Clinical trial NCT02634827
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
Start date: 2015-12-30; Completion date: 2018-06-12
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well midostaurin and decitabine work in treating older patients with newly diagnosed acute myeloid leukemia and FLT3 mutations. Midostaurin and decitabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the complete response rate for elderly patients with FLT3 mutated acute myeloid leukemia (AML) using midostaurin and decitabine.

SECONDARY OBJECTIVES:

I. Determine the 1-year overall survival (OS) and progression free survival (PFS) rates.

II. Determine overall response rates in patients treated with this regimen. III. Determine the complete response duration in patients treated with this regimen.

IV. Assess the safety and toxicity of this regimen based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

TERTIARY OBJECTIVES:

I. Assess the prognostic and predictive factors (FLT3 internal tandem duplication \[ITD\] versus \[vs\] tyrosine kinase domain \[TKD\] mutation) for patients treated with this regimen.

II. Explore genetic targets for this disease.

OUTLINE:

Patients receive decitabine intravenously (IV) over 1 hour on days 1-5 and midostaurin orally (PO) twice daily (BID) on days 8-21 of courses 1 and 2, and on days 1-28 of each subsequent course. Patients failing to achieve complete response (CR)/complete response with incomplete recovery (CRi)/partial response (PR)/morphologic leukemia-free state by end of course 2 receive midostaurin PO BID on days 1-28. Patients achieving CR/CRi/PR/morphologic leukemia-free state by end of course 8 may continue on current regimen. Patients failing to achieve a CR/CRi/PR/ morphologic leukemia-free state in bone marrow blasts by end of course 8 go to event monitoring. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2 years.

Arms: arm 1: Patients receive decitabine intravenously (IV) over 1 hour on days 1-5 and midostaurin orally (PO) twice daily (BID) on days 8-21 of courses 1 and 2, and on days 1-28 of each subsequent course. Patients failing to achieve complete response (CR)/complete response with incomplete recovery (CRi)/partial response (PR)/morphologic leukemia-free state by end of course 2 receive midostaurin PO BID on days 1-28. Patients achieving CR/CRi/PR/morphologic leukemia-free state by end of course 8 may continue on current regimen. Patients failing to achieve a CR/CRi/PR/ morphologic leukemia-free state in bone marrow blasts by end of course 8 go to event monitoring. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Decitabine intervention 2: Laboratory Biomarker Analysis intervention 3: Midostaurin
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
M C 1 4 8 3 
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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) 
M C C C A d de n d u m 1  
M C C C A d de n d u m 2 
M C C C A d de n d u m 3 
M C C C A d de n d u m 4  
 Ja n uar y 1 3, 2 0 1 6 
 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  
  8. 0 
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  


M C 1 4 8 3 
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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  


M C 1 4 8 3 
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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 
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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  
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 
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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 
6 9 
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