ures is pr o vi d e d i n  Secti o n  6. 1. 1 . 
A s u bject is c o nsi dere d e nr olle d i n t he st u d y  u p o n t he I n v esti gat or or desi g nee o btai ni n g writte n 
i nf or me d c o nse nt fr o m t he s u bject or t he s u bject’s le gall y acce pta ble re pres e ntati ve 
(Secti o n  6. 1. 1 ) a n d u p o n deter mi nati o n t hat all i ncl usi o n a n d e x cl usi o n criteria ha v e bee n 
satisfie d.  After assi g ni n g a s u bject i de ntificati o n n u m ber ( SI D) t o eac h s u bj ect at t he ti m e of 
Scree ni n g , I n v esti gat ors will assess t he eli gi bilit y of a s u bject base d o n t he i ncl usi o n a n d 
e x cl usi o n criteria after o btai ni n g writte n i nf or me d c o nse nt fr o m t he s u bject.  After assess me nt b y 
I n v esti gat ors, t he i ncl usi o n criteria/e xcl usi o n criteria f or m will be c o m plete d f or re gistrati o n.  
T he S p o ns or  will perf or m re gistrati o n after ve rif yi n g t hat t he s u bject meets t he 
i ncl usi o n/e xcl usi o n criteria pr o vi de d b y t he I n v esti gat or.  Directl y after re gistrati o n, t he S p o ns or  
will f or war d t he res ults of re gistrati o n t o t he I n vesti gat or.  At t hat ti me, t he s u bject will be 
assi g ne d t o st u d y dr u g tr eat me nt.  
Data f or all st u d y visits will be rec or de d o n t he e C R F f or s u bjects w h o recei ve st u d y dr u g 
treat me nt.  O nl y mi ni mal data (ie, de m o gra p h y  a n d reas o n f or wit h dra wal) will be rec or de d o n 
t he e C R F f or s u bjects w h o fail i ncl usi o n/e xcl usi o n criteria a n d/ or d o n ot recei ve st u d y dr u g.  
F urt her data, s uc h as A Es , will n ot be c ollecte d fr o m s u bjects o nce t he y are c o nsi dere d scree n 
fail ures or ha ve deci de d t o wit h dra w pri or t o recei vi n g st u d y dr u g.  
4. 1. 1.   
I ncl usi o n Criteri a  ( P a rt 1/ 1 A a n d P art 2) 
S u bjects m ust satisf y all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:  

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1.  S u bjects wit h hist ol o gical c o nfir mati o n of pri mar y , sec o n dar y, or t hera p y -relate d A M L 
acc or di n g t o t he 2 0 1 6 W orl d Healt h Or ga nizati o n criteria  classificati o n, or hi g h -ris k 
M D S ( defi ne d b y Re vise d I nter nati o nal Pr o g n ostic Sc ori n g S yste m sc ore of Hi g h or Ver y 
Hi g h [ Secti o n  1 7. 6 ]). 
 Part 1 a n d 1 A  ( D os e Escalati o n) 
o  S u bjects wit h R/ R A M L, O R  
S u bjects wit h u ntreate d, hi g h -ris k M D S or s u bjects w h o ha ve recei v e d pri or 
M D S treat me nt re gi me ns . 
o  S u bjects ≥1 8 years ol d . 
N ote :  T here is n o mi ni m u m or ma xi m u m n u m ber of pri or A M L or M D S treat me nt 
re gi me ns f or Part 1 a n d 1 A . 
 Part 2 ( D ose E x pa nsi o n)  
o  C o h ort 1:  R/ R A M L  
 S u bjects w h o ha ve treat me nt fail ure t o pri or A M L t hera p y ( defi ne d as 
fail ure t o ac hie ve at least C Ri) or ha ve rela pse d after pri or A M L 
t hera p y, A N D 
 S u bjects ha ve recei ve d 1 t o 3 pri or treat me nt re gi me ns f or 
A M L if pri or treat me nts i ncl u de d a n i nte nsi ve c h e m ot hera p y  
(e g, a nt hrac ycli ne-base d t hera p y a n d/ or i nter me di ate or hi g h 
d ose of c ytara bi ne) , O R 
S u bjects w h o ha ve recei v e d 1 t o 2 pri or treat me nt re gi me ns f or 
A M L if pri or treat me nts di d n ot i ncl u de a n i nte nsi ve 
c he m ot hera p y. 
 S u bject s ≥1 8 years ol d. 
o  C o h ort 2: ne wl y dia g n os e d A M L  
 S u bjects wit h ne wl y dia g n ose d A M L w h o are i neli gi ble f or i nte nsi ve 
i n d ucti o n c he m ot hera p y (e g, c o m bi nati o n of a n a nt hrac ycli ne a n d 
c yt ara bi ne) .  S u bjects m ust ha ve ha d n o  pri or A M L treat me nt, wit h t he 
e x ce pti o ns of t hera p y f or a ntece d e nt he mat ol o gic mali g na n cies (e g, 
azaciti di ne f or M D S) or h y dr o x y urea.  
 S u bjects ≥7 5 years ol d, O R  
S u bjects bet wee n 1 8 a n d 7 4 years ol d (i ncl usi ve) wit h at least o ne of 
t he f oll o wi n g c o m or bi dities: 
 E C O G Perf or ma nce Stat us of 3;  
 Car diac hist or y of c o n gesti ve heart fail ure ( C H F) re q uiri n g 
treat me nt, or left v e ntric ular ejecti o n fracti o n (L V E F) ≤5 0 %, or 
c hr o nic sta ble a n gi na;  

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 Diff usi n g ca p acit y of t he l u n g f or car b o n m o n o xi de ( D L C O) 
≤6 5 % or f orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V 1) ≤6 5 %;  
 A n y ot her c o m or bi dit y t hat t he I n vesti gat or j u d ges t o be 
i nc o m pati ble wit h i nte nsi ve c he m ot hera p y m ust be re vie we d 
b y t he S p o ns or Me di cal M o nit or d uri n g S cree ni n g a n d b ef ore 
st u d y e nr oll me nt. 
o  C o h ort 3: hi g h -ris k MD S  
 S u bjects wit h u ntreate d, hi g h -ris k M D S or w h o recei ve d u p t o 2  pri or 
M D S treat me nt re gi me ns.  Pri or M D S t hera p y here e x cl u des 
s u p p orti ve care s uc h as tr a nsf usi o n, or er yt hr o p oi esis-sti m ulati n g 
a ge nt. 
2.  Has a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G ) perfor ma n ce stat us  0 t o 2 . 
 As a n e x ce pti o n, s u bjects wit h ne wl y dia g n os e d A M L bet w ee n 1 8 a n d 7 4 years 
ol d (i ncl usi ve) i n Part 2 C o h ort 2 wit h E C O G Perf or ma nce Stat us of 3 will be 
eli gi ble.  
3.  Has a de q u ate re nal f u ncti o n, defi ne d as:  
 Creati ni ne cleara n ce ≥6 0 m L/ mi n, as cal c ulate d usi n g t he m o difie d C oc kcr oft 
Ga ult e q uati o n, ([ { 1 4 0 –  a ge i n years } × {act ual wei g ht i n k g }] di vi de d b y [ { 7 2 × 
ser u m creati ni ne i n m g/ d L }] m ulti pl y b y 0. 8 5 if fe male), O R creati ni ne cleara nce 
5 0 -6 0 m L/ mi n A N D h as ser u m creati ni ne ≤1. 5 × U L N.  I n o bes e s u bjects, t he 
lea n b o d y wei g ht ca n be use d i n t he e q uati o n i nstea d of act u al b o d y wei g ht. 
4.  Has a de q u ate he p atic f u ncti o n, defi ne d as:  
 A S T/ A L T ≤2. 5 × U L N ( ≤5  U L N if dee me d ele vate d d ue t o le u ke mia), a n d  
 Ser u m t otal bilir u bi n ≤1. 5 × U L N  (≤3  U L N if dee me d el e vate d d ue t o le u ke mia 
or i n s u bjects wit h d oc u me nte d Gil bert’s S y n dr o me).  
5.  S u bject ( or le gall y acce pt a ble re prese ntati ve) is a ble t o pr o vi de writte n i nf or me d c o nse nt, 
c o m pl y wit h pr ot oc ol visits a n d pr oce d ures, a n d ta ke oral me dicatio n, a n d d oes n ot ha ve 
a n y acti ve i nf ecti o n or c o m or bi dit y t h at w o ul d i nterfere wit h t hera p y.  
6.  S u bject, if fe male of c hil d beari n g p ote ntial , m ust ha ve a n e gati ve ser u m pre g n a nc y test 
u p o n e ntr y i nt o t his st u d y a n d m ust be willi n g t o use hi g hl y effecti ve birt h c o ntr ol  
( Secti o n 1 7. 9 ) d uri n g t he peri o d of  t hera p y a n d f or 6 m o nt hs f oll o wi n g t he last 
i n vesti gati o nal dr u g d ose.  A fe male is c o nsi dere d of c hil d beari n g p ote ntial f oll o wi n g 
me narc h e a n d u ntil bec o mi n g p ost me n o pa usal ( n o me nstr ual peri o d f or a mi ni m u m of 
1 2  m o nt hs), u nless per ma ne ntl y sterile ( u n der g o n e a h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect om y).  
If male, m ust be s ur gicall y sterile or be willi n g t o use 1 f or m of hi g hl y  effecti ve 
c o ntrace pti o n met h o d u p o n e nr oll me nt, d uri n g t h e c o urse of t he st u d y, a n d f or 6 m o nt hs 
f oll o wi n g t he last i n vesti gati o nal dr u g d os e. 

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7.  S u bject m ust be f ull y i nf or me d a b o ut t heir ill ness a n d t he i n vesti gati o nal nat ure of t he 
st u d y pr ot oc ol (i ncl u di n g f oreseea ble ris ks a n d p ossi ble si de effects). 
8.  S u bject  m ust si g n a n d date a n I nstit uti o nal Re vie w B oar d (I R B)-a p pr o ve d I C F (i ncl u di n g 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta b ilit y Act a ut h orizati o n, if a p plica ble) bef ore 
perf or ma n ce of a n y st u d y -s p ecific pr oce d ures or t ests. 
9.  A ble a n d  willi n g t o pr o vi de b o ne marr o w bi o psies /as pirates as re q ueste d b y t he pr ot oc ol . 
1 0.  Is willi n g t o u n der g o mali g na n c y ge n ot y pi n g f or T P 5 3 m utati o n, i nserti o n, or deleti o n at 
Scree ni n g . 
4. 1. 2.   
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be dis q ualifie d fr o m e nteri n g t he st u d y:  
1.  Has a d ia g n osis of ac ute pr o m yel o c yti c le u ke mia. 
2.  Has a mali g na nc y  t h at is kn o w n t o c o ntai n a n o n -s y n o n y m o us m utati o n, i nserti o n, or  
deleti o n  i n t he T P 5 3 ge n e deter mi ne d pre vi o usl y or at Scree ni n g . 
3.  Prese nce of C N S  i n v ol ve me nt of le u ke mia.  Patie nts wit h a hist or y of C N S le u ke mia ma y 
be eli gi ble if t h e C N S le u ke mia is a de q uatel y c o ntr olle d ( defi ne d as n o acti ve cli nical 
s y m pt o ms of C N S disease a n d at least 2 c o nsec uti ve l u m bar p u nct ures wit h n o e vi de nce 
of disease pri or t o st u d y e nr oll me nt) after disc ussi o n wit h  t he S p o ns or Me dical M o nit or . 
4.  Has ot her c o n c urre nt pri mar y m ali g n a nc y t h at re q uire d s yst e mic a nti-ne o plastic treat me nt 
wit hi n t he pre vi o us 2  years, e x ce pt f or l ocalize d ca ncers t h at ha ve a p pare ntl y bee n c ure d, 
s uc h as n o n-mela n o ma s ki n ca ncer, s u perficial bl a d der ca ncer, or carci n o ma i n sit u of t he 
cer vi x or breast.  
5.  A n y c o n diti o n t hat w o ul d precl u de a de q uat e a bs or pti o n of m ila de meta n, i ncl u di n g 
refract or y n a usea a n d v o miti n g, mala bs or pti o n, biliar y s h u nt , si g nifica nt b o wel resecti o n, 
a n d/ or graft -vers us -h ost disease ( G V H D) affecti n g t he g ut . 
6.  Has a n u nc o ntr olle d i nf ect i o n re q uiri n g I V a nti bi otics, a nti virals, or a ntif u n gals . 
7.  Has k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n wit h e vi de nce of acti ve 
i nfecti o n b y HI V R N A viral l oa d, or acti ve he patitis B or C i nfecti o n bas e d o n p ositi ve 
tests d uri n g Scree ni n g. 
8.  Has a c o n c o mita nt me dical c o n diti o n t hat w o ul d i ncreas e t he ris k of t o xicit y . 
9.  Has u nres ol ve d t o xicities fr o m pre vi o us a ntica ncer t hera p y, d efi ne d as t o xicities ( ot her 
t ha n alo pecia) n ot yet res ol ve d t o N CI -C T C A E G ra de ≤1 , or ba s eli ne.  S u bjects wit h 
c hr o nic Gra de 2 t o x icities ma y be eli gi ble p er discreti o n of t he  I n vesti gat or a n d S p o ns or 
(e g, Gra de 2 c h e m ot hera p y-i n d uce d ne ur o pat h y). 
1 0.  Has recei ve d h e mat o p oietic cell tra ns pla ntati o n (H C T ) wit hi n 6 0  da ys of t h e first d ose of  
st u d y dr u gs. 
1 1.  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 s yste mic treat me nt or 
s yste mic treat me nt escalati o n wit hi n 2 1 da ys pri or t o Scree ni n g a n d/ or > Gra de 1 

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persiste nt or cli nicall y si g nifica nt G V H D or ot her n o n -he mat ol o gi c t o xicit y relate d t o 
H C T.  
1 2.  Is recei vi n g c o nc o mita nt treat me nt wit h a str o n g i n d ucer of C Y P 3 A 4/ 5 or c o ns u m pti o n of 
St. J o h n’s W ort ( h y p erici n) wit hi n 3 da ys pri or t o t he first d ose a n d d uri n g treat me nt . 
1 3.  Recei ve d a nti-A M L t hera p y (e x ce pt f or h y dr o x y urea) or a nti -M D S t hera p y wit hi n t he 
f oll o wi n g was h o ut peri o ds bef ore starti n g st u d y me dicati o n. 
 Se ve n da ys O R 5 half -li v es, w hic he ver is l o n ger, f or s mall m olec ule dr u gs. 
 T we nt y -o ne d a ys O R 5 half -li ves, w hic he v er is s h orter, f or a nti b o d y-base d, 
i m m u ne-base d, bi ol o gi c, or cell ular t hera pies.  
 H y dr o x y urea m ust be disc o nti n ue d at least 4 8 h o urs pri or t o st u d y treat me nt.  
1 4.  Ha d maj or s ur ger y wit hi n 4 wee ks pri or t o st u d y dr u g treat me nt.  
1 5.  Partici pate d i n a t hera pe utic cli nical st u d y wit hi n a was h o ut ti me of 2 wee ks or 5  half -
li ves of t he dr u g/ bi ol o gic ( w hic he ver is l o n ger) bef ore starti n g st u d y dr u g treat me nt u n der 
t his pr ot oc ol, or c urre nt p artici pati o n i n ot her t hera pe utic i n vesti gati o nal pr oce d ures. 
1 6.  U nc o ntr olle d or si g nifica nt car di o vasc ul ar diseas e, i ncl u di n g:  
a. P r ol o n gati o n of Q Tc F at rest, w here t h e mea n Q Tc F i nter val is > 4 8 0 ms  base d o n 
tri plicate E C Gs. 
b.  Bra d ycar di a of less t ha n 5 0 b p m u nless t he s u bject has a pace ma ker.  
c. Dia g n os e 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 y n dr o me. 
d.  Hist or y of cli nicall y rele va nt ve ntric ular a rr h yt h mias, s uc h as ve ntric ul ar 
tac h ycar dia, ve ntric ul ar fi brillati o n, or t orsa de de p oi ntes. 
e. Hist or y of sec o n d or t hir d de gree h eart bl oc k.  S u bjects wit h a hist or y of heart 
bl oc k ma y b e eli gi ble if t he y c urre ntl y h a ve p ace ma kers a n d h a 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. 
f. M y ocar dial i nfarcti o n wit hi n 6 m o nt hs pri or t o Scree ni n g.  
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.  
h.  N Y H A Class III or I V c o n gesti ve h eart fail ure  (Secti o n  1 7. 8 ). 
i. K n o w n L V E F ≤5 0 % or i nstit uti o nal l o wer li mit of n or mal . 
 As a n e x ce pti o n, s u bjects wit h ne wl y dia g n os e d A M L bet w ee n 1 8 a n d 7 4 
years ol d i n Part 2  C o h ort 2 wit h L V E F ≤5 0 % or i nstit uti o nal l o wer li mit of 
n or mal will be eli gi ble.  
j. U nc o ntr olle d h y pert e nsi o n.  
k.  Left b u n dle bra n c h bl oc k.  
1 7.  K n o w n D L C O ≤6 5 % or F E V 1 ≤6 5 % . 

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 As a n e x ce pti o n, s u bjects wit h ne wl y dia g n os e d A M L bet w ee n 1 8 a n d 7 4 years 
ol d i n Part 2 C o h ort 2 wit h D L C O ≤6 5 % or F E V 1 ≤6 5 % will be eli gi ble.  
1 8.  P re g n a nt or breastfee di n g. 
1 9.  S u bsta nce a b use or me dical, ps yc h ol o gical, or s o cial c o n diti o ns t hat, i n t he o pi ni o n of t he 
I n v esti gat or, ma y i nterfere wit h t he s u bject’s partici pati o n i n t he cli nical st u d y or 
e val uati o n of t he cli nical st u d y res ults.  
2 0.  Pri or treat me nt wit h a n M D M 2  i n hi bit or. 
4. 2.   
D isc o nti n u ati o n 
A s u bject ma y disc o nti n ue fr o m st u d y dr u g treat me nt, b ut ma y a gree t o recei ve l o n g -ter m 
f oll o w-u p p h o ne call  a n d/ or site visit  t o c ollect s ur vi val data. 
4. 2. 1.   
St u d y Tre at me nt Disc o nti n u ati o ns  
T he f oll o wi n g reas o ns are c o nsi dere d s ufficie nt t o disc o nti n ue a s u bject fr o m st u d y dr u g 
treat me nt: 
 A E  
 Deat h  
 P r o gressi ve disease ( P D) or rela pse w hic h meets pr ot oc ol -defi ne d criteria  ( Secti o n 1 7. 4  
a n d Secti o n  1 7. 5 ) 
 Cli nical P D or rela pse base d o n I n vesti gat or’s j u d ge m e nt  
 All o ge n eic H C T  
 Pre g n a nc y  
 Pr ot oc ol de viati o n  
 L ost t o f oll o w -u p  
 Wit h dra wal b y s u bject’s decisi o n  
 Ot her (t he reas o n s h o ul d be disc usse d bet w ee n t he I n v esti gat or a n d S p o ns or Me dical 
M o nit or, a n d s h o ul d be rec or de d o n t h e cas e re p ort f or m [ C R F]) 
All s u bjects disc o nti n ue d fr o m st u d y tr eat me nt d u e t o a n y reas o n ot her t ha n wit h dra wal of 
c o nse nt f or f oll o w -u p will u n der g o assess me nt at f oll o w -u p visits.  
If t he s u bject disc o nti n ues st u d y treat me nt d ue t o a n A E, t he I n v esti gat or will f oll o w t he s u bject 
u ntil t he A E has res ol ve d or sta bilize d, or u ntil t he s u bject is a vaila ble f or f oll o w -u p.  
Res p o nse criteria -met or cli nical P D/rela pse is c o nsi dere d a s ufficie nt reas o n t o disc o nti n ue 
st u d y dr u g tr eat me nt; h o we ver, t he I n vesti gat or m a y co nti n ue st u d y dr u g treat me nt u ntil t he 
I n v esti gat or has alter nati ve A M L or M D S t hera pies a n d c o nsi ders t he st u d y dr u g treat me nt t o be 
n o l o n ger be neficial t o t he s u bject.  T he d ecisi o n t o disc o nti n ue a s u bject fr o m st u d y dr u g 
treat me nt re mai ns t he res p o nsibilit y of t he I n vesti gat or a n d s h o ul d n ot be dela ye d or ref use d b y 
t he S p o ns or. 

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W he n o ne of t he st u d y dr u gs is disc o nti n ue d d ue t o t o xicities, I n vesti gat ors ma y c o nti n ue t he 
ot her st u d y dr u g if t his is c o nsi dere d t o be safe a n d i n t he best i nterest of t h e s u bject aft er 
c o ns ultati o n wit h t he S p o ns or Me dical M o nit or.  
4. 2. 2.   
St u d y  Disc o nti n u ati o n  
S u bjects ma y be wit h dra w n fr o m t he st u d y at a n y ti me after si g ni n g t h e I C F f or t he f oll o wi n g 
reas o ns: 
 Wit h dra wal b y s u bject’s decisi o n  
 Deat h  
 P D or rela pse  
 L ost t o f oll o w -u p  
 Ot her (t he reas o n s h o ul d be s pecifie d o n t h e C R F)  
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete a n d re p ort t he 
o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he d ate of wit h dra wal , i ncl u di n g t he dat e of last 
treat me nt a n d t he reaso n f or wit h dra wal.  
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol -s p ecifie d E n d -of -
treat me nt ( Secti o n 6. 5 ) a n d F oll o w-u p pr oce d ures ( Secti o n 6. 6 ). 
4. 2. 3.   
S u bject Re pl ace me nt  
D uri n g Part s 1  a n d 1 A of t he st u d y, a n y s u bject w h o disc o nti n ues st u d y partici pati o n bef ore 
c o m pleti n g t he first c ycle of treat me nt a n d is n ot e val ua ble f or D L T ma y  be re place d.  See 
Secti o n 3. 4  f or defi niti o ns of D L Ts. 
4. 2. 4.   
S u bject Re -scree ni n g Pr oce d ures 
R e-scree ni n g is per mitte d f or a n y s u bject w h o faile d t o meet eli gi bilit y criteria u p o n i nitial 
scree ni n g.  T h e  SI D m ust re mai n t he sa m e at t he ti me of re-s cree ni n g.  T he i nitial scree ni n g 
i nf or mati o n a n d t he reas o n w h y t he s u bj ect is i neli gi ble f or t h e i nitial e val uati o n will be rec or de d 
o n t he Scree ni n g L o g.  
B o ne marr o w bi o ps y/as pirate is n ot re q uire d t o b e re peat e d if b o ne marr o w s peci me n were 
alrea d y s u b mitte d d uri n g t he pre vi o us scree ni n g a n d if t he disease c o n diti o n is n ot c o nsi dere d t o 
ha ve si g nifica ntl y c h a n ge d  si nce t he i nitial scree ni n g sa m ple b ase d o n t he I n vesti gat or’s cli nical 
j u d ge me nt.  A d diti o nall y, t he I n v esti gat or ma y o pt t o n ot re peat ot her scree ni n g tests after 
disc ussi o n wit h t he S p o ns or Me dical M o nit or.  

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5.   
T R E A T M E N T S A D MI NI S T E R E D  
5. 1.   
I n vesti g ati o n al Pr o d ucts 
5. 1. 1.   
R a n d o miz ati o n  a n d Bli n di n g  
N ot a p plica ble.  
5. 1. 2.   
L a beli n g a n d P ac k a gi n g  
Mila de meta n 5 m g, 2 0 m g, 8 0 m g, a n d / or 2 0 0 m g ca ps ule s will be s u p plie d i n i n di vi d uall y 
pac ka ge d desicca nt -e m b e d de d al u mi n u m blister  car ds ( wallets), eac h c o ntai ni n g 7 ca ps ules; 
mila de meta n 3 0 m g , 8 0 m g, a n d/ or 1 0 0 m g ca ps ules will be s u p plie d i n la bele d hi g h -de nsit y 
p ol yet h yle ne ( H D P E) b ottles wit h a c hil d-resista nt ca p, a n d eac h b ottle will c o ntai n 3 5 ca ps ules. 
Azaciti di ne f or i njecti o n is c o m merciall y a vaila bl e as a l y o p hilize d p o w der i n 1 0 0 m g 
si n gle-d os e vials, pac k a ge d i n cart o ns of 1 vial.  
T he cli nical site will dis pe nse ta ke -h o me mila de m eta n wit h la bels a n d i nstr ucti o ns.  
5. 1. 3.   
Pre p ar ati o n  
Pr oce d ures f or pr o per ha n dli n g a n d dis p osal of a ntica ncer dr u gs s h o ul d be f oll o we d 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) of t he st u d y site.  
5. 1. 4.   
A d mi nistr ati o n  
Mila de meta n will be a d mi nistere d as a si n gle oral ca ps ule or as a c o m bi nati o n of m ulti ple oral 
ca ps ules.   F or Part 1 A a n d Part 2, mila de meta n will be a d mi nistere d i n 2  sc he d ules i n 
c o m bi nati o n wit h A Z A:  Sc he d ule e o n Da ys 5 t o 1 4 a n d Sc he d ule f o n Da ys 8 t o 1 4.  
A Z A will be rec o nstit ute d i n ster ile water f or use acc or di n g t o t he p ac ka ge i nsert f or S Q or I V 
a d mi nistrati o n.   S u bjects will be treate d wit h A Z A at 7 5 m g/ m 2 S Q or I V a d mi nistere d o n Da ys 1 
t o 7 i n c o m bi nati o n wit h mila de meta n i n t he select e d d osi n g sc h e d ule.  After t he R D E is 
i de ntifie d, a n alter nati ve A Z A sc he d ule (a d mi nistrati o n o n Da ys 1 t o 5 f oll o we d b y Da ys 8 t o 9 , 
Fi g ure  3 .3 ) will  be e val u ate d  t o deter mi ne w het her treat me nt of A Z A i n b ot h t he sc he d ules ca n 
be all o we d i n t he D ose E x pa nsi o n c o h orts.  
St u d y dr u g a d mi nistrati o n t hat occ urs at cli nic visits will be s u per vise d b y a me m ber of t h e site 
staff. 
5. 1. 5.   
St or a ge  
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n de r t he rec o m me n d e d 
st ora ge c o n diti o ns liste d bel o w: 
 Mila de meta n  i n blister car ds:  St ore d at 2 C t o 8 C ( 3 6 F t o 4 6 F).  
 Mila de meta n i n H D P E b ottles:  St ore d at r o o m te m perat ure u p t o 2 5 C.  
 A Z A: St ore d acc or di n g t o la bel i nf or mati o n.  

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If st ora ge c o n diti o ns are n ot mai ntai ne d per s pecifie d re q uire m e nts, t he C R O or t he S p o ns or 
s h o ul d be c o ntacte d. 
5. 1. 6.   
Dr u g Acc o u nt a bilit y  
W he n a dr u g s hi p me nt is recei v e d, t he I n v esti gat or or desi g nee will c hec k t he a m o u nt a n d 
c o n diti o n of t he dr u g, c h ec k f or a p pr o priate l ocal la n g u a ge i n t he la bel, dr u g e x pirati o n date, a n d 
si g n t he Recei pt of S hi p me nt F or m pr o vi de d.  T h e Recei pt of S hi p me nt F or m s h o ul d be fa x e d as 
i nstr ucte d o n t he f or m.  T he ori gi n al will be retai n e d at t he site.  I n a d diti o n, t he I n v esti gat or or 
desi g nee s hall c o ntact t he S p o ns or as s o o n as p ossi ble if t here is a pr o ble m wit h t he s hi p me nt.  
A Dr u g Acc o u nta bilit y R ec or d will be pr o vi d e d f or t he st u d y dr u g.  T he rec or d m ust be ke pt 
c urre nt a n d s h o ul d c o ntai n t he dates a n d q ua ntiti es of dr u g rece i ve d, s u bject (i de ntificati o n 
n u m ber a n d/ or i nitials or s u p pl y n u m ber as a p plica ble ) f or w h o m t he st u d y dr u g was dis pe nse d, 
t he date a n d q u a ntit y of st u d y dr u g dis pe ns e d a n d re mai ni n g, if fr o m i n di vi d ual s u bject dr u g 
u nits , as well as t he i nitials of t he dis pe nser.  
At t he e n d of t he st u d y, or as direct e d, all m ila de m eta n ca ps ules  i n cl u di n g u n use d, partiall y use d, 
or e m pt y c o ntai ners will be ret ur n e d t o a desi g nee as i nstr u cte d b y t he S p o ns or.  St u d y dr u g  will 
be ret ur n e d o nl y after t he st u d y m o nit or has c o m pl ete d a fi nal i n ve nt or y t o verif y t he q ua ntit y t o 
be ret ur n e d.  T he ret ur n of st u d y dr u g m ust be d o c u me nte d a n d t he d oc u m e ntati o n i ncl u de d i n 
t he s hi p me nt.  At t he e n d of t he st u d y, a fi nal st u d y dr u g rec o n ciliati o n state me nt m ust be 
c o m plete d b y t he I n vesti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.  U n use d dr u g s u p plies 
ma y b e destr o ye d b y t h e I n v esti gat or w he n a p pr o ve d i n writi n g b y t he S p o ns or/ dele gate a n d t he 
S p o ns or / dele gate has recei ve d c o pies of t h e site’s dr u g h a n dli n g a n d dis p ositi o n S O Ps.  
All st u d y dr u g i n ve nt or y f or ms m ust be ma de a v aila ble f or i ns pecti o n b y a S p o ns or -a ut h orize d 
re pres e ntati ve or d esi g n ee a n d re g ul at or y a ge nc y i ns pect ors.  T he I n vesti gat or is res p o nsi ble f or 
t he acc o u nt a bilit y of all use d a n d u n use d st u d y s u p plies at t he site.  
5. 1. 7.   
Rete nti o n S a m ples  
N ot a p plica ble.  
5. 2.   
Met h o d of Assessi n g Tre at me nt C o m pli a nce  
T he f oll o wi n g m eas ures will be e m pl o ye d t o e ns ure treat me nt c o m plia nce d uri n g d osi n g at t he 
cli nical site:  
 Mila de meta n o nl y t o s u bjects partici pat i n g i n t he st u d y a n d c o m pl yi n g wit h t he 
i nstr ucti o ns fr o m t he cli nical st u d y pers o n nel. 
 D oses o n t he visit da ys s h o ul d be a d mi nistere d t o s u bjects u n der t he s u per visi o n of 
cli nical st u d y pers o n nel at t he site.  
 Mila de meta n ma y be dis pe nse d i n a m o u nts e x cee d i n g t he mi ni m u m a m o u nt re q uire d 
f or t he peri o d of ti me u ntil t he ne xt visit.  S u bjects will be i nstr ucte d t o ret ur n all 
u n use d mila de meta n at t he ne xt visit.  Alter nati vel y, t o e ns ure c o m plia nce, t he site 
pers o n nel ma y c h o os e t o dis pe nse o nl y t he a de q u ate a m o u nt of st u d y dr u g re q uire d 
u ntil t he ne xt sc he d ule d visit.  C o m plia nce wit h t he st u d y dr u g re gi me n will be 
deter mi ne d b y c o u nti n g u n use d ca ps ules.  

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 A Z A will be a d mi nistere d b y S Q or I V r o ute b y t he site staff d uri n g t he sit e visit t o 
e ns ure c o m plia nce.  
5. 3.   
C o nc o mit a nt Me dic ati o ns  
All a ntica ncer me dicati o ns t hat t he s u bject recei v e d at a n y ti me p oi nt will be rec or de d fr o m t he 
me dical hist or y irres pecti ve of t he ti me relati ve t o Scree ni n g.  All n o n -ca ncer me dicati o ns 
recei v e d b y s u bjects wit hi n 3 0 da ys pri or t o Scree ni n g will als o be rec or de d as pri or me dicati o ns.  
All c o nc o mita nt me dicati o ns will be rec or de d o n t he e C R F.  
C o nc o mita nt use of h y dr o x y urea is per mitte d i n C ycl e 1 u p t o a ma xi m u m of 8 da ys a n d u p t o a 
ma xi m u m d ose of 5 g/ da y.  If t here is a cli nical nee d t o a d mi nister h y dr o x y urea f or l o n ger t ha n 
8  da ys or be y o n d C ycle 1, it s h o ul d be disc usse d wit h S p o ns or.  H o we ver, h y dr o x y urea s h o ul d 
prefera bl y be a v oi de d  o n Da ys -2 t o 1 5 of C ycle 1 wit hi n w hic h bl o o d sa m ples will be c ollecte d 
f or c haract erizati o n of P D y  effects.  
S u bjects s h o ul d a v oi d str o n g C Y P 3 A 4 i n hi bit ors w hile e nteri n g t he st u d y.  See Secti o n  3. 7. 1  f or 
d osi n g i nstr ucti o ns if t he c o nc o mita nt a d mi nistrati o n of a str o n g C Y P 3 A i n hi bit or is re q uire d.  
5. 3. 1.   
Pr o hi bite d C o nc o mit a nt Me dic ati o ns / Acti vities 
T he f oll o wi n g m e dicati o ns a n d pr o d ucts will be pr o hi bite d:  
 Ot her he mat ol o gical mali g na n c y  t hera p y, i ncl u di n g c yt ot o xic, a nti b o d y, or reti n oi d, 
a n d s mall -m olec ule t yr osi ne ki nase i n hi bit ors.  
 Ot her i n vesti gati o nal a ge nts.  
 G ra pefr uit j uice, a C Y P 3 A i n hi bit or, a n d f o o ds or be vera ges c o ntai ni n g gra pefr uit 
sh o ul d be a v oi de d t hr o u g h o ut t he d urati o n of t he st u d y.  
 Dr u gs t hat are i n d ucers of C Y P 3 A or St. J o h n’s w ort ( h y p erici n)  will n ot be per mitte d 
f or 3 da ys bef ore a n d t hr o u g h o ut t he d ur ati o n of t he st u d y. 

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6.   
S T U D Y P R O C E D U R E S  
S u m mar y des cri pti o ns of t he st u d y pr oc e d ures are prese nte d bel o w.  Refer t o t he Sc he d ule of 
E ve nts ta bles  pr o vi de d i n  Secti o n  1 7. 1  f or visit-b y -visit listi n gs of pr oce d ures . 
6. 1.   
Scree ni n g/ S u bject Eli gi bilit y Pr oce d ures  
Ge nerate a s u bject I D ( SI D) a n d re vie w t he s u bject's de m o gra p hics, me dical a n d tar get diseas e 
hist or y (i ncl u di n g D o R f oll o wi n g t he m ost rece nt t hera p y a n d pri or me dicati o n hist or y 
i nf or mati o n f or ca ncer), vital si g ns, a n d e x a mi nati o ns (e g, p h ysical e xa m, E C O G/ M U G A, E C G, 
E C O G P S, la b orat or y ass ess me nts) a n d c o m pare a gai nst t he eli gi bilit y criteria.  
A ser u m sa m ple  f or pre g na nc y testi n g a n d a f ollicle sti m ulati n g h or m o ne ( F S H) test t o c o nfir m 
me narc h e  are re q uire d f or fe male s u bjects of c hil d beari n g p ote ntial. 
6. 1. 1.   
I nf or me d C o nse nt 
Bef ore a s u bj ect’s partici pati o n 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 freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject after a d e q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d b ef ore a n y pr ot oc ol -s pecific 
pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  S u bjects s h o ul d be gi ve n t he o p p ort u nit y t o as k 
q uesti o ns a n d recei ve res p o nses t o t heir i n q uiries a n d s h o ul d ha ve a d e q uat e ti me t o deci de 
w het her or n ot t o partici pate i n t he st u d y.  Refer t o Secti o n  1 5. 1. 2  f or a d diti o nal details. 
6. 1. 2.   
Ge ner al Me dic al Hist or y a n d B aseli ne C o n diti o ns  
S u bject’s me dical hist or y will be o btai ne d b y t h e i n vesti gat or or a q ualifie d desi g nee.  
U nt o war d me dical occ urre nce (i n cl u di n g cli nicall y rele va nt la b orat or y val u es t hat are n ot 
s y m pt o ms of A M L or M D S, or vital si g ns t hat are o ut of ra n ge) t hat were dia g n ose d or k n o w n t o 
e xist pri or t o t he first d ose of st u d y m e dicati o ns will be rec or de d o n t he Ge neral Me dical Hist or y 
a n d Bas eli ne C o n diti o ns e C R F, n ot o n t he A E  e C R F.  Rec or d t he start date of a n y me dical 
occ urre nce t hat starte d after I C F was si g n e d a n d is o n g oi n g at t he ti me of t h e first d ose of st u d y 
dr u g o n t h e Ge n eral Me dical Hist or y a n d Baseli ne C o n diti o ns e C R F.  
6. 1. 3.   
Left Ve ntric ul ar Ejecti o n Fr acti o n  
Meas ure L V E F b y eit her ec h ocar di o gra m ( E C H O) or m ulti gate d ac q uisiti o n ( M U G A) sca n.  
E C H O/ M U G A d o n ot nee d t o be re p eate d if t he pr oce d ure was d o ne wit hi n 6 0 da ys b ef ore t he 
first d ose of st u d y dr u gs a n d if n o c ha n ges i n car diac c o n diti o ns were o bser ve d base d o n t he 
I n v esti gat or’s cli nical assess me nt. 
6. 1. 4.   
Q u alif yi n g B o ne M arr o w E v al u ati o n  
A b o ne marr o w e val u ati o n is re q uire d at Scree ni n g f or all s u bjects i n t he st u d y.  B o ne marr o w 
bi o psies/as pirates or bl o o d sa m ples f or ce ntralize d T P 5 3 ge n ot y pi n g a n d/ or ot her mar kers s uc h 
as ge ne si g nat ur e will be re q uire d at Scree ni n g f or all s u bjects.  

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6. 2.   
Effic ac y Pr oce d ures  
B o ne marr o w bi o psies/as pirates a n d bl o o d sa m ples f or disease assess me nt will be perf or me d 
acc or di n g t o t he Sc h e d ule of E ve nts.  See Secti o n  7  f or a d diti o nal details. 
6. 3.   
S afet y Pr oce d ures  
6. 3. 1.   
A d verse E ve nts a n d C o n c o mit a nt Me dic ati o ns  
C ollect A Es a n d c o nc o mita nt me dicati o ns as i n dicate d i n t he Sc he d ul e of E ve nts.  Refer t o 
Secti o n  9. 3  f or a d diti o nal details o n A Es. 
6. 3. 2.   
Vit al Si g ns  
Vital si g ns will i ncl u de t he meas ure me nts of s yst olic a n d diast olic bl o o d  press ure, p ulse rate, 
res pirat or y rate, b o d y te m perat ure, h ei g ht ( o btai ne d o nce, pri or t o d osi n g), a n d b o d y wei g ht.  
Bl o o d press ur e a n d p ulse rate will be meas ure d after t he s u bject h as reste d s u pi ne f or 5 mi n utes 
or m ore a n d pri or t o la b orat or y dra ws.  
6. 3. 3.   
Cl i nic al L a b or at or y Assess me nts 
Cli nical la b orat or y tests, i ncl u di n g he mat ol o g y  a n d bl o o d c he mistr y , will b e perf or me d a n d will 
be se nt t o t he ce ntr al la b orat or y f or a nal ysis.  Refer t o Secti o n  9. 6  f or t he c o m plete list of 
la b orat or y para meters. 
6. 3. 4.   
1 2 -le a d Electr oc a r di o gr a m  
Tri plicate 1 2 lea d -electr o car di o gra ms ( E C Gs) will be perf or me d a n d rec or de d f or e v er y s u bject 
after t he s u bject has reste d i n a s u pi ne p ositi o n f or 5 mi n utes or m ore.  T he 3 i n di vi d ual E C G 
traci n gs s h o ul d be o btai n e d as cl osel y as p ossi ble i n s uccessi o n, b ut n o m ore t ha n 2 mi n utes 
a part.  T he f ull set of tri plicates s h o ul d be c o m plet e d i n less t ha n 4 mi n utes.  A b n or mal, 
cli nicall y rele va n t fi n di n gs occ urri n g p ost-b aseli ne will be re p orte d as A Es.  
6. 3. 5.   
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us  
Assess a n d rec or d t he s u bject’s E C O G perf or ma n ce stat us ( Secti o n  1 7. 1 ). 
6. 4.   
P h ar m ac o ki netic/ P h ar m ac o d y n a mic Pr oce d ures  
6. 4. 1.   
P h ar m a c o ki netic Bl o o d S a m ples  
Bl o o d sa m ples f or P K assess me nts will be c ollect e d at t he ti me p oi nts i n dicate d i n t he Sc he d ule 
of E ve nts .  Refer t o Secti o n 8. 1  f or details o n t he P K c ollecti o n ti me p oi nts b y st u d y part a n d 
sc he d ule. 
6. 4. 2.   
Bi o m ar ker A n al ysis Usi n g Bl o o d or B o ne M arr o w S a m ples  
Bl o o d sa m ples f or bi o mar ker a n al ys es will be  c oll ecte d per t he Sc he d ule of E ve nt s; a d diti o nall y, 
p ost -Scree ni n g, t he sa m ples s h o ul d be c ollecte d at matc hi n g ti me p oi nts t o b o ne marr o w 
bi o psies/as pirates if n ot ot her wise n ote d o n t he Sc he d ule of E ve nts ( e g, i n cases of u nsc h e d ule d 
b o ne marr o w bi o psies ). 

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S o me of t he bi o mar ker a nal ysis, s uc h as le u ke mic ste m cell e nric h me nt, T P 5 3, a n d MI C -1  
assa ys, will be d o ne usi n g bl o o d or b o ne marr o w bi o mar ker sa m ples  t hat will be c ollecte d as 
i n dicate d.  A n y left o ver sa m ples after t hese a n al ys es will be use d t o e x plore R N A, D N A, or 
ot her pr otei n assa ys.   U p o n c o m pleti o n of t he bi o mar ker a nal yses, t hese s a m ples will be st ore d 
f or 1 5 years f or f ut ure e x pl orat or y a nal ysis rel ate d t o dr u g or dis ease, or f or ot her bi o mar ker 
assa ys.  S u bject c o nse nt will be o btai ne d f or l o n g ter m st ora ge a n d us e of sa m ples.  
Refer t o Secti o n  8. 2  f or a d diti o nal details o n bi o mar ker tests a n d a nal yses. 
6. 4. 3.   
Bl o o d S a m ple f or B a n ki n g Pl as m a  
C ollect p eri p heral bl o o d f or ba n ki n g plas ma f or f ut ure e x pl orat or y m olec ul ar a nal ysis of 
bi o mar kers o n C ycle 1/ Da ys 1 a n d 1 4, C ycle 2/ Da y 1, C ycle 3/ Da y 1, a n d t he n e ver y 3 c ycles 
t hereafter (i e, C ycl es 6, 9, 1 2, etc) c orres p o n di n g t o t he ti me p oi nts f or b o ne marr o w 
bi o ps y/as pirate.   C ycl e  1/ Da y 1 4 sa m ple  c ollecti o n  will be m o ve d t o Da y 1 5 f or s u bjects o n t he 
alter nati ve ( 5 + 2) A Z A sc he d ule ( Fi g ure  3 .3 ). 
6. 4. 4.   
B ucc al S w a b f or P h ar m ac o ge n o mics  
O btai n a b uccal s wa b f or P G x.  Refer t o Secti o n  8. 3  f or a d diti o nal details a n d t o t he St u d y 
Ma n ual f or i nstr ucti o ns o n  ha n dli n g a n d s hi p pi n g of t he P G x sa m ple.  
6. 5.   
E n d -of -tre at me nt - P art 1 / P art 1 A a n d P art 2 ( P ost -c ycle) 
T he E n d -of -treat me nt visit s h o ul d occ ur at t he earliest da y p ossi ble wit hi n 3 0 da ys after t he last 
a d mi nistrati o n of st u d y dr u g, b ut b ef ore be gi n ni n g a n y oth er f or m of a ntica ncer t hera p y.  
Perf or m t he ass ess me nts as liste d i n t he Sc he d ule of E ve nts, i ncl u di n g b o n e marr o w 
re-bi o ps y/re -as pirate a n d ti me -matc he d bl o o d f or bi o mar kers.  
6. 5. 1.   
E n d -of -tre at me nt B o ne M arr o w Re -bi o ps y  ( P art 1/ P a rt 1 A a n d P a rt 2)  
T o searc h f or  p ossi ble m ec ha nis ms of ac q uire d resista nce t o mila de meta n a n d A Z A c o m bi nati o n, 
a b o ne marr o w re -bi o ps y or re -as pirate (a n d ti me-matc he d bl o o d f or bi o mar kers ) will be 
perf or me d i n A M L s u bjects w h o ha ve ac hie ve d a n i nitial C R, C Ri, M L F S, or P R b ut later 
rela pse (after C R or C Ri ) or de vel o p P D (after M L F S or P R) w hile o n t hera p y, a n d i n hi g h -ris k 
M D S s u bjects w h o ac hie ve d a n i nitial C R, m C R, or P R b ut later rela pse d w hile o n t hera p y w hile 
o n t hera p y.  B o ne marr o w re -bi o ps y or re -as pirat e s h o ul d be perf or me d wit hi n 3 0 da ys f oll o wi n g 
t he last d ose of st u d y dr u gs, pri or t o i nitiati n g s u bse q ue nt A M L or M D S t h era p y. 
6. 6.   
F oll o w -u p P h ase  
All s u bjects w h o c o m plete/ disc o nti n ue st u d y treat me nt will e nter t he F oll o w -u p p hase a n d will 
u n der g o t he f oll o wi n g assess me nts . 
6. 6. 1.   
F oll o w -u p 3 0 D a ys After E n d -of -tre at me nt 
T he 3 0 -da y F oll o w -u p visit s h o ul d occ ur 3 0 ( ± 5) da ys after t he last a d mi nistrati o n of st u d y 
me dicati o n(s).  F oll o w -u p i nf or mati o n will be c ollecte d via a p h o ne call or site visit.  If t he 
s u bject be gi ns a n ot her f or m of a ntica n cer t hera p y bef ore t h e e n d of t he 3 0 -da y p eri o d, e v er y 
eff ort s h o ul d be ma d e t o c o m plete all t he E n d -of -st u d y assess me nts pri or t o c o m me nci n g t he 

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ne w A M L or M D S t hera p y.  T he I n vesti gat or s h o ul d f oll o w s u bjects wit h A Es u ntil t he e ve nt 
has res ol ve d or t h e c o n diti o n has sta bilize d.  I n case of u nres ol ve d A Es, i ncl u di n g si g nifica nt 
a b n or mal la b orat or y val u es at t he E n d -of -treat me nt assess me nt, t hese e ve nts will be f oll o we d u p 
u ntil res ol uti o n or u ntil t he y b ec o me cli nicall y n ot rele va nt.  
T he f oll o wi n g i nf or mati o n will be c ollecte d at t he 3 0-da y F oll o w -u p visit:  
 Assess me nt of A Es.  
 C urre nt me dicati o ns.  
 S u bject s ur vi val stat us.  
 Date a n d ca use of deat h, if a p plica ble . 
 S u bse q ue nt A M L or M D S t hera p y. 
 H C T a n d H C T -rel e va nt i nf or mati o n, if perf or me d. 
6. 6. 2.   
L o n g -ter m Sur vi v al F oll o w -u p  
T he l o n g -ter m s ur vi val f oll o w-u ps s h o ul d occ ur e ver y 3 m o nt hs ( ± 2 wee ks) after t he first 
3 0 -da y F oll o w -u p visit u ntil s u bject deat h or u ntil t he S p o ns or ter mi nates t he st u d y.  
A d diti o nall y, t he m ost u p date d s ur vi val f oll o w -u p stat us ma y be c ollecte d w he n t he S p o ns or 
perf or ms s ur vi val a nal ysis (f or e x a m ple, as ki n g f or s ur vi val stat us a gai n w h e n a s u bject ha d 
s ur vi val f oll o w-u p 2 m o nt hs pri or).  
T he f oll o wi n g i nf or mati o n will be c ollecte d as feasi ble:  
 S u bject s ur vi val stat us.  
 Date a n d ca use of deat h, if a p plica ble.  
 S u bse q ue nt A M L or M D S t hera p y. 
 H C T a n d H C T - rel e va nt i nf or mati o n, if perf or me d. 
If direct c o ntacts are n ot p ossi ble or if L o n g-ter m S ur vi val F oll o w-u p is n ot perf or me d d ue t o 
wit h dra wal of c o nse nt, s u bject ref usal t o partici pate i n  l o n g-ter m f oll o w-u p, or l oss t o f oll o w -u p, 
t he site m ust 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 a n d d o c u me nt as best as p ossi ble t he s pecific reas o n 
f or i na bilit y t o c ollect l o n g-ter m f oll o w-u p dat a.  
6. 7.   
Pr ot oc ol De vi ati o ns  
T he I n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y t he 
S p o ns or a n d, if re q uir e d, b y t he re g ulat or y a ut h orit y(ies), a n d w hi c h was gi ve n 
a p pr o val/fa v ora ble o pi ni o n b y t he I R B.  
A de viati o n t o a n y pr ot oc ol pr oce d ure, or wai ver t o a n y stat e d criteria will n ot be all o we d i n t his 
st u d y e x ce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  T he S p o ns or m ust 
be n otifie d of all i nte n de d or u ni nte n de d de viati o ns t o t he pr ot oc ol (e g,  i ncl usi o n/e xcl usi o n 
criteria, d osi n g, misse d st u d y visits) o n a n e x pe dite d basis.  

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T he I n vesti gat or, or p ers o n desi g n ate d b y t he I n v esti gat or, s h o ul d d oc u m e nt a n d e x plai n a n y 
de viati o n fr o m t he a p pr o ve d pr ot oc ol.  
If a s u bject w as i neli gi ble or recei ve d t h e i nc orrect d ose of st u d y dr u g, a n d ha d at least 
1  a d mi nistrati o n of st u d y dr u g, d ata s h o ul d be c oll ecte d f or safet y p ur p oses.  
T he I n vesti gat or s h o ul d n otif y t he I R B of de vi ati o ns fr o m t he pr ot oc ol i n acc or da nce wit h l ocal 
pr oce d ures.  

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7.   
E F FI C A C Y A S S E S S M E N T S  
7. 1.   
Effic ac y V ari a ble(s ) 
Efficac y assess me nts will be base d o n In v esti gat or e val uati o ns of b o ne m arr o w , peri p heral, a n d 
p h ysical e x a mi nati o n or pat h ol o gical dia g n osis of e xtra me d ullar y disease at Scree ni n g a n d at 
pr ot oc ol -defi ne d ti me p oi nts (e g, C y cl e 2/ Da y 1, et c) .  T he A M L res p o nse i n Part 1 a n d Part 1 A 
will be assesse d acc or di n g t o t he 2 0 0 3  I W G res p o nse criteria (Secti o n  1 7. 4. 4 ), w hile i n Part 2, 
t he 2 0 1 7 E L N rec o m me n dati o ns will be a p plie d ( Secti o n  1 7. 4. 1 ).  T he res p o nse f or hi g h-ris k 
M D S i n all st u d y p arts will be assesse d acc or di n g t o t he 2 0 0 6 I W G res p o nse criteria 
(Secti o n  1 7. 5. 1 ). 
T he perce nta ge of s u bjects u n der g oi n g all o ge neic H 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 or M D S t hera p y a n d tra nsf usi o n i n de p e n de nc y is bas e d o n 
I n v esti gat ors’ re p orts.  T he effi cac y e n d p oi nts are liste d i n Secti o n 2. 3. 3 . 
7. 1. 1.   
B o ne M arr o w Bi o psies/ As pir ates ( S u bjects wit h A M L)  
Fi g ure  7 .1  prese nts t he sc he d ule f or b o n e marr o w bi o psies/as pirates i n s u bjects wit h A M L.  
D uri n g t h e first 1 2 c ycl es:  
 B o ne marr o w bi o psies/as pirates are ma n date d o n Da y 1 of C ycles 2 a n d 3 f or all s u bje cts.  
o  If s u bject ac hie ves C R, C Ri , or M L F S bef ore C ycl e 4/ Da y 1 ( e g,  C R o n 
C ycle  3/ D a y 1), b o ne m arr o w bi o psies/as pirates will n ot be re q uire d o n 
C ycle  4/ D a y 1.  
 Perf or m b o ne marr o w bi o psies/as pirates o n Da y 1 of C ycl e 6, 9, a n d 1 2 if 
s u bject re mai ns i n C R, C Ri, or M L F S . 
o  If s u bject does  n ot ac hie ve C R, C Ri , or M L F S bef ore C ycle 4/ Da y 1 ( e g, P R o n 
C ycle 3/ Da y 1), b o ne m arr o w bi o psies/as pirates will be re q uire d o n  Da y 1 of 
C ycle 4 a n d e ver y c ycl e t hereafter u ntil s u bject ac hie ves C R, C Ri, or M L F S.  
N ote :  I n t he e ve nt t hat t he s u bject e x perie nces pr ol o n ge d P R or S D be y o n d 
C ycle  4/ D a y 1, less fre q u e nt b o ne marr o w bi o ps y / as pirate ass ess me nts  ma y be 
all o we d after c o ns ultati o n wit h t he S p o ns or Me dical M o nit or.  
 Be y o n d C ycle 4/ Da y 1, i n s u bjects w h o ac hie ve first C R, C Ri or M L F S, perf or m b o ne 
marr o w bi o psies/as pirat es o n Da y 1 of C ycle 6, 9 , a n d 1 2.  F or e x a m ple:  
o  If s u bject ac hie ves first C Ri ( wit h o ut pri or M L F S) o n C ycle 5/ Da y 1, perf or m 
ne xt b o ne marr o w bi o psies/as pirates o n C ycle 6/ Da y 1.  
o  If s u bject ac hie ves first C R ( wit h o ut pri or C Ri or M L F S) o n C ycl e 7/ Da y 1, 
perf or m ne xt b o ne marr o w bi o psies/as pirates o n C ycl e 9/ Da y 1.  
 Be y o n d 1 2 c ycle (s ec o n d year or l ater) : 

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o  If s u bject r e mai ns i n C R, C Ri, or M L F S o n C ycle 1 2/ Da y 1, b o n e marr o w 
bi o psies/as pirates will be re q u ire d at Da y 1 of C ycles 1 8, 2 4, a n d e ver y 6 c ycles 
t hereafter. 
U nsc he d ule d b o n e marr o w bi o psies/as pirates ca n be perf or me d w he ne ver cli nicall y i n dicate d.  
All u nsc he d ule d b o ne marr o w assess me nts p erf or me d o n n o n -visit da ys m ust be re p orte d as 
u nsc he d ule d v isits. 
Fi g ure  7 .1 : 
B o ne M arr o w Bi o ps y/ As pir ate Sc he d ule  f or A M L 
 
E O T = E n d -of -trial; B M = b o ne marr o w; B M A = b o ne marr o w as pirate; B M B = b o ne marr o w bi o ps y; C R = 
c o m p lete re missi o n; C Ri = c o m plete re missi o n wit h i nc o m plete bl o o d c o u nt rec o ver y; M L F S = m or p h ol o gic 
le u ke mia-free state; P R = partial re missi o n  
7. 1. 2.   
B o ne M arr o w Bi o psies/ As pir ates ( S u bjects wit h Hi g h -ris k M D S) 
D uri n g t h e first 1 2 c ycl es:  
 B o ne marr o w bi o psies/as pi rates are ma n date d o n Da y 1 of C ycles 2 a n d 3 f or all s u bjects. 
o  If s u bject ac hie ves C R or m C R bef ore C ycl e 4/ Da y 1 (e g,  C R o n C ycle  3/ D a y  1), 
b o ne marr o w bi o psies/as pirates will n ot be re q uire d o n C ycl e 4/ Da y 1.  
 Perf or m b o ne marr o w bi o psies/as pirates o n Da y 1 of C ycl e 6, 9, a n d 1 2 if 
s u bject re mai ns i n C R or m C R. 
o  If s u bject does  n ot ac hie ve C R or m C R bef ore C ycle 4/ Da y 1 (e g,  P R o n 
C ycle  3/ D a y 1), b o ne m arr o w bi o psies/as pirates will be re q uire d o n Da y  1 of 
C ycle 4 a n d e ver y c ycl e t hereafter u ntil s u bject achie ve s C R or m C R i n pri nci ple.  

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N ote :  In t he e ve nt t hat t he s u bject e x perie nces pr ol o n ge d P R or S D be y o n d 
C ycle  4/ D a y  1, less fre q u e nt b o ne marr o w bi o ps y / as pirate ass ess me nts  ma y be 
all o we d after c o ns ultati o n wit h t he S p o ns or Me dical M o nit or.  
 Be y o n d C ycle 4/ Da y 1, i n s u bjects w h o ac hie ve first C R or m C R, perf or m b o ne marr o w 
bi o psies/as pirates o n Da y 1 of C ycl e 6, 9 , a n d 1 2.  F or e x a m ple:  
o  If s u bject ac hie ves first m C R o n C ycle 5/ Da y 1, perf or m ne xt b o ne marr o w 
bi o psies/as pirates o n C ycle 6/ Da y 1 . 
o  If s u bject ac hie ves first C R ( wit h o ut pri or m C R) o n C ycle 7/ Da y 1, perf or m ne xt 
b o ne marr o w bi o psies/as pirates o n C ycl e 9/ Da y 1.  
 Be y o n d 1 2 c ycle (s ec o n d year or l ater) : 
o  If s u bject r e mai ns i n C R or m C R o n C ycle 1 2/ Da y 1, b o ne marr o w 
bi o psies/as pirates will be re q uire d at Da y 1 of C ycles 1 8, 2 4 , a n d e ver y 6 c ycles 
t hereafter. 
U nsc he d ule d b o n e marr o w bi o psies/as pirates ca n be perf or me d w he ne ver cli nicall y i n dicate d.  
All u nsc he d ule d b o ne marr o w assess me nts p erf or me d o n n o n -visit da ys m ust be re p orte d as 
u nsc he d ule d visits.  
Fi g ure  7 .2 : 
B o ne M arr o w Bi o ps y/ As pir ate Sc he d ule f or Hi g h -ris k M D S  
 
E O T  = E n d -of -trial; B M = b o ne marr o w; B M A = b o ne marr o w as pirate; B M B = b o ne marr o w bi o ps y; C R = 
c o m plete re missi o n; m C R = marr o w c o m plete re missi o n; P R = partial re missi o n  

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7. 1. 3.   
B o ne M arr o w S a m ples f or Tr a nsl ati o n al Rese arc h ( A M L a n d H i g h-ris k M D S) 
B o ne marr o w sa m ples f or tra nslati o nal res earc h n ee d t o be s u b mitte d at t he f oll o wi n g visits.  
Please see t he i nstr ucti o ns i n t he La b orat or y Ma n u al.  
 B o ne marr o w sa m ples at Scree ni n g a n d o n Da y 1 of C ycl es 2, 3, 6, 9, 1 2, 1 8, a n d 2 4, a n d 
e ver y 6 c ycle s t hereafter. 
 B o ne marr o w sa m ple fr o m u nsc he d ule d b o ne marr o w bi o psies/as pirates w he n disease 
pr o gressi o n (rela pse or pr o gressi ve disease) i n A M L or hi g h -ris k M D S, or pr o gressi o n 
fr o m hi g h-ris k M D S t o A M L, is s us pect e d. 
 A d diti o nall y, s u b missi o n of b o ne marr o w sa m ples f or mi n i mal resi d ual disease a n al ysis 
(e g, fl o w c yt o metr y a n d/ or ne xt ge nerati o n se q ue nci n g) is re q uire d o n t h e da y w he n < 5 % 
blasts (f or A M L) or ≤5 % blasts (f or hi g h -ris k M D S) i n b o ne marr o w is o bs er ve d a n d/ or 
at t he s u bse q ue nt ti me p oi nts f or b o ne marr o w sa m ple c ollecti o n.  
 B o ne marr o w sa m ples fr o m ot her ti me p oi nts are n ot re q uire d t o be s u b mitte d (e g, 
C ycle  4/ D a y 1).  

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8.   
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S  
8. 1.   
P h ar m ac o ki netic  V ari a bl es 
T he P K para m eters  f or mila de meta n will i ncl u de C ma x , T ma x , Ctr o u g h , a n d A U C 2 4 h . 
As a n e x pl orat or y s u bst u d y, plas ma A Z A c o n ce ntrati o ns ma y b e meas ure d.  T he P K para m eters  
f or A Z A will i ncl u de C m a x, T ma x, a n d A U C 6 h . 
Bl o o d sa m ples f or P K a n al yses fr o m s u bjects r ecei vi n g si n gle a ge nt mila de meta n will be 
o btai ne d at t he ti me p oi nts s pecifi e d i n t he Sc he d ul e of E ve nts ( Ta ble  1 7 .1 ) f or s u bjects i n t he 
D ose Escalati o n part of t he st u d y.  
D uri n g D ose Escalati o n of mila de meta n i n c o m bi nati o n wit h A Z A, bl o o d sa m ples f or t he P K of 
mila de meta n will be c ollecte d at t he C ycl e 1 ti me p oi nts s h o w n i n Ta ble  8 .1  a n d Ta ble  8 .2  f or 
t he 2 d osi n g sc h e d ules. 
T a ble  8 .1 :  
C ycle 1 Bl o o d S a m ple C ollecti o n f or P h ar m a c o ki netics D uri n g D ose 
Esc al ati o n ( P art 1 A , Sc he d ule E)  
D a ys  
5  
6 a 
7 a 
1 4 a 
2 2  
H o ur  
0 b 
0. 5 c 
1 c  
2 c  
3 c  
4 c 
6 -1 0  
0 b   0 b   
0 b   
0. 5 c  
1 c  
2 c  
3 c  
4 c 
6 -1 0  
0 b  
a P K sa m ples o n t hese da ys will n ot be c ollecte d f or s u bj ects o n t he alter nati ve  ( 5 + 2) A Z A sc he d ule ( Fi g ure  3 .3 ) 
b Pre -d ose wit hi n 3 0 mi n u tes pri or t o dr u g a d mi nistrati o n 
c ± 1 0 mi n utes  
T a ble  8 .2 :  
C ycle 1 Bl o o d S a m ple C ollecti o n f or P h ar m a c o ki netics D uri n g D ose 
Esc al ati o n ( P art 1 A , Sc he d ule F)  
D a ys  
8  
9  
1 4 a 
2 2  
H o ur  
0 b 
0. 5 c 
1 c  
2 c  
3 c  
4 c 
6 -1 0  
0 b   
0 b   
0. 5 c  
1 c  
2 c  
3 c  
4 c 
6 -1 0  
0 b  
a Da y 1 4 P K sa m ples will n ot be c ollecte d if s u bj ects are treate d wit h A Z A i n t he 5 + 2 sc he d ule.  
b Pre -d ose wit hi n 3 0 mi n utes pri or t o dr u g  a d mi nistrati o n  
c ± 1 0 mi n utes  
T here is mi ni mal p ote ntial f or D DI bet wee n A Z A a n d mila de meta n bas e d o n i n vitr o data.  
H o we ver, t his e x pl orat or y s u bst u d y ( n  =  6) ma y b e use d t o e xcl u de a n y p ossi b le D DI (ie, P -g p or 
B C R P i n hi biti o n b y mila de meta n) si nce A Z A a n d mila de meta n ma y be c o -a d mi nistere d o n Da ys 
5 t o 7.  Prefere ntiall y, t he first 6  s u bjects recei vi n g mila de meta n o n Da y 5 will partici pate i n t his 
e x pl orat or y s u bst u d y.  Bl o o d sa m ples will be c ollecte d at C ycle 1/ Da y 1 ( A Z A al o ne) a n d 
C ycle  1/ D a y  7 ( A Z A  +  mila de meta n) f or p ot e ntial meas ure m e nt of plas m a A Z A c o n ce ntrati o ns 
as s h o w n i n Ta ble  8 .3 .  Plas ma A Z A c o n ce ntrati o ns ma y als o b e meas ure d fr o m sa m ples 
c ollecte d f or mila de meta n P K o n C ycle 1/ Da y 5 ( A Z A +  mila de meta n)  as s h o w n i n Ta ble  8 .1 . 

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T a ble  8 .3 :  
C ycle 1 Bl o o d S a m ple C ollecti o n f or P h ar m a c o ki netics of 5 -Az aciti di ne 
D uri n g D ose Esc al ati o n ( n  =  6, Mil a de met a n o n D a ys 5 t o 1 4 –  P art 1 A , 
Sc he d ule E)  
D a ys  
1  a n d 7  
H o ur  
0 a 
0. 5 b 
1 b  
2 b  
3 b  
6 b  
a Pre -d ose wit hi n 3 0 mi n utes pri or t o dr u g a d mi nistrati o n  
b ± 1 0 mi n utes  
D uri n g d os e ex pa nsi o n of mila de meta n i n c o m bi n ati o n wit h A Z A, bl o o d sa m ples f or t he P K of 
mila de meta n will be c ollecte d at t he C ycl e 1 ti me p oi nts s h o w n i n Ta ble  8 .4 . 
T a ble  8 .4 :  
C ycle 1 S p arse S a m ple C ollecti o n f or Mil a de met a n P h ar m ac o ki netics D uri n g 
D ose E x p a nsi o n f or A ll S u bjects 
D a ys  
1 st D a y of Mil a de met a n  
( C ycle 1/ D a y 5 or D a y 8)a 
2 n d  D a y of Mil a de met a n  
( C ycle 1/ D a y 6 or D a y 9) a 
C ycle 1/ D a y 1 4 a 
H o ur  
0. 5 b 
3 b  
6 -1 0  
0 c 
0 c 
3 -6  
a T his P K sa m ple c ollecti o n is o nl y a p plica ble f or Sc he d ule e a n d Sc he d ule f.  T he first a n d sec o n d da ys of 
mila de meta n d ose are de pe n de nt o n t he d osi n g sc he d ule c h ose n f or D ose E x pa nsi o n (ie, Da ys 5 a n d 6 if 
mila de meta n starts o n Da y 5 a n d Da ys 8 a n d 9 if mila de meta n starts o n Da y 8) .  P K sa m ples, f or C ycle 1/Da y 6 
a n d Da y 1 4 will n ot be c ollecte d f or s u bj ects o n t he alter nati ve ( 5 + 2) A Z A sc he d ule ( Fi g ur e  3 .3 ). 
b ± 1 0 mi n utes  
c Pre -d ose wit hi n 3 0 mi n utes pri or t o dr u g a d mi nistrati o n  
A d diti o nall y, sa m ples m a y b e o btai ne d at a n y ti me d uri n g t h e st u d y if dee me d cli nicall y 
necessar y.  At eac h ti me p oi nt, a p pr o xi matel y 5 m L of bl o o d will be c ollect e d.  I nstr ucti o ns f or 
t he ha n dli n g of bl o o d s a m ples a n d s hi p pi n g of P K sa m ples are i ncl u de d i n a se parate d oc u m e nt 
(L a b orat or y M a n ual).  T he act ual ti me of st u d y dr u g a d mi nistrati o n a n d t he e x act ti me of bl o o d 
sa m ple c ollecti o n m ust be rec or de d o n t he e C R F. 
T he P K sa m ples will be s hi p pe d t o a ce ntral la b orat or y f or f or war di n g t o a S p o ns or -desi g n ate d 
bi oa nal ytical la b orat or y.  Plas ma c o nce ntrati o ns of mila de meta n will be meas ure d usi n g a 
vali date d assa y at t he bi oa nal yti cal la b orat or y.  Plas ma c o nce ntrati o ns of A Z A will be meas ure d 
usi n g a v ali date d assa y, if deter mi ne d i m p orta nt t o e x cl u de p ote ntial D DI.  
8. 2.   
P h ar m ac o d y n a mic  a n d Pre dicti ve Bi o m ar ker V ari a ble(s)  
8. 2. 1.   
T u m or P r otei n p 5 3 St at us  
C o nfir mati o n of T P 5 3 wil d -t y pe stat us is N O T re q uire d pri or t o mila de meta n a n d A Z A d osi n g.  
If re q u este d, the I n v esti gat or a n d s u bject ma y b e  i nf or me d a b o ut t he ge n ot y pi n g res ult if t he 
testi n g res ult s h o ws t hat a s u bject’s mali g na nt cells c o ntai n a n o n-s y n o n y m o us m utati o n, 
i nserti o n, or deleti o n i n t he T P 5 3 ge ne.  If st u d y treat me nt has alrea d y be g u n, t he s u bject ma y 
c h o ose t o disc o nti n ue st u d y treat me nt or c o nti n ue st u d y treat me nt as l o n g as cli nical be nefit is 
n ote d per t he I n v esti gat or ’s j u d ge me nt.  T P 5 3 re-t esti n g ca n be c o nsi d ere d. 

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8. 2. 2.   
P h ar m a c o d y n a mi c V ari a bles  
I n d u cti o n of ser u m MI C-1 will be assesse d as a P D y bi o mar ker.  Ser u m  sa m ples will be 
c ollecte d at m ulti ple ti me p oi nts i n t he st u d y t o ass ess t he effect of m ila de m eta n treat me nt o n 
MI C -1 i n d ucti o n.  
8. 2. 3.   
E x pl or at or y Bi o m ar ker A n al ysis  
Le u ke mic cell e nric h me nt:  
S peci me ns of bl o o d a n d b o ne marr o w c ollecte d acc or di n g t o t he Sc he d ule of E ve nts ma y be 
e nric he d f or le u ke mic cells.  After e nri c h me nt, t he le u ke mic cells will be di vi d e d f or pre p arati o n 
of R N A, D N A, a n d pr otei n, or fres h -fr oze n t o a nal yz e T P 5 3 ge n ot y pe or ot her bi o mar kers. 
Le u k e mic sa m ples c ollecte d fr o m bl o o d a n d/ or b o ne marr o w m a y be e x a mi ne d f or c o m p o n e nts 
of t he p 5 3 pat h wa y i n t he f or m of m ulti -ge ne R N A a n d/ or pr ote i n si g n at ure.  Ot her bi o mar kers 
ma y i ncl u d e D N A a nal ysis t o deter mi ne ge ne m ut ati o ns, c o p y n u m ber variati o n s, a n d C p G 
met h ylati o n stat us.  A d diti o nal bi o mar kers b ot h i nsi de a n d/ or o utsi de of t he p 5 3 pat h wa y ma y be 
i ncl u de d i n or der t o better u n dersta n d t he res p o nsi ve ness t o t hera p y.  T hese ma y i ncl u d e pr otei n, 
meta b olite, ge ne e x pressi o n, a n d ge netic bi o mar kers.  
8. 3.   
Ge netic a n d P h ar m ac o ge n o mic  Testi n g  
As part of t his st u d y, a b uccal s wa b will als o be ba n ke d f or p ossi ble f ut ure ge n etic a n d/ or P G x  
a nal ysis of  ger mli ne D N A.  T he c ollect e d ger mli ne D N A will be use d as a c o ntr ol t o  deter mi n e 
w het her a ge ne m utati o n i de ntifie d i n t he mali g na nt cell D N A is u ni q ue t o t hat D N A  or w h et her 
t he m utati o n was i n herite d.  T his D N A sa m ple ma y als o be use d i n a P G x  a nal ysis .  T hes e 
a nal ys es ma y be r u n d uri n g t he c o urse of treat me nt or at t he E n d -of -treat me nt.  T he sa m ple will 
be st ore d u ntil t he ti me t hat it ma y be a nal yz e d.  
T he b uccal s wa b will  be c ollecte d  o n Da y 1 of C ycle 1 pri or t o st u d y dr u g a d mi nistrati o n fr o m 
all s u bj ects i n t he st u d y. 
T he r es ults ma y als o  pr o vi de i nf or mati o n o n h o w i n di vi d uals meta b olize a n d / or react t o t he st u d y 
dr u g or hel p t o i de ntif y s u bjects w h o are m ore li k el y or less li kel y t o be nefit fr o m t he st u d y dr u g.  
T he i nf or mati o n ma y be usef ul i n i ncre asi n g t he k n o wle d ge of differe nces a m o n g i n di vi d uals i n 
t he wa y t he y meta b olize t he st u d y dr u g, as well as hel pi n g i n t he de v el o p me nt of ne w dr u gs or 
i m pr o ve me nt of e xisti n g dr u gs. 
Beca use e mer gi n g i nf or mati o n re gar di n g t he safet y a n d efficac y of m ila d e meta n a n d A Z A ma y 
bec o me a v aila ble i n t he f ut ure, sa m ples will be ret ai ne d f or p ossi ble f ut ure a nal ysis.  Sa m ples 
will be retai ne d u ntil t he D N A has bee n e x ha uste d or u ntil t he S p o ns or  i nstr ucts t he ge n ot y pi n g 
c o ntract or t o d estr o y t he sa m ple (i n acc or da n ce w it h la b orat or y pr oce d ures).  D uri n g t h e peri o d 
of st ora ge, t he D N A sa m ple will n ot be i m m ortalize d or s ol d t o a n y o ne.  S u bjects will ha ve t he 
ri g ht t o wit h dra w c o nse nt a n d ha ve t heir s a m ple d estr o ye d at a n y ti me. 
T he b uccal s wa b will be s hi p pe d t o a ce ntra l la b orat or y f or pr ocessi n g. 
T o e ns ure s u bject c o nfi d e ntialit y, sa m ple t u bes will be i de ntifie d o nl y b y a barc o de l a bel.  T his 
barc o de will be li n ke d t o t he s u bject’s SI D n u m ber.  
Refer t o t he St u d y M a n u al f or i nstr ucti o ns f or sa m ple c ollecti o n, pre parati o n, ha n dli n g, st ora ge, 
a n d s hi p me nt.  

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9.   
S A F E T Y A S S E S S M E N T S  
9. 1.   
A d verse E ve nts  
All cli nical A Es  occ urri n g after t he s u bject si g ns t he I C F a n d u p t o 3 0 d a ys after t he l ast d ose of 
st u d y dr u g  d uri n g eit her Part s 1  a n d 1 A or Part 2 , w het her o bser ve d b y t he I n v esti gat or or 
re p orte d b y t he s u bject, will be rec or de d o n t he A E  e C R F pa ge.  M e dical c o n diti o ns (i ncl u di n g 
la b orat or y val u es/ vital si g ns t hat are o ut of ra n ge) t hat were dia g n os e d or k n o w n t o e xist pri or t o 
i nf or me d c o nse nt will be rec or de d as part of me dical hist or y.  All S A Es are t o be re p orte d 
acc or di n g t o t he pr oce d ures i n Secti o n  9. 4 .  Al wa ys re p ort dia g n osis as t he A E  or S A E ter m.  
W he n a dia g n osis is u na v aila ble, re p ort t he pri mar y si g n or s y m pt o m as t he A E  or S A E ter m 
wit h a d diti o nal details i ncl u de d i n t he narrati ve u ntil t he dia g n osis bec o mes a vaila ble.  If t he 
si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest a c o m m o n dia g n osis, re p ort t he m as 
i n di vi d ual e ntries of A E  or S A E.   F or e ve nts t hat are seri o us d ue t o h os pitalizati o n, t he reas o n f or 
h os pitalizati o n m ust be re p orte d as t he S A E ( dia g n osis or s y m p t o m re q uiri n g h os pitalizati o n).  A 
pr oce d ure is n ot a n A E  or S A E, b ut t he reas o n f or t he pr oce d ure ma y b e a n A E  or S A E.  
Pre -pla n ne d ( pri or t o si g ni n g t he I C F) pr o ce d ure s or treat me nt s re q uiri n g h os pitalizati o n f or pre-
e xisti n g c o n diti o ns w hic h d o n ot w ors e n i n se verit y s h o ul d n ot be re p orte d as S A Es (see 
Secti o n  9. 3. 2  f or d efi niti o ns).  F or deat hs, t he u n d erl yi n g or i m me diate  ca use of deat h s h o ul d 
alwa ys be re p orte d as a n  S A E.   Disease pr o gressi o n is a st u d y e n d p oi nt a n d c o nse q ue ntl y, s h o ul d 
n ot be re p orte d as a n A E  or S A E.  H o we ver, w he n a s u bject dies fr o m disease pr o gressi o n wit h 
n o ot her i m me diate ca us es, “ disease pr o gressi o n” s h o ul d be re p orte d a s a n S A E.  I n a d diti o n, a n y 
seri o us, u nt o war d e v e nt t hat ma y o cc ur s u bse q ue nt t o t he re p orti n g p eri o d t hat t he I n vesti gat or 
assesses as relate d t o st u d y dr u g s h o ul d als o b e re p orte d a n d ma na ge d as a n S A E.  
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y A Es  h a ve occ urre d b y e val uati n g t he 
s u bject.  A d verse e ve nts ma y b e directl y o bser ve d, re p orte d s p o nta n e o usl y b y t he s u bject , or 
disc o vere d b y q u esti o ni n g t he s u bject at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a 
ge n e ral w a y, wit h o ut as ki n g a b o ut t he o cc urre nce of a n y s pecifi c s y m pt o ms.  All la b orat or y 
val ues m ust be a p prais e d b y t he I n vesti gat or as t o cli nical si g nifica nce.  All p ost -baseli ne 
a b n or mal la b orat or y val u es c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti g at or m ust be rec or de d 
as a n A E  o n t he eC R F, a n d if seri o us, m ust be re p orte d as a n S A E f oll o wi n g t he pr o ce d ures i n 
Secti o n 9. 4 . 
I n v esti gat or s h o ul d f oll o w s u bjects wit h A Es  u ntil t he e ve nt has res ol ve d or t he c o n diti o n has 
sta bilize d.  I n cas e of u nres ol ve d A Es , i ncl u di n g si g nifica nt a b n or mal la b orat or y v al ues at t he 
E n d -of -treat me nt assess me nt, t hese e ve nts will b e f oll o we d u p u ntil res ol uti o n or u nt il t he y 
bec o me cli nicall y n ot r ele va nt.  
9. 2.   
E ve nts of S peci al I nterest  
N ot a p plica ble.  

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9. 3.   
Defi niti o ns  
9. 3. 1.   
A d verse E ve nt  
A n A E  is defi ne d as an y u nt o war d me dical o cc urre nce i n a s u bject or cli nical i n vesti gati o n 
s u bject a d mi nistere d a p h ar mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha v e t o ha ve a 
ca usal r elati o ns hi p wit h t his treat me nt.  A n A E  ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n d e d 
si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or e x a m ple), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d u ct, w het her or n ot c o nsi dere d relate d t o t he 
me dici nal pr o d uct (I C H  E 2 A  G ui deli ne.  Cli nical Safet y Data Ma na ge m e nt:  Defi niti o ns a n d 
Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4).  
It is t he res p o nsi bilit y of I n v esti gat ors, base d o n t h eir k n o wle d ge a n d e x perie nce, t o det er mi ne 
t h ose circ u msta nces or a b n or mal la borat or y  fi n di ngs t hat s h o ul d be c o nsi d ere d A Es . 
9. 3. 2.   
Seri o us A d verse E ve nt  
A n  S A E is defi ne d as a n y u nt o war d me dical o cc urre nce t hat at a n y d os e:  
 Res ults i n deat h . 
 Is life-t hreate ni n g. 
 Re q uires i n patie nt h os pitalizati o n or pr ol o n gat i o n of e xisti n g h os pitalizati o n. 
 Res ults i n  persiste nt or si g nifi ca nt disa bilit y/i n ca p acit y. 
 Is a c o nge nital a n o mal y/ birt h defect . 
 Is a n i m p orta nt me dical e ve nt. 
N ote :  T he ter m “life -t hreate ni n g” i n t he d efi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of d eat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere (I C H E 2 A G ui deli ne.  Cli nical 
Safet y Data M a na ge m e nt:  Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4).  
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n, b ut ma y je o par dize t he s u bject or ma y 
re q uire i nter ve nti o n t o pr e ve nt 1  of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve.  E xa m ples 
i ncl u de aller gic br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d d yscrasias, or de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e.  
N ote : 
 A pr oce d ure is n ot a n A E  or S A E, b u t t he reas o n f or t he pr oce d ure ma y b e a n A E . 
 Pre -pla n ne d ( pri or t o si g ni n g t he I C F) pr oce d ures or treat me nt s re q uiri n g 
h os pitaliz ati o ns f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n i n se verit y are n ot 
S A Es.  

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9. 3. 3.   
A d verse E ve nt  Se verit y  
All A Es  will be gra de d ( 1 t o 5) acc or di n g t o t he N CI-C T C A E Versi o n 5. 0  (Versi o n 4. 0 3 bef ore  
0 1 A pr 2 0 1 8) : 
 Gra de 1 Mil d A E . 
 Gra de 2 M o d erate A E . 
 Gra de 3 Se v ere A E . 
 Gra de 4 Lif e -t hr eate ni n g or disa bli n g A E . 
 Gra de 5 Deat h r elate d t o A E . 
Se verit y v ers us  Seri o us n ess:   Se verit y is use d t o d escri be t he i nte nsit y of a s pecific e v e nt w hile 
t he e ve nt itself, h o we v er, ma y b e of relati vel y mi n or me dical si g nifica n ce (s uc h as se vere 
hea dac he).  T his is n ot t he sa me as “seri o us ness,” w hic h is base d o n s u bject/e ve nt o utc o me at t he 
ti me of the e ve nt.  F or e x a m ple, t he N CI -C T C A E G ra de 4 (life-t hreate ni n g or disa bli n g A E ) is 
assesse d bas e d o n u ni q ue cli nical descri pti o ns of se verit y f or eac h A E , a n d t hese criteria ma y be 
differe nt fr o m t h ose use d f or t he assess me nt of A E  seri o us ness.  A n A E  assessed as G ra de 4 
base d o n t he N CI -C T C A E gra des ma y or ma y n ot be assesse d as seri o us base d o n t he 
seri o us ness criteria. 
9. 3. 4.   
C a us alit y Assess me nt  
T he I n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n A E  a n d m ila de meta n or A Z A  o n 
t he basis or his/ her cli nical j u d g me n t a n d t h e f oll o wi n g defi niti o ns.  T he ca usalit y assess me nt 
s h o ul d be ma de base d o n t he a vaila ble i nf or mati o n a n d ca n b e u p date d as ne w i nf or mati o n 
bec o mes a v aila ble.  
 1 = Relate d:  
T he A E  f oll o ws a reas o n a ble te m p oral se q ue nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d ca n n ot be reas o n a bl y e x plai ne d b y t he s u bject’s cli nical state or ot her fact ors 
(e g, disease u n der st u d y, c o nc urre nt diseases, a n d c o nc o mita nt me dicati o ns). 
T he A E  f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its c he mical gr o u p, or is 
pre dicte d b y k n o w n p har mac ol o g y.  
 2 = N ot Relate d:  
T he A E  d oes n ot f oll o w a reas o n a ble se q u e nce fr o m st u d y pr o d uct a d mi nistra ti o n, 
or ca n be reas o na bl y e x plai ne d b y t he s u bject’s cli nical state or ot her fact ors (e g, 
disease u n der st u d y, c o nc urre nt diseas es, a n d c o n c o mita nt me dicati o ns).  
9. 3. 5.   
Acti o n T a ke n Re g ar di n g t he St u d y Dr u g  
 1 = N o ne: N o c h a n ge i n st u d y dr u g d osa ge was m a de.  
 2 = Disc o nti n ue d Per ma n e ntl y: T he st u d y dr u g  was per ma ne ntl y st o p pe d.  
 3 = Re d uce d: T h e d osa ge of st u d y dr u g  was re d uce d.  

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 4 = I nterr u pte d: T he st u d y dr u g  was te m p oraril y st o p pe d.  
9. 3. 6.   
A d verse E ve nt O utc o me  
 1 = Rec o vere d/ Res ol ve d . 
T he s u bject f ull y rec o vere d fr o m t he  A E  wit h n o resi d ual effect o bser v e d.  
 2 = Rec o vere d/ Res ol ve d wit h Se q uelae . 
T he resi d ual effects of t h e A E  are still prese nt a n d o bser va ble.  
I d e ntif y se q uelae/resi d ual effects. 
 3 = N ot Rec o vere d/ N ot Res ol ve d . 
T he A E  itself is still prese nt a n d o bser va ble. 
 4 = Fat al . 
 5 = U n k n o w n . 
9. 3. 7.   
Ot her Acti o n T a ke n f or E ve nt  
 1 = N o ne . 
N o treat me nt was re q uir e d.  
 2 = Me dicati o n re q uire d . 
Prescri pti o n a n d/ or o ver t he c o u nter me di cati o n was re q uire d t o treat t he A E . 
 3 = H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n re q uire d . 
H os pitalizati o n  was re q uire d or pr ol o n ge d d ue t o t he A E , w het h er or n ot 
me dicati o n was re q uire d.  
 4 = Ot her . 
9. 4.   
Seri o us A d verse E ve nt Re p orti n g  Pr oce d ure f or I n vesti g at ors  
9. 4. 1.   
I niti al Re p orts 
Wit hi n 2 4 h o urs of recei pt of a n S A E re p ort:  
 Call  Me d pace st u d y pers o n nel i m me diatel y t o re p ort t he S A E . 
Safet y C o ntact I nf or m ati o n:  
Me d pace Cli ni cal Safet y 
Me d pace S A E h otli ne - U S:  
 C o m plete  a Daiic hi Sa n k y o Seri o us A d verse E ve nt Re p ort ( S A V E R) f or m , si g n it, 
a n d fa x  it t o Me d pace  usi n g t he desi g n ate d fa x tra ns mittal f or m.  Me d pace  will 
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re vie w a n d f or war d t he S A V E R f or m t o Daiic hi Sa n k y o Cli nical Safet y a n d 
P h ar mac o vi gila nce ( C S P V)  
. 
 Call t he Me d pace  S A E h otli ne f or a n y q uesti o ns re gar di n g S A E re p orti n g.  
 Pla ce t he i nitial versi o n of S A V E R i n t he s u bject’s file.  
9. 4. 2.   
F oll o w -u p Re p orts  
T his is f or N E W i nf or mati o n recei ve d o n a pre vi o usl y re p orte d S A E.  
Wit hi n 2 4 h o urs  of t he recei pt of ne w i nf or mati o n f or a re p orte d S A E:  
 C o m plete a Daiic hi Sa n k y o S A V E R f or m wit h t he ne w i nf or mati o n.  Please c o m plete 
Secti o ns 1 t hr o u g h 3 e v e n if t he y c o ntai n n o ne w i nf or mati o n.  F or Secti o ns 4 t hr o u g h 
1 0, pr o vi de o nl y t he ne w i nf or mati o n.  Si g n a n d fa x t he f or m t o Me d pace  usi n g t he 
fa x tra ns mittal f or m. 
 F or S A Es t hat res ulte d i n deat h, pr o vi de t he a ut o ps y re p ort via e -mail, fa x, or e x press 
mail.  
 Me d pace  will re vie w a n d f or war d t he f oll o w -u p S A V E R f or m a n d s u p p orti n g 
d oc u me nts t o Daiic hi Sa n k y o C S P V  
. 
 Place  t he f oll o w-u p v ersi o n of t he S A V E R f or m a n d all s u p p orti n g d oc u me ntati o n i n 
t he s u bject’s file. 
9. 4. 3.   
N otif yi n g  Re g ul at or y A ut h orities,  I n vesti g at ors, a n d Instit uti o n al R e vie w 
B o ar d / Et hics C o m mittee s 
Daiic hi Sa n k y o a n d/ or M e d pace  will i nf or m I n vesti gat ors a n d re g ulat or y a ut h orities of a n y 
S us pecte d U ne x pecte d S eri o us A d verse E ve nt Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u d y 
ce nters or ot h er D aiic hi S a n k y o st u dies of t he st u d y dr u g, as a p pr o priate per l ocal re p orti n g 
re q uire me nts. 
I n t he U S, it is t he I n vesti gat or’s res p o nsi bilit y t o i nf or m t he I R B u p o n recei pt of t he S p o ns or’s 
n otificati o n of S U S A Rs t hat occ urre d wit h t he st u d y dr u g. 
9. 5.   
E x p os ure I n Uter o D uri n g Cli nic al St u dies  
W o me n of c hil d beari n g p ote ntial m ust ha ve ne gati ve ser u m pre g na n c y test res ults at ti mes 
s pecifie d i n t he Sc he d ul e of E ve nts ( Secti o n 1 7. 1 ).  If re q uire d b y l ocal re g ulati o ns, a d diti o nal 
pre g na nc y t ests will be perf or me d.  
Daiic hi Sa n k y o m ust be n otifie d of a n y s u bject w h o bec o mes pre g na nt w hile recei vi n g  or wit hi n 
6 m o nt hs of disc o nti n ui n g t he st u d y dr u g . 
Alt h o u g h pre g na nc y is n ot tec h nicall y a n A E , all pre g na nci es m ust be f oll o we d t o c o ncl usi o n t o 
deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g safet y a n d p u blic h ealt h 
c o ncer ns.  It is t he res p o nsi bilit y of t he I n vesti gat or, or desi g nee, t o re p ort a n y pre g na nc y i n a 
fe male s u bject usi n g t he E x p os ure I n Uter o ( EI U) Re p orti n g f or m.  Please c o ntact y o ur st u d y 
m o nit or t o recei ve t he EI U Re p orti n g F or m u p o n l ear ni n g of a pre g n a nc y.  T he I n vesti gat or 
s h o ul d ma ke e ver y eff ort t o f oll o w t he s u bject u ntil c o m pleti o n of t he pre g na nc y a n d c o m plete 
P P D
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t he EI U Re p orti n g F or m wit h c o m plete pre g na n c y o utc o me i nf or mati o n, i ncl u di n g n or mal 
deli ver y a n d i n d uce d a b orti o n .  T he a d verse pre g n a nc y o utc o me, eit her seri o us or n o n -seri o us, 
s h o ul d be re p orte d i n acc or da nce wit h st u d y pr oce d ures.  If t he o utc o me of t he pre g na n c y meets 
t he criteria f or i m me diate classificati o n as an  S A E ( ie, p ost -part u m c o m plicati o ns, s p o nta ne o us 
or i n d uce d a b orti o n , still birt h, ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat i n a n a b orte d 
fet us), t he I n v esti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es as o utli ne d i n 
Secti o n  9. 4 . 
9. 6.   
Cli nic al L a b or at or y E v al u ati o ns  
T he f oll o wi n g cli nical la b orat or y tests will b e perf or me d:  
 He mat ol o g y v aria bles i n cl u de R B C  c o u nt, he m o gl o bi n , he mat ocrit, platelet c o u nt, 
a n d W B C  c o u nt  wit h 5 -part differe ntial, i ncl u di n g A N C  a n d retic ul oc yt e c o u nt . 
 Ser u m c he mistr y v aria bl es i ncl u de s o di u m, p otassi u m, bicar b o nate, c hl ori de, calci u m, 
ma g n esi u m, p h os p h or us, al b u mi n, gl uc ose, s er u m creati ni ne, uric aci d, t otal pr otei n, 
B U N , A S T, A L T, al kali n e p h os p hatase , a n d t otal a n d direct bilir u bi n . 
 Ser u m  pre g na n c y test . 
All la b orat or y val ues m ust be a p praise d b y t he I n vesti gat or as t o cli nical si g ni fica nce.  All 
a b n or mal la b orat or y val u es c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or m ust be rec or de d 
i n t he A E  pa ge of t h e e C R F.  A b n or mal la b orat or y val u es ( N CI -C T C A E G ra de 3 or 4) occ urri n g 
d uri n g t he cli nical st u d y will be f oll o we d u ntil re p e at test res ults ret ur n t o n or mal ( or bas eli ne), 
sta bilize, or are n o l o n ger cli nicall y si g nifica nt. 
9. 7.   
Vit al Si g ns  
Vital si g n meas ure me nts will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, 
res pirat or y rate, p ulse rat e, a n d b o d y te m perat ure.  
9. 8.   
Electr oc ar di o gr a ms  
Sta n dar d s u pi ne 1 2 -lea d E C Gs will be perf or me d b y q ualifie d t ec h nicia ns i n tri plicate as n ote d i n 
t he S c he d ule of E v e nts .  Electr ocar di o gra ms will be re vie we d at t he site f or treat me nt of a n y 
ur ge nt i ss ues.  T he cli nical si g nifica nce of a n y E C G c ha n ge m ust be assess e d b y t h e I n vesti gat or 
i n t he c o nte xt of t he s u bject’s me dical hist or y, p h ysical e x a mi nati o n, a n d c o nc o mita nt 
me dicati o ns.  T he I n vesti gat or or dele gate d p h ysicia n will re vie w, si g n, a n d date all E C Gs.  
9. 9.   
P h ysic al Fi n di n gs  
P h ysica l e xa mi nati o ns will e val uate t he f oll o wi n g b o d y s yste ms/ or ga ns: ge neral a p peara nce; 
der mat ol o gi cal; hea d a n d e yes; ears, n ose, m o ut h, a n d t hr oat; p ul m o nar y; car di o vasc ular ; 
a b d o mi nal; ge nit o uri nar y ( o pti o nal); l y m p hatic; m usc ul os keletal/e xtre mities; a n d ne ur ol o gical.  
Wei g ht a n d hei g ht will be rec or de d i n kil o gra ms  a n d ce nti meters, res pecti v el y. 
9. 1 0.   
Ot her S afet y Assess me nts  
N ot a p plica ble.  

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1 0.   
O T H E R A S S E S S M E N T S  
N ot a p plica ble.  

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1 1.   
S T A TI S TI C A L M E T H O D S  
1 1. 1.   
A n al ysis Sets  
T he f oll o wi n g a nal ysis sets will be defi ne d i n t his st u d y:  
 E nr olle d A nal ysis Set will i ncl u de all s u bjects w h o si g n t he I C F  a n d meet 
i ncl usi o n/e xcl usi o n criteria. 
 Safet y A nal ysis Set (a n d F ull A nal ysis Set) will i ncl u de all e nr olle d s u bjects w h o 
recei v e d at least 1 d ose of mila de meta n or A Z A. 
 D L T -e val u a ble Set will i ncl u de all s u bjects e nr oll e d i n t he D ose Escalati o n part w h o 
ha d a D L T wit hi n C ycle 1 ( 2 8 da ys) o n t he st u d y, or w h o di d n ot  ha ve a D L T b ut 
recei v e d at least 7 5 % s c h e d ule d d ose of mila de m eta n a n d A Z A a n d c o m plete d t he 
C ycle 1 e val ua ti o n. 
 P K A nal ysis Set will i ncl u de all s u bjects i n t he Safet y A nal ysis Set  w h o ha d  
meas ura ble pl as ma c o nce ntrati o n data t o c haracterize t he P K pr ofile  of mila de meta n 
or A Z A . 
1 1. 2.   
Ge ner al St atistic al C o nsi der ati o ns  
T he pri mar y a n al ysis is t o assess t he safet y a n d t olera bilit y of m ila de m eta n al o ne a n d i n 
c o m bi nati o n wit h A Z A  i n s u bjects wit h A M L or hi g h -ris k M D S. 
T he data c ut -off f or t he pri mar y a nal ysis w ill occ ur after all s u bjects ha ve eit her disc o nti n ue d t he 
st u d y or c o m plet e d at least 6 c ycl es of treat me nt.  After t he pri mar y a n al ysis, t he mai n st u d y will 
be cl ose d.  Aft er t he dat a  c ut-off dat e f or pri mar y a nal ysis, d ata of i nterest will be c ollecte d a n d 
a nal yze d (if dee me d necessar y) f or s u bj ects w h o are still benefiti n g fr o m t he st u d y dr u g u ntil 
st u d y c o m pleti o n. 
Descri pti ve statistics will be pr o vi de d f or select e d de m o gra p hic, safet y, P K , a n d P D y  d ata b y 
d ose c o h ort at eac h ti mep oi nt  as a p pr o priate.  Descri pti ve statistics o n c o nti n u o us data will 
i ncl u de mea ns, me dia ns, sta n dar d de viati o ns, a n d ra n ges, w hile cate g orical data will be 
s u m marize d usi n g fre q u e nc y c o u nts a n d perce nt a ges.  Gra p hical s u m maries of t he data ma y b e 
prese nte d.  
Assess me nts of c ha n ge fr o m baseli ne t o p ost -treat me nt or t he rati o of p ost-treat me nt t o baseli ne 
will i ncl u de o nl y t h ose s u bjects wit h b ot h baseli ne a n d p ost -treat me nt meas ure me nts.  T he last 
n o n -missi n g val ue of a v aria ble ta k e n bef ore t he first d ose of st u d y dr u g will be use d as t he 
baseli ne val ue, u nless ot h er wise s pecifie d.  I n ge neral, missi n g or dr o p o ut d ata will n ot be 
i m p ute d f or t he p ur p ose of data a n al ysis, u nless ot her wise s pecifie d. 
Safet y a nal yses a n d bi o mar ker a nal yses will be p erf or me d base d o n t he S afet y A nal ysis S et.  
A nal ysis of P K  p ara met ers will be base d o n t he P K  A nal ysis S et.  Efficac y e n d p oi nts will be 
a nal yze d b ase d  o n t he F ull A nal ysis S et.  Data fr o m t he D ose Escalati o n part will be s u m marize d 
b y d ose l e vel of m ila de m eta n al o ne a n d i n c o m bi nati o n wit h A Z A a n d o verall.  

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A detaile d Statistical A nal ysis Pla n ( S A P ) descri bi n g t he met h o d ol o g y t o b e use d i n t he fi nal 
a nal ysis will be pre pare d a n d fi nalize d bef ore data base l oc k.  Statistical met h o ds descri be d 
wit hi n  t his d oc u me nt ma y be c ha n ge d base d o n a d va nces i n r esearc h.  
1 1. 3.   
St u d y P o p ul ati o n D at a  
Dis p ositi o n a n d reas o ns f or e n di n g t he treat me nt a n d disc o nti n ui n g fr o m t h e st u d y will be 
s u m marize d a n d liste d f or s u bjects i n t he Safet y A nal ysis Set . 
De m o gra p hic a n d baseli n e c haracteristics s uc h as a ge, se x, race, baseli ne E C O G perf or ma nce 
stat us, hist ol o g y, ca ncer sta ge, b est res p o ns e t o pri or c he m ot hera p y, li nes of pri or re gi me ns, a n d 
pri or treat me nt t y pe will be s u m marize d f or t he E nr olle d A nal ysis Set , F ull A nal ysis S et, a n d 
S afet y A nal ysis S et.  If 2 a nal ysis s ets wit hi n a part of t he st u d y are i d e ntical t o eac h ot her,  t he 
ta ble will be prese nt e d o nl y o nce. 
St u d y dr u g e x p os ure, treat me nt d urati o n, a n d c o m plia nce wit h st u d y t hera p y will be s u m marize d 
usi n g descri pti ve statistics f or t he Safet y A nal ysis Set . 
1 1. 4.   
Ef fic ac y A n al yses 
F or A M L, t he s ec o n dar y e n d p oi nts of efficac y will i ncl u de t he rates of C R, C Ri, C Rc, M L F S, 
P R, S D, O R R, a n d D O R acc or di n g t o I n v esti gat or assess me nt ( Secti o n  2. 3. 3 ).  F or Part 1 a n d 1 A  
o nl y , treatme nt fail ure rat e is i ncl u de d w hereas S D is n ot i ncl u de d.  Sta ble disease rat e will be 
s u m marize d w he n S D has persiste d f or at least 3 m o nt hs.  A d diti o nall y, C R h rate will be 
e val uate d se p aratel y fr o m t he a b o ve me nti o ne d res p o nses . 
F or  s u bjects wit h M D S, t he effi cac y e n d p oi nts  will be C R rate, m C R rate, P R rate, c yt o ge nic 
res p o nse, S D rat e, diseas e pr o gressi o n,  tra nsf usi o n i n de pe n de nce, a n d O S.  A d diti o nall y, 
he mat ol o gical i m pr o ve m e nt will be e val uate d s e p aratel y fr o m t he a b o ve m e nti o ne d res p o nses.  
T he effi cac y e n d p oi nts will be liste d a n d s u m marize d usi n g descri pti ve statistics base d o n t he 
F A S b y d os e f or  t h e c o m bi ne d D ose E scalati o n a n d D ose E x pa nsi o n part s. 
Tra ns pla ntati o n rat e a n d tra nsf usi o n i n de pe n de n c y will be bas e d o n data re p orte d b y st u d y site s. 
F or res p o nse rate s (e g, C Rc, O R R, etc), p oi nt esti mates a n d 2 -si de d 9 5 % e x act bi n o mial 
c o nfi de nce i nter vals will be pr o vi de d.  Ti me -t o-e v e nt e n d p oi nt (D o R ) will be s u m mar ize d 
descri pti vel y usi n g t he Ka pla n -Meier met h o d.  
1 1. 5.   
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses  
1 1. 5. 1.   
P h ar m a c o ki netic A n al yses  
Plas ma c o nce ntr ati o n  data f or m ila de meta n a n d/or A Z A  will be s u m marize d usi n g descri pti ve  
statistics b y d os e c o h ort at eac h ti mep oi nt . 
F or D ose Escalati o n, t he P K para meters C ma x , T ma x , a n d A U C 2 4 h  f or m ila de meta n o n Da y 1 
f or si n gle a ge nt treat me nt ( or Da y 5 or Da y 8 de p e n di n g o n t he d ose sc he d ule i n c o m bi nati o n 
treat me nt wit h A Z A) a n d Da y 1 5 f or si n gle a ge nt ( or Da y 1 4 i n c o m bi nati o n treat me nt wit h 
A Z A , e x cl u di n g s u bjects t hat are tr eate d wit h A Z A i n t he 5 + 2 sc he d ule ) of C ycle 1 a n d Ctr o u g h  
o n m ulti ple visit da ys will be calc ulate d usi n g n o n -c o m part me ntal a nal ysis . 

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F or D ose E x pa nsi o n, o nl y s parse P K  sa m ples will be c ollecte d.  T h ese d ata will be a nal yze d 
usi n g P o p P K met h o ds . 
A Z A  c o nce ntrati o n sa m ples will be c ollecte d at C ycl e 1/ Da y 1 ( A Z A al o ne) a n d at 
C ycle  1/ Da y  7 ( A Z A + m ila de meta n) as a n e x pl orat or y s u bst u d y i n 6 s u bjects.  T he P K 
para meters C ma x, T ma x, a n d A U C 6 h  f or A Z A will be s u m marize d b y treat me nt usi n g 
descri pti ve statistics.  
A P o p P K  a nal ysis  a n d e x p os ure -res p o nse a n al ys es f or vari o us e n d p oi nts ma y be d e vel o pe d.  If 
de vel o pe d , t he n t he P o p P K pla n a n d t he T ec h nical R e p ort will be pr o vi de d se parat el y. 
1 1. 5. 2.   
P h ar m a c o d y n a mi c A n al yses  
C ha n ges i n MI C -1 l e vels i n ser u m  a n d ot her P D y para meters, if a v aila ble,  will be liste d a n d 
s u m marize d usi n g descri pti ve statistics b y d os e le vel c o h ort. 
1 1. 5. 3.   
Bi o m ar ker a n d E x pl or at or y A n al yses  
E x pl orati ve a nal yses f or p ote ntial bi o mar kers  t hat ma y b e pre dicti ve of be n efit fr o m 
m ila de meta n a nd A Z A  will be gra p h e d a n d/ or liste d a n d s u m marize d usi n g descri pti ve statistics 
b y d ose l e vel c o h ort.  
1 1. 6.   
S afet y A n al yses  
Safet y a nal ysis will be perf or me d usi n g t he Safet y A nal ysis Set a n d s u bjects will be a nal yze d 
acc or di n g t o t heir act ual treat me nt r ecei ve d .  Safet y e n d p oi nts will i ncl u de S A Es, T E A Es, D L Ts, 
p h ysical e x a mi nati o n fi n di n gs (i ncl u di n g E C O G perf or ma n ce stat us), vital si g n meas ure me nts, 
sta n dar d cli nical la b orat or y p ara m eters (ser u m c he mistr y a n d he m at ol o g y), a n d E C G para m eters 
(i ncl u di n g Q Tc F).  A d verse e ve nts will be cate g orize d usi n g Me d D R A  V ersi o n 1 7. 0 .  A d verse 
e ve nts a n d la b orat or y test res ults will be gra de d acc or di n g t o t he N CI -C T C A E Versi o n 5. 0 
(Versi o n 4. 0 3 bef ore 0 1  A pr 2 0 1 8).  I n t he D ose E scalati o n part, t he i nci d e nce of D L Ts will als o 
be e val uat e d . 
Safet y a nal yses i n ge n eral will be descri pti ve a n d will be prese nte d i n ta b ul ar f or mat wit h t he 
a p pr o priate s u m mar y statistics.  I n t he D ose Escal ati o n part , t he n u m ber of D L Ts i de ntifie d 
a m o n g t he D L T -e v al ua bl e s u bjects i n t he D L T -e v al ua ble set will be liste d a n d s u m marize d f or 
eac h d ose of m ila de meta n al o ne a n d i n c o m bi nati o n wit h  A Z A . 
1 1. 6. 1.   
A d verse E ve nt A n al yses  
A T E A E is defi ne d as a n A E  t hat e mer ges d uri n g t he treat me nt peri o d (fr o m first d ose date u n til 
3 0 da ys after t h e last d osi n g dat e), ha vi n g bee n a bs e nt at pre -treat me nt; ree mer ges d uri n g 
treat me nt, ha vi n g bee n prese nt at baseli ne b ut st o p pe d pri or t o treat me nt; or w orse ns i n se verit y 
after starti n g tr eat me nt relati ve t o t he pre -treat me nt state, w he n t he A E  is c o nti n u o us. 
T he n u m ber a n d p erce nta ge of s u bjects r e p orti n g T E A Es wil l be ta b ulate d b y t he w orst 
N CI -C T C A E gra de, s yst e m or ga n class ( S O C), a n d preferre d t er m.  
Si milarl y, t he n u m b er a n d perce nt a ge of s u bjects r e p orti n g treat me nt -e mer ge nt S A Es will be 
ta b ulate d, as well as TE A Es/ S A Es c o nsi dere d rel ate d t o m ila de meta n or A Z A . 

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A b y -s u bj ect A E  (i n cl u di n g T E A E) data listi n g will be pr o vi de d i ncl u di n g, b ut are n ot li mite d t o, 
ver bati m  ter m, preferre d ter m, S O C, N CI-C T C A E gra de, a n d relati o ns hi p t o st u d y dr u g.  
Deat hs, ot her S A Es, a n d ot her si g nifica nt A Es , i ncl u di n g t h ose lea di n g t o p er ma ne nt 
disc o nti n uati o n fr o m m ila de meta n, will be liste d. 
1 1. 6. 2.   
Cli nic al L a b or at or y E v al u ati o n A n al yses  
Descri pti ve statistics will be pr o vi de d f or select e d cli nical la b orat or y test res u lts ( he mat ol o g y 
a n d bl o o d c he mistr y) a n d c ha n ges fr o m baseli ne b y sc h e d ule d ti me of e v al uati o n, i ncl u di n g t he 
E n d -of -treat me nt V isit, ma xi m u m p ost-treat me nt val ue, a n d mi ni m u m p ost-treat me nt val ue. 
A b n or mal la b orat or y res ults will be gra d e d acc or di n g t o N C I-C T C A E Versi o n 5. 0  (Versi o n 4. 0 3 
bef ore  0 1  A pr  2 0 1 8) , if a p plica ble.  A s hift ta ble, prese nti n g t he 2-wa y fre q ue nc y ta b ulati o n f or 
baseli ne a n d t he w orst p ost -treatme nt val ue acc or di n g t o t he N CI -C T C A E gra de, will be 
pr o vi de d f or sel ecte d cli nical la b orat or y tests.  A b n or mal cli nical la b orat or y test res ults t hat are 
dee me d of cli nical si g nifi ca nce or are G ra de 3 or 4 will be liste d. 
1 1. 6. 3.   
Vit al Si g n s A n al yses  
Descri pti ve statistics will be pr o vi de d f or t he vital si g ns meas ure me nts a n d c ha n ges fr o m 
baseli ne b y sc he d ul e d ti me of e val uati o n, i ncl u di n g t he E n d -of -treat me nt Visit a n d t he ma xi m u m 
a n d mi ni m u m p ost -treat me nt val ues. 
1 1. 6. 4.   
Electr oc a r di o gr a m A n al yses  
Electr oca r di o gra m para m eters ( P R, R R , H R, Q R S, Q T, a n d Q Tc F) will be s u m marize d usi n g 
descri pti ve statistics f or act ual val ues a n d f or c h a n ges fr o m baseli ne b y s c h e d ule d ti me of 
e val uati o n, i ncl u di n g t he E n d -of -treat me nt V isit a n d t he ma xi m u m p ost-treat me nt val ue.  T he 
Q Tc F  will be calc ulat e d as f oll o ws:  Q Tc F = Q T/( R R) 1/ 3. 
T he i nci de nce of n ota ble E C G c ha n ges i n ma xi m u m a bs ol ute Q T a n d Q Tc F  i nter vals (> 4 5 0  ms , 
> 4 8 0  ms , a n d > 5 0 0 ms) o ver all p ost -treat me nt e val uati o ns, as well as i n Q T a n d Q TcF  
ma xi m u m c h a n ges fr o m baseli ne ( > 3 0  ms  a n d > 6 0 ms) o ver all p ost -treat me nt e val uati o ns will 
be s u m marize d.  A listi n g of E C G data will be pr o vi de d.  
1 1. 6. 5.   
P h ysic al E x a mi n ati o n Fi n di n g A n al yses  
P h ysical e xa mi nati o n fi n di n gs will be liste d f or t he S afet y A nal ysis S et.  
1 1. 6. 6.   
Ot her S afet y A n al yses  
T he E C O G perf or ma nce stat us at baseli ne will be s u m marize d f or t he S afet y A n al ysis S et.  A 
s hift ta ble, prese nti n g t he 2-wa y fre q ue n c y ta b ulati o n f or B aseli ne a n d E n d -of -treat me nt V isit, 
will be pr o vi de d f or E C O G perf or ma nce st at us.  
1 1. 7.   
Ot her A n al yses  
N ot a p plica ble.  

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1 1. 8.   
I nteri m A n al yses 
N o f or mal i nteri m a nal ysis is pla n ne d, e x ce pt f or t he assess me nt of t he M T D  after eac h 
escalati o n c o h ort i n t he D ose Escalati o n part . 
1 1. 9.   
D at a a n d S afet y M o nit ori n g B o ar d  
N ot a p plica ble.  
1 1. 1 0.  
S a m ple Size Deter mi n ati o n  
T he D ose Esca lati o n part of t his st u d y will be g ui de d b y a B L R M f or d ual a ge nt c o m bi nati o n 
a n d g o v er ne d b y t he E W O C pri nci ple.   C o h orts of at least 3 D L T -e val ua ble s u bjects per d ose 
le vel will be e nr olle d i n t he D ose Escalati o n  part .  As a n e x ce pti o n, t he m o del will be  
ree val u ate d bef ore e nr oll me nt of a n y a d diti o nal s u bjects t o t he c o h ort if 2 e val ua ble s u bjects i n 
t he c o h ort e x perie nce a D L T b ef ore t he e nr oll me nt of t he ne xt  s u bject.  F or a s u bject t o be 
c o nsi dere d e val ua ble f or d ose escal ati o n decisi o ns, t he s u bject m ust ha ve recei ve d at least 7 5 % 
of t he prescri be d d oses wit hi n t he D L T o bser vati o n peri o d i n C ycl e 1 or e x perie nce d a D L T  i n 
C ycle 1.  S u bjects w h o are u na ble t o  c o m plete at least 7 5 % of prescri be d d oses of m ila de meta n 
or A Z A wit hi n t he D L T o bser vati o n peri o d as a res ult of u ne q ui v ocal pr o gressi o n of disease m a y  
be re place d.  
I n D ose Escalati o n  ( Part 1 a n d Part 1 A ), a p pr o xi matel y 8 0 e val ua ble s u bjects ma y  be e nr oll e d t o 
esti mate t he M T Ds of m ila de meta n as a si n gl e a ge nt  a n d i n c o m bi nati o n wit h A Z A a n d t o 
i de ntif y R D E . 
I n D ose E x pa nsi o n  ( Part 2) t here will be  3 c o h orts:  C o h ort 1  (s u bjects wit h R/ R  A M L ), C o h ort 2  
(s u bjects wit h ne wl y dia g n ose d A M L u nfit f or i nt e nsi ve  c he m ot hera p y), a n d C o h ort  3  (s u bjects 
wit h  hi g h -ris k M D S ).  Si m o n 2 -sta ge o pti mal/ mi ni ma x desi g n will be use d t o i m ple me nt a 
f utilit y st o p gi ve n a 1 -si d e d t y p e 1-err or rate of 1 0 % a n d 8 0 % of p o wer .  A p pr o xi matel y  
4 0  s u bjects per c o h ort (a p pr o xi matel y 1 2 0 s u bjects i n t otal) will be e nr olle d: 
 C o h ort 1 ( R/ R A M L) :  H y p ot heses re gar di n g t he rates ( C R/ C Ri pl us M L F S) f or t he 
c o m bi nati o n t o be teste d are H 0:  p < 2 0 % a n d H1:  p > 3 5 %.  At sta ge 1, if C R/ C Ri pl us 
M L F S has bee n ac hie ve d as t he best res p o ns e i n less t h a n 5 s u bjects o ut of 2 2 e val ua ble 
s u bjects, e nr oll me nt will be st o p pe d.  Ot her wis e, t he e nr oll me nt f or sta ge 2 will be 
c o m plete d wit h a n a d diti o n of 1 9 s u bjects (f or a t otal of 4 1 s u bjects e val ua ble f or best 
res p o nse i n b ot h sta ge 1 a n d sta ge 2). 
 C o h ort 2 ( ne wl y dia g n os e d A M L u nfit f or i nte nsi ve c he m ot hera p y):  H y p ot heses 
re gar di n g t he rates ( C R/ C Ri pl us M L F S) f or t he c o m bi nati o n t o be teste d are H 0:  p 
< 1 5 % a n d H 1:  p > 3 0 %.  At sta ge 1, if C R/ C Ri pl us M L F S has bee n ac hie ve d as t he best 
res p o nse i n less t han 4 s u bjects o ut of 1 9 e val ua bl e s u bjects, e nr oll me nt will be st o p pe d.  
Ot her wise , t he e nr oll me nt f or sta ge 2 will be c o m plete d wit h a n a d diti o n of 2 0 s u bjects 
(f or a t otal of 3 9 s u bjects e val ua ble f or best r es p o nse i n b ot h sta ge 1 a n d sta ge 2). 
 C o h ort 3 ( hi g h -ris k M D S):  H y p ot h eses re gar di n g t he rates ( C R, m C R, a n d P R) f or t he 
c o m bi nati o n t o be teste d are H 0:  p < 1 5 % a n d H1:  p > 3 0 %.  At sta ge 1, if C R, m C R, a n d 
P R ha ve bee n ac hie ve d as t he best res p o nse i n less t ha n 4 s u bjects o ut of 1 9 e val ua ble 
s u bjects, e nr oll me nt will be st o p pe d.  Ot her wis e, t he e nr oll me nt f or sta ge 2 will be 

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c o m plete d wit h a n a d diti o n of 2 0 s u bjects (f or a t otal of 3 9 s u bjects e val ua ble f or best 
res p o nse i n b ot h sta ge 1 a n d sta ge 2). 
1 1. 1 1.  
S pecific ati o n of B a yesi a n L o gistic Re gressi o n M o del  wit h Esc al ati o n 
w it h O ver d ose C o ntr ol 
1 1. 1 1. 1.  
B a yesi a n L o gistic Re gressi o n M o del  Wit h Esc al ati o n Wit h O ver d ose C o ntr ol  
T he d ose -t o xicit y rel ati o ns hi p usi n g t he  E W O C pri nci ple f or si n gle a ge nt will be descri be d b y a 
2 -para m eter B L R M:  
l o git( π( d)) = l o g( α) + β l o g( d/ d *),  
α  > 0, β  > 0  
w here l o git( π( d))  = l n ( ( d)/( 1-( d))), π( d) is t he pr o ba bilit y of a D L T or t h e D L T rat e at d ose d.  
D oses are res cale d as d/ d * wit h t he refere nce d ose d * = 1 2 0 m g/ da y .  As a c o nse q ue nce, α is 
e q ual t o t he o d ds of t o xicit y at d *.  N ote t hat f or a d ose e q ual t o zer o, t he pr o ba bilit y of t o xicit y 
is z er o. 
1 1. 1 1. 2.  
Pri o r S pecific ati o n f or B a yesi a n L o gistic R e gressi o n M o del P ar a meters  
T he Ba yesia n a p pr oac h re q uires t he s pecificati o n of a pri or distri b uti o n f or t he B L R M 
para meters.  A mi ni mall y -i nf or mati ve bi variate n or mal pri or1 3 f or t he m o del para meters 
(l o g( α),l o g( β)) is o btai ne d as f oll o ws: 
 Base d o n  t h e D L T dat a fr o m t he o n g oi n g s oli d t u m or or l y m p h o ma st u d y ( D S 3 0 3 2-
A -U 1 0 1), t here are 1 3 D L T-e val ua bl e s u bjects a n d 3 D L T s fr o m 6 d ose c o h orts 
( # D L T/ # s u bjects): 1 5 m g ( 0/ 2) , 3 0 m g ( 0/ 1), 6 0 m g ( 0/ 1), 1 2 0 m g ( 0/ 3), 1 6 0  m g 
( 2/ 5), a n d 2 4 0 m g ( 1/ 1) as of 25 A pr 2 0 1 4.  T he m e dia n p osteri or pr o ba bilities of 
D L T are calc ul ate d t o be 7. 0 %, 1 9. 7 %, 3 1. 4 %, a n d 4 9. 0 % at 6 0 m g, 1 2 0 m g, 1 6 0 m g, 
a n d 2 4 0 m g, res pecti vel y.  
 F or t he re mai ni n g d oses, t he me dia ns of pr o ba bilit y of D L T are ass u me d li near i n 
l o g-d ose o n t h e l o git -s cal e. 
 Base d  o n t h e a b o ve m e dia ns f or t he pr o ba bilit y of D L T at eac h d ose a n d wi de pri or 
cre di ble i nter vals ( o btai n e d fr o m mi ni mall y i nf or mati ve Beta distri b uti o ns), t he 
o pti mal para meters of t he bi variate n or mal distri b uti o n ca n be o btai ne d as f oll o w s: 
P ar a meters   
Me a ns   
St a n d ar d D e vi ati o ns  
C orrel ati o n  
l o g( α), l o g( β)  
(-1. 4 1 6 5, 0. 1 8 4 9 )  
(2. 0 4 8 7, 1. 0 8 9 2 )  
-0. 5 6 6 9  
Pri or s pecificati o n f or alt er nati ve sc h e d ules of m il a de meta n as a si n gle a ge nt  a n d i n c o m bi nati o n 
wit h A Z A will be u p date d / deri ve d usi n g o n g oi n g D L T data fr o m e xisti n g d ose sc he d ules.  
1 1. 1 1. 3.  
Esc al ati o n w it h O ver d ose C o ntr ol Pri nci ple 
D ose rec o m me n dati o n f or t he ne xt c o h ort will be base d o n s u m maries of t h e p osteri or 
pr o ba bilit y of t he D L T rate f or  p o ssi ble d oses  i n t he q d  2 1/ 2 8 sc he d ule :  6 0, 8 0 , 1 2 0, 1 6 0, 2 0 0, 
2 4 0, 3 0 0, a n d 3 6 0  m g/ da y .  After a mi ni m u m  of 3 s u bjects of eac h c o h ort c o m pletes t he D L T 
e val uati o n d uri n g C ycle  1, t he p osteri or distri b uti o ns of t he D L T rate will be deri ve d f or all 

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pr o visi o nal d ose le vels b ase d o n t he B L R M usi n g t he D L T o utc o me dat a fr o m all assesse d d oses 
a n d a pres p ecifie d pri or distri b uti o n f or t he m o del para meters.  T he p osteri or pr o ba bilit y of t he 
D L T rate i n t he f oll o wi n g 4  i nter vals at eac h d ose le vel ([ 0% , 1 6 %) as t he D L T rate i nter val f or 
u n der d osi n g, [ 1 6 %, 3 3 %) as t he tar get D L T rate i nter val, [ 3 3 %, 6 0 %) as t h e D L T rat e i nter val 
f or e x cessi ve t o xicit y, a n d [ 6 0% , 1 0 0 %] as t he D L T rate i nter v al f or u nacce pta ble t o xicit y) will 
be calc ul ate d a n d use d f or d ose rec o m me n dati o n f or t he ne xt c o h ort acc or di n g t o t he E W O C 
pri nci ple.  T he a b o v e pr o visi o nal d oses are bas e d o n d ose escal ati o n i n t he s oli d t u m or or 
l y m p h o ma st u d y (S t u d y D S 3 0 3 2-A -U 1 0 1).   It is t heref ore c o n cei va bl e t hat t he p osteri or 
pr o ba bil it y of D L T rate f or d ose rec o m me n dati o n ma y b e ge nerate d usi n g alter nati ve pr o visi o nal 
d oses as l o n g as t he pre dicte d e x p os ure i ncre m e nts are bet w ee n 3 0 % a n d 1 0 0 % ( Secti o n  3. 1. 2 ). 
T he E W O C pri nci ple re q uires t hat t he B L R M rec o m me n de d d ose f or t he ne xt c o h ort of s u bjects 
is t he o ne  wit h t he hi g hest p osteri or pr o ba bilit y of t he D L T rate i n t he t ar get D L T rate i nter val of 
[ 1 6 %, 3 3 %] a m o n g all d oses f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt (t here is less t ha n 2 5% of 
pr o ba bilit y f or t h e D L T rate > 3 3 % [pr o ba bilit y f or e x cessi ve or u nacce pta bl e t o xicit y ]). 

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1 2.   
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  
T he In vesti gat or/i n vesti gati o n al site will per mit st u d y-relate d m o nit ori n g, a u dits, I R B re vie w, 
a n d re g ulat or y i ns pe cti o ns b y pr o vi di n g direct access  t o s o urce dat a/ d oc u m e nts.  Direct access 
i ncl u des per missi o n t o e xa mi ne, a nal yz e, verif y, a n d re pr o d uce a n y rec or ds a n d re p orts t hat are 
i m p orta nt t o t he e val uati o n of a cli nical st u d y. 
1 2. 1.   
M o nit ori n g a n d I ns pecti o ns  
T he S p o ns or  a n d t he C R O m o nit or a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or 
c o ntacti n g a n d visiti n g t h e I n vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, u p o n 
re q uest, i ns pecti n g t he vari o us rec or ds of t he st u d y (e g, eC R Fs , s o urce dat a, a n d ot her perti ne nt 
d oc u me nts).  
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals t hr o u g h o ut t he st u d y t o verif y 
a d here n ce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d c o nsiste nc y of t he d ata; a n d a d h ere n ce t o 
I C H G C P a n d l ocal re g ul ati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is res p o nsi ble 
f or i ns pecti n g t he eC R F s a n d e ns uri n g c o m plete ness of t he st u d y ess e ntial d oc u me nts.  T he 
m o nit or s h o ul d ha ve access t o s u bject me dical rec or ds a n d ot her st u d y -relate d rec or ds nee d e d t o 
verif y t he e ntri es o n t he e C R F s. 
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, G C P , a n d a p plica ble 
re g ulati o ns t o t he I n vesti gat or a n d will e ns ure t h at a p pr o priate acti o n desi g ne d t o pre ve nt 
rec urre nce of t he d etecte d de viati o ns is ta ke n a n d d oc u me nte d. 
T he  I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hes e m o nit ori n g visits are a d dress e d a n d d oc u me nte d.  
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be s electe d f or a udit 
b y  re pres e ntati ves fr o m t he S p o ns or.  I ns pecti o n of site facilities (e g, p h ar mac y, dr u g st ora ge 
areas, l a b orat ori es etc .) a n d re vie w of st u d y-relate d rec or ds will occ ur i n or der t o e val uat e t he 
st u d y c o n d u ct a n d c o m plia nce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble re g ulat or y 
re q uire me nts. 
1 2. 2.   
D at a C ollecti o n  
Electr o nic case re p ort f or m  c o m pleti o n s h o ul d be ke pt c urre nt t o e na ble t he m o nit or t o re vie w 
t he s u bject’s stat us t hr o u g h o ut t he c o urse of t he st u d y.  T he e C R Fs  will be c o m plete d, re vie we d , 
a n d si g ne d off o r e-si g ne d b y t he I n vesti gat or as d escri be d i n t he Data Ma n a ge me nt Pla n a n d i n 
t he m o nit ori n g pla n f or Cli nical Researc h Ass ociat es.  I nstr ucti o ns f or c o m pleti o n of t he e C R Fs 
will be pr o vi de d.  C orrecti o ns t o electr o nic f or ms will be a ut o maticall y d o c u me nt e d b y usi n g t he 
s oft ware’s “a u dit trail”. 
All writte n i nf or mati o n a n d ot her material t o be us e d b y s u bj ects a n d i n vesti gati ve staff m ust use 
v oca b ular y a n d la n g ua ge t hat are cl earl y u n derst o o d.  

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1 2. 3.   
D at a M a n a ge me nt  
T his is a n o pe n -la bel st u d y.  Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q u e SI D  as 
defi ne d b y t he S p o ns or. 
T o e ns ure t he q ualit y of cli nical data acr oss all s u bjects a n d sites, a Cli nical Data Ma na ge me nt 
re vie w will be perf or m e d o n s u bject data acc or di n g t o s pecificati o ns gi ve n t o t he C R O .  Data 
will be vette d b ot h electr o nicall y a n d ma n uall y .  For e C R Fs , t he data will be electr o ni call y vette d 
b y pr o gra m me d dat a r ules wit hi n t he a p plicati o n.  Q ueries ge n erat e d b y r ules a n d raise d b y 
re vie wers will be ge nerat e d wit hi n t he electr o nic d ata  ca pt ure (E D C ) a p plicati o n.  D uri n g t his 
re vie w, s u bject data will be c hec ke d f or c o nsiste nc y, o missi o ns, a n d a n y a p pare nt discre pa nci es.  
I n a d diti o n, t he data will be re vie we d f or a d here nce t o t he pr ot oc ol a n d G C P.  T o res ol ve a n y 
q uesti o ns arisi n g fr o m t he Cli nical Data Ma n a ge me nt re vie w pr ocess, e C R Fs q ueries will be 
raise d a n d res ol ve d wit hi n t he E D C a p plicati o n. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la bs will be rec o n cile d t o t he cli nical 
data base.  
S A E s i n t he cli nical data base will be rec o ncile d wit h t he safet y data base.  
All pri or ca ncer t hera p y a n d pri or/c o nc o mita nt m e dicati o ns e ntere d i nt o t he data bas e will be 
c o de d b y usi n g t he latest versi o n of W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y.  All A Es  will 
be c o de d b y usi n g Me d D R A  V ersi o n 1 7. 0 . 
1 2. 4.   
St u d y D oc u me nt ati o n a n d St or a ge  
T he I n vesti gat or will mai ntai n a Si g nat ure List of a p pr o priatel y q u alifie d p ers o ns t o w h o m 
he/s he has dele gate d st u d y d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n 
eC R F s will be i ncl u de d o n t he Si g nat ure List.  
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s eC R F  data 
are o btai ne d.  T hese i ncl u de , b ut are n ot li mite d t o , h os pital rec or ds, cli nical a n d office c h arts, 
la b orat or y a n d p h ar mac y rec or ds, diaries, micr ofi c hes, X-ra ys, a n d c orres p o n de nce. 
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d ce ntralize d 
fili n g s yste m ( Trial Mast er File) of all st u d y-relate d (esse ntial) d oc u m e ntati o n, s uita ble f or 
i ns pecti o n at a n y ti me b y re pres e ntati ves fr o m t he S p o ns or a n d/ or a p plica bl e re g ulat or y 
a ut h orities.  Esse ntial d oc u me nts i ncl u de:  
 S u bject files c o ntai ni n g c o m plete d eC R F s, I C Fs, a n d s u p p orti n g c o pies of s o urce 
d oc u me ntati o n (if ke pt) . 
 St u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I Bs, c o pies of rele va nt 
esse ntial d oc u me nts re q uire d pri or t o c o m me nci n g a cli nical st u d y, a n d all 
c orres p o n d e nce t o a n d fr o m t he I R B a n d t he S p o ns or. 
 Rec or ds  rel ate d t o t he st u d y dr u g(s) i ncl u di n g ac k n o wle d g m e nt of recei pt at site, 
acc o u nta bilit y rec or ds a n d fi nal rec o n ciliati o n a n d a p plica ble c orres p o n d e n ce . 
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he eC R F s m ust be mai ntaine d 
a n d be rea dil y a vaila ble.  

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1 2. 5.   
Rec or d Kee pi n g  
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, dat a c orrecti o n f or ms, eC R Fs, 
i n ve nt or y of st u d y pr o d uct, re g ulat or y d o c u me nts (e g, pr ot oc ol a n d a me n d me nts, I R B 
c orres p o n d e nce s a n d a p pr o vals, a p pr o v e d a n d si g ne d I C Fs, I n v esti gat or’s A gree me nt, cli nical 
s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her S p o ns or  c orres p o n de nce p ertai ni n g 
t o t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he site.  S o urce d oc u me nts i ncl u de all 
rec or din gs a n d o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p orts a n d rec or ds 
necessar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hese rec or ds will be 
retai ne d i n a s ec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or site p olic y.  Pri or t o tra nsfer 
or destr ucti o n of t hese rec or ds , t he S p o ns or m ust be n otifie d i n writi n g a n d be gi v e n t he 
o p p ort u nit y t o f urt her st ore s uc h rec or ds.  

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1 3.   
FI N A N CI N G A N D I N S U R A N C E  
1 3. 1.   
Fi n a nces  
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical st u d y 
a gree m e nt wit h t he S p o ns or.  T his a gree me nt will i ncl u de t he fi na nci al i nf or mati o n a gree d u p o n 
b y t he parties.  
1 3. 2.   
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce  
Rei m b urse me nt, i n de m nit y , a n d i ns ura nce s h all be a d dresse d i n a se parate a gree me nt o n ter ms 
a gree d u p o n b y t h e parties.  

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1 4.   
P U B LI C A TI O N P O LI C Y  
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter p u blicati o n 
has bee n s u b mitte d or u ntil 1  year after t he  st u d y has e n de d, w hi c he ver occ urs first.  T heref ore, 
t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t he res ults of t he st u d y, pr o vi de d t hat t he 
S p o ns or  has ha d t he o p p ort u nit y t o re vie w a n d c o m me nt o n t he st u d y site’s pr o p ose d p u blicati o n 
pri or t o it s bei n g s u b mitte d f or p u blicati o n wit h t h e pri or a d vice of D S I Le gal Affairs 
(i ntellect ual pr o pert y c o u ncil) a n d wit h pr o per re gar d t o t he pr otecti o n of s u bjects’ i de ntities. 

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1 5.   
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N  
1 5. 1.   
C o m pli a nce St ate me nt, Et hics, a n d Re g ul at or y C o m pli a nce  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve 
t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical P ractice ( G C P) ( C P M P/I C H/ 1 3 5/ 9 5), U S F o o d a n d 
Dr u g A d mi nistrati o n G C P Re g ulati o ns: C o de of Fe deral Re g ul ati o ns ( C F R) Title 2 1, Parts 1 1, 
5 0, 5 4, 5 6, a n d 3 1 2, as a p pr o priate, a n d ot h er a p pli ca ble l ocal re g ulati o ns.  
1 5. 1. 1.   
S u bject C o nfi de nti alit y  
T he I n vesti gat ors a n d t h e S p o ns or, Daiic hi Sa n k y o, I n c. ( D SI), will preser ve t he c o nfi de ntialit y 
of all s u bjects ta ki n g p art i n t he st u d y, i n acc or da n ce wit h G C P a n d l ocal re g ulati o ns.  
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he electr o ni c cas e 
re p ort f or ms (e C R Fs) or ot her d oc u me nts s u b mitte d t o t he S p o ns or a n d/ or its c o ntract res earc h 
or ga nizati o n ( C R O, Me d pace) desi g nee (“ A ge nt” or C R O), s u bjects s h o ul d be i de ntifie d b y a 
u ni q ue s u bject i de ntifier as desi g n ate d b y t he S p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o 
t he S p o ns or a n d/ or t he C R O (e g, si g n e d I C Fs) s h o ul d be ke pt i n strict c o nfi de nce b y t he 
I n v esti gat or. 
I n c o m plia nce wit h a p pli ca ble l ocal g ui deli nes a n d I C H G C P g ui deli nes, it is re q uire d t hat t he 
I n v esti gat or a n d i nstit utio n per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he re g ulat or y 
a ge nc y(s), a n d t he I R B direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or 
verificati o n of st u d y -relat e d pr oce d ures a n d data.  T he I n vesti gat or is o bli gate d t o i nf or m t he 
s u bject t hat his/ her st u d y-relate d rec or ds will be re vie we d b y t he a b o ve n a me d re prese ntati ves 
wit h o ut vi olati n g t he c o nfi de ntialit y of t he s u bject.  
1 5. 1. 2.   
I nf or me d C o nse nt Pr oce d ure 
Bef ore a s u bj ect’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o ns i bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject or le gall y acce pt a ble re prese nt ati ve after a de q u ate 
e x pla nati o n of t he ai ms, met h o ds, a ntici pate d be n efits, a n d p ote ntial hazar ds of t he st u d y, a n d 
bef ore a n y pr ot oc ol -s p ecific scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  A le gall y 
acce pta ble re pres e ntati ve is a n i n di vi d ual or ot her b o d y a ut h orize d u n der a p plica ble la w t o 
c o nse nt, o n be half of a pr os pecti ve s u bject, t o t he s u bject’s partici pati o n i n t he cli nical st u d y.  
T he w ritte n I C F s h o ul d b e pre pare d i n t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n. 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hic al pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y re visi o n(s) s h o ul d be 
a p pr o ve d b y t he I R B pri or t o bei n g pr o vi de d t o p ote ntial s u bjects.  
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or t o his/ her partici pati o n i n t he 
st u d y, a n d s h o ul d be d o c u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y 2 1  C F R Part 
3 1 2. 6 2.  T he I C F s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject or a le gall y acce pta ble 
re pres e ntati ve a n d b y t he pers o n w h o c o nd u cte d t he i nf or me d c o ns e nt disc ussi o n ( n ot necessaril y 

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t he I n v esti gat or).  T h e ori gi nal si g n e d I C F s h o ul d be retai ne d i n acc or da nce wit h i nstit uti o nal 
p olic y a n d a c o p y of t h e si g ne d c o nse nt f or m s h o ul d be pr o vi de d t o t he s u bject or le gal 
re pres e ntati ve.  T he d ate a n d ti me (if a p plica ble) t hat i nf or me d c o nse nt w as gi ve n s h o ul d be 
rec or de d o n t he e C R F. 
If t he s u bject or l e gall y acce pta bl e re prese ntati ve ca n n ot rea d, t he n acc or di n g t o I C H G C P 
G ui deli ne, Secti o n 4. 8. 9, a n i m partial wit ness s h o ul d be prese nt d uri n g t he e ntire i nf or me d 
c o nse nt disc ussi o n.  T his wit ness s h o ul d si g n t he I C F after t he s u bject or t h e le gall y acce pta ble 
re pres e ntati ve has orall y c o nse nte d t o t he s u bject’s partici pati o n a n d, if p ossi ble, si g ne d t he I C F.  
B y si g ni n g t he I C F, t he wit nes s attests t hat t he i nf or mati o n i n t he I C F a n d a n y ot h er writte n 
i nf or mati o n was a de q u at el y e x plai ne d t o a n d a p pare ntl y u n d erst o o d b y t he s u bject or t he le gall y 
acce pta ble re pres e ntati ve a n d t hat i nf or me d c o ns e nt was freel y gi v e n b y t he s u bject or t he le gal l y 
acce pta ble re pres e ntati ve.  
S u g geste d m o del te xt f or t he I C F f or t h e st u d y a n d a n y a p plica ble s u b parts ( ge n o mic, P K, etc.) 
a n d asse nt f or ms f or pe di atric s u bjects (if a p plica ble) are pr o vi de d i n t he D SI I C F te m plate f or 
t he I n v esti gat or t o pre p are t he d oc u me nts t o be us e d at his or her site.  U p d ates t o a p plica ble 
f or ms will be c o m m u nicate d via letter fr o m t he Cli nical St u d y M a na ger. 
T he c o nse nt f or ge netic a n d p har mac o ge n o mic ( P G x) sa m pli n g f or b uccal s wa b a n d bl o o d a n d/ or 
b o ne marr o w bi o psies/as pirates s h o ul d be d oc u me nte d i n t he s u bject’s writt e n i nf or me d c o ns e nt.  
T he c o nse nt f or m s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject or t h e s u bject’s le gall y 
acce pta ble re pres e ntati ve pri or t o his/ her partici pati o n i n t he st u d y.  
Pre dicti ve bi o mar kers wil l be a nal yze d wit h t he i nte nt of i de ntif yi n g s u bjects w h o will m ost 
li kel y deri v e cli nical be nefit fr o m treat me nt wit h mila de meta n.  T he f oll o wi n g 
ca n di date-pre dicti ve bi o mar kers are c urre ntl y e n visa ge d ( ot her pre dicti ve bi o mar kers i n a d diti o n 
t o or i n place of t hes e ma y be c o nsi dere d as s u g geste d b y e m er gi n g i nf or m ati o n):  c o m p o ne nts of 
t he p 5 3 pat h wa y i n t he f or m of m ulti-ge n e a n d/ or pr otei n si g nat ure w hic h ma y i ncl u d e, b ut are 
n ot li mite d t o, p 5 3, p 2 1, p 1 4, p 1 6, M D M 2, m uri ne d o u ble mi n ute 4 ( M D M 4) , a n d 
cycli n -de pe n d e nt ki nase i n hi bit or 2 A ( C D K N 2 A) c o p y n u m b er.  T hes e pre dicti ve bi o mar kers 
will be assesse d i n bl o o d sa m ples, b o ne marr o w sa m ples (arc hi ve d or rece nt bi o psies/as pirates), 
a n d/ or ot her c ollecte d sa m ples, usi n g assa ys t hat ha ve bee n esta blis he d o r are bei n g esta blis he d.  
F urt her e x pl orat or y st u di es ma y b e perf or me d o n tiss ue, s ol u ble, or ge n o mic bi o mar kers base d 
o n e mer gi n g scie ntific k n o wle d ge t o better u n d erst a n d t he tar get disease, t h e effects of st u d y 
treat me nt, a n d p ote ntial me diat ors of pri mar y a n d ac q uire d resista nce t o t hera p y.  
1 5. 1. 3.   
Re g ul at or y C o m pli a nce  
T he st u d y pr ot oc ol, s u bject i nf or mati o n a n d c o nse nt f or m, t he I B, a n y s u bject diar y car d or 
writte n i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble safet y i nf or mati o n, s u bject recr uit me nt 
pr o ce d ures (e g, a d vertise me nts), i nf or mati o n a b o ut pa y me nts a n d c o m pe nsati o n a vaila ble t o t he 
s u bjects, a n d d oc u me ntati o n e vi de nci n g t he I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o 
t he I R B f or et hical r e vie w a n d a p pr o val acc or di n g t o l ocal re g ulati o ns, pri or t o t he st u d y start.  
T he writte n a p pr o val s h o ul d i de ntif y all d oc u me nts re vie we d b y n a me a n d versi o n.  
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P.  

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T he I n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he I R B a n d/ or D SI f or 
all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o nse nt d oc u me nt or c ha n ges 
of t he i n vesti gati o nal site, facilities, or pers o n nel.  T he I n vesti gat or s h o ul d n otif y t he I R B of 
de viati o ns fr o m t he pr ot o c ol or S A Es occ urri n g at t he site a n d ot her A E  re p orts recei v e d fr o m 
t he S p o ns or a n d/ or t he C R O, i n acc or da nce wit h l ocal pr oce d ures. 
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p will e ns ure 
a p pr o val  fr o m t he a p pr o priate re g ul at or y a ut h orities is o btai ne d pri or t o st u d y i nitiati o n a n d t hat 
rele va nt r e g ulat or y a ut h orities recei v e a p pr o priate n otificati o n of, or if necessar y, a p pr o ve, 
s u bsta nti ve c ha n ges t o t h e i nitial pr ot oc ol. 
1 5. 2.   
Pr ot oc ol A me n d me nts  
A n y a me n d me nts t o t he st u d y pr ot oc ol t hat see m t o be a p pr o priate as t he st u d y pr o gresses will 
be c o m m u nicate d t o t he I n vesti gat or b y t h e S p o ns or or t he C R O .  All pr ot oc ol a me n d me nts will 
u n der g o t he sa me re vie w a n d a p pr o val pr ocess as t he ori gi nal pr ot oc ol.  A pr ot oc ol a me n d me nt 
ma y b e i m ple me nte d aft er it has bee n a p pr o ve d b y t he I R B, u nless i m me diate i m ple me ntati o n of 
t he c ha n ge is ne cessar y f or s u bject safet y.  I n t his case, t he sit uati o n m ust be d oc u me nte d a n d 
re p orte d t o t he I R B wit hi n 5  w or ki n g d a ys.  T he S p o ns or  will ass ure t he ti mel y s u b missi o n of 
a me n d me nts t o re g ulat or y a ut h orities.  
1 5. 3.   
A d dress List  
1 5. 3. 1.   
S p o ns or  
Daiic hi Sa n k y o, I nc.  
2 1 1 Mt . Air y R oa d  
Bas ki n g  Ri d ge , NJ 0 7 9 2 0 -2 3 1 1  
 
1 5. 3. 1. 1.  S p o ns or’s  Me di c al M o nit or 
 
Se ni or Direct or, Gl o bal O nc ol o g y R esearc h a n d De vel o p me nt  
1 5. 3. 1. 2.  S p o ns or’s Cli nic al S cie ntist 
 
Se ni or Direct or, Gl o bal O nc ol o g y R esearc h a n d De vel o p me nt  
Daiic hi Sa n k y o P har ma De vel o p me nt  
P P D
P P D
P P D
P P D
P P D

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1 5. 3. 1. 3.  S p o ns or’s Cli nic al St u d y M a n a ger / Deli ver y Le a d 
 
Sr. Cli nical St u d y Ma n a ger, Cli nical De vel o p me nt O perati o ns  
1 5. 3. 1. 4.  S p o ns or’s S afet y C o nt act  
 
Se ni or Direct or, Cli nical Safet y a n d P har mac o vi gila nce  
1 5. 3. 1. 5.  S p o n s or’s Bi ost atistici a n  
 
Direct or, Bi ostatistics a n d Data Ma na ge me nt  
1 5. 3. 2.   
C R O  
Me d pace, I nc.  
5 3 7 5 Me d pace Wa y  
Ci nci n nati, O H  4 5 2 2 7  
1 5. 3. 2. 1.  C R O Me dic al M o nit or  
 
Vice Presi de nt, Me dical Affairs  
 
1 5. 3. 2. 2.  C R O Pr oject M a n a g er  
 
Cli nical Trial Ma na ger  
 
1 5. 3. 2. 3.  C R O  Dr u g S afet y  
1 5. 3. 2. 4.  C R O D at a M a n a ge me nt  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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La b C or p Cli nical Trials (f or merl y C o va nce Ge n o mics La b orat or y)  
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Me d pace R efere nce La b orat or y  
5 3 6 5 Me d pace Wa y  
Ci nci n nati, O H 4 5 2 2 7  
1 5. 3. 4.   
Bi o a n al ytic al L a b or at or y  
 
A d vi o n Bi oa nal ytical La bs  
A Q ui ntiles C o m pa n y  
1 9 Br o w n R oa d  
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R E F E R E N C E S  
1.  Vi daza ®  (azaciti di ne f or i njecti o n) prescri bi n g i nf or mati o n . Cel ge n e C or p orati o n, 2 0 0 4 
[re vise d 2 0 1 8 Se p]. A vaila ble fr o m: htt ps:// me dia.cel ge ne. c o m/c o nte nt/ u pl oa ds/ vi daza -
pi. p df.  
2.  S ha n gar y S, Wa n g S. S mall -m olec ule i n hi bit ors of t he M D M 2 -p 5 3 pr otei n -pr otei n 
i nteracti o n t o reacti vate p 5 3 f u ncti o n: a n o vel a p pr oac h f or ca n cer t hera p y. A n n u Re v 
P har mac ol T o xic ol. 2 0 0 9; 4 9: 2 2 3 -2 4 1.  
3.  Le vi n e AJ, Ore n M. T he first 3 0 years of p 5 3: gr o wi n g e v er m ore c o m ple x. Nat Re v 
Ca ncer. 2 0 0 9; 9: 7 4 9 -7 5 8.  
4.  Vassile v L T, V u B T, Gra ves B, et al. I n vi v o acti v ati o n of t he p 5 3 pat h wa y b y s mall 
m olec ule a nta g o nists of M D M 2. Scie nce.  2 0 0 4; 3 0 3: 8 4 4 -8 4 8.  
5.  S ha n gar y S, Qi n D, Mc E ac her n D, et al. Te m p oral acti vati o n of p 5 3 b y a s p ecific M D M 2 
i n hi bit or is selecti vel y t o xic t o t u m ors a n d lea ds t o c o m plete t u m or gr o wt h i n hi biti o n. 
P N A S. 2 0 0 8; 1 0 5: 3 9 3 3 -3 9 3 8.  
6.  Vassile v L T. M D M 2 i n hi bit ors f or ca n ce r t hera p y. Tre n ds M ol Me d 2 0 0 7; 1 3: 2 3-3 1.  
7.  Mila de meta n ( D S -3 0 3 2 b) I n vesti gat or's Br oc h ure, Versi o n 6. 0. 2 9 J ul 2 0 1 9.  
8.  Haferlac h C, Dic k er F, Her h olz H, et al. M utati o ns of t he T P 5 3 ge ne i n ac ute m yel oi d 
le u ke mia are str o n gl y ass ociate d wit h a c o m ple x a berra nt k ar y ot y pe. Le u ke mia. 
2 0 0 8; 2 2: 1 5 3 9 -1 5 4 1.  
9.  Ka mi ns kas E, Farrell A T, Wa n g Y C, et al. F D A dr u g a p pr o val s u m mar y: azaciti di ne ( 5 
azac yti di ne, Vi daza) f or i njecta ble s us pe nsi o n. O nc ol o gist. 2 0 0 5; 1 0( 3): 1 7 6 -1 8 2.  
1 0.  A n dreeff M, Kell y K R, Yee K, et al. Res ults of t he P hase 1 trial of R G 7 1 1 2, a s mall 
m olec ule M D M 2 a nta g o nist, i n ac ute le u ke mia. A merica n S ociet y of He mat ol o g y ( A S H). 
2 0 1 2.  
1 1.  Ra y -C o q u ar d I, Bla y J Y, Italia n o A, et al. Effect of t he M D M 2 a nta g o nist R G 7 1 1 2 o n t he 
P 5 3 pat h wa y i n p atie nts wit h M D M 2 -a m plifie d, wel l-differe ntiate d or d e differe ntiat e d 
li p osarc o ma: a n e x pl orat or y pr o of-of -mec h a nis m st u d y. La n cet O nc ol. 2 0 1 2; 1 3: 1 1 3 3 -
1 1 4 0.  
1 2.  C he n Y, Li u L, Laille E, et al. I n vitr o assess me nt of c yt o c hr o me P 4 5 0 i n hi biti o n a n d 
i n d ucti o n p ote ntial of azac yti di ne. Ca n cer C hem ot her P har mac ol. 2 0 1 0; 6 5: 9 9 5 -1 0 0 0.  
1 3.  Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he Ba yesi a n a p pr oac h t o 
p hase I ca ncer trials. Stat Me d. 2 0 0 8; 2 7: 2 4 2 0 -2 4 3 9.  
1 4.  E C O G -A C RI N Ca ncer R esearc h Gr o u p. A vaila ble fr o m: htt ps://ec o g -
acri n. or g/r es o urces/ ec o g-perf or ma n ce -stat us. 
1 5.  C hes o n B, Be n nett J M, K o pec k y KJ, et al. Re vise d rec o m me n d ati o ns of t he I nter n ati 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 p e utic Trials i n Ac ute M y el oi d Le u k e mia. J 
Cli n O nc. 2 0 0 3; 2 1: 4 6 4 2 -4 6 4 9.  

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1 6.  D ö h ner H, Este y E, Gri m wa de D, et al. Dia g n osis a n d ma na ge m e nt of A M L i n a d ults: 
2 0 1 7 E L N rec o m me n dati o ns fr o m a n i nter nati o nal e x pert pa nel. Bl o o d. 2 0 1 7 J a n 
2 6; 1 2 9( 4): 4 2 4 -4 4 7.  
1 7.  N ors w ort h y KJ, L u o L, Hs u V, et al. F D A A p pr o val S u m mar y: I v osi de ni b f or Rela pse d 
or Refract or y Ac ut e M yel oi d Le u ke mia wit h a n Is ocitrate De h y dr o ge n ase -1 M utati o n. 
Cli n Ca ncer Res. 2 0 1 9 J u n 1; 2 5( 1 1): 3 2 0 5 -3 2 0 9. d oi: 1 0. 1 1 5 8/ 1 0 7 8 -0 4 3 2. C C R -1 8 -3 7 4 9. 
E p u b 2 0 1 9 J a n 2 8.  
1 8.  C hes o n B D, Gree n b er g P L,  Be n n ett J M, et al. Cli nical a p plicati o n a n d pr o p osal f or 
m o dificati o n of t he I nter nati o nal W or ki n g Gr o u p (I W G) res p o nse criteria i n 
m yel o d ys plasia. Bl o o d. 2 0 0 6; 1 0 8: 4 1 9 -4 2 5.  
1 9.  Gree n b er g P L, T uec hler H, Sc ha nz J, et al. Re vise d I nter nati o nal Pr o g n ostic Sc ori n g 
S yste m f or M yel o d ys plastic S y n dr o mes. Bl o o d. 2 0 1 2; 1 2 0: 2 4 5 4 -2 4 6 5.  
2 0.  A merica n Heart Ass ociati o n. Classes of Heart Fail ure. A vaila ble fr o m: 
htt p:// w w w. heart. or g/ H E A R T O R G/ C o n diti o ns/ Heart Fail ure/ A b o ut Heart Fail ure/ Classes o
f Heart Fail ure _ U C M _ 3 0 6 3 2 8 _ Article.js p? a pp Na me = M o bile A p p . 
2 1.  Cli nical Trial Facilitati o n Gr o u p ( C T F G) of t he E ur o pea n Hea ds of Me dici n es A ge ncies 
( H M A) –  Rec o m me n d ati o ns relate d t o c o ntrace pti o n a n d pre g na nc y testi n g ( 1 5 Se p 
2 0 1 4 ). A vaila ble fr o m: htt ps:// w w w. h ma.e u/filea d mi n/ dateie n/ H u ma n _ Me dici nes/ 0 1-
A b o ut _ H M A/ W or ki n g _ Gr o u ps/ C T F G/ 2 0 1 4 _ 0 9 _ H M A _ C T F G _ C o ntrace pti o n. p df  

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Sc he d ule of E ve nts

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a Eac h c ycle will last 2 8 da ys.  C o h ort safet y assess me nt f or D L Ts will be perf or me d after Da y 2 8 of C ycle 1.  
b E O T Visit will occ ur at t he earliest da y p ossi ble wit hi n 3 0 da ys after t he last a d mi nistrati o n of mila de meta n.  If t he s u bjec t be gi ns a n ot her f or m of a ntica ncer t hera p y bef ore t he e n d of t he 3 0-da y  
peri o d, e ver y eff ort s h o ul d be ma de t o c o m plete all t he E O T assess me nts pri or t o c o m me nci n g t he ne w t hera p y.  If t here is a n a b n or malit y i n nee d of m o nit ori n g be y o n d t he E O T Visit, s u bjects will be 
f oll o we d u ntil res ol uti o n or c o nfir me d sta bilit y of t he ab n or malit y.  
c F oll o w -u p will occ ur first at 3 0 ( ± 5) da ys after t he last d ose of t he st u d y dr u g (t his ca n be acc o m plis he d b y a site visit or p h o ne  call if t he s u bject ca n n ot ret ur n t o t he site) a n d t he n e ver y 3 m o nt hs ( ± 
2 wee ks) u ntil deat h or u ntil S p o ns or ter mi nates st u d y.  
d If t he S C R  Visit f or Part 1 is perf or me d wit hi n 2 4 h o urs of C ycle 1/ Da y 1, t he assess me nts perf or me d d uri n g S C R  d o n ot nee d t o be re peate d.  
e F or s u bjects i n t he q d 7/ 2 8 sc he d ule, t his visit is n ot nee de d, b ut safet y e val uati o ns (ie,  e ver yt hi n g b ut sa m pli n g f or P K m eas ure me nt a n d MI C -1) will be d o ne if t he s u bject prese nts wit h A Es of 
≥Gra de 3 o n Da y 1 5.  
f Pre g na nc y test (ser u m) will be perf or me d i n fe male s u bjects of c hil d beari n g p ote ntial at S C R , C ycle 3/ Da y 1, a n d E O T Visit. 
g Vita l si g n meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d b o d y te m perat ure. 
h Safet y la b orat or y sa m ples f or Da y 1 pre -d ose ( he mat ol o g y, ser u m c he mistr y, a n d c oa g ulati o n pr ofile) ca n be c ollecte d wit hi n 7 2 h o u rs bef ore t he first d ose.  C oa g ulati o n pr ofile will be perf or me d at 
S C R , C ycle 1/ Da y 1, C ycle 2/ Da y 1, E O T, a n d ot her visits as cli nicall y i n dicate d.  Creati ni ne cleara nce will be perf or me d at S C R . 
i Electr ocar di o gra ms will be perf or me d pre -d ose u nless s pecifie d, a n d at i n dicate d p ost-d ose ti me p oi nts o n C ycle 1/ Da y 1.  Pr oce d ure wi n d o w is ± 1 h o ur.  W he n t here is a P K sa m ple c ollecti o n 
c orres p o n di n g t o t he ti me p oi nt f or E C Gs, t he E C G s h o ul d be perf or me d wit hi n 1 0 mi n utes pri or t o P K sa m ple c ollecti o n.  Ot her u nsc he d ule d E C Gs ma y be perf or me d as cli nicall y i n dicate d.  
Electr ocar di o gra ms will be perf or me d i n tri plicate.  
j All u nsc he d ule d b o ne marr o w assess me nts of disease b ur de n perf or me d o n n o n -visit da ys m ust be re p orte d as u nsc h e d ule d visits.  B o ne mar r o w sa m ples o n C ycle 1/ Da y 1 5 are o pti o nal. 
k If b o ne marr o w a plasia is o bser ve d o n C ycle 2/ Da y 1, st u d y dr u g will be wit h hel d a n d a c o nfir mati o n b o ne marr o w assess me nt wil l be perf or me d i n 2 wee ks. 
l Bl o o d sa m ples dra w n pre -d ose of C ycle 1/ Da y 1, Da y 2, a n d Da y 8; C ycle 2/ Da y 1; a n d E O T Visit f or bi o mar ker a nal ysis.  
m  F or d ose sc h e d ules:  q d 2 1/ 2 8; q d 7/ 2 8; q d 3/ 1 4 × 2; or q d 1 4/ 2 8, mila de meta n is ta ke n o n Da ys 1 t o 2 1; 1 t o 7, 1 t o 3 a n d 1 5  t o 1 7; or 1 t o 1 4, res pecti vel y.  Mila de meta n is a d mi nistere d per pr ot oc ol, 
at t he cli nical site at t he i n dicate d ti me.  
n Bl o o d sa m ples f or P K meas ure me nt will be c ollecte d pre -d ose at t he i n dicate d visits ( C ycle 1/ Da ys 1, 2, 8, 1 5, a n d 2 2).  S u bjects will be i nstr ucte d n ot t o ta ke t heir d ose u ntil af ter t he sa m ple has bee n 
c ollecte d o n cli nic da ys.  A d diti o nal sa m ples will be c ollecte d at t he i n dicate d ti me p oi nts.  P ost -d ose P K sa m ples will n ot be c ollecte d f or s u bjects i n t he q d 7/ 2 8 a n d q d 1 4/ 2 8 sc he d ules.  T he wi n d o w 
f or sa m ple c ollecti o n will be ± 1 5 % of t he s pecifie d ti me.  Base d o n t he P K pr ofile esta blis he d fr o m t he i nitial s u bjects treate d i n t he st u d y, sa m ple c ollecti o n ti me p oi nts m a y be m o difie d u p o n 
n otificati o n b y t he S p o ns or.  
o Ser u m f or MI C -1 i n d ucti o n will be o btai ne d at t he i n dicate d ti me p oi nts ( pre -d os e a n d 6 h o urs p ost -d ose o n C ycle 1/ Da y 1 a n d pre -d ose o n C ycle 1/ Da ys 2, 8, 1 5, a n d 2 2).  
p A b o ne marr o w r e -bi o ps y or as pirate will be perf or me d wit hi n 3 0 da ys of t he last d ose of st u d y dr u gs, prefera bl y pri or t o i nitiati n g ne w a ntica ncer t hera p y, i n s u bjects w h o ha ve ac hie ve d a n i nitial C R 
or P R b ut later de vel o pe d P D w hile o n t hera p y.  
q If f easi ble, c ollect s u bject s ur vi val stat us, date a n d ca use of deat h (if a p plica ble), s u bse q ue nt a ntica ncer t hera p y, a n d H C T a n d H C T-rele va nt i nf or mati o n (if perf or me d). 

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g A Z A a n d mila de meta n a d mi nistrati o n will be d o ne q d o n C ycle 2/ Da ys 5 t o 7, a n d ot her assess me nts will be d o ne o n Da y 7 pre -d ose.  
h Pre g na nc y test (ser u m) will be perf or me d i n fe male s u bjects of c hil d beari n g p ote ntial at S C R , C ycle 3/ Da y 1, a n d E O T Visit. 
i O btai n a f ollicle sti m ulati n g h or m o ne ( F S H) test i n w o me n of c hil d beari n g p ote ntial t o c o nfir m me narc he.  
j At S C R, c ollect tra nsf usi o n hist or y f or t he 5 6 da ys pri or t o first d ose of st u d y dr u gs (first da y e xcl usi ve). 
k Vital si g n meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d b o d y te m perat ur e. 
l Safet y la b orat or y sa m ples f or Da y 1 pre -d ose ( he mat ol o g y a n d ser u m c he mistr y) ca n be c ollecte d wit hi n  7 2 h o urs bef ore t he first d ose.  Creati ni ne cleara nce will be calc ulate d at S C R . 
m  Electr ocar di o gra ms will be perf or me d pre -d ose u nless s pecifie d, a n d at i n dicate d p ost -d ose ti me p oi nts o n C ycle 1/ Da ys 1, 5, a n d 1 4.  Pr oce d ure wi n d o w is ±  1  h o ur.  W he n t h ere is a P K sa m ple 
c ollecti o n c orres p o n di n g t o t he ti me p oi nt f or E C Gs, t he E C G s h o ul d be perf or me d wit hi n 1 0 mi n utes pri or t o P K sa m ple c ollect i o n.  Ot her u nsc he d ule d E C Gs ma y be perf or me d as cli nicall y 
i n dicate d.  Electr ocar di o gra ms will be perf or me d i n tri plicate. 
n F or C ycle 1/ Da y 1 4, E C Gs will be c ollecte d at t he sa me ti me p oi nts as o n Da y 5.  F or s u bjects i n Part 2 ( D ose E x pa nsi o n), E C G s are ta ke n o nl y at pre-d ose a n d 3 h o urs p ost -d ose o n Da y 5, a n d at pre -
d ose o n Da y 1 4 a n d ot her i n dicate d visits.  
o E C H O/ M U G A d o n ot nee d t o be re peate d if t he pr oce d ure was d o ne wit hi n 6 0 da ys b ef ore t he first d ose of st u d y dr u gs a n d if n o c ha n ges i n car diac c o n diti o ns were o bser ve d base d o n t he 
I n vesti gat or’s cli nical assess me nt. 
p All u nsc he d ule d b o ne marr o w assess me nts of disease b ur de n perf or me d o n n o n -visit da ys m ust be re p orte d as u nsc h e d ule d visits.  B o ne marr o w sa m ples after t he p orti o n nee de d f or disease 
assess me nt s h o ul d be se nt t o t he bi o mar ker assess me nt per t he La b orat or y Ma n ual i nstr ucti o ns at S C R  ( Baseli ne), o n Da y 1 of C ycles 2 a n d 3 a n d t he n e ver y 3 c ycles t hereafter (ie, at Da y 1 of C ycles 
6, 9, etc).  B o ne marr o w re bi o ps y/as pirate after t he E O T will als o be se nt f or bi o mar ker a nal ysis.  
q If b o ne marr o w a plasia is o bser ve d o n C ycle 2/ Da y 1, st u d y dr u g will be wit h hel d a n d a c o nfir mati o n b o ne marr o w assess me nt will be perf or me d i n 2 wee ks. 
r Bl o o d sa m ples dra w n pre -d ose o n C ycle 1/ Da ys 1, 5, 7, a n d 1 4; C ycle 2/ Da ys 1 a n d 1 5; C ycle 3/ Da y 1 a n d t he n e ver y 3 c ycles t hereafter; a n d  o n  E O T Visit will be se nt f or bi o mar ker a nal ysis per t he 
La b orat or y Ma n ual.  
s Mila de meta n is ta ke n o n Da ys 5 t o 1 4 i n eac h 2 8 -da y c ycle.  
t Bl o o d sa m ples f or P K meas ure me nt will be c ollecte d pre -d ose at t he i n dicate d visits, u nless ot her wise s pecifie d, a n d at i n dicate d p ost -d ose ti me  p oi nts o n C ycle 1/ Da ys 5 a n d 1 4.  S u bjects will be 
i nstr ucte d n ot t o ta ke t heir d ose u ntil after t he sa m ple has bee n c ollecte d o n cli nic da ys.  A d diti o nal sa m ples will be c ollecte d at t he i n dicate d ti me p oi nts.  T he P K ti me p oi nts a n d wi n d o w f or sa m ple 
c ollecti o n are s pecifie d i n Ta ble  8 .1 .  Base d o n t he P K pr ofile esta blis he d fr o m t he i nitial s u bjects treate d i n t he st u d y, sa m ple c ollecti o n ti me p oi nts ma y be m o difie d u p o n n otificati o n b y t he S p o ns or.   
If s u bjects recei ve A Z A i n t he “ 5 + 2 sc he d ule ( Fi g ure 3. 3), t he C ycle 1/ Da ys 6, 7 a n d 1 4 P K sa m ples are n ot c ollecte d. 
u Si x s u bjects i n Part 1 A will partici pate i n a n e x pl orat or y s u bst u d y.  Bl o o d sa m ples will be c ollecte d at pre -d ose a n d 0. 5, 1, 2, 3, a n d 6 h o urs p ost -d ose o n C ycle  1/ Da y 1 ( A Z A al o ne) a n d C ycle 1/ Da y 
7 ( A Z A + mila de meta n) ( Ta ble  8 .3 ). 
v O n C ycle 1/ Da y 1 4, P K sa m ples will be c ollecte d at t he sa me ti me p oi nts as o n Da y 5 ( Ta ble  8 .1 ).  F or s u bjects i n Part 2 ( D ose E x pa nsi o n), s parse P K sa m ples will be c ollecte d o nl y o n C ycle 1/ Da ys 
5 ( 0. 5, 3, a n d 6 t o 1 0 h o urs p ost -d ose), 6 ( pre -d ose), a n d 1 4 ( pre -d ose a n d 3 t o 6 h o urs p ost -d ose) ( Ta ble  8 .4 ).  C ycle 1/ Da y s 6 , 7 , a n d 1 4 P K sa m ple will n ot be c ollecte d if s u bjects recei ve A Z A i n t he 
“ 5 + 2” sc he d ule ( Fi g ure  3 .3 ). 
w  A bl o o d sa m ple will be c ol lecte d f or ba n ki n g plas ma o n C ycle 1/ Da ys 1 a n d 1 4, C ycle 2/ Da y 1, C ycle 3/ Da y 1, a n d t he n e ver y 3 c ycles t hereafter (ie, C ycles 6, 9, 1 2, etc) c orres p o n di n g t o t he 
ti me p oi nts f or b o ne marr o w bi o ps y/as pirate. 
x O btai n bl o o d f or bi o mar kers fr o m s u bjects w h o  ac hie ve d a n i nitial C R, C Ri, M L F S, or P R b ut later rela pse d (after C R or C Ri) or de vel o pe d P D (after M L F S or P R) w hile o n t he ra p y. 
y Ser u m f or MI C -1 i n d ucti o n will be o btai ne d at t he i n dicate d ti me p oi nts ( pre -d ose o n C ycle 1/ Da y 1, pre -d ose a n d at 6 t o 1 0 h o urs p ost -d ose o n C ycle 1/ Da y 5, pre -d ose o n C ycle 1/ Da ys 1 4 a n d 2 2, 
a n d pre-d ose o n C ycle 2/ Da y 1 5).  
z A b o ne marr o w r e -bi o ps y or as pirate will be perf or me d wit hi n 3 0 da ys of t he last d ose of st u d y treat me nt, prefer a bl y pri or t o i nitiati n g ne w a ntica nc er t hera p y, i n s u bjects w h o ha ve ac hie ve d a n i nitial 
C R, C Ri, M L F S, or P R b ut later rela pse d (after C R or C Ri) or de vel o pe d P D (after M L F S or P R) w hile o n t hera p y.  
aa If f easi ble, c ollect s u bject s ur vi val stat us, date a n d ca use of deat h (if a p plica ble), s ubse q ue nt a ntica ncer t hera p y, a n d H C T a n d H C T -rele va nt i nf or mati o n (if perf or me d). 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 3  
A Z A = 5 -azaciti di ne; C R = c o m plete re missi o n; D L T = d ose -li miti n g t o xicit y; E C G = electr ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; E O T =  E n d -of -treat me nt; E X = e xa m; 
MI C -1  =  macr o p ha ge i n hi bit or y c yt o ki ne -1; M U G A = m ulti gate d ac q uisiti o n; N D = n ot deter mi ne d; P D = pr o gressi ve disease; P K  =  p har mac o ki netics; P R = partial re missi o n; q d = o nce dail y; S C R = 
Scree ni n g; SI D  =  s u bject i de ntificati o n n u m ber; T B D =  t o be deter mi ne d. 
a Eac h c ycle will last 2 8 da ys.  C o h ort safet y asses s me nt f or D L Ts will be perf or me d after Da y 2 8 of C ycle 1. 
b E O T Visit will occ ur at t he earliest da y p ossi ble wit hi n 3 0 da ys after t he last a d mi nistrati o n of mila de meta n or A Z A ( w hic he v er is later).  If t he s u bject be gi ns a n ot her f or m of a ntica ncer t hera p y  
bef ore t he e n d of t he 3 0 -da y peri o d, e ver y eff ort s h o ul d be ma de t o c o m plete all t he E O T assess me nts pri or t o c o m me nci n g t he ne w t hera p y.  If t here is  a n a b n or malit y i n nee d of m o nit ori n g be y o n d 
t he E O T Visit, s u bjects will be f oll o we d u ntil res ol uti o n or c o nfir me d sta bilit y of t he a b n or malit y.  
c F oll o w -u p will occ ur first at 3 0 ( ± 5) da ys after t he last d ose of t he st u d y dr u g (t his ca n be acc o m plis he d b y a site visit or p h o ne  call if t he s u bject ca n n ot ret ur n t o t he site) a n d t he n e ver y 3 m o nt hs ( ± 
2 wee k s) u ntil deat h or u ntil S p o ns or ter mi nates st u d y. 
d If t he S C R  Visit is perf or me d wit hi n 2 4 h o urs of C ycle 1/ Da y 1, t he assess me nts perf or me d d uri n g S C R  d o n ot nee d t o be re peate d.  
e A Z A a d mi nistrati o n will be d o ne q d o n Da ys 3 t o 7, a n d ot her assess me nts will be d o ne o n Da y 7 pre -d ose.   If s u bjects recei ve A Z A i n t he 5 + 2 sc he d ule (Fi g ure  3 .3 ), t he C ycle 1/ Da y 7 assess me nts 
will be m o ve d t o Da y 8 a n d Da y 1 4 assess me nts will be m o ve d t o Da y 1 5, a n d n o P K sa m ples will be c ollecte d o n t hese da ys . 
f A Z A a d mi nistrati o n will be d o ne q d o n Da ys 1 t o 7, a n d ot her assess me nts will be d o ne o n Da ys 1 a n d 7 pre -d ose.  
g Pre g na nc y test (ser u m) will be perf or me d i n fe male  s u bjects of c hil d beari n g p ote ntial at S C R , C ycle 3/ Da y 1, a n d E O T Visit. 
h O btai n a f ollicle sti m ulati n g h or m o ne ( F S H) test i n w o me n of c hil d beari n g p ote ntial t o c o nfir m me narc he.  
i At S C R, c ollect tra nsf usi o n hist or y f or t he 5 6 da ys pri or t o first d ose o f st u d y dr u gs (first da y e xcl usi ve). 
j Vital si g n meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d b o d y te m perat ur e. 
k Safet y la b orat or y sa m ples f or Da y 1 pre -d ose ( he mat ol o g y a n d ser u m c he mistr y) ca n be c o llecte d wit hi n 7 2 h o urs bef ore t he first d ose.  Creati ni ne cleara nce will be calc ulate d at S C R . 
l Electr ocar di o gra ms will be perf or me d pre -d ose u nless s pecifie d, a n d at i n dicate d p ost -d ose ti me p oi nts o n C ycle 1/ Da ys 1, 8, a n d 1 4.  Pr oce d ure wi n d o w is ±  1  h o ur.  W he n t here is a P K sa m ple 
c ollecti o n c orres p o n di n g t o t he ti me p oi nts f or E C Gs, t he E C G s h o ul d be perf or me d wit hi n 1 0 mi n utes pri or t o P K sa m ple c ollec ti o n.  Ot her u nsc he d ule d E C Gs ma y be perf or me d as cli nicall y 
i n dicate d.  Electr ocar di o gra ms will be perf or me d i n tri plicate.  
m  F or C ycle 1/ Da y 1 4, E C Gs will be c ollecte d at t he sa me ti me p oi nts as o n Da y 8.  F or s u bjects i n Part 2 ( D ose E x pa nsi o n), E C G s are ta ke n o nl y at pre-d ose a n d 3 h o urs p ost -d ose o n Da y 8, a n d at pre -
d ose o n Da y 1 4 a n d ot her i n dic ate d visits. 
n E C H O/ M U G A d o n ot nee d t o be re peate d if t he pr oce d ure was d o ne wit hi n 6 0 da ys b ef ore t he first d ose of st u d y dr u gs a n d if n o c ha n ges i n car diac c o n diti o ns were o bser ve d base d o n t he 
I n vesti gat or’s cli nical assess me nt. 
o All u nsc he d ule d b o ne marr o w assess me nts of disease b ur de n perf or me d o n n o n -visit da ys m ust be re p orte d as u nsc h e d ule d visits.  B o ne marr o w sa m ples after t he p orti o n nee de d f or t he disease 
assess me nt s h o ul d be se nt t o t he bi o mar ker assess me nt per La b orat or y Ma n ual i nstr ucti o ns at S C R  ( Baseli ne), o n Da y 1 of C ycles 2 a n d 3 a n d t he n e ver y 3 c ycles t hereafter (ie, at Da y 1 of C ycle 6, 9, 
etc).  B o ne marr o w re bi o ps y/as pirate after t he E O T will als o be se nt f or bi o mar ker a nal ysis.  
p If b o ne marr o w a plasia is o bser ve d o n C ycle 2/ Da y 1, st u d y dr u g will be wit h hel d a n d a c o nfir mati o n b o ne marr o w assess me nt will be perf or me d i n 2 wee ks. 
q Bl o o d sa m ples dra w n pre -d ose C ycle 1/ Da ys 1, 8, a n d 1 4; C ycle 2/ Da ys 1 a n d 1 5; C ycle 3/ Da y 1 a n d t he n e ver y 3 c ycles t hereafter; a n d o n E O T Visit will be se nt f or bi o mar ker a nal ysis p er t he 
La b orat or y Ma n ual.  
r Mila de meta n is ta ke n o n Da ys 8 t o 1 4 i n eac h 2 8 -da y c ycle.  
s Bl o o d sa m ples f or P K meas ure me nt will be c ollecte d pre -d ose at t he i n dicate d visits, u nless ot her wise s pecifie d, a n d at i n dicate d p ost -d ose ti me p oi nts o n C ycle 1/ Da ys 8 a n d 1 4.  S u bjects will be 
i nstr ucte d n ot t o ta ke t heir d ose u ntil after sa m ple has been c ollecte d o n cli nic da ys.  A d diti o nal sa m ples will be c ollecte d at t he i n dicate d ti me p oi nts a n d as cli nicall y i n dicate d.  T he P K ti me p oi nts 
a n d wi n d o w f or sa m ple c ollecti o n are s pecifie d i n Ta ble  8 .2 .  Base d o n t he P K pr ofile esta blis he d fr o m t he i nitial s u bjects treate d i n t he st u d y, sa m ple c ollecti o n ti me p oi nts ma y be mo difie d u p o n 
n otificati o n b y t he S p o ns or.  
t O n C ycle 1/ Da y 1 4, P K sa m ples will be c ollecte d at t he sa me ti me p oi nts as o n Da y 8 ( Ta ble  8 .2 ).  F or s u bjects i n Part 2 ( D ose E x pa nsi o n), s parse P K sa m ples will be c ollecte d o nl y o n C ycle 1/ Da ys 
8 ( 0. 5, 3, a n d 6 t o 1 0 h o urs p ost -d ose), 9 ( pre -d ose), a n d 1 4 ( pre -d ose a n d 3 t o 6 h o urs p ost -d ose) ( Ta ble  8 .4 ).  P K sa m ples, f or C ycle 1 Da y 6 a n d Da y 1 4 will n ot be c ollecte d f or s u bjects o n t he 
alter nati ve ( 5 + 2) A Z A sc h e d ule ( Fi g ure  3 .3 ). 
u A bl o o d sa m ple will be c ollecte d f or ba n ki n g plas ma o n C ycle 1/ Da ys 1 a n d 1 4, C ycle 2/ Da y 1, C ycle 3/ Da y 1, a n d t he n e ver y 3 c ycles t hereafter (ie, C ycles 6, 9, 1 2, etc)  c orres p o n di n g t o t he 
ti me p oi nts f or b o ne marr o w bi o ps y/as pirate. 
v Ser u m f or MI C -1 i n d ucti o n will be o btai ne d at t he i n dicate d ti me p oi nts  ( pre-d ose o n C ycle 1/ Da y 1, pre -d ose a n d at 6 t o 1 0 h o urs p ost -d ose o n C ycle 1/ Da y 8, pre -d ose o n C ycle 1/ Da ys 1 4 a n d 2 2, 
a n d pre-d ose o n C ycle 2/ Da y 1 5).  
w  A b o ne marr o w r e -bi o ps y or as pirate will be perf or me d wit hi n 3 0 da ys of t he last d ose of st u d y tre at me nt, prefer a bl y pri or t o i nitiati n g ne w  a ntica ncer t hera p y, i n s u bjects w h o ha ve ac hie ve d a n i nitial 
C R, C Ri, M L F S, or P R b ut later rela pse d (after C R or C Ri) or de vel o pe d P D (after M L F S or P R) w hile o n t hera p y.  
x If f easi ble, c ollect s u bject s ur vi val stat us, date a n d ca use of deat h (if a p plica ble), s u bse q ue nt a ntica ncer t hera p y, a n d H C T a n d H C T-rele va nt i nf or mati o n (if perf or me d). 

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Pa ge 1 1 4  
1 7. 2.   
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us Sc ale 1 4 
Gr a de   
E C O G P erf or m a nce St at us  
0   
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble  t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure (e g, li g ht h o use w or k, office w or k) 
2  
A m b ulat or y a n d ca pa ble of all selfcare b ut u na ble t o carr y o ut a n y w or k acti vities; u p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs  
3   
Ca pa ble of o nl y li mite d selfcare; c o n fi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs 
4   
C o m pletel y disa ble d; ca n n ot carr y o n a n y selfcare; t otall y c o nfi ne d t o be d or c hair  
5   
Dea d  

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1 7. 3.   
N ati o n al C a ncer I nstit ute C o m m o n Ter mi n ol o g y Criteri a f or 
A d verse E ve nts, Versi o n 5. 0  ( Versi o n 4. 0 3 bef ore 0 1  A pr  2 0 1 8)  
1.  T o xicit y gra de s h o ul d reflect t he m ost se vere d e gree occ urri n g d uri n g t he e val uate d peri o d, 
n ot a n a vera ge.  
2.  W he n 2 differe nt criteria gra des mi g ht be a p plica ble f or rati n g a p artic ular t o xicit y, or si milar 
t o xicities, t he m ore se vere gra de s h o ul d b e use d. 
3.  A n y t o xicit y re s ulti n g i n deat h is defi ne d as Gra d e 5. 
4.  T he e val uat or m ust atte m pt t o discri mi nate bet wee n disease/treat me nt a n d relate d 
si g ns/s y m pt o ms. 
5.  F or li n ks t o t he Nati o nal C a ncer Instit ute C o m m o n T er mi n ol o g y C riteria f or A d verse E ve nts  
refer t o: 
 Versi o n 4. 0 3:  
htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m #ctc _ 4 0  
 Versi o n 5. 0:  
htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m #ctc _ 5 0  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 6  
1 7. 4.   
Res p o nse  Criteri a  f or A M L 
1 7. 4. 1.   
2 0 1 7  E ur o pe a n Le u ke mi a Net  R ec o m me n d ati o ns f or Ac ute M yel o g e n o us 
Le u ke mi a wit h M o dific ati o ns  ( P art 2 O nl y)1 6 
C ate g or y  
Defi niti o n  
C o m plete Re missi o n ( C R)  
 
B o ne marr o w blasts < 5 %  
 
A bse nce of circ ulati n g blasts a n d blasts wit h A uer r o ds  
 
A bse nce of e xtra me d ullar y disease  
 
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 0  × 1 0 9/ L 
 
Platelet c o u nt ≥1 0 0  × 1 0 9/ L 
C R wit h I nc o m plete Bl o o d 
C o u nt Rec o ver y ( C Ri) 
(Fi g ure  1 7 .1 ) 
All C R criteria e xce pt f or resi d ual ne utr o pe nia ( A N C < 1. 0 × 1 0
9/ L) or 
t hr o m b oc yt o pe nia ( platelet c o u nt < 1 0 0 × 1 09/ L) 
M or p h ol o gic Le u ke mia -free 
State ( M L F S)  
 
B o ne marr o w blasts < 5 %  
 
A bse nce of blasts wit h A uer r o ds  
 
A bse nce of e xtra me d ullar y disease  
 
N o he mat ol o gic rec o ver y re q uire d  
o  N ote :  Marr o w s h o ul d n ot merel y be “a plastic”; at least 2 0 0 cells 
s h o ul d be e n u merate d or cell ularit y s h o ul d be at least 1 0 % 
Partial Re missi o n ( P R)  
 
Decrease of b o ne marr o w blast perce nta ge b y at least 5 0 % t o a val ue 
of 5 % t o 2 5 %  
 
All he mat ol o gic criteria of C R:  
o  A N C ≥1. 0 × 1 0 9/ L 
o  platelet c o u nt ≥1 0 0 × 1 0 9/ L 
Sta ble Disease ( S D)  
A bse nce of C R, C Ri, M L F S, or P R, a n d criteria f or P D n ot met  
o  N ote :  S D ca n be re p orte d as eac h assess me nt n ot persisti n g 
f or 3 m o nt hs, w hereas S D w hic h persists f or at least 3 m o nt hs 
will be s u m marize d f or t he efficac y a nal ysis.  
Rela pse (after C R or C Ri)  
 
B o ne marr o w blasts ≥5 %, or  
 
Rea p peara nce of le u ke mic blasts i n t he peri p heral bl o o d, or  
 
De vel o p me nt of e xtra me d ullar y disease  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 7  
C ate g or y  
Defi niti o n  
Pr o gressi ve Disease ( P D)  
E vi de nce f or a n i ncrease i n b o ne marr o w blast perce nta ge a n d/ or i ncrease 
of a bs ol ute blast c o u nts i n t he bl o o d:  
 > 5 0 % i ncrease i n marr o w blasts o ver baseli ne (a mi ni m u m 1 5 % p oi nt 
i ncrease is req uire d i n cases wit h < 3 0 % blasts at baseli ne; or 
persiste nt marr o w blast perce nta ge of > 7 0 % o ver at least 3 m o nt hs; 
wit h o ut at least a 1 0 0 % i m pr o ve me nt i n A N C t o a n a bs ol ute le vel of 
> 0. 5  × 1 0 9/ L, a n d/ or platelet c o u nt t o > 5 0 × 1 0 9/ L ( n o n-tra nsf use d); 
O R  
 > 5 0 % i ncrease i n peri p heral blasts ( W B C  × % blasts) t o > 2 5  × 1 0 9/ L 
(i n t he a bse nce of differe ntiati o n s y n dr o me); O R  
 Ne w e xtra me d ullar y disease  
A N C = a bs ol ute ne utr o p hil c o u nt; W B C = w hite bl o o d cells  
1 7. 4. 2.   
He m at ol o gic Rec o ver y Re q uire me nts f or C R a n d C Ri ( All P arts)  
Fi g ure  1 7 .1 : He m at ol o gic Rec o ver y Re q uire me nts f or C R a n d C Ri  ( All P arts) 
 
A N C = a bs ol ute ne utr o p hil c o u nt; C R = c o m plete re missi o n; C Ri = C R wit h i nc o m plete bl o o d c o u nt rec o ver y; 
M L F S = m or p h ol o gic le u ke mi a -free state 

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Pa ge 1 1 8  
1 7. 4. 3.   
C R h ( A d diti o n al Defi niti o ns/ Res p o nse Criteri a)  (All P a rts )1 7 
C R h e val uati o n will be c o n d ucte d se paratel y fr o m t h ose i n Secti o n  1 7. 4. 1 . 
C ate g or y  
Defi niti o n  
C R wit h Partial 
He mat ol o gical Rec o ver y 
( C R h) 
(Fi g ure  1 7 .2 ) 
All C R cr iteria e xce pt f or he mat ol o gic rec o ver y –  B U T partial 
he mat ol o gical rec o ver y ( A N C > 0. 5 × 1 0 9/ L a n d  platelet c o u nt > 5 0 × 
1 0 9/ L) were o bser ve d. 
Fi g ure  1 7 .2 : He m at ol o gic Rec o ver y Re q uire me nts f or C R a n d C R h  (All P arts ) 
 
A N C = a bs ol ute ne utr o p hil c o u nt; C R = c o m plete re missi o n; C R h = C R wit h partial he mat ol o gical rec o ver y  

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1 7. 4. 4.   
2 0 0 3 I nter n ati o n al W or ki n g Gr o u p Res p o nse Criteri a f or Ac ute M yel o ge n o us 
Le u ke mi a  wit h M o dific ati o ns ( P art 1 a n d P art 1 A O nl y) 1 5 
C ate g or y  
Defi niti o n  
C o m plete Re missi o n ( C R)  
 
B o ne marr o w blasts < 5 %  
 
A bse nce of circ ulati n g blasts a n d blasts wit h A uer r o ds  
 
A bse nce of e xtra me d ullar y disease  
 
A N C ≥1. 0 × 1 0 9/ L a n d platelet c o u nt ≥1 0 0 × 1 09/ L 
C R wit h I nc o m plete Bl o o d 
C o u nt Rec o ver y ( C Ri)  
 
All C R criteria e xce pt f or A N C < 1. 0 × 1 0 9/ L O R platelet c o u nt < 1 0 0 × 
1 0 9/ L 
Partial Re missi o n ( P R)  
 
Decrease of b o ne marr o w blast perce nta ge b y at least 5 0 % t o a val ue 
of 5 % t o 2 5 % a n d A N C ≥1. 0 × 1 0 9/ L; platelet c o u nt ≥1 0 0 × 1 09/ L 
M or p h ol o gic Le u ke mia -free 
State ( M L F S)  
 
B o ne marr o w blasts < 5 %  
 
A bse nce of blasts wit h A uer r o ds  
 
A bse nce of e xtra me d ullar y dis ease 
 
N o he mat ol o gic rec o ver y re q uire d  
Treat me nt Fail ure  
 Persiste nt A M L i n bl o o d or b o ne marr o w, or t hera p y fails t o ac hie ve a 
re missi o n of a n y cate g or y, or deat h pri or t o res p o nse assess me nt 
A M L = ac ute m yel o ge n o us le u ke mia; A N C = a bs ol ute ne utr o p hil c o u nt  

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1 7. 5.   
Res p o nse Criteri a f or M D S  
1 7. 5. 1.   
2 0 0 6 I nter n ati o n al W or ki n g Gr o u p Res p o nse Criteri a f or M y el o d ys pl astic 
S y n dr o me 1 6 
T a ble  1 7 .4 : 
Res p o nse Criteri a  
C ate g or y  
Res p o nse Criteri a a 
C o m plete Re missi o n ( C R)  
 
B o ne marr o w:  ≤5 % m yel o blasts wit h n or mal mat urati o n of all cell 
li nesb 
 
Persiste nt d ys plasia will be n ote d b 
 
Peri p heral bl o o d  
o  H g b ≥1 1 g/ d L  
o  Platelets ≥1 0 0 × 1 0 9/ L 
o  Ne utr o p hils ≥1. 0 × 1 0 9/ L 
o  Blasts 0 %  
Marr o w C R ( m C R)  
 
B o ne marr o w:  ≤5 % m yel o blasts a n d decrease b y ≥5 0 % o ver 
pretreat me nt  
 
Peri p heral bl o o d:  If he mat ol o gic i m pr o ve me nt  res p o nses, t he y will 
be n ote d i n a d diti o n t o m C R  
Partial Re missi o n ( P R)  
 
All C R criteria if a b n or mal bef ore treat me nt e xce pt:  
o  B o ne marr o w blasts decrease d b y ≥5 0 % o ver pretreat me nt b ut still 
> 5 %  
o  Cell ularit y a n d m or p h ol o g y n ot rele va nt  
C yt o ge netic Res p o nse  
 
C o m plete:  
o  Disa p peara nce of t he c hr o m os o mal a b n or malit y wit h o ut 
a p peara nce of ne w o nes  
 
Partial:  
o  At least 5 0 % re d ucti o n of t he c hr o m os o mal a b n or malit y  
Sta ble Disease ( S D)  
 
Fail ure t o ac hie ve at least P R, b ut n o e vi de nce of pr o gressi o n f or 
> 8  wee ks  
N ote :  S D ca n be re p orte d as eac h assess me nt n ot persisti n g f or 8 wee ks, 
w hereas S D w hic h persists f or at least 8 wee ks will be s u m marize d f or t he 
efficac y a nal ysis  
Rela pse after C R or P R  
 
At  least 1 of t he f oll o wi n g: 
o  Ret ur n t o pretreat me nt b o ne marr o w blast perce nta ge  
o  Decre me nt of ≥5 0 % fr o m ma xi m u m re missi o n/res p o nse le vels i n 
gra n ul oc ytes or platelets  
o  Re d ucti o n i n H g b c o nce ntrati o n b y ≥1. 5 g/ d L or tra nsf usi o n 
de pe n de nce  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 1  
C ate g or y  
Res p o nse Criteri a a 
Disease Pr o gressi o n  
 
F or s u bjects wit h:  
o  Less t ha n 5 % blasts:   ≥5 0 % i ncrease i n blasts t o > 5 % blasts  
o  5 %  t o 1 0 % blasts:  ≥5 0 % i ncrease t o > 1 0 % blasts  
o  1 0 %  t o 2 0 % blasts:   ≥5 0 % i ncrease t o > 2 0 % blasts  
o  2 0 %  t o 3 0 % blasts:  ≥5 0 % i ncrease t o > 3 0 % blasts  
A n y of t he f oll o wi n g:  
o  ≥5 0 % decr e me nt fr o m ma xi m u m re missi o n/res p o nse i n 
gra n ul oc ytes or platelets  
o  Re d ucti o n i n H g b b y ≥2 g/ d L  
o  Tra nsf usi o n de pe n de nce  
H g b = he m o gl o bi n  
a St u d y sites ca n re p ort C R, m C R, P R or cyt o ge netic res p o nse at eac h assess me nt e ve n w he n res p o nse d oes n ot 
persist f or 4 wee ks.  H o we ver, C R, P R, m C R or c yt o ge netic res p o nse w hic h persists f or at least 4 wee ks will be 
s u m marize d f or t he efficac y a nal ysis. 
b D ys plastic c ha n ges s h o ul d c o nsi der t he n or mal ra n ge of d ys plastic c ha n ges.  

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Pa ge 1 2 2  
T a ble  1 7 .5 : 
He m at ol o gic I m pr o ve me nt  
C ate g or y  
Res p o nse Criteri a a,b 
Er yt hr oi d res p o nse base d o n H g b 
i ncrease ( pretreat me nt, < 1 1 g/ d L)c 
 
H g b i ncrease b y ≥1. 5 g/ d L  
Er yt hr oi d res p o nse base d o n 
re d ucti o n of R B C tra nsf usi o n  
 
Rele va nt re d ucti o n of u nits of R B C tra nsf usi o ns b y a n a bs ol ute 
n u m ber of at least 4 R B C tra nsf usi o ns/ 8 wee ks c o m pare d wit h 
t he pretreat me nt tra nsf usi o n n u m ber i n t he pre vi o us 8 wee ks.  
O nl y R B C tra n sf usi o ns gi ve n f or a H g b of ≤9. 0 g/ d L 
pretreat me nt will c o u nt i n t he R B C tra nsf usi o n res p o nse 
e val uati o n. 
Platelet res p o nse ( pretreat me nt, 
< 1 0 0 × 1 0 9/ L)c 
 
A bs ol ute i ncrease of ≥3 0 × 1 0 9/ L f or s u bj ects starti n g wit h > 2 0 
× 1 0 9/ L platelets 
 
I ncrease fr o m < 2 0 × 1 0 9/ L t o > 2 0 × 1 09/ L a n d b y at least 1 0 0 % 
Ne utr o p hil res p o nse ( pretreat me nt, 
< 1. 0 × 1 0 9/ L)c 
 
At least 1 0 0 % i ncrease a n d a n a bs ol ute i ncrease > 0. 5 × 1 0
9/ L 
Pr o gressi o n or rela pse after 
he mat ol o gic i m pr o ve me nt d 
 
At least 1 of t he f oll o wi n g:  
o  ≥5 0 % decre me nt fr o m ma xi m u m res p o nse le vels i n 
gra n ul oc ytes or platelets  
o  Re d ucti o n i n H g b b y ≥1. 5 g/ d L  
o  Tra nsf usi o n de pe n de nce  
H g b = he m o gl o bi n; R B C = re d bl o o d cell  
a Res p o nses m ust last at least 8 wee ks.  
b St u d y sites ca n re p ort er yt hr oi d, platelet, or ne utr o p hil res p o nse at eac h assess me nt e ve n w he n res p o nse d oes n ot 
persist f or 8 wee ks.  H o we ver, er yt hr oi d, platelet, or ne utr o p hil res p o nse w hic h persists f or at least 8 wee ks will be 
s u m marize d f or t he efficac y a nal ysis. 
c Pretreat me nt c o u nts a vera ges of at least 2 meas ure me nts ≥1 wee k a part ( n ot i nfl ue nce d b y tra nsf usi o ns, ie, n o 
R B C tra nsf usi o ns f or at least 1 wee k a n d n o platelet tra nsf usi o ns f or at least 3 da ys).  
d I n t he a bse nce of a n ot her e x pl a nati o n, s uc h as ac ute i nfecti o n, re peate d c o urses of c he m ot hera p y,  gastr oi ntesti nal 
blee di n g, he m ol ysis, a n d s o f ort h.  It is rec o m me n de d t hat t he 2 ki n ds of er yt hr oi d a n d platelet res p o nses be 
re p orte d o verall as well as b y t he i n di vi d ual res p o nse patter n. 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 3  
1 7. 6.   
Re vise d I nter n ati o n al Pr o g n ostic Sc ori n g S yste m 1 9 
T a ble  1 7 .6 : 
T he I nter n ati o n al Pr o g n ostic Sc ori n g S yste m –  Re vise d P a r a meters a n d 
Sc ore V al ues  
Pr o g n ostic 
V ari a ble  
0   
0. 5   
1   
1. 5   
2  
3  
4  
C yt o ge netics  
Ver y G o o d   
  
G o o d   
  
I nter me diate  
P o or   
Ver y P o or  
B M Bl ast %  
≤2  
  
> 2 t o < 5 %   
  
5 t o 1 0 %   
> 1 0 %   
 
He m o gl o bi n  
≥1 0   
  
8 t o < 1 0   
< 8  
 
 
 
Pl atelets  
≥1 0 0   
5 0 t o < 1 0 0   
< 5 0   
 
 
 
 
A N C  
≥0. 8   
< 0. 8   
 
 
 
 
 
A N C = a bs ol ute ne utr o p hil c o u nt; B M = b o ne marr o w  
T a ble  1 7 .7 : 
T he I nter n ati o n al Pr o g n ostic Sc ori n g S yste m –  Re vise d Ris k Gr o u ps  
Ris k Gr o u p   
Ris k Sc ore  
Ver y L o w   
≤1. 5  
L o w  
> 1. 5  t o 3  
I nter me diate  
> 3  t o 4. 5  
Hi g h  
> 4. 5  t o 6  
Ver y Hi g h   
> 6  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 4  
1 7. 7.   
C yt oc hr o me P 4 5 0 3 A  I n d ucers a n d I n hi bit ors 
T he f oll o wi n g list descri bes me dicati o ns t hat are str o n g i n hi bit ors of C Y P 3 A t hat nee d 
mila de meta n  d ose a dj ust me nt if use d c o nc o mita ntl y, a n d i n d ucers of C Y P 3 A t hat are pr o hi bite d 
d uri n g tr eat me nt wit h azaciti di ne a n d mila de meta n c o m bi nati o n.   T his list s h o ul d n ot be 
c o nsi dere d all -i ncl usi ve. 
Str o n g C Y P 3 A I n hi bit ors  
Str o n g C Y P 3 A I n d ucers  
B oce pre vir  
A v asi mi be  
Clarit hr o m yci n  
Car ba maze pi ne  
C o ni va pta n  
P he n yt oi n  
Gra pefr uit  
Rifa m pi n  
Gra pefr uit j uice  
St. J o h n’s W ort  
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  
 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p x  

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Pa ge 1 2 5  
1 7. 8.   
Ne w Y or k He art Ass oci ati o n ( N Y H A) F u ncti o n al Cl assific ati o n s 
T he f oll o wi n g t a ble lists t he N Y H A Classes of Heart Fail ure. 2 0 
Cl ass   
P atie nt S y m pt o ms  
I 
N o li mitati o n of p h ysical acti vit y.  Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue fati g ue, 
pal pitati o n, d ys p nea (s h ort ness of breat h). 
II 
Sli g ht li mitati o n of p h ysical acti vit y.  C o mf orta ble at rest.  Or di nar y p h ysical acti vit y res ults 
i n fati g ue, pal pitati o n, d ys p nea (s h ort ness of breat h). 
III 
Mar ke d li mitati o n of p h ysical acti vit y.  C o mf orta ble at rest.  Less t h a n or di nar y acti vit y 
ca uses fati g ue, pal pitati o n, or d ys p nea.  
I V 
U na ble t o carr y o n a n y p h ysical acti vit y wit h o ut disc o mf ort.  S y m pt o ms of heart fail ure at 
rest.  If a n y p h ysical acti vit y is u n derta ke n, disc o mf ort i ncreases. 

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Pa ge 1 2 6  
1 7. 9.   
Hi g hl y Effecti ve Met h o ds of Birt h C o ntr ol  
Per t he g ui da nce fr o m t h e Cli nical Trial Facilitati o n Gr o u p ( C T F G) of t he E ur o pea n Hea ds of 
Me dici nes A ge n cies ( H M A),
2 1 6 6 met h o ds t hat ca n ac hie ve a fail ure rate of less t ha n 1 % per 
year w h e n use d c o nsiste ntl y a n d c orrectl y are c o nsi dere d as hi g hl y effecti ve birt h c o ntr ol 
met h o ds.  Per t he g ui d a n ce, s uc h met h o ds i ncl u de:  
 C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n i ncl u di n g oral, i ntra va gi nal a n d tra ns der mal f or m ulati o ns 
 Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n, 
i ncl u di n g oral, i njecta ble a n d i m pla nta ble f or m ulati o ns 
 I ntr a uteri ne de vice (I U D) 
 I ntr a uteri ne h or m o ne-rel easi n g s yst e m (I U S) 
 Bilateral t u bal occl usi o n  
 Vasect o mize d part ner ( pr o vi de d t hat t he part ner is t he s ole se x ual part ner of t he w o ma n 
of c hil d beari n g p ote ntial trial partici pa nt a n d t hat t he vasect o mize d part n er has recei ve d 
me dical assess me nt of t h e s ur gical s uccess)  
 C o m plete se x ual a bsti ne nce ( defi ne d as refrai ni n g fr o m heter os e x ual i nterc o urse d uri n g 
t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts.  T he relia bilit y of se x ual 
a bsti ne nce nee ds t o be e v al uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he 
preferre d a n d us ual lifest yl e of t he s u bject.)  
Pri or t o starti n g st u d y dr u gs, t he I n v esti gat or will disc uss hi g hl y effecti ve met h o ds of birt h 
c o ntr ol as defi ne d a b o ve wit h w o me n of c hil d beari n g p ote ntial (as d efi ne d i n Secti o n  4. 1. 1 ) a n d 
me n w h o are n ot s ur gicall y sterile.