Clinical trial NCT02319369
Conditions: Acute Myelogenous Leukemia Myelodysplastic Syndrome
Keywords: High Risk Myelodysplastic Syndrome Relapsed/Refractory Newly Diagnosed Unfit for Chemotherapy
Sponsor: Daiichi Sankyo
Start date: 2014-11-25; Completion date: 2020-08-21
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will take place in parts:

* Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
* Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules

The recommended dose for Part 2 will be selected.

* Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:

  1. refractory or relapsed acute myelogenous leukemia (AML)
  2. newly diagnosed AML unfit for intensive chemotherapy
  3. high-risk myelodysplastic syndrome (MDS)
* End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study.

The recommended dose for the next study will be selected.

Detailed description:
The primary analysis will occur after all participants have either discontinued the study or completed at least 6 months of treatment. After the primary analysis, the main study will be closed. Participants who are still on study at least 6 months after enrollment of the last participant in the study may be eligible to continue receiving study drug in a separate extension phase of the protocol

Arms: arm 1: Participants receive milademetan alone with different dose schedules arm 2: Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules arm 3: Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA) arm 4: Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA) arm 5: Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
Interventions: intervention 1: Milademetan intervention 2: AZA intervention 3: Milademetan
Intervention descriptions: intervention 1: Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg intervention 2: AZA will be administered at 75 mg/m\^2 subcutaneously or intravenously intervention 3: Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.

Protocol documents:
Prot_SAP_000.pdf: 
 
Pr o prietar y a n d C o nfi de ntial  
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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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 2  
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  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 4  
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 7  
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  
 


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  
 


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 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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Pr o prietar y a n d C o nfi de ntial  
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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Pr o prietar y a n d C o nfi de ntial  
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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Pa ge 3 4  
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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Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 6  
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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Pr o prietar y a n d C o nfi de ntial  
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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 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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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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Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 8  
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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Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 0  
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 
P P D


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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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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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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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1 5. 3. 3.   
Bi ol o gic al S peci me ns  
T P 5 3 Ge n ot y pi n g  
 
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)  
4 0 1 Terr y A ve n ue  N, S uite 2 0 0  
Seattle, W A 9 8 1 0 9  
MI C -1 T est  
 
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  
It haca, N Y 1 4 8 5 0 
P P D
P P D
P P D
P P D
P P D
P P D


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1 6.   
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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1 7.   
A P P E N DI C E S  
1 7. 1.   
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). 




Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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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Pr o prietar y a n d C o nfi de ntial  
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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Pr o prietar y a n d C o nfi de ntial  
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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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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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Pa ge 1 1 9  
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 0  
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.  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
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. 


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  


Pr ot oc ol D S 3 0 3 2 -A -U 1 0 2  
Versi o n 5. 0, 0 6 Mar 2 0 2 0  
 
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  


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 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. 


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 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.