A Phase II Study of Combination Midostaurin and Decitabine (MIDDAC) in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia and FLT3 Mutation
Phase: PHASE2
Conditions: Acute Myeloid Leukemia With FLT3/ITD Mutation, Acute Myeloid Leukemia With Gene Mutations, FLT3 Tyrosine Kinase Domain Point Mutation, Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Sponsor: Mayo Clinic

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M C 1 4 8 3 
 
 
 
Ma y o Cli nic Ca ncer Ce nter  
 
A P h ase II St u d y of C o m bi n ati o n M i d ost a uri n a n d Decit a bi ne ( MI D D A C)  in El derl y 
P atie nts Ne wl y Di a g n ose d wit h Ac ute M yel oi d Le u ke mi a a n d F L T 3  M ut ati o n   
 
 
 
 
St u d y C hairs: 
Aref Al -Kali, M D  
Ma y o Cli nic  
2 0 0 First Street, S W 
R oc hester, M N 5 5 9 0 5 
5 0 7/ 2 8 4- 2 5 1 1 
5 0 7/ 2 8 4- 5 2 8 0 ( F A X) 
 
 
St u d y C o- c hair: 
  
 
  
 
 
  
 
 
  
 
 
Statisticia n:  
 
 
    
 
 
Dr u g A v ail a bilit y  
C o m merci al A ge nts:  decita bi ne   
Dr u g C o m p a n y S u p plie d:  mi d osta uri n   
 
√St u d y c o ntri b ut or(s) n ot res p o nsi ble f or patie nt care.  
 
 
D oc u me nt Hist or y  
( Effecti ve D ate) 
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 Se pte m ber 1, 2 0 1 6  
J ul y 2 0, 2 0 1 7 
Dece m ber 1 2, 2 0 1 7 
 
 
  
 
 
 
 
 
 

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I n dex  
 
Sc he ma  
  1. 0  
Bac k gr o u n d 
  2. 0 
G oals  
  3. 0 
Patie nt Eli gi bilit y  
  4. 0 
T est Sc he d ule  
  5. 0   
Gr o u pi n g Fact ors  
  6. 0  
Re gistrati o n Pr oce d ures 
  7. 0 
Pr ot oc ol Treat me nt  
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D osa ge M o dificati o n Base d o n A d verse E ve nts  
  9. 0 
A ncillar y Treat me nt/ S u p p orti ve Car e 
1 0. 0  
A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
1 1. 0  
Treat me nt E val uati o n   
1 2. 0 
Descri pti ve Fact ors  
1 3. 0 
Treat me nt/ F oll o w - u p Decisi o n at E val uati o n of Patie nt  
1 4. 0  
B o d y Fl ui d Bi os peci me ns 
1 5. 0 
Dr u g I nf or mati o n  
1 6. 0  
Statistical C o nsi derati o ns a n d Met h o d ol o g y 
1 7. 0 
Pat h ol o g y C o nsi derati o ns/ Tiss ue Bi os peci me ns  
1 8. 0 
Rec or ds a n d Data C ollecti o n Pr oce d ures  
1 9. 0  
B u d get 
2 0. 0 
Refere nces  
C o nse nt F or m  
A p pe n di x Ia  
Dr u gs wit h Ris k of T orsa des de P oi ntes  
A p pe n di x I b  
Dr u gs wit h P ossi ble or C o n diti o nal Ris k of T ors a des de P oi ntes 
A p pe n di x II 
E C O G Perf or ma nce Stat us   
A p pe n di x I II  Patie nt Me dicati o n Diar y  
A p pe n di x I V  
Ac ute M yel oi d L e u ke mia W H O 2 0 0 8 Criteria  
A p pe n di x V  
S A E Re p ort C o vers heet  

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Sc he m a  
 
 
 
 
 
 
 
 
 
 
 
 
 
                             N o res p o nse                                                            C R/ C R i/ P R/ M L F S                                              
 
 
 
 
 
                                                                 
  
 C o nti n ue T her a p y  
 
 
 
                                                                   N o res p o nse  
 
C R/ C R i/ P R/ M L F  
  
  
   
  
  
 
Rel a pse  
 
 
                   C o nti n ue T her a p y                                              
                                                                    
 
 
 
 
 
 
 
 
                  
                       Rel a pse   
 
C ycle le n gt h 2 8 da ys -ma xi m u m 1 8 c ycles  (see Secti o n 7. 1 2).  T he ne xt c ycle of treat me nt ma y be dela ye d 
u p t o 2 8  da ys base d o n i n vesti gat or o pi ni o n.  If t he ne xt c ycle is dela ye d be y o n d 2 8 da ys, t he patie nt will 
g o t o e ve nt m o nit ori n g p er Secti o n 1 8. 0. 
 
Ge neric na me:  mi d osta uri n  
Bra n d na me:  n/a  
Ma y o a b bre viati o n: MI D O S T A U RI N  
A vaila bilit y:  N o vartis  
Ge neric na me:  decita bi ne  
Bra n d na me:  
Dac o ge n  
Ma y o a b bre viati o n:  D E CI T  
 
A vaila bilit y:  C o m mercial  
Re gistr ati o n  
El derl y A M L wit h F L T 3 m ut ati o n  
Tre at me nt  
Decit a bi ne D a ys 1 - 5 
Mi d ost a uri n D a ys 8- 2 1 
X 2 c ycles  
Decit a bi ne D a ys 1 -5 
Mi d ost a uri n D a ys 1- 2 8 
X 6 c ycles ( c ycle s 3- 8) 
Dise ase re l a pse at  
   a n y ti me  
U n acce pt a ble a d verse    
       
E ve nt  
    e ve nts    
  
  
       
M o nit ori n g  
P atie nt ref us al   
N o Res p o nse   
 

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                                       List of A b bre viati o ns  
 
 
A E  
a d verse e ve nt  
A L T  
ala ni n e a mi n otra nsferas e  
A M L  
Ac ute m yel oi d  le u ke mia 
A N C  
a bs ol ute n e utr o p hil c o u nt 
A S T  
as p artate a mi n otra nsferas e  
bi d  
bis i n die m/t wic e a d a y  
C H R  
c o m plete h e mat ol o gic res p o nse  
C M L  
c hr o nic m yel o ge n o us le u k e mia  
C R  
c o m plete res p o nse  
C R F 
case re p ort/rec or d f or m  
C S & E  
Cli nical Safet y a n d E pi d e mi ol o g y  
C T  
c o m p uterize d t o m o gra p h y  
C T C  
c o m m o n ter mi n ol o g y criteria  
C y R  
c yt o ge n etic res p o nse  
E C G  
electr o car di o gra m  
E C O G  
Easter n C o o p erati ve O n c ol o g y Gr o u p  
F L T 3  
F ms -li k e t yr osi n e ki n ase-3  
GI S T  
gastr oi ntesti n al str o mal t u m or  
H R  
h e mat ol o gic res p o nse  
I E C 
I n d e p e n d e nt Et hics C o m mittee 
I R B 
I nstit uti o n al Re vie w B o ar d 
I T D 
I nter n al ta n d e m d u plicates 
I T T 
i nte nti o n-t o-treat 
I U L N 
I nstit uti o n al U p p er Li mit of N or mal 
i v 
i ntra ve n o us(l y) 
L V E F  
left ve ntric ular ejecti o n fracti o n 
M C y R  
maj or c yt o g e n etic res p o nse  
M T D  
ma xi m u m t olerate d d ose  
N CI  
Nati o n al Ca n cer I nstit ute  
N E L  
n o e vi d e n ce of le u ke mia  
NI H  
Nati o n al I nstit utes f or Healt h  
P D  
pr o gressi o n of disease  
P F S  
pr o gressi o n f ree s ur vi val 
P K C 4 1 2  
Mi d osta uri n  
p o  
p er os/ b y m o ut h/ orall y  
P R  
p artial res p o nse  
q d  
q u a q u e die/e ver y d a y  
R E CI S T  
Res p o nse E val u ati o n Criteria i n S oli d T u m ors  
S A E  
seri o us a d verse e ve nt 
S D  
sta ble disease 
T K D  
T yr osi n e ki n ase d o mai n  
U L N  
u p p er li mit of n o r mal 
W B C  
W hite Bl o o d Cell C o u nt  

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1. 0 
B ac k gr o u n d 
1. 1  
O ver vie w of ac ute m yel oi d le u ke mi a, e pi de mi ol o g y a n d c urre nt tre at me nt  
 
Ac ute  m yel oi d  le u ke mia  ( A M L)  is  a  mali g na nt  dis or der  of  i m mat ure  
he mat o p oietic cells.  It is c haracterize d b y differe ntiati o n arrest  a n d mali g na nt  
pr oliferati o n of cl o nal m yel oi d prec urs ors of t he b o ne marr o w. A M L re prese nts 
a b o ut  3 0 %  of  t he  f or ms  of  a d ult  le u ke mia  a n d  t he  i nci de nce  is  esti mate d  at  
1 3, 0 0 0 ne w cases per year i n t he U. S. a n d i nci de nce i ncreases wit h a ge. T he 
A merica n Ca ncer S ociet y als o esti mates t he n u m ber of deat hs d ue t o A M L as 
9, 0 0 0 per year. ( A merica n Ca ncer S ociet y 2 0 1 1 ) 
 
T he dia g n ostic w or k u p of ac ute le u ke mia is m ultifacete d a n d ma y i ncl u de b o ne 
marr o w bi o ps y,  fl o w c yt o metr y, c yt o ge netics, a n d ge ne m utati o n a nal ysis. T he 
2 0 0 8 W H O classificati o n cate g orizes m yel oi d le u ke mia i nt o n u mer o us s u bt y pes 
a n d pr o g n ostic gr o u ps. T he prese nce of a b n or mal c yt o ge netics, or t he prese nce of 
le u ke mia-ass ociate d  ge ne  m utati o ns  ( F L T 3,  N P M 1,  C E P B A)  are  i m p orta nt  
pr o g n ostic  i n dicat ors.  ( Este y  2 0 1 0 )  Treat me nt  a p pr oac hes  i n  A M L  var y  f or  
patie nts wit h A P L ( M 3) b ut ha ve re mai ne d relati vel y u nc ha n ge d f or t he past 
t hree deca des f or all ot her t y pes of A M L. 
 
C o m bi nati o n c he m ot hera p y re gi me ns c o m m o nl y use d i n treat me nt of n o n -A P L 
A M L ha ve t y picall y i ncl u de d i n d ucti o n wit h a n a nt hrac ycli ne a n d n ucle osi de 
a nal o g. C o m plete re missi o n ( C R) rates of 6 5 -9 0 % i n y o u n ger A M L patie nts ca n 
be o bser ve d wit h da u n or u bici n or i dar u bici n gi ve n i n c o nj u ncti o n wit h c ytara bi ne 
f or o ne t o t w o c ycles. (Ra va n di 2 0 0 7 ) Rece ntl y, hi g her d oses of da u n or u bici n 
ha ve s h o w n better res ults i n y o u n ger A M L patie nts alt h o u g h t his be nefit di d n ot 
e xte n d  t o  t he  F L T 3  I T D  patie nts  ( Fer na n dez  2 0 0 9 ).  C o ns oli dati o n  t hera p y  
t y picall y i n v ol ves hi g h d ose c ytara bi ne a n d d urati o n is de bate d alt h o u g h t y picall y 
i ncl u des t hree t o f o ur c ycles of p ost-re missi o n t hera p y. (Este y 2 0 1 0 ) Des pite t he 
hi g h C R rate, t he maj orit y of a d ults wit h A M L will rela pse wit hi n 3 years wit h 
o nl y  4 0 -4 5 %  of  y o u n ger  patie nts  ac hie vi n g  c ure.  ( B ur nett  2 0 1 1 )  T here  are  
s u bsets of A M L patie nts wit h ver y p o or o utc o mes, i ncl u di n g i nter me diate or p o or 
ris k b y c yt o ge netics or m olec ular a nal ysis. I n s uc h cases, a p pr oac hes i ncl u di n g 
ste m cell tra ns pla ntati o n ( H S C T) are rec o m me n de d i n C R 1. (N C C N G ui deli nes 
v 1. 2 0 1 2 , Este y 2 0 1 0 ) 
   
F M S -like tyr osi ne ki n ase 3 m ut ati o ns 
 
T he F M S -li ke t yr osi ne ki nase 3 ( F L T 3) bel on gs t o t he gr o u p of class III rece pt or 
t yr osi ne  ki nases.  It  bel o n gs  t o  a  fa mil y  of  i m p orta nt  si g nali n g  rece pt ors  t hat  
i ncl u de c-KI T, c - F M S, a n d P D G F R. F L T 3 is a gr o wt h fact or rece pt or i n v ol ve d i n 
he mat o p oietic cell gr o wt h a n d differe ntiati o n. F L T 3 rece pt or  a n d its li ga n d ( F L) 
als o pla y a n i m p orta nt r ole i n s ur vi val a n d self -re ne wal of earl y he mat o p oietic 
pr o ge nit ors, m o n oc ytic prec urs ors a n d i n l y m p h oi d de vel o p me nt. Acti vati o n of 
F L T 3 res ults i n rece pt or a ut o -p h os p h or ylati o n lea di n g t o d o w nstrea m si g nali n g 
of  t he  R A S/ M A P K,  J A K/ S T A T 5,  a n d  PI 3 K/ A K T  pat h wa ys.  I n  n or mal  b o ne  
marr o w ( B M), F L T 3 is e x presse d o n pr o ge nit or cells a n d re g ulates ste m cell 
pr oliferati o n. As he mat o p oietic pr o ge nit or cells differe ntiate a n d mat ure, F L T 3 
e x pressi o n is n or mall y l ost. 

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I n A ML, si g nali n g of F L T 3 pat h wa y is ofte n acti vate d a n d lea ds t o mali g na nt 
blast  cell  pr oliferati o n,  i n  part  d ue  t o  o ver  e x pressi o n  of  F L T 3  rece pt or  i n  
le u ke mia  cells.  H o we ver,  a  maj or  researc h  a d va nce  was  t he  i de ntificati o n  of  
m utati o ns occ urri n g i n t he F L T 3 ge ne i n A M L patie nts. It is t he m ost c o m m o n 
s o matic m utati o n i de ntifie d i n A M L, wit h a n i nci de nce of a b o ut 2 5 % (Ki n dler 
2 0 1 0 , K ottari dis  2 0 0 1 ).  T w o  maj or  t y pes  of  F L T 3  ge ne  m utati o n  ha ve  bee n  
i de ntifie d: 1) i nter nal ta n de m d u plicati o n (I T D) a n d 2) t yr osi ne ki nase d o mai n 
( T K D) p oi nt m utati o ns ( P M) a n d I T Ds ma ke u p a maj orit y of F L T 3 m utati o ns i n 
ne wl y dia g n ose d patie nts ( T hie de 2 0 0 2 ). T hese d u plicati o ns are t he res ult of 3 t o 
> 4 0 0 base pairs i nserte d i nt o t he rece pt or i n -fra me (Sc h nitt ger 2 0 0 2 ). T he I T Ds 
pr o m ote li ga n d -i n de pe n de nt F L T 3 rece pt or di merizati o n a n d si g nal acti vati o n, 
c ul mi nati n g i n cell ular pr oliferati o n ( Ki y oi 1 9 9 8 , Ha ya ka wa 2 0 0 0 ). 
 
T he prese nce of F L T 3 -I T Ds has bee n f o u n d in certai n st u dies t o be t he str o n gest 
pre dict or  of  patie nt  o utc o me  ( K ottari dis  2 0 0 1 , Ki y oi  1 9 9 9 ).  A M L  patie nts  
har b ori n g F L T 3 I T D m utati o ns are c ha racterize d b y certai n pretreat me nt feat ures 
li ke hi g her le vels of w hite bl o o d cell c o u nts a n d bl o o d a n d b o ne marr o w blasts 
(Fr o hli n g 2 0 0 2 , T hie de 2 0 0 2 ). F L T 3 I T D has bee n re p orte d c o nsiste ntl y as a n 
u nfa v ora ble pr o g n ostic mar ker f or rela pse -free ( R F S) a n d o verall s ur vi val ( O S) 
(K ottari dis 2 0 0 1 , Fr o hli n g 2 0 0 2 , T hie de 2 0 0 2 , Gale 2 0 0 8 ). I n a st u d y of 8 5 4 
A M L patie nts, a n I T D was prese nt i n 2 7 % of t he patie nts. Alt h o u g h prese nce of 
F L T 3 m utat i o n di d n ot i m pact C R rate, l o n g ter m cli nical o utc o mes varie d base d 
o n t he prese nce of F L T 3 I T D. T he rela pse rate at 5 years was 6 4 % i n patie nts 
wit h t he m utati o n vers us 4 4 % i n t h ose wit h o ut. Disease free s ur vi val at 5 years 
was 3 0 % c o m pare d t o 4 6 % i n patie nts wit h o ut a m utati o n a n d o verall s ur vi val of 
3 2 % c o m pare d t o 4 4 % of patie nts wit h o ut t he m utati o n. ( K ottari dis 2 0 0 1 ) 
 
F urt her m ore, a d diti o nal fact ors of t he F L T 3 I T D m utati o n ma y i m pact o utc o me, 
i ncl u di n g size of t he base pair i nserti o n, hi g her allelic rati o ( m uta nt: wil d -t y pe 
F L T 3) a n d i nserti o n site ( Stire walt 2 0 0 6 , T hie de 2 0 0 2 , Ka yser 2 0 0 9 ) As details 
of F L T 3 I T D m utati o ns c o nti n ue t o be e val uate d, it re mai ns clear t hat A M L wit h 
a  F L T 3  I T D  m utati o n  res ults  i n  hi g her  rela pse,  s h orter  D F S  a n d  s h orter  O S  
w hic h has le d t o a n i ncrease d f oc us o n H S C T i n C R 1 i n t his gr o u p. 
1. 2  
I ntr o d ucti o n t o i n vesti g ati o n al tre at me nt(s) a n d ot her st u d y tre at me nt(s) 
   
Overvie w of mi d ost a uri n  
Mi d osta uri n is a n i n hi bit or of se veral pr otei n ki nase C ( P K C) is of or ms, of t he 
t yr osi ne ki nase of t he vasc ular e n d ot helial gr o wt h fact or rece pt or ( V E G F R) a n d 
m ost i m p orta ntl y of t he class III t yr osi ne pr otei n ki nases F L T 3 (f ms -li ke t yr osi ne 
ki nase -3) a n d KI T w hic h are i n v ol ve d i n he mat o p oiesis a n d pla y a ke y r ole i n 
certai n  he mat o p oietic  dis or ders.  Mi d osta uri n  bi n ds  t o  t he  c atal ytic  d o mai n  of 
t hese ki nases a n d i n hi bits t he si g nali n g of t he res pecti ve gr o wt h fact ors i n cells 
a n d res ults i n gr o wt h arrest. T he a nti -pr oliferati ve effects of mi d osta uri n were 
easil y detecta ble i n F L T 3 -I T D, F L T 3-T K D a n d F L T 3 W T cells ( Weis ber g 2 0 0 2 , 
Barr y 2 0 0 7 ). Mi d osta uri n has als o bee n f o u n d t o re vert t he P -gl yc o pr otei n ( P g p) 
me diate d M D R ( m ulti dr u g resista nce) p he n ot y pe b y i n hi biti n g t he f u ncti o n of 
P g p ( Utz 1 9 9 8 ). 
Mi d osta uri n is c urre ntl y i n P hase II/ P hase III cli nical de vel o p me nt i ncl u di n g:  
•  
T w o p hase II si n gle ar m si n gle a ge nt st u dies i n patie nts wit h a g gressi ve 
s yste mic mast oc yt osis / Mast Cell Le u ke mia 

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•  
O ne p hase III ra n d o mize d, d o u ble- bli n d st u d y ( C A L G B 1 0 6 0 3; 
R A TI F Y) i n patie nts wit h F L T 3 -m utate d A M L.  
T he f oll o wi n g is a brief s u m mar y of t he mai n c haracteristics of mi d osta uri n. 
M ore  c o m plete  i nf or mati o n  ca n  be  o btai ne d  fr o m  t he  c urre nt  versi o n  of  
I n vesti gat ors’ Br oc h ure. 
Cli nic al e x perie nce  
P h ar m ac oki netic a n d p h ar m ac o dy n a mic d at a 
T he cli nical p har mac ol o g y of mi d osta uri n has bee n e xte nsi vel y st u die d i n healt h y 
v ol u nteers as well as  patie nts wit h A M L a n d dia betes mellit us ( Yi n 2 0 0 8 ; St o ne 
2 0 1 2 ). Mi d osta uri n is ra pi dl y a bs or be d f oll o wi n g oral a d mi nistrati o n wit h pea k 
plas ma  c o nce ntrati o ns  o bser ve d  1 -3  h o urs  p ost -d ose.  U p o n  dail y oral   d osi n g, 
mi d osta uri n c o nce ntrati o ns acc u m ulate d i n a ti me li near ma n ner i n t he first 3 - 8 
da ys. T hereafter, t he P K bec o mes n o n -li near wit h a n a p pare nt lar ge i ncrease i n 
C L/ F. T his relati vel y hi g h a p pare nt oral cleara nce necessitates a hi g h d osi n g rate 
(e. g. bi d  a d mi nistrati o n)  t o  mai ntai n  tar get  dr u g  le vels  i n  t he  l o n g  ter m.  
Mi d osta uri n c o nce ntrati o ns reac h stea d y -state after 2 8 da ys of dail y d osi n g. (Yi n 
2 0 0 8 ) I n vitr o st u dies ha ve s h o w n t hat mi d osta uri n, C G P 6 2 2 2 1, a n d C G P 5 2 4 2 1 
i n hi bit m uta nt F L T 3 at l o w na n o m olar c o nce ntrati o ns, wit h I C 5 0s of 1 0-3 6 n M, 
2 6 n M a n d 5 8 4 n M, res pecti vel y. ( Ma nle y 2 0 0 3 ; St o ne 2 0 1 2 ) 
Mi d osta uri n is pre d o mi na ntl y meta b olize d b y C Y P 3 A 4 is o -e nz y mes t o f or m t w o 
maj or,  p har mac ol o gicall y  acti ve  meta b olites  w hic h  ma y  c o ntri b ute  t o  i n  viv o 
acti vit y: C G P 6 2 2 2 1 ( half -life ~ 3 0 h o urs, c o m para ble t o mi d osta uri n’s half-life 
of ~ 2 5 h o urs) a n d C G P 5 2 4 2 1 ( half -life of ~ 2 8 da ys). P hase I st u dies i n healt h y 
v ol u nteers e val uate d t he effects of a str o n g C Y P 3 A 4 i n hi bit or ( ket oc o naz ole) a n d 
a str o n g C Y P 3 A 4 i n d ucer (rifa m pi n) o n c o nce ntrati o ns of mi d osta uri n a n d its 
meta b olites a n d t he effect of mi d osta uri n o n mi daz ola m (a se nsiti ve C Y P 3 A 4 
s u bstrate).  C o nc o mita nt  a d mi nistrati o n  wit h  str o n g  C Y P 3 A 4  i n hi bit ors  or  
i n d ucers  si g nifica ntl y  alters  mi d osta uri n  c o nce ntrati o ns.  Mi d osta uri n  d oes  n ot  
ca use a dr u g - dr u g i nteracti o n wit h C Y P 3 A 4 s u bstrates. 
F or  a d diti o nal  p har mac o ki netic  i nf or mati o n,  please  refer  t o  t he  I n vesti gat ors  
Br oc h ure. 
Overvie w of effic acy wit h mi d ost a uri n  
 
Mi d osta uri n has de m o nstrate d acti vit y i n patie nts wit h F L T 3- m utate d 
A M L/ m yel o d ys plastic  s y n dr o me ( M D S) i n st u dies [ C P K C 4 1 2 A 2 1 0 4] a n d 
[ C P K C 41 2 A 2 1 0 4 E 1] . I n t he [ C P K C 4 1 2 A 2 1 0 4 E 1] t he rate of B R ( blast 
re d ucti o n) f or t he efficac y p o p ulati o n ( n = 9 2) was 7 1 % i n F L T 3-m uta nt patie nts 
a n d 4 2 % i n F L T 3-W T pati e nts. O ne partial res p o nse ( P R) occ urre d i n a F L T 3 -
m uta nt patie nt o n t he 1 0 0 m g b.i. d. d ose re gi m e n. B ot h d oses le vels e val uate d i n 
t his trial ( 5 0 m g b.i. d., a n d 1 0 0 m g b.i. d.) were well t olerate d; t he t o xicit y 
pr ofiles a n d res p o nse rates were si milar f or t he t w o d oses of mi d osta uri n. T he 
res ults s u g gest t hat mi d osta uri n has he mat ol o gic acti vit y i n b ot h F L T 3-m ut a nt 
a n d wil d-t y pe patie nts. T he de gree of cli nical acti vit y o bser ve d s u p p orts f urt her 
st u dies t hat c o m bi ne mi d osta uri n a n d ot her a ge nts s uc h as c he m ot hera p y 
es peciall y i n F L T 3 - m uta nt A M L (Fisc her et al 2 0 1 0 ). Preli mi nar y data fr o m t he 
p hase I b st u d y of [ C P K C 4 1 2 A 2 1 0 6] of mi d osta uri n i n c o m bi nati o n  wit h sta n dar d 

M C 1 4 8 3 
9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
da u n or u bici n a n d Ara - C t hera p y i n patie nts wit h ne wl y dia g n ose d A M L patie nts 
i n dicate t hat mi d osta uri n at 5 0 m g p. o. b.i. d. ca n be gi ve n wit h o ut maj or si de 
effects i n t his patie nt p o p ulati on ( St o ne et al 2 0 0 9 , St o ne et al 2 0 1 2 ). Efficac y 
data f or t he 5 0 m g b.i. d. p o p ulati o n was prese nte d at t he A merica n S ociet y of 
He mat ol o g y ( A S H) i n 2 0 0 9. T he i n vesti gat or assess me nt of c o m plete res p o ns e 
( C R) occ urre d i n 3 2/ 4 0 ( 8 0 %) of all patie nts ( 2 0/ 2 7 ( 74 %) of F L T 3 – W T  patie nts, 
1 2/ 1 3 ( 9 2 %) of F L T 3 – m uta nt patie nts). O ne a n d 2 year o verall s ur vi val ( O S) f o r 
t he patie nts wit h F L T 3– m uta nt A M L was 8 5 % a n d 6 2 %, res pecti vel y, a n d was 
c o m para ble t o t hat of t he F L T 3– W T s u b gr o u p ( 8 1 % a n d 5 9 %, res pecti vel y). T his 
d ata was base d o n s mall  n u m bers a n d n ot stratifie d f or t y pe of F L T 3 m utati o n 
(t yr osi ne ki nase d o mai n ( T K D), I T D, I T D le n gt h, l ocati o n, or allelic rati o) (St o ne 
et al 2 0 0 9; St o ne et al 2 0 1 2 ) 
T his  st u d y s u p p orte d  t he  o n g oi n g d o u ble  bli n d,  place b o  c o ntr olle d,  p hase  III  
st u d y,  C P K C 4 1 2 A 2 3 0 1  ( C A L G B  1 0 6 0 3,  Ratif y),  i n  ne wl y  dia g n ose d  F L T 3  
m utate d A M L. E nr oll me nt i n t hat trial is c o m plete ( N = 7 1 7) a n d a waiti n g t he 
O verall S ur vi val ( O S) e ve nts re q uire d f or fi nal a nal ysis.  
I n a d diti o n t o t he A M L pr o gra ms descri be d a b o ve, a n o n g oi n g si n gle ar m, p hase 
II st u d y, C P K C 4 1 2 D 2 2 0 1 ( 2 2 0 1) i n a g gressi ve s yste mic mast oc yt osis / mast cell 
le u ke mia has c o m plete d e nr oll me nt wit h sta ge I ( N = 4 0) a n d e xte nsi o n ( N = 4 0) t o 
deter mi ne t he efficac y a n d safet y of 1 0 0 m g t wice dail y oral mi d osta uri n as a 
si n gle a ge nt. T he O verall Res p o nse Rate, per Vale nt criteria, f or sta ge I is 6 0 % 
( 2 4/ 4 0 eli gi ble patie nts) i ncl u di n g a maj or res p o nse rate of 5 2. 5 % ( 2 1/ 4 0 eli gi ble 
patie nts). ( G otli b 2 0 1 2 ) 
Ove rvie w of s afety wit h mi d ost a uri n 
O verall, a p pr o xi matel y 1 6 8 7 s u bjects ha ve recei ve d mi d osta uri n i ncl u di n g ~ 6 5 0 
patie nts wit h A M L / M D S. I n A M L patie nts, d oses of u p t o 6 0 0 m g per da y ha ve 
bee n gi ve n, b ut t he 5 0 m g t wice dail y d ose is rec o m me n de d base d u p o n  reac hi n g 
t he I C 5 0 a n d s h o wi n g acce pta ble t olera bilit y. Safet y data i n A M L are base d u p o n 
t hree  st u dies:  m o n ot hera p y  i n  F L T 3  m utate d  patie nts  ( 2 1 0 4  C ore;  N = 2 0),  
m o n ot hera p y i n rela pse d A M L or i neli gi ble f or c he m ot hera p y ( 2 1 0 4 E 1; N = 9 5) 
a n d  fr o nt -li ne  c o m bi nati o n  t hera p y  wit h  da u n or u bici n  a n d  c ytara bi ne  ( 2 1 0 6;  
N = 6 9).  ( St o ne  2 0 0 5 , Fisc her  2 0 1 0 , St o ne  2 0 1 2 ).  Data  fr o m  t he  mai nte na nce  
p hase of t he P hase III ( 2 3 0 1, C A L G B 1 0 6 0 3 Ratif y)  st u d y w o ul d als o be ver y 
i nf or mati ve b ut t he o n g oi n g trial re mai ns bli n de d at t his ti me. Si n gle a ge nt safet y 
data fr o m 2 1 0 4 E 1 will be disc usse d. 
I n st u d y 2 1 0 4 E 1, patie nts were ra n d o mize d t o recei ve mi d osta uri n at d oses of 5 0 
m g b.i. d. or 1 0 0 m g b.i. d. Of t he patie nts e nr olle d, 7 3 % were rela pse d/refract or y 
a n d  6 1 %  were  greater  t ha n  6 0  years  of  a ge.  Si x  patie nts  ha d  pre vi o usl y  
u n der g o ne H S C T. Mi d osta uri n was ge nerall y well t ole rate d at b ot h d ose le vels. 
All 9 5 patie nts e x perie nce d at least o ne A E re gar dless of relati o ns hi p t o st u d y 
dr u g. T he m ost fre q ue nt e ve nts were gra des 1 or 2 na usea ( 6 1 %; Gra de 3 was 
1 %), v o miti n g ( 4 9 %; Gra de 3 was 1 %), diarr hea ( 4 4 %; Gra de 3 or 4 was 5 %), 
fati g ue ( 3 8 %; Gra de 3 was 3 %), p yre xia ( 3 5 %; Gra de 3 was 7 %) a n d d ys p nea 
( 2 9 %; Gra de 3 or 4 9 %). T he m ost c o m m o nl y re p orte d gra de 3 / 4 A Es were 
fe brile ne utr o pe nia ( 2 1 %), t hr o m b oc yt o pe nia ( 1 9 %), ne utr o pe nia ( 1 2 %), a ne mia 
( 1 3 %) a n d p ne u m o nia ( 1 2 %). [I n v Broc h ure e d 1 6, T a ble 6 -2 0] T he decreases 
o bser ve d  i n  t he  he mat ol o g y  para meters  were  as  e x pecte d  f or  t his  patie nt  
p o p ulati o n.  O nl y  o ne  patie nt  disc o nti n ue d  treat me nt  d ue  t o  a  he mat ol o gic  

M C 1 4 8 3 
1 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
a b n or malit y  ( gra de  3  fe brile  ne utr o pe nia).  T he  maj orit y  of  ne w  or  w orse ne d 
bi oc he mistr y a b n or malities were of C T C gra de 1 -2. T here were gra de 3 or 4 
a b n or malities i n A S T/ A L T i n 1 3 % patie nts ( 2 were Gra de 4, b ot h recei vi n g 1 0 0 
m g b.i. d.), a m ylase 7 % a n d al b u mi n 5 %. T he f ull ta ble of ne wl y occ urri n g or 
w orse ni n g he mat ol o g y a n d c he mistr y a b n or malities is s h o w n i n t he I n vesti gat ors 
Br oc h ure. 
S A Es were re p orte d f or 7 1 ( 7 5 %) patie nts a n d m ost c o m m o nl y i ncl u de d: fe brile 
ne utr o pe nia  ( 2 0  patie nts),  p ne u m o nia  ( 1 7  patie nts),  p yre xia  ( 1 3  patie nts),  
d ys p nea ( 8 patie nts), t hr o m b oc yt o pe nia ( 7 patie nts) a n d a ne mia ( 6 patie nts). T he 
i nci de nce  of  S A Es  was  si milar  f or  b ot h  d ose  gr o u ps.  S A Es  were  m ostl y  
c o nsi dere d t o be d ue t o disease pr o gressi o n. Ei g htee n ( 1 9 %) patie nts ha d S A Es 
t hat  were  c o nsi dere d  relate d  t o  st u d y  dr u g,  wit h  gra de  3/ 4  a ne mia  a nd 
t hr o m b oc yt o pe nia bei n g t he m ost fre q ue ntl y re p orte d. 
A p o ole d safet y a nal ysis was perf or me d usi n g data a vaila ble fr o m 1 6 s oli d t u m or 
or  A M L/ M D S  st u dies.  Trials  i ncl u de d  c o m bi nati o ns  wit h  5 -F U,  paclita xel,  
ge mcita bi ne,  car b o plati n,  cis plati n,  da u n or u bici n,  a n d  c ytara bi ne.  T he  p o ole d  
a nal ysis i ncl u de d 6 2 7 s u bjects a n d t he m ost c o m m o n dr u g relate d t o xicities ( > 
2 0 %) i n t hese p hase I/II trials were na usea, v o miti n g a n d diarr hea, fati g ue, fe ver, 
hea dac he,  c o nsti pati o n,  a ne mia  a n d  decrease d  a p petite..  A Es  occ ur ri n g  less  
fre q ue ntl y  ( 1 0-1 9 %)  i ncl u de d  peri p heral  ede ma,  t hr o m b oc yt o pe nia,  c o u g h,  
a b d o mi nal  pai n,  d ys p nea,  h y p o kale mia,  fe brile  ne utr o pe nia,  i ns o m nia,  
ne utr o pe nia,  dizzi ness,  ast he nia,  bac k  pai n,  c hills,  ras h  a n d  h y p ote nsi o n  
(I n vesti gat ors Br oc h ure, e d 1 7) I n t he p o ole d a nal ysis, fre q ue ncies of car diac 
e ve nts were c o nsiste nt wit h t he i n vesti gate d p o p ulati o ns.  
A P hase I trial e val uate d t he effect of mi d osta uri n o n t he Q T c i nter val i n healt h y 
v ol u nteers i n a t h or o u g h Q T c st u d y. T he mea n ma xi m u m c ha n ge fr o m ba seli ne 
( Q Tc F) f or mi d osta uri n c o m pare d wit h place b o de m o nstrate d a lac k of Q Tc F 
pr ol o n gati o n effects. ( Del C orral 2 0 1 2 ) T his trial e val uate d mi d osta uri n a n d t he 
s h ort  acti n g  meta b olite  b ut  c o ul d  n ot  i n vesti gate  effects  of  t he  l o n g-acti n g 
meta b olite  at  stea d y  state.  T he  l o n g  acti n g  meta b olite  i nf or mati o n  ca n n ot  be  
attai ne d fr o m a healt h y v ol u nteer st u d y t h us will be pr o vi de d fr o m t he C A L G B 
1 0 6 0 3 ( Ratif y) dataset. 
O verall, A Es s us pecte d t o be relate d t o mi d osta uri n treat me nt were m ostl y Gra de 
1 a n d 2 gastr oi ntesti nal  e ve nts re q uiri n g little or n o i nter ve nti o n. T hese were 
c o nsi dere d  relate d  t o  mi d osta uri n,  as  t he  fre q ue nc y  i ncrease d  at  hi g her  d ose  
le vels. At t he 1 0 0 m g t wice dail y d ose i n A M L patie nts wit h c h e m ot hera p y, 
patie nts  disc o nti n ue d  treat me nt  m ore  fre q ue ntl y  d ue  t o  na usea  a n d  v o miti n g  
des pite a d diti o n of a ntie metic t hera p y w hic h c o ntri b ute d t o selecti o n of a 5 0  m g 
t wice dail y d ose w hic h was f o u n d t o be well t olerate d. I n a d diti o n t o pr o p h ylactic 
a nti-e metics, a d mi nisteri n g t he d oses wit h meals ca n re d uce gastr oi ntesti nal A Es. 
T hese A Es are m ost c o m m o n i n t he earl y c ycles of a d mi nistrati o n. I n t he o n g oi n g 
A S M/ M C L st u dies, patie nts are t olerati n g t he 1 0 0 m g t wice dail y d ose f or u p t o 
4 years; h o we ver, pr o p h ylactic a nti- e metics are gi ve n t o all patie nts. 
 
O ver vie w of decita bi ne  
 

M C 1 4 8 3 
1 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
Decita bi ne,  o ne  of  t he  h y p o met h ylati n g  a ge nts,  is  F D A  a p pr o ve d  f or  t he  
ma na ge me nt of m yel o d ys plastic s y n dr o me. I n E ur o pe decita bi ne is als o a p pr o ve d 
f or A M L i n el derl y patie nts 6 5 or ol der. It has bee n als o f o u n d t o beffecti v ei n 
patie nts  wit h  A M L.  F or  el derl y  A M L  patie nts  u nfit  f or  c he m ot hera p y,  
h y p o met h ylati n g a ge nts are t he c or nerst o ne f or treat me nt d ue t o its l o w t o xicit y 
a n d  safe  pr ofile.  I n  a  p hase  III st u d y  ( Ka ntarjia n  2 0 1 2),  decita bi ne  gi ve n  2 0  
m g/ m 2  as  1 -h o ur  i ntra ve n o us  i nf usi o n  dail y  f or  fi ve  da ys  e ver y  f o ur  wee ks  
i m pr o ve d  res p o nse  rates  c o m pare d  wit h  sta n dar d  t hera pies  wit h o ut  maj or  
differe nces i n safet y. C R was ac hie ve d i n 1 8 % wit h decita bi ne vers us 8 % i n t he 
ot her ar m.  
 
 
 1. 3  
St u d y r ati o n ale/ p ur p ose  
 
A M L  has  bee n  a  c halle n gi n g  ca ncer  f or  he mat ol o gists  a n d  a d ult patie nts.  
C o m bi nati o n c he m ot hera p y usi n g c ytara bi ne a n d a nt hrac ycli ne ( k n o w n as 7 + 3 ) 
i n d ucti o n s uccess a n d rela pse rates ha ve bee n c halle n ge d b y ma n y c o nce pts but 
yet re mai ns t he sta n dar d t hera p y. T hese strate gies i ncl u de d usi n g hi g her d oses of 
a nt hrac ycli ne or c ytara bi ne, a d diti o n of n o vel a ge nts (li ke pr ote os o me i n hi bit ors 
or m o n ocl o nal a nti b o dies (li ke ge mt uz u ma b oz o ga mici n), or e ve n usi n g a ge nts 
directe d a gai nst dr u g -resista nce tar gets. Fer na n dez H et c ollea g ues ra n d o mize d 
6 5 7 patie nts dia g n ose d wit h A M L bet wee n t he a ges of 1 7 -6 0 t o recei ve 7 + 3  b ut 
at  differe nt  d oses  f or  da u n or u bici n  ( 9 0  m g/ m 2  vs  4 5  m g/ m 2).  Patie nts  w h o  
recei ve d hi g h d ose da u n or u bici n ha d hi g her c o m plete re missi o n rates ( 7 0 % vs 
5 7 %, p < 0. 0 0 1) a n d better me dia n o verall s ur vi val ( 2 3. 7 m o nt hs vs 1 5. 7 m o nt hs, 
p = 0. 0 0 3) { Fer na n dez, 2 0 0 9 }. I n a si milar st u d y re p orte d b y L o we n ber g et al, 8 1 3 
patie nts were ra n d o mize d t o t he sa me treat me nt b ut i n patie nts e q ual or ol der 
t ha n 6 0 years. T he c o m plete re missi o n rate fa v ore d t he hi g her d ose da u n or u bici n 
( 6 4 % vs 5 4 %, p = 0. 0 0 2), h o we ver t he o verall s ur vi val di d n ot differ si g nifica ntl y 
{ L o we n ber g, 2 0 0 9 } . D ose i nte nsificati o n of c ytara bi ne was st u die d c o m pare d t o 
sta n dar d d ose ( 2 g m/ m 2 I V q 1 2 h o urs x 1 2 d oses vs. 2 0 0 m g/ m 2/ da y c o nti n u os 
I V dail y x 7 da ys) i n a d diti o n t o da u n or u bici n 4 5 m g/ m 2 dail y x 3 da ys i n A M L 
patie nts less t ha n 6 5 years ol d. A t otal of 6 6 5 patie nts were treate d w here C R 
rates 5 5 % vs 5 8 % ( hi g h vs sta n dar d d ose c ytara bi ne) f or patie nts a ge d less t ha n 
5 0 a n d t here was n o si g nifica nt differe nce i n 4- year o verall s ur vi val ( 3 2 % vs 
2 2 %, p = 0. 4 1) { Weic k, 1 9 9 6 }. T he Britis h he mat ol o gists teste d t he r ole of a d di n g 
ge mt uz u ma b  oz o ga mici n  3 m g/ m 2  o n  da y  1  of  i n d ucti o n  a n d  c o urse  3  of  
c o ns oli dati o n) t o i n d ucti o n c he m ot hera p y i n t heir M R C A M L 1 5 trial i n 1 1 1 3 
patie nts  dia g n ose d  wit h  A M L  a n d  a ge  less  t ha n  6 0 { B ur nett,  2 0 1 1  # 5 8 }.  
U nf ort u natel y, n o o verall s ur vi val be nefit was f o u n d t o a d di n g t his treat me nt i n 
neit her  i n d ucti o n  n or  c o ns oli dati o n.  O n  s u bse q ue nt  a nal ysis,  patie nts  wit h  
fa v ora ble  c yt o ge netics  ha d  a  fa v ora ble  effect  fr o m  a d di n g  ge mt uz ua m b  
( p= 0. 0 0 1). Fi nall y, i n ra n d o mize d st u d y d o ne b y E C O G ( 3 9 9 9), t he a d diti o n of 
z os u q ui dar  (a  m o d ulat or  of  P -gl yc o pr otei n),  di d  n ot  i m pr o ve  t he  o utc o me  of  
ol der  patie nts  ne wl y  dia g n ose d  wit h  A M L  ( 4 9 9  patie nts) { Cri pe,  2 0 1 0 }. 
Re missi o n  rate  was  5 2 %  vs  4 9 %  ( p 0. 1 5 8)  o n  place b o,  w hile  me dia n  o verall  
s ur vi val was 7. 2 vs 9. 4 m o nt hs o n place b o c o m pare d t o patie nts w h o recei ve d 
z os u q ui dar. 
 

M C 1 4 8 3 
1 2 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
O ver t he last deca de, m olec ular brea kt hr o u g hs i n u n dersta n di n g t he ge nes r ole 
a n d pat h wa ys g o ver ni n g t he cell c ycles, pr oliferati o n, a p o pt osis a n d tra nscri pti o n 
ha ve  re v ol uti o nize d  o ur  u n dersta n di n g  a n d  treat me nt  of  m yel oi d  disease,  
es peciall y  c hr o nic  m yel oi d  le u ke mia,  m yel o pr oliferati ve  ne o plas ms  a n d  ac ute  
m yel oi d le u ke mias. Base d o n t his m olec ular pr ofili n g we are a ble t o i de ntif y hi g h 
ris k  A M L  cases  f or  l o w  c ha nce  of  re missi o n  a n d  hi g h  ris k  of  rela pse.  
C o nse q ue ntl y  t his  affecte d  o ur  treat me nt  rec o m me n dati o n,  es peciall y  wit h  
re gar ds t o w het her t o pr ocee d wit h all o ge neic tra ns pla ntati o n or n ot. F or e xa m ple 
patie nts har b ori n g C E B P A m utati o n (si n gle vs d o u ble m utati o ns) ha d a fa v ora ble 
o utc o me c o m pare d wit h wil d t y pe A M L cases { T as kese n, 2 0 1 1 }. I n fact d o u ble 
m utati o n  C E B P A  was  t he  o nl y  pr o g n ostic  fact or  f or  o verall  s ur vi val  o n  
m ulti variate a nal ysis ( hazar d rati o 0. 3 6, p < 0. 0 0 0 1). O n t he ot her ha n d , hi g h E VI 1 
e x pressi o n i n y o u n g patie nts dia g n ose d wit h A M L pre dicts w orse o utc o me b y 
ha vi n g l o w C R rates ( o d d rati o 0. 5 4, p = 0. 0 0 2) a n d a d verse e ve nt-free s ur vi val 
( hazar d rati o 1. 4 6, p < 0. 0 0 1) {Gr osc hel, 2 0 1 0 }. Patie nts w h o recei ve d all o ge neic 
ste m cell tra ns pla ntati o n i n C R 1 ha d a better 5-year rela pse free s ur vi val ( 3 3 % vs 
0 %) c o m pare d t o wit h o ut tra ns pla ntati o n. F L T 3 is a n ot her p ote ntial ge ne, w here 
m utati o ns  (i nter nal  ta n de m  d u plicate  or  t yr osi ne  ki nase  d o mai n  m utati o n)  
pre dicts  w orse  cli nical  o utc o me  (es peciall y  i n  patie nts  wit h  n or mal  
c yt o ge netics) {K ottari dis,  2 0 0 1 } { W hit ma n,  2 0 0 8  } { Stire walt,  2 0 0 6 }.  T his  
beca me  of ut m ost si g nifica nce si nce ma n y F L T 3 i n hi bit ors ha ve bee n teste d i n 
trials  wit h  e nc o ura gi n g  res ults.  T his  i ncl u de  b ot h  as  a  si n gle  a ge nt  a n d  i n  
c o m bi nati o n wit h c he m ot hera p y { Fisc her, 2 0 1 0 } { Le vis, 2 0 1 1 # 6 9 } { B ort ha k ur, 
2 0 1 1 } { Al - Kali, 2 0 1 1 } { Zarri n kar, 2 0 0 9 }.  
 
We pla n t o st u d y t he cli nical efficac y of P K C 4 1 2  i n c o m bi nati o n wit h sta n dar d 
decita bi ne  i n el derl y patie nts wit h F L T 3 m utate d A M L as a fr o ntli ne t hera p y. We 
will assess t heir C R rates, s ur vi val o utc o me ( pr o gressi o n- free s ur vi val ( PF S ) a n d 
o verall  s u r vi val  (O S) ) i n  a d diti o n  t o  pre dicti ve  fact ors  f or  s u peri or  o utc o me.  
Decita bi ne  is  o ne  of  t he  well -esta blis he d  a n d  wi del y  use d  re gi me n s f or  t he  
treat me nt  of  el derl y  A ML.  I n  a d diti o n,  it  has  bee n  F D A  a p pr o ve d  f or  t he  
treat me nt of patie nts wit h m yel o d ys plastic s y n dr o me ( M D S).  
 
2. 0  
G o als    
 
2. 1  
Pri mar y  
 
2. 1 1 
T o deter mi ne t he c o m plete res p o nse rate f or el derl y patie nts wit h F L T 3 
m utate d A M L usi n g mi d osta uri n a n d decita bi ne 
 
2. 2  
Sec o n dar y 
 
2. 2 1 
Deter mi ne  t he 1-year O S a n d P F S rates.  
 
2. 2 2 
Deter mi ne o verall  res p o nse rates i n patie nts treate d wit h t his re gi me n. 
 
2. 2 3 
Deter mi ne t he c o m plete res p o nse  d urati o n i n patie nts treate d wit h t his 
re gi me n. 
 
2. 2 4 
Assess t he safet y a n d t o xicit y of t his re gi me n base d o n N CI C T C A E 
versi o n 4. 0. 

M C 1 4 8 3 
1 3 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
2. 3 
C orrelati ve Researc h  
 
2. 3 1  
A ssess t he pr o g n ostic a n d pre dicti ve fact ors (F L T 3 I T D vs T K D 
m utati o n)  f or patie nts treate d wit h t his re gi me n. 
 
2. 3 2  
E x pl ore ge netic tar gets f or t his disease.  
 
 
3. 0 
P ati e nt Eli gi bilit y   
 
3. 1  
I ncl usi o n Criteria 
 
3. 1 1 
A ge ≥ 6 0 years ol d . 
 
3. 1 2  
U nfit f or c he m ot hera p y base d o n i n vesti gat or assess me nt  or patie nt n ot 
willi n g t o recei ve i nte nsi ve i n d ucti o n  as a d vise d b y i n vesti gat or. 
 
3. 1 3  
U ntreate d, h ist ol o gical c o nfir me d ac ute m yel oi d le u ke mia ( A M L) base d 
o n W H O 2 0 0 8 criteria ( See A p pe n di x I V)  wit h eit her/ or b ot h: 
  
 
•  
F L T 3 I T D m utati o n 
•  
F L T 3 T K D m utati o n  
 
3. 1 4 
E C O G Perf or ma nce Stat us ( P S)  0, 1, 2  or 3  ( A p pe n di x II). 
 
3. 1 5  
T he f oll o wi n g la b orat or y val ues o btai ne d  ≤ 7 da ys pri or t o re gistrati o n. 
•  
Ser u m a m ylase a n d li pase ≤ 1. 5 x U L N 
•  
T otal Bilir u bi n ≤1. 5  x U L N [ D oes n o t a p pl y t o patie nts wit h is olate d 
h y per bilir u bi ne mia (e. g., Gil bert’s disease), i n t hat case direct 
bilir u bi n s h o ul d be ≤ 2 x U L N ] 
•  
Al kali ne p h os p hatase ≤3 x U L N  
•  
S G O T ( A S T)  ≤2. 5  x U L N  
•  
S G P T ( A L T)  ≤2. 5 x U L N  
•  
Creati ni ne ≤2 x U L N  
 
3. 1 6 
Ne gati ve  pre g na nc y test d o ne ≤7 da ys pri or t o re gistrati o n, f or  w o me n of 
c hil d beari n g p ote ntial o nl y.  
 
3. 1 7  
Pr o vi de i nf or me d writte n c o nse nt. 
 
3. 1 8 
Willi n g t o ret ur n t o c o nse nti n g Ma y o Cli nic ( Ma y o Cli nic’s ca m p us i n 
R oc hester ), f or f oll o w- u p d uri n g t he Acti ve M o nit ori n g P hase of t he 
st u d y. 
 
3. 1 9       Willi n g t o pr o vi de b o ne marr o w as pirate a n d bl o o d sa m ples f or 
c orrelati ve researc h p ur p oses (see Secti o ns 6. 2 a n d 1 4. 1).  
 
  
3. 2  
E xcl usi o n Criteria  
 

M C 1 4 8 3 
1 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
3. 2 1a  W o me n of c hil d- beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y 
ca pa ble  of bec o mi n g pre g na nt, u nless t he y are usi n g hi g hl y effecti ve 
met h o ds of c o ntrace pti o n d uri n g d osi n g a n d f or 3 m o nt hs after treat me nt 
c o m pleti o n. 
 
Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de: 
•  
T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d  us ual 
lifest yle of t he s u bject. N O T E: Peri o dic a bsti ne nce (e. g., cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost - o v ulati o n met h o ds) a n d wit h dra wal 
are n ot acce pta ble met h o ds of c o ntrace pti o n  
•  
Fe male sterilizati o n ( ha ve ha d s ur gical bilateral o o p h orect o m y wit h 
or wit h o ut h ysterect o m y) or t u bal li gati o n at least si x wee ks bef ore 
ta ki n g st u d y treat me nt. I n c ase of o o p h orect o m y al o ne, o nl y w he n 
t he re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d b y f oll o w 
u p h or m o ne le vel assess me nt  
•  
Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). N O T E: F or 
fe male s u bjects o n t he st u d y t he vasect o mize d male part ner s h o ul d 
be t he s ole part ner f or t hat s u bj ect.  
•  
C o m bi nati o n of a n y t w o of t he f oll o wi n g (a + b or a +c, or b +c): 
a. Use of oral, i nj ecte d or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n or ot her 
f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y 
(fail ure rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or 
tra ns der mal h or m o ne c o ntrace pti o n. 
b.  Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m 
(I U S)      
c. Barrier met h o ds of c o ntrace pti o n: C o n d o m or Occl usi ve ca p 
( dia p hra g m or cer vical/ va ult ca ps) wit h s per mici dal 
f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y 
N O T E:  
•  
I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble 
o n t he sa me pill f or a mi ni m u m of  3 m o nt hs bef ore ta ki n g st u d y 
treat me nt. 
•  
W o me n  are  c o nsi dere d  p ost -me n o pa usal  a n d  n ot  of  c hil d  beari n g 
p ote ntial  if  t he y  ha ve  ha d  1 2  m o nt hs  of  nat ural  (s p o nta ne o us)  
a me n orr hea wit h a n a p pr o priate cli nical pr ofile (e. g. a ge a p pr o priate, 
hist or y of vas o m ot or s y m pt o ms). 
O R  
3. 2 1 b 
Se x uall y acti ve males u nless t he y use a c o n d o m d uri n g i nterc o urse w hile 
ta ki n g dr u g a n d f or 5 m o nt hs after st o p pi n g mi d osta uri n me dicati o n.  
 
N O T E:    
•  
T he y s h o ul d n ot fat her a c hil d i n t his peri o d.  
•  
A c o n d o m is re q uire d t o be use d als o b y vasect o mize d me n i n or der 
t o pre ve nt deli ver y of t he dr u g via se mi nal fl ui d. 
 

M C 1 4 8 3 
1 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
3. 2 2  
C o -m or bi d s yste mic ill nesses or o t her se vere c o nc urre nt disease w hic h, 
i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he patie nt i na p pr o priate 
f or e ntr y i nt o t his st u dy or i nterfere si g nifica ntl y wit h t he pr o per 
assess me nt of safet y a n d t o xicit y of t he prescri be d re gi me ns.  
 
3. 2 3 
I m m u n oc o m pr o mise d patie nts ( ot her t ha n t hat relate d t o t he use of 
c ortic oster oi ds) i ncl u di n g patie nts c o nfir me d  t o be HI V p ositi ve or ha ve 
active viral he patitis.  
 
3. 2 4  
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or 
acti ve i nfecti o n, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit 
c o m plia nce wit h st u d y re q uire me nts. Patie nts wit h a n y ot her k n o w n  
c o nc urre nt se vere a n d/or u nc o ntr o lle d me dical c o n diti o n ( e x ce pt 
car ci n o ma i n-sit u), w h ic h c o ul d c o m pr omi se partici pati o n i n t he 
st u d y ( e.g. u nc o ntr o lle d i nfecti o n, u nc o ntr olle d dia bet es, c hr o nic 
acti ve p a ncreatitis) . 
 
3. 2 5 
Recei vi n g a n y ot her i n vesti gati o nal a ge nt w hic h w o ul d be c o nsi dere d as 
a treat me nt f or t he pri mar y ne o plas m.  
 
3. 2 6 
Ot her acti ve m ali g na nc y ≤1 year  pri or t o re gistrati o n.  E X C E P TI O N S:  
N o n -mela n otic s ki n ca ncer or carci n o ma -i n-sit u of t he cer vi x.   
 
3. 2 7 
Pre vi o us treat me nt wit h s pecific c he m ot hera p y (c ytara bi ne, i dar u bici n, 
da u n or u bici n) or h y p o met h ylati n g dr u g ( decita bi ne or azaciti di ne) f or a 
he mat ol o gical dis or der. E X C E P TI O N S: Pri or h y dr o x y urea all o we d. 
Sec o n dar y A M L is all o we d.   
 
3. 2 8  
I m paire d car diac f u ncti o n i ncl u di n g a n y of t he f oll o wi n g: 
•  
I na bilit y t o m o nit or t he Q T i nter val o n E C G 
•  
C o n ge nital l o n g Q T s y n dr o me or a k n o w n fa mil y hist or y of l o n g Q T 
s y n dr o me. 
•  
Cli nicall y si g nifica nt resti n g brac h ycar dia ( < 5 0 beats per mi n ute)  
•  
Q T c > 4 5 0 msec o n baseli ne E C G. N O T E:  If t he E C G s h o ws a Q T c 
i nter val greater t ha n 4 5 0 msecs at scree ni n g tri plicates s h o ul d be 
perf or me d, o ne mi n ute a part t o c o nfir m t he fi n di n g (after 
re place me nt of a n y electr ol yte i m bala nce). If 2/ 3 or 3/ 3 of t he E C Gs 
c o nfir m t he Q T pr ol o n gati o n (i.e. Q T c i nter val > 4 5 0 msecs) t he 
patie nt m ust n ot be i ncl u de d i nt o t he trial.  
•  
M y ocar dial i nfarcti o n ≤3 m o nt hs pri or t o starti n g st u d y 
•  
O t her cli nicall y si g nifica nt u nc o ntr olle d heart disease (e. g. u nsta ble 
a n gi na, c o n gesti ve heart fail ure or u nc o ntr olle d h y perte nsi o n)  
•  
Hist or y of or prese nce of cli nicall y si g nifica nt ve ntric ular , atrial 
tac h yarr h yt h mias or ejecti o n fracti o n c ut off  
•  
L eft ve ntricle ejecti o n fracti o n < 4 5 %  
•  
Hist or y of  Co n gesti ve heart  fail ure re q uiri n g use of o n g oi n g 
  
mai nte na nce t hera p y f or life-t hreate ni n g ve ntric ular arr h yt h mias.  
 
3. 2 9a  Patie nts c urre ntl y recei vi n g treat me nt wit h str o n g C Y P 3 A 4 i n hi bit ors 

M C 1 4 8 3 
1 7 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
Etra viri ne (I ntele nce ®)  
M o dafi nil ( Pr o vi gil ®)  
Nafcilli n  
Ge nistei n  
Rit o na vir  
T al yirali ne  
T hi ori dazi ne 
Ti pra na vir 
Ne vira pi ne ( Vira m u ne ®)  
P he n o bar bital ( L u mi nal ®) 
Rifa b uti n ( M yc o b uti n ®) 
Tr o glitaz o ne  
 
3. 2 9c 
Patie nts c urre ntl y recei vi n g treat me nt wit h a n y me dicati o ns t hat ha ve t he 
p ote ntial t o pr ol o n g t he Q T i nter val a n d t he treat me nt ca n n ot be eit her 
disc o nti n ue d or s witc he d t o a differe nt me dicati o n pri or t o starti n g st u d y 
dr u g.  N O T E: Pr o hi bite d me dicati o ns are liste d i n A p pe n di x Ia “ Dr u gs 
Wit h Ris k of T orsa des de P oi ntes.” A p pe n di x I b c o ntai ns dr u gs t hat 
s h o ul d be use d wit h ca uti o n d ue t o p ossi ble or c o n diti o nal ris k of 
T orsa des de P oi ntes.  
 
3. 2 9 d 
I m paire d gastr oi ntesti nal ( GI) f u ncti o n or GI disease t hat ma y 
si g nifica ntl y alter t he a bs or pti o n of st u d y dr u g (e. g., ulcerati ve diseases, 
u nc o ntr olle d na usea, v o miti n g, diarr hea, mala bs or pti o n s y n dr o m e, s mall 
b o wel resecti o n or gastric b y pass s ur ger y).  
 
3. 2 9e 
Ac ute or c hr o nic pa ncreatic disease.  
 
3. 2 9f  
K n o w n c yt o pat h ol o gicall y c o nfir me d C N S i nfiltrati o n.  
 
3. 2 9 g 
Ac ute or c hr o nic li ver disease or se vere re nal disease c o nsi dere d 
u nrelate d t o t he ca ncer. 
 
3. 2 9 h  Hist or y of si g nifica nt c o n ge nital or ac q uire d blee di n g dis or der u nrelate d 
t o ca ncer. 
 
3. 2 9i 
Maj or s ur ger y ≤4 wee ks pri or t o re gistrati o n of t he st u d y or w h o ha ve 
n ot rec o vere d fr o m pri or s ur ger y re gard less of ti me si nce s ur ger y. 
 
3. 2 9j 
Treat me nt wi t h ot her i n vesti gati o nal a ge nts ≤3 0 da ys  or 5 half - li ves of 
re gistrati o n. 
 
3. 2 9 k    Dia g n osis of A M L- M 3 ( or ac ute pr o m yel oc ytic le u ke mia).  

M C 1 4 8 3 
1 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
4. 0 
Test Sc he d ule   
All r o uti ne assess me nts m ust be perf or me d wit hi n ±  7 da ys of t he da y i n dicate d o n t he Visit Sc he d ule. 
 
Pre -Treat me nt  
Acti ve Treat me nt  
 
T ests a n d  pr oce d ures  
≤ 7 da ys  
pri or t o  
re gistrati o n*  
 
C ycle 
1, 
Da y 1   
 
C ycle 
1, Da y 
8  
 
C ycle 1 
Da y 2 1  
 
C ycles 2 a n d 
a b o ve, Da y 1  
C ycles 2 a n d 
a b o ve, Da y 8 7 
Earl y Disc o nti n uati o n or 
E n d of Treat me nt  
Hist or y a n d e x a m, wei g ht, vit als, P S  
X  
X  
 
 
X  
X  
X  
Hei g ht  
X  
 
 
 
 
 
 
A d verse e ve nt assess me nt  
X  
X  
 
 
X  
 
X  
B M testi n g 2  
X  
 
 
 
X 2 
 
X  
    Bi o mar kers F L T 3  M utati o n  b y P C R  
X  
 
 
 
 
 
X  
Pre g na nc y T est  
X  
 
 
 
 
 
 
He mat ol o g y gr o u p ( C B C) 
 
H g B, , P L T, W B C wit h diff.
 1 
X 
X 1 
 
X 
 
X 
X 1 
X 
X 
S er u m C he mistr y  
( ma g nesi u m, p otassi u m, p h os p h or us, t otal 
bilir u bi n,  direct bilir u bi n 5, al kali ne 
p h os p hatase, A S T, A L T, creati ni ne ) 
X 
X 
 
X  
 
X 
X 
X 
X 
Ser u m C he mistr y  
( Ser u m A m ylase & Li pase) 
X 
X 
 
 
X 
 
X 
M U G A/ Ec h o  
X  
 
 
 
 
 
 
L D H  
X  
 
 
 
 
 
 
Uri ne a nal ysis   ( pr otei n uria, he mat uria)R  
X 
 
 
 
 
 
 
E C G ( Q T c F res ults preferre d) R 3  
X 
 
X  
 
 
X 3 
X  
P atie nt Me dicati o n Diar y ( A p pe n di x  III4) 
 
 
X  
 
X 
X 
 
Researc h C orrelati ves R, , 6 
X  
 
X  
 
X 6  
 
 
*     La bs d o ne o n t he sa me da y of c o nse nt b ut pri or t o c o nse nti n g d o n ot nee d t o be re peat e d.  
1. 
C B C will be d o ne wee kl y f or c ycle 1 - 4.  After c ycle 4, t o be perf or me d Da y 1 a n d Da y 8.  
2.  B o ne marr o w ( B M) sa m pli n g will be d o ne u p o n scree ni n g, a n d da y 1 of c ycle 3, 5, 9 a n d t he n as cli nicall y nee de d. Rece nt b o ne marr o w 
wit hi n 2 1 da ys  (e ve n pri or t o c o nse nti n g) will be acce pta ble a n d F L T 3 P C R c o ul d be d o ne o n peri p heral bl o o d if blasts > 1 0 %. O utsi de F L T 3 

M C 1 4 8 3 
1 9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
testi n g at b o ne marr o w bi o ps y will be all o we d a n d use d if d o ne. 
3. 
E C Gs will be perf or me d l ocall y at scree ni n g, Da y 8  ( pri or t o d osi n g) of eac h c ycle, a n d w he n t here’s a n y d ose c ha n ge d ue t o Q T c 
pr ol o n gati o n  or re -i nitiati o n after a d ose i nterr u pti o n. W he n a d ose c ha n ge occ urs d ue t o Q Tc pr ol o n gati o n or u p o n re -starti n g mi d osta uri n, a n 
E C G m ust be o btai ne d at 7 da ys after war ds. Q T c F res ults are preferre d, h o we ver all re p orti n g met h o ds will be acce pte d.  
4.  T he diar y m ust be gi n t he da y t he patie nt starts ta ki n g mi d osta uri n a n d m ust be c o m plete d per pr ot oc ol a n d ret ur ne d t o t he treati n g i nstit uti o n 
O R c o m plia nce m ust be d oc u me nte d i n t he me dical rec or d b y a n y me m ber of t he care tea m.  Patie nts will be as ke d t o ret ur n all u n use d 
me dicati o n at eac h visit.  
5. 
Get direct bilir u bi n  if t otal bilir u bi n > u p per n or mal li mit. 
6.  C orrelati ves f or bl o o d a n d b o ne marr o w.  See secti o n 1 4. 
7. 
If mi d osta uri n is starte d o n da y 1, t he n d o t hese tests o n da y 1.  If mi d osta uri n is starte d o n da y 8, t he n d o t hese tests o n da y 8. 
R  Researc h f u n de d (see Secti o n 1 9. 0). T his w ill be c har ge d t o st u d y a n d n ot t o patie nt’s acc o u nt. 

M C 1 4 8 3 
2 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
5. 0 
Gr o u pi n g F act ors: N o ne    
 
 
6. 0  
Re gistr ati o n Pr o ce d ures 
 
6. 1  
T o re gister a patie nt, access t he Ma y o Cli nic Ca ncer Ce nter ( M C C C) we b pa ge 
a n d e nter t he re gistrati o n/ra n d o mizati o n a p plicati o n.  T he 
re gistrati o n/ra n d o mizati o n a p plicati o n is a vaila ble 2 4 h o urs a da y, 7 da ys a wee k.  
Bac k u p a n d/ or s yste m s u p p ort c o ntact i nf or mati o n is a vaila ble o n t he We b site.  
If u na ble t o access t he We b site, call t he M C C C Re gistrati o n Office at 
 bet wee n t he h o urs of 8 a. m. a n d 4: 3 0 p. m. Ce ntral Ti me ( M o n da y t hr o u g h 
Fri da y).  
 
T he i nstr ucti o ns f or t he re gistr ati o n/ra n d o mizati o n a p plicati o n are a vaila ble o n 
t he M C C C we b pa ge (htt p://ccs w w w. ma y o.e d u/trai ni n g ) a n d detail t he pr ocess 
f or c o m pleti n g a n d c o nfir mi n g patie nt re gistrati o n.  Pri or t o i nitiati o n of pr ot oc ol 
treat me nt, t his pr ocess m ust be c o m plete d i n its e ntiret y a n d a M C C C s u bject I D 
n u m ber m ust be a vaila ble as n ote d i n t he i nstr ucti o ns.  It is t he res p o nsi bilit y of 
t he i n di vi d ual re gisteri n g t he patie nt t o c o nfir m t he pr ocess has bee n s uccessf ull y 
c o m plete d pri or t o release of t he st u d y a ge nt.  Patie nt  re gistrati o n via t he 
re gistrati o n/ra n d o mizati o n a p plicati o n ca n be c o nfir me d i n a n y of t he f oll o wi n g 
wa ys:  
•  
C o ntact t he M C C C Re gistrati o n Office 
  If t he patie nt was 
f ull y re gistere d, t he M C C C Re gistrati o n Office staff ca n access t he 
i nf or mati o n fr o m t he ce ntralize d data base a n d c o nfir m t he re gistrati o n. 
•  
Refer t o “I nstr ucti o ns f or Re m ote Re gistrati o n” i n secti o n 
“ Fi n di n g/ Dis pla yi n g I nf or mati o n a b o ut A Re gistere d S u bj ect.” 
 
6. 2 
C orrelati ve Researc h  
A ma n dat or y  c orrelati ve researc h c o m p o ne nt is part of t his st u d y. T he patie nt 
will be a ut o maticall y re gistere d o nt o t his c o m p o ne nt ( S ee Secti o ns 3. 1 9 a n d 
1 4. 0). 
 
6. 3  
D oc u me ntati o n of I R B a p pr o val m ust be o n file i n t he Re gistrati o n Office bef ore 
a n i n vesti gat or ma y re gister a n y patie nts.  
 
I n a d diti o n t o s u b mitti n g i nitial I R B a p pr o val d oc u me nts, o n g oi n g I R B a p pr o val 
d oc u me ntati o n m ust be o n file ( n o less t ha n a n n uall y) at t he Re gistrati o n Office 
  If t he necessar y d oc u me ntati o n is n ot s u b mitte d i n a d va nce 
of atte m pti n g patie nt re gi strati o n, t he re gistrati o n will n ot be acce pte d a n d t he 
patie nt ma y n ot be e nr olle d i n t he pr ot oc ol u ntil t he sit uati o n is res ol ve d. 
 
W he n t he st u d y has bee n per ma ne ntl y cl ose d t o patie nt e nr oll me nt, s u b missi o n of 
a n n ual I R B a p pr o vals t o t he Re gistrati o n O ffice is n o l o n ger necessar y. 
 
6. 4 
Pri or t o acce pti n g t he re gistrati o n, re gistrati o n a p plicati o n will verif y t he 
f oll o wi n g: 
•  
I R B a p pr o val at t he re gisteri n g i nstit uti o n 
•  
Patie nt eli gi bilit y  
•  
E xiste nce of a si g ne d c o nse nt f or m 

M C 1 4 8 3 
2 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
•  
E xiste nce of a si g ne d a ut h orizati o n f or use a n d discl os ure of pr otecte d healt h 
i nf or mati o n  
 
6. 5  
At t he ti me of re gistrati o n, t he f oll o wi n g will be rec or de d:  
•  
Patie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or 
f ut ure researc h of A M L  at Ma y o. 
•  
Patie nt has/ has n ot gi v e n per missi o n t o st ore a n d use his/ her sa m ple(s) f or 
f ut ure researc h t o lear n, pre ve nt, or treat ot her healt h pr o ble ms. 
•  
Patie nt has/ has n ot gi ve n per missi o n f or M C C C t o gi ve his/ her sa m ple(s) t o 
researc hers at ot her i nstit uti o ns. 
 
6. 6 
Treat me nt ca n n ot be gi n pri or t o re gistrati o n a n d m ust be gi n ≤ 7 da ys after 
re gistrati o n. 
 
6. 7 
Pretreat me nt tests/ pr oce d ures (see Secti o n 4. 0) m ust be c o m plete d wit hi n t he 
g ui deli nes s pecifie d o n t he test sc he d ule.  
 
6. 8  
All re q uire d baseli ne s y m pt o ms (see Secti o n 1 0. 5) m ust be d oc u me nte d a n d 
gra de d. 
 
6. 9a  
Treat me nt o n t his pr ot oc ol m ust c o m me nce at Ma y o Cli nic R oc hester  u n der t he 
s u per visi o n of a he mat ol o gist. 
 
6. 9 b  
St u d y dr u g is a vaila ble o n site.  
 
 
7. 0  
P r ot oc ol Tre at me nt  
 
7. 1 
Treat me nt Sc he d ule  
 
7. 1 1 
Patie nts eli gi ble f or t he st u d y base d o n scree ni n g tests will be e nr olle d o n 
t he st u d y.  
•  
Patie nts will pr ocee d t o ne xt c ycle e ver y 2 8 da ys ( or later) base d  o n 
i n vesti gat or o pi ni o n w he n re vie wi n g eac h case base d o n 
he mat ol o gical a n d p h ysical fi n di n gs.  
•  
Patie nts w h o t olerate c o m bi nati o n t hera p y well a n d fail t o ac hie ve 
C R/ C Ri/ P R/ m or p h ol o gic le u ke mia -free state b y e n d of c ycle 2, 
c o ul d get mi d osta uri n o n da ys 1 -2 8 of eac h s u bse q ue nt c ycle, rat her 
t ha n j ust da ys 8- 2 1, as per treati n g M D decisi o n. 
•  
Patie nts w h o ac hie ve a C R/ C Ri / P R/ m or ph ol o gic le u ke mia -free state 
b y e n d of c ycle 8 will c o nti n ue o n c urre nt re gi me n.   
•  
Patie nts w h o fail t o ac hie ve a C R/ C Ri/ P R/ m or p h ol o gic le u ke mia -
free state i n b o ne marr o w blasts b y e n d of c ycle 8 will g o t o e ve nt 
m o nit ori n g.  
•  
Patie nts will get a re peat b o n e marr o w bi o ps y o n da y o ne of c ycle s 3, 
5, 9 a n d t he n as cli nicall y i n dicate d (see T est Sc he d ule, secti o n 4. 0). 
Patie nts w h o ac hie ve C R/ C Ri will n ot nee d re peat b o ne marr o w 
assess me nt u nless dee me d necessar y b y i n vesti gat or.  
•  
H y dr o x y urea a n d/ or le u k oc yta p h eresis use is all o we d t o c o ntr ol 
risi n g blasts as dee me d necessar y b y treati n g i n vesti gat or at a n y 

M C 1 4 8 3 
2 2 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
ti me.  
 
 
C ycle le n gt h = 2 8 da ys ( +/- 7 da ys)  
A ge nt  
D ose  
R o ute  D a y  
C o m me nts  
D ecita bi ne 1 
2 0 m g/ m 2 
I V  
1 -5   
C o ul d be gi ve n da ys 2 -5 b y l ocal M D  
( o utsi de Ma y o Cli nic). 
Mi d osta uri n
2 
5 0 m g 
t wice/ da y 
Oral  
8 -2 1  
Mi d osta uri n c o ul d be gi ve n c o nti n u o usl y 
( da y 1- 2 8) starti n g c ycle 3 base d o n M D 
decisi o n (see 7. 1 1).  
1.  Ma y be hel d as per treati n g p h ysicia n j u d g me nt. 
2.  If d ecita bi ne is hel d , the n mi d osta uri n will be hel d. If d ecita bi ne is a d mi nistere d, 
mi d osta uri n ca n n ot be hel d, b ut ca n be o mitte d. 
 
7. 1 2  
Ma xi m u m c ycles of mi d osta uri n are 1 8, after w hic h a disc ussi o n wit h 
N o vartis will be d o ne o n a per patie nt  basis w het her t o kee p patie nt o n 
c o nti n ue d t hera p y wit h t he c o m bi nati o n of decita bi ne a n d mi d osta uri n  o n 
st u d y (c o nti n ue acti ve m o nit ori n g per secti o n 4. 0).    
 
7. 1 3      If mi d osta uri n is disc o nti n ue d, s i n gle a ge nt Decita bi ne ma y  be gi ve n 
be y o n d c ycle 1 8 off pr ot oc ol u ntil rela pse or disease pr o gressi o n  off 
pr ot oc ol. T he patie nt will g o t o e ve nt m o nit ori n g per secti o n 1 8. 0 
 
  
N ote:  If si n gle a ge nt Decita bi ne is bei n g gi ve n off pr ot oc ol, t he e n d of 
acti ve treat me nt f or m s h o ul d be fille d o ut at t he e n d of c ycle 1 8.  Reas o n 
treat me nt en de d s h o ul d be re p orte d as treat me nt  c o m plete d per pr ot oc ol 
criteria. 
 
7. 1 4 
Ste m Cell Tr a ns pl a nt ati o n ( S C T):  All o ge neic ste m cell tra ns pla ntati o n 
f or i nter me diate a n d hi g h ris k patie nts ( base d o n treati n g M D 
assess me nt) will be all o we d at a n y ti me if a s uita ble d o n or is f o u n d a n d 
patie nt perf or ma nce stat us all o ws. Decita bi ne a n d Mi d osta uri n will be 
disc o nti n ue d a n d t he patie nt will g o t o e ve nt m o nit ori n g per secti o n 1 8. 0 
 
7. 1 5 
If eit her dr u g is disc o nti n ue d d uri n g treat me nt, t he patie nt will g o t o 
e ve nt m o nit ori n g per secti o n 1 8. 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

M C 1 4 8 3 
2 3 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
8. 0  
D os a ge M o dific ati o n B ase d o n A d verse E ve nts  
 
A L E R T : 
A D R re p orti n g m ay be re q uire d f or s o me a dverse eve nts ( See Secti o n 1 0) 
 
•  
O mit = T he c urre nt d ose(s) f or t he s pecifie d dr u g(s) d uri n g a c ycle is s ki p pe d.  T he 
patie nt d oes n ot ma ke u p t he o mitte d d ose(s ) at a later ti me 
•  
H ol d/ Dela y = T he c urre nt d ose(s) of all dr u gs d uri n g a c ycle is dela ye d.  T he patie nt d oes 
ma ke u p t he dela ye d d ose(s) w he n t he patie nt meets t he pr ot oc ol criteria t o restart dr u gs.  
•  
Disc o nti n ue = T he s pecifie d dr u g(s) are t otall y st o p pe d.    
 
N ote:  If eit her dr u g is disc o nti n ue d d uri n g treat me nt, t he patie nt will g o t o e ve nt 
m o nit ori n g per secti o n 1 8. 0 
 
8. 1  
D ose Le vels ( Base d o n A d verse E ve nts i n T a bles bel o w)   
D ose 
Le vel  
D ose  
Dr u g N a me  
 0  
 
5 0 m g orall y bi d  
mi d osta uri n  
 
 

M C 1 4 8 3 
2 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
8. 2 
Mi d osta u ri n d ose a dj ust me nts f or A E at least p ossi bl y relate d t o treat me nt 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or ga n/ Class 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N  
A T TI M E O F N E X T D O S E ( All tre at me nt d ays of e ac h cycle)  
Bl o o d a n d l y m p hatic 
s yste m dis or ders 
Gra de 4 Fe brile 
Ne utr o pe nia  
Mi d osta uri n
1  
 
1 st e ve nt: 
First e ve nt  da ys 2 - 2 8, o mit  
mi d osta uri n d ose u ntil rec o ver y t he n 
restart at 5 0 m g b.i. d  
2 n d e ve nt  : 
O mit  mi d osta uri n u ntil rec o ver y t he n 
restart at 2 5 m g b.i. d f or 2 wee ks a n d 
t he n re-escalate t o 5 0 m g b.i. d as 
t olerate d. 
3r d e ve nt: 
T hir d e ve nt, patie nt s h o ul d be 
disc o nti n ue d if ne utr o pe nia is 
attri b uta ble t o mi d osta uri n 
I n vesti gati o ns 
Gra de  3 or 4 
i ncrease d Bilir u bi n, 
A S T , or A L T 
If alter nate ca uses of li ver 
d ysf u ncti o n ha ve bee n ma na ge d, b ut 
li ver d ysf u ncti o n persists, O mit  
mi d osta uri n u ntil rec o ver y t o Gra de 2 
t he n restart. 
 
If t his is felt t o be relate d t o st u d y 
dr u g a n d t he re- c halle n ge res ults i n a 
s u bse q ue nt Gra de 3 or 4 ele vati o n, 
t he n patie nt s h o ul d be disc o nti n ue d 
fr o m treat me nt. 
Gastr oi ntesti nal 
Dis or ders  
Gra de 2 Na usea or 
V o miti n g  
Mi d osta uri n
1  
 
If t his de vel o ps des pite use of 
sta n dar d a nti-e metic t hera p y a n d 
persists f or at least 3 da ys, O mit  
mi d osta uri n f or 3 da ys ( 6 d oses) a n d 
res u me mi d osta uri n as t olerate d. 
Gra de 3 or 4 Na usea 
or V o miti n g  
If t his de vel o ps a n d persists des pite 
use of sta n dar d a nti- e metic t hera p y, 
o mit  mi d osta uri n u ntil rec o ver y t o 
Gra de 2 ( or at least 3 da ys) t he n 
restart. If t his is felt t o be relate d t o 
st u d y dr u g a n d t he re- c halla n ge 
res ults i n a s u bse q ue nt Gra de 3 or 4 
t o xicit y t he n t he patie nt s h o ul d be 
disc o nti n ue d fr o m treat me nt. 
 

M C 1 4 8 3 
2 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
  Use t he N CI C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or ga n/ Class 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N  
Gastr oi ntesti nal 
Dis or ders  
Gra de 3 or 4 Diarr hea  
If t his de vel o ps a n d persists des pite 
use of sta n dar d a nti- diarr heal 
t hera p y(see sectio n 9. 4), o mit  
mi d osta uri n u ntil rec o ver y t o Gra de 2 
( or at least 3 da ys) t he n restart.  
 
Res pirat or y, t h oracic 
a n d me diasti nal 
dis or ders 
Gra de 3 or 4 
P ne u m o nitis 
O mit  mi d osta uri n u ntil rec o ver y t o < 
Gra de 1 a n d t he n res u me d osi n g.  
I n vesti gati o ns 
 
C urre ntl y t he effect of mi d osta uri n o n Q Tc i nter val pr ol o n gati o n is n ot f ull y 
c haracterize d. T heref ore, all patie nts e x perie nci n g a p ost baseli ne pr ol o n ge d 
Q T c  i nter val  m ust  ha ve  p otassi u m  a n d  ma g nesi u m  c hec ke d  a n d  a n y  
electr ol ytes  i m bala nces  c orrecte d.  A d diti o nall y,  t he  i n vesti gat or  s h o ul d  
c o nsi der t he ris k be nefit of a n y c o nc o mita nt me dicati o ns t hat ma y pr ol o n g t he 
Q T c i nter val. F or t he p ur p ose of t his trial, t he c orrecti o n f or m ula acc or di n g t o 
Fre dericia, i.e. Q Tc F  is bei n g referre d t o - w here ver Q T c is me nti o ne d.  
 
Electr ocar di o gra m 
Q T c orrecte d i nter val 
pr ol o n ge d- E C G > 
4 5 0 msec 
 
 
Mi d osta uri n
1 
If t he E C G s h o ws a Q T c i nter val 
greater t ha n 4 5 0 msecs d uri n g t he 
trial, tri plicates s h o ul d be perf or me d, 
o ne mi n ute a part t o c o nfir m  t he 
fi n di n g (after re place me nt of a n y 
electr ol yte i m bala nce).  
E C G  Q T c i nter val  > 
4 5 0 msecs a n d ≤ 4 7 0 
msecs  
C hec k ma g nesi u m a n d p otassi u m 
le vels a n d c orrect a n y a b n or malities. 
If p ossi ble, st o p a n y me dicati o ns t hat 
ma y pr ol o n g t he Q T c i nter val. 
C o nti n ue mi d osta uri n at t he sa me 
d ose.  
E C G Q T c i nter val > 
4 7 0 msecs a n d ≤ 5 0 0 
msecs,  
C hec k ma g nesi u m a n d p otassi u m 
le vels a n d c orrect a n y a b n or malities. 
If p ossi ble, st o p a n y me dicati o ns t hat 
ma y pr ol o n g t he Q T c i nter val. 
Decrease mi d osta uri n t o 2 5 m g t wice 
d ail y 1 d ose le vel f or t he re mai n der of 
t he c ycle Res u me mi d osta uri n at t he 
i nitial d ose i n t he ne xt c ycle pr o vi de d 
t hat Q Tc i nter val i m pr o ves t o ≤ 4 7 0 
msecs.  

M C 1 4 8 3 
2 6 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
  Use t he N CI C o m m o n Ter mi n ol o gy Criteri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or ga n/ Class 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N  
E C G Q T c i nter val > 
5 0 0 msecs 
Mi d osta uri n  
C hec k ma g nesi u m a n d p otassi u m 
le vels a n d c orrect a n y a b n or malities. 
O mit  mi d osta uri n f or t he re mai n der 
of t he c ycle, a n d, if p ossi ble, st o p a n y 
me dicati o ns t hat ma y pr ol o n g t he 
Q T c i nter val. If Q T c i m pr o ves t o ≤ 
4 7 0 msecs j ust pri or t o t he ne xt c ycle, 
res u me mi d osta uri n at t he i nitial d ose. 
If Q T c i nter val is n ot i m pr o ve d i n 
ti me t o start t he ne xt c ycle d o n ot 
a d mi nister mi d osta uri n d uri n g t hat 
c ycle. 
 
Ot her N o n -
he mat ol o gical  
 
Gra de 4 N o n - 
He mat ol o gic  
Disc o nti n ue  mi d osta uri n f or n o n-
he mat ol o gic gra de 4 t o xicit y 
(i ncl u di n g gra de 4 v o miti n g, diarr hea, 
a n d p ne um o nitis). Mi d osta uri n s h o ul d 
be hel d f or ot her n o n- he mat ol o gic 
gra de 3 t o xicit y u ntil rec o ver y t o < 
Gra de 2. U p o n rec o ver y, t he patie nt 
ma y restart d osi n g.  If a d diti o nal 
t o xicit y rec urs, t he mi d osta uri n d ose 
will be re d uce d t o 2 5 m g b.i. d.  I n t he 
e ve nt of a d diti o nal t o xicit y re q uiri n g 
d ose m o dificati o n, f urt her d ose 
re d ucti o ns t o mi d osta uri n 2 5 m g Q. D. 
will be all o we d.   If t he patie nt 
t olerates t he l o wer d ose of 
mi d osta uri n ( 2 5 m g b.i. d), a d ose 
i ncrease bac k t o 5 0 m g b.i. d ma y be 
atte m pte d as t olerate d. Fat i g ue a n d 
hair l oss are e xe m pte d.  
1If d ecita bi ne is hel d , the n mi d osta uri n will be hel d. If d ecita bi ne is a d mi nistere d, 
mi d osta uri n ca n n ot be hel d, b ut ca n be o mitte d. 
 
All d ose m o dificati o ns s h o ul d be base d o n t he w orst prece di n g t o xicit y.  C o m m o n 
T o xicit y Criteria f or A d verse E ve nts ( C T C A E Versi o n 4. 0) 
 
If mi d osta uri n  is o mitte d  d ue t o Q Tc pr ol o n gati o n  or w he n t here’s a n y d ose c ha n ge , a n E C G 
m ust be o btai ne d at 7 da ys after war ds .  
 

M C 1 4 8 3 
2 7 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
8. 3 
Decita bi ne d ose m o dificati o n: 
•  
M o dificati o n will be d o ne as per sta n dar d rec o m me n dati o n a n d treati n g 
p h ysicia n j u d ge me nt f or patie nt ’s best i nterest  a n d will be mai nl y base d o n 
n o n- he mat ol o gical A Es . 
•  
F or creati ni ne A Es, creati ni ne cleara nce will be calc ulate d usi n g C oc kcr oft 
f or m ula wit h t otal b o d y wei g ht a n d ge n der a dj ust me nt. 
  
 
 
9. 0 
A ncill ar y Tre at me nt/ S u p p orti ve C are  
 
9. 1  
A ntie metics ma y be use d at t he discreti o n of t he atte n di n g p h ysicia n.  
 
9. 2  
Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be utilize d as cli nicall y warra nte d a n d 
f oll o wi n g i nstit uti o nal p olicies a n d rec o m me n dati o ns.   
 
9. 3  
Patie nts s h o ul d recei ve f ull s u p p orti ve care w hile o n t his st u d y.  T his i ncl u des 
bl o o d pr o d uct s u p p ort, a nti bi otic treat me nt, a n d treat me nt of ot her ne wl y 
dia g n ose d or c o nc urre nt me dical c o n diti o ns.  All bl o o d pr o d ucts a n d 
c o nc o mita nt me dicati o ns  s uc h as a nti diarr heals, a nal gesics, a n d/ or a ntie metics 
recei ve d fr o m t he first da y of st u d y treat me nt a d mi nistrati o n u ntil 3 0 da ys 
after t he fi nal d ose will be rec or de d i n t he me dical rec or ds.  
 
9. 4 
A ntif u n g al a nti bi otics:   It is hi g hl y rec o m me n de d t o a v oi d c o nc o mita nt str o n g 
C Y P 3 A 4 i n hi bit ors (e. g., ket oc o naz ole, itrac o naz ole, v oric o naz ole, 
p osac o naz ole). T he s u g geste d a ntif u n gal re gi me ns fr o m a dr u g meta b olis m 
pers pecti ve t o a v oi d t o use is descri be d bel o w: 
 
Pr o p h yla xis:  
  
Fl uc o naz ole ( m o derate C Y P 3 A 4 i n hi bit or)  
  
Cas p of u n gi n 
 
 
If a patie nt re q uires acti ve treat me nt f or a f u n gal or m ol d i nfecti o n a n d t here are 
n o ot her treat me nt o pti o ns it bec o mes necessar y t o a d mi nister a n az ole w hic h is a 
str o n g C Y P 3 A 4 i n hi bit or.  If  t his  is  nee de d,  t he  s u g geste d  a ge nts  fr o m  a  
dr u g  meta b olis m  a n d  safet y pers pecti ve i ncl u de:  
 
 
Treat me nt  
  
V oric o naz ole  
 
P osac o naz ole  
  
T hese are b ot h str o n g C Y P 3 A 4 i n hi bit ors a n d will li kel y i ncrease mi d osta uri n 
c o nce ntrati o ns, t heref ore, if t here are n o ot her treat me nt o pti o ns t o treat t he 
i nfecti o n, a d ose re d ucti o n b y 5 0 % of mi d osta uri n is re q uire d t o c o m pe nsate f or 
t he dr u g i nteracti o ns wit h t hese str o n g C Y P 3 A 4 i n hi bit ors. Wit h i ntra-patie nt 
varia bilit y wit h re gar d t o C Y P 3 A 4 i n hi biti o n a n d mi d osta uri n p har mac o ki netics, 
t he s u g geste d a p pr oac h is t o a v oi d str o n g C Y P 3 A 4 i n hi bit ors u nless t here are n o 
treat me nt alter nati ves. 
 
9. 5        H y dr o x y urea: Ca n be use d f or c o ntr ol of ele vate d W B C / blasts at a n y ti me of 
treat me nt f or patie nt best care a n d a v oi d c o m plicati o ns of h y perle u k oc yt osis. 
 
 
 

M C 1 4 8 3 
2 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 0. 0 
A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
 
1 0. 1 
A d verse E ve nt C haracteristics  
 
C T C A E ter m ( A E descri pti o n) a n d gr a de:   T he descri pti o ns a n d gra di n g 
scales f o u n d i n t he re vise d N CI C o m m o n T er mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E) versi o n  4. 0 will be utilize d f or A E re p orti n g.  All a p pr o priate 
treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 4. 0.  A c o p y 
of t he C T C A E versi o n 4. 0 ca n be d o w nl oa de d fr o m t he C T E P we b site:  
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m )    
 
1 0. 1 1  A d verse e ve nt m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical 
trial.  First, i de ntif y a n d gra de t he se verit y of t he e ve nt usi n g t he C T C A E 
versi o n 4. 0 .  Ne xt, deter mi ne w het her t he e ve nt is e x pecte d or 
u ne x pecte d (see Secti o n 1 0. 2) a n d if t he a d verse e ve nt is relate d t o t he 
me dical treat me nt or pr oce d ure (see Secti o n 1 0. 3).  Wit h t his 
i nf or mati o n, deter mi ne w het her t he e ve nt m ust be re p orte d as a n 
e x pe dite d re p ort (see Secti o n 1 0. 4). E x pe dite d re p orts are t o be 
c o m plete d wit hi n t he ti mefra mes a n d via t he mec ha nis ms s pecifie d i n 
Secti o ns 1 0. 4. All A Es re p orte d via e x pe dite d mec ha nis ms m ust als o be 
re p orte d via t he r o uti ne data re p orti n g mec ha nis ms defi ne d b y t he 
pr ot oc ol (see Secti o ns 1 0. 5 2 a n d 1 8. 0). 
 
1 0. 1 2  Eac h C T C A E ter m i n t he c urre nt versi o n is a u ni q ue re prese ntati o n of a 
s pecific e ve nt use d f or me dical d oc u me ntati o n a n d scie ntific a nal ysis a n d is a 
si n gle Me d D R A L o west Le vel Ter m ( L L T).   
  
•  
N O T E:  A se vere A E, as d efi ne d b y t he a b o ve gra di n g scale, is 
N O T  t he sa me as seri o us A E w hic h is d efi ne d i n t he ta ble i n 
Secti o n 1 0. 4. 
 
1 0. 2  
E x pecte d vs. U ne x pecte d E ve nts  
 
•  
T he deter mi nati o n of w het her a n A E is e x pecte d is base d o n a ge nt-
s pecific inf or mati o n pr o vi de d i n Secti o n 1 5. 0 of t he pr ot oc ol. 
 
•  
U ne x pecte d A Es are t h ose n ot liste d i n t he a ge nt -s pecific 
i nf or mati o n pr o vi de d i n Secti o n 1 5. 0 of t he pr ot oc ol. 
 
N O T E : “ U ne x pecte d a d verse e x perie nces” mea ns a n y a d verse e x perie nce t hat is 
neit her i de ntifie d i n nat ure, se verit y, or fre q ue nc y of ris k i n t he i nf or mati o n 
pr o vi de d f or I R B re vie w n or me nti o ne d i n t he c o nse nt f or m.  
 
1 0. 3 
Assess me nt of Attri b uti o n  
 
W he n assessi n g w het her a n a dverse eve nt is rel ate d t o a me dic al tre at me nt or 
pr oce d ure, t he f oll o wi n g attri b uti o n c ate g ories are utilize d:  
 
Defi nite - T he a d verse e ve nt is cle arly rel ate d t o t he a ge nt(s). 
Pr o ba ble - T he a d verse e ve nt is likely rel ate d t o t he a ge nt(s). 
P ossi ble - T he a d verse e ve nt m ay be rel ate d t o t he a ge nt(s). 

M C 1 4 8 3 
2 9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
U nli kel y - T he a d verse  e ve nt is d o u btf ully rel ate d t o t he a ge nt(s). 
U nrelate d - T he a d verse e ve nt is cle arly N O T rel ate d t o t he a ge nt(s). 
 
E ve nts deter mi ne d t o be p ossi bl y, pr o b a bl y or defi nitel y attri b ute d 
t o a me dic al tre at me nt s u g gest t here is e vi de nce t o i n dic ate a c a us al 
rel ati o ns hi p bet wee n t he dr u g a n d t he a d verse e ve nt .  
 
1 0. 3 1  A Es E x perie n ce d Utilizi n g I n vesti g ati o n al A ge nts a n d C o m merci al 
A g e nt(s) o n t he S A M E  Ar m  
 
N O T E:  T he c o m bi nati o n of a n i n vesti gati o nal a ge nt wit h a c o m mercial 
a ge nt is c o nsi dere d i n vesti gati o nal. 
 
R o uti n e Re p orti n g 
 
•  R o uti ne A E re p orti n g f or P hase 1 a n d P hase 2 cli nical st u dies 
usi n g a n i n vesti gati o nal a ge nt /i nter ve nti o n i n c o mbi nati o n wit h a 
c o m mercial a ge nt is state d i n t he pr ot oc ol.  See Secti o n 1 0. 5 2.  
 
N O T E:   W he n a c o m mercial a ge nt(s) is (are) use d o n t he 
sa me treat me nt ar m as t he i n vesti gati o nal a ge nt/i nter ve nti o n 
(als o, i n vesti gati o nal dr u g, bi ol o gic, cell ular pr o d uct, or ot her 
i n vesti gati o nal t hera p y u n der a n I N D), t he e ntire c o m bi nati o n 
(ar m) is t he n c o nsi dere d a n i n vesti gati o nal i nter ve nti o n f or 
re p orti n g. 
 
E x pe dite d Re p orti n g  
 
•  A n A E t hat occ urs o n a c o m bi nati o n st u d y m ust be assesse d i n 
acc or da nce wit h t he g ui deli nes f or C T E P i n vesti gati o nal 
a ge nts/i nter ve nti o ns i n Secti o n 1 0. 4, a n d w here i n dicate d, a n e x pe dite d 
re p ort m ust be s u b mitte d. 
 
• A n A E t hat occ urs pri or t o a d mi nistrati o n of t he i n vesti gati o nal 
a ge nt/i nter ve nti o n m ust be assesse d as s pecifie d i n t he pr ot oc ol. I n 
ge neral, o nl y Gra de 4 a n d 5 A Es t hat are u ne x pecte d wit h at least 
p ossi ble attri b uti o n t o t he c o m mercial a ge nt re q uire a n e x pe dit e d 
re p ort.  Refer t o Secti o n 1 0. 4 f or s pecific A E re p orti n g 
re q uire me nts or e xce pti o ns. 
 
•  C o m mercial a ge nt e x pe dite d re p orts m ust be s u b mitte d t o t he F D A via 
Me d Watc h.  
 
•  A n i n vesti gati o nal a ge nt/i nter ve nti o n mi g ht e xacer bate t he e x pecte d 
A Es ass ociate d wit h a c o m mercial a ge nt.  T heref ore, if a n e x pecte d 
A E (f or t he c o m mercial a ge nt) occ urs wit h a hi g her de gree of se verit y, 
e x pe dite d re p orti n g is re q uire d.  T he cli nical i n vesti gat or m ust 
deter mi ne se verit y.  
 

M C 1 4 8 3 
3 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 0. 3 2  S p e ci al Sit u ati o ns f o r E x p e dit e d R e p o rti n g  a n d s u b mi ssi o n of 
N otific ati o n F or ms  
 
E xce pti o ns t o E x pe dite d Re p orti n g  a n d S u b missi o n of N otific ati o n 
F or ms : E X P E C T E D Seri o us A d verse E ve nts 1 
 
A n e x pe dite d re p ort or n otificati o n f or m ma y n ot be re q uire d f or s pecific 
Seri o us A d verse E ve nts w here t he A E is liste d i n Secti o n 1 5. 0 of t he 
pr ot oc ol as E X P E C T E D . A n y pr ot oc ol s pecific re p orti n g pr oce d ures 
M U S T B E S P E CI FI E D B E L O W a n d will s u perse de t he sta n dar d 
E x pe dite d A d verse E ve nt Re p orti n g a n d N otificati o n F or m 
Re q uire me nts (see f o ot n ote 1):  
 
  
 
S yste m Or ga n Class 
( S O C) 
 
A d verse e ve nt/ S y m pt o ms  
 
C T C A E Gra de at 
w hic h t he e ve nt will 
n ot be e x pe dite dl y 
re p orte d. 
Ge neral dis or ders a n d 
a d mi nistrati o n site 
c o n diti o ns 
Fati g ue  
Fe brile ne utr o pe nia  
≤Gra de 3  
Meta b olis m a n d n utriti o n 
dis or ders  
H y p o p h os p hate mia  
≤Gra de 3  
Bl o o d a n d ly m p hatic  
s yste m dis or ders 
A ne mia  
≤Gra de 4  
I n vesti gati o ns 
L y m p h oc yte c o u nt decrease d  
≤Gra de 4  
Ne utr o p hil c o u nt decrease d  
≤Gra de 4  
Platelet c o u nt decrease d  
≤Gra de 4  
W hi te bl o o d cell decrease d 
≤Gra de 4  
1  T hese e xce pti o ns o nl y a p pl y if t he a d verse e ve nt d oes n ot res ult i n h os pitalizati o n.  If t he 
a d verse e ve nt res ults i n h os pitalizati o n, t he n t he sta n dar d e x pe dite d a d verse e ve nts re p orti n g 
re q uire me nts m ust be f oll o we d. 
 
S pecific pr ot oc ol e xce pti o ns t o e x pe dite d re p orti n g s h o ul d be re p orte d 
e x pe diti o usl y b y i n vesti gat ors O N L Y  if t he y e xcee d t he e x pecte d gra de of t he 
e ve nt. 
 
1 0. 3 2 1  P ersiste nt or Si g nific a nt Dis a bilities/I nc a p acities  
A n y A E t hat res ults i n 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 
(f or merl y referre d t o as disa bilities), c o n ge nital a b n or malities or birt h 
defects, must be re p orte d i m me diatel y if t he y occ ur at a n y ti me 
f oll o wi n g treat me nt wit h a n a ge nt u n der a n I N D/I D E si nce t he y are 
c o nsi dere d t o be a seri o us A E a n d must be re p orte d t o t he s p o ns or as 
s pecifie d i n 2 1 C F R 3 1 2. 6 4( b). 
 
1 0. 3 2 2  De at h  
 
•  
A n y deat h occ urri n g wit hi n 3 0 d a ys of t he last d ose, 
re gar dless of attri b uti o n t o a n a ge nt/i nter ve nti o n 

M C 1 4 8 3 
3 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
u n der a n I N D/I D E r e q uir es e x p e dit e d r e p orti n g 
wit hi n 2 4 -h o urs.  
 
•  
A n y deat h occ urri n g greater t ha n 3 0 da ys wit h a n 
attri b uti o n of p ossi ble, pr o ba ble, or defi nite t o a n 
a ge nt/i nter ve nti o n u n der a n I N D/I D E r e q uir es 
e x p e dit e d r e p orti n g wit hi n 2 4 -h o urs.  
 
•  
Re p o rt a bl e c at e g o ri es of De at h   
 
•  
De at h attri b ut a bl e t o a C T C A E t er m.  
 
•  
De at h Ne o n at al:  A dis or d er c h ar a ct eri ze d 
b y c ess ati o n of lif e d uri n g t h e first 2 8 d a ys 
of lif e.  
 
•  
De at h N O S:  A c ess ati o n of lif e t h at c a n n ot b e 
attri b ut e d t o a C T C A E t er m ass o ci at e d wit h 
Gr a d e 5.  
 
•  
S u d d e n d e at h N O S:  A s u d d e n ( d efi n e d as 
i nst a nt or wit hi n o n e h o ur of t h e o ns et of 
s y m pt o ms) or a n u n o bs er v e d c ess ati o n of lif e 
t h at c a n n ot b e attri b ut e d t o a C T C A E t er m 
ass o ci at e d wit h Gr a d e 5.  
 
•  
De at h d u e t o pr o gr essi ve dis e as e s h o ul d b e 
r e p ort ed as Gr a d e 5 “ Ne o pl as ms b e ni g n , 
m ali g n a nt a n d u ns p e cifi e d (i n cl u di n g  c ysts 
a n d p ol y ps) – Ot h e r ( P r o g r essi v e Dis e as e) ” 
u n d er t h e s yst e m or ga n cl ass ( S O C) of t h e 
s a me n a me.  E vi d e n c e t h at t h e d e at h was a 
ma nif est ati o n of u n d erl yi n g dis e as e ( e. g., 
r a di ol o gi c al c h a n ges s u g g esti n g t u m or gr o wt h 
or pr o gr essi o n: cli ni c al d eteri or ati o n 
ass o ci at e d wit h a dis e as e pr o c ess) s h o ul d b e 
s u b mitt e d. 
 
1 0. 3 2 3   Sec o n d ar y M ali g n a nc y 
 
• 
A sec o n d ary m ali g n a ncy is a ca ncer ca use d b y treat me nt f or a 
pre vi o us mali g na nc y (e. g., treat me nt wit h i n vesti gati o nal 
a ge nt/i nter ve nti o n, ra diati o n or c he m ot hera p y).  A 
sec o n dar y mali g na nc y is n ot c o nsi dere d a metastasis of t he 
i nitial ne o plas m. 
 
• 
All sec o n dar y mali g na ncies t hat occ ur f oll o wi n g treat me nt 
wit h a n a ge nt u n der a n I N D/I D E nee d t o be re p or te d. T hree 
o pti o ns are a vaila ble t o descri be t he e ve nt:  
 

M C 1 4 8 3 
3 2 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
o  Le u ke mia sec o n dar y t o o nc ol o g y c he m ot hera p y (e. g., 
Ac ute M yel o i d Le u ke mia [ A M L])  
 
o  M yel o d ys plastic s y n dr o me ( M D S)  
 
o  Treat me nt -relate d sec o n dar y mali g na nc y 
 
•  
A n y mali g na nc y p ossi bl y relate d t o ca ncer treat me nt 
(i ncl u di n g A M L/ M D S) s h o ul d als o be re p orte d via t he 
r o uti ne re p orti n g mec ha nis ms o utli ne d i n eac h pr ot oc ol. 
 
1 0. 3 2 4  Sec o n d M ali g n a nc y  
• 
A sec o n d mali g na nc y is o ne u nrelate d t o t he treat me nt of a 
pri or mali g na nc y (a n d is N O T a metastasis fr o m t he i niti al 
mali g na nc y).  Sec o n d mali g na ncies re q uire O N L Y r o uti ne 
re p orti n g. 

M C 1 4 8 3 
3 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
A d diti o nal I nstr ucti o ns: 
1. 
A n i ncrease d i nci de nce of a n e x pecte d a d verse e ve nt ( A E) is base d o n t he patie nts 
treate d f or t his st u d y at t heir site.  A list of k n o w n/e x pecte d A Es is re p orte d i n t he 
pac ka ge i nsert or t he literat ure, i ncl u di n g A Es res ulti n g fr o m a dr u g o ver d ose. 
2.  S u b mit f or m t o t he F D A, Me d Watc h, 5 6 0 0 Fis hers La ne, R oc k ville, M D 2 0 8 5 2-
9 7 8 7, b y fa x at 
or o nli ne at 
htt p:// w w w.f da. g o v/ Safet y/ Me d Watc h/ H o w T o Re p ort/ defa ult. ht m .   
 
 
Ma y o Cli nic Ca ncer Ce nter ( M C C C) I nstit uti o ns:  Pr o vi de c o pies, al o n g wit h t he 
U PI R T S O c o ver s heet, b y fa x 
 t o t he M C C C Re g ulat or y Affairs 
U nit ( R A U) Ris k I nf or mati o n S pecialist w h o will deter mi ne a n d c o m plete I R B 
re p orti n g. T he R A U will s u b mit t o t he M C C C S A E C o or di nat or a n d t he M C C C 
I N D C o or di nat or t o deter mi ne if F D A s u b missi o n is nee de d 
  
 
 
R E P O R TI N G  T O N O V A R TI S  
 
 
C o ntact N o vartis wit hi n 2 4 h o urs: 8 7 7- 7 7 8- 9 7 3 9(see a p pe n di x V ) 
 
Re p orti n g  
F or patie nts w h o si g n t he mai n st u d y I C F, S A E c ollecti o n starts at ti me of mai n st u d y 
i nf or me d c o nse nt w het her t he patie nt is a scree n fail ure or n ot. 
T o e ns ure patie nt safet y, e ver y S A E, re gar dless of s us pecte d ca usalit y, occ urri n g after t he 
patie nt has pr o vi de d i nf or me d c o nse nt a n d u ntil at l east 3 0 da ys after t he patie nt has 
st o p pe d st u d y treat me nt m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its 
occ urre nce.  
A n y S A Es e x perie nce d after t his 3 0 da ys peri o d ( or 5 half -li ves) w hic he ver is l o n ger) 
s h o ul d o nl y be re p orte d t o N o vartis if t he i n vesti gat or s us pects a ca usal relati o ns hi p t o t he 
st u d y treat me nt.  Rec urre nt  e pis o des,  c o m plicati o ns,  or  pr o gressi o n of t he  i nitial  S A E 
m ust be re p orte d as f oll o w -u p t o t he ori gi nal e pis o de wit hi n 2 4 h o urs of t he i n vesti gat or 
recei vi n g t he f oll o w-u p i nf or mati o n. A n S A E occ urri n g at a differe nt ti me i nter val or 
ot her wise  c o nsi dere d  c o m pletel y  u nrelate d  t o  a  pre vi o usl y  re p orte d  o ne  s h o ul d  be  
re p orte d se paratel y as a ne w e ve nt. 
I nf or mati o n  a b o ut  all  S A Es  is  c ollecte d  a n d  rec or de d  o n  t he  Seri o us  A d verse  E ve nt  
Re p ort F or m, s uc h as a F D A Me d Watc h F or m; all a p plica ble secti o ns of t he f or m m ust 
be  c o m plete d  i n  or der  t o  pr o vi de  a  cli nicall y t h or o u g h  re p ort.  T he  i n vesti gat or  m ust  
assess a n d rec or d t he relati o ns hi p of eac h S A E t o eac h s pecific st u d y treat me nt (if t here is 
m ore t ha n o ne st u d y treat me nt), c o m plete t he S A E Re p ort F or m i n E n glis h, a n d se n d t he 
c o m plete d, si g ne d f or m b y fa x wit hi n 2 4 h o urs t o t he o nc ol o g y N o vartis Dr u g Safet y a n d 
E pi de mi ol o g y ( D S & E) de part me nt at Fa x N u m ber:  
. 
T he tele p h o ne a n d telefa x n u m ber of t he c o ntact pers o ns i n t he l ocal de part me nt of Dr u g 
Safet y a n d E pi de mi ol o g y ( D S & E), s pecific t o t he site, are liste d as a n a p pe n di x t o t he 
Site A gree me nt. T he ori gi nal c o p y of t he S A E Re p ort F or m a n d t he fa x c o nfir mati o n 
s heet m ust be ke pt wit h t he case re p ort f or m d oc u me ntati o n at t he st u d y site. 
F oll o w- u p i nf or mati o n is se nt t o t he sa me c o ntact(s) t o w h o m t he ori gi nal S A E Re p ort 
F or m was se nt, usi n g a ne w S A E Re p ort F or m stati n g t hat t his is a f oll o w -u p t o t he 
pre vi o usl y re p orte d S A E a n d gi vi n g t he date of t he ori gi nal re p ort. Eac h re - occ urre nce, 
c o m plicati o n, or pr o gressi o n of t he ori gi nal e ve nt s h o ul d be re p orte d as a f oll o w -u p t o 

M C 1 4 8 3 
3 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
t hat  e ve nt  re gar dless  of  w he n  it  occ urs.  T he  f oll o w-u p  i nf or mati o n  s h o ul d  descri be  
w het her t he e ve nt has res ol ve d or c o nti n ues, if a n d h o w it was treate d, w het her t he bli n d 
was  br o ke n  or  n ot,  a n d  w het her  t he  patie nt  c o nti n ue d  or  wit h dre w  fr o m  st u d y  
partici pati o n. 
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure ( ne w occ urre nce) 
a nd is t h o u g ht t o be relate d t o t he N o vartis st u d y treat me nt, a n o nc ol o g y N o vartis Dr u g 
Safet y  a n d  E pi de mi ol o g y  ( D S & E)  de part me nt  ass ociate  ma y  ur ge ntl y  re q uire  f urt her  
i nf or mati o n fr o m t he i n vesti gat or f or Healt h A ut h orit y re p orti n g. N o vartis ma y nee d t o 
iss ue a n I n vesti gat or N otificati o n (I N), t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y st u d y 
wit h  t he  sa me  dr u g  t hat  t his  S A E  has  bee n  re p orte d.  S us pecte d  U ne x pecte d  Seri o us  
A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities  
a n d  rele va nt  et hics  c o m mittees  i n  acc or da nce  wit h  Directi ve  2 0 0 1/ 2 0/ E C  or  as  per  
nati o nal re g ulat or y re q uire me nts i n partici pati n g c o u ntries.  
P re g n a nc y re p orti n g  
T o e ns ure patie nt safet y, eac h pre g na nc y occ urri n g w hile t he patie nt is o n st u d y treat me nt 
m u st be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na nc y 
s h o ul d  be  f oll o we d  u p  t o  deter mi ne  o utc o me,  i ncl u di n g  s p o nta ne o us  or  v ol u ntar y  
ter mi nati o n,  details  of  t he  birt h,  a n d  t he  prese nce  or  a bse nce  of  a n y  birt h  defects,  
c o n ge nital a b n or malities, or mater nal a n d/ or ne w b or n c o m plicati o ns.  
Pre g na nc y s h o ul d be rec or de d o n a Cli nical Trial Pre g na nc y F or m a n d re p orte d b y t he 
i n vesti gat or  t o  t he  o nc ol o g y  N o vartis  Dr u g  Safet y  a n d  E pi de mi ol o g y  De part me nt  
( D S & E). Pre g na nc y f oll o w-u p s h o ul d be rec or de d o n t he sa me f or m a n d s h o ul d i ncl u de 
a n assess me nt of t he p ossi ble relati o ns hi p t o mi d osta uri n. A n y S A E e x perie nce d d uri n g 
pre g na nc y m ust be re p orte d o n t he S A E Re p ort F or m. 
Pre g na nc y o utc o mes m ust be c ollecte d f or t he fe male part ners of a n y males w h o t o o k 
st u d y treat me nt i n t his st u d y. C o nse nt t o re p ort i nf or mati o n re gar di n g t hese pre g na nc y 
o utc o mes s h o ul d be o btai ne d fr o m t he m ot her. 
 
1.  Use pa per A dverse Eve nt Ex pe dite d Re p ort – Si n gle A ge nt or M ulti ple A ge nts re p ort 
 
a vaila ble  fr o m t he C T E P H o me Pa ge at 
 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ d ocs/ 3 4-
  
a deers v 4 _ mat. p df .  A d E E Rs Te m plates. S u b mit t o N o vartis (see fa x s heet i ncl u de d i n 
 
t he f or ms pac ket)  (see A p pe n di x V).  
 
  
Pr o vi de c o pies, al o n g wit h t he U PI R T S O c o ver s heet, b y fa x 
 t o t he 
 
M C C C Re g ulat or y Affairs U nit ( R A U) Ris k I nf or mati o n S pecialist w h o will  
  
deter mi ne a n d c o m plete I R B re p orti n g. T he R A U will s u b mit t o t he M C C C S A E 
  
C o or di nat or a n d t he M C C C I N D C o or di nat or t o deter mi ne if F D A s u b missi o n is nee de d.  
 
1 0. 5  
Ot her Re q uire d Re p orti n g 
 
1 0. 5 1 
A d verse e ve nts t o be gra de d at eac h e val uati o n a n d pretreat me nt 
s y m pt o ms/c o n diti o ns t o be e val uate d at baseli ne per t he C T C A E v 4. 0 
gra di n g u nless ot her wise state d i n t he ta ble bel o w:  
 
 
S yste m Or ga n Class 
( S O C) 
 
A d verse e ve nt/ S y m pt o ms  
 
Baseli ne  
Eac h  
e val uati o n 

M C 1 4 8 3 
3 6 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
I n vesti gati o ns 
Electr ocar di o gra m Q T 
c orrecte d i nter val pr ol o n ge d 
X  
X  
Bl o o d bilir u bi n i ncrease d  
X  
X  
A la ni ne a mi n otra nsferase 
i ncrease d 
X  
X  
As partate a mi n otra nsferase 
i ncrease d 
X  
X  
Li pase i ncrease d  
X  
X  
S ki n a n d s u bc uta ne o us 
tiss ue dis or ders 
R as h mac ul o-pa p ular  
X  
X  
 
1 0. 5 2  S u b mit via a p pr o priate M C C C Case Re p ort F or ms (i.e., pa per or 
electr o nic, as a p plica ble) t he f oll o wi n g A Es e x perie nce d b y a patie nt a n d 
n ot s pecifie d i n Secti o n 1 0. 5 1 : 
 
1 0. 5 2 1 Gra de 2 A Es dee me d p ossi bly, pr o b a bly, or defi nitely  relate d t o 
t he st u d y treat me nt or pr oce d ure. 
 
1 0. 5 2 2  Gra de 3 a n d 4 A Es re gar dless of attri b uti o n t o t he st u d y 
treat me nt or pr oce d ure. 
 
1 0. 5 2 3  Gra de 5 A Es ( Deat hs) 
 
1 0. 5 2 3 1   
A n y deat h wit hi n 3 0 da ys of t he patie nt’s last st u d y 
treat me nt or pr oce d ure re gar dless of attri b uti o n t o 
t he st u d y treat me nt or pr oce d ure. 
 
1 0. 5 2 3 2      A n y deat h m ore t ha n 3 0 da ys after t he patie nt’s last 
st u d y treat me nt or pr oce d ure t hat is felt t o be at least 
p ossi bl y treat me nt relate d m ust als o be s u b mitte d as 
a Gra de 5 A E, wit h a C T C A E t y pe a n d attri b uti o n 
assi g ne d. 
 
1 0. 5 3    Refer t o t he i nstr ucti o ns i n t he F or ms Pac ket ( or electr o nic  data e ntr y 
scree ns, as a p plica ble) re gar di n g t he s u b missi o n of late occ urri n g A Es 
f oll o wi n g c o m pleti o n of t he Acti ve M o nit ori n g P hase (i.e., c o m plia nce 
wit h T est Sc he d ule i n Secti o n 4. 0). 
 
1 1. 0  
Tre at me nt E v al u ati o n 
1 1. 1 
C o m plete he mat ol o gic res p o nse ( C R)  
Less t ha n 5 % blasts i n a n o n - h y p ocell ular marr o w wit h a gra n ul oc yte c o u nt ≥ 
1. 0 , a n d a platelets c o u nt ≥ 1 0 0  wit h c o m plete res ol uti o n of a n y e xtra me d ullar y 
disease  a n d a bse nce of peri p heral bl o o d blasts. T he patie nt is i n s ustai ne d C R if 
t he y ha ve pre vi o usl y ac hie ve d a C R a n d c o nti n ue t o meet t he C R criteria (at least 
2 8 da ys). 
 
C R i nc o m plete ( C Ri)  is calle d if patie nt meets all C R criteria e xce pt f or resi d ual 
ne utr o pe nia ( A N C < 1 x 1 0 9/ L) or t hr o m b oc yt o pe nia ( platelets <1 0 0 x 1 0 9/ L) 

M C 1 4 8 3 
3 7 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
1 1. 1 1  C o m plete c yt o ge netic re missi o n ( C C y R)  
T he a bse nce of c hr o m os o me  a b n or malities (if prese nt at dia g n osis) o n 
c o n ve nti o nal c yt o ge netic st u d y usi n g G -ba n di n g (at least 1 0 meta p hases 
prese nt). 
 
1 1. 1 2  C o m plete m olec ular re missi o n ( C M R)  
T he ac hie ve me nt of ne gati ve  P C R f or F L T 3  m utati o n (if  d o ne a n d if  
prese nt at dia g n osis) .  
1 1. 1 3     M R D: Mi ni mal Resi d ual Disease  
 
P ositi ve 
P C R  f or  F L T 3  m utati o n  or  fl o w  c yt o metr y  f or F L T 3 
o vere x pressi o n  fr o m peri p heral bl o o d or b o ne marr o w. 
 
1 1. 2  
M or p h ol o gic le u ke mia -free state ( M L F S): 
If b o ne marr o w blasts < 5 %, a bse nce of A uer r o ds blasts, a bse nce of 
e xtra me d ullar y disease wit h o ut he mat ol o gical rec o ver y. 
 
1 1. 3  
Partial res p o nse ( P R) 
T he prese nce of trili nea ge he mat o p oiesis i n t he b o ne marr o w wit h rec o ver y of 
A N C a n d platelet c o u nt t o a b o ve le vels, b ut wit h 5- 2 5 % b o ne marr o w blasts a n d 
≥5 0 % decrease i n b o ne marr o w blast perce nta ge fr o m baseli ne.  
 
1 1. 4   
N o res p o nse ( N R)  
F ail ure t o ac hie ve a P R, M L F S, C Ri, or C R.   
 
1 1. 5 
Rela pse:  
Disease rec urre nce after ac hie vi n g C R. Disease rec urre nce is defi ne d b y blast 
≥5 % i n t he b o ne marr o w, or rec urre nce of peri p heral bl o o d blasts or 
e xtra me d ullar y i n v ol ve me nt.  
 
1 1. 6  
Treat me nt fail ure:  
             Resista nt disease: Fail ure t o ac hie ve C R/ C Ri/ P R/ m or p h ol o gic le u ke mia -free state 
b y t he e n d of 8 c ycles of i n d ucti o n  . 
N ote:  T hese patie nts will be rec or de d as a n o bjecti ve sta t us of N R t o 
d oc u me nt de pt h of res p o nse b ut will be c o nsi dere d treat me nt fail ures at 
t he ti me of a nal ysis. 
   
Deat h  i n  a plasia:  Deat h  occ urri n g  ≥  7  da ys  f oll o wi n g  c o m pleti o n  of  treat me nt 
wit h a plastic/ h y p o plastic b o ne marr o w ( o btai ne d wit hi n 7 da ys of deat h) wit h n o 
e vi de nce of persiste nt le u ke mia  
   
 
Deat h fr o m i n deter mi nate ca use: Deat h occ urri n g d uri n g t hera p y or < 7 da ys 
f oll o wi n g  treat me nt  c o m pleti o n,  or ≥  7  da ys  f oll o wi n g  c o m pleti o n  of treat me nt 
wit h n o blast i n t he bl o o d b ut n o b o ne marr o w e xa mi nati o n a vaila ble 
 
 
 
1 2. 0 
Descri pti ve F act ors  

M C 1 4 8 3 
3 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
1 2. 1   
F L T 3 m utati o n at baseli ne:  I T D vs . T K D  vs. b ot h 
 
1 2. 2     B o ne marr o w tra ns pla nt ca n di date:  Yes vs. N o. 
 
1 2. 3 
N P M 1 ( M utati o n): P ositi ve vs. Ne gati ve vs. N ot D o ne 
 
    
 
1 3. 0 
Tre at me nt/ F oll o w – u p Decisi o n at E v al u ati o n of P atie nt   
 
1 3. 1 
Criteria f or Patie nt I nitiati o n of E ve nt M o nit ori n g:  
 
•  
Dela y > 2 8 da ys  f or t he ne xt c ycle  ( d ue t o n o n - he mat ol o gical dr u g t o xicit y ) 
•  
Disease rela pse  
•  
Fail ure t o ac hie ve C R or C Ri or P R or M L F S b y e n d of c ycle 8 
•  
Patie nt wit h dra ws c o nse nt t o c o nti n ue i n t he trial 
•  
Patie nt de vel o ps a n i nterc urre nt ill ness t hat p recl u des f urt her partici pati o n 
•  
T he I n vesti gat or wit h dra ws t he patie nt i n t he patie nt’s best i nterests  
•  
A d mi nistrati ve reas o ns (e. g., t he patie nt is tra nsferre d t o h os pice care)  
•  
A n a d verse e ve nt, w hic h i n t he o pi ni o n of t he I n vesti gat or precl u des f urt her  
trial partici pati o n 
•  
Patie nt disc o nti n ues eit her t he Decita bi ne or t he Mi d osta uri n  i n t he 
ma xi m u m 1 8 c ycles . 
 
  
All atte m pts s h o ul d be ma de t o c o m plete t he E n d of St u d y pr oce d ures if a patie nt 
wit h dra ws fr o m t he trial earl y.  T he patie nt will g o t o t he e ve nt- m o nit ori n g p hase 
per Secti o n 1 8. 0. 
 
1 3. 2 
Patie nts w h o ac hie ve a n d s ustai n a C R/ C Ri/ P R /M L F S  b y e n d of c ycle 8, will 
recei ve a ma xi m u m t otal of 1 8 c ycles of treat me nt .  After 1 8 c ycles, t he patie nt  
will g o t o e ve nt m o nit ori n g, u nless t he y are c o nti n ui n g t he c o m bi nati o n of 
mi d osta uri n a n d decita bi ne be y o n d 1 8 c ycles per secti o n 7. 1 2.   
  
 
1 3. 3      E ve nt m o nit ori n g:  Patie nts w h o are ali ve will be f oll o we d i n e ve nt m o nit ori n g 
e ver y 6 m o nt hs u ntil deat h or u p t o 2 years fr o m re gistrati o n.    
 
1 3. 4 
A patie nt is dee me d i neli gi ble if after re gistrati o n, it is deter mi ne d t hat at t he ti me 
of re gistrati o n, t he patie nt di d n ot satisf y eac h a n d e ver y eli gi bilit y criteria f or 
st u d y e ntr y.  T he patie nt ma y c o nti n ue treat me nt off-pr ot oc ol at t he discreti o n of 
t he p h ysicia n as l o n g as t here are n o safet y c oncer ns, a n d t he patie nt was 
pr o perl y re gistere d. T he patie nt will g o directl y t o t he e ve nt- m o nit ori n g p hase of 
t he st u d y ( or off st u d y, if a p plica ble).  
•  
If t he patie nt recei ve d treat me nt, all data u p u ntil t he p oi nt of c o nfir mati o n of 
i neli gi bilit y m ust be s u b mitte d.  E ve nt m o nit ori n g will be re q uire d per 
Secti o n 1 8. 0 of t he pr ot oc ol.  
•  
If t he patie nt ne ver recei ve d treat me nt, o n-st u d y material a n d t he E n d of 
Acti ve Treat me nt/ Ca ncel N otificati o n F or m m ust be s u b mitte d. N o f urt her 
data s u b missi o n is necessar y . 
 

M C 1 4 8 3 
3 9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 3. 5 
A patie nt is dee me d a m aj or vi ol ati o n , if pr ot oc ol re q uire me nts re gar di n g 
treat me nt i n c ycle 1 of t he i nitial t hera p y are se verel y vi olate d t hat e val ua bilit y 
f or pri mar y e n d p oi nt is q uesti o na ble.  All data u p u ntil t he p oi nt of c o nfir mati o n 
of a m aj or vi olati o n m ust be s u b mitte d.  T he patie nt will g o directl y t o t he e ve nt -
m o nit ori n g p hase of t he st u d y.  T he patie nt ma y c o nti n ue treat me nt off- pr ot oc ol 
at t he discreti o n of t he p h ysicia n as l o n g as t here are n o safet y c o ncer ns, a n d t he 
patie nt was pr o perl y re gistere d.  E ve nt m o nit ori n g will be re q uire d per Secti o n 
1 8. 0 of t he pr ot oc ol.  
 
1 3. 6 
A patie nt is dee me d a c a ncel  if he/s he is re m o ve d fr o m t he st u d y f or a n y reas o n 
bef ore a n y st u d y treat me nt is gi ve n.  O n- st u d y material a n d t he E n d of Acti ve 
Treat me nt/ Ca ncel N otificati o n F or m m ust be s u b mitte d.  N o f urt her data 
s u b missi o n is necessar y. 

M C 1 4 8 3 
4 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 4. 0 
B o d y Fl ui d Bi os peci me ns   
 
1 4. 1   
S u m mar y T a ble of Researc h Bl o o d a n d B o d y Fl ui d S peci me ns t o be c ollecte d f or t his Pr ot oc ol  
 
 
 
M a n d at or y 
( M) or 
O pti o n al 
( O) 
 
B l o o d or 
B o d y 
Fl ui d 
bei n g 
C ollecte d  
 
T y pe of 
C ollecti o n 
T u be (c ol or 
of t u be t o p)  
 
V ol u me t o 
c ollect per 
t u be ( # of 
t u bes t o be 
c ollecte d)  
 
 
 
Scree ni n g  
C ycle 1  D a y 
8 ( pre-
mi d ost a uri n 
tre at me nt, 
3 0 mi ns pre -
d osi n g ) 
 
 
D a y 1 C ycles 
3,  5,  a n d 9 
Te m per at ure  
 C o n d iti o ns f or 
St or a ge / S hi p pi n g  
C orrelati ve 
st u dies - See 
sect. 1 4. 2 1 
M  
Bl o o d  
B D 
Vac utai ner 
E D T A 1 0 ml 
3 6 6 6 4 3  
3 0 -4 0 ml 
i n t otal( 1 0 
ml t u bes)  
yes  
yes  
N o  
S hi p ri g ht a wa y 
a wa y (ice ba gs + 4 C)  
or pic k u p, r o o m 
te m perat ure 
C orrelati ve 
st u dies - See 
sect. 1 4. 2 1 
M  
B o ne 
marr o w 
as pirate 1 
B D 
Vac utai ner 
E D T A 1 0 ml 
3 6 6 6 4 3  
2 0 -3 0 ml 
i n t otal( 4 
ml t u bes)  
yes  
n o  
yes  
S hi p ri g ht a wa y 
a wa y (ice ba gs + 4 C)  
or pic k u p, r o o m 
te m perat ure 
1.  If b o ne marr o w d o ne pre vi o usl y , t his ma y be o mitte d. 
 
W he n p ossi ble, sa m ples s h o ul d be o btai ne d pri or t o t he mi d osta uri n  d ose. T he e xact ti me si nce t he last d ose  of mi d osta uri n s h o ul d be d oc u me nte d. 
F or t he c orrelati ve st u dies, bl o o d sa m ples s h o ul d be c ollecte d at scree ni n g, c ycle 1 da y 8. F or t he c orrelati ve st u dies, b o ne marr o w as pirate 
sa m ples s h o ul d be c ollecte d at scree ni n g, a n d da y 1 of c ycle 3, 5, 9.  

M C 1 4 8 3 
4 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
  
1 4. 2   
C ollecti o n a n d Pr ocessi n g  
 
1 4. 2 1  Ge netic  T ar gets  C orrelati ve  st u dies:  C o m pare  t he  pre -treat me nt  wit h  
p ost- treat me nt sa m ples f or t he alterati o ns of direct a n d p ote ntial-i n direct 
tar gets f or b ot h mi d osta uri n a n d decita bi ne:  
1) F L T 3 ge ne m utati o n stat us will be assesse d (at Ma y o Cli nic La bs) f or 
res p o nse stratificati o n a n d M R D assess me nt b y D N A se q ue nci n g; 
2) Meas ure me nt of F L T 3 ki nase acti vities b y P C R a n d Wester n bl ot, 
i ncl u di n g  FL T 3  p h os p h or ylati o n,  t otal  pr otei n  e x pressi o n  a n d  
d o w nstrea m effect ors (e. g. A K T, E R K, S T A T 5); 
3) Deter mi nati o n of D N M T acti vit y, i ncl u di n g D N M T R N A a n d pr otei n 
e x pressi o n  ( b y  P C R  a n d  Wester n  bl ot),  e x pressi o n  of  met h ylati o n -
sile nce d t u m or s u p press or ge nes ( b y P C R), gl o bal D N A met h ylati o n ( b y 
LI N E - 1 or  d ot bl ot),  ge ne  pr o m oter  met h ylati o n  a nal ysis  ( b y  bis ulfite  
se q ue nci n g); 
4)  Detecti o n  of  micr o R N A s e x pressi o n  ( b y  q P C R),  beca use  pre vi o us  
re p ort  s h o w  t hat  mi R 2 9 b  f u ncti o ns  as  D N A  met h ylati o n  m o d ulat or  
( Garz o n a n d Li u et al , 2 0 0 9), re g ulates t he acti vit y of c-KI T ( Li u et al, 
2 0 1 0), a F L T 3 -li ke rece pt or t yr osi ne ki nase a n d pre dicts t he o utc o me of 
decita bi ne t hera p y ( Bl u m W et al, 2 0 1 0). 
5) Deter mi nati o n of i n direct a n d p ote ntial tar gets, i ncl u di n g t he ge nes 
c o ntr olli n g  hist o ne  m o dificati o ns  a n d  R N A  met h ylati o n  b y  q P C R,  
Wester n bl ot, D ot bl ot a n d bis ulfite se q ue nci n g.  
6) I n vesti gate  t he  s y ner gistic  effect  ( usi n g  t he  met h o ds  a b o ve)  of  
decita bi ne c o m bi ne d wit h P K C 4 1 2 o n t he acti vities of D N A met h ylati o n  
a n d ki nases , i ncl u di n g t heir ge ne e x pressi o n, alterati o n of d o w nstrea m 
effect ors a n d ulti matel y t he s y ner getic cli nical o utc o mes.  
7 )  Ge ne  a n d  micr o R N A  pr ofili n g.  I n  or der  t o  f urt her  u n dersta n d  t he  
m olec ular mec ha nis m of dr u g effects, ge ne a n d mi R micr oarra ys will be 
pe rf or me d i n t he gr o u p of a) res p o n der vers us n o n-res p o n der; b) pre-
treat me nt  vers us  p ost-treat me nt. T hese  e x peri me nts  will  i de ntif y  
i n n o vati ve t hera pe utic tar gets. 
8) Deter mi nati o n of gr o wt h fact ors, li ga n ds a n d c yt o ki nes i n plas ma. It is 
i ncreasi n gl y rec o g nize d t hat le u ke mia are ca use d b y t he c o o perati o n of 
m ulti ple ge ne net w or ks, n ot j ust a si n gle pat h wa y. O ur preli mi nar y data 
s h o we d t hat t here e xists a cr osstal k/i nter pla y bet wee n met h ylati o n a n d 
ki nases  as  well  as  t he  rele va nt  c yt o ki nes,  gr o wt h  fact ors  a n d  li pi d  
bi n di n g  pr otei ns.  T o  precisel y  u n dersta n d  t he  m olec ular  mec ha nis ms  
u n derl yi n g t he a nti -le u ke mia effects of mi d osta uri n a n d decita bi ne , it is 
necessar y  t o  carr y  o ut  t he  Wester n  bl ot  or/a n d  E LI S A  t o  assess  t he  
c ha n ges of t hese ge ne net w or ks pre - vers us p ost- treat me nt. 
 
1 4. 3  
S hi p pi n g a n d Ha n dli n g 
 
1 4. 3 1  C orrelati ve st u dies will be perf or me d at H or mel  I nstit ute, U ni versit y of 
Mi n nes ota,  b y 
 Sa m ples ca n be s hi p pe d M o n da y -

M C 1 4 8 3 
4 3 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
  
I m p orta ntl y, mi d osta uri n has bee n f o u n d t o re vert t he P-
gl yc o pr otei n ( P g p) me diate d M D R ( m ulti dr u g resista nce) 
p he n ot y pe b y i n hi biti n g t he f u ncti o n of P g p.  St u dies w hic h 
a nal yze d t he se nsiti vit y of P g p e x pressi n g a n d n o n-e x pressi n g 
A M L blast cells wit h eit her F L T 3 -I T D (i nter nal ta n de m 
d u plicati o n) m utati o ns or F L T 3 wil d- t y pe ( W T) stat us t o war ds 
mi d osta uri n, i n dicate d si g nifica nt pr o -a p o pt otic acti vit y of 
mi d osta uri n a gai nst b ot h m utate d a n d n o n- F L T 3 -m utate d blast 
cells wit h P g p e x pressi o n. 
 
  
Efficac y of mi d osta uri n has als o bee n s h o w n f or 
m yel o pr oliferati ve dis or ders ( M P D) i n d uce d b y Z N F 1 9 8- F G F R 1 
or b y FI P 1 L 1 -P D G F R α . 
 
1 5. 1 2 
F or m ul ati o n:  Mi d osta uri n is a vaila ble as 2 5 m g s oft gelati n 
ca ps ules, a 2 5 m g/ m L oral s ol uti o n f or pe diatric patie nts, a n d a 5 0 
m g/ 5 m L I V s ol uti o n f or i nf usi o n (li mite d t o use i n t he a bs ol ute 
B A V st u d y C P K C 4 1 2 A 2 1 2 0) 
 
T he ca ps ule filli n g s ol uti o n c o ntai ns t he f oll o wi n g e xci pie nts, i n 
a d diti o n t o t he dr u g s u bsta nce:  all -rac-α - T oc o p her ol / vita mi n E, 
c or n oil- m o n o- di-tri gl yceri des, de h y drate d alc o h ol, p ol yet h yle ne 
gl yc ol 4 0 0, p ol y o x yl- 4 0- h y dr o ge nate d cast or oil. T he ca ps ule s hell 
c o ntai ns gelati n ( p orci ne), gl ycer ol, ir o n o xi de re d, ir o n o xi de 
yell o w, a n d tita ni u m di o xi de. T he ca ps ules are pri nte d a n d c o ntai n 
traces of t he f oll o wi n g e xci pie nts: car mi nic aci d E 1 2 0, al u mi n u m 
c hl ori de he xa h y drate / al u mi n u m c hl ori de, s o di u m h y dr o xi de, 
h y pr o mell ose, pr o p yle ne gl yc ol, a n d is o pr o p yl alc o h ol.  
 
T he 2 5 m g/ m L oral s ol uti o n c o ntai ns all- rac-α -t oc o p her ol / 
vita mi n E, c or n oil- m o n o- di -tri gl yceri des, de h y drate d alc o h ol, 
p ol yet h yle ne gl yc ol 4 0 0, p ol y o x yl 4 0 h y dr o ge nate d cast or oil. 
 
T he I V s ol uti o n f or i nf usi o n c o ntai ns pr o p yle ne gl yc ol 3 0 0, p ol ys or bate 
8 0, a n d de h y drate d alc o h ol.   
  
 
 
1 5. 1 3 
P re p a r ati o n a n d st or a ge:  T he s oft gelati n ca ps ules are pac ka ge d 
i n blister pac ks w hic h are t o be st ore d bel o w 2 5° C. T he oral 
s ol uti o n is pr o vi de d i n a 5 0 m L a m ber glass b ottle a n d s h o ul d be 
st ore d at 2- 8° C bef ore first use.  T he I V s ol uti o n f or i nf usi o n 
s h o ul d be st ore d at 2 -8° C, pr otecte d fr o m li g ht.  
N O T E  - T he me dici ne m ust be dis p ose d pr o perl y. After use, 
re mai ni n g ca ps ules, cl ose d oral s ol uti o n b ottles, a n d t he 
c orres p o n di n g dis pe nsi n g s yste m s h o ul d be ret ur ne d t o t he cli nical 
site. S pills s h o ul d be re m o ve d i m me diatel y b y t he use of pa per 
tiss ue a n d dis p ose d i n a tras h bi n. T he pr o d uct s h o ul d n ot be 
dis p ose d i n a si n k or t oilet. C o ntact of t he pr o d uct wit h t he s ki n 
s h o ul d be a v oi de d. 
 
1 5. 1 4 
A d mi nistr ati o n:   Mi d osta uri n s h o ul d be a d mi nistere d orall y, 
t wice dail y at t he sa me ti me e ver y da y a n d t o get her wit h f o o d. 

M C 1 4 8 3 
4 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
Ca ps ules s h o ul d be s wall o we d w h ole wit h a glass of water, a n d 
m ust n ot be c he we d or cr us he d. Re m o ve fr o m t he blister pac k j ust 
pri or t o a d mi nistrati o n.   
 
Mi d osta uri n 2 5 m g/ m L oral s ol uti o n s h o ul d be all o we d t o 
e q uili brate t o r o o m te m perat ure f or a p pr o xi matel y 1 h o ur u ntil t he 
s ol uti o n is clear.  D ose is wit h dra w n usi n g a 1 m L or 4 m L oral 
s yri n ge a n d dil ute d i n water pri or t o a d mi nistrati o n.  D ose m ust be 
ta ke n i m me diatel y after dil uti o n. 
  
 
1 5. 1 5 
P h ar m a c o ki netic i nf or m ati o n:  
a)  A bs or pti o n – ra pi d oral a bs or pti o n of mi d osta uri n wit h T ma x 
of 1- 3 h o urs. C ma x a n d A U C of mi d osta uri n i ncrease i n a n 
a p pare nt d ose pr o p orti o nal ma n ner after a d mi nistrati o n of si n gle 
d oses u p t o 5 0 m g a n d i n a less t ha n pr o p orti o nal ma n ner 
t hereafter. U p o n dail y oral d osi n g, mi d osta uri n c o nce ntrati o ns 
acc u m ulate d i n a ti me -li near ma n ner i n t he first 3- 6 da ys. 
T hereafter, t he P K bec o mes ti me -de pe n de nt; t he plas ma 
c o nce ntrati o ns of mi d osta uri n decrease d s u bsta ntiall y bet wee n 
Da ys 6 - 1 4, a n d reac he d a ne w platea u after 2 - 3 wee ks of dail y 
d osi n g. T he A U Ci nf of mi d osta uri n i ncrease d b y 2 2 % a n d b y 5 9 % 
wit h sta n dar d meal a n d hi g h fat meal res pecti vel y.  T he C ma x was 
decrease d b y 2 0 % a n d 2 7 %, res pecti vel y.  Me dia n T ma x of 
mi d osta uri n was dela ye d wit h a d mi nistrati o n of a meal c o m pare d 
t o t he faste d c o n diti o n b y 2. 5 t o 3 h.  T he rec o m me n dati o n is t o 
a d mi nister mi d osta uri n wit h f o o d. 
b)  Distri b uti o n – Mi d osta uri n was o bser ve d t o be wi del y 
distri b ute d i n h u ma ns wit h a hi g h tiss ue distri b uti o n of Vz / F = 9 9 
L. Mi d osta uri n a n d its meta b olites were distri b ute d mai nl y i n 
plas ma rat her t ha n re d bl o o d cells. [ 1 4 C] mi d osta uri n was hi g hl y 
b o u n d t o h u ma n plas ma pr otei ns ( 9 9. 2 %), w hic h was als o 
o bser ve d i n patie nts. T he bi n di n g was i n de pe n de nt of 
c o nce ntrati o n o ver t he c o nce ntrati o n ra n ge of 1 0 0 – 5 0 0 0 n g/ m L, 
a n d was u naffecte d b y hi g h c o nce ntrati o ns of α -aci d gl yc o pr otei n. 
  
c)  Meta b olis m – Mi d osta uri n is pre d o mi na ntl y meta b olize d b y 
C Y P 3 A 4 i nt o t w o maj or acti ve circ ulati n g meta b olites, C G P 6 2 2 2 1 
( via O- de met h ylati o n) a n d C G P 5 2 4 2 1 ( via h y dr o x ylati o n) i n 
h u ma ns.  T he c o nce ntrati o n of C G P 5 2 4 2 1 i ncrease d gra d uall y 
wit h ti me a n d a p peare d t o reac h a stea d y state after 2 8 da ys of a 
m ulti ple d osi n g re gi me n.  It is p ossi ble t hat a ut o -i n d ucti o n, pr otei n 
bi n di n g c o m petiti o n a n d dis place me nt, a n d/ or a c o m bi nati o n of 
b ot h pla y a r ole i n t he p har mac o ki netics of mi d osta uri n. 
d )  E xcreti o n – Eli mi nati o n of mi d osta uri n fr o m plas ma was sl o w 
wit h a n a p pare nt ter mi nal half -life of a b o ut 1 7 h o urs (ra n ge 5- 3 1 
h o urs). T he a p pare nt ter m i nal half-life of C G P 6 2 2 2 1 was 
esti mate d as 3 9 h o urs.  T he meta b olite C G P 5 2 4 2 1 acc u m ulate d i n 
plas ma o ver treat me nt c ycles a n d its a p pare nt ter mi nal half -life 
was esti mate d as > 1 m o nt h. Fecal e xcreti o n is t he maj or pat h wa y 
f or eli mi nati o n of mi d osta uri n, C G P 6 2 2 2 1, a n d C G P 5 2 4 2 1. 
Uri nar y e xcreti o n pla ys a mi n or r ole.  
  
 

M C 1 4 8 3 
4 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 5. 1 6 
P ote nti al Dr u g I nter acti o ns:   S o me precli nical o bser vati o ns 
s u g gest t hat mi d osta uri n ma y e n ha nce t he effect of irra diati o n, b ut 
t he p ote ntial cli nical si g nifica nce i n ter ms of ris k- be nefit of t his is 
c urre ntl y u n k n o w n.  T he effect is m ore pr o n o u nce d i n p 5 3 + t ha n 
i n p 5 3- cells. 
 
 
C o -a d mi nistrati o n of mi d osta uri n wit h t he p ote nt C Y P 3 A 4 
i n hi bit or ket oc o naz ole, res ulte d i n a 1 0-f ol d i ncrease d e x p os ure of 
mi d osta uri n. H o we ver, data fr o m st u dies e val uati n g t he c o -
a d mi nistrati o n of str o n g C Y P 3 A 4 i n hi bit ors wit h mi d osta uri n 
i n dicate t he p ote ntial t o i ncrease e x p os ure of mi d osta uri n, wit h 
little cli nical rele va nce.  Ne vert heless, c o-a d mi nistrati o n of a 
str o n g C Y P 3 A 4 i n hi bit or wit h mi d osta uri n s h o ul d be ha n dle d wit h 
ca uti o n. C Y P 3 A 4 str o n g i n hi bit ors i ncl u de: clarit hr o m yci n, 
telit hr o m yci n, tr olea n d o m yci n, i n di na vir, l o pi na vir, nelfi na vir, 
rit o na vir, sa q ui na vir, ti pra na vir, itrac o naz ole, ket oc o naz ole, 
p osac o naz ole, v oric o naz ole, b oce pre vir, tela pre vir, c o bicistat, 
c o ni va pta n, nefaz o d o ne.   
 
 
Ca uti o n s h o ul d be e xercise d f or patie nts recei vi n g m o derate 
C Y P 3 A 4 i n hi bit ors. A list of t hese a ge nts is f o u n d at:
 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n -ta ble 
 
 
 
C o -a d mi nistrati o n of mi d osta uri n wit h t he p ote nt C Y P 3 A 4 
i n d ucer, rifa m pici n, decrease d t he C ma x a n d A U C of mi d osta uri n 
b y 7 3 % a n d 9 4 %, res pecti vel y. T o a v oi d s u b- t hera pe utic e x p os ure 
t o mi d osta uri n, m o derate or str o n g C Y P 4 5 0 3 A 4 i n d ucers s h o ul d 
n ot be c o -a d mi nistere d. Str o n g C Y P 3 A 4 i n d ucers i ncl u de: 
a vasi mi be, car ba maze pi ne, mit ota ne, p he n o bar bital, p he n yt oi n, 
rifa b uti n, rifa m pi n (rifa m pici n), a n d St. J o h n's w ort.  M o derate 
C Y P 3 A 4 i n d ucers i ncl u de: b ose nta n, efa vire nz, etra viri ne, 
ge ni stei n, m o dafi nil, nafcilli n, rit o na vir, tal virali ne, t hi ori dazi ne, 
a n d ti pra na vir. 
 
1 5. 1 7 
K n o w n p ote nti al t o xicities :  A g gressi ve S yste mic Mast oc yt osis 
( A S M), a n d Ac ute M yel oi d Le u ke mia ( A M L)   
 
Ver y C o m m o n ( ≥1 0 %):  le u k o pe nia, l y m p h o pe nia, fe brile 
ne utr o pe nia ( A M L), petec hiae, si n us tac h ycar dia, a n orectal 
disc o mf ort, c o nsti pati o n, diarr hea, he m orr h oi ds, st o matitis, 
na usea, v o miti n g, fati g ue, peri p heral e de ma, p yre xia, 
h y perse nsiti vit y ( A M L), de vice relate d i nfecti o n, U R TI ( A S M), 
U TI, A P T T pr ol o n ge d, i ncreas e d A L T, i ncrease d A S T, i ncrease d 
a m ylase, i ncrease d li pase, decrease d he m o gl o bi n, decrease d 
ne utr o p hil c o u nt, decrease d a bs ol ute ne utr o p hils, decrease d 
a bs ol ute l y m p h oc ytes, h y per gl yce mia, i ncrease d gl uc ose, 
h y p o kale mia, h y p o natre mia, i ncrease d t otal bilir u bi n, 
h y per urice mia, bac k pai n, art hral gia, hea dac he, dizzi ness, 
i ns o m nia, c o u g h, d ys p nea, e pista xis, ple ural eff usi o n ( A S M), 
lar y n geal pai n, h y per hi dr osis, e xf oliati ve der matitis, h y perte nsi o n, 

M C 1 4 8 3 
4 6 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
h y p ote nsi o n ( A M L) 
C o m m o n ( ≥ 1 - 1 0 %): fe brile ne utr o pe nia ( A S M), pericar dial 
eff usi o n, e yeli d e de ma, verti g o, a b d o mi nal disc o mf ort, a b d o mi nal 
diste nsi o n, d ys pe psia, GI h e m orr ha ge, ast he nia, c hills, e de ma, 
cat heter relate d t hr o m b osis, h y perse nsiti vit y ( A S M), br o nc hitis, 
er ysi pelas, c ystitis,  her pes z oster, oral her pe s, p ne u m o nia, se psis, 
si n usitis, U R TI ( A M L), h y percalce mia, i ncrease d wei g ht, 
c o nf usi o n, fall, b o ne pai n, pai n i n e xtre mities, nec k pai n, s y nc o pe, 
tre m or, dist ur ba nce i n atte nti o n, A R D S,  ple ural eff usi o n ( A M L), 
or o p har y n geal pai n, nas o p har y n gitis, keratit is, dr y s ki n, 
he mat o ma, h y p ote nsi o n ( A S M)  
U nc o m m o n ( ≥ 0. 1 – 1 %):  a na p h ylactic s h oc k, ne utr o pe nic se psis  
 
1 5. 1 8 
Dr u g pr oc ure me nt:   Mi d osta uri n ca ps ules will be pr o vi de d free of 
c har ge t o st u d y s u bjects b y N o vartis.  
 
  
1 5. 1 9  N ursi n g G ui deli nes 
 
1 5. 1 9 1 Patie nt s s h o ul d be i nstr ucte d t o ta ke me dicati o n at t he sa me ti me 
e ver y da y, t wice dail y wit h f o o d. Ca ps ules m ust be s wall o we d 
w h ole wit h a glass of water a n d ca n n ot be c he we d or cr us he d. 
Oral s ol uti o n is a vaila ble f or pe diatric patie nts – f oll o w se parate 
pre parati o n i nstr ucti o n i n secti o n 1 5. 1 4. Me dici ne m ust be 
pr o perl y dis p ose d of. D o n ot p o ur d o w n a si n k or t oilet. Wi pe u p 
s pills i m me diatel y.  A v oi d s ki n c o ntact. 
 
1 5. 1 9 2 Assess patie nt’s c o nc o mita nt me dicati o ns, i ncl u di n g O T C a n d 
her bal pr o d ucts. Mi d osta uri n has i nteracti o ns wit h dr u gs t hat are 
meta b olize d via C Y P 3 A 4 a n d ca uti o n s h o ul d be e xercise d f or 
patie nts w h o are o n t hese a ge nts. F or m ore details refer t o 
secti o n 1 5. 1 6 of t he pr ot oc ol. 
 
1 5. 1 9 3 Gastr oi ntesti nal si de effects are c o m m o n, i ncl u di n g na usea, 
v o mi ti n g, a n d diarr hea. Treat s y m pt o maticall y a n d m o nit or f or 
effecti ve ness. Patie nts s h o ul d be pre me dicate d f or t he pre ve nti o n 
of na usea a n d v o miti n g. 
 
1 5. 1 9 4  M o nit or creati ni ne a n d re nal f u ncti o n as re nal i m pair me nt/fail ure 
has bee n see n.  
 
1 5. 1 9 5  I nstr uct p atie nts t o re p ort a n y si g ns/s y m pt o ms of C H F/ L V E F 
d ysf u ncti o n, i ncl u di n g c hest pai n, S O B, a n d e de ma. 
 
1 5. 1 9 6 M o nit or C B C w/ diff as c yt o pe nias ca n be see n. I nstr uct patie nts 
t o re p ort a n y si g ns/s y m pt o ms of i nfecti o n a n d/ or a n y u n us ual 
br uisi n g/ blee di n g t o t h e st u d y tea m.  
 
1 5. 1 9 7 M o nit or gl uc ose le vels per pr ot oc ol as h y per gl yce mia has bee n 
see n.  Dia betics ma y nee d a d diti o nal m o nit ori n g. 
 

M C 1 4 8 3 
4 7 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 5. 1 9 8 Bac k pai n a n d art hral gia’s ha ve bee n see n.  Treat 
s y m pt o maticall y a n d m o nit or f or effecti ve ness. 
 
1 5. 2 
D E CI T ( 2 – de o x y – 5 – azac yti di ne), Decita bi ne, Dac o ge n ®  
 
1 5. 2 1  Bac k gr o u n d:  Decita bi ne is directl y i nc or p orate d i nt o D N A a n d ca uses i n hi biti o n 
of D N A met h yltra nsferase, lea di n g t o h y p o met h ylati o n of D N A a n d cell ular 
differe ntiati o n or a p o pt osis. Decita bi ne- i n d uce d h y p o meth ylati o n i n ne o plastic cells ma y 
rest ore n or mal f u ncti o n t o ge nes t hat are critical f or t he c o ntr ol of cell ular differe ntiati o n 
a n d pr oliferati o n. 
 
1 5. 2 2 
F or m ulati o n:  Decita bi ne f or i njecti o n is a w hite t o al m ost w hite sterile 
l y o p hilize d p o w der s u p plie d i n a clear c ol orless glass vial. Eac h 2 0 m L, si n gle d ose, glass 
vial c o ntai ns 5 0 m g decita bi ne, 6 8 m g m o n o basic p otassi u m p h os p hate ( p otassi u m 
di h y dr o ge n p h os p hate) a n d 1 1. 6 m g s o di u m h y dr o xi de. 
 
1 5. 2 3 
Pre parati o n a n d St ora ge:  Decita bi ne s h o ul d be ase ptic all y rec o nstit ute d wit h 1 0 
m L of Sterile Water f or I njecti o n ( W FI); u p o n rec o nstit uti o n, eac h m L c o ntai ns 
a p pr o xi matel y 5 m g of decita bi ne at p H 6. 7- 7. 3. I m me diatel y after rec o nstit uti o n, t he 
s ol uti o n s h o ul d be f urt her dil ute d per rec o m me n de d pr oce d ure wit h i nf usi o n fl ui ds, s uc h 
as 0. 9 % S o di u m C hl ori de I nj ecti o n or 5 % De xtr ose I njecti o n t o a fi nal dr u g c o nce ntrati o n 
of 0. 1 - 1. 0 m g/ m L. U nless use d wit hi n 1 5 mi n utes u p o n rec o nstit uti o n, t he dil ute d 
s ol uti o n m ust be pre pare d usi n g c ol d i nf usi o n fl ui ds a n d st ore d at 2-8° C f or a ma xi m u m 
of 4 h o urs pri or t o a d mi nistrati o n.  Eac h 2 0- m L vial c o ntai ns 5 0 m g decita bi ne.  
 
1 5. 2 4  A d mi nistrati o n:  Decita bi ne is a d mi nistere d i ntra ve n o usl y o ver 1 h o ur. 
 
1 5. 2 5 
P har mac o ki netic i nf or mati o n  
 Distri b uti o n: A p pr o xi matel y 6 3 t o 89 L/ m 2  
 Meta b olis m: P ossi bl y via dea mi nati o n b y c yti di ne dea mi nase  
 Half -life eli mi nati o n: A p pr o xi matel y 3 0 t o 3 5 mi n utes 
 
1 5. 2 6  K n o w n p ote ntial dr u g i nteracti o ns:  N o k n o w n c yt oc hr o me P 4 5 0 dr u g- dr u g 
i nteracti o ns. C o nc o mita nt use wit h k n o w n m yel os u p pressi ve a ge nts ma y e n ha nce t he 
a d verse/t o xic effects. 
 
1 5. 2 7 
K n o w n p ote ntial t o xicities:  
C o m m o n k n o w n p ote ntial t o xicities, > 1 0 %:   
Car di o vasc ular: Peri p heral e de ma, pall or, e de ma, car diac m ur m ur, h y p ote nsi o n 
Ce ntral ner v o us s yste m: Fe ver, fati g ue, hea dac he, i ns o m nia, dizzi ness, c hills, pai n, 
c o nf usi o n, let har g y, a n xiet y, h y p oest hesia 
Der mat ol o gic:  Petec hiae, br uisi n g, ras h, er yt he ma, cell ulitis, lesi o ns, pr uritis 
E n d ocri ne & meta b olic: H y per gl yce mia, h y p oal b u mi ne mia, h y p o ma g nese mia, 
h y p o kale mia, h y per kale mia,  h y p o natre mia 
Gastr oi ntesti nal: Na usea, c o nsti pati o n, diarr hea, v o miti n g, a n ore xia, a b d o mi nal pai n, 
st o matitis, d ys pe psia 
He mat ol o gic: Ne utr o pe nia, t hr o m b oc yt o pe nia, a ne mia, fe brile ne utr o pe nia, le u k o pe nia, 
l y m p ha de n o pat h y 
He patic: H y per bilir u bi ne mia, al ka li ne p h os p hatase i ncrease d 
Ne ur o m usc ular & s keletal: Ri g ors, art hral gias, li m b pai n, bac k pai n, wea k ness 
Res pirat or y: C o u g h, d ys p nea, p ne u m o nia, p har y n gitis, l u n g crac kles, heart fail ure 

M C 1 4 8 3 
4 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
Less c o m m o n k n o w n p ote ntial t o xicities, 1 % - 1 0 %:  
Car di o vasc ular: T ac h ycar dia, c hest pai n/ disc o mf ort, facial e de ma, h y perte nsi o n, heart 
fail ure 
Ce ntral ner v o us s yste m: de pressi o n, malaise  
Der mat ol o gic: Al o pecia, dr y s ki n, urticarial 
E n d ocri ne & meta b olic: H y per urice mia, L D H i ncrease d, bicar b o nate i ncrease d or 
decrease d, d e h y drati o n, h y p oc hl ore mia, h y p o pr otei ne mia 
Gastr oi ntesti nal: M uc osal i nfla m mati o n, wei g ht l oss, gi n gi val blee di n g, he m orr h oi ds, 
l o ose st o ols, t o n g ue ulcerati o n, d ys p ha gia, oral ca n di diasis, t o ot hac he, a b d o mi nal 
diste nsi o n, gastr oes o p ha geal refl u x ( G E R D), gl oss o d y nia, li p ulcerati o n, oral pai n, t o ot h 
a bscess 
Ge nit o uri nar y, uri nar y tract i nfecti o n, d ys uria, p ol y uria 
He mat ol o gic: Bactere mia, he mat o ma, pa nc yt o pe nia, t hr o m b oc yt he mia 
He patic: Ascities, A S T i ncrease d, h y p o bilir u bi ne mia  
Ne ur o m usc ular & s keletal: M yal gias, falli n g, c hest wall pai n, m uscle s pas ms, b o ne pai n, 
m usc ul os keletal disc o mf ort  
Oc ular: Bl urre d visi o n  
Otic: Ear pai n  
Res pirat or y: A b n or mal breat h s o u n ds, h y p o xia, u p per res pirat or y tract i nfecti o ns, 
p har y n g olar y n geal pai n, rales, p ul m o nar y e de ma, si n usitis, ple ural eff usi o n, p ost nasal 
dri p, si n us c o n gesti o ns  
Miscella ne o us: Ca n di dal i nfecti o ns, sta p h yl oc occal i nfecti o n, tra nsf usi o n reacti o n, ni g ht 
s weats 
 
Rare k n o w n p ote ntial t o xicities, < 1 % ( Li mite d t o i m p orta nt or life-t hreate ni n g): 
A na p h ylactic re acti o n, atrial fi brillati o n, br o nc h o p ul m o nar y as per gill osis, 
car di o m y o pat h y, car di ores pirat or y arrest/fail ure, cat heter site he m orr ha ge, c h olec ystitis, 
f u n gal i nfecti o n, gastr oi ntesti nal he m orr ha ge, gi n gi val pai n, he m o pt ysis, h y perse nsiti vit y, 
i ntracra nial he m orr ha ge, me ntal stat us c ha n ge, MI, m yc o bacteri u m a vi u m c o m ple x 
i nfecti o n, peri di vertic ular a bscess, pse u d o m o nal l u n g i nfecti o n, p ul m o nar y e m b olis m, 
p ul m o nar y i nfiltrates, p ul m o nar y mass, re nal fail ure, res pirat or y arrest, se psis, 
s ple n o me gal y, s u pra ve ntric ular tac h ycar dia, S weet’s s y n dr o me (ac ute fe brile ne utr o p hilic 
der mat osis), uret hral he m orr ha ge  
 
1 5. 2 8 
Dr u g pr oc ure me nt: C o m mercial s u p plies. P har macies or cli nics s hall o btai n 
s u p plies fr o m n or mal c o m mercial s u p pl y c hai n or w h olesaler. 1 5. 2 
D E CI T ( 2 –
de o x y – 5 – azac yti di ne), Decita bi ne, Dac o ge n ®  
 
  
1 5. 2 9  N ursi n g G ui deli nes:   
 
1)   
M o nit or C B C. M yel os u p pressi o n is a d ose li miti n g fact or. 
I nstr uct patie nt t o re p ort a n y si g ns or s y m pt o ms of i nfecti o n, 
u n us ual br uisi n g or blee di n g t o t he healt h care tea m. 
 
  
2)   
Na usea a n d v o miti n g is c o m m o n. Pre me dicate wit h 
 
a ntie metics a n d assess f or t heir effecti ve ness . 
 
3)  
Certai n i nfecti o ns were see n m ore c o m m o nl y i n patie nts  treate d 
wit h decita bi ne; i ncl u di n g p ne u m o nia, f u n gal, ca n di dal, 
i nfecti o ns a n d cell ulitis. I nstr uct patie nt t o re p ort a n y si g ns or 

M C 1 4 8 3 
4 9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
s y m pt o ms of i nfecti o ns i m me diatel y. 
 
  
4)  
Patie nts ma y e x perie nce fati g ue. I nstr uct i n a n e ner g y 
 
c o nser vi n g lifest yle. 
 
5)  
M o nit or li ver f u ncti o n tests. Re p ort a n y a b n or malities t o  t he 
treati n g M D. 
 
6) 
Please n ote t hat n o t all n ursi n g g ui deli nes ma y be k n o w n at t his 
ti me. M o nit or patie nt caref ull y a n d re p ort all a d verse e ve nts t o 
t he M D a n d as re q uire d b y y o ur i nstit uti o n f or a d verse e ve nt 
m o nit ori n g. 
 
 
 
1 6. 0  
St atistic al C o nsi der ati o ns a n d Met h o d ol o g y  
 
1 6. 1    O ver vie w:  T his is a p hase II st u d y of a c o m bi nati o n of mi d osta uri n  a n d decita bi ne 
i n el derl y patie nts wit h ne wl y dia g n ose d A M L a n d F L T 3 m ut ati o n.   T his st u d y 
will use a o ne -sta ge bi n o mial desi g n  t o assess t he efficac y of t his c o m bi nati o n.   
 
1 6. 1 1 
E n d p oi nt:   T he p ri mar y e n d p oi nt i n t his trial is t he pr o p orti o n of 
c o m plete res p o nses d uri n g t hera p y.  A s uccess is defi ne d as a C R or C Ri 
as t he o bjecti ve stat us d uri n g t hera p y.  T hr o u g h o ut Secti o n 1 6. 0, 
c o m plete res p o nse will be c o nsi dere d s y n o n y m o us wit h “s uccess”, 
u nl ess s pecifie d ot her wise.   All patie nts meeti n g t he eli gi bilit y crite ria 
w h o ha ve si g ne d a c o nse nt f or m a n d ha ve be g u n treat me nt will be 
e val ua ble f or res p o nse . 
 
1 6. 2  
Statistical Desi g n:  
 
1 6. 2 1 
Decisi o n R ule:   
  
I n pre vi o us st u dies of el derl y A M L patie nts treate d wit h si n gle a ge nt 
decita bi ne as fr o ntli ne t hera p y, c o m plete res p o nse rates of 1 5 % - 2 4 % 
were see n ( { Cas he n, 2 0 1 0 # 8 1 3 } { L u b bert, 2 0 0 7 # 8 1 2 } ). A n 
i m pr o ve me nt i n c o m plete res p o nse rate wit h t he a d diti o n of mi d osta uri n 
t o decita bi ne w o ul d be of i nterest.   
 
T he lar gest s uccess pr o p orti o n w here t he pr o p ose d treat me nt re gi me n 
w o ul d be c o nsi dere d i neffecti ve i n t his p o p ulati o n is 1 0 %, a n d t he 
s mallest s uccess pr o p orti o n t hat w o ul d warra nt s u bse q ue nt st u dies wit h 
t he pr o p ose d re gi me n i n t his patie nt p o p ulatio n is 3 0 %.  A o ne -sta ge 
bi n o mial desi g n uses 2 4 e val ua ble patie nts t o test t he n ull h y p ot hesis t hat 
t he tr ue c o m plete res p o nse rate is at m ost 1 0 %.   
 
1 6. 2 1 1     Fi nal Decisi o n R ule:  E nter 2 4 e val ua ble patie nts i nt o t he 
st u d y.  If 4 or fe wer s uccesses are  o bser ve d i n t he first 2 4 
e val ua ble patie nts, we will c o nsi der t his re gi me n i neffecti ve i n 
t his patie nt p o p ulati o n. If 5 or m ore s uccesses are o bser ve d i n 
t he first 2 4 e val ua ble patie nts, we ma y rec o m me n d f urt her 
testi n g of t his re gi me n i n s u bse q ue nt st u dies i n t his p o p ulati o n. 

M C 1 4 8 3 
5 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
1 6. 2 1 2     O ver Accr ual: If m ore t ha n t he tar get n u m ber of patie nts are 
accr ue d, t he a d diti o nal patie nts will n ot be use d t o e val uate t he 
st o p pi n g r ule or use d i n a n y decisi o n ma ki n g pr ocess.  
A nal yses i n v ol vi n g o ver accr ue d patie nts are disc usse d i n 
Secti o n 1 6. 3 4. 
 
1 6. 2 2 
Sa m ple Size:  T his st u d y is e x pecte d t o re q uire 2 4 e val ua ble patie nts.  We 
a ntici pate accr ui n g 2 a d diti o nal patie nts t o acc o u nt f or i neli gi bilit y, 
ca ncellati o n, maj or treat me nt vi olati o n, or ot her reas o ns.  T heref ore , t he 
st u d y is e x pecte d t o accr ue a ma xi m u m of 2 6 patie nts o verall.  
 
1 6. 2 3  
Accr ual Rate a n d St u d y D urati o n:  T he a ntici pate d accr ual rate is 1 
e val ua ble patie nt per m o nt h.  T heref ore, t he accr ual peri o d is e x pecte d t o 
be a p pr o xi matel y 2 years.  T he pri mar y e n d p oi nt will be e val uate d 
a p pr o xi matel y 2. 7 5 years after t he trial o pe ns, or after t he last patie nt 
accr ue d has bee n o bser ve d f or at least 6 m o nt hs.  T he t otal st u d y d urati o n 
is e x pecte d t o be a p pr o xi matel y 3 years.    
 
1 6. 2 4 
P o wer a n d Si g nifica nce Le vel:   Ass u mi n g t hat t he n u m ber of s uccesses 
is bi n o miall y distri b ute d, t he si g nifica nce le vel is .0 9 , i.e. t here is a 9% 
c ha nce of fi n di n g t he dr u g t o be effecti ve w he n it tr ul y is n ot.  T he 
pr o ba bilit y of declari n g t hat t his re gi me n warra nts f urt her st u d y (i. e. 
statistical p o wer) u n der vari o us s uccess pr o p orti o ns ca n be ta b ulate d as a 
f u ncti o n of t he tr ue s uccess pr o p orti o n as s h o w n i n t he f oll o wi n g ta ble. 
 
If t he tr ue s uccess pr o p orti o n is... 
0. 1 0  
0. 1 5  
0. 2 0  
0. 2 5  
0. 3 0  
T he n t he pr o ba bilit y of declari n g 
t hat t he re gi me n warra nts f urt her 
st u d y is … 
0. 0 9 
0. 2 9 
0. 5 4 
0. 7 5 
0. 8 9 
 
1 6. 2 5 
Ot her c o nsi derati o ns:  A d verse e ve nts, q ualit y/ d urati o n of res p o nse, a n d 
patter ns of treat me nt fail ure o bser ve d i n t his st u d y, as well as scie ntific 
disc o veries or c ha n ges i n sta n dar d ca re will be ta ke n i nt o acc o u nt i n a n y 
decisi o n t o ter mi nate t he st u d y  
 
1 6. 3 
A nal ysis Pla n  
 
1 6. 3 1 
Pri mar y O utc o me A nal yses:  
 
1 6. 3 1 1 Defi niti o n:   T he pri mar y e n d p oi nt of t his trial is t he pr o p orti o n 
of c o m plete res p o nses  t o t hera p y. A s uccess is defi ne d as a C R 
or C Ri as t he o bjecti ve s tat us. All patie nts meeti n g t he eli gi bilit y 
criteria w h o ha ve si g ne d a c o nse nt f or m a n d ha ve be g u n 
treat me nt will be e val ua ble f or c o m plete res p o nse. 
 
1 6. 3 1 2 Esti mati o n:   T he pr o p orti o n of s uccesses will be esti mate d b y 
t he n um ber of s uccesses di vi de d b y t he t otal n u m ber of e val ua ble 
patie nts. E xact bi n o mial c o nfi de nce i nter vals f or t he tr ue s uccess 
pr o p orti o n will be calc ulate d . 
 

M C 1 4 8 3 
5 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
1 6. 3 2 
Sec o n dar y O utc o me A nal yses:    
 
1 6. 3 2 1 
O verall s ur vi val ti me is defi ne d as t he ti me fr o m re g istrati o n t o 
deat h d ue t o a n y ca use. T he distri b uti o n of o verall s ur vi val will 
be esti mate d usi n g t he met h o d of Ka pla n -Meier { Ka pla n E, 
1 9 5 8 # 8 3 1 } .  I n a d diti o n, t he o verall s ur vi val rate at 1 year after 
re gistrati o n will be re p orte d. 
 
1 6. 3 2 2   Pr o gressi o n- free s ur vi val ti me is defi ne d f or all e val ua ble 
patie nts as t he ti me fr o m re gistrati o n t o t he ti me of rela pse or 
deat h d ue t o a n y ca use.   T he distri b uti o n of pr o gressi o n-free 
s ur vi val will be esti mate d usi n g t he met h o d of Ka pla n-Meier.   
I n a d diti o n, t he pr o gressi o n-free s ur vi val rate at 1 year after 
re gistrati o n will be re p orte d. 
  
1 6. 3 2 3 T he o verall res p o nse rate will be esti mate d b y t he t otal n u m ber 
of c o m plete or partial res p o nses ( C R, C Ri, M L F S , or P R) 
di vi de d b y t he t otal n u m ber of e val ua ble patie nts. All e val ua ble 
patie nts will be use d f or t his a nal ysis. E xact bi n o mial 9 5 % 
c o nfi de nce i nter vals f or t he tr ue o verall res p o nse rate will be 
calc ulate d. 
 
1 6. 3 2 4 D urati o n of c o m plete res p o nse is defi ne d f or all e val ua ble 
patie nts w h o ha ve ac hie ve d a C R or C Ri as t he date at w hic h t he 
patie nt’s o bjecti ve stat us is first n ote d t o be a C R  or C Ri  t o t he 
earliest date rela pse is d oc u me nte d. T he distri b uti o n of d urati o n 
of c o m plete res p o nse  will be esti mate d usi n g t he met h o d of 
Ka pla n -Meier .  If t here are a s ufficie nt n u m ber of C R/ C Ri, a 
la n d mar k a nal yses ma y be perf or me d t o c o m pare d urati o n of 
C R/ C Ri  i n patie nts w h o first ac hie ve d a C R/ C Ri at 2 m o nt hs vs 
t h ose w h o first ac hie ve d a C R/ C Ri at 8 m o nt hs . 
 
 
1 6. 3 2 5 A d verse E ve nts:  All eli gi ble patie nts t hat ha ve i nitiate d  
treat me nt will be c o nsi dere d e val ua ble f or assessi n g a d verse 
e ve nt rate(s).  T he ma xi m u m gra de f or eac h t y pe of a d verse 
e ve nt will be rec or de d f or eac h patie nt, a n d fre q ue nc y ta bles will 
be re vie we d t o deter mi ne patter ns.  A d diti o nall y, t he relati o ns hi p 
o f t he a d verse e ve nt(s) t o t he st u d y treat me nt will be ta ke n i nt o 
c o nsi derati o n. 
 
1 6. 3 3  C orrelati ve A nal yses  
 
1 6. 3 3 1  Pr o g n ostic a n d pr e dicti ve fact ors i ncl u di n g a ge a n d F L T 3 
m utati o n b y I T D vs. T K D vs. b ot h will be assesse d. T hese 
fact ors will be s u m marize d a n d use d t o hel p c ha racterize t he 
t y pes of patie nts accr ue d t o t his trial. I n a d diti o n, we will e x pl ore 
differe nces i n t he distri b uti o ns of t hese ris k fact ors b y cli nical 
o utc o me ( C R/ C Ri vs. n ot, O S a n d D F S). N o n para metric 
q ua ntitati ve c o m paris o ns b y gr o u p will b e ma de as a p pr o priate 
( Fis her’s e xact or Wilc o x o n ra n k s u m). K a pla n-Meier met h o ds 

M C 1 4 8 3 
5 2 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
a n d l o g ra n k statistics will be use d t o c o mpare bet wee n gr o u ps 
f or ti me t o- e ve nt meas ures. Gi ve n t he li mite d n u m ber of 
patie nts, t he differe nce i n ris k fact or dist ri b uti o n b y o utc o me will 
be lar gel y e x pl orat or y. 
 
1 6. 3 3 2  M R D will be assesse d b y P C R f or F L T 3 m utati o n (if F L T 3 is 
re peate d) or fl o w c yt o metr y . M R D stat us will be c orrelate d wit h 
res p o nse usi n g Fis her’s e xact test. I n a d diti o n, t he relati o ns hi p 
bet wee n M R D stat us ( p ositi ve vs. ne gati ve) a n d disease -free 
s ur vi val will be e val uate d usi n g la n d mar k a nal yses.  
 
1 6. 3 4 
O ver Accr ual: If m ore t ha n t he tar get n u m ber of patie nts are accr ue d, t he 
a d diti o nal patie nts will n ot be use d t o e val uate t he st o p pi n g r ule or u se d 
i n a n y decisi o n ma ki n g pr ocesses; h o we ver, t he y will be i ncl u de d i n fi nal 
e n d p oi nt esti mates a n d c o nfi de nce i nter vals.  
 
1 6. 4 
Data & Safet y M o nit ori n g:  
 
1 6. 4 1 
T he pri nci ple i n vesti gat or(s) a n d t he st u d y statisticia n will re vie w t he 
st u d y at least t wice a year t o i de ntif y accr ual, a d verse e ve nt, a n d a n y 
e n d p oi nt pr o ble ms t hat mi g ht be de vel o pi n g. T he Ma y o Cli nic Ca ncer 
Ce nter ( M C C C) Data Safet y M o nit ori n g B oar d ( D S M B) is res p o nsi ble 
f or re vie wi n g accr ual a n d safet y data f or t his trial at least t wice a year, 
base d o n re p orts pr o vi de d b y t he M C C C Statistical Office.  
 
1 6. 4 2  A d verse E ve nt St o p pi n g R ules:   T he st o p pi n g r ules s pecifie d bel o w are 
base d o n t he k n o wle d ge a vaila ble at st u d y de vel o p me nt.  We n ote t hat 
t he A d verse E ve nt St o p pi n g R ule ma y be a dj uste d i n t he e ve nt of eit her 
( 1) t he st u d y re-o pe ni n g t o accr ual or ( 2) at a n y ti me d uri n g t he c o n d uct 
of t he trial a n d i n c o nsi derati o n of ne wl y ac q uire d i nf or mati o n re gar di n g 
t he a d verse e ve nt pr ofile of t he treat me nt(s) u n der i n vesti gati o n.  T he 
st u d y tea m may c h o ose t o s us pe n d accr ual beca use of u ne x pecte d 
a d verse e ve nt pr ofiles t hat ha ve n ot cr osse d t he s pecifie d r ule bel o w.  
 
Accr ual will be te m p oraril y s us pe n de d t o t his st u d y if at a n y ti me we 
o bser ve e ve nts c o nsi dere d at least p ossi bl y relate d t o st u d y tre at me nt (i.e. 
a n a d verse e ve nt wit h attri b ute s pecifie d as  “ p ossi ble,” “ pr o ba ble,” or 
“ defi nite”) t hat satisf y o ne of t he f oll o wi n g: 
 
•  
if 4 or m ore patie nts i n t he first 1 2 treate d patie nts e x perie nce a gra de 
4 or hi g her n o n- he mat ol o gic a d verse e ve nt at lea st p ossi bl y relate d t o 
treat me nt e xcl u di n g i nfecti o ns a n d h y p o p h os p hata mia, 
h y p ocalce mia, h y p o- or h y per kale mia, h y per urice mia as t hese 
a b n or mal la b res ults te n d t o res ol ve q uic kl y ( ≤7 da ys) wit h o ut 
affecti n g or je o par dizi n g patie nt safet y . 
 
•  
if after t he first 1 2 patie nts ha ve bee n treate d, 3 0 % of all patie nts 
e x perie nce a gra de 4 or hi g her n o n -he mat ol o gic a d verse e ve nt at 
least p ossi bl y relate d t o treat me nt e xcl u di n g i nfecti o ns a n d 
h y p o p h os p hata mia, h y p ocalce mia, h y p o- or h y per kale mia, 

M C 1 4 8 3 
5 3 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
h y per urice mia as t he se a b n or mal la b res ults te n d t o res ol ve q uic kl y 
( ≤7 da ys) wit h o ut affecti n g or je o par dizi n g patie nt safet y.  
 
We n ote t hat we will re vie w gra de 4 a n d 5 a d verse e ve nts dee me d 
“ u nrelate d” or “ u nli kel y t o be relate d”, t o verif y t heir attri b uti o n a n d t o 
m o nit o r t he e mer ge nce of a pre vi o usl y u nrec o g nize d treat me nt-relate d 
a d verse e ve nt. 
 
1 6. 5    Res ults Re p orti n g o n Cli nical Trials. g o v: At st u d y acti vati o n, t his st u d y will ha ve 
bee n re gistere d wit hi n t he “ Cli n icial Trials. g o v” we bsite. T he Pri mar y a n d 
Sec o n dar y E n d p oi nts al o n g wit h ot her re q uire d i nf or mati o n f or t his st u d y will be 
re p orte d o n Cli nical Trials. g o v. F or p ur p oses of ti mi n g of t he Res ults Re p orti n g, 
t he i nitial esti mate d c o m pleti o n date f or t he Pri mar y E n d p oi nt of t his st u d y is 2. 5 
years  after t he st u d y o pe ns t o accr ual. T he defi niti o n of “ Pri mar y E n d p oi nt 
C o m pleti o n Date” ( P E C D) f or t his st u d y is at t he ti me t he last patie nt re gistere d 
has bee n f oll o we d f or at least 6 m o nt hs. 
 
1 6. 6  
I ncl usi o n of W o me n a n d Mi n orities 
 
1 6. 6 1 
T his st u d y will be a vaila ble t o a ll eli gi ble patie nts, re gar dless of race, 
ge n der, or et h nic ori gi n. 
 
1 6. 6 2 
T here is n o i nf or mati o n c urre ntl y a vaila ble re gar di n g differe ntial effects 
of t his re gi me n i n s u bsets defi ne d b y race, ge n der, or et h nicit y, a n d t here 
is n o reas o n t o e x pect s uc h differe nces t o e xist. T heref ore, alt h o u g h t he 
pla n ne d a nal ysis will, as al wa ys, l o o k f or differe nces i n treat me nt effect 
base d o n racial a n d ge n der gr o u pi n gs, t he sa m ple size is n ot i ncrease d i n 
or der t o pr o vi de a d diti o nal p o wer f or s u bset a nal yses. 
 
1 6. 6 3  T he ge o gra p hical re gi o n ser ve d b y M C C C has a p o p ulati o n w hic h 
i ncl u des a p pr o xi matel y 3 % mi n orities.  Base d o n pri or M C C C 
st u dies i n v ol vi n g si milar disease sites, we e x pect a b o ut 3- 5 % of 
patie nts will be classifie d as mi n orities b y race a n d a b o ut 3 0 % of 
pati e nts will be w o me n. E x pecte d sizes of racial b y ge n der s u bsets 
are s h o w n i n t he f oll o wi n g ta ble: 
 
Accr ual Esti mates b y Ge n der/ Et h nicit y/ Race  
 
Et h nic Cate g or y  
Se x/ Ge n der  
Fe males  
Males  
U n k n o w n  
T otal  
His pa nic or Lati n o  
0  
1  
0  
1  
N ot His pa nic or Lati n o  
8  
1 7  
0  
2 5  
Et h nic Cate g or y: T otal of all s u bjects *  
8  
1 8  
0  
2 6  
Racial Cate g or y  
 
A merica n I n dia n or Alas ka n Nati ve  
0  
0  
0  
0  
Asia n  
0  
0  
0  
0  
Blac k or Africa n A merica n  
0  
1  
0  
1  
Nati ve Ha waiia n or ot her Pacific Isla n der  
0  
0  
0  
0  
W hite  
8  
1 7  
0  
2 5  
Racial Cate g or y: T o tal of all s u bjects * 
8  
1 8  
0  
2 6  

M C 1 4 8 3 
5 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
Et h nic 
Cate g ories:  
His pa nic or Lati n o – a pers o n of C u ba n, Me xica n, P uert o Ric o, S o ut h or Ce ntral 
A merica n, or ot her S pa nis h c ult ure or ori gi n, re gar dless of race. T he ter m “ S pa nis h 
ori gi n” ca n als o be use d i n a d diti o n t o “ His pa nic or Lati n o.”  
N ot His pa nic or Lati n o  
Racial 
Cate g ories:  
A merica n I n dia n or Alas ka n Nati ve – a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal 
pe o ples of N ort h, Ce ntral, or S o ut h A merica, a n d w h o mai ntai ns tri bal affiliati o ns or 
c o m m u nit y attac h me nt. 
A sia n – a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of t he Far East, 
S o ut heast Asia, or t he I n dia n s u bc o nti ne nt i ncl u di n g, f or e xa m ple, Ca m b o dia, C hi na, 
I n dia, J a pa n, K orea, Mala ysia, Pa kista n, t he P hili p pi ne Isla n ds, T haila n d, a n d 
Viet na m. ( N ote: I n di vi d uals fr o m t he P hili p pi ne Isla n ds ha ve bee n rec or de d as Pacific 
Isla n ders i n pre vi o us data c ollecti o n strate gies.)  
Blac k or Africa n A merica n – a pers o n ha vi n g ori gi ns i n a n y of t he blac k racial gr o u ps 
of Africa.  T er ms s uc h as “ Haitia n” or “ Ne gr o”  ca n be use d i n a d diti o n t o “ Blac k or 
Africa n A merica n.”  
Nati ve Ha waiia n or ot her Pacific Isla n der – a pers o n ha vi n g ori gi ns i n a n y of t he 
ori gi nal pe o ples of Ha waii, G ua m, Sa m oa, or ot her Pacific Isla n ds.  
W hite – a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of E ur o pe, t he Mi d dle 
East, or N ort h Africa.  
 
 
 
1 7. 0 
P at h ol o g y C o nsi der ati o ns/ Tiss ue Bi os peci me ns: N o ne.    
 
 
 
1 8. 0 
Rec or ds a n d D at a C ollecti o n P r oce d ures   
 
1 8. 1 
S u b missi o n Ti meta ble  
 
I niti al M ateri al(s) 
C ase Re p ort F or m ( C R F)  
Acti ve - M o nit orin g P h ase  
( C o m plia nce wit h T est Sc he d ule Secti o n 4. 0) 
 
O n -St u d y  
 
 
≤2 wee ks after re gistrati o n  
A d verse E ve nt - Baseli ne  
Researc h Bl o o d S u b missi o n  
Researc h B o ne Marr o w  S u b missi o n   
Meas ure me nt   B o ne Marr o w  a n d Bi o ps y  - 
Baseli ne    
B o ne Marr o w Bi o ps y  a n d As pirate Re p ort  
i ncl u di n g t he F L T 3 m utati o n b y P C R a n d 
c yt o ge netics .  
E n d of Acti ve Treat me nt/ Ca ncel N otificati o n  
S u b mit ≤2 wee ks after re gistrati o n if wit h dra wal/ref usal 
occ urs pri or t o be gi n ni n g pr ot oc ol t hera p y  

M C 1 4 8 3 
5 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 

M C 1 4 8 3 
5 6 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
Test Sc he d ule M ateri al(s)  
C R F  
Acti ve -M o nit ori n g P h ase  
( C o m plia nce wit h T est Sc he d ule Secti o n 4. 0) 
 
 
At eac h e val uati o n 
d uri n g treat me nt  
At e n d of treat me nt  
 
E val uati o n/ Treat me nt  
X  
X  
Na dir/ A d verse E ve nt  
X  
X  
Meas ure me nt a n d Disease Res p o nse  
X  
X  
B o ne Marr o w Bi o ps y a n d As pirate Re p ort  
i ncl u di n g t he F L T 3 m utati o n b y P C R a n d 
c yt o ge netics 
X 1 
X  
Researc h Bl o o d S u b missi o n  
X 1  
 
Researc h B o ne Marr o w S u b missi o n  
X 1  
 
E n d of Acti ve Treat me nt/ Ca ncel N otificati o n  
 
X  
A D R/ A E R  
At eac h occ urre nce  
(see Secti o n 1 0. 0) 
 
1.   O nl y w he n re q uire d b y t he T est Sc he d ule (see Secti o n 4. 0  a n d 1 4. 0)). 
 
F oll o w -u p M ateri al(s)   
C R F  
E ve nt M o nit ori n g P h ase 1 
 
 
q. 6 
m o nt hs 
u ntil P D 2  
 
 
 
At P D 2  
 
After 
P D q. 6 
m os.  
 
 
 
Deat h  
 
 
 
Ne w Pri mar y  
E ve nt M o nit ori n g  
X  
X  
X  
X  
At eac h occ urre nce  
1.  If a patie nt is still ali ve 2 ye ars after re gistrati o n, n o f urt her f oll o w- u p is re q uire d. 
2.  S u b mit c o p y of d oc u me ntati o n of res p o nse or pr o gressi o n t o t he  M C C C O perati o ns Office,  
Atte nti o n: Q A S f or  M C 1 4 8 3 . 
 
 
 
1 9. 0  
B u d get  
 
  
1 9. 1 
C osts c har ge d t o patie nt:  r o uti ne cli nical care . 
 
1 9. 2 
T ests  t o be researc h f u n de d: St u d y dr u g, uri nal ysis , E C G , bl o o d a n d as pirate 
c orrelati ves . 
 
1 9. 3  
Ot her b u d get c o ncer ns: Pr ot oc ol a d mi nistrati o n, data ma na ge me nt a n d statistical 
a nal ysis eff orts will be b y f u n de d b y N o vartis. 
 
 
 
 

M C 1 4 8 3 
5 7 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
2 0. 0 
Ref ere nces  
 
 
1. A merica n Ca n cer S oci et y ( 2 0 1 1) Ca ncer Facts & Fi g ures. Atla nta, G A.  
2. Barr y E V, Clar k JJ, C o ols J, et al ( 2 0 0 7) U nif or m se nsiti vit y of F L T 3 acti vati o n l o o p 
m uta nts t o t he t yr osi ne ki nase i n hi bit or mi d osta uri n. Bl o o d. 1 1 0( 1 3): 4 4 7 6- 4 4 7 9. 
3. B ur nett A ( 2 0 1 1) Ac ut e M yel oi d Le u ke mia i n P ost gra d u ate H e mat ol o g y. Si xt h 
E diti o n. Wile y- blac k well p u blis hi n g. E dite d b y A Vict or H off bra n d. West S usse x U K. 
4. B ur nett A, Wetzler M, L o w e n ber g B ( 2 0 1 1) T h era pe utic A d va nces i n A c ute M yel oi d 
Le u k e mia. J Cli n O nc ol. 2 9: 4 8 7- 4 9 4. 
5. Cas he n, A. F., G. J. Sc hiller, et al. ( 2 0 1 0). " M ultice nter, P hase II St u d y of Decita bi ne 
f or t he First-Li n e Tr eat m e nt of Ol der Patie nts Wit h Ac ute M yel oi d Le u k e mia." J o ur nal of 
Cli nical O nc ol o g y  2 8 ( 4): 5 5 6- 56 1.  
6. Del C orral A, D utri e x C, H u nts ma n- La be d A, et al ( 2 0 1 2) Mi d osta uri n d oes n ot 
pr ol o n g car diac re p ol arizati o n defi ne d i n a t h or o u g h el ectr ocar di o gra m trial i n healt h y 
v ol u nteers Ca ncer C he m ot hera p y a n d P har mac ol o g y; 6 9( 5): 1 2 5 5- 1 2 6 3. 
7. Este y E ( 2 0 1 0) U n d erst a n di n g a n d Ma na gi n g Ultra Hi g h -Ris k He mat ol o gical 
Mali g na n cies: Hi g h C yt o ge n etic or M olec ular G e netic Ris k Ac ute M yel oi d Le u k e mia. 
He mat ol o g y 2 0 1 0: 4 7 4- 4 8 0. 
8. Fer n a n dez H F, S u n Z, Ya o X, et al ( 2 0 0 9) A nt hrac ycli ne D ose I Nt e nstificati o n i n 
Ac ute M yel oi d Le u k e mia. Ne w E n gla n d J o ur nal of Me dici ne; 3 6 1: 1 2 4 9- 1 2 5 9. 
9. Fisc her T, St o ne R, De A n gel o D, et al ( 2 0 1 0) P hase II B trial of oral mi d osta uri n 
( P K C 4 1 2), t he F M S-li ke t yr osi ne ki nas e 3 rece pt or ( F L T 3), a n d m ulti-tar gete d ki nase 
i n hi bit or, i n patie nts wit h ac ute m yel oi d le u ke mia a n d hi g h ris k m yel o d ys pl astic 
s y n dr o me wit h eit her wil d t y pe or m utat e d F L T 3. J Cli n O nc ol; 2 8( 2 8): 4 3 3 9- 4 3 4 5. 
1 0. Fl oc k hart D A ( 2 0 0 9) Dr u g I nteracti o ns: C yt oc hr o me P 4 5 0 Dr u g I nteracti o n Ta ble. 
I n dia n a U ni versit y Sc h o ol of Me dici ne ( 2 0 0 7) Versi o n 5. 0 release d o n J a n 1 2, 2 0 0 9. 
htt p:// me dici ne.i u p ui.e d u/fl oc k hart/ta ble. ht m.  
1 1. Gale R E, Gr ee n C, Alle n C, et al ( 2 0 0 8) T he i m pact of F L T 3 i nter nal t a n de m 
d u plicati o n m uta nt le vel, n u m ber, size, a n d i nteracti o n wit h N P M 1 m utati o ns i n a lar ge 
c o h ort of y o u n g a d ult patie nts wit h ac ute m yel oi d le u ke mia. Bl o o d; 1 1 1: 2 7 7 6- 2 7 8 4. 
1 2. G otli b J, Kl ui n - Nele ma ns H, Ge or ge T, et al ( 2 0 1 2) KI T I n hi bit or Mi d osta uri n i n 
Patie nts wit h A d va nce d S yste mic Mast oc yt osis: Res ults of a Pla n ne d I nteri m A nal ysis of 
t he Gl o bal C P K C 4 1 2 D 2 2 0 1 Trial. Bl o o d. 2 0 1 0; 1 1 6:[a bstract 3 1 6]. 
1 3. Ha ya ka wa F, T o wat ari M, Ki y oi H, et al ( 2 0 0 0) Ta n de m- d u plicate d Flt 3 
c o nstit uti vel y acti vates S T A T 5 a n d M A P ki nase a n d i ntr o d uces a ut o n o m o us cell gr o wt h 
i n I L- 3- de p e n de nt cell li nes. O nc o ge n e; 1 9( 5): 6 2 4- 6 3 1. 
1 4. Ka ntarjia n H, T h o m as X, D m osz y ns k a A, et al ( 2 0 1 2) M ultice nter, Ra n d o mize d, 
O pe n -La b el, P hase III Trial of Decita bi ne Vers us Patie nt C h oice, Wit h P h ysicia n A d vice, 
of Eit her S u p p orti ve Car e or L o w- D ose C yt ara bi n e f or t he Treat 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 k e mia. J Cli n O nc ol; 3 0 ( 2 1): 2 6 7 0- 2 6 7 7 
1 5 . K a pla n E, M. P. ( 1 9 5 8). " N o n p ara m etric esti mati o n f or i nc o m plete o bser vati o ns." J 

M C 1 4 8 3 
5 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
A m Stat Ass oc ( 5 3): 4 5 7- 4 8 1. 
1 6. Ka yser S, Sc hle n k R F, L o n d o n o M C, et al ( 2 0 0 9) I nserti o n of F L T 3 i nter nal ta n de m 
d u plicati o n i n t he t yr osi n e ki nase d o mai n- 1 is ass o ciate d wit h resista nce t o c he m ot hera p y 
a n d i nferi or o utc o m e. Bl o o d; 1 1 4( 1 2): 2 3 8 6- 2 3 9 2. 
1 7. Ki n dler T, Li p k a D, Fis her T ( 2 0 1 0) F L T 3 as a t hera p e utic tar get i n A M L: still 
c halle n gi n g after all t hes e years. B l o o d; 1 1 6: 5 0 8 9- 5 1 0 2. 
1 8. Ki y oi H, N a oe T, N a ka n o Y, et al ( 1 9 9 9) Pr o g n ostic i m plicati o n of F L T 3 a n d N- R A S 
ge n e m utati o ns i n ac ute m yel oi d le u ke mia. Bl o o d; 9 3( 9): 3 0 7 4- 3 0 8 0. 
1 9. Ki y oi H, T o w atari M, Y o k ota S, et al ( 1 9 9 8) I nter nal ta n de m d u plicati o n of t he F L T 3 
ge n e is a n o vel m o dalit y of el o n gati o n m utati o n w hic h ca uses c o nstit uti ve acti vati o n of 
t he pr o d uct. Le u k e mia; 1 2( 9): 1 3 3 3- 1 3 3 7. 
2 0. K ottari dis P D, Gale R E, Fre w M E, et al ( 2 0 0 1) T he pres e nce of a F L T 3 i nter nal 
ta n de m d u plicati o n i n patie nts wit h ac ute m yel oi d le u ke mia ( A M L) a d ds i m p orta nt 
pr o g n ostic i nf or mati o n t o c yt o ge netic ris k gr o u p a n d res p o nse t o t he first c ycl e of 
c he m ot hera p y: a nal ysis of 8 5 4 patie nts fr o m t he U nite d Ki n g d o m Me dical Researc h 
C o u ncil A M L 1 0 a n d 1 2 trials. Bl o o d; 9 8: 1 7 5 2- 1 7 1 0. 
2 1. Le v is M ( 2 0 1 1) F L T 3/I T D A M L a n d t he la w of u ni nte n de d c o nse q u e n ces. Bl o o d 
1 1 7: 6 9 7- 6 9 9 0. 
2 2. Le vis M, Br o w n P, S mit h B, et al ( 2 0 0 6) Plas ma i n hi bit or y acti vit y ( PI A): a 
p har mac o d y n a mic assa y re veals i nsi g hts i nt o t he basis f or c yt o xic res p o nse t o F L T 3 
i n hi bit ors. Bl o o d 1 0 8: 3 4 7 7. 
2 3. L u b bert, M., B. R uter, et al. ( 2 0 0 7). " C o nti n ue d L o w -D ose Decita bi ne ( D A C) Is a n 
Acti ve  First -Li ne  Treat me nt  i n  All  C yt o ge neti c  S u b gr o u ps  of  Ol der  A M L  Patie nts:  
Res ults of t he F R 0 0 3 3 1 M ultice nter P hase II St u d y." A S H A n n ual Meeti n g A bstracts  
1 1 0 ( 1 1): 3 0 0-. 
2 4. Ma nle y P W, B o ult o n C, Cara vatti G, et al ( 2 0 0 3) Precli nical pr ofile of P K C 4 1 2 
( mi d osta uri n) as a n F L T 3 i n hi bit or f or t he t hera p y of A M L. Prese nte d at t he A merica n 
Ass ociati o n f or Ca ncer R esear c h A n n ual M eeti n g, Was hi n gt o n, D C, J ul y 1 1- 1 4, 2 0 0 3 
( p oster 1 0 0 4). 
2 5. Mes hi nc hi S, Al o nz o T A, Stire walt D L, et al ( 2 0 0 6) Cli nical i m plicati o ns of F L T 3 
m utati o ns i n pe diatric A M L. Bl o o d; 1 0 8( 1 2): 3 6 5 4- 3 6 6 1. 
2 6. N C C N G ui deli nes v 1. ( 2 0 1 2) Nati o nal C o m pre he nsi ve Care Net w or k. N C C N 
Cli nical Prac tice G ui deli nes i n O nc ol o g y – Ac ute M yel oi d Le u k e mia. Versi o n 2. 2 0 1 2. 
2 7. Ra va n di F, B ur nett A, A g ura E, et al ( 2 0 0 7) Pr o gress i n t he Treat me nt of Ac ute 
M yel oi d Le u k e mia. Ca ncer; 1 1 0: 1 9 0 0 – 1 0. 
2 8. Sat o T, Ya n g X, K na p per S, et al ( 2 0 1 1) F L T 3 li ga n d i m pe des t he effi cac y of F L T 3 
i n hi bit ors i n vitr o a n d i n vi v o. Bl o o d; 1 1 7( 1 2): 3 2 8 6- 3 2 9 3. 
2 9. Sc h nitt ger S, Sc h oc h C, D u gas M, et al ( 2 0 0 2) A nal ysis of F L T 3 le n gt h m utati o ns i n 
1 0 0 3 patie nts wit h ac ute m yel oi d le u ke mia: c orrel ati o n t o c yt o ge n etics, F A B s u bt y p e, 
a n d pr o g n osis i n t he A M L C G st u d y a n d usef ul ness as a mar ker f or t h e detecti o n of 
mi ni mal resi d ual disease. Bl o o d; 1 0 0( 1): 5 9- 6 6. 

M C 1 4 8 3 
5 9 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
3 0. St o ne R M, De A n gel o DJ, Kli me k V, et al ( 2 0 0 5) Patie nts wit h ac ute m yel oi d 
le u ke mia a n d a n acti vati n g m utati o n i n F L T 3 res p o n d t o a s mall- m olec ule F L T 3 t yr osi ne 
ki nase i n hi bit or, P K C 4 1 2. Bl o o d; 2 0 0 5; 1 0 5: 5 4- 6 0. 
3 1. St o ne R M, Fisc her T, Pa q uette R, et al ( 2 0 0 9) A p hase 1 b st u d y of mi d osta uri n 
( P K C 4 1 2) i n c o m bi nati o n wit h da u n or u bici n a n d c yt ara bi ne i n d u cti o n a n d hi g h- d ose 
c yt ara bi ne c o ns oli dati o n i n patie nts u n der a ge 6 1 wit h ne wl y dia g n os e d de n o v o ac ute 
m yel oi d le u ke mia: o verall s ur vi val of patie nts w h ose blasts ha ve F L T 3 m utati o ns is 
si milar t o t h ose wit h wil dt y pe F L T 3. A S H 2 0 0 9 A bstract # 6 3 4, Bl o o d, V ol 1 1 4. 
3 2. St o ne R M, Fisc her T, Pa q uette R, et al ( 2 0 1 2) P hase I B st u d y of F L T 3 ki nase 
i n hi bit or mi d osta uri n wit h c he m ot hera p y i n y o u n ger ne wl y dia g n os e d a d ult patie nts wit h 
ac ute m yel oi d le u ke mia. Le u k e mia 2 6, 2 0 6 1- 2 0 6 8. 
3 3. T hie de C, Ste u del C, M o hr B, et al ( 2 0 0 2) A n al ysis of F L T 3- activati n g m utati o ns i n 
9 7 9 patie nts wit h ac ute m yel o ge n o us le u k e mia: ass ociati o n wit h F A B s u bt y p es a n d 
i de ntificati o n of s u b gr o u ps wit h p o or pr o g n osis. Bl o o d; 9 9( 1 2): 4 3 2 6- 4 3 3 5. 
3 4. Utz I, S pitaler M, R y bcz y ns ka M, et al ( 1 9 9 8) Re versal of m ulti dr u g resista nce b y 
sta ur os p ori ne deri vati ves C G P 4 1 2 5 1 a n d C G P 4 2 7 0 0. I nt. J. Ca ncer.; 7 7: 6 4- 9. 
3 5. Weis ber g E, B o ult o n C, Kell y L M, et al ( 2 0 0 2) I n hi biti o n of m uta nt F L T 3 rece pt ors 
i n le u ke mia cells b y t he s mall m olec ule t yr osi ne ki nase i n hi bit or P K C 4 1 2. Ca ncer Cell; 
1: 4 3 3- 4 4 3. 
3 6. Yi n O, Wa n g Y, La n za C, et al ( 2 0 0 8) P har mac o ki netics ( P K) a n d 
p har mac o d y n a mics ( P D) of mi d osta uri n ( P K C 4 1 2) i n patie nts wit h ac ute m yel oi d 
le u ke mia ( A M L). J Cli n O nc ol 2 6: 3 8 8s, (a bstr 7 0 6 4). 
 

M C 1 4 8 3 
6 0 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
 
A p pe n di x I a:  Dr u gs wit h Ris k of T ors a des de P ointes  
 
T his list c o ntai ns me dicati o ns t hat are ge nerall y acce pte d (a n d d oc u me nte d i n p u blis he d data) as 
ha vi n g a n i ncrease d ris k of Q T pr ol o n gati o n a n d/ or t orsa des de p oi ntes.  C o nc o mita nt 
a d mi nistrati o n of mi d osta uri n  a n d a me dicati o n o n t his list is pr o hi bite d .  
 
 
Ge neric N a me  
B r a n d N a me  
C o m me nts  
A mi o dar o ne  
C or dar o ne ®, Pacer o ne ®  
L o w ris k t orsa des de p oi ntes  
Arse nic tri o xi de  
Trise n o x ®  
T orsa des de p oi ntes  
Be pri dil  
Vas oc or ®  
 
C hl or o q ui ne  
Arale n ®  
 
C hl or pr o mazi ne  
T h orazi ne ®  
 
Cisa pri de  
Pr o p ulsi d ®  
Restricte d  a vaila bilit y i n U. S. 
Clarit hr o m yci n  
Bia xi n ®  
 
Dis o p yra mi de  
N or pace ®  
T orsa des de p oi ntes  
D ofetili de  
Ti k os y n ®  
T orsa des de p oi ntes  
D olasetr o n  
A nze met ®  
 
Dr o peri d ol  
I na psi ne ® 
T orsa des de p oi ntes  
Er yt hr o m yci n  
Er yt hr oci n ®, E. E. S. ®  
I V > P O 
Hal ofa ntri ne  
Hal fa n ® 
 
Hal o peri d ol  
Hal d ol ®  
I V > P O, hi g h d oses i ncrease Q T 
pr ol o n gati o n a n d t orsa des de p oi ntes  
I b utili de 
C or vert ®  
T orsa des de p oi ntes, fe male > male, 
n o n -Ca ucasia n > Ca ucasia n  
Le v o met ha d yl  
Orlaa m ®  
 
Mes ori dazi ne  
Sere ntil ®  
 
Met ha d o ne  
D ol o p hi ne ®, Met ha d o se ® 
 
Pe nta mi di ne  
Pe nta m ®, Ne b u pe nt ®  
 
Pi m ozi de  
Ora p ®  
 
Pr ocai na mi de  
Pr o nest yl ®, Pr oca n ®, 
Pr oca n bi d ®  
N -acet yl pr ocai na mi de ca uses t orsa de de 
p oi ntes, n ot pare nt c o m p o u n d  
Q ui ni di ne  
Car di o q ui n ®, Q ui na gl ute ®  
T orsa des de p oi ntes  
S otal ol  
Beta pace ®  
T orsa de de p oi ntes fe male > male  
S parfl o xaci n  
Za ga m ®  
 
T hi ori dazi ne  
Mellaril ®  
 
N ote:  t he a b o ve list is n ot all -i ncl usi ve.   
 
Refere nces:   
 
Al - K hati b S M, Alle n La P oi nte N M, Kra mer J M, Califf R M.  W hat Cli nicia ns S h o ul d K n o w 
A b o ut t he Q T I nter val.  J o ur n al of t he A meric a n Me dic al Ass oci ati o n  2 0 0 3; 2 8 9: 2 1 2 0- 2 1 2 7. 
 
Cr o uc h M A, Li m o n L, Cassa n o A T. Cli nical Rele va nce a n d Ma na ge me nt of Dr u g- Relate d Q T 
I nter val Pr ol o n gati o n.  P h ar m ac ot her a py 2 0 0 3; 2 3: 8 8 7- 9 0 8. 
 
Kies SJ, Pa belic k C M et al.  A nest hesia f or Patie nts wit h C o n ge ni tal L o n g Q T S y n dr o me. 
A nest hesi ol o gy  2 0 0 5; 1 0 2: 2 0 4- 2 1 0 

M C 1 4 8 3 
6 1 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
Li E C, Esterl y J S, P o hl S, Sc ott S C, Mc Bri de B F.  Dr u g -I n d uce d Q T -I nter val Pr ol o n gati o n:  
C o nsi derati o ns f or Cli nica ns.  P h ar m ac ot her a py 2 0 1 0; 3 0: 6 8 4- 7 0 1. 
 
R o de n D M. Dr u g- I n d uce d Pr ol o n gati o n of t he Q T I nter val.  T he Ne w E n gl a n d J o ur n al of 
Me dici ne  2 0 0 4; 3 5 0: 1 0 1 3- 1 0 2 2. 
 
htt p:// w w w.azcert. or g/ me dical - pr os/ dr u gi nteracti o ns.cf m   Accesse d 5/ 1 3/ 1 1  
 
 

M C 1 4 8 3 
6 2 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
A p pe n di x I b:  Dr u gs wit h P ossi ble or C o n diti o n al Ris k of T ors a des de P oi ntes 
 
T his list c o ntai ns me dicati o ns t hat, i n s o me re p orts, ha ve bee n ass ociate d or wea kl y ass ociate d 
wit h ca usi n g t orsa des de p oi ntes a n d/ or Q T pr ol o n gati o n.  T here is i ns ufficie nt data t hat t hese 
me di cati o ns al o ne ma y ca use t orsa des de p oi ntes a n d/ or Q T pr ol o n gati o n, h o we ver w he n 
mi d osta uri n is gi ve n c o nc o mita ntl y wit h a me dicati o n o n t his list ( or ot her ris k fact ors are prese nt 
s uc h as bra d ycar dia, electr ol yte dist ur ba nces, c o n ge nital l o n g Q T s y n dr o me, or c o nc o mita nt 
dr u gs t hat i n hi bit meta b olis m), t here ma y be p ossi ble or c o n diti o nal ris k of t orsa des de p oi ntes 
a n d/ or Q T pr ol o n gati o n.  E xtre me ca uti o n a n d caref ul m o nit ori n g s h o ul d be i nstit ute d wit h 
c o nc o mita nt a d mi nistrati o n of mi d osta uri n a n d a me dicati o n o n t his list. 
 
Ge neric N a me  
B r a n d N a me  
C o m me nts  
Alf uz osi n  
Ur o xatral ®  
 
A ma nta di ne  
S y m metrel ®  
L o w  
A mitri pt yli ne  
Ela vil ®  
N o ns pecific E C G c ha n ges re p orte d.  
Ataza na vir  
Re yataz ®  
 
Azit hr o m yci n  
Zit hr o ma x ®  
 
C hl oral h y drate  
N octec ®  
 
Ci pr ofl o xaci n  
Ci pr o ®  
 
Cital o pra m  
Cele xa ®  
 
Cl o mi pra mi ne  
A nafra nil ®  
 
Desi pra mi ne  
Pert ofra ne ®  
Q T pr ol o n gati o n, V F/s u d de n deat h 
re p orte d 
Di p he n h y dra mi ne  
Be na dr yl ®, N yt ol ®  
 
D olasetr o n  
A nze met ®  
Gra nisetr o n < O n da nsetr o n < 
D olasetr o n  
D o xe pi n  
Si ne q ua n ®  
 
Dr o ne dar o ne  
M ulta q ®  
 
Escital o pra m  
Le xa pr o ®, Ci prale x ®  
 
Fel ba mate  
Fel batr ol ®  
 
Flecai ni de  
T a m b oc or ®  
 
F oscar net  
F osca vir ®  
 
F os p he n yt oi n  
Cere b y x ®  
 
Fl uc o naz ole  
Difl uca n ®  
I V > P O 
Fl u o xeti ne  
Pr ozac ®, Sarafe m ®  
1 i n 1 0, 0 0 0 ve ntric ular arr h yt h mias 
re p orte d 
Gala nta mi ne  
Re mi n yl ®  
 
Gatifl o xaci n  
T e q ui n ®  
 
Ge mifl o xaci n  
Facti ve ®  
 
Gra nisetr o n  
K ytril ®  
Gra nisetr o n < O n da nsetr o n < 
D olasetr o n  
I mi pra mi ne 
N orfra nil ®  
N o ns pecific arr h yt h mias re p orte d  
I n da pa mi de 
L oz ol ®  
 
Isra di pi ne 
D y nacirc ®  
 
Itrac o naz ole 
S p ora n o x ®  
 
Ket oc o naz ole  
Niz oral ®  
 
L a pati ni b 
T y ker b ®  
 
Le v ofl o xaci n  
Le va q ui n ®  
L o wer ris k t ha n t hat of si milar a ge nts  
Lit hi u m  
Lit h o bi d ®, Es kalit h ®  
 
M oe xi pril/ H C T Z  
U niretic ®  
 

M C 1 4 8 3 
6 3 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
M o xifl o xaci n  
A vel o x ®  
 
Nicar di pi ne  
Car de ne ®  
 
Nil oti ni b  
T asi g na ®  
 
N ortri pt yli ne  
Pa mel or ®  
N o ns pecific arr h yt h mias re p orte d  
Octre oti de  
Sa n d ostati n ®  
 
Ofl o xaci n  
Fl o xi n ®  
 
O n da nsetr o n  
Z ofra n ®  
Gra nisetr o n
 <
 O n da nsetr o n
 <
 
D olasetr o n  
O x yt oci n  
Pit oci n ®  
 
Pali peri d o ne  
I n ve ga®  
 
Par o xeti ne  
Pa xel ®  
L o wer ris k t ha n T C A’s  
Perfl utre n li pi d 
micr os p heres  
Defi nit y ®  
 
Pr otri pt yli ne  
V i vactil®  
 
Q uetia pi ne  
Ser o q uel ®  
Q T pr ol o n gati o n  
Ra n olazi ne  
Ra ne xa ®  
 
Ris peri d o ne  
Ris per dal ®  
Q T
 pr ol o n gati o n,
 s u d de n
 deat h
 
re p orte d 
Rit o na vir  
N or vir ®  
 
Sertrali ne  
Z ol oft ®  
L o wer ris k t ha n T C A’s  
S olife naci n  
V E SIcare ®  
 
S u niti ni b  
S ute nt ®  
 
T acr oli m us  
Pr o gra f®  
 
T a m o xife n  
N ol va de x ®  
 
T elit hr o m yci n  
Kete k ®  
 
Tiza ni di ne  
Za nafle x ®  
 
Traz o d o ne  
Des yrel ®  
 
Tri met h o pri m -S ulfa  
S ulfa ®, Bactri m ®, Bactri m 
D S ®  
L o w  
Tri mi pra mi ne  
S ur m o ntil ®  
 
Var de nafil  
Le vitra ®  
 
Ve nlafa xi ne  
Effe x or ®  
1  : 1 0 0 0 ris k of arr h yt h mia re p orte d 
V o ric o naz ole 
V Fe n d ®  
 
Zi prasi d o ne  
Ge o d o n ®  
Q T pr ol o n gati o n, 1: 1 0 0 0 ris k of 
arr h yt h mia 
N ote:  t he a b o ve list is n ot all -i ncl usi ve. 
 
Refere nces:   
 
Al - K hati b S M, Alle n La P oi nte N M, Kra mer J M, Califf R M.  W hat Cli nicia ns S h o ul d K n o w 
A b o ut t he Q T I nter val.  J o urn al of t he A meric a n Me dic al Ass oci ati o n  2 0 0 3; 2 8 9: 2 1 2 0- 2 1 2 7. 
 
Cr o uc h M A, Li m o n L, Cassa n o A T. Cli nical Rele va nce a n d Ma na ge me nt of Dr u g- Relate d Q T 
I nter val Pr ol o n gati o n.  P h ar m ac ot her a py 2 0 0 3; 2 3: 8 8 7- 9 0 8. 
 
Kies SJ, Pa belic k C M et al.  A nest hesia f or Patie nts  wit h C o n ge nital L o n g Q T S y n dr o me. 
A nest hesi ol o gy  2 0 0 5; 1 0 2: 2 0 4- 2 1 0 
 
Li E C, Esterl y J S, P o hl S, Sc ott S C, Mc Bri de B F.  Dr u g -I n d uce d Q T -I nter val Pr ol o n gati o n:  
C o nsi derati o ns f or Cli nica ns.  P h ar m ac ot her a py 2 0 1 0; 3 0: 6 8 4- 7 0 1. 
 

M C 1 4 8 3 
6 4 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
R o de n D M. Dr u g-I n d uce d Pr ol o n gati o n of t he Q T I nter val.  T he Ne w E n gl a n d J o ur n al of 
Me dici ne  2 0 0 4; 3 5 0: 1 0 1 3- 1 0 2 2. 
 
htt p:// w w w.azcert. or g/ me dical - pr os/ dr u gi nteracti o ns.cf m   Accesse d 5/ 1 3/ 1 1  
 

M C 1 4 8 3 
6 5 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
A p pe n di x II : E C O G Perf or m a nce St at us 
 
 
E C O G P erf or m a nce St at us Sc ale  
 
Gr a de  
Descri pti o ns  
0  
N or mal acti vit y.  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  
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht or 
se de ntar y nat ure (e. g., li g ht h o use w or k, office w or k). 
2  
I n be d < 5 0 % of t he ti me.  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  
I n be d > 5 0 % of t he ti me.  Ca pa ble of o nl y li mite d self-care, 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  
1 0 0 % be dri d de n.  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 ha ir. 
5  
Dea d.  

M C 1 4 8 3 
6 8 
M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
 
A p pe n di x I V 
Ac ute M y el oi d Le u ke mi a W H O 2 0 0 8 Criteri a  
 
 
Ac ute m y el oi d le u ke mi a a n d rel ate d prec urs or ne o pl as ms,  
a n d ac ute le u ke mi as of a m bi g u o us li ne a ge ( W H O 2 0 0 8) 
----------------------------------------------------------------------------- 
C ate g ories  
----------------------------------------------------------------------------- 
Ac ute m y el oi d le u ke mi a wit h rec urre nt ge netic a b n or m alities  
A M L wit h t( 8; 2 1 )( q 2 2; q 2 2); R U N X 1 -R U N X 1 T 1  
A M L wit h i n v( 1 6)( p 1 3. 1 q 2 2) or t( 1 6; 1 6)( p 1 3. 1; q 2 2); C B F B -M Y H 1 1  
A P L wit h t( 1 5; 1 7)( q 2 2; q 1 2); P M L -R A R A * 
A M L wit h t( 9; 1 1)( p 2 2; q 2 3); M L L T 3 -M L L † 
A M L wit h t( 6; 9)( p 2 3; q 3 4); D E K -N U P 2 1 4 
A M L wit h i n v( 3)( q 2 1 q 2 6. 2) or t( 3; 3)( q 2 1; q 2 6. 2); R P N 1 -E V I 1 
A M L ( me ga k ar y o blastic) wit h t( 1; 2 2)( p 1 3; q 1 3); R B M 1 5 -M K L 1  
Pr ovisi o n al e ntity: A M L wit h m ut ate d N P M 1  
Pr ovisi o n al e ntity: A M L wit h m ut ate d C E B P A  
Ac ute m y el oi d le u ke mi a wit h m yel o d ys pl asi a -rel ate d c h a n ges ‡ 
T her a p y -rel ate d m y el oi d ne o pl as ms § 
Ac ute m y el oi d le u ke mi a, n ot ot her wise s pecifie d ( N O S)  
Ac ute m yel oi d le u ke mia wit h mi ni mal differe ntiati o n  
Ac ute m yel oi d le u ke mia wit h o ut mat urati o n  
Ac ute m yel oi d le u ke mia wit h mat urati o n  
Ac ute m yel o m o n oc ytic l e u ke mia 
Ac ute m o n o blastic/ m o n oc ytic l e u ke mia  
Ac ute er yt hr oi d le u ke mia 
P ure er yt hr oi d le u ke mia 
Er yt hr ol e u ke mia, er yt hr oi d/ m yel oi d 
Ac ute me ga k ar y o blastic l e u ke mia  
Ac ute bas o p hilic le u ke mi a 
Ac ute pa n m yel osis wit h m yel ofi br osis (s y n.: ac ut e m yel ofi br osis; ac ute 

M C 1 4 8 3 
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M C C C A d d 4 
Versi o n Date: Oct o ber 2 5, 2 0 1 7  
A p pe n di x V  
 
S A E R E P O R T  
P R O C E S S I M M E DI A T E L Y  
T O: I N T E G R A T E D M EDI C A L S A F E T Y  
N O V A R TI S P H A R M A C E U TI C A L S C O R P O R A TI O N  
F A X: 
 
 
F R O M: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
P H O N E:( ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ F A X:( ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
N U M B E R O F P A G E S (I N C L U DI N G C O V E R S H E E T): _ _ _ _ _ _ _ _ _ _ _  
 
(If y o u e n co u nter pr o ble ms wit h t he f ax tr a ns missi o n ple ase c all 
) 
 
Ple ase c o m plete t he f oll o wi n g t o av oi d u n necess ary del ay i n pr ocessi n g y o ur 
S A E re p ort: 
 
I N V E S TI G A T O R N A M E: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
C E N T E R N U M B E R:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
T RI A L D R U G:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
S T U D Y/ P R O T O C O L N U M B E R:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
P A TI E N T I D/ N U M B E R:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
A R G U S C A S E I D N U M B E R ( F O L L O W -U P C A S E S)   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
C O M M E N T S:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
T HI S D O C U M E N T C O N T AI N S I M P O R T A N T S A F E T Y I N F O R M A TI O N.  
I F F A X I S R E C EI V E D I N E R R O R, P L E A S E F O R W A R D T O