A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination With Azacitidine in Subjects ≥ 18 Years of Age With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation
Phase: PHASE3
Conditions: Newly Diagnosed Acute Myeloid Leukemia (AML), Untreated AML, AML Arising From Myelodysplastic Syndrome (MDS), Leukemia, Myeloid, Acute
Sponsor: Institut de Recherches Internationales Servier

Offi ci al Titl e:  A P h a s e 3, M ulti c e nt er, D o u bl e -Bli n d, R a n d o mi z e d, Pl a c e b o -
C o ntr oll e d  St u d y of A G -1 2 0 i n C o m bi n ati o n wit h A z a citi di n e i n 
S u bj e ct s ≥1 8 Y e ar s of A g e wit h Pr e vi o u sl y U ntr e at e d A c ut e M y el oi d 
L e u k e mi a wit h a n I D H 1 M ut ati o n  
N C T N u m b er:  N C T 0 3 1 7 3 2 4 8  
D o c u m e nt  D at e s :  Pr ot o c ol  V er si o n 1 0: 0 7 -O ct o b er - 20 2 1 

St u d y A G 1 2 0 -C -0 0 9  
 
Cli nical St u d y Re p ort  A p pe n di x  
© I. R.I. S. –  C o nfi de ntial  
 
1  
1 6. 1. 1.  
P R O T O C O L A N D P R O T O C O L A M E N D M E N T S  
A G 1 2 0 -C -0 0 9 Pr ot oc ol v 1. 0 (0 6  Ja nuar y 2 0 1 7 ) 
A me n d me nt 1, Versi o n 2. 0  ( 0 7 Fe br uar y 2 0 1 7) Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 2, Versi o n 3. 0  ( 2 4 Marc h 2 0 1 7) Gl o b al / S u m mar y of C ha n ges 
A me n d me nt 3, Versi o n 4. 0  ( 1 4 A pril 2 0 1 7)  Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 4, Versi o n 5. 0  ( 3 1 Oct o ber 2 0 1 7) Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 4, Versi o n 5. 1  ( 0 4 Dece m ber 2 0 1 7) Ja pa n/ S u m mar y of C ha n g es 
A me n d me nt 4, Versi o n 5. 2 ( 2 3 A pril 2 0 1 8)  Ja pa n/ S u m mar y of C ha n ges 
A me n d me nt 4, Versi o n  5. 3  ( 1 1 Ja n uar y 2 0 1 9) Fra nce/ S u m mar y of C ha n ges 
A me n d me nt 4, Versi o n 5. 4  ( 3 0 Ma y 2 0 1 9) Ger ma n y/ S u m mar y of C ha n ges 
A me n d me nt 5, Versi o n 6. 0  ( 0 9 Ja n uar y 2 0 2 0) Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 5, Versi o n 6. 1  ( 0 9 Ja n uar y 2 0 2 0) Ja p a n/ S u m mar y of C ha n ges 
A me n d me nt 6, Versi o n 7. 0  ( 0 4 Marc h 2 0 2 0) Gl o b al / S u m mar y of C ha n ges 
A me n d me nt 6, Versi o n 7. 1  ( 0 4 Marc h 2 0 2 0) Ja pa n/ S u m mar y of C ha n ges 
A me n d me nt 7, Versi o n 8. 0 ( 1 6 Dece m ber 2 0 2 0) Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 7, Versi o n 8. 0 ( 1 6 Dece m ber 2 0 2 0) Ger ma n y / S u m mar y of C ha n ges  
A me n d me nt 7, Versi o n 8. 1 ( 1 6 Dece m ber 2 0 2 0) Ja pa n / S u m mar y of C ha n g es 
A me n d me nt 7, Versi o n 8. 2 ( 2 6 Ma y 2 0 2 1)  Ger ma n y / S u m mar y of C ha n ges 
A me n d me nt 8, Versi o n 9. 0 ( 0 1 J ul y 2 0 2 1)  Gl o bal / S u mmar y of C ha n ges  
A me n d me nt 8, Versi o n 9. 1 ( 0 1 J ul y 2 0 2 1)  Ja pa n/ S u m mar y of C ha n ges 
A me n d me nt 8, Versi o n 9. 2 ( 0 1 J ul y 2 0 2 1)  Ger ma n y / S u m mar y of C ha n ges 
A me n d me nt 9, Versi o n 1 0. 0 ( 2 9 Se pte m ber 2 0 2 1)  Gl o bal / S u m mar y of C ha n ges 
A me n d me nt 9, Versi o n 1 0. 1 ( 2 9 Se pte m ber 2 0 2 1)  Ja pa n/ S u m mar y of C ha n ges 
A me n d me nt 9, Versi o n 1 0. 2 ( 2 9 Se pte m ber 2 0 2 1)  Ger ma n y / S u m mar y of C ha n ges 
A me n d me nt 9, Versi o n 1 0. 3  (0 3 N o ve m ber 2 0 2 1) ( Re p u blic of S o ut h K orea) / 
S u m mar y of C ha n ges  
 

1.
TI T L E P A G E
C LI NI C A L S T U D Y P R O T O C O L A G 1 2 0 -C -0 0 9
A P h ase 3, M ultice nter, D o u ble -Bli n d, R a n d o mize d, Pl ace b o -C o ntr olle d St u d y 
of A G -1 2 0 i n C o m bi n ati o n wit h Az aciti di ne i n S u bjects ≥1 8 Ye ars  of A ge wit h 
Pre vi o usl y U ntre ate d Ac ute M yel oi d Le u ke mi a wit h a n I D H 1 M ut ati o n  
St u d y S p o ns or:  
I nstit ut de Rec herc hes I nter nati o nales Ser vier (I. R.I. S.) 
5 0, r ue Car n ot  
9 2 2 8 4 S ures nes ce de x - Fra nce  
Me dical Direct or:  
, M D 
 
Ser vier P har mace uticals  L L C  
De p ut y Hea d:  
, M D, P h D 
 
I. R.I. S.
Me dical M o nit or:  
, M D 
 
Ser vier P har mace uticals  L L C  
E u dra C T N u m ber:  
2 0 1 6 -0 0 4 9 0 7 -3 0  
D oc u me nt Versi o n ( Date):  
Re vise d:  
Ori gi nal Pr ot oc ol, Versi o n 1. 0 ( 0 6 Ja n uar y 2 0 1 7)  
A me n d me nt 1, Versi o n 2. 0 ( 0 7 Fe br uar y 2 0 1 7) ( Gl o bal)  
A me n d me nt 2, Versi o n 3. 0 ( 2 4 Marc h 2 0 1 7) ( Gl o bal) 
A me n d me nt 3, Versi o n 4. 0 ( 1 4 A pril 2 0 1 7) ( Gl o bal)  
A me n d me nt 4, Versi o n 5. 0 ( 3 1 Oct o ber 2 0 1 7) ( Gl o bal)  
A me n d me nt 4, Versi o n 5. 1 ( 0 4 Dece m ber 2 0 1 7) (Ja pa n)  
A me n d me nt 4, Versi o n 5. 2 ( 2 3 A pril 2 0 1 8) (Ja pa n)  
A me n d me nt 4, Versi o n 5. 3 ( 1 1 Ja n uar y 2 0 1 9) ( Fra nce)  
A me n d me nt 4, Versi o n 5. 4 ( 3 0 Ma y 2 0 1 9) ( Ger ma n y)  
A me n d me nt 5, Versi o n 6. 0 ( 0 9 Ja n uar y 2 0 2 0) ( Gl o bal)  
A me n d me nt 5, Versi o n 6. 1 ( 0 9  Ja n uar y 2 0 2 0) (J a pa n) 
A me n d me nt 6, Versi o n 7. 0 ( 0 4  Marc h  2 0 2 0) ( Gl o bal)  
A me n d me nt 6, Versi o n 7. 1 ( 0 4 Marc h 2 0 2 0) ( Ja pa n) 
A me n d me nt 7, Versi o n 8. 0 ( 1 6 Dece m ber 2 0 2 0 ) ( Gl o bal) 
A me n d me nt 7, Versi o n 8. 1 ( 1 6 Dece m ber 2 0 2 0 ) (Ja pa n)  
A me n d me nt 7, Versi o n 8. 2 ( 2 6 Ma y 2 0 2 1) ( Ger ma n y)  
A me n d me nt 8, Versi o n 9. 0 ( 0 1 J ul y  2 0 2 1) ( Gl o bal)  
A me n d me nt 8, Versi o n 9. 1 ( 0 1 J ul y  2 0 2 1) (J a pa n)  
A me n d me nt 8, Versi o n 9. 2 ( 0 1 J ul y  2 0 2 1) ( Ger ma n y)   
A me n d me nt 9, Versi o n 1 0. 0 ( 2 9 Se pte m ber 2 0 2 1 ) ( Gl o bal) 
A me n d me nt 9, Versi o n 1 0. 1 ( 2 9 Se pte m ber 2 0 2 1 ) (J a pa n) 
A me n d me nt 9, Versi o n 1 0. 2 ( 2 9 Se pte m ber 2 0 2 1 ) ( Ger ma n y) 
SIGN

 
 
T his st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m plia nce wit h G o o d Cli nical Practice, t he 
et hical pri nci ples state d i n t he Declarati o n of Helsi n ki, a n d ot her a p plica ble re g ulat or y re q uire me nts.  
C O N FI D E N TI A L  

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
3 /1 3 2  
 
S p o ns or si g n at ories 
I, t he u n d ersi g ne d, h a ve rea d t he f ore g oi n g pr ot oc ol f or t he st u d y a n d a gree t o 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, G o o d Cli nical Practice, a n d t he a p plica ble re g ul at or y 
re q uire me nts. 
VI C E P R E SI D E N T, C LI NI C A L D E V E L O P M E N T:  
N A M E  
D A T E  
 
SI G N A T U R E  
 
1 0 / 7 / 2 0 2 1

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
4 /1 3 2  
 
C o ntr act u al si g n at ories  
I, t he u n d ersi g ne d, h a ve rea d t he f ore g oi n g pr ot oc ol f or t he st u d y a n d a gree t o 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, G o o d Cli nical Practice, a n d t he a p plica ble re g ul at or y 
re q uire me nts. 
H E A D, L A T E S T A G E A N D LI F E C Y C L E M A N A G E M E N T & D E P U T Y H E A D 
O N C O L O G Y & I M M U N O -O N C O L O G Y T H E R A P E U TI C A R E A : 
N A M E  
D A T E  
 
SI G N A T U R E  
 
1 0 / 5 / 2 0 2 1

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
5 /1 3 2  
 
S p o ns or si g n at ories 
I, t he u n d ersi g ne d, h a ve rea d t he f ore g oi n g pr ot oc ol f or t he st u d y a n d a gree t o 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, G o o d Cli nical Practice, a n d t he a p plica ble re g ul at or y 
re q uire me nts. 
BI O S T A TI S TI C S P R O G R A M H E A D O R D E SI G N E E:  
N A M E  
D A T E  
 
SI G N A T U R E  
 
1 0 / 5 / 2 0 2 1

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
6 /1 3 2  
 
C o ntr act u al si g n at ories  
I, t he u n d ersi g ne d, h a ve rea d t he f ore g oi n g pr ot oc ol f or t he st u d y a n d a gree t o 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, G o o d Cli nical Practice, a n d t he a p plica ble re g ul at or y 
re q uire me nts. 
I N V E S TI G A T O R 
N A M E  
 
SI T E N U M B E R  
 
D A T E  
 
SI G N A T U R E  
 
 
 

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
7 /1 3 2  
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  
Assess me nt of A me n d me nt 9 ( Versi o n 1 0 . 0) 
T his a me n d me nt is c o nsi dere d s u bsta ntial beca use it c ha n ges t he S p o ns or f or t he st u d y . 
T he rati o nale f or t he pr ot oc ol a me n d me nt is descri be d i n t he f oll o wi n g s ecti o n; a detaile d 
s u m mar y of t he a me n d m e nt c ha n ges is pr o vi de d i n a se parate d oc u m e nt. 
P ur p ose a n d R ati o n ale f or t he Pr ot oc ol A me n d me nt  
T he pri mar y p ur p os e f or t he pr ot oc ol a me n d me nt is t o c ha n ge t he S p o ns or f or t he st u d y. 

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
8 /1 3 2
2.
S Y N O P SI S
N a me of S p o ns or/ C o m p a n y:
I. R.I. S.
N a me of I n vesti g ati o n al Pr o d uct:  
A G -1 2 0 (I nter nati o nal N o n pr o prietar y Na me: i v osi de ni b) 
St u d y Title:
A P hase 3, M ultice nter, D o u ble -Bli n d, Ra n d o mize d, Place b o -C o ntr olle d St u d y of A G -1 2 0 i n 
C o m bi nati o n wit h Azaciti di ne i n S u bjects ≥1 8 Years of A ge wit h Pre vi o usl y U ntreate d Ac ute M yel oi d 
Le u ke mia  wit h a n I D H 1 M utati o n  
St u d y Ce nter(s):  
U p t o 1 9 0 st u d y ce nters i n 2 0 c o u ntries will partici pate i n t his st u d y.  
P h ase of De vel o p me nt: 3  
St u d y O bjecti ves:
P ri m ar y O bjecti ve:  
•
T o c o m pare e ve nt -free s ur vi val ( E F S) bet wee n A G-1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
Ke y Sec o n d ar y O bjecti ves:
•
T o c o m pare t he c o m plete re missi o n ( C R) rate bet wee n A G -1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
•
T o c o m pare o verall s ur vi val ( O S) bet wee n A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne.
•
T o c o m pare t he C R + c o m plete re missi o n wit h partial he mat ol o gic rec o ver y ( C R h) rate
bet wee n A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne; C R h will be deri ve d b y t he S p o ns or.
•
T o c o m pare t he o bjecti ve res p o nse rate ( O R R) bet wee n A G -1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
A d diti o n al Sec o n d ar y O bjecti ves:
•
T o c o m pare t he C R + C R wit h i nc o m plete he mat ol o gic rec o ver y ( C Ri) (i ncl u di n g C R wit h
i nc o m plete platelet rec o ver y [ C R p]) rate bet wee n A G-1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
•
T o c o m pare d urati o n of C R ( D O C R), d urati o n of C R + C R h ( D O C R h), d urati o n of res p o nse
( D O R), a n d d urati o n of C R + C Ri (i ncl u di n g C R p) ( D O C Ri) bet wee n A G-1 2 0 + azaciti di ne
a n d place b o + azaciti di ne.
•
T o c o m pare ti me t o C R ( T T C R), ti me t o C R + C R h ( T T C R h), ti me t o first res p o nse ( T T R),
a n d ti me t o CR + C Ri (i ncl u di n g C R p) ( T T C Ri) bet wee n A G -1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
•
T o assess t he safet y a n d t olera bilit y of treat me nt wit h A G -1 2 0 + azaciti di ne c o m p are d wit h
place b o + azaciti di ne.
•
T o c o m pare tra nsf usi o n re q uire me nts ( platelet a n d re d  bl o o d cell [ R B C]; n u m ber of u nits
tra nsf use d), i nfecti o n rates, da ys s pe nt h os pitalize d, a n d ot her efficac y a n d safet y meas ures t hat
are p ote ntiall y i n dicati ve of cli nical be nefit bet wee n A G -1 2 0 + azaciti di ne a n d place b o +
azaciti di ne.
•
T o assess t he i m pac t of treat me nt o n q ualit y of life ( Q o L) usi n g t he E ur o pea n Or ga nisati o n f or
Researc h a n d Treat me nt of Ca ncer ( E O R T C) Q L Q -C 3 0 a n d E Q -5 D -5 L.

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
9 /1 3 2  
 
•  
T o e val uate t he p har mac o ki netics ( P K) of A G -1 2 0 as a d mi nistere d i n c o m bi nati o n wit h 
azaciti di ne. 
•  
T o e val uate t he P K/ p har mac o d y na mic ( P D) relati o ns hi p of A G -1 2 0 a n d 2 -h y dr o x y gl utarate 
( 2-H G) i n bl o o d sa m ples i n c o m paris o n wit h place b o.  
•  
T o c o m pare rates of C R wit h I D H 1 m utati o n cleara nce ( M C) bet wee n A G -1 2 0 + azaciti di ne 
a n d place b o + azaciti di ne.  
 
 
 
  
 
 
Met h o d ol o g y:  
St u d y A G 1 2 0 -C -0 0 9 is a gl o bal, P hase 3, m ultice nter, d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d 
cli nical trial t o e val uate t he efficac y a n d safet y of A G -1 2 0 + azaciti di ne vs place b o + azaciti di ne i n 
a d ult s u bjects wit h pre vi o usl y u ntreate d is ocitrate de h y dr o ge nase 1 m utati o n -p ositi ve (I D H 1 m) A M L 
w h o are c o nsi dere d a p pr o priate ca n di dates f or n o n -i nte nsi ve t hera p y.  
F oll o wi n g pr o visi o n of si g ne d i nf or me d c o nse nt, all s u bj ects will u n der g o Scree ni n g pr oce d ures wit hi n 
4 wee ks ( 2 8 da ys) pri or t o ra n d o mizati o n t o deter mi ne eli gi bilit y. Ge ne m utati o n a nal ysis f or 
c o nfir mati o n of I D H 1 m disease fr o m a b o ne marr o w a n d ger m -li ne m utati o n a nal ysis fr o m a b uccal 
s wa b will be c o n d ucte d f or all s u bjects, a n d ca n be c o n d ucte d pri or t o t he 2 8 -da y Scree ni n g wi n d o w. 
Ce ntral la b orat or y c o nfir mati o n of I D H 1 m stat us is re q uire d f or st u d y eli gi bilit y. Wit h Me dical 
M o nit or a p pr o val, s u bjects ma y be eli gi ble a n d ra n d o mize d wit h l ocal I D H 1 m testi n g res ults; h o we ver, 
b o ne marr o w as pirate f or ce ntral la b orat or y testi n g m ust ha ve bee n se nt wit h pr o of of s hi p me nt t o t he 
ce ntral la b orat or y pri or t o ra n d o mizati o n. I n cases w here b o ne marr o w as pirate is n ot a vaila ble (ie, dr y 
ta p), peri p heral bl o o d sa m ples ma y be use d f or I D H 1 m c o nfir mati o n wit h Me dical M o nit or a p pr o val. 
A d diti o nal Scree ni n g pr oce d ures i ncl u de, b ut are n ot li mite d t o: me dical a n d me dicati o n hist or y; b o ne 
marr o w as pirate/ bi o ps y f or
 c o m plete p h ysical e xa mi nati o n; 
vital si g ns; 1 2 -lea d electr ocar di o gra m ( E C G); Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) 
perf or ma nce stat us ( P S); 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; n ot per mitte d 
f or s u bjects i n Ger ma n y) sca n f or left ve ntric ular ejecti o n fracti o n ( L V E F); cli nical la b orat or y 
assess me nts ( he mat ol o g y, c he mistr y, c oa g ulati o n, a n d  ser u m pre g na nc y test); Q o L assess me nts; a n d 
.  
S u bj ects eli gi ble f or st u d y treat me nt base d o n Scree ni n g assess me nts will be ra n d o mize d 1: 1 t o recei ve 
oral A G -1 2 0 or matc he d place b o, b ot h a d mi nistere d i n c o m bi nati o n wit h s u bc uta ne o us ( S C) or 
i ntra ve n o us (I V) azaciti di ne. Ra n d o mizati o n will be stratifie d b y de n o v o stat us ( de n o v o A M L a n d 
sec o n dar y A M L) a n d ge o gra p hic re gi o n ( U nite d States a n d Ca na da; Wester n E ur o pe, Israel, a n d 
A ustralia; J a pa n; a n d rest of w orl d).  
S u bj ects s h o ul d be treate d f or a mi ni m u m of 6 c ycles of c o m bi nati o n t hera p y u nless t he y e x perie nce 
rela pse after ac hie vi n g a C R, C Ri (i ncl u di n g C R p), or m or p h ol o gic le u ke mia-free state ( M L F S); 
disease pr o gressi o n after ha vi n g pre vi o usl y attai ne d partial re missi o n ( P R) or sta ble disease; 
u nacce pta ble t o xicit y (a d verse e ve nt [ A E]); c o nfir me d pre g na nc y; wit h dra wal b y s u bj ect; pr ot oc ol 
vi olati o n; deat h; or E n d of St u d y.  
Treat me nt will be a d mi nistere d as f oll o ws:  
•  
All s u bj ects will recei ve azaciti di ne 7 5 m g/ m 2/ da y S C or IV f or t he first 1 wee k ( 7  da ys) ( or o n 
a 5-2 -2 sc he d ule) of eac h 4 -wee k ( 2 8 -da y) c ycle i n c o m bi nati o n wit h A G -1 2 0 or place b o o nce 

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt  9 , Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
1 0 /1 3 2  
 
dail y ( Q D) o n eac h da y of t he 4 -wee k c ycle. T he sa me sc he d ule s h o ul d be use d f or eac h 
s u bj ect t hr o u g h o ut t he d urati o n of treatme nt, w he n p ossi ble.  
•  
S u bj ects s h o ul d c o nti n ue t o recei ve treat me nt wit h A G -1 2 0 or place b o + azaciti di ne u ntil deat h, 
disease rela pse, disease pr o gressi o n, de vel o p me nt of u nacce pta ble t o xicit y ( A E), c o nfir me d 
pre g na nc y, wit h dra wal b y s u bj ect, pr ot oc ol vi ola ti o n, or E n d of St u d y.  
− Disease pr o gressi o n ( defi ne d o nl y f or s u bjects w h o ha ve n ot pre vi o usl y attai ne d C R, 
C Ri, C R p, or M L F S ) is defi ne d as 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: 1) > 5 0 % i ncrease i n 
b o ne marr o w blast c o u nt o ver baseli ne (a mi ni m u m 1 5 % p oi nt i ncrease is re q 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 bs ol ute n e utr o p hil 
c o u nt ( A N C) t o a n a bs ol ute le vel ( >  0. 5 × 1 0 9/ L [ 5 0 0/ µ L] a n d/ or platelet c o u nt t o > 5 0 
× 1 0 9/ L [ 5 0, 0 0 0/ µ L] n o n-tra nsf use d); 2) > 5 0 % i ncrease i n peri p heral blasts ( w hite 
bl o o d cell c o u nt × % blasts) t o > 2 5, 0 0 0/ µ L i n t he a bse nce of treat me nt -relate d 
differe ntiati o n s y n dr o me; or 3) ne w e xtra me d ullar y disease.  
− S u bj ects wit h a res p o nse less t ha n C R at 2 4 wee ks or be y o n d ca n c o nti n ue o n 
treat me nt if de m o nstrati n g treat me nt be nefit, defi ne d as a n y 1 of t he f oll o wi n g: 1) 
Tra nsf usi o n -i n de pe n de nce w hile o n st u d y treat me nt; 2) A N C > 0. 5 × 1 09/ L ( 5 0 0/ µ L); 
or 3) platelet c o u nt > 5 0 × 1 0 9/ L ( 5 0, 0 0 0/ µ L). 
All s u bj ects will ha ve t he e xte nt of t heir disease assesse d b y b o ne marr o w as pirate (e xte nt of disease 
ma y be assesse d b y bi o ps y if sta n dar d of care or i n t he e ve nt  of a dr y ta p or as pic ular [ dil ute d] sa m ple) 
a n d peri p heral bl o o d sa m ples at Scree ni n g ( or as part of Pre -scree ni n g as l o n g as t he disease 
assess me nt falls wit hi n 2 8 da ys pri or t o ra n d o mizati o n); Da y 1 ( ± 7 da ys) of Wee ks  9, 1 7, 2 5, 3 3, 4 1, 
5 3, a n d e ver y 2 4  wee ks t hereafter; E n d of Treat me nt ( E O T); d uri n g E F S f oll o w -u p o n t he sa me 
sc he d ule; as cli nicall y i n dicate d; a n d/ or a n y ti me t hat disease pr o gressi o n is s us pecte d. T he disease 
assess me nt sc he d ule s h o ul d n ot be altere d d ue t o c ha n ges i n t he start of treat me nt c ycles (e g, i n t he 
case of a treat me nt i nterr u pti o n t hat res ulte d i n a dela y t o t he start of s u bse q ue nt c ycles).  
D uri n g treat me nt, res p o nse will be e val uate d b y t he I n vesti gat or base d o n m o difie d I nter nati o nal 
W or ki n g Gr o u p (I W G) Res p o nse Criteria f or  A M L a n d E ur o pea n Le u ke mia Net g ui deli nes t o 
deter mi ne s u bject stat us a n d c o nti n uati o n o n st u d y treat me nt. I n vesti gat or res p o nse assess me nts will be 
use d f or t he a nal ysis of all efficac y e n d p oi nts, u nless ot her wise defi ne d.  
All s u bj ects will u n der g o safet y  assess me nts t hr o u g h o ut t he treat me nt peri o d, t o i ncl u de p h ysical 
e xa mi nati o n, vital si g ns, E C O G P S, E C G, E C H O or M U G A f or L V E F as cli nicall y i n dicate d ( met h o d 
per i nstit uti o nal sta n dar d of care, wit h t he sa me met h o d use d f or a n i n di vi d ual s u bject t hr o u g h o ut t he 
st u d y; sites i n Ger ma n y ma y o nl y use E C H O), cli nical la b orat or y assess me nts ( he mat ol o g y, c he mistr y, 
a n d c oa g ulati o n), a n d assess me nt of A Es, A Es of s pecial i nterest ( A E SIs), seri o us A Es ( S A Es), A Es 
lea di n g t o disc o nti n uati o n or deat h, a n d c o nc o mita nt me dicati o n use. T o xicit y se verit y will be gra de d 
acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A Es versi o n  4. 0 3.  
Safet y data will be re vie we d re g ularl y b y a n I n de pe n de nt Data M o nit ori n g C o m mittee t o e ns ure t he 
safet y of t he c o m bi nati o n t hera p y. T hese re vie ws will occ ur after t he first 6, 1 2, 2 4, a n d 3 6  s u bjects 
ha ve c o m plete d 1 c ycle of t hera p y or disc o nti n ue d, w hic h e ver s h o ul d occ ur first. T hereafter, safet y 
re vie ws will be c o n d ucte d a p pr o xi matel y e ver y 6 m o nt hs u ntil t he st u d y is u n bli n de d f or a nal ysis of t he 
pri mar y e n d p oi nt.  
All s u bj ects are t o u n der g o a n E O T assess me nt wit hi n 1 wee k of t heir last d ose of st u d y t reat me nt 
( A G-1 2 0/ place b o + azaciti di ne). If a s u bject disc o nti n ues st u d y treat me nt at a re g ularl y sc he d ule d visit, 
E O T assess me nts ma y be perf or me d at t hat visit. A p ost -treat me nt safet y assess me nt is t o be sc he d ule d 
4  wee ks ( ±  3 da ys) after t he last d ose of st u d y treat me nt.  

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All s u bj ects w h o disc o nti n ue st u d y treat me nt wit h o ut e x perie nci n g a n y 1 of t he f oll o wi n g: deat h, 
disease rela pse, treat me nt fail ure, or wit h dra wal of c o nse nt, will be f oll o we d e ver y Da y 1 ( ± 7 da ys) of 
Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4 wee ks t hereafter f or E F S u ntil t he y e x perie nce treat me nt 
fail ure, rela pse, deat h, wit h dra w fr o m t he st u d y, or u ntil t he ti me w he n 1 7 3 E F S e ve nts ha ve occ urre d  
or as dee me d necessar y b y t he i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) .  
O nce t he st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue. All s u bjects w h o are ali ve after a n E F S 
e ve nt will be c o ntacte d e ver y 8 wee ks f or s ur vi val f oll o w -u p u ntil deat h, wit h dra wal b y s u bject, l oss t o 
f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 
P ri m ar y E n d p oi nt Res ults a n d S u bse q ue nt St u d y U n bli n di n g:  O nce t he pri mar y e n d p oi nt of E F S is 
statisticall y a nal yze d, t he S p o ns or will c o m m u nicate t he t o pli ne a g gre gate res ults of t he st u d y t o 
partici pati n g site i n vesti gat ors a n d via p u blic discl os ure. S h or tl y after p u blic discl os ure of t he t o pli ne 
a g gre gate res ults, t he S p o ns or will c o m m u nicate t o all sites t he treat me nt assi g n me nts of all s u bjects 
a n d will als o i nf or m sites w hic h of t he 2 f oll o wi n g sce nari os t o p urs ue f oll o wi n g u n bli n di n g.  
If t he be nefit -ris k pr ofile fa v ors treat me nt, all o n g oi n g s u bj ects ra n d o mize d t o recei ve place b o + 
azaciti di ne w h o meet ke y safet y eli gi bilit y criteria will be gi ve n t he o p p ort u nit y t o recei ve A G -1 2 0 + 
azaciti di ne f oll o wi n g u n bli n di n g. S u bjects w h o were alrea d y recei vi n g A G -1 2 0 + azaciti di ne  ma y 
c o nti n ue t o recei ve treat me nt o n t he sa me assess me nt sc he d ule. Pri or t o cr oss o ver t o A G -1 2 0, 
i n vesti gat ors will e val uate s u bj ects f or I ncl usi o n Criteria 5 a n d 6 a n d E xcl usi o n Criteria 8, 1 2, 1 3, a n d 
1 7 t o deter mi ne safet y eli gi bili t y. 
If t he be nefit -ris k pr ofile d oes n ot fa v or treat me nt, cr oss o ver will n ot be per mitte d; h o we ver, all 
o n g oi n g patie nts will be per mitte d t o recei ve t heir assi g ne d st u d y treat me nt at t he discreti o n of t he 
treati n g i n vesti gat or. 
Esti m ate d N u m ber of S u bjec ts ( pl a n ne d): 
A t otal of a p pr o xi matel y 2 0 0 s u bjects wit h pre vi o usl y u ntreate d I D H 1 m A M L will partici pate i n t he 
st u d y.  
I n vesti g ati o n al Pr o d uct, D os a ge, a n d M o de of A d mi nistr ati o n:  
A G -1 2 0 ( 5 0 0 m g) or matc he d place b o will be a d mi nistere d orall y Q D (a p pr o xi matel y e ver y 2 4 h o urs) 
d uri n g Wee ks 1 t o 4 i n c o nti n u o us 4 -wee k ( 2 8 -da y) c ycles. S u bjects ma y ta ke A G -1 2 0 or place b o 
ta blets wit h or wit h o ut f o o d. S u bj ects s h o ul d be a d vise d t hat if A G-1 2 0/ place b o ta blets are ta ke n wit h 
f o o d, t he y s h o ul d a v oi d c o nsu mi n g a hi g h -fat meal. All s u bjects will als o be a d vise d t o a v oi d gra pefr uit 
a n d gra pefr uit pr o d ucts.  
Azaciti di ne will be a d mi nistere d S C or I V at a d ose of 7 5 m g/ m 2/ da y f or 1 wee k e ver y 4 wee ks u ntil 
t he e n d of t he st u d y ( u nless t he y are disc o nti n ue d fr o m treat me nt), starti n g o n Da y 1 ( ± 3 da ys). I n t he 
e ve nt t hat 2 or fe wer d oses are misse d d uri n g t he 7 -da y d osi n g peri o d, d osi n g s h o ul d c o nti n ue s o t hat 
t he s u bject recei ves t he f ull 7 da ys of t hera p y. If 3 or m ore d oses are misse d d uri n g t he 7 -da y d osi n g 
p eri o d, t he I n vesti gat or s h o ul d c o ntact t he Me dical M o nit or a n d a decisi o n o n d osi n g will be ma de o n 
a n i n di vi d ual case basis. A f ull 7 da ys of azaciti di ne are re q uire d, b ut as per i nstit uti o nal practice, a 
sc he d ule of 5 da ys of dail y d osi n g, f oll o we d b y n o d ose recei ve d o n t he wee ke n d a n d 2 dail y d oses 
gi ve n a gai n at t he start of t he ne xt wee k, is all o we d. T he sa me sc he d ule s h o ul d be use d f or eac h s u bject 
t hr o u g h o ut t he d urati o n of treat me nt, w he n p ossi ble. 
O n da ys w he n b ot h A G -1 2 0/ place b o a n d azaciti di ne a re gi ve n, A G-1 2 0 or place b o will be gi ve n pri or 
t o azaciti di ne. 

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Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
I ncl usi o n Criteri a: 
S u bj ects m ust meet all of t he f oll o wi n g criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y:  
1.  Be ≥1 8 years of a ge a n d meet at least 1 of t he f oll o wi n g criteria defi ni n g i neli gi bilit y f or 
i nte nsi ve i n d ucti o n c he m ot hera p y (I C):  
a. ≥ 7 5 years ol d  
b.  E C O G P S = 2  
c. Se vere car diac dis or der (e g, c o n gesti ve heart fail ure re q uiri n g treat me nt, L V E F ≤5 0 %, or 
c hr o nic  sta ble a n gi na) 
d.  Se vere p ul m o nar y dis or der (e g, diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de ≤6 5 % 
or f orce d e x pirat or y v ol u me i n 1 sec o n d ≤6 5 %)  
e. Creati ni ne cleara nce < 4 5 m L/ mi n ute  
f. Bilir u bi n > 1. 5 ti mes u p per li mit of n or mal ( × U L N)  
g.  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 I C 
m ust be re vie we d a n d a p pr o ve d b y t he Me dical M o nit or bef ore st u d y e nr oll me nt.  
2.  Ha ve pre vi o usl y u ntreate d A M L, defi ne d acc or di n g t o W orl d Healt h Or ga nizati o n criteria. 
S u bj ects wit h e xtra me d ullar y disease al o ne (ie, n o detecta ble b o ne marr o w a n d n o detecta ble 
peri p heral bl o o d A M L) are n ot eli gi ble f or t he st u d y.  
3.  Ha ve a n I D H 1 m utati o n res ulti n g i n a n R 1 3 2 C, R 1 3 2 G, R 1 3 2 H, R 1 3 2 L, or R 1 3 2 S s u bstit uti o n, 
as deter mi ne d b y ce ntral la b orat or y testi n g  ( usi n g a n i n vesti gati o nal p ol y merase c hai n reacti o n 
[ P C R] assa y, A b b ott Real Ti me I D H 1) i n t heir b o ne marr o w as pirate ( or peri p heral bl o o d 
sa m ple if b o ne marr o w as pirate is n ot a vaila ble, wit h Me dical M o nit or a p pr o val). 
( N ote: L ocal testi n g f or eli gi bilit y a n d ra n d o mizati o n is per mitte d wit h Me dical M o nit or 
a p pr o val; h o we ver, res ults m ust state a n I D H 1 m utati o n res ulti n g i n a n R 1 3 2 C, R 1 3 2 G, 
R 1 3 2 H, R 1 3 2 L, or R 1 3 2 S s u bstit uti o n. B o ne marr o w as pirate [ or peri p heral bl o o d sa m ple if 
b o ne marr o w as pirate is n ot a vaila ble , wit h Me dical M o nit or a p pr o val] f or ce ntral la b orat or y 
testi n g m ust ha ve bee n se nt wit h pr o of of s hi p me nt t o t he ce ntral la b orat or y pri or t o 
ra n d o mizati o n.) 
4.  Ha ve a n E C O G P S sc ore of 0 t o 2.  
5.  Ha ve a de q uate he patic f u ncti o n, as e vi de nce d b y:  
a. Ser u m t otal bilir u bi n ≤2 ×  U L N, u nless c o nsi dere d t o be d ue t o Gil bert’s disease or 
u n derl yi n g le u ke mia, w here it m ust be < 3 × U L N.  
b.  As partate a mi n otra nsferase ( A S T), ala ni ne a mi n otra nsferase ( A L T), a n d al kali ne 
p h os p hatase ( A L P) ≤3. 0  ×  U L N, u nless c o nsi de re d t o be d ue t o u n derl yi n g le u ke mia. 
6.  Ha ve a de q uate re nal f u ncti o n, as e vi de nce d b y ser u m creati ni ne ≤2. 0  ×  U L N or creati ni ne 
cleara nce 3 0 m L/ mi n base d o n t he C oc kcr oft -Ga ult gl o mer ular filtrati o n rate.  
7.  Ha ve a gree d t o u n der g o serial bl o o d a n d b o ne marr o w sa m pli n g. 
8.  Be a ble t o u n dersta n d a n d willi n g t o si g n a n i nf or me d c o nse nt f or m.  
9.  Be willi n g t o c o m plete Q o L assess me nts d uri n g st u d y treat me nt a n d at t he desi g nate d ti me 
p oi nts f oll o wi n g treat me nt disc o nti n uati o n.  
1 0.  If fe male wit h re pr o d ucti ve p ote ntial, m ust ha ve a ne gati ve ser u m pre g na nc y test pri or t o t he 
start of st u d y t hera p y. Fe male s u bjects wit h re pr o d ucti ve p ote ntial are defi ne d as se x uall y 
mat ure w o me n w h o ha ve n ot u n der g o ne a h ysterect o m y, bilateral o o p h orec t o m y, or t u bal 
occl usi o n or w h o ha ve n ot bee n nat urall y p ost me n o pa usal f or at least 2 4  c o nsec uti ve m o nt hs. 

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Fe males of re pr o d ucti ve p ote ntial, as well as fertile me n wit h fe male part ners of re pr o d ucti ve 
p ote ntial, m ust use 2 effecti ve f or ms of c o ntrace pti o n  (i ncl u di n g at least 1 barrier f or m) fr o m 
t he ti me of gi vi n g i nf or me d c o nse nt t hr o u g h o ut t he st u d y a n d f or 9 0 da ys ( b ot h fe males a n d 
males) f oll o wi n g t he last d ose of st u d y dr u g(s). Effecti ve f or ms of c o ntrace pti o n are defi ne d as 
h or m o nal oral c o ntrace pti v es, i njecta bles, patc hes, i ntra uteri ne de vices, i ntra uteri ne h or m o ne -
releasi n g s yste ms, bilateral t u bal li gati o n, c o n d o ms wit h s per mici de, or male part ner 
sterilizati o n. C oa d mi nistrati o n of A G-1 2 0 ma y decrease t he c o nce ntrati o ns of h or m o nal 
c o ntrace pti ves. 
E xcl usi o n Criteri a:  
S u bj ects w h o meet a n y of t he f oll o wi n g criteria will be e xcl u de d fr o m t he st u d y:  
1.  Are ca n di dates f or i nte nsi ve I C f or t heir A M L.  
2.  Ha ve recei ve d a n y pri or treat me nt f or A M L wit h t he e xce pti o n of n o n o nc ol ytic treat me nts t o 
sta bilize disease s uc h as h y dr o x y urea or le u ka p heresis.  
3.  Ha ve recei ve d a h y p o met h ylati n g a ge nt f or m yel o d ys plastic s y n dr o me ( M D S).  
4.  S u bj ects w h o ha d pre vi o usl y recei ve d treat me nt f or a n a ntece de nt he mat ol o gic dis or der, 
i ncl u di n g i n vesti gati o nal a ge nts, ma y n ot be ra n d o mize d u ntil a was h o ut peri o d of at least 
5  half -li ves of t he i n vesti gati o nal a ge nt has ela pse d si nce t he last d ose of t hat a ge nt.  
5.  Ha ve recei ve d pri or treat me nt wit h a n I D H 1 i n hi bit or.  
6.  Ha ve a k n o w n h y perse nsiti vit y t o a n y of t he c o m p o ne nts of A G -1 2 0,  matc he d place b o, or 
azaciti di ne. 
7.  Are fe male a n d pre g na nt or breastfee di n g.  
8.  Are ta ki n g k n o w n str o n g c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 i n d ucers or se nsiti ve C Y P 3 A 4 
s u bstrate me dicati o ns wit h a narr o w t hera pe utic wi n d o w, u nless t he y ca n be tra nsferre d t o 
ot her me dic ati o ns wit hi n ≥5 half -li ves pri or t o d osi n g.  
9.  E xcl usi o n Criteri o n # 9 was re m o ve d i n Pr ot oc ol A me n d me nt 5, Versi o n 6. 0.  
1 0.  Ha ve a n acti ve, u nc o ntr olle d, s yste mic f u n gal, bacterial, or viral i nfecti o n wit h o ut 
i m pr o ve me nt des pite a p pr o priate a nti bi otics, a nti viral t hera p y, a n d/ or ot her treat me nt. 
1 1.  Ha ve a pri or hist or y of mali g na nc y ot her t ha n M D S or m yel o pr oliferati ve dis or der, u nless t he 
s u bj ect has bee n free of t he disease f or ≥1 year pri or t o t he start of st u d y treat me nt. H o we ver, 
s u bj ects wit h t he f oll o wi n g hist or y/c o nc urre nt c o n diti o ns or si milar i n d ole nt ca ncer are all o we d 
t o partici pate i n t he st u d y: 
a. Basal or s q ua m o us cell carci n o ma of t he s ki n  
b.  Carci n o ma i n sit u of t he cer vi x  
c. Carci n o ma i n sit u of t he breast  
d.  I nci de ntal hist ol o gic fi n di n g of pr ostate ca ncer 
1 2.  H a ve ha d si g nifica nt acti ve car diac disease wit hi n 6 m o nt hs pri or t o t he start of st u d y 
treat me nt, i ncl u di n g Ne w Y or k Heart Ass ociati o n Class ( N Y H A) Class III or I V c o n gesti ve 
heart fail ure, m y ocar dial i nfarcti o n, u nsta ble a n gi na, a n d/ or str o ke.  
1 3.  Ha ve a hea rt-rate c orrecte d Q T i nter val usi n g Fri dericia’s met h o d ( Q T c F) ≥4 7 0 msec or a n y 
ot her fact or t hat i ncreases t he ris k of Q T pr ol o n gati o n or arr h yt h mic e ve nts (e g, N Y H A Class 
III or I V c o n gesti ve heart fail ure, h y p o kale mia, fa mil y hist or y of l o n g Q T i nter val s y n dr o me). 
S u bj ects wit h pr ol o n ge d Q T c F i nter val i n t he setti n g of b u n dle bra nc h bl oc k ma y partici pate i n 
t he st u d y. 

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1 4.  Ha ve a k n o w n i nfecti o n ca use d b y h u ma n i m m u n o deficie nc y vir us or acti ve he patitis B vir us 
( H B V) or he patitis C vir us t hat ca n n ot be c o ntr olle d b y treat me nt.  
1 5.  Ha ve d ys p ha gia, s h ort -g ut s y n dr o me, gastr o paresis, or a n y ot her c o n diti o n t hat li mits t he 
i n gesti o n or gastr oi ntesti nal a bs or pti o n of orall y a d mi nistere d dr u gs.  
1 6.  Ha ve u nc o ntr olle d h y perte nsi o n (s yst olic bl o o d press ure [ B P] > 1 8 0  m m H g or diast olic B P 
> 1 0 0  m m H g).  
1 7.  Ha ve cli nical s y m pt o ms s u g gesti ve of acti ve ce ntral ner v o us s yste m ( C N S) le u ke mia or k n o w n 
C N S le u ke mia. E val uati o n of cere br os pi nal fl ui d d uri n g Scree ni n g is o nl y re q uire d if t here is a 
cli nical s us pici o n of C N S i n v ol ve me nt b y le u ke mia d uri n g Scree ni n g.  
1 8.  Ha ve i m me diate, life -t hreate ni n g, se vere c o m plicati o ns of le u ke mia, s uc h as u nc o ntr olle d 
blee di n g, p ne u m o nia wit h h y p o xia or se psis, a n d/ or disse mi nate d i ntra vasc ular c oa g ulati o n.  
1 9.  Ha ve a n y ot her me dical or ps yc h ol o gical c o n di ti o n dee me d b y t he I n vesti gat or t o be li kel y t o 
i nterfere wit h t he s u bject’s a bilit y t o gi ve i nf or me d c o nse nt or partici pate i n t he st u d y. 
2 0.  Are ta ki n g me dicati o ns t hat are k n o w n t o pr ol o n g t he Q T i nter val u nless t he y ca n be 
tra nsferre d t o ot her me dicati o ns wit hi n ≥5 half -li ves pri or t o d osi n g, or u nless t he me dicati o ns 
ca n be pr o perl y m o nit ore d d uri n g t he st u d y. (If e q ui vale nt me dicati o n is n ot a vaila ble, heart 
rate c orrecte d Q T i nter val [ Q T c] will be cl osel y m o nit ore d.) 
2 1.  S u bj ects wit h a k n o w n me dical hist or y  of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y.  
D ur ati o n of Tre at me nt a n d E n d of St u d y:  
D ur ati o n of Tre at me nt  
Dail y treat me nt wit h A G -1 2 0 + azaciti di ne or place b o + azaciti di ne will be gi n o n t he first da y of 
C ycle  1. S u bjects s h o ul d be treate d f or a mi ni m u m of si x 4 -wee k ( 2 8 -da y) c ycles of c o m bi nati o n 
t hera p y. Wit h Me dical M o nit or a p pr o val, s u bjects ma y c o nti n ue to recei ve:  
•  
A G -1 2 0 or place b o f oll o wi n g disc o nti n uati o n of azaciti di ne, pr o vi de d t hat t he y are i n C R or 
C Ri (i ncl u di n g C R p) a n d nee d t o disc o nti n ue azaciti di ne d ue t o pr ot oc ol -s pecifie d 
azaciti di ne -relate d t o xicit y (e g, dela ye d b o ne marr o w rec o ver y), or  
•  
A zaciti di ne f oll o wi n g disc o nti n uati o n of A G -1 2 0 or place b o, pr o vi de d t hat t he y ha ve n ot met 
t he defi niti o n of rela pse or pr o gressi ve disease.  
S u bj ects s h o ul d c o nti n ue t o recei ve st u d y treat me nt u ntil disease rela pse, disease pr o gressi o n, 
de vel o p me nt of a n u nacce pta ble t o xicit y ( A E), c o nfir me d pre g na nc y, wit h dra wal b y s u bject, pr ot oc ol 
vi olati o n, deat h, or E n d of St u d y.  
S u bj ects wit h a res p o nse less t ha n C R at 2 4 wee ks or be y o n d ca n c o nti n ue o n treat me nt if 
de m o nstrati n g treat me nt be nefit, defi ne d as a n y 1 of t he f oll o wi n g: 1) Tra nsf usi o n -i n de pe n de nce w hile 
o n st u d y treat me nt; 2) A N C > 0. 5 × 1 0 9/ L ( 5 0 0/ µ L); or 3) platelets > 5 0 × 1 09/ L ( 5 0, 0 0 0/ µ L).  
E F S F oll o w -u p  
All s u bj ects w h o disc o nti n ue st u d y treat me nt wit h o ut e x perie nci n g a n y 1 of t he f oll o wi n g: deat h, 
d isease rela pse, treat me nt fail ure, or wit h dra wal of c o nse nt , will be f oll o we d e ver y Da y 1 ( ± 7 da ys) of 
Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4 wee ks t hereafter f or E F S u ntil t he y e x perie nce treat me nt 
fail ure, rela pse, deat h, wit h dra w fr o m t he st u d y, or u ntil t he ti me w he n 1 7 3 E F S e ve nts ha ve occ urre d  
or as dee me d necessar y b y t he I D M C . 
S urviv al F oll o w -u p  
O nce t he st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue.  All s u bjects w h o are ali ve after a n E F S 
e ve nt will be c o ntacte d e ver y 8 wee ks f or s ur vi val f oll o w -u p u ntil deat h, wit h dra wal b y s u bject, l oss t o 
f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 

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E n d of St u dy  
At t he ti me of t he pri mar y e n d p oi nt a nal ysis (a p pr o xi matel y 1 7 3 E F S e ve nts  or as dee me d necessar y b y 
t he I D M C), t he st u d y will be u n bli n de d. S u bjects o n treat me nt at t hat ti me ma y c o nti n ue recei vi n g 
st u d y dr u g. After t he pri mar y e n d p oi nt a nal ysis, a n d if t he be nefit -ris k pr ofile fa v ors treat me nt, s u bj ects 
ra n d o mize d t o place b o ma y be offere d t he c h oice t o recei ve acti ve A G-1 2 0. E n d of St u d y is defi ne d as 
t he ti me at w hic h all s u bjects ha ve die d, disc o nti n ue d t he st u d y, are l ost t o f oll o w-u p, or ha ve 
wit h dra w n c o nse nt; or w he n t he S p o ns or e n ds t he st u d y.  
St u d y Assess me nts: See Sc he d ule of Assess me nts i n b o d y of pr ot oc ol.  
Criteri a f or E v al u ati o n:  
D uri n g treat me nt, res p o nse will be e val uate d b y t he I n vesti gat or base d o n m o difie d I W G Res p o nse 
Criteria f or A M L a n d E ur o pea n Le u ke mia Net g ui deli nes t o deter mi ne s u bject stat us a n d c o nti n uati o n 
o n st u d y treat me nt; C R h will be deri ve d b y t he S p o ns or.  
P ri m ar y E n d p oi nt:  
T he pri mar y e n d p oi nt of t he st u d y is E F S, w hic h is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil 
treat me nt fail ure, rela pse fr o m re missi o n, or deat h fro m a n y ca use, w hic he ver occ urs first. Treat me nt 
fail ure is defi ne d as fail ure t o ac hie ve C R b y Wee k 2 4. 
Ke y Sec o n d ar y E n d p oi nts:  
•  
C R rate ( C R defi ne d as b o ne marr o w blasts < 5 % a n d n o 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 [ 1 0 0 0/ µ L], platelet c o u nt ≥1 0 0 × 1 0 9/ L [ 1 0 0, 0 0 0/ µ L], a n d 
i n de pe n de nce of R B C tra nsf usi o ns). 
•  
O S, defi ne d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h d ue t o a n y ca use.  
•  
C R + C R h rate ( C R h is defi ne d as a C R wit h partial rec o ver y of peri p heral bl o o d c o u n ts w here 
A N C is > 0. 5 × 1 0 9/ L [ 5 0 0/ µ L], a n d platelet c o u nt is > 5 0 × 1 09/ L [ 5 0, 0 0 0/ µ L]; C R h will be 
deri ve d b y t he S p o ns or).  
•  
O R R, defi ne d as t he rate of C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S.  
A d diti o n al Sec o n d ar y E n d p oi nts:  
•  
C R + C Ri (i ncl u di n g C R p) rate ( C R i [i ncl u di n g C R p] is defi ne d as all C R criteria e xce pt f or 
resi d ual ne utr o pe nia w here A N C is < 1. 0 × 1 09/ L [ 1 0 0 0/ µ L] or t hr o m b oc yt o pe nia w here 
platelet c o u nt is < 1 0 0  ×  1 0 9/ L [ 1 0 0, 0 0 0/ µ L]; wit h o ut platelet tra nsf usi o n f or at least 1 wee k 
pri or t o disease ass ess me nt).  
•  
D O C R, a m o n g s u bjects w h o ac hie ve d C R; D O C R h, a m o n g s u bjects w h o ac hie ve d C R or C R h; 
D O R, a m o n g s u bjects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, a n d/ or M L F S; a n d D O C Ri, 
a m o n g s u bj ects w h o ac hie ve d C R or C Ri (i ncl u di n g C R p).  
•  
T T C R, a m o n g s u bj ects w h o ac hie ve d C R; T T C R h, a m o n g s u bjects w h o ac hie ve d C R or C R h; 
T T R, a m o n g s u bj ects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, a n d/ or M L F S; a n d T T C Ri, 
a m o n g s u bj ects w h o ac hie ve d C R or C Ri (i ncl u di n g C R p).  
•  
Vital si g ns, a n d t he res ults of E C O G P S, E C G, a n d E C H O or M U G A f or L V E F as cli nicall y 
i n dicate d ( met h o d per i nstit uti o nal sta n dar d of care, wit h t he sa me met h o d use d f or a n 
i n di vi d ual s u bject t hr o u g h o ut t he st u d y; sites i n Ger ma n y ma y o nl y use E C H O). 
•  
Cli nical la b orat or y assess me nts ( he mat ol o g y, c he mistr y, a n d c oa g ulati o n).  
•  
A Es, A E SIs, S A Es, a n d A Es lea di n g t o disc o nti n uati o n or deat h.  
•  
C o nc o mita nt me dicati o n use.  

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•  
Tra nsf usi o n re q uire me nts ( platelet a n d R B C; n u m ber of u nits tra nsf use d), rates of i nfecti o n, 
da ys s pe nt h os pitalize d, a n d ot her efficac y a n d safet y meas ures t hat are p ote ntiall y i n dicati ve 
of cli nical be nefit.  
•  
C ha n ges fr o m baseli ne i n Q o L assess me nts ( E O R T C Q L C -C 3 0 a n d E Q -5 D -5 L).  
•  
Rates of C R wit h I D H 1 M C.  
•  
A G -1 2 0/ place b o a n d azaciti di ne dr u g e x p os ure, i ncl u di n g d ose m o dificati o ns a n d d ose 
i nte nsities. 
•  
A G -1 2 0 a n d 2 -H G c o nce ntrati o ns i n circ ulati n g plas ma.  
 
 
 
St atistic al Met h o ds:  
Ge ner al St atistic al Met h o ds:  
S u m maries will be pr o d uce d f or s u bject dis p ositi o n, de m o gra p hic a n d baseli ne disease c haracteristics, 
efficac y, safet y, P K, a n d P D, as a p pr o priate. Cate g orical data will be s u m marize d b y fre q ue nc y 
distri b uti o ns ( n u m bers a n d pe rce nta ges of s u bjects). C o nti n u o us data will be s u m marize d b y 
descri pti ve statistics ( mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m). Ti me -t o-e ve nt 
e n d p oi nts will be esti mate d usi n g t he Ka pla n -Meier ( K M) met h o d. P oi nt esti mates a n d 9 5 % c o nfi de nce 
i nter vals ( CIs) will be pr o vi de d w here a p pr o priate, a n d esti mates of t he me dia n a n d ot her q ua ntiles, as 
well as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h rates) will be pr o d uce d.  
A n al ysis f or t he P ri m ar y E n d p oi nt  
E ve nt -free s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil treat me nt fail ure, rela pse fr o m 
re missi o n, or deat h fr o m a n y ca use, w hic he ver occ urs first. Treat me nt fail ure is defi ne d as fail ure t o 
ac hie ve C R b y Wee k 2 4. S u bj ects w h o d o n ot ac hie ve C R b y Wee k 2 4 will be c o nsi dere d t o ha ve ha d 
a n e ve nt at Da y 1 of ra n d o mizati o n. F or t he re mai ni n g C R res p o n ders, t he e ve nt ti me will be t he ti me 
of eit her disease rela pse or deat h, w hic he ver occ urs first. E ve nt -free s ur vi val will be ce ns ore d u p o n 
i nitiati o n of a ne w a ntica ncer t hera p y s h o uld a ne w t hera p y be i nitiate d pri or t o a n y E F S e ve nt.  
Se nsiti vit y a nal yses will be perf or me d t o e x pl ore t he r o b ust ness of t he pri mar y a nal ysis res ults a n d will 
i ncl u de a n a nal ysis base d o n t he stratifie d l o g-ra n k test f oll o wi n g t he Inte nt -t o-Treat pri nci ple , w here 
t he ti me of rela pse or deat h is deter mi ne d usi n g t he act ual date of rela pse or deat h wit h o ut ce ns ori n g 
f or missi n g disease assess me nts or start of s u bse q ue nt a ntica ncer t hera p y. 
N o i nteri m a nal yses f or efficac y are pla n ne d. T he a nal ysis f or t he pri mar y e n d p oi nt E F S will be 
perf or me d at t he ti me w he n 1 7 3 E F S e ve nts ha ve occ urre d  or as dee me d necessar y b y t he I D M C . 
E ve nt -free s ur vi val will be teste d usi n g t he l o g-ra n k test stratifie d b y t he ra n d o mizati o n stratificati o n 
fact ors ( de n o v o stat us a n d ge o gra p hic re gi o n). T he basis f or a clai m of efficac y will be t he statistical 
si g nifica nce of E F S i n fa v or of t he A G-1 2 0 + azaciti di ne ar m w he n t he 1 -si de d p ≤0. 0 2 5 ( o bser ve d E F S 
hazar d rati o [ H R] ≤0. 7 4 2).  
T he distri b uti o n of E F S will be esti mate d usi n g t he K M met h o d. T he K M c ur ves a n d 2 5
t h, 5 0t h 
( me dia n), a n d 7 5t h perce ntiles (if esti ma ble), al o n g wit h t heir 2 -si de d 9 5 % CIs, will be prese nte d f or 
eac h treat me nt ar m. T he K M esti mates at i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h rates) will be 
prese nte d f o r eac h treat me nt ar m. A C o x re gressi o n m o del stratifie d b y ra n d o mizati o n stratificati o n 
fact ors will als o be use d t o esti mate t he H R of E F S. H o we ver, gi ve n t hat t he ass u m pti o n of 
pr o p orti o nal hazar ds is n ot met base d o n t he E F S defi niti o n, t he o verall H R i s less mea ni n gf ul i n t his 
c o nte xt. As E F S is a c o m p osite e n d p oi nt, t he esti mates prese nte d se paratel y b y eac h c o m p o ne nt are 
m ore mea ni n gf ul: C R rate b y 2 4 wee ks a n d E F S a m o n g s u bjects w h o ac hie ve d C R b y 2 4 wee ks. F or 
s u bj ects w h o ac hie ve C R b y 2 4 wee ks, t he K M c ur ves of t he E F S distri b uti o n a n d 2 5 t h, 5 0t h ( me dia n), 
a n d 7 5 t h perce ntiles (if esti ma ble) al o n g wit h t heir 2 -si de d 9 5 % CIs will be prese nte d f or eac h treat me nt 

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ar m. A C o x re gressi o n m o del stratifie d b y ra n d o mizati o n stratificati o n fact ors will als o be use d t o 
esti mate t he H R of E F S f or t hese s u bjects.  
It is ass u me d t hat t he C R rate b y 2 4 wee ks is 2 0 % a n d 4 0 % f or t he place b o + azaciti di ne ar m a n d t he 
A G -1 2 0 + azaciti di ne ar m, res pecti vel y. F or s u bjects w h o ac hie ve d C R b y 2 4 wee ks, a tar get H R of 
0. 7 6 is ass u me d f or E F S (e q ui vale nt t o a me dia n E F S a m o n g res p o n ders of 1 4. 6 m o nt hs i n t he place b o 
+ azaciti di ne ar m vs 1 9. 2 m o nt hs i n t he A G -1 2 0 + azaciti di ne ar m, ass u mi n g a n e x p o ne ntial 
distri b uti o n). U n der t hese ass u m pti o ns, a t otal of 1 7 3 E F S e ve nts are re q uire d t o pr o vi de 8 0 % p o wer at 
a 1-si de d al p ha of 0. 0 2 5 le vel of si g nifica nce t o reject t he n ull h y p ot hesis usi n g a stratifie d l o g -ra n k 
test. Ass u mi n g a recr uit me nt peri o d of a p pr o xi matel y 4 4 m o nt hs, wit h a n accr ual rate of 3 s u bjects per 
m o nt h d uri n g t he first 1 0 m o nt hs a n d 5 s u bjects per m o nt h t hereafter, al o n g wit h a n ass u me d 5 % 
o verall dr o p o ut rate, a p pr o xi matel y 2 0 0 s u bjects will be ra n d o mize d t o t he 2 treat me nt ar ms i n a 
1: 1  rati o. Gi ve n t he a b o ve ass u m pti o ns, it is esti mate d t hat t he a nal ysis of t he pri mar y e n d p oi nt f or E F S 
will occ ur a p pr o xi matel y 5 2 m o nt hs after t he first s u bject was ra n d o mize d.  
Ke y Sec o n d ar y E n d p oi nt A n al yses:  
C o m plete re missi o n rate is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a C R. A C oc hra n 
Ma ntel -Hae nszel ( C M H) test wil l be use d t o c o m pare C R rate bet wee n t he 2 treat me nt ar ms. A l o gistic 
re gressi o n m o del will be use d t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o 
a n d its ass ociate d 9 5 % CIs will be prese nte d.  
O verall s ur vi val is defi ne d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h d ue t o a n y ca use. 
Ka pla n -Meier c ur ves a n d K M esti mates of O S will be prese nte d f or eac h treat me nt ar m, i ncl u di n g 
esti mates of t he me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h 
rates). T he l o g-ra n k test stratifie d b y t he ra n d o mizati o n fact ors will be use d t o c o m pare O S bet wee n t he 
2 treat me nt ar ms. T he H R of O S wit h a 9 5 % CI c o m pari n g t he A G -1 2 0 + azaciti di ne  ar m wit h t he 
place b o + azaciti di ne  ar m will be esti mate d fr o m a C o x pr o p orti o nal hazar ds m o del stratifie d b y t he 
ra n d o mizati o n stratificati o n fact ors. 
T he C R + C R h rate is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d a C R or C R h. C R h is defi ne d 
as ha vi n g all C R criteria e xce pt t hat A N C is > 0. 5 × 1 0 9/ L ( 5 0 0/ µ L) a n d platelet c o u nt is > 5 0 × 1 09/ L 
( 5 0, 0 0 0/ µ L). Beca use C R h is n ot part of m o difie d I W G res p o nse criteria, it will be deri ve d b y S p o ns or. 
A C M H test will be use d t o c o m pare t he C R + C R h rate bet wee n t he 2  treat me nt ar ms. A l o gistic 
re gressi o n m o del will be use d t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o 
a n d its ass ociate d 9 5 % CIs will be prese nte d.  
O bjecti ve res p o nse rate is defi ne d as t he rate of C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S. T he best 
res p o nse is calc ulate d usi n g t he f oll o wi n g hierarc h y: 1) C R; 2) C Ri (i ncl u di n g C R p); 3) P R; a n d 4) 
M L F S. A s u m mar y of best res p o nse b y treat me nt ar m will be pr o d uce d. A C M H test will be use d t o 
c o m pare O R R bet wee n t he 2 treat me nt ar ms. A l o gistic re gressi o n m o del will be use d t o  esti mate t he 
treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o a n d its ass ociate d 9 5 % CIs will be prese nte d. 
A d diti o n al Sec o n d ar y E n d p oi nt A n al yses:  
A C M H test will be use d t o c o m pare t he C R + C Ri (i ncl u di n g C R p) rate bet wee n t he 2 treat me nt ar ms . 
A l o gistic re gressi o n m o del will be use d t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he 
o d ds rati o a n d its ass ociate d 9 5 % CIs will be prese nte d. Ka pla n -Meier met h o ds will be use d t o esti mate 
D O C R, D O C R h, D O R, a n d D O C Ri; s u bjects wit h o ut rela pse, disease pr o gressi o n, or deat h, as 
a p pr o priate, at t he ti me of a nal ysis will be ce ns ore d at t he last res p o nse assess me nt date. Ka pla n -Meier 
esti mates of D O C R, D O C R h, D O R, a n d D O C Ri will be prese nte d b y treat me nt ar m, i ncl u di n g 
esti mates of t he me di a n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h 
rates). Ti me t o C R, T T C R h, T T R, a n d T T C Ri will be prese nte d b y treat me nt ar m usi n g descri pti ve 
statistics. 
Tra nsf usi o n re q uire me nts ( platelet a n d R B C; n u m ber of u nits), rat es of i nfecti o n, da ys s pe nt 
h os pitalize d, a n d ot her efficac y a n d safet y meas ures t hat are p ote ntiall y i n dicati ve of cli nical be nefit 
will be s u m marize d b y treat me nt ar m usi n g descri pti ve statistics.  

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1 8 /1 3 2  
 
Q ualit y of life, as meas ure d b y E O R T C Q L Q -C 3 0, will be e v al uate d f or s u bjects wit h a baseli ne 
assess me nt a n d at least 1 p ost -baseli ne Q L Q -C 3 0 assess me nt t hat ge nerate a sc ore. F or t otal Q L Q -C 3 0, 
eac h d o mai n sc ore (e g, p h ysical f u ncti o ni n g, r ole f u ncti o ni n g, e m oti o nal f u ncti o ni n g, c o g niti ve 
f u ncti o ni n g, s ocial f uncti o ni n g), as well as s y m pt o m scales, baseli ne val ues, a n d c ha n ge fr o m baseli ne 
f or eac h ti me p oi nt will be s u m marize d b y treat me nt ar m usi n g descri pti ve statistics. Mi xe d m o dels 
will als o be a p plie d.  
A C M H test will be use d t o c o m pare t he rate of C R wit h  I D H 1 M C bet wee n A G -1 2 0 + azaciti di ne a n d 
place b o + azaciti di ne . A l o gistic re gressi o n m o del will be use d t o esti mate t he treat me nt effect i n ter ms 
of a n o d ds rati o. T he o d ds rati o a n d its ass ociate d 9 5 % CIs will be prese nte d.  
S af et y A n al yses:  
Safet y will be e val uate d b y vital si g ns, t he res ults of E C O G P S, E C G, a n d E C H O or M U G A f or L V E F 
as cli nicall y i n dicate d ( met h o d per i nstit uti o nal sta n dar d of care, wit h t he sa me met h o d use d f or a n 
i n di vi d ual s u bject t hr o u g h o ut t he st u d y; sites i n Ger ma n y ma y o nl y use E C H O), cli nical la b orat or y 
assess me nts ( he mat ol o g y, c he mistr y, a n d c oa g ulati o n), a n d assess me nt of A Es, A E SIs, S A Es, A Es 
lea di n g t o disc o nti n uati o n or deat h, a n d c o nc o mita nt me dicati o n use. All safet y data will be liste d b y 
s u bj ect a n d s u m marize d b y treat me nt ar m.  
 

St u dy A G 1 2 0 -C -0 0 9  
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3.
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F
FI G U R E S
T A B L E O F C O N T E N T S  
1.
TI T L E P A G E  ................................................................................................................1
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  ..........................................................7
2.
S Y N O P SI S  ...................................................................................................................8
3.
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ...............1 9
4.
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S .............................2 6
5.
I N T R O D U C TI O N ......................................................................................................3 0
5. 1.
Ac ute M yel oi d  Le u k e mia  ...........................................................................................3 0
5. 2.
A G -1 2 0  .......................................................................................................................3 1
5. 2. 1.
O ver vie w  .....................................................................................................................3 1
5. 2. 2.
S u m mar y of N o n cli nical Data  ....................................................................................3 1
5. 2. 2. 1.
P har mac o ki netic Dr u g -Dr u g I nteracti o ns  ...................................................................3 1
5. 2. 3.
S u m mar y of Cli nical Dat a  ..........................................................................................3 2
5. 2. 3. 1.
St u d y A G 1 2 0 -C -0 0 1  ...................................................................................................3 2
5. 2. 3. 2.
St u d y A G -2 2 1 -A M L -0 0 5  ...........................................................................................3 4
5. 3.
Azaciti di ne  ..................................................................................................................3 5
5. 4.
St u d y R ati o nale  ...........................................................................................................3 7
5. 4. 1.
P ur p o se of t he St u d y ...................................................................................................3 7
5. 4. 2.
J ustificati o n of t he St u d y Desi g n ................................................................................3 8
5. 4. 3.
Rati o nale f or t he D os e Selecte d  ..................................................................................3 9
5. 4. 3. 1.
P ote ntial P har mac o ki netic I nteracti o ns bet wee n A G -1 2 0 a n d Azaciti di ne  ................3 9
5. 4. 3. 2.
P ote ntial P har mac o d y n a mic I nteracti o n Bet w ee n A G -1 2 0 a n d Azaciti di ne  ..............4 0
6.
T RI A L O BJ E C TI V E S A N D  E N D P OI N T S  ...............................................................4 1
6. 1.
O bjecti ves  ...................................................................................................................4 1
6. 1. 1.
Pri mar y O bj ecti ve  .......................................................................................................4 1
6. 1. 2.
Sec o n dar y O bj ecti ves  .................................................................................................4 1
4 2
6. 2.
E n d p oi nts  ....................................................................................................................4 2
6. 2. 1.
Pri mar y E n d p oi nt  ........................................................................................................4 2
6. 2. 2.
Sec o n dar y E n d p oi nts  ..................................................................................................4 2

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4 3  
7.  
I N V E S TI G A TI O N A L P L A N .....................................................................................4 4  
7. 1.  
O verall St u d y Desi g n  ..................................................................................................4 4  
7. 2.  
Cri teria f or St u d y Cl os ur e ...........................................................................................4 7  
7. 3.  
Te m p orar y M o dificati o ns All o we d D uri n g P u blic Healt h E mer ge ncies  ...................4 7  
7. 3. 1.  
All o wa ble Te m p or ar y M o dificati o ns  .........................................................................4 8  
8.  
S T U D Y P O P U L A TI O N  .............................................................................................5 0  
8. 1.  
N u m ber of  S u bjects  ....................................................................................................5 0  
8. 2.  
I n cl usi o n Criteria ........................................................................................................5 0  
8. 3.  
E x cl usi o n Criteria  .......................................................................................................5 1  
8. 4.  
S u bject I d e ntificati o n a n d Re gistrati o n  ......................................................................5 3  
8. 5.  
S u bject Wit h dra wal Criteria  .......................................................................................5 3  
8. 5. 1.  
Wit h dra wal fr o m St u d y Treat me nt  .............................................................................5 3  
8. 5. 2.  
E ve nt -Free S ur vi val F oll o w -u p  ..................................................................................5 4  
8. 5. 3.  
S ur vi val F oll o w -u p  .....................................................................................................5 4  
8. 5. 4.  
Wit h dra wal fr o m t he St u d y  ........................................................................................5 4  
9.  
S T U D Y T R E A T M E N T  ..............................................................................................5 5  
9. 1.  
Descri pti o n of St u d y Dr u g  ..........................................................................................5 5  
9. 2.  
St u d y Dr u g Pac k a gi n g a n d La b eli n g  ..........................................................................5 5  
9. 3.  
St u d y Dr u g St ora ge  .....................................................................................................5 5  
9. 4.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt  ..............................................................5 5  
9. 5.  
Bli n di n g  ......................................................................................................................5 6  
9. 6.  
U n bli n di n g  ..................................................................................................................5 6  
9. 7.  
St u d y Dr u g Pr e p arati o n a n d A d mi nistrati o n  ..............................................................5 7  
9. 7. 1.  
A G -1 2 0 a n d Mat c he d Place b o  ....................................................................................5 7  
9. 7. 2.  
Azaciti di ne  ..................................................................................................................5 8  
9. 8.  
Criteria f or D os e Escal ati o n, D ose M o dificati o n, or Disc o nti n uati o n of St u d y 
Dr u g  ............................................................................................................................5 8  
9. 8. 1.  
A G -1 2 0/ Place b o D os e M o dificati o n a n d St o p pi n g Criteria  .......................................5 8  
9. 8. 2.  
Azaciti di ne D ose M o dificati o ns a n d St o p pi n g Criteria  ..............................................6 0  
9. 8. 2. 1.  
Azaciti di ne D ose M o dificati o ns d ue t o N o n -He mat ol o gic T o xicit y  ..........................6 1  
9. 8. 2. 2.  
Azaciti di ne D ose M o dificati o ns d ue t o He mat ol o gic T o xicit y  ..................................6 1  
9. 8. 2. 3.  
Azaciti di ne T hera p y a n d Re nal D ysf u ncti o n  ..............................................................6 2  

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9. 9.  
A d verse E v e nts of S peci al I nt erest f or A G -1 2 0  .........................................................6 3  
9. 9. 1.  
Q T Pr ol o n gati o n  .........................................................................................................6 3  
9. 9. 2.  
I D H Differe ntiati o n S y n dr o me ...................................................................................6 4  
9. 9. 3.  
Le u k o c yt osis  ...............................................................................................................6 5  
9. 1 0.  
Ot her P ote ntial Ris ks  ..................................................................................................6 6  
9. 1 0. 1.  
Le u k o e nce p hal o pat h y  .................................................................................................6 6  
9. 1 0. 2.  
Se ns ori m ot or Ne ur o pat h y/ P ol y n e ur o pat h y  ................................................................6 6  
9. 1 0. 3.  
T u m or L ysis S y n dr o me  ..............................................................................................6 7  
9. 1 1.  
D urati o n of S u bject Parti ci pati o n  ...............................................................................6 7  
9. 1 1. 1.  
Treat me nt D urati o n  .....................................................................................................6 7  
9. 1 1. 2 . 
E n d of St u d y  ...............................................................................................................6 8  
9. 1 1. 3.  
Treat me nt C o m plia nce  ................................................................................................6 8  
9. 1 2.  
St u d y Dr u g A cc o u nta bilit y  .........................................................................................6 8  
9. 1 3.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Treat me nts  .................................................6 9  
9. 1 3. 1.  
Pri or Me dicati o ns a n d Pr oce d ures  ..............................................................................6 9  
9. 1 3. 2.  
C o nc o mita nt T hera p y Re q uiri n g Caref ul M o nit ori n g  ................................................6 9  
9. 1 3. 3.  
C o nc o mita nt T hera p y t o be A v oi de d  ..........................................................................7 0  
9. 1 3. 4.  
All o we d C o nc o mita nt T hera p y  ...................................................................................7 0  
9. 1 3. 4. 1.  
Ne utr o pe nia T h era p e utics  ...........................................................................................7 0  
9. 1 3. 4. 2.  
A nti micr o bial Pr o p h yla xis  ..........................................................................................7 0  
9. 1 3. 4. 3.  
Le u k o c yt osis Pr o p h yla ctics a n d T hera pe utics ( H y dr o x y urea)  ...................................7 1  
9. 1 3. 4. 4.  
Ster oi ds  .......................................................................................................................7 1  
9. 1 3. 4. 5.  
Ca pt uri n g C o nc o mita nt T hera pies P ost -Treat me nt  ....................................................7 1  
1 0.  
S T U D Y A S S E S S M E N T S  ..........................................................................................7 2  
1 0. 1.  
Sc he d ule of Assess me nts  ............................................................................................7 2  
1 0. 2 . 
I nf or me d C o nse nt .......................................................................................................7 9  
1 0. 3.  
De m o gra p hic Data a n d Me dical, S ur gical, a n d M e dicati o n Hist or y  ..........................7 9  
1 0. 4.  
C yt o ge netics T esti n g  ..................................................................................................7 9  
1 0. 5.  
I D H 1 M utati o n A nal ysis .............................................................................................8 0  
1 0. 6 . 
Safet y Assess me nts  .....................................................................................................8 1  
1 0. 6. 1.  
I n d e pe n de nt Data M o nit ori n g C o m mittee ..................................................................8 1  
1 0. 6. 2.  
P h ysical E x a mi nati o n a n d E C O G Perf or ma nce St at us  ..............................................8 1  
1 0. 6. 3.  
Vital Si g ns  ..................................................................................................................8 1  

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1 0. 6. 4.  
Electr ocar di o gra m a n d Assess me nt of Left Ve ntric ular Ejecti o n Fracti o n  ................8 1  
1 0. 6. 5.  
Safet y La b orat or y Assess me nts  ..................................................................................8 2  
1 0. 6. 6.  
A d verse E v e nts  ...........................................................................................................8 2  
1 0. 7.  
B o ne  Marr o w Sa m ples a n d Peri p heral Bl o o d Le u ke mic Blast Cells  .........................8 2  
1 0. 8.  
Efficac y Assess me nts  .................................................................................................8 3  
1 0. 8. 1.  
Res p o nse t o Treat me nt  ...............................................................................................8 3  
1 0. 8. 2.  
I n dic at ors of Cli nical Be nefit ......................................................................................8 5  
1 0. 8. 3.  
Q ualit y of Lif e  ............................................................................................................8 5  
1 0. 9.  
P har mac o ki netic a n d P har mac o d y na mic Ass ess me nts  ..............................................8 6  
1 0. 1 0.  
Sa m ple Pr ocessi n g, St ora ge, a n d S hi p me nt  ................................................................8 6  
1 1.  
A D V E R S E E V E N T S ..................................................................................................8 7  
1 1. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................8 7  
1 1. 1. 1.  
A d verse E v e nt  .............................................................................................................8 7  
1 1. 1. 2.  
Relate d A d vers e E ve nt  ...............................................................................................8 8  
1 1. 1 . 3. 
Seri o us A d verse E v e nt  ................................................................................................8 9  
1 1. 2.  
Pr oce d ures f or Re p orti n g A d verse E v e nts a n d Seri o us A d verse E v e nts  ....................8 9  
1 1. 2. 1.  
Dia g n osis V ers us Si g ns a n d S y m pt o ms  .....................................................................9 1  
1 1. 2. 2.  
A d verse E v e nts Occ urri n g Sec o n d ar y t o Ot her E v e nts  ..............................................9 1  
1 1. 2. 3.  
A d verse E v e nts of S peci al I nt erest  .............................................................................9 2  
1 1. 2. 3. 1.  
Q T Pr ol o n gati o n  .........................................................................................................9 2  
1 1. 2. 3. 2.  
Le u k o c yt osis  ...............................................................................................................9 2  
1 1. 2. 3. 3.  
I D H Differe ntiati o n S y n dr o me ...................................................................................9 2  
1 1. 2. 4.  
Persiste nt or Rec urre nt A d verse E ve nts  .....................................................................9 2  
1 1. 2. 5.  
A b n or mal La b orat or y Val ues  .....................................................................................9 3  
1 1. 2. 6.  
Deat hs  .........................................................................................................................9 3  
1 1. 2. 7.  
Pr o gressi o n of A M L  ...................................................................................................9 4  
1 1. 2. 8.  
Pre -e xisti n g Me dical C o n diti o ns  ................................................................................9 4  
1 1. 2. 9.  
H os pitalizati o n  or Pr ol o n ge d H os pitalizati o n  .............................................................9 4  
1 1. 2. 1 0.  
O ver d ose or I nc orrect A d mi nistrati o n  ........................................................................9 5  
1 1. 3.  
Pre g n a nc y Re p orti n g  ..................................................................................................9 5  
1 1. 4.  
F oll o w -u p of S u bjects after A d verse E ve nts  ..............................................................9 6  
1 1. 4. 1.  
I n v esti gat or F oll o w-u p  ................................................................................................9 6  
1 1 . 4. 2. 
S p o ns or F oll o w -u p ......................................................................................................9 6  

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1 1. 4. 3.  
P ost -St u d y A d v erse E v e nts .........................................................................................9 7  
1 2.  
S T A TI S TI C A L M E T H O D S  .......................................................................................9 8  
1 2. 1.  
Ge ne ral Statistical Met h o ds ........................................................................................9 8  
1 2. 2.  
A nal ysis Sets  ...............................................................................................................9 8  
1 2. 3.  
Dis p ositi o n  ..................................................................................................................9 8  
1 2. 4.  
Baseli ne E v al uati o ns  ...................................................................................................9 8  
1 2. 5.  
Efficac y A nal yses  .......................................................................................................9 9  
1 2. 5. 1.  
A nal ys es of t he Pri mar y E n d p oi nt  ..............................................................................9 9  
1 2. 5. 2.  
A nal ys es of t he Sec o n dar y E n d p oi nts  ......................................................................1 0 0  
1 2. 5. 2. 1.  
Ke y Sec o n dar y E n d p oi nt A nal ys es  ..........................................................................1 0 0  
1 2. 5. 2. 2.  
A d diti o nal Sec o n dar y E n d p oi nt A nal yses  ................................................................1 0 1  
1 2. 6.  
E x p os ure a n d Safet y A nal yses  ..................................................................................1 0 3  
1 2. 6. 1.  
A d verse E v e nts  .........................................................................................................1 0 3  
1 2. 6. 2.  
La b orat or y A b n or malities  .........................................................................................1 0 4  
1 2. 6. 3.  
Ot her Safet y D ata  .....................................................................................................1 0 4  
1 2. 7.  
P har mac o ki netic A n al ys es  ........................................................................................1 0 4  
1 2 . 8. 
P har mac o d y na mic A n al yses  .....................................................................................1 0 4  
 
1 0 5  
1 2. 1 0.  
I nteri m A nal yses .......................................................................................................1 0 5  
1 2. 1 1.  
Pr oce d ures f or H a n dli n g Missi n g, U n use d, a n d S p uri o us Data  ...............................1 0 5  
1 2. 1 2.  
Sa m ple Siz e Esti mati o n  ............................................................................................1 0 5  
1 2. 1 3.  
P o wer f or A n al ysis of Ke y Sec o n d ar y E n d p oi nts  ....................................................1 0 6  
1 2. 1 3. 1.  
P o wer f or A n al ysis of O verall S ur vi val ....................................................................1 0 6  
1 2. 1 3. 2.  
P o wer f or A n al ysis of C o m plete Re missi o n Rate, C o m plete Re missi o n Pl us 
C o m plete Re missi o n wit h Partial He mat ol o gi c Rec o ver y Rate, a n d 
O bjecti ve Res p o ns e Rate  ..........................................................................................1 0 6  
1 3.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ................................................................1 0 8  
1 3. 1.  
G o o d Cli nical Practice  ..............................................................................................1 0 8  
1 3. 2.  
Et hical C o nsi derati o ns  ..............................................................................................1 0 8  
1 3. 3 . 
S u bject I nf or mati o n a n d I nf or me d C o nse nt  .............................................................1 0 8  
1 3. 4.  
S u bject C o nfi de ntialit y  .............................................................................................1 0 8  
1 3. 5.  
Pr ot oc ol C o m plia nce  ................................................................................................1 0 9  
1 3. 6.  
Data Ma na ge me nt  .....................................................................................................1 0 9  

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1 3. 7.  
S o urce D oc u m e nt/ Electr o nic Case Re p ort F or m C o m pleti o n  ..................................1 0 9  
1 3. 8.  
Direct Access t o S o urce Data  ...................................................................................1 1 0  
1 3. 9.  
Rec or d Rete nti o n  ......................................................................................................1 1 0  
1 3. 1 0.  
Lia bilit y a n d I ns ur a nce  .............................................................................................1 1 0  
1 3. 1 1.  
P u blicati o n of St u d y Fi n di n gs a n d Us e of I nf or mati o n  ............................................1 1 0  
1 4.  
LI S T O F R E F E R E N C E S  ..........................................................................................1 1 2  
1 5.  
A P P E N DI C E S  ..........................................................................................................1 1 7  
1 5. 1.  
Re prese ntati ve E x a m ples of L o w -Fat or Hi g h -Fat, Hi g h -Cal orie Meals  .................1 1 7  
1 5. 2.  
Ne w Y or k Heart Ass ociati o n Classificati o n  .............................................................1 1 7  
1 5. 3.  
Pre parati o n a n d A d mi nistrati o n of Azaciti di ne  ........................................................1 1 7  
1 5. 3. 1.  
S u bc uta ne o us A d mi nistrati o n of Azaciti di ne  ...........................................................1 1 7  
1 5. 3. 2.  
I ntr a ve n o us A d mi nistrati o n of Azaciti di ne ..............................................................1 1 8  
1 5. 4.  
Azaciti di ne D ose M o dificati o ns d ue t o He mat ol o gic T o xicit y  ................................1 1 9  
1 5. 5.  
Me dicati o ns K n o w n t o Pr ol o n g t he Q T I nter v al  ......................................................1 2 0  
1 5. 6.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  .......................................................................1 2 0  
1 5. 7.  
M o derate a n d Str o n g C Y P 3 A 4 I n hi bit ors  ................................................................1 2 1  
1 5. 8.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us Sc ori n g  ........................1 2 1  
1 5. 9.  
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 v e nts  .......1 2 1  
1 5. 1 0.  
D eclarati o n of Helsi n ki  .............................................................................................1 2 2  
1 5. 1 1.  
Pr ot oc ol A me n d me nt Hist or y  ...................................................................................1 2 8  
 

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LI S T O F T A B L E S  
Ta ble  1:  
Ma na ge me nt of A d vers e E ve nts  .................................................................................6 0  
Ta ble  2:  
He mat ol o gi c D ose Re d u cti o ns f or Azaciti di ne Base d o n A bs ol ute Ne utr o p hil 
C o u nt a n d Platelets  .....................................................................................................6 2  
Ta ble  3:  
He mat ol o gi c D ose Re d u cti o ns f or Azaciti di ne Base d o n B o ne M arr o w 
Cell ularit y  ...................................................................................................................6 2  
Ta ble  4:  
Ma na ge me nt of Q T Pr ol o n gati o n b y N CI C T C A E Gra de  .........................................6 4  
Ta ble  5:  
Rec o m me n de d  I nitial D oses of H y dr o x y urea f or Ma na ge me nt of 
Le u k o c yt osis  ...............................................................................................................7 1  
Ta ble  6:  
Sc he d ule of Assess me nts  ............................................................................................7 3  
Ta ble  7:  
P har mac o ki netic Sa m pli n g Sc he d ul e  .........................................................................7 7  
Ta ble  8:  
P har mac o d y na mic Sa m pli n g Sc he d ule  .......................................................................7 8  
 
 
8 0  
Ta ble  1 0:  M o difie d I nter nati o nal W or ki n g Gr o u p Res p o ns e Criteria f or Ac ute M yel oi d 
Le u k e mia  ....................................................................................................................8 4  
Ta ble  1 1:  Criteria f or Sta ble Diseas e a n d Diseas e Pr o gressi o n f or Ac ute M yel oi d 
Le u k e mia  ....................................................................................................................8 5  
Ta ble  1 2:  Ca usal Attri b uti o n G ui da nce  ......................................................................................8 8  
Ta ble  1 3:  P o wer f or A n al ysis of C R Rate, C R + C R h Rate, a n d O R R  ....................................1 0 7  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
Sc he ma f or St u d y A G 1 2 0 -C -0 0 9  ................................................................................4 5  

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4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
A b bre vi ati o n  
Defi niti o n  
2 -H G  
2 -h y dr o x y gl utarate  
α -K G  
Al p ha -ket o gl utarate  
β -h C G  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest 
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A M L  
Ac ute m yel oi d le u ke mia  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A P L  
Ac ute pr o m yel oc ytic le u ke mia  
A S T  
As partate a mi n otra nsferase  
B C R P  
Breast ca ncer resista nce pr otei n  
BI D  
T wice dail y  
B P  
Bl o o d press ure  
B S C  
Best s u p p orti ve care  
B S A  
B o d y s urface area  
B U N  
Bl o o d urea nitr o ge n  
C 1 D #  
C ycle 1, Da y #  
CI  
C o nfi de nce i nter val  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n o bser ve d  
C M H  
C oc hra n -Ma ntel -Hae nszel  
C N S  
Ce ntral ner v o us s yste m  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R  
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 gic rec o ver y  
C Ri  
C o m plete re missi o n wit h i nc o m plete he mat ol o gic ( ne utr o p hil a n d/ or platelet) 
rec o ver y 
C R p  
C o m plete re missi o n wit h i nc o m plete platelet rec o ver y  
C S R  
Cli nical st u d y re p ort  
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  

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A b bre vi ati o n  
Defi niti o n  
D L T  
D ose -li miti n g t o xicit y 
D O C R  
D urati o n of c o m plete re missi o n  
D O C R h  
D urati o n of c o m plete re missi o n wit h partial he mat ol o gic rec o ver y  
D O C Ri  
D urati o n of c o m plete re missi o n wit h i nc o m plete he mat ol o gic ( ne utr o p hil 
a n d/ or platelet) rec o ver y, i ncl u di n g c o m plete re missi o n wit h i nc o m plete 
platelet rec o ver y  
D O R  
D urati o n of res p o nse  
E C G  
Electr ocar di o gra m  
E C H O  
Ec h 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  
E F S  
E ve nt -free s ur vi val 
E L N  
E ur o pea n Le u ke mia Net  
E O R T C  
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer  
E O T  
E n d of Treat me nt  
G B S  
G uillai n -Barre s y n dr o me  
G C P  
G o o d Cli nical Practice  
H R  
Hazar d rati o 
I B 
I n vesti gat or’s Br oc h ure 
I C 
I n d ucti o n c he m ot hera p y 
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 u ncil f or Har m o nisati o n 
I D H, I D H 1, I D H 2 
Is ocitrate de h y dr o ge nase, 1, 2 
I D H 1 m 
Is ocitrate de h y dr o ge nase 1 m utati o n-p ositi ve  
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee  
I E C 
I n de pe n de nt Et hics C o m mittee 
I M P 
I n vesti gati o nal me dici nal pr o d uct 
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 R T 
I nteracti ve res p o nse tec h n ol o gies 
I T T 
I nte nt-t o-Treat  
I V 
I ntra ve n o us(l y) 

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A b bre vi ati o n  
Defi niti o n  
I W G 
I nter nati o nal W or ki n g Gr o u p 
L D A C  
L o w -d ose c ytara bi ne  
L V E F  
Left ve ntric ular ejecti o n fracti o n  
M C  
M utati o n cleara nce  
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  
M L F S  
M or p h ol o gic le u ke mia -free state 
M RI  
Ma g netic res o na nce i ma gi n g 
M T D  
Ma xi m u m t olerate d d ose  
M U G A  
M ulti -gate d ac q uisiti o n  
N C C N  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
O A T  
Or ga nic a ni o n tra ns p orter  
O A T P  
Or ga nic a ni o n tra ns p orti n g p ol y pe pti de 
O C T  
Or ga nic cati o n tra ns p orter  
O R R  
O bjecti ve res p o nse rate  
O S  
O verall s ur vi val  
P C R  
P ol y merase c hai n reacti o n  
P D  
P har mac o d y na mic(s)  
P -g p  
P -gl yc o pr otei n  
P K  
P har mac o ki netic(s)  
P M L  
Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
P P A S  
Per -Pr ot oc ol A nal ysis Set  
P R  
Partial re missi o n  
P R E S  
P osteri or re versi ble e nce p hal o pat h y s y n dr o me  
P R O  
Patie nt -re p orte d o utc o me(s) 
P S  
Perf or ma nce stat us  
Q D  
O nce dail y  
Q T c F  
Heart -rate c orrecte d Q T i nter val usi n g Fri dericia’s met h o d 
R B C  
Re d bl o o d cell  
R O W  
Rest of w orl d  
R P 2 D  
Rec o m me n de d P hase 2 d ose  

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A b bre vi ati o n  
Defi niti o n  
R/ R  
Rela pse d or refract or y  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S A S  
Safet y A nal ysis Set  
S C  
S u bc uta ne o us(l y)  
S O P  
Sta n dar d O perati n g Pr oce d ure  
t½   
Half -life 
T L S  
T u m or l ysis s y n dr o me  
T T C R  
Ti me t o c o m plete re missi o n  
T T C R h  
Ti me t o c o m plete re missi o n or c o m plete re missi o n wit h partial he mat ol o gic 
rec o ver y 
T T C Ri  
Ti me t o c o m plete re missi o n wit h i nc o m plete he mat ol o gic ( ne utr o p hil a n d/ or 
platelet) rec o ver y, i ncl u di n g c o m plete re missi o n wit h i nc o m plete platelet 
rec o ver y 
T T R  
Ti me t o first I W G res p o nse  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
 

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5.  
I N T R O D U C TI O N 
5. 1.  
Ac ute M yel oi d Le u ke mi a  
Ac ute m yel oi d le u ke mia ( A M L) is a mali g na nc y of m yel oi d prec urs or cells, w hic h u n der g o ra pi d 
pr oliferati o n, acc u m ulate i n t he b o ne marr o w, a n d se verel y c o m pr o mise n or mal bl o o d cell 
pr o d ucti o n. L o w bl o o d c o u nts res ult i n i ncrease d s usce pti bilit y t o i nfecti o ns, a ne mia wit h 
fati g u e, a n d t hr o m b oc yt o pe nia, lea di n g t o i ncrease d ris k of blee di n g. I nfecti o ns acc o u nt f or t he 
greatest ca use of A M L d eat hs, w hile a s mall p orti o n of patie nts s ucc u m b t o fatal blee di n g e v e nts. 
A p pr o xi matel y 1 9, 9 5 0 p e o ple were dia g n ose d wi t h A M L i n 2 0 1 6 i n t he U nite d States ( U S) a n d 
1 0, 4 3 0 patie nts will ha ve die d fr o m t he diseas e; t he a ge -a dj uste d i nci de n ce rate of A M L is 
a p pr o xi matel y 4 per 1 0 0, 0 0 0 me n a n d w o me n per year (N CI, 2 0 1 5 ).  
T he first st u d y of is ocitrate de h y dr o ge n ase (I D H) m utati o ns i n A M L re p ort e d t he i de ntificati o n 
of t he is ocitrate de h y dr o ge n ase 1 (I D H 1) m utati o n ( R 1 3 2 H) i n a p pr o xi matel y 8 % of t he 
1 8 8  cases a n al yze d (Mar dis et al, 2 0 0 9 ). I n a s mall c o h ort of wester n patie nts, t he I D H 1 
m utati o ns ( R 1 3 2 H, R 1 3 2 C, a n d R 1 3 2 G) were o bs er ve d i n 6 ( 8 %) of 7 8  sa m ples (War d et al, 
2 0 1 0 ). S u bse q ue ntl y, wit hi n a m ore h o m o ge n o us gr o u p c o m prise d of a d ult de n o v o 
c yt o ge neticall y n or mal A M L patie nts, m utati o ns i n I D H 1 were f o u n d i n 1 4 % of t he cases 
(Marc u cci et al, 2 0 1 0 ). C o nsi deri n g t hes e data, a p pr o xi matel y 2 8 0 0 p e o ple will ha ve bee n 
dia g n ose d  wit h I D H 1 m utati o n -p ositi ve (I D H 1 m) A M L i n t he U S i n 2 0 1 6; t he a ge -a dj uste d 
i nci de nce rate of I D H 1 m A M L is less t ha n 1 p er 1 0 0, 0 0 0 i n di vi d uals per ye ar (N CI, 2 0 1 5 ), 
ma ki n g t his a n e xtre mel y rare dise ase.  
Acc or di n g t o t he S ur veill a nce of R are Ca n cers i n E ur o pe (R A R E C A R E, 2 0 1 6 ) pr oject o n 
s u bjects dia g n os e d fr o m 1 9 9 5 t o 2 0 0 2 a n d arc hi ve d i n 6 4 E ur o pea n p o p ulati o n -base d ca ncer 
re gistries, t he o verall a n n ual cr u de i nci d e nce of A M L was 3. 7 per 1 0 0, 0 0 0 ( 4. 0 per 1 0 0, 0 0 0 f or 
males a n d 3. 4 per 1 0 0, 0 0 0 f or fe mal es) (Visser et al, 2 0 1 2 ). Base d o n t he i nci de nce d ata a n d t he 
t otal E ur o pea n U ni o n of 2 7 me m ber states ( E U -2 7) p o p ulati o n (as of 2 0 1 2 p u blicati o n date), 
4 2, 7 9 5 ne w dia g n oses of m yel oi d mali g na ncies o cc ur i n t he E U -2 7 a n n uall y, i ncl u di n g 
1 8, 3 7 6  cases of A M L ( 4 3 %). T he i nci de n ce of A M L gra d uall y i ncrease d wit h a ge wit h a n 
i nci de nce rate per 1 0 0, 0 0 0 of 0. 7 f or t he a ge gr o u p of 0-1 4 years, 0. 8 f or t he gr o u p 1 5 -2 4 years, 
2. 4 f or t he gr o u p 2 5 -6 4 years, a n d 1 3. 7 f or t he ol d est a ge gr o u p ( 6 5 years or ol der) (Visser et al, 
2 0 1 2 ). 
C urre nt strate gies f or A M L ca n be ge nerall y di vi de d i nt o i nte nsi ve a n d n o n -i nte nsi ve treat me nts. 
I nte nsi v e treat me nts are us uall y reser ve d f or fit i n di vi d uals a n d c o m prise d of i n d ucti o n a n d 
c o ns oli dati o n c he m ot hera p y a n d  ma y als o i ncl u de all o ge n eic ste m cell tra ns pla ntati o n. T he g o al 
of i nte nsi ve t hera p y is t o ac hie ve a l o n g -ter m c ure. I n c o ntrast, patie nts u na ble t o recei v e 
i nte nsi ve treat me nts ma y be treate d wit h l o w-i nte nsit y t h era pi es c o nsisti n g of h y p o m et h ylati n g 
a gents, bl o o d pr o d uct tra nsf usi o ns, a n d s u p p orti ve care i n cl u di n g a nti bi otics. T he o bjecti ve of 
l o w-i nte nsit y t hera p y is ofte n palliati ve. T he rec o m me n dati o n t o treat a patie nt wit h i nte nsi ve vs 
n o n -i nte nsi ve treat me nt is i n di vi d ualize d a n d i nc or p orates t he patie nt’s a ge, de n o v o vs 
sec o n dar y n at ure of t heir A M L, t he prese n ce of c o m or bi dities, a n d ot her fact ors. W hereas 
i nte nsi ve i n d ucti o n c he m ot hera p y (I C) re prese nts a sta n dar d of care f or fit patie nts, t he m ost 
a p pr o priate treat me nt f or ol der, u nfit patie nts  re m ai ns de bata ble. U nfit patie nts, t y picall y 
i ncl u di n g el derl y p atie nts wit h A M L ha ve a n i ncrease d i nci de nce of c o m or bi dities (e g, car diac 
a n d p ul m o nar y d ysf u ncti o n), p o or he mat ol o gic reser ves, a n d w orse E aster n C o o perati ve 

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O nc ol o g y Gr o u p ( E C O G) perf or ma n ce stat us ( P S)  d ue t o a ge al o ne. Ac ute m yel oi d le u ke mia i n 
t his patie nt gr o u p is als o m ore li kel y t o be prece de d b y a m yel o d ys plastic p hase a n d has a hi g her 
i nci de nce of u nfa v ora ble c yt o ge netic pr ofiles t ha n y o u n ger patie nts, k n o w n ris k fact ors f or p o or 
o u tc o me (A p pel ba u m et al, 2 0 0 6 ; D ö h ner et al, 2 0 1 7 ).  
C o nse q ue ntl y, w h e n c o m pare d t o y o u n ger a d ults, ol der a d ults w h o recei ve I C ha v e a l o w er 
c ha nce of re missi o n, a hi g her c ha n ce of i n d ucti o n -relate d m ort alit y, a n d s h orter s ur vi val. T h us, 
w hile s o me ol der a d ults are eli gi ble t o recei ve I C, t he maj orit y are tr eate d wit h l o w -i nte nsit y 
t hera pies or b est s u p p orti ve care ( B S C) al o ne (B u c h ner et al, 2 0 0 9 ; Kle pi n, 2 0 1 5 ; S perr et al, 
2 0 0 4 ). C urre nt treat me nt o pti o ns f or patie nts w h o are n ot c o nsi dere d ca n di dates f or i nte nsi ve I C 
d ue t o a ge, E C O G P S, or ot her c o m or bi dities, or t h ose w h o c h o ose n ot t o recei ve I C, i n cl u de 
B S C al o ne, l o w -d ose c yt ara bi ne ( L D A C), decita bi ne, or azaciti di ne (B ur nett et al, 2 0 0 7 ; 
Desc hler et al, 2 0 0 6 ; Fe n a u x et al, 2 0 1 0 ; Ka ntarjia n et al, 2 0 1 2 ). Best s u p p orti ve care, L D A C, 
decita bi ne, a n d azaciti di ne ha ve b ee n s h o w n t o ha ve a me dia n o v erall s ur vi val ( O S) of 2, 5, 8, 
a n d 1 0 m o nt hs, res pecti v el y, i n ol der patie nts w h o are n ot ca n di dates f or i nte nsi ve I C (B ur nett et 
al, 2 0 0 7; D o m bret et al, 2 0 0 8 ; D o m bret et al, 2 0 1 5 ; Ka ntarjia n et al, 2 0 1 2 ). 
5. 2.  
A G -1 2 0  
5. 2. 1.  
O ver vie w  
A G -1 2 0 (I nt er nati o nal N o n pr o prietar y Na me: i v osi de ni b) is a p ote nt i n hi bit or of t he I D H 1 
m uta nt pr otei n. A G -1 2 0 has bee n e v al uate d f or its p ote ntial t o i n hi bit bi n di n g a n d e nz y matic 
acti vit y i n a p a nel of 8 0  rece pt ors, i o n c ha n nels, a n d e nz y mes. A G-1 2 0 is selecti ve, wit h n o 
si gnifica nt off -tar get a cti vit y o bser ve d. T he c o m p o u n d has bee n d e m o nstrate d t o re d uce 
2 -h y dr o x y gl ut arate ( 2 -H G) le vels b y > 9 5 %, t o re verse gr o wt h fact or -i n de pe n de nt gr o wt h i n 
vitr o, a n d t o i n d uce differe ntiati o n i n le u ke mia cell m o dels.  
5. 2. 2.  
S u m m ar y of N o ncli nic a l D at a 
Details of t he n o ncli nical de vel o p me nt pr o gra m f or A G -1 2 0 are pr o vi d e d i n t he I n v esti gat or’s 
Br oc h ure (I B). A s u m mar y of t he ke y i nf or mati o n is pr o vi de d bel o w.  
5. 2. 2. 1.  
P h ar m a c o ki netic Dr u g -Dr u g I nter acti o ns  
A G -1 2 0 is mai nl y met a b olize d b y c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4, wit h mi n or c o ntri b uti o ns fr o m 
C Y P 2 B 6 a n d C Y P 2 C 8. T heref ore, c o -a d mi nistrati o n wit h C Y P 3 A 4 str o n g or m o derate i n hi bit ors 
or str o n g i n d u cers c o ul d ha ve a n effect o n t he P K of A G -1 2 0.  
A G -1 2 0 is a n i n d ucer of h u ma n C Y P 3 A 4 a n d ma y als o be a n i n d ucer of  C Y P 2 B 6, C Y P 2 C 8, a n d 
C Y P 2 C 9.  
A G -1 2 0 is a wea k direct i n hi bit or of C Y P 2 C 8, C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5 wit h 
half -ma xi mal i n hi bit or y c o nce ntr ati o n (I C 5 0) val ues > 5 0 μ M a n d s h o ws little or n o e vi de nce of 
direct i n hi biti o n of C Y P 1 A 2, C Y P 2 B 6, or C Y P 2 C 9. A G -1 2 0 s h o ws n o ti me - or 
meta b olis m -de pe n de nt i n hi biti o n of a n y of t he C Y P e nz y m es e val uat e d. T h e li keli h o o d of 
i n hi biti o n of C Y P e nz y mes b y A G-1 2 0 is, t heref ore, e xtre mel y l o w.  
A G -1 2 0 is a s u bstrate of P -gl yc o pr ot ei n ( P -g p), b ut n ot breast ca n cer resista n ce pr ot ei n ( B C R P). 
H o we ver, c oa d mi nistrati o n of itrac o naz ole (a str o n g P -g p i n hi bit or) ha d n o effect o n t he 

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ma xi m u m c o nce ntrati o n ( C ma x ) of A G-1 2 0 i n h u m a n s u bjects, s u g gesti n g t h e i n v ol ve me nt of 
i ntesti nal P-g p i n A G -1 2 0 dis p ositi o n i n vi v o is li kel y t o b e mi ni mal. A G-1 2 0 is n ot a s u bstrate 
of or ga nic a ni o n tra ns p orti n g p ol y p e pti de ( O A T P) 1 B 1 or O A T P 1 B 3 tra ns p orters.  
A G -1 2 0 d oes n ot i n hi bit P -g p, B C R P, O A T P 1 B 1, O A T P 1 B 3, or ga nic a ni o n tra ns p orter ( O A T) 1, 
a n d or ga nic cati o n tra ns p orter ( O C T) 2 at cli nicall y re le va nt c o nce ntr ati o ns. A G-1 2 0 a p p ears t o 
be a wea k i n hi bit or of O A T P 1 B 1 a n d O A T P 1 B 3, wit h I C 5 0 val ues of 9. 5 6 a n d 2 2. 8 μ M, 
res pecti vel y. A G-1 2 0 d o es n ot i n hi bit t he O A T 1 - a n d O C T 2 -me diate d u pta ke of t he pr o be 
s u bstrate (I C 5 0 > 6 5  μ M) b ut i n hi bits O A T 3 (I C 5 0 ~ 0. 3 2 2  μ M). A p h ysi ol o gicall y -b ase d 
p har mac o ki netic ( P K) si m ulati o n pre dicte d a n i ncrease ( <  3 0 %) i n t he area u n der t he 
c o nce ntr ati o n × ti me c ur ve of a se nsiti ve O A T 3 s u bstrate, s u g gesti n g t h at t he p ote ntial f or 
cli nicall y rele va nt dr u g i nteracti o ns d ue t o t he i n hi biti o n of O A T 3 a p pears t o be l o w.  
5. 2. 3.  
S u m m ar y of Cli nic al D at a  
T he A G -1 2 0 cli nical de v el o p me nt pr o gra m w as i nitiate d i n s u bjects wit h he mat ol o gic 
mali g na n cies i n Marc h 2 0 1 4 wit h a P hase 1 d ose escalati o n a n d e x pa nsi o n st u d y, A G 1 2 0 -C -0 0 1 
( Secti o n 5. 2. 3. 1 ). Base d o n t he res ults of t his P hase 1 b/ 2 st u d y, i v osi de ni b ( TI B S O V O® ) was 
a p pr o ve d b y t he F D A o n 2 0 J ul y 2 0 1 8 f or patie nts wit h rela pse d or re fract or y A M L wit h a 
s usce pti ble I D H 1 m utati o n. 
A P hase 1 b/ 2 st u d y of t h e c o m bi nati o n of A G -1 2 0 + azaciti di ne, A G -2 2 1 -A M L -0 0 5, was 
i nitiate d i n Marc h 2 0 1 6 ( Secti o n 5. 2. 3. 2 ). 
Refer t o t he A G -1 2 0 I n v esti gat or’s Br oc h ure (I B) f or f urt her details o n all st u dies bei n g 
c o n d ucte d wit h A G -1 2 0.  
5. 2. 3. 1.  
St u d y A G 1 2 0 -C -0 0 1  
St u d y A G 1 2 0 -C -0 0 1 is e val uati n g t he s afet y, p h ar mac o ki netics ( P K), p har mac o d y na mics ( P D), 
a n d cli nical acti vit y of A G -1 2 0 i n s u bjects wit h a d va nce d A M L a n d ot her he mat ol o gic 
mali g na n cies t hat har b or a n I D H 1 m utati o n. T he pri mar y o bjecti ves of t h e st u d y are t o assess t he 
safet y a n d t olera bilit y of treat me nt wit h A G-1 2 0 a d mi nistere d dail y i n s u bj ects wit h a d v a nce d 
he mat ol o gic m ali g na n cies, t o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) a n d/ or t he 
rec o m me n de d P has e 2 d ose ( R P 2 D) of A G-1 2 0 i n t his p o p ulati o n, a n d t o assess t he preli mi nar y 
cli nical acti vit y of A G -1 2 0 i n s u bjects wit h rela ps e d or refract or y ( R/ R) I D H 1 m A M L. T h e 
i nitial d osi n g re gi me n was t wice dail y ( BI D); bas e d o n t he fa v ora ble P K pr ofile s h o wi n g a l o n g 
eli mi nati o n half -life (t½ ), BI D d osi n g was disc o nti n ue d after t he first c o h ort a n d a o nce dail y 
( Q D) d osi n g re gi me n was i m ple me nte d. T his o n g oi n g st u d y is di vi de d i nt o a d ose escalati o n 
p hase a n d a s u bs e q ue nt e x pa nsi o n p hase t hat will all o w f or a m or e r o b ust e val uati o n of t he safet y 
pr ofile a n d cli nical a nti -le u ke mia acti vit y.  
As of 0 1 A u g ust 2 0 1 6, a t otal of 1 7 3 s u bjects ha d bee n a d mi nistere d A G -1 2 0 d uri n g t he d os e 
escalati o n a n d e x pa nsi o n p hases of St u d y A G 1 2 0 -C -0 0 1 acr oss 6 d osi n g c o h orts; 5 3 s u bjects 
re mai ne d o n tr eat me nt.  
O verall, 1 6 3 ( 9 4 %) of t h e 1 7 3 s u bjects ha d re p ort e d at least 1 a d v erse e ve nt ( A E). T he m ost 
c o m m o nl y re p orte d A Es ( ≥ 2 0 % of s u bjects) acr oss all 1 7 3 s u bjects were di arr hea ( 3 1 %), fati g ue 
( 2 7 %), na us ea ( 2 5 %), p yre xia ( 2 1 %), le u k oc yt osis ( 2 1 %), a n d fe brile n e utr o pe nia ( 2 1 %). 
O verall, 1 0 0 ( 5 8 %) of t h e 1 7 3 s u bjects ha d re p ort e d at least 1 A E assesse d as relate d t o treat me nt 

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b y t he I n vesti gat or. T he m ost c o m m o nl y re p orte d relate d A Es ( ≥ 1 0 % of s u bjects) were diarr hea 
( 1 4 %), na us ea ( 1 3 %), fati g ue ( 1 2 %), a n d pr ol o n ge d electr ocar di o gra m ( E C G) Q T ( 1 0 %). 
Fatal A Es w ere re p orte d i n 2 9 s u bjects i n St u d y A G 1 2 0 -C -0 0 1. S pecific A Es lea di n g t o d eat h 
t hat were re p orte d i n m ore t ha n 1 s u bject were: bactere mia/se psis ( 6 s u bjects), m ulti-or ga n 
fail ure ( 2 s u bjects), deat h ( 2 s u bjects), a n d res pirat or y fail ure ( 2 s u bjects). Ot her fat al A Es were 
re p orte d i n 1 s u bject eac h.  
Seri o us A Es ( S A Es) ha d bee n re p orte d i n 1 0 9 ( 6 3 %) of t he 1 7 3 s u bjects as of t he data c ut off. 
T he m ost c o m m o nl y re p orte d S A Es ( ≥ 5 % of s u bjects) were fe brile ne utr o pe nia ( 1 7 %), 
le u k oc yt osis ( 9 %), p ne u m o nia ( 8 %), ac ute pr o m yel oc yti c le u ke mia ( A P L) differe ntiati o n 
s y n dr o me ( 7 %), a n d p yre xia ( 7 %). I n t otal, 3 6 s u bjects e x perie nce d S A Es t hat were c o nsi dere d 
relate d t o treat me nt b y t h e I n vesti gat or, i ncl u di n g: 1 1 s u bjects re p orti n g A P L differe ntiati o n 
s y n dr o me; 5 s u bje cts eac h wit h pr ol o n ge d Q T i nter val a n d le u k oc yt osis; a n d 2 s u bjects eac h  wit h 
diarr hea, na usea, pa nc yt o pe nia, ras h, r eti n oic aci d s y n dr o me, a n d ple ural eff usi o n. All ot her 
relate d S A Es w ere re p ort e d i n 1 s u bject eac h.  
Preli mi nar y a nal ysis of a vaila ble P K data as of 0 1 A u g ust 2 0 1 6 has b ee n p erf or me d f or St u d y 
A G 1 2 0 -C -0 0 1. A G -1 2 0 was a d mi nistere d orall y Q D or BI D i n c o nti n u o us 4 -wee k ( 2 8 -da y) 
c ycles. A t otal of 1 7 3 s u bjects were treat e d wit h d oses of 1 0 0 m g BI D, 3 0 0 m g Q D, 4 0 0 m g Q D, 
5 0 0 m g Q D, 8 0 0 m g Q D, or 1 2 0 0 m g Q D i n t he d ose escal ati o n p hase, a n d 5 0 0 m g Q D i n t he 
d ose e x pa nsi o n p hase of t he st u d y. P har mac o ki netic e val uati o ns i ncl u de d t he assess me nt of d ose 
pr o p orti o nalit y f or si n gle a n d m ulti ple d ose plas ma e x p os ures of A G -1 2 0 ( ma xi m u m plas ma 
c o nce ntr ati o n o bser ve d [ C ma x ], area u n der t he c ur ve fr o m ti me 0 t o 2 4 h o urs [ A U C0 -2 4 hr], a n d 
area u n d er t he c ur ve fr o m ti me 0 t o 7 2 h o urs [ A U C 0 -7 2 hr]), stea d y-state P K, a n d acc u m ulati o n 
rati o. F oll o wi n g b ot h si n gle a n d m ulti ple d oses, e x p os ures of A G-1 2 0 i ncrease d less t ha n 
pr o p orti o nall y t o d ose fr o m 1 0 0 t o 1 2 0 0 m g.  
F oll o wi n g m ulti ple  d oses of A G -1 2 0, t here was n o a p pare nt i ncrease i n e x p os ure fr o m 5 0 0 t o 
8 0 0 m g Q D. F oll o wi n g a si n gle d ose, t ½ r a n ge d fr o m 7 1 t o 1 5 2 h o urs, s u p p orti n g a Q D d ose 
re gi me n. F oll o wi n g m ulti ple d oses of 5 0 0 m g Q D, stea d y-state was reac he d wit hi n 1 5 da ys, wit h 
~ 2. 2 f ol d acc u m ulati o n of A U C a n d ~ 1. 7 -f ol d acc u m ulati o n of Cma x . T he o bser ve d acc u m ulati o n 
rati o at stea d y-stat e was l ess t ha n a ntici pate d b ase d o n t he l o n g t ½  aft er a si n gle d ose, li kel y d u e 
t o t he c yt o c hr o me P 4 5 0 ( C Y P) 3 A i n d ucti o n of its o w n meta b olis m. Stea d y-state pre-d ose 
A G -1 2 0 tr o u g h le vels w ere mai ntai ne d a b o v e t he pre dicte d efficaci o us e x p os ure le vel 
t hr o u g h o ut treat me nt.  
After m ulti ple d oses, plas ma 2 -H G le vels w ere s u bsta ntiall y re d u ce d ( u p t o 9 9 % i n hi biti o n, t o 
le vels see n i n he alt h y v ol u nteers), a n d b o ne marr o w 2-H G c o n ce ntr ati o ns were als o s u bsta ntiall y 
re d uce d ( u p t o 9 9 % re d u cti o n), at all d ose le vels t este d. T here was a g o o d c o nc or da n ce b et wee n 
2 -H G i n plas ma a n d b o n e marr o w. T h e 5 0 0 m g Q D d ose has s h o w n t he lar gest ma g nit u de of 
plas ma 2 -H G i n hi biti o n f or t he maj orit y of s u bjects. T he mea n plas ma 2 -H G i n hi biti o n was 
a p pr o xi matel y 8 7 % a n d 9 3 % f or d ose escal ati o n a n d e x pa nsi o n, res pecti v el y.  
C o nsi d eri n g t hat A G -1 2 0 was ge nerall y well t olerate d i n st u d y A G 1 2 0 -C -0 0 1, t he M T D has n ot 
bee n reac h e d i n d ose escalati o n, a n d t he e n c o ura gi n g efficac y data i n s u bjects wit h a d va nce d 
he mat ol o gic m ali g na n cies, i ncl u di n g R/ R A M L, t he pr o p ose d A G -1 2 0 d os e of 5 0 0 m g Q D was 
selecte d f or e x pa nsi o n. F urt her, e x p os ures are c o m para ble bet w ee n 5 0 0 m g a n d 8 0 0 m g Q D, a n d 
a p pr o xi matel y 7 0 % of Ar m 1 +  s u bjects ha ve ac hi e ve d > 9 0 % i n hi biti o n of 2-H G at 5 0 0 m g Q D. 

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As of 0 1 A u g ust 2 0 1 6, 1 0 0 s u bjects i n t he st u d y were e val uate d f or  efficac y i n t he Ar m 1 +  
Res p o nse E val ua ble Set, defi ne d as all Ar m 1 +  s u bjects ( R/ R A M L s u bjects i n Ar m 1 of 
e x pa nsi o n a n d e q ui vale nt R/ R A M L s u bj ects fr o m d ose escal ati o n w h ose starti n g d os e was 
5 0 0  m g Q D a n d w h o met Ar m 1 eli gi bilit y criteria) w h o ha d at  least 1 p ost-baseli ne res p o ns e 
assess me nt or disc o nti n ue d earlier. T hirt y -se v e n ( 3 7 %) of t he 1 0 0 s u bjects ha ve ha d 
I n v esti gat or-ass esse d o bj ecti ve res p o ns es as defi ne d b y m o difie d I nter n ati o nal W or ki n g Gr o u p 
(I W G) Res p o nse Criteria (C hes o n et al, 2 0 0 3 ) as d efi ne d i n t he pr ot oc ol. As of 0 1 A u g ust 2 0 1 6, 
i n t he Ar m 1+  Res p o nse E val ua ble Set, t he o bjecti ve res p o nse rate ( O R R) was 3 7 % ( 9 5 % CI: 
2 7. 6 % , 4 7. 2 %); c o m plete re missi o n ( C R) rate was 1 8 % ( 9 5 % CI: 1 1. 0 %, 2 6. 9 %), base d o n 
I n v esti gat or res p o ns e ass ess me nts. T he C R + c o m plete re missi o n wit h partial he mat ol o gi c 
rec o ver y ( C R h) rat e was 2 4 % ( 9 5 % CI 1 6. 0 %, 3 3. 6 %). C R h was defi ne d as a C R wit h partial 
rec o ver y of peri p heral bl o o d c o u nts ( < 5 % b o n e marr o w blasts, A N C > 0. 5 × 1 0 9/ L [ 5 0 0/ µ L], a n d 
platelets > 5 0 × 1 0 9/ L [ 5 0, 0 0 0/ µ L]). Beca use C R h is n ot part of m o difie d I W G criteria, it was 
deri ve d b y t he S p o ns or. T hese res ults w ere c o nsiste nt wit h t he Pri mar y  Efficac y Set ( N = 8 2; 
s u bjects f oll o we d at least 4 m o nt hs or disc o nti n ue d earlier), w here O R R was 3 9 % ( 9 5 % CI: 
2 8. 4 %, 5 0. 4 %) a n d C R rate was 1 8 % ( 9 5 % CI: 1 0. 6 %, 2 8. 4 %).  
A m o n g all d ose escal ati o n s u bjects w h o were res p o nse e val ua ble ( N = 7 8), 3 0 ( 3 9 %) of t he 
7 8  s u bjects ha ve ha d I n v esti gat or-assess e d o bjecti ve res p o nses as defi ne d b y I W G Res p o nse 
Criteria as of t he d ata c ut off of 0 1 A u g ust 2 0 1 6. T he O R R f or t hese s u bjects was 3 9 % ( 9 5 % CI: 
2 7. 7 %, 5 0. 2 %) a n d C R rate was 1 8 % ( 9 5 % CI: 1 0. 2 %, 2 8. 3 %).  
Res p o nses i n t h e st u d y h a ve bee n d ura ble; s u bjects ha ve bee n o n treat me nt f or u p t o 2 4. 2 m o nt hs 
( N = 1 7 3; me dia n treat me nt d urati o n 3. 5 m o nt hs, ra n ge > 0 t o 2 4. 2 m o nt hs). A m o n g t he 
1 0 0  Ar m  1 +  res p o nse e v al ua ble s u bjects, 8 2 ha ve bee n f oll o we d f or at least 4 m o nt hs or 
disc o n ti n ue d earlier, 7 0 h a ve bee n f oll o we d f or at least 6 m o nt hs, a n d 5 6 ha ve bee n f oll o w e d f or 
at least 8  m o nt hs. Me dia n res p o nse d urati o ns were c o nsiste nt wit h t he Pri mar y Efficac y Set 
( N = 8 2; s u bjects f oll o we d at least 4 m o nt hs or disc o nti n ue d earlier), w here me dia n d urati o n of 
res p o nse ( D O R) was 6. 5 m o nt hs ( 9 5 % CI: 4. 6, N E); me dia n d urati o n of C R ( D O C R) was 
5. 6  m o nt hs ( 9 5 % CI: 4. 6, N E). Me dia n O S f or t he Ar m 1 +  Res p o nse E val ua ble Set ( N = 1 0 0) was 
8. 7  m o nt hs ( 9 5 % CI: 5. 8, 1 0. 4, wit h 5 1 % ce ns ori n g) as of t he dat a c ut off.  
5. 2. 3. 2.  
St u d y A G -2 2 1 -A M L -0 0 5  
St u d y A G -2 2 1 -A M L -0 0 5 is a n o n g oi n g P hase 1 b/ 2, o pe n -la bel, r a n d o mize d, m ultice nter trial i n 
s u bjects wit h ne wl y di a g n ose d A M L w h o are i neli gi ble f or i nte nsi ve I C. T he safet y a n d efficac y 
of A G -1 2 0 + azaciti di ne f or s u bjects w it h a n I D H 1 m utati o n a n d A G-2 2 1 + azaciti di ne f or 
s u bjects wit h a n is ocitrat e de h y dr o ge n ase 2 (I D H 2) m utati o n is bei n g e v al uate d. T he st u d y 
c o m prises a P hase 1 b d os e -escalati o n p orti o n a n d a P hase 2 ra n d o mize d p orti o n. T he P hase 1 b 
p orti o n of t he st u d y is e v al uati n g t he R P 2 D of A G -1 2 0 or A G -2 2 1 a d mi nistere d i n c o m bi nati o n 
wit h azaciti di ne.  
Safet y assess me nts, i ncl u di n g vital si g ns, E C Gs, h e mat ol o g y, ser u m c he mistr y, car diac mar k ers, 
fasti n g li pi d pa nel, pr e g n a nc y testi n g (f or fe males of re pr o d ucti ve p ote ntial), A Es, c o nc o mita nt 
me dicati o ns a n d pr oce d ures, a n d tra nsf usi o n re q uire me nts are bei n g e v al uate d re g ularl y 
t hr o u g h o ut t he st u d y. 
T he i nitiati o n of t his P hase 3 st u d y ( A G 1 2 0 -C -0 0 9) was pre dicate d o n t he de m o nstrate d safet y of 
A G -1 2 0 ( 5 0 0 m g Q D) a d mi nister e d i n c o m bi nati o n wit h azaciti di ne ( 7 5  m g/ m 2/ da y S C f or 

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7  da ys e ver y 2 8 d a ys) aft er 6 s u bjects e nr olle d i n st u d y A G -2 2 1 -A M L -0 0 5 c o m plete d at least 
o ne 2 8 -da y c ycle of t h e d osi n g re gi me n, or disc o nti n ue d earlier. N o e v e nts meeti n g t he criteria 
f or d ose-li miti n g t o xicities ( D L Ts) were re p orte d wit hi n t he first 2 8 da ys of treat me nt f or t he 
first 6 s u bjects. 
D L Ts f or A G -1 2 0 are as f oll o ws:  
•  He mat ol o gi c t o xicities:  W hile A G -1 2 0 is n ot ass ociate d wit h m yel os u p pressi o n, 
azaciti di ne has a well -c h aract erize d ass ociati o n wit h c yt o pe nia a n d ot her h e mat ol o gic 
t o xicities. F or t he P hase 1 b p orti o n of t his st u d y, he mat ol o gic t o xicities will n ot be 
c o nsi dere d as a D L T f or A G -1 2 0 a n d will be miti gat e d t hr o u g h d ose m o dificati o n of 
azaciti di ne i n s u bse q ue nt c ycles. T he S p o ns or will c o n ve ne a d ose re vie w t ea m t o re vie w 
he mat ol o g y la b d ata at t h e c o m pleti o n of eac h c o h ort t o deter mi ne w het h er a n y warra nt a 
D L T d esi g nati o n.  
•  N o n -he mat ol o gic t o xicities:  All cli nicall y si g nifica nt n o n -he mat ol o gic t o xicities C T C A E 
Gra de ≥3 t hat are t h o u g ht t o be ca usall y rel ate d will be c o nsi dere d D L Ts. ( N ote: T o xicit y 
t hat is clearl y a n d dir ectl y relate d t o t he pri mar y disease or t o a n ot her eti ol o g y is 
ex cl u de d fr o m t his defi niti o n.)  
Preli mi nar y res ults fr o m t he 2 3 s u bjects i n t he P hase 1 b p orti o n of t he st u d y w h o recei ve d 
A G -1 2 0 i n c o m bi nati o n wit h azaciti di ne de m o nstrate d t hat t he d osi n g re gi me n is safe a n d h as 
e nc o ura gi n g cli nical acti vit y. As of 1 9 Fe br uar y 2 0 1 9, t he me dia n treat me nt d urati o n was 
1 5. 1  m o nt hs (ra n ge: 0. 3 -3 2. 2  m o nt hs), a n d 1 0 ( 4 3. 5 %)  s u bjects were c o nti n ui n g t o recei ve 
treat me nt i n t he st u d y. 
Fre q u e ntl y re p orte d A Es ( >  2 0 % of s u bjects) were t hr o m b oc yt o pe ni a ( 6 5. 2 %); na usea ( 6 0. 9 %); 
diarr h oea ( 5 6. 5 %); a nae mia a n d c o nsti pati o n ( 5 2. 2 % eac h); fe brile ne utr o p e nia a n d p yre xia 
( 4 3. 5 % eac h); dizzi ness, fati g u e, h y p o kale mia, i ns o m nia, ne utr o pe nia, a n d v o miti n g ( 3 4. 8 % 
eac h); b ac k pai n ( 3 0. 4 %); c o u g h, d ecrease d a p petite, a n d electr ocar di o gra m Q T pr o l o n ge d 
( 2 6. 1 % eac h); a n d h ea dac he, i njecti o n site er yt he ma, oe de ma peri p heral, a n d se psis ( 2 1. 7 % 
eac h). C o m m o n seri o us a d verse e v e nts ( S A Es) ( ≥ 5 % of s u bjects) were fe brile ne utr o pe nia 
( 3 9. 1 %); I D H differe ntiati o n s y n dr o me, p yre xia, a n d se psis ( 1 3. 0 % eac h); a n d l u n g i nfecti o n, 
p ne u m o nia, a n d s y nc o pe ( 8. 7 % eac h). Seri o us a d v erse e v e nts of I D H differe ntiati o n s y n dr o me 
were relate d t o A G -1 2 0.  
T he O R R was 7 8. 3 % ( 9 5 % CI: 5 6. 3 0 %, 9 2. 5 4 %), a n d t he C R rate was 6 0. 9 % ( 9 5 % CI: 3 8. 5 4 %, 
8 0. 2 9 %). T he C R + C R h rate was 6 9. 6 % ( 9 5 % CI: 4 7. 0 8 %, 8 6. 7 9 %). C R h is defi ne d as a C R 
wit h partial rec o v er y of peri p heral bl o o d c o u nts ( < 5 % b o ne marr o w blasts, A N C > 0. 5 × 1 0 9/ L 
[ 5 0 0/ µ L], a n d platelets > 5 0 × 1 09/ L [ 5 0, 0 0 0/ µ L]). Beca use C R h is n ot part of m o difie d I W G 
criteria, it was d er i ve d b y t he S p o ns or. 
5. 3.  
Az aciti di ne  
T he 2 0 1 7 Nati o nal C o m pre he nsi ve Ca ncer Net w or k ( N C C N) G ui deli nes ( V 1. 2 0 1 7) rec o m me n d 
use of azaciti di ne ( Vi daz a ® ) i n p atie nts w h o are d ee me d u nfit f or I C or f or i nter me diate-i nte nsit y 
t hera p y a n d f or ol der p atie nts wit h previ o usl y u ntr eate d A M L (N C C N, 2 0 1 7 ). Azaciti di ne is a n 
a nal o g of t h e nat urall y occ urri n g p yri mi di ne n ucle osi de c yti di ne a n d is classifie d as a n 
a nti meta b olite. Azaciti di ne is a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n f or 5  s u bt y p es 
of m yel o d ys plastic s y n dr o me ( M D S). Azaciti di ne is als o a p pr o ve d b y t he E ur o pea n C o m mi ssi o n 

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f or t he treat me nt of a d ult patie nts w h o are n ot eli gi ble f or he mat o p oietic ste m cell tra ns pla ntati o n 
wit h: i nter me diate a n d hi g h -ris k M D S, acc or di n g t o t he I nt er nati o nal Pr o g n ostic Sc ori n g S yste m 
(I P S S); c hr o nic m yel o m o n oc ytic l e u ke mia wit h 1 0 % t o 2 9% marr o w bl asts wit h o ut 
m yel o pr oliferati ve dis or d er; a n d A M L wit h 2 0 % t o 3 0 % blasts a n d m ulti -li nea ge d ys plasia, 
acc or di n g t o W orl d Healt h Or ga niz ati o n ( W H O) classificati o n.  
Azaciti di ne has bee n e xte nsi vel y st u die d i n M D S a n d has bee n s h o w n i n a lar ge, ra n d o mize d 
P hase 3 trial of hi g h er -ris k M D S s u bjects t o pr o vi de a s ur vi val a d va nta ge of 9. 4 m o nt hs o ver 
c o n ve nti o nal care re gi me ns, t h us alteri n g t he nat ur al c o urse of M D S. T he m e dia n O S of 
azaciti di ne-treate d s u bj ects was 2 4. 5 m o nt hs c o m pare d wit h 1 5. 0 m o nt hs f or t he c o m bi ne d 
c o n ve nti o nal care re gi me n gr o u p, w hic h i ncl u de d B S C, L D A C, a n d i nte nsi ve I C (Fe na u x a n d 
A des, 2 0 0 9 ). I n t he s u bs et of 1 1 3 s u bjects i n t his st u d y w h o ha d A M L b y W H O criteri a ( ≥ 2 0 % 
blasts) fr o m t he lar ger M D S gr o u p ( m ea n a ge 7 0  years, 2 4 % wit h u nfa v ora ble kar y ot y pe, m e dia n 
b o ne marr o w bl asts 2 3 %), t he me dia n O S was 2 4. 5 m o nt hs ( N = 5 5) i n t he azaciti di ne ar m 
c o m pare d wit h 1 6. 0  m o nt hs ( N = 5 8) i n t he c o n v e nti o nal care re gi me n ar m (Fe na u x a n d A des, 
2 0 0 9 ). 
Azaciti d i ne was i nitiall y use d as a l o w-i nte nsit y tr eat me nt f or ol der a d ults wit h A M L f oll o wi n g 
re p orts of cli nic al acti vit y i n se veral s mall st u dies. Sil ver ma n et al, usi n g W H O A M L criteria f or 
dia g n osis, r e p orte d a m e dia n O S of 1 9. 3 m o nt hs ( N = 2 7) i n azaciti di ne -tr eate d s u bjects c o m pare d 
wit h 1 2. 9 m o nt hs ( N = 2 5) i n s u bjects w h o recei ve d best sta n dar d of care (Sil ver ma n et al, 2 0 0 6 ). 
A d diti o nall y, G ol d ber g et al, re p or te d o n 3 3 s u bjects w h o recei ve d azaciti di ne ( N = 1 1, me dia n 
a ge 7 4 years) or 7 + 3 i nte nsi ve I C ( N = 2 2, me dia n a ge 6 7 years). T h e me dia n O S was 
1 3. 2  m o nt hs i n azaciti di ne -treate d s u bjects c o m p are d wit h 9. 2 m o nt hs i n i nte nsi ve I C -treate d 
s u bjects (G ol d ber g et al, 2 0 0 6 ). 
M ore rece ntl y, a m ultice nter, pr os pecti ve, ra n d o mize d P hase 3 st u d y ( St u d y A Z A -A M L -0 0 1) i n 
4 8 8  ol der s u bjects ( ≥ 6 5  years) wit h u ntreate d A M L wit h > 3 0 % blasts w h o were n ot ca n di dates 
f or all o ge nei c b o ne marr o w or ste m cell tra ns pla ntati o n re p orted a cli nicall y mea ni n gf ul 
i m pr o ve me nt i n O S wit h azaciti di ne treat me nt ( N = 2 4 1) o ver c o n v e nti o nal care ( N = 2 4 7; 1 0. 4 vs 
6. 5  m o nt hs, res pecti vel y; hazar d rati o [ H R] = 0. 8 5; 9 5 % CI, 0. 6 9 t o 1. 0 3; p = 0. 1 0 0 9) (D o m bret et 
al, 2 0 1 5). E ve nt-free s ur vi val ( E F S) was m o destl y i m pr o ve d wit h azaciti di ne, alt h o u g h t he 
i m pr o ve me nt was n ot statisticall y si g nifica nt (6. 7 vs 4. 8  m o nt hs; H R = 0. 8 7; 9 5 % CI, 0. 7 2 t o 
1. 0 5; p = 0. 1 4 9 5). A pre -s pecifie d se nsiti vit y a nal ysis ce ns ori n g s u bj ects w h o recei v e d s u bse q ue nt 
A M L t hera p y f oll o wi n g st u d y dr u g disc o nti n uati o n s h o we d t hat t he me dia n O S wit h azaciti di ne 
vers us t he c o n v e nti o nal  care re gi me n was 1 2. 1 m o nt hs vers us 6. 9  m o nt hs, res pecti vel y 
( H R = 0. 7 6; 9 5 % CI, 0. 6 0 t o 0. 9 6; p = 0. 0 1 9 0). A d diti o nall y, a n o mi nall y si g nifica nt i ncrease i n O S 
was o bser v e d i n azaciti di ne -treate d s u bjects w h o di d n ot ac hie ve re missi o n ( 6. 9 vs 4. 2 m o nt hs 
wit h  c o n ve nti o nal care; p = 0. 0 1 7 0). Tra nsf usi o n i n de pe n de n ce, fe wer h os pitalizati o ns, a n d 
i m pr o ve me nt i n s ur vi val were als o o bser ve d i n s u bjects w h o di d n ot ac hie ve a C R (D o m bret et 
al, 2 0 1 5).  
All of t he af ore me nti o ne d st u dies use d t he sta n dar d azaciti di ne d ose of 7 5  m g/ m 2/ da y 
a d mi nistere d S C f or 7 da ys of eac h 4 -wee k ( 2 8 -d a y) c ycle. T he ris k of a dr u g -dr u g i nteracti o n 
( D DI) bet wee n A G-1 2 0 a n d azaciti di ne is l o w a n d t here are n o a ntici pat e d cli nicall y si g nifica nt 
o verla p pi n g t o xicities bet wee n t he 2 c o m p o u n ds (see t he azaciti di ne I B or l ocal la bel f or f urt her 
details re gar di n g t he a vaila ble p har mac ol o g y , t o xic ol o g y, dr u g meta b olis m, a n d cli nical 
e x perie nce wit h azaciti di ne).  

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5. 4.  
St u d y R ati o n ale  
5. 4. 1.  
P ur p ose of t he St u d y  
Ac ute m yel oi d le u ke mia is a n a g gressi ve h e mat ol o gic mali g na n c y wit h a p o or pr o g n osis. 
Patie nts n ot c o nsi dere d ca n di dates f or I C b eca us e of a ge a n d c o m or bi d c o n diti o ns, p o or E C O G 
P S, or disease -rel ate d a d verse pr o g n ostic ris k fact ors ha ve a n es peci all y p o or pr o g n osis, wit h a 
me dia n s ur vi val of 2 t o 1 0  m o nt hs; t hese patie nts are c o m m o nl y treate d wit h B S C or l o w 
i nte nsit y t h era pi es s uc h as L D A C or h yp o m et h yl ati n g a ge nts, i ncl u di n g azaciti di ne (B ur nett et al, 
2 0 0 7 ; B ur nett et al, 2 0 1 2 ; B ur nett et al, 2 0 1 3 ; D o m bret et al, 2 0 0 8 ; D o m bret et al, 2 0 1 5 ; 
Ka ntarjia n et al, 2 0 1 0 ; Ka ntarjia n et al, 2 0 1 2 ; Ora n a n d Weis d orf, 2 0 1 2 ; Visser et al, 2 0 1 2 ). 
Azaciti di ne, a n a nal o g of t he p yri mi di ne n ucl e osi de c yti di ne, is a D N A met h yltra n sferase 
i n hi bit or t hat has bee n s h o w n t o be ass ociate d wit h s ustai ne d decreases i n pr o m oter D N A 
met h ylati o n a n d altere d ge ne e x pressi o n at critical re g ulat or y pat h w a ys (Tsai et al, 2 0 1 2 ). I n 
a d diti o n, azaciti di ne is a c yt ot o xic a ge nt. Treat me nt wit h azaciti di ne has de m o nstrate d cli nical 
acti vit y i n A M L a n d a n e nc o ura gi n g me dia n O S of 9 t o 1 0 m o nt hs i n patie nts n ot c o nsi dere d t o 
be eli gi ble f or I C (D o m bret et al, 2 0 1 5 ; Fe na u x et al, 2 0 1 0 ; N C C N, 2 0 1 7 ; Ple yer et al, 2 0 1 4 ; 
Ple yer et al, 2 0 1 3 ; T he p ot et al, 2 0 1 4 ). 
M utati o ns of t he I D H 1 e nz y m e ha ve b ee n i de nti fi e d i n se veral t u m ors, i ncl u di n g A M L (Da n g et 
al, 2 0 1 0; Da n g et al, 2 0 0 9 ; Ye n et al, 2 0 1 0). T h e res ulti n g m uta nt I D H pr ot ei ns c o n vert al p h a-
ket o gl utarate ( α -K G) t o t he o nc o meta b olite 2 -H G, w hic h has bee n s h o w n t o ca use D N A 
h y per met h yl ati o n b y i n hi biti o n of met h yl c yt osi ne di o x y ge n ase T E T 2 (Fi g u er oa et al, 2 0 1 0 ; 
T urca n et al, 2 0 1 2 ) a n d hist o ne h y per met h yl ati o n t hr o u g h c o m petiti ve i n hi biti o n of 
α -K G -d e pe n d e nt J u m o nji -C hist o ne de met h ylas es (Ts u ka da et al, 2 0 0 6 ; T urca n et al, 2 0 1 2 ; 
Ya ma ne et al, 2 0 0 6 ), t here b y l ea di n g t o br oa d e pi ge netic c h a n ges a n d a bl oc k i n m yel oi d 
differe ntiati o n (C h o w d h ur y et al, 2 0 1 1 ).  
A G -1 2 0 is a s pecific i n hi bit or of I D H 1 m uta nt pr otei n; n o ncli nical st u dies ha ve de m o nstrat e d 
t hat A G-1 2 0 effecti vel y i n hi bits t he acti vit y of I D H m uta nt pr otei ns lea di n g t o t he re d ucti o n of 
2 -H G i n t u m ors a n d t he re versal of I D H m utati o n -i n d uce d hist o ne a n d DN A h y p er met h ylati o n 
(Ker n yts k y et al, 2 0 1 5 ). Preli mi nar y cli nical data fr o m t he o n g oi n g st u dies ( A G 1 2 0-C -0 0 1 a n d 
A G -2 2 1 -A M L -0 0 5) ha v e s h o w n t hat A G -1 2 0 is safe a n d res ults i n s u bsta ntial cli nical acti vit y 
(see Secti o n  5. 2. 3. 1  a n d Secti o n  5. 2. 3. 2 ). 
T hese data raise t he p ossi bilit y t hat t he c o m bi nati o n of a n i n hi bit or of t he I D H 1 m uta nt pr otei n 
wit h a D N A met h yltra nsf erase i n hi bit or s uc h as azaciti di ne ma y l ea d t o a n a d diti ve or s y n er gistic 
a ntit u m or effect. Azaciti di ne re d uces D N A met h ylati o n le vels n o n -s pecificall y, as it i n hi bits 
D N A met h yltra nsf eras e acti vit y, w hile A G -1 2 0 i n directl y re d u ces D N A met h ylati o n le v els b y 
de pleti n g 2 -H G a n d rest ori n g e nz y me f u n cti o n t o α -K G -d e pe n d e nt e nz y mes. A s y ner gistic 
i nteracti o n bet wee n azaciti di ne a n d A G-1 2 0 c o ul d ha ve a c o m bi ne d i m pact o n D N A 
met h ylati o n, eit her at t he sa me D N A l oci or p ot e ntiall y a t differe nt l oci. F urt her m ore, 
n o ncli nicall y, t he c o m bi nati o n of A G -1 2 0 + azaciti di ne has bee n s h o w n t o e n ha nce t he 
differe ntiati o n a n d a p o pt osis of a le u ke mic cell li ne ( T F -1) t hat har b ors a n I D H 1 R 1 3 2 m utati o n 
(S p o ns or data o n file).  
A G -1 2 0 has bee n wel l t olerate d i n st u dies i n patie nts wit h A M L a n d s oli d t u m ors ( A G 1 2 0-C -0 0 1 
a n d A G 1 2 0 -C -0 0 2). Dr u g -relate d o v erla p pi n g t o xicities are n ot e x pecte d t o be cli nicall y 
si g nifica nt, n or is a n o verla p pi n g Q T si g nal li kel y. E xte nsi ve i n de pe n de nt safet y re vie w b y a n  

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i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will be use d t o c o nti n ue t o m o nit or f or a n y 
u ne x pecte d c o m bi nati o n ris ks. Pri maril y, t o xicities o bser ve d wit h b ot h azaciti di ne - a n d 
A G -1 2 0 -tr eate d s u bjects i ncl u de disease-relate d e ve nts ( ne utr o pe nia, i nfecti o n, fati g ue) a n d GI 
t o xicit y ( diarr hea, n a usea) (see azaciti di ne a n d A G-1 2 0 I Bs f or m ore d etail o n t o xicities of t he 
i n di vi d ual dr u gs). 
5. 4. 2.  
J ustific ati o n of t he St u d y Desi g n  
I n d u cti o n c he m ot hera p y is t he sta n dar d treat me nt f or y o u n ger, fit patie nts wit h A M L; h owe v er, 
i n u nfit p o p ulati o ns, i n patie nts w h o are ol d er i n a ge, a n d i n t h ose w h o ha v e c o m or bi dities, I C 
treat me nt re mai ns a matter of de b ate (s ee Secti o n  5. 1 ); h y p o met h ylati n g a ge nts s uc h as 
azaciti di ne are oft e n use d t o atte m pt t o c o ntr ol A M L i n t hese p o p ulati o ns, gi ve n t heir i n crease d 
t olera bilit y. T here is a nee d t o c o m bi ne ne w a ge nts wit h azaciti di ne wit h t he g o al of i ncreasi n g 
t he fre q u e nc y a n d d urati o n of res p o nses t hat will tra nslate i nt o pr ol o n ge d s ur vi val, w hile 
mi ni mizi n g t o xicities a n d treat me nt -relate d deat hs i n t his p o p ulati o n. 
Rec urri n g m utati o ns i n I D H 1 ma y be i m p orta nt f or A M L pat h o ge n esis or disease pr o gressi o n 
(Mar dis et al, 2 0 0 9 ). S mall m olec ule i n hi biti o n of t he m uta nt I D H 1 pr otei n re prese nts a 
pr o misi n g tar get e d t hera p y f or A M L. Direct i n hi biti o n of t he gai n -of -f u ncti o n acti vit y of t he 
I D H 1 m utate d pr otei n is i nte n de d t o i n hi bit t he pr o d ucti o n of t he o nc o ge ni c meta b olite 2 -H G. 
A G -1 2 0 has bee n e v al uat e d i n b ot h n o ncli nical a n d cli nical st u dies a n d has bee n s h o w n t o 
effecti vel y i n hi bit t he gai n -of -f u ncti o n acti vit y of t he m utate d pr otei n, lea di n g t o u p t o 1 0 0 % 
re d ucti o n of 2-H G.  
Preli mi nar y cli nical data fr o m t he o n g oi n g, o p e n -l a bel, si n gle-a ge nt P hase 1 st u d y i n s u bjects 
wit h R/ R A M L ( A G 1 2 0 -C -0 0 1) ha ve s h o w n t hat A G -1 2 0 is ge nerall y well t olerate d a n d tri g gers 
t he differe ntiati o n of le u ke mic blast cells t hat ulti matel y lea d t o re d u cti o ns i n mea n plas ma 2 -H G 
c o nce ntr ati o ns a n d e vi de nce of s u bsta ntial cli nical acti vit y (see Secti o n  5. 2. 3. 1 ). T he 
de vel o p me nt of effecti ve p har mac ol o gic t hera pies f or patie nts wit h I D H 1 m A M L a d dress es a 
si g nifica nt u n met me dic al nee d. 
T his is a gl o bal, P hase 3, m ultice nter, d o u ble -bli n d, ra n d o mize d , place b o-c o ntr olle d cli nical 
st u d y t o e val uat e t he effi cac y a n d safet y of A G-1 2 0 + azaciti di ne vers us pl ace b o + azaciti di ne i n 
s u bjects wit h pre vi o usl y u ntreate d I D H 1 m A M L a n d w h o are c o nsi dere d a p pr o priate ca n di dates 
f or n o n-i nte nsi ve t hera p y. Ac ute m yeloi d le u ke mi a i n t his patie nt gr o u p is m ore li kel y t o be 
prece d e d b y a m yel o d ys plastic p hase a n d h as a hi g her i nci de nce of u nfa v ora ble c yt o ge n etic 
pr ofiles t ha n A M L i n y o u n ger patie nts, b ot h k n o w n ris k fact ors f or p o or o utc o me.  
T he pri mar y e n d p oi nt of t he s t u d y is E F S. E ve nt-free s ur vi val as a pri mar y e n d p oi nt i n 
ra n d o mize d P hase 3 st u dies i n s u bjects wit h A M L has bee n pr o p os e d as a m ore e x act meas ure of 
a dr u g’s efficac y t ha n O S (Este y et al, 2 0 1 6 ; Ot h us et al, 2 0 1 6 ). E ve nt-free s ur vi val ca n m or e 
acc uratel y des cri be t he c o ntri b uti o n of a n o vel t hera p y t o cli nical be nefit b y re m o vi n g t he 
p ote ntiall y c o nf o u n di n g effects of p ost -trial t hera pies, i ncl u di n g resc ue t hera pies, s u p p orti ve care 
a n d, p ote ntiall y, ot her I D H 1 -m uta nt i n hi bit ors. E ve nt -free s ur vi val is defi n e d as t he ti me fr o m 
ra n d o mizati o n u ntil treat me nt fail ure, rela pse fr o m C R, or deat h fr o m a n y ca use, w hic h e ver 
occ urs first. Treat me nt f ail ure s u bjects are defi ne d as fail ure t o ac hie ve C R b y Wee k 2 4. A 
res p o nse of C R re prese nts b ot h disease c o ntr ol a n d esta blis h me nt of he mat o p oiesis i n s u bjects 
wit h A M L a n d is a n i m p orta nt pre dict or of O S (D o m bret et al, 2 0 1 5 ). 

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5. 4. 3.  
R ati o n ale f or t he D ose Selecte d  
A G -1 2 0 was ge nerall y w ell -t olerate d i n St u d y A G 1 2 0-C -0 0 1, t he M T D has n ot bee n reac he d i n 
t he d ose escalati o n p hase of t he st u d y, a n d preli mi nar y efficac y data ha ve b ee n e n c o ura gi n g i n 
s u bjects wit h a d va nce d h e mat ol o gic m ali g na n cies, i ncl u di n g R/ R A M L. I n li g ht of t hese 
o bser vati o ns, t he pr o p ose d A G -1 2 0 d ose  of 5 0 0 m g Q D was selecte d f or e x pa nsi o n i n t hat st u d y. 
T he sa me d ose was als o selecte d f or t he o n g oi n g P hase 1 b/ 2 A G -1 2 0 + azaciti di ne c o m bi nati o n 
st u d y A G-2 2 1 -A M L -0 0 5 a n d f or t he o n g oi n g P hase 1, 7 + 3 c o m bi nati o n st u d y 
A G 1 2 0 -2 2 1 -C -0 0 1 a n d will be use d f or  t his P hase 3 st u d y. 
Plas ma A G -1 2 0 e x p os ure i ncreases i n a less -t h a n-pr o p orti o nal ma n ner acr oss d oses fr o m 1 0 0 m g 
BI D t o 1 2 0 0 m g Q D, n eari n g a pl atea u at 5 0 0 m g Q D. S ustai ne d a n d c o nsiste nt plas ma 2 -H G 
i n hi biti o n has bee n o bser ve d wit h plas ma 2-H G le vels r e d uce d t o t he n or m al ra n ge of healt h y 
v ol u nteers ( u p t o 1 0 0 % i n hi biti o n) at all d oses. T he 5 0 0 m g Q D d ose has s h o w n a ma xi m u m P D 
effect base d o n 2 -H G le v els f or t he maj orit y of s u bjects.  
Azaciti di ne has bee n st u die d as b ot h a si n gl e a ge nt a n d i n c o m bi nati o n i n A M L. A d osi n g 
sc he d ule of 7 5 m g/ m 2/ da y S C f or 7 da ys of eac h 4 -wee k ( 2 8 -da y) c ycl e has pr o ve n t o be well 
t olerate d a n d h as s h o w n b ot h s ur vi val a n d cli nical be nefit i n s u bjects wit h A M L. C o nsi deri n g t he 
lac k of a ntici pat e d cli nic all y si g nifica nt o v erlap pi n g t o xicities a n d l o w D DI ris k f or azaciti di ne 
a n d A G-1 2 0, d osi n g f or t he c o m bi nati o n will be 7 5  m g/ m 2 S C or i ntra ve n o us (I V) f or 1 wee k 
( 7 da ys) i n t his st u d y. T his re gi me n is als o c o nsiste nt wit h t he re gi me n use d i n t he c o m bi nati o n 
st u d y, A G-2 2 1 -A M L -0 0 5.  
5. 4. 3. 1.  
P ote nti al P h ar m ac o ki netic I nter a cti o ns bet wee n A G -1 2 0 a n d Az aciti di ne  
Az aciti di ne as a Per petr at or o n A G -1 2 0 P h ar m ac oki netics  
A G -1 2 0 is eli mi nate d i n h u ma ns mai nl y b y meta b olis m b y C Y P 3 A 4, wit h mi n or c o ntri b uti o ns 
fr o m C Y P 2 B 6 a n d C Y P 2 C 8 pat h wa ys. A G -1 2 0 is a s u bstrate of P -g p; h o w e ver, c oa d mi nistrati o n 
of itrac o naz ole (a str o n g P -g p i n hi bit or) ha d n o effect o n t he ma xi m u m c o nce ntrati o n of A G -1 2 0 
i n h u ma n s u bjects, s u g gesti n g t he i n v ol ve me nt of i ntesti nal P-g p i n A G -1 2 0 dis p ositi o n i n vi v o 
is li kel y t o be mi ni mal. I n vitr o st u dies i n dicate t hat azaciti di ne d oes n ot i n hi bit 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-, or C Y P 3 A 4-me diate d acti vities i n h u ma n li ver 
micr os o mes u p t o a c o nce ntrati o n of 1 0 0 µ M, w hile wea k i n hi biti o n ( <  3 0 % i n hi biti o n) of 
C Y P 1 A 2  a n d C Y P 2 E 1 acti vities has bee n o bser ve d at 1 0 0 µ M (C he n et al, 2 0 1 0 ). T here has 
bee n n o n ota ble re p ort of C Y P i n d ucti o n n or P -g p i n hi biti o n me diate d b y azaciti di ne. Bas e d o n 
t he C ma x  ( 3 μ M) f or t he azaciti di ne 7 5 m g/ m2 re gi me n, t he p ote ntial f or a cli nical D DI d ue t o 
azaciti di ne i n hi biti o n or i n d ucti o n of he patic meta b olis m of A G- 1 2 0 a p pears t o be l o w. 
Ne vert hel ess, a  p o p ulati o n P K a nal ysis will be utilize d t o e val uate t he effect of azaciti di ne o n t he 
P K of A G -1 2 0. I n t his P hase 3 st u d y, P K s a m ples of A G -1 2 0 ( A G -1 2 0 i n t he prese n ce of 
azaciti di ne or place b o) at pr ot oc ol -s pecifi e d pre- a n d p ost -d ose ti me p oi nts will be c ollecte d t o 
assess t he effect of azaciti di ne o n t he stea d y -state P K of A G-1 2 0.  
A G -1 2 0 as a Per petr at or  o n Az aciti di ne P h ar m ac oki netics  
A G -1 2 0 is a wea k direct i n hi bit or of C Y P 2 C 8, C Y P 2 C 1 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5, a n d s h o ws 
little or n o e vi de nce of direct i n hi biti o n of C Y P 1 A 2, C Y P 2 B 6, or C Y P 2 C 9. A G-1 2 0 is a n 
i n d ucer of C Y P 3 A 4 a n d ma y b e a n i n d ucer of C Y P 2 B 6, C Y P 2 C 8, a n d C Y P 2 C 9. A G -1 2 0 d oes 
n ot i n hi bit P -g p, O A T P 1 B 1, O A T P 1 B 3, O A T 1, or O C T 2 at cli nicall y rele va nt c o nce ntr ati o ns. 

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A G -1 2 0 a p p ears t o be a wea k i n hi bit or of P -g p, O A T P 1 B 1, a n d O A T P 1 B 3, wit h I C 5 0 val ues of 
~  1 9. 6, 9. 5 6, a n d 2 2. 8 µ M, res pecti vel y. A G -1 2 0 d oes n ot i n hi bit t he O A T 1 - a n d 
O C T 2 -me diate d u pta ke of t he pr o be s u bstrate (I C 5 0 > 6 5 µ M), b ut i n hi bits O A T 3 (I C 5 0 
a p pr o xi matel y 0. 3 2 2 µ M). T he a bilit y t o assess t he i m pact of A G -1 2 0 or a n ot her a ge nt o n t he P K 
of azaciti di ne ma y be ha m pere d b y t he i nsta bi lit y of azaciti di ne i n plas ma a n d varia ble S C 
a bs or pti o n i n s u bjects (R u de k et al, 2 0 0 5 ). H o we v er, A G -1 2 0, as a p er petr at or, is u nli kel y t o 
alter t he e x p os ure of azaciti di ne, f or t he f oll o wi n g reas o ns:  
•  C Y P e nz y m es are n ot i n v ol ve d i n t he cleara nce of azaci ti di ne. I ntr acell ular 
p h os p h or ylati o n is a pi v otal ste p f or azaciti di ne t o bec o me acti ve. F urt her, azaciti di ne 
u n der g oes n o n -e nz y mati c h y dr ol ysis i n a q ue o us s ol uti o n a n d dea mi nati o n me diate d 
b y c yti di ne d ea mi nase, w hic h is wi del y e x presse d i n h u ma n tiss ues  s uc h as li ver, 
i ntesti nal e pit heli u m, a n d w h ole bl o o d. 
•  Azaciti di ne is ra pi dl y a bs or be d aft er S C a d mi nistrati o n a n d is cleare d ra pi dl y wit h a 
mea n eli mi nati o n t ½  of 4 1 mi n utes. Stea d y -state plas ma c o nce ntrati o n is reac he d 
wit hi n t he first d ose, a n d t here i s n o e x p os ure acc u m ulati o n after m ulti ple S C d oses 
(Vi daza, 2 0 1 5 ). 
5. 4. 3. 2.  
P ote nti al P h ar m ac o d y n a mic I nt er acti o n Bet wee n A G -1 2 0 a n d Az a citi di ne  
Azaciti di ne is n ot a ntici pate d t o re d uce t he effect of A G -1 2 0 o n 2 -H G i n hi biti o n i n le u ke mic 
blasts. A G -1 2 0 m o n ot hera p y at d oses ≥2 0 0 m g dail y ha v e res ulte d i n > 9 0 % re d ucti o n of plas ma 
a n d b o ne marr o w 2 -H G t o le vels si milar t o t h ose o bser ve d i n healt h y s u bjects. I n t h e o n g oi n g 
P hase 1 b/ 2 St u d y A G -2 2 1 -A M L -0 0 5, peri p heral bl o o d f or 2 -H G assess me nts is bei n g c ollect e d 
f or e x pl orat or y p ur p oses. I n s u m mar y, t he ris k of cli nical D DI bet w ee n A G-1 2 0 a n d azaciti di ne 
is li kel y t o b e l o w. 

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6.  
T RI A L O B J E C TI V E S A N D E N D P OI N T S  
6. 1.  
O bjecti ves  
6. 1. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bje cti ve of t he st u d y is t o c o m pare e ve nt -free s ur vi val ( E F S) bet wee n A G-1 2 0 + 
azaciti di ne a n d place b o + azaciti di ne.  
6. 1. 2.  
Sec o n d ar y O bjecti ves  
T he ke y sec o n dar y o bje cti ves of t he st u d y are:  
•  T o c o m pare t h e c o m plete re missi o n ( C R) rate bet wee n A G -1 2 0 + azaciti di ne a n d 
place b o + azaciti di ne.  
•  T o c o m pare O S bet wee n A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne.  
•  T o c o m pare t h e C R + C R h rate bet wee n A G -1 2 0 + azaciti di ne a n d place b o + 
azaciti di ne; C R h will be deri ve d b y t he S p o ns or.  
•  T o c o m pare t h e O R R bet wee n A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne.  
A d diti o nal sec o n dar y o bj ecti ves are:  
•  T o c o m pare t h e C R + C R wit h i nc o m plete he mat ol o gic rec o ver y ( C Ri) (i n cl u di n g C R 
wit h i nc o m plete platelet rec o ver y [ C R p]) rate bet wee n A G -1 2 0 + azaciti di ne a n d 
place b o + azaciti di ne.  
•  T o c o m pare d urati o n of C R ( D O C R), d urati o n of C R + C R h ( D O C R h), d urati o n of 
res p o nse ( D O R), a n d d urati o n of C R + C Ri (i ncl u di n g C R p) ( D O C Ri) bet wee n 
A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne.  
•  T o c o m pare ti me t o C R ( T T C R), ti me t o C R + C R h ( T T C R h), ti me t o first res p o nse 
( T T R), a n d ti me t o C R + C Ri (i ncl u di n g C R p) ( T T C Ri) bet wee n A G-1 2 0 + 
azaciti di ne a n d place b o + azaciti di ne.  
•  T o assess t he safet y a n d t olera bilit y of treat me nt wit h A G -1 2 0 + azaciti di ne c o m pare d 
wit h place b o + azaciti di ne.  
•  T o c o m pare tr a nsf usi o n r e q uire me nts ( platel et a n d re d bl o o d cell [ R B C]; n u m ber of 
u nits tra nsf use d), i nfecti o n rates, da ys s pe nt h os pit alize d, a n d ot her efficac y a n d 
safet y meas ures t hat are p ote ntiall y i n dicati ve of cli nical be nefit bet w ee n A G-1 2 0 + 
azaciti di ne a n d place b o + azaciti di ne.  
•  T o assess t he i m pact of tr eat me nt o n q ualit y of life ( Q o L) usi n g t he E ur o pea n 
Or ga nisati o n f or Res earc h a n d Treat me nt of Ca ncer ( E O R T C) Q L Q -C 3 0 a n d 
E Q -5 D -5 L.  
•  T o e val uate t he P K of A G -1 2 0 as a d mi nistere d i n c o m bi nati o n wit h azaciti di ne.  
•  T o e val uate t he P K/ P D relati o ns hi p of A G -1 2 0 a n d 2 -H G i n bl o o d sa m ples i n 
c o m paris o n wit h place b o.  

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•  T o c o m pare rates of C R wit h I D H 1 m utati o n cleara nce ( M C) bet wee n A G -1 2 0 + 
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6. 2.  
E n d p oi nts  
I n v esti gat or res p o ns e ass ess me nts per m o difie d I W G res p o nse criteria  will be use d f or all 
effic ac y e n d p oi nts, wit h t he e x ce pti o n of C R h, w hic h will be deri ve d b y t he S p o ns or.  
6. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of t he st u d y is E F S, w hic h is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil 
treat me nt fail ure, rela ps e fr o m re missi o n, or deat h fr o m a n y ca use, w hic h e v er occ urs first. 
Treat me nt f ail ure is defi n e d as fail ure t o ac hie ve C R b y Wee k 2 4.  
6. 2. 2.  
Sec o n d ar y E n d p oi nts  
T he ke y sec o n dar y e n d p oi nts are:  
•  C R rate ( C R defi ne d as b o ne marr o w bl asts < 5 % a n d n o A uer r o ds, a bse nce of 
e xtra me d ullar y dise ase, A N C ≥1. 0 × 1 0 9/ L [ 1 0 0 0/µ L], platelet c o u nt ≥1 0 0 × 1 0 9/ L 
[ 1 0 0, 0 0 0/ µ L], a n d i n de p e n de nce of R B C tra nsf usi o ns). 
•  O S, defi ne d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h d ue t o a n y 
ca use.  
•  C R + C R h rate ( C R h is defi ne d as a C R wit h partial rec o v er y of peri p heral bl o o d 
c o u nts w here A N C is > 0. 5 × 1 0 9/ L [ 5 0 0/ µ L], a n d platelet c o u nt is > 5 0 × 1 09/ L 
[ 5 0, 0 0 0/ µ L]; C R h will be deri ve d b y t he S p o ns or). 
•  O R R, defi ne d as t he rate of C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S.  
A d diti o nal sec o n dar y e n d p oi nts are:  
•  C R + C Ri (i ncl u di n g C R p) rate ( C Ri [i ncl u di n g C R p] is defi ne d as all C R criteria 
e x ce pt f or resi d ual n e utr o pe nia w here A N C is < 1. 0 × 1 0 9/ L [ 1 0 0 0/ µ L] or 
t hr o m b oc yt o pe ni a w here platelet c o u nt is < 1 0 0 × 1 09/ L [ 1 0 0, 0 0 0/ µ L]; wit h o ut 
platelet tra nsf usi o n f or at least 1 wee k pri or t o dis ease ass ess me nt).  
•  D O C R, a m o n g s u bjects w h o ac hie ve d C R; D O C R h, a m o n g s u bjects w h o ac hie ve d 
C R or C R h; D O R, a m o n g s u bjects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, 
a n d/ or M L F S; a n d D O C Ri, a m o n g s u bjects w h o ac hie ve d C R or C Ri (i ncl u di n g 
C R p).  

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•  T T C R, a m o n g s u bjects w h o ac hie ve d C R; T T C R h, a m o n g s u bjects w h o ac hie ve d C R 
or C R h; T T R, a m o n g s u bjects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, a n d/ or 
M L F S; a n d T T C Ri, a m o n g s u bjects w h o ac hie ve d C R or C Ri (i ncl u di n g C R p).  
•  Vital si g ns, a n d res ults of E C O G P S, E C G, a n d 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) f or left ve ntric ul ar ejecti o n fracti o n ( L V E F) as 
cli nicall y i n dicat e d ( met h o d per i nstit uti o nal sta n dar d of care, wit h t he sa m e met h o d 
use d f or a n i n di vi d ual t hr o u g h o ut t he st u d y; sites i n Ger ma n y m a y o nl y use E C H O).  
•  Cli nical la b orat or y assess me nts ( he mat ol o g y, c he mistr y, a n d c o a g ulati o n).  
•  A Es, A Es of s peci al i nterest ( A E SIs), S A Es, a n d A Es lea di n g t o disc o nti n uati o n or 
deat h.  
•  C o nc o mita nt me dicati o n use.  
•  Tra nsf usi o n re q uire me nts ( platelet a n d R B C; n u m ber of u nits tra nsf us e d), rates of 
i nfecti o n, da ys s pe nt h os pitalize d, a n d ot her efficac y a n d safet y meas ures t hat are 
p ote ntiall y i n dicati ve of cli nical be nefit.  
•  C ha n ges fr o m bas eli ne i n Q o L assess me nts ( E O R T C Q L C -C 3 0 a n d E Q -5 D -5 L).  
•  Rates of C R wit h I D H 1 M C.  
•  A G -1 2 0/ place b o a n d azaciti di ne dr u g e x p os ure, i ncl u di n g d ose m o dificati o ns a n d 
d ose i nte nsities.  
•  A G -1 2 0 a n d 2 -H G c o n ce ntrati o ns i n circ ulati n g pl as ma.  
 
 
 
 

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7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n  
St u d y A G 1 2 0 -C -0 0 9 is a gl o bal, P hase 3, m ultice nter, d o u ble -bli n d, ra n d o mize d, place b o -
c o ntr olle d cli nic al trial t o e val uate t he efficac y a n d safet y of A G -1 2 0 + azaciti di ne vs 
place b o  +  azaciti di ne i n a d ult s u bjects wit h pre vi o usl y u ntreate d I D H 1 m A M L a n d w h o are 
c o nsi dere d a p pr o priat e ca n di dates f or n o n -i nte nsi ve t hera p y. U p t o 1 9 0 st u d y ce nters i n 
2 0  c o u ntries will partici p ate i n t his st u d y. 
F oll o wi n g pr o visi o n of i nf or me d c o ns e nt, all s u bjects will u n der g o Scree ni n g pr oce d ures wit hi n 
4 wee ks ( 2 8 d a ys) pri or t o ra n d o mizati o n t o deter mi ne eli gi bilit y. Ge n e m utati o n a nal ysis f or 
c o nfir mati o n of I D H 1 m disease fr o m a b o ne marr o w a n d ger m-li ne m utati o n a nal ysis fr o m a 
b uccal s wa b will be c o n d ucte d f or all s u bjects, a n d ca n be c o n d ucte d pri or t o t he 2 8 -da y 
Scree ni n g wi n d o w. Ce ntr al la b orat or y c o nfir mati o n of I D H 1 m stat us is re q uire d f or st u d y 
eli gi bilit y. Wit h Me d ical M o nit or a p pr o val, s u bjects ma y be eli gi ble a n d ra n d o mize d wit h l ocal 
I D H 1 m testi n g res ults; h o we ver, b o ne marr o w as pirate f or ce ntr al la b orat or y testi n g m ust ha ve 
bee n se nt wit h pr o of of s hi p me nt t o t he ce ntral la b orat or y pri or t o r a n d o mizati o n. In ca ses w here 
b o ne marr o w as pirate is n ot a vaila ble  (ie, dr y ta p), peri p heral bl o o d sa m ples ma y be use d f or 
I D H 1 m c o nfir m ati o n wit h Me dical M o nit or a p pr o val. A d diti o nal Scree ni n g pr oce d ures i ncl u de, 
b ut are n ot li mite d t o: me dical a n d me dicati o n hist or y; b o ne marr o w as pirat e/ bi o ps y f or 
; c o m plete p h ysical e x a mi nati o n; vital si g ns; 1 2-lea d 
E C G; E C O G P S; E C H O or M U G A sca n f or L V E F ( met h o d per i nstit uti o nal sta n dar d of care, 
wit h t he sa me met h o d use d f or a n i n di vi d ual s u bject t hr o u g h o ut t he st u d y; i n Ger ma n y, o nl y 
E C H O will be perf or me d); cli nical la b orat or y assess me nts ( he mat ol o g y, c h e mistr y, c o a g ulati o n, 
a n d ser u m pre g na nc y test); Q o L assess me nts; a n d 
. 
S u bjects eli gi ble f or st u d y treat me nt bas e d o n Scree ni n g assess me nts will be ra n d o mize d 1: 1 t o 
recei v e oral A G-1 2 0 or matc he d place b o, b ot h a d mi nistere d i n c o m bi nati o n wit h S C or I V 
azaciti di ne. Ra n d o mizati o n will be stratifie d b y d e n o v o stat us ( de n o v o  A M L a n d s ec o n d ar y 
A M L) a n d ge o gra p hic re gi o n ( U nite d States a n d Ca na da; Wester n E ur o p e, Israel, a n d A ustralia; 
J a pa n; a n d rest of w orl d).  
A n o ver vie w of t he st u d y desi g n is pr o vi de d i n Fi g ure  1 . 

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Fi g ure  1 : 
Sc he m a f or St u d y A G 1 2 0 -C -0 0 9  
 
A b bre viati o ns: C R = c o m plete re missi o n; C R h = C R wit h partial he mat ol o gic rec o ver y; E F S  =  e ve nt -free s ur vi val; 
I V =  i ntra ve no us; O R R = o bjecti ve res p o nse rate; O S = o verall s ur vi val; P O  =  oral; Q = e ver y; Q D = o nce dail y; R O W  =  Rest 
of  W orl d; S C  =  s u bc uta ne o us. 
S u bjects s h o ul d be treate d f or a mi ni m u m of 6 c ycles of c o m bi nati o n t hera p y u nless t he y 
e x perie nce rela pse after ac hie vi n g a C R, C Ri (i ncl u di n g C R p), or M L F S; disease pr o gressi o n 
pri or t o ac hie vi n g C R , C Ri (i ncl u di n g C R p), or M L F S ; u n acce pta ble t o xicit y ( A E); c o nfir me d 
pre g na nc y; wit h dra wal b y s u bject; pr ot o c ol vi olati o n; deat h; or E n d of St u d y.  
Treat me nt will be a d mi nis tere d as f oll o ws: 
•  All s u bjects will recei ve azaciti di ne 7 5 m g/ m 2/ da y S C or I V f or t he first w ee k 
( 7 da ys) ( or o n a 5 -2 -2 sc he d ule) of eac h 4 -wee k ( 2 8 -da y) c ycle i n c o m bi nati o n wit h 
A G -1 2 0 or pla ce b o Q D o n eac h d a y of t he 4 -wee k c ycle. T he s a me sc h e d ule s h o ul d 
be use d f or eac h s u bj ect t hr o u g h o ut t he d urati o n of treat me nt, w h e n p ossi ble.  
•  S u bjects s h o ul d c o nti n ue t o recei ve t h era p y wit h A G -1 2 0 or place b o + azaciti di ne 
u ntil deat h, disease rel a pse, disease pr o gressi o n, d e vel o p me nt of u nacce pt a ble 
t o xicit y (a d v erse e ve nt), c o nfir me d pre g na nc y, wit h dra wal b y s u bject, pr ot oc ol 
vi olati o n, or E n d of St u d y ( defi ne d i n Secti o n  9. 1 1. 1 ).  
− Disease pr o gressi o n ( defi ne d o nl y f or s u bjects w h o ha ve n ot pre vi o usl y att ai ne d 
C R, C Ri, C R p, or M L F S ) is defi ne d as e vi de nce f or a n i ncrease i n b o ne m arr o w 
blast perce nt a ge a n d/ or i ncreas e of a bs ol ute bl ast c o u nts i n t he bl o o d: 1) > 5 0 % 
i ncreas e i n b o ne marr o w blast c o u nt o ver baseli ne (a mi ni m u m 1 5 % p oi nt 
i ncreas e is re q uire d i n cases wit h < 3 0 % blasts at b aseli ne); or persiste nt marr o w 
blast perce nt a 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 ( > 5 0 0/ µ L, a n d/ or plat elet c o u nt t o 
> 5 0, 0 0 0/ µ L n o n -tr a nsf us e d); 2) > 5 0 % i ncrease i n peri p heral blasts ( w hite bl o o d 
cells [ W B Cs] × %  blasts) t o > 2 5, 0 0 0/ µ L i n t he a bs e nce of treat me nt -relate d 
differe ntiati o n s y n dr o me; or 3) ne w e xtra me d ullar y diseas e.  

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− S u bjects wit h a res p o nse less t ha n C R at 2 4 wee ks or be y o n d ca n c o nti n ue o n 
treat me nt if de m o nstrati n g treat me nt be nefit, defi n e d as a n y of t h e f oll o wi n g: 
1)  Tra nsf usi o n -i n d e pe n d e nce w hile o n st u d y tr eat me nt; 2) A N C > 5 0 0/ µ L; or 3) 
platelets > 5 0, 0 0 0/ µ L.  
All s u bjects will ha ve t he e xte nt of t heir disease assesse d b y b o ne marr o w as pirate (e xte nt of 
disease ma y be assesse d b y bi o ps y if sta n dar d of care or i n t he e ve nt of a dr y ta p or as pic ular 
[ dil ute d] sa mple) a n d peri p heral bl o o d sa m ples at Scree ni n g ( or as part of t he Pre -scree ni n g 
pr ocess, as l o n g as it is wit hi n 2 8 da ys pri or t o r a n d o mizati o n); a n d Da y 1 ( ±  7 da ys) of Wee ks 9, 
1 7, 2 5, 3 3, 4 1, 5 3 a n d e v er y 2 4 wee ks t hereafter; at E O T; d uri n g E F S f oll o w -u p o n t he sa me 
sc he d ule; as cli nic all y i n dicate d; a n d/ or a n y ti me t hat disease pr o gressi o n is s us pecte d. T he 
disease assess me nt s c he d ule s h o ul d n ot be altere d d ue t o c ha n ges i n t he start of treat me nt c ycl es 
(e g, i n t he cas e of a treat me nt i nterr u pti o n t hat res ulte d i n a dela y t o t he start of s u bse q ue nt 
c ycles).  
D uri n g tr eat me nt, r es p o nse will be e val uate d b y t h e I n vesti gat or bas e d o n m o difie d I W G 
Res p o nse Criteria f or A M L (C hes o n et al, 2 0 0 3 ) a n d E ur o pea n Le u ke mia Net ( E L N) g ui d eli nes 
(D ö h ner et al, 2 0 1 7) t o d eter mi ne s u bject stat us a n d c o nti n uati o n o n st u d y treat me nt (see 
Secti o n  1 0. 8. 1 ). I n vesti gat or res p o nse assess me nts will be use d f or t he a n al ysis of all efficac y 
e n d p oi nts, u nless ot her wise defi ne d.  
All s u bjects will u n der g o safet y assess me nts t hr o u g h o ut t he treat me nt peri o d, t o i ncl u de p h ysic al 
e x a mi nati o n, vital si g ns, E C O G P S, E C G, E C H O or M U G A f or L V E F as cli nicall y i n dicate d 
( met h o d per i nstit uti o nal sta n dar d of care, wit h t he sa me met h o d use d f or a n i n di vi d ual s u bject 
t hr o u g h o ut t he st u d y; sites i n Ger ma n y ma y o nl y use E C H O), cli nical la b orat or y assess me nts 
( he mat ol o g y, c he mistr y, c oa g ulati o n), a n d assess me nt of A Es, A E SIs, S A Es, A Es lea di n g t o 
disc o nti n uati o n or deat h, a n d c o nc o mita nt me dicati o n  use. T o xicit y se v erit y will be gra de d 
acc or di n g t o t he N ati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteri a f or A Es ( N CI 
C T C A E) versi o n  4. 0 3.  
Safet y d ata will be re vie we d re g ularl y b y a n I D M C t o e ns ure t he safet y of t he c o m bi nati o n 
t hera p y. T hes e re vi e ws will occ ur after t he first 6, 1 2, 2 4, a n d 3 6 s u bjects h a ve c o m plete d 
1  c ycle of t hera p y or dis c o nti n ue d, w hic he ver s h o ul d occ ur first. T hereafter, safet y re vie ws will 
be c o n d ucte d a p pr o xi matel y e ver y 6 m o nt hs u ntil t he st u d y is u n bli n de d f or t he a nal ysis  of t he 
pri mar y e n d p oi nt. N o i nteri m a nal yses f or efficac y are pla n ne d.  
All s u bjects are t o u n der g o a n E O T assess me nt wit hi n 1 wee k of t heir last d ose of st u d y 
treat me nt ( A G-1 2 0/ place b o or azaciti di ne). If a s u bject disc o nti n ues st u d y treat me nt at a 
re g ularl y sc h e d ule d visit, E O T assess me nts ma y b e perf or me d at t hat visit. A p ost-treat me nt 
safet y assess me nt is t o be sc he d ule d 4 wee ks ( ±  3 da ys) after t he last d ose of st u d y tr eat me nt.  
All s u bjects w h o disc o nti n ue st u d y tr eat me nt wit h o ut e x perie nci n g a n y 1 of  t he f oll o wi n g: deat h, 
disease rel a pse, treat me nt fail ure, or wit h dr a wal of c o nse nt, will be f oll o we d e ver y Da y 1 
( ± 7  da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4  wee ks t hereafter f or E F S u ntil t he y 
e x perie nce tr eat me nt fail ure, rel a pse, deat h, wit h dra w  fr o m t he st u d y, or u ntil t he ti me w he n 
1 7 3  E F S e ve nts ha v e occ urre d  or as dee m e d necessar y b y t he I D M C .  
O nce t he st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue. All s u bjects w h o are ali ve aft er a n 
E F S e ve nt will be c o nta cte d e ver y 8  w ee ks f or s ur vi val f oll o w -u p u ntil deat h, wit h dra wal b y 
s u bject, l oss t o f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 

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7. 2.  
Criteri a f or St u d y Cl os ure  
T his st u d y ma y be pre mat urel y cl ose d if, i n t he o pi ni o n of t he S p o ns or, t here is s ufficie ntl y 
reas o na bl e ca us e. I n t he e ve nt of s uc h acti o n, writte n n otificati o n d oc u me nti n g t he reas o n f or 
st u d y cl os ur e will be pr o vi de d t o eac h I n v esti gat or. 
Circ u msta nces t hat ma y warra nt pre mat ure st u d y cl os ure i ncl u de, b ut are n ot li mite d t o:  
•  Deter mi nati o n of u ne x pecte d, si g nifi ca nt, or u nacce pta ble ris k t o s u bjects  
•  Fail ure t o e nr oll s u bjects at a n acce pta ble rate  
•  I ns ufficie nt a d h ere n ce t o pr ot oc ol re q uire m e nts 
•  Pla ns t o m o dif y, s us p e n d, or disc o nti n ue t he de vel o p me nt of t he st u d y dr u g  
•  Ot her a d mi nistrati ve reas o ns  
S h o ul d t he st u d y b e cl ose d pre mat urel y, all st u d y materials m ust be destr o ye d or ret ur n e d t o t he 
S p o ns or or S p o ns or’s desi g nee u p o n re q u est. See Secti o n  8. 5  f or s pecifi c re q uire me nts f or 
s u bject ter mi nati o n fr o m t he st u d y. 
7. 3.  
Te m p or ar y M o dific ati o ns All o we d D uri n g P u blic He alt h 
E mer ge ncies  
I n t he e ve nt of a c or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) p u blic healt h e mer ge n c y  t hat affect s a 
ge o gra p hic area (e g, st ate, pr o vi nce, c o u ntr y, re gi o n, c o nti ne nt) a n d i m pe des a d here n ce t o 
pr ot oc ol -s pecifi e d pr oce d ures, certai n m o dificati o ns ( Secti o n 7. 3. 1 ) are te m p oraril y all o wa ble t o 
e ns ure s u b ject s afet y, mai ntai n c o m plia nce wit h G C P, a n d mi ni mize ris ks t o st u d y i nte grit y; t h e 
pr ot oc ol m ust be f oll o we d t o t he f ullest e xte nt p ossi ble.  
T hese m o dificati o ns are o nl y all o wa bl e 1) w he n c o nsiste nt wit h a p plica ble re g ulati o ns a n d 
g ui da n ce a n d 2) f or t he d urati o n of t he C O VI D -1 9 p u blic healt h e mer ge nc y. D uri n g t his peri o d, 
t he nee d f or all i m ple me nte d m o dificati o ns will be reass esse d a n d t h e S p o ns or will n o l o n ger 
all o w t hese m o dificati o ns o nce t he sit uati o n res ol ve s. 
D oc u me nte d a p pr o val fr o m t he S p o ns or is re q uire d bef ore t hese m o dificati o ns ca n be 
i m ple me nte d. 
I v osi de ni b Ass ess me nt: T he S p o ns or has c o n d uct e d a ris k assess me nt f or c o nc o mita nt use of a 
C O VI D -1 9 vacci ne wit h i v osi de ni b wit h s pecific c o nsi derati o n f or t h e trial p o p ulati o n a n d 
deter mi ne d t hat t he C O VI D -1 9 vacci ne gi ve n t o a trial s u bject is c o nsi dere d a si m ple 
c o nc o mita nt me dicati o n wit h n o i nteracti o n t hat re q uires a d vice o n ti mi n g of t he vacci ne or ot her 
as pects t hat ne e d t o be miti gate d.  
Azaciti di ne Assess me nt: T here is n o  k n o w n i nt eracti o n (eit her bi ol o gical or p har mac ol o gical) 
bet wee n i n vesti gati o nal pr o d uct a n d a v aila ble a ut h orize d C O VI D -1 9 vacci n es base d o n t he 
mec ha nis m of acti o n a n d meta b olis m of azaciti di ne. T here is li mite d data o n t he efficac y a n d 
safet y of C O VI D-1 9 vacci nes  i n patie nts wit h ca n cers, i ncl u di n g he mat ol o gic mali g na n cies. T he 
effic ac y a n d s afet y of vacci nati o n i n s u bjects w h o are recei vi n g azaciti di ne are u n k n o w n. 
C urre ntl y a p pr o ve d or a ut h orize d C O VI D -1 9 vacci ne gi ve n t o a trial s u bject is c o nsi dere d as a 
si m ple c o nc o mita nt me dicati o n wit h n o a ntici pate d i nteracti o n t hat re q uir es s pecific a d vice o n 
ti mi n g of t he vacci ne or ot her as pects d uri n g t h e treat me nt peri o d. 

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7. 3. 1.  
All o w a ble Te m p or a r y M o dific ati o ns  
T he f oll o wi n g t e m p orar y m o dificati o ns are all o we d i n t he e ve nt o f a C O VI D -1 9 p u blic healt h 
e mer ge n c y a n d m ust be re p orte d as pr ot o c ol de viati o ns; refer t o Sc he d ule of Assess me nts 
(Ta ble  6 ) f or t he ti mi n g of assess ments.  
•  Alter nati ve distri b uti o n of st u d y dr u g  
− A G -1 2 0 ma y be s hi p pe d t o a l ocal healt hcare pr o vi der or p har m ac y or, if 
necessar y, directl y t o a s u bject. T he q ua ntit y t o be s hi p pe d m ust be re vie we d a n d 
a p pr o ve d i n a d v a nce b y t he S p o ns or ( or desi g nee), i n a gree me nt wit h t he 
In v esti gat or.  
− Azaciti di ne ma y n ot  be s hi p pe d directl y t o a s u bject. Please refer t o Secti o n 9. 7. 2  
( Azaciti di ne) f or i nstr ucti o ns o n ma na ge me nt of azaciti di ne. 
− Sec ure, tr ac ka bl e deli ver y met h o ds ( deli ver y ser vi ce c o m pa ni es [e g, D H L], 
c o uriers, a n d ha n d deli ver y) m ust be use d.  
− S p o ns or ( or d esi g nee) a p pr o val is re q uire d b ef ore eac h s hi p me nt. S hi p me nt will 
o nl y be p er mitte d if, at mi ni m u m, a tele me dici ne visit has bee n c o n d ucte d t hat 
i nc or p orates a p pr o priat e safet y assess me nts. 
•  Ret ur ni n g u n use d st u d y dr u g, e m pt y st u d y dr u g p ac ka gi n g, a n d rele v a nt dr u g diar y 
pa ges  
− Ret ur n of u n use d st u d y dr u g a n d e m pt y st u d y dr u g pac ka gi n g ma y b e dela ye d 
u ntil t he s u bject’s ne xt visit t o t he st u d y site. I n certai n circ u msta nces, t he n at ure 
of t he ret ur n pr ocess ma y var y (e g, p ers o nal pr otecti ve e q ui p me nt ma y b e 
re q uire d).  
− Ret ur n of pa per dr u g diaries ma y b e dela ye d. Site, wit h S p o ns or a gree me nt, 
s h o ul d pr o vi de i nstr ucti o ns t o s u bjects re gar di n g ti mi n g a n d met h o d f or ret ur ni n g 
rele va nt dr u g di ar y pa ges. 
•  Tele me dici ne visits f or assess me nts ot her t ha n patie nt -re p orted o ut c o mes ( P R Os)  
− Tele me dici ne visits, prefera bl y via vi de o c o nfere n ce, are per missi ble f or all 
assess me nts t hat ca n be c o m plete d via t his m o de (e g, m e dical hist or y, 
c o nc o mita nt me dicati o ns, re vie w of a d verse e v e nts).  
•  Use of la b orat ories a n d h ealt hcare pr o vi ders n ot s pecifie d i n t he cli nical trial 
d oc u me ntati o n  
− F or ass ess me nts t hat ca n n ot be c o m plete d via tele me dici ne, t he use of healt hcare 
pr o vi ders a n d la b orat ories t hat are n ot s pecifie d i n t he cli nical trial d oc u me ntati o n 
(e g, a n i ma gi n g facilit y, cli nic , or l ocal practice t h at is m ore rea dil y accessi ble b y 
t he s u bject) is per missi ble f or all ass ess me nts t hat ca n be c o m plete d via t his m o de 
(e g, bl o o d c ollecti o n f or l a b orat or y assess me nts, E C G, p h ysical e x a mi nati o ns, 
i ma gi n g). 

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− Use of a la b orat or y or healt h care pr o vi der n ot s pecifie d i n t he cli nical trial 
d oc u me ntati o n re q uir es c o or di nati o n bet wee n t he s u bject, t he i n vesti gat or, a n d t he 
s u bject's l oc al healt hcare pr o vi der. 
− T he i n vesti gat or m ust d oc u me nt t heir re vie w of t h e res ults pr o vi de d b y 
la b orat ories a nd h ealt hcare pr o vi ders n ot s p ecifie d i n t he cli nical trial 
d oc u me ntati o n.  
•  H o me healt h st u d y s u p p ort  
− F or ass ess me nts t hat ca n n ot be c o m plete d via tele me dici ne, h o me healt hcare 
pr o vi der visits are per missi ble f or all assess me nts t hat ca n be c o m plete d via t hi s 
m o de (e g, p h ysical e x a mi nati o n, c ollecti o n of cli nical la b orat or y s a m ples).  
− T he S p o ns or ma y facilitate a n d c o or di nat e t hese visits wit h t he st u d y site.  
− T he I n vesti gat or m ust d o c u me nt t heir re vie w of t h e res ults of h o me healt hcare 
pr o vi der visits.  
•  Virt ual  i nf or me d rec o nse nt i n lie u of i n-pers o n i nf or me d rec o nse nt  
− Rec o nse nt (ie, c o ns e nti n g t o a n a me n de d v ersi o n of t he pr ot oc ol ) ma y b e 
c o m plete d virt uall y a n d d oc u me nte d i n t he rel e va nt s u bject me dical rec or ds. I n 
t hese i nsta nces, r ec o nse nt ma y be c o m plete d virt u all y w here all o we d b y t h e 
a p plica ble re g ulati o ns, a n d d oc u me nte d i n t he rel e va nt s u bject me dical rec or ds.  

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8.  
S T U D Y P O P U L A TI O N  
8. 1.  
N u m ber of S u bjects  
A t otal of a p pr o xi matel y 2 0 0 s u bjects wit h pre vi o usl y u ntreate d I D H 1 m A M L will partici pat e i n 
t his st u d y.  
8. 2.  
Incl usi o n Criteri a  
S u bjects m ust meet all of t he f oll o wi n g criteria t o be eli gi ble f or i ncl usi o n i n t he st u d y:  
1.  Be ≥1 8 years of a ge a n d meet at least 1 of t he f oll o wi n g criteria d efi ni n g i n eli gi bilit y f or 
i nte nsi ve I C:  
a. ≥ 7 5 years ol d  
b.  E C O G P S = 2  
c. Se vere car diac dis or der (e g, c o n gesti ve heart fail ure re q uiri n g tr eat me nt, L V E F 
≤5 0 %, or c hr o nic sta bl e a n gi n a)  
d.  Se vere p ul m o nar y dis or d er (e g, diff usi n g ca p acit y of t he l u n gs f or car b o n m o n o xi de 
≤6 5 % or f orce d e x pirat or y v ol u me i n 1 sec o n d ≤6 5 %)  
e. Creati ni ne cleara n ce < 4 5 m L/ mi n ute  
f. Bilir u bi n > 1. 5 ti mes t he u p per li mit of n or mal ( × U L N)  
g.  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 
I C m ust be re vie we d a n d a p pr o ve d b y t he M e dical M o nit or bef ore st u d y e nr oll me nt. 
2.  Ha ve pre vi o usl y u ntr eate d A M L, d efi ne d acc or di n g t o W H O criteria. S u bjects wit h 
e xtra me d ullar y dise ase al o ne (ie, n o detecta ble b o ne marr o w a n d n o detect a ble peri p heral 
bl o o d A M L) are n ot eli gi ble f or t he st u d y.  
3.  Ha ve a n I D H 1 m utati o n res ulti n g i n a n R 1 3 2 C, R 1 3 2 G, R 1 3 2 H, R 1 3 2 L, or R 1 3 2 S 
s u bstit uti o n, as deter mi ne d b y ce ntr al la b orat or y t esti n g ( usi n g a n i n vesti gati o nal 
p ol y merase c h ai n reacti o n [ P C R] assa y, A b b ott R eal Ti me I D H 1) i n t heir b o ne marr o w 
as pirate ( or peri p heral bl o o d sa m ple if b o ne marr o w as pirate is n ot a vaila bl e, wit h 
Me dical M o nit or a p pr o val ).  
( N ote: L ocal testi n g f or eli gi bilit y a n d ra n d o mizati o n is per mitte d wit h Me dical M o nit or 
a p pr o val; h o we v er, res ults m ust state a n I D H 1 m utati o n res ulti n g i n a n R 1 3 2 C, R 1 3 2 G, 
R 1 3 2 H, R 1 3 2 L, or R 1 3 2 S s u bstit uti o n. B o ne marr o w as pirate [ or peri p heral bl o o d 
sa m ple if b o ne marr o w as pirate is n ot a vaila ble, wit h Me dical M o nit or a p pr o val] f or 
ce ntral la b orat or y testi n g m ust ha ve bee n se nt wit h pr o of of s hi p me nt t o t he ce ntr al 
la b orat or y pri or t o r a n d o mizati o n.) 
4.  Ha ve a n E C O G P S sc ore of 0 t o 2.  
5.  Ha ve a d e q uate h e patic f u ncti o n, as e vi de nce d b y:  
a. Ser u m t otal bilir u bi n ≤2  ×  U L N, u nless c o nsi dere d t o be d ue t o Gil bert’s disease or 
u n derl yi n g le u k e mia, w h ere it m ust be < 3  × U L N.  
b.  As partate a mi n otra nsferase ( A S T), ala ni n e a mi n otra nsferase ( A L T), a n d al kali ne 
p h os p hatase ( A L P) ≤3. 0  ×  U L N, u nless c o nsi dere d t o be d ue t o u n derl yi n g le u ke mia.  

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6.  Ha ve a d e q uate re nal f u ncti o n, as e vi de nce d b y s er u m creati ni ne ≤2. 0  ×  U L N or creati ni ne 
cleara nce  3 0 m L/ mi n b ase d o n t he C oc kcr oft -Ga ult gl o mer ular filtr ati o n rate.  
7.  Ha ve a gree d t o u n d er g o s erial bl o o d a n d b o ne marr o w sa m pli n g.  
8.  Be a bl e t o u n dersta n d a n d willi n g t o si g n a n i nf or me d c o nse nt f or m (I C F).  
9.  Be willi n g t o c o m plete Q o L ass ess me nts d uri n g st u d y treat me nt a n d at t he desi g nat e d 
ti me p oi nts f oll o wi n g treat me nt disc o nti n uati o n. 
1 0.  If fe mal e wit h re pr o d ucti ve p ote ntial, m ust ha ve a ne gati ve ser u m pre g na n c y test pri or t o 
t he start of st u d y t h era p y. Fe male s u bjects wit h re pr o d ucti ve p ote ntial are defi ne d as 
se x uall y mat ure w o me n w h o ha ve n ot u n der g o ne a h ysterect o m y, bilateral 
o o p h orect o m y, or t u bal o ccl usi o n or w h o ha v e n ot bee n nat ur all y p ost me n o pa usal f or at 
least 2 4 c o nsec uti ve m o nt hs. Fe males of re pr o d ucti ve p ote ntial, as well as fertile me n 
wit h fe male part ners of re pr o d ucti ve p ote ntial, m ust use 2 effect i ve f or ms of 
c o ntrace pti o n (i ncl u di n g at least 1 barri er f or m) fr o m t he ti me of gi vi n g i nf or me d c o nse nt 
t hr o u g h o ut t he st u d y a n d f or 9 0 da ys ( b ot h fe males a n d males) f oll o wi n g t he last d ose of 
st u d y dr u g(s). Effecti ve f or ms of c o ntrace pti o n are defi ne d as h or m o nal or al 
c o ntrace pti ves, i njecta bles, patc hes, i ntra uteri ne de vices, i ntra uteri ne h or m o ne -rel easi n g 
s yste ms, bilateral t u bal li gati o n, c o n d o ms wit h s per mici de, or male p art ner sterilizati o n. 
C oa d mi nistrati o n of A G -1 2 0 ma y d ecrease t h e c o nce ntrati o ns o f h or m o n al c o ntrace pti ves 
( Secti o n 9. 1 3. 2 ). 
8. 3.  
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 criteri a will be e x cl u de d fr o m t he st u d y:  
1.  Are ca n di dates f or i nte nsi ve I C f or t heir A M L.  
2.  Ha ve recei v e d a n y pri or treat me nt f or A M L  wit h t he e x ce pti o n of n o n o nc ol ytic 
treat me nts t o sta biliz e disease s uc h as h y dr o x y urea or le u ka p heresis. 
3.  Ha ve recei v e d a h y p o met h ylati n g a ge nt f or m yel o d ys plastic s y n dr o me ( M D S).  
4.  S u bjects w h o ha d pre vi o usl y recei ve d treat me nt f or a n a ntece de nt h e mat ol o gic  dis or d er, 
i ncl u di n g i n vesti gati o nal a ge nts, ma y n ot be ra n d o mize d u ntil a was h o ut peri o d of at least 
5 half -li ves of t he i n vesti gati o nal a ge nt has el a pse d si nce t he last d ose of t h at a ge nt.  
5.  Ha ve recei v e d pri or tr eat me nt wit h a n I D H 1 i n hi bit or.  
6.  Ha ve a k n o w n h y pers e nsiti vit y t o a n y of t h e c o m p o ne nts of A G -1 2 0, mat c h e d place b o, or 
azaciti di ne.  
7.  Are fe male a n d pre g na nt or breastf ee di n g.  
8.  Are ta ki n g k n o w n str o n g C Y P 3 A 4 i n d ucers or se nsiti ve C Y P 3 A 4 s u bstrate me dicati o ns 
wit h a narr o w t h era p e utic wi n d o w, u nless  t he y ca n be tra nsferre d t o ot her me dicati o ns 
wit hi n ≥5 half -li ves pri or t o d osi n g ( A p pe n di x 1 5. 6 ).  
9.  E x cl usi o n Criteri o n # 9 was re m o ve d i n Pr ot oc ol  A me n d me nt 5, Versi o n 6. 0.  
1 0.  Ha ve a n acti ve, u n c o ntr olle d, s yste mic f u n gal, bacterial, or viral i nfecti o n wit h o ut 
i m pr o ve me nt des pite a p pr o priate a nti bi otics, a nti viral t hera p y, a n d/ or ot her treat me nt. 

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1 1.  Ha ve a pri or hist or y of m ali g na n c y ot her t ha n M D S or m ye l o pr oliferati ve dis or der, 
u nless t he s u bject has bee n free of t he dise ase f or ≥1 year pri or t o t he start of st u d y 
treat me nt. H o we v er, s u bj ects wit h t he f oll o wi n g hist or y/c o nc urre nt c o n diti o ns or si milar 
i n d ole nt ca ncer are all o w e d t o partici pate i n t he st ud y:  
a. Basal or s q u a m o us cell carci n o ma of t h e s ki n  
b.  Carci n o ma i n sit u of t he cer vi x  
c. Carci n o ma i n sit u of t he breast  
d.  I n ci de ntal hist ol o gic fi n di n g of pr ost ate ca n cer 
1 2.  Ha ve ha d si g nifica nt acti ve car di ac dise ase wit hi n 6 m o nt hs pri or t o t he start of st u d y 
treat me nt, i ncl u di n g Ne w Y or k Heart Ass ociati o n Class ( N Y H A) Class III or I V 
c o n gesti ve heart fail ure (see A p pe n di x  1 5. 2 ), m y o car dial i nfarcti o n, u nsta ble a n gi na, 
a n d/ or str o ke.  
1 3.  Ha ve a h eart -rate c orrect e d Q T i nter val usi n g Fri d ericia’s met h o d ( Q Tc F) ≥4 7 0 msec or 
a n y ot h er fact or t hat i ncreases t he ris k of Q T pr ol o n gati o n or arr h yt h mic e ve nts (e g, 
N Y H A Class III or I V c o n g esti ve h eart fail ure, h y p o kale mia, fa mil y hist or y of l o n g Q T 
i nter val s y n dr o me). S u bj ects wit h pr ol o n ge d Q Tc F i nter val i n t he setti n g of b u n dle 
bra nc h bl oc k ma y p artici pate i n t he st u d y.  
1 4.  Ha ve a k n o w n i nfecti o n ca use d b y h u ma n i m m u n o deficie nc y vir us ( HI V) o r acti ve 
he patitis  B vir us ( H B V) or he patitis C vir us t hat ca n n ot be c o ntr olle d b y tr eat me nt.  
1 5.  Ha ve d ys p ha gi a, s h ort -g ut s y n dr o me, gastr o paresis, or a n y ot h er c o n diti o n t hat li mits t he 
i n gesti o n or gastr oi ntesti nal a bs or pti o n of orall y a d mi nistere d dr u gs.  
1 6.  Ha ve u nc o ntr olle d h y p ert e nsi o n (s yst olic bl o o d press ure [ B P] > 1 8 0  m m H g or diast olic 
B P > 1 0 0  m m H g).  
1 7.  Ha ve cli nic al s y m pt o ms s u g gesti ve of acti ve ce ntr al ner v o us s yste m ( C N S) le u ke mia or 
k n o w n C N S le u ke mia. E val uati o n of cere br os pi nal fl ui d d uri n g Scree ni n g is o nl y 
re q uire d if t here is a cli nical s us pici o n of C N S i n v ol ve me nt b y le u ke mia d uri n g 
Scree ni n g.  
1 8.  Ha ve i m me diate, life -t hr eate ni n g, se vere c o m plicati o ns of le u ke mia, s uc h as u nc o ntr olle d 
blee di n g, p n e u m o nia wit h h y p o xia or se psis, a n d/ or disse mi nate d i ntr a vasc ular 
c oa g ulati o n.  
1 9.  Ha ve a n y ot h er me dic al or ps yc h ol o gi cal c o n diti o n dee me d b y t he I n v esti gat or t o be 
li kel y t o i nterfere wit h t h e s u bject’s a bilit y t o gi ve i nf or me d c o nse nt or p artici pate i n t he 
st u d y. 
2 0.  Are ta ki n g me dicati o ns t hat are k n o w n t o pr ol o n g  t he Q T i nter val ( A p p e n di x 1 5. 5 ) u nless 
t he y ca n be tr a nsferre d t o ot her me dicati o ns wit hi n ≥5 half-li ves pri or t o d osi n g, or u nless 
t he me dicati o ns ca n b e pr o perl y m o nit or e d d uri n g t he st u d y. (If e q ui val e nt me dicati o n is 
n ot a vaila ble, heart rate c orrect e d Q T i nter val [ Q Tc] will be cl osel y m o nit ore d as defi ne d 
i n Secti o n 9. 1 3. 2 ). 
2 1.  S u bjects wit h a k n o w n me dical hist or y of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y 
( P M L). 

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8. 4.  
S u bject I de ntific ati o n a n d Re gistr ati o n  
S u bjects w h o are ca n di dates f or e nr oll me nt i nt o t he st u d y will be e v al uate d f or eli gi bil it y b y t he 
I n v esti gat or t o e ns ure t h at t he i ncl usi o n a n d e x cl usi o n criteria (see Secti o n s 8. 2  a n d 8. 3 , 
res pecti vel y) ha ve b ee n s atisfie d a n d t hat t he s u bject is eli gi ble f or p artici pati o n i n t his cli nical 
st u d y. T he M e dical M o nit or will c o nfir m eli gi bilit y f or all s u bjects pri or t o recei pt of  t h e first 
d ose of A G -1 2 0 or place b o.  
8. 5.  
S u bject Wit h dr a w al Criteri a  
S u bjects ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y reas o n. A s u bject’s 
wit h dra wal fr o m treat me nt or t he st u d y will n ot je o par dize t he relati o ns hi p wit h t heir healt hcare 
pr o vi ders or affect t heir f ut ure care. S u bjects ma y c h o ose t o wit h dra w fr o m t he st u d y treat me nt 
b ut a gree t o r e mai n o n st u d y f or f oll o w -u p c o nt act. T his decisi o n m ust be rec or de d i n writi n g b y 
t he st u d y site. 
S h o ul d a s u bject deci de t o wit h dra w, all eff ort s will be ma de t o c o m plete a n d re p ort t he pr ot oc ol-
defi ne d st u d y o bser vati o ns as c o m pletel y as p ossi ble a n d t o deter mi ne t he reas o n f or wit h dra wal.  
I n t he e ve nt a s u bj ect is wit h dra w n fr o m st u d y treat me nt or fr o m t he st u d y, t he Me dical M o nit or 
m ust be i nf o r me d. If t here is a me dical r eas o n f or wit h dra wal, t he s u bject will re mai n u n der t he 
s u per visi o n of t he I n vesti gat or u ntil satisfact or y healt h has ret ur ne d.  
W he n a s u bject disc o nti n ues st u d y tr eat me nt or wit h dra ws fr o m t he st u d y, t he pri mar y reas o n f or 
dis c o nti n uati o n or wit h dra wal m ust be rec or de d i n t he a p pr o priat e Secti o n  of t he electr o nic cas e 
re p ort f or m (e C R F) a n d all eff orts will be ma de t o c o m plete a n d re p ort fi nal st u d y o bser vati o ns 
as t h or o u g hl y as p ossi ble.  
8. 5. 1.  
Wit h dr a w al fr o m St u d y Tre at me nt  
S u bjects ma y wit h dr a w or be wit h dra w n fr o m st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns:  
•  Wit h dra wal b y s u bject  
•  A E  
•  Deat h  
•  Rela pse/ disease pr o gressi o n  
•  Treat me nt f ail ure (s u bjects wit h a res p o nse less t h a n C R after recei vi n g tr eat me nt f or 
at least 2 4 wee ks ) 
•  Cli nical pr o gressi o n ( wit hi n 2 4 wee ks) n ot c o nfir me d b y I W G assess me nt  
•  S u bject l ost t o f oll o w -u p  
•  C o nfir me d pre g na n c y f or fe male s u bjects o nl y (st u d y t hera p y s h o ul d be i m me diatel y 
i nterr u pte d base d u p o n a p ositi ve uri nar y h u m a n c h ori o nic g o n a d otr o pi n [ h C G] test, 
a n d per ma n e ntl y disc o nti n ue d if c o nfir me d b y a ser u m beta -h u ma n c h ori o nic 
g o na d otr o pi n [ β -h C G] test)  
•  Pr ot oc ol vi olati o n: n o n -a d here nce t o st u d y tr eat m e nt re gi me n or pr ot o c ol 
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T he I n vesti gat or s h o ul d f oll o w eac h A E u ntil t he e ve nt has re s ol ve d t o bas eli ne gra de or better, 
t he e ve nt is assesse d as sta ble b y t he I n vesti gat or, t he s u bject is l ost t o f oll o w-u p, or t he s u bject 
wit h dra ws c o nse nt. If a s u bject wit h dre w fr o m treat me nt beca us e of a n A E, e ver y eff ort m ust be 
ma de t o perf or m pr ot oc o l-s pecifie d safet y f oll o w-u p pr oce d ures (see Secti o n  1 0. 6 ). 
8. 5. 2.  
E ve nt -Free S ur vi v al F oll o w -u p  
All s u bjects w h o disc o nti n ue st u d y tr eat me nt wit h o ut e x per ie nci n g a n y 1 of t he f oll o wi n g: deat h, 
disease rel a pse, treat me nt fail ure,  or  wit h dr a wal of c o nse nt, will be f oll o we d e ver y Da y 1 
( ± 7  da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4  wee ks t hereafter f or E F S u ntil t he y 
e x perie nce tr eat me nt fail ure, rel a pse, deat h, wit h dra w fr o m t he st u d y, or u ntil t he ti me w he n 
1 7 3  E F S e ve nts ha v e occ urre d  or as dee m e d necessar y b y t he I D M C . 
8. 5. 3.  
S ur vi v al F oll o w -u p  
O nce t he st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue.  All s u bjects w h o are ali ve aft er a n 
E F S e ve n t will be c o nta cte d e ver y 8 wee ks f or s ur vi val f oll o w-u p u ntil deat h, wit h dra wal b y 
s u bject, l oss t o f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 
8. 5. 4.  
Wit h dr a w al fr o m t he St u d y  
S u bjects disc o nti n ui n g st u d y treat me nt pri or t o e x perie nci n g dise ase pr o gressi o n/r ela pse will 
c o nti n ue t o be f oll o we d f or disease pr o gressi o n/rel a pse/ deat h. T h e reas o ns f or wit h dra wal fr o m 
t he st u d y i ncl u de: 
•  Wit h dra wal b y s u bject  
•  S u bject l ost t o f oll o w -u p  
•  St u d y t er mi nate d b y S p o ns or  
•  Deat h  

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9.  
S T U D Y T R E A T M E N T  
9. 1.  
Descri pti o n of St u d y Dr u g  
A G -1 2 0 will be s u p plie d as 2 5 0  m g -str e n gt h ta blets t o be a d mi nistere d orall y. Place b o will be 
s u p plie d as matc he d ta bl ets t o be a d mi nistere d orall y. I n acti ve i n gre die nts of A G -1 2 0 ta blets are 
h y pr o mell ose acetate s ucci nate, micr ocr ystalli ne cell ul ose, cr oscar me ll ose s o di u m, s o di u m la ur yl 
s ulfate, c oll oi dal silic o n di o xi de, ma g nesi u m stearate, a n d O pa dr y ®  II Bl u e. T he i nacti ve 
i n gre di e nts of place b o t o matc h A G-1 2 0 ta blets are micr ocr ystalli ne cell ul ose, ma n nit ol, 
ma g n esi u m stearate, a n d O pa dr y ®  II Bl ue. 
Azaciti d i ne will be s u p plie d b y t he S p o ns or as a st erile l y o p hilize d p o w der c o ntai ni n g 1 0 0 m g 
azaciti di ne a n d 1 0 0 m g ma n nit ol per vial, t o be rec o nstit ute d a n d a d mi nistere d S C or I V.  
A G -1 2 0 is pr o vi de d f or i n vesti gati o nal use o nl y (c o nsi dere d a n i n vesti gati o nal m e dici nal 
pr o d uct; I M P) a n d is t o be use d o nl y wit hi n t he c o nte xt of t his st u d y. Azaciti di ne is als o 
c o nsi dere d a n I M P f or t his P hase 3 st u d y, wit h t he e x ce pti o n of sites i n Brazil, w here azaciti di ne 
will be s u p plie d as c o m mercial pr o d u ct. All st u d y dr u g pr o d ucts will be s u p plie d b y t he S p o ns or. 
Please see t he res pecti ve I Bs f or f urt her details re gar di n g A G -1 2 0 a n d azaciti di ne.  
9. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
A G -1 2 0 a n d mat c he d pla ce b o will be s u p plie d i n a p pr o priate c o ntai ners wit h c hil d -resista nt 
cl os ures a n d will be la b ele d a p pr o pri atel y as I M P f or t his st u d y.  
Azaciti di ne will be s u p plie d i n sterile si n gle -use vials a n d will be la bele d a p pr o priatel y as I M P 
f or t his st u d y ( or f or i n vesti gati o nal use, f or sites i n Brazil). 
Pac ka gi n g a n d la b eli n g wil l be pre pare d t o meet all re g ulat or y re q uire me nts. 
9. 3.  
St u d y Dr u g St or a ge  
A G -1 2 0 ta blets, matc h e d place b o ta blets, a n d azaciti di ne vials m ust be st ore d acc or di n g t o t he 
res pecti ve p ac k a ge la bel. 
All st u d y dr u g pr o d u cts m ust be st ore d i n a sec ure, li mite d -access l ocati o n a n d ma y be dis pe nse d 
o nl y b y t he I n v esti gat or or b y a me m ber of t he staff s pecifi call y a ut h orize d b y t he I n vesti gat or.  
9. 4.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt  
S u bjects w h o meet all st u d y eli gi bilit y criteria will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o recei ve 
A G -1 2 0 5 0 0  m g orall y Q D pl us 7 5 m g/ m 2/ da y S C or I V azaciti di ne or A G-1 2 0 -matc he d place b o 
orall y Q D pl us 7 5 m g/ m 2/ da y S C or I V azaciti di ne. Ra n d o mizati o n will be stratifie d b y d e n o v o 
stat us ( de n o v o A M L a n d sec o n dar y A M L) a n d ge o gra p hic re gi o n ( U nite d States a n d Ca na da; 
Wester n E ur o pe, Israel, a n d A ustralia; J a pa n; a n d rest of w orl d).  
T he ra n d o mizati o n sc he d ule wil l be ge nerate d b y a n i n de pe n de nt statistical gr o u p; all st u d y site 
pers o n nel (I n v esti gat ors, st u d y c o or di n at ors, st u d y p har macists) a n d t h e S p o ns or will be bli n de d 
t o st u d y treat me nt. T h e ra n d o mizati o n assi g n me nt will be i m ple me nte d b y i nteracti ve res p o nse 
tec h n ol o gi es (I R T).  

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9. 5.  
Bli n di n g  
T he s u bjects, I n vesti gat ors, S p o ns or, a n d t he cli nical res earc h u nit staff w h o deal directl y wit h 
s u bjects will all be bli n de d t o st u d y treat me nt assi g n me nt. T he I R T will assi g n eac h s u bject 
s pecific Me dic ati o n I D-l a bele d stu d y dr u g c o nt ai ners a n d azaciti di ne vials. A G -1 2 0 a n d mat c he d 
place b o will be pac ka ge d a n d la bele d i de nticall y s o t hat t he st u d y p har macist will re mai n bli n de d 
t o treat me nt assi g n m e nt.  
T he s u bjects, I n vesti gat ors, S p o ns or, a n d t he cli nical res earc h u nit s taff will re mai n bli n de d f or 
t he d urati o n of t he st u d y u ntil t he fi nal a nal ysis f or t he pri mar y e n d p oi nt u nless e mer ge n c y 
u n bli n di n g is re q uire d (see Secti o n  9. 6 ). A n I D M C will re vie w u n bli n de d safet y data a n d ot her 
cli nical data, i ncl u di n g efficac y d ata, at sc h e d ule d meeti n gs; t he u n bli n de d s u m maries will be 
pre pare d b y a n i n de p e n d e nt statistical ce nter (see Secti o n  1 0. 6. 1 ). 
9. 6.  
U n bli n di n g  
T he nee d t o u n bli n d st u d y treat me nt s h o ul d first be disc usse d wit h t he S p o ns or’s Me dical 
M o nit or ( or Me dical Dir ect or). I n t h e e ve nt of a me dical e mer ge nc y or pre g n a nc y i n a fe male 
s u bject, or i n t he fe mal e se x ual part ner of a m ale s u bject, i n w hic h k n o wle d ge of t he 
i n vesti gati o nal pr o d u ct is critical t o t he s u bject’s ma na ge me nt, t he bli n d f or t hat s u bject ma y be 
br o ke n b y t he treati n g I n vesti gat or. I n vesti gat ors ar e e n c o ura ge d t o disc uss a pla n t o brea k t h e 
bli n di n g c o de wit h t he M e dical M o nit or.  
I n t he cas e of a n e mer ge nc y, t h e I n vesti gat or ma y access t he I R T t o re v eal t he i de ntit y of t he 
treat me nt f or t hat s u bject. O nce t he d ecisi o n t o u n bli n d has bee n ma de, t he In v esti gat or m ust 
rec or d t h e nat ure of t he e mer ge nc y t hat re q uire d t he u n bli n di n g, al o n g wit h t he date a n d ti me of 
t he u n bli n di n g o n t he pr o per s o urce d oc u me ntati o n a n d n otif y t he S p o ns or’s Me dical M o nit or ( or 
Me dical Direct or) of t h e u n bli n di n g.  
I n t he e vent t hat a s u bj ect’s treat me nt assi g n me nt is u n bli n de d, eit her acci de ntall y or i n t he cas e 
of e mer ge nc y u n bli n di n g, t he s u bject will be all o we d t o c o nti n ue st u d y treat me nt (if t here is n o 
disease pr o gressi o n).  
I n cases w here I n vesti gat ors ma y n ee d t o k n o w pri or st u d y tr eat me nt assi g n me nt, (e g, a n S A E is 
treate d differe ntl y bas e d o n e x p os ure stat us), a n I n vesti gat or m a y re q u est s u bject u n bli n di n g. I n 
s uc h sit uati o ns a n d wit h Me dical M o nit or a p pr o val, t he s u bject a n d site staff will be u n bli n de d t o 
a s u bject’s  treat me nt assi g n me nt after d oc u me nte d disease pr o gressi o n (as assesse d b y t h e 
I n v esti gat or a n d after dis c ussi o n wit h t he S p o ns or’s Me dical M o nit or). 
Pri m ar y E n d p oi nt Res ults a n d S u bse q ue nt St u d y U n bli n di n g:  O nce t he pri mar y e n d p oi nt of 
E F S is statisticall y a nal yze d, t he S p o ns or will c o m m u nicate t he t o pli ne a g gre gate res ults of t he 
st u d y t o partici pati n g site i n vesti gat ors a n d vi a p u blic discl os ure. S h ortl y after p u blic discl os ure 
of t he t o pli ne a g gre gate res ults, t he S p o ns or will c o m m u nicate t o all sites t he treat me nt 
assi g n me nts of all s u bjects a n d will als o i nf or m sites w hic h of t he 2  f oll o wi n g sce nari os t o 
p urs ue f oll o wi n g u n bli n di n g.  
If t he be n efit -ris k pr ofile fa v ors treat me nt, all o n g oi n g s u bjects r a n d o mize d t o recei ve pl ace b o + 
azaciti di ne w h o meet k e y safet y eli gi bilit y criteria will be gi ve n t he o p p ort u nit y t o recei ve 
A G -1 2 0 + azaciti di ne f oll o wi n g u n bli n di n g. S u bjects w h o were alrea d y recei vi n g A G -1 2 0 + 
azaciti di ne ma y c o nti n ue t o recei ve treat me nt o n t he sa me assess m e nt sc he d ule. Pri or t o 

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cr oss o ver t o A G-1 2 0, i n v esti gat ors will e val uate s u bjects f or I n cl usi o n C riteria 5 a n d 6 a n d 
E x cl usi o n Cri teria 8, 1 2, 1 3, a n d 1 7 t o deter mi ne s afet y eli gi bilit y.  
If t he be n efit -ris k pr ofile d oes n ot fa v or treat me nt, cr oss o ver will n ot be per mitte d; h o we ver, all 
o n g oi n g patie nts will be per mitte d t o recei v e t heir assi g ne d st u d y tr eat me nt at t he discreti o n of 
t he treati n g i n vesti gat or. 
9. 7.  
St u d y Dr u g Pre p ar ati o n a n d A d mi nistr ati o n  
S u bjects ma y n ot r ecei v e st u d y treat me nt f or eac h treat me nt c ycl e u ntil all Da y 1 pr oce d u res 
ha ve bee n c o m plete d a n d all d oses of st u d y tr eat m e nt fr o m t he pri or tr eat m e nt c ycle ha ve bee n 
acc o u nte d f or, i ncl u di n g t he n u m ber of misse d d oses ( w here a p plica ble). F or fe males of 
re pr o d ucti ve p ot e ntial, a ser u m β-h C G pre g n a nc y test (se nsiti vit y of at  least 2 5 mI U/ m L) m ust 
be perf or me d at Scree ni n g wit hi n 7 2 h o urs pri or t o st u d y treat me nt a d mi nistrati o n a n d be 
verifie d as n e gati ve.  
T he first da y of st u d y treat me nt d osi n g is c o nsi dere d Da y 1 of a c ycl e.  
S u bjects will be m o nit ore d f or he m at ol o gic t o xicit y a n d n o n -he mat ol o gic (if t h o u g ht t o be 
ca usall y rel ate d) t o xicit y, wit h t he N CI C T C A E versi o n 4. 0 3 use d as a g ui d e f or t he gra di n g of 
se verit y (see Secti o n  1 1. 2 ). D osi n g i nterr u pti o ns or dela ys or d ose m o dificati o ns ma y occ ur f or 
ma na gi n g t o xicities a n d/ or treat me nt r es p o nse d uri n g st u d y treat me nt (s ee Secti o n  9. 8 ). 
9. 7. 1.  
A G -1 2 0 a n d M atc he d Pl ace b o  
A G -1 2 0 ( 5 0 0 m g) or m atc he d place b o will be a d mi nistere d orall y Q D (a p pr o xi matel y e v er y 
2 4  h o urs) d uri n g Wee ks 1 t o 4 i n c o nti n u o us 4 -wee k ( 2 8 -da y) c ycl es. Cr oss o ver bet wee n 
treat me nt ar ms will n ot be per mi tte d u ntil t he st u d y is u n bli n de d a n d t he pri mar y e n d p oi nt 
reac h es statistical si g nifi ca nce (see Secti o n 9. 6 ). S u bjects s h o ul d be i nstr ucte d t o ta ke t heir Q D 
d ose at a p pr o xi matel y t h e sa me ti me eac h da y. E ac h d ose s h o ul d be ta ke n wit h a glass of water 
a n d c o ns u me d o ver as s h ort a ti me as p ossi ble.  
S u bjects s h o ul d be i nstr ucte d t o s wall o w ta blets w h ole a n d n ot t o c he w t he ta blets. S u bjects ma y 
ta ke A G-1 2 0 or place b o ta blets wit h or wit h o ut f o o d. S u bjects s h o ul d be a d vise d t hat if 
A G -1 2 0/ place b o ta blets are ta ke n wit h f o o d, t h e s u bject s h o ul d a v oi d gr a pefr uit or gra pefr uit 
pr o d ucts a n d a v oi d c o ns u mi n g a hi g h -fat meal (refer t o re prese ntati ve e x a m ples of l o w-fat a n d 
hi g h -fat, hi g h-cal orie me als i n A p pe n di x  1 5. 1 ). 
If t he s u bject f or gets t o ta ke t he dail y d ose, t he y s h o ul d ta ke A G-1 2 0 or pl ace b o wit hi n 1 2 h o urs 
after t he misse d d ose. If m ore t ha n 1 2 h o urs ha v e ela pse d or if t he d os e was v o mite d, t hat d ose 
s h o ul d be o mitte d a n d t he s u bject s h o ul d res ume treat me nt wit h t he ne xt sc he d ule d d ose.  
S u bjects will be dis pe nse d t he a p pr o priat e n u m ber of S p o ns or -pac k a ge d, la bele d b ottles t o all o w 
f or d osi n g f or a f ull c ycle; alter nati vel y, t he y ma y be dis pe nse d a p pr o priate b ottle(s) u ntil t he 
ne xt sc he d ule d visit. S u bjects are t o r et ur n all u n use d ta blet s ( or t he e m pt y b ottles) o n Da y 1 
( ± 3  da ys) of eac h tr eat m e nt c ycle or at t he ne xt sc he d ule d visit.  
S u bjects will be gi ve n a d osi n g diar y f or eac h treat me nt c ycl e. T he y s h o ul d rec or d rele va nt 
i nf or mati o n re gar di n g t h eir st u d y dr u g i n t he diar y (e g, c o nfir m ati o n t hat eac h dail y d ose was 
ta ke n, reas o ns f or misse d d oses). 

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Treat me nt c o m plia nce (s ee Secti o n  9. 1 1. 3 ) will be assesse d bas e d o n t he ret ur n of u n use d dr u g 
a n d t he d osi n g diar y (see Secti o n  9. 1 2  a n d Secti o n  9. 1 3 ). 
9. 7. 2.  
Az aciti di ne  
S u bc uta ne o us or I V azaciti di ne will be pre pare d a n d a d mi nistere d as detail e d i n A p pe n di x  1 5. 3 . 
S u bjects will recei ve azaciti di ne 7 5 m g/ m 2/ da y S C or I V f or 1 wee k e ver y 4 wee ks u ntil t he e n d 
of t he st u d y, u nless t he y are disc o nti n ue d fr o m t he treat me nt. A f ull 7 da ys of azaciti di ne is 
re q uire d, b ut as p er i nstit uti o nal practice, a sc he d ule of 5 da ys of dail y d osi n g, f oll o w e d b y n o 
d ose recei ve d o n t he w ee ke n d, a n d 2 dail y d oses gi ve n a gai n at t he start  of t he ne xt wee k, is 
all o we d. T he sa m e sc he d ule s h o ul d be use d f or eac h s u bject t hr o u g h o ut t he d urati o n of 
treat me nt, w he n p ossi ble. 
I n t he e ve nt t hat 2 or fe w er d oses are misse d d uri n g t he 7-d a y d osi n g peri o d, d osi n g s h o ul d 
c o nti n ue s o t hat t he s u bject r ecei ves t he f ull 7 da ys of t hera p y. If 3 or m or e da ys are misse d 
d uri n g t he 7 -da y d osi n g peri o d, t he I n vesti gat or s h o ul d c o ntact t he Me dical M o nit or, a n d a 
decisi o n o n d osi n g will b e ma de o n a n i n di vi d ual case basis.  
O n da ys w he n b ot h A G -1 2 0 or place b o a n d azaciti di ne are gi ve n, A G -1 2 0 or place b o will be 
gi ve n pri or t o azaciti di ne.  
9. 8.  
Criteri a f or D ose Esc al ati o n, D ose M o dific ati o n, or Disc o nti n u ati o n 
of St u d y Dr u g  
9. 8. 1.  
A G -1 2 0/ Pl ac e b o D ose M o dific ati o n a n d St o p pi n g Criteri a  
I ntr a-s u bject d ose escalati o n will n ot be per mitte d.  
F or a n y A E, i ncl u di n g A Es n ot s pecificall y me nti o ne d i n Ta ble  1 , t he I n v esti gat or ma y d eci de t o 
dela y d osi n g or m o dif y t he d ose of A G -1 2 0/ place b o base d o n cli nical j u d g me nt. All d ose 
m o dificati o ns of A G -1 2 0/ place b o s h o ul d be disc usse d wit h t he S p o ns or pri or t o i m ple me ntati o n. 
D ose m o dificati o ns of A G -1 2 0/ place b o fr o m 5 0 0 m g t o 2 5 0 m g will be per mitte d o n st u d y f or 
ma na ge me nt of A Es (see Ta ble  1 ). If m ore t ha n 1 A E occ urs t hat w o ul d re q uire a d ose 
m o dificati o n, u p o n  res ol uti o n of all A Es t o baseli ne or Gra de 1, A G-1 2 0/ place b o s h o ul d be 
d ose -re d u ce d t o 2 5 0 m g. S u bjects w h o ha ve ha d t h eir d ose of A G-1 2 0/ place b o re d uce d d u e t o a 
Gra de ≥3 A E will be per mitte d t o re -escal ate t o 5 0 0 m g aft er disc ussi o n wit h t he S p o ns or’s 
M e dical M o nit or.  
D ose dela ys f or reas o ns ot her t ha n ma na ge me nt of A Es are disc o ura ge d. D ose dela ys u p t o 
2 8  da ys will be per mitte d at t he discreti o n of t he I n vesti gat or i n c o ns ultati o n wit h t he Me dical 
M o nit or f or reas o ns i ncl u di n g ma na ge me nt of A Es a n d f or  miti gati n g circ u msta nces (e g, pla n ne d 
pr oce d ures).  
Azaciti di ne a n d A G 1 2 0/ place b o ca n be i nterr u pte d c o nc urre ntl y, or eit her a ge nt al o ne, 
de pe n di n g o n t he attri b uti o n t o a n A E b y t he I n vesti gat or. If azaciti di ne is per ma ne ntl y 
disc o nti n ue d, treat me nt wit h A G -1 2 0/ place b o ma y c o nti n ue at t he discreti o n of t he I n vesti gat or 
a n d wit h t he a gree me nt of t he Me dical M o nit or, pr o vi de d t hat t he s u bject is i n C R or C Ri 
(i ncl u di n g C R p). 

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If a s u bject ca n n ot r es u me A G-1 2 0/ place b o wit hi n 2 8 da ys, t h e s u bject s h o ul d be disc o nti n ue d 
fr o m st u d y tr eat me nt if t he y h a ve pre vi o usl y disc o nti n ue d treat me nt wit h azaciti di ne. Ot her 
reas o ns f or treat me nt ter mi nati o n are pr o vi de d i n Secti o n  8. 5 . If A G-1 2 0 or place b o is 
disc o nti n ue d, t he s u bject will c o m plete t he E O T a n d F oll o w -u p Visits, a n d will t he n e nter E F S 
F oll o w -u p (if t he s u bject has n ot alrea d y e x perie nce d a n E F S e ve nt [ e g, tr eat me nt fail ure, 
rela pse, or deat h]) a n d s u bse q ue nt S ur vi val F oll o w -u p. If a d ose is dela ye d, visit da ys (i n 
c ycles/ da ys) will be pa us e d u ntil t he ne xt pla n ne d st u d y visit (e g, if a d ose is hel d o n C 3 D 1, t he 
ne xt sc he d ule d visit w he n d osi n g be gi ns a gai n will bec o me C 3 D 1); diseas e res p o nse ass ess me nts 
s ho ul d c o nti n ue re gar dl ess of d ose dela ys.  

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T a ble  1 : 
M a n a ge me nt of A d vers e E ve nts  
A d verse E ve nts ( A Es)  
Acti o n  
Gra d e 2 na usea or 
v o miti n g (relate d or 
u nrelate d)  
•  
C o nsi der h ol di n g d ose of A G -1 2 0/ place b o u ntil res ol uti o n of A E t o Gra de < 1 
wit hi n 4 wee ks ( 2 8 da ys) of s u p p orti ve t hera p y.  
•  
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of care.  
•  
Res u me A G -1 2 0/ place b o at sa me d ose.  
Gra d e 3 A Es (re late d, 
first e ve nt) 
•  
H ol d d ose of A G -1 2 0/ place b o u ntil res ol uti o n t o Gra de < 1 or baseli ne wit hi n 
4  wee ks of s u p p orti ve t hera p y a n d t he n res u me d ose.  
•  
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of care.  
•  
If t he Gra d e 3 A E rec urs (a se c o n d ti me), h ol d d ose u ntil res ol uti o n, a n d t he n 
re d uce A G-1 2 0/ place b o t o 2 5 0 m g i n c o ns ultati o n wit h t he Me dical M o nit or. 
Re -escalati o n ma y be per mitte d after disc ussi o n wit h t he Me dical M o nit or.  
•  
If t he Gra d e 3 A E rec urs (a t hir d ti me) des pite d ose re ducti o n of A G -1 2 0/ place b o, 
t he n c o nsi der disc o nti n ui n g A G-1 2 0/ place b o i n c o ns ultati o n wit h t he Me dical 
M o nit or.  
Gra d e 4 he mat ol o gic 
A Es (relate d, first e ve nt)  
•  
H ol d A G -1 2 0/ place b o.  
•  
Ma na ge wit h s u p p orti ve t hera p y acc or di n g t o t he i nstit uti o nal sta n dar d of c are.  
•  
If t he A E res ol ves t o Gra de ≤1 or baseli ne wit hi n 4 wee ks, t he n restart 
A G -1 2 0/ place b o d osi n g at 2 5 0 m g i n c o ns ultati o n wit h t he Me dical M o nit or. Re -
escalati o n ma y be per mitte d after disc ussi o n wit h t he Me dical M o nit or.  
•  
If t he A E d oes n ot res ol ve t o Gra de ≤1 or baseli ne wit hi n 4 wee ks, c o nsi der 
disc o nti n ui n g st u d y treat me nt i n c o ns ultati o n wit h t he Me dical M o nit or.  
•  
If t he Gra d e 4 A E rec urs (a se c o n d ti me), des pite d ose re d ucti o n, h ol d d ose u ntil 
res ol uti o n. A G-1 2 0/ place b o s h o ul d be disc o nti n ue d i n c o ns ultati o n wit h t he 
Me dical M o nit or.  
Gra d e 4 n o n -he mat ol o gic 
A E (relate d)  
•  
Disc o nti n ue A G -1 2 0/ place b o . 
 
Refer t o Secti o n  9. 9  f or ma na ge me nt of A E SIs f or A G-1 2 0.  
If A G-1 2 0/ place b o is dis c o nti n ue d, t he s u bject ma y c o nti n ue tr eat me nt wit h azaciti di ne o n st u d y.  
If t he I n vesti gat or s us p ects t hat a s u bject has P M L, treatme nt wit h A G -1 2 0/ place b o s h o ul d be 
s us pe n de d u ntil a dia g n osis of P M L has bee n r ule d o ut. 
9. 8. 2.  
Az aciti di ne D ose M o dific ati o ns a n d St o p pi n g Criteri a  
T he first treat me nt c ycle of azaciti di ne s h o ul d al w a ys b e gi ve n at 1 0 0 % of t he d ose, re gar dless of 
a s u bject’s la b orat or y val ues ( pr o vi de d t hat t he s u bject is all o we d t o e nr oll i n t he st u d y base d o n 
t he i ncl usi o n a n d e x cl usi o n criteria). 
S u bjects s h o ul d be m o nit ore d f or h e mat ol o gi c t o xicit y a n d re nal t o xicit y; a dela y i n starti n g t h e 
ne xt azaciti di ne treat me nt c ycl e or a n azaciti di ne d ose re d ucti o n, as d escri be d bel o w, ma y be 
necessar y. If t he d ose of azaciti di ne is m o difie d d uri n g t he c o urse of t he st u d y (see bel o w) a n d 
be nefit is de m o nstrate d at t he re d uce d d os e, t hat d ose s h o ul d be mai ntai ne d d uri n g s u bse q ue nt 
c ycles ( u nless t o xicit y de vel o ps). T he I n v esti gat or s h o ul d c o ntact t he Me di cal M o nit or f or 
g ui da n ce o n azaciti di ne d ose m o dificati o n, if nee d e d.  

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T he i nitiati o n of a ne w c ycl e will start 2 1 da ys aft er a d mi nistrati o n of t he Da y 7 ( ±  3 da ys) d os e 
of azaciti di ne  if a d mi nistere d o ver 7 c o nti n u o us d a ys or 1 9 da ys after t he Da y 9 ( ± 3 da ys) d os e 
if a d mi nistere d o n a 5-2 -2 sc he d ule. T he i nitiati o n of a ne w c ycle will start u p o n t he a bilit y t o 
rei nitiate c o m bi nati o n t hera p y. 
If azaciti di ne is per ma n e ntl y disc o nti n ue d f or n o n-he mat ol o gi c or he m at ol o gic t o xicities, 
A G -1 2 0/ place b o ma y c o nti n ue at t he discreti o n of t he I n v esti gat or a n d wit h a gree m e nt fr o m t he 
Me dical M o nit or, pr o vi d e d t hat t he s u bject is i n C R or C Ri (i ncl u di n g C R p) a n d nee ds t o 
disc o nti n ue azaciti di ne d ue  t o pr ot oc ol-s pecifie d azaciti di ne-relate d t o xicit y (e g, dela ye d b o ne 
marr o w rec o ver y).  
9. 8. 2. 1.  
Az aciti di ne D ose M o dific ati o ns d ue t o N o n -He m at ol o gic T o xicit y  
F oll o wi n g recei pt of a n y d ose of azaciti di ne, s u bse q ue nt treat me nt c ycl es ma y b e dela ye d if a 
certai n lev el of t o xicit y o cc urs after t he pre vi o us d ose. A n y s u bject w h o e x perie nces a 
n o n -he mat ol o gi c A E of Gra de 3 or 4 t hat is t h o u g ht t o be ca usall y rel ate d a n d is a n escalati o n 
fr o m his or her stat us at b aseli ne s h o ul d ha ve azaciti di ne te m p oraril y disc o nti n ue d u ntil t he 
t o xicit y gra d e ret ur ns t o Gra de < 3. Azaciti di ne s h o ul d be per ma ne ntl y disc o nti n ue d if t he 
n o n -he mat ol o gi c t o xicit y persists as Gra d e 3 or 4 f or m ore t ha n 3 wee ks ( 2 1 da ys), des pite t he 
te m p orar y i nterr u pti o n of azaciti di ne. 
9. 8. 2. 2.  
Az aciti di ne D ose M o di fic ati o ns d ue t o He m at ol o gic T o xicit y  
Treat me nt wit h azaciti di ne is ass ociate d wit h a ne mia, ne utr o pe nia, a n d t hr o m b oc yt o pe ni a, 
partic ularl y d uri n g t he first 2 c ycl es. C o m plete bl o o d c o u nts s h o ul d be perf or me d as s pecifie d i n 
t he Sc he d ule of Ass ess me nts (Ta ble  6 ), a n d as nee de d t o m o nit or t o xicit y. 
Rec o ver y is defi ne d as a n i ncreas e of cell li ne(s) w here h e mat ol o gi c t o xicit y was o bs er ve d of at 
least half of t he differe nce of na dir a n d t he baseli n e c o u nt pl us t he na dir c o u nt (ie, bl o o d c o u nt at 
rec o ver y ≥Na dir C o u nt + ( 0. 5 × [ Baseli ne c o u nt –  Na dir c o u nt]).  
F or e x a m ple, if t he bas eli ne, pre -c ycle ne utr o p hil c o u nt is 5 0 0 × 1 0 9/ L a n d t he Na dir c o u nt is 
1 0 0  × 1 0 9/ L, rec o ver y is defi ne d as: ≥1 0 0 + ( 0. 5 [ 5 0 0 − 1 0 0]), ≥3 0 0 × 1 09/ L. 
S u bjects wit h o ut re d uce d b aseli ne bl o o d c o u nts (ie, W B C c o u nt > 3. 0  ×  1 0 9/ L, A N C 
> 1. 5  ×  1 0 9/ L, a n d pl atelets > 7 5. 0 × 1 09/ L) pri or t o first tre at me nt: 
If he mat ol o gic t o xicit y is o bser ve d f oll o wi n g azaciti di ne treat me nt, t he ne xt c ycl e of azaciti di ne 
t hera p y s h o ul d be del a ye d u ntil t he platelet c o u nt a n d t he A N C ha v e rec o v ere d. If rec o ver y is 
ac hie ve d wit hi n 2 wee ks ( 1 4 da ys), n o d ose a dj ust me nt is necessar y. H o we ver, if rec o ver y has 
n ot be e n ac hi e ve d wit hi n 2 wee ks, t he azaciti di ne d ose s h o ul d be re d u ce d acc or di n g t o Ta ble  2 . 
F oll o wi n g d os e m o dificati o ns, t he c ycl e d urati o n s h o ul d ret ur n  t o 4 wee ks ( 2 8 da ys). T he 
re d uce d d os e s h o ul d be mai ntai ne d d uri n g s u bs e q ue nt c ycles t hat are gi ve n ( u nless t o xicit y 
de vel o ps). A fl o w di a gra m f or t he deter mi nati o n of azaciti di ne d ose a dj ust me nt i n s u bjects 
wit h o ut re d uce d bas eli ne bl o o d c o u nts is pr o vi d e d i n A p pe n di x  1 5. 4 . 

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T a ble  2 : 
He m at ol o gic D ose Re d ucti o ns f or Az aciti di ne B ase d o n A bs ol ute Ne utr o p hil 
C o u nt a n d Pl atelets  
N a dir C o u nts  
% D ose i n t he ne xt c o urse if rec o ver y a is n ot 
ac hie ve d i n ne xt 2 w ee ks ( 1 4  d a ys)  
A N C ( × 1 0 9/ L) 
Pl atelets ( × 1 0 9/ L) 
≤ 1. 0  
≤ 5 0  
5 0 %  
> 1. 0  
> 5 0  
1 0 0 %  
A b bre viati o ns: A N C  =  a bs ol ute ne utr o p hil c o u nt.  
a Rec o ver y = c o u nts ≥ na dir c o u nt + ( 0. 5 ×  [ baseli ne c o u nt − na dir c o u nt]).  
S u bjects wit h re d uce d b aseli ne bl o o d c o u nts (ie, W B C c o u nt ≤3. 0 × 1 0 9/ L or A N C 
≤1. 5  ×  1 0 9/ L or pl atelets ≤7 5. 0 × 1 09/ L) pri or t o tre at me nt:  
F oll o wi n g azaciti di ne treat me nt, if t he decreas e i n W B Cs, A N C, or platelets fr o m t he val ue pri or 
t o treat me nt is less t ha n 5 0 %, or greater t ha n 5 0 % b ut wit h a n i m pr o ve me nt i n a n y cell li ne 
differe ntiati o n, t he n e xt c ycl e s h o ul d n ot be dela ye d a n d n o d ose a dj ust me nt ma de.  
If t he decrease i n W B C c o u nt, A N C, or platelets is greater t ha n 5 0 % fr o m t he val ue pri or t o 
treat me nt, wit h n o i m pr o ve me nt i n cell li ne differe ntiati o n, t he ne xt c ycle of azaciti di ne t hera p y 
s h o ul d be dela ye d u ntil t he platelet c o u nt a n d t he A N C ha ve rec o vere d. If rec o ver y is ac hie ve d 
wit hi n 2 wee ks, n o d ose a dj ust me nt is necessar y. H o we ver, if rec o ver y h as n ot bee n ac hi e ve d 
wit hi n 2 wee ks, b o ne marr o w cell ularit y s h o ul d b e deter mi ne d. If t he b o ne marr o w cell ularit y is 
> 5 0 %, n o d ose a dj ust me nts s h o ul d be ma de. If b o ne marr o w cell ularit y is ≤5 0 %, azaciti di ne 
treat me nt s h o ul d be dela ye d a n d t he d ose re d uce d acc or di n g t o T a ble  3 . 
T a ble  3 : 
He m at ol o gic D ose Re d ucti o ns f or Az aciti di ne B ase d o n B o ne M arr o w 
Cell ul arit y  
B o ne M arr o w Cell ul arit y  
% D ose i n t he ne xt c o urse if rec o ver y
a is n ot ac hie ve d i n ne xt 2 w ee ks 
( 1 4 d a ys)  
Rec o ver y ≤3 w ee ks  
Rec o ver y > 3 w ee ks  
1 5 % t o 5 0 %  
1 0 0 %  
5 0 %  
< 1 5 %  
1 0 0 %  
3 3 %  
a Rec o ver y = c o u nts ≥ na dir c o u nt + ( 0. 5 × [ baseli ne c o u nt - na dir c o u nt]).  
F oll o wi n g azaciti di ne d ose m o dificati o ns, t he c ycl e d urati o n s h o ul d ret ur n t o 4 wee ks ( 2 8 da ys). 
T he re d u ce d d ose s h o ul d be mai ntai ne d d uri n g s u bse q ue nt c ycles t h at are gi ve n ( u nless t o xicit y 
de vel o ps). A fl o w di a gra m f or t he deter mi nati o n of azaciti di ne d ose a dj ust me nt i n s u bjects wit h 
re d uce d b aseli ne bl o o d c o u nts is pr o vi de d i n A p pe n di x  1 5. 4 . 
9. 8. 2. 3.  
Az aciti di ne T her a p y a n d Re n al D ysf u ncti o n  
Re nal a b n or mal ities ra n gi n g fr o m ele vate d s er u m creati ni ne t o re nal f ail ure a n d deat h w ere 
re p orte d rarel y i n s u bje cts treate d wit h I V azaciti di ne i n c o m bi nati o n wit h ot her 
c he m ot hera p e utic a ge nts. I n a d diti o n, re nal t u b ular aci d osis, defi ne d as a fall i n ser u m 
bicar b o n ate t o < 2 0 m m ol/ L i n ass ociati o n wit h a n al kali ne uri ne a n d h y p o k ale mia (ser u m 
p otassi u m < 3 m m ol/ L) de vel o pe d i n 5 s u bjects wit h c hr o nic m yel o ge n o us l e u ke mia treate d wit h 
azaciti di ne a n d et o p osi de. If u ne x plai ne d re d ucti o ns i n ser u m bicar b o nat e ( < 2 0 m m ol/ L) occ ur, 
t he d ose s h o ul d be re d u ce 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 i n 

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ser u m creati ni ne or bl o o d urea nitr o ge n ( B U N) t o ≥2-f ol d a b o ve bas eli ne v al ues a n d a b o v e U L N 
occ ur, t he n e xt c ycle s h o ul d be dela ye d u ntil val u es ret ur n  t o n or mal or b aseli ne a n d t he 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 ycle. T he re d u ce d d ose of azaciti di ne s h o ul d 
be mai ntai ne d d uri n g s u bse q ue nt c ycles t h at are gi ve n ( u nless t o xicit y d e vel o ps).  
T he mai n e x creti o n r o ute of azaciti di ne is t h r o u g h t he uri ne; a d diti o nal ca uti o n is warra nte d if 
re nal i m pair me nt is pres e nt at baseli ne. 
A G -1 2 0/ place b o s h o ul d c o nti n ue t o be ta ke n if azaciti di ne is i nterr u pte d be y o n d t he 4 -wee k 
( 2 8-da y) c ycle as l o n g as dail y A G -1 2 0/ place b o d osi n g is n ot belie ve d, i n t he o pi ni o n of t he 
I n v esti gat or, t o ha ve b ee n part of t he reas o n f or i nterr u pti o n. 
9. 9.  
A d verse E ve nts of S peci al I nterest f or A G -1 2 0  
T he f oll o wi n g are g ui d eli nes f or t he ma n a ge me nt of A E SIs b ase d o n t he n o ncli nical a n d cli nical 
safet y fi n di n gs f or A G-1 2 0.  
9. 9. 1.  
Q T  Pr ol o n g ati o n  
T he disc ussi o n of t he e mer ge ncy m a n a ge me nt of T ors a des de p oi ntes a n d its he m o dy n a mic 
c o nse q ue nces is bey o n d t he sc o pe of t his g ui deli ne.  
Pr ol o n gati o n of heart -rat e c orrecte d Q T i nter val usi n g Bazett’s met h o d has bee n o bser ve d i n 
m o n ke ys at r elati vel y hi g h d oses of A G -1 2 0 a n d h as bee n i de ntifie d as a n e x pecte d ris k of 
treat me nt wit h A G-1 2 0 (see t he I B). E v e nts of Q T pr ol o n gati o n (i e, Q Tc F Gra de ≥3 s h o ul d be 
re p orte d as A E SIs t o t he S p o ns or wit hi n 2 4 h o urs, acc or di n g t o e x pe dite d re p orti n g pr oc e d ures 
(see Secti o n  1 1. 2. 3 ). 
S u bjects ma y be at i ncrease d ris k f or t he d e vel o p me nt of Q T pr ol o n gati o n w he n treate d wit h 
A G -1 2 0 i n c o m bi nati o n wit h f l u or o q ui n ol o nes, az ole a ntif u n gal a ge nts, or ser ot o ni n ( 5‐H T 3) 
a nta g o nists. I n v esti gat ors m ust be vi gila nt; refrai n fr o m a d mi nisteri n g c o nc o mita nt me dicati o ns 
ass ociate d wit h Q T pr ol o n gati o n a n d if n o ot h er t h era pe utic o pti o ns are a v aila ble, m o nit or 
s u bjects recei vi n g st u d y treat me nt wit h t he c o m bi nati o n of t hese dr u gs a n d e val uate E C G a n d 
electr ol ytes (i ncl u di n g p otassi u m, ma g nesi u m, a n d calci u m), partic ularl y i n s u bjects prese nti n g 
wit h na usea, v o miti n g, or diarr hea. S yste mic a d mi nistrati o n of a m o d erat e or str o n g C Y P 3 A 4 
i n hi bit or re q uires caref ul m o nit ori n g of Q Tc F. 
S u bjects w h o e x perie nce Q T pr ol o n gati o n (ie, Q Tc F > 4 8 0 ms ec; N CI C T C A E Gra d e ≥2) w hile 
recei vi n g st u d y treat me nt s h o ul d be pr o m ptl y e v al uate d f or ca usalit y of t he Q T pr ol o n gati o n a n d 
ma n a ge d acc or di n g t o t h e f oll o wi n g g ui deli nes a n d Ta ble  4 : 
•  Le v els of ele ctr ol ytes ( p otassi u m, calci u m, a n d ma g nesi u m) s h o ul d be c hec ke d a n d 
s u p ple me ntati o n gi ve n t o c orrect a n y val u es o utsi de t he n or mal r a n ge.  
•  C o nc o mita nt t hera pies s h o ul d be re vie we d a n d a dj uste d as a p pr o pri ate f or 
me dicati o ns wit h k n o w n Q T pr ol o n gi n g effects.  
•  If n o ot her ca use is i de ntifie d a n d t he I n v esti gat or belie ves it is a p pr o priate, 
p artic ularl y if Q T c F re m ai ns ele vate d (after t he a b o ve meas ures ha ve b ee n 
i m ple me nte d, or as deter mi ne d b y t he I n v esti gat or), st u d y tr eat me nt ma y b e 
i nterr u pte d, a n d a n E C G s h o ul d be rec h ec ke d i n a p pr o xi matel y 1 wee k after t he Q T 
pr ol o n gati o n e v e nt was firs t o bser ve d or m ore fre q ue ntl y as cli nicall y i n dicate d. If 

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Q Tc F h as rec o vere d or i m pr o ve d a n d t he I n v esti gat or belie ves it is safe t o d o s o, 
re-c h alle n ge wit h st u d y treat me nt s h o ul d be c o nsi dere d if h el d. D ose a dj ust me nts or 
i nterr u pti o ns f or Q Tc F pr ol o n gati o n i n t he c o nte xt of a pre-e xisti n g b u n dle bra nc h 
bl oc k s h o ul d be disc usse d wit h t he Me dical M o nit or. Rec o m me n dati o ns ma y d e viate 
fr o m Ta ble 4 de p e n di n g o n t he cli nical c o nte xt a n d t he a dj uste d Q Tc F val u e. 
C o ns ultati o n wit h a car di ol o gist is rec o m me n de d i n t hese circ u msta n ces.  
•  E C Gs s h o ul d be c o n d uct e d at least wee kl y (e g, at e ver y sc h e d ule d visit) f or 2  wee ks 
f oll o wi n g Q Tc F re d ucti o n t o ≤4 8 0 msec. 
T a ble  4 : 
M a n a ge me nt of Q T Pr ol o n g ati o n b y N CI C T C A E Gr a de  
N CI C T C A E Gr a de  
M a n a ge me nt  
Gra d e 2  
( Q T c F > 4 8 0 a n d ≤5 0 0 msec) 
•  
T he d ose of st u d y treat me nt ma y be re d uce d t o 2 5 0 m g Q D 
wit h o ut i nterr u pti o n of d osi n g. T he d ose of st u d y treat me nt 
ma y be re -escalate d t o t he pri or d ose i n ≥2 wee ks ( 1 4  da ys) 
after Q T pr ol o n gati o n has decrease d t o ≤Gra de 1.  
Gra d e 3  
( Q T c F > 5 0 0 msec o n at least 2 se p arate 
E C Gs)  
•  
H os pitalizati o n f or c o nti n u o us car diac m o nit ori n g a n d 
e val uati o n b y a car di ol o gist s h o ul d b ot h be c o nsi dere d.  
•  
M o nit or electr ol yte le vels a n d s u p ple me nt wit h electr ol ytes 
as cli nicall y i n dicate d.  
•  
Re vie w a n d a dj ust c o nc o mita nt me dicati o ns wit h k n o w n Q T 
pr ol o n gati o n effects.  
•  
D osi n g wit h st u d y treat me nt will be i nterr u pte d. If Q T c F 
ret ur ns t o wit hi n 3 0 msec of b aseli ne or < 4 7 0 msec wit hi n 
2  wee ks, treat me nt ma y be res u me d at a re d uce d d ose of 
2 5 0  m g Q D.  
•  
T he d ose of st u d y treat me nt c a n n ot be re -escalate d f oll o wi n g 
d ose re d ucti o n f or Gra de 3 Q T pr ol o n gati o n u nless t he 
pr ol o n gati o n was ass ociate d wit h a n electr ol yte a b n or malit y 
or c o nc o mita nt me dicati o n.  
Gra d e 4  
( Q T c F > 5 0 0 msec or > 6 0 mse c c ha n ge fr o m 
baseli ne wit h T orsa d es de p oi ntes or 
p ol y m or p hic ve ntric ular tac h ycar dia or 
si g ns/s y m pt o ms of seri o us arr h yt h mia)  
•  
S u bj ects s h o ul d be a d mitte d t o a h os pital f or c o nti n u o us 
car diac m o nit ori n g a n d disc har ge d o nl y after re vie w b y a 
car di ol o gist.  
•  
D osi n g wit h st u d y treat me nt s h o ul d be per ma ne ntl y 
disc o nti n ue d.  
A b bre viati o ns: N CI C T C A E = 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; Q D = o nce dail y; 
Q Tc F = heart -rate c orrecte d Q T i nter val usi n g Fri dericia’s met h o d.  
N ote: P er N CI C T C A E, versi o n 4. 0 3.  
9. 9. 2.  
I D H Differe nti ati o n S y n dr o me 
E ve nts of I D H differe ntiati o n s y n dr o me h a ve b ee n re p orte d i n s u bjects wit h he mat ol o gic 
mali g na n cies i n St u d y A G 1 2 0 -C -0 0 1 d uri n g treat me nt wit h A G -1 2 0 (see t he I B). A n y e v e nt of 
differe ntiati o n s y n dr o me assesse d as Gra de ≥2, irres pecti ve of seri o us ness, s h o ul d be re p orte d t o 
t he S p o ns or as a n A E SI wit hi n 2 4 h o urs (see Secti o n  1 1. 2. 3 ).  
S u bjects treate d wit h A G -1 2 0 ha ve de v el o pe d si g ns a n d s y m pt o ms of differe ntiati o n s y n dr o m e. 
Cli nical feat ures ma y i ncl u de s o me or all of t he f oll o wi n g: u ne x plai ne d fe v er, s ki n ras h, h y p o xia, 
res pirat or y c o m pr o mise, i nterstitial p ul m o nar y i nfiltrates, ple ural a n d/ or p ericar dial eff usi o n, 

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wei g ht gai n, a n d cli nical deteri or ati o n. La b orat or y feat ur es ma y i ncl u de a n i ncreas e i n A N C 
a n d/ or platelets. A n i ncrease i n mat ure le u k oc ytes ma y b e o bser ve d i n t he b o ne marr o w as pirate 
differe ntial if a b o ne marr o w bi o ps y is c o n d u cte d d uri n g t his ti me. H o we v er, n o si n gle si g n or 
s y m pt o m ma y b e c o nsi dere d p er s e as dia g n ostic of t he s y n dr o me, a n d ot h er ca us es s h o ul d be 
s o u g ht a n d e x cl u de d. If I D H Differe ntiati o n S y n dr o me is s us pecte d, a n d is Gra de ≥2, 
I n v esti gat ors m ust re p ort t he s us pecte d dia g n osis as t he A E: I D H Differe ntiati o n S y n dr o me. 
A n y e ve nt of I D H Differe ntiati o n S y n dr o me ass esse d as Gra de ≥2 s h o ul d b e re p ort e d t o t he 
S p o ns or as eit her a n S A E or A E SI de pe n di n g o n t he cli nical assess me nt of seri o us ness.  
It is rec o m me n de d t hat t h e pr o p h yl actic a n d t hera p e utic meas ures i n dicate d bel ow be u n derta ke n 
at t he earliest ma nif estati o ns of s us pecte d I D H differe ntiati o n s y n dr o me:  
•  Te m p orar y h ol d of A G -1 2 0/ place b o if cli nical f eat ures ca n n ot b e me dicall y ma na ge d 
wit h t he f oll o wi n g:  
− C o ntr ol of le u k oc yt osis wit h h y dr o x y urea (see Secti o n  9. 1 3. 4. 3 ) 
− Pr o m pt a d mi nistrati o n of c ortic oster oi ds at a s u g geste d d ose of 1 0 m g of 
de x a met has o ne I V e v er y 1 2 h o urs u ntil disa p peara nce of s y m pt o ms a n d si g ns, 
a n d f or a mi ni m u m of 3 da ys  
− I nitiati o n of f ur ose mi de, if cli nicall y re q uire d 
− Pr o m pt i nitiati o n of le u ka p heresis, if re q uire d  
I m me diat e c o m m u nicati o n wit h t he Me dical M o nit or is e nc o ura ge d f or g ui da nce re gar di n g 
treat me nt. O nce t he si g ns a n d s y m pt o ms res ol ve a n d t he s u bject’s cli nical c o n diti o n i m pr o ves, 
A G -1 2 0/ place b o ma y be rei nitiate d if st u d y tr eat m e nt was hel d. T he d os e of A G -1 2 0/ place b o at 
rei nitiati o n is t o be disc usse d wit h t he Me dical M o nit or. 
9. 9. 3.  
Le u k oc yt osis  
E ve nts of le u k oc yt osis ha ve bee n re p orte d i n s u bjects wit h he mat ol o gi c mali g na n cies i n St u d y 
A G 1 2 0 -C -0 0 1 d uri n g treat me nt wit h A G -1 2 0 (see t he I B). A n y e v e nt of le u k oc yt osis assess e d as 
Gra de ≥3, irres pecti ve of seri o us ness, s h o ul d be re p orte d t o t he S p o ns or as a n A E SI wit hi n 2 4 
h o urs (see Secti o n  1 1. 2. 3 ).  
See Secti o n  9. 1 3. 4  f or g ui da nce o n t he use of h y dr o x y urea i n t he e v e nt of le u k oc yt osis.  
T he f oll o wi n g g ui d eli nes m ust be use d w he n gra di n g t he A E of le u k oc yt osis:  
N CI C T C A E Gr a de  
A bs ol ute Ne utr o p hil C o u nt/ Cli nic al M a nifest ati o n H y dr o x y ure a Re gi me n  
Gra d e 3  
> 1 0 0, 0 0 0/ m m 3 
Gra d e 4  
Cli nical ma nifestati o ns of le u k ostasis; ur ge nt  i nter ve nti o n i n dicate d 
Gra d e 5  
Deat h  
N ote: P er Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y f or A d verse E v e nts Criteria ( C T C A E), versi o n 4. 0 3.  

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9. 1 0.  
Ot her P ote nti al Ris ks  
9. 1 0. 1.  
Le u k oe nce p h al o p at h y  
Le u k o e nce p hal o pat h y is a p ote ntial ris k ass ociate d wit h A G -1 2 0  treat me nt base d o n cli nical 
safet y fi n di n gs o bser v e d acr oss t he A G-1 2 0 cli nical de vel o p me nt pr o gra m. Pr o gressi ve 
m ultif ocal le u k oe nce p h al o pat h y a n d p osteri or re versi ble e nce p h al o pat h y s y n dr o me ( P R E S), b ot h 
Gra de 3 S A Es, h a ve eac h bee n re p orte d i n 1 s u bjec t.  
T he si g ns a n d/ or s y m pt o ms of P M L ma y be gi n gra d uall y, us u all y w orse n ra pi dl y, a n d v ar y 
de pe n di n g o n w hic h part of t he brai n is i nfecte d. Si g ns a n d s y m pt o ms ma y i ncl u de diffic ult y 
wit h wal ki n g a n d ot h er m o ve me nts, pr o gressi ve wea k ness, d ecli ne i n me ntal  f u ncti o n, vis ual 
fiel d deficits, a n d s peec h a n d la n g ua ge dist ur ba nces. Rarel y, hea d ac hes a n d seiz ures occ ur. 
S u bjects s h o ul d be m o nit ore d f or o ns et of si g ns or s y m pt o ms s u g gesti ve of P M L. Dia g n ostic 
e val uati o ns ma y i ncl u de c o ns ultati o n wit h a ne ur ol o gist,  ma g n etic res o na nce i ma gi n g ( M RI) of 
t he brai n, l u m bar p u nct ur e, a n d/ or brai n bi o ps y as cli nicall y warra nte d. T he I n v esti gat or s h o ul d 
i m me diatel y c o nta ct t he St u d y M e dical M o nit or w he n P M L is a s us p ecte d or c o nfir me d 
dia g n osis. Treat me nt wit h A G -1 2 0/ place b o s h o ul d be s us pe n de d i n t he setti n g of s us pecte d P M L 
a n d per ma n e ntl y disc o nti n ue d i n s u bjects wit h c o nfir me d P M L. S u bjects wit h a pri or hist or y of 
P M L s h o ul d n ot be treat e d wit h A G -1 2 0 a n d are e x cl u de d fr o m t his st u d y.   
P osteri or re versi ble e nce p hal o pat h y  s y n dr o me is a rare cli nic-ra di ol o gi cal ne ur ol o gi cal s y n dr o me 
(Li n d a a n d v o n H eij ne, 2 0 1 5 ). Cli nical c haracteristics ma y i ncl u de s u b ac ut e o nset of hea dac h e, 
h y perte nsi o n, seiz ures, altere d me ntal stat us, vis ual dist ur ba nces, a n d occasi o nall y ot her f ocal 
ne ur ol o gi cal si g ns. Ra di ol o gicall y, si g ns of vas o ge nic e de ma are us u all y see n bilaterall y i n t he 
w hite matter of t he p ariet o -occi pital l o bes, b ut c ha n ges ca n als o b e see n i n fr o ntal a n d te m p oral 
l o bes, brai nste m, cere bell u m, a n d i n c ortical as well as dee p gra y m atter. S u bjects s h o ul d be 
m o nit ore d f or o nset of ne ur ol o gic al  si g ns a n d/ or s y m pt o ms t hat are cli nicall y ass oci ate d wit h 
P R E S. Dia g n ostic e val uati o ns ma y i ncl u de c o ns ultati o n wit h a ne ur ol o gist, M RI of t he brai n, a n d 
ot her rec o g niz e d sta n dar d of care meas ures as cli nicall y warra nte d. A d diti o nall y, t he I n v esti gat or 
s ho ul d c o ns ult wit h t he St u d y Me dic al M o nit or f or ma na ge me nt g ui deli nes t o be utilize d i n t he 
setti n g of s us pecte d or c o nfir me d P R E S. 
Refer t o t he A G -1 2 0 I B f or f urt her details o n t hese e ve nts.  
9. 1 0. 2.  
Se ns ori m ot or Ne ur o p at h y/ P ol y ne ur o p at h y  
Se ns ori m ot or ne ur o pat h y/ p ol y ne ur o pat h y is a p ote ntial ris k ass ociate d wit h A G -1 2 0 treat me nt 
base d o n safet y fi n di n gs o bser ve d acr oss t he A G -1 2 0 cli nical de vel o p me nt pr o gra m. 
G uillai n -Barre s y n dr o m e are rare, s eri o us s y n dr o mes t hat affect t he ce ntral a n d peri p heral 
ner v o us s yst e ms .  
S u bjects s h o ul d be m o nit ore d f or o ns et of ne w si g ns or s y m pt o ms of m ot or a n d/ or se ns or y 
ne ur o pat h y s uc h as u nilateral or bilateral wea k ness, se ns or y alterati o ns, or parest hesia. If a 
s u bject e x perie nces si g ns or s y m pt o ms s u g gesti ve of se ns ori m ot or ne ur o p at h y, G uillai n -Barre 
s y n dr o me, or l u m b osacral ple x o pat h y, dia g n ostic e val uati o n ma y i ncl u de a c o ns ultati o n wit h a 
ne ur ol o gist, l u m bar p u nct ure, a n d ele ctr o m y o gra p h y. T he I n vesti gat or s h o ul d i m me diatel y 
c o ntact t he St u d y M e dical M o nit or w he n G uillai n -Barre  s y n dr o m e is a s us pecte d or c o nfir me d 

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dia g n osis. A G -1 2 0/ place b o s h o ul d be per ma ne ntl y disc o nti n ue d i n s u bjects wit h a c o nfir me d 
dia g n osis of G uillai n -Barre s y n dr o me.  
Refer t o t he A G -1 2 0 I B f or f urt her details o n t hese e ve nts.  
9. 1 0. 3.  
T u m or L ysis S y n dr o me  
T u m or l ysis s y n dr o me ( T L S) is a p ote ntial ris k ass ociate d wit h A G-1 2 0 tr eat me nt base d o n 
cli nical safet y fi n di n gs i n s u bjects wit h he mat ol o gic mali g na n cies.  Refer t o t he A G -1 2 0 I B f or 
f urt her det ails o n e ve nts of T L S. 
T u m or l ysis s y n dr o me w as o bser ve d i n 1 9 ( 7. 4 %) s u bjects wit h a d va nce d h e mat ol o gic 
mali g na n cies i n St u d y A G 1 2 0 -C -0 0 1, 2  ( 3. 3 %) s u bjects wit h ne wl y di a g n ose d A M L i n 
St u d y  A G 1 2 0 -2 2 1 -C -0 0 1, a n d 1  ( 4. 3 %) s u bject wit h ne wl y dia g n os e d A M L i n St u d y A G-2 2 1 -
A M L -0 0 5. N o e v e nts of T L S ha v e bee n re p ort e d i n St u d y A G 1 2 0 -C -0 0 9, St u dies A G 1 2 0 -C -0 0 2 
a n d A G 1 2 0 -C -0 0 5 i n s oli d t u m ors, or i n cli nical p har mac ol o g y st u dies.  
De vel o p me nt of T L S is a k n o w n ris k ass ociate d wit h A M L. Cli nical ris k fact ors i ncl u de 
le u k oc yt osis ( wit h or wit h o ut disease pr o gressi o n) a n d c o nc urre nt use of c yt ore d ucti ve a ge nts, 
s uc h as h y dr o x y urea. A G-1 2 0 ca n i n d uce m yel oi d pr oliferati o n res ulti n g i n a ra pi d r e d ucti o n i n 
t u m or cells, w hic h ma y p ose a ris k f or t u m or l ysis s y n dr o me. I n s o me i nsta nces, T L S e ve nts 
occ urre d i n s u bjects w h o als o ha d risi n g  W B C c o u nts, s u g gesti n g t he p ossi bilit y t hat t hes e e ve nts 
were relate d t o t he u n d erl yi n g mali g na nc y or were c o -occ urri n g wit h I D H differe ntiati o n 
s y n dr o me. Pr o p h yl actic a n d treat me nt meas ures f or T L S s h o ul d be e m pl o ye d as cli nicall y 
i n dicate d. 
9. 1 1.  
D ur ati o n of S u bject P artici p ati o n  
9. 1 1. 1.  
Tre at me nt D ur ati o n  
Dail y tr eat me nt wit h A G -1 2 0 + azaciti di ne or place b o + azaciti di ne will be gi n o n t he first da y of 
C ycle  1. S u bjects s h o ul d be treate d f or a mi ni m u m of si x 4 -wee k ( 2 8 -da y) c ycl es of c o m bi nati o n 
t hera p y. Wit h Me dical M o nit or a p pr o val, s u bjects ma y c o nti n ue t o recei ve:  
•  A G -1 2 0 or pla ce b o f oll o wi n g disc o nti n uati o n of azaciti di ne, pr o vi de d t hat t he y are i n 
C R or C Ri (i ncl u di n g C R p) a n d nee d t o disc o nti n u e azaciti di ne d ue t o 
pr ot oc ol -s pecifi e d azaciti di ne-relat e d t o xicit y (e g, dela ye d b o ne m arr o w rec o ver y), or  
•  Azaciti di ne f oll o wi n g dis c o nti n uati o n of A G -1 2 0 or place b o, pr o vi de d t hat t he y h a ve 
n ot met t he defi niti o n of disease rel a pse or pr o gressi ve disease.  
S u bjects s h o ul d c o nti n ue t o recei ve st u d y tr eat me nt u ntil diseas e rela pse, disease pr o gressi o n, 
treat me nt fail ure, de vel o p me nt of a n u nacce pta bl e t o xicit y ( A E), c o nfir me d pre g na nc y, 
wit h dra wal b y s u bject, pr ot oc ol vi olati o n, deat h, or E n d of St u d y.  
S u bjects wit h a res p o nse less t ha n C R at 2 4 wee ks or be y o n d ca n c o nti n u e o n treat me nt if 
de m o nstrati n g tr eat me nt be nefit, defi n e d as a n y of t he f oll o wi n g: 1)  Tra nsf usi o n -i n de pe n de nce 
w hile o n st u d y treat me nt; 2) A N C > 5 0 0/ µ L; or 3) platelets > 5 0, 0 0 0/ µ L.  
F oll o wi n g disc o nti n uati o n of st u d y dr u g, s u bjects are t o atte n d a F oll o w -u p Visit 4 wee ks 
( 2 8 da ys) after t he last d ose of st u d y dr u g f or fi nal assess me nts. W he n st u d y dr u g is wit h hel d 
fr o m a s u bject i n or der t o res ol ve a t o xicit y a n d t h e s u bject d oes n ot s u bse q ue ntl y restart 

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treat me nt, E O T is defi n e d as t he date w h e n t he st u d y dr u g was first hel d. S u bjects s h o ul d 
pr ocee d wit h E O T assess me nts, safet y assess me nts, a n d E F S/ S ur vi val F oll o w -u p. If t he d ecisi o n 
n ot t o restart st u d y tr eat me nt occ urs o utsi de of t h e 4 -wee k Safet y F oll o w -u p wi n d o w, t he s u bject 
s h o ul d pr ocee d wit h E F S/ S urvi val F oll o w -u p.  
All s u bjects w h o disc o nti n ue st u d y tr eat me nt wit h o ut e x perie nci n g a n y 1 of t he f oll o wi n g: deat h, 
disease rel a pse, treat me nt fail ure, or wit h dr a wal of c o nse nt , will be f oll o we d e ver y Da y 1 
( ± 7  da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4  wee ks t hereafter f or E F S u ntil t he y 
e x perie nce tr eat me nt fail ure, rel a pse, deat h, wit h dra w  fr o m t he st u d y, or u ntil t he ti me w he n 1 7 3 
E F S e ve nts ha v e occ urre d or as dee m e d necessar y b y t he I D M C .  
O nce t he st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue. All s u bjects w h o are ali ve aft er a n 
E F S e ve nt will be c o nta cte d e ver y 8  w ee ks f or s ur vi val f oll o w -u p u ntil deat h, wit h dra wal b y 
s u bject, l oss t o f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 
9. 1 1. 2.  
E n d of St u d y  
At t he ti me of pri mar y e n d p oi nt a nal ysis ( a p pr o xi matel y 1 7 3 E F S e ve nts  or as dee m e d necessar y 
b y t he I D M C ), t he st u d y will be u n bli n de d. S u bjects o n treat me nt at t hat ti me ma y c o nti n ue 
recei vi n g st u d y dr u g. After u n bli n di n g, a n d if t he be nefit-ris k pr ofile fa v ors treat me nt, s u bjects 
ra n d o mize d t o place b o m a y b e offere d t h e c h oice t o recei v e A G -1 2 0. E n d of St u d y is defi ne d as 
t he ti me at w hic h all s u bjects ha ve die d, dis c o nti n ue d t he st u d y, are l ost t o f oll o w-u p, or ha v e 
wit h dra w n c o nse nt; or w he n t he S p o ns or e n ds t he st u d y.  
9. 1 1. 3.  
Tre at me nt C o m pli a nce  
S u b jects will be dis pe nse d t he a p pr o priat e n u m ber of S p o ns or-pac k a ge d, la bele d b ottle(s) f or 
4  wee ks ( 2 8  d a ys) of d osi n g o n Da y 1 ( ±  3 da ys) of eac h 4 -wee k ( 2 8 -d a y) c ycle; alter nati vel y, 
s u bjects ma y b e dis pe nse d t he a p pr o priat e n u m ber of b ottle(s) nee d e d u nt il t he ne xt st u d y visit. 
T he s u bject will be as ke d t o ret ur n all b ottles a n d u n use d ta blets ( or e m pt y b ottles) o n Da y 1 
( ± 3  da ys) of eac h c ycle or at t heir ne xt st u d y visit f or assess me nt of c o m plia nce wit h t he d osi n g 
re gi me n. 
S u bjects will recei ve i nstr u cti o ns f or h o me a d mi nistrati o n of st u d y treat me nt al o n g wit h a diar y 
t o rec or d t he d ate a n d ti me of eac h d ose, as well as t he n u m ber of ta bl ets ta ke n (see 
Secti o n  9. 1 2 ). 
Site staff will a d mi nister all d oses of azaciti di ne w he n gi v e n as st u d y dr u g.  
9. 1 2.  
St u d y Dr u g Acc o u nt a bilit y  
Acc o u nta bilit y f or t he st u d y treat me nt at t he st u d y site is t he res p o nsi bilit y of t h e I n vesti gat or. 
T he I n vesti gat or will e ns ure t hat t he st u d y treat me nt is use d o nl y i n acc or da nce wit h t his 
pr ot oc ol. W here all o we d, t he I n v esti gat or ma y c h o ose t o assi g n dr u g acc o u nta bilit y 
res p o nsi bilities t o a p har macist or ot her a p pr o priate i n di vi d ual. 
T he I n vesti gat or or d ele gate will mai ntai n acc urat e dr u g acc o u nta bilit y rec or ds i n dicati n g t he 
dr u g’s deli ver y d ate t o t he site, i n ve nt or y at t he site, use b y eac h s u bject, a n d ret ur n t o t he 
S p o ns or or its desi g nee ( or dis p osal of t he dr u g, if a p pr o ve d b y t he S p o ns or). T hese rec or ds will 
a de q uatel y d o c u me nt t hat t he s u bjects were pr o vi de d t he d oses as s pecifie d i n t he pr ot oc ol a n d 
s h o ul d rec o ncile all st u d y treat me nt recei ve d fr o m t he S p o ns or. Acc o u nta bilit y rec or ds will 

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i ncl u de dates, q ua ntities, batc h/serial n u m bers, e x pirati o n dates (if a p plica ble), a n d s u bject 
n u m bers. T he S p o ns or or its desi g nee will re vie w dr u g acc o u nt a bilit y at t he site o n a n o n g oi n g 
basis d uri n g m o nit ori n g visits.  
St u d y treat me nt m ust n ot be use d f or a n y p ur p ose ot her t ha n t he prese n t st u d y. St u d y treat me nt 
t hat has bee n dis pe nse d t o a s u bject a n d ret ur ne d u n use d m ust n ot be re-dis pe nse d t o a differe nt 
s u bject. 
S u bjects will recei ve i nstr ucti o ns f or h o me a d mi nistrati o n of st u d y treat me nt al o n g wit h a diar y 
t o rec or d t he d ate a n d ti me of eac h d ose, as well as t he n u m ber of ta bl ets ta ke n.  
All u n use d a n d use d st u d y treat me nt s h o ul d be ret ai ne d at t he site u ntil t he y are i n ve nt ori e d a n d 
verifie d b y st u d y site pers o n nel a n d/ or t he st u d y m o nit or. All use d, u n use d, or e x pire d st u d y 
treat me nt will be ret ur n e d t o t he S p o ns or or its desi g nee or if a ut h orize d, dis p ose d of at t he st u d y 
site per t he site’s Sta n dar d O perati n g Pr oce d ures ( S O Ps), a n d d oc u me nte d. All material 
c o ntai ni n g A G -1 2 0 a n d/ or matc he d place b o will b e treate d a n d dis p ose d of as ha zar d o us waste i n 
acc or da nce wit h g o v er ni n g re g ulati o ns.  
9. 1 3.  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d Tre at me nts  
9. 1 3. 1.  
Pri o r Me dic ati o ns a n d Pr o ce d ures  
All me dicati o ns a d mi nistere d a n d pr oce d ures c o n d ucte d wit hi n 4 wee ks ( 2 8 da ys) pri or t o t he 
first da y of st u d y dr u g a d mi nistrati o n ( C 1 D 1) are t o be rec or de d i n t he e C R F.  
As a vaila ble, tra nsf usi o n hist or y, i ncl u di n g R B C a n d platelet tra nsf usi o n, f or u p t o 5 6 da ys pri or 
t o C 1 D 1 s h o ul d be rec or de d at t he Scree ni n g visit. T his d oc u me ntati o n s h o ul d i ncl u de dates of 
eac h tr a nsf usi o n a n d u nits a d mi nistere d.  
9. 1 3. 2.  
C o nc o mit a nt T her a p y Re q uiri n g C aref ul M o nit ori n g  
C o nc o mita nt use of dr u gs wit h a p ote ntial f or Q T pr ol o n ga ti o n s h o ul d be a v oi de d a n d re place d 
wit h alter nati ve treat me nts. If t his is n ot p ossi ble, s u bjects recei vi n g t hes e dr u gs s h o ul d be 
a de q uatel y m o nit ore d b y E C G c o ntr ols, dr u g c o nce ntrati o n ( w here a p plica ble), a n d ser u m 
electr ol ytes (ie,  p ot assi u m a n d ma g n es i u m). See Secti o n  9. 9. 1  f or g ui da nce o n ma na gi n g Q T 
pr ol o n gati o n.  
T hese me dicati o ns i ncl u de, b ut are n ot li mite d t o:  
•  Fl u or o q ui n ol o nes, s uc h as ci pr ofl o x aci n a n d m o xifl o x aci n.  
•  Az ole a ntif u n gals, s uc h as fl uc o naz ole a n d p osac o naz ole.  
•  Ser ot o ni n ( 5 -H T 3) a nta g o nists, s uc h as gra nisetr o n a n d o n da nsetr o n.  
Ot her e x a m ples of dr u gs k n o w n t o pr ol o n g t he Q T i nter val are liste d i n A p pe n di x  1 5. 5 .  
S yste mic a d mi nistrati o n of m o derate or str o n g C Y P 3 A 4 i n hi bit ors (see A p pe n di x  1 5. 7 ) re q uires 
caref ul m o nit ori n g of Q Tc F.  
C oa d mi nistrati o n of A G -1 2 0 wit h narr o w t hera pe utic i n de x dr u gs t hat are e xte nsi vel y 
meta b olize d b y C Y P 2 C 9 (e g, p he n yt oi n, warfari n) ma y res ult i n decreas e d c o nce ntr ati o ns of 
t hese dr u gs. C o nsi der alt er nati ve t hera pies t hat are n ot se nsiti ve s u bstrates of C Y P 2 C 9 d uri n g 

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treat me nt wit h A G-1 2 0. S u bjects s h o ul d be m o nit ore d f or l oss of t hera p e utic effect of t hes e 
me dicati o ns if c oa d mi nistrati o n wit h A G -1 2 0/ place b o ca n n ot be a v oi de d. M o nit or i nt er nati o nal 
n or malize d rati o (I N R) le vels m ore fre q ue ntl y i n s u bjects recei vi n g warfari n d uri n g i nitiati o n or 
disc o nti n uati o n of A G -1 2 0/ place b o.  
C oa d mi nistrati o n of A G -1 2 0 ma y d ecrease t h e c o nce ntrati o ns of h or m o n al c o ntrace pti ves. 
C o nsi der alter nati ve met h o ds of c o ntrace pti o n i n s u bjects recei vi n g A G -1 2 0/ place b o. Please 
refer t o I ncl usi o n Criteri o n 1 0  i n Secti o n 8. 2  f or c o ntrace pti o n re q uire me nts. 
9. 1 3. 3.  
C o nc o mit a nt T her a p y t o be A v oi de d  
T he f oll o wi n g t h era pies are c o ntrai n dicate d d uri n g t he st u d y  w hile s u bjects are recei vi n g st u d y 
dr u g : 
•  Str o n g C Y P 3 A 4 i n d ucers liste d i n A p pe n di x 1 5. 6 , u nless t he s u bject ca n b e 
tra nsferre d t o ot her m e dicati o ns wit hi n ≥5 half-li ves pri or t o d osi n g. 
•  Se nsiti ve C Y P 3 A 4 s u bstrate me dicati o ns wit h narr o w t hera pe utic wi n d o ws liste d i n 
A p pe n di x  1 5. 6 , u nless t he s u bject ca n b e tra nsferre d t o ot her me dicati o ns wit hi n 
≥5  h alf-li ves pri or t o d osi n g. 
•  A ntica ncer t hera p y ot her t ha n t he treat me nt o utli ne d i n t he pr ot oc ol is n ot per mitte d 
w hile s u bject is recei vi n g st u d y treat me nt, wit h t he e x ce pti o n of h y dr o x y urea as 
descri be d i n Secti o n  9. 1 3. 4. 3 . If alter nati ve t hera p y is re q uire d f or treat me nt of t he 
s u bject’s disease, t he s u bject s h o ul d be disc o nti n ue d fr o m t he st u d y treat me nt.  
T he a b o ve liste d me dic ati o ns will be all o we d  d uri n g t he E F S a n d S ur vi val F oll o w -u p peri o ds.  
9. 1 3. 4.  
All o w e d C o nc o mit a nt T her a p y  
Me dicati o ns a n d treat me nts ot her t ha n t h ose s pecifie d a b o ve are p er mitte d d uri n g t he st u d y. All 
i nterc urre nt me dical c o n diti o ns a n d c o m plicati o ns of t he u n derl yi n g mali g na nc y will be treate d 
at t he discreti o n of t he I n vesti gat or acc or di n g t o acce pta bl e l ocal sta n dar ds of me dical care. 
S u bjects s h o ul d recei ve a nal gesics, a ntie metics, a nti -i nfecti ves, a nti p yretics, a n d bl o o d pr o d ucts 
as necess ar y. S u bjects m a y als o recei ve a nti micr o bial pr o p h yla xis as necessar y.  
9. 1 3. 4. 1.  Ne utr o pe ni a T her a pe utics  
Gr o wt h fact ors ( gra n ul oc yt e c ol o n y -sti m ulati n g fact or, gra n ul oc yt e-macr o p ha ge 
c ol o n y-sti m ulati n g fact or) ca n be us e d t o s u p p ort s u bjects w h o ha ve d e vel o pe d d ose -li miti n g 
Gra de 4 n e utr o pe nia or Gra de 3  ne utr o pe nia wit h fe ver a n d/ or i nfecti o n. T h e use of 
er yt hr o p oiesis sti m ulati n g a ge nts is per mitte d acc or di n g t o t he A merica n S ociet y of Cli nical 
O nc ol o g y G ui deli nes (Riz z o et al, 2 0 1 0 ) a n d a d mi nistere d per l ocal sta n dar d of care.  
9. 1 3. 4. 2.  A nti mic r o bi al Pr o p h yl a xis  
S u bjects s h o ul d  recei ve a nti micr o bial pr o p h yla xis (N C C N, 2 0 1 8 ). S u bjects ma y b e at i ncrease d 
ris k f or t he de v el o p me nt of Q T pr ol o n gati o n w he n treate d wit h i v osi de ni b i n c o m bi nati o n wit h 
k n o w n Q T pr ol o n gi n g dr u gs li ke fl u or o q ui n ol o nes, az ole a ntif u n gal a ge nts, or ser ot o ni n ( 5 ‐H T 3) 
a nta g o nists (see Secti o n  1 1. 2. 3. 1 ). 

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9. 1 3. 4. 3.   Le u k oc yt osis Pr o p h yl actics a n d T her a pe utics ( H y dr o x y ure a)  
It is rec o m me n de d t hat t h e pr o p h yl actic a n d t hera p e utic meas ures i n dicate d bel o w are 
u n derta ke n at t he earliest ma nif estati o ns of le u k oc yt osis:  
•  Te m p orar y h ol d of st u d y treat me nt o nl y if s y m pt o ms ca n n ot be me dicall y ma na ge d 
wit h t he f oll o wi n g:  
− Pr o m pt i nitiati o n of h y dr o x y urea at u p t o a d os e of 2 0 0 0 or 3 0 0 0 m g P O BI D  
− Pr o m pt i nitiati o n of le u ka p heresis, if re q uire d  
Treat me nt wit h h y dr o x y urea is all o we d d uri n g treat me nt wit h A G -1 2 0/ place b o + azaciti di ne f or 
c o ntr ol of peri p heral le u k e mic blasts i n s u bjects wit h le u k oc yt osis ( W B C > 3 0, 0 0 0/ μ L). 
Treat me nt wit h h y dr o x y urea pri or t o ra n d o mizati o n is all o we d ( Ta ble  5 ). 
I m me diat e c o m m u nicati o n wit h t he Me dical M o nit or d uri n g acti ve ma na ge me nt of le u k oc yt osis 
is re q uire d. O n ce t he si g ns a n d s y m pt o ms res ol ve a n d t he s u bject’s cli nical c o n diti o n i m pr o ves, 
A G -1 2 0/ place b o ma y be rei nitiate d if st u d y tr eat m e nt was hel d. T he d os e of A G -1 2 0/ place b o at 
rei nitiati o n is t o be disc usse d wit h t he Me dical M o nit or. 
T a ble  5 : 
Rec o m me n de d I niti al D oses of H y dr o x y ure a f or M a n a ge me nt of 
L e u k oc yt osis  
A b bre viati o ns: Q D = o nce dail y, BI D = t wice dail y.  
9. 1 3. 4. 4.  Ster oi ds  
Ster oi ds are all o we d f or t he treat me nt of I D H Differe ntiati o n S y n dr o me, if warra nte d, as 
sta n dar d of care (a n d ma y be us e d pri or t o r a n d o mizati o n).  
All c o nc o mita nt t hera pies, i ncl u di n g a n y pr oce d ures perf or me d d uri n g t he st u d y, tra nsf usi o ns of 
bl o o d pr o d ucts (see Secti o n  1 0. 8. 2 ), a n d me dicati o ns  use d t o treat A Es, are t o be re p orte d o n t h e 
e C R F. 
9. 1 3. 4. 5.  C a pt uri n g C o nc o mit a nt T her a pies P ost -Tre at me nt  
O nl y ne w a ntica n cer t h era pies are re q uir e d t o be ca pt ure d i n t he e C R F d uri n g t he E F S a n d 
S ur vi val F oll o w -u p peri o d s. 
H y dr o x y ure a D ose a n d Re gi me n  
T ot al W hite Bl o o d Cell C o u nt 
(/ μ L) 
A bs ol ute I ncre ase i n T ot al W hite 
Bl o o d Cell C o u nt fr o m B aseli ne (/ μ L)  
1 0 0 0 m g Q D  
2 5, 0 0 0 t o 5 0, 0 0 0  
1 5, 0 0 0 t o 2 9, 0 0 0  
2 0 0 0 m g BI D  
5 1, 0 0 0 t o 7 5, 0 0 0  
3 0, 0 0 0 t o 4 9, 0 0 0  
3 0 0 0 m g BI D  
≥ 7 6, 0 0 0  
≥ 5 0, 0 0 0  

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1 0.  
S T U D Y A S S E S S M E N T S  
1 0. 1.  
Sc he d ule of Assess me n ts 
Ta ble  6  pr o vi des t he Sc h e d ule of Assess me nts f or all s u bjects e nr olle d i n t he st u d y, w hile 
Ta ble  7  s u m marizes t he P K sa m pli n g ti me p oi nts a n d Ta ble  8  s u m marizes t he P D sa m pli n g ti me 
p oi nts. A det aile d descri pti o n of st u d y assess me nts f oll o ws t hese ta bles . 
After pr o vi di n g writte n i nf or me d c o ns e nt, s u bjects will u n der g o Scree ni n g e val uati o ns. T he 
Scree ni n g Visit is t o be c o n d ucte d wit hi n 4 wee ks ( 2 8 da ys) pri or t o ra n d o mizati o n; h o we ver, t he 
I D H 1 m Prescree ni n g ca n be c o n d ucte d pri or t o t he 2 8-da y Scree ni n g wi n d o w. All Scree ni n g 
pr oce d ures s h o ul d be c o m plete pri or t o first st u d y dr u g a d mi nistrati o n. S u bjects are t o atte n d 
st u d y ce nt er visits as o utli ne d i n t he Sc he d ule of Assess me nts (see Ta bl e  6 ).  
St u d y ce nter visits will be c o n d ucte d o n a n o ut patie nt basis w he ne ver p ossi ble. St u d y visits 
s h o ul d occ ur o n t he sc h e d ule d visit da y; a ± 3-d a y wi n d o w ( ± 7 da ys f or b o ne marr o w 
as pirate/ bi o ps y, p eri p heral bl o o d sa m pli n g f or I D H -m utate d cells/le u ke mi c blasts, a n d e val u ati o n 
of disease stat us) is all o w e d t o acc o m m o dat e s u bjects’ sc he d ules. B o ne marr o w e val uati o ns a n d 
peri p heral bl o o d c o u nts f or res p o nse assess me nts s h o ul d be perf or m e d wit hi n 1 da y of eac h 
ot her.  
A n E O T Visit will be c o n d ucte d as s o o n as p ossi ble after disc o nti n ui n g b ot h ( or t he sec o n d 
disc o nti n ue d treat me nt if t he 2 st u d y treat me nts are disc o nti n ue d o n differe nt da ys) st u d y 
treat me nts ( wit hi n 1 wee k of t he last d ose of st u d y dr u g); i n a d diti o n, s u bjects are t o atte n d a 
F oll o w -u p Visit 4 wee ks after t he l ast d ose of st u d y dr u g f or fi nal assess me nts. If a s u bject’s 
d ose is hel d a n d it is s u bse q ue ntl y d eci de d t o disc o nti n ue treat me nt, t he E O T Visit s h o ul d be 
c o n d ucte d as s o o n as p ossi ble, b ut n o later t ha n  4 wee ks after t he last d ose of st u d y dr u g.  
All s u bjects w h o disc o nti n ue st u d y tr eat me nt wit h o ut e x perie nci n g a n y 1 of t he f oll o wi n g: deat h, 
disease rel a pse, treat me nt fail ure, or wit h dr a wal of c o nse nt , will be f oll o we d e ver y Da y 1 
( ± 7  da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4  wee ks t hereafter f or E F S u ntil t he y 
e x perie nce tr eat me nt fail ure, or rela pse, or deat h, or wit h dra w al of c o nse nt , or u ntil t he ti me 
w he n 1 7 3 E F S e v e nts ha ve occ urre d  or as dee me d necessar y b y t he I D M C .  
O nce t he st u d y is u n b li n de d, s ur vi val f oll o w u p will c o nti n ue. All s u bjects w h o are ali ve aft er a n 
E F S e ve nt will be c o nta cte d e ver y 8 w ee ks f or s ur vi val f oll o w -u p u ntil deat h, wit h dra wal b y 
s u bject, l oss t o f oll o w-u p, or w he n t he S p o ns or e n ds t he st u d y . 

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T a ble  6 : 
Sc he d ule of Assess me nts  
Visit/ C ycle:  Scree n 1*  
4 -Wee k ( 2 8 -D a y) Tre at me nt C ycles  
E O T 2  
4 Wee ks 
P ost -
Tre at me nt 3  
E F S 
F oll o w -
u p 4  
S ur vi v al 
F oll o w -
u p  
C ycle 1  
C ycle 2  
C ycles  
3 & 4  
C ycles 
5 +  
St u d y D a y ( ± 3 d a ys 
u nless ot her wise 
n ote d) ( Wee ks):  
D −2 8 t o 
−1  
( W −4 t o 
W −1)  
D 1 
( W 1) 
D 8 
( W 2) 
D 1 5 
( W 3)  
D 2 2 
( W 4) 
D 1 
( W 5)  
D 1 5 
( W 7) 
D 1 
( W 9, 
W 1 3)  
D 1 5 
( W 1 1, 
W 1 5)  
D 1 
( W 1 7 +) 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Eli gi bilit y 
Criteria  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical a n d S ur gical 
Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I D H 1 M utati o n 
A nal ysis 5  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
B uccal S wa b 6  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n 8  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or/ C o nc o mita nt 
Me dicati o ns a n d 
Pr oce d ures  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A d verse E ve nt 
Assess me nt 9  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Hei g ht, W ei g ht, 
B S A 1 0  
X  
X  
 
 
 
X  
 
X  
 
X  
 
 
 
 
Vital Si g ns 1 1  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
B o ne Marr o w 
As pirate/ Bi o ps y 1 2  
X  
 
 
 
 
 
 
X 1 2 
 
X 1 2 
X  
 
X  
 
P eri p heral Bl o o d 1 3  
X  
 
 
 
 
 
 
X 1 3 
 
X 1 3 
X  
 
X  
 
E val uate 
Disease/ Res p o nse 1 4  
X  
 
 
 
 
 
 
X 1 4 
 
X 1 4 
X  
 
X  
 

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Visit/ C ycle:  Scree n 1*  
4 -Wee k ( 2 8 -D a y) Tre at me nt C ycles  
E O T 2  
4 Wee ks 
P ost -
Tre at me nt 3  
E F S 
F oll o w -
u p 4  
S ur vi v al 
F oll o w -
u p  
C ycle 1  
C ycle 2  
C ycles  
3 & 4  
C ycles 
5 +  
St u d y D a y ( ± 3 d a ys 
u nless ot her wise 
n ote d) ( Wee ks):  
D −2 8 t o 
−1  
( W −4 t o 
W −1)  
D 1 
( W 1) 
D 8 
( W 2) 
D 1 5 
( W 3)  
D 2 2 
( W 4) 
D 1 
( W 5)  
D 1 5 
( W 7) 
D 1 
( W 9, 
W 1 3)  
D 1 5 
( W 1 1, 
W 1 5)  
D 1 
( W 1 7 +) 
P h ysical E xa mi nati o n  
X 
(c o m plete 
e xa m) 
X 
(li mite d 
e xa m 1 5) 
 
 
 
X 
(li mite d 
e xa m 1 5) 
 
X 
(li mite d 
e xa m 1 5) 
 
X 
(li mite d 
e xa m 1 5) 
X 
(c o m plete 
e xa m) 
 
 
  
E C O G P erf or ma nce 
Stat us  
X  
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
 
Pre g na nc y T est 1 6  
X  
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
 
He mat ol o g y, Ser u m 
C he mistr y 1 7  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C oa g ulati o n St u dies 1 8  
X  
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
 
P K/ P D Assess me nts  
 
See T a ble  7  f or P K sa m pli n g s c he d ule a n d T a ble  8  f or P D sa m pli n g 
sc he d ule 
 
 
 
 
E C H O/ M U G A f or 
L V E F 1 9  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
1 2 -lea d E C G2 0 
X  
X  
 
X  
 
X  
X  
X  
 
X  
X  
 
 
 
Q ualit y of Life 
Assess me nt 2 1  
 
X  
 
X  
 
X  
X  
X 2 1 
 
X 2 1 
X  
X  
 
 
A G -1 2 0 
A d mi nistrati o n 2 2  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
Azaciti di ne 
A d mi nistrati o n 2 3  
 
See Secti o n  9. 7. 2  f or details 
 
 
 
 
S u bj ect Diar y a n d 
St u d y Me dicati o n 
Acc o u nta bilit y 2 4  
 
X  
 
 
 
X  
 
X  
 
X  
X  
 
 
 
S ur vi val 2 5  
 
 
 
 
 
 
 
 
 
 
 
 
  
X  
S u bse q ue nt 
A ntica ncer T hera pies  
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
X  

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A b bre viati o ns: A E = a d verse e ve nt; A L P  =  al kali ne p h os p hatase; A L T  =  ala ni n e a mi n otra nsferase; A N C  =  a bs ol ute n e utr o p hil c o u nt; A S T  =  as partate a mi n otra nsferas e; 
β -h C G  =  beta -h u ma n c h ori o nic g o na d otr o pi n; B P  =  bl o o d press ure; B S A = b o d y s urfac e area; B U N  =  bl o o d urea nitr o ge n ; C 1 D 1 = C ycle 1, Da y 1; C R =  c o m plete re missi o n; 
D  =  Da y; E C G  =  electr o car di o gra m; E C H O  =  ec h ocar di o gra m; E C O G  =  East er 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 F S  =  e ve nt-free s ur vi val; 
E O T = E n d of Treat me nt; I C F  =  i nf or me d c o nse nt f or m; I D H  =  is ocitrate d e h y dr o ge nase; I D H 1 =  is ocitrate d e h y dr o ge nase 1; I V =  i ntra ve n o us; L V E F = left ve ntric ular ejecti o n 
fra cti o n; M U G A = m ulti-gate d ac q uisiti o n; P D  =  p har mac o d y na mi c; P K  =  p har mac o ki n etic; Q D  =  o nce dail y; R B C  =  re d bl o o d cell; S A E = seri o us a d verse e ve nt; 
S C  =  s u bc uta ne o us; W = we e k; W B C =  w hite bl o o d cell.  
 
* S u bjects ma y si g n a pre -Scree ni n g I C F t o all o w f or c ollecti o n of a b o ne marr o w a n d peri p heral bl o o d sa m ple f or ce ntral I D H 1 a n d
pri or t o t h e 4 -wee k ( 2 8 -da y) Scree ni n g wi n d o w. B o ne marr o w bi o ps y/as pirate a n d peri p heral bl o o d sa m ples m ust b e se nt wit h pr o of of s hi p me nt t o t he 
ce ntral la b orat or y as p art of Pre -scree ni n g t o satisf y t h e Scree ni n g ti me p oi nts f or t h ese sa m ple t y pes, as l o n g as t h e y are c ollecte d wit hi n 2 8 da ys pri or t o ra n d o mizati o n.  
 
1 
Scree ni n g assess me nts t hat ma y h a ve bee n c o n d ucte d pri or t o i nf or me d c o nse nt b ut wit hi n 2 8 da ys of C 1 D 1 nee d n ot be re peate d a n d res ults ma y be e ntere d i nt o t he e C R F. 
2  
All s u bjects are t o u n der g o a n E O T ass ess me nt wit hi n 1 wee k of t h e last d ose of st u d y treat me nt ( A G -1 2 0/ place b o a n d azaciti di ne). If a s u bject disc o nti n ues st u d y treat me nt 
at a re g ularl y sc he d ule d visit, E O T ass ess me nts ma y be perf or me d at t h at visit.  S u bjects’ eli gi bilit y t o cr oss o ver t o A G -1 2 0 + azaciti di n e after S p o ns or u n bli n di n g of t h e 
st u d y will be deter mi n e d base d o n pr oce d ures c o n d ucte d i n t he E O T Visit.  
3  
All s u bjects are t o ha ve a p ost -treat me nt visit 4 wee ks ( ± 3 da ys) aft er t h e last dose of st u d y treat me nt ( A G -1 2 0/ place b o a n d azaciti di n e).  
4  
All s u bjects w h o disc o nti n ue st u d y tre at me nt wit h o ut e x perie nci n g a n y 1 of t h e f oll o wi n g: deat h, disease rela pse, treat me nt f ail ure, or wit h dra wal of c o nse nt, will be f oll o we d 
e ver y D a y 1 ( ± 7 da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4 wee ks t h ereafter f or E F S u ntil t he y e x perie nce treat me nt fail ure, rela pse, de at h, wit h dra w fr o m t h e st u d y, 
or u ntil t h e ti me w he n 1 7 3 E F S e ve nts h a ve occ urre d  or as dee me d necessar y b y t h e I D M C .  
5  
Scree ni n g b o ne marr o w as pirate ( or peri p heral bl o o d sa m ple if b o ne marr o w as pirate is n ot a vaila ble , wit h Me dical M o nit or a p pr o val) will be c ollecte d f or ce ntral 
c o nfir mati o n of I D H 1 -m utate d disease pri or t o ra n d o mizati o n, a n d ca n be c o n d ucte d bef ore t h e 2 8 -da y Scre e ni n g wi n d o w.  
6  
A b uccal s wa b f or ger m -li ne m utati o n a nal ysis will be o btai ne d at Scree ni n g.  
 
 
 
 
8  
S u bjects s h o ul d start st u d y treat me nt (ie, C 1 D 1 [ Wee k 1]) wit hi n 3 da ys ( 7 2 h o urs) of ra n d o mizati o n.  
9  
Pri or t o first d ose of st u d y treat me nt, o nl y A Es t h at are classifie d as S A Es dee me d relate d t o st u d y pr oce d ures s h o ul d be re p orte d. Aft er i nitiati o n of st u d y dr u g, all A Es a n d 
S A Es, re gar dless of attri b uti o n, will be c ollecte d. S u bjects will be assesse d at t h e F oll o w -u p Visit ( 4 we e ks p ost -treat me nt) t o deter mi n e if a n y ne w A Es ha ve occ urre d. After 
t his p eri o d, I n vesti gat ors s h o ul d re p ort o nl y S A Es t h at are c o nsi dere d t o be relate d t o st u d y treat me nt ( A G-1 2 0/ place b o or azaciti di ne).  
1 0  
Hei g ht at Scree ni n g o nl y. Wei g ht a n d b o d y s urface are a calc ulati o n s h o ul d be c o n d ucte d o n Da y 1 of eac h c ycle, pri or t o d osi n g.  
1 1  
Vital si g ns (te m perat ure, B P [sitti n g f or 5 mi n utes], p ulse rate, res pirat or y rate) are t o be ta ke n at Scree ni n g a n d at a n y p oi nt w he n a b n or mal vital si g ns are s us pecte d. All 
cli nicall y rele va nt a b n or mal vital si g n res ults will be re p orte d as A Es.  
1 2  
A b o ne marr o w as pirate (a n d bi o ps y if sta n dar d of care, or i n case of a dr y ta p or as pic ular [ dil ute d] sa m ple) is re q uire d at: Scree ni n g (if a sa m ple was c ollecte d a n d s u b mitte d 
as part of Pre -scree ni n g wit hi n 2 8 da ys pri or t o ra n d o mizati o n, a n a d diti o nal Sc ree ni n g sa m ple is n ot re q uire d); Da y 1 ( ± 7 da ys) of We e ks 9, 1 7, 2 5, 3 3, 4 1, 5 3 , a n d e ver y 
2 4  wee ks t h ereafter; at E O T; d uri n g E F S f oll o w -u p (sa m ples s h o ul d c o nti n ue bei n g c ollecte d d uri n g E F S acc or di n g t o t h e sa me sc he d ule t hat was use d w he n t h e s u bject ha d 
t h e E F S e ve nt; b o ne marr o w sa m ples are o pti o nal d uri n g E F S f oll o w-u p f or p ost -tra ns pla nt s u bjects); as dictate d b y p h ysi cal e xa m a n d/ or bl o o d c o u nts; a n d/ or a n y ti me t h at 
disease pr o gressi o n is s us pecte d.  At E O T, a b o ne marr o w as pirate will be c ollecte d if it has n ot bee n c ollecte d wit hi n t h e pri or 8 wee ks. U p o n S p o ns or u n bli n di n g, b o ne 
marr o w as pirate will n o l o n ger be c ollecte d.  
 
Bl o o d dra ws f or re g ular h e mat ol o g y assess m e nts a n d ass ociate d C B C res ul ts 
(f o ot n ote 1 7) s h o ul d be re vie we d f or t h e nee d t o e val u ate disease stat us at a n u nsc he d ule d ti me p oi nt. 
1 3  
P eri p he ral bl o o d f or I D H-m utate d cells/le u ke mic blasts is re q uire d t o be sa m ple d at a n y ti me a b o ne marr o w as pirate/ bi o ps y is p erf or me d t o assess f or p ote ntial cli nical 
acti vit y. T hes e ti me p oi nts i n cl u de: Scree ni n g (if a sa m ple was c ollecte d a n d s u b mitte d as p ar t of Pre-scree ni n g wit hi n 2 8 da ys pri or t o ra n d o mizati o n, a n a d diti o nal Scree ni n g 
sa m ple is n ot re q uire d); Da y 1 ( ± 7 da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3 , a n d e ver y 2 4 wee ks  t h ereafter; at E O T; d uri n g E F S f oll o w -u p o n t he sa me sc he d ule; as cli nicall y 
i n dicate d; a n d/ or a n y ti me t h at disease pr o gressi o n is s us pecte d. 
 
Bl o o d dra ws f or re g ular h e mat ol o g y assess me nts a n d ass ociate d C B C res ul ts (f o ot n ote 1 7) s h o ul d be 

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re vie we d f or t h e nee d t o e val u ate disease stat us at a n u nsc he d ule d ti me p oi nt. 
1 4 
E val u ati o n of disease stat us, i n cl u di n g e val u ati o n of b o ne marr o w a n d/ or peri p heral bl o o d, t o be c o n d ucte d: at Scree ni n g ( or as part of Pre -scree ni n g as l o n g as it is wit hi n 
2 8  da ys pri or t o ra n d o mizati o n); Da y 1 ( ± 7 da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3 , a n d e ver y 2 4 wee ks t h ereafter; at E O T; d uri n g E F S f oll o w -u p o n t h e sa me sc he d ule; as 
cli nicall y i n dicate d; a n d/ or a n y ti me t h at disease pr o gressi o n is s us pecte d. U p o n S p o ns or u n bli n di n g, e val u ati o n of disease stat us will n o l o n ger be c ollecte d. S u bjects are 
e x pecte d t o re mai n o n treat me nt wit h A G -1 2 0 / place b o as l o n g as t here are n o u nacce pta ble t o xicities a n d t he s u bject has a res p o nse of at least sta ble disease. Als o i n cl u des 
assess me nt of tra nsf usi o ns ( R B C a n d pl atelet), i nfecti o ns, le n gt h of a n y h os pital sta ys, a n d ot her effi cac y a n d safet y meas ures t h at are p ote ntiall y i n dicati ve of cli nical be nefit. 
De -i d e ntifie d c o pies of e val u ati o n re p orts ( b o ne marr o w a n d/ or peri p heral bl o o d assess me nt of disease stat us) s h oul d be s u b mitte d. Bl o o d dra ws f or re g ular he mat ol o g y 
assess me nts (f o ot n ote 1 7) s h o ul d be re vie we d f or t h e nee d t o e val u ate disease stat us at a n u nsc he d ule d ti me p oi nt.   
1 5 
Cli nicall y directe d e xa mi n ati o ns, i n cl u di n g a s ki n e xa mi n ati o n.  
1 6 
F or fe male s u bjec ts wit h re pr o d ucti ve p ote ntial: A ser u m β-h C G pre g na nc y test is re q uire d at Scree ni n g a n d m ust b e verifie d as ne gati ve wit hi n 7 2 h o urs pri or t o st u d y 
treat me nt a d mi nistrati o n. A uri n e pre g na nc y test will be c o n d ucte d o n C 1 D 1 a n d c o nfir me d ne gati ve pri or t o d osi n g, a n d o n Da y 1 of all s u bse q ue nt c ycles. A uri n e 
pre g na nc y test s h o ul d be c o n d ucte d at t h e e n d of treat me nt visit.  
1 7  
He mat ol o g y: he m o gl o bi n, R B C c o u nt, W B C c o u nt wit h differe ntial, A N C, platelet c o u nt, a n d peri p heral blast c o u nt. He mat ol o g y b l o o d dra ws s h o ul d occ ur pri or t o 
a d mi nistrati o n of a n y st u d y dr u gs o n visit date.  
C he mistr y: s o di u m, p otassi u m, calci u m, ma g nesi u m, al b u mi n, gl u c ose, B U N, creati ni n e, lactate de h y dr o ge nas e, A L P, A S T, A L T, t o tal bilir u bi n, p h os p hate, a n d bicar b o nate. 
C he mistr y b l o o d dra ws s h o ul d occ ur pri or t o a d mi nistrati o n of a n y st u d y dr u gs o n visit date.  
Bl o o d f or he mat ol o g y a n d c he mistries is t o be o btai ne d: at Scree ni n g; o n Da ys 1, 8, 1 5, a n d 2 2 ( ±  3 da ys) of C ycle 1 ( Wee ks 1, 2, 3, a n d 4); o n Da ys 1 a n d 1 5 ( ±  3 da ys) of 
C ycles 2, 3, a n d 4 ( Wee ks 5, 7, 9, 1 1, 1 3, a n d 1 5); o n Da y 1 ( ±  3 da ys) of ea c h treat me nt c ycle t hereafter ( Wee ks 1 7 +); at E O T; a n d 4 we e ks p ost -treat me nt. 
1 8  
C oa g ulati o n: acti vate d partial t hr o m b o plasti n ti me (a P T T) at baseli n e a n d i nter nati o nal n or malize d rati o (I N R). Bl o o d f or c oa g ulati o n st u dies is t o be o btai ne d at Scree ni n g, 
o n Da y 1 ( ± 3 da ys) of eac h treat me nt c ycle, a n d at t h e E O T Visit.  
1 9  
L V E F assess me nt re q uire d wit hi n 4 wee ks pri or t o C 1 D 1 ( Wee k 1). E C H O/ M U G A s h o ul d be perf or me d at ot h er ti mes d uri n g t h e st u d y if cli nicall y i n dicate d; if re peate d, 
met h o d ( per i nstit uti o nal p olic y) s h o ul d be t he sa me t hr o u g h o ut t h e st u d y f or t h e i n di vi d ual s u bject. O nl y E C H O ma y be use d a t sites i n Ger ma n y.  
2 0  
Safet y E C Gs; n ot ce ntral or tri plicate. T o be o btai ne d at Scree ni n g, 4 -6 h o urs p ost -d ose o n C 1 D 1 ( Wee k 1)  o nl y,  a n d  d uri n g t h e visit wi n d o w  o n C 1 D 1 5 ( Wee k 3), C 2 D 1 
( Wee k 5), a n d C 2 D 1 5 ( Wee k 7). After C ycle 2, E C Gs s h o ul d be perf or me d o n D 1 of eac h c ycle a n d as cli nicall y i n dicate d. A n E C G  will als o  be perf or me d at E O T.  
2 1  
Q ualit y of life ass ess me nts will occ ur pri or t o d osi n g o n Da ys 1 a n d 1 5 ( ±  3 da ys) of t h e first 2 c ycles ( Wee ks 1 a n d 3 a n d Wee ks 5 a n d 7); Da y 1 ( ±  7 da ys) of o d d c ycl es 
( Wee ks 9, 1 7, 2 5, etc.); at E O T; a n d 4 wee ks p ost-treat me nt. U p o n S p o ns or u n bli n di n g , q ualit y of life assess me nts will n ot be c o n d ucte d.  
2 2  
A G -1 2 0/ place b o is a d mi nistere d Q D be gi n ni n g o n C 1 D 1 ( Wee k 1), pri or t o a d mi nistrati o n of azaciti di n e. If s u bjects f or get t o ta ke  t h e dail y d ose, t h e y s h o ul d ta ke A G-1 2 0 or 
plac e b o wit hi n 1 2 h o urs after t he misse d d ose. Misse d d oses o utsi de t his wi n d o w or v o mite d d oses s h o ul d n ot be ta ke n or re peate d.  
2 3  
Az aciti di n e will be a d mi nistere d S C or I V f or 1 wee k ( 7 da ys) of e ac h 4 -wee k ( 2 8 -da y) treat me nt c ycle, starti n g o n Da y 1 ( ±  3 d a ys) of Wee k 1. A f ull 7 da ys of a zaciti di n e is 
re q uire d, b ut as p er i nstit uti o nal practice, a sc he d ule of 5 da ys of dail y d oses, f oll o we d b y n o d ose recei ve d o n t he wee ke n d  a n d 2 dail y d oses gi ve n a gai n at t h e start of t he 
ne xt we e k, is all o we d. T he sa me sc he d ule s h o ul d be use d f or eac h s u bject t hr o u g h o ut t he d urati o n of treat me nt, w he n p ossi ble.  
2 4  
S u bject diar y t o be use d w he n s u bject is a n o ut patie nt t o rec or d d osi n g details f or A G -1 2 0/ place b o. W hile s u bject is a n i n patie nt, details of A G -1 2 0/ place b o a d mi nistrati o n 
ma y be ca pt ure d o n s u bject diar y or sta n dar d h os pital i n patie nt d osi n g rec or d. All misse d or v o mite d d oses s h o ul d be n ote d i n  t h e diar y. Treat me nt c o m plia nce of 
A G -1 2 0/ place b o a d mi nistrati o n is t o be assesse d base d o n ret ur n of u n use d st u d y dr u g as well as s u bject diaries. All d oses of st u d y dr u gs ( A G -1 2 0 or place b o; azaciti di ne) 
will be d oc u me nte d i n t h e e C R F, i n cl u di n g d oc u me ntati o n of a n y misse d d oses a n d d ose a d mi nistere d.  
2 5  
O nce t h e st u d y is u n bli n de d, s ur vi val f oll o w u p will c o nti n ue. Al l s u bjects w h o are ali ve after a n E F S e ve nt will be c o ntacte d e ver y 8 we e ks f or s ur vi val f oll o w-u p u ntil deat h, 
wit h dra wal b y s u bject, l oss t o f oll o w -u p, or w he n t h e  S p o ns or e n ds t h e st u d y . 

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T a ble  7 : 
P h ar m a c o ki netic S a m pli n g Sc he d ule  
Visit/ C ycle:  
C ycle 1  
C ycle 1  
C ycle 1  
 
C ycle 2  
 
C ycles 3 +  
 
St u d y D a y ( ± 3 d a ys)  
( Wee k): 
D 1 ( W 1)  
D 8 ( W 2)  
D 1 5 ( W 3)  
D 1 ( W 5)  
D 1 ( W 9 +)  
Pre -d ose 1 , 2 
X  
X  
X  
X  
X  
P ost -d ose  
 
 
 
 
 
 0. 5 hr ( ± 5 mi n)  
X  
 
 
X  
 
 2 hrs ( ± 1 5 mi n)  
X  
 
 
X  
 
 4 hrs ( ± 1 hr)  
X  
 
 
X  
 
A b bre viati o ns: D = da y; hr = h o ur; mi n = mi n ute; W = wee k.  
N otes:  Bl o o d sa m ples f or P K assess me nts will be dra w n pre -d ose a n d at 0. 5, 2, a n d 4 h o urs p ost -d ose o n Da y 1 ( ±  3 da ys) of C ycl es 1 a n d 2 ( Wee ks 1 a n d 5); pre -d ose o n Da ys 8 
a n d 1 5 ( ±  3 da ys) of  C ycle 1; a n d pre -d ose o n Da y 1 ( ±  3 da ys) of C ycles 3 a n d be y o n d ( Wee ks 9 +).  
If st u d y dr u g is n ot a d mi nistere d o n t he da y of a visit (ie, st u d y dr u g i nterr u pti o n or per ma ne nt disc o nti n uati o n of st u d y dr u g), o nl y 1 P K bl o o d sa m ple will be c ollecte d.  
1 
T o b e o btai ne d wit hi n 3 0 mi n utes bef ore d ose.   
2 
F or s u bjects w h o cr oss o ver, o nl y pre d ose P K sa m ples will be c ollecte d.  
 
 

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T a ble  8 : 
P h ar m a c o d y n a mi c S a m pli n g Sc he d ule  
Visit/ C ycle:  
C ycle 1  
C ycle 1  
St u d y D a y ( ± 3 d a ys) ( Wee k): 
D 1 ( W 1)  
D 1 5 ( W 3)  
Pre -d ose 1 
X  
X  
A b bre viati o ns: D = da y; W = we e k.  
N ote: Bl o o d sa m ples f or 2 -H G assess me nt will be dra w n at pre -d ose o n C 1 D 1 a n d C 1 D 1 5 ( ±  3 da ys).  
1  
T o be o btai ne d wit hi n 3 0 mi n utes bef ore d ose.  

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1 0. 2.  
I nf or me d C o nse nt  
A c o m plete descri pti o n of t he st u d y is t o be prese nte d t o eac h p ote ntial s u bj ect, a n d a si g ne d a n d 
date d I C F  is t o be o btai n e d bef ore a n y st u d y-s p ecific pr oce d ures are perf or me d. 
A c o m plete descri pti o n of t he c yt o ge netic a n d I D H 1 m testi n g pr oce d ures ma y b e pres e nte d t o 
p ote ntial s u bjects pri or t o u n der g oi n g c yt o ge netic a n d I D H 1 m testi n g as part of Pre -scree ni n g at 
a n y p oi nt pri or t o t he 2 8 -da y Scree ni n g wi n d o w. S u bjects ma y si g n a pre -Scree ni n g I C F t o all o w 
f or c ollecti o n of a b o ne marr o w a n d p eri p heral bl o o d sa m ple f or ce ntral I D H 1 a n d  
 
 pri or t o t he 4-wee k ( 2 8 -da y) Scree ni n g 
wi n d o w. B o ne m arr o w bi o ps y/as pir ate a n d peri p heral bl o o d sa m ples m ust be se nt wit h pr o of of 
s hi p me nt t o t he ce ntral la b orat or y as part of Pre-scree ni n g t o satisf y t he Scree ni n g ti me p oi nts f or 
t hese sa m ple t y pes, as l o n g as t he y are c ollecte d wit hi n 2 8 da ys pri or t o r a n d o mizati o n.  
1 0. 3.  
De m o gr a p hic D at a a n d Me dic al, S ur gic al, a n d Me dic ati o n Hist or y  
S u bject de m o gra p hic dat a, i ncl u di n g ge n der, date of birt h, a ge, race, a n d et h nicit y, will be 
o btai ne d d uri n g Scree ni n g, acc or di n g t o l ocal re g ulati o ns.  
A c o m plete me dic al a n d s ur gic al hist or y, i n cl u di n g t he t y pe of u n derl yi n g mali g na n c y a n d t he 
date of c o nfir mati o n of t he hist ol o gic dia g n osis of t he u n derl yi n g mali g na nc y, will be o btai ne d 
d uri n g Scree ni n g. T he m e dical hist or y is t o i nc l u de all rele va nt pri or me dical hist or y as well as 
all c urre nt me dic al c o n diti o ns. If a vaila ble fr o m t he me dical hist or y, res ults wit hi n t he pre vi o us 
6  m o nt hs f or diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de or f orce d e x pirat or y v ol u me i n 
1 sec o n d w ill als o be rec or de d. 
All me dicati o ns a d mi nistere d a n d pr oce d ures c o n d ucte d wit hi n 4 wee ks ( 2 8 da ys) pri or t o C 1 D 1 
s h o ul d be rec or de d i n t he e C R F.  
Re d bl o o d cell a n d platel et tra nsf usi o n hist or y, i n cl u di n g dates of t h e tra nsf usi o n a n d u nits 
a d mi nistere d, s h o ul d be ca pt ure d f or t h e 5 6-da y p eri o d pri or t o C 1 D 1.  
 
 
 
 
 
 

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1 0. 5.  
I D H 1 M ut ati o n A n al ysis  
A Scree ni n g b o n e marr o w as pirate (or peri p h eral bl o o d sa m ple  if b o ne marr o w as pirate is n ot 
a vaila ble, wit h Me dic al M o nit or a p pr o val) is re q uire d f or I D H 1 m c o nfir m ati o n at a ce ntr al 
la b orat or y. I D H 1 m utati o n p ositi vit y fr o m eit her b o ne marr o w as pirate or peri p heral bl o o d is 
re q uire d f or st u d y eli gi bilit y. 
Wit h Me dical M o nit or a p pr o val, s u bjects ma y be eli gi ble a n d ra n d o mize d wit h l ocal I D H 1 m 
testi n g res ults; h o we v er, b o ne marr o w as pirate f or ce ntral la b orat or y testi n g m ust have b ee n se nt 
wit h pr o of of s hi p me nt t o t he ce ntral la b orat or y pri or t o ra n d o mizati o n. I n cases w here b o ne 
marr o w as pir ate is n ot a v aila ble, peri p heral bl o o d sa m ples ma y b e use d f or I D H 1 m c o nfir m ati o n  
wit h Me dical M o nit or a p pr o val.  
A b uccal s w a b f or ger m -line m utati o n a nal ysis als o will be o btai ne d at Scree ni n g i n all s u bjects.  

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1 0. 6.  
S afet y Assess me nts  
1 0. 6. 1.  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
Safet y d ata will be re vie we d re g ularl y b y a n I D M C t o e ns ure t he safet y of t he c o m bi nati o n 
t hera p y. T hes e re vi e ws will occ ur after t he first 6, 1 2, 2 4, a n d 3 6 s u bjects h a ve c o m plete d 
1  c ycle of t hera p y or dis c o nti n ue d, w hic he ver s h o ul d occ ur first. T hereafter, safet y re vie ws will 
be c o n d ucte d a p pr o xi matel y e ver y 6 m o nt hs u ntil t he st u d y is u n bli n de d f or t he a nal ysis of t he 
pri ma r y e n d p oi nt. N o i nteri m a nal yses f or efficac y are pla n ne d. 
Me m bers of t he I D M C will be e xter nal t o t he S p o ns or a n d will f oll o w a c h arter t hat o utli nes 
t heir r oles a n d res p o nsi bilities. T he S p o ns or will re mai n bli n de d t o t he data u ntil t he a nal ysis of 
t he pri mar y e n d p oi nt.  
All s u m maries a n d a nal yses b y tr eat me nt ar m f or t he I D M C re vie w will be pre pare d b y a n 
i n de pe n de nt data c o or di n ati n g ce nter. T h e safet y d ata will i ncl u de de m o gra p hic data, A Es, 
S A Es, a n d rele v a nt la b orat or y d ata. F oll o wi n g t heir data re vi e w, t he I D M C will pr o vi de a 
rec o m me n dati o n as t o w het her t he st u d y ma y c o nti n ue, w het her a m e n d me nt(s) t o t he pr ot oc ol 
s h o ul d be i m ple me nte d, or w het her t h e st u d y s h o ul d be st o p pe d. T he fi nal decisi o n will rest wit h 
t he S p o ns or. 
T he re q uir e me nts of t hes e re vie ws will be s pecifie d i n t he I D M C c harter.  
1 0. 6. 2.  
P h ysic al E x a mi n ati o n a n d E C O G Perf or m a nce St at us  
A c o m plete p h ysical e x a mi nati o n, i ncl u di n g assess me nt of wei g ht a n d b o d y s urface area 
calc ulati o n, will be perf or me d at Scree ni n g a n d at t he E O T Visit. Hei g ht wil l be o btai ne d at t he 
Scree ni n g Visit. A li mite d p h ysical e x a mi nati o n (cli nicall y dir ecte d base d o n si g ns a n d 
s y m pt o ms) will be perf or me d o n Da y 1 ( ± 3 da ys) of eac h c ycle. A s ki n e x a mi nati o n as part of 
t he c o m plete a n d li mite d p h ysical e x a mi nati o n m ust be perf or m e d. After Scree ni n g, cli nicall y 
si g nifica nt p h ysic al e x a mi nati o n fi n di n gs are ca pt ure d as A Es. 
Deter mi nati o n of E C O G P S will be perf or me d at Scree ni n g, o n Da y  1 ( ±  3 da ys) of eac h 
treat me nt c ycl e, a n d at t h e E O T Visit. See A p pe n di x 1 5. 8  f or E C O G P S sc ori n g. 
1 0. 6. 3.  
Vit al Si g ns  
Vital si g ns, i ncl u di n g s yst olic a n d diast olic B P, heart rate, res pirat or y rate, a n d te m perat ure, will 
be o btai ne d at Scree ni n g a n d at a n y p oi nt a b n or mal vital si g ns are s us pecte d. All cli nicall y 
rele va nt a b n or mal vital si g n res ults will be re p orte d as A Es.  
1 0. 6. 4.  
Electr oc a r di o gr a m a n d Assess me nt of Left Ve ntric ul ar Ejecti o n Fr acti o n  
T he 1 2 -lea d E C Gs (safet y; n ot ce ntr al or tri plicate) are t o b e o btai ne d at Scree ni n g, 4 -6 h o urs 
p ost -d ose o n C 1 D 1 ( Wee k 1) o nl y a n d d uri n g t he visit wi n d o w o n C 1 D 1 5 ( Wee k 3), C 2 D 1 
( Wee k 5), a n d C 2 D 1 5 ( Wee k 7). After C ycl e 2, E C Gs s h o ul d be perf or m e d o n Da y 1 of eac h 
c ycle a n d as cli nicall y i n dicate d. A n E C G wi ll als o be perf or me d at E O T. L ocal E C Gs s h o ul d 
re mai n st ore d at t he l o cal site as l ocal s o urce d oc u me ntati o n. 
All 1 2 -lea d E C Gs s h o ul d be o btai ne d f oll o wi n g 3 mi n utes of rec u m be nc y or se mi-rec u m be nc y.  

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All s u bjects are t o ha v e L V E F det er mi ne d b y E C H O or M U G A s ca n wit hi n 4 wee ks pri or t o 
C 1 D 1 ( Wee k 1); re p eat assess me nts s h o ul d be perf or me d at ot her ti mes d uri n g t he st u d y if 
cli nicall y i n dicat e d. Met h o d s h o ul d be per i nstit uti o nal practice a n d t he sa me met h o d s h o ul d be 
use d f or a n y s u bs e q ue nt e x a mi nati o ns f or  t he i n di vi d ual s u bject. Sites i n Ger ma n y ma y n ot use 
M U G A a n d m ust use E C H O f or L V E F ass ess me nts.  
1 0. 6. 5.  
S afet y L a b or at or y Assess me nts  
Cli nical la b orat or y e val u ati o ns are t o be perf or m e d b y t he site’s l ocal la b orat or y. Pri or t o starti n g 
t he st u d y, t he I n v esti gator will pr o vi de t o t he S p o ns or ( or its desi g n ee) c o pies of all la b orat or y 
certificati o ns a n d n or mal ra n ges f or all la b orat or y para meters t o be perf or m e d b y t h at la b orat or y.  
Cli nical la b orat or y e val u ati o ns are t o be c o n d ucte d acc or di n g t o t he Sc h e d ule of As sess me nts 
( 6). I n a d diti o n, all cli nicall y si g nifica nt la b orat or y val u es will be f urt her i n vesti gate d acc or di n g 
t o t he j u d g me nt of t he I n vesti gat or. 
T he f oll o wi n g s afet y la b orat or y para meters are t o be e val uat e d b y t he I n vesti gat or:  
He m at ol o g y : 
He m o gl o bi n,  R B C c o u nt, W B C c o u nt wit h differe ntial, A N C, platelet 
c o u nt, peri p heral blast c o u nt  
C he mistr y : 
S o di u m, p otassi u m, calci u m, ma g nesi u m, al b u mi n, gl uc ose, B U N, 
creati ni ne, lactate d e h y dr o ge n ase, A L P, A S T, A L T, t otal bilir u bi n, 
p h os p hate, bicar b o nate  
C o a g ul at i o n St u dies: 
Acti vate d partial t hr o m b o plasti n ti me (a P T T), I N R  
Bl o o d f or h e mat ol o g y a n d c he mistries is t o be o btai ne d: at Scree ni n g; o n D a ys 1, 8, 1 5, a n d 2 2 
( ± 3 da ys) of C ycle 1 ( Wee ks 1, 2, 3, a n d 4); o n D a ys 1 a n d 1 5 ( ±  3 da ys) of C ycl es 2, 3, a n d 4 
( Wee ks 5, 7, 9, 1 1, 1 3, a n d 1 5); o n Da y 1 ( ± 3 da ys) of eac h treat me nt c ycle t hereafter ( Wee ks 
1 7 +); at E O T; a n d at 4 w ee ks p ost -treat me nt. All bl o o d sa m ples f or he mat ol o g y a n d c he mistries 
m ust be dra w n pri or t o a d mi nistrati o n of st u d y dr u gs.  
Bl o o d f or c oa g ulati o n st u dies is t o be o btai ne d at Scree ni n g, o n Da y  1 ( ±  3 da ys) of eac h 
treat me nt c ycl e, a n d at t h e E O T Visit. 
Pre g n a nc y Test:  
All w o me n of re pr o d ucti ve p ote ntial m ust ha ve a ne gati ve pre g n a nc y test 
t o be eli gi ble. A s er u m β-h C G pre g na nc y t est will be  perf or me d at 
Scree ni n g a n d m ust be c o nfir me d ne gati ve wit hi n 7 2 h o urs pri or t o st u d y 
treat me nt a d mi nistrati o n. 
1 0. 6. 6.  
A d verse E ve nts  
All A Es will be gra de d usi n g t he N CI C T C A E versi o n 4. 0 3 gra di n g s yste m (see A p pe n di x  1 5. 9 ). 
C o m plete details o n A E m o nit ori n g are pr o vi de d i n Secti o n  1 1 . 
1 0. 7.  
B o ne M arr o w S a m ples a n d Peri p her al Bl o o d Le u ke mic Bl ast Cells  
A b o ne marr o w as pirat e (a n d bi o ps y if sta n dar d of care, or i n cas e of a dr y ta p or as pic ular 
[ dil ute d] sa m ple) is re q uire d at: Scree ni n g (if a s a m ple was c ollecte d a n d s u b mitte d as part of 
Pre -scree ni n g wit hi n 2 8 da ys pri or t o ra n d o mizati o n, a n a d diti o nal Scree ni n g sa m ple is n ot 
re q uire d); Da y 1 ( ± 7 da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4 wee ks t hereafter; at 

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E O T; d uri n g E F S f oll o w -u p (sa m ples s h o ul d c o nti n ue bei n g c ollecte d d uri n g E F S acc or di n g  t o 
t he sa me sc he d ul e t hat w as use d w he n t he s u bj ect ha d t he E F S e v e nt b o ne marr o w sa m ples are 
o pti o nal d uri n g E F S f oll o w -u p f or p ost -tr a ns pla nt s u bjects); as dictate d b y p h ysical e x a m a n d/ or 
bl o o d c o u nts; a n d/ or a n y ti me t hat disease pr o gressi o n is s us pec te d.
 
 B o ne marr o w assess me nts o btai ne d f or t he e val uati o n of cli nical 
acti vit y will be c ollecte d. De -i de ntified c o pies of e val uati o n re p orts ( b o n e marr o w a n d/ or 
peri p heral bl o o d assess me nt of disease stat us) s h o ul d be s u b mitte d.  
B o ne marr o w as pirates a n d/ or c ore sa m pli n g s h o ul d be perf or m e d acc or di n g t o sta n dar d of care 
a n d a nal yz e d at t he l oc al site’s la b orat or y i n acc or da nce wit h t he I nt er nati o nal C o u ncil f or 
Sta n dar dizati o n i n He mat ol o g y (I C S H) G ui d eli nes (Lee et al, 2 0 0 8 ). 
T he dia g n osis a n d e val u ati o n of A M L ca n be ma de b y b o n e marr o w as pir ati o n w he n a c ore 
sa m ple is u n o btai na ble a n d/ or is n ot a part of t he sta n dar d of care. A b o ne marr o w bi o ps y is 
re q uire d i n c ase of dr y ta p or fail ure ( mai nl y dil uti o n) wit h t he as pirati o n. 
B o ne marr o w c ore bi o psi es a n d/ or as pir ates are t o be e val uat e d f or m or p h ol o g y a n d f or 
kar y ot y p e t o assess p ote ntial disease pr o g n osis (see Secti o n  1 0. 8 ). 
Peri p heral bl o o d f or I D H 1 m cells/le u ke mic blasts is re q uire d at a n y ti me a b o ne marr o w 
as pirate/ bi o ps y is p erf or me d t o assess p ote ntial cli nical acti vit y (see Secti o n  1 0. 8 ).  
 
 
I nstr u cti o ns f or t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt of sa m ples f or ce ntr al a nal ysis 
will be pr o vi de d i n a se p arate st u d y ma n ual. Sa m ples at pr o gressi o n will be st ore d f or p ot e ntial 
f urt her 
. 
1 0. 8.  
Effic ac y Assess me nts  
1 0. 8. 1.  
Res p o nse t o Tre at me nt  
T he effi cac y of A G -1 2 0 will be e val uate d b y I n v esti gat or -assesse d res p o ns e t o treat me nt bas e d 
o n m o difie d I W G Res p o nse Criteria f or A M L a n d E L N g ui d eli nes, i ncl u di n g ass ess me nt of t he 
f oll o wi n g (s ee Ta bl e  1 0 ): 
•  E F S is defi ne d as t he ti m e fr o m ra n d o mizati o n u ntil treat me nt fail ure, rela pse fr o m 
re missi o n, or deat h fr o m a n y ca use, w hic he v er occ urs first. Treat me nt fail ure is 
defi ne d as  fail ure t o a c hi e ve C R b y Wee k 2 4. S u bjects w h o d o n ot ac hie ve C R b y 
Wee k 2 4 will be c o nsi dere d t o ha ve ha d a n e v e nt at Da y 1 of ra n d o mizati o n. F or t he 
re mai ni n g C R res p o n ders, t he e ve nt ti me will be t he ti me of eit her disease rela pse or 
deat h, w hic he v er o cc urs first.  
•  C R is defi ne d as b o ne marr o w blasts < 5 % a n d n o A uer r o ds; a bs e nce of 
e xtra me d ullar y dise ase; A N C ≥1. 0 × 1 0 9/ L ( 1 0 0 0/ µ L); platelet c o u nt ≥1 0 0 ×  1 0 9/ L 
( 1 0 0, 0 0 0/ µ L); a n d i n de p e n de nce of re d bl o o d cell tra nsf usi o ns. 

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•  C R h is defi ne d as a C R wit h par tial rec o v er y of peri p heral bl o o d c o u nts ( < 5 % b o ne 
marr o w blasts, platelets > 5 0, 0 0 0/ µ L, a n d A N C > 5 0 0/ µ L). C R h will be deri ve d b y t he 
S p o ns or.  
•  O R R is defi ne d as t he rat e of C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S. T he best 
res p o nse is cal c ulate d usi n g t he f oll o wi n g or der: 1) C R; 2)  C Ri (i ncl u di n g C R p); 
3)  P R, a n d 4) M L F S.  
Disease res p o nse t o treat me nt will be assesse d t hr o u g h t he e val uati o n of b o ne marr o w bi o psies 
a n d/ or as pirates, al o n g wit h c o m plete bl o o d c o u nts a n d e x a mi nati o n of peri p heral bl o o d fil ms.  
T reat me nt de cisi o ns will be base d o n I n v esti gat or’s assess me nt.  
S u bjects will ha ve t he e xte nt of t heir disease assesse d a n d rec or de d: at Scree ni n g ( or as p art of 
t he Pre-scree ni n g pr ocess, as l o n g as it is wit hi n 2 8 da ys pri or t o ra n d o mizati o n); Da y 1 
( ± 7  da ys) of Wee ks 9, 1 7, 2 5, 3 3, 4 1, 5 3, a n d e ver y 2 4 wee ks t hereafter; at E O T; as dictate d b y 
p h ysical e x a m a n d/ or bl o o d c o u nts; a n d/ or a n y ti me t hat disease pr o gressi o n is s us pecte d. F or 
s u bjects w h o disc o nti n ue treat me nt pri or t o diseas e pr o gressi o n, dise ase ass ess me nts will be 
perf or me d o n t h e sa me s c he d ule u ntil disease pr o gressi o n/rela pse.  
S u bjects will als o be e val uate d f or t heir R B C a n d platelet tra nsf usi o n re q uire me nts, i ncl u di n g 
dates of t he tra nsf usi o n(s) a n d n u m ber of u nits a d mi nistere d, at eac h d iseas e res p o nse 
assess me nt.  
T he criteri a o utli ne d i n Ta ble  1 0  a n d Ta bl e  1 1  will be use d t o assess r es p o nse t o treat me nt.  
T a ble  1 0 : 
M o difie d 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 oi d 
Le u ke mi a  
C ate g or y  
Defi niti o n  
C o m plete re missi o n ( C R) a 
B o ne marr o w blasts < 5 % a n d n o 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 ( 1 0 0 0/ µ L); platelet c o u nt ≥1 0 0 × 1 09/ L 
( 1 0 0, 0 0 0/ µ L); i n de pe n de nce of re d bl o o d cell tra nsf usi o ns 
C R wit h i nc o m plete rec o ver y ( C Ri), 
i ncl u di n g C R wit h i nc o m plete 
p latelet rec o ver y ( C R p)b 
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 
[ 1 0 0 0/ µ L]) or t hr o m b oc yt o pe nia ( platelet c o u nts < 1 0 0 ×  1 0 9/ L 
[ 1 0 0, 0 0 0/ µ L]; wit h o ut platelet tra nsf usi o n f or at least 1 wee k pri or t o 
disease assess me nt)  
M or p h ol o gic le u ke mia-free st ate 
( M L F S) 
B o ne marr o w blasts < 5 % a n d n o 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  
P artial re missi o n ( P R)  
All he mat ol o gic criteria of C R; decrease of b o ne marr o w blast perce nta ge 
t o 5 %-2 5 %; a n d decrease  of pretreat me nt b o ne marr o w blast perce nta ge 
b y at least 5 0 %  
Rela pse ( defi ne d o nl y f or s u bj ects 
w h o ha ve pre vi o usl y attai ne d C R, 
C Ri, C R p, or M L F S) c 
B o ne marr o w blasts ≥5 %; or rea p peara nce of blasts i n t he bl o o d; or 
de vel o p me nt of e xtra me d ullar y disease  
S o urce: (C hes o n et al, 2 0 0 3 ; D ö h ner et al, 2 0 1 7 ; Sie vers et al, 2 0 0 1 ). 
A b bre viati o ns: A M L  =  a c ute m yel oi d le u ke mia; A N C  =  a bs ol ute ne utr o p hil c o u nt; I W G  =  I nter nati o nal W or ki n g Gr o u p; 
M D S  =  m yel o d ys plastic s y n dr o me.  
N ote: M o difie d t o re m o ve m olec ular c o m plete re mis si o n ( C R m) a n d c yt o ge nic c o m plete re missi o n ( C Rc). 
a All criteria nee d t o be f ulfille d; marr o w e val u ati o n s h o ul d be base d o n a c o u nt of 2 0 0 n ucleate d cells i n a n as pirate wit h 
s pic ules; if a m bi g u o us, c o nsi der re peat e xa m aft er 5 t o 7 da ys; fl o w c yt o metric e val u ati o n ma y hel p t o disti n g uis h bet wee n 
persiste nt le u ke mia a n d re ge nerati n g n or mal marr o w; a marr o w bi o ps y s h o ul d be perf or me d i n cases of dr y ta p, or if n o 

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s pic ules are o btai ne d; n o mi ni m u m d urati o n of res p o nse re q uire d. A N C ≥1. 0 × 1 0 9/ L ( 1 0 0 0/ µ L) per t he E ur o pea n 
Le u ke mia Net g ui d eli nes.  
b T he criteri o n of C Ri is of val u e i n pr ot oc ols usi n g i nte nsifie d i n d ucti o n or d o u ble i n d ucti o n strate gies, i n w hic h he mat ol o gi c 
rec o ver y is n ot a waite d, b ut i nte nsi ve t h era p y will be c o nti n ue d. I n s uc h pr ot o c ols, C R ma y e ve n n ot be ac hie ve d i n t he c o urse 
of t h e e ntire treat me nt pla n. I n t hese i nsta nces, t h e o verall re missi o n rate s h o ul d i ncl u de C R a n d C Ri s u bjects. S o me s u bject s 
ma y n ot ac hie ve c o m plete he mat ol o gic rec o ver y u p o n l o n ger o bser vati o n ti mes. C Ri i n cl u des s u bjects wit h C R p.  
c A re peat marr o w s h o ul d be perf or me d t o c o nfir m rela pse wit h 2 c o nsec uti ve assess me nts se parate d b y at least a m o nt h. 
A p peara nce of ne w d ys plastic c ha n ges s h o ul d be cl osel y m o nit ore d f or e mer gi n g rela pse. I n a s u bject w h o has b ee n rece nt l y 
treate d, d ys plasia or a tra nsie nt i ncrease i n blasts ma y reflect a c he m ot h era p y effect a n d rec o ver y of he mat o p oiesis. 
C R h is defi ne d as a C R wit h partial rec o v er y of peri p heral bl o o d c o u nts ( <  5 % b o ne marr o w 
blasts, A N C > 0. 5 × 1 0 9/ L [ 5 0 0/ µ L], a n d platelets > 5 0 × 1 0 9/ L [ 5 0, 0 0 0/ µ L]). Beca use C R h is n ot 
part of m o difie d I W G criteria, it will be deri ve d b y t he S p o ns or.  
T a ble  1 1 : 
Criteri a f or St a ble Dise ase a n d Dise ase Pr o gressi o n f or Ac ute M yel oi d 
Le u ke mi a  
C ate g or y  
Res p o nse criteri a  
Sta ble disease  
A bse nce of C R, C Ri (i ncl u di n g C R p), P R, or M L F S a n d n ot meeti n g t he criteria f or a 
P D ( disease pr o gressi o n)  
Disease pr o gressi o n 
( defi ne d o nl y f or 
s u bj ects w h o ha ve n ot 
pre vi o usl y attai ne d C R, 
C Ri, C R p, or M L F S ) 
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 b o ne marr o w blast c o u nt o ver baseli ne (a mi ni m u m 1 5 % 
p oi nt i ncrease is re q uire d i n cases wit h < 3 0 % blasts at baseli ne); or persiste nt 
m arr 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 ( > 5 0 0/ µ L, a n d/ or platelet 
c o u nt t o > 5 0, 0 0 0/ µ L n o n -tra nsf use d); 
•  
> 5 0 % i ncrease i n peri p heral blasts ( W B C × % blasts) t o > 2 5, 0 0 0/ µ L i n t he  
a bse nce of treat me nt -relate d differe ntiati o n s y n dr o me; 
•  
Ne w e xtra me d ullar y disease.  
S o urce: (D ö h n er et al, 2 0 1 7 ). 
N ote: “ N o n -tra nsf use d” refers t o n o tra nsf usi o n wit hi n 7 da ys of t h e la b assess me nt. 
A b bre viati o ns: 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 o m plete re missi o n wit h i nc o m plete 
he mat ol o gic ( ne utr o p hil a n d/ or platel et) rec o ver y; C R p = c o m plete re missi o n wit h i n c o m plete platelet rec o ver y; 
M L F S  =  m or p h ol o gic le u ke mia -free state; P L T =  platelet; W B C = w hite bl o o d cell.  
1 0. 8. 2.  
I n dic at ors of Cli nic al Be nefit  
T he cli nical a cti vit y of t h e c o m bi nati o n of A G -1 2 0/ place b o a n d azaciti di ne will als o be assesse d 
usi n g s urr o gate i n dicat ors of cli nical be nefit, i ncl u di n g tra nsf usi o n fre q u e nc y ( dates of t he 
tra nsf usi o n a n d u nits a d mi nistere d), i nfecti o n rates, da ys s pe nt h os pitalize d, a n d ot her efficac y 
a n d safet y me as ures t hat are p ote ntiall y i n dicati ve of cli nical be nefit. At eac h st u d y visit, t he 
I n v esti gat or will rec or d a n y c h a n ges t o t hese p ara meters. 
1 0. 8. 3.  
Q u alit y of Life  
Patie nt -re p orte d o utc o m e data will be elicite d fr o m t he s u bjects i n t his st u d y. T he 2 P R O 
q uesti o n naires, E O R T C Q L Q -C 3 0 a n d t he E Q -5 D -5 L, will be tra nslate d as re q uire d i n t he l o cal 
la n g u a ge. P R Os will be assesse d via a n el ectr o nic P R O t o ol.  
T he E O R T C Q L Q -C 3 0 is a vali date d a n d relia ble self -re p orte d meas ure of Q o L f or s u bjects wit h 
ca ncer w h o are recei vi n g ca ncer t reat me nt. T he q u esti o n naire c o nsists of 3 0 q uesti o ns t hat are 
i nc or p orate d i nt o 5 f u n cti o nal d o mai ns ( p h ysic al, r ole, c o g niti ve, e m oti o nal, a n d s ocial); a gl o bal 

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healt h stat us/ gl o bal q ualit y of life; 3 s y m pt o m scales (fati g ue, pai n, a n d na usea a n d v o miti n g ); 
a n d 6 si n gle ite ms t hat assess a d diti o nal s y m pt o ms ( d ys p n ea, a p p etite l oss, slee p dist ur ba nce, 
c o nsti pati o n, a n d diarr hea) a n d t he p ercei ve d fi na ncial b ur de n of treat me nt e x perie nce d b y 
s u bjects wit h ca ncer (A ar o ns o n et al, 1 9 9 3 ; S pra n gers et al, 1 9 9 3 ). T his q uesti o n naire has bee n 
use d eit her al o n e or wit h s pecific m o d ules i n 4 0 % of m ore t ha n 1 0 0  o nc ol o g y cli nical trials 
(Le mie u x et al, 2 0 1 1 ).  
T he E Q -5 D -5 L is a ge n eric, prefere n ce -b ase d healt h utilit y meas ure wit h q uesti o ns t hat s pa n 
5  di me nsi o ns of life, i ncl u di n g m o bilit y, self -care, us ual acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ d e pressi o n, w hic h are use d t o b uil d a c o m p osite of t he s u bject’s healt h stat us. A p plica ble 
t o a wi de ra n ge of healt h c o n diti o ns a n d treat me nts, E Q-5 D -5 L pr o vi d es a si m ple descri pti ve 
pr ofil e a n d a si n gle i n de x val ue f or healt h stat us. T he use of t he E Q -5 D -5 L i n ca ncer has 
i ncreas e d i n rece nt years, a n d p u blis he d st u dies pr o vi de e vi de nce t o s u p p ort its vali dit y a n d 
relia bilit y (Pic kar d et al, 2 0 0 7 ). T he E Q-5 D -5 L will be utilize d i n t his st u d y f or ec o n o mic 
m o deli n g.  
B ot h q uesti o n naires h a ve bee n use d i n st u dies of s u bjects wit h A M L (A mler et al, 2 0 1 5 ; Garcia -
Ma ner o et al, 2 0 1 6 ; Le v y et al, 2 0 1 4 ; M ar q ues da Sil va et al, 2 0 1 5 ; Ti mils hi na et al, 2 0 1 6 ). F or 
C 1 D 1, b ot h q uesti o n na ires s h o ul d be a d mi nistere d pri or t o i nitiati n g st u d y treat me nt. F or all 
ot her a p plica ble st u d y visits, b ot h q uesti o n naires  will be a d mi nistere d pri or t o starti n g a n y ot h er 
st u d y-relate d ass ess me nts.  
1 0. 9.  
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic Assess me nts  
Serial  bl o o d sa m ples will be dra w n b ef ore a n d after d osi n g of st u d y tr eat me nt i n or der t o 
deter mi ne cir c ulati n g pl as ma c o nce ntr ati o ns of A G -1 2 0 ( Ta ble  7 ). Bl oo d sa m ples will als o be 
use d f or t he d eter mi nati o n of 2 -H G c o n ce ntr ati o ns ( Ta ble  8 ). 
Bl o o d sa m ples f or P K assess me nts will be dra w n pre -d ose ( wit hi n 3 0 mi n utes bef ore d os e) a n d 
at 0. 5, 2, a n d 4 h o urs p ost -d ose o n Da y 1 ( ±  3 d a ys) of C ycl es 1 a n d 2 ( Wee ks 1 a n d 5); pr e -d ose 
o n Da ys 8 a n d 1 5 ( ±  3 d a ys) of C ycl e 1; a n d pre -d ose o n Da y 1 ( ±  3 d a ys) of C ycl es 3 a n d 
be y o n d ( Wee ks 9 +). F or s u bjects w h o cr oss o ver, o nl y pre d ose P K sa m ples will be c ollecte d.  
Bl o o d sa m ples f or 2 -H G assess me nts will be dra w n at pre -d ose o n Da y 1 a n d Da y 1 5 ( ±  3 da ys) 
of C ycl e 1.  
1 0. 1 0.  
S a m ple Pr ocessi n g, St or a ge, a n d S hi p me nt  
I nstr u cti o ns f or t he c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt of all st u d y sa m ples f or ce ntral 
a nal ysis will be pr o vi d e d i n a se parate st u d y m a n u al.  

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1 1.  
A D V E R S E E V E N T S  
M o nit ori n g of A Es will b e c o n d ucte d t hr o u g h o ut t he st u d y ( o nce s u bjects ha ve bee n c o nse nte d); 
S A Es t hat are ass esse d as relate d t o st u d y treat me nt t hat occ ur > 2 8 d a ys p ost -treat me nt als o are 
t o be re p orte d. All A Es s h o ul d be m o nit ore d u ntil t he y are res ol ve d or are clearl y deter mi ne d t o 
be d ue t o a s u bject’s sta ble or c hr o nic c o n diti o n or i nterc urre nt ill ness(es). Pri or t o first d ose of 
st u d y treat me nt, o nl y A Es t hat are cl assifie d as S A Es dee me d relate d t o st u d y pr oce d ures s h o ul d 
be re p ort e d.  
A d verse E ve nt Re p orti n g Peri o d  
I n v esti gat ors will see k i nf or mati o n o n A Es at eac h s u bject c o ntact, as o utli n e d bel o w. All A Es, 
w het her re p orte d b y t he s u bject or n ote d b y st u d y pers o n nel, will be rec or de d i n t he s u bject’s 
me dical rec or d a n d o n t h e A E e C R F.  
•  After i nf or m e d c o nse nt h as be e n o btai ne d b ut pri or t o i nitiati o n of st u d y dr u g, o nl y 
S A Es ca use d b y a pr ot oc ol -ma n date d i nter v e nti o n s h o ul d be re p orte d (e g, S A Es 
relate d t o i n vasi ve st u d y pr oce d ures s uc h as bi o psies). 
•  After i nitiati o n of st u d y dr u g, all A Es a n d S A Es, re gar dless of att ri b uti o n, will be 
c ollecte d. S u bjects will be assesse d at t he F oll o w -u p Visit ( 4 wee ks p ost -tr eat me nt) t o 
deter mi ne if a n y n e w A Es ha ve occ urre d. After t his peri o d, I n vesti gat ors s h o ul d 
re p ort o nl y S A Es t hat are c o nsi dere d t o be relate d t o st u d y treat me nt 
( A G-1 2 0/ place b o or azaciti di ne).  
1 1. 1.  
Defi niti o n of A d verse E ve nts  
1 1. 1. 1.  
A d verse E ve nt  
A n A E (als o r eferre d t o as a n a d vers e e x perie nce) is a n y u nt o w ar d me dical occ urre nce ass ociat e d 
wit h t he use of a dr u g i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. A n A E ca n  t heref ore 
be a n y of t he f oll o wi n g:  
•  A n y u nfa v ora ble a n d u ni nte n de d si g n (e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m, 
or disease te m p orall y ass ociate d wit h t he use of a dr u g, w het her or n ot c o nsi dere d 
relate d t o t he dr u g.  
•  A n y n e w diseas e or e x acer bati o n  of a n e xisti n g disease (a w ors e ni n g i n t he c haracter, 
fre q ue n c y, or se v erit y of a k n o w n c o n diti o n).  
•  Rec urre n ce of a n i nter mitte nt me dical c o n diti o n (e g, h ea d ac he) n ot prese nt at 
baseli ne.  
•  A n y d eteri or ati o n i n a la b orat or y val ue or ot her cli nical test (e g , E C G, X-ra y) t hat is 
ass ociate d wit h s y m pt o ms or lea ds t o a c h a n ge i n st u d y treat me nt or c o nc o mita nt 
treat me nt or disc o nti n uati o n fr o m st u d y treat me nt. 
•  A d verse e ve nts t hat are relate d t o a pr ot oc ol -ma n date d i nter ve nti o n, i ncl u di n g t h ose 
t hat occ ur pri or to assi g n me nt of st u d y treat me nt ( e g, Scree ni n g i n vasi v e pr oce d ures 
s uc h as bi o psies). 

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A n A E ca n arise fr o m a n y use of t he dr u g (e g, off -la bel use, use i n c o m bi n ati o n wit h a n ot her 
dr u g) a n d fr o m a n y r o ute of a d mi nistrati o n, f or m ulati o n, or d ose, i ncl u di n g a n o ver d ose.  
Disease pr o gressi o n or d eat h d ue t o diseas e pr o gressi o n will n ot be c o nsi dere d a n A E ( or a n 
S A E) i n t his st u d y, b ut will be c ollecte d as a n o ut c o me or reas o n f or disc o nti n uati o n, as 
a p pr o priate. A d vers e e ve nts ( or S A Es) c o nsi dere d as c o m plicati o ns of disease pr o gressi o n 
s h o ul d be re p orte d. See Secti o n  1 1. 2. 7  f or m ore d etaile d i nstr ucti o ns re gar di n g t he re p orti n g of 
disease pr o gressi o n a n d deat hs d ue t o disease pr o gressi o n.  
1 1. 1. 2.  
Rel ate d A d vers e E ve nt  
A relate d A E is a n y A E f or w hic h t here is a reas o na ble p ossi bilit y t h at t he dr u g ca use d t h e A E.  
Assess me nt of C a us alit y of A d verse E ve nts  
I n v esti gat ors s h o ul d use t heir k n o wle d ge of t he s u bject, t he circ u msta n ces s urr o u n di n g t h e e ve nt, 
a n d a n e v al uati o n of a n y p ote ntial alter nati ve ca us es t o deter mi ne w het her or n ot a n A E is 
c o nsi dere d t o be relate d t o t he st u d y t reat me nt, i n dicati n g " yes" or " n o" acc or di n gl y (see 
Ta ble  1 2 ). T he f oll o wi n g g ui da n ce s h o ul d be ta ke n i nt o c o nsi derati o n: 
•  Te m p oral rel ati o ns hi p of e ve nt  o nset t o t he i nitiati o n of st u d y tr eat me nt  
•  C o urse of t he e v e nt, c o nsi deri n g es peci all y t he effects of d ose re d ucti o n, 
disc o nti n uati o n of st u d y treat me nt, or rei ntr o d ucti o n of st u d y tr eat me nt ( w here 
a p plica ble)  
•  K n o w n ass ociati o n of t he e ve nt wit h t he st u d y  tr eat me nt or wit h si milar treat me nts 
•  K n o w n ass ociati o n of t he e ve nt wit h t he disease u n der st u d y  
•  Prese nce of ris k fact ors i n t he s u bject or use of c o nc o mita nt me dicati o ns k n o w n t o 
i ncreas e t he occ urre nce of t he e ve nt 
•  Prese nce of n o n -tr eat me nt-relate d factors t hat are k n o w n t o be ass ociate d wit h t he 
occ urre nce of t he e v e nt  
T a ble  1 2 : 
C a us al Attri b uti o n G ui d a nce  
Is t he a d verse e v e nt ( A E) s us pecte d t o be c a use d b y t he st u d y tre at me nt o n t he b asis of f acts, e vi de nce, 
scie nce-b ase d r ati o n ales, a n d cli nic al j u d g me nt ?  
Y E S  
T here is a pla usi ble te m p oral relati o ns hi p bet wee n t he o nset of t he A E a n d a d mi nistrati o n of t he st u d y 
treat me nt, a n d t he A E ca n n ot be rea dil y e x plai ne d b y t he s u bj ect’s cli nical state, i nterc urre nt ill ness, or 
c o nc o mita nt t hera pies; a n d/ or t he A E f oll o ws a k n o w n patter n of res p o nse t o t he st u d y treat me nt; a n d/ or 
t he A E a b ates or res ol ves u p o n disc o nti n uati o n of t he st u d y treat me nt or d ose re d ucti o n a n d, if a p plica ble, 
rea p pears u p o n re-c halle n ge.  
N O  
A d verse  e ve nts will be c o nsi d ere d relate d, u nless t he y f ulfill t he criteria as s pecifie d bel o w:  
E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y treat me nt (e g, pre -e xisti n g me dical 
c o n diti o n, u n derl yi n g disease, i nterc urre nt ill ness, or c o nc o mita n t me dicati o n); a n d/ or t he A E has n o 
pla usi ble te m p oral relati o ns hi p t o a d mi nistrati o n of t he st u d y treat me nt (e g, ca ncer dia g n ose d 2  da ys after 
first d ose of st u d y treat me nt). 

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1 1. 1. 3.  
Seri o us A d verse E ve nt  
A n A E or s us pect e d a d verse reacti o n is c o nsi dere d seri o us  (a n S A E) if, i n t he vie w of eit her t he 
I n v esti gat or or S p o ns or, it res ults i n a n y of t h e f oll o wi n g o utc o mes: 
•  Fatal (ie, t h e A E act uall y ca uses or lea ds t o deat h).  
•  Lif e -t hreate ni n g, mea ni n g t hat t he s u bject was at i m me diate ris k of deat h fr o m t he 
reacti o n as it occ urre d (ie, it d oes n ot i ncl u de a reacti o n t hat h y p ot heticall y mi g ht 
ha ve ca use d deat h ha d it occ urre d i n a m ore s e vere f or m).  
•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n. H os pitalizati o n 
a d missi o ns a n d/ or s ur gic al o perati o ns sc he d ul e d t o occ ur d uri n g t he st u d y peri o d, b ut 
pla n ne d pri or t o st u d y e ntr y are n ot c o nsi dere d A Es if t he ill ness or diseas e e xiste d 
bef ore t h e s u bject was e nr olle d i n t he st u d y, pr o vi de d t hat it di d n ot deteri orate i n a n 
u ne x pecte d ma n ner d uri n g t he st u d y (e g, s ur ger y p erf or me d earlier t ha n pla n ne d). 
•  A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or mal life f u ncti o ns.  
•  C o n ge nital a n o mal y/ birt h defect i n a n e o nate/i nf a nt b or n t o a m ot her or fat her 
e x p ose d t o st u d y tr eat me nt. 
•  I m p ort a nt me dical e v e nt as assesse d b y t he I n vesti gat or or S p o ns or. A n i m p orta nt 
me dical e ve nt is a n e ve nt t hat ma y n ot r es ult i n deat h, be life -t hr eate ni n g, or re q uire 
h os pitaliz ati o n b ut ma y b e c o nsi dere d a n S A E w he n, base d u p o n a p pr o pri ate me dical 
j u d g me nt, it ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his secti o n. E x a m ples of s uc h 
me dical e ve nts i ncl u de aller gi c br o nc h os p as m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitaliz ati o n, or t he de vel o p me nt of dr u g de p e n de n c y or dr u g a b use. 
T he ter ms “se v ere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y refers t o t he i nte nsit y of a n A E 
(rate d as mil d, m o derate, or se vere/life -t hr eate ni n g/fatal, or acc or di n g t o N CI C T C A E criteria); 
t he e ve nt itself ma y be of relati vel y mi n or me dical si g nifica n ce (s uc h as se vere hea dac he wit h o ut 
a n y f urt her fi n di n gs).  
Se verit y a n d seri o us ness nee d t o be i n de p e n de ntl y assesse d f or eac h A E rec or de d o n t he e C R F.  
1 1. 2.  
Pr oce d ures f or Re p orti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  
All A Es (seri o us a n d n o n -seri o us) s p o nta ne o usl y re p orte d b y t he s u bject a n d/ or i n res p o nse t o a n 
o pe n q uesti o n fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e xa mi nati o n, or ot her 
dia g n ostic pr o ce d ures will be rec or de d o n t he a p pr o priate pa ge of t he e C R F. A n y cli nicall y 
rele va nt det eri orati o n i n l a b orat or y assess me nts or ot her cli nical fi n di n gs is c o nsi dere d a n A E 
a n d m ust be rec or de d o n t he a p pr o priat e pa ges of t he e C R F.  
F or re p orts of S A Es, I n v esti gat ors s h o ul d rec or d all case det ails t hat ca n b e gat here d pr o m ptl y o n 
b ot h t he A E a n d t he S A E e C R Fs a n d s u b mit via t he Electr o nic Data Ca pt ur e ( E D C) s yste m. All 
S A Es are t o be re p o rte d wit hi n 2 4 h o urs fr o m t he p oi nt i n ti me w he n t he I n vesti gat or b ec o mes 
a ware of t he S A E. All S A Es m ust be re p orte d w het her or n ot t he y are c o nsi dere d ca usall y relat e d 

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t o A G-1 2 0/ place b o. Seri o us A E f or ms will be c o m plete d a n d t he i nf or mati o n c ollecte d wi ll 
i ncl u de s u bject n u m ber, a narrati ve descri pti o n of t he e ve nt, a n d a n assess me nt b y t he 
I n v esti gat or as t o t he se v erit y of t he e v e nt a n d rel ate d ness t o st u d y dr u g. F oll o w-u p i nf or mati o n 
o n t he S A E ma y b e re q u este d b y t h e S p o ns or or Me dical M o nit or.  
I n t he e ve nt t hat t he E D C s yste m is u na vaila ble, a pa per S A E a n d fa x c o vers heet s h o ul d be 
c o m plete d a n d fa x e d/e maile d wit hi n n o m ore t ha n 2 4 h o urs after l ear ni n g of t he e ve nt usi n g t he 
fa x n u m bers pr o vi de d t o I n v esti gat ors i n t he safet y re p orti n g i nstr ucti o ns. T he i nf or mati o n fr o m 
t he S A E re p ort f or m s h o ul d be e ntere d i nt o t he E D C s yste m as s o o n as it is a vaila ble.  
If t here are seri o us, u ne x pecte d relate d A Es ass ociate d wit h t he use of A G-1 2 0/ place b o, t he 
S p o ns or will n otif y t h e a p pr o priate re g ulat or y a ge nc y(i e s) a n d all partici pati n g I n vesti gat ors o n 
a n e x pe dite d basis. T he l ocal I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee 
(I R B/I E C) will be pr o m ptl y n otifie d base d o n l o cal re g ul ati o ns w here re q uire d b y t he I R B/I E C 
of all seri o us, u ne x pecte d relate d A Es i n v ol vi n g ris k t o h u ma n s u bjects.  
A ntici p ate d S A Es  
T he S p o ns or d oes n ot pla n t o re p ort i n di vi d uall y, i n a n e x pe dite d ma n ner, s pecific seri o us, 
fre q ue nt A Es b eca use t hese e ve nts are a ntici pat e d t o occ ur i n t he st u d y p o p ulati o n at s o me 
fre q ue n c y i n de pe n de nt of dr u g e x p os ure.  
T hese S A Es i ncl u de t he f oll o wi n g A M L -s pecific ma nifestati o ns: 
•  Ne utr o pe nia  
•  T hr o m b oc yt o p e nia  
•  A ne mia  
•  Viral, bacterial, a n d f u n gal i nfecti o ns  
All A Es, w het her seri o us or n ot, will be descri be d i n t he s o urce d oc u m e nts a n d o n t he A E pa ge 
of t he e C R F. All ne w e ve nts, as well as t h ose t hat w orse n i n se verit y or fre q ue nc y rel ati ve t o 
baseli ne, w hic h occ ur aft er s u bjects ha v e recei ve d at least 1 d ose of st u d y treat me nt t hr o u g h 
2 8  da ys f oll o wi n g t he l ast d ose of st u d y tr eat me nt, m ust be rec or de d. A d verse e ve nts t hat are 
o n g oi n g at t he ti me of tr eat me nt disc o nti n uati o n s h o ul d be f oll o we d t hr o u g h t he 4 -wee k ( 2 8 -d a y) 
p ost -treat me nt assess me nt. I n a d diti o n, S A Es t hat are ass esse d b y t he I n v esti gat or as relate d t o 
st u d y dr u g m ust be re p orte d a n y ti me t he I n vesti gat or bec o mes a ware of s uc h a n e v e nt, e ve n if 
t his occ urre n ce is m ore t ha n 2 8 da ys aft er t he last d ose of st u d y tr eat me nt. 
I nf or mati o n t o be re p orte d i n t he descri pti o n of eac h A E i ncl u des: 
•  A me dical dia g n osis of t he e ve nt (if a me dical dia g n os is ca n n ot b e deter mi ne d, a 
descri pti o n of eac h si g n or s y m pt o m c haract erizi n g t he e ve nt s h o ul d be rec or de d).  
•  T he date of o ns et of t he e ve nt.  
•  T he date of res ol uti o n of t he e ve nt.  
•  W het her t he e ve nt is seri o us or n ot.  
•  Se verit y of t he e v e nt (see bel o w f or defi niti o ns).  
•  Relati o ns hi p of t he e ve nt t o st u d y treat me nt (s ee T a ble  1 2  f or d efi niti o ns). 

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•  Acti o n ta ke n: n o ne; c h a n ge i n t he st u d y tr eat me nt a d mi nistrat i o n (e g, t e m p orar y 
i nterr u pti o n i n d osi n g); dr u g tr eat me nt r e q uire d; n o n-dr u g treat me nt re q uir e d; 
h os pitaliz ati o n or pr ol o n gati o n of h os pitalizati o n re q uire d (c o m plete S A E pa ge); 
dia g n ostic pr o ce d ure perf or me d; s u bject disc o nti n ue d fr o m st u d y treat me nt (c o m plete 
E O T Visit).  
•  O utc o me: s u bject rec o vere d wit h o ut se q uelae; s u bject rec o v ere d wit h se q uelae; e ve nt 
o n g oi n g; s u bject die d ( n otif y t he Me di cal M o nit or wit hi n 2 4 h o urs, a n d c o m plete t he 
S A E f or m).  
Severity  of all A Es, i ncl u di n g cli nicall y si g nifica nt trea t me nt-e mer ge nt la b orat or y a b n or m alities, 
will be gra de d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3 (see A p pe n di x  1 5. 9 ). A d verse e ve nts 
n ot liste d b y t h e C T C A E will be gra de d as f oll o ws:  
•  Mil d: T he e ve nt is n oticea ble t o t he s u bject b ut d o es n ot i nterfere wit h r o uti ne 
acti vit y.  
•  M o derate: T he e ve nt i nterferes wit h r o uti ne acti vit y b ut res p o n ds t o s y m pt o matic 
t hera p y or rest. 
•  Se vere: T he e ve nt si g nifi ca ntl y li mits t he s u bject’s a bilit y t o p erf or m r o uti ne 
acti vities des pite s y m pt o matic t hera p y.  
•  Lif e -t hreate ni n g: A n e v e nt i n w hic h t he s u bject w as at ris k of deat h at t he ti me of t he 
e ve nt.  
•  Fatal: A n e v e nt t hat res ults i n t he deat h of t he s u bject.  
1 1. 2. 1.  
Di a g n osis Vers u s Si g ns a n d S y m pt o ms 
A dia g n osis (if k n o w n) s h o ul d be rec or de d o n t he A d verse E v e nt e C R F rat her t ha n i n di vi d ual 
si g ns a n d s y m pt o ms (e g, rec or d o nl y li ver fail ure or he patitis rat her t h a n ja u n dice, asteri xis, a n d 
ele vate d tra nsa mi nases). H o we ver, if a c o nst ellati o n of si g ns a n d/ or s y m pt o ms ca n n ot be 
me dicall y c haracterize d as a si n gle dia g n osis or s y n dr o me at t he ti me of re p orti n g, eac h 
i n di vi d ual e ve nt s h o ul d be rec or de d o n t he A d verse E ve nt e C R F. If a dia g n osis is s u bse q ue ntl y 
esta blis he d, all pre vi o usl y r e p orte d A Es b ase d o n si g ns a n d s y m pt o ms s h o ul d be n ullifie d a n d 
re place d b y 1 A E ter m b ase d o n t he si n gle dia g n osis, wit h a starti n g date t h at c orres p o n ds t o t he 
starti n g dat e of t he first s y m pt o m of t he e v e nt ual dia g n osis. 
1 1. 2. 2.  
A d verse E ve nts Occ urri n g Sec o n d a r y t o Ot her E ve nts  
I n ge neral, A Es occ urri n g sec o n dar y t o ot her e ve nts (e g, casca de e ve nts or cli nical se q uelae) 
s h o ul d be i de ntifie d b y t h eir pri mar y ca use, wit h t he e x ce pti o n of se vere or seri o us sec o n dar y 
e ve nts. H o we v er, me dic all y si g nifi ca nt A Es occ ur ri n g sec o n dar y t o a n i nitiati n g e v e nt t hat are 
se parat e d i n ti me s h o ul d be rec or de d as i n de pe n de nt e ve nts o n t he A d verse E ve nt e C R F. F or 
e x a m ple:  
a. If v o miti n g res ults i n mil d de h y drati o n wit h n o a d diti o nal treat me nt i n a healt h y a d ult, 
o nl y v o miti n g s h o ul d be re p orte d o n t he e C R F.  
b.  If v o miti n g res ults i n se v ere de h y drati o n, b ot h e ve nts s h o ul d be re p orte d se paratel y 
o n t he e C R F.  

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c. If a se v ere gastr oi ntesti nal he m orr ha ge lea ds t o re nal fail ure, b ot h e ve nts s h o ul d be 
re p orte d se p aratel y o n t he e C R F. 
d.  If diz zi ness lea ds t o a fall a n d s u bse q ue nt fract ur e, all 3 e ve nts s h o ul d be re p orte d 
se parat el y o n t h e e C R F. 
e. If ne utr o pe ni a is acc o m pa nie d b y a se v ere or seri o us i nfecti o n, b ot h e ve nts s h o ul d be 
re p orte d se p aratel y o n t he e C R F. 
All A Es s h o ul d be rec or de d se paratel y o n  t he A d v erse E ve nt e C R F if it is u nclear as t o w het her 
t he e ve nts are ass oci ate d. 
1 1. 2. 3.  
A d verse E ve nts of S peci al I nterest  
A n A E SI ca n b e seri o us or n o n -seri o us a n d is a n e ve nt of s pecial i nterest t o t he S p o ns or. 
O n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n ( wit hi n 2 4 h o urs) b y t he I n v esti gat or t o t he 
S p o ns or is re q uire d t o all o w f or f urt h er c h aracteri zati o n a n d re p orti n g t o r e g ulat or y a ut h orities.  
1 1. 2. 3. 1.  Q T Pr ol o n g ati o n  
A n y Q T pr ol o n gati o n e v e nt assesse d as Gra d e ≥3 (ie, Q Tc F > 5 0 0 msec o n at least 2 se parate 
E C Gs, or Q Tc F > 5 0 0 ms ec or ≥6 0 msec c ha n ge fr o m baseli ne wit h T orsa d e de p oi ntes or 
p ol y m or p hic ve ntric ular t ac h ycar dia or si g ns/s y m pt o ms of seri o us arr h yt h mia), irres p ecti ve of 
t he seri o us ness, s h o ul d be re p ort e d as a n A E SI t o t he S p o ns or wit hi n 2 4 h o urs. See S ecti o n 9. 9. 1  
f or f urt her details o n ma n a gi n g s u bjects wit h Q T pr ol o n gati o n. Heart-rate c orrect e d Q T i nter val 
will be calc ulate d usi n g Fri deri cia’s f or m ula ( Q T c F = Q T/ R R 1/ 3).  
1 1. 2. 3. 2.  Le u k oc yt osis  
A n y e ve nt of le u k oc yt osis assesse d as Gra de ≥3, irres pecti ve of seri o us ness, s h o ul d be re p orte d 
t o t he S p o ns or as a n A E SI wit hi n 2 4 h o urs.  
See Secti o n  9. 1 3. 4. 3  f or f urt her details o n ma na gi n g s u bjects wit h le u k oc yt osis. 
1 1. 2. 3. 3.  I D H Differe nti ati o n S y n dr o me 
A n y e ve nt of differe ntiati o n s y n dr o me assesse d as Gra de ≥2, irres pecti ve of seri o us ness, s h o ul d 
be re p ort e d t o t he S p o ns or as a n A E SI wit hi n 2 4 h o urs. See Secti o n  9. 9. 2  f or f urt her details o n 
ma na gi n g s u bjects wit h differe ntiati o n s y n dr o me.  
1 1. 2. 4.  
Persiste nt or Rec u rre nt A d verse E ve nts  
A persiste nt A E is 1 t hat e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n s u bject e val uati o n 
ti me p oi nts. T he i nitial se verit y of t he e v e nt s h o ul d be rec or de d, a n d t he se v erit y s h o ul d be 
u p date d t o refl ect t he m ost e xtre me se verit y a n y ti me t he e ve nt w ors e ns i n i nte nsit y or gra de.  
W he n a n A E bec o mes s eri o us (re gar dless of c h a n ges i n gra de or se verit y), t he e C R F s h o ul d be 
u p d ate d t o refl ect t his. As s uc h, a ne w A E (seri o us e ve nt wit h o nset date f or w he n A E b eca m e 
seri o us) s h o ul d be a d d e d t o t he e C R F.  
H o we ver, t he sa me d o es n ot h ol d tr ue f or A Es t hat c ha n ge fr o m seri o us t o n o n -seri o us e ve nts. 
W he n a n A E d oes n ot res ol ve b ut is  d o w n gra de d fr o m a seri o us t o a n o n -s eri o us e ve nt, a ne w 
A E is n ot re q uire d t o be ca pt ure d o n t he e C R F. A res ol uti o n date is re q uire d t o be e ntere d o n t h e 

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S A E f or m o nce a n A E c h a n ges fr o m a s eri o us t o n o n -seri o us e ve nt si nce t his w o ul d res ult i n t he 
S A E re s ol vi n g. 
A rec urre nt A E is 1 t hat r es ol ves bet wee n s u bject e val uati o n ti me p oi nts a n d s u bse q ue ntl y 
rec urs. Eac h rec urre n ce of a n A E s h o ul d be rec or de d se paratel y o n t he A d v erse E ve nt e C R F. 
1 1. 2. 5.  
A b n or m al L a b or at or y V al ues  
N ot e ver y la b orat or y a b n or malit y q ualifi es as a n A E. A la b orat or y test res ult s h o ul d be re p orte d 
as a n A E if it meets a n y of t he f oll o wi n g criteri a:  
a. Acc o m pa nie d b y cli nical s y m pt o ms.  
b.  Res ults i n a c ha n ge i n st u d y treat me nt (e g, d os a ge m o dificati o n, treat me nt 
i nterr u pti o n, or treat me nt disc o nti n uati o n). 
c. Res ults i n a me dical i nter ve nti o n (e g, p otassi u m s u p ple me ntati o n f or h y p o k ale mia) or 
a c ha n ge i n c o nc o mita nt t hera p y . 
d.  Cli nicall y si g nifica nt i n t he I n vesti gat or’s j u d g me nt.  
It is t he I n v esti gat or’s r es p o nsi bilit y t o re vi e w all la b orat or y fi n di n gs. Me di cal a n d scie 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 a n is olate d la b orat or y a b n or malit y s h o ul d be 
classifie d as a n A E.  
If a cli nic all y si g nifica nt la b orat or y a b n or malit y is a si g n of a diseas e or s y n dr o me (e g, A L P a n d 
bilir u bi n 5 × U L N as s oci ate d wit h c h olec ystitis), o nl y t he dia g n osis (ie, c h olec ystitis) s h o ul d be 
rec or de d o n t he A d v erse E ve nt e C R F. 
If a cli nic all y si g nifica nt la b orat or y a b n or malit y is n ot a si g n of a disease or s y n dr o me, t h e 
a b n or malit y itself s h o ul d be rec or de d o n t he A d verse E ve nt e C R F, al o n g wit h a descri pt or 
i n dicati n g if t he test r es ult is a b o ve or bel o w t he n or mal ra n ge. W here p ossi ble, please e nter a 
c o n diti o n (e g, n e utr o pe ni a) rat h er t ha n t he la b fi n di n g (e g, d ecreas e d ne utr o p hils).  
1 1. 2. 6.  
De at hs  
Deat hs occ urri n g d uri n g t he pr ot oc ol-s pecifie d A E re p orti n g peri o d (s ee S ecti o n  1 1. 2 ) t hat are 
attri b ute d b y t he I n vesti gat or s olel y t o pr o gressi o n of A M L s h o ul d be rec or de d o nl y o n t he 
Treat me nt a n d/ or St u d y Disc o nti n uati o n e C R Fs. All ot her o n -treat me nt d eat hs, re gar dl ess of 
relati o ns hi p t o st u d y treat me nt, m ust be rec or de d o n t he A d verse E ve nt e C R F a n d re p orte d t o t he 
S p o ns or wit hi n 2 4 h o urs.  
Deat h s h o ul d be c o nsi dere d a n o utc o me a n d n ot a disti nct e ve nt. T he u n derl yi n g me dical 
dia g n osis or s us pecte d di a g n osis t hat ca use d o r c o ntri b ute d t o t he fatal o utc o me s h o ul d be 
rec or de d as t he si n gle me dical c o nce pt o n t he A d verse E ve nt e C R F. Ge n erall y, o nl y 1 s u c h e ve nt 
s h o ul d be re p orte d.  
T he ter m “s u d de n d eat h” s h o ul d o nl y be use d f or t he occ urre n ce of a n a br u pt a n d u ne x pecte d 
deat h d ue t o pres u m e d car diac ca uses i n a s u bject wit h or wit h o ut pree xisti n g heart diseas e, 
wit hi n 1 h o ur of t he o nset of ac ute s y m pt o ms or, i n t he case of a n u n wit nesse d deat h, wit hi n 
2 4  h o urs after t h e s u bject was last see n ali ve a n d sta ble. If t he ca use of  deat h is u n k n o w n a n d 
ca n n ot be as cert ai ne d at t he ti me of re p orti n g, “ u n e x plai ne d deat h” s h o ul d be rec or de d o n t he 
A d verse E v e nt e C R F. If t he ca use of deat h later bec o mes a vaila ble (e g, after a ut o ps y), 
“ u ne x plai ne d deat h” s h o ul d be re place d b y t he est a bli s he d ca use of deat h.  

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All deat hs will be c ollect e d. All o n -treat me nt d eat hs ( wit hi n t he 2 8 da ys aft er last d ose of st u d y 
treat me nt) s h o ul d ha ve a n ass ociate d S A E ca pt ure d f or t he e v e nt t hat le d t o deat h, e xce pt i n t he 
e ve nt of diseas e pr o gressi o n (see Sect i o n 1 1. 2. 7 ).  
D uri n g p ost -tr eat me nt s ur vi val f oll o w-u p, all deat hs will c o nti n ue t o be c ollecte d, b ut o nl y t h ose 
u nrelate d t o diseas e pr o gressi o n a n d c o nsi dere d relate d t o st u d y treat me nt b y t he I n v esti gat or 
will be ca pt ure d as S A Es.  
1 1. 2. 7.  
Pr o g ressi o n of A M L  
Pr o gressi o n of A M L (see Ta ble  1 1 ) s h o ul d n ot be re p orte d as a n A E if it is clearl y c o nsiste nt 
wit h t he s us pecte d pr o gressi o n of t he u n derl yi n g ca ncer. Cli nical s y m pt o ms  of pr o gressi o n ma y 
be re p ort e d as A Es if t he s y m pt o ms ca n n ot be deter mi ne d as e x cl usi vel y d u e t o t he pr o gressi o n 
of t he s u bject’s u n derl yi n g A M L or d oes n ot fit t he e x pecte d patter n of pr o gressi o n f or t he 
disease.  
If t here is a n y u ncertai nt y a b o ut a n A E bei n g d ue o nl y t o t he diseas e u n der st u d y, it s h o ul d be 
re p orte d as a n A E or S A E. 
1 1. 2. 8.  
Pre -e xisti n g Me dic al C o n diti o ns  
A pre -e xisti n g me dical c o n diti o n is 1 t hat is prese nt at t he Scree ni n g Visit f or t his st u d y. S uc h 
c o n diti o ns s h o ul d be rec or de d o n t he Me dical Hist or y e C R F.  
A pree xisti n g me dical c o n diti o n s h o ul d be rec or de d as a n A E o nl y if t he fre q ue nc y, se verit y, or 
c haracter of t he c o n diti o n w orse ns d uri n g t he st u d y. W he n rec or di n g s uc h e ve nts o n t he A d verse 
E ve nt e C R F, it is i m p orta nt t o c o n ve y t he c o n ce pt t hat t he pree xisti n g c o n diti o n has c ha n ge d b y 
i ncl u di n g a p plica ble descri pt ors (e g, “ m or e fre q ue nt hea dac h es”). 
1 1. 2. 9.  
H os pit aliz ati o n  or Pr ol o n ge d H os pit aliz ati o n  
A n y A E t hat res ults i n h os pitaliz ati o n or pr ol o n ge d h os pitalizati o n s h o ul d be d oc u me nte d a n d 
re p orted as a n S A E ( per t he defi niti o n of S A E i n Secti o n  1 1. 1. 3 ), e x ce pt as o utli ne d bel o w.  
T he f oll o wi n g h os pitaliz ati o n sce nari os are n ot c o nsi dere d  t o be S A Es: 
•  H os pitalizati o n f or res pite care.  
•  Sta n dar d pr oce d ure f or pr ot oc ol t hera p y a d mi nistrati o n; h o we ver, h os pitali zati o n or 
pr ol o n ge d h os pitaliz ati o n f or a c o m plicati o n of t hera p y a d mi nistrati o n will be 
re p orte d as a n S A E. 
•  R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n.  
•  A d mi nistrati o n of bl o o d or platelet tra nsf usi o n as r o uti ne treat me nt of st u di e d 
i n dicati o n; h o we ver, h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n 
of s uc h tra nsf usi o n r e mai ns a re p orta bl e S A E.  
•  A pr oce d ure f or pr ot oc ol/ disease -relate d i n vesti gati o ns (e g, s ur ger y, sca ns, 
e n d osc o p y, sa m pli n g f or la b orat or y tests, b o ne marr o w sa m pli n g); h o we v er, 
h os pitaliz ati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n of s uc h pr oce d ures 
re mai ns a re p orta ble S A E. 

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•  H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n f or tec h ni cal, practical, or s ocial 
reas o ns, i n a bse n ce of a n A E. 
•  A pr oce d ure t hat is pla n n e d (ie, pla n ne d pri or t o start of treat me nt o n st u d y); m ust be 
d oc u me nte d i n t he s o urce d oc u me nt a n d t he e C R F; h os pitalizati o n or pr ol o n ge d 
h os pitaliz ati o n f or a c o m plicati o n re mai ns a re p orta ble S A E. 
•  A n electi ve tr eat me nt of or a n electi ve pr oce d ure f or a pre -e xisti n g c o n diti o n, 
u nrelate d t o t he st u die d i n dicati o n, w hic h has n ot w orse ne d fr o m baseli ne.  
1 1. 2. 1 0.  
O ver d ose or I nc orrect A d mi nistr ati o n  
St u d y treat me nt o ver d ose is t he acci de ntal or i nte nti o nal use of t he dr u g i n a n a m o u nt hi g her t h a n 
t he d ose bei n g st u die d. A n o ver d ose or i n c orrect a d mi nistrati o n of st u d y tr eat me nt is n ot a n A E 
u nless it res ults i n u nt o war d me dical effects.  
A n y st u d y treat me nt o ver d ose or i nc orrect a d mi nistra ti o n of st u d y tr eat me nt s h o ul d be n ote d o n 
t he St u d y Dr u g A d mi nistrati o n e C R F.  
All A Es ass ociate d wit h a n o ver d ose or i nc orrect a d mi nistrati o n of st u d y tr eat me nt s h o ul d be 
rec or de d o n t he A d v erse E ve nt e C R F. If t he ass ociate d A E f ulfills seri o us criteria, t he e v e nt 
s h o ul d be re p orte d t o t he S p o ns or wit hi n 2 4 h o urs after lear ni n g of t he e ve nt.  
1 1. 3.  
Pre g n a nc y Re p orti n g  
Pre g n a nc y is neit her a n A E n or a n S A E, u nless a c o m plicati o n relati n g t o t he pre g na n c y occ urs 
(e g, s p o nta ne o us a b orti o n, w hic h ma y q ualif y as a n SA E).  
Pre g n a ncies a n d s us pecte d pre g na nci es (i ncl u di n g a p ositi ve pre g na n c y test re gar dl ess of a ge or 
disease state) of a fe male s u bject or part ner of a m ale s u bject occ urri n g w hile t he s u bject is o n 
st u d y treat me nt, or wit hi n 4 wee ks ( 2 8 da ys) of t h e s u bject’s last d ose of st u d y treat me nt, are 
c o nsi dere d i m me diatel y re p orta ble e v e nts. If a fe m ale part ner of a m ale s u bj ect ta ki n g 
i n vesti gati o nal pr o d u ct bec o mes pre g na nt, t he mal e s u bject ta ki n g st u d y tr eat me nt s h o ul d n otif y 
t he I n v esti gat or, a n d t he pre g na nt f e male part ner s h o ul d be a d vise d t o call her healt hcare 
pr o vi der i m me diatel y. I n pre g na nt f e male s u bjects, st u d y treat me nt is t o be disc o nti n ue d 
i m me diatel y a n d t he s u bj ect i nstr ucte d t o ret ur n a n y u n use d st u d y dr u g t o t h e I n vesti gat or. T he 
pre g na nc y, s u s p ecte d pre g na n c y, or p ositi ve pre g n a nc y test m ust be re p orte d i m me diatel y usi n g 
t he pre g na n c y re p ort f or m . T he I n vesti gat or m ust f oll o w u p a n d d oc u me nt t he c o urse a n d 
o utc o me of all pre g n a nci es e ve n if t he s u bject was disc o nti n ue d fr o m t he st u d y or if t h e  st u d y 
has fi nis he d. T he fe male s u bject or part ner of a m ale s u bject s h o ul d recei v e a n y necessar y 
c o u nseli n g re gar di n g t h e ris ks of c o nti n ui n g t he pre g n a nc y a n d t he p ossi ble effects o n t he fet us. 
M o nit ori n g s h o ul d c o nti n ue u ntil c o ncl usi o n of t he pre g na nc y . 
All o utc o mes of pre g na n c y (fr o m a fe mal e s u bject or t he se x ual part ner of a male s u bject) m ust 
be re p ort e d b y t he I n vesti gat or t o t he S p o ns or or Me dical M o nit or o n a Pre g n a nc y O ut c o me 
Re p ort f or m wit hi n 4 wee ks after he/s he has gai ne d k n o wle d ge of t he d e li ver y or el ecti ve 
a b orti o n.  
A n y S A E t hat o cc urs d uri n g pre g n a nc y m ust be rec or de d o n t he S A E re p ort f or m (e g, mater nal 
seri o us c o m plicati o ns, s p o nta ne o us or t hera pe utic a b orti o n, ect o pic pre g na n c y, still birt h, 

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ne o natal deat h, c o n ge nital a n o mal y, or birt h  defect) a n d re p orte d wit hi n 2 4 h o urs i n acc or da nce 
wit h t he pr oce d ure f or re p orti n g S A Es.  
Fe males of re pr o d ucti ve p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test pri or t o t he start of 
t hera p y, or a c o nfir m ati o n fr o m a n o bstetricia n i n case of e q ui v ocal ser u m pre g na nc y res ults. 
W o me n of re pr o d ucti ve p ote ntial, as well as fertile me n wit h part ners w h o are fe male wit h 
re pr o d ucti ve p ot e ntial, m ust a gree t o use 2 effecti ve f or ms of c o ntrace pti o n (i ncl u di n g 1 barrier 
f or m) fr o m t he ti me of gi vi n g i nfor me d c o nse nt, d uri n g t he st u d y, a n d f or 9 0  da ys (fe mal es a n d 
males) f oll o wi n g t h e last d ose of st u d y dr u g. Fe males of re pr o d ucti ve p ote ntial are defi ne d as 
se x uall y mat ure w o me n w h o ha ve n ot u n der g o ne a h ysterect o m y or bilat eral o o p h orect o m y, or 
w h o ha ve n ot be e n nat ur all y p ost me n o pa us al (ie, w h o ha ve n ot me nstr uat e d at all) f or at least 
2 4  c o nsec uti ve m o nt hs (i e,  has ha d me ns es at a n y ti me i n t he prece di n g 2 4  c o nsec uti ve m o nt hs).  
Males wit h part ners w h o are fe male wit h r e pr o d ucti ve p ote ntial m ust a gree t h at t he y or t h eir 
part ners will use at least 2  effecti ve c o ntr ace pti ve met h o ds (i ncl u di n g 1 barrier met h o d) w h e n 
e n ga gi n g i n re pr o d ucti ve se x ual acti vit y t hr o u g h o ut t he st u d y, a n d will a v oi d c o ncei vi n g f or 
9 0  da ys after t h e last d ose of st u d y treat me nt.  
A n effecti ve f or m of c o ntrace pti o n is defi n e d as h or m o nal oral c o ntrace pti v es, i njecta bles, 
patc hes, i ntra uteri ne de vi ces, i ntra uteri n e h or m o ne -release s yste ms, bilateral t u bal li gati o n, 
c o n d o ms wit h s per mici de, or male part ner sterilizati o n. If n ot usi n g a n effecti ve f or m of 
c o ntrace pti o n, partici pa nts m ust use 2  of t he f oll o wi n g met h o ds: pr o gest o ge n -o nl y h or m o nal 
c o ntrace pti o n; male or fe male c o n d o m wit h or wit h o ut s per mici de; ca p, dia p hra g m, or s p o n ge 
wit h s per mici de. Refer t o Secti o n  9. 1 3. 2  f or p ote ntial dr u g-dr u g i nteracti o ns wit h h or m o nal 
c o ntrace pti ves.  
Fe males of re pr o d ucti ve p ote ntial m ust u n der g o a uri ne pre g n a nc y test t o b e c o n d ucte d o n C 1 D 1 
a n d c o nfir me d n e gati ve pri or t o d osi n g, a n d o n Da y 1 of all s u bse q ue nt c ycl es. T he test s h o ul d 
be c o n d ucte d pre -d os e, a n d t hese s u bjects s h o ul d u n der g o a uri n e pre g n a nc y test at t he e n d of 
treat me nt visit. 
1 1. 4.  
F oll o w -u p of S u bjects after A d verse E ve nts  
1 1. 4. 1.  
I n vestig at or F oll o w -u p  
T he I n vesti gat or s h o ul d f oll o w eac h A E u ntil t he e ve nt has res ol ve d t o bas eli ne gra de or better, 
t he e ve nt is assesse d as sta ble b y t he I n vesti gat or, t he s u bject is l ost t o f oll o w-u p, or t he s u bject 
wit h dra ws c o nse nt. E v er y eff ort s h o ul d be  ma de t o f oll o w all S A Es c o nsi dere d relate d t o st u d y 
treat me nt or trial-relate d pr oce d ures u ntil a fi nal o utc o me ca n b e re p orte d. 
All pre g n a ncies re p ort e d d uri n g t he st u d y s h o ul d b e f oll o we d u ntil pre g na n c y o ut c o me. 
Pre g n a nc y o utc o mes s h o ul d be re p orte d f o ll o w re p orti n g i nstr ucti o ns pr o vi de d i n Secti o n  1 1. 3 .  
1 1. 4. 2.  
S p o ns or F oll o w -u p  
F or S A Es, A E SIs, a n d pre g n a ncies, t he S p o ns or or a desi g nee ma y f oll o w -u p b y E D C q uer y, 
tele p h o ne, fa x, electr o nic mail, a n d/ or a m o nit ori n g visit t o o btai n a d diti o nal case details a n d 
o utc o me i nf or mati o n (e g, fr o m h os pital disc har ge s u m maries, c o ns ulta nt re p orts, a ut o ps y 
re p orts) i n or d er t o perf or m a n i n de pe n de nt me dical assessme nt of t he re p orte d cas e.  

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1 1. 4. 3.  
P ost -St u d y A d verse E ve nts  
At t he E O T visit, t he I n v esti gat or s h o ul d i nstr uct eac h s u bject t o re p ort t o t he I n vesti gat or a n y 
s u bse q ue nt A Es t hat t he s u bject’s pers o nal p h ysicia n belie ves c o ul d be relate d t o pri or st u d y 
treat me nt or st u d y pr oce d ures. 
T he I n vesti gat or s h o ul d n otif y t he S p o ns or of a n y deat h or S A E of c o ncer n occ urri n g at a n y ti me 
after a s u bject has disc o nti n ue d st u d y partici p ati o n if t he e ve nt is belie ve d t o be relate d t o pri or 
st u d y treat me nt or st u d y pr oce d ures. T he S p o ns or s h o ul d als o be n otifie d if t he I n v esti gat or 
bec o mes a w are of t he de vel o p me nt of ca n cer or a c o n ge nital a n o mal y/ birt h defect i n a 
s u bse q ue ntl y c o ncei v e d offs pri n g of a s u bject t hat partici pate d i n t his st u d y.  

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1 2.  
S T A TI S TI C A L M E T H O D S  
1 2. 1.  
Ge ner al St atistic al Met h o ds  
S u m maries will be pr o d uce d f or s u bject dis p ositi o n, de m o gra p hic a n d b aseli ne disease 
c haracteristics, efficac y, safet y, P K, a n d P D, as a p pr o priate. Cate g orical dat a will be s u m marize d 
b y fre q ue n c y distri b uti o ns ( n u m ber a n d p erce nta ges o f s u bjects). C o nti n u o us data will be 
s u m marize d b y descri pti ve statistics ( mea n, sta n d ar d de viati o n, me dia n, mi ni m u m, a n d 
ma xi m u m). Ti me -t o-e ve nt e n d p oi nts will be esti mate d usi n g t he Ka pla n -Meier ( K M) met h o d. 
P oi nt esti mates a n d 9 5 % CIs will be pr o vi de d w here a p pr o priate, a n d esti mates of t he me dia n 
a n d ot her q ua ntiles, as w ell as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h rates), will be 
pr o d uce d.  
All data will be pr o vi de d i n b y -s u bject listi n gs. 
T he st u d y d ata will be a n al yze d a n d re p ort e d i n t he cli nical st u d y re p ort ( C S R) base d o n all 
s u bjects’ data u p t o t he ti me w he n 1 7 3 E F S e ve nts ha ve bee n reac he d i n t he st u d y. C o m plete 
details f or all a nal ys es will be pr o vi de d i n t he statistical a nal ysis pla n ( S A P).  
1 2. 2.  
A n al ysis Sets  
T he f oll o wi n g a nal ysis sets will be e val uate d a n d use d f or prese ntati o n of t he data:  
•  I nte nt-t o-Treat (I T T) A n al ysis Set: All s u bjects w h o are ra n d o mize d. S u bjects will be 
classifie d acc or di n g t o t h e ra n d o mize d treat me nt ar m. T he I T T A n al ysis Set will be 
t he defa ult a n al ysis set f or all a nal yses, u nless ot her wise s pecifi e d. 
•  Safet y A nal ysis Set ( S A S): All s u bjects w h o recei ve d at least 1 d ose of t he st u d y 
treat me nt. S u bjects will be classifie d acc or di n g t o t he treat me nt r ecei v e d. T h e S A S 
will be t he pri mar y a n al ysis set f or all safet y a n al yses, u nless ot her wise s pecifie d.  
•  Per -Pr ot oc ol A nal ysis Set ( P P A S): All s u bjects i n t he I T T w h o ha v e n o maj or 
pr ot oc ol de viati o ns. A d diti o nal efficac y a nal ys es ma y b e perf or me d usi n g t he P P A S. 
R ules f or maj or pr ot oc ol de viati o ns res ulti n g i n e xcl usi o n f r o m t he P P A S will be 
s pecifie d i n t he S A P. 
•  P har mac o ki netic A n al ysis Set ( P A S): All s u bjects w h o ha ve at least 1 p ost -d ose 
bl o o d sa m ple pr o vi di n g e val ua ble P K data f or A G -1 2 0.  
1 2. 3.  
Dis p ositi o n  
A ta b ulati o n of s u bject dis p ositi o n will be prese nte d b y treat me nt ar m ( A G -1 2 0 + azaciti di ne ar m 
vs place b o + azaciti di ne ar m), i ncl u di n g t he n u m b er ra n d o mize d, t he n u m b er treate d, t he reas o ns 
f or treat me nt disc o nti n uati o n, a n d t he reas o ns f or st u d y wit h dra wal. Pr ot oc ol de viati o ns will be 
liste d. 
1 2. 4.  
B aseli ne E v al u ati o ns  
De m o gra p hic a n d baseli n e disease c haracteristic data will be s u m marize d b y treat me nt ar m. D ata 
t o be ta b ulate d will i ncl u de se x, a ge, race, et h nicit y, a n d dis ease-s pecific i nf or mati o n. 

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1 2. 5.  
Effic ac y A n al yses  
D uri n g tr eat me nt, r es p o nse will be e val uate d b y t h e I n vesti gat or bas e d o n m o difie d I W G 
Res p o nse Criteria f or A M L (s ee Secti o n  1 0. 8. 1 ) t o deter mi ne s u bject stat us a n d c o nti n uati o n o n 
st u d y treat me nt. These res p o nse assess me nts will be use d f or t h e a nal ysis of all efficac y 
e n d p oi nts. Beca use C R h is n ot part of m o difie d I W G res p o nse criteria, it will be deri ve d b y t he 
S p o ns or.  
T o c o ntr ol t he o verall T y pe 1 err or rat e at t he 1 -si de d 2. 5 % le vel, t he fi x e d se q ue nce t esti n g 
pr oce d ure (Westfall a n d Kris he n, 2 0 0 1 ) will be us e d t o a dj ust f or m ulti ple statistical testi n g of 
t he pri mar y a n d k e y seco n dar y efficac y e n d p oi nts.  
T hese e n d p oi nts will be teste d i n t he f oll o wi n g or der:  
•  E F S  
•  C R rate  
•  O S  
•  C R + C R h rate  
•  O R R  
N o c o ntr ol of t he al p h a le vel will be ma de f or t he ot her a nal yses. N o i nteri m a nal ys es f or 
effic ac y are pla n n e d.  
1 2. 5. 1.  
A n al yses of t he Pri m ar y E n d p oi nt  
T he a nal ysis f or t he pri mar y e n d p oi nt will be perf or me d at t he ti me w he n 1 7 3 E F S e ve nts ha v e 
occ urre d. E ve nt -free s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil treat me nt fail ure, 
rela pse fr o m re missi o n, or deat h fr o m a n y ca us e, w hic he ver occ urs first. Treat me nt f ail ure is 
defi ne d as f ail ure t o a c hi e ve C R b y Wee k  2 4. S u bjects w h o d o n ot ac hie ve C R b y Wee k  2 4 will 
be c o nsi dere d t o ha ve h a d a n e ve nt at Da y 1 of ra n d o mizati o n. F or t he re m ai ni n g C R res p o n ders, 
t he e ve nt ti me will be t he ti me of eit her diseas e rel a pse or deat h, w hic he v er occ urs first. 
E ve nt -free s ur vi val will be ce ns or e d u p o n i nitiati o n of a ne w a ntica ncer t h era p y s h o ul d a n e w 
t hera p y be i nitiate d pri or t o a n y E F S e ve nt. 
E ve nt -free s ur vi val will be teste d usi n g t h e l o g-ra n k test stratifie d b y t h e ra n d o mizati o n 
stratificati o n fact ors ( de n o v o stat us a n d ge o gra p hic re gi o n) bas e d o n t he data i n t he I T T 
A nal ysis Set. T he b asis f or a clai m of efficac y will be t he statistical si g nifica nce of E F S i n fa v or 
of t he A G -1 2 0 + azaciti di ne ar m w he n t he 1 -si de d p ≤0. 0 2 5 ( o bser ve d E F S H R ≤0. 7 4 2). 
T he distri b uti o n of E F S will be esti mate d usi n g t he K M met h o d. T he K M c ur ves a n d 2 5 t h, 5 0t h 
( me dia n), a n d 7 5t h perce ntiles (if esti ma ble), al o n g wit h t heir 2 -si de d 9 5 % CIs, will be prese nte d 
f or eac h treat me nt ar m. T he K M esti mates at i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h 
rates) will als o be prese nt e d f or eac h tr eat me nt ar m. A C o x re gressi o n m o del stratifie d b y 
ra n d o mizati o n stratificati o n fact ors will als o be us e d t o esti mate t he H R of E F S. Ho we v er, gi ve n 
t hat t he ass u m pti o n of pr o p orti o nal hazar ds is n ot met base d o n t he E F S defi niti o n, t he o verall 
H R is less mea ni n gf ul i n t his c o nte xt. As E F S is a c o m p osite e n d p oi nt, t he esti mates prese nte d 
se parat el y b y eac h c o m p o ne nt are m or e mea ni n gf ul: CR rate b y 2 4 wee ks a n d E F S a m o n g t h ose 
w h o ha ve ac hie ve d C R b y 2 4 w ee ks. F or s u bjects w h o ac hie ve C R b y 2 4  wee ks, t he K M c ur ves 

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of t he E F S distri b uti o n a n d 2 5 t h, 5 0t h ( me dia n), a n d 7 5t h perce ntiles (if esti ma ble) al o n g wit h t heir 
2 -si de d 9 5 % CIs will be prese nte d f or eac h treat me nt ar m. A C o x re gressi o n m o del stratifie d b y 
ra n d o mizati o n stratificati o n fact ors will als o be us e d t o esti mate t he H R of E F S f or t hese 
s u bjects. I n a d diti o n, t he rati o of restrict e d mea n s ur vi val ti me, w hic h d oes n ot rel y o n 
pr o p or ti o nal hazar ds ass u m pti o ns, bet wee n t he 2 ar ms will als o be prese nte d t o s u m marize t he 
treat me nt effect. 
Se nsiti vit y a n al ys es will be perf or me d t o e x pl ore t he r o b ust ness of t he pri m ar y a nal ysis res ults 
a n d will i ncl u de a n a n al ysis base d o n t he stratifie d l o g -ra n k test f oll o wi n g t he I T T pri nci ple, 
w here t he ti me of rela ps e or deat h is deter mi ne d usi n g t he act ual date of rel a pse or deat h wit h o ut 
ce ns ori n g f or missi n g disease ass ess me nts or start of s u bse q ue nt a ntica n cer t hera p y. A d diti o nal 
se nsiti vit y a nal yses f or E F S will be pres pecifie d i n t he S A P a n d will i ncl u de:  
•  Stratifie d l o g -ra n k test usi n g t he P P A S 
•  U nstratifie d l o g -ra n k t est usi n g t he I T T  
•  Stratifie d l o g -ra n k test usi n g t he I T T, w here f or s u bjects w h o d o n ot ac hie ve C R b y 
Wee k 2 4, i nstea d of bei n g c o n si dere d t o ha ve ha d a n E F S e v e nt at Da y 1 of 
ra n d o mizati o n, t he e ve nt ti me will be eit her 2 4 wee ks or E O T, w hic h e ver is earlier. 
S u b gr o u p a n al ys es will be perf or me d bas e d o n t he stratificati o n fact ors. T he a nal yses will 
i ncl u de t he pres e ntati o n of C R rate b y 2 4 wee ks a n d K M esti mates of E F S a m o n g s u bjects w h o 
ac hie ve d C R b y 2 4  wee ks, u nstratifie d l o g -ra n k tests, a n d H Rs ( wit h ass ociate d 9 5 % CIs) fr o m 
u nstratifie d C o x re gressi o n m o dels. Ot her s u b gr o u p a nal ys es f or E F S, i ncl u di n g a n al ys es b y 
c yt o ge netic ris k,  will be s pecifie d i n t he S A P.  
1 2. 5. 2.  
A n al yses of t he Sec o n d ar y E n d p oi nts  
T he ke y sec o n dar y effic ac y e n d p oi nts are C R rat e, O S, C R + C R h rate, a n d O R R. A d diti o nal 
sec o n dar y effi cac y e n d p oi nts i ncl u de C R + C Ri (i ncl u di n g C R p) rat e, D O C R, D O C R h, D O R, 
D O C Ri, T T C R, T T C R h, T T R, T T C Ri, tra nsf usi o n re q uire me nts ( pl atelet a n d R B C), rates of 
i nfecti o n, da ys h os pitaliz e d, ot her efficac y a n d s afet y meas ures t hat are p ot e ntiall y i n dicati ve of 
cli nical be nefit, c h a n ge fr o m baseli ne i n Q o L assess me nts, a n d t he rates of C R wit h I D H 1 M C. 
S e nsiti vit y a n al ys es a n d s u b gr o u p a nal yses f or t he sec o n dar y efficac y e n d p oi nts will be s pecifie d 
i n t he S A P. 
1 2. 5. 2. 1.  Ke y Sec o n d ar y E n d p oi nt A n al yses  
1 2. 5. 2. 1. 1.  C o m plete R e missi o n R ate  
C o m plete re missi o n rate is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a C R . A 
C oc hra n -Ma nt el -Hae nszel ( C M H) test will be use d t o c o m pare C R rate bet wee n t he 2 treat me nt 
ar ms. A l o gistic re gressi o n m o del will be use d t o esti mate t he treat me nt effect i n ter ms of a n 
o d ds rati o. T he o d ds rati o a n d its ass ociate d 9 5 % CIs will be pres e nte d.  
1 2. 5. 2. 1. 2.  O ver all S ur vi v al  
O verall s ur vi val is defi n e d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h d ue t o a n y 
ca use. K a pla n -Mei er c ur ves a n d K M esti mates of O S will be prese nte d f or eac h tr eat me nt ar m, 

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i ncl u di n g esti mates of t h e me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -, 
6 -, a n d 1 2-m o nt h rates). T he l o g -ra n k test stratifie d b y t he ra n d o mizati o n fact ors will be use d t o 
c o m pare O S b et wee n t he 2  treat me nt ar ms. T h e H R of O S wit h a 9 5 % CI c o m pari n g t he A G-1 2 0 
+ azacit i di ne ar m wit h t h e place b o + azaciti di ne ar m will be esti mate d fr o m a C o x pr o p orti o nal 
hazar ds m o del stratifie d b y t he ra n d o mizati o n stratificati o n fact ors.  
1 2. 5. 2. 1. 3.  C o m plete R e missi o n Pl us C o m plete Re missi o n Wit h P arti al He m at ol o gic 
Rec o ver y R ate  
T he C R + C R h rate  is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d a C R or C R h. C R h is 
defi ne d as a C R wit h partial rec o ver y of peri p heral bl o o d c o u nts ( < 5 % b o n e marr o w bl asts, 
A N C > 0. 5 × 1 0 9/ L [ 5 0 0/ µ L], a n d platelets > 5 0 × 1 09/ L [ 5 0, 0 0 0/ µ L]). Beca use C R h is n ot part of 
m o difie d I W G criteria, it will be deri ve d b y t he S p o ns or. A C M H test will be use d t o c o m pare 
t he C R + C R h rate bet wee n t he 2 treat me nt ar ms. A l o gistic re gressi o n m o del will be use d t o 
esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds r ati o a n d its ass ociate d 9 5 % CIs 
will be prese nte d.  
1 2. 5. 2. 1. 4.  O bjecti ve R es p o nse R ate  
O bjecti ve res p o ns e rat e is defi ne d as t he rate of C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S. T he 
best res p o nse is calc ulate d usi n g t he f oll o wi n g hierarc h y: 1)  C R; 2)  C Ri (i ncl u di n g C R p) ; 3) P R; 
a n d 4) M L F S. A s u m mar y of best res p o nse b y tr eat me nt ar m will be pr o d uce d. A C M H test will 
be use d t o c o m pare O R R bet wee n t he 2  tr eat me nt ar ms. A l o gistic re gressi o n m o del will be use d 
t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o a n d its ass ociate d 9 5 % 
CIs will be prese nte d.  
1 2. 5. 2. 2.  A d diti o n al Sec o n d ar y E n d p oi nt A n al yses  
1 2. 5. 2. 2. 1.  C o m plete R e missi o n a n d C Ri (I ncl u di n g C R p) R ate  
T he C R + C Ri (i ncl u di n g C R p) rate is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d a C R 
or C Ri (i ncl u di n g  C R p). A C M H test will be use d t o c o m pare t he C R + C Ri (i ncl u di n g C R p) rat e 
bet wee n t he 2  tr eat me nt ar ms. A l o gistic re gressi o n m o del will be use d t o esti mate t he treat me nt 
effect i n ter ms of a n o d ds rati o. T he o d ds rati o a n d its ass ociate d 9 5 % CIs will be  prese nte d.  
1 2. 5. 2. 2. 2.  D O C R, D O C R h, D O R, a n d D O C Ri  
A m o n g s u bjects w h o ac hie ve d C R, D O C R will be calc ulate d as t he date of t he first occ urre nce 
of C R t o t he date of first d oc u me nte d diseas e rela pse, or deat h.  
A m o n g s u bjects w h o ac hie ve d C R or C R h, D O C R h will be calc u late d as t he date of t he first 
occ urre nce of C R or C R h t o t he date of first d oc u me nte d disease rela pse or deat h.  
A m o n g s u bjects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S, D O R will be 
calc ulate d as t he date of t he first res p o nse t o t he date of fir st d oc u m e nte d disease rel a pse, diseas e 
pr o gressi o n, or deat h.  
A m o n g s u bjects w h o ac hie ve d C R or C Ri (i ncl u di n g C R p), D O C Ri will be calc ulate d as t he date 
of t he first occ urre n ce of C R or C Ri (i ncl u di n g C R p) t o t he date of t he first d oc u me nte d rel a pse 
or de at h.  

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Ka pla n -Mei er met h o ds will be use d t o esti mate D O C R, D O C R h, D O R, a n d D O C Ri; s u bjects 
wit h o ut rela pse, diseas e pr o gressi o n, or deat h, as a p pr o priate, at t he ti me of a nal ysis will be 
ce ns ore d at t he last res p o nse assess me nt date. Ka pla n -Meier esti mates o f D O C R, D O C R h, D O R, 
a n d D O C Ri will be prese nte d b y tr eat me nt ar m, i ncl u di n g esti mates of t h e me dia n a n d ot her 
q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 1 2-m o nt h rates).  
S u bjects will be ce ns ore d f or D O C R, D O C R h, D O R, or D O C Ri at t he ti me of t he start of 
s u bse q ue nt a ntica n cer t h era p y, s h o ul d it occ ur pri or t o a n y D O C R, D O C R h, D O R, or D O C Ri 
e ve nt, as a p pr o priate. D etaile d ce ns ori n g r ules will be i ncl u de d i n t he S A P. Ka pla n -Mei er 
esti mates of D O C R, D O C R h, D O R, a n d D O C Ri will be prese nte d b y tr eat me nt ar m, i ncl u di n g 
esti mates of t he me dia n a n d ot her q ua ntiles, as well as i n di vi d ual ti me p oi nts (e g, 3 -, 6-, a n d 
1 2 -m o nt h rates).  
1 2. 5. 2. 2. 3.  T T C R, T T C R h, T T R, a n d T T C Ri  
A m o n g s u bjects w h o ac hie ve d C R, T T C R will be assesse d fr o m t he d ate of ra n d o mizati o n t o t he 
date of first oc c urre nce of C R.  
A m o n g s u bjects w h o ac hie ve d C R or C R h, T T C R h will be assesse d fr o m t he date of 
ra n d o mizati o n t o t he date of first occ urre n ce of C R or C R h. 
A m o n g s u bjects w h o ac hie ve d C R, C Ri (i ncl u di n g C R p), P R, a n d M L F S, T T R will be as sesse d 
fr o m t he date of ra n d o mi zati o n t o t he date of t he first res p o nse. 
A m o n g s u bjects w h o ac hie ve d C R or C Ri (i ncl u di n g C R p), T T C Ri will be assesse d fr o m t he 
date of ra n d o mizati o n t o t he date of first o cc urre n ce of C R or C Ri (i ncl u di n g C R p).  
Ti me t o C R, T T C R h, T T R, a n d T T C Ri will be s u m marize d b y treat me nt ar m. Ti me t o C R, 
T T C R h, T T R, a n d T T C Ri will be prese nte d b y treat me nt ar m usi n g d escri pti ve statistics.  
1 2. 5. 2. 2. 4.  A d diti o n al Cli nic al Be nefit  
Tra nsf usi o n re q uire me nts ( platelet a n d R B C; n u m ber of u nits), rates of  i nfecti o n, da ys s p e nt 
h os pitaliz e d, a n d ot her efficac y a n d safet y m eas ures t hat are p ot e ntiall y i n dicati ve of cli nical 
be nefit will be s u m marize d b y tr eat me nt ar m usi n g des cri pti ve statistics.  
1 2. 5. 2. 2. 5.  Q u alit y of Life Assess me nts  
Q ualit y of lif e, as meas ure d b y E O R T C Q L Q -C 3 0, will be e val uate d f or s u bjects wit h a baseli ne 
assess me nt a n d at least 1 p ost -baseli ne Q L Q -C 3 0 assess me nt t hat ge nerate a sc ore. F or t otal 
Q L Q -C 3 0, eac h d o mai n sc ore (e g, p h ysical f u n cti o ni n g, r ole f u ncti o ni n g, e m oti o nal f u ncti o ni n g, 
c o g niti ve f u ncti o ni n g, s o cial f u ncti o ni n g), as w ell as s y m pt o m scales, b aseli ne val ues, a n d 
c ha n ge fr o m baseli ne f or eac h ti me p oi nt will be s u m marize d b y treat me nt ar m usi n g d escri pti ve 
statistics. Mi x e d m o dels will als o be a p plie d a n d t he details will be s pecified i n t he S A P.  
Healt h ec o n o mic m eas ur es, as assesse d b y t h e E Q -5 D -5 L, will be e v al uate d f or s u bjects wit h a 
baseli ne assess me nt a n d at least 1 p ost -baseli ne E Q -5 D -5 L assess me nt t hat ge n erat e a sc ore. 
Sc ores at baseli ne a n d c h a n ge fr o m b aseli ne sc ores f or e ac h ti me p oi nt will be q ua ntifie d wit h 
descri pti ve statistics b y tr eat me nt ar m.  

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1 2. 5. 2. 2. 6.  E v al u ati o n of I D H 1 M ut ati o n Cle ar a nce  
C o m plete re missi o n wit h I D H 1 M C is defi ne d as a res p o nse of C R w here t here is n o e vi de nce of 
t he I D H 1 m utati o n b y m olec ular te c h ni q ues t o bel o w t he le vel of detecti o n ( 0. 0 2 % -0. 0 4 %) f or 
≥1 o n -treat me nt ti me p oi nt. A C M H test will be use d t o c o m pare t h e rate of C R wit h I D H 1 M C 
bet wee n A G -1 2 0 + azaciti di ne a n d place b o + azaciti di ne. A l o gistic re gressi o n m o del will be 
use d t o esti mate t he treat me nt effect i n ter ms of a n o d ds rati o. T he o d ds rati o a n d its ass ociate d 
9 5 % CIs will be prese nte d.  
1 2. 6.  
E x p os ure a n d S afet y A n al yses  
Safet y will be e val uat e d b y vital si g ns, t h e res ults of E C O G P S, E C G, a n d E C H O or M U G A f or 
L V E F as cli nicall y i n dicate d ( met h o d per i nstit uti o nal sta n dar d of care, wit h t he sa me met h o d 
use d f or a n i n di vi d ual s u bject t hr o u g h o ut t he st u d y; sites i n Ger ma n y m a y o nl y use E C H O), 
cli nical la b orat or y assess me nts ( he mat ol o g y, c he mistr y, a n d c o a g ulati o n), a n d assess me nt of 
A Es, A E SIs, S A E s, A Es lea di n g t o disc o nti n uati o n or deat h, a n d c o nc o mita nt me dicati o n use. 
All safet y data will be liste d b y s u bject a n d s u m marize d b y tr eat me nt ar m.  
Cli nicall y si g nifica nt p h ysical e x a mi nati o n fi n di n gs are ca pt ure d as A Es will be liste d b y s u bject.  
C o nc o mita nt me dicati o ns will be liste d b y s u bject a n d will be s u m marize d b y treat me nt ar m.  
A s u m mar y of st u d y dr u g e x p os ure, i ncl u di n g n u m ber of d oses a d mi nistere d, t otal d ose, d urati o n 
of treat me nt, d ose i nte nsit y, a n d t he pr o p orti o n of s u bjects wit h d ose m o di ficati o ns, will be 
s u m marize d b y treat me nt ar m. Reas o ns f or d os e m o dificati o ns will be liste d b y s u bject a n d 
s u m marize d. 
1 2. 6. 1.  
A d verse E ve nts  
S u m mar y ta bles f or A Es will i ncl u de a n y A E t hat occ urs bet w ee n t he first d ose of a n y st u d y 
dr u g a n d 2 8 da ys f oll o wi n g t h e last d ose of a n y st u d y dr u g. T h e i nci de n ce of A Es ( ne w or 
w orse ni n g fr o m bas eli ne) will be s u m marize d acc or di n g t o ( M e dical Dicti o nar y f or Re g ul at or y 
Acti vities [ Me d D R A]) b y s yste m or ga n class a n d/ or preferre d ter m, se v erit y ( base d o n N CI 
C T C A E versi o n 4 . 0 3 gra di n g as ass esse d b y t he I n vesti gat or; see A p pe n di x  1 5. 9 ), seri o us ness, 
a n d relati o n t o st u d y tr eat me nt. T he f oll o wi n g s u m maries will be pr o d u ce d: 
•  All A Es  
•  Treat me nt -relate d A Es 
•  Gra de ≥3 A Es  
•  Gra de ≥3 tr eat me nt -relat e d A Es 
•  T he m ost c o m m o nl y re p orte d A Es (ie, t h ose e ve nts re p orte d i n ≥1 0 % of all s u bjects)  
•  S A Es  
•  Treat me nt -relate d S A Es 
•  A E SIs  
•  Disc o nti n uati o ns d ue t o A Es  
•  A Es lea di n g t o d ose m o dificati o ns  

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•  O n -treat me nt d eat hs 
B y -s u bject listi n gs will be pr o vi de d f or o n-treat me nt deat hs ( o n-tr eat me nt is defi ne d as t he 
peri o d starti n g fr o m t he first d ose t o 2 8 da ys after t he last d ose), A Es, A E SIs, S A Es, a n d A Es 
lea di n g t o disc o nti n uati o n of treat me nt. 
1 2. 6. 2.  
L a b or at or y A b n or m alities  
F or la b orat or y tests i ncl u de d i n t he N CI C T C A E versi o n 4. 0 3, la b orat or y d ata will be gra d e d 
acc or di n gl y; a Gra d e 0 will be assi g ne d f or all n o n -missi n g val ues n ot gra d e d as 1 or hi g her. F or 
la b orat or y tests w here gra des are n ot defi ne d b y C T C A E, res ults will be gra de d b y t he 
l o w/ n or mal/ hi g h classificati o ns base d o n la b orat or y n or mal ra n ges. 
T he f oll o wi n g s u m maries will be ge n erat e d se paratel y f or he m at ol o g y, c he mistr y, a n d 
c oa g ulati o n st u dies:  
•  Descri pti v e statistics f or t he act ual val ues a n d/ or c ha n ge fr o m b aseli ne of cli nical 
la b orat or y para meters o v er ti me. 
•  S hift ta bles usi n g C T C A E gra des t o c o m pare b aseli ne t o t he w orst o n -treat me nt val ue 
(f or la b orat or y tests w here C T C A E gra des are n ot defi ne d, s hift ta bles usi n g t he 
l o w/ n or mal/ hi g h/[l o w a n d hi g h] classificati o n t o c o m pare bas eli ne t o t he w orst 
o n -treat me nt ma y b e ge n erate d). 
•  Listi n g of all la b orat or y data wit h val ues fla g ge d t o s h o w t he c orres p o n di n g C T C A E 
gra des a n d t h e classificati o ns relati ve t o t h e la b orat or y n or m al ra n ges.  
I n a d diti o n t o t he a b o ve-me nti o ne d ta bles a n d listi n gs, gra p hi cal dis pla ys of ke y safet y 
para meters, s uc h as s catt er pl ots of act ual or c ha n ge i n la b orat or y tests o ver ti me or b o x pl ots 
ma y b e s pecifi e d i n t he S A P.  
1 2. 6. 3.  
Ot her S afet y D at a  
Descri pti ve statistics of E C O G P S o ver ti me will be s u m marize d b y fre q u e nc y. S hift ta bles ma y 
be pr o vi de d f or E C O G P S fr o m baseli ne t o w orst val ue of p ost -bas eli ne assess me nts.  
A d diti o nal safet y a nal yses ma y be perf or me d if dee me d necessar y.  
1 2. 7.  
P h ar m ac o ki netic A n al yses  
A p o p ulati o n P K a p pr oac h will be perf or me d t o assess t y pical a n d i n di vi d ual s u bject P K 
para meters of A G -1 2 0. D escri pti ve statistics will be use d t o s u m marize A G -1 2 0 P K 
c o nce ntr ati o ns at differe nt n o mi nal ti me p oi nts acr oss s u bject s.  
1 2. 8.  
P h ar m ac o d y n a mic A n al yses  
Descri pti ve statistics will be use d t o s u m marize 2 -H G c o nce ntrati o ns at differe nt n o mi nal ti me 
p oi nts acr oss s u bjects. T he p ote ntial relati o ns hi p bet wee n plas ma e x p os ure of A G -1 2 0 a n d 
plas ma 2 -H G le v els will be e x pl ore d wit h de scri pti ve a n d gra p hical met h o ds as a p pr o priat e. 
F or t he s u bjects w h o ha v e I D H 1 m utati o n res ults fr o m b ot h l ocal e val uati o n a n d ce ntr al 
la b orat ories, t he c o nc or da nce b et wee n t h e 2 tests will be e x pl ore d. 

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1 2. 1 0.  
I nteri m A n al yses  
T here are n o i nteri m a nal ys es f or efficac y pla n ne d f or t his st u d y.  
Safet y d ata will be re vie we d re g ularl y b y a n I D M C t o e ns ure t he safet y of t he c o m bi nati o n 
thera p y. T hes e re vi e ws will occ ur after t he first 6, 1 2, 2 4, a n d 3 6 s u bjects h a ve c o m plete d 1 
c ycle of t hera p y or dis c o nti n ue d, w hic he ver s h o ul d occ ur first. T h ereafter, safet y re vi e ws will be 
c o n d ucte d a p pr o xi matel y e ver y 6  m o nt hs u ntil t he st u d y is u n bli n de d f or t he a nal ysis of t he 
pri mar y e n d p oi nt.  
1 2. 1 1.  
Pr oce d ures f or H a n dli n g Missi n g, U n use d, a n d S p uri o us D at a  
N o i m p utati o n will be perf or me d f or missi n g data ele me nts u nless s pecifie d ot her wise.  
W he n ta b ulati n g A E dat a, partial dates will be i m p ute d. R ules of  i m p utati o n will be s pecifie d i n 
t he S A P. All res p o nse assess me nts occ urri n g after d oc u me nte d c o nfir me d rela pse/ pr o gressi o n 
ma y b e be liste d a n d a n al yz e d se paratel y.  
1 2. 1 2.  
S a m ple Size Esti m ati o n  
A t otal of a p pr o xi matel y 2 0 0 s u bjects wit h pre vi o usl y u ntreate d I D H 1 m A M L will partici pat e i n 
t his st u d y.  
Ass u m pti o ns f or t he place b o + azaciti di ne ar m i n t his st u d y are base d o n res ults fr o m St u d y 
A Z A -A M L -0 0 1 i n n e wl y dia g n ose d A M L patie nts w h o are i neli gi ble f or i nte nsi ve I C recei vi n g 
A G -1 2 0 i n c o m bi nati o n wit h azaciti d i ne. Preli mi nar y data fr o m St u d y A Z A-A M L -0 0 1 were 
o btai ne d u n der a d ata e x c ha n ge a gree me nt wit h Cel ge n e. Base d o n res ults fr o m a retr os pecti ve 
a nal ysis of t hese dat a, t he C R rate at 2 4  wee ks is ass u me d t o be 2 0 % f or t he place b o + 
azaciti di ne ar m. F or s u bje cts w h o ac hi e ve C R b y 2 4 wee ks, t he me dia n E F S is ass u me d t o be 
1 4. 6 m o nt hs. Ass u m pti o ns f or t he A G -1 2 0 + azaciti di ne ar m i n t his st u d y are base d o n res ults 
fr o m St u d y A G-2 2 1 -A M L -0 0 5 i n n e wl y dia g n ose d A M L p atie nts w h o are i neli gi ble f or 
i nte nsi ve I C receivi n g A G -1 2 0 i n c o m bi nati o n wit h azaciti di ne. T he C R rate b y 2 4 wee ks is 

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ass u me d t o be 4 0 %. F or s u bjects w h o ac hie ve C R b y 2 4 wee ks, a t ar get H R of 0. 7 6 f or E F S 
(e q ui vale nt t o a me dia n E F S a m o n g res p o n d ers of 1 4. 6 m o nt hs i n t he place b o + azaciti di ne ar m 
vs 1 9. 2 m o nt hs i n t he A G -1 2 0 + azaciti di ne ar m, ass u mi n g a n e x p o ne ntial distri b uti o n) is 
ass u me d. Base d o n si m ulati o n res ults, t he a vera ge o verall H R o ver 1 0, 0 0 0  si m ulati o ns f or t he 
e ntire p o p ulati o n is 0. 6 4 1. Gi ve n t hat t he ass u m pti o n of pr o p orti o nal hazar ds  is n ot met base d o n 
t he E F S defi niti o n, t he o verall H R is less mea ni n gf ul i n t his c o nte xt. T heref ore, t h e o verall H R 
f or t he e ntire p o p ul ati o n was n ot part of t he st u d y desi g n ass u m pti o ns.  
U n der t hese ass u m pti o ns, a t otal of 1 7 3 E F S e v e nts are re q uire d t o pr o vi de 8 0 % p o wer at a 
1 -si de d al p ha of 0. 0 2 5 le vel of si g nifica nce t o reject t he n ull h y p ot hesis usi n g a str atifie d 
l o g-ra n k test. Ass u mi n g a recr uit me nt peri o d of a p pr o xi matel y 4 4 m o nt hs, wit h a n accr ual r ate of 
3  s u bjects per m o nt h d uri n g t he first 1 0 m o nt hs a n d 5 s u bjects per m o nt h t hereafter, al o n g wit h 
a n ass u me d 5 % o v erall dr o p o ut rate, a p pr o xi matel y 2 0 0 s u bjects will be ra n d o mize d t o t he 
2  treat me nt ar ms i n a 1: 1 rati o. Gi ve n t he a b o v e ass u m pti o ns, it is esti mate d t hat t he a nal ysis of 
t he pri mar y e n d p oi nt f or E F S will occ ur a p pr o xi matel y 5 2 m o nt hs after t he first s u bject is 
ra n d o mize d.  
1 2. 1 3.  
P o w er f or A n al ysis of Ke y Sec o n d ar y E n d p oi nts  
1 2. 1 3. 1.  
P o w er f or A n al ysis of O ver all S ur vi v al  
O verall s ur vi val will be c o m pare d bet w ee n t he 2 treat me nt ar ms, pr o vi de d t he pr i mar y e n d p oi nt 
of E F S is statisticall y si g nifica nt fa v ori n g t he A G -1 2 0 + azaciti di ne ar m. Base d o n a vaila bl e data 
(D o m bret et al, 2 0 1 5 ), t h e me dia n O S i n t he place b o + azaciti di ne ar m is e x pecte d t o be 
a p pr o xi matel y 1 0. 4 m o nt hs. A tar get H R of 0 . 7 1 f or O S (e q ui vale nt t o a m e dia n O S of 
1 0. 4  m o nt hs i n t he place b o + azaciti di ne ar m vs 1 4. 6 m o nt hs i n t he A G -1 2 0 + azaciti di ne ar m, 
ass u mi n g a n e x p o ne ntial distri b uti o n) is ass u me d. Base d o n t h e 2 0 0 s u bjects pla n ne d t o be 
e nr olle d i n t his st u d y t o detect  t he pri mar y e n d p oi nt of E F S, it is esti mate d t hat at t he ti me of t he 
fi nal a nal ysis f or E F S, a p pr o xi matel y 1 4 5 d eat hs will be o bser ve d a n d t his will pr o vi de 5 4 % 
p o wer at a 1 -si de d o verall 2. 5 % le vel of si g nifica n ce t o reject t he n ull h y p ot heses ( H R = 1) usi n g 
a l o g-ra n k test. 
1 2. 1 3. 2.  
P o w er f or A n al ysis of C o m plete Re missi o n R ate, C o m plete Re missi o n Pl us 
C o m plete R e missi o n wit h P arti al He m at ol o gic Rec o ver y R ate, a n d O bjecti v e 
Res p o nse R ate  
Base d o n a retr os pecti ve a nal ysis of St u d y A Z A -A M L -0 0 1, t he res p o ns e rates i n t he place b o + 
azaciti di ne ar m are e x pecte d t o be a p pr o xi matel y 2 0 %, 2 5 %, a n d 3 2 % f or C R rate, C R + C R h 
rate, a n d O R R, res pecti v el y. It is h y p ot hesize d t hat t he A G-1 2 0 + azaciti di ne ar m will res ult i n 
a n a bs ol ute 2 0 % i ncreas e i n t he C R rate, C R + C R h rate, a n d O R R. Base d o n t he 2 0 0  s u bjects 
pla n ne d t o be e nr olle d i n t his st u d y t o det ect t he pri mar y e n d p oi nt of E F S, t he p o wer f or t he 
a nal ysis of eac h of t hese e n d p oi nts at a 1 -si de d 2. 5 % le vel of si g nifica n ce t o reject t he n ull 
h y p ot hes es ( o d ds rati o = 1) usi n g a C M H test are prese nte d i n Ta ble  1 3 . 
 

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T a ble  1 3 : 
P o w er f or A n al ysis of C R R ate, C R + C R h R ate, a n d O R R  
E n d p oi nts  
N u m ber of S u bjects  
T ar get Res p o nse R ate  
( Az a citi di ne vs A G-1 2 0 + Az a citi di ne)  
P o w er  
C R rate  
2 0 0  
2 0 % vs 4 0 %  
8 6 %  
C R + C R h rate  
2 0 0  
2 5 % vs 4 5 %  
8 4 %  
O R R  
2 0 0  
3 2 % vs 5 2 %  
8 1 %  
A b bre viati o ns: C R  =  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 gic rec o ver y; O R R  =  o bjecti ve 
res p o nse rate; vs = vers us. 

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1 3.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  
1 3. 1.  
G o o d Cli nic al Pr actice  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he I nter n ati o nal C o u ncil f or Har m o nisati o n 
(I C H) G ui deli ne f or G o o d Cli nical Practice ( G C P) a n d t he a p pr o priate re g ulat or y re q uire m e nt(s). 
T he I n vesti gat or will be t h or o u g hl y fa miliar wit h t he a p pr o pri ate use of t h e st u d y dr u g as 
descri be d i n t he pr ot o c ol a n d rele v a nt I Bs. Ess e ntial cli nical d oc u me nts will be mai ntai ne d t o 
de m o nstrate t he vali di t y of t he st u d y a n d t he i nte grit y of t he d ata c ollecte d. Master files s h o ul d 
be esta blis he d at t he b e gi n ni n g of t he st u d y, mai nt ai ne d f or t he d urati o n of t he st u d y, a n d 
retai ne d acc or di n g t o t he a p pr o priate re g ulati o ns. 
1 3. 2.  
Et hic al C o nsi der ati o ns  
T he st u d y wil l be c o n d ucte d i n acc or da nce wit h et hical pri nci ples f o u n de d i n t he Declarati o n of 
Helsi n ki (see A p p e n di x  1 5. 1 0 ). 
T he I n vesti gat or m ust o btai n I R B/I E C a p pr o val f or t he i n vesti gati o n a n d m ust s u b mit writte n 
d oc u me ntati o n of t he a p pr o val t o t he S p o ns or bef ore he or s he ca n e nr oll a n y s u bject i nt o t he 
st u d y. T he I R B/I E C will re vie w all a p pr o priate st u d y d oc u m e ntati o n i n or der t o safe g u ar d t he 
ri g hts, safet y, a n d w ell-bei n g of t h e s u bjects. T he st u d y will o nl y be c o n d u cte d at sites w here 
I R B/I E C a p pr o v al has bee n o btai ne d. T he pr ot oc ol, I B, i nf or me d c o nse nt, a d vertise me nts (if 
a p plica ble), writte n i nf or mati o n gi ve n t o t he s u bjects (i ncl u di n g diar y car ds), s afet y u p dat es, 
a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hes e d oc u me nts will be pr o vi de d t o t he I R B/I E C. 
T he I R B/I E C is t o be n otifie d of a n y a m e n d me nt t o t he pr ot oc ol i n acc or da nce wit h l ocal 
re q uire me nts. Pr o gress re p orts a n d n otificati o ns of seri o us u ne x pecte d a d verse dr u g reacti o ns are 
t o be pr o vi de d t o t he I R B/I E C a cc or di n g t o l ocal r e g ul ati o ns a n d g ui d eli nes. 
1 3. 3.  
S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
T he I n vesti gat or at eac h ce nter will e ns ure t hat t h e s u bject is gi v e n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris k, a n d be nefit of t he st u d y. S u bjects 
m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he s u bject 
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 be all o we d ti me t o c o nsi der t he i nf or mati o n 
pr o vi de d.  
After t he st u d y has b ee n f ull y e x plai ne d, writte n i nf or me d c o ns e nt will be o btai ne d fr o m t he 
s u bject pri or t o st u d y p artici pati o n.  
T he s u bject’s si g ne d a n d date d i nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y 
st u d y-relate d pr oce d ures. T he I n vesti gat or m ust mai ntai n t he ori gi n al, si g ne d I C F. A c o p y of t he 
si g ne d f or m m ust be gi v e n t o t he s u bject. 
T he met h o d of o btai ni n g a n d d oc u me nti n g t he i nf or me d c o nse nt a n d t h e c o nte nts of t he c o nse nt 
will c o m pl y wit h I C H-G C P a n d all a p plica ble re g ulat or y re q uire m e nt(s).  
1 3. 4.  
S u bject C o nfi de nti alit y  
I n or der t o mai ntai n s u bj ect pri vac y, all s o urce d o c u me nts/e C R Fs, st u d y dr u g acc o u nta bilit y 
rec or ds, st u d y re p orts, a n d c o m m u nicati o ns will i de ntif y t he s u bj ect b y t he assi g ne d su bj ect 

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n u m ber. T he I n v esti gat or will gra nt m o nit or(s) a n d a u dit or(s) fr o m t he S p o ns or or its desi g n ee 
a n d re g ulat or y a ut h orit y(ies) access t o t he s u bject’s ori gi nal me dical rec or ds f or verificati o n of 
data gat here d o n t he s o urce d oc u me nts/e C R Fs a n d t o a u di t t he data c ollecti o n pr ocess. T he 
s u bject’s c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u blicl y a vaila ble t o t he e xte nt 
per mitte d b y t he a p plica ble la ws a n d re g ulati o ns.  
1 3. 5.  
Pr ot oc ol C o m pli a nce  
T he I n vesti gat or will c o n d uct t he st u d y i n c o m plia nc e wit h t he pr ot oc ol. M o dificati o ns t o t he 
pr ot oc ol s h o ul d n ot be ma de wit h o ut a gree me nt of b ot h t he I n v esti gat or a n d t he S p o ns or. 
C ha n ges t o t he pr ot oc ol will re q uire writte n I R B/I E C a p pr o val/fa v ora ble o pi ni o n pri or t o 
i m ple me ntati o n, e x ce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o 
s u bjects. T he I R B/I E C m a y pr o vi de, if a p plica ble, w here re g ulat or y a ut h orit y(ies) per mit, 
e x pe dite d re vie w a n d a p pr o val/fa v ora ble o pi ni o n f or mi n or c ha n ge(s) i n o n g oi n g st u dies t hat 
ha ve t he a p pr o val /fa v ora ble o pi ni o n of t he I R B/I E C. T he S p o ns or or desi g n ee will s u b mit all 
pr ot oc ol m o dificati o ns t o t he re g ulat or y a ut h orit y(ies) i n acc or da nce wit h t he g o v er ni n g 
re g ulati o ns.  
W he n i m me diate de viati o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate a n i m me dia te hazar d(s) t o 
s u bjects, t he I n vesti gat or will c o ntact t he S p o ns or or Me dical M o nit or, if circ u msta nces p er mit, 
t o disc uss t he pla n ne d c o urse of acti o n. A n y de part ures fr o m t he pr ot oc ol m ust be f ull y 
d oc u me nte d i n t he s o urce d oc u me nts/e C R F.  
1 3. 6.  
D at a M a n a ge me n t 
All data f or s u bjects r ecr uite d f or t he trial will be e ntere d o nt o t he e C R Fs via a n E D C s yst e m 
pr o vi de d b y t he S p o ns or or desi g n ee. O nl y a ut h orize d staff ma y e nter data o nt o t he e C R Fs. If a n 
e ntr y err or is ma de, t he c orrecti o ns t o t he e C R Fs will be ma de acc or di n g t o e C R F g ui d eli nes b y 
a n a ut h orize d me m ber of t he site staff.  
Electr o nic case re p ort f or ms will be c hec ke d f or c orrect n ess a gai nst s o urce d oc u me nt data b y t he 
S p o ns or’s m o nit or. If a n y e ntri es i nt o t he e C R F are i nc orrect or i n c o m plete, t he m o nit o r will as k 
t he I n v esti gat or or t he st u d y site staff t o ma ke a p pr o priate c orrecti o ns, a n d t he c orrecte d e C R F 
will a gai n b e re vie we d f or c o m plete ness a n d c o nsiste nc y. A n y discre pa ncies will be n ote d i n t he 
e C R F s yste m b y me a ns of electr o ni c data q ueries. A ut h orize d site staff will be as ke d t o r es p o n d 
t o all electr o nic q ueries acc or di n g t o t he e C R F g ui deli nes. 
1 3. 7.  
S o urce D oc u me nt/ Electr o nic C ase Re p ort F or m C o m pleti o n  
S o urce d oc u me nts/e C R Fs will be c o m plete d f or eac h st u d y s u bj ect. It is t he I n vesti gat or’s 
res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, a n d ti meli ness of t he data re p orte d i n t he 
s u bject’s s o urce d oc u me nt/e C R F. T he s o urce d o c u me nt/e C R F s h o ul d i n dicate t he s u bject’s 
partici pati o n i n t he st u d y a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr o ce d ures, A Es, 
a n d s u bject stat us.  
T he I n vesti gat or, or d esi g nat e d re prese ntati ve, s h o ul d c o m plete t he s o urce d oc u me nt/e C R F as 
s o o n as p ossi ble after i nf or mati o n is c ollecte d, prefera bl y o n t he s a me da y t hat a st u d y s u bject is 
see n f or a n e x a mi nati o n, treat me nt, or a n y ot h er st u d y pr oce d ure. A n y o utst a n di n g e ntries m ust 

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be c o m plete d i m me diatel y after t he fi nal e xa mi nati o n. A n e x pla nati o n s h o ul d be gi ve n f or all 
missi n g data.  
T he I n vesti gat or m ust si g n a n d date t he I n v esti gat or’s State me nt at t he e n d of t he s o urce 
d oc u me nt/e C R F t o e n d orse t he rec or de d d ata.  
T he I n vesti gat or will ret ai n all c o m plete d s o urce d oc u me nts.  
1 3. 8.  
Direct Access t o S o urce D at a  
T he st u d y will be m o nit ore d b y t he S p o ns or or its desi g nee , a n d will i ncl u de re vie w of t he s o urce 
d oc u me nts/e C R Fs f or c o m plete ness a n d clarit y, cr oss-c hec ki n g wit h s o urce d oc u me nts, a n d 
clarificati o n of a d mi nistrati ve matters will be perf or me d. T he re vie w of m e dical rec or ds will be 
perf or me d i n a ma n ner t o e ns ure t hat s u bject c o nfi de ntialit y is mai ntai ne d.  
T he S p o ns or  a n d/ or desi g nee  will e ns ure t h at t he i n vesti gati o n is c o n d ucte d acc or di n g t o 
pr ot oc ol desi g n a n d re g ul at or y re q uir e me nts b y fre q ue nt c o m m u nicati o ns (letter, tele p h o ne, e -
mail, a n d fa x).  
All u n use d st u d y dr u g a n d ot her st u d y mat erials s h o ul d be destr o ye d o r ret ur ne d t o t he S p o ns or 
or desi g n ee after t h e st u d y has b ee n c o m plet e d, as directe d b y t he S p o ns or.  
Re g ulat or y a ut h orities, t he I R B/I E C, a n d/ or t h e S p o ns or’s cli nical q ualit y ass ura nce gr o u p or 
desi g nee ma y re q uest a ccess t o all s o urce d oc u m e nts, e C R Fs, a n d ot her st u d y d oc u m e ntati o n f or 
a n o n-site a u dit or i ns pecti o n. Direct access t o t hese d oc u me nts m ust be g u ara ntee d b y t he 
I n v esti gat or, w h o m ust pr o vi de s u p p ort at all ti mes f or t hese acti vities. 
1 3. 9.  
Rec or d Rete nti o n  
T he I n vesti gat or will mai ntai n all st u d y  rec or ds acc or di n g t o I C H-G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s). Rec or ds will be retai ne d f or at least 2 years aft er t he last m ar keti n g a p plicati o n 
a p pr o val or 2 years after f or mal disc o nti n uati o n of t he cli nical de vel o p me nt of t he i n vesti gati o nal 
p r o d uct or acc or di n g t o a p plica ble re g ulat or y re q uire me nt(s). If t he I n vesti gat or wit h dra ws fr o m 
t he res p o nsi bilit y of kee pi n g t he st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o 
acce pt t he res p o nsi bilit y. T he S p o ns or m ust be n otifie d i n w riti n g if a c ust o dial c ha n ge o cc urs. 
1 3. 1 0.  
Li a bilit y a n d I ns ur a nce  
T he S p o ns or has s u bscri be d t o a n i ns ura nce p olic y c o v eri n g, i n its ter ms a n d pr o visi o ns, its le gal 
lia bilit y f or i nj uries ca us e d t o partici pati n g pers o ns a n d arisi n g o ut of t his researc h perf or med 
strictl y i n acc or da n ce wit h t he scie ntific pr ot oc ol as well as wit h a p plica ble la w a n d pr ofessi o nal 
sta n dar ds.  
1 3. 1 1.  
P u blic ati o n of St u d y Fi n di n gs a n d Use of I nf or m ati o n  
All i nf or mati o n re gar di n g A G -1 2 0 s u p plie d b y t he S p o ns or or desi g nee t o t he I n v esti gat or is 
pri vile ge d a n d c o nfi de ntial i nf or mati o n. T he I n v esti gat or a grees t o use t his i nf or mati o n t o 
acc o m plis h t he st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut c o nse nt fr o m t he S p o ns or. It 
is u n derst o o d t hat t here is a n o bli gati o n t o pr o vi de t he S p o ns or wit h c o m plete data o btai ne d 
d uri n g t he st u d y. T he i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he 

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de vel o p me nt of A G -1 2 0 a n d a c o m pa ni o n dia g n ostic de vice a n d ma y be dis cl ose d t o re g ulat or y 
a ut h orit y(i es), ot her I n vesti gat ors, c or p ora te part n ers, or c o ns ulta nts as re q uire d. 

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1 4.  
LI S T O F R E F E R E N C E S  
 
Aar o ns o n N, A h me dzai S, Ber g ma n B, B ulli n ger M, C ull A, D uez N. T he E ur o pea n 
Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q L Q -C 3 0: a q ualit y -of -life 
i nstr u me nt f or use i n inter nati o nal cli nical trials i n o nc ol o g y. J N atl C a ncer I nst. 
1 9 9 3; 8 5( 5): 3 6 5 -3 7 6.  
A mler S, Sa uerla n d M C, Deiters C, B ü c h ner T, Sc h u mac her A. Fact ors i nfl ue nci n g life 
satisfacti o n i n ac ute m yel oi d le u ke mia s ur vi v ors f oll o wi n g all o ge nei c ste m cell 
tra ns pla ntati o n: a cr oss -s ecti o nal st u d y. He alt h Q u al Life O utc o mes. 2 0 1 5; 1 3( 1): 2 8.  
A p pel ba u m F R, G u n d ac ker H, H ea d D R, et al. A ge a n d ac ute m yel oi d le u ke mia. Bl o o d. 
2 0 0 6; 1 0 7( 9): 3 4 8 1 -3 4 8 5.  
B uc h ner T, Ber del W E, Haferlac h C, et al. A ge -relate d ris k pr ofile a n d c h e m othera p y d ose 
res p o nse i n ac ute m yel oi d le u ke mia: a st u d y b y t h e Ger ma n Ac ute M yel oi d Le u k e mia 
C o o perati ve Gr o u p. J Cli n O nc ol. 2 0 0 9; 2 7( 1): 6 1 -6 9.  
B ur nett A K, Milli ga n D, Pre ntice A G, et al. A c o m paris o n of l o w -d ose c yt ara bi ne a n d 
h y dr o x y urea wit h or wit h o ut all -tra ns reti n oic aci d f or ac ut e m yel oi d le u ke mia a n d hi g h-
ris k m yel o d ys plastic s y n dr o me i n patie nts n ot c o nsi dere d fit f or i nte nsi ve treat me nt. 
C a ncer. 2 0 0 7; 1 0 9( 6): 1 1 1 4 -1 1 2 4.  
B ur nett A K, R ussell N H, Hills R K, et al. A d diti o n of ge mt uz u ma b oz o ga mici n t o i n d ucti o n 
c he m ot hera p y i m pr o ves s ur vi val i n ol der patie nts wit h ac ute m yel oi d le u ke mia. J Cli n 
O nc ol. 2 0 1 2; 3 0( 3 2): 3 9 2 4 -3 9 3 1.  
B ur nett A K, R ussell N H, H u nter A E, et al. Cl ofara bi ne d o u bles t he res p o nse rate i n ol der 
patie nts wit h ac ute m yel oi d le u ke mia b ut d oes n ot i m pr o ve s ur vi val. Bl o o d. 
2 0 1 3; 1 2 2( 8): 1 3 8 4 -1 3 9 4.  
C he n Y, Li u L, Laille E, K u mar G, S ura p a ne ni S. I n vitr o assess me nt of c yt oc hr o me P 4 5 0 
i nhi biti o n a n d i n d ucti o n p ote ntial of azaciti di ne. C a ncer C he m ot her P h ar m ac ol. 
2 0 1 0; 6 5( 5): 9 9 5 -1 0 0 0.  
C hes o n B D, 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, Trea t me nt 
O utc o mes, a n d Re p orti n g Sta n dar ds f or T h era p e utic Trials i n Ac ute M yel oi d Le u k e mia. J 
Cli n O nc ol. 2 0 0 3; 2 1( 2 4): 4 6 4 2 -4 6 4 9.  
C h o w d h ur y R, Y e o h K K, Tia n Y M, et al. T he o n c o meta b olite 2 -h y dr o x y gl utarate i n hi bits 
hist o ne l ysi ne de met h ylases. E M B O Re p. 2 0 1 1; 1 2( 5): 4 6 3 -4 6 9.  
Da n g L, Ji n S, S u S M. I D H m utati o ns i n gli o ma a n d ac ute m yel oi d le u ke mia. Tre n ds M ol Me d. 
2 0 1 0; 1 6( 9): 3 8 7 -3 9 7.  

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Da n g L, W hite D W, Gr oss S, et al. Ca ncer -ass oci ate d I D H 1 m utati o ns pr o d uce 2 -
h y dr o x y gl utarate. N at ure. 2 0 0 9; 4 6 2( 7 2 7 4): 7 3 9 -7 4 4.  
Desc hler B, d e Witte T, Mertels ma n n R, L u b b ert M. Treat me nt decisi o n -ma ki n g f or ol der 
patie nts wit h hi g h -ris k m yel o d ys plastic s y n dr o m e or ac ute m yel oi d le u ke mia: pr o ble ms 
a n d a p pr oac hes. H a e m at ol o gic a. 2 0 0 6; 9 1( 1 1): 1 5 1 3 -1 5 2 2.  
D ö h ner H, Este y E, Gri m wa de D, et a l. 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; 1 2 9( 4): 4 2 4 -4 4 7.  
D o m bret H, Raff o u x E, Gar di n C. Ac ute m yel oi d le u ke mia i n t he el derl y. Se mi n O nc ol. 
2 0 0 8; 3 5( 4): 4 3 0 -4 3 8.  
D o m bret H, Se y m o u r J F, B utr y m A, et al. I nt er nati o nal p hase 3 st u d y of azaciti di ne vs 
c o n ve nti o nal care re gi me ns i n ol der patie nts wit h ne wl y di a g n ose d A M L wit h > 3 0 % 
blasts. Bl o o d. 2 0 1 5; 1 2 6( 3): 2 9 1 -2 9 9.  
Este y E, Ot h us M, Lee SJ, A p pel ba u m F R, Gale R P. Ne w dr u g a p pr o vals i n ac ute m yel oi d 
le u ke mia: w hat's t he best e n d p oi nt? Le uke mi a. 2 0 1 6; 3 0( 3): 5 2 1 -5 2 5.  
Fe na u x P, A des L. Re vie w of azaciti di ne trials i n I nter me diate -2 -a n d Hi g h -ris k m yel o d ys plastic 
s y n dr o mes. Le u k Res. 2 0 0 9; 3 3 S u p pl 2: S 7 -1 1.  
Fe na u x P, M ufti GJ, Hellstr o m -Li n d ber g E, et al. Azaciti di ne pr ol o n gs o verall s ur vi val c o m pare d 
wit h c o n ve nti o nal care re gi me ns i n el derl y p atie nts wit h l o w b o ne marr o w blast c o u nt 
ac ute m yel oi d le u ke mia. J Cli n O nc ol. 2 0 1 0; 2 8( 4): 5 6 2 -5 6 9.  
Fi g u er oa M E, A b de l-Wa ha b O, L u C, et al. Le u k e mic I D H 1 a n d I D H 2 m utati o ns res ult i n a 
h y per met h yl ati o n p he n ot y p e, disr u pt T E T 2 f u ncti o n, a n d i m pair he mat o p oietic 
differe ntiati o n. C a ncer Cell. 2 0 1 0; 1 8( 6): 5 5 3 -5 6 7.  
Garcia -Ma ner o G, Al mei da A, Gia g o u ni dis A, et al. Desi g n a n d rati o nale of t he Q U A Z A R 
L o w er -Ris k M D S ( A Z A -M D S -0 0 3) trial: a ra n d o mize d p hase 3 st u d y of C C -4 8 6 ( oral 
azaciti di ne) pl us best s u p p orti ve care vs place b o pl us best s u p p orti ve care i n patie nts wit h 
I P S S l o wer-ris k m yel o d ys plastic s y n dr o mes a n d p o or pr o g n osis d ue t o re d bl o o d cell 
tra nsf usi o n-de p e n de nt a n e mia a n d t hr o m b oc yt o pe nia. B M C He m at ol. 2 0 1 6; 1 6: 1 2.  
G ol d ber g S L, Hs u J W, Orr A R, et al. 5 -Azaciti di ne t hera p y i n el d erl y patie nts wit h ac ute 
m yel o ge n o us le u k e mia yiel ds si milar s ur vi val c o m pare d t o 3 + 7 i n d ucti o n c he m ot hera p y 
wit h less tra nsf usi o nal s u p p ort, bactere mias, a n d h os pital da ys [ A S H a bstract]. Bl o o d. 
2 0 0 6; 1 0 8( 1 1): 4 5 6 9.  
Ka ntarjia n H, Ra va n di F, O' Brie n S, et al. I nte nsi v e c he m ot hera p y d oes n ot be nefit m ost ol der 
patie nts (a ge 7 0 years or ol der) wit h ac ut e m yel oi d le u ke mia. Bl o o d. 2 0 1 0; 1 1 6( 2 2): 4 4 2 2 -
4 4 2 9.  
Ka ntarjia n H M, T h o mas X G, D m osz y ns ka A, et al. M ultice nter, ra n d o mize d, o pe n -la bel, p has e 
III trial of d ecita bi ne v ers us patie nt c h oice, wit h p h ysicia n a d vice, of eit her s u p p orti ve 

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care or l o w-d ose c ytar a bi ne f or t he tr eat me nt of ol der patie nts wit h ne wl y dia g n ose d 
ac ute m yel oi d le u ke mia. J Cli n O nc ol. 2 0 1 2; 3 0( 2 1): 2 6 7 0 -2 6 7 7.  
Ker n yts k y A, Wa n g F, H a nse n E, et al. I D H 2 m utati o n -i n d uce d hist o ne a n d D N A 
h y per met h yl ati o n is pr o gressi vel y re v erse d b y s m all -m ole c ule i n hi biti o n. Bl o o d. 
2 0 1 5; 1 2 5( 2): 2 9 6 -3 0 3.  
Kle pi n H D. El derl y ac ute m yel oi d le u ke mia: ass essi n g ris k. C urr He m at ol M ali g Re p. 
2 0 1 5; 1 0( 2): 1 1 8 -1 2 5.  
Lee S H, Er ber W N, P or wit A, T o m o na ga M, Peters o n L C, He mat ol o g y I Cf SI. I C S H g ui deli nes 
f or t he sta n dar dizatio n of b o ne marr o w s p eci me ns a n d re p orts. I nt J L a b He m at ol. 
2 0 0 8; 3 0( 5): 3 4 9 -3 6 4.  
Le mie u x J, G o o d wi n PJ, B or del ea u LJ, La uzier S, T he ber ge V. Q ualit y -of -life meas ure me nt i n 
ra n d o mize d cli nical trials i n breast ca n cer: a n u p date d s yste matic re vie w ( 2 0 0 1-2 0 0 9). J 
N atl C a ncer I nst. 2 0 1 1; 1 0 3( 3): 1 7 8 -2 3 1.  
Le v y A R, Z o u D, Rise br o u g h N, B uc kste i n R, Ki m T, Breret o n N. C ost-effecti ve ness i n Ca n a da 
of azaciti di ne f or t he treat me nt of hi g her -ris k m yel o d ys plastic s y n dr o mes. C urr O nc ol. 
2 0 1 4; 2 1( 1):e 2 9 -4 0.  
Li n da H, v o n Heij ne A. A case of p osteri or re versi ble e nce p hal o p at h y s y n dr o me ass ociate d wit h 
Gi le n ya®  (fi n g oli m o d) treat me nt f or m ulti ple scler osis. Fr o nt Ne ur ol. 2 0 1 5; 6: 3 9.  
Marc ucci G, Ma h arr y K, W u Y Z, et al. I D H 1 a n d I D H 2 ge n e m utati o ns i de ntif y n o vel m olec ul ar 
s u bsets wit hi n de n o v o c yt o ge n eticall y n or mal ac ute m yel oi d le u ke mia: a Ca ncer a n d 
Le u k e mia Gr o u p B st u d y. J Cli n O nc ol. 2 0 1 0; 2 8( 1 4): 2 3 4 8 -2 3 5 5.  
Mar dis E R, Di n g L, D o oli n g DJ, et al. Rec urri n g m utati o ns f o u n d b y se q u e nci n g a n ac ute 
m yel oi d le u ke mia ge n o me. N E n gl J Me d. 2 0 0 9; 3 6 1( 1 1): 1 0 5 8 -1 0 6 6.  
Mar q ues da Sil va P, Haa g U, G u est J F, Brazier J E , S or o M. Healt h-rel ate d q ualit y of life i m pact 
of a tri ple c o m bi nati o n of ol mesarta n me d o x o mil, a ml o di pi ne bes ylat e a n d 
h y dr oc hl or otiazi de i n s u bjects wit h h y perte nsi o n. He alt h Q u al Life O utc o mes. 
2 0 1 5; 1 3: 2 4.  
N C C N Cli nic al Pr actice G ui deli nes i n O nc ol o gy ( N C C N G ui deli nes® ) Ac ute Myel oi d Le uke mi a 
( V ersi o n 1. 2 0 1 7). Nati o n al C o m pre he nsi ve Ca ncer Net w or k; 2 4 Fe br uar y 2 0 1 7. 
N C C N Cli nic al Pr actice G ui deli nes i n O nc ol o gy ( N C C N G ui deli nes ® ) Ac ute Myel oi d Le uke mi a 
( V ersi o n 2. 2 0 1 8). Nati o n al C o m pre he nsi ve Ca ncer Netw or k; A u g ust 2 0 1 8.  
Nati o nal Ca ncer I nstit ute, S ur veilla nce, E pi de mi ol o g y, a n d E n d Res ults ( S E E R) Pr o gra m. 
Ca ncer statistics facts heets: ac ute m yel oi d le u ke mia. Nati o nal Ca ncer I nstit ute, 
S ur veilla nce, E pi de mi ol o g y, a n d E n d Res ults ( S E E R) Pr o gra m we bsite. 
htt ps://seer.ca ncer. g o v/statfacts/ ht ml/a m yl. ht ml . Access e d 2 4 Marc h 2 0 1 5. 

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Ora n B, Weis d orf DJ. S ur vi val f or ol der p atie nts wit h ac ute m yel oi d le u ke mia: a p o p ulati o n -
base d st u d y. H ae m at ol o gic a.  2 0 1 2; 9 7( 1 2): 1 9 1 6 -1 9 2 4.  
Ot h us M, va n P utte n W, L o w e n ber g B, et al. Relati o n hi p bet wee n e ve nt -free s ur vi val a n d o verall 
s ur vi val i n ac ute m yel oi d le u ke mia: A re p ort fr o m S W O G, H O V N/ S A K K, a n d 
M R C/ N C RI. H a e m at ol o gic a. 2 0 1 6.  
Pic kar d A S, Near y M P, Cella D. Esti mati o n of mi ni mall y i m p orta nt differe nces i n E Q -5 D utilit y 
a n d V A S sc ores i n ca ncer. He alt h Q u al Life O utc o mes. 2 0 0 7; 5: 7 0.  
Ple yer L, B ur gstaller S, Sta u der R, et al. Azaciti di ne i n patie nts wit h rela ps e d/refract or y ac ute 
m yel oi d le u ke mia: r etr os pecti ve a n a l ysis of t he A ustria n Azaciti di ne Re gistr y. Bl o o d. 
2 0 1 4; 1 2 4( 2 1): 9 4 3 -9 4 3.  
Ple yer L, Sta u der R, B ur gstaller S, et al. Azaciti di ne i n patie nts wit h W H O -defi ne d A M L - 
res ults of 1 5 5 patie nts fr o m t he A ustria n Azaciti di ne Re gistr y of t he A G M T-St u d y 
Gr o u p. J H e mat ol O nc ol. 2 0 1 3; 6: 3 2.  
R A R E C A R E. S ur veilla nce of rare ca n cers i n E ur o pe: c h ola n gi ocarci n o ma. R A R E C A R E 
we bsite. htt p:// w w w.rarecare. e u/ . Accesse d 2 0 1 6. 
Rizz o J D, Br o u wers M, H urle y P, et al. A meri ca n S ociet y of He mat o l o g y/ A merica n S ociet y of 
Cli nical O nc ol o g y cli nic al practice g ui deli ne u p date o n t he use of e p oeti n a n d 
dar be p oeti n i n a d ult patie nts wit h ca ncer. Bl o o d. 2 0 1 0; 1 1 6( 2 0): 4 0 4 5 -4 0 5 9.  
R u de k M A, Z h a o M, He P, et al. P har mac o ki netics of 5 -azaciti di ne a d mi nistere d wit h 
p he n yl b ut yrate i n patie nts wit h refract or y s oli d t u m ors or he mat ol o gi c mali g na n cies. J 
Cli n O nc ol. 2 0 0 5; 2 3( 1 7): 3 9 0 6 -3 9 1 1.  
Sie vers E L, Lars o n R A, Sta dt ma uer E A, et al. Efficac y a n d s afet y of ge mt uz u ma b oz o ga mici n i n 
patie nts wit h C D 3 3 -p ositi ve ac ute m yel oi d le u ke mia i n first rela pse. J Cli n O nc ol. 
2 0 0 1; 1 9( 1 3): 3 2 4 4 -3 2 5 4.  
Sil ver ma n L R, Mc K e nzie D R, Peters o n B L, et al. F urt her a n al ysis of trials wit h azaciti di ne i n 
patie nts wit h m yel o d ys pl astic s y n dr o me: st u dies 8 4 2 1, 8 9 2 1, a n d 9 2 2 1 b y t he Ca ncer a n d 
Le u k e mia Gr o u p B. J Cli n O nc ol. 2 0 0 6; 2 4( 2 4): 3 8 9 5 -3 9 0 3.  
S perr W R, Piri ba uer M, Wi mazal F, et al. A n o vel effecti ve a n d safe c o ns oli dati o n f or patie nts 
o ver 6 0 years wit h ac ute m yel oi d le u ke mia: i nter me diate d ose c ytara bi ne ( 2 x 1 g/ m 2 o n 
da ys 1, 3, a n d 5). Cli n C a ncer Res. 2 0 0 4; 1 0( 1 2 Pt 1): 3 9 6 5 -3 9 7 1.  
S pra n gers M A, C ull A, Bj or dal K, Gr oe n v ol d M, Aar o ns o n N K. T he E ur o pea n Or ga nizati o n f or 
Researc h a n d Treat me nt of Ca ncer. A p pr oac h t o q ualit y of life assess me nt: g ui deli nes f or 
de vel o pi n g q u esti o n naire m o d ules. E O R T C St u d y Gr o u p o n Q ualit y of Lif e. Q u al Life 
Res. 1 9 9 3; 2( 4): 2 8 7 -2 9 5.  
T he p ot S, Itz y ks o n R, See gers V, et al. Azaciti di ne i n u ntreate d ac ute m yel oi d le u ke mia: a re p ort 
o n 1 4 9 patie nts. A m J He m at ol. 2 0 1 4; 8 9( 4): 4 1 0 -4 1 6.  

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Ti mils hi na N, Bre u nis H, T o mli ns o n G, Bra n d wei n J, Ali b hai S M. D o q ualit y of life, p h ysic al 
f u ncti o n, or t he W heatle y i n de x at dia g n osis pre dict 1-year m ortalit y wit h i nte nsi ve 
c he m ot hera p y i n ol der ac ute m yel oi d le u ke mia patie nts? Le uk Res. 2 0 1 6; 4 7: 1 4 2 -1 4 8.  
Tsai H C, Li H, V a n Nest e L, et al. Tra nsie nt l o w d oses of D N A -de met h ylati n g a ge nts e x e rt 
d ura ble a ntit u m or effects o n he mat ol o gical a n d e pit helial t u m or cells. C a ncer Cell. 
2 0 1 2; 2 1( 3): 4 3 0 -4 4 6.  
Ts u ka da Y, Fa n g J, Er dj u me nt -Br o ma ge H, et al. Hist o ne de met h yl ati o n b y a fa mil y of J mj C 
d o mai n -c o ntai ni n g pr otei ns. N at ure. 2 0 0 6; 4 3 9( 7 0 7 8): 8 1 1 -8 1 6.  
T urca n S, R o hle D, G o e n ka A, et al. I D H 1 m utati o n is s ufficie nt t o esta blis h t he gli o ma 
h y per met h yl at or p he n ot y pe. N at ure. 2 0 1 2; 4 8 3( 7 3 9 0): 4 7 9 -4 8 3.  
Vi daza. Pac ka ge I nsert. I n. S u m mit, NJ: Cel ge ne C or p orati o n; 2 0 1 5.  
Visser O, Tra ma A, Ma y na die M, et al. I n ci de nce, s ur vi val a n d pre v ale nce of m yel oi d 
mali g na n cies i n E ur o pe. E ur J C a ncer. 2 0 1 2; 4 8( 1 7): 3 2 5 7 -3 2 6 6.  
War d P S, Patel J, Wise D R, et al. T he c o m m o n feat ure of le u ke mia -ass oci ate d I D H 1 a n d I D H 2 
m utati o ns is a ne o m or p hic e nz y me acti vit y c o n verti n g al p ha -k et o gl utarate t o 2 -
h y dr o x y gl utarate. C a ncer Cell. 2 0 1 0; 1 7( 3): 2 2 5 -2 3 4.  
Westfall P H, Kris he n A. O pti mall y wei g hte d, fi x e d se q ue nce, a n d gate kee pi n g m ulti ple testi n g 
pr oce d ures. J St at Pl a n I nfere nce. 2 0 0 1; 9 9: 2 5 -4 0.  
Ya ma ne K, T o u maz o u C, Ts u ka da Y, et al. J H D M 2 A,  a J mj C -c o ntai ni n g H 3 K 9 de met h ylase, 
facilitates tra nscri pti o n acti vati o n b y a n dr o ge n rece pt or. Cell. 2 0 0 6; 1 2 5( 3): 4 8 3 -4 9 5.  
Ye n K E, Bitti n ger M A, S u S M, Fa nti n V R. Ca ncer -ass ociate d I D H m utati o ns: bi o mar ker a n d 
t hera pe utic o p p ort u nities. O nc o ge ne. 2 0 1 0; 2 9( 4 9): 6 4 0 9 -6 4 1 7.  
 

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1 5.  
A P P E N DI C E S  
1 5. 1.  
Re prese nt ati ve E x a m ples of L o w -F at or Hi g h -F at, Hi g h -C al orie 
Me als  
Re prese ntati ve l o w -fat br ea kfasts: 
a. 2 slices of w hite brea d t o ast, 1 ta bles p o o n li g ht fat mar gari ne, 1 t a bles p o o n of jell y, 
a n d 8 o u nces of s ki m mil k ( 3 1 9 cal ori es a n d 8. 2 gra ms of fat).  
b.  1 c u p of cereal, 1 slice of t oast wit h ja m, 8 o u nces of s ki m mil k, a n d 1 c u p of 
decaffei nat e d c offee or tea ( 5 2 0 cal ories a n d 2 gra ms of fat).  
A re prese ntati ve hi g h -fat brea kfast c o nsists of t he f oll o wi n g, a n d ma y b e a d a pte d t o t he l ocal 
re gi o nal prefere nce: 2 e g gs frie d i n b utter, 2 stri ps of bac o n, 2 slices of w hite brea d wit h b utter, 
1  cr oissa nt wit h 1 slice of c hees e, a n d 8 o u n ces of w h ole mil k. T his re prese ntati ve hi g h -fat 
brea kfast c o ntai ns a p pr o xi matel y 1 0 0 0 cal ories a n d 5 8 gra ms of fat.  
1 5. 2.  
Ne w Y or k He art Ass oci ati o n Cl assific ati o n  
 
Cl ass  
S y m pt o m at ol o g y  
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, or a n gi nal pai n. 
II 
Sli g ht li mitati o n of p h ysical acti vit y.  C o mf orta ble at rest, b ut 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, or a n gi nal pai n. 
III 
Mar ke d li mitati o n of p h ysical acti vit y. C o mf orta ble at rest, b ut less t ha n or di nar y 
acti vit y res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
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 at rest. If a n y 
p h ysical acti vit y is u n derta ke n, disc o mf ort is i ncrease d.  
S o urce: T he Criteria C o m mittee of t h e Ne w Y or k Heart Ass ociati o n. N o me nclat ure a n d Criteria f or Dia g n osis of Diseases of t h e 
Heart a n d Great V essels. 9t h e d. B ost o n, Mass: Little, Br o w n & C o; 1 9 9 4: 2 5 3 -2 5 6.  
1 5. 3.  
Pre p ar ati o n a n d A d mi nistr ati o n of Az aciti di ne  
1 5. 3. 1.  
S u bc ut a ne o us A d mi nistr ati o n of Az aciti di ne  
Rec o nstit uti o n:  Azaciti di ne de gra d es ra pi dl y at r o o m t e m perat ure f oll o wi n g rec o nstit uti o n; 
t heref ore, t he azaciti di ne s us pe nsi o n s h o ul d be pre pare d i m me diatel y bef ore use or s h o ul d be 
refri gerate d i m me diatel y after rec o nstit uti o n. 
Azaciti di ne m ust be rec o nstit ute d t o f or m a u nif or m s us pe nsi o n pri or t o a d mi nis trati o n. 
Ase pticall y a d d 4 m L of steriliz e d water f or i njecti o n sl o wl y i nt o t he vial. Vi g or o usl y s ha k e or 
r oll t he vial u ntil a u nif or m, cl o u d y s us pe nsi o n is ac hie ve d. T h e res ulti n g azaciti di ne 
c o nce ntr ati o n will be 2 5 m g/ m L. D o n ot filter t he s us pe nsi o n a fter rec o nstit uti o n as t his c o ul d 
re m o ve t he acti ve s u bsta nce. 
If a d ose i n e x cess of 1 0 0 m g ( 4 m L) is re q uire d, re peat t he a b o ve ste p f or pre parati o n of t he 
s us pe nsi o n. D oses great er t ha n 4 m L s h o ul d be e q uall y di vi de d i nt o 2 s yri n ges a n d i njecte d i nt o 
2 se parat e sites. F or e x a m ple a d ose of 1 5 0 m g (fi nal s us pe nsi o n v ol u me = 6 m L) s h o ul d be 

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e q uall y di vi de d i nt o 2 s yri n ges wit h 3 m L s us pe nsi o n i n eac h. All s yri n ges s h o ul d be pre pare d 
pri or t o starti n g a d mi nistrati o n.  
Azaciti di ne is s u p plie d i n si n gle -us e via ls t hat c a n n ot be use d m ore t ha n o nce.  
S u bc ut a ne o us A d mi nistr ati o n:  T o pr o vi de a h o m o ge n e o us s us pe nsi o n, t he c o nte nts of t he 
d osi n g s yri n ge m ust be re -s us pe n de d i m me diatel y pri or t o a d mi nistrati o n. T o re-s us pe n d, 
vi g or o usl y r oll t he s yri n ge bet wee n t he pal ms u ntil a u nif or m, cl o u d y s us pe nsi o n is ac hie ve d.  
F or S C d osi n g, r otat e sites f or eac h i njecti o n (t hi g h, a b d o me n, or u p per ar m). Ne w i njecti o ns 
s h o ul d be gi ve n at least 1 i nc h ( 2. 5 c m) fr o m t he pre vi o us site a n d ne ver i nt o areas w here t he site 
is te n der, br uise d, re d, or har d. S u bc uta ne o us d os es greater t h a n 1 0 0 m g ( 4 m L) s h o ul d be 
di vi de d e q uall y i nt o 2 s yri n ges a n d i njecte d i nt o 2 se parat e sites.  
S us pe nsi o n St a bilit y:  Azaciti di ne rec o nstit ute d f or S C a d mi nistrati o n s h o ul d be st ore d as 
directe d o n t he la b el.  
1 5. 3. 2.  
I ntr a ve n o us A d mi nistr ati o n of Az aciti di ne 
Rec o nstit uti o n:  Rec o nstit ute t he a p pr o priate n u m ber of vials t o ac hi e ve t h e desire d d ose. 
Rec o nstit ute eac h vial wit h 1 0 m L of sterile water f or i njecti o n. Vi g or o usl y s ha ke or r oll t he vial 
u ntil all s oli ds are diss ol ve d. T he res ulti n g s ol uti o n will c o ntai n azaciti di ne 1 0 m g/ m L. T he 
s ol uti o n s h o ul d be clear. Pare nteral dr u g pr o d uct s h o ul d be i ns pecte d vis uall y f or p artic ulate  
matter a n d disc ol orati o n pri or t o a d mi nistrati o n, w he ne ver s ol uti o n a n d c o ntai ner per mit.  
Wit h dra w t he re q uire d a m o u nt of azaciti di ne s ol uti o n t o deli ver t he desire d d ose a n d i nject i nt o a 
5 0 t o 1 0 0 m L i nf usi o n ba g of eit her 0. 9 % S o di u m C hl ori de I njecti o n  or Lactate d Ri n ger’s 
I nje cti o n. 
I ntr a ve n o us S ol uti o n I nc o m p ati bilit y: T his me dici nal pr o d uct m ust n ot be mi x e d wit h ot her 
me dici nal pr o d ucts. Azaciti di ne is i nc o m pati ble wit h de xtr ose s ol uti o ns, Hes pa n, or s ol uti o ns 
t hat c o ntai n bicar b o nate. T hese s ol uti ons ha ve t he p ote ntial t o i ncrease t he rate of de gra dati o n of 
azaciti di ne a n d s h o ul d t heref ore be a v oi de d.  
I ntr a ve n o us A d mi nistr ati o n: A d mi nister t he t otal d ose o ver a peri o d of 1 0 t o 4 0 mi n utes. T he 
a d mi nistrati o n m ust be c o m plete d wit hi n 4 5 mi n utes of rec o nstit uti o n.  
S ol uti o n St a bilit y:  Azaciti di ne rec o nstit ute d f or I V a d mi nistrati o n s h o ul d be st ore d as directe d 
o n t he la bel.  

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1 5. 4.  
Az aciti di ne D ose M o dific ati o ns d ue t o He m at ol o gic T o xicit y  
 
 
 

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1 5. 5.  
Me dic ati o ns K n o w n t o Pr ol o n g t he Q T I nter v al  
 
A mi o dar o ne  
D olasetr o n  
Hal o peri d ol  
O n da nsetr o n  
T erfe na di ne  
Aste miz ole  
D o m peri d o ne  
I b utili de  
P al o n osetr o n  
T hi ori dazi ne  
Azit hr o m yci n  
Dr o peri d ol  
Itrac o naz ole  
P e nta mi di ne  
V oric o naz ole  
B e pri dil  
Er yt hr o m yci n  
Ket oc o naz ole  
Pi m ozi de  
 
C hl or o q ui ne  
Escital o pra m  
Le v ofl o xaci n  
P osac o naz ole  
 
C hl or pr o mazi ne  
Flecai ni de  
Le v o met ha d yl  
Pr o b uc ol  
 
Ci pr ofl o xaci n  
Gatifl o xaci n  
Mes ori dazi ne  
Pr ocai na mi de  
 
Cital o pra m  
Ge mifl o xaci n  
Met ha d o ne  
Q ui ni di ne  
 
Clarit hr o m yci n  
Gra nisetr o n  
M o xifl o xaci n  
Se v ofl ura ne  
 
Dis o p yra mi de  
Gre p afl o xaci n  
N orfl o xaci n  
S otal ol  
 
D ofetili de  
Hal ofa ntri ne  
Ofl o xaci n  
S parfl o xaci n  
 
N ote t hat t his is n ot a n e x ha usti ve list. F or a n u p date d list, see t h e f oll o wi n g li n k:  
htt ps://cre di ble me ds. or g/ h ealt hcare -pr o vi d ers/ 
1 5. 6.  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
 
Pr o hi bite d me dic ati o ns a n d cert ai n f o o ds are n ot all o w e d i n t his st u d y ( Scree ni n g Pe ri o d t hr o u g h E n d of 
Tre at me nt) w hile s u bjects are recei vi n g st u d y dr u g.  
Str o n g C Y P 3 A I n d ucers 
C Y P 3 A S u bstr ates Wit h a N arr o w T her a pe utic I n de x  
A vasi mi be, car ba maze pi ne, p he n yt oi n, 
rifa m pi n, rifa b uti n, St. J o h n’s w ort 
Alfe nta nil, aste miz ole( 1), c ycl os p ori ne, di h y dr oer g ota mi ne, 
er g ota mi ne, fe nta n yl, pi m ozi de, q ui ni di ne, e ver oli m us, 
sir oli m us, tacr oli m us, terfe na di ne( 1) 
A b bre viati o ns: C Y P = c yt o c hr o me P 4 5 0.  
N ote t hat t his is n ot a n e x ha usti ve list. F or a n u p date d list, see t h e f oll o wi n g li n k: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns La beli n g/ u c m 0 9 3 6 6 4. ht m 
C Y P s u bstrates wit h narr o w t h era pe utic ra n ge  refers t o dr u gs w h ose e x p os ure-res p o nse relati o ns hi p i n dicates t h at s mall i n creases 
i n t heir e x p os ure le vels b y t h e c o nc o mita nt use of C Y P i n hi bit ors ma y lea d t o seri o us safet y c o ncer ns (e g, T orsa des d e P oi ntes).  
1  Wit h dra w n fr o m t h e U nite d States mar ket beca use of safet y re as o ns.  

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1 5. 7.  
M o der ate a n d Str o n g C Y P 3 A 4 I n hi bit ors  
 
M o der ate C Y P 3 A 4 I n hi bit ors  
A pre pita nt, ci meti di ne, ci pr ofl o xaci n, cl otri maz ole, criz oti ni b, c ycl os p ori ne, dr o ne dar o ne, er yt hr o m yci n, 
fl uc o naz ole, fl u v o xa mi ne, i mati ni b, t ofis o pa m, vera pa mil 
Str o n g C Y P 3 A 4 I n hi bit ors  
B oce pre vir, clarit hr o m yci n, c o ni va pta n, gra p efr uit j uice, i n di na vir, itrac o naz ole  
Ket o c o naz ole, l o pi na vir/rit o na vir, mi befra dil, nefaz o d o ne, nelfi na vir, p osa c 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  
N ote: Base d o n F D A g ui d eli nes; I n vesti gat ors s h o ul d f oll o w l o cal i nstit uti o nal g ui d eli nes, w here a p pr o priate.  
1 5. 8.  
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 ori n g  
 
Gr a de  
S y m pt o m at ol o g y  
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 d e 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 self -care 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 p a ble of o nl y li mite d self -c are, c o nfi 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 self -care. T otall y c o nfi ne d t o be d or c hair  
5  
Dea d  
S o urce: O ke n M M, Creec h R H, T or me y D C, H ort o n J, Da vis T E, Mc Fa d de n E T, et al. T o xicit y a n d Res p o nse Criteria of t h e 
Easter n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol.  1 9 8 2; 5: 6 4 9 -6 5 5.  
1 5. 9.  
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  
T he N CI C T C A E, versi o n 4. 0 3, ca n be accesse d usi n g t he f oll o wi n g li n k:  
htt p://e vs nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0 -0 6 -1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df  

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1 5. 1 0.  
Decl ar ati o n of Helsi n ki  
W O R L D M E DI C A L A S S O CI A TI O N D E C L A R A TI O N O F H E L SI N KI:  
Rec o m me n dati o ns G ui di n g Me dic al D oct ors i n Bi o me dical Researc h I n v ol vi n g H u ma n S u bjects  
A d o pte d b y t h e 1 8 t h W orl d Me dical Ass ociati o n ( W M A) Ge neral Asse m bl y, Helsi n ki, Fi nla n d, 
J u ne 1 9 6 4 a n d a me n de d b y t he 2 9 t h W M A Ge neral Asse m bl y, T o k y o, J a pa n, Oct o ber 1 9 7 5, 3 5
t h 
W M A Ge neral Asse m bl y, Ve nice, It al y, Oct o ber 1 9 8 3, a n d t he 4 1
st W M A Ge neral Asse m bl y, 
H o n g K o n g, Se pt e m ber 1 9 8 9, t he 4 8 t h W M A Ge neral Asse m bl y, S o merset West, Re p u blic of 
S o ut h Africa, Oct o b er 1 9 9 6; 5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0; 
5 3r d W M A Ge neral Asse m bl y, Was hi n gt o n 2 0 0 2 ( N ote of Clarificati o n o n para gra p h 2 9 a d d e d); 
5 5t h W M A Ge neral Asse m bl y, T o k y o 2 0 0 4 ( N ote of Clarificati o n o n Para gra p h 3 0 a d de d); a n d 
5 9t h W M A Ge neral  Asse m bl y, Se o ul, Oct o ber 2 0 0 8, 6 4t h W M A Ge neral Asse m bl y, F ortaleza, 
Brazil, Oct o ber 2 0 1 3.  
Prea m ble  
1.  T he W orl d Me dical Ass o ciati o n ( W M A) has de vel o pe d t he Declarati o n of Helsi n ki as a 
state me nt of et hical pri n ci ples f or me dical r esearc h i n v ol vi n g h u ma n s u b jects, i ncl u di n g 
researc h o n i de ntifia bl e h u ma n material a n d d ata. 
T he Decl arati o n is i nte n d e d t o be rea d as a w h ole a n d eac h of its c o nstit ue nt para gra p hs 
s h o ul d be a p plie d wit h c o nsi derati o n of all ot her rele va nt para gra p hs.  
2.  C o nsiste nt wit h t he ma n date o f t he W M A, t he Declarati o n is a d dresse d pri maril y t o 
p h ysicia ns. T h e W M A e nc o ura ges ot h ers w h o are i n v ol ve d i n me dical researc h i n v ol vi n g 
h u ma n s u bjects t o a d o pt t hese pri nci ples.   
Ge neral Pri nci ples  
3.  T he Decl arati o n of G e ne va of t he W M A bi n ds t he p h ysicia n  wit h t he w or ds, “ T he healt h 
of m y s u bject will be m y first c o nsi derati o n,” a n d t he I nter n ati o nal C o de of Me dical 
Et hics declares t hat, “ A p h ysicia n s h all act i n t he s u bject's b est i nterest w he n pr o vi di n g 
me dical care.”  
4.  It is t he d ut y of t he p h ysi cia n t o pr o m ote a n d safe g uar d t he healt h, well-bei n g, a n d ri g hts 
of s u bjects, i ncl u di n g t h ose w h o are i n v ol ve d i n me dical res earc h. T he p h ysicia n's 
k n o wle d ge a n d c o nscie n ce are de dicate d t o t he f ulfil me nt of t his d ut y.  
5.  Me dical pr o gress is base d o n researc h t hat ult i matel y m ust i ncl u de st u dies i n v ol vi n g 
h u ma n s u bjects.  
6.  T he pri mar y p ur p os e of me dical res earc h i n v ol vi n g h u ma n s u bjects is t o u n dersta n d t he 
ca uses, de v el o p me nt, a n d effects of diseas es a n d i m pr o ve pre v e nti ve, dia g n ostic, a n d 
t hera pe utic i nter ve nti o ns ( meth o ds, pr oce d ures, a n d treat me nts). E ve n t h e b est pr o ve n 
i nter ve nti o ns m ust be e val uate d c o nti n uall y t hr o u g h researc h f or t heir safet y, 
effecti ve ness, efficie n c y, accessi bilit y, a n d q ualit y.  
7.  Me dical res earc h is s u bje ct t o et hical sta n dar ds t hat pr o m ote a n d e ns ure res pect f or all 
h u ma n s u bjects a n d pr ote ct t heir healt h a n d ri g hts.  

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8.  W hile t he pri mar y p ur p ose of me dical r esearc h is t o ge n erate ne w k n o wle d ge, t his g oal 
ca n ne v er ta ke prece de n ce o ver t he ri g hts a n d i nterests of i n di vi d ual researc h s u bjects.  
9.  It is t he d ut y of p h ysicia ns w h o are i n v ol ve d i n me dical researc h t o pr otect t he life, 
healt h, di g nit y, i nte grit y, ri g ht t o self -d eter mi nati o n, pri vac y, a n d c o nfi de ntialit y of 
pers o nal i nf or mati o n of researc h s u bjects. T he res p o nsi bilit y f or t h e pr otecti o n of 
researc h s u bjects m ust al wa ys rest wit h t he p h ysicia n or ot her healt h care pr ofessi o nals 
a n d ne ver wit h t he researc h s u bjects, e ve n t h o u g h t he y h a ve gi ve n c o nse nt.  
1 0.  P h ysicia ns m ust c o nsi der t he et hical, le gal, a n d re g ulat or y n or ms a n d sta n d ar ds f or 
researc h in v ol vi n g h u m a n s u bjects i n t heir o w n c o u ntries as well as a p plica ble 
i nter nati o nal n or ms a n d sta n dar ds. N o nati o nal or i nter nati o nal et hical, le gal, or 
re g ulat or y re q uire me nt s h o ul d re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h 
s u bjects set f ort h i n t his Declarati o n. 
1 1.  Me dical res earc h s h o ul d be c o n d ucte d i n a ma n ner t hat mi ni mizes p ossi ble har m t o t he 
e n vir o n me nt.  
1 2.  Me dical res earc h i n v ol vi n g h u ma n s u bjects m ust be c o n d ucte d o nl y b y i n di vi d uals wit h 
t he a p pr o priat e et hics a n d scie ntific e d ucati o n, trai ni n g a n d q ualificati o ns. Researc h o n 
s u bjects or healt h y v ol u nteers re q uires t he s u per visi o n of a c o m pete nt a n d a p pr o priatel y 
q ualifie d p h ysi cia n or ot her healt h care pr ofessi o nal.  
1 3.  Gr o u ps t hat are u n derre prese nte d i n me dical res earc h s h o ul d be pr o vi de d a p pr o priate 
access t o partici pati o n i n researc h.  
1 4.  P h ysicia ns w h o c o m bi ne me dical res earc h wit h me dical care s h o ul d i n v ol v e t heir 
s u bjects i n researc h o nl y t o t he e xte nt t hat t his is j ustifie d b y its p ote ntial pre ve nti ve, 
dia g n ostic, or t h era p e utic val ue a n d  if t he p h ysici a n has g o o d reas o n t o b elie ve t hat 
partici pati o n i n t he researc h st u d y will n ot a d versel y affect t he healt h of t he s u bjects w h o 
ser ve as researc h s u bjects. 
1 5.  A p pr o priate c o m pe nsati o n a n d treat me nt f or s u bjects w h o are h ar me d as a res ult of 
par tici pati n g i n researc h m ust be e ns ure d. 
Ris ks, B ur de ns a n d Be n efits  
1 6.  I n me di cal pr actice a n d i n me dical res earc h, m ost i nter ve nti o ns i n v ol ve ris ks a n d 
b ur de ns.  
Me dical res earc h i n v ol vi n g h u ma n s u bjects ma y o nl y be c o n d ucte d if t he i m p orta nce of 
t he o bjecti ve o ut wei g hs t he ris ks a n d b ur de ns t o t he researc h s u bj ects.  
1 7.  All me dical researc h i n v ol vi n g h u ma n s u bjects m ust be prece de d b y caref ul assess me nt 
of pre dicta bl e ris ks a n d b ur de ns t o t he i n di vi d uals a n d gr o u ps i n v ol ve d i n t he researc h i n 
c o m paris o n wit h f ore s eea ble be nefits t o t he m a n d t o ot her i n di vi d uals or gr o u ps affecte d 
b y t he c o n diti o n u n der i n vesti gati o n.  
Meas ures t o mi ni mize t he ris ks m ust be i m ple me nte d. T he ris ks m ust be c o nti n u o usl y 
m o nit ore d, assesse d, a n d d oc u me nte d b y t he researc her.   

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1 8.  P h ysicia ns  ma y n ot be i n v ol ve d i n a researc h st u d y i n v ol vi n g h u m a n s u bjects u nless t he y 
are c o nfi de nt t hat t he ris ks ha ve bee n a de q u atel y assesse d a n d ca n be satisfact oril y 
ma na ge d.  
W he n t he ris ks are f o u n d t o o ut wei g h t he p ote ntial be nefits or w he n t here is c o ncl us i ve 
pr o of of defi niti ve o utc o mes, p h ysicia ns m ust ass ess w het her t o c o nti n ue, m o dif y or 
i m me diatel y st o p t he st u d y. 
V ul nera ble Gr o u ps a n d I n di vi d uals  
1 9.  S o me gr o u ps a n d i n di vi d uals are p artic ularl y v ul n era ble a n d ma y ha v e a n i ncreas e d 
li keli h o o d of bei n g wr o nge d or of i nc urri n g a d diti o nal har m.  
All v ul nera ble gr o u ps a n d i n di vi d uals s h o ul d recei ve s pecificall y c o nsi dere d pr otecti o n.  
2 0.  Me dical res earc h wit h a v ul nera ble gr o u p is o nl y j ustifie d if t he researc h is res p o nsi ve t o 
t he healt h nee ds or pri orities of t his gr o u p a n d t h e researc h ca n n ot be carri e d o ut i n a n o n -
v ul nera ble gr o u p. I n a d diti o n, t his gr o u p s h o ul d sta n d t o be nefit fr o m t he k n o wle d ge, 
practices, or i nter ve nti o ns t hat res ult fr o m t he res earc h.  
Scie ntific Re q uire me nts a n d Researc h Pr ot oc ols  
2 1.  Me dical r es earc h i n v ol vi n g h u ma n s u bjects m ust c o nf or m t o ge nerall y acce pte d scie ntific 
pri nci ples, be base d o n a t h or o u g h k n o wl e d ge of t he scie ntific literat ur e, ot her rel e va nt 
s o urces of i nf or mati o n, a n d a de q uate l a b orat or y a n d, as a p pr o pri ate, a ni mal 
e x peri me nta ti o n. T he welfare of a ni mals use d f or researc h m ust be res pect e d. 
2 2.  T he desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u m a n s u bjects m ust be 
clearl y des cri be d a n d j ustifie d i n a researc h pr ot oc ol.  
T he pr ot oc ol s h o ul d c o nt ai n a state me nt of t he et hi cal c o nsi derati o ns i n v ol ve d a n d s h o ul d 
i n dicate h o w t he pri nci pl es i n t his Declarati o n ha v e bee n a d dresse d. T he pr ot oc ol s h o ul d 
i ncl u de i nf or mati o n re gar di n g f u n di n g, s p o ns ors, i nstit uti o nal affiliati o ns, p ote ntial 
c o nflicts of i nterest, i nce nti ves f or s u b jects a n d i nf or mati o n re gar di n g pr o visi o ns f or 
treati n g a n d/ or c o m p e nsati n g s u bjects w h o are har me d as a c o ns e q ue nce of partici pati o n 
i n t he researc h st u d y. 
I n cli nical trials, t he pr ot oc ol m ust als o descri be a p pr o priate arra n ge me nts f or p ost-trial 
pr o visi o ns.  
Researc h Et hics C o m mittees  
2 3.  T he researc h pr ot oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d 
a p pr o val t o t he c o n cer ne d researc h et hics c o m mittee bef ore t he st u d y be gi ns. T his 
c o m mittee m ust be tra ns pare nt i n its f u ncti o ni n g, m ust  be i n de pe n de nt of t he researc h er, 
t he S p o ns or, a n d a n y ot h er u n d ue i nfl ue n ce, a n d m ust be d ul y q ualifie d. It m ust ta ke i nt o 
c o nsi derati o n t he la ws a n d re g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h t he researc h is 
t o be perf or m e d as w ell as a p plica ble inter n ati o nal n or ms a n d sta n dar ds b ut t hese m ust 
n ot be all o we d t o re d u ce or eli mi nate a n y of t he pr otecti o ns f or res earc h s u bjects set f ort h 
i n t his Declarati o n.  
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he researc her m ust 
pr o vi de m o n it ori n g i nf or mati o n t o t he c o m mittee, es peciall y i nf or mati o n a b o ut a n y 

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seri o us a d vers e e v e nts. N o a me n d me nt t o t he pr ot oc ol ma y b e ma de wit h o ut 
c o nsi derati o n a n d a p pr o val b y t he c o m mittee. After t he e n d of t he st u d y, t he researc hers 
m ust s u b mit a fi nal re p ort t o t he c o m mittee c o ntai ni n g a s u m mar y of t he st u d y’s fi n di n gs 
a n d c o ncl usi o ns.   
Pri vac y a n d C o nfi de ntialit y  
2 4.  E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h s u bjects a n d t he 
c o nfi de ntialit y of t heir pers o nal i nf or mati o n.  
I nf or me d C o nsent  
2 5.  Partici pati o n b y i n di vi d uals ca pa ble of gi vi n g i nf or me d c o nse nt as s u bjects i n me dical 
researc h m ust be v ol u ntar y. Alt h o u g h it ma y be a p pr o priate t o c o ns ult fa mil y me m bers or 
c o m m u nit y lea d ers, n o i n di vi d ual ca pa ble of gi vi n g i nf or m e d c o nse nt ma y be e nr olle d i n 
a researc h st u d y u nless h e or s he freel y a grees.  
2 6.  I n me di cal r esearc h i n v ol vi n g h u ma n s u bjects ca p a ble of gi vi n g i nf or me d c o nse nt, eac h 
p ote ntial s u bject m ust be a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces of f u n di n g, 
a n y p ossi ble c o nflicts o f i nterest, i nstit uti o nal affiliati o ns of t he researc h er, t he 
a ntici pate d be nefits a n d p ote ntial ris ks of t he st u d y a n d t h e disc o mf ort it ma y e ntail, p ost -
st u d y pr o visi o ns a n d a n y ot her rele va nt as pects of t he st u d y. T he p ot e ntial s u bject m ust 
be i nf or me d of t he ri g ht t o ref use t o partici pate i n t he st u d y or t o wit h dra w c o nse nt t o 
partici pate at a n y ti me wit h o ut re prisal. S pecial att e nti o n s h o ul d be gi ve n t o t he s pecific 
i nf or mati o n nee ds of i n di vi d ual p ote ntial s u bjects as well as t o t he met h o ds use d t o 
de li ver t he i nf or mati o n. 
After e ns uri n g t h at t he p ote ntial s u bject has u n derst o o d t he i nf or mati o n, t he p h ysici a n or 
a n ot her a p pr o priatel y q u alifie d i n di vi d ual m ust t he n see k t he p ote ntial s u bj ect’s freel y -
gi ve n i nf or me d c o nse nt, prefera bl y i n writi n g. If t he  c o nse nt ca n n ot be e x presse d i n 
writi n g, t he n o n -writte n c o nse nt m ust be f or mall y d oc u me nte d a n d wit ness e d.  
All me dical researc h s u bj ects s h o ul d be gi ve n t he o pti o n of bei n g i nf or m e d a b o ut t he 
ge n eral o utc o m e a n d res ults of t he st u d y.  
2 7.  W he n see ki n g i nf or me d  c o nse nt f or partici pati o n i n a researc h st u d y t he p h ysicia n m ust 
be partic ularl y ca uti o us if t he p ote ntial s u bject is i n a de pe n d e nt relati o ns hi p wit h t he 
p h ysicia n or ma y c o nse nt u n der d uress. I n s uc h sit uati o ns t he i nf or me d c o nse nt m ust be 
s o u g ht b y a n a p pr o priatel y q ualifie d i n di vi d ual w h o is c o m pletel y i n de pe n d e nt of t his 
relati o ns hi p. 
2 8.  F or a p ot e ntial researc h s u bject w h o is i nca pa ble of gi vi n g i nf or me d c o nse nt, t he 
p h ysicia n m ust see k i nf or me d c o nse nt fr o m t he le gall y a ut h orize d re pres e ntati ve. T hese 
i n di vi d uals m ust n ot be i ncl u de d i n a res earc h st u d y t hat has n o li keli h o o d of be nefit f or 
t he m u nless it is i nte n de d t o pr o m ote t he healt h of t he gr o u p re prese nte d b y t he p ote ntial 
s u bject, t he researc h ca n n ot i nstea d be perf or me d wit h pers o ns ca p a ble of pr o vi di n g 
i nf or me d c o nse nt, a n d t h e researc h e ntails o nl y mi ni mal ris k a n d mi ni mal b ur de n. 
2 9.  W he n a p ote ntial researc h s u bject w h o is dee me d i nca pa ble of gi vi n g i nf or me d c o nse nt is 
a ble t o gi v e asse nt t o de cisi o ns a b o ut partici pati o n i n researc h, t he p h ysici a n m ust see k 
t hat asse nt i n a d diti o n t o t he c o nse nt of t he le gall y a ut h orize d re pres e ntati v e. T he 
p ote ntial s u bject’s disse nt s h o ul d be res pecte d.  

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3 0.  Researc h i n v ol vi n g s u bjects w h o are p h ysi call y or me ntall y i nca pa ble of gi vi n g c o ns e nt, 
f or e x a m ple, u nc o nscio us s u bjects, ma y b e d o ne o nl y if t he p h ysic al or me ntal c o n diti o n 
t hat pre ve nts gi vi n g i nf or me d c o nse nt is a necessar y c haracteristic of t he researc h gr o u p. 
I n s u c h circ u msta n ces t h e p h ysici a n m ust see k i nf or me d c o nse nt fr o m t he le gall y 
a ut h orize d re pres e ntati ve. If n o s uc h re pres e ntati ve is a vaila ble a n d if t he researc h ca n n ot 
be dela ye d, t h e st u d y ma y pr ocee d wit h o ut i nf or me d c o nse nt pr o vi de d t h at t he s pecific 
reas o ns f or i n v ol vi n g s u bjects wit h a c o n diti o n t hat re n ders t he m u na bl e t o gi ve i nf or me d 
c o nsent ha ve b ee n state d i n t he researc h pr ot o c ol a n d t he st u d y has b ee n a p pr o ve d b y a 
researc h et hics c o m mittee. C o nse nt t o re mai n i n t he researc h m ust be o bt ai ne d as s o o n as 
p ossi ble fr o m t he s u bject or a le gall y a ut h orize d re prese nt ati ve.  
3 1.  T he p h ysi cia n m ust f ull y i nf or m t he s u bject w hic h as pects of t heir care are relate d t o t he 
researc h. T h e ref usal of a s u bject t o partici pate i n a st u d y or t h e s u bject’s d ecisi o n t o 
wit h dra w fr o m t he st u d y m ust ne ver a d versel y affect t he s u bject -p h ysici a n relati o ns hi p.  
3 2.  F or me dic al researc h usi n g i de ntifia ble h u m a n material or d ata, s uc h as researc h o n 
material or data c o ntai ne d i n bi o ba n ks or si milar re p osit ories, p h ysici a ns m ust see k 
i nf or me d c o nse nt f or its c ollecti o n, st ora ge, a n d/ or re use. T h ere m a y be e x ce pti o nal 
sit uati ons w here c o nse nt w o ul d be i m p ossi ble or i m practica ble t o o btai n f or s uc h 
researc h. I n s u c h sit uati o ns t he researc h ma y b e d o ne o nl y after c o nsi derati o n a n d 
a p pr o val of a res earc h et hics c o m mittee.  
Use of Place b o  
3 3.  T he be nefits, ris ks, b ur de ns a n d effecti ve ne ss of a ne w i nter ve nti o n m ust be teste d 
a gai nst t h ose of t he best pr o ve n i nter ve nti o n(s), e x ce pt i n t he f oll o wi n g cir c u msta nces:  
W here n o pr o ve n i nter ve nti o n e xists, t he use of place b o, or n o i nter ve nti o n, is acce pta bl e; 
or  
W here f or c o m p elli n g a n d scie nti ficall y s o u n d met h o d ol o gical r eas o ns t he use of a n y 
i nter ve nti o n less effecti v e t ha n t he best pr o v e n o n e, t he use of place b o, or n o i nter ve nti o n 
is necessar y t o d eter mi ne t he efficac y or safet y of a n i nter ve nti o n a n d t he s u bjects w h o 
recei v e a n y i nter ve ntio n less effecti ve t ha n t he b est pr o ve n o ne, place b o, or n o 
i nter ve nti o n will n ot be s u bject t o a d diti o nal ris ks of seri o us or irre versi ble har m as a 
res ult of n ot recei vi n g t h e best pr o ve n i nter ve nti o n.  
E xtre me care m ust be ta k e n t o a v oi d a b use of t his o p ti o n. 
P ost -Trial Pr o visi o ns  
3 4.  I n a d va nce of a cli nical trial, s p o ns ors, researc h ers, a n d h ost c o u ntr y g o ver n me nts s h o ul d 
ma ke pr o visi o ns f or p ost -trial access f or all partici pa nts w h o still nee d a n i nter ve nti o n 
i de ntifie d as be neficial i n t he trial. T his i nfor mati o n m ust als o be discl ose d t o partici pa nts 
d uri n g t he i nf or me d c o ns e nt pr ocess.  
Researc h R e gistrati o n a n d P u blicati o n a n d Disse mi nati o n of Res ults  
3 5.  E ver y res earc h st u d y i n v ol vi n g h u ma n s u bjects m ust be re gistere d i n a p u blicl y 
accessi ble data bas e bef or e recr uit me nt of t he first s u bject.  
3 6.  Researc h ers, a ut h ors, s p o ns ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h 
re gar d t o t he p u blicati o n a n d disse mi nati o n of t he res ults of researc h. Researc hers ha ve a 

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d ut y t o ma ke p u blicl y a v aila ble t he res u lts of t heir researc h o n h u ma n s u bjects a n d are 
acc o u nta bl e f or t he c o m plete ness a n d acc urac y of t heir re p orts. All parties s h o ul d a d here 
t o acce pt e d g ui deli nes f or et hical r e p orti n g. Ne gati ve a n d i nc o ncl usi ve as well as p ositi ve 
res ults m ust be p u blis he d or ot her wise ma d e p u blicl y a vaila ble. S o urces of f u n di n g, 
i nstit uti o nal affiliati o ns, a n d c o nflicts of i nterest m ust be declare d i n t he p u blicati o n. 
Re p orts of researc h n ot i n acc or da nce wit h t he pri nci ples of t his Declarati o n s h o ul d n ot 
be acce pte d f or p u blicati o n.  
U n pr o ve n I nter ve nti o ns i n Cli nical Practice  
3 7.  I n t he treat me nt of a n i n di vi d ual s u bject, w here pr o ve n i nter ve nti o ns d o n ot e xist or ot her 
k n o w n i nter ve nti o ns ha v e bee n i neffecti ve, t he p h ysicia n, after see ki n g e x pert a d vice, 
wit h i nf or me d c o nse nt fr o m t he s u bject or a le gall y a ut h orize d re pres e ntati ve, ma y use a n 
u n pr o ve n i nter ve nti o n if i n t he p h ysicia n's j u d g me nt it offers h o pe of sa vi n g life, re -
esta blis hi n g healt h or alle viati n g s ufferi n g. T his i nter ve nti o n s h o ul d s u bse q ue ntl y be 
ma de t he o bjec t of researc h, desi g ne d t o e val u ate its safet y a n d efficac y. I n all cases, ne w 
i nf or mati o n m ust be rec or de d a n d, w here a p pr o pri ate, ma de p u blicl y a v aila ble. 
 
 

St u dy A G 1 2 0 -C -0 0 9  
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1 5. 1 1.  
Pr ot oc ol A me n d me nt Hist or y  
C ha n ges t h at ha d a maj or i m pact o n t he c o n d uct of t he st u d y are s u m mar ize d bel o w . 
A me n d me nt 1, 
Versi o n 2. 0  
( 0 7 Fe br uar y 2 0 1 7) 
Gl o bal  
•  
Re d uce d s ur vi val f oll o w -u p assess me nts fr o m e ver y 4 t o e ver y 8  wee ks.  
•  
Re vise d P K a n d P D sa m pli n g ti me p oi nts.  S u bjects i n t he o pti o nal safet y 
r u n-i n will n ot u n der g o a d diti o nal P K assess me nts. S parse P K bl o o d 
sa m pli n g will n ot be c o n d ucte d. Sa m ples f or P D will be c ollecte d pre d ose 
o nl y o n s pecifie d da ys.  
•  
Clarifie d t hat pri or treat me nt wit h h y dr o x y urea is n ot e xcl u si o nar y. 
•  
Re vise d n u m ber of azaciti di ne treat me nt da ys, re prese nti n g at least 7 5 % of 
t he pla n ne d azaciti di ne d ose, fr o m 5 t o 6. 
•  
Clarifie d t he decisi o n t o i nitiate t he ra n d o mize d p orti o n of t he trial will be 
ma de after 3 0 % of s u bjects e x perie nce d a D L T wit hi n t he D L T e val uati o n 
wi n d o w of o ne  st u d y treat me nt c ycle. 
•  
R e m o ve d  a m bi g u o us w or di n g ar o u n d h ol di n g a n d re d uci n g st u d y treat me nt 
d oses  f or A E ma na ge me nt. 
•  
Clarifie d t hat wei g ht a n d b o d y s urface area ( B S A) assess me nts m ust be 
c o n d ucte d pre d ose o n Da y 1 of eac h c ycle.  
•  
A d de d a defi niti o n f or a li mite d p h ysical e xa mi nati o n.  
•  
Re vise d st u d y treat me nt disc o nti n uati o n re q uire me nts t o i n dicate t hat st u d y 
treat me nt ca n n ot c o nti n ue f or s u bjects wit h pr o gressi ve disease. 
•  
Clarifie d t hat perf or ma nce of t he E F S c o m paris o n de pe n ds s olel y o n 
statistical si g nifica nce f or t he O S e n d p oi nt; statistical si g nifica nce f or t he 
ke y sec o n dar y e n d p oi nts of C R rate a n d C R + C R h rate is n ot re q uire d.  
•  
Re vise d i nstr ucti o ns o n s u bc uta ne o us a d mi nistrati o n a n d a d de d i nstr ucti o ns 
f or i ntra ve n o us a d mi nistrati o n of azaciti di ne c o nsiste nt wit h t he azaciti di ne 
I B. 
A me n d me nt 2, 
Versi o n 3. 0  
( 2 4 Marc h 2 0 1 7) 
Gl o bal  
•  
Re m o ve d t he i ncl usi o n of a d ult i n di vi d uals w h o lac k t he ca pacit y t o 
c o nse nt f or t he msel ves fr o m t he eli gi bilit y criteria. 
•  
Clarifie d  t hat azaciti di ne ( Vi daza® ) will be s u p plie d as c o m mercial pr o d uct 
f or i n vesti gati o nal use i n Brazil. 
 
 
 
  
 
 
 
 
•  
S pecifie d t hat t he assa y t o be use d t o deter mi ne t he prese nce of a n I D H 1 
m utati o n is a n i n vesti gati o nal P C R assa y, A b b ott Real Ti me I D H 1.  
A me n d me nt 3, 
Versi o n 4. 0  
( 1 4 A pril 2 0 1 7) 
Gl o bal  
•  
Re m o ve d t he o pti o nal safet y r u n -i n p orti o n of t he st u d y base d o n 
preli mi nar y safet y res ults f or t he c o m bi nati o n of A G -1 2 0 a n d azaciti di ne i n 
St u d y A G 2 2 1 -A M L -0 0 5.  

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•  
Re vise d t he secti o n o n u n bli n di n g t o clarif y t hat t he res p o nsi bilit y f or 
brea k i n g t he treat me nt c o de i n e mer ge nc y sit uati o ns resides s olel y wit h t he 
I n vesti gat or a n d t hat ra pi d u n bli n di n g is p ossi ble w he n necessar y. 
•  
Re place d “treat me nt fail ure” wit h “fail ure t o ac hie ve C R or C R wit h C Ri 
(i ncl u di n g C R p) at 2 4 wee ks” f or clarit y. 
•  
A d de d s ec o n dar y o bj ecti ves of rate, d urati o n, a n d ti me t o C R + C Ri 
(i ncl u di n g C R p) t o ali g n wit h t he re vise d defi niti o n of E F S, wit h 
c orres p o n di n g e n d p oi nts a n d a nal yses.  
•  
A dj uste d t he ti mi n g of res p o nse assess me nts Wee k 9 a n d e ver y ei g ht h wee k 
t hereafter ( Wee ks 1 7, 2 5, etc) t o e ns ure res p o nse assess me nt after 2 4 wee ks 
( 6 m o nt hs) of treat me nt. Q ualit y of life assess me nts were ali g ne d wit h 
res p o nse assess me nts fr o m Wee k 9 o n war d. 
•  
Clarifie d t he c o n diti o ns u n der w hic h s u bjects ma y c o nti n ue t o recei ve 
A G -1 2 0/ place b o after disc o nti n ui n g azaciti di ne t o miti gate t he p ote ntial f or 
s u bj ects wit h o ut C R or C Ri (i ncl u di n g C R p) t o co nti n ue o n si n gle -a ge nt 
place b o. S u bjects ma y c o nti n ue t o recei ve A G -1 2 0/ place b o f oll o wi n g 
disc o nti n uati o n of azaciti di ne, pr o vi de d t he y are i n C R or C Ri (i ncl u di n g 
C R p) a n d nee d t o disc o nti n ue azaciti di ne d ue t o pr ot oc ol -s pecifie d 
azaciti di ne -relate d t o xicit y (e g, dela ye d b o ne marr o w rec o ver y). 
•  
I n res p o nse t o F D A fee d bac k, re m o ve d t he attai n me nt of a > 3 0 % re d ucti o n 
i n b o ne marr o w blast c o u nt perce nta ge as a p ote ntial i n dicat or f or c o nti n ue d 
treat me nt i n s u bjects wit h a res p o nse less t ha n C R or C Ri (i ncl u di n g C R p) 
at 2 4 wee ks or be y o n d.  
•  
F or c o nsiste nc y wit h t he A G -1 2 0 I B, Versi o n 5. 0, a d de d t hat s yste mic 
a d mi nistrati o n of a m o derate or st r o n g C Y P 3 A 4 i n hi bit or re q uires caref ul 
Q T c F m o nit ori n g a n d t hat s u bj ects s h o ul d be r o uti nel y m o nit ore d f or ras h.  
•  
Re m o ve d a bsti ne nce as a n acce pta ble f or m of c o ntrace pti o n.  
A me n d me nt 4, 
Versi o n 5. 0  
( 3 1 Oct o ber 2 0 1 7) 
Gl o bal  
•  
All o w e d ra n d o mizati o n base d o n l ocal I D H 1 m utati o n testi n g (ce ntral 
testi n g is still re q uire d h o we ver, a n d bl o o d a n d b o ne marr o w sa m ples m ust 
be recei ve d ce ntrall y pri or t o ra n d o mizati o n).  
•  
Clarifi e d per mitte d  prera n d o mizati o n t hera pies f or disease sta bilizati o n. 
•  
A d d e d a n e xcl usi o n criteri o n f or s u bjects ta ki n g me dicati o ns t hat pr ol o n g 
t he Q T i nter val, wit h certai n e xce pti o ns. 
•  
 
 
•  
C ha n ge d  disease assess me nt sc he d ule i ncl u di n g: fre q ue nc y of b o ne marr o w 
as pir ate c ollecti o n, s u b missi o n of b o ne marr o w as pirate, a n d peri p heral 
bl o o d sa m ples 
. 
•  
A d d e d a n E C G o n Da y 1 of eac h treat me nt c ycle.  
•  
A d d e d pre g na nc y testi n g f or fe males of re pr o d ucti ve a ge o n Da y 1 of eac h 
c ycle a n d at t he en d of treat me nt.  
A me n d me nt 4, 
Versi o n 5. 1  
( 0 4 Dece m ber 2 0 1 7) 
Ja pa n 
•  
U p date d J a pa n -s pecific s u bject e nr oll me nt a n d safet y m o nit ori n g. 
•  
A d de d a r e q uire me nt f or se q ue ntial e nr oll me nt of Ja pa nese s u bjects u ntil at 
least 3 s u bjects ha ve bee n treate d wit h t he c o m bi nati o n of A G -1 2 0 + 

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azaciti di ne a n d t he c o m bi nati o n has bee n  deter mi ne d t o be t olera ble i n 
Ja pa nese s u bjects. 
•  
Ja pa nese s u bjects assi g ne d t o t he i nitial safet y e val uati o n c o h orts will be 
h os pitalize d  d uri n g t he azaciti di ne treat me nt peri o d of t he first c ycle of 
treat me nt. 
•  
If A Es e x perie nce d b y Ja pa nese s u bjects e nr olle d i n t he safet y e val uati o n  
c o h orts meet t he criteria of a D L T , s u bse q ue nt e nr oll me nt of J a pa nese 
s u bj ects will st o p a n d t he I D M C will be c o ns ulte d wit h o ut dela y t o re vie w 
u n bli n de d data a n d  e val uate if it is safe t o c o nti n ue  e nr olli n g Ja pa nese 
s u bj ects. 
•  
A d de d a s e parate re vie w of safet y data b y t he I D M C f or s u bjects e nr olle d 
i n J a pa n. 
A me n d me nt 4, 
Versi o n 5. 2  
( 2 3 A pril 2 0 1 8) 
Ja pa n 
•  
Ali g ne d t he pr ot oc ol wit h P M D A re q uire me nts.  
•  
Pr o p h ylactic t reat me nt wit h gra n ul oc yte c ol o n y-sti m ulati n g fact or bef ore 
i nitiati n g treat me nt wit h st u d y dr u g was pr o hi bite d beca use t he pr o p h ylactic 
treat me nt ma y mas k D L Ts. Ne utr o pe nia treate d wit h gra n ul oc yte c ol o n y-
sti m ulati n g fact or d uri n g t he D L T e val uati o n wi n d o w will be c o nsi dere d a 
D L T.  
•  
If a s u bj ect misse d m ore t ha n 2 0 % of d oses of st u d y dr u g d uri n g t he D L T 
e val uati o n wi n d o w ( 2 da ys of azaciti di ne or 6 da ys of A G -1 2 0) d ue t o a n 
A E, t he A E will be c o nsi dere d a D L T.  
•  
Re vise d i ncl usi o n criteri o n # 8 t o i n dicate t hat i n c o u ntries w here t he a ge of 
c o nse nt is greater t ha n 1 8 years, f or s u bjects u n der t he a ge of c o nse nt, b ot h 
t he s u bject a n d his/ her g uar dia n or le gal re prese ntati ve m ust be willi n g t o 
si g n a n I C F. 
•  
Re vise d i ncl usi o n criteri o n # 1 0 t o i n dicate t hat fe male s u b j ects wit h 
a me n orr hea d ue t o me dicati o n m ust f oll o w t he g ui deli nes f or fe males of 
re pr o d ucti ve p ote ntial, a n d t hat t he 2 effecti ve f or ms of c o ntrace pti o n m ust 
be a p pr o ve d b y a l ocal re g ulat or y a ut h orit y.  
•  
Re vise d e xcl usi o n criteri o n # 7 t o e xcl u de s u bjects w h o i nterr u pt 
breastfee di n g.  
•  
A d de d he patitis B, he patitis C, a n d HI V testi n g as a Scree ni n g assess me nt, 
a n d f or ser o p ositi ve s u bj ects wit h viral i m m u nit y b ut n o e vi de nce of acti ve 
disease at Scree ni n g, viral reacti vati o n will be m o nit ore d at Scree ni n g a n d 
o n Da y 1 of eac h c ycle.  
A me n d me nt 4, 
Versi o n 5. 3  
( 1 1 Ja n uar y 2 0 1 9) 
Fra nce  
•  
A d de d la n g ua ge t o a d vise I n vesti gat ors t o s us pe n d treat me nt wit h 
A G -1 2 0/ place b o if a s u bject is s us pecte d of ha vi n g P M L.  
•  
A d de d a secti o n f or “ Ot her P ote ntial Ris ks” ass ociate d wit h A G -1 2 0 
i ncl u di n g le u k oe nce p hal o pat h y, se ns ori m ot or ne ur o pat h y/ p ol y ne ur o pat h y, 
a n d t u m o ur l ysis sy n dr o me.  
A me n d me nt 4, 
Versi o n 5. 4  
( 3 0 Ma y 2 0 1 9) 
Ger ma n y  
•  
U p date d  t he p ote ntial ris ks f or A G-1 2 0 t o  ali g n wit h t he c urre nt e diti o n of 
t he I B (Versi o n  8. 0, date d 0 7 Marc h 2 0 1 9)  a n d per Healt h A ut h orit y 
re q uest. 
•  
A d de d a n e xcl usi o n criteri o n f or s u bjects wit h a k n o w n me dical hist or y of  
P M L . 

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt 9 , Versi o n 1 0 . 0 
 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
1 3 1 /1 3 2  
 
•  
A d de d t he p ote ntial ris ks a n d ma na ge me nt g ui deli nes ass ociate d wit h 
A G -1 2 0,  i ncl u di n g le u k oe nce p hal o pat h y, se ns ori m ot or 
ne ur o pat h y/ p ol y ne ur o pat h y, a n d  t u m o ur l ysis s y n dr o me. 
•  
U p date d t he p ote ntial dr u g -dr u g i nteracti o ns bet wee n A G -1 2 0 a n d 
azaciti di ne. 
•  
U p date d t he c o nc o mita nt me dicati o ns re q uiri n g caref ul m o nit ori n g t o 
i ncl ude t h ose  t hat are e xte nsi vel y meta b olize d b y C Y P 2 C 9 a n d h or m o nal 
c o ntrace pti ves. 
•  
Re m o ve d t he e xcl usi o n criteri o n f or s u bj ects ta ki n g P -g p  
tra ns p orter-se nsiti ve s u bstrate me dicati o ns. 
•  
Wit h t he e xce pti o n of t he a b o ve me nti o ne d c ha n ges t o t he e xcl usi o n criteria, 
t his i nf or mati o n was pr o vi de d i n t he Ger ma n y -s pecific pr ot oc ol a d de n d u m 
( date d 1 0 A u g ust 2 0 1 8). 
A me n d me nt 5, 
Versi o n 6. 0  
(0 9 Ja n uar y 2 0 2 0)  
Gl o bal  
a n d 
A me n d me nt 5, 
Versi o n 6. 1  
( 0 9 Ja n uar y 2 0 2 0) 
Ja pa n 
•  
C ha n ge d t he pri mar y e n d p oi nt fr o m O S t o E F S a n d a d de d O S t o t he ke y 
sec o n dar y e n d p oi nts, a n d u p date d t he c orres p o n di n g statistical a nal yses. 
•  
U p date d t he a d diti o nal sec o n dar y e n d p oi nt e val uati n g I D H 1 m utati o n 
cleara nce ( M C) a n d t he c orres p o n di n g statistical  a nal yses. 
•  
U p date d t he i ncl usi o n criteri o n  t o m ore narr o wl y defi ne a p o p ulati o n of 
patie nts w h o are i neli gi ble f or i nte nsi ve I C, a n d ali g ne d t he ass ociate d li ver 
a n d re nal f u ncti o n criteria.  
•  
F or c o nsiste nc y wit h t he c urre nt e diti o n of t he A G -1 2 0 I B, r e m o ve d t he 
criteri o n e xcl u di n g s u bjects ta ki n g P -g p tra ns p orter se nsiti ve s u bstrate 
me dicati o ns ; ad de d a criteri o n e xcl u di n g s u bj ects wit h a me dical hist or y of 
P M L as P M L is a p ote ntial ris k of treat me nt wit h A G -1 2 0 ; a n d re vise d 
i nf or mati o n o n dr u g-dr u g i nterac ti o ns. 
•  
Re m o ve d t he i nteri m a nal yses f or efficac y.  
•  
Re d uce d t he n u m ber of s u bjects w h o will partici pate i n t his st u d y fr o m 3 9 2 
t o 2 0 0 base d o n u p date d sa m ple size esti mati o ns, a n d i ncrease d t he n u m ber 
of st u d y ce nters a n d c o u ntries.  
A me n d me nt 6, 
Versi o n 7. 0  
( 0 4 Marc h 2 0 2 0) 
Gl o bal  
a n d 
A me n d me nt 6, 
Versi o n 7. 1  
( 0 4 Marc h 2 0 2 0) 
Ja pa n 
•  
Clarifie d t hat peri p heral bl o o d sa m ples ma y o nl y be use d t o assess I D H 1 
m utati o n (I ncl usi o n Criteri o n # 3) if b o ne marr o w as pirate is n ot a vaila ble t o 
e ns ure clarit y a n d c o nsiste nc y ar o u n d t he sa m ples f or I D H 1 m utati o n 
testi n g. 
A me n d me nt 7, 
Versi o n 8. 0 ( 1 6 
Dece m ber 2 0 2 0) 
Gl o bal a n d 
A me n d me nt 7, 
Versi o n 8. 1 ( 1 6 
Dece m ber 2 0 2 0)  
Ja pa n 
•  
A d de d a secti o n descri bi n g te m p orar y pr ot oc ol m o dificati o ns t o e ns ure 
s u bj ect safet y, mai ntai n c o m plia nce wit h G C P, a n d mi ni mize ris ks t o st u d y 
i nte grit y d uri n g a C O VI D-1 9 p u blic healt h e mer ge nc y.  
•  
C o nti n ue d efficac y f oll o w -u p of s u bjects i n t he st u d y f or E F S after 
i nitiati o n of s u bse q ue nt a ntica ncer t hera p y f or s u bjects w h o di d n ot ha ve a n 
E F S e ve nt. 

St u dy A G 1 2 0 -C -0 0 9  
Pr ot oc ol A me n d me nt 9 , Versi o n 1 0 . 0 
 
© I. R.I. S. –  2 9 Se pte m ber 2 0 2 1  –  C o nfi de nti al  
1 3 2 /1 3 2  
 
•  
I nc or p orate d a se nsiti vit y a nal ysis f or t he pri mar y e n d p oi nt s u p p orti n g t he 
c o nti n ue d efficac y f oll o w -u p f or E F S after i nitiati o n of s u bse q ue nt 
a ntica ncer t hera p y f or s u bj ects w h o di d n ot ha ve a n E F S e ve nt.  
A me n d me nt 7, 
Versi o n 8. 2 ( 2 6 Ma y 
2 0 2 1)  
Ge r ma n y 
•  
Clarifie d la n g ua ge re gar di n g h o me healt h st u d y s u p p ort.  
•  
Re m o ve d t he la n g ua ge re gar di n g o btai ni n g virt ual i nf or me d rec o nse nt.  
A me n d me nt 8, 
Versi o n 9. 0 ( 0 1 J ul y 
2 0 2 1) Gl o bal,  
A me n d me nt 8, 
Versi o n 9. 1 ( 0 1 J ul y 
2 0 2 1) Ja pa n, a n d  
A me n d me nt 8, 
Versi o n 9. 2  ( 0 1 Ju l y 
2 0 2 1) Ger ma n y  
•  
T he ma na ge me nt of s u bj ects f oll o wi n g st u d y u n bli n di n g was a d de d.  
•  
A d de d t w o para gra p hs t o pr o vi de ris k assess me nts f or t he use of t he 
C O VI D -1 9 vacci ne t o f ulfill Healt h A ut h orit y re q uire me nts.  
•  
U p date d t o clarif y t hat A G -1 2 0 ma y be s h i p pe d t o a s u bj ect, b ut azaciti di ne 
ma y n ot, base d o n Healt h A ut h orit y fee d bac k.  
•  
Re m o ve d pers o nal visits a n d o nsite re vie w t o per mit fle xi bilit y u n der 
e xce pti o nal circ u msta nces.  
 

A G 1 2 0 -C -0 0 9  
 
Pr ot oc ol Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber  2 0 2 1 –  C o nfi de nti al  
1 /3  
 
 
P R O T O C O L A G 1 2 0 -C -0 0 9  
A M E N D M E N T 9 , V E R SI O N 1 0 . 0, 2 9 S E P T E M B E R  2 0 2 1  
S U M M A R Y O F C H A N G E S  F R O M  
A M E N D M E N T 8 , V E R SI O N 9 . 0, 0 1 J U L Y 2 0 2 1   
A P h ase 3, M ultice nter, D o u ble -Bli n d, R a n d o mize d, Pl ace b o -C o ntr olle d St u d y 
of A G -1 2 0 i n C o m bi n ati o n wit h Az aciti di ne i n S u bjects ≥1 8 Ye ars of A ge wit h 
Pre vi o usl y U ntre ate d Ac ute M yel oi d Le u ke mi a wit h a n I D H 1 M ut ati o n  
1.  
O V E R VI E W  
T he  pr ot oc ol  was pri maril y a me n d e d  t o c ha n ge t he S p o ns or f or t he st u d y.  
T he s u bsta ntial c ha n ges i ncl u de d i n t he c urre nt a m e n d me nt  are ite mize d as f oll o ws : 
•  C ha n ge d t h e S p o ns or fr o m A gi os P har mace uticals, I n c. ( A gi os) t o I nstit ut de 
Rec herc hes I nter nati o nal es Ser vier (I. R.I. S.)  
T he c ha n ges i n t he prece di n g list  are d etaile d i n Sectio n  2 ; a d de d te xt is i n b ol d  f o nt a n d delete d 
te xt is i n stri ket hr o u g h f o nt. 
N o ns u bsta ntial  c ha n ges are liste d i n Secti o n  3 . 
E dit orial c ha n ges f or i m pr o vi n g cl arit y a n d st yl e, f or matti n g c h a n ges, a n d c orrecti o ns of 
t y p o gra p hical err ors are n ot detaile d i n t his d oc u me nt. 

A G 1 2 0 -C -0 0 9  
 
Pr ot oc ol Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber  2 0 2 1 –  C o nfi de nti al  
2 /3  
 
2.  
D E T AI L S O F S U B S T A N TI A L  C H A N G E S  
S u bst a nti al C h a n ge  a n d R ati o n ale : C ha n ge d t he S p o ns or fr o m A gi os P har mace uticals, I nc. ( A gi os) 
t o I nstit ut de Rec herc hes I nter nati o nales Ser vier (I. R.I. S.). 
P ri m ar y Secti o n Affecte d: C o ver pa ge  
F or merl y 
Re a d  
St u d y S p o ns or:  
A gi os P har mace uticals, I nc.  
8 8 Si d ne y St  
Ca m bri d ge, M A 0 2 1 3 9 -4 1 6 9  
P h o ne: 6 1 7 -6 4 9 -8 6 0 0  
Fa x: 6 1 7 -6 4 9 -8 6 1 8  
Res p o nsi ble Me dical Officer:  
, M D 
 
A gi os P har mace uticals, I nc.  
N o w Re a ds  
St u d y S p o ns or:  
I nstit ut de Rec herc hes I nter n ati o n ales 
Ser vier (I. R.I. S.)  
5 0, r ue C ar n ot  
9 2 2 8 4 S ures nes ce de x - Fr a nce  
Res p o nsi ble Me dical Officer:  
, M D 
 
Ser vier P h ar m ace utic als  L L C  
De p ut y He a d:  
, M D, P h D 
 
 
 
I. R.I. S. 
Ot her Secti o ns Affecte d:  
Re m o ve d refere nces t o A gi os as t he S p o ns or t hr o u g h o ut a n d a d d e d ne w si g nat or y fr o m I. R.I. S. 
 

A G 1 2 0 -C -0 0 9  
 
Pr ot oc ol Versi o n 1 0 . 0 
© I. R.I. S. –  2 9 Se pte m ber  2 0 2 1 –  C o nfi de nti al  
3 /3  
 
3.  
LI S TI N G O F N O N S U B S T A N TI A L C H A N G E S  
P ri m ar y Secti o n (s) 
Affecte d  
C h a n ge  wit h  R ati o n ale  
Ot her Secti o ns Affecte d  
C o ver pa ge  
Re place d t he c o nfi de ntialit y state me nt 
wit h t he w or d “ C o nfi de ntial” t o reflect 
t he ne w S p o ns or’s sta n dar d practice. 
N/ A  
Pr ot oc ol A p pr o val  
Re vise d t he f or mat of t he pr ot oc ol 
a p pr o val pa ge t o reflect t he ne w 
S p o ns or’s sta n dar d f or mat.  
N/ A  
I n vesti gat or’s 
A gree me nt  
Re vise d t he f or mat of t he i n vesti gat or’s 
a gree me nt pa ge t o reflect t he ne w 
S p o ns or’s sta n dar d f or mat.  
N/ A  
Secti o n 1 1. 2, Pr oce d ures 
f or Re p orti n g A d verse 
E ve nts a n d Seri o us 
A d verse E ve nts  
Re place d t he c o ntact i nf or mati o n f or 
safet y re p orti n g wit h a refere nce t o t he 
safet y re p orti n g i nstr ucti o ns beca use 
t his c o ntact i nf or mati o n is alrea d y 
pr o vi de d i n t hese i nstr ucti o ns a n d/ or 
ot her d oc u me nts.  
N/ A  
A p pe n di x 1 5. 1 1 , 
Pr ot oc ol A me n d me nt 
Hist or y  
A d de d pre vi o us pr ot oc ol a me n d me nts  
t o s u m marize c ha n ges t hat ha d a maj or 
i m pact o n t he c o n d uct of t he st u d y. 
N/ A